Circulating Matrix Metalloproteinases in Adolescents With Hypertrophic Cardiomyopathy and Ventricular Arrhythmia

Abstract

Myocardial fibrosis is a hallmark of hypertrophic cardiomyopathy (HCM) and a risk factor for ventricular arrhythmia. Fibrosis can be reflected in circulating matrix remodeling protein concentrations. We explored differences in circulating markers of extracellular matrix turnover between young HCM patients with versus without history of serious arrhythmia. Using multiplexed and single ELISA, matrix metalloproteinases (MMPs) 1, 2, 3, and 9; tissue inhibitor of metalloproteinases (TIMPs) 1, 2, and 4; and collagen I carboxyterminal peptide (CICP) were measured in plasma from 45 young HCM patients (80% male patients; median age, 17 years [interquartile range, 15-20]). Participants were grouped into serious ventricular arrhythmia history (VA) versus no ventricular arrhythmia history (NoVA). Differences in MMPs between groups were examined nonparametrically. Relationships between MMPs and ventricular arrhythmia were assessed with linear regression, adjusted for interventricular septal thickness, family history of sudden death, abnormal exercise blood pressure, and implantable cardioverter-defibrillator (ICD). In post hoc sensitivity analysis, age was substituted for ICD. The 14 VA patients were older than 31 NoVA patients (median, 19 versus 17 years; P=0.03). All 14 VA and 12 NoVA patients had an ICD. MMP3 concentration was significantly higher in the VA group (VA median, 12.9 μg/mL [interquartile range, 5.7-16.7 μg/mL] versus NoVA, 5.8 μg/mL [interquartile range, 3.7-10.0 μg/mL]; P=0.01). On multivariable analysis, VA was independently associated with increasing MMP3 (standardized β, 0.37; P=0.01). Post hoc adjustment for age attenuated this association. Circulating MMP3 may be a marker of ventricular arrhythmia in adolescent patients with HCM. Because of our role as pediatric providers, we cannot exclude age-related confounding.