26 | Original Article
Journal of Advanced Therapies and Medical Innovation Sciences 1 (2016)
Hyperemic Instantaneous Wave-Free Ratio
Provides Improved Hemodynamic Outcome for
Moderate to Severe Coronary Artery Stenoses
Comparison with Fractional Flow Reserve
Yoshishige Kanamori, Fumitsugu Yoshikawa, Ryuichi Aikawa
Kuwana City Medical Center
Corresponding author:
Ryuichi Aikawa MD, PhD,
Address: Kuwana City Medical Center,
1-32-1, Chu-o, Kuwana, Mie 511-0068, Japan.
Tel: +81-594-22-0650
Fax: +81-594-22-5608
E-mail: [email protected]
Abstract
Background
The fractional flow reserve (FFR) has been established as a physiological tool for the assessment of coronary ischemia. The instantaneous
wave-free ratio (iFR) is an alternative pressure-derived physiologic index from the diastolic wave-free period in stable conditions. The
hyperemic iFR (h-iFR) may represent a diagnostic tool; however, its diagnostic performance is unclear. Thus, we aimed to assess the
diagnostic performance of the h-iFR compared with the conventional whole-cycle FFR.
Methods
Fifty consecutive lesions, which were diagnosed as 50-75% stenosis by coronary angiography, were analyzed regarding the h-iFR
and FFR during the intravenous administration of adenosine using a pressure wire. The h-iFR and FFR were calculated via automated
algorithms.
Results
Twenty-two stenoses were positive (FFR 0.8), and 28 stenoses were negative (FFR >0.8). The slope of the regression line was 1.28
in the positive group and 1.61 in the negative group. The FFR and h-iFR values ranged from 0.64 to 0.80 (0.75±0.04) and 0.52 to
0.82 (0.66±0.07), respectively, in the positive group and 0.81 to 1.02 (0.90±0.05) and 0.69 to 1.02 (0.87±0.08), respectively, in the
negative group. The means of the differences between the FFR and h-iFR were 0.027 and 0.090 in the FFR positive and negative
groups, respectively.
Conclusions
The hyperemic iFR, which is calculated using the diastolic phase and exhibited a larger dynamic range than the FFR, especially in FFRpositive stenosis, may be a better physiological tool than the cardiac full-cycle FFR in the evaluation of coronary ischemia.
Keywords:
Hyperemic iFR, FFR, diastolic wave-free period, whole-cycle
Citation:
Kanamori Y, Yoshikawa F, Aikawa R. Hyperemic Instantaneous Wave-Free Ratio Provides the Hemodynamic Outcome
for Moderate to Severe Coronary Artery Stenoses. JATAMIS 2016 1:26-29
Introduction
Fractional flow reserve (FFR) is considered a useful physiological
index to assess the functional status of coronary artery stenosis
severity.1-4 The FFR is calculated as the ratio of the mean distal
intracoronary artery pressure to the aortic pressure at maximal
hyperemia, and it has a normal value of 1.0.2-4 Recent mega
studies have demonstrated that a clinical cutoff FFR value of
0.80 is the threshold below which the stenosis is considered
for coronary artery intervention therapy, in addition to standard
medical therapy.5 This conventional FFR is obtained to utilize
* Corresponding author. E-mail: [email protected]
the mean intracoronary pressure during the full-cardiac cycle
of both systolic and diastolic phases.1-4 However, it has been
reported that the diastolic FFR (dFFR), which is obtained by the
mean pressure only during the diastolic phase, is more sensitive
and accurate regarding the physiological status in clinical and
animal studies.6,7
The instantaneous wave-free ratio (iFR) is an alternative
pressure index without hyperemia, which is used to assess
the physiological status of coronary artery stenosis. The
iFR is calculated as the intracoronary pressure during the
diastolic “wave-free” period, which is a period in the cardiac
Journal of Advanced Therapies and Medical Innovation Sciences 1 (2016)
Table 1. Baseline Clinical Characteristics
Age
70.3±5.8 years
Male
81%
Hypertension
85%
Diabetes mellitus
26%
Hypercholesterolemia
90%
Current smoking
19.5%
Diagnosis: Stable angina/ACS
100/0%
LAD lesions
50%
Single vessel disease
82%
Lesion length (QCA)
12.8±5.1 mm
Reference diameter (QCA)
2.88±0.52 mm
Percent diameter stenosis (QCA)
1.61±0.39 mm
Baseline characteristics of 41 consecutive patients.
cycle considered a state of minimal microvascular resistance.8
The ADVISE (Adenosine Vasodilator Independent Stenosis
Evaluation) study demonstrated that the classification of
stenosis severity was good between the iFR and FFR.9 Thus,
current investigations are focused on determining the precise
iFR value for performing intervention therapy for coronary artery
stenosis.
Original Article | 27
San Diego, California) was passed into the target vessel through a
guiding catheter. Pressure equalization was performed twice at the
catheter tip prior to its advancement into the peripheral portion.
A sharp wave form with a dicrotic notch was confirmed on aortic
pressure monitoring for measurement and to detect the final
value (0.98-1.02) without drifting when the pressure wire reached
the ostial portion of the coronary artery. The measurements were
repeated where drift was identified.
Data analysis
The iFR was calculated as the ratio of the distal to proximal
pressures over the diastolic wave-free period using a fully
automated, pressure–only algorithm, as previously described.8
This period corresponds to a time in the cardiac cycle when waves
are absent from the coronary artery.8 In the present study, the iFR
measurements were performed using a commercially available
console. An instantaneous, wave-free ratio during adenosine
administration (h-iFR) was also calculated using the same algorithm.
The FFR was calculated in all patients, as previously described.1,4
As shown in Figure 1, the results were used to determine the
equation of the regression line and the correlation coefficient
using Excel and StatView. In Figure 2, we calculated the
difference between the h-iFR and FFR. The FFR value was
increased compared with the h-iFR in the same coronary artery;
thus, the difference indicates the FFR value minus the h-iFR
value in each stenosis.
Statistical analysis
In the present study, we compared the values and examined
the relationships between the hyperemic iFR (h-iFR) and the
full-cycle FFR because the h-iFR indicates the intracoronary
pressure within the diastolic phase.
The data are expressed as the means±SDs. All indexes derived
from the pressure studies were compared between the FFR
positive (0.8) and FFR negative (>0.8) groups with 2-tailed
Student’s t tests. P<0.05 was considered statistically significant.
Materials And Methods
Results
Study population
Patient Characteristics
Forty-one patients who underwent coronary angiography for the
evaluation of angina pectoris participated in this trial. Patients with
unstable angina, acute myocardial infarction, in-stent restenosis
or congestive heart failure were excluded from this study. Fifty
moderate to severe stenoses (subjects 70.3±5.7 years of age;
81% male) underwent physiological studies (Table 1).
As shown in Table 1, all stenoses indicated moderate stenosis
from 50 to 75% by QCA.
FFR, iFR and h-iFR
Of the 50 stenoses, 22 stenoses were positive (FFR 0.8) in the
pressure studies, and 28 stenoses were negative (FFR >0.8).
To examine the relationships between the FFR and h-iFR, we
Study protocol
A pressure wire was made distal to the target vessel coronary
stenosis in 50 vessels. It was first used to analyze the iFR at rest.
The h-iFR was subsequently measured in a stable condition
approximately 2 min and 30 seconds later with continuous,
intravenous (140 mg/kg/min), adenosine-induced hyperemia.
Soon after measuring the h-iFR, we immediately switched to
the FFR mode, and the value was measured. Finally, the wire
was gradually pulled back to the guiding catheter. Each time,
the iFR, h-iFR or FFR values were measured twice, and the
means were calculated.
Cardiac catheterization
Cardiac catheterization was performed via a radial or brachial
approach using 5-French guiding catheters. Diagnostic
angiographic images were acquired after 1 mg glyceryl trinitrate
intracoronary injection and unfractionated intravenous heparin,
3000 IU. A 0.014-inch pressure wire (Verrata, Volcano Corporation,
Figure 1. Regression lines in the three groups, including the
positive (FFR 0.8) group, the negative (FFR >0.8) group or the
total group.
28 | Original Article
Journal of Advanced Therapies and Medical Innovation Sciences 1 (2016)
coronary flow of the h-iFR should be higher than the FFR in a
state of hyperemia (Figure 3). The regression line demonstrated
a slope of 1.6 in the FFR negative group and 1.2 in the FFR
positive group (Figure 1) as the line consists of the predicted
score on the h-iFR for each possible FFR value. The coronary
flow curve indicates that the difference between the h-iFR and
FFR curves depend on the stenosis severity (Figure 3). These
findings may indicate that the predicted value in the FFRnegative group, which is mild stenosis of the coronary artery,
may be augmented compared with the predicted value in the
FFR-positive group.
Figure 2. Difference between the FFR and iFR during hyperemia:
Δ h(FFR-iFR).
described the regression line in each group. The slopes were
1.28 and 1.61 for the positive and negative groups, respectively,
as shown in Figure 1. The regression line exhibited a slope of
1.43 for the total number of stenosis, and the value was between
1.28 and 1.61, as shown in Figure 1.
We subsequently determined which would be the better tool
between the FFR and h-iFR for the detection of ischemic heart
disease. The resting whole-cycle Pd/Pa data are distributed
within a narrow range of values compared with the iFR; thus,
small deviations from the optimal cut-off significantly affect
the diagnostic performance.10 Therefore, we determined which
data have a narrower range between the FFR and h-iFR. In the
positive FFR (0.8) group, the FFR values ranged from 0.64 to 0.80
(0.75±0.04), and the h-iFR ranged from 0.52 to 0.82 (0.66±0.07).
There was a significant difference between the mean FFR and
mean h-iFR values in the positive group (p<0.0001). In contrast,
in the negative FFR (>0.8) group, the FFR values ranged from
0.81 to 1.02 (0.90±0.05), and the h-iFR ranged from 0.69 to
1.02 (0.87±0.08). There was no significant difference between
the FFR and h-iFR values in the negative group (p=0.137). In
addition, we calculated the difference in the FFR value minus
the h-iFR value in each stenosis. The means were 0.027, 0.090
and 0.054 in the FFR negative, positive and total groups,
respectively (Figure 2). The statistical analysis demonstrated a
prominent significance between the positive FFR and negative
FFR groups (p<0.0001). As shown in Figure 2, the range of the
h-iFR was wider than the FFR in the FFR positive group.
Moreover, to identify the difference between the h-iFR and FFR,
we analyzed t-tests. The h-iFR values were lower than the FFR
values with a significant difference in the FFR-positive group
but not the FFR-negative group. In addition, we calculated the
difference in the (FFR-iFR) during hyperemia: Δ h(FFR-iFR). The Δ
h(FFR-iFR) in the FFR positive group was significantly increased
compared with the negative group. These findings also suggest
that the h-iFR has a substantial range in the severe stenosis
group and may represent a better tool to diagnose ischemia of
the coronary artery. There is a relationship among the coronary
flow velocity, stenosis pressure gradient and stenosis severity.13
We adapted the present data to this concept and speculated
on the mechanism. As shown in Figure 4, the pressure gradient
is augmented by not only the upregulation of the coronary flow
velocity but also the stenosis severity. In the severe stenosis
group, the pressure gradient was increased to a greater extent
than the mild stenosis group, which supports the present data.
It may be that linking to the h-iFR is a valuable index compared
with the FFR.
The aim of this study was to compare the FFR and h-iFR. We also
measured the iFR and Pd/Pa at rest without hyperemia; however,
this offered no further insights. In the present study, the h-iFR
represented a better index for evaluating cardiac ischemia than
the FFR. Sen S et al. have demonstrated that both the iFR and
adenosine-induced iFR exhibit an equal diagnostic value.14 We
are currently screening ischemic coronaries using the iFR at rest,
and we will subsequently evaluate the grey zone ischemia via
the hyperemic iFR instead of the FFR in the future. Similar to
the FAME3 studies, large clinical studies are required to confirm
these findings.
Discussion
It has recently been demonstrated that the iFR exhibits an
increased discriminatory power compared with the resting
whole-cycle Pd/Pa.10 The resting whole-cycle Pd/Pa data
were distributed within a narrow range of values compared
with the iFR; thus, small deviations from the optimal cut-off
significantly affected its diagnostic performance.10 The iFR
samples intracoronary artery pressure only during the diastolic
“wave-free” period. In the diastolic phase of the cardiac cycle,
the coronary flow velocity is substantially increased compared
with the systolic phase.11 Thus, the coronary flow velocity of
the diastolic phase should be higher than the mean of the
whole-cycle phase. Regarding the reason why the iFR is a
better index than the Pd/Pa, it is plausible that it is derived
from the difference in the coronary flow velocity. In addition,
Nijjer SS et al. have reported that the hyperemic coronary flow
is substantially increased compared with the resting coronary
flow.12 Thus, we propose a mechanism shown in Figure 3. The
Figure 3. A proposed mechanism regarding the difference in the
slopes between the positive and negative groups. The dotted line
indicates the h-iFR, and the upper solid line indicates the FFR. In
severe stenosis, the h-iFR/FFR value, which indicates the slope
of the regression line, was smaller than in mild stenosis.
Journal of Advanced Therapies and Medical Innovation Sciences 1 (2016)
6.
7.
8.
9.
Figure 4. A proposed mechanism regarding the difference
(ΔPG) in the pressure gradients between the FFR and h-iFR.
Relationships among the coronary flow velocity, stenosis
pressure gradient and stenosis severity have previously been
reported (13). The coronary flow of the h-iFR is faster than the
FFR, which leads to a difference in the ΔPG between the h-iFR
and FFR based on the stenosis severity.
10.
11.
12.
Conclusions
The hyperemic iFR, which is calculated using the diastolic phase
and exhibited a larger dynamic range than the FFR, especially
in FFR-positive stenosis, may be a better physiological tool
than the cardiac full-cycle FFR for the evaluation of coronary
artery ischemia.
13.
14.
Limitations
As a small, randomized, retrospective study, this study was
performed in one clinical hospital rather than multiple centers.
The number of patients was relatively small. In addition, the
procedures, including the FFR and iFR, were examined by the
physicians indicated in the acknowledgements, and these data
were collected. Thus, there may be some bias in the data.
Acknowledgements
The authors wish to thank Dr. Justin Davies for overlooking this
paper, Dr's K Hirata, M. Hanada, H. Yokoi, K. Tamura, and T.
Nakajima for data collection, and T. Mano, K. Kinoshita, M.
Kajiwara, A Yamanaka, T. Nakazawa, K. Sumi, H. Kato, and S.
Murata of the cath. lab group for their technical assistance.
There were no grants and funds for this study. The authors state
that they abide by the Requirements for Ethical Publishing in
Biomedical Journals.15
Declarations of Interest
The authors have no conflicts of interest to disclose.
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