Myocardial fibrosis as an early manifestation of hypertrophic cardiomyopathy

Abstract

Background: Myocardial fibrosis is a hallmark of hypertrophic cardiomyopathy and a proposed substrate for arrhythmias and heart failure. In animal models, profibrotic genetic pathways are activated early, before hypertrophic remodeling. Data showing early profibrotic responses to sarcomere-gene mutations in patients with hypertrophic cardiomyopathy are lacking.

Methods: We used echocardiography, cardiac magnetic resonance imaging (MRI), and serum biomarkers of collagen metabolism, hemodynamic stress, and myocardial injury to evaluate subjects with hypertrophic cardiomyopathy and a confirmed genotype.

Results: The study involved 38 subjects with pathogenic sarcomere mutations and overt hypertrophic cardiomyopathy, 39 subjects with mutations but no left ventricular hypertrophy, and 30 controls who did not have mutations. Levels of serum C-terminal propeptide of type I procollagen (PICP) were significantly higher in mutation carriers without left ventricular hypertrophy and in subjects with overt hypertrophic cardiomyopathy than in controls (31% and 69% higher, respectively; P<0.001). The ratio of PICP to C-terminal telopeptide of type I collagen was increased only in subjects with overt hypertrophic cardiomyopathy, suggesting that collagen synthesis exceeds degradation. Cardiac MRI studies showed late gadolinium enhancement, indicating myocardial fibrosis, in 71% of subjects with overt hypertrophic cardiomyopathy but in none of the mutation carriers without left ventricular hypertrophy.

Conclusions: Elevated levels of serum PICP indicated increased myocardial collagen synthesis in sarcomere-mutation carriers without overt disease. This profibrotic state preceded the development of left ventricular hypertrophy or fibrosis visible on MRI. (Funded by the National Institutes of Health and others.)

Figure 1. Gadolinium-Enhanced Cardiac MRI Scans in MYH7 Mutation Carriers with and Those without Overt Hypertrophic Cardiomyopathy

Panels A, C, and E show no morphologic abnormalities suggestive of hypertrophic cardiomyopathy in a carrier of a myosin heavy-chain missense mutation. Left ventricular hypertrophy and late gadolinium enhancement are absent. Panels B, D, and F show typical findings of hypertrophic cardiomyopathy in a relative of the subject in Panels A, C, and E with overt disease caused by the same myosin heavy-chain mutation. These findings include a markedly thickened septum (Panel B, arrow) associated with areas of heterogeneous late gadolinium enhancement, which affects 17% of the total left ventricular mass and involves the anteroseptum (Panel D, arrows) and the inferoseptum (Panels D and F, arrows). LA denotes left atrium, LV left ventricle, RA right atrium, and RV right ventricle.