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Familial dilated cardiomyopathy: Prevalence, diagnosis and treatment

Familial dilated cardiomyopathy: Prevalence, diagnosis and treatment
Literature review current through: Jan 2024.
This topic last updated: Apr 17, 2023.

INTRODUCTION — Dilated cardiomyopathy (DCM) is a common cause of heart failure (HF) and is the most common diagnosis in patients who undergo cardiac transplantation. DCM is characterized by dilatation and systolic dysfunction of one or both ventricles. (See "Definition and classification of the cardiomyopathies".)

DCM is classified as idiopathic (idiopathic dilated cardiomyopathy, or IDC) when all detectable causes have been excluded (except genetic causes). Potentially diagnosable causes of DCM include a variety of toxic, metabolic, or infectious agents (see "Causes of dilated cardiomyopathy"). Ischemic heart disease must also be excluded. Although specialists commonly apply the diagnosis of IDC to DCMs of unknown cause, clearly some etiology is present but not yet detected.

Family-based studies of first-degree relatives of patients with IDC have established that familial dilated cardiomyopathy (known as familial DCM, or FDC) can be identified in 20 to 35 percent of patients diagnosed with IDC by clinical screening of family members [1]. Most familial DCM is transmitted in an autosomal dominant inheritance pattern, although all inheritance patterns have been identified (autosomal recessive, X-linked, and mitochondrial). During the past 20 years, familial DCM genetic studies have identified rare variants that may plausibly be disease-associated in more than 30 genes.

Most patients with genetic DCM will have an initial diagnosis of idiopathic DCM. Given the frequency of familial DCM, evaluation of new idiopathic DCM cases should include a careful three to four generation family history, clinical screening of first-degree family members as described below, and in most cases, molecular genetic testing.

This topic will discuss the diagnosis and prevalence of familial DCM and guidelines for identifying and treating familial DCM. The phenotypes and genes associated with DCM are discussed separately. (See "Genetics of dilated cardiomyopathy".)

PREVALENCE — Although familial aggregation of idiopathic dilated cardiomyopathy (IDC) is often unrecognized, epidemiologic studies have found a variable rate of familial disease, ranging from 20 to over 50 percent of patients initially diagnosed with IDC who are found to have family members affected with dilated cardiomyopathy (DCM) [1-10]. Hence, the estimate of the prevalence of familial DCM is inferred from the prevalence of IDC.

One oft-cited estimate of IDC prevalence was 36.5:100,000 (approximately 1:2700) from an early study conducted in Olmsted County, Minnesota, from 1975 to 1984 [2]. In that study, the prevalence of hypertrophic cardiomyopathy was 19.7:100,000 (approximately 1:5000). Later estimates of hypertrophic cardiomyopathy have placed its prevalence 10-fold higher at 1:500 individuals. Similarly, it has been argued that the prevalence of IDC may be 10-fold higher, approximately 1:250 [11], based on several lines of evidence. This estimate is of fundamental importance when integrating the population frequencies of rare variants in genes relevant for DCM cause.

The frequency of FDC has been derived from clinical studies in which patients rigorously diagnosed with IDC have had first-degree relatives (parents, siblings, children) clinically screened for evidence of DCM. These studies have observed frequencies usually ranging from 20 to 35 percent [1-10]. A meta-analysis of 23 studies suggested the prevalence of FDC was 23 percent [12]. History, physical examination, electrocardiography, and echocardiography have been the principal methods used for diagnosis.

The following observations are summarized from four studies:

Clinical screening (history, examination, echocardiogram, and electrocardiogram) was conducted in a series of 59 patients identified with an idiopathic DCM and their willing family members, and 20 percent of the 59 patients had relatives that also were also diagnosed with IDC [4].

Detailed family histories were obtained to construct pedigrees in 445 patients who had idiopathic DCM by echocardiography and angiography [5]. Among 970 first- and second-degree relatives, definite familial DCM was present in 11 percent and suspected familial DCM in 24 percent.

A prospective cohort study evaluated 767 asymptomatic first- and second-degree relatives of 189 consecutive patients with idiopathic DCM (dilated left ventricle [LV] with fractional shortening <25 percent) [10]. Abnormalities were found in 23 percent of relatives: DCM was present in 4.6 percent, LV enlargement without systolic dysfunction in 15.5 percent, and decreased fractional shortening <25 percent without LV enlargement in 2.7 percent. The findings in each kindred were consistent with autosomal dominant inheritance.

Similar findings were noted in a report of 408 asymptomatic relatives of 110 consecutive patients with idiopathic DCM [6]. Echocardiography revealed abnormalities in 29 percent, with DCM in 3 percent, LV enlargement in 20 percent, and reduced fractional shortening in 6 percent.

Correlation between asymptomatic LV enlargement and histopathology was demonstrated in a study in which biopsies were obtained in 14 patients with DCM, 32 asymptomatic relatives with LV enlargement but normal systolic function, and in six control subjects [13]. The immunopathologic and histopathologic abnormalities were present in all patients with DCM, in 86 percent of asymptomatic relatives with LV enlargement, and in none of the control subjects.

Because the age of onset of DCM from genetic cause in adults varies greatly, the frequency of familial DCM is difficult to assess and may have been underestimated [1,9]. This is because screening genetically at-risk family members during a relative brief study period (eg, a few years) will not enable detection of disease that presents in subsequent years.

CLINICAL MANIFESTATIONS — Clinical features of patients with familial DCM are similar to those of patients with apparently sporadic DCM. In a series of 304 patients with idiopathic DCM (125 with confirmed familial DCM, 48 with probable familial DCM, 72 with possible familial DCM, and 59 with apparent sporadic idiopathic DCM), the clinical features of probands (and affected family members of those with familial disease) were similar and were not useful to distinguish familial from sporadic disease [14]. The median age of onset of those affected ranged from 40 to 46 years; the median duration of the DCM diagnosis ranged from five to six years, and the median time from diagnosis to transplant or death ranged from four to six years and were similar across all groups.

DIAGNOSIS OF FAMILIAL DCM — Most patients with idiopathic DCM will have an initial diagnosis of nonfamilial DCM. Evaluation of new idiopathic DCM cases should include a comprehensive three to four generation family history and clinical screening of first-degree family members.

Diagnosis of DCM — Most patients with genetic DCM will have an initial diagnosis of idiopathic DCM. A diagnosis of DCM requires evidence of dilatation and impaired systolic function of one or both ventricles (eg, LV ejection fraction [LVEF] ≤50 percent or fractional shortening less than 25 percent) [1,15-18]. The disease is considered idiopathic with exclusion of primary or secondary causes of heart muscle disease. (See "Causes of dilated cardiomyopathy", section on 'Definition'.)

Myocardial biopsy or postmortem examination typically reveals myocyte hypertrophy and replacement fibrosis with variable involvement of the conduction system [19].

Diagnosis of familial disease — The diagnosis of familial DCM is made when idiopathic DCM is diagnosed in two or more closely related family members [1,20,21]. A diagnosis of familial DCM, once established, is useful to infer an underlying genetic cause even if genetic testing is negative. However, establishing the familial DCM diagnosis has distinct limitations. It requires that the patient currently presenting to the practitioner (usually called the proband) have a positive family history of DCM or, if the family history is negative, which is usually the case, that the family members are living, available, and able to accomplish clinical screening for DCM. If a family member is found to have DCM, the diagnosis can be established. More commonly, some cardiovascular abnormalities may be found that are suggestive of early disease but do not fit the full diagnosis, or other conditions have complicated an “idiopathic DCM” diagnosis, such as coronary disease or prior chemotherapy exposure. Moreover, because adult-onset DCM has a variable age of onset, the DCM may not yet have become evident in the one or more family members who are clinically screened, even if the DCM in the proband is proven at genetic testing to have a genetic basis, and even if a first-degree relative shares the same genetic risk as the proband.

Family history — The Heart Failure Society of America (HFSA) genetic evaluation of cardiomyopathy practice guideline [18], updated in 2018 in conjunction with the American College of Medical Genetics [22], includes recommendations for obtaining a family history, screening family members, genetic counseling and genetic testing, and treatment [23].

The 2018 HFSA guideline recommends a comprehensive family history for three or more generations for all patients diagnosed with cardiomyopathy [18]. 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 [1]. Although the vast majority of adult patients present with nonsyndromic DCM, the examiner should be aware of syndromic disease with particular attention to muscular dystrophies. While most muscular dystrophy is diagnosed and managed by neurologists, awareness that more subtle proximal weakness of arms (eg, undue difficulty lifting usual weights) or legs (eg, difficulty climbing stairs not from shortness of breath) can be subtle signs of skeletal myopathy. (See "Genetics of dilated cardiomyopathy", section on 'Genes, phenotypes, and inheritance'.)

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. This is particularly relevant for suspected syndromic disease, especially for children. Specialized centers may also compile databases and perform research that promotes advances in this field.

Clinical screening — The rationale for the clinical screening of family members is that family members who have DCM are frequently asymptomatic [1,10,14,18,24,25]. Symptomatic disease may present within a relatively short period of time in initially asymptomatic family members with abnormal electrocardiographic or echocardiographic findings [1,10,24] (see "Approach to diagnosis of asymptomatic left ventricular systolic dysfunction"). However, as noted above, DCM has a variable age of onset, so a family member who at initial clinical screening does not have DCM may develop DCM at an older age. This drives the recommendation for serial clinical follow-up (unless a genetic cause can be identified that explains the DCM risk in the family, and the family member in question can be shown to not carry the family’s DCM genetic risk).

The 2018 HFSA genetic evaluation of cardiomyopathy guideline recommends the following screening for first-degree relatives of patients with DCM [18]:

Clinical screening for cardiomyopathy in asymptomatic first-degree relatives is recommended whether or not genetic testing has been undertaken, and whether or not 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; the physical examination may reveal evidence of syndromic disease that the examiner should be alert to detect).

Electrocardiogram.

Echocardiogram.

CK-MM (at initial evaluation only).

Asymptomatic first-degree relatives with negative findings should be rescreened at three- to five-year intervals beginning in childhood or any time symptoms or signs appear.

Annual repeated clinical screening is suggested in first-degree relatives with abnormal clinical screening suggestive of or consistent with DCM.

As noted above, asymptomatic first-degree relatives with negative findings should be rescreened at three- to five-year intervals. Rescreening studies in initially healthy relatives of an FDC family have demonstrated late development of evidence of DCM. In a report of 68 initially healthy members in a large kindred with familial DCM [24], repeat testing performed at six years showed that two individuals who were normal at initial examination had developed evidence of DCM. Two others presented with advanced HF and sudden death, respectively. At initial examination, both were asymptomatic, but the first patient had LV enlargement with normal contractility and the second had left bundle branch block.

A similar rate of development of new abnormalities was noted in another report of repeat testing in 238 initially healthy relatives [10]. At a median follow-up of 53 months, three developed DCM (1.3 percent) and 12 progressed to LV enlargement or systolic dysfunction (5.0 percent).

Progression is more common in relatives with abnormalities detected on initial screening. This was demonstrated in a study with complete follow-up (clinical evaluation, electrocardiography, and echocardiography) in 124 relatives with LV enlargement or fractional shortening <25 percent and 238 initially healthy relatives [10]. At a median follow-up of 53 months, progression to DCM occurred in 13 of the relatives with initially abnormal findings and three of the initially healthy relatives (10.4 versus 1.3 percent). In another report, 12 of 45 asymptomatic family members with LV enlargement developed symptomatic HF over a mean follow-up of 39 months [6].

Genetic testing and counseling — We agree with the following recommendations for genetic counseling and genetic testing in patients with DCM and at-risk family members from the 2018 HFSA genetic cardiomyopathy guideline [18,23]:

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

Genetic testing is indicated for all individuals with a DCM diagnosis. This recommendation applies regardless of a positive or negative family history, or whether apparently nonfamilial (sporadic) disease or if known familial involvement [18]. Notably, since the age of onset of DCM varies considerably, even with clinical screening of at-risk relatives most cases of DCM may appear to be sporadic.

Genetic testing should always be directed to the one most clearly affected person in a family, if multiple family members have clinical evidence to suggest involvement, to facilitate family screening and management. Clinical genetic testing of the most affected individual increases the likelihood of detecting a relevant rare variant.

Referral to centers expert in genetic evaluation and family-based management can be considered if sufficient expertise is not available locally. Genetic counseling and genetic testing of cardiomyopathy patients can be complex processes.

Molecular genetic testing for DCM using panels of genes (usually 30 to 50) driven by next generation sequencing methods is now available. Variants identified and classified as pathogenic or likely pathogenic are useful for predictive testing, that is, to use to assess the risk of DCM in the at-risk first-degree family members. From a practical standpoint, testing a panel of DCM genes has supplanted single gene or small panel testing as the standard of care [20,21]. Testing of larger numbers of genes, especially genes of uncertain significance for their association with DCM, increases the likelihood that variants of unknown significance (VUS) may be encountered. This makes pre- and posttest genetic counseling and result interpretation especially important, along with clarification of the phenotype and the selection of the optimal individual from a pedigree for testing [20,21].

Patients who are offered genetic testing should receive pretest genetic counseling, including explanation of genetic disease, heritability, genetic risk, test sensitivities, and possible testing outcomes including the possibility of ambiguous or uncertain results. The provision of pretest counseling can be exceptionally helpful in situations where the information obtained at testing or in the exploration of familial disease encounters issues beyond those of whether the variant is pathogenic, likely pathogenic, or a VUS. These topics entail complexities that may be unfamiliar to many clinicians, and for this reason, the assistance of a cardiovascular genetic medicine clinic, or genetic counselors and/or medical geneticists, should be sought if the clinician desires genetic testing but is uncomfortable or unable to provide these services. (See "Genetic testing".)

Phenotypes and genes associated with DCM are discussed separately. (See "Genetics of dilated cardiomyopathy".)

TREATMENT

Treatment guidelines — The 2018 Heart Failure Society of America (HFSA) guideline notes that the finding of a specific mutation does not generally govern therapy, although certain clinical characteristics associated with some genes may greatly influence screening, education, and counseling of family members and the threshold for primary prevention (eg, implantable cardioverter-defibrillator use) or presymptomatic therapy (eg, beta-blocker or angiotensin converting enzyme inhibitor administration) [18].

The 2018 HFSA guideline includes the following recommendations for therapy:

Medical therapy is recommended based on cardiac phenotype as outlined in the general guidelines. Guideline treatment recommendations for HF with reduced ejection fraction and asymptomatic left ventricular (LV) systolic dysfunction are discussed separately. (See "Management and prognosis of asymptomatic left ventricular systolic dysfunction" and "Overview of the management of heart failure with reduced ejection fraction in adults".)

Device therapies for conduction system disease and arrhythmia (pacemaker therapy and implantable cardioverter-defibrillator) are recommended based on cardiac phenotype as recommended in major society guidelines. (See "Overview of pacemakers in heart failure" and "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy".)

In addition, in patients with dilated cardiomyopathy (DCM) and significant arrhythmia or known risk of arrhythmia, an implantable cardioverter-defibrillator may be considered before the LV ejection fraction (LVEF) falls to ≤35 percent (the usual LVEF threshold for prophylactic implantable cardioverter-defibrillator placement). Specifically, an implantable cardioverter-defibrillator may be considered in patients with DCM with EF >35 percent with family history of sudden cardiac death OR with LMNA mutation (associated with high risk of sudden death). (See "Genetics of dilated cardiomyopathy", section on 'LMNA'.)

The 2011 Heart Rhythm Society/European Heart Rhythm Association consensus statement also notes possible consideration of a prophylactic pacemaker and/or implantable cardioverter-defibrillator in patients with DCM with syndromic disease (muscular dystrophy) or known arrhythmia and/or conduction system disease (LMNA or desmin) [26].

Early treatment — Early initiation of therapy (eg, with angiotensin converting enzyme inhibitors) has been proposed to slow progression in patients with LV enlargement, even in the absence of a reduced LVEF [1]. However, the efficacy of treating asymptomatic LV dysfunction has only been demonstrated in patients with a LVEF ≤35 to 40 percent. (See "Management and prognosis of asymptomatic left ventricular systolic dysfunction".)

Some experts recommend initiation of an angiotensin converting enzyme inhibitor or beta blocker with early signs of familial DCM (systolic dysfunction LVEF and/or LV dilatation) in an at-risk relative in a family with an established familial DCM diagnosis. While most cardiovascular professionals would consider this a reasonable and thoughtful approach, this has not yet been adopted in the major society guidelines.

All individuals with early signs of familial DCM should receive a full cardiovascular evaluation for DCM by a cardiovascular specialist, including the exclusion of other more common causes of DCM (especially ischemic disease in those with age and/or other coronary disease risk factors).

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: Arrhythmias in adults" and "Society guideline links: Cardiomyopathy".)

SUMMARY AND RECOMMENDATIONS

Dilated cardiomyopathy (DCM) is characterized by dilatation and systolic dysfunction of one or both ventricles. DCM is categorized as idiopathic (idiopathic DCM, or IDC) when all detectable causes have been excluded. (See 'Diagnosis of DCM' above.)

Family-based studies that included clinical screening of first-degree family members have established that 20 to 35 percent of patients diagnosed with idiopathic DCM have familial DCM. (See 'Prevalence' above.)

When a new diagnosis of idiopathic DCM is made, a three to four generation family history and clinical screening of first-degree relatives is indicated. Clinical screening (history, exam, electrocardiogram, and echocardiogram) has been recommended for first-degree relatives to identify asymptomatic or undetected disease.

Genetic testing with appropriate genetic counseling is indicated for all DCM to facilitate risk assessment of the individual and the at-risk family members.

The finding of a pathogenic or likely pathogenic variant of certain genes may influence screening, education, and counseling of family members, and the threshold for primary prevention (eg, implantable cardiac defibrillator use) or presymptomatic therapy (eg, beta-blocker or angiotensin converting enzyme inhibitor administration). (See 'Treatment' above.)

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References

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