Abstract
Hypoglycemia increases the risk for both overall and sudden death. At a cellular level, hypoglycemia causes alterations in the physiology of myocardial tissue that are identical to proarrhythmic medications. Reduced serum glucose blocks the repolarizing K+ channel HERG, which leads to action potential and QT prolongation and is uniformly associated with risk for torsades de pointes ventricular tachycardia. The sympathetic response induced by hypoglycemia also increases the risk of arrhythmias from Ca2+ overload, which occur with sympathomimetic medications and excessive beta adrenergic stimulation. Thus, hypoglycemia can be considered a proarrhythmic event. This review focuses on emerging evidence for two other important changes induced by hypoglycemia that promote arrhythmias: ischemia and bradycardia. Studies of patients with “insulin shock” therapy from the early twentieth century and other more recent data strongly suggest that hypoglycemia can cause ischemia of myocardial tissue, both in association with coronary artery obstructions and by cellular mechanisms. Ischemia induces multiple proarrhythmic responses. Since ischemia itself reduces the possibility of using energy substrates other than glucose, hypoglycemia may generate positive feedback for electrophyisologic destabilization. Recent studies also show that hypoglycemia can cause bradycardia and heart block. Bradycardia is known to cause action potential prolongation and potentiate the development of torsades de pointes, particularly with low-serum K+ which can be induced by hypoglycemic episodes. Thus, hypoglycemia-induced bradycardia may also create a dynamic, positive feedback for the development of arrhythmias and sudden death. These studies further support the hypothesis that hypoglycemia is a proarrhythmic event.
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References
Marques JL, George E, Peacey SR, Harris ND, Macdonald IA, Cochrane T, Heller SR (1997) Altered ventricular repolarization during hypoglycaemia in patients with diabetes. Diabet Med 14:648–654
Heller SR (2002) Abnormalities of the electrocardiogram during hypoglycaemia: the cause of the dead in bed syndrome? Int J Clin Pract Suppl 129:27–32
Robinson RT, Harris ND, Ireland RH, Lee S, Newman C, Heller SR (2003) Mechanisms of abnormal cardiac repolarization during insulin-induced hypoglycaemia. Diabetes 52:1469–1474
Lee S, Harris ND, Robinson RT, Yeoh L, Macdonald IA, Heller SR (2003) Effects of adrenaline and potassium on QTc interval and QT dispersion in man. Eur J Clin Invest 33:93–98
Murphy NP, Ford-Adams ME, Ong KK, Harris ND, Keane SM, Davies C, Ireland RH, MacDonald IA, Knight EJ, Edge JA, Heller SR, Dunger DB (2004) Prolonged cardiac repolarisation during spontaneous nocturnal hypoglycaemia in children and adolescents with type 1 diabetes. Diabetologia 47:1940–1947
Lee SP, Yeoh L, Harris ND, Davies CM, Robinson RT, Leathard A, Newman C, Macdonald IA, Heller SR (2004) Influence of autonomic neuropathy on QTc interval lengthening during hypoglycaemia in type 1 diabetes. Diabetes 53:1535–1542
Robinson RT, Harris ND, Ireland RH, Macdonald IA, Heller SR (2004) Changes in cardiac repolarization during clinical episodes of nocturnal hypoglycaemia in adults with type 1 diabetes. Diabetologia 47:312–315
Lee SP, Harris ND, Robinson RT, Davies C, Ireland R, Macdonald IA, Heller SR (2005) Effect of atenolol on QTc interval lengthening during hypoglycaemia in type 1 diabetes. Diabetologia 48:1269–1272
Eckert B, Agardh CD (1998) Hypoglycaemia leads to an increased QT interval in normal men. Clin Physiol 18:570–575
Landstedt-Hallin L, Englund A, Adamson U, Lins PE (1999) Increased QT dispersion during hypoglycaemia in patients with type 2 diabetes mellitus. J Intern Med 246:299–307
The Action to Control Cardiovascular Risk in Diabetes Study Group. Gerstein HC, Miller ME, Byintgton RP, Goff DC, Bigger JT, Buse JB, Cushman WC, Genuth S, Ismail-Beigi F, Grimm RH, Probstfield JL, Simons-Morton DG, Friedewald WT (2008) Effects of intensive glucose lowering in type 2 diabetes. New Engl J Med 358:2545–2559
Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD, Zieve FJ, Marks J, Davis SN, Hayward R, Warren SR, Goldman S, McCarren M, Vitek ME, Henderson WG, Huang GD, VADT Investigators (2009) Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med 360(2):129–139
ADVANCE Collaborative Group, Patel A, MacMahon S, Chalmers J, Neal B, Billot L, Woodward M, Marre M, Cooper M, Glasziou P, Grobbee D, Hamet P, Harrap S, Heller S, Liu L, Mancia G, Mogensen CE, Pan C, Poulter N, Rodgers A, Williams B, Bompoint S, de Galan BE, Joshi R, Travert F (2008) Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 358:2560–2572
Bonds DE, Miller ME, Bergenstal RM, Buse JB, Byington RP, Cutler JA, Dudl RJ, Ismail-Beigi F, Kimel AR, Hoogwerf B, Horowitz KR, Savage PJ, Seaquist ER, Simmons DL, Sivitz WI, Speril-Hillen JM, Sweeney ME (2010) The association between symptomatic, severe hypoglycaemia and mortality in type 2 diabetes: retrospective epidemiological analysis of the ACCORD study. BMJ 340:b4909. doi:10.1136/bmj.b4909
Nordin C (2010) The case for hypoglycaemia as a proarrhythmic event: basic and clinical evidence. Diabetologia 53(8):1552–1561
Zhang Y, Han H, Wang J, Wang H, Yang B, Wang Z (2003) Impairment of human ether-à-go–go-related gene (HERG) K+ channel function by hypoglycemia and hyperglycemia. Similar phenotypes but different mechanisms. J Biol Chem 278(12):10417–10426
Rosen MR, Gelband H, Merker C, Hoffman BF (1973) Mechanisms of digitalis toxicity. Effects of ouabain on phase four of canine Purkinje fiber transmembrane potentials. Circulation 47(4):681–689
Ferrier GR (1977) Digitalis arrhythmias: role of oscillatory afterpotentials. Prog Cardiovasc Dis 19(6):459–474
Kass RS, Tsien RW, Weingart R (1978) Ionic basis of transient inward current induced by strophanthidin in cardiac Purkinje fibres. J Physiol 281:209–226
Matsuda H, Noma A, Kurachi Y, Irisawa H (1982) Transient depolarization and spontaneous voltage fluctuations in isolated single cells from guinea pig ventricles. Calcium-mediated membrane potential fluctuations. Circ Res 51:142–151
Priori SG, Corr PB (1990) Mechanisms underlying early and delayed afterdepolarizations induced by catecholamines. Am J Physiol 258:H1796–H1805
Volders PG, Kulcsar A, Vos MA, Sipido KR, Wellens HJ, Lazzara R, Szabo B (1997) Similarities between early and delayed afterdepolarizations induced by isoproterenol in canine ventricular myocytes. Cardiovasc Res 34:348–359
Priori SG, Mantica M, Schwartz PJ (1988) Delayed afterdepolarizations elicited in vivo by left stellate ganglion stimulation. Circulation 78:178–185
Roden DM (2004) Drug-induced prolongation of the QT interval. N Engl J Med 350:1013–1022
Paul AA, Witchel HJ, Hancox JC (2002) Inhibition of the current of heterologously expressed HERG potassium channels by flecainide and comparison with quinidine, propafenone and lignocaine. Br J Pharmacol 136(5):717–729
Vandenberg JI, Perry MD, Perrin MJ, Mann SA, Ke Y, Hill AP (2012) hERGK(+) channels: structure, function, and clinical significance. Physiol Rev 92(3):1393–1478
Weil-Malherbe H (1952) The concentration of adrenaline-like substances in blood during insulin hypoglycaemia. J Ment Sci 98(413):565–578
Goldfien A, Moore R, Zileli S, Havens LL, Boling L, Thorn GW (1961) Plasma epinephrine and norepinephrine levels during insulin-induced hypoglycemia in man. J Clin Endocrinol Metab 21:296–304
Okazaki O, Suda N, Hongo K, Konishi M, Kurihara S (1990) Modulation of Ca2+ transients and contractile properties by beta-adrenoceptor stimulationin ferret ventricular muscles. J Physiol 423:221–240
Matsuda H, Noma A, Kurachi Y, Irisawa H (1982) Transient depolarization and spontaneous voltage fluctuations in isolated single cells from guinea pig ventricles. Calcium-mediated membrane potential fluctuations. Circ Res 51:142–151
Priori SG, Corr PB (1990) Mechanisms underlying early and delayed afterdepolarizations induced by catecholamines. Am J Physiol 258:H1796–H1805
Ming Z, Aronson R, Nordin C (1994) Mechanism of current-induced early afterdepolarizations in isolated guinea pig myocytes. Am J Physiol 267(4 Pt 2):H1419–H1428
Szabo B, Kovacs T, Lazzara R (1995) Role of calcium loading in arly afterdepolarizations generated by Cs+ in canine and guinea pig Purkinje fibers. J Cardiovasc Electrophysiol 6(10 Pt 1):796–812
Choi BR, Burton F, Salama G (2002) Cytosolic Ca2+ triggers early afterdepolarizations and Torsade de Pointes in rabbit hearts with type 2 long QT syndrome. J Physiol 543(Pt 2):615–631
Chvilicek JP, Hurlbert BJ, Hill GE (1995) Diuretic-induced hypokalaemia inducing torsades de pointes. Can J Anaesth 42:1137–1139
Nordin C, Kohli A, Beca S, Zaharia V, Grant T, Leider J, Marantz P (2006) Importance of hepatitis C coinfection in the development of QT prolongation in HIV-infected patients. J Electrocardiol 39:199–205
Aronson RS, Nordin C (1988) Arrhythmogenic interaction between low potassium and ouabain in isolated guinea-pig ventricular myocytes. J Physiol 400:113–134
Larkin EH (1937) Insulin shock treatment of schizophrenia. Br Med J 1(3979):745–747
[No authors listed] (1937) Insulin hypoglycemic shock in treatment of dementia praecox. J Natl Med Assoc 29(4):157–158
Cryer PE (2011) Death during intensive glycemic therapy of diabetes: mechanisms and implications. Am J Med 124(11):993–996
Wright RJ, Frier BM (2008) Vascular disease and diabetes: is hypoglycaemia an aggravating factor? Diabetes Metab Res Rev 24(5):353–363
Bellet S, Freed H, Dyer WW (1939) The electrocardiogram during insulin shock treatment of schizophrenia and other psychoses. Am J Med Sci 4:533–541
Bellet S, Finkelsetein D (1951) Significance of QT prolongation in the electrocardiogram: based on the study of 168 cases. Am J Med Sci 222(3):263–278
Scheflen AE, Reiner ER, Jetter WW (1952) Fatalities in insulin therapy of the psychoses. Arch Neurol Psychiat 67:32–43
Leitch A (1955) Sudden death in insulin coma treatment for schizophrenia. J Nerv Ment Dis 121(3):267–269
Kihara Y, Grossman W, Morgan JP (1989) Direct measurement of changes in intracellular calcium transients during hypoxia, ischemia, and reperfusion of the intact mammalian heart. Circ Res 65(4):1029–1044
Kenigsberg DN, Khanal S, Kowalski M, Krishnan SC (2007) Prolongation of the QTc interval is seen uniformly during early transmural ischemia. J Am Coll Cardiol 49(12):1299–1305
Friedman PL, Stewart JR, Fenoglio JJ Jr, Wit AL (1973) Survival of subendocardial Purkinje fibers after extensive myocardial infarction in dogs. Circ Res 33(5):597–611
Wong SS, Myerburg RJ, Ezrin AM, Gelband H, Bassett AL (1982) Electrophysiologic effects of encainide on acutely ischemic rabbit myocardial cells. Eur J Pharmacol 80(4):323–329
Desouza C, Salazar H, Cheong B, Murgo J, Fonseca V (2003) Association of hypoglycemia and cardiac ischemia: a study based on continuous monitoring. Diabetes Care 26(5):1485–1489
Pinto DS, Skolnick AH, Kirtane AJ, Murphy SA, Barron HV, Giugliano RP, Cannon CP, Braunwald E, Gibson DM, for the TIMI Study Group (2005) U-shaped relationship of blood glucose with adverse outcomes among patients with ST-segment elevation myocardial infarction. J Am Col Cardiol 46:178–180
Svensson AM, McGuire DK, Abrahamsson P, Dellborg M (2005) Association between hyper- and hypoglycaemia and 2 year all-cause mortality risk in diabetic patients with acute coronary events. Eur Heart J 26(13):1255–1261
Pinto DS, Kirtane AJ, Pride YB, Murphy SA, Sabatine MS, Cannon CP, Gibson CM, for the CLARITY-TIMI 28 Investigators (2008) Association of blood glucose with angiographic and clinical outcomes among patients with ST-segment elevation myocardial infarction (from the CLARITY-TIMI-28 Study). Am J Cardiol 101:303–307
Libby P, Maroko PR, Braunwald E (1975) The effect of hypoglycemia on myocardial ischemic injury during acute experimental coronary artery occlusion. Circulation 51(4):621–626
Scheuer J (1967) Myocardial metabolism in cardiac hypoxia. Am J Cardiol 19(3):385–392
Neely JR, Morgan HE (1974) Relationship between carbohydrate and lipid metabolism and the energy balance of heart muscle. Annu Rev Physiol 36:413–459
Seaquist ER, Anderson J, Childs B, Cryer P, Dagogo-Jack S, Fish L, Heller SR, Rodriguez H, Rosenzweig J, Vigersky R (2013) Hypoglycemia and diabetes: a report of a workgroup of the American Diabetes Association and the Endocrine Society. Diabetes Care 36(5):1384–1395
McCoy RG, Van Houten HK, Ziegenfuss JY, Shah ND, Wermers RA, Smith SA (2012) Increased mortality of patients with diabetes reporting severe hypoglycemia. Diabetes Care 35(9):1897–1901
Currie CJ, Peters JR, Tynan A, Evans M, Heine RJ, Bracco OL, Zagar T, Poole CD (2010) Survival as a function of HbA(1c) in people with type 2 diabetes: a retrospective cohort study. Lancet 375(9713):481–489
Östgren CJ, Sundström J, Svennblad B, Lohm L, Nilsson PM, Johansson G (2013) Associations of HbA1c and educational level with risk of cardiovascular events in 32,871 drug-treated patients with type 2 diabetes: a cohort study in primary care. Diabet Med 30(5):e170–e177
Huang ES, Liu JY, Moffet HH, John PM, Karter AJ (2011) Glycemic control, complications, and death in older diabetic patients: the diabetes and aging study. Diabetes Care 34(6):1329–1336
Colayco DC, Niu F, McCombs JS, Cheetham TC (2011) A1C and cardiovascular outcomes in type 2 diabetes: a nested case-control study. Diabetes Care 34(1):77–83
The ORIGIN Trial Investigators (2013) Does hypoglycaemia increase the risk of cardiovascular events? A report from the ORIGIN trial. Eur Heart J 34(40):3137–3144
Gill GV, Woodward A, Casson IF, Weston PJ (2009) Cardiac arrhythmia and nocturnal hypoglycaemia in type 1 diabetes—the “dead in bed” syndrome revisited. Diabetologia 52:42–45
Tanenberg RJ, Newton CA, Drake AJ (2010) Confirmation of hypoglycemia in the “dead-in-bed” syndrome, as captured by a retrospective continuous glucose monitoring system. Endocr Pract 16(2):244–248
Bolognesi R, Tsialtas D, Bolognesi MG, Giumelli C (2011) Marked sinus bradycardia and QT prolongation in a diabetic patient with severe hypoglycemia. J Diabetes Complications 25(5):349–351. doi:10.1016/j.jdiacomp.2011.01.001
Gundgurthi A, Kharb S, Dutta MK, Pakhetra R, Garg MK (2012) Insulin poisoning with suicidal intent Indian. J Endocrinol Metab 16(Suppl 1):S120–S122. doi:10.4103/2230-8210.94254
Navarro-Gutiérrez S, González-Martínez F, Fernández-Pérez MT, García-Moreno MT, Ballester-Vidal MR, Pulido-Morillo FJ (2003) Bradycardia related to hypoglycaemia. Eur J Emerg Med 10(4):331–333
Reno CM, Daphna-Iken D, Stefanie Chen Y, Vanderweele J, Jethi K, Fisher SJ (2013) Severe Hypoglycemia-Induced Lethal Cardiac Arrhythmias Are Mediated by Sympathoadrenal Activation. Diabetes (Epub ahead of print)
Fein FS, Aronson RS, Nordin C, Miller-Green B, Sonnenblick EH (1983) Altered myocardial response to ouabain in diabetic rats: mechanics and electrophysiology. J Mol Cell Cardiol 15(11):769–784
Nordin C, Gilat E, Aronson RS (1985) Delayed afterdepolarizations and triggered activity in ventricular muscle from rats with streptozotocin-induced diabetes. Circ Res 57(1):28–34
Aomine M, Nobe S, Arita M (1990) The making of diabetic guinea pigs by streptozotocin and high incidence of triggered activity in the ventricular muscle. Jpn J Physiol 40(5):651–663
Siri FM, Krueger J, Nordin C, Ming Z, Aronson RS (1991) Depressed intracellular calcium transients and contraction in myocytes from hypertrophied and failing guinea pig hearts. Am J Physiol 261(2 Pt 2):H514–H530
Brachmann J, Scherlag BJ, Rosenshtraukh LV, Lazzara R (1983) Bradycardia-dependent triggered activity: relevance to drug-induced multiform ventricular tachycardia. Circulation 68(4):846–856
Cranefield PF, Aronson RS (1991) Torsades de pointes and early afterdepolarizations. Cardiovasc Drugs Ther 5(2):531–537
Schwarts SP, Hallinger LN (1954) Transient ventricular fibrillation. VI. Observations on the peripheral arterial pulse pressures in the course of transient ventricular fibrillation during established auriculoventricular dissociation. Am Heart J 48(3):390–404
Dessertenne F (1966) Ventricular tachycardia with 2 variable opposing foci. Arch Mal Coeur Vaiss 59(2):263–272
Keren A, Tzivoni D (1991) Torsades de pointes: prevention and therapy. Cardiovasc Drugs Ther 5(2):509–513
Roden DM, Hoffman BF (1985) Action potential prolongation and induction of abnormal automaticity by low quinidine concentrations in canine Purkinje fibers. Relationship to potassium and cycle length. Circ Res 56(6):857–867
Taborsky GJ Jr, Mundinger TO (2012) Minireview: the role of the autonomic nervous system in mediating the glucagon response to hypoglycemia. Endocrinology 153(3):1055–1062. doi:10.1210/en.2011-2040
Laitinen T, Huopio H, Vauhkonen I, Camaro C, Hartikainen J, Laakso M, Niskanen L (2003) Effects of euglycaemic and hypoglycaemic hyperinsulinaemia on sympathetic and parasympathetic regulation of haemodynamics in healthy subjects. Clin Sci 105(3):315–322
Kass RS (1982) Tsien RW Fluctuations in membrane current driven by intracellular calcium in cardiac Purkinje fibers. Biophys J 38(3):259–269
Fedida D, Noble D, Rankin AC, Spindler AJ (1987) The arrhythmogenic transient inward current iTi and related contraction in isolated guinea-pig ventricular myocytes. J Physiol 392:523–542
MacConaill M (1988) Low potassium and high calcium thresholds for spontaneous ventricular fibrillation in Langendorff-perfused rabbit hearts. Can J Cardiol 4(1):49–55
Zaugg CE, Wu ST, Barbosa V, Buser PT, Wikman-Coffelt J, Parmley WW, Lee RJ (1998) Ventricular fibrillation-induced intracellular Ca2+ overload causes failed electrical defibrillation and post-shock reinitiation of fibrillation. J Mol Cell Cardiol 30(11):2183–2192
Cranefield PF (1977) Action potentials, afterpotentials, and arrhythmias. Circ Res 41(4):415–423
Roden DM (2004) Drug-induced prolongation of the QT interval. N Engl J Med 350:1013–1022
Singh K, Xiao L, Remondino A, Sawyer DB, Colucci WS (2001) Adrenergic regulation of cardiac myocyte apoptosis. J Cell Physiol 189(3):257–265
Shizukuda Y, Buttrick PM, Geenen DL, Borczuk AC, Kitsis RN, Sonnenblick EH (1998) Beta-adrenergic stimulation causes cardiocyte apoptosis: influence of tachycardia and hypertrophy. Am J Physiol 275(3 Pt 2):H961–H968
Ruiz-Meana M, Abellán A, Miró-Casas E, Garcia-Dorado D (2007) Opening of mitochondrial permeability transition pore induces hypercontracture in Ca2+ overloaded cardiac myocytes. Basic Res Cardiol 102(6):542–552
Ghatnekar GS, Barnes JA, Dow JL, Smoak IW (2004) Hypoglycemia induced changes in cell death and cell proliferation in the organogenesis stage embryonic mouse heart. Birth Defects Res A Clin Mol Teratol. 70(3):121–131
Arad M, Seidman CE (2007) Seidman JG.AMP-activated protein kinase in the heart: role during health and disease. Circ Res 100(4):474–488
Goto A, Arah OA, Goto M, Terauchi Y, Noda M (2013) Severe hypoglycaemia and cardiovascular disease: systematic review and meta-analysis with bias analysis.BMJ 347:f4533. doi:10.1136/bmj.f4533
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Nordin, C. The proarrhythmic effect of hypoglycemia: evidence for increased risk from ischemia and bradycardia. Acta Diabetol 51, 5–14 (2014). https://doi.org/10.1007/s00592-013-0528-0
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DOI: https://doi.org/10.1007/s00592-013-0528-0