Utilizing Invasive Coronary Functional Testing in a Coronary Microvascular and Vasomotor Dysfunction Program: Methods and Considerations

Abstract

Background:

Coronary microvascular and vasomotor dysfunction (CMVD) is associated with a threefold increased risk of major adverse cardiovascular events (MACE) and is the primary mechanism responsible for angina/ischemia in patients with nonobstructive coronary artery disease (ANOCA/INOCA). Proper assessment for CMVD is vital to provide targeted treatment and improve patient outcomes. Invasive coronary functional testing (ICFT) is the “gold standard,” for CMVD assessment and can be used to diagnose all endotypes. However, there is a lack of standardization for ICFT protocols and use in the treatment of CMVD.

Aims:

To provide a comprehensive overview of ICFT protocols utilized at the Christ Hospital Womens Heart Center (TCH-WHC).

Methods:

Here, we outline our standard operating procedures for ICFT utilized at TCH-WHC, including the procedures two main methods: Doppler and Thermodilution. We describe our structured approach for ICFT referral and postdiagnostic clinical management utilized at The Christ Hospital Women's Heart Center (TCH-WHC) CMVD program. We then quantified how ICFT has contributed to growth of the TCH-WHC.

Results:

From October of 2020 until July of 2024, a total of 422 patients have undergone ICFT at TCH-WCH, 64% were performed via the Doppler protocol and 36% were performed via the Thermodilution protocol. Based on exclusive endotype categories, 19% had an endothelial-independent CMD alone, 19% had endothelial-dependent CMD or microvascular VSA alone, 3% had epicardial VSA alone, 42% had mixed disease (any combination of the above categories), and 17% had a normal ICFT.

Conclusions:

ICFT provides opportunity to provide diagnostic clarity and optimize medical treatment for CMVD. TCH-WHC's structured approach for ICFT referral and protocol for conducting comprehensive ICFT which has been vital for the growth of our specialized CMVD program.

1 ∣. Introduction

Coronary microvascular and vasomotor dysfunction (CMVD) is defined as structural or functional abnormalities to the coronary microvasculature and is associated with an increased risk of major adverse cardiovascular events (MACE) and mortality [1-4]. CMVD is the predominant pathophysiological mechanism in patients with angina or ischemia with nonobstructive coronary artery disease (ANOCA/INOCA), affecting nearly 4 million individuals in the United States alone, 70% of which are women [5]. CMVD is also implicated in a range of cardiovascular diseases including myocardial infarction with nonobstructive coronary artery disease (MINOCA), heart failure with preserved ejection fraction (HFpEF) [6], Takotsubo cardiomyopathy [7], myocardial bridging [8], acute coronary syndromes [9], and refractory angina postrevascularization (percutaneous coronary intervention [PCI] or coronary artery bypass grafting [CABG]) in patients with history of obstructive coronary artery disease (CAD) [10, 11]. Proper assessment for CMVD is vital to provide targeted treatment and improve patient outcomes, and reduce economic burden [12, 13].

The 2021 American College of Cardiology/American Heart Association (ACC/AHA) Chest Pain guidelines and the 2024 European Society of Cardiology (ESC) guidelines for the Management of Chronic Coronary Syndromes recommend assessment of CMVD in patients with ANOCA/INOCA [14, 15]. Although, evidence of stress-induced ischemia on cardiac stress testing is highly specific for CMVD and is used to differentiate INOCA from ANOCA patients, noninvasive stress testing modalities have poor sensitivity for identifying CMVD [16, 17]. Noninvasive modalities (Class 2A ACC/AHA and Class 2B ESC guidelines), including myocardial perfusion stress positron emission tomography (PET), stress cardiac magnetic resonance imaging (CMRI), and stress echocardiogram with Doppler assessment of left anterior descending artery (LAD) are limited to the evaluation of endothelial-independent CMD [18]. Invasive Coronary Functional Testing (ICFT) is the “gold standard” technique (Class 2A ACC/AHA and 1B ESC) [14, 15] for the diagnosis of all CMVD endotypes: endothelial-independent CMD, endothelial-dependent CMD, and vasomotor dysfunction (microvascular vasospastic angina [VSA] and epicardial VSA). The Coronary Microvascular Angina (CORMICA) trial demonstrated the benefits of ICFT in the assessment of CMVD in ANOCA/INOCA patients, showing that an ICFT-confirmed diagnosis of CMVD in combination with targeted therapies by endotypes significantly improved patient outcomes [13].

The CMVD program at The Christ Hospital Heart and Vascular Institute was established in October 2020 as a sex-neutral program within the Women's Heart Center (TCH-WHC). The CMVD program is also a part of the Comprehensive Angina Relief (CARE) program in collaboration with the Chronic Total Occlusions (CTO) program that extends to patients with refractory angina postrevascularization. The CMVD program at TCH-WHC has become one of the fastest-growing programs in the United States, with specialized clinical care, diagnostic capabilities, and clinical research. Close collaboration with interventional cardiologists who perform ICFT is a core component of the integrative approach toward the diagnosis and treatment of CMVD at TCH-WHC. The simultaneous CCI publication entitled “Developing a Women's Heart Center with a Specialization in Coronary Microvascular and Vasomotor Dysfunction (CMVD): If You Build It, They Will Come,” is focused on how to develop a comprehensive CMVD program. This review builds on that publication and aims to provide an overview of when to refer for ICFT, specific ICFT protocols used, and the role of ICFT in the diagnosis and treatment of CMVD.

1.1 ∣. Referral to ICFT

1.1.1 ∣. ICFT in ANOCA/INOCA Patients

At TCH-WHC, ICFT is not performed ad hoc when routine coronary angiography demonstrates an absence of obstructive CAD. For patients who have undergone coronary evaluation within 5 years demonstrating an absence of obstructive CAD, either by coronary angiography or coronary computed tomography angiogram (CCTA), or patients in which obstructive CAD is thought to be unlikely based on negative stress testing, the decision to proceed with noninvasive testing or ICFT for assessment of CMVD depends on angina severity and response to empirical treatment (Figure 1). Broadly, angina (chest pain/pressure, dyspnea on exertion, jaw pain, and associated symptoms) in ANOCA/INOCA can be categorized as exertional, at rest or random, or mixed symptoms, with the severity of angina assessed using the Canadian Cardiovascular Society (CCS) angina scale [10]. For ANOCA/INOCA patients with mild to moderate anginal symptoms (CCS I/II), noninvasive testing with stress PET or CMRI is used to assess endothelial-independent CMD as the initial step in CMVD evaluation [19]. In patients with negative noninvasive testing for endothelial-independent CMD, but with high suspicion for CMVD and/or failure to improve symptoms with empiric therapy, referral to ICFT is made for a complete evaluation of endothelial-dependent CMD, microvascular VSA, and epicardial VSA. In ANOCA/INOCA patients with severe symptoms (CCS III/IV) despite medical therapy and in patients with mixed symptoms (exertional and rest angina), referral to ICFT occurs as part of the initial evaluation. In patients with MINOCA in which epicardial VSA is a suspected culprit, referral to ICFT occurs as part of the initial evaluation after the MINOCA event.

FIGURE 1 ∣.

Diagnostic approach and referral to invasive coronary functional testing in ANOCA/INOCA patients. BB, beta blockers; CCB, calcium channel blockers; RAS-I, renin angiotensin aldosterone system inhibitors.

1.1.2 ∣. ICFT in Special Populations

While most patients referred to ICFT have ANOCA/INOCA, there are other patient populations where ICFT is beneficial for the evaluation of CVMD. In patients with refractory angina with a history of obstructive CAD despite revascularization, who currently have patent epicardial arteries and are not eligible for additional revascularization, CMVD assessment should be considered [10]. Additionally, refractory symptoms in HFpEF patients may warrant ICFT, as there is a strong overlap between CMD and HFpEF [6]. For patients with dyspnea on exertion (DOE) and suspected of HFpEF, a right heart catheterization is performed at the time of ICFT for a complete evaluation. Angina-targeted therapy in patients with HFpEF and CMVD can lead to improvements in CCS and New York Heart Association class [20]. Other patient populations with refractory angina that have been referred for ICFT for assessment of CMVD include patients with clinically significant myocardial bridging [8, 21], post-COVID syndrome [22], recurrent Takotsubo cardiomyopathy [7], and selected patients with hypertrophic cardiomyopathy [23, 24], postural orthostatic tachycardiac syndrome, and postspontaneous coronary artery dissection [25].

1.2 ∣. Systematic Approach to Perform ICFT

There are two predominant methods to perform ICFT for CMVD assessment, and both have been successfully utilized at TCH-WHC: Doppler and Thermodilution. The Doppler method utilizes the Doppler-tipped guidewire (ComboWire XT or Flowire, Philips Volcano Corporation, San Diego, CA, USA), and the bolus Thermodilution method utilizes a pressure-temperature sensor guidewire (PressureWire X, Abbott Vascular, Santa Clara, CA, USA) [26, 27]. In late 2023, the Doppler-tipped guidewire became temporarily unavailable; however, a new wire by Philips Volcano Corporation is expected to be approved in 2025. A newer method of continuous Thermodilution is emerging but is infrequently used in the United States [28]. We summarize the detailed protocols for both methods utilized at TCH-WHC. ICFT endotype descriptions, including diagnostic cutoffs and physiological responses by method are summarized in Table 1.

TABLE 1 ∣.

Endotype descriptions.

CMVD endotypes	Pathophysiology	Diagnostic cut off	Technique
Adenosine testing
Endothelial independent CMD	Impaired vasodilation endothelial independent dysfunction	CFR < 2.5 HMR > 2.5 IMR > 25 MRR < 2.7	Doppler/thermodilution doppler thermodilution thermodilution
Acetylcholine testing
Endothelial dependent CMD	Impaired vasodilation endothelial dependent dysfunction	<50% ΔCBF Δ coronary diameter (%)	Doppler doppler/thermodilution
Microvascular vasospastic angina (MVA)	Abnormal microvascular vasoconstriction	<90% coronary constriction, Ischemic ECG, Angina	Doppler/thermodilution
Epicardial vasospastic angina (VSA)	Abnormal epicardial vasoconstriction	>90% coronary vasospasm, ischemic ECG, angina	Doppler/thermodilution

1.2.1 ∣. Drug Preparation

Close collaboration with the pharmacy department is essential to develop a consistent protocol for the preparation of Adenosine, acetylcholine (ACH), and Nitroglycerin. Dosing, infusion rates, and volumes of all agents utilized in ICFT are summarized in Table 2. Briefly, ACH is prepared by a series of dilutions as follows:

TABLE 2 ∣.

ICFT drug concentrations and infusion rates.

Method	Method of delivery	Drug concertation	Infusion rate (per minute)	Total infusion time	Total dose
Acetylcholine (ACH)
Doppler and thermodilution	IC pump infusion	2.68 μg/mL of D5W	0.75 mL	2.5 min	5 μg
	IC pump infusion	23.6 μg/mL of D5W	0.75 mL	2.5 min	44 μg
	IC pump infusion	23.6 μg/mL of D5W	1.875 mL	2.5 min	108 μg
Thermodilution	IC push by hand	23.6 μg/mL of D5W	8.5 mL total	1 mina	200 μg
Nitroglycerin
Doppler and thermodilution	IC push by hand	50 μg/mL Saline	4 mL total	20–30 sa	200 μg
Adenosine
Doppler	IC push by hand	6 μg/mL Saline	3 mL total	1 mina	18 μg
	IC push by hand	6 μg/mL Saline	12 mL total	1 mina	72 μg
Thermodilution	IV pump infusion	90 μg/mL Saline	140 μg/kg	2 min 45 s	300 μg/kg
	IC push by hand	6 μg/mL saline	12 mL total	1 mina	72 μg

Note: Total dosages rounded to nearest whole number.

^aInfusions by hand are approximations.

1. 20 mg of ACH powder for ophthalmic solution (Michol-E) is reconstituted with 2 mL Dextrose 5% solution (D5W).

2. From this solution (10 mg ACH/1 mL D5W), 0.91 mL (9.1 mg ACH/1 mL D5W) is diluted with 42 mL of D5W to form a 212 μg ACH/mL D5W solution (ACH stock solution).

3. 10 mL of ACH stock solution is diluted with 80 mL of D5W, for a final concentration of 23.6 μg/mL of D5W.

Due to the recent shortages in ACH worldwide and the need for compounding, special considerations are made to maximize the yield of ACH. At THC-WHC, all ICFTs are performed on 1 or 2 specific days per week to be able to use one vial of ACH to perform all cases. The final ACH solution is stable for at least 6 h at room temperature (further stability is likely, but additional quality assurance testing is necessary). In the absence of ACH availability, ICFT is not performed.

1.2.2 ∣. Preprocedure and Diagnostic Angiography

At THC-WHC all ICFTs are performed as outpatient scheduled procedures and patients are instructed to withhold antianginal cardiac medications (i.e. beta-blockers, calcium channel blockers, ranolazine, and nitrates) and caffeine for 48 h before their procedure. Minimal sedation with Versed (1 mg/mL IV) and Fentanyl (50 μg IV) is used to ensure patient comfort while allowing them to communicate anginal symptoms during ACH provocation testing. Patients are monitored with continuous electrocardiogram (ECG) for bradycardia, atrioventricular block, and tachyarrhythmias throughout ICFT. Therapeutic anticoagulation (2000 units IV heparin) is maintained throughout the procedure per standard of care to prevent catheter or wire thrombosis [29]. ICFT is performed through femoral access given the possibility of radial artery spasm; however, radial access is used in other centers and throughout Europe [30]. Before initiation of CMVD testing, a diagnostic angiogram in the right and left coronary arteries is performed to evaluate for the presence of obstructive CAD and/or baseline coronary vasoconstriction/spasm. Patients are monitored for ischemic ECG changes and anginal symptoms throughout ICFT.

1.2.3 ∣. CMVD Assessment Using the Doppler Method

The sequence of testing with the Doppler method consists of Adenosine testing, then ACH provocation testing, followed by nitroglycerin, and then repeat Adenosine testing (Figure 2). Our Doppler ICFT protocol was adopted from the Women's Ischemia Syndrome Evaluation-Coronary Microvascular Dysfunction (WISE-CVD) study [31]; where the proximal LAD has been the preferred vessel for Adenosine testinggiven its coronary dominance and myocardial mass [30]. Our ICFT protocol was modified to to address three key questions: (i) How does coronary flow reserve (CFR) correlate in the proximal LAD and proximal left circumflex? (ii) How does CFR correlate in the proximal and distal LAD? (iii) What is the impact of nitroglycerin on CFR in the proximal LAD, pre- versus postadministration? The total time needed to complete our comprehensive ICFT protocol is about 30–40 min.

FIGURE 2 ∣.

Overview of invasive coronary functional testing protocol and interpretation of results utilizing Doppler method.

1.2.4 ∣. Adenosine Testing Using Doppler Method

Adenosine testing is first performed in the proximal left circumflex (LCx), followed by the proximal LAD, then the distal LAD. Following nitroglycerin administration after ACH provocation testing, adenosine testing is repeated in the proximal LAD (Figure 2). For proximal coronary measurements, the wire is advanced at least 2–3 cm from the ostium, and co-axially aligned with the vessel to ensure optimal signals. The catheter is flushed with saline to allow for the Doppler-tipped guidewire and catheter's pressure to equalize. Fine rotational movements of the guidewire can minimize the signal-to-noise ratio [30, 32]. Once the Doppler wire is positioned, pressure stabilizes, and optimal flow signals are achieved, the baseline average peak velocity (APV) is recorded. A bolus hand injection of IC Adenosine is administered over approximately 1 min (dosing details in Table 2). Hyperemia APV is recorded typically within 7–15 s postbolus injection. Achievement of hyperemia is confirmed by an increase in APV from baseline. Once the APV returns to baseline and is recorded, Adenosine testing is repeated at a higher dose or a different location (Figure 2). The order of adenosine testing and corresponding locations is as follows using IC adenosine bolus hand injections: 18 and 72 μg in the proximal LCx, 18 and 72 μg in the proximal LAD, and 72 μg in the distal LAD. Once ACH provocation testing is complete and nitroglycerin is administered (as described below), repeat testing with 72 μg IC Adenosine occurs in the proximal LAD. The CFR post nitroglycerin in the proximal LAD is measured to assess the change in CFR following epicardial vasodilation, accounting for any potential microvascular or epicardial vasoconstriction.

CFR is the ratio between the hyperemic and baseline APV and is obtained with each IC Adenosine test administration [33]. In addition to CFR, the ComboWire XT measures hyperemic microvascular resistance (HMR), a measurement of microvascular resistance [34]. Endothelial-independent CMD is defined as CFR < 2.5 and/or HMR > 2.5 mmHg/cm/s in the proximal LAD at 72 μg Adenosine (Table 1) [35, 36].

1.2.5 ∣. Acetylcholine Testing Using Doppler Method

For ACH testing, the Doppler-tipped guidewire is relocated back to the proximal LAD following Adenosine testing in the distal LAD (Figure 2). A baseline angiogram is obtained in an 8-in. frame (recommended projections: 5° RAO, 35° CRA), minimizing distortion of the coronary artery. For ACH testing, IC infusions are delivered via the six French guide catheter using a micro-infusion pump and performed at three different doses: safety (5 μg total), mid-dose (44 μg), and high-dose (108 μg) (rates detailed in Table 2). Once the optimal flow signal is confirmed, baseline and peak APV are recorded for mid- and high-dose ACH. A cine angiogram with the same projections as the baseline is performed after infusion of each ACH dose. After ACH testing, an IC bolus hand injection of nitroglycerin (200 μg) over ~20 s is delivered, and an angiogram is performed. In patients with severe epicardial VSA, additional IC nitroglycerin may be necessary.

If patients present with severe catheter-induced spasm or baseline vasoconstriction, ACH provocation testing may be aborted [37]. If patients have >90% constriction to mid-dose, 200 μg of IC Nitroglycerin is promptly administered, and a high-dose ACH is not given. Extensive data has shown ACH is safe and can be administered in a monitored setting with IC bolus hand injections or via an IC infusion pump delivered into either a guide catheter or a micro-catheter in the LAD [38, 39]. The potential advantage of the micro-catheter is to ensure ACH is delivered directly into the LAD but delivery via the guiding catheter is less costly and has the advantage of assessment of spasm in both the circumflex and the LAD. ICFTs initially performed used the safety dose of ACH (5 μg); however, due to an absence of complications and for efficiency, this dose has been subsequently eliminated.

During the procedure, the interventional cardiologist visually assesses and reports the percentage of constriction in the epicardial vessels for each ACH dose. Ischemic ECG changes and angina reported (on a scale of 1–10) by the patient are recorded for each ACH dose. After the procedure, coronary blood flow (CBF) is calculated using the APV measured at baseline and mid-dose ACH testing, along with the vessel diameter obtained through quantitative coronary analysis (QCA) at both baseline and mid-dose ACH testing. When measuring vessel diameter, measurements are obtained 5 mm from the tip of the guidewire at the same position at baseline and mid-dose cine images. Thus, the formula to calculate Doppler CBF: CBF = 0.5 × APV × (diameter² × π)/4 [33].

As described in Table 1, microvascular endothelial-dependent CMD is defined as <50% change in CBF from baseline to mid-dose ACH and macrovascular endothelial-dependent CMD is defined as ≤ 0% vessel diameter changes from baseline to mid-dose ACH. The diagnostic criteria for epicardial VSA include ≥ 90% constriction, anginal symptoms, and ischemic EKG changes to ACH testing. While this can occur at any dose of ACH, epicardial VSA more commonly occurs in response to high-dose ACH [40]. Patients with < 90% constriction, anginal symptoms, and/or ischemic EKG changes are diagnosed with microvascular VSA. In patients who receive additional sedation, the absence of angina is to be interpreted with caution. Baseline vessel diameter is also compared to postnitroglycerin diameter, with a response < 20% considered abnormal [33].

1.2.6 ∣. CMVD Assessment Using Thermodilution Method

The sequence of testing with the Thermodilution method consists of ACH provocation testing, then nitroglycerin, followed by Adenosine testing (Figure 3). Similar to our Doppler protocol, we developed our Thermodilution protocol to capture essential diagnostic data while addressing two specific questions: (i) How does CFR differ when measured in the proximal-mid LAD compared to the mid-distal LAD? (ii) How does CFR vary when using IV versus IC adenosine in the distal LAD? The total time needed to complete this protocol is 35–45 min.

FIGURE 3 ∣.

Overview of invasive coronary functional testing protocols and interpretation of results utilizing thermodilution method.

1.2.7 ∣. Acetylcholine Testing Using Thermodilution Method

ACH provocation testing is first performed as outlined above with ACH infusion using an IC infusion pump into the guide catheter at mid- and high-dose ACH. Additionally, when there is high degree of suspicion or diagnostic uncertainty, we have added a 200 μg ACH dose delivered over 1 min as suggested by the recent guidelines [38].

Visual interpretation of vessel constriction after each dose of ACH is reported by the physician and is later measured by QCA. Since APV is not measured during Thermodilution, CBF cannot be calculated. Only macrovascular endothelial-dependent CMD based on percent diameter change can be assessed; a change of ≤ 0% is considered abnormal. Of note, data on the usefulness and prognostication of macrovascular endothelial-dependent CMD evaluated using the Thermodilution method is lacking. The diagnostic criteria for microvascular and epicardial VSA are the same as outlined for the Doppler method (Table 1).

1.2.8 ∣. Adenosine Testing Using Thermodilution Method

After ACH testing and Nitroglycerin, the PressureWire X (Abbott Vascular, Santa Clara, CA, USA) is flushed with 30 mL of saline and connected via blue tooth with the Coroventis CoroFlow software (Coroventis AB, Uppsala, Sweden) for the Thermodilution technique. Once pressures normalize, the PressureWire X is auto-calibrated on the console. Following advancement in the target vessel with a guide catheter, the wire is advanced until the radiopaque tip is outside the guide catheter to equalize. The catheter is flushed with saline to remove any blood and contrast, allowing the wire's pressure to equalize with the aortic pressure (P_a) at the ostium of the guide catheter. Once pressures are equal, the wire is advanced into the proximal-mid portion of the LAD, at least 5 cm from the ostium as recommended by the instructions for use [30]. Each position must remain stable for baseline and hyperemic measurements to ensure quality. The temperature is adjusted to zero to measure P_d/P_a, resting-full cycle ratio, and fractional flow reserve. To perform Thermodilution, 3 mL of sterile, room-temperature normal saline is rapidly injected intracoronary with a 3 mL Luer lock syringe three times to measure resting transit times on the console. Transit time measurements should be within < 15% variance, with repeat injections performed if there are significant variations between transit times. The average of the three resting transit times is the baseline mean transit time (T_mn), which is the time for room-temperature saline to travel down a coronary artery.

Once resting T_mn has been recorded, allow the temperature line to return to zero before proceeding. Maximal hyperemia is induced with IV Adenosine for about 1–3 min for a target dose of 300 μg/kg (Table 2). Three additional saline bolus injections are performed to determine a stable hyperemic T_mn [41]. The determination of maximal hyperemia remains controversial. We obtain hyperemic transit times starting at 1 min until we obtain three consistent measurements.

We allow adenosine to wear off for 2 min, then the Pressure wire is advanced to the distal LAD, and the steps above are repeated with IV adenosine. Finally, using the resting transit times from the distal LAD IV Adenosine run, we use IC adenosine to obtain two to three new hyperemic transit times. In Thermodilution, CFR is a ratio between hyperemic T_mn and baseline T_mn. The index of microvascular resistance (IMR) is calculated by multiplying the distal pressure (P_d) by the hyperemic T_mn. Endothelial-independent CMD is defined as CFR < 2.5 and/or IMR > 25 in the mid-distal LAD during IV Adenosine administration [42].

1.2.9 ∣. Differences in ICFT Diagnostic Methods

It is important to note the differences between Doppler and Thermodilution techniques. Traditionally, Doppler CFR is measured in the proximal LAD using IC adenosine, whereas Thermodilution CFR is assessed in the mid-distal LAD using IV adenosine. Variability exists between these methods, with evidence suggesting that Thermodilution tends to overestimate CFR, suggesting higher CFR cutoff values may be appropriate for the Thermodilution method [43].

Many questions regarding optimal ICFT procedures using the Thermodilution method remain. Our comprehensive protocols were designed not only to obtain critical data and to be efficient but to enable us to provide insight into these areas of uncertainty.

1.3 ∣. Section 3: Targeted Medical Therapy Based on ICFT Results

After ICFT is performed, an automatic referral is placed for the CMVD program to interpret ICFT results and adjust medical therapy for targeted treatment (Figure 4). All patients with CMD are first treated with statins [44] and renin-angiotensin system inhibitors (RASi) [45, 46]. Patients diagnosed with endothelial-independent CMD (reduced CFR and/or increased HMR or IMR) and endothelial-dependent CMD are started on antianginal therapy with first-line beta-blockers, followed by dihydropyridine calcium channel blockers (CCBs), and Ranolazine [47]. In patients with microvascular or epicardial VSA, nondihydropyridine CCBs (Diltiazem or Verapamil) are first-line treatment followed by long-acting nitrates (isosorbide mononitrate or nitroglycerin patch) while beta blockers are avoided [48]. For patients with severe epicardial VSA, after patients fail to improve on nondihydropyridine CCBs and nitrates at maximum doses, an addition of dihydropyridine CCB (amlodipine, felodipine) is recommended. All patients are advised to achieve appropriate cardiovascular exercise, and referrals to cardiac rehabilitation for patients to improve exercise tolerance are standard of care [14]. In patients with CCS class III/IV refractory anginal symptoms, enhanced external counter pulsation (EECP) is used as a treatment option, as our recent study suggests improvement in these challenging patients [49]. A similar treatment protocol based on ICFT findings was shown to improve patients' quality of life in the CORMICA study [50].

FIGURE 4 ∣.

Targeted treatment therapy based coronary functional testing diagnosis.

1.4 ∣. Utilization of CFT at TCH CMVD Program

Since the establishment of CMVD program, from October 2020 until July 2024, a total of 422 patients have undergone ICFT. Of these 281 (64%) were performed using the Doppler protocol and 151 (36%) using the Thermodilution protocol. When considering the proportionate ICFT conclusions (See Table 1 for endotype criteria) based on exclusive categories, 19% had an endothelial-independent CMD alone, 19% had endothelial-dependent CMD or microvascular VSA alone, 3% had epicardial VSA alone, 42% had mixed disease (any combination of the above categories), and 17% had a normal ICFT (Figure 5). Summarizing the data based on ICFT conclusion type (duplicating patients with mixed disease in respective categories), a total of 224 (53% of total) demonstrated endothelial-independent CMD, 249 (59% of total) demonstrated endothelial-dependent CMD and/or microvascular VSA, 37 patients (9%) demonstrated epicardial VSA and a total of 73 patients (17% of total) had normal ICFT without evidence of CMVD.

FIGURE 5 ∣.

Breakdown of ICFT endotype diagnoses based on exclusive categories. Mixed disease represents patients with an abnormality in more than one of the listed categories.

1.5 ∣. Barriers and Solutions to ICFT

Despite the essential role of ICFT in diagnosing CMVD, its availability remains limited across the nation. Limited awareness of CMVD among healthcare providers results in the underutilization of ICFT even in centers that perform these specialized tests. There is variability in how ICFT is performed across different institutions, with a lack of standardized protocols often leading to inconsistent results. Additionally, the high cost of ICFT, requiring additional catheterization laboratory time, specialized equipment and drugs, and trained staff pose barriers to widespread testing. Insurance coverage for ICFT is often contingent on a multitude of factors and can prevent timely testing despite guideline recommendations.

The Coronary Vasomotor Disorders International Study (COVADIS) group has been the international organization at the forefront of increasing awareness and advancing our knowledge of CMVD [36]. In the United States, the microvascular network (MVN) has been working on a multiprong approach to grow the number of centers that perform ICFT and standardize the approach to ICFT [45, 51]. With the 2021 AHA/ACC and 2024 ESC guidelines supporting the use of ICFT in a comprehensive evaluation for CMVD and targeted medical therapy in ANOCA/INOCA patients we expect for this testing to become more readily available [13-15].

2 ∣. Conclusions

ICFT is an integral component of a CMVD program. Given the economic burden, reduced quality of life, and increased risk of MACE and mortality in patients with CMVD, ICFT should be considered in patients with ANOCA/INOCA and other subgroups of patients with refractory angina. ICFT provides opportunity to provide diagnostic clarity and further guide medical treatment. This document provides TCH-WHC's structured approach for ICFT referral and protocol for conducting comprehensive ICFT which has been vital for the growth of our specialized CMVD program.

Abbreviations:

ANOCA

angina with nonobstructive coronary artery disease

CABG

coronary artery bypass grafting

CAD

coronary artery disease

CCS

Canadian Cardiovascular Society

CMD

coronary microvascular dysfunction

CMVD

coronary microvascular and vasomotor dysfunction

CVD

cardiovascular disease

HFpEF

heart failure with preserved ejection fraction

ICFT

invasive coronary functional testing

INOCA

ischemia with nonobstructive coronary artery disease

MINOCA

myocardial infarction with nonobstructive coronary artery disease

PCI

percutaneous coronary intervention

TCH-WHC

The Women's Heart Center at The Christ Hospital Heart and Vascular Institute

VSA

vasospastic angina