Background— Identification of patients at risk for drug-induced torsades de pointes arrhythmia (TdP) is difficult. Increased temporal lability of repolarization has been suggested as being valuable to predict proarrhythmia. The predictive value of different repolarization parameters, including beat-to-beat variability of repolarization (BVR), was compared in this serial investigation in dogs with chronic AV block. Methods and Results— In anesthetized dogs with electrically remodeled hearts, the dose-dependent difference in drug-induced TdP ( d -sotalol, 2 and 4 mg/kg IV over 5 minutes, 25% and 75% TdP, respectively) could not be accounted for by prolongation of QT _c (410±37 to 475±60 versus 415±47 to 484±52 ms, respectively). BVR was quantified by Poincaré plots at baseline and immediately before onset of d -sotalol–induced extrasystolic activity. TdP occurrence was associated with an increase in short-term variability (STV) of the left ventricular monophasic action potential duration (3.5±1.5 to 5.5±1.6 versus 3.0±0.7 to 8.6±3.8 ms, respectively), which was reversible when TdP was abolished by I _K,ATP activation. The absence of TdP despite QT _c prolongation after chronic amiodarone treatment could also be explained by an unchanged STV. In experiments with isolated ventricular myocytes, STV increased after I _Kr block and was highest in cells that subsequently showed early afterdepolarizations. Conclusions— Proarrhythmia is not related to differences in prolongation of repolarization but corresponds to BVR, here quantified as STV of the left ventricle. STV could be a new parameter to predict drug-induced TdP in patients.

Background— In large mammals and humans, the contribution of I _Ks to ventricular repolarization is still incompletely understood. Methods and Results— In vivo and cellular electrophysiological experiments were conducted to study I _Ks in canine ventricular repolarization. In conscious dogs, administration of the selective I _Ks blocker HMR 1556 (3, 10, or 30 mg/kg PO) caused substantial dose-dependent QT prolongations with broad-based T waves. In isolated ventricular myocytes under baseline conditions, however, I _Ks block (chromanols HMR 1556 and 293B) did not significantly prolong action potential duration (APD) at fast or slow steady-state pacing rates. This was because of the limited activation of I _Ks in the voltage and time domains of the AP, although at seconds-long depolarizations, the current was substantial. Isoproterenol increased and accelerated I _Ks activation to promote APD ₉₅ shortening. This shortening was importantly reversed by HMR 1556 and 293B. Quantitatively similar effects were obtained in ventricular-tissue preparations. Finally, when cellular repolarization was impaired by I _Kr block, I _Ks block exaggerated repolarization instability with further prolongation of APD. Conclusions— Ventricular repolarization in conscious dogs is importantly dependent on I _Ks . I _Ks function becomes prominent during β-adrenergic receptor stimulation, when it promotes AP shortening by increased activation, and during I _Kr block, when it limits repolarization instability by time-dependent activation. Unstimulated I _Ks does not contribute to cellular APD at baseline. These data highlight the importance of the synergism between an intact basal I _Ks and the sympathetic nervous system in vivo.

Introduction: Hypercapnic acidosis (HCA) that accompanies lung-protective ventilation may be considered permissive (a tolerable side effect), or it may be therapeutic by itself. Cardiovascular effects may contribute to, or limit, the potential therapeutic impact of HCA; therefore, a complex physiological study was performed in healthy pigs to evaluate the systemic and organ-specific circulatory effects of HCA, and to compare them with those of metabolic (eucapnic) acidosis (MAC). Methods: In anesthetized, mechanically ventilated and instrumented pigs, HCA was induced by increasing the inspired fraction of CO₂ (n = 8) and MAC (n = 8) by the infusion of HCl, to reach an arterial plasma pH of 7.1. In the control group (n = 8), the normal plasma pH was maintained throughout the experiment. Hemodynamic parameters, including regional organ hemodynamics, blood gases, and electrocardiograms, were measured in vivo. Subsequently, isometric contractions and membrane potentials were recorded in vitro in the right ventricular trabeculae. Results: HCA affected both the pulmonary (increase in mean pulmonary arterial pressure (MPAP) and pulmonary vascular resistance (PVR)) and systemic (increase in mean arterial pressure (MAP), decrease in systemic vascular resistance (SVR)) circulations. Although the renal perfusion remained unaffected by any type of acidosis, HCA increased carotid, portal, and, hence, total liver blood flow. MAC influenced the pulmonary circulation only (increase in MPAP and PVR). Both MAC and HCA reduced the stroke volume, which was compensated for by an increase in heart rate to maintain (MAC), or even increase (HCA), the cardiac output. The right ventricular stroke work per minute was increased by both MAC and HCA; however, the left ventricular stroke work was increased by HCA only. In vitro, the trabeculae from the control pigs and pigs with acidosis showed similar contraction force and action-potential duration (APD). Perfusion with an acidic solution decreased the contraction force, whereas APD was not influenced. Conclusions: MAC preferentially affects the pulmonary circulation, whereas HCA affects the pulmonary, systemic, and regional circulations. The cardiac contractile function was reduced, but the cardiac output was maintained (MAC), or even increased (HCA). The increased ventricular stroke work per minute revealed an increased work demand placed by acidosis on the heart.