Gudrun Antoons

Late Na Current Inhibition by Ranolazine Reduces Torsades de Pointes in the Chronic Atrioventricular Block Dog Model

OBJECTIVES This study investigated whether ranolazine reduces dofetilide-induced torsades de pointes (TdP) in a model of long QT syndrome with down-regulated K(+) currents due to hypertrophic remodeling in the dog with chronic atrioventricular block (cAVB). BACKGROUND Ranolazine inhibits the late Na(+) current (I(NaL)) and is effective against arrhythmias in long QT3 syndromes despite its blocking properties of the rapid component of delayed rectifying potassium current. METHODS Ranolazine was administered to cAVB dogs before or after TdP induction with dofetilide and electrophysiological parameters were determined including beat-to-beat variability of repolarization (BVR). In single ventricular myocytes, effects of ranolazine were studied on I(NaL), action potential duration, and dofetilide-induced BVR and early afterdepolarizations. RESULTS After dofetilide, ranolazine reduced the number of TdP episodes from 10 +/- 3 to 3 +/- 1 (p < 0.05) and partially reversed the increase of BVR with no abbreviation of the dofetilide-induced QT prolongation. Likewise, pre-treatment with ranolazine, or using lidocaine as a specific Na(+) channel blocker, attenuated TdP, but failed to prevent dofetilide-induced increases in QT, BVR, and ectopic activity. In cAVB myocytes, ranolazine suppressed dofetilide-induced early afterdepolarizations in 25% of cells at 5 micromol/l, in 75% at 10 micromol/l, and in 100% at 15 micromol/l. At 5 micromol/l, ranolazine blocked 26 +/- 3% of tetrodotoxin-sensitive I(NaL), and 49 +/- 3% at 15 micromol/l. Despite a 54% reduction of I(NaL) amplitude in cAVB compared with control cells, I(NaL) inhibition by 5 micromol/l tetrodotoxin equally shortened relative action potential duration and completely abolished dofetilide-induced early afterdepolarizations. CONCLUSIONS Despite down-regulation of I(NaL) in remodeled cAVB hearts, ranolazine is antiarrhythmic against drug-induced TdP. The antiarrhythmic effects are reflected in concomitant changes of BVR.

Na/Ca Exchange and Cardiac Ventricular Arrhythmias

Abstract:  Ventricular arrhythmias are a major cause of death in cardiovascular disease. Ca2+ removal from the cell by the electrogenic Na/Ca exchanger is essential for the Ca2+ flux balance during excitation–contraction coupling but also contributes to the electrical events. “Classic” views on the exchanger in arrhythmias include its well‐recognized role as depolarizing current underlying delayed afterdepolarizations (DADs) during spontaneous Ca2+ release and the alterations in expression in certain forms of cardiac hypertrophy and heart failure. “Novel” views relate to more subtle roles for the exchanger in arrhythmias. Na/Ca exchange function in disease could be modulated indirectly, through phosphorylation or anchoring proteins. Ongoing studies relate Na/Ca exchange to variability in action potential duration (APD) and early afterdepolarizations (EADs) in a dog model of cardiac hypertrophy and arrhythmias. Further research on drugs that target Na/Ca exchange will have to carefully examine the effects on Ca2+ balance.

Dominant arrhythmia vulnerability of the right ventricle in senescent mice

BACKGROUND Several cardiac disorders affect the right ventricle (RV) and left ventricle (LV) equally, but nevertheless, RV vulnerability to conduction slowing and arrhythmias exceeds that of the LV. OBJECTIVE This study sought to assess the mechanism of dominant RV arrhythmia vulnerability in senescent mice as a model of general reduced myocardial integrity. METHODS Epicardial ventricular activation mapping was performed on senescent (22 months) and adult (3 months) Langendorff perfused mouse hearts. Arrhythmia inducibility was tested by programmed stimulation. Conduction velocity longitudinal and transversal (CVT) to fiber orientation, conduction heterogeneity, and effective refractory period were determined. Subsequently, hearts were processed for immunohistochemistry, Western blotting, and Sirius red staining. RESULTS In senescent RV, but not LV, CVT was reduced and wavelength decreased, whereas anisotropic ratio and conduction heterogeneity increased. Arrhythmias, based on anisotropic reentry, were induced in 55% of senescent hearts only and predominantly in RV. In senescent mice, Connexin 43 (Cx43) and Cardiac Sodium Channel (Nav1.5) were decreased and interstitial fibrosis increased comparably in RV and LV. However, in senescent mice, heterogeneously distributed patches of replacement fibrosis were present throughout the entire RV myocardium, but only in midendocardium and subendocardium of LV. Cx43 expression in these areas was disrupted. CONCLUSION Widespread presence of replacement fibrosis in senescent RV compared with LV, combined with Cx43 and Nav1.5 disruption, potentiate shorter wavelength, conduction slowing, and conduction heterogeneity in RV, resulting in greater vulnerability of senescent RV to arrhythmias.

Robust anti‐arrhythmic efficacy of verapamil and flunarizine against dofetilide‐induced TdP arrhythmias is based upon a shared and a different mode of action

BACKGROUND AND PURPOSE The high predisposition to Torsade de Pointes (TdP) in dogs with chronic AV‐block (CAVB) is well documented. The anti‐arrhythmic efficacy and mode of action of Ca2+ channel antagonists, flunarizine and verapamil against TdP were investigated.

Increased sarcolemmal Na+/H+ exchange activity in hypertrophied myocytes from dogs with chronic atrioventricular block

Dogs with compensated biventricular hypertrophy due to chronic atrioventricular block (cAVB), are more susceptible to develop drug-induced Torsade-de-Pointes arrhythmias and sudden cardiac death. It has been suggested that the increased Na+ influx in hypertrophied cAVB ventricular myocytes contribute to these lethal arrhythmias. The increased Na+ influx was not mediated by Na+ channels, in fact the Na+ current proved reduced in cAVB myocytes. Here we tested the hypothesis that increased activity of the Na+/H+ exchanger type 1 (NHE-1), commonly observed in hypertrophic hearts, causes the elevated Na+ influx. Cardiac acid-base transport was studied with a pH-sensitive fluorescent dye in ventricular myocytes isolated from control and hypertrophied cAVB hearts; the H+ equivalent flux through NHE-1, Na+-HCO−3 cotransport (NBC), Cl−/OH− exchange (CHE), and Cl−/HCO−3 exchange (AE) were determined and normalized per liter cell water and corrected for surface-to-volume ratio. In cAVB, sarcolemmal NHE-1 flux was increased by 65 ± 6.3% in the pHi interval 6.3–7.2 and NBC, AE, and CHE fluxes remained unchanged. Accordingly, at steady-state intracellular pH the total sarcolemmal Na+ influx by NHE-1 + NBC increased from 8.5 ± 1.5 amol/μm2/min in normal myocytes to 15 ± 2.4 amol/μm2/min in hypertrophied cAVB myocytes. We conclude that compensated cardiac hypertrophy in cAVB dogs is accompanied with an increased sarcolemmal NHE-1 activity. This in conjunction with unchanged activity of the other acid-base transporters will raise the intracellular Na+ in hypertrophied cAVB myocytes.