Clinical Update: Angina and No Obstructive Coronary Artery Disease

Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide, posing a significant burden on individuals and healthcare systems. Angina affects >100 million people worldwide and is the most common symptom of myocardial ischemia. More than half of patients undergoing invasive coronary angiography for angina do not have clinically significant CAD. These patients are generally classified under Angina and No Obstructive Coronary Artery (ANOCA) disease. It is not uncommon to see coronary microvascular dysfunction (CMD) in ANOCA disease patients.[1] PATHOPHYSIOLOGY OF THE CORONARY ARTERIAL SYSTEM The coronary arterial system is morphologically similar to other vascular regions, but its functionality is unique due to intrinsic, extrinsic, and external factors. Within physiological limits, it functions as a finely orchestrated system, ensuring adequate blood flow to the heart muscle to meet its demands. The coronary arterial system consists of three distinct sections, each progressively decreasing in size and serving specialized functions. The proximal section contains the large epicardial coronary arteries, which feature all three layers of the vessel wall. These arteries primarily serve as capacitance vessels, offering minimal resistance to coronary blood flow (CBF) [Figure 1]. The intermediate section is composed of prearteriolar vessels, which introduce significant resistance to blood flow, causing a measurable pressure drop before reaching the intramural arterioles. This section is further subdivided into two regions: the proximal segment, which is more responsive to flow variations, and the distal segment, which is more sensitive to pressure changes. The vasomotor function of these vessels is generally not directly influenced by diffusible myocardial metabolites. The distal section comprises intramural arterioles that are in direct contact with intramyocardial metabolites and highly responsive to these metabolic signals. These arterioles play a crucial role in regulating CBF through metabolic control mechanisms. Together, the prearterioles, arterioles, and capillaries form the coronary microcirculation and dysfunction in this microvascular system can result in impaired CBF, leading to various clinical consequences.Figure 1: The morphology and various sections of the coronary arterial system. It mainly consists of epicardial artery prearterioles, intramural arterioles, and capillaries. Table showing sizes and various functions of these segments. Coronary pressure-flow relationship showing the effect on coronary blood flow from the various stages of myocardial demand. Adapted from Vande Hoef et al., 2013Coronary autoregulation and metabolic adaptation work in concert to maintain a stable CBF to the myocardium. Autoregulation ensures that at a given level of myocardial demand, CBF remains relatively constant within a physiological range of coronary perfusion pressures [Figure 1]. When myocardial demand increases or decreases, the pressure-flow relationship shifts accordingly, a process known as metabolic adaptation. Maximal coronary vasodilation can be achieved by administering endothelium-dependent and independent vasodilators such as adenosine and nitroglycerin. Under conditions of maximal hyperemia, however, the coronary circulation is unable to adapt to further pressure or metabolic changes, becoming entirely dependent on coronary perfusion pressure. As a result, a linear, incremental relationship between coronary pressure and flow can be observed [Figure 1]. This pressure-flow relationship during maximal vasodilation varies both within and between patients. It is influenced by factors such as heart rate, left ventricular filling pressures, and myocardial hypertrophy.[2] ANGINA AND NO OBSTRUCTIVE CORONARY ARTERY DISEASE Increased minimal microvascular resistance and impaired vasodilator reserve, resulting from abnormal autoregulation, are common causes of CMD and microvascular angina. Another frequent contributor to ANOCA (angina with ANOCA) is epicardial and/or microvascular vasospasm. The Coronary Vasomotion Disorders International Study Group standardized criteria for diagnosing microvascular angina are helpful in identifying most, although not all, patients with this condition.[3] CORONARY VASOMOTION DISORDERS INTERNATIONAL STUDY CLINICAL CRITERIA FOR MICROVASCULAR ANGINA Presence of angina or anginal equivalents at rest or with exertion Absence of obstructive CAD, defined as <50% stenosis or a fractional flow reserve ≥0.80, as confirmed by coronary computed tomography angiography (Cardiac CTA) or invasive coronary angiography Objective evidence of myocardial ischemia, including ischemic changes on an electrocardiogram (ECG) during a chest pain episode, stress-induced chest pain, and/or ischemic ECG changes. These may occur with or without transient or reversible abnormalities in myocardial perfusion or wall motion. Evidence of impaired coronary microvascular function, including: Reduced coronary flow reserve (CFR), with cutoff values depending on the methodology used (typically between ≤2.0 and ≤2.5). Coronary microvascular spasm is characterized by the reproduction of symptoms and ischemic ECG changes without epicardial spasm during acetylcholine (Ach) testing Abnormal coronary microvascular resistance indices, such as an index of microcirculatory resistance (IMR) >25 Coronary slow flow phenomenon indicated by a thrombolysis in myocardial infarction (TIMI) frame count >25. ETIOLOGY AND MECHANISM OF ANGINA AND NO OBSTRUCTIVE CORONARY ARTERY DISEASE Nonphysiological intrinsic, extrinsic, and external factors can disrupt autoregulation and metabolic adaptation, leading to a spectrum of reversible and irreversible changes within the coronary arterial system. Epicardial or microvascular spasms increased minimal microvascular resistance, and impaired vasodilator reserve is common contributors to angina in patients with ANOCA. Reactive oxygen species (ROS) can directly damage endothelium-dependent vascular function, and in some cases, extend this damage to the vascular smooth muscle layer. In acute coronary syndrome (ACS) and obstructive CAD, ischemic injury to the endothelium triggers acute inflammation. This leads to endothelial swelling, the formation of microaggregates made up of neutrophils and platelets, and the release of reactive oxygen species (ROS), cytokines, and autonomic mediators. These factors, along with microhemorrhage and distal embolization, contribute to severe microvascular dysfunction in ACS. In contrast, primary genetic cardiomyopathies, such as dilated or hypertrophic cardiomyopathy and secondary cardiomyopathies related to valvular dysfunction cause hemodynamic alterations. These lead to increased left ventricular hypertrophy, interstitial and perivascular fibrosis, reduced capillary density, increased vessel-to-myocyte distance, and heightened arterial stiffness. Ultimately, this results in a demand–supply mismatch and impaired oxygen diffusion to the myocytes. In addition, vasoconstriction, microhemorrhage, or distal embolization play a critical role in the “no-reflow” phenomenon during the percutaneous coronary intervention [Table 1].[3]Table 1: Clinical classification and mechanism of microvascular diseaseCLINICAL ASSESSMENT OF ANGINA AND NO OBSTRUCTIVE CORONARY ARTERY DISEASE There are several methods available to assess microvascular dysfunction, but no single test is definitive in confirming both the diagnosis and its underlying mechanisms. A thorough history and physical examination are crucial to avoid unnecessary testing. In patients presenting with cardiac or probable cardiac chest pain, noninvasive or invasive ischemic evaluations are recommended. The choice of test should be based on a mutual discussion between the patient and physician, taking individual circumstances into account.[4-6] NONINVASIVE TESTING Routine noninvasive evaluations such as exercise treadmill testing, echocardiography, nuclear imaging, and coronary computed tomography angiography or cardiac computed tomography angiography (CCTA) are helpful in ruling out epicardial CAD. However, if these tests are negative and clinical suspicion for microvascular dysfunction remains high based on the patient’s presentation, further perfusion imaging is warranted. Modalities such as positron emission tomography (PET), CCTA, cardiac magnetic resonance imaging (CMRI), and echocardiography can be useful. Perfusion imaging can be integrated into the initial ischemia evaluation without significantly increasing the overall cost. PET Scan: PET is considered the most accurate noninvasive test for diagnosing CMD. It allows the measurement of myocardial perfusion reserve (MPR) by quantifying myocardial blood flow (MBF) at rest and during pharmacologically induced hyperemia, assessing all coronary territories simultaneously. An MPR value <2 is suggestive of microvascular dysfunction Cardiac Magnetic Resonance Imaging: CMRI offers superior spatial and temporal resolution compared to PET. It evaluates cardiac morphology, function, and myocardial perfusion using a dynamic first-pass vasodilator stress test with gadolinium contrast, followed by rest perfusion imaging. A myocardial perfusion reserve index (MPRI) of less than 2 is indicative of abnormal perfusion Cardiac CT Angiogram (CCTA): CCTA has the best spatial and temporal resolution for ruling out epicardial CAD. It also assesses coronary anatomy, function, and perfusion using an iodine-based contrast agent, similar to CMRI. An MPR value of less than 2 is considered abnormal [Figure 2] Echocardiography: Echocardiography involves no radiation exposure. Using pulse-wave Doppler of the proximal left anterior descending artery (LAD), it measures CFR velocity (CFRV). A value of <2 indicates abnormal coronary microvascular function in the LAD territory. Figure 2: Clinical evaluation of coronary microvascular dysfunction (CMD). ETT: Exercise treadmill testing, SPECT: Single-photon emission computed tomography, PET scans: Positron emission tomography, CTA: Cardiac computed tomography angiography, EKG: Electrocardiogram, MPR: Myocardial perfusion reserve, MBF: Myocardial blood flow, MPRI: Myocardial perfusion reserve index, CFRV: Coronary flow velocity reserve, TIMI: Thrombolysis in myocardial infarction, TFC: TIMI frame count, CFR: Coronary flow reserve, IMR: Index of microcirculatory resistance, HMR: Hyperemic Microvascular Resistance. ∞Perfusion imaging can be performed concurrently as part of the initial ischemia evaluation imagingINVASIVE TESTING For patients who have undergone invasive coronary angiography, such as those with ACS or persistent angina despite guideline-directed medical therapy, microvascular dysfunction may be suspected after ruling out epicardial CAD. In such cases, intracoronary thermodilution wires (temperature–pressure wires) or intracoronary Doppler flow-pressure wires can be used to assess CFR, IMR, and hyperemic microvascular resistance (HMR), which are essential for evaluating microvascular function. If routine coronary angiography shows normal epicardial arteries but slow blood flow, this raises suspicion of microvascular dysfunction. Slow flow is considered abnormal when the TIMI flow is <2 or the TIMI frame count (TFC) exceeds 25. However, this approach has limited sensitivity and provides no insight into the mechanisms underlying CMD. The intracoronary temperature–pressure wire method estimates CBF using bolus or continuous thermodilution techniques without requiring pharmacologic hyperemia. A CFR of <2–2.5 and/or an IMR >25 units indicates microvascular dysfunction, with IMR being more specific for the microcirculation and unaffected by resting hemodynamics. CFR, however, does not differentiate between microvascular and epicardial disease. The intracoronary Doppler flow-pressure wire directly measures peak coronary flow velocity and requires adenosine to induce hyperemia. A CFR of <2.5 or HMR >1.7 mmHg/cm/sec suggests CMD, with HMR being independent of resting coronary flow. To evaluate coronary epicardial or microvascular spasm, Ach or ergonovine can be injected directly into the coronary arteries. Ach testing assesses endothelial integrity and vascular smooth muscle reactivity. A >90% reduction in coronary artery diameter during intracoronary provocative testing, along with ECG changes and ischemic symptoms, confirms epicardial coronary artery spasm. A diameter reduction of <90% with similar ischemic symptoms and ECG changes suggests microvascular spasm [Figure 2]. MANAGEMENT OF ANGINA AND NO OBSTRUCTIVE CORONARY ARTERY DISEASE Aerobic interval training, weight loss, smoking cessation, and regular exercise form the cornerstone of treatment for ANOCA disease secondary to CMD. Statin therapy (HMG-CoA reductase inhibitors) improves CFR in patients with microvascular dysfunction due to its anti-inflammatory and antioxidant effects. In patients with heart failure with reduced ejection fraction, beta-blockers play a critical role in controlling angina by improving endothelial function, reducing oxygen demand, and increasing diastolic perfusion time. However, their benefit in heart failure with preserved ejection fraction remains unclear. Nondihydropyridine calcium channel blockers are effective for managing angina associated with epicardial or microvascular spasms in patients with ANOCA. Quinapril has demonstrated improvements in endothelial dysfunction, whereas enalapril has been shown to enhance CFR. Sacubitril-valsartan, however, has shown no clear benefit in microvascular dysfunction. Antianginal drugs such as ivabradine, ranolazine, and trimetazidine alleviate angina by reducing oxygen demand, although they do not have a proven effect on improving CFR or addressing microvascular dysfunction. Nitrates can be beneficial in patients with epicardial or microvascular vasospasm. Phosphodiesterase-5 inhibitors have shown a significant increase in CFR. In addition, therapies such as Rho kinase inhibitors, endothelin receptor antagonists, pyruvate dehydrogenase kinase inhibitors, cardiac potassium channel blockers, colchicine, interleukin receptor antagonists, SGLT2 inhibitors, and PCSK9 inhibitors are being studied for their potential benefits in treating CMD.[1,4] CONCLUSION Angina with ANOCA is a relatively common clinical presentation within the spectrum of coronary artery disease, contributing significantly to both individual morbidity and mortality. Accurate diagnosis requires a high degree of clinical suspicion and a systematic approach using both noninvasive and invasive testing methods to identify ANOCA and its underlying mechanisms. Aerobic interval training, weight loss, smoking cessation, and regular exercise are fundamental components of treatment for ANOCA disease caused by CMD. Asodilators are effective when coronary artery spasm is present.