Coronary Microvascular Dysfunction Is Associated With Myocardial Ischemia and Abnormal Coronary Perfusion During Exercise

Abstract

Background: Coronary microvascular dysfunction (MVD) is defined by impaired flow augmentation in response to a pharmacological vasodilator in the presence of nonobstructive coronary artery disease. It is unknown whether diminished coronary vasodilator response correlates with abnormal exercise physiology or inducible myocardial ischemia.

Methods: Patients with angina and nonobstructive coronary artery disease had simultaneous coronary pressure and flow velocity measured using a dual sensor-tipped guidewire during rest, supine bicycle exercise, and adenosine-mediated hyperemia. Microvascular resistance (MR) was calculated as coronary pressure divided by flow velocity. Wave intensity analysis quantified the proportion of accelerating wave energy (perfusion efficiency). Global myocardial blood flow and subendocardial:subepicardial perfusion ratio were quantified using 3-Tesla cardiac magnetic resonance imaging during hyperemia and rest; inducible ischemia was defined as hyperemic subendocardial:subepicardial perfusion ratio <1.0. Patients were classified as having MVD if coronary flow reserve <2.5 and controls if coronary flow reserve ≥2.5, with researchers blinded to the classification.

Results: Eighty-five patients were enrolled (78% female, 57±10 years), 45 (53%) were classified as having MVD. Of the MVD group, 82% had inducible ischemia compared with 22% of controls (P<0.001); global myocardial perfusion reserve was 2.01±0.41 and 2.68±0.49 (P<0.001). In controls, coronary perfusion efficiency improved from rest to exercise and was unchanged during hyperemia (59±11% vs 65±14% vs 57±18%; P=0.02 and P=0.14). In contrast, perfusion efficiency decreased during both forms of stress in MVD (61±12 vs 44±10 vs 42±11%; both P<0.001). Among patients with a coronary flow reserve <2.5, 62% had functional MVD, with normal minimal MR (hyperemic MR<2.5 mmHg/cm/s), and 38% had structural MVD with elevated hyperemic MR. Resting MR was lower in those with functional MVD (4.2±1.0 mmHg/cm/s) than in those with structural MVD (6.9±1.7 mmHg/cm/s) or controls (7.3±2.2 mmHg/cm/s; both P<0.001). During exercise, the structural group had a higher systolic blood pressure (188±25 mmHg) than did those with functional MVD (161±27 mmHg; P=0.004) and controls (156±30 mmHg; P<0.001). Functional and structural MVD had similar stress myocardial perfusion and exercise perfusion efficiency values.

Conclusion: In patients with angina and nonobstructive coronary artery disease, diminished coronary flow reserve characterizes a cohort with inducible ischemia and a maladaptive physiological response to exercise. We have identified 2 endotypes of MVD with distinctive systemic vascular responses to exercise; whether endotypes have a different prognosis or require different treatments merits further investigation.

Keywords: coronary artery disease; exercise; microvascular angina; perfusion imaging.

Figure 1.

Study screening criteria and tests. Screening, and final study enrolment (left). Test completion for 85 patients enrolled into the study (right). Cath Lab Exercise indicates catheter laboratory supine bicycle exercise; CFR, coronary flow reserve; CMR, cardiac magnetic resonance imaging; and NOCAD, nonobstructive coronary artery disease.

Figure 2.

Catheter laboratory set up during experimental exercise protocol. The patient is cycling whilst catheterized via the right radial artery with the Combowire in the left anterior descending artery. The Combomap console (lower) is displaying continuous coronary pressure and flow velocity.

Figure 3.

Two examples of wave intensity analysis during peak exercise in a control patient with normal coronary flow reserve (CFR) (left) and microvascular dysfunction (MVD) patient (right). Ensemble averaged aortic pressure (top, light blue), coronary pressure (top, dark blue), flow velocity (top red) and wave intensity analysis (bottom). BCW indicates backward compression wave; BEW, backward expansion wave; and FCW, forward compression wave.

Figure 4.

Coronary wave intensity analysis during stress. (A) During exercise, microvascular dysfunction (MVD) patients have a smaller proportion backward expansion wave (BEW) and greater proportion of backward compression wave (BCW) energy than patients with normal coronary flow reserve (CFR). *P<0.001. (B) In patients with MVD, the total percentage of accelerating wave intensity decreases in response to exercise and during vasodilator mediated hyperemia (reduced coronary perfusion efficiency) from rest; in those with normal CFR, coronary perfusion efficiency remains unchanged during exercise or hyperemia from resting conditions (*P<0.05).

Figure 5.

Coronary and systemic hemodynamic responses to stress. Time points are 1 minute after onset of exercise, 50% of maximal exercise time and peak (immediately before termination of exercise). White area denotes physical exercise, gray area denotes pharmacological hyperemia. bpm indicates beats per minute; CFR, coronary flow reserve; hyperemia, adenosine-induced hyperemia; and MVD, microvascular dysfunction.

Figure 6.

Coronary flow reserve (CFR) measurement in patients with angina and nonobstructive coronary artery disease (NOCAD). Low CFR can arise via 2 distinct microvascular dysfunction endotypes, classified using hyperemic microvascular resistance. Functional and structural microvascular dysfunction (MVD) endotypes have differing degrees of systemic disease involvement, however both display reduced coronary perfusion efficiency during stress and higher rates of global myocardial ischemia compared with controls with normal CFR.