The higher peaks in free calcium have greater potential to cause store-overload induced calcium release from the sarcoplasmic reticulum, leading to afterdepolarisations.In addition to its role as a calcium buffer, calsequestrin also regulates the release of calcium from the sarcoplasmic reticulum by directly modulating ryanodine receptors. When the concentration of calcium is low, calsequestrin monomers form a complex with the proteins triadin and junctin, which inhibit ryanodine receptors. However, at high calcium concentrations, calsequestrin forms polymers that dissociate from the ryanodine receptor channel complex, removing the inhibitory response and increasing the sensitivity of the ryanodine receptor to spontaneously releasing calcium.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. In the absence of CASQ2, calreticulin levels increase and provide some compensatory calcium binding within the sarcoplasmic reticulum. It is possible that calreticulin may contribute to the generation of arrhythmias seen in association with CASQ2 mutations. Diagnosis
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. However, in response to exercise or catecholamines such as adrenaline, abnormal heart rhythms such as bidirectional ventricular tachycardia or frequent polymorphic ventricular ectopic beats may be seen.
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited genetic disorder that predisposes those affected to potentially life-threatening abnormal heart rhythms or arrhythmias. The arrhythmias seen in CPVT typically occur during exercise or at times of emotional stress, and classically take the form of bidirectional ventricular tachycardia or ventricular fibrillation. Those affected may be asymptomatic, but they may also experience blackouts or even sudden cardiac death. CPVT is caused by genetic mutations affecting proteins that regulate the concentrations of calcium within cardiac muscle cells. The most commonly identified gene is RYR2, which encodes a protein included in an ion channel known as the ryanodine receptor; this channel releases calcium from a cells internal calcium store, the sarcoplasmic reticulum, during every heartbeat. CPVT is often diagnosed from an ECG recorded during an exercise tolerance test, but it may also be diagnosed with a genetic test. The condition is treated with medication including beta-adrenoceptor blockers or flecainide, or with surgical procedures including sympathetic denervation and implantation of a defibrillator. It is thought to affect as many as one in ten thousand people and is estimated to cause 15% of all unexplained sudden cardiac deaths in young people. The condition was first defined in 1978, and the underlying genetics were described in 2001. Signs and symptoms
Although individuals with CPVT may not experience any symptoms, the most commonly reported symptoms are blackouts or sudden loss of consciousness, referred to as syncope.