Structure-Function Correlations in Normal Valves
Normal valve function requires structural integrity and coordinated interactions among multiple anatomical components. For the atrioventricular valves (mitral and tricuspid), these elements include leaflets, commissures, annulus, tendinous cords (chordae tendineae), papillary muscles, and the atrial and ventricular myocardium. For the semilunar valves (aortic and pulmonary), the key structures are the cusps, commissures, and their respective supporting structures in the aortic and pulmonary roots.
The anatomy of the mitral and aortic valves is illustrated in Fig. 5-13.
Normal mitral and aortic valves. In (A), opened left ventricle of the normal heart, demonstrating mitral valve and components of the mitral apparatus. (B) Aortic valve viewed from distal aspect in open (right) and closed (left) phases. (C) Normal aortic valve histology, demonstrating layered structure, including the fibrosa (f) spongiosa (s), and ventricularis (v) layers. The inflow surface is at bottom. Verhoeff van Giesen (stain for elastin, black) 150×. ([A] Reproduced with permission from Schoen FJ: Interventional and Surgical Cardiovascular Pathology: Clinical Correlations and Basic Principles. Philadelphia, WB Saunders, 1989. [B and C] Reproduced with permission from Schoen FJ, Edwards WD: Valvular heart disease: general principles and stenosis, in Silver MD, Gotlieb AI, Schoen FJ [eds]: Cardiovascular Pathology, 3rd ed. New York, Churchill Livingstone, 2001; p 402.)
Of the two leaflets of the mitral valve (see Fig. 5-13A), the anterior (also called septal, or aortic) leaflet is roughly triangular and deep, with the base inserting on approximately one-third of the annulus. The posterior (also called mural, or ventricular) leaflet, although more shallow, is attached to about two-thirds of the annulus and typically has a scalloped appearance. The mitral leaflets have a combined area approximately twice that of the annulus; they meet during systole with apposition to approximately 50% of the depth of the posterior leaflet and 30% that of the anterior leaflet. Each leaflet receives tendinous cords from both anterior and posterior papillary muscles. The mitral valve orifice is D-shaped, with the flat anteromedial portion comprising the attachment of the anterior mitral leaflet in the subaortic region. This part of the annulus is fibrous and noncontractile; the posterolateral portion of the annulus is muscular and contracts during systole to asymmetrically reduce the area of the orifice. The edges of the mitral leaflets are held in or below the plane of the orifice by the tendinous cords, which themselves are pulled from below by the contracting papillary muscles during systole. This serves to draw the leaflets to closure and maintain competence. The posterior leaflet is more delicate, has a shorter annulus-to-free-edge dimension than the anterior, and is therefore more prone to postinflammatory fibrous retraction and deformation owing to myxomatous degeneration. The posterior leaflet has distinct scallops that are designated P1, P2, P3, respectively, beginning from the anterolateral toward the posteromedial commissure. The orifice of the tricuspid valve is larger and less distinct than that of the mitral; its three leaflets (anterior, posterior, and septal) are larger and thinner than those of the mitral valve.
Although grossly less obviously complex than the mitral valve and apparatus, the aortic valve has structural complexity at several levels.60 The three aortic valve cusps (left, right, and noncoronary) attach to the aortic wall in a semilunar fashion, ascending to the commissures and descending to the base of each cusp (see Fig. 5-13B). Commissures are spaced approximately 120 degrees apart and occupy the three points of the annular crown, representing the site of separation between adjacent cusps. Behind the valve cusps are dilated pockets of aortic root, called the sinuses of Valsalva. The right and left coronary arteries arise from individual orifices behind the right and left cusps, respectively. At the midpoint of the free edge of each cusp is a fibrous nodule called the nodule of Arantius. A thin, crescent-shaped portion of the cusp on either side of the nodule, termed the lunula, defines the surface of apposition of the cusps when the valve is closed (approximately 40% of the cuspal area). Fenestrations (holes) near the free edges commonly occur as a developmental or degenerative abnormality, are generally small (<2 mm in diameter), and have no functional significance, because the lunular tissue does not contribute to separate aortic from ventricular blood during diastole. In contrast, defects in the portion of the cusp below the lunula are associated with functional incompetence; such holes also suggest previous or active infection. When the aortic valve is closed during diastole, there is a back pressure on the cusps of approximately 80 mm Hg. The pulmonary valve cusps and surrounding tissues have architectural similarity to but are more delicate than those of the corresponding aortic components, and lack coronary arterial origins.
All four cardiac valves essentially have the same microscopically inhomogeneous architecture, consisting of well-defined tissue layers, covered by endothelium. Using the aortic valve as the paradigm (see Fig. 5-13C), the ventricularis faces the left ventricular chamber, and is enriched in radially aligned elastic fibers, which enable the cusps to have minimal surface area when the valve is open but stretch during diastole to form a large coaptation area. The spongiosa is centrally located and is composed of loosely arranged collagen and abundant proteoglycans. This layer has negligible structural strength, but accommodates relative movement between layers during the cardiac cycle and absorbs shock during closure. The fibrosa provides structural integrity and mechanical stability through a dense aggregate of circumferentially aligned, densely packed collagen fibers, largely arranged parallel to the cuspal free edge. Normal human aortic and pulmonary valve cusps have few blood vessels; they are sufficiently thin to be perfused from the surrounding blood. In contrast, the mitral and tricuspid leaflets contain a few capillaries in their most basal thirds.
With specializations that include crimp of collagen fibers along their length, bundles of collagen in the fibrous layer oriented toward the commissures, and grossly visible corrugations, cusps are extremely soft and pliable when unloaded, but taut and stiff during the closed phase. Moreover, the orientation of connective tissue and other architectural elements is nonrandom in the plane of the cusp, yielding greater compliance in the radial than circumferential direction. The fibrous network within the cusps effectively transfers the stresses of the closed phase to the annulus and aortic wall. This minimizes sagging of the cusp centers, preserves maximum coaptation, and prevents regurgitation. During diastole, adjacent cusps of the aortic valve coapt over a substantial area (as much as one-third of the cuspal area). For the mitral valve, the subvalvular apparatus including tendinous cords and papillary muscles is the critical mechanism of valve competency.
Recent studies have fostered an emerging picture of how valves form embryologically, mature in the fetus, and function, adapt, maintain homeostasis, and change throughout life. These essential relationships facilitate an understanding of valve pathology and mechanisms of disease, foster the development of improved tissue heart valve substitutes, and inform innovative approaches to heart valve repair and regeneration.61
During normal development of the heart, the heart tube undergoes looping, following which the valve cusps/leaflets originate from mesenchymal outgrowths known as endocardial cushions.62 A subset of endothelial cells in the cushion-forming area, driven by a complex array of signals from the underlying myocardium, changes their phenotype to mesenchymal cells and migrates into the acellular extracellular matrix called cardiac jelly. Likely regulated by TGFβ and VEGF, the transformation of endocardial cells to mesenchymal cells is termed transdifferentiation or endothelial-to-mesenchymal transformation (EMT).
Subsequent to morphogenesis, embryonic fetal valves possess a dynamic structure composed of a nascent ECM and cells with characteristics of myofibroblasts.63 Changes in cell phenotype and ECM remodeling continue throughout human fetal and postnatal development, and throughout life, leading to ongoing changes in properties, as evidenced by increasing valve stiffness with increasing age.64
Two types of cells are present in the fully formed aortic valve: endothelial cells located superficially and interstitial cells located deep to the surface. Aortic valve endothelial cells (VEC) have a different phenotype than those in the adjacent aorta and elsewhere,65,66 but the implications of these differences are not yet known. The second cell type comprises the valvular interstitial cells (VICs). VICs have variable properties of fibroblasts, smooth muscle cells, and myofibroblasts; they maintain the valvular extracellular matrix, the key determinant of valve durability. To maintain integrity and pliability throughout life, the valve cusps and leaflets must undergo ongoing physiologic remodeling that entails synthesis, degradation and reorganization of its ECM, which depends on matrix degrading enzymes such as matrix metalloproteinases (MMPs). Although VIC are predominantly fibroblast-like in normal valves, VIC can become activated when exposed to environmental (ie, mechanical and chemical) stimulation. Activated VIC assume a myofibroblast-like phenotype and mediate connective tissue remodeling.
Pathologic Anatomy of Valvular Heart Disease
Cardiac valve operations utilizing replacement or repair usually are undertaken for dysfunction caused by calcification, fibrosis, fusion, retraction, perforation, rupture, stretching, infection, dilation, or congenital malformations of the valve leaflets/cusps or associated structures. Valvular stenosis, defined as inhibition of forward flow secondary to obstruction caused by failure of a valve to open completely, is almost always caused by a primary cuspal abnormality and is caused by a chronic disease process. In contrast, valvular insufficiency, defined as reverse flow caused by failure of a valve to close completely, may result from either intrinsic disease of the valve cusps or from damage to or distortion of the supporting structures (eg, the aorta, mitral annulus, chordae tendineae, papillary muscles, and ventricular free wall) without primary cuspal pathology. Regurgitation may appear either acutely, as with rupture of cords, or chronically, as with leaflet scarring and retraction. Both stenosis and insufficiency can coexist in a single valve. The most commonly encountered types of valvular heart disease are illustrated in Figs. 5-14 and 5-15.
Calcific aortic valve stenosis. (A) Calcific aortic valve disease causing aortic stenosis in an elderly patient, characterized by mineral deposits at basal aspect of cusps. (B) Calcification of congenitally bicuspid aortic valve, having two unequal cusps, the larger with a central raphe (arrow). (C and D) Photomicrographs of calcific deposits in calcific aortic valve disease. Hematoxylin and eosin 15×. Calcific aortic valve stenosis. (C) Nearly transmural deposits with only thin uninvolved cusp on inflow surface (at bottom). (D) Bone formation (osseous metaplasia).
Etiologies of mitral valvular disease. (A and B) Rheumatic valve disease. (A) Atrial view and (B) subvalvular aspect of valve from patient with rheumatic mitral stenosis. The valvular changes are severe, including diffuse leaflet fibrosis and commissural fusion and ulceration of the free edges of the valve, as well as prominent subvalvular involvement with distortion (arrow in [B]). (C and D) Myxomatous degeneration of the mitral valve. In (C) there is prolapse into the left atrium of a redundant posterior leaflet (arrow). (D) Surgically resected, markedly redundant myxomatous valve. Etiologies of mitral valvular disease. (E) Mitral valve lesion associated with the diet medication Phen-Fen. ([A and B] Reproduced with permission from Schoen FJ: Interventional and Surgical Cardiovascular Pathology: Clinical Correlations and Basic Principles. Philadelphia, WB Saunders, 1989.[E] Reproduced with permission from Schoen FJ, Edwards WD: Valvular heart disease: general principles and stenosis, in Silver MD, Gotlieb AI, Schoen FJ [eds]: Cardiovascular Pathology, 3rd ed. New York, Churchill Livingstone, 2001; p 402.)
Calcific Aortic Valve Stenosis
Calcific aortic stenosis (AS), the most frequent valvular abnormality requiring surgery, is usually the consequence of calcium phosphate deposition in either an anatomically normal aortic valve or in a congenitally bicuspid valve (see Fig. 5-14A,B).67 Stenotic, previously normal tricuspid valves present primarily in the seventh to ninth decades of life, while bicuspid valves with superimposed calcification generally become symptomatic earlier (usually sixth to seventh decades).68
Calcific aortic stenosis is characterized by heaped-up, calcified masses initiated in the cuspal fibrosa at the points of maximal cusp flexion (the margins of attachment); they protrude distally from the aortic aspect into the sinuses of Valsalva, inhibiting cuspal opening. However, although the ventricular surfaces of the cusps usually remain smooth, the calfic depoosits often extend close to ventricular surface (see Fig. 5-14C). The calcification process generally does not involve the free cuspal edges, appreciable commissural fusion is absent, and the mitral valve generally is uninvolved. Calcified material resembling bone is often present (see Fig. 5-14D). Aortic valve sclerosis comprises a common, earlier, and hemodynamically less significant stage of the calcification process. Nevertheless, aortic sclerosis is associated with an increase of approximately 50% in the risk of death from cardiovascular causes and the risk of myocardial infarction, even in the absence of hemodynamically significant obstruction of left ventricular outflow.69
Aortic stenosis induces a pressure gradient across the valve, which may reach 75 to 100 mg Hg in severe cases, necessitating a left ventricular pressure of 200 mg Hg or more to expel blood. Cardiac output is maintained by the development of concentric left ventricular hypertrophy secondary to the pressure overload. The onset of symptoms such as angina, syncope, or heart failure in aortic stenosis heralds the exhaustion of compensatory cardiac hyperfunction, and carries a poor prognosis if not treated by aortic valve replacement. Other complications of calcific aortic stenosis include embolization that may occur spontaneously or during interventional procedures, hemolysis, infective endocarditis, and extension of the calcific deposits into the ventricular septum causing conduction abnormalities.
Aortic valve calcification has been traditionally considered a degenerative, dystrophic, and passive process. However, recent studies suggest active regulation of calcification in aortic valves similar in some respects to that in the atherosclerotic process in arteries, with mechanisms that include inflammation, lipid infiltration, and phenotypic modulation of VIC to an osteoblastic phenotype,70 and overlapping risk factors. Similarities to atherosclerosis have stimulated interest in the possibility that statin drugs may decrease the rate of aortic stenosis progression; however, benefit of statins for AS has not been supported by clinical studies.71
Congenitally Bicuspid Aortic Valve
With a prevalence of approximately 1%, bicuspid aortic valve (BAV) is a frequent abnormality.72 The two cusps are typically of unequal size, with the larger (conjoined) cusp having a midline raphe, representing an incomplete separation or congenital fusion of two cusps. Less frequently, the cusps are of equal size (see Fig. 5-14B). Neither stenotic nor symptomatic at birth or throughout early life, BAV are predisposed to accelerated calcification; ultimately, almost all become stenotic. Aortic pathology, including dilation and/or dissection, commonly accompanies BAV. BAV and other congenital valve abnormalities underlie over two-thirds of aortic stenosis in children and almost 50% in adults. Infrequently, they become purely incompetent, or complicated by infective endocarditis, even when the valve is hemodynamically normal. Only rarely is an uncomplicated BAV encountered incidentally at autopsy.
Recent studies have confirmed previous reports of familial clustering of BAV and left ventricular outflow tract obstruction malformations, and their association with other cardiovascular malformations.73 For example, mutations in the signaling and transcriptional regulator NOTCH1 caused a spectrum of developmental aortic valve abnormalities and severe calcification in two families with nonsyndromic familial aortic valve disease.74
Mitral Annular Calcification
Calcific deposits also can develop in the ring (annulus) of the mitral valve of elderly individuals, especially women. Although generally asymptomatic, the calcific nodules may lead to regurgitation by interference with systolic contraction of the mitral valve ring or, very rarely, stenosis by impairing mobility of the mitral leaflets during opening. Occasionally, the calcium deposits may penetrate sufficiently deeply to impinge on the atrioventricular conduction system to produce arrhythmias (and rarely sudden death). Patients with mitral annular calcification have an increased risk of stroke, and the calcific nodules, especially if ulcerated, can be the nidus for thrombotic deposits or infective endocarditis.
Rheumatic fever is an acute, often recurrent, inflammatory disease that generally follows a pharyngeal infection with group A beta-hemolytic streptococci, principally in children. In the past several decades, rheumatic fever and rheumatic heart disease have declined markedly but not disappeared in the United States and other developed countries. Evidence strongly suggests that rheumatic fever is the result of an immune response to streptococcal antigens, inciting either a cross-reaction to tissue antigens, or a streptococcal-induced autoimmune reaction to normal tissue antigens.75
Chronic rheumatic heart disease most frequently affects the mitral and to a lesser extent the aortic and/or the tricuspid valves. Usually dominated by mitral stenosis,76 chronic rheumatic valve disease is characterized by fibrous or fibrocalcific thickening of leaflets and tendinous cords, and commissural and chordal fusion (see Fig. 5-15A and B). Stenosis results from leaflet and chordal fibrous thickening and commissural fusion, with or without secondary calcification. Regurgitation usually results from postinflammatory scarring-induced retraction of cords and leaflets. Combinations of lesions may yield valves that are both stenotic and regurgitant. Although considered the pathognomonic inflammatory myocardial lesions in acute rheumatic fever, Aschoff nodules are found infrequently in myocardium sampled at autopsy or at valve replacement surgery, most likely reflecting the extended interval from acute disease to critical functional impairment.
Myxomatous Degeneration of the Mitral Valve (Mitral Valve Prolapse)
Myxomatous mitral valve disease (mitral valve prolapse) causes chronic, pure, isolated mitral regurgitation.77 Owing to improved imaging technology and large community studies, a prevalence of mitral valve prolapse of approximately 2% has been established with a rate of the serious complications, including heart failure, mitral regurgitation, infective endocarditis, stroke, or other manifestation of thromboembolism, progressive congestive heart failure, sudden death, or atrial fibrillation of approximately 3%. Mitral valve prolapse is the most common indication for mitral valve repair or replacement.
In mitral valve prolapse (MVP), one or both mitral leaflets are enlarged, redundant, or floppy and will prolapse, or balloon back into the left atrium during ventricular systole (see Fig. 5-15C). The three characteristic anatomic changes in mitral valve prolapse are: (1) intercordal ballooning (hooding) of the mitral leaflets or portions thereof (most frequently involving the posterior leaflet), sometimes accompanied by elongated, thinned, or ruptured cords; (2) rubbery diffuse leaflet thickening that hinders adequate coaptation and interdigitation of leaflet tissue during valve closure; and (3) annular dilation, with diameters and circumferences that may exceed 3.5 and 11.0 cm, respectively (see Fig. 5-15D). Pathologic mitral annular enlargement predominates in and may be confined to the posterior leaflet, because the anterior leaflet is firmly anchored by the fibrous tissue at the aortic valve and is far less distensible. The key microscopic changes in myxomatous degeneration are attenuation or focal disruption of the fibrous layer of the valve, on which the structural integrity of the leaflet depends, and focal or diffuse thickening of the spongy layer by proteoglycan deposition (which gives the tissue an edematous, blue appearance on microscopy called myxomatous by pathologists).78 These changes in tissue structure and composition weaken the leaflet. Concomitant involvement of the tricuspid valve is present in 20 to 40% of cases, and the aortic and pulmonary valves also may be affected.
Secondary changes may occur, including: (1) fibrous thickening along both surfaces of the valve leaflets; (2) linear thickening of the subjacent mural endocardium of the left ventricle as a consequence of friction-induced injury by cordal hamstringing of the prolapsing leaflets; (3) thrombi on the atrial surfaces of the leaflets, particularly in the recesses behind the ballooned leaflet segments; (4) calcification along the base of the posterior mitral leaflet; and (5) cordal thickening and fusion that can resemble postrheumatic disease.
The pathogenesis of myxomatous degeneration is uncertain, but this valvular abnormality is a common feature of Marfan's syndrome and occasionally other hereditary connective tissue disorders such as Ehlers-Danlos syndrome, suggesting an analogous connective tissue defect. In these heritable disorders of connective tissue, including Marfan's syndrome, MVP is usually associated with mutations in fibrillin-1 (FBN-1); recent evidence also has implicated abnormal TGF-β signaling (similar to the aortic abnormalities in the pathogenesis of Marfan's syndrome and related disorders).79 Although it is unlikely that more than 1 to 2% of patients with MVP have an identifiable connective tissue disorder, studies utilizing genetic linkage analysis have mapped families with autosomal dominant mitral valve prolapse to specific chromosomal abnormalities, several of which involve genes that could be involved in valvular tissue remodeling.
Ischemic Mitral Regurgitation
In ischemic mitral regurgitation (IMR), also called functional mitral regurgitation, the leaflets are intrinsically normal, whereas myocardial structure and function are altered by ischemic injury.80 Present in 10 to 20% of patients with coronary artery disease, IMR worsens prognosis following myocardial infarction, with reduced survival directly related to the severity of the regurgitation. Mechanisms of IMR include an ischemic papillary muscle that fails to tighten the cords during systole, and fibrotic, shortened papillary muscle that fixes the chordae deeply within the ventricle. Nevertheless, papillary muscle dysfunction alone is generally insufficient to produce IMR, and regional dysfunction and dilation with an increasing spherical shape of the LV, which pulls the papillary muscles down and away from the center of the chamber, usually contributes. There is substantial interest in developing surgical and/or percutaneous approaches to the repair of ischemic mitral regurgitation.81
Carcinoid and Drug-Induced Valve Disease
Patients with the carcinoid syndrome often develop plaquelike intimal thickenings of the endocardium of the tricuspid valve, right ventricular outflow tract, and pulmonary valve superimposed on otherwise unaltered endocardium.82 The left side of the heart is usually unaffected. These lesions are related to elaboration by carcinoid tumors (most often primarily in the gut) of bioactive products, including serotonin, which cause valvular endothelial cell proliferation but are inactivated by passage through the lung.
Left-sided but similar valve lesions, have been reported to complicate the administration of fenfluramine and phentermine (fen-phen), appetite suppressants used for the treatment of obesity, which may affect systemic serotonin metabolism (see Fig. 5-15E).83 Typical diet drug-associated plaques have proliferation of myofibroblast-like cells in a myxoid stroma. Similar left-sided plaques may be found in patients who receive methysergide or ergotamine therapy for migraine headaches; these serotonin analogs are metabolized to serotonin as they pass through the pulmonary vasculature. Moreover, drug-related valve disease has been reported in patients taking pergolide mesylate, an ergot-derived dopamine receptor agonist used to treat Parkinson's disease and restless leg syndrome.84
Infective endocarditis is characterized by colonization or invasion of the heart valves, mural endocardium, aorta, aneurysmal sacs, or other blood vessels, by a microbiologic agent, leading to the formation of friable vegetations laden with organisms (Fig. 5-16).85 Although virtually any type of microbiologic agent can cause infective endocarditis, most cases are bacterial.
Infective (bacterial) endocarditis. (A) Endocarditis of mitral valve with damage to the anterior mitral leaflet. (B) Acute endocarditis of congenitally bicuspid aortic valve (caused by Staphylococcus aureus), with large vegetation, causing extensive cuspal destruction and ring abscess (arrow). ([B] Reproduced with permission from Schoen FJ: Interventional and Surgical Cardiovascular Pathology: Clinical Correlations and Basic Principles. Philadelphia, WB Saunders, 1989.) Infective (bacterial) endocarditis. (C) Photomicrograph of vegetation, showing extensive acute inflammatory cells and fibrin. Bacterial organisms were demonstrated by tissue Gram stain. ([C] Reproduced with permission from Schoen FJ. Surgical pathology of removed natural and prosthetic heart valves. Human Pathol 1987; 18:558.) (D) Healed endocarditis, demonstrating aortic valvular destruction but no active vegetations on a congenitally bicuspid aortic valve.
The clinical classification into acute and subacute forms is based on the range of severity of the disease and its tempo, on the virulence of the infecting microorganism, and presence of underlying cardiac disease. Acute endocarditis is a destructive infection by a highly virulent organism, often involving a previously normal heart valve and leading to death within days to weeks in more than 50% of patients if left untreated. In contrast, in a more indolent lesion, called subacute endocarditis, organisms of low virulence cause infection on previously deformed valves; in this situation, the infection may pursue a protracted course of weeks to months during which the infection may be undetected and untreated.
The modified Duke criteria provide a standardized assessment of patients with suspected infective endocarditis that integrates factors predisposing patients to the development of infective endocarditis, blood-culture evidence of infection, echocardiographic findings, and clinical and laboratory information.86 The previously important clinical findings of petechiae, subungual hemorrhages, Janeway's lesions, Osler's nodes, and Roth's spots in the eyes (secondary to retinal microemboli) have now become uncommon owing to the shortened clinical course of the disease as a result of antibiotic therapy.
Vegetations composed of fibrin, inflammatory cells, and organisms are the hallmark of endocarditis. Staphylococcus aureus is the leading cause of acute endocarditis and produces necrotizing, ulcerative, invasive, and highly destructive valvular infections. The subacute form is usually caused by Streptococcus viridans. Cardiac abnormalities, such as chronic rheumatic heart disease, congenital heart disease (particularly anomalies that have small shunts or tight stenoses creating high-velocity jet streams), myxomatous mitral valves, bicuspid aortic valves, and artificial valves and their sewing rings predispose to endocarditis. In intravenous drug abusers, left-sided lesions predominate, but right-sided valves are commonly affected. In about 5 to 20% of all cases of endocarditis, no organism can be isolated from the blood (culture-negative endocarditis), often because of prior antibiotic therapy or organisms difficult to culture.87
The complications of endocarditis include valvular insufficiency (rarely stenosis), abscess of the valve annulus (ring abscess), suppurative pericarditis, and embolization. With appropriate antibiotic therapy, vegetations may undergo healing, with progressive sterilization, organization, fibrosis, and occasionally calcification. Cusp or leaflet perforation, cordal rupture, or fistula formation from a ring abscess into an adjacent cardiac chamber or great vessel can cause regurgitation. Ring abscesses are generally associated with virulent organisms, and a relatively high mortality rate.
Valve Reconstruction and Repair
Reconstructive procedures to repair mitral insufficiency of various etiologies and to minimize the severity of rheumatic mitral stenosis are now highly effective and commonplace. A recent survey of practice in the United States showed that 69% of mitral valve operations for mitral regurgitation currently use repairs.88 Reconstructive therapy of selected patients with aortic insufficiency and aortic dilation may also be done occasionally, but repair of aortic stenosis has been notably less successful. The major advantage of repair over replacement relates to the elimination of both prosthesis-related complications and the need for chronic anticoagulation therapy. Other reported advantages include a lower hospital mortality, better long-term function owing to the ability to maintain the continuity of the mitral apparatus, and a lower rate of postoperative endocarditis. Figures 5-17 and 5-18 illustrate the pathologic anatomy of various open and catheter-based mitral valve reconstruction procedures. Figure 5-19 illustrates the difficulty of surgical repairs for aortic stenosis.
Open surgical reconstructive procedures for mitral valve disease. (A) Mitral commissurotomy in mitral stenosis; incised commissures are indicated by arrows. (B) Mitral valve repair with annuloplasty ring. (C) Dehiscence of mitral annuloplasty ring (arrow). (D) ePTFE suture replacement (arrow) of ruptured cord in myxomatous mitral valve. ([A] Reproduced with permission from Schoen FJ, St. John Sutton M: Contemporary issues in the pathology of valvular heart disease. Hum Pathol 1987; 18:568. Copyright WB Saunders, 1987. [C] Courtesy of William A. Muller, MD, PhD, Northwestern University School of Medicine, Chicago. [D] Reproduced with permission from Schoen FJ, Edwards WD: Valvular heart disease: general principles and stenosis, in Silver MD, Gotlieb AI, Schoen FJ [eds]: Cardiovascular Pathology, 3rd ed. Churchill Livingstone, 2001; p 402.)
Percutaneous correction of mitral regurgitation. (A) Schematic approach utilizing the proximity of the coronary sinus to the posterior mitral annulus to effect a simulated annuloplasty. Diagram showing the relationship of the coronary sinus and the posterior leaflet of the mitral valve. A remodeling device is seen within the coronary sinus. (B) The Monarc device consists of two anchoring stents with a bridge connector that shortens approximately 25% over the space of weeks with the intention of reducing the dimensions of the mitral annulus. Percutaneous correction of mitral regurgitation. (C and D) Edge-to-edge approximation of the anterior and posterior leaflets of the mitral valve is achieved by deployment of clip (Evalve mitral clip device) that is analogous to an Alfieri stitch, thereby creating a double orifice with improved leaflet coaptation. (Reproduced with permission from Schoen FJ, Webb JG: Prosthetics and the heart, in McManus BM, Braunwald E [eds]: Atlas of Cardiovascular Pathology for the Clinician. Philadelphia, Current Medicine, 2008; pp 241-256.)
Reconstructive procedures for aortic stenosis. (A) Aortic valve balloon valvuloplasty for degenerative calcific aortic stenosis, demonstrating fractures of nodular deposits of calcifications highlighted by tapes. [B and C] Operative decalcification of the aortic valve. (B) Aortic valve after operative mechanical decalcification demonstrating perforated cusp. (C) Low-power photomicrograph of cross-section of aortic valve cusp after decalcification with lithotripter. Weigert elastic stain. Ca = calcium. ([A] Reproduced with permission from Schoen FJ, Edwards WD: Valvular heart disease: general principles and stenosis, in Silver MD, Gotlieb AI, Schoen FJ [eds]: Cardiovascular Pathology, 3rd ed. New York, Churchill Livingstone, 2001; p 402. [B and C] Reproduced with permission from Schoen FJ: Interventional and Surgical Cardiovascular Pathology: Clinical Correlations and Basic Principles. Philadelphia, WB Saunders, 1989.)
Percutaneous endovascular repair approaches to valvular heart disease include balloon valvuloplasty, 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. Catheter-based endovascular valve repair is most likely to be used in patients with severe disease deemed inoperable and in patients with early-stage regurgitant lesions in whom valve repair may prevent progressive ventricular dilation. Percutaneous transluminal balloon dilation of stenotic valves has been used successfully to relieve some congenital and acquired stenoses of native pulmonary, aortic, and mitral valves, and stenotic right-sided porcine bioprosthetic valves.
Commissurotomy may be employed in the operative repair of some stenotic mitral valves in which fibrosis and shortening of both cords and leaflets have markedly decreased leaflet mobility and area. Factors that compromise the late functional results of or technically prevent mitral commissurotomy and thereby necessitate valve replacement include: (1) left ventricular dysfunction; (2) pulmonary venous hypertension and right-sided cardiac factors, including right ventricular failure, tricuspid regurgitation, or a combination of these; (3) systemic embolization; (4) coexistent cardiac disorders, such as coronary artery or aortic valve diseases; (5) residual or progressive mitral valve disease, including valve restenosis, residual (unrelieved) stenosis, or regurgitation induced at operation; (6) advanced leaflet (especially commissural) calcification; (7) subvalvar (predominantly chordal) fibrotic changes; and (8) significant regurgitation owing to retraction.
Percutaneous balloon mitral valvuloplasty has been used to treat mitral stenosis for over two decades, with excellent success in patients with suitable valvular and subvalvular morphology.89 However, because balloon valvuloplasty largely involves separation of the fused leaflets at the commissures, this procedure is also unlikely to provide significant benefit to patients with the valve features summarized in the preceding obviating surgical commissurotomy.
Reconstructive techniques are widely used to repair mitral valves with nonrheumatic mitral regurgitation.90–92 Structural defects responsible for chronic mitral regurgitation include: (1) dilation of the mitral annulus; (2) leaflet prolapse into the left atrium with or without elongation or rupture of chordae tendineae; (3) redundancy and deformity of leaflets; (4) leaflet perforations or defects; and (5) restricted leaflet motion as a result of commissural fusion in an opened position, and leaflet retraction, or chordal shortening or thickening.
Following surgical resection of excess anterior or posterior leaflet tissue in valves with redundancy, annuloplasty with or without a prosthetic ring is used to reduce the annulus dimension to correspond to the amount of leaflet tissue available. Edge-to-edge (Alfieri stitch) mitral valve repair has also been used.93 Tissue substitutes such as glutaraldehyde-pretreated xenograft or autologous pericardium can be used to repair or enlarge leaflets. Ruptured or elongated cords may be repaired by shortening or replacement with pericardial tissue or thick suture material.
Percutaneous approaches currently being evaluated for mitral regurgitation attempt to emulate one or more of the components of surgical mitral valve repair, including annular reduction and edge-to-edge mitral leaflet apposition.94 However, leaflet resection and cordal modification cannot be easily done via catheter, and there is considerable anatomical variability of the coronary sinus.95 Percutaneous approaches in various stages of development and clinical evaluation include implantation of a device in the coronary sinus, left atrium (or both), or by device placement behind the posterolateral leaflet of the mitral valve (see Fig. 5-18A and B). The goal is to plicate or straighten the posterior mitral annulus. Additional annuloplasty approaches, presently in preclinical testing, include a suture annuloplasty from the ventricular side of the mitral annulus, thermal modification of the annulus to obtain shrinkage, and a percutaneous ventricular restraint system that attempts to reshape the left ventricle. Another catheter-based approach uses an edge-to-edge clip prosthesis simulating the edge-to-edge surgical (Alfieri stitch) repair in which the midportions of the anterior and posterior mitral leaflets are clipped together (see Fig. 5-18C and D).
In balloon dilation of calcific aortic stenosis, individual functional responses vary considerably and data suggest a modest early incremental benefit, high early mortality, and high restenosis rate. Improvement derives from commissural separation, fracture of calcific deposits, and stretching of the valve cusps (see Fig. 5-19A). The major complications include cerebrovascular accident secondary to embolism, massive regurgitation owing to valve trauma, and cardiac perforation with tamponade. Fractured calcific nodules can themselves prove dangerous.96 In pediatric cases in which the cusps are generally pliable, cuspal stretching, tearing, or avulsion may also occur.
In calcific aortic stenosis the calcific deposits arise deep in the valve fibrous layer (see Fig. 5-14C). Their removal by sharp dissection or ultrasonic debridement generally removes a considerable fraction of the valve substance, resulting in severe compromise of mechanical integrity (see Fig. 5-19B and C).97
Severe symptomatic valvular heart disease other than pure mitral stenosis or incompetence is most frequently treated by excision of the diseased valve(s) and replacement by a functional substitute. Five key factors determine the results of valve replacement in an individual patient: (1) technical aspects of the procedure; (2) intraoperative myocardial ischemic injury; (3) irreversible and chronic structural alterations in the heart and lungs secondary to the valvular abnormality; (4) coexistent obstructive coronary artery disease; and (5) valve prosthesis reliability and host-tissue interactions.
Valve Types and Prognostic Considerations
Cardiac valvular substitutes are of two types, mechanical and biologic tissue (Fig. 5-20 and Table 5-2).98,99 Prostheses function passively, responding to pressure and flow changes within the heart. Mechanical valves are composed of nonphysiologic biomaterials and employ a rigid, mobile occluder (composed of pyrolytic carbon in contemporary valves), in a metallic cage (cobalt-chrome or titanium alloy) as in the Bjork-Shiley, Hall-Medtronic, or Omniscience valves, or two carbon hemidisks in a carbon housing (as in the St. Jude Medical, CarboMedics CPHV, and On-X prostheses). Pyrolytic carbon has high strength and fatigue and wear resistance and good thromboresistance. Tissue valves resemble natural semilunar valves, with pseudoanatomical central flow and biological material. In the past decade, innovations in tissue valve technologies and design have expanded indications for their use. Contemporary utilization of bioprosthetic tissue valves is estimated to be about 80% of all aortic and 69% of all mitral substitute heart valves.99–101 Most tissue valves are bioprosthetic xenografts fabricated from porcine aortic valve or bovine pericardium, which have been preserved in a dilute glutaraldehyde solution, and a small percentage are cryopreserved allografts.
Photographs of the widely used types of heart valve substitutes. (A) Bileaflet tilting disk mechanical heart valve (St. Jude Medical, St. Jude Medical Inc., St. Paul, MN). (B) Porcine aortic valve bioprosthesis (Hancock, Medtronic Heart Valves, Santa Ana, CA). (C) Bovine pericardial bioprosthesis (Carpentier-Edwards, Edwards Life Sciences, Santa Ana, CA). (From Cardiovasc Pathol 1995; 4:241, and Schoen FJ: Pathology of heart valve substitution with mechanical and tissue prostheses, in Silver MD, Gotlieb AI, Schoen FJ [eds]: Cardiovascular Pathology, 3rd ed. New York, Churchill Livingstone, 2001; p 629.)
Table 5-2 Types and Characteristics of Commonly Used Substitute Heart Valves* ||Download (.pdf)
Table 5-2 Types and Characteristics of Commonly Used Substitute Heart Valves*
|Valve type||Model(s)||Hemodynamics||Freedom from thrombosis/thromboembolism||Durability|
|Single tilting disk||Bjork-Shiley|
|Bileaflet tilting disk||St. Jude Medical||+++||+++||+++‡|
|Heterograft/xenograft bioprostheses||Carpentier-Edwards (porcine and bovine pericardial)||++||+++||++|
|Hancock (porcine) lonescu-Shiley (bovine pericardial)|
|Mitroflow (bovine pericardial)|
|Homograft/allograft||Cryopreserved human aortic/pulmonary valve||++++||++++||++|
In a recent compilation of risk models of isolated valve surgery by the Society for Thoracic Surgeons, the overall mortality was 3.4% (3.2% aortic and 5.7% mitral) and varied strongly with case mix.102 The majority of early deaths are caused by hemorrhage, pulmonary failure, low cardiac output, and sudden death with or without myocardial necrosis or documented arrhythmias. Potential complications related to mitral valve insertion include hemorrhagic disruption and dissection of the atrioventricular groove, perforation or entrapment of the left circumflex coronary artery by a suture, and pseudoaneurysm or rupture of the left ventricular free wall.
Improvement in late outcome has occurred predominantly from earlier referral of patients for valve replacement, decreased intraoperative myocardial damage, improved surgical technique and enhanced valve prostheses. Following valve replacement with currently used devices, the probability of 5-year survival is about 80% and of 10-year survival about 70%, depending on overall functional state, preoperative left ventricular function, left ventricular and left atrial size, and extent and severity of coronary artery disease.
Although early prosthetic valve–associated complications are unusual, prosthetic valve–associated pathology becomes an important consideration beyond the early postoperative period. Late death following valve replacement results predominantly from either cardiovascular pathology unrelated to the substitute valve or prosthesis-associated complications. In the few randomized studies of mechanical prosthetic and bioprosthetic valves (comprising Bjork-Shiley mechanical and porcine aortic bioprosthetic valves), approximately 60% or more patients had an important device-related complication within 10 years postoperatively. Moreover, long-term survival was better among patients with a mechanical valve, but with an increased risk of bleeding.103,104 Valve-related complications frequently necessitate reoperation, now accounting for approximately 10 to 15% of all valve procedures, and they may cause death. Four categories of valve-related complications are most important: thromboembolism and related problems, infection, structural dysfunction (ie, failure or degeneration of the biomaterials comprising a prosthesis), and nonstructural dysfunction (ie, miscellaneous complications and modes of failure not encompassed in the previous groups) (Table 5-3).105
Table 5-3 Complications of Substitute Heart Valves ||Download (.pdf)
Table 5-3 Complications of Substitute Heart Valves
|Infection||Prosthetic valve endocarditis|
|Structural dysfunction (intrinsic)|
Commisural region dehiscence
|Nonstructural dysfunction (most extrinsic)|
Pannus (tissue overgrowth)
Entrapment by suture or tissue
Thrombosis and Thromboembolism
Thromboembolic complications are the major valve-related cause of mortality and morbidity after replacement with mechanical valves, and patients receiving them require lifetime chronic therapeutic anticoagulation with warfarin derivatives.106,107 Thrombotic deposits on a prosthetic valve can immobilize the occluder(s) or cusps, or shed emboli (Fig. 5-21). Owing to their biologic material that comprises the cusps and central flow, tissue valves are less thrombogenic than mechanical valves; their recipients generally do not require long-term anticoagulation in the absence of another specific indication, such as atrial fibrillation. Nevertheless, the rate of thromboembolism in patients with mechanical valves on anticoagulation is not widely different from that in patients with bioprosthetic valves without anticoagulation (2 to 4% per year). Chronic oral anticoagulation also carries a risk of hemorrhage. Anticoagulation is particularly difficult to manage in pregnant women.108 The risk of thromboembolism is potentiated by preoperative or postoperative cardiac functional impairment.
Thrombotic occlusion of substitute heart valves. (A) Bileaflet tilting disk prosthesis, with thrombus initiated in the region of the pivot guard, causing near-total occluder immobility. (B) Porcine bioprosthesis, with thrombus filling the bioprosthetic sinuses of Valsalva. ([A] Reproduced with permission from Anderson JM, Schoen FJ: Interactions of blood with artificial surfaces, in Buchart EG, Bodnar E [eds]: Thrombosis, Embolism, and Bleeding. London, ICR Publishers, 1992; p 160. [B] Reproduced with permission from Schoen FJ, Hobson CE: Anatomic analysis of removed prosthetic heart valves: causes of failure of 33 mechanical valves and 58 bioprostheses, 1980 to 1983. Hum Pathol 1985; 16:549.)
“Virchow's triad” of factors promoting thrombosis (surface thrombogenicity, hypercoagulability, and locally static blood flow) largely predicts the relative propensity toward and locations of thrombotic deposits.109 For example, with caged-ball prostheses, thrombi form distal to the poppet at the cage apex. Tilting disk prostheses are particularly susceptible to total thrombotic occlusion or shedding emboli from small thrombi, with the thrombotic deposits generally initiated in a flow stagnation zone in the minor orifice of the outflow region of the prosthesis. In contrast, bileaflet tilting disk valves are most vulnerable to thrombus formation near the hinges where the leaflets insert into the housing (see Fig. 5-21A). Late thrombosis of a bioprosthetic valve is marked by large thrombotic deposits in one or more of the prosthetic sinuses of Valsalva (see Fig. 5-21B), and no causal underlying cuspal pathology can usually be demonstrated by pathologic studies. Some valve thromboemboli, especially early postoperatively with any valve type, can be initiated at the valve sewing cuff before it is healed, thus providing the rationale for early antithrombotic therapy for all types.
As with other devices in which nonphysiologic artificial surfaces are exposed to blood at high fluid shear stresses, platelet deposition dominates initial blood-surface interaction, and prosthetic valve thromboembolism correlates strongly with altered platelet function. Nevertheless, although platelet-suppressive drugs largely normalize indices of platelet formation and partially reduce the frequency of thromboembolic complications in patients with mechanical prosthetic valves, antiplatelet therapy alone is generally considered insufficient to adequately prevent thromboembolism. The lack of vascular tissue adjacent to thrombi that form on bioprosthetic or mechanical valves retards their histologic organization and may prolong the susceptibility to embolization as well as render the age of such thrombi difficult to determine microscopically. Nevertheless, this feature may allow thrombolytic therapy to be an option in some cases.110
Prosthetic Valve Endocarditis
Prosthetic valve infective endocarditis (Fig. 5-22) occurs in 3 to 6% of recipients of substitute valves.111 Infection can occur early (<60 days postoperative) or late. The microbial etiology of early prosthetic valve endocarditis is dominated by the staphylococcal species, Staphylococcus epidermidis and S. aureus, even though prophylactic regimens used today target these microorganisms. The clinical course of early prosthetic valve endocarditis tends to be fulminant, and accompanied by valvular or annular destruction or persistent bacteremia. In the generally less virulent late endocarditis, a source of infection and/or bacteremia can often be found; the most frequent initiators are dental procedures, urologic infections and interventions, and indwelling catheters. The most common organisms in these late infections are S. epidermidis, S. aureus, S. viridans, and enterococci. Rates of infection of bioprostheses and mechanical valves are similar, and previous endocarditis on a natural or substitute valve markedly increases the risk.
Prosthetic valve endocarditis. (A) Endocarditis with large ring abscess (arrow) observed from ventricular surface of aortic Bjork-Shiley tilting disk prosthesis in patient who died suddenly. Ring abscess impinged on proximal atrioventricular conduction system. (B and C) Bioprosthetic valve endocarditis viewed from inflow (B) and outflow (C) aspects. ([A] Reproduced with permission from Schoen FJ: Cardiac valve prostheses: pathological and bioengineering considerations. J Cardiac Surg 1987; 2:65.)
Infections associated with mechanical prosthetic valves and some with bioprosthetic valves are localized to the prosthesis-tissue junction at the sewing ring, and accompanied by tissue destruction around the prosthesis (see Fig. 5-22A). This comprises a ring abscess, with potential paraprosthetic leak, dehiscence, fistula formation, or heart block caused by conduction system damage. Bioprosthetic valve infections may involve, and are occasionally limited to, the cuspal tissue, sometimes causing secondary cuspal tearing or perforation with valve incompetence or obstruction (see Fig. 5-22B and C). Surgical reintervention usually is indicated for large highly mobile vegetations or cerebral thromboembolic episodes, or persistent ring abscess.
Structural Valve Dysfunction
Prosthetic valve dysfunction owing to materials degradation can necessitate reoperation or cause prosthesis-associated death (Fig. 5-23). Durability considerations vary widely for mechanical valves and bioprostheses, specific types of each, different models of a particular prosthesis (utilizing different materials or having different design features), and even for the same model prosthesis placed in the aortic rather than the mitral site. Mechanical valve structural failure is often catastrophic and may be life threatening; in contrast, bioprosthetic valve failure generally causes progressive symptomatic deterioration.
Fractures of metallic carbon components (disks or housing) are unusual in most contemporary mechanical valves.112 Fractures of bileaflet tilting disk valves are rare (see Fig. 5-23A). However, of approximately 86,000 Bjork-Shiley 60- and 70-degree Convexo-Concave heart valves implanted, a cluster of more than 500 cases has been reported in which the two attachment points of the welded outlet strut fractured because of metal fatigue, leading to disk escape and often death.113 Single leg strut fractures have been noted at a presymptomatic stage in some patients.114 In contrast, structural dysfunction of tissue valves is the major cause of failure of the most widely used bioprostheses (flexible-stent-mounted, glutaraldehyde-preserved porcine aortic valves, and bovine pericardial valves) (see Fig. 5-23B–D).115 Within 15 years following implantation, 30 to 50% of porcine aortic valves implanted as either mitral or aortic valve replacements require replacement because of structural dysfunction manifested as primary tissue failure. Cuspal mineralization is the key mechanism with regurgitation through secondary tears, the most frequent failure mode, particularly in porcine aortic bioprosthetic valves. Nevertheless, there is increasing recognition that noncalcific structural damage owing to collagen fiber disruption (independent of calcification) contributes to bioprosthetic heart valve failure.116 Pure stenosis owing to calcific cuspal stiffening occurs less frequently. Calcific deposits are usually localized to cuspal tissue (intrinsic calcification), but calcific deposits extrinsic to the cusps may occur in thrombi or endocarditic vegetations. Calcification is markedly accelerated in younger patients, with children and adolescents having an especially accelerated course. Bovine pericardial valves can also suffer tearing and calcification with abrasion of the pericardial tissue an important contributing factor in some designs.117
The morphology and determinants of calcification of bioprosthetic valve tissue have been widely studied in experimental models. The process is initiated primarily within residual membranes and organelles of the nonviable connective tissue cells that have been devitalized by glutaraldehyde pretreatment procedures, and involves reaction of calcium-containing extracellular fluid with membrane-associated phosphorus. The pathologic changes in bioprosthetic valves that occur following implantation are largely rationalized on the basis of changes induced by the preservation and manufacture of a bioprosthesis, including: (1) denudation of surface cells, including endothelial cells in porcine aortic valves, and mesothelial cells in bovine pericardium; (2) loss of viability of the interstitial cells; and (3) locking of the cuspal microstructure in a static geometry.
Extrinsic (nonstructural) complications of substitute heart valves are illustrated in Fig. 5-24. Paravalvular defects may be clinically inconsequential may aggravate hemolysis or may cause heart failure through regurgitation. Early paravalvular leaks may be related to suture knot failure, inadequate suture placement, or separation of sutures from a pathologic annulus in endocarditis with ring abscess, myxomatous valvular degeneration, or calcified valvular annulus as in calcific aortic stenosis or mitral annular calcification. Late small paravalvular leaks usually are caused by anomalous tissue retraction from the sewing ring between sutures during healing. Paravalvular defects tend to be small and difficult to locate by surgical or pathologic examination (see Fig. 5-24A).
Nonstructural dysfunction of prosthetic heart valves. (A) Paravalvular leak adjacent to mitral valve prosthesis (arrow). (B) Tissue overgrowth compromising inflow orifice of porcine bioprosthesis. (C) Tissue overgrowth incorporating and resultant retraction and obliteration of bioprosthetic valve cusps. (D) Immobility of tilting disk leaflet by impingement of retained component of submitral apparatus (arrow) that had moved through orifice late following mitral valve replacement surgery. (E) Suture (arrow) looped around central strut of a Hall-Medtronic tilting disk valve causing disk immobility. ([A and C] Reproduced with permission from Schoen FJ: Pathologic considerations in replacement heart valves and other cardiovascular prosthetic devices, in Schoen FJ, Gimbrone MA [eds]: Cardiovascular Pathology: Clinicopathologic Correlations and Pathogenetic Mechanisms. Philadelphia, Williams & Wilkins, 1995; p 194. [B] Reproduced with permission from Schoen FJ, et al: Pathologic considerations in substitute heart valves. Cardiovasc Pathol 1992; 1:29. [D] Reproduced with permission from Schoen FJ: Pathology of cardiac valve replacement, in Morse D, Steiner RM, Fernandez J [eds]: Guide to Prosthetic Cardiac Valves. New York, Springer-Verlag, 1985; p 209. Nonstructural dysfunction of prosthetic heart valves. [E] Photo courtesy of Office of the Chief Medical Examiner, New York City.)
Extrinsic factors can mediate late prosthetic valve stenosis or regurgitation, including a large mitral annular calcific nodule, septal hypertrophy, exuberant overgrowth of fibrous tissue (see Fig. 5-24B and C), interference by retained valve remnants (such as a retained posterior mitral leaflet or components of the submitral apparatus; Fig. 5-24D), or unraveled, long, or looped sutures or knots (see Fig. 5-24E). With bioprosthetic valves, cuspal motion can be restricted by sutures looped around stents, and suture ends cut too long may erode into or perforate a bioprosthetic valve cusp.
Aortic or pulmonary valves (with or without associated vascular conduits) transplanted from one individual to another have exceptionally good hemodynamic profiles, a low incidence of thromboembolic complications without chronic anticoagulation, and a low reinfection rate following valve replacement for endocarditis.118 Contemporary cryopreserved allografts, in which freezing is performed with protection from crystallization by dimethyl-sulfoxide and storage until use at −196°C in liquid nitrogen, have demonstrated freedom from degeneration and durability equal to or better than those of conventional porcine bioprosthetic valves (approximately 50 to 90% valve survival at 10 to 15 years compared with 40 to 60% for bioprostheses).
Morphologic changes are summarized in Fig. 5-25. Cryopreserved human allograft heart valves/conduits show gross changes of conduit calcification and cuspal stretching (see Figs. 5-25A and B). Microscopically, there is progressive loss of normal structural demarcations and cells beginning in days. Long-term explants are devoid of both surface endothelium and deep connective tissue cells; they have minimal inflammatory cellularity (Fig. 5-25C).119
Morphology of valve allografts (homografts) valve and pulmonary valve autografts. (A) Gross photograph of pulmonary valve allograft removed following 7 years for conduit stenosis in a child. The pulmonary arterial wall is heavily calcified but the cusps are not. (B) Gross appearance of cryopreserved aortic valve allograft removed at 3 years for aortic insufficiency. (C) Comparative morphologic features of autografts and homografts obtained from the same patients. Autograft valves had near-normal structure and cellular population (a, c, e), in contrast, homografts from the same patients (b, d, f) had a progressive collagen hyalinization and loss of cellularity. Bar = 200 μm. × 400. ([C] Reproduced with permission from Rabkin-Aikawa E, Aikawa M, Farber M, et al: Clinical pulmonary autograft valves: pathological evidence of adaptive remodeling in the aortic site. J Thorac Cardiovasc Surg 2004; 128:552-562.)
Pulmonary Valvular Autografts
Often called the Ross operation in recognition of its originator, Sir Donald Ross, pulmonary autograft replacement of the aortic valve yields excellent hemodynamic performance, avoids anticoagulation, and carries a low risk of thromboembolism.120 Explanted pulmonary autograft cusps show: (1) near-normal trilaminar structure; (2) near-normal collagen architecture; (3) viable endothelium and interstitial cells; (4) usual outflow surface corrugations; (5) sparse inflammatory cells; and (6) absence of calcification and thrombus (see Fig. 5-25).121 However, the arterial walls show considerable transmural damage (probably perioperative ischemic injury caused by disruption of vasa vasorum) with scaring and loss of medial smooth muscle cells and elastin. The early necrosis and healing with probable resultant loss of strength/elasticity of the aortic wall may potentiate late aortic root dilation.122,123
Stentless Porcine Aortic Valve Bioprostheses
Nonstented (stentless) porcine aortic valve bioprostheses consist of glutaraldehyde-pretreated pig aortic root and valve cusps that have no supporting stent.124 The most widely used models, St. Jude Medical Toronto SPV (St. Jude Medical Inc., St. Paul, MN), Medtronic Freestyle (Medtronic Heart Valves, Santa Ana, CA) and Edwards Prima (Edwards Life Sciences, Irvine, CA), bioprostheses differ slightly in overall configuration, details of glutaraldehyde fixation conditions, and anticalcification pretreatment. The principal advantage of a stentless porcine aortic valve is that it generally allows for the implantation of a larger bioprosthesis (than stented) in any given aortic root, which is hypothesized to enhance hemodynamics and thereby regression of hypertrophy and patient survival.125
The available evidence suggests that the durability of stentless bioprostheses is comparable with that of contemporary stented bioprostheses. However, nonstented porcine aortic valves have greater portions of aortic wall exposed to blood than in currently used stented valves, and calcification of the aortic wall and inflammation at the junction of aortic wall within the recipient's tissue, are potentially deleterious, owing to the large area of this interface. Calcification of the wall portion of a stentless valve could stiffen the root, cause nodular calcific obstruction potentiate wall rupture, or provide a nidus for emboli. Analyses of explanted nonstented valves show pannus and tissue degeneration, manifest as tears and cuspal calcification, but not substantial aortic wall calcification.126,127
Catheter-Based Valve Replacement
New catheter techniques for inserting foldable prosthetic valves within stenotic aortic and pulmonary valves, and for emulating surgical repair of regurgitant mitral valves are in various stages of preclinical development and early clinical use.128,129 Presently, catheter-based, often percutaneous valve replacement is most widely used in patients with severe aortic stenosis disease deemed otherwise inoperable as a bridge to valve replacement in patients in whom surgery needs to be delayed, and in congenital heart disease, in which percutaneous pulmonary valve replacement may find a distinct niche to obviate the morbidity of reoperation to replace malfunctioning pulmonary conduits.
Catheter-based valve replacement uses a device which has two components: (1) an outer stentlike structure and (2) leaflets; these two components together constitute a functioning valvular prosthesis. Representative designs are illustrated in Fig. 5-26. The stent holds open a valve annulus or segment of a prosthetic conduit and resists the tendency of a vessel, valve annulus and diseased native leaflets to recoil following balloon dilation, supports the valve leaflets, and provides the means for seating of the prosthesis in the annulus or vessel.
The devices generally consist of biologic tissue such as bovine, equine, or porcine pericardium and bovine jugular venous valves mounted within a collapsable stent. The stents can be made from self-expandable or shape-memory materials such as nickel-titanium alloys (eg, Nitinol), or from balloon-expandable materials such as stainless steel, platinum-iridium, or other alloys. For a balloon-expandable device the delivery strategy involves collapsing the device over a balloon and placing it within a catheter-based sheath. The catheter containing the device can be inserted into the femoral artery (or vein) using essentially the same technique for deployment of coronary artery stents. In aortic stenosis, the device is passed from the femoral artery retrograde up the aorta to the aortic valve and deployed between the cusps of the calcified aortic valve, pushing the diseased cusps out of the way. Alternatively, the device can be deployed in an antegrade fashion through a minimally invasive surgical approach exposing the apex of the left ventricle. The transapical approach is favored in patients with significant atherosclerotic disease of the femoral artery and aorta. These devices may also play a role in the treatment of surgically implanted bioprosthetic valves that are failing because of stenosis or regurgitation in a so-called “valve-in-valve” application, in which a new valve is placed via catheter into the lumen of the existing valve.
Several devices are currently in various stages of development and clinical use in the aortic and pulmonary position. The two transcatheter aortic valves with the largest clinical experience are the Edwards SAPIEN device and the CoreValve system.130,131 The SAPIEN device is composed of a balloon expandable stainless steel stent that houses a bovine pericardial valve. The stent has a low profile and is designed to be placed in the subcoronary position. There is a polymer skirt circumferentially attached to the stent to reduce paravalvular leaks. The CoreValve device is composed of a self-expandable Nitinol stent that houses a porcine pericardial trileaflet valve. The CoreValve stent is longer and is meant to be placed in the left ventricular outflow tract extending into the aortic root. These devices have been used in approximately 4000 patients worldwide, the first-in-man experience was reported in 2002, and clinical trials are ongoing. The Medtronic Melody transcatheter pulmonary valve is composed of a balloon expandable platinum-iridium alloy stent which houses a segment of bovine jugular vein containing its native venous valve. The Melody was designed to be used in children or young adults with congenital heart disease who have received surgically implanted right ventricular outflow tract conduits that are failing either because of stenosis or regurgitation.
Catheter-based stent-mounted prosthetic valves present novel challenges. Valved stents are significantly larger than most existing percutaneous cardiac catheters and devices, and are presently on the order of 22 to 24 Fr. In the aortic position, there is the potential to impede coronary flow, or interfere with anterior mitral leaflet mobility or the conduction system or the native diseased leaflets. Stent architecture may also preclude future catheter access to the coronaries for possible interventions. Secure seating within the aortic annulus or a pulmonary conduit and long-term durability of both the stent and the valve tissue are also major considerations.