Cardiac magnetic resonance imaging (MRI) scan demonstrating features of phenotypic overlap across the standard cardiomyopathy classification. In genetic cardiomyopathy, as in other forms of HF, advanced imaging offers refinement of this structurally based classification with functional information to complement the morphological phenotype, providing insight into contractility, diastolic function, strain, synchrony, fibrosis, and energetics ( Figure 1).

3 In practice, there is extensive overlap between these phenotypes for example, HCM, left ventricular noncompaction cardiomyopathy (LVNC), or AC may progress into a dilated ventricle with systolic dysfunction and hence the appearance of DCM. Although this traditional classification based on structural and functional changes at the whole-organ level is relatively crude, it has continuing relevance for clinical diagnosis and management. The focus of this review is the genetic cardiomyopathies, classically divided into dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), arrhythmogenic cardiomyopathy (AC), and restrictive cardiomyopathy (RCM), each of which may be the cause of a HF syndrome. This ranges from the monogenic HF syndromes caused largely by single underlying pathogenetic mutations to HF as a complex trait, for which susceptibility to environmental triggers is modified quantitatively by multiple genetic or epigenetic individually low-penetrance loci. This complexity is mirrored in the genetic architecture of HF. It is also a phenotype that represents a final common pathway of diverse causes, pathophysiology, and clinical course. 2 Although definable in its simplest form as insufficient cardiac output for adequate end-organ perfusion, HF is a complex and diverse disease phenotype with variable heritability. 1 Mortality rates exceed 40% at 5-year follow-up. The burden of heart failure (HF) in the developed world is rivaled only by cancer, in the United States affecting 2% of the population at a treatment cost to society of $28 billion per year. This represents a significant challenge and demands a sustained effort in analysis of extended family pedigrees, diligent clinical phenotyping, and systematic annotation of human genetic variation. However, continued progress requires the differentiation of pathogenic mutations, disease modifiers, and rare, benign variants in the deluge of data emerging from increasingly accessible novel sequencing technologies. As detailed in this review, efforts to unravel the basis of the familial cardiomyopathies at the mendelian end of the spectrum already have begun to deliver on the promise of informative mechanisms, novel gene-based diagnostics, and therapies for distinct subtypes of HF. At the other, HF susceptibility and course may be influenced by more common, less penetrant genetic variants. At one end of the spectrum are the familial monogenic HF syndromes in which causative mutations are rare but highly penetrant. There is increasing evidence that the risk and course of HF depend on genetic predisposition however, the genetic contribution to HF is heterogeneous and complex. Customer Service and Ordering Informationĭespite the striking advances in medical and surgical therapy, the morbidity, mortality, and economic burden of heart failure (HF) remain unacceptably high.Stroke: Vascular and Interventional Neurology.

Journal of the American Heart Association (JAHA).Circ: Cardiovascular Quality & Outcomes.Arteriosclerosis, Thrombosis, and Vascular Biology (ATVB).

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