Transmural APD gradient synchronizes repolarization in the human left ventricular wall

Boukens, Bastiaan J.; Sulkin, Matthew S.; Gloschat, Chris; Ng, Fu Siong; Vigmond, Edward J.; Efimov, Igor R.

doi:10.1093/cvr/cvv202

Cited by 53 publications

(46 citation statements)

References 37 publications

(47 reference statements)

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“…This technique has been extensively used by others in wedges from explanted human hearts 17, 18, 19, 20, 21, 22. Briefly, wedges of porcine myocardium were dissected from the mid apico‐basal region adjacent to the anterior infarct, a region known to support post‐MI arrhythmias.…”

Section: Methodsmentioning

confidence: 99%

Primary Effect of SERCA2a Gene Transfer on Conduction Reserve in Chronic Myocardial Infarction

Motloch

Cacheux

Ishikawa

et al. 2018

JAHA

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Background SERCA2a gene transfer (GT) improves mechano‐electrical function in animal models of nonischemic heart failure Whether SERCA2a GT reverses pre‐established remodeling at an advanced stage of ischemic heart failure is unclear. We sought to uncover the electrophysiological effects of adeno‐associated virus serotype 1.SERCA2a GT following myocardial infarction (MI).Methods and ResultsPigs developed mechanical dysfunction 1 month after anterior MI, at which point they received intracoronary adeno‐associated virus serotype 1.SERCA2a (MI+SERCA2a) or saline (MI) and were maintained for 2 months. Age‐matched naive pigs served as controls (Control). In vivo ECG‐and‐hemodynamic properties were assessed before and after dobutamine stress. The electrophysiological substrate was measured using optical action potential (AP) mapping in controls, MI, and MI+SERCA2a preparations. In vivo ECG measurements revealed comparable QT durations between groups. In contrast, prolonged QRS duration and increased frequency of R′ waves were present in MI but not MI+SERCA2a pigs relative to controls. SERCA2a GT reduced in in vivo arrhythmias in response to dobutamine. Ex vivo preparations from MI but not MI+SERCA2a or control pigs were prone to pacing‐induced ventricular tachycardia and fibrillation. Underlying these arrhythmias was pronounced conduction velocity slowing in MI versus MI+SERCA2a at elevated rates leading to ventricular tachycardia and fibrillation. Reduced susceptibility to ventricular tachycardia and fibrillation in MI+SERCA2a pigs was not related to hemodynamic function, contractile reserve, fibrosis, or the expression of Cx43 and Nav1.5. Rather, SERCA2a GT decreased phosphoactive CAMKII‐delta levels by >50%, leading to improved excitability at fast rates.Conclusions SERCA2a GT increases conduction velocity reserve, likely by preventing CAMKII overactivation. Our findings suggest a primary effect of SERCA2a GT on myocardial excitability, independent of altered mechanical function.

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Section: Methodsmentioning

confidence: 99%

Primary Effect of SERCA2a Gene Transfer on Conduction Reserve in Chronic Myocardial Infarction

Motloch

Cacheux

Ishikawa

et al. 2018

JAHA

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“…Other studies using optical and electrical mapping have demonstrated that the transmural repolarization gradient is small and cannot entirely account for the duration of the T-wave (Anyukhovsky et al, 1999;Boukens et al, 2015;Janse et al, 2011;Meijborg et al, 2014;Rodriguez-Sinovas et al, 1997). Furthermore, recent studies in human left ventricular wedge preparations did not show a subpopulation of M-cells Glukhov et al, 2012;Glukhov et al, 2010;Ng et al, 2014).…”

Section: Transmural Gradients In Repolarization: Where Are the M-cells?mentioning

confidence: 96%

Transmural electrophysiological heterogeneity, the T-wave and ventricular arrhythmias

Boukens

Walton

Meijborg

et al. 2016

Progress in Biophysics and Molecular Biology

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“…While access to animal tissues is typically plentiful, the availability of human cardiac samples is limited. When available, human tissues have typically been limited to fixed or frozen samples or very small amounts of fresh and viable tissues which were obtained from surgical discards (Boukens et al, 2015; Jost et al, 2005, 2013; Brandenburger et al, 2015; Näbauer, Beuckelmann, Überfuhr, & Steinbeck, 1996; Näbauer & Kääb, 1998; Wettwer et al, 1993; Wettwer, Amos, Posival, & Ravens, 1994). However, in the past, tissue recovery procedures, as well as tissue quality and quantity have been extremely variable, resulting in an unreliable source for robust and reproducible drug safety data.…”

Section: Introductionmentioning

confidence: 99%

Human ex-vivo action potential model for pro-arrhythmia risk assessment

Page

Ratchada

Miron

et al. 2016

Journal of Pharmacological and Toxicological Methods

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While current S7B/E14 guidelines have succeeded in protecting patients from QT-prolonging drugs, the absence of a predictive paradigm identifying pro-arrhythmic risks has limited the development of valuable drug programs. We investigated if a human ex-vivo action potential (AP)-based model could provide a more predictive approach for assessing pro-arrhythmic risk in man. Human ventricular trabeculae from ethically consented organ donors were used to evaluate the effects of dofetilide, d,l-sotalol, quinidine, paracetamol and verapamil on AP duration (APD) and recognized pro-arrhythmia predictors (short-term variability of APD at 90% repolarization (STV(APD90)), triangulation (ADP90-APD30) and incidence of early afterdepolarizations at 1 and 2 Hz to quantitatively identify the pro-arrhythmic risk. Each drug was blinded and tested separately with 3 concentrations in triplicate trabeculae from 5 hearts, with one vehicle time control per heart. Electrophysiological stability of the model was not affected by sequential applications of vehicle (0.1% dimethyl sulfoxide). Paracetamol and verapamil did not significantly alter anyone of the AP parameters and were classified as devoid of pro-arrhythmic risk. Dofetilide, d,l-sotalol and quinidine exhibited an increase in the manifestation of pro-arrhythmia markers. The model provided quantitative and actionable activity flags and the relatively low total variability in tissue response allowed for the identification of pro-arrhythmic signals. Power analysis indicated that a total of 6 trabeculae derived from 2 hearts are sufficient to identify drug-induced pro-arrhythmia. Thus, the human ex-vivo AP-based model provides an integrative translational assay assisting in shaping clinical development plans that could be used in conjunction with the new CiPA-proposed approach.

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Transmural APD gradient synchronizes repolarization in the human left ventricular wall

Abstract: The intrinsic transmural difference in APD compensates for the normal cardiac activation sequence, resulting in more homogeneous repolarization of the left ventricular wall. Our data suggest that the transmural repolarization differences do not fully explain the genesis of the T wave.

Cited by 53 publications

References 37 publications

Primary Effect of SERCA2a Gene Transfer on Conduction Reserve in Chronic Myocardial Infarction

Primary Effect of SERCA2a Gene Transfer on Conduction Reserve in Chronic Myocardial Infarction

Transmural electrophysiological heterogeneity, the T-wave and ventricular arrhythmias

Human ex-vivo action potential model for pro-arrhythmia risk assessment

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