Genotype-Positive Status in Patients With Hypertrophic Cardiomyopathy Is Associated With Higher Rates of Heart Failure Events

Abstract

Background-The aim of the study was to clarify the relationship between genotype status and major cardiovascular outcomes in a large cohort of patients with hypertrophic cardiomyopathy. Methods and Results-Genetic testing was performed in 558 consecutive proband patients with hypertrophic cardiomyopathy.Baseline and follow-up (mean follow-up 6.3 years) clinical and echocardiographic data were obtained. Pathogenic mutations were identified in 198 (35.4%) patients. Genotype-positive patients were more likely to be women (44% versus 30%; P=0.001), younger (39 versus 48 years; P<0.001), and have a family history of hypertrophic cardiomyopathy (53% versus 20%; P<0.001), as well as family history of sudden cardiac death (17% versus 7%; P=0.002). There were no significant differences in the rates of atrial fibrillation, stroke, or septal reduction procedures. Multivariable analysis demonstrated that genotype-positive status was an independent risk factor for the development of combined heart failure end points (decline in left ventricular ejection fraction to <50%, New York Heart Association III or IV in the absence of obstruction, heart failure-related hospital admission, transplantation, and heart failure-related death; hazards ratio, 4.51; confidence interval, 2.09-9.31; P<0.001). No difference was seen in heart failure events between the myosin heavy chain and myosin-binding protein C genotype-positive patients. Conclusions-The presence of a pathogenic sarcomere mutation in patients with hypertrophic cardiomyopathy was associated with an increase in heart failure events, with no differences in event rates seen between myosin heavy chain and myosin-binding protein C genotype-positive patients. The presence of a disease-causing mutation seems more clinically relevant than the specific mutation itself. (Circ Cardiovasc Genet. 2014;7:416-422.)

Clinical Characteristics and Long-Term Outcome of Hypertrophic Cardiomyopathy in Individuals With a MYBPC3 (Myosin-Binding Protein C) Founder Mutation

“…Several studies have previously demonstrated an increased risk of cardiac death in G+ versus G− HCM, [22][23][24] including studies of MYBPC3 founder mutations. 25,26 G− probands in this study were older and more symptomatic most likely related to LVOT obstruction and diastolic dysfunction.…”

Genetics of Sudden Cardiac Death

“…A sarcomere gene mutation is identified in 50% to 60% of cases, with the MYBPC3 or MYH7 gene being most commonly involved. 137,138 Albeit with varying evidence for causality, several genes encoding nonsarcomeric proteins have also been reported in patients with HCM, including Z-disk proteins (eg, ACTN2 and MYOZ2) and intracellular calcium modulators (eg, JPH2). 139 Several distinct disease entities, such as Pompe disease (GAA), Danon disease (LAMP2), left ventricular hypertrophy with Wolff-Parkinson-White syndrome (PRKAG2), Fabry disease (GLA), and familial amyloidosis (TTR), bear similarity to HCM because of presentation of left ventricular hypertrophy, but differ among others in inheritance (some are X-linked or recessive), pathophysiology, and in extracardiac features.…”

The 25-Year Genetic Era in Hypertrophic Cardiomyopathy: Revisited

“…Important insights in this regard are found in the single institution study of Li et al 3 from Toronto General Hospital, in which 558 probands with clinical expression of HCM were assessed by genetic testing; MYH7 and MYBPC3 were Figure 1. Top, Distribution of genetic test results in a population of clinically diagnosed probands with hypertrophic cardiomyopathy.…”

“…1,2 The article of Li et al 3 in this issue of the journal provides an opportunity to revisit and place into perspective several important principles related to the clinical application of genetic testing to the HCM patient population, thereby assessing progress in understanding this heterogeneous condition, the most common of the inherited heart diseases. 4,5 Article see p 416…”