Author + information
- Received February 15, 2020
- Revision received March 10, 2020
- Accepted March 17, 2020
- Published online May 18, 2020.
- Haseeb Rahman, PhD, BMBCha,
- Ozan M. Demir, MSc, MBBSa,
- Faisal Khan, BSc, MBBSa,
- Matthew Ryan, BSc, MBChBa,
- Howard Ellis, BSca,
- Mark T. Mills, MSc, MBBSa,
- Amedeo Chiribiri, PhD, MDb,
- Andrew Webb, PhD, MBBSa and
- Divaka Perera, MD, MB BChira,∗ (, )@UKheartresearch
- aBritish Heart Foundation Centre of Excellence and National Institute for Health Research Biomedical Research Centre at the School of Cardiovascular Medicine and Sciences, Kings College London, London, United Kingdom
- bSchool of Biomedical Engineering and Imaging Sciences, King’s College London, London, United Kingdom
- ↵∗Address for correspondence:
Prof. Divaka Perera, Department of Cardiology, St Thomas’ Hospital, London SE1 7EH, United Kingdom.
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 NG-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.
- coronary flow reserve
- endothelial dysfunction
- microvascular dysfunction
- nitric oxide
- stratified medicine
This work was supported by the British Heart Foundation (Fellowship FS/16/49/32320) and by the National Institute for Health Research via the Biomedical Research Centre award to Guy’s and St. Thomas’ Hospital and King’s College London. The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC author instructions page.
- Received February 15, 2020.
- Revision received March 10, 2020.
- Accepted March 17, 2020.
- 2020 The Authors