Peter Oosterhoff

Short-term variability of repolarization predicts ventricular tachycardia and sudden cardiac death in patients with structural heart disease: a comparison with QT variability index.

BACKGROUND Monitoring arrhythmic risk may improve management of patients with implantable cardioverter-defibrillators (ICD) and prevent ICD shocks. Changes in repolarization duration between subsequent beats quantified as short-term variability (STV) is associated with ventricular arrhythmias in several animal models. OBJECTIVE We evaluated STV of QT from right ventricular intracardiac ICD electrograms in patients with structural heart disease and compared its predictive value with the QT variability index (QTVI). METHODS In 233 patients, STV over 60 beats for QT and RR intervals and their ratio was calculated (STV(QT), STV(RR), STV(Ratio), respectively). QTVI was derived from mean and SD of QT and heart rate. Follow-up duration was 26 ± 15 months. Predictive value was determined for sudden arrhythmic death (SAD) defined as sudden cardiac death or fast ventricular tachycardia/fibrillation [CL < 240 ms]. RESULTS In univariate analysis, STV(Ratio), but not STV(QT) or STV(RR), was predictive of SAD. Hazard ratios for highest quartile STV(Ratio) and QTVI were comparable (STV(Ratio): 1.9, 95% confidence interval [CI] 1.1 to 3.3, P = .038, QTVI: 2.2, 95% CI 1.2 to 3.8, P = .010). In a multivariate model, highest quartile STV(Ratio) was predictive of SAD after adjustment for New York Heart Association class, history of ischemia, ICD indication, and use of class I antiarrhythmics (hazard ratio 1.8, 95% CI 1.0 to 3.4, P < .050). A combined criterion of highest quartile for both STV(Ratio) and QTVI identified patients at highest risk (hazard ratio 2.4, 95% CI 1.3 to 4.3, P = .005, positive predictive value 38%, negative predictive value 82%). CONCLUSION STV(Ratio) from ICD electrograms is predictive of SAD. Predictive value is similar for order-based STV(Ratio) and distribution-based QTVI, but the combination of both parameters can further improve results.

High-Rate Pacing Reduces Variability of Repolarization and Prevents Repolarization-Dependent Arrhythmias in Dogs With Chronic AV Block

High‐Rate Pacing Prevents Drug‐Induced Arrhythmias. Introduction: High‐rate pacing may have an inhibitory effect on the initiation of Torsade de Pointes arrhythmias (TdP). However, permanent pacing is only indicated in high‐risk patients. We performed a proof of concept study into automatic overdrive pacing for prevention of drug‐induced TdP, using short‐term variability of repolarization (STV) as a feedback parameter of arrhythmic risk.

Ventricular remodelling is a prerequisite for the induction of dofetilide-induced torsade de pointes arrhythmias in the anaesthetized, complete atrio-ventricular-block dog

INTRODUCTION A number of predisposing factors have been suggested to be contributing to drug-induced torsade de pointes (TdP) arrhythmias: short-long-short (SLS) sequence, bradycardia, timing of drug administration, anaesthesia, ventricular remodelling, and altered ventricular activation due to ventricular ectopic beats (SLS) or idioventricular rhythm (IVR). Chronic atrio-ventricular (AV)-block (CAVB) dogs are susceptible to dofetilide-induced TdP. METHODS AND RESULTS In 32 anaesthetized animals, the relevance of ventricular remodelling for TdP susceptibility was studied by dofetilide [0.025 mg/kg/5 min intravenously (iv)] during bradycardia in the presence (CAVB, n= 18) or absence [acute atrio-ventricular block (AVB), n= 32] of ventricular remodelling. In sub-protocols, the possible pro-arrhythmic effects of timing of dofetilide administration: prior to (n= 11), or after creation of AVB (n= 9) and relevance of SLS pacing (n= 17) was investigated during IVR. Dofetilide was also given after AVB when the activation of the ventricles was normal: pacing (1000 ms) from the high septum (n= 7) or abnormal but fixed from the left ventricular apex (n= 5). Torsade de pointes inducibility was defined as reproducible (≥ 3 times) occurrence. In acute AV block (AAVB), dofetilide did not induce TdP spontaneously (0 of 32), whereas TdP was seen in 10 out of 18 serially tested dogs in CAVB (P< 0.001). The other factors: timing of dofetilide (0 of 11 vs. 0 of 9), SLS pacing (0 of 17 vs. 1 of 17), or ventricular activation (0 of 7 vs. 0 of 5) did not increase TdP susceptibility. Beat-to-beat variability of repolarization increased after ventricular remodelling and was highest prior to TdP induction. CONCLUSION In AAVB dogs, TdP is not spontaneously seen, whereas it is present in CAVB. This implies that ventricular remodelling is a prerequisite for TdP induction in this model.

Anesthesia and Arrhythmogenesis in the Chronic Atrioventricular Block Dog Model

Background: Drug-induced torsade de pointes (TdP) arrhythmias can readily be induced in anesthetized dogs with remodeled hearts [chronic complete atrioventricular block (CAVB) dogs]. Similar studies in conscious CAVB dogs reveal lower TdP incidences. Regulations forced us to reconsider our anesthetic regimen, which consist of pentobarbital followed by halothane (P + H). We investigated the relevance of anesthesia for this enhanced susceptibility (part 1) and compared 3 anesthetic regimens (part 2). Methods: Part 1-Ten CAVB dogs paced from the high septum at 1000 milliseconds were challenged with dofetilide (25 μg·kg−1·5 min−1) twice: once under anesthesia and once awake. Anesthesia consisted of P + H (n = 5) and thiopental maintained by isoflurane (T + I). Part 2-In CAVB dogs (n = 6) with spontaneous idioventricular rhythm, the electrophysiological and arrhythmogenic consequences of different anesthetic regimens (P + H, T + I, and P + I) were serially compared. Results: Part 1-In paced dogs, dofetilide-induced TdP was higher under anesthetized than in conscious circumstances, with the more severe outcome seen after T + I as compared with P + H or control (2×): 5/5, 2/5, 0/5, and 0/5, respectively; P < 0.05. Part 2-Electrophysiologically, T accelerated idioventricular rhythm, increased QTc, and transiently induced polymorphic ventricular tachycardias in 2 of 6 dogs. This was not seen after P. At 120 minutes (end of the preparation), QTc increase was highest after T + I, intermediate with P + I, and the smallest after P + H. Dofetilide in combination with T + I induced the most severe arrhythmogenic outcome. Conclusions: Thiopental anesthesia causes arrhythmias sec, whereas anesthesia in general predisposes for drug-induced TdP in the CAVB dog. In combination with dofetilide, T + I has a more arrhythmic outcome than P + I or P + H.

The electromechanical window is no better than QT prolongation to assess risk of Torsade de Pointes in the complete atrioventricular block model in dogs.

The electromechanical window (EMW), the interval between the end of the T‐wave and the end of the left ventricular pressure (LVP) curve, has recently been proposed as a predictor of risk of Torsade de Pointes (TdP) in healthy animals, whereby a negative EMW (mechanical relaxation earlier than repolarization) after drug administration indicates an increased TdP risk. The aims of this study were to assess (i) the effect of the ventricular remodelling in the canine chronic, complete atrioventricular block (CAVB) model on EMW; (ii) the effect of the IKr‐blocker dofetilide on EMW; and (iii) the correlation of EMW with TdP inducibility.

Microvolt T-wave alternans and beat-to-beat variability of repolarization during early postischemic remodeling in a pig heart

BACKGROUND Repolarization variability is considered to predict sudden cardiac death. T-wave alternans (TWA) has been the subject of exhaustive research, whereas beat-to-beat variability of repolarization (BVR) is a new parameter that possibly predicts proarrhythmia. How these parameters interact has not been tested. OBJECTIVE The purpose of this study was to compare TWA and BVR as predictors of proarrhythmic substrate early after myocardial infarction (MI). METHODS In nine pigs, MI was induced by 1-hour occlusion of the left anterior descending coronary artery. Cardiac magnetic resonance imaging was performed at day 21. Six sham pigs served as control. Spectral TWA was tested during right atrial pacing before induction of MI and after 21 days. BVR was calculated from 60 consecutive QT intervals. RESULTS Magnetic resonance imaging showed transmural MI. TWA was negative in all pigs at clinical threshold rate and equally present in MI versus sham pigs at higher rates (170 bpm: 55% vs 50% positive TWA). In MI pigs, BVR of QT intervals increased significantly during acute ischemia (2.44 ± 0.43 ms vs 3.55 ± 0.41 ms, P <.01) and even more on day 21 (5.80 ± 1.12 ms), but it differed significantly from sham (2.14 ± 0.54 ms, P <.01). A clinical ventricular tachycardia induction protocol was positive in 2 of 8 MI pigs and in none of 6 shams. CONCLUSION In early remodeling after MI, BVR at intrinsic heart rate was a consistent phenomenon, whereas TWA during atrial pacing or baseline QT-interval changes were not. TWA and BVR could reflect different post-MI remodeling processes. BVR may be a new technique for predicting a potentially proarrhythmic substrate in the early postinfarction period.

Beat-to-Beat Variability in Preload Unmasks Latent Risk of Torsade de Pointes in Anesthetized Chronic Atrioventricular Block Dogs

BACKGROUND Beat-to-beat variability in ventricular repolarization (BVR) associates with increased arrhythmic risk. Proarrhythmic remodeling in the dog with chronic AV-block (CAVB) compromises repolarization reserve and associates with increased BVR, which further increases upon dofetilide infusion and correlates with Torsade de Pointes (TdP) arrhythmias. It was hypothesized that these pro-arrhythmia-associated increases in BVR are induced by beat-to-beat variability in preload. METHODSANDRESULTS Left ventricular monophasic action potential duration (LVMAPD) was recorded in acute (AAVB) and CAVB dogs, before and after dofetilide infusion. BVR was quantified as short-term variability of LVMAPD. The PQ-interval was controlled by pacing: either a constant or an alternating preload pattern was established, verified by PV-loop. The effect of the stretch-activated channel blocker, streptomycin, on BVR was evaluated in a second CAVB group. At alternating preload only, BVR was increased after proarrhythmic remodeling (0.45±0.14 ms AAVB vs. 2.2±1.1 ms CAVB, P<0.01). At CAVB, but not at AAVB, dofetilide induced significant proarrhythmia. Preload variability augmented the dofetilide-induced BVR increase at CAVB (+1.5±0.8 ms vs. +0.9±0.9 ms, P=0.058). In the second group, the increase in baseline BVR by alternating preload (0.3±0.03 ms to 1.0±0.8 ms, P<0.01) was abolished by streptomycin (0.5±0.2 ms, P<0.05). CONCLUSIONS In CAVB dogs, the inverse relation between BVR and repolarization reserve originates from an augmented sensitivity of ventricular repolarization to beat-to-beat preload changes. Stretch-activated channels appear to be involved in the mechanism of BVR. (Circ J 2016; 80: 1336-1345).