Functional identification of hot-spot mutations in cardiac calcium channel genes associated with the J wave syndromes

Zeng, Bin; Zhang, Xiang; Schimpf, Rainer; Powers, Andrew S.; Glikson, Michael; Antzelevitch, Charles; Hu, Dan; Barajas-Martínez, Héctor

doi:10.1098/rstb.2022.0286

Cited by 3 publications

(3 citation statements)

References 43 publications

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“…Third, similarly inward and depolarization-activated Cav1.2-mediated I Ca may initiate APs in the SAN and AVN besides prolonging atrial and ventricular phase 2 plateau activation. Their loss-of-function mutations, recently exemplified by CACNB2b-S143F and CACNA1C-G37R ( Zeng et al, 2023 ), resemble those involving Nav1.5 with pro-arrhythmic phenotypes accompanied by J wave syndromes ( Huang, 2017 ).…”

Section: Ion Channels Underlying Normal and Abnormal Rhythmic Activitymentioning

confidence: 99%

Cardiac arrhythmogenesis: roles of ion channels and their functional modification

Lei,

Salvage,

Jackson

et al. 2024

Front. Physiol.

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Cardiac arrhythmias cause significant morbidity and mortality and pose a major public health problem. They arise from disruptions in the normally orderly propagation of cardiac electrophysiological activation and recovery through successive cardiomyocytes in the heart. They reflect abnormalities in automaticity, initiation, conduction, or recovery in cardiomyocyte excitation. The latter properties are dependent on surface membrane electrophysiological mechanisms underlying the cardiac action potential. Their disruption results from spatial or temporal instabilities and heterogeneities in the generation and propagation of cellular excitation. These arise from abnormal function in their underlying surface membrane, ion channels, and transporters, as well as the interactions between them. The latter, in turn, form common regulatory targets for the hierarchical network of diverse signaling mechanisms reviewed here. In addition to direct molecular-level pharmacological or physiological actions on these surface membrane biomolecules, accessory, adhesion, signal transduction, and cytoskeletal anchoring proteins modify both their properties and localization. At the cellular level of excitation–contraction coupling processes, Ca2+ homeostatic and phosphorylation processes affect channel activity and membrane excitability directly or through intermediate signaling. Systems-level autonomic cellular signaling exerts both acute channel and longer-term actions on channel expression. Further upstream intermediaries from metabolic changes modulate the channels both themselves and through modifying Ca2+ homeostasis. Finally, longer-term organ-level inflammatory and structural changes, such as fibrotic and hypertrophic remodeling, similarly can influence all these physiological processes with potential pro-arrhythmic consequences. These normal physiological processes may target either individual or groups of ionic channel species and alter with particular pathological conditions. They are also potentially alterable by direct pharmacological action, or effects on longer-term targets modifying protein or cofactor structure, expression, or localization. Their participating specific biomolecules, often clarified in experimental genetically modified models, thus constitute potential therapeutic targets. The insights clarified by the physiological and pharmacological framework outlined here provide a basis for a recent modernized drug classification. Together, they offer a translational framework for current drug understanding. This would facilitate future mechanistically directed therapeutic advances, for which a number of examples are considered here. The latter are potentially useful for treating cardiac, in particular arrhythmic, disease.

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Section: Ion Channels Underlying Normal and Abnormal Rhythmic Activitymentioning

confidence: 99%

Cardiac arrhythmogenesis: roles of ion channels and their functional modification

Lei,

Salvage,

Jackson

et al. 2024

Front. Physiol.

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“…Notably, ERP exhibits a higher prevalence in physically active individuals, reported as reaching 33.9% [145]. Research on ERS consistently indicated a higher prevalence among men [153][154][155][156][157] and a younger age at diagnosis [154,156]. Identified independent risk factors associated with ERP include younger age, male gender, lower systolic blood pressure (SBP), shorter QRS duration, a shorter QTc interval, and hypothermia [145,146,151].…”

Section: Managementmentioning

confidence: 99%

Primary Electrical Heart Disease—Principles of Pathophysiology and Genetics

Badura,

Buławska,

Dąbek

et al. 2024

IJMS

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Primary electrical heart diseases, often considered channelopathies, are inherited genetic abnormalities of cardiomyocyte electrical behavior carrying the risk of malignant arrhythmias leading to sudden cardiac death (SCD). Approximately 54% of sudden, unexpected deaths in individuals under the age of 35 do not exhibit signs of structural heart disease during autopsy, suggesting the potential significance of channelopathies in this group of age. Channelopathies constitute a highly heterogenous group comprising various diseases such as long QT syndrome (LQTS), short QT syndrome (SQTS), idiopathic ventricular fibrillation (IVF), Brugada syndrome (BrS), catecholaminergic polymorphic ventricular tachycardia (CPVT), and early repolarization syndromes (ERS). Although new advances in the diagnostic process of channelopathies have been made, the link between a disease and sudden cardiac death remains not fully explained. Evolving data in electrophysiology and genetic testing suggest previously described diseases as complex with multiple underlying genes and a high variety of factors associated with SCD in channelopathies. This review summarizes available, well-established information about channelopathy pathogenesis, genetic basics, and molecular aspects relative to principles of the pathophysiology of arrhythmia. In addition, general information about diagnostic approaches and management is presented. Analyzing principles of channelopathies and their underlying causes improves the understanding of genetic and molecular basics that may assist general research and improve SCD prevention.

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“…Zeng et al . [ 72 ] associate variants of pro-arrhythmic J wave syndromes, also found with loss of Nav1.5 function, with loss of Ca 2+ channel function, CACNB2b-S143F and CACNA1C-G37R , mutations. AP repolarization ultimately restoring the resting potential is driven by a range of outward K + currents ( figure 2 b ) [ 23 , 73 ], for which a wide range of new K + channel subtypes have been described [ 73 – 77 ].…”

Section: Ion Channels Contributing To Cardiomyocyte Surface Membrane ...mentioning

confidence: 99%

Cardiomyocyte electrophysiology and its modulation: current views and future prospects

Huang

Lei

2023

Phil. Trans. R. Soc. B

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Normal and abnormal cardiac rhythms are of key physiological and clinical interest. This introductory article begins from Sylvio Weidmann's key historic 1950s microelectrode measurements of cardiac electrophysiological activity and Singh & Vaughan Williams's classification of cardiotropic targets. It then proceeds to introduce the insights into cardiomyocyte function and its regulation that subsequently emerged and their therapeutic implications. We recapitulate the resulting view that surface membrane electrophysiological events underlying cardiac excitation and its initiation, conduction and recovery constitute the final common path for the cellular mechanisms that impinge upon this normal or abnormal cardiac electrophysiological activity. We then consider progress in the more recently characterized successive regulatory hierarchies involving Ca 2+ homeostasis, excitation–contraction coupling and autonomic G-protein signalling and their often reciprocal interactions with the surface membrane events, and their circadian rhythms. Then follow accounts of longer-term upstream modulation processes involving altered channel expression, cardiomyocyte energetics and hypertrophic and fibrotic cardiac remodelling. Consideration of these developments introduces each of the articles in this Phil. Trans. B theme issue. The findings contained in these articles translate naturally into recent classifications of cardiac electrophysiological targets and drug actions, thereby encouraging future iterations of experimental cardiac electrophysiological discovery, and testing directed towards clinical management. This article is part of the theme issue ‘The heartbeat: its molecular basis and physiological mechanisms’.

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Functional identification of hot-spot mutations in cardiac calcium channel genes associated with the J wave syndromes

Cited by 3 publications

References 43 publications

Cardiac arrhythmogenesis: roles of ion channels and their functional modification

Cardiac arrhythmogenesis: roles of ion channels and their functional modification

Primary Electrical Heart Disease—Principles of Pathophysiology and Genetics

Cardiomyocyte electrophysiology and its modulation: current views and future prospects

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