Mechanisms of ventricular arrhythmogenesis in the age dependent Pgc-1β -/- model of mitochondrial dysfunction.
type: CreativeWork
description: 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 d…
abstract: 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 d…
author: Ahmad, Shiraz
language: en
keywords: PGC, cardiac, arrhythmia
license: https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/4ca120df-4b72-4a8a-8c83-ad9b37b70242/download
license: https://www.rioxx.net/licenses/all-rights-reserved/
date published: 2019-07-20
date modified: 2026-07-22T22:24:06Z
provider: Cambridge University
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Cambridge

PropertyValue
property ID: DOI
value: 10.17863/CAM.40743