Divergent antiarrhythmic effects of resveratrol and piceatannol in a whole-heart model of long QT syndrome

doi:10.1016/j.ijcard.2017.06.005

International Journal of Cardiology

Volume 243, 15 September 2017, Pages 233-238

https://doi.org/10.1016/j.ijcard.2017.06.005 Get rights and content

Abstract

Background

The polyphenol resveratrol and its metabolite piceatannol have beneficial health effects including antiarrhythmic properties in ischemia/reperfusion. The objective of this study was to determine potential antiarrhythmic effects in acquired long-QT-syndrome (LQTS).

Methods and results

26 rabbit hearts were isolated and Langendorff-perfused. The I_Kr-blocker sotalol (100 μM) was infused to mimic LQTS-2. Hearts were assigned to two groups. Sotalol significantly prolonged action potential duration (APD₉₀) and QT-interval in both groups (group 1:APD₉₀: + 18 ms, p < 0.01;QT: + 59 ms, p < 0.01; group 2: APD₉₀: + 22 ms, p < 0.01; QT: + 30 ms, p < 0.01) and also significantly increased dispersion of repolarization (group 1: + 21 ms, p < 0.01; group 2: + 23 ms, p < 0.01).

Thereafter, hearts were additionally perfused either with resveratrol (50 μM, group 1, n = 14) or with piceatannol (10 μM, group 2, n = 12).

Administration of resveratrol significantly reduced APD₉₀ (− 29 ms, p < 0.01), QT-interval(− 60 ms, p < 0.01) and dispersion of repolarization (− 26 ms, p < 0.01). In contrast, piceatannol did not significantly alter APD₉₀ (± 0 ms) but shortened QT-interval (− 19 ms, p < 0.01) and increased dispersion of repolarization (+ 15 ms, p < 0.01).

With sotalol, 7 of 14 bradycardic, AV-blocked hearts in group 1 and 8 of 12 in group 2 showed early afterdepolarizations (EAD) after lowering potassium concentration (p < 0.01each). Polymorphic ventricular tachycardia (PVT) occurred in 5 of 14 (p < 0.05) and 4 of 12 hearts (p = 0.09) with a total number of 42 (p < 0.05) and 44 episodes (p = 0.07), respectively.

Additional infusion of resveratrol reduced EAD (2 of 14, p = 0.11) and PVT (1 of 14 hearts, p = 0.16, 3 episodes, p < 0.05). Piceatannol did not suppress EAD or TdP (EAD in 9 of 12 and TdP in 7 of 12 hearts,50 episodes).

Conclusion

Resveratrol showed beneficial antiarrhythmic properties in acquired LQTS. Underlying mechanism is a substantial decrease dispersion of repolarization leading to a suppression of triggered activity.

Introduction

In recent years, the “French paradox”, suggesting that a moderate consumption of wine has beneficial cardiovascular effects [1], drew public interest to the bioactive compounds of red wine. One of them, the polyphenol resveratrol, has anti-inflammatory, anti-cancer, anti-oxidative and anti-diabetic properties. In the setting of ischemia/reperfusion-mediated ventricular arrhythmias resveratrol effectively suppressed arrhythmias [2] probably by inhibiting the H₂O₂-induced augmentation of late I_Na [3]. In addition to this cardioprotective effect resveratrol exerts a direct effect on cardiac electrophysiology by inhibiting late I_Na and blocking peak I_Na [4]. Recent whole-cell voltage-clamp studies demonstrated beneficial effects of resveratrol in drug-induced long QT syndrome (LQTS) [4], [5].

It is noteworthy that inhibition of late I_Na by ranolazine and vernakalant effectively suppressed arrhythmias in an experimental whole-heart model of LQTS [6], [7]. In addition, administration of ranolazine reduced QT interval in LQTS3 patients [8]. These studies indicate a beneficial role of resveratrol in the setting of LQTS. Oral intake of resveratrol is well tolerated with just a few side-effects.

The polyphenol piceatannol is a less extensively studied derivative and metabolite of resveratrol with a similar chemical structure. Therefore, it is assumed that piceatannol has comparable beneficial health effects [9]. In ischemia-reperfused rodent hearts, piceatannol was able to meet these expectations. Piceatannol decreased peak I_Na and slowed I_Na-inactivation. In the same study, resveratrol decreased peak I_Na but did not slow I_Na-inactivation [10].

The objective of this study was to determine potential antiarrhythmic effects of the two different polyphenols resveratrol and piceatannol in an established whole-heart model of LQTS-2.

Section snippets

Methods

All experimental protocols were approved by the local animal care committee and conformed to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 852–3, revised 1996).

The examinations on the Langendorff-preparated hearts have been described in detail previously [11]. Briefly, intact hearts of 26 female New Zealand white rabbits were isolated and Langendorff-perfused. A volume-conducted ECG was recorded and eight catheters

Drug effects on action potential duration and QT interval

Acute infusion of sotalol led to a significant increase in QT-interval in both groups (group 1: 240 ± 42 ms vs. 299 ± 47 ms, p < 0.01; group 2: 278 ± 13 ms vs. 308 ± 29 ms, p < 0.01; Fig. 1), thereby mimicking LQTS2. This was accompanied by a prolongation of APD₉₀ (group 1: 170 ± 24 ms vs. 188 ± 36 ms, p < 0.01; group 2: 174 ± 20 ms vs. 196 ± 34 ms, p < 0.01; Fig. 1). The increase in APD₉₀ ranged between 13% in group 1 and 25% in group 2 at a CL of 900 ms and 0% in both groups at a CL of 300 ms, demonstrating reverse

Discussion

To our best knowledge, the present study is the first to show beneficial effects of the polyphenol resveratrol in a whole-heart model of LQTS. Our results confirm the data generated in previous single-cell experiments [4], [5]. In contrast, piceatannol did not show any antiarrhythmic effects in this model of LQTS.

Conclusion

In this study, resveratrol shows significant antiarrhythmic effects in the presence of acquired LQTS. Though previous studies were promising, piceatannol could not prove its antiarrhythmic effects in this experimental model.

A crucial mechanism in resveratrol's antiarrhythmic effect is the reduction of spatial dispersion of repolarization leading to a suppression of triggered activity. Therefore, administration of resveratrol might be a potential therapeutic strategy for patients with congenital

Funding

This study was supported by the Dr. Peter Osypka Foundation and by the German Cardiac Society (to G.F.).

Conflict of interest

All authors declare to have no conflict of interest.

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Divergent antiarrhythmic effects of resveratrol and piceatannol in a whole-heart model of long QT syndrome

Abstract

Background

Methods and results

Conclusion

Introduction

Section snippets

Methods

Drug effects on action potential duration and QT interval

Discussion

Conclusion

Funding

Conflict of interest

Lancet

Heart Rhythm.

Mutat. Res.

Heart Rhythm.

Adv. Nutr.

Cardioprotective effect of resveratrol, a natural antioxidant derived from grapes

Cardiovasc. Res.

Resveratrol attenuates the Na(+)-dependent intracellular Ca(2 +) overload by inhibiting H(2)O(2)-induced increase in late sodium current in ventricular myocytes

PLoS One

Inhibition of cardiac voltage-gated sodium channels by grape polyphenols

Br. J. Pharmacol.