Dilated cardiomyopathy is a progressive disease of heart muscle that is characterized by ventricular chamber enlargement and contractile dysfunction. The right ventricle may also be dilated and dysfunctional. Dilated cardiomyopathy is the third most common cause of heart failure and the most frequent reason for heart transplantation.
Symptoms are a good indicator of the severity of dilated cardiomyopathy and may include the following:
On physical examination, look for signs of heart failure and volume overload. Assess vital signs with specific attention to the following:
Other pertinent findings include the following (the level of cardiac compensation or decompensation determines which signs are present):
Look for the following on examination of the neck:
Findings on examination of the heart may include the following:
See Presentation for more detail.
The workup in a patient with suspected cardiomyopathy may include the following:
In many cases of cardiomyopathy, endomyocardial biopsy is class II (uncertain efficacy and may be controversial) or class III (generally not indicated). Class II indications for endomyocardial biopsy include the following:
See Workup for more detail.
Treatment of dilated cardiomyopathy is essentially the same as treatment of chronic heart failure (CHF). Some therapeutic interventions treat symptoms, whereas others treat factors that affect survival.
Drug classes used include the following:
Anticoagulants may be used in selected patients.
Surgical options for patients with disease refractory to medical therapy include the following:
See Treatment and Medication for more detail.
Dilated cardiomyopathy is a progressive disease of heart muscle that is characterized by ventricular chamber enlargement and contractile dysfunction. The right ventricle may also be dilated and dysfunctional. Dilated cardiomyopathy is the third most common cause of heart failure and the most frequent reason for heart transplantation.
Dilated cardiomyopathy is 1 of the 3 traditional classes of cardiomyopathy, along with hypertrophic and restrictive cardiomyopathy. However, the classification of cardiomyopathies continues to evolve, based on the rapid evolution of molecular genetics as well as the introduction of recently described diseases.
Multiple causes of dilated cardiomyopathy exist, one or more of which may be responsible for an individual case of the disease (see Etiology). All alter the normal muscular function of the myocardium, which prompts varying degrees of physiologic compensation for that malfunction.
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 (LV) systolic dysfunction, LV diastolic dysfunction, or both. When compensatory mechanisms can no longer maintain cardiac output at normal LV filling pressures, the disease process is expressed with symptoms that collectively compose the disease state known as chronic heart failure (CHF).
Continuing ventricular enlargement and dysfunction generally leads to progressive heart failure with further decline in LV contractile function. Sequelae include ventricular and supraventricular arrhythmias, conduction system abnormalities, thromboembolism, and sudden death or heart failure–related death.
Cardiomyopathy is a complex disease process that can affect the heart of a person of any age, but it is especially important as a cause of morbidity and mortality among the world's aging population. It is the most common diagnosis in persons receiving supplemental medical financial assistance via the US Medicare program.
Nonpharmacologic interventions are the basis of heart failure therapy. Instruction on a sodium diet restricted to 2 g/day is very important and can often eliminate the need for diuretics or permit the use of reduced dosages. Fluid restriction is complementary to a low-sodium diet. Patients may be enrolled in cardiac rehabilitation involving aerobic exercise.
For patient education information, see the Heart Center, as well as Congestive Heart Failure.
Dilated cardiomyopathy is characterized by ventricular chamber enlargement and systolic dysfunction with greater left ventricular (LV) cavity size with little or no wall hypertrophy. Hypertrophy can be judged as the ratio of LV mass to cavity size; this ratio is decreased in persons with dilated cardiomyopathies.
The enlargement of the remaining heart chambers is primarily due to LV 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 is by far the primary abnormality due to adverse myocardial remodeling that eventually 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. In turn, this leads 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 × heart rate), which is also accompanied by an increase in peripheral vascular tone. The increase in peripheral tone helps maintain appropriate blood pressure. Also observed is an increased tissue oxygen extraction rate with a shift in the hemoglobin dissociation curve.
In decompensation of systolic heart failure, several changes in the pressure-volume (P-V) curve are seen. The entire P-V loop shifts to the right with an increased in end-diastolic pressure and end-diastolic volume. Coronary blood flow may also be impaired by hypotension and elevated wall stress, decreasing the perfusion gradient.
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, as compared with persons with normal LV systolic function. Additionally, these compensatory mechanisms lead to further myocardial injury, dysfunction, and geometric remodeling (concentric or eccentric).
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. Although these responses are initially compensatory, they 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. Theoretically, 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-adrenergic receptors, which leads to increased peripheral vascular tone, increases the myocardial workload, which can further decrease cardiac output. Circulating norepinephrine levels have been inversely correlated with survival.
Activation of the RAAS is a critical aspect of 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 atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide. ANP is primarily released by the atria (mostly the right atrium). 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. Although BNP was initially identified in brain tissue (hence its name), it is secreted from cardiac ventricles in response to volume or pressure overload. As a result, BNP levels are elevated in patients with CHF. BNP causes vasodilation and natriuresis.
Counterregulatory responses to neurohormonal activation involve increased release of prostaglandins and bradykinins. These do not significantly counteract the previously described compensatory mechanisms.
The body's compensatory mechanisms for a failing heart are eventually overwhelmed. Compensation for 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.
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 LV 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.
Elevated levels of several interleukins have been found 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 elevated levels have been found in patients with CHF. IL-6 has been found to correlate with hemodynamic measures in persons with left ventricular dysfunction.
Dilated cardiomyopathy has many causes, including inherited disease, infections, and toxins. A systematic approach to define the etiology is essential for determination of the most effective treatment strategy.
Causes of dilated cardiomyopathy include the following:
In many cases of dilated cardiomyopathy, the cause remains unexplained. However, some idiopathic cases may result from failure to identify known causes such as infections or toxins. The idiopathic category should continue to diminish as more information explaining pathophysiologic mechanisms, specifically genetic-environmental interactions, becomes available.
Toxins are a significant cause. Almost a third of cases may result from severe ethanol abuse (>90 grams/day, or 7 to 8 drinks per day) for more than 5 years.
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. Advances in genetic analysis, such as polymerase chain reaction testing, 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 may be caused by the following:
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. 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 years) are generally healthy and have no systemic disease.
Acute viral myocarditis can mimic acute myocardial infarction, with patients sometimes presenting in the emergency department with chest pain; nonspecific electrocardiographic (ECG) changes; and abnormal, often highly elevated serum markers such as troponin, creatine kinase, and creatine kinase-MB.
The diagnosis of viral myocarditis is mainly indicated by a compatible history and the absence of other potential etiologies, particularly if it can be supported by 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.
An important diagnostic tool in myocarditis is cardiac magnetic resonance imaging (MRI), which allows pertinent tissue characterization, specifically, myocardial edema, hyperemia and capillary leak, and necrosis/fibrosis. The classic finding in inflammatory injury is augmented permeability of cell membranes leading to tissue edema, which is detected using T2-weighted imaging. Intertwined with tissue edema is vasodilatation and increased blood tissue delivery to the site of inflammation. As gadolinium is rapidly distributed into the interstitium, using contrast-enhanced fast-spin echo T1-weighted MRI can facilitate myocardial early gadolinium enhancement to assess hyperemia and inflammation. Additionally, late gadolinium enhancement (LGE) can be used to assess necrosis/fibrosis as fibrocytes replace viable tissue in the natural evolution of the disease process. Characteristic distribution of LGE may aid in differentiation of the pathologic processes, such as ischemic versus nonischemic subtypes in which LGE distribution is located in the midwall whereas the subendocardium is involved in ischemia.[2]
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. The diagnostic sensitivity using endomyocardial biopsy is low due to the focal nature of the inflammatory process and to sampling error, leading to increased false negative rates.[3]
Tissue samples are conventionally analyzed by histologic means via light or electron microscopy (Dallas criteria) and modern immunohistochemical methods, but they are not universally assessed by molecular methods of viral genome analysis via polymerase chain reaction (PCR), which would significantly increase the diagnostic potential. Furthermore, on the basis of the combination of absence/scarcity of data on associations of viral loads with clinical outcomes and the uncertain sensitivity of viral genome data, routine testing for viral genome is not recommended outside centers with extensive experience in viral genome analysis.[4]
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.
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.
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. 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.[5]
A randomized study by McNamara et al (Intervention in Myocarditis and Acute Cardiomyopathy [IMAC]) did not show IVIG-treatment–related improvement in left ventricular ejection fraction (LVEF) at 6 and 12 months over placebo. Both groups had similar improvement in LVEF over the study period.[6] In contrast, in a small group of 21 pediatric patients with acute myocarditis, IVIG treatment showed a smaller LV end-diastolic dimension and higher fractional shortening at 12 months. Those treated with IVIG were also more likely to achieve normal LV function and had a higher probability of survival compared to placebo. Although IVIG and immunosuppression are used commonly in myocarditis, a review of studies on immunosuppression in the pediatric population concluded that there was insufficient date for its routine use due to small sample sizes, lack of control group, and differences in medical regimens.[7, 8]
Familial cardiomyopathy is a term that collectively describes several different inherited forms of heart failure. 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.
A study by van Spaendonck-Zwarts et al suggested that a subset of peripartum cardiomyopathy is an initial manifestation of familial dilated cardiomyopathy. This may have important implications for cardiologic screening in such families.[9]
Several forms of familial cardiomyopathy 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 genes and chromosomal aberrations have been described in studied families. Mutations include those affecting actin, a cardiac muscle fiber component; titin, a sarcomere structure scaffold; alpha- and beta-myosin heavy chains, which are sarcomeric structural proteins; troponins T, I, or C; dystrophin; and sodium channel mutations.
Anthracyclines, which are widely used as antineoplastic agents, have a high degree of cardiotoxicity and cause a characteristic form of dose-dependent toxic cardiomyopathy. Both early acute cardiotoxicity and chronic cardiomyopathy have been described with 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 results in clinical CHF varies. The development of heart failure is very rare at total doses less than 450 mg/m2 but is dose dependent.
The history of these patients, in addition to having classic heart failure symptoms or symptoms of acute myocarditis, involves a previous history of malignancy and treatment with doxorubicin.
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. Progressive deterioration is the norm for this toxic cardiomyopathy. Abnormal myocardial strain analysis by echocardiography precedes changes in LVEF. A peak systolic longitudinal strain reduction by 10-15% during therapy is a good predictor of cardiotoxicity (drop in LVEF of heart failure).[10]
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 by the FDA to reduce toxicity; however, it increases the risk of severe myelosuppression.
Several collagen-vascular diseases have been implicated in the development of cardiomyopathies. These include the following:
Diagnosis is based on identification of the underlying disease in conjunction with appropriate clinical findings of heart failure.
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. Cardiac involvement in sarcoidosis reportedly occurs in approximately 20% of cases.
Patients have signs and symptoms of sarcoidosis and CHF. Patients rarely present with CHF without evidence of systemic sarcoid. Bilateral mediastinal, paratracheal, and/or hilar lymphadenopathy may be evident.
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 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.
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.
Giant cell myocarditis (GCM) is a rare, rapidly progressive, and frequently fatal myocarditis. The clinical presentation is typically fulminant heart failure, ventricular dysrhythmias, and complete heart block. The myocardium is diffusely infiltrated by lymphocytes and multinucleated giant cells. The resulting necrosis and fibrosis leads to ventricular systolic dysfunction and fatal arrhythmias.
The etiology can be secondary to viral infections, autoimmune disorders, and drug hypersensitivity. Inflammatory bowel disease and tumors have also been implicated. Acute cardiac structural findings include wall thickening with normal chamber size that typically dilates with disease progression. Right ventricular dysfunction often follows, which is an independent predictor of death and transplantation.[11]
Right ventricular endomyocardial biopsy (EMB) is used to guide therapy; biopsy has a higher sensitivity (82-85%) than that of other myocarditis counterparts due to its diffuse endocardial involvement for tissue sampling.[12] Early diagnosis is key due to the high mortality nature of the pathologic process. As such, the 2007 American Heart Association, American College of Cardiology, and European Society of Cardiology (AHA/ACC/ESC) scientific statement recommends EMB as a class IB indication in unexplained new-onset heart failure of 2 weeks’ to 3 months’ duration that is associated with a dilated left ventricle, new ventricular arrhythmias, and heart block.[4]
Treatment of GCM is predicated on heart failure guideline–directed medical therapy plus immunosuppression with cyclosporine and corticosteroids; thus, timely diagnosis via EMB is prudent.[13, 14] Treatment with cyclosporine and corticosteroids is associated with a median transplant-free survival of 12.3 months compared to 3 months without immunosuppression.[15]
The European Study of Epidemiology and Treatment of Cardiac Inflammatory Diseases (ESETCID) showed that there was no benefit in treatment of cytomegalovirus (CMV)-induced myocarditis treated with hyperimmunoglobulin, enterovirus-positive myocarditis treated with interferon alpha, and adenovirus-positive myocarditis treated with IgG and IgM immunoglobulin as compared with placebo.[16]
The classic paradigm of hypertensive heart disease involves concentric left ventricular hypertrophy (LVH) as a mechanism to curtail wall stress, as demonstrated by LaPlace’s Law. As the disease progresses (“transition to failure”), the LV dilates and LVEF declines in what is described as a “burned out” LV (eccentric remodeling). This stepwise evolution of the hypertensive heart has been challenged such that progression to concentric versus eccentric remodeling is not set, and that the tendency toward one or the other remains uncertain. However, certain factors such as ethnicity (African Americans), female sex, and increased age have a disposition for the development of a concentric response, whereas obesity and lower plasma renin activity are predisposed to eccentric response. Furthermore, the “transition to failure” phase in which the concentric myocardium with intact LVEF progresses to eccentric myocardium with impaired LVEF is uncommon in the absence of myocardial infarction.[17]
The development from asymptomatic LV systolic dysfunction to symptomatic heart failure (Stage B to C) is not completely understood. However, a number of factors appear to govern this transition. First, the transition to decompensation is accelerated by degree of depressed ejection fraction.[18] As cardiac function worsens, compensating mechanisms such as enhanced salt and water retention, increased peripheral vasoconstriction, and increased sympathetic response add further insult and accelerate the development of a decompensated state. The accompanying myocardial remodeling is characterized by fibrosis and LV dilation, with LV geometry taking a less efficient spherical shape, and reduced systolic function is consider to play major roles ushering the development of the symptomatic state.
Also noteworthy is the progression of the hypertensive heart with concentric hypertrophy with normal (preserved) ejection fraction (HFpEF) to a symptomatic state. Although the exact mechanism is not well understood, evidence suggests that collagen deposition and titin impact adverse changes in myocardial compliance.[18, 19] Other factors that have been postulated to herald the development of clinical heart failure include increased mineralocorticoid receptor activation[20] and levels of matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs.[21] Finally, the increased filling pressure is most intertwined with the development of symptomatic HFpEF.
Chagas disease caused by Trypanosoma cruzi. The acute presentation is characterized by dyspnea, fever, myalgia, hepatosplenomegaly, and myocarditis. Chronic infection involves the esophagus, colon, and heart. The disease is mainly distributed across Latin America, but Chagas disease may also involve regions in the United States. Cardiac manifestations include biventricular enlargement with dysfunction, apical aneurysm, sinus node dysfunction, and high-degree atrioventricular (AV) block.[22]
The presentation of Takotsubo cardiomyopathy is similar to acute coronary syndrome (ACS) but in the absence of angiographic evidence of significant coronary artery disease. The classic echocardiographic finding is reversible LV apical ballooning with systolic dysfunction. This condition is triggered by high emotional stress with a preponderance in postmenopausal females. A mild increase in cardiac enzymes with electrocardiographic (ECG) changes including ST-segment elevation/depression or T-wave changes may be seen. Postulated pathophysiologic mechanisms include a heightened sympathetic nervous system/catecholaminergic response, coronary vasospasm, and myocarditis.[23]
Cardiac manifestations of infection with human immunodeficiency virus (HIV) include myocarditis, dilated cardiomyopathy, pericardial effusion, vasculitis, dyslipidemia and insulin resistance secondary to the use protease inhibitors, coronary artery disease, and hypertension secondary to highly active antiretroviral therapy (HAART)-related metabolic syndrome/lipodystrophy.[24] The hazard ratio for death with cardiomyopathy is 4.0.[25]
A high cardiac output is defined as above 8 L/min or a cardiac index beyond 3.9 L/min/m2. The fundamental derangement in high-output heart failure (HOHF) is reduced systemic vascular resistance due to peripheral vasodilation or systemic arteriovenous shunting, with both leading to a decreased mean arterial blood pressure. Consequently, there is a compensatory increase in sympathetic activation, cardiac output, renin-angiotensin-aldosterone system (RAAS), and vasopressin. The result is increased salt/water retention and heart failure. Conditions that cause increased cardiac output include thyrotoxicosis, beriberi, obesity, anemia, Paget disease, AV malformation, AV fistula, and tachycardia syndromes (atrial fibrillation, atrial flutter). Echocardiographic findings of HOHF include compensatory ventricular dilatation and preserved ejection fraction that may deteriorate over time. Mixed venous oxygen saturation is typically over 70%.[26]
Low to moderate levels of alcohol consumption have been shown to have positive cardiovascular benefits, but excessive, chronic use may lead to myocardial dysfunction.[27] According to the 2013 American College of Cardiology Foundation and American Heart Association (ACCF/AHA) heart failure guidelines, the clinical diagnosis of alcoholic cardiomyopathy is suspected in the presence of biventricular dysfunction and dilation in the setting of excessive alcohol use.[13] The risk is increased in individuals who consume more than 90 g of alcohol daily (approximately 7-8 drinks/day) for longer than 5 years.
The natural evolution of alcoholic cardiomyopathy has not adequately been assessed in light of the currently available heart failure therapy. A number of studies dating back to the 1970s show rates of overall mortality or the need for transplant ranging from 19% to 73%. Differences were due to different cut-offs in LVEF, variation in the use of beta-blockers/angiotension converting enzyme (ACE) inhibitors/spironolactone, and the use of implantable cardioverter-defibrillator (ICD)/cardiac resynchronization therapy.[27] Thus, the evolution of alcoholic cardiomyopath,y taken in consideration of contemporary therapy, requires further investigation for better understanding. Myocardial recovery has also been described with the cessation of alcohol intake.[28]
Cocaine is one of the most abused and addictive psychostimulants, with causal LV systolic depressant rate of 4% to 18%.[13] This drug is a potent sympathomimetic with the potential for devastating cardiovascular consequences, including fatal ventricular arrhythmias, acute myocardial infarction, hypertensive crisis, cerebral vascular accidents, and dilated cardiomyopathy.[29, 30] Its addictive nature is mediated by its alteration of the dopaminergic activity within the mesocorticolimbic circuitry. Cocaine binds to dopamine, serotonin, and norepinephrine transport proteins, preventing reuptake of these agents into presynaptic neurons, thereby increasing the synaptic presence for enhanced neuroactivity.[31]
Phenotypic characteristics of cocaine cardiomyopathy include chamber dilatation with depressed systolic function, diastolic dysfunction, and LV hypertrophy, particularly in patients with chronic use and secondary hypertension.[30, 32]
Treatment of cocaine cardiomyopathy is similar to that for other dilated cardiomyopathies. Note that acute nonselective beta blocker use in the setting of acute cocaine intoxication may result in unopposed alpha-adrenergic receptor stimulation that perpetuates the ongoing insult by increasing coronary vasoconstriction, increasing LV wall stress, and exacerbating hypertensive crisis.[33]
A number of reports have suggested that coronary vascular resistance is significantly increased after administration of beta-blockers, and that animal studies have associated the use of non-vasodilatory beta-blockers to decreased coronary blood flow and higher mortality.[33, 34, 35, 36]
Physiologic changes accompanying pregnancy can pose challenges to the cardiovascular system. One of these challenges is peripartum cardiomyopathy (PPCM), which has the potential for significant morbidity and mortality. This condition is characterized by LV systolic dysfunction during the last trimester of pregnancy or the early puerperium period. Cardiomegaly persisting longer than 4-6 months carries a mortality of 50% at 6 years. Subsequent pregnancies in women with cardiomyopathy carries a substantial risk of clinical deterioration, particularly in those who did not recover LV function. In those with recovered LV function, the risk of clinical deterioration is less, but the cardiac dysfunction frequently emerges in the peripartum period.[13, 37] Patients with PPCM should be counseled about the risks that potential pregnancies may have on their health as well as the health of their fetus(es). Genetic forms of PPCM may be at higher risk for clinical nonrecovery,.[38]
Cardiovascular changes during pregnancy include expansion of plasma volume, increased cardiac output, and increased activity of the renin-angiotensin-aldosterone system that increases salt and water retention.[37, 38] During labor, there is the potential to overwhelm the cardiovascular system due to the increased cardiac output from tachycardia, catecholamine surges, and deposition of 300-500 mL of blood from the uterus into the maternal circulation.[37]
A number of biomarkers have been studied for the diagnosis and risk stratification of PPCM. The only commercially available marker with adequate efficiency is N-terminal pro b-type natriuretic peptide (NT-proBNP), which is not specific for PPCM but has good sensitivity for heart failure. Other biomarkers of interest include microRNA-146a (MiR-146a), soluble fms-like tyrosine kinase (SFlt1), and cathepsin D (CTSD).[37, 39, 40]
Therapy for PPCM includes standard guideline-directed management, with cautious use of diuretic therapy because placental perfusion may be impaired as well as initiating postdelivery ACE inhibitors due to their teratogenicity. The potential benefit of administering pentoxyfylline or bromocriptine in addition to heart failure medications has been described.[41, 42, 43] Once full myocardial recovery is demonstrated for at least 6 months, a weaning protocol of heart failure therapy can be considered.[39]
Deposition of abnormal substances in patients with infiltrative cardiomyopathies can either increase the LV wall thickness or cause chamber enlargement with the attendant wall thinning and systolic impairment. Increased wall thickness is not necessarily indicative of myocyte hypertrophy; it may be a reflection of the accumulation of intracellular or interstitial substances. Low QRS voltage—despite a “hypertrophic” appearance—is observed more often with interstitial accumulation more than with intracellular accumulation.[44]
Amyloidosis
The most common type of amyloidosis involving the myocardium results from plasma cell dyscrasias. The extracellular deposition of insoluble amyloid fibrils due to protein misfolding causes predominantly diastolic heart failure, followed by systolic heart failure in advanced stages.[45] Conduction block is also present, as is pericardial involvement, manifested by pericardial effusion.[46] It is diagnosed via EMB or with noninvasive modalities, such as the following:
Fabry disease
Fabry disease is an X-linked recessive lysosomal storage disease that involves alpha galactosidase A deficiency, which leads to accumulation of glycosphingolipid deposition in the myocardium, skin, and kidneys.[49]
Echocardiographic findings of Fabry disease include concentric LV hypertrophy with diastolic dysfunction and normal LVEF and dimension. Athough such features may mimic hypertrophic cardiomyopathy, distinguishing characteristics of Fabry disease include the absence of asymmetrical hypertrophy causing LV outflow tract obstruction and a “binary” myocardial appearance due to the increased echogenicity of the subendocardial layer owing to the sphingolipid presence, paralleled by a less echogenic myocardium.[50, 51, 52] Cardiac MRI (CMRI) typically shows focal inferolateral midwall LGE sparing the subendocardium.[53, 54]
Other infiltrative diseases
Other infiltrative diseases that resemble hypertrophic/hypertensive heart disease include Danton disease, Friedreich ataxia, myocardial oxalosis, and mucopolysaccharidoses.
Cardiac sarcoidosis
Cardiac sarcoidosis, a noncaseating granulomatous disease, can involve a number of organs. Cardiac involvement affects the atrioventricular (AV) node, causing heart block, as well as the basal septum, papillary muscles, and focal regions in the free wall.[44]
Echocardiographic findings of cardiac sarcoidosis include wall thickening from granulomatous infiltration, with subsequent scarring/thinning that are seen as wall motion abnormalities, LV dilatation, and/or aneurysm. The wall motion abnormalities do not typically correspond to regions subtended by a specific coronary artery. Mitral regurgitation may be seen with papillary muscle involvement. Pulmonary involvement is also common and signs of pulmonary hypertension or RV dysfunction may be present. LGE is patchy and involves the basal and lateral LV walls.[55]
The diagnosis can be made via EMB, although its sensitivity is less than 20%.[56] This is due to the patchy nature of the myocardial involvement.
The use of corticosteroids is the hallmark of treatment and should be started in patients with a high suspicion of cardiac sarcoidosis, even in the presence of a negative biopsy, as early treatment is more effective than later treatment. Unfortunately, therapy does not appear to improve LV volume or function in those with an LVEF below 30%.[57] The presence of concurrent pulmonary sarcoidosis or a depressed LVEF carries a worse prognosis.[58, 59] Immunosuppressants such as methotrexate, azathioprine, and cyclophosphamide may be used in steroid-refractory or steroid-contraindicated cases.[58, 59]
Granulomatosis with polyangiitis (formerly Wegener’s granulomatosis) is a small- to medium-sized vasculitis that affects the airways, lungs, kidneys, and heart. Cardiac manifestations include pericarditis, supraventricular tachycardias, and heart block.[60] Myocardial involvement/systolic dysfunction has also been described, although not as commonly as the manifestations discussed above.[61, 62] Glucocorticoids and cyclophosphamide are the mainstay of therapy; however, keep in mind that cyclophosphamide itself may cause cardiomyopathy.
Iron deposition in the myocardium initially manifests as diastolic dysfunction from a restrictive pathophysiology that progresses to systolic dysfunction.[63] Iron accumulates first in the ventricular myocardium and then the atrial myocardium.[64] As iron itself is proarrhythmic, its involvement in the conduction system may explain the propensity for hemochromatosis toward atrial or ventricular tachyarrhythmias.[65] Iron deposition in the conduction system may cause bradyarrhythmias, warranting placement of pacemakers.[64]
Iron overload is characterized by a transferrin saturation above 55% and a transferrin level over 200 ng/mL for women and over 300 ng/mL for men (on the basis of the 2005 American College of Physicians [ACP] guidelines).[66, 67] However, the level of ferritin in which myocardial deposition is detected is not defined.[63]
As noted earlier, EMB has low sensitivity for hemochromatosis due to the patchy involvement of the myocardium.[12] Echocardiographic findings include ventricular dilatation and restrictively cardiomyopathy.[63] Iron removal may reverse these findings.
Generally, when detected early, this type of cardiomyopathy is reversible once treatment of the tachycardia is successful. Common etiologies include chronic untreated atrial fibrillation with rapid ventricular response and frequent (several thousand daily) premature ventricular contractions. Persistent tachycardia is known to lead to myocyte dysfunction and cardiomyopathy. If the tachycardia-induced cardiomyopathy is left untreated, the left ventricular dysfunction can become irreversible. The exact mechanisms by which tachycardia affects cell function are poorly understood. The following are possible mechanisms by which myocyte dysfunction arises from tachycardia:
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 appear to be increasing. The reported incidence is 400,000-550,000 cases per year, with a prevalence of 4-5 million people.
Cardiomyopathy is a complex disease process that can affect the heart of a person of any age, and clinical manifestations appear most commonly in the third or fourth decade.
Although some cases of dilated cardiomyopathy reverse with treatment of the underlying disease, many progress inexorably to heart failure. With continued decompensation, mechanical circulatory support or heart transplantation may be necessary.
The prognosis for patients with heart failure depends on several factors, with the etiology of disease being the primary factor. Other factors play important roles in determining prognosis; for example, higher mortality rates are associated with increased age, male sex, and severe congestive heart failure (CHF). Prognostic indices include the New York Heart Association (NYHA) functional classification.
The Framingham Heart Study found that approximately 50% of patients diagnosed with CHF died within 5 years.[68] 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.
Individuals with a high likelihood of myocardial recovery following appropriate therapy include those with alcohol-induced cardiomyopathy, hypertensive cardiomyopathy, tachycardia-induced cardiomyopathy, Takotsubo cardiomyopathy, or ischemic cardiomyopathy after revascularization.
An important determinant of prognosis is peak VO2 (oxygen consumption) obtained with cardiopulmonary exercise testing (CPX). It is known that an inverse relationship exists between exercise duration and mortality. Because exercise capacity is variable among individuals and reproducibility is not always achieved, exercise testing with respiratory gas analysis provides a standardized method for heart transplant selection.[69] Peak VO2 reflects functional capacity and cardiac reserve.[70] It is a good predictor of mortality, as its decline precedes cardiac decompensation.[71]
Cardiac transplantation appears to have the potential to be deferred in a subset of ambulatory patients with heart failure. In a study that assessed mortality in 116 patients with chronic heart failure stratified into 3 groups, Mancini et al found that peak VO2 was the best predictor for survival, with supporting prognostic information from pulmonary capillary wedge pressure.[70] Group 1 had a peak VO2 below 14 mL/kg/min and was accepted for transplantation; the survival rate at 1 year was 48%. Group 2 had a peak VO2 above 14 mL/kg/min, with patients deemed too well for transplantation; the survival rate at 1 year was 94%, which was comparable to that of their counterparts who underwent transplantation. Group 3 had a peak VO2 below 14 mL/kg/min, along with comorbidities that precluded transplantation; the survival rate at 1 year was 47%.[70]
The three groups had comparable NYHA functional class, cardiac index, and ejection fraction. Thus, based on these findings on mortality, patients with intact exercise capacity (peak VO2 >14 ml/kg/min) can be medically managed. That is, deferring cardiac transplantation may be safe in ambulatory patients with severe left ventricular dysfunction and a peak exercise VO2 above 14 mL/min/kg.[70] Similarly, Stelken et al showed that a peak VO2 below 50% of the predicted was a strong predictor of 12-month survival in ambulatory patients with heart failure with an ischemic or dilated etiology.[72]
Ventilatory anaerobic threshold (VAT) is a parameter of CPX that provides an index of submaximal exercise capacity, independent of patient motivation. It is the point when aerobic metabolism transitions to aerobic plus anaerobic metabolism in which lactate increases. Inability to achieve VAT suggests noncardiovascular limitations of exercise tolerance or poor motivation.[73] In individuals with VAT identified, the reported cardiac event rate was 59% in those with a peak VO2 of 10 mL/kg/min or lower, and 15% in those with a peak VO2 above 18 mL/kg/min.[74] In patients in whom VAT was not detected, the cardiac event rate was 46% in those with peak VO2 of 10 mL/kg/min or below, but for those with a peak VO2 above 10 mL/kg/min, the risk stratification was inconclusive.[74]
Additionally, ventilatory expired gas parameters (VE/VCO2 slope [minute ventilation/carbon dioxide output]) also carry prognostic capability.[69, 75] VE/VCO2 is a ratio relating liters of inspired air to remove 1 L of CO2. A high ratio or slope carries a worse prognosis. Patients with VE/VCO2 slope of 35 or higher had a higher mortality compared to those with a slope below 35 (30% vs 10%, respectively).[75]
Determine the severity of disease, possible causes (eg, alcohol or drug use), and symptoms when taking the history of a patient with suspected cardiomyopathy. Symptoms are a good indicator of the severity of the disease and may include the following:
Note other important patient information, including age, sex, race, and medical history, especially the following:
For additional information on dilated cardiomyopathy from specific causes, see the Medscape Reference articles Alcoholic Cardiomyopathy, Cocaine-Related Cardiomyopathy, and Pregnancy and Cardiomyopathy.
On physical examination, look for signs of heart failure and volume overload. Assess vital signs with specific attention to the following:
Other pertinent findings include the following:
The level of cardiac compensation (or decompensation) determines which signs are present.
Look for the following on examination of the neck:
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.
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 may be present in persons with dilated cardiomyopathy.
The workup in a patient with suspected cardiomyopathy may include the following:
In addition, a urine toxicology screen is used to detect drugs associated with risk for dilated cardiomyopathy, including cocaine and methamphetamine.
Endomyocardial biopsy has limited usefulness in the evaluation of dilated cardiomyopathy. However, it may be helpful in diagnosing myocarditis, connective tissue disorders, and amyloidosis.
The principal use of the complete blood cell (CBC) count in these patients is to document anemia. Anemia can be associated with a high-output state.
Hyponatremia signifies a poor prognosis. An elevated creatinine level may represent a primary or drug-related etiology (eg, hypovolemia, azotemia from ACE inhibitors). Contraction alkalosis can be observed secondary to diuretic therapy. Magnesium levels should be closely followed because low levels may cause chronic hypokalemia by dependent potassium uptake.
Liver function test results can be elevated. Possible causes in these patients include one or more of the following:
Cardiac enzymes are useful for assessing acute or recent myocardial injury. Serum markers for myocardial necrosis (eg, troponin, creatine kinase, creatine kinase-MB) may be acutely elevated in persons with myocarditis. Levels are markedly elevated in persons with muscular dystrophy.
Elevated biomarker levels may indicate acute coronary syndrome, which should be considered as a potential etiology for acute decompensation in a patient with a history of heart failure. Further, while the precise role of cardiac biomarkers is still being defined, there is evidence that patients who present with elevated markers experience more severe heart failure and higher mortality.[76, 77]
B-type natriuretic peptide (BNP) assays help monitor the presence and severity of fluid overload. Changes in BNP level can reflect response to treatment. A low level of BNP is helpful in ruling out the condition.
In one study, a serum BNP below 100 pg/mL proved useful in excluding heart failure as a cause of dyspnea in emergency department (ED) patients.[78] A number of studies have correlated BNP or NT-proBNP with a worse prognosis.
Tsutamoto et al found that plasma levels of BNP may be a better prognostic indicator of mortality in patients with chronic heart failure than atrial natriuretic peptide (ANP) and is able to provide prognostic information independent of other poor prognostic variables.[79] In their study of 85 patients with chronic heart failure (left ventricular ejection fraction [LVEF] < 45%) who were followed for 2 years, the nonsurvivors' (n = 25) BNP levels were 436 ± 83 pg/mL as compared to that of the survivors (n = 60), 89 ± 15 pg/mL. Of note, only 25 patients total were on beta blockers.[79]
In the PARADIGM-HF trial (Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure), patients with heart failure and reduced LVEF who received sacubitril/valsartan had lower NT-proBNP levels after 12 weeks (from 783 pg/mL to 605 pg/mL) compared to patients on valsartan alone (from 862 pg/mL to 835 pg/mL).[80] The decreased in NT-proBNP levels were associated with improved mortality (13.3% vs 16.5%, respectively).
In an analysis of data from 1215 patients with systolic heart failure to determine the utility of 5 predictors of mortality—blood urea nitrogen (BUN), BNP, peak VO2 (oxygen consumption), systolic blood pressure (SBP), and pulmonary capillary wedge pressure (PCWP)—BNP was the strongest predictor for death, urgent transplantation, and all-cause mortality in the 2-year follow-up period.[81] The C-statistic (concordance statistic; measures the predictive accuracy of a logistic regression model) for BNP was 0.756 (ie, a good model). On multivariate analysis of all-cause mortality, patients with BNP levels above 579 pg/mL had an odds ratio of 4.4. The 2-year survival for those with BNP levels over 579 pg/mL was 44% compared to 82% for those with BNP levels below 579 pg/mL.[81]
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 (ED) suggests that cardiomegaly is one of the most sensitive and specific signs in diagnosing cardiomyopathies. The absence of cardiomegaly on chest radiographs decreases the likelihood of heart failure. 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. The presence of pulmonary vascular congestion and interstitial edema on chest radiograph increases the likelihood of acute decompensated heart failure about 12-fold.
Echocardiography has become one of the most useful and most efficient diagnostic modalities in attaining a diagnosis and classification of cardiomyopathy. Echocardiography may be indicated in the ED when a patient has findings suggestive of failure (eg, jugular venous distention) but the diagnosis is unclear.
In this setting, the differential diagnosis may include pulmonary embolism or cardiac tamponade. On echocardiography, secondary findings associated with pulmonary embolism such as right ventricular distention or pericardial effusion with tamponade may be seen. Pericardial effusion can be easily excluded or characterized using this imaging modality.
Different forms of echocardiography offer different information. Two-dimensional echocardiography allows for assessment of overall function.
M-mode assists in measurement of chamber sizes (end-diastolic left ventricular dimensions are usually greater than 65 mm in patients with dilated cardiomyopathy) and wall thickness. Hypertrophy is defined as and LV mass index greater than 115 g/m2 in men, or over 95 g/m2 in women. Doppler echocardiography facilitates the measurement and assessment of flow and valvular pathologies. It also allows for measurements of diastolic and systolic dynamics.
The physician must assess the E wave–to–A wave ratio (E/A) when evaluating left ventricular filling and pulmonary venous flow by Doppler echocardiography during left atrial filling. This provides important information on diastolic function and left atrial pressure. For example, a pattern with an E:A ratio above 2:1 and a short mitral deceleration time suggest a restrictive physiology with elevated left atrial pressure.
Tissue Doppler interrogation 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. Reversal of the E'/A' amplitude signifies likely diastolic dysfunction.
Segmental wall motion abnormalities may suggest an ischemic etiology for the cardiomyopathy. While ischemic cardiomyopathy is a common cause of such abnormalities, however, they can often be observed in association with other forms of cardiomyopathy, as well.
Echocardiography is used to help differentiate dilated cardiomyopathy from restrictive and hypertrophic cardiomyopathy. Dilated chambers and thin walls are the most prominent features of dilated cardiomyopathy.
MRI with gadolinium–diethylene-triamine pentaacetic acid (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.[82]
Cardiac CT scanning with angiography (CTA) can be used in the workup of undifferentiated heart failure. Biventricular volume and ejection fraction can be calculated with good correlation to echocardiography. With cine-loop formatting, regional wall motion can be assessed, with the highest accuracy for wall motion subtended by the left anterior descending and left circumflex arteries.[83]
In the assessment of ischemic cardiomyopathy, an Agatston coronary calcium score (CAC) of 0 has 100% specificity in excluding high-risk coronary artery disease (ie, the left main coronary artery, or stenosis of at least 2 major epicardial vessels).[84, 85] Cardiac CTA has a 98% diagnostic sensitivity and 97% specificity for excluding ischemic cardiomyopathy.[86]
Myocardial perfusion analysis of the coronary arteries is also feasible; however, it has yet to mature to the level of diagnostic accuracy of cardiac MRI.
Finally, anatomic features specific to an inciting disease can be differentiated on CTA, such as infiltrative diseases (heterogeneous attenuation of myocardium), the location of hypertrophic cardiomyopathy, left ventricular noncompaction, arrhythmogenic right ventricular dysplasia, and congenital malformations.[85]
An electrocardiogram (ECG) is helpful in identifying left ventricular enlargement and estimating the other chamber sizes. 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.
An ECG showing atrial fibrillation increases the likelihood of heart failure. The absence of any ECG abnormality decreases the likelihood of heart failure. This is an important screening tool in differentiating ischemic heart disease from dilated cardiomyopathy.
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 patient with dilated cardiomyopathy demonstrates elevated filling pressures (central venous pressure, pulmonary artery wedge pressure, right ventricular end-diastolic pressure) and decreased cardiac output. RHC is also important for assessing pulmonary vascular resistance, mixed venous saturation, and the adequacy of cardiac output in patients who are hemodynamically compromised.
In 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, but in restrictive cardiomyopathy, the left ventricular end-diastolic pressure generally exceeds the right ventricular end-diastolic pressure by 6 mm Hg or more and the entire diastolic filling period is abnormal, while constrictive pericarditis is associated with normal or increased early filling.
In many cases of cardiomyopathy, endomyocardial biopsy 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:
Evidence does not indicate a benefit for performing myocardial biopsy when evaluating the likelihood of patient survival with current therapies.
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. Changes suggestive of 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 the following:
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.
Hypothyroidism, hyperthyroidism, and thyroid hormone toxicity are all problems to be considered in the differential diagnosis of cardiomyopathy. For example, thyrotoxicosis is associated with a high-output state that may predispose to dilated cardiomyopathy. Results of thyroid function tests are not usually available to assist in decision making in the ED but may be sent for convenience.
On oxygen consumption testing, an oxygen consumption per minute (VO2) maximum of less than 14 mL/kg/min signifies a poor prognosis. Such patients should be given early consideration to heart transplantation.
A central venous line or pulmonary artery catheter provides a good measure of filling pressures, and the latter can be used to estimate cardiac output. However, neither has been shown to improve outcomes when used in acute decompensated heart failure.
Classic staging of heart failure is based on the New York Heart Association (NYHA) system. It may also be classified by the the American College of Cardiology/American Heart Association (ACC/AHA) system, which emphasizes the progressive nature of heart failure, as follows[87] :
Treatment of dilated cardiomyopathy is essentially the same as treatment of chronic heart failure (CHF). 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. Some therapeutic interventions treat symptoms, whereas others treat factors that affect survival.
Drug classes used to manage cardiomyopathies include, but are not limited to, the following:
Based on this trial, the 2016 American College of Cardiology/American Heart Association (ACC/AHA) focused update on new pharmacologic therapy for heart failure gives sacubitril-valsartan an IB-R indication for patients with heart failure with reduced ejection fraction to reduce morbidity and mortality.[88]
Anticoagulants may be used in selected patients.
Various surgical options are available for patients with disease refractory to medical therapy. These include the following:
In cases of severe acute heart failure, emergency medical services (EMS) personnel may initiate treatment with oxygen, nitrates, and furosemide en route to the hospital. Cardiac monitoring, continuous pulse oximetry, and electrocardiography (ECG) may also be performed by units with advanced life support (ALS) certification. Further ventilatory support or even intubation may be indicated if the patient is in extremis.
Treatment of dilated cardiomyopathy is essentially the same as treatment of chronic heart failure (CHF) and pulmonary edema; however, obtaining a thorough history from patients with dilated cardiomyopathy helps determine the etiology. When beginning treatment, administer oxygen, initiate continuous pulse oximetry and cardiac monitoring, and obtain intravenous access.
Mainstays of medical therapy are preload reduction, afterload reduction, diuresis, and airway support. In patients with severe refractory pulmonary edema, a trial of continuous positive airway pressure (CPAP) or bimodal positive airway pressure (BiPAP) may obviate intubation.
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.
Use of angiotensin-converting enzyme (ACE) inhibitors is the current criterion standard in the treatment of left ventricular dysfunction. 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 has been a matter of debate. 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 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 chronic heart failure (CHF) (atrial and B-type natriuretic peptides).[91] Authorities have generally accepted that maximizing ACE inhibitor therapy is important and should be accomplished in conjunction with other necessary therapies.
The Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS) group in 1987 showed that the addition of enalapril to the conventional treatment of CHF yielded a 31% reduction in mortality rate at 1 year.[92] A similar study by Studies of Left Ventricular Dysfunction (SOLVD) investigators in 1991 revealed a 16% risk reduction.[93] Losartan, an angiotensin II receptor blocker (ARB), also has been effective in decreasing mortality rates.
Other ACE inhibitor trials include the following:
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 and that adding beta-blockers to outpatient management of chronic heart failure (CHF) yields great reductions in mortality rates.
Carvedilol, bisoprolol, and metoprolol CR/XL are the only agents currently approved by the US Food and Drug Administration (FDA) for use in patients 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.[96]
The SENIORS trial (Study of Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors With Heart Failure) showed that patients older than 70 years regardless of LVEF, nebivolol, a beta blocker with vasodilating properties, reduced the primary outcome of all-cause mortality or hospitalization for cardiovascular events.[97] However, the seconday outcome of all-cause mortality was not significant reduced.
The 1993 Metoprolol in Dilated Cardiomyopathy (MDC) study reported a 34% reduction in primary endpoints (ie, need for heart transplant, death) in heart failure patients who were treated with metoprolol in addition to conventional therapies.[98] In 1996, the US Carvedilol Study showed a 65% reduction in mortality in patients with predominantly mild symptoms of heart failure (New York Heart Association [NYHA] class II) treated with carvedilol.[99]
The international Metoprolol CR/XL Randomized Intervention Trial in CHF (MERIT-HF), the largest trial ever completed using a beta-blocker in heart failure, closed prematurely following an interim analysis that identified a highly positive effect of metoprolol-XL on all causes of mortality.[100] MERIT-HF was a randomized, double-blind trial that compared the effects of extended-release metoprolol (metoprolol-XL) with the effects of a placebo on survival and other outcome measures (eg, sudden death, hospitalization for heart failure, quality of life) in patients with mostly mild symptoms (NYHA class II).
A statistically significant 34% reduction in relative risk for total mortality at 1 year was observed; mortality rates were 7.2% in the metoprolol-XL group and 11% in the placebo group. Results at the time of study termination also revealed a 38% reduction in cardiovascular mortality, a 41% reduction in sudden death, and a 49% reduction in CHF mortality.[100, 101]
Beta-blocker trials include the following (all trials used beta-blockers in addition to standard therapy for heart failure):
Angiotensin receptor blockers
Data have demonstrated that angiotensin II receptor blockers (ARBs) are as effective as angiotensin-converting enzyme (ACE) inhibitors in the treatment of heart failure. Their adverse-effect profile is similar to that of ACE inhibitors with regard to renal insufficiency or hyperkalemia, but they do not cause potentiation of bradykinin and therefore do not cause cough.
ARB trials include the following:
Spironolactone acts as an aldosterone receptor blocker and, with concomitant use of angiotensin-converting enzyme (ACE) inhibitors, helps break the cycle of sodium retention and fluid overload via the renin-aldosterone axis. In the Randomized Aldactone Evaluation Study (RALES) (spironolactone vs placebo), the addition of 25 mg of spironolactone daily to a standard treatment regimen for chronic heart failure (CHF) yielded a 35% reduction in hospitalization, significant improvements in New York Heart Association (NYHA) functional class, and a 30% reduction in risk of death.[108]
In the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) (eplerenone vs placebo), the addition of eplerenone to standard therapy resulted in a 15% reduction in all-cause mortality and a 17% reduction in cardiovascular mortality; the combined primary endpoint of cardiovascular (CV) mortality and CV hospitalization was reduced by 13%. EPHESUS was conducted in patients with ejection fractions less than 40% post myocardial infarction and either clinical symptoms of decompensated heart failure or diabetes.[109]
The Emphasis-HF trial noted a 30% reduction in mortality and heart failure hospitalizations when eplerenone was used in addition to standard therapy in patients with class II heart failure who had a left ventricular ejection fraction (LVEF) of less than 35%. However, an increased risk of hyperkalemia was noted, similar to findings from the RALES and EPHESUS trials.[110]
Foxglove and its derivatives are the oldest treatment of heart failure, but they still have a place in medicine despite advances in other drug categories. Although little controversy exists as to the benefit of digoxin in patients with symptomatic left ventricular dysfunction and concomitant atrial fibrillation, the debate continues over its role in patients with normal sinus rhythm.
A meta-analysis of 7 double-blind, placebo-controlled trials by Jaeschke et al revealed that 1 in 9 patients with chronic heart failure showed significant clinical benefit from treatment with digoxin, but not a reduction in mortality.[111] The Digitalis Investigation Group trial demonstrated that digoxin decreases heart failure hospitalizations but has no effect on long-term survival.[112]
Loop diuretics are necessary adjuncts in the medical therapy for heart failure when symptoms are due to sodium and water retention. They are the mainstay of diuretic therapy because they produce significantly more natriuresis than other diuretics, particularly in the setting of decreased glomerular rate. They provide symptomatic relief without prolonging life or altering disease course.
Loop diuretics have a tendency to cause hypokalemia and hypomagnesemia. Therefore, monitor electrolyte levels and replace as necessary.
Antiarrhythmics are 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.
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.[113] Sublingual nitroglycerin spray, nitro paste, and intravenous nitroglycerin have also been advocated in the treatment of pulmonary edema secondary to chronic heart failure.
The combination of isosorbide dinitrate and hydralazine is indicated for heart failure in black patients, based in part on results of the African American Heart Failure Trial.[114] Two previous trials in patients with severe heart failure had found no benefit in the general population but suggested a benefit in black patients. Compared with placebo, black patients on standard therapy in addition to isosorbide dinitrate/hydralazine showed a 43% reduction in mortality rate, a 39% decrease in hospitalization rate, and a decrease in symptoms from heart failure in patients with NYHA class III symptoms of heart failure, when added to standard therapy.
Intravenous nitrate therapy resulted in acute improvement of dyspnea in 2 randomized trials. Similarly, morphine acts as a venodilator, and it suppresses symptoms of breathlessness; however, no rigorous studies of morphine have been performed in acute decompensated heart failure.
Human B-type natriuretic peptide (BNP) (nesiritide [Natrecor]) is a new class of drug in the treatment of heart failure. It is produced through recombinant DNA technology and has the same amino acid sequence as naturally occurring human BNP.
Natriuretic peptides have demonstrated effectiveness in correcting hemodynamic derangements in patients with acutely decompensated heart failure via their vasodilatory and diuretic effects. Data suggest that combined blockade of angiotensin-converting enzyme (ACE) and neutral endopeptidase also has hemodynamic and clinical benefits.
In the Vasodilation in the Management of Acute Congestive Heart Failure (VMAC) trial (nesiritide vs nitroglycerin vs placebo plus standard care), human BNP improved hemodynamics and symptomatology more effectively and with fewer adverse effects than intravenous nitroglycerin during 24 hours in patients with acute decompensated chronic heart failure (CHF).[115] In the Prospective Randomized Evaluation of Cardiac Ectopy with Dobutamine or Natrecor Therapy (PRECEDENT) trial, nesiritide was not associated with the increased heart rate or ventricular ectopy that occurred with dobutamine therapy.[116]
In the ASCEND-HF trial (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure Trial), in which nesiritide was compared with placebo in the treatment of acute heart failure, there was no difference in the rate of rehospitalization for heart failure or all-cause death within 30 days.[117] Although there was no association with worsened renal function, defined as a more than 25% decrease in estimated glomerular filtration rate, increased rates of hypotension were noted. Given these findings, the investigators could not recommend nesiritide for routine use in the broad population of patients with acute heart failure.[117]
Long-term use of the phosphodiesterase inhibitor milrinone has deleterious effects on survival in patients with heart failure. Improvement of chronic heart failure (CHF) symptoms occurs as the trade-off for this increase in mortality. Inotropic agents are reserved for patients who need hemodynamic-directed treatment during acute decompensation, for those who are refractory to maximal standard therapy, as palliation for end-stage heart failure, or as a bridge to transplantation for appropriate candidates.
Inotrope trials include the following:
Restrict the use of anticoagulants to those patients in atrial fibrillation, with artificial valves, or with known mural thrombus.
The WATCH trial (Warfarin and Antiplatelet Therapy in Chronic Heart Failure) evaluated antithrombotics (aspirin, clopidogrel, and warfarin) in patients with a left ventricular ejection fraction (LVEF) of 35% or less in sinus rhythm and found no significant differences between the agents in the primary composite endpoints of all-cause mortality, nonfatal myocardial infarction, and nonfatal stroke.[120] There was a 26% in reduction of heart failure hospitalization for those receiving warfarin over aspirin, but this was at the expense of greater bleeding than seen with aspirin or clopidogrel use.
Similarly, in the WARCEF trial (Warfarin Versus Aspirin in Reduced Cardiac Ejection Fraction) that involved patients with an LVEF of 35% or below who were in sinus rhythm, there was no significant difference seen in treatment with aspirin versus warfarin in the composite end point of ischemic stroke, intracranial hemorrhage, or death from any cause.[121] Warfarin was associated with a reduction in ischemic stroke but at an increased overall rate of major hemorrhage (intracerebral, intracranial, gastrointestinal, or other bleeding causing a 2-g/dL decline in hemoglobin within 48 hours). However, when further subclassified, rates of intracranial/intracerebral hemorrhage did not differ between the two groups.[121]
Implantable left ventricular assist devices (LVADs) have been proven as a standard of care for suitable candidates with advanced heart failure when a bridge to transplantation (BTT) is needed. LVADs have also been approved for permanent implantations (ie, as destination therapy [DT]) in patients who are not candidates for heart transplantation.
The HeartMate XVE LVAD (HeartMate I) and HeartMate II LVAD were approved for destination therapy by the US Food and Drug Administration in 2004[122] and 2010,[123] respectively.[124]
Of 281 heart failure patients with New York Heart Association (NYHA) class IV symptoms and who were ill enough to have high priority for transplantation (United Network for Organ Sharing [UNOS] status 1A or 1B) who underwent implantation of HeartMate II LVAD for bridge to cardiac transplant, at 18-month follow-up, 79% underwent transplantation, LVAD removal for cardiac recovery, or had ongoing device support.[125] The investigators reported significant functional status improvements and 6-minute walk test evident at 6 months, and an actuarial survival of 72% at 18 months. Findings from this study demonstrated the HeartMate II provided effective hemodynamic support for at least 18 months in patients with advanced heart failure awaiting transplantation.[125]
In the HeartMate II destination therapy trial, 200 patients who were ineligible for heart transplantation and also had symptoms refractory to medical management, a left ventricular ejection fraction (LVEF) below 25%, a peak oxygen consumption (VO2) below 14 mL/kg/min (or < 50% of predicted value), and NYHA class IIIB or IV symptoms, or dependence on an intraaortic balloon pump were randomized to a continuous flow device (HeartMate II) versus a pulsatile device (HeartMate XVE). Patients in the continuous flow group (n = 134) had a better 2-year survival period free from the primary endpoints of disabling stroke and reoperation to repair/replace the device.[126] These patients also had superior actuarial survival rates and fewer adverse events.
The HeartWare Ventricular Assist System is a continuous-flow blood pump. In a study comprising 332 patients with NYHA class IV symptoms with UNOS class 1A or 1B listed for cardiac transplantation, survival was high 91% at 180 days and 84% at 360 days in those who received the HeartWare device.[127, 128] There was also significant improvement in quality of life.[128]
For biventricular pacing, a pulse generator is implanted under the skin, with leads positioned in the right atrium, right ventricle, and coronary sinus to pace the left ventricle. Resynchronization pacing generators also have defibrillation capabilities. The benefits of pacing solutions for dyssynchrony were confirmed in multiple studies from the mid 1990s, which demonstrated acute and long-term functional improvements and reduced mortality and hospitalization rates compared with optimal medical therapy.[129]
A Dutch study found that heart failure patients with impaired renal function were less likely to respond to cardiac resynchronization therapy and have higher mortality rates. In patients who do respond to resynchronization, however, renal function is preserved.[130]
Current indications for class I cardiac resynchronization therapy based on the 2013 American College of Cardiology Foundation/American Heart Association (ACCF/AHA) heart failure guidelines are as follows[13] :
Automatic implantable cardioverter-defibrillators (AICDs) are designed to detect and correct ventricular tachycardia/ventricular fibrillation. 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.
AICD trials (ie, the Multicenter Automatic Defibrillator Implantation Trial II [MADIT II],[132] Sudden Cardiac Death in Heart Failure Trial [SCD-HeFT][133] ) have defined a clear mortality benefit in patients with a history of significant left-sided ventricular dysfunction.
Indications for ICD according to 2013 ACC/AHA include[13] :
In the Danish ICD Study in Patients With Dilated Cardiomyopathy (DANISH), which assessed the benefit of prophylactic ICDs in patients with nonischemic cardiomyopathy and an LVEF below 35%, the primary outcome of death from any cause was not statistically different from those on standard heart failure therapy.[134] SCD occurred less often in the ICD group (4.3%) than in the control group (8.2%). When stratified by age, patients younger than 59 years old derived a mortality benefit with ICD as compared to those older than 59 years who had no difference in primary outcome. Background beta blocker therapy was administered to more than 90% of patients in both groups.[134]
When progressive end-stage heart failure occurs despite maximal medical therapy, when the prognosis is poor, and when there is no viable therapeutic alternative, the criterion standard for therapy has been heart transplantation. Absolute indications for heart transplantation are as follows:
Relative indications are as follows:
The importance of patient education cannot be overemphasized, especially regarding dietary restrictions. Dietary recommendations include sodium and water restrictions. An average United States diet contains 6 g of salt per day. Avoiding extra table salt decreases this intake to 3 g/day. Patients with chronic heart failure should restrict their salt intake to less than 2-4 g/day.
Fluid restriction is necessary in symptomatic stages of the disease. Patients with hyperkalemia due to angiotensin-converting enzyme (ACE) inhibitor therapy sometimes respond to a low-potassium diet.
Encourage patients to exercise moderately, because deconditioning is a very common cause of dyspnea. Cardiac rehabilitation has been shown to improve patient outcomes.
Benefits of cardiac rehabilitation include a 20-30% reduction in all-cause mortality rates; decreased mortality up to 5 years following rehabilitation; reduced symptoms of dyspnea, angina, and fatigue; reduction in nonfatal recurrent myocardial infarction over follow-up period of 12 months; and increased exercise performance.[135, 136, 137, 138, 139, 140]
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.
The CUPID-2 trial (calcium upregulation by percutaneous administration of gene therapy in patients with cardiac disease) assessed the effectiveness of a gene transfer vector on the basis of adeno-associated virus 1 (AAV1)'s ability to deliver SERCA2a (sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase)–complementary DNA in patients with heart failure and reduced ejection fraction (LVEF < 35%).[141] Compared to placebo, there were no differences in recurrent heart failure-related hospitalizations or ambulatory treatment for heart failure, as well as no difference in the rate of death, heart transplantation, or mechanical circulatory support implantation.[141]
Myoblast transplantation involves the injection of skeletal myoblasts as an autograft into damaged myocardium (scar).
In the Poznan (phase I) trial in Poznan, Poland, which studied 10 patients with postinfarction heart failure without viable myocardium but who had adequate coronary flow from revascularization or collateral vessels and underwent skeletal myoblast transplant injection through catheterization of cardiac veins via intravascular ultrasonographic guidance, 9 patients showed improvement in New York Heart Association (NYHA) symptoms from class II-III to class I.[142] Segmental contractility was not statistically evaluated owing to the small number of patients.
The Myoblast Autologous Grafting in Ischemic Cardiomyopathy (MAGIC) trial was the first randomized placebo-controlled trial that studied myoblast transplantation in patients with left ventricular ejection fraction (LVEF) below 35% as well as with myocardial infarction and indication for coronary artery bypass graft (CABG) surgery.[143] At 6-month follow-up, autologous skeletal myoblast transplantation (low and high doses) via intraoperative injection in and around myocardial scars did not improve regional or global LV function compared to the control group, although the high-dose cell transplant group had a significant decrease in LV volumes. There was also a higher rate of postoperative arrhythmic events in myoblast-treated patients, but there were no differences in 6-month rates of major adverse cardiac events and ventricular arrhythmias.[143]
In a study evaluating autologous skeletal myoblast transplantation in patients undergoing CABG or left ventricular assist device (LVAD) implantation, follow-up positron-emission tomography (PET) scans showed glucose uptake within infarcted scars (ie, new areas of viability).[144] LVEF also increased from 28% to 36% after 2 years. Moreover, the explanted hearts showed survival of the transplanted fibroblasts.[144]
Human embryonic stem cells have been differentiated ex vivo to derive cardiac myocyte stem cells. When transplanted into rats that had left anterior descending coronary artery ligation, these stem cells have been shown to attenuate the adverse remodeling seen with extensive infarcts.[145]
Autologous stem cells have been given both intramyocardially and intravenously 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.[146]
An evaluation of the safety and efficacy of ixmyelocel-T, administered via minithoracotomy or intramyocardial catheter injections, in 2 prospective randomized phase 2A trials in patients with dilated cardiomyopathy (DCM) stratified by ischemic or nonischemic status revealed evidence that intramyocardial injection with ixmyelocel-T reduced major adverse cardiovascular events and improved symptoms in patients with ischemic DCM but not in patients with nonischemic DCM.[147] In the IMPACT-DCM trial, 39 patients were randomized to either ixmyelocel-T or standard-of-care control in a 3:1 ratio; ixmyelocel-T was administered intramyocardially via minithoracotomy. In the Catheter-DCM trial, 22 patients were randomized to either ixmyelocel-T or standard-of-care control in a 2:1 ratio; ixmyelocel-T was administered intramyocardially with the NOGA Myostar catheter.
Relative to control patients, fewer ischemic patients treated with ixmyelocel-T experienced a major adverse cardiovascular event during follow-up, but nonischemic patients did not have a similar benefit.[147] The most common major adverse cardiovascular event was exacerbation of heart failure. Those in the ischemic population who received ixmyelocel-T had improved NYHA class, 6-minute walk distance, and Minnesota Living with Heart Failure Questionnaire scores compared to the control group; again, the nonischemic group did now demonstrate a similar trend.[147]
In a nonrandomized prospective study involving 14 patients with end-stage ischemic heart disease who underwent transendocardial injection of autologous mononuclear bone marrow cells, Perin et al noted a significant reduction in total reversible defect, improvement in global LV function, reduction in end-systolic volume, and improvement in LVEF from 20% at baseline to 29%.[148]
CardioMEMS is a wireless implantable pulmonary artery (PA) pressure monitoring system used to guide management and reduce hospital stay. In the Cangrelor vs Standard Therapy to Achieve Optimal Management of Platelet Inhibition (CHAMPION) trial, which studied patients with NYHA class III symptoms and a previous heart failure hospitalization, during the mean follow-up period of 15 months, the treatment group demonstrated a 39% reduction in heart-failure related hospitalizations relative to the control group.[149] Eligible patients included those with NYHA III symptoms for at least 3 months and a hospitalization for heart failure for the past 12 months. Ejection fraction was not an inclusion criteria.
The 2016 European Society of Cardiology (ESC) guidelines has a class IIB recommendation for CardioMEMS placement in patients with heart failure and a previous heart failure hospitalization to reduce the risk of recurrent heart failure hospitalizations.[150]
Consult an internist, an intensivist, or a cardiologist as indicated for admission when a patient has been diagnosed with dilated cardiomyopathy for the first time or for continued inpatient treatment or monitoring. Emergent consultation with a cardiologist is indicated in unstable patients for echocardiography in the emergency department.
Refer appropriate patients with New York Heart Association (NYHA) functional class III-IV dilated cardiomyopathy to cardiology services for consideration of advanced therapies, including implantation of left ventricular assist devices (LVADs) or heart transplantation.
Patients with familial dilated cardiomyopathy can register with the Dilated Cardiomyopathy Research Project (formerly Familial Dilated Cardiomyopathy [FDC] Research Group), whose contact information is as follows:
Dilated Cardiomyopathy Research Project
Telephone (toll free): (877) 800-3430
E-mail: DCM.Research@osumc.edu
The goals of pharmacotherapy include symptom relief, improved cardiac output, shortened hospital stay, fewer emergency department visits, reversal of injury process, and decreased mortality. Drug classes used include angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers, beta-blockers, aldosterone antagonists, cardiac glycosides, diuretics, nitrates, vasodilators, sacubitril-valsartan, ivabradine, antiarrhythmics, and inotropic agents.
In cases of dilated cardiomyopathy secondary to myocarditis, corticosteroids have been suggested to be helpful in decreasing inflammation; however, the Multicenter Myocarditis Treatment Trial showed no benefit in the use of corticosteroids and azathioprine for treatment of biopsy-proven inflammation in dilated cardiomyopathy. Some smaller uncontrolled studies have shown benefit, but these results have not been confirmed with a controlled study.
Clinical Context: Enalapril prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in increased levels of plasma renin and a reduction in aldosterone secretion. This agent helps control blood pressure and proteinuria. It decreases pulmonary-to-systemic flow ratio in the catheterization laboratory and increases systemic blood flow in patients with relatively low pulmonary vascular resistance.
Enalapril has a favorable clinical effect when administered over a long period. It helps prevent potassium loss in distal tubules. Because the body conserves potassium, less oral potassium supplementation is needed.
Clinical Context: Lisinopril prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in increased levels of plasma renin and a reduction in aldosterone secretion.
Clinical Context: Ramipril prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in increased levels of plasma renin and a reduction in aldosterone secretion.
Use of ACE inhibitors (in the absence of contraindications to ACE inhibition) is the current criterion standard in the treatment of left ventricular dysfunction. 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. However, authorities have generally accepted that maximizing ACE inhibitor therapy is important and should be accomplished in conjunction with other necessary therapies.
Clinical Context: Valsartan is used in patients who cannot tolerate ACE inhibitors. It may induce more complete inhibition of the renin-angiotensin system than ACE inhibitors. Valsartan does not affect the response to bradykinin and is less likely to be associated with cough and angioedema.
Clinical Context: Losartan is an ARB that blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II. It may induce a more complete inhibition of the renin-angiotensin system than ACE inhibitors, it does not affect the response to bradykinin, and it is less likely to be associated with cough and angioedema. It is used for patients unable to tolerate ACE inhibitors.
Clinical Context: Candesartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II. It may induce more complete inhibition of renin-angiotensin system than ACE inhibitors, it does not affect response to bradykinin, and it is less likely to be associated with cough and angioedema. It is used in patients unable to tolerate ACE inhibitors.
Clinical Context: Olmesartan blocks the vasoconstrictor effects of angiotensin II by selectively blocking binding of angiotensin II to the AT-1 receptor in vascular smooth muscle. Its action is independent of pathways for angiotensin II synthesis.
Angiotensin receptor blockers are as effective as ACE inhibitors in the treatment of heart failure. Their adverse-effect profile is similar to that of ACE inhibitors with regard to renal insufficiency or hyperkalemia but they do not cause potentiation of bradykinin and therefore do not cause cough.
Clinical Context: Carvedilol blocks beta1-, alpha-, and beta2-adrenergic receptor sites, decreasing adrenergic-mediated myocyte damage.
Clinical Context: Metoprolol is a selective beta1-adrenergic receptor blocker that decreases automaticity of contractions. During intravenous administration of metoprolol, carefully monitor the patient's blood pressure, heart rate, and electrocardiogram.
Clinical Context: Bisoprolol is a selective beta1-adrenergic receptor blocker that decreases automaticity of contractions.
Clinical Context: Nesiritide is a recombinant DNA form of human BNP that dilates veins and arteries. Human BNP binds to the 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. 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 temporary use in patients with acutely decompensated CHF.
Human BNP has additional beneficial effects for heart failure patients. Neurohormonal effects on the rennin-angiotensin-aldosterone system (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.
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 (FDA) for use in persons with heart failure. Carvedilol acts in 3 ways: as a beta-blocker, an alpha-blocker, and an antioxidant and may be more beneficial than metoprolol in heart failure.
Human B-type natriuretic peptide (BNP) is produced through recombinant DNA technology and has the same amino acid sequence as naturally occurring human BNP. Nesiritide is a human BNP.
Clinical Context: Eplerenone selectively blocks aldosterone at the mineralocorticoid receptors in epithelial (eg, kidney) and nonepithelial (eg, heart, blood vessels, and brain) tissues; thus, it decreases blood pressure and sodium reabsorption. This agent is indicated to improve survival for congestive heart failure or left ventricular dysfunction following acute myocardial infarction (MI). It is a more specific mineralocorticoid antagonist than spironolactone, and thus avoids the gynecomastia, breast pain, and menstrual disturbances common in patients on spironolactone.
Clinical Context: Spironolactone is indicated for management of edema resulting from excessive aldosterone excretion. It competes with aldosterone for receptor sites in distal renal tubules, increasing water excretion while retaining potassium and hydrogen ions. Therapy may be switched to eplerenone in the presence of gynecomastia.
Spironolactone is complementary to standard therapy in modulating the renin-angiotensin-aldosterone system (RAAS) because aldosterone levels remain elevated despite ACE inhibitor therapy. Spironolactone is currently indicated for treating patients with mild-to-severe heart failure (NYHA class II-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 greater than 5 mmol/L or those with serum creatinine levels greater than 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.
Clinical Context: Furosemide increases excretion of water by interfering with the chloride-binding cotransport system, which, in turn, inhibits sodium and chloride reabsorption in the ascending loop of Henle and distal renal tubule. The bioavailability of oral furosemide is 50%. If a switch is made from IV to oral administration, an equivalent oral dose should be used. Doses vary depending on the patient's clinical condition.
Clinical Context: Bumetanide increases the excretion of water by interfering with the chloride-binding cotransport system, which, in turn, inhibits sodium and chloride reabsorption in the ascending loop of Henle. This agent does not appear to act in the distal renal tubule.
Clinical Context: Torsemide is well-absorbed, with a peak plasma concentration within 1 hour. Oral bioavailability does not differ between patients with CHF and normal patients (80-90%).
The bioavailability of furosemide is aoout 50%, but it is highly variable (10-90%). In patients with severe edema that may impair absorption, the furosemide effect may be limited, and therapy should be switched to torsemide.
Bumetanide has an oral bioavailability of 80-100%. Torsemide is considered superior to furosemide and bumetanide: Its bioavailability is superior to that of furosemide, and it has a longer half-life than bumetanide.
Clinical Context: Ethacrynic acid increases the excretion of water by interfering with the chloride-binding cotransport system, which, in turn, inhibits sodium and chloride reabsorption in the ascending loop of Henle and distal renal tubule. This agent is used only in refractory cases. Continuous IV infusion is preferable in many cases. It is indicated for temporary treatment of edema associated with heart failure when greater diuretic potential is needed. It is useful for patients who have a true sulfonamide allergy.
Diuretics are reserved for congestive states. They are not indicated for patients with functional restriction in the absence of edema/congestion.
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 days, they should be advised to double their diuretic dose and potassium supplement for 1 day. 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.
Clinical Context: Amiodarone is a class III antiarrhythmic agent (K-channel blocker) with class I activity that may inhibit atrioventricular conduction and sinus node function. It prolongs the action potential and refractory period in myocardium and inhibits adrenergic stimulation.
In patients with recent myocardial infarction and congestive heart failure, amiodarone reduces sudden cardiac death but is inferior compared to ICDs.
For patients with heart failure presumed to be resultant from atrial fibrillation, rhythm control should be attempted. Amiodarone is commonly initiated, with cardioversion attempted 1 month later.[60] Amiodarone is among the most effective antiarrhythmic agents for suppression of atrial fibrillation. In patients with systolic heart failure and atrial fibrillation, rhythm control does not improve mortality, hospitalization for heart failure exacerbation, or stroke as compared to rate control. [Roy D, Talajic M, Nattel S, et al, for the Atrial Fibrillation and Congestive Heart Failure Investigators. Rhythm control versus rate control for atrial fibrillation and heart failure. N Engl J Med. 2008 Jun 19. 358 (25):2667-77.]
Monitoring of pulmonary, thyroid, and liver toxicity while patients are on amiodarone therapy is advised.
Clinical Context: Dofetilide is the prototype of a "pure" class III agent. It has been approved by the US Food and Drug Administration (FDA) for maintenance of sinus rhythm after conversion from atrial fibrillation or atrial flutter lasting longer than 1 week. It is also indicated for conversion of atrial fibrillation and atrial flutter to normal sinus rhythm. If patients do not convert within 24 hours of initiation of therapy, electrical cardioversion should be considered.
Torsade de pointes is the only complicating arrhythmia showing dose-response relationship. The prevalence with supraventricular arrhythmia is 0.8%. Majority of torsade de pointes episodes occur within first 3 days of therapy.
Dofetilide has no effect on cardiac output, cardiac index, stroke volume index, or systemic vascular resistance in patients with ventricular tachycardia, mild-to-moderate heart failure, angina, and either normal or reduced left ventricular ejection fraction (LVEF). It does not affect blood pressure.
Dofetilide blocks delayed rectifier current (IKr) and prolongs action potential duration; indeed, even at higher magnitudes, it has no effect upon other depolarizing potassium currents (IKs and IKl). It terminates induced re-entrant tachyarrhythmias (atrial fibrillation/flutter and ventricular tachycardia) and prevents their re-induction. At clinically prescribed concentrations, it has no effect on sodium channels, which are associated with class I effects. Furthermore, no effect is noted on alpha- or beta-adrenergic receptors.
Dofetilide must be initiated with continuous ECG monitoring and monitoring must be continued for more than 12 hours after conversion. Dose must be individualized according to creatinine clearance (CrCl) and QTc (use QT interval if heart rate < 60/min). There is no information on use of this drug for heart rates less than 50 beats per minute.
Antiarrhythmics are useful in patients with supraventricular and nonsustained ventricular tachycardias. Not all antiarrhythmics are considered safe in patients with structural heart disease. The class III antiarrhythmics amiodarone and dofetilide are favored in these patients for the treatment of supraventricular and ventricular dysrhythmias.
Clinical Context: Hydralazine decreases systemic resistance through direct vasodilation of arterioles.
Clinical Context: This product is a 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. It is indicated for heart failure in black patients.
Clinical Context: Nitroglycerin causes relaxation of vascular smooth muscle by stimulating intracellular cyclic guanosine monophosphate (cGMP) production, resulting in a decrease in blood pressure.
Clinical Context: Sacubitril-valsartan may replace ACE inhibitors in patients who are symptomatic on optimal heart failure therapy.
Clinical Context: In patients with systolic heart failure with an LVEF below 35%, who are in sinus rhythm, have a resting heart rate more than 70 beats per minute, and are on maximally tolerated doses of beta-blockers or who were intolerant to beta blockers, ivabradine reduces cardiovascular death and hospital admission for worsened heart failure.
Preload reduction with venodilators is thought to be helpful in acute decompensated heart failure by reducing congestions and minimizing cardiac oxygen demand. Afterload reduction is also thought to be helpful in some patients with acute decompensated heart failure by decreasing myocardial oxygen demand and improving forward flow.
Sublingual nitroglycerin spray, nitropaste, and IV nitroglycerin have been advocated in the treatment of pulmonary edema secondary to CHF. Morphine also has significant vasodilatory effects and can be useful.
Clinical Context: Milrinone is a phosphodiesterase III inhibitor that prevents degradation of cAMP, ultimately leading to increased myocardial contraction and lusitropy, decreased pulmonary vascular resistance, and reduced afterload. It differs in mode of action from both digitalis glycosides and catecholamines. This agent is used for the short-term management of acute decompensated heart failure.
Clinical Context: In patients with cardiogenic shock/decompensated heart failure due to myocardial dysfunction, dobutamine is a beta-agonist that may be acutely used to increase cardiac output. In those with low-flow heart failure, chronic dobutamine infusion may be considered in those awaiting transplant or for those who are not candidates for advanced therapies (transplant, ventricular assist device).
Note that chronic infusion may be associated with an increased mortality risk due to ventricular arrhythmias.
Clinical Context: Digoxin is a cardiac glycoside with direct inotropic effects in addition to indirect effects on the cardiovascular system. It 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.
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. 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 dobutamine in that it can be used for acute inotropic support during introduction of beta-blocker therapy, particularly in those who are beta-blocker intolerant due to the myocardial depressant effects.[151]
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.
Clinical Context: Warfarin interferes with the hepatic synthesis of vitamin K–dependent coagulation factors. Tailor the dose to maintain the International Normalized Ratio (INR) in the range of 2-3.
The use of anticoagulants is restricted to patients in atrial fibrillation, with artificial valves, and with known mural thrombus. Some data support their use in patients with low ejection fractions.