Dr. Chandwaney is a Cardiology Fellow at Northwestern
University Medical School, Section of Cardiology, Chicago, IL.
He received his MD from the University of Illinois at Chicago
in 1996 and completed his internal medicine residency at Baylor
College of Medicine, Houston, TX, in 1999.
Since the introduction of coronary angioplasty by Andreas
Gruentzig in 1977,
percutaneous coronary intervention has evolved rapidly as an
integral component in the management of patients with coronary
artery disease (CAD). More than 700,000 percutaneous coronary
interventions are performed annually in the United States, and it
has been estimated that more than 1,000,000 procedures are
performed worldwide each year.
Generally, in terms of coronary angiography, critical coronary
stenoses are defined as those that appear to have >50% luminal
diameter narrowing in the left main coronary artery or >70%
luminal diameter narrowing elsewhere.
Interventional cardiologists commonly encounter situations in which
they are faced with intermediate coronary lesions of indeterminate
significance. These intermediate lesions present a special
challenge to cardiologists as it is difficult to determine whether
the potential benefits of a mechanical intervention outweigh the
potential risks. Several adjunctive technologies have been
developed that enable interventional cardiologists to better assess
intermediate coronary lesions.
Quantitative coronary angiography
In many catheterization laboratories, clinical decision-making
regarding coronary stenoses is based on qualitative readings of
angiographic lesions rather than quantitative assessment.
Qualitative visual assessment of angiographic lesions is limited by
bias, intraobserver variability, and interobserver variability.
Quantitative methods use automated or manual edge-detection systems
to quantify coronary stenoses more accurately. When compared with
quantitative coronary angiography, visual estimation of lesion
stenosis correlates poorly.
Clearly, the difficult assessment of intermediate coronary lesions
is improved by the more accurate and reproducible determination of
luminal narrowing obtained with quantitative coronary
Despite the more accurate assessment of luminal narrowing
provided by quantitative coronary angiography, the technique has
limitations. Several studies have challenged the accuracy of
coronary angiography to assess the true extent of atherosclerosis.
Necropsy studies demonstrate that angiography significantly
underestimates the extent of atherosclerosis.
Quantitative coronary angiography compares the luminal diameter
within a lesion with the caliber of an adjacent normal-appearing
reference segment. Autopsy studies reveal that coronary
atherosclerosis is often diffuse, involving long segments of the
diseased vessel. Therefore, in many patients, no truly normal
segment exists, which precludes accurate assessment of disease
Diffuse, concentric, and symmetric coronary disease can affect the
entire length of the vessel, resulting in an angiographic
appearance of a small artery with minimal luminal irregularities.
Precise assessment of the severity of coronary atherosclerosis
by angiography is further limited by the phenomenon of remodeling,
which is the process in which the external vessel wall enlarges in
areas of atherosclerosis. During the early development of
atherosclerosis, outward displacement of the external vessel wall
prevents plaque from encroaching into the lumen, thereby limiting
the detection of a lesion by angiography.
Evidently, the limitations of quantitative coronary angiography
often hamper the interventional cardiologist's ability to assess
intermediate coronary lesions adequately. Adjunctive techniques
that provide more detailed anatomical information are often
required to perform a complete evaluation.
Intravascular ultrasound uses miniaturized transducers that are
advanced through guide catheters into coronary arteries of
interest. The technique permits detailed, high-quality,
cross-sectional imaging of the coronary arteries in vivo.
Intravascular ultrasound allows detection of coronary artery
anatomy and coronary plaque characteristics in a manner otherwise
not possible by conventional contrast angiography.
Several characteristics of intravascular ultrasound imaging
allow more precise quantification of atherosclerotic coronary
disease that may be useful in assessing intermediate coronary
The tomographic orientation of ultrasound enables visualization of
the full 360° circumference of the vessel wall, rather than a
two-dimensional projection of the lumen. Measurement of lumen area
is performed by direct planimetry on cross-sectional images. Since
the velocity of sound within soft tissues is essentially constant,
ultrasound measurements are accurate and require no special
calibration methods. Ultrasound images rely only on an electronic
distance scale that is generated internally and overlaid on the
image. The tomographic perspective of intravascular ultrasound
facilitates visualization of the true extent of ath-erosclerotic
disease. This tomographic perspective enables examination of
lesions such as diffusely diseased segments, bifurcation lesions,
ostial stenoses, and highly eccentric plaques
that are typically difficult to assess by angiographic
Several studies demonstrate the utility of intravascular
ultrasound in assessing angiographically intermediate lesions. In
two large prospective series, intracoronary ultrasound imaging
performed immediately prior to coronary intervention changed the
management strategy in more than 20% of the examinations by
providing a better understanding of the severity of disease.
Another study demonstrated low event rates during the long-term
follow-up of patients in whom percutaneous coronary intervention
was deferred based on intravascular ultrasound findings.
The authors reported especially low event rates in patients with a
minimum lumen area >= 4.0 mm
. In another study by the same authors, 1-year follow-up after
intravascular ultrasound assessment of moderate left main CAD in
patients with ambiguous angiograms was reported.
Intravascular ultrasound-derived minimum lumen diameter was the
most important quantitative predictor of cardiac events.
There is still no consensus regarding the intravascular
ultrasound measurement at which left main stenosis is considered
critical. However, an absolute area <7.0 mm
or >50% area stenosis are criteria often used as thresholds for
left main stenosis requiring revascularization.
An ongoing multicenter registry of intermediate left main coronary
lesions will assist in defining these patients. An example of the
application of intravascular ultrasound to assess an intermediate
coronary stenosis is demonstrated in figure 1.
Although intravascular ultrasound provides an accurate anatomic
assessment of intermediate coronary lesions, it does not provide
data concerning the physiologic significance of a coronary lesion.
Adjunctive techniques exist that allow one to measure the
physiologic significance of a coronary lesion rapidly.
Coronary flow velocity reserve
Measurements of coronary flow velocity reserve are obtained
utilizing a Doppler-sensor-tipped intracoronary wire to determine
the ratio of hyperemic to basal mean flow velocity just distal to
the coronary stenosis in question.
This ratio is obtained from flow measurements before and
immediately after the administration of a vasodilator, such as
adenosine. The coronary flow velocity reserve in angiographically
normal vessels from adult patients with CAD risk factors is
A coronary flow velocity reserve <2.0 is reproducibly and
positively correlated to abnormal stress perfusion testing
and is therefore used as a threshold to determine if an
intermediate coronary lesion is physiologically significant.
The major limitation in assessing an intermediate stenosis using
coronary flow velocity reserve is microcirculatory impairment.
In the absence of coronary stenosis, the coronary flow velocity
reserve may be <2.0 (abnormal) when the microcirculation is
compromised by left ventricular hypertrophy, chronic or acute
ischemia, or diabetes mellitus. An abnormal coronary flow velocity
reserve does not differentiate whether an abnormality exists in the
epicardial coronary artery or in the microcirculation. To overcome
this limitation of coronary flow velocity reserve, the concept of
relative coronary flow velocity reserve has been introduced.
Relative coronary flow velocity reserve requires that an
additional measurement of coronary flow velocity reserve be
performed in an adjacent normal vessel as a reference value. The
relative coronary flow velocity reserve is calculated by dividing
the target vessel coronary flow velocity reserve by the reference
vessel coronary flow velocity reserve. Assuming that hemodynamic
and microcirculatory abnormalities affect different regions of the
myocardium similarly, the relative coronary flow velocity reserve
provides a better discrimination of flow impairment due to a
A normal measurement of the relative coronary flow velocity is
>0.8 and has been shown to be similar to negative stress testing
in prognostic value.
An example of the applications of coronary flow velocity and
relative coronary flow velocity to assess an intermediate coronary
stenosis is demonstrated in figure 2.
The major limitation in assessing coronary lesions with coronary
flow reserve velocity is the question of microcirculatory
This limitation can usually be overcome by the use of relative
coronary flow velocity reserve. However, in patients who have
three-vessel coronary disease, a suitable normal reference vessel
may not exist. Additionally, physicians may no longer assume the
microcirculation is uniform in patients with a history of
myocardial infarction. Hence, the application of relative coronary
flow velocity reserve may be invalid in some patients.
Fractional flow reserve
Fractional flow reserve is defined as the maximal blood flow to
the myocardium in the presence of a stenosis in the supplying
coronary artery divided by the theoretical normal maximal flow in
the same distribution.
This index represents the fraction of the normal maximal myocardial
flow that can be achieved despite coronary stenosis. Fractional
flow reserve can be derived from the ratio of the mean distal
coronary artery pressure to the aortic pressure during maximal
Measurements are obtained readily by advancing a fiberoptic
pressure-monitoring guidewire through a standard coronary guide
catheter distal to the coronary lesion of interest. After the
administration of adenosine to achieve maximal hyperemia, the
fractional flow reserve is calculated as the ratio of the mean
distal intracoronary pressure measured by the wire to the mean
arterial pressure measured by the coronary catheter.
The normal fractional flow reserve for all vessels under all
hemodynamic conditions is 1.0, regardless of the status of the
microcirculation. An intermediate coronary lesion with a fractional
flow reserve <0.75 is considered abnormal.
Several studies have correlated abnormal fractional flow reserve
values with the presence of myocardial ischemia on exercise
treadmill testing, nuclear stress imaging, and/or stress
Other studies have demonstrated that deferring intervention of an
intermediate stenosis on the basis of fractional flow reserve
values >0.75 is safe and is associated with a low clinical event
An example of the application of fractional flow reserve in a
patient with a moderately severe coronary lesion is presented in
The calculation of fractional flow reserve from measurements of
pressure is limited by the presence of small-vessel disease,
diffuse CAD, and left ventricular hypertrophy. These conditions
restrict the increase in blood flow after pharmacologic
vasodilatation and the corresponding decrease in distal coronary
pressure. Under these conditions, the severity of the stenosis may
be underestimated because of the limited increase in flow and the
associated limitation in the pressure gradient.
Furthermore, several potential pitfalls that may influence the
accuracy of fractional flow reserve measurements have been
These include pressure damping by guide catheters, side-hole
catheters leading to inaccurate proximal coronary pressure
measurements, signal drift during procedures, paradoxical gradients
because the aortic root is lower than the apex of the heart in the
recumbent position, and inadequate hyperemia. Most of these
potential pitfalls can be remedied if the interventional
cardiologist is aware of them.
Coronary lesions of intermediate stenosis present a challenging
dilemma for the interventional cardiologist. Modern adjunctive
technologies such as quantitative coronary angiography,
intravascular ultrasound, coronary flow velocity reserve, and
fractional flow reserve, are able to more precisely examine the
potential significance of an intermediate coronary lesion. A
thorough understanding of each technique's advantages and
limitations is required so that physicians can determine which
technique, or combination of techniques, is best suited for the