Curr Atheroscler Rep (2016) 18:62
DOI 10.1007/s11883-016-0613-2
CORONARY HEART DISEASE (S. VIRANI AND S. NADERI, SECTION EDITORS)
Coronary Physiology Assessment for the Diagnosis
and Treatment of Stable Ischemic Heart Disease
1 1 1
Ali E. Denktas & David Paniagua & Hani Jneid
# Springer Science+Business Media New York (outside the USA) 2016
Abstract Coronary artery disease is the most prevalent car-
diovascular disease in the USA. In the majority of settings,
percutaneous coronary intervention (PCI) for stable coronary
artery disease (CAD) reduces angina and improves quality of life;
however, it does not improve survival and is associated with
infrequent but serious complications. Selection of appro-priate
patients and coronary lesions for revascularization with PCI is
crucial to maximize the benefit-to-risk ratio. The as-sessment of
the hemodynamic significance of intermediate coronary lesions
has been shown to improve outcomes and reduce healthcare
costs. The current review summarizes the existing evidence
regarding the physiological assessment of coronary lesions, with
emphasis on fractional flow reserve, the most common invasive
hemodynamic assessment modality.
. .
Keywords Coronary Physiology Coronary artery disease
. .
Fractional flow reserve Catheterization Angiography Stenosis
Introduction
Coronary artery disease is the most prevalent cardiovascular
disorder and the number one killer in the USA [1]. Every 34 s,
one American suffers a coronary event [1]. While timely
This article is part of the Topical Collection on Coronary Heart Disease
* Ali E. Denktas
ali.denktas@bcm.edu
1 Baylor College of Medicine, Michael E. DeBakey VA
Medical Center, 2002 Holcombe Blvd., 111B Cardiology,
Houston, TX 77030, USA
reperfusion in STEMI patients is known to improve
mortality [2, 3], percutaneous coronary intervention (PCI)
of patients with chronic stable angina, guided by coronary
angiography alone, has failed to demonstrate a survival
benefit in random-ized controlled trials [4]. These patients
still carry an annual death rate of 1.2 to 2.4 % per year [4
9]. Ischemia-driven revascularization with fractional flow
reserve (FFR) guidance, on the other hand, was shown to
be superior to angiography-guided PCI in reducing the
composite of death, myocardial infarction, or repeat
revascularization, as well as decreasing cost [10, 11, 12].
Although the assessment of stenosis severity visually using
coronary angiography alone is the most frequent method used
today, it is subjective and correlates modestly with physiolog-
ical significance. Quantitative methods such as quantitative
. coronary angiography (QCA) are also discordant with hemo-
. dynamic measurements with FFR in one third of the cases
[13]. Therefore, angiography-guided intervention may not be
the optimal interventional treatment of stable coronary artery
disease. Coronary physiological assessment does not evaluate
the severity of the stenosis only, but also factors in the impact
of collaterals, subtended myocardium in jeopardy, and other
contributing factors [14].
Coronary Physiology and Fractional Flow Reserve
Assessment of flow through an epicardial artery is complex
and is influenced by many factors. The coronary circulation
consists of the epicardial, collateral, and microvascular arteri-
al, as well as the venous components. True assessment of
coronary flow physiology accounts for all of these compo-
nents [15]. The concept of coronary flow reserve (CFR) was
introduced by Gould et al. [16]. CFR (also called absolute
CFR) is the ratio of peak coronary flow in milliliters per
62 Page 2 of 7
minute or myocardial perfusion in milliliters per minute per
gram during vasodilator stress to resting flow as a quantitative
measure of increasing capacity. It is blunted by the presence
of coronary artery stenosis, diffuse disease, and small-vessel
dis-ease [17]. Relative CFR is the ratio of the peak flow in
an abnormal region that of the most normal appearing region.
Therefore, it reflects relative severity of focal disease but fails
to identify coexisting diffuse disease [17]. FFR is indepen-
dent of changes in systemic blood pressure and heart rate, is
unaffected by conditions known to increase baseline myocar-
dial flow, and is reproducible and easy to measure. It has thus
emerged as the preferred method for the assessment of epicar-
dial coronary stenoses. This is performed in the cardiac cath-
eterization laboratory with a coronary guidewire capable of
measuring pressure that is introduced past the coronary steno-
sis. The ratio of the pressure distal to the stenosis (P d) to the
pressure in the aorta (P a) is then calculated during maximal
hyperemia achieved by intravenous or intracoronary microcir-
culation vasodilator (e.g., adenosine) administration. The sim-
ple formula of FFRmyo = Pd/Pa is used and has been validated
in large clinical trials [11, 18, 19].
FFR measurements are reproducible [20]. Hyperemia is
usually induced by adenosine (intracoronary or intravenous),
and patients are usually advised to refrain from caffeine for
>24 h [21]. Lim et al. investigated 628 patients with 658
intermediate lesions. Excellent correlation and close classifi-
cation agreement (FFR 0.80) were observed between IV vs.
IC adenosine (r = 0.980, CA = 92.9 %, P < 0.001), between
IV adenosine/ATP vs. IC nicorandil (r = 0.962, CA = 91.2 %,
P < 0.001), and between IV adenosine vs. regadenoson (r =
0.990, CA = 100 %, P < 0.001). The FFR measurement was
reproducible regardless of the route or method of hyper-emia
[22]. Adenosine IV or intracoronary (IC) as well as IV ATP,
IV regadenoson, and IC papaverine use has been de-scribed
for the induction of maximal hyperemia [2330]. Adjedj et al.
suggested that an IC adenosine bolus injection of 100 g in
the RCA and 200 g in the LCA induces max-imum
hyperemia in their dose-response study [31]. It should be
noted that an epicardial vasodilator, such as nitroglycerin,
should also be used to mitigate epicardial vasoconstriction
before the hyperemic drug administration [28]. When the FFR
measurements were correlated with the intravascular ul-
trasound findings in the FIRST (Fractional Flow Reserve and
Intravascular Ultrasound Relationship) study, the optimal cut-
off for the minimum lumen area was found to depend on the
reference vessel, and overall, a minimum lumen area (MLA)
2
<3.07 mm (64.0 % sensitivity, 64.9 % specificity, area under
curve [AUC] = 0.65) was the best threshold value to identify
FFR <0.8 which is now considered the standard cutoff value
for ischemia [32]. In another study by Kang et al., the best
2
cutoff value of the MLA to predict FFR <0.80 was <2.4 mm ,
with a diagnostic accuracy of 68 % (90 % sensitivity, 60 %
specificity, and area under the curve = 0.800; 95 % CI, 0.742
Curr Atheroscler Rep (2016) 18:62
to 0.848; P < 0.001) [33]. Although the intravascular ultra-
sound might help with planning the interventional strategy
and stent optimization after stenting, it does not provide
phys-iological assessment of the lesion.
Age and sex are important considerations when performing
FFR measurements. In the FAME (Fractional Flow Reserve
versus Angiography for Multivessel Evaluation) trial
substudy, FFR-guided PCI was beneficial regardless of age.
However, older patients had fewer functionally significant le-
sions, despite a similar angiographic appearance [34]. Kang et
al. examined the IRIS FFR-DEFER registry and showed that,
for a given degree of stenosis, FFR in women was much
higher than men. It was speculated that the smaller body size,
smaller left ventricular mass, and the relatively smaller myo-
cardial territory might be responsible. Since there was a great-
er rate of angiographic and functional mismatch, physiologi-
cal assessment of intermediate lesions in women is even more
important so as not to do unnecessary procedures [35]. Li et
al. reported an increase in death or myocardial infarction in
wom-en with an FFR between 0.75 and 0.80 who did not
undergo a PCI [36].
Contrast agents are vasodilators and the hyperemia
caused by the contrast injection can be used in some cases
as a sur-rogate. However, this is seldom done clinically.
Leone et al. used contrast media to induce hyperemia, and
despite the fact that contrast medium induced Pd/Pa values
(CMR) significant-ly higher than FFR values, a strong
correlation between con-trast mediated and FFR values
was observed (r = 0.94, P < 0.001). ROC curve analysis
showed an excellent accuracy of CMR cutoff of 0.83 in
predicting a FFR value 0.80 (AUC 0.97 [95 % CI 0.91
0.99, specificity 96.1, sensitivity 85.7]). Moreover, no FFR
value 0.80 corresponded to a CMR 0.88 [37].
However, since FFR reflects relative flow reserve, in pa-
tients with diffuse or small vessel disease, it may be high
(normal) because of low flow despite a severe stenosis.
Conversely, it may be low (abnormal) in a patient with high
flow despite a moderate stenosis [17]. Johnson et al. sug-
gested that when FFR measurements are performed in popu-
lations with reduced CFR, cutoffs of 0.75 or 0.85 are reason-
able because of lower baseline CFR due to moderate diffuse
disease. If FFR is applied to populations with severe diffuse
disease, even higher FFR values may represent significant
disease and, conversely, if the FFR is measured in populations
with high CFR values, lower FFR cutoffs are needed [38].
The Setup and the Performance of the FFR
Measurement
The typical setup for the FFR measurement includes the pres-sure
wire, the Y-connector, and the usual manifold for pressure
monitoring and contrast injection. After calibration outside the
Curr Atheroscler Rep (2016) 18:62
body, the pressure wire is advanced to the tip of the guide and
the pressure is equilibrated with the guide pressure. The wire
is then advanced beyond the lesion in question. Although both
intracoronary and intravenous administration of adenosine can
be used, our preference is intravenous (140 g/kg/min) since
it allows for pull back and precise lo-calization of the
hemodynamically significant lesion. It is im-portant to
administer intracoronary nitroglycerin (or any epi-cardial
vasodilator) before the measurement to mitigate coro-nary
spasm that may prevent maximal hyperemia. The doses of
intracoronary adenosine used to determine the thresholds of
0.75 and 0.80 were 2040 g, although much higher doses are
used today [23, 39].
FFR Using Non-invasive Methods
There is considerable interest in providing a non-invasive
method for determining coronary flow. The discussion regard-
ing conventional stress testing and myocardial perfusion im-
aging is beyond the scope of this review. However, we will
briefly touch upon computed tomography, magnetic reso-
nance, and positron emission tomography imaging for myo-
cardial perfusion and coronary flow measurements.
The DeFACTO (Determination of Fractional Flow Reserve
by Anatomic Computed Tomographic Angiography) study
showed improved area under the curve for CT-FFR than for
CTA alone, but the study did not meet its pre-specified prima-
ry outcome goal for the level of per-patient diagnostic accu-
racy [40]. The Diagnosis of Ischemia Causing Stenoses
Obtained Via Noninvasive Fractional Flow Reserve
(DISCOVER-FLOW) study investigated 159 vessels in 103
patients and showed a diagnostic accuracy of 84.3 % for the
FFR calculated from coronary computed tomography angiog-
raphy (CCTA), and certainly improved the diagnostic ability
of CCTA alone which was only 58.5 % [41]. The NXT trial
(Analysis of Coronary Blood Flow Using CT Angiography:
Next Steps) included 254 patients and 484 vessels [42]. On a
per-vessel basis, the diagnostic accuracy of the FFR CT was 86
%. If the analysis was restricted to patients with interme-diate
stenoses, the diagnostic accuracy was 80 %. The corre-lation
of FFRCT with FFR was good (0.82; P < 0.001), with slight
underestimation of FFRCT with FFR with slightly lower actual
FFR values [42]. Notably, if the FFRCT was negative,
myocardial ischemia was unlikely (NPV 93 %).
The PLATFORM (Prospective Longitudinal Trial of
FFRCT: Outcome and Resource Impacts) trial compared the
effect of FFRCT-guided testing or standard testing on clinical
outcomes and resource utilization [43]. In this study, 584 pa-
tients with new onset chest pain were prospectively assigned
to receive either usual testing or CTA/FFR(CT). The primary
endpoint (percentage of subjects with planned invasive coro-
nary angiography in whom no significant obstructive
Page 3 of 7 62
coronary artery disease (CAD) was found at angiography
within 90 days) occurred more in the usual care arm than the
CTA/FFRCT arm (risk difference 60.8 %, 95 % CI 5369 %)
[43]. By using this strategy, unnecessary invasive coronary
angiograms can be eliminated to a degree. It should be noted
that 39 % of the patients in the FFR CT group underwent cor-
onary angiography, of whom 32 % had no obstructive CAD.
In summary, FFRCT is a promising technology that can add to
the diagnostic accuracy of the coronary CT angiograms.
However, more protocol refinement and additional trial data
are needed for it to replace invasive FFR.
MRI stress tests have been compared to FFR in identifying
coronary stenoses. In a meta-analysis of 12 studies inclusive
of 761 patients, Desai et al. showed that MRI stress testing
had a sensitivity of 87.7 % and a specificity of 88.6 % [44].
The use of positron emission tomography (PET) allows
also for the calculation of regional and global maximum stress
flow [17, 45, 46]. The MRI and PET need more discussion
on their own but it is beyond the scope of this article.
The Clinical Correlates of FFR
In a patient-level meta-analysis, Johnson et al. showed that
clinical events increased as the FFR value decreased and the
FFR post procedure was inversely proportional to adverse
events [47]. Outcomes of medical treatment and PCI were
plotted against the FFR values: for high FFR values, the prog-
nosis was good, and the event rate increased as the FFR de-
creased. The PCI and medical management lines crossed at an
FFR value of 0.67. For the study level analysis, the lines
crossed at a threshold of 0.75. This suggests that if patients
with FFR values greater than the threshold are treated with
PCI, there is a potential for harm. Also, if a lower threshold is
chosen, the benefits of PCI are more readily discernable.
This raises the question of whether FFR should be done in
all patients routinely. This was investigated in the RIPCORD
study by routinely performing FFR during coronary angiog-
raphy. In 74 % of cases, there was an agreement in the man-
agement plan between angiographic and FFR assessment [48].
Optimum medical therapy was recommended in 89 of the 200
patients after the FFR results were available. However, PCI
was recommended for 25 of those patients after angiography.
This study showed that significantly stenosed coronary
arteries incorrectly diagnosed by coronary angiogra-phy alone
occurred in 32 % of cases, and that the management plan
changed in 26 % of cases once the FFR measurements were
available. This suggests that almost one third of PCIs
performed today based on angiography alone may be unnec-
essary and potentially harmful [47]. The Registre Franais de
la FFR (R3F) study enrolled 1075 patients from 20 centers in
France. FFR was performed in the vessel of interest, and in-
vestigators were asked to define prospectively their
 62 Page 4 of 7
revascularization strategy a priori based on angiography
be-fore performing the FFR. The final strategy differed
when FFR was disclosed in 43 % of patients [49]. These
two studies make a strong case for routine FFR analysis in
patients with coronary lesions with more than 30 %
angiographic narrowing.
Clinical Trials of FFR for Patients with CAD
Clinical trials of FFR have aimed to examine its clinical im-
pact. The Fractional Flow Reserve Versus Angiography for
Multivessel Evaluation (FAME) study randomized patients to
angiography-guided PCI vs. FFR-guided PCI. The
angiography-guided PCI patients underwent revascularization
of all angiographic stenoses with drug-eluting stents, and pa-
tients allocated to FFR-guided PCI had FFR measurements of
all stenotic arteries and PCI done only if FFR was 0.80 or less
[11]. The 1-year event rate was 18.3 % (91 patients) in the
angiography alone group and 13.2 % (67 patients) in the FFR
group (P = 0.02). The 2-year mortality or myocardial infarc-
tion rate was also favorable for the FFR-guided group (12.9
vs. 8.4 %; P = 0.02) [50]. However, after 5 years, major ad-
verse cardiac events occurred in 31 % of patients in the
angiography-guided group vs. 28 % in the FFR-guided group
which was not significantly different (P = 0.31). The number
of stents placed per patient was significantly higher in the
angiography-guided group than in the FFR-guided group
(mean 2.7 vs. 1.9, P < 0.0001) [51].
The FAME 2 trial randomized patients with at least one
significant stenosis (FFR <0.80) to PCI with optimal medical
therapy vs. optimal medical therapy alone. It was stopped early
because of a decreased need for urgent revascularization in the
PCI arm [19]. The important finding of this study is that
outcomes of patients with PCI were similar to those without
ischemia in the first place (FFR >0.80). This suggests that PCI
itself does not introduce significant harm. However, both the
participants and their physicians were unblinded and knew that
the PCI was canceled due to the study protocol. This might have
introduced bias that may have contributed to in-creased urgent
revascularization in the medical management group. In patients
with borderline FFR (0.750.80), deferral of PCI was associated
with higher ischemia-driven target vessel revascularization
compared to patients with FFR >0.80 [52].
The DEFER study included 325 patients with stable chest
pain and an intermediate stenosis without an objective evi-
dence of ischemia, and randomized patients with FFR >0.75
to deferral or performance of angioplasty; however, if FFR
was <0.75, angioplasty was performed as planned [18]. The
main aim of this study was to test the safety of deferring the
PCI of stenosis not responsible for inducible ischemia as in-
dicated by FFR >0.75. The investigators also looked at symp-
tom relief and antianginal drug use as secondary endpoints.
Curr Atheroscler Rep (2016) 18:62
Patients who had an FFR value <0.75 had PCI of the lesion in
question. If the FFR was >0.75 then the PCI was performed only
if the patients were randomized into the performance of PCI
group. The results of this study are interesting because the worst
outcome was seen in the FFR <0.75 patients regardless of the PCI
and the deferral of PCI group had the best outcome [18]. The
outcome benefit remained up to 5 years of follow-up [53]. Thus,
the stenting of non-ischemic segments was shown not to benefit.
Also, the deferral of angioplasty in pa-tients with non-ischemic
lesions was shown to be safe. It should be noted that the patients
with non-invasive testing showing ischemia were excluded from
this study.
The ACC/AHA/SCAI guidelines for percutaneous inter-
vention give a class IIa recommendation for the use of
intra-vascular ultrasound (IVUS) or FFR for intermediate
lesions [54]. However, their use in the contemporary era
has been limited as suggested by a report by Dattilo et al.
[55]. In their analysis of the NCDR database, evaluation of
intermediate lesions was done only in a minority of cases
(IVUS 20.3 %, FFR 6.1 %) [55].
Also, the use of these methods is time consuming and
the outcome data is not widely known by the practicing
physi-cians. For inpatient outcomes, IVUS use was
associated with less inpatient mortality but FFR use did not
show any differ-ence in in-patient outcomes [55].
Instantaneous Wave-Free Ratio (iFR) and Its Use
in Lesion Assessment
iFR is a resting index measured in a specific period in
diastole, the so-called wave free period. During this peri-
od, the wave activity in the coronary is quiescent and the
microcirculatory resistance is at its minimum [56]. Since in
this period the pressure and flow velocity are linearly
related, the pressure difference can represent flow limita-
tion [56]. The fundamental basis of iFR approximation to
FFR is the assumption that diastolic resting myocardial
resistance equals mean hyperemic resistance [56, 57]. The
first human study of iFR was the (Adenosine Vasodilator
Independent Stenosis Evaluation) ADVISE study [56]. In
157 stenoses, iFR correlated closely with FFR (r = 0.9, P <
0.001) with excellent diagnostic efficien-cy (ROC area
under the curve of 93 %, at FFR <0.8) and specificity,
sensitivity, and negative and positive predic-tive values of
91, 85, 85, and 91 %, respectively [56]. In the ADVISE
registry, which included 312 patients and 339 stenoses, the
optimal iFR cutoff (for an FFR of 0.80) was 0.89. After
adjustment for the intrinsic variabil-ity of FFR, the
classification agreement (accuracy) be-tween iFR and FFR
was 94 % [58]. Since iFR and FFR can have discrepancies,
they were compared to the hyper-emic stenosis resistance
(HSR) index (an invasive
Curr Atheroscler Rep (2016) 18:62
pressure and flow-based index HSR = (Pa Pd) / v) in the
CLARIFY study [59]. In this study, FFR and iFR had
equally good agreement with the HSR. When iFR and FFR
were compared with PET myocardial blood flow (cutoff
value of 2.3 mL/min/g), the classification agree-ment was
76 % with FFR and 76 % with iFR where 0.80 and 0.90
were used as cutoff values, respectively [60]. In the
RESOLVE study, 1768 patients from 15 clinical sites had
iFR, Pd/Pa, and FFR measured. Both non-hyperemic
indices showed an 80 % accuracy rate [61]. However,
since iFR relies on assumptions, there will be conditions
that will not allow the FFR and iFR to be used inter-
changeably. Johnson et al. elegantly showed that the iFR
was +0.09 higher than FFR with 0.17 limits of agree-
ment. Diastolic resistance was also 2.5 times higher than
the mean hyperemic resistance [57]. The recently pub-
lished (ADenosine Vasodilator Independent Stenosis
Evaluation II) ADVISE II study used an iFR cutoff of 0.89
[62]. The ADVISE II investigators suggested that their
study proves the diagnostic value of a hybrid iFR-FFR
diagnostic approach, as it properly classified 94.2 % of
total stenoses, with specificity, sensitivity, and positive and
negative predictive values >90 %. With this strategy,
adenosine would not be required in 69 % of the stenoses,
and in 65 % of patients [62]. The proposed hybrid iFR-
FFR approach (summarized by the following protocol:
performance of revascularization in patients with iFR
values 0.85; revascularization deferral in patients with
iFR values 0.94; and the use of FFR to dictate the treat-
ment strategy in patient iFR values with the 0.86 and 0.93
range) resulted in an overall 95 % classification agree-
ment with a lone-FFR strategy. Although this approach
may obviate the need for adenosine in some patients, the
ease of use and relative safety of a limited adenosine
infusion makes one question the true value of this new
modality, especially when it is based on assumptions and
lacks robust clinical validation.
Conclusions
The journey for the determination of significant coronary le-
sions, from coronary angiography to the contemporary inva-
sive and non-invasive physiological assessment modalities, is
fascinating. With the availability of invasive and non-invasive
hemodynamic and physiological methods for determining
coronary flow and flow reserve, revascularization can be tai-
lored not only to specific patients but also to discrete coronary
lesions. Coronary physiological assessment in patients with
intermediate disease has been shown to improve outcomes
and reduce healthcare costs. Interventional cardiologists
should incorporate these modalities in their interventional ar-
mamentarium and utilize them in their daily practices.
Page 5 of 7 62
Compliance with Ethical Standards
Conflict of Interest Ali E. Denktas, David Paniagua, and Hani Jneid
declare that they have no conflict of interest.
Human and Animal Rights and Informed Consent This article does
not contain any studies with human or animal subjects performed by
any of the authors.
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