Electrocardiographic marker of the cardiac action potential triangulation induced by antiarrhythmic drugs in perfused guinea-pig heart.

NEW FINDINGS: What is the central question of this study? Can the triangular appearance of ventricular action potential, indicating proarrhythmic profile of antiarrhythmic agent, be approximated by specific changes on an electrocardiogram (ECG)? What are the main finding and its importance? The triangulation of the ventricular action potential seen when antiarrhythmic drugs induce a greater lengthening of the late repolarization compared to the initial repolarization in epicardium is closely approximated by a greater prolongation of the T wave upslope relative to the interval between the J point and the start of the T wave (the JTstart interval) on the ECG. These findings may improve the power of ECG assessments in predicting the drug-induced arrhythmia resulting from slowed phase 3 repolarization. ABSTRACT: Antiarrhythmic drugs prescribed to treat atrial fibrillation can occasionally precipitate ventricular tachyarrhythmia through a prominent slowing of the phase 3 repolarization. The latter results in the triangular shape of ventricular action potential, indicating high arrhythmic risk. However, clinically, the utility of triangulation assessments for predicting arrhythmia is limited owing to the invasive nature of the ventricular action potential recordings. This study examined whether the triangulation effect can be detected indirectly from electrocardiogram (ECG) analysis. Epicardial monophasic action potentials and the ECG were simultaneously recorded in perfused guinea-pig hearts. With antiarrhythmics (dofetilide, quinidine, procainamide and flecainide), a prolongation of the initial repolarization seen in the action potential recordings was closely approximated by lengthening of the interval between the J point and the start of the T wave (the JTstart interval) on the ECG, whereas a prolongation of the late repolarization was paralleled by widening of the T wave upslope. Dofetilide, quinidine and procainamide induced a prominent slowing of the phase 3 repolarization in epicardium, leading to triangulation of the action potential. These effects were accompanied by a greater prolongation of the T wave upslope compared to the JTstart interval. Flecainide elicited a proportional prolongation of the initial and the late ventricular repolarization, and therefore failed to induce triangulation, based on analysis of both epicardial action potential and ECG profiles. Collectively, these findings suggest that the ratio between the durations of the T wave upslope and the JTstart interval may represent the ECG metric of the ventricular action potential triangulation induced by antiarrhythmic drugs.

Antiarrhythmic drug effects on premature beats are partly determined by prior cardiac activation frequency in perfused guinea-pig heart.

NEW FINDINGS: What is the central question of this study? Can antiarrhythmic drug effects on repolarization, conduction time and excitation wavelength in premature beats be determined by prior cardiac activation frequency? What is the main finding and its importance? In premature beats induced after a series of cardiac activations at a slow rate, antiarrhythmics prolong repolarization but evoke little or no conduction delay, thus increasing the excitation wavelength, which indicates an antiarrhythmic effect. Fast prior activation rate attenuates prolongation of repolarization, while amplifying the conduction delay induced by drugs, which translates into the reduced excitation wavelength, indicating proarrhythmia. These findings suggest that a sudden increase in heart rate can shape adverse pharmacological profiles in patients with ventricular ectopy. ABSTRACT: Antiarrhythmic drugs used to treat atrial fibrillation can occasionally induce ventricular tachyarrhythmia, which is typically precipitated by a premature ectopic beat through a mechanism related, in part, to the shortening of the excitation wavelength (EW). The arrhythmia is likely to occur when a drug induces a reduction, rather than an increase, in the EW of ectopic beats. In this study, I examined whether the arrhythmic drug profile is shaped by the increased cardiac activation rate before ectopic excitation. Ventricular monophasic action potential durations, conduction times and EW values were assessed during programmed stimulations applied at long (S1 -S1 [basic drive cycle length] = 550 ms) and short (S1 -S1  = 200 ms) cycle lengths in perfused guinea-pig hearts. The premature activations were induced with extrastimulus application immediately upon termination of the refractory period. With dofetilide, a class III antiarrhythmic agent, a prolongation in action potential duration and the resulting increase in the EW obtained at S1 -S1  = 550 ms were significantly attenuated at S1 -S1  = 200 ms, in both the regular (S1 ) and the premature (S2 ) beats. With class I antiarrhythmic agents (quinidine, procainamide and flecainide), fast S1 -S1 pacing was found to attenuate the drug-induced increase in action potential duration, while amplifying drug-induced conduction slowing, in both S1 and S2 beats. As a result, although the EW was increased (quinidine and procainamide) or not changed (flecainide) at the long S1 -S1 intervals, it was invariably reduced by these agents at the short S1 -S1 intervals. These findings indicate that the increased heart rate before ectopic activation shapes the arrhythmic profiles by facilitating drug-induced EW reduction.

Effects of antiarrhythmics on the electrical restitution in perfused guinea-pig heart are critically determined by the applied cardiac pacing protocol.

NEW FINDINGS: What is the central question of this study? Are modifications in the restitution of ventricular action potential duration induced by antiarrhythmic drugs the same when assessed with premature extrastimulus application at variable coupling intervals (the standard stimulation protocol) and with steady state pacing at variable rates (the dynamic stimulation protocol)? What is the main finding and its importance? With class I and class III antiarrhythmics, the effects on electrical restitution determined with the standard stimulation protocol dissociate from those obtained during dynamic pacing. These findings indicate a limited value of the electrical restitution assessments based on extrasystolic stimulations alone, as performed in the clinical studies, in estimating the outcomes of antiarrhythmic drug therapies. ABSTRACT: A steep slope of the ventricular action potential duration (APD) to diastolic interval (DI) relationships (the electrical restitution) can precipitate tachyarrhythmia, whereas a flattened slope is antiarrhythmic. The derangements in APD restitution responsible for transition of tachycardia to ventricular fibrillation can be assessed with cardiac pacing at progressively increasing rates (the dynamic stimulation protocol). Nevertheless, this method is not used clinically owing to the risk of inducing myocardial ischaemia. Instead, the restitution kinetics is determined with a premature extrastimulus application at variable coupling intervals (the standard stimulation protocol). Whether the two protocols are equivalent in estimating antiarrhythmic drug effects is uncertain. In this study, dofetilide and quinidine, the agents blocking repolarizing K+ currents, increased epicardial APD in perfused guinea-pig hearts, with effects being greater at long vs. short DIs. These changes were more pronounced during dynamic pacing compared to premature extrastimulations. Accordingly, although both agents markedly steepened the dynamic restitution, there was only a marginal increase in the standard restitution slope with dofetilide, and no effect with quinidine. Lidocaine and mexiletine, selective Na+ channel blockers, prolonged the effective refractory period without changing APD, and increased the minimum DI that enabled ventricular capture during extrastimulations. No change in the minimum DI was noted during dynamic pacing. Consequently, although lidocaine and mexiletine reduced the standard restitution slope, they failed to flatten the dynamic restitution. Overall, these findings imply a limited value of the electrical restitution assessments with premature extrastimulations alone in discriminating arrhythmic vs. antiarrhythmic changes during drug therapies.

Determinants of slowed conduction in premature ventricular beats induced during programmed stimulations in perfused guinea-pig heart.

NEW FINDINGS: What is the central question of this study? Is the slowed conduction upon premature ventricular activations during clinical electrophysiological testing attributable to the prolonged activation latency, or increased impulse propagation time, or both? What is the main finding and its importance? Prolonged activation latency at the stimulation site is the critical determinant of conduction slowing and associated changes in the ventricular response intervals in premature beats initiated during phase 3 repolarization in perfused guinea-pig heart. These relations are likely to have an effect on arrhythmia induction and termination independently of the presence of ventricular conduction defects or the proximity of the stimulation site to the re-entrant circuit. ABSTRACT: During cardiac electrophysiological testing, slowed conduction upon premature ventricular activation can limit the delivery of the closely coupled impulses from the stimulation site to the region of tachycardia origin. In order to examine the contributing factors, in this study, cardiac conduction intervals and refractory periods were determined from left ventricular (LV) and the right ventricular (RV) monophasic action potential recordings obtained in perfused guinea-pig hearts. A premature activation induced immediately after the termination of the refractory period was associated with conduction slowing. The latter was primarily accounted for by the markedly increased (+54%) activation latency at the LV stimulation site, with only negligible changes (+12%) noted in the LV-to-RV delay. The prolonged activation latency was acting to limit the shortest interval at which two successive action potentials can be induced in the LV and RV chambers. The prolongation of the activation latency in premature beats was accentuated upon an increase in the stimulating current intensity, or during hypokalaemia. This change was related to the reduced ratio of the refractory period to the action potential duration, which allowed extrastimulus capture to occur earlier during phase 3 repolarization. Flecainide, a Na+ channel blocker, prolonged both the activation latency and the LV-to-RV delay, without changing their relative contributions to conduction slowing. In summary, these findings suggest that the activation latency is the critical determinant of conduction slowing and associated changes in the ventricular response intervals upon extrastimulus application during phase 3 of the action potential.

Effects of antiarrhythmics and hypokalemia on the rate adaptation of cardiac repolarization.

OBJECTIVES: In normal conditions, sudden heart rate acceleration provokes a rapid reduction in ventricular action potential duration (APD). The protracted APD rate adaptation favors early afterdepolarizations and precipitates arrhythmia. Nevertheless, it is uncertain as to whether the rate-dependent changes of ventricular repolarization can be adversely modified by arrhythmogenic drugs (quinidine and procainamide) and hypokalemia, in comparison to the agents with safe therapeutic profile, such as lidocaine. DESIGN: The rate adaptation of QT interval and monophasic APD obtained from the left ventricular (LV) and the right ventricular (RV) epicardium was examined during rapid cardiac pacing applied in isolated, perfused guinea-pig heart preparations. RESULTS: At baseline, an abrupt increase in cardiac activation rate was associated with a substantial reduction of the QT interval and ventricular APD in the first two cardiac cycles, which was followed by a gradual shortening of repolarization over subsequent pacing intervals. The time constants of the fast (τfast) and slow (τslow) components of the APD dynamics determined from a double exponential fit were longer in RV compared to LV chamber. Quinidine, procainamide, and hypokalemia prolonged ventricular repolarization and delayed the rate adaptation of the QT interval and APD in LV and RV, as evidenced by increased τfast and τslow values. In contrast, lidocaine had no effect on the dynamic changes of ventricular repolarization upon heart rate acceleration. CONCLUSIONS: The rate adaptation of ventricular repolarization is delayed by arrhythmogenic interventions, such as quinidine, procainamide, and hypokalemia, but not changed by lidocaine, a clinically safe antiarrhythmic agent.

Arrhythmogenic drugs can amplify spatial heterogeneities in the electrical restitution in perfused guinea-pig heart: An evidence from assessments of monophasic action potential durations and JT intervals.

Non-uniform shortening of the action potential duration (APD90) in different myocardial regions upon heart rate acceleration can set abnormal repolarization gradients and promote arrhythmia. This study examined whether spatial heterogeneities in APD90 restitution can be amplified by drugs with clinically proved proarrhythmic potential (dofetilide, quinidine, procainamide, and flecainide) and, if so, whether these effects can translate to the appropriate changes of the ECG metrics of ventricular repolarization, such as JT intervals. In isolated, perfused guinea-pig heart preparations, monophasic action potentials and volume-conducted ECG were recorded at progressively increased pacing rates. The APD90 measured at distinct ventricular sites, as well as the JTpeak and JTend values were plotted as a function of preceding diastolic interval, and the maximum slopes of the restitution curves were determined at baseline and upon drug administration. Dofetilide, quinidine, and procainamide reverse rate-dependently prolonged APD90 and steepened the restitution curve, with effects being greater at the endocardium than epicardium, and in the right ventricular (RV) vs. the left ventricular (LV) chamber. The restitution slope was increased to a greater extent for the JTend vs. the JTpeak interval. In contrast, flecainide reduced the APD90 restitution slope at LV epicardium without producing effect at LV endocardium and RV epicardium, and reduced the JTpeak restitution slope without changing the JTend restitution. Nevertheless, with all agents, these effects translated to the amplified epicardial-to-endocardial and the LV-to-RV non-uniformities in APD90 restitution, paralleled by the increased JTend vs. JTpeak difference in the restitution slope. In summary, these findings suggest that arrhythmic drug profiles are partly attributable to the accentuated regional heterogeneities in APD90 restitution, which can be indirectly determined through ECG assessments of the JTend vs. JTpeak dynamics at variable pacing rates.

Assessments of the QT/QRS restitution in perfused guinea-pig heart can discriminate safe and arrhythmogenic drugs.

INTRODUCTION: Drug-induced arrhythmia remains a matter of serious clinical concern, partly due to low prognostic value of currently available arrhythmic biomarkers. METHODS: This study examined whether arrhythmogenic risks can be predicted through assessments of the rate adaptation of QT interval, ventricular effective refractory period (ERP), or the QT/QRS ratio, in perfused guinea-pig hearts. RESULTS: When the maximum restitution slope was taken as a metric of proarrhythmia, neither QT interval nor ERP measurements at progressively increased pacing rates were found to fully discriminate arrhythmogenic drugs (dofetilide, quinidine, flecainide, and procainamide) from those recognized as safe antiarrhythmics (lidocaine and mexiletine). For example, the slope of QT restitution was increased by dofetilide and quinidine, but remained unchanged by flecainide, procainamide, lidocaine, and mexiletine. With ERP rate adaptation, even though the restitution slope was increased by dofetilide, all class I agents reduced the slope value independently of their safety profile. The QRS measurements revealed variable drug effects, ranging from significant use-dependent conduction slowing (flecainide, quinidine, and procainamide) to only modest increase in QRS (lidocaine and mexiletine), or no change at all (dofetilide). However, with the QT/QRS rate adaptation, the restitution slope was significantly increased by all agents which have been reported to produce proarrhythmic effects (dofetilide, quinidine, flecainide, and procainamide), but not changed by lidocaine and mexiletine. DISCUSSION: These findings suggest that the slope of the QT/QRS rate adaptation can be considered as a novel electrophysiological biomarker in predicting potential arrhythmic risks associated with pharmacotherapy in cardiac patients.

Effects of Na+ channel blockers on the restitution of refractory period, conduction time, and excitation wavelength in perfused guinea-pig heart.

Na+ channel blockers flecainide and quinidine can increase propensity to ventricular tachyarrhythmia, whereas lidocaine and mexiletine are recognized as safe antiarrhythmics. Clinically, ventricular fibrillation is often precipitated by transient tachycardia that reduces action potential duration, suggesting that a critical shortening of the excitation wavelength (EW) may contribute to the arrhythmic substrate. This study examined whether different INa blockers can produce contrasting effects on the rate adaptation of the EW, which would explain the difference in their safety profile. In perfused guinea-pig hearts, effective refractory periods (ERP), conduction times, and EW values were determined over a wide range of cardiac pacing intervals. All INa blockers tested were found to flatten the slope of ERP restitution, indicating antiarrhythmic tendency. However, with flecainide and quinidine, the beneficial changes in ERP were reversed owing to the use-dependent conduction slowing, thereby leading to significantly steepened restitution of the EW. In contrast, lidocaine and mexiletine had no effect on ventricular conduction, and therefore reduced the slope of the EW restitution, as expected from their effect on ERP. These findings suggest that the slope of the EW restitution is an important electrophysiological determinant which can discriminate INa blockers with proarrhythmic and antiarrhythmic profile.

Flecainide attenuates rate adaptation of ventricular repolarization in guinea-pig heart.

OBJECTIVES: Flecainide is class Ic antiarrhythmic agent that was found to increase the risk of sudden cardiac death. Arrhythmic responses to flecainide could be precipitated by exercise, suggesting a role played by inappropriate rate adaptation of ventricular repolarization. This study therefore examined flecainide effect on adaptation of the QT interval and ventricular action potential duration (APD) to abrupt reductions of the cardiac cycle length. DESIGN: ECG and ventricular epicardial and endocardial monophasic APD were recorded in isolated, perfused guinea-pig heart preparations upon a sustained cardiac acceleration (rapid pacing for 30 s), and following a single perturbation of the cycle length evoked by extrasystolic stimulation. RESULTS: Sustained increase in heart rate was associated with progressive bi-exponential shortening of the QT interval and APD. Flecainide prolonged ventricular repolarization, delayed its rate adaptation, and decreased the amplitude of QT interval and APD shortening upon rapid cardiac pacing. During extrasystolic stimulation, flecainide attenuated APD shortening in premature ventricular beats, with effect being greater upon using a longer basic drive cycle length (S1-S1=550 ms versus S1-S1=300 ms). CONCLUSIONS: Flecainide-induced arrhythmia may be partly accounted for by attenuated adaptation of ventricular repolarization to sudden changes in cardiac cycle length provoked by transient tachycardia or ectopic beats.

Emerging role of neurotensin in regulation of the cardiovascular system.

There is increasing evidence in support of an important role played by neurotensin (NT), a tridecapeptide originally found in bovine hypothalamus, in regulation of cardiovascular system. Elevated systemic levels of NT may contribute to pathogenesis of acute circulatory disoders, and predict the risk for cardiovascular morbidity and mortality in population-based studies. Within cardiovascular system, NT-containing neural fibers are found in close contact with atrial and ventricular cardiac myocytes, cardiac conduction system, intracardiac ganglia, as well as coronary vessels in humans and various animal species. The density of NT-immunoreactive innervation is reduced in cardiac disease. NT produces a variety of cardiovascular actions including effects on heart rate, myocardial contractility, systemic blood pressure, coronary vascular tone, venous smooth muscle tone, and regional blood flow in gastrointestinal tract, cutaneous and adipose tissue. NT could trigger cardiovascular reflexes by stimulating primary visceral afferents synaptically connected with preganglionic sympathetic neurons at the spinal cord. Structural determinants of biological activity of NT reside primarily in the C-terminal portion of its molecule which is responsible for receptor activation. NT effects are mediated via activation of NT receptors, or produced indirectly via stimulation of release of various endogenous neuromodulators/neurotransmitters such as histamine, catecholamines and prostaglandins. Three subtypes of NT receptor (NTS1, NTS2 and NTS3) have been shown to be expressed in the myocardium. NTS1, a high-affinity NT binding site coupled to phospholipase C-inositoltrisphosphate transduction pathway, is thought to mediate NT-induced cardiovascular responses.

Reduced intrinsic heart rate is associated with reduced arrhythmic susceptibility in guinea-pig heart.

OBJECTIVES: In the clinical setting, patients with slower resting heart rate are less prone to cardiovascular death compared with those with elevated heart rate. However, electrophysiological adaptations associated with reduced cardiac rhythm have not been thoroughly explored. In this study, relationships between intrinsic heart rate and arrhythmic susceptibility were examined by assessments of action potential duration (APD) rate adaptation and inducibility of repolarization alternans in sinoatrial node (SAN)-driven and atrioventricular (AV)-blocked guinea-pig hearts perfused with Langendorff apparatus. DESIGN: Electrocardiograms, epicardial monophasic action potentials, and effective refractory periods (ERP) were assessed in normokalemic and hypokalemic conditions. RESULTS: Slower basal heart rate in AV-blocked hearts was associated with prolonged ventricular repolarization during spontaneous beating, and with attenuated APD shortening at increased cardiac activation rates during dynamic pacing, when compared with SAN-driven hearts. During hypokalemic perfusion, the inducibility of repolarization alternans and tachyarrhythmia by rapid pacing was found to be lower in AV-blocked hearts. This difference was ascribed to prolonged ERP in the setting of reduced basal heart rate, which prevented ventricular capture at critically short pacing intervals required to induce arrhythmia. CONCLUSIONS: Reduced basal heart rate is associated with electrophysiological changes that prevent electrical instability upon an abrupt cardiac acceleration.

Impact of hypokalemia on electromechanical window, excitation wavelength and repolarization gradients in guinea-pig and rabbit hearts.

Normal hearts exhibit a positive time difference between the end of ventricular contraction and the end of QT interval, which is referred to as the electromechanical (EM) window. Drug-induced prolongation of repolarization may lead to the negative EM window, which was proposed to be a novel proarrhythmic marker. This study examined whether abnormal changes in the EM window may account for arrhythmogenic effects produced by hypokalemia. Left ventricular pressure, electrocardiogram, and epicardial monophasic action potentials were recorded in perfused hearts from guinea-pig and rabbit. Hypokalemia (2.5 mM K(+)) was found to prolong repolarization, reduce the EM window, and promote tachyarrhythmia. Nevertheless, during both regular pacing and extrasystolic excitation, the increased QT interval invariably remained shorter than the duration of mechanical systole, thus yielding positive EM window values. Hypokalemia-induced arrhythmogenicity was associated with slowed ventricular conduction, and shortened effective refractory periods, which translated to a reduced excitation wavelength index. Hypokalemia also evoked non-uniform prolongation of action potential duration in distinct epicardial regions, which resulted in increased spatial variability in the repolarization time. These findings suggest that arrhythmogenic effects of hypokalemia are not accounted for by the negative EM window, and are rather attributed to abnormal changes in ventricular conduction times, refractoriness, excitation wavelength, and spatial repolarization gradients.

Effects of Na+ channel blockers on extrasystolic stimulation-evoked changes in ventricular conduction and repolarization.

Antiarrhythmic agents which belong to class Ia (quinidine) and Ic (flecainide) reportedly increase propensity to ventricular tachyarrhythmia, whereas class Ib agents (lidocaine and mexiletine) are recognized as safe antiarrhythmics. Clinically, tachyarrhythmia is often initiated by a premature ectopic beat, which increases spatial nonuniformities in ventricular conduction and repolarization thus facilitating reentry. This study examined if electrical derangements evoked by premature excitation may be accentuated by flecainide and quinidine, but unchanged by lidocaine and mexiletine, which would explain the difference in their safety profile. In perfused guinea pig hearts, a premature excitation evoked over late repolarization phase was associated with prolonged epicardial activation time, reduced monophasic action potential duration (APD), and increased transepicardial dispersion of the activation time and APD. Flecainide and quinidine increased conduction slowing evoked by extrasystolic stimulation, prolonged APD, and accentuated spatial heterogeneities in ventricular conduction and repolarization associated with premature excitation. Spontaneous episodes of nonsustained monomorphic ventricular tachycardia were observed in 50% of heart preparations exposed to drug infusion. In contrast, lidocaine and mexiletine had no effect on extrasystolic stimulation-evoked changes in ventricular conduction and repolarization or arrhythmic susceptibility. These findings suggest that flecainide and quinidine may promote arrhythmia by exaggerating electrophysiological abnormalities evoked by ectopic beats.

Procainamide and lidocaine produce dissimilar changes in ventricular repolarization and arrhythmogenicity in guinea-pig.

Procainamide is class Ia Na(+) channel blocker that may prolong ventricular repolarization secondary to inhibition of IK r , the rapid component of the delayed rectifier K(+) current. In contrast to selective IN a blockers such as lidocaine, procainamide was shown to produce arrhythmogenic effects in the clinical setting. This study examined whether pro-arrhythmic responses to procainamide may be accounted for by drug-induced repolarization abnormalities including impaired electrical restitution kinetics, spatial gradients in action potential duration (APD), and activation-to-repolarization coupling. In perfused guinea-pig hearts, procainamide was found to prolong the QT interval on ECG and left ventricular (LV) epicardial monophasic APD, increased the maximum slope of electrical restitution, enhanced transepicardial APD variability, and eliminated the inverse correlation between the local APD and activation time values determined at distinct epicardial recording sites prior to drug infusion. In contrast, lidocaine had no effect on electrical restitution, the degree of transepicardial repolarization heterogeneities, and activation-to-repolarization coupling. Spontaneous episodes of monomorphic ventricular tachycardia were observed in 57% of procainamide-treated heart preparations. No arrhythmia was induced by lidocaine. In summary, this study suggests that abnormal changes in repolarization may contribute to pro-arrhythmic effects of procainamide.

Quinidine elicits proarrhythmic changes in ventricular repolarization and refractoriness in guinea-pig.

Quinidine is a class Ia Na(+) channel blocker that prolongs cardiac repolarization owing to the inhibition of I(Kr), the rapid component of the delayed rectifier current. Although quinidine may induce proarrhythmia, the contributing mechanisms remain incompletely understood. This study examined whether quinidine may set proarrhythmic substrate by inducing spatiotemporal abnormalities in repolarization and refractoriness. The monophasic action potential duration (APD), effective refractory periods (ERPs), and volume-conducted electrocardiograms (ECGs) were assessed in perfused guinea-pig hearts. Quinidine was found to produce the reverse rate-dependent prolongation of ventricular repolarization, which contributed to increased steepness of APD restitution. Throughout the epicardium, quinidine elicited a greater APD increase in the left ventricular chamber compared with the right ventricle, thereby enhancing spatial repolarization heterogeneities. Quinidine prolonged APD to a greater extent than ERP, thus extending the vulnerable window for ventricular re-excitation. This change was attributed to increased triangulation of epicardial action potential because of greater APD lengthening at 90% repolarization than at 30% repolarization. Over the transmural plane, quinidine evoked a greater ERP prolongation at endocardium than epicardium and increased dispersion of refractoriness. Premature ectopic beats and monomorphic ventricular tachycardia were observed in 50% of quinidine-treated heart preparations. In summary, abnormal changes in repolarization and refractoriness contribute greatly to proarrhythmic substrate upon quinidine infusion.

Dofetilide promotes repolarization abnormalities in perfused Guinea-pig heart.

PURPOSE: Dofetilide is class III antiarrhythmic agent which prolongs cardiac action potential duration because of selective inhibition of I (Kr), the rapid component of the delayed rectifier K(+) current. Although clinical studies reported on proarrhythmic risk associated with dofetilide treatment, the contributing electrophysiological mechanisms remain poorly understood. This study was designed to determine if dofetilide-induced proarrhythmia may be attributed to abnormalities in ventricular repolarization and refractoriness. METHODS: The monophasic action potential duration and effective refractory periods (ERP) were assessed at distinct epicardial and endocardial sites along with volume-conducted ECG recordings in isolated, perfused guinea-pig heart preparations. RESULTS: Dofetilide was found to produce the reverse rate-dependent prolongation of ventricular repolarization, increased the steepness of action potential duration rate adaptation, and amplified transepicardial variability in electrical restitution kinetics. Dofetilide also prolonged the T peak-to-end interval on ECG, and elicited a greater prolongation of endocardial than epicardial ERP, thereby increasing transmural dispersion of refractoriness. At epicardium, dofetilide prolonged action potential duration to a greater extent than ERP, thus extending the critical interval for ventricular re-excitation. This change was associated with triangulation of epicardial action potential because of greater dofetilide-induced prolonging effect at 90 % than 30 % repolarization. Premature ectopic beats and spontaneous short-lasting episodes of monomorphic ventricular tachycardia were observed in 44 % of dofetilide-treated heart preparations. CONCLUSIONS: Proarrhythmic potential of dofetilide in guinea-pig heart is attributed to steepened electrical restitution, increased transepicardial variability in electrical restitution kinetics, amplified transmural dispersion of refractoriness, increased critical interval for ventricular re-excitation, and triangulation of epicardial action potential.

Flecainide-induced proarrhythmia is attributed to abnormal changes in repolarization and refractoriness in perfused guinea-pig heart.

Flecainide is nonselective Na(+) channel blocker which may also inhibit I(Kr), the rapid component of the delayed rectifier. This study was designed to explore if proarrhythmic responses to flecainide noted in cardiac patients may be partly attributed to abnormal changes in repolarization and refractoriness. Monophasic action potential duration (APD) and effective refractory periods (ERP) were assessed at distinct epicardial and endocardial sites along with volume-conducted ECG recordings in isolated perfused guinea-pig heart preparations. Flecainide was found to prolong ventricular repolarization, with effect being greater at the left ventricular compared with the right ventricular epicardium. This change translated to reversal of the normal right ventricular-to-left ventricular transepicardial APD difference determined before drug infusion. An inverse correlation between local epicardial APD and corresponding activation time values seen at baseline was eliminated in flecainide-treated hearts, indicating the activation-to-repolarization uncoupling. Over transmural plane, flecainide produced a greater ERP lengthening at endocardium than epicardium, thus markedly increasing ERP dispersion across ventricular wall. Spontaneous short-lasting episodes of monomorphic ventricular tachycardia were observed in 45% of heart preparations upon flecainide infusion. In conclusion, in nonischemic guinea-pig heart, flecainide-induced proarrhythmia may be partly attributed to abnormal spatial gradients in repolarization and refractoriness and impaired transepicardial activation-to-repolarization coupling.

Impact of Na⁺ channel blockers on transmural dispersion of refractoriness and arrhythmic susceptibility in guinea-pig left ventricle.

Clinically, class Ib antiarrhythmic agents (selective I(Na) blockers) are considered to be safe drugs, whereas class Ia and Ic agents (non-selective blockers of both I(Na) and I(Kr), the rapid component of the delayed rectifier) may evoke proarrhythmia. I hypothesized that this difference is accounted for by differential drug effects on transmural dispersion of refractoriness, in the presence of the reciprocal distribution profile of I(Na) and I(Kr) across ventricular wall, as determined in previous studies. Specifically, less epicardial than endocardial I(Na) reserve would likely contribute to a greater prolongation of the effective refractory period (ERP) at epicardium by the I(Na) blocker, thereby reducing epicardial-to-endocardial ERP dispersion, with resulting antiarrhythmic effect. In contrast, less endocardial than epicardial I(Kr) reserve would likely contribute to a greater prolongation of repolarization at the endocardium by the I(Kr) blocker, thereby amplifying transmural ERP dispersion and inducing arrhythmia. In perfused guinea-pig hearts, dofetilide, a specific I(Kr) blocker, as well as class Ia (quinidine, procainamide) and class Ic agents (flecainide), were found to prolong the QT interval and monophasic action potential duration, and elicited greater endocardial than epicardial ERP prolongation, thus markedly increasing transmural ERP dispersion. These changes were associated with episodes of monomorphic ventricular tachycardia in 30-40% of experiments. In contrast, class Ib agents (lidocaine, mexiletine) evoked greater epicardial than endocardial ERP lengthening, thereby decreasing transmural ERP dispersion, and produced no tachyarrhythmia. These findings suggest that transmural ERP dispersion is the electrophysiological determinant which may shape the profile of class I agent effects on arrhythmic susceptibility.

Effects of ventricular pacing protocol on electrical restitution assessments in guinea-pig heart.

The steep slope of the rate adaptation of ventricular action potential duration (APD) is thought to indicate profibrillatory tendency. In cardiac patients, APD restitution is commonly assessed by extrasystolic (S(1)-S(2)) stimulations rather than dynamic pacing, because the latter may provoke myocardial ischaemia. In this study, ventricular APD and effective refractory period (ERP) were measured in perfused guinea-pig hearts to determine whether S(1)-S(2) stimulations and dynamic pacing may have similar value in APD restitution assessments aimed to predict arrhythmic risk. The maximal restitution slope was greater upon S(1)-S(2) stimulation than dynamic pacing at the epicardium (S(1)-S(2), 1.2 ± 0.08; dynamic, 0.72 ± 0.06; P = 0.0004) and endocardium (S(1)-S(2), 1.45 ± 0.08; dynamic, 0.95 ± 0.06; P = 0.0003). This difference was partly accounted for by an effect of the previous pacing history, as evidenced by flattening of APD restitution upon reductions in the regular beating interval prior to S(2) application. Furthermore, shorter ERP than APD relationships enabled ventricular capture at shorter diastolic intervals during S(1)-S(2) stimulation than dynamic pacing at the epicardium (S(1)-S(2), -1 ± 3 ms; dynamic, 35 ± 3 ms; P < 0.0001) and endocardium (S(1)-S(2), -1 ± 7 ms; dynamic, 38 ± 3 ms; P < 0.0001), thereby contributing to greater maximal restitution slope values. Flecainide, a Na(+) channel blocker, increased the ERP-to-APD ratio and eliminated early premature beats (diastolic interval of ∼0 ms), thereby flattening the S(1)-S(2) restitution curve, but had no effect on dynamic restitution. In hypokalaemia-induced arrhythmogenicity, a reduction in ventricular fibrillation threshold was paralleled by increased steepness of dynamic APD restitution, while no change in the maximal restitution slope was revealed by S(1)-S(2) stimulations. In summary, changes in electrical restitution obtained from extrasystolic stimulations may dissociate from those revealed by dynamic pacing. These findings therefore challenge the value of electrical restitution assessments based on extrasystolic stimulation alone, as commonly performed in the clinical setting.