Association of fatal and non-fatal adverse health outcomes with urinary peptides reflecting collagen I turnover

Abstract

Abstract Background Imbalance of collagen I (COL1) turnover, featured by increased synthesis and decreased degradation of collagen fibers, is a hallmark of fibrosis in the heart and blood vessels that associates with poor cardiovascular outcomes. Such as imbalance of COL1 turnover could be reflected in urine and serve as fingerprint for future adverse outcomes in general population, and high risk subjects. Purpose We hypothesize that imbalance of proteomic signatures of urinary peptides (UPs) reflecting COL1 turnover relate to adverse health outcomes in participants from a general population Methods We randomly recruited 776 participants (51.2% women; 50.5 years) from the Flemish Study on Environment, Genes and Health Outcomes cohort and measured UPs proteome by capillary electrophoresis coupled with mass spectrometry. Our analyses focused on 148 peptides of COL1 alpha-1 (COL1A1) chain that retained ≥70% signal in the whole sample. The primary endpoint included fatal and nonfatal cardiovascular endpoints. Secondary endpoints consisted of total mortality, fatal and nonfatal cardiac, coronary, and heart failure endpoints. Multivariate Cox proportional models, partial least squares analysis (PLS), log-likelihood test, and receiver operating characteristics (ROC) curve were applied. Results Over a median follow up of 12.4 years, 110 primary endpoints occurred, 61 participants died, 81, 41 and 24 experienced cardiac, coronary, and heart failure endpoints; respectively. In PLS analyses, upregulation of UPs signatures closer to C- and N-terminal locations of the COL1A1 chain whereas downregulation of mid-region UPs were associated with lower risk of adverse health outcomes. This pattern was inverted in subjects with cardiovascular disease, as upregulation of terminal and downregulation of mid region UPs increased risk. Adding UPs to a basic model including sex, age and usual cardiovascular risk factors significantly improved model performance between 2.54% to 4.93% (P≤0.001) for prediction of adverse health outcomes. In ROC plots, adding UPs to the basic model increased the area under the curve up to 4.00% (P<0.012). Conclusions UPs reflecting COL1 turnover predicted adverse health outcomes. The inverted up- and down regulations of UPs in between participants with and without previous cardiovascular diseases might be explained by a shift in the UPs signatures of COL1 fragments linked to distinct fibrotic processes. Urinary proteomic might have clinical importance in documenting the extent of collagen accumulation that relates to adverse health outcomes. In patients at high cardiovascular risk, modification of collagen I fibers turnover might be a potential treatment target Funding Acknowledgement Type of funding sources: Public grant(s) – EU funding. Main funding source(s): The European Union the European Research Council and the European Research Area Net for Cardiovascular Diseases.