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Ventricular hypertrophy amplifies transmural repolarization dispersion and induces early afterdepolarization. Am J Physiol Heart Circ Physiol 281: H1968-H1975, 2001.--The effects of left ventricular hypertrophy (LVH) on the generation of phase 2 early afterdepolarization (EAD) and transmural dispersion of repolarization (TDR) were assessed using arterially perfused rabbit ventricular wedge preparations. Transmembrane action potentials from epicardium, subendocardium, and endocardium were simultaneously recorded together with a transmural ECG. Transmural action potential duration (APD) was also mapped. LVH (renovascular hypertension model) produced significant prolongation in ventricular APD and QT interval. Preferential APD prolongation in subendocardium and endocardium was associated with a marked increase in TDR. Phase 2 EADs were generated from subendocardium or endocardium in all LVH rabbits (15 of 15) in the absence of APD prolonging agents at basic cycle lengths of 2,000-4,000 ms. Phase 2 EAD could produce 'R on T' extrasystoles, initiating polymorphic ventricular tachycardia (VT). This study provides the first direct evidence from intracellular recordings that phase 2 EAD could be generated from rabbit intact hypertrophied LV wall in the absence of APD prolonging agents, resulting in R on T extrasystoles capable of initiating polymorphic VT under enhanced TDR. action potential; ventricular tachycardia; epicardium; endocardium

Mutations in the human ether-a-go-go-related gene ( hERG) are responsible for congenital Type 2 long QT syndrome ( LQT2). Previously, we reported a truncated mutation of hERG in a Chinese family with LQT2, namely L539 fs/47, which is composed of a 19 bp deletion mutation and an A1692G polymorphism. This mutation was found to cause an LQT2 phenotype. The aim of the present study was to investigate the functional role of L539 fs/47 at the cellular level and its potential contribution to the loss of function of hERG channels., The function of the truncated mutation L539 fs/47 was evaluated by constructing a mutated plasmid, transfection of the mutated cDNA into HEK 293 cells and subsequent patch-clamp, western blotting and immunostaining experiments., Homologous expression of L539 fs/47 in HEK 293 cells produced a non-functional protein that was detected in cell membranes. When L539 fs/47 was expressed simultaneously with wild-type hERG, it suppressed wild-type hERG currents in a dose-dependent manner and changed the gating properties of the channel., Although L539 fs/47 hERG proteins were detected on plasma membranes, they failed to generate hERG currents. In general, L539 fs/47 dose-dependently decreases hERG ion channel currents and suppresses the function of wild-type channels function. This may explain, in part, the clinical manifestations of LQT2 in the family with this mutation. [ABSTRACT FROM AUTHOR]

Background and Purpose: Drug-induced torsades de pointes (TdP) often occurs during bradycardia due to reverse use-dependence. We tested the hypothesis that inhibition or enhancement of late sodium current (I(Na,L) ) could modulate the drug-induced reverse use-dependence in QT and T(p-e) (an index of dispersion of repolarization), and therefore the liability for TdP.Experimental Approach: Arterially perfused rabbit left ventricular wedge preparations were used. Action potentials from the endocardium were recorded simultaneously with a transmural ECG. The effects of Anemonia sulcata toxin (ATX-II) (an I(Na,L) enhancer), d,l-sotalol, clarithromycin and ranolazine (an I(Na,L) blocker) on rate-dependent changes in QT, T(p-e) and proarrhythmic events were tested, either alone or in combination. Rate-dependent QT and T(p-e) slopes and TdP score (a combined index of TdP liability) were calculated at control and during drug infusion.Key Results: ATX-II (30 nM) and sotalol (300 µM) caused a marked increase in QT and T(p-e) intervals, steeper QT-basic cycle length (BCL) and T(p-e) -BCL slopes (i.e. reverse use-dependence), and TdP. Addition of ranolazine (15 µM) to ATX-II or sotalol significantly attenuated QT-BCL, T(p-e) -BCL slopes and the increased TdP scores. In contrast, clarithromycin (100 µM) moderately prolonged QT and T(p-e) without causing R-on-T extrasystole or TdP, but addition of ATX-II (1 nM) to clarithromycin markedly amplified the QT-BCL and T(p-e) -BCL slopes and further increased TdP score.Conclusion and Implications: Modulation of I(Na,L) altered drug-induced reverse use-dependence related to QT as well as T(p-e) , indicating that inhibition of I(Na,L) can markedly reduce the TdP liability of agents that prolong QT intervals. [ABSTRACT FROM AUTHOR]

Background and Purpose: The regulatory guidelines (ICHS7B) for the identification of only drug-induced long QT and pro-arrhythmias have certain limitations.Experimental Approach: Conduction time (CT) was measured in isolated Purkinje fibres, left ventricular perfused wedges and perfused hearts from rabbits, and sodium current was measured in Chinese hamster ovary cells, transfected with Na(v)1.5 channels.Key Results: A total of 355 compounds were screened for their effects on CT: 32% of these compounds slowed conduction, 65% had no effect and 3% accelerated conduction. Lidocaine and flecainide, which slow conduction, were tested in more detail as reference compounds. In isolated Purkinje fibres, flecainide largely slowed conduction and markedly increased triangulation, while lidocaine slightly slowed conduction and did not produce significant triangulation. Also in isolated left ventricular wedge preparations, flecainide largely slowed conduction in a rate-dependent manner, and elicited ventricular tachycardia (VT). Lidocaine slightly slowed conduction, reduced Tp-Te and did not induce VT. Similarly in isolated hearts, flecainide markedly slowed conduction, increased Tp-Te and elicited VT or ventricular fibrillation (VF). The slowing of conduction and induction of VT/VF with flecainide was much more evident in a condition of ischaemia/reperfusion. Lidocaine abolished ischaemia/reperfusion-induced VT/VF. Flecainide blocked sodium current (I(Na)) preferentially in the activated state (i.e. open channel) with slow binding and dissociation rates in a use-dependent manner, and lidocaine weakly blocked I(Na).Conclusion and Implications: Slowing conduction by blocking I(Na) could be potentially pro-arrhythmic. It is possible to differentiate between compounds with 'good' (lidocaine-like) and 'bad' (flecainide-like) I(Na) blocking activities in these models. [ABSTRACT FROM AUTHOR]

The J wave, also referred to as an Osborn wave, is a deflection immediately following the QRS complex of the surface ECG. When partially buried in the R wave, the J wave appears as J-point elevation or ST-segment elevation. Several lines of evidence have suggested that arrhythmias associated with an early repolarization pattern in the inferior or mid to lateral precordial leads, Brugada syndrome, or arrhythmias associated with hypothermia and the acute phase of ST-segment elevation myocardial infarction are mechanistically linked to abnormalities in the manifestation of the transient outward current (Ito)-mediated J wave. Although Brugada syndrome and early repolarization syndrome 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 that we propose be termed J-wave syndromes. This review summarizes our current state of knowledge concerning J-wave syndromes, bridging basic and clinical aspects. We propose to divide early repolarization syndrome into three subtypes: type 1, which displays an early repolarization pattern predominantly in the lateral precordial leads, is prevalent among healthy male athletes and is rarely seen in ventricular fibrillation survivors; type 2, which displays an early repolarization pattern predominantly in the inferior or inferolateral leads, is associated with a higher level of risk; and type 3, which displays an early repolarization pattern globally in the inferior, lateral, and right precordial leads, is associated with the highest level of risk for development of malignant arrhythmias and is often associated with ventricular fibrillation storms. [Copyright &y& Elsevier]

Cellular Electrophysiology of Vanoxerine. Introduction: There remains an unmet need for safe and effective antiarrhythmic drugs, especially for the treatment of atrial fibrillation. Vanoxerine is a drug that is free of adverse cardiac events in normal volunteers, yet is a potent blocker of the hERG (hKv11.1) cardiac potassium channel. Consequently,we hypothesized that vanoxerine might also be a potent blocker of cardiac calcium (Ca) and sodium (Na) currents, and would not affect transmural dispersion of repolarization. Methods: The whole cell patch clamp technique was used to measure currents from cloned ion channels overexpressed in stable cell lines and single ventricular myocytes. We measured intracellular action potentials from canine ventricular wedges and Purkinje fibers using sharp microelectrode technique. Results: We found that vanoxerine was a potent hKv11.1 blocker, and at submicromolar concentrations, it blocked Ca and Na currents in a strongly frequency-dependent manner. In the canine ventricular wedge preparation vanoxerine did not significantly affect transmural action potential waveforms, QT interval or transmural dispersion of repolarization. Conclusions: Vanoxerine (1) is a potent blocker of cardiac hERG, Na and Ca channels; (2) block is strongly frequency-dependent especially for Na and Ca channels; and (3) transmural dispersion of ventricular repolarization is unaffected. The multichannel block and repolarization uniformity resemble the effects of amiodarone, the exemplar atrial fibrillation drug. Vanoxerine is a completely different chemical and has none of amiodarone's toxic effects. Vanoxerine has characteristics of a potentially effective and safe antiarrhythmic. [ABSTRACT FROM AUTHOR]

Cardiac arrhythmias occur in approximately 5.3% of the population and contribute substantially to morbidity and mortality. Pharmacological therapy still remains the major approach in management of patients with nearly every form of cardiac arrhythmia. Effective and safe management of cardiac arrhythmias with antiarrhythmic drugs requires understanding of basic mechanisms for various cardiac arrhythmias, clinical diagnosis of an arrhythmia and identification of underlying cardiac diseases, pharmacokinetics, and antiarrhythmic properties of each individual antiarrhythmic drug. Most cardiac arrhythmias occur via one of the two mechanisms: abnormal impulse formation and reentry or both. Antiarrhythmic drugs primarily work via influencing cardiac automaticity or triggered activity or by their effects on effective refractoriness of cardiac cells. Proarrhythmic effects of antiarrhythmic drugs are also briefly discussed in this review article. [ABSTRACT FROM AUTHOR]

Background: Arrhythmic risk stratification in patients with Brugada syndrome remains controversial. Several recent reports have highlighted the possible role of late potential (LP) on the signal-averaged electrocardiogram (SAECG) as a noninvasive risk stratification tool in Brugada syndrome, but further prospective study is required before its general applicability. Objective: The purpose of this study was to investigate the role of LP in arrhythmic risk stratification of Brugada syndrome patients. Methods: Forty-three patients with Brugada syndrome were enrolled and divided into a symptomatic group (group A, n = 24) and an asymptomatic group (group B, n = 19). SAECG was performed to analyze the characteristics of LP in all subjects. The prospective study was conducted to observe the occurrence of arrhythmic events. Results: LP was positive in 22 (91.7%) of 24 patients in the symptomatic group and in 7 (36.8%) of 19 patients in the asymptomatic group. During mean follow-up of 33.8 ± 9.0 months, the incidence rate of arrhythmic events was 72.4% (21/29) in LP-positive [LP(+)] patients compared with 14.3% (2/14) in LP-negative [LP(−)] patients. Multivariate Cox proportional hazard analyses revealed that the presence of LP had the most significant hazard ratio of 10.9 (95% confidence interval 1.1–104.3, P = .038), with sensitivity of 95.7%, specificity 65.0%, positive predictive value 75.9%, negative predictive value 92.9%, and predictive accuracy 81.4%. Kaplan-Meier curves plotted for event-free survival according to LP showed a significant difference between LP(+) and LP(−) patients (log rank, P = .003). Conclusion: The results of this study support the role of LP detected by SAECG in arrhythmic risk stratification of Brugada syndrome patients. [Copyright &y& Elsevier]

Background: Quinidine is used to treat atrial fibrillation and ventricular arrhythmias. However, at low concentrations, it can induce torsade de pointes (TdP). Objective: The purpose of this study was to examine the role of late sodium current (INa) as a modulator of the arrhythmogenicity of quinidine in female rabbit isolated hearts and cardiomyocytes. Methods: Epicardial and endocardial monophasic action potentials (MAPs), ECG signals, and ion channel currents were measured. The sea anemone toxin ATX-II was used to increase late INa. Results: Quinidine had concentration-dependent and often biphasic effects on measures of arrhythmogenicity. Quinidine increased the duration of epicardial MAP (MAPD90), QT interval, transmural dispersion of repolarization (TDR), and ventricular effective refractory period. Beat-to-beat variability of MAPD90 (BVR), the interval from peak to end of the T wave (Tpeak-Tend) and index of Tpeak-Tend/QT interval were greater at 0.1 to 3 μmol/L than at 10–30 μmol/L quinidine. In the presence of 1 nmol/L ATX-II, quinidine caused significantly greater concentration-dependent and biphasic changes of Tpeak-Tend, TDR, BVR, and index of Tpeak-Tend/QT interval. Quinidine (1 μmol/L) induced TdP in 2 and 13 of 14 hearts in the absence and presence of ATX-II, respectively. Increases of BVR, index of Tpeak-Tend/QT interval, and Tpeak-Tend were associated with quinidine-induced TdP. Quinidine inhibited IKr, peak INa, and late INa with IC50s of 4.5 ± 0.3 μmol/L, 11.0 ± 0.7 μmol/L, and 12.0 ± 0.7 μmol/L. Conclusion: Quinidine had biphasic proarrhythmic effects in the presence of ATX-II, suggesting that late INa is a modulator of the arrhythmogenicity of quinidine. Enhancement of late INa increased proarrhythmia caused by low but not high concentrations of quinidine. [Copyright &y& Elsevier]

Abstract: An increasing number of basic and clinical studies have suggested that the interval from the peak to the end of the electrocardiographic T wave (Tp-e) may correspond to the transmural dispersion of repolarization and that amplification of the Tp-e interval is associated with malignant ventricular arrhythmias. In this review, we outline the utility of the Tp-e interval and the Tp-e/QT ratio as an electrocardiographic index of arrhythmogenesis for both congenital and acquired ion channel disease leading to ventricular arrhythmias. In healthy individuals, the Tp-e/QT ratio has a mean value of approximately 0.21 in the precordial leads and it remains relatively constant between the heart rates from 60 to 100 beats per minute. Interestingly, the Tp-e/QT ratio is significantly greater in the patients at risk for arrhythmic event such as those with long QT syndrome, Brugada syndrome, short QT syndrome, and also in patients with organic heart disease such as acute myocardial infarction. Functional reentry is the underlying mechanism for arrhythmogenesis associated with an increased Tp-e/QT ratio. [Copyright &y& Elsevier]

Background: Long QT syndrome is associated with early afterdepolarization (EAD) that may result in torsade de pointes (TdP). Interestingly, the corrected QT interval seems to be proportional to body mass across species under physiologic conditions. Objective: The purpose of this study was to test whether recovery of L-type calcium current (ICa,L), the primary charge carrier for EADs, from its inactivated state matches ventricular repolarization time and whether impairment of this relationship leads to development of EAD and TdP. Methods: Transmembrane action potentials from the epicardium, endocardium, or subendocardium were recorded simultaneously with a transmural ECG in arterially perfused left ventricular wedges isolated from cow, dog, rabbit, and guinea pig hearts. ICa,L recovery was examined using action potential stimulation in isolated left ventricular myocytes. Results: The ventricular repolarization time (action potential duration at 90% repolarization [APD90]), ranging from 194.7 ± 1.8 ms in guinea pig to 370.2 ± 9.9 ms in cows, was linearly related to the thickness of the left ventricular wall among the species studied. The time constants (τ) of ICa,L recovery were proportional to APD90, making the ratios of τ to APD90 fall into a relatively narrow range among these species despite markedly different ventricular repolarization time. Drugs with risk for TdP in humans were shown to impair this intrinsic balance by either prolongation of the repolarization time and/or acceleration of ICa,L recovery, leading to the appearance of EADs capable of initiating TdP. Conclusion: An adequate balance between ICa,L recovery and ventricular repolarization serves as a “physiologic stabilizer” of ventricular action potentials in repolarization phases. [Copyright &y& Elsevier]

Introduction: The morphology of the mammalian cardiac action potential (AP) is an important factor in the susceptibility to drug-induced early afterdepolarizations (EADs) that may initiate Torsade de Pointes (TdP). AP triangulation has been shown to be an important predictor of drug-induced TdP. Methods and Results: APs from guinea pig and rabbit left ventricular single myocytes were recorded using a microelectrode-recording technique. ICa-L currents were recorded in ventricular myocytes of guinea pig and rabbit using patch-clamping technique. At a stimulus frequency of 0.5 Hz, guinea pig ventricular myocytes displayed a square-like AP, whereas rabbit ventricular myocytes exhibited a triangle-like AP. Dofetilide-induced EADs were observed only in rabbit ventricular myocytes. Under the guinea pig AP clamping condition, the normalized ICa-L instant reactivation currents in guinea pig and rabbit myocytes at voltages of –40 mV were 0.13 ± 0.01 and 0.14 ± 0.01, respectively. However, when rabbit AP served as the first clamping voltage, the normalized ICa-L reactivation currents at –40 mV in guinea pig and rabbit myocytes were 0.20 ± 0.01, 0.21 ± 0.01, respectively, indicating that the ICa-L recovery from inactivation in the rabbit triangular AP condition was significantly faster than in the guinea pig square AP condition. Comparison of the voltage clamp using the triangular waveform with the square waveform further confirmed that triangulation accelerates ICa-L recovery from inactivation. Conclusions: In rabbit ventricular myocardium, AP triangulation accelerates ICa-L channel recovery from inactivation, leading to instability of the cell membrane potential during repolarization, which is capable of initiating TdP. [ABSTRACT FROM AUTHOR]

Background: The development of preclinical models with high predictive value for the identification of drugs with a proclivity to induce Torsade de Pointes (TdP) in the clinic has long been a pressing goal of academia, industry and regulatory agencies alike. The present study provides a blinded appraisal of drugs, in an isolated arterially-perfused rabbit ventricular wedge preparation, with and without the potential to produce TdP.Methods and Results: Thirteen compounds were tested for their potential for TdP using the rabbit left ventricular wedges. All investigators were blinded to the names, concentrations and molecular weights of the drugs. The compounds were prepared by the study sponsor and sent to the investigator as 4 sets of 13 stock solutions with the order within each set being assigned by a random number generator. Each compound was scored semi-quantitatively for its relative potential for TdP based on its effect on ventricular repolarization measured as QT interval, dispersion of repolarization measured as T(p-e)/QT ratio and early afterdepolarizations. Disclosure of the names and concentrations after completion of the study revealed that all compounds known to be free of TdP risk received a score of less or equal to 0.25, whereas those with known TdP risk received a score ranging from 1.00 to 7.25 at concentrations less than 100X their free therapeutic plasma C(max).Conclusions: Our study provides a blinded evaluation of the isolated arterially-perfused rabbit wedge preparation demonstrating both a high sensitivity and specificity in the assessment of 13 agents with varying propensity for causing TdP. [ABSTRACT FROM AUTHOR]

Abstract: Background: Action potential duration in the right ventricle is normally shorter than that in the left. We tested the hypothesis that there may be intrinsic differences in the QT and Tp-e (an interval from the peak to the end of the T wave) intervals between the left and right chest leads that can be exaggerated by systemic hypertension but attenuated by pulmonary hypertension in humans. Methods: Electrocardiograms in the left (V4L-V6L) and right (V4R-V6R) chest leads were obtained in 40 healthy individuals, 29 patients with systemic hypertension and left ventricular hypertrophy, and 15 patients with pulmonary hypertension. Results: In healthy individuals, the corrected QT (QTc) and corrected Tp-e [T(p-e)c] intervals were 421 ± 5 and 86 ± 3 milliseconds in V4L through V6L, respectively, significantly longer than those recorded from V4R through V6R (383 ± 5 and 62 ± 4 milliseconds, respectively; P < .01). Left ventricular hypertrophy prolonged the QTc interval in V4L through V6L (456 ± 5 milliseconds), exaggerating the difference in the QTc interval between the left and right chest leads (61 ± 4 vs 40 ± 3 milliseconds in healthy control subjects; P < .01). Left ventricular hypertrophy also resulted in a small but significant increase in the T(p-e)c interval in V4L through V6L (97 ± 3 vs 86 ± 3 milliseconds in control subjects; P < .05) but exerted no significant effect on the T(p-e)c interval in the right. In contrast, pulmonary hypertension lengthened the QTc interval in the right chest leads, reducing the difference in the QTc interval between the left and right chest leads (3 ± 8 vs 40 ± 3 milliseconds in control subjects; P < .01). Conclusions: There are intrinsic differences in the QT and Tp-e intervals between V4L-V6L and V4R-V6R that are significantly amplified by systemic hypertension but markedly attenuated by pulmonary hypertension. [Copyright &y& Elsevier]

Proarrhythmic Potential of the Novel Antiarrhythmic Agent AZD7009 and Dofetilide. Background: This study examined the proarrhythmic potential of the novel antiarrhythmic agent AZD7009 and dofetilide. Methods and Results: The electrophysiological and proarrhythmic effects of AZD7009 and dofetilide were assessed in the arterially perfused canine and rabbit left ventricular wedge preparation. The proarrhythmic potential of AZD7009, dofetilide, and azimilide was further assessed in the methoxamine-sensitized rabbit model of torsades de pointes (TdP) in vivo. AZD7009 lengthened the action potential duration (APD) and the QT interval in a bell-shaped manner (15.9 ± 1.3% in canine wedge and 46.1 ± 2.9% in rabbit wedge) occurring at 3 and 1 μM. In contrast, dofetilide did not show the bell-shaped concentration response and the QT interval was lengthened more extensively (27.7 ± 1.6% and 100.8 ± 10.0%). Furthermore, whereas dofetilide prolonged the midmyocardial and endocardial APD predominantly, resulting in an increased transmural dispersion of repolarization (TDR), AZD7009 prolonged the APD more homogenously in all cell layers. At 1 μM, AZD7009 produced phase 2 early afterdepolarizations (EADs) in 1/4 rabbit preparations but without ventricular R-on-T extrasystoles or TdP. In contrast, starting at 0.03 μM, dofetilide-induced EADs, R-on-T extrasystoles and TdP in 6/6, 5/6, and 4/6 preparations. Following intravenous infusion of AZD7009 (210 nmol/kg/minute), dofetilide (2 nmol/kg/minute) or azimilide (3.33 μmol/kg/minute), TdP was induced in 0/8, 5/8, and 5/8 rabbits (P = 0.026 vs AZD7009), respectively. In 5/5 rabbits, AZD7009 promptly suppressed TdP induced by dofetilide. Conclusions: In animal models of TdP, AZD7009 delays ventricular repolarization in a self-limited way associated with a low risk of repolarization-related proarrhythmia. (J Cardiovasc Electrophysiol, Vol. 16, pp. 1-7, July 2005) [ABSTRACT FROM AUTHOR]

The electrocardiographic (ECG) manifestation of ventricular repolarization includes J (Osborn), T, and U waves. On the basis of biophysical principles of ECG recording, any wave on the body surface ECG represents a coincident voltage gradient generated by cellular electrical activity within the heart. The J wave is a deflection with a dome that appears on the ECG after the QRS complex. A transmural voltage gradient during initial ventricular repolarization, which results from the presence of a prominent action potential notch mediated by the transient outward potassium current (I(to)) in epicardium but not endocardium, is responsible for the registration of the J wave on the ECG. Clinical entities that are associated with J waves (the J-wave syndrome) include the early repolarization syndrome, the Brugada syndrome and idiopathic ventricular fibrillation related to a prominent J wave in the inferior leads. The T wave marks the final phase of ventricular repolarization and is a symbol of transmural dispersion of repolarization (TDR) in the ventricles. An excessively prolonged QT interval with enhanced TDR predisposes people to develop torsade de pointes. The malignant "R-on-T" phenomenon, i.e., an extrasystole that originates on the preceding T wave, is due to transmural propagation of phase 2 reentry or phase 2 early afterdepolarization. A pathological "U" wave as seen with hypokalemia is the consequence of electrical interaction among ventricular myocardial layers at action potential phase 3 of which repolarization slows. A physiological U wave is thought to be due to delayed repolarization of the Purkinje system. [ABSTRACT FROM AUTHOR]

Provides information on a study which investigated whether benzodiazepine-induced activation of a slowly activating delayed rectifier potassium current (I[subKs]) could abbreviate action potential and suppress early afterdepolarization resulting from I[subKs] in left ventricular hypertrophy. Methodology of the study; Results and discussion on the study.

Characteristics of the M Cell. The discovery and characterization of the M cell, a unique cell type residing in the deep layers of the ventricular myocardium, has opened a new door in our understanding of the electrophysiology and pharmacology of the heart in both health and disease. The hallmark of the M cell is the ability of its action potential to prolong much more than that of other ventricular myocardial cells in response to a slowing of rate and/or in response to agents that act to prolong action potential duration. Our goal in this review is to provide a comprehensive characterization of the M cell, its contribution to transmural heterogeneity, and its role in the normal electrical function of the heart, in the inscription of the ECG (particularly the T wave), and in the development of QT dispersion, T wave alternans, long QT intervals, and cardiac arrhythmias, such as torsades de pointes. Our secondary goal is to address the controversy that has arisen relative to the functional importance of the M cell in the normal heart. The controversy derives largely from the failure of some investigators to demonstrate transmural heterogeneity of repolarization in the dog in vivo under control conditions and after administration of quinidine. The inability to demonstrate transmural heterogeneity under these conditions may be due to the use of bipolar recording techniques that, in our experience, seriously underestimate transmural dispersion of repolarization (TDR). The use of sodium pentobarbital and α-chloralose as anesthesia also is problematic, because these agents reduce or eliminate TDR by affecting a variety of ion channel currents. Finally, attempts to amplify transmural dispersion of repolarization with an agent such as quinidine must take into account that relatively high concentrations can result in effects opposite to those desired due to drug inhibition of multiple ion channels. These observations may explain the Inability of earlier studies to detect the M cell. [ABSTRACT FROM AUTHOR]