Abstract
Left-to-right ventricular (LV/RV) differences in repolarization have been implicated in lethal arrhythmias in animal models. Our goal is to quantify LV/RV differences in action potential duration (APD) and APD rate adaptation and their contribution to arrhythmogenic substrates in the in vivo human heart using combined in vivo and in silico studies. Electrograms were acquired from 10 LV and 10 RV endocardial sites in 15 patients with normal ventricles. APD and APD adaptation were measured during an increase in heart rate. Analysis of in vivo electrograms revealed longer APD in LV than RV (207.8±21.5 vs 196.7±20.1 ms; P<0.05), and slower APD adaptation in LV than RV (time constant τs = 47.0±14.3 vs 35.6±6.5 s; P<0.05). Following rate acceleration, LV/RV APD dispersion experienced an increase of up to 91% in 12 patients, showing a strong correlation (r2 = 0.90) with both initial dispersion and LV/RV difference in slow adaptation. Pro-arrhythmic implications of measured LV/RV functional differences were studied using in silico simulations. Results show that LV/RV APD and APD adaptation heterogeneities promote unidirectional block following rate acceleration, albeit being insufficient for establishment of reentry in normal hearts. However, in the presence of an ischemic region at the LV/RV junction, LV/RV heterogeneity in APD and APD rate adaptation promotes reentrant activity and its degeneration into fibrillatory activity. Our results suggest that LV/RV heterogeneities in APD adaptation cause a transient increase in APD dispersion in the human ventricles following rate acceleration, which promotes unidirectional block and wave-break at the LV/RV junction, and may potentiate the arrhythmogenic substrate, particularly in patients with ischemic heart disease.
Highlights
Ventricular heterogeneity in repolarization is one of the most important contributors to the electrophysiological substrate leading to the occurrence of lethal arrhythmias such as ventricular fibrillation [1,2,3,4,5]
The analysis of the in vivo electrograms revealed significant LV/ RV differences in steady-state action potential duration (APD) and slow APD adaptation dynamics (P,0.05, paired Student’s t-test), whereas no statistical LV/RV differences were found for the time constant of the fast phase of APD adaptation
Different mechanisms than LV/RV differences might be involved in the establishment of reentrant arrhythmias for ischemic regions located outside this functional boundary, our findings provide supporting evidence of the important role of these interventricular differences in promoting the occurrence of arrhythmic events following rate acceleration [15,16,17], in patients with protracted rate adaptation [21,22]
Summary
Ventricular heterogeneity in repolarization is one of the most important contributors to the electrophysiological substrate leading to the occurrence of lethal arrhythmias such as ventricular fibrillation [1,2,3,4,5]. Research using animal models has shown that both functional and structural differences between the left and the right ventricles (LV and RV) determine the spatio-temporal organization of ventricular fibrillation [6,7], the generation of arrhythmias in sudden cardiac death syndromes [8], cardiac vulnerability to electric shocks [9], and epicardial repolarization gradient during global ischemia [10]. Ventricular heterogeneity in repolarization and arrhythmic risk are known to increase with sudden changes in rate [15,16,17], due to the highly rate-dependent properties of the APD. Very little is known about LV/RV differences in APD rate adaptation, which, if present, could contribute to increased interventricular dispersion in repolarization and arrhythmic risk following rate changes
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