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Chapter 1 explains the relative importance of diabetes mellitus (DM) and cardiovascular complications in a global perspective. It then describes the current understanding of how diabetic cardiomyopathy develops and what the underlying mechanisms are. Afterwards, atrial fibrillation (AF), another DM-related complication, is presented followed by the description of the main related pathological mechanisms. Finally, the chapter discusses the therapeutic potential of tetrahydrobiopterin (BH4) as a cofactor of nitric oxide synthase (NOS). Chapter 2 describes in full detail all methods used in the experimental work of this research thesis. Chapter 3 shows that the myocardial overexpression of the rate-limiting enzyme for the synthesis of BH4, GTP cyclohydrolase 1 (GCH1), in mice (mGCH1-Tg) prevents the development of left ventricular (LV) diastolic dysfunction in the presence of streptozotocin (STZ)-induced diabetes. Interestingly, the mechanism underpinning this beneficial effect is not suppression of myocardial superoxide production, prevention of BH4 oxidation and restoration of coupled NOS activity, or reduction of interstitial myocardial fibrosis. Instead, the overexpression of GCH1 with an associated increase in the myocardial BH4 level and myocardial NOS activity prevents myocardial energetic impairment in diabetic hearts by increasing glucose uptake via the insulin-independent glucose transporter 1 (GLUT-1). Chapter 4 explores the atrial electrophysiological characteristics of STZ diabetic mice. Diabetic mice have increased risk for in vivo pacing-induced AF, enlarged relative atrial size and impaired in vivo atrial conduction, as indicated by prolonged ECG PQ interval. Furthermore, experiments in isolated whole atria demonstrate a significant focal increase in fibrosis in the medial part of the right atrium, which results in a significant decrease in the conduction velocity in the same area followed by an increase in the conduction wave-front heterogeneity in the left atrium. Chapter 5 investigates the electrophysiological phenotype of the mGCH1-Tg mice. The transgenic mice have lower heart rates, they spontaneously develop AV nodal escape rhythm, and have prolonged ECG QT interval. The underlying mechanisms for those changes are a global decrease in the atrial conduction velocity, decrease in the conduction through the AV node, as well an increase in the action potential duration (APD). Furthermore, oral BH4 treatment was also tested in diabetic mice, but it did not decrease the risk of AF or improved LV diastolic dysfunction significantly. Chapter 6 summarises the key results and presents the relative impact of each finding. It also discusses the main limitations of the study as well as future research directions. |
