Prevalence of coronary artery disease and coronary microvascular dysfunction in heart failure with preserved ejection fraction

Rush, Christopher James (2020) Prevalence of coronary artery disease and coronary microvascular dysfunction in heart failure with preserved ejection fraction. PhD thesis, University of Glasgow.

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Abstract

Background
Heart failure (HF) is a major cause of morbidity and mortality worldwide. HF with preserved ejection fraction (HFpEF) now accounts for around half of the HF population. To date, no treatments for HFpEF have proven effect and outcomes have not improved in recent decades. The heterogeneity of the HFpEF population and the failure of randomised controlled trials (RCTs) to demonstrate effective therapies has led to attempts to identify sub-phenotypes of HFpEF which may respond to targeted therapies.

Recent studies suggest that epicardial coronary artery disease (CAD) and coronary microvascular dysfunction (CMD) may play an important role in a substantial group of patients with HFpEF. A novel paradigm has been proposed suggesting that endothelium-dependent CMD may play a key role in the unifying pathophysiology of HFpEF.

I performed a systematic review of the literature describing the prevalence of epicardial CAD and CMD in HFpEF populations. Most studies were retrospective observational and population-based studies with inconsistent definitions of HF, preserved left ventricular ejection fraction (LVEF) and CAD. Studies which documented CAD angiographically were almost exclusively performed in highly-selected convenience cohorts. Consequently, prevalence estimates of CAD in HFpEF varied considerably between studies. Similarly, studies assessing CMD in HFpEF reported inconsistent results due to variable definitions of CMD and methods of assessing coronary microvascular function. Therefore, the prevalence of epicardial CAD and CMD have not been prospectively and systematically studied in an unselected HFpEF population.

Aims
The main aims of this study were to determine the prevalence of obstructive epicardial CAD, CMD and previous myocardial infarction (MI) in an unselected cohort of patients hospitalised with HFpEF using reference standard invasive investigations.

Methods
This was a prospective, multicentre, observational study of patients hospitalised with HFpEF. All patients recruited had a confirmed diagnosis of HFpEF according to the 2016 European Society of Cardiology (ESC) HF guidelines. Participants underwent invasive coronary angiography with guidewire-based assessment of coronary flow reserve (CFR) and the index of microcirculatory resistance (IMR), followed by vasoreactivity testing with intra-coronary acetylcholine. This allowed the comprehensive assessment of epicardial and microvascular structure and function to determine the prevalence of CAD, CMD and coronary endothelial dysfunction in the cohort. Adenosine perfusion cardiac magnetic resonance (CMR) imaging was also performed to assess the burden of myocardial infarction (MI), diffuse fibrosis and inducible ischaemia in the study population. Patients were followed up by electronic medical record linkage for a minimum of 12 months.

Results
Of 2285 near-consecutive patients hospitalised with suspected HF, 628 were confirmed to have a diagnosis of HFpEF, and 106 HFpEF patients met the inclusion criteria and agreed to participate in the study. A total of 83 participants underwent invasive coronary angiography or CMR. Seventy-five participants underwent invasive coronary angiography, 62 had guidewire-based coronary physiology testing, and 41 underwent vasoreactivity testing. Fifty-two participants underwent CMR and 44 had both invasive coronary angiography and CMR. Twenty-three patients did not proceed to the study investigations, predominantly due to a decline in health, functional status or renal function making proceeding with the study investigations inappropriate or unsafe.

In this unselected hospitalised HFpEF cohort, the prevalence of obstructive epicardial CAD on invasive assessment was 51% (95% confidence interval [CI] 39-62%); half of patients with obstructive epicardial disease had no clinical history of CAD. On invasive coronary physiological testing, 41 patients (66% [95% CI 53-77%]) had endothelium-independent CMD, and 10 (24% [95% CI 13-40%]) had endothelium-dependent CMD. Overall, 91% of participants had evidence of macrovascular and/or microvascular CAD. Of those who underwent CMR, 27% (95% CI 16-41%) had evidence of previous MI and 32% (95% CI 19-48%) had inducible ischaemia. Over half of patients with CMR-proven MI had no history of clinically apparent MI.

Over a median follow-up period of 18 months, study participants with obstructive epicardial CAD had significantly more hospitalisations (for any cause, a cardiovascular cause or HF) than those without obstructive CAD. There was no significant difference in outcomes between those with or without endothelium-independent or -dependent CMD.

Conclusion
Both epicardial CAD and CMD are common in the HFpEF population, and there is a high prevalence of clinically unrecognised obstructive epicardial CAD and previous MI. Patients with obstructive epicardial CAD had significantly more hospitalisations than those without obstructive disease. Treatments for epicardial CAD (e.g. coronary revascularisation) might improve quality of life and reduce hospitalisations in HFpEF patients with CAD.

Although it has been hypothesised that CMD in HFpEF is the result of endothelial dysfunction, it appears to be predominantly due to endothelium-independent mechanisms. This may have important implications for future treatments directed at CMD in patients with HFpEF.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: Heart failure, Heart failure with preserved ejection fraction, Coronary artery disease, Coronary microvascular dysfunction.
Subjects: R Medicine > R Medicine (General)
R Medicine > RC Internal medicine
Colleges/Schools: College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences > Cardiovascular Science
Funder's Name: Chief Scientist Office (CSO)
Supervisor's Name: McMurray, Professor John J.V. and Petrie, Professor Mark C.
Date of Award: 2020
Depositing User: Dr Christopher J Rush
Unique ID: glathesis:2020-81763
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 28 Oct 2020 12:12
Last Modified: 28 Oct 2020 15:22
URI: http://theses.gla.ac.uk/id/eprint/81763
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