Impact of metformin on endothelial ischemia-reperfusion injury in humans in vivo: a prospective randomized open, blinded-endpoint study

Saloua El Messaoudi, Tim H Schreuder, Roel D Kengen, Gerard A Rongen, Petra H van den Broek, Dick H J Thijssen, Niels P Riksen, Saloua El Messaoudi, Tim H Schreuder, Roel D Kengen, Gerard A Rongen, Petra H van den Broek, Dick H J Thijssen, Niels P Riksen

Abstract

Introduction: Large prospective studies in patients with type 2 diabetes mellitus have demonstrated that metformin treatment improves cardiovascular prognosis, independent of glycemic control. Administration of metformin potently limits infarct size in murine models of myocardial infarction. This study examined, for the first time in humans, whether metformin limits ischemia-reperfusion (IR) injury in vivo using a well-validated forearm model of endothelial IR-injury.

Methods: Twenty-eight healthy volunteers (age 41±6 years, 10 male/16 female) were randomized between pretreatment with metformin (500 mg three times a day for 3 days) or no treatment in a Prospective Randomized Open Blinded Endpoint study. Brachial artery flow mediated dilation (FMD) was measured before and after 20 minutes of forearm ischemia and 20 minutes of reperfusion. FMD analysis was performed offline by investigators blinded for the treatment arm.

Results: Baseline FMD did not differ between metformin pretreatment and no pretreatment (6.9±3.6% and 6.1±3.5%, respectively, p = 0.27, n = 26). FMD was significantly lower after forearm IR in both treatment arms (4.4±3.3% and 4.3±2.8%, respectively, P<0.001 in both conditions). A linear mixed model analysis revealed that metformin treatment did not prevent the decrease in FMD by IR.

Conclusion: A 3 day treatment with metformin in healthy, middle-aged subjects does not protect against endothelial IR-injury, measured with brachial artery FMD after forearm ischemia. Further studies are needed to clarify what mechanism underlies the cardiovascular benefit of metformin treatment.

Trial registration: ClinicalTrials.gov NCT01610401.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. Consort 2012 flow diagram of…
Figure 1. Consort 2012 flow diagram of the study.
Figure 2. Brachial artery flow mediated dilation…
Figure 2. Brachial artery flow mediated dilation (presented as percentage change from baseline ±SE) before (black) and after (white) 20-minutes for forearm ischemia and 20-minutes reperfusion preceded by pretreatment with metformin or no pretreatment.

References

    1. Hausenloy DJ, Yellon DM (2013) Myocardial ischemia-reperfusion injury: a neglected therapeutic target. J Clin Invest 123: 92–100.
    1. The United Kingdom Prospective Diabetes Study (UKPDS) Group (1998) Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet 352: 854–865.
    1. Roussel R, Travert F, Pasquet B, Wilson PW, Smith SC Jr, et al. (2010) Metformin use and mortality among patients with diabetes and atherothrombosis. Arch Intern Med 170: 1892–1899.
    1. Jorgensen CH, Gislason GH, Andersson C, Ahlehoff O, Charlot M, et al. (2010) Effects of oral glucose-lowering drugs on long term outcomes in patients with diabetes mellitus following myocardial infarction not treated with emergent percutaneous coronary intervention–a retrospective nationwide cohort study. Cardiovasc Diabetol 9: 54.
    1. Selvin E, Bolen S, Yeh HC, Wiley C, Wilson LM, et al. (2008) Cardiovascular outcomes in trials of oral diabetes medications: a systematic review. Arch Intern Med 168: 2070–2080.
    1. Saenz A, Fernandez-Esteban I, Mataix A, Ausejo M, Roque M, et al... (2005) Metformin monotherapy for type 2 diabetes mellitus. Cochrane Database Syst Rev: CD002966.
    1. El Messaoudi S, Rongen GA, de Boer RA, Riksen NP (2011) The cardioprotective effects of metformin. Curr Opin Lipidol 22: 445–453.
    1. Bhamra GS, Hausenloy DJ, Davidson SM, Carr RD, Paiva M, et al. (2008) Metformin protects the ischemic heart by the Akt-mediated inhibition of mitochondrial permeability transition pore opening. Basic Res Cardiol 103: 274–284.
    1. Calvert JW, Gundewar S, Jha S, Greer JJ, Bestermann WH, et al. (2008) Acute metformin therapy confers cardioprotection against myocardial infarction via AMPK-eNOS-mediated signaling. Diabetes 57: 696–705.
    1. Paiva M, Riksen NP, Davidson SM, Hausenloy DJ, Monteiro P, et al. (2009) Metformin prevents myocardial reperfusion injury by activating the adenosine receptor. J Cardiovasc Pharmacol 53: 373–378.
    1. Gundewar S, Calvert JW, Jha S, Toedt-Pingel I, Ji SY, et al. (2009) Activation of AMP-activated protein kinase by metformin improves left ventricular function and survival in heart failure. Circ Res 104: 403–411.
    1. Laude K, Beauchamp P, Thuillez C, Richard V (2002) Endothelial protective effects of preconditioning. Cardiovasc Res 55: 466–473.
    1. Loukogeorgakis SP, Panagiotidou AT, Yellon DM, Deanfield JE, MacAllister RJ (2006) Postconditioning protects against endothelial ischemia-reperfusion injury in the human forearm. Circulation 113: 1015–1019.
    1. van den Munckhof I, Riksen N, Seeger JP, Schreuder TH, Borm GF, et al. (2013) Aging attenuates the protective effect of ischemic preconditioning against endothelial ischemia-reperfusion injury in humans. Am J Physiol Heart Circ Physiol 304: H1727–1732.
    1. Hashimoto M, Akishita M, Eto M, Ishikawa M, Kozaki K, et al. (1995) Modulation of endothelium-dependent flow-mediated dilatation of the brachial artery by sex and menstrual cycle. Circulation 92: 3431–3435.
    1. Williams MR, Westerman RA, Kingwell BA, Paige J, Blombery PA, et al. (2001) Variations in endothelial function and arterial compliance during the menstrual cycle. J Clin Endocrinol Metab 86: 5389–5395.
    1. Schreiber-Deturmeny E, Bruguerolle B (1996) Simultaneous high-performance liquid chromatographic determination of caffeine and theophylline for routine drug monitoring in human plasma. J Chromatogr B Biomed Appl 677: 305–312.
    1. Thijssen DH, Black MA, Pyke KE, Padilla J, Atkinson G, et al. (2011) Assessment of flow-mediated dilation in humans: a methodological and physiological guideline. Am J Physiol Heart Circ Physiol 300: H2–12.
    1. Woodman RJ, Playford DA, Watts GF, Cheetham C, Reed C, et al. (2001) Improved analysis of brachial artery ultrasound using a novel edge-detection software system. J Appl Physiol 91: 929–937.
    1. Black MA, Cable NT, Thijssen DH, Green DJ (2009) Impact of age, sex, and exercise on brachial artery flow-mediated dilatation. American journal of physiology Heart and circulatory physiology 297: H1109–1116.
    1. Thijssen DH, Dawson EA, Tinken TM, Cable NT, Green DJ (2009) Retrograde flow and shear rate acutely impair endothelial function in humans. Hypertension 53: 986–992.
    1. Atkinson G, Batterham AM, Thijssen DH, Green DJ (2013) A new approach to improve the specificity of flow-mediated dilation for indicating endothelial function in cardiovascular research. J Hypertens 31: 287–291.
    1. Whittington HJ, Hall AR, McLaughlin CP, Hausenloy DJ, Yellon DM, et al. (2013) Chronic metformin associated cardioprotection against infarction: not just a glucose lowering phenomenon. Cardiovasc Drugs Ther 27: 5–16.
    1. Yin M, van der Horst IC, van Melle JP, Qian C, van Gilst WH, et al. (2011) Metformin improves cardiac function in a nondiabetic rat model of post-MI heart failure. Am J Physiol Heart Circ Physiol 301: H459–468.
    1. El Messaoudi S, Rongen GA, Riksen NP (2013) Metformin therapy in diabetes: the role of cardioprotection. Curr Atheroscler Rep 15: 314.
    1. Kaeffer N, Richard V, Francois A, Lallemand F, Henry JP, et al. (1996) Preconditioning prevents chronic reperfusion-induced coronary endothelial dysfunction in rats. Am J Physiol 271: H842–849.
    1. VanBenthuysen KM, McMurtry IF, Horwitz LD (1987) Reperfusion after acute coronary occlusion in dogs impairs endothelium-dependent relaxation to acetylcholine and augments contractile reactivity in vitro. J Clin Invest 79: 265–274.
    1. Kharbanda RK, Peters M, Walton B, Kattenhorn M, Mullen M, et al. (2001) Ischemic preconditioning prevents endothelial injury and systemic neutrophil activation during ischemia-reperfusion in humans in vivo. Circulation 103: 1624–1630.
    1. Inaba Y, Chen JA, Bergmann SR (2010) Prediction of future cardiovascular outcomes by flow-mediated vasodilatation of brachial artery: a meta-analysis. Int J Cardiovasc Imaging 26: 631–640.
    1. Yeboah J, Folsom AR, Burke GL, Johnson C, Polak JF, et al. (2009) Predictive value of brachial flow-mediated dilation for incident cardiovascular events in a population-based study: the multi-ethnic study of atherosclerosis. Circulation 120: 502–509.
    1. Kitta Y, Obata JE, Nakamura T, Hirano M, Kodama Y, et al. (2009) Persistent impairment of endothelial vasomotor function has a negative impact on outcome in patients with coronary artery disease. J Am Coll Cardiol 53: 323–330.
    1. Devan AE, Umpierre D, Harrison ML, Lin HF, Tarumi T, et al. (2011) Endothelial ischemia-reperfusion injury in humans: association with age and habitual exercise. Am J Physiol Heart Circ Physiol 300: H813–819.
    1. Charakida M, Masi S, Luscher TF, Kastelein JJ, Deanfield JE (2010) Assessment of atherosclerosis: the role of flow-mediated dilatation. Eur Heart J 31: 2854–2861.
    1. Wouters CW, Wever KE, Bronckers I, Hopman MT, Smits P, et al. (2012) Short-term statin treatment does not prevent ischemia and reperfusion-induced endothelial dysfunction in humans. J Cardiovasc Pharmacol 59: 22–28.
    1. Kilian JG, Nakhla S, Griffith K, Harmer J, Skilton M, et al. (2005) Reperfusion injury in the human forearm is mild and not attenuated by short-term ischaemic preconditioning. Clin Exp Pharmacol Physiol 32: 86–90.
    1. Luca MC, Liuni A, McLaughlin K, Gori T, Parker JD (2013) Daily ischemic preconditioning provides sustained protection from ischemia-reperfusion induced endothelial dysfunction: a human study. J Am Heart Assoc 2: e000075.
    1. Bailey TG, Birk GK, Cable NT, Atkinson G, Green DJ, et al. (2012) Remote ischemic preconditioning prevents reduction in brachial artery flow-mediated dilation after strenuous exercise. Am J Physiol Heart Circ Physiol 303: H533–538.
    1. Liuni A, Luca MC, Gori T, Parker JD (2010) Rosuvastatin prevents conduit artery endothelial dysfunction induced by ischemia and reperfusion by a cyclooxygenase-2-dependent mechanism. J Am Coll Cardiol 55: 1002–1006.
    1. van der Worp HB, Howells DW, Sena ES, Porritt MJ, Rewell S, et al. (2010) Can animal models of disease reliably inform human studies? PLoS Med 7: e1000245.
    1. Pitocco D, Zaccardi F, Tarzia P, Milo M, Scavone G, et al. (2013) Metformin improves endothelial function in type 1 diabetic subjects: a pilot, placebo-controlled randomized study. Diabetes Obes Metab 15: 427–431.
    1. Jensterle M, Sebestjen M, Janez A, Prezelj J, Kocjan T, et al. (2008) Improvement of endothelial function with metformin and rosiglitazone treatment in women with polycystic ovary syndrome. Eur J Endocrinol 159: 399–406.
    1. Takase B, Uehata A, Akima T, Nagai T, Nishioka T, et al... (1998) Endothelium-dependent flow-mediated vasodilation in coronary and brachial arteries in suspected coronary artery disease. Am J Cardiol 82: 1535–1539, A1537–1538.
    1. Takase B, Hamabe A, Satomura K, Akima T, Uehata A, et al. (2005) Close relationship between the vasodilator response to acetylcholine in the brachial and coronary artery in suspected coronary artery disease. Int J Cardiol 105: 58–66.

Source: PubMed

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