Pascal Daleau

Block of the rapid component of the delayed rectifier potassium current by the prokinetic agent cisapride underlies drug-related lengthening of the QT interval.

BACKGROUND Lengthening of the QT interval and torsades de pointes resulting in cardiac arrests and deaths have been noticed during treatment with cisapride, a newly developed gastrointestinal prokinetic agent. The rapid (I[Kr]) and slow (I[Ks]) components of the delayed rectifier current (I[K]) are candidate ionic currents to explain cisapride-related toxicity because of their role in repolarization of cardiac ventricular myocytes. Our objectives were to (1) characterize effects of cisapride on two major time-dependent outward potassium currents involved in the repolarization of cardiac ventricular myocytes, I(Kr) and I(Ks), and (2) determine action potential-prolonging effects of cisapride on isolated hearts. METHODS AND RESULTS A first set of experiments was performed in isolated guinea pig ventricular myocytes with the whole-cell configuration of the patch-clamp technique. Cells were held at -40 mV while time-dependent outward currents were elicited by depolarizing pulses lasting either 250 ms (I[K250]) or 5000 ms (I[K5000]). Effects of cisapride on the I(Kr) component were assessed by measurement of time-dependent activating currents elicited by short pulses (250 ms; I[K250]) to low depolarizing potentials (-20, -10, and 0 mV). Time-dependent activating currents elicited by long pulses (5000 ms; I[K5000]) to positive potentials (>+30 mV) were recorded to assess effects of the drug on the I(Ks) component. A second set of experiments was conducted in isolated guinea pig hearts buffer-perfused in the Langendorff mode to assess effects of the drug on monophasic action potential duration measured at 90% repolarization (MAPD90). Hearts were exposed to cisapride 100 nmol/L at decremental pacing cycle lengths of 250, 225, 200, 175, and 150 ms to determine reverse frequency-dependent effects of the drug. Overall, 112 myocytes were exposed to seven concentrations of cisapride (10 nmol/L to 10 micromol/L). Cisapride inhibited I(Kr), the major time-dependent outward current elicited by short pulses (I[K250]) to low depolarizing potentials, in a concentration-dependent manner with an IC50 of 15 nmol/L (therapeutic levels, 50 to 200 nmol/L). Conversely, block of I(Ks) by the drug was less potent (estimated IC50 >10 micromol/L). In isolated hearts (n=9 experiments), cisapride 100 nmol/L increased MAPD90 by 23+/-3 (P<.05) at a basic cycle length of 250 ms but by only 7+/-1 ms (P<.05) at a basic cycle length of 150 ms. CONCLUSIONS Block of I(Kr) gives an explanation to lengthening of cardiac repolarization observed in isolated guinea pig hearts. Potent block of I(Kr) is also likely to underlie prolongation of the QT interval observed in patients receiving clinically recommended doses of cisapride as well as severe cardiac toxicity (torsades de pointes) observed in patients with increased plasma concentrations of the drug.

Obesity and Metabolic Syndrome Are Independent Risk Factors for Atrial Fibrillation After Coronary Artery Bypass Graft Surgery

Background— Postoperative atrial fibrillation (POAF) is a highly prevalent complication after cardiac surgery with substantial effects on outcomes. Previous studies have reported that obesity is a risk factor for POAF after cardiac surgery. However, it is unknown whether the metabolic syndrome (MS) also increases the risk of postoperative atrial fibrillation. Methods and Results— We retrospectively analyzed the association between obesity and MS and the incidence of new-onset POAF in a total of 5085 patients who underwent isolated coronary artery bypass grafting surgery with no concomitant valvular surgery. Of these patients, 1468 (29%) were obese (body mass index ≥30 kg/m2) and 2320 (46%) had a MS as defined by the NCEP-ATPIII. POAF occurred in 1374 (27%) of the patients. Obesity was associated (P<0.001) with increased incidence of POAF in the whole cohort as well as in patients >50 years old but not in patients ≤50 years old. In these patients, MS was the only metabolic factor to be significantly associated with higher incidence of POAF (12% versus 6%, P=0.01). In >50-year-old patients, mild (30 ≤ body mass index <35 kg/m2) and moderate–severe (body mass index ≥35 kg/m2) obesity were independently associated with a 1.4-fold (95% CI: 1.10 to 1.71; P=0.004) and 2.3-fold (95% CI: 1.71 to 3.13; P<0.0001) increase in the risk of POAF, respectively. In ≤50-year-old patients, MS (relative risk [RR]: 2.36; 95% CI: 1.10 to 5.12; P=0.02) but not obesity was independently associated with POAF. Conclusion— This study demonstrates that obesity is a powerful risk factor for the occurrence of POAF after isolated coronary artery bypass grafting surgery in patients older than 50 years. However, in the younger population, this association is not observed and MS is the only metabolic risk factor to be independently associated with POAF.

Erythromycin Blocks the Rapid Component of the Delayed Rectifier Potassium Current and Lengthens Repolarization of Guinea Pig Ventricular Myocytes

BACKGROUND Administration of erythromycin to humans has been associated with lengthening of cardiac repolarization and even proarrhythmia. The objectives of our study were to describe effects of erythromycin on repolarization of isolated hearts and to determine effects of the drug on major K+ currents involved in cardiac repolarization. METHODS AND RESULTS A first set of experiments was conducted in isolated, buffer-perfused guinea pig hearts electrically stimulated at a basic cycle length of 250 ms. In this model, erythromycin 10(-4) mol/L increased monophasic action potential duration measured at 90% repolarization (MAPD90) by 40 +/- 7 ms. Increase in MAPD90 was reproducibly observed in seven hearts studied. To study the mechanism of these effects on cardiac repolarization, a second set of experiments was performed in isolated guinea pig ventricular myocytes using the whole cell configuration of the patch-clamp technique. In these cells, erythromycin 10(-4) mol/L decreased by about 40% (P < .05 versus baseline) the time-dependent outward K+ current elicited by short depolarizations (250 ms) to low depolarizing voltages (-20 to 0 mV). In contrast, the drug was without significant effects on the time-dependent K+ current elicited by long pulses (5000 ms) to high depolarizing voltages (+10 to +50 mV), on the time-independent background current (mostly IKl), and on the slow inward calcium current. CONCLUSIONS The outward time-dependent K+ current blocked by erythromycin in isolated guinea pig ventricular myocytes had characteristics similar to those described for IKr. Selective block of this component of IK gives an explanation for the effects of erythromycin on cardiac repolarization. These effects were observed at clinically relevant concentrations reached after intravenous administration of the drug and warn for potential interactions with other action potential-lengthening drugs.

Sildenafil (Viagra) Prolongs Cardiac Repolarization by Blocking the Rapid Component of the Delayed Rectifier Potassium Current

BACKGROUND-Several cases of unexpected death have been reported with sildenafil in patients predisposed to ischemic cardiac events. Although acute episodes of ischemia could account for some of these deaths, we hypothesized that sildenafil may have unsuspected electrophysiological effects predisposing some patients to proarrhythmia. METHODS AND RESULTS-Studies were undertaken in 10 isolated guinea pig hearts that demonstrated prolongation of cardiac repolarization in a reverse use-dependent manner by sildenafil 30 mcmol/L. Action potential duration increased 15% from baseline 117+/-3 to 134+/-2 ms with sildenafil during pacing at 250 ms cycle length, whereas a 6% increase from 99+/-2 to 105+/-2 ms was seen with pacing at 150 ms cycle length. Experiments in human ether-a-go-go-related gene (HERG)-transfected HEK293 cells (n=30) demonstrated concentration-dependent block of the rapid component (I(Kr)) of the delayed rectifier potassium current: activating current was 50% decreased at 100 mcmol/L. This effect was confirmed using HERG-transfected Chinese hamster ovary (CHO) cells, which exhibit no endogenous I(K)-like current. CONCLUSIONS-Sildenafil possesses direct cardiac electrophysiological effects similar to class III antiarrhythmic drugs. These effects are observed at concentrations that may be found in conditions of impaired drug elimination such as renal or hepatic insufficiency, during coadministration of another CYP3A substrate/inhibitor, or after drug overdose and offer a new potential explanation for sudden death during sildenafil treatment.

Middle-aged men with increased waist circumference and elevated C-reactive protein level are at higher risk for postoperative atrial fibrillation following coronary artery bypass grafting surgery

INTRODUCTION We recently demonstrated that metabolic syndrome (MetS) is an independent risk factor for postoperative atrial fibrillation (POAF) following coronary artery bypass grafting (CABG). In the present work, we sought to determine which feature of the MetS is associated with POAF. METHODS AND RESULTS We retrospectively analysed the association between metabolic features and the incidence of new-onset POAF in a total of 2214 male patients <65 years who underwent first isolated CABG. Anthropometric data including waist circumference (WC) and complete preoperative lipid profile were available. We also conducted a nested case-control substudy including 147 patients who developed POAF, and were matched for age with a control population. In these patients, C-reactive protein, interleukin-6 (IL-6), and thiobarbituric acid-reactive substances (TBARS; evaluating the oxidative stress) blood levels were determined. In the whole cohort, 19.6% of patients developed POAF. On univariate analysis, body mass index (BMI; P = 0.002) and WC (P = 0.001) were the only anthropometric variables significantly associated with increased incidence of POAF. In the multivariable logistic model, the only independent predictors of POAF were a WC > 102 cm [odds ratio (OR) = 1.40, P = 0.04)] and older age (OR = 1.08, P < 0.001). In the nested case-control substudy C-reactive protein, IL-6, and TBARS levels were not significantly different in patients with or without POAF. Of particular significance, patients with elevated WC > 102 cm and C-reactive protein > 1.5 mg/L or IL-6 >2.2 pg/mL were at a high risk of developing POAF (respectively, OR = 2.32, P = 0.02 and OR = 2.27, P = 0.03). CONCLUSION Patients with increased WC combined with elevated C-reactive protein levels are at higher risk for POAF. Thus, interventions targeting inflammation related to visceral obesity might help reducing the incidence of POAF.

Angiotensin II modulates the delayed rectifier potassium current of guinea pig ventricular myocytes

Amplitude of the delayed rectifier (IK) tail current measured following long (5000msec) depolarizing pulses (−10 to +50mV) was decreased 19±3% (P<0.05) in a voltage-independent manner by angiotensin II (AII) 100nM. In contrast, amplitude of tail current measured following short (250msec) depolarizing pulses to potentials > + 10mV was increased 13±3 % (P< 0.05) by AII 30nM. Deactivation kinetics of IK measured at −30mV were altered by AII 30nM and 100nM; time constant of the faster deactivating phase (τ1) was decreased 1.4-fold. In summary, data obtained demonstrated that physiological concentrations of AII modulates major outward potassium currents involved in cardiac repolarization. Results suggest that AII increases amplitude of the rapid component of Ik (IKr) but decreases its slow component IKs. Thus, we postulate that modulators of AII effects may exhibit direct cardiac electrophysiological properties.

Risperidone Prolongs Cardiac Repolarization by Blocking the Rapid Component of the Delayed Rectifier Potassium Current

Cases of QT prolongation and sudden death have been reported with risperidone, a neuroleptic agent increasingly prescribed worldwide. Although hypokalemia was present in some of these events, we hypothesized that risperidone may have unsuspected electrophysiologic effects predisposing patients to proarrhythmia. In six isolated guinea pig hearts, risperidone elicited prolongation of cardiac repolarization: action potential duration increased from a baseline value of 128 ms ± 5 to 147 ms ± 5 (15%) with risperidone 1 &mgr;M during pacing at 250-ms cycle length, whereas the increase was only 10%, from 101 ms ± 2 to 111 ms ± 4, with pacing at a cycle length of 150 ms. In human ether-a-go-go (HERG)-transfected Chinese hamster ovary cells (n = 16), risperidone caused concentration-dependent block of the rapid component (IKr) of the delayed rectifier potassium current with an IC50 for tail block of 261 n M. Risperidone did not block IKs. Risperidone exerts cardiac electrophysiologic effects similar to those of Class III antiarrhythmic drugs. These effects are observed at clinically relevant concentrations. Because risperidone is metabolized primarily by CYP2D6, these actions likely enhance risk for risperidone-related QT prolongation and proarrhythmia in specific patient subsets (e.g., poor metabolizers and those taking interacting drugs).

Modulation of HERG potassium channel properties by external pH.

Abstract We expressed the human eag-related gene (HERG), known to encode for the cardiac potassium channel IKr, in Chinese hamster ovary (CHO) cells. This study investigated effects of external pH (pHo) on HERG current properties using the whole-cell patch-clamp technique. We observed that current amplitude was decreased and kinetics of activation and deactivation were faster when pHo was lowered from 7.4 to 6.0, while activation was accelerated and V1/2 negatively shifted when pHo was changed from 7.4 to 8.0. These effects can be explained by surface charge screening, amino acid group titration and/or changes in ionic atmosphere. We conclude that alterations of HERG channel by pHo could have consequences for the onset of arrhythmias during cardiac ischemia.

Pimozide (Orap®) Prolongs Cardiac Repolarization by Blocking the Rapid Component of the Delayed Rectifier Potassium Current in Native Cardiac Myocytes

Background: Several cases of QT prolongation and ventricular tachyarrhythmia have been reported with pimozide, a potent neuroleptic useful in the management of motor and phonic tics associated with Tourette syndrome. To further elucidate the mechanism underlying these clinical observations, the effects of pimozide on monophasic action potential duration (MAPD9O) and on potassium currents involved in the repolarization of native isolated ventricular myocytes were examined. Methods and Results: Studies were undertaken in eight isolated guinea pig hearts that demonstrated reverse rate-dependent prolongation of cardiac repolarization by pimozide 100 nmol/L. Action potential duration increased 24% from baseline 115 ± 2 to 142 ± 4 msec with pimozide 100 nmol/L during pacing at 250 msec cycle length, while a 10% increase from 97 ± 2 to 107 ± 3 msec was seen with pacing at a cycle length of 150 msec. Experiments in native isolated ventricular myocytes (n = 20) demonstrated concentration-dependent block of the rapid component (I,) of the delayed rectifier potassium current: tail current was decreased by 50% at 15 nmol/L. Conclusions: Pimozide possesses cardiac electrophysiological effects similar to those of class III antiarrhythmic drugs. These effects are concentration-dependent and observed at recommended dosages of the drug. Since pimozide is strongly metabolized by CYP3A4, special care should be taken to avoid potential pharmacokinetic interactions leading to high plasma levels of pimozide and proarrhythmia.

QRS widening and QT prolongation under bupropion: a unique cardiac electrophysiological profile

QRS widening and QT prolongation are associated with bupropion. The objectives were to elucidate its cardiac electrophysiological properties. Patch‐clamp technique was used to assess the IKr‐, IKs‐, and INa‐blocking effects of bupropion. Langendorff retroperfusion technique on isolated guinea‐pig hearts was used to evaluate the MAPD90‐, MAP amplitude‐, phase 0 dV/dt‐, and ECG‐modulating effects of bupropion and of two gap junction intercellular communication inhibitors: glycyrrhetinic acid and heptanol. To evaluate their effects on cardiac intercellular communication, fluorescence recovery after photobleaching (FRAP) technique was used. Bupropion is an IKr blocker. IC50 was estimated at 34 μm. In contrast, bupropion had hardly any effect on IKs and INa. Bupropion had no significant MAPD90‐modulating effect. However, as glycyrrhetinic acid and heptanol, bupropion caused important reductions in MAP amplitude and phase 0 dV/dt. A modest but significant QRS‐widening effect of bupropion was also observed. FRAP experiments confirmed that bupropion inhibits gap junctional intercellular communication. QT prolongation during bupropion overdosage is due to its IKr‐blocking effect. QRS widening with bupropion is not related to cardiac sodium channel block. Bupropion rather mimics the QRS‐widening, MAP amplitude‐ and phase 0 dV/dt ‐reducing effect of glycyrrhetinic acid and heptanol. Unlike class I anti‐arrhythmics, bupropion causes cardiac conduction disturbances by reducing cardiac intercellular coupling.