enalapril and Ventricular-Dysfunction--Left

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

Retrospective analyses of the Studies of Left Ventricular Dysfunction (SOLVD) and Vasodilator Heart Failure Trials (V-HeFT) have addressed the question of whether angiotensin-converting enzyme (ACE) inhibitors are equally efficacious in black patients and white patients with heart failure. In SOLVD, there was no ethnic difference in the efficacy of enalapril for reducing mortality and preventing the development of heart failure, but enalapril was more effective in whites in reducing hospitalizations. In V-HeFT II, enalapril was more efficacious than the combination of isosorbide dinitrate and hydralazine in whites in reducing mortality, but not in blacks. However, the combination of isosorbide dinitrate and hydralazine may be particularly advantageous in black patients as suggested by V-HeFT I and the recent African American Heart Failure Trial. In aggregate, the available data suggest that ACE inhibitors should remain a cornerstone of therapy for heart failure with a reduced ejection fraction in white patients and black patients.

Topics: Angiotensin-Converting Enzyme Inhibitors; Black People; Clinical Trials as Topic; Diuretics, Osmotic; Drug Therapy, Combination; Enalapril; Heart Failure; Humans; Hydralazine; Isosorbide; Vasodilator Agents; Ventricular Dysfunction, Left; White People

To review whether brain natriuretic peptides (BNP) can be used as a surrogate for the traditional methods of assessing functional status in interventional studies of patients with left ventricular systolic dysfunction (LVSD).. The traditional methods for assessing functional status including New York Heart Association (NYHA) class, exercise intolerance and quality of life were reviewed in relation to BNP measurements in patients with LVSD. A meta-analysis of four studies evaluating BNP levels versus exercise peak oxygen uptake or 6-minute walking distance showed a significant correlation, but a low R-value of -0.59. Studies using BNP levels for optimisation of heart failure therapy showed conflicting results concerning the correlation between the functional improvement and changes in BNP levels. Conflicting results were also found concerning the utility of BNP levels as a surrogate to predict efficacy of the various anti-congestive therapies on heart failure outcome.. The results of the studies examining BNP measurement as a surrogate for functional status and drug efficacy in patients with LVSD are conflicting. Further studies are necessary to settle the place of BNP measurement as surrogate marker for exercise tolerance, NYHA classification and in assessing efficacy of different interventions in the clinical trials.

Topics: Angiotensin-Converting Enzyme Inhibitors; Biomarkers; Carbazoles; Carvedilol; Clinical Trials as Topic; Data Collection; Drug Administration Schedule; Enalapril; Exercise Test; Exercise Tolerance; Health Status; Heart Failure; Humans; Imidazolidines; Meta-Analysis as Topic; Metoprolol; Natriuretic Peptide, Brain; Propanolamines; Quality of Life; Statistics as Topic; Treatment Outcome; Ventricular Dysfunction, Left

Topics: Adrenergic beta-Antagonists; Aged; Angiotensin-Converting Enzyme Inhibitors; Carbazoles; Carvedilol; Confidence Intervals; Death, Sudden, Cardiac; Enalapril; Female; Follow-Up Studies; Heart Failure; Hospitalization; Humans; Male; Meta-Analysis as Topic; Middle Aged; Myocardial Infarction; Placebos; Propanolamines; Randomized Controlled Trials as Topic; Recurrence; Risk Factors; Time Factors; Ventricular Dysfunction, Left; Ventricular Function, Left

In arterial hypertension, left ventricular (LV) hypertrophy (H) is a prognostically relevant target organ damage associated with systolic and diastolic LV dysfunction. The level of LV dysfunction seems to be related to the degree of myocardial fibrosis. Prognosis of hypertensive patients who have LVH regression appears to be improved. Therefore, LVH regression is an important antihypertensive treatment goal. The renin-angiotensin-aldosterone system is implicated in LVH development and myocardial fibrosis in essential arterial hypertension. Early studies in the 80s and 90s have led expectations that angiotensin converting enzyme (ACE) inhibitors could induce greater LVH regression than other antihypertensive drugs at similar blood pressure reduction. In the late 90s, the double-blind randomized controlled PRESERVE trial (Prospective Randomize Enalapril Study Evaluating Reversal of Ventricular Enlargement) has been designed to evaluate whether the ACE inhibitor enalapril was more effective than nifedipine GITS in regressing LVH and improving LV diastolic dysfunction. The PRESERVE study demonstrated a mildly higher antihypertensive effect of nifedipine GITS than enalapril, which required more frequently association with hydrochlorothiazide to control blood pressure. However, at similar level of blood pressure reduction achieved with enalapril and long-acting nifedipine in association with hydrochlorothiazide or atenolol, both antihypertensive treatments showed similar efficacy in LVH regression and LV diastolic filling improvement.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Atenolol; Calcium Channel Blockers; Dihydropyridines; Disease Models, Animal; Diuretics; Drug Therapy, Combination; Enalapril; Follow-Up Studies; Humans; Hydrochlorothiazide; Hypertension; Hypertrophy, Left Ventricular; Meta-Analysis as Topic; Nifedipine; Prognosis; Prospective Studies; Randomized Controlled Trials as Topic; Rats; Rats, Inbred SHR; Renin-Angiotensin System; Sodium Chloride Symporter Inhibitors; Time Factors; Ventricular Dysfunction, Left

During the past 10 years, the philosophy of heart failure treatment has evolved from symptom control to a combined prevention and symptom-management strategy. Recent clinical trials have proved that early detection can delay progression. Treatment of asymptomatic left ventricular dysfunction is as important as treatment of symptomatic disease. The purpose of this review is to simplify recent guidelines for pharmacological management of chronic systolic heart failure for the primary care physician and the heart failure specialist. Early recognition and prevention therapies, combined with lifestyle modification, are essential in the treatment of heart failure. Therapy with angiotensin-converting enzyme inhibitors, beta-blockers, and diuretics is now standard. Digoxin is added to improve clinical symptoms, especially in patients with atrial fibrillation. Aldosterone antagonists may be recommended in select patients with stable New York Heart Association class III or IV heart failure. If angiotensin-converting enzyme inhibitors are not tolerated, angiotensin receptor blockers, hydralazine hydrochloride, and isosorbide dinitrate are recommended. The data on antiarrhythmic and anticoagulation therapies are inconclusive.

Topics: Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Anti-Arrhythmia Agents; Disease Progression; Enalapril; Heart Failure; Humans; Life Style; Practice Guidelines as Topic; Randomized Controlled Trials as Topic; Ventricular Dysfunction, Left

This review has been focused on the new insights in the pathophysiology of mitral and aortic regurgitation and on the role of ACE-inhibitor therapy in children with chronic volume overload due to left-sided valvular lesions. Recent clinical studies show that these drugs have favorable effects when administered orally in chronic mitral and aortic regurgitation. Interestingly, the beneficial effects of ACE-inhibition regard the basic anatomic, hemodynamic and adaptive pathologic conditions related to volume overload, namely, the regurgitant orifice area and volume and ventricular remodeling. The heart is a plastic structure, constantly being altered in size, shape and composition in response to chronic volume overload. Thus, modulation of cardiac plasticity by ACE-inhibition raises the possibility of using new therapeutic strategies specifically designed to prevent and/or antagonize the mechanical disadvantages secondary to volume overload-induced cardiac remodeling. The beneficial effects of ACE-inhibition have also been observed in growing children with asymptomatic valvular regurgitation; thus, it appears that the unloading therapy has the potential of influencing the natural history of both mitral and aortic regurgitation and possibly delays surgical valve repair or replacement. These data justify early inhibition of the renin-angiotensin system in children with left ventricular volume overload due to mitral and aortic regurgitation.

Topics: Angiotensin-Converting Enzyme Inhibitors; Aortic Valve Insufficiency; Child; Chronic Disease; Enalapril; Hemodynamics; Humans; Mitral Valve Insufficiency; Renin-Angiotensin System; Ventricular Dysfunction, Left

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 level of inhibition of the angiotensin-converting enzyme (ACE) provided by standard doses of ACE inhibitors may only be partial during long-term treatment in patients with severe chronic heart failure (CHF). Partial ACE inhibition with time is often referred to as escape from ACE inhibition and labeled ACE escape. Several lines of evidence suggest that ACE escape occurs in patients with severe CHF. Plasma levels of angiotensin II rise above initial values during long-term ACE inhibition, and the effects of ACE inhibitors on cardiac remodeling and lowering of sympathetic nervous system activity attenuate after 1 year of treatment. Moreover, angiotensin II type I receptor blockade (ARB) produces clinical and hemodynamic benefits in patients with CHF who are already receiving ACE inhibitors. The therapeutic implications of ACE escape include evaluation of higher- than-standard doses of ACE inhibitors and routine addition of ARB to ACE inhibition in patients with severe CHF. Data are reviewed to demonstrate that ACE escape reflects inadequate ACE dosage rather than a decrease in ACE inhibition occurring with time.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Drug Therapy, Combination; Enalapril; Heart Failure; Humans; Randomized Controlled Trials as Topic; Tetrazoles; Ventricular Dysfunction, Left

Topics: Angiotensin-Converting Enzyme Inhibitors; Enalapril; Glomerular Filtration Rate; Humans; Kidney; Kidney Failure, Chronic; Uremia; Ventricular Dysfunction, Left

Plasma norepinephrine levels, which reflect sympathetic nervous system activity, are almost universally elevated in patients with left ventricular dysfunction. This elevation occurs in patients with overt, symptomatic heart failure (HF) and in patients with asymptomatic left ventricular dysfunction. Evidence suggests that the elevation in plasma norepinephrine levels can be at least partly attributed to an increase in sympathetic nervous system activity. It has become evident that elevated plasma norepinephrine levels are directly related to prognosis; patients with levels > 900 pg/ml have a poor prognosis and shortened life expectancy. However, plasma norepinephrine levels bear little relationship to physiologic and clinical variables observed in HF, including ejection fraction and exercise capacity. Data from the V-HeFT II show that at 2-year follow-up, a progressive rise of plasma norepinephrine was observed in both treatment arms, suggesting that disease progresses despite treatment with either an angiotensin-converting enzyme inhibitor, enalapril, or vasodilator therapy with hydralazine/isosorbide dinitrate. It is possible that interventions aimed at the progressive neurohormonal activation that occurs in HF may improve the course of illness. Further study is needed to test this hypothesis.

Topics: Enalapril; Heart Failure; Humans; Hydralazine; Isosorbide Dinitrate; Norepinephrine; Prognosis; Sympathetic Nervous System; Ventricular Dysfunction, Left

Benefit achieved through use of angiotensin converting enzyme (ACE) inhibitors in patients with reduced left ventricular (LV) systolic function is not confined to those with clinical manifestations of heart failure. Although rates of adverse clinical events are lower in asymptomatic patients, within this population ACE inhibitors have been shown to prevent adverse ventricular remodelling, prevent the development of clinical heart failure, reduce rates of hospitalization for heart failure and, in some studies, reduce mortality. Most of the benefit derived appears to be associated with preventing the progression of LV hypertrophy, dilatation, and dysfunction, resulting in prevention of heart failure. Additionally, the incidence of myocardial infarction is decreased, although the exact physiological basis for this benefit remains uncertain. Given the enormity and growth of heart failure as a public health problem and the potential for influencing the underlying pathophysiology, ACE inhibitor treatment offers substantial benefit for patients with asymptomatic LV systolic dysfunction.

Topics: Angiotensin-Converting Enzyme Inhibitors; Cardiac Volume; Drug Administration Schedule; Enalapril; Heart Failure; Hemodynamics; Humans; Hypertrophy, Left Ventricular; Prognosis; Randomized Controlled Trials as Topic; Survival Rate; Treatment Outcome; Ventricular Dysfunction, Left

The aim of this study was to investigate the effect of sacubitril/valsartan (Sal/Val) on left ventricular (LV) remodeling in patients with LV systolic dysfunction following acute anterior wall myocardial infarction (AAMI).. AAMI patients with LV systolic dysfunction were enrolled in this study. All patients underwent percutaneous coronary intervention. After hemodynamic stabilization, patients were randomly assigned either to group T (Sal/Val treatment) or group C (enalapril treatment). Changes in echocardiographic parameters and plasma biochemical markers were used to evaluate the effects of Sal/Val on LV remodeling and cardiac function. The incidence of major cardiac adverse events (MACEs) and adverse reactions during follow-ups was also recorded.. In total, 137 eligible patients were prospectively included. Compared to group C, LV ejection fraction significantly improved (P < 0.05), while the LV end-systolic volume index and wall motion score index showed a tendency to decrease in group T. There was no difference in the LV end-diastolic volume index between groups. During follow-ups, the plasma N-terminal pro-B-type natriuretic peptide and soluble suppression of tumorigenesis-2 levels in both groups decreased (all P < 0.05), and the change was more prominent in group T. Additionally, drug-related adverse effects were similar between the two groups (P > 0.05); however, the incidence of MACEs was lower in group T than in group C (39.71% vs. 53.62%, P = 0.103), although the difference was insignificant.. Sac/Val attenuated LV remodeling and dysfunction and was safe and effective in LV systolic dysfunction patients post AAMI.

Topics: Aminobutyrates; Angiotensin Receptor Antagonists; Anterior Wall Myocardial Infarction; Biphenyl Compounds; Drug Combinations; Drug Monitoring; Echocardiography; Enalapril; Female; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Percutaneous Coronary Intervention; Stroke Volume; Treatment Outcome; Valsartan; Ventricular Dysfunction, Left; Ventricular Remodeling

In the Prospective Comparison of angiotensin receptor neprilysin inhibitor (ARNI) With ACEi to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) study, treatment with sacubitril/valsartan reduced the primary outcome of cardiovascular (CV) death and heart failure (HF) hospitalization compared with enalapril in patients with chronic HF and reduced ejection fraction (HFrEF). A prospective randomized trial was conducted to assess the efficacy and safety of sacubitril/valsartan in Japanese HFrEF patients.Methods and Results:In the Prospective comparison of ARNI with ACEi to determine the noveL beneficiaL trEatment vaLue in Japanese Heart Failure patients (PARALLEL-HF) study, 225 Japanese HFrEF patients (New York Heart Association [NYHA] class II-IV, left ventricular ejection fraction [LVEF] ≤35%) were randomized (1 : 1) to receive sacubitril/valsartan 200 mg bid or enalapril 10 mg bid. Over a median follow up of 33.9 months, no significant between-group difference was observed for the primary composite outcome of CV death and HF hospitalization (HR 1.09; 95% CI 0.65-1.82; P=0.6260). Early and sustained reductions in N-terminal pro-brain natriuretic peptide (NT-proBNP) from baseline were observed with sacubitril/valsartan compared with enalapril (between-group difference: Week 2: 25.7%, P<0.01; Month 6: 18.9%, P=0.01, favoring sacubitril/valsartan). There was no significant difference in the changes in NYHA class and Kansas City Cardiomyopathy Questionnaire (KCCQ) clinical summary score at Week 8 and Month 6. Sacubitril/valsartan was well tolerated with fewer study drug discontinuations due to adverse events, although the sacubitril/valsartan group had a higher proportion of patients with hypotension.. In Japanese patients with HFrEF, there was no difference in reduction in the risk of CV death or HF hospitalization between sacubitril/valsartan and enalapril, and sacubitril/valsartan was safe and well tolerated.

Topics: Aminobutyrates; Angiotensin Receptor Antagonists; Biphenyl Compounds; Drug Combinations; Enalapril; Heart Failure; Humans; Japan; Prospective Studies; Stroke Volume; Tetrazoles; Treatment Outcome; Valsartan; Ventricular Dysfunction, Left; Ventricular Function, Left

X-linked Duchenne muscular dystrophy (DMD), the most frequent human hereditary skeletal muscle myopathy, inevitably leads to progressive dilated cardiomyopathy. We assessed the effect and safety of a combined treatment with the ACE-inhibitor enalapril and the β-blocker metoprolol in a German cohort of infantile and juvenile DMD patients with preserved left ventricular function.. Sixteen weeks single-arm open run-in therapy with enalapril and metoprolol followed by a two-arm 1:1 randomized double-blind placebo-controlled treatment in a multicenter setting.. DMD boys aged 10-14 years with left ventricular fractional shortening [LV-FS] ≥ 30% in echocardiography. Primary endpoint: time from randomization to first occurrence of LV-FS < 28%. Secondary: changes of a) LV-FS from baseline, b) blood pressure, c), heart rate and autonomic function in ECG and Holter-ECG, e) cardiac biomarkers and neurohumeral serum parameters, f) quality of life, and g) adverse events.. From 3/2010 to 12/2013, 38 patients from 10 sites were centrally randomized after run-in, with 21 patients continuing enalapril and metoprolol medication and 17 patients receiving placebo. Until end of study 12/2015, LV-FS < 28% was reached in 6/21 versus 7/17 patients. Cox regression adjusted for LV-FS after run-in showed a statistically non-significant benefit for medication over placebo (hazard ratio: 0.38; 95% confidence interval: 0.12 to 1.22; p = 0.10). Analysis of secondary outcome measures revealed a time-dependent deterioration of LV-FS with no statistically significant differences between the two study arms. Blood pressure, maximal heart rate and mean-NN values were significantly lower at the end of open run-in treatment compared to baseline. Outcome analysis 19 months after randomization displayed significantly lower maximum heart rate and higher noradrenalin and renin values in the intervention group. No difference between treatments was seen for quality of life. As a single, yet important adverse event, the reversible deterioration of walking abilities of one DMD patient during the run-in period was observed.. Our analysis of enalapril and metoprolol treatment in DMD patients with preserved left ventricular function is suggestive to delay the progression of the intrinsic cardiomyopathy to left ventricular failure, but did not reach statistical significance, probably due to insufficient sample size.. DRKS-number 00000115, EudraCT-number 2009-009871-36.

Topics: Adolescent; Adrenergic beta-1 Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Cardiomyopathies; Child; Double-Blind Method; Enalapril; Female; Humans; Kaplan-Meier Estimate; Male; Metoprolol; Muscular Dystrophy, Duchenne; Treatment Outcome; Ventricular Dysfunction, Left

Troponin changes over time have been suggested to allow for an early diagnosis of cardiac injury ensuing cancer chemotherapy; cancer patients with troponin elevation may benefit of therapy with enalapril. It is unknown whether a preventive treatment with enalapril may further increase the benefit.. The International CardioOncology Society-one trial (ICOS-ONE) was a controlled, open-label trial conducted in 21 Italian hospitals. Patients were randomly assigned to two strategies: enalapril in all patients started before chemotherapy (CT; 'prevention' arm), and enalapril started only in patients with an increase in troponin during or after CT ('troponin-triggered' arm). Troponin was assayed locally in 2596 blood samples, before and after each anthracycline-containing CT cycle and at each study visit; electrocardiogram and echocardiogram were done at baseline, and at 1, 3, 6 and 12-month follow-up. Primary outcome was the incidence of troponin elevation above the threshold.. Of the 273 patients, 88% were women, mean age 51 ± 12 years. The majority (76%) had breast cancer, 3% had a history of hypertension and 4% were diabetic. Epirubicin and doxorubicin were most commonly prescribed, with median cumulative doses of 360 [270-360] and 240 [240-240] mg/m. Low cumulative doses of anthracyclines in adult patients with low cardiovascular risk can raise troponins, without differences between the two strategies of giving enalapril. Considering a benefit of enalapril in the prevention of LV dysfunction, a troponin-triggered strategy may be more convenient.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Anthracyclines; Antineoplastic Agents; Cardiotoxicity; Enalapril; Female; Humans; Male; Middle Aged; Neoplasms; Troponin C; Ventricular Dysfunction, Left

Sacubitril/valsartan (LCZ696) is an angiotensin receptor neprilysin inhibitor approved for the treatment of adult heart failure (HF); however, the benefit of sacubitril/valsartan in pediatric HF patients is unknown.. This global multi-center study will use an adaptive, seamless two-part design. Part 1 will assess the pharmacokinetics/pharmacodynamics of single ascending doses of sacubitril/valsartan in pediatric (1 month to <18 years) HF patients with systemic left ventricle and reduced left ventricular systolic function stratified into 3 age groups (Group 1: 6 to <18 years; Group 2: 1 to <6 years; Group 3: 1 month to <1 year). Part 2 is a 52-week, efficacy and safety study where 360 eligible patients will be randomized to sacubitril/valsartan or enalapril. A novel global rank primary endpoint derived by ranking patients (worst-to-best outcome) based on clinical events such as death, initiation of mechanical life support, listing for urgent heart transplant, worsening HF, measures of functional capacity (NYHA/Ross scores), and patient-reported HF symptoms will be used to assess efficacy.. The PANORAMA-HF study, which will be the largest prospective pediatric HF trial conducted to date and the first to use a global rank primary endpoint, will determine whether sacubitril/valsartan is superior to enalapril for treatment of pediatric HF patients with reduced systemic left ventricular systolic function.

Topics: Adolescent; Aminobutyrates; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Biphenyl Compounds; Child; Child, Preschool; Dose-Response Relationship, Drug; Drug Combinations; Drug Therapy, Combination; Enalapril; Female; Follow-Up Studies; Heart Failure; Humans; Infant; Infant, Newborn; Male; Myocardial Ischemia; Prospective Studies; Systole; Tetrazoles; Time Factors; Treatment Outcome; Valsartan; Ventricular Dysfunction, Left; Ventricular Function, Left

Anthracycline (ANT) is a topoisomerase-interacting agent that is used in most malignancy treatments. We investigated the efficacy of enalapril (angiotensin-converting enzyme inhibitor) in the prevention of ANT-induced cardiomyopathy. In this randomized, single-blind, and placebo-controlled study, 69 patients with a newly diagnosed malignancy for which ANT therapy was planned were randomly assigned to either a group receiving enalapril (n = 34) or placebo (n = 35). Echocardiography studies were performed before chemotherapy and at 6 months after randomization. Additionally, troponin I and creatinine kinase-MB (CK-MB) were measured 1 month after the initiation of chemotherapy. In the enalapril group, the mean left ventricular ejection fraction (LVEF) (p = 0.58) was the same at baseline and 6 months after randomization. Conversely, LVEF significantly decreased in the control group (p < 0.001). Additionally, LV end systolic volume and left atrial diameter were significantly increased compared with the baseline measures in the control group. According to the tissue Doppler study, the mitral annuli early diastolic (e') and peak systolic (s') velocities were significantly reduced, and the E (the peak early diastolic velocity)/e' ratio was significantly increased in the control group. Furthermore, the TnI and CK-MB levels were significantly higher in the control group than in the enalapril group. Enalapril appears efficacious in preserving systolic and diastolic function in cancer patients treated with ANTs.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Anthracyclines; Antibiotics, Antineoplastic; Biomarkers; Cardiomyopathies; Cardiotoxicity; Creatine Kinase, MB Form; Cytoprotection; Echocardiography, Doppler; Enalapril; Female; Humans; Iran; Male; Middle Aged; Myocardial Contraction; Single-Blind Method; Stroke Volume; Time Factors; Topoisomerase Inhibitors; Treatment Outcome; Troponin I; Ventricular Dysfunction, Left; Ventricular Function, Left

To: (i) describe the baseline characteristics of patients in ATMOSPHERE and the changes in the planned analysis of ATMOSPHERE resulting from the mandated discontinuation of study treatment in patients with diabetes; (ii) compare the baseline characteristics of patients in ATMOSPHERE with those in the Prospective comparison of Angiotensin Receptor neprilysin inhibitors with Angiotensin converting enzyme inhibitors to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF); and (iii) compare the characteristics of patients with and without diabetes at baseline in ATMOSPHERE.. A total of 7063 patients were randomized into ATMOSPHERE April 2009-April 2014 at 755 sites in 43 countries. Their average age was 63 years and 78% were men. ATMOSPHERE patients were generally similar to those in PARADIGM-HF although fewer had diabetes, renal dysfunction, and were treated with a mineralocorticoid receptor antagonist. In ATMOSPHERE, patients with diabetes differed in numerous ways from those without. Patients with diabetes were older and had worse heart failure status but a similar left ventricular ejection fraction (mean 28%); they had a higher body mass index and more co-morbidity, especially hypertension and coronary heart disease. Mean estimated glomerular filtration rate was slightly lower in those with diabetes compared with those without.. ATMOSPHERE will determine whether patients with HF and reduced ejection fraction (particularly those without diabetes) benefit from the addition of a direct renin inhibitor to standard background therapy, including an angiotensin-converting enzyme inhibitor, beta-blocker, and a mineralocorticoid receptor antagonist. ATMOSPHERE will also determine whether aliskiren alone is superior to, or at least non-inferior to, enalapril.

Topics: Amides; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Agents; Diabetes Mellitus; Drug Therapy, Combination; Enalapril; Female; Fumarates; Heart Failure; Humans; Male; Middle Aged; Renin; Stroke Volume; Ventricular Dysfunction, Left

Comorbidities are frequent in heart failure and impact outcomes. It is not known whether comorbidities are associated with outcomes in asymptomatic left ventricular dysfunction compared to clinical heart failure and whether comorbidities interfere with treatment effects. Our objective was to assess comorbidities and their effects on outcomes in predominantly asymptomatic populations without previous heart failure treatment of the SOLVD prevention trial, compared to symptomatic heart failure patients of SOLVD treatment and to evaluate associations to the effect of enalapril.. This post hoc analysis from the SOLVD prevention and SOLVD treatment trials includes 4228 patients with left ventricular dysfunction and 2569 patients with heart failure. The preexisting comorbidities hypertension, diabetes mellitus, pulmonary disease, angina pectoris, renal impairment, and anaemia were similar in SOLVD treatment and SOLVD prevention, with a higher prevalence in SOLVD treatment. Comorbidities are significantly associated with the primary composite of SOLVD time to death or heart failure hospitalization (SOLVD prevention: HR 4.8, CI: 3.2-7.18, P < 0.0001; SOLVD treatment: HR 2.9, CI: 2.12-3.95, P < 0.0001 for more than four comorbidities vs. no comorbidities), and to death, heart failure hospitalization, and cardiovascular death where the effect of the number of coexisting comorbidities was additive. There was no significant interaction of comorbidities with treatment effects of enalapril.. Comorbidities increased events in asymptomatic left ventricular dysfunction and in symptomatic heart failure, but did not interfere with the effects of enalapril. Comorbidities need to be adequately addressed in clinical trials, which should also involve non-cardiac treatments in order to improve outcome for heart failure patients.

Topics: Angiotensin-Converting Enzyme Inhibitors; Comorbidity; Enalapril; Female; Heart Failure; Humans; Male; Middle Aged; Prognosis; Survival Rate; Ventricular Dysfunction, Left

This study sought to evaluate the efficacy of enalapril and carvedilol to prevent chemotherapy-induced left ventricular systolic dysfunction (LVSD) in patients with hematological malignancies.. Current chemotherapy may induce LVSD. Angiotensin-converting enzyme inhibitors and beta-blockers prevent LVSD in animal models of anthracycline-induced cardiomyopathy.. In this randomized, controlled study, 90 patients with recently diagnosed acute leukemia (n = 36) or patients with malignant hemopathies undergoing autologous hematopoietic stem cell transplantation (HSCT) (n = 54) and without LVSD were randomly assigned to a group receiving enalapril and carvedilol (n = 45) or to a control group (n = 45). Echocardiographic and cardiac magnetic resonance (CMR) imaging studies were performed before and at 6 months after randomization. The primary efficacy endpoint was the absolute change from baseline in LV ejection fraction (LVEF).. The mean age of patients was 50 ± 13 years old, and 43% were women. At 6 months, LVEF did not change in the intervention group but significantly decreased in controls, resulting in a -3.1% absolute difference by echocardiography (p = 0.035) and -3.4% (p = 0.09) in the 59 patients who underwent CMR. The corresponding absolute difference (95% confidence interval [CI]) in LVEF was -6.38% (95% CI: -11.9 to -0.9) in patients with acute leukemia and -1.0% (95% CI: -4.5 to 2.5) in patients undergoing autologous HSCT (p = 0.08 for interaction between treatment effect and disease category). Compared to controls, patients in the intervention group had a lower incidence of the combined event of death or heart failure (6.7% vs. 22%, p = 0.036) and of death, heart failure, or a final LVEF <45% (6.7% vs. 24.4%, p = 0.02).. Combined treatment with enalapril and carvedilol may prevent LVSD in patients with malignant hemopathies treated with intensive chemotherapy. The clinical relevance of this strategy should be confirmed in larger studies. (Prevention of Left Ventricular Dysfunction During Chemotherapy [OVERCOME]; NCT01110824).

Topics: Adult; Antineoplastic Agents; Carbazoles; Carvedilol; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Echocardiography, Doppler; Enalapril; Female; Follow-Up Studies; Hematologic Neoplasms; Humans; Male; Middle Aged; Propanolamines; Reference Values; Risk Assessment; Severity of Illness Index; Survival Rate; Treatment Outcome; Ventricular Dysfunction, Left

Diastolic dysfunction (DD) is a frequent condition in hypertensive patients whose presence increases mortality and whose treatment remains unclear. The aim of this study was to investigate in a prospective, double-blinded, placebo-controlled randomized design the additive effect of simvastatin on DD in enalapril-treated hypertensive patients with average cholesterol levels.. Hypertensive patients with DD and LDL-cholesterol <160 mg/dL underwent a run-in phase to achieve a systolic blood pressure (SBP) <135 mmHg and diastolic blood pressure (DBP) <85 mmHg with enalapril. Hydrochlorothiazide was added when need to achieve blood pressure control. Four weeks after reaching the optimum anti-hypertensive regimen patients were randomized to receive 80 mg simvastatin (n=27) or placebo (n=28) for a period of 20 weeks. Echocardiograms were performed before and after treatment with measurement of maximum left atrial volume (LAV), conventional and tissue Doppler velocities in early diastole (E, e') and late diastole (A, a').. After 20 weeks, the simvastatin group presented reduction in SBP (-4±2 mmHg, p=0.02), increase in E/A ratio (1.0±0.05 to 1.2±0.06, p=0.03) and decrease of LAV indexed to body surface area (24.5±0.9 to 21.1±0.8 ml/m(2), p=0.048), as compared with placebo arm. No change in systolic function and no correlation between the E/A ratio, LAV and changes in blood pressure or lipid profile were observed.. The addition of simvastatin to enalapril in hypertensive patients with average cholesterol levels improves parameters of diastolic function independently of changes in blood pressure or cholesterol.

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Biomarkers; Blood Pressure; Brazil; Chi-Square Distribution; Cholesterol; Diastole; Diuretics; Double-Blind Method; Drug Therapy, Combination; Echocardiography, Doppler; Enalapril; Female; Humans; Hydrochlorothiazide; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertension; Male; Middle Aged; Prospective Studies; Regression Analysis; Simvastatin; Stroke Volume; Time Factors; Treatment Outcome; Ventricular Dysfunction, Left; Ventricular Function, Left

The current treatment of hematologic malignancies includes diverse potentially cardiotoxic chemotherapy agents, including high-dose myeloablative regimens used in autologous hematopoietic stem cell transplantation (HSCT). Many of these treatments could induce left ventricular dysfunction (LVD), and limit their efficacy. Angiotensin-converting enzime inhibitors and beta-blockers prevent LVD and prolong survival after infarction, and recent animal and pilot clinical studies suggest that they can prevent the development of chemotherapy-induced cardiac toxicity.. This is a prevention, parallel-assignment, randomized, controlled, clinical efficacy study. Ninety patients recently diagnosed of acute leukemia or undergoing autologous HSCT and with normal LV ejection fraction will be randomized to enalapril and carvedilol or to the control group. Echocardiogram and a cardiac magnetic resonance imaging studies will be performed at baseline and 6-9 months after randomization. The primary efficacy endpoint is the change from baseline in LV ejection fraction. Secondary endpoints include the assessment of LV volumes and diastolic function, and the incidence of death, heart failure, or LVD.. The OVERCOME study will be the first clinical trial to test the preventive efficacy on LVD of combined treatment with enalapril and carvedilol administered to patients with hematologic malignancies submitted to current treatment with intensive chemotherapy.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Carbazoles; Carvedilol; Drug Therapy, Combination; Enalapril; Female; Follow-Up Studies; Humans; Male; Middle Aged; Propanolamines; Sample Size; Treatment Outcome; Ventricular Dysfunction, Left; Young Adult

Worsening renal function (WRF) in the setting of heart failure has been associated with increased mortality. However, it is unclear if this decreased survival is a direct result of the reduction in glomerular filtration rate (GFR) or if the mechanism underlying the deterioration in GFR is driving prognosis. Given that WRF in the setting of angiotensin-converting enzyme inhibitor (ACE-I) initiation is likely mechanistically distinct from spontaneously occurring WRF, we investigated the relative early WRF-associated mortality rates in subjects randomized to ACE-I or placebo.. Subjects in the Studies Of Left Ventricular Dysfunction (SOLVD) limited data set (n=6337) were studied. The interaction between early WRF (decrease in estimated GFR ≥20% at 14 days), randomization to enalapril, and mortality was the primary end point. In the overall population, early WRF was associated with increased mortality (adjusted hazard ratio [HR], 1.2; 95% CI, 1.0-1.4; P=0.037). When analysis was restricted to the placebo group, this association strengthened (adjusted HR, 1.4; 95% CI, 1.1-1.8; P=0.004). However, in the enalapril group, early WRF had no adverse prognostic significance (adjusted HR, 1.0; 95% CI, 0.8-1.3; P=1.0; P=0.09 for the interaction). In patients who continued to receive study drug despite early WRF, a survival advantage remained with enalapril therapy (adjusted HR, 0.66; 95% CI, 0.5-0.9; P=0.018).. These data support the notion that the mechanism underlying WRF is important in determining its prognostic significance. Specifically, early WRF in the setting of ACE-I initiation appears to represent a benign event that is not associated with a loss of benefit from continued ACE-I therapy.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Cardio-Renal Syndrome; Enalapril; Female; Glomerular Filtration Rate; Heart Failure; Humans; Kidney; Male; Middle Aged; Prognosis; Retrospective Studies; Survival Rate; Ventricular Dysfunction, Left

A provocative finding from several double-blind clinical trials has been the association between greater adherence to placebo study medication and better health outcomes. We used data from the Studies of Left Ventricular Dysfunction (SOLVD) Treatment Trial (SOLVD-TT) and the SOLVD Prevention Trial (SOLVD-PT) to examine whether such associations could be validated and to examine several sources of bias and potential confounding.. Survival analytic methods were used to estimate the association between placebo adherence and several health outcomes, employing a number of modeling techniques to test for the existence of alternative explanations for the association. Higher adherence was defined as having taken ≥75% of prescribed study medication.. Higher placebo adherence was associated with improved overall survival in both SOLVD-TT and SOLVD-PT [hazard ratio (HR) = 0.52, 95% confidence interval (CI): 0.35 to 0.79 and HR = 0.52, 95%CI: 0.38 to 0.71, respectively]. Associations were similar for fatal or non-fatal cardiovascular or coronary heart disease events. Adjustment for both modifiable and non-modifiable cardiac risk factors (including age, gender, diabetes, blood pressure, smoking, weight, alcohol use, and levels of education) had minimal effect on the strength of the association. Little evidence of bias was found as an explanation for this relationship.. In these two trials, better adherence to placebo was associated with markedly superior health outcomes, including total in-study mortality and incident cardiovascular events. No important confounders were identified. These data suggest there may exist strong but unrecognized determinants of health outcomes for which placebo adherence is a marker.

Topics: Adult; Aged; Double-Blind Method; Enalapril; Female; Follow-Up Studies; Heart Failure; Humans; Male; Middle Aged; Morbidity; Patient Compliance; Placebo Effect; Treatment Outcome; Ventricular Dysfunction, Left

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) effectively interfere with the sympathetic nerve activity in patients with left ventricular (LV) dysfunction. The aim of this study was to examine the effect of ARBs on sympathetic nerve activity and baroreflex function in patients with LV dysfunction already receiving ACE inhibitors.. Twenty patients with LV dysfunction already treated with ACE inhibitor (enalapril 5 mg/day) were randomly divided into two groups: treatment with 10 mg/day enalapril (control group) or 5 mg/day enalapril plus 80 mg/day valsartan (combination group). In both groups, resting muscle sympathetic nerve activity (MSNA; microneurography), arterial baroreflex sensitivity, and cardiopulmonary baroreflex sensitivity were measured at baseline and 4 weeks after the treatment. Arterial baroreflexes were perturbed by phenylephrine method, and cardiopulmonary baroreflexes were perturbed by lower body negative pressure (-10 mmHg).. Baseline characteristics in both groups were similar. Resting MSNA decreased significantly from 35.4+/-10.8 to 26.4+/-5.1 burst/min (p<0.05), while arterial baroreflex sensitivity improved significantly from 6.0+/-2.0 to 10.1+/-2.6 ms/mmHg in the combination group. Moreover, cardiopulmonary baroreflex control of MSNA improved significantly from 15.8+/-12.2 to 42.0+/-26.7% (p<0.05) in the combination group. However, there were no significant changes in arterial baroreflex sensitivity and cardiopulmonary baroreflex of MSNA in the control group.. Addition of ARB to ACE inhibitor treatment reduced sympathetic nerve activity and augmented arterial and cardiopulmonary baroreflex sensitivity in patients with LV dysfunction.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Arteries; Baroreflex; Drug Synergism; Enalapril; Female; Heart; Hemodynamics; Humans; Lung; Male; Middle Aged; Sympathetic Nervous System; Tetrazoles; Valine; Valsartan; Ventricular Dysfunction, Left

Genetic factors play an important role in linking insulin resistance and hypertension, also influencing insulin sensitivity changes during antihypertensive treatment. This study was aimed to evaluate whether genetic predisposition to hypertension can also influence left ventricular (LV) changes during antihypertensive treatment.. We enrolled 36 never-treated hypertensives: 18 with both parents hypertensive (F+) and 18 with both parents normotensive (F-), matched for age, gender, and body mass index (BMI). The patients were evaluated twice, before and after 2.5 years of treatment with enalapril. At both evaluations the patients underwent: 24-h blood pressure (BP) monitoring, LV echocardiogram, and oral glucose tolerance test, with measurements of glucose and insulin levels.. At basal evaluation the two groups were not different with regard to gender, age, BMI, 24-h BP, and fasting glucose; glucose metabolic clearance rate was significantly lower in F+. The LV mass index was similar between the groups, whereas diastolic parameters were significantly lower in F+. At second evaluation, 24-h BP and LV mass were decreased to the same extent in both groups; glucose metabolic clearance rate significantly increased in F- and remained unchanged in F+. The improvement of LV diastolic function, found in both group, was significantly greater in F-.. Genetic predisposition to hypertension, in addition to affecting insulin sensitivity, influences LV functional changes during antihypertensive treatment. Despite a similar extent of 24-h BP and LV mass decrease, F+ patients showed no changes in insulin sensitivity and a smaller improvement in LV diastolic function than F-.

Topics: Adult; Antihypertensive Agents; Blood Glucose; Blood Pressure; Cardiomegaly; Electrocardiography; Enalapril; Female; Genetic Predisposition to Disease; Glucose Tolerance Test; Heart Rate; Humans; Hypertension; Insulin Resistance; Male; Middle Aged; Ventricular Dysfunction, Left

Mitral insufficiency is known to occur in a substantial proportion of patients with heart failure. Its relationship with morbidity and mortality is poorly described.. The mortality and hospitalization for heart failure were retrospectively examined in patients who underwent baseline echocardiography in the Studies Of Left Ventricular Dysfunction (SOLVD) treatment and prevention trials. The presence and grade of mitral insufficiency was assessed, and patients with and without mitral insufficiency were compared.. Patients with left ventricular dysfunction and mitral insufficiency had greater than twofold increased risk of death or admission for heart failure over two years (RR 2.38, 95% CI 1.43 to 3.97). This excess risk persisted after adjustment for the severity of heart failure, etiology and differences in treatment (RR 1.82, 95% CI 1.04 to 3.17; P=0.04). The presence of moderate mitral insufficiency versus no insufficiency was associated with even greater independent risk (RR 2.20, 95% CI 1.01 to 4.80; P=0.05). Results were consistent with binary and ordinal analysis of mitral insufficiency.. The presence of mitral insufficiency in patients with left ventricular dysfunction is independently associated with adverse outcomes, including death and hospitalization for heart failure. This has potentially important clinical implications for the assessment and management of patients with heart failure.

Topics: Adult; Aged; Aged, 80 and over; Comorbidity; Enalapril; Female; Heart Failure; Hospitalization; Humans; Male; Middle Aged; Mitral Valve Insufficiency; Risk Factors; Stroke Volume; Ultrasonography; Ventricular Dysfunction, Left

Impaired cardiac function is frequently accompanied by peripheral vascular dysfunction and a pro-inflammatory condition, which may be associated with elevated levels of angiotensin II. We hypothesized that the magnitude of flow mediated dilatation (FMD) of the brachial artery of post myocardial infarction patients will correlate with serum levels of tumor necrosis factor alpha (TNFalpha) and C-reactive protein (CRP), and that treatment with angiotensin converting enzyme inhibitors (ACEI) will increase FMD by reducing TNFalpha and CRP. Patients were treated with low dose (10 mg/day) quinapril (Q) or enalapril (E) and their effects on FMD and inflammatory markers were evaluated after 8 and 12 weeks. Before treatment, in both groups FMD showed a low value (Q: 2.95+0.42% and E: 3.3+/-0.33%), whereas TNF-alpha (Q: 31.65+/-8.23 pg/ml and E: 29.5+/-5.9 pg/ml) and CRP (Q: 7.28+/-2.96 mg/ml and E: 7.08+/-3.02 mg/ml) were elevated. In the Q group, but not in the E group FMD increased significantly, (to 5.96+1.10%), whereas TNF-alpha (19.0+/-12.21 pg/ml) and CRP (to 3.91+/-1.82 mg/L) significantly decreased after 8 and 12 weeks of Q treatment. Moreover, the magnitude of FMD showed a strong inverse correlation with serum levels of TNF-alpha and CRP after Q treatment. Thus, in post myocardial infarction patients endothelial dysfunction assessed by FMD correlates with elevated levels of plasma inflammatory markers, and low dose quinapril improves endothelial function, likely by reducing vascular inflammation.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Brachial Artery; C-Reactive Protein; Enalapril; Endothelium, Vascular; Female; Humans; Male; Middle Aged; Quinapril; Regional Blood Flow; Stroke Volume; Tetrahydroisoquinolines; Tumor Necrosis Factor-alpha; Ultrasonography, Doppler; Vasodilation; Ventricular Dysfunction, Left; Ventricular Function, Left

To compare the effect of the dual endothelin A/B receptor antagonist enrasentan with enalapril on left ventricular (LV) remodelling.. Multicentre, randomised, double blind, parallel group study of 72 asymptomatic patients with LV dysfunction. Patients received enrasentan (60-90 mg/day) or enalapril (10-20 mg/day). The primary end point was the change in LV end diastolic volume index (EDVI) after six months' treatment.. LV EDVI increased with enrasentan but decreased with enalapril (3.9 (1.8) v -3.4 (1.4) ml/m2, p = 0.001). Enrasentan increased resting cardiac index compared with enalapril (0.11 (0.07) v -0.10 (0.07) l/m2, p = 0.04), as well as LV mass index (0.67 (1.6) v -3.6 (1.6) g/m2, p = 0.04). Other variables were comparable between groups. Enalapril lowered brain natriuretic peptide more than enrasentan (-19.3 (9.4) v -5.8 (6.9) pg/ml, p = 0.005). Noradrenaline (norepinephrine) (p = 0.02) increased more with enrasentan than with enalapril. Enrasentan was associated with more serious adverse events compared with enalapril (six (16.7%) patients v one (2.8%), p = 0.02); the rate of progression of heart failure did not differ.. In asymptomatic patients with LV dysfunction, LV EDVI increased over six months with enrasentan compared with enalapril treatment, with adverse neurohormonal effects. This suggests that enrasentan at a dose of 60-90 mg/day over six months causes adverse ventricular remodelling despite an increase in the resting cardiac index.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Carboxylic Acids; Disease Progression; Enalapril; Female; Heart Failure; Humans; Indans; Magnetic Resonance Angiography; Male; Middle Aged; Neurotransmitter Agents; Treatment Outcome; Ventricular Dysfunction, Left; Ventricular Remodeling

An increase in troponin I soon after high-dose chemotherapy (HDC) is a strong predictor of poor cardiological outcome in cancer patients. This finding has important clinical implications and provides a rationale for the development of prophylactic strategies for preventing cardiotoxicity. Angiotensin-converting enzyme inhibitors slow the progression of left ventricular dysfunction in different clinical settings, but their role in the prevention of cardiotoxicity has never been investigated.. Of the 473 cancer patients evaluated, 114 (72 women; mean age, 45+/-12 years) who showed a troponin I increase soon after HDC were randomized to receive (angiotensin-converting enzyme inhibitor group; 20 mg/d; n=56) or not to receive (control subjects; n=58) enalapril. Treatment was started 1 month after HDC and continued for 1 year. Cardiological evaluation was performed at baseline and at 1, 3, 6, and 12 months after HDC. The primary end point was an absolute decrease >10 percent units in left ventricular ejection fraction, with a decline below the normal limit value. A significant reduction in left ventricular ejection fraction and an increase in end-diastolic and end-systolic volumes were observed only in untreated patients. According to the Kaplan-Meier analysis, the incidence of the primary end point was significantly higher in control subjects than in the angiotensin-converting enzyme inhibitor group (43% versus 0%; P<0.001).. In high-risk, HDC-treated patients, defined by an increased troponin I value, early treatment with enalapril seems to prevent the development of late cardiotoxicity.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Antineoplastic Agents; Cardiomyopathies; Disease Progression; Dose-Response Relationship, Drug; Enalapril; Endpoint Determination; Female; Humans; Male; Middle Aged; Predictive Value of Tests; Prospective Studies; Risk Factors; Stroke Volume; Troponin I; Ventricular Dysfunction, Left

The use of digitalis is recommended for the treatment of heart failure to reduce hospitalization. Recent data suggest that digitalis treatment may adversely affect survival in women but not in men. We studied patients with left ventricular dysfunction enrolled in the Studies of Left Ventricular Dysfunction (SOLVD) to determine whether there was a gender-based survival difference in patients treated with digitalis.. Symptomatic (n = 2569) and asymptomatic (n = 4228) patients with left ventricular ejection fraction < or = 0.35 were studied. Digitalis use was assessed at baseline and baseline demographic variables were catalogued and compared. A multivariate analysis, incorporating known covariates of risk for adverse cardiovascular events, was used to examine the association of digitalis with all-cause mortality, cardiovascular death, death from heart failure, and arrhythmic death, with, or without, worsening heart failure in women compared with men. Analysis for an interaction between digitalis and gender on mortality was also performed. No interaction between gender and digitalis treatment on survival was found, and there was no significant difference in the hazard ratios for men and women on digitalis either with respect to all-cause mortality, cardiovascular mortality, heart failure mortality, or arrhythmic death with worsening heart failure. When mortality for arrhythmic death without worsening heart failure was adjusted for the probability of being treated with digitalis (propensity analysis), women fared better than men.. Data from the SOLVD trials suggest that digitalis treatment of heart failure does not result in a difference in survival between men and women. Because a randomized trial to definitively answer the question is unlikely, and perhaps inappropriate, examination of other heart failure populations for a gender-digitalis interaction is indicated.

Topics: Angiotensin-Converting Enzyme Inhibitors; Cause of Death; Digitalis Glycosides; Double-Blind Method; Enalapril; Female; Heart Failure; Humans; Male; Middle Aged; Multivariate Analysis; Sex Factors; Survival Analysis; Treatment Outcome; Ventricular Dysfunction, Left

Although various neurohormones at initial measurement confer prognostic value in heart failure and correlate with the left ventricular ejection fraction (EF) and cardiac volumes, the significance of their temporal changes (Delta) remains undetermined. This study examined temporal changes in neurohormones related to cardiac remodeling and prognosis in patients with systolic dysfunction and heart failure receiving therapeutic inhibition of the renin-angiotensin-aldosterone system. Temporal changes in plasma renin, angiotensin-II, aldosterone, epinephrine, norepinephrine, B-type natriuretic peptide (BNP), and N-terminal atrial natriuretic peptide (NT-ANP) in 768 treated patients with heart failure measured at baseline and 17 and 43 weeks after randomization were examined for their relations with concurrent changes in the EF, cardiac volumes, and risk for subsequent adverse clinical outcomes. Increasing BNP (p < 0.0001) and NT-ANP (p = 0.01) over time were associated with a concurrent decreasing EF, increasing end-diastolic volume (EDV), and increasing end-systolic volume (ESV; all p < 0.0001). In multivariable analysis, DeltaBNP and DeltaNT-ANP were independent predictors of DeltaESV and DeltaEDV, whereas DeltaBNP also predicted DeltaEF (all p < 0.0001). Patients who died or experienced heart failure hospitalization had larger antecedent increases in NT-ANP (+293.7 vs -21.5 pmol/ml, p = 0.006) and lesser decreases in norepinephrine (-22.3 vs -48.5 pg/ml, p = 0.04). Increasing NT-ANP (hazard ratio [HR] 3.45, p = 0.009) and norepinephrine (HR 2.04, p = 0.02) over time independently predicted increased risk for subsequent death or heart failure hospitalization. In conclusion, in treated patients with heart failure, increasing NT-ANP and BNP over time predict a decreasing EF and ventricular dilatation, while increasing NT-ANP and norepinephrine independently predict greater mortality and morbidity. Serial measurements of these neurohormones may serve as useful surrogate markers of ventricular remodeling and prognosticators for clinical risk stratification.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Biomarkers; Biphenyl Compounds; Cardiac Output; Chromatography, High Pressure Liquid; Double-Blind Method; Drug Therapy, Combination; Enalapril; Female; Heart Failure; Humans; Male; Middle Aged; Neurotransmitter Agents; Prognosis; Systole; Tetrazoles; Treatment Outcome; Ventricular Dysfunction, Left; Ventricular Remodeling

Management guidelines for heart failure recommend ACE-I and beta-blockers. The perception of difficult up-titration might have added to the slow uptake of beta-blockers despite their mortality and morbidity benefits.. CARMEN offered a possibility to study safety and tolerability of enalapril against carvedilol and their combination.. Five hundred and seventy-two patients were blindly up-titrated on carvedilol (target 25 mg bid) and/or enalapril (target 10 mg bid), and continued for 18 months. In the combination arm, carvedilol was up-titrated before enalapril.. There was no group related difference in adverse events during up-titration. Withdrawal rates were 31, 30 and 30%, and serious adverse events 28, 29 and 34% in the combination, carvedilol and enalapril arms. Mortality was similar in all groups (all-cause N=14, 14 and 14; cardiovascular N=9, 13 and 14). All-cause and cardiovascular hospitalizations occurred in 26, 27 and 32%, and in 12, 16 and 22% in the combination, carvedilol and enalapril arms, respectively.. The safety profile was similar in all treatment arms. In contrast to common perception, there was no difference in tolerability between the ACE-I and carvedilol. This result is even more remarkable as the high prestudy use of ACE-I (65%) might have introduced a bias by selecting ACE-I tolerant patients, who were only switched from their former ACE-I to enalapril.

Topics: Adolescent; Adrenergic beta-Antagonists; Adult; Aged; Aged, 80 and over; Angiotensin-Converting Enzyme Inhibitors; Biomarkers; Blood Pressure; Carbazoles; Carvedilol; Creatinine; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Enalapril; Female; Follow-Up Studies; Heart Failure; Heart Rate; Hospitalization; Humans; Kidney; Male; Middle Aged; Propanolamines; Severity of Illness Index; Survival Analysis; Time Factors; Treatment Outcome; Ventricular Dysfunction, Left; Ventricular Remodeling; Withholding Treatment

In the studies of left ventricular dysfunction (SOLVD), enalapril reduced mortality in patients with symptomatic but not asymptomatic left ventricular systolic dysfunction during the trial. We did a 12-year follow-up of SOLVD to establish if the mortality reduction with enalapril among patients with heart failure was sustained, and whether a subsequent reduction in mortality would emerge among those with asymptomatic ventricular dysfunction.. Of the 6797 patients previously enrolled in the SOLVD prevention and treatment trials, we ascertained the subsequent vital status of 5165 individuals who were alive when the trials had been completed. Follow-up was done through direct contacts in Belgium and linkages with national death registries and federal beneficiary or historic tax summary files in the USA and Canada.. Follow-up was 99.8% (6784/6797) complete. In the prevention trial, 50.9% (1074/2111) of the enalapril group had died compared with 56.4% (1195/2117) of the placebo group (generalised Wilcoxon p=0.001). In the treatment trial, 79.8% (1025/1285) of the enalapril group had died compared with 80.8% (1038/1284) of the placebo group (generalised Wilcoxon p=0.01). The reductions in cardiac deaths were significant and similar in both trials. When data for the prevention and treatment trials were combined, the hazard ratio for death was 0.90 for the enalapril group compared with the placebo group (95% CI 0.84-0.95, generalised Wilcoxon p=0.0003). Enalapril extended median survival by 9.4 months in the combined trials (95% CI 2.8-16.5, p=0.004).. Treatment with enalapril for 3-4 years led to a sustained improvement in survival beyond the original trial period in patients with left ventricular systolic dysfunction, with an important increase in life expectancy.

Topics: Angiotensin-Converting Enzyme Inhibitors; Cause of Death; Enalapril; Female; Follow-Up Studies; Heart Failure; Humans; Life Expectancy; Male; Middle Aged; Ventricular Dysfunction, Left

The overall effect sizes estimated from randomized clinical trials may not apply similarly to all patients. Univariate subgroup analyses are often used to help determine the generalizability of a trial's results, but may themselves be misleading. We reanalyzed the Studies of Left Ventricular Dysfunction (SOLVD) to determine whether the treatment effect depended on the patients' baseline prognosis, defined on the basis of multiple clinical variables.. The SOLVD prevention (4228 patients) and the SOLVD treatment (2569 patients) trials were randomized, double-blind trials that studied the effect of enalapril in patients with reduced left-ventricular function or congestive heart failure. We combined both SOLVD populations and compared the results of a univariate analysis to a multivariate approach in which 3 patient subgroups were defined according to baseline risks for the combined end point of death or hospitalization for heart failure.. Enalapril treatment resulted in 24% fewer events. The strongest predictors of an event were ejection fraction, New York Heart Association classification and age, antiplatelet agents, history of diabetes mellitus, treatment with digoxin or diuretics, and race. Only ejection fraction produced a significant treatment interaction (P =.004). Consistent with the original SOLVD reports, this interaction was also demonstrable when ejection fraction was scaled into tertiles and examined on its own (P =.012). However, there was no interaction present when patients were divided into tertiles of multifactorial baseline risk.. We confirmed the treatment effect of enalapril, the impact of left-ventricular systolic function, and the negative prognostic importance of diabetes mellitus in this population. Although ejection fraction led to a subgroup-treatment interaction in the main SOLVD publications, a multifactorial approach to prognostic grouping abolished the interaction. These findings highlight the limitations of univariate subgroup analyses and illustrate that multivariate risk group analysis may be a complementary method for assessing the generalizability of the overall treatment effects observed in randomized trials.

Topics: Angiotensin-Converting Enzyme Inhibitors; Data Interpretation, Statistical; Enalapril; Heart Failure; Humans; Logistic Models; Multivariate Analysis; Prognosis; Randomized Controlled Trials as Topic; Risk; Treatment Outcome; Ventricular Dysfunction, Left

This study was undertaken to determine whether enalapril had comparable efficacy in black and white patients with asymptomatic left ventricular dysfunction (ALVD) in preventing the development of symptomatic heart failure (HF).. Recent studies have suggested that black patients with HF due to systolic dysfunction may derive less benefit than white patients with HF when treated with the same medication.. This is a post hoc analysis of the 4,054 black and white participants of the Studies of Left Ventricular Dysfunction Prevention Trial.. Randomization to enalapril was associated with a comparable reduction in the relative risk of the development of symptomatic HF in black (relative risk [RR] 0.67, 95% confidence interval [CI] 0.49, 0.92, p = 0.01) and white patients (RR 0.61, 95% CI 0.53, 0.70, p < 0.001). Treatment with enalapril was also associated with a comparable reduction in the risk of the development of HF requiring medical therapy and the composite end point of death or development of HF in black and white patients. Black as compared with white patients with ALVD were at increased risk of the development of symptomatic HF (RR 1.81, 95% CI 1.51, 2.17, p < 0.001) despite adjustment for available measures of disease severity.. Despite the increased absolute risk in black patients compared with white patients for the progression of ALVD, enalapril was equally efficacious in reducing the risk of progression of ALVD in these two ethnic groups.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Belgium; Black or African American; Black People; Canada; Double-Blind Method; Enalapril; Female; Heart Failure; Humans; Incidence; Male; Middle Aged; Multivariate Analysis; Risk; Time Factors; Treatment Outcome; United States; Ventricular Dysfunction, Left; White People

Few studies have prospectively and systematically explored the factors that acutely precipitate exacerbation of congestive heart failure (CHF) in patients with left ventricular dysfunction. Knowledge of such factors is important in designing measures to prevent deterioration of clinical status. The objective of this study was to prospectively describe the precipitants associated with exacerbation of CHF status in patients enrolled in the Randomized Evaluation of Strategies for Left Ventricular Dysfunction Pilot Study.. We conducted a 2-stage, multicenter, randomized trial in 768 patients with CHF who had an ejection fraction of less than 40%. Patients were randomly assigned to receive enalapril maleate, candesartan cilexetil, or both for 17 weeks, followed by randomization to receive metoprolol succinate or placebo for 26 weeks. Investigators systematically documented information on clinical presentation, management, and factors associated with the exacerbation for any episode of acute CHF during follow-up.. A total of 323 episodes of worsening of CHF occurred in 180 patients during 43 weeks of follow-up; 143 patients required hospitalization, and 5 died. Factors implicated in worsening of CHF status included noncompliance with salt restriction (22%); other noncardiac causes (20%), notably pulmonary infectious processes; study medications (15%); use of antiarrhythmic agents in the past 48 hours (15%); arrhythmias (13%); calcium channel blockers (13%); and inappropriate reductions in CHF therapy (10%).. A variety of factors, many of which are avoidable, are associated with exacerbation of CHF. Attention to these factors and patient education are important in the prevention of CHF deterioration.

Topics: Adrenergic beta-Antagonists; Aged; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Disease Progression; Double-Blind Method; Drug Therapy, Combination; Enalapril; Female; Heart Failure; Hospitalization; Humans; Male; Metoprolol; Middle Aged; Patient Compliance; Precipitating Factors; Prospective Studies; Severity of Illness Index; Stroke Volume; Tetrazoles; Treatment Outcome; Ventricular Dysfunction, Left

We recently reported a beneficial clinical effect of atenolol, a beta(1) selective adrenergic antagonist, in 100 ambulatory heart failure patients with low left ventricular ejection fraction (LVEF,

Topics: Adrenergic beta-Antagonists; Atenolol; Double-Blind Method; Enalapril; Exercise Test; Exercise Tolerance; Humans; Oxygen Consumption; Prospective Studies; Stroke Volume; Ventricular Dysfunction, Left

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Cross-Over Studies; Double-Blind Method; Drug Therapy, Combination; Enalapril; Fibrinolysis; Heart Failure; Humans; Losartan; Plasminogen Activator Inhibitor 1; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Ventricular Dysfunction, Left

The present analysis examines the prognostic implications of moderate renal insufficiency in patients with asymptomatic and symptomatic left ventricular systolic dysfunction.. Chronic elevations in intracardiac filling pressures may lead to progressive ventricular dilation and heart failure progression. The ability to maintain fluid balance and prevent increased intracardiac filling pressures is critically dependent on the adequacy of renal function.. This is a retrospective analysis of the Studies of Left Ventricular Dysfunction (SOLVD) Trials, in which moderate renal insufficiency is defined as a baseline creatinine clearance <60 ml/min, as estimated from the Cockroft-Gault equation.. In the SOLVD Prevention Trial, multivariate analyses demonstrated moderate renal insufficiency to be associated with an increased risk for all-cause mortality (Relative Risk [RR] 1.41; p = 0.001), largely explained by an increased risk for pump-failure death (RR 1.68; p = 0.007) and the combined end point death or hospitalization for heart failure (RR 1.33; p = 0.001). Likewise, in the Treatment Trial, multivariate analyses demonstrated moderate renal insufficiency to be associated with an increased risk for all-cause mortality (RR 1.41; p = 0.001), also largely explained by an increased risk for pump-failure death (RR 1.49; p = 0.007) and the combined end point death or hospitalization for heart failure (RR 1.45; p = 0.001).. Even moderate degrees of renal insufficiency are independently associated with an increased risk for all-cause mortality in patients with heart failure, largely explained by an increased risk of heart failure progression. These data suggest that, rather than simply being a marker of the severity of underlying disease, the adequacy of renal function may be a primary determinant of compensation in patients with heart failure, and therapy capable of improving renal function may delay disease progression.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Cause of Death; Creatinine; Disease Progression; Enalapril; Female; Heart Failure; Humans; Male; Middle Aged; Prognosis; Renal Insufficiency; Risk Factors; Stroke Volume; Survival Rate; Ventricular Dysfunction, Left

Clinical proteinuria is a risk factor for both end-stage renal disease and cardiovascular disease. The prevalence of clinical proteinuria, its correlates and predictive value, and the effect of ACE inhibitors in preventing clinical proteinuria in diabetic and nondiabetic patients with left ventricular (LV) dysfunction are unknown.. The Studies of Left Ventricular Dysfunction (SOLVD) trials were analyzed to determine the baseline distribution of clinical proteinuria and related cardiovascular risk factors, the effect of baseline proteinuria on the risk of hospitalization for congestive heart failure (CHF) and mortality, and the effect of enalapril in preventing new clinical proteinuria.. A total of 5,487 out of 6,797 SOLVD participants (81%) were assessed for proteinuria at baseline. A total of 177 patients (3.2%) had baseline proteinuria. These patients had significantly higher systolic (137 vs. 125 mmHg, P < or = 0.001) and diastolic (83 vs. 77 mmHg, P < or = 0.001) blood pressure levels, a higher prevalence of diabetes (41 vs. 18%, P < or = 0.001), a lower ejection fraction (26.2 vs. 27.3%, P < or = 0.05), and greater degree of CHF (New York Heart Association [NYHA] class III/IV in 22 vs. 10%, P < or = 0.001) than patients without baseline proteinuria. Patients with baseline proteinuria also had higher rates of hospitalization for CHF (relative risk 1.81 [95% CI 1.37-2.41], P = 0.0001) and mortality (1.73 [1.34-2.24], P = 0.0001). Enalapril prevented clinical proteinuria in diabetic patients (0.38 [0.17-0.81], P = 0.0123) but not in nondiabetic patients (1.43 [0.77-2.63], P = 0.2622) without baseline proteinuria.. Clinical proteinuria is an independent predictor of hospitalization for CHF and mortality in diabetic and nondiabetic patients with LV dysfunction. Enalapril significantly reduces the risk of clinical proteinuria in diabetic patients with LV dysfunction.

Topics: Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Double-Blind Method; Enalapril; Female; Humans; Male; Middle Aged; Proteinuria; Ventricular Dysfunction, Left; Ventricular Function, Left

This analysis was performed to assess whether beta-adrenergic blocking agent use is associated with reduced mortality in the Studies of Left Ventricular Dysfunction (SOLVD) and to determine if this relationship is altered by angiotensin-converting enzyme (ACE) inhibitor use.. The ability of beta-blockers to alter mortality in patients with asymptomatic left ventricular dysfunction is not well defined. Furthermore, the effect of beta-blocker use, in addition to an ACE inhibitor, on these patients has not been fully addressed.. This retrospective analysis evaluated the association of baseline beta-blocker use with mortality in 4,223 mostly asymptomatic Prevention trial patients, and 2,567 symptomatic Treatment trial patients.. The 1,015 (24%) Prevention trial patients and 197 (8%) Treatment trial patients receiving beta-blockers had fewer symptoms, higher ejection fractions and different use of medications than patients not receiving beta-blockers. On univariate analysis, beta-blocker use was associated with significantly lower mortality than nonuse in both trials. Moreover, a synergistic reduction in mortality with use of both a beta-blocker and enalapril was suggested in the Prevention trial. After adjusting for important prognostic variables with Cox multivariate analysis, the association of beta-adrenergic blocking agent use with reduced mortality remained significant for Prevention trial patients receiving enalapril. Lower rates of arrhythmic and pump failure death and risk of death or hospitalization for heart failure were observed.. The combination of a beta-blocker and enalapril was associated with a synergistic reduction in the risk of death in the SOLVD Prevention trial.

Topics: Adrenergic beta-Antagonists; Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Cause of Death; Drug Therapy, Combination; Enalapril; Female; Hemodynamics; Humans; Male; Middle Aged; Retrospective Studies; Survival Rate; Systole; Ventricular Dysfunction, Left; Ventricular Function, Left

The purpose of this study was to evaluate the relationship of baseline pulse pressure and mean arterial pressure to mortality in patients with left ventricular dysfunction.. Increased conduit vessel stiffness increases pulse pressure and pulsatile load, potentially contributing to adverse outcomes in patients with left ventricular dysfunction.. Pulse and mean arterial pressure were analyzed for their effect on mortality, adjusting for other modifiers of risk, using Cox proportional hazards regression analysis of data collected from 6,781 patients randomized into the Studies of Left Ventricular Dysfunction trials.. Pulse and mean arterial pressure were related positively to each other, age, ejection fraction and prevalence of diabetes and hypertension and inversely to prior myocardial infarction and beta-adrenergic blocking agent use. Higher pulse pressure was associated with increased prevalence of female gender, greater calcium channel blocking agent, digoxin and diuretic use, lower heart rate and a higher rate of reported smoking history. Higher mean arterial pressure was associated with higher heart rate, lower calcium channel blocker and digoxin use and lower New York Heart Association functional class. Over a 61-month follow-up 1,582 deaths (1,397 cardiovascular) occurred. In a multivariate analysis adjusting for the above covariates and treatment assignment, higher pulse pressure remained an independent predictor of total and cardiovascular mortality (total mortality relative risk, 1.05 per 10 mm Hg increment; 95% confidence interval, 1.01 to 1.10; p = 0.02). Mean arterial pressure was inversely related to total and cardiovascular mortality (total mortality relative risk, 0.89; 95% confidence interval, 0.85 to 0.94; p <0.0001).. One noninvasive blood pressure measurement provides two independent prognostic factors for survival. Increased conduit vessel stiffness, as assessed by pulse pressure, may contribute to increased mortality in patients with left ventricular dysfunction, independent of mean arterial pressure.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Double-Blind Method; Enalapril; Female; Humans; Male; Middle Aged; Myocardial Contraction; Prognosis; Pulsatile Flow; Sphygmomanometers; Survival Rate; Ventricular Dysfunction, Left; Ventricular Function, Left

Angiotensin converting enzyme (ACE) inhibition after myocardial infarction is associated with an improvement in plasma fibrinolytic parameters. The aim of the present study was to determine whether acute ACE inhibition and angiotensin II type 1 (AT1) receptor antagonism have similar effects in patients with heart failure.. Twenty patients with moderately severe chronic heart failure received enalapril 10 mg and losartan 50 mg on 2 separate occasions in a single-blind, randomized, crossover design. Plasma tissue plasminogen activator (t-PA) and plasminogen activator inhibitor type 1 (PAI-1) antigen and activity were measured at baseline and 6 hours after the dose. Acute administration of losartan but not of enalapril reduced plasma t-PA (11%; P=0.003) and PAI-1 (38%; P<0.001) antigen concentrations, which was associated with increases in t-PA (29%; P=0.03) and decreases in PAI-1 (48%; P=0.01) activity. Changes in plasma fibrinolytic parameters were more marked during losartan treatment (P<0.02), with a 3-fold greater reduction in plasma PAI-1 antigen concentrations (P<0.05).. Acute AT1 antagonism in patients with heart failure is associated with a significant improvement in plasma fibrinolytic parameters that is greater than during ACE inhibition. These beneficial effects of AT1 antagonism and ACE inhibition would therefore appear to be mediated principally through suppression of angiotensin II.

Topics: Aged; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Atrial Natriuretic Factor; Blood Pressure; Cardiomyopathy, Dilated; Cross-Over Studies; Enalapril; Female; Fibrinolysis; Heart Failure; Heart Rate; Hemodynamics; Humans; Losartan; Male; Myocardial Ischemia; Plasminogen Activator Inhibitor 1; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Single-Blind Method; Tissue Plasminogen Activator; Ventricular Dysfunction, Left

Topics: Adrenergic beta-Antagonists; Adult; Angiotensin-Converting Enzyme Inhibitors; Cardiomyopathy, Dilated; Enalapril; Female; Humans; Male; Metoprolol; Middle Aged; Ventricular Dysfunction, Left

We investigated the effects of candesartan (an angiotensin II antagonist) alone, enalapril alone, and their combination on exercise tolerance, ventricular function, quality of life (QOL), neurohormone levels, and tolerability in congestive heart failure (CHF).. Seven hundred sixty-eight patients in New York Heart Association functional class (NYHA-FC) II to IV with ejection fraction (EF) <0.40 and a 6-minute walk distance (6MWD) <500 m received either candesartan (4, 8, or 16 mg), candesartan (4 or 8 mg) plus 20 mg of enalapril, or 20 mg of enalapril for 43 weeks. There were no differences among groups with regard to 6MWD, NYHA-FC, or QOL. EF increased (P=NS) more with candesartan-plus-enalapril therapy (0.025+/-0.004) than with candesartan alone (0.015+/-0.004) or enalapril alone(0.015+/-0.005). End-diastolic (EDV) and end-systolic (ESV) volumes increased less with combination therapy (EDV 8+/-4 mL; ESV 1+/-4 mL; P<0.01) than with candesartan alone (EDV 27+/-4 mL; ESV 18+/-3 mL) or enalapril alone (EDV 23+/-7 mL; ESV 14+/-6 mL). Blood pressure decreased with combination therapy (6+/-1/4+/-1 mm Hg) compared with candesartan or enalapril alone (P<0.05). Aldosterone decreased (P<0.05) with combination therapy (23.2+/-5.3 pg/mL) at 17 but not 43 weeks compared with candesartan (0.7+/-7.8 pg/mL) or enalapril (-0.8+/-11. 3 pg/mL). Brain natriuretic peptide decreased with combination therapy (5.8+/-2.7 pmol/L; P<0.01) compared with candesartan (4. 4+/-3.8 pmol/L) and enalapril alone (4.0+/-5.0 pmol/L).. Candesartan alone was as effective, safe, and tolerable as enalapril. The combination of candesartan and enalapril was more beneficial for preventing left ventricular remodeling than either candesartan or enalapril alone.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Creatinine; Drug Combinations; Enalapril; Female; Heart Failure; Heart Rate; Hormones; Humans; Male; Middle Aged; Pilot Projects; Potassium; Tetrazoles; Ventricular Dysfunction, Left; Ventricular Function

Although angiotensin-converting enzyme inhibitor therapy reduces mortality rates in patients with congestive heart failure (CHF), it may also cause decreased renal function. Little information is available to predict which patients are at highest risk for this complication.. To quantify specific clinical predictors of reduction in renal function in patients with CHF who are prescribed angiotensin-converting enzyme inhibitor therapy.. We analyzed data from the Studies of Left Ventricular Dysfunction (SOLVD), a randomized, double-blind, placebo-controlled trial of enalapril for the treatment of CHF. There were 3379 patients randomly assigned to enalapril with a median follow-up of 974 days and 3379 patients randomly assigned to placebo with a mean follow-up of 967 days. Decreased renal function was defined as a rise in serum creatinine >/=0.5 mg/dL (44 micromol/L) from baseline. We used time-to-event analysis to identify potential predictors of decrease in renal function including age, baseline ejection fraction, baseline creatinine, low systolic blood pressure (<100 mm Hg), history of hypertension, diabetes, and use of antiplatelet, diuretic, and beta-blocker therapy.. Patients randomly assigned to enalapril had a 33% greater likelihood of decreased renal function than controls (P =.003). By multivariate analysis, in both the placebo and enalapril groups older age, diuretic therapy, and diabetes were associated with decreased renal function, whereas beta-blocker therapy and higher ejection fraction were renoprotective. Older age was associated with a greater risk of developing decreased renal function in both groups, but significantly more so in the enalapril group (enalapril: risk ratio [RR] 1.42 per 10 years, 95% confidence interval [CI] 1.32-1.52 with enalapril; placebo: RR 1.18, 95% CI 1.12-1.25). Diuretic therapy was likewise associated with a greater risk of decreased renal function in the enalapril group (RR 1.89, 95% CI 1.70-2.08) than in the placebo group (RR 1.35, 95% CI 1.09-1.66). Conversely, enalapril had a relative renoprotective effect (RR 1.33, 95% CI 1.13-1.53) compared with placebo (RR 1.96, 95% CI 1.57-2.44) in patients with diabetes. A lower risk of renal impairment was seen in both groups with beta-blocker therapy (RR 0.70, 95% CI 0.57-0.85) and higher baseline ejection fraction (RR 0.93 per 5% increment, 95% CI 0.91-0. 96).. Enalapril use caused a 33% increase in the risk of decreased renal function in patients with CHF. Diuretic use and advanced age increased this risk. Diabetes was associated with an increased risk of renal impairment in all patients with CHF, but this risk was reduced in the enalapril group compared with the placebo group. beta-Blocker therapy and higher ejection fraction were renoprotective in all patients regardless of therapy.

Topics: Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Creatinine; Diuretics; Enalapril; Female; Follow-Up Studies; Heart Failure; Humans; Kidney; Kidney Failure, Chronic; Kidney Function Tests; Male; Middle Aged; Prognosis; Risk Factors; Stroke Volume; Ventricular Dysfunction, Left

This study sought to evaluate the relation between antiplatelet agent (APA) use and survival and morbidity from cardiac disease in patients with left ventricular (LV) systolic dysfunction.. APAs play an important role in the prevention and treatment of coronary disease. Their effects in patients with LV systolic dysfunction are unknown.. We reviewed data on APA use in 6,797 patients enrolled in the Studies of Left Ventricular Dysfunction (SOLVD) trial and analyzed the relation between their use and all-cause mortality as well as the combined end point of death or hospital admission for heart failure (HF). We used Cox regression to adjust for differences in baseline characteristics and to test for the interaction between APA use and selected patient variables in relation to outcome.. APA use (46.3% of patients) was associated with significantly reduced mortality from all causes (adjusted hazard ratio [HR] 0.82, 95% confidence interval [CI] 0.73 to 0.92, p = 0.0005) and reduced risk of death or hospital admission for HF (adjusted HR 0.81, 95% CI 0.74 to 0.89, p < 0.0001) but was not influenced by trial assignment, gender, LV ejection fraction, New York Heart Association class or etiology. A strong interaction was observed among APA use, randomization group and all-cause mortality. The association between APA use and survival was not observed in the enalapril group, nor was an enalapril benefit on survival detectable in patients receiving APAs at baseline. However, randomization to enalapril therapy significantly reduced the combined end point of death or hospital admission for HF in APA users.. In patients with LV systolic dysfunction, use of APAs is associated with improved survival and reduced morbidity. This association is retained after adjustment for baseline characteristics. APA use is associated with retained but reduced benefit from enalapril.

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Cardiac Output, Low; Cause of Death; Cohort Studies; Confidence Intervals; Coronary Disease; Death, Sudden, Cardiac; Double-Blind Method; Enalapril; Female; Follow-Up Studies; Humans; Male; Middle Aged; Odds Ratio; Patient Admission; Placebos; Platelet Aggregation Inhibitors; Regression Analysis; Risk Factors; Sex Factors; Stroke Volume; Survival Analysis; Treatment Outcome; Ventricular Dysfunction, Left; Ventricular Function, Left

In the Cooperative New Scandinavian Enalapril Survival Study (CONSENSUS II), in which enalapril treatment was initiated intravenously within 24 h after acute myocardial infarction, there was a neutral effect on 6-month mortality, whereas a beneficial effect on the progression of congestive heart failure was noted. We studied the effect of enalapril on left ventricular systolic function in terms of cardiac output and mean acceleration time measured by pulsed-wave Doppler in the left ventricular outflow tract and peripheral resistance. Early angiotensin-converting enzyme inhibition after acute myocardial infarction did not result in a general improvement of cardiac output. However, a small increase in cardiac output was observed in a subgroup of enalapril-treated patients with ejection fraction > or = 45%, probably due to a reduction in peripheral resistance in these patients.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Cardiac Output; Chi-Square Distribution; Clinical Trials, Phase II as Topic; Echocardiography, Doppler, Pulsed; Enalapril; Female; Heart Rate; Humans; Male; Middle Aged; Myocardial Infarction; Prospective Studies; Scandinavian and Nordic Countries; Statistics, Nonparametric; Vascular Resistance; Ventricular Dysfunction, Left

This study undertook to determine if the presence of atrial fibrillation in patients with asymptomatic and symptomatic left ventricular dysfunction was associated with increased mortality and, if so, whether the increase could be attributed to progressive heart failure or arrhythmic death.. Atrial fibrillation is a common condition in heart failure with the potential to impact hemodynamics and progression of left ventricular systolic dysfunction as well as the electrophysiologic substrate for arrhythmias. The available data do not conclusively define the effect of atrial fibrillation on prognosis in heart failure.. A retrospective analysis of the Studies of Left Ventricular Dysfunction Prevention and Treatment Trials was conducted that compared patients with atrial fibrillation to those in sinus rhythm at baseline for the risk of all-cause mortality, progressive pump-failure death and arrhythmic death.. The patients with atrial fibrillation at baseline, compared to those in sinus rhythm, had greater all-cause mortality (34% vs. 23%, p < 0.001), death attributed to pump-failure (16.7% vs. 9.4%, p < 0.001) and were more likely to reach the composite end point of death or hospitalization for heart failure (45% vs. 33%, p < 0.001), but there was no significant difference between the groups in arrhythmic deaths. After multivariate analysis, atrial fibrillation remained significantly associated with all-cause mortality (relative risk [RR] 1.34, 95% confidence interval [CI] 1.12 to 1.62, p=0.002), progressive pump-failure death (RR 1.42, 95% CI 1.09 to 1.85, p=0.01), the composite end point of death or hospitalization for heart failure (RR 1.26, 95% CI 1.03 to 1.42, p=0.02), but not arrhythmic death (RR 1.13; 95% CI 0.75 to 1.71; p=0.55).. The presence of atrial fibrillation in patients with asymptomatic and symptomatic left ventricular systolic dysfunction is associated with an increased risk for all-cause mortality, largely explained by an increased risk for pump-failure death. These data suggest that atrial fibrillation is associated with progression of left ventricular systolic dysfunction.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Atrial Fibrillation; Cause of Death; Dose-Response Relationship, Drug; Double-Blind Method; Enalapril; Female; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Retrospective Studies; Risk; Survival Rate; Systole; Ventricular Dysfunction, Left

This study examined the effect of enalapril on survival, resource use, and cost of care in patients with left ventricular dysfunction and hypertension using a retrospective analysis of patients who participated in the Studies of Left Ventricular Dysfunction (SOLVD). Among the 6797 SOLVD participants, 1917 patients had either elevated systolic (> or = 140 mm Hg) or diastolic (> or = 90 mm Hg) blood pressure. Therapy with enalapril was associated with a significant relative risk reduction for mortality (RR = 0.819, 95% CI: 0.68 to 0.98; P = .03). This resulted in a gain of 0.11 years (95% CI: 0.00 to 0.20 years) of survival during the average 2.8 year follow-up for this subgroup and was projected to result in a gain of 2.14 years (95% CI: 0.05 to 4.21 years) during the patient's lifetime. Enalapril significantly reduced the risk of first hospitalization for heart failure by 37%. For all types of hospitalizations, there was an average reduction of 32 hospitalizations per 100 patients treated with enalapril during the trial period (95% CI: 11.8 to 52.2 hospitalizations avoided per 100 patients), resulting in an estimated net savings of $1656 per patient during the trial period (95% CI: increased cost of $191 to savings of $3502). Although the projected lifetime net savings of $1456 was not significant (95% CI: increased cost of $9243 to saving of $12,527), evaluation of the cost per life year saved indicated that enalapril represented a cost-effective strategy. The estimated clinical benefit of enalapril among the hypertensive subgroup in SOLVD supports the recommendation that angiotensin converting enzyme (ACE) inhibitors should be considered as first line pharmacologic therapy for hypertensive patients with left ventricular dysfunction. From both the clinical and economic viewpoints, ACE inhibitors provide important clinical benefits and are cost-effective.

Topics: Angiotensin-Converting Enzyme Inhibitors; Cost-Benefit Analysis; Double-Blind Method; Enalapril; Female; Health Care Costs; Hospitalization; Humans; Hypertension; Male; Ventricular Dysfunction, Left

The effects of enalapril on 50 patients with left ventricular diastolic dysfunction (LVDD), confirmed by clinical features and radionuclid ventriculography, were assessed in a randomized, double-blind, and controlled method for eight weeks. The results showed that left atrial diameters (LAD), interventricular septum thicknesses (IVST) and left ventricular mass indexes (LV-MI) except left ventricular diameters (LVD) were decreased in the enalapril treatment group. The left ventricular diastolic function parameters such as the early peak filling velocity (EPAV), the atrial peak filling velocity (APAV), the deceleration of early peak filling velocity (DC) and the isovolumic relaxation time (IRT) were improved, the NYHA class and the exercise tolerance were increased, the left ventricular ejection fraction (LVEF), and the cardiac index (CI) were not altered in the enalapril treatment group. The patients with LVDD were well tolerated with enalapril. The parameters mentioned above were not altered in control group. It is suggested that enalapril is an effective drug in the treatment of LVDD.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Diastole; Double-Blind Method; Enalapril; Exercise Test; Female; Humans; Male; Middle Aged; Radionuclide Imaging; Stroke Volume; Ultrasonography; Ventricular Dysfunction, Left

Treatment of abnormal remodeling and dysfunction of left ventricle after myocardial infarction is one of the major goals of recent therapeutic interventions. The current study, the Nisoldipine Enalapril Anterior Myocardial infarction Study pilot investigation, was designed to investigate the effects of 12 weeks of treatment with enalapril or nisoldipine or their combination on left ventricular (LV) function and exercise capacity in patients with recent (< 1 month) anterior myocardial infarction and mild LV dysfunction (LV ejection fraction [EF] 38% to 48%). Forty-six patients were studied and received, by random assignment, enalapril (5 mg once per day) plus placebo (n = 14) or nisoldipine (10 mg two times per day) plus placebo (n = 18) or enalapril (5 mg once per day) plus nisoldipine (10 mg two times per day) (n = 14). All patients received aspirin (325 mg) throughout the study. Data on LV EF and peak filling rate at rest and LV EF during exercise were collected during radionuclide ventriculography. In addition, the product of heart rate and systolic blood pressure (rate-pressure product) and exercise time were determined during exercise stress testing. The analyzed parameters were not significantly modified after treatment with enalapril or with nisoldipine. In contrast, the combination of enalapril and nisoldipine significantly raised LV EF at rest (from 43% +/- 3% to 48% +/- 6%, p < 0.01) and during exercise (from 45% +/- 8% to 50% +/- 9%, p < 0.01) and raised peak filling rate at rest (fraction of end-diastolic volume per second) from 1.57 +/- 0.3 to 1.67 +/- 0.3 (p < 0.05). In addition, the combined administration of the two drugs increased the rate-pressure product (values x 10(3)) (from 20.7 +/- 5 to 22.7 +/- 4, p < 0.05) and increased exercise time (from 573 +/- 173 seconds to 668 +/- 178 seconds, p < 0.05). These results show that in patients with recent anterior myocardial infarction and mild LV dysfunction, the combination of the angiotensin-converting enzyme inhibitor enalapril and the dihydropyridine nisoldipine improves resting LV systolic and diastolic function and exercise LV systolic function and exercise capacity.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Calcium Channel Blockers; Drug Therapy, Combination; Enalapril; Exercise Test; Female; Heart Ventricles; Humans; Male; Middle Aged; Myocardial Infarction; Nisoldipine; Radionuclide Imaging; Technetium Compounds; Treatment Outcome; Ventricular Dysfunction, Left; Ventricular Function, Left

The Studies of Left Ventricular Dysfunction (SOLVD) assessed the effect of enalapril in patients with systolic left ventricular dysfunction (LVD). We performed retrospective analyses of the association between calcium channel blocker (CCB) use and fatal and nonfatal myocardial infarction (MI) in these patients. MI occurred in 11.5% of 845 patients receiving CCBs versus 7.5% of 2551 patients not receiving CCBs in the enalapril group and in 14.4% of 874 patients receiving CCBs versus 9.3% of 2527 patients not receiving CCBs in the placebo group. By multivariate Cox regression analysis, adjusting for comorbidity, cause and severity of LVD, heart failure, and concomitant drug use, CCB use was an independent predictor of MI (relative risk [RR] 1.37, confidence interval [CI] 1.14 to 1.63). The increase in MI risk was greater among patients with a higher heart rate (RR 1.46, CI 1.14 to 1.86) and lower blood pressure (RR 1.45, CI 1.14 to 1.86). The adjusted risk ratio for all-cause mortality associated with CCB use was 1.14 (CI 1.00 to 1.28; p = 0.0454). In this analysis of patients with LVD, CCB use was associated with significantly increased risk of fatal or nonfatal MI.

Topics: Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Calcium Channel Blockers; Comorbidity; Enalapril; Female; Heart Rate; Humans; Incidence; Male; Middle Aged; Myocardial Infarction; Proportional Hazards Models; Retrospective Studies; Risk Factors; Ventricular Dysfunction, Left

Patients with heart failure and left ventricular systolic dysfunction exhibit increased adrenergic activity but blunted adrenergic responsiveness. We studied patients enrolled in the Studies of Left Ventricular Dysfunction, examining exercise responses of heart rate (HR) and plasma norepinephrine (PNE). Eighty-seven patients were studied before randomization; 65 of these were examined 1 year after randomization to placebo or enalapril. Compared with prevention trial (asymptomatic) patients, patients in the treatment trial (symptomatic) had higher resting HR and PNE levels and less increase in HR with a greater increase in PNE with exercise. Acute administration of enalapril increased the resting HR in patients in the prevention trial only but had no significant effect on PNE. After 1 year of therapy, patients in the prevention trial exhibited no change. Within the treatment trial, the placebo group displayed both a higher peak PNE and increase in PNE with exercise than did the enalapril group, whose HR response was maintained in spite of a reduction of exercise PNE. We conclude that (1) compared with asymptomatic patients, symptomatic patients with reduced left ventricular ejection fraction manifest greater resting and exercise adrenergic activity, with blunted HR response; and (2) in symptomatic patients, 1 year of enalapril treatment effected an augmented HR response to adrenergic stimulation, supporting an interaction between the renin/angiotensin and adrenergic nervous systems. Normalization of adrenergic tone and response likely contributes to the benefits of long-term angiotensin-converting enzyme inhibitor therapy.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Cardiac Output, Low; Enalapril; Exercise Test; Female; Heart Rate; Humans; Longitudinal Studies; Male; Middle Aged; Norepinephrine; Physical Exertion; Placebos; Renin-Angiotensin System; Rest; Stroke Volume; Sympathetic Nervous System; Sympathomimetics; Systole; Time Factors; Ventricular Dysfunction, Left

Morbidity and mortality data in Switzerland underline the socioeconomic importance of heart failure. In the SOLVD study (Study on Left Ventricular Dysfunction), cardiovascular morbidity and mortality were reduced with the ACE inhibitor enalapril in patients with heart failure. The economic implications of this treatment were analyzed in a retrospective economic analysis from the perspective of Swiss third party payers.. Source of the economic analysis was the SOLVD study data. This prospective study was placebo-controlled, double-blind and had a mean follow-up of 3.45 years (41.4 months), involving 2569 patients with heart failure, mainly in NYHA classes II and III. Costing data for treatment with enalapril, the per diem charges for hospitalization and the average length of hospital stay were retrieved from published national sources. The costs of in- and output were calculated and compared for the two treatment groups in a cost-efficacy analysis.. Additional treatment with enalapril resulted in an additional cost of 2.5 million Swiss francs. These incremental costs were, however, offset by reduced hospital costs (CHF 6.45 million savings) in the enalapril group. For the complete treatment cohort of the SOLVD study, the net savings were approximately 4.26 million Swiss francs.. From the clinical point of view, treatment with ACE inhibitors leads to a reduction in the progression of heart failure and reduced cardiovascular morbidity and mortality. With respect to health economics, it can be demonstrated that treatment with enalapril does not only offer clinical benefits, but that these also translate into impressive economic savings of CHF 3315 per patient.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Cost-Benefit Analysis; Double-Blind Method; Enalapril; Female; Heart Failure; Humans; Length of Stay; Male; Middle Aged; Patient Admission; Prospective Studies; Switzerland; Ventricular Dysfunction, Left

In the Studies of Left Ventricular Dysfunction (LVD), enalapril or placebo was administered in a double-blind fashion to 6797 participants with ejection fraction < or = 0.35. During 40 months' average follow-up, 28.1% of participants randomized to enalapril reported side effects compared with 16.0% in the placebo group (p < 0.0001). Enalapril use was associated with a higher rate of symptoms related to hypotension (14.8% vs 7.1%, p < 0.0001), azotemia (3.8% vs 1.6%, p < 0.0001), cough (5.0% vs 2.0%, p < 0.0001), fatigue (5.8% vs 3.5%, p < 0.0001), hyperkalemia (1.2% vs 0.4%, p = 0.0002), and angioedema (0.4% vs 0.1%, p < 0.05). Side effects resulted in discontinuation of blinded therapy in 15.2% of the enalapril group compared with 8.6% in the placebo group (p < 0.0001). Thus enalapril is well tolerated by patients with LVD; however, hypotension, azotemia, cough, fatigue, and other side effects result in discontinuation of therapy in a significant minority of patients.

Topics: Aged; Angioedema; Angiotensin-Converting Enzyme Inhibitors; Cough; Double-Blind Method; Enalapril; Fatigue; Female; Follow-Up Studies; Heart Failure; Humans; Hyperkalemia; Hypotension; Male; Middle Aged; Sex Factors; Time Factors; Uremia; Ventricular Dysfunction, Left

Elevated plasma neurohormonal levels are associated with increased mortality rates in patients with symptomatic heart failure. A previous Studies of Left Ventricular Dysfunction (SOLVD) trial suggested that neurohumoral activation precedes the development of symptoms as demonstrated by increased neurohormonal levels in patients with asymptomatic left ventricular dysfunction. However, the significance of this early neurohumoral activation is unclear. The goals of this study were to determine the prognostic significance of the plasma concentrations of plasma norepinephrine (PNE) and atrial natriuretic peptide (ANP) and the renin activity (PRA) in patients with asymptomatic left ventricular dysfunction.. PNE and PRA were measured before randomization in 514 patients with left ventricular ejection fractions < or = 35% who did not require treatment for congestive heart failure and were enrolled in the SOLVD Prevention Trial. Plasma ANP levels were measured in a subset of 241 patients owing to study design. Using the Cox proportional hazards model that included left ventricular ejection fraction, New York Heart Association functional class, age, sex, treatment assignment to placebo or enalapril, and cause of heart failure, we examined whether these neurohormones predicted all-cause mortality, cardiovascular mortality, hospitalization for heart failure, development of heart failure, or development of ischemic events (myocardial infarction or unstable angina). PNE was the strongest predictor of clinical events in this patient population. PNE levels above the median of 393 pg/mL were associated with a relative risk of 2.59 (P = .002) for all-cause mortality, 2.55 (P = .003) for cardiovascular mortality, 2.55 (P = .005) for hospitalization for heart failure, 1.88 (P = .002) for development of heart failure, 1.92 (P = .001) for ischemic events, and 2.59 (P = .005) for myocardial infarction. PNE remained the most powerful predictor for all-cause mortality and ischemic events when the analysis included only the patients with histories of ischemic left ventricular dysfunction. The increases in other neurohormonal levels were not useful in predicting the subsequent development of clinical events.. Increased PNE levels in patients with asymptomatic left ventricular dysfunction appear to predict all-cause and cardiovascular mortalities and development of clinical events related to the onset of heart failure or acute ischemic syndromes. Thus, measurement of PNE may be a possible early marker for assessment of disease progression in patients with left ventricular dysfunction, and modulating the release or effect of PNE may lead to improved prognosis and/or a reduction in morbidity.

Topics: Angina, Unstable; Angiotensin-Converting Enzyme Inhibitors; Biomarkers; Enalapril; Female; Heart Failure; Humans; Male; Middle Aged; Myocardial Infarction; Myocardial Ischemia; Norepinephrine; Placebos; Predictive Value of Tests; Prognosis; Renin; Risk Factors; Survival Rate; Ventricular Dysfunction, Left

Nanterinone (UK-61,260) is a novel positive inotropic and balanced-type vasodilating drug, only partially based on phosphodiesterase III inhibition. Preliminary data from controlled studies suggest satisfactory long-term efficacy and safety. As its acute hemodynamic effects in humans are unknown, an oral dose of 2 mg nanterinone was studied in 14 patients with heart failure (NYHA class II-III) on chronic diuretic and angiotensin-converting enzyme (ACE) inhibitor treatment. Before the study, patients were on a 2 g salt-balanced diet, and they received their last medication 16 hours before each study day. Hemodynamic measurements were carried out before and 0.5, 1, 1.5, 2, 2.5, 3, 4, 8, 12, and 24 hours after administration of the study drug. All patients received placebo and nanterinone on 2 consecutive days. Following nanterinone, systemic vascular resistance decreased immediately from 1699 +/- 82 (mean +/- SEM) at baseline to 1368 +/- 80 at 1 hour. Changes persisted for 12 hours. Concomitantly, there was an immediate and significant fall in pulmonary wedge pressure to 38% of baseline at 1.5 hours, together with a 20% reduction in pulmonary artery pressure. Heart rate remained unchanged and arterial pressures showed only a short, significant decrease. Cardiac index rose significantly from 2.28 +/- 0.15 at baseline to a highest value of 2.65 +/- 0.14 1/min/m2 at 1 hour. Changes persisted for 3 hours. Placebo had no effect on these variables. As, in view of its potential venodilating properties, hemodynamic improvement by nanterinone may depend on pre-existing left ventricular filling pressure, patients were subsequently grouped according to baseline pulmonary wedge pressure of > 12 mmHg (H-PCWP) and < or = 12 mmHg (L-PCWP). Cardiac index improved by 26% in H-PCWP and by 17% in L-PCWP (NS). In contrast, PCWP fell more markedly in H-PWCP than in L-PCWP (40% and 23%, respectively, p < 0.05). Thus, oral nanterinone results in a significant acute hemodynamic improvement and is well tolerated. Although changes in left ventricular filling pressure are more pronounced in patients with elevated pre-existing PCWP, cardiac pump function improves equally in patients with normal or low left ventricular filling pressure at baseline.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Cross-Over Studies; Diuretics; Enalapril; Female; Heart Failure; Hemodynamics; Humans; Imidazoles; Male; Middle Aged; Phosphodiesterase Inhibitors; Pulmonary Wedge Pressure; Quinolones; Single-Blind Method; Vascular Resistance; Ventricular Dysfunction, Left

This study examined the independent relation of health-related quality of life (HRQL) to mortality and congestive heart failure (CHF)-related hospitalizations in patients with an ejection fraction of < 0.35 followed for a mean of 36.5 months. A brief HRQL questionnaire was administered at baseline to patients randomized to placebo or enalapril in the Studies of Left Ventricular Dysfunction (SOLVD) trial. Participants had an ejection fraction of < 0.35 and either symptomatic CHF (treatment trial, n = 2,465) or asymptomatic CHF (prevention trial, n = 2,560). Baseline assessment of HRQL predicted mortality and CHF-related hospitalizations in symptomatic and asymptomatic patients randomized to enalapril and placebo treatment. Domains that were the stronger univariate predictors of mortality and CHF-related hospitalizations were activities of daily living (relative risk [RR] for mortality: 1.163, p < 0.000; for hospitalization: 1.215, p < 0.000), general health (RR for mortality: 1.205, p < 0.000; for hospitalization: 1.188, p < 0.000), and social functioning (RR for mortality 1.098, p < 0.000; for hospitalization: RR 1.156, p < 0.000). In the multivariate model, activities of daily living (RR for mortality 1.41, p < 0.000; for hospitalization: RR 1.43, p < 0.002), general health (RR for mortality 1.21, p < 0.000; for hospitalization RR 1.16, p < 0.013) and heart failure symptoms (RR for mortality 1.02, p < 0.025; for hospitalization RR 1.03, p < 0.004) were found to be independent risk factors. HRQL independently predicted mortality and CHF-related hospitalizations after adjustment for ejection fraction, age, treatment, and New York Heart Association classification in patients with an ejection fraction of < 0.35, randomized to enalapril and placebo treatment. HRQL provides additional clinical information regarding disease course and outcome that is not captured by traditional indexes of clinical status.

Topics: Activities of Daily Living; Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Double-Blind Method; Enalapril; Female; Follow-Up Studies; Heart Failure; Hospitalization; Humans; Male; Middle Aged; Proportional Hazards Models; Quality of Life; Risk Factors; Severity of Illness Index; Time Factors; Ventricular Dysfunction, Left

The randomized angiotensin receptor antagonist--angiotensin converting enzyme (ACE)--Inhibitor Study (RAAS) was designed to test the hypothesis that the addition of an angiotensin II type 1 receptor blocking agent, losartan 50 mg/day, to an ACE-inhibitor, enalapril 10 mg twice a day (group 1), will be more effective than standard-dose enalapril 10 mg twice a day (group 2) or high-dose enalapril alone 20 mg twice a day (group 3), in blocking the activation of the renin angiotensin aldosterone system in patients with heart failure and left ventricular systolic dysfunction. The addition of an angiotensin II type 1 receptor blocking agent to an ACE inhibitor would theoretically block ACE as well as non-ACE-dependent angiotensin II formation while maintaining the potential beneficial effect of ACE inhibitor-induced bradykinin formation. One hundred twenty patients with left ventricular systolic dysfunction and moderate to severe heart failure despite treatment with an ACE inhibitor will be randomized to 1 of the 3 groups and followed for 6 weeks, with an optional long-term week extension to determine the safety and tolerability of the combination of losaratan and enalapril, its effectiveness in preventing rest and exercise-induced neurohumoral activation (plasma norepinephrine, N-terminal proatrial natriuretic factor, angiotensin II, and aldosterone), as well as quality of life and exercise performance (6-minute walk test).

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Biphenyl Compounds; Double-Blind Method; Drug Therapy, Combination; Enalapril; Heart Failure; Humans; Imidazoles; Losartan; Pilot Projects; Randomized Controlled Trials as Topic; Research Design; Tetrazoles; Titrimetry; Ventricular Dysfunction, Left

Large-scale drug trials have focused primarily on mortality and morbidity and less on the functional state of the myocardium. A model was developed to assess myocardial contractile state in patients with left ventricular (LV) dysfunction and to address the questions of differences in function between patients with and without overt heart failure, effects of enalapril, and best predictors of functional outcome. Pressure-angiographic data were obtained from 16 patients with overt heart failure and 47 without heart failure. Repeat studies were conducted in 41 patients following 1 year's treatment with enalapril or placebo. Left ventricular silhouettes were divided into 18 segments to estimate regional ejection fraction, wall stress and myocardial damage (% myocardial damage). Contractile state was assessed and ranked by ejection rate-preload-afterload relationships and by a score method based on 10 myocardial and ventricular function parameters. End-diastolic and end-systolic volumes (EDV, ESV) were significantly greater (P < 0.001), ejection fraction (EF) lower (P < 0.009), % myocardial damage greater (P < 0.008) and contractile state more depressed in patients with overt heart failure. Changes in EDV and ESV (delta placebo vs delta enalapril) were significant (delta EDV, P < 0.003; delta ESV, P < 0.014). Directional shifts in the diastolic pressure-volume relationships with enalapril or placebo depended primarily on the basal contractile state and diastolic volume range. The best single predictors of post-treatment EF were the score index (a surrogate parameter for the contractile state) and ESV. Added benefits of enalapril include the prevention of further dilatation in patients with less depressed contractile state and delay in the onset of heart failure. Asymptomatic patients with LV dysfunction should also be considered for angiotensin converting enzyme (ACE) inhibitor therapy.

Topics: Blood Pressure; Blood Volume; Diastole; Enalapril; Female; Forecasting; Hemodynamics; Humans; Male; Middle Aged; Multivariate Analysis; Myocardial Contraction; Myocardium; Stroke Volume; Treatment Outcome; Ventricular Dysfunction, Left

Acute myocardial infarction (AMI) leads to left ventricular dysfunction, the extent of which predicts mortality. We studied the effect of very early enalapril treatment in patients with left ventricular failure (Killip classification II-III) resulting from AMI. In a double-blind randomized trial, patients on conventional treatment were started on placebo (PL, n = 15) or 2.5 mg enalapril (EN, n = 15) twice daily as early as 24 to 30 h after AMI and were followed up over a period of 21 days. One patient died in each treatment group. There were three dropouts in the placebo group (progressive heart failure requiring antiotensin-converting enzyme inhibition) and one dropout in the enalapril group (malignant ventricular arrhythmias). Plasma atrial natriuretic peptide (ANP) and norepinephrine decreased similarly in both groups from elevated baseline concentrations. The patients with the highest baseline ANP levels died in both groups: EN: 579 fmol/ml (mean 65.3 +/- 34.4 fmol/ml), PL: 403 fmol/ml (mean 63.5 +/- 37.6 fmol/ml). Killip classification improved in 9 of 13 patients on enalapril but only in 5 of 11 patients on placebo. On echocardiography an increase in fractional shortening (FS) (3.2 +/- 7.5%, p < 0.05) was found with enalapril only. Patients on placebo required more diuretics, and plasma aldosterone increased threefold. Thus, very early enalapril treatment may help prevent left ventricular failure after AMI. Extremely high initial plasma ANP concentrations may predict an unfavorable outcome.

Topics: Aged; Atrial Natriuretic Factor; Biomarkers; Double-Blind Method; Drug Administration Schedule; Echocardiography; Enalapril; Female; Heart Failure; Humans; Male; Middle Aged; Myocardial Infarction; Prognosis; Survival Rate; Ventricular Dysfunction, Left

Studies of Left Ventricular Dysfunction (SOLVD) demonstrated that enalapril therapy significantly improved the clinical course of patients with left ventricular (LV) dysfunction. The goals of this substudy were to evaluate changes in LV structure and function in SOLVD patients and to test the hypothesis that enalapril inhibits remodeling in patients with LV dysfunction.. Patients entering both the prevention and treatment arms of SOLVD from 5 of the 23 clinical centers were recruited for this substudy. The 301 patients who participated underwent Doppler-echocardiographic evaluation according to standard protocol before randomization to either enalapril or placebo and again after 4 and 12 months of therapy. Recorded data were analyzed in a blinded fashion at a central core laboratory. Analysis of baseline clinical characteristics showed that patients enrolled in the substudy were generally representative of the SOLVD population, although prevention arm patients were slightly overrepresented in the substudy group (69.8% compared with 61.9% of remaining SOLVD patients). The enalapril group demonstrated significant reductions in the mitral annular E-wave-to-A-wave velocity ratio (due predominantly to a reduction in E-wave velocity), and this response was different from that seen in the placebo group (P = .030). Changes in the E-to-A ratio in the enalapril group correlated significantly with changes in plasma atrial natriuretic peptide (r = .56; P < or = .01). LV end-diastolic and end-systolic volumes increased in placebo but not enalapril-treated patients, and the differences in response between the treatment groups were significant (P = .025 and .019, respectively). LV mass tended to increase in placebo patients and to be reduced in enalapril-treated patients, and the difference in response between the groups was highly significant (P < or = .001).. These data demonstrate that enalapril attenuates progressive increases in LV dilatation and hypertrophy in patients with LV dysfunction. The results support the possibility that the favorable effects of enalapril reported in the SOLVD trials were related to inhibition of LV remodeling.

Topics: Adult; Aged; Aged, 80 and over; Blood Pressure; Coronary Circulation; Echocardiography; Enalapril; Female; Heart; Heart Rate; Humans; Male; Middle Aged; Myocardium; Stress, Mechanical; Time Factors; Ventricular Dysfunction, Left; Ventricular Function, Left

Plasma norepinephrine levels, which reflect sympathetic nervous system activity, are almost universally elevated in patients with left ventricular dysfunction. This elevation occurs in patients with overt, symptomatic heart failure (HF) and in patients with asymptomatic left ventricular dysfunction. Evidence suggests that the elevation in plasma norepinephrine levels can be at least partly attributed to an increase in sympathetic nervous system activity. It has become evident that elevated plasma norepinephrine levels are directly related to prognosis; patients with levels > 900 pg/ml have a poor prognosis and shortened life expectancy. However, plasma norepinephrine levels bear little relationship to physiologic and clinical variables observed in HF, including ejection fraction and exercise capacity. Data from the V-HeFT II show that at 2-year follow-up, a progressive rise of plasma norepinephrine was observed in both treatment arms, suggesting that disease progresses despite treatment with either an angiotensin-converting enzyme inhibitor, enalapril, or vasodilator therapy with hydralazine/isosorbide dinitrate. It is possible that interventions aimed at the progressive neurohormonal activation that occurs in HF may improve the course of illness. Further study is needed to test this hypothesis.

Topics: Enalapril; Heart Failure; Humans; Hydralazine; Isosorbide Dinitrate; Norepinephrine; Prognosis; Sympathetic Nervous System; Ventricular Dysfunction, Left

Angiotensin-converting-enzyme inhibitor therapy can preserve left ventricular (LV) function and geometric features and improve survival in subsets of patients with acute myocardial infarction (AMI). We investigated the effect of enalapril treatment initiated < 24 hours after AMI on global and regional echocardiographic wall motion indexes obtained at 2 to 5 days and at 1 and 6 months in 428 consecutive patients enrolled in the randomized, placebo-controlled Cooperative New Scandinavian Enalapril Survival Study II. In anterior AMIs, the non-infarct-zone index deteriorated in the placebo group but remained unchanged in the enalapril-treated group (0.18 vs 0.02; p < or = 0.05), an effect related to attenuated LV volume expansion. No treatment effects were observed in nonanterior AMIs or in the entire unselected population. Thus in an unselected population with AMI, early enalapril treatment had no effect on LV function; yet in patients with anterior infarcts, LV function was maintained through preservation of function in the noninfarcted myocardium.

Topics: Aged; Cardiac Volume; Cohort Studies; Double-Blind Method; Echocardiography; Enalapril; Female; Follow-Up Studies; Heart; Humans; Male; Myocardial Infarction; Placebos; Recurrence; Survival Rate; Ventricular Dysfunction, Left; Ventricular Function, Left

The aim of this study was to compare the long-term effects of treatment with enalapril or placebo on plasma neurohormones in patients with left ventricular (LV) dysfunction. Elevated neurohormonal levels are associated with increased mortality in patients with congestive heart failure. Multiple studies have shown that angiotensin-converting enzyme inhibitors decrease mortality and morbidity in these patients. In Studies of Left Ventricular Dysfunction (SOLVD), enalapril significantly reduced mortality in patients with symptomatic LV dysfunction (treatment trial). In contrast, in patients with asymptomatic LV dysfunction (prevention trial), there was no significant reduction in mortality with enalapril therapy. The effect of enalapril was examined in 333 prevention trial and 129 treatment trial patients. Plasma norepinephrine (NE) and plasma renin activity were measured in these patients at baseline, and at 4 and 12 months of follow-up. In a subset of these patients, atrial natriuretic peptide (ANP) and arginine vasopressin were also measured. Analysis of covariance models were used to determine the effect of enalapril on each neurohormone. Participants in the treatment trial had significantly higher neurohormonal levels when compared with those in the prevention trial or normal control subjects. In the treatment trial, patients taking enalapril had a greater decrease in plasma NE levels than patients taking placebo (p < 0.08).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aged; Analysis of Variance; Arginine Vasopressin; Canada; Chi-Square Distribution; Enalapril; Female; Follow-Up Studies; Humans; Male; Middle Aged; Natriuretic Agents; Norepinephrine; Regression Analysis; Renin; United States; Ventricular Dysfunction, Left

Previous studies have indicated that angiotensin-converting enzyme inhibitors may reduce the frequency of ventricular arrhythmias in patients with heart failure. These reports were mostly small and of short duration. We prospectively studied 734 patients recruited in 11 universities for 1 year who were enrolled in the Studies of Left Ventricular Dysfunction (SOLVD) to determine the long-term effects of enalapril and placebo on the frequency and complexity of ventricular arrhythmias in patients with symptomatic (treatment trial) or asymptomatic (prevention trial) heart failure and depressed left ventricular function (ejection fraction < or = 35%). Five hundred fifty-three patients from the prevention trial and 181 from the treatment trial of SOLVD underwent ambulatory electrocardiographic monitoring at baseline, and then at 4 and 12 months of double-blind therapy with either placebo or enalapril (2.5 to 10 mg twice daily). The prospectively defined primary analysis was by intent-to-treat and revealed no significant differences in ventricular premature complexes between the placebo and enalapril groups at baseline (87 +/- 13 vs 84 +/- 13/hour), 4 months (100 +/- 15 vs 85 +/- 12/hour), or 12 months (80 +/- 12 vs 90 +/- 14/hour). Likewise, there was no difference between the placebo and enalapril groups in runs of nonsustained ventricular tachycardia: baseline (8.3 +/- 4.1 vs 1.9 +/- 0.4 runs/day), 4 months (16 +/- 12 vs 7.2 +/- 4.1 runs/day), or after 12 months of blinded therapy (11 +/- 7.0 vs 6.1 +/- 4.4 runs/day).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Arrhythmias, Cardiac; Double-Blind Method; Electrocardiography, Ambulatory; Enalapril; Female; Heart Ventricles; Humans; Male; Middle Aged; Prospective Studies; Ventricular Dysfunction, Left

The objective of this study was to examine the effect of enalapril on morbid and mortal events in patients with left ventricular dysfunction and hypertension using a retrospective analysis of patients with systolic left ventricular dysfunction (ejection fraction < or = 0.35) who participated in the Studies of Left Ventricular Dysfunction (SOLVD). Among the 6797 patients who were randomized to enalapril or placebo, 2652 had history of hypertension, 1508 had systolic blood pressure (SBP) > or = 140 mm Hg, and 985 had diastolic blood pressure (DBP) > or = 90 mm Hg. During average follow-up of 40 months, the rate of hospitalization for congestive heart failure was lower in the enalapril group than the placebo group among patients with history of hypertension (20.6% v 28.3%, P < .001, relative risk [RR] 0.664), and among those with elevated DBP (16.5% v 26.0%, P < .001, RR = 0.574), or SBP (19.5% v 27.7%, P < .001, RR = 0.647) at baseline. These risk ratios were similar to those observed in patients without history of hypertension (RR = 0.647). Also, the decreased rates of mortality, myocardial infarction, stroke, and unstable angina observed in SOLVD were seen, with similar relative risks, in patients with (RR = 0.927, 0.836, 0.979, 0.900, respectively) and without (RR = 0.866, 0.729, 0.775 and 0.743) history of hypertension as well in those with elevated SBP (RR = 0.841, 0.806, 0.707, 0.867) or DBP (RR = 0.791, 0.889, 0.755, 0.872) at baseline.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Aged, 80 and over; Angiotensin-Converting Enzyme Inhibitors; Enalapril; Female; Follow-Up Studies; Humans; Hypertension; Male; Middle Aged; Morbidity; Risk Factors; Ventricular Dysfunction, Left

It has not been determined previously whether patients with severe chronic congestive heart failure differ in demographic characteristics with respect to left ventricular systolic dysfunction (LVD). In patients with severe chronic congestive heart failure in NYHA IV, an optional protocol in the CONSENSUS-I trial was designed to ascertain whether there were any differences in patient characteristics regarding the degree of LVD defined as left ventricular fractional shortening (FS). A subgroup of 54 patients from the CONSENSUS-I trial were evaluated with M-mode echocardiography. Patients with FS above median (14%) were older (74 +/- 7 vs. 68 +/- 7, p < 0.01), more often female (48 vs. 15%, p < 0.05) and had lower heart rates (77 +/- 15 vs. 95 +/- 17, p < 0.01). Analysis of the 2-year follow-up from the end of the trial was also performed. In the placebo group, patients with FS > 14% had significantly better prognosis than patients with FS < 14%. In the enalapril-treated group no such difference in survival was seen. The difference between the original treatment groups remained, despite the fact that treatment with enalapril was then made available to all surviving patients. In conclusion, patients with advanced chronic congestive heart failure and less severe LVD have different demographic characteristics than patients with more severe LVD. In the placebo group, but not in the enalapril group, prognosis was better in patients with less severe LVD.

Topics: Aged; Chronic Disease; Echocardiography; Enalapril; Female; Heart Failure; Humans; Male; Systole; Ventricular Dysfunction, Left; Ventricular Function, Left

The study objective was to evaluate the effect of bilateral sympathectomy on ventricular remodeling and function in a rat model of dilated cardiomyopathy induced by doxorubicin.. Dilated cardiomyopathy was induced in male Wistar rats by weekly intraperitoneal injection of doxorubicin (2 mg/kg) for 9 weeks. Animals were divided into 4 groups: dilated cardiomyopathy; bilateral sympathectomy, submitted on day 15 of the protocol to bilateral sympathectomy; angiotensin-converting enzyme inhibitor, treated with enalapril through day 15 until the end of the experimental protocol; and sham, nonsubmitted through doxorubicin protocol, with weekly intraperitoneal injections of saline solution (0.9%). The left ventricular function was assessed, and the heart was collected for posterior analyses.. Bilateral sympathectomy was effective in preventing remodeling and left ventricular dysfunction in a rat model of dilated cardiomyopathy induced by doxorubicin.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Cardiomyopathy, Dilated; Disease Models, Animal; Doxorubicin; Enalapril; Humans; Male; Rats; Rats, Wistar; Sympathectomy; Ventricular Dysfunction, Left; Ventricular Remodeling

Clinical studies suggest beneficial effects of renin-angiotensin system blockade for prevention of left ventricular (LV) dysfunction after chemotherapy. However, the efficacy of this strategy as primary prevention has been poorly studied. This study aimed at identifying the pathophysiological mechanisms by which mineralocorticoid receptor antagonism (MRA) or angiotensin converting enzyme inhibition (ACEi) provide protection against doxorubicin-induced cardiotoxicity (DIC) in mouse models of acute and chronic toxicity.. Acute DIC was induced by a single injection of Dox at 15 mg/kg and chronic DIC applied 5 injections of Dox at 4 mg/kg/week. MRA was achieved using eplerenone or cardiomyocyte-specific ablation of the MR gene in transgenic mice and ACEi using enalapril. Drugs were provided with the first dose of Dox and applied until the end of the study. In both model of DIC, Dox induced cardiac atrophy with decreased LV volume, reduced cardiomyocyte cell size, and cardiac dysfunction. In the acute model, neither MRA nor ACEi protected against these manifestations of DIC. In the chronic model, concomitant treatment with eplerenone did not protect against DIC and drastically increased plasma aldosterone levels and cardiac levels of angiotensin II type 1 receptor and of connective tissue growth factor (CTGF), as observed in acute DIC. Enalapril treatment in the chronic model, however, protected against cardiac dysfunction and cardiomyocyte atrophy and was associated with increased activation of the PI3K/AKT/mTOR pathway along with normal levels of CTGF.. Enalapril and eplerenone disparately impact on cellular signalling in DIC. Eplerenone, on top of Dox treatment was not protective and associated with increased levels of plasma aldosterone and of cardiac CTGF. In contrast, we show that primary prevention with enalapril preserves LV morphology and function in a clinically relevant model of chronic DIC, with increased stimulation of the PI3K/AKT/mTOR axis and normal CTGF levels suggesting potential therapeutic implications.

Topics: Aldosterone; Angiotensin-Converting Enzyme Inhibitors; Animals; Cardiotoxicity; Connective Tissue Growth Factor; Disease Models, Animal; Doxorubicin; Enalapril; Eplerenone; Male; Mice, Inbred C57BL; Mice, Knockout; Mineralocorticoid Receptor Antagonists; Myocytes, Cardiac; Phosphatidylinositol 3-Kinase; Primary Prevention; Proto-Oncogene Proteins c-akt; Receptor, Angiotensin, Type 1; Receptors, Mineralocorticoid; Renin-Angiotensin System; Signal Transduction; TOR Serine-Threonine Kinases; Ventricular Dysfunction, Left; Ventricular Function, Left

Soluble ST2 (sST2) is associated with cardiac remodeling and fibrosis. In chronic heart failure, the predictive value of sST2 has not been evaluated in a model that includes both NT-proBNP (N-terminal pro-B-type natriuretic peptide) and hs-TnT (high-sensitivity cardiac troponin T), in a trial in which treatment had a major impact. Therefore, the effects of treatment on sST2 levels in PARADIGM-HF trial (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure), the relationships between sST2 and outcomes, and the prognostic utility of various sST2 partition values were examined.. Baseline (n=2002), 1-month (n=1936), and 8-month postrandomization (n=1758) sST2 levels were compared between treatment groups (sacubitril/valsartan versus enalapril). Relationships between baseline sST2 and (1) heart failure hospitalization, (2) cardiovascular death, and (3) combined heart failure hospitalization and cardiovascular death were assessed using restricted cubic spline models. Adjusted Cox proportional hazards models were used to examine the impact of sST2 change from baseline to 1 month on the hazard of experiencing each outcome. Sacubitril/valsartan led to more reductions and fewer increases in sST2 levels versus enalapril. After adjusting for other predictors, including NT-proBNP and hs-TnT, baseline sST2 remained an independent predictor of outcomes. Associations between baseline sST2 and outcomes were linear. sST2 increases at 1 month were associated with worse subsequent outcomes and decreased with better outcomes (. Sacubitril/valsartan resulted in greater reductions and less increases in sST2 levels than enalapril. No specific threshold was associated with risk, as linear relationships between baseline sST2 and outcomes were observed. Changes in sST2 from baseline to 1 month were independently associated with the risk of outcomes.. URL: https://www.clinicaltrials.gov. Unique identifier: NCT01035255.

Topics: Aged; Aminobutyrates; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Biphenyl Compounds; Drug Combinations; Enalapril; Female; Heart Failure; Humans; Male; Middle Aged; Prognosis; Stroke Volume; Tetrazoles; Treatment Outcome; Valsartan; Ventricular Dysfunction, Left

Sacubitril-valsartan is a new medication that has recently been recommended as a replacement for enalapril in the treatment of patients with heart failure with reduced ejection fraction (HFrEF).. This study aimed to determine the cost effectiveness of sacubitril-valsartan compared with enalapril.. An analytical decision model was developed to estimate the long-term costs and outcomes from a healthcare perspective. Clinical inputs were mostly derived from the PARADIGM-HF study. Enalapril-related costs, risk of non-cardiovascular death, and all-cause readmission rate were based on data from Thailand. The costs and outcomes were discounted at 3% annually. The incremental cost-effectiveness ratio (ICER) was calculated and presented for the year 2017. A series of sensitivity analyses were also performed.. For the base-case, the increased cost (144,146 vs. 16,048 Thai baht [THB]) of sacubitril-valsartan was associated with gains in both life-years (9.214 vs. 8.367 years) and quality-adjusted life-years (QALYs) (7.698 vs. 6.909) compared with enalapril, yielding an ICER of 162,276 THB/QALY ($US4857.11/QALY). This ICER is not considered to be cost effective at the willingness-to-pay (WTP) level of 160,000 THB/QALY. The risk of cardiovascular death and costs of both sacubitril-valsartan and hospitalization influenced the ICER. At a WTP of 160,000 THB/QALY, sacubitril-valsartan had a 48% probability of being a cost-effective treatment.. At its current price in Thailand, sacubitril-valsartan may not represent good value for the nations's limited healthcare resources. The cost of sacubitril-valsartan needs to reduce by approximately 2% to yield an ICER below the threshold.

Topics: Aged; Aminobutyrates; Biphenyl Compounds; Cost-Benefit Analysis; Drug Combinations; Enalapril; Female; Heart Failure; Hospitalization; Humans; Male; Middle Aged; Needs Assessment; Outcome and Process Assessment, Health Care; Quality-Adjusted Life Years; Stroke Volume; Survival Analysis; Tetrazoles; Thailand; Valsartan; Ventricular Dysfunction, Left

Renal dysfunction (RD) is associated with reduced survival in HF; however, not all RD is mechanistically or prognostically equivalent. Notably, RD associated with "pre-renal" physiology, as identified by an elevated blood urea nitrogen to creatinine ratio (BUN/Cr), identifies a particularly high risk RD phenotype. Proteinuria, another domain of renal dysfunction, has also been associated with adverse events. Given that several different mechanisms can cause proteinuria, we sought to investigate whether the mechanism underlying proteinuria also affects survival in HF.. Subjects in the Studies of Left Ventricular Dysfunction (SOLVD) trial with proteinuria assessed at baseline were studied (n=6439). All survival models were adjusted for baseline characteristics and estimated glomerular filtration rate (eGFR). Proteinuria (trace or 1+) was present in 26% and associated with increased mortality (HR=1.2; 95% CI, 1.1-1.3, p=0.006). Proteinuria >1+ was less common (2.5%) but demonstrated a stronger relationship with mortality (HR=1.9; 95% CI, 1.5-2.5, p<0.001). In patients with BUN/Cr in the top tertile (≥17.3), any proteinuria (HR=1.3; 95% CI, 1.1-1.5, p=0.008) and >1+ proteinuria (HR=2.3; 95% CI, 1.7-3.3, p<0.001) both remained associated with mortality. However, in patients with BUN/Cr in the bottom tertile (≤13.3), any proteinuria (HR=0.95; 95% CI, 0.77-1.2, p=0.63, p interaction=0.015) and >1+ proteinuria (HR=1.3; 95% CI, 0.79-2.2, p=0.29, p interaction=0.036) were not associated with worsened survival.. Analogous to a reduced eGFR, the mechanism underlying proteinuria in HF may be important in determining the associated survival disadvantage.

Topics: Aged; Blood Urea Nitrogen; Enalapril; Female; Glomerular Filtration Rate; Heart Failure; Humans; Male; Middle Aged; Prognosis; Proteinuria; Randomized Controlled Trials as Topic; Renal Insufficiency; Risk Factors; Survival Analysis; Ventricular Dysfunction, Left

Vitamin D receptor (VDR) agonists (VDRAs) are commonly used to manage hyperparathyroidism secondary to chronic kidney disease (CKD). Patients with CKD experience extremely high risks of cardiovascular morbidity and mortality. Clinical observations show that VDRA therapy may be associated with cardio-renal protective and survival benefits in patients with CKD. The 5/6 nephrectomized (NX) Sprague-Dawley rat with established uremia exhibits elevated serum parathyroid hormone (PTH), hypertension, and abnormal cardiac function. Treatment of 5/6 NX rats with VS-105, a novel VDRA (0.05 and 0.5 μg/kg po by gavage), once daily for 8 wk in the presence or absence of enalapril (30 mg/kg po via drinking water) effectively suppressed serum PTH without raising serum calcium. VS-105 alone reduced systolic blood pressure (from 174 ± 6 to 145 ± 9 mmHg, P < 0.05) as effectively as enalapril (from 174 ± 6 to 144 ± 7 mmHg, P < 0.05). VS-105 improved cardiac functional parameters such as E/A ratio, ejection fraction, and fractional shortening with or without enalapril. Enalapril or VS-105 alone significantly reduced left ventricular hypertrophy (LVH); VS-105 plus enalapril did not further reduce LVH. VS-105 significantly reduced both cardiac and renal fibrosis. The lack of hypercalcemic toxicity of VS-105 is due to its lack of effects on stimulating intestinal calcium transport and inducing the expression of intestinal calcium transporter genes such as Calb3 and TRPV6. These studies demonstrate that VS-105 is a novel VDRA that may provide cardiovascular benefits via VDR activation. Clinical studies are required to confirm the cardiovascular benefits of VS-105 in CKD.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Calcitriol; Cardiotonic Agents; Disease Models, Animal; Dose-Response Relationship, Drug; Enalapril; Fibrosis; Hyperparathyroidism; Hypertension; Hypertrophy, Left Ventricular; Kidney; Male; Myocardial Contraction; Myocardium; Nephrectomy; Parathyroid Hormone; Rats, Sprague-Dawley; Receptors, Calcitriol; Recovery of Function; Renal Insufficiency, Chronic; Stroke Volume; Time Factors; Ventricular Dysfunction, Left; Ventricular Function, Left

What is the central question of this study? Although cardioprotective effects of dipeptidyl peptidase-4 (DPP-4) inhibitors have been demonstrated, their cardiac effects in chronic myocardial infarction (MI) are unclear. We determined the effects of a DPP-4 inhibitor on cardiac function and remodelling in rats with chronic MI. What is the main finding and its importance? We demonstrated, for the first time, that DPP-4 inhibitor, but not metformin, exerted similar efficacy in improving cardiac function and attenuating cardiac fibrosis compared with enalapril in rats with chronic MI. These findings reveal benefits additional to the glycaemic control by the DPP-4 inhibitor in chronic MI, and it might become the new drug of choice for MI in patients with diabetes mellitus. Adverse cardiac remodelling after myocardial infarction (MI) leads to progressive heart failure. Dipeptidyl peptidase-4 (DPP-4) inhibitors are new antidiabetic drugs that exert cardioprotection. However, their role in cardiac function and remodelling in chronic MI is unclear. We hypothesized that the DPP-4 inhibitor vildagliptin reduces adverse cardiac remodelling and improves cardiac function in rats with chronic MI. These effects were also compared with enalapril and metformin. Male Wistar rats (n = 36) with chronic MI induced by ligation of the left anterior descending coronary artery were divided into six groups to receive vehicle, vildagliptin (3 mg kg(-1)  day(-1) ), metformin (30 mg kg(-1)  day(-1) ), enalapril (10 mg kg(-1)  day(-1) ), combined metformin and enalapril or combined vildagliptin and enalapril for 8 weeks. At the end of the study, plasma malondialdehyde (MDA), heart rate variability (HRV), left ventricular (LV) function, pathological and biochemical studies of cardiac remodelling were investigated. Our study demonstrated that rats with chronic MI had increased oxidative stress levels, depressed HRV, adverse cardiac remodelling, indicated by cardiac fibrosis, and LV dysfunction. Treatment with vildagliptin or enalapril significantly decreased oxidative stress, attenuated cardiac fibrosis and improved HRV and LV function. We conclude that vildagliptin exerts similar cardioprotective effects to enalapril in attenuating oxidative stress and cardiac fibrosis and improving cardiac function in rats with chronic MI. Metformin does not provide these benefits in this model. Moreover, addition of either metformin or vildagliptin to enalapril does not provide additional benefit in a

Topics: Adamantane; Angiotensin-Converting Enzyme Inhibitors; Animals; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Enalapril; Fibrosis; Heart Rate; Hypoglycemic Agents; Male; Metformin; Myocardial Infarction; Myocardium; Nitriles; Oxidative Stress; Pyrrolidines; Rats, Wistar; Recovery of Function; Signal Transduction; Time Factors; Ventricular Dysfunction, Left; Ventricular Function, Left; Ventricular Remodeling; Vildagliptin

Topics: Antineoplastic Agents; Carbazoles; Carvedilol; Enalapril; Female; Hematologic Neoplasms; Humans; Male; Propanolamines; Ventricular Dysfunction, Left

Understanding how individuals vary in their response to treatment is an important task of clinical research. For standard regression models, a proportional interactions model first described by Follmann and Proschan (1999) offers a powerful approach for identifying effect modification in a randomized clinical trial when multiple variables influence treatment response. In this paper, we present a framework for using the proportional interactions model in the context of a parallel-arm clinical trial with multiple prespecified candidate effect modifiers. To protect against model misspecification, we propose a selection strategy that considers all possible proportional interactions models. We develop a modified Bonferroni correction for multiple testing that accounts for the positive correlation among candidate models. We describe methods for constructing a confidence interval for the proportionality parameter. In simulation studies, we show that our modified Bonferroni adjustment controls familywise error and has greater power to detect proportional interactions compared with multiplcity-corrected subgroup analyses. We demonstrate our methodology by using the Studies of Left Ventricular Dysfunction Treatment trial, a placebo-controlled randomized clinical trial of the efficacy of enalapril to reduce the risk of death or hospitalization in chronic heart failure patients. An R package called anoint is available for implementing the proportional interactions methodology.

Topics: Computer Simulation; Confidence Intervals; Enalapril; Heart Failure; Humans; Models, Statistical; Randomized Controlled Trials as Topic; Ventricular Dysfunction, Left

Topics: Antineoplastic Agents; Carbazoles; Enalapril; Female; Hematologic Neoplasms; Humans; Male; Propanolamines; Ventricular Dysfunction, Left

Topics: Antineoplastic Agents; Carbazoles; Enalapril; Female; Hematologic Neoplasms; Humans; Male; Propanolamines; Ventricular Dysfunction, Left

Topics: Antineoplastic Agents; Carbazoles; Enalapril; Female; Hematologic Neoplasms; Humans; Male; Propanolamines; Ventricular Dysfunction, Left

A 22-year old woman visited the LAMB Hospital, Parbatipur, Dinajpur, Bangladesh, in February 2010, with exertional dyspnea for three weeks. She had had a normal vaginal delivery four months ago; 2-dimensional echocardiogram showed severe left ventricular dysfunction and biventricular thrombi, which resolved without complications after anticoagulation. Biventricular thrombosis with peripartum cardiomyopathy is quite a rare finding, and its clinical course and proper management is not known. No such case has previously been reported in Bangladesh.

Topics: Bangladesh; Cardiomyopathies; Drug Combinations; Echocardiography; Enalapril; Female; Furosemide; Humans; Peripartum Period; Puerperal Disorders; Thrombosis; Ventricular Dysfunction, Left; Warfarin; Young Adult

Topics: Angiotensin-Converting Enzyme Inhibitors; Cardio-Renal Syndrome; Enalapril; Female; Humans; Kidney; Male; Ventricular Dysfunction, Left

Imidapril is an angiotensin converting enzyme (ACE) inhibitor without a sulfhydril group which has been shown from previous study to have low incidence of ACE inhibitor induced cough.. To compare the incidence of cough between two ACE inhibitors, imidapril and enalapril.. A comparative cross over study was performed in 119 patients with hypertension or left ventricular dysfunction. Patients were assigned to one of the two treatment groups, either a group receiving imidapril or enalapril for 4 weeks (Period I) and then these same groups were crossed over to receive either enalapril or imidapril for 4 weeks (Period II). The occurrence of cough during treatment was monitored by interviewing the patients.. The incidence of cough was 44 % while on imidapril treatment and 66% while on enalapril treatment (p = 0.0014). The antihypertensive effects of two drugs were not different.. The incidence of cough was significantly less under imidapril than under enalapril treatment, while there was no difference in the antihypertensive effects between the two ACE inhibitors.

Topics: Administration, Oral; Aged; Angiotensin-Converting Enzyme Inhibitors; Cough; Cross-Over Studies; Enalapril; Female; Humans; Hypertension; Imidazolidines; Incidence; Male; Middle Aged; Treatment Outcome; Ventricular Dysfunction, Left

So far, a beneficial effect of combined angiotensin-converting enzyme inhibitors (ACEI) and β-blocker therapy for systolic dysfunction in Duchenne muscular dystrophy (DMD) has been reported only in patients in whom DMD was due to deletions in the dystrophin gene.. In a 24-year-old male with DMD due to the point mutation c.4213C>T (p.Gln1405X) in exon 30 of the dystrophin gene, cardiologic examination at the age of 23 years revealed asymptomatic severely reduced systolic dysfunction with a fractional shortening of 14% in the absence of dilated cardiomyopathy. A combined therapy with enalapril (2.5 mg/day) and bisoprolol (1.25 mg/day) was initiated. After a slow increase in the dosage to 10 mg enalapril/day and 2.5 mg bisoprolol/day, systolic dysfunction resolved to a fractional shortening of 26% already after 7 months.. This case shows that asymptomatic reduced systolic function also in patients with DMD due to a point mutation responds favourably to a combination therapy with ACEI and β-blockers.

Topics: Adult; Antihypertensive Agents; Bisoprolol; Drug Therapy, Combination; Enalapril; Humans; Male; Muscular Dystrophy, Duchenne; Point Mutation; Systole; Treatment Outcome; Ventricular Dysfunction, Left

The study was designed to evaluate effect of enalapril and telmisartan on hemodynamic characteristics and diastolic function (DF) of left ventricle (LV) in patients with type 2 diabetes and arterial hypertension (AH). It included 64 patients aged 54.3 +/- 5.2 years. Those in group 1 (n = 31) were given enalapril (enap), patients of group 2 (n = 33) were treated with telmisartan (micardis). Examination included 24 hour AP monitoring, Holter ECG monitoring, and echocardiography. Compensation of metabolic disorders was evaluated from fasting and postprandial blood glucose and HbAc1 levels. Impaired LV DF was the main feature of affected myocardium in patients with DM2 and elevated AP in the absence of contractility disturbance. Enalapril therapy ensured the desired level of systolic and diastolic AP in 77 and 64.5% of the patients respectively in association with a decreased number of non-dippers and night-peakers in 45.4% of the observations in the absence of changes in HbAc1 level and LV DF. Treatment with telmisartan ensured within 24 weeks efficacious control of systolic AP and normalization of its daily profile in 87.5% patients with pathological circadian rhythm, besides improvement of carbohydrate metabolism and LV DF.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Blood Glucose; Blood Pressure Monitoring, Ambulatory; Diabetes Mellitus, Type 2; Diastole; Dose-Response Relationship, Drug; Drug Therapy, Combination; Enalapril; Female; Follow-Up Studies; Hemodynamics; Humans; Hypertension; Male; Middle Aged; Myocardial Contraction; Telmisartan; Treatment Outcome; Ultrasonography; Ventricular Dysfunction, Left

Acute intravenous infusion of ranolazine (Ran), an anti-ischemic/antiangina drug, was previously shown to improve left ventricular (LV) ejection fraction (EF) without a concomitant increase in myocardial oxygen consumption in dogs with chronic heart failure (HF). This study examined the effects of treatment with Ran alone and in combination with metoprolol (Met) or enalapril (Ena) on LV function and remodeling in dogs with HF. Dogs (n = 28) with microembolization-induced HF were randomized to 3 mo oral treatment with Ran alone [375 mg twice daily (bid); n = 7], Ran (375 mg bid) in combination with Met tartrate (25 mg bid; n = 7), Ran (375 mg bid) in combination with Ena (10 mg bid; n = 7), or placebo (PL; Ran vehicle bid; n = 7). Ventriculographic measurements of LV end-diastolic volume (EDV) and end-systolic volume (ESV) and LV EF were obtained before treatment and after 3 mo of treatment. In PL-treated dogs, EDV and ESV increased significantly. Ran alone prevented the increase in EDV and ESV seen in the PL group and significantly increased EF, albeit modestly, from 35 +/- 1% to 37 +/- 2%. When combined with either Ena or Met, Ran prevented the increase in EDV, significantly decreased ESV, and markedly increased EF compared with those of PL. EF increased from 35 +/- 1% to 40 +/- 1% with Ran + Ena and from 34 +/- 1% to 41 +/- 1% with Ran + Met. Ran alone or in combination with Ena or Met was also associated with beneficial effects at the cellular level on histomorphometric parameters such as hypertrophy, fibrosis, and capillary density as well as the expression for pathological hypertrophy and Ca2+ cycling genes. In conclusion, Ran prevented progressive LV dysfunction and global and cellular myocardial remodeling, and Ran in combination with Ena or Met improved LV function beyond that observed with Ran alone.

Topics: Acetanilides; Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Cardiotonic Agents; Disease Models, Animal; Disease Progression; Dogs; Drug Therapy, Combination; Enalapril; Heart Failure; Metoprolol; Myocardium; Piperazines; Proteins; Ranolazine; Ventricular Dysfunction, Left; Ventricular Remodeling

To investigate the mechanisms underlying the depressed sarcolemmal (SL) Na(+)-K(+)-ATPase activity in congestive heart failure (CHF), different isoforms and gene expression of Na(+)-K(+)-ATPase were examined in the failing left ventricle (LV) at 8 weeks after myocardial infarction (MI). In view of the increased activity of renin-angiotensin system (RAS) in CHF, these parameters were also studied after 5 weeks of treatment with enalapril (10 mg x kg-1 x day-1), an angiotensin-converting enzyme inhibitor, and losartan (20 mg.kg-1.day-1), an angiotensin II type 1 receptor antagonist, starting at 3 weeks after the coronary ligation in rats. The infarcted animals showed LV dysfunction and depressed SL Na(+)-K(+)-ATPase activity. Protein content and mRNA levels for Na(+)-K(+)-ATPase alpha2 isoform were decreased whereas those for Na(+)-K(+)-ATPase alpha3 isoform were increased in the failing LV. On the other hand, no significant changes were observed in protein content or mRNA levels for Na(+)-K(+)-ATPase alpha1 and beta1 isoforms. The treatment of infarcted animals with enalapril or losartan improved LV function and attenuated the depression in Na(+)-K(+)-ATPase alpha2 isoform as well as the increase in alpha3 isoform, at both the protein and mRNA levels; however, combination therapy with enalapril and losartan did not produce any additive effects. These results provide further evidence that CHF due to MI is associated with remodeling of SL membrane and suggest that the blockade of RAS plays an important role in preventing these alterations in the failing heart.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Disease Models, Animal; Enalapril; Gene Expression Regulation, Enzymologic; Heart Failure; Hemodynamics; Losartan; Male; Myocardial Infarction; Myocardium; Rats; Rats, Sprague-Dawley; Renin-Angiotensin System; RNA, Messenger; Sarcolemma; Sodium-Potassium-Exchanging ATPase; Time Factors; Ventricular Dysfunction, Left; Ventricular Remodeling

Topics: Adolescent; Adult; Angiotensin-Converting Enzyme Inhibitors; Child; Enalapril; Humans; Muscular Dystrophy, Duchenne; Ventricular Dysfunction, Left; Ventricular Function, Left

To determine whether therapy with the angiotensin II type 1 receptor blocker (ARB) candesartan and the comparator angiotensin-converting-enzyme inhibitor (ACEI) enalapril during healing after reperfused ST-elevation myocardial infarction (RSTEMI) limit adverse remodeling of infarct zone (IZ) collagens and left ventricular (LV) diastolic dysfunction, we randomized 24 dogs surviving anterior RSTEMI (90-min coronary occlusion) to placebo, candesartan, and enalapril therapy between day 2 and 42. Six other dogs were sham. We measured regional IZ and non-infarct zone (NIZ) collagens (hydroxyproline; types I/III; cross-linking), transforming growth factor-beta (TGF-beta) and topography at 6 weeks, and hemodynamics, LV diastolic and systolic function, and remodeling over 6 weeks. Compared to sham, placebo-RSTEMI differentially altered regional collagens, with more pronounced increase in TGF-beta, hydroxyproline, and type I, insoluble, and cross-linked collagens in the IZ than NIZ, and increased IZ soluble and type III collagens at 6 weeks, and induced persistent LV filling pressure elevation, diastolic and systolic dysfunction, and LV remodeling over 6 weeks. Compared to placebo-RSTEMI, candesartan and enalapril limited adverse regional collagen remodeling, with normalization of type III, soluble and insoluble collagens and decrease in pyridinoline cross-linking in the IZ at 6 weeks, and attenuation of LV filling pressure, diastolic dysfunction, and remodeling over 6 weeks. The results suggest that candesartan and enalapril during healing after RSTEMI prevent rather than worsen adverse remodeling of IZ collagens and LV diastolic dysfunction, supporting the clinical use of ARBs and ACEIs during subacute RSTEMI.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzimidazoles; Biphenyl Compounds; Collagen; Dogs; Enalapril; Hydroxyproline; Myocardial Infarction; Myocardial Reperfusion; Peptidyl-Dipeptidase A; Tetrazoles; Transforming Growth Factor beta1; Ventricular Dysfunction, Left; Ventricular Remodeling; Wound Healing

Topics: Angiotensin-Converting Enzyme Inhibitors; Cardiomyopathies; Enalapril; Humans; Randomized Controlled Trials as Topic; Ventricular Dysfunction, Left

Kidney disease has emerged as a risk factor for mortality in heart failure populations. The objective of this study was to determine the impact of different stages of kidney dysfunction (defined using the Kidney Disease Outcomes Quality Initiative [K/DOQI] classification system) and changes in kidney function on mortality in a cohort of patients with heart failure. A retrospective analysis was conducted of data from the randomized controlled trials Studies of Left Ventricular Dysfunction. A total of 6640 participants with asymptomatic and symptomatic heart failure were studied. Estimated GFR (eGFR) were calculated and then categorized according to the K/DOQI classification system into the following categories: > or =90, 60 to 89, 30 to 59, and 15 to 29 ml/min per 1.73 m2. Reduction in eGFR from baseline was calculated and subsequently categorized according to rate of decline (<5, 5 to 10, 11 to 15, and >15 ml/min per 1.73 m2 per year). Independent of baseline differences, lower levels of eGFR were associated with a higher total mortality compared with those with eGFR > or =90 ml/min (30 to 59 ml/min per 1.73 m2: hazard ratio [HR] 1.32, 95% confidence interval [CI] 1.10 to 1.59, P = 0.004; 15 to 29 ml/min per 1.73 m2: HR 2.54, 95% CI 1.54 to 4.19, P < 0.001). eGFR deteriorated rapidly (>15 ml/min per 1.73 m2 per year) in 12% of participants. This decline was associated with a significant increase in mortality compared with slower decline (<5 ml/min per 1.73 m2 per year), despite adjustments for baseline kidney function, baseline heart failure, or change in heart failure (HR 5.63; 95% CI 4.90 to 6.46; P < 0.0001). The levels of eGFR from the K/DOQI classification system are associated with mortality in a well-characterized heart failure population. Rate of decline in kidney function is a strong predictor of increased mortality in this population, independent of worsening heart failure and baseline kidney function.

Topics: Adult; Aged; Enalapril; Female; Glomerular Filtration Rate; Humans; Kidney; Male; Middle Aged; Randomized Controlled Trials as Topic; Systole; Ventricular Dysfunction, Left

Topics: Angiotensin-Converting Enzyme Inhibitors; Enalapril; Female; Follow-Up Studies; Humans; Male; Middle Aged; Randomized Controlled Trials as Topic; Ventricular Dysfunction, Left

The implication of various cytokines in a subclinical inflammatory process has been documented in heart failure (HF). The role of temporal changes of more conventional markers of inflammation, such as the white blood cell (WBC) count, on clinical outcomes remains largely unknown.. We performed a retrospective analysis of patients included in the Studies Of Left Ventricular Dysfunction that had documented eligibility at the baseline visit, a documented WBC count at baseline and at least 1 measurement during follow-up. We evaluated the association between variations in WBC count, WBC subfractions and mortality and non-fatal events. An increase in WBC count during follow-up compared with baseline was associated with a significantly higher risk of all-cause and cardiovascular (CV) mortality, HF mortality and arrhythmic death (all P < .05). A relative increase in the neutrophil count was associated with higher risk of all-cause and CV mortality, HF mortality and cardiac ischemic events (all P < .05). No significant interaction was present in regards to the etiology of HF.. Temporal increases in WBC and neutrophil counts are associated with increased risks of death and CV events. This relationship appears to be independent of HF etiology.

Topics: Aged; Blood Cell Count; Cardiovascular Diseases; Enalapril; Female; Follow-Up Studies; Humans; Inflammation; Leukocyte Count; Lymphocyte Count; Male; Middle Aged; Neutrophils; Prognosis; Retrospective Studies; Risk Assessment; Time Factors; Ventricular Dysfunction, Left

The role of angiotensin-converting enzyme inhibitors in the management of cardiomyopathy related to Duchenne muscular dystrophy has not been completely defined. The purposes of this study were to describe the response to enalapril and its relation to dystrophin mutation type, ventricular size, or age at the onset of left ventricular (LV) systolic dysfunction. Serial clinical and echocardiographic data from 50 patients with Duchenne muscular dystrophy (aged 10 to 20 years) were retrospectively reviewed. Twenty-seven patients (46%) developed LV systolic dysfunction (mean age 13.2 +/- 2.4 years). Ten (43%) responded to enalapril with the normalization of function. Responders and nonresponders developed LV systolic dysfunction at similar ages (p = 0.91). At the onset of LV systolic dysfunction, only 2 patients (1 responder, 1 nonresponder) had dilated left ventricles. The positive response to enalapril was sustained in 7 patients (median follow-up 23 months, range 5 to 58). No specific mutation was associated with the response to enalapril (p = 0.66) or predictive of the development of LV systolic dysfunction (p = 0.8). In conclusion, 10 of 26 patients (43%) with Duchenne muscular dystrophy responded to the use of enalapril with normalization of the shortening fraction. Age at the onset of LV systolic dysfunction and the type of mutation were not predictors of response to enalapril.

Topics: Adolescent; Age of Onset; Angiotensin-Converting Enzyme Inhibitors; Cardiomyopathies; Child; Dystrophin; Enalapril; Humans; Muscular Dystrophy, Duchenne; Mutation; Ventricular Dysfunction, Left; Ventricular Function, Left

Limited data are available to predict the occurrence of hyperkalemia. Risk assessment is complicated by the lack of consistency of definition between trials.. We conducted a retrospective analysis of the SOLVD to evaluate the incidence of hyperkalemia and the value of several baseline characteristics as predictors of hyperkalemia in patients with left ventricular dysfunction.. The incidence of hyperkalemia was 6.0% and 1.1% using a definition of > or = 5.5 and > or = 6.0 mmol/L, respectively. Independent predictors of hyperkalemia (> or = 5.5 mmol/L) were randomization to enalapril, baseline serum creatinine, serum potassium, New York Heart Association functional class III or IV, a history of diabetes, and atrial fibrillation (all P < .05). The use of loop diuretics was also associated with an increased risk of hyperkalemia but only in patients included in the SOLVD prevention trial. Similar results were obtained when renal function was evaluated using the estimated creatinine clearance.. The definition of hyperkalemia is important when evaluating its incidence in clinical trials. Renal dysfunction, baseline serum potassium, diabetes, atrial fibrillation, New York Heart Association functional class, and treatment with an angiotensin-converting enzyme inhibitor are factors associated with the development of hyperkalemia in patients with left ventricular dysfunction. More specifically, our results suggests that before initiating drugs that can cause hyperkalemia in patients with heart failure, a strong consideration should be given to calculate creatinine clearance and that patients with a creatinine clearance < 60 mL/min should undergo a close monitoring of their serum potassium to prevent the development of hyperkalemia.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Atrial Fibrillation; Creatinine; Diabetes Complications; Enalapril; Female; Humans; Hyperkalemia; Incidence; Male; Middle Aged; Multicenter Studies as Topic; Potassium; Predictive Value of Tests; Randomized Controlled Trials as Topic; Retrospective Studies; Risk Assessment; Severity of Illness Index; Sodium Potassium Chloride Symporter Inhibitors; Ventricular Dysfunction, Left

Although the defects in the sarcolemma (SL) and sarcoplasmic reticulum (SR) membranes are known to be associated with cardiac dysfunction in chronic diabetes, very little information regarding the mechanisms of these membrane abnormalities is available in the literature. For this reason, rats were treated daily for 8 weeks with and without enalapril, an angiotensin-converting enzyme inhibitor, or losartan, an angiotensin receptor antagonist, 3 days after inducing diabetes with an injection of streptozocin. Treatment of diabetic animals with both enalapril and losartan attenuated alterations in cardiac function and the left ventricular redox potential without any changes in the increased plasma glucose or reduced plasma insulin levels. The SL Na+-K+ ATPase, Ca2+ pump, Na+-dependent Ca2+-uptake, Ca2+-channel density, and low-affinity Ca2+-binding activities were depressed whereas Ca2+ ecto-ATPase activity was increased in the diabetic heart. Furthermore, the SR Ca2+-release and Ca2+-pump activities in the diabetic hearts were decreased without any changes in the Mg2+-ATPase activity. These alterations in SL and SR membranes in diabetic animals were partly prevented by treatments with enalapril and losartan. The results suggest that the activation of the renin-angiotensin system plays an important role in diabetes-induced changes in SL and SR membranes as well as cardiac function.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Enalapril; Losartan; Male; Malondialdehyde; Rats; Rats, Sprague-Dawley; Renin-Angiotensin System; Sarcolemma; Sarcoplasmic Reticulum; Ventricular Dysfunction, Left; Ventricular Function, Left

We aimed to investigate the impact of angiotensin-converting enzyme inhibitors (ACEIs) on hematocrit values in those with heart failure, and the relationship between incident anemia and mortality.. Prevalent anemia is an independent risk factor for morbidity and mortality in those with heart failure. Studies in patients with polycythemia have demonstrated that ACEIs are effective in lowering hematocrit values.. We used the Studies Of Left Ventricular Dysfunction (SOLVD) database to compare the odds of developing new anemia at one year in patients who were not anemic at entry and who were randomized to enalapril or placebo. Cox proportional hazards models were utilized to determine the impact of incident and prevalent anemia on subsequent mortality.. Enalapril increased the odds of incident anemia (hematocrit < or =39% in men or < or =36% in women) at one year by 48% (odds ratio [OR] 1.48, 95% confidence interval [CI] 1.20 to 1.82) in unadjusted and 56% (OR 1.56, 95% CI 1.26 to 1.93) in adjusted models. With multivariate analysis, prevalent anemia at randomization was associated with a 44% (hazard ratio [HR] 1.44, 95% CI 1.31 to 1.66) increase in all-cause mortality, whereas incident anemia after randomization was associated with a 108% increase (HR 2.08, 95% CI 1.82 to 2.38). After adjusting for incident and prevalent anemia, use of enalapril was associated with a survival benefit.. Enalapril was associated with increased odds of developing anemia at one year. Those with periods of time with incident anemia had the poorest survival, followed by those with prevalent anemia, then those without anemia. Enalapril was protective of overall mortality after adjusting for incident anemia and in those with prevalent anemia.

Topics: Aged; Anemia; Angiotensin-Converting Enzyme Inhibitors; Enalapril; Female; Follow-Up Studies; Hematocrit; Humans; Male; Middle Aged; Proportional Hazards Models; Risk Factors; Treatment Outcome; Ventricular Dysfunction, Left

The objective was to assess the cardiac effects of growth hormone (GH) therapy. Anthracycline-treated childhood cancer survivors frequently have reduced left ventricular (LV) wall thickness and contractility, and GH therapy may affect these factors.. We examined serial cardiac findings for 34 anthracycline-treated childhood cancer survivors with several years of GH therapy and baseline cardiac z scores similar to those of a comparison group (86 similar cancer survivors without GH therapy).. LV contractility was decreased among GH-treated patients before, during, and after GH therapy (-1.08 SD below the age-adjusted population mean before therapy and -1.88 SD 4 years after therapy ceased, with each value depressed below normal). Contractility was higher in the control group than in the GH-treated group, with this difference being nearly significant. The GH-treated children had thinner LV walls before GH therapy (-1.38 SD). Wall thickness increased during GH therapy (from -1.38 SD to -1.09 SD after 3 years of GH therapy), but the effect was lost shortly after GH therapy ended and thickness diminished over time (-1.50 SD at 1 year after therapy and -1.96 SD at 4 years). During GH therapy, the wall thickness for the GH-treated group was greater than that for the control group; however, by 4 years after therapy, there was no difference between the GH-treated group and the control group.. GH therapy among anthracycline-treated survivors of childhood cancer increased LV wall thickness, but the effect was lost after therapy was discontinued. The therapy did not affect the progressive LV dysfunction.

Topics: Adolescent; Angiotensin-Converting Enzyme Inhibitors; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Body Height; Cardiovascular Agents; Child; Child, Preschool; Enalapril; Female; Heart Ventricles; Hemodynamics; Human Growth Hormone; Humans; Hypertrophy, Left Ventricular; Hypopituitarism; Infant; Male; Myocardial Contraction; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Survivors; Ultrasonography; Ventricular Dysfunction, Left

Matrix metalloproteinases (MMPs) are activated in dilated failing hearts, and angiotensin-converting enzyme (ACE) inhibition prevents left ventricular (LV) dilatation. However, it remains unclear whether activation of MMPs precedes or is secondary to LV remodeling, and an effect of ACE inhibition on MMPs is unknown.. Dahl salt-sensitive rats fed a high-salt diet from 8 weeks served as the hypertensive heart failure (HF) model. LV echo, histological study, measurement of mRNA levels, and gelatin zymography were performed before (at 23 weeks) and after (at 26 weeks) the development of LV dilatation and pulmonary edema. The same procedures were conducted in the HF model rats treated with a subdepressor dose of ACE inhibitor (enalapril 5 mg x kg(-1) x d(-1)) from 9 weeks. Rats fed on normal chow served as age-matched controls. In the untreated HF model rats, gene expression of MMP-2 and MMP-9 and tissue gelatinase activity were elevated at 23 weeks without LV dilatation. LV dilatation, LV systolic dysfunction, and pulmonary edema occurred at 26 weeks, with further enhancement of the expression and activity of MMPs. ACE inhibition prevented such geometrical and functional deterioration. The gene expression and activity of MMPs were suppressed by ACE inhibition at 23 weeks without a decrease in blood pressure, and the suppressive effects continued at 26 weeks.. MMPs are likely to trigger and promote LV remodeling, and ACE inhibition directly exerts inhibitory effect on MMPs, leading to the prevention of LV remodeling and dysfunction.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Echocardiography; Enalapril; Enzyme Activation; Enzyme Induction; Heart Failure; Hypertension; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Protease Inhibitors; Pulmonary Edema; Rats; Rats, Inbred Dahl; RNA, Messenger; Tissue Inhibitor of Metalloproteinase-2; Ventricular Dysfunction, Left; Ventricular Remodeling

Effects of enalapril on a canine model of atrial pacing-induced atrial fibrillation (AF) with rapid ventricular responses were determined.. Four weeks of atrial rapid pacing was performed on twenty-four beagles pretreated with placebo (Group I, n = 14) or enalapril 1 mg/kg (Group II, n = 10). Atrial effective refractory period (ERP), P-wave width, duration of AF, and left ventricular ejection fraction (LVEF) were evaluated every week. AF cycle length was determined by spectral analyses of fibrillation waves. Quantitative analysis of histology was added.. After 4 weeks of pacing, P-wave width was longer in Group I than in Group II, and the duration of induced AF was significantly longer in Group I (59.6 +/- 66.3 seconds) than in Group II (3.6 +/- 3.4 seconds, P < 0.05). AF cycle length was longer in Group I than in Group II despite similar shortening of atrial ERP. Mean ventricular rate during rapid atrial pacing was not different between the two groups. LVEF similarly decreased in both groups. Interstitial fibrosis and expression of connexin43 was greater in Group I than in Group II (interstitial fibrosis, 9.2 +/- 8.4 versus 1.9 +/- 2.1%, P < 0.05; connexin43, 5.3 +/- 2.2 versus 1.1 +/- 1.1%, P < 0.05).. Enalapril suppressed atrial pacing-induced AF with tachycardia-mediated cardiomyopathy by suppressing interstitial fibrosis, connexin43 over-expression and conduction delay.

Topics: Animals; Atrial Fibrillation; Cardiac Pacing, Artificial; Connexin 43; Disease Models, Animal; Dogs; Enalapril; Female; Fibrosis; Male; Ventricular Dysfunction, Left

Experimental and clinical evidence suggests a preventive role for agiotensin-coverting enzyme (ACE) inhibitors on the development of atrial fibrillation. However, the effect of ACE inhibition on hospitalization with atrial tachyarrhythmias in patients with left ventricular (LV) dysfunction is not known. We sought to determine whether enalapril treatment reduced hospitalizations with atrial tachyarrhythmias in patients with LV dysfunction.. We performed a retrospective analysis of the Studies of Left Ventricular Dysfunction (SOLVD) trial. Hospitalizations with atrial tachyarrhythmias were noted.. A total of 192 hospitalizations with atrial tachyarrhythmias occurred in 158 patients during a follow-up period of 34 months. The time to first hospitalization with atrial tachyarrhythmias or death was significantly lower in the enalapril group (P =.005). In a multivariate analysis adjusting for the presence of atrial fibrillation at study entry, enalapril treatment was associated with a reduction in the rate of hospitalization with atrial tachyarrhythmias or death (RR, 0.87; 95% CI, 0.79-0.96; P =.007). The incidence of hospitalization with atrial tachyarrhythmias was 7.9 hospitalizations per 1000 patient-years of follow-up in the enalapril group, compared with 12.4 per 1000 patient-years in the placebo group (RR, 0.64; 95% CI, 0.48-0.85; P =.002).. Enalapril is associated with a decreased incidence of hospitalization with atrial tachyarrhythmias in patients with LV dysfunction.

Topics: Angiotensin-Converting Enzyme Inhibitors; Atrial Fibrillation; Comorbidity; Enalapril; Female; Follow-Up Studies; Hospitalization; Humans; Incidence; Male; Middle Aged; Multivariate Analysis; Randomized Controlled Trials as Topic; Retrospective Studies; Survival Rate; Ventricular Dysfunction, Left

Sample size calculations for survival trials typically include an adjustment to account for the expected rate of noncompliance, or discontinuation from study medication. Existing sample size methods assume that when patients discontinue, they do so independently of their risk of an endpoint; that is, that noncompliance is noninformative. However, this assumption is not always true, as we illustrate using results from a published clinical trial database. In this article, we introduce a modified version of the method proposed by Lakatos (1988, Biometrics 44, 229-241) that can be used to calculate sample size under informative noncompliance. This method is based on the concept of two subpopulations: one with high rates of endpoint and discontinuation and another with low rates. Using this new method, we show that failure to consider the impact of informative noncompliance can lead to a considerably underpowered study.

Topics: Biometry; Clinical Trials as Topic; Enalapril; Humans; Models, Statistical; Patient Compliance; Sample Size; Survival Analysis; Ventricular Dysfunction, Left

Diabetes mellitus is a predictor of morbidity and mortality in patients with heart failure. The effect of angiotensin-converting enzyme (ACE) inhibitors on the prevention of diabetes in patients with left ventricular dysfunction is unknown. The aim of this retrospective study was to assess the effect of the ACE inhibitor enalapril on the incidence of diabetes in the group of patients from the Montreal Heart Institute enrolled in the Studies of Left Ventricular Dysfunction (SOLVD).. Clinical charts were evaluated for fasting plasma glucose (FPG) levels by blinded reviewers. A diagnosis of diabetes was made when a FPG > or =126 mg/dL (7 mmol/L) was found at 2 visits (follow-up, 2.9+/-1.0 years). Of the 391 patients enrolled at the Montreal Heart Institute, 291 were not diabetic (FPG <126 mg/dL without a history of diabetes), 153 of these were on enalapril and 138 were on placebo. Baseline characteristics were similar in the 2 groups. Forty patients developed diabetes during follow-up, 9 (5.9%) in the enalapril group and 31 (22.4%) in the placebo group (P<0.0001). By multivariate analysis, enalapril remained the most powerful predictor for risk reduction of developing diabetes (hazard ratio, 0.22; 95% confidence intervals, 0.10 to 0.46; P<0.0001). The effect of enalapril was striking in the subgroup of patients with impaired FPG (110 mg/dL [6.1 mmol/L] < or =FPG <126 mg/dL) at baseline: 1 patient (3.3%) in the enalapril group versus 12 (48.0%) in the placebo group developed diabetes (P<0.0001).. Enalapril significantly reduces the incidence of diabetes in patients with left ventricular dysfunction, especially those with impaired FPG.

Topics: Angiotensin-Converting Enzyme Inhibitors; Blood Glucose; Chronic Disease; Diabetes Mellitus; Enalapril; Female; Heart Failure; Humans; Incidence; Male; Middle Aged; Randomized Controlled Trials as Topic; Retrospective Studies; Risk Factors; Ventricular Dysfunction, Left

Atrial fibrillation (AF) is frequently encountered in patients with heart failure (HF) and is also a predictor of morbidity and mortality in this population. Recent experimental studies have shown electrical and structural atrial remodeling with increased fibrosis in animals with HF and have suggested a preventive effect of ACE inhibitors (ACEi) on the development of AF. To verify the hypothesis that ACEi prevent the development of AF in patients with HF, we conducted a retrospective analysis of the patients from the Montreal Heart Institute (MHI) included in the Studies Of Left Ventricular Dysfunction (SOLVD).. Clinical charts were reviewed and serial ECGs interpreted by a single cardiologist blinded to drug allocation. Patients with AF or flutter on the baseline ECG were excluded. Baseline characteristics were obtained from the SOLVD databases. The mean follow-up was 2.9+/-1.0 years. Of the 391 patients randomly assigned at MHI, 374 were in sinus rhythm at the time of random assignment, with 186 taking enalapril and 188 taking placebo. Baseline characteristics were similar in the two groups except for a higher incidence of previous myocardial infarction in the enalapril group. Fifty-five patients had AF during the follow-up: 10 (5.4%) in the enalapril group and 45 (24%) in the placebo group (P<0.0001). By Cox multivariate analysis, enalapril was the most powerful predictor for risk reduction of AF (hazard ratio, 0.22; 95% CI, 0.11 to 0.44; P<0.0001).. Treatment with the ACEi enalapril markedly reduces the risk of development of atrial fibrillation in patients with left ventricular dysfunction.

Topics: Angiotensin-Converting Enzyme Inhibitors; Atrial Fibrillation; Canada; Comorbidity; Disease-Free Survival; Electrocardiography; Enalapril; Female; Follow-Up Studies; Humans; Incidence; Male; Middle Aged; Multivariate Analysis; Proportional Hazards Models; Randomized Controlled Trials as Topic; Retrospective Studies; Ventricular Dysfunction, Left

Interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) levels increase after acute myocardial infarction (AMI) in humans. Experimental data suggest that these cytokines regulate the initiation of scar formation after AMI. We investigated the interrelationships of IL-6 and TNF-alpha, tissue injury, infarct size, cardiac function, and collagen formation in humans.. Serum and plasma samples were taken on 93 patients receiving thrombolytic treatment for their first AMI. Collagen formation was evaluated by measuring concentrations of serum aminoterminal propeptide of type III procollagen (PIIINP).. IL-6 levels increased by 44% (P<.001) and peaked at 24 hours. Peak IL-6 levels correlated positively with area under the curve of creatine kinase MB mass (r=.31, P<.01), peak troponin T level (r=.34, P<.005), and PIIINP measured at discharge (r=.46, P<.001). There were no changes in TNF-alpha levels, and patients with left ventricular dysfunction (EF<40%) had similar TNF-alpha levels as those with preserved left ventricular function.. IL-6 may regulate collagen formation and thus remodeling of the left ventricle after AMI. In addition, TNF-alpha measurement is useless in the assessment of infarct size or left ventricular function during the immediate post-infarction period.

Topics: Angiotensin-Converting Enzyme Inhibitors; Area Under Curve; Arrhythmias, Cardiac; Biomarkers; C-Reactive Protein; Collagen; Creatine Kinase; Creatine Kinase, MB Form; Electrocardiography; Enalapril; Female; Finland; Humans; Interleukin-6; Isoenzymes; Male; Myocardial Infarction; Peptide Fragments; Procollagen; Quinapril; Severity of Illness Index; Statistics as Topic; Stroke Volume; Tetrahydroisoquinolines; Time Factors; Treatment Outcome; Trinitrotoluene; Tumor Necrosis Factor-alpha; Ventricular Dysfunction, Left

To estimate the independent effects of kidney disease, anemia, and the treatment effects of angiotensin-converting enzyme (ACE) inhibitors on hospitalization cost in patients with heart failure, we used data from the prevention and treatment trials of the Studies of Left Ventricular Dysfunction trial and retrospectively estimated the relative effects of decreased kidney function, as measured by estimated glomerular filtration rate (GFR) at enrollment, and anemia, as measured by hematocrit levels at enrollment, on hospital utilization and expense. Independent of the effects of age, gender, New York Heart Association (NYHA) class, ejection fraction, and the presence of diabetes mellitus, GFR was significantly related to hospitalization expense (percent change in hospitalization expense -16.8%, 95% confidence interval [CI] -11.9% to -21.5%) for GFR >/=90 ml/min/1.73 m(2) compared with GFR <60 ml/min/1.73 m(2)). Similarly, hematocrit levels were significantly related to hospitalization expense (percent change in hospitalization expense -19.9%, 95% CI -10.2% to -28.6%) for hematocrit >/=36% compared with hematocrit <33%). The beneficial effect of the ACE inhibitor enalapril was significantly related to hospitalization expense independent of the effects of GFR and hematocrit (percent change in hospitalization expense -6.8%, 95% CI -3.6% to -9.9% for treatment vs the placebo group), and the beneficial effect was preserved when independently estimated for subgroups with decreased kidney function. Adjusted mean expense per patient per month (PPPM) in the enalapril group was $708 versus $792 in the placebo group. Comparing survivors, enalapril generated annual cost savings greater than the average wholesale price of the drug at Studies of Left Ventricular Dysfunction mean dosage levels. Adjusted expected hospitalization expense varied from $636 PPPM for patients in the lowest hematocrit-GFR risk class (hematocrit >/=36%, GFR >/=90 ml/min/1.73 m(2)) to $1,127 PPPM for those in the highest risk class (hematocrit <33%, GFR <60 ml/min/1.73 m(2)). For patients who survived with reduced kidney function and anemia, ACE inhibitor therapy with enalapril reduced hospitalization expense more than the additional expense of the drug therapy. Thus, kidney disease and anemia are independent risk factors for hospitalization cost in patients with heart failure, and the beneficial effect of ACE inhibitors on hospitalization expense appears to be preserved within kidney disease and a

Topics: Aged; Anemia; Angiotensin-Converting Enzyme Inhibitors; Chi-Square Distribution; Enalapril; Female; Glomerular Filtration Rate; Hospital Costs; Hospitalization; Humans; Kidney Failure, Chronic; Male; Middle Aged; Randomized Controlled Trials as Topic; Regression Analysis; Retrospective Studies; Risk Factors; Ventricular Dysfunction, Left

Angiotensin-converting enzyme inhibitors have been shown to reduce morbidity and mortality in patients with heart failure. The angiotensin type-1 blocking and cardioprotective properties of perindopril and enalapril were studied in a rat model of dilated cardiomyopathy after autoimmune myocarditis. Enalapril at 20 mg/kg showed the same angiotensin type-1 blocking action as perindopril at 2 mg/kg in rats with heart failure. Twenty-eight days after immunization, surviving Lewis rats (90/120 = 75%) were divided into six groups and administered perindopril at 0.02, 0.2 and 2 mg/kg per day (Groups P0.02, P0.2 and P2), enalapril at 2 and 20 mg/kg per day (Groups E2 and E20) or vehicle alone (Group V, all groups n = 15). After oral administration for 1 month, four of 15 (27%) rats in Group V, and two (13%) in Groups P0.02 and E2 died. None of the animals in Groups P0.2, P2 and E20, or normal rats (Group N) died. Although both angiotensin-converting enzyme inhibitors improved ventricular function in a dose-dependent manner, the left ventricular end-diastolic pressure and area of myocardial fibrosis were lower, and +/- dP/dt was higher in Group P2 (4.9 +/- 0.6 mmHg, 7.5 +/- 1.4% and +2651 +/- 254/-2622 +/- 189 mmHg/s, respectively) than in Group V (16.7 +/- 1.3, 36 +/- 2.6 and +2659 +/- 176/-2516 +/- 205, respectively) and Group E20 (7.5 +/- 2.5, 15.6 +/- 2.0 and +2018 +/- 110/-2097 +/- 102, respectively). Although the expression levels of transforming growth factor-beta1 and collagen-III mRNA in Group V (36.3 +/- 5.7 and 157.6 +/- 12.7%) were significantly higher than those in Group N (19.6 +/- 3.0 and 65.2 +/- 1.5%, both p < 0.01), they were reduced in Group P2 (21.4 +/- 5.9 and 75.2 +/- 9.3%, both p < 0.01). These results suggest that although enalapril can block increases in blood pressure caused by circulating angiotensin type-1, perindopril at 2 mg/kg may confer greater protection than enalapril at 20 mg/kg against injury from the renin-angiotensin system in heart failure.

Topics: Administration, Oral; Angiotensin I; Animals; Cardiomyopathy, Dilated; Collagen Type III; Disease Models, Animal; Dose-Response Relationship, Drug; Enalapril; Endomyocardial Fibrosis; Gene Expression; Heart Failure; Hemodynamics; Hypertension; Infusions, Intravenous; Male; Pericardial Effusion; Perindopril; Rats; Rats, Inbred Lew; RNA, Messenger; Survival Rate; Time Factors; Transforming Growth Factor beta; Transforming Growth Factor beta1; Ventricular Dysfunction, Left; Ventricular Pressure

The extent to which age plays a role in the underutilization of angiotensin-converting enzyme (ACE) inhibitors in heart failure patients has not been well studied.. We studied age-related variation in the use of ACE inhibitors in older Medicare beneficiaries discharged alive in Alabama with a diagnosis of heart failure with left ventricular systolic dysfunction.. A total of 285 patients had a mean age +/- SD of 78 +/- 6.9 years; 59% were female and 21% were African American. Of the 285 patients, 181 (63%) were prescribed ACE inhibitors at discharge. Therapy with ACE inhibitors was initiated in 47% of the patients. Compared with patients 65 to 74 years, those 85 years and older had lower odds of receiving ACE inhibitors at discharge. Among patients not admitted on an ACE inhibitor, those 85 years and older also had lower odds of ACE inhibitor therapy being initiated.. The overall rate of ACE inhibitor use was low, and age of 85 years and older was independently associated with lower use and initiation of ACE inhibitors. Opportunities remain to increase the use of ACE inhibitors in older patients with heart failure.

Topics: Age Factors; Aged; Aged, 80 and over; Alabama; Angiotensin-Converting Enzyme Inhibitors; Captopril; Cardiac Output, Low; Cardiology; Drug Utilization; Enalapril; Female; Hospitalization; Humans; Logistic Models; Male; Odds Ratio; Referral and Consultation; Retrospective Studies; Ventricular Dysfunction, Left

Topics: Angina Pectoris; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Cardiovascular Diseases; Clinical Trials as Topic; Enalapril; Humans; Perindopril; Protease Inhibitors; Pyridines; Stroke; Thiazepines; Ventricular Dysfunction, Left

When a medical treatment influences a variety of outcomes, describing the global effect of treatment can be difficult. Traditional approaches specify how treatment affects each separate outcome. This can be done with separate models for each outcome, or by using a combined multivariate model. Describing the overall effect of a treatment thus requires combining these separate effects in some fashion and can be difficult to explain. In this paper, I specify a regression model for use with multiple outcomes where the outcome histories for each pair of patients are ranked. Pairs of patients with different lengths of follow-up are evaluated solely over the common follow-up interval. The logit of the probability that the outcome for patient i is better than that of patient j is assumed to depend on a linear function of the difference of the covariate vectors (for example, treatment indicators) for persons i and j. Thus covariates directly affect the entire clinical history, rather than directly affecting specific outcomes that comprise the history. The idea is that ranking outcomes is more relevant and interpretable than statistically combining separate effects. An estimating equations approach for estimation is described and an example of a clinical trial involving patients with heart failure is provided.

Topics: Angiotensin-Converting Enzyme Inhibitors; Clinical Trials as Topic; Diabetes Complications; Enalapril; Heart Failure; Hospitalization; Humans; Medical Records; Regression Analysis; Treatment Outcome; Ventricular Dysfunction, Left

The purpose of this study was to determine that the administration of an angiotensin converting enzyme (ACE) inhibitor enalapril would confer protection against doxorubicin-induced experimental heart failure, and attenuate the development of left ventricular dysfunction.. Seventeen dogs were chronically instrumented with an intracoronary catheter and received doxorubicin weekly for 4 weeks. Animals were assigned to two groups: group 1: untreated heart failure; and group 2: simultaneous enalapril administration (5 mg twice a week). Hemodynamic data were obtained at week 0 and 12. Echocardiography was performed weekly.. Survival improved with simultaneous enalapril administration (36% in group 1 vs. 100% in group 2, P=0.04). The increase in the left ventricular end-diastolic pressure was significantly reduced at week 12 (17+/-1 mmHg in group 1 vs. 9+/-1 mmHg in group 2, P=0.0042). The fall in left ventricular stroke work index was significantly prevented (52% in group 1 vs. 21% in group 2, P=0.006). The increase in right ventricular end-diastolic diameter was significantly reduced by enalapril prophylaxis.. Simultaneous treatment with enalapril was beneficial in the prevention of doxorubicin-induced cardiomyopathy.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antineoplastic Agents; Blood Pressure; Disease Models, Animal; Dogs; Doxorubicin; Enalapril; Heart Failure; Heart Rate; Male; Models, Cardiovascular; Stroke Volume; Time Factors; Treatment Outcome; Vascular Resistance; Ventricular Dysfunction, Left

A common late effect of doxorubicin therapy for childhood cancer is reduced left-ventricular (LV) wall thickness resulting in elevated LV afterload and depressed LV function. Many children are given angiotensin-converting enzyme inhibitors, which have been studied primarily in adults. We document the long-term effects of angiotensin-converting enzyme inhibitors in doxorubicin-treated survivors of childhood cancer.. In this retrospective study, we reviewed records of 18 children who had regular echocardiographic examinations during enalapril therapy (mean age at cancer diagnosis, 8 years; mean time between completion of doxorubicin therapy and start of enalapril, 7 years; median follow-up since the start of enalapril, 10 years).. Over the first 6 years of enalapril therapy, there was progressive improvement toward normal values in LV dimension, afterload, fractional shortening, and mass, but all these parameters deteriorated between 6 and 10 years. LV wall thickness deteriorated throughout the study period, as did LV contractility and systolic blood pressure. Diastolic blood pressure fell slightly. By 6 years on enalapril, all six patients who had had congestive heart failure at the start of enalapril therapy had either died or undergone cardiac transplantation, compared with three of the 12 asymptomatic patients.. In doxorubicin-treated long-term survivors of childhood cancer, enalapril-induced improvement in LV structure and function is transient. The primary defect, which is LV wall thinning, continues to deteriorate, and thus the short-term improvement was mostly related to lowered diastolic blood pressure.

Topics: Adolescent; Adult; Angiotensin-Converting Enzyme Inhibitors; Antibiotics, Antineoplastic; Antihypertensive Agents; Blood Pressure; Child; Death, Sudden, Cardiac; Diastole; Doxorubicin; Drug Administration Schedule; Echocardiography; Enalapril; Heart Failure; Heart Transplantation; Humans; Neoplasms; Retrospective Studies; Risk; Survivors; Ventricular Dysfunction, Left

We sought to describe the dosages of angiotensin-converting enzyme (ACE) inhibitor prescribed to elderly patients with heart failure at hospital discharge, the factors associated with dosing level, and the association of these dosages with 1-year outcomes.. Demographic, procedural, and medication data were collected retrospectively from medical records at 18 Connecticut hospitals. Information on mortality and readmission was obtained from the Health Care Financing Administration administrative databases. Dosages of ACE inhibitor were grouped into 3 categories: dosages recommended in practice guidelines or higher (target dose), dosages used in clinical trials but lower than guideline recommendations (subtarget dose), and dosages lower than those used in clinical trials (low dose).. A total of 554 patients, 65 years old or less with confirmed heart failure and systolic dysfunction, were prescribed an ACE inhibitor at discharge. Target, subtarget, and low doses were given in 19%, 63%, and 18% of the patients, respectively. Few demographic or clinical factors were related to lower dosages. Both subtarget and target doses of ACE inhibitors were associated with a significantly lower adjusted 1-year mortality (relative risk 0.67, P =.04; relative risk 0.51, P =.02, respectively) compared with low doses of ACE inhibitors.. In a representative elderly cohort of patients with heart failure with systolic dysfunction, the majority (82%) were discharged on doses of ACE inhibitors consistent with those used in clinical trials. We observed a dose-response relationship between higher doses and lower mortality. Future studies will need to determine whether this association is causal.

Topics: Aged; Aged, 80 and over; Angiotensin-Converting Enzyme Inhibitors; Captopril; Enalapril; Female; Heart Failure; Humans; Lisinopril; Male; Retrospective Studies; Treatment Outcome; Ventricular Dysfunction, Left

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

Mice lacking natriuretic peptide receptor A (NPRA) have marked cardiac hypertrophy and chamber dilatation disproportionate to their increased blood pressure (BP), suggesting, in support of previous in vitro data, that the NPRA system moderates the cardiac response to hypertrophic stimuli. Here, we have followed the changes in cardiac function in response to altered mechanical load on the heart of NPRA-null mice (Npr1-/-). Chronic treatment with either enalapril, furosemide, hydralazine, or losartan were all effective in reducing and maintaining BP at normal levels without affecting heart weight/body weight. In the reverse direction, we used transverse aortic constriction (TAC) to induce pressure overload. In the Npr1-/- mice, TAC resulted in a 15-fold increase in atrial natriuretic peptide (ANP) expression, a 55% increase in left ventricular weight/body weight (LV/BW), dilatation of the LV, and significant decline in cardiac function. In contrast, banded Npr1+/+ mice showed only a threefold increase in ANP expression, an 11% increase in LV/BW, a 0.2 mm decrease in LV end diastolic dimension, and no change in fractional shortening. The activation of mitogen-activated protein kinases that occurs in response to TAC did not differ in the Npr1+/+ and Npr1-/- mice. Taken together, these results suggest that the NPRA system has direct antihypertrophic actions in the heart, independent of its role in BP control.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Cardiomegaly; Enalapril; Furosemide; Guanylate Cyclase; Hydralazine; Losartan; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitogen-Activated Protein Kinases; Myocardium; Organ Size; Propranolol; Receptors, Atrial Natriuretic Factor; Telemetry; Ventricular Dysfunction, Left

Black patients with heart failure have a poorer prognosis than white patients, a difference that has not been adequately explained. Whether racial differences in the response to drug treatment contribute to differences in outcome is unclear. To address this issue, we pooled and analyzed data from the Studies of Left Ventricular Dysfunction (SOLVD) prevention and treatment trials, two large, randomized trials comparing enalapril with placebo in patients with left ventricular dysfunction.. We used a matched-cohort design in which up to four white patients were matched with each black patient according to trial, treatment assignment, sex, left ventricular ejection fraction, and age. A total of 1196 white patients (580 from the prevention trial and 616 from the treatment trial) were matched with 800 black patients (404 from the prevention trial and 396 from the treatment trial). The average duration of follow-up was 35 months in the prevention trial and 33 months in the treatment trial.. The black patients and the matched white patients had similar demographic and clinical characteristics, but the black patients had higher rates of death from any cause (12.2 vs. 9.7 per 100 person-years) and of hospitalization for heart failure (13.2 vs. 7.7 per 100 person-years). Despite similar doses of drug in the two groups, enalapril therapy, as compared with placebo, was associated with a 44 percent reduction (95 percent confidence interval, 27 to 57 percent) in the risk of hospitalization for heart failure among the white patients (P<0.001) but with no significant reduction among black patients (P=0.74). At one year, enalapril therapy was associated with significant reductions from base line in systolic blood pressure (by a mean [+/-SD] of 5.0+/-17.1 mm Hg) and diastolic blood pressure (3.6+/-10.6 mm Hg) among the white patients, but not among the black patients. No significant change in the risk of death was observed in association with enalapril therapy in either group.. Enalapril therapy is associated with a significant reduction in the risk of hospitalization for heart failure among white patients with left ventricular dysfunction, but not among similar black patients. This finding underscores the need for additional research on the efficacy of therapies for heart failure in black patients.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Black People; Cohort Studies; Enalapril; Female; Heart Failure; Hospitalization; Humans; Male; Middle Aged; Mortality; Randomized Controlled Trials as Topic; Stroke Volume; Treatment Outcome; Ventricular Dysfunction, Left; White People

OBJECTIVE - To describe clinical observations of marked improvement in ventricular dysfunction in a medical office environment under circumstances differing from those in study protocols and multicenter studies performed in hospital or with outpatient cohorts. METHODS - Eleven cardiac failure patients with marked ventricular dysfunction receiving treatment at a doctors office between 1994 and 1999 were studied. Their ages ranged from 20 and 66 years (mean 39.42+/-14.05 years); 7 patients were men, 4 were women. Cardiopathic etiologies were arterial hypertension in 5 patients, peripartum cardiomyopathy in 2, nondefined myocarditis in 2, and alcoholic cardiomyopathy in 4. Initial echocardiograms revealed left ventricular dilatation (average diastolic diameter, 69.45+/-8.15mm), reduced left ventricular ejection fraction (0.38+/-0.08) and left atrial dilatation (43.36+/-5.16mm). The therapeutic approach followed consisted of patient orientation, elimination of etiological or causal factors of cardiac failure, and prescription of digitalis, diuretics, and angiotensinconverting enzyme inhibitors. RESULTS - Following treatment, left ventricular ejection fraction changed to 0.63+/-0.09; left ventricular diameters changed to 57.18+/-8.13mm, and left atrium diameters changed to 37.27+/-8.05mm. Maximum improvement was noted after 16.9+/-8.63 (6 to 36) months. CONCLUSION - Patients with serious cardiac failure and ventricular dysfunction caused by hypertension, alcoholism, or myocarditis can experience marked improvement in ventricular dysfunction after undergoing appropriate therapy within the venue of the doctor's office.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Anti-Arrhythmia Agents; Captopril; Digoxin; Diuretics; Enalapril; Female; Follow-Up Studies; Heart Failure; Humans; Male; Middle Aged; Treatment Outcome; Ventricular Dysfunction, Left

Inhibition of dopamine beta-hydroxylase (DBH) results in a decrease in norepinephrine synthesis. The present study was a randomized, blinded, placebo-controlled investigation of the long-term effects of therapy with the DBH inhibitor nepicastat (NCT) on the progression of left ventricular (LV) dysfunction and remodeling in dogs with chronic heart failure (HF).. Moderate HF (LV ejection fraction [LVEF] 30% to 40%) was produced in 30 dogs by intracoronary microembolization. Dogs were randomized to low-dose NCT (0.5 mg/kg twice daily, n=7) (L-NCT), high-dose NCT (2 mg/kg twice daily, n=7) (H-NCT), L-NCT plus enalapril (10 mg twice daily, n=8) (L-NCT+ENA), or placebo (PL, n=8). Transmyocardial (coronary sinus-arterial) plasma norepinephrine (tNEPI), LVEF, end-systolic volume, and end-diastolic volume were measured before and 3 months after initiating therapy. tNEPI levels were higher in PL compared with NL (86+/-20 versus 13+/-14 pg/mL, P:<0.01). L-NCT alone and L-NCT+ENA reduced tNEPI toward normal (28+/-4 and 39+/-17 pg/mL respectively), whereas HD-NCT reduced tNEPI to below normal levels (3+/-10 pg/mL). In PL dogs, LVEF decreased but was unchanged with L-NCT and increased with L-NCT+ENA. L-NCT and L-NCT+ENA prevented progressive LV remodeling, as evidenced by lack of ongoing increase in end-diastolic volume and end-systolic volume, whereas H-NCT did not. In dogs with HF, therapy with L-NCT prevented progressive LV dysfunction and remodeling. The addition of ENA to L-NCT afforded a greater increase in LV systolic function. NCT at doses that normalize tNEPI may be useful in the treatment of chronic HF.

Topics: Animals; Chronic Disease; Disease Models, Animal; Disease Progression; Dogs; Dopamine beta-Hydroxylase; Dose-Response Relationship, Drug; Enalapril; Enzyme Inhibitors; Heart Failure; Imidazoles; Norepinephrine; Stroke Volume; Thiones; Ventricular Dysfunction, Left; Ventricular Function, Left

Topics: Angiotensin-Converting Enzyme Inhibitors; Enalapril; Heart Failure; Humans; Ventricular Dysfunction, Left

Population-based studies have found that black patients with congestive heart failure have a higher mortality rate than whites with the same condition. This finding has been attributed to differences in the severity, causes, and management of heart failure, the prevalence of coexisting conditions, and socioeconomic factors. Although these factors probably account for some of the higher mortality due to congestive heart failure among blacks, we hypothesized that racial differences in the natural history of left ventricular dysfunction might also have a role.. Using data from the Studies of Left Ventricular Dysfunction (SOLVD) prevention and treatment trials, in which all patients received standardized therapy and follow-up, we conducted a retrospective analysis of the outcomes of asymptomatic and symptomatic left ventricular systolic dysfunction among black and white participants. The mean (+/-SD) follow-up was 34.2+/-14.0 months in the prevention trial and 32.3+/-14.8 months in the treatment trial among the black and white participants.. The overall mortality rates in the prevention trial were 8.1 per 100 person-years for blacks and 5.1 per 100 person years for whites. In the treatment trial, the rates were 16.7 per 100 person-years and 13.4 per 100 person-years, respectively. After adjustment for age, coexisting conditions, severity and causes of heart failure, and use of medications, blacks had a higher risk of death from all causes in both the SOLVD prevention trial (relative risk, 1.36; 95 percent confidence interval, 1.06 to 1.74; P=0.02) and the treatment trial (relative risk, 1.25; 95 percent confidence interval, 1.04 to 1.50; P=0.02). In both trials blacks were also at higher risk for death due to pump failure and for the combined end point of death from any cause or hospitalization for heart failure, our two predefined indicators of the progression of left ventricular systolic dysfunction.. Blacks with mild-to-moderate left ventricular systolic dysfunction appear to be at higher risk for progression of heart failure and death from any cause than similarly treated whites. These results suggest that there may be racial differences in the outcome of asymptomatic and symptomatic left ventricular systolic dysfunction.

Topics: Analysis of Variance; Angiotensin-Converting Enzyme Inhibitors; Black People; Enalapril; Female; Heart Failure; Humans; Male; Middle Aged; Randomized Controlled Trials as Topic; Retrospective Studies; Socioeconomic Factors; Treatment Outcome; Ventricular Dysfunction, Left; White People

The backward effects of left ventricular dysfunction include alterations in alveolar-capillary gas transfer and ventilation-perfusion coupling. Because the angiotensin-converting enzyme (ACE) is highly concentrated in the vascular endothelium of the lungs, we examined whether ACE inhibitors may influence the pulmonary function in patients with congestive heart failure.. In 20 patients with idiopathic cardiomyopathy, pulmonary function and exercise capacity were evaluated at baseline and 6 and 12 months after treatment with enalapril (10 mg twice a day) was started. The study also included 19 age- and sex-matched control subjects with mild primary hypertension and normal left ventricular function who were given enalapril as a standard treatment of high blood pressure.. In congestive heart failure, forced expiratory volume in 1 second, vital capacity, and total lung capacity did not vary significantly with enalapril; alveolar-capillary diffusion of carbon monoxide (DL(CO)) increased toward normal; exercise tolerance time, peak exercise oxygen uptake (peak VO2), minute ventilation and tidal volume (peak VT) also increased; and the ratio of volume of dead space (VD) to VT (peak VD/VT) at peak exercise reduced. Changes in peak VO2 showed a direct correlation with those in DL(CO) and an inverse correlation with those in peak VD/VT. Results at 6 and 12 months were comparable. Enalapril did not affect these variables in the control population.. In patients with idiopathic cardiomyopathy heart failure, but not in control subjects, gas transfer and ventilation-perfusion improved with ACE inhibition. These pulmonary changes may contribute to the associated increase in exercise tolerance.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Capillaries; Carbon Dioxide; Cardiomyopathies; Case-Control Studies; Enalapril; Exercise; Exercise Test; Female; Heart Failure; Humans; Male; Matched-Pair Analysis; Middle Aged; Oxygen; Pulmonary Alveoli; Respiratory Function Tests; Time Factors; Treatment Outcome; Ventilation-Perfusion Ratio; Ventricular Dysfunction, Left

The cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) are increased in the circulation of patients with chronic heart failure. However, their correlation with left ventricular dysfunction has not yet been thoroughly evaluated, and their interrelation with other neurohumoral systems, such as the adrenergic system and endothelin, is unclear. Therefore TNF-alpha, its soluble receptor II, IL-6, big endothelin, and noradrenaline levels were simultaneously measured in venous blood from 65 patients with heart failure in New York Heart Association (NYHA) class II to IV during therapy with digitalis, furosemide, and enalapril. TNF-alpha plasma levels were 3.2+/-0.2 SEM pg/ml in 38 patients in NYHA function class II, 4.0+/-0.3 SEM pg/ml in 16 patients in NYHA function class III, and 5.3+/-0.9 SEM pg/ml in 11 patients in NYHA function class IV (p < 0.001 vs NYHA function class II). IL-6 plasma levels were 3.1+/-0.6 SEM pg/ml in 38 patients in NYHA function class II, 5.2+/-0.8 SEM pg/ml in 16 patients in NYHA function class III, and 13.3+/-3.9 SEM pg/ml in 11 patients in NYHA function class IV (p < 0.0001 vs NYHA function class II andp < 0.0001 vs NYHA class III). Thus both cytokines increased with increasing severity of heart failure, but only IL-6 plasma levels were different in patients in the more severe function classes. TNF-alpha correlated closely with TNF soluble receptor II (r = 0.8, p < 0.0001) and modestly with serum creatinine (r = 0.6, p < 0.0001), whereas IL-6 plasma levels were not statistically related to kidney function. Significant modest correlations were also found among TNF-alpha and IL-6 (r = 0.3, p < 0.01), big endothelin (r = 0.3, p < 0.01), and noradrenaline levels (r = 0.4, <0.001). This study supports the hypothesis that in heart failure both cytokines, TNF-alpha, and IL-6, as well as neurohumoral factors, play a role in the clinical progression of the disease. Thereby levels of TNF-alpha but not IL-6 seem to be related to concomitant kidney dysfunction.

Topics: Adrenergic Agonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Cardiotonic Agents; Chronic Disease; Creatinine; Digitalis Glycosides; Disease Progression; Diuretics; Enalapril; Endothelin-1; Endothelins; Female; Furosemide; Heart Failure; Humans; Interleukin-6; Kidney; Linear Models; Male; Middle Aged; Multivariate Analysis; Neurotransmitter Agents; Norepinephrine; Protein Precursors; Receptors, Tumor Necrosis Factor; Tumor Necrosis Factor-alpha; Ventricular Dysfunction, Left

The prehypertrophic state of hypertensive heart disease is characterized by morphologic changes (interstitial fibrosis, increase in intramyocardial arteriolar wall thickness) as well as by functional alterations (diastolic dysfunction, decrease in coronary reserve). These changes most probably represent the earliest cardiac end-organ lesions that can clinically be detected. In cardiac hypertrophy, long-term (9-12 months) pharmacotherapy with beta-blockers, calcium channel blockers, or ACE inhibitors reverses left ventricular hypertrophy by 8% to 14%, whereas marked improvement in coronary reserve and diastolic dysfunction is achieved by calcium blocker and preferably by ACE inhibitors.

Topics: Antihypertensive Agents; Arterioles; Bisoprolol; Blood Pressure; Coronary Circulation; Diastole; Diltiazem; Disease Progression; Enalapril; Fibrosis; Heart Ventricles; Hemodynamics; Humans; Hypertension; Hypertrophy, Left Ventricular; Isradipine; Treatment Outcome; Ventricular Dysfunction, Left

To determine the effect of preoperative therapy with angiotensin-converting enzyme (ACE) inhibitors on clinical outcome after cardiovascular surgery.. Inception cohort.. A tertiary care 54-bed cardiothoracic ICU.. All admissions to an ICU over a 42-month period after cardiovascular surgery.. Extraction of preoperative, operative, and ICU data from a database.. Incidence of acute organ dysfunction, length of mechanical ventilation, ICU stay, and death after cardiovascular surgery.. The study cohort consisted of four groups: normal or moderately impaired left ventricular function control (group A, n=6,400); normal or moderately impaired left ventricular function treated with ACE inhibitors (group B, n=1,375); severe left ventricular dysfunction control (group C, n=1,905); and severe left ventricular dysfunction treated with ACE inhibitors (group D, n=1,650). The incidence of three or more organ dysfunction was similar on comparison of group A vs group B (5% vs 6%) or group C vs group D (15% vs 13%). There were no differences in the total duration of mechanical ventilation or length of stay in the ICU in group A vs group B or group C vs group D. Death occurred in 2% of groups A and B, and at 6% in groups C and D. Preoperative severe left ventricular dysfunction in both groups C and D was associated with an increased incidence of three or more organ dysfunction, duration of mechanical ventilation, length of stay in ICU, and death after surgery. Multivariate analysis indicated that therapy with ACE inhibitors did not affect the clinical outcome after cardiovascular surgery.. Preoperative therapy with ACE inhibitors did not influence the clinical outcome after cardiac surgery. It is unlikely that therapy with ACE inhibitors can alter the clinical sequelae of cardiopulmonary bypass and cardiac surgical procedures performed in high-risk patients because of underlying severe left ventricular dysfunction.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Captopril; Cardiopulmonary Bypass; Cardiovascular Diseases; Cardiovascular Surgical Procedures; Case-Control Studies; Electrocardiography; Enalapril; Female; Follow-Up Studies; Hospital Mortality; Humans; Incidence; Intra-Aortic Balloon Pumping; Lisinopril; Male; Middle Aged; Multiple Organ Failure; Postoperative Complications; Preoperative Care; Retrospective Studies; Treatment Outcome; Ventricular Dysfunction, Left

Topics: Angiotensin-Converting Enzyme Inhibitors; Enalapril; Humans; Hypertension; Ventricular Dysfunction, Left

Topics: Angiotensin-Converting Enzyme Inhibitors; Enalapril; Humans; Hypertrophy, Left Ventricular; Multicenter Studies as Topic; Myocardial Infarction; Scandinavian and Nordic Countries; Time Factors; Ventricular Dysfunction, Left; Ventricular Function, Left

We consider a latent variable hazard model for clustered survival data where clusters are a random sample from an underlying population. We allow interactions between the random cluster effect and covariates. We use a maximum pseudo-likelihood estimator to estimate the mean hazard ratio parameters. We propose a bootstrap sampling scheme to obtain an estimate of the variance of the proposed estimator. Application of this method in large multi-centre clinical trials allows one to assess the mean treatment effect, where we consider participating centres as a random sample from an underlying population. We evaluate properties of the proposed estimators via extensive simulation studies. A real data example from the Studies of Left Ventricular Dysfunction (SOLVD) Prevention Trial illustrates the method.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Cluster Analysis; Computer Simulation; Double-Blind Method; Enalapril; Humans; Likelihood Functions; Middle Aged; Proportional Hazards Models; Randomized Controlled Trials as Topic; Survival Analysis; Ventricular Dysfunction, Left

Topics: Angiotensin-Converting Enzyme Inhibitors; Coronary Disease; Enalapril; Heart Failure; Humans; Prognosis; Ventricular Dysfunction, Left

Diabetes is an independent predictor of morbidity and mortality in patients with symptomatic heart failure, patients with asymptomatic left ventricular dysfunction (defined as an ejection fraction of 35% or less), and in a broader registry population with less stringent entry criteria. Although the SOLVD Trials made a major clinical contribution by proving the value of enalapril, diabetes remains a significant predictor of outcome even after adjusting for treatment with enalapril.

Topics: Angiotensin-Converting Enzyme Inhibitors; Diabetes Complications; Diabetes Mellitus; Enalapril; Female; Heart Failure; Humans; Male; Multicenter Studies as Topic; Odds Ratio; Prognosis; Randomized Controlled Trials as Topic; Registries; Regression Analysis; Risk Factors; Ventricular Dysfunction, Left

Topics: Angiotensin-Converting Enzyme Inhibitors; Enalapril; Humans; Research Design; Ventricular Dysfunction, Left

Topics: Angiotensin-Converting Enzyme Inhibitors; Enalapril; Humans; Research Design; Ventricular Dysfunction, Left

Topics: Cardiac Output, Low; Enalapril; Fatigue; Humans; Ventricular Dysfunction, Left

To assess the effect of ACE-inhibition on left ventricular filling and wall motion in patients with a clinical diagnosis of heart failure.. Prospective examination of left ventricular systolic and diastolic function using M mode echocardiography and pulsed and continuous wave Doppler before and three weeks after starting an ACE inhibitor.. A tertiary referral centre for cardiac disease equipped with non-invasive facilities.. 30 outpatients with a clinical diagnosis of heart failure in whom treatment with an ACE inhibitor was started; age 61 (SD 11) years; 27 male; 3 female; 21 healthy controls of similar age.. Left ventricular cavity was dilated both at end systole and end diastole, and fractional shortening reduced. Although mean isovolumetric relaxation time (IVRT) and transmitral E (early) to A (late) filling velocity (E/A) ratio were not different from normal, a value of 1.0 on the normal frequency plot of the E/A ratio divided the patients bimodally into two groups: 20 patients (group A) with E/A ratio > 1.0 and 10 patients (group B) < 1.0. In group A patients, IVRT was short as was transmitral E wave deceleration time compared to normal (P < 0.001), fulfilling the criteria of restrictive left ventricular physiology. Left ventricular wall motion during IVRT was coordinate and left ventricular end diastolic pressure was raised on the apex-cardiogram (P < 0.001). In group B, E wave deceleration time was longer, relaxation incoordinate, and apexcardiogram normal. With an ACE inhibitor: in group A, left ventricular dimensions fell at end diastole (P < 0.05) and end systole (P < 0.01) but fractional shortening did not change; long axis total excursion (P < 0.01) and peak rate of shortening (P < 0.05) both increased; IVRT increased (P < 0.001) with the appearance of markedly incoordinate wall motion, minor axis lengthening, and long axis shortening (P < 0.001 for both); A wave amplitude also consistently increased (P < 0.001); finally, transmitral E wave velocity fell and A wave velocity increased. ACE inhibition did not alter any of the left ventricular minor and long axis or transmitral Doppler variables in patients in group B.. Patients with a clinical diagnosis of heart failure differ in their presentation and response to ACE inhibition according to baseline haemodynamics. In restrictive left ventricular physiology, ACE inhibition reduces cavity size and prolongs IVRT, compatible with a fall in left atrial pressure. At the same time, ventricular relaxation becomes very delayed and incoordinate, greatly reducing early diastolic left ventricular filling velocity. Thus ACE inhibition unmasks major diastolic abnormalities in patients with restrictive left ventricular disease.

Topics: Angiotensin-Converting Enzyme Inhibitors; Captopril; Echocardiography; Enalapril; Female; Heart Failure; Humans; Lisinopril; Male; Middle Aged; Signal Processing, Computer-Assisted; Ventricular Dysfunction, Left

This study sought to evaluate the changes in direct medical costs and life-years gained or lost by adding enalapril to conventional treatment (digoxin and diuretics) for heart failure (HF). The published results of the Studies of Left Ventricular Dysfunction (SOLVD) Treatment Trial, and a decision analytical model developed by the University of Pennsylvania, were used in combination with New Zealand data to undertake the evaluation. All costs were measured in 1993 New Zealand dollars ($NZ) [$NZ1 = $US0.5509, September 1993]. Potential net cost savings per patient treated over a 4-year period were $NZ652 together with an additional 2 months of life gained. If these individual potential cost savings are extended to the New Zealand population who have HF (but are at present not receiving an ACE inhibitor) then $NZ6 517 000 in discounted health sector costs could be avoided. The model was sensitive to changes in the price of enalapril, to estimates of the population with HF, the percentage of the population with HF treated with enalapril, and to hospital unit costs for nonfatal cases of HF. The study demonstrated that the addition of enalapril to the conventional treatment of HF was cost effective when compared with conventional medical therapy alone.

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Costs and Cost Analysis; Decision Support Techniques; Digoxin; Diuretics; Enalapril; Female; Heart Failure; Humans; Male; New Zealand; Ventricular Dysfunction, Left

That the cardiopulmonary baroreflex control of sympathetic nerve activity is impaired in dogs with left ventricular (LV) dysfunction has been shown previously. This study tested the hypothesis that treatment with the angiotensin-converting enzyme inhibitor enalapril prevents or delays the development of abnormalities of cardiopulmonary baroreflexes in dogs with LV dysfunction. Serial changes in LV volumes and neurohumoral profiles (plasma norepinephrine and renin activity) were assessed in conscious dogs with progressive LV dysfunction due to rapid ventricular pacing. Enalapril 5 mg orally twice daily was administered from days 4 to 12 of pacing. Cardiopulmonary baroreflexes were assessed in enalapril-treated paced dogs (n = 8) and untreated paced dogs (n = 8) by recording changes in renal nerve activity and pulmonary capillary wedge pressure during volume infusion in anesthetized sinoaortic denervated dogs on day 12 of rapid pacing. There was no difference in LV volume in the two groups. Neurohumoral factors were similar in both groups except for the expected high plasma renin activity in enalapril-treated dogs. Hemodynamic parameters also were comparable in the two groups. Cardiopulmonary baroreflex sensitivity for enalapril-treated dogs was not different from that of untreated paced dogs, and baroreflex gain in both groups was significantly lower than for the nonpaced control dogs (P < .05). Despite adequate converting enzyme blockade, treatment with enalapril failed to prevent the development of attenuated cardiopulmonary baroreflex control of sympathetic nerve activity in dogs with developing LV dysfunction.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Baroreflex; Cardiac Pacing, Artificial; Dogs; Enalapril; Female; Heart; Lung; Male; Models, Animal; Renin; Stroke Volume; Sympathetic Nervous System; Ventricular Dysfunction, Left

Pre-existing left ventricular dysfunction in patients undergoing induction therapy with cyclophosphamide prior to bone marrow transplantation (BMT) has resulted in overt heart failure in a large number of patients. This fact excludes the majority of such patients from consideration for BMT at many centers. We sought to determine if prophylactic treatment with the angiotensin converting enzyme inhibitor enalapril prevents this deterioration in pre-existing left ventricular dysfunction. We treated six consecutive patients with initial left ventricular ejection fractions (LVEF) by radionuclide gated blood pool imaging (RGBP) of < 50% (42 +/- 7%) with enalapril 5 mg orally twice per day started 48 h prior to induction therapy and continued throughout the follow-up period. Serial RGBP imaging demonstrated an increase in LVEF in all patients to 54 +/- 6% (P < 0.005). No patient experienced clinical deterioration during a follow-up period of 18 +/- 11 months. We conclude that prophylactic treatment with enalapril may prevent deterioration in pre-existing mild left ventricular dysfunction during BMT.

Topics: Adolescent; Adult; Angiotensin-Converting Enzyme Inhibitors; Antibiotics, Antineoplastic; Antineoplastic Agents; Bone Marrow Transplantation; Breast Neoplasms; Combined Modality Therapy; Cyclophosphamide; Daunorubicin; Doxorubicin; Echocardiography, Doppler, Color; Enalapril; Female; Gated Blood-Pool Imaging; Heart Failure; Humans; Idarubicin; Leukemia; Male; Middle Aged; Radiation Injuries; Radiotherapy; Ventricular Dysfunction, Left; Ventricular Function, Left