A unifying mechanism for the initiation of torsade de pointes: blurring the distinction between trigger and substrate

This editorial refers to ‘Initiation of ventricular arrhythmia in the acquired long QT syndrome’, by C. Alexander et al., https://doi.org/10.1093/cvr/cvac103. The long QT syndrome (LQTS) is a primary electrical disorder of impaired ventricular repolarization. It was recognized as a genetic disorder with autosomal recessive and dominant transmission patterns by Jervell and Lange-Nielsen in 1957 and Romano-Ward in 1963.1 Insights into the molecular basis of this inherited arrhythmia syndrome came with the seminal identification of both loss and gain of function mutations that altered the activities of the delayed rectifier K-channels or the fast inward Na-channels, respectively. In either case, those mutations impaired cellular repolarization, and in doing so, prolonged the QT-interval. Carriers of these mutations are prone to syncope and sudden cardiac death (SCD), most often heralded by a distinct polymorphic ventricular tachycardia known as torsade de pointes (TdP). The French nomenclature is in reference to the peculiar undulating TdP morphology that is hallmarked by the twisting of QRS complexes around the isoelectric axis. While TdP is often self-terminating, it has the strong potential to degenerate into ventricular fibrillation culminating in SCD, often in young healthy individuals with structurally normal hearts. Hence, early identification of LQTS patients is of utmost importance especially considering that the first manifestation of the disease is often in the form of a cardiac arrest. Since the pioneering works of Keating and colleagues,2 the list of LQTS-causing mutations has expanded considerably to encompass multiple pore-forming and auxiliary ion channel subunits as well as a host of regulatory, structural and adaptor proteins which modulate ventricular repolarization. Indeed, congenital LQTS is now classified into 17 distinct subtypes according to the individual susceptibility genes that are adversely affected by hundreds of mutations.1 While inherited LQTS affects ∼1 in 2000 individuals, an acquired form of the disease has emerged as an important clinical entity and a relatively frequent cause of SCD in the general population. Specifically, drug-induced LQTS-type 2 (LQT2) stems from electrophysiological toxicity associated with the use of multiple cardiac and non-cardiac drugs, including some class III anti-arrhythmic agents that block the Human Ether-a-go-go-Related Gene, which encodes the rapidly activating delayed rectifier K current (IKr).3 Of note, the severity of this acquired form is compounded by commonly encountered clinical stressors such as hypokalaemia and prevalent diseases such as hypertrophy and heart failure, all of which synergistically prolong the QT-interval and promote SCD. Mechanisms underlying LQTS-related TdP have been extensively investigated. Initially, TdP was thought to be caused primarily, or even exclusively, by triggered activity arising from competing foci within the ventricles. In support of this hypothesis was evidence from experimental observations and computer simulations demonstrating a heightened propensity of cardiac myocytes to the generation of early afterdepolarizations (EADs) in settings that prolong the action potential duration (APD) to levels seen in LQTS.4 Because patients who present with TdP harbour the very same conditions that promote the development of EADs in the experimental setting, TdP has been attributed to repetitive EAD-mediated triggered beats. The ionic mechanism underlying these cell-autonomous triggers typically involves the premature reactivation of L-type calcium (Ca) channels during the delayed repolarization phase of an ongoing action potential. This results in an inward window current during the plateau phase when membrane resistance is high; thereby, generating disproportionately large net depolarizations that reach sufficient magnitudes to form successfully propagating premature impulses, which register on the surface ECG as so-called R-on-T events. Triggered activity as an exclusive mechanism of TdP, however, has been challenged in large part because robust APD adaptation to the short diastolic intervals that coincide with the onset of TdP, negate the very condition that favours the continued development of EADs, namely long APD.4 As such, additional mechanisms to explain the early maintenance of TdP were explored. Work by multiple groups, including our own,5 have highlighted the importance of the electrophysiological substrate in the onset and maintenance of TdP. In 2002, we developed the technique of transmural optical action potential mapping and showed in an ex-vivo canine model of drug-induced LQT2 that a unique topographical distribution of mid-myocardial cells with enhanced sensitivity to bradycardia and IKr blockade, formed discrete islands of increased refractoriness within the ventricular wall.5 When these islands were encountered by properly timed premature impulses which we imposed by programmed electrical stimulation, decremental conduction leading to intramural block occurred, followed by the genesis of transmural re-entrant circuits that maintained TdP. Others documented qualitatively similar islands of increased refractoriness on the epicardium of congenital models of LQTS6; thereby, establishing the premise that TdP likely requires two factors: (1) cellular triggers in the form of EAD-mediated premature beats which are facilitated by APD prolongation, and (2) tissue-level electrophysiological substrate in the form of repolarization heterogeneity. The interaction of those two seemingly independent factors was therefore thought to underlie both the initiation and early maintenance of TdP. A major issue regarding the onset of TdP that has remained enigmatic is the mechanism by which cellular triggers can synchronize within the milieu of the native myocardium to overcome source-sink mismatches and generate successfully propagating premature impulses in the form of R-on-T events. Elegant theoretical work by Liu et al.7 using computational modelling gave rise to the intriguing postulate that LQTS triggers, like the substrate, are also tissue-level phenomena rather than single cell events that require synchronization. They showed that spatial repolarization heterogeneity in the form of large voltage gradients (VGs) across small segments of myocardial tissue was sufficient to activate the L-type Ca current through electrotonus-mediated membrane depolarization. Indeed, Qu and colleagues put forth a novel concept that premature beats do not always encounter the vulnerable window of repolarization by coincidence but rather can be generated by and from that vulnerable window7. This is perhaps analogous to events leading to the formation of phase 2 re-entry in the Brugada Syndrome.8 This prompted those investigators to advocate for an intriguing ‘R-from-T’ postulate that extends the classic R-on-T phenomenon.7 In this issue of the Journal, Alexander et al.9 provide the most direct and comprehensive experimental evidence to date in support of this novel ‘R-from-T’ concept, which we schematize in the Figure. In an ex-vivo two-hit surrogate model of LQT2 in rabbit hearts, these authors documented the presence of discrete islands of refractoriness that were reminiscent of those we had reported transmurally in canine wedges. Using high-resolution optical action potential and intracellular Ca mapping, they rigorously and quantitatively demonstrated that steep VGs across the tissue were much more likely to act as the sources of arrhythmia-provoking triggers than classic EADs since the latter did not coincide in time, location or take-off potential with arrhythmia-inducing R-on-T events. A major advance of the current work was the impressive ability of the authors to define the dynamic interaction between spontaneously arising triggers and the electrophysiological substrate; thereby, avoiding the reliance on artificial programmed stimulation. Because EADs were difficult to separate pharmacologically from VG-dependent R-on-T events in their experiments, detailed computer simulations were performed to assess the independent influence of VGs vs. EADs on arrhythmia-provoking triggers. To that end, Alexander et al.9 created 2D in-silico models of the myocardium with areas of long (but EAD-deficient) action potentials merged with areas of normal excitability. This allowed them to systematically study the role of large VGs without the confounding influence of classical EADs. At a certain VG threshold, premature beats arose at the boundary of the long APD island closely mimicking their experimental observations. Both the whole heart and computer simulations documented the importance of the L-type Ca current (ICaL) in VG-mediated triggers and TdP induction. Modest block of ICaL that was insufficient to reverse QT-interval (and APD) prolongation was nonetheless highly effective in preventing TdP. While classic EADs were also found to occasionally form at the VG boundaries, they did not constitute a necessary requirement for TdP initiation. As such, the mere presence of classic EADs may be better regarded as a harbinger of an arrhythmic substrate rather than bona fide arrhythmia triggering events in LQTS (Figure). The findings of this elegant study provide a novel mechanistic framework to explain why QT-interval prolongation, on its own, is a poor predictor of SCD in LQTS, since APD prolongation per se may only be a modulatory factor that generates benign EAD-mediated triggers as opposed to arrhythmia-inducing ‘R-from-T’ triggers that culminate in TdP (Figure). This observation may be of particular significance and utility if we are able to identify occult ECG signatures that accurately predict the presence of refractory islands and their associated pathologic VGs non-invasively in patients, perhaps using advanced machine and deep learning approaches. Such ability may ultimately help us distinguish who amongst LQTS patients is truly at risk of SCD. Follow-up studies aimed at determining the plasticity of these arrhythmia-inducing islands of high VG will help uncover how and when they emerge in response to TdP-provoking stimuli such as abrupt startling behaviour as is the case in congenital LQT2. Indeed, the ability to abrogate rogue VG-mediated triggers at sub-maximal Ca channel blockade offers the potential to prevent SCD while avoiding confounding issues related to the chronic use of Ca channel blockers at therapeutic doses. Finally, the translatability of the current findings to other disease states in which transepicardial or transmural APD heterogeneities10 form arrhythmogenic islands of steep VGs remains to be seen. Nonetheless, Alexander et al.9 in this issue of Cardiovascular Research have provided us with a clear rationale for testing the efficacy of low-dose calcium channel blockade as an arrhythmia-suppressing measure in common settings of impaired repolarization that mimic LQTS (Figure). Margaret McKay, and Fadi G. Akar (PhD) FGA is supported by grants from the National Institutes of Health (1R01HL149344, 1R01HL148008 and 1R21HL165147).