Journal of Diabetes Research

Journal of Diabetes Research / 2016 / Article
Special Issue

Complications of Diabetes 2016

View this Special Issue

Review Article | Open Access

Volume 2016 |Article ID 2848759 |

Gary Tse, Eric Tsz Him Lai, Vivian Tse, Jie Ming Yeo, "Molecular and Electrophysiological Mechanisms Underlying Cardiac Arrhythmogenesis in Diabetes Mellitus", Journal of Diabetes Research, vol. 2016, Article ID 2848759, 8 pages, 2016.

Molecular and Electrophysiological Mechanisms Underlying Cardiac Arrhythmogenesis in Diabetes Mellitus

Academic Editor: Konstantinos Papatheodorou
Received20 Mar 2016
Accepted28 Apr 2016
Published23 Aug 2016


Diabetes is a common endocrine disorder with an ever increasing prevalence globally, placing significant burdens on our healthcare systems. It is associated with significant cardiovascular morbidities. One of the mechanisms by which it causes death is increasing the risk of cardiac arrhythmias. The aim of this article is to review the cardiac (ion channel abnormalities, electrophysiological and structural remodelling) and extracardiac factors (neural pathway remodelling) responsible for cardiac arrhythmogenesis in diabetes. It is concluded by an outline of molecular targets for future antiarrhythmic therapy for the diabetic population.

1. Introduction

Cardiometabolic disorders place significant burdens on the healthcare system worldwide [1]. Their prevalence has been rising over the past decades due to an aging population and an increasing level of obesity [2, 3]. Diabetes mellitus is an endocrine disorder characterized by reduced insulin production (type 1) or increased insulin resistance (type 2), leading to hyperglycaemia. There is increasing evidence that diabetes increases the risk of cardiac arrhythmias. This involves abnormalities in action potential conduction or repolarization (Figures 1 and 2), due to a complex interplay of ion channel abnormalities and electrophysiological remodelling superimposed upon a cardiomyopathic process together with autonomic dysregulation (Figure 3). Some of these findings are derived from experiments performed in animal models, which have been proven extremely useful for dissecting the molecular mechanisms responsible for arrhythmic phenotypes [4]. In this review, the pathophysiology underlying cardiac arrhythmias in diabetes mellitus is explored in detail, followed by an outline of potential therapeutic targets for reducing arrhythmic risk and sudden death in diabetic patients.

2. Arrhythmogenic Mechanisms in Diabetes Mellitus

The common arrhythmogenic mechanism is reentry, which occurs when an action potential fails to extinguish itself and reactivates a region that has recovered from refractoriness. This can arise from abnormalities in conduction or repolarization or both [5]. Circus reentry requires three prerequisites: (i) conduction velocity (CV) which must be sufficiently slowed so that the tissue ahead of the action potential (AP) wavefront remains excitable, (ii) unidirectional conduction block which must be present to prevent waves from self-extinguishing when they collide, and (iii) an obstacle around which an AP can circulate [6]. This need not be a structural defect but can be a functional core of refractory tissue, which may arise dynamically from ectopic activity [7]. Repolarization abnormalities can result in early or delayed afterdepolarizations (EADs and DADs), which can initiate triggered activity when their magnitudes are sufficiently large to reach the threshold potential for sodium channel reactivation. They can also increase the dispersion of repolarization, promoting unidirectional conduction block and reentry. In diabetes mellitus, arrhythmogenesis can be due to the following mechanisms. Abnormalities in conduction are mediated by myocardial ischaemia [8] or in repolarization [9, 10] by ion channel dysfunction, increased adrenergic drive, and calcium overload [11]. These abnormalities are superimposed upon a cardiomyopathy, in which the structural changes also predispose to arrhythmias. Extracardiac abnormalities, for example, neural pathway remodelling, can further promote arrhythmogenesis [12]. Ventricular arrhythmias are thought to underlie sudden cardiac death (SCD) in type 2 diabetic patients and also the “dead-in-bed syndrome” observed in otherwise young healthy adults with type 1 diabetes [13].

3. Abnormal Conduction

CV depends upon sodium channel activation followed by electrotonic spread of the ionic currents via gap junctions, which are electrical coupling pathways located between adjacent cardiomyocytes [14]. Each gap junction is made of two connexons, and each connexon is a hexamer of connexins (Cx). Altered gap junction expression or function can produce conduction abnormalities and in turn predispose to reentrant excitation. Protein kinase C- (PKC-) mediated phosphorylation, a calcium-dependent process, at serine 368 of Cx43, has been linked to reduced gap junction conductance [15, 16]. Dephosphorylation of gap junctions results in their uncoupling [17] and lateralization [18, 19]. There is consistent evidence demonstrating altered gap junction function or expression in different experimental models of diabetes. Thus, in transgenic mice with cardiac-specific overexpression of peroxisome proliferator-activated receptor γ 1 (PPARγ1) modelling human diabetes, reduced Cx43 expression without alterations in CV was observed [20]. This may increase anisotropy and higher likelihood of reentry. In streptozotocin- (STZ-) induced diabetic rats, expression levels of Cx40, 43 and 45 in the SA node, are significantly increased, which were associated with SA conduction delay [21]. This can be explained by increased expression levels of Cx45, which has the lowest unitary conductance and whose expression reduces CV. In both atria and ventricles of the same model, Cx43 phosphorylation was decreased because of reduced PKCε expression [22]; Cx43 was upregulated in the atria, whereas its expression level was unchanged in the ventricles [23]. Furthermore, the lack of insulin signalling can lead to reduced CV of propagating APs.

Myocardial fibrosis is increasingly recognized to be a pathogenic factor in diabetic cardiomyopathy [24]. Fibrosis resulting from fibroblast activation is mediated by growth factors, such as transforming growth factor-β [25]. This produces conduction abnormalities via two mechanisms: (i) reduced coupling between cardiomyocytes, leading to increased axial resistance; (ii) increased coupling between fibroblast and cardiomyocyte, increasing membrane capacitance [26]. Both mechanisms lead to a decrease in CV. Cardiac magnetic resonance (CMR) with late gadolinium enhancement is used for the diagnosis and monitoring of cardiomyopathy [2729] and is potentially useful for examining fibrosis in diabetic cardiomyopathy.

Hypoglycemic episodes are associated with myocardial ischaemia [8], which may predispose to ventricular arrhythmias by producing conduction defects via the following mechanisms [14]. Ischaemia results in ATP depletion, metabolic switching to anaerobic glycolysis, extracellular H+ accumulation, and intracellular Ca2+ overload. Cytosolic Ca2+ binds to the conserved C2 domain of PKC, thereby activating it [30]. There are several downstream targets of PKC. Firstly, PKC phosphorylates the serine residue at 1505 position of the sodium channel inactivation gate between domains III and IV, which decreases [31]. Secondly, it also phosphorylates connexins (Cx) 43 at serine 368, reducing gap junction conductance [15, 16]. Ca2+ overload is also associated with dephosphorylation of gap junctions [32], resulting in their uncoupling [17] and lateralization [18, 19]. Thus, myocardial ischaemia secondary to hypoglycaemia reduces CV and increases dispersion of conduction, predisposing to reentrant excitation.

4. Abnormal Repolarization

Action potential repolarization has two phases: (i) early rapid repolarization resulting from the activation of the fast and slow transient outward potassium currents, and , and (ii) prolonged plateau resulting from a balance between the inward currents mediated by the voltage-gated L-type calcium channel (LTCC, ) and sodium-calcium exchanger () and the outward currents mediated by the voltage-gated delayed rectifier potassium channels (: rapid and slow currents, and ) [33]. There is also contribution from the inward rectifying current (). Of these, the human ether-à-go-go-related gene (HERG) K+ channel is the major component of delayed rectifier K+ current [34].

In diabetes mellitus, prolongations in action potential durations (APDs) are due to several mechanisms. The lack of insulin signalling resulted in electrophysiological remodelling: is reduced as a result of reduced expression of Kv4.2 and KChiP2 genes [35]. This current is posttranslationally regulated by a number of different kinases. For example, the p90 ribosomal S6 kinase (p90RSK) is a serine/threonine kinase with N- and C-terminal kinase domains. Reactive oxygen species (ROS), which are raised in diabetes [36], increases the activity of p90RSK and reduced the activity of , , and channels [37]. Moreover, transgenic mice with cardiac-specific overexpression of peroxisome proliferator-activated receptor γ 1 (PPARγ1) showed abnormal lipid accumulation in cardiomyocytes and reduced expression as well as function of and [20]. The Rad (Ras associated with diabetes) protein is implicated in diabetes: in its dominant negative mutant, LTCC was upregulated [38]. Together, increased inward currents and decreased outward currents lead to prolonged ventricular repolarization. Conversely, genetic mutations of key ion channel genes causing prolonged ventricular repolarization can also lead to diabetes. For example, mutations in KCNE2 are responsible for long QT syndrome type 5. Whole-transcript transcriptomics demonstrated that KCNE2−/− mice additionally showed diabetes mellitus, hypercholesterolemia, and elevated angiotensin II levels [39]. Hypoglycaemia causes intracellular depletion of ATP in cardiomyocytes and hyperglycaemia increases the production of reactive oxygen species (ROS), both leading to HERG channel dysfunction [40]. channels are thought to provide a link between cellular energy status and membrane electrophysiology. They are normally inhibited by ATP and activated by ADP. During ischaemia, there are ATP depletion and ADP accumulation, activating and promoting APD shortening [41]. In diabetes, initial APD shortening is also observed but this becomes fully reversed in a time-dependent manner. This failure of APD adaptation, when accompanied by increased adrenergic drive, can engage in steep APD restitution, in turn leading to the production of arrhythmogenic APD alternans [7].

Hypoglycaemia is also associated with another cause of delayed repolarization, hypokalaemia [42, 43], which arises from insulin therapy or increased adrenergic drive [44, 45]. Hypokalaemia inhibits , thereby prolonging APDs and causing L-type Ca2+ channel reactivation [46]. This then leads to early afterdepolarizations (EADs) and consequent triggered activity [47]. Hypokalaemia also preferentially prolongs epicardial APDs and leaving endocardial APDs unchanged, increasing the transmural repolarization gradient [47]. In combination with reduced effective refractory periods (ERPs), excitation wavelength (conduction velocity (CV) × ERP) is reduced. Furthermore, increased steepness of APD restitution results in the development of APD alternans [48] and in turn in wavebreak, conduction block, and initiation and maintenance of reentrant activity [7, 49].

Hypoglycaemia also increases adrenergic drive with the following proarrhythmic consequences [50]. Firstly, the release of catecholamines leads to abnormal Ca2+ cycling and intracellular Ca2+ accumulation. This in turn stimulates spontaneous Ca2+ release from the sarcoplasmic reticulum, thereby activating three calcium-sensitive currents: the nonselective cationic current, , the sodium-calcium exchange current, , and the calcium-activated chloride current, . Thus, such inward currents observed during phase 4 of the action potential lead to delayed afterdepolarizations (DADs), eliciting triggered activity.

Abnormal Ca2+ dynamics have been implicated in diabetes. For example, cardiomyocytes of leptin-deficient ob/ob mice showed reduced amplitudes of Ca2+ transients, and insulin elicited extra transients via inositol 1,4,5-trisphosphate (IP3) signalling and impaired mitochondrial Ca2+ handling [51]. Furthermore, decreases in DAG-mediated nonselective cation currents were associated with reduced TRPC3 expression at the plasma membrane, which increases Ca2+ influx [52]. Dysregulation of the type 2 ryanodine receptor (RyR2) has been detected in a STZ-induced diabetes rat model, in which increased frequency of Ca2+ sparks with reduced amplitudes was associated with increased sensitivity to Ca2+ activation and dyssynchronous Ca2+ release [53, 54]. Abnormal RyR2 gating mechanism may arise from increased phosphorylation by protein kinase A (PKA, serine 2808) and Ca2+/calmodulin-dependent protein kinase II (CaMKII, serine 2808 and serine 2814) [5557], as well as oxidation by ROS and reactive carbonyl species (RCS), which are increased in diabetes [5860]. Uncontrolled hyperglycaemia can lead to activation of CaMKII and subsequent Ca2+ release from the SR [61]. Dyssynchronous Ca2+ release can be explained by remodelling of the transverse tubular system, whereby RyR2 become orphaned when they are decoupled from LTCCs [62]. Interestingly, catecholaminergic polymorphic ventricular tachycardia (CPVT) is caused by RyR2 mutation, and patients suffering from this condition are also prone to impaired glucose homeostasis and insulin secretion [63]. It would be interesting to determine whether diabetic patients with acquired dysfunction in RyR2 develop bidirectional VT classically associated with CPVT.

Moreover, diabetes mellitus is an independent risk factor for atrial fibrillation, yet the underlying physiological mechanisms are incompletely understood. It may involve ion channel remodelling in the atria. For example, the small conductance Ca2+-activated K+ (SK) channels contribute to atrial repolarization. SK2 and SK3 isoforms are downregulated, leading to APD prolongation [64]. Normally, SK channels do not play a role in ventricular repolarization. In heart failure, SK currents and ion channel expression can be upregulated and become more sensitive to Ca2+ modulation, potentially leading to ventricular arrhythmias [65]. Altered expression of SK channels in the ventricles may play a role in diabetes but this remains to be tested experimentally.

5. Diabetic Cardiomyopathy: Cardiac Electrophysiological and Structural Remodelling with Superimposed Autonomic Dysregulation

Diabetic cardiomyopathy is characterized by diastolic dysfunction with preserved systolic function, findings that are similarly observed in genetically modified, leptin receptor deficient, diabetic db/db mice on echocardiography [66, 67]. Cardiac magnetic resonance imaging is excellent for characterizing structural abnormalities, such as areas of fibrosis by late gadolinium enhancement [2729]. Afferent and efferent neural pathways normally regulate inotropic, lusitropic, chronotropic, and dromotropic responses of the heart. In diabetes, these can become dysregulated with impaired baroreceptor control of heart rate [68]. Reduced heart rate variability (HRV) has long been associated with increased mortality [69]. In diabetes, a reduction in HRV was associated with increased incidence of inducible VT by programmed electrical stimulation [70]. Electrophysiological modelling is likely to be an early event, appearing before structural abnormalities. Thus, STZ-induced diabetic rats showed decreases in both maximal transport capacity of SERCA2a and RyR2 conductance, associated with impairment of both inotropic and lusitropic responses in response to adrenergic stimulation [71]. This finding differs from human findings with impaired positive inotropic response with preservation of positive lusitropic effects of beta-adrenoceptor stimulation [72].

Brady-arrhythmias in the form of sinoatrial (SA) and atrioventricular (AV) nodal blocks are seen in diabetes [73, 74]. Sinoatrial node (SAN) dysfunction was demonstrated in db/db mice, which demonstrated prolonged SAN recovery time [66]. These mice showed no significant differences in conduction intervals and wave amplitudes compared to control mice. By contrast, sinus tachycardia at rest has been associated with excessive mortality in diabetic patients [75]. This may be related to autonomic dysregulation, with increased adrenergic drive with or without impairment of parasympathetic response. Thus, in Akita diabetic mice, the SA node is less responsive to acetylcholine because of a reduction in acetylcholine-activated K+ current (), which is due to altered phosphoinositide 3-kinase (PI3K) signalling [76].

Some aspects of altered cardiac electrophysiology in diabetes do not arise from abnormalities in the heart itself, but instead from neural pathways innervating it. Thus, in STZ-induced diabetic mice, both baroreflex tachycardia and bradycardia were blunted. This was associated with remodelling of the baroreceptor circuitry, in which the sizes of cardiac ganglia and ganglionic principal neurons were decreased. In a different model, the OVE26 diabetic mice showed neural degeneration in the nucleus ambiguus, which is one of the two brainstem nuclei innervating the cardiac ganglia [77]. Furthermore, altered balance between chemoattractants (e.g., nerve growth factor) and chemorepellants (Sema3a) leads to disruptions in innervation pattern, precipitating arrhythmias, and sudden death [78].

6. Clinical Relevance and Future Therapies

Traditional agents used for treatment of diabetes or associated comorbidities such as hypertension have been shown to exert cardiac protective effects in diabetes by previously unknown mechanisms. Thus, for example, in the STZ-induced diabetic rat model, and are downregulated and the cardiac renin-angiotensin system is activated. Experimental evidence has demonstrated augmentation of both currents by the antihypertensive angiotensin II receptor blockers [79]. The ACE inhibitor enalapril [80] and angiotensin II receptor blocker losartan [81] were also shown to exert antifibrotic effects in hypertension and may have similar cardioprotective effects in diabetes by similar mechanisms. The antifibrotic hormone relaxin could be delivered using adenoviruses [82] and may reverse fibrosis in diabetic cardiomyopathy. Ion channels represent an attractive target for managing arrhythmic complications of diabetes mellitus (Table 1). Novel agents such as late sodium current blockers [83] and gap junction openers [49] can be used to reduce abnormal repolarization and conduction, respectively. Alternatively, gap junction inhibitors can prolong effective refractory periods and exert antiarrhythmic effects [47]. Paradoxically, mild gap junction uncoupling could improve the safety margin of conduction and increase CV, removing unidirectional conduction blocks and converting these into bilateral conduction. Their use in diabetes warrants future exploration. Ryanodine receptor stabilizers have the potential to normalize Ca2+ handling in diabetes, which remains to be tested [84]. However, caution must be exercised to screen for deleterious, ventricular proarrhythmic effects. channels play a role in not only insulin secretion but also cardiac repolarization. Whilst the channel activators have been used to increase insulin release, they have the potential to cause life-threatening ventricular arrhythmias, especially in a subset of patients with ischaemic complications. In diabetes, mitochondrial channel activation in cardiomyocytes by dioxide led to impaired APD adaptation, which promoted the occurrence of VT [85]. Future efforts therefore require an integrated approach by computation modelling, where effects of drugs on complex spatiotemporal properties of cardiac dynamics are tested to reduce the likelihood of life-threatening side effects. Animal models will be useful for studying arrhythmogenic mechanisms and provide a platform for assessing the efficacy of pharmacological therapy with translational applications [8688].

Molecular targetMechanism of actionReferences

Gap junction inhibitorsIncrease refractory period
Improve conduction

Gap junction openersIncrease conduction velocity and decrease heterogeneity in repolarization or refractoriness [49]

Late sodium channel blockersInhibit afterdepolarizations[83]

Ryanodine receptor stabilizersDecrease heterogeneity in transients and inhibit afterdepolarizations [84]

Antifibrotic agentsReduce cardiac fibrosis[82]

Competing Interests

The authors declare that they have no competing interests.


Gary Tse was awarded a BBSRC Doctoral Training Award at the University of Cambridge for his Ph.D. degree.


  1. L. Choy, J. M. Yeo, V. Tse, S. P. Chan, and G. Tse, “Cardiac disease and arrhythmogenesis: mechanistic insights from mouse models,” IJC Heart & Vasculature, vol. 12, pp. 1–10, 2016. View at: Publisher Site | Google Scholar
  2. R. S. M. Chan and J. Woo, “Prevention of overweight and obesity: how effective is the current public health approach,” International Journal of Environmental Research and Public Health, vol. 7, no. 3, pp. 765–783, 2010. View at: Publisher Site | Google Scholar
  3. E. L. Yi Wong, J. Woo, E. Hui, C. Chan, W. L. S. Chan, and A. W. L. Cheung, “Primary care for diabetes mellitus: perspective from older patients,” Patient Preference and Adherence, vol. 5, pp. 491–498, 2011. View at: Publisher Site | Google Scholar
  4. G. Tse, S. T. Wong, V. Tse, and J. M. Yeo, “Monophasic action potential recordings: which is the recording electrode?” Journal of Basic and Clinical Physiology and Pharmacology, 2016. View at: Publisher Site | Google Scholar
  5. G. Tse, E. T. H. Lai, J. M. Yeo et al., “Mechanisms of electrical activation and conduction in the gastrointestinal system: lessons from cardiac electrophysiology,” Frontiers in Physiology, vol. 7, article 182, 2016. View at: Publisher Site | Google Scholar
  6. G. Tse, E. T. Lai, A. P. Lee, B. P. Yan, and S. H. Wong, “Electrophysiological mechanisms of gastrointestinal arrhythmogenesis: lessons from the heart,” Frontiers in Physiology, vol. 7, article 230, 2016. View at: Publisher Site | Google Scholar
  7. G. Tse, S. T. Wong, V. Tse, Y. T. Lee, H. Y. Lin, and J. M. Yeo, “Cardiac dynamics: alternans and arrhythmogenesis,” Journal of Arrhythmia, 2016. View at: Publisher Site | Google Scholar
  8. C. Desouza, H. Salazar, B. Cheong, J. Murgo, and V. Fonseca, “Association of hypoglycemia and cardiac ischemia: a study based on continuous monitoring,” Diabetes Care, vol. 26, no. 5, pp. 1485–1489, 2003. View at: Publisher Site | Google Scholar
  9. J. L. B. Marques, E. George, S. R. Peacey et al., “Altered ventricular repolarization during hypoglycaemia in patients with diabetes,” Diabetic Medicine, vol. 14, no. 8, pp. 648–654, 1997. View at: Publisher Site | Google Scholar
  10. R. Bolognesi, D. Tsialtas, M. G. Bolognesi, and C. Giumelli, “Marked sinus bradycardia and QT prolongation in a diabetic patient with severe hypoglycemia,” Journal of Diabetes and its Complications, vol. 25, no. 5, pp. 349–351, 2011. View at: Publisher Site | Google Scholar
  11. G. Tse, E. T. H. Lai, J. M. Yeo, and B. P. Yan, “Electrophysiological mechanisms of Bayés syndrome: insights from clinical and mouse studies,” Frontiers in Physiology, vol. 7, article 188, 2016. View at: Publisher Site | Google Scholar
  12. P. Coumel, “Cardiac arrhythmias and the autonomic nervous system,” Journal of Cardiovascular Electrophysiology, vol. 4, no. 3, pp. 338–355, 1993. View at: Publisher Site | Google Scholar
  13. R. B. Tattersall and G. V. Gill, “Unexplained deaths of Type 1 diabetic patients,” Diabetic Medicine, vol. 8, no. 1, pp. 49–58, 1991. View at: Publisher Site | Google Scholar
  14. G. Tse and J. M. Yeo, “Conduction abnormalities and ventricular arrhythmogenesis: the roles of sodium channels and gap junctions,” IJC Heart & Vasculature, vol. 9, pp. 75–82, 2015. View at: Publisher Site | Google Scholar
  15. A. P. Moreno, J. C. Sáez, G. I. Fishman, and D. C. Spray, “Human connexin43 gap junction channels: regulation of unitary conductances by phosphorylation,” Circulation Research, vol. 74, no. 6, pp. 1050–1057, 1994. View at: Publisher Site | Google Scholar
  16. B. R. Kwak, M. M. P. Hermans, H. R. De Jonge, S. M. Lohmann, H. J. Jongsma, and M. Chanson, “Differential regulation of distinct types of gap junction channels by similar phosphorylating conditions,” Molecular Biology of the Cell, vol. 6, no. 12, pp. 1707–1719, 1995. View at: Publisher Site | Google Scholar
  17. M. A. Beardslee, D. L. Lerner, P. N. Tadros et al., “Dephosphorylation and intracellular redistribution of ventricular connexin43 during electrical uncoupling induced by ischemia,” Circulation Research, vol. 87, no. 8, pp. 656–662, 2000. View at: Publisher Site | Google Scholar
  18. J. H. Smith, C. R. Green, N. S. Peters, S. Rothery, and N. J. Severs, “Altered patterns of gap junction distribution in ischemic heart disease: an immunohistochemical study of human myocardium using laser scanning confocal microscopy,” American Journal of Pathology, vol. 139, no. 4, pp. 801–821, 1991. View at: Google Scholar
  19. P. D. Lampe, E. M. TenBroek, J. M. Burt, W. E. Kurata, R. G. Johnson, and A. F. Lau, “Phosphorylation of connexin43 on serine368 by protein kinase C regulates gap junctional communication,” The Journal of Cell Biology, vol. 149, no. 7, pp. 1503–1512, 2000. View at: Publisher Site | Google Scholar
  20. J. P. Morrow, A. Katchman, N.-H. Son et al., “Mice with cardiac overexpression of peroxisome proliferator-activated receptor γ have impaired repolarization and spontaneous fatal ventricular arrhythmias,” Circulation, vol. 124, no. 25, pp. 2812–2821, 2011. View at: Publisher Site | Google Scholar
  21. F. C. Howarth, N. Nowotny, E. Zilahi, M. A. El Haj, and M. Lei, “Altered expression of gap junction connexin proteins may partly underlie heart rhythm disturbances in the streptozotocin-induced diabetic rat heart,” Molecular and Cellular Biochemistry, vol. 305, no. 1-2, pp. 145–151, 2007. View at: Publisher Site | Google Scholar
  22. H. Lin, M. Mitasikova, K. Dlugosova et al., “Thyroid hormones suppress ε-PKC signalling, down-regulate connexin-43 and increase lethal arrhythmia susceptibility in non-diabetic and diabetic rat hearts,” Journal of Physiology and Pharmacology, vol. 59, no. 2, pp. 271–285, 2008. View at: Google Scholar
  23. M. Mitašíková, H. Lin, T. Soukup, I. Imanaga, and N. Tribulová, “Diabetes and thyroid hormones affect connexin-43 and PKC-ε expression in rat heart atria,” Physiological Research, vol. 58, no. 2, pp. 211–217, 2009. View at: Google Scholar
  24. J. Asbun and F. J. Villarreal, “The pathogenesis of myocardial fibrosis in the setting of diabetic cardiomyopathy,” Journal of the American College of Cardiology, vol. 47, no. 4, pp. 693–700, 2006. View at: Publisher Site | Google Scholar
  25. A. Leask, “Potential therapeutic targets for cardiac fibrosis: TGFβ, angiotensin, endothelin, CCN2, and PDGF, partners in fibroblast activation,” Circulation Research, vol. 106, no. 11, pp. 1675–1680, 2010. View at: Publisher Site | Google Scholar
  26. M. Miragoli, G. Gaudesius, and S. Rohr, “Electrotonic modulation of cardiac impulse conduction by myofibroblasts,” Circulation Research, vol. 98, no. 6, pp. 801–810, 2006. View at: Publisher Site | Google Scholar
  27. G. Tse, A. Ali, F. Alpendurada, S. Prasad, C. E. Raphael, and V. Vassiliou, “Tuberculous constrictive pericarditis,” Research in Cardiovascular Medicine, vol. 4, no. 4, Article ID e29614, 2015. View at: Publisher Site | Google Scholar
  28. G. Tse, A. Ali, S. K. Prasad, V. Vassiliou, and C. E. Raphael, “Atypical case of post-partum cardiomyopathy: an overlap syndrome with arrhythmogenic right ventricular cardiomyopathy?” BJR: Case Reports, vol. 1, no. 2, Article ID 20150182, 2015. View at: Publisher Site | Google Scholar
  29. V. Vassiliou, C. Chin, A. Perperoglou et al., “93Ejection fraction by cardiovascular magnetic resonance predicts adverse outcomes post aortic valve replacement,” Heart, vol. 100, supplement 3, pp. A53–A54, 2014. View at: Publisher Site | Google Scholar
  30. J.-H. Luo and I. B. Weinstein, “Calcium-dependent activation of protein kinase C: the role of the C2 domain in divalent cation selectivity,” The Journal of Biological Chemistry, vol. 268, no. 31, pp. 23580–23584, 1993. View at: Google Scholar
  31. Y. Qu, J. C. Rogers, T. N. Tanada, W. A. Catterall, and T. Scheuer, “Phosphorylation of S1505 in the cardiac Na+ channel inactivation gate is required for modulation by protein kinase C,” Journal of General Physiology, vol. 108, no. 5, pp. 375–379, 1996. View at: Publisher Site | Google Scholar
  32. X.-D. Huang, G. E. Sandusky, and D. P. Zipes, “Heterogeneous loss of connexin43 protein in ischemic dog hearts,” Journal of Cardiovascular Electrophysiology, vol. 10, no. 1, pp. 79–91, 1999. View at: Publisher Site | Google Scholar
  33. E. Carmeliet, “Cardiac ionic currents and acute ischemia: from channels to arrhythmias,” Physiological Reviews, vol. 79, no. 3, pp. 917–1017, 1999. View at: Google Scholar
  34. M. C. Sanguinetti, C. Jiang, M. E. Curran, and M. T. Keating, “A mechanistic link between an inherited and an acquird cardiac arrthytmia: HERG encodes the IKr potassium channel,” Cell, vol. 81, no. 2, pp. 299–307, 1995. View at: Publisher Site | Google Scholar
  35. A. Lopez-Izquierdo, R. O. Pereira, A. R. Wende, B. B. Punske, E. Dale Abel, and M. Tristani-Firouzi, “The absence of insulin signaling in the heart induces changes in potassium channel expression and ventricular repolarization,” American Journal of Physiology—Heart and Circulatory Physiology, vol. 306, no. 5, pp. H747–H754, 2014. View at: Publisher Site | Google Scholar
  36. G. Tse, B. P. Yan, Y. W. F. Chan, X. Y. Tian, and Y. Huang, “Reactive oxygen species, endoplasmic reticulum stress and mitochondrial dysfunction: the link with cardiac arrhythmogenesis,” Frontiers in Physiology, vol. 7, article 313, 2016. View at: Publisher Site | Google Scholar
  37. Z. Lu, J.-I. Abe, J. Taunton et al., “Reactive oxygen species-induced activation of p90 ribosomal s6 kinase prolongs cardiac repolarization through inhibiting outward K+ channel activity,” Circulation Research, vol. 103, no. 3, pp. 269–278, 2008. View at: Publisher Site | Google Scholar
  38. H. Yada, M. Murata, K. Shimoda et al., “Dominant negative suppression of Rad leads to QT prolongation and causes ventricular arrhythmias via modulation of L-type Ca2+ channels in the heart,” Circulation Research, vol. 101, no. 1, pp. 69–77, 2007. View at: Publisher Site | Google Scholar
  39. Z. Hu, R. Kant, M. Anand et al., “Kcne2 deletion creates a multisystem syndrome predisposing to sudden cardiac death,” Circulation: Cardiovascular Genetics, vol. 7, no. 1, pp. 33–42, 2014. View at: Publisher Site | Google Scholar
  40. Y. Zhang, H. Han, J. Wang, H. Wang, B. Yang, and Z. Wang, “Impairment of human ether-à-go-go-related gene (HERG) K+ channel function by hypoglycemia and hyperglycemia: similar phenotypes but different mechanisms,” The Journal of Biological Chemistry, vol. 278, no. 12, pp. 10417–10426, 2003. View at: Publisher Site | Google Scholar
  41. C. Xie, J. Hu, L. J. Motloch, B. S. Karam, and F. G. Akar, “The classically cardioprotective agent diazoxide elicits arrhythmias in type 2 diabetes mellitus,” Journal of the American College of Cardiology, vol. 66, no. 10, pp. 1144–1156, 2015. View at: Publisher Site | Google Scholar
  42. S. R. Heller and R. T. C. E. Robinson, “Hypoglycaemia and associated hypokalaemia in diabetes: mechanisms, clinical implications and prevention,” Diabetes, Obesity and Metabolism, vol. 2, no. 2, pp. 75–82, 2000. View at: Publisher Site | Google Scholar
  43. T. F. Christensen, M. Bækgaard, J. L. Dideriksen et al., “A physiological model of the effect of hypoglycemia on plasma potassium,” Journal of Diabetes Science and Technology, vol. 3, no. 4, pp. 887–894, 2009. View at: Publisher Site | Google Scholar
  44. B. M. Fisher, I. Thomson, D. A. Hepburn, and B. M. Frier, “Effects of adrenergic blockade on serum potassium changes in response to acute insulin-induced hypoglycemia in nondiabetic humans,” Diabetes Care, vol. 14, no. 7, pp. 548–552, 1991. View at: Publisher Site | Google Scholar
  45. K. G. Petersen, K. J. Schluter, and L. Kerp, “Regulation of serum potassium during insulin-induced hypoglycemia,” Diabetes, vol. 31, no. 7, pp. 615–617, 1982. View at: Publisher Site | Google Scholar
  46. C. T. January and J. M. Riddle, “Early afterdepolarizations: mechanism of induction and block. A role for L-type Ca2+ current,” Circulation Research, vol. 64, no. 5, pp. 977–990, 1989. View at: Publisher Site | Google Scholar
  47. G. Tse, V. Tse, J. M. Yeo, B. Sun, and A. Talkachova, “Atrial anti-arrhythmic effects of heptanol in Langendorff-perfused mouse hearts,” PLoS ONE, vol. 11, no. 2, Article ID e0148858, 2016. View at: Publisher Site | Google Scholar
  48. G. Tse, S. T. Wong, V. Tse, and J. Yeo, “Restitution analysis of alternans using dynamic pacing and its comparison with S1S2 restitution in heptanol-treated, hypokalaemic Langendorff-perfused mouse hearts,” Biomedical Reports, vol. 4, no. 6, pp. 673–680, 2016. View at: Publisher Site | Google Scholar
  49. Y.-C. Hsieh, J.-C. Lin, C.-Y. Hung et al., “Gap junction modifier rotigaptide decreases the susceptibility to ventricular arrhythmia by enhancing conduction velocity and suppressing discordant alternans during therapeutic hypothermia in isolated rabbit hearts,” Heart Rhythm, vol. 13, no. 1, pp. 251–261, 2016. View at: Publisher Site | Google Scholar
  50. A. Goldfien, R. Moore, S. Zileli, L. L. Havens, L. Boling, and G. W. Thorn, “Plasma epinephrine and norepinephrine levels during insulin-induced hypoglycemia in man,” The Journal of clinical endocrinology & metabolism, vol. 21, pp. 296–304, 1961. View at: Publisher Site | Google Scholar
  51. J. Fauconnier, J. T. Lanner, S. J. Zhang et al., “Insulin and inositol 1,4,5-trisphosphate trigger abnormal cytosolic Ca2+ transients and reveal mitochondrial Ca2+ handling defects in cardiomyocytes of ob/ob mice,” Diabetes, vol. 54, no. 8, pp. 2375–2381, 2005. View at: Publisher Site | Google Scholar
  52. J. Fauconnier, J. T. Lanner, A. Sultan et al., “Insulin potentiates TRPC3-mediated cation currents in normal but not in insulin-resistant mouse cardiomyocytes,” Cardiovascular Research, vol. 73, no. 2, pp. 376–385, 2007. View at: Publisher Site | Google Scholar
  53. C.-H. Shao, G. J. Rozanski, K. P. Patel, and K. R. Bidasee, “Dyssynchronous (non-uniform) Ca2+ release in myocytes from streptozotocin-induced diabetic rats,” Journal of Molecular and Cellular Cardiology, vol. 42, no. 1, pp. 234–246, 2007. View at: Publisher Site | Google Scholar
  54. C.-H. Shao, X. H. T. Wehrens, T. A. Wyatt et al., “Exercise training during diabetes attenuates cardiac ryanodine receptor dysregulation,” Journal of Applied Physiology, vol. 106, no. 4, pp. 1280–1292, 2009. View at: Publisher Site | Google Scholar
  55. J. Hain, H. Onoue, M. Mayrleitner, S. Fleischer, and H. Schindler, “Phosphorylation modulates the function of the calcium release channel of sarcoplasmic reticulum from cardiac muscle,” The Journal of Biological Chemistry, vol. 270, no. 5, pp. 2074–2081, 1995. View at: Publisher Site | Google Scholar
  56. X. H. T. Wehrens, S. E. Lehnart, S. R. Reiken, and A. R. Marks, “Ca2+/calmodulin-dependent protein kinase II phosphorylation regulates the cardiac ryanodine receptor,” Circulation Research, vol. 94, no. 6, pp. e61–e70, 2004. View at: Publisher Site | Google Scholar
  57. D. B. Witcher, R. J. Kovacs, H. Schulman, D. C. Cefali, and L. R. Jones, “Unique phosphorylation site on the cardiac ryanodine receptor regulates calcium channel activity,” The Journal of Biological Chemistry, vol. 266, no. 17, pp. 11144–11152, 1991. View at: Google Scholar
  58. K. R. Bidasee, K. Nallani, H. R. Besch Jr., and U. Deniz Dincer, “Streptozotocin-induced diabetes increases disulfide bond formation on cardiac ryanodine receptor (RyR2),” Journal of Pharmacology and Experimental Therapeutics, vol. 305, no. 3, pp. 989–998, 2003. View at: Publisher Site | Google Scholar
  59. K. R. Eager, L. D. Roden, and A. F. Dulhunty, “Actions of sulfhydryl reagents on single ryanodine receptor Ca2+-release channels from sheep myocardium,” The American Journal of Physiology, vol. 272, no. 6, part 1, pp. C1908–C1918, 1997. View at: Google Scholar
  60. L. Xu, J. P. Eu, G. Meissner, and J. S. Stamler, “Activation of the cardiac calcium release channel (ryanodoine receptor) by poly-S-nitrosylation,” Science, vol. 279, no. 5348, pp. 234–237, 1998. View at: Publisher Site | Google Scholar
  61. J. R. Erickson, L. Pereira, L. Wang et al., “Diabetic hyperglycaemia activates CaMKII and arrhythmias by O-linked glycosylation,” Nature, vol. 502, no. 7471, pp. 372–376, 2013. View at: Publisher Site | Google Scholar
  62. L.-S. Song, E. A. Sobie, S. McCulle, W. J. Lederer, C. W. Balke, and H. Cheng, “Orphaned ryanodine receptors in the failing heart,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 11, pp. 4305–4310, 2006. View at: Publisher Site | Google Scholar
  63. G. Santulli, G. Pagano, C. Sardu et al., “Calcium release channel RyR2 regulates insulin release and glucose homeostasis,” The Journal of Clinical Investigation, vol. 125, no. 5, pp. 1968–1978, 2015. View at: Publisher Site | Google Scholar
  64. F. Yi, T.-Y. Ling, T. Lu et al., “Down-regulation of the small conductance calcium-activated potassium channels in diabetic mouse atria,” The Journal of Biological Chemistry, vol. 290, no. 11, pp. 7016–7026, 2015. View at: Publisher Site | Google Scholar
  65. P.-C. Chang and P.-S. Chen, “SK channels and ventricular arrhythmias in heart failure,” Trends in Cardiovascular Medicine, vol. 25, no. 6, pp. 508–514, 2015. View at: Publisher Site | Google Scholar
  66. E. Soltysinska, T. Speerschneider, S. V. Winther, and M. B. Thomsen, “Sinoatrial node dysfunction induces cardiac arrhythmias in diabetic mice,” Cardiovascular Diabetology, vol. 13, no. 1, article 122, 2014. View at: Publisher Site | Google Scholar
  67. C. Basso, F. Calabrese, A. Angelini, E. Carturan, and G. Thiene, “Classification and histological, immunohistochemical, and molecular diagnosis of inflammatory myocardial disease,” Heart Failure Reviews, vol. 18, no. 6, pp. 673–681, 2013. View at: Publisher Site | Google Scholar
  68. K. Fukuda, H. Kanazawa, Y. Aizawa, J. L. Ardell, and K. Shivkumar, “Cardiac innervation and sudden cardiac death,” Circulation Research, vol. 116, no. 12, pp. 2005–2019, 2015. View at: Publisher Site | Google Scholar
  69. F. Lombardi, “Chaos theory, heart rate variability, and arrhythmic mortality,” Circulation, vol. 101, no. 1, pp. 8–10, 2000. View at: Publisher Site | Google Scholar
  70. M. Rajab, H. Jin, C. M. Welzig et al., “Increased inducibility of ventricular tachycardia and decreased heart rate variability in a mouse model for type 1 diabetes: effect of pravastatin,” American Journal of Physiology—Heart and Circulatory Physiology, vol. 305, no. 12, pp. H1807–H1816, 2013. View at: Publisher Site | Google Scholar
  71. L. Ligeti, O. Szenczi, C. M. Prestia et al., “Altered calcium handling is an early sign of streptozotocin-induced diabetic cardiomyopathy,” International Journal of Molecular Medicine, vol. 17, no. 6, pp. 1035–1043, 2006. View at: Google Scholar
  72. J. Amour, X. Loyer, P. Michelet, A. Birenbaum, B. Riou, and C. Heymes, “Preservation of the positive lusitropic effect of β-adrenoceptors stimulation in diabetic cardiomyopathy,” Anesthesia & Analgesia, vol. 107, no. 4, pp. 1130–1138, 2008. View at: Publisher Site | Google Scholar
  73. C. Hasslacher and P. Wahl, “Diabetes prevalence in patients with bradycardiac arrhythmias,” Acta Diabetologica Latina, vol. 14, no. 5-6, pp. 229–234, 1977. View at: Publisher Site | Google Scholar
  74. M.-R. Movahed, M. Hashemzadeh, and M. M. Jamal, “Increased prevalence of third-degree atrioventricular block in patients with type II diabetes mellitus,” Chest, vol. 128, no. 4, pp. 2611–2614, 2005. View at: Publisher Site | Google Scholar
  75. G. S. Hillis, M. Woodward, A. Rodgers et al., “Resting heart rate and the risk of death and cardiovascular complications in patients with type 2 diabetes mellitus,” Diabetologia, vol. 55, no. 5, pp. 1283–1290, 2012. View at: Publisher Site | Google Scholar
  76. P. S. Krishnaswamy, E. E. Egom, M. Moghtadaei et al., “Altered parasympathetic nervous system regulation of the sinoatrial node in Akita diabetic mice,” Journal of Molecular and Cellular Cardiology, vol. 82, pp. 125–135, 2015. View at: Publisher Site | Google Scholar
  77. B. Yan, L. Li, S. W. Harden et al., “Diabetes induces neural degeneration in nucleus ambiguus (NA) and attenuates heart rate control in OVE26 mice,” Experimental Neurology, vol. 220, pp. 34–43, 2009. View at: Google Scholar
  78. M. Ieda, K. Kimura, H. Kanazawa, and K. Fukuda, “Regulation of cardiac nerves: a new paradigm in the management of sudden cardiac death?” Current Medicinal Chemistry, vol. 15, no. 17, pp. 1731–1736, 2008. View at: Publisher Site | Google Scholar
  79. Y. Shimoni, “Inhibition of the formation or action of angiotensin II reverses attenuated K+ currents in type 1 and type 2 diabetes,” Journal of Physiology, vol. 537, no. 1, pp. 83–92, 2001. View at: Publisher Site | Google Scholar
  80. M. Pahor, R. Bernabei, A. Sgadari et al., “Enalapril prevents cardiac fibrosis and arrhythmias in hypertensive rats,” Hypertension, vol. 18, no. 2, pp. 148–157, 1991. View at: Publisher Site | Google Scholar
  81. G. Gay-Jordi, E. Guash, B. Benito et al., “Losartan prevents heart fibrosis induced by long-term intensive exercise in an animal model,” PLoS ONE, vol. 8, no. 2, Article ID e55427, 2013. View at: Publisher Site | Google Scholar
  82. R. A. D. Bathgate, E. D. Lekgabe, J. T. McGuane et al., “Adenovirus-mediated delivery of relaxin reverses cardiac fibrosis,” Molecular and Cellular Endocrinology, vol. 280, no. 1-2, pp. 30–38, 2008. View at: Publisher Site | Google Scholar
  83. A. S. Alves Bento, D. Bacic, J. Saran Carneiro et al., “Selective late INa inhibition by GS-458967 exerts parallel suppression of catecholamine-induced hemodynamically significant ventricular tachycardia and T-wave alternans in an intact porcine model,” Heart Rhythm, vol. 12, no. 12, pp. 2508–2514, 2015. View at: Publisher Site | Google Scholar
  84. S. E. Lehnart, C. Terrenoire, S. Reiken et al., “Stabilization of cardiac ryanodine receptor prevents intracellular calcium leak and arrhythmias,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 20, pp. 7906–7910, 2006. View at: Publisher Site | Google Scholar
  85. Y. Xie, Z. Liao, E. Grandi, Y. Shiferaw, and D. M. Bers, “Slow Nai changes and positive feedback between membrane potential and Cai underlie intermittent early afterdepolarizations and arrhythmias,” Circulation: Arrhythmia and Electrophysiology, vol. 8, no. 6, pp. 1472–1480, 2015. View at: Publisher Site | Google Scholar
  86. G. Tse, V. Tse, and J. M. Yeo, “Ventricular anti-arrhythmic effects of heptanol in hypokalaemic, Langendorff-perfused mouse hearts,” Biomedical Reports, vol. 4, no. 3, pp. 313–324, 2016. View at: Publisher Site | Google Scholar
  87. G. Tse, J. M. Yeo, Y. W. Chan, E. T. Lai, and B. P. Yan, “What is the arrhythmic substrate in viral myocarditis? Insights from clinical and animal studies,” Frontiers in Physiology, vol. 7, article 308, 2016. View at: Publisher Site | Google Scholar
  88. G. Tse, “(Tpeak-Tend)/QRS and (Tpeak-Tend)/(QT x QRS): novel markers for predicting arrhythmic risk in Brugada syndrome,” Europace, 2016. View at: Publisher Site | Google Scholar

Copyright © 2016 Gary Tse et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

More related articles

 PDF Download Citation Citation
 Download other formatsMore
 Order printed copiesOrder

Related articles

We are committed to sharing findings related to COVID-19 as quickly as possible. We will be providing unlimited waivers of publication charges for accepted research articles as well as case reports and case series related to COVID-19. Review articles are excluded from this waiver policy. Sign up here as a reviewer to help fast-track new submissions.