Familial Dilated Cardiomyopathy

I. Familial Dilated Cardiomyopathy: What every physician needs to know

Dilated cardiomyopathy (DCM) is a myocardial disorder characterized by ventricular chamber enlargement and systolic dysfunction that can occur as a primary cardiomyopathy or in association with other cardiac or systemic disorders. Inherited gene variants can be sufficient to cause DCM or may modify disease susceptibility and phenotypic manifestations.

For new cases of DCM, it is important to think of the possibility of a genetic cause, and take a detailed family history going back 3 to 4 generations. Familial DCM is suspected when two or more individuals in a family have DCM that is otherwise unexplained. In families in which DCM shows Mendelian patterns of inheritance, there is likely to be a single "driver" variant that has a substantial functional effect. In many patients, however, DCM may have a complex etiology with contributions from one or more genetic variants of lesser effect size together with acquired factors. In this setting, DCM may appear to be a sporadic occurrence or there may be a non-Mendelian pattern of inheritance.

When taking a family history, it is important to note that familial DCM is clinically variable, and while some families have DCM alone, in others, DCM may be associated with a range of electrocardiographic (ECG) changes, other cardiac structural defects, or extracardiac manifestations. Taking a verbal family history alone can have a relatively low yield (<10%) of detecting familial disease.

Clinical screening of asymptomatic first-degree relatives is highly recommended to detect asymptomatic cases of DCM and to look for early signs of disease. Studies in which asymptomatic relatives have been systematically evaluated have shown that at least 20-35% of cases of "idiopathic" DCM will have other family members affected.

More than 40 chromosomal loci and disease genes have been associated with adult-onset DCM. Genetic testing of subsets of the more commonly-mutated disease genes has had a low yield, with putative mutations identified in only 20-30% cases. Consequently, genetic testing has not been widely used in patient management.

The development of next-generation sequencing technologies over recent years has enabled high-throughput screening of the human genome and has provided new options for genetic testing, including targeted re-sequencing of large panels of cardiomyopathy-related genes, whole-exome sequencing and whole-genome sequencing. It is expected that these technologies will expedite new disease gene discovery as well as facilitating investigation of structural variants and copy number variants in known disease genes.

As more genes as sequenced, increasing numbers of genetic variants are being identified in every patient. Stratifying these variants and working out which of these, if any, are responsible for DCM, is a major challenge. There are now numerous examples of variants that had been reported to be pathogenic in cardiomyopathy patients but that are now being found in the general population Improved and more stringent criteria are clearly required to identify variants that have a high probability of being disease-causing. Assessment of co-segregation of variants in families has a key role in determining likely pathogenicity.

Next-generation sequencing facilitates screening of large genes and has already provided new insights into DCM genetics. A major advance was the discovery that 1 in 4 patients with familial DCM carry truncating variants in the TTN gene that encodes the giant sarcomeric protein, titin. However, truncating TTN variants also occur in 1-3% of the general population. Elucidating the clinical significance and predictive value of truncating TTN variants in affected and unaffected family members is a topic of current investigation.

With inclusion of the TTN gene, the yield of genetic testing in DCM has increased to approximately 50%, which is similar to that of other inherited cardiac disorders such as hypertrophic cardiomyopathy and long QT syndrome. It can be expected that genetic testing in DCM will play an increasingly important role in family management and that consensus expert guidelines for indications for genetic testing will be revised in the near future.

Insights gained into the functional consequences of disease-associated variants suggest that gene mutations can result in diverse molecular defects, including alterations of sarcomere assembly, cytoskeletal stability, mechanical stretch responses, cell survival, signaling, cellular electrophysiology, energetics, gene transcription, and protein turnover. No single final common pathway for the pathogenesis of familial DCM has been established.

In most families, discovery of a causative gene mutation does not directly influence the choice of drug therapy, but early identification of asymptomatic genotype-positive carriers may impact on the timing for commencement of conventional heart failure treatments. In selected cases, specific gene-targeted interventions that reverse the underlying functional defects may be possible.

Priorities for future research in familial DCM include:

  • More genetic studies in families to identify new disease genes and new types of mutations in the known disease genes. This will facilitate genetic testing and enable cohorts of genotyped family members to be assembled.

  • Genotype-phenotype correlations and risk stratification algorithms in genotyped families.

  • Animal models to study disease mechanisms and new drug therapies.

  • Clinical trials in genotyped patients to evaluate preventative therapies.

  • A better understanding of the genetic burden in individual cases (combined effects of common and rare variants) and interactions between genetic and environmental factors.

II. Diagnostic Confirmation: Are you sure your patient has Familial Dilated Cardiomyopathy?

Affected individuals usually present with typical symptoms and signs of heart failure, conduction-system abnormalities, or arrhythmias. The diagnosis of DCM is made by conventional criteria using transthoracic echocardiography.

There are no specific clinical manifestations that are definitive, and a positive family history is the main factor that distinguishes familial DCM from other causes of DCM. The gold standard for confirming familial DCM is the identification of a genetic variant in affected family members that that fulfils criteria to be deemed disease-causing.

A. History Part I: Pattern Recognition

Families with adult-onset DCM typically show autosomal dominant inheritance. This is not always the case, however, and there can be varying inheritance patterns and a spectrum of associated clinical features. Establishing the mode of inheritance and obtaining a detailed phenotype, has implications for the expectation of disease in male and female family members and potentially also for the selection of genes for testing.

With autosomal dominant inheritance, males and females are equally affected and there is a 50% chance that each child of an affected parent will inherit the disease-causing gene variant. It has been estimated that at least 90% DCM families will show autosomal dominant inheritance. X-linked, autosomal recessive, and matrilineal patterns of inheritance may also be found.

DCM may be associated with conduction abnormalities or arrhythmias, and in many families, these features may precede the onset of DCM. For example, in families with LMNA mutations, family members may present with sinus bradycardia, first- or second-degree heart block, or atrial fibrillation in the second to third decades, with the subsequent development of DCM in later adult life.

Mutations in the SCN5A gene, which encodes the cardiac sodium channel, have been associated with diverse atrial and ventricular phenotypes including DCM and conduction-system disease.

Other cardiac features that may occur in DCM families include left ventricular hypertrophy, valvular abnormalities (e.g. mitral valve prolapse), congenital heart defects (e.g. atrial/ventricular septal defects), or left ventricular compaction. Other extra-cardiac features may include skeletal myopathy, partial lipodystrophy, and sensorineural deafness.

A number of factors can complicate finding a clinical 'pattern'.

  • Autosomal dominant or X-linked? In X-linked DCM, young males characteristically have rapidly progressive DCM and female carriers appear normal or have mild DCM in later life. However, it is now recognized that the age of onset and severity of disease in both males and females can vary considerably. In many families, especially small families, it is difficult to be certain whether the inheritance pattern is autosomal dominant or X-linked.

  • Variable expressivity. When looking for the possibility of familial disease, it is important to keep in mind that the clinical phenotype can vary between families with the same gene mutation and also among family members who all have the same mutation. For example, a single genetic defect may be present in a family in which some individuals have DCM while others have pacemakers or sudden death.

  • Overlap syndromes. As gene mutations are being found in more families, it is increasingly appreciated that some gene mutations can give rise to different forms of cardiomyopathy not only in different families but also within a single family. This has been seen with genes that cause DCM and hypertrophic cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy.

  • Multiple mutations. Atypical inheritance patterns and varying severity of clinical features may be indicative that more than one gene mutation of a large size is present in a family, or that there is a main 'driver' mutation with additional genetic modifiers.

  • Variable penetrance. Sometimes, family members will carry a gene mutation but have completely normal cardiac function (genotype-positive, phenotype-negative). Most gene mutations in autosomal dominant DCM have a high penetrance (i.e., genotype-positive family members will eventually show signs of disease). The issue of variable penetrance should not be confused with age-related penetrance, which refers to the fact that individuals who carry an abnormal gene variant from birth do not manifest clinical signs of disease until they reach a certain age range, which is usually typical for their family.

  • Family size. In small families, especially if there are varying phenotypes, it may be difficult to recognize familial disease or see a clear inheritance pattern.

  • Comorbidities. Common things occur commonly, and it would not be surprising for one or more members of a family to have a gene mutation and other risk factors, such as coronary artery disease or alcohol excess. These comorbidities can modify the age of onset, severity, or type of clinical manifestations.For example, the question should be asked in family members with ischemic heart disease whether the extent of left ventricular dysfunction is disproportional to the burden of coronary atherosclerosis. It would also not be unusual for young males who are heavy drinkers or drug users to present with DCM a decade or more before abstinent family members.

  • Peripartum cardiomyopathy. In genotype-positive women, DCM may be unmasked at an earlier age by the hemodynamic stresses of pregnancy. A family history should be taken for all women who present with peripartum cardiomyopathy and any familial clustering determined. In the event of a negative family history, any new diagnosis of DCM in another family member should raise the possibility of an underlying familial DCM.

  • Athlete's heart. Family members who regularly engage in high-level competitive athletic activity, particularly endurance sports such as cycling, rowing, triathlons, distance running, and swimming, may undergo physiological left ventricular remodeling and show chamber dilation and increased ventricular mass. Differentiating between athlete's heart and early DCM may be difficult. A history of relevant sporting activity, bradycardia, normal left ventricular systolic function, and reversibility with deconditioning may provide clues to the presence of athlete's heart. Regular echocardiographic follow-up of these family members is recommended.

B. History Part 2: Prevalence

Careful history-taking, clinical examination, and investigation in newly diagnosed patients with DCM will result in identification of an associated condition that could cause DCM in approximately 50% of cases. In the remaining 50% of cases, DCM is often termed 'idiopathic'.

Clinical screening of large kindreds has suggested that approximately 1 in 3 of these individuals with 'idiopathic' DCM will have affected relatives, implicating genetic factors. It should be noted also that familial aggregation of DCM could be explained by shared exposure to acquired 'environmental' factors or heritable comorbidities.

Due to the low yield of genetic testing to date, the true prevalence of familial DCM that is definitively attributable to a pathogenic genetic variant is unknown. Familial DCM can affect males and females of all ages and ethnicities, and is not necessarily restricted to those with 'idiopathic' DCM. The extent to which patients with acquired causes of DCM might have an underlying genetic predisposition to disease remains to be investigated.

C. History Part 3: Competing diagnoses that can mimic Familial Dilated Cardiomyopathy

All patients newly diagnosed with DCM should have a history taken and be investigated to exclude the common treatable and/or reversible causes of DCM. Even in families where there is a predominant genetic etiology of DCM, additional comorbidities may be present that contribute to, or exacerbate, the phenotype.

Some of these conditions include coronary artery disease, cardiac valvular abnormalities, diabetes mellitus, thyroid disease, nutritional deficiencies, myocardial infection/inflammation, alcohol excess, and chemotherapeutic drugs. The term 'familial DCM' should be used to describe families in which DCM is the primary manifestation of disease.

DCM may also be seen as one of diverse manifestations of heritable systemic disorders, including Duchenne/Becker muscular dystrophies, Emery-Dreifuss muscular dystrophy, limb girdle muscular dystrophy, myotonic muscular dystrophy, hemochromatosis, mitochondrial myopathy, Kearns-Sayre syndrome, myotubular (centronuclear) myopathy, nemaline myopathy, cytochrome C oxidase deficiency, Barth syndrome, Danon disease, Fanconi anemia, Diamond-Blackfan syndrome, sickle cell anemia, medium-chain acyl CoA dehydrogenase deficiency (MCAD), long-chain acyl CoA dehydrogenase deficiency (LCAD), Maroteaux-Lamy syndrome, andFabry disease.

D. Physical Examination Findings

A thorough cardiovascular examination should be performed, with an emphasis on signs of left and right heart failure, including elevated jugular venous pressure, displaced apex beat, third heart sound, lung crackles, hepatic congestion, and peripheral edema. A slow or irregular pulse, or a cardiac murmur, may provide clues to the presence of heart rhythm or structural abnormalities that are complications of DCM or that are part of the cardiac phenotype of the family gene mutation.

All new patients should have a complete physical examination to look for other causes of DCM, as well as extracardiac phenotypic features associated with an underlying gene mutation. In particular, the neuromuscular system should be evaluated to look for muscle wasting or weakness that could suggest skeletal myopathy.

E. What diagnostic tests should be performed?

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

The major objectives of investigation are summarized in Figure 1 and include:

  • Confirm the diagnosis of DCM in the index case (and other symptomatic family members).

  • Look for possible causes of DCM other than an inherited gene mutation.

  • Document any other cardiac and systemic manifestations of the disease phenotype.

  • Screen asymptomatic family members.

  • Identify an underlying gene defect in the family.

Flow diagram with steps in clinical assessment of patients with a possible genetic cause of DCM.

Symptomatic family members. The major modality used to diagnose DCM is transthoracic echocardiography (see section2 below) and a 12-lead ECG should be done in all cases. The initial evaluation should also include a complete blood count, serum electrolytes (including calcium and magnesium), urea, creatinine, liver enzymes, iron studies, thyroid function, blood glucose, blood lipids, and urinalysis.

Specific assays for myocardial infection, autoimmune or connective tissue disorders, pheochromocytoma, or Chagas disease should be performed if there is a high clinical suspicion based on history and physical examination. Elevated levels of brain natriuretic peptide (BNP, NT-pro-BNP) may be useful to confirm a diagnosis of heart failure but alone, are not diagnostic of heart failure.

Creatine kinase levels should be assessed to exclude skeletal myopathy, even if the neuromuscular examination is normal. In symptomatic patients aged over 50 years, the possibility of underlying coronary artery disease should be considered and appropriate testing undertaken according to local facilities and expertise (e.g. exercise stress test, exercise echo, nuclear perfusion imaging, coronary CT, coronary angiography).

Endomyocardial biopsy is not routinely performed in new cases of DCM due to the frequently nonspecific findings and potential procedural risks. A biopsy may be indicated in selected cases when there is a high clinical suspicion of specific abnormalities, such as hemochromatosis, endomyocardial fibroelastosis, Loeffler's syndrome, amyloidosis, or in specific situations where treatment may be altered by the biopsy findings, such as prior to cardiac transplantation, repeated anthracycline therapy for cancer, or in patients with giant cell myocarditis.

Asymptomatic family members. The main screening tool for asymptomatic relatives is transthoracic echocardiography (see section 2 below). An ECG should also be performed to look for conduction-system abnormalities or arrhythmias that might precede the development of DCM. Identification of biomarkers of early disease is a topic of ongoing research, but as yet, the role of parameters such as circulating cardiac antibody levels, BNP levels, etc., remains to be established.

Genetic testing. In current expert consensus guidelines, genetic testing for familial DCM is not recommended for all patients, with the exception of families with distinctive phenotypes, such as those with DCM and conduction-system abnormalities, in whom testing of the LMNA and SCN5A genes is warranted. Next-generation sequencing technologies are now providing cost-effective options for genetic testing and the yield of testing should increase dramatically. It can be expected that the standard-of-care guidelines for genetic testing in familial DCM will be revised in the near future.

Data for the yield of genetic testing in familial DCM have been based largely on research or commercial testing of single genes or panels of subsets of the more common disease genes. In the next-generation sequencing era, genetic testing can now be performed by targeted re-sequencing of extended 'pan-cardiomyopathy' panels that are comprised of genes (usually 100-200) associated with DCM or other cardiomyopathies, or by whole-exome sequencing (includes 1-2% of a person's genetic makeup and is comprised of the coding-sequences of genes), or whole-genome sequencing.

There is no clear consensus for the optimal method for genetic testing and the choice will depend to some extent on availability, expertise and costs.

Interpretation of the results of gene sequencing is often not straightforward and needs to be undertaken by experienced cardiology and genetics personnel, with a number of factors taken into account, including the pattern of segregation of the variant with disease status in affected and unaffected family members, whether the variant is known or novel, its allele frequency in a healthy control population, the sequence conservation in different species at the mutated residue, and predicted or experimentally demonstrated functional effects.

Numerous bioinformatics programs have been developed to help predict the likely pathogenicity of non-synonymous sequence variants. These programs all have their limitations and can have false-positive and false-negative predictions. Using the consensus predictions of a number of programs may give more reliable results. New programs are also being developed that generate ensemble scores from multiple different prediction algorithms and these may also increase the predictive accuracy.

Caution is urged in using the output of these programs alone as the basis of result-giving in the clinical setting. Since coding-sequence variants in known disease genes account for only a minority of all cases of familial DCM, there is a need for ongoing research to find new disease genes and pathogenetic mechanisms. Interested families should be encouraged to participate in familial DCM research studies.

In the event of a gene mutation being found in the index case (family proband), genotyping of other family members should be performed. The pros and cons of predictive testing of young children (<16 years) have been debated, and includes consideration of factors such as medical impact, informed consent, and the psychosocial impact on parents, affected children, unaffected siblings, friends, and relatives. Decisions about whether to proceed with genetic testing in a proband and cascade testing in relatives are ideally made in conjunction with genetic counseling.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Symptomatic family members. The diagnosis of DCM is usually made by transthoracic echocardiography, and requires the presence of both left ventricular dilatation and reduced systolic contraction.

Although standard laboratory reference ranges for the upper limits of normal left ventricular end-diastolic diameter (LVEDD) are usually provided, these do not take into account individual patient height and weight, and hence, may give rise to misleading results. For example, a LVEDD measurement of 56 mm may be regarded as normal for a tall adult male, but could represent significant left ventricular dilatation in a small adult female.

To address these issues, a number of normalization formulae have been developed that variably incorporate age, height, weight, sex, and body surface area. These formulae include correction of M-mode dimensions by Henry's formula to assess LVEDD (%predicted), and the NHLBI and Framingham standards.

The accurate estimation of left ventricular size is important in familial DCM, particularly for assessment of early disease when left ventricular systolic function may remain normal. Several groups have performed comparative analyses of various normalization formulae, and no one formula is clearly superior to all others.

One commonly used set of criteria for DCM are: LVEDD >112% predicted and left ventricular fractional shortening <25%. In individuals who have 'technically difficult' echocardiographic studies, or if additional information is required such as assessment of coronary artery disease or the extent of myocardial fibrosis, other imaging modalities can be used to quantifyleft ventricular size and function, including left ventriculography, or gated radionuclide scans. Cine magnetic resonance imaging is regarded as a gold-standard method for assessment of ventricular size and function.

Asymptomatic family members. In kindreds with suspected familial DCM, asymptomatic relatives should undergo baseline transthoracic echocardiography. There are a number of key questions that the physician needs to ask:

  • What am I looking for? It has been proposed that left ventricular dilatation, with normal or borderline systolic function, is a marker of early disease when seen in asymptomatic relatives in DCM families. Echocardiographic screening of asymptomatic relatives in large cohorts of DCM families has shown that approximately 25% will meet criteria for left ventricular dilation.

    To detect left ventricular dilatation, it is important to correct the standard LVEDD M-mode measurements as noted above. LVEDD >112% predicted is one threshold that has been used to define left ventricular dilatation in studies of the natural history of early disease.

    When unrelated age- and sex-matched control subjects are evaluated, it is evident that some healthy individuals also meet this criterion for left ventricular enlargement. This may be the case in young fit athletes or obese individuals.

    Until more sensitive and specific clinical criteria for early disease are developed, the presence of left ventricular dilatation in the context of a DCM family is not diagnostic but should raise a suspicion of possible preclinical cardiomyopathy. In a minority of asymptomatic relatives, left ventricular dimensions are normal but there may be isolated mild impairment of systolic contraction. The presence of other cardiac structural or functional abnormalities should be noted, as these may or may not be related to the family phenotype.

  • At what age should I start screening asymptomatic relatives? There are no hard and fast rules about this. Screening recommendations are usually tailored to some extent by the typical age of onset in affected family members.

    It is usually not necessary to screen young children in families with adult-onset DCM. Baseline screening usually commences around 18 years of age in families with onset of DCM in their 30s or above, while screening from early adolescence may be indicated in families with DCM onset in the late teens or early 20s.

    In families with X-linked DCM, males will need to be screened from an earlier age and more frequently than females. The presence of additional DCM risk factors may also influence the age of onset of screening programs.

  • How often should follow-up screening be performed? The finding of a normal echocardiogram in the baseline screening study does not mean that an asymptomatic family member does not carry the family DCM gene mutation. Unless demonstrated to be genotype-negative by genetic testing, follow-up echocardiographic studies in asymptomatic relatives are recommended at periodic intervals ranging generally from 3 to 5 years.

    In family members who are genotype-positive, or in those in whom echo abnormalities are detected, repeat screening should be undertaken at 6 to 12 months in the first instance, then at 1 to 3 year intervals. The frequency of follow-up studies needs to be individually tailored and will be influenced by the echo findings, by the family disease pattern, and by any genotype results that may be obtained.

III. Management

In familial DCM, management strategies need to consider not only the individual patient, but also the extended family kindred.

The main objectives of management are:

  • To monitor and treat symptomatic family members for DCM and its complications.

  • To follow-up asymptomatic family members for the new onset of DCM (or associated phenotype features) with a focus on identifying those at high risk and early intervention to prevent DCM.

  • To provide supportive education and genetics counseling to all family members.

A. Immediate management

There are no specific acute management recommendations for familial DCM, and treatment of heart failure and cardiac arrhythmias should be initiated according to standard clinical guidelines.

B. Physical Examination Tips to Guide Management

Symptomatic family members should be monitored for responses to treatment and complications from DCM due to any cause.

In family members who are asymptomatic at the time of initial screening, the new onset of symptoms and/or signs of heart failure, valve dysfunction, cardiac arrhythmias, or conduction-system abnormalities, should alert the physician to the possible development of symptomatic disease.

C. Laboratory Tests to Monitor Response to, and Adjustments in, Management

There are no specific laboratory tests that are used to monitor responses to treatment in familial DCM.

D. Long-term management

Symptomatic family members. For most families, individuals who have been diagnosed with DCM are treated with conventional heart failure therapies (e.g. angiotensin-converting enzyme inhibitors, beta-blockers, diuretics), and conventional strategies for arrhythmia treatment and prevention (e.g. antiarrhythmic drugs, implantable cardioverter-defibrillators).

In families with LMNA mutations, there is often severe heart failure that is refractory to medical therapy and heart transplantation may be considered at a relatively early stage. Young genotype-positive individuals who have conduction-system abnormalities need to be monitored for the subsequent development of DCM.

These conduction abnormalities are often progressive and require permanent pacemaker implantation. If there is any family history of sudden death, a history of syncope, or high-grade ventricular arrhythmias, implantation of a cardioverter-defibrillator may be warranted. In general, however, there are very few genotype-phenotype correlations or gene-based treatment guidelines identified to date in familial DCM.

An ultimate goal of genetics studies is to understand the molecular mechanisms underpinning DCM development and to devise therapies that will reverse or stop the primary disease pathophysiology. This is a topic of ongoing research and a number of agents have shown promising results in animal models. In-depth evaluation of the functional consequences of genetic variants can be highly worthwhile, and there are seminal examples in which effective, gene-targeted therapy has been possible.

Asymptomatic family members. In families in which a disease-causing gene mutation has not been identified, all clinically unaffected siblings of affected individuals and all children aged over 18 years who have an affected parent need ongoing clinical follow-up. This is currently done using history, physical examination, ECG, and transthoracic echocardiography (see section 2 above).

In families where a disease-causing mutation has been identified, greater emphasis needs to be placed on regular surveillance of genotype-positive individuals who have a high likelihood of developing DCM. It is current practice to discharge genotype-negative family members from follow-up; however, one cannot exclude the possibility that there might be a second pathogenic variant in the family, or other acquired risk factors, and so these individuals should be encouraged to seek medical attention if symptoms develop in the future.

The finding of left ventricular dilatation on a screening echocardiogram raises the possibility of an early stage of cardiomyopathy and warrants close follow-up. Studies of the natural history of asymptomatic relatives with left ventricular dilation have shown that 1 in 10 of these individuals will progress to DCM within a 5-year period.

Early identification of individuals at risk is of paramount importance as this provides an opportunity for early intervention and prevention of DCM development. There is a paucity of human data looking at treatment strategies for relatives with suspected early disease and there are currently no evidence-based best practice guidelines.

Further studies to identify who to treat, when to treat, and what to treat with, are urgently required. It is hoped that the increasing use of genetic testing will provide cohorts of genotyped patients for future clinical trials.

Exercise and lifestyle advice. There have been many studies that have shown that regular moderate exercise is beneficial in patients with ischemic heart failure. In mouse models of DCM, the effects of exercise training differ according to the underlying genetic defect, and may be beneficial or exacerbate the disease phenotype.

Further evaluation of the effects of exercise in human families with different genotypes is needed. In the meantime, the general recommendation for members of DCM families is that regular moderate exercise can be undertaken but that high-level competitive sporting activities should be avoided. Other lifestyle advice includes reduction of alcohol consumption, cessation of smoking, a balanced healthy diet, and avoidance of obesity.

Genetics counseling. The investigation and management of families with DCM requires time and expertise, and is ideally undertaken in a multidisciplinary clinic where there is a team of personnel that may include molecular cardiologists, clinical geneticists, clinical nurse specialists, and genetics counselors. Although a role for genetic testing has not been strongly established in familial DCM, there are many aspects of family management that need to be considered.

Many individuals are not aware that there is a family history of DCM and require education about the disease and its risks to themselves and their children. The decision to undertake genetic testing requires pre- and post-test counseling about the medical and psychosocial impact of a positive or negative result.

As noted in a previous section, predictive testing in young children can be a complex issue and needs to be handled on a case-by-case basis. Female family members (and their spouses) contemplating pregnancy require counseling about the cardiovascular risks for the mother, predicted chances that a baby will inherit the family gene mutation, and prenatal diagnostic testing.

Having a family history of DCM, or receiving a positive genetic test result may have implications for some types of health insurance, especially life insurance, and up-to-date statutory guidelines may need to be consulted with respect to disclosure and discrimination.

E. Common Pitfalls and Side-Effects of Management

Some of the common pitfalls in familial DCM are:

  • Familial DCM is missed, due to assumption that a new case of DCM of unknown cause is 'idiopathic' or 'viral' and no family history is taken, OR lack of recognition of a familial pattern if there are variable clinical manifestations (e.g. DCM in one individual, conduction disease with another), OR if there are additional DCM risk factors such as alcohol excess in some individuals. (The net result is that other family members are not considered further or investigated.)

  • Young symptomatic family members are treated for asthma and an echo is not performed, because DCM is not clinically suspected in someone of that age. (The net result is that a diagnosis may not be made until severe heart failure is clearly evident.)

  • Young asymptomatic family members are told that they have not inherited the family gene mutation if their baseline screening study is normal. (The net result is that they are not followed up.)

  • Echocardiographic M-mode measurements of left ventricular size are not corrected for body size and family members with possible left ventricular dilatation are incorrectly reassured they are unaffected if values lie within the laboratory reference range. (The net result is that they may not be followed up.)

  • Despite the best and well-intentioned efforts of health personnel, some family members do not comply with screening recommendations, because they don't want to know about undiagnosed or possible future DCM, do not get on with other family members, are too busy, etc.This is often the case in families in which affected members have severe DCM and/or a complicated course of disease. (The net result is that some of these individuals will present with symptomatic DCM and may have a worse outcome than if detected early.)

IV. Management with Co-Morbidities

Optimal medical management of comorbidities that could contribute to DCM is indicated in all symptomatic and asymptomatic family members.

V. Patient Safety and Quality Measures

A. Appropriate Prophylaxis and Other Measures to Prevent Readmission

Avoidance of lifestyle factors that could contribute to DCM is recommended for all symptomatic and asymptomatic family members.

B. What's the Evidence for specific management and treatment recommendations?

Some consensus guidelines for management of symptomatic heart failure and its complications, and evaluation of inherited cardiomyopathies are outlined in:

Yancy, CW. "2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines". J Am Coll Cardiol. vol. 62. 2013. pp. e147-239.

McMurray, JJ. "ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC". Eur J Heart Fail. vol. 14. 2013. pp. 803-869.

Hershberger, RE. "Genetic evaluation of cardiomyopathy - a Heart Failure Society of America practice guideline". J Card Fail. vol. 15. 2009. pp. 83-97.

Ackerman. "HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies". Europace. vol. 13. 2011. pp. 1077-109.

C. DRG Codes and Expected Length of Stay

The ICD10AM code for familial DCM is I42.0

The DRG codes used for hospital admissions are:

F75A Other circulatory system diagnoses with catastrophic complications (average LOS 10 days)

F75B Other circulatory system diagnoses with severe or moderate complications (average LOS 5.1 days)

F75C Other circulatory system diagnoses without complications (average LOS 2.7 days)

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