Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.706864
Title: Diabetes and obesity : evidence for a cardiomyopathy
Author: Ashrafi, R.
ISNI:       0000 0004 6059 4269
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2016
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Abstract:
Introduction: Obesity and type 2 diabetes are leading causes of cardiovascular morbidity and mortality most commonly through accelerated atherosclerotic disease. Researchers have recognised clearly that there is a cardiac pathological process that is over and beyond any damage secondary to accelerated atherosclerosis or associated hypertension. There has been much research into the histological, genetic and functional changes that may underpin these specific processes; these demonstrate structural hypertrophic and fibrotic changes accompanied by changes in energy metabolism, nervous control, contractile performance and electrical conduction. To date, there is very little in the way of comparative study between animal diabetes and obesity models or of cardiac gene expression in the human type 2 diabetes phenotype, which in many individuals comprises both diabetes and obesity. Aim: To investigate cardiac genetic expression of proteins and ion channels in obesity and diabetes to identify changes underpinning the pathological processes and to characterise features common to both conditions, specifically features that may affect contractile performance and secondly, changes that may lead to increased arrhythmogenesis. Methods: A streptozocin rat model of type 1 diabetes was compared with a high fat diet rat model of obesity and finally a human group with type 2 diabetes to understand the gene expression changes in the left ventricle characterising the obesity and diabetic cardiomyopathy. Gene expression of left ventricle tissue was measured using qPCR and compared to a control group; followed by mathematical modelling to predict changes in the cardiac action potential. This was used to investigate specific changes to each condition and common changes between the groups to identify if there was a common genotype and action potential phenotype. In addition, echocardiography, the standard ECG and the signal averaged ECG were used to assess the human study group for early signs of cardiac dysfunction related to diabetes. Results: All three groups had gene expression changes likely to lead to action potential prolongation and higher rates of arrhythmias, with ERG (Human Ether Related a Go-Go) mRNA reduced in all 3 study groups responsible for IK,r. AP modelling, suggested that the likely functional change of the gene expression alterations would be to cause AP prolongation and in the human study, early-after depolarizations at the endocardial level. As part of the confirmatory process for one of the more unexpected gene changes, up-regulation in HCN4 gene expression in the obese rats was associated with a significant increase in HCN4 protein immunofluorescence in the ventricles. In addition, the human type 2 diabetes group had evidence of reduced ventricular contractile function, atrial changes and strain rate changes suggestive of myocardial fibrosis. No significant alterations were noted in the signal averaged ECG between groups but as has been seen in other studies, QT prolongation was found in the type 2 diabetes group. Conclusion: Diabetes and obesity lead to changes in cardiac gene expression that when modelled will prolong the action potential, possibly as a compensatory mechanism to maintain contractile function at the expense of an arrhythmogenic phenotype.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.706864  DOI: Not available
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