First discovered in 1973 by Harvey Kemp [1], ischemia with no obstructive coronary arteries (INOCA) refers to patients with stable ischemic symptoms and visually normal or non-obstructive coronary arteries (i.e., <50% reduction in coronary artery diameter appreciated on invasive or CT angiography) [2]. The mechanism of INOCA involves coronary microvascular dysfunction and/or coronary vasospasm, which is explained further below. Though initially considered benign, INOCA is now known to represent true cardiac disease and increases morbidity and mortality. For accurate diagnosis and risk stratification of these patients, a combination of anatomical and functional testing of the epicardial arteries and the microvasculature is crucial [3]. However, diagnostic tests remain underutilized in INOCA [3]; as the current gold standard, coronary reactivity testing is invasive, expensive, and technically challenging ^[4][5][4,5]. Fortunately, non-invasive perfusion imaging techniques are emerging that can provide comparably accurate vasomotor measurements and lower the barrier for evaluation ^[3][6][7][3,6,7].

2. Epidemiology, Prevalence, Risk Factors, and Outcomes of INOCA

INOCA is a relatively common condition, affecting 3 to 4 million individuals in the United States alone [8]. Among patients undergoing coronary angiography for suspected angina, approximately 60% of women and 30% of men have INOCA [8]. It is thought that this demographic disparity in the prevalence of INOCA is due to sex-related differences in normal cardiac physiology as well as a heterogenous representation of risk factors in women compared to men [8]. There are several risk factors associated with INOCA, including traditional cardiovascular risk factors (i.e., hypertension, diabetes, hyperlipidemia, age, and smoking), non-traditional risk factors (i.e., psychosocial stress, autoimmune disorders, and hormonal changes), female sex, and postmenopausal status ^[9][10][9,10]. There is also growing evidence for drug-induced INOCA, including one study that found microvascular disease associated with the use of anthracycline [11]. Several studies have highlighted the significant morbidity and mortality associated with INOCA, including an increased risk of major adverse cardiac events (MACE), heart failure with preserved ejection fraction (HFpEF), stroke, and coronary microvascular dysfunction (CMD) ^[9][10][9,10]. INOCA has been found to increase the risk of MACE 1.5–1.8-fold and the risk of all-cause mortality 1.3–1.5-fold ^[9][10][12][9,10,12]. The WISE study demonstrated that symptomatic women with INOCA experienced a 10-fold increase in heart failure hospitalizations compared to healthy asymptomatic women [10]. Overall, INOCA reduces a patient’s quality of life with increased symptom burden, cardiac anxiety, emergency room visits, and repeated testing with invasive angiography ^[13][14][13,14]. INOCA also comprises a substantial healthcare burden, with costs comparable to obstructive CAD [9]. It accounts for almost half of all angiography procedures ^[10][15][10,15]. Unfortunately, INOCA is often under-detected and undertreated in both men and women due to limitations in theour current diagnostic tools, inadequate awareness, and bias [3]. Early identification and appropriate management of INOCA are essential to reduce the risk of adverse outcomes in affected individuals.

3. INOCA Endotypes: Pathophysiology and Current Diagnostic Criteria

The coronary microvasculature (especially the small arterioles) provides a significant component of the overall coronary vascular resistance and is thereby a pivotal regulator of myocardial blood flow [16]. Disturbances in the microvascular structure and/or vasodilator responses can lead to INOCA [16]. The two endotypes of INOCA include microvascular dysfunction (MVD) and vasospastic angina (VSA). They represent distinct but frequently coexistent mechanisms [17]. A meta-analysis examining the distribution of these endotypes found that approximately 41% of INOCA cases are MVD, 40% are VSA, and 23% are a combined endotype [3]. Table 1 outlines the diagnostic criteria for each endotype and compares them to non-cardiac chest pain [18]. Physiologically, endothelium-independent and endothelium-dependent vasodilator responses regulate the coronary vasculature [16]. Adenosine, which is released by cardiac tissue in the setting of insufficient oxygen supply, stimulates endothelium-independent vasodilation in the microvasculature in order to increase myocardial blood flow (MBF) [16]. This process then promotes flow-mediated acetylcholine (ACh) release, which triggers the endothelium to produce nitric oxide (NO), causing endothelium-dependent vasodilation in larger epicardial and microvascular vessels ^[16][17][16,17]. ACh also induces smooth muscle vasoconstriction, but normally, endothelium-dependent vasodilation predominates ^[19][20][19,20]. Additionally, other chemical stimuli like histamine, bradykinin, serotonin, adenosine diphosphate (ADP), substance P, and thrombin can trigger NO release, contributing to further vasodilation [16]. Aberrancies in the above pathway can lead to INOCA [16]. Just as atherosclerotic vascular disease is known to involve remodeling of the arteries, the coronary microvasculature can develop structural changes that can impair vasodilation and flow. The coronary arteries may also develop functional dysregulation, leading to enhanced response to vasoconstrictive stimuli. When the endothelium fails to release NO in response to ACh, ACh will induce unrestrained smooth muscle vasoconstriction, leading to vasospasm [19]. The physiology of coronary vasodilation and pathophysiology of INOCA are illustrated in Figure 1.

3.1. Microvascular Dysfunction Endotype (MVD)

The MVD endotype is characterized by coronary microvascular disease due to structural remodeling and/or microvascular vasospasm. Structural remodeling in the microvasculature leads to an increased wall-to-lumen ratio and a loss of myocardial capillary density (capillary rarefaction) [17]. This increases the index of microvascular resistance (IMR) and impairs vasodilation [17]. Traditional cardiovascular risk factors (i.e., smoking, hypertension, hyperlipidemia, diabetes, insulin resistance, and obstructive CAD), left ventricular hypertrophy, and cardiomyopathies can predispose one to structural microvascular remodeling, which can decrease microvascular vasodilatory capacity and limit the blood and oxygen reserve to the myocardium in response to stress or exercise [17]. Microvascular vasospasm due to enhanced vasoreactivity may also comprise part of MVD’s pathophysiology. The current criteria for diagnosing MVD include the clinical presence of myocardial ischemia (i.e., symptoms of angina and/or ECG changes during stress testing), the absence of obstructive CAD on coronary CTA or invasive angiography, and evidence of microvascular dysfunction on invasive or non-invasive coronary reactivity testing [4]. The findings of coronary microvascular dysfunction include a measurement of CFR ≤ 2 or 2.5 after adenosine administration, an IMR > 25, and/or a corrected TIMI frame count ≥ 3 beats to fill a vessel ^[4][21][22][4,21,22].

3.2. Vasospastic Angina Endotype (VSA)

As opposed to the microvascular disease found in MVD, VSA is characterized by epicardial dysfunction without evidence of obstruction. Though functional dysregulation may lead to enhanced vasoconstriction in either epicardial and/or microvascular vessels [17], VSA is defined by coronary vasospasm that is predominately evidenced in the epicardial vessels ^[19][20][23][19,20,23]. According to the COVADIS criteria, definitive vasospastic angina is diagnosed when nitrate-responsive angina (either during a spontaneous episode or due to a trigger such as exercise, hyperventilation, or acetylcholine stimulation) is accompanied by either transient ischemic electrocardiographic changes (e.g., ST elevation or depression ≥ 0.1 mV, new negative U-wave) or coronary artery spasm (e.g., >90% coronary artery constriction) [5].