The paradigm for understanding the genesis of ventricular tachyarrhythmias (VT) rests on the notion that structural heart disease provides an electroanatomic substrate for re-entrant arrhythmias. Although this is sufficient for explaining most forms of clinical VT, approximately 10% occur in the absence of structural heart disease. Pioneering studies within the last few years have shown that some of these arrhythmias are caused by inherited channelopathies—for example, long QT syndrome, Brugada syndrome, and catecholaminergic VT.^1,2 The mechanisms underlying some other forms of idiopathic VT, such as verapamil sensitive fascicular tachycardia³ and idiopathic ventricular fibrillation,⁴ remain unclear, although it is known that they originate from Purkinje fibres.

The most common form of idiopathic VT originates from the ventricular outflow tract. Approximately 90% arise from the right ventricular outflow tract (RVOT), whereas the remainder are from the left.³ Two clinical manifestations of this tachycardia have been described: exercise (stress) induced VT and repetitive monomorphic VT (which occurs at rest). The latter, as first described by Gallavardin in 1922, is characterised by ventricular extrasystoles, couplets, and recurrent salvos of non-sustained VT. This editorial will highlight some of the insights gained into the mechanisms of outflow tract tachycardia over the past decade.

DIAGNOSIS AND MECHANISM

Outflow tract tachycardia is often induced with programmed stimulation and has a characteristic electropharmacologic response. Unlike any other form of VT, this tachycardia terminates in response to adenosine, β blockers, calcium channel blockers, and Valsalva manoeuvres.^5,6 Mechanistically, these findings are consistent with triggered activity secondary to cyclic adenosine monophosphate (cAMP) mediated delayed afterdepolarisations (DADs). DADs are oscillations of membrane potential that occur after the action potential repolarises and depend on the preceding action potential for their initiation. When a DAD achieves sufficient amplitude to reach threshold potential, another action potential is triggered. This action potential may in turn be followed by another DAD and the sequence of events is repeated, resulting in a sustained “triggered arrhythmia”.

DAD induced triggered action potentials have been shown to occur under a variety of conditions that cause increased intracellular calcium (Ca²⁺) concentrations, including catecholamine stimulation and digitalis exposure. In the case of catecholamines, stimulation of the β adrenergic receptor results in increased intracellular concentrations of cAMP and activation of protein kinase A (fig 1). This results in an increase of the slow inward Ca²⁺ current (I_Ca(L)) as well as increased calcium release from the sarcoplasmic reticulum through phosphorylation of the ryanodine receptor. Increased intracellular Ca²⁺ in turn leads to further release of Ca²⁺ from the sarcoplasmic reticulum and activation of the transient inward sodium current I_Ti, giving rise to a DAD. I_Ti is generated by the Na⁺-Ca²⁺ exchanger.

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Figure 1

 Receptor schema for activation and inactivation of cAMP mediated triggered activity caused by delayed afterdepolarisations. β adrenergic receptor stimulation (β-AR) results in the stimulatory G-protein (G_s) releasing its bound GDP and binding GTP. The active G_αs-GTP complex then dissociates from G_βγ and stimulates adenylyl cyclase (AC), leading to an increase in cAMP and activation of protein kinase A (PKA). This results in an increase of the slow inward calcium current (I_Ca(L)) as well as an increase in calcium release from the sarcoplasmic reticulum (SR), with consequent activation of a transient inward current (I_TI) through the Na⁺-Ca²⁺ exchanger (Na-CaX). Adenosine (ADO), by binding to the adenosine A₁ receptor (A₁R), acts via an inhibitory G-protein G_i. In response to adenosine binding, G_i releases its bound GDP and binds GTP. The active G_αi-GTP complex then dissociates from G_βγ and inhibits adenylyl cyclase. This leads to a decrease in I_Ca(L) and SR calcium release with consequent attenuation of (I_TI). ACh, acetylcholine; ISO, isoproterenol; M₂R, muscarinic cholinergic receptor.

Adenosine terminates cAMP mediated triggered activity through its antiadrenergic effects. The inhibitory G protein G_i couples the A₁ receptor to adenylyl cyclase, decreasing stimulated concentrations of intracellular cAMP (fig 1). Increased release of acetylcholine during the Valsalva manoeuvre acts via muscarinic–cholinergic receptors and G_i to also decrease cAMP concentrations. Calcium channel blockers terminate VT due to triggered activity by directly inhibiting I_Ca(L), whereas β blockers exert their antiarrhythmic effects through inhibition of β receptor activation.

Although β blockers and calcium antagonists (unlike adenosine) can be effective in certain forms of VT because of re-entry and abnormal automaticity, termination of outflow tract tachycardia by adenosine is thought to be pathognomonic for VT caused by cAMP triggered DADs. This is based on several lines of evidence. Firstly, adenosine’s electrophysiologic effects in ventricular myocardium and Purkinje fibres are singularly antiadrenergic, having no known direct effect on these tissues.^7,8 Therefore in the presence of catecholamine stimulation, adenosine reverses the electrophysiologic effects mediated by stimulation of cAMP—that is, increases in I_Ca(L) and I_Ti—but has no effect on these currents in the absence of cAMP stimulation. Secondly, adenosine abolishes DADs caused by cAMP stimulation, but it has no effect on digitalis induced DADs, which are mediated by a different mechanism (inhibition of Na⁺, K⁺-ATPase).⁷ Thirdly, adenosine has no effect on triggered activity caused by early afterdepolarisations.⁷ Fourthly, adenosine’s effect on VT caused by automaticity is readily differentiated from its effect on VT caused by triggered activity. Adenosine transiently suppresses (<20 s) catecholamine induced automaticity,⁸ whereas it terminates VT caused by triggered activity. Finally, adenosine appears to have no effect on re-entrant VT caused by structural heart disease, including that which is catecholamine facilitated.⁹

STRUCTURAL INVESTIGATION

The possibility that subtle structural defects in the right ventricle might contribute to the pathogenesis of RVOT tachycardia is based on provocative data derived from magnetic resonance imaging (MRI). These studies show that as many as two thirds of patients may have right ventricular thinning, fatty infiltration of the myocardium, or wall motion abnormalities.^10–13 This raises two important issues: (1) Are these MRI abnormalities causative or simply epiphenomena? (2) Is there a relationship between ventricular outflow tract tachycardia and arrhythmogenic right ventricular dysplasia (ARVD)?

Curiously, the right ventricular MRI abnormalities are identified at sites disparate from the outflow tract and remote from the sites of successful catheter ablation,¹¹ so a causative relationship is difficult to invoke. Furthermore, the technology and the criteria for identifying MRI abnormalities have changed during the last 10 years when most of these studies were performed. False positive identification of intramyocardial fat has been reduced by the use of black blood imaging techniques with double inversion recovery fast spin echo imaging. In addition, improved edge detection and volumetric data can now be obtained by ECG gated, steady state free precession imaging pulse sequence.¹⁴ Therefore, reassessment of outflow tract tachycardia patients with newer MRI technologies will be required before we can define the significance of the original findings.

Difficulties in differentiating between outflow tract tachycardia and ARVD will, however, likely remain despite improvements in MRI technologies. This is because VT in patients with ARVD may occur when anatomic involvement is relatively modest, eluding detection by MRI. Although other clinical criteria have been proposed for establishing the diagnosis of ARVD, their sensitivity and specificity have not been rigorously established. We believe that the response of VT to adenosine may prove to be an important criterion for distinguishing between ARVD and RVOT tachycardia since preliminary data suggest that adenosine has no effect on VT related to ARVD.⁹

BIOCHEMICAL AND MOLECULAR SUBSTRATE

In the absence of a clear anatomic substrate to account for arrhythmogenesis in outflow tract tachycardia and because of the lack of a familial inheritance pattern, we hypothesised that somatic mutations in the cAMP signalling pathway could contribute to the arrhythmogenic substrate. To that end, we identified a somatic point mutation in the inhibitory G protein Gα_i2, from the myocardial site of origin of the arrhythmia in a patient with an atypical or adenosine insensitive form of RVOT tachycardia.¹⁵ The mutation (F200L) localises to the guanosine triphosphate (GTP) binding domain and functionally increases intracellular cAMP concentration in response to catecholaminergic stimulation. This mutation was not identified at myocardial sites disparate from the site of origin or from peripheral lymphocytes, consistent with a somatic origin of the tachycardia. Preliminary data have identified additional mutations in the cAMP signalling cascade in other patients that may be responsible for the typical adenosine sensitive form of outflow tract tachycardia.

CONCLUSION

Outflow tract tachycardia remains an intriguing clinical entity. Although its clinical presentation and amenability to therapeutic cure through catheter ablation have been well delineated, its pathogenesis remains more obscure. We have outlined some of the recent findings in this regard. Despite the obstacles ahead, it is likely that within the next decade, the cellular and molecular pathogenesis of this entity will be more fully elucidated.