Heterogeneity of the action potential duration is required for sustained atrial fibrillation

Avula, Uma Mahesh R.; Abrams, Jeffrey S.; Katchman, Alexander N.; Zakharov, Sergey I.; Mironov, Sergey V.; Bayne, Joseph; Roybal, Daniel; Gorti, Anirudh; Yang, Lin; Iyer, Vivek; Waase, Marc; Saluja, Deepak; Ciaccio, Edward J.; Garan, Hasan; Marks, Andrew R.; Marx, Steven O.; Wan, Elaine

doi:10.1172/jci.insight.128765

Cited by 20 publications

(23 citation statements)

References 30 publications

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“…In the F1759A mutant mice, we observed APD prolongation ( Figure 3, E and F ). As we have previously described for the atria ( 5 , 30 ), there was considerable heterogeneity in the APD, likely caused by the variable expression of the F1759A-Na + channels. In contrast, the IQ/AA transgenic mice had uniformly normal ventricular repolarization ( Figure 3, F and G ).…”

Section: Resultsmentioning

confidence: 60%

“…Epicardial surface optical voltage mapping of the anterior surface of Langendorff-perfused IQ/AA and F1759A-NaV1.5 hearts was used to assess ventricular repolarization ( Figure 3, E–G ). As we have done previously ( 29 ), the Langendorff apparatus–mounted hearts were perfused with a hyperkalemic solution to terminate the spontaneous arrhythmias in order to elucidate the underlying electrophysiologic substrate. Thereafter, a normokalemic solution was infused, and the ventricular APD was assessed.…”

Section: Resultsmentioning

confidence: 99%

“…In cardiomyocytes, late Na + current caused by delayed or incomplete inactivation of Na V 1.5 channels underlies diverse cardiac disorders. Our previous studies using a transgenic Na V 1.5 F1759A mutant channel illustrated the contribution of late current for cardiac disease pathogenesis ( 5 , 30 ). Although diminutive compared with the peak Na + current that initiates the cardiac action potential, the depolarizing late current counteracts repolarization, resulting in heterogenous action potential prolongation that may trigger atrial ( 5 ) or ventricular arrhythmias ( Figure 3 ).…”

Section: Discussionmentioning

confidence: 98%

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Fibroblast growth factor homologous factors tune arrhythmogenic late NaV1.5 current in calmodulin binding–deficient channels

Abrams¹,

Roybal²,

Chakouri³

et al. 2020

JCI Insight

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The Ca 2+ -binding protein calmodulin has emerged as a pivotal player in tuning Na + channel function, although its impact in vivo remains to be resolved. Here, we identify the role of calmodulin and the Na V 1.5 interactome in regulating late Na + current in cardiomyocytes. We created transgenic mice with cardiac-specific expression of human Na V 1.5 channels with alanine substitutions for the IQ motif (IQ/AA). The mutations rendered the channels incapable of binding calmodulin to the C-terminus. The IQ/AA transgenic mice exhibited normal ventricular repolarization without arrhythmias and an absence of increased late Na + current. In comparison, transgenic mice expressing a lidocaine-resistant (F1759A) human Na V 1.5 demonstrated increased late Na + current and prolonged repolarization in cardiomyocytes, with spontaneous arrhythmias. To determine regulatory factors that prevent late Na + current for the IQ/AA mutant channel, we considered fibroblast growth factor homologous factors (FHFs), which are within the Na V 1.5 proteomic subdomain shown by proximity labeling in transgenic mice expressing Na V 1.5 conjugated to ascorbate peroxidase. We found that FGF13 diminished late current of the IQ/AA but not F1759A mutant cardiomyocytes, suggesting that endogenous FHFs may serve to prevent late Na + current in mouse cardiomyocytes. Leveraging endogenous mechanisms may furnish an alternative avenue for developing novel pharmacology that selectively blunts late Na + current.

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Section: Resultsmentioning

confidence: 60%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 98%

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Fibroblast growth factor homologous factors tune arrhythmogenic late NaV1.5 current in calmodulin binding–deficient channels

Abrams¹,

Roybal²,

Chakouri³

et al. 2020

JCI Insight

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“…Re-entry anchor location and driver formation may also depend on electrophysiology, conduction velocity dynamics, cardiac wavelength and anisotropy. 52,[121][122][123][124] approach that aims to streamline activation patterns. 127 Roney et al…”

Section: Differentiating Between Mechanisms Using Limited Data and Inmentioning

confidence: 99%

Challenges Associated with Interpreting Mechanisms of AF

Roney

Wit

Peters

2020

Arrhythm Electrophysiol Rev

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Determining optimal treatment strategies for complex arrhythmogenesis in AF is confounded by the lack of consensus regarding the mechanisms causing AF. Studies report different mechanisms for AF, ranging from hierarchical drivers to anarchical multiple activation wavelets. Differences in the assessment of AF mechanisms are likely due to AF being recorded across diverse models using different investigational tools, spatial scales and clinical populations. The authors review different AF mechanisms, including anatomical and functional re-entry, hierarchical drivers and anarchical multiple wavelets. They then describe different cardiac mapping techniques and analysis tools, including activation mapping, phase mapping and fibrosis identification. They explain and review different data challenges, including differences between recording devices in spatial and temporal resolutions, spatial coverage and recording surface, and report clinical outcomes using different data modalities. They suggest future research directions for investigating the mechanisms underlying human AF.

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“…Epidemiologic observations report a 5% increase in risk of atrial fibrillation (AF) per each unit increase in body mass index (BMI) [ 2 , 25 , 54 ]. There are data from humans and mouse models supporting the idea that increased heterogeneity of atrial repolarization contributes to the increased risk of AF [ 55 ].…”

Section: Cardiac Abnormalities Caused By Diet-induced Obesity (Diomentioning

confidence: 99%

Mechanisms of Chronic Metabolic Stress in Arrhythmias

et al. 2020

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Cardiac arrhythmias are responsible for many cardiovascular disease-related deaths worldwide. While arrhythmia pathogenesis is complex, there is increasing evidence for metabolic causes. Obesity, diabetes, and chronically consuming high-fat foods significantly increase the likelihood of developing arrhythmias. Although these correlations are well established, mechanistic explanations connecting a high-fat diet (HFD) to arrhythmogenesis are incomplete, although oxidative stress appears to be critical. This review investigates the metabolic changes that occur in obesity and after HFD. Potential therapies to prevent or treat arrhythmias are discussed, including antioxidants.

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Heterogeneity of the action potential duration is required for sustained atrial fibrillation

Cited by 20 publications

References 30 publications

Fibroblast growth factor homologous factors tune arrhythmogenic late NaV1.5 current in calmodulin binding–deficient channels

Fibroblast growth factor homologous factors tune arrhythmogenic late NaV1.5 current in calmodulin binding–deficient channels

Challenges Associated with Interpreting Mechanisms of AF

Mechanisms of Chronic Metabolic Stress in Arrhythmias

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