JACC: CARDIOVASCULAR INTERVENTIONS
© 2011 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
PUBLISHED BY ELSEVIER INC.
VOL. 4, NO. 5, 2011
ISSN 1936-8798/$36.00
DOI: 10.1016/j.jcin.2011.02.009
EDITORIAL COMMENT
Insights From a Virtual World*
Stephen J. Nicholls, MBBS, PHD
Cleveland, Ohio
For more than half a century, angiography has been widely
used to diagnose and quantify the extent of obstructive
disease within the coronary arteries. As a result, angiography
is used to triage patients to a range of medical and
revascularization strategies. This has largely been fueled by
advances in bypass surgery and percutaneous coronary intervention (PCI), and by the observation of a relationship
between the extent of angiographic disease and clinical
outcome. Accordingly, coronary angiography has become an
essential clinical tool for the cardiologist in the evaluation of
patients with ischemic symptoms.
See page 503
At the same time, however, we began to appreciate that
angiography has its limitations. It involves an invasive procedure, thus limiting its use to patients with suspected ischemic
symptoms. Numerous reports emerged that many patients
with myocardial infarction had culprit lesions that were minimally diseased on angiography (1). This was largely explained
by the importance of plaque composition in determining the
propensity to develop acute ischemic events and by the understanding that angiography only images the lumen and fails to
visualize the vessel wall, the site where plaque accumulates.
Immense interest subsequently developed in the need to
develop novel imaging modalities that could provide potentially more important insights.
Developing new imaging modalities has had 2 major
objectives. First, can we perform imaging in a noninvasive
fashion? This would theoretically broaden the scope of
individuals who could be imaged, potentially including
those who are deemed to be of intermediate risk by
conventional risk prediction algorithms. Developments in
carotid intimal medial thickness and coronary calcification
have been reported to provide incremental risk prediction,
*Editorials published in JACC: Cardiovascular Interventions reflect the views of the
authors and do not necessarily represent the views of JACC: Cardiovascular Interventions or the American College of Cardiology.
From the Departments of Cardiovascular Medicine and Cell Biology and the
Center for Cardiovascular Diagnostics and Prevention, Cleveland Clinic, Cleveland, Ohio. Dr. Nicholls has received research support from AstraZeneca, Roche,
LipoScience, Eli Lilly, Novartis, Anthera, and Resverlogix; and he has received
honoraria and consulting fees from AstraZeneca, Merck, Roche, Takeda, Anthera, Omthera, and Eli Lilly.
stimulating a proliferation of their use without any robust
evidence from clinical trials that their use is either costeffective or makes a definitive change to the management or
outcome of patients. A positive finding from such a study
would represent a major advance for the cause of integrating
noninvasive arterial imaging into risk prediction algorithms.
In a similar fashion, there has been interest in the development of computed tomography and magnetic resonance
imaging to noninvasively image atherosclerotic plaque, although limited resolution continues to plague their ability to
visualize coronary plaque with the accuracy required by a
useful clinical tool. Nevertheless, there remains optimism
that ongoing advances may overcome these challenges.
The second major objective in advancing arterial wall
imaging has been the ability to characterize plaque composition. Moving beyond demonstrating plaque burden to
image its individual components is based on the premise
that a plaque containing greater amounts of lipids, inflammatory cells, and necrotic material is more likely to rupture
and promote acute ischemia (2). Intravascular ultrasound
permits imaging of the full extent of plaque in the artery wall
and has provided important insights into the vascular changes
following PCI and factors that slow progression of atherosclerosis. Yet, the inability to optimally characterize plaque composition has limited its ability to precisely characterize the
compositional changes within the artery wall.
Technological advances in radiofrequency analysis of ultrasound backscatter enable generation of a spectral tissue map
that separates plaque into fatty, fibrofatty, necrotic, and calcific
components. The early experience imaging human coronary
arteries ex vivo revealed good correlation between the features
demonstrated by the virtual histology–intravascular ultrasound
(VH-IVUS) approach and histology (3). This finding stimulated considerable optimism that this approach would become
a useful tool to the clinician, vascular biologist, and drug
developer in their evaluation of coronary atherosclerosis.
Since its development, VH-IVUS has been increasingly
used in case-control studies to characterize the relationship
between clinical characteristics and plaque components. These
reports have demonstrated the presence of more necrotic
material in patients with acute coronary syndromes compared
with patients with stable symptoms and in patients with a
greater number of comorbid cardiovascular risk factors (4).
Such volumetric measures have been incorporated in clinical
trials to demonstrate potential efficacy of a novel antiinflammatory therapy (5). An alternative approach has been to
classify focal lesions into a number of plaque subtypes, the most
clinically important proposed to be the virtual histology–
intravascular ultrasound-derived thin-cap fibroatheroma (VHTCFA), identified on the basis of large plaque burden and
necrotic core size, with no overlying fibrous tissue demonstrable (6). Therefore, VH-IVUS has evolved to provide a range of
methods to characterize plaque composition in different clinical
and therapeutic settings.
512
Nicholls
Editorial Comment
In this issue of JACC: Cardiovascular Interventions, Zheng
et al. (7) provide further insights into the findings of
VH-IVUS in patients with the metabolic syndrome. Multivessel ultrasonic imaging was performed in 63 patients
with angiographic coronary artery disease at a single center.
Although the number of subjects was relatively small,
patients with either diabetes or the metabolic syndrome
were found to have not only more atherosclerotic plaque,
but, in particular, more necrotic and calcific material and
plaques classified as VH-TCFA. These are interesting observations that provide further mechanistic support linking the
metabolic syndrome to adverse cardiovascular outcomes. However, the challenge remains to determine whether these features
relate specifically to the presence of the metabolic syndrome or
whether they simply reflect the presence of its individual
components. The findings of similar reports that have focused
on either plaque burden or cardiovascular outcomes would
suggest that it simply represents the impact of multiple risk
factors, rather than an independent entity (8,9). Regardless,
the findings support the concept that patients meeting the
diagnostic criteria for the metabolic syndrome warrant more
intensive management of their global cardiovascular risk.
So how does one interpret the findings of studies such as
these? In many of these reports, the differences in the size of
necrotic core appear relatively small, while maintaining statistical significance. The question is to what degree does that
translate to clinical significance? The PROSPECT (Providing
Regional Observations to Study Predictors of Events in the
Coronary Tree) trial (10) investigators recently aimed to
provide clarity with regard to this issue. In a report of 697
patients undergoing multivessel imaging following PCI for an
acute coronary syndrome, the presence of a VH-TCFA was
associated with a more than 3-fold greater likelihood of
subsequent major adverse cardiovascular event (10). Though
this provides some degree of clinical link to the imaging
findings, it is important to note that this reflected observations
of very focal lesions, whereas most reports using VH-IVUS,
such as reported by Zheng et al. (7) focus on the percentage of
plaque occupied by various components throughout a segment of
vessel. The degree to which small differences in these parameters
relate to clinical outcome remains to be determined. Given the
immense interest in use of this technology to evaluate novel
antiatherosclerotic therapies in early stages of clinical development,
this will be important to establish and quickly!
The increasing use of VH-IVUS in clinical trials presents a
number of ongoing challenges. Use of volumetric measures
may seem relatively straightforward, but with no robust evidence of a clear link between small changes in individual
components and clinical outcome, it remains to be determined
how to interpret these findings. In contrast, a focal approach
may potentially have more evidence supporting a correlation
with clinical outcome; the difficulty matching focal lesions and
finding that these lesions often “disappear” on serial evaluation
makes it difficult to know what information this will provide.
JACC: CARDIOVASCULAR INTERVENTIONS, VOL. 4, NO. 5, 2011
MAY 2011:511–2
More serial clinical data are clearly required linking changes of
these parameters to changes in established biochemical parameters, measures of plaque burden, and clinical events.
More important, how does one integrate such findings into
their clinical practice? Does the presence of more necrotic
material or a VH-TCFA make an argument for intensification
of medical therapy or use of experimental, focally based
therapeutic approaches? The trend toward more aggressive use
of lipid-lowering therapy would suggest that radiofrequency
analysis is unlikely to be necessary for this. Similarly, more
aggressive use of PCI or experimental intravascular therapies
requires definitive evidence from clinical trials that they reduce
cardiovascular morbidity before they can be advocated. For the
time being, it would appear that although the virtual world can
provide important insights into reality, much more work is
needed for us to know what to do with these findings.
Reprint requests and correspondence: Dr. Stephen J. Nicholls,
Department of Cardiovascular Medicine, Heart and Vascular
Medicine, Cleveland Clinic, 9500 Euclid Avenue, Cleveland,
Ohio 44195. E-mail: [email protected].
REFERENCES
1. Ambrose JA, Tannenbaum MA, Alexopoulos D, et al. Angiographic
progression of coronary artery disease and the development of myocardial infarction. J Am Coll Cardiol 1988;12:56 – 62.
2. Falk E, Shah PK, Fuster V. Coronary plaque disruption. Circulation
1995;92:657–71.
3. Nair A, Kuban BD, Tuzcu EM, Schoenhagen P, Nissen SE, Vince
DG. Coronary plaque classification with intravascular ultrasound radiofrequency data analysis. Circulation 2002;106:2200 – 6.
4. Garcia-Garcia HM, Gonzalo N, Regar E, Serruys PW. Virtual
histology and optical coherence tomography: from research to a broad
clinical application. Heart 2009;95:1362–74.
5. Serruys PW, Garcia-Garcia HM, Buszman P, et al., for the Integrated
Biomarker and Imaging Study-2 Investigators. Effects of the direct
lipoprotein-associated phospholipase A(2) inhibitor darapladib on human
coronary atherosclerotic plaque. Circulation 2008;118:1172– 82.
6. Garcia-Garcia HM, Mintz GS, Lerman A, et al. Tissue characterisation using intravascular radiofrequency data analysis: recommendations
for acquisition, analysis, interpretation and reporting. EuroIntervention
2009;5:177– 89.
7. Zheng M, Choi S-Y, Tahk S-J, et al. The relationship between
volumetric plaque components and classical cardiovascular risk factors and
the metabolic syndrome: a 3-vessel coronary artery virtual histology–
intravascular ultrasound analysis. J Am Coll Cardiol Intv 2011;4:503–10.
8. Bayturan O, Tuzcu EM, Lavoie A, et al. The metabolic syndrome, its
component risk factors, and progression of coronary atherosclerosis.
Arch Intern Med 2010;170:478 – 84.
9. Mente A, Yusuf S, Islam S, et al., for the INTERHEART Investigators. Metabolic syndrome and risk of acute myocardial infarction a
case-control study of 26,903 subjects from 52 countries. J Am Coll
Cardiol 2010;55:2390 – 8.
10. Stone GW, Maehara A, Lansky AJ, et al., for the PROSPECT
Investigators. A prospective natural-history study of coronary atherosclerosis. N Engl J Med 2011;364:226 –35.
Key Words: cardiovascular risk factors 䡲 coronary artery
disease 䡲 imaging 䡲 plaque vulnerability 䡲 virtual histology–
intravascular ultrasound.