Abstract-Heart Failure (HF) is associated with an increased risk of sudden death caused by ventricular tachyarrhythmias.Recent studies have implicated repolarization abnormalities and, in particular, exaggerated heterogeneity of transmural repolarization in the genesis of polymorphic ventricular tachycardia in a canine model of nonischemic dilated cardiomyopathy. The presence and degree to which conduction abnormalities play a role in arrhythmogenesis in this model are uncertain. HF was produced in dogs by rapid RV-pacing for 3 to 4 weeks. High-resolution optical action potentials were recorded from epicardial and endocardial surfaces of arterially perfused canine wedge preparations isolated from LV and RV of normal and failing dogs. Cellular and molecular determinants of conduction were investigated using patch-clamp recordings, Western blot analysis, and immunocytochemistry. HF was associated with marked prolongation (by 33%) of the QRS duration of the volume conducted electrocardiogram and significant (Ͼ20%) slowing of epicardial and endocardial conduction velocities (CV) in both LV and RV. Cx43 expression was reduced by Ͼ40% in epicardial and endocardial layers of the LV, but was unchanged in the RV of failing hearts. Despite greater epicardial than endocardial Cx43 expression, epicardial CV was consistently slower (PϽ0.01). Immunocytochemical analysis revealed predominant colocalization of Cx43 with N-cadherin in normal versus failing samples, because Cx43 was redistributed from the intercalated disk to lateral cell borders in failing tissue. Moreover, a significant (PϽ0.05) increase in hypophosphorylated Cx43 was detected in the LV and RV of failing hearts. Action potential upstroke velocities in isolated ventricular myocytes from normal and failing hearts were not different (Pϭ0.8, not significant), and Masson trichrome staining revealed no significant change in fibrosis content in HF. Nonischemic dilated cardiomyopathy is associated with significant slowing of CV that was not directly related to reduced Cx43 expression. Changes in phosphorylation and localization of Cx43 may contribute to gap-junction dysfunction, CV slowing, and arrhythmias in HF. Key Words: heart failure Ⅲ arrhythmias Ⅲ optical mapping Ⅲ connexin Ⅲ gap junctions S udden cardiac death (SCD), presumably because of ventricular tachyarrhythmias, accounts for Ϸ50% of the mortality in patients with congestive heart failure (HF). 1,2 Recent studies have highlighted the importance of repolarization abnormalities, including nonuniform prolongation of action potential durations (APD) across the ventricular wall in a canine model of nonischemic dilated cardiomyopathy. 3 Such repolarization changes may lead to the development of reentrant arrhythmias in HF. 3 When considering the prerequisites for reentry, however, two conditions must be met: (1) the excitation wavefront must undergo unidirectional conduction block; and (2) the path of the reentrant circuit must be sufficiently long or conduction of the wavefront sufficiently slow, such that ...
Atrial fibrillation (AF) -the most common arrhythmia -significantly increases the risk of stroke and heart failure. Although catheter ablation can restore normal heart rhythms, patients with persistent AF who develop atrial fibrosis often undergo multiple failed ablations and thus increased procedural risks. Here, we present personalized computational modelling for the reliable predetermination of ablation targets, which are then used to guide the ablation procedure in patients with persistent AF and atrial fibrosis. We first show that a computational model of the atria of patients identifies fibrotic tissue that if ablated will not sustain AF. We then integrated the target-ablation sites in a clinical-mapping system, and tested its feasibility in 10 patients with persistent AF. The computational prediction of ablation targets avoids lengthy electrical mapping Reprints and permissions information is available at www.nature.com/reprints.Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:
Complication rates from AF ablation remain significant, despite improved techniques and increased awareness of procedural risks. Both advanced age and female gender predict major adverse events, suggesting careful consideration of the risk/benefit profile in these patients prior to ablation.
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