ramipril and Myocardial-Infarction

Topics: Aged; Aminobutyrates; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Biphenyl Compounds; Cardiovascular Diseases; Drug Combinations; Enalapril; Enzyme Inhibitors; Female; Heart Failure; Hospitalization; Humans; Male; Middle Aged; Myocardial Infarction; Neprilysin; Ramipril; Severity of Illness Index; Stroke Volume; Valsartan; Ventricular Dysfunction, Left

Renin inhibitors (RIs) reduce blood pressure more than placebo, with the magnitude of this effect thought to be similar to that for angiotensin converting enzyme (ACE) inhibitors. However, a drug's efficacy in lowering blood pressure cannot be considered as a definitive indicator of its effectiveness in reducing mortality and morbidity. The effectiveness and safety of RIs compared to ACE inhibitors in treating hypertension is unknown.. To evaluate the benefits and harms of renin inhibitors compared to ACE inhibitors in people with primary hypertension.. The Cochrane Hypertension Group Information Specialist searched the following databases for randomized controlled trials up to August 2020: the Cochrane Hypertension Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (from 1946), Embase (from 1974), the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov. We also contacted authors of relevant papers about further published and unpublished work. The searches had no language restrictions.. We included randomized, active-controlled, double-blinded studies (RCTs) with at least four weeks follow-up in people with primary hypertension, which compared renin inhibitors with ACE inhibitors and reported morbidity, mortality, adverse events or blood pressure outcomes. We excluded people with proven secondary hypertension.. Two review authors independently selected the included trials, evaluated the risks of bias and entered the data for analysis.. We include 11 RCTs involving 13,627 participants, with a mean baseline age from 51.5 to 74.2 years. Follow-up duration ranged from four weeks to 36.6 months. There was no difference between RIs and ACE inhibitors for the outcomes: all-cause mortality: risk ratio (RR) 1.05, 95% confidence interval (CI) 0.93 to 1.18; 5 RCTs, 5962 participants; low-certainty evidence; total myocardial infarction: RR 0.86, 95% CI 0.22 to 3.39; 2 RCTs, 957 participants; very low-certainty evidence; adverse events: RR 0.98, 95% CI 0.93 to 1.03; 10 RTCs, 6007 participants;  moderate-certainty evidence; serious adverse events: RR 1.21, 95% CI 0.89 to 1.64; 10 RTCs, 6007 participants; low-certainty evidence; and withdrawal due to adverse effects: RR 0.85, 95% CI 0.68 to 1.06; 10 RTCs, 6008 participants; low-certainty evidence. No data were available for total cardiovascular events, heart failure, stroke, end-stage renal disease or change in heart rate. Low-certainty evidence suggested that RIs reduced systolic blood pressure: mean difference (MD) -1.72, 95% CI -2.47 to -0.97; 9 RCTs, 5001 participants;  and diastolic blood pressure: MD -1.18, 95% CI -1.65 to -0.72; 9 RCTs, 5001 participants,  to a greater extent than ACE inhibitors, but we judged this to be more likely due to bias than a true effect.  AUTHORS' CONCLUSIONS: For the treatment of hypertension, we have low certainty that renin inhibitors (RI) and angiotensin converting enzyme (ACE) inhibitors do not differ for all-cause mortality and myocardial infarction. We have low to moderate certainty that they do not differ for adverse events. Small reductions in blood pressure with renin inhibitors compared to ACE inhibitors are of low certainty.  More independent, large, long-term trials are needed to compare RIs with ACE inhibitors, particularly assessing morbidity and mortality outcomes, but also on blood pressure-lowering effect.

Topics: Aged; Amides; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Cardiovascular Diseases; Cause of Death; Female; Fumarates; Heart Rate; Humans; Irbesartan; Kidney Failure, Chronic; Lisinopril; Male; Middle Aged; Myocardial Infarction; Patient Dropouts; Ramipril; Randomized Controlled Trials as Topic; Renin

Zofenopril is a lipophilic, sulfhydryl group-containing angiotensin-converting enzyme (ACE)-inhibitor, characterized by wide tissue distribution, long duration of action, and pleiotropic effects on endothelial dysfunction. Its clinical efficacy and safety have been described in the four randomized controlled trials of the SMILE program, which globally enrolled more than 3600 patients in post-acute myocardial infarction (AMI) setting. The SMILE-4 study specifically selected patients with left ventricular dysfunction at admission, and compared the effects of zofenopril or ramipril in combination with acetylsalicylic acid (ASA). Zofenopril demonstrated its superiority over ramipril in reducing the combined occurrence of death or hospitalization for cardiovascular causes both in the overall population included in the original study and in subgroups of patients at highest risk, namely hypertensive and diabetic subjects. The effects of the early treatment with zofenopril were sustained over time, and, after 5 years of follow-up, zofenopril increased the survival likelihood and reduced the hospitalization rate. Compared to ramipril, zofenopril was cost-effective with a number to treat of 13 and an incremental cost-effectiveness ratio (ICER) of 2125.45 euros for any additional event prevented. Furthermore, in real-world settings, zofenopril decreased the risk of death in patients with heart failure, particularly in men, and in subjects older than 76 years or with ejection fraction lower than 54%. These results support the early use of zofenopril immediately after AMI, even in the presence of comorbidities, and its maintenance over time to reduce the risk of heart failure.. Menarini International Operations Luxembourg S.A.

Topics: Angiotensin-Converting Enzyme Inhibitors; Captopril; Double-Blind Method; Heart Failure; Humans; Myocardial Infarction; Ramipril; Randomized Controlled Trials as Topic; Treatment Outcome

Oxidative stress is increased in hyperuricemic patients with acute myocardial infarction (AMI). Use of sulfhydryl ACE-inhibitors (ACEIs), such as zofenopril or captopril, plus xanthine oxidase inhibitors (XOIs), may potentially result in enhanced antioxidant effects and improved survival.. We verified the benefit of such combination in a randomly stratified sample of 525 of the 3630 post-AMI patients of the four randomized prospective SMILE (Survival of Myocardial Infarction Long-term Evaluation) studies.. One hundred sixty-five (31.4%) patients were treated with XOIs (79 under zofenopril, 86 placebo, lisinopril or ramipril), whereas 360 were not (192 zofenopril, 168 placebo or other ACEIs). In these four groups, we separately estimated the 1-year combined risk of major cardiovascular events (MACE, death or hospitalization for cardiovascular causes).. MACE occurred in 10.1% of patients receiving zofenopril + XOIs, in 18.6% receiving placebo or other ACEIs + XOIs, in 13.5% receiving zofenopril without XOIs and in 22.0% receiving placebo or other ACEIs, but no XOIs (p = 0.034 across groups). Rate of survival free from MACE was significantly larger under treatment with zofenopril + XOIs than with other ACEIs with no XOIs [hazard ratio: 2.29 (1.06-4.91), p = 0.034]. A non-significant trend for superiority of zofenopril + XOIs combination was observed vs. zofenopril alone [1.19 (0.54-2.64), p = 0.669] or vs. placebo or other ACEIs + XOIs [1.82 (0.78-4.26), p = 0.169].. Our retrospective analysis suggests an improved survival free from MACE in post-AMI patients treated with a combination of an urate lowering drug with antioxidant activity and an ACEI, with best effects observed with zofenopril.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Captopril; Double-Blind Method; Enzyme Inhibitors; Female; Humans; Lisinopril; Male; Middle Aged; Myocardial Infarction; Progression-Free Survival; Prospective Studies; Ramipril; Randomized Controlled Trials as Topic; Retrospective Studies; Risk Factors; Time Factors; Treatment Outcome; Xanthine Oxidase

Angiotensin-converting enzyme (ACE) inhibitors are a heterogeneous class, varying in pharmacologic properties, which have different therapeutic impacts on patient profiles, including lipophilicity, tissue-ACE binding, duration of action, half-life, and increased bradykinin availability. Among the ACE inhibitor class, the agent perindopril, in particular, has pleiotropic effects that are not equally shared by other ACE inhibitors, including bradykinin site selectivity and subsequent enhancement of nitric oxide and inhibition of endothelial cell apoptosis. Moreover, there is a large amount of evidence to suggest that perindopril therapy may reduce cardiovascular event rates in patients, yet perindopril is rarely prescribed in the United States. Ramipril is another ACE inhibitor with both a favorable clinical profile and impressive outcomes data. Our review compares the pharmacologic and trial data among perindopril, ramipril, and other ACE inhibitors. In patients with or at high risk for coronary heart disease who do not have heart failure, or in patients with heart failure with preserved ejection fraction, perindopril should be among the preferred treatment agents in the ACE inhibitor class. Ramipril has an impressive track record of improving cardiovascular outcomes, too, and should be considered a preferred agent among the ACE inhibitor class.

Topics: Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Cardiovascular System; Coronary Disease; Heart Failure; Humans; Hypertension; Myocardial Infarction; Perindopril; Ramipril

Cardiovascular disease (CVD) places a significant burden on healthcare providers. High blood pressure (BP) is the single most prevalent risk factor for CVD worldwide and is responsible for more deaths than any other risk factor. 'Cardiovascular (CV) high-risk patients' make up the broad cross-section of patients in the middle of the risk spectrum for CVD progression that is referred to as the CV continuum and includes those with atherothrombotic disease, those with target organ damage associated with type 2 diabetes and those with multiple risk factors. Angiotensin II is involved in CVD progression at every stage of the CV continuum, making the renin-angiotensin system a rational target for pharmacologic intervention. Angiotensin II receptor blockers (ARBs) offer a better tolerated alternative to angiotensin converting enzyme inhibitors, with greater long-term adherence. The ARB telmisartan recently received an indication for CV prevention.. A PubMed literature search was conducted to identify evidence on the use of telmisartan for preventing CV events.. Telmisartan has a favourable safety and tolerability profile, and has demonstrated efficacious and long-lasting 24-hour BP reductions, whether as monotherapy or in combination with hydrochlorothiazide or amlodipine. In the largest CV prevention trial program undertaken with an ARB (the ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial; ONTARGET), telmisartan 80 mg/day alone was as effective as ramipril in reducing the composite primary endpoint of CV mortality, non-fatal myocardial infarction, non-fatal stroke and hospitalization for heart failure in CV high-risk patients. However, patients were significantly more likely to adhere to treatment with telmisartan than ramipril due to its better tolerability.. To date, telmisartan is the only ARB indicated to reduce CV morbidity in a broad CV high-risk population.

Topics: Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Cost of Illness; Heart Failure; Humans; Myocardial Infarction; PubMed; Ramipril; Telmisartan; Time Factors

Nowadays angiotensin-converting enzyme inhibitors (ACE-Is) are considered to be a cornerstone in the treatment of congestive heart failure (CHF). These agents have been shown to improve survival and functional status of patients with CHF. It is logical to start therapy with ACE-Is in the first hours or days of acute myocardial infarction (MI) to further improve survival and prevent CHF after MI. The several randomized placebo-controlled trials were performed to assess the effects of early therapy with ACE-Is on the outcomes of MI. Mortality after MI was significantly reduced only in these trials in which therapy with ACE-Is was introduced 3-16 days after MI in patients with clinical evidence of CHF or left ventricular systolic dysfunction as well as in patients with noneffective thrombolysis (or without thrombolysis) or diabetes mellitus.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Captopril; Diabetes Complications; Enalapril; Heart Failure; Humans; Indoles; Middle Aged; Myocardial Infarction; Ramipril; Randomized Controlled Trials as Topic; Time Factors; Treatment Outcome; Ventricular Dysfunction

Topics: Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Double-Blind Method; Evidence-Based Medicine; Humans; Hypertension; Multicenter Studies as Topic; Myocardial Infarction; Placebos; Ramipril; Randomized Controlled Trials as Topic; Research Design; Risk Factors; Treatment Outcome

Perindopril is a long-acting, once-daily lipophilic angiotensin-converting enzyme inhibitor with high tissue angiotensin-converting enzyme affinity, lowering angiotensin II and potentiating bradykinin. Efficacy, safety, and tolerability of perindopril are well established in the treatment of hypertension and heart failure. Moreover, large morbidity-mortality trials, such as the EUROPA, PROGRESS, and PREAMI have shown that treatment with perindopril reduces morbidity and mortality and prevents cardiovascular disease in a large range of patients with vascular diseases, whether or not they are hypertensive. Thus, the outcomes of these and other trials support the concept of cardiovascular protective properties of angiotensin-converting enzyme inhibition with perindopril in addition to the obvious blood-pressure-lowering effect. Considering its properties and the clinical evidence on efficacy and tolerability that has been gathered, perindopril should be considered a first-line therapeutic agent in hypertension, heart failure and acute myocardial infarction and a tool of secondary prevention of coronary artery disease.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Heart Failure; Humans; Hypertension; Indoles; Male; Middle Aged; Multicenter Studies as Topic; Myocardial Infarction; Perindopril; Prospective Studies; Ramipril; Randomized Controlled Trials as Topic; Risk; Risk Factors; Stroke; Time Factors

The results of the major clinical outcome trials related to the potential antiatherosclerotic effects of the angiotensin convertase (ACE) inhibitors are reviewed after the recently published EUROPA trial results. In the postinfarction clinical situation mortality reduction was revealed in the ISIS-4 (captopril), GISSI-3 (lisinopril), AIRE (ramipril), TRACE (trandolapril), CONSENSUS (enalapril), SAVE (captopril) and in the SOLVD (enalapril) trials. In the HOPE trial performed in a high risk population the preventive antiatherosclerotic, endothel-preserving effects of ramipril resulted in a significant mortality and morbidity reduction. In the EUROPA trial a lower risk population--symptomfree coronary patients--were treated by perindopril, and it was proven also in this cohort, that the long term ACE inhibitor treatment decreased the combined endpoint of cardiovascular mortality, myocardial infarction and resuscitated sudden death. Based on the above data it can be advised, that all coronary patients regardless of left ventricular function and symptoms should receive long term ACE inhibitor treatment besides the other established preventive medications (platelet aggregation inhibitors + statins + beta receptor blockers).

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Captopril; Clinical Trials as Topic; Coronary Disease; Death, Sudden, Cardiac; Enalapril; Humans; Indoles; Lisinopril; Myocardial Infarction; Perindopril; Ramipril; Treatment Outcome

Topics: Angiotensin-Converting Enzyme Inhibitors; Arteriosclerosis; C-Reactive Protein; Cardiovascular Diseases; Humans; Inflammation; Myocardial Infarction; Prognosis; Ramipril; Risk Factors; Stroke

When first introduced in 1981, angiotensin-converting enzyme (ACE) inhibitors were indicated only for treatment of refractory hypertension. Since then, they have been shown to reduce morbidity or mortality in congestive heart failure, myocardial infarction, diabetes mellitus, chronic renal insufficiency, and atherosclerotic cardiovascular disease. Pathologies underlying these conditions are, in part, attributable to the renin-angiotensin-aldosterone system. Angiotensin II contributes to endothelial dysfunction. altered renal hemodynamics, and vascular and cardiac hypertrophy. ACE inhibitors attenuate these effects. Clinical outcomes of ACE inhibition include decreases in myocardial infarction (fatal and nonfatal), reinfarction, angina, stroke, end-stage renal disease, and morbidity and mortality associated with heart failure. ACE inhibitors are generally well tolerated and have few contraindications. (Am Fam Physician 2002;66:473.)

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Benzazepines; Captopril; Cardiovascular Diseases; Clinical Trials as Topic; Contraindications; Diabetic Nephropathies; Drug Costs; Enalapril; Fosinopril; Heart Failure; Humans; Hypertension; Indoles; Isoquinolines; Lisinopril; Meta-Analysis as Topic; Myocardial Infarction; Perindopril; Quinapril; Ramipril; Renin-Angiotensin System; Risk; Tetrahydroisoquinolines; United States

Asymptomatic left ventricular dysfunction should be treated as an early stage on the continuum that is chronic heart failure. The author presents the clinical trial data on which current management with angiotensin-converting enzyme inhibitors and beta-blockers is based. Issues surrounding screening are also discussed.

Topics: Adrenergic beta-Antagonists; Aged; Aged, 80 and over; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Captopril; Coronary Disease; Drug Therapy, Combination; Echocardiography; Enalapril; Female; Heart Failure; Humans; Hypertension; Indoles; Male; Middle Aged; Myocardial Infarction; Norepinephrine; Ramipril; Randomized Controlled Trials as Topic; Retrospective Studies; Risk Factors; Ventricular Dysfunction, Left; Ventricular Function, Left

The Heart Outcomes Prevention Evaluation study was a landmark study employing the angiotensin-converting enzyme inhibitor ramipril in a patient population pre-destined for vascular events. This study found that a 10 mg dose of ramipril in comparison with placebo reduced the incidence of death, myocardial infarction, stroke, and death from cardiovascular causes by 22%. This improvement in outcome was viewed as a direct consequence of ramipril, although the fact that blood pressure was reduced with ramipril has cast some considerable doubt on this supposition. Whether the observed findings in this study are a 'class effect' for all angiotensin-converting enzyme inhibitors is unclear. To its credit, ramipril is the first angiotensin-converting enzyme inhibitor shown to prevent ischemic events in high-risk patients without discernible left ventricular dysfunction. Other similar trials are underway, which are studying similar populations to those included in this landmark study and should resolve the question of whether the cardioprotective effects of angiotensin-converting enzyme inhibitors are a 'class effect'.

Topics: Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Controlled Clinical Trials as Topic; Evaluation Studies as Topic; Humans; Multicenter Studies as Topic; Myocardial Infarction; Ramipril; Stroke

Ramipril is a long-acting, lipophylic angiotensin converting enzyme inhibitor, its principle action is to inhibit the conversion of angiotensin I to the active angiotensin II. Ramipril is indicated in the treatment of hypertension, congestive cardiac failure (including that following acute myocardial infarction), nephropathy (with and without diabetes mellitus) and now, following the findings of the HOPE study, in the prevention of cardiovascular events (including myocardial infarction) in high risk individuals. This article concentrates on reviewing the evidence supporting ramipril's use in these indications.

Topics: Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Diabetes Mellitus; Heart Failure; Humans; Hypertension; Myocardial Infarction; Proteinuria; Ramipril

Topics: Angina, Unstable; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Captopril; Diabetes Mellitus, Type 2; Humans; Myocardial Infarction; Ramipril; Risk Factors

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Captopril; Humans; Hypertension; Myocardial Infarction; Ramipril; Risk Factors

Based on the results of large clinical trials, ACE inhibitors are established as routine treatment after acute myocardial infarction accompanied by heart failure. Pathophysiologically, the benefit of ACE inhibitors has been attributed to an effect on remodelling of the left ventricle. In the past decade, it has been suggested that ACE inhibitors might have other important mechanisms of action and accordingly be useful for other conditions than those they have been used for until now.. We reviewed clinical studies of ACE inhibitors with special emphasis on the use of these agents in the acute phase of myocardial infarction and in the follow-up period. These studies were assessed together with the recently published Heart Outcomes Prevention Evaluation (HOPE) study.. In the HOPE study it was found that ACE inhibition protected against cardiovascular events in patients at high risk due to atherosclerotic disease, but without dysfunction of the left ventricle. The effect is most likely a retarding of the atherothrombotic process in the coronary arteries.. The latest results are important for clinical practice. Other post-infarction patients than those with myocardial failure may benefit from treatment with ACE inhibitors. We also discuss the timing of ACE inhibitor treatment, the importance of an adequate ACE inhibitor dose, and combination with other treatment regimens used in secondary prevention.

Topics: Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Controlled Clinical Trials as Topic; Follow-Up Studies; Humans; Myocardial Infarction; Ramipril; Randomized Controlled Trials as Topic; Risk Factors; Vitamin E

Topics: Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin; Endothelium, Vascular; Humans; Muscle, Smooth, Vascular; Myocardial Infarction; Nitric Oxide; Ramipril; Vasodilation

Ramipril is a second generation angiotensin converting enzyme (ACE) inhibitor. Like enalapril, it is a prodrug and is hydrolysed in vivo to release the active metabolite, ramiprilat, which has a long elimination half-life, permitting once-daily administration. The antihypertensive efficacy of ramipril has been confirmed in large-scale noncomparative studies conducted in general practice as well as in more rigorously controlled clinical trials. In the former, approximately 85% of patients with mild to moderate essential hypertension have responded successfully to treatment with ramipril 2.5 or 5 mg/day, while comparative trials indicate that the antihypertensive efficacy of the drug is equivalent to that of other established ACE inhibitors and the beta-adrenoceptor antagonist atenolol. As expected, the response rate to ramipril monotherapy is lower in patients with severe hypertension (around 40%), although the blood pressure lowering effect can be enhanced with the addition of a diuretic such as hydrochlorothiazide or piretanide. The antihypertensive efficacy of ramipril is maintained in patients with diabetes mellitus and preliminary data indicate that the drug has the beneficial effect of decreasing urinary albumin excretion in diabetic patients with nephropathy. Ramipril is superior to atenolol in causing regression of left ventricular hypertrophy, although the clinical significance of this effect per se remains to be established. The large-scale Acute Infarction Ramipril Efficacy (AIRE) study demonstrated that ramipril 5 or 10 mg/day significantly decreased the risk of all-cause mortality by 27% in patients with clinical evidence of heart failure after acute myocardial infarction, even if transient. The beneficial effect of ramipril was apparent by 30 days of treatment and appeared to be greatest in patients with more severe ventricular damage after infarction. Ramipril is well tolerated in general practice, with 5% or fewer patients discontinuing therapy because of drug intolerance. The data available suggest that ramipril shares a similar tolerability profile to that of other established ACE inhibitors. Thus, clinical data confirm ramipril as a useful alternative ACE inhibitor for the treatment of patients with mild to moderate hypertension, and indicate a beneficial effect of the drug in patients with clinical evidence of heart failure after acute myocardial infarction. It is also reasonable to assume that ramipril will be of value in the treatment

Topics: Aging; Diabetes Complications; Female; Heart Failure; Hemodynamics; Humans; Hypertension; Hypertrophy, Left Ventricular; Kallikrein-Kinin System; Kidney; Male; Myocardial Infarction; Ramipril; Vascular Resistance

Potential benefit or harm of drug therapy in patients with chronic congestive heart failure and those later presenting to hospital after an acute myocardial infarction (AMI) have been studied in a number of large-scale survival studies during the last few decades. Currently available data are reviewed in order to consider both methodology and also the clinical relevance of findings with emphasis on trials with ACE-inhibitors like CONSENSUS-II, the ISIS-4, GISSI-3 and Chinese mega-trials, TRACE, SAVE and AIRE. Results of SAVE and AIRE show a clear survival benefit for the patients. Furthermore, the benefit of both trials was in addition to any other benefit which resulted from aspirin, thrombolytic and beta-blocker therapies. In absolute terms, treatment of 1,000 patients with ramipril (AIRE) for 1 year would be expected to result in the prevention/delay of 40 premature deaths. The beneficial effects of ramipril were clearly apparent by 30 days though additional benefit beyond this point was also present. Furthermore, prespecified subgroup analysis revealed significant benefit for patients at risk like women and the elderly. A selective approach is argued for the treatment of patients with ACE-inhibitors after myocardial infarction.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Clinical Trials as Topic; Female; Heart Failure; Humans; Male; Multicenter Studies as Topic; Myocardial Infarction; Ramipril; Survival Rate

Up to September, 1993, several questions were open on the use of angiotensin converting enzyme (ACE) inhibitors after myocardial infarction. The SAVE trial has shown that patients with left ventricular dysfunction and a recent (mean 11 days) myocardial infarction benefit from assuming captopril per os during the subsequent clinical course. The SOLVD trials have indicated that therapy with enalapril per os increases the survival of patients with left ventricular dysfunction, a history of myocardial infarction and hemodynamic decompensation. However, the CONSENSUS II trial has not shown similar results on patients with all range left ventricular function, treated within 24 hours of infarction with i.v. enalaprilat and then enalapril per os. In this study, 6-month mortality has been slightly better in the placebo group, and there seems not to be any subgroup benefitting from the ACE inhibitor. In October and November, 1993, the International Cardiologic Community has received the results of 3 large multicenter trials on postinfarction patients: the AIRE (ramipril per os), the GISSI 3 (lisinopril per os) and the ISIS 4 (captopril per os) studies. These trials has pointed out the followings: 1) prompt therapy (within 24 hours of chest pain) with ACE inhibitors is able to improve short term survival in patients with clinical evidence of heart failure, in women and old patients; 2) ACE inhibitors and nitro derivatives are complementary therapies in the acute and subacute phase of infarction, and their association produces the best improvement in short-term survival. There seems to be no intelligible reason, up to now, to deem that any ACE inhibitor should be considered better than another one in the acute phase of infarction, but still during the first 72 hours after the onset of chest pain the advantages have been shown only with lisinopril and captopril. The negative results of the CONSENSUS II trial are probably dependent on the excessively abrupt acute hypotensive effect of i.v. enalaprilat. This last "large trial" decade has taught us that many treatments can be advantageous for acute myocardial infarction but, apart from thrombolysis, all other medical therapies should not be given extensively, but to peculiar patients carefully selected on clinical grounds. Guidelines from official consensus conferences are expected now, to segregate different patterns of clinical presentations to be treated differently.

Topics: Administration, Oral; Aged; Angiotensin-Converting Enzyme Inhibitors; Captopril; Clinical Trials as Topic; Enalapril; Female; Humans; Injections, Intravenous; Lisinopril; Male; Multicenter Studies as Topic; Myocardial Infarction; Nitroglycerin; Ramipril; Thrombolytic Therapy; Time Factors

Preclinical data suggest that central renin-angiotensin system blockade by the brain aminopeptidase-A inhibitor firibastat can improve left ventricular ejection fraction (LVEF) after myocardial infarction (MI).. This study aimed to compare the effect of firibastat versus ramipril on post-MI LVEF.. In this phase 2, randomized, double-blind trial, patients selected within 24 h of first acute anterior MI treated by primary percutaneous coronary intervention were randomly assigned (1:1:1) to firibastat 100 mg, firibastat 500 mg or ramipril 5 mg, each twice daily for 12 weeks. The primary endpoint was change in LVEF on cardiac magnetic resonance imaging (cMRI) from baseline to day 84 in the modified intent-to-treat (mITT) population (at least one dose received and one follow-up cMRI available) for each treatment group.. From June 4, 2019 to April 12, 2021, 294 patients were randomized and 229 were evaluable for the mITT analysis. After 12 weeks, mean ± standard deviation (SD) percent change in LVEF was 5.6 ± 1.2 with firibastat 100 mg, 5.3 ± 1.1 with firibastat 500 mg and 5.7 ± 1.1 with ramipril. The absolute ± SE adjusted difference in LVEF change from baseline between firibastat 500 mg and ramipril was - 0.36 ± 1.32% (p = 0.79). Occurrence of treatment-related adverse events was similar in the three groups.. Firibastat was not superior to ramipril for prevention of left ventricular dysfunction after first acute anterior MI, and their safety profiles were similar.. ClinicalTrials.gov identifier NCT03715998.

Topics: Humans; Myocardial Infarction; Ramipril; Reperfusion; Stroke Volume; Ventricular Function, Left

In patient with symptomatic heart failure sacubitril valsartan has been found to reduces the risk of hospitalization and death from cardiovascular causes more effectively then angiotensin converting enzymes inhibitor trail comparing the effect of these drugs in acute myocardial infarction is lacking.. We randomly assigned patient with acute myocardial infarction complicated with reduced LVEF, or pulmonary congestion to recieve sacubitril 97mg-valsartan 103mg and ramipril 5mg twice daily the primary outcome was death from cardiovascular causes or incident heart failure, outpatient symptomatic heart failure or heart failure leading to hospitalization whichever occure first.. Total 566 patient was taken in randomization 283 receive sacubitril-valsartan and 283 receive ramipril over a median of 22 months total outcome occure in 138 patient in sacubitril-valsartan group and in137 patient with ramipril group(hazard ratio 0.90: 95%confidence interval death from cardiovascular causes or hospitalization for heart failure occure i 10.9% patient reciveing sacubitril-valsartan and in 11.8%patient with ramipril group death from cardiovascular causes is 5.9 and 6.7% respectively death from anyother causes is 7.5 and 8.5 % respectively in both sacubitril-valsartan and ramipril group.. Sacubitril-valsartan was not associated with significantly lower incidence of death from cardiovascular causes or incidents heart failure then ramipril in patients with acute myocardial infarction.

Topics: Aminobutyrates; Angiotensin Receptor Antagonists; Antihypertensive Agents; Biphenyl Compounds; Drug Combinations; Heart Failure; Humans; Myocardial Infarction; Neprilysin; Ramipril; Receptors, Angiotensin; Stroke Volume; Tetrazoles; Treatment Outcome; Valsartan

A polypill that includes key medications associated with improved outcomes (aspirin, angiotensin-converting-enzyme [ACE] inhibitor, and statin) has been proposed as a simple approach to the secondary prevention of cardiovascular death and complications after myocardial infarction.. In this phase 3, randomized, controlled clinical trial, we assigned patients with myocardial infarction within the previous 6 months to a polypill-based strategy or usual care. The polypill treatment consisted of aspirin (100 mg), ramipril (2.5, 5, or 10 mg), and atorvastatin (20 or 40 mg). The primary composite outcome was cardiovascular death, nonfatal type 1 myocardial infarction, nonfatal ischemic stroke, or urgent revascularization. The key secondary end point was a composite of cardiovascular death, nonfatal type 1 myocardial infarction, or nonfatal ischemic stroke.. A total of 2499 patients underwent randomization and were followed for a median of 36 months. A primary-outcome event occurred in 118 of 1237 patients (9.5%) in the polypill group and in 156 of 1229 (12.7%) in the usual-care group (hazard ratio, 0.76; 95% confidence interval [CI], 0.60 to 0.96; P = 0.02). A key secondary-outcome event occurred in 101 patients (8.2%) in the polypill group and in 144 (11.7%) in the usual-care group (hazard ratio, 0.70; 95% CI, 0.54 to 0.90; P = 0.005). The results were consistent across prespecified subgroups. Medication adherence as reported by the patients was higher in the polypill group than in the usual-care group. Adverse events were similar between groups.. Treatment with a polypill containing aspirin, ramipril, and atorvastatin within 6 months after myocardial infarction resulted in a significantly lower risk of major adverse cardiovascular events than usual care. (Funded by the European Union Horizon 2020; SECURE ClinicalTrials.gov number, NCT02596126; EudraCT number, 2015-002868-17.).

Topics: Angiotensin-Converting Enzyme Inhibitors; Aspirin; Atorvastatin; Cardiovascular Diseases; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Ischemic Stroke; Myocardial Infarction; Platelet Aggregation Inhibitors; Ramipril; Secondary Prevention

The win ratio can incorporate different types of outcomes and enhance statistical power, making it a useful method for analysing composite outcomes in cardiovascular trials. The application of this approach to the PARADISE-MI trial provides an additional perspective into understanding the effects of sacubitril/valsartan in patients with acute myocardial infarction.. We conducted a post-hoc analysis of the PARADISE-MI trial, which randomly assigned patients with acute myocardial infarction complicated by a reduced left ventricular ejection fraction, pulmonary congestion, or both to receive either sacubitril/valsartan (97 mg of sacubitril and 103 mg of valsartan twice daily) or ramipril (5 mg twice daily) in addition to guideline-recommended therapy. The principal composite outcome was analysed in the hierarchical order of death due to cardiovascular causes, first hospitalization for heart failure, and first outpatient episode of symptomatic heart failure. We included events confirmed by the clinical events classification (CEC) committee as well as events identified by investigators that did not meet study definitions. Results were analysed by the unmatched win-ratio method. A win ratio that exceeds 1.00 reflects a better outcome. A total of 5661 patients underwent randomization; 2830 were assigned to receive sacubitril/valsartan and 2831 to receive ramipril. The hierarchical analysis of the principal composite outcome demonstrated a larger number of wins (1 265 767 [15.7%]) than losses (1 079 502 [13.4%]) in the sacubitril/valsartan group (win ratio of 1.17, 95% confidence interval [CI] 1.03-1.33; p = 0.015). Sensitivity analyses using alternative definitions of the composite outcome showed results similar to those of the principal analysis, except for analysis restricted to events that met CEC definitions (win ratio of 1.11, 95% CI 0.96-1.30; p = 0.16).. In this post-hoc analysis of the PARADISE-MI trial using the win ratio and including investigator-identified events not having CEC confirmation, sacubitril/valsartan was superior to ramipril among high-risk survivors of acute myocardial infarction.

Topics: Aminobutyrates; Angiotensin Receptor Antagonists; Biphenyl Compounds; Drug Combinations; Heart Failure; Humans; Myocardial Infarction; Neprilysin; Ramipril; Stroke Volume; Tetrazoles; Valsartan; Ventricular Function, Left

In patients who survive an acute myocardial infarction (AMI), angiotensin-converting enzyme inhibitors decrease the risk of subsequent major cardiovascular events. Whether angiotensin-receptor blockade and neprilysin inhibition with sacubitril/valsartan reduce major coronary events more effectively than angiotensin-converting enzyme inhibitors in high-risk patients with recent AMI remains unknown. We aimed to compare the effects of sacubitril/valsartan on coronary outcomes in patients with AMI.. We conducted a prespecified analysis of the PARADISE-MI trial (Prospective ARNI vs ACE Inhibitors Trial to Determine Superiority in Reducing Heart Failure Events After MI), which compared sacubitril/valsartan (97/103 mg twice daily) with ramipril (5 mg twice daily) for reducing heart failure events after myocardial infarction in 5661 patients with AMI complicated by left ventricular systolic dysfunction, pulmonary congestion, or both. In the present analysis, the prespecified composite coronary outcome was the first occurrence of death from coronary heart disease, nonfatal myocardial infarction, hospitalization for angina, or postrandomization coronary revascularization.. In survivors of an AMI with left ventricular systolic dysfunction and pulmonary congestion, sacubitril/valsartan-compared with ramipril-reduced the risk of a prespecified major coronary composite outcome. Dedicated studies are necessary to confirm this finding and elucidate its mechanism.. URL: https://www.. gov; Unique identifier: NCT02924727.

Topics: Aminobutyrates; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Angiotensins; Biphenyl Compounds; Heart Failure; Humans; Myocardial Infarction; Neprilysin; Prospective Studies; Ramipril; Receptors, Angiotensin; Stroke Volume; Tetrazoles; Valsartan; Ventricular Dysfunction, Left

In patients with symptomatic heart failure, sacubitril-valsartan has been found to reduce the risk of hospitalization and death from cardiovascular causes more effectively than an angiotensin-converting-enzyme inhibitor. Trials comparing the effects of these drugs in patients with acute myocardial infarction have been lacking.. We randomly assigned patients with myocardial infarction complicated by a reduced left ventricular ejection fraction, pulmonary congestion, or both to receive either sacubitril-valsartan (97 mg of sacubitril and 103 mg of valsartan twice daily) or ramipril (5 mg twice daily) in addition to recommended therapy. The primary outcome was death from cardiovascular causes or incident heart failure (outpatient symptomatic heart failure or heart failure leading to hospitalization), whichever occurred first.. A total of 5661 patients underwent randomization; 2830 were assigned to receive sacubitril-valsartan and 2831 to receive ramipril. Over a median of 22 months, a primary-outcome event occurred in 338 patients (11.9%) in the sacubitril-valsartan group and in 373 patients (13.2%) in the ramipril group (hazard ratio, 0.90; 95% confidence interval [CI], 0.78 to 1.04; P = 0.17). Death from cardiovascular causes or hospitalization for heart failure occurred in 308 patients (10.9%) in the sacubitril-valsartan group and in 335 patients (11.8%) in the ramipril group (hazard ratio, 0.91; 95% CI, 0.78 to 1.07); death from cardiovascular causes in 168 (5.9%) and 191 (6.7%), respectively (hazard ratio, 0.87; 95% CI, 0.71 to 1.08); and death from any cause in 213 (7.5%) and 242 (8.5%), respectively (hazard ratio, 0.88; 95% CI, 0.73 to 1.05). Treatment was discontinued because of an adverse event in 357 patients (12.6%) in the sacubitril-valsartan group and 379 patients (13.4%) in the ramipril group.. Sacubitril-valsartan was not associated with a significantly lower incidence of death from cardiovascular causes or incident heart failure than ramipril among patients with acute myocardial infarction. (Funded by Novartis; PARADISE-MI ClinicalTrials.gov number, NCT02924727.).

Topics: Aged; Aminobutyrates; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Biphenyl Compounds; Cardiovascular Diseases; Double-Blind Method; Drug Combinations; Female; Heart Failure; Hospitalization; Humans; Hypotension; Male; Middle Aged; Myocardial Infarction; Proportional Hazards Models; Ramipril; Stroke Volume; Valsartan; Ventricular Dysfunction, Left

The role of sacubitril and/or valsartan in patient with heart failure (HF) is established. Whether sacubitril and/or valsartan plays a role in improving outcomes in patients after ST-segment elevation myocardial infarction (STEMI) is unknown. The current study aims to comparing the efficacy and safety of sacubitril and/or valsartan versus ramipril in post-STEMI patients. Patients presenting with STEMI were randomized to receive either sacubitril and/or valsartan or ramipril after primary percutaneous coronary intervention. The main efficacy endpoint was major adverse cardiac events (MACE) at 30 days and 6 months, defined as a composite of cardiac death, myocardial infarction, and HF hospitalizations. Multiple secondary clinical safety and efficacy endpoints were examined. A total of 200 patients were randomized from January 2018 to March 2019, mean age 54.5±10.4, 87% men, 75% presented with anterior wall STEMI. Baseline clinical and echocardiographic characteristics were comparable between groups. The primary endpoint of MACE was similar with sacubitril/valsartan versus ramipril at 30 days (p = 0.18); however, at 6 months, sacubitril/valsartan was associated with significant reduction of MACE (p = 0.005), mainly driven by reduction in HF hospitalizations (18% vs 36%, OR 0.40, 95% 0.22 to 0.75; p = 0.004). At 6 months, LV ejection fraction was higher with sacubitril/valsartan (46.8±12.5% vs 42.09±13.8%; p = 0.012), with improved LV remodelling (LV end diastolic dimension 50.6±3.9 mm vs 53.2±2.7 mm, p = 0.047; and LV end systolic dimension 36.1±3.4 mm versus 39.9±6.3 mm, p = 0.001) compared with ramipril. No difference in other efficacy or safety clinical endpoints was observed. In conclusion, early initiation of sacubitril/valsartan may offer clinical benefit and improvement in myocardial remodelling in post-STEMI patients.

Topics: Adult; Aged; Aminobutyrates; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Biphenyl Compounds; Double-Blind Method; Drug Combinations; Female; Heart Diseases; Heart Failure; Hospitalization; Humans; Male; Middle Aged; Myocardial Infarction; Percutaneous Coronary Intervention; Ramipril; ST Elevation Myocardial Infarction; Stroke Volume; Tetrazoles; Treatment Outcome; Valsartan

ACE inhibition reduces mortality and morbidity in patients with heart failure after acute myocardial infarction (AMI). However, there are limited randomised data about the long-term survival benefits of ACE inhibition in this population.. In 1993, the Acute Infarction Ramipril Efficacy (AIRE) study randomly allocated patients with AMI and clinical heart failure to ramipril or placebo. The duration of masked trial therapy in the UK cohort (603 patients, mean age=64.7 years, 455 male patients) was 12.4 and 13.4 months for ramipril (n=302) and placebo (n=301), respectively. We estimated life expectancy and extensions of life (difference in median survival times) according to duration of follow-up (range 0-29.6 years).. By 9 April 2019, death from all causes occurred in 266 (88.4%) patients in placebo arm and 275 (91.1%) patients in ramipril arm. The extension of life between ramipril and placebo groups was 14.5 months (95% CI 13.2 to 15.8). Ramipril increased life expectancy more for patients with than without diabetes (life expectancy difference 32.1 vs 5.0 months), previous AMI (20.1 vs 4.9 months), previous heart failure (19.5 vs 4.9 months), hypertension (16.6 vs 8.3 months), angina (16.2 vs 5.0 months) and age >65 years (11.3 vs 5.7 months). Given potential treatment switching, the true absolute treatment effect could be underestimated by 28%.. For patients with clinically defined heart failure following AMI, ramipril results in a sustained survival benefit, and is associated with an extension of life of up to 14.5 months for, on average, 13 months treatment duration.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Female; Heart Failure; Humans; Life Expectancy; Male; Middle Aged; Myocardial Infarction; Ramipril; United Kingdom

Studies have shown a non-linear relationship between systolic blood pressure (SBP) and diastolic blood pressure (DBP) and outcomes, with increased risk observed at both low and high blood pressure (BP) levels. We hypothesized that the BP-risk association is different in individuals with and without diabetes at high cardiovascular risk.. We identified patients with (N = 11 487) or without diabetes (N = 19 450), from 30 937 patients, from 133 centres in 44 countries with a median follow-up of 56 months in the ONTARGET/TRANSCEND studies. Patients had a prior history of stroke, myocardial infarction (MI), peripheral artery disease, or were high-risk diabetics. Patients in ONTARGET had been randomized to ramipril 10 mg daily, telmisartan 80 mg daily, or the combination of both. Patients in TRANSCEND were ACE intolerant and randomized to telmisartan 80 mg daily or matching placebo. We analysed the association of mean achieved in-trial SBP and DBP with the composite outcome of cardiovascular death, MI, stroke and hospitalization for congestive heart failure (CHF), the components of the composite, and all-cause death. Data were analysed by Cox regression and restricted cubic splines, adjusting for risk markers including treatment allocation and accompanying cardiovascular treatments. In patients with diabetes, event rates were higher across the whole spectrum of SBP and DBP compared with those without diabetes (P < 0.0001 for the primary composite outcome, P < 0.01 for all other endpoints). Mean achieved in-trial SBP ≥160 mmHg was associated with increased risk for the primary outcome [diabetes/no diabetes: adjusted hazard ratio (HR) 2.31 (1.93-2.76)/1.66 (1.36-2.02) compared with non-diabetics with SBP 120 to <140 mmHg], with similar findings for all other endpoints in patients with diabetes, and for MI and stroke in patients without diabetes. In-trial SBP <120 mmHg was associated with increased risk for the combined outcome in patients with diabetes [HR 1.53 (1.27-1.85)], and for cardiovascular death and all-cause death in all patients. In-trial DBP ≥90 mmHg was associated with increased risk for the primary outcome [diabetes/no diabetes: HR 2.32 (1.91-2.82)/1.61 (1.35-1.93) compared with non-diabetics with DBP 70 to <80 mmHg], with similar findings for all other endpoints, but not for CHF hospitalizations in patients without diabetes. In-trial DBP <70 mmHg was associated with increased risk for the combined outcome in all patients [diabetes/no diabetes: HR 1.77 (1.51-2.06)/1.30 (1.16-1.46)], and also for all other endpoints except stroke.. High on treatment BP levels (≥160 or ≥90 mmHg) are associated with increased risk of cardiovascular outcomes and death. Also low levels (<120 or <70 mmHg) are associated with increased cardiovascular outcomes (except stroke) and death. Patients with diabetes have consistently higher risks over the whole BP range, indicating that achieving optimal BP goals is most impactful in this group. These data favour guidelines taking lower BP boundaries into consideration, in particular in diabetes.. http://clinicaltrials.gov.Unique identifier: NCT00153101.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Blood Pressure Determination; Cardiovascular Diseases; Case-Control Studies; Diabetes Mellitus; Diastole; Drug Therapy, Combination; Heart Failure; Hospitalization; Humans; Hypertension; Myocardial Infarction; Peripheral Arterial Disease; Ramipril; Retrospective Studies; Risk Factors; Stroke; Systole; Telmisartan

Current guidelines of hypertensive management recommend upper limits for systolic (SBP) and diastolic blood pressure (DBP). J-curve associations of BP with risk exist for some outcomes suggesting that lower limits of DBP goals may also apply. We examined the association between mean attained DBP and cardiovascular (CV) outcomes in patients who achieved an on-treatment SBP in the range of 120 to <140 mmHg in the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) and Telmisartan Randomized AssessmeNt Study in ACE iNtolerant participants with cardiovascular Disease (TRANSCEND) trials on patients with high CV risk. This SBP range was associated with the lowest CV risk.. We analysed the outcome data from patients age 55 years or older with CV disease from the ONTARGET and TRANSCEND trials that randomized high-risk patients to ramipril, telmisartan, and the combination. In patients with controlled SBP (on-treatment 120 to <140 mmHg), the composite outcome of CV death, myocardial infarction, stroke and hospital admission for heart failure, the components thereof, and all-cause mortality were analysed according to mean on-treatment DBP as categorical (<70, 70 to <80, 80 to <90, and ≥90 mmHg) and continuous variable as well as the change of DBP according to baseline DBP. Pulse pressure (PP) was related to outcomes as a continuous variable.. In 16 099 of 31 546 patients, mean achieved SBP was 120 to <140 mmHg. The nominally lowest risk for all outcomes was observed at an achieved DBP of 70 to <80 mmHg. A higher achieved DBP was associated with a higher risk for the outcomes of stroke and of hospitalization for heart failure (≥80 mmHg) and myocardial infarction (≥90 mmHg). A lower achieved DBP (<70 mmHg) was associated with a higher risk for the primary outcome [hazard ratio (HR) 1.29, 95% confidence interval (95% CI) 1.15-1.45; P < 0.0001], myocardial infarction HR 1.54 (95% CI 1.26-1.88, P < 0.0001) and hospitalization for heart failure HR 1.81 (95% CI 1.47-2.24, P < 0.0001) and all-cause death (HR 1.19, 95% CI 1.04-1.35; P < 0.0001) while there was no signal for stroke and CV death compared to DBP 70 to <80 mmHg. A decrease of DBP was associated with lower risk when baseline DBP was >80 mmHg. The associations to outcomes were similar when patients were divided to SBP 120 to <130 mmHg or 130 to <140 mmHg for DBP or PP.. Compared to a DBP of 70 to <80 mmHg, lower and higher DBP was associated with a higher risk in patients achieving a SBP of 120 to <140 mmHg. Associations of DBP and PP to risk were similar notably at controlled SBP. These data suggest at optimal achieved SBP, risk is still defined by low or high DBP. These findings support guidelines which take DBP at optimal SBP control into consideration.

Topics: Aged; Antihypertensive Agents; Blood Pressure; Cardiovascular Diseases; Drug Therapy, Combination; Female; Follow-Up Studies; Heart Failure; Hospitalization; Humans; Hypertension; Male; Middle Aged; Myocardial Infarction; Ramipril; Risk Assessment; Single-Blind Method; Stroke; Telmisartan; Treatment Outcome

Blocking the renin-angiotensin-aldosterone system in ST-elevation myocardial infarction (STEMI) patients prevents heart failure and recurrent thrombosis. Our aim was to compare the effects of ramipril and losartan upon the markers of heart failure, endogenous fibrinolysis, and platelet aggregation in STEMI patients over the long term.. After primary percutaneous coronary intervention (PPCI), 28 STEMI patients were randomly assigned ramipril and 27 losartan, receiving therapy for six months with dual antiplatelet therapy (DAPT). We measured N-terminal proBNP (NT-proBNP), ejection fraction (EF), plasminogen-activator-inhibitor type 1 (PAI-1), and platelet aggregation by closure times (CT) at the baseline and after six months.. Baseline NT-proBNP ≥ 200 pmol/mL was observed in 48.1% of the patients, EF < 55% in 49.1%, and PAI-1 ≥ 3.5 U/mL in 32.7%. Six-month treatment with ramipril or losartan resulted in a similar effect upon PAI-1, NT-proBNP, EF, and CT levels in survivors of STEMI, but in comparison to control group, receiving DAPT alone, ramipril or losartan treatment with DAPT significantly increased mean CT (226.7 ± 80.3 sec versus 158.1 ± 80.3 sec, p < 0.05).. Ramipril and losartan exert a similar effect upon markers of heart failure and endogenous fibrinolysis, and, with DAPT, a more efficient antiplatelet effect in long term than DAPT alone.

Topics: Aged; Biomarkers; Cardiovascular Agents; Fibrinolysis; Heart Failure; Humans; Losartan; Middle Aged; Myocardial Infarction; Platelet Aggregation; Ramipril

This was a propensity score analysis of the prospective, randomized, double-blind Survival of Myocardial Infarction Long-term Evaluation (SMILE) 4 study in which one-year treatment with zofenopril 60 mg plus acetylsalicylic acid (ASA) 100 mg gave superior results compared to ramipril 10 mg plus ASA in terms of death or hospitalization for cardiovascular causes in patients with acute myocardial infarction (AMI) complicated by left ventricular dysfunction (LVD).. A total of 716 patients of the intention-to-treat population were divided into homogeneous propensity quintiles (Q) using a logistic regression model (QI: best risk profile; QV: worst risk profile).. Treatment was associated with a similar low rate of major cardiovascular events in any Q. However, the efficacy of zofenopril was better than that of ramipril in QII, QV, and particularly QIII (odds ratio (OR) and 95% confidence interval: 0.43 (0.21-0.87), p<0.05]. This result was primarily attributed to a decrease in the risk of cardiovascular hospitalization, particularly striking in the QIII (OR: 0.40, 0.19-0.85; p<0.05). Mortality rate did not significantly differ between the two treatments in any Q.. In the SMILE-4 study the propensity analysis confirmed the efficacy of zofenopril in the prevention of long-term cardiovascular outcomes irrespective of the cardiovascular risk profile of post-AMI patients.

Topics: Captopril; Demography; Drug Therapy, Combination; Endpoint Determination; Female; Hospitalization; Humans; Intention to Treat Analysis; Male; Middle Aged; Myocardial Infarction; Propensity Score; Ramipril; Survival Analysis; Time Factors; Ventricular Dysfunction, Left

Excessively high and low achieved blood pressure (BP) may be associated with a bad outcome in patients with coronary artery disease, the J curve phenomenon. The effect of BP changes from baseline in relation with the subsequent risk of stroke and myocardial infarction (MI) is unknown. Of the 25 620 patients randomized in the Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) study, we selected 19 102 patients with coronary artery disease at baseline. BP at entry was 141/82 mm Hg, and its average decrease during follow-up was 7/6 mm Hg. BP entered the analysis as time-varying variable modeled with restricted cubic splines. After adjustment for several potential determinants of reverse causality, a change in BP from baseline by -34/-21 mm Hg (10th percentile) was associated with a lesser risk of stroke without any significant increase in the risk of MI. A rise in systolic/diastolic BP from baseline by 20/10 mm Hg (90th percentile) was associated with an increased risk of stroke, whereas the risk of MI increased with systolic BP and not with diastolic BP. In conclusion, in patients with coronary artery disease and initially free from congestive heart failure, a BP reduction from baseline over the examined BP range had little effect on the risk of MI and predicted a lower risk of stroke. An increase in systolic BP from baseline increased the risk of stroke and MI. The relationships of BP with risk were much steeper for stroke than for MI. A treatment-induced BP reduction over the explored range seems to be safe in patients with coronary artery disease.. http://www.clinicaltrials.gov. Unique identifier: NCT00153101.

Topics: Aged; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Blood Pressure; Coronary Artery Disease; Diastole; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Male; Myocardial Infarction; Ramipril; Stroke; Systole; Telmisartan; Time Factors; Treatment Outcome

In the Ongoing Telmisartan Alone and in Combination with Ramipril Trial (ONTARGET), dual agent renin-angiotensin-aldosterone system (RAAS) blockade with angiotensin-converting-enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) did not reduce the risk of renal and cardiovascular outcomes compared with the single use of either agent. Dual therapy however increased the incidence of hyperkalemia. We examined risk factors for hyper- and hyokalemia and hypothesized that both would be associated with worse cardiovascular and renal outcomes.. A post-hoc analysis of the ONTARGET trial comparing dual therapy (ramipril and telmisartan) vs monotherapy (ramipril or telmisartan) was performed. The association between serum potassium at week 6 on cardiovascular and renal outcomes during the 56 months follow-up was assessed by multivariate Cox analysis. The main cardiovascular outcome was the composite of cardiovascular death, myocardial infarction, stroke, or hospitalization for heart failure. The renal outcome was defined as the composite of a doubling of serum creatinine or chronic dialysis.. Six weeks after randomization, hyperkalemia developed in 210 (2.7%) patients on dual therapy vs. 264 (1.6%) patients on monotherapy (p < 0.001 vs. dual therapy). Hypokalemia developed in 87 (1.1%) patients on dual therapy vs. 200 (1.2%)patients on monotherapy. Serum potassium was nonlinearly associated with cardiovascular and renal events with a nadir between 4.0-5.0 mmol/l for cardiovascular and 4.0-4.5 mmol/l for renal events such that subjects above or below these values exhibited higher risks. This association was independent of age, gender, diabetes, estimated glomerular filtration rate, systolic blood pressure and diuretic use.. With the precautions stipulated by the protocol of the ONTARGET trial, hypokalemia and hyperkalemia were infrequent events. Nevertheless, both high and low serum potassium were associated with an increased risk of cardiovascular and renal disease.

Topics: Aged; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Benzimidazoles; Benzoates; Blood Pressure; Creatinine; Drug Therapy, Combination; Female; Heart Failure; Hospitalization; Humans; Hyperkalemia; Hypertension; Hypokalemia; Kidney; Kidney Diseases; Logistic Models; Male; Middle Aged; Multivariate Analysis; Myocardial Infarction; Nonlinear Dynamics; Odds Ratio; Potassium; Proportional Hazards Models; Ramipril; Renal Dialysis; Renin-Angiotensin System; Risk Assessment; Risk Factors; Stroke; Telmisartan; Time Factors; Treatment Outcome

Antecedent hypertension represents a risk factor for adverse outcomes in survivors of acute myocardial infarction (AMI). Prognosis of such patients might be greatly improved by drugs enhancing blood pressure control. In the present retrospective analysis of the randomized, double-blind, parallel-group, SMILE-4 study we compared the efficacy of zofenopril 60 mg and acetylsalicylic acid (ASA) 100 mg versus ramipril 10 mg and ASA in patients with AMI complicated by left ventricular dysfunction, classified according to a history of hypertension.. The primary study end-point was 1-year combined occurrence of death or hospitalization for cardiovascular causes. Hypertension was defined according to medical history and current blood pressure values at entry and could be determined in 682 of 716 patients of the intention-to-treat analysis.. One hundred and fifty-seven patients (23%) were normotensives and 525 (77%) hypertensives. In the normotensive population the primary end-point occurred in 19 of 76 zofenopril-treated patients (25%) and in 23 of 81 ramipril-treated patients (28%) [odds ratio (95% confidence interval): 0.84 (0.41-1.71), P = 0.631]. In the hypertensive population, major cardiovascular outcomes were reported in 84 of 273 zofenopril-treated patients (31%) and in 99 of 252 ramipril-treated patients (39%), with a 31% significantly (P = 0.041) lower risk with zofenopril [0.69 (0.48-0.99)]. The superiority of zofenopril versus ramipril was particularly evident in patients with isolated systolic hypertension [n = 131, 0.48 (0.23-0.99), P = 0.045].. This retrospective analysis of the SMILE-4 study confirmed the good efficacy of zofenopril and ASA in the prevention of long-term cardiovascular outcomes also in the subgroup of patients with hypertension.

Topics: Aged; Antihypertensive Agents; Aspirin; Blood Pressure; Captopril; Europe; Female; Humans; Hypertension; Male; Middle Aged; Myocardial Infarction; Platelet Aggregation Inhibitors; Ramipril; Randomized Controlled Trials as Topic; Retrospective Studies; Ventricular Dysfunction, Left

The impact of nonpersistence on events and of events on persistence is unclear. We studied the effects of nonpersistence on outcomes and events on nonadherence in a randomized placebo controlled trial in 40 countries on 25,620 patients.. In the ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET), persistent patients (n = 20,991) were compared with individuals who had permanently stopped study medications (n = 4,629).. Older age, female gender, less physical activity, less education, and history of stroke/transient ischemic attack, depression, and diabetes were associated with nonpersistence. After adjustment, nonpersistence was associated with the composite end point of cardiovascular death, myocardial infarction, stroke, or hospitalization for heart failure (hazard ratio 1.24, 99% CI 1.09-1.40, P < .0001), cardiovascular death alone (1.87, 1.60-2.19, P < .0001), and heart failure hospitalization alone (1.32, 1.04-1.67, P = .0023). Cardiovascular events increased when medications were stopped, whereas noncardiovascular outcomes did not. Nonpersistence rapidly increased within the first year after nonfatal events such as myocardial infarction (hazard ratio 3.37, 99% CI 2.72-4.16, P < .0001), stroke (3.25, 2.59-4.07, P < .0001), and hospitalization for heart failure (3.67, 2.95-4.57, P < .0001). Persistence was poorer with more frequent and earlier events. Patients stopping medication after an event were at greater risk for subsequent events.. Improving medications persistence could interrupt this vicious circle and may improve outcomes.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Cardiovascular Diseases; Drug Therapy, Combination; Female; Humans; Male; Medication Adherence; Middle Aged; Myocardial Infarction; Proportional Hazards Models; Ramipril; Risk; Telmisartan

Angiotensin-converting enzyme inhibitors (ACEIs) are largely employed for treating patients with left ventricular dysfunction (LVD), but their efficacy may be negatively affected by concomitant administration of acetylsalicylic acid (ASA), with some difference among the different compounds.. The interaction between ASA and the two ACEIs zofenopril and ramipril may result in a different impact on survival of cardiac patients, due to differences in the pharmacological properties of the two ACEIs.. This phase IIIb, randomized, double-blind, parallel-group, multicenter, European study compared the safety and efficacy of zofenopril (60 mg/day) and ramipril (10 mg/day) plus ASA (100 mg/day), in 771 patients with LVD (clinical signs of heart failure or a left ventricular ejection fraction <45%) following acute myocardial infarction (AMI). The primary study end point was 1-year combined occurrence of death or hospitalization for cardiovascular causes.. In the intention-to-treat population, the primary outcome was significantly reduced by zofenopril (n = 365) vs ramipril (n = 351) (odds ratio [OR]: 0.70, and 95% confidence interval [CI]: 0.51-0.96; P = 0.028) as a result of a decrease in cardiovascular hospitalization (OR: 0.64,95% CI: 0.46-0.88; P = 0.006). Mortality rate was not significantly different between the 2 treatments (OR: 1.51, 95% CI: 0.70-3.27; P = 0.293). Blood pressure values did not significantly change during the 1-year follow-up. N-terminal pro-brain natriuretic peptide levels were progressively reduced during the study, with no statistically significant between-treatment differences. Proportion of patients with deterioration of renal function during the study was similar between the 2 groups. Drug safety profile was comparable between treatments.. In patients with LVD following AMI, the efficacy of zofenopril associated with ASA was superior to that of ramipril plus ASA, indicating some important clinical implications for the future use of ACEIs in patients with LVD or overt heart failure.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Aspirin; Captopril; Chi-Square Distribution; Double-Blind Method; Drug Therapy, Combination; Europe; Female; Heart Failure; Hospitalization; Humans; Kaplan-Meier Estimate; Logistic Models; Male; Middle Aged; Myocardial Infarction; Odds Ratio; Platelet Aggregation Inhibitors; Prospective Studies; Ramipril; Risk Assessment; Risk Factors; Stroke Volume; Systole; Time Factors; Treatment Outcome; Ventricular Dysfunction, Left; Ventricular Function, Left

Epidemiological data suggest that sex independently contributes to cardiovascular risk. Clinical trials are often hampered by the enrollment of few female patients.. The Ongoing Telmisartan Alone and in Combination With Ramipril Global End Point Trial (ONTARGET) and the parallel Telmisartan Randomized Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease (TRANSCEND) included a large proportion of female patients (9378 female versus 22 168 male patients). Differences in male and female patients enrolled in ONTARGET/TRANSCEND were analyzed for the primary 4-fold end point (composite of cardiovascular death, myocardial infarction, stroke, or admission to hospital for heart failure), a secondary 3-fold end point (cardiovascular death, myocardial infarction, stroke), and individual components of the primary composite. Baseline characteristics included age, ethnicity, body mass index, physical activity, tobacco use, alcohol consumption, formal education, clinical diagnosis for study entry, patient history, and concomitant medication. Patients were followed up until death or the end of the study (median, 56 months). Compared with male patients, female patients had a 19% significantly lower risk for the 4-fold end point and 21% for the 3-fold end point (after adjustment for study, treatment, and the above baseline values). Similarly, the adjusted risk for cardiovascular death (17%) and myocardial infarction (22%), but not for stroke and hospitalization for heart failure, was also significantly lower in women. Diabetic female patients were characterized by a higher risk for acute myocardial infarction compared with diabetic male patients, whereas alcohol consumption resulted in significantly lower risk in women.. In our analysis made up of 70.3% male and 29.7% female patients, an ≈20% lower risk for the combined cardiovascular end points in female patients was observed despite treatment with cardioprotective agents. This difference was driven primarily by a significantly lower incidence of myocardial infarction. Thus, we demonstrate in a large interventional trial that sex greatly affects the occurrence of cardiovascular events in patients with vascular disease or high-risk diabetes mellitus.. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00153101.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Female; Humans; Incidence; Male; Middle Aged; Myocardial Infarction; Ramipril; Research Design; Risk Assessment; Risk Factors; Sex Distribution; Sex Factors; Stroke; Telmisartan

In the Ongoing Telmisartan Alone and in Combination With Ramipril Global End Point Trial (ONTARGET), dual therapy did not reduce cardiovascular or renal outcomes compared with either angiotensin-converting enzyme inhibitors or angiotensin receptor blockers alone. Previous controlled trials with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers have demonstrated greater cardiovascular and renal benefit in people with renal risk. We hypothesized that dual therapy would be more effective than monotherapy in patients with low glomerular filtration rate and elevated albuminuria.. Post hoc analysis was performed of renal subgroups of dual therapy versus monotherapy for the ONTARGET study and angiotensin receptor blocker versus placebo for the Telmisartan Randomized Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease (TRANSCEND). The studies featured hazard ratios by subgroups and Cox regression models with factors for treatment, subgroup, and interactions. The main cardiovascular outcome was the composite of cardiovascular death, myocardial infarction, stroke, or hospitalization for heart failure, and the main renal outcome was the composite of chronic dialysis or doubling of creatinine. In ONTARGET, there was no cardiovascular or renal benefit from dual over monotherapy in any subgroup, even with low glomerular filtration rate and/or elevated albuminuria. In TRANSCEND, in the comparison of angiotensin receptor blocker with placebo, there was a significant interaction for the main renal outcome (P = 0.01) in the direction of harm for patients with normoalbuminuria (0.37 versus 0.16 events per 100 patient-years; hazard ratio, 2.35; confidence interval, 1.33 to 4.15) but a trend to benefit with microalbuminuria (0.52 versus 0.89 events per 100 patient-years; hazard ratio, 0.60; confidence interval, 0.25 to 1.46) and macroalbuminuria (1.57 versus 2.60 events per 100 patient-years; hazard ratio, 0.71; confidence interval, 0.21 to 2.44).. This post hoc analysis does not support dual therapy over monotherapy in high-vascular risk patients with low glomerular filtration rate or albuminuria. This observation is a post hoc comparison and should be interpreted appropriately.. URL: http://clinicaltrials.gov Identifier: NCT00153101.

Topics: Aged; Albuminuria; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Creatinine; Drug Therapy, Combination; Female; Glomerular Filtration Rate; Heart Failure; Heart Rate; Humans; Kidney Failure, Chronic; Male; Middle Aged; Myocardial Infarction; Ramipril; Stroke; Telmisartan; Treatment Outcome

Topics: Adrenergic beta-Antagonists; Aged; Angiotensin-Converting Enzyme Inhibitors; Carbazoles; Carvedilol; Dose-Response Relationship, Drug; Drug Therapy, Combination; Echocardiography; Electrocardiography; Follow-Up Studies; Humans; Myocardial Infarction; Propanolamines; Quality of Life; Ramipril; Retrospective Studies; Time Factors; Treatment Outcome; Trimetazidine; Vasodilator Agents

The prognostic significance of left and right bundle branch block (LBBB and RRBB) in patients with chronic stable cardiovascular (CV) disease is not well characterized and was evaluated in the Heart Outcomes Prevention Evaluation (HOPE) study cohort.. Observational analysis of data prospectively collected in the HOPE trial.. HOPE was a multicenter, international trial, which evaluated ramipril and vitamin E in 9,541 patients aged > or = 55 years with CV disease or diabetes with > or = 1 CV risk factor(s) but without heart failure (HF) or known left ventricular systolic dysfunction. Follow-up extended for a median of 4.5 years. Electrocardiograms were obtained at baseline in all study participants and were read centrally.. Major CV events (defined as CV death, myocardial infarction, or stroke), heart failure, CV death, all-cause death, and sudden death.. Baseline LBBB was present in 246 (2.6%) patients and was associated with increased risk for major CV events (HR = 1.54; 95% CI, 1.18-2.02), CV death (HR 2.29; 95% CI, 1.63-3.20), heart failure (HR 2.99; 95% CI, 2.31-3.87), sudden death (HR 3.17; 95% CI, 2.13-4.73), and all-cause death (HR = 2.10; 95% CI, 1.59-2.77). In multivariate models, LBBB remained an independent predictor of heart failure, sudden death, CV death, and all-cause death (P < or = 0.002 for all). Baseline RBBB was present in 428 (4.5%) of patients and was not associated with increased CV risk.. In patients with stable chronic CV disease, LBBB but not RBBB is an independent predictor of heart failure, sudden death, CV death, and all-cause death.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Bundle-Branch Block; Cardiovascular Diseases; Chronic Disease; Death, Sudden; Double-Blind Method; Drug Therapy, Combination; Electrocardiography; Europe; Female; Heart Failure; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Myocardial Infarction; North America; Proportional Hazards Models; Prospective Studies; Ramipril; Risk Assessment; Risk Factors; Stroke; Time Factors; Treatment Outcome; Vascular Diseases; Vitamin E

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Dose-Response Relationship, Drug; Electrocardiography; Female; Follow-Up Studies; Humans; Male; Middle Aged; Myocardial Infarction; Ramipril; Treatment Outcome

Previous studies support a role of oxygen-free radicals in the development of congestive heart failure (CHF). The aim of this study was to investigate whether lipid peroxidation is increased in CHF patients on modern pharmacological therapy and whether there is a positive correlation between plasma levels of markers of lipid peroxidation and severity of heart failure (HF). Plasma malondialdehyde (MDA) and isoprostanes are often used as markers of lipid peroxidation and oxidative stress. We also studied whether long-term treatment with isosorbide-5-mononitrate (IS-5-MN) in combination with standard HF therapy affects P-MDA levels in patients with evidence of left ventricular (LV) dysfunction following acute myocardial infarction (AMI).. Ninety-two patients with clinical or echocardiographic evidence of LV-dysfunction following AMI were randomized to treatment with either IS-5-MN or placebo. In a subgroup of 83 patients with available plasma MDA, echocardiography, right-heart catherization, and plasma natriuretic peptides were evaluated. Control subjects were 80 healthy blood donors. A second study group consisted of 56 patients with CHF, evaluated with respect to LV function, brain natriuretic peptide and markers of oxidative stress (P-MDA and 8-isoprostane). The second control group comprised 50 healthy subjects.. Lipid peroxidation measured by P-MDA and 8-isoprostane was not increased in patients with LV dysfunction treated with standard HF therapy. No positive correlation was found to the severity of HF. Long-term IS-5-MN therapy did not influence P-MDA concentrations.. Although results from many experimental and clinical studies suggest that oxidative stress is increased in HF, this may not be true for patients treated with beta blockers and inhibitors of the renin-angiotensin system.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Atrial Natriuretic Factor; Captopril; Comorbidity; Delayed-Action Preparations; Dinoprost; Female; Heart Failure; Hemodynamics; Humans; Isosorbide Dinitrate; Lipid Peroxidation; Losartan; Male; Malondialdehyde; Middle Aged; Myocardial Infarction; Natriuretic Peptide, Brain; Nitric Oxide Donors; Oxidative Stress; Ramipril; Stroke Volume; Ultrasonography; Ventricular Dysfunction, Left

Individual markers of inflammation may add incremental predictive value in the context of conventionally available risk factors. We evaluated the ability of 9 inflammatory biomarkers, microalbuminuria, and N-terminal pro-brain natriuretic peptide (Nt-proBNP) to improve cardiovascular risk prediction beyond that obtained from traditional risk factors in a secondary-prevention population.. We measured biomarkers representing the acute-phase reaction (C-reactive protein, fibrinogen, and interleukin-6), proinflammatory pathways (soluble tumor necrosis factor receptor-1 and -2, soluble interleukin-1 receptor antagonist, and interleukin-18), endothelial activation (soluble vascular adhesion molecule-1 and soluble intercellular adhesion molecule-1), Nt-proBNP, and microalbuminuria in 3199 study individuals of the Heart Outcomes Prevention Evaluation (HOPE) Study and assessed their association with risk of myocardial infarction, stroke, or cardiovascular death (primary outcome, n=501) over 4.5 years of follow-up. In a backward Cox regression procedure that included risk factors and biomarkers, Nt-proBNP (hazard ratio [HR] 1.72 per increment SD, 95% CI 1.39 to 2.12; P<0.0001), soluble intercellular adhesion molecule-1 (HR 1.46, 95% CI 1.19 to 1.80; P=0.0003), microalbuminuria (HR 1.55, 95% CI 1.22 to 1.98; P=0.0004), soluble interleukin-1 receptor antagonist (HR 1.30, 95% CI 1.05 to 1.61; P=0.02), and fibrinogen (HR 1.31, 95% CI 1.05 to 1.62; P=0.02) remained significantly related to the primary outcome. Only inclusion of Nt-proBNP provided incremental information above that obtained by models of traditional risk factors.. Although levels of various inflammatory biomarkers are significantly related to future cardiovascular risk, their incremental predictive value is modest. A model consisting of simple traditional risk factors and Nt-proBNP provided the best clinical prediction in the secondary-prevention population.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Biomarkers; C-Reactive Protein; Coronary Artery Disease; Female; Fibrinogen; Heart Diseases; Humans; Interleukin-6; Male; Middle Aged; Myocardial Infarction; Natriuretic Peptide, Brain; Predictive Value of Tests; Ramipril; Risk Factors; Vitamin E

In recent large cardiovascular trials done in stable patients, 14-31% of the participants were smokers; the consequences of smoking in these trials using medications known to reduce cardiovascular events, have not been assessed.. We evaluated the cardiovascular outcomes according to smoking status of men and women participating in the Heart Outcomes Prevention Evaluation trial.. The occurrence of cardiovascular events was documented among participants who did not change their smoking status during the trial. There were 2728 'never smokers', 5241 'former smokers' and 936 'current smokers', and all had stable cardiovascular disease or diabetes with at least one other risk factor. None had previous congestive heart failure or known left ventricular ejection fraction < 0.40.. During the 4.5-year follow-up, there were 641 cardiovascular deaths, 978 myocardial infarctions, 358 strokes and 1021 deaths. In comparison to 'never smokers', smokers had relative risks adjusted for confounding variables including medications known to reduce cardiovascular mortality and morbidity, for cardiovascular death of 1.65 [95% confidence interval (CI), 1.28-2.14], for myocardial infarction of 1.26 (95% CI, 1.01-1.58), for stroke of 1.42 (95% CI, 1.00-2.04), and for total mortality of 1.99 (95% CI, 1.63-2.44). The rates of these events among 'former smokers' were not different from those of 'never smokers'.. Smoking increased the risk of mortality and morbidity among high-risk patients despite the use of medications known to reduce cardiovascular events. Smoking cessation programs should be reinforced even for patients participating in clinical trials.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Antioxidants; Cardiovascular Diseases; Female; Humans; Incidence; Male; Middle Aged; Morbidity; Myocardial Infarction; Preventive Medicine; Ramipril; Risk Factors; Smoking; Stroke; Treatment Outcome; Vitamin E

The HOPE study was a 19 country, prospective randomized trial in which the ACE-inhibitor Ramipril but not Vitamin E significantly reduced the risk of future cardiovascular events in a high-risk population of men and women, including many with diabetes. The benefits were present in all sub-groups, independent of the presence or absence of diabetes, hypertension, evidence of cardiovascular disease, microalbuminuria, blood pressure lowering, the use of aspirin, lipid-lowering or antihypertensive medication. It provided clear evidence that Ramipril should safely and cost-effectively be used in individuals not known to have low ventricular ejection fraction or heart failure but at high-risk of cardiovascular events. It was also beneficial in patients with renal insufficiency, reducing progression of proteinuria and development of new microalbuminuria. It provided micro- and macrovascular benefits in people with diabetes, reduced the development of new cases of diabetes and showed a positive and graded association between the waist-to-hip ratio and the risk of developing diabetes. Sub-studies completed and on-going into the predictive role of natriuretic peptides, infectious and inflammatory markers, provide insight into possible mechanisms of action of Ramipril.

Topics: Angiotensin-Converting Enzyme Inhibitors; Aspirin; Cost-Benefit Analysis; Diabetes Complications; Female; Heart Failure; Humans; Inflammation; Kidney Diseases; Male; Myocardial Infarction; Natriuretic Peptide, Brain; Peptide Fragments; Prospective Studies; Ramipril; Stroke; Ventricular Function, Left; Vitamin E

To investigate the hypothesis that prior angina pectoris confers protection from remodeling occurring after myocardial infarction (MI), we analyzed echocardiograms from the Healing and Early Afterload Reducing Therapy (HEART) trial.. Ischemia occurring before MI has been shown to reduce infarct size in experimental models and to improve outcomes in patients. The extent to which ischemia occurring before MI influences subsequent changes in ventricular size and function is unclear.. We studied 283 patients enrolled in the HEART trial who had echocardiograms at days 1 and 90 after MI. Left ventricular (LV) dilation from days 1 to 90 was used as a measure of LV remodeling. We explored the relationship between symptomatic angina occurring before infarction and subsequent LV remodeling.. In patients who reported angina (n = 111) during the three months preceding MI, LV volume change was -0.73 +/- 2.6 ml over the 90-day post-MI period, compared with 6.8 +/- 2.6 ml for patients (n = 172) without angina (p = 0.017). In contrast, there were no differences in changes in ejection fraction based on prior angina. Maximal creatine kinase was significantly lower in patients with prior angina (2,119 +/- 1,729 vs. 2,701 +/- 2,088, p = 0.016). In a multivariate model, prior angina remained protective for ventricular remodeling after adjusting for age, gender, baseline ejection fraction, Killip class, baseline end-diastolic volume, and drug treatment group (p = 0.042). However, the protective effect of pre-infarction angina appeared to be attenuated in diabetic patients.. Ischemic symptoms occurring before MI may protect against LV remodeling. These protective effects may be secondary to recruitment of collaterals or ischemic preconditioning of the myocardium, and they appear to be attenuated in diabetic patients.

Topics: Aged; Angina Pectoris; Angiotensin-Converting Enzyme Inhibitors; Biomarkers; Creatine Kinase; Diabetes Mellitus; Double-Blind Method; Echocardiography; Female; Humans; Male; Middle Aged; Multivariate Analysis; Myocardial Infarction; Predictive Value of Tests; Prevalence; Ramipril; Stroke Volume; Ventricular Remodeling

We hypothesized that the benefit from ramipril on cardiac events and on left ventricular end-systolic volume (ESVI) in the Angiotensin-converting enzyme inhibition Post-revascularization Study (APRES) randomized controlled trial (RCT) was associated with long-term improvement.. For the 3.2 years after the end of the RCT, we obtained information from a national database regarding date and cause of death and hospitalization for the 159 enrolled patients.. Assignment to ramipril in the RCT resulted in a lower rate of cardiac death or hospitalization with heart failure up to the time of complete follow-up of all patients at 4.3 years (relative risk [RR], 0.28; P =.018) and up to 1.5 years after the end of the RCT (RR, 0.35; P =.042) but not up to the complete extended follow-up time at 6.9 years (RR, 0.65; P =.27). Independent predictors for risk of future cardiac death or hospitalization with heart failure were (a) left ventricular dilation (LVD) (RR, 2.84; P =.031), defined as an increase in ESVI greater than the reproducibility coefficient, and (b) composite event of acute myocardial infarction or development of heart failure or LVD (RR, 12.44; P <.001). Ramipril significantly reduced events (a) (P =.046) and (b) (P =.015) during the RCT.. There is congruence between the beneficial effect of ramipril on LVD, acute myocardial infarction, or heart failure and the prognostic importance of these factors and on cardiac death and hospitalization with heart failure. This observation supports and reinforces conclusions from previous APRES reports that ramipril benefits non-high-risk patients after revascularization.

Topics: Analysis of Variance; Angina Pectoris; Angioplasty, Balloon, Coronary; Angiotensin-Converting Enzyme Inhibitors; Coronary Artery Bypass; Follow-Up Studies; Heart Diseases; Heart Failure; Hospitalization; Humans; Myocardial Infarction; Proportional Hazards Models; Ramipril; Risk; Ventricular Dysfunction, Left

Nitrates are often administrated with a variety of other pharmacologic agents in the management of chronic heart failure (CHF). However, limited information is available concerning the long-term effects in patients with evidence of left ventricular (LV) dysfunction after acute myocardial infarction (AMI) already treated with standard heart failure therapy.. In a randomized, double-blind, placebo-controlled trial, we evaluated the effects of a 60 mg dose of isosorbide-5-mononitrate (IS-5-MN) given daily for 11 months to 47 patients with clinical or echocardiographic evidence of left ventricular dysfunction after acute myocardial infarction. Forty-five patients received a placebo.. Invasive hemodynamic measurements did not show any difference between the treatment regimens. Overall changes in echocardiographic measurements were not significantly different between IS-5-MN therapy and the placebo groups. However, in a prespecified subgroup with left ventricular ejection fraction < or =40% at baseline, IS-5-MN therapy resulted in a lesser increase of end-diastolic volume index than the placebo (P =.047). IS-5-MN significantly reduced the serum concentration of atrial natriuretic peptide (mean 20.0 pmol/L, 95% CI 7.7-32.3, P =.002), whereas the placebo did not (P =.041 for the difference between the groups). The proportion of patients taking diuretics was significantly reduced in the IS-5-MN group, from 30 of 44 to 20 of 44 (P =.02), but not with placebo, which remained at 27 of 43 (P = 1.0, with P =.048 for the difference between the regimens).. Oral, long-term IS-5-MN therapy resulted in lower atrial natriuretic peptide levels and reduced the need for additional diuretics. Less LV dilatation was observed in patients with more severe LV dysfunction at baseline.

Topics: Aged; Atrial Natriuretic Factor; Delayed-Action Preparations; Diuretics; Double-Blind Method; Drug Therapy, Combination; Echocardiography; Female; Hemodynamics; Humans; Isosorbide Dinitrate; Male; Middle Aged; Myocardial Infarction; Peptide Fragments; Ramipril; Ventricular Dysfunction, Left

Previous trials in the prevention of heart failure have been restricted to patients with low ejection fraction or hypertension. We assessed an angiotensin-converting enzyme (ACE) inhibitor, ramipril, to prevent the development of heart failure in high-risk patients without known low ejection fraction or heart failure.. We randomly assigned 9297 patients to receive double-blind ramipril (10 mg daily) or matching placebo for 4.5 years. Death attributable to heart failure, hospitalization for heart failure, initiation of open-label ACE inhibitor for heart failure, or development of typical signs or symptoms of heart failure developed in 951 patients and was associated with a 4.01-fold increase in the risk of death (P<0.0001). The rate of developing heart failure was significantly increased with coronary disease (risk ratio, 2.17), microalbuminuria (1.82), left ventricular hypertrophy (1.47), increasing age (by decade, 1.37), and diabetes (1.36). Ramipril reduced new-onset heart failure rate from 11.5% to 9.0% (relative risk, 0.77; 95% CI, 0.68 to 0.87; P<0.0001). Ramipril consistently reduced heart failure rate both in those with (relative risk, 0.87) and those without an interim myocardial infarction (relative risk, 0.78). Ramipril also reduced the heart failure rate more in patients with baseline systolic pressure above the median (139 mm Hg) (relative risk, 0.67) compared with those below the median (relative risk, 0.91; P=0.024 for interaction of group by treatment).. Ramipril significantly reduces the rate of development of heart failure in patients at high risk of cardiovascular events.

Topics: Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Double-Blind Method; Follow-Up Studies; Heart Failure; Humans; Incidence; Myocardial Infarction; Ramipril; Treatment Outcome

In a placebo-controlled, double-blinded, randomized study we evaluated the effect of ramipril prior to thrombolysis on the course of PAI-1 plasma levels and on the frequency of postinfarct ischemic events in patients with acute myocardial infarction. Fifty-one out of 99 patients received 2.5 mg ramipril orally prior to thrombolysis and 12 h later. The blood samples for determination of PAI-1 plasma levels were collected on admission and 2, 4, 8, 12 and 24 h after thrombolysis. Postinfarct ischemic events were registered until coronary angiography was performed and defined as recurrent chest pain and/or evidence of ischemic signs on the ECG (ST-depression or ST-segment elevation of 1 mm in one or more inferior or anterior leads). Coronary angiography was performed within 7 days after the onset of myocardial infarction. Patients were classified into two groups: those without reperfusion of the infarct-related artery (TIMI grade 0 or 1) and those with reperfusion of the infarct-related artery (TIMI grade 2.3). On admission, PAI-1 plasma levels were similar in both groups (ramipril: 47.1 [4.8] ng/ml; placebo: 49.1 [4.8] ng/ml). The PAI-1AUC was 77.2 [6.7] ng/ml/h in the ramipril group and 95.4 [6.2] ng/ml/h in the placebo group (p = 0.013). Significant differences between groups were observed at 4, 8 and 12 h after thrombolysis (4 h: 85.5 (11.3) vs. 116 (12.3) ng/ml, p < 0.01; 8 h: 79.1 (11.2) vs. 100.9 (9.3) ng/ml, p < 0.01; 12 hrs: 71.3 (9.5) vs. 87.4 (7.7) ng/ml, p < 0.05). The relative frequency of postinfarct ischemic events was significantly lower in the ramipril group (2.5% versus 7.1%, p = 0.001). Additionally, we observed a significant higher rate of TIMI grade 2 and 3 of the infarct-related artery in patients receiving oral ramipril compared to the placebo group (73% versus 54%; p = 0.035). Our study demonstrates a favorable effect of ramipril on the fibrinolytic system after thrombolysis associated with a lower rate of postinfarct ischemic events within the first days after myocardial infarction. Therefore, the application of ramipril prior to thrombolysis appears to be a reasonable concomitant treatment which may reduce early infarct-related complications.

Topics: Adult; Aged; Cause of Death; Double-Blind Method; Drug Therapy, Combination; Emergency Medical Services; Female; Hemodynamics; Humans; Hypotension; Ischemia; Middle Aged; Myocardial Infarction; Plasminogen Activator Inhibitor 1; Ramipril; Thrombolytic Therapy

We evaluated the effects of long-term therapy with the angiotensin-converting enzyme (ACE) inhibitor ramipril on major cardiovascular (CV) outcomes in high-risk women.. The effect of long-term ACE inhibitor therapy in high-risk women without heart failure and with preserved left ventricular (LV) systolic function has not been previously reported.. The Heart Outcomes Prevention Evaluation (HOPE) trial is a large, randomized clinical trial that evaluated ramipril and vitamin E in high-risk patients. We present the preplanned analysis of the effects of ramipril in women in the HOPE study. The study randomized 2,480 women aged >or=55 years with vascular disease or diabetes and at least one additional CV risk factor and without heart failure or a known low LV ejection fraction to ramipril (10 mg/day) or placebo. The primary outcome was the composite of myocardial infarction, stroke or CV death. Average follow-up was 4.5 years.. Treatment with ramipril resulted in reduced primary end point rates (11.3% vs. 14.9% in the placebo arm; relative risk [RR] 0.77, 95% confidence interval [CI] 0.62 to 0.96; p = 0.019), fewer strokes (3.1% vs. 4.8%; RR 0.64, 95% CI 0.43 to 0.96; p = 0.029) and fewer CV deaths (4.2% vs. 6.9%; RR 0.62, 95% CI 0.44 to 0.88; p = 0.0068). There were trends toward reduced rates of myocardial infarction, heart failure and all-cause death. The beneficial effect of ramipril was similar in women and men.. Treatment with ramipril reduces the CV risk in high-risk women without heart failure and with preserved LV systolic function.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Female; Follow-Up Studies; Humans; Middle Aged; Myocardial Infarction; Ramipril; Randomized Controlled Trials as Topic; Risk Factors; Stroke; Treatment Outcome

The D/I (deletion, D, insertion, I) polymorphism of the angiotensin-converting enzyme (ACE) gene has been extensively studied for its association with a number of cardiovascular and other disease states. However, its potential association with differential clinical efficacy of ACE inhibitors (ACE-I) administered to patients who had suffered a myocardial infarction (MI), i.e. the prevention of left ventricular (LV) remodeling, has so far not been specifically studied. The aim of the study was to investigate whether the D/I polymorphism of the ACE gene is associated with the incidence of post-MI LV remodeling in patients drawn from the 'Healing and Early Afterload Reducing Therapy' (HEART) Study. The ACE D/I polymorphism was characterized by the polymerase chain reaction (PCR) in 265 subjects from the 'Healing and Early Afterload Reducing Therapy' Study, a double-blind, placebo-controlled trial with the objective of determining whether early or delayed administration of the ACE-I, ramipril, in patients with acute anterior wall MI would be optimal in reducing LV enlargement. Selected frequencies for the ACE D and I alleles were 0.59 and 0.41 (placebo-high dose group), 0.56 and 0.44 (low dose-low dose group), and, 0.60 and 0.40 (high dose-high dose group), respectively. All observed genotype frequencies were in Hardy-Weinberg equilibrium. There was no evidence for an association between genotype and outcome regarding LV size or function, nor with the initial blood pressure response after ACE-I administration (adjusted for covariates). Our data provide no evidence for an association of the ACE D/I polymorphism with the risk of LV remodeling post-MI in the presence of ACE-I therapy, and therefore do not suggest that differential clinical efficacy of ACE-inhibitors is related to this genetic marker.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Double-Blind Method; Electrocardiography; Gene Frequency; Genetic Markers; Genotype; Humans; Male; Middle Aged; Myocardial Infarction; Peptidyl-Dipeptidase A; Pharmacogenetics; Phenotype; Polymorphism, Genetic; Ramipril; Treatment Outcome; Ventricular Remodeling

Increased left ventricular (LV) wall stress after myocardial infarction (MI) has been implicated in LV remodeling. However, the relationship between LV wall stress and LV remodeling is incompletely defined.. We prospectively studied the relationship between regional wall stress and LV remodeling by application of the finite element method to end-systolic LV models from patients enrolled in the Healing and Early Afterload Reducing Therapy (HEART) Trial. Individual LV models were constructed from orthogonal apical echocardiographic views obtained at day 14 after anteroseptal MI in 64 patients. Of these, 31 patients received low-dose (0.625 mg) ramipril and 33 patients received full-dose (10 mg) ramipril. LV wall stress was calculated by the finite element method and correlated with change in LV volume from day 14 to day 90 after MI.. Among all patients, increases in apical regional wall stress were associated with LV volume changes (P -trend =.015). The relationship between apical regional wall stress and change in LV volume was strongest in the low-dose ramipril group (r = 0.53, P =.002) and remained significant after adjustment for end-diastolic volume, infarct size, ejection fraction, and systolic blood pressure yet was attenuated in the full-dose ramipril group.. Apical regional wall stress is an independent predictor of subsequent LV remodeling after MI. The relationship between increased apical wall stress and LV dilatation appears to be attenuated by full-dose angiotensin-converting enzyme inhibition.

Topics: Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Double-Blind Method; Echocardiography; Female; Finite Element Analysis; Heart Septum; Heart Ventricles; Humans; Male; Middle Aged; Myocardial Contraction; Myocardial Infarction; Prognosis; Prospective Studies; Ramipril; Safety; Stress, Physiological; Stroke Volume; Ventricular Dysfunction, Left; Ventricular Remodeling

Patients with reduced left ventricular function and ventricular enlargement after myocardial infarction are at significantly greater risk for congestive heart failure and death. Nevertheless, recovery of ventricular function occurs in a significant proportion of patients after myocardial infarction, and modern reperfusion strategies have been associated with increased recovery of function.. To determine the extent and predictors of recovery of ventricular function after anterior Q-wave myocardial infarction in the reperfusion era.. Subgroup analysis of the Healing and Early Afterload Reducing Therapy study.. 35 medical centers in the United States and Canada.. 352 patients with Q-wave anterior myocardial infarction.. Placebo for 14 days, followed by full-dose (10 mg) ramipril until day 90; low-dose (0.625 mg) ramipril for 90 days; or full-dose ramipril for 90 days. All patients underwent reperfusion therapy.. Echocardiography was performed on day 1 (before randomization), day 14, and day 90 after myocardial infarction. Left ventricular volume and ejection fraction were measured and wall-motion analyses were performed at all three time points in 249 patients and at baseline in an additional 12 patients who died during follow-up. Echocardiographic and nonechocardiographic predictors of ventricular recovery were examined.. By day 90, 55 of 252 (22%) patients who had abnormal ejection fraction and wall-motion abnormalities on day 1 demonstrated complete recovery of function (ejection fraction in the normal range and infarct segment length of 0%), and an additional 36% (91 of 252 patients) demonstrated partial recovery of function. At 90 days, 53% (132 of 249) of patients had greater than 5% improvement in ejection fraction, whereas only 16% (39 of 249) had a decrease in ejection fraction of more than 5%. The majority of functional improvement occurred by day 14 after infarction. Of various clinical and echocardiographic measures obtained on day 1, peak creatine kinase level was the strongest independent predictor of subsequent recovery of ventricular function in multivariate analysis. Each 100-unit increase in peak creatine kinase was associated with a 4.3% decreased odds of recovery (P < 0.001) after adjustment for ejection fraction on day 1, extent of akinesis or dyskinesis, treatment regimen, Killip class, age, and sex.. Significant myocardial stunning with subsequent improvement of ventricular function occurred in the majority of patients after Q-wave anterior myocardial infarction. A lower peak level of creatine kinase, an estimate of the extent of necrosis, is independently predictive of recovery of function. Early functional assessment (day 1 after acute myocardial infarction) had limited ability to predict recovery of ventricular function.

Topics: Angiotensin-Converting Enzyme Inhibitors; Cardiomegaly; Creatine Kinase; Double-Blind Method; Echocardiography; Female; Humans; Male; Middle Aged; Myocardial Infarction; Myocardial Reperfusion; Ramipril; Recovery of Function; Risk Factors; Stroke Volume; Ventricular Dysfunction, Left

In trials of patients with left ventricular dysfunction or heart failure, ACE inhibitor use was unexpectedly associated with reduced myocardial infarction (MI). Using the Heart Outcomes Prevention Evaluation (HOPE) trial data, we tested prospectively whether ramipril, an ACE inhibitor, could reduce coronary events and revascularization procedures among patients with normal left ventricular function.. In the HOPE trial, 9297 high-risk men and women, >/=55 years of age with previous cardiovascular disease or diabetes plus 1 risk factor, were randomly assigned to ramipril (up to 10 mg/d), vitamin E (400 IU/d), their combination, or matching placebos. During the mean follow-up of 4.5 years, there were 482 (10.4%) patients with clinical MI and unexpected cardiovascular death in the ramipril group compared with 604 (12.9%) in the placebo group [relative risk reduction (RRR), 21% (95% CI) (11,30); P<0.0003]. Ramipril was associated with a trend toward less fatal MI and unexpected death [4.0% versus 4.7%; RRR, 16% (-3, 31)] and with a significant reduction in nonfatal MI [5.6% versus 7.2%; RRR, 23% (9,34)]. Risk reductions in MI were documented in participants taking or not taking beta-blockers, lipid lowering, and/or antiplatelet agents. Although ramipril had no impact on hospitalizations for unstable angina [11.9% versus 12.2%; RRR, 3% (-9,14)], it reduced the risk of worsening and new angina [27.2% versus 30.0%; RRR, 12% (5,18); P<0.0014] and coronary revascularizations [12.5% versus 14.8%; RRR, 18%; (8,26) P<0.0005].. In this high-risk cohort, ramipril reduced the risk of MI, worsening and new angina, and the occurrence of coronary revascularizations.

Topics: Aged; Angina, Unstable; Angiotensin-Converting Enzyme Inhibitors; Double-Blind Method; Female; Humans; Male; Middle Aged; Myocardial Infarction; Myocardial Ischemia; Myocardial Revascularization; Ramipril; Risk Factors; Survival Analysis

Diabetes is a major risk factor for cardiovascular events. Indeed, people with diabetes are 2-4 times more likely to die from cardiovascular causes than individuals without diabetes. Despite evidence to suggest that the burden of cardiovascular disease may be decreasing in Western populations, this trend has not been repeated in diabetic populations. Diabetes is also the most common cause of new-onset end-stage renal disease, blindness and amputations. The growing incidence of diabetes throughout the world, particularly in developing nations, suggests that diabetes-related cardiovascular disease and other chronic cardiovascular diseases will constitute a serious global threat to health and well-being. The HOPE (Heart Outcomes Prevention Evaluation) study was designed to determine if the angiotensin converting enzyme (ACE) inhibitor, ramipril, prevents cardiovascular events in high risk patients. As people with diabetes have a high risk of such events, this group was specified for inclusion and analysis in the HOPE study. The HOPE study was designed to include up to 4,000 people with diabetes and was designed with high power to detect an 18% risk reduction in the diabetic sub group alone. A total of 3,577 individuals with diabetes were randomised to receive either 10 mg of ramipril or placebo. After a period of 4.5 years of follow-up, the group of patients receiving ramipril had a statistically and clinically significant risk reduction of 25% in the primary outcome of myocardial infarction (MI), stroke or cardiovascular (CV) death. This comprises a 37% risk reduction in CV death, a 22% risk reduction in MI, a 33% reduction in stroke and a 24% reduction in all-cause mortality. The MICRO-HOPE (Microalbuminuria, Cardiovascular, and Renal Outcomes) sub study assessed the effect of ramipril on diabetic nephropathy. This was detected by a centrally measured urine albumin:creatinine ratio and confirmed by timed urine collection. Ramipril significantly reduced the risk of overt nephropathy by 22% (P = 0.045), and overt nephropathy, laser therapy or dialysis by 15% (P = 0.05). ACE inhibition with ramipril represents a new macrovascular and microvascular preventive therapy for people with diabetes.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Diabetic Angiopathies; Diabetic Nephropathies; Female; Humans; Male; Myocardial Infarction; Ramipril; Stroke; Treatment Outcome

Our purpose was to study the changes in vasoconstrictive neurohormones, N-terminal proatrial natriuretic peptide (Nt-proANP), and brain natriuretic peptide (BNP) and their relationship with left ventricular (LV) remodeling soon after anterior myocardial infarction (MI).. The Healing and Afterload Reducing Therapy (HEART) trial has shown that early use of ramipril improves left ventricular ejection fraction (LVEF) and attenuates LV remodeling when initiated soon after MI. This neurohumoral substudy of HEART investigates the changes in vasoconstrictive and natriuretic peptides and their relationship with LV remodeling.. One hundred twenty-two patients had blood drawn for the measurement of catecholamines, endothelin-I, angiotensin II, Nt-proANP and BNP, and prostacyclins within 24 hours of an MI, and at 3, 14, and 90 days after the MI. Quantitative echocardiograms were performed at baseline and at 14 days.. All neurohormones except angiotensin II (P =.12) and prostaglandins were significantly elevated at baseline. Vasoconstrictive neurohormones decreased significantly over time but remained elevated at 14 days. Both Nt-proANP and BNP were elevated within the first 14 days. BNP decreased significantly by 90 days, whereas Nt-proANP exhibited no change between 14 and 90 days. Ramipril decreased plasma levels of angiotensin II at 3 days but had no effect on the other neurohormones.. Neurohumoral activation occurs and persists in patients with anterior MI and overall preserved LV function. Ramipril had only a modest impact on neurohormones despite its significant benefits on LV remodeling soon after MI.

Topics: Angiotensin II; Atrial Natriuretic Factor; Biomarkers; Catecholamines; Dopamine; Double-Blind Method; Epinephrine; Epoprostenol; Female; Humans; Male; Middle Aged; Myocardial Infarction; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Norepinephrine; Ramipril; Stroke Volume; Ventricular Remodeling

Angiotensin-converting-enzyme inhibitors improve the outcome among patients with left ventricular dysfunction, whether or not they have heart failure. We assessed the role of an angiotensin-converting-enzyme inhibitor, ramipril, in patients who were at high risk for cardiovascular events but who did not have left ventricular dysfunction or heart failure.. A total of 9297 high-risk patients (55 years of age or older) who had evidence of vascular disease or diabetes plus one other cardiovascular risk factor and who were not known to have a low ejection fraction or heart failure were randomly assigned to receive ramipril (10 mg once per day orally) or matching placebo for a mean of five years. The primary outcome was a composite of myocardial infarction, stroke, or death from cardiovascular causes. The trial was a two-by-two factorial study evaluating both ramipril and vitamin E. The effects of vitamin E are reported in a companion paper.. A total of 651 patients who were assigned to receive ramipril (14.0 percent) reached the primary end point, as compared with 826 patients who were assigned to receive placebo (17.8 percent) (relative risk, 0.78; 95 percent confidence interval, 0.70 to 0.86; P<0.001). Treatment with ramipril reduced the rates of death from cardiovascular causes (6.1 percent, as compared with 8.1 percent in the placebo group; relative risk, 0.74; P<0.001), myocardial infarction (9.9 percent vs. 12.3 percent; relative risk, 0.80; P<0.001), stroke (3.4 percent vs. 4.9 percent; relative risk, 0.68; P<0.001), death from any cause (10.4 percent vs. 12.2 percent; relative risk, 0.84; P=0.005), revascularization procedures (16.3 percent vs. 18.8 percent; relative risk, 0.85; P<0.001), cardiac arrest (0.8 percent vs. 1.3 percent; relative risk, 0.62; P=0.02), [corrected] heart failure (9.1 percent vs. 11.6 percent; relative risk, 0.77; P<0.001), and complications related to diabetes (6.4 percent vs. 7.6 percent; relative risk, 0.84; P=0.03).. Ramipril significantly reduces the rates of death, myocardial infarction, and stroke in a broad range of high-risk patients who are not known to have a low ejection fraction or heart failure.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Diabetes Complications; Diabetes Mellitus; Double-Blind Method; Female; Humans; Male; Middle Aged; Myocardial Infarction; Ramipril; Risk Factors; Stroke; Treatment Outcome

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Death, Sudden, Cardiac; Female; Humans; Male; Middle Aged; Myocardial Infarction; Ramipril; Stroke; Survival Analysis; Treatment Outcome; Ventricular Dysfunction, Left

This study was performed to assess the effect of treatment with ramipril on the incidence of cardiac events after invasive revascularization in patients with asymptomatic moderate left ventricular dysfunction.. In patients with angina pectoris and left ventricular dysfunction, both invasive revascularization and treatment with angiotensin-converting enzyme inhibitors reduce cardiac mortality and morbidity. Whether there is a benefit from combining the two treatment strategies has never been evaluated prospectively.. After invasive revascularization, 159 patients with preoperative chronic stable angina pectoris, left ventricular ejection fraction between 0.30 and 0.50 and no clinical heart failure were randomly assigned to receive double-blind treatment with either ramipril or placebo and subsequently followed for a median of 33 months.. Ramipril reduced the incidence of the triple-composite end point of cardiac death, acute myocardial infarction or clinical heart failure (risk reduction 58%; 95% confidence interval 7% to 80%, p = 0.031). The incidence of the quadruple-composite end point of cardiac death, acute myocardial infarction, clinical heart failure or recurrent angina pectoris was not altered with ramipril. These findings were consistent across subgroups with respect to left ventricular ejection fraction below or above 0.40, and whether coronary artery bypass grafting or percutaneous transluminal coronary angioplasty was performed.. In patients with angina pectoris and asymptomatic moderate left ventricular dysfunction, long-term treatment with ramipril after invasive revascularization significantly reduced the incidence of the composite end point of cardiac death, acute myocardial infarction or clinical heart failure, indicating that the beneficial effects of angiotensin-converting enzyme inhibitor treatment may be extended to include treatment of this patient group.

Topics: Adult; Aged; Angina Pectoris; Angiotensin-Converting Enzyme Inhibitors; Double-Blind Method; Female; Follow-Up Studies; Heart Failure; Humans; Male; Middle Aged; Myocardial Infarction; Myocardial Revascularization; Ramipril; Stroke Volume; Survival Rate; Treatment Outcome; Ventricular Dysfunction, Left

In a cohort of 67 patients from the Acute Infarction Ramipril Efficacy study, we showed that ramipril therapy was associated with a significant reduction in QT dispersion over a 2-month period after acute myocardial infarction. This reduction of ventricular repolarization inhomogeneity indicates an antiarrhythmic effect and may be an important additional mechanism for the reduced all-cause mortality and sudden death incidence achieved with angiotensin-converting enzyme inhibition after acute myocardial infarction.

Topics: Angiotensin-Converting Enzyme Inhibitors; Electrocardiography; Female; Heart Failure; Humans; Male; Middle Aged; Myocardial Infarction; Ramipril; Single-Blind Method

To examine clinical outcomes associated with optional beta blockade in a population of patients with evidence of heart failure after myocardial infarction.. Data from the acute infarction ramipril efficacy (AIRE) study were analysed retrospectively. At baseline 22.3% of the patients were receiving a beta blocker. To minimise confounding, beta blocker and diuretic treatments, presence of clinical signs of heart failure, left ventricular ejection fraction, and 16 other baseline clinical variables were simultaneously entered in a multivariate Cox regression model. In addition, the same analysis was repeated separately within a high and a low risk group of patients, as defined according to the need for diuretic treatment.. beta Blocker treatment was an independent predictor of reduced risk of total mortality (hazard ratio 0.66, 95% confidence interval (CI) 0. 48 to 0.90) and progression to severe heart failure (0.58, 95% CI 0.40 to 0.83) for the entire study population. There were similar findings in high risk patients requiring diuretics (0.59, 95% CI 0.40 to 0.86; and 0.58, 95% CI 0.38 to 0.89).. beta Blocker treatment is associated with improved outcomes in patients with clinical evidence of mild to moderate heart failure after myocardial infarction. Most importantly, high risk patients with persistent heart failure appear to benefit at least as much as lower risk patients with transient heart failure.

Topics: Adrenergic beta-Antagonists; Aged; Angiotensin-Converting Enzyme Inhibitors; Diuretics; Double-Blind Method; Drug Therapy, Combination; Female; Heart Failure; Humans; Male; Middle Aged; Myocardial Infarction; Ramipril; Regression Analysis; Retrospective Studies; Risk Factors; Treatment Outcome

After acute myocardial infarction (AMI), patients with a history of arterial hypertension (AH) have a worse prognosis than normotensives. Whether this adverse risk is beneficially modulated by treatment with angiotensin-converting enzyme (ACE) inhibitors is unknown. We evaluated the prognostic value of antecedent hypertension in post-AMI patients given ACE inhibitor therapy.. We analysed retrospectively data from the AIRE study (randomised, placebo-controlled trial of ramipril in 2006 post-AMI patients with clinical heart failure). A history of AH was present in 28% of the patients. We examined the prognostic value of antecedent hypertension separately among placebo and ramipril treated patients and also the effect of ramipril on clinical outcomes according to whether or not a history of AH was present.. Antecedent hypertension was a significant indicator of adverse prognosis in the placebo (P) treated patients (Hazard Ratio 1.49, 95% Confidence Intervals 1.13 to 1.97, P = 0.005) but not in the ramipril (R) treated patients (1.17, 0.84 to 1.61, P = 0.34). A similar pattern was observed for the risks of sudden death (P: 1.75, 1.21 to 2.54, P = 0.003; R: 1.34, 0.86 to 2.07, P = 0.18) and severe/resistant heart failure (P: 1.48, 1.08 to 2.03, P = 0.014; R: 1.18, 0.83 to 1.68, P = 0.37). Treatment with ramipril reduced the all-cause mortality risk in both hypertensive (0.63, 0.44 to 0.89, P = 0.009) and normotensive patients (0.78, 0.61 to 0.99, P = 0.041).. Antecedent hypertension is not a significant prognosticator in patients with AMI and clinical heart failure given ACE inhibitor therapy.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Cardiac Output, Low; Cohort Studies; Death, Sudden, Cardiac; Female; Humans; Hypertension; Male; Medical Records; Middle Aged; Multivariate Analysis; Myocardial Infarction; Placebos; Prognosis; Proportional Hazards Models; Ramipril; Retrospective Studies

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Female; Humans; Male; Middle Aged; Myocardial Infarction; Ramipril; Stroke

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Humans; Myocardial Infarction; Ramipril; Stroke; Vitamin E

We evaluated global and segmental left ventricular (LV) mass and LV mass/volume ratio in patients with LV dysfunction receiving angiotensin-converting enzyme (ACE) inhibitor therapy after acute myocardial infarction (MI).. ACE inhibitors attenuate LV dilatation and compensatory hypertrophy after acute MI in animal models. However, LV remodeling in patients after acute MI has been largely defined on the basis of changes in chamber volume alone.. Twenty-nine patients with LV ejection fraction <40% received the ACE inhibitor ramipril (range 2.5 to 20 mg/day) within 5 days of their first Q-wave MI. Magnetic resonance imaging was performed at baseline and at 3 months, providing global and regional LV volumes and mass from summated serial short-axis slices. Mean arterial blood pressure was unchanged from baseline to 3-month follow-up (89 +/- 10 to 92 +/- 17 mm Hg). LV mass decreased (90 +/- 25 to 77 +/- 21 gm/m2, p < 0.0005) as LV end-diastolic volumes increased (65 +/- 13 to 73 +/- 22 ml/m2, p < 0.01). Global LV mass to volume ratio decreased from 1.40 +/- 0.28 to 1.08 +/- 0.18 gm/ml (p < 0.0001), as did circumferential wall thickness to volume ratio of noninfarcted myocardium at the base of the LV (0.06 +/- 0.02 to 0.05 +/- 0.02 mm/ml, p < 0.001). LV ejection fraction increased from 35 +/- 6 to 40 +/- 9% (p < 0.001) in the presence of an increase in calculated end-systolic wall stress (185 +/- 57 to 227 +/- 54 gm/cm2, p < 0.01).. ACE inhibitor therapy was associated with improved LV function in the face of a decrease in mass to volume ratio of the LV as well as a decrease in wall thickness to volume ratio of noninfarcted myocardium. Whether ACE inhibitor therapy had direct or indirect effects on these changes in LV mass and function are open questions that require further investigation.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Cardiac Volume; Electrocardiography; Female; Follow-Up Studies; Heart Ventricles; Humans; Hypertrophy, Left Ventricular; Magnetic Resonance Imaging, Cine; Male; Middle Aged; Myocardial Infarction; Ramipril; Stroke Volume; Treatment Outcome; Ventricular Dysfunction, Left; Ventricular Function, Left

Clinical signs of heart failure such as pulmonary rales and dyspnea, ventricular dysfunction, and ventricular arrhythmia are independent predictors of a poor prognosis after acute myocardial infarction (AMI).. The study aimed to assess the effect of ramipril treatment on mildly depressed left ventricular (LV) systolic function, assessed by atrioventricular (AV) plane displacement in patients with congestive heart failure after AMI.. The study was a substudy in the Acute Infarction Ramipril Efficacy Study, a double-blind, randomized, place-bo-controlled trial of ramipril versus placebo in patients with symptoms of heart failure after AMI. In all, 56 patients were included in the main study, 4 refused to participate in the substudy, and 4 were excluded for logistical reasons. Echocardiography was performed at entry and after 6 months. Patients who underwent coronary artery bypass grafting during the follow-up period were excluded.. At baseline, the patients had modest LV dysfunction, and mean AV plane displacement of 9.7 mm. During follow-up, AV plane displacement increased in ramipril-treated patients from 9.5 to 10.9 mm (p < 0.01). No statistically significant changes were seen in the placebo group.. Ramipril improves LV systolic function in patients with clinical signs of heart failure and only modest systolic dysfunction after AMI. Measurement of AV plane displacement is a simple and reproducible method for detection of small changes in systolic function and may be used instead of ejection fraction in patients with poor image quality.

Topics: Adult; Aged; Aged, 80 and over; Angiotensin-Converting Enzyme Inhibitors; Double-Blind Method; Echocardiography; Female; Heart Failure; Humans; Male; Middle Aged; Myocardial Infarction; Ramipril; Ventricular Dysfunction, Left; Ventricular Function, Left

We tested the hypothesis that angiotensin-converting enzyme (ACE) inhibitor therapy decreases left ventricular (LV) mass in patients with a left ventricular ejection fraction (LVEF) > 40% and no evidence of heart failure after their first acute Q wave myocardial infarction (MI).. Recently, ACE inhibitor therapy has been shown to have an early mortality benefit in unselected patients with acute MI, including patients without heart failure and a LVEF > 35%. However, the effects on LV mass and volume in this patient population have not been studied.. Thirty-five patients with a LVEF > 40% after their first acute Q wave MI were randomized to titrated oral ramipril (n = 20) or conventional therapy (control, n = 15). Magnetic resonance imaging (MRI) performed an average of 7 days and 3 months after MI provided LV volumes and mass from summated serial short-axis slices.. Left ventricular end-diastolic volume index did not change in ramipril-treated patients (62 +/- 16 [SD] to 66 +/- 17 ml/m2) or in control patients (62 +/- 16 to 68 +/- 17 ml/m2), and stroke volume index increased significantly in both groups. However, LV mass index decreased in ramipril-treated patients (82 +/- 18 to 73 +/- 19 g/m2, p = 0.0002) but not in the control patients (77 +/- 15 to 79 +/- 23 g/m2). Systolic arterial pressure did not change in either group at 3-month follow-up.. In patients with a LVEF > 40% after acute MI, ramipril decreased LV mass, and blood pressure and LV function were unchanged after 3 months of therapy. Whether the decrease in mass represents a sustained effect that is associated with a decrease in morbid events requires further investigation.

Topics: Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Female; Humans; Hypertrophy, Left Ventricular; Magnetic Resonance Imaging; Male; Middle Aged; Myocardial Infarction; Ramipril; Stroke Volume; Ventricular Function, Left

The importance of the effects of ACE inhibitors on sudden death, progressive heart failure and recurrent infarction to the reduction in overall mortality in heart failure and after myocardial infarction is disputed.. The AIRE study randomized 2006 patients with clinical or radiological evidence of heart failure within 2-9 days of a myocardial infarction to receive ramipiril 5 mg b.d. or matching placebo. Outcomes were assessed independently by members of an end-points committee blinded to treatment allocation.. Fewer patients developed severe resistant heart failure as their first validated end-point on rampril, despite the greater number of at-risk survivors, compared to placebo (n = 143 vs 178; risk reduction 23%; CI 5 to 39%; P = 0.017). Ramipril did not alter the rate of reinfarction or stroke. Irrespective of treatment allocation 182 (46%) patients developed resistant heart failure prior to death. A validated acute or remote myocardial reinfarction occurred in 76 (19%) patients prior to death and chest pain occurred in 90 (23%) patients around the time of death suggesting an ischaemic element to these deaths Eighty deaths occurred on the index admission, 167 during re-admission and 145 out-of-hospital. Sudden death accounted for 54% of all deaths and 93% of out-of-hospital deaths. Ramipril reduced the risk of sudden death by 30% (95% CI: 8-47%; P = 0.011). However, overall, 45% of those patients who died suddenly had severe or worsening heart failure prior to their death. Only 39% of sudden deaths were considered to be due to arrhythmias. Ramipril reduced the risk of death from circulatory failure by 18%, but this did not reach statistical significance (95% CI; 41 to -14%; P = 0.237). The magnitude of the effects on sudden death and death due to circulatory failure were not significantly different. However, 38% of the reduction in overall mortality was from the subgroup with sudden death who had developed prior severe resistant heart failure (placebo n = 35, ramipril n = 15), again emphasizing the marked benefit in preventing failure. Ramipril did not selectively alter the proportion of in- to out-of-hospital deaths.. Ramipril reduces mortality and progression to resistant heart failure among patients with evidence of heart failure early after myocardial infarction. Retarding the progression of heart failure appears to be a major factor contributing to the reduction in mortality both by reducing circulatory failure and by reducing sudden death.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Cause of Death; Death, Sudden, Cardiac; Female; Heart Failure; Humans; Male; Middle Aged; Myocardial Infarction; Ramipril; Recurrence; Survival Analysis; Survival Rate; Treatment Outcome

In the Acute Infarction Ramipril Efficacy (AIRE) Study, the effect of angiotensin-converting-enzyme (ACE) inhibition on the survival of patients with clinical heart failure after acute myocardial infarction (AMI), was assessed. At an average follow-up time of 15 months after randomisation, all-cause mortality was reduced from 22.6% (placebo group) to 16.9% (ramipril group) representing an absolute mortality reduction of 5.7% and a relative risk reduction of 27% (95% CI 11-40%; p = 0.002). Our aim in this study was to assess the long-term (3 years after the AIRE Study closed) magnitude, duration, and reliability of the survival benefits observed after treatment with ramipril (target dose 5 mg twice a day) when compared with placebo.. We investigated the mortality status of all 603 patients recruited from the 30 UK centres involved in the AIRE Study. Through government records we were able to confirm the death or survival of all 603 patients exactly 3 years after the close of the AIRE Study. Follow-up was for a minimum of 42 months and a mean of 59 months. The average duration of treatment with masked trial medication was 13.4 months for placebo and 12.4 months for ramipril.. By 0000 h March 1, 1996, death from all causes had occurred in 117 (38.9%) of 301 patients randomly assigned placebo and 83 (27.5%) of 302 patients randomly assigned ramipril, representing a relative risk reduction of 36% (95% CI 15-52%; p = 0.002) and an absolute reduction in mortality of 11.4% (114 additional 5-year survivors per 1000 patients treated for an average of 12.4 months).. Our data provide robust evidence that administration of ramipril to patients with clinically defined heart failure after AMI results in a survival benefit that is not only large in magnitude, but also sustained over many years.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Cardiac Output, Low; Cause of Death; Double-Blind Method; Female; Follow-Up Studies; Heart Failure; Humans; Longitudinal Studies; Male; Middle Aged; Multivariate Analysis; Myocardial Infarction; Placebos; Ramipril; Regression Analysis; Reproducibility of Results; Retrospective Studies; Risk Factors; Sensitivity and Specificity; Survival Rate

Although ACE inhibitor therapy has been shown to reduce mortality in patients with acute myocardial infarction (MI), the optimal dose and the timing of its initiation have not been determined.. In a double-blind trial of 352 patients with anterior MI, we compared the safety and effectiveness of early (day 1) versus delayed (day 14) initiation of the ACE inhibitor ramipril (10 mg) on echocardiographic measures of left ventricular (LV) area and ejection fraction (EF). An early, low-dose ramipril (0.625 mg) arm was also evaluated. Clinical events did not differ. During the first 14 days, the risk of manifesting a systolic arterial pressure of < or = 90 mm Hg was increased in both ramipril groups. LVEF increased in all groups during this period, but the early, full-dose ramipril group had the greatest improvement in EF (increase: full, 4.9 +/- 10.0; low, 3.9 +/- 8.2%; delayed, 2.4 +/- 8.8%; P for trend < .05) and was the only group that did not demonstrate a significant increase in LV diastolic area.. The results of the present study demonstrated that in patients with anterior MI, the early use of ramipril (titrated to 10 mg) attenuated LV remodeling and was associated with a prompter recovery of LVEF. The use of low-dose regimen did not prevent hypotension and had only intermediate benefits on LV size and function. The more favorable effects on LV topography of the early use of full-dose ramipril support the results of the major clinical trials, which have demonstrated an early survival benefit of ACE inhibition.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Dose-Response Relationship, Drug; Double-Blind Method; Echocardiography; Female; Humans; Male; Middle Aged; Myocardial Infarction; Ramipril; Recurrence; Stroke Volume; Survival Analysis; Time Factors

The long-term administration of ACE inhibitors to selected patients with left ventricular dysfunction appears to reduce the incidence of recurrent myocardial infarction (MI) and unstable angina pectoris. The mechanisms responsible for the reduction in ischemic events are unknown, but likely candidates include effects on the atherosclerotic process, thrombosis, and/or vascular tone.. The effects of ACE inhibitor therapy with ramipril on plasma fibrinolytic variables were assessed in 120 subjects participating in the Healing and Early Afterload Reduction Therapy (HEART) study, a double-blind, placebo-controlled trial of acute anterior MI patients who were randomly assigned within 24 hours of the onset of symptoms to receive low-dose ramipril (0.625 mg daily), full-dose ramipril (1.25 mg titrated to 10 mg/d), or placebo for 14 days. Plasma levels of plasminogen activator inhibitor-1 (PAI-1) activity and PAI-1 antigen and tissue plasminogen activator (TPA) antigen were measured before randomization and on day 14. Clinical characteristics of the three study groups were similar, as were the prerandomization plasma levels of PAI-1 antigen, PAI-1 activity, and TPA antigen. Compared with the placebo group, PAI-1 antigen levels were 44% lower (P=.004) at day 14 in the ramipril-treated patients, and PAI-1 activity levels were 22% lower (P=.02). In contrast, plasma TPA levels were not significantly different between the placebo-treated and ramipril-treated groups.. Treatment with ramipril has a significant impact on plasma fibrinolytic variables during the recovery phase after acute MI. The renin-angiotensin system appears to play an important role in the regulation of vascular fibrinolysis, and interruption of this regulatory pathway may contribute to the clinical benefits of ACE inhibitors.

Topics: Angiotensin-Converting Enzyme Inhibitors; Double-Blind Method; Fibrinolysis; Humans; Male; Middle Aged; Myocardial Infarction; Plasminogen Activator Inhibitor 1; Ramipril; Tissue Plasminogen Activator

Previous studies have reported left ventricular (LV) thrombus in 20% to 56% of patients after anterior wall acute myocardial infarction (AMI). The Healing and Early Afterload Reducing Therapy (HEART) study was a prospective study comparing effects of early (24 hours) or delayed (14 days) initiation of ramipril, an angiotensin-converting enzyme inhibitor, on LV function after anterior wall AMI. This ancillary study assessed prevalence of LV thrombus. Two-dimensional echocardiography was performed on days 1, 14, and 90 after myocardial infarction. The cohort consisted of 309 patients. Q-wave anterior wall AMI occurred in 78%; 87% received reperfusion therapy. The prevalence of LV thrombus was 2 of 309 (0.6%) at day 1, 11 of 295 (3.7%) at day 14, and 7 of 283 (2.5%) at day 90. One patient had thrombus at 2 examinations. The day 1 echocardiogram was not correlated with thrombus development. LV size increased more in patients with thrombus than in those without thrombus. Patients with thrombus had more wall motion abnormality after day 1 than patients without thrombus (p = 0.03). Thus, the current prevalence of LV thrombus in anterior wall AMI is lower than previously reported, possibly due to changes in AMI management. Preservation of LV function is likely to be an important mechanism. Most thrombi are seen by 2 weeks after AMI. Resolution documented by echocardiography is frequent.

Topics: Adult; Aged; Aged, 80 and over; Angiotensin-Converting Enzyme Inhibitors; Echocardiography; Female; Heart Diseases; Humans; Incidence; Male; Middle Aged; Myocardial Infarction; Prospective Studies; Ramipril; Thrombosis; Time Factors; Ventricular Dysfunction, Left; Ventricular Function, Left

Studies have shown that angiotensin converting enzyme (ACE) inhibition prevents left ventricular remodeling and cardiovascular events after an acute myocardial infarction. The role of aldosterone in ventricular remodeling after a myocardial infarction has not been addressed.. To compare the effects of an ACE inhibitor, an aldosterone receptor antagonist and placebo on left ventricular remodeling after a first episode of transmural acute myocardial infarction.. Patients hospitalized for a first episode of acute myocardial infarction were blindly and randomly assigned to receive ramipril (2.5 mg bid), spironolactone (25 mg tid) or placebo. Ejection fraction, left ventricular end diastolic and end systolic volumes were measured by multigated radionuclide angiography, at baseline and after six months of treatment.. Twenty four patients were assigned to placebo, 31 to ramipril and 23 to spironolactone. Age, gender, Killip class, treatment with thrombolytics, revascularization procedures and use of additional medications were similar in the three groups. After six months of treatment, ejection fraction increased from 34.5 +/- 2.3 to 40.2 +/- 2.4% in patients on ramipril, from 32.6 +/- 2.9 to 36.6 +/- 2.7% in patients on spironolactone, and decreased from 37 +/- 3 to 31 +/- 3% in patients on placebo (ANOVA between groups p < 0.05). Basal end systolic volume was similar in all three groups, increased from 43.4 +/- 3.4 to 61.4 +/- 6.0 ml/m2 in patients on placebo and did not change in patients on spironolactone or ramipril (ANOVA p < 0.05). End diastolic volume was also similar in the three groups, increased from 70.6 +/- 4.3 to 92.8 +/- 6.4 ml/m2 in patients on placebo and did not change with the other treatments.. Ramipril and spironolactone had similar effects on ventricular remodeling after acute myocardial infarction, suggesting that aldosterone contributes to this phenomenon and that inhibition of its receptor may be as effective as ACE inhibition in its prevention.

Topics: Analysis of Variance; Angiotensin-Converting Enzyme Inhibitors; Disease-Free Survival; Double-Blind Method; Female; Humans; Hypertrophy, Left Ventricular; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Ramipril; Spironolactone; Stroke Volume; Ventricular Dysfunction, Left; Ventricular Function, Left

Although increased deposition of collagen proteins has been described after myocardial infarction (MI), little is known of time-dependent transcriptional alteration of specific cardiac collagen sub-types as well as the degradative mechanisms for cardiac collagens in right and left ventricular myocardium remote to large left ventricular infarction. We sought to study collagen mRNA abundance and the deposition of specific collagen subtypes in noninfarcted left and right rat heart muscle at different times after MI. We also assessed the activity of different myocardial matrix metalloproteinases (MMP) using zymography to gain some information about degradative pathways for collagen. Furthermore, we assessed passive compliance properties of the right ventricle in experimental hearts. Finally we investigated the role of the renin angiotensin system in the collagen gene expression by administration of an angiotensin converting enzyme (ACE) inhibitor (ramipril) and an angiotensin II receptor type I antagonist (losartan) in experimental animals. We observed that the mRNA abundance of types I and III collagen were increased 3 days after myocardial infarction in both viable left and uninfarcted right ventricular tissues, that they peaked at 7-14 days, and were maintained at relatively high levels in the 28 and 56 days experimental groups. Stiffness of the right ventricular myocardium was significantly increased in the 56 days experimental group when compared to that of control values. These findings correlated with increased immunohistochemical staining patterns of different collagen species in the surviving right (and left) cardiac interstitium of 14, 28, and 56 day experimental cardiac groups. The elevation of fibrillar collagen mRNA abundance in noninfarcted muscle from ventricular chambers was not significantly altered after treatment of experimental animals with ramipril and losartan for up to 14 days. MMP activity was increased in viable left ventricle at 14, 28 and 56 days and at 14 days in the right ventricle in experimental animals when compared to controls. These results indicated that (1) activation of transcription of collagen types I and III gene occurs in acute and chronic MI, and that fibrillar collagen proteins are deposited in the noninfarcted cardiac interstitium after a lag period relative to increased corresponding mRNA abundance; (2) an increase in MMP activity in chronic experimental hearts indicates that increased collagen deposition may be du

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Anti-Arrhythmia Agents; Biphenyl Compounds; Blotting, Northern; Collagen; Collagenases; Extracellular Matrix; Gene Expression Regulation; Imidazoles; Immunohistochemistry; Losartan; Male; Metalloendopeptidases; Myocardial Infarction; Myocardium; Ramipril; Rats; Rats, Sprague-Dawley; RNA, Messenger; Tetrazoles; Transcription, Genetic; Ventricular Function, Right; Wound Healing

Neurohormonal activation may provide a pathophysiological link between acute myocardial infarction and chronic congestive heart failure, and modulation of neurohormonal activity may be an important therapeutic target in these conditions. Plasma neurohormones were studied in 55 patients with acute myocardial infarction. Angiotensin II, noradrenaline and ANP were elevated in the early phase but tended to normalize during the first week in patients without signs of heart failure. In patients with heart failure angiotensin II and noradrenaline remained elevated for 1 month and ANP for 4-6 months. During head-up tilt, angiotensin II and noradrenaline increased most in patients with heart failure. In patients with a first myocardial infarction there was a positive correlation between sustained neurohormonal activity and infarct size. Almost complete suppression of plasma ACE activity was achieved within 30 min in 48 patients treated with intravenous enalaprilat, initiated within 24 h from the onset of infarction. The drug was tolerated in dosages of 1.0-1.2 mg given over 1-2h. Patients with systolic blood pressure between 100 and 110 mmHg incurred a greater risk of hypotension than those with higher blood pressure at baseline. Tolerance was not worse among patients treated with intravenous diuretics, metoprolol or nitroglycerin. A total of 98 patients were randomized to treatment with enalapril or placebo, initiated within 24 h from onset of infarction and continued for 4-6 months. During treatment there were no significant differences in plasma levels of angiotensin II, aldosterone, ANP or catecholamines between groups. Echocardiographic recordings were performed in 28 patients. Among patients on placebo there was a positive correlation between plasma levels of noradrenaline at days 5-7 and the increase in left ventricular volumes during the study period, and an inverse correlation between plasma aldosterone at days 5-7 and the increase in left ventricular ejection fraction during the study. No such correlation was found among patients on enalapril. ANP levels at 1 month correlated inversely with the left ventricular ejection fraction at the same time. Plasma neurohormones were measured in 223 patients with mild or moderately severe chronic heart failure, randomized to treatment with ramipril or placebo for 3 months. There was wide variation in hormone levels. Noradrenaline and aldosterone correlated inversely with exercise duration at baseline. Noradrenaline

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Atrial Natriuretic Factor; Blood Pressure; Enalapril; Enalaprilat; Exercise; Female; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Myocardial Infarction; Neurosecretory Systems; Norepinephrine; Peptidyl-Dipeptidase A; Ramipril; Ventricular Function, Left

Unlike most cell-types in the body, cardiomyocytes do not replicate in adult life. Consequently myocardial infarction produces irreparable damage to the heart which in turn increases the likelihood of premature death. Recent trials indicate that immediate aspirin and thrombolytic therapy beneficially modify the natural history of myocardial infarction, reducing both short- and long-term mortality rates. However, the occurrence of early heart failure in as many as one third of patients continues to carry with it a particularly poor prognosis. Recent trials with ACE inhibitors indicate that delayed initiation (beyond 24 h) and long-term maintenance treatment of patients selected on the basis of either heart failure (AIRE Study) or an ejection fraction of less than 40% (SAVE Study) result in large reductions in all-cause mortality. Although the exact mechanism of this benefit remains uncertain the reduction of further myocyte death due to reinfarction or gradual toxic attrition has been suggested. The currently unreported ISIS-4 and GISSI-3 should provide additional information as to whether the clinical indications for ACE-inhibitor therapy should be extended to other patient groups.

Topics: Coronary Artery Disease; Heart Failure; Humans; Myocardial Infarction; Ramipril; Recurrence; Risk Factors; Stroke Volume; Survival Analysis; Ventricular Function, Left

The AIRE study--a trial involving over 2,000 patients with clinical heart failure after myocardial infarction--assessed different outcomes. The primary outcome was total mortality. The secondary outcome was time to death, or progression to severe/resistant heart failure, reinfarction or stroke. Tertiary analyses included hospitalization and mode of death. To obtain maximum quality in the validation of outcomes and to optimize the quality of the data in the study, an end-points committee reviewed all data following preset definitions prior to code break. All definitions used are reported here. Experience of the validation process demonstrated that there are wide variations in clinical practice and terminology not only among countries but also among individual investigators. Variation in the clinical handling and treatment of patients makes it imperative to validate outcomes centrally on the basis of available facts.

Topics: Cause of Death; Heart Failure; Hospitalization; Humans; Myocardial Infarction; Outcome Assessment, Health Care; Prognosis; Ramipril; Retrospective Studies

Survival after acute myocardial infarction has been enhanced by treatment with thrombolytic agents, aspirin, and beta-adrenoceptor blockade. However there remains a substantial subgroup of patients who manifest clinical evidence of heart failure despite the first two of these treatments, and for whom beta-adrenoceptor antagonists are relatively or absolutely contraindicated. These patients have a greatly increased risk of fatal and non-fatal ischaemic, arrhythmic, and haemodynamic events. In this selected high-risk subset of patients we investigated the effect of therapy with the angiotensin converting enzyme (ACE) inhibitor rampiril, postulating that it would lengthen survival. 2006 patients who had shown clinical evidence of heart failure at any time after an acute myocardial infarction (AMI) were recruited from 144 centres in 14 countries. Patients were randomly allocated to double-blind treatment with either placebo (992 patients) or ramipril (1014 patients) on day 3 to day 10 after AMI (day 1). Patients with severe heart failure resistant to conventional therapy, in whom the attending physician considered the use of an ACE inhibitor to be mandatory, were excluded. Follow-up was continued for a minimum of 6 months and an average of 15 months. On intention-to-treat analysis mortality from all causes was significantly lower for patients randomised to receive ramipril (170 deaths; 17%) than for those randomised to receive placebo (222 deaths; 23%). The observed risk reduction was 27% (95 % Cl 11% to 40%; p = 0.002). Analysis of prespecified secondary outcomes revealed a risk reduction of 19% for the first validated outcome (i.e., first event in an individual patient)--namely, death, severe/resistent heart failure, myocardial infarction, or stroke (95% Cl 5% to 31%; p = 0.008). Oral administration of rampiril to patients with clinical evidence of either transient or ongoing heart failure, initiated between the second and ninth day after myocardial infarction, resulted in a substantial reduction in premature death from all causes. This benefit was apparent as early as 30 days and was consistent across a range of subgroups.

Topics: Adult; Aged; Double-Blind Method; Female; Heart Failure; Humans; Male; Middle Aged; Myocardial Infarction; Proportional Hazards Models; Ramipril; Risk Factors; Survival Analysis; Treatment Outcome

The rationale, design, organization, and outcome definitions of the Acute Infarction Ramipril Efficacy (AIRE) Study are described prospectively. A total of 2,000 patients (1,000 per treatment group) will be recruited to this multicenter, multinational, double-blind, randomized, placebo-controlled study investigating the effect of oral treatment with ramipril (2.5 or 5 mg twice daily) on the total mortality of survivors of an acute myocardial infarction (AMI) with early clinical evidence of heart failure. Secondary outcomes of the study include progression to severe/resistant heart failure (at which time the patient will be withdrawn from the study treatment), reinfarction, and stroke. Treatment will be initiated in hospital between day 3 and day 10 following AMI, and follow-up continued for an average of 15 months and a minimum of 6 months. The study data will be analyzed on an intention-to-treat basis: a single formal interim analysis will be conducted after 175 deaths. An Independent Adjudicating Panel will act as the overall ethical supervisory body for the study and will retain the randomization code. An International Steering Committee will be responsible for the clinical definitions of the secondary study outcomes, and will regularly review progress of the study. We believe that early treatment with ramipril may reduce the total mortality of patients surviving an AMI with clinical evidence of heart failure.

Topics: Acute Disease; Adult; Angiotensin-Converting Enzyme Inhibitors; Bridged Bicyclo Compounds; Follow-Up Studies; Humans; Myocardial Infarction; Ramipril; Research Design

Cardiac ischemia-related myocardial damage has been considered a major reason for heart failure. We aimed to investigate the role of levosimendan (LEVO) in comparison to ramipril and sacubitril/valsartan (Sac/Val) in preventing damage associated with isoproterenol (ISO) induced myocardial infarction.. Myocardial infarction was induced by injecting subcutaneous isoproterenol (5 mg/kg once for 7 consecutive days) to establish an experimental heart failure model. Simultaneously, LEVO (1 mg/kg/day), ramipril (3mg/kg/day) and Sac/Val (68 mg/kg/day) suspension were administered orally for four weeks.. We observed a significant correlation between ISO-induced ischemia with cardiac remodeling and alterations in myocardial architecture. LEVO, ramipril, and Sac/Val significantly prevented lipid peroxidation and damaged antioxidant enzymes like superoxide dismutase, catalase, glutathione and thioredoxin reductase. We also observed their ameliorative effects in myocardium's cardiac hypertrophy, evidenced by reduced heart weight to body weight ratio and transforming growth factor β related collagen deposition. LEVO, ramipril, and Sac/Val also maintained cardiac biomarkers like lactate dehydrogenase, creatine kinase-MB, brain natriuretic peptide and cardiac Troponin-I, indicating reduced myocardial damage that was further demonstrated by histopathological examination. Decreased sarcoplasmic endoplasmic reticulum Ca2+ATPase2a and sodium-calcium exchanger-1 protein depletion after LEVO, ramipril, and Sac/Val administration indicated improved Ca2+ homeostasis during myocardial contractility.. Our findings suggest that LEVO has comparable effects to ramipril, and Sac/Val in preventing myocardial damage via balancing oxidant-antioxidant system, decreased collagen deposition, reduced myocardial stress as well as improved Ca2+ homeostasis during myocardial contractility.

Topics: Antioxidants; Calcium; Collagen; Heart Failure; Hemodynamics; Humans; Isoproterenol; Myocardial Infarction; Ramipril; Simendan; Valsartan

Blockade of brain renin-angiotensin system (RAS) overactivity by firibastat, the first centrally acting aminopeptidase A (APA) inhibitor prodrug, has already demonstrated its effectiveness in improving cardiac function after myocardial infarction (MI). We developed QGC606, a more potent and more selective APA inhibitor prodrug and studied its effects after long-term oral administration in mice post-MI.. Two days after MI induced by the left anterior descending artery ligation, adult male mice were randomized into 4 groups to receive oral treatment during 4 weeks with vehicle; QGC606; firibastat; or the angiotensin-I converting enzyme inhibitor ramipril, used as positive control.. Four weeks post-MI, brain APA was overactivated in vehicle-treated MI mice. QGC606 treatment normalized brain APA hyperactivity to control values measured in sham-operated mice. Four weeks post-MI, QGC606-treated mice had higher left ventricular (LV) ejection fractions, significantly smaller LV end-systolic diameter and volume, significantly lower HF biomarkers mRNA expression (Myh7 and Anf) and plasma N-terminal pro B-type natriuretic peptide (NT-pro-BNP) and noradrenaline levels than saline-treated mice. QGC606 treatment significantly improved the dP/dt max and min, LV end-diastolic pressure without affecting blood pressure (BP), whereas we observed a decrease in BP in ramipril-treated mice. We observed also a reduction of cardiac fibrosis, highlighted by lower connective tissue growth factor mRNA levels and a reduction of both the fibrotic area and MI size in QGC606-treated mice.. Chronic oral QGC606 administration in post-MI mice showed beneficial effects in improving cardiac function and reducing cardiac remodeling and fibrosis but, unlike ramipril, without lowering BP.

Topics: Animals; Fibrosis; Glutamyl Aminopeptidase; Heart Failure; Humans; Male; Mice; Myocardial Infarction; Myocardium; Prodrugs; Ramipril; RNA, Messenger; Ventricular Remodeling

Topics: Angioedema; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Agents; Coronary Angiography; COVID-19; COVID-19 Nucleic Acid Testing; Drug Substitution; Humans; Male; Middle Aged; Myocardial Infarction; Patient Care Management; Platelet Aggregation Inhibitors; Ramipril; SARS-CoV-2; Treatment Outcome

The aim: To compare the long-term effects of different angiotensin-converting enzyme inhibitors in post-myocardial infarction (MI) patients.. Materials and methods: Of 445 consecutive patients with myocardial infarction, 76 (17%) patients had co-morbid conditions, as well as were found to be compliant with secondary prevention treatment and eligible for follow-up. These patients were assigned to ramipril, perindopril or zofenopril groups in complex management of post-MI period. Subsequently, the patients were followed-up prospectively for a period of up to 24 months.. Results: Patients of zofenopril group performed better in terms of post-MI biventricular remodeling and left ventricular function recovery. Also, patients receiving zofenopril showed benefits in terms of short-term and long-term mortality as compared with patients of ramipril and perindopril groups.. Conclusion: Zofenopril may have advantages over perindopril and ramipril in the complex management of post-MI patients in terms of prevention of negative myocardial remodeling, onset of congestive heart failure and major adverse events.

Topics: Angiotensin-Converting Enzyme Inhibitors; Angiotensins; Heart Failure; Humans; Myocardial Infarction; Ramipril

The SMILE-4 study showed that in patients with left ventricular dysfunction (LVD) after acute myocardial infarction, early treatment with zofenopril plus acetyl salicylic acid is associated with an improved 1-year survival, free from death or hospitalization for cardiovascular (CV) causes, as compared to ramipril plus acetyl salicylic acid. We now report CV outcomes during a 5-year follow-up of the patients of the SMILE-4 study. Three hundred eighty-six of the 518 patients completing the study (51.2%) could be tracked after the study end and 265 could be included in the analysis. During the 5.5 (±2.1) years of follow-up, the primary endpoint occurred in 27.8% of patients originally randomized and treated with zofenopril and in 43.8% of patients treated with ramipril [odds ratio (OR) and 95% confidence interval, 0.65 (0.43-0.98), P = 0.041]. Such a result was achieved through a significantly larger reduction in CV hospitalization under zofenopril [OR: 0.61 (0.37-0.99), P = 0.047], whereas reduction in mortality rate with zofenopril did not achieve statistical significance versus ramipril [OR: 0.75 (0.36-1.59), P = 0.459]. These results were in line with those achieved during the initial 1-year follow-up. Benefits of early treatment of patients with LVD after acute myocardial infarction with zofenopril are sustained over many years as compared to ramipril.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Aspirin; Captopril; Chi-Square Distribution; Clinical Trials, Phase III as Topic; Disease-Free Survival; Drug Administration Schedule; Drug Therapy, Combination; Early Medical Intervention; Female; Follow-Up Studies; Hospitalization; Humans; Kaplan-Meier Estimate; Logistic Models; Male; Middle Aged; Myocardial Infarction; Odds Ratio; Ramipril; Randomized Controlled Trials as Topic; Recovery of Function; Retrospective Studies; Risk Factors; Systole; Time Factors; Treatment Outcome; Ventricular Dysfunction, Left; Ventricular Function, Left

The treatment of elderly multimorbid patients according to clinical guidelines often results in polypharmacy. An individual risk assessment is required to consider the possibility of deprescribing especially potentially inappropriate medication in the elderly. This exemplary case report describes a medication review of a patient with multiple chronic cardiovascular diseases taking into account the impact on renal function.

Topics: Aged, 80 and over; Atrial Fibrillation; Carbazoles; Carvedilol; Diclofenac; Digoxin; Drug Interactions; Drug Therapy, Combination; Female; Heart Failure; Humans; Hypertension; Kidney Failure, Chronic; Myocardial Infarction; Potassium; Potentially Inappropriate Medication List; Propanolamines; Ramipril; Risk Factors; Spironolactone

Interruption of blood supply to the heart results in acute myocardial infarction (AMI), and further damages the heart muscles. Available drugs for the treatment MI have one or other side effects, and there is a need for development of better alternative drugs from herbal sources. Here, we evaluated cardioprotective effect of Cyperus rotundus on isoprenaline- induced myocardial infarction. Thirty five Wistar rats, aged 60-100 days with body wt. 150-200 g, pretreated with ethanolic extract of Cyperus rotundus L. (@ 250 and 500 mg/kg body wt.) orally before induction of myocardial necrosis by administrating isoprenaline (85 mg/kg, s.c.) on 19th and 20th day of the pretreatment period. The treated rats were examined for gross functioning of heart, heart weight/body wt. Ratio, and also observed histopathologically. Further, activities of various cardiac enzymes such as aspartate transaminase, alanine transaminase, creatinine kinase-myoglobulin, lactate dehydrogenase, and the gold marker troponin-I were also determined. The levels altered by isoproterenol were found to be restored significantly by the test extracts especially at higher dose. Biochemical observations viz., serum ALT (P <0.0001), AST (P <0.0001), creatine kinase-myoglobulin (CK-MB) (P <0.0001), LDH (P <0.0001) demonstrated significant cardioprotective activity of the ethanolic extract of C. rotundus (500 mg/kg body wt.), against isoprenaline induced myocardial infarction. These results were also substantiated by physical parameters and histopathological observations. All these results were comparable with that of two standard drugs metoprolol (10 mg/kg/day), ramipril (3 mg/kg/day) as well as polyherbal formulation Abana (50 mg/kg/day).

Topics: Adrenergic beta-1 Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Biomarkers; Cardiotoxicity; Cardiovascular Agents; Cyperus; Cytoprotection; Disease Models, Animal; Ethanol; Isoproterenol; Male; Metoprolol; Myocardial Infarction; Myocardium; Necrosis; Phytotherapy; Plant Extracts; Plants, Medicinal; Ramipril; Rats, Wistar; Rhizome; Solvents

In the SMILE-4 study, zofenopril + acetyl salicylic acid (ASA) was more effective than ramipril + ASA on 1-year prevention of major cardiovascular events (MACE) in patients with acute myocardial infarction complicated by left ventricular dysfunction. In this retrospective analysis, we evaluated drug efficacy in subgroups of patients, according to a history of diabetes mellitus.. The primary study endpoint was 1-year combined occurrence of death or hospitalization for cardiovascular causes. Diabetes was defined according to medical history (previous known diagnosis).. A total of 562 of 693 (81.0%) patients were classified as nondiabetics and 131 (18.9%) as diabetics. The adjusted rate of MACE was lower under zofenopril than under ramipril in both nondiabetics [27.9% vs. 34.9% ramipril; odds ratio, OR and 95% confidence interval: 0.55 (0.35, 0.86)] and diabetics [30.9% vs. 41.3%; 0.56 (0.18, 1.73)], although the difference was statistically significant only for the nondiabetic group (P = 0.013). Zofenopril was superior to ramipril as regards to the primary study endpoint in the subgroup of 157 patients with uncontrolled blood glucose (≥ 126 mg/dL), regardless of a previous diagnosis of diabetes [0.31 (0.10, 0.90), P = 0.030]. Zofenopril significantly reduced the risk of hospitalization for cardiovascular causes in both nondiabetics [0.64 (0.43, 0.96), P = 0.030] and diabetics [0.38 (0.15, 0.95), P = 0.038], whereas it was not better than ramipril in terms of prevention of cardiovascular deaths.. This retrospective analysis of the SMILE-4 study confirmed the good efficacy of zofenopril plus ASA in the prevention of long-term MACE also in the subgroup of patients with diabetes mellitus.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Aspirin; Captopril; Cardiovascular Diseases; Diabetic Cardiomyopathies; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Myocardial Infarction; Platelet Aggregation Inhibitors; Ramipril; Randomized Controlled Trials as Topic; Retrospective Studies; Systole; Ventricular Dysfunction, Left

Zofenopril, a sulfhydrylated angiotensin-converting enzyme inhibitor (ACEI), reduces mortality and morbidity in infarcted patients to a greater extent than do other ACEIs. Zofenopril is a unique ACEI that has been shown to increase hydrogen sulfide (H2S) bioavailability and nitric oxide (NO) levels via bradykinin-dependent signaling. Both H2S and NO exert cytoprotective and antioxidant effects. We examined zofenopril effects on H2S and NO bioavailability and cardiac damage in murine and swine models of myocardial ischemia/reperfusion (I/R) injury.. Zofenopril (10 mg/kg PO) was administered for 1, 8, and 24 hours to establish optimal dosing in mice. Myocardial and plasma H2S and NO levels were measured along with the levels of H2S and NO enzymes (cystathionine β-synthase, cystathionine γ-lyase, 3-mercaptopyruvate sulfur transferase, and endothelial nitric oxide synthase). Mice received 8 hours of zofenopril or vehicle pretreatment followed by 45 minutes of ischemia and 24 hours of reperfusion. Pigs received placebo or zofenopril (30 mg/daily orally) 7 days before 75 minutes of ischemia and 48 hours of reperfusion. Zofenopril significantly augmented both plasma and myocardial H2S and NO levels in mice and plasma H2S (sulfane sulfur) in pigs. Cystathionine β-synthase, cystathionine γ-lyase, 3-mercaptopyruvate sulfur transferase, and total endothelial nitric oxide synthase levels were unaltered, while phospho-endothelial nitric oxide synthase(1177) was significantly increased in mice. Pretreatment with zofenopril significantly reduced myocardial infarct size and cardiac troponin I levels after I/R injury in both mice and swine. Zofenopril also significantly preserved ischemic zone endocardial blood flow at reperfusion in pigs after I/R.. Zofenopril-mediated cardioprotection during I/R is associated with an increase in H2S and NO signaling.

Topics: Animals; Antihypertensive Agents; Biological Availability; Blotting, Western; Captopril; Cystathionine beta-Synthase; Cystathionine gamma-Lyase; Heart; Hydrogen Sulfide; Mice; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Nitric Oxide; Nitric Oxide Synthase Type III; Ramipril; Random Allocation; Regional Blood Flow; Reverse Transcriptase Polymerase Chain Reaction; Sulfurtransferases; Swine; Swine, Miniature; Troponin I

Prior studies have shown that overexpression of ACT A can lead to ventricular remodeling in rat models of heart failure. Furthermore, recently work studying demonstrated that stimulation of activin An expression in rat aortic smooth muscle (RASM) cells by angiotensin II (Ang II). Ramipril is a recently developed angiotensin converting enzyme (ACE) inhibitor. To investigate the effects of Ramipril on expression of ACT A-FS, we established the rat model of heart failure after myocardial infarction (MI), and divided into either a sham operation (SO), MI, or MI-Ramipril group. We found that Ramipril significantly attenuates collagen-I and III deposition (col-I and III). Notably, we determined that expression of ACT A and II activin receptor (ActRII) were significantly down-regulated in the non-infarcted area of the left ventricle in the Ramipril group, whereas the mRNA and protein levels of FS were markedly up-regulated. Our data suggested that Ramipril benefited left ventricular remodeling by reducing fibrosis and collagen accumulation in the left ventricle of rats after myocardial infarction. This observation was also associated with down-regulation of ACT A expression. This study elucidated a new protective mechanism of Ramipril and suggests a novel strategy for treatment of post-infarct remodeling and subsequent heart failure.

Topics: Activins; Animals; Biomarkers; Biopsy; Disease Models, Animal; Female; Fibrosis; Follistatin; Gene Expression Regulation; Heart Failure; Heart Function Tests; Heart Ventricles; Hemodynamics; Immunohistochemistry; Myocardial Infarction; Ramipril; Rats; Ventricular Remodeling

Topics: Benzimidazoles; Benzoates; Blood Pressure; Coronary Artery Disease; Female; Humans; Male; Myocardial Infarction; Ramipril; Stroke; Telmisartan

Clopidogrel and angiotensin converting enzyme (ACE) inhibitors are commonly co-prescribed drugs. Clopidogrel inhibits carboxylesterase 1 (CES1), the enzyme responsible for converting prodrug ACE inhibitors (such as ramipril and perindopril) to their active metabolites. The clinical implications of this potential drug interaction are unknown. The clinical consequences of the potential drug interaction between clopidogrel and prodrug ACE inhibitors were examined.. We conducted a nested case-control study of Ontarians aged 66 years and older treated with clopidogrel between September 1 2003 and March 31 2013 following acute myocardial infarction. Cases were subjects who died or were hospitalized for reinfarction or heart failure in the subsequent year, and each was matched with up to four controls. The primary outcome was a composite of reinfarction, heart failure or death. The primary analysis examined whether use of the prodrug ACE inhibitors ramipril or perindopril was more common among cases than use of lisinopril, an active ACE inhibitor.. Among 45 918 patients treated with clopidogrel following myocardial infarction, we identified 4203 cases and 14 964 controls. After adjustment, we found no association between the composite outcome and use of perindopril (adjusted odds ratio (aOR) 0.94, 95% confidence interval (CI) 0.76, 1.16) or ramipril (aOR 0.97, 95% CI 0.80, 1.18), relative to lisinopril. Secondary analyses of each element of the composite outcome yielded similar findings.. Following myocardial infarction, use of clopidogrel with ACE inhibitors activated by CES1 is not associated with an increased risk of adverse cardiovascular outcomes relative to lisinopril. These findings suggest that the recently described drug interaction between clopidogrel and prodrug ACE inhibitors is of little clinical relevance.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Case-Control Studies; Clopidogrel; Databases, Factual; Drug Interactions; Drug Therapy, Combination; Female; Heart Failure; Humans; Lisinopril; Male; Myocardial Infarction; Perindopril; Platelet Aggregation Inhibitors; Ramipril; Recurrence; Ticlopidine; Treatment Outcome

Impaired nitric oxide (NO)-soluble guanylate cyclase (sGC)-cGMP signaling is involved in the pathogenesis of ischemic heart diseases, yet the impact of long-term sGC activation on progressive cardiac remodeling and heart failure after myocardial infarction (MI) has not been explored. Moreover, it is unknown whether stimulating the NO/heme-independent sGC provides additional benefits to ACE inhibition in chronic ischemic heart failure. Starting 10 days after MI, rats were treated with placebo, the sGC activator ataciguat (10 mg/kg/twice daily), ramipril (1 mg/kg/day), or a combination of both for 9 weeks. Long-term ataciguat therapy reduced left ventricular (LV) diastolic filling pressure and pulmonary edema, improved the rightward shift of the pressure-volume curve, LV contractile function and diastolic stiffness, without lowering blood pressure. NO/heme-independent sGC activation provided protection over ACE inhibition against mitochondrial superoxide production and progressive fibrotic remodeling, ultimately leading to a further improvement of cardiac performance, hypertrophic growth and heart failure. We found that ataciguat stimulating sGC activity was potentiated in (myo)fibroblasts during hypoxia-induced oxidative stress and that NO/heme-independent sGC activation modulated fibroblast-cardiomyocyte crosstalk in the context of heart failure and hypoxia. In addition, ataciguat inhibited human cardiac fibroblast differentiation and extracellular matrix protein production in response to TGF-β1. Overall, long-term sGC activation targeting extracellular matrix homeostasis conferred cardioprotection against progressive cardiac dysfunction, pathological remodeling and heart failure after myocardial infarction. NO/heme-independent sGC activation may prove to be a useful therapeutic target in patients with chronic heart failure and ongoing fibrotic remodeling.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Cardiotonic Agents; Cell Communication; Cells, Cultured; Disease Models, Animal; Drug Therapy, Combination; Enzyme Activation; Enzyme Activators; Extracellular Matrix; Fibrosis; Guanylate Cyclase; Heart Failure; Hemodynamics; Humans; Male; Mice; Mitochondria, Heart; Myocardial Contraction; Myocardial Infarction; Myocytes, Cardiac; Myofibroblasts; Nitric Oxide; Nitric Oxide Synthase Type III; ortho-Aminobenzoates; Oxidative Stress; Ramipril; Rats, Wistar; Receptors, Cytoplasmic and Nuclear; Soluble Guanylyl Cyclase; Sulfonamides; Superoxides; Time Factors; Ventricular Function, Left; Ventricular Remodeling

HYPOTHESIS/INTRODUCTION: Our aim was to investigate whether a non-hypotensive dose of ramiprilat and losartan has myocardial protective effects during myocardial ischemia/reperfusion in vivo.. Three groups of rats were given 10 mg/kg per day of losartan for one (L-1W), four (L-4W) or 10 (L-10W) weeks. Another three groups were given 50 µg/kg per day of ramiprilat for one (R-1W), four (R-4W) or 10 (R-10W) weeks. The animals underwent 30 min of left anterior descending artery occlusion and subsequent reperfusion for 120 min.. Myocardial infarct size (IS) was reduced in R-1W (28.4 ± 6.3%, p < 0.001), R-4W (27.8 ± 7.4, p < 0.001), L-4W (31.8 ± 6%, p < 0.05) and L-10W (25.3 ± 5.7, p < 0.001) groups compared with a saline group (48.3 ± 7.8%). A significant reduction in the number of ventricular ectopic beats (VEBs) was noted in groups R-1W (209 ± 41, p < 0.01), R-4W (176 ± 39, p < 0.01), L-4W (215 ± 52, p < 0.05) and L-10W (191 ± 61, p < 0.01 vs. saline 329 ± 48). The incidence of irreversible ventricular fibrillation (VF) and mortality were decreased significantly only in L-10W group. There were no significant decreases in episodes of VT, the incidence of irreversible VF and mortality in all of the groups treated with ramiprilat.. These data indicate that losartan and ramiprilat protect the heart against ischemia/reperfusion injury independently of their hemodynamic effects but in a time-dependent manner.

Topics: Animals; Antihypertensive Agents; Arrhythmias, Cardiac; Drug Therapy, Combination; Heart; Heart Rate; Kaplan-Meier Estimate; Losartan; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Ramipril; Rats; Rats, Wistar

Angiotensin converting enzyme inhibitors have been used clinically to prevent myocardial infarction (MI). The angiotensin converting enzyme inhibitors attenuated ventricular remodeling and improved cardiac function by inhibition of matrix metalloproteinases after MI. Although the effect is thought to be a class effect, there are significant differences among the drugs. The aim of this study was to compare the effects of imidapril and ramipril on ventricular remodeling after MI.. The middle portion of left anterior descending artery was ligated to induce a moderate size MI in rats (moderate MI group). The proximal portion of the artery was ligated to induce a large size MI (large MI group). The animals were assigned to subgroups in moderate MI group and large MI group: (1) nontreated group, (2) ramipril group (1 mg/kg daily), and (3) imidapril group (1 mg/kg daily). All rats were killed on day 28 after the MI operation.. Although the nontreated MI group showed impaired ventricular contraction and severe fibrosis, imidapril significantly negated ischemia-induced changes. Imidapril had a superior effect for preventing ventricular remodeling characterized by fibrosis and collagen accumulation in left ventricle compared with ramipril in the moderate and large MI groups, even though the dosage used in this study was too small to reduce systemic blood pressure.. Imidapril can be used as a substitute for ramipril to prevent ventricular remodeling after MI.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Collagen; Disease Models, Animal; Fibrosis; Imidazolidines; Male; Myocardial Contraction; Myocardial Infarction; Ramipril; Rats; Rats, Sprague-Dawley; Ventricular Remodeling

In this study, the effects of lacidipine (LAC), ramipril (RAM), and valsartan (VAL) on biochemical and histopathologic changes in heart tissue were studied in rats with isoproterenol-induced (ISO-induced) myocardial infarction (MI). LAC, RAM, and VAL had been administered via oral gavage at 3, 3, and 30 mg/kg doses, respectively, once per day during a 30-day time period. On days 29 and 30, the drug treatment group and the control group (with the exception of the intact control group, in which no medications were given, and ISO was not administered) were administered 180 mg/kg ISO subcutaneously over an interval of 24 h. After this period, the hearts of the rats were removed and processed for biochemical and histopathologic studies. The antioxidant parameters superoxide dismutase (SOD), catalase (CAT), and malondialdehyde (MDA) were estimated. A diagnosis of MI was confirmed with antioxidant parameters and histopathologic findings. In MI control groups, histopathologic indicators were found to be statistically higher than those in drug groups; an increase in histopathologic indicators of MI correlates with significant decreases in SOD and CAT levels, and an increase in MDA level. Histopathologic grades of MI indicators were significantly higher in MI group that did not receive any cardioprotective medications in comparison with MI groups that received LAC, RAM, and VAL. Each of the three medications favorably modulated most of the biochemical and histopathologic parameters observed. No significant difference existed with regard to any of the estimated parameters in the rat groups that received medications without MI induction. In conclusion, results indicate that LAC, RAM, and VAL significantly reduced myocardial injury and emphasize the cardioprotective nature of these agents.

Topics: Administration, Oral; Animals; Cardiotonic Agents; Dihydropyridines; Dose-Response Relationship, Drug; Isoproterenol; Male; Myocardial Infarction; Ramipril; Rats; Rats, Sprague-Dawley; Tetrazoles; Valine; Valsartan

The current study aims to explore the effect of ramipril on the occurrence of ventricular arrhythmias and its possible mechanism after myocardial infarction (MI) in rabbits.. A total of 24 rabbits were divided into three groups: the sham operation group (SHAM), the MI group, and the ramipril group (RAM). All groups were subjected to thoracotomy under sterile conditions; the MI and RAM groups underwent ligation of the left anterior descending coronary artery. On the second day after surgery, the RAM group was given ramipril (1 mg/kg per day). The rabbits in each group were fed for 12 weeks. The monophasic action potentials of the epicardium, mid-myocardium and endocardium in each group were, respectively, recorded before the MI and at 12 weeks after the MI. Meanwhile, the episodes of ventricular tachycardia or fibrillation (VT/VF) induced by procedure stimulations were counted, and the changes in L-type Ca flux (Ica-L) were recorded by means of the whole-cell patch-clamp technique.. The episodes of VT/VF were decreased in the RAM group after MI. At 12 weeks after MI, the transmural dispersion of repolarization (TDR) in the MI group was prolonged significantly compared with the SHAM and RAM groups. The density of Ica-L in the MI group was significantly lower than that any other group.. Ramipril manifestly decreases the incidence of VT/VF after MI in rabbits, and the mechanism may be associated with its inhibitory effect on electrical remodeling after MI.

Topics: Action Potentials; Angiotensin-Converting Enzyme Inhibitors; Animals; Calcium Channels, L-Type; Calcium Signaling; Cardiac Pacing, Artificial; Disease Models, Animal; Electrocardiography; Heart Ventricles; Myocardial Infarction; Myocardium; Patch-Clamp Techniques; Rabbits; Ramipril; Tachycardia, Ventricular; Time Factors; Ventricular Fibrillation

The RAS (renin-angiotensin system) is activated after MI (myocardial infarction), and RAS blockade with ACEis [ACE (angiotensin-converting enzyme) inhibitors] or ARBs (angiotensin receptor blockers) slows but does not completely prevent progression to heart failure. Cardiac ACE is increased after MI and leads to the formation of the vasoconstrictor AngII (angiotensin II). The enzyme ACE2 is also activated after MI and degrades AngII to generate the vasodilator Ang-(1-7) [angiotensin-(1-7)]. Overexpression of ACE2 offers cardioprotective effects in experimental MI, but there is conflicting evidence as to whether the benefits of ACEis and ARBs are mediated through increasing ACE2 after MI. In the present study, we assessed the effect of an ACEi and ARB, alone and in combination, on cardiac ACE2 in a rat MI model. MI rats received vehicle, ACEi (ramipril; 1 mg/kg of body weight), ARB (valsartan; 10 mg/kg of body weight) or combination (ramipril at 1 mg/kg of body weight and valsartan at 10 mg/kg of body weight) orally for 28 days. Sham-operated rats were also studied and received vehicle alone. MI increased LV (left ventricular) mass (P<0.0001), impaired cardiac contractility (P<0.05) and activated cardiac ACE2 with increased gene (P<0.05) and protein expression (viable myocardium, P<0.05; border zone, P<0.001; infarct, P<0.05). Ramipril and valsartan improved remodelling (P<0.05), with no additional effect of dual therapy. Although ramipril inhibited ACE, and valsartan blocked the angiotensin receptor, neither treatment alone nor in combination augmented cardiac ACE2 expression. These results suggest that the cardioprotective effects of ramipril and valsartan are not mediated through up-regulation of cardiac ACE2. Strategies that do augment ACE2 after MI may be a useful addition to standard RAS blockade after MI.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme 2; Angiotensin-Converting Enzyme Inhibitors; Angiotensins; Animals; Drug Therapy, Combination; Female; Gene Expression Regulation, Enzymologic; Heart; Hemodynamics; Immunohistochemistry; Myocardial Infarction; Myocardium; Organ Size; Peptidyl-Dipeptidase A; Ramipril; Rats; Rats, Sprague-Dawley; Renin; Renin-Angiotensin System; Reverse Transcriptase Polymerase Chain Reaction; Tetrazoles; Valine; Valsartan

To examine the impact of tissue selectivity of angiotensin-converting enzyme (ACE) inhibitors on mortality and morbidity in patients following acute myocardial infarction (AMI).. A retrospective cohort study using a Medicaid claims database was conducted. Patients hospitalized for an AMI and subsequently filling a prescription for an ACE inhibitor were followed longitudinally for the occurrence of cardiovascular-related hospitalizations and all-cause mortality. A subanalysis was also conducted to account for switching/discontinuation of ACE inhibitor therapy. Stepwise (forward conditional) Cox-proportional hazards models were used to analyze the effect of tissue selectivity on study outcomes.. The final study sample consisted of 689 AMI and the results indicated that tissue-selective ACE inhibitors had a protective effect against hospitalization due to stroke/transient ischemic attack (TIA) (hazard ratio [HR] = 0.265; 95% confidence interval [CI] = 0.101-0.698). A similar lower rate in hospitalizations due to heart failure was observed in the group using tissue-selective ACE inhibitors; however, the results were not statistically significant (HR = 0.681; 95% CI = 0.436-1.063). A protective effect was also observed on the combined outcome of hospitalization due to any cardiovascular condition (HR = 0.712; 95% CI = 0.536-0.945). Hospitalizations due to recurrent AMI, need for coronary revascularization procedures, and mortality were not significantly different between patients using tissue-selective and non-tissue-selective ACE inhibitors. The completer subanalysis provided similar findings regarding the impact of tissue selectivity on study outcomes.. Tissue-selective ACE inhibitors may have a protective effect against hospitalization due to stroke/TIA or heart failure when compared to non-tissue-selective ACE inhibitors for patients following AMI.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Cardiovascular Diseases; Comorbidity; Enalapril; Female; Heart Failure; Humans; Lisinopril; Longitudinal Studies; Male; Middle Aged; Multivariate Analysis; Myocardial Infarction; Organ Specificity; Proportional Hazards Models; Ramipril; Retrospective Studies; Secondary Prevention; Stroke; Survival Analysis

The recently published ONTARGET trial found that telmisartan was non-inferior to ramipril in reducing CV death, MI, stroke, or heart failure in patients with vascular disease or high-risk diabetes. The cost implications of ramipril and telmisartan monotherapy use based on the ONTARGET study are reported here.. Only healthcare system costs were considered. Healthcare resource utilization was collected for each patient during the trial. The authors obtained country-specific unit costs to the different healthcare care resources consumed (i.e., hospitalizations events, procedures, non-study, and study drugs) for all enrolled patients. Purchasing power parities were used to convert country-specific costs into US dollars (US$ 2008). The total undiscounted costs of the study for the telmisartan group was $12,762 per patient and is higher than the ramipril group at $12,007 per patient, an un-discounted difference of $755 (95% confidence interval [CI], $218-$1292); The discounted costs for the telmisartan group was $11,722 compared with $11,019 for the ramipril group; a difference of $703 (95% CI, $209-$1197). The difference in costs is exclusively related to the acquisition cost of telmisartan over generic ramipril.. This analysis only considered direct healthcare system costs. Costs accrued outside the hospital were not collected. Combination therapy was excluded since it would likely be more expensive than ramipril alone, with no additional benefit and a risk of some harm.. Based on these results, it is suggested that for the ONTARGET patients, the use of telmisartan instead of ramipril increases costs by 6.3%. These findings suggest that the choice to put patients on telmisartan should be justified based on the patient?s susceptibility to specific adverse events to minimize the cost implications.

Topics: Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Cardiovascular Diseases; Cost of Illness; Diabetes Complications; Health Services; Heart Failure; Humans; Multicenter Studies as Topic; Myocardial Infarction; Ramipril; Randomized Controlled Trials as Topic; Risk Factors; Stroke; Telmisartan

Angiotensin-converting enzyme (ACE) inhibitors after acute myocardial infarction (MI) prevent heart failure and recurrent ischemic events. Our aim was to evaluate the effect of ramipril on N-terminal pro-brain natriuretic peptide (NT-proBNP) and on markers of hemostasis, including plasminogen-activator-inhibitor-1 (PAI-1), von Willebrand factor (vWF), factor VIII (FVIII) and fibrinogen, in patients after acute MI, with emphasis on those over 55 years of age.. In this prospective, single-center, observational study 38 patients were treated with ramipril after the first Q-wave MI. Markers of hemostasis and NT-proBNP were estimated before and two weeks after ramipril treatment.. Significant differences were observed in PAI-1 and NT-proBNP levels in patients over 55 years. In this age group the mean PAI-1 level decreased significantly after ramipril therapy (3.6 +/- 1.25 U/ml vs. 2.65 +/- 1.4 U/ml, P = 0.011) and was significantly lower than in younger (<55 years) patients (2.65 +/- 1.4 U/ml vs. 4.39 +/- 1.7 U/ml, P = 0.002). In addition, in the older patients the mean baseline NT-proBNP level was significantly higher than in the younger age group (258.35 +/- 347.6 pmol/l vs. 17.1 +/- 22 pmol/l, P = 0.028) and was also higher after ramipril therapy (240.5 +/- 254.3 pmol/l vs. 67.3 +/- 75.2 pmol/l, P = 0.034). In the younger patients, mean NT-proBNP after short-term ramipril therapy increased significantly in comparison with baseline (67.3 +/- 75.2 pmol/l vs. 17.15 +/- 22.0 pmol/l, P = 0.046).. In acute Q-wave MI, increased PAI-1 levels, but not increased NT-proBNP, respond rapidly to early ACE inhibition by ramipril in patients over 55 years of age but not in younger patients.

Topics: Age Factors; Angiotensin-Converting Enzyme Inhibitors; Dose-Response Relationship, Drug; Drug Administration Schedule; Factor VII; Female; Fibrinogen; Hemostasis; Humans; Male; Middle Aged; Myocardial Infarction; Natriuretic Peptide, Brain; Peptide Fragments; Plasminogen Activator Inhibitor 1; Prospective Studies; Ramipril; Slovenia; von Willebrand Factor

The cardioprotective property of Spondias mombin (SM) was investigated and compared with that of the ACE inhibitor, ramipril. Alterations to markers of myocardial injury and indices of antioxidant capacity by isoproterenol (ISP) intoxication were significantly corrected in groups treated with SM. The inflammatory index was increased by 24% in ISP-intoxicated group compared with control (P < 0.001) but reduced in the groups administered ISP and treated with 100 or 250 mg/kg SM by 17% (P < 0.001) and 11% (P < 0.05) respectively. Serum lactate dehydrogenase activity and cholesterol level which were significantly increased in ISP-intoxicated group compared with control were reduced in groups administered ISP and treated with SM. Serum phosphate levels in groups administered ISP and treated with SM were significantly lower than values obtained for the ISP-intoxicated group (P < 0.001). Tissue catalase and superoxide dismutase activities as well as glutathione level were significantly increased in groups administered ISP and treated with SM compared to ISP-intoxicated group while MDA and nitrite levels were decreased. Disruption in the structure of cardiac myofibrils by ISP intoxication was reduced by treatment with SM. Comparable results were obtained for ramipril. These results are indicative of the potent cardioprotective property of SM.

Topics: Anacardiaceae; Angiotensin-Converting Enzyme Inhibitors; Animals; Cardiovascular Agents; Catalase; Cholesterol; Disease Models, Animal; Dose-Response Relationship, Drug; Glutathione; Isoproterenol; L-Lactate Dehydrogenase; Male; Malondialdehyde; Myocardial Infarction; Myocardial Ischemia; Myocardium; Nitrites; No-Reflow Phenomenon; Phosphates; Plant Extracts; Plant Leaves; Ramipril; Rats; Rats, Sprague-Dawley; Superoxide Dismutase; Time Factors

Recent studies have shown that inhibition of angiotensin-converting enzyme (ACE) or angiotensin II receptors causes upregulation of the B(1) receptor (B(1)R). Here we tested the hypothesis that activation of the B(1)R partly contributes to the cardiac beneficial effect of ACE inhibitor (ACEi) and angiotensin II receptor blockers (ARB). B(1)R knockout mice (B(1)R(-/-)) and C57Bl/6J (wild-type control animals, WT) were subjected to myocardial infarction (MI) by ligating the left anterior descending coronary artery. Three weeks after MI, each strain of mice was treated with vehicle, ACEi (ramipril, 2.5 mg kg(-1) day(-1) in drinking water) or ARB (valsartan, 40 mg kg(-1) day(-1) in drinking water) for 5 weeks. We found that: (1) compared with WT mice, B(1)R(-/-) mice that underwent sham surgery had slightly but significantly increased left ventricular (LV) diastolic dimension, LV mass and myocyte size, whereas systolic blood pressure, cardiac function and collagen deposition did not differ between strains; (2) MI leads to LV hypertrophy, chamber dilatation and dysfunction similarly in both WT and B(1)R(-/-) mice; and (3) ACEi and ARB improved cardiac function and remodelling in both strains; however, these benefits were significantly diminished in B(1)R(-/-) mice. Our data suggest that kinins, acting via the B(1)R, participate in the cardioprotective effects of ACEi and ARB.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Collagen; Disease Models, Animal; Female; Heart Rate; Hypertrophy, Left Ventricular; Ligation; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocardial Infarction; Myocytes, Cardiac; Ramipril; Receptor, Bradykinin B1; Tetrazoles; Valine; Valsartan; Ventricular Dysfunction, Left

In this study, effects of Lacidipine (LAC), Ramipril (RAM) and Valsartan (VAL) on DNA damage and oxidative stress occurred in acute and chronic periods after isoproterenol (ISO)-induced myocardial infarct (MI) were investigated in rats. LAC, RAM and VAL had been administered by oral gavage at 3, 3 and 30 mg/kg doses, respectively, in acute and chronic periods following MI. In acute MI model, LAC, RAM and VAL had been administered once per day to rat groups during 30 days. On days 29 and 30, the rats of the acute MI control and drug treatment groups were administered 180 mg/kg ISO, subcutaneously at an interval of 24 h. In chronic MI model, LAC, RAM and VAL had been administered to rat groups during 30 days, and on the 1st and 2nd days, the rats of the chronic MI control and drug treatment groups were administered ISO, by the same way. After this period, routine biochemistry indicators of MI, alanin aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), creatine kinase (CK), creatine kinase-isoenzymes (CK-MB), troponin I (TnI) and nitric oxide (NO), oxidative stress indicator, has been measured in the serums obtained from rat's blood. Also, 7,8-Dihydro-8-oxo-guanine (8-OHGua), which is an indicator of DNA damage level, has been determined in whole blood. After MI diagnosis, the relationships among the 8-OHGua, NO and clinic MI indicators have been determined. Results have been evaluated by comparing with that of control group. In control groups, the clinic MI indicators have been found to be statistically higher than the drug groups. In parallel to this increase in MI indicators, there have been determined a significant decrease in NO levels and an increase in 8-OHGua level. There was no significant difference in the rat groups which received drugs without MI induction. We have observed that the level of 8-OHGua which increased after MI in both acute and chronic periods decreased by LAC, RAM and VAL when compared to acute and chronic MI control groups. In conclusion, it has been determined that oxidative stress has been increased after ISO induced MI model and this stress reduces NO and even damages DNA. LAC, RAM and VAL may decrease the severity of MI and prevent DNA damage by reducing oxidative stress.

Topics: Animals; Antihypertensive Agents; Biomarkers; Dihydropyridines; DNA Damage; Guanine; Isoproterenol; Myocardial Infarction; Nitric Oxide; Oxidative Stress; Ramipril; Rats; Tetrazoles; Valine; Valsartan

In this study, we used a proteomic approach to investigate the potential proteins regulated by ramipril in post-infarction left ventricular remodelling in the rabbit.. Myocardial infarction (MI) was induced in male New Zealand White rabbits (2.5-3 kg) by ligation of the left anterior descending coronary artery. Two months later, the rabbits were either left untreated (MI group) or were treated daily for one month with 0.1 mg/kg wt of ramipril (ramipril group), then sacrificed. One month of ramipril treatment resulted in a significant improvement in the LV ejection fraction (LVEF) and a decrease in hydroxyproline content. The protein profiles of LV tissue showed that ramipril caused upregulation of glutathione peroxidase, superoxide dismutase (SOD), and heart-type fatty acid binding-protein (h-FABP) and downregulation of HSP27 and cyclophilin A. Ramipril treatment caused an increase in catalase, glutathione peroxidase, and SOD activity in the LV tissue. Oxidized glutathione levels and the GSSG/GSH ratio in the heart tissue were lower in the ramipril group than in the MI group.. Ramipril increased antioxidative protein expression and enzyme activity, which could partly explain the role of ramipril in attenuating LV remodelling. In addition, the present study identifies several potential protein targets which may help to explain the mechanism by which ramipril exerts its effect in post-infarction LV remodelling in the rabbit.

Topics: Animals; Blotting, Western; Catalase; Cyclophilin A; Down-Regulation; Echocardiography; Electrophoresis, Gel, Two-Dimensional; Fatty Acid-Binding Proteins; Glutathione Peroxidase; Heart Ventricles; HSP27 Heat-Shock Proteins; Hydroxyproline; Male; Mass Spectrometry; Myocardial Infarction; Rabbits; Ramipril; Reverse Transcriptase Polymerase Chain Reaction; Stroke Volume; Superoxide Dismutase; Up-Regulation; Ventricular Remodeling

Bradykinin (BK) coronary outflow and left ventricular (LV) performance of kininogen-deficient Brown Norway Katholiek (BNK) rats and Brown Norway Hannover (BNH) controls were investigated. We analyzed whether the angiotensin-converting enzyme (ACE) inhibitor ramipril is able to attenuate LV dysfunction after induction of myocardial infarction (MI) in this animal model. Ex vivo, the basal BK content in the coronary outflow of buffer-perfused, isolated hearts was measured by specific radioimmunoassay. In vivo, left ventricular pressure (LVP), the maximal rate of LVP increase, LV end-diastolic pressure, the maximal rate of LVP decrease and heart rate were determined using a tip catheter 3 weeks after induction of MI. Compared to BNK rats, basal BK outflow was increased 30-fold in controls (p<0.01). In vivo, we found no significant differences between sham-ligated BNK and BNH rats in basal LV function. After MI, the impairment of LV function was significantly worse in BNK rats when compared to BNH rats. ACE inhibition significantly attenuated this LV dysfunction in both groups, when compared to untreated animals. Reduced basal BK level resulting from kininogen deficiency has no effect on basal LV function, but remains to be a risk factor for the ischemic heart. However, ACE inhibition is sufficient to improve LV function despite kininogen deficiency.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin; Kininogens; Male; Mutation; Myocardial Infarction; Ramipril; Rats; Ventricular Dysfunction, Left

p38 mitogen-activated protein kinase (p38 MAPK) inhibition exerts beneficial effects on left ventricular (LV) remodeling and dysfunction. p38 MAPK activity is transiently increased soon after myocardial infarction (MI), suggesting brief inhibition may afford the same benefit as long-term inhibition. We examined chronic 12-week p38 MAPK inhibition compared with short-term (7-day) inhibition, and then we discontinued inhibition after MI. Post-MI rats at day 7 received either vehicle, 4-[4-(4-fluorophenyl)-1-(3-phenylpropyl)-5-(4-pyridinyl)-1H-imidazol-2-yl]-3-butyn-1-ol (RWJ67657; RWJ) for 12 weeks (long term; LT-RWJ), RWJ for 1 week and discontinued for 11 weeks (1-week RWJ), or continuous ramipril for 12 weeks. In separate groups of animals, 24 h after MI, vehicle or RWJ was administered for 7 days. Cardiac function was assessed by echocardiography and hemodynamic measurements. Percentage of fractional shortening improved after LT-RWJ and ramipril, but not after 1-week RWJ treatment. Likewise, LV contractility and maximal first derivative of left ventricular pressure (dP/dt(max)) was improved (12.5 and 14.4%) and LV end diastolic pressure (LVEDP) was reduced (49.4 and 54.6%) with both treatments. Functional outcomes were accompanied by regression of interstitial collagen I and alpha-smooth muscle actin expression in LV noninfarct, border, and infarct regions with LT-RWJ and ramipril treatment. Hypertrophy was reduced in noninfarct (18.3 and 12.2%) and border regions (16.3 and 12.0%) with both treatments, respectively. Animals receiving RWJ 24 h after MI for 7 days showed similar improvements in fractional shortening, dP/dt(max), LVEDP, including reduced fibrosis and hypertrophy. In vitro experiments confirmed a dose-dependent reduction in hypertrophy, with RWJ following tumor necrosis factor-alpha stimulation. Continuous but not short-term p38 MAPK blockade attenuates post-MI remodeling, which is associated with functional benefits on the myocardium.

Topics: Actins; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Cells, Cultured; Collagen; Heat-Shock Proteins; HSP27 Heat-Shock Proteins; Imidazoles; Myocardial Infarction; Myocytes, Cardiac; Neoplasm Proteins; Organ Size; p38 Mitogen-Activated Protein Kinases; Protein Kinase Inhibitors; Pyridines; Ramipril; Rats; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha; Ventricular Dysfunction, Left; Ventricular Remodeling

Diabetes mellitus (DM) is a worldwide epidemic. Its prevalence is rapidly increasing in both developing and developed countries. Coronary heart disease (CHD) is highly prevalent and is the major cause of morbidity and mortality in patients with diabetes. Individuals with prediabetes states, with or without known CHD, should undergo lifestyle modifications aimed at preventing DM. In patients with CHD and DM, routine use of aspirin and an angiotensin-converting enzyme inhibitor, along with strict glycemic, blood pressure, and lipid control, is strongly recommended. Intense insulin therapy may be needed for glycemic control, and high-dose statin therapy may be needed for lipid control. For blood pressure control, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are considered first-line therapy. Noncompliance with medications and/or lifestyle measures and underprescription of evidence-based therapies remain important unsolved problems.

Topics: Antihypertensive Agents; Cholesterol, HDL; Cholesterol, LDL; Coronary Artery Disease; Diabetes Mellitus; Diabetic Angiopathies; Humans; Hyperglycemia; Hypoglycemic Agents; Hypolipidemic Agents; Insulin Resistance; Life Style; Myocardial Infarction; Obesity; Pioglitazone; Piperidines; Platelet Aggregation Inhibitors; Prediabetic State; Pyrazoles; Ramipril; Rimonabant; Risk Assessment; Thiazolidinediones; Triglycerides; Weight Loss

This study was performed to investigate the role of chronic pretreatment with angiotensin II type 1 receptor antagonists (ARB) and angiotensin converting enzyme inhibitors (ACE-I) in myocardial infarction (MI) and ischemic preconditioning (iPC). Little is known about molecular mechanisms of MI and iPC, especially about protein kinase C (PKC) isozyme levels induced by chronic pharmacologic pretreatment with ARB and ACE-I. To address one of the most important signal molecules in iPC, the PKC system was investigated in an ischemia/reperfusion model using isolated mouse hearts.. C57/BL6 mice were treated orally with candesartan cilexetil or ramipril for 2 weeks. Isolated perfused hearts were subjected to 60 minutes of left anterior descending occlusion and 30 minutes of reperfusion. IPC was performed by 3 cycles of 5 minutes of ischemia prior to the infarct ischemia. Infarct size was measured using the propidium iodide method, and PKC isoenzymes were detected by immunoblotting in the membrane and cytosolic fraction.. In the control group, iPC reduced infarct size from 59.8 +/- 4.2% to 24.5 +/- 1.7%. ARB pretreatment itself reduced the infarct size significantly (38.1 +/- 3.0%) in hearts without iPC. This protection could neither be enhanced by additional iPC (40.3 +/- 3.4%) nor blocked by the AT2-receptor antagonist PD123.319 (40.7 +/- 3.7%). The ARB-induced cardio protection, however, was abolished by chelerythrine (5 micromol/L) (71.7 +/- 6.6%, n = 11, P < 0.001). Furthermore, PKC-epsilon (PKC-epsilon) was significantly increased in the particulate fraction of ARB-pretreated mice. On the contrary, chronic treatment with ACE-I completely blocked iPC (57.7 +/- 3.9%, n = 12, P < 0.001) without any effect on infarct size itself (51.5 +/- 3.0%, n = 12). PKC-epsilon expression was significantly reduced.. Chronic AT1-receptor antagonism is capable of protecting the heart against myocardial infarction in a PKC-epsilon-dependent way. Furthermore, chronic treatment with ACE-I is suggested to have suppressing effects on iPC, possibly caused by reduced PKC-epsilon expression.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzimidazoles; Biphenyl Compounds; Heart; Male; Mice; Mice, Inbred C57BL; Myocardial Infarction; Myocardial Ischemia; Myocardium; Protein Kinase C-epsilon; Ramipril; Tetrazoles; Time Factors

This study compares the effect of two different strategies to inhibit the renin-angiotensin system in the setting of acute myocardial infarction (MI). Male Wistar rats were treated with placebo, the angiotensin-converting enzyme (ACE) inhibitor ramipril (1 mg/kg/day), or the AT1 receptor antagonist, olmesartan (1 mg/kg/day), both initiated 1 week before induction of MI and continued for 6 weeks after MI. The inflammatory reaction in the heart was investigated 7 days post-MI by determination of macrophage infiltration and the expression of tumor necrosis factor (TNF-alpha), interleukin (IL)-1beta and IL-6 at mRNA and protein levels. Six weeks post-MI, cardiac function was measured following chronic implantation of catheters in the LV and femoral artery, and cardiac morphology and coronary structure were investigated in picrosirius-red stained hearts. In placebo-treated rats, macrophage infiltration was accompanied by upregulation of IL-1beta and IL-6 mRNA in the peri-infarct zone. TNF-alpha and IL-1beta mRNA and protein were also upregulated in the non-infarcted myocardium. Whereas both treatment regimes significantly reduced IL-6 upregulation, olmesartan additionally reduced macrophage infiltration and IL-1beta expression. Six weeks post-MI, placebo-treated MI animals developed an impaired cardiac function with structural remodeling of the myocardium and coronaries. While olmesartan and ramipril both improved cardiac function and reduced infarct size and myocardial/coronary remodeling, olmesartan was more effective not only in increasing vascular perimeter, inner vascular diameter and septal thickness but also in lowering media thickness of coronary arteries, inner left ventricular diameter, left ventricular circumference and left ventricular end-diastolic pressure than ramipril. Thus, following MI the AT1 receptor blocker, olmesartan, attenuated cardiac inflammatory reactions and protected myocardial/coronary structure and function of the failing heart proving to be of similar, in some cases superior effectiveness in this respect than the ACE inhibitor, ramipril.

Topics: Acute Disease; Animals; Anti-Inflammatory Agents; Cardiovascular Diseases; Cardiovascular System; Disease Models, Animal; Dose-Response Relationship, Drug; Imidazoles; Inflammation; Interleukin-1; Interleukin-6; Male; Myocardial Infarction; Placebos; Ramipril; Rats; Rats, Wistar; Renin-Angiotensin System; RNA, Messenger; Tetrazoles; Tumor Necrosis Factor-alpha

Whether angiotensin-converting enzyme (ACE) inhibitors are interchangeable and equally efficacious after acute myocardial infarction (AMI) is controversial. We assessed whether ramipril was superior to other ACE inhibitors after AMI as suggested by a previously published study. We performed a retrospective cohort study using linked administrative databases on >1.4 million elderly residents in the province of Ontario who were admitted to the hospital for AMI, survived >or=30 days after discharge, and were initiated on an ACE inhibitor after AMI and remained on the same ACE inhibitor from April 1, 1997 to March 31, 2000. We followed patients for 2 years and measured readmission for AMI or mortality, together or alone. Our cohort included 5,408 elderly patients. Compared with patients on enalapril, there was no significant difference for the combined end points of readmission for AMI or mortality across users of ramipril (adjusted hazard ratio 0.95, 95% confidence interval 0.79 to 1.15), lisinopril (adjusted hazard ratio 1.02, 95% confidence interval 0.84 to 1.25), or other ACE inhibitors (adjusted hazard ratio 1.08, 95% confidence interval 0.88, 1.32). In conclusion, the findings of this study support a class effect among ACE inhibitors in treatment after AMI.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Anti-Arrhythmia Agents; Cohort Studies; Female; Humans; Male; Myocardial Infarction; Ontario; Ramipril; Retrospective Studies; Secondary Prevention; Survival Rate; Treatment Outcome

Onset of acute myocardial infarction (AMI) follows a diurnal periodicity, with a peak incidence between 6:00 a.m. and noon. Beta blockers and aspirin decrease the rate of AMI and blunt the peak incidence, but such an effect has not been evaluated for angiotensin-converting enzyme inhibitors. The effect of ramipril on onset of symptomatic AMI was evaluated in 4-hour periods over a 24-hour cycle in men and women who were > or =55 years of age, had cardiovascular disease or diabetes mellitus with > or =1 other risk factor, and participated in the Heart Outcomes Prevention Evaluation (HOPE) trial. During the 4.5-year follow-up, AMI was documented in 383 of 4,596 participants allocated to ramipril and in 491 of 4,598 participants allocated to placebo (8.3% vs 10.7%, p <0.001). Ramipril decreased rates of AMI at each period and attenuated, but did not blunt, the peak incidence. In conclusion, inhibiting angiotensin-converting enzyme decreased AMI over a 24-hour period, but this enzyme does not seem to play a major role in the circadian periodicity of this acute event.

Topics: Angiotensin-Converting Enzyme Inhibitors; Circadian Rhythm; Female; Follow-Up Studies; Humans; Male; Myocardial Infarction; Ramipril; Randomized Controlled Trials as Topic

The blood pressure-lowering dose-response relationship for angiotensin converting enzyme (ACE) inhibitors is assumed to flatten at doses higher than those conventionally used in clinical practice. However, existing clinical trial data do not adequately address the haemodynamic effects of high ACE inhibitor dosages. Therefore, we examined the blood pressure responses in patients presenting to hospital following a deliberate ACE inhibitor overdose.. The study design was a retrospective case review, and included all patients who presented to our hospital in the past 5 years after an ACE inhibitor overdose. The data collected were heart rate and systemic blood pressure at various times after ingestion and maximum haemodynamic derangement; these were compared to baseline or recovered values.. Data from 33 patients (24 men) were evaluated. The median (inter-quartile range, IQR) age of the patients was 49 years (IQR: 42-56 years). The median stated dose ingested was 140 mg (IQR: 60-280 mg), which is 20x (IQR: 7-42) the defined daily dose. The maximum fall in systolic blood pressure was 50 mmHg (IQR: 40-64 mmHg), diastolic blood pressure was 35 mmHg (IQR: 26-43 mmHg) and mean blood pressure was 39 mmHg (IQR: 30-47 mmHg).. The observed reduction in blood pressure following an overdose of an ACE inhibitor was greater than anticipated based on data from therapeutic doses. We conclude that a blood pressure-lowering dose-response relationship extends to higher ACE inhibitor doses than those conventionally used in clinical practice.

Topics: Adrenergic beta-Antagonists; Adult; Angiotensin-Converting Enzyme Inhibitors; Anti-Inflammatory Agents, Non-Steroidal; Blood Pressure; Calcium Channel Blockers; Creatinine; Diuretics; Dose-Response Relationship, Drug; Drug Overdose; Drug Utilization Review; Electrocardiography; Emergency Service, Hospital; Female; Humans; Hypertension; Male; Middle Aged; Myocardial Infarction; Norepinephrine; Ramipril; Retrospective Studies

Congestive heart failure (CHF) is a major cause of morbidity and mortality worldwide and angiotensin converting-enzyme inhibitor (ACEI) is the cornerstone in its treatment. However, CHF continues to progress despite this therapy, perhaps because of production of angiotensin II (Ang II) by alternative pathways. The present study was conducted to examine the combined effects of a chronic ACEI, ramipril, and a chronic Ang II type 1 receptor blocker, TCV116, on rat CHF after myocardial infarction (MI).. Congestive heart failure was caused by MI in rats, which was induced by ligating the left anterior descending coronary artery. The experiment protocol included sham-operated rats (Sham), MI-control rats (MI-control), MI rats treated with ramipril 3 mg/kg (MI-ramipril) or TCV116 2 mg/kg (MI-TCV116) per day, half dosage (MI-1/2R&T) or full dosage (MI-R&T) combination of the two. At 22 weeks, cardiac hemodynamic parameters such as mean arterial pressure (MAP), left ventricular systolic pressure (LVSP), maximal rate of left ventricule pressure development and decline (LV dP/dtmax) and left ventricular end diastolic pressure (LVEDP), and cardiac morphometric parameters such as heart weight (HW), left ventricular weight (LVW) and left ventricular cavity area (LVCA) were measured, mRNA expressions of cardiac molecule genes such as beta myosin heavy chain (betaMHC), B-type natriuretic peptide (BNP), transforming growth factor-beta1 (TGF-beta1), collagen I and III were quantified with reverse transcription polymerase chain reaction (RT-PCR) in the surviving septum myocardium, and survival rates were calculated.. There were no significant differences in MI sizes (%) among each MI related experimental groups (33 +/- 13, 34 +/- 14, 33 +/- 13, 35 +/- 13 and 33 +/- 14 for MI-control, MI-ramipril, MI-TCV116, MI-1/2R&T and MI-R&T, respectively, no statistical significance for all). Compared with sham-operated rats, MI rats without therapy showed significant increases in morphometric parameters as well as in mRNA expressions of cardiac molecule genes (P < 0.01); while their hemodynamic parameters were significantly impaired (P < 0.01), and in terms of spontaneous deaths survival rate shortened (P < 0.05). Compared with MI rats without therapy, MI rats treated with each single drug showed significant attenuation of mRNA expressions of cardiac molecule genes (P < 0.01); while their hemodynamic parameters were significantly improved (P < 0.05 or P < 0.01), and in terms of spontaneous deaths survival rate prolonged (P < 0.05). Both half and full dosage combined treatments exerted more powerful effects on improvement of cardiac phenotypic changes and on attenuation of betaMHC, BNP mRNA expressions (P < 0.05 vs monotherapy); while LVEDP was further lowered (P < 0.05 vs monotherapy). However, the total death in MI rats with full dosage combined treatment was more though there were no significant differences when compared with other treatments.. The results suggest that treatment with appropriate dosage combination of a chronic ACEI and a chronic ARB may further improve cardiac remodeling and cardiac function after MI.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Drug Therapy, Combination; Heart Failure; Male; Myocardial Infarction; Myocardium; Ramipril; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Tetrazoles; Ventricular Function, Left

Angiotensin converting enzyme (ACE) 2 catalyses the cleavage of angiotensin (Ang) I to Ang 1-9 and of Ang II to Ang 1-7. ACE2 deficiency impairs cardiac contractility and upregulates hypoxia-induced genes, suggesting a link with myocardial ischaemia. We studied the expression of ACE2 after myocardial infarction (MI) in the rat as well as in human failing hearts.. Rats were killed at days 1, 3, and 28 after MI, or treated for 4 weeks with the ACE inhibitor ramipril (1 mg/kg). Cardiac gene and protein expression of ACE and ACE2 were assessed by quantitative real-time reverse transcriptase-polymerase chain reaction and immunohistochemistry/activity assays/in vitro autoradiography, respectively. Both ACE (P = 0.022) and ACE2 (P = 0.015) mRNA increased in the border/infarct area compared with the viable area at day 3 after MI. By day 28, increases in ACE (P = 0.005) and ACE2 (P = 0.006) mRNA were also seen in the viable myocardium of MI rats compared with myocardium of control rats. ACE2 protein localized to macrophages, vascular endothelium, smooth muscle, and myocytes. Ramipril attenuated cardiac hypertrophy and inhibited cardiac ACE. In contrast, ramipril had no effect on cardiac ACE2 mRNA, which remained elevated in all areas of the MI rat heart. Immunoreactivity of both ACE and ACE2 increased in failing human hearts.. The increase in ACE2 after MI suggests that it plays an important role in the negative modulation of the renin angiotensin system in the generation and degradation of angiotensin peptides after cardiac injury.

Topics: Aged; Angiotensin-Converting Enzyme 2; Angiotensin-Converting Enzyme Inhibitors; Animals; Carboxypeptidases; Gene Expression Regulation, Enzymologic; Humans; Male; Middle Aged; Myocardial Infarction; Myocardium; Peptidyl-Dipeptidase A; Ramipril; Rats; Rats, Sprague-Dawley; Renin-Angiotensin System; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

In the current study, we compared purified Salvia miltiorrhiza extract (PSME) with Angiotensin-converting enzyme inhibitor, Ramipril, in in vitro experiments and also in vivo using animal model of myocardial infarction. PSME was found to have a significantly higher trolox equivalent antioxidant capacity which indicated a great capacity for scavenging free radicals. PSME could also prevent pyrogallo red bleaching and DNA damage. After 2 weeks treatment with PSME or Ramipril, survival rates of rats with experimental myocardial infarction were marginally increased (68.2% and 71.4%) compared with saline (61.5%). The ratios of infarct size to left ventricular size in both PSME-and Ramipril-treated rats were significantly less than that in the saline-treated group. Activity of cardiac antioxidant enzyme superoxide dismutase (SOD) was significant higher while level of Thiobarbituric acid-reactive substances (TBARs) was lower in the PSME treated group. Purified and standardized Chinese herb could provide an alternative regimen for the prevention of ischemic heart disease.

Topics: Analysis of Variance; Animals; Antioxidants; Benzothiazoles; DNA Damage; Drugs, Chinese Herbal; Gas Chromatography-Mass Spectrometry; Male; Myocardial Infarction; Myocardial Ischemia; Phytotherapy; Pyrogallol; Ramipril; Rats; Rats, Wistar; Salvia miltiorrhiza; Spectrophotometry; Sulfonic Acids; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances; Ventricular Remodeling

Tissue kallikrein (TK), a major kinin-forming enzyme, is synthesized in the heart and arteries. We tested the hypothesis that TK plays a protective role in myocardial ischemia by performing ischemia-reperfusion (IR) injury, with and without ischemic preconditioning (IPC) or ACE inhibitor (ramiprilat) pretreatment, in vivo in littermate wild-type (WT) or TK-deficient (TK-/-) mice. IR induced similar infarcts in WT and TK-/-. IPC reduced infarct size by 65% in WT, and by 40% in TK-/- (P<0.05, TK-/- vs WT). Ramiprilat also reduced infarct size by 29% in WT, but in TK-/- its effect was completely suppressed. Pretreatment of WT with a B2, but not a B1, kinin receptor antagonist reproduced the effects of TK deficiency. However, B2 receptor-deficient mice (B2-/-) unexpectedly responded to IPC or ramiprilat like WT mice. But pretreatment of the B2-/- mice with a B1 antagonist suppressed the cardioprotective effects of IPC and ramiprilat. In B2-/-, B1 receptor gene expression was constitutively high. In WT and TK-/- mice, both B2 and B1 mRNA levels increased several fold during IR, and even more during IPC+IR. Thus TK and the B2 receptor play a critical role in the cardioprotection afforded by two experimental maneuvers of potential clinical relevance, IPC and ACE inhibition, during ischemia.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Ischemic Preconditioning, Myocardial; Mice; Mice, Inbred C57BL; Myocardial Infarction; Myocardial Reperfusion Injury; Ramipril; Receptor, Bradykinin B1; Receptor, Bradykinin B2; RNA, Messenger; Tissue Kallikreins

1 We investigated the single vs the combined long-term inhibition of Na(+)-H(+) exchanger-1 (NHE-1) and ACE in rats with congestive heart failure induced by myocardial infarction (MI). 2 Rats with MI were randomized to receive either placebo, cariporide (3000 p.p.m. via chow), ramipril (1 mg kg(-1) day(-1) via drinking water) or their combination for 18 weeks starting on day 3 after surgery. 3 Cardiac morphology and function was assessed by echocardiography and by means of a 2.0 F conductance catheter to determine left ventricular (LV) pressure volume relationships. 4 MI for 18 weeks resulted in an increase in LV end-diastolic diameter (LVDed) in the placebo-treated group when compared to sham (placebo: 1.1+/-0.04 cm; sham: 0.86+/-0.01; P<0.05). Combined inhibition of NHE-1 and ACE, but not the monotherapies, significantly reduced LVDed (1.02+/-0.02 cm). 5 Preload recruitable stroke work (PRSW), dp/dt(max) (parameter of systolic function) and end-diastolic pressure volume relationship (EDPVR, diastolic function) were significantly impaired in placebo-treated MI group (PRSW: 39+/-7 mmHg; dp/dt(max): 5185+/-363 mmHg s(-1); EDPVR: 0.042+/-0.001 mmHg microl(-1); all P<0.05). Cariporide treatment significantly improved PRSW (64+/-7 mmHg), dp/dt(max) (8077+/-525 mmHg s(-1)) and EDPVR (0.026+/-0.014 mmHg microl(-1)), and reduced cardiac hypertrophy in rats with MI. Combined inhibition of NHE-1 and ACE had even a more pronounced effect on PRSW (72+/-5 mmHg) and EDPVR (0.026+/-0.014 mmHg microl(-1)), as well as cardiac hypertrophy that, however, did not reach statistical significance compared to cariporide treatment alone. 6 The NHE-1 inhibitor cariporide significantly improved LV remodeling and function in rats with congestive heart failure induced by MI. The effect of cariporide was comparable or tended to be stronger (e.g. systolic function) compared to ramipril. Combined treatment with cariporide and ramipril tended to be more effective on LV remodeling in rats with heart failure than the single treatments. Thus, inhibition of the NHE-1 may be a promising novel therapeutic approach for the treatment of congestive heart failure.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Guanidines; Heart; Heart Failure; Lung; Male; Myocardial Infarction; Organ Size; Peptidyl-Dipeptidase A; Ramipril; Rats; Rats, Sprague-Dawley; Sodium-Hydrogen Exchangers; Sulfones

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Cardiotonic Agents; Diet, Atherogenic; Drug Evaluation, Preclinical; Imidazoles; Myocardial Infarction; Ramipril; Rats; Tetrazoles

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure Determination; Cardiovascular Diseases; Humans; Hypertension; Myocardial Infarction; Placebos; Ramipril; Randomized Controlled Trials as Topic; Risk Factors; Stroke; Treatment Outcome

It has been suggested that the beneficial effects of reperfusing the myocardium might be in part reversed by the occurrence of reperfusion injury. Oxidative stress was suggested to be implicating in the pathogenesis of ischemia-reperfusion (I/R) injury. Many antioxidative plants were shown to be cardioprotective in experimental models of myocardial ischemia-reperfusion (I/R) injury. The present study was designed to investigate the effects of pretreatment with alcoholic extract of Tinospora cordifolia in an in vivo rat model. The model adopted was that of surgically-induced myocardial ischemia, performed by means of left anterior descending coronary artery occlusion (LAD) for 30 min followed by reperfusion for another 4 h. Infarct size was measured by using the staining agent TTC (2,3,5-triphenyl tetrazolium chloride). Lipid peroxide levels in serum and in heart tissue were estimated spectrophotometrically by the methods developed by Yagi and Ohkawa et al. respectively. A lead II electrocardiogram was monitored at various intervals throughout the experiment. A dose dependent reduction in infarct size and in lipid peroxide levels of serum and heart tissue were observed with the prior treatment of T. cordifolia with various doses for 7 d compared to control animals. Hence, the present study suggests the cardioprotective activity of T. cordifolia in limiting ischemia-reperfusion induced myocardial infarction.

Topics: Alcohols; Animals; Antihypertensive Agents; Cardiotonic Agents; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Heart Rate; Intubation, Gastrointestinal; Male; Malondialdehyde; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Plant Extracts; Ramipril; Rats; Rats, Sprague-Dawley; Tinospora

The use of angiotensin-converting enzyme (ACE) inhibitors has increased markedly during the last decade. It has been claimed that doses of ACE inhibitors prescribed in clinical practice are considerably lower than the target doses used in randomized clinical trials. The aim of the study was to investigate dosing of ACE inhibitors in patients discharged from the hospital after an acute myocardial infarction (AMI) and, furthermore, to compare these doses with the doses actually reached in clinical trials.. From 16 hospitals, we drew a sample of patients who were discharged alive with the diagnosis of AMI during a 3-month period in 1999/2000. From medical records, physicians in each hospital obtained the observed rate of cardiovascular drugs at discharge, including type and doses of ACE inhibitors. The clinicians' main indication for ACE inhibitor use was also reported. Outcome variables, including deaths and drug utilization with dosing after 6 months, were collected.. Of a total of 767 patients discharged alive, 274 patients received an ACE inhibitor. The daily mean doses of the four ACE inhibitors used in the study were as follows: captopril 69.8+/-36.9 mg (n=44), enalapril 13.6+/-8.1 mg (n=75), lisinopril 11.0+/-7.2 mg (n=114), and ramipril 8.4+/-4.5 mg (n=38). The doses were unchanged after 6 months except for captopril, which showed a rise in mean daily dose to 84.4+/-36.7 mg. Ramipril compared most favorably with clinical trial medications, while captopril deviated most. The indication of hypertension was associated with slightly higher doses than the indication of secondary prevention.. AMI patients were discharged from the hospital with ACE inhibitor doses fairly close to the ones achieved in clinical trials showing survival benefits for ACE inhibitors. A distinction should be made between target doses and doses actually obtained in clinical trials.

Topics: Acute Disease; Aged; Angiotensin-Converting Enzyme Inhibitors; Captopril; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Utilization; Enalapril; Evaluation Studies as Topic; Female; Hospitalization; Humans; Lisinopril; Male; Myocardial Infarction; Patient Discharge; Pharmacoepidemiology; Ramipril; Randomized Controlled Trials as Topic

Topics: Angina Pectoris; Angiotensin-Converting Enzyme Inhibitors; Coronary Disease; Humans; Ischemic Preconditioning, Myocardial; Myocardial Infarction; Ramipril; Stroke Volume; Ventricular Remodeling

To elucidate the cardioprotective effects of T-type calcium channel blocker mibefradil and compare with that of the angiotensin-converting enzyme inhibitor ramipril in a stroke-prone spontaneously hypertensive rats (SHR-SP) model of congestive heart failure (CHF) after myocardial infarction (MI).. SHR-SP rats were subjected to permanent ligation of the left anterior decending coronary artery. Treatment with mibefradil (10 mg.kg(-1).d(-1)), ramipril (10 mg.kg(-1).d(-1)), or placebo was initiated 4 weeks before surgery and continued up to 6 weeks after induction of MI. Sham-operated rats served as controls.. In placebo-treated MI rats, six weeks after MI, left ventricular circumference, inner diameter, and left ventricular end-diastolic pressure (LVEDP) were increased, whereas mean arterial blood pressure (MAP) and maximum rate of rise of left ventricular pressure (dp/dt(max)) were decreased compared with sham-operated controls (P<0.01). In ramipril-treated MI rats, heart weight, heart weight to body weight ratio and interstitial collagen content were reduced (P<0.05, P<0.01), LVEDP was slightly decreased (P>0.05), and dp/dt(max) was improved (P<0.01) compared with placebo-treated MI rats. In contrast, in mibefradil-treated MI rats, heart weight, heart weight to body weight ratio were slightly but not significantly reduced, LVEDP was slightly elevated compared with placebo-treated MI rats, and was elevated (P<0.05) compared with ramipril-treated MI rats, although interstitial collagen content were reduced (P<0.01) compared with placebo-treated MI rats.. Chronic treatment with ramipril diminishes cardiac remodeling of heart failure after MI to a greater extent than mibefradil. Moreover, 6 weeks after MI, mibefradil treatment results in a slight rise in LVEDP compared with placebo-treated rats. Therefore, treatment with mibefradil might be deleterious rather than beneficial compared with ramipril or even placebo treatment in experimental MI.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Calcium Channel Blockers; Cardiotonic Agents; Heart; Heart Rate; Mibefradil; Myocardial Infarction; Organ Size; Ramipril; Rats; Rats, Inbred SHR; Ventricular Pressure; Ventricular Remodeling

The HOPE study has demonstrated that ramipril is beneficial (ie, prevents cardiovascular death, myocardial infarction, and stroke) for a broad range of patients without evidence of left ventricular dysfunction or heart failure who are at high risk for cardiovascular event. In this study, we report the cost implications, in both the United States and Canada, of the use of ramipril after the HOPE study.. A third-party perspective was chosen (Medicare for the United States and Ministry of Health for Canada). We calculated the costs of the management strategies of ramipril and placebo. An annual discount rate of 3% was used over the 4.5 years of follow-up. Sensitivity analyses were performed. Costs are reported in United States dollars and in Canadian dollars, respectively. The total costs per patient (including acquisition costs of ramipril) were not different between the groups in both countries (United States, $13 520 versus $13 631; Canada, $8702 versus $8588). From the distribution of cases in the bootstrap analysis, we found that 90% of cases fall either into a cost-neutral or cost-saving situation (64% in United States and 27% in Canada) or into a cost-effectiveness situation with an incremental cost-effectiveness ratio <$10 000 (in respective currency) per primary event saved.. On the basis of these results, we suggest that the use of ramipril is likely to represent an efficient use of resources in both countries. These findings support the use of ramipril in populations included in the HOPE study.

Topics: Angiotensin-Converting Enzyme Inhibitors; Canada; Cost-Benefit Analysis; Drug Costs; Health Care Costs; Heart Diseases; Hospitalization; Humans; Multicenter Studies as Topic; Myocardial Infarction; Placebos; Ramipril; Randomized Controlled Trials as Topic; Risk; Sensitivity and Specificity; Stroke; Treatment Outcome; United States

To estimate differences in direct costs attributable to avoided hospitalizations and procedures during the years of the HOPE (Heart Outcomes Prevention Evaluation) study after the cost of treatment with ramipril or alternative angiotensin-converting enzyme inhibitor therapy was taken into account.. A decision analytical model was developed to estimate the economic impact of reductions in hospitalizations and/or procedures both at annual increments and over the first 4 years of the HOPE study. The analysis compared the number of cardiovascular events per endpoint per year in the intervention and placebo group with hospitalization and procedural costs. Cost data were derived from the literature and inflated to the appropriate index year using the consumer price index.. For approximately 9000 patients studied, the gross estimated savings in direct costs for 297 events avoided were more than $5 million over 4 years. After the cost of treatment was deducted for both groups, the net estimated savings were $871 000 over 4 years.. The results demonstrate that the use of ramipril provides cost-effective treatment for high-risk cardiovascular patients with an ejection fraction >40%.

Topics: Angioplasty, Balloon, Coronary; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Coronary Artery Bypass; Cost Savings; Cost-Benefit Analysis; Decision Support Techniques; Heart Failure; Hospitalization; Humans; Middle Aged; Multicenter Studies as Topic; Myocardial Infarction; Ramipril; Risk Factors; Stroke

Inhibition of angiotensin-converting enzyme (ACEI) after myocardial infarction reduces remodeling of the surviving myocardium. The cellular signaling mechanisms contributing to remodeling are not fully elucidated. Goal of the current study was to test whether protein kinase C (PKC) is regulated in the surviving myocardium shortly after infarction and whether this regulation is influenced by ACEI. Rats were subjected to anterior wall myocardial infarction in vivo or sham operation. After 15-45 min, mRNA levels and protein expression of the major cardiac PKC isoforms were measured in the ischemic and the remote myocardium. The influence of ACEI on PKC was tested by pretreating the rats with ramiprilat. In the ischemic region of the myocardium, a significant increase of the mRNA for PKC-delta and PKC-epsilon was observed in close correlation with increased isoform protein expression. In the surviving, remote myocardium, however, only PKC-epsilon expression was significantly augmented both at the mRNA level (158%) and at the protein level (149%). PKC-delta and PKC-alpha were unchanged. Treatment with ramiprilat could abolish this isoform-specific PKC regulation in both areas. These data characterize for the first time an isoform-specific transcriptional regulation process of PKC in the surviving myocardium after infarction. This induction of PKC-epsilon can be prevented by ACEI. It is speculated that PKC-epsilon plays a role in the signal transduction of early remodeling after infarction.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Coronary Vessels; Isoenzymes; Ligation; Male; Myocardial Infarction; Protein Kinase C; Protein Kinase C-alpha; Protein Kinase C-delta; Protein Kinase C-epsilon; Ramipril; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Up-Regulation; Ventricular Remodeling

To investigate the effects of aldosterone receptor blockade in postinfarction heart failure.. Eighty-seven rats with moderate myocardial infarction were randomized to receive either no drug or canrenone, the active metabolite of spironolactone, 20 mg/kg/day, or ramipril, 1 mg/kg/day, or a combination of the two drugs. Treatment was initiated 1 month after coronary ligation and lasted 4 weeks. Echocardiography was performed at baseline and after 4 weeks. LV catheterization, isolated heart studies, morphometric histology, myocardial norepinephrine and SERCA-2 mRNA were assessed at the end of the treatment period.. Infarct sizes were 33+/-3, 32+/-3, 34+/-3, and 34+/-4% in the placebo, canrenone, ramipril, and combination groups, respectively. Canrenone attenuated LV remodeling, improved LV systolic and diastolic function, and markedly reduced interstitial and perivascular fibrosis. These effects were increased by concomitant ramipril therapy. Moreover, myocardial norepinephrine content was decreased while ventricular fibrillation threshold significantly augmented by canrenone. SERCA-2 levels remained unchanged.. Canrenone attenuated LV dilation and interstitial remodeling, and improved LV filling dynamics and systolic function in the rat model of postinfarction heart failure. Addition of ramipril conferred further cardioprotection. Canrenone also reduced myocardial norepinephrine content and increased ventricular fibrillation threshold. The data provide a potential explanation for the decreased sudden death observed in the RALES study. The mechanisms of action of aldosterone inhibition are still poorly understood, despite its proven efficacy in heart failure. Rats with postinfarction heart failure were randomized to receive for 1 month either no drug or canrenone, or ramipril, or a combination of canrenone and ramipril. Canrenone treatment was associated with a significant attenuation of LV dilation, better LV diastolic and systolic dynamics, and a marked reduction of reactive fibrosis. These effects were enhanced by concomitant ramipril therapy. Moreover, canrenone increased ventricular fibrillation threshold and reduced myocardial norepinephrine content. The data may explain the reduced mortality demonstrated by the RALES.

Topics: Animals; Calcium-Transporting ATPases; Canrenone; Drug Therapy, Combination; Heart Failure; Male; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Myocardium; Norepinephrine; Ramipril; Random Allocation; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Ventricular Dysfunction, Left; Ventricular Remodeling

Cardiac angiotensin converting enzyme (ACE) is activated by an increase in wall stress and is involved in remodeling processes. Heart failure is often treated with ACE inhibitors and diuretics although diuretic treatment could activate the renin-angiotensin system (RAS).. To examine the effects of diuretic treatment on cardiac and circulating RAS in post-infarction chronic heart failure.. Myocardial infarction was produced by coronary artery ligation in spontaneously hypertensive rats. The rats were randomly assigned to receive either ramipril (1 mg/kg/day), furosemide (4 mg/kg/day), or combination therapy for 6 weeks, commencing 2 weeks after infarction.. All three treatment protocols equivalently attenuated reactive hypertrophy of the right ventricle and ventricular septum and improved left ventricular systolic function. Both cardiac ACE mRNA and activity were significantly increased in untreated rats. This increase was attenuated by both ramipril and furosemide and further depressed by the combination. The increase in activity was completely inhibited by either agent alone. Plasma renin activity was upregulated by ramipril or ramipril plus furosemide but not influenced by infarction or furosemide alone.. Furosemide and ramipril significantly reduced cardiac ACE and remodeling. Diuretics work favorably and do not interfere with the effects of ACE inhibitors. Possibly, a reduction in wall stress due to decreased volume overload accounts for the effects of diuretics on cardiac ACE in the treatment of post-infarction remodeling in hypertensive hearts. These data suggest a new mechanism for the frequently observed beneficial effect of diuretics in heart failure.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Chronic Disease; Disease Models, Animal; Diuretics; Drug Therapy, Combination; Furosemide; Heart Failure; Heart Ventricles; Hypertrophy, Left Ventricular; Male; Models, Cardiovascular; Myocardial Infarction; Peptidyl-Dipeptidase A; Placebos; Ramipril; Randomized Controlled Trials as Topic; Rats; Rats, Inbred SHR; Renin; Renin-Angiotensin System; RNA, Messenger; Statistics as Topic; Survival Analysis; Treatment Outcome; Ventricular Pressure; Ventricular Remodeling

Adding angiotensin II type 1 receptor blockade (ARB) to angiotensin-converting enzyme inhibition (ACEI) further attenuates left ventricular (LV) remodeling in an ovine model of myocardial infarction (MI). We hypothesized that combined therapy with ACEI and ARB (CT) would be additive in the limitation of the myocyte hypertrophy and dysfunction that occurs in untreated adjacent noninfarcted regions during remodeling.. Nineteen sheep underwent coronary ligation to create a moderate-sized anteroapical infarction. Post-MI day 2, sheep were randomized to therapy with ramipril (ACEI, n = 5) or ramipril plus losartan (CT, n = 6) or none (untreated, n = 8). Infarct size was similar between groups. At 8 weeks post-MI, myocytes were isolated from regions adjacent to and remote from the infarct to measure morphometric indices (cell volume, length, cross-sectional area, width) and parameters of contraction (% shortening and -dL/dt, rate of shortening) and relaxation (+dL/dt [rate of relengthening] and TR 70% [time for 70% relengthening]). Volume % collagen was measured from adjacent and remote regions. Adjacent myocyte volume was different between groups (2.5 +/- 0.1 x 10(4) microm(3) in CT, 3.0 +/- 0.4 x 10(4) microm(3) in ACEI, 3.5 +/- 0.2 x 10(4) microm(3) in untreated, analysis of variance [ANOVA] P =.001) as was length (158 +/- 4 microm, 161 +/- 9 microm, 189 +/- 8 microm, respectively, ANOVA P <.001). Adjacent cell volume and length in CT were lower than untreated (P <.05). Percent shortening and -dL/dt of isolated adjacent myocytes were improved with both ACEI (7.9 +/- 0.3%, -131 +/- 6 microm/sec, P <.05) and CT (7.7 +/- 0.3%, -144 +/- 8 microm/sec, P <.05) compared with no therapy (6.4 +/- 0.4%, -104 +/- 7 microm/sec), as was both +dL/dt and TR 70%. No between-group difference in volume % collagen was found in adjacent or remote regions.. Compared with ACEI alone, the addition of ARB further limits adjacent noninfarcted myocyte hypertrophy during post-MI LV remodeling. Both ACEI alone and CT preserve isolated unloaded myocyte function, but neither significantly reduce interstitial collagen. The additional benefit of ARB on regional and global function in vivo may also be due to other factors including regional load.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Female; Losartan; Myocardial Infarction; Myocardium; Ramipril; Sheep; Ventricular Remodeling

In the present study, we compared cardioprotective effects of DanShen (an extract from Salvia miltiorrhiza) and the angiotensin-converting enzyme inhibitor, ramipril, in rats. With both treatment regimens, DanShen- and ramipril similar effects were observed: (1) a higher survival rate, (2) a significant reduction of infarct size, (3) significantly lower ratios of heart weight to the body weight as well as the left and right ventricular weights to body weight. DanShen showed some unique effects in the following aspects: (1) higher activities of antioxidant defense enzymes such as superoxide dismutase (SOD), catalase (CAT), glutatione perioxidase (GSH-Px) and glutathione S-transferase (GST) in the liver of rats with acute myocardial infarction (AMI), (2) lower myocardial and hepatic TBARS values; (3) augmented VEGF mRNA expressions in the non-ischemic parts of rat hearts with AMI. These results were consistent with the findings of a slight increase in myocardial capillary density and the special distribution pattern of coronary blood vessels in DanShen-treated rats.

Topics: Animals; Antioxidants; Capillaries; Cardiotonic Agents; Catalase; Coronary Vessels; Endothelial Growth Factors; Glutathione Peroxidase; Glutathione Transferase; Intercellular Signaling Peptides and Proteins; Liver; Lymphokines; Myocardial Infarction; Myocardium; Organ Size; Phytotherapy; Plant Extracts; Ramipril; Rats; Rats, Wistar; Renin-Angiotensin System; RNA, Messenger; Salvia miltiorrhiza; Superoxide Dismutase; Survival Rate; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

Topics: Adolescent; Adult; Angiotensin-Converting Enzyme Inhibitors; Coronary Disease; Follow-Up Studies; Humans; Myocardial Infarction; Perindopril; Ramipril; Randomized Controlled Trials as Topic; Research Design; Stroke; Treatment Outcome

Bradykinin is a potent vasoactive peptide that is known to elicit a number of biological responses. A number of peptidases have been identified to possess kininase activity, the inhibition of which increases the availability and effectiveness of kinins. We wished to determine the cardioprotective actions of an aminopeptidase P inhibitor, apstatin alone and in combination with enalapril/lisinopril/ramipril in an in vivo rat model of acute ischemia (30 min) and reperfusion (4 h). Myocardial infarction was produced by occlusion of the left anterior descending coronary artery for 30 min followed by 4 h of reperfusion. Infarct size was measured by using the staining agent 2,3,5-triphenyl tetrazolium chloride (TTC). Lipid peroxide levels in serum and in heart tissue were estimated spectrophotometrically. A lead II electrocardiogram was monitored at various intervals throughout the experiment. Infarct size was reduced to a greater extent with apstatin and with combined inhibition it was further reduced. Infarct size reduction obtained with the combined inhibition came to normal with the prior administration of B2 bradykinin antagonist HOE140 suggests the involvement of bradykinin in the cardioprotective actions of apstatin.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin; Bradykinin Receptor Antagonists; Drug Therapy, Combination; Enalapril; Female; Heart Rate; Lipid Peroxides; Lisinopril; Male; Malondialdehyde; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Peptides; Ramipril; Rats; Rats, Sprague-Dawley; Time Factors

A markedly decreased aortic nitric oxide (NO) availability, probably due to impaired endothelial nitric oxide synthase activity with enhanced O2- and peroxynitrite production, seems to be attributable to endothelial dysfunction in spontaneously hypertensive rats (SHR) with severe congestive heart failure (CHF). In this study, we investigated the chronic effect of the angiotensin-converting enzyme inhibitor, ramipril (RA) and the loop diuretic, frusemide (FU), as well as the combination of both on endothelial NO, O2- and peroxynitrite production in aortae from SHR with failing hearts after myocardial infarction (MI). Heart failure was induced by permanent occlusion of the left coronary artery. SHR were randomised to receive either placebo, RA, (1 mg/kg/day), FU (4 mg/kg/day) or RA+FU (1 and 4 mg/kg/day, respectively). Treatments were started two weeks following MI and continued for six weeks. Reduced aortic and coronary flow indices in the working heart, which can be considered as markers for endothelial function, were significantly normalised and improved, respectively, by RA, FU or RA+FU-treatment. Similarly, all three treatment regimens significantly enhanced the reduced calcium ionophore (CaI)-induced NO-release (assessed by a NO-sensitive microsensor) from aortic endothelial cells of placebo-treated animals with CHF. Concomitantly, the increased CaI-stimulated O2- production (assessed by an electrochemical sensor) in aortic endothelial cells of placebo-treated animals with CHF was significantly reduced by RA and RA+FU-treatment. Treatment with RA and RA+FU also attenuated the dramatic increase in endothelial peroxynitrite concentration (chemiluminescence method), which was observed in placebo-treated rats with CHF. FU did not counteract improved haemo- and cardiodynamic parameters by RA. Thus, RA and FU act synergistically to enhance bioavailability of endothelium-derived NO, and this may contribute to the clinical usefulness of the combination of these drugs in treatment of heart failure.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Coronary Circulation; Endothelium, Vascular; Heart Failure; Heart Rate; Hypertension; Male; Myocardial Contraction; Myocardial Infarction; Nitric Oxide; Peroxynitrous Acid; Ramipril; Rats; Rats, Inbred SHR; Reactive Oxygen Species

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Clinical Trials as Topic; Follow-Up Studies; Hospital Mortality; Humans; Myocardial Infarction; Placebos; Prognosis; Ramipril; Risk Factors; Time Factors

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Arteriosclerosis; Diabetes Mellitus; Disease Models, Animal; Humans; Hypertension; Imidazoles; Myocardial Infarction; Olmesartan Medoxomil; Rabbits; Ramipril; Rats; Tetrazoles; Time Factors

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Benzimidazoles; Benzoates; Clinical Trials as Topic; Drug Therapy, Combination; Heart Failure; Humans; Hypertension; Myocardial Infarction; Ramipril; Receptor, Angiotensin, Type 1; Stroke; Telmisartan; Treatment Outcome

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Benzimidazoles; Benzoates; Cardiovascular Diseases; Diabetes Complications; Drug Therapy, Combination; Humans; Myocardial Infarction; Placebos; Ramipril; Randomized Controlled Trials as Topic; Risk Factors; Telmisartan; Time Factors

To estimate the cost-effectiveness of adding ramipril to conventional treatment in patients with heart failure after myocardial infarction from the perspective of the Spanish National Health System.. A retrospective analysis of the AIRE study was made, using previously published data from the clinical trial combined with local Spanish resource and cost data. A typical rehospitalisation for a heart failure episode would last an average of 11.6 days with an average cost of 350.80 per day. The incremental cost of ramipril per life-year gained in the baseline case was 1550.10 after 3.8 years of follow-up. Sensitivity analysis showed that the basic conclusions were robust in spite of extreme variations in the values of the key parameters of the model.. The use of ramipril in addition to conventional treatment in heart failure patients after myocardial infarction is cost-effective both according to currently accepted international standards of what constitutes a cost-effective intervention and also indirectly by comparing the results with similar pharmaceutical products financed under the Spanish National Health System.

Topics: Angiotensin-Converting Enzyme Inhibitors; Clinical Trials as Topic; Cost-Benefit Analysis; Drug Therapy, Combination; Heart Failure; Humans; Length of Stay; Myocardial Infarction; Patient Readmission; Ramipril; Retrospective Studies; Spain

Topics: Angiotensin-Converting Enzyme Inhibitors; Arteriosclerosis; Cerebral Infarction; Clinical Trials as Topic; Humans; Myocardial Infarction; Ramipril; Risk Factors; Simvastatin

We examined the impact of treatment with ramipril versus other angiotensin-converting enzyme (ACE) inhibitors on clinical outcome in unselected patients of the prospective multicenter registry Maximal Individual Therapy of Acute Myocardial Infarction PLUS registry (MITRA PLUS). Of 14,608 consecutive patients with ST-elevation acute myocardial infarction, 4.7% received acute therapy with ramipril, 39.0% received other ACE inhibitor therapy, and 56.3% received no ACE inhibitor therapy. In a multivariate analysis, the treatment with ramipril compared with the treatment without ACE inhibitors was associated with a significantly lower hospital mortality and a lower rate of nonfatal major adverse coronary and cerebrovascular events. Compared with other generic ACE inhibitors, ramipril therapy was independently associated with a significantly lower hospital mortality (odds ratio [OR] 0.54, 95% confidence interval [CI] 0.32 to 0.90) and a lower rate of nonfatal major adverse coronary and cerebrovascular events (OR 0.65, 95% CI 0.46 to 0.93), but not with a lower rate of heart failure at discharge (OR 0.79, 95% CI 0.50 to 1.27).

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Female; Germany; Hospital Mortality; Hospitalization; Humans; Male; Multivariate Analysis; Myocardial Infarction; Odds Ratio; Outcome Assessment, Health Care; Patient Selection; Ramipril; Registries; Retrospective Studies; Survival Analysis

Topics: Angiotensin-Converting Enzyme Inhibitors; Heart Failure; Humans; Hypertrophy, Left Ventricular; Myocardial Infarction; Ramipril; Stroke

Extracellular matrix (ECM) remodeling and increased matrix metalloproteinase (MMP) expression and activity have been observed to be relevant in the development of heart failure (HF). We examined the effects of ramipril alone or with furosemide on ECM in a heart failure model. HF was induced by occlusion of the left coronary artery in spontaneously hypertensive rats (SHR). Rats were assigned to placebo (n=9), ramipril 1 mg/kg/day (n=11), furosemide 2 x 2 mg/kg/day (n=7) or both (1 mg/kg/day + 2 x 2 mg/kg/day n=8). LV-function, collagen content, MMP/TIMP (tissue inhibitor of matrix metalloproteinases) protein- and mRNA-expression were examined in non-infarcted LV tissue. MMP-2/TIMP-4 ratio was increased in HF. Ramipril reduced MMP-2 expression (active form), collagen type I mRNA expression and content and increased TIMP-4 levels associated with decreased left ventricular end diastolic pressure (LVEDP), mortality rate and increased LV pressure (LVP). Combination therapy with furosemide is less efficient with regard to collagen content and MMP-2 (active form) reduction but did not worsen beneficial effects of ramipril on LV function and mortality rate. Furosemide alone had no effect on MMP-2 (active form) expression, collagen content, LV function and mortality rate. Prevention of LV dilatation by ramipril was associated with decreased gelatinolytic activity and increased MMP-inhibition in heart failure SHR. Furthermore, ramipril reduced fibrosis by enhanced interstitial collagenase expression. Furosemide did not show the beneficial effects of ramipril on ECM remodeling but did not worsen LV function. Positive effects of furosemide treatment alone on LV remodeling and function were not observed.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Diuretics; Extracellular Matrix; Extracellular Matrix Proteins; Furosemide; Heart; Heart Failure; Male; Metalloendopeptidases; Myocardial Infarction; Myocardium; Ramipril; Rats; Rats, Inbred SHR; Ventricular Remodeling

Heart rate variability (HRV) is a measure of cardiac autonomic control and is therefore subject to regulation by the renin-angiotensin system. The primary objective of this study was to determine the effect of an insertion/deletion polymorphism within the angiotensin-converting enzyme (ACE) gene on HRV in the early stages after a myocardial infarction at a time when cardiac autonomic control is deranged. The secondary objective was to determine whether this polymorphism affected the HRV response to inhibition of ACE.. 149 Caucasian subjects were studied 25 +/- 16 h following MI using time and frequency domain measures of HRV derived from two 5-minute ECG recordings. Recordings were repeated at 182 +/- 65 h following MI, when subjects had been stabilised on ramipril 2.5 mg bd. The study included 46 subjects with the DD genotype, 69 with the ID genotype, and 34 with the II genotype. No effect of the I/D polymorphism on short-term recordings of HRV was found. There was no difference in HRV response to the introduction of ramipril according to the genotypes.. The I/D polymorphism within the ACE gene does not influence HRV after MI or the HRV response to ACE inhibitor therapy with ramipril. These findings may reflect the relative lack of importance of the I/D polymorphism and ACE activity in determining plasma and tissue angiotensin II concentration after a major stimulus to the renin-angiotensin system as occurs after myocardial infarction.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Female; Genotype; Heart Rate; Humans; Male; Middle Aged; Myocardial Infarction; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Ramipril; Renin-Angiotensin System

Several reports indicate the benefit of ACE inhibitors for patients with left ventricular systolic dysfunction after acute myocardial infarction (MI). We sought to determine the implementation of the treatment guidelines in patient samples from the general population. Furthermore we aimed to identify patient characteristics associated with the use of ACE inhibitors. Screening of two MI-registries allowed the identification of 226 MI patients with left ventricular dysfunction. Patients were considered to be eligible for ACE inhibitor therapy when a EF < or = 40% was documented in the patient records of cardiac rehabilitation clinics (REG-MI, n = 147) or detected by standardised echocardiography (KORA, n = 78). On average 5.5 years following MI, a standardised questionnaire and a detailed medical history was obtained. Specifically, information was collected regarding current medication and potential contraindications for ACE inhibitors. MI patients with LV dysfunction received ACE inhibitors in 62% (REG-MI) and 45% (KORA). The doses prescribed were substantially smaller than target doses used in the large-scale studies (REG-MI: 40 +/- 4%, KORA: 23 +/- 3%, % of target doses). Only 13% (REG-MI) and 3% (KORA) received more than 50% of the target dosage. Additionally, actual doses of the most frequently used ACE inhibitors were significantly different (captopril: 23 +/- 2%, enalapril: 42 +/- 5% of target doses). The likelihood of receiving ACE inhibitors was significantly higher in patients with written recommendation for such medication (odds ratio 6.02, confidence interval 1.93-20.16) and in patients visiting cardiologists (odds ratio 3.69, confidence interval 1.26-11.07) as revealed by multivariate analysis of the REG-MI database. Despite national and international guidance, a large proportion of MI patients with left ventricular dysfunction is not receiving ACE inhibitors, and when used, the doses prescribed are markedly smaller than target doses used in clinical trials that established the utility of these drugs. Medical care by cardiologists and written recommendation of ACE inhibition in patient records were independent predictors of a more appropriate prescription of ACE inhibitors.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Captopril; Clinical Trials as Topic; Confidence Intervals; Echocardiography; Enalapril; Female; Follow-Up Studies; Humans; Male; Middle Aged; Myocardial Infarction; Odds Ratio; Practice Guidelines as Topic; Ramipril; Registries; Sampling Studies; Surveys and Questionnaires; Time Factors; Ventricular Dysfunction, Left

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Captopril; Cardiovascular Diseases; Clinical Trials as Topic; Enalapril; Heart Failure; Humans; Indoles; Isoquinolines; Myocardial Infarction; Perindopril; Prodrugs; Quinapril; Ramipril; Stroke; Stroke Volume; Tetrahydroisoquinolines; Treatment Outcome; Ventricular Dysfunction, Left

Topics: Angiotensin-Converting Enzyme Inhibitors; Arteriosclerosis; Clinical Trials as Topic; Diabetic Angiopathies; Humans; Myocardial Infarction; Ramipril

Using B(2) kinin receptor gene knockout mice (B(2)(-/-)), we tested the hypothesis that (l) lack of B(2) receptors may affect blood pressure and cardiac function and aggravate cardiac remodeling after myocardial infarction (MI), and (2) kinins partially mediate the cardiac beneficial effect of angiotensin-converting enzyme inhibitors (ACEi) or angiotensin II type 1 receptor antagonists (AT(1)-ant), whereas lack of B(2) receptors may diminish this cardioprotective effect. Chronic heart failure (HF) was induced by MI, which was caused by coronary artery ligation in both B(2)(-/-) and 129/SvEvTac mice (wild-type control, B(2)(+/+)). An ACEi (ramipril, 2.5 mg/kg/d) or AT(1)-ant (L-158809, 3 mg/kg/d) was given 1 week after MI and was continued for 12 weeks. Left ventricular (LV) ejection fraction, cardiac output (CO), diastolic LV dimension (LVDd), and LV mass were evaluated by echocardiography. Myocyte cross-sectional area and interstitial collagen fraction were studied histopathologically. We found that basal blood pressure and cardiac function were similar in B(2)(+/+) and B(2)(-/-) mice. After MI, development of HF and remodeling were also similar between the 2 strains. The ACEi improved cardiac function and remodeling in both strains; however, its effects were attenuated in B(2)(-/-) mice (respective values for B(2)(+/+) versus B(2)(-/-) mice: overall increase in ejection fraction, 64+/-10% versus 21+/-5% [P<0.01]; increase in CO, 69+/-17% versus 23+/-9% [P<0.01]; overall decrease in LVDd, -24+/-3% versus -7+/-4% [P<0.01]; and decrease in LV mass, -38+/-3% versus -6+/-6% [P<0.01]). AT(1)-ant had a beneficial cardiac effect similar to that produced by ACEi, and this effect was also diminished in B(2)(-/-) mice (respective values for B(2)(+/+) versus B(2)(-/-) mice: overall increase in ejection fraction, 46+/-10% versus 25+/-9% [P<0.01]; increase in CO, 44+/-14% versus 15+/-5% [P<0.01]; overall decrease in LVDd, -14+/-4% versus -6+/-3% [P<0.01]; and decrease in LV mass, -33+/-4 versus -16+/-7% [P<0.01]). The effect of ACEi or AT(1)-ant on myocyte cross-sectional area was similar between strains; however, their effect on the interstitial collagen fraction was diminished in B(2)(-/-) mice. We concluded that (1) lack of B(2) kinin receptors does not affect cardiac phenotype or function, either under normal physiological conditions or during the development of HF; and (2) kinins acting via the B(2) receptor play an important role in the cardioprotective effect

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Collagen; Cytoprotection; Disease Models, Animal; Disease Progression; Enzyme Inhibitors; Heart Failure; Heart Function Tests; Imidazoles; Mice; Mice, Inbred Strains; Mice, Knockout; Myocardial Infarction; Myocardium; Ramipril; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptor, Bradykinin B2; Receptors, Bradykinin; Tetrazoles; Ventricular Remodeling

In an ovine model of left ventricular (LV) remodeling after transmural anteroapical myocardial infarction (MI), we have previously demonstrated that the combination of angiotensin converting enzyme (ACE) inhibition and AT(1) receptor blockade is more effective at limiting LV remodeling than either therapy alone. We hypothesized that the beneficial effect of combined therapy is due in part to upregulation of AT(2) receptor levels.. Two days after transmural anteroapical MI by coronary ligation, 16 sheep were randomized to losartan (50 mg/day), ramipril (10 mg/day), ramipril+losartan (combined therapy), or no therapy. At 8 weeks after MI, radioligand receptor assay were deployed with homogenates from regional LV tissues.. We found that AT receptors in normal sheep myocardium are predominantly of the AT(2) receptor subtype. Binding studies of remodeled myocardium 8 weeks later showed that the apparent maximum binding (B(max)) was increased from 23 to 48 fmol/mg protein only in animals with combined therapy. The AT(2)/AT(1) proportion was increased significantly in animals with combined therapy compared to infarcted controls (18.0 vs. 5.17).. These results indicate that AT(2) receptor expression increased significantly during LV remodeling with combined therapy but not with either therapy alone. In combination with prior work demonstrating the effectiveness of combined therapy in limiting LV remodeling, this study is consistent with the hypothesis that AT(2) receptors play a cardioprotective role in LV remodeling after MI.

Topics: Analysis of Variance; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Drug Therapy, Combination; Female; Imidazoles; Losartan; Models, Animal; Myocardial Infarction; Myocardium; Pyridines; Radioligand Assay; Ramipril; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Regression Analysis; Sheep; Ventricular Remodeling

ACE inhibition (ACEI) attenuates post-myocardial infarction (MI) LV remodeling, but the effects of angiotensin II type 1 receptor (AT(1)) antagonism alone or in combination with ACEI are unclear. Accordingly, we investigated the effects of AT(1) antagonism, ACEI, and their combination in a well-characterized ovine postinfarction model.. Beginning 2 days after transmural anteroapical MI, 62 sheep were treated with 1 of 5 treatment regimens: no therapy (control, n=12), standard-dose ACEI (sACEI; ramipril 10 mg/d, n=14), high-dose ACEI (hACEI; ramipril 20 mg/d, n=8), AT(1) blockade (losartan 50 mg/d, n=13), and combination therapy with sACEI+AT(1) blockade (CT; ramipril 10 mg/d+losartan 50 mg/d, n=15). MRI was performed before and 8 weeks after MI to quantify changes in LV end-diastolic and end-systolic volume indices (DeltaEDVI, DeltaESVI) and ejection fraction (DeltaEF). Change in regional percent intramyocardial circumferential shortening in noninfarcted segments adjacent to the infarct (Adj Delta%S) was measured by tagged MRI. CT resulted in the most marked blunting of LV remodeling: DeltaESVI (+1.0+/-0.4, +0.7+/-0.4, +0.6+/-0.3, +0.9+/-0.5, and +0.4+/-0.2* mL/kg); DeltaEDVI (+0.9+/-0.4, +0.7+/-0.5, +0.6+/-0.5, +0.9+/-0.5, and +0.4+/-0.3 mL/kg); DeltaEF (-24+/-7, -18+/-6, -14+/-7, -18+/-10, and -11+/-9* %); and Adj Delta%S (-8+/-4, -7+/-3, -5+/-3, -5+/-3, and -2+/-3* %) for Control, sACEI, hACEI, AT(1) blockade, and CT, respectively (*P<0.04 versus sACEI, AT(1) blockade, and control; P<0.05 versus control; P<0.002 versus AT(1) blockade and control). EDVI and ESVI at 8 weeks after MI were smallest with CT (P<0.02 versus all).. Combination therapy with sACEI+AT(1) blockade shows promise in attenuating postinfarction LV remodeling but was not clearly superior to hACEI in the present study.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Electrocardiography; Female; Image Processing, Computer-Assisted; Losartan; Magnetic Resonance Imaging, Cine; Myocardial Infarction; Myocardium; Ramipril; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Sheep; Stroke Volume; Systole; Ventricular Function, Left; Ventricular Remodeling

Inhibitors of bradykinin (BK)-inactivating enzymes protect from myocardial ischemia/reperfusion injury after short periods of reperfusion. However, protection after 2 to 3 h of reperfusion does not mean that myocardium remains viable for an extended time. Therefore, we examined the effects of inhibitors of angiotensin-converting enzyme (ramiprilat), EP24.11 (cFP-F-pAB), and EP24.15 (cFP-AAF-pAB) in a chronic model of myocardial ischemia/reperfusion injury. A left descending coronary artery was occluded for 30 min in anesthetized rabbits. Saline, ramiprilat, or endopeptidase inhibitors were given after 27 min of occlusion. The BK(2) receptor antagonist HOE140 was administered in certain experiments. After ischemia, the occlusion was released, and the animal allowed to recover for 3 or 7 days. Surgery was then repeated, and the heart removed for determination of infarct size. In separate experiments, the heart was removed after 2 h of reperfusion for determination of BK tissue levels. Ramiprilat and endopeptidase inhibitors reduced infarct size at 3 and 7 days. Combining inhibitors further reduced infarct size after 3 days. The protective effect of the endopeptidase inhibitors was blocked by HOE140. Infarct sizes at 7 days were larger than at 3 days. The additive effect of multiple inhibitors was absent at 7 days. Ramiprilat and cFP-F-pAB significantly increased tissue BK levels. We conclude that inhibition of BK-inactivating enzymes protects endogenous BK from degradation and provides long-lasting protection from myocardial ischemia/reperfusion injury. A single treatment at the time of reperfusion does not prevent extension of the infarction between 3 and 7 days.

Topics: 4-Aminobenzoic Acid; Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin; Female; Heart Ventricles; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Oligopeptides; para-Aminobenzoates; Phenylalanine; Protease Inhibitors; Rabbits; Ramipril; Sex Characteristics; Time Factors

1. Inhibitors of the angiotensin converting enzyme (ACE) have been shown to exert their cardioprotective actions through a kinin-dependent mechanism. ACE is not the only kinin degrading enzyme in the rat heart. 2. Since aminopeptidase P (APP) has been shown to participate in myocardial kinin metabolism to the same extent as ACE, the aims of the present study were to investigate whether (a) inhibition of APP leads to a reduction of myocardial infarct size in a rat model of acute ischaemia and reperfusion, (b) reduction of infarct size is mediated by bradykinin, and (c) a combination of APP and ACE inhibition leads to a more pronounced effect than APP inhibition alone. 3. Pentobarbital-anaesthetized rats were subjected to 30 min left coronary artery occlusion followed by 3 h reperfusion. The APP inhibitor apstatin, the ACE-inhibitor ramiprilat, or their combination were administered 5 min before ischaemia. Rats receiving HOE140, a specific B(2) receptor antagonist, were pretreated 5 min prior to enzyme inhibitors. Myocardial infarct size (IS) was determined by tetrazolium staining and expressed as percentage of the area at risk (AAR). 4. IS/AAR% was significantly reduced in rats that received apstatin (18+/-2%), ramiprilat (18+/-3%), or apstatin plus ramiprilat (20+/-4%) as compared with those receiving saline (40+/-2%), HOE (43+/-3%) or apstatin plus HOE140 (49+/-4%). 5. Apstatin reduces IS in an in vivo model of acute myocardial ischaemia and reperfusion to the same extent than ramiprilat. Cardioprotection achieved by this selective inhibitor of APP is mediated by bradykinin. Combined inhibition of APP and ACE did not result in a more pronounced reduction of IS than APP-inhibition alone.

Topics: Aminopeptidases; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Bradykinin; Bradykinin Receptor Antagonists; Heart; Heart Rate; Hemodynamics; Kinins; Male; Myocardial Infarction; Myocardium; Peptides; Protease Inhibitors; Ramipril; Rats; Rats, Wistar; Receptor, Bradykinin B2

Topics: Angiotensin-Converting Enzyme Inhibitors; Humans; Hypertension; Myocardial Infarction; Ramipril; Randomized Controlled Trials as Topic; Recurrence; Risk Factors; Stroke

Topics: Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Diabetes Complications; Diabetes Mellitus; Humans; Myocardial Infarction; Ramipril; Risk Factors; Stroke

The effects of chronic treatment with the beta-adrenoceptor antagonist metoprolol, the angiotensin converting enzyme inhibitor ramipril, their combination, or placebo on action potential configuration 6 weeks after myocardial infarction in rats were studied. Action potentials were measured in isolated left ventricular posterior papillary muscles and compared with action potentials from a sham operated group without infarction. After infarction, the action potential amplitude was reduced and this phenomenon was partially reversed by metoprolol- and ramipril-treatment. Prolonged repolarisation after infarction compared to sham operated animals was additionally delayed after metoprolol treatment. Thus, metoprolol extends the refractory period, which may counteract tachyarrhythmia.

Topics: Action Potentials; Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Electric Stimulation; Heart; Male; Metoprolol; Myocardial Infarction; Ramipril; Rats; Rats, Wistar

Topics: Angiotensin-Converting Enzyme Inhibitors; Coronary Disease; Humans; Middle Aged; Myocardial Infarction; Ramipril

The effects of the angiotensin-converting-enzyme inhibitor (ACEI) ramiprilat, the angiotensin II type 1 receptor antagonist (AT(1)A) candesartan, and the combination of both drugs on infarct size (IS) resulting from regional myocardial ischaemia were studied in pigs. Both ACEI and AT(1)A reduce myocardial IS by a bradykinin-mediated process. It is unclear, however, whether the combination of ACEI and AT(1)A produces a more pronounced IS reduction than each of these drugs alone. Forty-six enflurane-anaesthetized pigs underwent 90 min low-flow ischaemia and 120 min reperfusion. Systemic haemodynamics (micromanometer), subendocardial blood flow (ENDO, microspheres) and IS (TTC-staining) were determined. The decreases in left ventricular peak pressure by ACEI (by 9+/-2 (s.e. mean) mmHg), AT(1)A (by 11+/-2 mmHg) or their combination (by 18+/-3 mmHg, P<0.05 vs ACEI and AT(1)A, respectively) were readjusted by aortic constriction prior to ischaemia. With placebo (n=10), IS averaged 20.0+/-3.3% of the area at risk. IS was reduced to 9.8+/-2.6% with ramiprilat (n=10) and 10.6+/-3.1% with candesartan (n=10). Combined ramiprilat and candesartan (n=10) reduced IS to 6.7+/-2.1%. Blockade of the bradykinin-B(2)-receptor with icatibant prior to ACEI and AT(1)A completely abolished the reduction of IS (n=6, 22.8+/-6.1%). The relationship between IS and ischaemic ENDO with placebo was shifted downwards by each ACEI and AT(1)A and further shifted downwards with their combination (P<0.05 vs all groups); icatibant again abolished such downward shift. The combination of ACEI and AT(1)A enhances the reduction of IS following ischaemia/reperfusion compared to a monotherapy by either drug alone; this effect is mediated by bradykinin.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzimidazoles; Biphenyl Compounds; Drug Therapy, Combination; Hemodynamics; Myocardial Infarction; Ramipril; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Swine; Tetrazoles

We tested the hypothesis that a combination of angiotensin-converting enzyme inhibitor (ACEi) and angiotensin II type 1 receptor antagonist (AT1-ant) may have an additive cardioprotective effect in mice with heart failure (HF), because these two agents could have other mechanisms of action besides interrupting the renin-angiotensin system. ACEi prevent degradation of bradykinin. During treatment with AT1-ant, increased angiotensin II could activate AT2 receptors, with an antitrophic effect. To test this hypothesis, we used a mouse model of HF induced by myocardial infarction. Seven days after surgery, mice were divided into six groups and treated for 23 weeks: (a) sham ligation; (b) HF-vehicle; (c) HF-ACEi; (d) HF-AT1-ant; (e) HF-ACEi + AT1-ant (half dose of each); and (f) HF-ACEi + AT1-ant (full dose of each). Cardiac function was evaluated in conscious mice during the treatment period. The HF-vehicle group showed significantly decreased left ventricular (LV) ejection fraction (EF), shortening fraction (SF), and cardiac output (CO) and increased LV dimensions, interstitial collagen, and myocyte cross-sectional area (MCSA) compared with controls. Treatment with ACEi or AT1-ant significantly increased EF, SF, and CO and decreased LV dimensions and MCSA in mice with HF. However, a combination of these drugs did not improve cardiac function more than ACEi or AT1-ant alone. We concluded that ACEi and AT1-ant have similar cardioprotective effects and may reach maximal effect when given individually; thus no further improvement can be achieved with combined therapy in mice with HF.

Topics: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Cardiac Output; Chronic Disease; Echocardiography; Female; Heart; Heart Failure; Imidazoles; Male; Mice; Mice, Inbred C57BL; Myocardial Infarction; Myocardium; Organ Size; Ramipril; Stroke Volume; Tetrazoles; Ventricular Remodeling

Topics: Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Nephropathies; Humans; Male; Middle Aged; Myocardial Infarction; Ramipril; Randomized Controlled Trials as Topic; Treatment Outcome

Beneficial effects of monotherapy with ACE inhibitors or beta-blockers on hemodynamic function after myocardial infarction are well known. Until now, the effects of combined treatment on cardiac function and energy metabolism have been poorly described. This study examines the effects of combined ramipril and metoprolol treatment on the creatine kinase (CK) system and hemodynamic function in rats after infarction. Wistar rats with experimental infarction were randomized for treatment with ramipril (R), metoprolol (M), combined treatment (MR), or placebo (P). Sham-operated (SO) animals served as controls. After 6 weeks, we assayed for CK isoenzymes and performed hemodynamic measurements. In P versus SO, left ventricular systolic pressures (dp/dt(max) and dp/dt(min)) diminished, whereas left ventricular end-diastolic pressure (LVEDP) increased. Decreased total CK activity and mitochondrial CK isoenzyme, increased CK-MB, and increased CK-BB isoenzymes were measured in P versus SO. With infarct size < or =45%, mitochondrial CK increased in M and R versus P. Combined treatment had an additional enhancing effect on mitochondrial CK isoenzyme level versus M and R, decreased LVEDP versus P, as well as increased dp/dt(max) and dp/dt(min) versus R. These results provide evidence of an interaction between normalization of energy metabolism and improvement in cardiac function due to a combination of ACE inhibition and beta blockade after myocardial infarction.

Topics: Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Cardiomegaly; Creatine Kinase; Drug Therapy, Combination; Hemodynamics; L-Lactate Dehydrogenase; Male; Metoprolol; Myocardial Infarction; Ramipril; Rats; Rats, Wistar; Ventricular Function, Left

The effect of beta-blockade on left ventricular (LV) remodeling, when added to angiotensin-converting enzyme inhibition (ACEI) after anterior myocardial infarction (MI), is incompletely understood. On day 2 after coronary ligation-induced anteroapical infarction, 17 sheep were randomized to ramipril (ACEI, n = 8) or ramipril and metoprolol (ACEI-beta, n = 9). Magnetic resonance imaging was performed before and 8 wk after MI to measure changes in LV end-diastolic, end-systolic, and stroke volume indexes, LV mass index, ejection fraction (EF), and regional percent intramyocardial circumferential shortening. (123)I-labeled m-iodobenzylguanidine (MIBG) and fluorescent microspheres before and after adenosine were infused before death at 8 wk post-MI for quantitation of sympathetic innervation, blood flow, and blood flow reserve in adjacent and remote noninfarcted regions. Infarct size, regional blood flow, blood flow reserve, and the increase in LV mass and LV end-diastolic and end-systolic volume indexes were similar between groups. However, EF fell less over the 8-wk study period in the ACEI-beta group (-13 +/- 11 vs. -22 +/- 4% in ACEI, P < 0.05). The ratio of adjacent to remote region (123)I-MIBG uptake was greater in ACEI-beta animals than in the ACEI group (0.93 +/- 0.06 vs. 0.86 +/- 0.07, P < 0.04). When added to ACE inhibition after transmural anteroapical MI, beta-blockade improves EF and adjacent regional sympathetic innervation but does not alter LV size.

Topics: Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Female; Heart Conduction System; Hemodynamics; Magnetic Resonance Imaging; Metoprolol; Myocardial Infarction; Ramipril; Sheep; Stroke Volume; Sympathetic Nervous System; Ventricular Remodeling

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Female; Health Education; Humans; Male; Middle Aged; Myocardial Infarction; Ramipril; Risk Factors; Stroke; United States

To study the early changes of cardiac angiotensin (Ang) II receptor gene transcription after myocardial infarction (MI) in rats chronically treated with the angiotensin-converting enzyme (ACE) inhibitor ramipril.. MI was induced by left anterior descending coronary artery ligation in rats and sham-operated rats were used as control. Rats were treated daily with ramipril (1 mg.kg-1) or water, initiated 1 wk before surgery. Quantitative RT-PCR was applied to determine the Ang II receptors AT1, AT2 receptor gene mRNA levels in the non-infarcted myocardium.. AT1 and AT2 mRNA levels increased time point-dependently in the cardiac septum after MI reaching a peak on d 1. There was no significant difference of the myocardial AT1 and AT2 receptor mRNA levels between the ramipril-treated and water-treated rats after MI.. The AT1 and AT2 receptor gene transcription in the non-infarcted myocardium was associated with the process of cardiac remodeling after MI but not affected by ACE inhibition.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Heart Septum; Male; Myocardial Infarction; Ramipril; Rats; Rats, Wistar; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; RNA, Messenger; Transcription, Genetic; Ventricular Remodeling

Cardioprotective effects of the angiotensin-converting enzyme inhibitors captopril and ramiprilat were studied in two in vivo canine models of myocardial ischemic injury: 90 min of regional ischemia with 18 h reperfusion (protocol I) and 6 h of continuous ischemia without reperfusion (protocol II). In protocol I, neither ramiprilat (50 micrograms/kg) nor captopril (5 mg/kg + 0.25 mg/kg/h) reduced infarct size after 18 h of reperfusion (vs. controls). In protocol II, drugs were administered directly into both left anterior descending coronary artery and left circumflex branch. Compared to controls, continuous intracoronary administration of ramiprilat (40 ng/kg/min) or captopril (400 ng/kg/min) did not reduce infarct size. Thus neither captopril nor ramiprilat protected the heart from injury under conditions of ischemia with reperfusion or ischemia without reperfusion.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Captopril; Coronary Circulation; Coronary Vessels; Disease Models, Animal; Dogs; Evaluation Studies as Topic; Heart Rate; Hemodynamics; Male; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion; Myocardial Reperfusion Injury; Ramipril

Hypertensive patients with left ventricular hypertrophy (LVH) have been found to have greater peri-infarction and postinfarction mortality. In this study, we evaluated the postinfarction survival, susceptibility to ventricular arrhythmias, and degree of LVH and cardiac fibrosis in the spontaneously hypertensive rat (SHR) and the effects of the ACE inhibitor ramipril and the direct vasodilator hydralazine on these characteristics.. An acute myocardial infarction (MI) was produced by ligation of the left anterior descending coronary artery. Rats were randomized to either control (n=50), hydralazine (n=41), or ramipril (n=45). Treatments were started 4 hours after infarction and continued for 8 weeks. Ramipril and hydralazine reduced arterial pressure similarly. Medications were stopped 72 hours before euthanasia, at which time hemodynamic, programmed electrophysiological stimulation (PES), and morphological studies were performed. Mortality was decreased in ramipril (56%) compared with hydralazine (78%) and control (82%) SHRs (P=0.008). This was accompanied by a decrease in myocardial hypertrophy and fibrosis and a decrease in inducibility of ventricular arrhythmias by PES in the ramipril group regardless of MI size. Treatment with hydralazine had little or no effect on LVH and cardiac fibrosis and did not modify inducibility of ventricular arrhythmias by PES. Ramipril but not hydralazine prevented the increase in LV end-diastolic pressure in rats with large MIs.. In the SHR, the ACE inhibitor ramipril reduces LVH, cardiac fibrosis, and susceptibility to ventricular arrhythmias by PES and improves survival and LV function. Despite a similar decrease in arterial pressure, hydralazine does not have these beneficial effects.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Arrhythmias, Cardiac; Blood Pressure; Cardiac Pacing, Artificial; Fibrosis; Heart Rate; Hemodynamics; Hydralazine; Hypertrophy, Left Ventricular; Male; Myocardial Infarction; Myocardium; Ramipril; Rats; Rats, Inbred SHR; Survival Analysis; Vasodilator Agents

Data from the Acute Infarction Ramipril Efficacy (AIRE) study were used in a cost-effectiveness analysis to determine the incremental cost per life-year gained (LYG) when the ACE inhibitor ramipril was added to conventional treatment in patients with heart failure after acute myocardial infarction. In the AIRE trial, the addition of ramipril significantly lowered rates of total mortality and rehospitalisation due to heart failure.. The cost-effectiveness analysis was conducted from the perspective of the Statutory Health Insurance (SHI) provider in Germany. A modelling approach was used which was based on secondary analysis of existing data, and costs were those incurred by SHI (i.e. expenses of SHI). In the base-case analysis, average case-related expenses of SHI were applied and LYG were quantified by the method of Kaplan and Meier.. The incremental cost-effectiveness ratios of ramipril varied between 2500 and 8300 deutschmarks (DM) per LYG (1993 values for inpatient and 1995 values for outpatient treatment; DM1 approximately $US0.70), according to the treatment periods of 3.8 years and 1 year, respectively. In the sensitivity analysis, the robustness of the model and its results was shown when the extent of influence of different model variables on the base-case results was investigated. First, survival probability and LYG were estimated according to the Weibull method. Second, the dependency of the target variable (i.e. incremental cost per LYG) on random variables was described in a simulation. Third, the influence of the model variables on the target variable was quantified using a deterministic model. The variance of the target variable was broad and the hospitalisation impact of adding ramipril to conventional treatment was an independent variable with much greater influence on the target variable than the parameter of clinical effectiveness, i.e. the number of LYG.. Results of this evaluation showed that ramipril has a favourable incremental cost-effectiveness ratio for the treatment of heart failure in post myocardial infarction patients and can be considered an economical therapeutic agent from the perspective of SHI (third-party payer) in Germany.

Topics: Angiotensin-Converting Enzyme Inhibitors; Cost-Benefit Analysis; Germany; Heart Failure; Humans; Models, Economic; Myocardial Infarction; Outpatients; Patient Admission; Ramipril; Retrospective Studies

Topics: Angiotensin-Converting Enzyme Inhibitors; Cause of Death; Death, Sudden, Cardiac; Heart Failure; Humans; Myocardial Infarction; Ramipril; Risk Factors; Treatment Outcome

Angiotensin-converting enzyme inhibitors (ACEi) improve cardiac function and remodeling and prolong survival in patients with heart failure (HF). Blockade of the renin-angiotensin system (RAS) with an angiotensin II type 1 receptor antagonist (AT1-ant) may have a similar beneficial effect. In addition to inhibition of the RAS, ACEi may also act by inhibiting kinin destruction, whereas AT1-ant may block the RAS at the level of the AT1 receptor and activate the angiotensin II type 2 (AT2) receptor. Using a model of HF induced by myocardial infarction (MI) in rats, we studied the role of kinins in the cardioprotective effect of ACEi. We also investigated whether an AT1-ant has a similar effect and whether these effects are partly due to activation of the AT2 receptor. Two months after MI, rats were treated for 2 mo with: (a) vehicle; (b) the ACEi ramipril, with and without the B2 receptor antagonist icatibant (B2-ant); or (c) an AT1-ant with and without an AT2-antagonist (AT2-ant) or B2-ant. Vehicle-treated rats had a significant increase in left ventricular end-diastolic (LVEDV) and end-systolic volume (LVESV) as well as interstitial collagen deposition and cardiomyocyte size, whereas ejection fraction was decreased. Left ventricular remodeling and cardiac function were improved by the ACEi and AT1-ant. The B2-ant blocked most of the cardioprotective effect of the ACEi, whereas the effect of the AT1-ant was blocked by the AT2-ant. The decreases in LVEDV and LVESV caused by the AT1-ant were also partially blocked by the B2-ant. We concluded that (a) in HF both ACEi and AT1-ant have a cardioprotective effect, which could be due to either a direct action on the heart or secondary to altered hemodynamics, or both; and (b) the effect of the ACEi is mediated in part by kinins, whereas that of the AT1-ant is triggered by activation of the AT2 receptor and is also mediated in part by kinins. We speculate that in HF, blockade of AT1 receptors increases both renin and angiotensins; these angiotensins stimulate the AT2 receptor, which in turn may play an important role in the therapeutic effect of the AT1-ant via kinins and other autacoids.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin; Bradykinin Receptor Antagonists; Cardiovascular System; Disease Models, Animal; Drug Interactions; Heart Failure; Imidazoles; Kinins; Male; Models, Cardiovascular; Myocardial Infarction; Myocardium; Pyridines; Ramipril; Rats; Rats, Inbred Lew; Receptor, Angiotensin, Type 1; Tetrazoles

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Heart Failure; Humans; Myocardial Infarction; Ramipril

We hypothesized that angiotensin-converting enzyme inhibitors would limit dysfunction in the first 8 weeks after transmural infarction in adjacent noninfarcted regions, as well as attenuate left ventricular remodeling.. Angiotensin-converting enzyme inhibition limits ventricular dilation and hypertrophy and improves survival after anterior infarction, but its effect on regional function during remodeling is not well characterized.. Thirteen sheep underwent coronary ligation to create an anteroapical infarction. At postinfarction day 2, eight sheep were randomized to therapy with the angiotensin-converting enzyme inhibitor ramipril, and five sheep received no therapy. Animals were studied with magnetic resonance myocardial tagging before and 8 weeks after infarction. Left ventricular volume, mass and ejection fraction were measured, as were changes in percent circumferential shortening within the subendocardium and subepicardium of infarcted and noninfarcted myocardium, both adjacent to and remote from the infarction.. Angiotensin-converting enzyme inhibition limited the increase in end-diastolic volume from a mean (+/- SD) of +1.5 +/- 0.7 ml/kg in control animals to +0.5 +/- 0.8 ml/kg in the treated group (p < 0.04). Segmental function within infarcted and remote noninfarcted tissue did not differ between groups. However, angiotensin-converting enzyme inhibition limited the decline in function in the adjacent noninfarcted region 8 weeks after infarction. Percent circumferential shortening in the subendocardium decreased by -13 +/- 5% in the control group compared with -5 +/- 5% in the treated group (p < 0.03).. In concert with a reduction in left ventricular remodeling after anterior infarction, angiotensin-converting enzyme inhibition limits the decline in function in the adjacent noninfarcted region. Dysfunction in adjacent noninfarcted regions may be an important determinant of left ventricular remodeling after infarction.

Topics: Analysis of Variance; Angiotensin-Converting Enzyme Inhibitors; Animals; Heart; Humans; Myocardial Contraction; Myocardial Infarction; Peptidyl-Dipeptidase A; Ramipril; Sheep; Stroke Volume; Ventricular Dysfunction, Left

After transient episodes of ischemia, benefits of thrombolytic or angioplastic therapy may be limited by reperfusion injury. Angiotensin-converting enzyme inhibitors protect the heart against ischemia/reperfusion injury, an effect mediated by kinins. We examined whether the protective effect of the angiotensin-converting enzyme inhibitor ramiprilat on myocardial ischemia/reperfusion is due to kinin stimulation of prostaglandin and/or nitric oxide release. The left anterior descending coronary artery of Lewis inbred rats was occluded for 30 minutes, followed by 120 minutes of reperfusion. Immediately before reperfusion rats were treated with vehicle, ramiprilat, or the angiotensin II type 1 receptor antagonist losartan. We tested whether pretreatment with the kinin receptor antagonist Hoe 140, the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester, or the cyclooxygenase inhibitor indomethacin blocked the effect of ramiprilat on infarct size and reperfusion arrhythmias. In controls, infarct size as a percentage of the area at risk was 79 +/- 3%; ramiprilat reduced this to 49 +/- 4% (P < .001), but losartan had little effect (74 +/- 6%, P = NS). Pretreatment with Hoe 140, NG-nitro-L-arginine methyl ester, or indomethacin abolished the beneficial effect of ramiprilat. Compared with the 30-minute ischemia/120-minute reperfusion group, nonreperfused hearts with 30 minutes of ischemia had significantly smaller infarct size as a percentage of the area at risk, whereas in the 150-minute ischemia group it was significantly larger. This suggests that reperfusion caused a significant part of the myocardial injury, but it also suggests that compared with prolonged ischemia, reperfusion salvaged some of the myocardium. Ventricular arrhythmias mirrored the changes in infarct size. Thus, angiotensin-converting enzyme inhibitors protect the myocardium against ischemia/reperfusion injury and arrhythmias; these beneficial effects are mediated primarily by a kinin-prostaglandin-nitric oxide pathway, not inhibition of angiotensin II formation.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arginine; Arrhythmias, Cardiac; Bradykinin; Bradykinin Receptor Antagonists; Cyclooxygenase Inhibitors; Enzyme Inhibitors; Hemodynamics; Indomethacin; Male; Myocardial Infarction; Myocardial Ischemia; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Ramipril; Rats; Rats, Inbred Lew; Reperfusion Injury

In male Sprague Dawley rats with left ventricular hypertrophy (LVH) and hypertension induced by aortic constriction (AC) and subsequent myocardial infarction (MI) by occlusion of the left coronary artery the effects of ACE inhibition with ramipril (RA 1 mg/kg/day via the drinking water during 6 weeks) on survival as well as cardiac function and metabolism were investigated. Respective groups (sham AC; AC; AC + sham MI; normotensive animals with sham MI; MI; MI + RA) served as comparisons. Following MI hypertensive rats with AC and LVH revealed an increased postoperative mortality (68%) when compared to normotensives without AC (28%). ACE inhibition with ramipril significantly reduced mortality in hypertensive rats by 26%. Untreated hypertensive animals with LVH clearly showed reduced MI size (6.2 +/- 2.3%) in comparison with untreated normotensive animals and MI (31.0 +/- 3.3%). In hypertensive rats with MI which died during the study a significant increase in infarct size was found compared to those which survived MI. In normotensive animals ramipril reduced infarct size by 50%. Due to the quite small infarct size observed in hypertensive rats, ACE inhibition did not further reduce MI in these animals. LVH as well as hydroxyproline/proline ratio was diminished by ACE inhibitor treatment. In the isolated hearts of ramipril treated rats contractility was improved when compared to the respective untreated groups with MI. In the coronary effluent of isolated hearts from rats with AC and MI lactate dehydrogenase and creatine kinase activities as well as lactate levels were increased. Ramipril treatment starting one week before MI normalized these parameters and in addition increased prostacyclin output. Hearts with MI from treated normotensive animals contained increased energy rich phosphates when compared to hearts from untreated rats with MI.. Hypertensive rats with LVH undergoing MI experience increased postoperative mortality probably due to a reduced tolerance to myocardial ischemia and occurrence of arrhythmias. In these animals ACE inhibition with ramipril increased survival. Both, increased survival in hypertensive and reduction in infarct size in normotensive rats by ACE inhibition with ramipril was accompanied by an improved myocardial metabolism.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta; Blood Pressure; Constriction, Pathologic; Coronary Vessels; Heart; Hypertension; Hypertrophy, Left Ventricular; Male; Myocardial Infarction; Myocardium; Postoperative Period; Ramipril; Rats; Rats, Sprague-Dawley; Reference Values; Survival Analysis

Doctors treat patients, not populations. 'Evidence-based' practice is essential but extrapolation to the individual patient is always necessary and this fact is well illustrated by data from trials of ACE inhibitors post-myocardial infarction. In the AIRE (Acute Infarction Ramipril Efficacy) study, 2,006 patients with some evidence of heart failure, even if transient, after a myocardial infarction, were randomised to receive oral ramipril or placebo in addition to standard treatment. Follow-up was for a minimum of six and an average of 15 months. The risk reduction in total mortality was 27% (95% CI 11-40%; p = 0.002); approximately 40 lives might be expected to be saved for every 1000 patients treated for one year. Benefit was apparent within weeks of starting treatment. Additional data from the AIRE study are considered in relation to the findings of other mortality trials. It is argued that ACE inhibitors offer most to those patients with impaired left ventricular function through a mechanism not related to the prevention of myocardial re-infarction.

Topics: Angiotensin-Converting Enzyme Inhibitors; Clinical Trials as Topic; Diuretics; Humans; Myocardial Infarction; Ramipril

The angiotensin-converting enzyme inhibitor ramiprilat has been previously demonstrated to protect myocardium from ischemia/reperfusion injury. The objective of these investigations was to examine the roles of bradykinin, angiotensin II, and nitric oxide in the cardioprotective effects of ramiprilat.. Anesthetized, open-chest rabbits were instrumented for production of myocardial ischemia (30 minutes) and subsequent reperfusion (120 minutes), after which myocardial infarct size was measured. Animals were treated intravenously with either saline solution, ramiprilat (50 micrograms/kg), the bradykinin2 receptor antagonist HOE 140 (1 microgram/kg), ramiprilat + HOE 140, angiotensin II (2.5 ng.kg-1.min-1), the angiotensin II receptor antagonist losartan (20 mg/kg), ramiprilat + angiotensin II, the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (100 micrograms.kg-1.min-1), or ramiprilat + NG-nitro-L-arginine methyl ester.. Among all treatment groups myocardial infarct size was reduced significantly below saline control only by ramiprilat (-54%) and ramiprilat + angiotensin II (-37%). Pretreatment with HOE 140 or NG-nitro-L-arginine methyl ester abolished the cardioprotective effect of ramiprilat. Neither stimulation nor antagonism of angiotensin II receptors altered infarct size from the saline control level. Also, when isolated neonatal rat cardiomyocytes were exposed to hypoxia/reoxygenation, ramiprilat (100 mumol/L) and bradykinin (10 nmol/L) improved cell viability (approximately 60%), and the protective effect of both agents was reversed by administration of HOE 140 (10 mumol/L).. These results indicate that the in vivo cardioprotective effect of ramiprilat can be abolished by antagonizing bradykinin receptors or inhibiting nitric oxide synthase, and that the effect is not related to angiotensin II receptor activity. The potential bradykinin-sparing property of ramiprilat may promote increased bradykinin-stimulated nitric oxide production leading to cardioprotection. Part of the cardioprotective effects of ramiprilat/bradykinin/nitric oxide may occur locally as demonstrated by the in vitro results using isolated cardiomyocytes.

Topics: Adrenergic beta-Antagonists; Amino Acid Oxidoreductases; Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Arginine; Biphenyl Compounds; Bradykinin; Bradykinin Receptor Antagonists; Heart; Imidazoles; Losartan; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion; Myocardial Reperfusion Injury; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Rabbits; Ramipril; Receptors, Angiotensin; Receptors, Bradykinin; Tetrazoles

Topics: Echocardiography; Humans; Hypertrophy, Left Ventricular; Myocardial Infarction; Ramipril; Randomized Controlled Trials as Topic; Ventricular Dysfunction, Left

Although a major goal in the treatment of chronic heart failure is to improve daily physical activity levels, this has not been assessed quantitatively. An increased daily activity level may be reflected by an increase in daily energy expenditure. In the present study, measurements of energy expenditure with a commercially available ambulatory calorimeter were first validated using cardio-pulmonary exercise tests in 5 normal volunteers. The energy expenditure measured by the calorimeter correlated well with that estimated from oxygen uptake (r = 0.89). Subsequently, the daily energy expenditure was serially measured with the calorimeter during long-term administration of the converting enzyme inhibitor ramipril for 24 weeks in 8 patients with chronic heart failure. Changes in echocardiographic parameters and exercise capacity were also studied. Peak oxygen uptake and anaerobic threshold assessed with symptom-limited maximal bicycle exercise were significantly increased 12 weeks or more after the initiation of treatment (P < 0.01 and P < 0.01, respectively). Left ventricular fractional shortening substantially, but not significantly, increased during this period (P < 0.1). These results strongly suggest that an overall improvement in heart failure was achieved after long-term ramipril therapy. The energy expenditure during daily activities was also significantly increased after ramipril therapy for 24 weeks (P < 0.01). Thus, the daily energy expenditure increased with improvement of heart failure, probably reflecting an increase in daily activity levels. We conclude that calorimetric measurement of daily energy expenditure is a novel and simple technique for quantitative evaluation of the effect of therapy on daily physical activity levels in patients with chronic heart failure.

Topics: Activities of Daily Living; Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Calorimetry; Cardiomyopathy, Dilated; Drug Therapy, Combination; Echocardiography; Energy Metabolism; Evaluation Studies as Topic; Exercise Test; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Myocardial Infarction; Oxygen Consumption; Physical Exertion; Ramipril; Vasodilator Agents; Ventricular Function, Left

It is known that angiotensin converting enzyme (ACE) inhibitors not only prevent the formation of angiotensin II, but also potentiate the activity of bradykinin. We investigated the effects of the ACE-inhibitor ramipril in two models of cardiac ischemia. In anesthetized dogs with a coronary occlusion of 6-h duration, both ramiprilat and bradykinin significantly reduced infarct-size. This effect was prevented by the co-administration of the bradykinin antagonist HOE 140. In rats with a coronary occlusion of 6-weeks duration, ramipril administration significantly reduced infarct-size and prevented the development of left ventricular hypertrophy. Thus, ramipril showed a cardioprotective activity in models of acute as well as of chronic myocardial ischemia. These effects are probably mediated by the potentiation of bradykinin.

Topics: Animals; Bradykinin; Dogs; Dose-Response Relationship, Drug; Drug Therapy, Combination; Heart Failure; Myocardial Infarction; Myocardium; Ramipril; Rats

Topics: Death, Sudden, Cardiac; Heart Failure; Humans; Myocardial Infarction; Ramipril; Risk Factors

We wished to determine, using a novel specific antagonist of BK2, HOE 140, (a) if the angiotensin-converting enzyme (ACE) inhibitor, ramiprilat, reduces myocardial infarct size in a well-established animal model of ischemia/reperfusion with minimal coronary collateralization, and (b) if the reduction in myocardial infarct size occurred through a bradykinin-dependent mechanism Saline vehicle, ramiprilat, HOE 140, or ramiprilat plus HOE 140 (n = 6 each group), was administered intravenously (i.v.) in intact animal preparations of experimentally induced acute myocardial ischemia. Anesthetized, open-chest rabbits were instrumented for measurement of systemic hemodynamics and left ventricular pressure (LVP), from which LV + dP/dtmax was derived. Animals were subjected to 30-min left main coronary artery occlusion (marginal branch) followed by 2-h reperfusion. Ramiprilat (50 micrograms/kg) or saline was administered before reperfusion, and rabbits receiving HOE 140 were pretreated before occlusion (1 microgram/kg). In separate duration of action experiments (n = 6 each group), the above doses of ramiprilat or HOE 140 had significant vascular antagonism of sufficient duration against serial challenge with angiotensin I (AI) or bradykinin, respectively. After reperfusion, myocardial infarct size (IS) was determined by tetrazolium staining and expressed as a percentage of area at risk (AR). IS/AR% was significantly reduced in rabbits that received ramiprilat (20 +/- 6%, p < 0.05) as compared with those that received saline (41 +/- 6%), ramiprilat plus HOE 140 (47 +/- 2%), or HOE 140 alone (43 +/- 4%, mean +/- SEM). AR as a percentage of total LV mass was not different between any of the four treatment groups. Tachycardia was observed during early reperfusion in each group treated with ramiprilat.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Angiotensin I; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Bradykinin; Female; Heart Rate; Male; Myocardial Infarction; Myocardial Reperfusion; Rabbits; Ramipril

1. Effects of captopril, ramiprilat and Hoe 140, a specific bradykinin receptor antagonist, on infarct size were assessed in a rabbit model of myocardial infarction. 2. Rabbits were untreated or pretreated with 0.5 mg/kg of captopril, 0.05 mg/kg of ramiprilat or 20 nmol/kg of Hoe 140 before 30 min coronary artery occlusion and 72 h reperfusion. 3. Captopril and ramiprilat treatment reduced systemic blood pressure by about 10 mmHg without alteration of heart rate, and the dose of Hoe 140 almost completely blocked hypotensive response to intravenous injection of bradykinin (100 ng/kg). 4. Infarct size expressed as percentage of area at risk was 44.5 +/- 3.3% in the control group, 41.9 +/- 1.6% in the captopril group, 51.8 +/- 2.7% in the ramiprilat group and 46.7 +/- 2.2% in the Hoe 140 group. All percentages were not significantly different. 5. These data suggest that angiotensin converting enzymes (ACE), with or without sulfhydryl groups do not limit myocardial infarct size and that endogenous bradykinin in ischaemic myocardium does not play a major protective role against ischaemic myocardial necrosis.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Bradykinin; Captopril; Heart Rate; Injections, Intravenous; Male; Myocardial Infarction; Rabbits; Ramipril; Renin

The angiotensin-converting enzyme inhibitor ramiprilat, the angiotensin II receptor antagonist losartan, angiotensin II, ramiprilat plus angiotensin II, or saline (N = 6 each group), were administered i.v. in anesthetized, open-chest rabbit preparations of acute myocardial ischemia. Animals were instrumented for measurement of systemic hemodynamics and left ventricular +dP/dtmax, then subjected to 30 min of left anterior descending coronary artery occlusion (marginal branch) followed by 2 h of reperfusion. Ramiprilat (50 micrograms/kg), losartan (10 mg/kg), or saline were administered prior to reperfusion, and angiotensin II (2.5 ng/kg per min) was infused 15 min prior to occlusion and throughout the remainder of the experiment. Losartan was supplemented (10 mg/kg) after 1 h of reperfusion. These non-hypotensive doses of ramiprilat and losartan were demonstrated to significantly antagonize the systemic pressor effects of i.v. challenge with angiotensin I (15% of control, maximum) and II (5% of control, maximum), respectively, for the duration of the experiment. Systemic hemodynamic and +dP/dtmax changes due to occlusion/reperfusion or drug administration were similar between treatment groups. Infarct size was measured post-experimentally using tetrazolium staining and is reported as a percent of area at risk. Infarct size/area at risk (%) was significantly lower in rabbits administered ramiprilat only (20 +/- 6%*) or ramiprilat plus angiotensin II (26 +/- 5%*), compared to those receiving saline (41 +/- 6%), angiotensin II (51 +/- 4%), or losartan (52 +/- 4%, mean +/- S.E.M., * P < 0.05). These data indicate that direct angiotensin II receptor stimulation or receptor antagonism does not alter the degree of myocardial necrosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Biphenyl Compounds; Blood Pressure; Electrophysiology; Female; Hemodynamics; Imidazoles; Losartan; Male; Myocardial Infarction; Myocardial Ischemia; Rabbits; Ramipril; Tetrazoles

Two models of right ventricular (RV) hypertrophy in rats have been created and characterized: chronic myocardial infarction and pulmonary artery stenosis. A Millar ultraminiature catheter pressure transducer designed specifically for right heart catheterization was used for the measurement of RV function in closed-chest, anesthetized rats. Four weeks after coronary artery ligation, left ventricular (LV) function was depressed as evidenced by the reduction of LV systolic pressure (LVSP), the maximal rate of rise in LV pressure (LV dp/dtmax), cardiac output, and by the elevation of LV end-diastolic pressure (LVEDP). There was an increase in RVSP and an elevation in RV dp/dtmax as well as an increase in the RV weight/body weight ratio. Myocytes isolated from the RV 4 weeks after coronary artery ligation had a greater volume and cross-sectional area. In addition, 14 days after pulmonary artery stenosis, there also was an elevation in RVSP and in RV dp/dtmax. In this model, the effect of angiotensin-converting enzyme (ACE) inhibition with ramipril (1 mg/kg daily) was examined. The increase in RVSP from 35 +/- 2 to 61 +/- 4 mm Hg after pulmonary artery stenosis was not influenced by ramipril (63 +/- 4 mm Hg), neither was the elevation of RV weight. However, the increase in cell volume and cross-sectional area of myocytes isolated from the RV was less pronounced in the ramipril-treated group (+27% compared with +58% in untreated animals). Thus, ACE inhibition with ramipril altered the hypertrophic response at the cellular level.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Bridged Bicyclo Compounds; Cardiomegaly; Disease Models, Animal; Female; Hemodynamics; Myocardial Infarction; Myocardium; Pulmonary Valve Stenosis; Ramipril; Rats; Rats, Inbred Strains; Ventricular Function, Left; Ventricular Function, Right

The ACE-inhibitor ramiprilat (40 ng/kg/min) was infused for 6 h into the left coronary artery of anesthetized dogs with ligation of the descending branch of this artery. This route of administration and the low dose were chosen to achieve local cardiac effects without affecting systemic hemodynamics. Ramiprilat significantly reduced infarct-size expressed as percentage of the area at risk. The cardioprotective effect of ramiprilat was mimicked by bradykinin and abolished by coadministration of a bradykinin antagonist. These results strongly suggest that bradykinin plays a role in the cardioprotective effect of the ACE-inhibitor ramiprilat.

Topics: Amino Acid Sequence; Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin; Coronary Vessels; Dogs; Infusions, Intra-Arterial; Molecular Sequence Data; Myocardial Infarction; Myocardial Ischemia; Ramipril

Topics: Abbreviations as Topic; Angiotensin-Converting Enzyme Inhibitors; Bridged Bicyclo Compounds; Humans; Myocardial Infarction; Ramipril

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin; Dogs; Hydrogen-Ion Concentration; Myocardial Infarction; Oligopeptides; Pyrroles; Ramipril