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

Anne G Raafs; Bouke P Adriaans; Michiel T H M Henkens; Job A J Verdonschot; Myrurgia A Abdul Hamid; Javier Díez; Christian Knackstedt; Vanessa P M van Empel; Hans-Peter Brunner-La Rocca; Arantxa González; Joachim E Wildberger; Stephane R B Heymans; Mark R Hazebroek

doi:10.3390/jcm12175695

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

J Clin Med. 2023 Sep 1;12(17):5695. doi: 10.3390/jcm12175695.

Authors

Anne G Raafs^{1

2}, Bouke P Adriaans^{1

2

3}, Michiel T H M Henkens^{1

2

4

5}, Job A J Verdonschot^{1

2

6}, Myrurgia A Abdul Hamid⁵, Javier Díez^{7

8}, Christian Knackstedt¹, Vanessa P M van Empel¹, Hans-Peter Brunner-La Rocca¹, Arantxa González^{7

8}, Joachim E Wildberger^{2

3}, Stephane R B Heymans^{1

2

9}, Mark R Hazebroek^{1

2}

Affiliations

¹ Department of Cardiology, Maastricht University Medical Centre, 6229 HX Maastricht, The Netherlands.
² Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, 6229 HX Maastricht, The Netherlands.
³ Department of Radiology and Nuclear Medicine, Maastricht University Medical Centre, 6229 HX Maastricht, The Netherlands.
⁴ Netherlands Heart Institute (NLHI), 3511 EP Utrecht, The Netherlands.
⁵ Department of Pathology, Maastricht University Medical Centre, 6229 HX Maastricht, The Netherlands.
⁶ Department of Clinical Genetics, Maastricht University Medical Centre, 6229 HX Maastricht, The Netherlands.
⁷ Program of Cardiovascular Diseases, CIMA Universidad de Navarra and IdiSNA, 31008 Pamplona, Spain.
⁸ CIBERCV, Carlos III Institute of Health, 28029 Madrid, Spain.
⁹ Department of Cardiovascular Research, University of Leuven, 3000 Leuven, Belgium.

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.

Grants and funding

This work was supported by the Instituto de Salud Carlos III (CIBERCV CB16/11/00483, PI18/01469, and PI21/00946 co-financed by ERDF funds); Kootstra Talented Post-Doctoral Fellowship; and the European Union Commission’s Seventh Framework Program under grant agreement no. 305507 (HOMAGE [Heart OMics in AGEing consortium]).