Circulating levels of procollagen type I carboxy‐terminal propeptide reflect myocardial fibrosis

This article refers to ‘The combination of carboxy-terminal propeptide of procollagen type I blood levels and late gadolinium enhancement at cardiac magnetic resonance provides additional prognostic information in idiopathic dilated cardiomyopathy – A multilevel assessment of myocardial fibrosis in dilated cardiomyopathy’ by A.G. Raafs et al., published in this issue on pages 933–944. Myocardial fibrosis is a consequence of a profound change in the architecture and composition of the cardiac extra-cellular matrix affecting the structure and function of the heart. Non-specific insults to the cardiovascular system (e.g. hypertension, diabetes, ageing, ischaemia, genetic alterations) may dysregulate various cell types and signalling pathways, ultimately resulting in myocardial fibrosis.1, 2 Once established, myocardial fibrosis is strongly associated with a poor prognosis, including in patients with idiopathic dilated cardiomyopathy (DCM).3, 4 Despite the sound pathophysiological background and prognostic impact of myocardial fibrosis, its assessment remains challenging in clinical practice. Circulating markers reflecting collagen synthesis are under investigation as potential means for evaluating myocardial fibrosis non-invasively. In this regard, procollagen type I carboxy-terminal propeptide (PICP) may directly reflect the synthesis of collagen type 1 because it is produced during the conversion of procollagen type I to collagen type I in a 1:1 ratio.1 Furthermore, serum PICP levels have been correlated with total myocardial collagen volume fraction (CVF) (assessed in myocardial samples with collagen-specific staining) in patients with hypertension, heart failure and DCM.4, 5 Another potential marker of collagen synthesis is N-terminal propeptide of type III collagen (PIIINP). PIIINP is generated from the conversion of procollagen type III into collagen type III and has been correlated with the amount of collagen type III fibres in the myocardium of heart failure patients, but it may not directly reflect collagen synthesis (because PIIINP is a small circulating N-terminal portion).1 Moreover, type I collagen is composed by large-diameter fibres with a high capacity for cross-linking, contributing more to myocardial stiffness than the finer type III collagen fibres.1 Pathological myocardial fibrosis is characterized by an excess of type I compared to type III collagen, including in patients with DCM.3, 4, 6 Mineralocorticoid receptor antagonists have been shown to substantially reduce PICP levels, suggesting that these drugs can actively reduce myocardial fibrosis.1, 7-9 However, further studies are needed to establish PICP as a reliable circulating marker reflecting in situ myocardial fibrosis; the use of cardiac magnetic resonance (CMR) techniques and heart biopsies may help confirming PICP as the ‘fibrosis marker’ of choice (Figure 1). In this issue of the Journal, Raafs and colleagues quantified fibrosis in 209 patients with DCM using (i) CMR non-invasive late gadolinium enhancement (LGE), (ii) invasive endomyocardial biopsy (EMB) with determination of CVF, and (iii) circulating levels of PICP and PIIINP.10 The authors found that PICP (but not PIIINP) was positively correlated with myocardial fibrosis as determined by CMR-LGE (R2 = 0.39) and by EMB-CVF, particularly among severely symptomatic patients with reduced ejection fraction (R2 = 0.68). RNA-sequencing and gene enrichment analysis of EMB confirmed an increased expression of pro-fibrotic and pro-inflammatory pathways in patients with elevated PICP and fibrosis-positive CMR-LGE. Importantly, PICP (but not PIIINP) and CMR-LGE were independently associated with the occurrence of cardiovascular events and death, particularly among patients with a combination ‘positive’ myocardial fibrosis determined CMR-LGE and elevated PICP levels who had the worst prognosis. The study by Raafs and colleagues is the first to evaluate myocardial fibrosis by multiple modalities in patients with DCM, and the findings here reported are important for several reasons: (i) PICP positively correlates with myocardial fibrosis and should be the circulating marker of choice for the assessment of cardiovascular fibrosis, (ii) patients with elevated circulating PICP levels and fibrosis-positive CMR-LGE expressed a pro-fibrotic and pro-inflammatory transcriptome profile in cardiac tissue, and (iii) PICP has prognostic value in patients with DCM, particularly when combined with CMR-LGE. Together, these findings suggest that PICP can be used as a non-invasive and readily available tool (biomarker) to assess the burden of cardiac fibrosis, monitor the course of the disease, obtain updated prognostic information, and possibly monitor the response to anti-fibrotic therapies. The latter was not evaluated in the present study, but in people at risk for heart failure participating in the Heart ‘OMics’ in AGEing (HOMAGE) randomized clinical trial, treatment with spironolactone (vs. usual care) for a 9-month period led to a statistically significant and clinically important drop in circulating PICP, accompanied by blood pressure reduction, improvement of cardiac structure and decrease of N-terminal pro B-type natriuretic peptide levels.8, 11, 12 Whether mineralocorticoid receptor antagonists or other anti-fibrotic therapies can improve the outcomes of patients with DCM and a pro-fibrotic profile should be adequately tested in a randomized controlled trial; the background for such a trial in now robust. Conflict of interest: J.P.F. is a consultant for Boehringer Ingelheim, and receives research support from AstraZeneca and Novartis.