Myocardial Collagen Cross-Linking Is Associated With Heart Failure Hospitalization in Patients With Hypertensive Heart Failure.

BACKGROUND: Excessive myocardial collagen cross-linking (CCL) determines myocardial collagen's resistance to degradation by matrix metalloproteinase (MMP)-1 and interstitial accumulation of collagen fibers with impairment of cardiac function. OBJECTIVES: This study sought to investigate whether CCL and a newly identified biomarker of this alteration are associated with hospitalization for heart failure (HHF) or cardiovascular death in patients with HF and arterial hypertension in whom other comorbidities were excluded. METHODS: Endomyocardial biopsies and blood samples from 38 patients (invasive study), and blood samples from 203 patients (noninvasive study) were analyzed. Mean follow-ups were 7.74 ± 0.58 years and 4.72 ± 0.11 years, respectively. Myocardial CCL was calculated as the ratio between insoluble and soluble collagen. The ratio between the C-terminal telopeptide of collagen type I (CITP) and matrix metalloproteinase-1 (CITP:MMP-1) was determined in blood samples. RESULTS: Invasive study: CCL was increased (p < 0.001) in patients compared with controls. Patients were categorized according to normal or high CCL values. Patients with high CCL exhibited higher risk for subsequent HHF (log-rank test p = 0.022), but not for cardiovascular death. CITP:MMP-1 was inversely associated with CCL (r = -0.460; p = 0.005) in all patients. Receiver operating characteristic curves rendered a CITP:MMP-1 cutoff ≤1.968 (80% sensitivity and 76% specificity) for predicting high CCL. Noninvasive study: Patients were categorized according to CITP:MMP-1 ratio values as normal ratio (>1.968) or low ratio (≤1.968). Patients with a low ratio exhibited higher risk for HHF (log-rank test p = 0.014), which remained significant after adjustment for relevant covariables (adjusted hazard ratio: 2.22; 95% CI: 1.37 to 3.59, p = 0.001). In addition, CITP:MMP-1-based categorization yielded significant integrated discrimination and net reclassification improvements (p = 0.003 and p = 0.009, respectively) for HHF over relevant risk factors. CITP:MMP-1 was not associated with the risk of cardiovascular death. CONCLUSIONS: Excessive myocardial CCL is associated with HHF in hypertensive patients with HF. In this population, the serum CITP:MMP-1 ratio identifies patients with increased CCL and high risk of HHF.

Association of cystatin C with heart failure with preserved ejection fraction in elderly hypertensive patients: potential role of altered collagen metabolism.

OBJECTIVES: Cystatin C has been shown to be associated with heart failure with preserved ejection fraction (HFPEF). In addition, myocardial fibrosis has been involved in diastolic dysfunction in HFPEF. Therefore, we hypothesized that increased cystatin C levels may be associated with altered collagen metabolism, contributing to diastolic dysfunction in patients with HFPEF. METHODS: One hundred and forty-one elderly hypertensive patients with HFPEF were included. Cardiac morphology and function was assessed by echocardiography. Circulating levels of cystatin C, biomarkers of collagen type I synthesis (carboxy-terminal propeptide of procollagen type I) and degradation [matrix metalloproteinase-1 (MMP-1) and its inhibitor TIMP-1] and osteopontin were analyzed by ELISA. Twenty elderly sex-matched patients with no identifiable cardiac disease were used as controls. In-vitro studies were performed in human cardiac fibroblasts. RESULTS: Compared with controls, cystatin C was increased (P < 0.001) in patients with HFPEF, even in those with a normal estimated glomerular filtration rate (eGFR; P < 0.05). Cystatin C was directly correlated with the estimated pulmonary capillary wedge pressure (P < 0.01), TIMP-1 and osteopontin (P < 0.001) and inversely correlated with MMP-1:TIMP-1 (P < 0.01), but not with carboxy-terminal propeptide of procollagen type I or MMP-1 in all patients with HFPEF. These associations were independent of eGFR. In vitro, osteopontin (P < 0.01) and TIMP-1 (P < 0.001) increased in the supernatant of cardiac fibroblasts exposed to cystatin C. CONCLUSION: In patients with HFPEF of hypertensive origin, cystatin C is increased and associated with diastolic dysfunction and alterations in collagen metabolism independently of eGFR. An excess of cystatin C might contribute to diastolic dysfunction in HFPEF by facilitating myocardial fibrosis via accumulation of osteopontin and TIMP-1.