Stable coronary syndromes: pathophysiology, diagnostic advances and therapeutic need

Abstract

The diagnostic management of patients with angina pectoris typically centres on the detection of obstructive epicardial CAD, which aligns with evidence-based treatment options that include medical therapy and myocardial revascularisation. This clinical paradigm fails to account for the considerable proportion (approximately one-third) of patients with angina in whom obstructive CAD is excluded. This common scenario presents a diagnostic conundrum whereby angina occurs but there is no obstructive CAD (ischaemia and no obstructive coronary artery disease-INOCA). We review new insights into the pathophysiology of angina whereby myocardial ischaemia results from a deficient supply of oxygenated blood to the myocardium, due to various combinations of focal or diffuse epicardial disease (macrovascular), microvascular dysfunction or both. Macrovascular disease may be due to the presence of obstructive CAD secondary to atherosclerosis, or may be dynamic due to a functional disorder (eg, coronary artery spasm, myocardial bridging). Pathophysiology of coronary microvascular disease may involve anatomical abnormalities resulting in increased coronary resistance, or functional abnormalities resulting in abnormal vasomotor tone. We consider novel clinical diagnostic techniques enabling new insights into the causes of angina and appraise the need for improved therapeutic options for patients with INOCA. We conclude that the taxonomy of stable CAD could improve to better reflect the heterogeneous pathophysiology of the coronary circulation. We propose the term 'stable coronary syndromes' (SCS), which aligns with the well-established terminology for 'acute coronary syndromes'. SCS subtends a clinically relevant classification that more fully encompasses the different diseases of the epicardial and microvascular coronary circulation.

Keywords: cardiac computer tomographic (ct) imaging; cardiac magnetic resonance (cmr) imaging; cardiac risk factors and prevention; chronic coronary disease; pharmacology.

Figure 1

Hierarchical nomenclature of coronary artery disease endotypes that cause ischaemic heart disease. Modified with permission. CAD, coronary artery disease; INOCA, ischaemia and no obstructive coronary artery disease; MINOCA, myocardial infarction with no obstructive coronary artery disease.

Figure 2

Structural and functional disorders of the coronary circulation. CFR, coronary flow reserve; FFR, fractional flow reserve; IMR, index of microcirculatory resistance; HMR, hyperaemic microvascular resistance; ACh, Acetycholine; LVH, left ventricular hypertrophy

Figure 3

Clinical case demonstrating the utility of non-invasive and invasive diagnostic tests for coronary artery function. A 73-year-old woman presented with a 2-year history of typical Canadian cardiovascular society (CCS) class 2 angina. The patient had type 2 diabetes mellitus, an elevated body mass index and had previously been documented to have a normal invasive coronary angiogram 8 years previously. Invasive coronary angiography (A,B) demonstrated unobstructed epicardial coronary arteries. In the left anterior descending artery, the fractional flow reserve (FFR) value was 0.95, consistent with no epicardial flow-limiting stenosis (C). The coronary flow reserve (CFR) was reduced (1.3, normal >2.0), and the index of microcirculatory resistance (IMR) was elevated (33 units, normal <25), indicative of impaired epicardial and microvascular vasodilation and increased microvascular resistance respectively (C). Coronary endothelial function assessment using graded intracoronary acetylcholine infusion revealed mild vasoconstriction (dashed line) consistent with endothelial dysfunction (D) compared with endothelial-independent function testing with intracoronary glyceryl trinitrate (E). There was inducible coronary vasospasm using 100 µg acetylcholine bolus over 20 s (not shown). The patient subsequently underwent adenosine stress perfusion CMR, which demonstrated an inducible circumferential subendocardial perfusion defect in the basal short axis slice (arrows) with adenosine stress (F), compared with the corresponding rest perfusion imaging (G). A pixel-wide fully quantitative myocardial blood flow analysis confirmed markedly reduced myocardial blood flow in the subendocardium with adenosine stress (H) compared with the corresponding rest perfusion image (I). A diagnosis of coronary microvascular dysfunction was made. The patient was symptomatically improved at 3-month follow-up after treatment with nebivolol, statin and ACE inhibitors was started. The CMR methods were provided by Andrew Arai and Li-Yueh Hsu, National Institutes of Health, MD.

Figure 4

Schematic illustration of the diagnostic work-up for SCS following exclusion of obstructive epicardial CAD. (1) Non-invasive diagnostic testing with multiparametric stress perfusion CMR imaging assessment demonstrating pixel-wide fully quantitative myocardial blood flow analysis from cardiac base to apex, cine imaging, native T1 parametric mapping and late gadolinium enhancement imaging. (2) Invasive diagnostic testing with (A) dual pressure-sensitive and temperature-sensitive coronary wire or coronary Doppler and pressure-sensitive wire, and (B) endothelial and vasospastic testing with intracoronary acetylcholine. CAD, coronary artery disease; CFR, coronary flow reserve; CMR, cardiac magnetic resonance; FFR, fractional flow reserve; HMR, hyperaemic microvascular resistance; iFR, instantaneous wave-free ratio; IMR, index of microcirculatory resistance; PET, positron emission tomography; SCS, stable coronary artery syndrome; TTDE, transthoracic Doppler echocardiography.