Chapter 9 Valvular Heart Disease: Stenosis and Regurgitation © 2014, Elsevier Inc., Willis, et.al., Cellular and Molecular Pathobiology of Cardiovascular Disease

FIGURE 9. 1 Normal aortic and mitral valves FIGURE 9.1 Normal aortic and mitral valves. (A) Outflow aspect of aortic valve in open (top) and closed (bottom) configurations, corresponding to systole and diastole, respectively. (B) Normal mitral valve and associated structures, after opening left ventricle. (A) Reproduced from Schoen FJ, Edwards WD. Valvular heart disease: General principles and stenosis. In: Cardiovascular Pathology 3rd Ed., Silver MD, Gotlieb AI, Schoen FJ (eds.), WB Saunders; 2001, pp. 402–442. © 2014, Elsevier Inc., Willis, et.al., Cellular and Molecular Pathobiology of Cardiovascular Disease

FIGURE 9. 2 Aortic valve functional structure FIGURE 9.2 Aortic valve functional structure. (A) Schematic representation of architecture and configuration of aortic valve cusp in cross-section and of collagen and elastin in systole and diastole. (B) Schematic diagram of the detailed cellular and extracellular matrix architecture of a normal aortic valve. (C) Tissue architecture, shown as low-magnification photomicrograph of cross-section cuspal configuration in the non-distended state (corresponding to systole), emphasizing three major layers: ventricularis (v), spongiosa (s), and fibrosa (f). The outflow surface is at the top. Original magnification: 100×. Movat pentachrome stain (collagen, yellow; elastin, black). (D) Transmission electron photomicrograph of relaxed fresh porcine aortic valve (characteristic of the systolic configuration), demonstrating the fibroblast morphology of valvular interstitial cells (VICs, indicated by arrow); the dense, surrounding closely apposed collagen with wavy crimp; and the potential for VIC–collagen and VIC–VIC interactions. Scale bar: 5 μm. (E) Transmission electron photomicrograph at the surface of the aortic valve demonstrating valvular endothelial cell (VEC, arrow) and proximity of deeper VICs and potential for VEC–VIC interactions. Scale bar: 5 μm. (A, B, D, and E) Reproduced with permission from Schoen FJ. Mechanisms of function and disease in natural and replacement heart valves. Annual Review of Pathology: Mechanisms of Disease 2012; 7:161–183. (C) Reproduced with permission from Schoen FJ, Edwards WD. Valvular heart disease: General principles and stenosis, In: Cardiovascular Pathology 3rd Ed., Silver MD, Gotlieb AI, Schoen FJ (eds.). WB Saunders; 2001, pp. 402–442. © 2014, Elsevier Inc., Willis, et.al., Cellular and Molecular Pathobiology of Cardiovascular Disease

FIGURE 9. 3 Spectrum of valvular interstitial cell (VIC) phenotypes FIGURE 9.3 Spectrum of valvular interstitial cell (VIC) phenotypes. VIC functions can be conveniently organized into five phenotypes: embryonic progenitor endothelial/mesenchymal cells, quiescent VICs, activated VICs, adult, circulating stem-cell-derived progenitor VICs, and osteoblastic VICs. TGF, transforming growth factor. Modified by permission from Schoen FJ. Evolving concepts of heart valve dynamics. The continuum of development, functional structure, pathology and tissue engineering. Circulation 2008; 118:1864–1880, and reproduced with permission from Schoen FJ. Mechanisms of function and disease in natural and replacement heart valves. Ann Rev Path Mech Dis 2012; 7:161–183. © 2014, Elsevier Inc., Willis, et.al., Cellular and Molecular Pathobiology of Cardiovascular Disease

FIGURE 9.4 Evolving ECM structural composition of human cardiac valves. At 14–19 weeks of gestation, fetal valve ECM is composed mostly of glycosaminoglycans. At 20–39 weeks, fetal valves have a bilaminar structure with elastin in the ventricularis and increased unorganized collagen in the fibrosa. A trilaminar structure becomes apparent in children’s valves but remains incomplete compared with normal adult valve layered architecture with collagen in the fibrosa, glycosaminoglycans in the spongiosa, and elastin in the ventricularis. Top, Movat pentachrome (collagen, yellow; glycosaminoglycans, blue-green; elastin, black); bottom, picrosirius red under circular polarized light. Original magnification ×200. Adapted from Aikawa E, Whittaker P, Farber M, Mendelson K, Padera RF, Aikawa M, Schoen FJ. Human semilunar cardiac valve remodeling by activated cells from fetus to adult: Implications for postnatal adaptation, pathology, and tissue engineering. Circulation 2006;113:1344–1352. © 2014, Elsevier Inc., Willis, et.al., Cellular and Molecular Pathobiology of Cardiovascular Disease

FIGURE 9. 5 Calcific aortic valve disease (CAVD) FIGURE 9.5 Calcific aortic valve disease (CAVD). (A) Calcific aortic stenosis of a previously normal valve having three cusps (viewed from aortic aspect). Nodular masses of calcium are heaped-up within the sinuses of Valsalva. (B) Low-magnification histologic appearance of CAVD/aortic stenosis similar to lesion in (A) showing large amorphous calcium mass that obliterated fibrosa and grew toward but did not penetrate the ventricular surface at bottom. (C, D) Ossification, focal in (C) and extensive with bone marrow formation in (D). (E) Congenitally bicuspid aortic valve with aortic stenosis. The conjoined cusp at the bottom of the photo has a line of failed separation at its center, called a raphe. © 2014, Elsevier Inc., Willis, et.al., Cellular and Molecular Pathobiology of Cardiovascular Disease

FIGURE 9.6 Schematic diagram describing hypothetical inflammatory mechanisms contributing to CAVD. Proinflammatory monocytes (1) are recruited to a site via activated endothelial cells (2) followed by subsequent macrophage (3) accumulation. Tissue macrophages then release pro-osteogenic cytokines, which stimulate the differentiation of VIC myofibroblasts (4) into osteoblast-like cells (6) resulting in generation of calcified matrix vesicles (7) or apoptotic bodies (8) followed by formation of micro- and macrocalcifications (9). Modified from New EP and Aikawa E. Molecular imaging insights into early inflammatory stages of arterial and aortic valve calcification. Circulation Research 2011;108:1381–1391. Illustration credit: Cosmocyte/Ikumi Kayama. © 2014, Elsevier Inc., Willis, et.al., Cellular and Molecular Pathobiology of Cardiovascular Disease

FIGURE 9.7 Gross morphology and molecular imaging (ex vivo near-infrared fluorescence microscopy; image stacks) of calcified aortic valves visualizes osteogenic activity (red fluorescence) in the areas of leaflet attachment to the aortic wall in inflamed valves (green fluorescence). Adapted from Aikawa E, Aikawa M, Libby P, Figueiredo JL, Rusanescu G, Iwamoto Y, Fukuda D, Kohler RH, Shi GP, Jaffer FA, Weissleder R. Arterial and aortic valve calcification abolished by elastolytic cathepsin S deficiency in chronic renal disease. Circulation 2009;119:1785-1794. © 2014, Elsevier Inc., Willis, et.al., Cellular and Molecular Pathobiology of Cardiovascular Disease

FIGURE 9. 8 Myxomatous degeneration of the mitral valve FIGURE 9.8 Myxomatous degeneration of the mitral valve. Left panel: Long axis of left ventricle demonstrating hooding with prolapse of the posterior mitral leaflet into the left atrium (arrow). (Courtesy of William D. Edwards, MD, Mayo Clinic, Rochester, MN). Morphological features of normal and myxomatous mitral valves. Right panel: Normal mitral valve (left) and valve with myxomatous degeneration (right). Myxomatous valves have an abnormal layered architecture: loose collagen in fibrosa, expanded spongiosa strongly positive for proteoglycans, and disrupted elastin in atrialis (top). Top, Movat pentachrome stain (collagen stains, yellow; proteoglycans, blue-green; and elastin, black). Bottom, Picrosirius red staining viewed under polarized light detected disruption and lower birefringence of collagen fibers in myxomatous leaflets. Magnification ×100. Left panel reproduced by permission from Schoen FJ, Mitchell RN: The heart. In: Robbins/Cotran Pathologic Basis of Disease, 8th Ed., Kumar V, Fausto N, Aster JC, Abbas A (eds.), Philadelphia: W.B. Saunders, 2010, pp. 529–587. Right panel adapted from Rabkin E, Aikawa M, Stone JR, Fukumoto Y, Libby P, Schoen FJ. Activated interstitial myofibroblasts express catabolic enzymes and mediate matrix remodeling in myxomatous heart valves. Circulation 2001;104:2525–2532. © 2014, Elsevier Inc., Willis, et.al., Cellular and Molecular Pathobiology of Cardiovascular Disease

FIGURE 9.9 Characterization of quiescent VICs in normal mitral valves and activated myofibroblast-like VICs in myxomatous mitral valves. Interstitial cells in both normal and myxomatous leaflets stained positively for vimentin (top). Cells in normal valves showed low levels of α-SMA (middle left). However, interstitial cells in the spongiosa of myxomatous valves expressed vimentin and α-SMA, suggesting an activated phenotype (top and middle). In both groups, smooth muscle cells (detected by both α-SMA and SM1) accumulated in the subendothelial layer (middle and bottom). Note that interstitial cells in myxomatous valves showed undetectable levels of SM1 myosin (bottom right). Magnification ×400. Adapted from Rabkin E, Aikawa M, Stone JR, Fukumoto Y, Libby P, Schoen FJ. Activated interstitial myofibroblasts express catabolic enzymes and mediate matrix remodeling in myxomatous heart valves. Circulation 2001;104:2525–2532. © 2014, Elsevier Inc., Willis, et.al., Cellular and Molecular Pathobiology of Cardiovascular Disease

FIGURE 9.10 In the panel on the far left, a normal unstretched sheep mitral valve shows negative α-SMA staining along the CD31-positive endothelium. In the panel on the left, α-SMA-positive staining in the atrial endothelium (also CD31-positive) of a stretched mitral valve, with nests of α-SMApositive cells appearing to penetrate the interstitium. Adapted from Dal-Bianco JP, Aikawa E, Bischoff J, Guerrero JL, Handschumacher MD, Sullivan S, Johnson B, Titus JS, Iwamoto Y, Wylie-Sears J, Levine RA, Carpentier A. Active adaptation of the tethered mitral valve: Insights into a compensatory mechanism for functional mitral regurgitation. Circulation 2009;120:334–342. 11 © 2014, Elsevier Inc., Willis, et.al., Cellular and Molecular Pathobiology of Cardiovascular Disease

FIGURE 9.11 Schematic representation of general mechanisms of valve disease and adaptation in CAVD and DMVD. © 2014, Elsevier Inc., Willis, et.al., Cellular and Molecular Pathobiology of Cardiovascular Disease