Mechanisms underlying the antiarrhythmic and arrhythmogenic actions of quinidine in a Purkinje fiber-ischemic gap preparation of reflected reentry

The effects of therapeutic levels of quinidine were studied in an ischemic gap preparation of reflected reentry. The preparation consisted of a Purkinje fiber mounted in a three-compartment chamber. A narrow central compartment was perfused with a solution prepared to mimic the extracellular milieu at a site of ischemia. Quinidine in concentrations that exert little effect on normal Purkinje tissue, 1 to 2 micrograms/ml, greatly impaired conduction and markedly prolonged refractoriness across the ischemic gap. The drug effected these changes by (1) extending the inexcitable zone within the depressed region, (2) decreasing the amplitude of the input signal entering this zone, and (3) decreasing the excitability of the tissue beyond the depressed zone (evaluated by current clamp techniques). These actions of the drug produced both antiarrhythmic and proarrhythmic effects. When the initial level of conduction impairment was high, quinidine totally suppressed reflected reentry at all frequencies by precipitating complete anterograde conduction block. At intermediate levels of block, the drug generally caused a prominent shift of the frequency dependence of reentrant activity to lower stimulation rates. Finally, when conduction was relatively less impaired, quinidine created the conditions for reflected reentry to occur. Our results suggest that the heart rate dependence of reentrant arrhythmias might be of prognostic value in the administration of antiarrhythmic drugs.     

Transient outward current prominent in canine ventricular epicardium but not endocardium

Previous studies have denied the presence of a transient outward current (Ito) in ventricular myocardium of dog, sheep, and calf. Using conventional microelectrode techniques, we provide evidence for a significant contribution of Ito to epicardial, but not endocardial, activity of canine ventricular myocardium. The epicardial action potential when compared with that of endocardium shows a smaller phase 0 amplitude, a much more prominent phase 1, and a phase 2 amplitude that is greater than that of phase 0. Epicardial action potentials, unlike those of endocardium, display a "spike and dome" morphology that becomes progressively more accentuated at slower stimulation rates. Using the restitution of phase 1 amplitude as a marker for the process responsible for the spike and dome phenomenon, we were able to delineate two exponential components: 1) a slow component that recovers with a time constant of 350-570 msec and 2) a fast component with a time constant of 41-85 msec. The slow component was largely abolished by 1-5 mM 4-aminopyridine, an Ito blocker. The fast component was diminished by 4-aminopyridine, but it was also inhibited by ryanodine and by Sr2+ replacement of Ca2+, which are interventions known to inhibit the Ca2+-activated component of Ito. Following 4-aminopyridine and Sr2+ or ryanodine treatment, the epicardial responses more closely resembled those of endocardium. In summary, the data demonstrate a marked heterogeneity of active membrane properties in canine ventricular muscle. These observations may aid in understanding the basis for rate-dependent changes in the T wave of the ECG, supernormal conduction in ventricular muscle, the greater sensitivity of epicardium to ischemia, and the rate dependence of some cardiac arrhythmias.     

Cellular basis for the electrocardiographic and arrhythmic manifestations of Timothy syndrome: effects of ranolazine.

BACKGROUND: Timothy syndrome is a multisystem disorder associated with QT interval prolongation and ventricular cardiac arrhythmias. The syndrome has been linked to mutations in Ca(V)1.2 resulting in gain of function of the L-type calcium current (I(Ca,L)). Ranolazine is an antianginal agent shown to exert an antiarrhythmic effect in experimental models of long QT syndrome. OBJECTIVE: The purpose of this study was to develop and characterize an experimental model of Timothy syndrome by using BayK8644 to mimic the gain of function of I(Ca,L) and to examine the effects of ranolazine. METHODS: Action potentials from epicardial and M regions and a pseudo-electrocardiogram (ECG) were simultaneously recorded from coronary-perfused left ventricular wedge preparations, before and after addition of BayK8644 (1 microM). RESULTS: BayK8644 preferentially prolonged action potential duration of the M cell, leading to prolongation of the QT interval and an increase in transmural dispersion of repolarization (from 44.3 +/- 7 ms to 86.5 +/- 25 ms). Stimulation at cycle lengths of 250-500 ms led to ST-T wave alternans due to alternation of the plateau voltage of the M cell action potential as well as development of delayed afterdepolarizations in epicardial and M cell action potentials. Ventricular extrasystoles and tachycardia (monomorphic, bidirectional, or torsades de pointes) developed spontaneously or after rapid pacing. Peak and late I(Na) were unaffected by BayK8644. Clinically relevant concentrations of ranolazine (10 microM) suppressed all actions of BayK8644. CONCLUSION: A left ventricular wedge model of long QT syndrome created by augmentation of I(Ca,L) recapitulates the ECG and arrhythmic manifestations of Timothy syndrome, which can be suppressed by ranolazine.     

Ranolazine versus amiodarone for prevention of postoperative atrial fibrillation

Postoperative atrial fibrillation (AF) is a major complication of cardiothoracic surgery, leading to significant consequences, including a higher rate of stroke, longer hospital stays and increased costs. Amiodarone is among the most widely used agents for prevention of postoperative AF. Ranolazine, a US FDA-approved antianginal agent, has been shown to effectively, safely prevent and terminate nonpostoperative AF in both experimental and clinical studies. In a recent publication, Miles and colleagues directly compared the efficacy and safety of amiodarone and ranolazine for prevention of postoperative AF in 393 patients. The patients were pretreated with amiodarone and ranolaizne for >1 week and 1 day, respectively, and the treatment continued for 10-14 days after surgery. Following coronary artery bypass grafting (CABG), AF occurred in 26.5% of patients taking amiodarone and in 17.5% of patients taking ranolazine (34% reduction; p < 0.035). No differences in adverse events between the two groups of patients were recorded. The results of this retrospective nonrandomized single-center study indicate that ranolazine may be used to effectively and safely prevent postoperative AF. These results need to be confirmed in a larger randomized study. If confirmed, ranolazine may be a good choice for preventing AF in patients undergoing CABG.     

J-wave syndromes. from cell to bedside

The J wave, a deflection that follows the QRS complex of the surface electrocardiogram, is usually partially buried in the R wave in humans, appearing as a J-point elevation. An early repolarization (ER) pattern characterized by J-point elevation, slurring of the terminal part of the QRS, and ST-segment elevation has long been recognized and considered to be totally benign. Recent studies have presented evidence demonstrating that an ER pattern in inferior leads or inferolateral leads is associated with increased risk for life-threatening arrhythmias, named early repolarization syndrome. Early repolarization syndrome and Brugada syndrome share similar electrocardiographic characteristics, clinical outcomes, risk factors, as well as a common arrhythmic platform related to amplification of I_to-mediated J waves. 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, termed J-wave syndromes. Early repolarization syndrome has been proposed to be divided into 3 subtypes: type 1, displaying an ER pattern predominantly in the lateral precordial leads, is prevalent among healthy male athletes and rarely seen in ventricular fibrillation survivors; type 2, displaying an ER pattern predominantly in the inferior or inferolateral leads, is associated with a higher level of risk; whereas type 3, displaying an ER 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.     

Chromanol 293B inhibits slowly activating delayed rectifier and transient outward currents in canine left ventricular myocytes

INTRODUCTION: Drugs that selectively inhibit the slowly activating component of the delayed rectifier potassium current (I(Ks)) are being considered as possible antiarrhythmic agents, because they produce more prolongation of action potential duration at fast rates with less transmural dispersion of repolarization compared with blockers of the rapidly activating component (I(Kr)). Although the chromanol derivative chromanol 293B has been shown to be relatively selective in blocking I(Ks) in some species, its selectivity is far from established. METHODS AND RESULTS: The present study uses whole-cell, patch-clamp technique to examine the selectivity of this compound for inhibition of I(Ks) in comparison with other repolarizing ionic currents, such as I(Kr), inward rectifier potassium current (I(Kl)), transient outward current (I(to)), and L-type calcium current (I(Ca-L)) in canine left ventricular mid-myocardial and endocardial cells. Chromanol 293B blocked I(Ks) with an IC50 of 1.8 microM and I(to) with an IC50 of 38 microM. Concentrations as high as 30 microM did not affect I(Kl), I(Kr), or I(Ca-L). Higher concentrations of chromanol 293B (100 microM) caused a slight, but statistically insignificant, inhibition of I(Kr). CONCLUSION: Our results indicate that chromanol 293B is a relatively selective blocker of I(Ks) in canine left ventricular myocytes.     

Modulation of canine cardiac sodium current by Apelin

Apelin, a ligand of the G protein-coupled putative angiotensin II-like receptor (APJ-R), exerts strong vasodilating, cardiac inotropic and chronotropic actions. Its expression is highly up-regulated during heart failure. Apelin also increases cardiac conduction speed and excitability. While our knowledge of apelin cardiovascular actions is growing, our understanding of the physiological mechanisms behind the cardiac effects remains limited. We tested the effects of apelin on the cardiac sodium current (I_Na) using patch clamp technique on cardiac myocytes acutely dissociated from dog ventricle. We found that apelin-13 and apelin-17 increased peak I_Na by 39% and 61% and shifted its mid-activation potential by − 6.8 ± 0.6 mV and − 17 ± 1 mV respectively thus increasing channel opening at negative voltage. Apelin also slowed I_Na recovery from inactivation. The effects of apelin on I_Na amplitude were linked to activation of protein kinase C. Apelin also increased I_Na “window” current by up to 600% suggesting that changes in intracellular sodium may contribute to the apelin inotropic effects. Our results reveal for the first time the effects of apelin on I_Na. These effects are likely to modulate cardiac conduction and excitability and may have beneficial antiarrhythmic action in sodium chanelopathies such as Brugada Syndrome where I_Na amplitude is reduced.