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      Increased Right Ventricular Repolarization Gradients Promote Arrhythmogenesis in a Murine Model of Brugada Syndrome

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          Abstract

          Repolarization Gradients in Brugada Syndrome. Introduction: Brugada syndrome (BrS) is associated with loss of Na + channel function and increased risks of a ventricular tachycardia exacerbated by flecainide but reduced by quinidine. Previous studies in nongenetic models have implicated both altered conduction times and repolarization gradients in this arrhythmogenicity. We compared activation latencies and spatial differences in action potential recovery between different ventricular regions in a murine Scn5a+/− BrS model, and investigated the effect of flecainide and quinidine upon these.

          Methods and Results: Langendorff-perfused wild-type and Scn5a+/− hearts were subjected to regular pacing and a combination of programmed electrical stimulation techniques. Monophasic action potentials were recorded from the right (RV) and left ventricular (LV) epicardium and endocardium before and following flecainide (10 μM) or quinidine (5 μM) treatment, and activation latencies measured. Transmural repolarization gradients were then calculated from the difference between neighboring endocardial and epicardial action potential durations (APDs). Scn5a+/− hearts showed decreased RV epicardial APDs, accentuating RV, but not LV, transmural gradients. This correlated with increased arrhythmic tendencies compared with wild-type. Flecainide increased RV transmural gradients, while quinidine decreased them, in line with their respective pro- and antiarrhythmic effects. In contrast, Scna5+/− hearts showed slowed conduction times in both RV and LV, exacerbated not only by flecainide but also by quinidine, in contrast to their differing effects on arrhythmogenesis.

          Conclusion: We use a murine genetic model of BrS to systematically analyze LV and RV action potential kinetics for the first time. This establishes a key role for accentuated transmural gradients, specifically in the RV, in its arrhythmogenicity. (J Cardiovasc Electrophysiol, Vol. 21, pp. 1153-1159)

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          Cellular basis for the Brugada syndrome and other mechanisms of arrhythmogenesis associated with ST-segment elevation.

          C Antzelevitch, X. Steven Yan (1999)
          The Brugada syndrome is characterized by marked ST-segment elevation in the right precordial ECG leads and is associated with a high incidence of sudden and unexpected arrhythmic death. Our study examines the cellular basis for this syndrome. Using arterially perfused wedges of canine right ventricle (RV), we simultaneously recorded transmembrane action potentials from 2 epicardial and 1 endocardial sites, together with unipolar electrograms and a transmural ECG. Loss of the action potential dome in epicardium but not endocardium after exposure to pinacidil (2 to 5 micromol/L), a K(+) channel opener, or the combination of a Na(+) channel blocker (flecainide, 7 micromol/L) and acetylcholine (ACh, 2 to 3 micromol/L) resulted in an abbreviation of epicardial response and a transmural dispersion of repolarization, which caused an ST-segment elevation in the ECG. ACh facilitated loss of the action potential dome, whereas isoproterenol (0.1 to 1 micromol/L) restored the epicardial dome, thus reducing or eliminating the ST-segment elevation. Heterogeneous loss of the dome caused a marked dispersion of repolarization within the epicardium and transmurally, thus giving rise to phase 2 reentrant extrasystole, which precipitated ventricular tachycardia (VT) and ventricular fibrillation (VF). Transient outward current (I(to)) block with 4-aminopyridine (1 to 2 mmol/L) or quinidine (5 micromol/L) restored the dome, normalized the ST segment, and prevented VT/VF. Conclusions-Depression or loss of the action potential dome in RV epicardium creates a transmural voltage gradient that may be responsible for the ST-segment elevation observed in the Brugada syndrome and other syndromes exhibiting similar ECG manifestations. Our results also demonstrate that extrasystolic activity due to phase 2 reentry can arise in the intact wall of the canine RV and serve as the trigger for VT/VF. Our data point to I(to) block (4-aminopyridine, quinidine) as an effective pharmacological treatment.
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            Pathophysiological mechanisms of Brugada syndrome: depolarization disorder, repolarization disorder, or more?

            Elisabeth A. Wilde, P Meregalli, Aaitje Tan (2005)
            After its recognition as a distinct clinical entity, Brugada syndrome is increasingly recognized worldwide as an important cause of sudden cardiac death. Brugada syndrome exhibits autosomal dominant inheritance with SCN5A, which encodes the cardiac sodium channel, as the only gene with a proven involvement in 20-30% of patients. Its signature feature is ST segment elevation in right precordial ECG leads and predisposition to malignant ventricular tachyarrhythmias. The pathophysiological mechanism of ST elevation and ventricular tachyarrhythmia, two phenomena strongly related, is controversial. Here, we review clinical and experimental studies as they provide evidence to support or disprove the two hypotheses on the mechanism of Brugada syndrome that currently receive the widest support: (1) nonuniform abbreviation of right ventricular epicardial action potentials ("repolarization disorder"), (2) conduction delay in the right ventricular outflow tract ("depolarization disorder"). We also propose a schematic representation of the depolarization disorder hypothesis. Moreover, we review recent evidence to suggest that other derangements may also contribute to the pathophysiology of Brugada syndrome, in particular, right ventricular structural derangements. In reviewing these studies, we conclude that, similar to most diseases, it is likely that Brugada syndrome is not fully explained by one single mechanism. Rather than adhering to the notion that Brugada syndrome is a monofactorial disease, we should aim for clarification of the contribution of various pathophysiological mechanisms in individual Brugada syndrome patients and tailor therapy considering each of these mechanisms.
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              Efficacy of quinidine in high-risk patients with Brugada syndrome.

              Bernard Belhassen, Sami Viskin, Aharon Glick (2004)
              Automatic implantable cardioverter-defibrillator therapy is considered the only effective treatment for high-risk patients with Brugada syndrome. Quinidine depresses I(to) current, which may play an important role in the arrhythmogenesis of this disease. The effects of quinidine bisulfate (mean dose, 1483+/-240 mg) on the prevention of inducible and spontaneous ventricular fibrillation (VF) were prospectively evaluated in 25 patients (24 men, 1 woman; age, 19 to 80 years) with Brugada syndrome. There were 15 symptomatic patients (including 7 cardiac arrest survivors and 7 patients with unexplained syncope) and 10 asymptomatic patients. All 25 patients had inducible VF at baseline electrophysiological study. Quinidine prevented VF induction in 22 of the 25 patients (88%). After a follow-up period of 6 months to 22.2 years, all patients are alive. Nineteen patients were treated with quinidine for 6 to 219 months (mean+/-SD, 56+/-67 months). None had an arrhythmic event, although 2 had non-arrhythmia-related syncope. Administration of quinidine was associated with a 36% incidence of side effects that resolved after drug discontinuation. Quinidine effectively prevents VF induction in patients with Brugada syndrome. Our data suggest that quinidine also suppresses spontaneous arrhythmias and could prove to be a safe alternative to automatic implantable cardioverter-defibrillator therapy for a substantial proportion of patients with Brugada syndrome. Randomized studies comparing these two therapies seem warranted.
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                Author and article information

                Journal
                Journal ID (nlm-ta): J Cardiovasc Electrophysiol
                Journal ID (publisher-id): jce
                Title: Journal of Cardiovascular Electrophysiology
                Publisher: Blackwell Publishing Inc
                ISSN (Print): 1045-3873
                ISSN (Electronic): 1540-8167
                Publication date (Print): October 2010
                Volume: 21
                Issue: 10
                Pages: 1153-1159
                Affiliations
                [* ]simplePhysiological Laboratory, University of Cambridge Downing Site, Cambridge, United Kingdom
                [† ]simpleDepartment of Paediatrics, First Affiliated Hospital, Xi'an Jiaotong University Xi'an, Peoples Republic of China
                [‡ ]simpleDepartment of Biochemistry, University of Cambridge Downing Site, Cambridge, United Kingdom
                Author notes

                Re-use of this article is permitted in accordance with the Terms and Conditions set out at http://wileyonlinelibrary.com/onlineopen# OnlineOpen_ Terms

                Funding was provided by the British Heart Foundation, the Medical Research Council, the Wellcome Trust and the Biotechnology and Biological Research Council, UK. C. Martin was supported by a Medical Research Council Clinical Research Fellowship and a Sackler Studentship of the University of Cambridge School of Clinical Medicine. Y. Zhang was partially supported by the Chinese Nature Science Foundation (project numbers 30371571 and 30672209).

                No disclosures.

                Address for correspondence: Dr. Claire Martin, M.R.C.P., Physiological Laboratory, University of Cambridge, Downing Site, Cambridge CB2 3EG, United Kingdom. Fax: +441223333840; E-mail: clairemartin@ 123456gmail.com
                Article
                DOI: 10.1111/j.1540-8167.2010.01767.x
                PMC ID: 3084998
                PubMed ID: 20384647
                SO-VID: 38f0d247-ed87-4535-b153-b7222cf0087a
                Copyright © Journal compilation © 2010 Wiley Periodicals, Inc.
                License:

                Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation.

                History
                Date received : 04 January 2010
                Date revision received : 18 February 2010
                Date accepted : 22 February 2010
                Categories
                Subject: Original Articles
                Subject: Experimental

                ScienceOpen disciplines: Cardiovascular Medicine
                Keywords: ion channels,conduction velocity,sodium channels,antiarrhythmic drugs,ventricular tachycardia,arrhythmia,brugada syndrome,action potentials,repolarization,sudden death
                Data availability:
                ScienceOpen disciplines: Cardiovascular Medicine
                Keywords: ion channels, conduction velocity, sodium channels, antiarrhythmic drugs, ventricular tachycardia, arrhythmia, brugada syndrome, action potentials, repolarization, sudden death

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