11/23/2019 Determining the etiology and severity of heart failure or cardiomyopathy - UpToDate

Official reprint from UpToDate®

www.uptodate.com ©2019 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Determining the etiology and severity of heart failure or

cardiomyopathy
Author: Wilson S Colucci, MD
Section Editor: Stephen S Gottlieb, MD
Deputy Editor: Susan B Yeon, MD, JD, FACC

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Oct 2019. | This topic last updated: Nov 15, 2019.

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 "Evaluation of the patient with
suspected heart failure" 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

Heart failure (HF) is a common clinical syndrome that can result from any structural or functional
cardiovascular disorder causing systemic perfusion inadequate to meet the body’s metabolic
demands without excessively increasing left ventricular filling pressures [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 "Evaluation of
the patient with suspected heart failure".)

https://www.uptodate.com/contents/determining-the-etiology-and-severity-of-heart-failure-or-cardiomyopathy/print?search=iron overload cardiomyopathy&source=… 1/17

11/23/2019 Determining the etiology and severity of heart failure or cardiomyopathy - UpToDate

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 [3]:

● 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 ejection fraction (EF) with
systolic dysfunction, serum brain natriuretic peptide concentrations, and a variety of other factors are
also important. (See "Predictors of survival in heart failure with reduced ejection fraction".)
https://www.uptodate.com/contents/determining-the-etiology-and-severity-of-heart-failure-or-cardiomyopathy/print?search=iron overload cardiomyopathy&source=… 2/17
11/23/2019 Determining the etiology and severity of heart failure or cardiomyopathy - UpToDate

Etiology

Categories of disease — HF is caused by a variety of disorders, including diseases affecting the

pericardium, myocardium, endocardium, cardiac valves, vasculature, or metabolism [3]. 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 and causes 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) [4,5].
Conditions that were missed clinically included cardiac sarcoidosis, myocarditis, arrhythmogenic right
ventricular cardiomyopathy (in both series), and hypertrophic cardiomyopathy and noncompaction (in
one series [5]).

Heart failure with reduced ejection fraction — HF with reduced EF ([HFrEF] left ventricular EF
≤40 percent) is also known as systolic HF or HF due to systolic dysfunction. Most randomized
controlled trials for HF have enrolled patients with HFrEF, and therapy with established efficacy is
available for HFrEF but not HF with preserved EF (HFpEF). (See "Overview of the management of
heart failure with reduced ejection fraction in adults".)

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 [6,7]. In one review, coronary disease and hypertension accounted for 62 and 10 percent of cases,
respectively [6]. (See "Epidemiology and causes 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 1230 such patients, the
relative frequency of the different causes was as follows [8]:

● Idiopathic – 50 percent
● Myocarditis – 9 percent
● Ischemic heart disease – 7 percent
https://www.uptodate.com/contents/determining-the-etiology-and-severity-of-heart-failure-or-cardiomyopathy/print?search=iron overload cardiomyopathy&source=… 3/17
11/23/2019 Determining the etiology and severity of heart failure or cardiomyopathy - UpToDate

● 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, refers to
HF in patients with a left ventricular EF ≥50 percent or >50 percent [3]. Patients with left ventricular
EFs between 41 and 49 may be categorized as having "HFpEF, borderline" with characteristics similar
to patients with HFpEF. (See "Clinical manifestations and diagnosis of heart failure with preserved
ejection fraction".)

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 left ventricular 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 [9].
(See "Clinical manifestations and diagnosis of heart failure with preserved ejection fraction".)

Classification of cardiomyopathy — Cardiomyopathies are diseases of heart muscle. This term is

often used to refer to genetically determined diseases with recognizable phenotypes (hypertrophic
cardiomyopathy, DCM, restrictive cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy,
and left ventricular noncompaction) (table 2A-B). However, terms such as "ischemic cardiomyopathy"
and "nonischemic cardiomyopathy" are also frequently used clinically. Classification of
cardiomyopathies is discussed further separately. (See "Definition and classification of the
cardiomyopathies".)

DETERMINING THE CAUSE AND SEVERITY OF HEART FAILURE OR

CARDIOMYOPATHY

Diagnostic approach — The approach to determining the cause and severity of heart failure (HF) or
cardiomyopathy includes the history, physical examination, and diagnostic tests. Initial tests include
an electrocardiogram, initial blood tests, echocardiogram, and assessment for coronary artery
disease. Recommendations for the evaluation of patients with HF were included in the 2013 American

https://www.uptodate.com/contents/determining-the-etiology-and-severity-of-heart-failure-or-cardiomyopathy/print?search=iron overload cardiomyopathy&source=… 4/17

11/23/2019 Determining the etiology and severity of heart failure or cardiomyopathy - UpToDate

College of Cardiology Foundation guideline [3], the 2010 Heart Failure Society of America guidelines
[10], and the 2012 European Society of Cardiology heart failure guidelines [11].

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 "Evaluation of the patient with suspected heart failure", section
on 'History'.)

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 alcoholic cardiomyopathy.

● A diagnosis of amyloidosis should be strongly considered in patients who have a family history of
unexplained cardiomyopathy or amyloidosis, low voltage on electrocardiogram, left ventricular
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 [12].

● 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 "Evaluation of the patient with suspected heart
failure", 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.

https://www.uptodate.com/contents/determining-the-etiology-and-severity-of-heart-failure-or-cardiomyopathy/print?search=iron overload cardiomyopathy&source=… 5/17

11/23/2019 Determining the etiology and severity of heart failure or cardiomyopathy - UpToDate

● 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: Clinical manifestations
and diagnosis", section on 'Clinical manifestations'.)

• 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 electrocardiogram (ECG) may show findings that favor the presence of a
specific cause of heart failure (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.

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

https://www.uptodate.com/contents/determining-the-etiology-and-severity-of-heart-failure-or-cardiomyopathy/print?search=iron overload cardiomyopathy&source=… 6/17

11/23/2019 Determining the etiology and severity of heart failure or cardiomyopathy - UpToDate

● 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 [3]:

● 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 [13]. 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 brain natriuretic peptide and N-terminal pro-brain natriuretic peptide in diagnosis of HF is
discussed separately. (See "Evaluation of the patient with suspected heart failure", section on 'BNP
and NT-proBNP' and "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 [13]. 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
https://www.uptodate.com/contents/determining-the-etiology-and-severity-of-heart-failure-or-cardiomyopathy/print?search=iron overload cardiomyopathy&source=… 7/17
11/23/2019 Determining the etiology and severity of heart failure or cardiomyopathy - UpToDate

dilated cardiomyopathy [14].

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 [15].

● Pericardial thickening suggestive of constrictive pericarditis.

● Valvular structure and function in valve disease.

● Interatrial and interventricular shunts.

● Abnormal myocardial texture in infiltrative cardiomyopathies, with left ventricular 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 [16]. Use and limitations of this method are discussed
separately. (See "Echocardiographic evaluation of left ventricular diastolic function", 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 left
ventricular ejection fraction ≤30 percent, the E/e' ratio did not correlate with PCWP [17]. 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 [18].

● A short deceleration time (≤125 ms) is an independent predictor of poor prognosis in patients with
left ventricular dysfunction, regardless of the presence or absence of symptoms [19].

● Right atrial and pulmonary artery pressures, determined by the peak velocity of tricuspid
regurgitation on Doppler echocardiography. These findings correlate with the pulmonary artery

https://www.uptodate.com/contents/determining-the-etiology-and-severity-of-heart-failure-or-cardiomyopathy/print?search=iron overload cardiomyopathy&source=… 8/17

11/23/2019 Determining the etiology and severity of heart failure or cardiomyopathy - UpToDate

wedge pressure, regardless of the etiology of HF or severity of tricuspid regurgitation; they can
be used to assess changes in left ventricular filling pressures resulting from therapy [12].

● Limited data suggest that the cardiac output can be measured accurately by pulsed-wave
Doppler from the left ventricular outflow tract, even in the presence of a low output state or
tricuspid regurgitation (image 2) [20].

Echocardiography in conjunction with dobutamine is also useful in predicting recovery of cardiac

function [21,22]. (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. As noted above, however, occult disease is a
not uncommon cause of dilated cardiomyopathy, accounting for as many as 7 percent of initially
unexplained cases [8]. 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 ejection fraction 32
percent) [23]. 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 left ventricular dysfunction and the

https://www.uptodate.com/contents/determining-the-etiology-and-severity-of-heart-failure-or-cardiomyopathy/print?search=iron overload cardiomyopathy&source=… 9/17

11/23/2019 Determining the etiology and severity of heart failure or cardiomyopathy - UpToDate

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 "Ischemic
cardiomyopathy: Treatment and prognosis".)

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 [3]. 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 [24].

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 [25,26].

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 [25]. 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 left ventricular dysfunction, and left ventricular
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 [26]. (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

https://www.uptodate.com/contents/determining-the-etiology-and-severity-of-heart-failure-or-cardiomyopathy/print?search=iron overload cardiomyopathy&source… 10/17

11/23/2019 Determining the etiology and severity of heart failure or cardiomyopathy - UpToDate

above [23]. 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 heart failure (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 [3]:

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

● 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.

https://www.uptodate.com/contents/determining-the-etiology-and-severity-of-heart-failure-or-cardiomyopathy/print?search=iron overload cardiomyopathy&source… 11/17

11/23/2019 Determining the etiology and severity of heart failure or cardiomyopathy - UpToDate

● 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 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 heart failure (unexplained new-onset HF of two weeks
to three months’ duration with a dilated left ventricle). (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'.)

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:

https://www.uptodate.com/contents/determining-the-etiology-and-severity-of-heart-failure-or-cardiomyopathy/print?search=iron overload cardiomyopathy&source… 12/17

11/23/2019 Determining the etiology and severity of heart failure or cardiomyopathy - UpToDate

Clinical manifestations and diagnosis" and "Hypertrophic cardiomyopathy: Gene mutations and
clinical genetic testing" and "Idiopathic restrictive cardiomyopathy".)

For example, among patients with idiopathic dilated cardiomyopathy (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 [27]. This recommendation applies to patients with hypertrophic
cardiomyopathy (HCM), DCM, arrhythmogenic right ventricular cardiomyopathy (ARVC), left
ventricular 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 [27]. Progressive
disease may occur within a relatively short period of time in initially asymptomatic family members
with abnormal electrocardiographic or echocardiographic findings [28-30]. (See "Clinical
manifestations and diagnosis of asymptomatic left ventricular systolic dysfunction".)

The following screening is recommended for first-degree relatives of patients with cardiomyopathy
[27]:

● 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

https://www.uptodate.com/contents/determining-the-etiology-and-severity-of-heart-failure-or-cardiomyopathy/print?search=iron overload cardiomyopathy&source… 13/17

11/23/2019 Determining the etiology and severity of heart failure or cardiomyopathy - UpToDate

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)

• Electrocardiogram (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 [27]:

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

https://www.uptodate.com/contents/determining-the-etiology-and-severity-of-heart-failure-or-cardiomyopathy/print?search=iron overload cardiomyopathy&source… 14/17

11/23/2019 Determining the etiology and severity of heart failure or cardiomyopathy - UpToDate

● 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
[27]. 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 [31].

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".)

INFORMATION FOR PATIENTS

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The
Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and
they answer the four or five key questions a patient might have about a given condition. These articles
are best for patients who want a general overview and who prefer short, easy-to-read materials.
Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These
articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth
information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-
mail these topics to your patients. (You can also locate patient education articles on a variety of
subjects by searching on "patient info" and the keyword(s) of interest.)

● Basics topic (see "Patient education: Dilated cardiomyopathy (The Basics)")

● Beyond the Basics topic (see "Patient education: Dilated cardiomyopathy (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

https://www.uptodate.com/contents/determining-the-etiology-and-severity-of-heart-failure-or-cardiomyopathy/print?search=iron overload cardiomyopathy&source… 15/17

11/23/2019 Determining the etiology and severity of heart failure or cardiomyopathy - UpToDate

● 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 "Evaluation of the patient with suspected heart failure".)

● 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'.)

https://www.uptodate.com/contents/determining-the-etiology-and-severity-of-heart-failure-or-cardiomyopathy/print?search=iron overload cardiomyopathy&source… 16/17

11/23/2019 Determining the etiology and severity of heart failure or cardiomyopathy - UpToDate

• 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.

Use of UpToDate is subject to the Subscription and License Agreement.

Topic 3485 Version 36.0

https://www.uptodate.com/contents/determining-the-etiology-and-severity-of-heart-failure-or-cardiomyopathy/print?search=iron overload cardiomyopathy&source… 17/17