New clue to sudden cardiac death in children

Cardiff University researchers have discovered a cause of sudden cardiac death in young children, opening up the possibility for a therapeutic target to develop a cure. Incoherent communication between calmodulin and RyR – two vital proteins in heart cells – is to blame for sudden cardiac death, a condition similar to sudden adult death syndrome, but which affects children over the age of one. "A healthy and regular heartbeat is maintained by precise control of the calcium level in heart muscle cells, but our experiments have identified a genetic flaw that invites chaos to this process," said Professor Tony Lai from the School of Medicine’s Sir Geraint Evans Wales Heart Research Institute (WHRI). "When calcium levels rise the heart contracts and when the calcium levels drop the heart muscle relaxes,” said Dr Michail Nomikos, lead author of the study in FEBS Letters. “The precise control of this movement relies on the direct physical interaction between a calcium channel protein ryanodine receptor (RyR), and a calcium-sensing protein called calmodulin." A genetic mutation in calmodulin causes the loss of regular heart rhythm and disrupts communication between calmodulin and RyR. “Our findings show that there is inadequate binding between these proteins due to the mutated calmodulin gene resulting in the loss of control of cell calcium levels and thereby abnormal heart function,” Nomikos said. "Abnormal changes in calcium levels disrupt the smooth cycling between cardiac contraction and relaxation and this can lead to irregular heartbeat and sudden death." Lai hopes that finding a way to ensure a stable interaction between calmodulin and RyR in the heart could give doctors a new weapon in the fight against sudden cardiac death. “I believe this finding should help potential therapy in the future, as it identifies the putative molecular mechanism of the pathology (i.e. mis-communication between calmodulin and ryanodine receptor) that may now become a viable target for drug interaction,” Lai told Laboratory News. “Our anticipated next line of research aims to explore this specific approach to develop a therapy, by determining whether this protein interaction can be modulated by drugs.” Altered RyR2 regulation by the calmodulin F90L mutation associated with idiopathic ventricular fibrillation and early sudden cardiac death