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Short-term Variability of Repolarization Is Superior to Other Repolarization Parameters in the Evaluation of Diverse Antiarrhythmic Interventions in the Chronic Atrioventricular Block Dog - PubMed

Review

Short-term Variability of Repolarization Is Superior to Other Repolarization Parameters in the Evaluation of Diverse Antiarrhythmic Interventions in the Chronic Atrioventricular Block Dog

Alexandre Bossu et al. J Cardiovasc Pharmacol. 2017 Jun.

Abstract

Short-term variability (STV), to quantify beat-to-beat variability of repolarization, is a surrogate parameter that reliably identifies proarrhythmic risk in preclinical models. Examples include not only the use in the chronic atrioventricular block (CAVB) dog model whereby it was developed but also in vulnerable patients with heart failure or drug-induced long QT syndrome. In the CAVB dog model, STV can specifically distinguish between safe and unsafe drugs in proarrhythmic screening. Conversely, this dog model also offers the possibility to evaluate antiarrhythmic strategies in a setting of Torsades de Pointes (TdP) induction with a standard IKr inhibitor. The different antiarrhythmic interventions studied in suppression and prevention of drug-induced TdP in vivo in the CAVB dog model and in vitro in canine ventricular cardiomyocytes are described in this overview. We provide evidence that STV predicts the magnitude of antiarrhythmic effect against TdP better than other repolarization parameters in both suppression and prevention conditions. Moreover, suppression and prevention experiments revealed the same level of antiarrhythmic efficacy, whereas cellular experiments seem more sensitive in comparison with drug testing in vivo. Together, these observations suggest that STV could be used as a consistent indicator to rank efficacy of antiarrhythmic interventions in a number of conditions.

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Conflict of interest statement

The authors report no conflicts of interest.

Figures

FIGURE 1.
FIGURE 1.

A, Arrhythmogenesis in the CAVB dog model. B, Suppression and prevention experimental setups for antiarrhythmic drug evaluation. Lines define intervals during which arrhythmias were monitored to determine TdP inducibility and AS at corresponding periods. Dots define timepoints at which electrophysiological parameters (ECG intervals, MAPD, and STV) were measured. For the proarrhythmic challenge period, they were measured before incidence of the first ectopic beat or (if possible) TdP episode. In the prevention experiments, in the absence of arrhythmias, these parameters were measured at the end of the proarrhythmic challenge infusion (15 minutes). C, Induction of EADs by a proarrhythmic challenge in isolated canine ventricular cardiomyocytes. EADs occur under conditions of increased action potential duration and STV of repolarization. AS, arrhythmia score; MAPD, monophasic action potential duration; STV, short-term variability of repolarization; X, End of antiarrhythmic drug in suppression experiment; Y, end of antiarrhythmic drug in prevention experiment; EB, ectopic beat; TdP, Torsade de Pointes; EADs, early afterdepolarizations.

FIGURE 2.
FIGURE 2.

Temporal dispersion of repolarization (STV) is superior to repolarization (QTc) and its spatial (interventricular ΔMAPD) dispersion parameters in reflecting the magnitude of antiarrhythmic effect in suppression (A) and prevention (B) experiments against TdP arrhythmias. Moderate antiarrhythmic effect by low-dose levcromakalim was accompanied by the reduction of STV but not of other repolarization parameters (QTc and ∆MAPD). Subsequent administration of high-dose levcromakalim exerted stronger antiarrhythmic activity associated with a further STV reduction. Arrhythmias are plotted as percentage (number of TdP observed/number of experiments). Electrophysiological parameters: values are represented as mean ± SD. QTc, QT corrected for heart rate (van de Water formula); STV of repolarization (derived from LV MAPD); ΔMAPD, interventricular dispersion of repolarization (determined as LV−RV MAPD).

FIGURE 3.
FIGURE 3.

STV of repolarization strongly indicates the pharmacological antiarrhythmic efficacy in suppression (A) and prevention (B) experiments. STV values (dots), depicted for suppression (after antiarrhythmic drug administration) and prevention (after dofetilide administration) experiments are represented as mean ± SD. AS (bars) is expressed as mean ± SD. TdP inducibility is indicated as number of dogs with TdP/number of experiments. nq: not quantifiable. STV, short-term variability of repolarization (derived from LV MAPD).

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References

    1. Huikuri HV, Castellanos A, Myerburg RJ. Sudden death due to cardiac arrhythmias. N Engl J Med. 2001;345:1473–1482. - PubMed
    1. Moss AJ, Zareba W, Hall WJ, et al. Multicenter automatic defibrillator implantation trial III. prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med. 2002;346:877–883. - PubMed
    1. Bardy GH, Lee KL, Mark DB, et al. Sudden cardiac death in heart failure trial I. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med. 2005;352:225–237. - PubMed
    1. Koller MT, Schaer B, Wolbers M, et al. Death without prior appropriate implantable cardioverter-defibrillator therapy: a competing risk study. Circulation. 2008;117:1918–1926. - PubMed
    1. Echt DS, Liebson PR, Mitchell LB, et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The cardiac arrhythmia suppression trial. N Engl J Med. 1991;324:781–788. - PubMed

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