Proposed section structure
For this topic, a clinically appropriate structure is: Highlights; Clinical background and unmet need; Study design and coronary function testing framework; Key results; Clinical interpretation and mechanistic implications; Strengths and limitations; Practice and research implications; Funding, registration, and citation. This structure emphasizes translational relevance while keeping the main findings central.
Highlights
Multiple coronary functional endotypes frequently coexisted in patients with angina and nonobstructive coronary arteries (ANOCA), with 61% of this cohort demonstrating at least 2 abnormalities on comprehensive testing.
Angina burden worsened stepwise as the number of endotypes increased. Mean Seattle Angina Questionnaire (SAQ) summary scores declined from 55.9 in patients with normal coronary function testing to 45.7 in those with 3 endotypes.
After multivariable adjustment, each additional ANOCA endotype was associated with a 3.55-point lower SAQ summary score, supporting a cumulative symptom burden across overlapping coronary mechanisms.
The findings reinforce the value of comprehensive invasive coronary function testing rather than a single-mechanism approach in patients with persistent ischemic symptoms despite nonobstructive epicardial coronary anatomy.
Clinical background and unmet need
ANOCA is increasingly recognized as a major clinical syndrome rather than a reassuring angiographic label. Many patients with exertional or rest angina, ischemia on testing, or both are found to have no flow-limiting epicardial stenosis at angiography. Yet symptoms, recurrent emergency visits, impaired quality of life, and downstream healthcare utilization often remain substantial. Historically, such patients were frequently categorized as having “normal coronaries,” but contemporary work has shown that coronary vasomotor dysfunction, microvascular dysfunction, endothelial dysfunction, and myocardial bridging may all contribute to ischemic symptoms.
The challenge in practice is that these mechanisms often overlap. A patient may have acetylcholine-provoked spasm, impaired adenosine-mediated microvascular reserve, and a functionally important myocardial bridge at the same time. However, the extent to which this overlap translates into worse patient-reported angina has not been well quantified. That question matters because symptom burden is one of the most clinically meaningful outcomes in ANOCA, often driving medication escalation, repeat testing, and quality-of-life impairment.
Coronary function testing (CFT) provides a mechanistic framework for ANOCA. Endothelium-dependent abnormalities are typically probed with acetylcholine provocation to identify epicardial or microvascular spasm and endothelial dysfunction. Endothelium-independent abnormalities are commonly assessed using adenosine-based physiology, including impaired coronary flow reserve or elevated microvascular resistance, which suggest coronary microvascular dysfunction. In selected patients, intravascular imaging and hemodynamic assessment can also identify functionally significant myocardial bridging, another underappreciated cause of ischemia and angina.
The study by Wong and colleagues addresses a practical and clinically important issue: whether the number of abnormal endotypes identified during comprehensive CFT correlates with the severity of angina symptoms.
Study design and methods
This was a cross-sectional observational study conducted at Stanford Hospital, including patients with suspected ANOCA who underwent comprehensive invasive CFT between August 2007 and February 2025. Data analysis occurred from March 2025 through May 2025. The study population comprised 485 patients with a mean age of 52 years; 73% were women, consistent with prior ANOCA cohorts in which women are disproportionately represented.
The investigators evaluated three broad ANOCA endotype domains. First, endothelium-dependent abnormalities were assessed using acetylcholine provocation testing. Second, endothelium-independent abnormalities were assessed with adenosine-mediated physiology testing. Third, myocardial bridging was evaluated using intravascular ultrasound and hemodynamic testing to identify a bridge that was functionally significant rather than merely anatomically present.
The primary outcome was the association between the number of endotypes identified and angina burden. Symptom burden was quantified using the Seattle Angina Questionnaire, a validated patient-reported instrument widely used in ischemic heart disease research. The SAQ summary score integrates angina frequency, physical limitation, and quality-of-life domains, with lower scores indicating worse symptom burden.
The central exposure of interest was not simply the presence or absence of any abnormality, but the cumulative number of endotypes detected on CFT. This is an important design choice because it moves ANOCA phenotyping beyond mutually exclusive categories and closer to the biologic reality of overlapping mechanisms.
Key results
CFT abnormalities were common, and multiple abnormalities were more common than isolated findings
Only 36 of 485 patients, or 7%, had no abnormality identified on comprehensive testing. By contrast, 150 patients (31%) had 1 endotype, 215 patients (44%) had 2 endotypes, and 84 patients (17%) had 3 endotypes. In other words, 299 patients, representing 62% of the cohort when rounded from the reported values, had at least 2 mechanistic abnormalities.
This distribution is clinically striking. It suggests that, in a referral population undergoing comprehensive invasive evaluation for suspected ANOCA, isolated single-pathway disease is less common than combined vasomotor and microvascular abnormalities. For clinicians, this finding argues against anchoring on one positive test result and stopping there.
Individual endotypes had similar average angina burden
Mean SAQ summary scores were broadly similar among patients with an endothelium-dependent abnormality (50.5 [18.3]), an endothelium-independent abnormality (49.3 [19.9]), and myocardial bridging (49.8 [19.2]). This suggests that no single endotype dominated symptom severity in an obvious way when considered in isolation.
That similarity is useful because it implies that clinicians should not assume, for example, that vasospasm is inherently more symptomatic than microvascular dysfunction or vice versa. From the patient perspective, different mechanisms may produce a comparably heavy symptom burden.
Angina burden worsened as the number of endotypes increased
The most important result was the graded inverse relationship between endotype count and SAQ score. Mean SAQ summary scores were 55.9 (17.6) in patients with normal CFT findings, 53.8 (17.7) in those with 1 endotype, 51.2 (18.3) in those with 2 endotypes, and 45.7 (20.0) in those with 3 endotypes. The overall trend was statistically significant (P = .003).
Although the absolute score differences may appear numerically modest at first glance, the separation between normal CFT and 3 endotypes was approximately 10 points. On the SAQ, differences of this magnitude are generally considered clinically meaningful in chronic coronary syndromes, particularly when viewed at the population level. The pattern is also monotonic, strengthening the inference that symptom burden accumulates as coronary pathophysiology becomes more complex.
Adjusted analysis confirmed a cumulative association
In multivariable analysis, each additional endotype identified on CFT was associated with a lower SAQ summary score, with a beta coefficient of -3.55 (95% CI, -5.56 to -1.54; P < .001). This indicates that the association persisted after accounting for potential confounders included by the investigators.
Clinically, the adjusted result suggests that the observed relationship is not merely a reflection of demographic differences or referral bias alone. Rather, there appears to be an independent link between mechanistic complexity and symptom burden.
Clinical interpretation and mechanistic implications
The study supports a multimorbidity model of coronary dysfunction in ANOCA. Rather than representing a single disease entity, ANOCA often appears to be a layered syndrome in which endothelial dysfunction, microvascular dysfunction, vasospasm, and dynamic extrinsic compression from myocardial bridging may coexist. Each mechanism may reduce ischemic threshold through distinct but interacting pathways. Endothelial dysfunction may predispose to abnormal vasoconstriction; microvascular dysfunction may impair vasodilator reserve during stress; myocardial bridging may create phasic systolic and sometimes diastolic compromise; and vasospasm may superimpose episodic ischemia at rest.
When several of these are present together, patients may experience more frequent symptoms, greater physical limitation, and less predictable triggers. That biologic plausibility aligns well with the observed stepwise decline in SAQ scores as endotype number rises.
The findings also have implications for diagnostic strategy. If symptom burden reflects overlapping mechanisms, then limited testing may underestimate disease complexity and lead to incomplete treatment. A patient diagnosed only with microvascular dysfunction, for instance, may not respond optimally if concurrent vasospasm or a significant bridge is missed. This is especially relevant because pharmacologic management differs by endotype. Calcium channel blockers and nitrates are central for vasospastic disease, while beta-blockers may be useful in myocardial bridging but may be less effective or even undesirable in some vasospastic phenotypes. Renin-angiotensin system inhibition and statins may help endothelial dysfunction in selected patients, whereas tailored antianginal therapy is often needed for microvascular disease.
In this sense, the study complements the mechanistic precision-medicine framework introduced by prior work such as the CorMicA trial, which showed that stratified medical therapy informed by invasive coronary function testing improved angina and quality of life. The present study extends that literature by emphasizing not just identification of any abnormality, but recognition of cumulative endotype burden.
Strengths of the study
A major strength is the use of comprehensive invasive phenotyping within a single experienced center. The inclusion of acetylcholine testing, adenosine-based physiology, and bridge-specific imaging and hemodynamic assessment provided a broad view of potential ANOCA mechanisms. This is more informative than studies limited to a single physiologic axis.
The cohort size of 485 patients is substantial for an invasive ANOCA study, and the patient-reported outcome was clinically meaningful. The SAQ remains one of the best validated tools for symptom burden in chronic coronary syndromes. The predominance of women is also important because women have historically been underrecognized in ischemic heart disease research but are highly represented in ANOCA populations.
Limitations and caution in interpretation
Several limitations should temper clinical extrapolation. First, the study was cross-sectional. It demonstrates association, not causation. Although greater endotype burden was linked to worse angina, the data cannot prove that each additional abnormality directly caused lower SAQ scores or that treating all abnormalities would proportionally improve symptoms.
Second, this was a single-center referral cohort from Stanford Hospital. Patients referred for comprehensive CFT may represent a more symptomatic, diagnostically challenging population than typical community practice. Generalizability to broader ANOCA populations, including less symptomatic patients or those evaluated noninvasively, is uncertain.
Third, symptom burden in ANOCA is multifactorial. Psychological distress, autonomic dysfunction, deconditioning, overlapping noncardiac chest pain syndromes, and medication effects may all influence SAQ scores. Multivariable adjustment helps but cannot eliminate residual confounding.
Fourth, the abstract does not provide granular definitions of each abnormal endotype threshold, nor does it report domain-specific SAQ analyses, sex-stratified results, or interactions between specific endotype combinations. Those details will matter for translation into practice. For example, it would be useful to know whether vasospasm plus microvascular dysfunction is especially symptomatic compared with myocardial bridging plus microvascular dysfunction.
Finally, the study focuses on angina burden rather than hard cardiovascular outcomes. Symptom burden is highly relevant, but the prognostic implications of accumulating endotypes remain to be clarified.
Practice implications
For clinicians evaluating persistent angina with nonobstructive coronary arteries, this study reinforces several practical points. First, a normal angiogram should not end the diagnostic process when symptoms remain convincing for ischemia. Second, ANOCA is often mechanistically heterogeneous; identifying one abnormal pathway does not exclude others. Third, patient-reported symptoms may provide a clue to hidden complexity, as heavier angina burden may reflect multiple coexisting functional abnormalities.
These findings also support broader implementation of invasive coronary function assessment in appropriately selected patients, particularly at centers with expertise in acetylcholine provocation and microvascular physiology. The goal is not merely diagnosis for its own sake, but more precise treatment selection and more credible counseling for patients who have often been told that “nothing is wrong.”
At a systems level, the study adds to the argument that ANOCA care should move from exclusion-based management to mechanism-based management. That transition has implications for cath lab protocols, operator training, reimbursement, and guideline adoption.
Research implications
Future studies should test whether treatment strategies tailored to multiple simultaneous endotypes yield greater symptom relief than approaches targeting only the dominant abnormality. Longitudinal cohorts are also needed to determine whether cumulative endotype burden predicts hospitalization, recurrent testing, functional status, or cardiovascular events.
Additional work should examine sex-specific and age-specific patterns, as well as reproducibility across centers. Standardized definitions for endotype combinations and integration with noninvasive imaging, endothelial biomarkers, and possibly machine learning phenotyping could further refine risk stratification and treatment selection.
Funding and clinicaltrials.gov
The abstract provided does not report a funding source. A ClinicalTrials.gov registration number is not listed in the abstract, and this study appears to be an observational cross-sectional analysis rather than a registered interventional trial.
Conclusion
This JAMA Cardiology study provides an important message for contemporary ischemia care: in ANOCA, coronary dysfunction is commonly plural rather than singular, and that complexity matters clinically. Patients with more coexisting ANOCA endotypes had progressively worse angina, with each additional abnormality associated with a meaningful decrement in SAQ summary score. The findings support comprehensive coronary function testing as a tool not only for diagnosis but also for understanding why some patients remain highly symptomatic despite the absence of obstructive epicardial disease. The next step for the field is to determine whether identifying and treating this layered coronary physiology can produce sustained improvements in symptoms and outcomes.
References
1. Wong CCY, Pargaonkar VS, Dawson LP, Penumaka RR, Rehan R, Yong ASC, Ng MKC, Honda Y, Fearon WF, Schnittger I, Tremmel JA. Multiple Endotypes and Angina Burden in Patients With Nonobstructive Coronary Arteries. JAMA Cardiology. Published online May 27, 2026. PMID: 42201701.
2. Ford TJ, Stanley B, Good R, Rocchiccioli P, McEntegart M, Watkins S, Shaukat A, Lindsay M, Robertson K, Hood S, McGeoch R, McDade R, Spence MS, Ariti C, Sidik N, McCartney P, Corcoran D, Collison D, Rush C, Carrick D, Oldroyd KG, Berry C. Stratified Medical Therapy Using Invasive Coronary Function Testing in Angina: The CorMicA Trial. Journal of the American College of Cardiology. 2018;72(23 Pt A):2841-2855.
3. Knuuti J, Wijns W, Saraste A, Capodanno D, Barbato E, Funck-Brentano C, et al. 2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes. European Heart Journal. 2020;41(3):407-477.
4. Kunadian V, Chieffo A, Camici PG, Berry C, Escaned J, Maas AHEM, et al. An EAPCI Expert Consensus Document on Ischaemia with Non-Obstructive Coronary Arteries in collaboration with European Society of Cardiology Working Group on Coronary Pathophysiology and Microcirculation endorsed by Coronary Vasomotor Disorders International Study Group. European Heart Journal. 2020;41(37):3504-3520.
5. Taqueti VR, Di Carli MF. Coronary Microvascular Disease Pathogenic Mechanisms and Therapeutic Options: JACC State-of-the-Art Review. Journal of the American College of Cardiology. 2018;72(21):2625-2641.