| Zusammenfassung: | <p>Since its development in the 1990s, cardiac resynchronisation therapy has evolved to occupy a key position in the management of heart failure with a reduced ejection fraction and broadened QRS duration, inducing both acute haemodynamic improvements as well as chronic reverse remodelling. However, approximately 30% of patients appear to not respond to CRT. Whilst factors such as heart failure aetiology and patient comorbidity, e.g. diabetes mellitus, have been shown to correlate with poor response, the mechanisms responsible for this and strategies to improve response have in large part remained elusive. Meanwhile, changes in myocardial metabolic substrate usage and flux are increasingly thought to play a causative role in heart failure. Given the changes in cardiac efficiency and regional substrate uptake which are induced by CRT, this raises the intriguing possibility that changes in myocardial metabolism may influence reverse remodelling. This thesis aims to therefore further investigate the links between CRT and myocardial metabolism.</p>
<p>In Chapter 3, the effects of substrate manipulation on cardiac function and energetics are assessed in participants with diabetes mellitus, with and without systolic heart failure. While metabolic flexibility appears to be maintained in participants with diabetes mellitus alone, with improved cardiac contractility and efficiency on a free fatty acid infusion, this flexibility is reduced or lost in participants with both diabetes mellitus and systolic heart failure. This loss of flexibility may in part account for the reduced CRT response rates seen in these patients.</p>
<p>In Chapter 4, the acute effects of CRT are assessed invasively. Cardiac contractility and oxygen efficiency are shown to be improved regardless of substrate manipulation. In addition, CRT induces a change in cardiac substrate uptake within 2 minutes of the commencement of pacing, with a more physiological picture of lipid derived metabolism as seen in the healthy heart. This increase correlates with improvements in acute cardiac contractility.</p>
<p>In Chapter 5, the influence on reverse remodelling of both baseline cardiac energetics before CRT implant and the acute changes in substrate uptake discussed in Chapter 4, are assessed. Baseline energetic efficiency, in terms of metabolic flux, and changes in free fatty acid uptake appear to correlate with measures of reverse remodelling at 6 months. In addition, calculation of cardiac volumes and QRS duration in response to CRT both acutely (with a pressure-volume loop catheter) and at follow up (using MR-conditional devices) allows the acute influence of electrical resynchronisation to be distinguished from the long term structural reverse remodelling which occurs.</p>
<p>In Chapter 6, optimal CRT programming during exercise stress is assessed, with CPET and 12 lead ECG monitoring used to assess the effectiveness of fusion pacing. Whilst there is no difference between fusion pacing and standard biventricular pacing on QRS duration or exercise capacity, use of whichever programming gives the narrowest QRS duration at rest results in a narrower QRS duration during exercise and improvement in stroke volume and peak cardiac efficiency. This therefore supports the use of fusion pacing in the 40% of patients where this gives a narrower QRS duration and suggests that optimal QRS narrowing at rest should be the target of CRT optimisation.</p>
<p>Together, these results suggest that CRT and myocardial metabolism have reciprocal influences and that the assessment and manipulation of metabolism may help improve CRT rates of response.</p>
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