At the end of each heartbeat, calcium is pumped back by a protein called SERCA along with its regulatory protein phospholamban. The calcium is then held within the sarcoplasmic reticulum by a protein called calsequestrin.Fine-tuning of this process can be achieved by phosphorylating these proteins. As an example, during exercise catecholamines activate beta-adrenoceptors on the cell surface, which trigger protein kinase A to phosphorylate the L-type calcium channel, increasing the flow of calcium into the cell. Simultaneously, phosphorylation of the regulatory protein phospholamban causes more calcium to be drawn up into the sarcoplasmic reticulum. The overall effect of this is to generate a larger calcium transient with each beat, leading to a more forceful contraction. Calcium-dependent arrhythmias
Alterations to the proteins involved in excitation-contraction coupling can disrupt this carefully regulated process. In those with CPVT, the normally tight regulation of calcium can become deranged, leading to arrhythmias. While calcium is generally released from the sarcoplasmic reticulum in response to an action potential, calcium sparks can also occur spontaneously. In a healthy heart, a spontaneous calcium spark is generally an isolated event and goes no further, but if ryanodine receptors or the proteins that regulate them are abnormal, these sparks can trigger releases from neighbouring ryanodine receptors which spread throughout the cell as a calcium wave. These calcium waves are much more likely to occur when cardiac muscle cells are stimulated by catecholamines such as adrenaline, which increase the concentration of calcium within the sarcoplasmic reticulum and sensitise the ryanodine receptors.
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.