Conditional Up-Regulation of SERCA2a Exacerbates RyR2-Dependent Ventricular and Atrial Arrhythmias

Liu, Bin; Lou, Qing; Smith, Heather N.; Velez-Cortes, Florencia; Dillmann, Wolfgang H.; Knollmann, Björn C.; Armoundas, Antonis A.; Györke, Sándor

doi:10.3390/ijms21072535

Cited by 11 publications

(4 citation statements)

References 56 publications

(85 reference statements)

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“…High level of SR Ca 2+ leak triggered by increased RyR2, together with upregulated NCX, could contribute to the pathogenesis of AF ( 37 ). Acute upregulation of SERCA2a by doxycycline in the setting of hyperactive RyR2 exacerbates dysregulated myocyte Ca 2+ handling and arrhythmogenesis in both ventricular and atrial myocardium in rodent model ( 38 ). However, overexpression of SERCA2a could suppress ERP shortening and AF induced by rapid pacing atrium in rabbit model ( 39 ).…”

Section: Discussionmentioning

confidence: 99%

Effect of angiotensin receptor-neprilysin inhibitor on atrial electrical instability in atrial fibrillation

Zhu

Zhang

Yang

et al. 2022

Front. Cardiovasc. Med.

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Background and objectiveAround 33.5 million patients suffered from atrial fibrillation (AF), causing complications and increasing mortality and disability rate. Upstream treatment for AF is getting more popular in clinical practice in recent years. The angiotensin receptor-neprilysin inhibitor (ARNI) is one of the potential treatment options. Our study aimed to investigate the effect of ARNI on atrial electrical instability and structural remodeling in AF.MethodsOur research consisted of two parts – a retrospective real-world clinical study and an animal experiment on calmness to verify the retrospective founding. In the retrospective study, we reviewed all patients (n = 110) who had undergone the first AF ablation from 1 August 2018 to 1 March 2022. Patients with ARNI (n = 36) or angiotensin II receptor antagonist (ARB) (n = 35) treatment were enrolled. Their clinical data, ultrasound cardiogram (UCG) and Holter parameters were collected before radiofrequency catheter ablation (RFCA) as baseline and at 24-week follow-up. Univariate and multivariate logistic regression analysis were performed. In the animal experiment, we established an AF model (n = 18) on canines by rapid atrial pacing. After the successful procedure of pacing, all the 15 alive beagles were equally and randomly assigned to three groups (n = 5 each): Control group, ARB group, and ARNI group. UCG was performed before the pacing as baseline. Physiological biopsy, UCG, and electrophysiological study (EPS) were performed at 8-week.ResultsClinical data showed that the atrial arrhythmia rate at 24-week was significantly lower in ARNI group compared to ARB group (P < 0.01), and ARNI was independently associated with a lower atrial arrhythmia rate (P < 0.05) at 24-week in multivariate regression logistic analysis. In the animal experiment, ARNI group had a higher atrial electrical stability score and a shorter AF duration in the EPS compared to Control and ARB group (P < 0.05). In the left atrium voltage mapping, ARNI group showed less low voltage and disordered zone compared to Control and ARB group. Compared to Control group, right atrium diameter (RAD), left ventricle end-diastolic volume index (LVEDVI), E/A, and E/E′ were lower in ARNI group (P < 0.05) at the 8-weeks follow-up, while left atrium ejection fraction (LAEF) and left ventricle ejection fraction (LVEF) were higher (P < 0.01). Compared to ARB group, LVEF was higher in ARNI group at the 8-week follow-up (P < 0.05). ARB and ARNI group had a lower ratio of fibrotic lesions in the left atrium tissues compared to Control group (P < 0.01), but no difference was found between the ARB and the ARNI group.ConclusionARNI could reduce atrial electrical instability in AF in comparison with ARB in both retrospective study and animal experiment.

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Section: Discussionmentioning

confidence: 99%

Effect of angiotensin receptor-neprilysin inhibitor on atrial electrical instability in atrial fibrillation

Zhu

Zhang

Yang

et al. 2022

Front. Cardiovasc. Med.

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“…While these results clearly demonstrate a detrimental effect, the severe cardiomyopathy phenotype due to chronic SERCA overexpression masks the effect of the genetic manipulation on arrhythmias. A follow-up study from the same group conditionally overexpressed SERCA2a in the same CASQ2 KO mice and found that both atrial and ventricular arrhythmias were exacerbated due to acute upregulation of SERCA activity [75]. In contrast, in another study employing a different CPVT model of RyR2 knock in mouse (R4496C +/− ), upregulation of SERCA activity by knocking out its inhibitor PLN suppressed arrhythmias in vivo.…”

Section: Cellular Arrhythmogenesis: Sr Ca Loadmentioning

confidence: 98%

Molecular Mechanism and Current Therapies for Catecholaminergic Polymorphic Ventricular Tachycardia

Liu¹,

Tow²,

Bonilla³

2022

Cardiac Arrhythmias - Translational Approach From Pathophysiology to Advanced Care

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The rhythmic contraction of the heart relies on tightly regulated calcium (Ca) release from the sarcoplasmic reticulum (SR) Ca release channel, Ryanodine receptor (RyR2). Genetic mutations in components of the calcium release unit such as RyR2, cardiac calsequestrin and other proteins have been shown to cause a genetic arrhythmic syndrome known as catecholaminergic polymorphic ventricular tachycardia (CPVT). This book chapter will focus on the following: (1) to describing CPVT as a stress-induced cardiac arrhythmia syndrome and its genetic causes. (2) Discussing the regulation of SR Ca release, and how dysregulation of Ca release contributes to arrhythmogenesis. (3) Discussing molecular mechanisms of CPVT with a focus on impaired Ca signaling refractoriness as a unifying mechanism underlying different genetic forms of CPVT. (4) Discussing pharmacological approaches as CPVT treatments as well as other potential future therapies. Since dysregulated SR Ca release has been implicated in multiple cardiac disorders including heart failure and metabolic heart diseases, knowledge obtained from CPVT studies will also shed light on the development of therapeutic approaches for these devastating cardiac dysfunctions as a whole.

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“…In fact, the acceleration of Ca 2+ uptake has been shown to promote rather than prevent arrhythmias attributable to SR overload. 14 In this context, an additional aim of this work is to gain insight into this mechanistic aspect by comparing the effects promoted by istaroxime and ouabain in cardiomyocytes lacking phospholamban (phospholamban‐knockout myocytes).…”

mentioning

confidence: 99%

Cellular Mechanisms Underlying the Low Cardiotoxicity of Istaroxime

Racioppi

Burgos

Morell

et al. 2021

JAHA

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Background Istaroxime is an inhibitor of Na + /K + ATPase with proven efficacy to increase cardiac contractility and to accelerate relaxation attributable to a relief in phospholamban‐dependent inhibition of the sarcoplasmic reticulum Ca 2+ ATPase. We have previously shown that pharmacologic Na + /K + ATPase inhibition promotes calcium/calmodulin‐dependent kinase II activation, which mediates both cardiomyocyte death and arrhythmias. Here, we aim to compare the cardiotoxic effects promoted by classic pharmacologic Na + /K + ATPase inhibition versus istaroxime. Methods and Results Ventricular cardiomyocytes were treated with ouabain or istaroxime at previously tested equi‐inotropic concentrations to compare their impact on cell viability, apoptosis, and calcium/calmodulin‐dependent kinase II activation. In contrast to ouabain, istaroxime neither promoted calcium/calmodulin‐dependent kinase II activation nor cardiomyocyte death. In addition, we explored the differential behavior promoted by ouabain and istaroxime on spontaneous diastolic Ca 2+ release. In rat cardiomyocytes, istaroxime did not significantly increase Ca 2+ spark and wave frequency but increased the proportion of aborted Ca 2+ waves. Further insight was provided by studying cardiomyocytes from mice that do not express phospholamban. In this model, the lower Ca 2+ wave incidence observed with istaroxime remains present, suggesting that istaroxime‐dependent relief on phospholamban‐dependent sarcoplasmic reticulum Ca 2+ ATPase 2A inhibition is not the unique mechanism underlying the low arrhythmogenic profile of this drug. Conclusions Our results indicate that, different from ouabain, istaroxime can reach a significant inotropic effect without leading to calcium/calmodulin‐dependent kinase II–dependent cardiomyocyte death. Additionally, we provide novel insights regarding the low arrhythmogenic impact of istaroxime on cardiac Ca 2+ handling.

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Conditional Up-Regulation of SERCA2a Exacerbates RyR2-Dependent Ventricular and Atrial Arrhythmias

Cited by 11 publications

References 56 publications

Effect of angiotensin receptor-neprilysin inhibitor on atrial electrical instability in atrial fibrillation

Effect of angiotensin receptor-neprilysin inhibitor on atrial electrical instability in atrial fibrillation

Molecular Mechanism and Current Therapies for Catecholaminergic Polymorphic Ventricular Tachycardia

Cellular Mechanisms Underlying the Low Cardiotoxicity of Istaroxime

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