Cardiac tissue perfusion at rest correlates with systemic microvascular function in those with and without atherosclerotic coronary artery disease; a cross-sectional study

Background Coronary microvascular disease is often defined by symptoms in the absence of epicardial coronary artery stenosis. There is, however, a growing interest in exploring the vascular physiology of patients with chest pain syndromes who have been confirmed to have unobstructed coronary arteries. As it is known that people with microvascular coronary disease have an additive poor prognosis, we aimed to determine whether this was part of a systemic microvascular dysregulation. As such, we explored the correlations between cardiovascular magnetic resonance (CMR) myocardial perfusion with cutaneous maximal hyperaemic response (MHR) and post-occlusive reactive hyperaemia (PORH), as assessed by laser Doppler fluximetry, in patients with known coronary anatomy determined via computed tomography coronary angiography (CTCA).

MHR was measured in response to local heating to 42°C and PORH was measured in response to a 4-minute ischaemic stimulus in 102 participants with and without diabetes and/or coronary artery disease, defined as coronary artery calcification of >0 Agatston units. Subepicardial and subendocardial perfusion at rest and in response to adenosine stress was measured via CMR.

Out of 102 participants, 47 (45.1%) had diabetes, and 59 (57.8%) had coronary artery disease, with 32 (31.4%) having both. MHR and PORH were attenuated in participants with diabetes. Resting, but not stressed, CMR perfusion in all subepicardial and subendocardial territories was proportionately impaired in those with attenuated MHR. This association was independent of conventional risk factors including age, sex, blood pressure, glycaemia, coronary artery disease and body habitus (standardised beta 0.315, p=0.012). Conversely, PORH did not correlate with CMR perfusion at rest or after stress.

Maximal hyperaemic response is associated with resting CMR perfusion independent of conventional risk factors. This suggests that cardiac microvascular dysfunction may represent a manifestation of wider microcirculatory derangements. Further research is required to determine whether interventions that improve systemic vascular disturbances may improve cardiac microcirculation. Translational Perspective It is recognised that coronary microvascular dysfunction is associated with residual symptoms in people with angina, after the correction of occlusive coronary arterial disease. As such it is a promising target for symptom control, however development of proof-of-concept trials is limited by the ability to monitor the coronary microcirculation in those trials. This manuscript identifies an appropriate surrogate endpoint that can be easily and non-invasively monitored and validates it against MRI imaging of the coronary microcirculation. Competing Interest Statement The authors have declared no competing interest. Funding Statement This work was supported by the Innovative Medicines Initiative (the SUMMIT consortium, IMI-2008/115006). OG was funded by The Gawthorn Cardiac Trust fellowship. JW was supported by an academic clinical fellowship with the NIHR. This paper presents independent research supported by the NIHR Exeter Clinical Research Facility and the NIHR Collaboration for Leadership in Applied Health Research and Care (CLAHRC) for the South West Peninsula. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study conformed to the Declaration of Helsinki and was approved by the National Research Ethics Service Southwest (10/H0206/67 and 10/H0102/66). All participants gave informed written consent. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability All data produced in the present study are available upon reasonable request to the authors.