The collagen metabolism, disrupted endothelium, the endothelial progenitor cells and their microvesicles in acute rheumatic fever

Background Acute rheumatic fever (ARF) and its chronic sequelae, rheumatic heart disease (RHD) contributes to valvular dysfunction and significant cardiovascular disability and endocardial damage is considered the primary pathophysiological mechanism underlying ARF. This study examined peripheral blood markers of endothelial injury and function in ARF and RHD patients and compared them to healthy controls. Method In this prospective observational study, the levels of collagen intermediates, matrix metalloproteinases, tissue inhibitors of matrix metalloproteinases, brain natriuretic peptide, Anti-DNaseB, VEGF, E-selectin, VCAM, and ICAM in circulation were estimated. The study also isolated hemangioblastic and monocytic endothelial progenitor cells and their respective microvesicles from the peripheral blood of patients and control samples. Results Procollagen type I carboxy-terminal propeptide, cross-linked c-telopeptide of type I, and procollagen III c-terminal propeptide levels were higher in RHD subjects compared to patients with ARF. The ARF patients had the highest levels of matrix metalloproteinases 10 (MMP-10) followed by chronic patients and healthy controls. The ratio of tissue inhibitors of matrix metalloproteinases TIMP-1 and MMP-10 was lowest in healthy controls. At the cellular level, there were higher number of monocytic endothelial progenitor cells (EPCs) in ARF subjects as compared to healthy controls. For hemangioblastic EPCs, there was no significant difference between chronic subjects and healthy controls, though their early subtype was higher in chronic subjects. The hemangioblastic EPCs microvesicles were more abundant in ARF compared to RHD patients. Conclusion The greater number of EPCs and respective microvesicles confirm the continued disruption of the endothelium in ARF, and during the progression of the disease, the majority of EPCs undergo apoptosis. Obituary Statement This study was conceived and designed by SR, PU, and Prof. Rajnish Juneja, Professor at AIIMS. Prof. Rajnish Juneja expired in April 2018 while the study was ongoing ([1][1]). Mr. Suran Nambisan, a research fellow at NII, was part of the team who initiated the experimental work. Dr. Suran Nambisan expired in January 2023. This paper is dedicated to both of them. It was the profound love for mankind and unwavering dedication to perfection by Prof. Rajnish Juneja that brought together a remarkable team to undertake this study. Dr. Suran Nambisan embarked on his professional research journey by successfully establishing and standardizing a few intricate protocols used in this study. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by in part by grant received from the Indian Council of Medical Research and the core grant received from the Department of Biotechnology, Government of India to National Institute of Immunology, New Delhi. The funders had no role in study design, data collection, analysis, decision to publish and preparation of the manuscript. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The protocol was approved by the Human Ethics Committee of All India Institute of Medical Sciences, New Delhi (IEC/NP-88/2010, IEC/NP-88/2010, OP-03/09.10.2015, IEC-226/05.04.2019, RP-34/2019) and Institutional Human Ethics Committee of National Institute of Immunology (NII), New Delhi (IHEC#115/19). Written informed consent/assent were obtained from all subjects/guardians before enrolment into the study. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes [1]: #ref-1