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
{"title":"伊可新戊酯可调节循环血管再生细胞的含量：IPE-PREVENTION CardioLink-14 试验。","authors":"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","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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<sup>hi</sup>) 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<sup>hi</sup>side scatter (SSC)<sup>low</sup>CD133<sup>+</sup> progenitor cells. Change in frequencies of ALDH<sup>hi</sup>SSC<sup>mid</sup> monocyte and ALDH<sup>hi</sup>SSC<sup>hi</sup> granulocyte precursor subsets, reactive oxygen species production, serum biomarkers, and omega-3 levels were also evaluated.</p><p><strong>Findings: </strong>Baseline characteristics, cardiovascular risk factors, and medications were balanced between the groups. Compared to usual care, IPE increased the mean frequency of ALDH<sup>hi</sup>SSC<sup>low</sup>CD133<sup>+</sup> cells (-1.00% ± 2.45% vs. +7.79% ± 1.70%; p = 0.02), despite decreasing overall ALDH<sup>hi</sup>SSC<sup>low</sup> cell frequency. IPE assignment also reduced oxidative stress in ALDH<sup>hi</sup>SSC<sup>low</sup> progenitors and increased ALDH<sup>hi</sup>SSC<sup>hi</sup> granulocyte precursor cell content.</p><p><strong>Conclusions: </strong>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.</p><p><strong>Funding: </strong>HLS Therapeutics provided the IPE in kind and had no role in the study design, conduct, analyses, or interpretation.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"718-734.e4"},"PeriodicalIF":12.8000,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Icosapent ethyl modulates circulating vascular regenerative cell content: The IPE-PREVENTION CardioLink-14 trial.\",\"authors\":\"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\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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<sup>hi</sup>) 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<sup>hi</sup>side scatter (SSC)<sup>low</sup>CD133<sup>+</sup> progenitor cells. Change in frequencies of ALDH<sup>hi</sup>SSC<sup>mid</sup> monocyte and ALDH<sup>hi</sup>SSC<sup>hi</sup> granulocyte precursor subsets, reactive oxygen species production, serum biomarkers, and omega-3 levels were also evaluated.</p><p><strong>Findings: </strong>Baseline characteristics, cardiovascular risk factors, and medications were balanced between the groups. Compared to usual care, IPE increased the mean frequency of ALDH<sup>hi</sup>SSC<sup>low</sup>CD133<sup>+</sup> cells (-1.00% ± 2.45% vs. +7.79% ± 1.70%; p = 0.02), despite decreasing overall ALDH<sup>hi</sup>SSC<sup>low</sup> cell frequency. IPE assignment also reduced oxidative stress in ALDH<sup>hi</sup>SSC<sup>low</sup> progenitors and increased ALDH<sup>hi</sup>SSC<sup>hi</sup> granulocyte precursor cell content.</p><p><strong>Conclusions: </strong>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.</p><p><strong>Funding: </strong>HLS Therapeutics provided the IPE in kind and had no role in the study design, conduct, analyses, or interpretation.</p>\",\"PeriodicalId\":29964,\"journal\":{\"name\":\"Med\",\"volume\":\" \",\"pages\":\"718-734.e4\"},\"PeriodicalIF\":12.8000,\"publicationDate\":\"2024-07-12\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Med\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1016/j.medj.2024.03.009\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/3/28 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"MEDICINE, RESEARCH & EXPERIMENTAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Med","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1016/j.medj.2024.03.009","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/3/28 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
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 (ALDHhi) 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 ALDHhiside scatter (SSC)lowCD133+ progenitor cells. Change in frequencies of ALDHhiSSCmid monocyte and ALDHhiSSChi 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 ALDHhiSSClowCD133+ cells (-1.00% ± 2.45% vs. +7.79% ± 1.70%; p = 0.02), despite decreasing overall ALDHhiSSClow cell frequency. IPE assignment also reduced oxidative stress in ALDHhiSSClow progenitors and increased ALDHhiSSChi 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.
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Med is a flagship medical journal published monthly by Cell Press, the global publisher of trusted and authoritative science journals including Cell, Cancer Cell, and Cell Reports Medicine. Our mission is to advance clinical research and practice by providing a communication forum for the publication of clinical trial results, innovative observations from longitudinal cohorts, and pioneering discoveries about disease mechanisms. The journal also encourages thought-leadership discussions among biomedical researchers, physicians, and other health scientists and stakeholders. Our goal is to improve health worldwide sustainably and ethically.
Med publishes rigorously vetted original research and cutting-edge review and perspective articles on critical health issues globally and regionally. Our research section covers clinical case reports, first-in-human studies, large-scale clinical trials, population-based studies, as well as translational research work with the potential to change the course of medical research and improve clinical practice.
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