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 sarcoplasmic reticulum (SR). The protein responsible for this release is the cardiac ryanodine receptor (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. Arrhythmias occur when this electrical pulse and opening of the RyR2 gate become disassociated.
Our research exposed a novel molecular mechanism which causes RyR2 to open in the absence of an electrical pulse. Studying a number of rare, arrhythmogenic, genetic mutations within RyR2, using advanced intra-SR calcium imaging we found that these mutations caused RyR2 to open due to a sensitisation of RyR2 to SR calcium (Fig. 1A, B). This sensitization of RyR2 to SR calcium causes the channel to release calcium whenever the concentration of calcium within the SR passes a certain threshold (Fig. 1C). Therefore we termed this molecular mechanism Store Overload Induced Calcium Release (SOICR).
We have subsequently shown that other more common triggers of arrhythmia, such as caffeine andstress, also cause arrhythmia by reducing the threshold for SOICR (Fig. 2). Accordingly, we found that caffeine and phosphorylation of RyR2 by protein kinase A, which occurs during stress, both sensitise RyR2 to SR calcium which leads to SOICR.
By understanding the mechanism of SOICR we have been able to create a new class of anti-arrhythmic compounds designed to prevent SOICR. Excitingly, we have recently shown, in a mouse model of arrhythmia, these new drugs are very effective at both supressing and preventing arrhythmia.
Our current work is focused on understanding if SOICR underlies other, even more common, causes of arrhythmia such as ischemia-reperfusion injury (heart attack) and end-stage heart failure. Specifically, we are focusing on a number of proteins which are known to interact with RyR2 (Fig. 3) and are thought to assist with controlling its gating, as other researchers have found that the amount and cellular distribution of many of these proteins is altered in heart disease.