Echocardiographic strain imaging to assess early and late consequences of sarcomere mutations in hypertrophic cardiomyopathy

Abstract

Background: Genetic testing identifies sarcomere mutation carriers (G+) before clinical diagnosis of hypertrophic cardiomyopathy (HCM), allowing characterization of initial disease manifestations. Previous studies demonstrated that impaired relaxation develops before left ventricular hypertrophy (LVH). The precise impact of sarcomere mutations on systolic function in early and late disease is unclear.

Methods and results: Comprehensive echocardiography with strain imaging was performed on 146 genotyped individuals with mutations in 5 sarcomere genes. Contractile parameters were compared in 68 preclinical (G+/LVH-), 40 overt (G+/LVH+) subjects with HCM, and 38 mutation (-) normal control relatives. All subjects had normal left ventricular ejection fraction. In preclinical HCM, global and regional peak systolic strain (epsilon(sys)) and longitudinal systolic strain rate were not significantly different from controls, but early diastolic mitral annular velocity (Ea) was reduced by 13%. In overt HCM, there was a significant 27% and 14% decrease in global longitudinal epsilon(sys) and systolic strain rate, respectively, compared with both preclinical HCM and controls (P<0.013 for all comparisons), and a 33% reduction in Ea.

Conclusions: Sarcomere mutations have disparate initial effects on diastolic and systolic functions. Preclinical HCM is characterized by impaired relaxation but preserved systolic strain. In contrast, both diastolic and longitudinal systolic abnormalities are present in overt disease despite normal ejection fraction. We propose that diastolic dysfunction is an early consequence of sarcomere mutations, whereas systolic dysfunction results from mutations combined with subsequent pathological remodeling. Identifying mechanistic pathways triggered by these mutations may begin to reshape the clinical paradigm for treatment, based on early diagnosis and disease prevention.

Figure 1. Representative longitudinal strain and strain rate tracings

Representative 2DS longitudinal strain (left) and strain rate (right) tracings from echocardiographic strain analysis in control, preclinical, and overt HCM subjects. Measurements are taken from the interventricular septum. Tracings from the basal, mid, and apical segments are depicted in yellow, blue, and green, respectively. Arrows indicate peak values.

Figure 2. Global longitudinal systolic strain and strain rate preserved in preclinical HCM but decreased in overt HCM

Global longitudinal systolic strain and strain rate preserved in preclinical HCM but decreased in overt HCM. Values for strain and strain rate are represented as mean adjusted for age and family relations ± standard error. Left: Global longitudinal strain is preserved in preclinical HCM. Mean longitudinal strain is −21.8 ± 0.5% in the preclinical HCM cohort and −21.5± 0.5% in the control cohort (p=0.66). Overt HCM is associated with a significant 27% reduction in peak longitudinal systolic strain (−15.8 ± 1.0%, p<0.0001 vs both control and preclinical cohorts). Right: Similar results are seen for global longitudinal systolic strain rate. There is no significant difference between the preclinical and control cohorts (−1.38 ± 0.04 vs −1.41 ± 0.05 1/sec, respectively, p=0.54). A significant 14% reduction in systolic strain rate is seen in the overt HCM cohort (SSR = −1.21 ± 0.05 1/sec; p<0.01 vs both control and preclinical cohorts).