REVIEW Clinical and genetic issues in dilated cardiomyopathy: A review for genetics professionals Ray E. Hershberger, MD, Ana Morales, MS, CGC, and Jill D. Siegfried, MS, CGC Abstract: Dilated cardiomyopathy (DCM), usually diagnosed as idio- based on four key facts. First, DCM of all causes underlies at pathic dilated cardiomyopathy (IDC), has been shown to have a familial least half of the heart failure epidemic in the United States, basis in 20–35% of cases. Genetic studies in familial dilated cardiomy- where the heart failure syndrome is defined as an inadequate opathy (FDC) have shown dramatic locus heterogeneity with mutations cardiac output to provide circulatory and nutrient support to the identified in Ͼ30 mostly autosomal genes showing primarily dominant body. Heart failure, from American Heart Association statistics in 2 transmission. Most mutations are private missense, nonsense or short 2010, affected approximately 5.8 million US citizens, of which a insertion/deletions. Marked allelic heterogeneity is the rule. Although to significant portion will be diagnosed with DCM of unknown cause date most DCM genetics fits into a Mendelian rare variant disease (otherwise characterized as idiopathic DCM [IDC]). Second, a paradigm, this paradigm may be incomplete with only 30–35% of FDC genetic cause has been demonstrated for an estimated 30–35% of genetic cause identified. Despite this incomplete knowledge, we predict IDC (in familial or apparently sporadic cases), making testing that DCM genetics will become increasingly relevant for genetics and feasible. Third, the recent dramatic progress with more cost- cardiovascular professionals. This is because DCM causes heart failure, effective genetic testing makes predictive diagnosis possible a national epidemic, with considerable morbidity and mortality. The fact and enhances presymptomatic diagnosis. Finally, and per- that early, even pre-symptomatic intervention can prevent or ameliorate haps most importantly, presymptomatic interventions of DCM, coupled with more cost-effective genetic testing, will drive DCM have proven value to prevent morbidity and mortality. further progress in the field. Ongoing questions include: whether spo- We also note that the classic Mendelian rare variant para- 3 radic (IDC) disease has a genetic basis, and if so, how it differs from digm may be incomplete to characterize genetic DCM. Al- familial disease; which gene-specific or genetic pathways are most though considerable progress has been made in discovering the relevant; and whether other genetic mechanisms (e.g., DNA structural genetic cause of a fraction of DCM, providing an initial foot- variants, epigenetics, mitochondrial mutations and others) are operative hold for clinical practice, we also predict that with the avail- in DCM. We suggest that such new knowledge will lead to novel ability of exome and whole genome sequencing, our under- approaches to the prevention and treatment of DCM. Genet Med 2010: standing of DCM genetics will transition into a more complex 3 12(11):655–667. rare variant paradigm. Hence, we will need genetics profes- sionals to contribute to the DCM research effort and to help Key Words: genetics, dilated cardiomyopathy, genetic testing, genetic manage the clinical aspects of this important entity. counseling DCM: EPIDEMIOLOGY, NOMENCLATURE, AND ilated cardiomyopathy (DCM) has recently emerged as CLINICAL CHARACTERISTICS Dhaving a genetic basis, much as did hypertrophic cardio- myopathy (HCM) in the 1990s. The discovery of genetic cause Definition and diagnosis of DCM for some of DCM, otherwise thought to be idiopathic, and the DCM is characterized by left ventricular enlargement (LVE) rapid development of more cost-effective molecular genetic and systolic dysfunction with an ejection fraction (EF) Ͻ 50%,4 testing for rare variants bring an opportunity for collaboration or, more stringently, Ͻ45% (Table 1).5 Approximately 35–40% between genetics professionals and cardiovascular specialists in of DCM cases are assigned a diagnosis of IDC after detectable DCM evaluation and diagnosis. causes have been excluded. The most common DCM cause in Knowledge of DCM is increasingly essential for genetics the United States, ischemic heart disease due to coronary artery professionals in both general genetics practices staffed by clin- disease (CAD), needs to be excluded in men older than 40 years ical geneticists and genetic counselors and in cardiovascular and women older than 45 years (or at younger ages if risk genetic medicine clinics staffed by cardiovascular and genetic factors are present, e.g., cigarette smoking, diabetes, hyperten- professionals.1 This is because we predict that genetic DCM sion, or a strong family history of early coronary disease). Less will rapidly emerge from an uncommon diagnosis rarely seen in common causes of DCM that need to be excluded include either genetics or cardiology clinics, to a mainstream genetics structural heart disease (congenital or valvular), thyroid disease, diagnosis, now associated with Ͼ30 genes. This prediction is iron overload, and exposure to cardiotoxins such as anthracy- clines, chest radiation, and other much less common conditions, From the Cardiovascular Division, Department of Medicine, University of including those accompanying inflammatory arthritides, myo- Miami Miller School of Medicine, Miami, Florida. carditis (e.g., giant cell myocarditis), protozoal infections (e.g., Ray E. Hershberger, MD, Biomedical Research Building (R-125) Rm 811, Chagas disease), and many others (Table 2). HCM may occa- University of Miami Miller School of Medicine, 1501 NW 10th Avenue, sionally show characteristics of DCM (reduced systolic function Miami, FL 33136. E-mail: [email protected] or www.fdc.to. and some dilatation) late in its course (Table 1). Extensive 9–12 Disclosure: The authors declare no conflict of interest. literature, not reviewed in this study, is available for HCM. Submitted for publication May 4, 2010. DCM nomenclature: IDC Accepted for publication July 9, 2010. DCM can be used either as a generic term to include all Published online ahead of print September 22, 2010. causes of LVE and systolic dysfunction, separating DCM from DOI: 10.1097/GIM.0b013e3181f2481f the two other classic cardiomyopathy categories, HCM or re- Genetics IN Medicine • Volume 12, Number 11, November 2010 655 Hershberger et al. Genetics IN Medicine • Volume 12, Number 11, November 2010 Table 1 Characteristics of dilated (DCM), hypertrophic Table 2 Selected reported causes of nongenetic DCM6–8 (HCM), or restrictive (RCM) cardiomyopathies Ischemic Type of Coronary heart disease, myocardial infarction, and associated conditions cardiomyopathy Characteristics Comments Toxins DCM LV dilatation Can also be accompanied by Systolic dysfunction RV dilatation or atrial and Ethanol/alcohol ventricular (four chamber) dilatation Cobalt Usually defined as ejection Carbon monoxide/smoking fraction Ͻ50 or 45%; the ejection fraction may be Lead 10–20% with advanced disease Cadmium HCM LV hypertrophy May show asymmetric septal Mercury No dilatation hypertrophy or concentric Chemotherapeutic agents May be LV hypertrophy hypercontractile Hypertrophy occurs Anthracyclines (e.g., doxirubucin) In late stage may commonly with LV wall occasionally thickness Ͼ15 mm but can Trastuzumab resemble DCM be severe (Ͼ20 mm) or Other drugs very severe (ϾϾ20 mm), where normal LV wall Cocaine thickness is Յ12 mm. Normal to smaller LV cavity Sympathomimetics Ejection fraction at times Metabolic Ͼ80% The “burned out” phase in Nutritional deficiencies: Thiamin, selenium, and carnitine late-stage disease may show a diminished Electrolyte disturbances: Hypocalcemia and hypophosphatemia ejection fraction and at Endocrine times some dilatation. It is unusual for “true” HCM Hypothyroidism to present in the “burned out” DCM phase. Acromegaly RCM Mild LV RCM is usually defined Thyrotoxicosis hypertrophy physiologically, where an Cushing disease Systolic function elevated left ventricular normal to mildly end diastolic pressure is Pheochromocytoma decreased required to reach a normal left ventricular end Inflammatory or infectious causes diastolic volume. Infectious The ejection fraction may be normal and is usually not Viral (enteroviruses, influenza, and HIV) less than 40%. Rickettsiual Normal ejection fraction usually considered 55–75%. Usual LV wall thickness is 9–11 mm. RCM at times can be difficult to categorize clinically; it can commonly Bacterial overlap with HCM, and part of this is phenotypic plasticity with genetically mediated HCM/RCM. Mycobacterial LV, left ventricle; RV, right ventricle. Fungal Parasitic (toxoplasmosis, trichinosis, and Chagas disease) 11 strictive cardiomyopathy (RCM) (Table 1). Further, it has Noninfectious become common practice within heart failure clinical trials to assign patients into categories of “ischemic” or “nonischemic” Hypersensitivity myocarditis DCM. The former category includes anyone with ischemic heart Infiltrative disease, most commonly from prior myocardial infarction and/or CAD, defined most stringently for research purposes as Sarcoidosis Ͼ at least one epicardial coronary artery with 50% narrowing. Amyloidosis However, this research standard may be too stringent for clin- ical (or clinical trial) purposes, as it is not uncommon to observe Other DCM with CAD and coronary narrowing of 50–70% (and at Tachycardia mediated times involving multiple vessels) without evidence of prior myocardial infarction that may be adjudicated by cardiovascular