Title: Why is lamin cardiomyopathy a perfect storm for arrhythmias?
Funder: The Academy of Medical Sciences

Abstract: It is unclear why arrhythmias occur in lamin heart disease (LHD). Our hypothesis and preliminary data these arise through aberrant Ca2+ handling mechanisms due to abnormal mechanotransduction associated with the pathogenic mutation. Strong circumstantial evidence supports this hypothesis and we have expertise and interest in novel therapies for ventricular arrhythmias arising via this mechanism. In combination our hope is that these will result in new therapies for a disease currently only amenable to device and/or heart transplant therapies. LHD accounts for 8-10% of genetic dilated cardiomyopathy and carries an appalling prognosis. Mutations in the gene LMNA manifest as a dilated cardiomyopathy uniquely susceptible to arrhythmia. Despite understanding the genetic defects responsible, mechanisms underlying contractile dysfunction and ventricular arrhythmias are ill-defined. Ventricular arrhythmias in LHD arise independent of structural changes such as fibrosis and ventricular dilatation, and cardiac myocytes display spontaneous pro-arrhythmic activity. The underlying cellular mechanism is however unclear and accordingly there are no disease-specific treatments. Aims and Objectives In this starter grant proposal, the inherent propensity to arrhythmia in LHD will be characterised. By unravelling how dysfunctional Ca2+ cycling contributes to arrhythmias, and how this synergises with aberrant transduction of force, the data gathered herein will shed new insight into dysfunctional mechanotransduction pathways implicated as causal mechanisms in the wider epidemic of dilated cardiomyopathy. It is anticipated this will result in a successful intermediate fellowship application to develop new disease-specific treatments in LHD, while supporting my long-term goal of becoming a world-renowned clinician scientist specialising in genetic cardiomyopathies.

Lay abstract: Lamin heart disease is a life-threatening genetic condition which can be passed down from a parent to their child. It leads to weakening of the heart muscle, which can make patients breathless and exhausted. It also causes dangerous abnormal rhythms of the heart (arrhythmias) which can become so fast and disorganised that the heart muscle stops pumping. This can lead to sudden death. While lamin heart disease can now be efficiently diagnosed with a genetic test, there are still no specific treatments available. One reason for this is that we don’t fully understand what is going awry, and therefore cannot develop a plan to solve it. In particular, we do not understand why patients develop arrhythmias. A starter grant will afford a unique opportunity of understanding the causes of heart failure and abnormal heart rhythms in this condition, by using a mouse model which faithfully reproduces the disease in humans. These mice develop arrhythmias in a similar way to humans, and allow us tease out the different mechanisms involved as well as allowing us to test out new drug treatments. There is strong circumstantial evidence to suggest that arrhythmias in lamin heart disease are caused by extra electrical activity of the building blocks of the heart (cells). We will investigate how this electrical activity comes about, and then test new drugs on them to see whether we can restore this activity back to normal. It is expected that this research will uncover new mechanisms of arrhythmia in this life-threatening condition.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR