Determining the etiology and severity of heart failure or cardiomyopathy

INTRODUCTION — Heart failure (HF) is a common clinical syndrome caused by a variety of cardiac diseases [1]. Evaluation of the etiology and severity of HF is discussed here. Initial evaluation of suspected HF and the management and prognosis of HF are discussed separately. (See "Heart failure: Clinical manifestations and diagnosis in adults" and "Overview of the management of heart failure with reduced ejection fraction in adults" and "Prognosis of heart failure" and "Treatment and prognosis of heart failure with preserved ejection fraction".)

Evaluation of patients with HF should also include evaluation for concurrent conditions as appropriate, such as sleep-disordered breathing. (See "Sleep-disordered breathing in heart failure".)

DEFINITION — HF is a common clinical syndrome with symptoms caused by impaired ability of one or both ventricles to pump at a normal pressure due to a structural or functional cardiac disorder [2]. It is characterized by specific symptoms, such as dyspnea and fatigue, and signs, such as fluid retention. There are many ways to assess cardiac function. However, there is no diagnostic test for HF, since it is largely a clinical diagnosis that is based upon a careful history and physical examination. (See "Heart failure: Clinical manifestations and diagnosis in adults".)

Classification of HF severity — The history, including assessment of New York Heart Association (NYHA) functional class, and physical examination in conjunction with the diagnostic tests reviewed below should both establish the primary cause of the HF and provide a reasonable estimate of its severity.

The classification system that is most commonly used to quantify the degree of functional limitation imposed by HF is one first developed by the NYHA. This system assigns patients to one of four functional classes, depending on the degree of effort needed to elicit symptoms (table 1):

●Class I – Patients with heart disease without resulting limitation of physical activity. Ordinary physical activity does not cause HF symptoms such as fatigue or dyspnea.

●Class II – Patients with heart disease resulting in slight limitation of physical activity. Symptoms of HF develop with ordinary activity but there are no symptoms at rest.

●Class III – Patients with heart disease resulting in marked limitation of physical activity. Symptoms of HF develop with less than ordinary physical activity but there are no symptoms at rest.

●Class IV – Patients with heart disease resulting in inability to carry on any physical activity without discomfort. Symptoms of HF may occur even at rest.

Stages in the development of HF — There are several stages in the evolution of HF, as outlined by the American College of Cardiology Foundation/American Heart Association guidelines [2]:

●Stage A – At high risk for HF but without structural heart disease or symptoms of HF.

●Stage B – Structural heart disease but without signs or symptoms of HF. This stage includes patients in NYHA functional class I with no prior or current symptoms or signs of HF.

●Stage C – Structural heart disease with prior or current symptoms of HF. This stage includes patients in any NYHA functional class (including class I with prior symptoms).

●Stage D – Refractory HF requiring specialized interventions. This stage includes patients in NYHA functional class IV with refractory HF.

This staged system, in contrast to the NYHA classification, emphasizes the progressive nature of HF and defines the appropriate therapeutic approach for each stage.

The long-term prognosis can also be estimated. The peak VO₂ is a helpful predictor of prognosis, but functional class and exercise capacity, the magnitude of the reduction in left ventricular ejection fraction (LVEF) with systolic dysfunction, serum B-type natriuretic peptide concentrations, and a variety of other factors are also important. (See "Predictors of survival in heart failure with reduced ejection fraction".)

Etiology

Categories of disease — HF is caused by a variety of disorders, including diseases affecting the pericardium, myocardium, endocardium, cardiac valves, vasculature, or metabolism [2]. The discussion here will focus primarily on myocardial causes of HF. There are two basic pathophysiologic myocardial mechanisms that cause reduced cardiac output and HF: systolic and diastolic dysfunction. Systolic and diastolic dysfunction each may be due to a variety of etiologies. Effective management is often dependent upon establishing the correct etiologic diagnosis. As an example, coronary revascularization may be beneficial in patients with ischemic cardiomyopathy who have evidence of hibernating myocardium. (See "Epidemiology of heart failure" and 'Detection of coronary artery disease' below.)

The challenge of finding the correct etiology in patients with HF is illustrated by studies that have compared the clinical (pre-transplant) diagnosis and morphologic diagnosis (based upon pathologic examination of the explanted heart) in heart transplant recipients. In two series, each spanning two decades, 17 and 13 percent of patients were misdiagnosed prior to transplantation, particularly patients with nonischemic cardiomyopathy (30 and 22 percent with clinical misdiagnosis) [3,4]. Conditions that were missed clinically included cardiac sarcoidosis, myocarditis, arrhythmogenic right ventricular cardiomyopathy (in both series), and hypertrophic cardiomyopathy and noncompaction (in one series [4]).

Heart failure with reduced ejection fraction — HF with reduced EF (HFrEF; LVEF ≤40 percent) is also known as systolic HF or HF due to systolic dysfunction.

The most common causes of systolic dysfunction are coronary (ischemic) heart disease, idiopathic dilated cardiomyopathy (DCM), hypertension, and valvular disease. Effective therapy of hypertension has led to a changing pattern in which coronary disease has become more prevalent as a cause of HF [5,6]. In one review, coronary disease and hypertension accounted for 62 and 10 percent of cases, respectively [5]. (See "Epidemiology of heart failure".)

As compared with all patients presenting with HF, patients who present with initially unexplained DCM have a different distribution of etiologies. After a complete evaluation of 1278 such patients, the relative frequency of the different causes was as follows [7]:

●Idiopathic – 50 percent

●Myocarditis – 9 percent

●Ischemic heart disease – 7 percent

●Infiltrative disease – 5 percent

●Peripartum cardiomyopathy – 4 percent

●Hypertension – 4 percent

●HIV infection – 4 percent

●Connective tissue disease – 3 percent

●Substance abuse – 3 percent

●Doxorubicin – 1 percent

●Other – 10 percent

Heart failure with preserved ejection fraction — HFpEF is also known as diastolic HF and refers to HF in patients with an LVEF ≥50 percent or >50 percent [2].

Diastolic dysfunction can be caused by many of the same conditions that lead to systolic dysfunction. The most common causes are hypertension, ischemic heart disease, diabetes, hypertrophic obstructive cardiomyopathy, and restrictive cardiomyopathy. However, many patients with symptoms suggestive of HF (shortness of breath, ankle edema, or paroxysmal nocturnal dyspnea) who have intact LV systolic function may not have diastolic dysfunction, but have other etiologies that can account for their symptoms, including obesity, lung disease, or occult coronary ischemia [8]. (See "Heart failure with preserved ejection fraction: Clinical manifestations and diagnosis".)

Heart failure with midrange ejection fraction — Patients with LVEF between 41 and 49 are categorized as HF with mid-range ejection fraction (HFmrEF), and share characteristics with both HFpEF and HFrEF. (See "Treatment and prognosis of heart failure with mildly reduced ejection fraction".)

DETERMINING THE CAUSE AND SEVERITY OF HEART FAILURE OR CARDIOMYOPATHY

Diagnostic approach — The approach to determining the cause and severity of HF or cardiomyopathy includes the history, physical examination, and diagnostic tests. Initial tests include an electrocardiogram (ECG), initial blood tests, echocardiogram, and assessment for coronary artery disease.

Clinical presentation — Symptoms of HF include those due to excess fluid accumulation (dyspnea, ankle or abdominal swelling) and those due to a reduction in cardiac output (fatigue, weakness) that is most pronounced with exertion. (See "Heart failure: Clinical manifestations and diagnosis in adults", section on 'Symptoms and associated conditions'.)

The history and clinical presentation may be helpful in identifying the etiology of HF. As examples:

●Classic exertional angina usually indicates ischemic heart disease.

●Acute HF after an antecedent flu-like illness suggests viral myocarditis.

●Long-standing hypertension or alcohol use suggests hypertensive or alcohol-induced cardiomyopathy.

●A diagnosis of amyloidosis should be strongly considered in patients who have a family history of unexplained cardiomyopathy or amyloidosis, low voltage on ECG, LV hypertrophy by echocardiography (especially without hypertension), and a history of heavy proteinuria. It should be appreciated, however, that mild proteinuria can be seen with HF alone. (See "Predictors of survival in heart failure with reduced ejection fraction", section on 'Albuminuria'.)

●HF may be provoked or worsened by drugs, including antiarrhythmic agents such as disopyramide and flecainide; calcium channel blockers, particularly verapamil; beta blockers; and nonsteroidal antiinflammatory drugs [9].

●Acute pulmonary edema occurring during or shortly after infusion of blood products suggests transfusional volume overload.

Physical examination — The physical examination can provide evidence of the presence and extent of cardiac filling pressure elevation, volume overload, ventricular enlargement, pulmonary hypertension, and reduction in cardiac output. (See "Heart failure: Clinical manifestations and diagnosis in adults", section on 'Physical examination'.)

Findings that suggest particular causes of HF include:

●Primary valvular dysfunction should be considered in a patient with a cardiac murmur. (See "Auscultation of cardiac murmurs in adults".)

●The presence of hypertension suggests hypertension as a cause of HF and/or as an exacerbating factor.

●Extracardiac findings may suggest specific types of cardiomyopathy such as the following:

•The presence of periorbital purpura (nearly pathognomonic for AL amyloid cardiomyopathy) or peripheral neuropathy (a nonspecific finding seen in some patients with AL or mutant transthyretin amyloid cardiomyopathy). (See "Cardiac amyloidosis: Epidemiology, clinical manifestations, and diagnosis".)

•The classic triad of cirrhosis, diabetes mellitus, and skin pigmentation ("bronze diabetes") suggests late stage hemochromatosis, but most patients with iron overload present at an earlier stage without these findings. (See "Clinical manifestations and diagnosis of hereditary hemochromatosis", section on 'Clinical manifestations'.)

INITIAL TESTS

Electrocardiogram — The ECG may show findings that favor the presence of a specific cause of HF and can also detect arrhythmias such as asymptomatic ventricular premature beats, runs of nonsustained ventricular tachycardia, or atrial fibrillation, which may be the cause of or exacerbate HF. (See "Arrhythmia-induced cardiomyopathy".)

Patients with dilated cardiomyopathy frequently have first degree atrioventricular block, left bundle branch block, left anterior fascicular block, or a nonspecific intraventricular conduction abnormality.

Potentially diagnostic findings on ECG include the following:

●Evidence of ischemic heart disease, including evidence of prior or acute myocardial infarction or ischemia.

●LV hypertrophy due to hypertension; a pseudoinfarct pattern may also be present representing significant posterior forces of the increased LV mass.

●Low limb lead voltage on the surface ECG with a pseudo-infarction pattern (loss of precordial R wave progression in leads V1-V6) can suggest an infiltrative process such as amyloidosis.

●Low limb lead voltage with precordial criteria for LV hypertrophy is most suggestive of idiopathic dilated cardiomyopathy. A widened QRS complex and/or a left bundle branch block pattern is also consistent with this diagnosis.

●Heart block, that may be complete, and various types of intraventricular conduction defects are observed in patients with cardiac sarcoidosis.

●The presence of a persistent tachycardia such as atrial fibrillation with a rapid ventricular response may result from or lead to HF, since this arrhythmia can cause cardiomyopathy (tachycardia-mediated cardiomyopathy).

Initial blood tests — Recommended initial blood tests for patients with symptoms and signs of HF include [2]:

●A complete blood count, which may suggest concurrent or alternate conditions. Anemia or infection can exacerbate pre-existing HF. (See "Evaluation and management of anemia and iron deficiency in adults with heart failure".)

●Serum electrolytes (including calcium and magnesium), blood urea nitrogen, and creatinine may indicate associated conditions. Hyponatremia generally indicates severe HF, though it may occasionally result from excessive diuresis [10]. Renal impairment may be caused by and/or contribute to HF exacerbation. Baseline evaluation of electrolytes and creatine is also necessary when initiating therapy with diuretics and/or angiotensin converting enzyme inhibitors.

●Liver function tests, which may be affected by hepatic congestion.

●Fasting blood glucose and lipid profile to detect underlying diabetes mellitus and lipid disorders. (See "Heart failure in patients with diabetes mellitus: Epidemiology, pathophysiology, and management" and "Screening for lipid disorders in adults".)

●Thyroid stimulating hormone, since hyperthyroidism or hypothyroidism can precipitate HF. (See "Cardiovascular effects of hyperthyroidism" and "Cardiovascular effects of hypothyroidism".)

The role of B-type natriuretic peptide (BNP) and N-terminal pro-BNP in diagnosis of HF is discussed separately. (See "Natriuretic peptide measurement in heart failure".)

Echocardiography — Echocardiography should be performed in all patients with new onset HF and can provide important information about ventricular size and function. For example, patients with idiopathic dilated cardiomyopathy typically have both left and right ventricular enlargement (four chamber dilatation) with decreased left systolic ventricular function. (image 1 and figure 1 and movie 1 and movie 2 and movie 3). (See "Echocardiographic recognition of cardiomyopathies".)

The sensitivity and specificity of two-dimensional echocardiography for the diagnosis of systolic dysfunction are as high as 80 and 100 percent, respectively [10]. A number of other important findings also can be detected:

●Although regional wall motion abnormalities are compatible with coronary heart disease, they are not specific for ischemia since they also occur in 50 to 60 percent of patients with idiopathic dilated cardiomyopathy [11].

However, regional wall motion assessment using dobutamine stress echocardiography may increase the ability to distinguish among ischemic and nonischemic cardiomyopathies. The presence of six or more akinetic segments, for example, was 80 percent sensitive and 96 percent specific for ischemic dilated cardiomyopathy in one report [12].

●Pericardial thickening suggestive of constrictive pericarditis.

●Valvular structure and function in valve disease.

●Interatrial and interventricular shunts.

●Abnormal myocardial texture in infiltrative cardiomyopathies, with LV hypertrophy and a "sparkling" pattern being suggestive of cardiac amyloidosis (movie 4 and movie 5 and movie 6). (See "Echocardiographic recognition of cardiomyopathies".)

●Right ventricular size and function in right HF.

●Estimation of pulmonary capillary wedge pressure (PCWP) via the ratio (E/Ea or E/E') of tissue Doppler of early mitral inflow velocity (E) to early diastolic velocity of the mitral annulus (Ea or e'). An E/e' ratio >15 suggests a PCWP >15 mmHg when e' is the mean of medial and lateral mitral annulus early diastolic velocities [13]. Use and limitations of this method are discussed separately. (See "Echocardiographic evaluation of left ventricular diastolic function in adults", section on 'Tissue Doppler imaging'.)

•However, the E/e' ratio may not be a reliable indicator of PCWP in patients with acute decompensated HF. In a series of 106 patients with acute decompensated HF and LVEF ≤30 percent, the E/e' ratio did not correlate with PCWP [14]. One limitation of this study is that patients with significant mitral valve disease were not excluded.

•One limitation of use of the E/e' ratio is that it does not predict PCWP in patients with significant mitral valve disease (either mitral stenosis or mitral regurgitation). In patients with mitral valve disease, a preliminary report indicates that the ratio of isovolumetric relaxation time to the time interval between the onset of E and Ea (TE-Ea) correlates with PCWP [15].

●A short deceleration time (≤125 ms) is an independent predictor of poor prognosis in patients with LV dysfunction, regardless of the presence or absence of symptoms [16].

●Right atrial and pulmonary artery pressures, determined by the peak velocity of tricuspid regurgitation on Doppler echocardiography. These findings correlate with the pulmonary artery wedge pressure, regardless of the etiology of HF or severity of tricuspid regurgitation; they can be used to assess changes in LV filling pressures resulting from therapy [9].

●Limited data suggest that the cardiac output can be measured accurately by pulsed-wave Doppler from the LV outflow tract, even in the presence of a low output state or tricuspid regurgitation (image 2) [17].

Echocardiography in conjunction with dobutamine is also useful in predicting recovery of cardiac function [18,19]. (See "Prognosis of heart failure".)

Exercise testing — Exercise testing should be part of the initial evaluation of virtually all patients with HF. In addition to detection of ischemic heart disease, assessment of exercise capacity can be used for risk stratification and determining prognosis; serial measurements also can assess the efficacy of therapy and clinical stability of patients over time.

With severe HF, measurement of the maximal oxygen uptake (VO₂max) provides an objective estimate of the functional severity of the myocardial dysfunction. VO₂max is one of the best indices of prognosis in patients with symptomatic HF and can aid in the determination of the necessity and timing of listing for cardiac transplantation. A simple alternative that may provide an estimate of exercise function is the six-minute walk test. However, peak VO₂ and exercise capacity can be affected by factors other than cardiac status, including deconditioning, pulmonary disease, and anemia. One advantage of measuring VO₂max directly is that cardiac and non-cardiac causes of impaired exercise can be distinguished by assessing the anaerobic threshold and related indices. (See "Exercise capacity and VO2 in heart failure".)

Detection of coronary artery disease — Virtually all patients with unexplained HF should be evaluated for the presence of coronary heart disease. Most patients with HF due to ischemic cardiomyopathy have known coronary heart disease. However, occult disease is a common cause of dilated cardiomyopathy, accounting for as many as 7 percent of initially unexplained cases [7]. On the other hand, chest pain alone is not sufficient to make the diagnosis since up to one-third of patients with nonischemic cardiomyopathy have chest pain that may resemble angina or be atypical. Revascularization may be of benefit in the appreciable number of patients in whom hibernating myocardium or silent ischemia is in part responsible for the decline in myocardial function.

This was illustrated in a meta-analysis of 24 studies involving 3088 patients (mean LVEF 32 percent) [20]. The 42 percent of patients with documented viability by thallium perfusion imaging, positron emission tomography (PET) scanning, or dobutamine echocardiography had a significant 80 percent reduction in annual mortality with revascularization (3.2 versus 16 percent for medical therapy). There was a direct relationship between the severity of LV dysfunction and the magnitude of benefit. In contrast, there was no difference in outcome with revascularization or medical therapy in patients without viability (annual mortality 7.7 versus 6.2 percent). (See "Treatment of ischemic cardiomyopathy".)

Stress testing — Noninvasive stress testing is a reasonable first step in the evaluation of coronary artery disease, as it not only provides information about the presence of ischemic heart disease, but also can be used for risk stratification and prognostic purposes. However, coronary angiography can be considered an alternative to stress testing in high-risk patients. (See "Stress testing for the diagnosis of obstructive coronary heart disease".)

Coronary arteriography — The 2013 American College of Cardiology Foundation/American Heart Association guideline made a weak recommendation for coronary arteriography when ischemia may be contributing to HF [2]. The diagnosis of an ischemic cardiomyopathy is an independent predictor of mortality; the extent of coronary artery disease as determined by angiography contributes more prognostic information than the clinical diagnosis of ischemic cardiomyopathy alone [21].

However, the angiographic findings must be considered in the context of the patient's history and other data. The presence of asymptomatic angiographic coronary artery disease in patients with dilated cardiomyopathy does not prove causality unless there is evidence of prior infarction or hibernating myocardium [22,23].

This was illustrated in a study of 55 patients who underwent heart transplantation; the patients carried a diagnosis of idiopathic dilated cardiomyopathy and all had had a normal coronary arteriogram within the preceding 10 years and no ischemic events [22]. Examination of the explanted heart revealed critical lesions in at least one coronary artery segment in 15 patients (27 percent) with no evidence of scars.

In addition to defining coronary artery anatomy, other useful information can be obtained from cardiac catheterization:

●Measurements of cardiac output, the degree of LV dysfunction, and LV end-diastolic pressure are helpful in assigning a severity score.

●Right (or left) ventricular endomyocardial biopsy can be performed if amyloidosis or an unusual cause of myocarditis is suspected [23]. (See 'Endomyocardial biopsy' below.)

●Intracardiac shunts/anomalies and anomalous coronary arteries can be detected, and the magnitude of secondary pulmonary hypertension can be assessed.

If significant coronary disease is documented, an improvement in outcome with revascularization compared with medical therapy appears to be limited to those with hibernating myocardium, as noted above [20]. Myocardial viability can be assessed by thallium perfusion imaging, PET scanning, or dobutamine echocardiography. (See "Evaluation of hibernating myocardium".)

Potential complications — Cardiac catheterization with coronary angiography is an invasive procedure with potentially serious complications such as atheroemboli and rarely myocardial infarction, ventricular tachyarrhythmias, stroke, and death. (See "Complications of diagnostic cardiac catheterization".)

Noninvasive coronary angiography — Because of concerns about the risk of invasive coronary angiography, noninvasive methods have been evaluated for the diagnosis of ischemic cardiomyopathy, although none are as yet recommended as a replacement for cardiac catheterization in patients with HF. Coronary artery disease can be directly imaged by computed tomography (CT) or cardiovascular magnetic resonance (CMR). Studies using MDCT or CMR have shown this to be a promising approach to the noninvasive distinction between ischemic and nonischemic cardiomyopathy. (See "Cardiac imaging with computed tomography and magnetic resonance in the adult".)

ADDITIONAL TESTS — If a cause of HF is not determined from the above assessment, the initial evaluation can help guide further testing.

Blood tests — If it is determined that dilated cardiomyopathy is responsible for HF and the cause is not apparent after the initial evaluation, several other blood tests may be warranted (see "Causes of dilated cardiomyopathy"). As noted above, thyroid disease should be considered in the initial evaluation.

Other studies that may be undertaken in selected patients depending upon results of initial evaluation include the following [2]:

●Screening for human immunodeficiency virus. (See "Cardiac and vascular disease in patients with HIV".)

●Iron studies (ferritin and total iron binding capacity) are helpful to screen for hereditary hemochromatosis (HH). Prior to increased screening, cardiac disease was the presenting manifestation in up to 15 percent of patients with HH. Thus, the absence of other characteristic findings of HH does not preclude the diagnosis. (See "Clinical manifestations and diagnosis of hereditary hemochromatosis", section on 'Cardiac iron overload'.)

●Antinuclear antibodies and other serologic tests for lupus and other rheumatologic diseases.

●Viral serologies and antimyosin antibody if myocarditis is suspected.

●Evaluation for pheochromocytoma.

●Thiamine, carnitine, and selenium levels.

●Genetic testing and counseling (eg, in patients suspected of familial cardiomyopathy after obtaining a detailed family history). (See 'Genetic evaluation of cardiomyopathy' below.)

Cardiovascular magnetic resonance — Cardiovascular magnetic resonance (CMR) imaging can be used to identify late gadolinium enhancement patterns suggestive of myocardial infarction or various types and causes of cardiomyopathy such as hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, sarcoidosis, cardiac amyloidosis, and myocarditis (which were among the diagnoses that were missed in some series). (See 'Etiology' above and 'Noninvasive coronary angiography' above and "Clinical utility of cardiovascular magnetic resonance imaging" and "Cardiac imaging with computed tomography and magnetic resonance in the adult".)

Endomyocardial biopsy — Endomyocardial biopsy is recommended in clinical scenarios in which its diagnostic and prognostic value is felt to outweigh the procedural risks. The diagnostic value of endomyocardial biopsy depends upon the anticipated yield of the procedure and also the availability of effective therapy. The indications, potential benefit, and risks of endocardial biopsy in identifying the etiology of dilated cardiomyopathy are discussed in detail separately. (See "Endomyocardial biopsy".)

In summary, endomyocardial biopsy is recommended in patients with fulminant HF (unexplained new-onset HF of less than two weeks duration with hemodynamic compromise) and in patients with early atrioventricular block, arrhythmias, or refractory HF (unexplained new-onset HF of two weeks to three months’ duration with a dilated LV). (See "Endomyocardial biopsy", section on 'EMB recommended'.)

Endomyocardial biopsy is suggested in other specific clinical scenarios when other evaluation is inconclusive. (See "Endomyocardial biopsy", section on 'EMB suggested in selected cases'.)

Genetic evaluation of cardiomyopathy — The importance of genetic factors in patients with cardiomyopathy has been increasingly recognized. The following considerations and recommendations apply to patients with cardiomyopathies as formally defined (ie, do not apply to patients with primarily valvular, ischemic, or hypertensive heart disease). (See "Definition and classification of the cardiomyopathies", section on 'Definition and classification'.)

Recognition of the genetic basis for various cardiomyopathies has implications for diagnosis and timely management. (See "Genetics of dilated cardiomyopathy" and "Arrhythmogenic right ventricular cardiomyopathy: Pathogenesis and genetics" and "Isolated left ventricular noncompaction in adults: Clinical manifestations and diagnosis" and "Hypertrophic cardiomyopathy: Gene mutations and clinical genetic testing" and "Restrictive cardiomyopathies".)

For example, among patients with idiopathic DCM, it is estimated that at least 25 percent have familial disease. No clinical or histologic criteria, other than family history and careful examination of relatives (including those who are asymptomatic), have been derived to distinguish familial from nonfamilial disease. The mode of inheritance is usually autosomal dominant, although autosomal recessive, X-linked, and mitochondrial inheritance have also been described. These disorders are discussed separately. (See "Familial dilated cardiomyopathy: Prevalence, diagnosis and treatment".)

Family history — The 2009 Heart Failure Society of America (HFSA) genetic evaluation of cardiomyopathy guideline recommends a careful family history for three or more generations for all patients with cardiomyopathy [24]. This recommendation applies to patients with hypertrophic cardiomyopathy (HCM), DCM, arrhythmogenic right ventricular cardiomyopathy (ARVC), LV noncompaction (LVNC), restrictive cardiomyopathy (RCM), and cardiomyopathies associated with extracardiac manifestations (eg, muscular dystrophy, Fabry disease, amyloidosis, or sarcoidosis).

The initial evaluation of the index patient should include family history and pedigree analysis for unexplained HF before age 60 or sudden cardiac death in the absence of ischemic symptoms.

Referral to a center with expertise in genetic cardiomyopathies may be helpful in obtaining and reviewing family history and pedigree information, as well as providing genetic counseling and testing. Specialized centers may also compile databases and perform research that promotes advances in this field.

Family screening — We agree with the 2009 HFSA guideline recommendation of screening first-degree relatives of patients with cardiomyopathy (including all types for which the guidelines recommend detailed family history). These guidelines are supported by evidence that cardiomyopathy is frequently familial and that affected family members are frequently asymptomatic [24]. Progressive disease may occur within a relatively short period of time in initially asymptomatic family members with abnormal ECG or echocardiographic findings [25-27]. (See "Approach to diagnosis of asymptomatic left ventricular systolic dysfunction".)

The following screening is recommended for first-degree relatives of patients with cardiomyopathy [24]:

●Clinical screening for cardiomyopathy in asymptomatic first-degree relatives is recommended whether or not genetic testing has been undertaken, and whether or not a genetic cause has been found if genetic testing was performed. Screening should include the following:

•History (with special focus on HF symptoms, arrhythmias, presyncope, and syncope)

•Physical examination (with special attention to the cardiac and skeletal muscle systems)

•ECG

•Echocardiogram

•Creatine kinase MM fraction (at initial evaluation only)

•Signal-averaged ECG in ARVC only

•Holter monitoring in HCM and ARVC

•Exercise treadmill testing in HCM

•Cardiovascular magnetic resonance imaging in ARVC

●Asymptomatic first-degree relatives with negative clinical and/or genetic screening should be rescreened at intervals or any time that symptoms or signs appear. The frequency of recommended rescreening varies with cardiomyopathy type:

•HCM – Every three years until 30 years old, except yearly during puberty

•DCM – Every three to five years beginning in childhood

•ARVC – Every three to five years after age 10

•LVNC – Every three years beginning in childhood

•RCM – Every three to five years beginning in adulthood

More frequent screening is recommended if a mutation is present.

●Repeat clinical screening at one year is suggested in first-degree relatives with any abnormal clinical screening tests.

Genetic counseling and testing — We agree with the following 2009 HFSA guideline recommendations for genetic counseling and genetic testing in patients with DCM and at-risk family members [24]:

●Genetic and family counseling is recommended for all patients and families with cardiomyopathy.

●Genetic testing should be considered for the one most clearly affected person in a family to facilitate family screening and management. Screening the most affected individual increases the likelihood of detecting a relevant mutation.

This is the first major society guideline recommending routine consideration of genetic testing in a patient with cardiomyopathy of unknown cause. The HFSA guideline limits the purpose of genetic testing to enabling the screening of family members at risk of carrying a disease-causing mutation [24]. The HFSA guideline does not include a recommendation for genetic testing in cardiomyopathy patients with apparently sporadic (non-familial) disease. However, genetic testing to facilitate diagnosis in the patient is also at times compelling [28].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Heart failure in adults" and "Society guideline links: Cardiomyopathy".)

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SUMMARY AND RECOMMENDATIONS

●Clinical assessment of the patient with heart failure (HF) or cardiomyopathy includes history, physical examination, initial blood tests, electrocardiogram, chest radiograph, and echocardiography. (See 'Determining the cause and severity of heart failure or cardiomyopathy' above and "Heart failure: Clinical manifestations and diagnosis in adults".)

●Echocardiography should be performed in all patients with new onset HF. Echocardiography has a high sensitivity and specificity for the diagnosis of myocardial dysfunction, and may also establish the etiology of HF. (See 'Echocardiography' above.)

●Virtually all patients with unexplained HF should be evaluated for the presence of coronary heart disease. (See 'Detection of coronary artery disease' above.)

•Noninvasive exercise testing is a reasonable first step, as it not only provides information about the presence of ischemic heart disease, but also can be used for risk stratification and prognostic purposes. The role of other types of noninvasive imaging is less well established.

•Coronary catheterization with angiography should be considered in patients with angina or a positive exercise test. Even in patients with a normal exercise test, however, cardiac catheterization should be considered if HF is otherwise unexplained and there is a reasonable likelihood that coronary artery disease is present.

●Beyond an initial evaluation, echocardiography, and assessment for coronary artery disease, additional tests may be warranted to establish the etiology of cardiomyopathy. (See 'Additional tests' above and "Causes of dilated cardiomyopathy".)

•Cardiovascular magnetic resonance imaging may be helpful in distinguishing ischemic heart disease from cardiomyopathy and in identifying the type of cardiomyopathy. (See 'Cardiovascular magnetic resonance' above and "Clinical utility of cardiovascular magnetic resonance imaging", section on 'CMR characterization of myocardial diseases'.)

•Endomyocardial biopsy should be reserved for patients with established indications. (See 'Endomyocardial biopsy' above and "Endomyocardial biopsy".)

●Many cardiomyopathies (hypertrophic cardiomyopathy, dilated cardiomyopathy, restrictive cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, and left ventricular noncompaction) have a substantial genetic basis and this has implications for diagnosis and timely management. The following considerations and recommendations apply to patients with cardiomyopathies as formally defined (ie, do not apply to patients with primarily valvular, ischemic, or hypertensive heart disease). (See 'Genetic evaluation of cardiomyopathy' above and "Definition and classification of the cardiomyopathies", section on 'Definition and classification'.)

•A careful family history for at least three generations is recommended for all patients with cardiomyopathy.

•Clinical screening for cardiomyopathy in asymptomatic first-degree relative is recommended.

•Genetic testing should be considered for the one most clearly affected person in a family to facilitate family screening and management.