AimsThe steepness of the action potential duration (APD) restitution curve and local tissue refractoriness are both thought to play important roles in arrhythmogenesis. Despite this, there has been little recognition of the apparent association between steady-state APD and the slope of the restitution curve. The objective of this study was to test the hypothesis that restitution slope is determined by APD and to examine the relationship between restitution slope, refractoriness and susceptibility to VF.Methods and resultsExperiments were conducted in isolated hearts and ventricular myocytes from adult guinea pigs and rabbits. Restitution curves were measured under control conditions and following intervention to prolong (clofilium, veratridine, bretylium, low [Ca]e, chronic transverse aortic constriction) or shorten (catecholamines, rapid pacing) ventricular APD. Despite markedly differing mechanisms of action, all interventions that prolonged the action potential led to a steepening of the restitution curve (and vice versa). Normalizing the restitution curve as a % of steady-state APD abolished the difference in restitution curves with all interventions. Effects on restitution were preserved when APD was modulated by current injection in myocytes pre-treated with the calcium chelator BAPTA-AM – to abolish the intracellular calcium transient. The non-linear relation between APD and the rate of repolarization of the action potential is shown to underpin the common influence of APD on the slope of the restitution curve. Susceptibility to VF was found to parallel changes in APD/refractoriness, rather than restitution slope.Conclusion(s)Steady-state APD is the principal determinant of the slope of the ventricular electrical restitution curve. In the absence of post-repolarization refractoriness, factors that prolong the action potential would be expected to steepen the restitution curve. However, concomitant changes in tissue refractoriness act to reduce susceptibility to sustained VF. Dependence on steady-state APD may contribute to the failure of restitution slope to predict sudden cardiac death.

No abstract

No abstract

Dyssynchronous heart failure (HF) is routinely treated with cardiac resynchronization therapy (CRT). During conventional biventricular (BV) CRT, pacing is applied to the right ventricle (RV) endocardium and the left ventricle (LV) epicardium via the coronary sinus (EPI-CRT BV ). Current best practice results in 30% to 40% of CRT patients failing to display improved clinical response.1 Recent clinical 2-5 and experimental 6,7 evidence suggests that BV CRT with an endocardial pacing strategy for the LV lead (ENDO-CRT BV ) can provide an improvement in acute hemodynamic response and stroke work over EPI-CRT BV and offers a novel approach for increasing CRT response rates. However, the relative importance of cardiac physiology or better access to optimal pacing sites in causing this improved outcome remains controversial. Identifying and understanding physiological mechanisms behind improved ENDO-CRT BV response are crucial for optimizing clinical procedures and identifying patients who will receive the maximal benefit from this therapy.In acute left bundle branch block (LBBB) canine studies, ENDO-CRT BV improved the systolic LV function over conventional EPI-CRT BV .6 Electric activation times (ATs) as measured by contact mapping were decreased with ENDO-CRT BV © 2015 American Heart Association, Inc. Original Article Circ Arrhythm Electrophysiol Background-Cardiac resynchronization therapy (CRT) delivered via left ventricular (LV) endocardial pacing (ENDO-CRT) is associated with improved acute hemodynamic response compared with LV epicardial pacing (EPI-CRT).The role of cardiac anatomy and physiology in this improved response remains controversial. We used computational electrophysiological models to quantify the role of cardiac geometry, tissue anisotropy, and the presence of fast endocardial conduction on myocardial activation during ENDO-CRT and EPI-CRT. Methods and Results-Cardiac activation was simulated using the monodomain tissue excitation model in 2-dimensional (2D) canine and human and 3D canine biventricular models. The latest activation times (LATs) for LV endocardial and biventricular epicardial tissue were calculated (LVLAT and TLAT), as well the percentage decrease in LATs for endocardial (en) versus epicardial (ep) LV pacing (defined as %dLV=100×(LVLAT ep −LVLAT en )/LVLAT ep and %dT=100×(TLAT ep −TLAT en )/TLAT ep , respectively). Normal canine cardiac anatomy is responsible for %dLV and %dT values of 7.4% and 5.5%, respectively. Concentric and eccentric remodeled anatomies resulted in %dT values of 15.6% and 1.3%, respectively. The 3D biventricular-paced canine model resulted in %dLV and %dT values of −7.1% and 1.5%, in contrast to the experimental observations of 16% and 11%, respectively. Adding fast endocardial conduction to this model altered %dLV and %dT to 13.1% and 10.1%, respectively. Conclusions-Our results provide a physiological explanation for improved response to ENDO-CRT. We predict that patients with viable fast-conducting endocardial tissue or distal Purkinje network or both, as we...