{"doi":"10.1111/jch.14205","title":"The significance of plasma collagen degradation products as biomarkers for advanced hypertensive heart disease","abstract":"Fibroblast activation and subsequent collagen deposition in the heart is a one of the most deleterious consequences of hypertension and is an indicator of hypertensive heart disease. It contributes to ventricular stiffness and impaired relaxation and is considered as the main mechanism of heart failure in patients with preserved ejection fraction (HFpEF). The excessive myocardial cross-linking of collagen type I, a process catalyzed by the enzyme lysyl oxidase increases the insolubility, stiffness, and resistance to degradation of the collagen fibers and contributes to elevated filling pressures in patients with HFpEF. Transvenous myocardial biopsy to assess collagen deposition is considered the gold standard for the diagnoses of myocardial fibrosis. The levels of collagen in the biopsies have been shown to correlate with the degree of heart failure and inversely correlate with the ejection fraction by independent studies. Considering the invasive nature of the needle, biopsy serum biomarkers have been studied as surrogates for myocardial fibrosis. Collagens are synthesized from procollagen types I and III are secreted from fibroblasts and myofibroblasts as a triple-helix procollagen precursor containing terminal propeptides. The propeptides are cleaved by procollagen proteinases and released to the bloodstream. The carboxy-terminal propeptide of procollagen type I (PICP) is one of the propeptides generated during the extracellular conversion of procollagen type I into collagen type I by the enzyme procollagen carboxy-terminal proteinase (Figure 1). Since PICP is formed in a 1:1 stoichiometric ratio to the collagen type I molecule, its concentrations in blood is a direct indicator of collagen type I synthesis.1 The synthesized collagen is subsequently degraded by matrix metalloproteinases (MMP) such as MMP-1, which releases the carboxy-terminal telopeptide of collagen type I (CITP), a collagen type I degradation-derived serum peptide into circulation. The higher the cross-linking of collagen type I fibers, the lower the cleavage of the carboxy-terminal telopeptide of collagen type I (CITP) by the enzyme MMP-1. Accordingly, excessive myocardial collagen cross-linking enhances myocardial collagen's resistance to degradation by MMP-1 and triggers interstitial accumulation of collagen fibers with impairment of cardiac function. The intensity of collagen cross-linking can be assessed by the CITP/MMP-1 ratio, where a higher value is associated with less crosslinked cardiac collagen. The MMP-1 is inhibited by tissue inhibitors of metalloproteinase 1 (TIMP--1), which restrict ECM proteolysis and promote ECM deposition. To maintain hemostasis, human body also synthesizes antifibrotic proteins. N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is an endogenous anti-fibrotic and anti-inflammatory tetra-peptide generated from the N-terminal sequence of thymosin β4 (Tβ4) by the action of propyl oligopeptidases. Ac-SDKP inhibits human mesangial cell, renal, and cardiac fibroblast proliferation. In addition, it has been shown to inhibit collagen deposition in mouse cardiac fibroblasts. Ac-SDKP is degraded by angiotensin-converting enzyme (ACE). ACE has N-terminal and C-terminal catalytic domains. The in vivo studies have suggested that N-terminal catalytic domain has relatively lower catalytic effects compared to C-terminal. The affinity of ACE inhibitors for the ACE catalytic domains is structure dependent. Captopril, the first clinically used ACE inhibitor has greater affinity for the N-terminal domain compared to the C-terminal domain, while lisinopril has much greater affinity for the C-terminal domain. Ac-SDKP is hydrolyzed only by the N-terminal catalytic ACE domain and is released by ACE inhibitors, and hence, their levels are also used to detect adherence to the medication. Overall, the activation of renin-angiotensin-aldosterone (RAAS) system in hypertension is a major inducer of fibroblast activation and collagen deposition. The role","journal":"Journal of Clinical Hypertension","year":2021,"id":205847,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":7,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9541,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":471888,"name":"Arya Mani","orcid":"0000-0001-6699-259X","position":1,"is_corresponding":false},{"id":789662,"name":"K Mani","orcid":"0000-0002-7883-8351","position":0,"is_corresponding":true}],"reference_count":9,"raw_metadata":null,"created_at":"2026-07-18T23:51:37.630221Z","pmid":"33932079","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}