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

Ehab Bakbak; Aishwarya Krishnaraj; Deepak L Bhatt; Adrian Quan; Brady Park; Asaad I Bakbak; Basel Bari; Kristin A Terenzi; Yi Pan; Elizabeth J Fry; Daniella C Terenzi; Pankaj Puar; Tayyab S Khan; Ori D Rotstein; C David Mazer; Lawrence A Leiter; Hwee Teoh; David A Hess; Subodh Verma

doi:10.1016/j.medj.2024.03.009

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

Med. 2024 Jul 12;5(7):718-734.e4. doi: 10.1016/j.medj.2024.03.009. Epub 2024 Mar 28.

Authors

Ehab Bakbak¹, Aishwarya Krishnaraj², Deepak L Bhatt³, Adrian Quan⁴, Brady Park², Asaad I Bakbak⁵, Basel Bari⁶, Kristin A Terenzi⁷, Yi Pan⁴, Elizabeth J Fry⁸, Daniella C Terenzi⁹, Pankaj Puar¹⁰, Tayyab S Khan¹¹, Ori D Rotstein¹², C David Mazer¹³, Lawrence A Leiter¹⁴, Hwee Teoh¹⁵, David A Hess¹⁶, Subodh Verma¹⁷

Affiliations

¹ 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.
² 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.
³ Mount Sinai Fuster Heart Hospital, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁴ 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.
⁵ Lakeridge Health Oshawa, Oshawa, ON, Canada.
⁶ Markham Health+ Plex, Markham, ON, Canada.
⁷ Langstaff Medical Centre, Woodbridge, ON, Canada.
⁸ HLS Therapeutics, Inc., Dorval, QC, Canada.
⁹ Faculty of Medicine, University College Dublin, Dublin, Ireland.
¹⁰ 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.
¹¹ Division of Endocrinology and Metabolism, St. Joseph's Healthcare Centre, London, ON, Canada; Department of Medicine, Western University, London, ON, Canada.
¹² 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.
¹³ 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.
¹⁴ 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.
¹⁵ 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.
¹⁶ 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.
¹⁷ 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.

PMID: 38552629
DOI: 10.1016/j.medj.2024.03.009

Abstract

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^hiside scatter (SSC)^lowCD133⁺ progenitor cells. Change in frequencies of ALDH^hiSSC^mid monocyte and ALDH^hiSSC^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^hiSSC^lowCD133⁺ cells (-1.00% ± 2.45% vs. +7.79% ± 1.70%; p = 0.02), despite decreasing overall ALDH^hiSSC^low cell frequency. IPE assignment also reduced oxidative stress in ALDH^hiSSC^low progenitors and increased ALDH^hiSSC^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.

Keywords: Translation to patients; aldefluor; cardiovascular disease; granulocytes; icosapent ethyl; omega-3; progenitor cells; vessel repair.

Publication types

Randomized Controlled Trial

MeSH terms

Aged
Aldehyde Dehydrogenase / metabolism
Atherosclerosis / drug therapy
Cardiovascular Diseases / prevention & control
Diabetes Mellitus, Type 2 / drug therapy
Diabetes Mellitus, Type 2 / metabolism
Eicosapentaenoic Acid* / administration & dosage
Eicosapentaenoic Acid* / analogs & derivatives
Eicosapentaenoic Acid* / pharmacology
Female
Humans
Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology
Hydroxymethylglutaryl-CoA Reductase Inhibitors / therapeutic use
Male
Middle Aged
Triglycerides / blood

Substances

Eicosapentaenoic Acid
eicosapentaenoic acid ethyl ester
Aldehyde Dehydrogenase
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Triglycerides

Associated data

ClinicalTrials.gov/NCT04562467