Beta blockers with ACE inhibitors in mild heart failure

ACE inhibitors are standard therapy for treating both symptomatic and asymptomatic patients with left ventricular dysfunction. However, recent clinical trials have shown that beta blockers further reduce mortality in patients with symptomatic heart failure treated with ACE inhibitors. However, the evidence in support of adding beta blockers to ACE inhibitor therapy in patients with asymptomatic left ventricular dysfunction is less certain. The mechanisms by which ACE inhibitors and beta blockers may exert benefit in patients with heart failure are discussed, and studies assessing the association of beta blockade with outcome in patients with mild heart failure receiving ACE inhibitor therapy are reviewed. (c)2000 by CHF, Inc.     

Optimal treatment of hypertension with diastolic heart failure

Approximately 5 million people in the United States have heart failure. Epidemiologic studies have demonstrated that at least one half of patients who have clinically overt heart failure have diastolic heart failure (DHF), or heart failure with preserved ejection fraction. DHF is characterized by concentric remodeling with normal left ventricular end-diastolic volume, abnormalities of active relaxation, and increased passive ventricular stiffness. Diuretics are an essential component of therapy for most patients who have DHF, and treatment of hypertension is a cornerstone of therapy designed to prevent or to treat DHF. Several antihypertensive agents have been shown to effectively reduce wave reflection, including angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, calcium antagonists, and nitrates. Lifestyle changes may also be helpful.     

Hypertension and diastolic heart failure

In patients with hypertension, pressure overload leads to left ventricular hypertrophy (LVH), myocardial fibrosis, and impaired diastolic filling without systolic dysfunction. Presently, diastolic heart failure accounts for about 50% of the heart failure population. Fatigue, dyspnea, reduced exercise tolerance, and peripheral edema are common presenting complaints. As a group, patients with diastolic heart failure are older and predominantly female. Diuretics are effective for treating congestive symptoms. β Blockers and heart rate-lowering calcium blockers show benefit in smaller studies but have not been evaluated in definitive clinical trials. Renin-angiotensin-aldosterone system blockers reduce blood pressure, LVH, and myocardial fibrosis; however, long-term studies with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers demonstrate little effect on symptoms or survival, and inconsistent effects on heart failure hospitalization. At present, evidence-based treatment includes antihypertensive therapy to reduce progression from hypertension to heart failure. In patients with established heart failure, diuretics and other empiric treatments are used to control symptoms.     

Summary of randomized trials of angiotensin converting enzyme inhibitors.

Angiotensin converting enzyme (ACE) inhibitors have been shown to reduce the risk of death, worsening heart failure and recurrent infarction in patients with left ventricular dysfunction and heart failure. They have also been shown to reduce mortality in the acute phase of myocardial infarction. They have been demonstrated to reduce major vascular events and progression of renal disease in diabetes with hypertension, compared to placebo and to calcium channel blockers. Current trials are evaluating their role in preventing major vascular events in patients with coronary artery disease, strokes and Type II diabetes who are normotensive.     

Arterial hypertension and systolic left ventricular dysfunction: therapeutic approach

Arterial hypertension is a cardinal precursor of congestive heart failure, and diastolic dysfunction is the most frequent mechanism for it. Systolic left ventricular dysfunction, although less frequent, has a worse prognosis. Most cases of systolic dysfunction in patients with hypertension is due to acute myocardial infarction, although other mechanisms can be involved. In some studies, non-ischemic hypertensive systolic dysfunction is the etiology of chronic heart failure in up to 10% of patients with dilated cardiomyopathy. Diastolic dysfunction and left ventricular hypertrophy are also associated with a higher risk of heart failure and systolic dysfunction. Given the poor prognosis of patients with congestive heart failure and dilated cardiomyopathy, it is fundamental to try to prevent the development of left ventricular dysfunction by means of a correct control of blood pressure, regression of left ventricular hypertrophy and prevention of coronary artery disease. When systolic dysfunction is established, angiotensin converting enzyme inhibitors are the treatment of choice; diuretics and digoxin can be added in patients with overt congestive heart failure. Recent studies suggest that other drugs, such as carvedilol and losartan, can be beneficial, but current evidence is still scarce.     

Summary of Randomized Trials of Angiotensin Converting Enzyme Inhibitors

Angiotensin converting enzyme (ACE) inhibitors have been shown to reduce the risk of death, worsening heart failure and recurrent infarction in patients with left ventricular dysfunction and heart failure. They have also been shown to reduce mortality in the acute phase of myocardial infarction. They have been demonstrated to reduce major vascular events and progression of renal disease in diabetes with hypertension, compared to placebo and to calcium channel blockers. Current trials are evaluating their role in preventing major vascular events in patients with coronary artery disease, strokes and Type II diabetes who are normotensive.     

Diastolic dysfunction

Opinion statement Heart failure is a leading cause of hospital admissions in North America. Approximately half of patients with symptoms of heart failure have normal or minimally impaired systolic function and are therefore diagnosed, by exclusion, with diastolic dysfunction. The therapy of diastolic dysfunction to date is largely unsatisfactory. There have been few outcome-based clinical trials to guide clinicians, and most treatments have been empirically derived from the data from systolic heart failure studies. In general, acute management consists of central volume reduction with loop diuretics and long-acting nitrates. In some cases improvement in left ventricular filling can be achieved by reducing heart rate, usually with either β blockers or calcium channel blockers. The role of digoxin is unclear and it should be used with caution. Theoretically, it has the capacity to further impair ventricular function, but one of the few trials in diastolic heart failure suggested that it improves symptoms and reduces hospitalization. Renin-angiotensin system blockade is a very attractive therapeutic avenue; angiotensin-converting enzyme inhibitors and angiotensin receptor blockers effectively reduce afterload, induce regression of left ventricular hypertrophy in excess of their blood pressure-lowering effect, and confer survival benefits to patients at high risk for cardiovascular death. Although the results of a recent trial using an angiotensin receptor blocker in patients with primarily diastolic heart failure were unimpressive, renin-angiotensin system blockade should still be considered because of its aforementioned benefits. The long-term management of these patients includes a careful assessment for and treatment of myocardial ischemia, treatment of hypertension, and reduction in left ventricular hypertrophy. For the treatment of ischemia, long-acting nitrates and calcium channel blockers may be particularly useful. The results of new trials in this area are expected soon, and hopefully therapy that directly targets the pathophysiologic pathways of this important disease is on the horizon.     

Risk stratification and prevention of sudden death in patients with heart failure

Patients with heart failure can die of progressive refractory heart failure or sudden cardiac death. This article reviews the major clinical predictors of sudden death in patients with heart failure due to left ventricular systolic dysfunction. Although earlier studies have identified many independent univariate predictors of reduced survival in these patients, the positive predictive value of most of them is low. Cardioverter defibrillator implantation has been shown to be the most effective therapy in patients resuscitated after cardiac arrest caused by ventricular fibrillation or poorly tolerated ventricular tachycardia. Low left ventricular ejection fraction, low New York Heart Association functional class, unsustained ventricular tachycardia and inducibility of ventricular arrhythmia in electrophysiological studies may also identify high-risk patients who are candidates for cardioverter defibrillator implantation. The role of amiodarone in preventing sudden death in high-risk patients with heart failure seems to be small. Further studies are needed to improve risk stratification criteria to select patients with heart failure who are candidates for cardioverter defibrillator implantation.     

Current perspectives for AT(1)-receptor blockers in the management of heart failure

Despite improvements in therapy, long-term mortality remains high in patients with heart failure and thus there remains a need for new treatment strategies to reduce the burden of mortality and morbidity associated with this condition. AT(1)-receptor blockers represent a rational approach to the management of heart failure, and have been shown to have beneficial effects on heart failure symptoms and exercise tolerance. However, the two outcome trials reported to date have not shown conclusive evidence of improvements in mortality. The potential benefits of AT(1)-receptor blockers in heart failure are currently being investigated in several trials. The CHARM programme (Candesartan in Heart failure - Assessment of Reduction in Mortality and morbidity) is the largest heart failure trial so far. This comprises three trials: CHARM Alternative, in patients with left ventricular dysfunction who are intolerant to ACE inhibitors; CHARM Added, in patients with left ventricular dysfunction who are also receiving ACE inhibitors; CHARM Preserved, in patients with preserved left ventricular systolic function (ejection fraction >40%). The primary end point will be a composite of cardiovascular mortality and hospitalisation for the treatment of heart failure. Other trials are currently investigating the effects of AT(1)-receptor blockers when used as an alternative or in addition to ACE inhibitors. The CHARM programme, together with other studies, should clarify the role of these agents in the management of heart failure.     

Primary diastolic heart failure

Diastolic heart failure is defined clinically when signs and symptoms of heart failure are present in the presence of preserved left ventricular systolic function (ejection fraction >45%). The incidence and prevalence of primary diastolic heart failure increases with age and it may be as high as 50% in the elderly. Age, female gender, hypertension, coronary artery disease, diabetes, and increased body mass index are risk factors for diastolic heart failure. Hemodynamic consequences such as increased pulmonary venous pressure, post-capillary pulmonary hypertension, and secondary right heart failure as well as decreased cardiac output are similar to those of systolic left ventricular failure, although the nature of primary left ventricular dysfunction is different. Diagnosis of primary diastolic heart failure depends on the presence of preserved left ventricular ejection fraction. Assessment of diastolic dysfunction is preferable but not mandatory. It is to be noted that increased levels of B-type natriuretic peptide does not distinguish between diastolic and systolic heart failure. Echocardiographic studies are recommended to exclude hypertrophic cardiomyopathy, infiltrative heart disease, primary valvular heart disease, and constrictive pericarditis. Myocardial stress imaging is frequently required to exclude ischemic heart disease. The prognosis of diastolic heart failure is variable; it is related to age, severity of heart failure, and associated comorbid diseases such as coronary artery disease. The prognosis of severe diastolic heart failure is similar to that of systolic heart failure. However, cautious use of diuretics and/or nitrates may cause hypotension and low output state. Heart rate control is essential to improving ventricular filling. Pharmacologic agents such as angiotensin receptor blockers, angiotensin-converting enzyme inhibitors, and calcium channel blockers are used in selected patients to decrease left ventricular hypertrophy. To decrease myocardial fibrosis, aldosterone antagonists have a potential therapeutic role. However, prospective controlled studies will be required to establish their efficacy in primary diastolic heart failure.     

Therapy for diastolic heart failure

There is little objective to guide the therapy of patients with diastolic heart failure. Because of the similarities of pathophysiology abnormalities in diastolic and systolic heart failure, it is a reasonable inference to suggest that the proven therapy for systolic heart failure may also be of benefit in patients with diastolic heart failure. Treatment of underlying or exacerbating conditions in diastolic heart failure, such as hypertension, left ventricular hypertrophy, ischemia, diabetes, anemia, obesity and pulmonary disease is an important means of managing diastolic heart failure. Control of systolic blood pressure is effective in improving and preventing the development of diastolic heart failure. Treatment of diastolic heart failure is most effective when it is associated with hypertension. Production of systolic arterial pressure acutely reduces pulmonary congestion, ischemia, and chronically may lead to regression of left ventricular hypertrophy. Patients with diastolic heart failure in the absence of hypertension are very difficult to treat.     

Aldosterone and aldosterone antagonism in cardiovascular disease: focus on eplerenone (Inspra)

Aldosterone has long been known to mediate water and electrolyte balance by acting on mineralocorticoid receptors in the kidneys. However, recent studies have demonstrated the presence of these receptors in nonclassical locations, including the brain, blood vessels, and the heart. This finding suggests that aldosterone may play a larger role than once appreciated in normal physiologic function and cardiovascular disease. Some of the adverse cardiovascular effects that have been described include cardiac and vascular fibrosis, left ventricular hypertrophy, congestive heart failure, hypertension, endothelial dysfunction, reduced fibrinolysis, and cardiac arrhythmias. In light of these findings, aldosterone receptor blockers have become increasingly more important. This is especially true considering the fact that traditional therapies, such as angiotensin-converting enzyme inhibitors and angiotensin II-receptor blockers, may not be effective in maintaining long-term suppression of aldosterone. Therefore, a great deal of focus has been placed on spironolactone, which has proven to be an effective, albeit nonselective, aldosterone receptor blocker. The Randomized Aldactone Evaluation Study has shown that spironolactone results in a 30% reduction in mortality among patients with severe congestive heart failure. Other studies have shown spironolactone to lower high blood pressure, improve endothelial dysfunction, reduce left ventricular hypertrophy, and lower the incidence of fatal arrhythmias. However, spironolactone, because of its interaction with other steroid receptors, is not without its limitations, which include gynecomastia, breast tenderness, menstrual irregularities, and impotence. As a result, eplerenone (INSPRA), a selective aldosterone blocker, is currently being investigated for its efficacy and side-effect profile compared with spironolactone. Eplerenone has already been approved for the treatment of systemic hypertension, and several clinical trials are currently underway to identify other therapeutic uses for this agent in cardiovascular disease management.     

Update on the drug treatment of hypertension in patients with cardiovascular disease

The management of the high-risk patient with hypertension has become more challenging in recent years. Drug therapy should be initiated earlier and at lower blood pressure levels in patients with coexisting cardiovascular or kidney diseases. The blood pressure goals of drug therapy are substantially lower when patients have concomitant heart or kidney disease or diabetes mellitus. Numerous clinical trials in tens of thousands of hypertensive patients with increased cardiovascular risk have demonstrated that the calcium antagonists are as effective and safe as diuretics, beta-adrenergic blockers, and renin-angiotensin blocking agents to prevent heart attack and stroke but not heart failure. Several recent studies also demonstrate that angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers are effective in preventing stroke, progressive renal insufficiency, and heart failure in higher risk patients with hypertension. To achieve the aggressive blood pressure goals in patients with cardiovascular disease, thoughtful combinations of additive or synergistic agents improve efficacy and tolerability and have become an integral part of the modern management of hypertensive patients with coexisting cardiovascular disease.     

New Information on the Role of Beta-Blockers in Cardiac Therapy

Summary. Hypertension and ischemic heart disease are important precursors of heart failure. The prevention of progression to heart failure is a prime objective when treating patients with hypertension or ischemic heart disease. In patients with hypertension, treatment with either diuretics or beta-blockers reduces the risk of chronic heart failure. In patients with ischemic heart disease, beta-blocker therapy reduces the risk of recurrent myocardial infarction and ensuing cardiac dysfunction. The beneficial effects of beta-blocker therapy may be greater in post-infarction patients who have impaired left ventricular function than in those patients without such impairment.When considering heart failure itself, the efficacy of angiotensin-converting enzyme (ACE) inhibitors has been demonstrated in patients with mild-to-severe left ventricular dysfunction and their use is indicated for all stages of heart failure to reduce symptoms and retard further impairment of left ventricular function. Diuretics and digitalis offer relief from the symptoms of the disease, while positive inotropes are reserved for parenteral administration in end-stage heart failure, as a bridge to transplantation, or in acute exacerbations of the disease. Added to standard therapy, beta-blockade is of value in the treatment of heart failure, preventing further deterioration and improving hemodynamics, exercise tolerance, quality of life, and long-term prognosis.     

Diabetes mellitus, left ventricular dysfunction and congestive heart failure]

Diabetes is a well known risk factor for the development of congestive heart failure. Epidemiological evidence in the community underscores the prevalence of left ventricular systolic dysfunction in diabetic patients as 2-fold with respect to non-diabetic ones, with half of them completely asymptomatic. Diastolic dysfunction in diabetic hearts, in comparison with non-diabetic, is even more frequent. The high prevalence has been explained by the frequent coexistence of an underlying diabetic cardiomyopathy, hypertension and ischemic heart disease. In these patients, the diabetic metabolic derangement, together with the early activation of sympathetic nervous system, induce a decrease of myocardial function. The activation of renin-angiotensin system results in an unfavorable cardiac remodeling. The progression from myocardial damage to overt dysfunction and heart failure is often asymptomatic for a long time and frequently undiagnosed and untreated. Currently, the widespread availability of echocardiography and possibly the use of cardiac natriuretic peptides, may allow for an earlier recognition of most of such patients. In heart failure, diabetic patients have a worse prognosis than non-diabetics. The available pharmacological treatments, such as ACE-inhibitors, beta-blockers and possibly angiotensin receptor blockers, togheter with a tight glycemic control, may be effective to reverse the remodeling process and prevent cardiovascular events. In order to identify most of the diabetic patients at risk of development of left ventricular dysfunction and to prevent its progression to overt heart failure, it seems important to elaborate a screening strategy in order to diagnose and treat most of diabetic patients with myocardial damage.     

Vascular selective calcium entry blockers in the treatment of cardiovascular disorders: Focus on felodipine

Summary Calcium entry through L-type calcium channels is essential for contraction of both arterial smooth muscle and the myocardium, and is important in cardiac conduction. First-generation calcium entry blockers lack or have a modest degree of vascular selectivity and inhibit cardiac function at doses producing therapeutic arterial dilatation. Such agents may cause deterioration in patients with left ventricular dysfunction, and their combination with a beta-adrenergic blocker may adversely affect cardiac contractility and conduction. Development of newer agents has focused on obtaining a higher degree of vascular selectivity. Felodipine is a highly vascular selective calcium entry blocker, with a vascular selectivity ratio greater than 100, as shown experimentally. Isradipine and nicardipine are also vascularly selective calcium entry blockers. Hemodynamic studies in patients with hypertension, coronary artery disease, congestive heart failure, or in patients receiving beta-adrenergic blockade, show that felodipine can produce profound arteriolar dilatation without the negative effects of left ventricular systolic performance. Furthermore, felodipine alone or when added to a beta-adrenergic blocker does not interfere with cardiac conduction. The primary mechanism that accounts for the efficacy of dihydropyridine calcium entry blockers in hypertension and angina pectoris is arterial dilation, whereas nondihydropyridines may also derive part of their effect from inhibition of cardiac performance. As some of these patients, most commonly the elderly, have concomitant left ventricular dysfunction, it should be advantageous to avoid myocardial depression in the treatment of their primary disease. Preliminary studies in patients with heart failure indicate that felodipine and amlopidine may improve hemodynamics, reduce neurohormonal activation, and increase exercise tolerance, but final conclusions must await the randomized clinical trials now underway.     

Arterial hypertension and chronic heart failure

Arterial hypertension, alone or in combination with ischemic heart disease, precedes the development of heart failure. The Framingham study demonstrated that hypertension was the major risk factor in the development of heart failure. Arterial hypertension is not a sole factor contributing to the development of heart failure. The syndrome of heart failure is a consequence of multiple systemic responses and the development of heart failure is a complex and progressive process associated with cardiovascular disease resulting from risk factors: hypertension, obesity, smoking and dyslipidaemia. Arterial hypertension is the main precursor of left ventricular hypertrophy. Initially, this process causes diastolic dysfunction in the early stages of primary hypertension. Systolic dysfunction is rarely observed in those subjects. Left ventricular hypertrophy is also an important risk factor for myocardial infarction and ventricular arrhythmias. Asymptomatic systolic and diastolic left ventricular dysfunction may both progress to overt HFThe primary prevention of heart failure patients should be based upon strategies providing tight and sustained blood pressure control. This therapy should include an agent that inhibits the renin–angiotensin–aldosterone system. Treatment of arterial hypertension in patients with HF must take into account the prevalent type of cardiac dysfunction—diastolic or systolic.     

Left ventricular diastolic dysfunction as a cause of congestive heart failure. Mechanisms and management.

OBJECTIVE: To define the mechanisms underlying left ventricular diastolic dysfunction in patients with congestive heart failure and normal systolic function and to identify the patients at risk for this syndrome. STUDY SELECTION: Studies were selected that describe the clinical observations of congestive heart failure with normal systolic function and that provide experimental and clinical insights into the mechanisms responsible for ventricular diastolic dysfunction. DATA SYNTHESIS: Recent studies indicate that a large number of patients (up to 40% in some series) presenting with congestive heart failure have preserved left ventricular systolic function. The factors contributing to altered left ventricular diastolic function include fibrosis, hypertrophy, ischemia, and increased afterload. The latter three factors, alone or in combination, predispose to impaired left ventricular relaxation, an active energy-requiring process. Thus, decreased left ventricular diastolic distensibility (increased diastolic pressure at any level of diastolic volume) may arise not only from altered passive elastic properties stemming from fibrosis or increased muscle mass but also from derangements in the dynamics of ventricular relaxation. RESULTS: In patients with essential hypertension, all four of the above mechanisms may be operative. Considering the prevalence of hypertension in the general population, hypertension appears to be an important underlying factor in many patients with heart failure on the basis of diastolic mechanisms. In the patient presenting with dyspnea and elevated filling pressures, but with a nondilated, normally contracting ventricle, treatment with standard heart failure medications (such as digitalis, diuretics, and vasodilators) is often ineffective and may be deleterious. Such patients may respond more favorably to beta-blockers and calcium-channel blockers. CONCLUSIONS: Diastolic dysfunction should be considered in the patient presenting with heart failure symptoms but with normal systolic function, particularly in hypertensive patients with left ventricular hypertrophy.     

Cardiovascular diseases in obstructive sleep apnea

Obstructive sleep apnea (OSA) affects approximately 5% of women and 15% of men in the middle-aged adults, and associated with adverse health outcomes. Cardiovascular disturbances are the most serious complications of OSA. These complications include heart failure, left/right ventricular dysfunction, acute myocardial infarction, arrhythmias, stroke, systemic and pulmonary hypertension. All these cardiovascular complications increase morbidity and mortality of OSA. Several epidemiologic studies have demonstrated that sleep related breathing disorders are an independent risk factor for hypertension, probably resulting from a combination of intermittent hypoxia and hypercapnia, arousals, increased sympathetic activity, and altered baroreflex control during sleep. Arterial hypertension, obesity, diabetes mellitus and coronary artery disease (CAD) which are independent predictors of left ventricular dysfunction, often have co-existence with OSA. Especially severe OSA patients having diastolic dysfunction might have an increased risk of heart failure, since diastolic dysfunction might be combined with systolic dysfunction. Early recognition and appropriate therapy of ventricular dysfunction is advisable to prevent further progression to heart failure and death. Patients with acute myocardial infarction, especially if they had apneas and hypoxemia without evident heart failure should be evaluated for sleep disorders. So, patients with CAD should be evaluated for OSA and vice versa. Early recognition and treatment of OSA may improve cardiovascular functions. Continuous positive airway pressure (CPAP) applied by nasal mask, is still the gold standard method for treatment of the disease and prevention of complications.     

A hard look at angiotensin receptor blockers in heart failure

Multiple trials over the past several years have examined indications for angiotensin receptor blockers (ARBs) in the treatment of left ventricular dysfunction, both acutely after myocardial infarction and in chronic heart failure. Yet despite these data, there is still confusion regarding the efficacy of ARBs as monotherapy in these patient populations, as well as the specific indications for combination ARB/angiotensin-converting enzyme (ACE) inhibitor therapy. We examine the key differences among the trials-including the ACE inhibitor dose, the ARB and its dose, blood pressure reduction, and patient populations-to present our perspective on ARB use, alone or in combination with ACE inhibitors, in patients with chronic heart failure and post-myocardial infarction left ventricular dysfunction. We conclude that ACE inhibitors remain the first-line therapy for left ventricular dysfunction. Angiotensin receptor blockers should be reserved for monotherapy in ACE intolerant patients and for combination therapy in symptomatic class II/III patients with chronic heart failure.