Diagnosing the cause of chest pain in women is challenging and is often not accomplished in routine clinical practice. Underdiagnosis may reflect unrecognized atypical symptom patterns, delays in seeking care, and persistent gaps in risk perception and clinical suspicion.¹² Another contributing factor is the high prevalence of ischemia with nonobstructive coronary arteries (INOCA) in women. Contemporary criteria for microvascular angina include ischemic symptoms, the absence of obstructive coronary lesions, objective evidence of ischemia, and evidence of coronary microvascular dysfunction or vasospasm.^3,4 Documentation of vasomotor disorders using invasive and noninvasive approaches remains the most reliable strategy. PET-based quantification of myocardial blood flow is often considered a reference standard when available, although access and cost limit its widespread implementation.^3,4 However, PET has been associated with lower use of additional health care resources, with only 25% to 37% of patients undergoing the test requiring further interventions.¹³ Dynamic cadmium-zinc-telluride (CZT) SPECT may also enable noninvasive assessment of myocardial blood flow and is an emerging alternative in some centers.¹⁴ Additionally, pulse wave velocity (PWV) has emerged as a noninvasive marker of arterial stiffness and endothelial dysfunction that may complement the evaluation of systemic vascular health. Although PWV does not diagnose CMD, elevated values may indicate vascular aging and endothelial dysfunction, support overall risk stratification, and prompt consideration of more definitive functional testing when symptoms persist despite nonobstructive angiography.

A practical diagnostic sequence for suspected INOCA is to:

Importantly, ischemic syndromes in women often reflect overlapping phenotypes rather than a single mechanism.^16–18 CMD may coexist with epicardial vasospasm, diffuse nonobstructive atherosclerosis, and systemic endothelial dysfunction, and symptom burden may also be influenced by inflammation, autonomic dysregulation, psychosocial stressors, and nonischemic mechanisms of chest pain. Recognizing these interacting endotypes supports more individualized diagnostic pathways and helps avoid overattributing symptoms to CMD alone.^4,16–18

Although symptom control is unquestionably highly relevant to the patient's quality of life, clinical evidence indicates that CMD also has important prognostic implications. In this context, assessment of reduced CFR, which can serve as an indicator of microvascular dysfunction, is particularly relevant, as both are associated with a significantly higher incidence of cardiovascular events, including acute myocardial infarction, heart failure, and cardiovascular death, regardless of the presence of obstructive coronary artery disease. This underscores the need for early diagnosis and rigorous therapeutic management beyond pain control.¹⁹

Management options are summarized in Figure 3.

A phenotype-based approach can help align therapy with the predominant underlying mechanism:

INOCA treatment is challenging because of its heterogeneous underlying mechanisms and the relative scarcity of randomized trials in women. Current guidance emphasizes mechanism-guided therapy, when endotyping is available, along with aggressive risk factor control and the early use of combination antianginal therapy based on symptom profile and comorbidities.^4,15,16

In coronary microvascular dysfunction, vasodilators may have variable efficacy, and treatment often relies on a combination of antianginal agents, such as beta-blockers, calcium channel blockers, ACE inhibitors or ARBs, and statins, together with lifestyle interventions. Long-acting nitrates may provide limited benefit in microvascular angina and may, in some cases, worsen symptoms because of coronary steal.^4,15

The 2025 Brazilian Guideline for Chronic Coronary Syndrome, published by the Sociedade Brasileira de Cardiologia (SBC), emphasizes the early use of combination antianginal therapy with complementary mechanisms rather than a strictly stepwise escalation. It notes that no single drug class has demonstrated clear superiority for symptom relief or long-term outcomes, supporting a personalized approach that may combine beta-blockers, calcium channel blockers, nitrates, ranolazine, or trimetazidine. This direction is consistent with broader international guidance, including the 2024 ESC guideline on chronic coronary syndromes, which reinforces mechanism-based evaluation and individualized antianginal therapy. This framework is particularly relevant for women with INOCA/CMD and a high symptom burden.^15,20

Trimetazidine is an established treatment for angina pectoris in IHD and CCS, improving exercise tolerance and quality of life without significantly affecting blood pressure or heart rate.²¹ Its mechanism of action involves shifting myocardial energy metabolism from fatty acid oxidation toward glucose oxidation (Figure 4). This effect occurs through inhibition of fatty acid β-oxidation, thereby increasing glucose oxidation and reducing intracellular lactate accumulation, which helps minimize intracellular acidosis and preserve cell membrane integrity.²²

In women with INOCA/CMD, the overall evidence remains limited and is based largely on small studies and physiologic end points. However, trimetazidine has shown promising results in some clinical studies. In the PATMOS study, which included patients with stable coronary artery disease undergoing elective PCI, trimetazidine was associated with improvements in physiologic indices of the coronary microcirculation, such as the index of microcirculatory resistance (IMR) and coronary flow reserve (CFR).²³ A small randomized study by Bol'dueva et al. also reported symptom improvement in patients with microvascular angina treated with trimetazidine.²⁴ Accordingly, current guidelines position trimetazidine as an antianginal option across nine of ten patient profiles, cite the 80 mg formulation as favorable for adherence, and emphasize early combination strategies tailored to phenotype and symptom burden.²⁰ In addition, the Position Paper on IHD in Women recognizes trimetazidine as a key pharmacologic treatment option.^6,7

Key evidence gaps include the absence of randomized trials specifically focused on women with INOCA, the limited external validity of existing studies, and the lack of hard clinical end points, such as myocardial infarction, hospitalization, and mortality. For this reason, metabolic or antianginal agents such as ranolazine and ivabradine, as well as nicorandil in vasospastic phenotypes, should be viewed within the same critical framework: symptom-focused options that require more robust comparative data and outcome-based trials.^4,15–18