Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited genetic disorder that predisposes those affected to potentially life-threatening abnormal heart rhythms or arrhythmias.

CPVT is caused by genetic mutations affecting proteins that regulate the concentrations of calcium within cardiac muscle cells.

[1] Approximately 30% of those with CPVT will have a family member who has experienced blackouts, seizures, or sudden death in response to exercise or stress.

However, if the abnormal heart rhythm continues, it can degenerate into a more dangerous arrhythmia known as ventricular fibrillation causing a cardiac arrest and, if untreated, sudden death.

However, those with CPVT may develop a less serious heart rhythm disturbance called atrial fibrillation, which can be detected on examination as an irregular pulse.

[4] The arrhythmias that those with CPVT experience are caused by abnormalities in the way that cardiac muscle cells control their levels of calcium.

[14] The uncontrolled wave of calcium can be forced out through the cell membrane via the sodium-calcium exchanger, causing an electric current known as a delayed afterdepolarisation.

[16] Mutations associated with CPVT have also been identified in the CASQ2 gene which encodes calsequestrin,[17] a protein that binds calcium within the sarcoplasmic reticulum.

[11] Two theories have been proposed for the underlying mechanism by which mutations in RYR2 promote store-overload induced calcium release: domain unzipping and FKBP12.6 unbinding.

[10] Mutations affecting domains III and IV of the gene (corresponding to the N-terminal region of the protein and cytosolic linker respectively) occur in 46% of cases.

More damaging nonsense mutations have not been reported in association with CPVT, potentially because these variants may lead to different cardiac diseases such as cardiomyopathies.

When the concentration of calcium is low, calsequestrin monomers form a complex with the proteins triadin and junctin, which inhibit ryanodine receptors.

[10] Decreased CASQ2 is also associated with high levels of calreticulin, a protein which among other roles regulates the reuptake of calcium into the sarcoplasmic reticulum by SERCA.

[21] CPVT may be challenging to diagnose as the structure of the heart appears normal in those affected by the condition when assessed using an echocardiogram, cardiac MRI scan or cardiac CT scan, while the electrical function of the heart also appears normal at rest when assessed using a standard 12-lead ECG.

During the test, those with CPVT often experience ectopic beats, which may progress to bidirectional and then polymorphic ventricular tachycardia as the intensity of exercise increases.

[25] This drug lowers the heart rate to a greater extent than other beta blockers and only needs to be taken once daily, reducing the risk of missed doses.

Nadolol may be difficult to obtain and is not available in all countries, and an alternative beta blocker suitable for use in CPVT may be propranolol, which however has a more complex dosing regimen.

[25] Recently published data suggest that the use of selective beta blockers, such as atenolol, bisoprolol, or metoprolol, is associated with very high treatment failure rates.

[25] Flecainide is a class 1c antiarrhythmic drug that is recommended for those with CPVT who experience abnormal heart rhythms despite taking a beta blocker.

[26] Verapamil is a calcium channel antagonist that, when combined with a beta blocker, may reduce the risk of arrhythmias in patients with CPVT.

If a life-threatening arrhythmia is detected, the device can deliver a small electric shock to terminate the abnormal rhythm and restart the heart.

[1] Implantable defibrillators are often recommended for those with CPVT who have experienced blackouts, ventricular arrhythmias or cardiac arrest despite taking appropriate medication.

[25] It has been suggested that the resulting surge of adrenaline caused by the pain of an electric shock from the device could theoretically bring on a cycle of recurrent arrhythmias and shocks known as an electrical storm,[4] and therefore it is strongly recommended that those with an ICD implanted for CPVT take a beta blocker to dampen the effects of adrenaline.

[4] A significant proportion of those with CPVT will experience a life-threatening abnormal heart rhythm, with estimates of this risk ranging from 13 to 20% over the course of 7–8 years.

In patients treated with beta blockers, life-threatening arrhythmias are more likely if a person had already survived a cardiac arrest, had a syncope, or are carriers of disease-causing mutations affecting the highly conserved terminal portion of RYR2 gene,[25] called the C-terminal domain (amino acids 4889–4969).

[4] Symptoms from CPVT are typically first seen in the first or second decade of life,[25] and more than 60% of affected individuals experience their first episode of syncope or cardiac arrest by age 20.

[4] In 1960, Norwegian cardiologist Knut Berg published a report on three sisters who had blackouts during exercise or emotional stress in what is now recognised as the first description of CPVT.