title: Coronary vascular dysfunction: diagnostic evaluation and therapeutic modification
Creators: name: Corcoran, David
Publisher: name: University of Glasgow
Year: 2019

description: Introduction: There is a stenosis-centred concept of myocardial ischaemia, whereby angina pectoris is the consequence of obstructive epicardial coronary artery disease (CAD) that reduces myocardial blood flow (MBF) due to supply-demand mismatch. In clinical practice, the diagnostic management of patients with angina focusses on testing for epicardial CAD. This clinical paradigm fails to account for the approximately one-third of patients who suffer from angina and non-obstructive coronary artery disease (ANOCA). Similarly, patients with obstructive epicardial CAD may have recurrent symptoms following myocardial revascularisation. The management of this cohort of patients in heterogeneous. Patients may fail to have a diagnosis made for the aetiology of their symptoms, receive no further diagnostic work-up, and have no therapeutic intervention. Microvascular angina and vasospastic angina secondary to coronary vascular dysfunction may be relevant. I aimed to investigate the diagnostic role of invasive and non-invasive vascular function testing in patients presenting with stable angina, and the role of therapeutic interventions which may modulate coronary vascular function: 1. The proportion of abnormal invasive parameters of coronary vascular function in patients with both ANOCA and obstructive epicardial CAD. 2. The proportion of abnormal myocardial perfusion (as revealed by perfusion cardiac magnetic resonance (CMR) imaging) in patients with ANOCA. 3. The associations between baseline characteristics and coronary vascular dysfunction. 4. To determine whether remote ischaemic preconditioning (RIPC) might enhance endothelium-dependent and -independent coronary vascular function in patients with stable angina. 5. To evaluate the effects of recombinant relaxin-2 (serelaxin) on coronary microvascular and systemic macrovascular function in patients with stable angina. Methods: I performed two studies of diagnostic testing of vascular function, and two mechanistic trials of novel therapeutic modifications of coronary vascular function: 1. Clinical evaluation of magnetic resonance imaging in coronary heart disease 2 (CE-MARC 2) Coronary Physiology sub-study (NCT01664858): a pre-specified sub-study of a UK prospective multicentre randomised controlled trial of patients presenting with stable angina undergoing invasive coronary angiography (n=67). All patients undergoing invasive diagnostic coronary angiography had invasive parameters of coronary microvascular function measured. The primary outcome was the proportion of patients with coronary vascular dysfunction as defined by abnormal invasive tests (reduced coronary flow reserve (CFR, &lt;2.0), increased index of microcirculatory resistance (IMR, ≥25 U), and reduced resistance reserve ratio (RRR, &lt;2.0). 2. The Coronary Microvascular Angina Cardiac Magnetic Resonance imaging (CorCMR) study: an observational study of multiparametric CMR imaging in the diagnostic pathway of a contemporary UK cohort of patients with ANOCA (n=143). Consecutive patients undergoing clinically-indicated invasive coronary angiography for the investigation angina found to have no obstructive epicardial CAD were invited to undergo multiparametric CMR imaging. The primary outcome was the proportion of patients with coronary vascular dysfunction (defined by reduced global myocardial perfusion reserve (MPR &lt;2.0)). 3. The Effects of Remote Ischaemic Preconditioning on Coronary Artery Function in Patients with Stable Coronary Artery Disease (RIC-COR) (NCT02666235): a mechanistic, randomised, sham-controlled, blinded clinical trial of the effect of remote ischaemic preconditioning (RIPC) on coronary vascular function in patients with stable CAD (n=60). Consecutive patients undergoing clinically-indicated invasive management were prospectively enrolled, and randomised to RIPC or sham (1:1) prior to angiography. Coronary endothelial-dependent vasodilator function was assessed in a non-target coronary artery with intracoronary infusion of incremental acetylcholine doses. The primary outcome was the mean percentage change in coronary artery luminal diameter from baseline to the maximum administered acetylcholine infusion. 4. The Effects of Intravenous Serelaxin on Myocardial Blood Flow and Vascular Function in Patients with Stable Coronary Artery Disease (RELAXCAD) trial (NCT01979614): a mechanistic, randomised, double-blind, placebo controlled trial of recombinant relaxin-2 (serelaxin) on coronary microvascular and macrovascular function in patients with stable CAD (n=51). Consecutive patients referred for the invasive assessment of stable CAD were randomised (1:1) to 48 h intravenous serelaxin (30 μg/kg/day) or matching placebo. Patients underwent assessment of coronary microvascular (myocardial blood flow by stress perfusion CMR) and systemic (aortic) macrovascular function (augmentation index by applanation tonometry) at baseline and 47 h post-serelaxin or placebo. The co-primary outcome was the between-group difference in change from baseline to 47 h in MPR and augmentation index. Results: In summary, the main findings of this thesis are: 1. Abnormal invasive parameters of coronary vascular function are prevalent in patients with both ANOCA and obstructive epicardial CAD: In the CEMARC 2 Coronary Physiology sub-study, 25/67 (40%) patients were classified as having ANOCA. Of these patients, 17/25 (68%) had an abnormality in at least one measurement of microvascular function. There were 38/67 (60%) classified as having obstructive epicardial CAD. Of these patients, 15/38 (39%) had an abnormal IMR, 12/38 (32%) had an abnormal RRR, and a reduced CFR concordant with the abnormal FFR, was present in 20/38 (53%). 3. In patients with ANOCA, abnormalities in CMR-derived myocardial perfusion are a frequent finding: Using MPR thresholds of &lt;2.0 and &lt;1.5, there were 101 (71%) and 39 (27%) patients with reduced global MPR. 4. RIPC results in enhanced coronary endothelial function: The mean percentage change in coronary luminal diameter from baseline to the maximum administered acetylcholine dose was -13.3±22.3% and - 2.0±17.2% in the sham and RIPC groups (mean difference 11.32%, 95% CI: 1.2 to 21.4, p=0.032). That is, RIPC performed prior to invasive management results in a lower reduction in mean percentage coronary artery luminal diameter in patients with stable CAD. 4. Recombinant relaxin-2 had no effect of on coronary microvascular or macrovascular function. Compared to placebo, serelaxin did not result in a significant change in MPR from baseline to 47 h (serelaxin vs. placebo adjusted mean difference: –0.112, 95% CI: –0.4-0.18, p=0.44), or augmentation index (serelaxin vs. placebo adjusted mean difference 3.45, 95% CI: −2.04-8.95, p=0.21). Conclusions: Coronary vascular dysfunction is relevant in patients with both ANOCA and obstructive epicardial CAD, and the findings of this PhD have clinical implications. Invasive coronary vascular function testing provides an insight into the underlying disease endotypes in these patients, but routine use of the tests is limited by their invasive nature and cost. Multiparametric perfusion CMR is promising as a non-invasive alternative to reference invasive tests of coronary vascular function. I present novel insights into the mechanistic effects of RIPC and recombinant relaxin-2 on coronary vascular function in patients with stable CAD, and these studies inform the limited evidence base for disease-modifying agents. Current ongoing clinical trials in our research group will inform these uncertainties and define comprehensively endotyped patients in whom novel disease-modifying agents may be investigated.