Editorial
Simultaneous Assessment of Systemic and
Coronary Endothelial Function
Can We Kill Two Birds With One Stone?
Andrea Cardona, MD; Giuseppe Ambrosio, MD, PhD
B
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esides lining the inner surface of vessels, endothelium
serves other important functions, including keeping
blood and platelets in a nonthrombotic status, avoiding intravascular activation of inflammatory cells, and finally what is
possibly the most important function—and definitely the most
actively investigated—namely regulation of vascular tone
and blood flow. To a large extent, these various functions can
be traced to the effects of nitric oxide (NO) produced by a
healthy endothelium.1,2
diameter and flow has been considered the gold standard
for endothelial function evaluation.8 However, intracoronary
catheterization has obvious limitations, being invasive and
restricted to patients with suspected coronary artery disease.
As such, it does not lend itself to prevention studies (which
typically investigate large cohorts and often low-risk individuals), nor to intervention studies requiring repeat assessment
over time. To some extent, similar considerations also apply
to coronary positron emission tomography assessment, which
makes use of radioactive tracers and complex instrumentation.9
Hence, a major advance was the demonstration that endothelial function can be investigated noninvasively at the level
of peripheral vascular beds, typically as postischemia-induced
flow-mediated dilation of the brachial artery.10 Several studies
indicate that impaired flow-mediated dilation is a hallmark of
various clinical conditions associated with increased cardiovascular risk; as for its prognostic capability, this seems to
have been established in patients with relatively high cardiovascular risk profile.11–14
All set, then? Well, not quite. For one thing, there is
controversy over the prognostic role of endothelial function
assessment in subjects at the lower end of cardiovascular risk
profile,13,14 in whom refining of classical indicators of cardiovascular risk would be most helpful. In addition, a major issue
has to do with an overarching question: is endothelial function of peripheral arteries representative of what occurs at the
coronary artery level? Advocates say yes, as atherosclerosis
is a systemic disease; critics retort that atherosclerosis at the
brachial artery level is virtually unheard of, and that peripheral
arteries and coronary arteries are not always simultaneously
affected in a given patient: hence, peripheral artery dilation
might have little direct bearing on coronary artery function.
Clearly, whether endothelium-mediated dilation of peripheral arteries can be measured as an easier proxy for coronary
artery dilation is not an issue to be dismissed as a controversy among academicians. Direct, head-to-head comparison
between cardiac and peripheral endothelial function assessment has been made only in small studies, and for obvious
reasons not in healthy subjects; furthermore, correlation
tended to be modest, suggesting that endothelium-dependent
vasoreactivity may not be uniform across vascular regions in
the same individual.15,16 Also, because of technical constraints,
studies comparing endothelial function of peripheral versus
coronary vascular beds in the same patients have been performed using different modalities, and at different experimental time points. Overall, a recent meta-analysis points to
a modest correlation between the 2 approaches.13 However,
meta-analysis findings provide indirect information, gathered
See Article by Iantorno et al
A first corollary of the theory, which puts healthy endothelium center stage in vascular homeostasis, is that the opposite
condition (ie, endothelial dysfunction) fosters vasoconstriction, thrombosis, and vascular smooth muscle cell proliferation. Accordingly, development of endothelial dysfunction
can be viewed as a mechanistic link between cardiovascular
risk factors (hypercholesterolemia, hypertension, diabetes
mellitus, and smoking) and morbidity.3,4 A second corollary
then is that, should we be able to gauge endothelial (dys)function, we would also be able to check vascular health, and consequently to afford better assessment of cardiovascular risk
and improved prognostication of vascular events.5
The central question is how to translate a nice theory into
clinical practice. How can we reliably measure endothelial
function? Because NO-mediated vascular dilatation apparently goes hand-in-glove with the various activities of healthy
endothelium, it would seem logical to measure endotheliummediated dilatation and, through it, assess the degree of
vascular (dys)function and possibly correlate it with future
cardiovascular events.6 The problem, though, is the choice of
the most appropriate methodology.
Since the pivotal study by Ludmer et al,7 which demonstrated the lack of vasodilation in response to intracoronary
acetylcholine in patients with atherosclerotic coronary arteries, assessment of response to acetylcholine of coronary artery
The opinions expressed in this article are not necessarily those of the
editors or of the American Heart Association.
Division of Cardiology, University of Perugia School of Medicine,
Perugia, Italy.
Correspondence to Andrea Cardona, MD, Cardiologia e Fisiopatologia
Cardiovascolare, Ospedale S. Maria della Misericordia, Via S. Andrea
delle Fratte, 06156 Perugia, Italy. E-mail [email protected]
(Circ Cardiovasc Imaging. 2016;9:e004182.
DOI: 10.1161/CIRCIMAGING.116.004182.)
© 2016 American Heart Association, Inc.
Circ Cardiovasc Imaging is available at
http://circimaging.ahajournals.org
DOI: 10.1161/CIRCIMAGING.116.004182
1
2 Cardona and Ambrosio Cardiac MRI Assessment of Endothelial Function
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through comparisons of cohorts, and not at individual patient
level. Although differences in population characteristics may
explain to some extent the underlying heterogeneity between
the 2 approaches, it is also conceivable that the observed differences are in fact genuine, reflecting different behavior of
different vessels.
In this issue of Circulation: Cardiovascular Imaging,
Iantorno et al17 from Johns Hopkins present an elegant
approach to evaluate endothelial function at systemic and coronary circulation level—noninvasively and simultaneously—
by use of cardiac magnetic resonance imaging. In this proof of
concept study right coronary artery (RCA) and internal mammary artery (IMA) were both visualized simultaneously in 25
patients with coronary artery disease (CAD) and 26 healthy
volunteers. Parameters of endothelial function (changes in
cross-sectional area [CSA] and blood flow [ie, flow velocity
and blood flow per minute]) were measured at rest, and during NO release elicited by isometric handgrip exercise (IHE).
In a subset of 8 healthy individuals, the NO-synthase inhibitor monomethyl-l-arginine was infused, and it confirmed that
IHE-induced changes were indeed NO-mediated, and hence
endothelium dependent.
Consistent with current understanding of endothelial (dys)
function in atherosclerosis, IHE elicited different effects on
CSA and blood flow parameters depending on whether the
protocol was conducted in healthy volunteers, or in patients
with CAD. In healthy subjects, both RCA and IMA dilated
significantly in response to IHE (P<0.001). In contrast, in
patients with CAD the RCA did not vasodilate in response to
IHE, and the IMA showed modest vasodilation with IHE, significantly less than in healthy subjects (% IMA change from
baseline: 16.4±2.5% in healthy versus 9.1±1.6% in patients
with CAD; P=0.02). As for flow velocity and blood flow
per minute in IMA, both increased significantly with IHE in
healthy individuals (P<0.001). In contrast, in patients with
CAD, an attenuated increase was seen in IMA blood flow
with IHE. When comparing the 2 vascular beds, the RCA
flow response was less than the IMA response in patients with
CAD, which did not reach statistical significance.
Thus, the study did achieve its primary goal, as it nicely
demonstrates the feasibility of simultaneous and noninvasive investigation of endothelial function in distinct vascular
territories, in healthy subjects as well as in patients. It also
reinforces the notion that atherosclerotic endothelial dysfunction is a diffuse phenomenon, which can be documented in
different vascular territories of the same patient. However, to
correctly gauge its relevance and how it may help future investigations in the field, it is also crucial to put in proper perspective some pathophysiological aspects of the study.
A clear finding is the abolished/reduced vasodilator
response to IHE (in terms of changes in CSA) of RCA and
IMA of patients with CAD, which the authors correctly interpret as evidence of impairment of NO-mediated dilation. The
question, though, is: at what level of vascular tree does NO
impairment actually takes place? We should be cognizant of
the peculiarities of endothelium-mediated dilation of large
conduit vessels (such as IMA and RCA) in vivo, as impaired
lumen dilatation at the level of coronary and mammary arteries in patients with CAD may be the product of different
mechanisms. In principle, on exposure to an NO-stimulating
challenge (such as IHE), 3 different scenarios can occur: (1)
NO-mediated dilation is primitively impaired in the large vessel; (2) NO-mediated dilation is primitively impaired in the
distal microcirculation, which in turn blunts/abolishes dilation of large vessels. Specifically, if hyperemia after IHE
is reduced at the microcirculation level, the lack of flow
increase through distal vascular bed will obviously reverberate upstream, blunting flow-induced shear stress in the conduit
artery and hence blunting flow-mediated endothelial production of NO at the large artery level.18,19 In other words, lack of
dilation of a large artery does not necessarily imply intrinsic
NO dysfunction locally. (3) NO-mediated dilation is impaired
throughout proximal and distal portions of the vessel. Careful
evaluation of the data presented provides some hints. Because
blood flow increase in response to IHE was blunted in both
RCA and IMA of patients with CAD, there is no question
that microcirculatory response was impaired, and that this
occurred both in systemic and in coronary territories. At the
same time, this finding allows us to discard the possibility that
lack of dilation of large vessels was due solely to local impairment of endothelial function of conduit vessels. Whether the
primary dysfunction is represented primarily or exclusively
by impaired ability of microcirculation to increase blood flow
(ie, the stimulus inducing vasodilatation of RCA and IMA), or
whether intrinsic impairment of NO-mediated dilatation also
occurs upstream in large vessels remains to be elucidated.
Another issue deserving commenting is the choice to
investigate the RCA. Authors clearly explain the technical
constraints that currently preclude simultaneous acquisition
of IMA and left anterior descending coronary artery. Yet, it
is important to understand the intrinsic differences between
right and left coronary vascular beds. It is well known that
phasic changes in blood flow during the cardiac cycle differ
between RCA and left anterior descending coronary artery,
that is, presence of systodiastolic flow in the RCA versus
predominantly diastolic flow in left anterior descending coronary artery. Hence, it is not known whether this physiological
difference between RCA and left anterior descending artery
phasic flow patterns might influence the changes of vascular
parameters in response to IHE to a similar extent in both territories. Future investigations should clarify this issue.
Germane to the above comment about differences in phasic
flow between different coronary arteries, is the equally obvious fact that, unlike coronary arteries, flow in the IMA occurs
almost entirely during systole. Furthermore, one would expect
that under resting conditions (such as during magnetic resonance imaging acquisition) basal perfusion of skeletal muscle
is decidedly much lower than that of cardiac muscle: hence,
basal tone of distal microcirculation and its gain on a vasodilating stimulus will be different in skeletal versus cardiac muscle. Together, these intrinsic physiological differences might
explain why the effects of IHE (although directionally similar)
are numerically different when comparing changes in CSA and
in flow between IMA and RCA in patients with CAD (see Figs
4 and 5 of Iantorno et al17). Indeed, these inherent differences of
perfusion between systemic and coronary arteries might be substantial enough to preclude a perfect matching when comparing
the response to vasodilator stimuli in systemic versus coronary
3 Cardona and Ambrosio Cardiac MRI Assessment of Endothelial Function
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territories. In fact, although–on the average–both CSA and
blood flow behaved similarly in RCA and IMA, the correlation
actually seen between RCA and IMA for each parameter at the
individual patient level was rather weak (see Fig. 6 of Iantorno
et al17). However, one may look at this finding not so much as
a limitation, but as a sobering (yet important) demonstration
that different vessels behave (to some extent) differently; this
is something that has always lingered in the mind of vascular
physiologists, and that now it has been directly documented.
What lies ahead of this study? In the past decade, many
studies have suggested that, in addition to its well-established
role in clinical research, noninvasive assessment of endothelial function may provide prognostic information for individual patient risk. Now the time has come to move forward,
and to firmly establish whether detection of endothelial function will be useful in the clinical arena. We need to ascertain
whether evidence of endothelial dysfunction can be used to
refine stratification of subjects (otherwise) considered to be
at relatively low risk, and to guide treatment for those who
already show clinical manifestations, or have a high-risk profile. A better tool for coronary and systemic endothelial function assessment will also allow us to tease out the distinct role
of concomitant vascular conditions, which may affect endothelial function and, at the same time, influence prognosis.20
Clearly, the clever approach by Iantorno et al17 needs to
be reproduced on a larger scale, by different investigators,
using different magnetic resonance imaging scanners. Efforts
to visualize the left anterior descending coronary artery territory simultaneously with, or at least in very close temporal
proximity to, IMA imaging are similarly welcome. However,
the most exciting (and long awaited) consequence of it is to
have in sight at last a methodology, which provides a direct
and objective assessment of vascular reactivity, which allows
clinicians and investigators to precisely assess endothelial
function in the vast category of subjects with low or moderate cardiovascular risk profile, and which lends itself to being
repeated over time, thus allowing one to assess the effects of
therapy or lifestyle modifications on vascular health. The elegant approach devised by Iantorno et al17 is a major move forward in this important area, as it paves the road to an entirely
new field of investigation to better understand the complex
pathophysiology of endothelial function, and its role in the
progression of cardiovascular diseases, ultimately to improve
outcome of cardiovascular patients.
Disclosures
None.
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Key Words: Editorials ◼ endothelial function ◼ magnetic resonance
imaging ◼ nitric oxide
Simultaneous Assessment of Systemic and Coronary Endothelial Function: Can We Kill
Two Birds With One Stone?
Andrea Cardona and Giuseppe Ambrosio
Downloaded from http://circimaging.ahajournals.org/ by guest on June 18, 2017
Circ Cardiovasc Imaging. 2016;9:e004182
doi: 10.1161/CIRCIMAGING.116.004182
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