# Coronary Physiology: Delivering Precision Medicine?

Laura Maitre-Ballesteros, Laurent Riou, Stephanie Marliere, Marjorie Canu, Estelle Vautrin, Nicola Piliero, Oliviez Ormezzano, Helene Bouvaist, Alexis Broisat, Catherine Ghezzi, et al.

► To cite this version:

Laura Maitre-Ballesteros, Laurent Riou, Stephanie Marliere, Marjorie Canu, Estelle Vautrin, et al. Coronary Physiology: Delivering Precision Medicine?. Reviews in Cardiovascular Medicine, 2022, 23, 10.31083/j.rcm2305158. hal-05010710

HAL Id: hal-05010710

https://hal.science/hal-05010710v1

Submitted on 28 Mar 2025

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_1.png" /></figure>
Review

# Coronary Physiology: Delivering Precision Medicine?

Laura Maitre-Ballesteros<fnref n="1" />, Laurent Riou<fnref n="2" />, Stephanie Marliere<fnref n="1" />, Marjorie Canu<fnref n="1" />,
Estelle Vautrin<fnref n="1" />, Nicola Piliero<fnref n="1" />, Oliviez Ormezzano<fnref n="1" />, Helene Bouvaist<fnref n="1" />, Alexis Broisat<fnref n="2" />,
Catherine Ghezzi<fnref n="2" />, Daniel Fagret<fnref n="2" />, Gérald Vanzetto<fnref n="1" />,<fnref n="2" />,<fnref n="3" />, Loïc Djaïleb<fnref n="2" />,
Gilles Barone-Rochette<fnref n="1" />,<fnref n="2" />,<fnref n="3" />,*

## Abstract

Coronary physiological assessment is now widely used to assess epicardial coronary lesions in cath lab. Based on clinical evidence, fractional flow reserve (FFR) is the gold standard method to select whether epicardial coronary lesions need revascularization. While additional epicardial indexes, such as instantaneous wave-free ratio (iFR), are also used for revascularization decision-making, several indexes are now also available to explore the coronary microcirculation. Therefore, coronary physiological assessment now allows to explore the entire coronary tree and offer the potential of precision medicine for patients affected by coronary artery disease (CAD). This paper will provide review of the epicardial and microvascular indexes available for the assessment of coronary physiology. More specifically, the already demonstrated contributions of these indexes in the management of CAD and the role they could play in precision medicine will be reviewed with special emphasis on chronic coronary syndrome.

**Keywords:** coronary physiology assessment; coronary microcirculation dysfunction; precise medicine

## 1. Introduction

Coronary physiological assessment is usually used to assess epicardial coronary lesions in cath lab. Based on clinical evidence, fractional flow reserve (FFR) is the gold standard method to select whether epicardial coronary lesions need revascularization. While additional epicardial indexes, such as instantaneous wave-free ratio (iFR), are also used for revascularization decision-making, several indexes are now also available to explore the coronary microcirculation. Therefore, coronary physiological assessment now allows to explore the entire coronary tree and offer the potential of precision medicine for patients affected by coronary artery disease (CAD).

This paper will provide a review of the epicardial and microvascular indexes available for the assessment of coronary physiology. More specifically, the already demonstrated contributions of these indexes in the management of CAD and the role they could play in precision medicine will be reviewed with special emphasis on chronic coronary syndromes.

## 2. Definition of CAD and Pathophysiology

The relevance of the invasive coronary angiography (ICA) assessment of CAD severity is limited. Indeed, ICA predicts the hemodynamic significance of 40–70% coronary stenoses in less than 50% of cases [1]. This can be

explained by the fact that ICA does not allow the functionality of the entire coronary tree to be explored. The coronary vasculature may be divided into two components [2]. First, the macroscopic compartment assessed by ICA constitutes less than 10% of the coronary vasculature and is formed by the epicardial arteries (>400 µm) that have a conductance function. At this level the resistance to coronary flow is minimal in absence of epicardial stenosis. Second constitutes 90% of coronary vasculature, the microvascular compartment is constituted by pre-arterioles (100 to 400 µm), arterioles (40 to 100 µm), and capillaries (<10 µm). Pre-arterioles and arterioles regulate and distribute blood flow with maximum resistance to coronary flow to respond to the demands of tissue metabolism through capillaries. Arteriolar tone maintains coronary blood flow (CBF) constant over a wide range of coronary perfusion pressures, thereby attenuating ischemia during process of obstructive epicardial atherosclerosis. While ICA is unable to assess coronary microcirculation, the clinical manifestation of coronary disease depends on the involvement-possibly simultaneous-of these two compartments. ICA with coronary physiological indexes therefore have higher clinical relevance since they allow the analysis of the whole coronary tree. Several presentations are possible. Obstructive CAD occurs in patients with epicardial atherosclerotic lesions responsible for ischemia due to an increased oxygen demand not covered by a corresponding increase in CBF. Non-obstructive coro-

<figure><img src="image_2.png" /></figure>

<footnote n="1">¹Department of Cardiology, University Hospital, 38000 Grenoble Alpes, France</footnote>

<footnote n="2">²Univ. Grenoble Alpes, INSERM, CHU Grenoble Alpes, LRB, 38000 Grenoble, France</footnote>

<footnote n="3">³French Alliance Clinical Trial, French Clinical Research Infrastructure Network, 75018 Paris, France</footnote>

<footnote>*Correspondence: GBarone@chu-grenoble.fr (Gilles Barone-Rochette)</footnote>

<footnote>Academic Editors: Marco Zimarino and Nick Curzen</footnote>

<footnote>Submitted: 31 December 2021</footnote>

<footnote>Revised: 28 February 2022</footnote>

<footnote>Accepted: 17 March 2022</footnote>

<footnote>Published: 27 April 2022</footnote>
nary artery disease (NOCAD) represents an alternative clinical presentation, in which the evolutive risk corresponds to plaque rupture or erosion leading to an acute event. Several pathways are responsible for angina in non-obstructive CAD (ANOCA) or ischemia with nonobstructive CAD (INOCA). First, vasospastic angina (VSA), in which epicardial coronary artery are the site of vasospasm impairing coronary flow [3]. Second, coronary microvascular dysfunction (CMVD), whether due to structural abnormalities or the inability of the coronary microcirculation to vasodilate appropriately including vasospasm microvascular. There are several possibilities of structural microcirculatory abnormalities, which may be caused by inward remodeling of arterioles with a decreased lumen, or by capillary rarefaction or even capillary compression by myocardial hypertrophy and fibrosis [2].

**3. Methods of Coronary Physiology Assessment**

Recently published data indicate that inaccurate diagnosis of CAD leads to inappropriate treatment and is associated with major adverse cardiovascular events (MACE), persistent symptoms with reduced quality of life, repeated hospitalizations and unnecessary diagnostic procedures [4]. The key to a precise diagnosis is to explore the whole coronary tree with coronary physiological indexes, which cannot be performed by non-invasive methods [4]. Positron emission tomography (PET), transthoracic echocardiography, and cardiac magnetic resonance can detect CMVD by measure of coronary flow reserve (CFR). However, these techniques do not allow assessment of the relative participation of epicardial and microvascular diseases in the reduction of myocardial blood flow. Consequently, the etiology of ischemia as due to obstructive CAD or CMVD may not be systematically identified [5].

**3.1 Epicardial Coronary Artery Assessment**

**3.1.1 Fractional Flow Reserve**

FFR represents the ratio of maximal myocardial blood flow in the territory supplied by the coronary stenosis being interrogated to maximal myocardial blood flow in the same territory if the considered coronary artery was normal (no stenosis). Accordingly, FFR is derived from the ratio between mean coronary blood pressure distal to a stenosed segment (Pd) and mean proximal coronary pressure (Pa) during maximum CBF and a state of minimum microvascular resistance. Essentially, FFR is computed as Pd/Pa during hyperemia induced by intravenous infusion of adenosine for 3 minutes (140 µg/kg/min), or by intravenous bolus regadenoson (400 µg) [6], or by an adenosine intracoronary bolus injection (100 µg) in the right or left coronary artery (100 µg and 200 µg, respectively) [7], or by a papaverine intracoronary injection in the left or right coronary artery (12 mg and 8 mg, respectively). The correlations between these methods are excellent, but it can be noted that Regadenoson and intracoronary injections are faster methods with fewer side effects, especially flushing [6].

**3.1.2 Non-Hyperemic Pressure Ratios (NHPR)**

NHPRs obviate the necessity of adenosine administration. iFr (Philips/Volcano) is the first NHPR that have been proposed [8]. The study of the relationship between coronary pressure and coronary flow leads to the determination of a wave-free period which allowed the measurement of the Pd/Pa ratio during an interval in which microcirculatory resistance is constant but not necessarily minimal [9]. This mimics the constant microcirculatory resistance during the hyperaemic state whereby measured pressure is proportional to flow. Several other NHPRs have been developed with variations in the timepoint at which the Pd/Pa ratio is measured such as the resting full-cycle ratio (RFR) (Abbott), the diastolic hyperemia-free ratio (Boston Scientific), and the diastolic pressure ratio (Opsens Medical). It should be noted that NHPRs can be used only with vendor proprietary software. However, all these indexes appear comparable [10].

**3.1.3 Hyperaemic Stenosis Resistance (HSR)**

Even though the severity of the epicardial and microcirculatory damage are not related [11], the status of the microcirculation will influence the FFR measurement [12]. The HSR index is calculated using the formula (Pa - Pd)/average peak velocity (APV) during maximal hyperemia, and is defined as the resistance provided by the assessed coronary lesion [13]. Although HSR uses flow velocity measurement that depends on epicardial vasculature and microcirculation, it is an index only of epicardial lesions. A HSR value <0.80 mmHg/cm/sec is considered to indicate a significant epicardial stenosis [14].

**3.1.4 Angiography-Derived FFR**

Advances in computational power have allowed the development of angiography-derived FFR obviating the need for hyperemia and for a pressure wire. Angiography-derived FFR combines two projections to provide a 3D quantitative coronary angiography, which allows the reconstruction of the specific coronary geometry. An analysis using computational fluid dynamic (CFD) techniques or mathematical formulas then provides a rapid estimation of the pressure drop across a lesion. Angiography-derived FFR demonstrated excellent performances for the diagnosis of hemodynamically significant stenoses defined by FFR <0.80 [15]. Several angiography-derived FFR software packages have been developed. Specifically, Quantitative Flow Ratio (QFR), Cardiovascular Angiographic Analysis Systems for vessel Fractional Flow Reserve (CAAS vFFR), and FFRangio system are angiographically derived estimates of FFR with comparable performances [16]. Suboptimal performances of angiography-derived FFR have been shown for lesions located at bifurcations, for ostial lesions,

<figure><img src="image_3.png" /></figure>
or for lesions of left main coronary artery. Angiography-
derived FFR is also dependent on the quality of angio-
graphic images. It is recommended to have a good catheter
engagement in order to optimize contrast artery opacifica-
tion, to have two optimal angiographic projections >25°,
to avoid excessive movement of the X-ray tube, and to use
a zoom that cuts parts of the coronary to be analyzed. Like
NHPR, the main scientific limitation and challenge in these
technologies consists in the unassessed variability of the re-
sistance of the coronary microvascular bed which is not be-
ing evaluated.

3.1.5 FFR Derived from Computed Tomography (FFR CT)

As for the angiography-Derived FFR several steps will
be necessary to obtain the FFT CT from the Coronary com-
puted tomography angiography (CCTA) imaging. First
step, with CCTA image data set an anatomic model of coro-
nary arteries is performed. Then a physiologic model of
coronary circulation is produced. Resting coronary flow is
modelled on the basis of myocardial mass, and maximal hy-
peremia is modelled in agreement with the expected reduc-
tion in resistance if adenosine injection would be achieved.
Finally, supercomputers use computational fluid dynamics
methods to measure FFR CT. The HeartFlow FFR CT soft-
ware (FFR<sub>CT</sub>, HeartFlow Inc, Redwood city, CA, USA) is
the most successful technology that has demonstrated its
diagnostic performance compared to FFR in 3 significant
studies [17–19]. The diagnostic performance is interest-
ing compared to other non-invasive tests. The PACIFIC
trial showed it comparable to PET and superior to SPECT
[20]. The use in real life has also been evaluated in a large
register prospective multicenter registry [21]. The weak-
ness remains an off-line analysis. FFRCT analysis is only
available at a central laboratory in California. CCTA image
data set must be sent to post processing which still takes 1
to 4 hours. In addition to the cost of process, the perfor-
mance also depends strongly on the quality of the image.
Motion artifact, severe calcification, and stenting decrease
analyzability. For example, in PACIFIC trial, analyzability
of FFRCT was only 75% at the patient level [20].

## 3.2 Whole Coronary Tree Assessment

3.2.1 Assessment of Endothelial Dysfunction and Spasm

Acetylcholine provides an endothelium-dependent
stimulation. In normal individuals, acetylcholine causes the
vasodilatation of epicardial and micro vessels. Paradoxi-
cal vasoconstriction occurs in patients with endothelial dys-
function or vasospastic angina. Acetylcholine challenges
endothelium-dependent microvascular function. Acetyl-
choline is usually administered by sequential manual infu-
sion at progressive concentrations of 2 µg, 20 µg, 100 µg
and 200 µg over a period of 3 minutes via the diagnostic
catheter used for the assessment of the left coronary artery
(LCA). The assessment of the right coronary artery is per-
formed when the LCA shows no abnormal result and a dose
of 50 µg is then applied prior to 300 mg of glyceryl trini-

trate. Manual infusion should be slow (1–2 mL/min). It
is more straightforward but possibly less standardized than
mechanical sequential infusion. Indeed, mechanical infu-
sion pump can infuse (1 mL/min for 2 minutes) precise
progressive concentration of 0.182, 1.82, and 18.2 µg/mL
(10⁻⁶, 10⁻⁵, and 10⁻⁴ mol/L, respectively). After each
dose, an angiogram is performed. Two criteria are used for
diagnosing endothelial dysfunction. Following intracoro-
nary injection of any dose of acetylcholine, endothelial-
dependent microvascular dysfunction is defined as a change
CBF ≤50% and epicardial endothelial dysfunction is de-
fined as a reduced coronary artery diameter ≥20%. The
method of CBF and coronary flow reserve (CFR) compu-
tation are detailed below. The change in CBF is provided
by the equation (peak at Ach CBF-baseline CBF)/(baseline
CBF).

Using Doppler data. It is possible to use the bolus ther-
modilution technique to diagnose endothelial-dependent
microvascular dysfunction through the assessment of en-
dothelial coronary flow reserve with acetylcholine (eCFR)
<1.5 [22].

Progressive concentrations of acetylcholine may in-
duce epicardial or microcirculatory spasm. VSA and mi-
crovascular spasm (MVS) are defined as follows:

VSA: angina symptoms, ischemic ECG modification
and ≥90% constriction in epicardial artery,

MVS: angina symptoms, ischemic ECG modification
(≥1 mm) and constriction in epicardial <90%.

It should be noted that acetylcholine test patients with
microvascular spasm or a history of myocardial infarction
with nonobstructive coronary arteries (MINOCA) have a
higher risk of myocardial infarction and recurrent chest pain
requiring hospitalization at follow-up despite appropriate
post-test therapy [23].

3.2.2 CFR by Endothelium-Independent Stimulation

CFR provides information on both the epicardial and
microvascular compartments by quantifying the ratio of hy-
peremic to resting CBF. Maximal hyperemia is induced by
the intravenous infusion of 140 µg/kg/min of adenosine.
The assessment of CFR using thermodilution tends to over-
estimate values than those measured using Doppler [24].
The absolute cut-off values are <2.0 and <2.5 by thermod-
ilution and Doppler, respectively [25]. CFR reflects the
vasodilator capacity of the coronary circulation and does
not allow to differentiate the epicardial or microcirculatory
involvement. CFR has less reproducibility than FFR due
to its dependence on systemic haemodynamics (diastolic
time, intramyocardial pressure) and to the high variability
of basal flow [26].

The vasodilatory capacity of whole coronary tree is
therefore measured using two distinct methods, i.e., acetyl-
choline testing in order to monitor changes in CBF or eCFR,
and adenosine testing in order to quantify CFR. The poten-
tially complementary nature of both remains to be deter-
mined.

<figure><img src="image_4.png" /></figure>
## 3.3 Coronary Microcirculation

### 3.3.1 Measure of CBF

The principles of CBF measurement must be known in order to understand how to obtain the coronary micro-circulation indexes. The microcirculation is invisible to all imaging techniques, which explains that functional tests are the only methods of analysis. The determination of CBF can be performed according to two methods.

Based on bolus thermodilution modelling, flow can be calculated from the mean time it takes a fixed vascular volume to travel from an injector to a sensor (Tmn). De Bruyne et al. [27] and Pijls et al. [28] conducted the bolus thermodilution technique in animal model and human and found a strong correlation between 1/Tmn and absolute CBF. Absolute CBF assessment is possible using the continuous thermodilution method. It requires a dedicated monorail infusion (RayFlow, Hexacath, Paris, France), an infusion pump, a pressure/temperature wire (PressureWire, Abbott Vascular, Santa Clara, California) and a dedicated software (CoroFlow, Cardiovascular System, Coroventis Research, Uppsala, Sweden). Absolute CBF in mL/min is then given by the equation:

$$1.08 \times \text{Ti/T} \times \text{Qi},$$

Qi is the infusion rate of saline at room temperature (20 mL/min). T is the temperature of blood (in °C) mixed with saline in the distal part of the vessel. Ti is the temperature (in °C) of the saline as it enters the coronary artery; and the constant 1.08 accounts for the densities and specific heat of blood and saline. Saline infusion with RayFlow induces maximal hyperemia within seconds, which obviates the need for adenosine [29]. It has been shown that absolute CBF and resting resistance can be achieved by continuous thermodilution and a fixed rate of 10 mL/min of saline [30]. This technique reduces the variability of calculated CFR [31].

Hyperemic APV measured using Doppler is used as a surrogate of absolute CBF. Because the Doppler signal provides only flow velocity, quantification of volumetric flow requires exact knowledge of the vessel lumen size, which can be obtained by quantitative coronary angiography (QCA) or intravascular ultrasound (IVUS). The simultaneous measurement of the vessel cross-sectional area and mean velocity (Vmean) allows to CBF in mL/min. Doppler-based wireline systems measure APV. To calculate the mean Vm, a constant coefficient of 0.5 is used, i.e., mean Vm = 0.5 × APV. However, this coefficient is not valuable in the case of pulsatile flow, which is why this method only gives a surrogate for the absolute CBF.

### 3.3.2 Index of Microcirculatory Resistance (IMR)

The index of microcirculatory resistance (IMR) is based also on the bolus thermodilution principle. IMR is calculated by: $Pd \times Tmn$. IMR is measured with a pressure/temperature wire (PressureWire, Abbott Vascular, Santa Clara, California). In case of significant epicardial

stenosis, the IMR value is corrected using Yong's formula ($\text{Corrected IMR} = Pa \times Tmn \times ([1.35] \times Pd/Pa - 0.32)$) [32]. A clear cut-off for the diagnosis of CMVD is IMR ≥25 [33]. The variability of IMR quantification represents a limit. It is due to the fact that the measurement depends upon the operator's bolus injection technique. However, IMR does not depend upon resting measurements or on myocardial mass.

### 3.3.3 Hyperaemic Microvascular Resistance (HMR)

HMR is measured using a Doppler-equipped guidewire (ComboWire XT; Philips Volcano, San. Diego, CA, USA). It is determined by: $Pd/Hyperemic APV$. There is no clear cut-off for the diagnosis of CMVD. HMR >1.9 or ≥2.5 mmHg/cm/s have been proposed [34,35].

### 3.3.4 Resistive Reserve Ratio (RRR)

RRR represents the vasodilatory capacity of microvasculature during hyperemia. It is calculated using the following validated equation [36]: $RRR = BRI/IMR$. The baseline resistance index (BRI) is a measure of the coronary microcirculatory resting tone and is calculated using the formula: $Pd Baseline \times Tmn Baseline$ [37]. It can be performed with either the bolus or doppler thermodilution techniques. There is no clear cut-off for the diagnosis of CMVD but RRR <2.62 by Doppler was associated with a 1.6-fold higher risk of death in patients with angina or ischemia with NOCAD [38].

### 3.3.5 Instantaneous Hyperemic Diastolic Velocity Pressure Slope (IHDVPS)

The simultaneous acquisition of phasic pressure and flow velocity signals is required to measure IHDVPS. However, this approach is rather complicated in terms of instrumentation. IHDVPS correlates significantly with arteriolar obliteration, capillary density, or arteriolar density [39]. IHDVPS is defined as the slope (β-coefficient) of the relationship between hyperaemic intracoronary pressure and flow in mid-to end diastole, which is displayed by a single regression line ($y = a + \beta x$) expressed in cm/s/mmHg. IHDVPS provides a combined view of the arteriolar and capillary domains. IHDVPS normal range has not been established.

### 3.3.6 Zero-Flow Pressure (Pzf)

Pzf is extrapolated from the regression line of the relationship between hyperaemic intracoronary pressure and flow in mid- to end diastole and is defined as the intercept of the regression line with the pressure axis. Pzf represents the distal coronary pressure in the theoretical situation of coronary flow cessation. Pzf measured after percutaneous coronary intervention (PCI) is a better predictor of the extent of myocardial infarction than HMR or IMR [40] but no normal range has been established. In addition, the methodology required for Pzf assessment is complex with important offline postprocessing.
### 3.3.7 Wave Intensity Analysis (WIA)

A wave is a change in pressure and flow that propagates along a blood vessel. There are four wave types: forward compression waves (FCW), forward decompression wave (FDW), backward compression wave (BCW), and backward decompression wave (BDW). The units of wave intensity (Watts/m² or J/sec/m²) reflect the rate at which the wave energy passes through a given cross-section of a coronary vessel. BDW originates from the microcirculation and is supposed to quantitatively reflect the re-expansion of the intramyocardial network in early diastole, thereby reflecting in turn capillary density [41]. Here gain a normal range has not been established yet.

The main common problem with the above-described techniques (HMR, IHDVPS, Pzf, WIA) using the Doppler method is that an optimal Doppler signal is obtained in only 69% of the patients [42]. Repositioning and the use of an intracoronary microcatheter to stabilize the position can improve signal quality.

### 3.3.8 Absolute Resistance, and Microvascular Resistance Reserve (MRR)

Once again, Ohm's law with ratio of pressure and flow provides absolute resistance expressed in Wood units. The following parameters may then be computed:

$$ \text{total coronary resistance} = Pa/\text{absolute CBF} $$

$$ \text{epicardial resistance} = Pa-Pd/\text{absolute CBF} $$

$$ \text{microvascular resistance} = Pd/\text{absolute CBF} $$

Absolute CBF and resistance as assessed using continuous thermodilution display high reproducibility and low intraobserver variability [43]. A strong agreement has been observed with [¹⁵O] H₂O PET-derived flow and resistance [44] following normalization for the myocardial mass of the perfused territory with different algorithms applied to cardiac CT data [45,46] or intracoronary physiological data [47]. However, the range of normal absolute resistance values have not been extensively investigated yet. Due to interindividual variability that persisted even after normalization for myocardial mass of the perfused territory, the measures are therefore less well suited for individual clinical decision.

Microvascular resistance reserve (MRR) is a novel index which presents several advantages. Because it uses the continued thermodilution method and since it relies on baseline and hyperemic measurements in the same epicardial territory, MRR is independent of myocardial mass, and operator independent. MRR is obtained as follows:

$$ \text{MRR} = \frac{\text{Absolute resistance at rest}}{\text{absolute resistance at hyperemia}} $$

$$ \text{Absolute resistance at rest} = Pa/\text{rest/absolute CBF} $$

$$ \text{Absolute resistance at hyperemia} = Pd/\text{hyperemia/absolute CBF hyperemia} $$

$$ \text{MRR} = \frac{(\text{absolute CBF hyperemia})}{(\text{absolute CBF rest})} \times (Pa/\text{rest/absolute CBF hyperemia}) $$

$$ \text{MRR} = CFR \times (Pa/\text{rest/absolute CBF hyperemia}) $$

If MRR is expressed in terms of CFR and FFR the equation is:

$$ \text{MRR} = CFR/FFR \times (Pa/\text{rest/absolute CBF hyperemia}) $$

By continue thermodilution method: Pa rest = Pa hyper and final equation is:

$$ \text{MRR} = CFR/FFR $$

MRR represents a very promising index since it is specific for the microcirculation, and independent of autoregulation and epicardial resistance [31].

### 3.3.9 Angiography-Derived IMR

An elegant use of the QFR in hyperemia has allowed to obtain an angiography-derived IMR [48], which is obtained as follows:

$$ \text{IMR} = Pd/\text{hyperemia} \times Tmean/\text{hyperemia} $$

$$ \text{IMR} = Pa/\text{hyperemia} \times Pd/\text{hyperemia} \times Tmean/\text{hyperemia} $$

$$ Pd/\text{hyperemia}/Pa/\text{hyperemia} \sim QFR $$

Tmean hyperemia can be expressed as the ratio between the number of frames (Nframes) that the contrast agent travels from the guiding catheter to a distal marker of the pressure wire to the acquisition rate (fps).

$$ \text{Angiography-Derived IMR} = Pa/\text{hyperemia} \times QFR \times \frac{Nframes/\text{hyperemia}}{fps} $$

Data post-processing allows to obtain an angiography-derived IMR value without the need for hyperemia. The initial steps are similar to those used for QFR, a 3D reconstruction of the coronary artery and estimation of QFR was performed using CFD. The estimated hyperemic Pa is calculated according to the mean arterial pressure (MAP) with the following weighting:

$$ MAP \times 0.2 \text{ when MAP} > 95 \text{ mm Hg and MAP} \times 0.15 \text{ when MAP} < 95 \text{ mm Hg.} $$

Finally, angiography-derived IMR is computed using the equation:

$$ \text{Angiography-Derived IMR} = Pa/\text{hyperemia} \times QFR \times \frac{Nframes/\text{hyperemia}}{fps} $$

Vdiastole is the resting flow velocity during diastole and is derived of the TIMI frame count method multiplied by K which is the constant to adjust the difference between resting and hyperemic flow velocity. Vessel length is determined by the length of vessel opacified by the contrast from the ostium to the distal part [49]. These data are currently monocentric and additional data are needed.

## 3.4 General Comparison between Methods

Several techniques are needed to explore the whole coronary tree. The analysis of endothelial function and the detection of spasm by the acetylcholine test must be used more and more systematically. For the other indexes, each index explores a part of the coronary tree. At this time, it is not possible to say which technique is the best. However, the interventional cardiologist must know the strengths and weaknesses of each technique and choose and implement
<figure><img src="image_5.png" /><figcaption>Table 1. Strengths and weaknesses of coronary physiology assessment.</figcaption></figure>

<table><thead><tr><th></th><th>Advantages</th><th>Limitations</th></tr></thead><tbody><tr><td>FFR</td><td><ul><li>Best evidences</li><li>Prognostic studies available</li></ul></td><td><ul><li>Guidewire: cost, complication</li><li>Hyperemia: cost and side effect of adenosine</li><li>Increase time of the procedure</li></ul></td></tr><tr><td>iFR</td><td><ul><li>Validated by non-inferiority studies vs. FFR</li><li>Hyperemia independent</li><li>Quicker than FFR</li></ul></td><td><ul><li>Guidewire: cost, complication</li><li>Increase time of the procedure</li><li>Specific software required</li></ul></td></tr><tr><td>Other NHPR</td><td><ul><li>Hyperemia independent</li><li>Quicker than FFR</li></ul></td><td><ul><li>Guidewire: cost, complication</li><li>Increase time of the procedure</li><li>Specific software required</li><li>No evidence regarding outcome prediction</li></ul></td></tr><tr><td>HSR</td><td><ul><li>Stenosis resistance based on a combination of intracoronary pressure and flow velocity</li></ul></td><td><ul><li>Guidewire: cost, complication</li><li>Increase time of the procedure</li><li>Specific software required</li></ul></td></tr><tr><td>QFR, CAAS<br>vFFR, FFRangio system</td><td><ul><li>Hyperemia independent</li><li>No pressure wire</li><li>Quicker than FFR if high expertise in post treatment software</li></ul></td><td><ul><li>No evidence for outcomes</li><li>Specific software required</li><li>Precise acquisition of angiography</li><li>Manual correction by expert</li></ul></td></tr><tr><td>FFR CT</td><td><ul><li>Non invasive</li><li>Increase performance of CCTA</li></ul></td><td><ul><li>Cost</li><li>Off line analysis</li></ul></td></tr><tr><td>CFR</td><td><ul><li>Study all coronary tree</li><li>Prognostic performance</li></ul></td><td><ul><li>Overall assessment (macro and microcirculation)</li><li>Variability: intrinsic + variable resting condition</li><li>Guidewire: cost, complication</li><li>Hyperemia: cost and side effect of adenosine</li><li>Increase time of the procedure</li></ul></td></tr><tr><td>IMR</td><td><ul><li>Microcirculation study</li></ul></td><td><ul><li>Guidewire: cost, complication</li><li>Hyperemia: cost and side effect of adenosine</li><li>Increase time of the procedure</li><li>Guidewire: cost, complication</li><li>Hyperemia: cost and side effect of adenosine</li><li>Increase time of the procedure</li></ul></td></tr><tr><td>HMR</td><td><ul><li>Microcirculation study</li></ul></td><td><ul><li>Doppler: additional cost, Doppler signal not analyzable (30% of patients)</li><li>No cutoff value</li></ul></td></tr></tbody></table>
<table><caption>Table 1. Continued.</caption><thead><tr><th></th><th>Advantages</th><th>Limitations</th></tr></thead><tbody><tr><td>RRR</td><td>- Microcirculation study</td><td>- Guidewire: cost, complication<br>- Hyperemia: cost and side effect of adenosine<br>- Increase time of the procedure<br>- No evidence regarding outcome prediction<br>- No cutoff values<br>- Long-lasting procedure</td></tr><tr><td>Absolute CBF and resistance</td><td>- Operator-independent</td><td>- Dependent upon myocardial mass<br>- Additional cost<br>- Increase time of the procedure</td></tr><tr><td>MRR</td><td>- Operator-independent</td><td>- Additional cost</td></tr><tr><td>IHDVPS</td><td>- Independent from autoregulation and myocardial mass</td><td>- Increase time of the procedure</td></tr><tr><td>Pzf</td><td>- More targeted (theoretically) of Microcirculation study</td><td>- Doppler: additional cost, Doppler signal not analyzable (30 % of patients)</td></tr><tr><td>WIA</td><td></td><td>- Specific equipment required</td></tr></tbody></table>

CAAS vFFR, Cardiovascular Angiographic Analysis Systems for vessel Fractional Flow Reserve; CBF, Coronary blood flow; CFR, Coronary flow reserve; CT, computed tomography; FFR, fractional flow reserve; HMR, Hyperaemic Microvascular Resistance; HSR, Hyperaemic Stenosis Resistance; iFR, instantaneous wave-free ratio; IHDVPS, Instantaneous Hyperemic Diastolic Velocity Pressure Slope; IMR, Index of Microcirculatory Resistance; MRR, Microvascular Resistance Reserve; Pzf, Zero-Flow Pressure; QFR, Quantitative Flow Ratio; RRR, Resistive reserve ratio; WIA, Wave Intensity Analysis.
a strategy exploring the whole coronary tree through coronary physiology for all his patients. So, each method has strengths and weaknesses that are summarized in Table 1.

# 4. Demonstrated Contribution of Coronary Physiological Indexes to the Management of CAD Through Randomized Trials

## 4.1 For Epicardial Stenotic Lesions

### 4.1.1 FFR and IFR

Coronary physiological assessment now plays a major role in the decision for PCI revascularization. According to the recommendations, a physiological assessment must be performed before revascularization, when the location of ischemia is not documented for 50% and 90% stenosis by visual estimation or in patients with multivessel CAD [50]. FFR and IFR have been shown to be useful in large randomized studies and should be used as a priority. Accordingly, FFR is currently considered the gold standard because its use has been validated in several large randomized studies. The results of the FAME-1 [1] and FAME-2 trials [51,52] have demonstrated a clinical benefit in using FFR with a cut off ≤0.8 to guide PCI revascularization. Interestingly, the first major clinical trial using FFR, the DEFER trial, have showed that an FFR-guided PCI strategy is effective and safe in patients >15 years-old [53]. A meta-analysis showed the benefit of FFR-guided PCI over medical therapy alone on the combined end point of cardiovascular death and myocardial infarction [54].

The two largest randomized trials showed that iFR-guided PCI was noninferior to FFR-guided PCI in rates of MACE at 12 months [55,56]. These results prompted the appearance of iFR in the recommendations using a cut off ≤0.89 [50]. It is regrettable that iFR has less evidence than FFR on long-term results.

Discordance between FFR and iFR appears in an average of 20% of cases. This discordance results from interactions between clinical characteristics, severity or shape of the stenosis [57,58], variability in coronary physiological responses to rest and hyperemia [59], and location of the stenosis [60]. Indeed, for the localization some studies have shown that lesion of left main (LM) might be associated with a higher discordance between iFR and FFR values (iFR-/FFR+) questioning the use of iFR in this setting. The DEFINE-LM registry shows that deferral or perform revascularization of LM stenosis based on iFR appears to be secure [61].

Finally, because the discordance between FFR and iFR does not lead to differences in outcomes [59], it is more interesting to discuss of practical use on specific clinical setting. For example, iFR could be an attractive alternative to FFR in patients with multivessel CAD to perform multiple measurements without inducing hyperemia. There may also be a reluctance by many operators to use vasodilators in patients with bradycardia or hypotension. iFR could be an alternative. The value of iFR in cases of abnormal coronary

microcirculation is suggested especially in acute coronary syndrome (ACS) and in patients with severe aortic stenosis. However, the evaluation of non-infarct-related arteries in the early phase of ACS creates diagnostic problems for the FFR but also for the IFR. The first is explained to a blunted hyperemia associated to ACS and the second by increased coronary resting flow on territory of remote myocardial infarction with compensatory hyperkinesia [62]. Recently, FLOWER MI trial failed to prove that a complete revascularization that is guided by FFR is superior to an angiography-guided procedure in STEMI patients [63]. If we can evoke the problem of the use of the FFR at the time of primary PCI due to blunted hyperemia associated to ACS [62], these results were more explained to a lack of statistical power due to lower-than-expected incidence of events. Probably future studies will precise the optimal time to use FFR or iFR to evaluate non-infarct-related arteries. In the setting of patient with severe aortic stenosis, conflicting data of evolution of FFR after TAVR implantation create debate with either a decrease in FFR after TAVR implantation [64] or stability [65]. So, further studies are needed in this area to clarified use of iFR and FFR.

To complete, several recent studies on the FFR appear with negative results in patients with multivessel CAD. However, negative results are probably due to reasons other than a questioning of the FFR performance.

The FUTURE trial compared an FFR-guided strategy with a traditional non-FFR strategy in the treatment of multivessel CAD. The trial was stopped prematurely by data safety and monitoring board due to higher all-cause mortality associated with FFR-guided strategy. This observation was not confirmed by the intention-to treat analysis at 1-year follow-up. At follow up, there was no significant difference between both strategies [66]. It is really difficult to conclude given the limited statistical power of the study. The higher all-cause mortality initial was probably due to chance.

The results of the FAME 3 trial are more instructive [67]. FAME 3 was a multicenter, international, non-inferiority trial, patients with multivessel CAD were randomly assigned to undergo CABG or FFR-guided PCI with zotarolimus-eluting stents. The composite primary end point was death from any cause, myocardial infarction, stroke, or repeat revascularization at 1 year. FFR-guided PCI was not found to be noninferior to CABG. Probably it is not the performance of FFR that can be questioned. FAME 3 confirms that CABG is the best treatment for multivessel CAD [50]. Indeed, previous randomized clinical trials that assessed use of FFR were performed in patients eligible for PCI. Patients with multivessel CAD presented often long and severe diffuse lesions and PCI tends to be more appropriate for focal disease where the FFR is known to be more efficient [57,58].

<figure><img src="image_6.png" /></figure>
### 4.1.2 QFR

QFR has an advantage over alternative angiography-derived FFR indexes since the publication of the FAVOR III China study results. This prospective study included 3825 patients from China in which the QFR-guided PCI was used with a cut off ≤0.89 and compared with an angiography-guided PCI. All cause death, MI and ischemia driven revascularization were the composite endpoint and occurred in 5.8% (11/1913) of patients in the QFR group compared to 8.8% (167/1912) in the angiography group (HR 0.65, 95% CI 0.51–0.83, *p* = 0.004) at 1 year [68]. The results of FAVOR III EJ (NCT03729739) will be more interesting since the study design investigates whether QFR-guided PCI will be non-inferior at 12 months compared to an FFR-guided PCI.

### 4.1.3 FFR CT

The number of randomized studies is still limited. The PLATFORM trial, which evaluated FFR CT in patients with planned ICA for chronic coronary syndrome. FFR CT was a feasible and safe with a significantly lower rate of NOCAD at ICA. At 1-year follow-up, the FFR CT strategy appeared lower cost than the ICA strategy with an equivalent cardiac event rate and the same level of quality of life [69,70]. The SYNTAX III trial, in patients with left main or 3-vessel coronary artery disease, showed that CCTA analysis made the same revascularization decision as ICA analysis, and that the use of FFR CT changed the decision in 7% of cases [71]. In FORECAST trial, use of FFR CT reduced ICA, and did not differ significantly from control group in cost or clinical outcomes [72]. However, control group had mainly CCTA (63%) as the initial test. Studies with adequate statistical power to compare the performance of FFR CT with other non-invasive tests in the management of chronic coronary syndrome are expected.

## 4.2 For Coronary Microcirculation

Up to 70% of patients with angina or myocardial ischemia will have a NOCAD at ICA [73]. The underlying cause of ANOCA (or INOCA) should be assessed systematically using invasive coronary physiology [25,74]. The CorMicA randomized trial showed that the use of coronary physiological measures for the assessment of microvascular and/or vasospastic angina to introduce stratified medicine in patients with stable angina and NOCAD is superior to standard care. Coronary physiological assessment was found to be relevant to introduce a tailored treatment that improved symptoms, quality of life, and decreased unnecessary ICA [75,76]. The use of coronary physiological measurements in INOCA, also called interventional diagnostic procedures, follows an expert consensus developing diagnostic and therapeutic strategies [77]. This expert consensus allows to choose the sequence of testing. Performing adenosine testing first without nitroglycerin is the most suitable choice due to the pharmacodynamics of vasoactive

drugs [78]. The sequence consists in coronary angiography and FFR in order to exclude obstructive CAD, then the assessment of vasodilatation is performed first by adenosine and then followed by acetylcholine test. Then, patient can be classified according to endotypes. Endotype 1 is the microvascular angina (MVA) (abnormal vasodilatation and/or microvascular spasm (MVS)); Endotype 2 is VSA (epicardial spasm); endotype 3 is a mixed MVA and VSA (epicardial spasm + abnormal vasodilatation); and endotype 4, extra-cardiac chest pain. This classification follows different therapeutic recommendations.

The diagnostic criteria are:

* VSA: angina symptoms, ischemic ECG modification and ≥90% constriction in epicardial artery.

* MVA: angina, no obstructive CAD plus objective evidence of coronary microvascular dysfunction (MVS and/or CFR <2 and/or IMR ≥25).

* MVS: angina, ischemic ECG modification (≥1 mm) and absence of constriction in epicardial artery <90%.

* Mixed MVA and VSA: angina with no obstructive CAD plus both evidence of invasive coronary microvascular dysfunction and epicardial vasospasm to acetylcholine (≥90% epicardial constriction).

* Extracardiac chest pain: normal results of coronary physiology assessment.

* Endothelial dysfunction is defined by ≥20% luminal constriction during acetylcholine test.

# 5. Towards Precision Medicine

The term “precision medicine” refers to a medical concept where diseases are managed according to the individual characteristics of each patient. Precise medicine is applicable for prevention, diagnostic and therapeutic strategies. Oncology is far ahead of cardiology in this field by using critical data sources ranging from genomics, transcriptionics, proteomics, and metabolomics. In cardiology, the use of coronary physiological assessment already allows the implementation of personalized medicine in several situations (Fig. 1).

## 5.1 Personalized Medicine in Agreement of Endotypes

CorMicA trial has paved the way for precision medicine in patients with ANOCA or INOCA by identification of endotypes. For the CMVD, an even more specific distinction can be recognized, i.e., structural and functional CMVD. Functional CMVD is distinguished by elevated CBF at rest, due to increased nitric oxide synthase (NOS) activity, and by normal maximal CBF during exercise. Alternatively, patients with structural CMVD present an endothelial dysfunction, which results in decreased peak CBF during exercise and normal CBF at rest [79,80]. Whether functional and structural CMVD may translate into distinct prognosis or require distinct treatments warrants further investigation.
<figure><img src="image_7.png" /></figure>

- Personalized medicine in agreement of endotypes
- Reducing refractory angina by PCI optimized
- Identification of patients at risk for intensification or specific treatments

<caption>**Fig. 1.** **Proposition of utilization of coronary physiology assessment to precise medicine.** CFR, Coronary flow reserve; FFR, fractional flow reserve; HMR, Hyperaemic Microvascular Resistance; HSR, Hyperaemic Stenosis Resistance; iFR, instantaneous wave-free ratio; IHDVPS, Instantaneous Hyperemic Diastolic Velocity Pressure Slope; IMR, Index of Microcirculatory Resistance; MRR, Microvascular Resistance Reserve; PPG, Pullback pressure gradient; Pzf, Zero-Flow Pressure; QFR, Quantitative Flow Ratio; RRR, Resistive reserve ratio; WIA, Wave Intensity Analysis.</caption>

## 5.2 Reducing Refractory Angina by PCI Optimized

Following PCI and despite adequate anti-ischemic therapy, 20% to 30% of patients continue to present angina [81]. Assessing coronary physiology after angioplasty will provide access to data useful for the improvement of patient management. First, coronary physiological assessment can detect microvascular and/or vasospastic angina which may be associated with epicardial stenosis and which will require an adjusted treatment [82]. Second, physiological indexes can be used to detect and understand mechanisms of suboptimal PCI results associated with wrong prognosis. Thus, an FFR <0.86, an iFR <0.89, or a QFR <0.89

post-angioplasty may be considered pejorative [83]. There are several reasons for incorrect FFR values after PCI such as stent-related cause (stent edge dissection or underexpansion), significant stenosis located proximally to the target PCI, diffuse vessel disease, or coronary spasm pseudostenoses caused by the pressure guidewire [83]. In 24% of cases with iFR <0.89 a suboptimal result after PCI is explained mainly by focal lesions outside the stent [84]. Once the alert is given, these causes must be identified and managed using a dedicated treatment. Coronary physiological assessment can help with FFR pullback, IFR scout pullback or QFR virtual pullback to understand the problem by de-

<figure><img src="image_8.png" /></figure>
<figure><img src="image_9.png" /><figcaption>**Fig. 2.** Schematic illustration of the use of pullback index by FFR, iFR and QFR to characterize a coronary lesion. FFR, fractional flow reserve; iFR, instantaneous wave-free ratio; QFR, Quantitative Flow Ratio.</figcaption></figure>

termining if it is focal and whether it requires an additional stent. In such cases, endocoronary imaging such as IVUS or OCT may be used. In case of diffuse the damage, an intensification of cardioprotective treatments will be required, especially anti-ischemic treatments, together with the prevention of the possibility of refractory angina, in which case education and cardiovascular rehabilitation can be very useful. In this setting, the pullback pressure gradient (PPG) index is interesting because it is a continuous measure with values close to 0 indicating diffuse CAD, whereas those close to 1 suggest focal CAD. PPG index is given by the equation:

$$ \frac{\text{maxPPG } 20 \text{ mm}/\Delta \text{ FFR vessel} + (1\text{-Length with functional disease (mm)}/\text{Total vessel length (mm)})}{2} $$

MaxPPG is the maximum pressure gradient over 20 mm. Δ FFR vessel is the difference between the FFR values obtained along the complete length of the explored vessel (ostium to distal part). Functional disease length and total vessel length are derived from the vessel length explored by a motorized pullback system and FFR data on that vessel length. Functional disease length is determined

as the length where the FFR drops >0.0015/mm. The system allows to obtain a real physiological map of the vessel. However, there are still limits such as the use of a motorized pullback system during prolonged adenosine infusions; index calculation is offline; and usefulness in clinical practice will require validation [85]. Feasibility of PPG by QFR was showed without guide pressure and motorized pullback system [86]. Finally, pullback technic with FFR, iFR, or QFR physiological map of the vessel very useful to program PCI and to evaluate its results [87–89] (Fig. 2).

However, the above mentioned pull back assessments are not yet supported by prospective randomized studies and cut-offs for the prediction of clinical events are not well defined. In this setting, the following sequence might reveal useful. A Pd/Pa <0.96 leads to FFR assessment, and if FFR <0.86, then FFR pullback and PPG are performed [90]. The use of virtual PCI is even more futuristic. Mapping of the artery before PCI and simulation of the PCI result is now possible. Virtual PCI is probably another step for precision medicine.

<figure><img src="image_10.png" /></figure>
<table><caption>Table 2. Cut off and significations to coronary physiology assessment.</caption><thead><tr><th></th><th>Cut off</th><th>Meaning</th></tr></thead><tbody><tr><td>FFR</td><td>- Pre PCI ≤0.8<br>- Post PCI ≤0.86</td><td>- Significant stenosis<br>- Worse prognosis</td></tr><tr><td>iFR</td><td>- Pre PCI ≤0.89<br>- Post PCI ≤0.89</td><td>- Significant stenosis<br>- Worse prognosis</td></tr><tr><td>Other NHPR</td><td>- Pre PCI ≤0.89</td><td>- Significant stenosis</td></tr><tr><td>HSR</td><td>- Pre PCI &lt;0.80 mmHg/cm/sec</td><td>- Significant stenosis</td></tr><tr><td>QFR, CAAS vFFR, FFRangio system</td><td>- Pre PCI ≤0.89<br>- Post PCI ≤0.89 for QFR</td><td>- Significant stenosis<br>- Worse prognosis</td></tr><tr><td>FFR CT</td><td>- Pre PCI ≤0.8</td><td>- Significant stenosis</td></tr><tr><td>CFR</td><td>- Thermodilution &lt;2<br>- Doppler &lt;2.5</td><td>- Worse prognostic</td></tr><tr><td>IMR</td><td>- ≥25 mm Hg × seconds or units<br>- Post PCI ≥25 mm Hg × seconds or units</td><td>- Microvascular dysfunction<br>- Worse prognostic</td></tr><tr><td>HMR</td><td>- ≥1.9 or ≥2.5 mmHg/cm/s</td><td>- Microvascular dysfunction<br>- Predictor of recurrent chest pain</td></tr><tr><td>RRR</td><td>- No clear cut off &lt;2.62 or &lt;1.7 or &lt;1.5</td><td>- CMVD diagnosis<br>- Lower is worse for prognosis</td></tr><tr><td>Absolute CBF and resistance</td><td>- NA</td><td>- NA</td></tr><tr><td>MRR</td><td>- NA</td><td>- NA</td></tr><tr><td>IHDVPS, Pzf, WIA</td><td>- NA</td><td>- NA</td></tr></tbody></table>

Same abbreviations in Table 1.

## 5.3 Identification of Patients at Risk

In the perspective of stratified medicine, coronary physiological indexes may represent theragnostic biomarkers, i.e., metrics that predict the therapeutic response. IMR measured after PCI allows for the identification of a group of patients with adverse prognosis when using a categorical value of 25 [91].

All indexes have diagnostic cutoffs and some also have prognostic cutoffs (Table 2). Coronary physiological assessment could help identify patients at risk for adverse events. The identification of patients at higher risk of adverse events will provide the possibility to implement specific therapies aimed at microvascular recovery and will lead to closer follow-up. However, randomized clinical trials are needed to validate these strategies.

# 6. Conclusions

The assessment of coronary physiology has become an indispensable technique for deciding on epicardial revascularization as well as for the exploration of the entire coronary tree and that of the coronary microcirculation in order to improve patient management. The range of available coronary physiological indexes has the potential to allow for individualized therapeutic strategies, therefore representing an additional step towards precision medicine.

## Author Contributions

Conceptualization—LMB and GBR; writing—original draft preparation—LMB, LR, GBR; writing—

review and editing—SM, MC, EV, NP, OO, HB, CG, DF, GV, LD; visualization—LMB, LR, SM, MC, EV, NP, OO, HB, AB, CG, DF, GV, LD, and GBR; supervision—GBR. All authors have read and agreed to the published version of the manuscript.

## Ethics Approval and Consent to Participate

Not applicable.

## Acknowledgment

We would like to express our gratitude to all those who helped us during the writing of this manuscript. Thanks to all the peer reviewers for their opinions and suggestions.

## Funding

This research received no external funding.

## Conflict of Interest

Gilles Barone-Rochette has received research grants from Merck Sharp and Dohme, and consulting fees from Bayer, Abbott vascular, Novo Nordisk, Sanofi, and AMGEN. The others authors declare no conflict of interest.

## References

[1] Tonino PAL, Fearon WF, De Bruyne B, Oldroyd KG, Leesar MA, Ver Lee PN, et al. Angiographic versus functional severity of coronary artery stenoses in the FAME study fractional flow reserve versus angiography in multivessel evaluation. Journal of the American College of Cardiology. 2010; 55: 2816-2821.

[2] Camici PG, d'Amati G, Rimoldi O. Coronary microvascular

<figure><img src="image_11.png" /></figure>
dysfunction: mechanisms and functional assessment. Nature Reviews Cardiology. 2015; 12: 48–62.

[3] Beltrame JF, Crea F, Kaski JC, Ogawa H, Ong P, Sechtem U, et al. International standardization of diagnostic criteria for vasospastic angina. European Heart Journal. 2017; 38: 2565–2568.

[4] Kogame N, Ono M, Kawashima H, Tomaniak M, Hara H, Leipsic J, et al. The Impact of Coronary Physiology on Contemporary Clinical Decision Making. JACC: Cardiovascular Interventions. 2020; 13: 1617–1638.

[5] Mathew RC, Bourque JM, Salerno M, Kramer CM. Cardiovascular Imaging Techniques to Assess Microvascular Dysfunction. JACC: Cardiovascular Imaging. 2020; 13: 1577–1590.

[6] Nair PK, Marroquin OC, Mulukutla SR, Khandhar S, Gulati V, Schindler JT, et al. Clinical Utility of Regadenoson for Assessing Fractional Flow Reserve. JACC: Cardiovascular Interventions. 2011; 4: 1085–1092.

[7] Adjedj J, Toth GG, Johnson NP, Pellicano M, Ferrara A, Floré V, et al. Intracoronary Adenosine: Dose-Response Relationship with Hyperemia. JACC: Cardiovascular Interventions. 2015; 8: 1422–1430.

[8] Sen S, Escaned J, Malik IS, Mikhail GW, Foale RA, Mila R, et al. Development and validation of a new adenosine-independent index of stenosis severity from coronary wave-intensity analysis: results of the ADVISE (ADenosine Vasodilator Independent Stenosis Evaluation) study. Journal of the American College of Cardiology. 2012; 59: 1392–1402.

[9] Berry C, van 't Veer M, Witt N, Kala P, Bocek O, Pyxaras SA, et al. VERIFY (VERification of Instantaneous Wave-Free Ratio and Fractional Flow Reserve for the Assessment of Coronary Artery Stenosis Severity in EverydaY Practice): a multicenter study in consecutive patients. Journal of the American College of Cardiology. 2013; 61: 1421–1427.

[10] Van't Veer M, Pijls NHJ, Hennigan B, Watkins S, Ali ZA, De Bruyne B, et al. Comparison of Different Diastolic Resting Indexes to iFR: Are They All Equal? Journal of the American College of Cardiology. 2017; 70: 3088–3096.

[11] Kobayashi Y, Lee JM, Fearon WF, Lee JH, Nishi T, Choi D, et al. Three-Vessel Assessment of Coronary Microvascular Dysfunction in Patients with Clinical Suspicion of Ischemia: prospective observational study with the index of microcirculatory resistance. Circulation: Cardiovascular Interventions. 2017; 10: e005445.

[12] Meuwissen M, Chamuleau SAJ, Siebes M, Schotborgh CE, Koch KT, de Winter RJ, et al. Role of Variability in Microvascular Resistance on Fractional Flow Reserve and Coronary Blood Flow Velocity Reserve in Intermediate Coronary Lesions. Circulation. 2001; 103: 184–187.

[13] Meuwissen M, Siebes M, Chamuleau SAJ, van Eck-Smit BLF, Koch KT, de Winter RJ, et al. Hyperemic stenosis resistance index for evaluation of functional coronary lesion severity. Circulation. 2002; 106: 441–446.

[14] van de Hoef TP, Nolte F, Echavarría-Pinto M, van Lavieren MA, Damman P, Chamuleau SAJ, et al. Impact of hyperaemic microvascular resistance on fractional flow reserve measurements in patients with stable coronary artery disease: insights from combined stenosis and microvascular resistance assessment. Heart. 2014; 100: 951–959.

[15] Ramasamy A, Jin C, Tufaro V, Bajaj R, Kilic Y, Safi H, et al. Computerised Methodologies for Non-Invasive Angiography-Derived Fractional Flow Reserve Assessment: a Critical Review. Journal of Interventional Cardiology. 2020; 2020: 6381637.

[16] Collet C, Onuma Y, Sonck J, Asano T, Vandeloo B, Kornowski R, et al. Diagnostic performance of angiography-derived fractional flow reserve: a systematic review and Bayesian meta-analysis. European Heart Journal. 2018; 39: 3314–3321.

[17] Koo BK, Erglis A, Doh JH, Daniels DV, Jegere S, Kim HS, et al. Diagnosis of ischemia-causing coronary stenoses by noninvasive fractional flow reserve computed from coronary computed tomographic angiograms. Results from the prospective multicenter DISCOVER-FLOW (Diagnosis of Ischemia-Causing Stenoses Obtained via Noninvasive Fractional Flow Reserve) study. Journal of the American College of Cardiology. 2011; 58: 1989–1997.

[18] Min JK, Leipsic J, Pencina MJ, Berman DS, Koo BK, van Mieghem C, et al. Diagnostic accuracy of fractional flow reserve from anatomic CT angiography. Journal of the American Medical Association. 2012; 308: 1237–1245.

[19] Nørgaard BL, Leipsic J, Gaur S, Seneviratne S, Ko BS, Ito H, et al. Diagnostic performance of noninvasive fractional flow reserve derived from coronary computed tomography angiography in suspected coronary artery disease: the NXT trial (Analysis of Coronary Blood Flow Using CT Angiography: next Steps). Journal of the American College of Cardiology. 2014; 63: 1145–1155.

[20] Driessen RS, Danad I, Stuijfzand WJ, Raijmakers PG, Schumacher SP, van Diemen PA, et al. Comparison of Coronary Computed Tomography Angiography, Fractional Flow Reserve, and Perfusion Imaging for Ischemia Diagnosis. Journal of the American College of Cardiology. 2019; 73: 161–173.

[21] Patel MR, Nørgaard BL, Fairbairn TA, Nieman K, Akasaka T, Berman DS, et al. 1-Year Impact on Medical Practice and Clinical Outcomes of FFR_CT: The ADVANCE Registry. JACC: Cardiovascular Imaging. 2020; 13: 97–105.

[22] Díez-Delhoyo F, Gutiérrez-Ibañes E, Sanz-Ruiz R, Vázquez-Álvarez ME, González Saldívar H, Rivera Juárez A, et al. Prevalence of Microvascular and Endothelial Dysfunction in the Nonculprit Territory in Patients with Acute Myocardial Infarction. Circulation: Cardiovascular Interventions. 2019; 12: e007257.

[23] Bil J, Moženška O, Segiet-Święcicka A, Gil RJ. Revisiting the use of the provocative acetylcholine test in patients with chest pain and nonobstructive coronary arteries: a five-year follow-up of the AChPOL registry, with special focus on patients with MINOCA. Translational Research. 2021; 231: 64–75.

[24] Everaars H, de Waard GA, Driessen RS, Danad I, van de Ven PM, Raijmakers PG, et al. Doppler Flow Velocity and Thermodilution to Assess Coronary Flow Reserve: a Head-to-Head Comparison with [¹⁵O] H_2O PET. JACC: Cardiovascular Interventions. 2018; 11: 2044–2054.

[25] Ong P, Camici PG, Beltrame JF, Crea F, Shimokawa H, Sechtem U, et al. International standardization of diagnostic criteria for microvascular angina. International Journal of Cardiology. 2018; 250: 16–20.

[26] Gould KL, Johnson NP. Coronary Physiology beyond Coronary Flow Reserve in Microvascular Angina: JACC State-of-the-Art Review. Journal of the American College of Cardiology. 2018; 72: 2642–2662.

[27] De Bruyne B, Pijls NH, Smith L, Wievegg M, Heyndrickx GR. Coronary thermodilution to assess flow reserve: experimental validation. Circulation. 2001; 104: 2003–2006.

[28] Pijls NHJ, De Bruyne B, Smith L, Aarnoudse W, Barbato E, Bartunek J, et al. Coronary thermodilution to assess flow reserve: validation in humans. Circulation. 2002; 105: 2482–2486.

[29] De Bruyne B, Adjedj J, Xaplanteris P, Ferrara A, Mo Y, Penicka M, et al. Saline-Induced Coronary Hyperemia: Mechanisms and Effects on Left Ventricular Function. Circulation: Cardiovascular Interventions. 2017; 10: e004719.

[30] Gallinoro E, Candreva A, Colaiori I, Kodeboina M, Fournier S, Nelis O, et al. Thermodilution-derived volumetric resting coronary blood flow measurement in humans. EuroIntervention. 2021; 17: e672–e679.

[31] De Bruyne B, Pijls NHJ, Gallinoro E, Candreva A, Fournier
S, Keulards DCJ, et al. Microvascular Resistance Reserve for Assessment of Coronary Microvascular Function: JACC Technology Corner. Journal of the American College of Cardiology. 2021; 78: 1541–1549.

[32] Yong AS, Layland J, Fearon WF, Ho M, Shah MG, Daniels D, et al. Calculation of the index of microcirculatory resistance without coronary wedge pressure measurement in the presence of epicardial stenosis. JACC: Cardiovascular Interventions. 2013; 6: 53–58.

[33] Fearon WF, Kobayashi Y. Invasive Assessment of the Coronary Microvasculature: The Index of Microcirculatory Resistance. Circulation: Cardiovascular Interventions. 2017; 10: e005361.

[34] Sheikh AR, Zeitz CJ, Rajendran S, Di Fiore DP, Tavella R, Beltrame JF. Clinical and coronary haemodynamic determinants of recurrent chest pain in patients without obstructive coronary artery disease—a pilot study. International Journal of Cardiology. 2018; 267: 16–21.

[35] Williams RP, de Waard GA, De Silva K, Lumley M, Asrress K, Arri S, et al. Doppler Versus Thermodilution-Derived Coronary Microvascular Resistance to Predict Coronary Microvascular Dysfunction in Patients with Acute Myocardial Infarction or Stable Angina Pectoris. The American Journal of Cardiology. 2018; 121: 1–8.

[36] Maznyczka AM, Oldroyd KG, Greenwood JP, McCartney PJ, Cotton J, Lindsay M, et al. Comparative Significance of Invasive Measures of Microvascular Injury in Acute Myocardial Infarction. Circulation: Cardiovascular Interventions. 2020; 13: e008505.

[37] Layland J, Carrick D, McEntegart M, Ahmed N, Payne A, McClure J, et al. Vasodilatory capacity of the coronary microcirculation is preserved in selected patients with non-ST-segment-elevation myocardial infarction. Circulation: Cardiovascular Interventions. 2013; 6: 231–236.

[38] Toya T, Ahmad A, Corban MT, Özcan I, Sara JD, Sebaali F, et al. Risk Stratification of Patients with NonObstructive Coronary Artery Disease Using Resistive Reserve Ratio. Journal of the American Heart Association. 2021; 10: e020464.

[39] Escaned J, Flores A, García-Pavía P, Segovia J, Jimenez J, Aragóncillo P, et al. Assessment of Microcirculatory Remodeling with Intracoronary Flow Velocity and Pressure Measurements: validation with endomyocardial sampling in cardiac allografts. Circulation. 2009; 120: 1561–1568.

[40] Patel N, Petraco R, Dall'Armellina E, Kassimis G, De Maria GL, Dawkins S, et al. Zero-Flow Pressure Measured Immediately after Primary Percutaneous Coronary Intervention for ST-Segment Elevation Myocardial Infarction Provides the Best Invasive Index for Predicting the Extent of Myocardial Infarction at 6 Months: An OxAMI Study (Oxford Acute Myocardial Infarction). JACC: Cardiovascular Interventions. 2015; 8: 1410–1421.

[41] Broyd CJ, Hernández-Pérez F, Segovia J, Echavarría-Pinto M, Quirós-Carretero A, Salas C, et al. Identification of capillary refaction using intracoronary wave intensity analysis with resultant prognostic implications for cardiac allograft patients. European Heart Journal. 2018; 39: 1807–1814.

[42] Barbato E, Aarnoudse W, Aengevaeren WR, Werner G, Klauss V, Bojara W, et al. Validation of coronary flow reserve measurements by thermodilution in clinical practice. European Heart Journal. 2004; 25: 219–223.

[43] Xaplanteris P, Fournier S, Keulards DCJ, Adjedj J, Ciccarelli G, Milkas A, et al. Catheter-Based Measurements of Absolute Coronary Blood Flow and Microvascular Resistance: feasibility, safety, and reproducibility in humans. Circulation: Cardiovascular Interventions. 2018; 11: e006194.

[44] Everaars H, de Waard GA, Schumacher SP, Zimmermann FM, Bom MJ, van de Ven PM, et al. Continuous thermodilution to

assess absolute flow and microvascular resistance: validation in humans using [15O] H2O positron emission tomography. European Heart Journal. 2019; 40: 2350–2359.

[45] Ide S, Sumitsuji S, Yamaguchi O, Sakata Y. Cardiac computed tomography-derived myocardial mass at risk using the Voronoi-based segmentation algorithm: a histological validation study. Journal of Cardiovascular Computed Tomography. 2017; 11: 179–182.

[46] Keulards DCJ, Fournier S, van 't Veer M, Colaiori I, Zelis JM, El Farissi M, et al. Computed tomographic myocardial mass compared with invasive myocardial perfusion measurement. Heart. 2020; 106: 1489–1494.

[47] Murai T, van de Hoef TP, van den Boogert TPW, Wijntjens GWM, Stegehuis VE, Echavarria-Pinto M, et al. Quantification of Myocardial Mass Subtended by a Coronary Stenosis Using Intracoronary Physiology. Circulation: Cardiovascular Interventions. 2019; 12: e007322.

[48] De Maria GL, Scarsini R, Shanmuganathan M, Kotronias RA, Terentes-Printzios D, Borlotti A, et al. Angiography-derived index of microcirculatory resistance as a novel, pressure-wire-free tool to assess coronary microcirculation in ST elevation myocardial infarction. The International Journal of Cardiovascular Imaging. 2020; 36: 1395–1406.

[49] Choi KH, Dai N, Li Y, Kim J, Shin D, Lee SH, et al. Functional Coronary Angiography-Derived Index of Microcirculatory Resistance in Patients with ST-Segment Elevation Myocardial Infarction. JACC: Cardiovascular Interventions. 2021; 14: 1670–1684.

[50] Neumann FJ, Sousa-Uva M, Ahlsson A, Alfonso F, Banning AP, Benedetto U, et al. 2018 ESC/EACTS guidelines on myocardial revascularization. European Heart Journal. 2019; 40: 87–165.

[51] De Bruyne B, Fearon WF, Pijls NHJ, Barbato E, Tonino P, Piroth Z, et al. Fractional flow reserve-guided PCI for stable coronary artery disease. The New England Journal of Medicine. 2014; 371: 1208–1217.

[52] van Nunen LX, Zimmermann FM, Tonino PA, Barbato E, Baumbach A, Engström T, et al. Fractional flow reserve versus angiography for guidance of PCI in patients with multivessel coronary artery disease (FAME): 5-year follow-up of a randomised controlled trial. The Lancet. 2015; 386: 1853–1860.

[53] Zimmermann FM, Ferrara A, Johnson NP, van Nunen LX, Escaned J, Albertsson P, et al. Deferral vs. performance of percutaneous coronary intervention of functionally non-significant coronary stenosis: 15-year follow-up of the DEFER trial. European Heart Journal. 2015; 36: 3182–3188.

[54] Zimmermann FM, Omerovic E, Fournier S, Kelbæk H, Johnson NP, Rothenbühler M, et al. Fractional flow reserve-guided percutaneous coronary intervention vs. medical therapy for patients with stable coronary lesions: meta-analysis of individual patient data. European Heart Journal. 2019; 40: 180–186.

[55] Davies JE, Sen S, Dehbi HM, Al-Lamee R, Petraco R, Nijjer SS, et al. Use of the Instantaneous Wave-free Ratio or Fractional Flow Reserve in PCI. New England Journal of Medicine. 2017; 376: 1824–1834.

[56] Götberg M, Christiansen EH, Gudmundsdottir IJ, Sandhall L, Danielewicz M, Jakobsen L, et al. Instantaneous Wave-free Ratio versus Fractional Flow Reserve to Guide PCI. The New England Journal of Medicine. 2017; 376: 1813–1823.

[57] Kern MJ, Seto AH. Vive la différence: Factors and mechanisms predicting discrepancy between iFR and FFR. Catheterization and Cardiovascular Interventions. 2019; 94: 364–366.

[58] Dérimay F, Johnson NP, Zimmermann FM, Adjedj J, Witt N, Hennigan B, et al. Predictive factors of discordance between the instantaneous wave-free ratio and fractional flow reserve. Catheterization and Cardiovascular Interventions. 2019; 94: 356–363.

<figure><img src="image_12.png" /></figure>
[59] Lee SH, Choi KH, Lee JM, Hwang D, Rhee TM, Park J, et al. Physiologic Characteristics and Clinical Outcomes of Patients with Discordance between FFR and iFR. JACC: Cardiovascular Interventions. 2019; 12: 2018-2031.

[60] Kobayashi Y, Johnson NP, Berry C, De Bruyne B, Gould KL, Jeremias A, et al. The Influence of Lesion Location on the Diagnostic Accuracy of Adenosine-Free Coronary Pressure Wire Measurements. JACC: Cardiovascular Interventions. 2016; 9: 2390-2399.

[61] Warisawa T, Cook CM, Rajkumar C, Howard JP, Seligman H, Ahmad Y, et al. Safety of Revascularization Deferral of Left Main Stenosis Based on Instantaneous Wave-Free Ratio Evaluation. JACC: Cardiovascular Interventions. 2020; 13: 1655-1664.

[62] Thim T, van der Hoeven NW, Musto C, Nijveldt R, Götberg M, Engström T, et al. Evaluation and Management of Nonculprit Lesions in STEMI. JACC: Cardiovascular Interventions. 2020; 13: 1145-1154.

[63] Puymirat E, Cayla G, Simon T, Steg PG, Montalescot G, Durand-Zaleski I, et al. Multivessel PCI Guided by FFR or Angiography for Myocardial Infarction. New England Journal of Medicine. 2021; 385: 297-308.

[64] Ahmad Y, Vendrik J, Eftekhari A, Howard JP, Cook C, Rajkumar C, et al. Determining the Predominant Lesion in Patients with Severe Aortic Stenosis and Coronary Stenoses: A Multi-center Study Using Intracoronary Pressure and Flow. Circulation: Cardiovascular Interventions. 2019; 12: e008263.

[65] Pesarini G, Scarsini R, Zivelonghi C, Piccoli A, Gambaro A, Gottin L, et al. Functional Assessment of Coronary Artery Disease in Patients Undergoing Transcatheter Aortic Valve Implantation: Influence of Pressure Overload on the Evaluation of Lesions Severity. Circulation: Cardiovascular Interventions. 2016; 9: e004088.

[66] Rioufol G, Dérimay F, Roubille F, Perret T, Motreff P, Angoulant D, et al. Fractional Flow Reserve to Guide Treatment of Patients with Multivessel Coronary Artery Disease. Journal of the American College of Cardiology. 2021; 78: 1875-1885.

[67] Fearon WF, Zimmermann FM, De Bruyne B, Piroth Z, van Straten AHM, Szekely L, et al. Fractional Flow Reserve-Guided PCI as Compared with Coronary Bypass Surgery. New England Journal of Medicine. 2022; 386: 128-137.

[68] Xu B, Tu S, Song L, Jin Z, Yu B, Fu G, et al. Angiographic quantitative flow ratio-guided coronary intervention (FAVOR III China): a multicentre, randomised, sham-controlled trial. The Lancet. 2021; 398: 2149-2159.

[69] Douglas PS, Pontone G, Hlatky MA, Patel MR, Norgaard BL, Byrne RA, et al. Clinical outcomes of fractional flow reserve by computed tomographic angiography-guided diagnostic strategies vs. usual care in patients with suspected coronary artery disease: the prospective longitudinal trial of FFR (CT): outcome and resource impacts study. European Heart Journal. 2015; 36: 3359-3367.

[70] Douglas PS, De Bruyne B, Pontone G, Patel MR, Norgaard BL, Byrne RA, et al. 1-Year Outcomes of FFRCT-Guided Care in Patients with Suspected Coronary Disease: The PLATFORM Study. Journal of the American College of Cardiology. 2016; 68: 435-445.

[71] Collet C, Onuma Y, Andreini D, Sonck J, Pompilio G, Mushtaq S, et al. Coronary computed tomography angiography for heart team decision-making in multivessel coronary artery disease. European Heart Journal. 2018; 39: 3689-3698.

[72] Curzen N, Nicholas Z, Stuart B, Wilding S, Hill K, Shambrook J, et al. Fractional flow reserve derived from computed tomography coronary angiography in the assessment and management of stable chest pain: the FORECAST randomized trial. European Heart Journal. 2021; 42: 3844-3852.

[73] Patel MR, Peterson ED, Dai D, Brennan JM, Redberg RF, Anderson HV, et al. Low diagnostic yield of elective coronary angiography. The New England Journal of Medicine. 2010; 362: 886-895.

[74] Ford TJ, Yli E, Sidik N, Good R, Rocchiccioli P, McEntegart M, et al. Ischemia and no Obstructive Coronary Artery Disease: Prevalence and Correlates of Coronary Vasomotion Disorders. Circulation: Cardiovascular Interventions. 2019; 12: e008126.

[75] Ford TJ, Stanley B, Good R, Rocchiccioli P, McEntegart M, Watkins S, et al. Stratified Medical Therapy Using Invasive Coronary Function Testing in Angina: The CorMicA Trial. Journal of the American College of Cardiology. 2018; 72: 2841-2855.

[76] Ford TJ, Stanley B, Sidik N, Good R, Rocchiccioli P, McEntegart M, et al. 1-Year Outcomes of Angina Management Guided by Invasive Coronary Function Testing (CorMicA). JACC: Cardiovascular Interventions. 2020; 13: 33-45.

[77] Kunadian V, Chieffo A, Camici PG, Berry C, Escaned J, Maas AHEM, et al. An EAPCI Expert Consensus Document on Ischaemia with Non-Obstructive Coronary Arteries in Collaboration with European Society of Cardiology Working Group on Coronary Pathophysiology & Microcirculation Endorsed by Coronary Vasomotor Disorders International Study Group. European Heart Journal. 2020; 41: 3504-3520.

[78] Beck S, Pereyra VM, Seitz A, McChord J, Hubert A, Bekeredjian R, et al. Invasive Diagnosis of Coronary Functional Disorders Causing Angina Pectoris. European Cardiology. 2021; 16: e27.

[79] Rahman H, Ryan M, Lumley M, Modi B, McConkey H, Ellis H, et al. Coronary Microvascular Dysfunction is Associated with Myocardial Ischemia and Abnormal Coronary Perfusion during Exercise. Circulation. 2019; 140: 1805-1816.

[80] Rahman H, Demir OM, Khan F, Ryan M, Ellis H, Mills MT, et al. Physiological Stratification of Patients with Angina Due to Coronary Microvascular Dysfunction. Journal of the American College of Cardiology. 2020; 75: 2538-2549.

[81] Gallone G, Baldetti L, Tzanis G, Gramegna M, Latib A, Colombo A, et al. Refractory Angina: From Pathophysiology to New Therapeutic Nonpharmacological Technologies. JACC: Cardiovascular Interventions. 2020; 13: 1-19.

[82] Niccoli G, Montone RA, Lanza GA, Crea F. Angina after percutaneous coronary intervention: the need for precision medicine. International Journal of Cardiology. 2017; 248: 14-19.

[83] Biscaglia S, Uretsky B, Barbato E, Collet C, Onuma Y, Jeremias A, et al. Invasive Coronary Physiology after Stent Implantation: Another Step Toward Precision Medicine. JACC: Cardiovascular Interventions. 2021; 14: 237-246.

[84] Jeremias A, Davies JE, Maehara A, Matsumura M, Schneider J, Tang K, et al. Blinded Physiological Assessment of Residual Ischemia after Successful Angiographic Percutaneous Coronary Intervention: The DEFINE PCI Study. JACC: Cardiovascular Interventions. 2019; 12: 1991-2001.

[85] Collet C, Sonck J, Vandeloo B, Mizukami T, Roosens B, Lochy S, et al. Measurement of Hyperemic Pullback Pressure Gradients to Characterize Patterns of Coronary Atherosclerosis. Journal of the American College of Cardiology. 2019; 74: 1772-1784.

[86] Dai N, Hwang D, Lee JM, Zhang J, Jeon K, Paeng JC, et al. Feasibility of Quantitative Flow Ratio-Derived Pullback Pressure Gradient Index and its Impact on Diagnostic Performance. JACC: Cardiovascular Interventions. 2021; 14: 353-355.

[87] Lee SH, Shin D, Lee JM, Lefieux A, Molony D, Choi KH, et al. Automated Algorithm Using Pre-Intervention Fractional Flow Reserve Pullback Curve to Predict Post-Intervention Physiological Results. JACC: Cardiovascular Interventions. 2020; 13: 2670-2684.

[88] Nijjer SS, Sen S, Petraco R, Escaned J, Echavarria-Pinto M,

<figure><img src="image_13.png" /></figure>
Broyd C, et al. Pre-angioplasty instantaneous wave-free ratio pullback provides virtual intervention and predicts hemodynamic outcome for serial lesions and diffuse coronary artery disease. JACC: Cardiovascular Interventions. 2014; 7: 1386–1396.

[89] Shin D, Dai N, Lee SH, Choi KH, Lefieux A, Molony D, et al. Physiological Distribution and Local Severity of Coronary Artery Disease and Outcomes after Percutaneous Coronary Intervention. JACC: Cardiovascular Interventions. 2021; 14: 1771–1785.

[90] Hakeem A, Ghosh B, Shah K, Agarwal S, Kasula S, Hacioglu Y, et al. Incremental Prognostic Value of Post-Intervention Pd/Pa in Patients Undergoing Ischemia-Driven Percutaneous Coronary Intervention. JACC: Cardiovascular Interventions. 2019; 12: 2002–2014.

[91] Nishi T, Murai T, Ciccarelli G, Shah SV, Kobayashi Y, Derimay F, et al. Prognostic Value of Coronary Microvascular Function Measured Immediately After Percutaneous Coronary Intervention in Stable Coronary Artery Disease: An International Multicenter Study. Circulation: Cardiovascular Interventions. 2019; 12: e007889.

<figure><img src="image_14.png" /></figure>