Cardiovascular Calcification and Bone Mineralization (Contemporary Cardiology)

564 Pages·2020·18.416 MB·English

by  Elena Aikawa (editor), Joshua D. Hutcheson (editor)

Contemporary Cardiology
Series Editor: Peter P. Toth
Elena Aikawa
Joshua D. Hutcheson   Editors
Cardiovascular
Calcification
and Bone
Mineralization
Contemporary Cardiology
Series Editor
Peter P. Toth
Ciccarone Center for the Prevention of Cardiovascular Disease
Johns Hopkins University School of Medicine
Baltimore, MD, USA
For more than a decade, cardiologists have relied on the Contemporary Cardiology
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Each title is carefully crafted by world-renown cardiologists who comprehensively
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Elena Aikawa • Joshua D. Hutcheson
Editors
Cardiovascular Calcification
and Bone Mineralization
Editors
Elena Aikawa Joshua D. Hutcheson
Department of Medicine Department of Biomedical Engineering
Brigham and Women’s Hospital Florida International University
Harvard Medical School Miami, FL
Boston, MA USA
USA
ISSN 2196-8969 ISSN 2196-8977 (electronic)
Contemporary Cardiology
ISBN 978-3-030-46724-1 ISBN 978-3-030-46725-8 (eBook)
https://doi.org/10.1007/978-3-030-46725-8
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Foreword
Cardiovascular calcification is the most common type of ectopic calcification. It is
a frequent complication of vascular disease such as atherosclerosis and constitutes
an important vascular aspect of systemic disorders including diabetes, renal failure,
premature aging, and inflammatory disease. Furthermore, calcific aortic valve dis-
ease, considered a distinct type of cardiovascular calcification, is the most prevalent
form of heart valve disease in the developed world and is projected to steadily
increase during the next few decades. The calcific changes augment morbidity and
mortality in cardiovascular disease and create significant obstacles during vascular
interventions and surgeries such as coronary artery bypass grafting and heart valve
replacement. Overall, the number of patients with complications of cardiovascular
calcification and the cost in terms of human suffering and healthcare costs are rising.
Historically, the interest in cardiovascular calcification was triggered by a num-
ber of observations by early pathologists, who reported the resemblance of the cal-
cification to bona fide bone as well as associations between calcification and
vascular disease. As early as 1863 Rudolph L.C. Virchow, “the father of modern
pathology,” noted that “we have really to do with an ossification” and “the plates,
which pervade the inner wall of the vessel, are real plates of bone.”
The descriptions of the cardiovascular calcification involved elements of bone,
cartilage, and even bone marrow-like tissues and fat. In light of these observations
together with the more recent findings of bone-regulatory factors, our perception of
calcification as something irreversible and unregulated changed. The prospects of
prevention and treatment became tangible as we realized that the trajectory of car-
diovascular calcification could indeed be modified. This realization coincided with
the emergence of new approaches in cell and molecular biology and improved clini-
cal imaging for quantification of calcification and percutaneous vascular and valvu-
lar interventions. The discovery of osteochondrogenic differentiation in vascular
cells could also be seen as a precursor to the subsequent rise of the stem cell field,
all of which contributed to the establishment of cardiovascular calcification as a
highly translational, evolving, and dynamic research field.
The integration of the different aspects of calcification led to a greater under-
standing of how mineralization impairs the physiology of the cardiovascular
v
vi Foreword
system. We know that calcified regions can influence the stability of atherosclerotic
lesions depending on the size, shape, and location of the mineral. We have examined
how vascular cells derived from the endothelium, vascular media, or adventitia turn
normally compliant vessels into bone and cartilage and how extensive mineraliza-
tion alters the elasticity of the arteries. As a consequence, blood pressure regulation
and organ perfusion will suffer. We are also familiar with the deleterious effects of
calcific build-up on the aortic valve that results in aortic stenosis, impaired coronary
blood flow, and ultimately heart failure.
We later discovered how essential signaling in bone growth is re-purposed to
promote cardiovascular calcification. Enhanced levels of phosphate, glucose, and
lipids resulting from kidney disease, diabetes, and atherosclerosis have powerful
effects on mineral precipitation and the reactivation of developmental factors. Bone-
promoting factors such as the bone morphogenetic proteins, Wnt signaling, and
alkaline phosphatase are activated in the vessels, but can also be counteracted by an
array of calcification inhibitors. The formation of osteoclasts, central in bone resorp-
tion, is activated in the calcified vessels through osteoprotegerin and its ligands.
This has allowed for an understanding of the role of bone-remodeling in shaping
vascular calcification, a process that could be exploited for therapeutic aims. The
emergence of new tools such as single cell sequencing and “omics” approaches will
enable us to further characterize the individual calcifying cells and their signaling
patterns, and thereby enhance our understanding of their unique features. We should
also be able to better examine cell responses elicited by the surrounding matrix and
how modifications of matrix components such as elastin would alter the course of
calcification.
The similarities between arteries and bone also extend to extracellular vesicles.
These bone-related mediators of mineral precipitation have similarly been shown to
drive smooth muscle cell mineralization in the vascular wall. Moreover, we have
gained insight into the interactions between biomechanical factors, oxidative stress,
and inflammation that are able to create “perfect storms” that can further cardiovas-
cular calcification. This is especially notable in the aortic valves where the two sides
of the valves experience striking differences in flow conditions and calcific changes.
Simultaneously, biomineralization of prosthetic valves is continuing to gain in
importance given the growing number of valve replacement and the effects of calci-
fication on the integrity and longevity of the prosthetic valves.
In order to address the differences between the cardiovascular calcification and
normal bone mineralization, new bridges had to be created between vascular, valvu-
lar, and bone biology. Paradoxes were found in these comparisons between bones
and arteries, allowing us to obtain information that will eventually assist in the tar-
geting of anti-calcific treatments to the vessels while sparing the bones. This is a
critical point since cardiovascular calcification frequently coexists with bone disor-
ders, which are characterized by deficiencies in mineralized bone such as
osteoporosis.
The last few decades have radically changed our view of cardiovascular calcifi-
cation, and this newfound awareness is finding its way into day-to-day patient care.
The underlying basic science of cardiovascular calcification is moving swiftly to
Foreword vii
suggest new treatment strategies. The clinical sciences are continuously enhancing
the imaging modalities used to detect and monitor calcification over time. There is
a clear expectation that our expanding knowledge will ultimately be translated to
new and better strategies for prevention and treatment of clinical calcific disease. It
will be greatly supported by the effort to summarize the present understanding of
cardiovascular calcification in this comprehensive scientific work. This volume is
written and edited by experts in different areas of cardiovascular calcification, sev-
eral of which have made ground-breaking discoveries and created new perspectives
on calcification. Their combined efforts are certain to prove useful to trainees and
experts at all levels who wish to broaden their knowledge base in cardiovascular
calcification.
Kristina I. Boström, MD, PhD
Division of Cardiology,
David Geffen School of Medicine, UCLA
Los Angeles, CA, USA
Preface
Calcification—the formation of calcium-based minerals—is an integral part of
human physiology and disease. Calcium mineral in bones provides the structural
support required for uprightness and locomotion, and interacts with other tissues to
maintain whole body homeostasis. Bone is remarkably dynamic with active turn-
over governed by precise cellular and molecular mechanisms that adapt the skeleton
in response to cues such as mechanical loading, fracture, and inflammation. The
underlying mechanisms remain poorly understood and constitute active areas of
research that seek to develop therapeutics and engineered tissues to promote miner-
alization, treat bone disorders, and restore normal skeletal function.
Humans have long recognized, however, the harmful effects of excessive miner-
alization. In Greek mythology, the sheer sight of the monster Medusa turned onlook-
ers to stone. Christianity, Judaism, and Islam all describe the fate of Lot’s wife, who
turned to salt after looking back on the condemned city of Sodom. As bones provide
mechanical rigidity and structure for the body, the function of all other organs relies
on varying degrees of compliance. Pathological mineral formation in soft tissues—
known as ectopic calcification—compromises organs’ biomechanical integrity and
function. This is perhaps most apparent and widely studied in the context of cardio-
vascular disease. Calcification of arteries and the aortic valve increases the resis-
tance to blood flow from the heart. The resultant increase in cardiac work can lead
to heart failure. The presence of small calcium mineral deposits—known as micro-
calcification—in atherosclerotic plaques causes mechanical stress. Elevated
mechanical stress can result in plaque rupture, the most common cause of acute
heart attacks and strokes. The recognition that many of the mechanisms that lead to
cardiovascular calcification mirror the active processes that regulate bone remodel-
ing has led to hope that therapeutics could prevent or reverse this pathology in at-
risk individuals. To date, however, treatment strategies do not exist, and ongoing
research continues to fill critical knowledge gaps in cardiovascular calcification.
Likely due to the appreciation that aortic valve and arterial calcification are the
best predictors of and direct contributors to general morbidity and mortality, cardio-
vascular calcification is the most commonly reported form of ectopic calcification.
Mineralization, however, has been noted in a myriad of tissues and pathologies,
ix
x Preface
including degenerative brain diseases, cancers, the placenta, and traumatic injuries,
and ongoing studies seek to understand the associated mechanisms and significance
of calcification in these contexts. Calcification studies, including those on cardio-
vascular and bone mineral, often exist within field-specific silos. Even within a
given field, such as cardiovascular calcification, communication barriers often occur
between scientists who focus on specific topics such as calcific aortic valve disease,
atherosclerotic calcification, diabetes or chronic kidney disease-mediated calcifica-
tion, and peripheral artery disease. The disease context frequently takes precedence
over calcification when researchers seek the most appropriate audience at confer-
ences or through journal publications. The unique goal of this book is to break these
silos and aggregate knowledge and research techniques from across various fields of
calcification into a single source. This will provide a resource to researchers, clini-
cians, and other medical professionals and promote interdisciplinary dialogue,
potentially leading to solutions to problems within fields through cross-disciplinary
knowledge transfer.
Reflecting both the expertise of the editors and the large associated clinical sig-
nificance, discussions on cardiovascular calcification comprise a majority of the
text. The associated chapters, written by renowned experts from across cardiovascu-
lar research and medicine, discuss the current mechanistic hypotheses in various
vascular beds and disease contexts. The contributions conclude with chapters that
provide a translational view that describe how mechanistic insight from basic
research has begun to transform cardiovascular diagnostics and clinical decision-
making, including potential forthcoming therapeutic approaches. Between the car-
diovascular-focused sections, experts in bone mineralization and non-cardiovascular
forms of ectopic calcification provide insight into current paradigms from across the
spectrum of calcification. Being the most mature of these fields, bone research has
informed many of the mechanistic pathways and methodologies utilized in other
calcification studies. The section on bone mineralization may continue to serve as a
useful reference for investigators in ectopic calcification, but as these fields continue
to mature, bone researchers may begin to learn from approaches developed to
address pathological mineral formation.
The mechanisms, experimental methods, and clinical insight presented in the
following chapters provide a starting point for future conversations and collabora-
tions to advance all areas of calcification research. Initiating interdisciplinary con-
versations can often be a daunting task, and much credit goes to the authors who
contributed chapters to this book for their enthusiasm to participate in this effort.
The contributions were written with a goal of appealing to all interested readers.
The authors elegantly delivered on this goal without sacrificing depth. Where pos-
sible, the chapters are cross-referenced within the text such that the interested read-
ers can take their own starting point and allow the material to suggest the next
relevant chapter—a choose your own adventure approach! We (not completely
objectively), however, suggest starting with The History of Cardiovascular
Calcification, which provides some historical context to frame the subsequent
chapters.