Investigating myofilaments as a trigger for spontaneous systolic calcium release

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac syndrome, usually caused by mutations in sarcomere proteins.

Sudden cardiac death is the leading cause of death in young HCM patients, but the cellular mechanisms responsible are incompletely understood.

Myofilaments play a major role in Ca2+ buffering in the heart and mutations or post-translational modifications that alter Ca2+ binding can impact the amplitude and kinetics of the Ca2+ transient.

This may influence the electrical properties of the heart through effects on inward Na+/Ca2+ exchange current (INCX) and early afterdepolarizations (EADs).

Late Ca2+ sparks (LCS) occur during the normal Ca2+ transient decline and can provide a regenerative source of INCX to trigger and sustain EADs.

It is not known whether changes in Ca2+ transient decay caused by altered myofilament sensitivity, in response to drugs or mechanical load, impact LCS production.

This project will investigate whether Ca2+ release from myofilaments influences arrhythmogenic LCS production, and whether new disease-specific therapies could provide some protection.

This project will employ a range of experimental techniques, from confocal Ca2+ imaging of single ventricular myocytes, to whole organ physiology and computer modelling, to address the role of myofilaments as a potential trigger for spontaneous Ca2+ release.