**4. Structure and constituents of normal heart valves**

small molecules, such as sulfate groups onto GalNAc and other moieties and the epimerization of GlcUA to IdUA residues. Following glycosylation, the completed proteoglycan is then

**Figure 3.** Biosynthesis of proteoglycans, showing the case of the linking of chondroitin sulfate chains to their core protein. Ser: serine residue; Gal: galactose residue; GlcUA: glucuronic acid residue; Xyl: xylose residue. Modified from

In the extracellular space, proteoglycans bind various secreted signal molecules, such as growth factors, enhancing or inhibiting their signaling activity [13]. They also bind to other types of secreted proteins, including proteases and protease inhibitors, regulating their activities [1, 4]. Moreover, GAGs and proteoglycans can associate to each other to form big aggregates. Such a case is the aggrecan proteoglycans, which comprise chondroitin sulfate and keratan sulfate, and assemble with hyaluronic acid. GAGs and proteoglycans also associate with fibrous proteins, such as collagen and basal laminae, creating extremely complex structures. Such a proteoglycan is decorin, which comprises chondroitin sulfate and dermatan sulfate, and binds to collagen fibrils, aiding in collagen fiber formation. Decorin deficiency has been reported to lead to reduced tensile strength in tissues [13, 49–52]. Another proteoglycan of this type is perlecan, which is major proteoglycan of basal laminae, consisting of heparan sulfate and chondroitin sulfate chains linked to a large multi-domain core protein. Perlecan is incorporated in the basal laminae by binding to both laminin and collagen IV, connecting the two networks, and defining the structure and function of basal laminae. Owing to its multi-domain components, perlecan can also crosslink cell surface molecules to ECM components [4]. In addition to proteoglycans that fully reside in the extracellular space, some proteoglycans form integral components of the cell membranes by having their core protein spanning or attached to the lipid bilayer of the cell membrane. Such proteoglycans are the syndecans, which comprise three chondroitin sulfate and heparan sulfate chains and are expressed by many cell types, including epithelial cells and fibroblasts [13, 53–55]. Syndecans bind to ECM collagens and other ECM proteins such as the fibronectins, anchoring

cells to the ECM, while interacting with the intracellular actin cytoskeleton [4].

The importance of GAGs and proteoglycans is emphasized by the severe developmental defects that can occur when specific proteoglycans are inactivated by mutation. A number of congenital enzyme deficiencies have been linked to GAG metabolic disorders (mucopolysaccharidoses) [13]. Among mucopolysaccharidoses, the Hurler [56–59] and Hunter [60–62] syndromes are the most widely studied. Mucopolysaccharidoses are associated with mutations in the gene encoding lysosomal hydrolases, including endoglycosidases and exoglycosidases,

exported in secretory vesicles to the ECM [1, 4, 13].

Alberts et al. (2014) [13] and Lodish et al. (2003) [4].

14 Structural Insufficiency Anomalies in Cardiac Valves

Depending on the functional requirements for a particular tissue, the organization of fibers, cells and other ECM macromolecules in the tissue and, thus, the mechanical properties of the tissue vary. The simplest structure from the point of view of the collagen fibers consists of parallel fibers as in tendons and ligaments. The 2D and 3D networks of the skin are more complex, whereas the structures of aortic, pulmonary, mitral and tricuspid valves in the heart are the most complex ones. The structure of the heart valves is adapted to allow unidirectional and unobstructed passage of blood without regurgitation, trauma to blood elements, thromboembolism, and excessive stress concentrations in the valve leaflets and supporting tissue. The cellular and extracellular elements of normal valves accommodate repetitive changes in shape and dimension throughout the cardiac cycle. They provide effective stress transfer to the annulus and adjacent tissue, and mediate functional remodeling and repair of injury caused by the large repetitive deformations. The aortic and pulmonary valves comprise three similar-size leaflets, and are located between the left ventricle and aorta, and the right ventricle and pulmonary artery, respectively. Their leaflets resemble half-moons and, thus, they are referred to as semilunar (SL) valves. The mitral valve (MV) is located between the left ventricle and left atrium, and comprises two noticeably different leaflets that resemble a bishop's miter when they are closed. The tricuspid valve is located between the right ventricle and right atrium, and comprises three leaflets. Owing to their location between the atria and the ventricles, the mitral and tricuspid valves are referred to as the atrioventricular (AV) valves. In addition to their leaflets, the AV valves also comprise fan-shaped tendinous chord (chordae tendinae) that link the AV valve leaflets to protrusions on the ventricular wall, the papillary muscles, and act similarly to the parachute chords, preventing the AV valve leaflets to prolapse into the atria when they are fully closed.

The aortic and pulmonary valve leaflets open against the aorta and pulmonary artery, respectively, during ventricular systole, whereas the mitral and tricuspid valve leaflets open against the myocardial wall of the right and left ventricle, respectively, during ventricular diastole. The semilunar valves close during ventricular diastole and the atrioventricular valves during systole. All four valves close rapidly and completely under minimal reverse pressure, stretching to maintain full competence during diastole. During these opening and closing movements, the valve leaflets withstand cyclic strains as high as 50%, whereas despite the pressure difference across the closed valves, which imposes large load on their leaflets, leaflet prolapse is prevented by large coaptation of the leaflets, reaching up to 40% of their surfaces [18, 64–68]. Even though each of the four heart valves has its own individual unique anatomical, structural and constitutional features that are adapted to their specific localization and function, they share common structural, constitutional and functional features. Moreover, the aortic and mitral valves are the ones most prone to disease, since they reside in the high pressure environment of the left ventricle. Owing to these, the discussion in the following paragraphs is focused on the aortic and mitral valves, as representatives of the SL and AV valves, respectively. Moreover, the discussion will focus on valve leaflets, since these are the most structurally complex and constitutionally diverse components of the heart valves.

The heart valve leaflets are layered with a highly specialized ECM, which provides the basis for normal valve function. Two types of cells are present, including a layer of endothelial cells (ECs) that covers the luminal surface of the leaflets and a deep layer of interstitial cells (VICs) that consists of SMCs and fibroblasts, which replenish and remodel the valvular ECM [69]. The EC layer is continuous with the luminal surface of the atrium and ventricle, in the case of the AV valves, and ventricle and adjacent artery (pulmonary artery or aorta) in the case of the SL valves. The aortic valve leaflets comprise three distinct layers, including the fibrosa, spongiosa and ventricularis, each enriched in a different ECM component (**Figure 4a**–**c**, **e**). The MV leaflets present a slightly different architecture, with four layers instead of three, including a ventricularis, a fibrosa, a spongiosa and an atrialis layer (**Figure 4c**, **e**). Within these layers, the structural elements are arranged in a methodical orientation, leading to leaflet properties that are highly anisotropic. Several structural features enable the semilunar and atrioventricular leaflets to be extremely soft and pliable when unloaded and inextensible when high transvalvular pressure is applied during the time the valves are fully closed [18, 65, 70, 71]. In the case of the aortic valve, the fibrosa layer faces the outflow (aorta side) of the valve, whereas in the case of the MV the fibrosa lies below a ventricularis layer, which faces the outflow (left ventricle side) of the valve. The fibrosa in both valve types is the primary structural layer and major load bearing layer that offers the mechanical integrity of the valve leaflets [72]. The predominant constituent of the fibrosa are large amounts of highly-aligned collagen I fibers (**Figure 4c**), which are organized into large bundles and are predominantly aligned along the circumferential direction of the leaflets. The collagen I fibers of the fibrosa are surrounded by glycosaminoglycans and proteoglycans, as well as a network of elastic fibers, which maintains the microstructure of the valve leaflet during unloading [73]. This directionality of the collagen fibers results in aortic and MV leaflet structures that are considerably stiffer along their circumferential direction than their radial [18, 67, 73]. Moreover, folds in the collagen layer of the fibrosa generate a macroscopically visible corrugations on the surface of the leaflets when they are un-stretched (**Figure 4a**).

The ventricularis layer of the aortic valve is equivalent to the atrialis of the MV in function and organization, with both facing the inflow of the valves. Although these layers are less organized than the fibrosa, they still contain significant amounts of collagen I (**Figure 4c**) and radially aligned elastic fibers (**Figure 4d**). However, because the collagen is not oriented in any

specific direction, they tend to be more flexible than the fibrosa. The elastic fibers of the aortic valve ventricularis and MV atrialis extend when the leaflets stretch to enlarge the coaptation area, but recoil to make the leaflet smaller in the open valve phase. The ventricularis of the MV

blue: acid mucosubstances (GAGs) and proteoglycans; magenta: Neutral polysaccharides.

**Figure 4.** (a) Trilaminar leaflet structure of semilunar valves, showing the fibrosa, spongiosa and ventricularis layers, together with their major constituents. Note the macroscopically visible corrugations of the fibrosa layer. (b) H & E histological staining of the aortic valve leaflet (radial direction). ECM proteins were stained pink/light purple; cells were stained deep/purple. (c) Immunohistochemical staining against collagen I of the mitral valve posterior leaflet (radial direction). Collagen I was stained brown. (d) Miller's elastic histological staining of the aortic valve leaflet (radial direction). Elastic fibers were stained deep blue/black. (e) Alcian blue/PAS histological staining of the mitral valve anterior leaflet (radial direction), showing the ventricularis, fibrosa, spongiosa and atrialis layers; dark blue: cell nuclei;

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during systole. All four valves close rapidly and completely under minimal reverse pressure, stretching to maintain full competence during diastole. During these opening and closing movements, the valve leaflets withstand cyclic strains as high as 50%, whereas despite the pressure difference across the closed valves, which imposes large load on their leaflets, leaflet prolapse is prevented by large coaptation of the leaflets, reaching up to 40% of their surfaces [18, 64–68]. Even though each of the four heart valves has its own individual unique anatomical, structural and constitutional features that are adapted to their specific localization and function, they share common structural, constitutional and functional features. Moreover, the aortic and mitral valves are the ones most prone to disease, since they reside in the high pressure environment of the left ventricle. Owing to these, the discussion in the following paragraphs is focused on the aortic and mitral valves, as representatives of the SL and AV valves, respectively. Moreover, the discussion will focus on valve leaflets, since these are the most structurally complex and constitutionally diverse components of the heart valves.

16 Structural Insufficiency Anomalies in Cardiac Valves

The heart valve leaflets are layered with a highly specialized ECM, which provides the basis for normal valve function. Two types of cells are present, including a layer of endothelial cells (ECs) that covers the luminal surface of the leaflets and a deep layer of interstitial cells (VICs) that consists of SMCs and fibroblasts, which replenish and remodel the valvular ECM [69]. The EC layer is continuous with the luminal surface of the atrium and ventricle, in the case of the AV valves, and ventricle and adjacent artery (pulmonary artery or aorta) in the case of the SL valves. The aortic valve leaflets comprise three distinct layers, including the fibrosa, spongiosa and ventricularis, each enriched in a different ECM component (**Figure 4a**–**c**, **e**). The MV leaflets present a slightly different architecture, with four layers instead of three, including a ventricularis, a fibrosa, a spongiosa and an atrialis layer (**Figure 4c**, **e**). Within these layers, the structural elements are arranged in a methodical orientation, leading to leaflet properties that are highly anisotropic. Several structural features enable the semilunar and atrioventricular leaflets to be extremely soft and pliable when unloaded and inextensible when high transvalvular pressure is applied during the time the valves are fully closed [18, 65, 70, 71]. In the case of the aortic valve, the fibrosa layer faces the outflow (aorta side) of the valve, whereas in the case of the MV the fibrosa lies below a ventricularis layer, which faces the outflow (left ventricle side) of the valve. The fibrosa in both valve types is the primary structural layer and major load bearing layer that offers the mechanical integrity of the valve leaflets [72]. The predominant constituent of the fibrosa are large amounts of highly-aligned collagen I fibers (**Figure 4c**), which are organized into large bundles and are predominantly aligned along the circumferential direction of the leaflets. The collagen I fibers of the fibrosa are surrounded by glycosaminoglycans and proteoglycans, as well as a network of elastic fibers, which maintains the microstructure of the valve leaflet during unloading [73]. This directionality of the collagen fibers results in aortic and MV leaflet structures that are considerably stiffer along their circumferential direction than their radial [18, 67, 73]. Moreover, folds in the collagen layer of the fibrosa generate a macroscopically visible corrugations on the surface of the leaflets when they are un-stretched (**Figure 4a**).

The ventricularis layer of the aortic valve is equivalent to the atrialis of the MV in function and organization, with both facing the inflow of the valves. Although these layers are less organized than the fibrosa, they still contain significant amounts of collagen I (**Figure 4c**) and radially aligned elastic fibers (**Figure 4d**). However, because the collagen is not oriented in any

**Figure 4.** (a) Trilaminar leaflet structure of semilunar valves, showing the fibrosa, spongiosa and ventricularis layers, together with their major constituents. Note the macroscopically visible corrugations of the fibrosa layer. (b) H & E histological staining of the aortic valve leaflet (radial direction). ECM proteins were stained pink/light purple; cells were stained deep/purple. (c) Immunohistochemical staining against collagen I of the mitral valve posterior leaflet (radial direction). Collagen I was stained brown. (d) Miller's elastic histological staining of the aortic valve leaflet (radial direction). Elastic fibers were stained deep blue/black. (e) Alcian blue/PAS histological staining of the mitral valve anterior leaflet (radial direction), showing the ventricularis, fibrosa, spongiosa and atrialis layers; dark blue: cell nuclei; blue: acid mucosubstances (GAGs) and proteoglycans; magenta: Neutral polysaccharides.

specific direction, they tend to be more flexible than the fibrosa. The elastic fibers of the aortic valve ventricularis and MV atrialis extend when the leaflets stretch to enlarge the coaptation area, but recoil to make the leaflet smaller in the open valve phase. The ventricularis of the MV is similar in structure and constituents to the MV atrialis and aortic valve ventricularis, with loosely arranged collagen fibers and radially-aligned elastic fibers (**Figure 5a**). The spongiosa layer is located between the fibrosa and ventricularis of the aortic valve, and between the fibrosa and atrialis in the MV. This layer is primarily composed of water, GAGs and proteoglycans (**Figure 4e**), but also contains loosely arranged collagens and elastin, which connect the fibrosa and ventricularis (or atrialis) together. Shear stresses caused by the differential movements of the leaflet layers and the shock of the valve closure are dissipated in the ground substance of the spongiosa, whose hydrophilic GAGs and proteoglycans absorb water and swell to form a deformable gel [69]. The thickness of the leaflet layers varies from the attachment site (basal area) at the valvular annulus to the free edge of the leaflets [72, 73]. At the basal area, the fibrosa comprises the thickest layer, becoming thinner and gradually overtaken by the spongiosa towards the free edge of the leaflets (**Figure 5b**). The spongiosa is the main component of both the SL and AV valve leaflets at their free edge, providing a natural shock-absorption mechanism along the coaptation region of the leaflets that dissipates the shocks of valve closure [67, 73]. The thickest regions of the leaflets, especially close to their basal regions, also feature venules and arterioles, which facilitate supplementary oxygen and nutrient transport in regions where simple diffusion is not sufficient for cell nourishment (**Figure 5a** and **b**) [18, 66, 72, 74].

During the cardiac cycle, the SL and AV valve leaflets undergo significant changes in their macroscale and microscale architectural configuration. When the valves are fully open, the gross corrugations of the fibrosa, which are caused by folds in the collagen fiber layer, produce a visible surface wrinkling (**Figure 5c**), which disappears when the leaflets are fully extended when the valve is fully closed and loaded under the peak transvalvular pressure (**Figure 5d**). During valve closing, the corrugations of the fibrosa expand along the radial direction, which is accompanied by radial stretching of the radially-aligned elastic fibers of the SL ventricularis (or MV atrialis) layer, permitting initial increase in dimension with minimal stress. Further stretching of the leaflets causes uncrimping of the collagen fibers along the circumferential direction. When the valve is fully closed, the collagen-layer folds are fully extended and the corrugations in the fibrosa are fully flattened along the radial direction, whereas collagen fibers are uncrimped along the circumferential direction. These changes produce stiffening of the leaflets, preventing their exaggerated sagging and ensuring optimal coaptation with the adjacent leaflets when the valve is fully closed [64, 69]. On the other hand, the stretching of the elastic fibers provides the energy that is necessary for the elastic recoil of the leaflets to their upstretched configuration when the valve is fully open. Moreover, the multilayered structure of the valve leaflets has been reported to contribute to the low flexural rigidity of the leaflets when the valves are fully open, possibly also due to interlayer slippage, that allows their passive interaction with the surrounding blood [75]. The multilayered leaflet structure also provides additional support during valve closure and coaptation, assisting the extended collagen fibers to generate a stiffened leaflet structure that prevents exaggerated sagging under the high transvalvular pressure [73].

In addition to collagen I, collagens III, IV, V and VI have also been identified in the heart valves [72, 76–78]. Even though these collagens are expressed in varying concentrations in the four valves, their localization and distribution has been shown to be similar in all valves. Apart from the fibrosa layer, were it is has a dominant presence, collagen I is expressed throughout the SL and AV valve leaflets (**Figure 4c**), whereas collagen III is most evident in the less-dense regions of the leaflets, such as the spongiosa [76]. Collagen IV has been shown to be localized in the basal lamina of the leaflets and collagen V to be predominantly distributed around interstitial cells. Collagen VI has been shown to form distinct structures within the fibrosa, surrounding the dense collagen I fibers of this layer [76]. The total collagen content in normal valve leaflets is approximately 50–63% (dry tissue weight ratio) [68, 71, 79, 80], and the elastin content is approximately 10–11% (dry tissue weight ratio), depending on the valve type (**Table 3**) [78, 80–83]. Previous studies have reported the relative percentages of

(d; fully closed). Redrawn and modified from Schoen (1999) [64].

**Figure 5.** (a) Radial histological section of the basal region of the posterior MV leaflet stained with Miller's elastic and sirius red (red: collagen; blue/black: elastin). indicates elastic fibers; ► indicates blood vessels. Note the dominance of the fibrosa and ventricularis layers in the expense of the spongiosa layer in the basal region. (b) Radial histological section of the posterior MV leaflet stained with Masson's Trichrome stain (blue/black: cell nuclei; red: cytoplasm; blue: collagen). ► indicates blood vessels. Note the increase in the thickness of the spongiosa layer and the decrease in the thickness of the fibrosa layer towards the free edge of the leaflet. Adopted with permission from Roberts et al. (2016) [18]. (c, d) leaflet configuration and architecture of semilunar valves during peak systole (c; fully open) and peak diastole

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is similar in structure and constituents to the MV atrialis and aortic valve ventricularis, with loosely arranged collagen fibers and radially-aligned elastic fibers (**Figure 5a**). The spongiosa layer is located between the fibrosa and ventricularis of the aortic valve, and between the fibrosa and atrialis in the MV. This layer is primarily composed of water, GAGs and proteoglycans (**Figure 4e**), but also contains loosely arranged collagens and elastin, which connect the fibrosa and ventricularis (or atrialis) together. Shear stresses caused by the differential movements of the leaflet layers and the shock of the valve closure are dissipated in the ground substance of the spongiosa, whose hydrophilic GAGs and proteoglycans absorb water and swell to form a deformable gel [69]. The thickness of the leaflet layers varies from the attachment site (basal area) at the valvular annulus to the free edge of the leaflets [72, 73]. At the basal area, the fibrosa comprises the thickest layer, becoming thinner and gradually overtaken by the spongiosa towards the free edge of the leaflets (**Figure 5b**). The spongiosa is the main component of both the SL and AV valve leaflets at their free edge, providing a natural shock-absorption mechanism along the coaptation region of the leaflets that dissipates the shocks of valve closure [67, 73]. The thickest regions of the leaflets, especially close to their basal regions, also feature venules and arterioles, which facilitate supplementary oxygen and nutrient transport in regions where

18 Structural Insufficiency Anomalies in Cardiac Valves

simple diffusion is not sufficient for cell nourishment (**Figure 5a** and **b**) [18, 66, 72, 74].

During the cardiac cycle, the SL and AV valve leaflets undergo significant changes in their macroscale and microscale architectural configuration. When the valves are fully open, the gross corrugations of the fibrosa, which are caused by folds in the collagen fiber layer, produce a visible surface wrinkling (**Figure 5c**), which disappears when the leaflets are fully extended when the valve is fully closed and loaded under the peak transvalvular pressure (**Figure 5d**). During valve closing, the corrugations of the fibrosa expand along the radial direction, which is accompanied by radial stretching of the radially-aligned elastic fibers of the SL ventricularis (or MV atrialis) layer, permitting initial increase in dimension with minimal stress. Further stretching of the leaflets causes uncrimping of the collagen fibers along the circumferential direction. When the valve is fully closed, the collagen-layer folds are fully extended and the corrugations in the fibrosa are fully flattened along the radial direction, whereas collagen fibers are uncrimped along the circumferential direction. These changes produce stiffening of the leaflets, preventing their exaggerated sagging and ensuring optimal coaptation with the adjacent leaflets when the valve is fully closed [64, 69]. On the other hand, the stretching of the elastic fibers provides the energy that is necessary for the elastic recoil of the leaflets to their upstretched configuration when the valve is fully open. Moreover, the multilayered structure of the valve leaflets has been reported to contribute to the low flexural rigidity of the leaflets when the valves are fully open, possibly also due to interlayer slippage, that allows their passive interaction with the surrounding blood [75]. The multilayered leaflet structure also provides additional support during valve closure and coaptation, assisting the extended collagen fibers to generate a stiffened leaflet structure that prevents exaggerated sagging under the high transvalvular pressure [73].

In addition to collagen I, collagens III, IV, V and VI have also been identified in the heart valves [72, 76–78]. Even though these collagens are expressed in varying concentrations in the four valves, their localization and distribution has been shown to be similar in all valves. Apart from the fibrosa layer, were it is has a dominant presence, collagen I is expressed throughout the SL and AV valve leaflets (**Figure 4c**), whereas collagen III is most evident in

**Figure 5.** (a) Radial histological section of the basal region of the posterior MV leaflet stained with Miller's elastic and sirius red (red: collagen; blue/black: elastin). indicates elastic fibers; ► indicates blood vessels. Note the dominance of the fibrosa and ventricularis layers in the expense of the spongiosa layer in the basal region. (b) Radial histological section of the posterior MV leaflet stained with Masson's Trichrome stain (blue/black: cell nuclei; red: cytoplasm; blue: collagen). ► indicates blood vessels. Note the increase in the thickness of the spongiosa layer and the decrease in the thickness of the fibrosa layer towards the free edge of the leaflet. Adopted with permission from Roberts et al. (2016) [18]. (c, d) leaflet configuration and architecture of semilunar valves during peak systole (c; fully open) and peak diastole (d; fully closed). Redrawn and modified from Schoen (1999) [64].

the less-dense regions of the leaflets, such as the spongiosa [76]. Collagen IV has been shown to be localized in the basal lamina of the leaflets and collagen V to be predominantly distributed around interstitial cells. Collagen VI has been shown to form distinct structures within the fibrosa, surrounding the dense collagen I fibers of this layer [76]. The total collagen content in normal valve leaflets is approximately 50–63% (dry tissue weight ratio) [68, 71, 79, 80], and the elastin content is approximately 10–11% (dry tissue weight ratio), depending on the valve type (**Table 3**) [78, 80–83]. Previous studies have reported the relative percentages of


**5. Physiological behavior of heart valves under loading**

strength of approximately 2 MPa, which limits their load-bearing capacity [35].

**Material Young's modulus / Elastic phase** 

**modulus (MPa)**

Aortic leaflet (R) 0.04 2.1

Pulmonary leaflet (R) 0.34 1.2

Mitral leaflet (R) 0.02 2.1 Mitral chordae 0.10 113.7

**Table 4.** Indicative low-strain and high-strain modulus of valvular tissue and constituents.

C: Circumferential direction, R: radial direction. \*Data obtained under uniaxial tensile testing.

During the cardiac cycle, valvular tissue deforms to relative large strains, exhibiting non-linear stress-strain behavior. A typical stress-strain behavior for SL valve leaflet tissue within its physiological range is shown in **Figure 6a**. The graph describes the behavior of SL valve leaflets

Tropoelastin 0.003 - [37] Microfibrils 78-96 [38] Mature cross-linked elastin 0.3-1.1 - [6, 35] Collagen 1 fibrils 95.5 [75] Mature cross-linked collagen 1 - 1.0 - 1.2×103 [6, 35] Aortic leaflet (C) 0.07 39.0 [65, 66]\*

Pulmonary leaflet (C) 0.76 15.3 [71]\*

Mitral leaflet (C) 0.02 10.2 [68]\*

**Collagen phase modulus** 

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**Source**

**(MPa)**

The ultrastructural histoarchitecture of the valvular tissue and the interaction of its collagen fibers with its non-collagenous components form the basis of the mechanical properties of heart valves. Similarly to other biological tissues that are subjected to high deformation and loading, collagen and elastic fibers act synergistically in heart valves to provide valvular tissue with strength and elasticity, respectively, which are required for their efficient function. The strength and stiffness of the collagen fibers prevent fracture of the valvular components when they are subjected to the peak transvalvular pressure during the time the valves are fully closed. The tensile strength of collagen is approximately 120 MPa, which is only one order of magnitude lower than high tensile steel (about 1110 MPa) and an elastic modulus of about 1.2 GPa, which confers substantial stiffness (**Table 4**) [35, 87]. However they stretch only minimally (about 13%) [35, 88]. On the other hand, elastic fibers are the most extensible biosolids known with very low modulus of approximately 0.3–1.1 MPa (**Table 4**) and capable of reaching failure strains in excess of 150%. However, elastic fibers demonstrate a low tensile

The results indicate mean ± 95% confidence intervals, or mean ± standard deviation (\*), or means ± standard error (\*\*). H: Human; P: porcine; N.A.: not available. Numbers in brackets indicate source document.

**Table 3.** Hydroxyproline, collagen, sulfated GAG and elastin content of normal heart valves.

collagen I, III, and V in normal human MV leaflets to be approximately 74, 24 and 2% of the total collagen content, respectively, whereas collagen IV and VI were below the detection limit of the technique used in those studies [72, 77]. A similar study by Lis et al. [78] reported a collagen I to collagen III ratio of 2.4 and 2.7 for human MV leaflets and chordae, respectively.

Three major GAGs have been identified in varying concentrations in heart valves, including chondroitin sulfate, dermatan sulfate and hyaluronic acid, together with decorin, biglycan and versican, which are chondroitin and dermatan sulfate proteoglycans [51, 84, 85]. The total content of sulfated GAGs (chondroitin and dermatan sulfate) in normal heart valves has been reported to range between 11 and 27% (dry tissue weight ratio), depending on valve type and site (**Table 3**) [68, 71, 78, 79]. Hyaluronic acid is the most abundant GAG in normal heart valves, accounting for up to half of the total leaflet GAG content, with chondroitin and dermatan sulfate accounting for about a quarter of the total GAG content of the leaflet each [86]. The relative percentages reported for normal human MV leaflets were 49, 25 and 23% of the total GAG content, for hyaluronic acid, chondroitin sulfate and dermatan sulfate, respectively, with the remaining 3% attributed to hyper-sulfated chondroitin/dermatan sulfate. In the case of the normal MV chordae, the corresponding percentages have been reported to be 24 (hyaluronic acid), 26 (chondroitin sulfate), 43 (dermatan sulfate) and 7% (hyper-sulfated chondroitin/dermatan sulfate) [84–86]. Moreover, differences in the absolute and relative GAG contents have been reported for different regions of the valves, subjected to different modes of loading during the cardiac cycle. Specifically, regions of the valves that are predominantly subjected to tensile loading, such as the leaflet belly and chordae (in the case of the AV valves), present a reduced overall GAG content compared to regions such as the free edge of the valve leaflets, which are predominantly subjected to compressive loading during coaptation with the other valve leaflets when the valve is fully closed. In addition, the regions that are predominantly subjected to tensile loading present significantly increased levels of chondroitin and dermatan sulfate compared to hyaluronic acid [85].
