Icosapent ethyl modulates circulating vascular regenerative cell content: The IPE-PREVENTION CardioLink-14 trial.

Autor:	Bakbak E; Division of Cardiac Surgery, St. Michael's Hospital of Unity Health Toronto, Toronto, ON, Canada; Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, ON, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada; Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia., Krishnaraj A; Division of Cardiac Surgery, St. Michael's Hospital of Unity Health Toronto, Toronto, ON, Canada; Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, ON, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada., Bhatt DL; Mount Sinai Fuster Heart Hospital, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Quan A; Division of Cardiac Surgery, St. Michael's Hospital of Unity Health Toronto, Toronto, ON, Canada; Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, ON, Canada., Park B; Division of Cardiac Surgery, St. Michael's Hospital of Unity Health Toronto, Toronto, ON, Canada; Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, ON, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada., Bakbak AI; Lakeridge Health Oshawa, Oshawa, ON, Canada., Bari B; Markham Health+ Plex, Markham, ON, Canada., Terenzi KA; Langstaff Medical Centre, Woodbridge, ON, Canada., Pan Y; Division of Cardiac Surgery, St. Michael's Hospital of Unity Health Toronto, Toronto, ON, Canada; Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, ON, Canada., Fry EJ; HLS Therapeutics, Inc., Dorval, QC, Canada., Terenzi DC; Faculty of Medicine, University College Dublin, Dublin, Ireland., Puar P; Division of Cardiac Surgery, St. Michael's Hospital of Unity Health Toronto, Toronto, ON, Canada; Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, ON, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada; Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada., Khan TS; Division of Endocrinology and Metabolism, St. Joseph's Healthcare Centre, London, ON, Canada; Department of Medicine, Western University, London, ON, Canada., Rotstein OD; Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, ON, Canada; Division of General Surgery, St. Michael's Hospital of Unity Health Toronto, Toronto, ON, Canada; Department of Surgery, University of Toronto, Toronto, ON, Canada., Mazer CD; Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, ON, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada; Department of Anesthesia, St. Michael's Hospital of Unity Health Toronto, Toronto, ON, Canada; Department of Anesthesiology and Pain Medicine, University of Toronto, Toronto, ON, Canada; Department of Physiology, University of Toronto, Toronto, ON, Canada., Leiter LA; Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, ON, Canada; Division of Endocrinology and Metabolism, St. Michael's Hospital of Unity Health Toronto, Toronto, ON, Canada; Department of Medicine, University of Toronto, Toronto, ON, Canada; Department of Nutritional Sciences, University of Toronto, Toronto, ON, Canada., Teoh H; Division of Cardiac Surgery, St. Michael's Hospital of Unity Health Toronto, Toronto, ON, Canada; Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, ON, Canada; Division of Endocrinology and Metabolism, St. Michael's Hospital of Unity Health Toronto, Toronto, ON, Canada., Hess DA; Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, ON, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada; Department of Physiology and Pharmacology, Western University, London, ON, Canada; Molecular Medicine Research Labs, Robarts Research Institute, London, ON, Canada. Electronic address: dhess@robarts.ca., Verma S; Division of Cardiac Surgery, St. Michael's Hospital of Unity Health Toronto, Toronto, ON, Canada; Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, ON, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada; Department of Surgery, University of Toronto, Toronto, ON, Canada. Electronic address: subodh.verma@unityhealth.to.
Jazyk:	angličtina
Zdroj:	Med (New York, N.Y.) [Med] 2024 Jul 12; Vol. 5 (7), pp. 718-734.e4. Date of Electronic Publication: 2024 Mar 28.
DOI:	10.1016/j.medj.2024.03.009
Abstrakt:	Background: REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial) showed that icosapent ethyl (IPE) reduced major adverse cardiovascular events by 25%. Since the underlying mechanisms for these benefits are not fully understood, the IPE-PREVENTION CardioLink-14 trial (ClinicalTrials.gov: NCT04562467) sought to determine if IPE regulates vascular regenerative (VR) cell content in people with mild to moderate hypertriglyceridemia. Methods: Seventy statin-treated individuals with triglycerides ≥1.50 and <5.6 mmol/L and either atherosclerotic cardiovascular disease or type 2 diabetes with additional cardiovascular risk factors were randomized to IPE (4 g/day) or usual care. VR cells with high aldehyde dehydrogenase activity (ALDH hi ) were isolated from blood collected at the baseline and 3-month visits and characterized with lineage-specific cell surface markers. The primary endpoint was the change in frequency of pro-vascular ALDH hi side scatter (SSC) low CD133 + progenitor cells. Change in frequencies of ALDH hi SSC mid monocyte and ALDH hi SSC hi granulocyte precursor subsets, reactive oxygen species production, serum biomarkers, and omega-3 levels were also evaluated. Findings: Baseline characteristics, cardiovascular risk factors, and medications were balanced between the groups. Compared to usual care, IPE increased the mean frequency of ALDH hi SSC low CD133 + cells (-1.00% ± 2.45% vs. +7.79% ± 1.70%; p = 0.02), despite decreasing overall ALDH hi SSC low cell frequency. IPE assignment also reduced oxidative stress in ALDH hi SSC low progenitors and increased ALDH hi SSC hi granulocyte precursor cell content. Conclusions: IPE-PREVENTION CardioLink-14 provides the first translational evidence that IPE can modulate VR cell content and suggests a novel mechanism that may underlie the cardioprotective effects observed with IPE in REDUCE-IT. Funding: HLS Therapeutics provided the IPE in kind and had no role in the study design, conduct, analyses, or interpretation. Competing Interests: Declaration of interests D.L.B. discloses the following relationships—advisory board: Angiowave, Bayer, Boehringer Ingelheim, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, and Stasys; board of directors: American Heart Association New York City, Angiowave (stock options), Bristol Myers Squibb (stock), DRS.LINQ (stock options), and High Enroll (stock); consultant: Broadview Ventures, Hims, SFJ, and Youngene; data monitoring committees: Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; for the PORTICO trial, funded by St. Jude Medical, now Abbott), Boston Scientific (chair, PEITHO trial), Cleveland Clinic, Contego Medical (chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo; for the ABILITY-DM trial, funded by Concept Medical; for ALLAY-HF, funded by Alleviant Medical), Novartis, Population Health Research Institute, and Rutgers University (for the NIH-funded MINT Trial); honoraria: American College of Cardiology (senior associate editor, Clinical Trials and News, ACC.org; chair, ACC Accreditation Oversight Committee), Arnold & Porter law firm (work related to Sanofi/Bristol-Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (editor-in-chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), CSL Behring (AHA lecture), Cowen and Company, Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (editor-in-chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (guest editor; associate editor), K2P (co-chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Oakstone CME (course director, Comprehensive Review of Interventional Cardiology), Piper Sandler, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), WebMD (CME steering committees), and Wiley (steering committee); other: Clinical Cardiology (deputy editor); patent: sotagliflozin (named on a patent for sotagliflozin assigned to Brigham and Women’s Hospital, who is assigned to Lexicon; neither I nor Brigham and Women’s Hospital receive any income from this patent); research funding: Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Alnylam, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CinCor, Cleerly, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Otsuka, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, and 89Bio; royalties: Elsevier (editor, Braunwald’s Heart Disease); site co-investigator: Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St. Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte, and Vascular Solutions; trustee: American College of Cardiology; and unfunded research: FlowCo. B.B. reports receiving speaking honoraria from HLS Therapeutics and Pfizer. K.A.T. reports receiving honoraria and serving on the advisory boards for AbbVie, Allergan, Amgen, Astellas, Aspen, Astra Zeneca, Bayer, Boehringer Ingelheim, Eli Lily, GlaxoSmithKline, Humber River Health, Lundbeck, Moderna, Novo Nordisk, Novartis, Pfizer, Takeda, and Eli Lily. E.J.F. is an employee of HLS Therapeutics. T.S.K. reports receiving honoraria from Abbott, Amgen, AstraZeneca, Bausch, Boehringer Ingelheim, the Canadian Medical and Surgical Knowledge Translation Research Group, the CPD Network Association, Eli Lily Canada, Janssen, Novo Nordisk Canada, and Sutherland Global Services Canada ULCA . He has served on advisory boards for Amgen, Eli Lily Canada, and Novo Nordisk. C.D.M. is supported by a Merit Award from the University of Toronto Department of Anesthesiology and Pain Medicine, holds the Cara Phelan Chair in Critical Care at St. Michael’s Hospital-Unity Health Toronto, and reports advisory board honoraria/consulting fees from Amgen, AstraZeneca, BioAge, Boehringer Ingelheim, and PhaseBio and DSMB stipends from Beth Israel Deaconess Medical Center, Cerus, and Takeda. L.A.L. has received research funding from, has provided CME on behalf of, and/or has acted as an adviser to Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, HLS Therapeutics, Kowa, Merck, Novartis, Novo Nordisk, Pfizer, Sanofi, and Servier. H.T. reports personal fees from the Canadian Medical and Surgical Knowledge Translation Research Group. S.V. holds a Tier 1 Canada Research Chair in Cardiovascular Surgery and reports receiving research grants and/or speaking honoraria from Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Canadian Medical and Surgical Knowledge Translation Research Group, Eli Lilly, HLS Therapeutics, Janssen, Novartis, Novo Nordisk, Pfizer, PhaseBio, Sanofi, and S&L Solutions; he is the president of the Canadian Medical and Surgical Knowledge Translation Research Group, a federally incorporated not-for-profit physician organization. (Copyright © 2024 Elsevier Inc. All rights reserved.)
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