The Significance of the Late Na+ Current for Arrhythmia Induction and the Therapeutic Antiarrhythmic Potential of Ranolazine

Mason, Fleur E.; Sossalla, Samuel

doi:10.1177/1074248416644989

Cited by 6 publications

(2 citation statements)

References 129 publications

(216 reference statements)

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“…Greater intracellular Ca 2+ leak, together with increased NCX1 function, promotes the aforementioned DADs, which have the potential to trigger extrasystolic activity [118]. Intracellular Ca 2+ overload, secondary to intracellular Na + overload, also leads to this type of activity, as previously reviewed [80].…”

Section: Abnormal Ca 2+ Handling Contributes To Initiation and Maintementioning

confidence: 83%

Cellular and mitochondrial mechanisms of atrial fibrillation

et al. 2020

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The molecular mechanisms underlying atrial fibrillation (AF), the most common form of arrhythmia, are poorly understood and therefore target-specific treatment options remain an unmet clinical need. Excitation–contraction coupling in cardiac myocytes requires high amounts of adenosine triphosphate (ATP), which is replenished by oxidative phosphorylation in mitochondria. Calcium (Ca2+) is a key regulator of mitochondrial function by stimulating the Krebs cycle, which produces nicotinamide adenine dinucleotide for ATP production at the electron transport chain and nicotinamide adenine dinucleotide phosphate for the elimination of reactive oxygen species (ROS). While it is now well established that mitochondrial dysfunction plays an important role in the pathophysiology of heart failure, this has been less investigated in atrial myocytes in AF. Considering the high prevalence of AF, investigating the role of mitochondria in this disease may guide the path towards new therapeutic targets. In this review, we discuss the importance of mitochondrial Ca2+ handling in regulating ATP production and mitochondrial ROS emission and how alterations, particularly in these aspects of mitochondrial activity, may play a role in AF. In addition to describing research advances, we highlight areas in which further studies are required to elucidate the role of mitochondria in AF.

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Section: Abnormal Ca 2+ Handling Contributes To Initiation and Maintementioning

confidence: 83%

Cellular and mitochondrial mechanisms of atrial fibrillation

et al. 2020

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“…12, 13 Inhibition of late INa by ranolazine has been reported to attenuate AP prolongation, intracellular Ca 2+ overload, dynamic instability and regional heterogeneity of electrical activity, as well as arrhythmia in a wide variety of models in which late INa was increased by heart failure, exposure to reactive oxygen species or toxins, mutations of SCN5A and activation of CaMKII. 8,15- 17 We hypothesized that if late INa-mediated arrhythmogenic activities contribute to the maintenance of acute ischemia-induced ventricular tachyarrhythmia, then ranolazine should terminate ischemic VT/VF. In the present study, we investigated the effects of ranolazine on VT/VF induced in isolated rabbit hearts with regional ventricular ischemia by quantitative analysis of optical mapping data.…”

Section: Assessment Of Ischemia-dependent Electrophysiological Changesmentioning

confidence: 99%

Ranolazine Facilitates Termination of Ventricular Tachyarrhythmia Associated With Acute Myocardial Ischemia Through Suppression of Late INa-Mediated Focal Activity

Ogawa

Honjo

Yamazaki

et al. 2017

Circ J

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of Na + channel inactivation, may contribute to arrhythmogenesis in a variety of pathological conditions. 7-10 Late INa is small in normal cardiac myocytes and is enhanced by heart failure, exposure to oxidative stress, hypoxia and ischemia/reperfusion. 7-10 Late INa during the action potential (AP) plateau reduces repolarization reserve and may prolong AP duration (APD), which renders the membrane potential vulnerable for early afterdepolarization (EAD). In addition, increased late INa-dependent sarcolemmal Na + entry leads to intracellular Na + accumulation, which in turn produces Ca 2+ overload by reduced cellular Ca 2+ extrusion and increased Ca 2+ entry via the Na + /Ca 2+ exchanger. Ca 2+ overload is associated with increased diastolic Ca 2+ leak from the sarcoplasmic reticulum resulting in delayed afterdepolarization (DAD). 11 Moreover, Ca 2+ overload activates Ca 2+ /calmodulin-dependent protein kinase II (CaMKII), which enhances late INa. 9,11 Thus, such a late INa-mediated positive feedback loop might make a profound contribution V entricular tachyarrhythmia, including sustained ventricular tachycardia/fibrillation (VT/VF), associated with acute myocardial ischemia, is the most common immediate cause of sudden cardiac death. 1 In Japan, arrhythmic mortality in patients with acute myocardial infarction is approximately 14%, and the prevalence of coronary artery disease is increasing in step with the rapid aging of the population. 2,3 Although percutaneous coronary interventions have been well established as an effective first-line therapy for acute myocardial infarction, therapeutic strategy for ischemia-associated lethal ventricular arrhythmia remains to be developed.Acute myocardial ischemia is known to cause various changes in the electrophysiological characteristics of ventricular myocardium, and precise mechanisms of acute ischemia-associated arrhythmia are incompletely understood. 4-6 A number of recent reports suggest that late Na + current (INa), which is generated by dysfunctional regulation Background: Ventricular tachycardia/fibrillation (VT/VF) associated with acute myocardial ischemia is the most common cause of sudden cardiac death, but its underlying mechanisms are incompletely understood. It is hypothesized that late Na + current (INa) contributes to arrhythmogenic activity in ischemic myocardium.

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Reduction of SR Ca2+ leak and arrhythmogenic cellular correlates by SMP-114, a novel CaMKII inhibitor with oral bioavailability

et al. 2017

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Sarcoplasmic reticulum (SR) Ca leak induced by Ca/calmodulin-dependent protein kinase II (CaMKII) is centrally involved in atrial and ventricular arrhythmogenesis as well as heart failure remodeling. Consequently, treating SR Ca leak has been proposed as a novel therapeutic paradigm, but compounds for use in humans are lacking. SMP-114 ("Rimacalib") is a novel, orally available CaMKII inhibitor developed for human use that has already entered clinical phase II trials to treat rheumatoid arthritis. We speculated that SMP-114 might also be useful to treat cardiac SR Ca leak. SMP-114 significantly reduces SR Ca leak (as assessed by Ca sparks) in human atrial (0.72 ± 0.33 sparks/100 µm/s vs. control 3.02 ± 0.91 sparks/100 µm/s) and failing left ventricular (0.78 ± 0.23 vs. 1.69 ± 0.27 sparks/100 µm/s) as well as in murine ventricular cardiomyocytes (0.30 ± 0.07 vs. 1.50 ± 0.28 sparks/100 µm/s). Associated with lower SR Ca leak, we found that SMP-114 suppressed the occurrence of spontaneous arrhythmogenic spontaneous Ca release (0.356 ± 0.109 vs. 0.927 ± 0.216 events per 30 s stimulation cessation). In consequence, post-rest potentiation of Ca-transient amplitude (measured using Fura-2) during the 30 s pause was improved by SMP-114 (52 ± 5 vs. 37 ± 4%). Noteworthy, SMP-114 has these beneficial effects without negatively impairing global excitation-contraction coupling: neither systolic Ca release nor single cell contractility was compromised, and also SR Ca reuptake, in line with resulting cardiomyocyte relaxation, was not impaired by SMP-114 in our assays. SMP-114 demonstrated potential to treat SR Ca leak and consequently proarrhythmogenic events in rodent as well as in human atrial cardiomyocytes and cardiomyocytes from patients with heart failure. Further research is necessary towards clinical use in cardiac disease.

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The Significance of the Late Na⁺ Current for Arrhythmia Induction and the Therapeutic Antiarrhythmic Potential of Ranolazine

Cited by 6 publications

References 129 publications

Cellular and mitochondrial mechanisms of atrial fibrillation

Cellular and mitochondrial mechanisms of atrial fibrillation

Ranolazine Facilitates Termination of Ventricular Tachyarrhythmia Associated With Acute Myocardial Ischemia Through Suppression of Late <b><i>I</i></b><sub>Na</sub>-Mediated Focal Activity

Reduction of SR Ca2+ leak and arrhythmogenic cellular correlates by SMP-114, a novel CaMKII inhibitor with oral bioavailability

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