Contemporary Functional Coronary Angiography: An Update

Abstract

Functional coronary angiography (FCA) is a novel modality for assessing the physiology of coronary lesions, going beyond anatomical visualization by traditional coronary angiography. FCA incorporates indices like fractional flow reserve (FFR) and instantaneous wave-free ratio (IFR), which utilize pressure measurements across coronary stenoses to evaluate hemodynamic impacts and to guide revascularization strategies. In this review, we present traditional and evolving modalities and uses of FCA. We will also evaluate the existing evidence and discuss the applicability of FCA in various clinical scenarios. Finally, we provide insight into emerging evidence, current challenges, and future directions in FCA.

Plain Language Summary

Functional coronary angiography is a technique that combines detailed imaging of the coronary arteries with assessments of how well they function, helping physicians evaluate both large and small arteries in the heart. Unlike traditional angiography, functional coronary angiography uses advanced methods to measure the impact of any abnormalities, without needing extra invasive procedures. This approach is especially useful for patients who have cardiac symptoms but don't show significant blockages on standard tests. Functional coronary angiography is increasingly used to guide treatment decisions, ensuring patients receive the right care while avoiding unnecessary interventions. Functional Coronary Assessment primarily enhances coronary artery disease management by integrating various techniques to measure the hemodynamic significance of coronary lesions, guiding treatment decisions, and improving outcomes. The gold-standard Fractional Flow Reserve, along with alternatives like instantaneous wave-free ratio, resting-full cycle ratio, and diastolic pressure ratio, provides precise lesion severity assessments, reducing unnecessary interventions and enabling tailored revascularization strategies. Emerging technologies like Ultrasound-based fractional flow reserve and Optical Flow Ratio (OFR) offer promising, less invasive alternatives, while tools such as Coronary Flow Reserve and Index of Microvascular Resistance expand FCA's diagnostic scope to microvascular dysfunction and ischemia without obstructive coronary artery disease. FCA also plays a key role in personalized revascularization strategies, from routine management to high-risk, improving clinical decisions, reducing adverse events, and enhancing survival across diverse patient groups.

In this review, we present traditional and evolving uses of functional coronary angiography by evaluating its broad applicability across a variety of clinical indications.

Plain language summary

Article highlights.

• Functional Coronary Angiography (FCA) addresses the limitations of traditional coronary angiography by determining the hemodynamic significance of coronary lesions, guiding management decisions, and improving patient outcomes. Fractional Flow Reserve (FFR) is the gold standard but other measures are being explored.

• FFR uses invasive pressure measurements under hyperemic conditions to assess lesion severity. Studies like DEFER and FAME have shown that revascularization based on FFR significantly improves outcomes and reduces unnecessary interventions, though it remains underutilized due to procedural complexity.

• Instantaneous Wave-free Ratio (IFR) offers an alternative to FFR by eliminating the need for a hyperemic agent. Studies show IFR is non-inferior to FFR but brings similar procedural challenges. While less invasive, IFR has shown mixed results, with some evidence of higher long-term mortality.

• Resting Full-Cycle Ratio (RFR) is another non-hyperemic method that simplifies measurements by avoiding specific timing requirements. RFR has been validated against IFR but shows some discordance with FFR, leading to the suggestion that FFR be used when RFR values are in an intermediate range.

• Diastolic Pressure Ratio (dPR), like RFR, is a non-hyperemic functional assessment. While validated against IFR and FFR, and shown to predict outcomes in deferred interventions, dPR has less supporting data and is not yet recommended in clinical guidelines.

• Ultrasonic Flow Ratio (UFR) uses Intravascular Ultrasound (IVUS) for FFR analog calculations, avoiding pressure wires or adenosine. It has strong correlation with and good accuracy in predicting FFR <0.8. It is promising but requires expensive equipment and hasn't been evaluated for clinical outcomes.

• Optical Flow Ratio (OFR) uses Optical Coherence Tomography (OCT) to calculate an FFR analog without pressure wires or hyperemic agents. It also correlates well with FFR.

• Coronary Flow Reserve (CFR) measures coronary blood flow at rest vs. hyperemia and quantifies the ability to augment coronary blood flow. Abnormal CFR (<2–2.5) is linked to higher risks of mortality and Major Adverse Cardiovascular Event (MACE).

• Index of Microcirculatory Resistance (IMR) assesses microvascular function using coronary thermodilution and pressure measurement.

• FCA has various uses for distinct clinical scenarios. In myocardial bridging, coronary arteries travel inside the myocardium, affecting blood flow. FCA methods like FFR help in managing hemodynamically significant cases with medical or procedural interventions.

• FFR-guided Coronary Artery Bypass Grafting (CABG) has shown mixed results regarding graft occlusion rates and clinical outcomes. Post-operative Coronary Computed Tomography Angiography (CCTA) and Invasive Coronary Angiography (ICA) assessments remain important for evaluating graft patency and stenoses in native arteries.

• FCA tools (CFR, IMR, FFR) are critical in diagnosing microvascular dysfunction, especially in cases of ischemia without obstructive Coronary Artery Disease (CAD) (INOCA). Tailored medical therapy based on FCA improves outcomes, particularly in microvascular angina cases.

• Complete revascularization of all hemodynamically significant lesions during ST-Elevation Myocardial Infarction (STEMI), based on FFR measurements, reduces MACE rates. However, during cardiogenic shock, culprit-lesion-only intervention is preferred due to better survival outcomes.

1. Introduction

Functional coronary angiography (FCA) is a technique that integrates anatomical imaging with physiological assessments to evaluate both epicardial coronary arteries and microcirculation via assessment of coronary flow reserve, microcirculatory resistance and provocation testing, with the specifics of the FCA employed being guided by the clinical scenario and the results of the diagnostic angiogram [1,2]. Unlike traditional coronary angiography, which primarily focuses on visualizing luminal obstructions, FCA employs computational fluid dynamics and other advanced imaging techniques to derive functional indices such as fractional flow reserve (FFR), instantaneous wave free ratio (IFR) and quantitative flow ratio (QFR) from angiographic data. This allows for more comprehensive assessment of the hemodynamic significance of coronary lesions without requiring additional invasive procedures or pharmacological stress agents. FCA can even facilitate the diagnosis of coronary microvascular disease (CMD) and improve the management of patients with coronary artery disease (CAD) by providing anatomical and functional information. This approach is particularly useful in cases where traditional angiography shows non-obstructive coronaries, yet the patient exhibits symptoms of myocardial ischemia.

Literature is emerging on the use of FCA, particularly for evaluation of stable chest pain suspected to be cardiac in nature [1,3,4]. The current American College of Cardiology (ACC)/American Heart Association (AHA) and Society for Cardiovascular Angiography and Interventions (SCAI) guidelines endorse FCA (FFR and IFR) for guiding coronary revascularization due to its superior ability to determine functional significance of coronary artery stenoses compared to angiography alone [5,6].

Historically, coronary angiography had been the gold standard for diagnosing CAD; however, it has limitations in evaluating the functional impact or hemodynamic significance of a coronary lesion [7]. Notable reasons for the poor correlation between coronary angiography and evaluation of functional stenosis are attributable to ventricular hypertrophy, myocardial metabolic status, and microvascular disease [7]. Furthermore, a stenosis incapable of producing angina in one patient may result in severe functional limitation in another [7]. Consequently, the sole use of coronary angiography without functional assessment may be associated with unnecessary interventions or the postponement of necessary revascularization [7]. A large meta-analysis of randomized controlled trials comparing coronary angiography with FCA for diagnosing significant CAD demonstrated that FCA decreased unnecessary revascularization in up to 25% of patients [8]. The In the Management of Coronary Artery Disease, Does Routine Pressure Wire Assessment at the Time of Coronary Angiography Affect Management Strategy, Hospital Costs and Outcomes? (RIPCORD 2) trial showed that systematic FFR assessment, as opposed to angiography alone, did not result in significant financial loss or decrease in quality of life and reduced the need for invasive coronary angiography (ICA) [9]. FCA may also be done invasively, however, it is often done without the need for invasive intracoronary instrumentation [4]. These findings emphasize the role of functional assessment in CAD management, potentially averting overtreatment, and decreasing healthcare resource utilization while preserving clinical outcomes. Moreover, emerging non-invasive angiography techniques like vessel fractional flow reserve (CAAS vFFR) and computational pressure-flow dynamics derived FFR (caFFR) [4] are being explored for functional relevance in cases where lesion severity is intermediate or when alternate non-invasive functional testing yields inconclusive results or is impractical [4,10]. Ultimately, FCA has proven to be paramount in treatment decision-making for revascularization, strategy planning for percutaneous coronary intervention (PCI), and procedure optimization [4,5,8,11].

In this review, we present traditional and evolving modalities and uses of FCA (Figure 1). We will also evaluate the existing evidence and discuss the applicability of FCA in certain clinical scenarios. Finally, we provide insight into emerging evidence, current challenges and future directions in FCA.

Figure 1.

Potential uses for functional coronary angiography in clinical practice. This figure depicts the various clinical contexts in which functional coronary angiography (FCA) may be utilized for diagnosis. These include coronary artery bypass grafting, myocardial bridging, revascularization of additional non-culprit lesions in the setting of acute coronary syndrome, in-stent restenosis, coronary microvascular dysfunction and subclinical atherosclerosis.

2. Functional Coronary Angiography Methods

Coronary angiography and the use of PCI created new diagnostic and treatment opportunities for CAD. With these interventions came the question, who would benefit from an intervention and why? As mentioned, traditional angiography lacks the ability to determine the significance of a lesion and had historically used visual estimation of stenosis alone to determine which lesions require intervention [7]. This uncertainty left operators wondering which patients might benefit from revascularization. FCA was developed to determine the hemodynamic significance of a coronary lesion, and guide management decisions. This field of FCA has been expanding rapidly and looks to address this question. While FFR is the gold standard and most widely used FCA method currently [12–14], several other measures have been developed and have shown promise in their correlation with FFR and in prognostication of patient outcomes (Table 1).

Table 1.

Comparison of Functional Coronary Angiography Methods.

Method	Advantages	Disadvantages	Ideal clinical scenario	Guidelines
Fractional Flow Reserve (FFR)	Gold Standard	Requires invasive approach Requires additional instrumentation with pressure wire Requires adenosine administration	Anginal symptoms with intermediate stenosis on ICA	IA ACC/AHA/SCAI for FFR to assist in decision making if angina and intermediate stenosis on ICA IIIB ACC/AHA/SCAI for no revascularization if FFR >0.8 IA ESC/EACTS to assist in decision making if intermediate stenosis on ICA
Coronary CT-derived FFR (FFRCT)	Non-invasive	Contrast and radiation exposure Motion artifact and calcium can skew results	Evaluation of stable CAD when CCTA has stenosis between 40–99%	IIA 2021 AHA/ACC guidelines for the evaluation of stable CAD recommend CT-FFR for intermediate high-risk individuals with stable chest pain and 40–99% stenosis on CCTA 2022 CAD-RADS 2.0 recommends deferral from catheterization if CT-FFR >0.8
IVUS-derived FFR (UFR)	Does not require pressure wiring Does not require adenosine	Requires invasive approach Requires additional instrumentation with IVUS Requires complex computational models	Evaluation of coronary stenosis if already utilizing IVUS and software is available	Not Mentioned
OCT-derived FFR (OFR)	Does not require pressure wiring Does not require adenosine	Requires invasive approach Requires additional instrumentation with OCT Requires complex computational models	Evaluation of coronary stenosis if already utilizing OCT and software is available	Not Mentioned
Instantaneous Wave-Free Ratio (iFR)	No adenosine required	Requires invasive approach Requires additional instrumentation with pressure wire Complicated timing in obtaining pressure reading during wave free period	Anginal symptoms with intermediate stenosis on ICA in patient where there might be risk in giving adenosine	IA ACC/AHA/SCAI for FFR to assist in decision making if angina and intermediate stenosis on ICA IIIB ACC/AHA/SCAI for no revascularization if FFR >0.8 IA ESC/EACTS to assist in decision making if intermediate stenosis on ICA
Resting Full-Cycle Ratio (RFR)	No adenosine required Timing of pressure measurement is simpler	Requires invasive approach Requires additional instrumentation with pressure wire	Anginal symptoms with intermediate stenosis on ICA in patient where there might be risk in giving adenosine and iFR is not available	Not Mentioned
Index of Microcirculatory Resistance (IMR)	Isolates microvascular resistance May be obtained non-invasively	Does not offer functional significance of a single lesion akin to FFR	Risk stratification and assessment of microvascular dysfunction	Invasive, PET, CMR - 2a, stress echocardiography 2b
FFR angiography (FFRangio)	No pressure wire or adenosine required	Requires invasive approach Software is proprietary and not widely available	Anginal symptoms with intermediate stenosis on ICA in a patient who you wish to avoid adenosine and pressure wiring and software is available	Not Mentioned
Quantitative Flow Ratio (QFR)	No pressure wire or adenosine required	Requires invasive approach Software is proprietary and not widely available	Anginal symptoms with intermediate stenosis on ICA in a patient who you wish to avoid adenosine and pressure wiring and software is available	Not Mentioned
Diastolic Pressure Ratio (dPR)	No adenosine required Timing of pressure measurement is simpler	Requires invasive approach Requires additional instrumentation with pressure wire	Anginal symptoms with intermediate stenosis on ICA in patient where there might be risk in giving adenosine and iFR is not available	Not Mentioned
Coronary Flow Reserve (CFR)	Assesses epicardial and microvascular resistance May be obtained non-invasively	Does not offer functional significance of a single lesion akin to FFR	Risk stratification and assessment of microvascular dysfunction	Invasive, PET, CMR - 2a, stress echocardiography 2b

ACC: American College of Cardiology; AHA: American Heart Association; CAD: Coronary artery disease; CMR: Cardiac magnetic resonance imaging; EACTS: European Association for Cardiothoracic Surgery; ESC: European Society of Cardiology; ICA: Invasive coronary angiography; IVUS: Intravascular ultrasound; OCT: Optical coherence tomography; PET: Positron emission tomography; SCAI: Society for Coronary Angiography and Intervention.

2.1. Fractional Flow Reserve

FFR is measured invasively during coronary angiography under hyperemic conditions using adenosine to augment coronary vasodilation and create constant coronary blood flow. Using a pressure transducing catheter, pressures from proximal and distal to a stenotic lesion are measured and mathematical principles are borrowed from fluid dynamics to determine stenosis significance. Simplified, the pressure distal to the lesion is divided by the aortic pressure with a normal FFR being around 1. Revascularization of lesions with FFR <0.75–0.8 has been shown to provide benefit [15–18]. Sentinel studies such as the Deferral vs. Performance of Percutaneous Coronary Intervention of Functionally Non-Significant Coronary Stenosis (DEFER) trial found no difference in 5-year survival or event-free survival in patients with lesions of FFR >0.75 when comparing revascularization with medical management [19]. 15-year follow up of the DEFER trial demonstrated that deferring PCI based on a FFR of ≥0.75 is safe and associated with excellent long-term outcomes, with a significantly lower rate of myocardial infarction (MI) compared to performing PCI. This supports the use of FFR in guiding PCI for intermediate coronary stenoses, confirming its long-term safety and efficacy [20]. Furthermore, trials such as the Fractional Flow Reserve Versus Angiography for Multivessel Evaluation (FAME) trial showed improved outcomes, and fewer stents placed in patients who received revascularization driven by FFR <0.8 as opposed to angiography alone [21]. The FAME-2 trial showed that those with FFR <0.8 who underwent medical management had worse outcomes than those who received revascularization [22]. Due to these studies, and others, FFR has been recommended to assist in guiding decisions for treatment in patients with anginal symptoms and intermediate stenoses on ICA (1A ACC/AHA/SCAI and IA European Society of Cardiology [ESC]) with a recommendation against PCI in patients with FFR >0.8 (3B ACC/AHA/SCAI) [6,23]. Despite its excellent performance, FFR has been underutilized in clinical practice [24]. The argument against the use of FFR includes the additional time required to complete this testing, additional costs, technical difficulty, procedural risk of dissection, discomfort of hyperemic agent and the complexity of the timing of its introduction [25,26]. Given these considerations, investigations into a less procedurally complex or non-invasive method of FCA has been an exciting area of research.

2.2. Instantaneous Wave-Free Ratio

IFR was developed to address some of the limitations of FFR by providing an invasive functional evaluation which does not require a hyperemic agent. To calculate IFR, a pressure wire measures pressures proximal and distal to the stenotic lesion. To avoid the use of a coronary vasodilator such as adenosine, IFR measures pressures during the “wave-free” period between cardiac systole, thus mimicking the stable microvascular resistance conditions which are obtained by vasodilators [27,28]. Several studies have compared IFR and FFR such as the Instantaneous Wave-Free Ratio Versus Fractional Flow Reserve Guided Intervention (IFR SWEDEHEART) study which showed that IFR was non-inferior to FFR in 12-month major adverse cardiovascular event rates and the Functional Lesion Assessment of Intermediate Stenosis to Guide Revascularisation (DEFINE-FLAIR) study, which showed non-inferiority in addition to IFR being more cost-effective but proposed a higher cutoff for intervention (<0.89) [29,30]. Despite many positive studies, some have shown poor correlation of IFR with FFR, and a large analysis of 5-year outcomes from the IFR SWEDEHEART and DEFINE-FLAIR studies showed increased five-year all-cause mortality and major adverse cardiovascular events (MACEs) for those who received IFR-guided interventions [31]. Along with these mixed results, IFR brings the same issues as FFR including requirement of an invasive approach, precise measurements, added time and complexity of additional wiring during ICA. Current AHA/ACC/SCAI and ESC guidelines recommend using either FFR or IFR in patients with angina and intermediate stenosis on ICA to guide further intervention (1A) and AHA/ACC/SCAI guidelines recommend against intervention when IFR >0.89 (3B) [6,23].

2.3. Resting Full-Cycle Ratio

Another non-hyperemic invasive measurement of functional significance is the Resting Full-Cycle Ratio (RFR). This ratio is calculated using an invasive pressure measurement proximal and distal to the stenotic lesion. It divides the lowest pressure measurement distal to the lesion throughout the cardiac cycle by the aortic pressure. The cutoff value has been validated with revascularization of lesions with RFR values <0.89 deriving benefit from intervention. As RFR is independent of hyperemia or pressure measurement based on specific timing during the cardiac cycle, it improves upon the complexity and time-intensive nature of previous FCA measures. The Validation of a Novel Non-Hyperaemic Index of Coronary Artery Stenosis Severity: The Resting Full-Cycle Ratio (VALIDATE RFR) study was a retrospective study which showed that RFR was non-inferior to IFR and correlated well with IFR values [32], which was later confirmed by the Real World Validation of the Nonhyperemic Index of Coronary Artery Stenosis Severity-Resting Full-Cycle Ratio (RE-VALIDATE RFR) study [33]. RFR has also been compared to FFR with overall favorable results but at least one study showed some discordance between values up to 20% [34,35]. Another study suggests using FFR when RFR falls into an intermediate zone (0.86–0.92) where the measurement may be less predictive to reduce the need for hyperemic agents but improve diagnostic yield [36]. Despite this favorable evidence, AHA/ACC/SCAI and ESC guidelines do not recommend its use currently [6,23]. The issues with RFR are like previously described methods including its invasiveness, cost, and possibly lower accuracy compared to other FCA methods.

2.4. Diastolic Pressure Ratio

dPR is another invasive functional assessment which does not require a hyperemic agent. Similar to RFR, dPR divides a distal coronary pressure by the aortic pressure. Unlike in RFR, dPR uses a mean diastolic pressure in its calculations as opposed to the lowest pressure as used in RFR [37]. The dPR Study validated dPR against IFR, showing a strong linear correlation (R = 0.997) and slightly less robust relationship with FFR (R = 0.770) with a predictive value of dPR <0.89, similar to IFR [37]. Additional studies have validated dPR against FFR and IFR using positron emission tomography (PET) imaging to determine ischemic significance and has shown comparable predictive value [38,39]. dPR has also been shown to predict 2-year risk of vessel-oriented composite outcomes in vessels with deferred interventions [38,40]. dPR is comparable in procedural measurement and efficacy to RFR, but RFR has shown some possible superiority in the post-PCI population due to diastolic reactive hyperemia [41]. Despite improving on basic FCA measurements such as FFR due to procedural ease, calculating dFR still requires invasive pressure measurements and has less data to support its use than other functional measures. The AHA/ACC/SCAI and ESC guidelines currently do not recommend the use of dPR to guide interventional strategy [6,23].

2.5. IVUS-derived FFR

Ultrasonic Flow Ratio (UFR) utilizes intravascular ultrasound (IVUS) to calculate an FFR analog, which does not require the use of pressure wires or adenosine administration. Images are obtained through IVUS pullbacks, and a prototype software is used to generate a 3D model of the coronaries. Pressures are then calculated using computational fluid dynamics to derive the UFR value [42]. UFR has been validated against invasively obtained FFR, showing a strong correlation (R = 0.87) with 92% accuracy in predicting FFR<0.8 [42]. These findings were further validated trials demonstrating a strong correlation with FFR as well as QFR [43–45]. Despite its validation with regards to FFR, UFR has not been evaluated for clinical outcomes. UFR shows promise as an analog to FFR, but requires expensive equipment, novel computer software, and it continues to be invasive and time-consuming. UFR might be useful once more validated and in circumstances where operators utilize IVUS and choose to bypass pressure wire introduction to assess lesions. UFR has not been explicitly discussed in clinical practice guidelines.

2.6. OCT-derived FFR

Optical Flow Ratio (OFR) utilizes Optical Coherence Tomography (OCT) to create an FFR analog and does not require the use of pressure wires or hyperemic agents. OCT is an invasive coronary imaging technology which uses near-infrared light to obtain detailed images of the coronary vessel wall. A sample software uses images from OCT pullbacks to create 3D models of the coronaries which allows for the use of computational FFR mechanisms to derive the OFR value. OFR was initially validated against FFR with a strong correlation (R = 0.72) and 88% accuracy in predicting lesions which had FFR<0.8, when using a cutoff of OFR<0.8 [46]. A recent meta-analysis of 5 studies showed a strong correlation and accuracy in identifying lesions with FFR<0.8 (86–93%) [47]. Furthermore, one study showed that lower post-PCI OCT-derived FFR (OCT-FFR) is significantly associated with higher rates of target vessel failure (TVF) in acute coronary syndrome (ACS) patients. Thus, incorporating vessel-level OCT-FFR into post-PCI assessments may improve the ability to predict long-term TVF, highlighting potential clinical utility in guiding PCI decisions and improving patient outcomes [48]. Notably, the FFR or OCT Guidance to Revascularize Intermediate Coronary Stenosis Using Angioplasty (FORZA) trial compared FFR and OCT guidance in patients with intermediate coronary lesions, and the results showed that OCT guidance was associated with a lower occurrence of composite MACE and significant angina, compared to FFR guidance [49]. Furthermore, FFR guidance led to a higher rate of medical management and lower costs, thus suggesting a slight advantage in support of OCT in functional testing for CAD [49]. Like UFR and FFR, OFR is invasive, expensive, and requires the use of procedurally difficult methods to obtain the OFR value, but it could have benefit if the operator is using OCT already. Guidelines have not yet included OFR in their recommendations.

2.7. Coronary Flow Reserve

Coronary Flow Reserve (CFR) compares coronary blood flow at hyperemia and at rest to quantify the ability to augment coronary blood flow during times of increased demand. CFR has been measured using various methods from invasive pressure wires and thermodilution, to newer noninvasive methods such as doppler echocardiography, PET, and cardiac magnetic resonance imaging (CMR) [50–53]. CFR offers a quantitative measure of epicardial and microvascular coronary disease and its capacity for augmentation, but its value lies primarily in risk stratification and determination of possible microvascular ischemia. The cutoff CFR value used in studies to define risk stratification generally lies in the 2–2.5 range, with CFR <2–2.5 being abnormal; however, these cutoffs vary based on study and mechanism of measurement. One large meta-analysis including 76 studies and almost 60,000 patients showed that an abnormal CFR was associated with Hazard Ratios (HR) of 3.78 for all-cause mortality and 3.45 for MACE, respectively [54]. This measure, when taken invasively, has many of the disadvantages as aforementioned FCA modalities because it requires pressure wires and hyperemic agents. Fortunately, other non-invasive mechanisms have been developed to derive this value. In its optimal use, CFR can be used to risk stratify patients, allowing for early, aggressive risk factor modification and microvascular dysfunction assessment.

2.8. Microvascular Resistance

FCA also employs the measurement of microvascular resistance to assess coronary microvascular function, particularly through the index of microcirculatory resistance (IMR) and hyperemic microvascular resistance (hMR). Both indices are derived using an extrapolation of Ohm's law, which relates pressure and flow.

The IMR is an invasive method to determine the significance of microvascular dysfunction. Microvascular dysfunction is often considered a cause of anginal symptoms in the absence of significant CAD. However, measuring microvascular dysfunction accurately has been a persistent challenge. IMR utilizes isolated coronary thermodilution as well as a pressure measurement distal to any stenotic lesion at hyperemia to isolate the microvascular system. CFR, as previously described, reports epicardial and microvascular resistance and does not offer the same level of microvascular assessment as IMR. The IMR value is calculated by dividing the distal coronary perfusion pressure by the inverse of the hyperemic mean transit time and represents microvascular resistance [55,56]. An IMR measurement of <25 has been validated to represent no clinically significant microvascular dysfunction. Additionally, IMR is a proficient prognosticating tool, and has been shown to predict increased risk of death and admissions for heart failure following PCI [57,58]. IMR has also been shown to determine which patients presenting with ST-elevation myocardial infarction (STEMI) should receive targeted interventions for microvascular disease such as intracoronary thrombolytics, or pressure-controlled intermittent coronary sinus occlusion [59–61]. IMR may also hold prognostic implications for STEMI patients as one study found that STEMI patients with high IMR levels had a significantly higher risk for cardiac death or readmission for heart failure at 10-years post-revascularization follow up [62]. The 2021 AHA/ACC guidelines for the evaluation and management of stable CAD recommend using myocardial blood flow reserve testing (CFR and IMR) to enhance risk stratification and assess for microvascular dysfunction (invasive, PET, CMR - 2a, stress echocardiography 2b) [5].

Meanwhile, hMR is derived using Doppler flow velocity and distal coronary pressure. It is calculated as the ratio of distal coronary pressure to Doppler-derived flow velocity during hyperemia. Studies have shown that hMR has better diagnostic accuracy than IMR in predicting CFR and myocardial perfusion reserve index, making it a robust measure for assessing microvascular dysfunction.

Both IMR and hMR provide critical insights into microvascular function, with hMR demonstrating superior diagnostic performance in certain contexts. These measurements are integral to the comprehensive assessment of coronary microvascular dysfunction.

2.9. Quantitative Flow Ratio

The next group of measures in FCA determine the functional significance of lesions without the need of pressure wires, pharmacologic hyperemia, or thermodilution. Images obtained during diagnostic coronary angiography may be analyzed using computational models to derive FFR-like measures. These mechanisms such as QFR, and angio-FFR, among other older models like vFFR and CAAS first create a 3D reconstruction of the coronary anatomy, and then apply complex fluid dynamic flow analysis to create an analog for traditionally measured FFR [63,64]. QFR utilizes coronary angiographic images to create a 3D reconstruction of the coronaries and uses Thrombolysis in Myocardial Infarction (TIMI) flow rates in computational fluid dynamic models to determine a calculated analog to invasively obtained FFR [65]. The Wire-Free Functional Imaging II (WIFI II) study supported QFR as a non-inferior alternative to FFR for evaluating CAD, demonstrating similar diagnostic accuracy as compared to FFR; QFR correctly classified 83% of lesions using FFR as the reference standard [66]. QFR has been tested against FFR in multiple studies, each showing that QFR reliably identifies lesions which are hemodynamically significant at similar rates to FFR with 83–93% accuracy [67,68]. Furthermore, QFR has been shown in the Comparison of Quantitative Flow Ratio Guided and Angiography Guided Percutaneous Intervention in Patients with Coronary Artery Disease (FAVOR III) trial and its follow up to have improved 1- and 2-year clinical outcomes compared to standard angiographical guidance [69,70]. When using QFR, several disadvantages must be considered. The presence of tandem lesions can reduce its diagnostic accuracy, often necessitating a hybrid approach combining QFR with invasive FFR [71]. Furthermore, QFR's diagnostic performance may be compromised in cases of discordance between FFR and resting distal-to-aortic pressure ratio (Pd/Pa), requiring careful patient selection and potential additional testing [72]. Similar to other functional modalities, QFR's reproducibility can vary significantly, with variability reaching up to 10.5% [73]. Lastly, in patients with prior MI, QFR may underestimate the severity of coronary stenosis, compared to FFR, due to altered myocardial viability [74].

2.10. FFRangio

Angiography-derived Fractional Flow Reserve (FFRangio) utilizes a proprietary software created by CathWorks which uses 2D coronary angiography images to create a 3D model of the coronary tree and estimates FFR values with advanced computational modeling derived from Poiseuille's law [75]. FFRangio has similar diagnostic accuracy to FFR and was shown to perform well in diagnosing hemodynamically significant lesions in large validation studies with diagnostic accuracy of 87–96% [75–77]. While QFR and FFRangio allows patients to avoid the cost and procedural risk of pressure wiring and pharmacologic hyperemia, they still require an invasive approach and require time to run the computational models (∼5 minutes), limiting its clinical use. Furthermore, certain anatomical features, such as left main coronary artery and bifurcation lesions, may limit the diagnostic utility of these methods. QFR and FFRangio are not discussed in the ACC/AHA/SCAI or ESC guidelines at this time.

2.11. Coronary Computed Tomography-derived FFR

While the aforementioned modalities offer a less complicated method of FCA, they all require invasive assessment. Coronary Computed Tomography Angiography (CCTA) offers a non-invasive anatomic evaluation of the coronary arteries, which may be augmented by Computed Tomography Fractional Flow Reserve (CT-FFR) to derive a measure of functional significance. Like QFR and FFRangio which used angiographic images to create a 3D model of the coronary tree, CT-FFR is able to do this using non-invasive CCTA images. From these renderings, computer models and fluid dynamics are utilized to derive CT-FFR values [78,79]. CT-FFR has shown excellent diagnostic accuracy in predicting FFR<0.8 when CT-FFR is <0.6 or >0.8, but it does have reduced accuracy for mid-range values. CT-FFR has also been prognostic, with CT-FFR >0.8 predicting decreased 1-year all-cause mortality and MACE [80–82]. Furthermore, CT-FFR <0.8 has been associated with increased incidence of all-cause mortality, MI, hospitalization for angina, and unplanned revascularization at 2 years [83]. When using CT-FFR guided PCI strategy, studies have shown that fewer interventions are completed without an increase in MACE [80]. However, CT-FFR can be influenced by coronary calcifications and motion artifacts. Moreover, while CT-FFR avoids the need for invasive data or adenosine, it still exposes the patient to radiation and contrast which may be contraindicated in select patients [84]. The 2021 AHA/ACC guidelines for the evaluation of stable CAD recommend CT-FFR for intermediate high-risk individuals with stable chest pain and 40–99% stenosis on CCTA (2a) with 2022 Coronary Artery Disease - Reporting and Data System (CAD-RADS) 2.0 indicating deferral of catheterization if CT-FFR >0.8 [85,86].

3. Interrogation of Functional Coronary Angiography with Intravascular Imaging

IVUS is a catheter-based imaging modality that shows high-resolution cross-sectional images of the coronary arteries and provides information on both the lumen and the vessel wall, thus yielding value in the assessment and treatment of stenoses that coronary angiography alone cannot show [87]. IVUS has greater spatial resolution in comparison to angiography and provides an accurate depiction of luminal dimensions, lesion length, plaque morphology, presence of intraluminal thrombus, wall dissection, stent placement and characteristics [6]. The addition of virtual histology IVUS, which uses large databases to classify plaques as containing fibrous, fibrofatty, necrotic core, or dense calcium, can accurately depict the qualities and assist with risk stratification of plaques and intervention [88]. The uses of IVUS are multiple and ever-increasing, and the use of IVUS can even minimize or completely reduce the need for contrast imaging [89]. There are minimal complications with the use of IVUS, with transient spasm being a known reaction, and its use does not appear to accelerate atherosclerosis when introduced to the coronary arteries [90].

The minimal lumen area (MLA) seen on IVUS has been shown to correspond with physiologic indices, and thus can provide functional value from anatomic assessment [91]. Optimal MLA cutoff values for predicting FFR lack robust correlation and are vessel diameter dependent, limiting their exclusive use in identifying and treating ischemia-inducing lesions [92]. MLA values may have utility in their negative predictive value, and therefore can identify lesions that can be safely deferred at MLA >6–7.5 mm² (4.5–4.8 mm² in Asian patients due to smaller heart weights) [6,92]. The An Imaging Study in Patients With Unstable Atherosclerotic Lesions (PROSPECT) trial included patients with ACS who underwent coronary angiography and IVUS and showed that at 3-year follow up, IVUS-measured plaque burden (>70%), plaque composition (specifically thin cap fibroadenoma, and MLA (<4 mm²) were predictors of future MACE [88,89]. In this study, over half of the culprit lesions that contributed to future MACE were deemed to be angiographically mild on initial presentation, suggesting that IVUS in conjunction with angiography can increase predictive value for future events in comparison to angiography alone [88]. For patients undergoing PCI, when comparing IVUS-guided PCI with angiography-guided PCI, the IVUS arm demonstrated a lower rate of MACE, TVF at 12 months, stent thrombosis and vessel revascularization at 3 years, and had lower MACE rates for complex lesions; however the data for these is not as robust [6]. IVUS has also been shown to detect calcium better than angiography (73% vs 38%), with unstable lesions correlating with spotty calcium, defined as calcium deposit with an arc <90.

IVUS also has value in optimizing stent deployment, which represents its most common use in current practice. IVUS provides full-thickness visibility of the vessel wall and may be useful prior to PCI in assessing calcium burden, plaque burden, lesion length, and vessel diameter for stent position, as well as stratifying risk for stent-related complications [6]. Severe calcification, defined as a 180–270 degree arc of calcification, is associated with inadequate vessel expansion with ballooning or stenting [88,89]. Identification of these high-risk lesions can prompt lesion preparation with cutting/scoring balloon or atherectomy prior to intervention to reduce the risk of operative complications such as dissection [88–90]. Identification of thrombus using IVUS can guide the use of distal embolic protection devices [88]. IVUS also allows for appropriate stent placement and reduces the risk for under-expansion of stent or geographical miss (inflow-outflow disease), which are predictors of early thrombosis and in-stent restenosis [89]. Angiography alone underestimates vessel diameter, potentially leading to mispositioning and reduced drug delivery as undersized drug-eluting balloons may not be in direct contact with the vessel wall [89]. IVUS-associated stenting yields greater use of post-dilation with large balloons, larger stent size, and more/longer stents, which reduces geographical miss and treats edge dissections [89]. In the case of chronic total occlusions,IVUS is useful for catheter positioning and confirmation of access from the false lumen to the true lumen [89].

3.1. OCT

OCT is a catheter-based technique that utilizes infrared light to provide high resolution imaging of superficial structures within the vessel. OCT has higher spatial resolution than angiography or IVUS with 40 times greater speed of image acquisition compared to IVUS. This provides significant information on superficial plaque composition, including calcium thickness, thrombus, fibroatheroma, and plaque rupture, as well as vessel characteristics important for stent sizing, optimizing stent positioning, and identifying complications of stent placement [6,89,93,94]. Due to the phenomenon of light scattering in the presence of red blood cells, OCT requires flushing with contrast to clear the cells to obtain adequate visualization of structures [6,89,95]. OCT is also limited in its depth of imaging, preventing visualization of transmural vessels [6]. OCT is superior to IVUS for lumen measurements due to higher spatial resolution and flushing with contrast and was found to correlate with actual lumen area with low standard deviation compared to IVUS [89,95,96]. OCT is inferior to IVUS in measuring plaque burden and visualizing the full vessel wall thickness [89]. Additionally, due to contrast, OCT may be limited in imaging ostial left main disease, particularly in individuals with renal insufficiency [6,89]. To overcome each of these limitations, combined OCT-IVUS devices are emerging to take advantage of the high-resolution superficial imaging of OCT with transmural visualization of IVUS [89].

OCT is effective at assessing plaque rupture, plaque erosion, and is superior to angiography and IVUS in the detection of thrombus and can even be used to monitor interval change in thrombus size with pharmacotherapy or mechanical aspiration [89]. OCT, with its high-resolution spatial imaging, can accurately identify thin fibrous cap lesions, which are vulnerable to progression and eventually rupture, although current consensus cannot unequivocally state its superiority to IVUS and other advanced imaging techniques [89]. OCT can be used to optimize stent deployment in multiple ways. OCT can assist with identifying lesions that need preparation prior to stent deployment, choosing appropriate stent diameters and lengths to maximize stent area and cover residual disease adjacent to the lesion, identifying acute complications of stent placement, and evaluating for etiology of late stent failure [95]. One registry showed a reduction in “unidentified mechanism of stent thrombosis” from 48% to 13% using angiography alone vs angiography with OCT [95]. OCT penetrates calcium superior to IVUS and provides measurements of thickness, area, and volume [89,95]. OCT is superior to IVUS at detecting intrastent tissue protrusion, incomplete stent apposition, stent edge dissection, and in-stent thrombus [96]. OCT also is more effective than angiography alone at improving surrogate markers for late thrombotic events, such as incomplete strut coverage [97].

OCT is emerging as an important adjunct to coronary angiography and is non-inferior to angiography with IVUS. One trial revealed OCT-guided PCI yielded improved post-PCI FFR in comparison to angiography-guided PCI and was associated with reduced rates of stent thrombosis [6,94,98]. In this trial, the OCT arm vessels were post-dilated if stent expansion was <80%, again suggestive that OCT imaging metrics serve to optimize stent deployment with consequential improvements in robust functional parameters such as FFR [94]. OCT-guided PCI was also associated with lower risk for cardiac death or MI in comparison to angiography-guided PCI [99]. The Optical Coherence Tomography Imaging During Percutaneous Coronary Intervention Impacts Physician Decision-Making (ILUMIEN) and Optical Frequency Domain Imaging vs. Intravascular Ultrasound in Percutaneous Coronary Intervention (OPINION) trials showed that, compared to IVUS, angiography with OCT was non-inferior for post-PCI minimum stent area assessment with similar rates of procedural MACE, 1-year cardiac death, target vessel MI, and target vessel revascularization due to ischemia [96,98]. OCT measured values also have value in predicting adverse outcomes. OCT minimum stent area <4.5–5 mm² has been shown to independently predict MACE, while residual distal edge dissection >200 μm, large lipid plaques >185 degrees, and lumen area <4.1 mm² predicted edge restenosis [100–102]. Based on these trials, the value of OCT in assisting with PCI is clear and similar in utility to IVUS. Contemporary guidelines suggest the use of OCT to evaluate etiology for stent failure and for specific patients for stent optimization, but the uses of OCT go far beyond this and will increase in practice as more data is collected [93].

4. Clinical Scenarios for Functional Coronary Angiography

Subclinical atherosclerosis represents atherosclerotic burden without clinical symptoms [103]. ICA can identify high-grade stenoses in coronary arteries, which can portend risk for future coronary events [104]. Since the advent of coronary angiography in the 1960s, percent diameter of stenosis has been used to identify culprit lesions, with >70% stenosis being significant (Figure 2) [105]. However, this anatomical evaluation alone has not demonstrated more than modest correlation with physiologic indicators of myocardial ischemia, as short stretches of focal narrowing may not be as flow-limiting as longer anatomical stretches of moderate narrowing [106,107]. For patients without clear symptoms, high grade stenoses seen on angiographic imaging in the past would have been intervened upon due to anatomical considerations. This algorithm has changed in recent years as intervening with PCI or coronary artery bypass grafting (CABG) on non-ischemic lesions has not shown any clinical benefit and is associated with procedural risk and even clinical disease progression in CABG patients [19,108]. FCA methods such as FFR have value in providing physiological context for lesions, with FFR values >0.8 deemed as non-ischemic, FFR 0.75 – 0.80 as indeterminate, and FFR<0.75 designated as ischemia-producing with intervention recommended [109–111]. Using FCA over time to track the progression of subclinical atherosclerosis can lead to earlier detection of hemodynamically significant lesions and lead to intervention that may reduce the risk for MACE.

Figure 2.

Timeline Evolution of Non-Invasive Coronary Physiology and Functional Coronary Angiography.

This figure illustrates the timeline Evolution of Non-Invasive Coronary Physiology and Functional Coronary Angiography. The figure demonstrates the change from more angiography-based measures to assess coronary disease and to keep healthy.

4.1. Myocardial bridging

Myocardial bridging refers to epicardial coronary arteries which travel inside the myocardium. Due to alterations in coronary artery physiology in these cases, blood flow can be limited and lead to myocardial ischemia. Most patients with myocardial bridging are asymptomatic, and as such, diagnosis is generally made when imaging or angiography is obtained to evaluate other clinical entities. Anatomical factors that increase the risk for hemodynamic significance, such as depth of segment and length of buried segment, can be determined via coronary angiography or CCTA [112]. The value of FCA in determining distal blood flow limitation that the bridged segment may provoke is used to determine management strategy [113–116]. Bridged segments that alter coronary hemodynamics warrant medical treatment as well as consideration for procedural intervention [117].

4.2. Coronary artery bypass grafting

CABG remains the standard of care revascularization method for individuals with complex CAD [118]. Associations between pre-operative FFR and rate of graft occlusion have been shown, with an FFR >0.74 predicting post-CABG graft occlusion with a sensitivity of 0.66 and specificity of 0.63 [118]. This is postulated to be due to increased native coronary competitive flow leading to increased stagnation through the graft and consequent obstruction [118]. However, a meta-analysis of the several trials showed that FFR-guided CABG showed no significant change in death rates, MACE, target vessel revascularization, or spontaneous MI compared to angiography-guided CABG [119]. For post-CABG symptomatic individuals, CCTA alone has been shown to be successful in evaluating graft patency, while ICA with functional assessment is required to determine the presence of hemodynamically significant stenoses in distal runoff regions or in native coronary arteries [120].

4.3. Coronary microvascular dysfunction & vasospasm

Up to 50% of elective coronary angiograms performed in the United States and Europe for chest pain yield no evidence of obstructive CAD [121,122]. Because ischemia with nonobstructive coronary arteries (INOCA) is difficult to diagnose, FCA has significant value for its evaluation. The Coronary Microvascular Angina (Cor-MicA) trial used CFR, a measure of impaired coronary vasorelaxation, IMR, a measure of coronary vessel resistance independent of epicardial stenosis, and FFR with the use of adenosine, incremental acetylcholine, and bolus acetylcholine, to stratify patients into microvascular dysfunction, coronary vasospasm, both, or none [123,124]. Using this stratification process tailored medical therapy to each group and led to significant reduction in angina frequency and severity, with improvements in quality of life [123]. Additionally, the Women's Ischemia Syndrome Evaluation (WISE) study identified an effective protocol for identifying diagnostic strategies for women with non-obstructive CAD including similar measurements as the Cor-MicA trial [125]. Further information regarding management strategies for microvascular dysfunction are needed; Neverthless, FCA has value in diagnosing this clinical entity.

4.4. Non-culprit vessel assessment in ACS & cardiogenic shock

It is important to recognize that up to 40–50% of individuals with acute STEMI have concomitant significant multivessel CAD [126]. Amongst this population, it is unclear whether to treat all hemodynamically significant lesions or the culprit lesion alone. Two large trials, the Primary PCI in Patients With ST-elevation Myocardial Infarction and Multivessel Disease: Treatment of Culprit Lesion Only or Complete Revascularization (PRIMULTI) and the Comparison Between FFR Guided Revascularization Versus Conventional Strategy in Acute STEMI Patients With Multivessel Disease (COMPARE-ACUTE) trials, showed that complete revascularization of all hemodynamically significant lesions using FFR measurements led to reduced rates of future MACE, driven by fewer revascularizations [127,128]. The Complete vs Culprit-only Revascularization to Treat Multi-vessel Disease After Early PCI for STEMI (COMPLETE) trial showed that there was a significant reduction in cardiovascular death, MI, or ischemia driven revascularization in this same group [129]. However, during STEMI, alterations to coronary hemodynamics have been shown to reduce non-culprit CFR and increase FFR transiently, suggesting that FFR during the time of STEMI may underestimate the severity of non-culprit lesions [130]. Due to long-term benefits of complete revascularization, there was no significant difference in cardiovascular death or new MI if non-culprit lesions were treated during index hospitalization compared to after discharge, within 40 days of initial MI [131,132]. Guidelines from ACC, ESC, and Japan all recommend initial PCI for culprit lesion and staged PCI or CABG for non-culprit lesions [132].

In the setting of acute MI complicated by cardiogenic shock, data has been conflicting. Evidence from the Should We Emergently Revascularize Occluded Coronaries for Cardiogenic Shock (SHOCK) trial and the Korean Acute Myocardial Infarction Registry suggest that multivessel revascularization of all hemodynamically significant lesions in the setting of STEMI and cardiogenic shock was associated with better outcomes, while the Culprit Lesion Only PCI Versus Multivessel PCI in Cardiogenic Shock (CULPRIT-SHOCK) trial showed culprit lesion intervention alone was superior to revascularization of all lesions with reduced FFR on functional angiography [132–135]. Guidelines currently suggest against complete revascularization of non-culprit lesions due to increased rates of composite 30-day and 1-year mortality or severe renal failure seen in the CULPRIT-SHOCK trial and follow-up analysis [136,137].

4.5. In-stent restenosis

In-stent restenosis is clinically defined by greater than 50% stent diameter stenosis with one of clinical signs of angina, objective ischemic signs such as electrocardiogram (ECG) changes, IVUS minimum stent area <4 mm², or FFR across lesion <0.8 [138]. Angiography alone is poor at identifying restenosis due to the presence of metal struts in the region of interest. In one study, there was discrepancy noted between visually estimated percent diameter stenosis using coronary angiography compared to functional ischemia measured with FFR, specifically in diffuse re-stenotic lesions [139]. Angiographic quantification of moderately stenotic lesions (40–70% stenosis) was also shown to have poor correlation with FFR value, so in these intermediate ranges, deferral of intervention is generally safe if FFR is greater than or equal to 0.75 [140].

4.6. Pre-transcatheter aortic valve replacement PCI

CAD and aortic stenosis coexist in many patients as 15–80% of patients enrolled in landmark trials for transcatheter aortic valve replacement (TAVR) have had evidence of obstructive CAD [6,141]. Presence of significant CAD prior to TAVR has been associated with increased 1-year mortality [142]. FFR-guided revascularization in this population has been shown in observational studies to have superior MACE and cerebrovascular-event free survival compared to angiography-guided PCI [141,143]. The utility of FFR pre-TAVR in the setting of significant aortic stenosis in measuring relevant hemodynamic parameters, however, has conflicting data. Stundl et al. noted that FFR did not significantly change pre- and post-TAVR, while Ahmad et al. showed that FFR values were overestimated pre-TAVR [144,145]. Utilization of IFR seems to be less influenced by the presence of a severely stenotic aortic valve [145]. Current evidence suggests utilizing FFR cutoffs <0.8 in conjunction with IFR thresholds of <0.89 to drive intervention in pre-TAVR candidates [141]. Regardless, there are no clear randomized controlled trials (RCTs) to show the utility of FCA in improving clinical outcomes pre and post TAVR.

5. INOCA vs MINOCA

Ischemia with Non-Obstructive Coronary Arteries (INOCA) is a condition characterized by signs and symptoms of ischemia in the absence of obstructive CAD [146]. Conversely, Myocardial Infarction with Non-Obstructive Coronary Arteries (MINOCA) is defined by clinical evidence of acute MI, without angiographic obstructive CAD [147]. Distinguishing between INOCA and MINOCA hinges on the clinical presentation and evidence of myocardial necrosis. Specifically, MINOCA is diagnosed by a rise and/or fall of cardiac troponin values with at least one value above the 99th percentile upper reference limit, corroborative clinical evidence of MI, documentation of coronary stenosis less than 50% in any potential infarct-related artery by coronary angiography, and exclusion of specific overt causes for the clinical presentation [147,148]. Conversely, the ischemia in INOCA lacks significant biomarker or ECG evidence of MI. INOCA can result from various pathophysiological mechanisms, including CMD, vasomotor disorders, or endothelial dysfunction [146,149–152]. MINOCA also has diverse etiologies, including atherosclerotic plaque disruption, coronary artery spasm, coronary embolism, CMD, and supply-demand mismatch [153]. CMD in both INOCA and MINOCA not only correlates with diminished quality of life [154] but also an increased risk of mortality and MACE [155]. Similarly, patients with INOCA and vasomotor disorders, including vasospasm, often experience persistent angina and impaired quality of life, yielding adverse prognosis [156,157]. INOCA is not a benign condition and is also associated repeated hospital admissions and increased healthcare costs [149,152]. Current AHA/ACC guidelines on the evaluation and diagnosis of chest pain highlight the importance of assessing CMD and other causes of INOCA in symptomatic patients without obstructive CAD on previous workup, underscoring the importance of FCA [5].

Current AHA/ACC guidelines on evaluation and diagnosis of chest pain elucidate evidence gaps in diagnostic management of INOCA and MINOCA [5]. Roughly 6% to 15% of cases of troponin-positive ACS occur without obstructive CAD [5]. Additionally, the ESC and AHA consider MINOCA a working diagnosis that warrants additional diagnostic assessment [147,158].FCA is utilized to assess MINOCA and INOCA through a comprehensive assessment of CFR, microcirculatory resistance, and provocation/reactivity testing [159–161]. CFR is typically assessed using adenosine to induce hyperemia, with a CFR <2.0 indicating impaired CFR. Microcirculatory resistance is quantified using an IMR, with an IMR ≥25 indicating increased resistance. Endothelial-independent microvascular function is evaluated by measuring CFR and hyperemic microvascular resistance after adenosine administration, with hMR ≥2 considered abnormal. Endothelial-dependent microvascular function is assessed using intracoronary acetylcholine, where a <50% increase in coronary blood flow or any epicardial vasoconstriction indicates endothelial dysfunction. Provocation of coronary vasospasm is performed using high-dose acetylcholine, with a reduction in coronary diameter >90% along with symptoms and ST-segment changes confirming vasospastic angina. The ACC and AHA recommend these invasive coronary function tests as part of the diagnostic work-up for patients with INOCA and MINOCA to tailor appropriate therapy [162]. FCA with invasive coronary reactivity testing may guide targeted medical therapy and lifestyle interventions as evidenced by the CORonary MICrovascular Angina (CorMicA) trial that stratified medical therapy based on invasive coronary function testing and led to symptom relief and improved quality of life [5,163]. In addition, in MINOCA patients suspected of having coronary vasomotor abnormalities, provocative testing for spasm has been shown to be safe and may identify patients at high-risk of adverse events [164]. Overall, FCA plays a pivotal role in both MINOCA and INOCA by providing insights into the physiological significance of coronary lesions and guiding appropriate treatment.

6. Role of artificial intelligence in assisting functional coronary angiography

Artificial intelligence (AI) has shown potential in enhancing the interpretation of FCA. Three-dimensional coronary anatomy reconstruction and post-PCI FFR computation is being integrated into AI cloud-based platforms with algorithms capable of medical information processing, offering instant treatment recommendations [165]. Additionally, AI, combined with coronary angiography videos using a 3D convolutional neural network, has been shown to predict the presence or absence of clinically significant coronary artery stenosis [166]. Furthermore, AutocathFFR, an automated AI angiography-based FFR software, has demonstrated excellent accuracy in predicting clinically significant wire-based FFR (PPV of 94% and NPV of 87%, indicating AUC 0.91), offering promising technology that may guide management in patients with functionally significant CAD [167]. AI Quantitative coronary angiography (QCA) has been proposed as an automated tool for the analysis of major vessels in coronary angiography, showing strong correlations with manual QCA for major vessel lesions; however, smaller vessel branches need further AI integrated analysis [168]. Similarly, a retrospective post hoc analysis derived from the Computed TomogRaphic Evaluation of Atherosclerotic DEtermiNants of Myocardial IsChEmia (CREDENCE) trial demonstrated that CCTA with AI-quantitative CT (QCT) had higher diagnostic performance than myocardial perfusion imaging (MPI) for detecting obstructive CAD. Such utility may reduce unnecessary subsequent invasive testing [169].

7. Current challenges

While the scientific community has established the benefits of functional evaluation prior to coronary intervention, these modalities continue to be underutilized [24]. FFR has been slowly adopted since it is expensive, time-consuming, and technologically challenging and requires the use of a hyperemic agent which can be procedurally challenging [25,26]. Methods derived after FFR attempt to improve upon FFR by removing the need for hyperemic agents (IFR, RFR, dPR) but continue to require pressure wiring and sometimes are limited by the challenging timing of pressure measurements throughout the cardiac cycle. Furthermore, these measures have less data supporting their use and have not yet been included in clinical guidelines (with the exception of IFR). Additional measures such as OFR and UFR still require expensive OCT or IVUS to obtain measurements as well as novel software. Methods independent of invasive pressure wiring such as QFR or FFRangio show promise but have limited data. Additionally, these methods use complex novel software and calculations, assume population level blood flow characteristics, and require high computational time. As these methods improve, and additional randomized data is obtained, it may be possible to provide functional assessment with similar accuracy to invasively obtained measures.

8. Future directions

There are several ongoing and recent trials evaluating additional uses of FCA across a variety of clinical indications. These trials are summarized in Table 2.

Table 2.

Current and Ongoing Clinical Trials.

Study	Design	Objective	Outcomes	Enrollment	Anticipated Completion
QFR-Guided Revascularization Strategy for Patients Undergoing Primary Valve Surgery With Comorbid Coronary Artery Disease (FAVOR4-QVAS) NCT03977129	Multicenter, prospective, randomized, blinded, controlled	Compare a QFR-guided revascularization strategy to a coronary angiography-guided strategy in patients undergoing primary valve surgery	30-day incidence of MACE-5 (all-cause death, myocardial infarction, stroke, unplanned coronary revascularization, and new renal failure requiring dialysis)	792	December 2026
FAVOR V AMI NCT05669222	Prospective, multicenter, blinded, randomized, sham-controlled trial	Compare a strategy implementing next-generation quantitative flow ratio (μQFR) and radial wall strain (RWS) assessment vs standard treatment strategy in guiding revascularization in patients with STEMI and multivessel disease	Incidence of MACE (all-cause death, MI, or ischemia-driven revascularization)	5000 (Estimated)	June 2028
Clinical Outcomes of CT-FFR Versus QFR-guided Strategy for Decision-Making in Patients With Stable Chest Pain (CONFIDENT) NCT05857904	Prospective, multicenter, blinded, randomized controlled trial	Non-inferiority trial investigating CT-FFR versus QFR in decision-making for patients with stable chest pain	Incidence of MACE (all-cause death, MI, or ischemia-driven revascularization, non-lethal stroke) at 1 year	4648	May 2028
The Value of FFR Derived From Coronary CT Angiography as Compared to CCTA or CCTA and Stress MPI in the Triage of Low to Intermediate Emergent Chest Pain Patients With Toshiba CT-FFR NCT03329469	Prospective, observational trial	Investigate the use of CT-FFR to CCTA in patients presenting to the emergency department presenting with chest pain meeting criteria for CCTA	Evaluate sensitivity, specificity, positive and negative predictive value for CT-FFR, compared to invasive FFR	1142	March 2024
CT Stress Myocardial Perfusion, FFR and Angiography in Patients With Stable Chest Pain Syndromes (DYNAMITE) NCT04709900	Randomized controlled, open label trial	Compare a combined anatomical and functional assessment (CT angiography, CT-FFR, and dynamic CT stress myocardial perfusion) to standard care	Incidence of MACE (cardiovascular death, acute myocardial infarction, stroke, or hospitalization for heart failure)	2000 (Estimated)	December 2031
Comparison of Flow Ratio Derived From IVUS With Coronary Angiography in Stable CAD: Correlation With FFR NCT06322355	Retrospective, observational trial	Compare IVUS determined UFR to QFR in detection of functionally significant coronary lesions	Comparative performance	250	December 2023
Angiography-Derived FFR And IVUS for Clinical Outcomes in Patients With CAD (FLAVOUR II) NCT04397211	Prospective, multicenter, randomized trial	Non-inferiority trial for angiographically derived FFR-guided strategy to PCI versus IVUS-guided strategy to PCI	Incidence of MACE (all death, MI, or any revascularization at 12 months)	1872	September 2028
Selective Coronary Revascularization in PAD Patients After Lower-extremity Revascularization (SCOREPAD) NCT06250790	Prospective, observational, randomized trial	Assess the efficacy of CT-FFR guided revascularization in improving cardiac outcomes in patients without known coronary disease who recently received revascularization for PAD	Incidence of MACE (cardiac death, MI or urgent coronary revascularization)	600	February 2029
Safety and Feasibility Evaluation of Planning and Execution of Surgical Revascularization Solely Based on Coronary CTA and FFRCT in Patients With Complex CAD (FASTTRACK CABG) NCT0414202	Multicenter, observational, prospective cohort trial	Assess the safety and feasibility of CABG decision making based solely on CCTA and CTFFR.	Rate of graft stenosis 1 month after surgery	114	December 2022

CABG: Coronary artery bypass grafting; CCTA: Coronary computed tomography angiography; CT-FFR: Computed tomography derived fractional flow reserve; MACE: Major adverse cardiovascular events; MI: Myocardial infarction; PAD: Peripheral artery disease; PCI: Percutaneous coronary intervention; QFR: Quantitative flow ratio; STEMI: ST elevation myocardial infarction; UFR: Intravascular ultrasound derived fractional flow reserve.

8.1. Utility in CABG

FCA has established the use of IFR and FFR in angiographically indeterminant disease, with a class Ia recommendation from the 2021 AHA/ACC/SCAI guidelines [6]. However, the guidelines call for more data on the use of FCA in CABG decision-making. A 2020 metanalysis on outcomes in the use FFR-guided CABG vs. angiography-guided CABG disclosed improved outcomes in all-cause mortality, but did not establish benefit in reducing MI or revascularization [170]. Safety and feasibility of CT-FFR guided CABG is also being evaluated over ICA in the Safety and Feasibility Evaluation of Planning and Execution of Surgical Revascularization Solely Based on Coronary CTA and FFRCT in Patients With Complex Coronary Artery Disease (FASTTRACK CABG) study. Positive results could suggest a role for non-invasive methods in CABG decision-making [171]. However, FFR is far from overtaking ICA in determining need for CABG.

8.2. FFR-CT

The integration of FCA has guided the need for investigating non-invasive methods of functional assessment for risk stratification. With the increasing use of CCTA, FCA has also expanded. The Effect of on-Site CT-derived Fractional Flow Reserve on the Management of Decision Making for Patients With Stable Chest Pain (TARGET) showed efficacy of CT-FFR following CCTA in reducing unnecessary ICA over CCTA followed by standard care [172]. This study was closely followed by the Prospective Randomized Trial of the Optimal Evaluation of Cardiac Symptoms and Revascularization (PRECISE) RCT comparing standard care of stress testing and ICA to a cohort utilizing the Prospective Multicenter Imaging Study for the Evaluation of Chest Pain (PROMISE) trial's validated risk stratification tool followed by CCTA with FFR-CT to determine need for ICA. The primary endpoint was a composite of clinical efficiency and safety, with the CCTA and selective FFR-CT group demonstrating a lower rate of ICA without obstructive disease, MI, or death than the usual care group [173]. These studies further the discussion of CT-FFR over other forms of evaluating patients with stable chest pain [174,175].

8.3. Developments in quantitative flow ratio

QFR has been studied with consistent advancements noted in the FAVOR China trials [176]. The FAVOR III China Study (FAVORIII) demonstrated efficacy in QFR-guided PCI selection versus angiography guided selection, with evidence of fewer MIs and ischemia-driven revascularizations in the QFR-guided group [177]. Further clinical trials continue to explore the utility of QFR in various coronary pathologies, with ongoing trials assessing the need for revascularization prior to surgical valve replacement and in patients with STEMI [178,179]. QFR advancements have continued with the investigations of non-invasive methods of measurement, namely CT-QFR.

8.4. Integration of novel techniques & technologies

8.4.1. Murray's law based QFR & CT-QFR

Traditional QFR measurement requires two angiographic views at least 25° apart which can prove difficult with curved coronary anatomy. A novel approach to QFR utilizes one view of a coronary, titled Murray's Law-Based QFR (μQFR). The principle states that when a parent blood vessel branches into daughter vessels, the cube of the radius of the parent vessel is equal to the sum of the cubes of the radii of daughter blood vessels [180]. Applying this law to traditional QFR allows for more accurate vessel size calculation and better assessment of bifurcation. This approach demonstrated high correlation and agreement with FFR with comparable results to QFR in the FAVOR II population [181]. Application of μQFR over QFR in clinical research is currently underway [179].

CT-QFR has emerged as a novel non-invasive method of measuring QFR. The method has demonstrated excellent sensitivity (87.7%) and specificity (86.8) in determining lesions with an FFR of ≤0.8 [182]. The Diagnostic Accuracy of CCTA-derived Versus AngiogRaphy-dErived QuantitativE Flow Ratio (CAREER) study is investigating the diagnostic accuracy of CT-QFR in determining physiologically significant stenosis and is assessing for non-inferiority with QFR [183].

8.5. Exploration of new clinical applications & research directions

With the rise of non-invasive FCA, a reasonable clinical application is screening for CAD in patients at risk for cardiac death without active angina. Such is the case in the Selective Coronary Revascularization in Peripheral Artery Disease Patients (SCOREPAD) trial, which is evaluating coronary CT-FFR in patients with recent interventions for peripheral artery disease (PAD) [184]. Similarly, the diagnostic accuracy of CT-FFR for significant CAD has also been in those undergoing liver transplant, demonstrating efficacy in excluding hemodynamically significant CAD in 69% of cases [185]. Further research in FCA can be directed outside the realm of CAD. Ultimately, expansion into non-invasive measurements could encourage research into functionally-guided intervention of vascular disease, such as ischemic stroke, carotid stenosis, or PAD.

CT-FFR has the potential to progress substantially. Spectral photon-counting CT (SPCCT) can increase resolution and decrease artifacts as compared to conventional computed tomography, and has shown efficacy at reduced radiation doses [186]. The reduction in artifacts applies to coronaries with prior stenting, thereby improving diagnostic accuracy in this group [187]. Applying FFR-CT to this novel method of CT could allow for diagnostic utility in patients with prior coronary stenting.

The future of AI and machine learning can be utilized to expedite clinical decision making directly in the catheterization lab [188,189]. Beyond the catheterization lab, AI assisted-CCTA can be used in conjunction with CT-FFR as a tool to assess coronary lesions that would benefit from PCI [190,191]. Further research can be directed at the use of machine learning as a tool in clinical decision making for PCI compared to current standard of care. By nature of AI, the tools will continue to improve, and it is important that interventionalists embrace it as capable of reducing procedure time and radiation exposure and improving patient outcomes.

9. Conclusion

FCA is an emerging field that continues to be valuable in detecting clinically significant obstructive or nonobstructive CAD. While there are many gold standard methods utilized in FCA (eg, FFR and IFR), many newer methods within this review may show promising utility in the future (eg, QFR, CFR), especially when integrated with AI. The future of FCA is characterized by a shift towards non-invasive, precise, and technologically advanced approaches, driven by innovations in FFR-CT, QFR, μQFR, CT-QFR, and AI-driven applications. In both INOCA and MINOCA, FCA has proven to be indispensable for diagnosing underlying pathophysiological mechanisms and guiding appropriate treatment strategies. The methods outlined above highlight the utility of FCA in various clinical scenarios, such as subclinical atherosclerosis, myocardial bridging, and in-stent restenosis, among others. FCA improves the accuracy of diagnosing hemodynamically significant lesions, guides effective treatment strategies, and informs clinical decisions, thus enhancing patient outcomes in CAD management. While current challenges facing FCA such as technological complexity, cost, and limitations of newer modalities hinder widespread adoption in clinical practice, ongoing research and development in FCA techniques hold promise for overcoming these obstacles.

Ultimately, FCA advancements hold promise for optimizing patient care, improving diagnostic accuracy, and reducing unnecessary invasive procedures. The evolving landscape of FCA may extend beyond CAD, potentially influencing various vascular pathologies, thus paving the way for personalized and functionally guided interventions in cardiovascular medicine. Ongoing clinical trials and research endeavors will continue to shape and refine the role of FCA in clinical practice, with the goal of improving patient outcomes and healthcare efficiency.

10. Future perspective

Future directions for FCA in the next 10 years, particularly for diagnosing conditions like MINOCA and INOCA are poised to advance significantly. One key area of development is the integration of multimodality imaging techniques. The use of stress perfusion CMR and CCTA is expected to become more prevalent, providing comprehensive anatomical and functional assessments in a single session. Additionally, the refinement of microvascular resistance measurements, such as the IMR and hMR, will likely enhance diagnostic accuracy and therapeutic decision-making. These indices offer precise insights into microvascular function and are expected to be more widely adopted in clinical practice.

The ACC and the AHA emphasize the importance of invasive FCA for risk stratification and guiding therapy in patients with INOCA, a practice that is anticipated to expand [5,6]. Furthermore, ongoing and future clinical trials aim to address current knowledge gaps and optimize management strategies for these patients [4].

Overall, the future of FCA will likely involve a more integrated, multimodal approach, combining advanced imaging techniques and physiological assessments to improve diagnostic accuracy.

Author contributions

Conceptualization: C Krittanawong, M Khawaja, M Alam, SK Sharma, H Jneid. Data curation: S Chandrasekhar, B Montelaro, E Woods, P McLean, J Bennett. Project administration: C Krittanawong. Resources: J Bennett, S Chandrasekhar, B Montelaro, E Woods, P McLean.

Visualization: N Newman, HUV Virk, M Khawaja. Writing – original draft: P McLean, S Chandrasekhar, B Montelaro, E Woods, J Bennett, M Khawaja, C Krittanawong. Writing – review & editing: HUV Virk, C Krittanawong, M Khawaja.

Competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.