Circulating Matrix Metalloproteinases in Adolescents With Hypertrophic Cardiomyopathy and Ventricular Arrhythmia

Abstract

Background 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. Methods and Results Using multiplexed and single ELISA, MMP 1,2,3,9; tissue inhibitor of metalloproteinase (TIMP) 1,2,4; and collagen I carboxyterminal peptide (CICP) were measured in plasma from 45 young HCM patients (80% male, median age 17 years[IQR 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 vs. 17 years, p=0.03). All 14 VA and 12 NoVA patients had ICD. MMP3 concentration was significantly higher in the VA group (VA median 12.9 [IQR 5.7-16.7] mcg/mL vs. NoVA 5.8 [IQR 3.7-10.0 mcg/mL]; p=0.01). On multivariable analysis, VA was independently associated with increasing MMP3 (standardized b 0.37, p=0.01). Post hoc adjustment for age attenuated this association. Conclusions Circulating MMP3 may be a marker of ventricular arrhythmia in adolescent patients with HCM. Due to our role as pediatric providers, we cannot exclude age related confounding.

Serum Matrix Metalloproteinases as Quantitative Biomarkers for Myocardial Fibrosis and Sudden Cardiac Death Risk Stratification in Patients With Hypertrophic Cardiomyopathy

“…In line with Zaccharia et al (12), MMP-3 serum levels were associated with a higher cardiac event rate. These data were adjusted by age and gender, which might suggest MMP-3 as a gender-(and fibrosis-) independent circulating biomarker for VT and syncope in HCM patients.…”

“…In previous studies investigating MMP and cardiac fibrosis, female patients have been underrepresented with 20 to 40% of the study populations (2,4,5,12,13).…”

Aortic Stiffness in Youth with Hypertrophic Cardiomyopathy Genotype

“…[15, 18] Circulating regulators of fibrosis may play a role in stiffening ventricles, large conduit arteries, or both. [20–22]…”

Theranostic biomarkers in hypertrophic cardiomyopathy insights in a long road ahead

“…In fact, marked increases in TNF-α have been reported in the end-stage phase of HCM (53). Finally, several metalloproteinases (MMPs), are increased in the serum of HCM patients, such as MMP-9 and MMP-3, respectively associated with LGE and increased arrhythmic risk (54).…”