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Title: Mechanistic insights in the autonomic modulation of ventricular arrhythmia
Author: Kalla, Manish
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2015
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Cardiovascular disease is the leading cause of mortality in the developed world with up to fifty percent of cases being due to sudden cardiac death. Changes in sympatho-vagal balance underpin many cardiovascular conditions including heart failure and myocardial infarction. Neuraxial modulation of the autonomic nervous system is an emerging therapy to prevent ventricular arrhythmias, the main cause of sudden cardiac death. Chapter One reviews our current understanding of how the cardiac autonomic nervous system influences ventricular arrhythmogenesis. A particular focus was on the controversial role of cholinergic receptors and nitric oxide (NO) in parasympathetic protection from ventricular arrhythmias. Tetrahydrobiopterin (BH4), a critical cofactor for both tyrosine hydroxylase and NO synthases, and the co-transmitter neuropeptide-Y (NPY) may also influence sympathetic triggering of ventricular arrhythmias. This leads to the specific aims of the thesis which were to determine the mechanisms of the cholinergic antifibrillatory effect, investigate the role of cotransmission in arrhythmogenesis and, the mechanistic role of BH4 in autonomic cardiovascular control. Chapter Two detailed the experimental approach taken to investigate the hypotheses. A novel Langendorff heart preparation was developed with intact autonomic nerves to investigate how the stable analogue of acetylcholine, carbamylcholine (CCh) raises ventricular fibrillation threshold (VFT) and whether exogenous or endogenously released NPY lowers VFT. These actions are further investigated using optical mapping, dye free imaging of ventricular cell monolayers, immunohistochemistry, ELISA assays and measurements of NO metabolite production. To investigate the role of BH4 in the sympathetic control of the heart, an IRES-cre recombinase strategy was used to produce genomic deletion of GCH1 (the gene encoding BH4) in sympathetic neurons. Biopterins and plasma catecholamines were measured using HPLC, and blood pressure and heart rate via tail cuff plethysmography. Chapter 3 showed that CCh increased VFT, prolonged action potential duration and flattened the electrical restitution curve. This effect required stimulation of both muscarinic and nicotinic receptors and the generation of nNOS derived NO utilising a cGMP dependent pathway. These observations are in keeping with established evidence demonstrating the obligatory role of the muscarinic receptor and indicate that the role of NO is likely to be via modulation of cholinergic neurotransmission. Chapter 4 studied the role of the sympathetic co-transmitter NPY. NPY has been shown to increase ventricular myocyte calcium dynamics. Plasma levels are also increased post myocardial infarction and during heart failure, and correlate with outcomes. Perfusion of NPY decreased VFT via a Y1 receptor dependent mechanism and increased arrhythmic activity in myocyte monolayers. Direct sympathetic stimulation resulted in NPY release and remained pro-arrhythmic despite β-blockade, an effect that could be abolished by combined β-Y1 receptor blockade. These observations indicated that NPY may be a novel, pro-arrhythmic trigger amenable to therapeutic pharmacological modulation. Chapter 5 details the generation and phenotyping of two tissue specific Gch1 knockout mouse models. Whilst one model failed to produce significant lowering of BH4 in sympatho-adrenal tissue, the other did result in a marked neuro-motor phenotype. A biochemical rescue or alternative genomic modification approach would be required to study the cardiovascular phenotype of sympathetic Gch1 deletion in more detail. Chapter 6 is a concluding discussion summarising the main findings of the thesis, placing them in a clinical context and discussing avenues for further research.
Supervisor: Channon, Keith ; Herring, Neil ; Paterson, David Sponsor: British Heart Foundation
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: sympathetic co-transmission ; autonomic nervous system ; Cardiovascular system ; neuromodulation ; ventricular arrhythmia ; tetrahydrobiopterin physiology