Ignatios Ikonomidis1, Dimitrios Vlastos2,3, Ioanna Andreadou4, Maria Gazouli5, Panagiotis Efentakis6, Maria Varoudi2, George Makavos2, Alkistis Kapelouzou7, John Lekakis2, John Parissis2, Spiridon Katsanos2, Damianos Tsilivarakis2, Derek J Hausenloy8,9,10,11,12, Dimitrios Alexopoulos2, Dennis V Cokkinos7, Hans-Eric Bøtker13, Efstathios K Iliodromitis2. 1. 2nd Department of Cardiology, Medical School, Attikon Hospital, National and Kapodistrian University of Athens, Rimini 1, Haidari, 12462, Athens, Greece. ignoik@gmail.com. 2. 2nd Department of Cardiology, Medical School, Attikon Hospital, National and Kapodistrian University of Athens, Rimini 1, Haidari, 12462, Athens, Greece. 3. Department of Cardiac Surgery, Royal Brompton Hospital, London, UK. 4. Laboratory of Pharmacology, School of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece. jandread@pharm.uoa.gr. 5. Laboratory of Biology, Department of Basic Medical Sciences, Medical School, National and Kapodistrian University of Athens, Athens, Greece. 6. Laboratory of Pharmacology, School of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece. 7. Biomedical Research Foundation, Academy of Athens, Athens, Greece. 8. National Heart Centre, National Heart Research Institute Singapore, Singapore, Singapore. 9. Yong Loo Lin School of Medicine, National University Singapore, Singapore, Singapore. 10. The Hatter Cardiovascular Institute, University College London, London, UK. 11. The National Institute of Health Research University College London Hospitals Biomedical Research Centre, Research and Development, London, UK. 12. Centro de Biotecnologia-FEMSA, Tecnologico de Monterrey, Monterrey, Mexico. 13. Department of Cardiology, Aarhus University Hospital Skejby, Aarhus N, Denmark.
Abstract
AIMS: Remote ischemic conditioning (RIC) alleviates ischemia-reperfusion injury via several pathways, including micro-RNAs (miRs) expression and oxidative stress modulation. We investigated the effects of RIC on endothelial glycocalyx, arterial stiffness, LV remodelling, and the underlying mediators within the vasculature as a target for protection. METHODS AND RESULTS: We block-randomised 270 patients within 48 h of STEMI post-PCI to either one or two cycles of bilateral brachial cuff inflation, and a control group without RIC. We measured: (a) the perfusion boundary region (PBR) of the sublingual arterial microvessels to assess glycocalyx integrity; (b) the carotid-femoral pulse wave velocity (PWV); (c) miR-144,-150,-21,-208, nitrate-nitrite (NOx) and malondialdehyde (MDA) plasma levels at baseline (T0) and 40 min after RIC onset (T3); and (d) LV volumes at baseline and after one year. Compared to baseline, there was a greater PBR and PWV decrease, miR-144 and NOx levels increase (p < 0.05) at T3 following single- than double-cycle inflation (PBR:ΔT0-T3 = 0.249 ± 0.033 vs 0.126 ± 0.034 μm, p = 0.03 and PWV:0.4 ± 0.21 vs -1.02 ± 0.24 m/s, p = 0.03). Increased miR-150,-21,-208 (p < 0.05) and reduced MDA was observed after both protocols. Increased miR-144 was related to PWV reduction (r = 0.763, p < 0.001) after the first-cycle inflation in both protocols. After one year, single-cycle RIC was associated with LV end-systolic volume reduction (LVESV) > 15% (odds-ratio of 3.75, p = 0.029). MiR-144 and PWV changes post-RIC were interrelated and associated with LVESV reduction at follow-up (r = 0.40 and 0.37, p < 0.05), in the single-cycle RIC. CONCLUSION: RIC evokes "vascular conditioning" likely by upregulation of cardio-protective microRNAs, NOx production, and oxidative stress reduction, facilitating reverse LV remodelling. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov . Unique identifier: NCT03984123.
AIMS: Remote ischemic conditioning (RIC) alleviates ischemia-reperfusion injury via several pathways, including micro-RNAs (miRs) expression and oxidative stress modulation. We investigated the effects of RIC on endothelial glycocalyx, arterial stiffness, LV remodelling, and the underlying mediators within the vasculature as a target for protection. METHODS AND RESULTS: We block-randomised 270 patients within 48 h of STEMI post-PCI to either one or two cycles of bilateral brachial cuff inflation, and a control group without RIC. We measured: (a) the perfusion boundary region (PBR) of the sublingual arterial microvessels to assess glycocalyx integrity; (b) the carotid-femoral pulse wave velocity (PWV); (c) miR-144,-150,-21,-208, nitrate-nitrite (NOx) and malondialdehyde (MDA) plasma levels at baseline (T0) and 40 min after RIC onset (T3); and (d) LV volumes at baseline and after one year. Compared to baseline, there was a greater PBR and PWV decrease, miR-144 and NOx levels increase (p < 0.05) at T3 following single- than double-cycle inflation (PBR:ΔT0-T3 = 0.249 ± 0.033 vs 0.126 ± 0.034 μm, p = 0.03 and PWV:0.4 ± 0.21 vs -1.02 ± 0.24 m/s, p = 0.03). Increased miR-150,-21,-208 (p < 0.05) and reduced MDA was observed after both protocols. Increased miR-144 was related to PWV reduction (r = 0.763, p < 0.001) after the first-cycle inflation in both protocols. After one year, single-cycle RIC was associated with LV end-systolic volume reduction (LVESV) > 15% (odds-ratio of 3.75, p = 0.029). MiR-144 and PWV changes post-RIC were interrelated and associated with LVESV reduction at follow-up (r = 0.40 and 0.37, p < 0.05), in the single-cycle RIC. CONCLUSION: RIC evokes "vascular conditioning" likely by upregulation of cardio-protective microRNAs, NOx production, and oxidative stress reduction, facilitating reverse LV remodelling. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov . Unique identifier: NCT03984123.
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