Faulkner, Ashton R M

Jover, Eva

López-Andrés, Natalia

Madeddu, Paolo R

English

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                          Jover, E., Faulkner, A. R. M., Madeddu, P. R., & López-Andrés, N.(2022). Editorial: Inflammation, Metabolism and Epigenetics inValvular Heart Disease. Frontiers in Cardiovascular Medicine, 9,[880015]. https://doi.org/10.3389/fcvm.2022.880015Publisher's PDF, also known as Version of recordLicense (if available):CC BYLink to published version (if available):10.3389/fcvm.2022.880015Link to publication record in Explore Bristol ResearchPDF-documentThis is the final published version of the article (version of record). It first appeared online via Frontiers Media athttps://doi.org/10.3389/fcvm.2022.880015.Please refer to any applicable terms of use of the publisher.University of Bristol - Explore Bristol ResearchGeneral rightsThis document is made available in accordance with publisher policies. Please cite only thepublished version using the reference above. Full terms of use are available:http://www.bristol.ac.uk/red/research-policy/pure/user-guides/ebr-terms/EDITORIALpublished: 11 April 2022doi: 10.3389/fcvm.2022.880015Frontiers in Cardiovascular Medicine | www.frontiersin.org 1 April 2022 | Volume 9 | Article 880015Edited and reviewed by:Elena Aikawa,Brigham and Women’s Hospital andHarvard Medical School,United States*Correspondence:Eva Jovereva.jover.garcia@navarra.es†These authors have contributedequally to this workSpecialty section:This article was submitted toHeart Valve Disease,a section of the journalFrontiers in Cardiovascular MedicineReceived: 20 February 2022Accepted: 07 March 2022Published: 11 April 2022Citation:Jover E, Faulkner A, Madeddu P andLópez-Andrés N (2022) Editorial:Inflammation, Metabolism andEpigenetics in Valvular Heart Disease.Front. Cardiovasc. Med. 9:880015.doi: 10.3389/fcvm.2022.880015Editorial: Inflammation, Metabolismand Epigenetics in Valvular HeartDiseaseEva Jover 1*†, Ashton Faulkner 2†, Paolo Madeddu 3† and Natalia López-Andrés 1†1Cardiovascular Translational Research, Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública deNavarra (UPNA), Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain, 2 School of Biochemistry,University of Bristol, Bristol, United Kingdom, 3 Bristol Medical School, Translational Health Sciences, University of Bristol,Bristol, United KingdomKeywords: valvular heart disease, inflammation, metabolism, sex-differences, epigenetics, non-coding RNA,biomarkersEditorial on the Research TopicInflammation, Metabolism and Epigenetics in Valvular Heart DiseaseThe prevalence of valvular heart disease (VHD) within the elderly increases from 2.8% inindividuals aged 60–74 years to 13.1% in the over 75’s. Moreover, with a continually agingpopulation, VHD is predicted to become the forthcoming cardiac epidemic (1). Owing to thesevere disease burden, VHD is a major source of morbidity and mortality. More than three decadesof research have revealed that highly multifactorial and complex cues trigger molecular, cellularand interstitial events. Valve resident cells, namely valve interstitial (VIC) and endothelial cells(VEC), are instrumental to the VHD pathogenesis (2). Although valve replacement remains theprimary therapeutic choice, current limitations entail expensive treatments, hospital readmissionand reintervention. Accumulating evidence suggests that inflammation from different sources(e.g., atherosclerosis, autoimmune diseases, diabetes) might be mechanistically relevant duringearly and late stages of VHD. This Research Topic “Inflammation, Metabolism and Epigeneticsin Valvular Heart Disease” includes four articles gathering an interdisciplinary overview of thecontribution of inflammation to disease progression and prognosis, and explores the interplayamong inflammation, metabolism, epigenetics and sex-related mechanisms underpinning VHD.As reviewed by Ferrari and Pesce, the endothelial insult exerted by different risk factorsmay initiate and exacerbate the damage of the aortic valve. Interleukins, oxidative stress andapoptotic pathways promote a myriad of aberrant events. Inflammatory stimuli may underpinmetabolic switches in quiescent VIC and VEC to accommodate the energetic requirementsof divergent pathologic phenotypes, including differentiation into myofibroblast, osteoblast orpericyte-like phenotypes. It is now becoming evident that metabolites can raise regulatoryeffects on a vast array of pharmacologically targetable epigenetic regulators and vice versa(Ferrari and Pesce). Methylation and acetylation status or the non-coding RNAs can regulateNOTCH1 potentially impacting the expression of inflammatory and osteogenic genes. The roleof miRNAs as biomarkers, therapeutic targets or therapeutic alternatives is additionally discussed.Jover et al. Editorial: New Insights in Valvular DiseaseDifferent miRNome signatures may support specific forms ofVHD. Importantly, the authors describe sex-related differencesin aortic valve stenosis (AVS) phenotypes. The ideologicaltrend linking calcification to AVS severity might be becomingobsolete in light of the phenotypic presentation of AVS inwomen. The increasing number of publications and specialissues launched by internationally indexed journals, such asFrontiers in Cardiovascular Medicine, evidence the growinginterest on elucidating sex-related differences in AVS. Thisexhaustive review prompts to investigate in depth the molecularand metabolic mechanisms underlying AVS to develop newtherapeutic opportunities.Diabetes increases the rate of progression from mild to severeforms, thus being acknowledged as a marker of poor prognosis inAVS. The naïve aortic valve is one of the earliest cardiovascularbeds affected by concomitant hyperglycemia and hyperlipidemia,and bioprosthetic valves implanted in diabetic patients aremore prone to deterioration. Cecoltan et al. demonstratethat high glucose triggers pro-inflammatory phenotypesand endothelial-to-mesenchymal transition in human VECsengineered on a physiologically relevant extracellular matrix(ECM). Decellularized collagen type I and III-rich ECMderived from porcine aortic roots were re-populated withhuman VECs and VICs to mimic the valve cell disposition inthe naïve fibrosa. Accordingly, this study confers a valuableinsight into the contribution of diabetes-related dysfunctionof the VEC and offers a novel methodological approach to therepertoire of VHD research models. Moreover, the authorspropose the pro-inflammatory endothelin-1 (ET-1) signalingto be potentially targetable to prevent the secretory and pro-inflammatory switch of the VEC, likely contributing to thedevelopment of AVS in diabetic patients. They also speculate thathigh glucose-related up-regulation of ET-1 and interleukin-1βmight contribute to the endothelial-to-mesenchymal activationof the VEC, in a similar manner to that observed in diabeticcardiac fibrosis.Park et al. have systematically reviewed the literatureto provide a thorough vision of the actual prevalenceand presentation of VHD in patients with autoimmunespondyloarthritis. It is not a new concept that patients withspondyloarthritis develop cardiovascular arrythmias andVHD (e.g., “HLA-B27 associated cardiac disease”). Amongmore than 500 indexed publications, aortic insufficiencywas found to be the most prevalent form of VHD with ahazard ratio of 1.8–2.0 and an increased risk of undergoingelective surgical valve replacement, while after adjusting forage such association was not significant. Other reportedabnormalities were mitral valve prolapse, calcification, valveand aorta thickening or aortic root dilatation. Althoughinteresting, preliminary findings are based on heterogeneous,small sample-sized and non-adjusted case-control studiesthat preclude the drawing of actual associations betweenspondyloarthritis and cardiac manifestations. Moreover, theSIGN Approach used in this review rates these studies tohave a low evidence quality. Indeed, several recent studies didnot find significant associations among spondyloarthritis andVHDs. Nevertheless, owing to the autoimmune inflammatoryburden and the histological similarities (e.g., resident T cells)reported between the aortic valve attachment site and thearticular enthesis, the authors hypothesize a distinctive formof valvular tissue degeneration exists in spondyloarthritispatients leading to different VHD phenotypes. Accordingly, theyencourage to systematically reappraise the evidence of VHDin spondyloarthritis.Lin et al. have prospectively assessed the inflammatoryC-reactive protein (CRP) (cut-off 6.5 mg/mL) at hospitaldischarge to predict the excessive 1-year mortality of acuteinfective endocarditis (IE) patients. This observational studyrecruited 343 patients with acute IE who were categorizedas low or high-CRP patients at hospital discharge. Mortalityrate was consistently higher in high-CRP compared withlow-CRP patients after 1-year follow-up with an excesshazard ratio of 4.2 after multivariate analysis. The occurrenceof paravalvular abscess was also enhanced in high-CRPpatients, whilst no differences were seen at the cumulativerate of re-hospitalization. This study suggests that highlevels of CRP at hospital discharge might be a marker ofpoor prognosis in acute IE patients. As per other formsof cardiovascular disease, researching and elaboratingappropriate panels of VHD prognosis markers must befostered to identify patients at high risk and provide usefulmanagement tools.A better understanding of the inflammatory sourcesand its contribution to the VHD pathogenesis, as wellas the interplay among inflammation, metabolism andepigenetic regulation might open new avenues to identifydruggable targets and improve current therapies. Itis also clear that sex-related differences also need tobe considered in the current and future research ofthe VHD.AUTHOR CONTRIBUTIONSAll authors listed have made a substantial, direct, and intellectualcontribution to the work and approved it for publication.FUNDINGThis work was supported by a Sara Borrell grant (CD19/00251)from the Instituto de Salud Carlos III by a Miguel Servetcontract CP13/00221 from the Instituto de Salud Carlos 674III-FEDER, Fondo de Investigaciones Sanitarias (PI18/01875),and by the British Heart Foundation (BHF) Centre forCardiovascular Regenerative Medicine Award (II)-Centre forVascular Regeneration (RM/17/3/33381).Frontiers in Cardiovascular Medicine | www.frontiersin.org 2 April 2022 | Volume 9 | Article 880015Jover et al. Editorial: New Insights in Valvular DiseaseREFERENCES1. De Sciscio P, Brubert J, De Sciscio M, Serrani M, Stasiak J, MoggridgeGD. Quantifying the shift toward transcatheter aortic valve replacement inlow-risk patients: a meta-analysis. Circ Cardiovasc Qual Outcomes. (2017)10:e003287. doi: 10.1161/CIRCOUTCOMES.116.0032872. Rutkovskiy A, Malashicheva A, Sullivan G, Bogdanova M, Kostareva A,Stensløkken KO, et al. Valve interstitial cells: the key to understandingthe pathophysiology of heart valve calcification. J Am Heart Assoc. (2017)6:e006339. doi: 10.1161/JAHA.117.006339Conflict of Interest: The authors declare that the research was conducted in theabsence of any commercial or financial relationships that could be construed as apotential conflict of interest.Publisher’s Note: All claims expressed in this article are solely those of the authorsand do not necessarily represent those of their affiliated organizations, or those ofthe publisher, the editors and the reviewers. Any product that may be evaluated inthis article, or claim that may be made by its manufacturer, is not guaranteed orendorsed by the publisher.Copyright © 2022 Jover, Faulkner, Madeddu and López-Andrés. This is an open-access article distributed under the terms of the Creative Commons AttributionLicense (CC BY). The use, distribution or reproduction in other forums is permitted,provided the original author(s) and the copyright owner(s) are credited and that theoriginal publication in this journal is cited, in accordance with accepted academicpractice. No use, distribution or reproduction is permitted which does not complywith these terms.Frontiers in Cardiovascular Medicine | www.frontiersin.org 3 April 2022 | Volume 9 | Article 880015

Editorial:Inflammation, Metabolism and Epigenetics in Valvular Heart Disease

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Editorial:Inflammation, Metabolism and Epigenetics in Valvular Heart Disease

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