Physiological Stratification of Patients With Angina Due to Coronary Microvascular Dysfunction

Abstract

Background: Coronary microvascular dysfunction (CMD) is defined by diminished flow reserve. Functional and structural CMD endotypes have recently been described, with normal and elevated minimal microvascular resistance, respectively.

Objectives: This study determined the mechanism of altered resting and maximal flow in CMD endotypes.

Methods: A total of 86 patients with angina but no obstructive coronary disease underwent coronary pressure and flow measurement during rest, exercise, and adenosine-mediated hyperemia and were classified as the reference group or as patients with CMD by a coronary flow reserve threshold of 2.5; functional or structural endotypes were distinguished by a hyperemic microvascular resistance threshold of 2.5 mm Hg/cm/s. Endothelial function was assessed by forearm blood flow (FBF) response to acetylcholine, and nitric oxide synthase (NOS) activity was defined as the inverse of FBF reserve to N^G-monomethyl-L-arginine.

Results: Of the 86 patients, 46 had CMD (28 functional, 18 structural), and 40 patients formed the reference group. Resting coronary blood flow (CBF) (24.6 ± 2.0 cm/s vs. 16.6 ± 3.9 cm/s vs. 15.1 ± 4.7 cm/s; p < 0.001) and NOS activity (2.27 ± 0.96 vs. 1.77 ± 0.59 vs. 1.30 ± 0.16; p < 0.001) were higher in the functional group compared with the structural CMD and reference groups, respectively. The structural group had lower acetylcholine FBF augmentation than the functional or reference group (2.1 ± 1.8 vs. 4.1 ± 1.7 vs. 4.5 ± 2.0; p < 0.001). On exercise, oxygen demand was highest (rate-pressure product: 22,157 ± 5,497 beats/min/mm Hg vs. 19,519 ± 4,653 beats/min/mm Hg vs. 17,530 ± 4,678 beats/min/mm Hg; p = 0.004), but peak CBF was lowest in patients with structural CMD compared with the functional and reference groups.

Conclusions: Functional CMD is characterized by elevated resting flow that is linked to enhanced NOS activity. Patients with structural CMD have endothelial dysfunction, which leads to diminished peak CBF augmentation and increased demand during exercise. The value of pathophysiologically stratified therapy warrants investigation.

Keywords: coronary flow reserve; endothelial dysfunction; microvascular dysfunction; nitric oxide; stratified medicine.

Graphical abstract

Figure 1

Final Studies Undertaken All patients with angina and no obstructive coronary disease (NOCAD) enrolled in the study had assessment of coronary flow reserve (n = 86). Cath Lab Exercise = invasive catheter laboratory exercise physiology; Vascular Study = forearm venous occlusion plethysmography.

Figure 2

Resting Physiological Abnormalities in CMD (Top) Patients with functional coronary microvascular dysfunction (CMD) have higher supply/demand_EXT (average peak velocity/rate−pressure product, in cm/mm Hg × 10⁻²) than structural CMD and reference group patients. (Middle) Both functional and structural CMD have elevated nitric oxide synthase (NOS) activity calculated as resting forearm blood flow/forearm blood flow during infusion of N^G-monomethyl-L-arginine. (Bottom) Both functional and structural CMD have increased resting wave energy calculated using wave intensity analysis. ∗Statistically significant different from reference group, where p < 0.05. Numbers depict mean values and error bars depict SD. BCW = backward compression wave; BEW = backward expansion wave; FCW = forward compression wave; FEW = forward expansion wave.

Figure 3

Changes in Coronary Wave Energies During Exercise in Reference Group Patients and in Patients With Functional and Structural CMD ∗Significant difference from reference group. †Significant difference between CMD endotypes, both p < 0.05. Numbers depict mean values and error bars depict SD. Abbreviations as in Figure 2.

Figure 4

Systemic Hemodynamic and Coronary Circulation Response to Stress Patients with structural CMD had varying hemodynamic responses to supine bicycle exercise and adenosine-induced hyperemia compared with those with functional CMD and those in the reference group. Numbers depict mean values. 1 min = after 1 min of exercise; 50% = 50% of maximal exercise time; hyperemia = adenosine-induced hyperemia; MR = microvascular resistance; peak = immediately before exercise was discontinued due to exhaustion; RPP = rate−pressure product.

Figure 5

Results From Venous Occlusion Plethysmography Both functional and structural CMD demonstrate greater vasoconstriction in response to N^G-monomethyl-L-arginine (L-NMMA), whereas structural CMD also demonstrated reduced vasodilatation to acetylcholine (ACh) and adenosine (Ado). Numbers depict mean values.

Central Illustration

Coronary Microvascular Dysfunction Disease Endotypes Summary of distinct coronary, myocardium, and systemic changes associated with each disease endotype compared with the reference group of patients (3). CMD = coronary microvascular dysfunction; NT-proBNP = N-terminal pro–brain natriuretic peptide.