Complex excitation dynamics underlie polymorphic ventricular tachycardia in a transgenic rabbit model of long QT syndrome type 1

Abstract

BACKGROUND Long QT syndrome type 1 (LQT1) is a congenital disease arising from a loss of function in the slowly activating delayed potassium current IKs, 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 (INa)-mediated fast conduction and L-type Ca2+ current (ICa)-mediated slow conduction coexist, manifesting as pVT. Addition of 2 μM tetrodotoxin to reduce INa converted pVT into monomorphic VT. Reducing late INa 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 INa and slow wavefronts driven by ICa co-exist during pVT.

Potassium currents in the heart: functional roles in repolarization, arrhythmia and therapeutics

“…; Kim et al . ). More recently, a novel transgenic rabbit LQT5 model, produced by cardiac specific expression of a KCNE1 mutant that functions as a dominant negative, was described with markedly altered repolarization reserve attributed to changes in both I Ks and I Kr (Major et al .…”

Fragmented endocardial signals and early afterdepolarizations during torsades de pointes tachycardia

“…[4,[15][16][17][18]. They are an important cause of ventricular arrhythmias in the LQTS, but the mechanisms by which EADs at the cellular scale cause arrhythmias such as TdP are unclear.…”

Genetics of Sudden Cardiac Death

“…Unfortunately, the lack of knockin animal models that replicate the LQTS phenotype has to date limited the ability to dissect the arrhythmogenic mechanisms further. Data from transgenic rabbits, 71 despite the limitation of the presence of multiple, randomly inserted copies of the mutant gene in the genome of the animals, have recently been instrumental to support a novel view on the arrhythmogenesis in LQTS by Chang et al 72 These authors developed an in silico model of prolonged repolarization in 2-dimensional cardiac tissue by increasing I Ca and I ks to induce action potential prolongation and early after depolarizations. In this model, they demonstrated that arrhythmogenesis is caused by 2 types of spiral waves: short cycle rapid I Na generated waves ( Figure 5A) and long cycle, slow L-type calcium current (I Ca ) generated spiral waves ( Figure 5B).…”

“…72 Interestingly, in this model, the alternation of the 2 types of spiral waves generated a torsades des pointes-like ECG. Subsequently Kim et al 71 investigated arrhythmogenesis in the LQT1 transgenic rabbit models inducing polymorphic VT with isoproterenol and they demonstrated the presence of complex focal excitations occurring in both ventricles and causing oscillations of the QRS complexes consistent with multiple early after depolarizations-generated foci. They also showed a bimodal distribution of the action potential supporting the coexistence of 2 types of excitation that contribute to arrhythmogenesis: I Na -mediated fast conduction and I Ca -mediated slow conduction coexist supporting the biexcitability hypothesis by Chang et al…”