Ventricular tachycardia in patients without apparent structural heart disease : Focus on ventricular outflow tract tachycardia

Background

Idiopathic ventricular tachycardia (IVT), a term that has been used for ventricular tachycardia (VT) in the absence of clinically apparent structural heart disease (1), accounts for around 10% of all VTs evaluated in specialised arrhythmia services. Several types have been reported according to their clinical presentation, ventricular origin, response to drugs, electrocardiographic pattern, among others. The most common type is the so called ventricular outflow tract (VOT-T) or adenosine-sensitive tachycardia while other monomorphic forms of IVT, not explained in this review, include intrafascicular verapamil-sensitive reentrant tachycardia and ventricular tachycardia in patients with structural heart disease (1).
Adenosine-sensitive tachycardia commonly originated in the right ventricular outflow tract (80% of all locations). Other less frequent sites of endocardial and epicardial origin are the left ventricular outflow tract (12% of all locations), the pulmonary artery, the basal area of interventricular septum, near mitral and tricuspid annulus and the aortic sinuses of Valsalva (2-4). All of them, including those originating in places remote from the ventricular outflow tract (such as the coronary sinus and cardiac veins, other ventricular regions, the atrioventricular annulus, etc), behave in a similar way. Therefore, classifying them according to its behaviour may be more appropriate than according to their anatomical location.

1 - Mechanism

These tachycardias share a common mechanism: triggered activity (figure 1). Cytosolic calcium overload mediated by increased levels of cyclic adenosine monophosphate (cAMP) lead to delayed afterdepolarisations which, when reaching the cardiomyocite threshold, may cause another action potential and initiate tachycardia (5). Reentry and enhanced automaticity have been also postulated as other potential mechanisms of these tachycardias. However, the former is the most accepted one due to the following factors:

• The effectiveness of adenosine, which by reducing cAMP levels often terminates these tachycardias (6).
• Tachycardia catecholamine-dependent behaviour. Both exogenous and endogenous catecholamines increase cAMP concentration through the modulation of adenylate cyclise and facilitate tachycardia induction. Probably because to their inhibition effect on this enzyme, beta-blockers will most often effectively suppress this VT. However, this effect can be also seen in an abnormal automatism.
•  The response to verapamil, a well known inhibitor of L-type of calcium channel, and vagal manoeuvres, that inhibit the activity of adenylate cyclise.
• The difficulty to induce and the inability to entrain tachycardia by ventricular stimulation make reentry unlikely.

Nevertheless, it is not uncommon to observe the same response to verapamil and beta-blockers in other forms of IVT, such as intrafascicular reentrant tachycardia and IVT due to abnormal automatism respectively. Therefore, sensitivity to adenosine and response to stimulation may be the most specific criteria that support this mechanism.

2 - Epidemiology and clinical presentation

Ventricular outflow tract tachycardia (VOT-T) typically presents in young people, usually in the second to fourth decades of life. It appears to have similar distribution between the two sexes, though it has been reported that it will depend on the anatomic location. According to this, a right ventricular outflow tract origin (RVOT-T) could occur more often in females (69.6%) while a left origin apparently predominates in males (2).
The most frequent clinical complaint is palpitations (48-80%). Other common symptoms are lightheadness and presyncope (28-50%), chest pain, and, less frequently, syncope (10%). Since it typically affects young people without structural heart disease, it is usually well tolerated. Tachycardiomyopathy has also been described as part of this condition, although it is usually reversible after successful ablation.
The adrenergic-dependent character of this arrhythmia has been well documented. The majority of patients experience episodes during or after exercise (7). Other common triggers are emotional stress, anxiety, stimulants such as caffeine and, in the hospital setting, the infusion of catecholamines. Interestingly, it has been described as responding to hormonal variations in women, with states of hormonal flux (premenstrual, gestational and perimenopausal periods and the administration of contraceptives) the most common recorded trigger (59%) (8).
Although it is considered an arrhythmia with a benign course, some cases of sudden death and malignant polymorphic VT have been reported at follow-up (9, 10).  In fact, ventricular fibrillation and polymorphic ventricular tachycardia initiated by ventricular premature complexes with a short coupling interval originated in RVOT have been recently described (11). As we will see further on, excluding other pathologies with similar presentation is essential to avoid the overestimation of malignant cases.

3 - Electrocardiographical features

Ventricular outflow tract tachycardia typically shows an ECG pattern consisting of QS complex morphology of left bundle branch block and inferior axis. The QRS complex duration is usually <140 ms and longer durations should lead to ruling out mechanisms other than idiopathic VT (figure 2). Small differences in QRS complex morphology can be found during ongoing tachycardia but multiple morphologies should alert us about underlying structural heart disease. The most frequent form of presentation (90%) is the one originally described by Gallavardin (12): repetitive non-sustained ventricular tachycardia, couplets and ventricular ectopic beats present at rest (figure 3). On the other hand, it can also manifest as paroxysmal, exercise induced, sustained monomorphic VT. Considerable overlap exists between both forms of presentation that appear to be on a continuum of the same process.

The electrocardiographical pattern is useful for diagnostic purposes and to help differentiate the site of origin of the tachycardia, as we will see later, to approach the electrophysiological study. Some useful features would be the following:

• QRS is typically positive in inferior leads in all patients. However, a wide and notched QRS in inferior leads is typical of a origin in the lateral wall of the right ventricular outflow tract. The opposite could be said about septal wall (13).
• Positive polarity of the QRS complex in lead I is often seen when the origin is posterior, while a negative polarity is seen when it is anterior (14).
• Positive polarity of QRS in lead aVL is seen when the origin is on the lateral wall while the negative polarity is seen when it is on the septal wall (15).
• In right ventricular outflow tract tachycardia, precordial transition usually occurred by lead V3 to V4. Earlier precordial transition should alert us about a supravalvular or left ventricular outflow tract origin, which also includes the coronary cusps. On the opposite, the later the transition occurs, the more lateral is the VT site of origin.
• Slow initial forces in precordial leads should guide us to an epicardial location (16).
• A broad R wave in V1 or V2 suggests an aortic cuspid origin (17).
• Though left bundle branch block morphology is the standard, right bundle branch block and qR morphology are possible and typical of tachycardias arising form the mitro-aortic continuity.

Several complex algorithms have been developed combining these ECG signs to predict VT location. However, we must consider that even if there is some correlation to anatomical position, it is not certain in all cases.

4 - Complementary tests and differential diagnosis

Idiopathic ventricular tachycardia is a diagnosis of exclusion. It is important to distinguish idiopathic VOT-T from VT related to structural heart diseases, arrhythmogenic right ventricular cardiomyopathy (ARVC) in particular. VT often originates from the RVOT in both entities (18) but treatment and prognosis are completely different. Traditional tests for this purpose include:

• Electrocardiogram: Several degrees of right bundle branch block have been described in up to 10% of the patients but, as a general rule, ECG is normal. Typical features of ARVC (19) must be excluded such as T wave inversion and wide QRS complex (>110 ms) in V1 to V3 leads, epsilon waves, and tachycardia with multiple QRS morphologies.  Late potentials on signal averaged ECG may also suggest this latter diagnosis. They are more prominent in right precordial leads (20) as other ECG abnormalities in ARVC.
• Blood tests: Plasma brain natriuretic peptide (BNP) levels have been proposed to distinguish VOT-T from ARVC. BNP levels are normal in VOT-T patients and increased in ARVC, in which they are most likely the result of increased secretion by the residual myocytes within the atrophic tissue. In addition, these levels correlate with both the severity of RV dysfunction and the arrhythmogenic substrate (21).
• Echocardiography: It is usually normal in patients with RVOT-T, though mild dilation of right ventricular outflow tract has been described in a minority of them. The presence of global or regional dysfunction and structural alterations of the right ventricle support the diagnosis of ARVC. The areas typically affected include the apex, interventricular septum below the tricuspid septal leaflet and the RVOT.
• Exercise test: It is frequently used to evaluate and initiate VOT-T (7). As previously mentioned, VT can be initiated during exercise or recovery. However, this phenomenon only occurred in 25-50% of patients and, in some cases, exercise can even suppress ectopic ventricular activity.
• Right ventricular angiography: Right ventricular angiography has usually been regarded as the standard of reference for the diagnosis of ARVD. While it is usually normal in patients with VOT-T, it can show the previously described structural alterations of the right ventricle in ARVC.
• Myocardial perfusion scintigraphy: The clinical behaviour of this tachycardia suggests an involvement of the sympathetic nervous system in its mechanism. 123I-meta-iodobenzylguanidine (123I-MIBG) scintigraphy was proposed as a method to analyze the presence, extent, and location of impaired myocardial sympathetic innervation. Initially, denervation was reported the presence of regional in up to 55% of patients with VT in the absence of coronary artery disease(22) but subsequent studies have not corroborated these results and the visualisation of the right ventricle is quite poor(23).
• Right ventricular biopsy: Myocardial tissue is usually normal in most of these patients, but some unspecific alterations have been reported such as myocellular hypertrophy, interstitial and perivascular fibrosis, myocarditis, or even small amounts of fat, present in the epicardial layer and within the RV myocardium in normal subjects. Though frequently these are minor changes, the histological differential diagnosis of ARVC may be difficult in borderline cases.
• Magnetic resonance imaging (MRI): It is a useful test for the differential diagnosis of ARVC since it allows detailed visualisation of anatomy and motion of right ventricle and tissue characterisation. RVOT-T has been associated with mild focal structural and wall motion abnormalities (fixed focal wall thinning, focal fatty infiltration, excavation, diminished systolic wall thickening and abnormal systolic wall motion) in some series. However, the frequency (22%, 54%, 95% in some series) (24, 20, 25) and location (distributed similarly between the right ventricular outflow and the anterior free wall) of these findings are inconsistent between studies and its meaning is unknown. In contrast, MRI constitutes the optimal technique for detection of the characteristic high signal intensity of fat in the RV myocardium of ARVC patients and therefore, it is essential for its diagnosis and follow-up (26).

Although ARVC exclusion is critical for its therapeutic and prognostic implications, differential diagnosis of VOT-T also includes tachycardias associated with atriofascicular fibers (Mahaim fibers), atrioventricular reentrant tachycardia using a right-sided accessory pathway, and VT occurring in patients after repair of tetralogy of Fallot.

5 - Treatment

A) Acute management

As in other cases of wide QRS tachycardia, we should evaluate the hemodynamic status of the patient. Electrical cardioversion is emergent in case of tachycardia intolerance. In stable patients, we could recommend the following steps (Figure 2):

1. Vagal manoeuvres or carotid sinus massage: as previously mentioned, their effects on adenylate cyclase can interrupt the tachycardia.
2. Adenosine: the sensitivity to this drug is one of the main characteristics of this tachycardia, such that intravenous administration of adenosine (6 mg which can be titrated to 24 mg if necessary) can achieve acute termination in many cases.
3. Verapamil: intravenous administration of 10 mg (given over 1 minute) can interrupt this tachycardia due to its calcium-dependence. The risk of hemodynamic collapse in case of wrong diagnosis makes advisable to administrate it only in stable patients with an established diagnosis.
4. Lidocaine: this class IB antiarrhythmic can also be effective in the suppression of triggered rhythms.

B) Long-term management

Taking into account the fact that truly VOT-T is not considered a life-threatening arrhythmia, decisions upon its treatment depend on the frequency and severity of the symptoms. Treatment options include antiarrhythmic drugs and catheter ablation.

• Antiarrhythmic drugs

Although RVOT VT shows a better response to antiarrhythmic drugs than VT related to structural heart disease, their overall efficacy is moderate with 30 to 40% recurrences.
Beta-blockers and calcium channel blockers (including verapamil and diltiazem) are the first line therapy in symptomatic patients (27). Their efficacy has been proved to be from 25 to 50% with a synergistic effect when administered in combination.
Alternative therapy includes class I and class III antiarrhythmic drugs. Gill et al (28) reported that even if flecainide, sotalol and verapamil can suppress RVOT_VT, sotalol was the most frequently effective drug (>89%) in their population.

• Catheter ablation

The procedure is usually initiated by tachycardia induction (usually facilitated by the infusion of isoproterenol and burst pacing), followed by mapping of the same either looking for the site with the earliest activation or by stimulating and comparing with the morphology of paced QRS complex with that one recorded during VT. The choice of mapping method will depend on the easiness of VT induction. In case of impossibility, premature ventricular complex and runs of non sustained VT can be really useful. Mapping usually begins at the RVOT and, if necessary, is followed by mapping the pulmonary artery, great cardiac vein, LVOT, and aortic cusps. Once localised, radiofrequency delivery from a 4-mm-tip ablation catheter usually ablates the tachycardia.

Acute success rate has been reported to be over 80%. The most common cause of failure is an inability to induce tachycardia. After successful ablation, a 5% of VT recurrences has been reported, the majority within the first year and successfully ablated with a second procedure (1). Serious complications are rare (< 1% of procedures) and include:

• Complete AV block or RBBB in cases of VT foci near the His Bundle or the right bundle branch, respectively.
• Aortic regurgitation in tachycardias originating in the LVOT.
• Cardiac tamponade due to perforation and hemopericardium.
• Left main coronary injury during ablation of LVOT tachycardia originating above the aortic valve.

The recommendations for electrophysiology testing and catheter ablation according to the last guidelines for the management of patients with ventricular arrhythmias are listed in the table below (27):

Traditionally, medical therapy has been considered of first choice, especially in patients with mild and infrequent symptoms. Catheter ablation was reserved for patients with frequent and drug-refractory symptoms, severe symptoms (such as syncope or tachycardiomyopathy), or drug intolerance. However, the curative character of ablation, the low risk of serious complications and the young age of patients with VOT-T, makes it an attractive initial treatment in many patients.

Figure 1. Mechanism of triggered activity



Figure 2. Typical electrocardiographical pattern of ventricular outflow tract tachycardia




Figure 3. Repetitive non-sutained ventricular outflow tract tachycardia




Figure 4. Acute management

Conclusion:

Tachycardia originating from the ventricular outflow tracts constitutes the most frequent form of idiopathic ventricular tachycardia. Triggered activity related to delayed afterdepolarizations seems to be its main mechanism. It is typical of young people without overt structural heart disease and usually presents with palpitations related to exercise. It shows a typical ECG pattern consisting of left bundle branch block configuration and inferior axis of the QRS complex.  It can presents in repetitive or sustained forms. VOT-T is a diagnosis of exclusion and imaging techniques should be performed to exclude other causes, above all ARVC. Treatment options include antiarrhythmic drugs and catheter ablation. The curative character of ablation, the low risk of serious complications and the young age of patients with VOT VT, makes of this procedure an attractive initial treatment in many patients. Antiarrhythmic therapy is considered of fist choice in patients with mild and infrequent symptoms.