Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare genetic disease with an incidence of approximately 1:10,000 in the European population and a very high mortality rate if left untreated, reaching 31% by the age of 30 years . It is characterized by bidirectional or polymorphic ventricular tachycardias (VT) induced by an adrenergic triggering factor, such as emotional stress or physical activity, while some patients may also develop episodes of atrial fibrillation [1,2]. Stress-related syncope is the most common symptom in otherwise healthy children or adolescents, while sudden cardiac death due to degeneration of VT to ventricular fibrillation (VF) may also occur. Palpitations and dizziness during exercise represent more benign manifestations of the disorder .
A family history of syncopal episodes or sudden cardiac death exists in 30-35% of patients . Sometimes the condition is misdiagnosed and mistreated as epilepsy in patients with syncope, especially if accompanied by incontinence .
Genetic mechanisms include mutations in the cardiac ryanodine receptor gene (RyR2) – calcium ions release channel – which are found in about 50% of CPVT patients and are responsible for the autosomal dominant inheritance of the disorder, known as CPVT1. On the other hand, mutations in cardiac calsequestrin gene (CASQ2) – a major calcium binding protein within sarcoplasmic reticulum – are the cause of the rare autosomal recessive type, described as CPVT2 [1,3,4,6].
In both types, there is abnormal release of calcium ions from the sarcoplasmic reticulum causing asynchrony in cardiac excitation and contraction . As a result of calcium excess, delayed after-depolarizations and triggered activity constitute the pathophysiologic background of the disease .
Regarding diagnosis, patients with CPVT have normal resting electrocardiograms (ECGs), without QT prolongation or any other characteristic abnormality. Additionally, there are no echocardiographic or other imaging signs of cardiac structural abnormalities . The tilt table testing is negative. Apart from the bidirectional VT with the alternating direction of QRS complexes from beat-to-beat, another distinctive marker of the disease is the conversion of premature complexes to malignant ventricular arrhythmias as the workload level increases; VT/VF appear frequently at heart rates of 110-130/min [2,4]. Induction and progressive deterioration of ventricular arrhythmias during stress testing or isoproterenol infusion are diagnostic hallmarks of CPVT [1,4]. Exercise stress tests and ECG Holter recordings (24h) represent invaluable diagnostic tools [3,4].
Treatment modalities, apart from avoidance of forceful physical activity, competitive athletics, and emotional stress, include beta blocker therapy (sotalol, nadolol, metoprolol) at doses titrated to achieve maximal efficacy . Nadolol is the preferred beta blocker, due to its long duration of action . Compliance to therapy is of vital importance, even for those with positive genetic but negative exercise tests, as missing doses may induce malignant arrhythmias [1,3]. Unfortunately, beta blocker therapy may not be enough to prevent cardiac events in a significant percentage of patients . There is limited evidence on the advantageous addition of a calcium channel blocker, such as verapamil, while some data support the use of flecainide in addition to beta blocking therapy. Among invasive treatments, implantation of a cardioverter – defibrillator (ICD) represents a class I recommendation for CPVT diagnosed patients who experience cardiac arrest, recurrent syncope or polymorphic/bidirectional VT despite optimal drug therapy and/or left cardiac sympathetic denervation . Nevertheless, cardiologists try to avoid ICDs in this population because of the potential for precipitating repetitive episodes of VT (“VT storm”) in response to ICD shocks and consequent catecholamine release .
Patients with ICDs should continue beta blocker treatment for prevention of ventricular arrhythmias and any adverse/proarrhythmic effects of ICDs’ discharges [1,3]. Left cardiac sympathetic denervation represents an invasive therapeutic approach which is reported to decrease significantly (>90%) the arrhythmic events ; it may be considered in patients with recurrent syncope or arrhythmias requiring frequent ICD shocks while on beta-blockers and in those who do not tolerate medication or continue to be symptomatic while on maximum drug doses (Class IIb) . Catheter ablation is another invasive method which may be performed in patients with refractory arrhythmias; nevertheless, it is used far less often than the other treatments, since its efficacy in CPVT has not been proved yet. Thus, catheter ablation for CPVT is not included in the relevant 2013 guidelines/recommendations .