Abstract
Background
Coronary microvascular dysfunction (MVD) is defined by impaired flow augmentation in response to a vasodilator, the pathophysiological basis of which is unclear. This study sought to address two major gaps in our understanding of MVD: firstly, whether diminished flow reserve is due to structural changes within the microvasculature or potentially reversible dysfunction and secondly to unravel the mechanism of exercise-induced ischemia in the absence of obstructive disease.
Methods
Simultaneous intracoronary pressure and flow velocity recordings were made in the left anterior descending artery of patients with angina and no obstructive epicardial disease (Fractional Flow Reserve >0.80). Measurements were made at rest, during adenosine-mediated hyperaemia and supine bicycle exercise. Wave intensity analysis was used to quantify waves that accelerate and decelerate coronary blood flow, coronary perfusion efficiency being defined as the proportion of total wave energy that accelerates blood flow. Patients were prospectively classified into MVD (coronary flow reserve <2.5) and controls with researchers blinded to the classification throughout the protocol. Myocardial perfusion and vascular function were assessed by 3T cardiac MRI and venous occlusion plethysmography with forearm blood flow (FBF) assessment during serial infusions of acetylcholine, adenosine and the nitric oxide synthase inhibitor NG-monomethyl-L-arginine (L-NMMA).
Results
78 patients were enrolled (42 patients had MVD and 36 were controls), with no differences in cardiovascular risk factors between groups. The MVD group had elevated coronary blood flow (21.3±6.4 vs. 15.1±4.5cm s–1; p<0.001) and global myocardial perfusion (1.36±0.37 vs. 1.13±0.22ml/min/g; p=0.01) at rest. Maximum coronary and myocardial blood flow during hyperaemia was similar in both groups. During exercise, MVD patients achieved similar peak flow (30.5±10.0 vs. 26.3±7.7cm s–1; p=0.07) despite a higher rate-pressure product (20777±5205 vs. 17450±4710bpm.mmHg; p=0.01). Coronary perfusion efficiency, decreased with exercise in the MVD group (61±11% vs. 44±10% p<0.001) but was unchanged in controls. On MRI, MVD had lower hyperaemic endo-epicardial perfusion ratio than controls (0.94±0.08 vs. 1.04±0.13; p=0.001). Augmentation of FBF with acetylcholine was attenuated in MVD patients compared to controls (p=0.02) but the response to adenosine was similar (p=0.13). Infusion of L-NMMA caused a significantly greater reduction in FBF in MVD patients compared to controls (p<0.001).
Exercise Physiology in MVD
Conclusion
Impaired flow reserve in MVD represents a dysfunctional state, characterised by inappropriately elevated resting flow due to increased nitric-oxide synthase mediated vasodilatation. There is abnormal flow distribution in the myocardium predisposing to subendocardial ischaemia, associated with and exacerbated by impaired cardiac-coronary coupling during exercise. These novel findings may represent distinct therapeutic targets.
Acknowledgement/Funding
British Heart Foundation
Development of anEx Vivo, Beating Heart Model for CT Myocardial Perfusion