Genetics and genomics of dilated cardiomyopathy and systolic heart failure

Abstract

Heart failure is a major health burden, affecting 40 million people globally. One of the main causes of systolic heart failure is dilated cardiomyopathy (DCM), the leading global indication for heart transplantation. Our understanding of the genetic basis of both DCM and systolic heart failure has improved in recent years with the application of next-generation sequencing and genome-wide association studies (GWAS). This has enabled rapid sequencing at scale, leading to the discovery of many novel rare variants in DCM and of common variants in both systolic heart failure and DCM. Identifying rare and common genetic variants contributing to systolic heart failure has been challenging given its diverse and multiple etiologies. DCM, however, although rarer, is a reasonably specific and well-defined condition, leading to the identification of many rare genetic variants. Truncating variants in titin represent the single largest genetic cause of DCM. Here, we review the progress and challenges in the detection of rare and common variants in DCM and systolic heart failure, and the particular challenges in accurate and informed variant interpretation, and in understanding the effects of these variants. We also discuss how our increasing genetic knowledge is changing clinical management. Harnessing genetic data and translating it to improve risk stratification and the development of novel therapeutics represents a major challenge and unmet critical need for patients with heart failure and their families.

Fig. 1

An overview of heart failure syndromes showing where dilated cardiomyopathy (DCM) and systolic heart failure fit in relation to all heart failure syndromes. Heart failure syndromes encompass clinical symptoms and/or signs of heart failure and evidence of myocardial dysfunction. This can occur in the setting of reduced (HFrEF; left ventricular ejection fraction <40%) or preserved (HFpEF; left ventricular ejection fraction >50%) left ventricular ejection fraction. The contribution of HFpEF, previously referred to as diastolic heart failure, to heart failure syndromes ranges from 22 to 73%, reflecting the difficulties in defining the condition and the diversity of the populations studied [8]. Recently, a third category of heart failure with mid-range ejection fraction (HFmrEF; left ventricular ejection fraction 40–49%) has been identified [8], although it has not yet been encompassed into clinical studies. The commonest cause of HFrEF is myocardial ischemia. DCM can be a subset of HFrEF and is the commonest cardiomyopathy (CM) to cause heart failure syndromes. Although DCM can present with the clinical syndrome of systolic heart failure, it can also present with arrhythmias or thrombo-embolic disease or be detected in the asymptomatic patient. DCM therefore does not equate with systolic heart failure. DCM is predominantly an imaging diagnosis, whereas heart failure is a clinical and imaging diagnosis. DCM dilated cardiomyopathy; Other CMs other cardiomyopathies, including hypertrophic cardiomyopathy