eMedicine Specialties > Cardiology > Myocardial Disease and Cardiomyopathies

Cardiomyopathy, Dilated

Frank E Wilklow, MD, Principal Investigator, Sub-Investigator, Cardiovascular Research Lab, Louisiana State University Health Sciences Center; Principal Investigator, Sub-Investigator, Gulf Regional Research and Education
Murat M Celebi, MD, Consulting Staff, Crescent City Cardiovascular Associates; Amer Suleman, MD, Consultant in Electrophysiology and Cardiovascular Medicine, Department of Internal Medicine, Division of Cardiology, Medical City Dallas Hospital; Gary E Sander, MD, PhD, Professor, Department of Internal Medicine, Division of Cardiology, Tulane University Health Sciences Center

Updated: Nov 19, 2008

Introduction

Background

Cardiomyopathy is a complex disease process that can affect the heart of a person of any age. It is a common problem throughout the world and is the most common diagnosis in persons receiving supplemental medical financial assistance via the US Medicare program. Cardiomyopathy is an important cause of morbidity and mortality among the world's aging population.

Cardiomyopathies are conditions in which the normal muscular function of the myocardium has been altered by specific or multiple etiologies, with varying degrees of physiologic compensation for that malfunction. Cardiomyopathies have multiple etiologies. The degree and time course of malfunction are variable and do not always coincide with a linear expression of symptoms. Persons with cardiomyopathy may have asymptomatic left ventricular systolic dysfunction, left ventricular diastolic dysfunction, or both.

When the balance between malfunction and compensation is disrupted such that cardiac output can no longer be maintained at normal left ventricular filling pressures, the disease process is expressed with symptoms that collectively compose the disease state known as congestive heart failure (CHF). This article addresses etiologies and pathophysiology in addition to diagnostic and treatment modalities not discussed in other articles. General considerations and the direction of heart failure therapy are also reviewed.

For related information, see Medscape's Heart Failure Resource Center.

Pathophysiology

Because the etiology for cardiomyopathies varies, so does the pathophysiology that may lead to its clinical expression as CHF. Although the pathophysiologic mechanisms are different, the hemodynamic consequences and neurohormonal abnormalities associated with the different causes of cardiomyopathies remain very similar. Dilated cardiomyopathy (DCM) manifests hemodynamically as decreased cardiac output and increased pulmonary venous pressure. The pathophysiologic mechanisms associated with CHF may be considered secondary to a dilated physiology or to a restrictive physiology.

Anatomically, the heart has greater left ventricular cavity size with little or no wall hypertrophy. Hypertrophy is judged as the ratio of left ventricular mass to cavity size, which is decreased in persons with dilated cardiomyopathies. The enlargement of the remaining heart chambers is primarily due to left ventricular failure, but it may be secondary to the primary cardiomyopathic process. Dilated cardiomyopathies are associated with both systolic and diastolic dysfunction. The decrease in systolic function of the myocardium is by far the primary abnormality. This leads to an increase in the end-diastolic and end-systolic volumes.

Progressive dilation can lead to significant mitral and tricuspid regurgitation, which may further diminish the cardiac output and increase end-systolic volumes and ventricular wall stress, thus leading to further dilation and myocardial dysfunction. Early compensation for systolic dysfunction and decreased cardiac output is accomplished by increasing the stroke volume, the heart rate, or both (cardiac output = stroke volume X heart rate), which is also accompanied by an increase in peripheral tone.

The basis for compensation of low cardiac output is explained by the Frank-Starling Law, which states that myocardial force at end-diastole compared with end-systole increases as muscle length increases, thereby generating a greater amount of force as the muscle is stretched. Overstretching, however, leads to failure of the myocardial contractile unit. These compensatory mechanisms are blunted in persons with dilated cardiomyopathies compared with persons with hearts with normal left ventricular systolic function. Additionally, these compensatory mechanisms lead to further myocardial injury, dysfunction, and geometric remodeling (concentric or eccentric).

Compensatory mechanisms

The 2 most important initial mechanisms of compensation involve alterations in stroke volume and heart rate (increases in heart rate and venous filling). The increase in peripheral tone noted with decreased cardiac output maintains appropriate blood pressure. Also observed is an increased tissue oxygen extraction rate with a shift in the hemoglobin dissociation curve.

Neurohormonal activation

At the CNS level, decreased cardiac output with resultant reductions in organ perfusion results in neurohormonal activation, including stimulation of the adrenergic nervous system and the renin-angiotensin-aldosterone system (RAAS). Additional factors important to compensatory neurohormonal activation include the release of arginine vasopressin and the secretion of natriuretic peptides (eg, atrial natriuretic peptide [ANP], brain natriuretic peptide [BNP], C-type natriuretic peptide). Unfortunately, initially compensatory mechanisms ultimately lead to further disease progression.

Alterations in the adrenergic nervous system induce significant increases in circulating levels of dopamine and, especially, norepinephrine. By increasing sympathetic tone and decreasing parasympathetic activity, an increase in cardiac performance (beta-adrenergic receptors) and peripheral tone (alpha-adrenergic receptors) is attempted. Unfortunately, long-term exposure to high levels of catecholamines leads to down-regulation of receptors in the myocardium and blunting of this response. The response to exercise in reference to circulating catecholamines is also blunted. On a theoretical level, the increased catecholamine levels observed in cardiomyopathies due to compensation may in themselves be cardiotoxic and lead to further dysfunction. In addition, stimulation of the alpha-adrenoreceptors, which leads to increased peripheral vascular tone, increases the myocardial work load, which can further decrease cardiac output. Circulating norepinephrine levels have been inversely correlated with survival.

Activation of the RAAS is critically important when discussing neurohormonal alterations in persons with CHF. Angiotensin II potentiates the effects of norepinephrine by increasing systemic vascular resistance. It also increases the secretion of aldosterone, which facilitates sodium and water retention and may contribute to myocardial fibrosis.

The release of arginine vasopressin from the hypothalamus is controlled by both osmotic (hyponatremia) and nonosmotic stimuli (eg, diuresis, hypotension, angiotensin II). Arginine vasopressin may potentiate the peripheral vascular constriction because of the aforementioned mechanisms. Its actions in the kidneys reduce free-water clearance.

Natriuretic peptide levels are elevated in individuals with dilated cardiomyopathy. Natriuretic peptides in the human body include ANP (source is mostly right atrium), BNP (source is ventricles), and C-type natriuretic peptide.

ANP is primarily released by the atria. Right atrial stretch is an important stimulus for its release. The effects of ANP include vasodilation, possible attenuation of cell growth, diuresis, and inhibition of aldosterone.

BNP was initially identified in brain tissue and is a 32–amino acid polypeptide neurohormone. BNP is secreted from cardiac ventricles in response to volume or pressure overload, and it causes vasodilation and natriuresis. As a result, BNP levels are elevated in patients with CHF.

Counterregulatory processes to neurohormonal activation involve the increase in release of prostaglandins and bradykinins. These mechanisms do not significantly counteract the previously mentioned compensatory mechanisms. The body's compensatory mechanisms for a failing heart are evidently short sighted. Compensation of decreased cardiac output cannot be sustained without inducing further decompensation. The rationale for the most successful medical treatment modalities for cardiomyopathies is therefore based on altering these neurohormonal responses.

Circulating cytokines as mediators of myocardial injury

Tissue necrosis factor-alpha (TNF-alpha) is involved in all forms of cardiac injury. In cardiomyopathies, TNF-alpha has been implicated in the progressive worsening of ventricular function, but the complete mechanism of its actions is poorly understood. Progressive deterioration of left ventricular function and cell death (TNF plays a role in apoptosis) are implicated as some of the mechanisms of TNF-alpha. It also directly depresses myocardial function in a synergistic manner with other interleukins.

Several interleukins have been found at elevated levels in patients with left ventricular dysfunction. Interleukin (IL)–1b has been shown to depress myocardial function. One theory is that elevated levels of IL-2R in patients with class IV CHF suggest that T lymphocytes play a role in advanced stages of heart failure. IL-6 stimulates hepatic production of C-reactive protein, which serves as a marker of inflammation. IL-6 has also been implicated in the development of myocyte hypertrophy, and its level has been found to be elevated in patients with CHF. IL-6 has been found to correlate with hemodynamic measures in persons with left ventricular dysfunction.

Frequency

United States

The true incidence of cardiomyopathies is unknown. As with other diseases, authorities depend on reported cases (at necropsy or as a part of clinical disease coding) to define the prevalence and incidence rates. The inconsistency in nomenclature and disease coding classifications for cardiomyopathies has led to collected data that only partially reflect the true incidence of these diseases. Whether secondary to improved recognition or other factors, the incidence and prevalence of cardiomyopathy appears to be increasing. The reported incidence is 400,000-550,000 cases per year, with a prevalence of 4-5 million people.

Mortality/Morbidity

Cardiomyopathy is an important cause of morbidity and mortality among the world's aging population.

Age

Cardiomyopathy is a complex disease process that can affect the heart of a person of any age.

Clinical

History

Details of specific causes of cardiomyopathies are covered within their respective articles. For example, see Cardiomyopathy, Alcoholic; Cardiomyopathy, Cocaine; Cardiomyopathy, Diabetic; Cardiomyopathy, Hypertrophic; Cardiomyopathy, Restrictive; and Cardiomyopathy, Peripartum.

One manifestation of congestive heart failure is decreased exercise tolerance, depending on the level of compensation. This leads to symptoms of shortness of breath, orthopnea, dyspnea upon exertion, and edema. However, these symptoms occur primarily in the late stages of cardiomyopathy. The clinician should pay special attention to details in the history that suggest an increased risk for developing cardiomyopathy or early stages of cardiomyopathy, such as angina, indicative family history, social history (eg, alcohol or drug use), and palpitations. Notably, atrial fibrillation and ventricular dysrhythmias may be early signs of myocardial disease.

Physical

The level of compensation (or decompensation) determines which signs are present.

• Neck
  • Jugular venous distention (as an estimate of central venous pressure)
  • Hepatojugular reflux
  • a wave
  • Large cv wave (observed with tricuspid regurgitation)
  • Goiter
• Lungs: Crackles (pulmonary rales) or signs of pleural effusion may be noted.
• Heart
  • Inspection and palpation
    • Palpate for heaves, shifted point of maximal impulse, and cardiomegaly (broad and displaced point of maximal impulse, right ventricular heave).
    • The normal apical impulse should be approximately the size of a quarter and should be located in one (fourth or fifth) intercostal space. The apical impulse is normally within 10 cm of the midsternal line. In a person with dilated cardiomyopathy, the clinician may be able to palpate an apical presystolic impulse.
    • Observe for signs of previous surgery.
  • Auscultation
    • Murmurs (with appropriate maneuvers), tachycardia, S₂ at the base (paradoxical splitting, prominent P₂), S₃, and S₄ may be noted.
    • Remember that S₃/S₄ are low-frequency sounds heard best with the bell and that a prominent pulmonic component of the S₂ audible at the apex can be misinterpreted as an S₃ if care is not taken to distinguish the frequency of the sound.
    • An irregularly irregular rhythm (atrial fibrillation) may be noted. Gallops are almost always present in persons with dilated cardiomyopathy.
• Abdomen: Percussion and palpation of the liver may reveal hepatomegaly due to elevated venous pressure, infiltrative disease, hepatojugular reflux, or ascites.
• Musculoskeletal system: Most muscular diseases can involve myocardium. Observe for cardiac cachexia, peripheral edema, cyanosis, and clubbing.

Causes

The classification of cardiomyopathy has varied over the past century. Cardiomyopathies may be simply divided into dilated or nondilated categories. Within each of these groups, the myocardium may be hypertrophic or nonhypertrophic, and it may be accompanied by a restrictive (diastolic ventricular dysfunction) and/or congestive (systolic ventricular dysfunction) physiology. This form of classification may assist in specifying a cause for a cardiomyopathy based on the predominant clinical picture. However, this classification has a significant degree of overlap compared with a specific etiology for a cardiomyopathy. For example, in ischemic cardiomyopathy, diastolic and systolic dysfunction often coexist.

Cardiomyopathy has many causes. Finding a specific cause for a cardiomyopathy is often difficult, especially when it is multifactorial. Traditionally, ischemic cardiomyopathy is listed as the most common cause of cardiomyopathy in North America and Europe.

Idiopathic cardiomyopathy is the second most common cause, although this may partially reflect undiagnosed etiologies such as infectious (viral) or toxic (ethanol-induced) cardiomyopathies. The idiopathic category should continue to diminish as more information explaining pathophysiological mechanisms, specifically genetic-environmental interactions, becomes available. Hypertensive disease is also a prime cause of cardiomyopathy in North America and Europe. Every cardiomyopathy has a cause for which the specific incidence varies with geographic location. For example, in Africa, idiopathic congestive cardiomyopathy, endomyocardial fibrosis, and rheumatic heart disease all are more prevalent than disease due to atherosclerotic coronary artery disease.

Cardiomyopathies

• Idiopathic
  • Dilated
    • Sporadic
    • Genetic (familial)
    • Mitral valve prolapse
  • Hypertrophic - With or without asymmetric septal hypertrophy
  • Nondilated, nonhypertrophic - Endomyocardial fibrosis, Löffler endocarditis
• Specific cardiomyopathies
  • Secondary to other cardiovascular disease
    • Ischemia
    • Hypertension
    • Valvular disease
    • Tachycardia induced
  • Infectious
    • Viral
    • Rickettsial
    • Bacterial
    • Metazoal
    • Protozoal
    • Probable infectious - Whipple disease, Lyme disease
  • Metabolic
    • Endocrine diseases - Hyperthyroidism, hypothyroidism, acromegaly, myxedema, hypoparathyroidism, hyperparathyroidism, other
    • Diabetes mellitus
    • Electrolyte imbalance - Potassium, phosphate, magnesium, other
    • Nutritional - Thiamine deficiency (beriberi), protein deficiency, starvation, carnitine deficiency
  • Toxic
    • Drugs
    • Poisons
    • Foods
    • Anesthetic gases
    • Heavy metals
    • Alcohol
  • Collagen vascular disease
    • Systemic lupus erythematosus
    • Rheumatoid arthritis
    • Progressive systemic sclerosis
    • Polymyositis
    • HLA-B12–associated cardiac disease
  • Infiltrative
    • Hemochromatosis
    • Amyloidosis
    • Glycogen storage disease
  • Granulomatous (sarcoidosis)
  • Physical agents
    • Extreme temperatures
    • Ionizing radiation
    • Electric shock
    • Nonpenetrating thoracic injury
  • Neuromuscular disorders
    • Muscular dystrophy - Limb-girdle (Erb dystrophy), Duchenne dystrophy, fascioscapulohumeral (Landouzy-Dejerine dystrophy)
    • Friedreich disease
    • Myotonic dystrophy
  • Primary cardiac tumor (myxoma)
  • Senile
  • Peripartum
  • Immunological
    • Postvaccination
    • Serum sickness
    • Transplant rejection
• Specific cardiomyopathies: These include cardiomyopathies of infectious origin (eg, viral cardiomyopathy). Infectious cardiomyopathies can occur as a result of bacterial, viral, rickettsial, fungal, or parasitic infection of the heart. Viral myocarditis is an important entity within the category of infectious cardiomyopathy. Viruses have been implicated in cardiomyopathies as early as the 1950s, when coxsackievirus B was isolated from the myocardium of a newborn baby with a fatal infection. Advancements in genetic analysis, such as polymerase chain reaction, have aided in the discovery of several viruses that are believed to have roles in viral cardiomyopathies.
• Viral infections and viruses associated with myocardial disease
  • Coxsackievirus (A and B)
  • Influenza virus (A and B)
  • Adenovirus
  • Echovirus
  • Rabies
  • Hepatitis
  • Yellow fever
  • Smallpox
  • Lymphocytic choriomeningitis
  • Epidemic hemorrhagic fever
  • Chikungunya fever
  • Dengue fever
  • Cytomegalovirus
  • Epstein-Barr virus
  • Rubeola
  • Rubella
  • Mumps
  • Respiratory syncytial virus
  • Varicella-zoster virus
  • Human immunodeficiency virus
• Viral myocarditis: Viral myocarditis can produce variable degrees of illness, ranging from focal disease to diffuse pancarditis involving myocardium, pericardium, and valve structures. Viral myocarditis is usually a self-limited, acute-to-subacute disease of the heart muscle that most often leads to the dilated type of cardiomyopathy. Symptoms are similar to those of CHF and often are subclinical. Many patients experience a flulike prodrome. Confirming the diagnosis can be difficult because symptoms of heart failure can occur several months after the initial infection. Patients with viral myocarditis (median age, 42 y) are generally healthy and have no systemic disease. Myocarditis is almost always a clinically presumed diagnosis because it is not associated with any pathognomonic sign or specific, acute diagnostic laboratory test result. In the past, percutaneous transvenous right ventricular endomyocardial biopsy has been used, but the Myocarditis Treatment Trial revealed no advantage for immunosuppressive therapy in biopsy-proven myocarditis, so biopsy is not routinely performed in most cases. Importantly, note that myocarditis can mimic acute myocardial infarction, with patients sometimes presenting in the emergency department with chest pain, nonspecific ECG changes, and abnormal, often highly elevated serum markers such as troponin, creatine kinase, and creatine kinase-MB.
  • Diagnosis
    • The diagnosis of viral myocarditis is mainly indicated by a compatible history and the absence of other potential etiologies, particularly if it can be confirmed with acute or convalescent sera.
    • An ECG demonstrates varying degrees of ST-T wave changes reflecting myocarditis and, sometimes, varying degrees of conduction disturbances.
    • Echocardiography is a crucial aid in classifying this disease process, which manifests mostly as a dilated type of cardiomyopathy.
    • The utility of endomyocardial biopsy is very limited. If a patient is thought to have viral myocarditis, the initial diagnostic strategies should be to evaluate cardiac troponin I or T levels and to perform antimyosin scintigraphy. Positive troponin I or T findings in the absence of myocardial infarction and the proper clinical setting confirm acute myocarditis. Negative antimyosin scintigraphy findings exclude active myocarditis.
  • Pathophysiology
    • The exact mechanism for myocardial injury in viral cardiomyopathy is controversial.
    • Several mechanisms have been proposed based on animal models. Viruses affect myocardiocytes by direct cytotoxic effects and by cell-mediated (T-helper cells) destruction of myofibers. Other mechanisms include disturbances in cellular metabolism, vascular supply of myocytes, and other immunologic mechanisms.
  • Prognosis
    • Viral myocarditis may resolve over several months during the treatment of left ventricular systolic dysfunction. However, it can progress to a chronic cardiomyopathy. The main issue in recovery is ventricular size. Reduction of ventricular size is associated with long-term improvement; otherwise, the course of the disease is characterized by progressive dilation.
    • Because of an immunologic mechanism of myocyte destruction, several trials have investigated the use of immunomodulatory medications. (Other trials are currently being conducted.) According to Mason et al in 1995, the Myocarditis Treatment Trial demonstrated no survival benefit with prednisone plus cyclosporine or azathioprine in patients with viral (lymphocytic) myocarditis.⁴⁶ Randomized trials are underway to evaluate intravenous immunoglobulin as treatment for viral myocarditis.
• Familial cardiomyopathy: Familial cardiomyopathy is a term that collectively describes several different inherited forms of heart failure.
  • Diagnosis
    • Familial dilated cardiomyopathy is diagnosed in patients with idiopathic cardiomyopathy who have 2 or more first- or second-degree relatives with the same disease (without defined etiology).
    • Establishing a diagnosis with more-distant affected relatives (third degree and greater) simply requires identifying more family members with the same disease. Genetic screening has been recommended for patients fulfilling the above criteria.
  • Pathophysiology
    • This form of cardiomyopathy has a poorly characterized etiology. Several forms have been described, and theories postulate its association with other causes of cardiomyopathy. Inheritance is autosomal dominant; however, autosomal recessive and sex-linked inheritance have been reported.
    • Several different diseased genes and chromosomal aberrations have been described in studied families. One example is associated with actin, a cardiac muscle fiber component. Other forms of familial cardiomyopathy involve a strong association with active or previous conduction system disease. As research continues, the knowledge database of etiologies for familial cardiomyopathies is likely to expand.
• Toxic cardiomyopathy (doxorubicin induced): Toxic cardiomyopathies can be difficult to diagnose. The common use of anthracyclines as antineoplastic agents and their high degree of cardiotoxicity predispose these patients to a characteristic form of dose-dependent toxic cardiomyopathy. Both an early acute cardiotoxicity and chronic cardiomyopathy have been described for these agents. Anthracyclines can also be associated with acute coronary spasm. The acute toxicity can occur at any point from the onset of exposure to several weeks after drug infusion. Radiation and other agents may potentiate the cardiotoxic effects of anthracyclines. Cardiac injury occurs even at doses below the empiric limitation of 550 mg/m². However, whether injury translates to clinical CHF varies. The development of heart failure is very rare at total doses less than 450 mg/m² but is dose dependent.
  • History: The history of these patients, in addition to classic heart failure symptoms or symptoms of acute myocarditis, involves a previous history of malignancy and treatment with doxorubicin.
  • Pathophysiology
    • Anatomically, these patients' hearts vary from having bilaterally dilated ventricles to being of normal size.
    • The mechanism of myocardial injury is related to degeneration and atrophy of myocardial cells, with loss of myofibrils and cytoplasmic vacuolization. The generation of free radicals by doxorubicin has also been implicated.
  • Prognosis: Progressive deterioration is the norm for this toxic cardiomyopathy.
  • Prevention
    • Prevention is based on limiting dosing after 450 mg/m² and on serial functional assessments (ie, resting and exercise evaluation of ejection fraction).
    • The drug should be discontinued if the ejection fraction is less than 0.45, if it falls by more than 0.05 from baseline, or if it fails to increase by more than 0.05 with exercise.
    • Dexrazoxane is an iron-chelating agent approved to reduce toxicity; however, it increases the risk of severe myelosuppression.
• Cardiomyopathy associated with collagen-vascular disease: Several collagen-vascular diseases have been implicated in the development of cardiomyopathies. These include rheumatoid arthritis, systemic lupus erythematosus, progressive systemic sclerosis, and polymyositis. Diagnosis is based on identification of the underlying disease in conjunction with appropriate clinical findings of heart failure.
• Granulomatous cardiomyopathy (sarcoidosis): Endomyocardial biopsy may be helpful in establishing the diagnosis, especially in sarcoidosis in which the myocardium may be involved. Involvement may be patchy, resulting in a negative biopsy finding. The diagnosis can also be made if some other tissue diagnosis is possible or available in conjunction with the appropriate clinical picture for heart failure. The following discussion concentrates on cardiomyopathy associated with sarcoidosis. Cardiac involvement in sarcoidosis reportedly occurs in approximately 20% of cases.
  • History
    • Patients have signs and symptoms of sarcoidosis and CHF. Patients rarely present with CHF without evidence of systemic sarcoid.
    • Look for bilateral mediastinal, paratracheal, and/or hilar lymphadenopathy.
  • Pathophysiology
    • Noncaseating granulomatous infiltration of the myocardium occurs as with other organs affected by this disease.
    • Sarcoid granulomas can show a localized distribution within the myocardium. The granulomas particularly affect the conduction system of the heart, left ventricular free wall, septum, papillary muscles, and, infrequently, heart valves.
    • Fibrosis and thinning of the myocardium occurs as a result of the infiltrative process affecting the normal function of the myocardium.
  • Diagnosis
    • Diagnosis involves finding noncaseating granulomas from cardiac biopsy or other tissues.
    • Often, patients present with conduction disturbances or ventricular arrhythmias. In fact, in patients with normal left ventricular function, these conduction disturbances may be the primary clinical feature.
  • Prognosis
    • Treatment of cardiac sarcoidosis with low-dose steroids may be beneficial, especially in patients with progressive disease, conduction defects, or ventricular arrhythmias.
    • The true benefit is unknown because of the lack of placebo-controlled studies. This also holds true for the use of other immunosuppressive agents (eg, chloroquine, hydroxychloroquine, methotrexate) in the treatment of cardiac sarcoidosis.
• Carnitine deficiency: A carnitine transporter defect is characterized by severely reduced transport of carnitine into skeletal muscle, fibroblasts, and renal tubules. All children with dilated cardiomyopathy or hypoglycemia and coma should be evaluated for this transporter defect because it is readily amenable to therapy, which results in prolonged prevention of cardiac failure. The prognosis for long-term survival in pediatric dilated cardiomyopathy is poor.
• Tachycardia-induced cardiomyopathy: Generally, this type of cardiomyopathy is reversible once treatment of the tachycardia is successful. Persistent tachycardia is known to lead to myocyte dysfunction and cardiomyopathy. The exact mechanisms by which tachycardia affects cell function are poorly understood. The following are possible mechanisms by which myocyte dysfunction arises from tachycardia:
  • Depletion of energy stores
  • Abnormal calcium channel activity
  • Abnormal subendocardial oxygen delivery secondary to abnormalities in blood flow
  • Reduced responsiveness to beta-adrenergic stimulation

Differential Diagnoses

Other Problems to Be Considered

Alcohols
Amphetamine toxicity
Collagen-vascular disorders
Congestive heart failure
Ischemic and hypertensive heart disease
Neuromuscular disorders
Other drugs (emetine, doxorubicin, cobalt)
Thyroid hormone toxicity

Workup

Laboratory Studies

• Laboratory testing should be directed to evaluating a specific cause. Recent data have shown that the measurement of plasma BNP is sensitive and specific in diagnosing heart failure. Serum markers for myocardial necrosis (eg, troponin, creatine kinase, creatine kinase-MB) may be acutely elevated in persons with myocarditis.
  • Hyponatremia signifies a poor prognosis.
  • An elevated creatinine level may represent a primary or drug-related etiology (eg, hypovolemia, azotemia from ACE inhibitors).
  • A low bicarbonate level is a poor prognostic sign.
  • Contraction alkalosis can be observed secondary to diuretic therapy.
  • Magnesium levels should be closely followed because low levels may cause chronic hypokalemia.
• Liver function test results can be elevated, which may suggest alcoholic disease, hemochromatosis, hepatic congestion (nutmeg liver), and/or infarction in inotrope-dependent CHF.
• CBC count
  • Investigate any cause of anemia.
  • Treat iron deficiency anemia.
  • ACE inhibitors can cause leukopenia.
• Cardiac enzymes
  • Cardiac enzymes are useful for assessing acute or recent myocardial injury.
  • Levels are markedly elevated in persons with muscular dystrophy.
• Thyroid function tests
• Urine pregnancy test
• Urine toxicology screen

Imaging Studies

• Radiography
  • Assess for enlargement and configuration of the cardiac silhouette. A study investigating the specificity and sensitivity of physical and laboratory findings in patients with dyspnea in the emergency department suggests that cardiomegaly is one of the most sensitive and specific signs in diagnosing cardiomyopathies.
  • Remember that patients with left ventricular hypertrophy and pericardial effusion can also present with an enlarged cardiac silhouette.
  • Pulmonary vascular congestion may be observed.
    • Hilar vessels may appear more concave, with prominent vasculature of the upper lung fields.
    • Kerley B lines may be present.
    • Pleural effusion usually occurs first on the right side, but it can be bilateral.
    • Abnormal calcifications may be valvular, atherosclerotic, or pericardial in nature.
    • Congenital malformations may be noted.
• Echocardiography
  • Echocardiography has become one of the most useful and most efficient diagnostic modalities in attaining a diagnosis and classification of cardiomyopathy.
  • Two-dimensional echocardiography allows for assessment of overall function. M-mode assists in measurement of chamber sizes (end-diastolic left ventricular dimensions are usually >65 mm in persons with dilated cardiomyopathy) and wall thickness. (Hypertrophy is defined as posterior wall or septal thickness >11 mm, although this guideline is not absolute and must be viewed in the context of cavity size.)
  • Doppler facilitates the measurement and assessment of flow and valvular pathologies. It also allows for measurements of diastolic and systolic dynamics.
    • The physician must look for the reversal of the E wave–to–A wave ratio (E/A) when evaluating left ventricular filling and pulmonary venous flow by Doppler during left atrial filling. This suggests decreased compliance, which should be viewed in the context of whether the myocardium is dilated, hypertrophied, or both. For example, a restrictive process would show E/A reversal and normal-to-moderately enlarged cavitary dimensions. More recently, tissue Doppler interrogation has been used in many cardiac ultrasound laboratories; this modality measures the velocity of portions of the heart wall, most often the left ventricular basilar annular area. Just as in the blood velocity parameters of E and A amplitudes, similar measurements of wall velocity, E' and A' are made, and a reversal of the E'/A' amplitude signifies likely diastolic dysfunction.
    • Segmental wall motion abnormalities may suggest an ischemic etiology for the cardiomyopathy, but these abnormalities are not limited to this common cause, which can often be observed in association with other forms of cardiomyopathy.
    • Echocardiography is also useful in providing information about myocardial texture and surrounding structures. Pericardial effusion can be easily excluded or characterized using this imaging modality.
• Cardiovascular magnetic resonance/magnetic resonance imaging
  • MRI with gadolinium-DTPA has been used to evaluate the extent of mid-wall fibrosis, which may correlate with risk of arrhythmias and failure to respond to treatment. Further investigation is ongoing in the role that subendocardial sparing mid-wall fibrosis plays in the pathogenicity of arrhythmias.
  • In the future, MRI with gadolinium may be used for the risk stratification of patients with dilated cardiomyopathy; and in the criteria for automatic implantable cardioverter-defibrillator placement.

Other Tests

• Electrocardiography
  • Nonspecific ST-T wave changes and Q waves are characteristic.
  • Atrial fibrillation or premature ventricular complexes are noted.
  • Left ventricular hypertrophy or other chamber enlargement is observed.
  • Conduction delay, particularly left bundle-branch block, can be observed.
  • Varying degrees of atrioventricular block are noted.
• Oxygen consumption testing
  • Oxygen consumption per minute (VO₂) maximum of less than 14 mL/kg/min signifies a poor prognosis.
  • Give early consideration to heart transplantation.

Procedures

• Right-sided heart catheterization
  • Right-sided heart catheterization (RHC) can be beneficial in initially determining the volume status of a patient with equivocal clinical signs and symptoms of heart failure.
  • RHC in a person with dilated cardiomyopathy demonstrates elevated filling pressures (central venous pressure, pulmonary artery wedge pressure, right ventricular end-diastolic pressure) and decreased cardiac output.
  • In a person with restrictive cardiomyopathy, RHC demonstrates a pattern in the ventricular hemodynamic tracing referred to as the "square root sign" or "dip-and-plateau pattern." This pattern is similar to that observed in patients with constrictive pericarditis. The difference between the two is suggested by 2 findings.
    • In a person with restrictive cardiomyopathy, the left ventricular end-diastolic pressure generally exceeds the right ventricular end-diastolic pressure by 6 mm Hg or more.
    • In a person with restrictive cardiomyopathy, the entire diastolic filling period is abnormal. This is in contrast to constrictive pericarditis, which is associated with normal or increased early filling (see Cardiomyopathy, Restrictive).
• Left-sided heart catheterization
  • The risks and costs of cardiac catheterization should be considered before RHC or left-sided heart catheterization. Little additional prognostic information can be obtained from cardiac catheterization that cannot be obtained from echocardiography.
  • Consider whether the study outcome will influence treatment of the patient (eg, patients with ischemic etiologies). The utility of cardiac catheterization in a person with dilated cardiomyopathy is very limited and should be undertaken only when a strong likelihood of an ischemic etiology (eg, Q waves with systolic dysfunction, angina, positive imaging stress test finding) is present.
• Endomyocardial biopsy
  • The utility of endomyocardial biopsy is limited. In many cases of cardiomyopathy, it is class II (uncertain efficacy and may be controversial) or class III (generally not indicated). The exception to this is in cardiac transplant recipients, in whom routine periodic assessment of transplant rejection is necessary.
  • Class II indications for endomyocardial biopsy include the following:
    • Recent onset of rapidly deteriorating cardiac function
    • Patients receiving chemotherapy with doxorubicin
    • Patients with systemic diseases with possible cardiac involvement (eg, Hemochromatosis, sarcoidosis, amyloidosis, Löffler endocarditis, endomyocardial fibroelastosis)
  • Evidence does not indicate a benefit for performing myocardial biopsy when evaluating patient survival based on current therapies.

Histologic Findings

Findings may include myocardial injury with inflammatory mediators (eg, macrophage derived, antibody/complement). Physical disruption of myocytes by inflammatory cells, proliferation of interstitial cells, and increased fibrous matrix may also be found.

Lymphocytic myocarditis is the most common finding in human cardiac tissue biopsy specimens. Myocyte necrosis, degeneration, or both with adjacent inflammatory infiltrate may be present. Significant coronary artery disease may be present. A predominance of lymphocytes and some monocytes without significant eosinophils may be present. Lymphocytic myocarditis is likely related to viral or other infections.

Eosinophilic myocarditis, sometimes called Löffler or Loeffler myocarditis, is usually due to the effects of a drug allergy. Perivascular infiltrates with eosinophil predominance, lymphocytes, and macrophages may be present. Eosinophilic myocarditis usually occurs with peripheral eosinophilia, rash, and/or fever.

Giant cell myocarditis is a rare condition usually associated with systemic illnesses such as infections (eg, tuberculosis, endocarditis, fungi, syphilis, leprosy), rheumatologic illnesses (eg, rheumatoid arthritis, lupus, vasculitides, polymyositis, dermatomyositis), gastrointestinal conditions (eg, Crohn disease, ulcerative colitis, chronic hepatitis), autoantibody-associated conditions (eg, myasthenia gravis, Hashimoto thyroiditis), or sarcoidosis. Giant cell myocarditis is often associated with conduction abnormalities and may progress rapidly. Necrotizing or nonnecrotizing granulomas are found, often with eosinophilia. T-cell infiltrates have been documented, and anti-CD3 antibody therapy may be effective. The idiopathic type is most often progressive and may require cardiac transplantation. Patients are usually young and present with heart failure or ventricular arrhythmias.

Peripartum myocarditis may be a variant of lymphocytic myocarditis and worsens during pregnancy.

In AIDS-related myocarditis, inflammatory infiltrates are observed in cardiac tissue, usually consisting of CD8⁺ T lymphocytes.

Staging

Classic staging of heart failure is based on the New York Heart Association (NYHA) system. The following is a new approach to the classification of heart failure:

• Stage A (high risk for developing heart failure) - Hypertension, coronary artery disease, diabetes mellitus, family history of cardiomyopathy
• Stage B (asymptomatic heart failure) - Previous myocardial infarction, left ventricular systolic dysfunction, asymptomatic valvular disease
• Stage C (symptomatic heart failure) - Structural heart disease, dyspnea, fatigue, reduced exercise tolerance
• Stage D (refractory end-stage heart failure) - Marked symptoms at rest despite maximal medical therapy, recurrent hospitalizations

Treatment

Medical Care

CHF is a complex clinical syndrome for which many treatment modalities have emerged. Research into the biochemical alterations that occur in persons with cardiomyopathies has led to the development of many medications designed to affect these alterations. The medications available for the treatment of heart failure and the key clinical trials supporting their use are reviewed in Medication. Features of therapeutic interventions vary, ie, some elements may treat symptoms, whereas others may treat factors that affect survival.

Surgical Care

Various surgical options are available for patients with disease refractory to medical therapy. The following new surgical therapies are evolving for patients with end-stage heart disease:

• Left ventricular assist devices
  • Portable electric left ventricular assist devices have been proven as the standard of care when a bridge to transplantation is needed.
  • Left ventricular assist devices are being evaluated as permanent implantations in patients who are not candidates for heart transplantation (ie, "destination therapy"). Current limitations include high infection rates and mechanical malfunction.
• Endoventricular circular patch-plasty (Dor procedure): This is for patients with ischemic cardiomyopathy with dyskinetic, aneurysmal, or akinetic left ventricle walls
• Partial left ventriculectomy (Batista procedure) for idiopathic dilated cardiomyopathy
  • Reducing the left ventricular diameter (Laplace law) in patients with dilated cardiomyopathy is thought to improve ventricular function.
  • In a study at a Cleveland clinic, partial left ventriculectomy was performed on 120 patients with end-stage dilated cardiomyopathies of varying causes. The authors concluded that partial left ventriculectomy can be used to treat end-stage dilated cardiomyopathy, but further studies and a longer follow-up period are needed to fully assess the effects of this procedure.
• Heart transplantation
  • Absolute indications are as follows:
    • Refractory cardiogenic shock
    • Dependence on intravenous inotropes for organ perfusion
    • Peak VO₂ less than 10 mL/kg/min with achievement of anaerobic threshold
    • Severe ischemia not amenable to any intervention
    • Symptomatic ventricular arrhythmias refractory to all therapies
  • Relative indications are as follows:
    • Peak VO₂ of 11-14 mL/kg/min (or <50-55% predicted for age and sex) and major limitation of daily activity
    • Recurrent instability of CHF not due to noncompliance or suboptimal medical therapy
• Cardiac resynchronization therapy (biventricular pacing)
  • Pacing solutions for dyssynchrony are as follows:
    • Confirmed benefit based on studies from the mid 1990s - Acute functional improvements with cardiac resynchronization therapy; multiple studies confirm symptomatic benefits. A recent trial showed that cardiac resynchronization therapy reduced mortality and hospitalization rates compared to those achieved with optimal medical therapy.¹
    • Lead positioning - Atrial lead, right ventricular lead, coronary sinus lead
    • Resynchronization pacing generators have defibrillation capabilities.
  • Current indications for cardiac resynchronization therapy are as follows:
    • NYHA class III or IV heart failure and intraventricular conduction delay
    • Patients who are symptomatic despite optimal medical therapy with ACE inhibitors, beta-blockers, and/or other appropriate pharmacologic measures
• Automatic implanted cardioverter-defibrillators
  • Automatic implanted cardioverter-defibrillators (AICDs) monitor for malignant rhythms and treat patients if programmed to do so.
  • AICDs are designed to treat ventricular tachycardia/ventricular fibrillation with appropriate therapy. Programmable therapies include antitachycardia pacing for ventricular tachycardia and/or defibrillatory shocks when appropriate.
  • Indications for implantation continue to evolve, and the patient populations eligible for AICDs continue to expand. Current recommendations include patients who are clearly at high risk for ventricular arrhythmias and sudden cardiac death. Those with moderately severe left-sided ventricular dysfunction account for a significant proportion of these patients.
  • The most recent AICD trials (ie, Multicenter Automatic Defibrillator Implantation Trial II [MADIT II], Sudden Cardiac Death in Heart Failure Trial [SCD-HeFT]) have defined a clear mortality benefit in patients with a history of significant left-sided ventricular dysfunction. As reported by Moss in 1996² and 2000³ , updated guidelines published by the American College of Cardiology and the American Heart Association have made MADIT II criteria for AICD implantation class IIa indications.

Consultations

• Refer patients to a heart failure specialist.
• Patients with familial dilated cardiomyopathy can register with the Familial Dilated Cardiomyopathy registry. Contact information is as follows:

  Familial Dilated Cardiomyopathy Project Group
  Oregon Health Sciences University
  Portland, OR 97201
  (Toll free) (877) 800-3430
  fdcgroup@mail.fdc

Diet

The importance of patient education cannot be overemphasized, especially regarding dietary restrictions.

• Dietary recommendations include sodium and water restrictions.
  • An average American diet contains 6 g/d of salt. Avoiding extra table salt decreases this intake to 3 g/d.
  • Patients with CHF should restrict their salt intake to less than 2-4 g/d.
• Fluid restriction is only necessary in very late stages of the disease.
• Patients with hyperkalemia due to ACE inhibitor therapy sometimes respond to a low-potassium diet.

Activity

• Encourage patients to exercise moderately because deconditioning is a very common cause of dyspnea.
• Cardiac rehabilitation has been shown to improve patient outcomes.

Medication

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Angiotensin-converting enzyme (ACE) inhibitors

Use of ACE inhibitors (in the absence of contraindications to ACE inhibition) is the current criterion standard in the treatment of left ventricular dysfunction. Multiple trials support the use of these agents.

ACE inhibitors have been shown to decrease mortality rates in both symptomatic and asymptomatic patients with left ventricular dysfunction and to reduce readmissions caused by heart failure. The absolute benefits are greater in patients with severe heart failure.

The dosage necessary for maximal benefit is debatable. One study that investigated low- and high-dose lisinopril found no significant difference in mortality rates, although it did find a difference in a combined endpoint of rehospitalization and death in favor of high-dose lisinopril.
 
A 1998 study by van Veldhuisen et al examined high- and low-dose ACE inhibition using imidapril and demonstrated improved exercise capacity and decreased levels of neurohormonal markers of CHF (ANP and BNP).⁴ Authorities have generally accepted that maximizing ACE inhibitor therapy is important and should be accomplished in conjunction with other necessary therapies.

ACE inhibitor trials

• Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS) (enalapril vs placebo) - Reduced mortality rate in severe left ventricular dysfunction
• Studies of Left Ventricular Dysfunction (SOLVD) (enalapril vs placebo) - Reduced mortality rate and hospitalizations for heart failure⁵
• Vasodilator Heart Failure Trial II (VHeFT II) (enalapril vs hydralazine plus isosorbide dinitrate) - Improved survival better than combined treatment with hydralazine and isosorbide dinitrate
• Assessment of Treatment with Lisinopril and Survival in Heart Failure (ATLAS) (lisinopril [low and high dose]) - Insignificant trend toward reduced mortality rate with high-dose lisinopril and significant reduction in hospitalization⁶
• Survival and Ventricular Enlargement (SAVE) (captopril vs placebo) - Decreased mortality rate, progression of disease, and recurrent myocardial ischemia⁷

Enalapril (Vasotec)

Prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in increased levels of plasma renin and a reduction in aldosterone secretion.

Helps control blood pressure and proteinuria. Decreases pulmonary-to-systemic flow ratio in the catheterization laboratory and increases systemic blood flow in patients with relatively low pulmonary vascular resistance. Has favorable clinical effect when administered over a long period. Helps prevent potassium loss in distal tubules. Body conserves potassium; thus, less oral potassium supplementation needed.

Dosing

Adult

2.5-5 mg/d PO (increase as necessary)
Dosing range: 10-40 mg/d PO in 1-2 divided doses
Alternatively, 1.25 mg/dose IV over 5 min q6h

Pediatric

Not established

Interactions

NSAIDs may reduce hypotensive effects of enalapril; ACE inhibitors may increase digoxin, lithium, and allopurinol levels; rifampin decreases enalapril levels; probenecid may increase enalapril levels; the hypotensive effects of ACE inhibitors may be enhanced when given concurrently with diuretics

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution in renal impairment, valvular stenosis, or severe congestive heart failure; IV formulation not recommended in managing neonatal hypertension because of risk of acute renal failure and oliguria

Lisinopril (Prinivil, Zestril)

Prevent conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in increased levels of plasma renin and a reduction in aldosterone secretion.

Dosing

Adult

10 mg/d PO qd or divided bid; increase by 5-10 mg/d at 1- to 2-wk intervals; not to exceed 80 mg/d

Pediatric

Not established

Interactions

NSAIDs may reduce hypotensive effects of lisinopril; ACE inhibitors may increase digoxin, lithium, and allopurinol levels; rifampin decreases lisinopril levels; probenecid may increase lisinopril levels; the hypotensive effects of ACE inhibitors may be enhanced when given concurrently with diuretics

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution in renal impairment, valvular stenosis, or severe congestive heart failure

Ramipril (Altace)

Prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in increased levels of plasma renin and a reduction in aldosterone secretion.

Dosing

Adult

2.5 mg PO bid initially; titrate up to 5 mg bid, when possible

Pediatric

Not established

Interactions

NSAIDs may reduce hypotensive effects of ramipril; ACE inhibitors may increase digoxin, lithium, and allopurinol levels; rifampin decreases ramipril levels; probenecid may increase ramipril levels; the hypotensive effects of ACE inhibitors may be enhanced when given concurrently with diuretics

Contraindications

Documented hypersensitivity; history of angioedema

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution in renal impairment, valvular stenosis, or severe congestive heart failure

Beta-adrenergic blocking agents

Previously believed to be contraindicated in patients with left ventricular dysfunction, this class of medications has moved to the forefront of heart failure treatment. Several trials have shown that beta-blockers are both safe and effective in the treatment persons with any class of heart failure.

General guidelines for initiating beta-blocker therapy include treating all patients with left ventricular dysfunction except those who are acutely decompensated. Therapy should be initiated at low dosages, which should be increased gradually over several weeks. Patients' conditions may deteriorate over the short term, but they generally improve in the long term with continued therapy.

Carvedilol, bisoprolol, and metoprolol CR/XL are the only agents currently approved by the US Food and Drug Administration for use in persons with heart failure. Head-to-head studies (Carvedilol or Metoprolol European Trial [COMET], carvedilol vs metoprolol) indicated that carvedilol (a beta-1, alpha, and beta-2 receptor blocker), improved survival and cardiovascular hospitalizations more than the beta-1 selective beta-blocker metoprolol tartrate.⁸

Beta-blocker trials*

• US Carvedilol Heart Failure Study Group from 1996
• Cardiac Insufficiency Bisoprolol Study II (CIBIS II) from 1999 (bisoprolol vs placebo), NYHA class III-IV - Reduced mortality and hospitalization rates⁹
• Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF) from 2000 (metoprolol CR/XL vs placebo), NYHA class II-IV - Reduced mortality and hospitalization rates and improved NYHA functional class¹⁰
• Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) from 2000 (carvedilol vs placebo) - Terminated because of a significant reduction in mortality¹¹

*All trials in addition to standard therapy for heart failure

Carvedilol (Coreg)

Blocks beta1-, alpha-, and beta2-adrenergic receptor sites, decreasing adrenergic-mediated myocyte damage.

Dosing

Adult

3.125 mg PO qd/bid; titrate q2wk to 50 mg bid

Pediatric

Not established

Interactions

May increase potassium in combination with ACE inhibitors; aluminum salts, barbiturates, calcium salts, cholestyramine, NSAIDs, penicillins, and rifampin may decrease bioavailability and plasma levels, possibly resulting in decreased effect; haloperidol, hydralazine, loop diuretics, and MAOIs may increase levels

Contraindications

Documented hypersensitivity; cardiogenic shock, pulmonary edema, bradycardia, AV block, uncompensated CHF, reactive airway disease, severe bradycardia

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Lower response rate and higher frequency of toxicity may be observed in elderly patients

Metoprolol (Lopressor)

Selective beta1-adrenergic receptor blocker that decreases automaticity of contractions. During IV administration of metoprolol, carefully monitor blood pressure, heart rate, and ECG.

Dosing

Adult

6.25 mg PO; gradually increase to 50 mg bid or as tolerated

Pediatric

Not established

Interactions

Aluminum salts, barbiturates, NSAIDs, penicillins, calcium salts, cholestyramine, and rifampin may decrease bioavailability and plasma levels, possibly resulting in decreased pharmacologic effects; toxicity may increase with coadministration of sparfloxacin, phenothiazines, astemizole, calcium channel blockers, quinidine, flecainide, and contraceptives; may increase toxicity of digoxin, flecainide, clonidine, epinephrine, nifedipine, prazosin, verapamil, and lidocaine

Contraindications

Documented hypersensitivity; uncompensated CHF, bradycardia, cardiogenic shock, AV conduction abnormalities; asthma

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Beta-adrenergic blockade may reduce signs and symptoms of acute hypoglycemia and may decrease clinical signs of hyperthyroidism; abrupt withdrawal may exacerbate symptoms of hyperthyroidism, including thyroid storm; monitor patient closely and withdraw drug slowly

Bisoprolol (Zebeta)

Selective beta1-adrenergic receptor blocker that decreases automaticity of contractions.

Dosing

Adult

2.5 mg PO qd; may increase to 10 mg and then to 20 mg qd if necessary; not to exceed 40 mg/d

Pediatric

Not established

Interactions

Aluminum salts, barbiturates, NSAIDs, penicillins, calcium salts, cholestyramine, and rifampin may decrease bioavailability and plasma levels of metoprolol, possibly resulting in decreased pharmacologic effects; toxicity of metoprolol may increase with coadministration of sparfloxacin, phenothiazines, astemizole, calcium channel blockers, quinidine, flecainide, and contraceptives; metoprolol may increase toxicity of digoxin, flecainide, clonidine, epinephrine, nifedipine, prazosin, verapamil, and lidocaine

Contraindications

Documented hypersensitivity; uncompensated congestive heart failure, bradycardia, asthma, cardiogenic shock, and A-V conduction abnormalities

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Beta-adrenergic blockade may reduce signs and symptoms of acute hypoglycemia and may decrease clinical signs of hyperthyroidism; abrupt withdrawal may exacerbate symptoms of hyperthyroidism, including thyroid storm; monitor patient closely and withdraw the drug slowly; during IV administration, carefully monitor blood pressure, heart rate, and ECG

Aldosterone antagonists

Spironolactone is complementary to standard therapy in modulating the RAAS because aldosterone levels remain elevated despite ACE inhibitor therapy. Spironolactone is currently indicated for treating patients with moderate-to-severe heart failure (NYHA class III-IV) in addition to ACE inhibitors, beta-blockers, diuretics, and digoxin. Aldosterone antagonist therapy should be used with great caution in patients with serum potassium levels >5 mmol/L or those with serum creatinine levels >2.5 mg/dL. Whether mortality is more significantly lowered by reduction and reversal of fibrosis or by maintenance of potassium/magnesium tissue levels is unclear.

Aldosterone antagonist trials

• Randomized Aldactone Evaluation Study (RALES) (spironolactone vs placebo),  NYHA class III-IV - Ejection fraction of <0.35; 38% reduction in death and risk of hospitalization; significant improvement in NYHA functional class
• Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) (eplerenone vs placebo) - Patients with ejection fraction <40% postmyocardial infarction and either clinical symptoms of decompensated heart failure or diabetes; addition of eplerenone resulted in a 15% reduction in all-cause mortality, a 17% reduction in CV mortality, and the combined primary endpoint of CV mortality and CV hospitalization was reduced by 13%. The beneficial effects of eplerenone were consistent across patient subgroups.¹²

Eplerenone (INSPRA)

Selectively blocks aldosterone at the mineralocorticoid receptors in epithelial (eg, kidney) and nonepithelial (eg, heart, blood vessels, and brain) tissues; thus, decreases blood pressure and sodium reabsorption. Indicated to improve survival for congestive heart failure or left ventricular dysfunction following acute MI. Compared to placebo, a significant risk reduction (15%) was observed.

Dosing

Adult

25 mg PO qd initially, titrate as tolerated up to 50 mg/d within 4 wk

Pediatric

Not established

Interactions

CYP450 3A4 substrate; potent CYP3A4 inhibitors (eg, ketoconazole) increase serum levels about 5-fold; less potent CYP3A4 inhibitors (eg, erythromycin, saquinavir, verapamil, fluconazole) increase serum levels about 2-fold; grapefruit juice increases serum levels about 25%; coadministration with potassium supplements, salt substitutes, or drugs known to increase serum potassium (eg, amiloride, spironolactone, triamterene, ACE inhibitors, angiotensin II inhibitors) increases risk of hyperkalemia

Contraindications

Documented hypersensitivity; hyperkalemia or coadministration with drugs causing increased potassium; type 2 diabetes with microalbuminuria; moderate-to-severe renal insufficiency (eg, CrCl <50 mL/min or serum creatinine >2 mg/dL in males, or >1.8 mg/dL in females)

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

May cause hyperkalemia, headache, and dizziness; caution with hepatic insufficiency

Spironolactone (Aldactone)

For management of edema resulting from excessive aldosterone excretion. Competes with aldosterone for receptor sites in distal renal tubules, increasing water excretion while retaining potassium and hydrogen ions.

Dosing

Adult

12.5-25 mg/d PO

Pediatric

1.5-3.5 mg/kg/d PO in divided doses q6h

Interactions

May decrease effect of anticoagulants; potassium and potassium-sparing diuretics may increase toxicity

Contraindications

Documented hypersensitivity; anuria, renal failure, hyperkalemia

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution in renal and hepatic impairment

Cardiac glycosides

Digoxin therapy for heart failure has no benefit on mortality rates. However, it does improve NYHA functional class, hemodynamics, symptoms, exercise capacity, and quality of life and reduces hospitalizations for heart failure. Patients with worse NYHA functional class and lower left ventricular ejection fraction benefit most from digoxin therapy.

Digoxin (Lanoxin)

Cardiac glycoside with direct inotropic effects in addition to indirect effects on the cardiovascular system. Acts directly on cardiac muscle, increasing myocardial systolic contractions. Indirect actions result in increased carotid sinus nerve activity and enhanced sympathetic withdrawal for any given increase in mean arterial pressure.

Dosing

Adult

0.125-0.25 mg IV or PO qd as indicated

Pediatric

8-50 mcg/kg IV based on age and ideal body weight

Interactions

Medications that may increase levels include alprazolam, benzodiazepines, bepridil, captopril, cyclosporine, propafenone, propantheline, quinidine, diltiazem, aminoglycosides, oral amiodarone, anticholinergics, diphenoxylate, erythromycin, felodipine, flecainide, hydroxychloroquine, itraconazole, nifedipine, omeprazole, quinine, ibuprofen, indomethacin, esmolol, erythromycin, clarithromycin, tetracycline, tolbutamide, and verapamil
Medications that may decrease serum levels include aminoglutethimide, antihistamines, metoclopramide, cholestyramine, neomycin, penicillamine, aminoglycosides, oral colestipol, hydantoins, hypoglycemic agents, antineoplastic treatment combinations (including carmustine, bleomycin, methotrexate, cytarabine, doxorubicin, cyclophosphamide, vincristine, and procarbazine), aluminum or magnesium antacids, rifampin, sucralfate, sulfasalazine, barbiturates, kaolin/pectin, and aminosalicylic acid

Contraindications

Documented hypersensitivity; beriberi heart disease, idiopathic hypertrophic subaortic stenosis, constrictive pericarditis, carotid sinus syndrome

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Hypokalemia (<2) may reduce positive inotropic effect; IV calcium may produce arrhythmias in digitalized patients; hypercalcemia predisposes patient to digitalis toxicity, and hypocalcemia can make digoxin ineffective until serum calcium levels are normal; magnesium replacement therapy must be instituted in patients with hypomagnesemia to prevent digitalis toxicity; patients with incomplete AV block may progress to complete block when treated with digoxin; caution in hypothyroidism, hypoxia, and acute myocarditis; impaired renal function prolongs half-life

Diuretics

Reserved for congestive states and are not indicated for daily use for patients who are in NYHA functional class I or II (and even some class III patients). Patients can effectively adjust their diuretic use by weighing themselves at home. If patients have a 3- to 5-lb weight gain in 1-7 d, they should be advised to double their diuretic dose and potassium supplement for 1 d. Additional treatment should be based on the effectiveness of this increased dose to reduce weight or symptoms. Agents such as metolazone, hydrochlorothiazide, and acetazolamide may be used to augment effects of loop diuretics.

Furosemide (Lasix)

Increases excretion of water by interfering with chloride-binding cotransport system, which, in turn, inhibits sodium and chloride reabsorption in ascending loop of Henle and distal renal tubule. Bioavailability of PO furosemide is 50%. If switch is made from IV to PO, an equivalent PO dose should be used. Doses vary depending on clinical condition.

Dosing

Adult

20-80 mg/d PO/IV/IM; titrate not to exceed 1 g/d

Pediatric

2 mg/kg/d PO

Interactions

Metformin decreases concentrations; interferes with hypoglycemic effect of antidiabetic agents and antagonizes muscle-relaxing effect of tubocurarine; auditory toxicity appears to be increased with coadministration of aminoglycosides; hearing loss of varying degrees may occur; anticoagulant activity of warfarin may be enhanced when taken concurrently; increased plasma lithium levels and toxicity are possible when taken concurrently

Contraindications

Documented hypersensitivity; hepatic coma, anuria, state of severe electrolyte depletion

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Perform frequent serum electrolyte (may increase urinary excretion of magnesium and calcium), carbon dioxide, glucose, creatinine, uric acid, calcium, and BUN determinations during first few months of therapy and periodically thereafter (observe for blood dyscrasias and liver or kidney damage)

Bumetanide (Bumex)

Increases excretion of water by interfering with chloride-binding cotransport system, which, in turn, inhibits sodium and chloride reabsorption in ascending loop of Henle. Does not appear to act in distal renal tubule.

Dosing

Adult

0.5 mg PO/IV, titrate not to exceed 2 mg/d, usually given as a once daily dose

Pediatric

Not established

Interactions

Decreases effects of indomethacin and probenecid; may increase lithium toxicity

Contraindications

Documented hypersensitivity; anuria, increasing azotemia

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Profound diuresis with fluid and electrolyte loss may occur; caution in hepatic failure

Ethacrynic acid (Edecrin)

Increases excretion of water by interfering with chloride-binding cotransport system, which, in turn, inhibits sodium and chloride reabsorption in ascending loop of Henle and distal renal tubule.
Use only in refractory cases. Continuous IV infusion is preferable in many cases.
Indicated for temporary treatment of edema associated with heart failure when greater diuretic potential is needed.

Dosing

Adult

50 mg IV; titrate, not to exceed 200 mg bid

Pediatric

Not established

Interactions

Metformin decreases concentrations; interferes with hypoglycemic effect of antidiabetic agents and antagonizes muscle-relaxing effect of tubocurarine; auditory toxicity appears to be increased with coadministration of aminoglycosides; hearing loss of varying degrees may occur; anticoagulant activity of warfarin may be enhanced when taken concurrently; increased plasma lithium levels and toxicity are possible when taken concurrently

Contraindications

Documented hypersensitivity; hepatic coma, anuria, state of severe electrolyte depletion

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Perform frequent serum electrolyte, carbon dioxide, glucose, creatinine, uric acid, calcium, and BUN determinations during first few months of therapy and periodically thereafter

Antiarrhythmics

Useful in patients with supraventricular and nonsustained ventricular tachycardias. Not all antiarrhythmics are considered safe in patients with structural heart disease. The Cardiac Arrhythmia Suppression Trial (CAST) 1 and 2 implicated class IC agents as causing increased mortality in this population. Similarly, the Survival With Oral d-Sotalol (SWORD) trial reported increased total and cardiac mortality in patients after myocardial infarction with a reduced left ventricular ejection fraction when treated with oral d-sotalol. The class III antiarrhythmics amiodarone and dofetilide are favored in these patients for the treatment of supraventricular and ventricular dysrhythmias.

Amiodarone (Cordarone)

May inhibit AV conduction and sinus node function. Prolongs action potential and refractory period in myocardium and inhibits adrenergic stimulation. Has been shown in select studies to improve mortality rates in patients with cardiomyopathy.

Dosing

Adult

Variable dosing

Pediatric

Not established

Interactions

Increases effect and blood levels of theophylline, quinidine, procainamide, phenytoin, methotrexate, flecainide, digoxin, cyclosporine, beta-blockers, and anticoagulants; cardiotoxicity increased by ritonavir, sparfloxacin, and disopyramide; coadministration with calcium channel blockers may cause an additive effect and further decrease myocardial contractility; cimetidine may increase levels

Contraindications

Documented hypersensitivity; complete AV block, intraventricular conduction defects; patients taking ritonavir or sparfloxacin

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in thyroid or liver disease

Vasodilators

In 1986, the US Veterans Administration Cooperative study showed a 36% mortality risk reduction in patients treated with preload and afterload reducers (eg, isosorbide dinitrate, hydralazine) in addition to conventional heart failure medications. Sublingual nitroglycerin spray, nitro paste, and intravenous nitroglycerin have also been advocated in the treatment of pulmonary edema secondary to CHF. Morphine also has significant vasodilatory effects and can be useful.

Hydralazine (Apresoline)

Decreases systemic resistance through direct vasodilation of arterioles.

Dosing

Adult

10-20 mg/dose IV q4-6h prn initially; increase to 40 mg/dose prn; change to PO as soon as possible

Pediatric

0.1-0.2 mg/kg/dose IV q4-6h prn; not to exceed 20 mg or 1.7-3.5 mg/kg/d divided q4-6h

Interactions

MAOIs and beta-blockers may increase toxicity; pharmacologic effects may be decreased by indomethacin

Contraindications

Documented hypersensitivity; mitral valve rheumatic heart disease

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Has been implicated in myocardial infarction; caution in possible coronary artery disease

Isosorbide dinitrate and hydralazine (BiDil)

Fixed-dose combination of isosorbide dinitrate (20 mg/tab), a vasodilator with effects on both arteries and veins, and hydralazine (37.5 mg/tab), a predominantly arterial vasodilator. Indicated for heart failure in black patients, based in part on results of the African American Heart Failure Trial. Two previous trials in the general population of patients with severe heart failure found no benefit but suggested a benefit in black patients. Compared with placebo, black patients showed a 43% reduction in mortality rate, a 39% decrease in hospitalization rate, and a decrease in symptoms from heart failure.

Dosing

Adult

1 tab PO tid; may titrate upward, not to exceed 2 tab tid

Pediatric

Not established

Interactions

Hydralazine may increase propranolol, metoprolol, and lisinopril AUC and C_max; isosorbide dinitrate may cause additive vasodilating effects with other vasodilators (eg, sildenafil [Viagra], vardenafil [Levitra]), especially when coadministered with alcohol

Contraindications

Documented hypersensitivity; allergy to organic nitrates

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

May cause symptomatic hypotension even with small doses; careful hemodynamic monitoring required if administered in patients with acute MI
Hydralazine: May cause SLE-like symptoms, including glomerulonephritis, tachycardia, hypotension, and peripheral neuritis (pyridoxine therapy may be required)
Isosorbide dinitrate: If hypotension exists, may aggravate angina associated with hypertrophic cardiomyopathy

Nitroglycerin (Nitro-Bid)

Causes relaxation of vascular smooth muscle by stimulating intracellular cGMP production, resulting in a decrease in blood pressure.

Dosing

Adult

Injection: 10-20 mcg/min IV continuous infusion
Spray: Single spray (0.4 mg), which is equivalent to a single 1/150 SL dose; dose may be repeated q3-5min as hemodynamics permit; not to exceed 1.2 mg
Ointment: Apply 1-2 in of nitro paste to chest wall

Pediatric

0.1-1 mcg/kg/min IV continuous infusion; used temporarily during heart failure exacerbations when rapid control of blood pressure is needed

Interactions

Aspirin may increase nitrate serum concentrations; marked symptomatic orthostatic hypotension may occur with coadministration of calcium channel blockers (dose adjustment of either agent may be necessary)

Contraindications

Documented hypersensitivity; severe anemia; shock; postural hypotension; head trauma; closed-angle glaucoma; cerebral hemorrhage

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in coronary artery disease and low systolic blood pressure

Angiotensin II receptor blockers

Data have demonstrated that angiotensin receptor blockers are as equally effective as ACE inhibitors in the treatment of heart failure. Adverse effect profile is similar to that of ACE inhibitors with regard to renal insufficiency or hyperkalemia. An added advantage of angiotensin receptor blockers is that they do not cause potentiation of bradykinin and therefore do not cause cough.

Angiotensin receptor blocker trials

• Evaluation of Losartan in the Elderly (ELITE) (losartan vs captopril) - Losartan associated with lower mortality, better tolerated¹³
• Evaluation of Losartan in the Elderly II (ELITE II) - Conducted to confirm results of first trial; losartan not superior to captopril in elderly patients with left ventricular dysfunction but was better tolerated¹⁴
• Valsartan Heart Failure Trial, ie, VALHeFT (valsartan vs placebo) in addition to standard therapy - Combined mortality and morbidity rates from heart failure decreased by 13.3% (P = .009) in patients receiving valsartan in addition to standard therapy

Valsartan (Diovan)

For patients unable to tolerate ACE inhibitors. May induce more complete inhibition of renin-angiotensin system than ACE inhibitors. Does not affect response to bradykinin and is less likely to be associated with cough and angioedema.

Dosing

Adult

80 mg/d PO; may increase to 160 mg/d if needed

Pediatric

Not established

Interactions

Ketoconazole, troleandomycin, sulfaphenazole, and phenobarbital may decrease effects; cimetidine and monoxidine may increase effects

Contraindications

Documented hypersensitivity; severe hepatic insufficiency, biliary cirrhosis or obstruction, primary hyperaldosteronism, bilateral renal artery stenosis

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in hyperkalemia, possible bilateral renal artery stenosis or solitary kidney with unilateral RAS

Inotropic agents

Long-term use of the phosphodiesterase inhibitor milrinone has deleterious effects on survival in patients with heart failure. Improvement of CHF symptoms occurs as the trade-off for this increase in mortality rates. Inotropic agents are reserved for patients who need hemodynamic-directed treatment during acute decompensation, those refractory to maximal standard therapy, as palliation for end-stage heart failure, or as a bridge to transplantation for appropriate candidates. Milrinone may have an advantage over beta-agonists in that it can be used for acute inotropic support during introduction of beta-blocker therapy.

Inotrope trials

• Prospective Randomized Milrinone Survival Evaluation (PROMISE) (milrinone vs placebo) NYHA class III-IV - Increased mortality and morbidity rates with long-term therapy¹⁵
• Xamoterol in Severe Heart Failure Study (xamoterol vs placebo), NYHA class III-IV - Terminated because of excess mortality rate in xamoterol group¹⁶
• Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME-CHF) (milrinone or dobutamine vs placebo) - Routine administration of inotrope to hospitalized patients with decompensation who normally would not require it, no impact on length of hospitalization, increased adverse events with milrinone
• Vesnarinone Trial (VEST) (vesnarinone vs placebo), NYHA class III-IV - Increased mortality rates

Milrinone (Primacor)

Bi-pyridine positive inotrope and vasodilator with little chronotropic activity. Different in mode of action from both digitalis glycosides and catecholamines. Used for the short-term management of acute decompensated heart failure.

Dosing

Adult

50 mcg/kg IV loading dose over 10 min followed by continuous infusion at 0.375-0.75 mcg/kg/min

Pediatric

Administer as in adults; although used as DOC in many pediatric intensive care units, safety and efficacy not well established

Interactions

Precipitates in presence of furosemide

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Monitor fluids, electrolyte changes, and renal function during therapy; excessive diuresis may increase potassium loss and predispose digitalized patients to arrhythmias; important to correct hypokalemia with potassium supplementation prior to treatment; patients showing excessive decreases in blood pressure should have infusion rates slowed or stopped; previous vigorous diuretic therapy has caused significant decreases in cardiac filling pressure; administer cautiously and monitor blood pressure, heart rate, and clinical symptomatology

Anticoagulants

In 1994, Baker and Wright¹⁷ reviewed the frequency of thromboembolism in patients with heart failure due to left ventricular systolic dysfunction and found that clinical evidence did not support the use of anticoagulants in patients in sinus rhythm. Therefore, the use of anticoagulants is restricted to patients in atrial fibrillation, with artificial valves, and with known mural thrombus. Some data support use in patients with low ejection fraction values.

Warfarin (Coumadin)

Interferes with hepatic synthesis of vitamin K–dependent coagulation factors. Tailor dose to maintain INR in range of 2-3.

Dosing

Adult

5-15 mg/d PO qd for 2-5 d; adjust dose to target INR of 2

Pediatric

Not established

Interactions

Drugs that may decrease anticoagulant effects include griseofulvin, carbamazepine, glutethimide, estrogens, nafcillin, phenytoin, rifampin, barbiturates, cholestyramine, colestipol, vitamin K, spironolactone, oral contraceptives, and sucralfate
Medications that may increase anticoagulant effects include oral antibiotics, phenylbutazone, salicylates, sulfonamides, chloral hydrate, clofibrate, diazoxide, anabolic steroids, ketoconazole, ethacrynic acid, miconazole, nalidixic acid, sulfonylureas, allopurinol, chloramphenicol, cimetidine, disulfiram, metronidazole, phenylbutazone, phenytoin, propoxyphene, sulfonamides, gemfibrozil, acetaminophen, and sulindac

Contraindications

Documented hypersensitivity; severe liver or kidney disease; open wounds; GI ulcers

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Do not switch brands after achieving therapeutic response; caution in active tuberculosis or diabetes; patients with protein C or S deficiency are at risk of developing skin necrosis

Human B-type natriuretic peptide

New class of drug in treatment of heart failure; produced through recombinant DNA technology and has same amino acid sequence as naturally occurring human BNP. Human BNP binds to guanylyl cyclase-A receptors on the cell surface of vascular smooth muscle and endothelial cells, which activates cGMP. This, in turn, leads to smooth muscle relaxation and vasodilation. Venous and arterial dilation results in decreased preload and afterload and reductions in pulmonary capillary wedge pressure. Human BNP is indicated for patients with acutely decompensated CHF.

Human BNP has additional beneficial effects for heart failure patients. Neurohormonal effects on the RAAS result in reductions in plasma norepinephrine and a trend toward a decrease in aldosterone levels. Renal effects include diuresis and natriuresis with at least preservation, if not an increase, in renal blood flow and glomerular filtration rate.

Human BNP trials

• Vasodilation in the Management of Acute Congestive Heart Failure (VMAC) (nesiritide vs nitroglycerin vs placebo plus standard care): In patients with acute decompensated CHF, human BNP improved hemodynamics and symptomatology more effectively and with fewer adverse effects than intravenous nitroglycerin through 24 h.¹⁸
• Prospective Randomized Evaluation of Cardiac Ectopy with Dobutamine or Natrecor Therapy (PRECEDENT): Natrecor was not associated with the increased heart rate or ventricular ectopy that occurred with dobutamine therapy.¹⁹

Nesiritide (Natrecor)

Recombinant DNA form of human BNP that dilates veins and arteries. Human BNP binds to particulate guanylate cyclase receptor of vascular smooth muscle and endothelial cells. Binding to receptor causes increase in cGMP, which serves as second messenger to dilate veins and arteries. Reduces pulmonary capillary wedge pressure and improves dyspnea in patients with acutely decompensated CHF. Used temporarily in the management of decompensated heart failure.

Dosing

Adult

IV bolus of 2 mcg/kg then a continuous infusion at 0.01 mcg/kg/min; infusion dose may be increased by 0.005 mcg/kg/min (preceded by a bolus of 1 mcg/kg), no more frequently than q3h, not to exceed 0.03 mcg/kg/min; dose-limiting adverse effect is hypotension

Pediatric

Not established

Interactions

Concurrent administration with ACE inhibitors and other vasodilators may potentially cause hypotension; no trials specifically examining potential drug interactions have been conducted

Contraindications

Documented hypersensitivity; systolic blood pressure <90 mm Hg; patients with possible or confirmed low cardiac filling pressures, significant valvular stenosis, restrictive or obstructive cardiomyopathy, constrictive pericarditis, pericardial tamponade, or conditions in which cardiac output is dependent on venous return; hypotension, cardiogenic shock

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Do not initiate at dose higher than recommended; may affect renal function in patients whose renal function may depend on activity of RAAS; may cause hypotension (administer in settings in which blood pressure can be monitored closely); discontinue if hypotension develops; ventricular tachycardia, nonsustained VT, headache, abdominal pain, back pain, insomnia, anxiety, angina pectoris, nausea, and vomiting may occur

Follow-up

Prognosis

The prognosis for patients with heart failure depends on several factors, with the etiology of disease being the primary factor. Other factors (eg, age, sex, disease severity) play important roles in determining prognosis. A higher mortality rate is associated with increased age, male sex, and severe CHF. Prognostic indices include the NYHA functional classification. Despite improved medical therapies, patients with severe heart failure have more than a 50% yearly mortality rate. Patients with mild heart failure have significantly better prognoses, especially with optimal medical therapy.

Patient Education

• Nonpharmacologic interventions are the basis of heart failure therapy. Instruction on a sodium diet restricted to 2 g/d is very important and can often obviate the need for diuretics or reduce their dosages. Fluid restriction is complementary to a low-sodium diet. Patients should be enrolled in cardiac rehabilitation involving aerobic exercise. These nonpharmacologic therapies are paramount in the treatment of heart failure.
• For excellent patient education resources, visit eMedicine's Heart Center. Also, see eMedicine's patient education article Congestive Heart Failure.

Miscellaneous

Medicolegal Pitfalls

• Failure to search for an etiology for heart failure: CHF is a syndrome, not a disease.
• Failure to place a patient on an ACE inhibitor
• Failure to monitor digoxin levels, which may result in toxicity
• Failure to recognize the need for advanced care
• Failure to institute timely care to the point at which the patient is no longer a candidate for heart transplantation

Special Concerns

• Blood pressure control: Appropriate control of blood pressure is essential to effective therapy for persons with heart failure. The systolic blood pressure must be less than 120 mm Hg (preferably <110 mm Hg). Patients taking medications should not be deemed hypotensive based solely on blood pressure measurements; instead, this determination should be made based primarily on symptoms and the effectiveness of organ perfusion.
• The future of pharmacologic therapy in persons with heart failure
  • RAAS: The next generation of medications affecting the RAAS are the selective aldosterone receptor antagonists. Eplerenone is currently being evaluated in the treatment of heart failure.
  • Cytokine antagonists: Based on findings of TNF-alpha involvement in persons with cardiomyopathies, agents aimed at blocking TNF-alpha have been developed. Etanercept has shown benefit in animal models and short clinical trials. However, phase 3 trials were discontinued because of a lack of benefit.
  • Endothelin blockade: Endothelin-1 has deleterious hemodynamic effects on left ventricular dysfunction. Over 6 months, bosentan has been shown to increase the likelihood of improvement and decrease the likelihood of deterioration in persons with NYHA class IIIB-IV. Trials with other agents are under way.
  • Natriuretic peptides: Augmentation of natriuretic peptides can be accomplished via exogenous administration (ie, with nesiritide) or blockade of the catalytic enzyme neutral endopeptidase (ie, with omapatrilat). Administration of exogenous peptide is clinically available for the treatment of patients with salt and volume overload. These agents have demonstrated effectiveness in correcting hemodynamic derangements in patients with acutely decompensated heart failure via their vasodilatory and diuretic effects. Recent data suggest that combined blockade of ACE and neutral endopeptidase also has hemodynamic and clinical benefits.
• Protein, stem cell, and gene therapies
  • Early animal studies using recombinant adeno-associated viral gene therapy with gene transfer of phospholamban prevented deterioration of left ventricular systolic and diastolic function in genetically predisposed animals.
  • The use of vascular endothelial growth factor may have beneficial effects in persons with ischemic cardiomyopathies. This form of gene therapy has demonstrated the benefits of reducing revascularization and improving angina and quality of life. Many formats of gene delivery are under investigation.
  • Fibroblast growth factor has also been investigated in the realm of ischemic heart disease, with mixed results 
• Myoblast transplantation
  • This procedure involves the injection of skeletal myoblasts as an autograft into damaged myocardium (scar) at the time of bypass surgery.
  • In early investigations, this therapy has consistently resulted in improved contraction and viability of the myocardium.
  • Further investigation is needed to establish a more prominent role for myoblast transplantation in heart failure therapy. Additional studies are also being performed with other progenitor cells.
• Embryonic stem cells hESC
  • Human embryo stem sells differentiated ex-vivo to derive cardiac myocyte stem cells and transplanted into rats who had LAD ligation have been shown to attenuate the adverse remodeling seen with extensive infarct.²⁰
  • Autologous stem cells have been given both intramyocardial and intravenously experimentally for the treatment of congestive heart failure with varying results. Much of the early data from these trials seem to suggest that delivery mechanisms to the myocardium and the use of concomitant cytokines are equally in need of further investigation.²¹

References

1. Bristow MR, Saxon LA, Boehmer J, et al. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med. May 20 2004;350(21):2140-50. [Medline].

2. Moss AJ, Hall WJ, Cannom DS, et al. Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia. Multicenter Automatic Defibrillator Implantation Trial Investigators. N Engl J Med. Dec 26 1996;335(26):1933-40. [Medline].

3. Moss AJ. Implantable cardioverter defibrillator therapy: the sickest patients benefit the most. Circulation. Apr 11 2000;101(14):1638-40. [Medline].

4. van Veldhuisen DJ, Genth-Zotz S, Brouwer J, et al. High- versus low-dose ACE inhibition in chronic heart failure: a double-blind, placebo-controlled study of imidapril. J Am Coll Cardiol. Dec 1998;32(7):1811-8. [Medline].

5. SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. The SOLVD Investigators. N Engl J Med. Aug 1 1991;325(5):293-302. [Medline].

6. Packer M, Poole-Wilson PA, Armstrong PW, et al. Comparative effects of low and high doses of the angiotensin-converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure. ATLAS Study Group. Circulation. Dec 7 1999;100(23):2312-8. [Medline].

7. Pfeffer MA, Braunwald E, Moyé LA, et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. The SAVE Investigators. N Engl J Med. Sep 3 1992;327(10):669-77. [Medline].

8. Poole-Wilson PA, Swedberg K, Cleland JG, Di Lenarda A, Hanrath P, Komajda M, et al. Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol Or Metoprolol European Trial (COMET): randomised controlled trial. Lancet. Jul 5 2003;362(9377):7-13. [Medline].

9. Cardiac Insufficiency Bisoprolol Study Group. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet. Jan 2 1999;353(9146):9-13. [Medline].

10. Hjalmarson A, Goldstein S, Fagerberg B, et al. Effects of controlled-release metoprolol on total mortality, hospitalizations, and well-being in patients with heart failure: the Metoprolol CR/XL Randomized Intervention Trial in congestive heart failure (MERIT-HF). JAMA. Mar 8 2000;283(10):1295-302. [Medline].

11. Packer M, Fowler MB, Roecker EB, et al. Effect of carvedilol on the morbidity of patients with severe chronic heart failure: results of the carvedilol prospective randomized cumulative survival (COPERNICUS) study. Circulation. Oct 22 2002;106(17):2194-9. [Medline].

12. Bertram Pitt, M.D., Willem Remme, M.D., Faiez Zannad, M.D., et al. Eplerenone, a Selective Aldosterone Blocker, in Patients with Left Ventricular Dysfunction after Myocardial Infarction (The EPHESUS Trial). N Engl J Med. April 2003;348(14):1309-1321. [Full Text].

13. Pitt B, Segal R, Martinez FA, et al. Randomised trial of losartan versus captopril in patients over 65 with heart failure (Evaluation of Losartan in the Elderly Study, ELITE). Lancet. Mar 15 1997;349(9054):747-52. [Medline].

14. Pitt B, Poole-Wilson P, Segal R, et al. Effects of losartan versus captopril on mortality in patients with symptomatic heart failure: rationale, design, and baseline characteristics of patients in the Losartan Heart Failure Survival Study--ELITE II. J Card Fail. Jun 1999;5(2):146-54. [Medline].

15. Packer M, Carver JR, Rodeheffer RJ, et al. Effect of oral milrinone on mortality in severe chronic heart failure. The PROMISE Study Research Group. N Engl J Med. Nov 21 1991;325(21):1468-75. [Medline].

16. Xamoterol in Severe Heart Failure Study Group. Xamoterol in severe heart failure. The Xamoterol in Severe Heart Failure Study Group. Lancet. Jul 7 1990;336(8706):1-6. [Medline].

17. Baker DW, Wright RF. Management of heart failure. IV. Anticoagulation for patients with heart failure due to left ventricular systolic dysfunction. JAMA. Nov 23-30 1994;272(20):1614-8. [Medline].

18. VMAC Investigators Committee. Intravenous nesiritide vs nitroglycerin for treatment of decompensated congestive heart failure: a randomized controlled trial. JAMA. Mar 27 2002;287(12):1531-40. [Medline].

19. Burger AJ, Horton DP, LeJemtel T, et al. Effect of nesiritide (B-type natriuretic peptide) and dobutamine on ventricular arrhythmias in the treatment of patients with acutely decompensated congestive heart failure: the PRECEDENT study. Am Heart J. Dec 2002;144(6):1102-8. [Medline].

20. Caspi O, Huber I, Kehat I, Habib M, Arbel G, Gepstein A. Transplantation of human embryonic stem cell-derived cardiomyocytes improves myocardial performance in infarcted rat hearts. J Am Coll Cardiol. Nov 6 2007;50(19):1884-93. [Medline].

21. Patel, Amit N; Genovese, Jorge A. Stem cell therapy for the treatment of heart failure. Current Opinion in Cardiology. September 2007;Volume 22(5):p 464-470. [Medline].

22. Abraham WT, Lowes BD, Ferguson DA, et al. Systemic hemodynamic, neurohormonal, and renal effects of a steady-state infusion of human brain natriuretic peptide in patients with hemodynamically decompensated heart failure. J Card Fail. Mar 1998;4(1):37-44. [Medline].

23. Agatston AS, Snow ME, Samet P. Regression of severe alcoholic cardiomyopathy after abstinence of 10 weeks. Alcohol Clin Exp Res. Aug 1986;10(4):386-7. [Medline].

24. Assomull RG, Prasad SK, Lyne J. Cardiovascular magnetic resonance, fibrosis, and prognosis in dilated cardiomyopathy. J Am Coll Cardiol. Nov 21 2006;48(10):1977-85.

25. Baboonian C, Treasure T. Meta-analysis of the association of enteroviruses with human heart disease. Heart. Dec 1997;78(6):539-43. [Medline].

26. Barbaro G, Di Lorenzo G, Grisorio B, Barbarini G. Incidence of dilated cardiomyopathy and detection of HIV in myocardial cells of HIV-positive patients. Gruppo Italiano per lo Studio Cardiologico dei Pazienti Affetti da AIDS. N Engl J Med. Oct 15 1998;339(16):1093-9. [Medline].

27. Berko BA, Swift M. X-linked dilated cardiomyopathy. N Engl J Med. May 7 1987;316(19):1186-91. [Medline].

28. Burchell SA, Spinale FG, Crawford FA, et al. Effects of chronic tachycardia-induced cardiomyopathy on the beta-adrenergic receptor system. J Thorac Cardiovasc Surg. Oct 1992;104(4):1006-12. [Medline].

29. Chatterjee K. Pathophysiology of cardiomyopathy. In: Giles TD, Sander SE, eds. Cardiomyopathy. 1st ed. Littleton, Mass: PSG Publishers; 1988.

30. Cohn JN. Is there a common mechanism of benefit for effective treatment of heart failure?. Eur J Heart Fail. Mar 1999;1(1):31-4. [Medline].

31. Cohn JN, Johnson G, Ziesche S, et al. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med. Aug 1 1991;325(5):303-10. [Medline].

32. Cohn JN, Tognoni G. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med. Dec 6 2001;345(23):1667-75. [Medline].

33. Colucci WS, Packer M, Bristow MR, et al. Carvedilol inhibits clinical progression in patients with mild symptoms of heart failure. US Carvedilol Heart Failure Study Group. Circulation. Dec 1 1996;94(11):2800-6. [Medline].

34. Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. The Digitalis Investigation Group. N Engl J Med. Feb 20 1997;336(8):525-33. [Medline].

35. Eichhorn EJ. The paradox of beta-adrenergic blockade for the management of congestive heart failure. Am J Med. May 1992;92(5):527-38. [Medline].

36. Etoch SW, Koenig SC, Laureano MA, et al. Results after partial left ventriculectomy versus heart transplantation for idiopathic cardiomyopathy. J Thorac Cardiovasc Surg. May 1999;117(5):952-9. [Medline].

37. Felker GM, Hu W, Hare JM, et al. The spectrum of dilated cardiomyopathy. The Johns Hopkins experience with 1,278 patients. Medicine (Baltimore). Jul 1999;78(4):270-83. [Medline].

38. Ghali JK, Piña IL, Gottlieb SS, et al. Metoprolol CR/XL in female patients with heart failure: analysis of the experience in Metoprolol Extended-Release Randomized Intervention Trial in Heart Failure (MERIT-HF). Circulation. Apr 2 2002;105(13):1585-91. [Medline].

39. Giles TD. General aspects of cardiomyopathy. In: Giles TD, Sander SE, eds. Cardiomyopathy. 1st ed. Littleton, Mass: PSG Publishers; 1988.

40. Grunig E, Tasman JA, Kucherer H, et al. Frequency and phenotypes of familial dilated cardiomyopathy. J Am Coll Cardiol. Jan 1998;31(1):186-94. [Medline].

41. Hershberger RE, Ni H, Crispell KA. Familial dilated cardiomyopathy: echocardiographic diagnostic criteria for classification of family members as affected. J Card Fail. Sep 1999;5(3):203-12. [Medline].

42. Jensen KT, Eiskjaer H, Carstens J, Pedersen EB. Renal effects of brain natriuretic peptide in patients with congestive heart failure. Clin Sci (Lond). Jan 1999;96(1):5-15. [Medline].

43. Johnson RA, Palacios I. Dilated cardiomyopathies of the adult (first of two parts). N Engl J Med. Oct 21 1982;307(17):1051-8. [Medline].

44. Marcus LS, Hart D, Packer M, et al. Hemodynamic and renal excretory effects of human brain natriuretic peptide infusion in patients with congestive heart failure. A double-blind, placebo-controlled, randomized crossover trial. Circulation. Dec 15 1996;94(12):3184-9. [Medline].

45. Marius-Nunez AL, Heaney L, Fernandez RN, et al. Intermittent inotropic therapy in an outpatient setting: a cost-effective therapeutic modality in patients with refractory heart failure. Am Heart J. Oct 1996;132(4):805-8. [Medline].

46. Mason JW, O''Connell JB, Herskowitz A, et al. A clinical trial of immunosuppressive therapy for myocarditis. The Myocarditis Treatment Trial Investigators. N Engl J Med. Aug 3 1995;333(5):269-75. [Medline].

47. McKee PA, Castelli WP, McNamara PM, Kannel WB. The natural history of congestive heart failure: the Framingham study. N Engl J Med. Dec 23 1971;285(26):1441-6. [Medline].

48. McMinn TR, Ross J. Hereditary dilated cardiomyopathy. Clin Cardiol. Jan 1995;18(1):7-15. [Medline].

49. Mestroni L, Rocco C, Gregori D. Familial dilated cardiomyopathy: evidence for genetic and phenotypic heterogeneity. Heart Muscle Disease Study Group. J Am Coll Cardiol. Jul 1999;34(1):181-90. [Medline].

50. Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet. Jun 12 1999;353(9169):2001-7. [Medline].

51. Michels VV, Moll PP, Miller FA, et al. The frequency of familial dilated cardiomyopathy in a series of patients with idiopathic dilated cardiomyopathy. N Engl J Med. Jan 9 1992;326(2):77-82. [Medline].

52. Moss AJ, Zareba W, Hall WJ, et al. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med. Mar 21 2002;346(12):877-83. [Medline].

53. Moyé LA, Pfeffer MA, Braunwald E. Rationale, design and baseline characteristics of the survival and ventricular enlargement trial. SAVE Investigators. Am J Cardiol. Nov 18 1991;68(14):70D-79D. [Medline].

54. Packer M, Colucci WS, Sackner-Bernstein JD, et al. Double-blind, placebo-controlled study of the effects of carvedilol in patients with moderate to severe heart failure. The PRECISE Trial. Prospective Randomized Evaluation of Carvedilol on Symptoms and Exercise. Circulation. Dec 1 1996;94(11):2793-9. [Medline].

55. Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med. Sep 2 1999;341(10):709-17. [Medline].

56. Popović Z, Mirić M, Gradinac S, et al. Partial left ventriculectomy improves left ventricular end systolic elastance in patients with idiopathic dilated cardiomyopathy. Heart. Mar 2000;83(3):316-9. [Medline].

57. Rishi Sharma, Ram Raghubir. Stem Cell Therapy: A Hope for Dying Hearts. Stem Cells and Development. August 1, 2007;16(4):517-536. [Medline].

58. Smith RF, Germanson T, Judd D, et al. Plasma norepinephrine and atrial natriuretic peptide in heart failure: influence of felodipine in the third Vasodilator Heart Failure Trial. V-HeFT III investigators. J Card Fail. Jun 2000;6(2):97-107. [Medline].

59. SOLVD Investigators. Studies of left ventricular dysfunction (SOLVD)--rationale, design and methods: two trials that evaluate the effect of enalapril in patients with reduced ejection fraction. Am J Cardiol. Aug 1 1990;66(3):315-22. [Medline].

60. St John Sutton M, Pfeffer MA, Moyé L, et al. Cardiovascular death and left ventricular remodeling two years after myocardial infarction: baseline predictors and impact of long-term use of captopril: information from the Survival and Ventricular Enlargement (SAVE) trial. Circulation. Nov 18 1997;96(10):3294-9. [Medline].

61. Uemura A, Morimoto S, Hiramitsu S, et al. Histologic diagnostic rate of cardiac sarcoidosis: evaluation of endomyocardial biopsies. Am Heart J. Aug 1999;138(2 Pt 1):299-302. [Medline].

62. Wolff MR, de Tombe PP, Harasawa Y, et al. Alterations in left ventricular mechanics, energetics, and contractile reserve in experimental heart failure. Circ Res. Mar 1992;70(3):516-29. [Medline].

63. Yoshimura M, Yasue H, Morita E, et al. Hemodynamic, renal, and hormonal responses to brain natriuretic peptide infusion in patients with congestive heart failure. Circulation. Oct 1991;84(4):1581-8. [Medline].

Keywords

congestive cardiomyopathy, heart failure, congestive heart failure, CHF, dilated cardiomyopathy, DCM, cardiac failure, cardiomyopathies, viral DCM, familial DCM, dilated cardiomyopathy, dilatated cardiomyopathy, viral dilated cardiomyopathy, familial dilated cardiomyopathy, toxic DCM, toxic dilated cardiomyopathy, granulomatous dilated cardiomyopathy, granulomatous DCM, collagen vascular disease DCM, collagen vascular disease dilated cardiomyopathy, carnitine DCM, carnitine dilated cardiomyopathy, carnitine deficiency, tachycardia-induced DCM, tachycardia-induced dilated cardiomyopathy, doxorubicin-induced DCM, doxorubicin-induced dilated cardiomyopathy, sarcoidosis, end-stage heart disease, end stage heart disease, end-stage cardiac disease, end stage cardiac disease

Contributor Information and Disclosures

Author

Frank E Wilklow, MD, Principal Investigator, Sub-Investigator, Cardiovascular Research Lab, Louisiana State University Health Sciences Center; Principal Investigator, Sub-Investigator, Gulf Regional Research and Education
Frank E Wilklow, MD is a member of the following medical societies: American College of Cardiology and American College of Physicians
Disclosure: Nothing to disclose.

Coauthor(s)

Murat M Celebi, MD, Consulting Staff, Crescent City Cardiovascular Associates
Murat M Celebi, MD is a member of the following medical societies: American College of Cardiology, Heart Rhythm Society, Louisiana State Medical Society, and Orleans Parish Medical Society
Disclosure: Nothing to disclose.

Amer Suleman, MD, Consultant in Electrophysiology and Cardiovascular Medicine, Department of Internal Medicine, Division of Cardiology, Medical City Dallas Hospital
Amer Suleman, MD is a member of the following medical societies: American College of Physicians, American Heart Association, American Institute of Stress, American Society of Hypertension, Federation of American Societies for Experimental Biology, Royal Society of Medicine, and Society of Cardiac Angiography and Interventions
Disclosure: Nothing to disclose.

Gary E Sander, MD, PhD, Professor, Department of Internal Medicine, Division of Cardiology, Tulane University Health Sciences Center
Gary E Sander, MD, PhD is a member of the following medical societies: Alpha Omega Alpha, American College of Cardiology, American College of Chest Physicians, American College of Physicians, American Federation for Medical Research, American Heart Association, American Society of Hypertension, Heart Failure Society of America, Louisiana State Medical Society, and Southern Society for Clinical Investigation
Disclosure: Nothing to disclose.

Medical Editor

Robert E Fowles, MD, Clinical Professor of Medicine, University of Utah College of Medicine; Consulting Staff, Intermountain Medical Center and LDS Hospital; Director and Consulting Staff, Department of Cardiology, Salt Lake Clinic
Robert E Fowles, MD is a member of the following medical societies: American College of Cardiology, American College of Physicians, and American Heart Association
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Ronald J Oudiz, MD, FACP, FACC, Associate Professor of Medicine, Division of Cardiology, The David Geffen School of Medicine at UCLA; Director, Liu Center for Pulmonary Hypertension, LA Biomedical Research Institute at Harbor-UCLA Medical Center
Ronald J Oudiz, MD, FACP, FACC is a member of the following medical societies: American College of Cardiology, American College of Physicians, and American Heart Association
Disclosure: Actelion Grant/research funds Clinical Trials + honoraria; Encysive Grant/research funds Clinical Trials + honoraria; Gilead Grant/research funds Clinical Trials + honoraria; Pfizer Grant/research funds Clinical Trials + honoraria; United Therapeutics Grant/research funds Clinical Trials + honoraria

CME Editor

Amer Suleman, MD, Consultant in Electrophysiology and Cardiovascular Medicine, Department of Internal Medicine, Division of Cardiology, Medical City Dallas Hospital
Amer Suleman, MD is a member of the following medical societies: American College of Physicians, American Heart Association, American Institute of Stress, American Society of Hypertension, Federation of American Societies for Experimental Biology, Royal Society of Medicine, and Society of Cardiac Angiography and Interventions
Disclosure: Nothing to disclose.

Chief Editor

Patrice Delafontaine, MD, FACC, FAHA, FACP, FESC, Sidney W and Marilyn S Lassen Professor of Cardiovascular Medicine, Chief, Section of Cardiology, Director, Cardiovascular Center of Excellence, Tulane University; Professor of Physiology, Chair, Department of Medicine, Tulane University School of Medicine
Patrice Delafontaine, MD, FACC, FAHA, FACP, FESC is a member of the following medical societies: Alpha Omega Alpha, American Association for the Advancement of Science, American College of Cardiology, American College of Physicians, American Diabetes Association, American Federation for Clinical Research, American Federation for Medical Research, American Heart Association, American Medical Association, American Society for Clinical Investigation, Association of American Physicians, Association of Professors of Cardiology, Association of Professors of Medicine, Endocrine Society, European Society of Cardiology, Louisiana State Medical Society, and Southern Society for Clinical Investigation
Disclosure: Nothing to disclose.

© 1994- by Medscape.
All Rights Reserved
(http://www.medscape.com/public/copyright)