Coronary microvascular dysfunction: a narrative review

Introduction

Background

Coronary artery disease (CAD) is the leading cause of death worldwide (1). The primary symptom of CAD is chest pain or angina, and is the second-most frequent presenting complaint for emergency departments across the developed world (2,3). Invasive coronary angiography (ICA) remains the gold standard of diagnosis, requiring an operator to selectively engage the coronary arteries and inject contrast to perform a visual assessment of arterial stenoses and determine their severity (4). However, between 25–50% of patients who undergo clinically-indicated ICA are not found to have obstructive CAD, thus revealing no cause for the presentation (5). This ambiguity leads to significant patient anguish, worse quality of life, and more frequent healthcare utilisation (6). Many of this cohort are living with coronary microvascular dysfunction (CMD), a multifactorial pathology of the microscopic circulation of the coronary arteries (7).

Rationale and knowledge gap

This under-recognised condition responds to treatment differently to macrovascular disease, with identification and targeted therapies required to reduce symptom burden and improve quality of life (8). Although traditional cardiovascular risk factors have been linked to CMD, there is incongruence between large trials as to which are most relevant in reducing symptom burden (5,6,9,10). Historical data for CMD is limited by prior diagnostic methodology and ambiguous terminology, resulting in a perceived steep increase in incidence in the modern era of cardiac catheterisation. With the advent of ICA, clinicians as early as 1967 were perplexed by a subset of patients who had demonstrable ischaemia via non-invasive, functional assessment yet paradoxically patent coronary arteries (11). Patients who had angina without evidence of epicardial CAD received a variety of diagnostic labels including cardiac syndrome X, microvascular angina (MVA), and more recently, angina with non-obstructive coronary arteries (ANOCA), each with varying degrees of accuracy (5). This is further obfuscated by a deficit in testing, with clinicians either unable or unwilling to perform the required invasive assessments to conclusively diagnose CMD.

Objectives

This contemporary narrative review aims to outline the established epidemiology, physiopathology, and prognosis of CMD, with a particular emphasis on recent advances in its clinical manifestations and treatment. Additionally, recent research, emerging technologies, and new diagnostic techniques have been highlighted. As the clinical substrate and relevance of CMD continues to rise, areas of ongoing expert discourse persist and aspects that require further investigation for consensus are included as potential directions for future research. We present this article in accordance with the Narrative Review reporting checklist (available at https://cdt.amegroups.com/article/view/10.21037/cdt-2025-1-545/rc).

Methods

A search of the PubMed database was completed covering the period from 1990 to July 2024. Please see Table 1 below for search strategy details. The articles incorporated were limited to English language original research, review articles, and expert consensus documents. The reference lists of relevant literature were also used to identify additional articles.

Discussion

Definition

CMD is an encompassing term for several pathological mechanisms within the micro-circulation of the myocardium which lead to impaired myocardial blood flow and coronary flow reserve (CFR) and subsequent myocardial ischaemia (12,13). The phenomenon may be derived from either functional or structural deviation from standard coronary physiology, with significant overlap between aetiologies (6). The resultant clinical syndrome is typically one of refractory angina in the absence of macrovascular CAD, with a rare subset of diagnoses made after presentation with heart failure or dysrhythmia (8).

With various aetiologies and improved recognition, definitions of CMD have shifted over time. In 2017, the Coronary Vasomotion Disorders International Study Group (COVADIS) proposed the following diagnostic criteria: symptoms of myocardial ischemia, absence of obstructive CAD, objective evidence of myocardial ischemia, and lastly, evidence of impaired coronary microvascular function (12). This definition has subsequently been adopted by both clinicians and researchers (13).

Epidemiology

CMD has been perpetually underdiagnosed due to variable diagnostic criteria, under-recognition, lack of resources for invasive assessment of the microcirculation, and widespread use of vasoactive anti-anginal medications, complicating epidemiological analyses.

Ischaemic heart disease (IHD) represents a very common condition, with the United States alone averaging over 2,500 ICAs performed daily (14). However, 25–50% of patients who undergo ICA for angina do not have obstructive (defined as >50% luminal stenosis), obstructive CAD demonstrated (5,6) and are labelled ANOCA presentations. It is estimated within this cohort, 50% have functional or structural pathology of the coronary microcirculation (6,15-18) underscoring the high prevalence of CMD amongst the ANOCA population. There is an additional patient population who have co-existing macro- and microvascular disease, and CMD is often demonstrated following percutaneous coronary intervention (PCI) in thrombotic lesions (19).

Multiple registries and trial data, most saliently CorMICA (CORonary MICrovascular Angina), iPOWER (ImProve diagnOsis and treatment of Women with angina pEctoris and micRovessel disease), and WISE (Women’s Ischemia Syndrome Evaluation), have demonstrated the prevalence of CMD is elevated amongst patients with the traditional metabolic and cardiovascular risk factors of diabetes, systemic hypertension, obesity, active smoking, sedentary lifestyle, and dyslipidaemia (particularly low high-density lipoprotein) (6,9,10). Non-modifiable risk factors for CMD include family history of premature macrovascular disease, female sex, and advanced age, with the incidence seen to increase across the lifespan (6,10,15).

Iatrogenic factors, including prior PCI and cardiac transplantation, can predispose to CMD. Lastly, comorbidities of aortic stenosis, heart failure with preserved ejection fraction (HFpEF), pulmonary hypertension, left ventricular hypertrophy, inflammatory states, and distant microvascular pathology (central and peripheral) have all been shown to correlate with a higher incidence of CMD (20-22).

The mechanism that causes certain populations to develop microvascular disease rather than obstructive, epicardial CAD remains unknown. A recent single-centre study showed that older age and prior CAD were associated with CMD in women, but not men (23). This disparity phenomenon requires further investigation.

The link between female sex and CMD is so strong that a significant portion of research in the area has specifically examined its incidence amongst women. iPOWER systematically evaluated CFR abnormalities in women and found increased prevalence of CMD (9), and WISE linked presence of impaired microvascular function in women to adverse outcomes with ten-year follow-up data showing an association with premature death regardless of presence of epicardial disease (24). Most recently, WARRIOR (Women’s IschemiA TRial to Reduce Events In Non-ObstRuctive CAD) was a female-only, prospective RCT investigating intensive versus standard medical therapy for CMD, with findings discussed further below. Several physiological factors have been proposed to explain the difference in men and women, including the endothelial effects of oestrogen, sex-specific endothelial dysfunction via impaired nitric oxide (NO)-dependent vasodilation, heightened inflammatory and autonomic responses, and a higher prevalence of associated comorbidities such as obesity, HFpEF, and inflammatory pathology (7,20,25).

Lastly, certain comorbid conditions are associated with a higher incidence—most notably inflammation, with raised inflammatory biomarkers consistently shown to be elevated in CMD patients diagnosed invasively (21,22,26). An overlap with peripheral vascular endothelial dysfunction suggests a potential, collective, and as-yet-uncharacterised aetiology (27-29). The risk factors of CMD are further detailed in Table 2 below and displayed in Figure 1.

Figure 1 Risk factors for coronary microvascular dysfunction. Created in BioRender. O’Brien JM [2025]. https://BioRender.com/4d9d2ot. CMD, coronary microvascular dysfunction.

Pathogenesis and pathophysiology

Multiple complex, overlapping pathophysiological pathways may result in the clinical syndrome of CMD, with the common endpoint being abnormal coronary function due to coronary microvascular endothelial cell (CMEC) injury (13,30,31). The coronary vascular bed consists of a series of increasingly small calibre vessels, ranging from epicardial arteries (diameter >500 µm) to pre-arterioles (200–500 µm), arterioles (<200 µm), and capillaries (≤10 µm). The arterioles are the branches that under normal physiological conditions regulate coronary flow and resistance through constriction and dilation, triggered by myocardial oxygen requirements, pressure changes, neurogenic stimulation, endogenous metabolites, inflammatory cytokines, and medications (7,31). CMD may affect any vessel distal to the conductive epicardial branches. This calibre of vessel cannot be directly visualised with conventional angiography, and our knowledge is derived from in vivo physiological assessments and in vitro studies.

The pathogenesis of CMD is broadly divided into structural or functional subtypes (31,32). Structural remains the more traditionally recognised variant, with CFR reduced in the presence of elevated microvascular resistance. In structural CMD, the microcirculation undergoes architectural changes at the level of the capillaries or arterioles due to a combination of oedematous CMECs, loss of capillary density, luminal stenosis, vascular smooth muscle cell proliferation, impaired sensitivity to NO, and/or external compression (33,34). The terminal consequence is vascular tissue which may function adequately in a resting state, but cannot adapt appropriately during times of increased myocardial demand (33). This phenotype has a strong association with cardiomyopathic processes including valvulopathy and HFpEF (20).

Conversely, functional CMD is characterised by reduced CFR with normal or reduced microvascular resistance. This endotype is increasingly recognised and is thought to be due to dysregulated coronary endothelial behaviour. This can be demonstrated through the inability of the microcirculation to react, constrict, and dilate via standard physiological mechanisms, with near-maximal vasodilation present at baseline. Thus when myocardial demand is increased, there is no potential for additional vasodilation or capacity for increased myocardial blood flow (31,33,35). The most common manifestation is microvascular coronary spasm, in large part due to increased activity of Rho-kinase and the subsequent hyper-contractibility of the vascular bed. These physiological factors are exacerbated by low-levels of chronic inflammation and autonomic hypersensitivity frequently encountered in CMD populations (36).

Comorbid inflammation is so prevalent in CMD cohorts it is felt to play a central role in its underlying pathology. Inflammatory sequelae that could contribute to CMD include reduction in bioavailability of NO, chronic endothelial injury, and propagation of negative microvascular remodelling—all of which subsequently lead to increased vascular resistance. Presence of both localised and systemic inflammation has been correlated with higher incidence of CMD, and the role of reducing this inflammation in minimising symptom burden is an area of ongoing research (21,37,38).

Whether mediated via structural or functional mechanisms, both endotypes overlap in the endpoints of reduced exercise capacity and maladaptive stress response with inducible ischaemia (33). Some common contributory factors have been identified, including oxidative stress, pro-inflammatory states, arterial stiffness (as seen in ageing) and loss of pericytes, a mural vascular cell. Patients with traditional cardiovascular risk factors may be higher risk for CMD, with strong correlation between incidence of dyslipidaemia, systemic hypertension, obesity, and diabetes (9,10,39). Cigarette smoking in particular has a strong association with vasospastic dysfunction (40). Furthermore, there may be a genetic association to the pathogenesis of CMD, although the association between genotype and phenotype is not well understood (38).

Classification and terminology

In 1973, 6 years after first reporting a subset of patients with objective evidence of ischaemia but no significant visualised CAD on ICA, Kemp labelled the phenomenon as ‘cardiac syndrome X’ (41). The term MVA was initially proposed by Cannon and Epstein in the late 1980s to describe a syndrome with three clinical features—non-obstructive epicardial coronary arteries, presence of typical angina, and demonstrable myocardial ischaemia (42).

As understanding of the pathophysiology slowly improved in the early-to-mid 1990s, several seminal papers reframed the language used to describe this patient cohort with the encompassing term ‘coronary microvascular dysfunction’—a term solidified by Camici and Crea in their 2007 paper that proposed a new classification system for CMD (38,42-45). Their subtypes of CMD were determined by the presence or absence of obstructive CAD, myocardial disease, and/or prior procedural intervention (38). A suggested revision by Herrmann et al. [2012] incorporated the endotype of CMD described in cardiac transplant recipients due to its unique mechanism of reduced autonomic tone and altered inflammatory pathways, and included modifiers to the classification system dependent on duration, symptoms, and therapy (46).

The most recent effort to amalgamate the inconsistent terminology used in this area is derived from the COVADIS working group. This collaboration of international experts in vasomotor abnormalities established MVA as a clinical syndrome attributable to CMD, with patients presenting with typical angina pectoris in the absence of flow-limiting CAD (12,47). COVADIS outline a set of criteria for raising suspicion of MVA in patients with angina, including symptoms of myocardial ischemia (such as angina or equivalents such as dyspnoea), absence of obstructive CAD [defined as <50% diameter reduction or fractional flow reserve (FFR) >0.80], objective evidence of myocardial ischemia [such as ischaemic electrocardiogram (ECG) changes during an episode of chest pain or stress-induced symptoms], and evidence of impaired coronary microvascular function [including but not limited to impaired CFR of ≤2.5, coronary microvascular spasm, abnormal coronary microvascular resistance indices, or coronary slow flow phenomenon with a thrombolysis in myocardial infarction (TIMI) frame count >25]. The term ‘suspected MVA’ is used if both symptoms are characteristic and there is no epicardial disease found with appropriate investigation, but only criterion 3 or 4 (i.e., objective evidence of ischaemia or impaired microcirculatory function) remain present (12).

Whereas cardiac syndrome X has fallen out of favour, both the terms MVA and CMD remain in use, but are not directly interchangeable. MVA refers to the lived patient experience with symptoms in the absence of obstructive epicardial disease, with CMD used specifically after objective evidence of abnormal microcirculatory behaviour is obtained (7,12,13).

Diagnosis

Patients with CMD typically present with symptoms indistinguishable from obstructive macrovascular CAD, including typical angina, atypical chest discomfort, or angina-equivalent symptoms such as dyspnoea (13,15). Whilst symptoms are often exertional, unstable angina can occur (15). CMD may also be detected incidentally in asymptomatic patients, however this is uncommon as ICA is rarely performed on asymptomatic individuals (48).

Despite research into several biochemical markers of endothelial dysfunction, vascular inflammation, and oxidative stress, there are currently no validated serological markers for diagnosing nor quantifying CMD (49). If differentiation between stable disease and acute coronary syndrome is required, troponin should be measured, and it is standard practice to quantify the glycosylated haemoglobin (HbA_1c) and fasting lipid profile as contributory factors. Inflammatory biomarkers may be elevated, but with little change to clinical management they are not routinely measured (49).

Multiple non-invasive imaging modalities exist, each possessing a limited role in the diagnosis of CMD, predominantly through demonstration of reduced CFR. The advantage of non-invasive testing is the ability to perform interval assessments of CMD with less significant risks. An estimation of CFR may be derived from Doppler-based transthoracic echocardiography (TTE) of the left anterior descending artery (LAD) during chemical stress initiated with adenosine or dipyridamole (50). This ratio of hyperaemic to resting absolute myocardial flow serves as an indicator of microvascular function in patients who do not have limitations in epicardial coronary flow. Unfortunately, this technique is difficult to replicate and requires extensive sonographer training and resources (50,51). Additionally, the addition of myocardial contrast to echocardiographic assessment uses the refractory properties of infused inert, gas-filled microbubbles with similar physical properties to erythrocytes can add non-invasive data. By destroying the microbubbles with pulsed ultrasonic waves and measuring their replenishment time, an accurate measurement of myocardial perfusion can be obtained (52). However, despite wide availability and low-cost, this technique has not seen widespread utilisation, perhaps in part due to its technical challenges in reproducibility, small evidence base for invasive correlation, and requirement of exclusion of epicardial disease prior to validation (53).

The advent of computed tomography coronary angiography (CTCA) changed routine investigation of stable angina at the epicardial level, and its role in microvascular assessment continues to expand. Contrast CTCA has been used to reliably calculate absolute coronary flow and epicardial resistance when validated against invasive indices, with CT-FFR displaying high sensitivity and specificity for macrovascular disease (54). CT-perfusion utilises resting and stress image acquisitions allows quantification of iodine uptake and distribution, with several proprietary applications for generation of colour-coded perfusion maps (55). More dynamic CT perfusion techniques exist with more frequent time points of acquisition, ECG-gating, and large coverage machines, but are currently limited to research settings (56). Lastly, the CT-derived coronary lumen volume to myocardial mass ratio (V/M) has revealed a linear relationship between reduced myocardial mass in patients with CMD diagnosed invasively (54,57). Calculation of V/M is dependent on several vendor-specific software.

Another validated non-invasive technique is the use of positron emission tomography (PET) to assess myocardial perfusion at rest and stress to quantify numerous indices of microvascular disease, including myocardial flow (51,58). Links with cardiovascular outcomes are improving and radiation doses are being minimised (59), but the ability to perform this investigation is limited to few centres making accessibility problematic.

Cardiovascular magnetic resonance imaging (CMR) is another non-invasive imaging modality used in CMD assessment. Similar to the previous methods, CMR requires resting and stress image acquisition to provide high-quality images with excellent spatial resolution, no radiation, and superb mechanistic insights into myocardial perfusion at rest and during hyperaemia (34,51). It has been compared with PET imaging to accurately estimate myocardial blood flow and perfusion reserve, and overcomes the heterogeneous distribution of CMD by capturing all coronary territories (51). Barriers to widespread CMR utility in diagnosis CMD include highly variable protocols, limited patient access, expense, and time-cost. Prognostic data linked to major adverse cardiovascular and cerebrovascular events (MACCE) also remain limited (51).

Ultimately, all non-invasive modalities currently offer quantification of surrogate measures of microvascular function. A systematic review of the diagnostic yield of these investigations [specifically TTE, PET, and magnetic resonance imaging (MRI)] is highly variable with reduced sensitivity and specificity when compared with the predictive power of non-invasive tests for obstructive CAD (60). The gold standard investigation in CMD remains ICA and subsequent physiological assessments. When clinicians perform ICA, they conduct visual assessment on larger branches comprising less than 5% of the total surface area of the coronary arterial tree. Prior to widespread availability of coronary pressure wires, a diagnosis of CMD was supported angiographically by a TIMI frame count of >25 frames (at 15 frames/s), seen as slow flow of contrast through the epicardial vessels with delayed clearance in the distal vascular bed. This method was not sufficiently specific nor sensitive, with the coronary catheter gauge, framerate, and intra-cardiac pressures altering flow (61). Despite the advantage of not requiring additional equipment, TIMI frame analyses have largely been supplanted by physiological wire assessment.

With the inability to anatomically assess the coronary microcirculation invasively, proceduralists require a functional method of diagnosis. Since 1970s, invasive measurement of coronary pressure and thus resistance was possible using existing technology (62). By the 1990s, multiple laboratories validated invasive techniques for quantifying intravascular flow and resistance (63). The first mainstream method used the above principles of Doppler ultrasonography, determining that the hyperaemic flow divided by the resting flow was a suitable surrogate for calculating CFR (64,65). This technique came to be described as the hyperaemic microvascular resistance (hMR) and whilst popularised in catheterisation labs globally, it suffered several limitations. Aside from requiring a delicate and costly Doppler guidewire, the calculation of hMR made assumptions about haemodynamic status that could affect results, was highly operator-dependent, and failed to assess the microcirculation in isolation.

In 2003, Fearon et al. proposed a novel index to assess coronary microvasculature, designated the index of microcirculatory resistance (IMR) (66). This technique requires the use of a specific pressure guidewires that utilise proximal and distal piezoelectric pressure sensors, rather than the optical pressure method employed by analogous guidewires on the market. It builds upon the principles established in Pijls and De Bruyne et al.’s seminal work in the field of coronary physiology (67,68), again using hyperaemia to draw conclusions about the microcirculation.

As resistance cannot be directly measured, calculating IMR becomes a clinical application of Ohm’s law. This principle states voltage is directly proportional to the current flowing through a material and its resistance, or expressed mathematically, Voltage (V) = Current (I) × Resistance (R), or R = V/I. In a coronary context, voltage refers to the difference in pressure across the microvascular bed (the distal coronary pressure subtract venous pressure, or P_d − P_v, where P_v is assumed as zero) and the current is myocardial flow (69,70). Pressure is measured directly by sensors. Myocardial flow can be quantified using thermodilution, where saline is injected into the artery being examined and the time taken for the reduced temperature to transit from proximal to distal thermistors is recorded. Saline may be administered via bolus or continuously infused. With two of three variables measured, coronary resistance can thus be determined. The formula can be distilled to mean transit time (T_mn) multiplied by distal coronary pressure (P_d), or (IMR = T_mn × P_d) (71). Hyperaemia is necessary to achieve minimum resistance, and an antithrombotic agent and intracoronary nitrates are advised (69,70,72).

IMR has become the gold standard for diagnosing CMD (48), as it is microcirculation-specific, can mathematically account for interference from epicardial stenoses, remains unaffected by haemodynamic compromise, and is more highly reproducible across patient demographics and operators than hMR or CFR (66,73,74). The normal value was determined to be ≤25 after assessing patients with and without known atherosclerotic disease, having been compared against non-invasive stress testing (75,76). IMR calculation allows derivation of the resistive reserve ratio (RRR), i.e., the ratio of baseline to hMR. RRR reflects the microcirculation’s vasodilatory capacity, complementing IMR and CFR as IMR does isolate resting vascular tone, and CFR can be confounded by elevated resting flow. As a derivative index, RRR can amplify measurement error (5,37,71,77).

In addition, acetylcholine (ACh) infusion can be performed in a graded manner to test endothelial dysfunction. ACh has a predictable vasomotor effect and the vascular response can be used to differentiate healthy or pathological endothelium. ACh should induce NO release in endothelial cells through its action on both sub-types of cholinergic receptors—nicotinic (vasodilatory) and muscarinic (vasoconstrictive). The balance of receptor activation typically favours nicotinic, and as a result vasodilation occurs. However in a diseased state the endothelium cannot produce sufficient NO to meet demand, and the sum of ACh-driven cholinergic activity leads to vasoconstriction with clinically-detectable symptoms and potentially electrocardiographic changes (78,79). Peripherally- or centrally-infused ACh, initially low-dose but gradually escalated, can be used to induce vasospasm in the microcirculatory bed if endothelial dysfunction is present (48). ACh response is prognostic, with abnormal results associated with higher anginal burden, and in modern labs spasm testing has an acceptable safety profile (80).

The LAD is the most common coronary artery assessed, as the volume of subtended myocardium is greatest and thus yield is theorised to be the highest. However, it is known that CMD is a patchy and heterogenous disease which does not affect all coronary vessels. Thus, isolated IMR study of the LAD may lead to false negative assessment. Small studies have reported statistically significant increase in diagnostic yield with multivessel coronary functional testing in the ANOCA cohort (81). The European Society of Cardiology (ESC) 2024 algorithm for diagnosis in this sphere is outline in Figure 2 below.

Figure 2 Diagnostic algorithm for patients with ANOCA/INOCA. Reproduced with permission from European Heart Journal (Oxford University Press). ANOCA, angina with non-obstructive coronary arteries; CAD, coronary artery disease; CCS, chronic coronary syndrome; CCTA, coronary computed tomography angiography; CFR, coronary flow reserve; ECG, electrocardiogram; FFR, fractional flow reserve; GDMT, guideline-directed medical therapy; HMR, hyperaemic microvascular resistance; ICA, invasive coronary angiography; iFR, instantaneous wave-free ratio; IMR, index of microcirculatory resistance; INOCA, ischaemia with non-obstructive coronary arteries; MRI, magnetic resonance imaging; PET, positron emission tomography; SPECT, single-photon emission computed tomography.

To mitigate the risk of perforation, dissection, and plaque disruption that is inherent with invasive wiring, a novel index has been proposed—the quantitative microcirculatory resistance or ‘Angio-IMR’ (Medis, Leiden, the Netherlands) (82). Building upon technology used to determine functional significance of epicardial vessels, this software-based measurement utilises flow dynamics and computational analysis of invasively-obtained angiographic images to recreate a three-dimensional model of the coronary artery, risk-stratifying people suspected of experiencing CMD (82,83). Further data are required associating Angio-IMR with clinical outcomes.

Lastly, research has indicated that structural changes occur at the level of the myocyte in CMD, with distinct histopathological and immuno-histological features on endomyocardial biopsy (EMB)—particularly in the ACh-responsive cohort (84). However, EMB is not performed routinely due to its highly-invasive nature, low yield, and requirement for specialist Pathologist interpretation (84).

Management

Managing patients with CMD can be challenging, with heterogenous pathological and clinical phenotypes leading to highly variable responses to traditional anti-anginal agents and frequently, a significant residual symptom burden (48). Additionally, large-scale trials examining management and outcomes of CMD remain lacking, with many of treatments used by clinicians supported by small studies, registry data, or retrospective analyses.

As in all cases of cardiovascular disease, a patient-centred, multidisciplinary approach incorporating non-pharmaceutical strategies, risk factor modification, and medical therapy guided by their pathophysiological endotypes is associated with the greatest improvement in symptoms and quality of life (6,14,48,85). Suggested lifestyle modifications include nutritional improvement, stress reduction, and increasing exercise capacity, with a heavy focus on smoking cessation and weight management. Smoking has clear links to endothelial dysfunction (40), with morbidly obese patients showing dramatic improvement in endothelial function following weight loss (86), and management of stress, anxiety and depression through psychological counselling and physical exercise leading to symptom improvement (87). These measures should be in conjunction with risk factor optimisation, focussing on managing systemic hypertension, dyslipidaemia, and glycaemic control and were highlighted in the ESC guidelines for management of chronic coronary syndromes released in August 2024 (48), as highlighted in Figure 3 below.

Figure 3 Treatment of ANOCA/INOCA. Reproduced with permission from European Heart Journal (Oxford University Press). ACEi, angiotensin converting enzyme inhibitor; ANOCA, angina with non-obstructive coronary arteries; CCB, calcium channel blocker; ESC, European Society of Cardiology; INOCA, ischaemia with non-obstructive coronary arteries.

Amongst patients diagnosed with a vasospastic component on acetylcholine challenge without elevated IMR, calcium channel blockers (CCBs) are the first-line recommendation for anti-anginal effect. CCBs have been frequently validated in reducing symptom burden through a number of trials (88), and objectively demonstrated to reduced epicardial spasm in a placebo-controlled randomised controlled trial (RCT)—the Dutch EDIT-CMD study (89). It is worth noting this same trial suggested no objective improvement with short-term calcium channel blockade in CFR or IMR, but was limited to only 6 weeks administration. Beta-blockers, frequently employed as first-line anti-anginal agents, should be avoided in the presence of confirmed vasospasm as they can potentiate spasm via vasoconstriction from unopposed alpha receptor activation (90).

With symptoms breaking through CCBs, guidelines suggest utilisation of long-acting nitrates, statins, and nicorandil, a potassium channel opener and established anti-anginal (27,47,90). Limited data from small-scale studies support the use of contextually novel agents including perhexiline, pioglitazone, and cilostazol (88). Vasospastic angina patients have an increased risk of MACCE (18,47), and management should also aim to optimise traditional cardiovascular risk factors—prominently including smoking cessation (48). Refractory cases may even derive benefit from thoracic sympathectomy due to the hyperalgesic component of vasospasm (88).

Once a functional CMD diagnosis is established via elevated IMR or reduced CFR, first-line medical therapy is typically a combination of high-dose statins, angiotensin converting enzyme (ACE) inhibition, and beta-blockers or CCBs for anginal control. In addition to their role in reducing systemic dyslipidaemia, statins have been shown to enhance endothelial function through reduced oxidative stress and inflammation and are a mainstay of CMD treatment (91). ACE inhibitors reduce systemic blood pressure, and were theorised to contribute specifically to improved microvascular function through correction of aberrant adrenergic activation, remodelling, and reducing extravascular compressive stress (92). However, this was recently evaluated in the WARRIOR trial (NCT03417388), a randomised study in women with ischaemia with non-obstructive coronary arteries (INOCA) that investigated ACE inhibitor and statin therapy in those without conventional indications. The trial was terminated early and presented as a late-breaker at the American College of Cardiology Scientific Sessions in 2025, showing no significant difference in outcomes between treatment and placebo arms. While yet to be published, these findings raise important questions about indiscriminate use of these agents in this cohort of patients (93).

In the presence of insulin resistance, metformin, exogenous insulin, and other anti-diabetic agents have been shown to improve vascular resistance by weight reduction and improved glycaemic control (94). Despite hypotheses about their role in CMEC regulation, there is little-to-no data supporting their use in a non-diabetic population. Emerging evidence suggests sodium-glucose cotransporter 2 (SGLT2) inhibitors may have several positive effects on CMD via improved glycaemic control, reduction in systolic and diastolic blood pressure, anti-inflammatory effects, and enhancement of NO bioavailability, causing microcirculatory vasodilation (95-97).

For symptom reduction among patients with CMD, CCBs supplemented by short-acting nitrates can be highly effective. The addition of beta-blockade for refractory cases may further improve symptoms at the cost of bradycardia (34,48,85). CCBs have additionally been shown in meta-analyses to improve CFR (48,98). They are the mainstay of therapy for patients with a vasospastic anginal component, with beta-blockers being relatively contraindicated—further supporting the need for thorough coronary functional assessment to determine clinical endotype (48). None of these agents have been associated with reduction in MACCE (48). A tailored approach should be taken to each individual in light of comorbidities, existing medications, costs, and underlying pathology. Debate continues regarding up-front mono- vs. dual anti-anginal therapy with only limited data from secondary outcomes in small trials (48).

The role of antiplatelet agents in CMD remains contentious. Intra-coronary imaging has repeatedly demonstrated a high incidence of atherosclerotic disease in CMD cohorts, and if present, may necessitate treatment with aspirin. As a thromboxane A2 inhibitor, it theoretically improves microvascular function via prevention of vasoconstriction and platelet aggregation. Ticagrelor has been proposed to improve symptoms through modulating microcirculatory adenosine levels, but this is unsupported by appropriately-sized data (48,99). It should be noted that many patients do not have CMD in isolation, but experience symptoms from concurrent macrovascular CAD as visualised in Figure 4. This overlapping cohort are poorly described, with recommendations remaining to perform revascularisation in the epicardial vessel and medically managing the microvascular component (48,85).

Figure 4 Shared risk factors for macro- and microvascular coronary disease. Created in BioRender. O’Brien JM [2025]. https://BioRender.com/k78m600.

Novel agents for CMD include nicorandil, ranolazine (a late sodium channel inhibitor), and ivabradine (an I_f-channel blocker). Each has a niche role in select patient groups, such as those with prohibitive hypotension, refractory symptoms, or beta-blocker insensitivity (30,48,85,100). Investigation into additional therapies continues, with promise amongst the Rho-kinase inhibitors, endothelin receptor antagonists (ETRAs), and soluble guanylate cyclase inhibitors.

Natural history and prognosis

The natural history and progression of CMD is highly variable. On-going disruption of normal micro-coronary physiology leads to impaired myocardial blood flow, which in turn causes adaptations in myocardial oxygen demand (7). Myocardial ischaemia in affected vascular territories has been demonstrated through exercise stress and metabolite testing, with traditional sequelae of ischaemia being possible (8). Poor long-term control can lead to an increased sensitivity to angina, and breakthrough symptoms after well-controlled disease may suggest progression of pathology (8,101).

Prognostic data in the field of CMD has been mixed, complicated by the various associated pathologies, underlying mechanisms, and definitions used. Originally thought not to significantly affect mortality (8,41), increasing evidence indicates the presence of CMD carries a heightened risk of MACCE (6,9,10,39). What is clear is that patients with untreated CMD are more likely to require repeated hospital admissions, suffer more angina, and experience an inferior quality of life (5,6,9). Those with demonstrable ischaemia or reduced CFR (regardless of microvascular resistance) are particularly vulnerable to impaired symptom control and are at higher-risk of infarction (32,46,85).

Future directions and current knowledge gaps

The key direction of future CMD research is to identify improved therapeutic options for those who affected. An ideal agent would be easily administered, safe, well-tolerated, economically viable, and effective in reducing symptom burden and therefore improving quality of life. Upon review, existing studies are being undertaken in CMD to assess the clinical utility of a number of different agents including anti-inflammatories, colchicine, ivabradine, soluble guanylate cyclase stimulators, ranolazine, SGLT2 inhibitors, ETRAs, and even monoclonal antibodies which act on inflammatory cytokines (30,34). More invasive potential therapies include implantation of coronary sinus reducers and CD34⁺ stem cell transplantation (30,102).

The strong overlap between CMD and obesity, with approximately 50% of patients experiencing both conditions, weight reduction via traditional methods or pharmaceutical assistance (such as glucagon-like peptide-1 agonists) offers another potential treatment pathway. Obesity is known to contribute to systemic inflammation, insulin resistance, and endothelial dysfunction, which are suspected to play a central role in microvascular spasm and CMD pathophysiology, as seen in Figure 5.

Figure 5 The metabolic overlay of obesity and inflammation in CMD. CMD, coronary microvascular dysfunction.

The multiple potential treatments listed above have shown therapeutic promise using various parameters, however the field of CMD research is highly lacking in prospective, randomized controlled trials measuring objective changes or improvements in coronary flow or microvascular resistance over the medium-to-long term. The oft-referenced CorMICA showed improvement in symptom burden and quality of life with tailored therapy, but did not include repeat invasive measurements of coronary physiology (6). The Dutch EDIT-CMD provided useful data for the short-term impact of a single agent (diltiazem) on these indices, however there are many therapies both routinely-prescribed and novel which require similar scientific interrogation (89).

This leads into the next significant knowledge gap, as clinicians and researchers remain without diagnostic nor quantitative biomarkers. The identification of a serological marker of CMD could theoretically be used analogous to uric acid in gout, treating to target to achieve adequate disease control. The correlation between CMD and peripheral macro- and microvascular disease suggests a common, inflammatory cause with research on-going into potential culprit cytokines.

Additionally, there is significant interest in determining the mechanism that leads some patients to develop epicardial coronary disease, and others microvascular dysfunction despite the underlying substrate appearing to be highly similar. Whilst several theories have been proposed, no definitive conclusion has been reached. Investigation into the determinants of disease may shed further light on the atypical disparity between presentations of CMD when divided by biological sex.

Lastly, and perhaps most importantly, clinicians require a safe, easily accessible, non-invasive method of diagnosing CMD with links to hard outcome data. Although Angio-IMR avoids the need for invasive pressure wire assessment, it requires ICA imagery and carries the inherent, procedural risk. Its use in multivessel assessment warrants characterisation. Promising work has been completed using pericoronary adipose tissue (PCAT) analysis of CTCAs, with further data required to support widespread utility. Few centres perform the ultra-specialised, stress PET or cardiac MRI studies required for a non-invasive diagnosis, and thus the ability to perform analysis on CTCA—an imaging modality available at most major hospitals and many outpatient services—would allow much greater access to diagnosis for patients with CMD.

Strengths and limitations

This review has several limitations. The area of CMD continues to rapidly evolve, despite the authors’ best efforts to accurately and comprehensively cover key concepts. Additionally, not all articles the authors reviewed were of equal quality and despite appropriate scrutiny the subjective nature of analysis may have led to inclusion of some work via selection bias. To minimise this effect, multiple authors reviewed key articles to determine their weighting with every endeavour made to provide thorough, balanced, and accessible coverage of CMD.

Conclusions

CMD remains an umbrella term that represents a complex and challenging area of cardiovascular medicine, with heterogenous pathological and clinical endotypes, a complicated journey to definitive diagnosis, and an unpredictable therapeutic response leading to significant residual symptom burden, reduced quality of life, and worse prognosis. Many patients are refractory to traditional anti-anginal agents, requiring a longitudinal relationship with their physician to test and titrate their medical therapy. Additionally, the long-held belief CMD holds no influence over long-term survival is increasingly being challenged. Fortunately, promising research continues into improved, economically-feasible, and non-invasive methods of diagnosis, and several new agents to bridge the existing treatment gap. Large-scale randomised trials into the effect of these novel drugs and existing treatments on invasive measurements and MACCE would be welcomed by clinicians. In combination with lifestyle modification and aggressive risk factor optimisation, modern medical therapy may improve the quality of life and cardiovascular outcomes of patients living with CMD.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://cdt.amegroups.com/article/view/10.21037/cdt-2025-1-545/rc

Peer Review File: Available at https://cdt.amegroups.com/article/view/10.21037/cdt-2025-1-545/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cdt.amegroups.com/article/view/10.21037/cdt-2025-1-545/coif). D.T.L.W. serves as an unpaid editorial board member of Cardiovascular Diagnosis and Therapy from February 2025 to June 2027. J.M.O.B. reports PhD scholarships from the National Heart Foundation of Australia (No. 107718), the NHMRC, and Australian Government Research Training Program Scholarship from Monash University; a travel fellowship to present PhD work at the American Heart Association from CSANZ; and speaker honoria for an educational event from Pfizer. A.Y. reports honoraria and research support from Abbott Vascular and research support (as equipment) from Philips. J.S. reports honoraria and research support from Abbott Vascular. P.J.P. reports the Future Leaders Fellowship from the National Heart Foundation of Australia (No. 106656); research support from Amgen and Biotronik; consulting fees from Amgen, Eli Lilly, Novartis, Sanofi, and CSL Seqirus; speaker honoraria from Amgen, CSL Seqirus, Novartis, and Novo Nordisk; and support for travel from Novo Nordisk and Amgen. P.J.P. is an unpaid non-executive board director of Corcillum Systems and ACvA. D.T.L.W. reports the Future Leaders Fellowship from the National Heart Foundation of Australia (No. 107170); honoraria and research support from Abbott Vascular; and research support in the form of discounted software access from Medis. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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