Schoen2012 PDF

PM07CH07-Schoen ARI 12 December 2011 8:45
ANNUAL
REVIEWS Further
Mechanisms of Function
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Frederick J. Schoen
Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School,
Boston, Massachusetts 02115; email: fschoen@partners.org
by Duke University on 07/10/12. For personal use only.
Annu. Rev. Pathol. Mech. Dis. 2012. 7:161–83 Keywords

First published online as a Review in Advance on heart valve pathology, bioprosthesis, tissue engineering
September 19, 2011
The Annual Review of Pathology: Mechanisms of Abstract

Disease is online at pathol.annualreviews.org
Over the past several decades, there has been substantial progress to-
This article’s doi:
ward understanding the mechanisms of heart valve function and dys-
10.1146/annurev-pathol-011110-130257
function. This review summarizes an evolving conceptual framework
Copyright c 2012 by Annual Reviews.
of heart valve functional structure, developmental biology, and patho-
All rights reserved
biology and explores the implications of key insights. I emphasize:
1553-4006/12/0228-0161$20.00
(a) valve cell and extracellular matrix biology and the impact of biome-
chanical factors on function, homeostasis, environmental adaptation,
and key pathological processes; (b) the role of developmental processes,
valvular cell behavior, and extracellular matrix remodeling in congeni-
tal and acquired valve abnormalities; and (c) the cell/matrix biology of
degeneration in replacement tissue valves. I also summarize how these
considerations may ultimately inform the potential for prevention and
treatment of major diseases and potentially therapeutic regeneration of
the cardiac valves. Recent advances and opportunities for research and
clinical translation are highlighted.
161
INTRODUCTION cles to the atria during systole, when blood is

expelled from the right and left ventricles into
Heart valve disease is an important public
the pulmonary artery and aorta, respectively.
health problem in both developed and devel-
With a cardiac cycle that is approximately 1 s
oping regions of the world (1). Key concepts
in duration, human heart valves open and close
of the dynamic functional, biological, and me-
approximately 40 million times a year and 3 bil-
chanical behavior of the cardiac valves in health
lion times over a typical lifetime. The cyclical
and disease have been elucidated in recent years
motions of the principal valvular components,
through studies using in vitro cultures of heart
known as leaflets (in the TV and MV) and cusps
valve cells; in vivo and ex vivo experimental
(in the PV and AV), are driven by mechanical
systems that model elements of valve biolog-
forces exerted by the surrounding blood and
ical and pathobiological activity; and targeted
heart, which impose tension, shear, and flexure
study of native and substitute human valves,
within the cuspal tissue (4).
both normally functioning and pathological.

The AV cusps (normally three) attach to
Principles of short- and long-term biological
the aortic wall in a crescentic (or semilunar)
and biomechanical valve function at the or-
fashion, along the basal attachments, and
gan level, tissue and cell structure, pathologic
ascending to the commissures, where adjacent
anatomy, and mechanisms of valvular disease
cusps come together at the aortic wall. Between

have emerged (2). These developments have
the free edge and the closing margin are two
fostered improvements in tissue heart valve sub-
thin, crescent-shaped regions termed lunulae;
stitutes and surgical repairs and have informed
a competent seal during diastole depends on
innovative approaches to heart valve tissue en-
firm contact between the lunulae of adjacent
gineering and regeneration that may someday
cusps. Below the lunulas is the cuspal belly,
achieve clinical implementation (3). This re-
which separates left ventricular from aortic
view highlights the mechanisms of normal heart
blood in the closed phase. Developmental
valve function and morphogenesis; the pathobi-
or acquired defects in the belly regions but
ology of native and substitute tissue valve dys-
not the lunulae permit backflow when the
function; and implications for the prevention,
valve is closed. Closure of the valve cusps is
diagnosis, and treatment of heart valve disease.
facilitated through both local vortices, which
are generated in dilated pockets in the aortic
DYNAMIC VALVULAR root (known as sinuses of Valsalva) that bulge
FUNCTIONAL MACRO- with each ejection of blood, and aortic wall
AND MICROSTRUCTURE, pliability. Thus, either dilation or stiffening of
DEVELOPMENTAL BIOLOGY, the aortic root can hinder movement and/or
AND POSTDEVELOPMENTAL proper coaptation of the AV cusps and can
CHANGES thereby promote regurgitation. PV structural
Normal function of the cardiac valves enables components and function are largely analogous
unidirectional blood flow through the heart to those of the AV but are less robust (5).
with minimal obstruction and without regur- Competency of the atrioventricular valves
gitant flow. The semilunar valves [i.e., the pul- (TV and MV) involves a more complex mech-
monary valve (PV) and the aortic valve (AV)] anism (6). The leaflet free margins are tethered
prevent retrograde flow into the ventricles dur- to the underlying muscular ventricular walls
ing diastole, when the pulmonary artery and by many delicate tendinous cords (chordae
aorta are filled with blood under pressure and tendineae), which themselves are attached
blood from the atria fills the systemic ventri- to intracavitary extensions of the muscular
cles. In addition, the atrioventricular valves [i.e., ventricular wall termed the papillary muscles.
the tricuspid valve (TV) and the mitral valve Normal apposition of mitral valve leaflets
(MV)] prohibit reverse flow from the ventri- and, thus, MV competency depend on the
162 Schoen
coordinated actions of the annulus (the outer and these three layers, known as the fibrosa,
edge of the valve orifice, where the leaflets spongiosa, and ventricularis, respectively, are
attach), leaflets, cords, papillary muscles, and populated by valvular interstitial cells (VICs).
associated left ventricular wall—collectively Most frequently diseased and most fre-
termed the mitral apparatus—which act to quently requiring valve substitution, the AV has
maintain leaflet coaptation and prevent back- the most illustrative structural specializations
flow. Left ventricular dilation (as in congestive and tissue dynamics (12–14). The back pres-
heart failure), or a scarred or ruptured papillary sure on the AV in diastole (normally, approx-
muscle (as a complication of acute myocar- imately 80 mm Hg) stretches the valve cusps
dial infarction), can interrupt or distort the as they appose and seal the orifice to prevent
tethering of the leaflets and thereby interfere backflow. AV cuspal mechanical properties are
with MV closure [known as functional valve anisotropic (i.e., different in the radial and cir-
regurgitation, of which ischemic mitral regur- cumferential directions); specifically, the AV
gitation is a particular case (7)]. The structures cusps are more compliant (i.e., achieve large
of the TV and MV are analogous. strains with low stress) in the radial direction
Sufficiently thin to be nourished by diffu- in order to coapt and close the orifice area, yet
sion from the blood bathing the valves, normal they must withstand significant pressure from
leaflets and cusps have only scant and incon- the blood to avoid prolapse and prevent retro-
sistent blood vessels at their proximal portions grade flow (necessitating low strains and high
(8). Indeed, valvular angiogenesis is generally stresses circumferentially).
associated with disease (9). Although the valve Collagen, the major stress-bearing compo-
leaflets and cusps also have nerves, and AV nent of the heart valves, maintains apposition of
cusps exhibit receptor-mediated contraction, cusps without prolapse into the LV and trans-
the functional role of neural elements and fers the load from the cusps to the aortic wall
contractile responses in valve function and when the valve is closed. Collagen fibers with-
hemodynamic adaptation and disease has not stand high tensile forces when taut but cannot
yet been clarified (10). be compressed. Thus, the changes in shape and
size of the cusps during the cardiac cycle must
involve rearrangements in collagen structure
The Functional Role of Valvular other than stretching, including alignment
Extracellular Matrix in diastole and more random orientation in
Short-term responsiveness, coordinated move- systole, as well as crimping (analogous to the
ments, and mechanical integrity, as well as pleating of an accordion) in systole and flatten-
long-term durability of the heart valves, are ing in diastole. The diastolic rearrangements
accomplished by an extraordinarily complex, of collagen are extraordinarily responsive to
functionally adapted, dynamic, and highly changes in load; for example, collagen crimp
responsive tissue macro- and microstructure is flattened rapidly as pressure is applied (90%
(Figure 1) (2, 11). The four cardiac valves lost at a back pressure of only 20 mg Hg; little
have a similar, layered architectural pattern; further rearrangement occurs to full diastole at
each valve has (beginning near the outflow 80 mm Hg) (15). In systole, the AV cusps open
aspect) (a) a dense collagenous layer, close rapidly and completely and have decreased
to the outflow surface and continuous with surface area, consolidation, and relaxation of
valvular supporting structures, that provides the cuspal tissue previously stretched during
the primary strength component of the valves; diastole. These rearrangements during open-
(b) a central core of loose connective tissue rich ing are facilitated by the pull of the stretched
in glycosoaminoglycans (GAGs); and (c) a layer elastin, and are accompanied by restoration of
rich in elastin below the inflow surface. The collagen folding in a more random orientation.
valves are covered by an endothelial monolayer, The GAG-rich spongiosa facilitates the relative
www.annualreviews.org • Cardiac Valve Mechanisms 163

a b
Systole (open) Diastole (closed)
Collagen is
crimped and 80 mm Hg
unaligned
Elastin is Elastin is
relaxed stretched
Collagen is uncrimped
Corrugations and aligned
c Outflow
Endothelial
cells
d
VICs
Fibrosa
Collagen
VICs
Spongiosa
GAGs
VICs
Ventricularis
Elastin
Endothelial
cells
Inflow
e f
*
5 μm
5 μm
164 Schoen
internal rearrangements and cushions local boresistance, inflammation, and maintenance

shock during the cardiac cycle. of valvular tone and may interact with VICs
The above discussion emphasizes that the to maintain the integrity of valve tissues (19).
cycle-to-cycle biomechanical function of the VECs are phenotypically different from vascu-
valve is accomplished by a highly developed lar endothelial cells of the adjacent aorta with
and dynamic structure. It follows that the respect to both response to fluid shear stress
ongoing quantity, quality, and architecture of (20) and the transcriptional gene-expression
the valvular extracellular matrix (ECM), partic- profiles when exposed to the same mechanical
ularly collagen, elastin, and GAGs, determine environment (21). Furthermore, endothelial
the long-term (lifetime) durability of a valve. gene expression differs between the aortic and
Moreover, macroscopic forces on the valve are ventricular faces of a normal adult pig AV (22).
transduced into cell-cell and cell-ECM interac- In addition, the physical proximity of VECs
tions and, potentially, ECM changes owing to and VICs and the well-known functional inter-
physiological function and/or pathological pro- actions between endothelial and vascular wall
cess that impact biological phenomena at the cells in other contexts has raised speculation
cell and tissue levels. Through as-yet-unknown that communication between them may be im-
mechanisms, superficial valvular endothelial portant (23). Studies suggest that VECs regu-
cells (VECs) and deep VICs sense the local late the phenotype of VICs in coculture and that
tissue mechanical environment and maintain VEC stimulation by endothelin 1 and serotonin
homeostasis; adapt to altered stress states; and [also known as 5-hydroxytryptamine (5-HT)]
repair injury via connective tissue remodeling can change AV tissue properties by contraction
mediated by the synthesis, repair, and remodel- or relaxation, possibly mediated by VICs (24).
ing of the several ECM components. Valvular
signaling mechanisms and ECM biology are
subjects of active investigation (16–18). The Role of Valvular Interstitial Cells
VICs are the most abundant cell type in normal
heart valves and are distributed throughout
The Role of Valvular Endothelial Cells all of its layers; they are crucial to function.
Endothelial cells line the blood-contacting Through their ability to synthesize ECM and
surfaces of the valves and are crucial to valve de- express matrix-degrading enzymes [including
velopment (see the section titled Development, matrix metalloproteinases (MMPs) and their
Postdevelopmental Evolution, and Adapta- inhibitors, tissue inhibitors of metallopro-
tion of the Cardiac Valves). Subsequent to teinases] that remodel collagen and other
development, VECs probably regulate throm- matrix components (25), VICs continuously
←−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−
Figure 1
Aortic valve functional structure at macroscopic and microscopic levels. (a) Outflow aspect of aortic valve in open (top) and closed
(bottom) configurations, corresponding to systole and diastole, respectively. (b) Schematic representation of architecture and
configuration of aortic valve cusp in cross section and of collagen and elastin in systole and diastole. Modified from Reference 11.
(c) Schematic diagram of the detailed cellular and extracellular matrix architecture of a normal aortic valve. Modified with permission
from Reference 12. (d ) Tissue architecture, shown as low-magnification photomicrograph of cross-section cuspal configuration in the
nondistended state (corresponding to systole), emphasizing three major layers: ventricularis, spongiosa, and fibrosa. Valvular interstitial
cells (VICs) are denoted by arrows. The outflow surface is at the top. Original magnification: 100×. Hematoxylin and eosin stain.
(e) Transmission electron photomicrograph of relaxed fresh porcine aortic valve (characteristic of the systolic configuration),
demonstrating the fibroblast morphology of VICs (arrow); the dense, surrounding closely apposed collagen (asterisk) with wavy crimp;
and the potential for VIC-collagen and VIC-VIC interactions. Reproduced with permission from Reference 2. ( f ) Transmission
electron photomicrograph of surface of aortic valve demonstrating valvular endothelial cell (VEC; arrow) and proximity of deeper VICs
(double arrows) and potential for VEC-VIC interactions. Reproduced with permission from Reference 14. Abbreviation: GAG,
glycosoaminoglycan.

Circulating endothelial cell

Embryonic progenitor cells precursors
Developmental source of VICs Postdevelopmental source of VICs
Environmental
Quiescent (fibroblast-like) VICs stimulation, e.g.,
Resting state of VICs TGF-β,
mechanical stress
Restoration of
Osteoblastic VICs equilibrium Activated
Mediate calcification (myofibroblast-like) VICs

and disease Mediate remodeling, adaptation,
and disease
Figure 2
Spectrum of valvular interstitial cell (VIC) phenotypes. VIC functions can be conveniently organized into
five phenotypes: embryonic progenitor endothelial/mesenchymal cells; quiescent VICs; activated VICs;
adult, circulating stem cell–derived progenitor VICs; and osteoblastic VICs. Abbreviation: TGF,
transforming growth factor. Modified from Reference 26 and reproduced with permission from Reference 2.
repair functional damage to collagen and the chanical stress state of valves. Ex vivo stretch
other ECM components and mediate matrix of fresh porcine AV upregulates remodeling
remodeling in adaptation and disease. events (29). Moreover, either induced mechan-
The VIC population is diverse and plastic; ical stretch (30) or transforming growth factor
their function is modulated along a spectrum (TGF)-β treatment of isolated VICs from
of five distinct VIC phenotypes regulated by mature valves increases these cells’ growth and
local mechanical and chemical conditions: em- synthetic activity (31–33), and the effects of
bryonic progenitor endothelial/mesenchymal stress and TGF-β on cultured aortic VICs
VICs, quiescent VICs, activated VICs, post- are synergistic (32). VIC activation by TGF-β
developmental/adult progenitor VICs, and os- augments stress fiber formation and alignment,
teoblastic VICs (Figure 2) (26). During valvu- leading to enhanced contractility and increased
lar homeostasis and response to injury, adapta- stress on the adjacent ECM, which may pro-
tion, and pathology, VICs transition (reversibly mote alterations to the valve ECM in disease
under some circumstances) from one pheno- (33). Because the macroscopic mechanical state
typic state to another (2). VICs in adult heart of the valve is probably transmitted to the VICs
valves in situ are predominantly fibroblast-like through interactions with the surrounding
and quiescent; only 2–5% of normal adult VICs ECM, there is considerable interest in the
in situ show evidence of activation. In contrast, effects of matrix mechanical properties on VIC
50–78% of cells isolated from heart valves cul- function (34, 35), the mechanisms of response
tured in vitro are found to be α–smooth muscle of VICs to their physical environment (20, 21,
actin (α-SMA) positive (27, 28), suggesting 32), and the mechanical properties of VICs (36,
that manipulation stimulates or activates VICs. 37). Several lines of evidence suggest that VICs
VIC phenotypes in normal valves change from AV and PV have different mechanical
with age and environmental conditions (see properties and remodeling potential (38), and
below). For example, VICs are activated in vivo both express higher levels of proinflammatory
during intrauterine development and valvular and pro-osteogenic markers after stimulation
maturation and by abrupt changes in the me- (39, 40). Moreover, chemical and mechanical
166 Schoen
VIC-ECM interactions may promote valve jelly. Interestingly, and of potential importance
calcification (41, 42). Regional heterogeneity in the mechanisms of calcific AV disease
of synthetic response in VICs from the mitral discussed below, there are gene-expression
valve has also been demonstrated (43). profiles and protein products that are shared
between normally developing and diseased
valves and bone osteoblast precursor cells (49,
Development, Postdevelopmental 50). Although human cardiac morphogenesis is
Evolution, and Adaptation complete within 8 to 10 weeks, several lines of
of the Cardiac Valves evidence suggest that VICs in postnatal valves
The mechanisms of valve morphogenesis in the may continuously arise via circulating endothe-
atrioventricular canal and ventricular outflow lial or mesenchymal cell precursors derived
tracts, namely valvular maturation in the fe- from the bone marrow and later from EMT
tus, adaptation, homeostasis, and structural and (i.e., to become the postdevelopmental/adult
functional change throughout life, have been progenitor VICs described above) (51, 52).
elucidated by studies using zebrafish, chicken, The role of ECM components in mediat-
mouse, and human valves. Key molecular and ing the creation and subsequent remodeling
cellular pathways in normal and abnormal car- of the endocardial cushions into mature valves
diac development have been defined, and dis- is poorly understood. Nevertheless, the GAG
ruption of key developmental pathways leads to hyaluronan is known to have multiple func-
valvular abnormalities (44–46). Moreover, de- tions in EMT (53) and, therefore, in valve de-
velopmental mechanisms underlie some adult velopment. Also, periostin, an ECM protein
valve diseases (47). Members of the TGF-β su- that influences matrix remodeling via cell mi-
perfamily (including TGF-β1, TGF-β3, and gration, adhesion, and collagen formation, me-
bone morphogenetic protein 2), vascular en- diates post-EMT valvular maturation (54, 55).
dothelial growth factor and its receptors, the Several lines of evidence suggest that cardiac
NFATc (nuclear factor of activated T cells) morphogenesis and function and heart valve de-
transcription factor, the Notch transcription velopment are regulated by mechanical forces
factor, Wnt/β-catenin, and other pleiotropic (56–58). Implantation of polymeric beads in the
signaling pathways are particularly important inflow or outflow tract of the zebrafish heart,
regulators. which lowers the shear stress across the endo-
In normal cardiac development, the cardial cushions and valves, leads to abnormal
myocardium of the heart tube is separated valve phenotypes (59), and a cardiofunk (cfk)
from the endocardium by an acellular ECM gene mutation that encodes an abnormal sar-
known as cardiac jelly. After heart looping is comeric actin and causes poor contractility and
complete, the valve cusps/leaflets form from blood flow in zebrafish leads to abnormal cush-
mesenchymal outgrowths termed endocardial ion/valve formation (60).
cushions (48). Driven by signals from the un- ECM architecture and VIC phenotype
derlying myocardium, a subset of endothelial are dynamic, and proliferation and apoptosis
cells in the cushion-forming area take on a continue throughout human fetal and postnatal
mesenchymal cell phenotype and migrate into maturation, in normal adult life, and in re-
the cardiac jelly to form VICs (i.e., the em- sponse to altered environmental conditions and
bryonic progenitor endothelial/mesenchymal disease (61). Fetal VICs have a myofibroblast-
VICs described above) in a process known like phenotype (α-SMA expression, abundant
as epithelial-to-mesenchymal transformation embryonic myosin, and MMP collagenases)
(EMT). During EMT, the activated endothe- that reflects an activated phenotype engaged
lial cells lose cell-cell contacts, gain markers in matrix remodeling, and fetal VECs express
such as α-SMA and MMPs, and reduce their markers of an activated phenotype, including
endothelial markers as they invade the cardiac intercellular adhesion molecule 1 and vascular

cell adhesion molecule 1. Collagen content and pathology involves disruption of normal
alignment increase during valve maturation structure-function correlations by genetic, me-
in utero, and the characteristic trilaminar chanical, inflammatory, immunological, and
valvular architecture appears late in gestation. soluble factors, which are often mediated
With increasing age, VIC density decreases; through abnormal complex interactions among
indeed, VIC density of aged adult valves is only VECs, VICs, ECM, and their environment.
approximately 10% of that in fetal valves. Addi-
tionally, collagen fibers become progressively
more aligned with age (i.e., more characteristic Bicuspid Aortic Valve
of a diastolic configuration). This finding The most frequent gross developmental
suggests that there is an ongoing “creep” of cardiovascular malformation in humans, con-
AV structure during adult life, which is congenital bicuspid aortic valve (BAV), is usually
sistent with the progressive loss of mechanical uncomplicated in early life but frequently
compliance with increasing age (62, 63). eventuates in calcific aortic stenosis or regurgi-
Normal and pathological cardiac valves tation in later life; infective endocarditis along
respond to changes in mechanical loading with aortic dilation and/or dissection are less
by cell activation and matrix remodeling. frequent but important potential complications
For example, in myxomatous mitral valve (68). The prevalence of BAV is approximately
disease (64), adaptation (as exemplified by the 1% in the overall population, but congenital
first several months of PV-to-AV autograft BAV is the anatomic substrate in approximately
remodeling) (65) or early tissue-engineered half of adults who have calcific aortic stenosis.
valve maturation (66), VICs have an activated Calcification of a BAV occurs approximately
(i.e., myofibroblast-like) phenotype. More- a decade earlier in these patients than in those
over, following adaptive ECM remodeling, who have an anatomically normal valve (69).
VICs return to their normal fibroblast-like BAV, left ventricular outflow tract–
quiescent phenotype, as exemplified by late obstruction malformations, and other car-
clinical PV-to-AV autografts (more than three diovascular malformations show familial
years postoperation) and experimental tissue- clustering (70) and probably arise from faulty
engineered valves implanted in vivo. Therefore, valvulogenesis and/or cardiogenesis that derive
heart valves can respond to environmental from genetic defects. For example, signaling
change via reversible phenotypic modulation through the Notch transcription factor com-
of quiescent VICs to activated VICs; activated plex is critical in cardiac valve development
VICs regulate repair, adaptation, remodeling, (71, 72), and Notch gene mutations were
and potentially pathology. We hypothesize associated with a spectrum of developmental
that the adaptation maintains a normal stress AV abnormalities and severe calcification in
profile in the tissue that is analogous to the two families with nonsyndromic familial AV
putative regulatory principle for mechanical disease (73). Nevertheless, although Notch
load–induced cardiac hypertrophy (67). and TGF-β1 type II receptor gene mutations
are associated with BAV, some individuals with
these mutations do not have BAV, and these
PATHOBIOLOGY OF VALVULAR gene defects are rare relative to the incidence
HEART DISEASE of BAV (74). Moreover, Notch signaling
In this section, I discuss evolving data and represses osteoblast-like calcification pathways
mechanistic concepts of the common forms (75). Thus, BAV must have a heterogeneous
of valve disease. Figure 3 summarizes key pathogenesis, and the expression of this ab-
structural and functional changes and mecha- normality and later pathologic effects probably
nisms of valve aging and diseases. I emphasize depend on other genetic and potentially
the theme that clinically important heart valve environmental factors. Key questions in BAV
168 Schoen
Congenital valve abnormalities
Incomplete cusp/commissure formation;

secondary abnormal biomechanical function
Aging valve Aberrant morphogenesis or maturation Calcific aortic valve
Valve stiffening and decreased Gross calcific nodules, begin near

ECM turnover the outflow aspect
Progressive collagen alignment Calcification of individual VICs,

and loss of VICs coalescence into microscopic nodules
Normal/homeostatic valve
Healthy, responsive VECs, VICs, and ECM
VECs of normal valve maintain

thromboresistance; healthy VICs in the
normal valve are quiescent and mediate

slow, ongoing turnover of matrix
Myxomatous mitral valve Rheumatic valve
Weakening/stretching of leaflet; Transmural, postinflammatory

disrupted fibrillar ECM; fibrosis; disruption of layer

deposition of excess GAGs Carcinoid/drug-induced architecture; neovascularization
Inadequate ECM remodeling; Accumulation of intimal fibrous tissue, Antigen mimicry; inflammatory
genetic or acquired abnormal TGF-β devoid of elastin; underlying valve intact destruction of tissue; granulation
tissue and scar
Stimulation of VECs and VICs;
VIC proliferation; ECM accumulation
Structural/functional changes
Mechanisms
Figure 3
Structural and functional changes and mechanisms of the major forms of heart valve diseases. Abbreviations: ECM, extracellular matrix;
GAG, glycosoaminoglycan; TGF, transforming growth factor; VEC, valvular endothelial cell; VIC, valvular interstitial cell.
relate to the mechanisms of faulty valvular sclerosis; these percentages double for individu-
morphogenesis and the mechanistic basis for als older than 85 years. Smoking, hypertension,
the propensity for accelerated calcification and renal dysfunction increase risk. The cal-
and other complications of BAV, including cific deposits typically occur in the attachments
the potentially primary vascular basis for of the cusps in the regions of highest functional
BAV-associated aortic dissection. valve stresses (78), which suggests that mechan-
ical factors potentiate valve calcification. The
calcific deposits are initiated within the cusp be-
Calcific Aortic Valve Stenosis ginning below the aortic face of the cusps and
Calcified AV disease (which comprises aortic primarily grow distally but extend deep into the
stenosis and the earlier-stage aortic sclerosis) cuspal matrix—frequently almost to the ven-
occurs because of calcification intrinsic to the tricular surface.
cuspal tissue of either previously anatomically Calcific deposits are initiated predomi-
normal AVs or BAV (12, 76, 77). Calcification nantly in VICs (79). Thus, AV calcification
of the AV restricts cuspal opening and decreases has traditionally been considered to have a
the effective valve orifice area. Approximately degenerative, dystrophic mechanism with pas-
2% of individuals older than 65 years have aor- sive accumulation of hydroxyapatite mineral
tic stenosis, and an additional 20% have aortic in dead or damaged cells. However, several

lines of evidence suggest that calcific aortic upregulate Kruppel-like factor 2 (91). This
stenosis and atherosclerosis share risk factors transcription factor is regulated by shear stress
(such as male sex, hypertension, elevated serum profile and selectively induced in endothelial
low-density lipoprotein cholesterol, smoking, cells exposed to a biomechanical stimulus that is
and renal failure) and mechanistic features, characteristic of the regions of the arterial tree
including inflammation, lipid infiltration, and protected from atherosclerosis (92).
active regulation of calcification (80). Regret-
tably, animal models that faithfully reproduce
the morphology of human calcific AV disease Myxomatous Degeneration
are not available. Nevertheless, the finding of the Mitral Valve
that animal models of hypercholesterolemia The most common indication for surgical re-
develop atherosclerotic lesions involving the pair or replacement of the mitral valve, mitral
AV (81, 82) and the shared risk factors between valve prolapse (MVP), is the displacement of
atherosclerosis and calcific AV disease have the mitral leaflet(s) into the left atrium during
stimulated interest in the possibility that the systole (93). MVP increases the risk of several
statin drugs, which lower systemic cholesterol serious cardiovascular complications, includ-
and decrease inflammation in atherosclerosis, ing heart failure, mitral regurgitation, bacte-
may decrease the rate of aortic stenosis pro- rial endocarditis, thromboembolism, and atrial
gression. However, clinical studies performed fibrillation.
to date have not supported this hypothesis (83). Grossly, the leaflets are usually enlarged in
Calcified AVs show markers of osteoblastic surface area, thickened, and redundant. His-
activity, such as osteopontin, bone sialoprotein, tologically, the essential changes are attenua-
alkaline phosphatase, and bone morphogenetic tion and/or disorganization of the collagen-rich
proteins 2 and 4 (markers that characterize fibrosa layer of the valve, on which the struc-
osteoblasts in bone), in at least some VICs in tural integrity of the leaflet depends, accompa-
calcifying valves (84, 85). Cartilaginous and nied by thickening of the spongiosa layer with
osseous metaplasia, with mature lamellar bone deposition of material rich in proteoglycans
and maturing trilineage hematopoietic marrow, (termed myxomatous degeneration). These
are frequently observed in surgically explanted changes cause mechanical weakening of both
AVs (86). Heart valves and bone share reg- the leaflets and the chordae (94). The prevailing
ulatory mechanisms for connective tissue hypothesis is that altered ECM synthesis and/or
formation and remodeling (49, 50, 87), and ob- remodeling by VICs of the essential structural
servations from an in vivo animal model of AV proteins and proteoglycans creates a defect in
disease and in vitro calcification models support the mechanical integrity of the leaflet that,
the hypothesis that osteoblastic differentiation together with physiological stresses, leads to
of VICs contributes to calcific AV disease (88). stretching, elongation, and other features of the
The role of altered microRNAs in calcific valve clinical phenotype of MVP. VICs in MVP are
disease is also beginning to be explored (89). activated, which suggests a state of chronic me-
The vulnerability of the aortic side of the chanical disequilibrium as the adaptive ECM
valve cusp to calcification is well known but remodeling potential is exceeded (64).
poorly understood. Endothelial gene expres- In some cases, MVP is related to geneti-
sion differs between the inflow and outflow cally determined abnormal signaling and/or
surfaces, which may be related to the differ- structure-function relationships of key remod-
ent hemodynamic wave forms experienced by eling events involved in valve homeostasis (95).
the two faces of the valve cusps (90). Indeed, For example, MVP is associated with some her-
endothelial cells exposed to shear profiles pre- itable disorders of connective tissue, including
dicted (by finite element–analysis modeling) for Marfan syndrome, in which it is usually asso-
the inflow (but not outflow) surface of the valve ciated with mutations in fibrillin 1. Moreover,
170 Schoen
abnormal expression, formation, and distribu- fusion of the chordae tendineae. Mortality rates
tion of key valvular ECM proteins, including of rheumatic fever have declined remarkably in
elastin, collagen, and periostin (which regulates many parts of the world over the past 30 years
collagen fibrillogenesis), are associated with owing to improved socioeconomic conditions,
developmental valve abnormalities in mice rapid diagnosis and treatment of streptococcal
and humans; proteoglycan gene mutants that pharyngitis, and an unexplained decrease
cause human valve disease have not yet been in the virulence of group A streptococci.
recognized. Nevertheless, most cases of MVP Nevertheless, in developing countries and in
are not associated with fibrillin 1 nor with other many crowded, economically depressed urban
characterized abnormalities. Indeed, it is un- areas in the Western world, RHD remains an
likely that more than 1% to 2% of patients with important problem. Indeed, RHD accounts for
MVP have an associated, clearly identifiable a major proportion of all cardiovascular disease
connective tissue disorder (96). Several recent in children and young adults in the low- and
experimental and clinical findings implicate middle-income countries inhabited by 80% of

a key pathogenetic role for dysregulation of the world population (104).
TGF-β, a key cytokine regulator of ECM Although it is widely accepted that ARF is
assembly and remodeling in connective tissue a hypersensitivity reaction induced by group
(97), as the common mechanism of Marfan A streptococci, the exact pathogenesis remains
syndrome–related MVP and possibly other under investigation. Antibodies directed
syndromic and nonsyndromic forms of MVP against the M proteins of certain strains
(98). Studies utilizing genetic linkage analysis of streptococci cross-react with antigens in
have mapped families with autosomal dominant the heart, joints, and other tissues through
MVP to an X-linked filamin mutation (99) and a mechanism known as antigenic mimicry.
to chromosomes 11p15.4 (100), 16p11.2–p12.1 In affected valvular tissue, antigen-driven
(101), and 13q31.3–q32.1 (102). Filamin is oligoclonal CD4+ T cells expressing TNF-α
particularly interesting in that it is associated and interferon-γ predominate, and there is
with a protein expressed during cardiac mor- a relative paucity of interleukin (IL)-4- and
phogenesis and is the first mutation in familial IL-10-expressing T cells. The most important
MVP known not to be linked to a syndrome autoantigens include cardiac myosin epitopes,
widely affecting connective tissue (103). vimentin, and several other recently charac-
terized intracellular proteins (105). Only a
small fraction of patients who are infected with
Rheumatic Heart Disease rheumatogenic group A streptococci develop
Acute rheumatic fever (ARF) is an immuno- an abnormal immune response that leads to
logically mediated, multisystem inflammatory ARF; genetic susceptibility factors may include
disease that occurs a few weeks following human leukocyte antigen class II alleles, B
pharyngitis due to group A streptococci. cell alloantigens, and immune and other gene
Cardiac involvement during the active phase of polymorphisms (106).
rheumatic fever (acute rheumatic carditis) may
progress to chronic rheumatic heart disease
(RHD) decades later. Chronic RHD is char- Chemical- and Drug-Induced
acterized by microscopic organization of acute Valve Disease
inflammation and subsequent postinflamma- Clinical disorders associated with increased
tory scarring that manifest as chronic fibrotic levels of 5-HT, such as carcinoid syndrome,
valvular deformities, most frequently mitral and the use of 5-HT agonists, such as fenflu-
stenosis. The cardinal anatomic changes of the ramine (part of the fen-phen combination of
mitral valve are leaflet thickening, commissural appetite suppressants used for the treatment of
fusion and shortening, and thickening and obesity) (107), some anti-Parkinsonian drugs,

and methysergide or ergotamine therapy for the interplay between these factors and/or to
migraine headaches (108) are associated with polymorphisms in gene expression (113).
valvular heart disease in some patients.
Lesions associated with the carcinoid syn-
drome (a systemic syndrome that occurs in one- HEART VALVE SUBSTITUTION
half of patients who have carcinoid tumors) Diseased cardiac valves are frequently replaced
contain plaque-like intimal fibrous thickenings by mechanical prostheses and bioprostheses,
composed predominantly of smooth muscle which benefit inpatient survival and quality of
cells and sparse collagen fibers embedded in an life. The tendency of mechanical prosthetic
acid mucopolysaccharide–rich matrix material valves to cause thromboembolic complications
on the inside surfaces of the cardiac chambers necessitates long-term anticoagulation, which
and the tricuspid valve and PV. Occasionally, carries inherent risks of hemorrhagic compli-
the lesions involve major right-sided blood ves- cations. Tissue heart valves (usually biopros-
sels. Drug-induced valve disease is character- theses derived from either glutaraldehyde-fixed
ized by similar lesions, particularly on valves of porcine AV or bovine pericardium) are used in
the left side of the heart. half or more of valve replacements and gener-
The mechanism responsible for valve injury ally do not require anticoagulation (114, 115).
in carcinoid- and drug-related valve disease is However, tissue degeneration commonly leads
not completely understood. Carcinoid lesions to failure of bioprostheses and other tissue
relate to the elaboration by carcinoid tumors of valves used in cardiac surgery; cuspal miner-
various bioactive products, particularly 5-HT; alization and noncalcific structural damage are
plasma levels and urinary excretion of the 5-HT the major causal mechanisms (116).
metabolite 5-hydroxyindoleacetic acid gener-
ally correlate with the lesion severity. 5-HT
upregulates TGF-β1 in AV VICs (109), and in Bioprosthetic Valve
carcinoid heart disease, TGF-β is associated Structural Degeneration
with VIC formation of fibrotic lesions (110). Structural deterioration of bioprosthetic heart
In a mouse model, deficiency of the gene for valves is the unintended consequence of the
the 5-HT transporter (5-HTT), a protein that chemical, mechanical, and morphological
causes cellular internalization and clearance of changes that occur during fabrication of
5-HT, induces valvular fibrosis (111). Both in bioprosthetic valves (116). Most importantly,
vitro studies and animal models demonstrate during the preparation of bioprosthetic valves,
that excessive 5-HT levels may cause both chemical fixation of porcine AV or bovine
increased VIC proliferation and upregulation pericardial tissue with glutaraldehyde destroys
of ECM production, and reduced 5-HTT the viability of the resident cells of the tissues,
activity causes cardiac valve abnormalities in which are either VICs (of porcine AVs) or
5-HTT-deficient transgenic mice (probably fibroblasts (of bovine pericardial valves). This
because of delayed processing of 5-HT), process has several key consequences that con-
thereby sustaining 5-HT receptor (5-HTR) tribute to durability limitations. First, because
signaling (112). Fenfluramine-induced valvu- nonviable cells are incapable of remodeling
lopathy also involves activation of 5-HTRs on collagen, ongoing repair of the bioprosthetic
heart valves by the metabolite norfenfluramine. valve ECM by the cells of the transplanted
Thus, the development of drug-induced valvu- tissue is impossible, and any damage to the
lar heart disease is probably a manifestation of ECM is cumulative. Second, devitalized VIC
a complex yet presently poorly understood in- fragments serve as nuclei for calcification (see
teraction among 5-HT, 5-HTRs, and 5-HTT; below). Third, devitalized VECs of porcine
individual susceptibility to drug-induced AV bioprostheses are largely denuded by
valvular disease may be partly attributable to handling, thereby increasing the permeability
172 Schoen
of the tissue to fluid. Finally, fixation locks crystals. Collagen and elastic fibers can also
the collagenous network mechanically into a serve as nucleation sites for calcium phosphate
configuration that inhibits the smooth, internal mineral, independent of cellular components
cuspal structural rearrangements of the ECM (121). Initial calcific deposits eventually enlarge
that accompany normal valvular function, and coalesce, resulting in grossly mineralized
thereby inducing buckling of the cuspal tissue nodules that stiffen, weaken, and tear the tissue,
during functional opening and closing of a thereby causing prosthesis malfunction.
fixed bioprosthesis and causing cumulative Collectively, these studies confirm the key
internal structural damage (117). determinants of bioprosthetic valve mineraliza-
Calcification is the principal mechanism tion: (a) biochemical environment, (b) implant
of tissue damage causing bioprosthetic valve structure and chemistry, and (c) mechanical
failure. Figure 4 summarizes the events and factors. Calcification is accelerated by young
mechanisms of this process. Pathological anal- recipient age, probably because of age-related
ysis of tissue valve explants from patients and biochemical differences in systemic calcium
animal models—including tissue implanted and phosphorus metabolism. Moreover, evi-
subcutaneously in very young, rapidly growing dence does not support a causal immunologic
rats and orthotopic valve replacements in or inflammatory basis for bioprosthetic valve
sheep—has elucidated the mechanisms of valve calcification or failure. As a result of these stud-
mineralization and facilitated the testing of ies, the primary approaches to inhibiting valve
hypotheses for preventive approaches (118, calcification now target the nucleation of cal-
119). In these animal models, bioprosthetic cific deposits and, thus, have sought to remove
tissue calcifies progressively with a similar mor- or alter the cell-based phospholipid substrate.
phology and with markedly accelerated kinetics However, because of progressive collagen dam-
relative to that observed in clinical specimens. age, which cannot be repaired in a devitalized
Mineralization is initiated predominantly valve (containing no functional VICs), degra-
(a) at the devitalized VIC membranes and other dation of the valvular collagenous skeleton
intercellular structures that are high in phos- may become the limiting factor in durability of
phorus (as phospholipids) of the devitalized valves protected from calcification (122). The
connective tissue cells and (b) at areas where role of the degradation of GAGs in limiting
mechanical stress is concentrated, such as the bioprosthetic valve durability is less well char-
points of flexion in heart valves (120). We hy- acterized, but evidence suggests that improved
pothesize (summarized in Reference 116) that GAG preservation also may be beneficial (123).
the essential reaction occurs between the phos-
phates of the devitalized cells and calcium in the
surrounding fluid to yield calcium phosphate Other Tissue Valves
mineral. Normally, the plasma/extracellular Tissue degeneration also causes failure of the
calcium concentration is 1 mg ml−1 (approxi- less commonly used allografts (or homograft
mately 10−3 M); in contrast, the concentration heart valves), which are AV or PV valves ob-
of calcium in the cytoplasm is normally 103 –104 tained from cadavers (and occasionally from
times lower (approximately 10−7 M). In normal diseased hearts removed at transplantation) that
cells, this gradient is maintained by calcium then are transplanted from one individual to an-
pumps at the cell membrane. However, in the other after preservation by freezing in dimethyl
nonviable VICs of bioprosthetic valves, the sulfoxide, followed by storage at −196◦ C (124).
normal extrusion of calcium ions is disrupted, Pathologic evaluation of implanted cryopre-
and the relatively high concentrations of served allograft valves demonstrates an absence
calcium in the vicinity of the high phosphorus– of viable cells, a loss of distinct normal struc-
containing cell membranes and other structural features, and progressive collagen degen-
tures induce nucleation of calcium-phosphorus eration. Although the pathological changes in

a b
c
5 μm
d Mechanical damage Chemical cross-linking
Cells and cell fragments in

bioprosthetic tissue
Calcium in blood and
interstitial fluid
Increase in calcium influx Increase in Decrease in calcium efflux

due to membrane damage intracellular calcium due to membrane pump
inactivation
Existing phosphorus,
largely in cell membranes Loss of mineralization
inhibitors
Calcium phosphate
crystal nucleation
Host factors Mechanical deformation
Crystal growth
Independent
mineralization of
collagen and elastin
Valve failure, with

tearing or stenosis
174 Schoen
allograft valves are largely analogous to those valves in the pediatric population is their fail-
of the bioprosthetic valves described above, the ure to repair, remodel, and grow. The evolu-
loss of viable VICs and other changes result not tion in the scientific knowledge of heart valves
from chemical cross-linking but from prepara- in recent years has stimulated and, indeed, has
tion ischemia and/or cryopreservation and han- been stimulated by the holy grail of the heart
dling damage. Immunologically mediated de- valve field: heart valve replacements that have
struction has not been documented as a general viable cellular components (VECs and VICs),
mechanism of degradation. As in chemically repair ECM damage that occurs during rou-
preserved bioprosthetic valves, the collagenous tine function, adapt to changing environmental
network is largely preserved but (owing to the conditions, and potentially grow (2, 3). Inno-
absence of viable VICs) is incapable of remodel- vative work toward this objective, often termed
ing. Failure of allograft valves on the left side of tissue engineering, is under way in many lab-
the heart is generally caused by cuspal stretch- oratories and may eventually lead to clinical
ing or fibrosis; in contrast, right-sided valves in application, despite many technical and other
children usually suffer from stenosis as a result challenges (125,126).
of somatic growth of the recipient, with or with- A widely studied paradigm of tissue en-
out calcification of the cusps or distal aortic wall. gineering to facilitate valve regeneration
Replacement of a diseased AV by surgi- uses cells that are preseeded on a synthetic,

cal transfer of an individual’s PV to the aortic biodegradable polymer scaffold fabricated in
site (PV-to-AV autograft) is occasionally per- the shape of a trileaflet valve and matured in
formed, particularly to treat younger patients vitro in a controlled metabolic and mechanical
with AV disease. Pulmonary autograft valves in environment (that is, in a bioreactor) (3, 126).
place for up to six years have near-normal tril- The goal is for the cells to differentiate, prolif-
aminar and ECM architecture as well as viable erate, and produce ECM to form a living tissue
VECs and VICs, and they may permit growth model known as a construct. Subsequently, the
of the autograft proportional to the somatic construct would be implanted orthotopically
growth of a child or young adult (65). Heart as a valve prosthesis, and further remodeling
valves from orthotopic whole-heart transplants in vivo would recapitulate the normal tissue
also appear normal (124). functional architecture. Key processes occur-
ring during the in vitro and in vivo phases of
tissue formation and maturation would be:
(a) cell proliferation, sorting, and differenti-
HEART VALVE TISSUE ation; (b) ECM synthesis and organization;
ENGINEERING AND (c) biodegradation of the polymer scaffold;
REGENERATION (d ) remodeling; and potentially, (e) growth of
A fundamental problem inherent to the use of the tissue commensurate with the growth of
existing mechanical and biological substitute the individual.
←−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−
Figure 4
Initiation of bioprosthetic valve calcification in structural tissue elements. (a) Gross photograph of an
explanted porcine bioprosthetic valve that failed because of calcification and cuspal tearing.
(b) Photomicrograph of the edge of a calcific deposit in an experimental porcine aortic valve bioprosthesis,
demonstrating both round and streak-like calcific densities that represent calcification initiated in cells (large
arrow) and collagen (small arrow), respectively. Original magnification: 400× (von Kossa stain: calcium
phosphates stained brown-black). (c) Transmission electron microscopy photomicrograph of cell
fragment–associated calcific deposits (arrows). (d ) Proposed mechanistic model of calcification in
bioprosthetic heart valve tissue. Panels a and b reproduced with permission from Reference 114. Panel c
reproduced with permission from Reference 118. Panel d reproduced with permission from Reference 116.

a b
c d e
Figure 5
Tissue-engineered heart valves in vitro and in vivo. (a) Gross photo of tissue-engineered heart valve after
14 days of conditioning the cell-seeded polymeric scaffold in a bioreactor (in vitro). (b) Cross section of tissue
forming around the scaffold in a cuspal construct following in vitro fabrication and prior to implantation.
(c–e) Photomicrographs of heart valve cusps in vivo, demonstrating evolution to near-normal structure after
16–20 weeks. (c) At six weeks, there is early organization of tissue predominantly in the outer (outflow) layer
(top). Magnification: 50×. (d ) Cross section of leaflet at 16 weeks showing layered cellular fibrous tissue,
which is more dense near the outflow surface (top). Original magnification: 100×. (e) Cross section of leaflet
at 20 weeks, demonstrating collagen ( yellow), glycosoaminoglycans (blue), and elastin (arrow indicates the
inflow surface). Original magnification: 100×. The slides in panels b–d are stained with hematoxylin and eosin;
the slide in panel e is a Movat stain. Reproduced with permission from Reference 127.
Tissue-engineered heart valves grown as processes that occur during both morphogene-
valved conduits from autologous cells (derived sis and physiologic valve remodeling (described
from vascular wall or bone marrow) seeded on above) (2, 66, 126). This approach has been
biodegradable synthetic polymers and matured used clinically to produce pulmonary arterial
in vitro have functioned in the pulmonary cir- wall replacements to repair complex congenital
culation of growing lambs for up to five months heart disease in children (129). Other ap-
(Figure 5) (127, 128) and have evolved into proaches to engineer living tissue heart valves
functionally appropriate structures that mimic are also being investigated; these approaches
the complex architecture of native semilunar include a strategy termed guided tissue regen-
valves. Moreover, the progression of the cell eration (130), in which an implanted scaffold
and ECM changes is analogous to some key of degradable biomaterial or a decellularized,
176 Schoen
nonaldehyde-fixed or otherwise chemically CONCLUSIONS

preserved valve is designed to attract en-
dogenous circulating endothelial and other There has been considerable recent progress in
precursor cells and provide a fertile envi- our understanding of the dynamic pathophys-
ronment for their adherence, growth, and iologic basis of heart valve function and adap-
differentiation. Decellularized tissue scaffolds tation; the pathologic basis, pathobiology, and
derived from valve (in some cases with in vitro genetic aspects of common valvular lesions; and
reendothelialization performed prior to im- novel approaches to tissue-engineered valve re-
plantation of the valve) have been successfully pair and therapeutic regeneration. Elucidation
used in clinical studies in the pulmonary po- of the integrated functional roles of valvular
sition (131) but have had problems in systemic matrix and resident cells and the effects of their
circulation (132). Thus, despite the exciting mechanical and chemical environment has been
possibility of therapeutic regeneration of the critical. Investigators hope that the key con-
heart valves, immense technical, regulatory, cepts that unify the dynamic pathobiology of
and other challenges remain before this form heart valves and the mechanisms of heart valve
of therapy can be validated as sufficiently safe disease can be used to improve biologic valve
and effective to warrant translation to clinical substitutes and potentially to enable heart valve
regeneration.
use (125, 126, 133).
FUTURE ISSUES
1. What are the relative roles of genetics, mechanical factors, and extravalvular cells and
regulatory factors in heart valve morphogenesis, postdevelopmental valve maturation
and homeostasis?
2. What are the principles and regulatory factors in VIC loss, proliferation, and recruitment
and VIC-matrix interactions in health and disease?
3. How are structural changes transduced or regulated by VICs in the adaptive response to
mechanical stimulation of immature and mature heart valves?
4. What determines the asymmetry between architectural features, gene expression, and
pathophysiology across the thickness of the valve cusps and leaflets?
5. What is the role of the valvular endothelium in heart valve function, remodeling, pathol-
ogy, and tissue engineering?
6. What are the events and mechanisms of in vivo remodeling of heart valve constructs en-
gineered in vitro? Does in vitro tissue formation prior to implantation make a difference?
7. Does engineered valve tissue have the capacity to grow? If so, what factors regulate
growth?
8. What are the most relevant animal models in which to study heart valve remodeling,
pathology, and tissue-engineering strategies?
DISCLOSURE STATEMENT
The author is and/or has been a consultant to Celxcel, Corazon, Cordis, Direct Flow Medical,
Ethicon, Edwards Lifesciences, Medtronic, Pi-R-Square, Sadra Medical, Sorin Medical, St. Jude
Medical, and Sulzer Carbomedics during the past five years.

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• Top downloaded articles

Annu. Rev. Pathol. Mech. Dis. 2012. 7:161–83 Keywords

The Annual Review of Pathology: Mechanisms of Abstract

INTRODUCTION cles to the atria during systole, when blood is

both normally functioning and pathological.

cusps come together at the aortic wall. Between

www.annualreviews.org • Cardiac Valve Mechanisms 163

internal rearrangements and cushions local boresistance, inﬂammation, and maintenance

www.annualreviews.org • Cardiac Valve Mechanisms 165

Circulating endothelial cell

Mediate calcification (myofibroblast-like) VICs

www.annualreviews.org • Cardiac Valve Mechanisms 167

Congenital valve abnormalities

Incomplete cusp/commissure formation;

Valve stiffening and decreased Gross calcific nodules, begin near

Progressive collagen alignment Calcification of individual VICs,

Healthy, responsive VECs, VICs, and ECM

VECs of normal valve maintain

normal valve are quiescent and mediate

Myxomatous mitral valve Rheumatic valve

Weakening/stretching of leaflet; Transmural, postinflammatory

disrupted fibrillar ECM; fibrosis; disruption of layer

www.annualreviews.org • Cardiac Valve Mechanisms 169

experimental and clinical ﬁndings implicate middle-income countries inhabited by 80% of

www.annualreviews.org • Cardiac Valve Mechanisms 171

www.annualreviews.org • Cardiac Valve Mechanisms 173

d Mechanical damage Chemical cross-linking

Cells and cell fragments in

Increase in calcium influx Increase in Decrease in calcium efflux

Host factors Mechanical deformation

Valve failure, with

Replacement of a diseased AV by surgi- uses cells that are preseeded on a synthetic,

www.annualreviews.org • Cardiac Valve Mechanisms 175

nonaldehyde-ﬁxed or otherwise chemically CONCLUSIONS

use (125, 126, 133).

www.annualreviews.org • Cardiac Valve Mechanisms 177

www.annualreviews.org • Cardiac Valve Mechanisms 179

J. Am. Coll. Cardiol. 50:1205–13

www.annualreviews.org • Cardiac Valve Mechanisms 181

autosomal dominant myxomatous mitral-valve prolapse to chromosome 16p11.2–p12.1. Am. J. Hum.

autologous semilunar heart valve. Circulation 111:2783–91

www.annualreviews.org • Cardiac Valve Mechanisms 183

Contents Volume 7, 2012

Instantiating a Vision: Creating the New Pathology Department

Lessons Learned from the Gut

The Pathogenesis of Mixed-Lineage Leukemia

Caveolin-1 and Cancer Metabolism in the Tumor Microenvironment:

Pathogenesis of Plexiform Neuroﬁbroma:

Cumulative Index of Contributing Authors, Volumes 1–7 p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 497

An online log of corrections to Annual Review of Pathology: Mechanisms of Disease articles

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