Clinical Review & Education

JAMA Cardiology | Review

Physiology-Guided Management
of Serial Coronary Artery Disease
A Review
Bhavik N. Modi, MA, MBBS; Kalpa De Silva, MBBS, PhD; Ronak Rajani, MBBS, PhD; Nick Curzen, BM, PhD;
Divaka Perera, MA, MBBChir, MD

Editorial
IMPORTANCE Ischemia-guided revascularization is the cornerstone of contemporary
management of coronary artery disease and has evolved from noninvasive functional
evaluation to real-time assessment with invasive physiological indices during diagnostic
catheterization. However, serial/diffuse disease is common, and revascularization decisions
often need to be made about individual lesions within the same vessel. It is unclear whether
current physiological techniques, such as fractional flow reserve, can be reliably used to
discern the individual contribution of lesions within a serially diseased vessel with erroneous
measurements, potentially leading to suboptimal revascularization decisions. This review
addresses the application of physiological techniques to serial coronary disease, highlighting
challenges and potential solutions.

OBSERVATIONS Physiological indices, such as fractional flow reserve, are well validated and
correlated with clinical outcomes; however, the challenging physiology of serial stenoses
makes it difficult to apply conventional techniques to identify the physiological significance of
individual lesions. The 2 methods are most accurate in assessing serial disease are the manual
pullback, with treatment of the greatest pressure gradient, or adopting the use of a large
disease-free side branch to isolate the significance of the proximal lesion in the context of
serial disease involving the left main coronary artery. In addition, resting indices, such as
instantaneous wave-free ratio, have theoretical benefits that may make them more reliable in
serial disease, with further data awaited.

CONCLUSIONS AND RELEVANCE Serial coronary artery disease is common, and physiological
assessment is prone to errors. The future, whether it be in improving the interpretation of
fractional flow reserve, using resting indices such as instantaneous wave-free ratio, or
examining novel flow-based resistance indices, will hopefully improve our management of
this common yet unresolved clinical conundrum. In the meantime, revascularisation decisions
in this challenging scenario should focus on clinical presentation and physiologic evaluation
using a pressure-wire pullback maneuver and left main disease-free side branch where
appropriate.

Author Affiliations: Cardiovascular

Division, St Thomas’ Hospital
Campus, King’s College London,
England (Modi, De Silva, Rajani,
Perera); Royal North Shore Hospital
and University of Sydney, Sydney,
Australia (De Silva); University
Hospital Southampton and Faculty of
Medicine, University of
Southampton, England (Curzen).
Corresponding Author: Divaka
Perera, MA, MBBChir, MD,
Cardiovascular Division, Rayne
Institute, St. Thomas’ Hospital,
JAMA Cardiol. doi:10.1001/jamacardio.2018.0236 London SE1 7EH, England (divaka
Published online March 21, 2018. .perera@kcl.ac.uk).

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 Clinical Review & Education Review
T
here is growing evidence that the greatest benefit of revas-
cularizationforcoronaryarterydiseaseisderivedfromtarget-
ing myocardial ischemia. Traditionally, functional assessment
to identify patients with coronary artery disease was based on nonin-
vasive tests prior to angiography.1 This has subsequently evolved to
identifying vessels with functionally significant disease at the time of
angiography, such as with fractional flow reserve (FFR) and instanta-
neous wave-free ratio (iFR).2-4
Coronary artery disease is the result of atherosclerosis, which is
systemic in nature, and therefore, an element of serial/diffuse disease
is common. In the presence of serial disease that an interventional car-
diologist would consider treating separately, there is the need to iden-
tifythephysiologicalsignificanceofindividuallesions:thisispotentially
challenging because of physiological interplay that alters the apparent
functional severity of each lesion. This review examines the physiol-
ogy of serial stenoses and discusses current and emerging techniques
that may be used to assess the functional significance of individual le-
sions in series when planning revascularization strategies.
The Era of Ischemia-Guided Revascularization
Data are accumulating to suggest revascularization decisions based on
detecting ischemia improves clinical outcomes.2-7 In particular, the as-
sessment of pressure change (Pd/Pa) along a vessel has been increas-
ingly adopted for assessing myocardial ischemia in a specific coronary
territory at the time of angiography. The Pd/Pa during the wave-free
periodofdiastole,whenmicrovascularresistanceissaidtobeconstant,8
isreferredtoasiFR,whereasPd/Paduringmaximaladenosine-induced
hyperemia, when the reduction in flow in the distal vessel is assumed
proportional to the change in pressure across it, is referred to as FFR
andisthemostwidelyusedpressureindexofmyocardialischemia.Frac-
tional flow reserve was initially validated against noninvasive surrogate
markersofischemiainpatientswithstablecoronaryarterydiseasewith
single-vessel disease and focal stenoses.9 Since then, there has been
increasing evidence demonstrating that visual assessment of angio-
graphic stenosis severity is prone to significant error and does not re-
liably correlate to underlying functional significance.1,10
As a consequence, ischemia-guided revascularization with FFR or
iFR confers clinical and prognostic benefit vs treatment based on an-
giography alone.2,4,6,7,11 However, this is when the pressure sensor is
placed in the distal vessel, with the gradient capturing the cumulative
effect of all disease. When faced with sequential lesions within a ves-
sel,itisimportanttoascertaintheindividualhemodynamicsignificance
of diseased segments for guiding subsequent revascularization strat-
egy. For example, if the pressure gradient is suggestive of a long seg-
ment of diffuse disease, surgical revascularisation or medical therapy
may be more appropriate.12
The Physiology of Serial Stenoses
To understand serial stenosis interplay, we must first understand the
factors that lead to pressure changes across a lesion (ΔP). Pressure
changeisdeterminedbyseveralfactorsthataregovernedbyprinciples
enshrined in the Bernoulli equation and Poiseuille Law. As summarized
in Figure 1, ΔP across a stenosis, as demonstrated in seminal canine
experiments,13 can be summarized as ΔP = fQ+sQ,2 in which ΔP indi-
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Physiology-Guided Management of Serial Coronary Artery Disease
Figure 1. Factors Influencing the Pressure Gradient Across a Stenosis
ΔP
/
•
Q As An
(mL/min)
• •
ΔP = f1(1/As2, l, Q) + f2(1/An2, 1/As2, Q2)
Viscous Separation
Simplified to: ΔP = fQ + sQ2
Pressure gradients across a stenosis can be described by a relationship from the
energy losses by viscous friction and flow separation,13 which takes the form of
ΔP = fQ+sQ,2 in which ΔP indicates change in pressure, f indicates frictional
coefficient of a lesion (influenced by lesion length and diameter stenosis), s
indicates separation coefficient of a lesion (influenced by diameter stenosis and
the laminar flow separation), and Q indicates flow.
cates change in pressure, f indicates the frictional coefficient of a le-
sion, s indicates the separation coefficient of a lesion, and Q indicates
blood flow through the stenosis. This relationship, including both the
frictional and separation coefficients, embody the Bernoulli principle
and Poiseuille Law and are determined largely by specific lesion geom-
etry. Aside from how the specific shape of a stenosis affects these co-
efficients, it is worth considering other important factors.
Luminal Narrowing
This contributes to both frictional (f) and separation coefficient (s)
of a lesion. According to Poiseuille law, ΔP across a stenosis is the
product of volumetric flow rate and viscous resistance (R), with the
latter defined as R = 8ηL/πr4, in which η is the viscosity of the fluid,
L is the length of the vessel, and r is the radius of the vessel. Al-
though blood flow in smaller vessels may depart from this relation-
ship, for most epicardial vessels within a physiological range of pres-
sures, resistance and and hence ΔP varies inversely with the fourth
power of vessel radius.
Lesion Length
This contributes linearly to viscous resistance (by Poiseulle Law) and
to the viscous coefficient of the equation in Figure 1. Although the
effect on ΔP may not be as profound as the degree of stenosis, le-
sion length is important, especially in long diffusely diseased seg-
ments.
Flow Conditions
In fluid dynamics, laminar flow is orderly, and turbulent flow is ran-
dom. Within a pipe, flow is laminar; however, in the presence of a
stenosis, flow separation increases as eddy currents begin to form
and flow becomes nonlaminar beyond a certain threshold (the Reyn-
olds Number) with subsequently increased flow separation.14 Such
changes in flow conditions form the basis of the flow separation co-
efficient in Figure 1.
Flow Velocity
This factor is influenced by changes in downstream resistance. We
know from work by Uren et al15 that as a stenosis is removed, resis-
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 Physiology-Guided Management of Serial Coronary Artery Disease
tance falls and hyperaemic flow increases, and as inlet flow veloc-
ity changes for any remaining stenosis, so will ΔP across it. Based
on these principles, any significant accompanying disease will, in turn,
increase total resistance, regardless of whether that disease is up-
stream or downstream of the stenosis in question.
Therefore, it follows that the significance of stenosis may be ar-
tificially underestimated by pressure-based indices. In addition, the
presence of stenoses elsewhere can alter flow conditions signifi-
cantly such that laminar flow becomes more turbulent with subse-
quent energy loss (and therefore pressure). The degree to which this
factor influences ΔP depends on the individual frictional (f) and sepa-
ration (s) coefficients of the stenoses within the serially diseased ves-
sel (Figure 1). In a serially diseased vessel, ΔP and thus the indi-
vidual contribution of an individual stenosis to overall FFR is therefore
likely to be determined by not just ΔP = fQ+sQ2 but also total ves-
sel resistance and the alteration of these laminar fluid dynamics.
Theoretical Solutions to Overcome Serial Stenosis
Interplay
Various theoretical solutions have been examined to define an algo-
rithm for determining the individual contribution of each stenosis to
total vessel FFR (true FFR, where each stenosis present in isolation).
Such a solution was determined in vitro and subsequently tested in ca-
nines by De Bruyne et al16 to show that predicted FFR from the theo-
reticalequationmadesomeimprovementsinidentifyingtrueFFR.This
solution, requiring knowledge of wedge pressure between stenoses,
wassubsequentlyvalidatedinasmallclinicalstudybyPijlsetal,17 where
a pressure wire was used as a standard angioplasty wire in the assess-
ment of 32 tandem lesions, enabling a wedge pressure measurement
duringballooningofeachlesion.Theyfoundimprovedaccuracyiniden-
tifying the attributable true FFR of individual lesions.18 However, this
technique is difficult to use in clinical practice because it involves bal-
looning arterial segments to measure a wedge pressure17 without hav-
ing first determined an appropriate revascularization strategy.
Current Clinical Strategies in Using FFR for Serial
Lesions
Isolating Lesions With an Interlesion FFR
Thepresenceofserialstenosisinterplayisoftenignored,withmeasure-
mentofintracoronarypressurebetweenanddistaltosequentiallesions
beingusedtoerroneouslyestimatewhateachlesioncontributestototal
FFR, with significant theoretical limitations (Figure 2). Measuring in-
tracoronary pressure between lesions (without ballooning to measure
wedge pressure) disregards the fact that total vessel resistance is
greater in the presence of an accompanying stenosis (with subsequent
underestimation of pressure gradients). Furthermore, the presence of
an accompanying lesion, particularly up to a certain distance apart, also
affects flow conditions and turbulence within the vessel (contributing
to coefficient “s” in Figure 1).
The Educated Guess
Another commonly adopted but imperfect solution is to make a visual
educatedguessregardingwhichsegmentismostsignificantinthepres-
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Figure 2. Serial Stenosis Interplay
Lesion 1 Lesion 1
A A
Lesion 2 Lesion 2
B B
Pressure wire placed between Pressure wire placed between
lesions and then distal to both lesions
ΔP of lesion 1 is likely to be ΔP of lesion 2 is likely to be
underestimated underestimated
The smaller the distance between lesions, the greater the potential
for flow turbulence and further error
Diagrammatic representation of how serial stenosis interplay can result in
erroneous results using a pressure wire. Both lesions contribute to total vessel
resistance. In absence of either lesion, flow is greater and therefore change in
pressure across the remaining lesion is likely to be underestimated.
ence of a vessel with FFR less than 0.80 and treating this first. Follow-
inginitialpercutaneouscoronaryintervention(PCI),theFFRisrepeated,
with further PCI performed if FFR is less than 0.8. This is based on an
interpretation of data by Pijls et al,19 who, in a 750-patient registry,
showed that FFR after stenting was a significant predictor of events at
6 months. The study showed that patients with post-PCI FFR greater
than 0.95 had an event rate of 4.9%; whereas in the group with post-
PCI FFR of 0.80 to 0.90, event rate was 29.5%.19 While these data sup-
port ensuring the best possible physiological result, they do not tell us
how to achieve this with serial disease. By attempting to identify the
lesion that has the “most functional significance,” there is a possibility
that an accompanying lesion is underestimated, and therefore the
wrong revascularization strategy is chosen, for example, if a left main
coronaryartery(LMCA)ismistakenlyunderestimated.Alesion-specific
physiological strategy that counteracts serial stenosis interplay would
therefore be theoretically superior to a strategy that combines whole-
vessel FFR with an angiographic visual guess of the contribution of in-
dividual segments.
The Manual Pullback
Pullingbackapressurewireunderfluoroscopyisincreasinglyperformed
to assess for increments in coronary pressure (ΔP), with the assump-
tion that ΔP is indicative of lesion significance. This method, illustrated
in Figure 3, was examined by 2 observational studies20,21 in which PCI
strategy was guided by stenting the stenosis with the greatest ΔP. Kim
et al21 found that in 131 stable patients with total vessel FFR less than
0.80, PCI was safely deferred in 61.1% of lesions based on FFR after ini-
tial targeted PCI, with no clinical events related to deferral. Park et al20
studied 52 patients (104 lesions) and found the practice of treating the
lesion with greatest ΔP, remeasuring FFR and carrying out further PCI
until FFR is greater than 0.8, is also associated with good clinical
outcomes.20 However, the method of treating the greatest ΔP follow-
ing manual pullback does have potential pitfalls:
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 Clinical Review & Education Review
Figure 3. The Pressure-Wire Pullback Maneuver
A Apparent pressure change B True pressure change
1.0
0.76
0.6 0.69
1. Although underestimation is more common, overestimation is
possible, although rare: this has been observed in several stud-
ies showing apparent ΔFFR of lesions is, on rare occasions, greater
than the true ΔFFR.16,17,20,21 A potential reason for this is that in-
creased flow tubulence in serial disease may be more influential
than the increased vessel resistance that usually causes under-
estimation. Overestimation means stenting the largest ΔP could
result in stenting functionally nonsignificant stenoses.
2. Treating the greatest ΔP following manual pullback has poten-
tial for operator error. For example, there is natural tendency to
pause pullback for fluoroscopic guidance halfway through iden-
tifying a gradient. This can result in artifactual plateaus, with mis-
interpretation of 1 pressure gradient as 2. Additionally, opera-
tors may only pull back through segments they believe visually
significant.1,10
3. Without the ability to accurately assess the true physiological con-
tribition of each lesion at the outset, after treating the lesion con-
tributing the greatest ΔP, a physiologically significant remaining
lesion maybe uncovered that may have been better served with
coronary artery bypass graft (eg, diffuse or LMCA disease).22
The Disease-Free Side Branch
This scenario is relevant to serial disease affecting the LMCA when a
lesion in the parent vessel is accompanied by disease in 1 daughter
vessel. Theoretically, because the LMCA perfuses both left anterior
descending and left circumflex territories, if there is a hemodynami-
cally significant stenosis in either/both the left anterior descending or
circumflex, this could lead to an underestimation of the LMCA lesion
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Physiology-Guided Management of Serial Coronary Artery Disease
Representation of manual pullback
method in a right coronary artery
with the fractional flow reserve
change seen on the console at each
point. A, The largest pressure
1.0 gradient (ΔP) corresponds to
proximal lesion with an apparent
assessment of pressure change
attributable to the distal lesion of
0.16. On treating the proximal lesion
(B), a repeated pullback reveals the
change in pressure (ΔP) of the distal
lesion was originally underestimated
(the true Pd/Pa attributable to the
lesion being 0.31).
significance. However, despite the theoretical limitation, it has been
suggested that one can isolate the true FFR (Figure 4) of the LMCA
lesion (Figure 4A) by placing the distal pressure wire in a large
unobstructed side branch (Figure 4B).
This method was initially validated in animal studies that showed
physiologically assessing intermediate LMCA lesions with the pres-
ence of a disease-free daughter vessel is reliable unless down-
stream disease is severe (FFR in serially diseased branch,
<0.45).23-25 Fearon et al26 then demonstrated this in a clinical study
of 91 LMCA lesions following PCI of the left anterior descending,
left circumflex, or both. Fractional flow reserve was measured in
the left anterior descending and left circumflex coronary arteries
before and after creation of downstream stenoses by inflating bal-
loons within newly placed stent(s) and measuring FFR within the
accompanying disease-free vessel. They then compared the true
LMCA FFR measured in the disease-free vessel with the apparent
FFR measured in the stenosed vessel, and found the LMCA true
FFR was significantly lower than the apparent FFR (mean [SD], 0.81
[0.08] vs 0.83 [0.08]), although the numerical difference was not
deemed clinically significant. They concluded that in most cases,
downstream disease does not significantly affect LMCA FFR when
the pressure wire is positioned in the disease-free vessel and that
even if there is severe serial disease, an FFR of greater than 0.85 in
the disease-free side branch means the LMCA lesion can be safely
assumed as functionally nonsignificant.26 The practice of using a
disease-free side branch is therefore an acceptable solution in the
unique case of LMCA disease with serial disease in 1 downstream
daughter vessel.
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 Physiology-Guided Management of Serial Coronary Artery Disease
Figure 4. The Disease-Free Side Branch Method
A Left main stenosis with further serial stenoses in LAD B Pressure-wire pullback from diseased LAD
An example of a left main coronary artery, with sequential disease in the left
anterior descending (LAD; yellow arrowhead), that allows us to identify the
Resting Physiological Indices
Instantaneous Wave-Free Ratio
Instantaneous wave-free ratio is defined as Pd/Pa during the latter
75% of diastole, when resistance is purported to be constant and
pressure can be assumed proportional to flow, without the need to
modulate resistance with adenosine-induced hyperaemia.7 Instan-
taneous wave-free ratio–guided revascularization has in 2017 been
shown to have comparable outcomes with FFR in a relatively low-
risk group of patients, with data awaited on more complex subsets.6,7
It has been suggested that serial stenosis interplay and altera-
tion in flow conditions may be amplified in hyperemic conditions.
This is based on an interpretation of canine experiments by Gould
et al2 that demonstrated the ΔP = fQ+sQ2 relationship. These ex-
periments showed that, for a fixed lesion, when flow transitioned
from rest to hyperemic flow, the pressure-velocity gradient grew
steeper.13,27 Proponents of iFR therefore argue that serial stenosis
interplay is potentially less at rest, with iFR in particular having added
spatial resolution advantages compared with Pd/Pa because it is not
calculated from pressures averaged during several cardiac cycles and
the fact that diastolic resistance may be lower than whole-cycle re-
sistance. On this basis, iFR has been used to study serial disease in a
small study of 32 coronary arteries.28 In this study, pressure wire pull-
back at rest was used to demonstrate how iFR changed along each
artery; this was then used to virtually remove the accompanying le-
sion, with the residual expected iFR correlating well with observed
iFR after PCI. This led to the development of the iFR Scout software
(Volcano, Phillips Inc), based on the manual pullback maneuver per-
formed for FFR, and aims to predict the residual iFR where 1 lesion
was removed and presumes that the change in iFR across a steno-
sis remains unchanged regardless of coexistent disease. The use of
iFR in serial disease is yet to be validated in large-scale studies or with
a more severe spectrum of serial disease when stenosis interplay is
likely to be more significant.
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C Pressure-wire pullback from disease-free circumflex
individual contribution from the proximal lesion (blue arrowhead) by using the
disease-free side branch (black arrowhead).
As the evidence base supporting resting indices in clinical prac-
tice grows, there will be an opportunity to systematically test the
hypothesis that serial stenosis interplay is lessened at rest. In the
meantime, iFR in serial disease has the potential to provide a solu-
tion to overcome some of the difficulties in assessing the relative le-
sion significance in serially diseased vessels; we eagerly await fur-
ther data to support this notion.
Resting Pd/Pa Ratio
The ratio of whole-cycle distal coronary pressure to aortic pressure
at rest (Pd/Pa) was originally used by Gruentzig et al29 to rational-
ize balloon angioplasty decisions.30 Although clinical outcome data
are absent, 1 study found accuracy of more than 80% when com-
pared with FFR,31 and subgroup analyses of the Verification of In-
stantaneous Wave-Free Ratio and Fractional Flow Reserve for the
Assessment of Coronary Artery Stenosis Severity in Everyday Practice
(VERIFY) and Continuum of Vasodilator Stress From Rest to Con-
trast Medium to Adenosine Hyperemia for Fractional Flow Reserve
Assessment (CONTRAST) studies suggested resting Pd/Pa and iFR
correlate almost perfectly.32,33
With more data emerging to show near-perfect agreement of
iFR and PdPa,33 there is drive to suggest using it in a similar fashion
to iFR with a threshold of Pd/Pa of 0.91 or less suggested to corre-
late excellently with IFR of 0.89 or less.33 While there is a lack of data
for resting Pd/Pa in serial disease at present, there is increasing in-
terest in resting indices, with the suggestion of less serial disease in-
terplay, and so we are likely to see data emerge for the use of rest-
ing Pd/Pa in serial disease, just as we are seeing for iFR.
Pressure-Flow Derived Resistance Indices
Measuring flow enables us to establish coronary resistance (where
resistance = ΔP / flow) because at the physiological range of pres-
sures, the relationship curve between coronary flow and pressure
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 Clinical Review & Education Review
Figure 5. An Example of Physiological-Anatomical Coregistration
may be presumed to be linear. The resistance posed by an indi-
vidual stenosis should theoretically be independent of hemody-
namic and flow interdependence resulting from serial lesions. The
criterion standard of assessing the physiological resistance posed
by a specific segment of a diseased vessel is hyperemic stenosis re-
sistance, where hyperemic stenosis resistance = hyperaemic pres-
sure gradient / hyperaemic mean peak flow velocity, and allows as-
sessment of the individual resistance to flow posed by any coronary
segment, irrespective of disease elsewhere (the resting equivalent
is basal stenosis resistance).34 To our knowledge, there are no stud-
ies that have shown the value of translesional resistance indices in
serial disease, with the main obstacle being the complexity of ob-
taining reliable intracoronary flow signals.
Current Best Practice in Serial Stenosis
Assessment?
As described, the assessment of serial stenoses is complex and in-
completely understood. While we await more definitive data on ac-
curately determining the individual lesion significance in serial dis-
ease, it remains evident that physiology-guided revascularization is
superior to angiography-guided treatment alone, and increased
adoption, regardless of the configuration of coronary artery dis-
ease, is likely to yield better outcomes.3,4,6,7
There are 2 methods when using FFR that represent the most
accurate method of assessing serial disease: manual pullback and
disease-free side branch. Perhaps one of the main reasons for lim-
ited adoption of FFR pullback since it was first proposed has been
the relatively rare use of intravenous adenosine (a prerequisite for
this technique, as opposed to intracoronary boluses). With this
method, as is the case for iFR pullback, care must be taken to en-
sure pullback speed is as constant as possible, to limit bias and in-
accuracy. If LMCA disease exists with sequential lesions down-
stream, then a disease-free daughter vessel can be used to assess
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Physiology-Guided Management of Serial Coronary Artery Disease
Example of physiological
coregistration with the coronary
angiogram. An instantaneous
wave-free ratio (iFR) pullback was
performed, and using a commercially
available system (SyncVision, Philips),
the pullback is coregistered on the
coronary angiogram. Each yellow dot
represents a change in iFR of 0.01,
with the graphic pullback depicted on
the right of the figure. The distal iFR
at the cursor point is 0.49. The cursor
can be moved to assess the iFR at any
point along the pullback, allowing the
operator to assess the drop in iFR
across serial stenoses.
LMCA signicance.26 If possible, the disease-free side branch method
should be performed in addition to pullback to ensure as much in-
formation is assimilated about the vessel prior to deciding revascu-
larisation strategy.
For iFR, there are limited data for iFR Scout technology in a
large-scale setting, and the use of this tool should be used with
the understanding that it remains incompletely understood but is
nonetheless an improvement on using visual angiographic assess-
ment alone. Whether FFR or iFR pullback is used, one of the major
difficulties remains marrying the pullback trace to the angiogram.
Eventually, innovations in the field of intravascular imaging, physi-
ology, and perhaps noninvasive estimation of invasive physiology
(eg, FFR by computed tomography and angiographically deter-
mined FFR) will hopefully enable coregistration of physiology to
anatomy (Figure 5), so that we can identify exactly where within
the vessel a physiologically significant lesion begins and ends.
Conclusions
Although physiological indices, such as FFR, are well validated
and correlated with clinical outcomes, the uniquely challenging
physiology of serial stenoses makes it difficult to apply conven-
tional techniques to identify the physiological significance of indi-
vidual lesions for this yet unresolved clinical scenario. As a result,
robust physiological assessment of serially diseased coronary
arteries remains an unmet need in an era of ischemia-guided
management. Future developments will hopefully improve the
use and interpretation of physiological indices, perhaps with the
aid of innovations such as physiological-anatomical coregistra-
tion. In the meantime, revascularisation decisions in this challeng-
ing scenario should focus on multiple modalities, including clinical
presentation, intravascular imaging, and physiologic evaluation,
using a pressure-wire pullback maneuver and disease-free side
branch where appropriate.
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 Physiology-Guided Management of Serial Coronary Artery Disease
ARTICLE INFORMATION
Accepted for Publication: January 31, 2018.
Published Online: March 21, 2018.
doi:10.1001/jamacardio.2018.0236
Author Contributions: Drs Modi and Perera had
full access to all of the data in the study and take
responsibility for the integrity of the data and the
accuracy of the data analysis.
Concept and design: Modi, Rajani, Curzen, Perera.
Acquisition, analysis, or interpretation of data:
Modi, De Silva.
Drafting of the manuscript: Modi, De Silva, Rajani,
Curzen.
Critical revision of the manuscript for important
intellectual content: Modi, De Silva, Curzen, Perera.
Administrative, technical, or material support: Modi,
De Silva, Curzen, Perera.
Supervision: De Silva, Rajani, Perera.
Conflict of Interest Disclosures: All authors have
completed and submitted the ICMJE Form for
Disclosure of Potential Conflicts of Interest and
none were reported.
Funding/support: Dr Modi is funded by British
Heart Foundation Clinical Research Training
Fellowship (FS/15/78/31678).
Role of the Funder/Sponsor: The funding source
had no role in the design and conduct of the study;
collection, management, analysis, and
interpretation of the data; preparation, review, or
approval of the manuscript; and decision to submit
the manuscript for publication.
Additional Contibutions: We thank Ajay Kirtane,
MD, SM, Columbia University Medical Center, New
York, New York, for the screenshot image of Figure
5. No compensation was received from a funding
source for this contribution.
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