Catecholaminergic polymorphic ventricular tachycardia

Signs and symptoms

The most common symptom is dizziness or syncope which often occurs during exercise or as a response to emotional stress.

Age at onset

CPVT typically start manifesting during the first or second decade of life. The majority of events occur during childhood with more than 60% of affected individuals having their first episode of syncope or cardiac arrest by age 12-20.

Triggers

Symptoms are typically precipitated ("triggered") by exercise-induced ventricular arrhythmias during periods of physical activity or acute emotional stress.

Molecular Genetics

CPVT can be caused by mutations in either one of at least five genes, four of which are currently known. Mutations in two genes cause CPVT inherited by an autosomal dominant (AD) inheritance pattern while the other ones follow autosomal recessive (AR) inheritance

CPVT1 (RYR2)

Mutation of the Ryanodine receptor isoform 2 (RYR2) gene has been linked to catecholaminergic polymorphic ventricular tachycardia (CPTV). Under normal physiological conditions, RYR2 mutation has no discernable effect on calcium induced-calcium release from the sarcoplasmic reticulum (SR). Ryr2 is normally activated by increased cytosolic calcium, but under stressful conditions such as increased beta adrenergic activation, RYR2 is activated by luminal calcium in association with increased SR calcium loading. The increased luminal calcium activation occurs because of a phenomenon termed store-overload induced calcium release (SOICR). SOICR leads to spontaneous and inappropriate action potentials, generating arrhythmias. A Ryr2 mutation may increase sensitivity to luminal calcium activation, therefore increasing calcium release from the SR under store-overload conditions and thus triggered arrhythmias.

RYR2 mutations have been well characterized and been found to occur primarily in 4 major domains. Mutations in domains III and IV of the protein (amino acid range from 3778 to 4201 and 4497 to 4959 respectively) occur in 46% of reported mutations. Mutations occur less frequently in domains I and II (amino acid 77-466 and 2246-2534 respectively). Causative RYR2 mutations outside these four domains are very rare, occurring in as little as 10% of reported cases. Ryr2 mutations are most often single nucleotide substitutions resulting in a different amino acid substitution, however some in-frame substitutions and duplications have been documented . It is commonly accepted that more severe mutations have not been linked to CPTV as they are more likely to underlie different cardiac pathologies.

Recent findings have characterized the pathology of RYR2 mutations and how they relate to SOICR as a matter of the intrinsic properties of the ryanodine channel. Two theories propose the underlying mechanism, domain unzipping and FKBP12.6 unbinding. Firstly, domain unzipping refers to the separation of the N-terminal domain's interaction with the central domain; destabilizing the receptor. The mutation would compromise the stability of the Ryr2's closed state and increase its sensitivity to stimuli like luminal and cytosolic calcium. Domain unzipping coincides with the specific Ryr2 domain mutations associated with CPTV . The second theory of FKBP12.6 is more controversial . FKBP12.6 is a RYR2 binding protein that stabilizes the receptor. FKBP12.6 binding to RYR2 is regulated by RYR2 phosphorylation via PKA that results in the dissociation of FKBP12.6, rendering Ryr2 more sensitive to cytosolic calcium activation . However, as mentioned above, evidence has been conflicted in determining FKBP12.6's role in CPTV. So far the literature concludes that FKBP12.6 may play a role in certain CPTV mutations but not others, further research needs to clarify this protein's role.

CPVT2 (CASQ2)

Mutations in the Calsequestrin isoform 2 (CASQ2) gene has been linked to CPVT. Under normal physiological conditions, CASQ2 is the major luminal Ca²⁺ binding protein in the sarcoplasmic reticulum (SR) ), which in the main Ca²⁺ storage organelle in cardiac muscle. CASQ2 is also associated with regulating SR Ca²⁺ release when bound to triadin, junctin and RYR2, forming a complex . This cytosolic to luminal Ca²⁺ activation process that RYR2 regulates is termed store-overload induced calcium release (SOICR). CASQ2 is responsible for initiating and terminating this process. CASQ2 acts in low levels of SR Ca²⁺, where CASQ2 monomers inhibit RYR2 by forming the triadin-junctin-RYR2 complex, however at high levels of SR Ca²⁺, CASQ2 monomers form polymers and dissociate from the RYR2 channel complex, removing the inhibitory response activating the channel to spontaneously release Ca²⁺. A mutation, specifically R33Q and D307H in CASQ2 tend to alter the Ca²⁺ binding capacity or alter the interactions between CASQ2 and RYR2 channel complex, potentially affecting the response of RYR2.

Mutations in the CASQ2 gene have been classified into 12 CPVT associated mutations: 4 are nonsense mutations causing shortening of proteins, and 8 are missense mutations. R33Q and D307H reduce CASQ2 protein to 5% and 45% of normal levels respectively, which reduces SR Ca²⁺ buffering and binding capacity. The most severe missense mutation, D307H, converts aspartic acid (negatively charged) to a histidine within a Ca²⁺ chelating region. This disrupts Ca²⁺ binding to CASQ2, but the specific mechanism behind this mutation is still undetermined. The missense mutation R33Q causes a substitution of glutamine for arginine, decreasing the total amount of Ca²⁺ stored in the SR, thus increasing the Ca²⁺ buffering system causing Ca²⁺ leak through RYR2, where the mechanism behind this mutation is proposed to interact with triadin and/or junction forming "polar zippers".

There are two major theories as to what is occurring when CASQ2 is deficient. It was found that decreased CASQ2 is associated with high levels of calreticulin (CRT). In the absence of CASQ2 signal, CRT levels increase and provide some compensatory SR Ca²⁺ binding activity. CRT levels decrease significantly after birth and high levels are only present in the developing heart, leading to the theory of caused bradycardia and sinus node dysfunction which is found in CPTV patients. With the absence of CASQ2, it was also found that RYR2 activity remained high in diastole since CASQ2 could not provide the inhibitory response, causing a prolonged Ca²⁺ leak which triggers early action potentials. With reduced SR Ca²⁺ buffering capacity, is a faster recovery of SR free Ca²⁺ after each Ca²⁺ release, resulting in higher levels of SR free Ca²⁺ and SR Ca²⁺ loading, both increasing trigger activity and SOICR recurrence . The exact mechanisms by which the mutations occur in the CASQ2 gene are still under investigation. Research underway is analyzing strategies to target RYR2 inhibition and approaches to increasing SR Ca²⁺.

Diagnosis

Affected patients demonstrate no structural problems of the heart upon echocardiographic, CT or MRI imaging.

CPVT diagnosis is based on reproducing irregularly shaped ventricular arrhythmias during ECG exercise stress testing, syncope occurring during physical activity and acute emotion, and a history of exercise or emotion-related palpitations and dizziness with an absence of structural cardiac abnormalities.

Because its symptoms are usually only triggered when the body is subjected to intense emotional or physical stress, the condition is often not detected by the traditional methods of electrophysiologic examination such as a resting electrocardiogram.

Medication

Medications to treat CPVT include beta blockers and verapamil.

Flecainide inhibits the release of the cardiac ryanodine receptor–mediated Ca²⁺, and is therefore believed to medicate the underlying molecular cause of CPVT in both mice and humans.

Implantable cardioverter-defibrillator

Implantable cardioverter-defibrillators are used to prevent sudden death.

Sympathectomy

In recent reports, left cardiac sympathetic denervation and bilateral thoracoscopic sympathectomy have shown promising results in individuals whose symptoms cannot be controlled by beta blockers.