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Reduced effect of ischemic preconditioning against endothelial ischemia-reperfusion injury with cardiovascular risk factors in humans

Journal of Human Hypertension volume 35, pages 870–879 (2021)Cite this article

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Abstract

The extent that clustered CVD risk factors interfere with ischemic preconditioning (IPC) to protect against microvascular endothelial dysfunction with ischemia-reperfusion (I/R) injury in humans is unclear. We hypothesized that adults with a clustered burden of ≥3 CVD risk factors would demonstrate a reduced capacity of IPC to protect endothelial function with I/R injury. Twenty-two (age: 45 ± 14 year) adults [12 healthy controls; 10 raised risk (10-year FRS risk score ~3%)] were studied using a 2 × 2 randomized cross-over design. Pulse arterial tonometry was used to assess microvascular endothelium-dependent vasodilation during reactive hyperemia in response to endothelial I/R injury (20 min brachial artery occlusion/45 min reperfusion) that was preceded by remote IPC (3 × 5 min ischemia/reperfusion) or mock IPC. In both groups, microvascular reactive hyperemia was reduced ~20% (both P < 0.01) after endothelial I/R injury without remote IPC. However, in control subjects remote IPC prevented endothelial I/R injury (from baseline reactive hyperemic ratio: 2.1 ± 0.4 AU to post I/R injury: 2.5 ± 0.5 AU; P = 0.09). In contrast, the reactive hyperemia ratio in raised risk subjects was significantly reduced from 2.2 ± 0.6 AU to 1.9 ± 0.5 AU (P = 0.0087) despite attempts to induce protection by remote IPC, with the magnitude of reduction similar to their mock IPC trial. The magnitude of remote IPC-mediated endothelial protection against I/R injury was inversely related to the number of risk factors. CVD risk factors diminish the effect of IPC to protect the microvasculature from I/R injury in humans. Translating IPC to clinical practice for vasculoprotection will continue to be challenging in patients with increased CVD risk.

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Fig. 1: Schematic of the experimental protocol.
Fig. 2: Representative tracing of PAT data acquisition.
Fig. 3: Box and whisker plots of the reactive hyperemic response at baseline and with endothelial I/R injury in controls (white circles) and raised risk (black squares) subjects for the mock IPC (left panel) and remote IPC (right panel) trials.
Fig. 4: Reactive hyperemic response to endothelial I/R injury at 30 s intervals in the presence of remote IPC.
Fig. 5: Top panel: bivariate relations between the reactive hyperemia ratio with endothelial I/R injury in the remote IPC trial and the total number of risk factors (left) and HDL-cholesterol (right).

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References

  1. Kloner RA. No-reflow phenomenon: maintaining vascular integrity. J Cardiovasc Pharm Ther. 2011;16:244–50.

    Article  Google Scholar 

  2. Bolognese L, Carrabba N, Parodi G, Santoro GM, Buonamici P, Cerisano G, et al. Impact of microvascular dysfunction on left ventricular remodeling and long-term clinical outcome after primary coronary angioplasty for acute myocardial infarction. Circulation 2004;109:1121–6.

    Article  Google Scholar 

  3. McGeoch R, Watkins S, Berry C, Steedman T, Davie A, Byrne J, et al. The index of microcirculatory resistance measured acutely predicts the extent and severity of myocardial infarction in patients with ST-segment elevation myocardial infarction. JACC Cardiovasc Inter. 2010;3:715–22.

    Article  Google Scholar 

  4. Valgimigli M, Campo G, Malagutti P, Anselmi M, Bolognese L, Ribichini F, et al. Persistent coronary no flow after wire insertion is an early and readily available mortality risk factor despite successful mechanical intervention in acute myocardial infarction: a pooled analysis from the STRATEGY (Single High-Dose Bolus Tirofiban and Sirolimus-Eluting Stent Versus Abciximab and Bare-Metal Stent in Acute Myocardial Infarction) and MULTISTRATEGY (Multicenter Evaluation of Single High-Dose Bolus Tirofiban Versus Abciximab With Sirolimus-Eluting Stent or Bare-Metal Stent in Acute Myocardial Infarction Study) trials. JACC Cardiovasc Inter. 2011;4:51–62.

    Article  Google Scholar 

  5. Kharbanda RK, Mortensen UM, White PA, Kristiansen SB, Schmidt MR, Hoschtitzky JA, et al. Transient limb ischemia induces remote ischemic preconditioning in vivo. Circulation. 2002;106:2881–3.

    Article  CAS  Google Scholar 

  6. Zhou K, Yang B, Zhou X-M, Tan C-M, Zhao Y, Huang C, et al. Effects of remote ischemic preconditioning on the flow pattern of the left anterior descending coronary artery in normal subjects. Int J Cardiol. 2007;122:250–1.

    Article  Google Scholar 

  7. Aggarwal S, Randhawa PK, Singh N, Jaggi AS. Preconditioning at a distance: involvement of endothelial vasoactive substances in cardioprotection against ischemia-reperfusion injury. Life Sci. 2016;151:250–8.

    Article  CAS  Google Scholar 

  8. Bell RM, Yellon DM. Conditioning the whole heart–not just the cardiomyocyte. J Mol Cell Cardiol. 2012;53:24–32.

    Article  CAS  Google Scholar 

  9. Badalzadeh R, Mohammadi M, Yousefi B, Farajnia S, Najafi M, Mohammadi S. Involvement of Glycogen Synthase Kinase-3beta and Oxidation Status in the Loss of Cardioprotection by Postconditioning in Chronic Diabetic Male Rats. Adv Pharm Bull. 2015;5:321–7.

    Article  CAS  Google Scholar 

  10. Wu N, Zhang X, Jia P, Jia D. Hypercholesterolemia abrogates the protective effect of ischemic postconditioning by induction of apoptosis and impairment of activation of reperfusion injury salvage kinase pathway. Biochem Biophys Res Commun. 2015;458:148–53.

    Article  CAS  Google Scholar 

  11. Katakam PV, Jordan JE, Snipes JA, Tulbert CD, Miller AW, Busija DW. Myocardial preconditioning against ischemia-reperfusion injury is abolished in Zucker obese rats with insulin resistance. Am J Physiol Regul Integr Comp Physiol. 2007;292:R920–6.

    Article  CAS  Google Scholar 

  12. Ebrahim Z, Yellon DM, Baxter GF. Ischemic preconditioning is lost in aging hypertensive rat heart: independent effects of aging and longstanding hypertension. Exp Gerontol. 2007;42:807–14.

    Article  CAS  Google Scholar 

  13. Hamburg NM, Benjamin EJ. Assessment of endothelial function using digital pulse amplitude tonometry. Trends Cardiovasc Med. 2009;19:6–11.

    Article  CAS  Google Scholar 

  14. Weihl FM, Van Guilder GP. Endothelial vasodilation after a high-volume training load and tapered training in collegiate female swimmers. J Strength Cond Res. 2018.

  15. Nohria A, Gerhard-Herman M, Creager MA, Hurley S, Mitra D, Ganz P. Role of nitric oxide in the regulation of digital pulse volume amplitude in humans. J Appl Physiol (1985). 2006;101:545–8.

    Article  CAS  Google Scholar 

  16. Kuvin JT, Patel AR, Sliney KA, Pandian NG, Sheffy J, Schnall RP, et al. Assessment of peripheral vascular endothelial function with finger arterial pulse wave amplitude. Am Heart J. 2003;146:168–74.

    Article  Google Scholar 

  17. Bonetti PO, Pumper GM, Higano ST, Holmes DR Jr., Kuvin JT, Lerman A. Noninvasive identification of patients with early coronary atherosclerosis by assessment of digital reactive hyperemia. J Am Coll Cardiol. 2004;44:2137–41.

    Article  Google Scholar 

  18. Paull EJ, Van Guilder GP. Remote Ischemic Preconditioning Increases Accumulated Oxygen Deficit in Middle-Distance Runners. J Appl Physiol (1985). 2019;126:1193–203.

    Article  CAS  Google Scholar 

  19. Eitel I, Stiermaier T, Rommel KP, Fuernau G, Sandri M, Mangner N, et al. Cardioprotection by combined intrahospital remote ischaemic perconditioning and postconditioning in ST-elevation myocardial infarction: the randomized LIPSIA CONDITIONING trial. Eur Heart J. 2015;36:3049–57.

    Article  Google Scholar 

  20. Przyklenk K. Efficacy of cardioprotective ‘conditioning’ strategies in aging and diabetic cohorts: the co-morbidity conundrum. Drugs Aging. 2011;28:331–43.

    Article  Google Scholar 

  21. White SK, Frohlich GM, Sado DM, Maestrini V, Fontana M, Treibel TA, et al. Remote ischemic conditioning reduces myocardial infarct size and edema in patients with ST-segment elevation myocardial infarction. JACC Cardiovasc Inter. 2015;8:178–88.

    Article  Google Scholar 

  22. van den Munckhof I, Riksen N, Seeger J, Schreuder T, Borm G, Eijsvogels T, et al. Aging attenuates the protective effect of ischemic preconditioning against endothelial ischemia-reperfusion in humans. Am J Physiol Heart Circ Physiol. 2013;304:1727–32.

    Article  Google Scholar 

  23. Sloth AD, Schmidt MR, Munk K, Schmidt M, Pedersen L, Sorensen HT, et al. Impact of cardiovascular risk factors and medication use on the efficacy of remote ischaemic conditioning: post hoc subgroup analysis of a randomised controlled trial. BMJ Open. 2015;5:e006923.

    Article  Google Scholar 

  24. Crimi G, Pica S, Raineri C, Bramucci E, De Ferrari GM, Klersy C, et al. Remote ischemic post-conditioning of the lower limb during primary percutaneous coronary intervention safely reduces enzymatic infarct size in anterior myocardial infarction: a randomized controlled trial. JACC Cardiovasc Inter. 2013;6:1055–63.

    Article  Google Scholar 

  25. van den Munckhof I, Riksen N, Seeger JP, Schreuder TH, Borm GF, Eijsvogels TM, et al. Aging attenuates the protective effect of ischemic preconditioning against endothelial ischemia-reperfusion injury in humans. Am J Physiol Heart Circ Physiol. 2013;304:H1727–32.

    Article  Google Scholar 

  26. Van Guilder GP, Stauffer BL, Greiner JJ, Desouza CA. Impaired endothelium-dependent vasodilation in overweight and obese adult humans is not limited to muscarinic receptor agonists. Am J Physiol Heart Circ Physiol. 2008;294:H1685–92.

    Article  Google Scholar 

  27. Hausenloy DJ, Candilio L, Evans R, Ariti C, Jenkins DP, Kolvekar S, et al. Remote Ischemic Preconditioning and Outcomes of Cardiac Surgery. N Engl J Med. 2015;373:1408–17.

    Article  CAS  Google Scholar 

  28. Meybohm P, Bein B, Brosteanu O, Cremer J, Gruenewald M, Stoppe C, et al. A Multicenter Trial of Remote Ischemic Preconditioning for Heart Surgery. N Engl J Med. 2015;373:1397–407.

    Article  CAS  Google Scholar 

  29. Thielmann M, Kottenberg E, Kleinbongard P, Wendt D, Gedik N, Pasa S, et al. Cardioprotective and prognostic effects of remote ischaemic preconditioning in patients undergoing coronary artery bypass surgery: a single-centre randomised, double-blind, controlled trial. Lancet 2013;382:597–604.

    Article  Google Scholar 

  30. Wagner C, Ebner B, Tillack D, Strasser RH, Weinbrenner C. Cardioprotection by ischemic postconditioning is abrogated in hypertrophied myocardium of spontaneously hypertensive rats. J Cardiovasc Pharm. 2013;61:35–41.

    Article  CAS  Google Scholar 

  31. Bouhidel O, Pons S, Souktani R, Zini R, Berdeaux A, Ghaleh B. Myocardial ischemic postconditioning against ischemia-reperfusion is impaired in ob/ob mice. Am J Physiol Heart Circ Physiol. 2008;295:H1580–6.

    Article  CAS  Google Scholar 

  32. Sivaraman V, Hausenloy DJ, Wynne AM, Yellon DM. Preconditioning the diabetic human myocardium. J Cell Mol Med. 2010;14:1740–6.

    Article  CAS  Google Scholar 

  33. Lee TM, Chou TF. Impairment of myocardial protection in type 2 diabetic patients. J Clin Endocrinol Metab. 2003;88:531–7.

    Article  CAS  Google Scholar 

  34. Kharbanda RK, Peters M, Walton B, Kattenhorn M, Mullen M, Klein N, et al. Ischemic preconditioning prevents endothelial injury and systemic neutrophil activation during ischemia-reperfusion in humans in vivo. Circulation. 2001;103:1624–30.

    Article  CAS  Google Scholar 

  35. Heitzer T, Schlinzig T, Krohn K, Meinertz T, Munzel T. Endothelial dysfunction, oxidative stress, and risk of cardiovascular events in patients with coronary artery disease. Circulation 2001;104:2673–8.

    Article  CAS  Google Scholar 

  36. Chan SY, Mancini GBJ, Kuramoto L, Schulzer M, Frohlich J, Ignaszewski A. The prognostic importance of endothelial dysfunction and carotid atheromaburden in patients with coronary artery disease. J Am Coll Cardiol. 2003;42:1037–43.

    Article  CAS  Google Scholar 

  37. Kono Y, Fukuda S, Hanatani A, Nakanishi K, Otsuka K, Taguchi H, et al. Remote ischemic conditioning improves coronary microcirculation in healthy subjects and patients with heart failure. Drug Des Devel Ther. 2014;8:1175–81.

    PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We would like to thank all subjects who participated in the study and the Department of Health & Nutritional Sciences at South Dakota State University for the use of laboratory space and supplies necessary to conduct the study.

Funding

This work was supported by a South Dakota State University Research Scholarship Support award (GPVG).

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Authors and Affiliations

  1. Exercise & Sport Science Department, Western Colorado University, Paul Wright Gym 209, 1 Western Way, Gunnison, CO, 81231, USA

    Tiffany E. Trachte, Brian A. Hemenway & Gary P. Van Guilder

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Correspondence to Gary P. Van Guilder.

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Trachte, T.E., Hemenway, B.A. & Van Guilder, G.P. Reduced effect of ischemic preconditioning against endothelial ischemia-reperfusion injury with cardiovascular risk factors in humans. J Hum Hypertens 35, 870–879 (2021). https://doi.org/10.1038/s41371-020-00440-0

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