We present data showing increased myocardial type I collagen synthesis in both early and established hypertrophic cardiomyopathy. Elevated serum PICP levels in mutation carriers with normal cardiac morphologic features constitute a potentially useful phenotype for sarcomere mutations and a serologic marker of genetic risk that can be detected before clinical diagnosis. These observations offer insights into the pathophysiology of hypertrophic cardiomyopathy, suggesting that the stimulus for myocardial fibrosis is an early manifestation of sarcomeregene mutations.
In contrast to collagen synthesis, biomarkers of collagen degradation in isolation were not informative regarding genotype or clinical status. However, the PICP:CITP ratio, an index of the dynamic equilibrium between collagen type I synthesis and degradation,44
was unchanged in mutation carriers without left ventricular hypertrophy but increased in subjects with overt disease. We propose that sarcomere mutations trigger an early increase in collagen synthesis that is initially balanced by degradation, thereby limiting fibrogenesis. In overt hypertrophic cardiomyopathy, synthesis exceeds degradation, resulting in frank myocardial fibrosis. Although our study was not longitudinal, these results are consistent with the natural history of hypertrophic cardiomyopathy and suggest that collagen accumulation increases as disease develops. Indeed, these findings may partially explain why late gadolinium enhancement on cardiac MRI was present in the majority of our subjects with overt hypertrophic cardiomyopathy, as observed in other studies,10,13,14,16-18
but absent in the mutation carriers without left ventricular hypertrophy, despite elevated PICP levels.
Increased myocardial fibrosis is a hallmark of overt hypertrophic cardiomyopathy and is frequently interpreted as a secondary response to the pathophysiological remodeling of long-standing disease, including ischemia, obstruction, and microvascular abnormalities.9,12,23
This interpretation is challenged by studies showing early activation of profibrotic genetic pathways in a mouse model of hypertrophic cardiomyopathy. In young mice with a myosin heavy-chain mutation, comprehensive transcriptional profiling revealed increased expression of genes that drive extracellular-matrix formation before fibrosis or left ventricular hypertrophy develops.25
RNA levels of connective-tissue growth factor, periostin, transforming growth factor β
1 and β
2, fibronectin, and type I collagen were increased despite normal cardiac histologic findings.
Our data translate these findings from mouse models to human disease, providing further evidence that fibrosis is a fundamental, early consequence of sarcomere mutations. On the basis of the elevated PICP levels in mutation carriers without left ventricular hypertrophy, we propose that increased collagen synthesis contributes to the emergence of the pathophysiological changes that characterize overt hypertrophic cardiomyopathy. Analysis of additional biomarkers (collagen type III–derived peptides, other matrix metalloproteinases, and TIMPs) may provide a more comprehensive picture of how sarcomere mutations affect the complex and dynamic nature of fibrillar collagen metabolism.
We could not identify significant correlations between biomarker levels and other clinical variables, including late gadolinium enhancement on cardiac MRI and ECG abnormalities. These results are not surprising, given the limited resolution of late gadolinium enhancement for the detection of focal myocardial fibrosis (theoretical detection limit, approximately 0.2 g of scar; a clinical detection limit of approximately 2.0 g in infarct studies45,46
) and estimates of the amount of scar (approximately 3% of left ventricular mass) needed to produce changes visible on ECG studies.47
Moreover, diffuse interstitial fibrosis is common in hypertrophic cardiomyopathy but cannot be visualized by means of cardiac MRI. In contrast, immunoassays detect micrograms of circulating PICP. Serum biomarkers consequently provide a more sensitive index of extracellular-matrix remodeling and may reflect subtle changes in myocardial composition and biochemical features that are not detectable by means of noninvasive cardiac imaging. Notably, we observed that MYH7
mutation carriers without left ventricular hypertrophy had both higher PICP levels (indicating increased collagen synthesis) and lower early diastolic levels (indicating more impaired relaxation) than MYBPC3
mutation carriers. Previous studies suggest that mutations in MYH7
result in an earlier onset of overt hypertrophic cardiomyopathy than do MYBPC3
Our data provide a potential mechanism for this genotype–phenotype correlation — namely, that MYH7
mutations, as compared with MYBPC3
mutations, trigger earlier extracellular-matrix remodeling, more extensive remodeling, or both.
The identification of increased myocardial collagen synthesis in mutation carriers without left ventricular hypertrophy, as with diastolic dysfunction in this population,5-7
shows that sarcomere-gene mutations have a considerable effect on the heart before the onset of hypertrophy. The detection of a profibrotic myocardial milieu in mutation carriers without left ventricular hypertrophy has intriguing clinical implications. Increased serologic markers of collagen synthesis may identify persons 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 hypertrophic cardiomyopathy. We suggest that incorporating genetic testing to identify at-risk mutation carriers, defining features of early disease, and developing therapies to mitigate fibrosis will foster vital new opportunities to change the natural history of hypertrophic cardiomyopathy.