Excessive Myocardial Collagen Cross-Linking Associated With Hospitalization in Heart Failure

In patients with heart failure of a hypertensive etiology, excessive myocardial collagen cross-linking is associated with hospitalization.

The ratio of C-terminal telopeptide of collagen type I (CITP) to matrix metalloproteinase-1 (MMP-1) serum can identify patients with increased myocardial collagen cross-linking (CCL) and high risk of hospitalization for heart failure (HHF).

Invasive and noninvasive studies were conducted with 38 and 203 hypertensive patients, respectively, with previous clinical diagnosis of chronic stage C HF, the results of which were published in the Journal of the American College of Cardiology.

Two-dimensional echocardiographic, pulsed Doppler, and tissue Doppler imaging were performed, and LV mass and dimensions, and parameters to assess systolic and diastolic function were obtained. Plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP), serum CITP, MMP-1, and tissue inhibitor of matrix metalloproteinases (TIMP-1) were also measured.  

First HHF after enrollment was the primary outcome, defined as “worsening signs and symptoms of HF that required urgent therapy and resulted in hospitalization.” Death from cardiovascular causes (eg, congestive HF, acute myocardial infarction, malignant arrhythmias, sudden death, stroke, or cardiorespiratory arrest) served as the secondary outcome.

In the invasive study, CCL was increased (P<.001) in the whole group compared with controls (3.31 ± 0.14 vs 1.43 ± 0.29). Normal CCL values were found in 11 patients (2.30 ± 0.11) and high CCL values were found in 27 patients (3.73 ± 0.13). The ratio between CITP and MMP-1 was reduced in patients with high CCL compared with patients with normal CCL in both coronary sinus blood (1.38 ± 0.15 vs 1.77 ± 0.15; P=.026) and antecubital vein blood (1.61 ± 0.14 vs 2.83 ± 0.35; P=.006).

Patients with high CCL had lower CITP:(MMP-1:TIMP-1)  ratios compared to patients who had normal CCL in both coronary sinus blood (79.05 ± 10.17 vs 111.55 ± 14.21; P=.043) and antecubital vein blood (79.96 ± 8.84 vs 142.17 ± 20.24; P=.009).

In the noninvasive study, patients were classified into 2 subgroups: those with CITP:MMP-1 ratio values >1.968, predicting a normal myocardial CCL and patients with ratio values ≤1.968, predicting high myocardial CCL.

Of the patients with normal CITP:MMP-1 ratios, 30 (34%) presented with HHF compared to  62 patients (54%) with low CITP-MMP-1 ratios (chi-square test P=.003). In a longitudinal analysis, patients with low CITP:MMP-1 ratios had a higher risk of HHF than patients with normal ratios (log-rank test P=.014).

Researchers noted that “compared with patients with normal CCL, patients with high CCL exhibited more severe LV diastolic and systolic dysfunction, but similar CVF [collagen volume fraction] and C1VF:CIIIVF ratio.”

“These findings suggest that an altered organization of the collagen fibril to form the collagen fiber may be more determinant than the amount of fibers per se in the detrimental impact of myocardial fibrosis on LV function in HF patients of hypertensive etiology,” they concluded.

Further studies are needed to understand these mechanisms and to determine how they play a role in the deterioration of ventricular function in patients with HF of hypertensive etiology.


Lopez B, Ravassa S, Gonzalez A, et al. Myocardial collagen cross-linking is associated with heart failure hospitalization in patients with hypertensive heart failure. J Am Coll Cardiol. 2016;67(3):251-260. doi: 10.1016/j.jac.2015.10.063.