Sarcoplasmic reticulum calcium content increases in response to stimulation from catecholamines, explaining why arrhythmias in those with CPVT occur at times when catecholamine levels are elevated. Some suggest that the increased sensitivity to calcium occurs only when the ryanodine receptor is phosphorylated by protein kinase A, while other suggest that the increased sensitivity also occurs under resting conditions.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. Domain unzipping refers to the separation of two important regions of the ryanodine receptor, the N-terminus and the central domain. Through this mechanism, a mutation might destabilise the ryanodine receptors closed state and increase its sensitivity to calcium. A second potential mechanism involves the regulatory protein FKBP12.6, a protein that binds to and stabilises the ryanodine receptor. The binding of FKBP12.6 to the ryanodine receptor is regulated by phosphorylation. Phosphorylation by protein kinase A leads to the dissociation of FKBP12.6, rendering the ryanodine receptor more sensitive to cytosolic calcium. RYR2 mutations may interfere with the binding of FKB12.6 to the ryanodine receptor and thereby increase sensitivity to calcium. It is likely that FKBP12.6 plays a role in some CPVT mutations but not others.RYR2 mutations responsible for CPVT are mainly found in four major domains of the gene. 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.
Prognosis
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. Life-threatening arrhythmias are more likely to occur if CPVT has been diagnosed in childhood, if a person with CPVT does not take beta blockers, and if arrhythmias occur on exercise testing despite taking beta blockers.During treatment with nadolol, the preferred beta blocker for the treatment of CPVT, event rates have been estimated to be 0.8% per year. 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, called the C-terminal domain (amino acids 4889–4969). Epidemiology
CPVT is estimated to affect 1 in 10,000 people. Symptoms from CPVT are typically first seen in the first or second decade of life, and more than 60% of affected individuals experience their first episode of syncope or cardiac arrest by age 20. Syncope during exercise or strong emotion should be considered a red flag, as it is a characteristic of the disease. Lastly, a small number of patients may present later in life, and genetic testing in these patients frequently fails to identify a causative gene. History
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.