Masonic Medical Research Laboratory

Utica, NY, United States

Masonic Medical Research Laboratory

Utica, NY, United States

Time filter

Source Type

Burashnikov A.,Masonic Medical Research Laboratory | Antzelevitch C.,Masonic Medical Research Laboratory
Nature Reviews Cardiology | Year: 2010

Atrial fibrillation (AF) is a growing clinical problem associated with increased morbidity and mortality. Currently available antiarrhythmic drugs (AADs), although highly effective in acute cardioversion of paroxysmal AF, are generally only moderately successful in long-term maintenance of sinus rhythm. The use of AADs is often associated with an increased risk of ventricular proarrhythmia, extracardiac toxicity, and exacerbation of concomitant diseases such as heart failure. AF is commonly associated with intracardiac and extracardiac disease, which can modulate the efficacy and safety of AAD therapy. In light of the multifactorial intracardiac and extracardiac causes of AF generation, current development of anti-AF agents is focused on modulation of ion channel activity as well as on upstream therapies that reduce structural substrates. The available data indicate that multiple ion channel blockers exhibiting potent inhibition of peak INa with relatively rapid unbinding kinetics, as well as inhibition of late INa and I Kr, may be preferable for the management of AF when considering both safety and efficacy. © 2010 Macmillan Publishers Limited. All rights reserved.


Sicouri S.,Masonic Medical Research Laboratory | Belardinelli L.,Gilead Sciences Inc. | Antzelevitch C.,Masonic Medical Research Laboratory
Heart Rhythm | Year: 2013

Background Previous studies have shown that late sodium channel current (INa) blockers such as ranolazine can exert antiarrhythmic effects by suppressing early and delayed afterdepolarization (EAD and DAD)-induced triggered activity. Objective To evaluate the electrophysiological properties of GS-458967 (GS967), a potent and highly selective late INa blocker, in canine Purkinje fibers (PFs) and pulmonary vein (PV) and superior vena cava (SVC) sleeve preparations. Methods Transmembrane action potentials were recorded from canine PFs and PV and SVC sleeve preparations by using standard microelectrode techniques. The rapidly activating delayed rectifier potassium channel current blocker E-4031 (2.5-5 μM) and the late INa agonist ATX-II (10 nM) were used to induce EADs in PFs. Isoproterenol (1 μM), high calcium ([Ca2+]o = 5.4 mM), or their combination was used to induce DADs and triggered activity. Results In PFs, GS967 (10-300 nM) caused a significant concentration-dependent reduction in action potential duration without altering the maximum rate of rise of the action potential upstroke, action potential amplitude, or resting membrane potential at any rate studied (basic cycle lengths of 1000, 500, and 300 ms) or concentration evaluated (n = 5; P <.05). GS967 (30-100 nM) abolished EADs and EAD-induced triggered activity elicited in PFs by exposure to E-4031 (n = 4) or ATX-II (n = 4). In addition, GS967 reduced or abolished DADs and suppressed DAD-induced triggered activity elicited in PFs (n = 4) and PV (n = 4) and SVC (n = 3) sleeve preparations by exposure to isoproterenol, high calcium, or their combination. Conclusions Our data suggest that the selective inhibition of late I Na with GS967 can exert antiarrhythmic effects by suppressing EAD- and DAD-mediated extrasystolic activity in PFs and PV and SVC sleeve preparations. © 2013 Heart Rhythm Society.


Antzelevitch C.,Masonic Medical Research Laboratory
Circulation Journal | Year: 2012

An early repolarization (ER) pattern in the ECG, distinguished by J-point elevation, slurring of the terminal part of the QRS and ST-segment elevation has long been recognized and considered to be a benign electrocardiographic manifestation. Experimental studies conducted over a decade ago suggested that some cases of ER may be associated with malignant arrhythmias. Validation of this hypothesis was provided by recent studies demonstrating that an ER pattern in the inferior or inferolateral leads is associated with increased risk for life-threatening arrhythmias, termed ER syndrome (ERS). Because accentuated J waves characterize both Brugada syndrome (BS) and ERS, these syndromes have been grouped under the term "J wave syndromes". ERS and BS share similar ECG characteristics, clinical outcomes and risk factors, as well as a common arrhythmic platform related to amplification of Itomediated J waves. Although BS and ERS differ with respect to the magnitude and lead location of abnormal J wave manifestation, they can be considered to represent a continuous spectrum of phenotypic expression. Although most subjects exhibiting an ER pattern are at minimal to no risk, mounting evidence suggests that careful attention should be paid to subjects with "high risk" ER. The challenge ahead is to be able to identify those at risk for sudden cardiac death. Here I review the clinical and genetic aspects as well as the cellular and molecular mechanisms underlying the J wave syndromes.


Burashnikov A.,Masonic Medical Research Laboratory | Antzelevitch C.,Masonic Medical Research Laboratory
Cardiovascular Drugs and Therapy | Year: 2013

The anti-arrhythmic efficacy of the late sodium channel current (late INa) inhibition has been convincingly demonstrated in the ventricles, particularly under conditions of prolonged ventricular repolarization. The value of late INa block in the setting of atrial fibrillation (AF) remains poorly investigated. All sodium channel blockers inhibit both peak and late INa and are generally more potent in inhibiting late vs. early INa. Selective late INa block does not prolong the effective refractory period (ERP), a feature common to practically all anti-AF agents. Although the late INa blocker ranolazine has been shown to be effective in suppression of AF, it is noteworthy that at concentrations at which it blocks late INa in the ventricles, it also potently blocks peak INa in the atria, thus causing rate-dependent prolongation of ERP due to development of post-repolarization refractoriness. Late I Na inhibition in atria is thought to suppress intracellular calcium (Cai)-mediated triggered activity, secondary to a reduction in intracellular sodium (Nai). However, agents that block late I Na (ranolazine, amiodarone, vernakalant, etc) are also potent atrial-selective peak INa blockers, so that the reduction of Na i loading in atrial cells by these agents can be in large part due to the block of peak INa. The impact of late INa inhibition is reduced by the abbreviation of the action potential that occurs in AF patients secondary to electrical remodeling. It stands to reason that selective late INa block may contribute more to inhibition of Ca i-mediated triggered activity responsible for initiation of AF in clinical pathologies associated with a prolonged atrial APD (such as long QT syndrome). Additional studies are clearly needed to test this hypothesis. © 2012 Springer Science+Business Media New York.


Antzelevitch C.,Masonic Medical Research Laboratory
Journal of Electrocardiology | Year: 2013

An early repolarization (ER) pattern in the ECG, consisting of J point elevation, distinct J wave with or without ST segment elevation or slurring of the terminal part of the QRS, was long considered a benign electrocardiographic manifestation. Experimental studies a dozen years ago suggested that an ER is not always benign, but may be associated with malignant arrhythmias. Validation of this hypothesis derives from recent case-control and population-based studies showing that an ER pattern in inferior or infero-lateral leads is associated with increased risk for life-threatening arrhythmias, termed early repolarization syndrome (ERS). Because accentuated J waves characterize both Brugada syndrome (BrS) and ERS, these syndromes have been grouped under the heading of J wave syndromes. BrS and ERS appear to share common ECG characteristics, clinical outcomes, risk factors as well as a common arrhythmic platform related to amplification of Ito-mediated J waves. However, they differ with respect to the magnitude and lead location of abnormal J waves and can be considered to represent a continuous spectrum of phenotypic expression. Recent studies support the hypothesis that BrS and ERS are caused by a preferential accentuation of the AP notch in right or left ventricular epicardium, respectively, and that this repolarization defect is accentuated by cholinergic agonists. Quinidine, cilostazol and isoproterenol exert ameliorative effects by reversing these repolarization abnormalities. Identifying subjects truly at risk is the challenge ahead. Our goal here is to review the clinical and genetic aspects as well as the cellular and molecular mechanisms underlying the J wave syndromes. © 2013 Elsevier Inc.


Burashnikov A.,Masonic Medical Research Laboratory | Sicouri S.,Masonic Medical Research Laboratory | Di Diego J.M.,Masonic Medical Research Laboratory | Belardinelli L.,Gilead Sciences | Antzelevitch C.,Masonic Medical Research Laboratory
Journal of the American College of Cardiology | Year: 2010

Objectives The aim of this study was to evaluate the effectiveness of a combination of dronedarone and ranolazine in suppression of atrial fibrillation (AF). Background Safe and effective pharmacological management of AF remains one of the greatest unmet medical needs. Methods The electrophysiological effects of dronedarone (10 μmol/l) and a relatively low concentration of ranolazine (5 μmol/l) separately and in combination were evaluated in canine isolated coronary-perfused right and left atrial and left ventricular preparations as well as in pulmonary vein preparations. Results Ranolazine caused moderate atrial-selective prolongation of action potential duration and atrial-selective depression of sodium channelmediated parameters, including maximal rate of rise of the action potential upstroke, leading to the development of atrial-specific post-repolarization refractoriness. Dronedarone caused little or no change in electrophysiological parameters in both atrial and ventricular preparations. The combination of dronedarone and ranolazine caused little change in action potential duration in either chamber but induced potent use-dependent atrial-selective depression of the sodium channelmediated parameters (maximal rate of rise of the action potential upstroke, diastolic threshold of excitation, and the shortest cycle length permitting a 1:1 response) and considerable post-repolarization refractoriness. Separately, dronedarone or a low concentration of ranolazine prevented the induction of AF in 17% and 29% of preparations, respectively. In combination, the 2 drugs suppressed AF and triggered activity and prevented the induction of AF in 9 of 10 preparations (90%). Conclusions Low concentrations of ranolazine and dronedarone produce relatively weak electrophysiological effects and weak suppression of AF when used separately but when combined exert potent synergistic effects, resulting in atrial-selective depression of sodium channeldependent parameters and effective suppression of AF. © 2010 American College of Cardiology Foundation.


Szel T.,Masonic Medical Research Laboratory | Szel T.,University of Szeged | Antzelevitch C.,Masonic Medical Research Laboratory
Journal of the American College of Cardiology | Year: 2014

Objectives The aim of this study was to test the hypothesis that late potentials and fractionated electrogram activity are due to delayed depolarization within the anterior aspects of right ventricular (RV) epicardium in experimental models of Brugada syndrome (BrS). Background Clinical reports have demonstrated late potentials on signal-averaged electrocardiography (ECG) recorded in patients with BrS. Recent studies report the appearance of late potentials and fractionated activity on bipolar electrograms recorded in the epicardium of the RV outflow tract in patients with BrS. Methods Action potential and bipolar electrograms were recorded at epicardial and endocardial sites of coronary-perfused canine RV wedge preparations, together with a pseudo-ECG. The transient outward potassium current agonist NS5806 (5 μM) and the Ca2+-channel blocker verapamil (2 μM) were used to pharmacologically mimic the BrS genetic defect. Results Fractionated electrical activity was observed in RV epicardium, but not in endocardium, as a consequence of heterogeneities in the appearance of the second upstroke of the epicardial action potential, and discrete high-frequency spikes developed as a result of concealed phase 2 re-entry. In no case did we observe primary conduction delay as the cause of the BrS ECG phenotype or of late potential or fractionated electrogram activity. Quinidine (10 μM) and the phosphodiesterase-3 inhibitors cilostazol (10 μM) and milrinone (2.5 μM) restored electrical homogeneity, thus abolishing all late potentials and fractionated electrical activity. Conclusions These data point to an alternative pathophysiological basis for late potentials and fractionated electrical activity recorded in the right ventricle in the setting of BrS. We demonstrate an association of such activity with abnormal repolarization and not with abnormal depolarization or structural abnormalities.


Burashnikov A.,Masonic Medical Research Laboratory | Antzelevitch C.,Masonic Medical Research Laboratory
Pharmacology and Therapeutics | Year: 2011

Atrial fibrillation (AF) is a growing clinical problem associated with increased morbidity and mortality. Development of safe and effective pharmacological treatments for AF is one of the greatest unmet medical needs facing our society. In spite of significant progress in non-pharmacological AF treatments (largely due to the use of catheter ablation techniques), anti-arrhythmic agents (AADs) remain first line therapy for rhythm control management of AF for most AF patients. When considering efficacy, safety and tolerability, currently available AADs for rhythm control of AF are less than optimal. Ion channel inhibition remains the principal strategy for termination of AF and prevention of its recurrence. Practical clinical experience indicates that multi-ion channel blockers are generally more optimal for rhythm control of AF compared to ion channel-selective blockers. Recent studies suggest that atrial-selective sodium channel block can lead to safe and effective suppression of AF and that concurrent inhibition of potassium ion channels may potentiate this effect. An important limitation of the ion channel block approach for AF treatment is that non-electrical factors (largely structural remodeling) may importantly determine the generation of AF, so that "upstream therapy", aimed at preventing or reversing structural remodeling, may be required for effective rhythm control management. This review focuses on novel pharmacological targets for the rhythm control management of AF. © 2011 Elsevier Inc. All rights reserved.


Di Diego J.M.,Masonic Medical Research Laboratory | Antzelevitch C.,Masonic Medical Research Laboratory
Heart Rhythm | Year: 2011

In the United States, sudden cardiac death accounts for an estimated 300,000 to 350,000 cases each year, with 80,000 presenting as the first manifestation of a preexisting, sometimes unrecognized, coronary artery disease. Acute myocardial infarction (AMI)-induced ventricular fibrillation frequently occurs without warning, often leading to death within minutes in patients who do not receive prompt medical attention. Identification of patients at risk for AMI-induced lethal ventricular arrhythmias remains an unmet medical need. Recent studies suggest that a genetic predisposition may significantly contribute to the vulnerability of the ischemic myocardium to ventricular tachycardia/ ventricular fibrillation. Numerous experimental models have been developed for the purpose of advancing our understanding of the mechanisms responsible for the development of cardiac arrhythmias in the setting of ischemia and with the aim of identifying antiarrhythmic therapies that could be of clinical benefit. While our understanding of the mechanisms underlying AMI-induced ventricular arrhythmias is coming into better focus, the risk stratification of patients with AMI remains a major challenge. This review briefly discusses our current state of knowledge regarding the mechanisms of ischemic ventricular arrhythmias and their temporal distribution as revealed by available experimental models, how these correlate with the clinical syndromes, as well as prospective prophylactic therapies for the prevention and treatment of ischemia-induced life-threatening arrhythmias. © 2011 Heart Rhythm Society. All rights reserved.


Previously unknown mutations of the CACNA1C and CACNB2b genes are disclosed which are involved in ion channel disruptions associated with shorter than normal QT interval and ST segment elevation syndrome. These mutations are utilized to diagnose and screen for shorter than normal QT interval and ST segment elevation syndrome, thus providing modalities for diagnosing syncope and/or sudden cardiac death and/or predicting susceptibility to syncope and/or sudden cardiac death. Nucleic acid probes are provided which selectively hybridize to the mutant nucleic acids described herein. Antibodies are provided which selectively bind to the mutant polypeptides described herein. The mutations described herein are also utilized to screen for compounds useful in treating the symptoms manifest by such mutations.

Loading Masonic Medical Research Laboratory collaborators
Loading Masonic Medical Research Laboratory collaborators