It’s Never Too Early to Look

Abstract

The observation that ≈30% of nonischemic dilated cardiomyopathy (DCM) is genetic in origin represents one of the most important advances in modern cardiology and has transformed our view of this common disorder.1 Equally surprising is the more recent finding that sarcomeric genes previously linked to the development of hypertrophic cardiomyopathy (HCM) were also causative in the pathogenesis of DCM.2 Mutations in most of the protein components of the cardiac sarcomere have now been linked to DCM, many of them arising in close proximity to known HCM mutations, and provide a unique challenge: how can such divergent patterns of ventricular remodeling arise from such closely related structural changes? Although it may appear to be straightforward that discrete alterations in sarcomeric function caused by gene mutations could eventually lead to either left ventricular (LV) dilation or hypertrophy, our lack of understanding regarding the earliest clinical stages of DCM before the effects of secondary changes are manifest have precluded mechanistic insight. In this issue of Circulation Genetics , Lakdawala et al used a unique and well-characterized sarcomeric DCM cohort to directly determine whether abnormal systolic function can be detected in genotype-positive patients with normal LV ejection fraction and size. Their robust approach, including determination of echo strain and systolic myocardial tissue velocity and comparisons among sublinical DCM, overt DCM, and control (genotype-negative) family members across 4 independent mutation groups, revealed a significant decrease in systolic function in the subclinical group. These results complement their previous findings that gene mutations linked to HCM cause diastolic dysfunction in subclinical cohorts and fully establish that the primary mechanisms driving diverse ventricular remodeling in sarcomeric cardiomyopathies are tightly coupled to the underlying changes in sarcomere dynamics.4 Article see p 503 Since the publication of the first linkage studies in 1990, >1000 mutations in genes …