CPVT is one of the most malignant forms of ventricular arrhythmia. On the basis of the clinical features, resting ECG patterns, and CPVT characteristics, our cases were quite similar to those of Leenhardt10
; however, the prognosis was different.
From a clinical standpoint, syncope during exercise or during sympathetic activation is the key to this disease. Ninety three per cent of the CPVT patients in the present investigation experienced syncope or cardiac arrest. Exercise could induce CPVT in all patients, but unless CPVT deteriorated to ventricular fibrillation, syncope did not occur. It seems likely that most patients with CPVT experience ventricular fibrillation during syncope—in other words, without treatment patients with CPVT are prone to ventricular fibrillation and sudden death.
A normal QT interval and sinus bradycardia were characteristic resting ECG features of CPVT. There was no prolongation of the QT interval during exercise, and there was no ST-T change before CPVT onset or ventricular fibrillation. These characteristics are different from congenital long QT syndrome and the Brugada syndrome.15
In addition, the coupling interval and the induction pattern of polymorphic ventricular tachycardia was different from the short coupled variant torsade de pointes.16
Polymorphic or bidirectional ventricular tachycardia may develop in association with a prolonged QT interval.17–19
When provoked by exercise, it is unclear whether the resulting polymorphic ventricular tachycardia is the same clinical entity and has the same mechanism with a long QT interval as without.
CPVT was induced by exercise or catecholamine infusion. However, programmed stimulation could not induce CPVT. The late potential in the signal averaged ECG was negative. These findings strongly suggest that catecholamine sensitive automaticity functions as the mechanism of CPVT. Aberrant conduction from a single focus or triggered activity that may cause ventricular tachycardia, resembling torsade de pointes, cannot be ruled out. However, the change in QRS morphology is not gradual but abrupt, and in this it is very different from torsade de pointes.
With respect to the morphology of bidirectional ventricular tachycardia, we showed that the recording lead was important. If the maximal QRS vector changed in one lead during bidirectional ventricular tachycardia, the axis perpendicular to the former lead showed polymorphic ventricular tachycardia. Thus the morphology of ventricular tachycardia, which is polymorphic or bidirectional, is strongly dependent on the ECG recording lead. However, unlike other polymorphic ventricular tachycardias such as torsade de pointes, the QRS morphology is not chaotic but has some regularity. It is difficult to determine whether the morphology of bidirectional ventricular tachycardia is derived from multiple ventricular foci. An easier explanation is that the conduction direction changes with every other beat—from a single focus, one focus triggers another focus or double foci interfere with each other. However, from the programmed stimulation study, it is difficult to conclude that one focus triggers another, and the likelihood that double foci have almost the same tachycardia rate is small. The QRS morphology of bidirectional ventricular tachycardia is inconsistent in the same recording lead, so we feel that the focus of the arrhythmia cannot be pinpointed but may vary to some extent. focus may be situated in the ventricle. CPVT onset is mostly of single or double origin and usually originates from the right ventricular outflow tract, while the ensuing beat tends to originate from the left ventricle; however, Maia and colleagues reported that the majority had a left posterior inferior origin.20
If the triggering focus is from one site, successful catheter ablation is possible.
Sudden death in cases of polymorphic ventricular tachycardia is associated with a longer QRS duration than in surviving patients. It has been reported that tachycardia originating close to the proximal conduction system or the ventricular septum has a narrow QRS,21
suggesting that the onset focus in sudden death cases may lie distant from the normal conduction system. In both the sudden death group and the surviving group of our cohort, the onset focus was close to the His-Purkinje system; however, in the sudden death cases it was further from the His–Purkinje system and the interventricular septum than in the surviving cases.
A recent study suggested that familial CPVT is a genetic disorder. The chromosome involved was located in 1q42–q43 in patients with an autosomal dominant inheritance22
and in 1q31–21 in patients with an autosomal recessive inheritance. More recently, ryanodine receptor gene (RyR2) mutations were found in the autosomal dominant form of familial CPVT.23,24
In patients with malignant hyperthermia25,26
and central core disease,27
an MH/CCD gene mutation was previously found. A mutation of the RyR1 receptor results in hypersensitivity to an inward calcium current. In an analogous fashion, Priori and colleagues suggested that RyR2 gene mutation might increase sensitivity to calcium ions and lead to Ca2+
release from the sarcoplasmic reticulum.23
This may increase the delayed afterdepolarisation, causing triggered activity and ventricular tachycardia. As Laitinen and colleagues suggested,24
this autosomal type of CPVT may suppress the induction of ventricular tachycardia by blocking the L type calcium channel. We showed that a calcium channel blocker suppressed some of the autosomal dominant forms of CPVT, which supports the above suggestions.
Some families with arrhythmogenic right ventricular dysplasia (ARVD) show similarities in the chromosome abnormality of 1q42–43.28–31
A ryanodine receptor abnormality was also reported. The different clinical features of ARVD and CPVT are obvious. The mechanism of ARVD is re-entry, and the late potential is positive. However, as suggested in the present study, most cases of CPVT originate in the right ventricular outflow tract.
CPVT onset occurs during childhood and adolescence. None of the patients experienced syncope during infancy. There are two possible explanations for these results. The first is the intensity of exercise. In infancy, the amount of catecholamine during physical activity is not sufficient to cause CPVT because the activity is not strenuous enough. When children enter school, the possibility of syncope occurring is greater because they have many opportunities to run, play sports, and exercise. The other possibility could be the development of the ryanodine receptor. It has been reported that the ryanodine receptors are underdeveloped during infancy.32
Infants often go into cardiac arrest when they receive a calcium channel blocker. It has been suggested that immature ryanodine receptors are highly sensitive to calcium channel blockers. When infants receive a calcium channel blocker, Ca2+
cannot be released from the sarcoplasmic reticulum, so the myocardium can no longer contract. It is easy to theorise that the effects of ryanodine receptor hypersensitivity may be cancelled by receptor immaturity.
Only a few cases of CPVT have been reported in adult patients; indeed, there is a decrease in the number of episodes of syncope when the patients become adults. There are several explanations for this. For example, people tend to become more sedentary after graduation from school, with fewer opportunities for vigorous exercise. Affected individuals may also refrain from exercise to protect themselves from syncopal experiences. In addition, some children with severe forms of CPVT die during childhood, while those with benign forms of CPVT survive. Figure 5 shows how the likelihood of sudden death decreases significantly with increasing age.
β Blockers completely controlled CPVT in only 41% of our patients, and 22% died during follow up. A sodium channel blocker was prescribed in five cases (mexiletine in three and disopyramide and flecainide in one case each). Three of these patients died suddenly and one had syncopal attacks. Although amiodarone was not used, these results suggest that drug treatment has only limited success.
If an electrical disorder can easily cause ventricular fibrillation, an implanted cardioverter-defibrillator (ICD) combined with β blocker or calcium channel blocker treatment may well be the best choice for patients with CPVT. However, it remains unclear whether adult patients with CPVT need an ICD.
The identification of the origin of ventricular tachycardia from 12 lead ECGs is difficult. The origin was usually considered to be in the right ventricle when the QRS morphology showed a left bundle branch block pattern and in the left ventricle when a right bundle branch block pattern was observed. However, in some cases left bundle branch block patterns originate from the left ventricle, as confirmed by radiofrequency catheter ablation. In this multicentre study, endocardial mapping and catheter ablation were tried in only two patients. Therefore, we schematically identified from the bundle branch block pattern and the QRS axis four ventricular areas that were likely to form the origin of the ventricular tachycardia. Figure 1 may not represent the precise origin of the ventricular tachycardia.
With regard to the sodium channel blocker and prognosis, only four of our patients received a sodium channel blocker and three of these died suddenly. From this limited number, it is difficult to conclude that sodium channel blockers worsen the prognosis.