Update in Coronary Physiology

INTRODUCTION

A physiologic assessment of coronary artery disease (CAD) is used to determine the need for myocardial revascularization. Although we have numerous modalities available for coronary physiological assessment, their adoption is limited due to several factors.^[1]

It is performed:

1. To determine the hemodynamic significance of native coronary lesions

2. To determine whether optimal results were obtained after percutaneous coronary intervention (PCI).

3. To stratify revascularization-PCI versus coronary artery bypass grafting (CABG).

In addition to hyperemic indices (adenosine fractional flow reserve [FFR]), non-hyperemic indices (Instantaneous Wave- Free Ratio [iFR], diastolic pressure ratio [dPR], and relative flow ratio [RFR]) are also available. A thorough understanding of coronary anatomy is essential for treating CADs such as overlap, foreshortening of vessels, angulations, tortuosity, ectasia, and calcified lesions which may further affect our decision-making on lesion severity.^[2,3]

In fact, coronary image-based physiology has demonstrated promising results with a reduction in time, costs, radiation exposure, and patient risks.

CURRENTLY AVAILABLE PHYSIOLOGICAL ASSESSMENTS

Current cutoff criteria for revascularization:

• ≤0.80 for computed tomography (CT)-derived FFR

• 0.91–0.93 for hyperemic pressure ratio

• ≤0.89 for non-hyperemic wire-derived pressure ratios

• ≤0.80 for angiography-derived FFR.

Accordingto Kogame et al.,^[1] available physiological asessments are depicted in Table 1.

FFR

FFR is the gold standard invasive diagnostic test derived by the mean ratio of distal coronary pressure to aortic pressure at maximum hyperemia.^[1] This measurement is usually taken during maximal hyperemia, which is induced by administering a vasodilator (such as adenosine) to ensure that the coronary artery is maximally dilated.^[1,2,4]

• FFR ≤ 0.80: Implies that the lesion is significantly impairing the blood flow and is likely to benefit from revascularization

• FFR > 0.80: Implies that the lesion is less likely to benefit from revascularization.^[1]

An example of Fractional flow reserve evaluation done to intermediate lesion in LAD has been shown in Figure 1.

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Figure 1

(a) Coronary angiogram in left anterior oblique view showed left anterior descending artery ostio-proximal lesion of maximum 60% stenosis-intermediate lesion. Red arrow indicates lesion in ostio proximal LAD. (b) Fractional Flow reserve done to LAD showed phsyiologically significant lesion with value of 0.77 for which he underwent further revascularization. (CAG: Coronary angiogram, FFR: Fractional Flow Reserve, Pa: Aortic pressure (blood flow in coronary artery without stenosis), Pd: Distal pressure (blood flow in stenotic coronary artery).

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Pressure guide wire interrogation is currently recommended to assess hemodynamic relevance in intermediate-grade coronary stenosis (Class I, level of evidence A) and in patients with multivessel disease undergoing PCI (Class IIa, level of evidence B).^[3]

Both fractional flow reserve versus angiography for guiding percutaneous coronary intervention (FAME) 1 and FAME 2 trials demonstrated that FFR-guided PCI significantly reduced major adverse cardiac events compared to angiography-guided PCI. The FAME II trial, in particular, showed a significant benefit of FFR-guided revascularization in improving outcomes and reducing the need for subsequent procedures. ADVANCE study, objective randomized blinded investigation with optimal medical therapy of Angioplasty in Stable angina (ORBITA) trial, and DEFINE-functional lesion assessment of intermediate stenosis to guide revascularization (FLAIR) trial supported the role of FFR in multivessel diseases and reduction in the number of unnecessary interventions.^[1,2]

The advent of FFR is not only useful in detecting intermediate lesions but also in myocardial bridging which is a silent bystander. The presence of atherosclerotic plaque proximal to the bridged segment may lead to chronic coronary syndrome (CCS) and acute coronary syndromes, due to mechanisms such as plaque erosion or rupture, vasospasm, or even spontaneous coronary dissection.^[5]

According to Escaned et al., physiological assessment before PCI plays a key role in determining the need for intervention, identifying flow-limiting lesions, and guiding stent strategy.^[6] FFR helps to identify ischemic lesions and avoid unnecessary procedures. Longitudinal vessel analysis further characterizes disease patterns whether they are focal, tandem, or diffuse guiding stent length, number, and placement. Likewise, post-PCI physiological assessment confirms whether the intervention has effectively restored coronary flow. This includes evaluating the treated vessel and any jailed side branches (SBs) to identify residual ischemia that may not be apparent on angiography. Longitudinal post-PCI analysis can uncover the cause of suboptimal results and guide further optimization strategies. Repeat measurements after additional PCI help determine if remaining issues are treatable or if alternative approaches such as medical therapy or surgery are needed. Together, these steps ensure a functional, patient-specific, and outcome-driven approach to PCI.^[6-8]

IFR-INSTANTANEOUS FLOW RATIO

The potential advantage of iFR is that it obviates the use of adenosine because it does not require the wave-free period, which occurs during diastole when coronary flow is relatively stable and less affected by changes in myocardial demand.

It is calculated using the ratio of the average pressure distal to the lesion to the average pressure proximal to the lesion during this wave-free period as shown in Figure 2.^[2,5]

DEFER, DEFINE FLAIR, iFR-SWEDEHEART study demonstrated that iFR is an alternative to FFR for assessing the need for revascularization, especially in patients with intermediate lesions. Furthermore, the follow-up trials at 1 and 5 years showed that iFR-guided procedures were much safer and had low event rates compared to FFR. It is helpful in serial lesions or complex mixed patterns where the coregistered segment is responsible for the highest iFR loss in the vessel which in turn reduces the number and length of stents during PCI planning. In REFINE-RPG study, no statistical difference was found between iFR and FFR in the revascularization follow-up arm. Hence, with available techniques with a pressure wire and thermal dilutional sensor, we are able to perform a comprehensive single assessment of coronary circulation including epicardial, microvascular, and vasomotor function.^[2,7,9,10]

iFR has some drawbacks compared to FFR:

1. Smaller gradients make iFR more sensitive to noise.

2. Hydrostatic effects can distort measurements.

3. Wire drift during pullback can reduce accuracy.

4. Hemodynamic sensitivity to blood pressure and heart rate variations can affect baseline coronary flow readings.^[2,6]

ANGIOGRAPHIC-BASED PHYSIOLOGY

The first software available was based on coronary CT. Multiple software programs varying from using one angiographic projection view to three views are available. Professor Serruys showed that the overall performance of the software as compared to wire-based physiology was far superior.

Quantitative flow ratio (QFR) represents an advanced, noninvasive method for assessing the physiological significance of coronary lesions, offering a convenient alternative to traditional FFR.^[11,12]

FFR angio is far more specific and accurate than conventional FFR. It can gradually overtake conventional FFR in delineating lesions and helps in improved patient outcomes.^[6] Advantages and limitations of QFR is shown in Table 2.^[2,5]

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Figure 2:

On cardiac cycle showing timing of iFR. Hyperemic and non-hyperemic pressure ratios (fractional flow reserve, dFFR, iFR, relative flow ratio, diastolic pressure ratio) proposed for the invasive functional assessment of patients with myocardial bridging. [Pa: Aortic pressure (blood flow in coronary artery without stenosis), Pd: Distal pressure(blood flow in stenotic coronary artery), RFR: resting full-cycle ratio, iFR: Instantaneous wave free ratio, dFFR: diastolic Fractional flow reserve, dPR: diastolic Pressure ratio. Red line-PaAortic pressure (blood flow in coronary artery without stenosis), Green line-Pd-Distal pressure (blood flow in stenotic coronary artery)], Yellow line-Pressure in mm. FFR: Fractional flow reserve

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Key features of QFR:

1. Derived from standard coronary angiography images using advanced software algorithms

2. No hyperemic agents

3. The technique analyzes the flow dynamics of contrast within the coronary arteries to calculate a flow ratio reflecting the lesion’s physiological impact

4. It uses a geometric analysis of angiograms, considering vessel dimensions and contrast flow characteristics, to estimate pressure drop across a lesion

5. QFR value of ≤0.80 indicates a functionally significant lesion that may benefit from revascularization.^[2,11-13]

6. The FAST-FFR study was a prospective, multicenter trial that aimed to assess the accuracy of FFR angio compared to standard FFR as it eliminates the need of pressure wires and hyperemia. It worked by generating a three-dimensional (3D) reconstruction of the coronary arteries and estimating resistance and flow across stenoses.^[4]

The FAST-FFR study was a prospective, multicenter trial that aimed to assess the accuracy of FFR angio compared to standard FFR as it eliminates the need for pressure wires and hyperemia. It worked by generating a 3D reconstruction of the coronary arteries and estimating resistance and flow across stenoses. FFR angio is far more specific and accurate than conventional FFR. It can gradually overtake conventional FFR in delineating lesions and help in improved patient outcomes.^[4]

After FAVOUR II, a multicentric trial showed QFR being superior, FAVOR III China study was done, and follow-up study of 3285 patients after 2 years revealed QFR-guided PCI resulted in 35% risk reduction of major adverse cardiovascular events (MACE) compared to angiographic-guided PCI.^[2,12]

FIRE trial subanalysis done to support QFR showed non-inferiority to wire-based FFR in these elderly patients with high bleeding risk.^[14]

AQVA (Angio based Quantitative Flow ratio virtual PCI versus Conventional Angio guided PCI in the Achievemnt of an Optimal Post PCI QFR) trial and AQVA-II trial confirmed that QFR was better in simple and complex lesions such as longer lesion (>28 mm), tandem lesions, severe calcifications, severe tortuosity, true bifurcation, in-stent restenosis, and left main stem disease.^[15,16]

QFR-based virtual PCI requires advanced software and expertise to accurately perform and interpret QFR measurements.^[2,17,18]

CORONARY MICROCIRCULATION DYSFUNCTION (CMD) AND THE INDEX OF MICROCIRCULATORY RESISTANCE (IMR)

Non-obstructive CAD (NOCAD) should be considered in patients with persistent angina after complete revascularization. Systematic evaluation using non-invasive or invasive tests for coronary microvascular dysfunction (CMD) is essential, as these patients often undergo repeated coronary imaging, increasing healthcare costs. Angina in NOCAD is also linked to a higher risk of adverse clinical events.^[1]

CMD is a critical contributor to CAD. IMR helps in understanding the interactions between epicardial (large coronary vessels) and microcirculatory (small vessels) dysfunctions. This is crucial because microcirculatory dysfunction can occur even when major coronary arteries appear normal. IMR is calculated using hemodynamic parameters, including coronary flow rate, distal coronary pressure, and aortic pressure.

According to European Society of Cardiology updated guidelines, invasive coronary functional testing is now upgraded to class 1B and now extends to recognize that CCSs may be caused due to dysfunction of the microcirculation.^[19] Figure 3 depicting coronary flow reserve and index of microcirculatory resistance.

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Figure 3:

Diagram depicting CFR and IMR. (IMR: Index of microcirculatory resistance, CFR: Coronary flow reserve, RFR: Resting full -cycle Ratio, FFR: Fractional flow reserve.)

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Figure 4:

An example of computed tomography-derived fractional flow reserve with total occlusion. Blue-represents normal blood flow fractional flow reserve (FFR)>0.80, Red- abnormal FFR- < 0.75, Yellow/orange-between the value 0.76 -0.80.

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Figure 5

(a) Coronary angiogram, red arrows showing significant lesions of 80% and 99% lesion each. (b) FFR tracing of the same vessel. A 45-year-old gentlemen, a known diabetic, came with unstable angina. His coronary angiogram showed single vessel coronary artery disease – two tandem lesions in RCA 80% and 99% each. Fractional flow reserve (FFR) done in RCA pre-percutaneous coronary intervention (PCI) showed an initial FFR value of 0.35. Subsequently, FFR post-PCI showed 0.88. Yellow arrow- indicates dip in pressure suggesting significant lesion. (RCA: Right coronary artery).

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Figure 6

(a) shows RCA after revascularization, (b) shows pullback showing no further lesion ie post PCI FFR shows no pressure drop. Subsequently, fractional flow reserve post-percutaneous coronary intervention of the same patient showed 0.88. (RCA-Right coronary artery, FFR-Fractional flow reserve, PCI-Percutaneous coronary intervention)

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Figure 7

(a) Computed tomography (CT) coronary angiography revealed calcified plaques in the left anterior descending and left circumflex (LCX) arteries, with the LCX showing approximately 90% stenosis in the mid and another distal lesion of 60%. Red arrow shows significant lesion in left circumflex artery. b) Conventional coronary angiogram shows similar LCX lesion. Red arrow shows significant lesion in left circumflex artery. Black arrow shows area with non -significant lesion. c) CT-derived fractional flow reserve (CT-FFR) showed value of 0.84 depicting black arrow suggesting it is not significant . Black arrow shows area with non -significant lesion, red arrow shows significant lesion in left circumflex artery. d) invasive FFR showed similar value of 0.84 in distal LCX accurately thereby helping to avoid unnecessary invasive evaluation.

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CT-FFR

Computed tomography-derived FFR (FFR-CT) is derived by merging a three-dimensional (3D) reconstruction of vessels from CTCA with computational fluid dynamics, thereby providing a reliable estimate of invasive FFR.^[21,22]

The advantages of CT-QFR (over CT-FFR) are the fast analysis time and the inclusion of distal vessels down to 1.5 mm. A physiologic model is developed based on individual patient hemodynamic conditions, focusing on inflow and outflow dynamics. The resting myocardial blood flow is considered proportional to the myocardial mass, while microvascular resistance is inversely related to the size of the epicardial coronary arteries. This model allows for a more tailored assessment of coronary function, considering individual variations.^[2,23,24]

FFR-CT is a powerful non-invasive tool for assessing coronary lesions, but its interpretation should be comprehensive, factoring in clinical and anatomical details. Combining FFRCT with clinical judgment ensures more accurate decision-making for patient management and revascularization strategies.^[2,21,23,25] Figure 4 depictingComputed tomography dervied FFR ( Fractional flow reserve)with total occlusion of LCX- FFR is 0.75. Table 3 represents the colour coding and respective FFR values.

DISCUSSION

Target FFR is the first randomized trial specifically focused on post-PCI FFR done by Collison et al. in 2021.^[26] According to his study, one-third of patients achieved an FFR value of >0.9, whereas one-third of patients still had an FFR <0.8. Post-PCI intracoronary pressure measurements can identify residual flow-limiting disease in 10–36% of cases despite successful PCI. It is important to differentiate residual focal lesions from diffuse disease and provide prognostic information.^[26,27]

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Figure 8:

Case IV - Another patient with single vessel disease of left anterior descending (LAD) - coronary angiography done showed proximal to mid LAD had long-segment diffuse 90% stenosis, followed by distal LAD 50% stenosis and major diagonal had 60% stenosis. CT-FFR was as accurate as conventional fractional flow reserve done to LAD and D1. (a) Red arrow indicates the lesion in LAD of interest in CTCAG, (b) CAG showing proximal to mid significant lesion, (red arrow) (c) CT FFR showing Red arrow-the area of interest of narrowing according to CAG, black arrow- significant lesion in distal LAD and diagonal side branch (FFR-Fractional flow reserve CAG: Coronary angiogram).

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Figure 9:

Computed tomography (CT) coronary angiography and conventional angiography showed that mid RCA had 95% stenosis and it correlated accurately with CT-FFR. (a) CT CAG showing significant stenosis in RCA -mid part, black arrow indicating the lesion site, (b) CT-FFR done to distal part of RCA, (black arrow pointing it) is non -significant showing 0.87 and proximal arrow shows mid RCA with tight lesion (c) CAG showing similar lesion. Black arrow indicates lesion of interest in the mid RCA with tight lesion and distal arrow pointing RCA shows 0.88 -non significant. (FFR: Fractional flow reserve, CAG: Coronary angiogram, CT-FFR: computed tomography, CT CAG: Computed tomography coronary angiogram, RCA: Right coronary artery).

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Figure 10:

Another case of single vessel disease of left anterior descending (LAD) showing calcified plaque of 90% stenosis, followed by long-segment diffuse disease of distal LAD. Fractional fl ow reserve (FFR) value was 0.65. CT-FFR confirmed the same-FFR was 0.62. (a) CT CAG showing proximal LAD lesion (black arrows shows lesion of interest in proximal LAD), (b) CT FFR showing lesion in LAD (0.62) indicated by black arrow (c) CAG showing lesion in LAD black arrows indicate lesion of interest, black arrowheads indicate lesion of interest in LAD. Value was 0.65 (LAD: Left anterior descending artery).

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According to Johnson and Collet,^[28] Collet et al.^[29] events can occur inside or near the stent after implantation. Therefore, performing post-PCI FFR helps to reduce target vessel failure.

Figure 5 and 6 shows Fractional Flow reserve done to Right coronary artery before and after revascularization. Post revascularization fractional flow reserve shows no difference with value being 0.95.

The double kissing crush technique (DKCRUSH)-VI trial suggests that FFR-guided intervention may reduce the need for SB treatment compared to traditional angiography.^[30]

In a study conducted over 3336 vessels in 9 studies, left anterior descending (LAD) was found to be associated with a lower post-PCI FFR than non-LAD arteries, emphasizing the importance of interpreting post-PCI-FFR on a vessel-specific basis. FFR value in LAD is lower than non-LAD vessels by 0.06. It is due to the large amount of myocardium supplied by LAD, amount of flow that goes through the vessels. Hence, post-PCI should be vessel specific. Furthermore, mechanisms leading to low FFR should be elucidated by pressure pull-back to differentiate between focal pressure gradients or diffuse pressure loss. RCA in comparison to the other left coronary artery has a better cut-off value.^[8,17,28]

Figure 7-10 depicts comparison of conventional coronarary angiogram (CAG) and fractional flow reserve and computed tomography CAG to Computed tomography fractional flow reserve.

Furthermore, the FAME 3 trial shows that FFR-guided PCI had comparable outcomes to CABG patients with triple vessel disease. Post-PCI-FFR measurement can also predict long-term outcomes and help to identify patients at risk for adverse events.^[19]

Post-stent FFR ≥0.89 was relevant to intravascular ultrasound (IVUS) minimal stent area (MSA) ≥5.4 mm² in terms of physiologic and anatomic parameters of optimal stent deployment and cut-off value for prediction of Target vessel failure (TVF)-free survival. FFR post-PCI can prevent unnecessary repeat procedures and correct improper peristent problems.^[29,31-33]

According to Dr Hwang et al.,^[27] 30% of angiographically successful lesions had low FFR in the target FFR trial and required additional procedure. Following stenting a stenosis, blood flow in the artery will increase and other gradients within the vessel may be unmasked or increase. There is no specific target for FFR post-PCI; however, a value between 0.85 and 0.9 is acceptable. FFR value of 0.8 or less is associated with residual ischemia and is known to cause increased risk of death and myocardial infarction (MI). One exception of focus step up post-PCI low FFR can be due to angiographically hidden lesion and image-guided physiology s helps in delineating it.^{[29,31,32-35]}

The prognostic value of post-stenting FFR appeared to be limited after the application of an imaging-guided optimal stenting strategy in a study conducted by Ahn et al. in 326 lesions.^[31]

FFR CT PLANNER

It is important to administer vasodilators before performing CT-FFR as they affect the diameter and calculation. It helps in defining plaque morphology, especially thin cap fibroatheromas. One of the advantages is that obtaining the results before entering the laboratory minimizes the radiation. Furthermore, It also helps in calulating post PCI FFR value, recalculates the flow rate to immediately assess the pressure loss after removal of these lesions.^[23,25]

The SYNTAX III revolution trial and RIPCORD study involved two heart teams that demonstrated incorporating CTA and FFRCT compared to CTA alone resulted in notable changes in treatment decisions.^[23]

Two large prospective multicenter studies such as DISCOVER-FLOW (Diagnosis of Ischemia-Causing Stenoses Obtained Via Noninvasive FFR) and DeFACTO (Determination of FFR by Anatomic Computed Tomographic Angiography) evaluated the diagnostic accuracy of computed tomography (CT)-based non-invasive FFR measurements.^[23-25]

Both trials found that non-invasive FFR significantly outperformed coronary CT angiography (CTA) alone in detecting hemodynamically significant coronary stenoses. For example, in the discover-flow study, the diagnostic accuracy of non-invasive FFR was approximately 84%, compared to only 59% for CTA alone. This improvement was primarily due to a reduction in false-positive findings associated with CTA.^[23-25]

IVUS BASED PHYSIOLOGY

Intravascular imaging (IVI) such as optical coherence tomography (OCT) and IVUS is considered as class I A recommendation, especially in the revascularization of complex PCI - left main, true bifurcations and long lesions in the new ESC 2024 guidelines.^[19]

ULTRASONIC FLOW RATIO (UFR)

It is also called ultrasound-based FFR that is a novel method designed for the rapid computation of FFR using IVUS images. The goal of UFR is to provide a fast and reliable assessment of coronary lesion significance by evaluating coronary physiology based on ultrasound-derived images.^[25]

The study demonstrated the feasibility of using morpho-functional computational methods to accurately estimate coronary physiology from IVUS images. It was found to be significantly better than IVUS-derived Minimal Lumen Area (MLA) in assessing coronary lesions. UFR benefits from a high level of automation through artificial intelligence, resulting in fast computational times and excellent reproducibility for flow estimation, especially in cases of complex coronary anatomy and assessing stent malposition or under-expansion. The current study showed that 64.9% of the vessels had bifurcation lesions, supporting the frequent use of IVUS in these settings.^[25]

Both IVUS and FFR provide complementary information that helps in clinical decision-making for interventions, especially in complex cases.^[22]

Application in left main coronary artery lesions has been a topic of significant clinical interest due to the complexity and critical nature of left main CAD. The MAIN-COMPARE trial and CART study showed that both IVUS and FFR are valuable, but combining them could offer a more comprehensive assessment, potentially leading to better outcomes in terms of reducing procedural complications and improving long-term prognosis. Many ongoing registries and smaller studies are looking into IVUS-FFR-guided approach. Ongoing studies are expected to further solidify the role of this integrated approach in coronary interventions. Limits of IVUS-FFR are due to vessel instrumentation.^[2]

Coregistration of physiological data with angiography, along with intracoronary imaging, ensures precise stent placement and avoids missing critical segments. Table 4 showing comparison of OFR and UFR.

THE VIRTUAL FLOW RESERVE (VFR) AND OPTICAL FLOW RATIO (OFR)

They represent advancements in the non-invasive assessment of CAD, particularly in the evaluation of intermediate lesions during coronary angiography.

VFR is derived from OCT data. It is technically feasible, easy to perform, requires minimal computation time, and also, shows a high diagnostic accuracy when compared to invasive FFR. Accuracy improves when accounting for the gray zone around the VFR cutoff of 0.80.

The combined use of VFR physiology and OCT morphology changes clinical decision-making compared to angiography or IVI-guided PCI without physiological guidance.^[22,36,37]

OFR’s integration in virtual PCI planning helps in eliminating the need for pressure wires or induced hyperemia. It automatically delineates lumen contours (MLA) and performs 3D reconstruction from OCT pullback, using computational fluid dynamics for assessment. OFR incorporates the fractal law to account for natural changes in lumen size due to bifurcations, improving reliability in complex anatomical scenarios. OFR has been validated against FFR in both de novo lesions and in-stent restenosis, demonstrating over 90% diagnostic accuracy.^[2,8,37] Furthermore, the accuracy and sensitivity were reassuring compared to positive FFR and QFR by overcoming the limitations like vessel shortening or overlap.^[37]

AFFE (angio based Final functional percutaneous coronary intervention study) PCI study showed that the combination of FFR and OCT improved the accuracy of lesion evaluation and treatment decisions, reducing the risk of unnecessary PCI or inadequate treatment.^[38]

COMBINE (OCT-FFR) is the first large prospective multi-center study that included diabetic patients who underwent angiography with at least 1 lesion ≥40-≤80% diameter stenosis on visual angiographic estimation. OCT helped in morphological evaluation of plaque, especially thin cap fibroatheroma along with functional assessment through FFR which in turn led to predicting MACE and revascularization rates.^[39]

The invasive nature and cost of FFR limit its wider use. In addition, a single main vessel pullback may inaccurately assess SB (side branch), as SB ostium disease and angulation can affect size quantification and vessel tapering models [Table 5].^[2]

CONCLUSION

Although FFR is a game changer in the assessment of intermediate CAD, alternative tools discussed here review present and future alternatives. Some of them simplify the procedure (by avoiding hyperemia, wires, or invasive catheterization) but may sacrifice diagnostic accuracy. While PCI is well accepted for focal CAD, the best approach for patients with significant blockages alongside diffuse disease remains under active study. Studies show that integrating FFR into clinical practice can lead to treatment reclassification in 30-50% of cases.