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The initiation of polymorphic ventricular tachycardia in long QT syndrome type 2 (LQT2) has been associated with a characteristic ECG pattern of short-long RR intervals. We hypothesize that this characteristic pattern increases APD dispersion in LQT2, thereby promoting arrhythmia. We investigated APD dispersion and its dependence on two previous cycle lengths (CLs) in transgenic rabbit models of LQT2, LQT1, and their littermate controls (LMC) using random stimulation protocols. The results show that the short-long RR pattern was associated with a larger APD dispersion in LQT2 but not in LQT1 rabbits. The multivariate analyses of APD as a function of two previous CLs (APDn = C + α1CLn−1 + α2CLn−2) showed that α1 (APD restitution slope) is largest and heterogeneous in LQT2 but uniform in LQT1, enhancing APD dispersion under long CLn−1 in LQT2. The α2 (short-term memory) was negative in LQT2 while positive in LQT1, and the spatial pattern of α1 was inversely correlated to α2 in LQT2, which explains why a short-long combination causes a larger APD dispersion in LQT2 but not in LQT1 rabbits. In conclusion, short-long RR pattern increased APD dispersion only in LQT2 rabbits through heterogeneous APD restitution and the short-term memory, underscoring the genotype-specific triggering of arrhythmias in LQT syndrome.

Background Long QT syndrome type 1 (LQT1) is a congenital disease arising from a loss of function in the slowly activating delayed potassium current I Ks , which causes early afterdepolarizations (EADs) and polymorphic ventricular tachycardia (pVT). Objective The purpose of this study was to investigate the mechanisms underlying pVT using a transgenic rabbit model of LQT1. Methods Hearts were perfused retrogradely, and action potentials were recorded using a voltage-sensitive dye and CMOS cameras. Results Bolus injection of isoproterenol (140 nM) induced pVT initiated by focal excitations from the right ventricle (RV; n=16 of 18 pVTs). After the pVT was initiated, complex focal excitations occurred in both the RV and the left ventricle, which caused oscillations of the QRS complexes on ECG, consistent with the recent proposal of multiple shifting foci caused by EAD chaos. Moreover, the action potential upstroke in pVT showed a bimodal distribution, demonstrating the coexistence of 2 types of excitation that interacted to produce complex pVT: Na + current (I Na )-mediated fast conduction and L-type Ca 2+ current (I Ca )-mediated slow conduction coexist, manifesting as pVT. Addition of 2 μM tetrodotoxin to reduce I Na converted pVT into monomorphic VT. Reducing late I Na in computer simulation converted pVT into a single dominant reentry, agreeing with experimental results. Conclusion Our study demonstrates that pVT in LQT1 rabbits is initiated by focal excitations from the RV and is maintained by multiple shifting foci in both ventricles. Moreover, wave conduction in pVT exhibits bi-excitability, that is, fast wavefronts driven by I Na and slow wavefronts driven by I Ca co-exist during pVT.

Ventricular arrhythmias in the setting of a healed myocardial infarction have been studied to a much lesser degree than acute and subacute infarction, due to the pericardial scarring, which results from the traditional open-chest techniques used for myocardial infarction (MI) induction. We sought to develop a segmental MI with low perioperative mortality in the rabbit that allows optimal visualization and therefore improved study of the infarction borderzone. Rabbits underwent MI using endovascular coil occlusion of the first obtuse marginal artery. Three weeks postprocedure, we evaluated our model by echocardiography and electrophysiology studies, optical mapping of isolated hearts, and histological studies. Seventeen rabbits underwent the protocol (12 MI and 5 sham) with a 92% survival to completion of the study (11 MI and 5 sham). MI rabbits demonstrated wall motion abnormalities on echocardiography while shams did not. At electrophysiological study, two MI rabbits had inducible ventricular tachycardia and one had inducible ventricular fibrillation. Isolated hearts demonstrated no pericardial scarring with a smooth, easily identifiable infarct borderzone. Optical mapping of the borderzone region showed successful mapping of peri-infarct reentry formation, with ventricular fibrillation inducible in 11 of 11 MI hearts and 1 of 5 sham hearts. We demonstrate successful high resolution mapping in the borderzone, showing delayed conduction in this region corresponding to late deflections in the QRS on ECG. We report the successful development of a minimally invasive MI via targeted coil delivery to the obtuse marginal artery with an exceptionally high rate of procedural survival and an arrhythmogenic phenotype. This model mimics human post-MI on echocardiography, gross pathology, histology, and electrophysiology.

Long QT syndrome Type 2 (LQT2) is a congenital disease with abnormal prolongation of APD and sudden cardiac death (SCD) due to polymorphic ventricular tachycardia (pVT). These arrhythmias are often preceded by a characteristic initiation mode of short-long-short alternating cycle lengths (CL) in surface electrocardiograms. We hypothesized that alternating CLs in LQT2 cause increased APD dispersion, which may promote reentry formation.We used transgenic LQT2 rabbits (lacking, IKr) to investigate the potential role of alternating CLs on APD dispersion. Hearts (n=4 & 5 for littermate control (LMC) and LQT2) were perfused and action potentials were recorded with voltage sensitive dye (di-4 ANEPPS) and CMOS camera (100x100 pixels, 1000 f/s) from anterior region of the heart. Hearts were stimulated at computer-generated random intervals (ranging from its refractory period plus 50 ms, typically 220-270 ms) and the pattern of stimulation logic pattern that creates enhanced APD dispersion was identified from LQT2 and LMC.While APD dispersion from LMC had no clear patterns (S1/S2/S3=232/224/225 ms) preceding enhanced APD dispersion (n=4/4), enhanced APD dispersion from LQT2 consistently showed alternating CL dynamics (S1/S2/S3= 253/250/262 ms, with increased APD dispersion from 19±10 to 40±1 ms, n=5/5). The detail analysis shows that spatially heterogeneous APD restitution in LQT2 promoted APD dispersion. In addition, lack of IKr in LQT2 increased cardiac memory effect; APD was dependent on the short-term of heart rate variation with higher coefficients from previous CLs (S1/S2 = 0.67/0.27 in LQT2 vs. 0.31/0.08 in LMC) due to slow kinetics of remaining repolarizing current (IKs), enhancing APD dispersion under alternating CLs.In conclusion, combined with heterogeneous restitution and memory effect of APD, short-long CLs in LQT2 may precipitate polymorphic VTs by creating large APD dispersion.