trandolapril and Myocardial-Ischemia

Topics: Adrenergic beta-Antagonists; Amlodipine; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Atenolol; Calcium Channel Blockers; Controlled Clinical Trials as Topic; Enalapril; Female; Humans; Hypertension; Indoles; Male; Middle Aged; Myocardial Ischemia; Nifedipine; Perindopril; Placebos; Risk Factors; Surveys and Questionnaires; Time Factors; Vasodilator Agents; Verapamil

CLINICAL TRIALS WITH VERAPAMIL AND TRANDOLAPRIL: In the Danish Verapamil Infarction Trial II, verapamil improved survival in patients without heart failure but had no effect in patients with heart failure who were receiving diuretic treatment. In the Acute Infarction Ramipril Efficacy study ramipril improved survival in patients receiving diuretic treatment but had no effect in patients not receiving diuretics. COMBINATION WITH THERAPY WITH VERAPAMIL AND TRANDOLAPRIL: By combining verapamil with trandolapril we hypothesized that we could obtain an improvement in left ventricular function and prevent cardiac events. In an open study of 14 patients with angina pectoris and left ventricular ejection fraction below 40%, treatment with trandolapril-verapamil significantly improved left ventricular function. In a double-blind randomized study of 100 postinfarct patients with congestive heart failure the cardiac event rate was significantly lower in verapamil-trandolapril-treated than in the trandolapril-treated patients. These results indicate that the combined treatment with verapamil and trandolapril might be beneficial in patients with ischaemic heart disease and congestive heart failure.

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Calcium Channel Blockers; Clinical Trials as Topic; Drug Therapy, Combination; Heart Failure; Humans; Indoles; Myocardial Infarction; Myocardial Ischemia; Recurrence; Verapamil

Klotho, an essential co-receptor for fibroblast growth factor (FGF)-23, has potentially beneficial inhibitory effects on the renin-angiotensin system. Limited data exist on the prognostic value of Klotho and FGF-23 levels in combination or their ability to predict benefit from angiotensin-converting enzyme (ACE) inhibition.. A total of 3555 patients with stable ischaemic heart disease and left ventricular ejection fraction > 40% enrolled in the PEACE trial of trandolapril vs. placebo had Klotho levels drawn at randomization. Patients were characterized by quartiles of Klotho and FGF-23 concentrations. Six-year Kaplan-Meier rates and adjusted risk were calculated in the placebo arm for the composite of cardiovascular (CV) death or hospitalization for heart failure and its components. Low [quartile (Q) 1-3] Klotho concentration was associated with an increased rate of CV death or hospitalization for heart failure as compared with Q4 (8.2% vs. 4.2%; P = 0.03). After multivariable adjustment for clinical variables and renal and CV biomarkers (estimated glomerular filtration rate, cystatin-C, urine albumin-to-creatinine ratio, FGF-23, high-sensitivity troponin T, N-terminal pro-B-type natriuretic peptide, and high-sensitivity C-reactive protein), low Klotho concentration remained strongly associated with increased risk of CV death or hospitalization for heart failure [adjusted hazard ratio (HR) 2.62; 95% confidence interval (CI) 1.35-5.08; P < 0.01]. The combination of low Klotho and high (Q4) FGF-23 concentration identified patients at particularly elevated risk (adjusted HR 3.99; 95% CI 1.67-9.56; P < 0.01). This high-risk combination additionally predicted benefit from trandolapril (HR 0.39; 95% CI 0.23-0.68; P. Low Klotho concentration is associated with an increased risk of CV death or heart failure hospitalization in patients with stable ischaemic heart disease. The combination of low Klotho and high FGF-23 further identifies patients at distinctly elevated risk who derive clinical benefit from the ACE-inhibitor trandolapril.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Biomarkers; Female; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Glucuronidase; Heart Failure; Hospitalization; Humans; Indoles; Klotho Proteins; Male; Middle Aged; Myocardial Ischemia; Predictive Value of Tests; Prognosis; Renin-Angiotensin System; Stroke Volume

There have been significant advances in the treatment of patients with cardiomyopathy with reduced ejection fraction (EF < 40%). However, there is a dearth of information in the treatment of patients with cardiomyopathy and midrange EF (40-50%). Current guidelines state to treat these patients similarly to patients with cardiomyopathy and preserved EF. Data from the Prevention of Events with Angiotensin-Converting Enzyme Inhibition (PEACE) trial were used to elucidate whether angiotensin-converting enzyme (ACE) inhibitors improve clinical outcomes in patients with ischemic cardiomyopathy and midrange EF.. A post hoc subgroup analysis of the PEACE trial was conducted to evaluate the effect of ACE inhibitors in a subgroup of patients with ischemic cardiomyopathy and midrange EF (40-50%). A Chi-square test and a Student's t-test were used to examine and compare the binary and continuous variables of baseline characteristics and outcomes between experimental and comparison groups.. We studied a subgroup of patients from the PEACE trial with ischemic cardiomyopathy and midrange EF ( n = 2512 of 8290 total patients). Patients were assigned to either the interventional group ( n = 1247) or the placebo group ( n = 1265). There were no significant differences in baseline demographic and health characteristics between the two groups. During a total of 7 years (mean 4.7 years) of follow up, the risk of composite outcomes [all-cause mortality, nonfatal myocardial infarction, and stroke; relative risk (RR) 0.79, 95% confidence interval (CI) 0.63-0.98; p = 0.03] and all-cause mortality (RR 0.85, 95% CI 0.73-0.99; p = 0.03) was reduced in patients treated with trandolapril.. This study revealed the benefit of ACE inhibitors among patients with ischemic cardiomyopathy and midrange EF.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Cardiomyopathies; Double-Blind Method; Female; Heart Failure; Humans; Indoles; Male; Middle Aged; Myocardial Ischemia; Stroke Volume; Time Factors; Treatment Outcome; Ventricular Function, Left

This study sought to test 2 hypotheses: 1) fibroblast growth factor (FGF)-23 identifies patients with stable ischemic heart disease (SIHD) at high risk of cardiovascular events independent of clinical factors, renal function, and established cardiovascular biomarkers; and 2) FGF-23 identifies patients who derive greater clinical benefit from angiotensin-converting enzyme inhibitor therapy.. FGF-23 is an endocrine regulator of mineral metabolism and markedly elevated levels are associated with cardiovascular events in patients with chronic kidney disease. Data in patients with SIHD are more sparse.. FGF-23 levels were measured in 3,627 patients with SIHD randomly assigned to trandolapril or placebo within the PEACE (Prevention of Events With Angiotensin-Converting Enzyme) trial and followed up for a median of 5.1 years.. After adjustment for clinical risk predictors, left ventricular ejection fraction, markers of renal function, and established cardiovascular biomarkers, FGF-23 concentration was independently associated with an increased risk of cardiovascular death or heart failure among patients allocated to placebo (quartile 4 hazard ratio: 1.73; 95% confidence interval, 1.09 to 2.74; p = 0.02) and significantly improved metrics of discrimination. Furthermore, among patients in the top quartile of FGF-23 levels, trandolapril significantly reduced cardiovascular death or incident heart failure (hazard ratio: 0.45; 95% confidence interval: 0.28 to 0.72), whereas there was no clinical benefit in the remaining patients (hazard ratio: 1.07; 95% confidence interval: 0.75 to 1.52; p interaction = 0.0039). This interaction was independent of and additive to stratification based on renal function.. Elevated levels of FGF-23 are associated with cardiovascular death and incident heart failure in patients with SIHD and identify patients who derive significant clinical benefit from angiotensin-converting enzyme inhibitor therapy regardless of renal function. (Prevention of Events With Angiotensin-Converting Enzyme Inhibitor Therapy [PEACE]: NCT00000558).

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Biomarkers; Cardiovascular Diseases; Female; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Humans; Indoles; Male; Middle Aged; Myocardial Ischemia; Prognosis; Risk

CLINICAL TRIALS WITH VERAPAMIL AND TRANDOLAPRIL: In the Danish Verapamil Infarction Trial II, verapamil improved survival in patients without heart failure but had no effect in patients with heart failure who were receiving diuretic treatment. In the Acute Infarction Ramipril Efficacy study ramipril improved survival in patients receiving diuretic treatment but had no effect in patients not receiving diuretics. COMBINATION WITH THERAPY WITH VERAPAMIL AND TRANDOLAPRIL: By combining verapamil with trandolapril we hypothesized that we could obtain an improvement in left ventricular function and prevent cardiac events. In an open study of 14 patients with angina pectoris and left ventricular ejection fraction below 40%, treatment with trandolapril-verapamil significantly improved left ventricular function. In a double-blind randomized study of 100 postinfarct patients with congestive heart failure the cardiac event rate was significantly lower in verapamil-trandolapril-treated than in the trandolapril-treated patients. These results indicate that the combined treatment with verapamil and trandolapril might be beneficial in patients with ischaemic heart disease and congestive heart failure.

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Calcium Channel Blockers; Clinical Trials as Topic; Drug Therapy, Combination; Heart Failure; Humans; Indoles; Myocardial Infarction; Myocardial Ischemia; Recurrence; Verapamil

Women are at greater risk of developing resistant hypertension (RH) than men, yet scarce data exist on RH-associated outcomes in women. We aimed to determine all-cause mortality risk associated with apparent RH (aRH) among women across the spectrum of underlying coronary disease.. We analyzed data from St. James Women Take Heart (WTH; women without coronary disease at baseline), Women's Ischemia Syndrome Evaluation (women with signs/symptoms of ischemia at baseline), and the INternational VErapamil-Trandolapril STudy (INVEST; women with coronary artery disease and hypertension at baseline), totaling 15,108 adult women with no hypertension, non-RH (blood pressure [BP] ≥140/90 mmHg on ≤2 drugs or BP <140/90 mmHg on 1-3 drugs), or aRH (BP ≥140/90 mmHg on ≥3 drugs or anyone on ≥4 drugs) at baseline. The primary outcome was all-cause mortality.. Prevalence of aRH ranged from 0.4% (WTH) to 10.6% (INVEST). Women with aRH, compared to those without, were older, more often black, and more likely to be obese or diabetic. Pooling all cohorts, risk for all-cause death was greater in women with aRH than in women with non-RH (adjusted HR 1.40; 95% CI 1.27-1.55) and women without hypertension (adjusted HR 2.34; 95% CI 1.76-3.11) over a median follow-up of 14.3 years.. aRH prevalence in women varies according to underlying coronary disease, and aRH is associated with a substantial, early, and sustained increased risk of all-cause death. Additional research into early recognition and prevention strategies for RH are needed, especially in black and older women, and those with known cardiovascular risk factors.

Topics: Adult; Aged; Antihypertensive Agents; Blood Pressure; Coronary Artery Disease; Drug Resistance; Female; Humans; Hypertension; Indoles; Middle Aged; Myocardial Ischemia; Obesity; Prospective Studies; Risk Factors; Stroke; Treatment Outcome; United States; Verapamil

Topics: Angiotensin-Converting Enzyme Inhibitors; Enalapril; Humans; Indoles; Myocardial Ischemia; Perindopril; Quinapril; Ramipril; Tetrahydroisoquinolines

1. Angiotensin converting enzyme (ACE) inhibitors are under study in ischaemic heart diseases, their mechanism of action being still unknown. 2. The anti-ischaemic effect of trandolapril and the possible involvement of a bradykinin-modulation on endothelial constitutive nitric oxide synthase (eNOS) in exerting this effect, were investigated. 3. Three doses of trandolapril, chronically administered in vivo, were studied in isolated perfused rat hearts subjected to global ischaemia followed by reperfusion. 4. Trandolapril has an anti-ischaemic effect. The dose of 0.3 mg kg(-1) exerted the best effect reducing diastolic pressure increase during ischaemia (from 33.0+/-4.5 to 14.0+/-5.2 mmHg; P<0.05 vs control) and reperfusion (from 86.1+/-9.4 to 22.2+/-4.1 mmHg; P<0.01 vs control), improving functional recovery, counteracting creatine phosphokinase release and ameliorating energy metabolism after reperfusion. 5. Trandolapril down-regulated the baseline developed pressure. 6. Trandolapril increased myocardial bradykinin content (from 31.8+/-6.1 to 54.8+/-7.5 fmol/gww; P<0.05, at baseline) and eNOS expression and activity in aortic endothelium (both P<0.01 vs control) and in cardiac myocytes (from 11.3+/-1.5 to 17.0+/-2.0 mUOD microg protein(-1) and from 0.62+/-0.05 to 0.80+/-0.06 pmol mg prot(-1) min(-1); both P<0.05 vs control). 7. HOE 140 (a bradykinin B(2) receptor antagonist) and NOS inhibitors counteracted the above-reported effects. 8. There was a negative correlation between myocyte's eNOS up-regulation and myocardial contraction down-regulation. 9. Our findings suggest that the down-regulation exerted by trandolapril on baseline cardiac contractility, through a bradykinin-mediated increase in NO production, plays a crucial role in the anti-ischaemic effect of trandolapril by reducing energy breakdown during ischaemia.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta; Bradykinin; Dose-Response Relationship, Drug; Energy Metabolism; Heart Ventricles; In Vitro Techniques; Indoles; Male; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Rats; Rats, Sprague-Dawley; Ventricular Pressure

We investigated whether angiotensin I-converting enzyme inhibition (ACEI) and angiotensin II AT1-receptor blockade (AT1-) would exert beneficial additive effects on coronary hemodynamics and on cardiac remodeling in post-myocardial infarction (MI) heart failure in rats. Wistar rats with MI were treated daily for 6 weeks with either trandolapril (0.1 mg/kg), losartan (3 mg/kg), or their combination, after which coronary hemodynamics (basal and at maximal vasodilation, fluospheres), systemic hemodynamics, and cardiac remodeling were investigated. Neither trandolapril nor losartan (both in nonantihypertensive doses) nor their combination (which significantly decreased blood pressure) proved to be effective at improving MI-induced impairments of basal coronary hemodynamics and of coronary flow reserve, and at preventing cardiac fibrosis development. In contrast, both trandolapril and losartan significantly improved the hemodynamic status [e.g., left ventricular end diastolic pressure: -27% and -39%, urinary cyclic guanosine monophosphate (GMP): -37%, and -26%, respectively] and slightly limited cardiac hypertrophy (-5% and -3%, respectively), and, in their combination, tended to exert additive effects on these three parameters (-49, -42, and -10%, respectively). Thus whereas the ACEI/AT1- combination tended to exert additive effects on systemic hemodynamics and cardiac hypertrophy in post-MI heart failure rats, no such effect was found for coronary hemodynamics, probably in relation to the lack of prevention of cardiac fibrosis. We conclude that an early (6 weeks) drug-induced improvement in coronary hemodynamics does not contribute to the long-term survival prolongation observed in this experimental model after either ACEI or AT1-.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Cardiomegaly; Coronary Circulation; Cyclic GMP; Heart Failure; Hemodynamics; Indoles; Losartan; Male; Myocardial Infarction; Myocardial Ischemia; Myocardium; Rats; Rats, Wistar; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Renin-Angiotensin System

To investigate clinical efficacy of angiotensin-converting enzyme inhibitor trandolapril and its effects on myocardial function.. 20 patients with ischemic heart disease (IHD) aged 33-74 years with chronic cardiac failure NYHA class II-IV. 4 of them survived myocardial infarction. In addition to the routine tests, the patients underwent echocardiography, radionuclide ventriculography. Trandolapril was given once a day for 28 days in a dose 2 mg, then a repeat examination was performed.. Trandolapril produced a subjective effect in 80% of patients. There was also improvement of hemodynamic parameters, an increase in the ejection fraction, sensitivity to nitroglycerin, decline of asynchrony. The drug was well tolerated.. Trandolapril (Gopten) is effective in IHD patients with chronic cardiac failure.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Chronic Disease; Drug Evaluation; Female; Heart Failure; Humans; Indoles; Male; Middle Aged; Myocardial Contraction; Myocardial Ischemia

The combination of a calcium antagonist with an angiotensin-converting enzyme (ACE) inhibitor is increasingly used in the therapy of hypertension, but there are no experimental data supporting the use of this combination in acute myocardial ischemia and reperfusion. We tested the effects of oral pretreatment in a pig model, paying special attention to arrhythmias and adverse hemodynamic effects. Pigs received verapamil 240 mg + trandolapril 4 mg, verapamil 240 mg, or placebo orally once daily for 10 days, after which a coronary artery was ligated for 20 minutes and then allowed to reperfuse. The ventricular fibrillation threshold (VFT) was measured during ischemia to assess the vulnerability of the heart to ventricular fibrillation, whereas spontaneous tachyarrhythmias were monitored during reperfusion. Regional left ventricular (LV) blood flow was measured with radioactive microspheres. During the ischemic period, both the combination of verapamil plus trandolapril, and verapamil alone, prevented a fall in the VFT, indicating antiarrhythmic activity. The combination maintained LV contractile activity and cardiac output (CO) at preligation levels, whereas verapamil alone decreased cardiac output. During reperfusion, verapamil plus trandolapril prevented spontaneous ventricular tachyarrhythmias and increased blood flow in the reperfused zone. In contrast, verapamil was not antiarrhythmic and decreased CO. Thus the addition of the ACE inhibitor trandolapril to the calcium antagonist verapamil resulted in antiarrhythmic activity during ischemia and reperfusion, and produced a better hemodynamic profile.

Topics: Administration, Oral; Angiotensin-Converting Enzyme Inhibitors; Animals; Anti-Arrhythmia Agents; Calcium Channel Blockers; Cardiac Output; Hemodynamics; Indoles; Male; Myocardial Ischemia; Myocardial Reperfusion Injury; Premedication; Swine; Time Factors; Ventricular Function, Left; Verapamil