Cardiff, UK - British researchers have identified how a mutation in a cardiac receptor leads to abnormal calcium release, causing the condition catecholaminergic polymorphic ventricular tachycardia (CPVT) [1].

Dr Christopher H George (Wales Heart Research Institute, Cardiff) and colleagues report their findings online December 8, 2005 in Circulation Research.

"This is crucial new evidence that mutation-linked abnormalities in cardiac calcium release may arise from defects in the channel structure," George says.

CPVT is an inherited disorder that often strikes in childhood or adolescence. It is characterized by stress-induced bidirectional VT, in the absence of structural heart abnormalities or prolonged QT. Patients experience recurrent syncope in stressful situations and are at risk of cardiac arrest and sudden death.

George told heartwirethat the 10 culprit mutations were first identified in 2000 and shown to be located in the gene of a cardiomyocyte calcium channel known as the ryanodine receptor. "In 2003, there followed the first characterization of what the mutations did—they cause the channel to produce too much calcium when stimulated," he explains.

Now, with the aid of the world's only source of human cloned ryanodine receptors, George and his team believe they have found the link between the mutations, the inappropriate response to stimulation, and the abnormal calcium release.

"The mutations lie in the region of the molecule that holds it together, and they weaken it, so that it becomes inherently unstable and falls apart," he says. ""It's literally like the receptor 'flickering' or like a door being open and wobbling. This is the first demonstration of how these receptors are physically rubbish."

George and his team are now looking at pharmacological and protein-based approaches to try to stabilize the receptor structure, which he says "may also be applicable to other cardiopathologies, specifically ventricular tachycardias."

He adds that although CPVT is "rare," it is not really known how many people it affects. In one study that looked at patients suffering sudden cardiac death and who were normal for long-QT syndrome, researchers found that 90% had the mutations for CPVT, he says.

"There is a huge gray area of those who are not long-QT but some other condition. This could be a walking population time bomb," he concludes.