Dr Pete Jones, Department of Physiology, was recently awarded $307,000 by the Marsden Fund for research into cardiac arrhythmias.
Irregular heart rhythms, otherwise known as cardiac arrhythmias, are the leading cause of death in patients with heart disease and are responsible for almost a quarter of all deaths in New Zealand.
This is largely because the underlying molecular mechanisms of arrhythmia are poorly understood which limits the effectiveness of treatments.
It has long been known that adequate and timely contraction of the heart relies enormously on the regulation of calcium release within each cardiac muscle cell.
More recently has it emerged that improper regulation calcium release is also a major driving force of arrhythmia. On a beat-to-beat basis calcium is released, in a highly regulated manor, into each cell from an internal calcium reservoir.
The protein gate that is responsible for this release is named the cardiac ryanodine receptor or RyR2.
Each time RyR2 opens, the cell and as a result the heart contracts, generating a heartbeat.
Normally RyR2 opens in response to a small electrical pulse that passes through the heart (the electrical pulse that is recorded on an ECG/EKG).
Arrhythmias occur when this electrical pulse and opening of the RyR2 gate become disconnected.
The purpose of our research is to discover what causes this to happen.
Our previous research exposed a molecular mechanism which causes RyR2 to open in the absence of an electrical pulse.
We began by studying a number of rare genetic mutations within the RyR2 protein which we knew caused arrhythmia in patients.
We found that these mutations caused RyR2 to open between the normal electrical pulses.
Importantly, we discovered that the mutations allowed an increased level of calcium within the internal reservoir to open the gate directly, akin to weakening a door so that pushing on it can cause it to open without unlocking it.
This insight into the mechanism by which RyR2 can open without an electrical trigger led us to study some more common causes of arrhythmia, such as stress and certain drugs.
We found that all of these causes of arrhythmia shared a common mechanism; this mechanism being the opening of RyR2 by high levels of reservoir calcium.
The new funding from the Marsden Fund will allow us to extend these findings further, by studying more general causes of arrhythmia.
Specifically we will focus on a number of proteins which are known to interact with RyR2 and are thought to assist with controlling its opening and closing.
Other researchers have found that the amount and cellular distribution of many of these proteins is altered in the heart during disease.
We believe that the altered association of these proteins with RyR2 may affect RyR2 in a similar way to mutations, stress and the drugs we have studied.
If we are correct this will show that the opening of RyR2 by high reservoir calcium is a major molecular mechanism behind arrhythmia.
This knowledge will allow the development of new treatments designed to strengthen the RyR2 gate which will prevent increases in reservoir calcium from causing the fatal arrhythmias that accompany heart disease.