Table Of ContentCardiovascular
Imaging
Arterial and Aortic
Valve Infl ammation and
Calcifi cation
Elena Aikawa
Editor
Cardiovascular Imaging
Elena Aikawa
Editor
Cardiovascular Imaging
Arterial and Aortic Valve Infl ammation
and Calcifi cation
Editor
Elena Aikawa, MD, PhD, FAHA
Cardiovascular Medicine
Brigham and Women’s Hospital
Harvard Medical School
Boston , MA
USA
ISBN 978-3-319-09267-6 ISBN 978-3-319-09268-3 (eBook)
DOI 10.1007/978-3-319-09268-3
Springer Cham Heidelberg New York Dordrecht London
Library of Congress Control Number: 2014954989
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Foreword
S ince Roentgen’s day imaging has contributed to the diagnosis and understanding
of cardiovascular diseases. In the fi rst half of the twentieth century, radiographic
plain fi lms and fl uoroscopy provided essential tools to the clinical cardiovascular
specialist. In the latter half of the twentieth century the advent of image intensifi ca-
tion, contrast angiography, and the introduction of cross-sectional imaging modali-
ties such as computed tomography and magnetic resonance augmented the
armamentarium of radiographic imaging tools modalities applied to cardiovascular
disease. Simultaneously, the development of echocardiography beginning with
M-mode, and evolving to two-dimensional and ultimately three-dimensional echo-
cardiography, not only permitted the in vivo evaluation of ventricular function and
cardiac structure but also enabled the in-depth assessment of cardiac valves. These
tools opened the door to a golden era of non-invasive cardiovascular imaging that
permitted the study of pathophysiology of cardiac and valvular diseases in intact
humans and indeed experimental animals and, in the case of ultrasound, without
using ionizing radiation. The concurrent evolution of nuclear imaging offered the
opportunity to reach beyond defi ning structures to probe metabolism and perform
quantitative and regional fl ow studies, further expanding the repertoire of imaging
tools available to the cardiovascular specialist and investigator.
I n the twenty-fi rst century, molecular or functional imaging has provided a new
frontier for advancing the fi eld of cardiovascular imaging [1, 2]. This approach joins
the traditional quest for defi ning structure and physiologic function with advances
in understanding the cells and molecules involved in the pathogenesis of cardiovas-
cular diseases. Molecular imaging weds basic science discoveries to imaging in a
manner that promises to transform cardiovascular medicine and science.
This volume edited by Elena Aikawa provides us with an updated and comprehen-
sive overview of this promising landscape. Much of the initial foray into the applica-
tion of molecular imaging to cardiovascular diseases targeted atherosclerosis, which
is the subject of Part I of this book [3]. After a masterful review of the basic pathobio-
logical mechanisms at play in atherosclerosis (Chap. 1 ) , a series of a uthoritative chap-
ters reviews modalities ranging from contrast enhanced ultrasound (Chap. 2 ), magnetic
resonance imaging (MRI) (Chap. 3 ) , and optical approaches such as near-infrared
fl uorescence and optical coherence tomography (Chaps. 4 , 5 , 6 , 7 , and 8 ) . Various
chapters emphasize different pathophysiologic targets such as infl ammation (Chap. 5 ) ,
endothelial activation (Chap. 2 ) , macrophage activity (Chap. 3 ) , protease activity
v
vi Foreword
(Chap. 4 ) , oxidation and lipid content (Chap. 6 ) , thrombosis (Chap. 8 ) , and calcifi ca-
tion (Chap. 5 . ) The laboratory applications of intravital microscopy that have proven
of immense value to cardiovascular researchers also receive expert discussion in this
part (Chap. 7 ).
The second part of this book delves more deeply into the imaging of calcifi cation
as applied particularly to cardiac valves, an area that has evolved far beyond the
fl uorographic estimation of calcifi cation in cardiac structures by traditional roent-
genography. Long-regarded as a passive degenerative process, we now appreciate
the active nature of calcifi cation, its relation to infl ammation (a special interest of
Dr. Aikawa herself [4, 5]), and its importance not only in atherosclerosis, but also in
the growing epidemic of sclerocalcifi c aortic valvular disease. After an authoritative
and up-to-date review of the pathobiology of aortic valve calcifi cation (Chap. 9 ), a
report on work from the Edinburgh group on fl uoride imaging sheds new light on
the investigation of calcifi cation as an active process in humans (Chap. 1 0 ). Other
chapters by established experts focus on the well-validated use of ultrasound in the
imaging of aortic valve disease in humans (Chap. 1 1) , and on experimental
approaches to the imaging of microcalcifi cation (Chap. 12 .) Indeed, foci of micro-
calcifi cation not only provide a nidus for the growth of calcium mineral deposits in
cardiovascular structures but may also have important biomechanical consequences
that relate to the stability of atherosclerotic plaques [6, 7].
The third part strives to illustrate the clinical applications of molecular and func-
tional imaging to the cardiovascular system. This includes expert reviews on MRI
of atherosclerosis (Chap. 1 3 ), positron emission tomography (PET) in coronary
artery disease (Chap. 1 4 ), and the use of PET combined with computed tomography
for the clinical imaging of infl ammation and anti-infl ammatory interventions as
well as calcifi cation (Chaps. 1 5 and 1 6 .)
The timely and comprehensive compilation assembled in this volume gives an
overview of the established and emerging tools provided by molecular and func-
tional imaging. As with all emerging fi elds, however, a number of issues regarding
their use remain unsettled. One area of application related to these techniques
engenders no controversy: their use in animal and human investigation. The ability
to probe pathophysiologic functions in vivo using minimally invasive approaches
has transformed cardiovascular research. Well-controlled animal studies using
molecular imaging now permit in vivo probing of mechanisms unraveled by studies
conducted in cell culture or in excised specimens of human tissues. The nascent
application of molecular imaging to patients has provided a pathway to affi rming
the human relevance of laboratory studies or inferences obtained from soluble bio-
marker studies in humans.
A major unmet investigative need revolves around resolving contemporary bar-
riers to the clinical evaluation and development of new cardiovascular therapies [8].
In face of the effi cacy of the current standard of care, for many cardiovascular dis-
eases, event rates have fallen, raising the bar for clinical trials required to demon-
strate the value of new therapies and obtain registration of new pharmacologic
agents. Molecular and functional imaging provide a potential path to overcome
some of the hurdles facing current cardiovascular drug development.
Foreword vii
B efore embarking on a lengthy and resource-intensive clinical endpoint trial,
illumination of two critical issues would help to attenuate the risk inherent in clini-
cal drug development. First, such programs would profi t enormously from the abil-
ity to obtain signals that a novel agent actually alters the intended particular
biological pathway in intact humans. Molecular imaging promises an avenue to
achieving this goal. Second, many clinical trials fail because they test doses of a new
agent that seem ill-chosen in hindsight. Molecular and functional imaging can fur-
nish a way in which doses can be evaluated in a relatively small number of intact
humans using imaging biomarkers to help ascertain the most appropriate dose to use
in a clinical endpoint trial. Such in vivo methodologies in humans would comple-
ment the usual inferences based on pharmacokinetic modeling and observations on
non-human species that may vary substantially in their responses to various doses
of agents.
Beyond these clear unmet needs in investigation, the human application of
molecular and functional imaging requires careful consideration regarding clinical
and cost-effectiveness. For imaging modalities to prove clinically useful as addi-
tions to the current panel of validated biomarkers of prospective risk, they require
rigorous evaluation. While coronary calcium scanning indubitably predicts pro-
spective risk of cardiovascular events, adding to traditional risk and emerging bio-
markers, its clinical utility remains incompletely validated. No study has yet tested
whether the targeting of therapy based on coronary calcium score leads to greater
cardiovascular event reduction than therapy directed by already validated markers
such as the Framingham covariates or high-sensitivity C-reactive protein. The con-
tention that imaging studies such as coronary artery calcium scores can motivate
patients to adopt a healthy lifestyle or adhere to therapies has not received consistent
validation when studied rigorously [9].
Much of the interest in molecular and functional imaging of the cardiovascular
system over the last decade or so has focused on the quest to identify the so-called
“vulnerable” plaque. This goal assumes implicitly that identifi cation of a plaque
that has characteristics associated in post-mortem studies with plaque rupture and
fatal thrombosis could direct a local therapy that would forestall such complications
of atherosclerosis. Multiple lines of evidence cast doubt on this simplistic notion
[7]. First, plaques with thin fi brous caps, large lipid cores, and active infl ammation
tend to occur in clusters rather than singly within the coronary circulation. Moreover,
patients who harbor such plaques in their coronary arteries likely have activated
atherosclerotic plaques in other arterial beds, such as in the carotid circulation.
Many plaques that have the characteristics of “vulnerability” may not rupture.
Autopsy studies provide us with a numerator but not a denominator with regard to
the fatal thrombotic potential of plaques with the characteristic attributed to “vul-
nerability”. Indeed, in the PROSPECT study, during a more than 3-year observation
period, fewer than 5 % of plaques, judged by intravascular ultrasound virtual histol-
ogy study to have characteristics of vulnerability, actually caused clinical events
[10]. Thus, the vast majority of so-called “vulnerable” plaques will not cause a
clinical complication over a period of several years. These various observations sug-
gest that systemic therapy, often directed by non-imaging biomarkers, may prove
viii Foreword
more clinically effective at targeting therapy and reducing events than the applica-
tion of imaging modalities.
L ikewise, as illustrated in this volume, while calcium provides an attractive
imaging target, its mutability remains questionable. Although the ability to prevent
or retard calcifi cation of cardiovascular structures such as the aortic valve, the ath-
erosclerotic plaques, or the mitral annulus might be desirable, we currently lack
clinical tools to this end. Perhaps the application in investigation of the modalities
described in this volume will enable research that renders the modulation of calcifi -
cation a realistic therapeutic target. Molecular and functional imaging of the cardio-
vascular system, like any emerging tool, must overcome a number of challenges.
First, while well-developed preclinically, molecular imaging must traverse the “val-
ley of death” to clinical application for it to achieve its promise of transforming the
practice of cardiovascular medicine [8, 11].
C linical use of molecular imaging probes requires toxicologic evaluation and
preparation of material according to “good manufacturing practices” (GMP) [11].
These expensive undertakings lie beyond the resources of most academic research
groups. While many have made experimental animals “glow in the dark” by the use
of molecular imaging modalities, the realization of the promise in patients remains
rudimentary. As illustrated in the excellent chapters in Part I II of this volume, some
of the most mature modalities for clinical application include PET and MRI. The
work with fl uorodeoxyglucose and sodium fl uoride uptake provide examples of the
application of the principles of molecular imaging to human patients. Yet, we must
remain mindful of the need to validate the interpretation of the origin of signals
attributed to infl ammation in the case of FDG or calcifi cation, as in the case of
sodium fl uoride imaging [12]. We must also require rigorous clinical validation of
the relationship between these imaging biomarkers and clinical events and patient
outcomes.
The compendium of chapters in this collection provide with a proper support and
guidepost to the future of realizing the promise both in investigation and in the
clinic of molecular and functional imaging of the cardiovascular system.
Peter Libby
Division of Cardiovascular Medicine
Brigham and Women’s Hospital
Harvard Medical School
Boston , MA 02115 , USA
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Foreword ix
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