Although it has become the central modality for the diagnosis and management of coronary disease, coronary angiography has its limitations. Intracoronary injections provide information about the coronary artery lumen without assessing the entire artery or the physiological importance of a stenosis. Three more recently developed techniques address these limitations: the measurement of the coronary flow reserve, the measurement of the fractional flow reserve, and intravascular ultrasound.
John S. Harris, MD
received his medical degree from Temple University School of
Medicine Philadelphia, PA. He is currently a fellow in the
Department of Cardiology, Temple University Hospital.
Brian O'Murchu, MD
is an Assistant Professor of Medicine and the Associate Director of
the Cardiac Catheterization Laboratory, Department of Cardiology,
Temple University Hospital, Philadelphia, PA.
Although it has become the central modality for the
diagnosis and management of coronary disease, coronary
angiography has its limitations. Intracoronary injections provide
information about the coronary artery lumen without assessing the
entire artery or the physiological importance of a stenosis.
Three more recently developed techniques address these
limitations: the measurement of the coronary flow reserve, the
measurement of the fractional flow reserve, and intravascular
Since its origins in the early 1960s,
selective coronary angiography has remained the central imaging
modality used by cardiologists in the diagnosis and management of
coronary artery disease (CAD). Early randomized studies
demonstrated the importance of angiographic data in the management
The initial technology of percutaneous coronary catheterization
developed into balloon angioplasty in the 1970s
and later to stenting
Current and emerging therapeutic technologies include
brachytherapy, gene therapy, and the direct administration of
antimitotic therapy by drug-eluting stents. The available
technologies continue to have significant limitations, however, and
management of CAD will improve as new technologies emerge.
One well-recognized limitation of contrast angiography is that
it provides a two-dimensional visual representation of the
three-dimensional vessel lumen.
Angiography frequently fails to provide information about either
the vessel wall or the physiologic importance of a lesion. As
revealed by a better understanding of coronary artery disease
progression, angiography may underestimate the true degree of
stenosis. In current diagnostic and interventional cardiology,
newer techniques are being used to overcome these limitations,
including intravascular flow measurements, pressure measurements,
and ultrasound. This article will review these technologies and
their current applications to the diagnosis and management of
As an introduction to a discussion of the techniques used to
improve the diagnostic accuracy of coronary angiography, a brief
review of certain features of the pathophysiology of CAD
progression is appropriate. First shown in the simian model,
and later in humans,
an artery that has developed plaque will demonstrate a change in
dimension prior to any encroachment upon its lumen, a process
called remodeling. Glagov et al
showed that before a stenosis reaches 40% of the "potential lumen
area," the lumen remains essentially unchanged. A compensatory
enlargement of the artery attenuates the degree of stenosis, and
only after the lesion grows past 40% of the potential lumen area
will the lumen begin to narrow (Figure 1).
With this concept of remodeling in mind, the main pitfall
associated with conventional coronary angiography becomes apparent:
the intracoronary injection of contrast into an artery provides
information chiefly about the lumen, not about the entire vessel.
Thus, an angiographically normal or slightly irregular lumen may
conceal significant CAD. Also, because a "normal" appearing vessel
segment adjacent to a stenosis is typically used as a reference to
grade lesion severity and to guide interventional therapy, the
operator will compare two diseased segments to each other.
An understanding of the response of the microvasculature is
needed to interpret data derived from the measurement of coronary
flow and pressure in the setting of CAD. When an epicardial
coronary lesion compromises oxygen delivery to the myocardium, the
microvasculature responds by dilating. This dilation maintains
basal flow at a level appropriate to meet the needs of myocardial
oxygen demands during resting states. However, in the setting of
increased oxygen demand or hyperemia, whether pharmacologically or
exercise-induced, the ability of resistance vessels to dilate
further is limited as compared with a healthy vascular bed. This
translates into a decreased coronary flow velocity reserve
and fractional flow reserve, which are discussed in the following
Coronary flow velocity reserve
The concept of directly measuring coronary flow with Doppler
ultrasound is not a new one. The initial use of Doppler coronary
flow assessment was during direct external examination of the
epicardial arteries, an application limited to animal models
and open-chest patients. Next, transesophageal echocardiography
(TEE) Doppler technology was used to evaluate coronary artery flow
and, while minimally invasive, it became apparent that this
application was limited to the proximal portion of the artery.
Later, catheter-based, closed-chest intravascular coronary Doppler
measurement was developed. Although initial catheters were small
enough to enter a coronary artery, they were large enough to impede
flow and, thereby, distort the data obtained. Finally, a Doppler
probe was attached to a standard angioplasty wire, and this is the
method used today.
Assessment of flow in a coronary artery begins with the delivery
of a Doppler device to the site of a stenosis. Typically, the
patient is prepared in a fashion similar to that of angioplasty
preparation. Anticoagulants are administered and a Doppler-tipped
0.014-in guidewire is advanced though a 6F to 8F coronary catheter
and placed distal to the stenosis of interest. Next, the time
velocity integral (TVI) of coronary flow is recorded both at rest
and at maximal hyperemia, achieved with an intracoronary injection
of a potent vasodilator, such as adenosine. The ratio of the
measured maximal flow under hyperemic conditions to baseline flow
defines the coronary flow velocity reserve (CFVR).
Studies in angiographically normal coronary arteries have
determined that the normal range of CFVR for both men and women is
>= 2.7 ± 0.6.
In patients with angiographically evident coronary artery disease,
a poststenotic CFVR of >2.0 correlated well with negative
myocardial perfusion studies. Miller et al
compared CFVR measurements with
Tc-sestamibi imaging in symptomatic patients undergoing diagnostic
cardiac catheterization. A CFVR ¾ 2.0 was found in association with
at least one reversible defect in all 14 patients and results of
Tc-sestamibi imaging agreed in 24 of 27 patients (89%). Using a
cutoff of CFVR ¾ 2.0, Joye et al
compared coronary flow measurements with single-photon emission
computed tomographic (SPECT) thallium-201 imaging and found a
sensitivity of 94%, a specificity of 95%, and overall predictive
accuracy of 94%. Deychak et al
found a strong concordance (96%) between a reversible thallium
defect and a CFVR <1.8.
The clinical application of CFVR measurement to the management
of CAD has been investigated. Blinded to the results of noninvasive
testing, Kern et al
studied 88 patients with anginal symptoms in whom angioplasty was
deferred on the basis of a normal translesional hemodynamic
evaluation. Compared with a cohort of patients who underwent
angioplasty after the finding of an abnormal CFVR, a decision to
defer intervention was found to be both safe and clinically
effective. Similarly, the DEBATE study evaluated the use of CFVR
after angioplasty as a predictor of late outcomes.
A CFVR >2.5, in combination with a percent diameter stenosis
(PDS) ¾ 35%, was predictive of a low recurrence of symptoms or
ischemia at 1 and 6 months and a lower rate of restenosis and need
for revascularization. DEBATE II, however, a study that
investigated the cost and clinical role of using CFVR to guide the
need for stenting after balloon angioplasty, did not support these
In this trial, patients were randomized to receive either primary
stenting or balloon angioplasty. The latter group underwent stent
placement only when the postprocedure CFVR was <2.5 and the PDS
was >36%. After 1 year, there was no clinical difference between
the two groups, but "provisional angioplasty" carried a higher
Although easily measured, there are limitations to the clinical
application of CFVR measurement. The finding of a truly normal CFVR
requires both nonsignificant epicardial artery disease and a normal
microvascular circulation. Microvascular disease--as found in left
ventricular hypertrophy, chronic or acute ischemia, and
diabetes--can confound the findings.
An abnormal CFVR cannot differentiate between epicardial and
microvascular components. This limitation can be overcome by
comparing CFVR in the artery of interest with that measured in a
normal vessel; this is called relative coronary flow velocity
reserve (rCFVR). In this way, the confounding effect of a diseased
microcirculation is negated. Baumgart et al
reported that, compared with the CFVR, rCFVR has a strong
relationship to lesion percent area stenosis. Additionally, the
clinical usefulness of CFVR is limited when the target artery
supplies infarcted myocardium, since the assumption of a normal
microvasculature is no longer valid. In patients with multivessel
disease, a normal reference artery may not be present, which
precludes the assessment of rCFVR.
Fractional flow reserve
As an alternative to CFVR, a technique for direct catheter-based
measurement of intracoronary pressure has been developed. With this
technique, the mean intracoronary pressure distal to a stenosis is
compared with the mean aortic pressure during conditions of maximal
hyperemia. Fractional flow reserve (FFR) is then derived from these
values and is defined as the ratio of maximal blood flow to the
myocardium in the presence of a coronary artery stenosis to the
theoretical flow that could be achieved without that stenosis.
First described by Pijls et al,
FFR differs from CFVR in that it is independent of changes in blood
pressure, heart rate, and other conditions known to affect baseline
myocardial flow. Normal FFR for every coronary artery is 1.0. This
value, unlike CFVR, can be measured easily in multivessel disease
without the need for a reference vessel. Several investigators have
evaluated the diagnostic accuracy and clinical relevance of FFR and
have compared it with noninvasive imaging including positron
emission tomography (PET),
nuclear imaging, and stress echocardiography.
An FFR <0.75 correlates well with findings of myocardial
In a study by Pijls et al,
patients with an intermediate stenosis were assessed with both
noninvasive imaging and FFR. Every patient with an FFR <0.75 had
findings of ischemia on at least one noninvasive modality, and FFR
reverted to normal after revascularization in all patients.
Conversely, 21 of 24 patients with an FFR >0.75 had negative
noninvasive stress testing. Sensitivity was 88%, specificity was
100%, positive predictive value was 88%, and negative predictive
value was 93%.
Beyond assessment of an individual lesion, FFR has value in
defining a culprit lesion in the setting of multivessel disease, as
well as in pinpointing the point of severity in a diffusely
diseased segment. By slowly withdrawing the pressure wire across a
diffusely diseased segment, one can identify the point at which the
FFR falls to <0.75; it may then be possible to direct an
intervention accordingly. Likewise, by interrogating multiple
diseased vessels, a culprit lesion may be identified in the setting
of multivessel disease.
Several studies have looked at the safety of basing clinical
decisions on the results of FFR calculations. Bech et al
found that coronary artery bypass graft surgery could be deferred
safely in patients with angiographic left main disease of 40% to
60% when FFR was >= 0.75. Survival and freedom from events
during a 3-year follow-up were excellent. Likewise, basing therapy
decisions on FFR data has been justified in single-vessel disease,
while disregarding a positive FFR has proven to be unwise.
Chamuleau et al
showed that patients with an FFR <0.75--but with a negative
SPECT--in whom angioplasty was deferred had a higher incidence of
adverse outcomes as compared with those patients with FFR >=
Fractional flow reserve also may be used to assess adequacy of
stent deployment. Fearon et al,
comparing intravascular ultrasound (IVUS) data to FFR measurements,
found that an FFR <0.96 measured after stent deployment
predicted a sub-optimal result by IVUS. In contrast, however, they
found that an FFR >= 0.96 did not regularly predict a good
outcome by IVUS. Bech et al
examined the clinical outcome of patients with a postangioplasty
FFR >= 0.90 and reported an excellent prognosis after 2 years.
Likewise, a small study from The Netherlands examining coil stents,
found a correlation with an FFR of >0.94 and optimal stent
deployment by IVUS.
Though the data conflict somewhat, it is clear that the closer the
postrevascularization FFR is to 1.0, the better the stent
deployment and clinical outcome. Thus, FFR can be a useful
adjunctive tool in assessing the success and clinical efficacy of
Collateral flow has long been known to contribute to myocardial
blood flow, but the exact extent of this contribution has been
difficult to quantify. Recently, FFR has been used to address this
question. Defining recruitable collateral blood flow (Q
) as a fraction of normal maximal myocardial perfusion (Q
), Pijls et al
proposed the pressure-derived fractional collateral blood flow (Q
). This is defined as (P
) where coronary wedge pressure (P
), mean central venous (P
), and arterial (P
) pressures are measured simultaneously. Among 119 patients
undergoing elective coronary angioplasty, a Q
of ¾ 23% (inferring a lack of collateral flow) occurred in 82 of 90
patients experiencing ischemia during intracoronary balloon
inflation, while a Q
>24% was present in all of the 29 patients who did not
experience ischemia. During follow-up, 15 of 16 patients with
ischemic events fell into the group with poorer collateral
circulation. Matsuo et al
duplicated these findings in a recent publication.
As with CFVR, however, measurement of FFR is limited in the
setting of microvascular disease. Small vessel disease may restrict
the increase in blood flow that occurs during maximum hyperemia
induced by adenosine. This translates into an attenuated decline of
distal pressures and may cause an underestimation of lesion
Recent studies, however, suggest that this limitation may not bear
greatly on the effect of FFR calculations, thereby allowing its
application to a more general population.
Intravascular ultrasound, in use for well over two decades, is
performed using a catheter that incorporates a miniaturized
ultrasound transducer to directly image the vessel wall. Given the
close proximity of the catheter to the vessel wall, current IVUS
catheters emit high frequency ultrasound (30 to 40 mHz) to obtain
an axial resolution of up to 100 µm and a lateral resolution of up
to 250 µm.
Ultrasonography of a normal artery may identify three layers:
the intima, media, and adventitia. In diseased vessels the
intima/media border may be difficult to separate due to the
relatively high reflectivity of the intima, thus giving a
The inner layer is defined by the vessel lumen internally and by
the external elastic membrane externally (which separates the media
from the adventitia); the outer layer represents the adventitia.
Intravascular ultrasound in diseased vessels produces images of
three general types. Low-density echo images characterize
lipid-infiltrated lesions. Bright echo density lesions indicate
dense fibrous disease, and bright lesions with acoustic shadowing
are found with calcification.
By outlining the borders of the endovascular lumen and the external
elastic membrane, a ratio of the areas as measured by planimetry
produces a percent area stenosis. Additionally, by measuring the
maximal and minimal plaque thickness, the eccentricity of a plaque
can be further described.
Intravascular ultrasound is exquisitely sensitive for the
detection of coronary disease,
and its measurements of disease tend to be more severe than
estimates from angiography. Alfonso et al
performed IVUS evaluations of 25 patients with angiographically
normal coronary arteries and found that 80% had at least some
degree of plaque burden. Likewise, Mintz et al
used IVUS in angiographically normal reference segments in 884
patients undergoing percutaneous transluminal coronary angioplasty
(PTCA) for symptomatic coronary disease; on IVUS, only 6.8% of
these vessel segments were found to be disease free. These studies
underscore the failings of coronary angiography in the estimation
of CAD severity and have revealed that segments that appear
angiographically normal may be significantly diseased (Figure 2).
Also, studies from Mintz et al
and Hoffman et al
provided data that were pivotal in advancing the understanding of
the mechanism of restenosis following either angioplasty or
As with FFR and CFVR, data derived from IVUS may contribute to
the planning of optimal coronary intervention. Intravascular
ultrasound is more sensitive in detecting calcium and
postangioplasty dissections than standard angiography.
Additionally, IVUS can be used to assess the degree and quality of
stent expansion and deployment. As previously noted, IVUS performed
after stent deployment has revealed that between 40% and 70% of
stents that appear well-deployed angiographically are actually
underexpanded in at least one segment as compared with the rest of
the stent or as compared with the reference vessel.
In as many as 90% of patients with subacute stent thrombosis, IVUS
revealed an abnormality that could explain the event, compared with
abnormalities defined angiographically, which were seen in only
Thus, IVUS can help direct larger and higher pressure balloon
inflations of a stent that would otherwise have remained
underdeployed. In a randomized trial, Fitzgerald et al
showed that IVUS-directed angioplasty leads to less restenosis and
less repeat revascularization. Some other studies that have
investigated this finding failed to reach a primary end point.
Also, in the case of failed stent deployment, stent dislodgement,
or stent embolism, IVUS can be an invaluable tool used to locate
the stent and confirm its relationship to the guidewire, thereby
facilitating decision making about salvage.
Recent uses of IVUS have also involved the differentiation of
vulnerable versus stable plaque. Angioscopy studies have revealed
that yellow plaques are associated more frequently with acute
coronary events than white plaques.
By quantifying the echodensity of the plaque, several investigators
have attempted to predict the degree to which a plaque is
vulnerable to rupture. However, some studies produced conflicting
One suggested that plaques with a high distensibility and a
compensatory enlargement, as diagnosed by IVUS, may be more
vulnerable to rupture.
Despite these advances, IVUS technology has its limitations.
It can only be used to assess one vessel at a time and can be used
on only those vessels that are large enough to accommodate the IVUS
catheter. Also, IVUS is limited by artifacts and shadowing.
Conventional angiography can both underestimate and overestimate
the extent of CAD. Furthermore, it does not reveal the physiologic
significance of a stenosis. Pressure and flow wires and IVUS are
additional tools that contribute to the diagnosis, management, and
our understanding of coronary atherosclerotic disease.