Impact of Systolic Dysfunction in Genotyped Hypertrophic Cardiomyopathy

Abstract

Background: Hypertrophic cardiomyopathy (HCM) is a disease of the sarcomere, and approximately 5% of cases of HCM show systolic dysfunction with poor prognosis. Few data exist regarding the systolic dysfunction in a large population of genotyped HCM subjects. Hypothesis: The aim of this study was to assess the systolic dysfunction and prognosis in sarcomere gene mutation carriers. Methods: The study included 157 sarcomere gene mutation carriers from 69 unrelated HCM families (87 males; mean age, 46.5 ± 20.5 years). After exclusions for systolic dysfunction at baseline, 107 subjects underwent serial echocardiograms. Results: At a mean follow-up of 7.0 years, 12 subjects experienced systolic dysfunction. In multivariate Cox analysis, systolic dysfunction was related to age and ejection fraction at initial evaluation (P < 0.001 and P = 0.020, respectively), and was associated with the absence of mutations in the cardiac myosin-binding protein C gene (MYBPC3) (P = 0.042). When the subjects were divided into MYBPC3 and non-MYBPC3 mutation carriers, and time from birth to development of systolic dysfunction was compared, the rate of systolic dysfunction was higher in the non-MYBPC3 group than in MYBPC3 group (Kaplan-Meier, log-rank test, P = 0.010). After the onset of systolic dysfunction, 11 of 12 subjects died during a mean follow-up of 8.3 years. Conclusions: Non-MYBPC3 mutation carriers developed left ventricular systolic dysfunction more frequently than MYBPC3 mutation carriers, and the majority of sarcomere gene mutation carriers with systolic dysfunction had fatal outcomes during follow-up. This suggests that subjects with mutations in sarcomeric genes require careful management for systolic dysfunction.

Increased extent of myocardial fibrosis in genotyped hypertrophic cardiomyopathy with ventricular tachyarrhythmias

“…Patients with coronary artery disease, intrinsic valve dysfunction, and idiopathic pulmonary artery hypertension were excluded from the study. We screened for mutations in sarcomere genes in 488 unrelated HCM probands (377 men) who were diagnosed at Kanazawa University Hospital and affiliated hospitals [12]. Sarcomere gene mutations were identified in 69 of the 488 probands.…”

Right Ventricular Hypertrophy Is Associated With Cardiovascular Events in Hypertrophic Cardiomyopathy: Evidence From Study With Magnetic Resonance Imaging

“…Hypertrophic cardiomyopathy (HCM) is defined as a form of idiopathic cardiomyopathy characterized by left ventricular (LV) and/or right ventricular (RV) symmetric or asymmetric hypertrophy, which is mainly associated with sarcomeric gene mutations (1)(2)(3)(4)(5)(6).…”

Whole exome sequencing combined with integrated variant annotation prediction identifies a causative myosin essential light chain variant in hypertrophic cardiomyopathy

“…Abnormal ECG findings were observed in seven carriers with an apparent HCM phenotype. [3] D3S3647 to [6] D3S1568 in both families, indicating that the MYL3 Arg94His variant originated from the same ancestor. Three subjects had left ventricular hypertrophy, two had first-degree atrioventricular block, two had bundle branch block, and one had atrial fibrillation with an enlarged left atrium.…”

“…Hypertrophic cardiomyopathy (HCM) is a genetically heterogeneous myocardial disorder with various morphological, functional, and clinical characteristics [1][2][3][4][5]. Familial HCM, which has a prevalence of up to 1 in 500 individuals, is one of the most common autosomal dominant inherited disorders [6].…”

“…Familial HCM, which has a prevalence of up to 1 in 500 individuals, is one of the most common autosomal dominant inherited disorders [6]. Myosin heavy chain (MYH7, OMIM#: 160760), myosin binding protein C (MYBPC3, OMIM#: 600958), troponin T (TNNT2, OMIM#: 191045), tropomyosin (TPM1, OMIM#: 191010), and troponin I (TNNI3, OMIM#: 191044) have been reported to be the main causal genes [2][3][4][7][8][9][10][11]. To date, candidate-gene approaches using traditional Sanger sequencing have enabled the identification of causative variants in approximately 50% of HCM patients [8].…”