Myocardial infarction and heart failure. The common ground.
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Captopril↗
Biomedical subjects
N Sharpe
Publications and source records attributed to N Sharpe.
The effects of ACE inhibition on progression of atherosclerosis.
Angiotensin-converting enzyme inhibitors have been extensively studied and established in the treatment of hypertension, heart failure, and ventricular dysfunction. They have various cardiac and vascular protective effects, but the relevant mechanisms of action in these areas remain to be fully understood. Possible effects of converting-enzyme inhibition related to maintenance of normal endothelial function and inhibition of atherosclerosis should be distinguished from effects on myointimal proliferation related to vascular injury and regression of vascular hypertrophy from blood pressure reduction. Experimental animal studies have showed benefit from converting-enzyme inhibition in preventing myointimal proliferation after vascular injury in some species, but no such effect has been shown in clinical studies of restenosis following coronary angioplasty. Laboratory studies have demonstrated a protective effect of converting-enzyme inhibition on endothelial vasomotor function. Further studies have demonstrated prevention of atherosclerosis in hyperlipidemic rabbits and cholesterol-fed cynomolgus monkeys. Possible mechanisms of action apart from blood pressure lowering include inhibition of angiotensin II and other tissue growth factors and accumulation of kinins. These data, among others, provide sufficient rationale for clinical studies to determine whether converting-enzyme inhibitors can reduce atherosclerotic disease and thus widen their application as cardiac and vascular protective agents.
Angiotensin-Converting Enzyme Inhibitors↗
Ventricular remodeling following myocardial infarction.
Ventricular remodeling denotes structural changes that occur in ventricular chamber size, wall thickness, and composition following myocardial damage. Following acute coronary occlusion, there are various factors to consider at different times that may contribute to subsequent ventricular dilation. Early infarct expansion and later healing may be accompanied by compensatory hypertrophy in the noninfarcted region and progressive global dilation, that may progress long term, the major stimulus being increased wall stress. The 2 major factors influencing ventricular remodeling following myocardial infarction are infarct artery patency and the ventricular loading conditions. Thrombolytic therapy may produce coronary reperfusion and limit infarct size. Patency of the infarct-related artery may also provide later benefits for ventricular remodeling. Following infarct evolution, pharmacologic intervention provides the potential to minimize the sequelae of infarct expansion and ventricular dilation. Clinical studies indicate that treatment of symptomless left ventricular dysfunction with angiotensin-converting enzyme inhibition at greater than or equal to 1 week following myocardial infarction may prevent further ventricular dilation and reduce the probability of progression to heart failure. Earlier intervention, at 24-48 hours following Q-wave myocardial infarction, is also practicable and effective. Even earlier intervention, in combination with or immediately following thrombolysis, is being assessed in other studies. The timing of treatment is of considerable importance because blockade of compensatory mechanisms activated at the time of infarction may not be desirable immediately, even though these mechanisms may be deleterious later. The results of large-scale mortality studies are awaited to indicate the benefit of this type of treatment in terms of heart failure prevention and survival long term.
Humans↗
Early preventive treatment of left ventricular dysfunction following myocardial infarction: optimal timing and patient selection.
Treatment for clinical congestive heart failure is effective, but because severe ventricular dysfunction is often present at the time of clinical presentation, it may only be palliative. Recent clinical studies indicate that treatment of symptomless left ventricular dysfunction from 1 week following myocardial infarction or later may prevent further ventricular dilation and possibly reduce the occurrence of heart failure. Considering the potential for progressive ventricular dilation that exists from the time of myocardial infarction, early intervention following myocardial infarction may provide greater benefit. In a double-blind study, 100 patients with Q-wave myocardial infarction, but without clinical heart failure, were randomized to treatment with captopril 50 mg twice daily or placebo, 24-48 hours following onset of symptoms. During 3 months of treatment, the placebo group showed significant increases in left ventricular end-diastolic and end-systolic volume indices with ejection fraction unchanged. In contrast, the captopril group showed a slight but insignificant increase in left ventricular end-diastolic volume index and a significant reduction in end-systolic volume index with ejection fraction increased. Thus, early treatment of patients following Q-wave myocardial infarction with converting enzyme inhibition is effective in preventing ventricular dilation and provides an advantage over later treatment. Selection of patients with Q-wave infarction at 24 hours, after thrombolysis, provides therapy for those most likely to benefit, which is well tolerated without risk of hypotension.
Captopril↗
Early prevention of left ventricular dysfunction after myocardial infarction with angiotensin-converting-enzyme inhibition.
Left ventricular dysfunction can be improved with angiotensin-converting-enzyme inhibition started 1 week after myocardial infarction or later. To see whether earlier intervention may confer greater benefit, a double-blind study was carried out in which 100 patients with Q wave myocardial infarction, but without clinical heart failure, were randomly allocated treatment with captopril 50 mg twice daily or placebo starting 24-48 h after onset of symptoms. Left ventricular volumes were measured regularly during 3 months of treatment and after a 48 h withdrawal period by means of two-dimensional echocardiography. The placebo group showed significant increases in left ventricular end-diastolic (LVEDVI) and end-systolic (LVESVI) volume indices, with the ejection fraction unchanged. By contrast, the captopril group showed a slight but not significant rise in LVEDVI and a significant reduction in LVESVI with ejection fraction increased significantly. At 3 months there was a 4.6% difference in the change in ejection fraction from baseline between the groups (p less than 0.0001). Most of the treatment benefit was evident at 1 month and there were no changes in left ventricular volumes after 48 h withdrawal of treatment at 3 months. Heart failure requiring treatment with frusemide developed in 7 patients in each group during the study period; 3 of these (1 captopril-treated, 2 placebo-treated) had to be withdrawn from the trial with severe heart failure requiring open treatment. Thus early treatment with captopril is effective in preventing the ventricular dilatation that can occur after Q wave myocardial infarction.
Angiotensin-Converting Enzyme Inhibitors↗
Long-term antiplatelet therapy for the prevention of vascular disease.
OBJECTIVE: To estimate the effects of prolonged antiplatelet therapy on the primary and secondary incidence of vascular disease. DATA SOURCES: Twenty-five randomised trials in 29,000 patients with a history of vascular disease (the Antiplatelet Trialists' Collaboration) and two randomised trials in 27,000 individuals without a history of vascular disease (the British doctors' and American physicians' studies). STUDY SELECTION: The Antiplatelet Trialists' Collaboration obtained data from all randomised trials of secondary prevention completed before January 1988. The British doctors' and American physicians' studies are the only two completed randomised trials of primary prevention. DATA EXTRACTION: Data from the secondary prevention trials were provided by the Antiplatelet Trialists' Collaboration. Data from the primary prevention trials were extracted from the final published reports of these studies. DATA SYNTHESIS: In the secondary prevention trials, antiplatelet therapy reduced the rate of vascular disease by about 15% and the incidence of non-fatal myocardial infarction and stroke by about 30%. In the American physicians' study, but not the British doctors' study, the incidence of non-fatal myocardial infarction was also reduced. In neither primary prevention trial was there evidence of reduced rates of non-fatal stroke or vascular death; overall, fatal or disabling strokes were slightly more frequent among those assigned aspirin. CONCLUSIONS: For patients with a history of vascular disease, the benefits of antiplatelet therapy appear to outweigh any risks. Among 100 such patients, antiplatelet therapy for two years would prevent one death and two major non-fatal events. The balance of benefits and risks for individuals without a history of vascular disease is less clear because there is no firm evidence of a net reduction in either vascular death or disabling non-fatal vascular events among those treated with aspirin.
Aspirin↗
Echocardiographic prediction of left ventricular volume after myocardial infarction.
Left ventricular volume is a strong determinant of survival after acute myocardial infarction. The aim of this study was to determine which clinical and echocardiographic criteria assessed early after myocardial infarction would predict later left ventricular dilation. Forty-eight patients with uncomplicated transmural myocardial infarction had echocardiography 5 to 10 days after myocardial infarction and assessment of clinical variables including peak creatine kinase and sum of electrocardiographic ST segment elevation. Left ventricular dimensions were measured from the echocardiogram in the parasternal view and also in the apical four and two chamber views at the level of the mitral leaflets, papillary muscles and apex. A cardiac wall motion score was obtained by segmental analysis of the apical views. Echocardiographic left ventricular volume was measured after 1 year from the apical views with use of a Simpson's rule method. Initial clinical and echocardiographic variables were correlated with the left ventricular volume at 1 year. There was a significant relation between the initial four and two chamber end-diastolic dimensions and the left ventricular volume at 1 year, particularly for dimensions measured at the apical level (four chamber R2 = 0.66, p = 0.0001, two chamber R2 = 0.61, p = 0.0001). Other clinical variables, parasternal left ventricular dimensions and cardiac wall motion score were not significantly related to left ventricular volume. A powerful three variable model obtained by multiple regression and including the initial two chamber apical dimension, cardiac wall motion score and body surface area accounted for 82% of the variation in left ventricular volume at 1 year.
Cardiac Volume↗
Angiotensin-converting enzyme inhibitors in heart failure: a role after myocardial infarction.
The prognosis for clinical congestive heart failure remains poor even with modern treatment as severe ventricular dysfunction is often present at the time of clinical presentation. A substantial improvement in prognosis might be achieved through earlier intervention and a preventive approach to treatment following myocardial infarction to delay progressive ventricular dilation and the occurrence of clinical heart failure. The rationale for treatment of left ventricular dysfunction following myocardial infarction is further supported by the prognostic importance of ventricular dilation and by experimental animal studies that demonstrate that converting enzyme inhibition can improve ventricular function and survival following myocardial infarction. Similarly, clinical studies have demonstrated that converting enzyme inhibition can improve ventricular function during the year following transmural myocardial infarction. Possible mechanisms of action that require further understanding include ventricular afterload reduction and direct coronary and tissue effects of angiotensin II blockade. The further benefit to be obtained from very early intervention following myocardial infarction is currently being addressed in several studies. Large-scale studies also in progress should determine the mortality benefit of such treatment. Further questions that remain include the optimal timing of intervention, comparison with other treatments such as nitrates and beta-blockade, and also the use of appropriate combination treatments.
Angiotensin-Converting Enzyme Inhibitors↗
Studies of left ventricular dysfunction following myocardial infarction.
Early treatment of patients with myocardial infarction and left ventricular dysfunction was performed in 90 patients aiming at influencing left ventricular remodelling. After twelve months of treatment with 25 mg captopril t.i.d. left ventricular ejection fraction was improved by 10% in comparison to a treatment with 40 mg of frusemide or placebo (p = 0.001). Late treatment of the patients not treated with captopril resulted in partial reversal of left ventricular dilatation, while withdrawal of captopril therapy in stable patients with ejection fractions over 30% and without clinical signs of congestive heart failure did not result in deterioration of left ventricular function. These results give a sound rationale for the earlier use of ACE-inhibitors in the treatment of congestive heart failure and left ventricular dysfunction.
Captopril↗
Cardiac effects of angiotensin converting enzyme inhibitors.
ACE inhibitors have provided a major advance in cardiovascular therapeutics. The rationale for their use in hypertension and heart failure, and their cardiac effects are well documented. Further information is required on the relevance of their direct myocardial and other tissue effects, and it is likely that their use in hypertension and heart failure will increase further over the next several years.
Angiotensin-Converting Enzyme Inhibitors↗
Preventive treatment of asymptomatic left ventricular dysfunction following myocardial infarction.
Progressive asymptomatic ventricular dilatation can occur following myocardial infarction and severe ventricular dysfunction is often present by the time clinical congestive heart failure occurs. In a randomized, double-blind trial, the effects of captopril 25 mg tid, frusemide 40 mg daily and placebo were studied in 90 patients with asymptomatic left ventricular dysfunction (ejection fraction less than 45%) 1 week following Q wave myocardial infarction. Left ventricular volumes and function were assessed at intervals during the subsequent year using two-dimensional echocardiography. The frusemide and placebo groups showed significant increases in ventricular volumes with stroke volume index unchanged and ejection fraction slightly reduced, whereas the captopril group showed a significant reduction in left ventricular end-systolic volume index with stroke volume index and ejection fraction increased. At 12 months the difference in the change in ejection fraction from baseline between the captopril and frusemide groups was 10.5% and captopril and placebo groups 9.6% (both P less than 0.0001). There was a significant difference in occurrence of clinical heart failure in the placebo group compared with the other groups (P less than 0.05). Blood pressure increased significantly within the normal range in the placebo and frusemide groups whereas there was essentially no change from baseline in the captopril group. There was no significant correlation between baseline left ventricular volumes and function and subsequent change, and anterior and inferior infarct subgroups showed similar responses within the treatment groups. In conclusion, captopril improves asymptomatic ventricular dysfunction and prevents clinical heart failure during the year following myocardial infarction. Frusemide may also prevent clinical heart failure but not progressive ventricular dilatation.
Adult↗
Left ventricular dysfunction and progression to clinical congestive heart failure: the case for earlier intervention.
Progressive left ventricular dilatation and dysfunction can occur following transmural myocardial infarction and ventricular volumes are primary predictors of survival. The relationship between left ventricular dysfunction and clinical congestive heart failure is variable and left ventricular dysfunction is often advanced at the time of clinical presentation. Although modern treatment can provide definite haemodynamic and symptomatic benefit for patients with congestive heart failure and improve survival, such treatment is essentially palliative in many cases; there is therefore a need to consider earlier intervention. Experimental animal studies which have shown improved ventricular performance and survival with treatment following myocardial infarction strengthen the rationale for a preventive approach. Initial clinical studies have demonstrated that treatment can improve asymptomatic ventricular dysfunction following myocardial infarction. Immediate intervention following infarction may provide even more significant benefit and the results of ongoing large-scale studies are awaited to determine the value of this approach.
Heart Failure↗
Future directions for randomized trials of cardiovascular disease prevention in hypertensive patients.
Coronary artery disease (CAD) is the major cause of death in hypertensive patients in Western populations and further efforts are required to determine how best to reduce its incidence. Large-scale placebo-controlled trials of blood pressure reduction could resolve the uncertainty about the effects of antihypertensive treatment on CAD incidence, but at present, such trials could probably only be conducted in patients with mild hypertension (or normotension). If such patients were selected on the basis of clinically manifest vascular disease, the sample size necessary to detect plausible treatment effects may be practicable (i.e., several thousand patients). In moderately or severely hypertensive patients, "active-controlled" trials could be conducted to determine the relative effects of different anti-hypertensive drugs on CAD morbidity and mortality. However, because any difference between such regimens is likely to be modest in magnitude (and smaller than the difference between treatment and no treatment), the sample size required to detect such differences would be very large (i.e., tens of thousands). With somewhat smaller numbers of patients, it would be possible to conduct placebo-controlled trials to study the effects on CAD of other potentially cardioprotective interventions, such as cholesterol reduction and aspirin, both of which may offer effective means for CAD prevention in hypertensive patients.
Cardiovascular Diseases↗
Treatment of patients with symptomless left ventricular dysfunction after myocardial infarction.
In a randomised, double-blind trial 60 patients with left ventricular dysfunction (ejection fraction less than 45%) but without clinical evidence of heart failure 1 week after Q wave myocardial infarction were given captopril 25 mg thrice a day, frusemide 40 mg daily, or placebo. Left ventricular volumes were measured at baseline and at 1, 3, 6, 9, and 12 months with cross-sectional echocardiography and Simpson's rule analysis of standardised apical views. The captopril group showed no significant change in left ventricular end-diastolic volume index but left ventricular end-systolic volume index was significantly reduced and stroke volume index and ejection fraction were significantly increased from 1 month on. In contrast, the frusemide and placebo groups showed significant increases in ventricular volumes, with stroke volume index unchanged and ejection fraction slightly reduced. The changes in the captopril group were significantly different from those in the other groups.
Adult↗
Nitrate tolerance--a therapeutic dilemma.
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Angina Pectoris↗
Hemodynamic effects of intermittent transdermal nitroglycerin in chronic congestive heart failure.
The hemodynamic effects of intermittent and continuous treatment with transdermal nitroglycerin, 10 mg/24 hours, were compared in 10 patients with chronic congestive heart failure (CHF). Eight patients responded to initial application with more than a 20% reduction in mean pulmonary artery wedge pressure. Cardiac index increased from a control value of 2.1 +/- 0.5 to 2.4 +/- 0.6 liters/min/m2 at 2 hours (p less than 0.05) and mean pulmonary wedge pressure was reduced from 22 +/- 5 to 16 +/- 6 mm Hg (p less than 0.01). The 2 nonresponders had the largest left ventricular volumes on 2-dimensional echocardiograms. Responders were randomized to intermittent (16 hours/day) or continuous (24 hours/day) treatment for 1 month followed by a month of the alternate treatment. After 1 month of intermittent treatment, the hemodynamic response after reapplication was similar to the initial response. After another month of continuous treatment, hemodynamic values 24 hours after application were similar to initial control values and there was no change after removal and reapplication. Thus, the moderate vasodilator effect of transdermal nitroglycerin in CHF is maintained with intermittent treatment, whereas tolerance develops with continuous treatment.
Administration, Cutaneous↗
Transdermal nitroglycerin in angina pectoris: efficacy of intermittent application.
Continuous application of transdermal nitroglycerin appears to result in tolerance to the antianginal effect. In a double-blind study the effects of continuous (24 h/day) and intermittent (16 h/day) application of transdermal nitroglycerin in a dosage of 10 mg/day were compared with the effects of placebo in 12 patients with chronic stable angina receiving treatment with beta-adrenergic blocking or calcium channel blocking agents. Exercise performance was assessed 2 to 4 hours after initial application and after 1 week of each treatment given in random order with a 3 day interval between treatments. Exercise time to onset of angina, total exercise duration and time to 1 mm ST segment depression were all significantly increased after initial application during the continuous and intermittent treatment periods. These increases were maintained after 1 week of intermittent but not continuous treatment. Thus the benefit of initial application of transdermal nitroglycerin is maintained with intermittent treatment and a daily nitrate-free interval, whereas tolerance to antianginal effect occurs with continuous treatment.
Administration, Cutaneous↗
Resuscitation outside hospital in Auckland.
All resuscitation attempts outside hospital attended by the Auckland life support unit ambulances during 1983 were reviewed. There were 405 attempted resuscitations during the 12 month period. Of the 344 patients who arrested before the life support unit arrived, 189 (55%) had cardiopulmonary resuscitation initiated by bystanders and 34 (10%) by conventional ambulance personnel. Sixty one patients suffered their arrest after the arrival of the life support unit. One hundred and ninety two patients (47% of the total 405 patients) died at the scene of collapse, 95 patients (24%) died in accident and emergency departments and 46 (11%) died in hospital. Eighteen of the 213 patients successfully resuscitated and transported to hospital had complications related to cardiopulmonary resuscitation. Of the 72 patients discharged, 65 (90%) were alive one year after discharge. Of all patients in whom resuscitation was attempted, 75% were males. This male predominance was present in all age groups and disease categories except subarachnoid haemorrhage and stroke. Myocardial infarction and other ischaemic heart disease accounted for the great majority of cases, followed by asthma and a variety of other conditions. Below 30 years of age the causes of collapse were predominantly noncardiac, and with age increasing above 30 years there was increasing likelihood of a cardiac cause for the collapse.
Adolescent↗