Background-Genetic testing identifies sarcomere mutation carriers (Gϩ) 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 (Gϩ/LVHϪ), 40 overt (Gϩ/LVHϩ) subjects with HCM, and 38 mutation (Ϫ) normal control relatives. All subjects had normal left ventricular ejection fraction. In preclinical HCM, global and regional peak systolic strain ( 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 sys and systolic strain rate, respectively, compared with both preclinical HCM and controls (PϽ0.013 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. (Circ Cardiovasc Genet. 2009;2:314-321.)
In hypertrophic cardiomyopathy (HC), ECG changes have been postulated to be an early marker of disease, detectable in sarcomere mutation carriers when LV wall thickness is still normal However, the ECG features of mutation carriers have not been fully characterized. Therefore, we systematically analyzed ECG’s in a genotyped HC population to: 1. Characterize ECG findings in mutation carriers (G+) with and without echocardiographic left ventricular hypertrophy (LVH), and 2. Evaluate the accuracy of the ECG to differentiate at- risk mutation carriers from genetically unaffected relatives during family screening. ECGs and echocardiograms were analyzed in 213 genotyped subjects (76 G+/LVH−, 57 G+/LVH+ overt HC, 80 genetically unaffected controls). Cardiac magnetic resonance imaging (CMR) was available on a subset. Q waves and repolarization abnormalities (QST) were highly specific (98%) markers for LVH− mutation carriers, present in 25% of G+/LVH− subjects and 3% of controls (p<0.001). QST ECG abnormalities remained independently predictive of carrying a sarcomere mutation after adjusting for age and impaired relaxation, another distinguishing feature of G+/LVH− subjects (OR 8.4, p=0.007). Myocardial scar or perfusion abnormalities were not detected on CMR in any G+/LVH− subjects, irrespective of ECG features. In overt HC, 75% had Q waves and/or repolarization changes but <25% demonstrated common isolated voltage criteria for LVH. In conclusion, Q waves and repolarization abnormalities are the most discriminating ECG features of sarcomere mutation carriers with and without LVH. However, due to the limited sensitivity of ECG and echocardiographic screening, genetic testing is required to definitively identify at-risk family members.
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