Ischemia and No Obstructive Coronary Arteries (INOCA): A narrative review

Abstract

Myocardial ischemia with no obstructive coronary arteries (INOCA) is a chronic coronary syndrome condition that is increasingly being recognized as a substantial contributor to adverse cardiovascular mortality and outcomes, including myocardial infarction and heart failure with preserved ejection fraction (HFpEF). While INOCA occurs in both women and men, women are more likely to have the finding of INOCA and are more adversely impacted by angina, with recurrent hospitalizations and a lower quality of life with this condition. Abnormal epicardial coronary vascular function and coronary microvascular dysfunction (CMD) have been identified in a majority of INOCA patients on invasive coronary function testing. CMD can co-exist with obstructive epicardial CAD, diffuse non-obstructive epicardial CAD, and with coronary vasospasm. Epicardial vasospasm can also occur with normal coronary arteries that have no atherosclerotic plaque on intravascular imaging. While all predisposing factors are not clearly understood, cardiometabolic risk factors, and endothelium dependent and independent mechanisms that increase oxidative stress and inflammation are associated with microvascular injury, CMD and INOCA. Cardiac autonomic dysfunction has also been implicated in abnormal vasoreactivity and persistent symptoms. INOCA is under-recognized and under-diagnosed, partly due to the heterogenous patient populations and mechanisms. However, diagnostic testing methods are available to guide INOCA management. Treatment of INOCA is evolving, and focuses on cardiac risk factor control, improving ischemia, reducing atherosclerosis progression, and improving angina and quality of life. This review focuses on INOCA, relations to HFpEF, available diagnostics, current and investigational therapeutic strategies, and knowledge gaps in this condition.

Graphical Abstract

1. Introduction

Approximately 50% of patients with chest pain and objective evidence of myocardial ischemia are found to have non-obstructive coronary artery disease (CAD) on angiography, which is defined as <50% stenosis in any major epicardial vessel.^1–4 Evidence of ischemia usually refers to abnormal stress electrocardiogram, abnormal cardiac stress imaging test, or biomarker evidence (i.e. troponin elevation). This chest pain syndrome, termed ischemia with no obstructive coronary arteries (INOCA), is increasingly being recognized as a significant contributor to adverse cardiovascular outcomes such as myocardial infarction and heart failure with preserved ejection fraction (HFpEF) at long-term follow-up.^1,5,6 While there is considerable heterogeneity in INOCA patients, mounting evidence over the past two decades indicates that INOCA patients are at risk for adverse cardiovascular morbidity and mortality.^1,2,4 While patients with obstructive CAD and high CAD burden are the highest MACE risk group, having non-obstructive CAD is not benign and portends an intermediate prognosis, with a MACE risk that is higher than those with minimal to no atherosclerosis.^7–9 Furthermore, there is significant symptom-related disability, recurrent hospitalizations for chest pain, and poor quality of life (QoL) in patients with INOCA, who often do not receive appropriate medical management because of the false perception that they are a low-risk group.^1,10–13 Angina symptoms and functional disability in women does not seem to be associated with extent of atherosclerotic burden.¹⁰ INOCA is considered as a diagnosis when there is no obstructive CAD, no overt cardiomyopathy or heart failure, no valvular or structural heart disease, and no pericardial disease as an explanation of patient’s anginal symptoms (Figure 1). This syndrome is more common in women compared to men for reasons that are not clear, although INOCA also occurs in men and associated with adverse prognosis.¹⁴

Figure 1.

Etiology of chest pain without obstructive coronary artery disease.

The differential diagnosis of chest pain with no obstructive coronary artery disease is broad. If signs and symptoms point to angina, then abnormal coronary vascular dysfunction should be considered. Vascular mechanisms include coronary vasospasm (macro and microvascular spasm), coronary endothelial dysfunction, coronary microvascular dysfunction, capillary obstruction, or rarefaction. Image created using Biorender.com.

Studies such as the Women’s Ischemia Syndrome Evaluation (WISE) and others have found that a vast majority of patients with INOCA have coronary vascular dysfunction, which can be present in the epicardial vessels or the smaller arteries and the microcirculation.^15–17 In this narrative review, we focus on these observations from the WISE and other recent studies that offer mechanistic insights in INOCA. Underlying cardiac risk factors such as hypertension, hyperlipidemia, diabetes, obesity, and menopause contribute to inflammation and oxidative stress that are associated with endothelial dysfunction and coronary microvascular dysfunction (CMD). CMD can lead to myocardial supply-demand mismatch and is defined as abnormal myocardial blood flow reserve in response to vasodilatory stimuli. Abnormalities in myocardial blood flow can occur due to both endothelium-dependent and endothelium-independent vascular dysfunction due to a variety of factors such as inflammation, capillary obliteration/obstruction, autonomic dysregulation, as well as local metabolic disruptions (e.g. hyperglycemia) (Figure 2). Over time this can lead to perivascular inflammation, microvascular injury, arteriolar remodeling, microthrombi, or capillary obliteration, which all contribute to CMD.

Figure 2.

Coronary vascular dysfunction.

Cardiac risk factors such as age, hypertension, insulin resistance, hyperlipidemia, smoking, obesity, menopause, and chronic autoimmune inflammatory disorders, lead to abnormal coronary vascular function (functional abnormalities as well as structural abnormalities from arteriolar remodeling) that impair myocardial blood flow and cause microvascular ischemia even in the absence of epicardial obstructive stenosis. The main stimulus for vascular reactivity varies along the coronary vascular tree depending on the vessel caliber and the surrounding myocardial matrix; for example, while changes in sheer stress and pressure stimulate periarteriolar vessels, the micro vessels are under metabolic control (pH, adenosine, hypoxia, K⁺_, etc). Comprehensive coronary function testing using adenosine and acetylcholine interrogates coronary epicardial and microcirculatory function. Image created using Biorender.com.

A majority of women who present with signs and symptoms of ischemia but no obstructive CAD at coronary angiography continue to have chest pain at 1 year and 5 years.^1,18 INOCA is also associated with anxiety, depression, and poor QoL in this group of patients.¹⁸ While CMD occurs in both men and women, it is unclear why women tend to have more angina and lower QoL compared to men. CMD can also be present in the setting of obstructive CAD, but usually once CAD is identified, anti-anginal and anti-atherosclerotic medications are deployed. The risk is higher in the presence of CMD and epicardial obstructive CAD.¹⁹ There are patients who have persistent angina even after percutaneous coronary angiography, where coronary vasospasm or CMD may be an explanation. A recent study noted a high prevalence of CMD in patients with recurrent angina post-PCI, and increased BMI and LDL correlated with CMD.²⁰ A definitive diagnosis of CMD requires access to advanced imaging modalities and coronary function testing, which is not widely available in most centers. Pharmacologic and nonpharmacologic angina management strategies are currently used to treat INOCA. This review focuses on our current understanding of INOCA and addresses knowledge gaps (Table 2) that remain to reduce the morbidity and mortality caused by this underappreciated condition.

Table 2.

Knowledge gaps and future directions in INOCA

Mechanistic research

➢ Are there sex differences in human coronary artery innervation and blood flow regulation

➢ What is the impact on microvascular function with premature estrogen loss?

➢ Sex-differences in myocardial energy utilization

➢ Investigation of pathways that lead to diastolic dysfunction and fibrosis in cardiometabolic inflammation

➢ Chronic psychological stress, coronary inflammation, and immune dysfunction

➢ Is CMD a systemic process: brain, renal, cardiac, retinal, skeletal muscle

➢ Sex-differences in Central pain processing in INOCA syndrome

➢ Are mechanisms of stress-induced abnormal microvascular reactivity in INOCA different than in obstructive CAD?

identification of at risk subsets

➢ Using precision medicine methods – i.e. proteomic profiling

➢ Leveraging electronic health record to better characterize INOCA phenotypes for risk stratification

➢ Clarifying race/ethnic differences in CMD as a contributor to adverse outcomes

Improving diagnostic strategies

➢ Utility & safety of functional testing in the setting of ACS/MINOCA

➢ Improved imaging techniques/cost for radiotracers to detect coronary inflammation

➢ Utility of cardiac sympathetic imaging in INOCA

Improving therapeutics/management

➢ Can microvascular function be restored with angiogenic factors or stem cells?

➢ Can nutraceuticals with flavonoids/polyphenols in berries, beets, dark chocolate, etc. impact microvascular flow reserve?

➢ Will anti-atherosclerotic medications alter outcomes in INOCA?

➢ GLP-1A and impact of weight loss on CMD-ischemia and INOCA symptoms

➢ Use of endothelin receptor antagonists in INOCA

➢ Testing autonomic modulation strategies for improvement in CFR and angina

1.1. Terminology

Harvey Kemp used the term “Cardiac Syndrome X” (CSX) in 1973 to describe patients who had exercise induced angina and normal coronary angiograms.²¹ This general definition did not necessarily include objective evidence of ischemia and represented a broad heterogenous group. However, a stricter definition of CSX included not only exercise-induced, angina-like chest discomfort and normal epicardial coronary arteries, but also ST-segment depression during angina, and exclusion of coronary artery vasospasm (inducible or spontaneous), and also absence of myocardial disease that is associated with CMD such as hypertrophic cardiomyopathy.^22–24 There are patients who have angina-like chest pain and no obstructive CAD on angiography but fail to meet the above CSX criteria. For example, patients who have angina predominantly at rest or those without ST changes noted during angina do not meet the strict definition of CSX. Chest pain in these cases is often attributed to non-cardiac, psychological, or gastrointestinal causes. The broad and strict definitions of CSX are used variably in the literature, and the historical heterogenous CSX cohorts lacked objective measures of coronary blood flow reserve and coronary vascular reactivity assessments, resulting in low ischemic burden and therefore relatively low MACE risk.²⁴ As advanced imaging techniques such as cardiac PET and cardiac MRI have become more routine in clinical practice, along with evolution of invasive coronary function testing to interrogate various vascular dysfunction pathways, the term INOCA is increasing being used. INOCA was coined during an NHLBI-ACC sponsored think tank and includes all objective evidence of ischemia (whether it be electrocardiographic or by imaging).¹ While INOCA improves on the CSX definitions, it still refers to a heterogenous group, and therefore specific criteria are proposed to standardize definitions of vasomotor disorders.^25–27 There are many knowledge gaps and conundrums in INOCA, and the field of vasomotor disorders continues to evolve as our pathophysiologic understanding improves and newer imaging/interventional techniques emerge to assess coronary vascular function and its impact on the myocardium.

2. Myocardial Infarction with No Obstructive Coronary Artery Disease (MINOCA)

Myocardial Infarction with Non-Obstructive Coronary Artery (MINOCA) characterized by evidence of myocardial infarction (MI) in the absence of obstructive CAD. MINOCA accounts for up to 14% of patients with acute MI. MINOCA patients are more likely to be younger and female compared to patients with obstructive CAD.^28,29 The pathogenesis of MINOCA is wide and includes vascular and non-vascular etiologies. Vascular causes include plaque rupture/erosion, coronary embolism/thrombosis, vasospasm, spontaneous coronary artery dissection and CMD. Takotsubo syndrome and myocarditis should be considered in the differential when a patient has a troponin elevation that is unexplained by obstructive CAD.³⁰ Of note, per the International Takotsubo Registry (InterTAK) diagnostic criteria, a diagnosis of Takotsubo can coexist with obstructive CAD.³¹ To confirm a diagnosis of typical Takotsubo syndrome of apical ballooning and akinesia, obstructive CAD in the left anterior descending artery must be excluded. Nonetheless, obstructive CAD in other coronary arteries can coexist. The wide umbrella of diverse etiologies may contribute to confusion and misnomer and it has recently been proposed to use the term MINOCA exclusively to describe patients with evidence of ischemia-related myocardial necrosis.³² Understanding and identifying the underlying etiology of MINOCA is important to implement specific therapeutic plans and target the underlying pathogenesis. In the setting of MINOCA, use of advanced imaging (e.g., optical coherence tomography [OCT]) and cardiac magnetic resonance imaging [CMR]) is may be helpful beyond coronary angiography alone; in fact, multimodality imaging helps better characterize the mechanism of MINOCA.^33,34 The Women’s Heart Attack Research Program (HARP), a prospective, multicenter, international, observational study, showed that multimodality imaging in women with MINOCA (N=170) identified potential mechanisms in 84.5% of patients (ischemic: 63.8%, myocarditis: 14.7%, takotsubo 3.4%, non-ischemic cardiomyopathy 2.6%, no cause identified: 15.5%).³⁴ The ongoing HARP-2 study will further build on this work of multi-modality imaging by including both men and women with MINOCA to study sex-differences in pathophysiologic mechanisms of MINOCA (NCT02905357). Coronary artery spasm provocation and coronary function testing to diagnose CMD was not done in the HARP study. The ESC and AHA have provided diagnostic algorithms to aid in management of MINOCA.^30,35

In a recent metanalysis of 14 studies with 30,733 MINOCA patients, the all-cause mortality and major cardiovascular events at 1 year were 3.4% and 9.6% respectively.³⁶ A population-level Alberta COPAT study reported that 5-year mortality was 10.9% in patients with MINOCA.³⁷ In addition, medical therapy was lower in the MINOCA group compared to the obstructive CAD group at 6 months. In another metanalysis, comparison showed that MINOCA patients (N=12,983) have more favorable prognosis than MI-CAD patients (N=133,247) (12-month all-cause mortality: 3.3% [95% CI, 2.5–4.1%] vs 5.6% [95% CI, 4.1–7.0%]; odds ratio, 0.60 [95% CI,0.520.70], p<0.001).²⁸ When compared to patients with no MI, there was a trend that did not reach statistical significance toward a worse prognosis in the MINOCA patients. ²⁸ In an observational study, Biere et al. reported that in 131 MINOCA patients with a normal left ventricular systolic function, ventricular arrythmia was noted in 13.8% of patients.³⁸ Furthermore, 25% of MINOCA patients suffer from a high angina burden in 1 year similar to those with obstructive disease.³⁹

MINOCA patients are less likely to receive secondary prevention treatment compared to patients with obstructive CAD.^40,41 In addition, there is a lack of prospective randomized controlled trials and limited evidence-based literature on the management of patients with MINOCA.^42–44 The SWEDHEART (Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapy) registry showed that after 4.1 years mean follow up of MINOCA patients, there were lower adverse cardiac events rates (all-cause mortality, hospitalization for MI, ischemic stroke, and heart failure) with angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin-receptor blockers, and a trend for lower event rate with beta-blockers. However, the use of dual antiplatelet agents was not associated with a lower cardiac event rate. ⁴²

3. CMD and heart failure with preserved ejection fraction (HFpEF)

HFpEF is a heterogenous syndrome that is clinically characterized by symptoms and signs of heart failure (HF) with a normal or near-normal left ventricular ejection fraction. ⁴⁵ HFpEF accounts for 50% of all diagnosed HF. ⁴⁵ Myocardial overload secondary to hypertension has been traditionally considered as the mechanism of HFpEF development.⁴⁶ Emerging data points towards relations between CMD and HFpEF, and cardiometabolic risk factors of obesity, insulin resistance, and related hypertension are all associated with both CMD and HFpEF. There is a high prevalence of CMD in HFpEF patients. 75%−81% of patients hospitalized with HFpEF were found to have CMD without obstructive epicardial CAD.^47,48 Furthermore, women with CMD have more diastolic dysfunction and more fibrosis detected by (cardiac magnetic resonance) CMR imaging compared to non-CMD women.^49,50 In 208 women with INOCA in the WISE study, a majority were found to have elevated resting left ventricular end diastolic pressure (LVEDP) with an elevated, and NT-pro BNP levels in this group correlated directly with age and inversely with BMI, but not coronary flow reserve.⁵¹ Compared to reference controls, women with INOCA were found to have greater aortic stiffness and lower early diastolic circumferential strain rate on CMR imaging.⁴⁹

Early in vivo data in animal models has shown that HFpEF is associated with coronary microvascular endothelial activation from oxidative stress. A reduction in vascular nitic oxide (NO)-dependent signaling to myocardial tissue, which in turn could contribute to the elevated myocardial stiffness and hypertrophy that are characteristic of HFpEF.⁵² In an autopsy study patients with HFpEF had more cardiac hypertrophy, myocardial fibrosis, and coronary microvascular rarefaction than controls. These pathologic findings demonstrate an association between microvascular damage and LV diastolic dysfunction and impairment in cardiac reserve function.⁵³

An exercise hemodynamics study by Van Empel et al. evaluated the role of impaired myocardial oxygen delivery in the pathophysiology of HFpEF. They found significantly lower transcardiac oxygen gradient in HFpEF patients compared to controls. This finding suggests that the abnormal diastolic reserve observed during exertion in HFpEF patients could be explained by impaired myocardial oxygen delivery, possibly explained by microvascular dysfunction. ⁵⁴ Alterations in endothelial function of the peripheral vasculature have also been demonstrated in patients with HFpEF. Lee et al. found that reactive hyperemia, an index of microvascular function, was significantly reduced in patients with HFpEF, demonstrating that maladaptation at the microvascular level is present in HFpEF patients.⁵⁵ Maréchaux et al. found that patients with HFpEF had abnormal endothelial function in the forearm microvasculature.⁵⁶

Moreover, evidence of low vasodilatory reserve is an independent predictor of prognosis. Srivaratharajah et al. used Rb-82 positron emission tomography (PET) to evaluate global myocardial flow reserve (MFR) and found that a HFpEF diagnosis was associated with 2.6-fold greater risk of having low global MFR (<2.0). HFpEF remained a significant predictor of reduced global MFR after adjusting for comorbidities.⁵⁷ Taqueti et al. reported that in patients with angina without epicardial CAD, impaired MFR was associated with diastolic dysfunction and increased hospitalization rates. The presence of CMD was associated with a markedly increased risk of HFpEF events.⁵⁸ A similar result was observed in a recent prospective observational study where the presence of microvascular disease (defined as MFR < 2.0) was present in 70% of patients with HFpEF and was an independent predictor of prognosis.⁵⁹ Dryer et al. evaluated coronary flow reserve (CFR) and the index of microvascular resistance (IMR) during cardiac catheterization and found that patients with HFpEF had more abnormalities of CFR and microvascular resistance, implicating CMD in HFpEF.⁶⁰ In a recent study by Ahmad et al., participants underwent coronary function testing and exercise right heart catheterization to determine the relationship between CMD and filling pressures.⁶¹ Those with HFpEF were found to have a significantly lower CFR, and CFR was inversely correlated with pulmonary wedge pressure at rest and with exercise.

PROMIS-HFpEF (Prevalence of Microvascular Dysfunction in Heart Failure With Preserved Ejection Fraction) was a multicenter, prospective study that also recently demonstrated a high prevalence of CMD in HFpEF (75% of patients) in the absence of macrovascular obstructive CAD. HFpEF patients with CMD had markers of systemic endothelial dysfunction and markers of HF severity (elevated NTproBNP and right ventricular dysfunction) after multivariate adjustment. These findings further suggest that HFpEF is associated with endothelial and microvascular dysfunction.⁴⁷ CMD-related HFpEF may represent a distinct subgroup of HFpEF patients where recurrent CMD-related microvascular ischemia causes myocardial shifts in energy metabolism, myocardial fibrosis, and diastolic dysfunction.⁶² A deeper understanding of the interrelatedness of CMD and HFpEF pathophysiology is needed to develop strategies that may halt the progression to HFpEF in the setting of cardiac risk factors, and to develop novel therapeutics in HFpEF.

4. INOCA, recurrent angina hospitalizations, and symptom disability

Patients with INOCA have recurrent angina hospitalizations and a reduced quality of life.^10–13 In the WISE study of 883 women who were followed for a mean of 5 years, those with non-obstructive CAD (62% of the cohort) were compared to those with obstructive CAD. Myocardial infarction and cardiovascular death rates were higher in the obstructive CAD group. However, there was almost a two-fold increase in recurrent angina hospitalizations and repeat catheterizations in the non-obstructive group at one year follow-up.¹⁰ In another subsequent study from the WISE that focused on 224 women with INOCA, abnormal coronary endothelium-dependent vasoreactivity was associated with angina hospitalization at 5 year follow-up.⁶³ In a large meta-analysis including 35,039 patients (49% women) with no obstructive CAD, while the prognosis was heterogenous and depended on presence of atherosclerosis, there was a high incidence of recurrent hospitalizations and testing in this cohort.¹²

COVADIS, which was an international cohort study consisting of 14 medical centers in seven countries, showed that patients with microvascular angina also reported having more physical limitations.⁶⁴ A recent study evaluated quality of life measures in INOCA patients with either definite CMD (MPR<2.0) or borderline CMD (MPR 2.0–2.4).⁶⁵ These patients reported greater physical limitations, angina frequency, and reduced QoL compared to stable CAD and acute MI patients. The exercise capacity for patients with and without definite CMD was also compared: no patients with CMD were able to achieve ≥10 METs. As a complement to these findings, Bechsgaard et al. found that although there was no difference in self-reported physical activity levels in patients with CMD compared to controls, patients with angina and CMD had severely reduced exercise capacity compared with sex-matched controls according to cardiopulmonary exercise testing results.⁶⁶ In this study, women with CMD had lower peak VO₂ values, with a median peak of 17.3 (IQR 15.5–21.3, p = 0.001) ml/kg/min compared to 21.8 (18.5–25.4) ml/kg/min in patients with normal coronary flow reserve. A study conducted in Poland investigated the role of exercise as a treatment for CMD. Fifty-five women with microvascular angina completed a cardiac rehabilitation program. Baseline and post-program exercise treadmill testing, myocardial perfusion imaging, and QoL surveys were administered. Regular exercise was shown to lead to improvement in patient symptoms and QoL (median score of 156 for baseline vs 159 after cardiac rehabilitation, p<0.05).⁶⁷

5. INOCA pathophysiologic mechanisms and contributors

5.1. CVD risk factors

Traditional atherosclerotic risk factors of age, hypertension, insulin resistance, smoking, hyperlipidemia, and obesity are associated with INOCA. Furthermore, women have unique sex-specific risk factors⁶⁸ such as preeclampsia/eclampsia and gestational diabetes, and whether these and other adverse pregnancy outcomes are associated with increased future CMD risk is unknown. Effects of aging and CVD risk factor burden increase during the menopause transition can all contribute to endothelial dysfunction. Polycystic ovarian syndrome (PCOS) is also associated with increased metabolic syndrome risk, endothelial dysfunction, and premature carotid atherosclerosis.⁶⁹ Impaired arginine metabolism was reported in PCOS compared to women with normal menstrual cycles, along with reduced plasma nitric oxide levels, due to reduced inducible nitric oxide synthase (iNOS)/endothelial NOS (eNOS) transcript expression, low hydrogen peroxide levels, and high Asymmetric Dimethyl Arginine (ADMA) synthesis.⁷⁰ INOCA studies have found significant coronary plaque burden,^71,72 and it should be noted that extent of CAD is prognostic, even if it is non-obstructive. In the WISE study of symptomatic women with no obstructive CAD, 70–80% were found to have coronary plaque and positive remodeling detected by intra-vascular ultrasound study (IVUS) of the left coronary artery.⁷³ Although studies have also shown that epithelial dysfunction and epicardial vasospasm can cause INOCA in the absence plaque demonstrated on IVUS as normal coronary arteries.⁷⁴

Cardiometabolic risk factors of obesity, insulin resistance, and related hypertension are all associated with CMD and HFpEF. Emerging data has demonstrated the presence of CMD in obese individuals and CMD has been shown to be independently associated with higher BMI.⁷⁵ Recently, Bajaj et al. reported a correlation between BMI and decreased CFR. A higher BMI in obese patients was associated with worsening coronary microvascular function, independent from other clinical risk factors. Interestingly, in obese patients, only those with impaired CFR demonstrated a significantly increased risk of major adverse cardiovascular events.⁷⁶ A potential mechanism could be that obesity triggers systemic inflammation and, as adipose tissue is infiltrated with macrophages, the release of pro-inflammatory cytokines stimulates myocardial fibrosis and endothelial dysfunction at the microvasculature level.⁷⁷

The relationship between diabetes and CMD has been explored extensively. Two major mechanisms, altered coronary autoregulation and impaired microvascular vasodilatory function, have been proposed to contribute to diabetes related CMD. Jaskanwal et al. reported an association between poor glycemic control and CMD among female patients with diabetes who presented with chest pain and non-obstructive CAD. These findings also highlight the importance of sex stratification models.⁷⁸ Gallinoro et al. found that CFR and microvascular resistance reserve by coronary angiography were lower in patients with DM with no obstructive CAD compared with non-diabetic controls. Left atrial reservoir strain, an early marker of diastolic dysfunction, was decreased in diabetic patients, suggesting an early subtle diastolic dysfunction associated with microcirculatory impairment.⁷⁹ Hyperglycemia has adverse effects on vascular endothelium.⁸⁰ Diabetes also impairs autoregulatory responses, thereby exposing coronary microcirculation to higher resting flow.⁸¹ With time, diabetes leads to a significant structural microvascular remodeling with increased microvascular resistance in combination with reduced coronary flow velocity, which may be a consequence of prior exposure to continuously increased blood flow.⁸²

5.2. Inflammation

The role of inflammation in endothelial dysfunction, atherosclerotic plaque initiation, progression, and destabilization of plaque is established and has been recently reviewed.^83,84 Chronic underlying inflammatory and autoimmune disorders are considered risk enhancing factors that are not only associated with premature and accelerated atherosclerosis, but also CMD, even in the absence of obstructive CAD.⁸⁵ Patients with conditions such as lupus, psoriasis, and rheumatoid arthritis are found to have evidence of low MFR, not explained by traditional CAD risk factors.^86–89 In the WISE study of women with INOCA, an elevated IL-6 level predicted heart failure hospitalization and all-cause mortality at 6 years.⁹⁰ Soluble urokinase plasminogen activator receptor (suPAR) is a circulating biomarker of inflammation and immune regulation that is released from various cell types including leukocytes and endothelial cells and is an independent predictor of outcomes in patients with CAD. In men and women with no obstructive CAD, plasma suPAR level was an independent predictor of CMD and predictive of MACE along with high sensitivity troponin I (hs-TnI).^91,92 Interestingly, cross-coronary suPAR and plasminogen activator inhibitor (PAI-1) production rates were higher in those with coronary microvascular endothelial dysfunction compared to those without, as assessed by simultaneous measurements of these markers from the left main and the coronary sinus.⁹³ Understanding the relationships between local vascular inflammatory cytokines, immune dysregulation, and impaired fibrinolytic pathways in contributing to CMD remains to be investigated for potential therapeutic options.

5.3. Autonomic nervous system

In addition to metabolic autoregulatory mechanisms that control vasomotor function, the cardiac autonomic nervous system (ANS) plays a critical role in myocardial blood flow regulation.⁹⁴ It is hypothesized that the disruption of adventitial baroreceptors and chemoreceptors by advancing plaque may interfere with homeostatic autonomic regulation.⁹⁵ There is also evidence implicating sympathetic dysfunction in vascular remodeling and microvascular complications.⁹⁶ Prior cardiac syndrome X (CSX) literature has investigated the role of ANS and found impaired parasympathetic tone as well as sympathetic predominance.⁹⁷ Low heart rate variability has been shown to precede episodes of myocardial ischemia, implicating the ANS in the pathophysiology of angina.⁹⁸

In the Cardiac Autonomic Nervous System (CANS) study, women with INOCA (mean age 58 ± 9 years) had greater peripheral microvascular vasoconstriction in response to arithmetic mental stress compared to age-matched asymptomatic reference control women.⁹⁹ Both groups had similar mean increases in blood pressures and heart rates with mental stress, so while hemodynamic reactivity was similar, the INOCA group experienced more chest pain and greater microvascular reactivity.⁹⁹ In the CANS substudy over a quarter of women with INOCA had abnormal cardiac sympathetic activity, detected by ¹²³I-meta-iodobenzylguanidine (mIBG) cardiac imaging, compared to reference controls.¹⁰⁰ Cardiac sympathetic function has been investigated using the radiotracer mIBG in a variety of settings, including heart failure, to assess for potential of developing lethal arrhythmias¹⁰¹ and diabetic autonomic neuropathy.^102–104 Low cardiac retention of mIBG at 4 hours after injection, measured by the heart to mediastinal ratio (HMR), is associated with ventricular tachyarrhythmias and adverse outcomes in patients with heart failure.^101,105 Di Monaco et al..¹⁰⁶ assessed whether mIBG uptake predicts symptomatic outcome in 40 participants with CSX with an average follow up of 79 months. Participants with worsening angina status, with hospital readmission for recurrent chest pain, and those who had repeat angiography had lower MIBG uptake, indicating that abnormal cardiac adrenergic nerve function predicts worse clinical outcomes. The role of heightend sympathetic activation in INOCA as a contributor to symptoms and microcirculatory dysfunction warrants further investigation.

Advancing age in women is marked by decreased vagal tonic modulation of heart rate and predominance of sympathetic tone.¹⁰⁷ Furthermore, there is a reduction in β-receptor responsiveness and increase in α₁-receptor responsiveness. One clinical syndrome related to INOCA where there is a clear sex difference is in Takotsubo Syndrome or stress cardiomyopathy.¹⁰⁸ The prevalence is highest in post-menopausal women and is characterized by an abnormal response to a catecholamine surge due to emotional or a physical stressor, which leads to troponin elevation and acute heart failure, irrespective of obstructive CAD.¹⁰⁹ The most common variant of apical ballooning may be secondary to the regional variation in the density of β-adrenergic receptors and cardiac sympathetic hyperactivity has been demonstrated based on abnormal cardiac mIBG uptake.¹¹⁰ It remains unclear why a majority of cases present in women but in addition to multi-vessel spasm, coronary endothelial and microvascular dysfunction are implicated.^111,112 A possible mechanism for post-menopausal female prevalence may include the age-specific decrease in vagal tone and baroreflex sensitivity from reduced estrogen levels. Increased sympathetic activity and impaired baroreflex sensitivity were shown in women with takotsubo compared to women with chronic heart failure.¹¹³

6. Coronary microvascular dysfunction diagnosis

6.1. Non-invasive methods

Our currently used traditional diagnostic tests are designed to detect ischemia due to obstructive flow-limiting lesions. When a patient has a positive stress ECG but is found to have no obstructive CAD on angiography, the EKG ST segment depressions are dismissed as being “false positive”. Previously, this group of patients who were more likely to be female were referred to as having CSX which was believed to be benign. However, this term is now no longer used since a majority of these patients likely had CMD-related ischemia.¹¹⁴ In the CANS study, on 24-hour ambulatory monitoring of women with INOCA who were diagnosed with CMD by invasive evaluation and were compared to age-matched, asymptomatic reference controls, more than one-third of INOCA women had ST-segment depression, while control group had no depressions detected.¹¹⁵ If there are EKG changes indicative of ischemia or symptoms during exercise epicardial endothelial dysfunction or CMD should be suspected, even in the absence of wall motion or prefusion abnormalities (Table 1).¹¹⁶ Doppler echocardiography is used mainly in Europe to detect impaired coronary flow velocity reserve in response to hyperemia.^117,118

Table 1.

Differences between INOCA and MINOCA.

	INOCA	MINOCA
Symptoms	Yes	Yes
Resting EKG abnormalities	Possible	Possible
Exercise EKG abnormalities	Usually	N/A*
Abnormal wall motion on stress echo	Possible, but usually not	N/A
Abnormal perfusion on SPECT	Possible, but usually “breast artifact” or “probably normal”	N/A
Abnormal PET-derived myocardial flow reserve	If yes, diagnose CMD If no, could still be CMD due to a vasocontrictor problem; definitive diagnosis requires invasive coronary function testing	N/A
Troponin elevation	May have a prior history of troponin elevation, and now recurrent non-MI chest pain	Yes

^*Not applicable in acute coronary syndrome

Cardiac positron emission tomography (PET) is a non-invasive method for CMD diagnosis because of its ability to quantify rest and stress myocardial blood flow per gram of tissue and it provides myocardial flow reserve (MFR). A low MFR is associated with adverse outcomes regardless of CAD severity and in both men and women.^19,58,119 Cardiac magnetic resonance (CMR) imaging detects semi-quantitative myocardial perfusion reserve index and may detect CMD, but is only available at select academic centers.^120–123 Rahman et al. reported that highresolution CMR techniques using fully quantitative perfusion had a good accuracy and were better than visual assessment, for detecting CMD.¹²⁴ Cardiac imaging modalities to detect abnormal vasodilator response to diagnose CMD have been recently reviewed.¹²⁵

None of the non-invasive stress testing modalities can reliably detect microvascular spasm or coronary endothelial dysfunction, and a negative noninvasive stress test does not rule out coronary vasomotor dysfunction, especially in symptomatic patients. Invasive coronary function testing (CFT) is often needed to assess coronary vascular function pathways. Cassar et al. reported on limited accuracy of stress testing in patients with non-obstructive CAD who underwent both non-invasive stress testing (stress ECG, echocardiogram, or nuclear imaging) and invasive CFT within 6 months.¹²⁶ Exercise ECG was found to be more specific but least sensitive for detecting vascular dysfunction compared to imaging tests, although only 9% had a cardiac PET in this study. A comprehensive CFT that includes testing for impaired vasodilatory reserve as well as heightened vasoreactivity is often needed for an accurate diagnosis.

6.2. Coronary function testing (CFT)

Invasive CFT, also referred to as coronary reactivity testing (CRT) or interventional diagnostic procedure (IDP) in the literature, is pursued to diagnose abnormal coronary vascular function and to guide therapy as well as for prognostication. In patients with persistent symptoms with INOCA, the differential includes epicardial coronary endothelial dysfunction, CMD, coronary vasospasm, myocardial bridging, and/or cardiac nociceptive abnormality. Invasive CFT can help diagnose micro- and macro-vascular dysfunction due to endothelial and nonendothelial pathways, and one example is shown (Figure 3), although there are variations in the methods and protocols among centers.^15,127 Lack of standardized methods makes it difficult to combine results from various studies, but data point to the benefit of CFT to clarify diagnosis, for prognosis, and for improved patient-reported outcomes of angina and QoL.^63,128 Safety of CFT has been published and it is typically done in the stable ischemic heart disease patients in the United States since it requires withholding vasoactive medications prior to testing, although testing in unstable angina and MI population has been reported.^15,16 The European Society of Cardiology 2019 guidelines on management of chronic coronary syndromes give “guidewirebased CFR and/or microcirculatory resistance measurements” a IIa (level of evidence B) indication in those suspected of CMD, while intracoronary acetylcholine testing to assess microvascular spasm is a Class IIb (level of evidence B) recommendation.¹²⁹

Figure 3.

Coronary Function Testing (CFT) components.

Vasoactive agents such as adenosine (that causes hyperemia) and acetylcholine (which tests NO-dependent pathway) are used in a comprehensive evaluation to diagnose coronary vasomotor disorders. Spasm testing is done using high dose acetylcholine.

There are four main vascular pathway abnormalities that are discussed in the literature: (1) CMD, assessed using vasodilatory agents such as adenosine^5,14,15,64 (2) coronary microvascular spasm, diagnosed when acetylcholine testing induces ischemic ST changes and/or symptoms, but there is no visible epicardial spasm¹³⁰; (3) epicardial endothelial dysfunction, typically diagnosed as abnormal decrease in epicardial coronary artery diameter to intracoronary acetylcholine;¹⁵ (4) coronary vasospasm (i.e. abnormal smooth muscle hyperactivity) with acetylcholine or ergonovine with >90% narrowing of the epicardial artery.^25,26 Of note, testing protocols vary among various countries. For example, in the United States, endothelium-dependent CMD is also diagnosed based on percent change in coronary blood flow (CBF) in response to acetylcholine, which is calculated based on change in coronary artery diameter and flow velocity change in response to acetylcholine.^15,131 EKG changes and symptoms are assessed during CFT, as well as pain with contrast and catheter is also noted to diagnose a nociceptive abnormality. Prior studies in CSX have reported abnormal pain sensitivity in women who present with persistent chest pain and are found to have no obstructive CAD.^132,133

Abnormal hyperemic response to adenosine with a diminished CFR is associated with adverse CV outcomes.⁵ CFR is a combined measure that interrogates the flow through the epicardial artery and the downstream microvasculature, and is dependent on hemodynamic factors such as blood pressure; CFR ranges less than 2.0 – 2.5 are considered abnormal depending on the method used.^134,135 In order to independently assess the microcirculatory function, the index of microcirculatory resistance (IMR) was developed.¹³⁶ IMR is defined as the distal coronary pressure divided by the inverse of the hyperemic mean transit time and is a reproducible measure of microcirculatory function.^136,137 An elevated IMR predicts major adverse cardiac events in patients with both stable and unstable angina.^138,139 In addition, abnormal coronary endothelial function response to acetylcholine testing is also associated with adverse prognosis.^25,63,140 While low doses of acetylcholine are used to test for endothelial dysfunction, high doses are used to test for coronary vasospasm, since at higher doses of acetylcholine, muscarinic receptors on vascular smooth muscle cells are activated.²⁶

7. INOCA management

Management of INOCA centers around 3 main strategies: 1) Treatment of CVD risk factors, such as hypertension, diabetes, obesity, hyperlipidemia, and smoking since they contribute to endothelial dysfunction, CMD, and atherosclerosis; 2) Use of therapies to improve angina burden and QoL; 3) Use of therapies that would potentially improve MACE (trials are on-going). Given that a majority of INOCA patients do have coronary plaque on imaging, treatment of risk factors is imperative in this condition. The ongoing multicenter Women’s Ischemia Trial to Reduce Events in Non-Obstructive CAD (WARRIOR) trial is testing whether optimal medical therapy with maximally tolerated statin (atorvastatin or rosuvastatin), ACE-I (lisinopril)/ARB (losartan), and low dose aspirin leads to a reduction in MACE in women with INOCA (NCT03417388).¹⁴¹ The KAMIR‐NIH (Korean Acute Myocardial Infarction‐National Institutes of Health) registry demonstrated that the use of renin‐angiotensin system blockers and statins was associated with lower mortality in patients with MINOCA.⁴³ An international, randomized trial in patients with Myocardial Infarction with No Obstructive Coronary Artery testing Beta Blocker and ACEI/ARB Treatment (MINOCA-BAT) is ongoing (NCT03686696). One important consideration for management is that information from invasive testing improves patient-oriented outcomes. The CORMICA trial enrolled 157 patients with angina and non-obstructive CAD and used invasive CFT to guide treatment compared to standard of care according to provider preference (with provider’s blinded to results of CFT),¹²⁸ and found that therapy guided by CFT improved angina at 6 months and sustained improvement in angina and QoL at 1 year.

7.1. Traditional anti-anginals

Traditional anti-anginal therapy with beta-blockers and calcium channel blockers are usually the first line agents used in INOCA. Of note, published reports indicate that beta-blockers may be more beneficial than calcium channel blockers in Cardiac Syndrome X population;^142,143 however, this has not been adequately investigated in CMD. Traditional, first and second generation beta-blockers (such as atenolol, metoprolol, and propranolol) are non-vasodilating, do not impact vascular resistance significantly, and have variable effects on flow reserve. In contrast, third generation vasodilating beta-blockers such as carvedilol and nebivolol improve vascular resistance and have shown to improve CFR in patients with dilated and hypertrophic cardiomyopathy.^144,145 Carvedilol is a commonly prescribed lipophilic, non-selective β1/β2 receptor antagonist and a selective α1 adrenergic receptor antagonist that improves mortality in heart failure and reduces events after myocardial infarction.¹⁴⁶ It has anti-oxidant properties,^147,148 promotes nitric oxide release, improves endothelial function,¹⁴⁹ induces vasodilation¹⁵⁰ and inhibits vascular smooth muscle proliferation.¹⁵¹ Carvedilol has a stronger inhibitory effect on sympathetic nervous system compared to traditional beta-blockers and lacks sympathomimetic activity. It lowers coronary sinus norepinephrine levels, decreases muscle sympathetic nerve activity, and improves HRV (by both decreasing adrenergic activity and increasing vagal tone) in congestive heart failure.^152–154 In contrast, calcium channel blockade does not affect plasma catecholamine levels. Studies with calcium channel blockers have shown variable results on INOCA patients.^155–157 Patient with abnormal vasodilator reserve taking either verapamil or nifedipine may have improved angina, less nitrate use, and improved exercise tolerance.¹⁵⁶ The ENCORE I (Evaluation of Nifedipine and Cerivastatin On Recovery of coronary Endothelial function) trial showed improved coronary endothelial function in patients taking nifedipine and cerivastatin for at least 6 months.¹⁵⁸ However, a recent study testing Efficacy of Diltiazem to Improve Coronary Microvascular Dysfunction (EDIT-CMD) found that diltiazem did not improve angina or QoL in patients with CMD,¹⁵⁹ although the subgroup of patients with coronary epicardial vasospasm improved. Limitations of this trial are notable for being underpowered, and including a heterogenous INOCA endo-type population, with several study dropouts who did not undergo a repeat CFT. There are no head-to-head contemporary clinical trials testing the impact of beta-blockers vs. calcium channel blockers in patients with INOCA based on specific vascular dysfunction pathways. Often there are inter-related mixed vascular pathway abnormalities in CMD patients, and a subset have concomitant coronary vasospasm in addition abnormal CFR and endothelial dysfunction. Use of late sodium channel blocker, ranolazine, has been established as an anti-anginal, with the advantage of not having significant hemodynamic effects on blood pressure, which enables its use in patients who do not tolerate other agents due to low blood pressures.¹⁶⁰ Short acting nitrates are helpful in patients with vasospastic angina and stable angina from epicardial CAD. While nitrates do not have an effect on the microcirculation, since many patients with INOCA have a mixed pattern of spasm and abnormal vasodilatory reserve, nitrates are commonly used in management. In a study of 99 patients with CSX¹⁶¹ nitrates were effective in 40–50% of the patients. Long-acting nitrates did not improve exercise stress testing in patients with CMD compared to those with stable epicardial disease in one study.¹⁶² The vasodilator, Nicorandil, was found to improve exercise ischemia, without altering autonomic activity,¹⁶³ and is another anti-anginal option but is not available in the United States. Nicorandil has nitrate-like properties and is available in Europe but not available in the United States.¹⁶⁴ L-arginine, a nitric oxide precursor, showed an improvement in endothelial function and symptoms after 6 months of treatment.¹⁶⁵ However, in the setting of post-myocardial infarction, this supplement had an adverse effect,¹⁶⁶ and therefore, we recommend caution in those with a prior history of MI.

7.2. Other agents and strategies

Ivabradine is a selective inhibitor of the I_f current of the sinoatrial node and it is mainly used for heart rate control. In patients with stable CAD, treatment with Ivabradine has shown to significantly improve hyperemic coronary flow velocity and CFR.¹⁶⁷ Compared to Bisoprolol, Ivabradine improved hyperemic peak coronary flow velocity and coronary flow velocity reserve in CAD patients more than Bisoprolol despite similar decrease in heart rate.¹⁶⁸ When studied in patients with CMD, Ivabradine had no effect on the coronary microvascular function assessed by coronary blood flow nor on the peripheral endothelial function. However, Ivabradine was associated with improvement in angina and QoL.¹⁶⁹ The Rho-kinase inhibitor, fasudil, is available in Japan to treat epicardial and microvascular vasospasm but is also not available in the United States.¹⁷⁰ Trimetazidine is a metabolic modulator that inhibits beta-oxidation of fatty acids and improves myocardial ischemia and may be useful in some CMD patients.¹⁷¹ It is however only available in Europe, and not available in the United States.

In the Precision Medicine with Zibotentan in Microvascular Angina (PRIZE trial, NCT04097314), oral endothelin A (ET-A) receptor blockade is being tested. In the ESCAPE-CMD pilot feasibility study, injection of autologous CD34+ stem cells intracoronary demonstrated an improvement in CFR, angina, and QoL. CD34+ cells may repair the microcirculation via their ability to differentiate into endothelial cells and promote angiogenesis and improve microvascular ischemia.¹⁷² In another study, Corban et al. showed significant improvement in microvascular endothelial function with autologous intracoronary CD34+ cells.¹⁷³ This strategy was being tested in a larger randomized multicenter FREEDOM trial (NCT04614467), which was terminated prematurely. Implantation of a device to create narrowing in the coronary sinus (Neovasc Reducer^™) and increase back pressure in the venous system, leading to vasodilation of arterioles, is also being tested for treatment of microvascular angina (NCT04523168 and NCT04606459).¹⁷⁴

Enhanced External Counterpulsation (EECP) is an FDA approved therapy that is used to manage refractory angina from either CAD or microvascular angina (typically 35 hours of total therapy, delivered over 3.5 to 7 weeks). It has been shown to improve angina class, functional capacity, and time to ST-segment depression during exercise.^175–177 Augmentation of myocardial perfusion during diastole by inflation of pneumatic cuffs on lower extremities is thought to improve endothelial function and also improve collateral blood flow circulation.

SGLT2 inhibitors have been shown to improve endothelial function by multiple mechanisms including its anti-inflammatory effect, improving flow-mediated dilation, reducing oxidative stress, increasing nitric oxide bioavailability, regulating vascular repair and angiogenesis, promoting endothelial cells viability and suppressing endothelial cells senescence.¹⁷⁸ For example, Dapagliflozin has been shown to reduce oxidative stress, improves flow-mediated vasodilation and decreases arterial stiffness in type 2 DM.¹⁷⁹ Canagliflozin and Tofogliflozin have also been shown to ameliorate endothelial function.^180,181 Interestingly, Empagliflozin was not associated with improvement in endothelial function in relatively well-controlled type 2 diabetic patients.¹⁸² Given the key role of inflammation in INOCA, agents that attenuate inflammation (IL-6 signaling, IL-1a, IL-1b, TNF-α inhibitors) are of interest but whether they have impact on angina and outcomes is needed. Role of these and other agents in INOCA population remain to be tested. Mechanistic trials with pharmacotherapy for CMD has been comprehensively reviewed recently, and a selected list is shown in Figure 4.¹⁶⁰

Figure 4.

INOCA anti-anginal management strategies.

INOCA patients have a variable response to traditional anti-anginal therapies. Optimal medical therapy with statins, ACE-I, and Aspirin as anti-atherosclerotic medications are used in INOCA, and the results of the WARRIOR trial are pending.

7.3. Cardiac nociceptive and neuromodulatory agents

Aminophylline is a non-selective adenosine receptor antagonist, which was shown to improve effort angina and ischemia by ECG in patients with CSX.¹⁸³ This is a xanthine derivative which may also have an effect on cardiac nociception but is reserved in refractory cases.¹⁸⁴ In some INOCA patients, abnormal cardiac nociceptive abnormality with enhanced pain sensitivity is the dominant cause of pain. Prior work has shown that catheter manipulation in the right heart, atrial pacing, or intracoronary contrast injection causes chest pain in a large percentage of CSX patients.^133,185 Whether enhanced pain is due to abnormal myocardial pain fiber signaling or abnormality with central pain processing is unclear and remains to be more fully investigated in INOCA patients with objective measures of microvascular dysfunction.

Low dose tri-cyclic anti-depressant medications, such as imipramine or amitriptyline can be used in patients with refractory cases where abnormal cardiac nociception is suspected.¹³² They may have an analgesic effect via modulation of norepinephrine uptake as well as anticholinergic effects. In patients who have considerable anxiety related to chest pain syndrome, it is important to refer to a mental health provider who can help with anti-anxiety medications such as selective serotonin-receptor antagonists.^132,186 Neuromodulation is an alternative treatment strategy for those with refractory angina and while the mechanisms are not clear, it reduces duration and frequency of angina, and is thought to reduce myocardial oxygen consumption.¹⁸⁷ Other strategies such as left stellate ganglion blockade are considered in refractory cases.^188,189

8. Conclusions

Our current understanding of INOCA places it as a major concerning health treat that is associated with MACE in both men and women, although women are more often diagnosed with this condition and are more adversely impacted by angina. Coronary endothelial dysfunction and CMD found in a majority of INOCA patients. Heart disease risk factors, increased inflammation, oxidative stress, and autonomic dysregulation are implicated pathophysiologic mechanisms in INOCA. Invasive CFT is often needed to diagnose vascular dysfunction (epicardial and/or microvascular) and is helpful for guiding management of INOCA. Given the heterogenous nature of INOCA patients, strategies for improved identification of high-risk INOCA subgroups are needed. Clinical trials are ongoing to determine optimal medical therapy in INOCA.

Highlights.

• Myocardial ischemia and no obstructive coronary arteries (INOCA) is a chronic coronary syndrome that predominates in women and is associated with adverse cardiovascular mortality and outcomes, including myocardial infarction and heart failure with preserved ejection fraction (HFpEF).

• INOCA occurs in both men and women and portends an adverse prognosis in both sexes; however, women are more impacted by angina, with recurrent hospitalizations, and report a lower quality of life compared to men with INOCA.

• In addition to diffuse coronary plaque and epicardial coronary endothelial dysfunction that are prevalent in INOCA, coronary microvascular dysfunction (CMD) is implicated as a key contributor to microvascular ischemia and symptoms in this INOCA. Epicardial vasospasm can also coexist with normal coronary arteries that have no visible plaque on intravascular imaging.

• In the setting of risk factors that lead to oxidative stress and inflammation, CMD occurs due to structural and/or functional causes, resulting in impaired blood flow supply to match myocardial demand.

• While non-invasive stress testing modalities detect abnormal flow reserve, invasive coronary function testing is needed to assess abnormal coronary vasoreactivity (epicardial and microcirculatory dysfunction) as well as vasospasm.

• In addition to pharmacologic anti-anginal and anti-ischemic strategies, nonpharmacologic treatments are used to manage INOCA, while large, outcomes-based trials are ongoing.