Electrocardiographic marker of ventricular action potential triangulation (the simulation study).

Background: The aim of this simulation was to examine the utility of a novel ECG-based index of cardiac action potential (AP) triangulation, the Tstart-to-Tpeak (TsTp) interval-to-JTstart (JTs) interval ratio, for assessment of changes in AP profile imposed through variations in the duration of the plateau phase and the phase 3 repolarization.

Methods: ECGs were simulated using a realistic rabbit model based on experimental data. The AP plateau was measured at APD30, and the phase 3 was assessed as APD90-to-APD30 difference (AP durations at 90 % and 30 % repolarization, respectively).

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 JT 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.

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.

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.

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.

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.

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.

Role of abnormal repolarization in the mechanism of cardiac arrhythmia.

In cardiac patients, life-threatening tachyarrhythmia is often precipitated by abnormal changes in ventricular repolarization and refractoriness. Repolarization abnormalities typically evolve as a consequence of impaired function of outward K currents in cardiac myocytes, which may be caused by genetic defects or result from various acquired pathophysiological conditions, including electrical remodelling in cardiac disease, ion channel modulation by clinically used pharmacological agents, and systemic electrolyte disorders seen in heart failure, such as hypokalaemia. Cardiac electrical instability attributed to abnormal repolarization relies on the complex interplay between a provocative arrhythmic trigger and vulnerable arrhythmic substrate, with a central role played by the excessive prolongation of ventricular action potential duration, impaired intracellular Ca handling, and slowed impulse conduction.

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).

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.

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.

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.

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.

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.

Impaired epicardial activation-repolarization coupling contributes to the proarrhythmic effects of hypokalaemia and dofetilide in guinea pig ventricles.

Aim: Activation-repolarization coupling refers to the inverse relationship between action potential duration and activation time in myocardial regions along the path of ventricular excitation. This study examined whether the activation-repolarization coupling plays a role in coordinating repolarization times between the right ventricular (RV) and left ventricular (LV) chambers, and if impaired coordination contributes to electrical instability produced by hypokalaemia or dofetilide, a blocker of the delayed rectifier K(+) current.

Methods: In Langendorff-perfused, isolated guinea pig hearts, six monophasic action potential recording electrodes were attached to RV and LV epicardium.

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.

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.

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.

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.

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.

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.

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.

Electrophysiological determinants of arrhythmic susceptibility upon endocardial and epicardial pacing in guinea-pig heart.

Aim: Endocardial pacing instituted to treat symptomatic bradycardia may nevertheless promote tachyarrhythmia in some pacemaker-implanted patients. We sought to determine the contributing electrophysiological mechanisms.

Methods: Left ventricular (LV) monophasic action potential duration (APD(90)) and effective refractory periods were determined in perfused guinea-pig hearts along with volume-conducted ECG recordings during epicardial and endocardial stimulations.