Roles of impaired intracellular calcium cycling in arrhythmogenicity of diabetic mouse model

Chou, Chung Chuan; Ho, Chien Te; Lee, Hui Ling; Chu, Yen-Chang; Yen, Tzung Hai; Wen, Ming; Lin, Shien‐Fong; Lee, Cheng Hung; Chang, Po‐Cheng

doi:10.1111/pace.13166

Cited by 11 publications

(22 citation statements)

References 33 publications

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“…Direct evidence that diabetes-related aberrant Ca 2+ homeostasis can contribute to reentrant mechanisms of arrhythmia was obtained by Chou et al (2017) who showed that optically mapped hearts from obese db/db mice exhibit concordant Ca 2+ /Vm alternans at lower stimulation frequencies than controls. The authors attributed it to lower expression levels of RyR2 and enhanced activity of CaMKII.…”

Section: Mechanisms Of Ca 2+ Dependent Arrhythmia mentioning

confidence: 99%

Proarrhythmic Remodeling of Calcium Homeostasis in Cardiac Disease; Implications for Diabetes and Obesity

Hamilton

Terentyev

2018

Front. Physiol.

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A rapid growth in the incidence of diabetes and obesity has transpired to a major heath issue and economic burden in the postindustrial world, with more than 29 million patients affected in the United States alone. Cardiovascular defects have been established as the leading cause of mortality and morbidity of diabetic patients. Over the last decade, significant progress has been made in delineating mechanisms responsible for the diminished cardiac contractile function and enhanced propensity for malignant cardiac arrhythmias characteristic of diabetic disease. Rhythmic cardiac contractility relies upon the precise interplay between several cellular Ca2+ transport protein complexes including plasmalemmal L-type Ca2+ channels (LTCC), Na+-Ca2+ exchanger (NCX1), Sarco/endoplasmic Reticulum (SR) Ca2+-ATPase (SERCa2a) and ryanodine receptors (RyR2s), the SR Ca2+ release channels. Here we provide an overview of changes in Ca2+ homeostasis in diabetic ventricular myocytes and discuss the therapeutic potential of targeting Ca2+ handling proteins in the prevention of diabetes-associated cardiomyopathy and arrhythmogenesis.

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Section: Mechanisms Of Ca 2+ Dependent Arrhythmia mentioning

confidence: 99%

Proarrhythmic Remodeling of Calcium Homeostasis in Cardiac Disease; Implications for Diabetes and Obesity

Hamilton

Terentyev

2018

Front. Physiol.

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“…Action potential duration at 80% repolarization (APD 80 ) and Ca i transient duration at 80% decay (Ca i TD 80 ) were measured at two PCLs of 200 and 100 ms. [12] The differences between the longest and shortest APD 80 and Ca i TD 80 were used to represent APD 80 and Ca i TD 80 dispersion. To estimate conduction velocity (CV), we measured the distance and conduction time between the earliest activation point and two epicardial points: one was from the pacing site to the left ventricular apex (CV IR ), and the other was along an axis parallel to the atrioventricular ring (CV non−IR ).…”

Section: Discussionmentioning

confidence: 99%

“…In vivo electrophysiological study was performed after reperfusion for 10 min. [12] Burst pacing (pacing cycle length (PCL) = 50 ms, 2 sec) and extrastimulus pacing (S 1 -S 4 ) were applied to test VT (≥ three consecutive premature ventricular beats) inducibility to all mice. The severity of inducible VT was classified as < 10 beats, between 10 to 30 sec, and > 30 beats.…”

Section: Methodsmentioning

confidence: 99%

“…Studies have shown reduced cardiac conduction reserve in diabetic animal models. [12,29,30] Therefore, propagation of activity through the myocardium in diabetic hearts is more sensitive to conditions influencing cellular excitability or intercellular electrical coupling. For example, more pronounced activation of Ca 2+ -independent phospholipase A 2 in response to acute ischemia was reported to contribute to arrhythmogenic conduction slowing in the diabetic rat heart.…”

Section: Ranolazine Administration Ameliorates Conduction Inhomogeneimentioning

confidence: 99%

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Mechanisms of Ranolazine Pretreatment in Preventing Ventricular Tachyarrhythmias in Diabetic db/db Mice with Acute Regional Ischemia-Reperfusion Injury

Chou

Lee

Chang

et al. 2020

Preprint

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Background: Studies have demonstrated that db/db mice have increased susceptibility to myocardial ischemia-reperfusion (IR) injury and ventricular tachyarrhythmias (VA). We aimed to investigate the antiarrhythmic and molecular mechanisms of ranolazine in db/db mouse hearts with acute IR injury.Methods: Ranolazine was administered for 1 week before coronary artery ligation. Diabetic db/db and control db/+ mice were divided into ranolazine-given and -nongiven groups. IR model was created by 15-min left coronary artery ligation and 10-min reperfusion. In vivo electrophysiological studies and optical mapping to simultaneously record intracellular Ca2+ (Cai) and membrane voltage in Langendorff-perfused hearts were performed. Western blotting and whole-cell patch clamp study were performed to evaluate the effect of ranolazine in the non-IR and IR zones. Results: The severity of VA inducibility by burst pacing was higher in db/db mice than db/+ mice with acute IR injury. Ranolazine suppressed VA inducibility and severity in db/db and db/+ mice. Optical mapping studies showed that ranolazine significantly shortened action potential duration (APD80), Cai transient duration (CaiTD80), Cai decay time, ameliorated conduction inhomogeneity, and suppressed arrhythmogenic alternans induction. The expression of pThr17-phospholamban, calsequestrin 2 and SCN5A in the IR zone was significantly downregulated in db/db mice, which was ameliorated by ranolazine. Conclusions: Ranolazine pretreatment shortens APD80 and CaiTD80, reduces Cai decay time, and ameliorates conduction velocity inhomogeneity to suppress induction of arrhythmogenic alternans and VA; and amelioration of downregulation of pThr17-phospholamban, calsequestrin 2 and SCN5A may partly underlie the anti-arrhythmic molecular mechanisms of ranolazine in db/db mouse hearts with IR injury.

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“…Ranolazine administration ameliorates conduction inhomogeneity in regional IR injury. Stud-ies have shown reduced cardiac conduction reserve in diabetic animal models[24][25][26] . Therefore, propagation of activity through the myocardium in diabetic hearts is more sensitive to conditions influencing cellular excitability or intercellular electrical coupling.…”

mentioning

confidence: 99%

Mechanisms of ranolazine pretreatment in preventing ventricular tachyarrhythmias in diabetic db/db mice with acute regional ischemia–reperfusion injury

Chou

Lee

Chang

et al. 2020

Sci Rep

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Studies have demonstrated that diabetic (db/db) mice have increased susceptibility to myocardial ischemia–reperfusion (IR) injury and ventricular tachyarrhythmias (VA). We aimed to investigate the antiarrhythmic and molecular mechanisms of ranolazine in db/db mouse hearts with acute IR injury. Ranolazine was administered for 1 week before coronary artery ligation. Diabetic db/db and control db/+ mice were divided into ranolazine-given and -nongiven groups. IR model was created by 15-min left coronary artery ligation and 10-min reperfusion. In vivo electrophysiological studies showed that the severity of VA inducibility was higher in db/db mice than control (db/ +) mice. Ranolazine suppressed the VA inducibility and severity. Optical mapping studies in Langendorff-perfused hearts showed that ranolazine significantly shortened action potential duration, Cai transient duration, Cai decay time, ameliorated conduction inhomogeneity, and suppressed arrhythmogenic alternans induction. Western blotting studies showed that the expression of pThr17-phospholamban, calsequestrin 2 and voltage-gated sodium channel in the IR zone was significantly downregulated in db/db mice, which was ameliorated with ranolazine pretreatment and might play a role in the anti-arrhythmic actions of ranolazine in db/db mouse hearts with IR injury.

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Roles of impaired intracellular calcium cycling in arrhythmogenicity of diabetic mouse model

Cited by 11 publications

References 33 publications

Proarrhythmic Remodeling of Calcium Homeostasis in Cardiac Disease; Implications for Diabetes and Obesity

Proarrhythmic Remodeling of Calcium Homeostasis in Cardiac Disease; Implications for Diabetes and Obesity

Mechanisms of Ranolazine Pretreatment in Preventing Ventricular Tachyarrhythmias in Diabetic db/db Mice with Acute Regional Ischemia-Reperfusion Injury

Mechanisms of ranolazine pretreatment in preventing ventricular tachyarrhythmias in diabetic db/db mice with acute regional ischemia–reperfusion injury

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