钾离子通道与肥胖致心律失常的研究进展
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摘要
肥胖易诱发心律失常,并且治疗手段有限。现有证据表明肥胖致心律失常与心脏钾离子通道异常有关。研究肥胖患者心脏钾离子通道功能表达和电生理机制,有利于提高对肥胖致心律失常的认识,发现新的致病机制,找出新的治疗靶点,对于肥胖患者意义重大。本文旨在探讨心脏钾离子通道与肥胖致心律失常的研究进展。
Obesity predisposes to arrhythmia and treatment is limited. Existing evidence suggests that obesity-induced arrhythmia is associated with abnormal cardiac potassium channels. The study of cardiac potassium channel expression and electrophysiological mechanism in obese patients should improve understanding of obesity-induced arrhythmia, potentially discover new pathological mechanisms, and identify potentially new therapeutic targets. Given the worldwide epidemic of obesity, this information could be highly beneficial for obese patients. This article, therefore, reviews research progress of cardiac potassium channels and arrhythmia induced by obesity.
Obesity predisposes to arrhythmia and treatment is limited. Existing evidence suggests that obesity-induced arrhythmia is associated with abnormal cardiac potassium channels. The study of cardiac potassium channel expression and electrophysiological mechanism in obese patients should improve understanding of obesity-induced arrhythmia, potentially discover new pathological mechanisms, and identify potentially new therapeutic targets. Given the worldwide epidemic of obesity, this information could be highly beneficial for obese patients. This article, therefore, reviews research progress of cardiac potassium channels and arrhythmia induced by obesity.
引文
[1] Ng M,Fleming T,Robinson M,et al.Global,regional,and national prevalence of overweight and obesity in children and adults during 1980-2013:a systematic analysis for the Global Burden of Disease Study 2013[J].The Lancet,2014,384(9945):766-781.
[2] Adabag S,Huxley RR,Lopez FL,et al.Obesity related risk of sudden cardiac death in the atherosclerosis risk in communities study[J].Heart,2015,101(3):215-221.
[3] Scherer PE,Hill JA.Obesity,diabetes,and cardiovascular diseases:a compendium[J].Circ Res,2016,118 (11):1703-1705.
[4] Lin YK,Chen YC,Chen JH,et al.Adipocytes modulate the electrophysiology of atrial myocytes:implications in obesity-induced atrial fibrillation[J].Basic research in cardiology,2012,107(5):293.
[5] McCully BH,Hasan W,Streiff CT,et al.Sympathetic cardiac hyperinnervation and atrial autonomic imbalance in diet-induced obesity promote cardiac arrhythmias[J].Am J Physiol Heart Circ Physiol,2013,305(10):1530-1537.
[6] Aubin MC,Cardin S,Comtois P,et al.A high-fat diet increases risk of ventricular arrhythmia in female rats:enhanced arrhythmic risk in the absence of obesity or hyperlipidemia[J].J Appl Physiol (1985),2010,108(4):933-9404.
[7] Ramirez AH,Schildcrout JS,Blakemore DL,et al.Modulators of normal electrocardiographic intervals identified in a large electronic medical record [J].Heart Rhythm,2011,8(2):271-277.
[8] Calloe K,Nof E,Jespersen T,et al.Comparison of the effects of a transient outward potassium channel activator on currents recorded from atrial and ventricular cardiomyocytes[J].J Cardiovasc Electrophysiol,2011,22(9):1057-1066.
[9] Grandinetti A,Chow DC,Miyasaki M,et al.Association of increased QTc interval with the cardiometabolic syndrome[J].J Clin Hypertens (Greenwich),2010,12(4):315-320.
[10]Guo W,Li H,London B,et al.Functional consequences of elimination of i(to,f) and i(to,s):early afterdepolarizations,atrioventricular block,and ventricular arrhythmias in mice lacking Kv1.4 and expressing a dominant-negative Kv4 alpha subunit[J].Circ Res,2000,87(1):73-79.
[11]Finck BN,Lehman JJ,Leone TC,et al.The cardiac phenotype induced by PPARalpha overexpression mimics that caused by diabetes mellitus[J].J Clin Invest,2002,109(1):121-130.
[12]Marionneau C,Aimond F,Brunet S,et al.PPARalpha-mediated remodeling of repolarizing voltage-gated K+ (Kv) channels in a mouse model of metabolic cardiomyopathy[J].J Mol Cell Cardiol,2008,44(6):1002-1015.
[13]Yarla NS,Polito A,Peluso I.Effects of Olive Oil on TNF-and IL-6 in Humans:Implication in Obesity and Frailty[J].Endocr Metab Immune Disord Drug Targets,2018,18(1):63-74.
[14]Grandy SA,Fiset C.Ventricular K+ currents are reduced in mice with elevated levels of serum TNFalpha[J].J Mol Cell Cardiol,2009,47(2):238-246.
[15]Fernandez-Velasco M,Ruiz-Hurtado G,Hurtado O,et al.TNF-alpha downregulates transient outward potassium current in rat ventricular myocytes through iNOS overexpression and oxidant species generation[J].Am J Physiol Heart Circ Physiol,2007,293(1):H238-H245.
[16]Duncan DJ,Yang Z,Hopkins PM,et al.TNF-alpha and IL-1beta increase Ca2+ leak from the sarcoplasmic reticulum and susceptibility to arrhythmia in rat ventricular myocytes[J].Cell Calcium,2010,47(4):378-386.
[17]O’Connell RP,Musa H,Gomez MS,et al.Free fatty acid effects on the atrial myocardium:membrane ionic currents are remodeled by the disruption of T-tubular architecture[J].PLoS ONE,2015,10(8):e0133052.
[18]Oudit GY,Kassiri Z,Sah R,et al.The molecular physiology of the cardiac transient outward potassium current (I(to)) in normal and diseased myocardium[J].J Mol Cell Cardiol,2001,33(5):851-872.
[19]Zhang F,Hartnett S,Sample A,et al.High fat diet induced alterations of atrial electrical activities in mice[J].Am J Cardiovasc,2016,6(1):1-9
[20]Tipparaju SM,Li XP,Kilfoil PJ,et al.Interactions between the C-terminus of Kv1.5 and Kvbeta regulate pyridine nucleotide-dependent changes in channel gating[J].Pflugers Arch,2012,463(6):799-818.
[21]Huang H,Amin V,Gurin M,et al.Diet-induced obesity causes long QT and reduces transcription of voltage-gated potassium channels[J].J Mol Cell Cardiol,2013,59:151-158.
[22]Morrow JP,Katchman A,Son NH,et al.Mice with cardiac overexpression of peroxisome proliferator-activated receptor gamma have impaired repolarization and spontaneous fatal ventricular arrhythmias[J].Circulation,2011,124(25):2812-2821.
[23]Bhuyan R,Seal A.Dynamics and modulation studies of human voltage gated Kv1.5 channel[J].J Biomol Struct Dyn,2017,35(2):380-398.
[24]Christophersen IE,Olesen MS,Liang B,et al.Genetic variation in KCNA5:impact on the atrialspecific potassium current IKur in patients with lone atrial fibrillation[J].Eur Heart J,2013,34(20):1517-1525.
[25]Nunez L,Vaquero M,Gomez R,et al.Nitric oxide blocks hKv1.5 channels by Snitrosylation and by a cyclic GMP-dependent mechanism[J].Cardiovasc Res,2006,72(1):80-89.
[26]Aromolaran AS,Subramanyam P,Chang DD,et al.LQT1 mutations in KCNQ1 C-terminus assembly domain suppress IKs using different mechanisms[J].Cardiovasc Res,2014,104(3):501-511.
[27]Aromolaran AS,Colecraft HM,Boutjdir M.High-fat diet-dependent modulation of the delayed rectifier K(+) current in adult guinea pig atrial myocytes[J].Biochem Biophys Res Commun,2016,474(3):554-559.
[28]Haim TE,Wang W,Flagg TP,et al.Palmitate attenuates myocardial contractility through augmentation of repolarizing Kv currents[J].J Mol Cell Cardiol,2010,48(2):395-405
[29]Caillier B,Pilote S,Patoine D,et al.Metabolic syndrome potentiates the cardiac action potential-prolonging action of drugs:a possible ‘anti-proarrhythmic’ role for amlodipine[J].Pharmacol Res,2012,65(3):320-327.
[30]Kannankeril PJ,Norris KJ,Carter S,et al.Factors affecting the degree of QT prolongation with drug challenge in a large cohort of normal volunteers[J].Heart Rhythm,2011,8(10):1530-1534.
[31]Leong IU,Skinner JR,Shelling AN,et al.Expression of a mutant kcnj2 gene transcript in Zebrafish[J].ISRN Mol Biol,2013,2013:324839.
[32]Ashrafi R,Yon M,Pickavance L,et al.Altered left ventricular ion channel transcriptome in a high-fat-fed rat model of obesity:insight into obesity-induced arrhythmogenesis[J].J Obes,2016,2016:7127898.
[33]Mustroph J,Maier LS,Wagner S.CaMKII regulation of cardiac K channels[J].Front Pharmacol,2014,5:20.
[34]Zhong P,Quan D,Huang Y,et al.CaMKII Activation Promotes Cardiac Electrical Remodeling and Increases the Susceptibility to Arrhythmia Induction in High-fat Diet-Fed Mice With Hyperlipidemia Conditions [J].J Cardiovasc Pharmacol,2017,70(4):245-254.
[2] Adabag S,Huxley RR,Lopez FL,et al.Obesity related risk of sudden cardiac death in the atherosclerosis risk in communities study[J].Heart,2015,101(3):215-221.
[3] Scherer PE,Hill JA.Obesity,diabetes,and cardiovascular diseases:a compendium[J].Circ Res,2016,118 (11):1703-1705.
[4] Lin YK,Chen YC,Chen JH,et al.Adipocytes modulate the electrophysiology of atrial myocytes:implications in obesity-induced atrial fibrillation[J].Basic research in cardiology,2012,107(5):293.
[5] McCully BH,Hasan W,Streiff CT,et al.Sympathetic cardiac hyperinnervation and atrial autonomic imbalance in diet-induced obesity promote cardiac arrhythmias[J].Am J Physiol Heart Circ Physiol,2013,305(10):1530-1537.
[6] Aubin MC,Cardin S,Comtois P,et al.A high-fat diet increases risk of ventricular arrhythmia in female rats:enhanced arrhythmic risk in the absence of obesity or hyperlipidemia[J].J Appl Physiol (1985),2010,108(4):933-9404.
[7] Ramirez AH,Schildcrout JS,Blakemore DL,et al.Modulators of normal electrocardiographic intervals identified in a large electronic medical record [J].Heart Rhythm,2011,8(2):271-277.
[8] Calloe K,Nof E,Jespersen T,et al.Comparison of the effects of a transient outward potassium channel activator on currents recorded from atrial and ventricular cardiomyocytes[J].J Cardiovasc Electrophysiol,2011,22(9):1057-1066.
[9] Grandinetti A,Chow DC,Miyasaki M,et al.Association of increased QTc interval with the cardiometabolic syndrome[J].J Clin Hypertens (Greenwich),2010,12(4):315-320.
[10]Guo W,Li H,London B,et al.Functional consequences of elimination of i(to,f) and i(to,s):early afterdepolarizations,atrioventricular block,and ventricular arrhythmias in mice lacking Kv1.4 and expressing a dominant-negative Kv4 alpha subunit[J].Circ Res,2000,87(1):73-79.
[11]Finck BN,Lehman JJ,Leone TC,et al.The cardiac phenotype induced by PPARalpha overexpression mimics that caused by diabetes mellitus[J].J Clin Invest,2002,109(1):121-130.
[12]Marionneau C,Aimond F,Brunet S,et al.PPARalpha-mediated remodeling of repolarizing voltage-gated K+ (Kv) channels in a mouse model of metabolic cardiomyopathy[J].J Mol Cell Cardiol,2008,44(6):1002-1015.
[13]Yarla NS,Polito A,Peluso I.Effects of Olive Oil on TNF-and IL-6 in Humans:Implication in Obesity and Frailty[J].Endocr Metab Immune Disord Drug Targets,2018,18(1):63-74.
[14]Grandy SA,Fiset C.Ventricular K+ currents are reduced in mice with elevated levels of serum TNFalpha[J].J Mol Cell Cardiol,2009,47(2):238-246.
[15]Fernandez-Velasco M,Ruiz-Hurtado G,Hurtado O,et al.TNF-alpha downregulates transient outward potassium current in rat ventricular myocytes through iNOS overexpression and oxidant species generation[J].Am J Physiol Heart Circ Physiol,2007,293(1):H238-H245.
[16]Duncan DJ,Yang Z,Hopkins PM,et al.TNF-alpha and IL-1beta increase Ca2+ leak from the sarcoplasmic reticulum and susceptibility to arrhythmia in rat ventricular myocytes[J].Cell Calcium,2010,47(4):378-386.
[17]O’Connell RP,Musa H,Gomez MS,et al.Free fatty acid effects on the atrial myocardium:membrane ionic currents are remodeled by the disruption of T-tubular architecture[J].PLoS ONE,2015,10(8):e0133052.
[18]Oudit GY,Kassiri Z,Sah R,et al.The molecular physiology of the cardiac transient outward potassium current (I(to)) in normal and diseased myocardium[J].J Mol Cell Cardiol,2001,33(5):851-872.
[19]Zhang F,Hartnett S,Sample A,et al.High fat diet induced alterations of atrial electrical activities in mice[J].Am J Cardiovasc,2016,6(1):1-9
[20]Tipparaju SM,Li XP,Kilfoil PJ,et al.Interactions between the C-terminus of Kv1.5 and Kvbeta regulate pyridine nucleotide-dependent changes in channel gating[J].Pflugers Arch,2012,463(6):799-818.
[21]Huang H,Amin V,Gurin M,et al.Diet-induced obesity causes long QT and reduces transcription of voltage-gated potassium channels[J].J Mol Cell Cardiol,2013,59:151-158.
[22]Morrow JP,Katchman A,Son NH,et al.Mice with cardiac overexpression of peroxisome proliferator-activated receptor gamma have impaired repolarization and spontaneous fatal ventricular arrhythmias[J].Circulation,2011,124(25):2812-2821.
[23]Bhuyan R,Seal A.Dynamics and modulation studies of human voltage gated Kv1.5 channel[J].J Biomol Struct Dyn,2017,35(2):380-398.
[24]Christophersen IE,Olesen MS,Liang B,et al.Genetic variation in KCNA5:impact on the atrialspecific potassium current IKur in patients with lone atrial fibrillation[J].Eur Heart J,2013,34(20):1517-1525.
[25]Nunez L,Vaquero M,Gomez R,et al.Nitric oxide blocks hKv1.5 channels by Snitrosylation and by a cyclic GMP-dependent mechanism[J].Cardiovasc Res,2006,72(1):80-89.
[26]Aromolaran AS,Subramanyam P,Chang DD,et al.LQT1 mutations in KCNQ1 C-terminus assembly domain suppress IKs using different mechanisms[J].Cardiovasc Res,2014,104(3):501-511.
[27]Aromolaran AS,Colecraft HM,Boutjdir M.High-fat diet-dependent modulation of the delayed rectifier K(+) current in adult guinea pig atrial myocytes[J].Biochem Biophys Res Commun,2016,474(3):554-559.
[28]Haim TE,Wang W,Flagg TP,et al.Palmitate attenuates myocardial contractility through augmentation of repolarizing Kv currents[J].J Mol Cell Cardiol,2010,48(2):395-405
[29]Caillier B,Pilote S,Patoine D,et al.Metabolic syndrome potentiates the cardiac action potential-prolonging action of drugs:a possible ‘anti-proarrhythmic’ role for amlodipine[J].Pharmacol Res,2012,65(3):320-327.
[30]Kannankeril PJ,Norris KJ,Carter S,et al.Factors affecting the degree of QT prolongation with drug challenge in a large cohort of normal volunteers[J].Heart Rhythm,2011,8(10):1530-1534.
[31]Leong IU,Skinner JR,Shelling AN,et al.Expression of a mutant kcnj2 gene transcript in Zebrafish[J].ISRN Mol Biol,2013,2013:324839.
[32]Ashrafi R,Yon M,Pickavance L,et al.Altered left ventricular ion channel transcriptome in a high-fat-fed rat model of obesity:insight into obesity-induced arrhythmogenesis[J].J Obes,2016,2016:7127898.
[33]Mustroph J,Maier LS,Wagner S.CaMKII regulation of cardiac K channels[J].Front Pharmacol,2014,5:20.
[34]Zhong P,Quan D,Huang Y,et al.CaMKII Activation Promotes Cardiac Electrical Remodeling and Increases the Susceptibility to Arrhythmia Induction in High-fat Diet-Fed Mice With Hyperlipidemia Conditions [J].J Cardiovasc Pharmacol,2017,70(4):245-254.