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. Afterdepolarisations, if large enough, can trigger additional action potentials, premature ventricular contractions, or sustained arrhythmias. Causes
CPVT can be caused by mutations in several genes, all of which are responsible for regulating the concentrations of calcium within cardiac muscle cells. The most commonly identified genetic mutation in CPVT is a mutation in the RYR2 gene that encodes the cardiac ryanodine receptor, responsible for releasing calcium from the sarcoplasmic reticulum. Mutations associated with CPVT have also been identified in the CASQ2 gene which encodes calsequestrin, a protein that binds calcium within the sarcoplasmic reticulum. Other genes associated with rarer, atypical forms of CPVT include TECRL encoding Trans-2,3-enoyl-CoA reductase-like protein, CALM1, CALM2 and CALM3 all encoding Calmodulin, and TRDN encoding Triadin. CPVT1: RYR2 mutations
The most commonly identified genetic mutations in those with CPVT occur in the RYR2 gene which encodes the cardiac ryanodine receptor. Mutations in this gene lead to an autosomal dominant form of typical CPVT known as CPVT1. While the precise effect differs between specific mutations in this gene, many RYR2 mutations cause the ryanodine receptor to open in response to lower concentrations of calcium—the threshold for calcium release is lower. As a result, the sarcoplasmic reticulum spontaneously releases calcium through these abnormal ryanodine receptors when the concentration of calcium within the sarcoplasmic reticulum rises, a process known as store-overload induced calcium release.
These blackouts often occur during exercise or as a response to emotional stress—situations in which chemical messengers known as catecholamines, such as adrenaline, are released within the body. Blackouts may be misinterpreted as being caused by simple faints or epilepsy, often leading to delays in reaching the correct diagnosis. In a third of those affected, the first manifestation of the disease may be cardiac arrest, potentially leading to sudden death. This can occur in very young children, presenting as sudden infant death syndrome or cot death. 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.In those with CPVT, catecholamine release can lead to an abnormal heart rhythm or arrhythmia known as ventricular tachycardia. The ventricular tachycardia may take a characteristic form known as bidirectional ventricular tachycardia. This form of ventricular tachycardia occurs relatively infrequently, but if seen is suggestive of an underlying diagnosis of CPVT or the related condition Andersen-Tawil syndrome. These ventricular arrhythmias in some cases terminate by themselves, causing a blackout from which the person then recovers. 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.There are typically very few abnormal signs on clinical examination in persons with CPVT. 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.