Catheterization and Cardiovascular Interventions

ORIGINAL ARTICLE ‐ CLINICAL SCIENCE

Novel Non‐Hyperemic Coronary Physiology Indices for

Vessel Longitudinal Analysis
Simone Fezzi1 | Guy F. A. Prado1,2 | Luigi Alberto Iossa1 | Daixin Ding3 | Elisabetta Pianezzola1 |
1 1
Federico Cesar Vigo | Paolo Alberto Del Sole | Verdiana Galli | Stefano Andreaggi1
1,2
| Domenico Tavella1 |
3 1 1 1
Shengxian Tu | Gabriele Pesarini | Flavio Ribichini | Roberto Scarsini

1
Division of Cardiology, Department of Medicine, University of Verona, Verona, Italy | 2Department of Clinical and Molecular Medicine, Sapienza University,
Rome, Italy | 3Department of Cardiology, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University,
Shanghai, China

Correspondence: Roberto Scarsini ([email protected])

Received: 2 May 2025 | Revised: 12 July 2025 | Accepted: 25 July 2025

Funding: The authors received no specific funding for this work.

Keywords: coronary artery disease | Instantaneous Free‐ratio Pullback Pressure Gradient | percutaneous coronary intervention | quantitative flow ratio

ABSTRACT
Background: Physiological pattern of coronary artery disease, whether focal or diffuse, is critical in guiding physicians during
the decision‐making process for percutaneous coronary interventions.
Aims: This study introduces two novel non‐hyperemic coronary physiology indices designed for longitudinal vessel analysis.
Methods: In this prospective observational study, 415 patients underwent pressure‐wire functional assessments using
instantaneous wave‐free ratio (iFR) pullback traces between March 2015 and November 2023 at Verona University Hospital.
After applying exclusion criteria, the final study population comprised 198 patients with 209 intermediate coronary lesions.
Vessels were qualitatively categorized as focal, diffuse, mixed‐focal, or mixed‐diffuse based on expert panel interpretation. The
novel iFR Pullback Pressure Gradient (iPG) was derived from pullback curves to quantify the atherosclerotic pattern along the
vessel. The local severity of lesions was assessed using the instantaneous iFR gradients per unit of length (diFR/ds). Addi-
tionally, based on Murray law‐based Quantitative Flow Ratio (µFR), both µFR‐PPGi and dµFR/ds were computed, to evaluate
their correlation with iFR‐derived metrics.
Results: The optimal iPG threshold for defining focal disease was 0.71 (Youden index = 0.456), demonstrating good accuracy in
predicting the predominant disease pattern (AUC 0.785, p < 0.001). iPG provided an accuracy of 72%, with a sensitivity, specificity,
positive predictive value, negative predictive value of 86.5%, 59%, 67.6%, 81.5%, respectively. The µFR‐PPGi and dµFR/ds showed
significant correlations with iPG and diFR/ds, respectively (r = 0.238, p < 0.001; r = 0.528, p < 0.001).
Conclusions: iPG and diFR/ds are novel quantitative indices for assessing physiological patterns of coronary artery disease,
without the need for hyperemia induction. Moderate agreement between angio‐ and iFR‐based indices was found.

Abbreviations: ACS, acute coronary syndrome; AUC, area under the curve; BMI, body mass index; CABG, coronary artery bypass graft; CAD, coronary artery disease; diFR/ds, iFR gradient per unit
length; DS%, diameter stenosis percentage; dµFR/ds, instantaneous µFR gradient per unit length; FFR, fractional flow reserve; iFR, instantaneous wave‐free ratio; iPG, iFR Pullback Pressure Gradient;
NPV, negative predictive value; PAD, peripheral artery disease; PCI, percutaneous coronary intervention; PPGi, pullback pressure gradient index; PPV, positive predictive value; PW, pressure wire;
ROC, receiver operating characteristic; RVD, reference vessel diameter; STEMI, ST‐elevation myocardial infarction; µFR, Murray's law–derived quantitative flow ratio; µFR PPGi, µFR Pullback
Pressure Gradient.

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cited.

© 2025 The Author(s). Catheterization and Cardiovascular Interventions published by Wiley Periodicals LLC.

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1 | Introduction pullback system (Philips Medical Systems, Best, the Nether-
lands) at Verona University Hospital (Verona, Italy) between
Relieving symptoms and the burden of myocardial ischemia is the March 2015 and November 2023 were included in the study.
primary goal of revascularization in patients with chronic or acute The analysis of coronary physiology traces was centralized and
obstructive coronary artery disease (CAD) [1, 2]. The physiological performed blinded by expert independent operators.
pattern of CAD significantly influences percutaneous coronary
intervention (PCI) outcomes, with diffuse disease being associated Patients with unavailable or poor‐quality coronary angio-
with suboptimal post‐PCI physiology, increased risk of periproce- grams, suboptimal quality of pressure traces, severe tortuosity,
dural myocardial infarction, and higher burden of residual symp- as well as those with previous coronary artery bypass grafting,
toms at follow‐up [3, 4]. The classification of disease as focal or angiographically identifiable myocardial bridging, or col-
diffuse has been formalized using physiological indices such as the laterals, were excluded. Vessels with a distal iFR > 0.95 were
hyperemic PPG, although differentiating between these patterns in considered physiologically unobstructed and were also ex-
practice may remain challenging due to intermediate or mixed cluded. The final study population comprised 198 patients
presentations [5]. To address these limitations, several mathematical with 209 vessels.
metrics have been developed to quantitatively classify physiological
patterns, including fractional flow reserve (FFR) gradient per unit
time (dFFR[t]/dt) and pullback pressure gradient index (PPGi). 2.2 | Wire‐Based Physiological Assessments (FFR
These metrics were applied to determine the disease severity along and iFR)
the course of the vessel and predict post‐PCI outcomes. Both are
calculated based on pressure‐wire (PW)‐pullback performed during Coronary physiology assessment was performed using the
continuous hyperemia. PPGi quantitatively measures the physio- Verrata Plus or Omniwire pressure wire (Philips Volcano, San
logical distribution of coronary plaques along the vessel and is Diego, CA), following standardized guidelines and the local
capable of distinguishing between focal and diffuse disease. On a institutional protocol [14].
scale from 0 to 1, low PPGi is suggestive of diffuse disease, high
PPGi of focal. dFFR[t]/dt reflects the local physiological disease Briefly, after normalization of the PW at the ostium of the
severity, distinguishing between minor or major pressure drops on interrogated vessel and consequent positioning in the distal
the physiological map of the vessel [5–8]. PPGi and dFFR/dt pro- segment, fluoroscopy was used and recorded to confirm wire's
vide a second dimension to epicardial coronary physiology, and position, and the iFR spot value was measured. Subsequently,
their clinical importance is increasingly recognized. While FFR FFR was assessed under steady state hyperemia, induced by
guides revascularization decisions, PPGi and dFFR/dt provide in- systemic administration of adenosine (140 mcg/kg/min) or by
sights on the potential physiological benefits achievable with PCI intracoronary bolus injection of adenosine (100 μg for the right
[9]. However, the use of FFR remains limited in clinical practice, coronary artery and 200 μg for the left coronary artery). After
due to procedural complexities, increased costs and the need for the complete remission of the hyperemic state, the iFR pull-
hyperemia induction. Consequently, many operators favor alterna- back evaluation was performed manually using the iFR Scout
tive methods, such as non‐hyperemic pressure ratios or system (Philips Medical Systems, Best, The Netherlands).
angiography‐derived surrogates [10]. Operators were instructed to maintain a controlled pullback
pace of approximately 0.5–1 mm/s and perform the pullback
Recently, angiography‐derived physiological indices able to com- manoeuvre over 20–30 s. The presence of a significant
pute FFR from coronary angiography have been endorsed by pressure‐wire drift (+/− 0.03) was excluded as the pressure
international guidelines [11]. Quantitative measures of coronary sensor reached the ostium of left main or right coronary artery.
disease spatial distribution derived from quantitative flow ratio Cases were included exclusively when pullback started at an
(QFR) virtual pullback traces have been already validated [12, 13]. adequately distal point of the vessel or if fluoroscopy was
provided to confirm the distal wire position. To ensure mea-
In this study we aimed to develop two novel indices of vessel surement reliability, multiple recordings were obtained for
longitudinal analysis based on instantaneous wave free ratio each assessment. Clinically recommended cut‐off values
(iFR) scout‐pullback: the Instantaneous Free‐ratio Pullback (FFR ≤ 0.80 and iFR ≤ 0.89) were applied.
Pressure Gradient (iPG) and the instantaneous iFR gradients
per unit of length (diFR/ds). Secondly, we sought to test the
accuracy of iPG in characterizing the disease pattern, com- 2.3 | Angiography‐Derived Coronary Physiology
pared to a consensus of expert operators based on qualitative Assessment
pullback traces interpretation. Lastly, we compared the iPG
and diFR/ds classification with Murray's law quantitative Angiography‐derived coronary physiology assessment was per-
flow ratio (µFR)‐derived indices. formed using the AngioPlus Core Software (Pulse Medical, Shang-
hai, China) to derive the Murray's law quantitative flow ratio (µFR).

2 | Methods µFR assessment was performed off‐line by expert certified

operators blinded to invasive coronary physiology mea-
2.1 | Study Population surements and to clinical data. µFR computations adhered
to the workflow provided by Pulse Medical, with the single
Consecutive patients with intermediate coronary lesions who view 2D µFR applied in all cases [15, 16]. To ensure con-
underwent vessel longitudinal analysis with the iFR Scout sistency and accuracy in vessel length measurements across

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cases, we retrospectively matched the distal pressure‐wire position The local physiological disease severity was estimated using the
at the start of the iFR pullback, recorded by fluoroscopy, with the instantaneous iFR gradient per unit of length (diFR/ds), defined as
corresponding anatomical segment identified by µFR‐based re- the maximum iFR gradient in 1 mm. The mean value of diFR/ds
constructions. These reconstructions provide both physiological was applied to identify the presence or the absence major gradients.
data and QCA‐derived anatomical vessel length. The µFR‐derived
length was then used as a standardized spatial reference for all
subsequent analyses, including iFR and µFR pullbacks (Supporting
2.6 | µFR‐Derived Pullback Pressure Gradient
Information S1: Figure 1). The virtual pullback was automatically
Index (µFR‐PPGi) and Instantaneous µFR Gradient
generated by the AngioPlus Core Software. Conventional validated
Per Unit of Length (dµFR/ds)
cut‐off values for ischemia (μFR ≤ 0.80) were applied [17].
Quantitative measures of longitudinal analysis were derived
from the µFR virtual pullback as previously described [20].
2.4 | Pullback Data Extractions Briefly, µFR‐PPGi was derived applying the PPGi formula to the
µFR virtual pullback as follows:

 
 Max µFR PPG20mm  Length with functional disease(mm)  

Graphical data from both invasive iFR pullback and virtual
 + 1 −  
 
 ∆ µFR vessel
µFR pullbacks were extracted using WebPlotDigitizer
  
(Automeris LLC), an open‐source software designed to Total vessel length(mm)
digitize plots from image files. High‐resolution screenshots
2
of the pullback curves were uploaded and manually cali-
brated using a Cartesian coordinate system. The Y‐axis
The length of functional CAD was defined as the length, in
corresponded to iFR or µFR values, while the X‐axis repre-
millimeters, with µFR drop ≥ 0.0015/mm.
sented the total vessel length as derived from µFR‐based
anatomical reconstructions. Data points were extracted at
The local physiological disease severity was estimated using the
fixed 1 mm intervals using the X step/interpolation algo-
instantaneous µFR gradient per unit of length (dµFR/ds),
rithm (X‐step function, ΔX = 1.0 mm). This approach was
defined as the maximum µFR gradient in 1 mm. The mean
applied consistently across all pullbacks, providing high‐
value of dµFR/ds was applied to identify the presence or the
resolution, reproducible datasets for subsequent quantita-
absence major gradients.
tive analysis (Supporting Information S1: Figure 2). This
method has been previously validated and used in cardio-
vascular research, with good reproducibility and accu-
racy [18]. 2.7 | Physiological Pattern Characterization

Five expert interventional cardiologists specialized in coro-

nary physiology were asked to review and interpret the iFR
2.5 | Instantaneous Free‐Ratio Pullback Pressure
and µFR pullback traces, in a blind fashion. Operators were
Gradient (iPG) and the Instantaneous iFR Gradient
instructed to categorize the traces according to previously
Per Unit Length (diFR/ds)
reported criteria [19, 20]. Focal lesions were defined as an
abrupt pressure drop (ΔiFR ≥ 0.03) localized over a relatively
The Instantaneous Free‐ratio Pullback Pressure Gradient index
short vessel segment (20 mm), whereas the rest of the pull-
(iPG) was developed based on FFR‐derived PPGi formula pre-
back does not reveal a further significant pressure gradient.
viously described [5]. iPG provides a continuous metric that
Diffuse disease was characterized by a progressive decrease of
integrates the magnitude of the maximum pressure drop over a
the pressure gradient in a diseased segment > 20 mm without
20 mm segment and the extent of functional disease across the
clearly identifiable focal pressure drops. Mixed patterns of
interrogated vessel. The iPG is calculated as follows:

 
disease were further classified as mixed‐focal or mixed‐

 Max iFR PPG20mm  Length with functional disease(mm)  


 ∆ iFR + 1 −  
diffuse [19].

  
vessel
 Total vessel length(mm)
  The 20 mm segment length was chosen based on prior studies
2 that define focal disease as a significant pressure drop occurring
within ≤ 20 mm [6, 15, 17], both in hyperemic and non‐
MaxPPG 20mm corresponds to the maximum gradient hyperemic conditions.
observed over a continuous 20 mm segment of the vessel.
ΔiFRvessel represents total pressure drop along the vessel. The inter‐operator consensus was used in the present anal-
Length of functional disease refers to the cumulative num- ysis as reference standard. All operators analyzed the iFR
ber of 1 mm segments along the vessel exhibiting a contin- Pullback traces in a blinded manner. The vessel was classified
uous pressure drop equal to or greater than 0.0015 per mm. based on the most chosen pattern. In case of a tie, classifi-
Total vessel length used in the formula was defined as the cation was determined through a consensus reached via
anatomical length derived from µFR reconstructions. collegial discussion.

High iPG values (close to 1) suggest predominantly focal disease, Central illustration shows examples of both qualitative and
whereas low values (close to 0) predominantly diffuse disease. quantitative physiological pattern of CAD.

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2.8 | Statistical Analysis 3 | Results

Continuous variables are presented as mean and standard deviation 3.1 | Clinical and Angiographic Characteristics of
if normally distributed or with median value and interquartile range the Study Cohort
otherwise. Continuous variables were compared with unpaired
t‐test, one way ANOVA or the Mann Whitney test as appropriate. Overall, 198 patients with 209 coronary vessels were included in the
Categorical data are reported as number (percentage) and compared study. The clinical characteristics of the study cohort are reported in
with the χ2 test or Fisher exact test as appropriate. Correlation Table 1. Briefly, the mean age was 67.7 ± 11.0 SD years and 17.7% of
among variables was determined by Pearson correlation tests and patients were female. The clinical presentation was chronic coro-
expressed as r value. The agreement between physiology indices nary syndrome in 60.3% and acute coronary syndrome (ACS) in
including iFR, FFR, and µFR was assessed with scatter plots and 39.7%. Most of the interrogated vessels showed lesions of interme-
with the Bland Altman analysis. Sensitivity, specificity, diagnostic diate angiographic severity with a mean diameter stenosis of
accuracy, and optimal cut‐off value were defined from the calcu- 43.4 ± 8.90 SD%. The mean FFR, iFR, and µFR were 0.79 ± 0.08 SD,
lated receiver operator characteristic (ROC) curve. Inter‐rater 0.83 ± 0.12 SD, and 0.74 ± 0.14 SD, respectively. Correlation
agreement for visual classification was assessed using Fleiss' between FFR and iFR was r = 0.706.
kappa (κ). A p‐value < 0.05 indicated that the agreement was sig-
nificantly greater than expected by chance. All analyses were per-
formed with Jamovi® (Version 2.5.7, @jamoviStats Sydney,
Australia).
3.2 | iFR‐Based Qualitative Vessel Longitudinal
Analysis

2.9 | Ethical Considerations At the iFR qualitative vessel longitudinal analysis, experts classified
105 vessels (51%) as predominantly focal (focal and mixed‐focal)
The study was conducted in accordance with the ethical principles and 104 vessels (49%) as predominantly diffuse (diffuse and mixed‐
of the Declaration of Helsinki and was approved by the local diffuse) (Figure 1, Table 2). Mixed patterns were identified in 95
institutional ethics board. Written informed consent was obtained vessels (45%) (Supporting Information S1: Figure 3). The inter‐
from all patients. operator agreement for iFR pullback visual interpretation was
TABLE 1 | Baseline clinical characteristics according to disease patterns determined by iFR pullback qualitative longitudinal analysis.

Total Focal Mixed focal Mixed diffuse Diffuse

(n = 209) (n = 44, 22%) (n = 61, 29%) (n = 34, 16%) (n = 70, 33%) p value
Demographics
Age, y 67.7 ± 11.0 68.8 ± 11.9 68.9 ± 11.7 66.4 ± 10.1 66.6 ± 10.3 0.531
Male 172 (82.3) 35 (79.5) 43 (70.5) 28 (82.3) 66 (94.3) 0.005
BMI 26.8 ± 3.78 26.5 ± 3.55 26.4 ± 4.53 27.8 ± 3.67 26.7 ± 3.67 0.715
Risk factors
Hypertension 156 (74.6) 34 (77.2) 46 (75.4) 24 (70.6) 52 (74.3) 0.923
Hyperlipidaemia 138 (66.0) 27 (61.3) 44 (72.1) 21 (61.7) 46 (65.7) 0.633
Diabetes mellitus 67 (32.1) 12 (27.2) 19 (31.1) 14 (41.1) 22 (31.4) 0.616
Insulin therapy 20 (9.6) 4 (9.1) 6 (9.8) 4 (11.7) 6 (8.5) 0.814
Current smoking 51 (24.4) 11 (25.0) 16 (26.2) 4 (11.7) 20 (28.5) 0.010
Chronic kidney disease 53 (25.4) 14 (31.8) 17 (27.8) 8 (23.5) 14 (20.0) 0.571
Dialysis 6 (2.9) 1 (2.2) 2 (3.2) 1 (2.9) 2 (2.8) 0.632
PAD 67 (32.1) 14 (31.8) 19 (31.1) 9 (26.4) 25 (35.7) 0.815
Previous PCI 62 (29.6) 10 (22.7) 18 (29.5) 12 (35.3) 22 (31.4) 0.651
Previous CABG 2 (1.0) 1 (2.2) 1 (1.6) 0 (0.0) 0 (0.0) 0.550
Clinical presentation
ACS 83 (39.7) 18 (40.9) 28 (45.9) 11 (32.3) 26 (37.1) 0.580
STEMI 26 (12.4) 8 (18.1) 7 (11.4) 4 (11.7) 7 (10.0) 0.686
Culprit lesion 24 (11.5) 3 (6.8) 7 (11.4) 4 (11.7) 10 (14.3) 0.686
functionally
investigated
Stable CAD 126 (60.3) 26 (59.1) 33 (54.1) 23 (67.6) 44 (62.8) 0.580
Abbreviations: ACS, acute coronary syndrome; BMI, body mass index; CABG, coronary artery bypass graft; CAD, coronary artery disease; PAD, peripheral artery disease;
PCI, percutaneous coronary intervention; STEMI, ST‐Elevation myocardial infarction.

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FIGURE 1 | Physiological pattern of disease classification across different pullback analysis methods. Proportion of vessels classified as
focal (focal plus mixed‐focal is reported in blue) or diffuse (diffuse plus mixed‐diffuse is reported in green), at the qualitative longitudinal
interpretation from experts based on iFR pullback curves (A) and µFR virtual pullback curves (B), and at the quantitative assessment with iPG
(C) and µFR PPGi (D). Panels A and B show similar distributions of focal and diffuse patterns in qualitative analyses of iFR (51% vs. 49%) and
μFR (49% vs. 51%). Panel C (quantitative iPG) highlights a higher prevalence of diffuse disease (64% vs. 36%), while Panel D (quantitative μFR
PPGi) mirrors the qualitative distributions (49% vs. 51%). Significant correlations are observed between qualitative and quantitative methods
(p < 0.001) and between qualitative iFR and μFR (p = 0.003), but not between quantitative evaluation based on iPG and μFR PPGi (p = 0.403).
These findings highlight the complementary roles of qualitative and quantitative approaches, with quantitative methods like iPG providing
greater sensitivity in identifying diffuse disease patterns. iFR, instantaneous wave‐free ratio; iPG, Instantaneous free‐ratio pullback pressure
gradient index; µFR, Murray's law quantitative flow ratio; µFR PPGi, µFR pullback pressure gradient index. [Color figure can be viewed at
wileyonlinelibrary.com]

moderate (K Fleiss 0.480, p < 0.001). Each operator indepen- compared to vessels with mixed‐focal (0.702 ± 0.058 SD),
dently and in a blinded manner classified the vessels into focal, mixed‐diffuse (0.650 ± 0.066 SD), or diffuse pattern (0.661 ±
mixed‐focal, mixed‐diffuse, and diffuse patterns. Of the 209 iFR 0.048 SD) (p < 0.0001 for all comparisons) (Figure 2, Table 2).
pullback traces analyzed, 196 (93.8%) showed sufficient agree- Similarly, the diFR/ds was significantly higher in vessels with focal
ment (≥ 3 out of five reviewers with the same classification), (0.0391 ± 0.0470 SD) compared with vessels with mixed‐focal
while 13 (6.2%) required collegial discussion to achieve consen- (0.0290 ± 0.0292 SD), mixed‐diffuse (0.0176 ± 0.0078 SD) or diffuse
sus (Supporting Information S1: Figure 4). For binary analyses, pattern (0.0129 ± 0.0072 SD) (p < 0.0001 for all comparisons)
when necessary, mixed‐focal was grouped with focal, and mixed‐ (Figure 2, Table 2). iPG demonstrated an overall good accuracy in
diffuse was grouped with diffuse. In analyses using three cate- predicting the predominant pattern of disease, based on iFR‐
gories, mixed‐focal and mixed‐diffuse were combined into a pullback qualitative interpretation (AUC 0.785, CI 0.95: 0.724–0.846;
single “mixed” category. p < 0.001, Figure 3). iPG reclassified 44% of the patterns compared
with the qualitative angiographic interpretation (Figure 4). The
mean value of diFR/ds (0.0239 ± 0.0289 SD) in the present popu-
3.3 | iFR‐Based Quantitative Vessel Longitudinal lation was used to define the presence or absence of major pressure
Analysis drops. Patients with major drops showed higher mean iPG values
compared to those without, although this difference was not sta-
The mean value of iPG was 0.697. iPG was significantly higher tistically significant (0.716 ± 0.0987 SD vs 0.692 ± 0.0725 SD;
in vessels classified by experts as focal (iPG: 0.786 ± 0.081 SD) p = 0.067) (Supporting Information S1: Figure 5).

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TABLE 2 | Angiographic characteristics according to disease patterns determined by iFR pullback qualitative longitudinal analysis.

Focal Mixed focal Mixed diffuse Diffuse

Total (n = 209) (n = 44, 22%) (n = 61, 29%) (n = 34, 16%) (n = 70, 33%) p value
Target vessel < 0.001
Left Main 4 (1.9) 0 (0.0) 1 (1.6) 0 (0.0) 3 (4.2)
LAD 187 (89.5) 32 (72.7) 56 (91.8) 33 (97.0) 66 (94.2)
LCX 12 (5.7) 8 (18.1) 3 (4.9) 0 (0.0) 1 (1.4)
RCA 6 (2.9) 4 (9.1) 1 (1.6) 1 (2.9) 0 (0.0)
Quantitative coronary analysis
RVD 2.77 ± 0.52 2.74 ± 0.48 2.86 ± 0.55 2.75 ± 0.45 2.72 ± 0.54 0.514
DS% 43.4 ± 8.90 47.66 ± 9.53 43.52 ± 8.54 43.16 ± 8.61 40.64 ± 7.99 0.001
Physiological indices
FFR 0.78 ± 0.07 0.77 ± 0.11 0.77 ± 0.07 0.77 ± 0.06 0.80 ± 0.05 0.022
iFR 0.83 ± 0.12 0.79 ± 0.178 0.81 ± 0.13 0.84 ± 0.07 0.80 ± 0.08 0.016
µFR 0.73 ± 0.14 0.73 ± 0.15 0.73 ± 0.13 0.77 ± 0.13 0.72 ± 0.13 0.011
iPG 0.69 ± 0.07 0.78 ± 0.08 0.70 ± 0.08 0.65 ± 0.06 0.66 ± 0.04 0.002
diFR/ds 0.023 ± 0.028 0.039 ± 0.047 0.029 ± 0.029 0.017 ± 0.007 0.021 ± 0.024 0.020
µFR PPGi 0.66 ± 0.09 0.70 ± 0.11 0.65 ± 0.08 0.69 ± 0.08 0.65 ± 0.08 0.019
dµFR/ds 0.030 ± 0.029 0.045 ± 0.049 0.028 ± 0.021 0.029 ± 0.020 0.022 ± 0.018 0.022
Note: Numbers are count (percentage) or mean (±standard deviation) diFR/ds, instantaneous iFR gradients per unit of length; dµFR/ds, instantaneous µFR gradients
per unit of length; DS, diameter stenosis; FFR, fractional flow reserve; iFR, instantaneous wave‐free ratio; iPG, instantaneous free‐ratio pullback pressure gradient index;
LAD, left anterior descending artery; LCX, left circumflex artery; µFR, Murray's law quantitative flow ratio; µFR PPGi, µFR pullback pressure gradient index; RCA, right
coronary artery; RVD, reference vessel diameter.

3.4 | µFR‐Based Qualitative Vessel Longitudinal Supporting Information S1: Figure 8 and Supporting Infor-
Analysis mation S1: Table 1).

Based on µFR virtual pullback, 102 (49%) vessels were classified as The µFR‐derived PPGi demonstrated an overall good accuracy in
predominantly focal and 107 (51%) as predominantly diffuse predicting the predominant pattern of disease (AUC 0.77, CI
(Figure 1). The overall agreement with the iFR based pullback 0.95, p < 0.001). The best threshold of µFR‐derived PPGi to define
analysis was 60.3% (k = 0.206, p = 0.003, Supporting Information focal disease was 0.66 (Youden index = 0.426) providing a sen-
S1: Figure 6). sitivity, specificity, positive predictive value, negative predictive
value and accuracy of 71.96%, 70.59%, 71.96%, 70.59% and 0.71
Mixed patterns were observed in 81 (39%) vessels (Supporting respectively (Supporting Information S1: Figure 9).
Information S1: Figure 7).
Based on µFR‐derived PPGi, 102 (49%) vessels were classified as
The inter‐operator agreement on µFR virtual pullback was mod- predominantly focal and 107 (51%) as predominantly diffuse
erate (K Fleiss 0.440). Of the 209 µFR pullback traces analyzed, 200 (Figure 1).
(95.7%) showed sufficient agreement (≥ 3 out of five reviewers with
the same qualitative classification), while 10 (4.3%) required colle-
gial discussion to achieve consensus (Supporting Information S1: 3.6 | Comparison of µFR‐ and iFR‐Based
Figure 4). Quantitative Vessel Longitudinal Analysis

µFR‐derived PPGi demonstrated a modest, but significant correla-

3.5 | µFR‐Based Quantitative Vessel Longitudinal tion with iPG (r = 0.238, p < 0.001). The Bland Altman analysis
Analysis showed a bias of 0.03 and it is reported in Supplementary Figure 10.
dµFR/ds demonstrated a moderate significant correlation with
The mean value of µFR‐derived PPGi was 0.663. µFR‐derived diFR/ds (r = 0.528; p < 0.001). The Bland Altman analysis showed a
PPGi was significantly higher in vessels with focal lesions bias of −0.006.
(0.776 ± 0.060 SD) compared with vessels with diffuse patterns
(0.627 ± 0.084 SD) or mixed patterns, both mixed‐focal
(0.660 ± 0.066 SD) and mixed‐diffuse (0.595 ± 0.071 SD). Also, 4 | Discussion
the dµFR/ds was significantly higher in vessels with focal
disease (0.051 ± 0.048 SD) with respect to vessels with mixed‐ This study introduces iPG and diFR/ds as novel, non‐hyperemic
focal (0.037 ± 0.024 SD), mixed‐diffuse (0.024 ± 0.017 SD) or physiological indices that provide complementary insights into the
diffuse disease (0.015 ± 0.007 SD) (p < 0.0001) (Table 2, distribution and severity of coronary artery disease.

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FIGURE 2 | Distribution of iPG and diFR/ds indices across different disease patterns. Distribution of iPG and diFR/ds indices across different disease
patterns (Focal, Mixed Focal, Mixed Diffuse, and Diffuse) as determined by qualitative longitudinal iFR analysis. In the upper panel, iPG data are represented
through boxplot (on the left) and density plot (on the right). Significant differences are observed among all groups, with focal lesions displaying the highest iPG
values and diffuse disease showing the lowest (p < 0.001 for most comparisons, p = 0.04 between mixed focal and mixed diffuse, and mixed diffuse and
diffuse). In the lower panel, diFR/ds values distribution is represented in a bar chart (on the left) and in a density plot (on the right). Focal and mixed focal
lesions show significantly higher diFR/ds values compared to mixed diffuse and diffuse disease (p < 0.001 for most comparisons, p = 0.04 between mixed
categories). The density plot for diFR/ds in predominantly focal lesions exhibits a secondary hump, which likely reflects the heterogeneity within this category.
This may correspond to subgroups of focal lesions with varying hemodynamic impacts: those with mild pressure gradients (lower diFR/ds values) and those
with steeper gradients localized in short segments (higher diFR/ds values). Alternatively, anatomical or technical factors, as well as overlaps with mixed
patterns, might contribute to this distribution. These visualizations underline the complementary roles of iPG and diFR/ds in differentiating focal, mixed, and
diffuse disease patterns, with diFR/ds providing a more localized assessment of pressure gradients along the vessel. diFR/ds, Instantaneous iFR gradients
per unit of length; iFR, instantaneous wave‐free ratio; iPG, Instantaneous free‐ratio pullback pressure gradient index. [Color figure can be viewed at
wileyonlinelibrary.com]

The iPG offers a continuous, vessel‐level metric that reflects coronary lesions, capturing both diffuse and focal
the overall physiological distribution of disease, while components.
diFR/ds quantifies local pressure gradients, highlighting
major focal drops along the vessel. Their combined use These findings suggest that iPG and diFR/ds may enhance
enables a more refined, non‐hyperemic assessment of physiological interpretation of coronary disease beyond binary

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FIGURE 3 | Diagnostic performance of iPG in predicting the physiological pattern of disease. AUC, area under the curve; iPG, instan-
taneous free‐ratio pullback pressure gradient index; NPV, negative predictive value; PPV, positive predictive value; ROC, receiver operating
characteristic. [Color figure can be viewed at wileyonlinelibrary.com]

FIGURE 4 | Reclassification of the angiographic patterns based on the quantitative iFR pullback evaluation (iPG). Reclassification of
disease patterns at the alluvional plot. 8.6% of vessels classified as diffuse at the angiographic evaluation, was re‐evaluated as focal at the
quantitative longitudinal analysis. 35.4% of vessel classified as focal at the angiographic analysis had an iPG indicative of diffuse disease. iFR,
instantaneous wave‐free ratio; iPG, Instantaneous free‐ratio pullback pressure gradient index. [Color figure can be viewed at
wileyonlinelibrary.com]

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significance thresholds, supporting a more comprehensive Similar to what has been observed for FFR‐based PPGi, the higher
evaluation of intermediate lesions in real‐world practice. the iPG, the more focal the lesion, while lower iPG values indicate
more diffuse disease [3, 5]. This finding mirrors the results
iPG and diFR/ds provide complementary insights into coronary obtained from μFR‐PPGi, a purely angiogram‐based method that
physiology, as they assess different aspects of vascular disease. also demonstrated higher values in focal lesions [19]. In our
Specifically: analysis, iPG and μFR‐PPGi were significantly correlated. More-
over, iPG also correlated with local lesion severity, as evidenced by
• iPG offers a global assessment of the overall disease burden its relationship with diFR/ds (r = 0.528, p < 0.001).
in the vessel, reflecting the total physiological impact of
stenoses. The combination of iPG and diFR/ds provides complementary
insights into the overall and localized physiological impact of
• ΔiFR/ds, on the other hand, provides a spatially resolved
CAD, offering clinicians a robust set of tools to guide
measure of pressure gradients along the vessel, capturing
revascularization strategies.
how pressure changes across different segments.
The potential clinical impact of iPG is significant, particularly in
For example, a vessel with diffuse disease might still exhibit
light of its ability to reclassify lesions previously deemed focal
localized regions of higher pressure gradients. In such cases,
based on visual angiographic assessment. Notably, iPG re-
ΔiFR/ds could help identify focal segments within a diffusely
classified 35.4% of vessels initially interpreted as focal, sug-
diseased artery that may serve as potential targets for
gesting that relying solely on qualitative analysis may lead to
revascularization, even when the global iPG value alone does
misclassification, with potential consequences for treatment
not clearly indicate a specific intervention site.
decisions. Therefore, the integration of quantitative tools such
as iPG into routine clinical practice could reduce subjectivity
The main findings of the present study are as follows:
and improve decision‐making accuracy in PCI planning.
1. The visual interpretation of the pressure‐wire pullback is
A key finding of our study is that mixed patterns are both
flawed by significant interobserver variability (K Fleiss 0.440).
common (~45% of cases) and often underrecognized when
2. The iPG and diFR/ds are practical tools for characterizing dichotomous variables, such as the PPGi, are used. In this
physiological CAD patterns obviating the need for steady‐ context, coregistered techniques can be instrumental in accu-
state hyperemia. An iPG cut‐off value of 0.71 accurately rately identifying focal pressure drops that may be amenable to
differentiates between focal and diffuse patterns of CAD treatment with PCI. Careful evaluation of both the length and
(AUC 0.785; p < 0.05). magnitude of the focal drop is essential to predict the antici-
pated physiological benefit following PCI. Notably, in cases of
3. Using the ROC derived cut‐off of 0.71, the iPG reclassified
mixed patterns, PCI tends to yield less favorable physiological
44% of the patterns compared with the angiographic visual
outcomes compared to scenarios with isolated focal lesions, due
interpretation.
to the concurrent presence of diffuse disease [3, 23, 24, 27].
4. iPG and diFR/ds provided a moderate agreement with From a procedural standpoint, in patients with a functional
μFR‐derived metrics including μFR‐PPGi and dμFR/ds. mixed pattern, as for diffuse disease, intracoronary imaging
should be utilized to identify a disease‐free landing zone for
Diffuse disease poses several challenges in patients undergoing stenting. This approach helps optimize post‐PCI outcomes by
PCI including long coronary segments requiring treatment, a allowing detailed assessment of stent edges, which is crucial
lack of adequate landing zone for stenting and impairment of given the heightened risk of complications such as dissections
coronary flow related to the diffuse atherosclerotic burden along or plaque shift associated with diffusely diseased segments.
the vessel [19, 21, 22]. Moreover, diffuse disease is associated
with higher risk of suboptimal functional results and residual Future research could explore several avenues. Prospective
symptoms after PCI [23–25]. Therefore, determining the distri- studies should evaluate whether the use of iPG can improve
bution pattern of disease, with the identification of focal lesions clinical outcomes by influencing PCI strategies.
versus segments of diffuse disease, has become one of the cor-
nerstones of decision‐making for myocardial revascularization. Finally, efforts should be made to improve the inter‐operator
reliability of qualitative assessments, possibly through advanced
The global use of wire‐based physiological assessments in clinical machine learning algorithms that can standardize interpreta-
practice remains low and inconsistent. Some reasons for this low tion. The ongoing DEFINE GPS (NCT04451044) study will
adoption include longer procedure times, the invasive nature of contribute to a comprehensive understanding of how invasive
the instruments, and the use of vasodilator agents, which can physiological assessments with iFR can optimize PCI compared
cause undesirable side effects [26]. The non‐hyperemic nature of to angiography alone in terms of clinical outcomes.
iPG is especially advantageous, given that traditional hyperemic
methods, such as FFR, require the use of adenosine, which can
be time‐consuming and uncomfortable for patients. 4.1 | Limitations

Our study confirmed that the qualitative interpretation of iFR This study has several limitations. First, selection bias may have
pullbacks is hampered by significant interobserver variability, occurred due to its observational, single‐center design. How-
emphasizing the need for standardization in clinical practice. ever, efforts were made to minimize confounding factors, such

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CENTRAL ILLUSTRATION 1 | Novel non‐hyperemic coronary physiology indices for vessel longitudinal analysis. Novel coronary physi-
ology indices, iPG and diFR/ds, characterize the physiological patterns of coronary vessels and local disease severity without the need of
hyperemia. In panel A, an illustrative case of each type of disease is given. For each case, angiography (pointing out the presence of disease), iFR
pullback, µFR pullback, iPG and diFR/ds values are reported. In the upper part of panel B, iPG values are reported in reference to the disease
pattern in form of box plot (on the left) and density plot (on the right). In the lower part of panel B, diFR/ds values are reported in reference to the
disease pattern in form of bar chart (on the left) and density plot (on the right). Higher iPG and diFR/ds values are associated with focal disease,
while lower values of iPG and diFR/ds are indicative of diffuse disease. diFR/ds, Instantaneous iFR gradients per unit of length; iFR, instanta-
neous wave‐free ratio; iPG, Instantaneous free‐ratio pullback pressure gradient index; µFR, Murray's law quantitative flow ratio. [Color figure can
be viewed at wileyonlinelibrary.com]

as excluding angiograms and pullback traces with poor quality; analysis to preserve physiological relevance. Central
all analyses were conducted by experienced operators. Low‐ Illustration 1.
quality angiographic analyses and pullback traces could have
negatively impacted the reproducibility of µFR assessments and
the accuracy of pullback graphical data extraction.
5 | Conclusion
Second, iFR pullback traces do not allow precise determination
The integration of novel non‐hyperemic indices (iPG and diFR/
of vessel length, as the curves are plotted with time on the x‐axis.
ds) enhances the physiological interpretation of coronary artery
To address this, vessel length extrapolated from the µFR analysis
disease by enabling longitudinal vessel and lesion‐level analysis.
was used for both iFR and virtual µFR pullback data extractions.
iPG, based on resting physiology, offers a simple and user‐
friendly alternative to PPGi without requiring steady‐state
Third, manual iFR pullback may have influenced trace shape.
hyperemia. These indices provide objective, reproducible met-
Nonetheless, all procedures were performed by experienced
rics, reducing interobserver variability and improving lesion
operators instructed to maintain pullback velocities between 0.5
classification, especially in distinguishing focal from diffuse
and 1.0 mm/s. Avoiding motorized pullback may even reflect
patterns. The ability of iPG to reclassify nearly 30% of lesions
real‐world clinical practice. Furthermore, previous studies have
previously considered focal underscores its value in refining
demonstrated that manual pullbacks offer comparable accuracy
atherosclerotic disease assessment. Incorporating iPG and
to motorized systems, with validated inter‐operator reproduc-
diFR/ds into clinical practice may optimize treatment strategies
ibility and strong clinical relevance [28].
through more accurate lesion characterization, identification of
disease‐free stent landing zones, and improved PCI planning
Fourth, the cohort predominantly included LAD vessels (~90%),
and outcomes.
which may limit generalizability. Future studies with a more
balanced vessel distribution are warranted.

Lastly, iPG and diFR/ds were not compared with hyperemic Acknowledgments
counterparts. However, since µFR‐based PPGi and FFR‐based Open access publishing facilitated by Universita degli Studi di Verona,
PPGi are correlated, µFR PPGi was used as a surrogate in this as part of the Wiley ‐ CRUI‐CARE agreement.

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Consent 11. C. Vrints, F. Andreotti, K. C. Koskinas, et al., “2024 ESC Guidelines
All patients provided written informed consent for inclusion in the for the Management of Chronic Coronary Syndromes,” European Heart
Journal 45 (2024): 3415–3537.
study and for the use of anonymized data for research purposes.
12. N. Dai, D. Hwang, J. M. Lee, et al., “Feasibility of Quantitative Flow
Ratio‐Derived Pullback Pressure Gradient Index and Its Impact on
Ethics Statement
Diagnostic Performance,” JACC: Cardiovascular Interventions 14 (2021):
The study was conducted in accordance with the Declaration of Hel- 353–355.
sinki. Ethical approval was obtained from the local institutional ethics
board. 13. R. Scarsini, S. Fezzi, G. Pesarini, et al., “Impact of Physiologically
Diffuse Versus Focal Pattern of Coronary Disease on Quantitative Flow
Reserve Diagnostic Accuracy,” Catheterization and Cardiovascular
Conflicts of Interest Interventions 99 (2022): 736–745.
R. Scarsini has received speaker and consultation fees from Abbott and 14. S. S. Nijjer, S. Sen, R. Petraco, et al., “Pre‐Angioplasty Instantaneous
B‐Braun, and institutional research grants from Edwards Lifesciences, Wave‐Free Ratio Pullback Provides Virtual Intervention and Predicts
Abbott and Medis. S. Fezzi has received consultancy fees from Boston Hemodynamic Outcome for Serial Lesions and Diffuse Coronary Artery
Scientific and Biotronik. S. Tu is a cofounder of Pulse Medical and Disease,” JACC: Cardiovascular Interventions 7 (2014): 1386–1396.
reports research grant and consultancy from Pulse Medical. Dr. Prado
15. S. Tu, D. Ding, Y. Chang, C. Li, W. Wijns, and B. Xu, “Diagnostic
has been supported by a research grant provided by the DigiCardiopaTh
PhD Program. All other authors declare that they have no conflicts of Accuracy of Quantitative Flow Ratio for Assessment of Coronary Ste-
interest related to this study. nosis Significance From a Single Angiographic View: A Novel Method
Based on Bifurcation Fractal Law,” Catheterization and Cardiovascular
Interventions 97 (2021): 1040–1047.
Data Availability Statement
16. Y. Fan, S. Fezzi, P. Sun, et al., “In Vivo Validation of a Novel
The data that support the findings of this study are not publicly avail- Computational Approach to Assess Microcirculatory Resistance Based
able due to their potential use in future related publications. Reasonable on a Single Angiographic View,” Journal of Personalized Medicine 12
requests for access may be considered by the corresponding author. (2022): 1798.
17. S. Fezzi, D. Ding, R. Scarsini, et al., “Integrated Assessment of
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Supporting Information
Additional supporting information can be found online in the
Supporting Information section.
Supplementary Data.

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