HCM is the commonest cardiac single-gene disorder, with a prevalence of approximately 1 in 500 in the general population. The diagnosis depends on the identification of unexplained left ventricular hypertrophy, but this finding is present only in people with established disease and is typically absent in childhood. In contrast, genetic diagnosis can identify carriers without hypertrophy who are at high risk for the development of disease and in particular myocardial fibrosis, which is thought to contribute to sudden cardiac death, ventricular tachyarrhythmias, left ventricular dysfunction and heart failure. The trigger for fibrosis is unclear but animal studies indicate that a profibrotic milieu is present early in hearts with HCM, even when cardiac histological findings are normal.
In this study the authors measured a variety of markers of collagen metabolism (which are known to reliably reflect myocardial collagen synthesis) in 38 subjects with pathogenic sarcomere mutations and overt HCM, 39 subjects with mutations but no left ventricular hypertrophy and 30 controls who did not have mutations. Participants also underwent imaging by echocardiography and cardiac MRI. 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 HCM 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 HCM, suggesting that in this group with clinical disease, collagen synthesis exceeds degradation. Cardiac MRI studies showed late gadolinium enhancement, indicating myocardial fibrosis, in 71% of subjects with overt HCM but in none of the mutation carriers without left ventricular hypertrophy and none of the controls.
Importantly, these observations offer insights into the pathophysiology of HCM and translate findings from mouse models to human disease, providing further evidence that fibrosis is a fundamental, early consequence of sarcomere mutations in HCM and that increased collagen synthesis contributes to the emergence of the pathophysiological changes of this disease. Increased serological markers of collagen synthesis may identify people at risk for arrhythmias, sudden death, or heart failure. If so, monitoring levels of these markers may guide new strategies to attenuate disease development or adverse outcomes in HCM and be an important advance in the treatment of this not uncommon condition.
Figure 1. KaplaneMeier curves for time to occurrence of composite primary end point.
Elevated levels of serumPICPwere able to identifysubjectswithHCMand also asymptomatic carriers, preceding the development of left ventricular hypertrophy or fibrosis visible on MRI, suggesting that this simple test may reflect a potentially useful serological marker of genetic risk.
• Ho CY, Lo´pez B, Coelho-Filho OR, et al. Myocardial fibrosis as an early manifestation of hypertrophic cardiomyopathy. N Engl J Med 2010;363:552e63.