Negative Hypertrophic Cardiomyopathy Research Articles

Health Status of Cardiac Genetic Disease Patients and Their At-risk Relatives

Background: Health status is an important outcome measure incorporating multiple dimensions of health. While health status has been shown to be a predictor for hospital readmission, morbidity and mortality in the heart failure setting, there are limited data in cardiac genetic disease. This study sought to examine the health status in a number of cardiac genetic disease groups compared to the general population. Methods: Individuals with inherited cardiomyopathies [hypertrophic cardiomyopathy (HCM), familial dilated cardiomyopathy (FDC), arrhythmogenic right ventricular cardiomyopathy] and primary arrhythmogenic disorders [long QT syndrome (LQTS), catecholaminergic polymorphic ventricular tachycardia], as well as their first-degree relatives, completed the Medical Outcomes Survey Short Form-36 (MOS SF-36v2). The physical and mental component scores (PCS and MCS) and SF-6D utility score were assessed. Results: A total of 409 individuals were assessed. Patients with HCM (p < 0.001), FDC (p < 0.05), and CPVT (p < 0.05) were found to have a significantly lower PCS, while patients with LQTS (p < 0.01) had a lower MCS. Individuals at risk of HCM (p < 0.0001) and genotype positive-phenotype negative HCM patients (p < 0.01) both had a higher PCS and utility scores compared to the HCM group. Individuals at risk of LQTS had significantly higher PCS than those with clinical LQTS (p < 0.05) and similarly individuals at risk of FDC had significantly higher PCS than FDC patients (p < 0.05). In HCM, female gender (p = 0.002), presence of co-morbidities (p < 0.0001) and higher NYHA functional class (p < 0.0001) were predictors of a lower PCS. Conclusions: Patients with a clinical diagnosis of a genetic heart disease have an impaired health status, related to both physical and mental function. Clinical management strategies need to consider health status as an important outcome measure.

A missense mutation in a ubiquitously expressed protein, vinculin, confers susceptibility to hypertrophic cardiomyopathy

The R975W mutation, in the alternatively spliced exon 19 of vinculin ( VCL) which yields the isoform metavinculin, was associated previously with hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM), and shown to alter in vivo organization of intercalated discs. We tested the hypothesis that alterations in the ubiquitously expressed, VCL-encoded protein, vinculin, may provide a pathogenic substrate for HCM. Comprehensive mutational analysis of VCL’s 22 translated exons was performed in a cohort of 228 unrelated patients with genotype negative HCM, having no identifiable mutations in 12 HCM-associated myofilament/Z-disc-encoding genes. A novel missense mutation, L277M-VCL, involving a conserved residue was identified in a patient with severely obstructive, mid-ventricular hypertrophy. This mutation was not detected in 400 reference alleles. Immunohistochemical analysis of the proband’s myectomy specimen demonstrated markedly reduced vinculin levels in the intercalated discs. We provide the first report of a cardiomyopathy associated mutation in vinculin. Despite its ubiquitous expression, the HCM-associated VCL mutation clinically yielded a cardiac-specific phenotype.