Biomarkers of Collagen Metabolism Are Associated with Left Ventricular Function and Prognosis in Dilated Cardiomyopathy: A Multi-Modal Study

Abstract

Background: Collagen cross-linking is a fundamental process in dilated cardiomyopathy (DCM) and occurs when collagen deposition exceeds degradation, leading to impaired prognosis. This study investigated the associations of collagen-metabolism biomarkers with left ventricular function and prognosis in DCM.

Methods: DCM patients who underwent endomyocardial biopsy, blood sampling, and cardiac MRI were included. The primary endpoint included death, heart failure hospitalization, or life-threatening arrhythmias, with a follow-up of 6 years (5-8).

Results: In total, 209 DCM patients were included (aged 54 ± 13 years, 65% male). No associations were observed between collagen volume fraction, circulating carboxy-terminal propeptide of procollagen type-I (PICP), or collagen type I carboxy-terminal telopeptide [CITP] and matrix metalloproteinase [MMP]-1 ratio and cardiac function parameters. However, CITP:MMP-1 was significantly correlated with global longitudinal strain (GLS) in the total study sample (R = -0.40, p < 0.0001; lower CITP:MMP-1 ratio was associated with impaired GLS), with even stronger correlations in patients with LVEF > 40% (R = -0.70, p < 0.0001). Forty-seven (22%) patients reached the primary endpoint. Higher MMP-1 levels were associated with a worse outcome, even after adjustment for clinical and imaging predictors (1.026, 95% CI 1.002-1.051, p = 0.037), but CITP and CITP:MMP-1 were not. Combining MMP-1 and PICP improved the goodness-of-fit (LHR36.67, p = 0.004).

Conclusion: The degree of myocardial cross-linking (CITP:MMP-1) is associated with myocardial longitudinal contraction, and MMP-1 is an independent predictor of outcome in DCM patients.

Keywords: CITP/MMP-1; cardiovascular magnetic resonance; dilated cardiomyopathy; feature tracking; fibrosis; global longitudinal strain.

Figure 1

Associations of collagen biomarkers with histological CVF. PICP is correlated with CVF (A), but CITP, MMP-1, and CITP:MMP-1 ratio arenot (B–D). Abbreviations: CVF: collagen volume fraction, PICP: carboxy-terminal propeptide of procollagen type I, CITP: collagen type I carboxy-terminal telopeptide, MMP-1: matrix metalloproteinase-1. Red line = linear regression line. Dotted lines = 95% CI.

Figure 2

Associations of collagen biomarkers with LGE extent. PICP (A) and MMP-1 (C) are correlated with LGE extent, but CITP (B) and CITP:MMP-1 ratio are not (D). Abbreviations: LGE: late gadolinium enhancement, PICP: carboxy-terminal propeptide of procollagen type I, CITP: collagen type 1 carboxy-terminal telopeptide, MMP-1: matrix metalloproteinase-1. Red line = linear regression line. Dotted lines = 95% CI.

Figure 3

Associations of collagen cross-linking (CITP:MMP-1) with cardiac function parameters (LVEF and GLS). CITP:MMP-1 is not correlated with LVEF in the total study sample, as well as in the subgroups of patients with LVEF above or below 40% (A,C,E). Significant correlations were found between CITP:MMP-1 and GLS in the total study sample (B) and in patients with LVEF ≤ 40% (D). This correlation is even stronger in patients with mildly reduced LVEF of ≥40% (F). Abbreviations: LVEF: left ventricular ejection fraction, GLS: global longitudinal strain, CITP: collagen type I carboxy-terminal telopeptide, MMP-1: matrix metalloproteinase-1. Red line = linear regression line. Dotted lines = 95% CI.

Figure 4

The addition of MMP-1 and PICP improves the goodness-of-fit of the model. MMP-1 and PICP improve the goodness-of-fit as individual markers. Combining MMP-1 and PICP improves the goodness-of-fit even further.