Serum and urinary biomarkers of collagen type‐I turnover predict prognosis in patients with heart failure

Abstract

Serum and urinary biomarkers of collagen type-I turnover predict prognosis in patients with heart failure Dear Editor, Previous studies indicated an association of biomarkers reflecting collagen turnover with heart failure. 1,2 However, their value in predicting unfavorable outcomes is unknown. In the myocardium, the collagen matrix forms a scaffold that maintains the anatomical integrity and function of the heart. Collagen I is dominant among the four primary types of cardiac collagen. 3 The abundance of collagen is the net result of the balance between synthesis and degradation. 4,5 Collagen degradation releases fragments to the circulation and urine. Here, we investigate if specific changes in collagen I turnover, detected based on urinary peptide fragments and circulating biomarkers, are associated with heart failure and subsequent clinical events. Our study includes all 354 participants with suspected heart failure from the HOMAGE-HULL subcohort 6,7 recruited between 2010 and 2014, whose baseline serum and urine samples were available. Table S1 shows their demographic and clinical data. We used capillary electrophoresis coupled with mass spectrometry (CE-MS) to quantify type I alpha-1 (COL1A1) fragments in urine, confining the analyses to 293 fragments present in at least 30% of subjects. For serum samples, we used ELISA Kit to quantify the collagen synthesis biomarkers carboxyterminal propeptide of procollagen type I (PICP), 8 collagen degradation biomarkers carboxy-terminal telopeptide of collagen type I (CITP), 9 and matrix metalloproteinase (MMP-1) 10 , which are known as good indicators of collagen turnover (Figure S1). The primary outcome is heart failure death. The rank-normalized biomarker abundance was regressed with the time of survival in a Cox proportional hazard model corrected for six confounders: age, sex, body mass index, history of ischemic disease, heart rate, and serum creatinine. Significant biomarkers were combined into a classifier, using the support vector machinebased MosaCluster software. 2 Cox regression was used to determine if prognosis via the classifier was independent of the six confounders plus NT-proBNP. All analyses were This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Collagen-Derived Peptides in CKD: A Link to Fibrosis

“…When investigating the distribution of the few highly negatively (rho < −0.3) correlated significant peptides, it appears that the first and last peptides, that show such an inverse association with eGFR, originate from the N-and C-termini of the mature col1a1, respectively. This observation is similar to an observation recently reported by He et al [10], where the authors found an increase of N-and C-terminal collagen type I fragments associated with death in the context of heart failure, while the peptides from the central part of collagen type I that were significantly associated with death in this prospective study were all reduced. Based on these data, the hypothesis was presented that increasing cross-linking over time as a result of chemical modification due to ageing, inflammation or diabetes renders collagen fibers more resistant to degradation.…”

“…For example, in a fibrosis-focusing study, two specific col1a1 peptides, among other collagen fragments, demonstrated a negative correlation with the degree of fibrosis [9]. This is in agreement with the observation that the downregulation of the col1a1 degradation process appears to be associated with progression of fibrosis in heart failure [10]. In the context of obesity-related nephropathy, col1a1 fragments were also among the most significant peptides correlating (negatively) to body mass index (BMI) and (positively) to estimated glomerular filtration rate (eGFR) [11].…”

Urinary peptides in heart failure: a link to molecular pathophysiology

“…However, in a recent study the value of urinary collagen type I peptides in predicting outcome in HF has been demonstrated. 32 …”

“…Moreover, associations between urinary markers and clinical outcomes were not investigated. However, in a recent study the value of urinary collagen type I peptides in predicting outcome in HF has been demonstrated 32 …”

Biomarkers in Heart Failure: From Research to Clinical Practice

“…Elucidating the role of each of these molecules warrants comprehensive and thorough investigation, because they are heavily involved in the pathogenesis of myocardial fibrosis and are related to arrhythmogenesis [69,70]. Although numerous clinical trials have been performed in the last two decades to evaluate the utility of these molecules as diagnostic or prognostic biomarkers in patients with HF, collagen turnover biomarkers and bone-related proteins have been found to be closely associated with all-cause and CV mortality and HF hospital admission [71,72]. These markers are not highly specific for detecting adverse cardiac remodeling, and abnormal concentrations have often been found in acute and stable coronary artery disease, valvular heart disease, cardiac hypertrophy, and cardiomyopathy (Table 3).…”