Hypernatremia and intercalated disc edema synergistically exacerbate long-QT syndrome type 3 phenotype

Abstract

Background: Cardiac voltage-gated sodium channel gain-of-function prolongs repolarization in the Long-QT Syndrome Type 3 (LQT3). Previous studies suggest that narrowing the perinexus within the intercalated disc, leading to rapid sodium depletion, attenuates LQT3-associated action potential duration (APD) prolongation. However, it remains unknown whether extracellular sodium concentration modulates APD prolongation during sodium channel gain-of-function. We hypothesized that elevated extracellular sodium concentration and widened perinexus synergistically prolong APD in LQT3. Methods and Results: LQT3 was induced with anemone toxin type II (ATXII) in Langendorff-perfused guinea pig hearts (n=20). Sodium concentration was increased from 145 to 160 mM. Perinexal expansion was induced with mannitol or the sodium channel β1-subunit adhesion domain antagonist (βadp1). Epicardial ventricular action potentials were optically mapped. Individual and combined effects of varying clefts and sodium concentrations were simulated in a computational model. With ATXII, both mannitol and βadp1 significantly widened the perinexus and prolonged APD, respectively. The elevated sodium concentration alone significantly prolonged APD as well. Importantly, the combination of elevated sodium concentration and perinexal widening synergistically prolonged APD. Computational modeling results were consistent with animal experiments. Conclusions: Concurrently elevating extracellular sodium and increasing intercalated disc edema prolongs repolarization more than the individual interventions alone in the LQT3. This synergistic effect suggests an important clinical implication that hypernatremia in the presence of cardiac edema can markedly increase LQT3-associated APD prolongation. Therefore, this is the first study to provide evidence of a tractable and effective strategy to mitigate LQT3 phenotype by managing patient sodium levels and preventing cardiac edema.

Epicardial adipose tissue as a mediator of cardiac arrhythmias

“…Along these lines, other inflammatory proteins such as vascular endothelial growth factor also disrupt gap junctions resulting in conduction slowing predisposing normal hearts to arrhythmias (137). Langendorff-perfused guinea pig heart preparations have also been used to investigate the effects of perinexal width variation on arrhythmia susceptibility and how this may be modulated by extracellular sodium and calcium concentrations experimentally (138)(139)(140). It is therefore possible that the inflammatory secretome of EAT may exert proarrhythmic effects by modulating both gap junction and ephaptic coupling.…”

Guidelines for assessment of cardiac electrophysiology and arrhythmias in small animals

“…In terms of species used, the majority of these studies (∼67%) used rodents, with approximately equal distribution between mice ( 23 – 33 ) and rats ( 34 – 42 ). Guinea pig ( 43 – 45 ) and porcine hearts ( 46 – 48 ) were each used in ∼10% of studies, followed by a small number of reports in rabbit ( 49 ), zebrafish ( 50 ), quail ( 51 ), and canine ( 52 ) hearts. Overall, there was good reporting of sex, age, and strain, yet only ∼30% of studies evaluated both male and female animals, whereas ∼40% exclusively reported data from male animals.…”

“…In terms of disease models, genetically modified mice ( 23 , 26 , 28 – 33 ) or specific rat strains (e.g., spontaneously hypertensive rat) ( 34 , 35 , 40 ) were most commonly assessed (∼37% of studies), and myocardial infarction, ischemia, or hypoxia were evaluated in ∼27% of studies ( 25 , 31 , 35 , 38 , 42 , 44 , 45 , 47 ). Around 16% of investigations used pharmacological modulation ( 24 , 43 , 49 , 50 , 52 ). A small number of studies investigated environmental effects [including herbicide ( 36 ), vaping ( 27 ), and alcohol ( 51 )], aging and development ( 25 , 28 , 41 ), nonischemic heart failure ( 39 ), and the remaining studies performed electrophysiological assessments in nondiseased hearts ( 37 , 46 , 48 ).…”

“…A small number of studies investigated environmental effects [including herbicide ( 36 ), vaping ( 27 ), and alcohol ( 51 )], aging and development ( 25 , 28 , 41 ), nonischemic heart failure ( 39 ), and the remaining studies performed electrophysiological assessments in nondiseased hearts ( 37 , 46 , 48 ). The most commonly used techniques to evaluate electrophysiological parameters and arrhythmia susceptibility were in vivo electrocardiogram (ECG) or electrode recordings in conscious or anesthetized animals (∼56% of studies) ( 23 – 28 , 30 , 32 , 36 , 38 , 40 – 42 , 46 – 48 , 52 ) or optical mapping in excised hearts or tissues (∼47% of studies) ( 27 , 30 , 31 , 33 – 35 , 39 , 41 , 43 – 45 , 49 – 51 ). The remaining studies used electrode-based or ECG recordings in excised hearts and tissues ( 24 , 25 , 29 , 31 , 32 , 35 , 40 , 41 , 50 ) or in vivo ECG telemetry ( 27 , 29 , 33 , 37 ), and often, a combination of multiple approaches were used to rigorously evaluate electrophysiological properties (including experiments in isolated cardiomyocytes, which are not covered in detail in these guidelines).…”

Demographic and Methodological Heterogeneity in Electrocardiogram Signals From Guinea Pigs

“…This lack of information can affect the candidacy of an animal model to predict human cardiovascular behavior as it relates to normal cardiac physiology, pathophysiology, or drug safety and efficacy testing. Guinea pigs have been used as a translational model for preclinical assessment of cardiac electrophysiology ( Greer-Short et al, 2017 ; Cooper et al, 2021 ; Wu et al, 2021 ) and arrhythmia susceptibility ( Woulfe et al, 2018 ), due in part to similarities in ionic currents, cardiac action potential shape, and the influence of excitation-contraction coupling ( Luo and Rudy, 1994 ; Bers, 2000 ; Edwards and Louch, 2017 ). Indeed, a validation study reported that guinea pig models have a high level of specificity and sensitivity in predicting clinical outcomes to reference compounds known to widen the QRS complex, lengthen QT duration, or precipitate heart block ( Guo et al, 2009 ).…”