I(to) and action potential notch are smaller in left vs. right canine ventricular epicardium

Diego, José M. Di; Sun, Zhuoqian; Antzelevitch, Charles

doi:10.1152/ajpheart.1996.271.2.h548

Cited by 174 publications

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“…Our data also indicate that I to is still smaller in LV than in RV epicardium but that sex-related differences are not significant in the LV. These distinctions in I to between LV and RV epicardium, previously reported, 16 form the basis for why the Brugada syndrome is an RV disease. 7 The functional significance of a prominent I to has long been recognized.…”

Section: Discussionmentioning

confidence: 66%

“…Indeed, the presence of a much greater I to in right versus left ventricular epicardium (RV versus LV epicardium) accounts for the RV nature of the disease. 16 The present study tests the hypothesis that the disparity in penetrance of the Brugada phenotype between the sexes is caused by a more prominent I to -mediated action potential notch in the RV epicardium of males versus females.…”

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confidence: 85%

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Ionic and Cellular Basis for the Predominance of the Brugada Syndrome Phenotype in Males

et al. 2002

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Background-The Brugada syndrome displays an autosomal dominant mode of transmission with low penetrance. Despite equal genetic transmission of the disease, the clinical phenotype is 8 to 10 times more prevalent in males than in females. The basis for this intriguing sex-related distinction is unknown. The present study tests the hypothesis that the disparity in expression of the Brugada phenotype is a result of a more prominent I to -mediated action potential notch in the right ventricular (RV) epicardium of males versus females. Methods and Results-We studied epicardial tissue slices, arterially perfused wedge preparations, and dissociated epicardial myocytes isolated from male and female canine hearts. RV epicardium action potential phase 1 amplitude was 64.8Ϯ2.0% of that of phase 2 in males compared with 73.8Ϯ4.4% in females (PϽ0.05) at a cycle length of 2000 ms. I to density was 26% smaller and time constant for inactivation 17% smaller at ϩ40 mV in female versus male RV epicardial cells (PϽ0.05). The other functional characteristics of I to , including the voltage dependence of inactivation and time course of reactivation, were no different between the sexes. Pinacidil caused loss of action potential dome in male, but not female, RV epicardial tissue slices. Terfenadine (5 mol/L) induced phase 2 reentry in 6 of 7 male but only 2 of 7 female arterially perfused wedge preparations. Two of 6 male and 1 of 2 female preparations developed polymorphic ventricular tachycardia/ventricular fibrillation. Conclusions-Our results suggest that the predominance of the Brugada phenotype in males is a result of the presence of a more prominent I to in males versus females.

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Section: Discussionmentioning

confidence: 66%

mentioning

confidence: 85%

Ionic and Cellular Basis for the Predominance of the Brugada Syndrome Phenotype in Males

et al. 2002

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“…3A, right (Fig. 3A) (3,7,25). The cause of different AP spike-and-dome morphology in different tissue experiments is unknown, but possibilities include heterogeneity in the density and recovery kinetics of I to1 due to age (31), sex (59), and precise apicobasal or transmural location (25,49).…”

Section: Methodsmentioning

confidence: 99%

Properties and ionic mechanisms of action potential adaptation, restitution, and accommodation in canine epicardium

Decker¹,

Heijman²,

Silva³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

117

121

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Decker KF, Heijman J, Silva JR, Hund TJ, Rudy Y. Properties and ionic mechanisms of action potential adaptation, restitution, and accommodation in canine epicardium. Am J Physiol Heart Circ Physiol 296: H1017-H1026, 2009. First published January 23, 2009 doi:10.1152/ajpheart.01216.2008.-Computational models of cardiac myocytes are important tools for understanding ionic mechanisms of arrhythmia. This work presents a new model of the canine epicardial myocyte that reproduces a wide range of experimentally observed rate-dependent behaviors in cardiac cell and tissue, including action potential (AP) duration (APD) adaptation, restitution, and accommodation. Model behavior depends on updated formulations for the 4-aminopyridine-sensitive transient outward current (Ito1), the slow component of the delayed rectifier K ϩ current (IKs), the L-type Ca 2ϩ channel current (ICa,L), and the Na ϩ -K ϩ pump current (INaK) fit to data from canine ventricular myocytes. We found that Ito1 plays a limited role in potentiating peak ICa,L and sarcoplasmic reticulum Ca 2ϩ release for propagated APs but modulates the time course of APD restitution. IKs plays an important role in APD shortening at short diastolic intervals, despite a limited role in AP repolarization at longer cycle lengths. In addition, we found that ICa,L plays a critical role in APD accommodation and rate dependence of APD restitution. Ca 2ϩ entry via ICa,L at fast rate drives increased Na ϩ -Ca 2ϩ exchanger Ca 2ϩ extrusion and Na ϩ entry, which in turn increases Na ϩ extrusion via outward INaK. APD accommodation results from this increased outward INaK. Our simulation results provide valuable insight into the mechanistic basis of rate-dependent phenomena important for determining the heart's response to rapid and irregular pacing rates (e.g., arrhythmia). Accurate simulation of rate-dependent phenomena and increased understanding of their mechanistic basis will lead to more realistic multicellular simulations of arrhythmia and identification of molecular therapeutic targets. arrhythmia; cardiac electrophysiology; mathematical modeling; ion channels CARDIAC ARRHYTHMIAS and sudden death involve complex myocardial activation patterns, including unidirectional block, reentry, and fibrillation. To understand the relations and transitions between these patterns, the ionic determinants of the response of healthy and diseased cardiac myocytes to complex patterns of excitation must be understood. The single-cell response to such excitation patterns depends on the complex interaction between ionic currents, intracellular ion concentrations, and membrane voltage. Computational cell models provide critical tools for exploring these interactions, allowing the development and testing of hypotheses about underlying ionic mechanisms based on careful integration of available experimental data (37). The dog is a common animal model for studying cell electrophysiology in a range of disease states. Our group and others have developed detailed mathematical models of the canine action ...

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“…Phase 2 reentry-induced extrasystoles leading to polymorphic VT or VF was also anticipated [9,20,21], In addition, the presence of a much greater I to in right-vs left ventricular epicardium has also been proposed to account, at least in part, for the RV nature of this disease [15].…”

Section: Introductionmentioning

confidence: 93%

“…It is for this reason that loss of the Epi action potential dome observed under ischemic conditions and conditions mimicking "components" of ischemia (pinacidil-induced I K(ATP) activation [11], elevated extracellular calcium combined with rapid pacing [12]) occurs almost exclusively in right ventricular (RV) Epi tissues, where I to is most prominent [15]. These observations suggest that loss of the Epi AP dome may contribute to the ST-segment elevation observed in patients with RV AMI.…”

Section: Introductionmentioning

confidence: 99%

Brugada syndrome and ischemia-induced ST-segment elevation. Similarities and differences

Diego

Fish

Antzelevitch

2005

Journal of Electrocardiology

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Introduction-ST-Segment elevation is a common electrocardiogram (ECG) manifestation of acute transmural myocardial ischemia in leads facing the injury. Acute myocardial ischemia involving the right-ventricular (RV) outflow tract is known to induce a Brugada-like ECG. In this paper, we examined the electrophysiological bases for the similarities between the ECG characteristics of the Brugada syndrome model induced by terfenadine (5 μmol/L) and the ECG manifestations of the acute transmural no-flow ischemia model.Methods-For both experimental simulations, we used isolated arterially perfused canine RV wedge preparations to record transmembrane action potentials (AP) from endocardium and epicardium together with a transmural pseudo-ECG (ECG); basic cycle length = 400 to 2000 ms.Results-In the presence of a prominent I to -mediated AP notch, no-flow ischemia causes true STsegment elevation because of selective depression and loss of the AP dome at some epicardial sites. In the absence of a prominent AP notch, ischemia ultimately produces an apparent ST-segment elevation, which is secondary to a prolongation of the R wave caused by marked transmural conduction delays. Similarly, in the Brugada syndrome model generated in preparations displaying a large epicardial I to , ST-segment elevation was due to loss of the epicardial AP dome at some sites but not at others. Transmural conduction delay giving the appearance of ST-segment elevation is also observed in the Brugada model in preparations exhibiting smaller AP notch. In both models, propagation of the dome from the site at which it is maintained to a site at which it is lost may result in closely coupled phase 2 reentrant extrasystoles.Conclusion-Our results suggest that I to can modulate the electrocardiographic manifestation of acute ischemia as well as that of the Brugada syndrome, and that both clinical entities are the result of a similar electrophysiological substrate.

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I(to) and action potential notch are smaller in left vs. right canine ventricular epicardium

Cited by 174 publications

References 0 publications

Ionic and Cellular Basis for the Predominance of the Brugada Syndrome Phenotype in Males

Ionic and Cellular Basis for the Predominance of the Brugada Syndrome Phenotype in Males

Properties and ionic mechanisms of action potential adaptation, restitution, and accommodation in canine epicardium

Brugada syndrome and ischemia-induced ST-segment elevation. Similarities and differences

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