Introduction

Angina pectoris affects more than 100 million persons worldwide. According to the OFRECE study, the prevalence of angina in Spain is around 2.6%, indicating that there are more than 270 000 affected individuals. A significant number of stable patients referred for coronary angiography due to angina or a positive ischemia test do not have obstructive coronary artery disease. Many of these patients have ANOCA (angina with nonobstructive coronary arteries), or INOCA (ischemia with nonobstructive coronary artery disease) of nonobstructive origin. These 2 entities are manifestations of the same disease, which is why the recommendations provided by this document are applicable to both.

Angina pectoris is more prevalent among women (50%-70%) than men (30%-50%), although its true prevalence remains unknown. In these patients, angina or ischemia is produced by coronary vascular dysfunction due to vasomotor disorders of the epicardial vessels or arterioles, and/or coronary microvascular dysfunction.

An important point is that, currently, angina pectoris is significantly underdiagnosed, and consequently many patients suffer its consequences without receiving potentially effective treatment. The reasons for this lack of diagnosis and treatment are various. First, there is the inertia associated with the paradigm that has dominated the diagnostic approach to patients with angina for decades focused on identifying coronary artery stenosis rather than vasomotor or coronary microvascular disorders. Additionally, patients with angina without coronary artery stenosis have generally been considered low-risk patients with poor response to conventional antianginal medical therapy. Second, and partly related to the previous point, many noninvasive techniques are based on identifying the regional ischemia that is characteristic of coronary artery stenosis (dysregulated contraction or isotope uptake during exertion or stress), making them less sensitive and specific for the detection of nonobstructive ischemia. Third, most cardiologists have not had access to the invasive techniques that provide objective evidence of vascular dysfunction in their patients. These intracoronary techniques have been considered the sole domain of interventional cardiologists, who do not usually play a key role in the management and follow-up of patients with INOCA. These barriers prevent the valuable information provided by invasive techniques from being used in the clinical management of these patients. Finally, patients with ANOCA/INOCA often have extracardiac diseases and conditions that require a multidisciplinary approach, complicating follow-up for specialized cardiologists.

In 2019, the European Society of Cardiology guidelines on the diagnosis and management of patients with chronic coronary syndrome represented a significant advance in the recognition of microvascular angina and the value of specific diagnostic techniques. Therefore, in the diagnostic approach in patients with suspected coronary microvascular angina, the guidelines indicate that coronary flow reserve (CFR) and microcirculatory resistance should be measured through pressure-guided techniques in patients with persistent symptoms but angiographically normal coronary arteries, or moderate stenosis and a normal fractional flow reserve (recommendation IIaB). Even the remaining recommendations, such as the administration of intracoronary acetylcholine during coronary angiography, or the use of transthoracic Doppler echocardiography of the anterior descending artery, cardiac magnetic resonance (CMR), or positron emission tomography (PET) for the noninvasive evaluation of CFR, have a lower level of recommendation (IIbB). In patients with suspected vasospastic angina, the guidelines recommend intracoronary provocation testing to identify coronary artery spasm (recommendation IIaB).

However, over the past few years, numerous studies have been conducted in patients with ANOCA to assess the efficacy profile of new invasive diagnostic tests for their specific diagnosis, as well as randomized clinical trials assessing symptomatic improvement with individualized therapies. These trials consistently suggest that individualized and multidisciplinary approaches to these patients help to relieve symptoms, reduce the number of medical visits and prescribed therapies, and lower the costs associated with this syndrome.

Objectives of this document

This document is endorsed by the Clinical Cardiology Association, and the Interventional Cardiology Association, Ischemic Heart Disease and Acute Cardiac Care Association, and Cardiovascular Imaging Association of the Spanish Society of Cardiology (SEC) and aims to:

1. Review the various causes of ANOCA syndrome and current methods for its diagnosis and individualized treatment.
2. Propose a diagnostic and treatment algorithm for the approach to these patients in compliance with the clinical practice guidelines of the European Society of Cardiology on the management chronic coronary syndrome and the latest evidence.
3. Encourage various health care entities to create multidisciplinary pathways for the diagnosis, treatment, and targeted follow-up of these patients.

This document was drafted based on the interpretation of the latest scientific evidence, with an eminently practical focus so that the recommendations can be effectively applied in our setting. Each Association of the SEC provided scientific evidence and their view of their respective fields. Afterward, through consensus, they all created a single document including practical recommendations. The selection of the members that would eventually draft the document was left to the presidents of these Associations and was based on their clinical experience and expertise in the field.

Importance of ANOCA in routine clinical practice

While it has been acknowledged for decades that angina without coronary artery lesions could constitute a separate nosological entity (initially called syndrome X), routine clinical practice has paid little attention to affected patients, primarily due to the widespread notion that their prognosis is good. However, numerous subsequent studies in which the diagnosis of ANOCA was based on objective evidence of coronary vascular dysfunction, unlike that of syndrome X, consistently showed that nonobstructive ischemia has a significant prognostic impact. The risk of adverse coronary events in these patients is largely determined by factors such as plaque burden, demonstration of myocardial ischemia, microvascular dysfunction, and the presence of vasospasm or coronary endothelial dysfunction. For example, a study of 917 women with signs or symptoms of myocardial ischemia showed that the composite endpoint of myocardial infarction or cardiac death occurred in 6.5% of women without coronary artery disease, 12.8% of those with nonobstructive atherosclerosis, and 25.9% of those with obstructive coronary artery disease at 10 years of follow-up (figure 1). A meta-analysis of 54 studies and 35 039 patients confirmed an increased risk of nonfatal myocardial infarction and death, with an incidence rate of 0.98 per 100 person-years in patients with ANOCA at 5 years of follow-up. The risk was higher in individuals with confirmed ischemia (vs those without ischemia) and patients with nonobstructive coronary artery disease (vs those with normal coronary arteries).

Figure 1. Risk of myocardial infarction or cardiovascular death at 10 years of follow-up in a cohort of women. ANOCA/INOCA, angina/ischemia with nonobstructive coronary arteries; CAD, coronary artery disease.

Similarly, even in the presence of angiographically normal coronary arteries, microvascular dysfunction demonstrated by a reduced CFR has proven to be a powerful determinant of the risk of death and myocardial infarction in these patients. Additionally, more cardiovascular complications, including stroke and heart failure, have also been reported in these individuals, along with a higher prevalence of small vessel cerebral disease. In conclusion, patients with coronary microvascular dysfunction, identified by an impaired CFR, have a higher risk of major cardiovascular events.

Intracoronary acetylcholine provocation testing also allows coronary risk stratification. An abnormal response to intracoronary acetylcholine indicates vasomotor disorders due to endothelial dysfunction or smooth muscle cell hyperreactivity. In addition to causing vasospastic angina, coronary vasomotor disorders are associated with a higher long-term risk of cardiovascular events in patients with angina, especially when associated with increased coronary microcirculation. Even moderate vasoconstrictor responses to acetylcholine can be predictive of a worse prognosis in this context.

Additionally, patients with ANOCA often show persistent symptoms, partly due to the lack of an early diagnosis, thus leading to treatment delay. This is associated with a higher number of unnecessary diagnostic tests to rule out obstructive coronary artery disease, visits to the emergency room, hospital admissions, anxiety, impaired quality of life, episodes of sick leave, and higher direct and indirect health care costs.

Diagnosing INOCA is essential to provide effective therapies to control angina symptoms. The CorMicA trial (Coronary microvascular angina) included 151 patients with ANOCA who underwent cardiac catheterization and invasive functional assessment (CFR determination, index of microcirculatory resistance, and fractional flow reserve) followed by acetylcholine vasoreactivity testing. The patients were randomized to reveal their specific endotype, which would guide treatment based on the results (intervention group), vs standard treatment, which would be administered blind to the test results (control group). Targeted therapy was individualized based on the endotypes documented in the invasive study (vasospastic angina: smoking cessation, long-acting calcium channel blockers, long-acting nitrates, and lifestyle changes; microvascular angina: beta-blockers, lifestyle changes, possible angiotensin-converting enzyme inhibitors and statins; noncardiac chest pain: withdrawal of antianginal treatment). Targeted therapy was significantly associated with an improved angina-related quality of life at 6 months (measured using the Seattle Angina Questionnaire), disease perception, and treatment satisfaction, although no differences were reported in the risk of major adverse cardiovascular events. More antianginal drugs were prescribed in the intervention group (87.8% vs 48.7%; P < .001). While these results are very interesting, it is important to note that this was a single study with a limited number of patients.

Endotypes of patients with ANOCA

The specific causes of ANOCA are not yet fully described, and are likely multifactorial in most patients. Figure 2 illustrates the specific causes discovered so far and the pathophysiological mechanisms involved in their genesis. Of note, specific diagnostic techniques often do not allow us to differentiate among the various pathophysiological mechanisms. In fact, in many patients, these mechanisms overlap. Four pathophysiological mechanisms causing ANOCA have been described to date:

Figure 2. Possible results of an invasive functional study in a patient with ANOCA. Specific causes discovered to date with the pathophysiological mechanisms involved in their genesis. Ach, acetylcholine; ANOCA, angina with nonobstructive coronary arteries; CFR, coronary flow reserve; IMR, index of microcirculatory resistance. (Figure self-developed from Meeder et al., Jansen et al., Kunadian et al., Kunadian et al., and Hokimoto et al..)

1. Microvascular dysfunction due to structural changes to the microcirculation. The density of microvessels in patients with hypertensive cardiomyopathy is lower than that in patients without this condition. Remodeling of the coronary microcirculation has also been described, including arteriolar medial layer hypertrophy and induration in patients with hypertension, added to other cardiovascular risk factors, vascular infiltration by amyloid in cardiac amyloidosis, and reduced luminal caliber due to extrinsic compression in cases of ventricular hypertrophy or increased left intraventricular pressure. These changes reduce microcirculatory conductance, resulting in increased microvascular resistances (index of microcirculatory resistance [IMR] ≥ 25). Elevated IMR values are associated with older age and left ventricular hypertrophy, with no clear difference between the sexes.
2. Functional microvascular disease. An increase in resting coronary blood flow, leading to reduced CFR levels has been reported, especially in women with few risk factors and no objectively observable structural heart disease. Although coronary flow is usually preserved at maximum hyperemia, many of these patients have a low exercise capacity. These patients may have an imbalance in oxygen availability (due to increased demand), with endothelial involvement being the main mechanism (due to increased nitric oxide synthesis). In addition, these patients tend to have a greater number of associated ischemic abnormalities in organs such as the kidneys, retina, and central nervous system, suggesting systemic involvement.
3. Microvascular dysfunction due to microcirculatory spasm. Microvascular dysfunction due to vasospasm is more common in women with cardiovascular risk factors, with endothelial dysfunction likely playing a significant role. It is a common finding in larger and medium-sized arterioles and manifests as paradoxical vasoconstriction in response to increased myocardial oxygen demand, which becomes apparent after intracoronary of acetylcholine administration.
4. Epicardial spasm. Epicardial spasm is not usually associated with traditional risk factors, except for smoking. This type of vasospasm is believed to be caused by 2 main mechanisms: endothelial dysfunction and smooth muscle cell hyperreactivity. These 2 mechanisms respond differently to stimuli from the autonomic nervous system, depending on whether the stimuli are from the sympathetic system (such as exercise or a cold stimulation test), or whether the stimuli are from the parasympathetic system and provoke an exacerbated response (eg, nocturnal spasms).