Abstract
Heart failure with preserved ejection fraction (HFpEF) accounts for 50% of heart failure. However, effective treatments remain elusive and outcomes are poor. A key barrier to progress is inadequate understanding of the underlying pathophysiology. Co-morbidity induced microvascular endothelial inflammation driving cardiomyocyte dysfunction and left ventricular remodelling has emerged as an overarching paradigm, although investigationacross HFpEF clinical phenotypes is crucial to understand its potential role as a critical and common driver.
The main aims of my work are threefold:
• Firstly, to understand the complex interaction between coronary filling and
ventricular function in patients with HFpEF. I hypothesise there is an ttenuation in the maximal increase in backward expansion wave with exercise and denosine in patients associated with HFpEF, and that the degree of this attenuation is related to impaired myocardial relaxation. This will be investigated by a combined analysis of coronary wave intensities and left ventricular dynamics. Furthermore, patients with HFpEF have increased levels of microvascular inflammation and capillary rarefaction, I will assess if these pathological changes are related to the impaired diastolic function, increased microvascular resistance and the backward expansion wave. This will be examined by correlating the findings of histological assessment left ventricular endomyocardial biopsy with invasive physiological measures of
coronary and ventricular function.
• Secondly, I aim to explore the potential for less invasive surrogate measures of ventricular function, without the need for instrumentation of the left ventricular cavity which is costly both in terms of the required cost, experience and procedural risk involved. I will compare diastolic strain and strain rate determined by tissue tracking of cardiac magnetic resonance imaging to invasive indices of diastolic function. Furthermore, using the aortic pressure trace, the validity of a modified Windkessel RC model to estimate changes in stroke volume will be assessed using simultaneously acquired aortic pressure traces and ventricular stroke volumes across a range of loading conditions.
• Thirdly, given implication of microvascular inflammation and resultant dysfunction driving the pathogenesis in HFpEF, I will assess the feasibility of an oral CXCR2 inhibitor (which inhibits inflammatory cell endothelial migration) to reduce markers of vascular inflammation and improve microvascular function.
| Date of Award | 1 Mar 2021 |
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| Original language | English |
| Awarding Institution |
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| Supervisor | Simon Redwood (Supervisor) & Michael Marber (Supervisor) |