Catecholaminergic Polymorphic Ventricular Tachycardia

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is usually diagnosed in children over 2 years of age and adolescents because symptoms first appear in these age groups, but a postmortem study draws attention to the fact that this condition can be an under evaluated cause of infant sudden death syndrome [1]. However, before the age of 1, literature does not describe symptoms attributable to CPVT-related arrhythmias, but this may be caused by good tolerance of the rapid ventricular rate or by the difficulty to recognize the signs of arrhythmia in toddlers, unless the first symptom is represented by syncope. Loss of consciousness has been described in patients as young as 10 months [2], but usually occurs after the age of 2 or 3, but inside the first two decades of life. It is triggered by emotional stress or physical effort and accompanied by seizures, therefore being often misinterpreted as epilepsy. This way, the correct diagnosis can be delayed for over 2 years, when symptoms are thought to be caused by neurological or vasovagal abnormalities. A family history of sudden death, seizure or effort induced syncope, if present, as it is in 30% of cases, may decrease this duration by pointing towards a cardiac cause. Conversely, when a patient is diagnosed with this condition, all family members should be screened, since asymptomatic carriers of the gene defect are often detected, and they might pass it on to their offspring, if unaware of the situation.

Complaints related to the disease differ in adults and children. Older individuals describe palpitations, shortness of breath or chest pain, making the need for a cardiology consultation obvious. Chest pain does not necessarily mean severe coronary atherosclerosis, but merely the imbalance between the myocardial need for oxygen, dictated by its increased activity during the tachycardia event and oxygen supply, decreased at that moment because coronary filling is achieved during the diastole, whose duration is shortened because of the high heart rate. However, this explanation does not eliminate the need to also look for signs of myocardial ischemia, if clinical judgment dictates, as the two diseases do not exclude each other.

Children, on the other hand, consult a specialist due to symptoms triggered by activity or emotion, but if the physician performing the initial evaluation fails to establish this link, the real diagnosis can be unacceptably delayed. The signs of the disease in this age group consist of lightheadedness, dizziness, faintness, minor fits, hypotonia, episodes of paleness or visual abnormalities. As the severity of the episode progresses, syncope, accompanied by hypertonia, convulsions and loss of urine or feces occurs, incorrectly leading to the diagnosis of epilepsy. Consciousness is usually regained in under a minute up to a few minutes. Syncope normally occurs after the age of 3, with a mean age of 7.7 to 8 years [3]. 75% of patients have already had discomfort caused by their disease before the age of 20 years. Unfortunately, in some cases, the first manifestation of catecholaminergic polymorphic ventricular tachycardia is sudden death.

Clinical examination of a catecholaminergic polymorphic ventricular tachycardia patient is usually normal, probably due to the fact that the heart has no structural abnormalities. The resting ECG is also normal, as is the QTc interval. In some cases, an abnormal u wave regarding amplitude or shape can be noticed [4]. The QT interval can be borderline prolonged in some patients. The heart rate can be lower than normal [3], especially in the male sex. According to different studies, boys and men may [5] or may not [6] be more prone to develop a syncope than their female peers.

The thoracic radiography and echocardiography show no structural abnormalities [7] and ways to reproduce the arrhythmia include an exercise stress test, such as a treadmill test or a pharmacological stress test, such as an isoproterenol infusion, both combined with Holter monitorization. The heart rate becomes arrhythmic after a threshold of about 120-130 beats per minute. The sinus rhythm is replaced by junctional tachycardia and, as the heart rate increases, ventricular extrasystoles appear. First they have a monomorphic character and then become bidirectional (the QRS complex axis changes by 180 degrees from beat to beat [8]). Their origin is usually located in the left ventricle (but any myocardial locus can be responsible), thus explaining the right bundle branch block aspect, with right axis deviation alternating with left axis deviation. If the exercise session is not interrupted, the ectopic premature beats organize into quadrigeminy, trigeminy, bigeminy or salvos of polymorphic ventricular tachycardia (first unsustained, that become sustained after a period of time) or ventricular fibrillation and syncope sets in. When heart rate diminishes, ventricular extrasystoles disappear. However, not all patients that develop bidirectional tachycardia during an exercise test have catecholaminergic polymorphic ventricular tachycardia. This entity can only be differentiated from long-QT syndrome and Andersen-Tawil syndrome by genetic testing [9]. Atrial arrhythmia, including fibrillation can also be induced by stress tests, especially in adults [10].

In cases where patient history is highly suggestive, but the arrhythmia was not reproduced during evaluation, an alternative for correct diagnosis is represented by implantable loop recorders. As an electrophysiological study most often proved unuseful by failing to trigger the abnormal heart rhythm, thus highlighting the role of circulating cathecolamines in the pathogenesis of the disease, the next step is represented by genetic testing, and this is important because abnormal gene carriers, even if they have not yet experienced any symptoms, are still at increased risk for sudden cardiac death [11].

One study measured thyroid hormone levels and epinephrine and norepinephrine levels at rest in diagnosed patients and discovered normal values [3]. Postmortem examination of the heart may reveal mild fatty infiltration [12].

The cornerstone of catecholaminergic polymorphic ventricular tachycardia treatment is represented by beta blockers without sympathomimetic activity, proven to reduce the incidence of syncope. However, medical therapy should be completed by lifestyle alterations, namely exercise avoidance. Naturally, a long term acting agent should be chosen. Nadolol is a valid choice, and one article [13] has established an optimum dose of 1.8 mg/kg. Propranolol (2-4 mg/kg/day divided into 3-4 doses per day) can also be used. The genetic background, drug compliance and dosage may influence cardiac event rates even in patients undergoing treatment, with an 8 year relapse probability of 27% [11]. The optimum dose of beta blocker is the maximum one that is well tolerated. This way, the sinus tachycardia threshold after which arrhythmic events occur should never be reached. Doses can be gradually increased under Holter monitoring. Even if premature ventricular beats cannot be completely eradicated, the presence of couplets should not be tolerated, as they are significant predictors of arrhythmic events [11]. The dosage of the beta blockers should be increased in these patients.

If, under maximal treatment, sustained ventricular tachycardia and syncope still occur, an implantable cardioverter defibrillator should be recommended [14]. Patients with poor tolerance or compliance to medical therapy and those with previous aborted cardiac arrest also benefit from this type of device (class I indication ) [15]. However, the physician should keep in mind the fact that discharges of a cardioverter defibrillator can induce catecholamine release, triggering the arrhythmia and thus forming a vicious circle [16].

In cases where the exercise heart rate is difficult to control using only beta blockers, flecainide [17] or verapamil [18] can also be prescribed. Both agents reduce the ventricular arrhythmia burden, but flecainide directly inhibits cardiac ryanodine receptor-mediated Ca2+ release [19].

When all else fails, namely the arrhythmia remains resistant to optimal pharmacological therapy, the physician is left with the only alternative of recommending left cardiac sympathetic denervation [20]. However, one should keep in mind that this technique, despite promising results in studies based on short term follow-up, it requires more data from long-term follow-up patients. Moreover, the surgical technique is difficult and needs to be performed by well-trained physicians.

More studies are needed to validate the efficiency of other therapeutic agents, that have proven effective for arrhythmia control in animal models, such as propafenone [21], dantrolene [22], RyR2 channel inhibitors [23] and calcium/calmodulin-dependent protein kinase II inhibitors [24]. Amiodarone was deemed ineffective by one study [3], the same one that states that symptoms reoccur as soon as the beta blocker treatment is discontinued. For this reason, the patient must be instructed to never skip a dose or risk syncope or even sudden death.

Since the beta blocker treatment needs to be administered for the entire lifetime of the patient, the physician should recommend periodical glucose metabolism evaluation, keeping in mind that these agents might slightly deteriorate glucose metabolism [25].

Mortality in catecholaminergic polymorphic ventricular tachycardia is extremely high if left untreated, reaching 31-35% in 30 years old patients [26] [5]. Individuals that have experienced the first syncope at a younger age have even more grim prognosis [11]. High risk is also encountered in patients that have already had one episode of ventricular fibrillation or unstable ventricular tachycardia. However, children younger than 10 years old rarely suffer sudden death because ventricular fibrillation does not often occur in this age group.

The disease is caused by mutations of the cardiac ryanodine receptor gene [27] or of the cardiac calsequestrin gene [28]. The first form is more frequent than the latter. Autosomal dominant [29] and autosomal recessive [ 28] transmission of the disease to the offspring was documented.

Approximately 1 in 10.000 individuals is estimated to suffer from this condition worldwide, but true prevalence is yet considered unknown. The first case was documented in 1975 [30].

The genetic mutations cause the sarcoplasmic reticulum to release excessive amount of calcium into the cytosol, leading to delayed afterdepolarizations that, in turn, cause ventricular premature contractions that originate in the Purkinje fibers [31] or ventricular myocytes. Abnormal intracellular calcium uptake [32] may represent another mechanism of the disease, therefore a unifying hypothesis on the pathophysiology of this condition remains to be drafted.

All family members of the patient must be tested for the disease by means of electrocardiography, Holter monitoring and stress tests, even if they exhibit no symptoms. Genetic testing and counseling is also appropriate, keeping in mind that the disease is transmitted in an autosomal dominant manner, has a high penetrance (80%) and that de novo mutations can also be encountered (20-50% of cases). Even completely asymptomatic gene carriers should be treated with beta blockers [11].

Secondary prevention refers to prevention of arrhythmic events in individuals that have been diagnosed with the disease and is achieved by pharmacological and non-pharmacological measures discussed above.

Embolism prevention may be necessary in children who have received an implantable device that required looping. Prevention of medication side effects also deserves consideration, since beta blockers can worsen asthma.

Catecholaminergic polymorphic ventricular tachycardia is a potentially life-threatening condition that may affect both children and adults. Symptoms are triggered by physical exercise or emotions and have variable severity, ranging from lightheadedness to syncope and sudden death. No structural abnormalities of the heart are present and the resting electrocardiogram may be normal. Physical and pharmacological stress tests cause premature ectopic ventricular contractions that tend to organize into salvoes and degenerate to ventricular tachycardia and fibrillation. Patients must receive lifelong beta blocker treatment and/or undergo interventional procedures such as cardioverter/defibrillator implantation or left cardiac sympathetic denervation.

Catecholaminergic polymorphic ventricular tachycardia is a serious genetic disease characterized by abnormal heart contractions that occur after physical effort or emotions. Patients may feel dizziness or light-headedness, may have visual abnormalities, palpitations or fainting, depending on the duration of the arrhythmia. Symptoms usually begin during childhood and do not disappear unless the patient receives medication. Diagnosis is established by stress tests performed under electrocardiography monitorization or by receiving an intravenous infusion that has the same effect, that of accelerating heart beats and triggering the arrhythmia. Treatment consists of beta blockers administration. If they fail to control symptoms, they physician may order implantation of a device that triggers shocks inside the heart to stop the episode or a surgical procedure (left heart denervation). If oral treatment does prove effective, it is extremely important that no doses are omitted, because this may cause syncope or sudden death. Intense physical exercise should be strictly avoided.

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