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PubMed2004

Altered connexin43 expression produces arrhythmia substrate in heart failure.

Recently, we found that repolarization heterogeneities between subepicardial and midmyocardial cells can form a substrate for reentrant ventricular arrhythmias in failing myocardium. We hypothesized that the mechanism responsible for maintaining transmural action potential duration heterogeneities in heart failure is related to intercellular uncoupling from downregulation of cardiac gap junction protein connexin43 (Cx43). With the use of the canine model of pacing-induced heart failure, left ventricles were sectioned to expose the transmural surface (n = 5). To determine whether heterogeneous Cx43 expression influenced electrophysiological function, high-resolution transmural optical mapping of the arterially perfused canine wedge preparation was used to measure conduction velocity (theta(TM)), effective transmural space constant (lambda(TM)), and transmural gradients of action potential duration (APD). Absolute Cx43 expression in failing myocardium, quantified by confocal immunofluorescence, was uniformly reduced (by 40 +/- 3%, P < 0.01) compared with control. Relative Cx43 expression was heterogeneously distributed and lower (by 32 +/- 18%, P < 0.05) in the subepicardium compared with deeper layers. Reduced Cx43 expression in heart failure was associated with significant reductions in intercellular coupling between transmural muscle layers, as evidenced by reduced theta(TM) (by 18.9 +/- 4.9%) and lambda(TM) (by 17.2 +/- 1.4%; P < 0.01) compared with control. Heterogeneous transmural distribution of Cx43 in failing myocardium was associated with lower subepicardial theta(TM) (by 12 +/- 10%) and lambda(TM) (by 13 +/- 7%), compared with deeper transmural layers (P < 0.05). APD dispersion was greatest in failing myocardium, and the largest transmural APD gradients were consistently found in regions exhibiting lowest relative Cx43 expression. These data demonstrate that reduced Cx43 expression produces uncoupling between transmural muscle layers leading to slowed conduction and marked dispersion of repolarization between epicardial and deeper myocardial layers. Therefore, Cx43 expression patterns can potentially contribute to an arrhythmic substrate in failing myocardium.

Action Potentials↗
PubMed2003

Age-related sensitivity to nicotine for inducible atrial tachycardia and atrial fibrillation.

The influence of nicotine in modulating vulnerability to atrial tachycardia and fibrillation (AT/AF) remains ill defined. The isolated hearts of six young (2-3 mo) and six old (22-24 mo) male Fischer 344 rats were Langendorff perfused at 5 ml/min with oxygenated Tyrode solution at 37 degrees C, and the whole heart was also super-fused with warmed oxygenated Tyrode solution at 15 ml/min. Nicotine prolonged the interatrial conduction time and effective refractory period that were significantly (P < 0.05) higher in the old than in the young rats in a concentration-dependent manner. Nicotine had a biphasic effect on burst atrial pacing-induced AT in both groups, increasing it at 10-30 ng/ml while decreasing it at 50-100 ng/ml (P < 0.01). Nicotine at 10-100 ng/ml increased burst atrial pacing-induced AF in the young rats but suppressed it in the old rats (P < 0.01). Optical mapping showed the presence of multiple independent wavefronts during AF and a single periodic large wavefront during AT in both groups. Nicotine, at concentrations found in the blood of smokers (30-85 ng/ml), exerts biphasic effects on inducible AT/AF in young rats and suppresses it in the old rats by causing high degrees of interatrial conduction block.

Action Potentials↗
PubMed2002

Calcium-dependent arrhythmias in transgenic mice with heart failure.

Transgenic mice overexpressing the inflammatory cytokine tumor necrosis factor (TNF)-alpha (TNF-alpha mice) in the heart develop a progressive heart failure syndrome characterized by biventricular dilatation, decreased ejection fraction, atrial and ventricular arrhythmias on ambulatory telemetry monitoring, and decreased survival compared with nontransgenic littermates. Programmed stimulation in vitro with single extra beats elicits reentrant ventricular arrhythmias in TNF-alpha (n = 12 of 13 hearts) but not in control hearts. We performed optical mapping of voltage and Ca(2+) in isolated perfused ventricles of TNF-alpha mice to study the mechanisms that lead to the initiation and maintenance of the arrhythmias. When compared with controls, hearts from TNF-alpha mice have prolonged of action potential durations (action potential duration at 90% repolarization: 23 +/- 2 ms, n = 7, vs. 18 +/- 1 ms, n = 5; P < 0.05), no increased dispersion of refractoriness between apex and base, elevated diastolic and depressed systolic [Ca(2+)], and prolonged Ca(2+) transients (72 +/- 6 ms, n = 10, vs. 54 +/- 5 ms, n = 8; P < 0.01). Premature beats have diminished action potential amplitudes and conduct in a slow, heterogeneous manner. Lowering extracellular [Ca(2+)] normalizes conduction and prevents inducible arrhythmias. Thus both action potential prolongation and abnormal Ca(2+) handling may contribute to the initiation of reentrant arrhythmias in this heart failure model by mechanisms distinct from enhanced dispersion of refractoriness or triggered activity.

Action Potentials↗
PubMed2003

Regional upregulation of Kv2.1-encoded current, IK,slow2, in Kv1DN mice is abolished by crossbreeding with Kv2DN mice.

Overexpression of a truncated Kv1.1 channel transgene in the heart (Kv1DN) resulted in mice with a prolonged action potential duration due to marked attenuation of a rapidly activating, slowly inactivating potassium current (I(K,slow1)) in ventricular myocytes. Optical mapping and programmed electrical stimulation revealed inducible ventricular tachycardia due to spatial dispersion of repolarization and refractoriness. Here we show that a delayed rectifier with slower inactivation kinetics (I(K,slow2)) was selectively upregulated in Kv1DN cardiocytes. This electrical remodeling was spatially restricted to myocytes derived from the apex of the left ventricle. Biophysical and pharmacological studies of I(K,slow2) indicate that it resembles Kv2-encoded currents. Northern blot analyses and real-time PCR revealed upregulation of Kv2.1 transcript in Kv1DN mice. Crossbreeding of Kv1DN mice with mice expressing a truncated Kv2.1 polypeptide (Kv2DN) eliminated I(K,slow2). In summary, our data indicate that the spatially restrictive upregulation of Kv2.1-encoded currents underlies the increased dispersion of the repolarization observed in Kv1DN mice.

4-Aminopyridine↗
PubMed2002

Sildenafil-nitric oxide donor combination promotes ventricular tachyarrhythmias in the swine right ventricle.

We tested the hypothesis that sildenafil, singly or in combination with nitric oxide (NO) donors, promotes ventricular tachycardia (VT) and ventricular fibrillation (VF). Vulnerability to VT/VF was tested by rapid pacing in eight isolated normal swine right ventricles (RV). The endocardial activation was optically mapped, and the dynamic action potential duration (APD) restitution curves were constructed with metal microelectrodes. At baseline, no VT/VF could be induced. Sildenafil (0.2 microg/ml) or NO donor singly or in combination did not alter VT/VF vulnerability. However, when 2 microg/ml sildenafil was combined with NO donors, the incidence of VT and VF rose significantly (P < 0.01). VT with a single periodic wavefront was induced in five of eight RVs, and VF with multiple wavefronts was induced in all eight RVs. The sildenafil-NO donor pro-VT/VF combination significantly increased the maximum slope of the APD restitution curve and the amplitude of the APD alternans. The pro-VT/VF effects of sildenafil were reversible after drug-free Tyrode solution perfusion. We conclude that a sildenafil (2 microg/ml) and NO donor combination increases VT/VF vulnerability in the normal RV by a mechanism compatible with the restitution hypothesis.

Action Potentials↗
PubMed2002

Effects of amiodarone on wave front dynamics during ventricular fibrillation in isolated swine right ventricle.

The effects of acute amiodarone infusion on dynamics of ventricular fibrillation (VF) are unclear. Six isolated swine right ventricles (RVs) were studied in vitro. Activation patterns during VF were mapped optically, whereas action potentials were recorded with a glass microelectrode. At baseline, VF was associated with frequent spontaneous wave breaks. Amiodarone (2.5 microg/ml) reduced spontaneous wave breaks and increased the cycle length (CL) of VF from 83.3 +/- 17.8 ms at baseline to 118.4 +/- 25.8 ms during infusion (P < 0.05). Amiodarone increased the reentrant wave front CL (114.4 +/- 15.5 vs. 78.2 +/- 19.0 ms, P < 0.05) and central core area (4.1 +/- 3.8 vs. 0.9 +/- 0.3 mm2, P < 0.05). Within 30 min of infusion, VF terminated (n = 1), converted to ventricular tachycardia (VT) (n = 1) or continued at a slower rate (n = 4). Amiodarone flattened the APD restitution curves. We conclude that amiodarone reduced spontaneous wave breaks. It might terminate VF or convert VF to VT. These effects were associated with the flattening of APD restitution slope and increased core size of reentrant wave fronts.

Action Potentials↗
PubMed2004

Virtual electrode theory explains pacing threshold increase caused by cardiac tissue damage.

The virtual electrode polarization (VEP) effect is believed to play a key role in electrical stimulation of heart muscle. However, under certain conditions, including clinically, its existence and importance remain unknown. We investigated the influence of acute tissue damage produced by continuous pacing with strong current (40-mA, 4-ms biphasic pulses with 4-Hz frequency for 5 min) on stimulus-generated VEPs and pacing thresholds. A fluorescent optical mapping technique was used to obtain stimulus-induced transmembrane potential distribution around a pacing electrode applied to the ventricular surface of a Langendorff-perfused rabbit heart (n = 5). Maps and pacing thresholds were recorded before and after tissue damage. Spatial extents of electroporation and cell uncoupling were assessed by propidium iodide (n = 2) and connexin43 (n = 3) antibody staining, respectively. On the basis of these data, passive and active three-dimensional bidomain models were built to determine VEP patterns and thresholds for different-sized areas of the damaged region. Electrophysiological results showed that acute tissue damage led to disappearance of the VEP with an associated significant increase in pacing thresholds. Damage was expressed in electroporation and cell uncoupling within an approximately 1.0-mm-diameter area around the tip of the electrode. According to computer simulations, cell uncoupling, rather than electroporation, might be the direct cause of VEP elimination and threshold increase, which was nonlinearly dependent on the size of the damaged region. Fiber rotation with depth did not substantially affect the numerical results. The study explains failure to stimulate damaged tissue within the concepts of the VEP theory.

Acute Disease↗
PubMed2005

Atrial contractile dysfunction, fibrosis, and arrhythmias in a mouse model of cardiomyopathy secondary to cardiac-specific overexpression of tumor necrosis factor-{alpha}.

Transgenic mice overexpressing the inflammatory cytokine TNF-alpha in the heart develop a progressive heart failure syndrome characterized by biventricular dilatation, decreased ejection fraction, decreased survival compared with non-transgenic littermates, and earlier pathology in males. TNF-alpha mice (TNF1.6) develop atrial arrhythmias on ambulatory telemetry monitoring that worsen with age and are more severe in males. We performed in vivo electrophysiological testing in transgenic and control mice, ex vivo optical mapping of voltage in the atria of isolated perfused TNF1.6 hearts, and in vitro studies on isolated atrial muscle and cells to study the mechanisms that lead to the spontaneous arrhythmias. Programmed stimulation induces atrial arrhythmias (n = 8/32) in TNF1.6 but not in control mice (n = 0/37), with a higher inducibility in males. In the isolated perfused hearts, programmed stimulation with single extra beats elicits reentrant atrial arrhythmias (n = 6/6) in TNF1.6 but not control hearts due to slow heterogeneous conduction of the premature beats. Lowering extracellular Ca(2+) normalizes conduction and prevents the arrhythmias. Atrial muscle and cells from TNF1.6 compared with control mice exhibit increased collagen deposition, decreased contractile function, and abnormal systolic and diastolic Ca(2+) handling. Thus abnormalities in action potential propagation and Ca(2+) handling contribute to the initiation of atrial arrhythmias in this mouse model of heart failure.

Action Potentials↗
PubMed2006

Calcium-mediated triggered activity is an underlying cellular mechanism of ectopy originating from the pulmonary vein in dogs.

Paroxysmal atrial fibrillation associated with focal ectopy originating from the pulmonary vein (PV) can be preceded by variations in autonomic tone; however, the underlying cellular mechanisms are not clear. To determine the mechanisms of autonomically mediated PV ectopy, high-resolution optical mapping techniques were used to measure action potentials and Ca(2+) transients from the PV and the ligament of Marshall area in the arterially perfused canine left atrium. Rapid pacing was used to initiate ectopic activity during pituitary adenylate cyclase-activating polypeptide (PACAP) injection (1 nmol), as a surrogate for autonomic imbalance, before (n = 9) and after (n = 6) verapamil (10 nmol) administration. In all preparations, spontaneous activity was absent before rapid pacing. During PACAP injection, rapid pacing induced ectopic activity in eight of nine preparations. In contrast, before PACAP injection, rapid pacing did not induce ectopic activity. Activation maps of each episode of ectopic activity indicated that the site of origin occurred more frequently in the PV (70%) than in the ligament of Marshall (30%) area. As rapid pacing cycle length increased, so did the ectopic beat coupling interval. In addition, PACAP-induced ectopic activity was associated with large Ca(2+) transient amplitudes and was always suppressed by verapamil, a Ca(2+) channel blocker (P < 0.05). Finally, during PACAP injection in the absence of an ectopic beat, spontaneous Ca(2+) release and delayed afterdepolarizations were observed simultaneously after termination of rapid pacing. In conclusion, these data suggest that autonomically mediated PV ectopy may be due to Ca(2+)-mediated triggered activity arising from delayed afterdepolarizations.

Action Potentials↗
PubMed2002

Action potential duration restitution and ventricular fibrillation due to rapid focal excitation.

The focal source hypothesis of ventricular fibrillation (VF) posits that rapid activation from a focal source, rather than action potential duration (APD) restitution properties, is responsible for the maintenance of VF. We injected aconitine (100 microg) into normal isolated perfused swine right ventricles (RVs) stained with 4-[beta-[2-(di-n-butylamino)-6-naphthyl]vinyl]pyridinium (di-4-ANEPPS) for optical mapping studies. Within 97 +/- 163 s, aconitine induced ventricular tachycardia (VT) with a mean cycle length 268 +/- 37 ms, which accelerated before converting to VF. Drugs that flatten the APD restitution slope, including diacetyl monoxime (10-20 mM, n = 6), bretylium (10-20 microg/ml, n = 3), and verapamil (2-4 microg/ml, n = 3), reversibly converted VF to VT in all cases. In two RVs, VF persisted despite of the excision of the aconitine site. Simulations in two-dimensional cardiac tissue showed that once VF was initiated, it remained sustained even after the "aconitine" site was eliminated. In this model of focal source VF, the VT-to-VF transition occurred due to a wave break outside the aconitine site, and drugs that flattened the APD restitution slope converted VF to VT despite continuous activation from aconitine site.

Aconitine↗
PubMed2003

Functional and morphological evidence for a ventricular conduction system in zebrafish and Xenopus hearts.

Zebrafish and Xenopus have become popular model organisms for studying vertebrate development of many organ systems, including the heart. However, it is not clear whether the single ventricular hearts of these species possess any equivalent of the specialized ventricular conduction system found in higher vertebrates. Isolated hearts of adult zebrafish (Danio rerio) and African toads (Xenopus laevis) were stained with voltage-sensitive dye and optically mapped in spontaneous and paced rhythms followed by histological examination focusing on myocardial continuity between the atrium and the ventricle. Spread of the excitation wave through the atria was uniform with average activation times of 20 +/- 2 and 50 +/- 2 ms for zebrafish and Xenopus toads, respectively. After a delay of 47 +/- 8 and 414 +/- 16 ms, the ventricle became activated first in the apical region. Ectopic ventricular activation was propagated significantly more slowly (total ventricular activation times: 24 +/- 3 vs. 14 +/- 2 ms in zebrafish and 74 +/- 14 vs. 35 +/- 9 ms in Xenopus). Although we did not observe any histologically defined tracts of specialized conduction cells within the ventricle, there were trabecular bands with prominent polysialic acid-neural cell adhesion molecule staining forming direct myocardial continuity between the atrioventricular canal and the apex of the ventricle; i.e., the site of the epicardial breakthrough. We thus conclude that these hearts are able to achieve the apex-to-base ventricular activation pattern observed in higher vertebrates in the apparent absence of differentiated conduction fascicles, suggesting that the ventricular trabeculae serve as a functional equivalent of the His-Purkinje system.

Animals↗
PubMed2003

Effects of heart isolation, voltage-sensitive dye, and electromechanical uncoupling agents on ventricular fibrillation.

We tested whether the interventions typically required for optical mapping affect activation patterns during ventricular fibrillation (VF). A 21 x 24 unipolar electrode array (1.5 mm spacing) was sutured to the left ventricular epicardium of 16 anesthetized pigs, and four episodes of electrically induced VF (30-s duration) were recorded. The hearts were then rapidly excised and connected to a Langendorff perfusion apparatus. Four of the hearts were controls, in which 24 additional VF episodes were then mapped. In the remaining 12 hearts, four VF episodes were mapped after isolation, four more episodes were mapped after exposure to the voltage-sensitive dye di-4-ANEPPS, and six more episodes were mapped after exposure to the electromechanical uncoupling agents diacetyl monoxime (DAM; 20 mmol/l, n = 6) or cytochalasin D (CytoD; 10 micromol/l, n = 6). VF episodes were separated by 4 min. VF activation patterns were quantified using custom pattern analysis algorithms. From comparisons with time-corrected control data, all interventions significantly changed VF patterns. Most changes were broadly consistent with slowing and regularization due to loss of excitability. Heart isolation had the largest effect on VF patterns, followed by CytoD, DAM, and dye.

Animals↗
PubMed2006

Ryanodine receptor dysfunction and triggered activity in the heart.

Arrhythmogenesis has been increasingly linked to cardiac ryanodine receptor (RyR) dysfunction. However, the mechanistic relationship between abnormal RyR function and arrhythmogenesis in the heart is not clear. We hypothesize that, under abnormal RyR conditions, triggered activity will be caused by spontaneous calcium release (SCR) events that depend on transmural heterogeneities of calcium handling. We performed high-resolution optical mapping of intracellular calcium and transmembrane potential in the canine left ventricular wedge preparation (n = 28). Rapid pacing was used to initiate triggered activity under normal and abnormal RyR conditions induced by FKBP12.6 dissociation and beta-adrenergic stimulation (20-150 microM rapamycin, 0.2 microM isoproterenol). Under abnormal RyR conditions, almost all preparations experienced SCRs and triggered activity, in contrast to control, rapamycin, or isoproterenol conditions alone. Furthermore, under abnormal RyR conditions, complex arrhythmias (monomorphic and polymorphic tachycardia) were commonly observed. After washout of rapamycin and isoproterenol, no triggered activity was observed. Surprisingly, triggered activity and SCRs occurred preferentially near the epicardium but not the endocardium (P < 0.01). Interestingly, the occurrence of triggered activity and SCR events could not be explained by cytoplasmic calcium levels, but rather by fast calcium reuptake kinetics. These data suggest that, under abnormal RyR conditions, triggered activity is caused by multiple SCR events that depend on the faster calcium reuptake kinetics near the epicardium. Furthermore, multiple regions of SCR may be a mechanism for multifocal arrhythmias associated with RyR dysfunction.

Animals↗
PubMed2002

Increased vulnerability to inducible atrial fibrillation caused by partial cellular uncoupling with heptanol.

We hypothesized that partial cellular uncoupling produced by low concentrations of heptanol increases the vulnerability to inducible atrial fibrillation (AF). The epicardial surface of 12 isolated-perfused canine left atria was optically mapped before and after 1-50 microM heptanol infusion. At baseline, no sustained (>30 s) AF could be induced in any of the 12 tissues. However, after 2 microM heptanol infusion, sustained AF was induced in 9 of 12 tissues (P < 0.001). Heptanol >5 microM caused loss of 1:1 capture during rapid pacing, causing no AF to be induced. AF was initiated by conduction block across the fiber leading to reentry, which broke up after one to two rotations into two to four independent wavelets that sustained the AF. Heptanol at 2 microM had no effect on the cellular action potential duration restitution or on the maximal velocity rate over time of the upstroke. The effects of heptanol were reversible. We conclude that partial cellular uncoupling by heptanol without changing atrial active membrane properties promotes wavebreak, reentry, and AF during rapid pacing.

Action Potentials↗
PubMed2003

In vivo gene transfer of Kv1.5 normalizes action potential duration and shortens QT interval in mice with long QT phenotype.

Mutations in cardiac voltage-gated K+ channels cause long QT syndrome (LQTS) and sudden death. We created a transgenic mouse with a long QT phenotype (Kv1DN) by overexpression of a truncated K+ channel in the heart and investigated whether the dominant negative effect of the transgene would be overcome by the direct injection of adenoviral vectors expressing wild-type Kv1.5 (AV-Kv1.5) into the myocardium. End points at 3-10 days included electrophysiology in isolated cardiomyocytes, surface ECG, programmed stimulation of the right ventricle, and in vivo optical mapping of action potentials and repolarization gradients in Langendorff-perfused hearts. Overexpression of Kv1.5 reconstituted a 4-aminopyridine-sensitive outward K+ current, shortened the action potential duration, eliminated early afterdepolarizations, shortened the QT interval, decreased dispersion of repolarization, and increased the heart rate. Each of these changes is consistent with a physiologically significant primary effect of adenoviral expression of Kv1.5 on ventricular repolarization of Kv1DN mice.

4-Aminopyridine↗
PubMed2004

Heterogeneous connexin43 expression produces electrophysiological heterogeneities across ventricular wall.

Recently we found that electrophysiological (EP) heterogeneities between subepicardial and midmyocardial cells can form a substrate for reentrant ventricular arrhythmias. However, cell-to-cell coupling through gap junctions is expected to attenuate transmural heterogeneities between cell types spanning the ventricular wall. Because connexin43 (Cx43) is the principal ventricular gap junction protein, we hypothesized that transmural EP heterogeneities are in part produced by heterogeneous Cx43 expression across the ventricular wall. The left ventricles of eight dogs were sectioned to expose the transmural surface. To determine whether heterogeneous Cx43 expression influenced EP function, high-resolution transmural optical mapping of the arterially perfused canine wedge preparation was used to measure transmural conduction velocity (thetaTM), dV/dt(max), transmural space constant (lambdaTM), and transmural gradients of action potential duration (APD). Relative Cx43 expression, quantified by confocal immunofluorescence, was significantly lower (by 24 +/- 17%; P < 0.05) in subepicardial compared with deeper layers. Importantly, reduced subepicardial Cx43 was associated with transmural heterogeneities of EP function evidenced by selectively reduced subepicardial thetaTM (by 18 +/- 9%; P < 0.05) compared with deeper layers. In subepicardial regions, dV/dt(max) was fastest (by 19 +/- 15%) and lambdaTM was smallest (by 18.1 +/- 2%), which suggests that conduction slowing was attributable to localized uncoupling rather than reduced excitability. The maximum transmural APD gradients occurred in the same regions where Cx43 expression was lowest; this suggests that Cx43 expression patterns served to maintain APD gradients across the transmural wall. These data demonstrate that heterogeneous Cx43 expression is closely associated with functionally significant EP heterogeneities across the transmural wall. Therefore, Cx43 expression patterns can potentially contribute to arrhythmic substrates that are dependent on transmural electrophysiological heterogeneities.

Action Potentials↗
PubMed2006

Changes in activation sequence of embryonic chick atria correlate with developing myocardial architecture.

To characterize developmental changes in impulse propagation within atrial musculature, we performed high-speed optical mapping of activation sequence of the developing chick atria using voltage-sensitive dye. The activation maps were correlated with detailed morphological studies using scanning electron microscopy, histology, and whole mount confocal imaging with three-dimensional reconstruction. A preferential pathway appeared during development within the roof of the atria, transmitting the impulse rapidly from the right-sided sinoatrial node to the left atrium. The morphological substrate of this pathway, the bundle of Bachman, apparent from stage 29 onward, was a prominent ridge of pectinate muscles continuous with the terminal crest. Further acceleration of impulse propagation was noted along the ridges formed by the developing pectinate muscles, ramifying from the terminal crest toward the atrioventricular groove. In contrast, when the impulse reached the interatrial septum, slowing was often observed, suggesting that the septum acts as a barrier or sink for electrical current. We conclude that these inhomogeneities in atrial impulse propagation are consistent with existence of a specialized network of fast-conducting tissues. The purpose of these preferential pathways appears to be to assure synchronous atrial activation and contraction rather than rapid impulse conduction between the sinoatrial and atrioventricular nodes.

Animals↗
PubMed2006

T wave alternans in an in vitro canine tissue model of Brugada syndrome.

Macroscopic T wave alternans (TWA) associated with increased occurrence of ventricular arrhythmias has been reported in patients with Brugada syndrome. However, the mechanisms in this syndrome are still unclear. We evaluated the hypothesis that TWA in Brugada syndrome was caused by the dynamic instability and heterogeneity of action potentials (APs) in the right ventricle. Using an optical mapping system, we mapped APs on the epicardium or transmural surfaces of 28 isolated and arterially perfused canine right ventricular preparations having drug-induced Brugada syndrome (in micromol/l: 2.5-15 pinacidil, 5.0 terfenadine, and 5.0-13 pilsicainide). Bradycardia at cycle length (CL) of 2,632 +/- 496 ms (n = 19) induced alternating deep and shallow T waves in the transmural electrocardiogram. Compared with the shallow T waves, deep T waves were associated with epicardial APs having longer durations and larger domes. Adjacent regions having APs with alternating domes, with constant domes, and without domes coexisted simultaneously in the epicardium and caused TWA. In contrast to the alternating epicardial APs, midmyocardial and endocardial APs did not change during TWA. Alternans could be terminated by rapid (CL: 529 +/- 168 ms, n = 7) or very slow (CL: 3,000 ms, n = 7) pacing. The heterogeneic APs during TWA augmented the dispersion of repolarization both within the epicardium and from the epicardium to the endocardium and caused phase 2 reentry. In this drug-induced model of Brugada syndrome, heterogeneic AP contours and dynamic alternans in the dome of right ventricular epicardial, but not midmyocardial or endocardial, APs caused TWA and heightened arrhythmogenicity in part by increasing the dispersion of repolarization.

Action Potentials↗