Highlights
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CMD is a key pathophysiological mechanism underlying ANOCA.
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The precision and reproducibility of bolus thermodilution remain limited.
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MRR is a novel index for evaluating coronary microvascular function.
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MACCE rates were compared between ANOCA patients with and without CMD.
ABSTRACT
Introduction
Coronary microvascular dysfunction (CMD) is increasingly recognized as an important cause of anginal symptoms and poor outcomes. Angina with nonobstructive coronary arteries (ANOCA) is often related to CMD. While physiological assessment of microcirculatory function by coronary bolus thermodilution is widely practiced, more precise and reproducible methodology as well as systematic assessment are necessary. Recently, absolute flow measurements by coronary continuous thermodilution and the concept of Microvascular Resistance Reserve (MRR) have been introduced.
Aim
The European microCirculatory Resistance and Absolute Flow Team (EuroCRAFT) registry aims to compare major adverse cardiac and cerebrovascular events (MACCE)-rates in patients with and without CMD based on MRR at 1-year follow-up.
Methods
This prospective international, investigator-initiated, multicenter study is enrolling patients with stable chest pain suggestive of angina and nonobstructive epicardial coronary arteries on invasive coronary angiography, defined as fractional flow reserve >0.80. Patients will undergo coronary angiography and microvascular assessment using bolus and continuous thermodilution methods. The primary endpoint is to compare the rate of MACCE in patients with and without CMD assessed with MRR at 1 year. Based on the sample size estimation, 671 patients are initially planned for enrollment.
We hypothesize that coronary continuous thermodilution-derived MRR has superior prognostic value for MACCE at 1 year compared to bolus thermodilution-derived microvascular metrics.
Results
Study recruitment started in September 2022 and has been completed in May 2025, resulting in a total of 678 patients enrolled.
Background
While epicardial stenosis has been considered the primary cause of symptomatic ischemic heart disease, a substantial proportion of patients with anginal symptom exhibit no evidence of obstructive epicardial disease, suggesting that microvascular or vasomotor dysfunction may be an underlying cause of the symptoms. ,
The coronary microcirculation comprises small resistance vessels (<400 μ m in diameter), which are not visualizable by conventional coronary angiography Its primary function is to regulate blood flow in response to the metabolic demands of the cardiac muscle. Disturbances in the microcirculation leading to impaired blood flow to the myocardium are referred to as coronary microvascular dysfunction (CMD).
CMD is increasingly recognized as an important cause of chest pain and a determinant of clinical outcomes in patients with angina and nonobstructive coronary arteries (ANOCA), in whom the diagnosis of classical “coronary artery disease” ie, atherosclerotic disease was initially considered. ,
The reported prevalence of CMD is highly variable and mainly depends on the definition and the methods of assessment. The presence of CMD is generally considered when coronary flow reserve (CFR) is ≤2.5 in the presence of suggestive chest pain and nonobstructive epicardial coronary arteries However, the methods to measure coronary flow in humans are inaccurate and poorly reproducible. Furthermore, the very concept of CFR is debatable in microcirculatory disease, as it is influenced by systemic hemodynamic factors, including heart rate, blood pressure, and the rate–pressure product. Establishing an unequivocal diagnosis of CMD without over-diagnosing this condition (ie, reaching high diagnostic specificity) is paramount in these patients because CMD can be associated with debilitating symptoms that can be improved by medications when the right patients are targeted
Currently, the Index of Microcirculatory Resistance (IMR) derived from bolus thermodilution method is considered the standard of reference due to its accessibility and simplicity. ,,, Yet, IMR is semi-quantitative, and its clinical value is not well validated in stable patients. In addition, IMR expresses only microcirculatory resistance during hyperemia. There is therefore an unmet need to have access to more accurate and reproducible metrics of the microcirculation.
We introduced coronary continuous thermodilution as a means of measuring absolute coronary blood flow and absolute microvascular resistance. The practicalities to perform such measurements have been recently described in detail by Belmonte et al The accuracy of continuous thermodilution-derived flow measurements has been validated against 15 H 2 O-PET flow measurements Furthermore, we recently proposed a new metric, Microvascular Resistance Reserve (MRR), to specifically assess microvascular function In line with the accuracy of continuous thermodilution, the diagnostic performance of MRR in identifying CMD has also been reported to be favorable
The present study was designed to assess the relationship between microvascular assessment by continuous thermodilution-derived MRR and both symptoms and clinical events in patients with ANOCA.
Methods
Study design
The European Microcirculatory Resistance and Absolute Flow Team (Euro-CRAFT Registry) is an investigator-initiated prospective, multicenter, international registry (NCT05805462). The patients were enrolled from 19 expert cardiovascular centers across Europe. The inclusion and exclusion criteria are as shown in Table 1 . Briefly, we enrolled consecutive patients in whom a clinically indicated physiological assessment of the microcirculatory function was performed.
Table 1
Inclusion and exclusion criteria.
| Inclusion criteria | |
|---|---|
| 1. | Age ≥18 years old |
| 2. | Stable patients presenting with chest pain suspected of angina pectoris or other symptoms indicative of ischemic heart disease, and possessing nonobstructive epicardial coronary arteries as confirmed by invasive coronary angiography |
| 3. | Diameter stenosis of ≤50% and FFR>0.80 |
| 4. | Patients for whom coronary angiography and physiological assessment using bolus and continuous thermodilution methods are clinically indicated |
| Exclusion criteria | |
| 1. | Unable to provide written informed consent |
| 2. | Unstable hemodynamics |
| 3. | Ongoing chest pain |
| 4. | Previous CABG |
| 5. | Moderate to severe valvular heart disease |
| 6. | Uncontrolled or recurrent ventricular tachycardia |
| 7. | Active liver disease or hepatic dysfunction, defined as aspartate aminotransferase or alanine aminotransferase >3 times the upper limit of normal |
| 8. | Comorbidity with life expectancy ≤2 years |
| 9. | Severe renal dysfunction, defined as an eGFR <30 mL/min/1.73 m 2 |
| 10. | Current participation in another investigational drug or device clinical study |
| 11 | Presence of other anatomic or comorbid conditions, or other medical, social, or psychological conditions that, in the investigator’s opinion, could limit the subject’s ability to participate in the clinical investigation or to comply with follow-up requirements, or impact the scientific soundness of the clinical investigation results |
CABG, coronary artery bypass graft; eGFR, estimated glomerular filtration rate; FFR, fractional flow reserve.
Study population
The study population consists of stable patients who report chest pain suggestive of angina pectoris, or other symptoms suggestive of ischemic heart disease (IHD), and have nonobstructive epicardial coronary arteries as defined by a diameter stenosis ≤50% by invasive coronary angiography and a fractional flow reserve (FFR) value greater than 0.80. The details of the inclusion/exclusion criteria are described in Table 1 . Patients with a history of heart failure were not explicitly excluded and could be enrolled. However, patients whose clinical condition was considered by the investigator to potentially impact data integrity could be excluded at the physician’s discretion. Any clinical scenarios, including those related to acute coronary syndrome (ACS), that lead a physician to evaluate the function of the coronary microvasculature are also eligible for inclusion. Even in the acute setting, stabilized patients, including those with myocardial infarction with nonobstructive coronary arteries, were enrolled if free of ongoing chest pain, and coronary function testing was performed at the discretion of the investigators. Baseline characteristics including age, sex, race, hypertension, diabetes mellitus, smoking history, and history of myocardial infarction or percutaneous coronary intervention were collected at the time of enrollment.
Primary and secondary objectives and endpoints
The primary objective of this study is to assess the rate of major adverse cardiac and cerebrovascular events (MACCE) in patients with and without CMD based on MRR at 1 year ( Table 2 ). The primary endpoint will be MACCE, defined as the composite of a cardiovascular death, myocardial infarction, revascularization, angina and heart failure-related hospitalization and stroke.
Table 2
Study endpoints.
| Primary endpoint | The rate of MACCE at 1 year defined as cardiovascular death, myocardial infarction, revascularization, angina and heart failure-related hospitalizations, and stroke, between patients with and without CMD based on MRR at 1 year follow-up. |
| Secondary endpoints | Relationship between MACCEs and each thermodilution-derived microvascular function metrics including absolute hyperemic flow, absolute hyperemic resistance, IMR and CFR. |
| Relationship between the presence and severity of angina, assessed by SAQ- 19, and each individual thermodilution-derived metrics of microvascular function including absolute hyperemic flow, absolute hyperemic resistance, IMR and CFR. | |
| Relationship between the presence and severity of angina and each individual thermodilution-derived metrics of microvascular function including absolute hyperemic flow, absolute hyperemic resistance, IMR and CFR. | |
| Safety of continuous and bolus thermodilution measurements, as assessed by adverse event registration. | |
| To determine cut-off values of thermodilution-derived indices. | |
| To assess the prevalence of CMD based on MRR in patients with angina and nonobstructive coronary artery disease. |
CFR, coronary flow reserve; CMD, coronary microvascular dysfunction; IMR, index of microcirculatory resistance; MACCE, major adverse cardiac and cerebrovascular events; MRR, microvascular resistance reserve.
Angina-related hospitalization was defined in accordance with criteria for unstable angina requiring admission—ischemic chest pain or equivalent symptoms leading to unplanned admission, accompanied by objective evidence of myocardial ischemia and negative cardiac biomarkers Heart failure–related hospitalization was defined as an admission for worsening heart failure symptoms or signs requiring intensified oral therapy or initiation of intravenous treatment
The secondary objectives are:
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To assess the relationship between MACCE and each thermodilution-derived metrics of microvascular function.
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To assess the relationship between the presence or severity of angina assessed by Seattle Angina Questionnaire (SAQ-19) and each thermodilution-derived metric.
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To assess the feasibility and safety of continuous and bolus thermodilution measurements.
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To determine normal range and clinically useful cut-off values of continuous thermodilution-derived indices.
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To assess the prevalence of CMD based on MRR in patients with ANOCA.
Catheterization laboratory protocol for bolus and continuous thermodilution
A left heart catheterization will be performed as a part of the clinically indicated diagnostic procedure. The access route for the procedure may be either transfemoral or transradial, depending on the institutional protocol.
As part of the diagnostic procedure, coronary pressure measurement (including FFR) and flow measurement using both bolus and continuous thermodilution methods in any coronary vessel will be mandatory. The assessment will be performed with Pressure-wire X (Abott Vascular, St Paul, MN, USA) within the context of standard of care. The choice of coronary arteries for assessment will be left to the operator’s discretion. Yet, if only 1 coronary artery can be investigated, assessment of the left anterior-descending artery will be recommended. The principle and techniques of coronary thermodilution have been previously described In brief, through 6 Fr catheter, a pressure/temperature sensor-tipped wire connected to dedicated software for tracing analysis (Coroflow Cardiovascular System, Coroventis Research AB, Uppsala, Sweden) will be advanced in the distal part of the coronary artery. The performance of acetylcholine test to look for a spastic component will be encouraged but not mandated per protocol. The sequence of testing in relation to physiological measurements was left to the discretion of each institution. When performed, the results will be prospectively registered. Of the 19 participating sites, 18 (94.7%) conducted at least 1 spasm provocation test. Vasodilators (nitrates, beta-blockers, and calcium-channel blockers) were in principle withheld before testing, although the exact duration and scope of discontinuation were left to the discretion of each site, in line with recent recommendations suggesting interruption
Coronary bolus thermodilution:
The foundational concepts for calculating CFR and the IMR using bolus thermodilution have been detailed previously. ,, To perform bolus thermodilution, 3 boluses of each 3 ml of normal saline at room temperature is briskly injected through the guide catheter thus producing a thermodilution curve, and the results of the calculated mean transit times (T mn ) are averaged. Subsequently, hyperemic agents are administered to induce hyperemia. Once steady state is achieved, 3 additional bolus injections of saline are administered to measure T mn during hyperemia. From the bolus thermodilution curves the mean transit times (T mn ) of resting and hyperemic flows are derived and used to CFR and IMR as follows:
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