Myocardial Collagen Turnover in Hypertrophic Cardiomyopathy

Abstract

Background-Myocardial interstitial fibrosis is a characteristic of hypertrophic cardiomyopathy (HCM). This study evaluates the collagen turnover in HCM and its impact on left ventricular (LV) diastolic function. Methods and Results-Thirty-six HCM patients and 14 sex-and age-matched controls were studied. Collagen turnover was assessed as follows. By radioimmunoassay, a byproduct of collagen III synthesis (PIIINP) and 3 peptides resulting from collagen I synthesis (PICP and PINP) and degradation (ICTP) were measured. By ELISA, matrix metalloproteinases (MMPs) were determined, as follows: active MMP-2; active MMP-9; and MMP-1 as active, free (as active MMP-1 plus its precursor), and total (as free MMP-1 plus MMP-1/tissue inhibitor complexes). Tissue inhibitor of metalloproteinases-1 (TIMP-1) was also assayed. All patients underwent echocardiography. The difference in duration between transmitral forward (A) and pulmonary venous retrograde (AR) waves (AϪAr) was considered an estimate of passive diastolic function. Furthermore, restrictive or pseudonormal LV filling patterns were considered to identify patients with passive diastolic dysfunction. Patients had higher levels of PIIINP, ICTP, MMP-2, MMP-9, and total TIMP-1 than did controls. PIIINP was inversely related to LV end-diastolic diameter. AϪAr was inversely related to PICP, PINP, and their differences with ICTP (estimates of collagen I buildup). Furthermore, AϪAr was directly related to MMP-1 and MMP-2. Conclusions-As compared with controls, collagen turnover is enhanced in HCM patients. As collagen I synthesis prevails over degradation and MMP-1 and MMP-2 are inhibited, passive diastolic dysfunction occurs in patients with HCM.

Clinical and echocardiographic correlates of plasma procollagen type III amino-terminal peptide levels in the community

“…5,7,[25][26][27] Prior studies have documented elevated PIIINP levels in patients with a variety of abnormalities influencing cardiac structure or function. 7,8 In an adequately 'powered' study of a community-based sample, we found that plasma PIIINP levels were correlated with age and BMI, but not with LV structure or function after adjustment for conventional risk factors. These findings suggest limited utility for measurement of plasma PIIINP levels to detect subclinical cardiac disease in the ambulatory setting.…”

“…The N-terminal and Cterminal peptides are cleaved by endopeptidases after pro-collagen has been secreted from the cell. Elevated levels of pro-collagen type III N-terminal peptide (PIIINP) have been observed in individuals with hypertension, 5,6 dilated cardiomyopathy, 7 hypertrophic cardiomyopathy, 8 and recent myocardial infarction, 9,10 suggesting that the circulating peptide may be a useful marker of active myocardial collagen synthesis. In a retrospective analysis from the Randomized Aldactone Evaluation Study, high baseline levels of circulating PIIINP were predictive of death and hospitalization in heart failure patients.…”

Treatment with spironolactone for 24 weeks decreases the level of matrix metalloproteinases and improves cardiac function in patients with chronic heart failure of ischemic etiology

“…The diastolic functions assessed by E/A were clearly impaired in our patients. This may be explained by the slightly increased concentration of PICP and highly elevated TIMP-1 level, which probably aggravated myocardial stiffness, mainly by facilitating interstitial fibrosis in myocardial tissue (2).…”

Improvement in collagen metabolism after 12 weeks’ cardiac resynchronization therapy in patients with ischaemic cardiomyopathy

“…However, noninvasive ways of assessing collagen metabolism (by measuring the biomarkers MMP and TIMP) have been developed and may replace myocardial biopsy. 6,10,11,[17][18][19] In the present study, MMP-9 and its inhibitor TIMP-1 were chosen as markers of collagen haemostasis in ischaemic myocardium. 20 Due to the antagonistic relationship between MMP-9 and TIMP-1, the ratio of MMP-9 to TIMP-1 can reflect MMP hydrolyzing ability and activity, and can also indirectly estimate the balance between collagen synthesis and degradation.…”

“…During collagen synthesis, carboxyterminal propeptide of type I procollagen (PICP) is cleaved from procollagen I and released into the blood, while during collagen degradation by MMP, carboxyterminal telopeptide of type I collagen (ICTP) is cleaved and released into the blood. Thus, PICP 9 and ICTP 10 can also be used as biomarkers of collagen synthesis and degradation, respectively.…”