AUTHOR=Sprenkeler David J. , Bossu Alexandre , Beekman Jet D. M. , Schoenmakers Marieke , Vos Marc A. 

TITLE=An Augmented Negative Force-Frequency Relationship and Slowed Mechanical Restitution Are Associated With Increased Susceptibility to Drug-Induced Torsade de Pointes Arrhythmias in the Chronic Atrioventricular Block Dog

JOURNAL=Frontiers in Physiology

VOLUME=9

YEAR=2018

URL=https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2018.01086

DOI=10.3389/fphys.2018.01086

ISSN=1664-042X

ABSTRACT=<p><bold>Introduction:</bold> In the chronic AV-block (CAVB) dog model, structural, contractile, and electrical remodeling occur, which predispose the heart to dofetilide-induced Torsade de Pointes (TdP) arrhythmias. Previous studies found a relation between electrical remodeling and inducibility of TdP, while structural remodeling is not a prerequisite for arrhythmogenesis. In this study, we prospectively assessed the relation between <italic>in vivo</italic> markers of contractile remodeling and TdP inducibility.</p><p><bold>Methods:</bold> In 18 anesthetized dogs, the maximal first derivative of left ventricular pressure (LV dP/dt<sub>max</sub>) was assessed at acute AV-block (AAVB) and after 2 weeks of chronic AV-block (CAVB2). Using pacing protocols, three markers of contractile remodeling, i.e., force-frequency relationship (FFR), mechanical restitution (MR), and post-extrasystolic potentiation (PESP) were determined. Infusion of dofetilide (0.025 mg/kg in 5 min) was used to test for TdP inducibility.</p><p><bold>Results:</bold> After infusion of dofetilide, 1/18 dogs and 12/18 were susceptible to TdP-arrhythmias at AAVB and CAVB2, respectively (<italic>p</italic> = 0.001). The inducible dogs at CAVB2 showed augmented contractility at a CL of 1200 ms (2354 ± 168 mmHg/s in inducible dogs versus 1091 ± 59 mmHg/s in non-inducible dogs, <italic>p</italic> &lt; 0.001) with a negative FFR, while the non-inducible dogs retained their positive FFR. The time constant (TC) of the MR curve was significantly higher in the inducible dogs (158 ± 7 ms versus 97 ± 8 ms, <italic>p</italic> &lt; 0.0001). Furthermore, a linear correlation was found between a weighted score of the number and severity of arrhythmias and contractile parameters, i.e., contractility at CL of 1200 ms (<italic>r</italic> = 0.73, <italic>p</italic> = 0.002), the slope of the FFR (<italic>r</italic> = -0.58, <italic>p</italic> = 0.01) and the TC of MR (<italic>r</italic> = 0.66, <italic>p</italic> = 0.003). Thus, more severe arrhythmias were seen in dogs with the most pronounced contractile remodeling.</p><p><bold>Conclusion:</bold> Contractile remodeling is concomitantly observed with susceptibility to dofetilide-induced TdP-arrhythmias. The inducible dogs show augmented contractile remodeling compared to non-inducible dogs, as seen by a negative FFR, higher maximal response of MR and PESP and slowed MR kinetics. These altered contractility parameters could reflect disrupted Ca<sup>2+</sup> handling and Ca<sup>2+</sup>-overload, which predispose the heart to delayed- and early afterdepolarizations that could trigger TdP-arrhythmias.</p>