Biomedical Engineering

Department of Engineering

Hypertrophic Cardiomyopathy (HCM) is the most common form of Mendelian-inherited heart disease, affecting approximately 0.2% of the global population. HCM can be defined as a thickening of the left ventricular wall, in the absence of abnormal loading conditions. Histologically it is characterised by myocardial disarray, fibrosis and small vessel disease. The clinical phenotype for HCM is variable, ranging from lifelong asymptomatic forms, dyspnea on exertion to early sudden cardiac death. HCM is the most common cause of sudden cardiac death in individuals younger than 35 years of age.

Increased alterations in calcium homeostasis at a cardiomyocyte level and increased calcium sensitivity at the myofilament cause the generation of ventricular tachycardia and are recognised features of HCM. Yet, the underlying biochemical and physical mechanisms as to how calcium induces ventricular arrhythmias remains unclear. Furthermore, the majority of such studies have taken place in the mice, which has distinct electrophysiological differences to humans.

The advent of somatic cell reprogramming to generate human induced pluripotent stem cells (hiPSC) has not only allowed unique patient and disease specific cell lines but has provided a new model system for studying cellular function and signaling in tissues which would have otherwise required highly invasive procedures from patients. We have developed an efficient cardiomyocyte differentiation protocol for hiPSC and are now able to differentiate these cells in spontaneously beating ventricular myocytes that spatially self-organise into an intricate network. However, during the differentiation of such cells into beating networks, the role of mechanical transduction in the generation of mature electrically stable cardiomyocytes remains unknown.

The development of specific time lapse imaging tools will allow us to fully quantify the evolution of the cellular network structure and the establishment of the beating dynamics. We will then correlate theseprocesses with recorded cellular and molecular states. An understanding of these correlations will allow us to elucidate the interaction between mechanotransduction, tissue morphogenesis and differentiation in this model tissue. The work will help optimise the generation of such tissue culture work at high throughput, with direct clinical application for the development of future therapeutics.

Dr. Alex Kabla Department of Engineering
Dr. Rameen Shakur Wellcome Trust Sanger Institute