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Title: Mechanisms of ventricular arrhythmogenesis in the age dependent Pgc-1β -/- model of mitochondrial dysfunction
Author: Ahmad, Shiraz
ISNI:       0000 0004 7968 4272
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2019
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Sudden cardiac death is a leading cause of mortality worldwide. Ventricular arrhythmias, both ventricular tachycardia and ventricular fibrillation, are the primary arrhythmias that lead to sudden cardiac death. A large proportion of ventricular arrhythmias are ischaemic in origin. However, increasing clinical and experimental evidence links metabolic disease, mitochondrial dysfunction and ageing as independent risk factors for arrhythmogenesis beyond the risk they confer to coronary artery disease. To date, researchers have focused upon investigation of monogenic ion channel disorders as well circumscribed diseases to investigate the principles of arrhythmogenesis. This has given insight into the basic theories of arrhythmogenesis as well as the tools needed to dissect them. In this study, we use Pgc-1β-/- mice as a murine model of mitochondrial dysfunction, to further investigate the link between mitochondrial and energetic insufficiency and arrhythmias. The study uses electrocardiographic data to characterise the phenotype at the whole animal level, revealing significant age related abnormalities in ventricular activation and abnormal nodal tissue phenotypes. Single cell action potential characteristics in intact Langendorff perfused whole hearts were then used both in programmed electrical stimulation studies and at incrementally paced steady states to investigate the electrophysiological characteristics that give rise to arrhythmia. These experiments revealed a significant deficit in maximal rate of depolarisation and consequent effects on conduction wavelengths, accompanied by instabilities in activation characteristics as evidenced by the presence of electrical alternans. Finally, patch-clamp studies are performed to confirm the hypotheses of the earlier experiments and their effect on cellular currents in a physiological environment which show a physiological deficit in sodium current density. At all stages care was taken to perform experiments in the least disruptive manner, maintaining as much physiological relevance as possible. The series of experiments reveal that not only is mitochondrial dysfunction related to arrhythmias in an age dependant manner, but that it leads to altered sodium current density with a plausible role of Ca2+ as a central mediator of this, allowing future studies to build on this.
Supervisor: Huang, Christopher Sponsor: MRC
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
Keywords: PGC ; cardiac ; arrhythmia