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. [1]

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. [2] 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 [3] and response to injury [4] 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 stimulation. [5, 6, 7] 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 [8]), activated myofibroblasts persist.

Valvular Pathology/Pathobiology
Valvular involvement by disease causes stenosis, insufficiency (regurgitation or incompetence) or both. The most frequent etiologies of the major functional lesions are: [9]

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. [10]

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. [11] 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 osteoblastic phenotype. [12, 13, 14] 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 [15] 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. [16]

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. [17]

Heart Valve Substitution and Repair
Replacement of damaged cardiac valves by prostheses is common and often life-saving. [18] 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. [19] 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. [20] 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. [21] 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 regurgitation.

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. [22]

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 tissue.

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. [23] 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. [24] 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. [25] 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 repopulation.

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