Subtle abnormalities in contractile function are an early manifestation of sarcomere mutations in dilated cardiomyopathy

Abstract

Background: Sarcomere mutations cause both dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM); however, the steps leading from mutation to disease are not well described. By studying mutation carriers before a clinical diagnosis develops, we characterize the early manifestations of sarcomere mutations in DCM and investigate how these manifestations differ from sarcomere mutations associated with HCM.

Methods and results: Sixty-two genotyped individuals in families with sarcomeric DCM underwent clinical evaluation including strain echocardiography. The group included 12 subclinical DCM mutation carriers with normal cardiac dimensions and left ventricular ejection fraction (LVEF ≥55%), 21 overt DCM subjects, and 29 related mutation (-) normal controls. Results were compared with a previously characterized cohort of 60 subclinical HCM subjects (sarcomere mutation carriers without left ventricular hypertrophy). Systolic myocardial tissue velocity, longitudinal, circumferential, and radial strain, and longitudinal and radial strain rate were reduced by 10%-23% in subclinical DCM mutation carriers compared with controls (P<0.001 for all comparisons), after adjusting for age and family relations. No significant differences in diastolic parameters were identified comparing the subclinical and control cohorts. The opposite pattern of contractile abnormalities with reduced diastolic but preserved systolic function was seen in subclinical HCM.

Conclusions: Subtle abnormalities in systolic function are present in subclinical DCM mutation carriers, despite normal left ventricular size and ejection fraction. In contrast, impaired relaxation and preserved systolic function appear to be the predominant early manifestations of sarcomere mutations that lead to HCM. These findings support the theory that the mutation's intrinsic impact on sarcomere function influences whether a dilated or hypertrophic phenotype develops.

Figure 1

Systolic function is reduced in subclinical dilated cardiomyopathy (DCM). Global peak systolic myocardial tissue velocity (S′) was reduced in subclinical DCM compared with controls. Black dots represent individual unadjusted global S′ values. The horizontal black bar indicates mean global S′, adjusted for age and family relations. P values also reflect this adjustment.

Figure 2

Sarcomere mutations associated with hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) have divergent effects on contractile function before clinical disease. A, Systolic function is reduced and diastolic function is preserved in subclinical DCM (subDCM) compared with controls. B, In contrast, systolic function is preserved and diastolic function is reduced in subclinical HCM (subHCM) compared with controls. ε_sys long indicates global, peak longitudinal systolic strain, %; E′, global, peak early diastolic myocardial tissue velocity, cm/s; and NS, not signficant. Values are adjusted for age and family relations, error bars represent SE.