Background and aims: Cardiac dysfunction is often seen in patients with advanced cirrhosis. Diffuse myocardial fibrosis (DMF) seems to play an important role in the underlying pathophysiology of cirrhotic cardiomyopathy. Thus, the myocardial extracellular volume (ECV), which reflects the degree of myocardial fibrosis as assessed by cardiac MRI seems to be increased in cirrhosis and associated with liver and cardiac dysfunction. Upregulation of collagen production and deposition in the heart is the main feature of DMF. Elevated biomarkers of collagen formation indicate an ongoing process of fibrogenesis. PRO-C3 has previously proven to be a marker of hepatic fibrosis in patients with different liver diseases and PRO-C6 has been associated with adverse outcomes in kidney failure. Our aim was therefore to evaluate the association between presence of DMF as assessed by cardiac MRI with ECV quantification and circulating levels of two novel biomarkers of collagen type III and type VI formation.
Methods: Sixty-three stable cirrhotic patients underwent a cardiac MRI with ECV quantification, ECG including QTc interval, clinical and biochemical assessments. Formation of collagen type III and type VI was assessed in serum by means of enzyme-linked immunosorbent assays (PRO-C3 and PRO-C6, respectively), measuring the concentration of the pro-peptides of the two collagens, which are cleaved and released in circulation during maturation of newly synthesized collagen molecules.
Results: PRO-C3 and PRO-C6 were increased in serum of the investigated patients in comparison to the assay normal range (mean (2.5–97.5 percentile) PRO-C3: 54.3 (11.2–147.2) vs. 12.1 (6.7–22.2) ng/ml, p<0.0001 and mean (2.5–97.5 percentile) PRO-C6: 14.5 (5.1–34.7) vs. 8.0 (4.9–12.2) ng/ml, p<0.0001). Moreover, there was a positive correlation of both markers to ECV (PRO-C3: r=0.33 p=0.016; PRO-C6: r=0.39 p=0.005) and QTc (PRO-C3: r=0.314, p=0.016; PRO-C6: r=0.343, p=0.008). When dividing the patients in two groups according to the median myocardial ECV level (31%), levels of both markers were significantly more elevated in patients in the high ECV group (PRO-C3 p=0.031; PRO-C6 p=0.003).
Conclusion: In stable cirrhotic patients, PRO-C3 and PRO-C6 are associated with increased myocardial ECV, which reflects DMF. In addition, the association of the biomarkers to the prolonged QTc interval suggests that increased cardiac fibrosis is involved in the electrophysiological abnormalities in cirrhosis. The novel biomarkers of collagen formation may therefore be valuable in the investigation of presence and pathophysiology of cardiac dysfunction in cirrhosis.