Valvular Heart Disease
Frederick J. Schoen
Brigham & Women's Hospital
This presentation summarizes selected contributions over the past several decades by pathologists and
others to the pathological basis and improved management of valvular heart disease, including
understanding the structural basis of valve function, the pathology/pathobiology of common
naturally-occurring and iatrogenic lesions, developments in valve substitution and endovascular repair,
and novel approaches to valve repair, replacement and regeneration.
The Structural Basis of Cardiac Valve Function
Appreciation of physiologic structure-function correlations facilitates an understanding of valve
pathology and mechanisms of disease, fosters the development of improved tissue heart valve substitutes
and informs innovative approaches to heart valve repair and regeneration. 
The cardiac valves permit unidirectional flow of blood without causing obstruction or regurgitation,
trauma to blood elements, thromboembolism, or excessive mechanical stress in the cusps and leaflets.
Normal valve function requires structural integrity and coordinated interactions among multiple critical
components -- for semilunar valves (aortic and pulmonary): the cusps, commissures, and their respective
supporting structures in the aortic and pulmonary roots; for atrioventricular valves (mitral and
tricuspid): the leaflets, commissures, annulus, chordae tendineae (tendinous cords), papillary muscles,
and the atrial and ventricular myocardium.
The aortic valve (the most extensively studied, most frequently diseased, and most widely transplanted
valve) best illustrates the essential concepts.  Forming a nearly circular orifice when open
during ventricular systole, aortic valve cusps close rapidly and completely under minimal reverse
pressure. Despite the pressure differential across the closed valve, which imposes a large mechanical
load on the cusps, cuspal prolapse is prevented by substantial cuspal coaptation. The cusps provide
mutual support by the stretching of a microscopically inhomogeneous architecture consisting of
well-defined tissue layers, each of which is enriched in a specific extracellular matrix (ECM)
component. For the aortic valve, the thin layer closest to the left ventricular chamber (ventricularis) is comprised predominantly of collagen with radially aligned
elastic fibers. This layer enables the cusps to have minimal surface area when the valve is open stretch
in response to the backpressure of the closed phase to maximize coaptation area. The central layer of
the aortic valve cusp (spongiosa) is composed of loosely arranged collagen
and abundant glycosoaminoglycan, and has negligible structural strength, but accommodates the shape
changes of the cusp during the cardiac cycle. The fibrosa is a thick
fibrous layer, which is composed predominantly of circumferentially, aligned, densely packed collagen
fibers, largely arranged parallel to the cuspal free edge. The fibrosa
provides strength and stiffness, minimizes sagging of the cusp centers, and thus prevents regurgitation.
The geometry of the whole valve and the fibrous network within the cusps effectively transfer the
stresses induced by diastolic backpressure (approximately 80 mm Hg) to the annulus and aortic wall.
The principal determinant of valve durability is valvular ECM, and its quantity and quality depend on
viability and function of valvular interstitial cells
(VIC), the cells that are present in abundance in the valve tissue and which synthesize the
several types of valvular ECM molecules. To maintain integrity and pliability, the aortic valve must
undergo constant physiologic remodeling that entails degradation and reorganization of its ECM mediated
by matrix degrading enzymes such as matrix metalloproteinases (MMPs). Basic investigation of the
mechanisms of heart valve development  and response to injury  have shown that
valvular cells have remarkably plasticity, and that dramatic phenotypic modulation can occur in fully
mature valves. Although interstitial cells are fibroblast-like in normal valves, VIC become activated
and mediate functional biomechanical adaptation of valves when they are exposed to environmental
When stimulated by mechanical loading and other environmental stimuli (as
in valve development, adaptation, pathology and substitution), VIC become activated to a myofibroblast
phenotype and mediate connective tissue remodeling to restore the normal stress profile in the tissue.
When equilibrium is restored, the cells return to the quiescent state. However, when equilibrium is not
achieved, as in myxomatous valves (see below ), activated myofibroblasts persist.
Valvular involvement by disease causes stenosis, insufficiency (regurgitation or incompetence) or
both. The most frequent etiologies of the major functional lesions are: 
| mitral stenosis || rheumatic heart disease|
| mitral insufficiency || myxomatous degeneration (mitral valve prolapse)|
| aortic stenosis || calcification of anatomically normal and congenitally bicuspid aortic valves|
| aortic insufficiency || dilation of the ascending aorta, related to hypertension and aging.|
Calcific Aortic Stenosis
Aortic stenosis, the most frequent of all valvular abnormalities, can be congenital (when the valvular
obstruction is present from birth) or acquired. Acquired aortic stenosis
is usually the consequence of calcification intrinsic to the cuspal tissue owing to progressive and
advanced age-associated "wear and tear" of either previously anatomically normal aortic valves or
congenitally bicuspid valves (BAV, in approximately 1 percent of the population). With the rising
average age of the population the prevalence of aortic stenosis, estimated at 2%, is increasing. With
the decline in the incidence of rheumatic fever in North America, rheumatic aortic stenosis now accounts
for less than 10% of cases of acquired aortic stenosis. Although BAVs usually have normal hemodynamics
at birth and in early life, they are predisposed to progressive calcification. Aortic stenosis comes to
clinical attention primarily in the sixth to seventh decades of life with BAV but not until the eighth
and ninth decades with previously normal valves. BAV may also become incompetent as a result of aortic
dilation, cusp prolapse or infective endocarditis.
In calcific aortic stenosis (superimposed on a previously normal or BAV) the obstruction to left
ventricular outflow leads to a gradually increasing pressure gradient across the calcified valve, to 75
to 100 mm Hg in severe cases (valve area 0.5-1 cm2; normal approximately 4 cm2).
Cardiac output is maintained by the development of concentric left ventricular (pressure overload)
hypertrophy. Eventually, cardiac decompensation may ensue. The onset of symptoms (angina, CHF, or
syncope) heralds the exhaustion of compensatory cardiac hyperfunction and carries a poor prognosis (for
example, 50% with dyspnea will die within 2 years) if not treated by surgery. 
The mechanisms of aortic valve calcification are traditionally believed to be due to degenerative,
dystrophic and passive accumulation of hydroxyapatite mineral in the setting of sclerosis. 
However, recent studies suggest active regulation of calcification in aortic valves similar to that in
atherosclerotic arteries, with inflammation, lipid infiltration, and phenotypic modulation of VIC to an
Interestingly, statin drugs may decrease the rate of aortic
stenosis progression, not explained simply by changes in plasma lipids.
Myxomatous Degeneration of the Mitral Valve
(Mitral valve prolapse)
Estimated to affect 1-3% or more of adults in the United States  and usually an incidental
finding on physical examination, this lesion may lead to serious complications in a small minority of
those affected. Mitral valve prolapse (MVP) is the displacement of abnormally thickened, redundant
mitral leaflet(s) into left atrium during systole, defined echocardiographically. Most patients with
mitral valve prolapse are asymptomatic, and the condition is discovered only on routine exam. However,
valves with thick leaflets (>2mm) having displacement >5mm are associated with serious
complications such as bacterial endocarditis and sudden death, and the primary indication for mitral
valve surgery is currently MVP. By the age of 70, approximately 11% of men and 6% of women with classic
MVP will need mitral valve replacement.
The basis for the changes within the valve leaflets and associated structures is unknown. However,
MVP is associated with a variety of heritable disorders of connective tissue including Marfan syndrome,
in which it is usually associated with mutations in Fibrillin-1 (FBN-1).
MVP is generally sporadic and it is unlikely that more than 1-2% of patients with MVP have an associated
connective tissue disorder. No convincing association has been found to date that sporadic MVP is
associated with FBN-1 abnormalities. The final common pathway for the development of MVP in genetic and
acquired disorders is the weakening of valvular connective tissue that leads to leaflet elongation,
thickening, and degeneration. A recently developed mouse model of MVP has suggested that TGF-β
dysregulation in connective tissue plays an important role in Marfan Syndrome-related and possibly other
forms of MVP. 
Diet-Drug Induced Valve Disease
Patients with the carcinoid syndrome often developplaque-like intimal
thickenings of the endocardium of the tricuspid valve, right ventricular flow tract, and pulmonic valve
superimposed on otherwise unaltered endocardium. The left side of the heart is usually unaffected.
These lesions are related to elaboration by carcinoid tumors of bioactive products, including serotonin,
which cause valvular endothelial cell proliferation but are inactivated by passage through the lung.
Rarely, left-sided plaques are found in patients who receive methysergide or ergotamine therapy for
migraine headaches; these serotonin analogs are metabolized to active serotonin as they pass through the
pulmonary vasculature. Left-sided but similar valve lesions, usually causing regurgitation, have been
reported to complicate the use of fenfluramine and phentermine (fen-phen), appetite suppressants used for
the treatment of obesity, which may affect systemic serotonin metabolism. Typical plaques have
proliferation of myofibroblasts-like cells in a myxoid stroma with variable vascular channels and
lymphocytic and deep fibroelastic tissue. 
Heart Valve Substitution and Repair
Replacement of damaged cardiac valves by prostheses is common and often life-saving. 
Artificial valves fall primarily into two categories— mechanical prostheses,
such as caged ball, tilting disk or hinged semicircular rigid flap valves, and tissue valves, consisting of chemically treated animal tissue, either porcine
aortic valve or bovine pericardium preserved in dilute glutaraldehyde and mounted on a prosthetic frame.
Tissue valves are flexible and function somewhat like natural semilunar valves.
Approximately 60% of substitute valve recipients develop a serious prosthesis-related complication
within 10 years postoperatively.  The frequency of total
prosthetic valve-related events is similar among valve types, but the nature
of these complications differs among types. Thromboembolic
complications comprise the major problem with mechanical valves. This necessitates long-term
anticoagulation in patients with these devices, which can induce hemorrhagic complications. Infective endocarditis is an infrequent but serious potential complication with
all types of valves. Structural deterioration uncommonly causes failure of
contemporary mechanical valves but is a major failure mode of bioprostheses, usually with calcification
and/or tearing, causing secondary regurgitation.
Cuspal mineralization and non-calcific structural damage are the major mechanisms of tissue failure
causing structural deterioration.  Experimental and clinical studies have shown that
calcification is a dystrophic process caused by reaction of calcium in the serum with the residual
phospholipids of the cells of the tissue valve matrix made non-viable by tissue treatment during valve
fabrication. New prostheses pretreated with anticalcification agents are being used in several
commercial valves, but the extent of improvement in long-term durability is not yet known.
Recent reports indicate that endovascular procedures may provide an alternative to open heart
operations. Percutaneous valve implantation is the development of a foldable heart valve that can be
mounted on an expandable stent, delivered percutaneously through standard catheter-based techniques and
implanted within a diseased valve annulus.  Other endovascular approaches include
percutaneous placement of a mitral annular constraint device in the coronary sinus and double-orifice
edge-to-edge mitral valve repair without cardiopulmonary bypass for the treatment of mitral
Heart Valve Regeneration/Tissue Engineering
Innovative work to generate a living valve replacement is active in many laboratories, and may
eventually lead to clinically applicable approaches. The long-term success of a tissue engineered (living) valve replacement will depend on the ability of its
living cellular components to assume normal function with the capacity to repair structural injury,
remodel the ECM, and potentially grow. 
In the general paradigm of tissue engineering, cells are seeded on a synthetic polymer or natural
material that serves as a scaffold and then a tissue is matured in vitro (in
a bioreactor that provides a suitable metabolic and mechanical environment),
until proliferating cells produce a sufficient amount and quality of ECM to form the construct. In the second step, the construct is implanted in the appropriate
anatomic location, where further remodeling in-vivo may occur to
recapitulate the normal functional architecture of an organ or tissue. Key processes occurring during
the in vitro and in vivo phases of tissue
formation and maturation are 1) cell proliferation, sorting and differentiation, 2) extracellular matrix
production and organization, 3) degradation of the scaffold, and 4) remodeling and potentially growth of
The heart valve tissue engineering group at Children's Hospital, Boston has fabricated and implanted
tissue-engineered valved conduits in the pulmonary arterial circulation in lambs.  Using
autologous cells and biodegradable synthetic polymers, Tissue engineered heart valves (TEHV) grown in vitro have functioned in the pulmonary circulation of growing lambs for up to
five months, and evolved to a specialized layered structure that resembles that of native semilunar
valve. These studies demonstrate that a tissue grown in vitro can function
as a valve replacement in vivo and serve as a template for remodeling of
tissue toward a structure with morphologic characteristics of native valve cusps.
An alternative tissue engineering strategy uses naturally derived biomaterials to fabricate a
functional valve. This approach differs from conventional bioprosthetic heart valves in that the
materials are not aldehyde-preserved and are designed to attract and provide a fertile environment for
the adherence and growth of circulating endothelial and other precursor cells. These have included
decellularized tissue scaffolds derived from a natural tissue source, such as valve or pericardium, or
natural degradable polymeric scaffolds, such as collagen or fibrin gel and cell-free porcine small
intestine submucosa.  Natural valve scaffolds possess desirable three-dimensional
architecture, mechanical properties, and potential adhesion/migration sites for cell ingrowth.
Decellularized porcine valves implanted in humans had some in-growth of host cells, no evidence of
calcification, a strong inflammatory response and suffered structural failure, which has inhibited them
further use.  Nevertheless, the concept is exciting in that it may eliminate the problems
associated with xenogenic cells, avoid calcification associated with glutaraldehyde fixation, and permit
investigation of a biologic matrix that would provide a matrix microenvironment suitable for cellular
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