Characterization of a novel multifunctional resveratrol derivative for the treatment of atrial fibrillation

Baczkó, István; Liknes, David; Yang, Wei; Hamming, Kevin C.; Searle, Gavin J.; Jaeger, Kristian; Husti, Zoltán; Juhász, Viktor; Klausz, Gergely; Pap, Róbert; Sághy, László; Varró, András; Dolinsky, Vernon W.; Wang, Shaohua; Rauniyar, Vivek; Hall, Dennis G.; Dyck, Jason R.B.; Light, Peter E.

doi:10.1111/bph.12409

Cited by 34 publications

(26 citation statements)

References 59 publications

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“…Due to its atrial specificity, drugs that affect I kur have atrium-specific effects without affecting ventricular function. Certain studies suggested that K v 1.5 channels may represent novel targets for the treatment of AF (25,26). The present study demonstrated that Myr was able to block I kur in a dose-, time-and frequency-dependent manner.…”

Section: A B C Dsupporting

confidence: 68%

Myricetin inhibits Kv1.5 channels in HEK293 cells

Bin

Wang

et al. 2015

Molecular Medicine Reports

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Abstract. Myricetin (Myr) is a flavonoid that exerts anti-arrhythmic effects. However, its potential effects on ion channels have remained elusive. The aim of the present study was to investigate the effects of Myr on K v 1.5 channels in HEK293 cells. The current of K v 1.5 channels (I kur ) in HEK293 cells was recorded using the whole-cell patch-clamp technique and the expression of the K v 1.5 protein was measured using western blot analysis 24 h after treatment with Myr. The results showed that 5 µM Myr significantly reduced I kur from 215.04±40.59 to 77.72±17.94 pA/pF (P<0.05; n=5). Myr increased the current suppression from 0 to 0.31±0.12 and 0.55±0.11 over 5 or 20 min, respectively. In addition, I kur decreased from 376.23±1.30 to 270.19±4.28 pA/pF when the frequency was increased from 0.5 to 4 Hz in HEK293 cells treated with 10 µM Myr for 5 min. Furthermore, Myr reduced hK v 1.5 protein expression in a dose-dependent manner. These results demonstrated that Myr inhibited I kur and the expression of hK v 1.5 in HEK293 cells in a dose-, time-and frequency-dependent manner. These observations partly explained the mechanisms by which Myr exerts anti-arrhythmic effect.

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Section: A B C Dsupporting

confidence: 68%

Myricetin inhibits Kv1.5 channels in HEK293 cells

Bin

Wang

et al. 2015

Molecular Medicine Reports

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“…For instance, atrial fibrillation (AF), which is the most common cardiac arrhythmia, remains a significant risk factor for stroke, heart failure, and cardiovascular-related mortality [282]. Despite the availability of a number of anti-arrhythmic medications, the safety profile of most of them is far from optimum [283].…”

Section: Arrhythmiamentioning

confidence: 99%

“…Of interest, resveratrol inhibited delayed after depolarization induced by ouabain in guinea pig papillary muscle independently from its NO or estrogen-modulating effects [289], suggesting that the anti-arrhythmic properties of resveratrol may be distinct from its other cardioprotective effects. To optimize the antiarrhythmic potential of resveratrol, a new resveratrol derivative has also been shown to be a multi-functional molecule that targets key pathways involved in the pathogenesis of atrial fibrillation [282]. To the best of our knowledge, there are no human studies that investigated the anti-arrhythmic effect of resveratrol.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Preclinical and clinical evidence for the role of resveratrol in the treatment of cardiovascular diseases

Zordoky

Robertson

Dyck

2015

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

288

217

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Cardiovascular disease is the leading cause of death worldwide. Despite advancements in diagnosis and treatment of cardiovascular disease, the incidence of cardiovascular disease is still rising. Therefore, new lines of medications are needed to treat the growing population of patients with cardiovascular disease. Although the majority of the existing pharmacotherapies for cardiovascular disease are synthesized molecules, natural compounds, such as resveratrol, are also being tested. Resveratrol is a non-flavonoid polyphenolic compound, which has several biological effects. Preclinical studies have provided convincing evidence that resveratrol has beneficial effects in animal models of hypertension, atherosclerosis, stroke, ischemic heart disease, arrhythmia, chemotherapy-induced cardiotoxicity, diabetic cardiomyopathy, and heart failure. Although not fully delineated, some of the beneficial cardiovascular effects of resveratrol are mediated through activation of silent information regulator 1 (SIRT1), AMP-activated protein kinase (AMPK), and endogenous anti-oxidant enzymes. In addition to these pathways, the anti-inflammatory, anti-platelet, insulin-sensitizing, and lipid-lowering properties of resveratrol contribute to its beneficial cardiovascular effects. Despite the promise of resveratrol as a treatment for numerous cardiovascular diseases, the clinical studies for resveratrol are still limited. In addition, several conflicting results from trials have been reported, which demonstrates the challenges that face the translation of the exciting preclinical findings to humans. Herein, we will review much of the preclinical and clinical evidence for the role of resveratrol in the treatment of cardiovascular disease and provide information about the physiological and molecular signaling mechanisms involved. This article is part of a Special Issue entitled: Resveratrol: Challenges in translating pre-clinical findings to improved patient outcomes.

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“…4) was synthesized, that did not affect other currents [230] and exhibited protective effects against experimental ventricular and atrial arrhythmias [231][232]. In a very recent publication, a novel small molecule targeting multiple mechanisms involved in atrial fibrillation showed a 3-fold higher I Na, late inhibition over peak I Na inhibition, in addition to other ion channel blocking properties, and exhibited efficacy against AF in a chronic atrial tachypacing induced AF dog model [233]. Another novel I Na, late inhibitor, F 15845, reduced the incidence of coronary artery ligation induced arrhythmias in rats [234].…”

Section: Na Late Inhibitorsmentioning

confidence: 99%

“…Indeed, in a very recent study Compound 1 (C1; Fig. 9), a resveratrol derivative was shown to possess multi-channel blocking properties and exhibited efficacy against AF in a chronic atrial tachypacing induced atrial fibrillation dog model [233]. This novel compound inhibited peak and late I Kur (IC 50 : 0.36 and 0.11 mol/l, respectively), I K, ACh (IC 50 : 1.9 mol/l), peak I Na and I Na, late (IC 50 : 3.0 and 1 mol/l, respectively), demonstrated NFAT inhibitory and antioxidant properties that were similar to those of resveratrol.…”

Section: Dronedaronementioning

confidence: 99%

Future Perspectives in the Pharmacological Treatment of Atrial Fibrillation and Ventricular Arrhythmias in Heart Failure

Baczkó

Leprán

Kiss

et al. 2014

CPD

Self Cite

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Heart failure (HF) is a clinical syndrome characterized by significant impairment of cardiac ventricular function. Atrial fibrillation (AF) is the most commonly observed sustained arrhythmia in clinical practice. Both HF and AF are associated with increased morbidity and mortality and their prevalence increases with age. Approximately 50% of patients with moderate HF die due to ventricular fibrillation that leads to sudden cardiac death. Patients with AF exhibit increased mortality due to HF and stroke. HF and AF often co-exist, and the development of the other condition further deteriorates prognosis. Both chronic HF and AF lead to structural and electrophysiological changes in the heart called remodeling, modifying therapeutic targets including those for antiarrhythmic intervention. Current pharmacological treatment of arrhythmias has major limitations due to low efficacy and serious adverse effects. In this review, the main aspects of electrical remodeling in HF and AF are discussed along with possible novel targets identified for future pharmacological antiarrhythmic therapy.Keywords: Heart failure, atrial fibrillation, cardiac arrhythmias, electrical remodeling, potassium channel expression, multi-channel blocking drugs. I. OVERVIEW AND CURRENT STATUS Epidemiology of Heart Failure, Atrial Fibrillation and their CombinationHeart failure (HF) is a clinical syndrome resulting from a wide range of cardiovascular disorders, featuring significant impairment of cardiac function that leads to reduced ventricular filling or ejection of blood. HF markedly reduces health-related quality of life [1], causes significant morbidity and high mortality and represents an enormous economic burden for the health care system [2]. The incidence of HF is increasing with age, with 20 per 1000 persons 65-69 years old and more than 80 per 1000 persons older than 85 [3] and its prevalence is increasing in a continuously aging population [2]. In spite of the significant advances in the treatment of HF, mortality rates remain poor at approximately 50% of patients dying within 5 years of diagnosis [4]. Serious ventricular arrhythmias are common in HF [5] and approximately 50% of HF patients die due to ventricular fibrillation leading to sudden cardiac death (SCD), the rate of which is several times higher in HF patients compared to the general population [6]. In addition to severe ventricular arrhythmias, atrial arrhythmias often develop in heart failure. Bradycardia can develop due to sinoatrial function impairment [7] that can exacerbate cardiac dysfunction [8], can lead to syncope and haemodynamic collapse and can be resolved by application of implantable devices [9].Atrial fibrillation (AF) is the most common sustained arrhythmia and it is associated with significant morbidity and mortality, especially due to the increased risk of heart failure and stroke [10][11][12]. The prevalence of AF increases with age, with 0.5% of patients affected in the 50 year old range, ~10% over the age of 80 [13] and the prediction is that it...

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Characterization of a novel multifunctional resveratrol derivative for the treatment of atrial fibrillation

Cited by 34 publications

References 59 publications

Myricetin inhibits Kv1.5 channels in HEK293 cells

Myricetin inhibits Kv1.5 channels in HEK293 cells

Preclinical and clinical evidence for the role of resveratrol in the treatment of cardiovascular diseases

Future Perspectives in the Pharmacological Treatment of Atrial Fibrillation and Ventricular Arrhythmias in Heart Failure

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