ExperimentalBidirectional ventricular tachycardia: Ping pong in the His–Purkinje system
Introduction
Bidirectional ventricular tachycardia (BVT) is characterized by beat-to beat alternation of the QRS axis on the electrocardiogram (ECG). Although uncommon, it has fascinated clinicians since its original description in 1922 as a manifestation of digitalis toxicity.1, 2, 3, 4 It has also been reported in the setting of hypokalemic periodic paralysis,5 Andersen-Tawil syndrome,6 and fulminant myocarditis.7 More recently, BVT has also been recognized as a hallmark of catecholaminergic polymorphic ventricular tachycardia (CPVT) syndrome, a familial disorder with a high risk of sudden cardiac death during sympathetic stimulation.8 During exercise testing, these patients typically develop premature ventricular complexes (PVCs) and sometimes ventricular bigeminy9, 10, 11 in association with BVT, which can self-terminate or degenerate into polymorphic VT and ventricular fibrillation (VF).8, 11, 12 Although the most characteristic ECG pattern of BVT is right bundle branch (RBB) block with an alternating QRS axis,8 other patterns, such as alternating RBB and left bundle branch (LBB) block or alternating QRS axis with a narrow QRS,13 have also been observed. Recent genetic studies have attributed familial CPVT syndromes to defects in the cardiac ryanodine receptor (RyR2) or to calsequestrin, an associated regulatory protein in the sarcoplasmic reticulum (SR), and CPVT has been recapitulated in genetically engineered mouse models incorporating the analogous RyR2 mutations.14, 15 In these mice, abnormal RyR2 regulation predisposes myocytes to delayed afterdepolarizations (DADs) and triggered activity, analogous to digitalis toxicity. A recent optical mapping study in a mouse CPVT model due to the mutation R4496C in RyR2 (RyR2-R4496C) showed that BVT was caused by two foci in the distal His–Purkinje system (HPS), one in the right ventricle and the other in the left ventricle, alternately activating the ventricles.16 Moreover, ablation of the right ventricular HPS with Lugol solution converted BVT to monomorphic VT. These authors went on to show in a computer model of the anatomic mouse ventricles that alternate pacing from the right ventricular and left ventricular septum produced a characteristic ECG pattern of BVT. However, they did not address the mechanism by which triggered activity spontaneously generated this pattern.
Based on the observation that PVCs and ventricular bigeminy are common precursors to BVT,9, 10, 11 it occurred to us that a simple “ping pong” mechanism, which we call reciprocating bigeminy, could readily account for the pattern of alternating foci observed during BVT. Although a number of mechanisms for BVT have been suggested,10, 11, 17, 18, 19 the straightforward, conceptually intuitive mechanism of reciprocating bigeminy has not, to our knowledge, been explicitly proposed previously yet is fully consistent with well-known properties of triggered activity caused by DADs. We demonstrate its plausibility by incorporating these experimentally well-documented properties into computer simulations to reproduce the characteristics of BVT.
Section snippets
Ventricular and Purkinje action potential cell models
For ventricular cells, we used the model of Mahajan et al,20 a detailed model of rabbit ventricular action potential (AP) that includes intracellular Ca (Cai) dynamics (Figure 1A, red trace). To model the Purkinje cell AP (Figure 1A, black trace), we modified Ito,f, Ito,s, Ikr, Iks, and Ik1 as described by Cordeiro et al.21 We also added a background Ca current (adopted from the Luo-Rudy model22), using the following formulation:
where Ca,b = maximal
Results
The proposed “ping pong” mechanism of BVT is based on the following two commonly observed behaviors of DAD-mediated triggered activity: (1) above a certain threshold heart rate, a DAD triggers a single AP after each paced AP, initiating ventricular bigeminy (Figure 1B); and (2) the threshold heart rate for bigeminy varies at different locations in the heart (Figure 1B, a and b, respectively). From the experimental evidence indicating that BVT arises from the bundle branches of the HPS,16 we
Discussion
Both supraventricular or ventricular mechanisms of BVT involving either focal or reentrant mechanisms have been proposed.10 A supraventricular mechanism with alternating left anterior and left posterior fascicular block17 was largely excluded with the advent of intracardiac recordings, which failed to show a His-bundle potential preceding the alternating QRS complexes during BVT.18, 19 Postulated ventricular mechanisms have included a single focus in the proximal His bundle or bundle branches
Acknowledgment
We thank Tannaz Tebbi for technical assistance.
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Cited by (0)
This study was supported by NIH/NHLBI Grants P01 HL078931 and R01 HL103662, and by Laubisch and Kawata Endowments.
Dr. Baher's current address is Department of Medicine, Methodist Hospital, Houston, Texas 77030.