ACP medicine, 3rd Edition

Cardiovascular Medicine

Heart Failure

Mariell Jessup MD, FACP1

Professor of Medicine

1University of Pennsylvania School of Medicine; Medical Director, Heart Failure/Transplant Program; Hospital of the University of Pennsylvania

The author has received grants for clinical research from, and served as an advisor or consultant to, Acorn Cardiovascular, Inc.; Medtronic, Inc.; GlaxoSmithKline; AstraZeneca Pharmaceuticals LP; and Ventracor.

August 2006


Heart failure is a clinical syndrome resulting from a structural or functional cardiac disorder that impairs the ability of the ventricle to fill with or eject blood to meet the needs of the body. This syndrome, which is a constellation of signs and symptoms, is primarily manifested by dyspnea, fatigue, fluid retention, and decreased exercise tolerance. Heart failure may result from disorders of the pericardium, myocardium, endocardium, valvular structures, or great vessels of the heart or from rhythm disturbances. It is important to emphasize that not all patients with heart failure symptoms have similar cardiac structural abnormalities. Indeed, the major aim of an initial evaluation of a patient with heart failure is to define the cardiac abnormalities responsible for the symptoms.


Heart failure has been classified in many ways. One useful framework involves describing the underlying cardiomyopathy, which frequently will suggest the etiology [see Table 1] and [see Figure 1].1,2,3,4 Some examples of the World Health Organization (WHO) classification are ischemic, hypertrophic, restrictive, and idiopathic dilated cardiomyopathy. In the United States, the most common cause of heart failure is ischemic cardiomyopathy resulting from coronary artery disease (CAD).5,6

Table 1 Examples of Descriptive and Etiologic Classifications of Heart Failure

Classification Scheme

Disorder or Disease Process


By disorder

Dilated cardiomyopathy

Dilatation and impaired function of left ventricle or both ventricles; multiple etiologies: ischemia, valvular disease, infectious process, inflammatory process, toxins, familial/ genetic cause, idiopathic

Hypertrophic cardiomyopathy

Hypertrophy of left ventricle or both ventricles, often asymmetrical and involving the interventricular septum; often associated with mutations in sarcoplasmic proteins; associated with arrhythmias and sudden death

Restrictive cardiomyopathy

Usually associated with normal systolic function and impaired diastolic function; can be idiopathic or associated with infiltrative diseases, such as amyloidosis, sarcoidosis, and endomyocardial fibrosis

Arrhythmogenic right ventricular cardiomyopathy

Replacement of myocardium with fatty tissue; can involve left ventricle as well; associated with ventricular arrhythmias; may have a genetic component

By underlying disease process

Ischemic heart disease

Secondary to coronary artery disease

Valvular disease

Caused by primary valvular disease


Usually associated with left ventricular hypertrophy; can involve systolic and/ or diastolic dysfunction

Diabetes mellitus

Associated with systolic and/ or diastolic dysfunction and left ventricular hypertrophy, even independent of coexisting hypertension or coronary artery disease

Inflammatory / infectious disease

Systolic dysfunction from myocarditis; multiple infectious etiologies, both viral (e.g., coxsackievirus, echovirus, HIV) and bacterial (rheumatic fever)

Metabolic disorders

Associated with endocrine abnormalities (e.g., hyperthyroidism, hypothyroidism), electrolyte deficiencies (potassium, magnesium), nutritional deficiencies (e.g., beriberi), and glycogen storage disease (e.g., Pompe disease, Gaucher disease)

General systemic disease

Associated with connective tissue diseases (e.g., systemic lupus erythematosus, rheumatoid arthritis) and infiltrative diseases (e.g., sarcoidosis, amyloidosis)

Muscular dystrophies

Includes Duchenne, Becker, and myotonic muscular dystrophies

Neuromuscular disease

Includes Friedreich ataxia and Noonan syndrome


Associated with alcohol and cocaine abuse, treatment with cardiotoxic chemotherapeutic agents (e.g., anthracyclines), and radiation therapy


Associated with uncontrolled tachycardias (e.g., atrial fibrillation and other supraventricular tachycardias)

Genetic/familial disorders

Associated with a family history of cardiomyopathy and/ or sudden death; many cardiomyopathies previously designated as idiopathic may fall into this category


Manifests in peripartum period


Figure 1. Cardiac Morphologies in Heart Failure

The different cardiac morphologies in heart failure: (a) normal, (b) dilated cardiomyopathy, (c) hypertrophic cardiomyopathy, and (d) diastolic dysfunction. The heart is viewed from the left side, with the mitral valve partially cut away; the aortic valve is visible in the upper portion of the left ventricle.

Another practical approach for classification is to divide patients with heart failure into groups of patients with primarily systolic dysfunction and those with diastolic dysfunction. For the clinician, this usually means assessing the patient's left ventricular ejection fraction (LVEF), most commonly with echocardiography.7,8,9,10 Patients with systolic heart failure typically have a low LVEF (usually less than 40% to 45%), a dilated left ventricular cavity, and a reduced cardiac output because of diminished contractility of the myocardium. In contrast, patients with diastolic heart failure have a normal LVEF and normal contractility, but filling of the heart is impaired by a variety of pathophysiologic abnormalities, and salt and water homeostasis is abnormal.11,12,13,14 Despite an increased understanding of the etiologies and pathophysiology of heart failure and significant advances in treatment, morbidity and mortality from this disorder remain unacceptably high.15,16,17,18 Most experts agree that earlier recognition of the syndrome or better identification of patients at risk for heart failure may offer the best hope for the future reduction of heart failure's death toll. This is analogous to the concerted efforts to screen for cancer at its earliest stages, before the disease can defy therapy. Consequently, in 2001, the committee charged with revising the American College of Cardiology/American Heart Association (ACC/AHA) Guidelines for the Evaluation and Management of Heart Failure took the bold step of developing a new classification for patients with heart failure.19 These guidelines can be obtained from the ACC Web site ( or the AHA Web site ( The guidelines were updated in 2005, and once again this new approach was used to craft specific recommendations.20

The ACC/AHA classification emphasizes the evolution and progression of heart failure; it defines four stages of the disorder [see Table 2 and see Figure 2]. Stage A identifies patients who are at high risk for developing heart failure but who have no apparent structural abnormality of the heart. This includes patients with hypertension, diabetes, or CAD; patients with a history of rheumatic fever, alcohol abuse, or exposure to cardio toxic drugs; and patients with a family history of cardio myopathy. Stage B denotes patients with a structural abnormality of the heart but in whom symptoms of heart failure have not yet developed. This group includes patients who have left ventricular hypertrophy or dilatation, a decreased LVEF, or valvular disease, as well as patients with prior myocardial infarction. Stages A and B can be viewed as preclinical stages. Stage C refers to patients with a structural abnormality of the heart and symptoms of clinical heart failure. This group includes patients with dyspnea, fatigue, or fluid overload, as well as patients with a prior diagnosis of heart failure who are receiving treatment that has relieved their symptoms. Importantly, once patients have had symptoms of heart failure, they remain in stage C even if they subsequently experience clinical improvement. Stage D includes patients with end-stage heart failure that is refractory to standard treatment. Typical stage D patients include those who require frequent hospital admissions for heart failure, are awaiting a heart transplant, are being supported with intravenous agents or mechanical assist devices, or are receiving hospice care for end-stage heart failure.

Table 2 Stages of Heart Failure19





Patients at high risk for heart failure because of the presence of conditions strongly associated with the development of heart failure; no identified structural or functional abnormalities of the pericardium, myocardium, or cardiac valves; no current or previous history of signs or symptoms of heart failure

Patients with systemic hypertension, coronary artery disease, diabetes mellitus, history of cardiotoxic drug therapy or alcohol abuse, history of rheumatic fever, family history of cardiomyopathy


Patients with structural heart disease that is strongly associated with the development of heart failure but who have no current or previous history of signs or symptoms of heart failure

Patients with left ventricular hypertrophy or fibrosis, left ventricular dilatation or hypocontractility, asymptomatic valvular heart disease, previous myocardial infarction


Patients who currently have or who in the past have had symptoms of heart failure associated with underlying structural heart disease

Patients with dyspnea or fatigue due to left ventricular systolic dysfunction; asymptomatic patients undergoing treatment for prior symptoms of heart failure


Patients with advanced structural heart disease and marked symptoms of heart failure at rest despite maximal medical therapy; need for specialized interventions

Patients who are frequently hospitalized for heart failure and cannot be safely discharged from the hospital; patients in hospital awaiting heart transplantation; patients at home receiving continuous intravenous support for symptom relief or support with a mechanical circulatory assist device; patients in a hospice setting for the management of heart failure


Figure 2. Stages of Heart Failure

The evolution of heart failure by stage.19

The ACC/AHA classification is a departure from the traditional New York Heart Association (NYHA) classification, which characterizes patients by symptom severity.21 Patients with heart failure may progress from stage A to stage D, but never the reverse. In contrast, many patients with NYHA class IV symptoms can be restored to class II with appropriate therapy. The ACC/AHA classification highlights the importance of known risk factors and structural abnormalities in the development of heart failure. Additionally, it reinforces the concept that heart failure is a progressive disease whose onset can be prevented, or its progression halted, by early identification and intervention.

It is important to note that other guidelines have been published that do not use this stage classification, including a revision of the guidelines from the Heart Failure Society of America.22,23 Irrespective of the guidelines used, all sources agree on the fundamental value of heart failure prevention and the recognition of those risk factors that can be modified. In addition, there is unanimity about the dynamic nature of heart failure symptoms and the poor correlation between functional capacity and structural abnormalities in the syndrome.


Heart failure is one of the most important cardiac disorders in the United States, both in terms of the number of patients affected and the health care dollars spent. Nearly five million people have heart failure, and almost 500,000 new patients are diagnosed with the disease each year. The estimated direct and indirect costs of heart failure were $21 billion in 2001, more than 5% of the total amount spent on health care24; annual spending on drugs for heart failure is about $500 million.19 Hospitalizations for heart failure increased by 159% from 1979 to 1998,24 and this trend will likely continue as the United States population ages.

Heart failure is primarily a disease of the elderly.25 Approximately 6% to 10% of people older than 65 years have heart failure,26 and roughly 80% of patients hospitalized with heart failure are older than 65 years.27 More Medicare dollars are spent on heart failure than on any other disease, and heart failure is the most common Medicare diagnosis-related group.5

It is important to recognize that heart failure has diverse causes and affects diverse populations. Until recently, this diversity was not reflected in the composition of heart failure trials in the United States, which typically enrolled middle-aged white men with ischemic cardiomyopathy. In fact, the heart failure population in the United States includes significant numbers of women, elderly persons, and members of racial minorities—and these patients tend to have various forms of heart failure. For example, in an estimated 20% to 50% of patients with heart failure, ventricular systolic function is preserved (i.e., the patients have diastolic heart failure), and these patients are more likely to be elderly women.28,29,30,31 Moreover, there are substantial data to suggest that the etiology and natural history of heart failure in African Americans and whites may be different.32 Heart failure therapy has also been shown to have different efficacies depending on racial, ethnic, and genetic backgrounds. It is clear that the role of pharmacogenomics will continue to expand in the near future.33


CAD is responsible for roughly two thirds of cases of heart failure in the United States.34 Coronary ischemia or infarction can lead to heart failure through a variety of mechanisms: acute coronary syndromes or infarction can cause acute heart failure in an otherwise normal heart; likewise, repeated insults of ischemia or infarction can cause a chronic cardiomyopathy. Moreover, many patients with diastolic heart failure, or heart failure with a preserved LVEF, have underlying CAD.

Ventricular dysfunction can result from a multitude of nonischemic causes [see Table 1]. These include hypertension, diabetes, valvular disease, arrhythmias, myocardial toxins, myocarditis from a variety of infectious agents (including HIV), and hypothyroidism. Infiltrative causes of ventricular dysfunction, which are usually associated with restrictive cardiomyopathy, include amyloidosis, hemochromatosis, and sarcoidosis. Myocardial systolic dysfunction for which there is no apparent cause is labeled idiopathic cardiomyopathy. Over the past several years, there has been increased recognition that many of these so-called idiopathic dilated cardiomyopathies are familial; a number of centers are actively focusing on the identification of the genetic irregularities responsible for the abnormal phenotypes.35


There is no single, simple model that effectively explains the syndrome of heart failure; currently, the consensus view integrates multiple pathophysiologic models to explain the complex cascade of events leading to this clinical syndrome.36,37 The different structural, functional, and biologic changes that culminate in heart failure have led to a variety of treatment modalities to target this array of causative factors.38For example, for many years, beta blockers were contraindicated in patients with heart failure because the disorder was thought to be primarily a result of decreased myocardial contractility that would worsen with negative inotropic therapy. However, that older model of heart failure has been replaced by one that gives a central role to pathologic sympathetic activation—the maladaptive mechanisms that lead to vasoconstriction, arrhythmias, and ventricular remodeling (see below). This model explains the therapeutic benefits of beta blockade.

The hemodynamic model of heart failure concentrated on the role of increased load on a failing ventricle; this conceptual approach led to the successful use of vasodilators and inotropes. Later, the neurohormonal model of heart failure identified the critical importance of the renin-angiotensin-aldosterone axis and the sympathetic nervous system in the progression of cardiac dysfunction, leading to widespread use of angiotensin-converting enzyme (ACE) inhibitors and beta blockers.

The recognition that progressive ventricular dilatation serves as a marker for disease progression has focused attention on the myocyte and on the role of the cardiac interstitium. Both medical and surgical therapies have been directed at this mechanism.

Left ventricular dysfunction begins with an injury to the myocardium. The unanswered question is why ventricular systolic dysfunction continues to worsen in the absence of recurrent insults. This pathologic process, which has been termed remodeling, is the structural response to the initial injury. Mechanical, neurohormonal, and possibly genetic factors alter ventricular size, shape, and function to decrease wall stress and compensate for the initial injury. Remodeling involves hypertrophy, loss of myocytes, and increased fibrosis and is secondary to both neurohormonal activation and other mechanical factors.39,40,41 Ultimately, the changes in ventricular shape lead to a less efficient cardiac pump. Functional mitral regurgitation often occurs as the left ventricle dilates and becomes more globular, increasing volume overload. Remodeling seems to beget more adverse remodeling.

Arrhythmias often contribute to myocardial dysfunction and are an unwelcome side effect of heart failure. Supraventricular arrhythmias, particularly atrial fibrillation, often unmask systolic or diastolic dysfunction in a previously asymptomatic patient.42 In addition, intraventricular conduction delays and bundle branch block are often present in patients with heart failure. Abnormal ventricular conduction, particularly left bundle branch block, has significant detrimental hemodynamic effects.43,44,45,46,47 In addition to contributing to worsening heart failure, ventricular arrhythmias are likely a direct cause of death in many of these patients; the rate of sudden cardiac death in persons with heart failure is six to nine times that seen in the general population.48

These pathophysiologic models do not easily explain diastolic heart failure.49 In the 20% to 50% of patients who have heart failure with normal systolic function, cardiac output is limited by abnormal filling and disordered relaxation of the ventricles, especially during exercise. Ventricular pressures are elevated for a given ventricular volume, leading to pulmonary congestion, dyspnea, and peripheral edema identical to that seen in patients with a dilated, poorly contracting heart.11,13,14,50,51 CAD or ischemia frequently compounds the impairment of ventricular performance in patients with diastolic heart failure, who typically are elderly women28 with hypertension, diabetes, and obesity.


Stage A

The first step in the diagnosis of heart failure is to identify patients who are at risk for developing the syndrome; this concept was part of the reasoning behind the ACC/AHA staging system.19 Patients in stage A are those with CAD, hypertension, diabetes, a history of alcohol abuse or exposure to cardiotoxic drugs (e.g., certain chemotherapeutic agents, cocaine), a history of rheumatic fever, or a family history of cardiomyopathy or sudden death. In these high-risk patients, reversible risk factors should be aggressively treated to prevent heart failure from developing.52,53

Stage B

Stage B patients have asymptomatic, structural heart disease. Echocardiography is easily the best diagnostic tool to uncover left ventricular hypertrophy or dilatation, valvular disease, or wall motion abnormalities indicative of previous myocardial infarction. Patients in stage B represent a significant portion of the heart failure population and constitute a key opportunity for intervention. In a community-based survey, less than half of patients with moderate or severe systolic or diastolic dysfunction, as defined by echocardiographic parameters, had recognized heart failure.54 Current ACC/AHA guidelines do not recommend routine screening echocardiography for the large number of patients at risk for the development of heart failure. The guidelines do, however, include a class I recommendation that a noninvasive evaluation of left ventricular function be performed in patients who have a strong family history of cardiomyopathy or have been exposed to cardiotoxic therapies.20

Stages C and D

Stages C and D represent the traditional definition of heart failure. Patients in stage C or D usually present with decreased exercise tolerance, fluid retention, or both. Initial assessment of these patients should focus on the structural abnormality leading to heart failure, as well as evaluation of its etiology. Initial testing should include a 2-D echocardiogram with Doppler flow studies, a chest x-ray, electrocardiography, and laboratory studies, including urinalysis, complete blood count, serum chemistries, liver function studies, and thyroid-stimulating hormone measurement. These tests serve primarily to exclude other potential causes of dyspnea or fatigue.19 In patients with dyspnea, measurement of serum brain natriuretic peptide (BNP) may aid in the diagnosis; marked elevation of BNP levels suggests that the dyspnea is cardiac rather than pulmonary in origin.55,56 Strong consideration should be given to excluding significant CAD, because CAD is the leading cause of left ventricular dysfunction.34 The ACC/AHA guidelines strongly encourage coronary angiography rather than noninvasive testing for the evaluation of patients with heart failure, even if they do not have a known history of CAD; the guidelines cite the fact that noninvasive testing can often lead to inaccurate results in patients with cardiomyopathies (e.g., perfusion defects or wall motion abnormalities in patients with a nonischemic cardiomyopathy).20 Some clinicians argue that there is little evidence that revascularization changes the outcome or prognosis in patients with left ventricular dysfunction and that it should therefore be used only to relieve angina.57

Several clinical parameters are useful for the subsequent evaluation and management of heart failure. A patient's weight should be measured in the office, and patients should be taught to follow their weight at home to assess for fluid retention. Office evaluation of jugular venous pressure, hepatojugular reflux, gallop rhythm, and peripheral edema can aid in making the initial diagnosis and guiding the need for diuresis. In addition, these signs of heart failure may be prognostically important.58

Diastolic Heart Failure

There is no universally accepted definition of diastolic heart failure,11,13,59,60 although a number of investigators have suggested options. The diagnosis is usually made by a clinician who recognizes the typical signs and symptoms of heart failure despite the finding of normal systolic function (i.e., a normal LVEF) on an echocardiogram. Doppler echocardiographic techniques can also aid in establishing the diagnosis of diastolic dysfunction.10,61


Treatment for heart failure is keyed to the stage of the syndrome as defined by the ACC/AHA guidelines [see Table 3]. Treatment in all stages is aimed at preventing or palliating the remodeling process [see Pathophysiology, above]. In addition, therapy for stages C and D heart failure is intended to relieve the disabling symptoms of the disease.

Table 3 Treatment of Heart Failure20

Stage A

Treat hypertension

Encourage smoking cessation

Treat lipid disorders

Encourage regular exercise

Discourage alcohol intake, illicit drug use

Prescribe ACE inhibitors or ARBs in appropriate patients with vascular disease or diabetes

Stage B

All measures used for stage A

ACE inhibitors or ARBs if appropriate

Beta blockers if appropriate

Stage C

All measures used for stage A

Dietary salt restriction

Drugs for routine use:

   ACE inhibitors or ARBs

   Beta blockers

   Diuretics for fluid retention

Drugs or devices for selected patients:

   Aldosterone antagonists


   Other vasodilators

   Biventricular pacing

   Implantable defibrillators

Stage D

All measures used for stages A, B, and C

Mechanical assist devices

Heart transplantation

Continuous (not intermittent) I.V. inotropic infusions for palliation

Hospice care

Experimental surgery or drugs

ACE—angiotensin-converting enzyme   ARBs—angiotensin receptor blockers

Stage A

The goal of treatment of stage A heart failure is to prevent structural heart disease. This is achieved by controlling risk factors (e.g., hypertension, CAD, diabetes mellitus, hyperlipidemia, smoking, alcohol ingestion, and use of cardiotoxic drugs), which lowers the incidence of later cardiovascular events. For example, effective treatment of hypertension decreases left ventricular hypertrophy and cardiovascular mortality; it can also reduce the incidence of heart failure by 30% to 50%.52,53

Diabetes deserves particular attention because patients with diabetes mellitus have a high incidence of CAD and of heart failure in the absence of CAD; diabetes causes many detrimental biochemical and functional cardiac changes independent of ischemia.62,63 ACE inhibitors and angiotensin receptor blockers (ARBs) have assumed a major role in risk reduction for diabetes patients (see below). In asymptomatic high-risk patients with diabetes or vascular disease who have no history of heart failure or left ventricular dysfunction, treatment with these agents has been shown to yield significant reductions in death, myocardial infarction, and stroke,64,65 as well as delays in the first hospitalization for heart failure.66

Stages B, C, and D

The goals of therapy for patients with heart failure and a low LVEF are to decrease the progression of disease and the number of hospitalizations, improve symptoms and survival, and minimize risk factors. Simple interventions can help patients control their disease. For example, basic habits of moderate sodium restriction, weight monitoring, and adherence to medication schedules serve to prevent hospitalizations for rapid fluid overload. Other frequent causes of decompensation in heart failure include anemia, arrhythmias (especially atrial fibrillation), noncompliance with medications and diet, and the use of nonsteroidal anti-inflammatory drugs (NSAIDs).67,68

Medical Therapy

Pharmacologic treatment of heart failure with low LVEF routinely includes diuretics, angiotensin antagonists, and beta blockers. Digoxin and aldosterone antagonists or inotropes may be utilized in some cases [see Table 4].

Table 4 Pharmacotherapy of Heart Failure


Drug (Trade Name)



Initial Daily Dose

Maximum Daily Dose

Loop diuretics

Bumetanide (Bumex)

0.5–1 mg q.d. or b.i.d.

Up to 10 mg

Titrate to achieve dry weight; carefully monitor serum potassium and creatinine levels

Furosemide (Lasix)

20–40 mg q.d. or b.i.d.

Up to 400 mg

Torsemide (Demadex)

10–20 mg q.d. or b.i.d.

Up to 200 mg

ACE inhibitors

Captopril (Capoten)

6.25 mg t.i.d.

50 mg t.i.d.

Carefully monitor serum potassium and creatinine levels

Enalapril (Vasotec)

2.5 mg b.i.d.

10–20 mg b.i.d.

Fosinopril (Monopril)

5–10 mg

40 mg

Lisinopril (Prinivil, Zestril)

2.5–5 mg

20–40 mg

Quinapril (Accupril)

10 mg b.i.d.

40 mg b.i.d.

Ramipril (Altace)

1.25–2.5 mg

10 mg

Beta blockers

Bisoprolol (Zebeta)

1.25 mg

10 mg

Titrate dosage up over 2- to 4-week intervals, carefully monitoring for signs and symptoms of fluid overload

Carvedilol (Coreg)

3.125 mg b.i.d.

25 mg b.i.d. (50 mg b.i.d. for patients > 85 kg)

Metoprolol tartrate (Lopressor)

6.25 mg b.i.d.

75 mg b.i.d.

Metoprolol succinate extended release (Toprol-XL)

12.5–25 mg

200 mg

Digitalis glycosides

Digoxin (Lanoxin)

0.125–0.25 mg

0.125–0.25 mg

Narrow therapeutic window; monitor levels carefully in older patients and those with renal insufficiency

Aldosterone inhibitors

Spironolactone (Aldactone)

25 mg

50 mg

50 mg q.d. was maximum spironolactone dosage used in RALES trial78; use carefully with concurrent ACE inhibitor or ARB; carefully monitor serum potassium and creatinine levels; use if potassium < 5.0 mmol/L, creatinine < 2.5 mg/dl

Eplerenone (Inspra)

25 mg

50 mg

Angiotensin receptor blockers

Candesartan (Atacand)

8 mg

32 mg

Use if patients have cough or angioedema on ACE inhibitor; may be used as first-line therapy

Irbesartan (Avapro)

75 mg

300 mg

Losartan (Cozaar)

25 mg

100 mg

Valsartan (Diovan)

80 mg

320 mg

ACE—angiotensin-converting enzyme   ARB—angiotensin receptor blocker   RALES—Randomized Aldosterone Evaluation Study


In symptomatic patients in stages C and D, diuretics are often the first drugs prescribed to decrease fluid overload and congestive symptoms. Loop diuretics are most often given to these patients, either as maintenance therapy or on an as-needed basis. Loop diuretics can be combined with thiazides to optimize diuresis.69,70

ACE inhibitors

ACE inhibitors are recommended for all patients with low LVEF in stages B, C, and D. By decreasing the conversion of angiotensin I to angiotensin II, ACE inhibitors minimize the multiple pathophysiologic effects of angiotensin II, such as vasoconstriction and fibrosis. ACE inhibitors (but not ARBs) also decrease the degradation of brady kinin, a substance that causes vasodilatation and natriuresis. In patients with heart failure, ACE inhibitors have been shown to increase survival, improve cardiac performance, decrease symptoms and hospitalizations, and decrease or slow the remodeling process.71,72,73

It is not clear whether all ACE inhibitors are equally effective in all forms of heart failure. There are few data from controlled trials, for example, regarding the efficacy of ACE inhibitors in diastolic heart failure. Moreover, although several guidelines have emphasized the need to maximize the dose of an ACE inhibitor to target levels (rather than using blood pressure alone to guide dose titration), current recommendations underscore the need to add beta blockers to the regimen of patients in stage C early in the course of treatment, even if target ACE inhibitor doses have not been achieved.

Angiotensin receptor blockers

What is the role of ARBs in heart failure? These agents block the effects of angiotensin II at the angiotensin II type 1 receptor site. Initially, recommendations for the use of ARBs were limited to patients who cannot tolerate ACE inhibitors because of cough or angioedema19; the guidelines stress that ARBs are comparable, but not superior, to ACE inhibitors.74,75,76 Several key trials, however, have reported successful intervention with ARBs in stage B and C patients.77,78,79 Possible roles for ARBs in patients who are already on beta blockers, with or without an ACE inhibitor, have likewise been explored in trials.80,81,82 There is considerable debate about the appropriate sequence of the addition of drugs to the regimens of patients who remain symptomatic after treatment with a diuretic, an ACE inhibitor, and a beta blocker. Some clinicians add an ARB, whereas others add aldosterone antagonists, digoxin, or other vasodilators.82,83

Beta blockers

Although it was once taught that beta blockers were contraindicated in patients with heart failure secondary to systolic dysfunction, multiple studies have shown remarkable effects of these drugs on many aspects of heart failure at all stages. The primary action of these agents is to counteract the harmful effects of the increased sympathetic nervous system activity in heart failure. Beta blockers increase survival and improve ejection fraction and quality of life; they also decrease morbidity, hospitalizations, sudden death, and the maladaptive effects of remodeling.84,85 Long-term, placebo-controlled trials have shown improvement in systolic function and reversal of remodeling after 3 to 4 months of treatment with beta blockers.86,87,88 A topical analysis showed that even in the sickest of heart failure patients, beta-blocker therapy was well tolerated and led to decreases in mortality and hospitalizations as early as 14 to 21 days after initiation of therapy.89Clinicians should be extremely cautious, however, about starting beta blockers in patients with significant reactive airway disease, in diabetic patients with frequent episodes of hypoglycemia, and in patients with bradyarrhythmias or heart block who do not have a pacemaker implanted.

In the United States, two beta blockers are specifically approved for treatment of heart failure: carvedilol and long-acting metoprolol. Beta blockers should be started at the lowest possible dose and titrated up slowly at 2- to 4-week intervals. Patients should be closely monitored for worsening of symptoms or fluid retention, which can sometimes occur early in therapy with these agents. If patients do have exacerbations during initiation of beta blockade, diuretic therapy can be increased, and titration of the beta blocker can proceed more slowly.


Digoxin has long been a mainstay of treatment of left ventricular dysfunction in symptomatic patients, despite a lack of data from clinical trials showing survival benefit.90 A large randomized study demonstrated that digoxin was successful in decreasing hospitalizations for heart failure—an important clinical end point—but did not decrease mortality.91 Post hoc analysis of data from this trial showed that in the patients randomized to receive digoxin therapy, mortality may have been higher in women than in men.92 It is hypothesized that the therapeutic windows for digoxin may be different in men and women, with women perhaps needing a lower dose of the drug.93 Indeed, data suggest that digoxin improves morbidity as effectively at low serum concentrations (0.5 to 0.9 ng/ml) as it does at higher levels, with less toxicity at the lower concentrations.94 Clinicians should carefully monitor all patients for signs and symptoms of digoxin toxicity, especially patients who are elderly or have renal dysfunction. Physicians and patients should also keep in mind that digoxin interacts with numerous other drugs.

Aldosterone antagonists

The aldosterone antagonists (i.e., spironolactone and eplerenone) are another relatively old class of drugs with new data to support use in heart failure.95 Because of the activation of the renin-angiotensin-aldosterone axis, which is incompletely suppressed by ACE inhibitors, patients with heart failure have increased circulating levels of aldosterone, leading to sodium retention and potassium loss. Aldosterone also works locally in the myocardium, contributing to hypertrophy and fibrosis in the failing heart.96 A large randomized trial showed that the addition of low-dose spironolactone to standard treatment reduces morbidity and mortality in patients with NYHA class III and IV heart failure (stage C and stage D patients).97 Subsequently, eplerenone was shown to be efficacious in a slightly different heart failure population.98 Despite the noteworthy results, these drugs are associated with a smaller safety margin than ACE inhibitors and beta blockers. Clinicians are urged to use caution in the selection of patients for this class of therapy and to follow serum electrolyte levels and renal function carefully after initiation of the drug.82

Other vasodilators

Symptomatic patients who cannot tolerate ACE inhibitors or ARBs, usually because of renal insufficiency, may benefit from a combination of hydralazine and isosorbide dinitrate for afterload reduction.99 In a study of advanced heart failure in black patients, the addition of this drug combination to standard heart failure therapy resulted in a lower rate of death and of first hospitalization for heart failure, as well as an improvement in the quality of life; indeed, the trial was terminated early because of significantly higher mortality in the placebo group.100 It is not clear whether this benefit will be operative in other ethnic or racial groups, however.

Intravenous inotropes

Patients with refractory heart failure (stage D patients) often require intermittent intravenous inotropic therapy to aid in diuresis and to improve symptoms.101 No survival benefit has been demonstrated with inotropic treatment given in any form. These agents should be regarded as palliative or as maintenance therapy for patients awaiting heart transplantation.19

Diastolic Heart Failure

Despite the large number of patients with primarily diastolic heart failure, few clinical trials have addressed the management of these cases. Physiologic principles used to guide treatment of these patients include control of blood pressure, heart rate, myocardial ischemia, and blood volume.19,20,22

Revascularization and Surgical Therapy

Patients in all stages of heart failure must be evaluated for CAD. Angioplasty and surgical revascularization improve ischemic symptoms and can lead to improved ejection fraction and decreased incidence of sudden death.102

Clinical trials to investigate the role of surgical interventions in halting or reversing the remodeling process are now under way. Such interventions include mitral valve repair or replacement, mechanical devices to reduce wall stress, and surgical excision of infarcted tissue.103,104,105,106

Cardiac transplantation remains the only definitive treatment for stage D patients, but it is available only to roughly 2,500 patients a year in the United States.107 Left ventricular assist devices are available to support patients waiting for a heart transplant. There is growing evidence supporting the use of these devices as destination therapy for stage D patients, many of whom are not eligible for cardiac transplantation.108,109,110 One such left ventricular assist device has been approved for use as permanent replacement therapy for stage D heart failure.

Implanted Electrical Devices

Biventricular Pacing Systems

Many heart failure patients have intraventricular conduction delays that may contribute to altered myocardial contractility or dyssynchrony. Biventricular pacing is a novel therapy for patients with left ventricular systolic dysfunction, particularly those with left bundle branch block. In this procedure, pacing leads are placed in the right atrium and the right ventricle and into a cardiac vein in the lateral wall of the left ventricle via the coronary sinus. The goal of this therapy is to restore the usual pattern of electrical activation of the left ventricle and thereby restore ventricular synchrony.111,112 There is evidence that with restored ventricular synchrony from a biventricular pacing system, the remodeling process is halted and reversed. Trials have shown that implantation of a biventricular pacer results in decreased ventricular size and volumes, improved ventricular function, and less mitral regurgitation. This has led to improved exercise tolerance, decreased hospitalizations, and improved quality of life.113,114,115 A meta-analysis of the largest trials showed a 51% decrease in death from progressive heart failure.116 In addition, a large clinical trial of biventricular pacing in patients with heart failure was stopped early because resynchronization therapy was found to confer a statistically significant benefit regarding the combined end point of mortality and hospitalization.117 Finally, a large randomized trial examining the role of biventricular pacing showed a significant reduction in mortality with the pacing system alone, in the absence of a concomitant defibrillator.118

A number of ongoing trials are exploring alternative methods of identifying appropriate candidates for this therapy (e.g., by identifying dyssynchrony). In addition, there are continued efforts to understand why certain patients fail to respond to pacing.


The use of implantable cardioverter-defibrillators (ICDs) for the primary prevention of sudden death in patients with left ventricular dysfunction has grown enormously [see 1: VI Ventricular Arrhythmias]. There is increasing evidence that ICD placement reduces mortality in patients with ischemic cardiomyopathy, irrespective of whether they have nonsustained ventricular arrhythmias.119 The role of these devices in patients with heart failure of a nonischemic cause has likewise been expanded after several important trials.117,120 All patients with an LVEF less than 35% and stage B or C heart failure, regardless of etiology, should be considered for ICD therapy. Important exclusions for consideration include shortened life expectancy, end-stage heart failure symptoms, or psychiatric disorders. A current debate centers on the extent and duration of medical therapy that should be given before the ICD is implanted.20,22


Despite many advances in the management of heart failure, it remains life threatening. Symptomatic heart failure continues to confer a worse prognosis than the majority of cancers in the United States, with 1-year mortality averaging 45%.15,16 None-theless, it is difficult to discuss the prognosis of heart failure as a whole, because an individual patient's likelihood of survival is related to the cause of the heart failure, as well as multiple other clinical factors.121,122,123,124,125 For example, given the same severity of heart failure symptoms, an 85-year-old woman with ischemic cardiomyopathy would have a lower likelihood of survival than a 45-year old man with idiopathic cardiomyopathy. One study of 1,230 patients with cardiomyopathy found that survival was significantly worse in patients with cardiomyopathy from ischemia, infiltrative disease, cardiotoxic chemotherapy, HIV infection, or connective tissue disease than in patients with idiopathic cardiomyopathy.126

There are conflicting data about the prognosis of patients with diastolic heart failure. Studies have shown, however, that mortality in these patients may be as high as the mortality in patients with systolic heart failure, and hospitalization rates are equal.54,123,127,128,129,130

It is also important for clinicians to remember that a low LVEF is not universally predictive of poor outcome. In patients referred for cardiac transplantation, survival has correlated more closely with other variables—notably, peak exercise oxygen consumption.131 One prospectively validated model for predicting survival in patients with severe heart failure incorporates LVEF with six other clinical factors: presence of coronary disease, resting heart rate, mean arterial blood pressure, presence of intraventricular conduction delays, serum sodium concentration, and peak exercise oxygen consumption.132 These tools can be used to stratify patients according to risk and to make the most appropriate use of modern therapies and treatment modalities.

How can physicians improve the prognosis of patients with heart failure? A 2002 report from the Framingham Heart Study showed promising evidence of increased survival after the diagnosis of heart failure [see Figure 3].133 To further this trend, physicians must work toward widespread implementation of the therapies known to decrease morbidity and mortality in heart failure. Researchers must also investigate more completely the impact of medical therapy on the survival of patients with diastolic heart failure. There should be continued effort to increase the number of traditionally underrepresented patients (e.g., women and minorities) enrolled in heart failure trials. Finally, in keeping with the emphasis of the ACC/AHA guidelines, clinicians must concentrate on identifying and treating those patients at greatest risk for heart failure to prevent it from occurring.


Figure 3. Age-adjusted Survival After Onset of Heart Failure

Data from the Framingham Heart Study indicate a steady upward trend since the 1950s in age-adjusted survival after the onset of heart failure.133 Estimates shown are for patients 65 to 74 years of age.


Figure 1 Alice Y. Chen


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Editors: Dale, David C.; Federman, Daniel D.