Highlight
1) In a prospective, nine‑centre study of 1,001 patients with angina and no obstructive coronary stenosis (FFR >0.80), comprehensive intracoronary testing with adenosine and acetylcholine identified eight reproducible haemodynamic endotypes. 2) Each endotype showed distinct clinical correlates and 100% Delphi agreement on endotype‑specific medical therapy, supporting mechanism‑guided, stratified treatment in ANOCA.
Background and disease burden
Angina with non‑obstructive coronary arteries (ANOCA) — also described as ischemia with non‑obstructive coronary arteries (INOCA) when objective ischemia is present — is common and under‑recognized. Many patients with typical angina have no epicardial obstructive lesion on angiography, yet remain symptomatic and at increased risk for adverse cardiovascular events. Women are disproportionately affected. Diagnosis has historically been challenging because standard angiography does not assess coronary microvascular function, resting flow, or dynamic vasomotor responses, and empirical therapy often fails to control symptoms.
Study design
Miner and colleagues performed a prospective, multicentre study across nine centres in Europe and North America enrolling consecutive patients referred for coronary angiography who had angina (or equivalents), no angiographically severe stenosis, and fractional flow reserve (FFR) >0.80. Coronary functional testing used an intracoronary pressure‑ and temperature‑sensitive sensor with bolus thermodilution to measure coronary flow reserve (CFR) and resistances at rest and after pharmacologic provocations.
Testing protocol highlights:
- Baseline haemodynamic measurements using a sensor/thermodilution technique.
- Adenosine to provoke maximal hyperemia and assess CFR and microvascular resistance.
- Acetylcholine to test endothelial function and provoke epicardial or microvascular spasm.
- Prospective recording of chest pain and electrocardiographic ischemic changes during testing.
The investigators predefined haemodynamic patterns (“endotypes”) based on responses to adenosine and acetylcholine. Clinical correlates for each endotype were evaluated using regression analysis. Finally, a three‑step Delphi process among experts produced consensus recommendations for endotype‑targeted medical therapy.
Key findings
Population: 1001 participants (mean age 62 ± 11 years; 56% female).
Eight distinct haemodynamic endotypes were delineated and their frequencies were:
- High resting coronary blood flow: 195 patients (19%)
- High resistance: 125 patients (13%)
- Compensated high resistance: 112 patients (11%)
- Epicardial coronary spasm: 162 patients (17%)
- Microvascular spasm: 75 patients (8%)
- Endothelial dysfunction: 96 patients (10%)
- Ischaemia without haemodynamic changes: 68 patients (7%)
- Enhanced cardiac nociception: 79 patients (8%)
Additional observations:
- Overlap: More than one endotype occurred in 119 patients (12%).
- Normal responses were recorded in 234 patients (23%).
- Each endotype exhibited distinct clinical correlates on regression analysis, suggesting differing demographic and risk factor profiles across mechanistic groups.
Interpretation of major endotypes
High resting coronary blood flow describes elevated baseline flow values leading to a reduced CFR despite preserved hyperemic flow. High resistance and compensated high resistance indicate increased microvascular resistance either manifest at baseline or compensated during stress. Epicardial and microvascular spasm were distinguished by angiographic epicardial constriction versus ischemic signs without epicardial narrowing during acetylcholine provocation. Endothelial dysfunction was characterized by impaired vasodilatory responses to acetylcholine. Ischemia without haemodynamic changes captured patients with provoked ischemia (symptoms/ECG changes) without measurable flow or resistance abnormalities. Enhanced cardiac nociception denotes heightened symptom perception with limited objective ischaemic correlates.
Delphi consensus on therapy
A three‑step Delphi method among experts achieved unanimous (100% agree/strongly agree) consensus identifying endotype‑specific medical therapies, with each recommendation scoring ≥6 on a Likert scale. Although the study report describes the consensus process and agreement, treatment details were framed as mechanism‑directed strategies (for example, vasodilators for vasospasm, agents improving endothelial function for endothelial dysfunction, and symptom‑directed neuropathic pain strategies for enhanced nociception). The high level of consensus reinforces face validity for tailoring pharmacotherapy to invasive functional test results.
Clinical significance and comparison with prior evidence
This study extends several prior observations. Randomized evidence from the CorMicA trial (Ford et al., 2018) demonstrated that an invasive management strategy guided by coronary function testing improved angina and quality of life in patients with ANOCA. The current multicentre work scales that approach to a much larger cohort and formalizes a reproducible endotype taxonomy grounded in objective haemodynamic measures obtained with established invasive physiology techniques.
Practical implications:
- Mechanism‑specific diagnosis: Integrating adenosine and acetylcholine testing differentiates vasomotor disorders, microvascular resistance abnormalities, and sensory‑dominant presentations — categories that are indistinguishable on angiography alone.
- Therapeutic stratification: The unanimous Delphi consensus supports using endotype information to select drug classes more likely to be effective. This may reduce empirical polypharmacy and accelerate symptom control.
- Research prioritization: The taxonomy provides a framework to power and target randomized trials testing endotype‑directed therapies and to link endotypes to hard outcomes such as hospitalizations and cardiovascular events.
Expert commentary, strengths, and limitations
Strengths of the study include large sample size, multicentre design across continents, standardized invasive physiology methods, prospective symptom and ECG recording during provocation, and application of formal consensus methodology for treatment recommendations.
Limitations and considerations:
- Generalisability: Participating centres were experienced in invasive coronary physiology; implementation in less‑experienced centres may be challenging and may require training and quality control.
- Resource intensity: Invasive testing is time‑consuming, requires pharmacologic provocation, and carries procedural risks, which necessitates careful patient selection.
- Treatment details: The Delphi process yielded unanimous agreement on using endotype‑directed therapies, but long‑term outcome data demonstrating improved hard endpoints for specific regimens were not presented here. Randomized trials per endotype remain necessary.
- Overlap of endotypes: 12% had more than one endotype, highlighting biological complexity and suggesting that multimodal therapy may be needed for some patients.
- Sex differences: The cohort was 56% female, consistent with ANOCA epidemiology, but sex‑specific response to testing and treatment warrants further analysis.
Translational and mechanistic insights
Mechanistically, the study underscores that angina without obstructive coronary disease is rarely a single‑pathway problem. Elevated resting flow and microvascular resistance are physiologically distinct states with different pharmacologic targets. Vasospasm is a hyperreactivity phenomenon involving smooth muscle constriction and endothelial dysfunction, whereas enhanced nociception implicates altered cardiac afferent signaling and central sensitization. Translational efforts should pursue biomarkers and non‑invasive surrogates that reliably predict invasive endotypes and enable broader access to mechanism‑guided care.
Conclusions and practice implications
Miner et al. provide compelling evidence that systematic invasive haemodynamic testing using adenosine and acetylcholine can classify ANOCA into eight reproducible endotypes. This mechanistic taxonomy correlates with clinical features and reached unanimous expert consensus for endotype‑specific medical therapies. The findings support a paradigm shift from empiric symptomatic treatment toward mechanism‑guided, stratified medicine in ANOCA.
Clinicians should consider invasive functional testing when non‑invasive evaluation is inconclusive and symptoms persist despite standard therapy, especially in centers with expertise. Future work should focus on randomized outcome trials testing endotype‑tailored treatments, development of validated non‑invasive diagnostic algorithms, and strategies to disseminate testing capability while maintaining quality and safety.
Funding and clinicaltrials.gov
The published article includes funding and disclosures; readers should consult the original paper for detailed funding sources and potential conflicts of interest. No clinicaltrials.gov identifier was provided in the summary citation above; check the full manuscript for trial registration information.
Selected relevant references
Readers may find the following resources helpful for background and complementary evidence: CorMicA trial (Ford TJ et al., JACC 2018) demonstrating benefits of stratified therapy guided by coronary function testing; ESC guidelines and consensus documents on chronic coronary syndromes and coronary vasomotion disorders for contemporary recommendations on diagnosis and management; and foundational papers on acetylcholine and adenosine testing methodologies for coronary physiology.
Practical takeaways
- Consider invasive coronary function testing in patients with angina and non‑obstructive coronary arteries when symptoms are limiting or diagnosis is uncertain.
- Expect to find heterogeneous mechanistic endotypes; tailor therapy to the dominant mechanism whenever possible (e.g., vasodilators for spasm, agents targeting microvascular dysfunction, and neuromodulatory strategies for enhanced nociception).
- Recognize the need for randomized, endotype‑specific treatment trials and scalable non‑invasive diagnostic approaches.
AI thumbnail prompt
High‑resolution image of a modern catheterization laboratory: an interventional cardiologist reviewing a live angiogram and invasive physiology waveforms on large monitors, a pressure‑temperature sensor guidewire highlighted, and a semi‑transparent overlay of stylized coronary arteries showing microvascular network in contrasting color — clinical, technical, and human elements combined.
