**6. Structural, constitutional and biomechanical alterations in pathological heart valves**

Heart valve surgery for repairing or replacing dysfunctional represents the second most common major heart operation in the western world [93]. In the US alone, approximately 5 million patients are diagnosed annually with heart valve disease [75, 94, 95]. Any one of the heart valves can potentially demonstrated valve disease; however, the aortic and mitral valves are most prone to disease, predominantly due to the higher stress that are subjected to and generated by the high pressure environment of the left heart [75]. Various conditions in isolation or in combination can cause valve dysfunction, including inflammation, degenerative valve disease, calcification, rheumatic or infective endocarditis, myocardial infarction and congenital defects, such as bicuspid aortic valve (BAV), MV prolapse (MVP), isolated anomalous lobar pulmonary veins and silent patent ductus arteriosus [96, 97]. Valve disease is manifested by disruptions and alterations in the ECM histoarchitecture and constitution, disruptions in the distribution and organization of the EC and VIC populations, and malformation of the heart valves, which can render them stenotic and/or regurgitant [74, 75]. Moreover, several ECM gene mutations have been linked to valve disease, including fibrillin 1 gene mutations, which have been associated with BAVs and MVP, and elastic fiber component gene mutations also associated with MVP (Williams and Marfan syndromes) [98–100]. MVP and pulmonary valve stenosis have also been linked to collagen III and tenascin X gene mutations [98], whereas Notch1 gene mutations have been associated with BAV development and early calcification [101, 102]. Several studies have suggested that the abnormal organization of the ECM induced by these mutations may lead to abnormal VIC signaling and subsequent dysregulation of ECM synthesis [98, 103–105].

Following altered loading conditions, valvular tissue reorganizes itself to compensate for the altered mechanical stress, demonstrating an initial period of adjustment in its stress-strain behavior under cyclic loading [75]. This adjustment is manifested by an increased hysteresis loop, which subsequently decreases, tending to a steady state after a number of loading/ unloading cycles. Once this steady state is reached, no further change occurs in the stressstrain behavior, unless the loading routine is changed again. This period of adjustment after a large disturbance is called preconditioning and occurs due to internal changes in the structure of the tissue during cycling [6]. The viscoelastic feature of stress relaxation is manifested by the reduction of the stress generated in the tissue over time under constant strain (**Figure 6c**).

is the counterpart of stress relaxation in the sense that the tissue is loaded to a strain ε<sup>o</sup>

**6. Structural, constitutional and biomechanical alterations in** 

Heart valve surgery for repairing or replacing dysfunctional represents the second most common major heart operation in the western world [93]. In the US alone, approximately 5 million patients are diagnosed annually with heart valve disease [75, 94, 95]. Any one of the heart valves can potentially demonstrated valve disease; however, the aortic and mitral valves are most prone to disease, predominantly due to the higher stress that are subjected to and generated by the high pressure environment of the left heart [75]. Various conditions in isolation or in combination can cause valve dysfunction, including inflammation, degenerative valve disease, calcification, rheumatic or infective endocarditis, myocardial infarction and congenital defects, such as bicuspid aortic valve (BAV), MV prolapse (MVP), isolated anomalous lobar pulmonary veins and silent patent ductus arteriosus [96, 97]. Valve disease is manifested by

stress is held constant. Under these conditions the specimen continuous to deform asymptoti-

nificant stress relaxation, but negligible creep over time, suggesting that they behave more like anisotropic quasi-elastic materials rather than viscoelastic materials. This behavior suggests that valve leaflets exhibit a load-locking behavior under maintained loading conditions that enables them to withstand high loading without any time-dependent deformation effects [75]. The degrees of non-linear stress-strain behavior, hysteresis, preconditioning, stress relaxation and creep are different for different tissues, depending on the type and amount of their individual constituents [6, 92]. Along these lines, the variability in the biomechanical properties between the different valves and valve components (**Table 4**) is predominantly due to the different fractions and organization of the major ECM constituents, including collagen fibers, elastic fibers, GAGs and proteoglycans, present in the different valves and valve components. These constitutional and organizational variations, which are dictated by the specific hemodynamic and biomechanical environment that the valves reside in, bequeath high directional and regional histoarchitectural and biomechanical anisotropy to the valvular tissue, assisting the heart valves to perform their specific function in the four different sites of the heart.

(**Figure 6d**) [92]. Studies have reported that valve leaflets exhibit sig-

and its length held constant,

and the

following an exponential decay. Creep

Specifically, if the tissue is suddenly loaded to an initial stress σ<sup>o</sup>

the stress relaxes asymptotically to a limiting value σ<sup>1</sup>

cally to a limiting value ε<sup>1</sup>

24 Structural Insufficiency Anomalies in Cardiac Valves

**pathological heart valves**

BAVs in the most common form of congenital valve disease, affecting 1–2% of the general population and eventually leading to aortic valve stenosis or regurgitation, infective endocarditis, and aortic dilation and/or dissection later in life [80, 97, 98, 106, 107]. Stenotic BAVs explanted from pediatric patients have been reported to exhibit excessive ECM production and disorganization, and VIC disarray without calcification. [98]. Specifically, the valve leaflets demonstrated loss of the typical trilaminar structure of the normal aortic valve leaflets, with disorganized, fragmented and abnormally oriented collagen and elastic fibers, increased proteoglycan presence throughout the leaflets, leaflet thickening, and large areas relatively void of cells. Moreover, elastin content was decreased, whereas collagen and proteoglycan content were substantially increased [75, 98]. The abnormalities in BAV histoarchitecture, constitution and anatomy, have been show to affect leaflet kinematics and stress distribution in computational studies, suggesting that early occurrence of regurgitation or stenosis might strictly depend on those abnormalities [107]. Alterations in the mechanical loading of the heart valves, due to abnormalities in histoarchitecture, constitution and anatomy, induce tissue remodeling though abnormal VIC mechanotransduction, which can lead to further valvular disease and dysfunction. Several studies have characterized VIC response against alterations in the biomechanical environment, and demonstrated a clear link between abnormal VIC stimulation, valvular tissue deformations and disease development and progression, highlighting the fundamental role of the mechanical environment on the mechanobiology of VICs [108–111]. As a result, BAVs are highly susceptible to calcification in later life, due to an induced osteoblastic VIC phenotype and subsequent matrix mineralization [80, 112]. Calcification causes valvular tissue to become thicker and stiffer (representative of a higher modulus), which eventually leads to valve stenosis and inevitable valve replacement [75].

Calcified aortic valve disease (CAVD) is not restricted to BAVs alone. CAVD is a slow, progressive, multifactorial disorder that is frequently driven by aging and the obesity-associated metabolic syndrome, and affects 25–30% of the population aged over 65 years old [75, 84, 100, 105, 113, 114]. Initially, the disease in manifested by mild leaflet thickening of the leaflets alongside with increase in the proteoglycan and hyaluronic acid content, which progressively become more severe and lead to impaired leaflet motion, valvular tissue adaptation and stenosis, [75, 84]. In spite of the leaflet thickening, studies have indicated that there is little change in the mechanical properties of the valve at the early stages of the disease [75]. Although this makes the condition asymptomatic at its initial phases, 10% of the patients develop severe symptoms within 10 years of the initial diagnosis, and require immediate AV replacement [115]. Accumulating evidence suggests that apart from the upregulation of certain cellular pathways that can activate VIC transdifferentiation into osteogenic phenotype and promote osteogenic ECM remodeling, several non-cellular mechanisms, such as epitaxial calcification, can also induce calcium deposition in heart valves [116]. Calcific deposits in CAVD typically occur in regions of high stress concentration [117], highlighting the importance of mechanical factors in valve calcification, and initiate on the outflow surface of the leaflets [80, 106, 118]. It has been hypothesized that valvular ECs may regulate VIC function, and that the initiation of calcific deposits on the outflow, rather than the inflow, surface of the leaflets is due to differences in the hemodynamic microenvironment on the two sides of the leaflet. Elaborating, the different hemodynamic environments generate different mechanical forces that induce different phenotypic modulations on the ECs on the opposing sides. This, in turn, causes variations in the regulation of VIC function [80, 119]. Moreover, accumulating evidence suggests that CAVD shares common features with atherosclerosis, particularly the early accumulation of low-density lipoproteins (LDL), possibly by proteoglycan retention, and the attraction of inflammatory cells by hyaluronic acid, in the early stages of both pathologies [84]. These commonalities have led to the suggestion that there might be an regulatory mechanism of CAVD, similar to that in arterial atherosclerosis [84, 106, 120]. It has been suggested that a potential mediator of the hemodynamics-induced differential EC modulation might be Kruppel-like factor 2 (KLF2) [80]. KLF2 is a shear-stress-regulated transcription factor that is selectively induced in ECs localized in arterial regions that are protected from atherosclerosis [121]. Along these lines, ECs exposed to the same shear stress as the inflow surface of the aortic valve leaflets, demonstrated upregulation of KLF2 relatively to ECs exposed to shear stress levels equivalent to the outflow surface the aortic leaflets [80]. Moreover, it has also been suggested that the initiation of calcific deposits on the outflow surface of the leaflets might be due to the presence of nucleation sites, which provide the starting point for calcium nodule formation [75].

involve chordal elongation and/or rupture rather than isolated leaflet prolapse due to annular dilation [86, 122]. In terms of constitution, human myxomatous MV leaflets and chordae have been reported to contain 3–9% more water and 2.4–7% more collagen compared to the normal tissues. In addition, the myxomatous leaflets and chordae contained 30–150% more GAGs compared to the normal tissues, with chordae from unileaflet prolapsing valves demonstrating 62% more GAGs than chordae from bileaflet ones [86]. The alteration in the histoarchitecture and biochemical constitution is an attribute of the altered biosynthetic response of the VICs [80]. This leads to the pathological remodeling of the myxomatous valves, which coupled with their normal wear induced during the cyclic loading, leads to the deterioration of their mechanical integrity. As discussed above, abnormalities in histoarchitecture and constitution cause alterations in the mechanical loading generated in the heart valves and, thus, abnormal VIC mechanotransduction. Indeed, VICs have been shown to respond to mechanical strain *in vitro* and modulate their biosynthetic and ECM-degradation activity. Under cyclic straining, VICs, isolated from porcine MV leaflets and chordae, produced upregulation of GAGs, with chordal VICs responding more rapidly to the cyclic strain than leaflet VICs [127, 128]. Moreover, studies with human MV explants have reported that during MVP development, healthy quiescent VICs undergo a phenotypic activation though the upregulation of the BMP4-mediated pathway [75, 129, 130]. BMP4 is an osteogenic morphogen that, together with BMP2, have been shown to be present in ossified valves [131]. BMP4 is also a potent inducer of collagen and proteoglycan

Structure-Function Relationship of Heart Valves in Health and Disease

http://dx.doi.org/10.5772/intechopen.78280

27

This work was supported by the People Programme (Marie Curie Actions) of the EU 7th Framework Programme FP7/2007–2013/ under the REA Grant Agreement Number 317512, and the German Research Foundation through the Cluster of Excellence REBIRTH (From Regenerative Biology to Reconstructive Therapy; EXC 62). The author is also funded by the German Centre for Lung Research (DZL) BREATH (Biomedical Research in End-stage and Obstructive Lung Disease Hannover) (DZL: 82DZL00201), and the German Research

synthesis, and matrix mineralization [75].

Foundation through a Project Grant (348028075).

The author has no conflict of interest to report.

Hannover Medical School, Hannover, Germany

Address all correspondence to: korossis.sotirios@mh-hannover.de

**Acknowledgements**

**Conflict of interest**

**Author details**

Sotirios Korossis

MVP is another common form of congenital valve disease that affects more than 2% of the general population, and it is the most common indication for surgical MV repair or replacement. MVP refers to the displacement of one (unileaflet MVP) or both (bileaflet MVP) MV leaflets into the left atrium during systole [80]. MVP is not apparent at birth and it usually remains asymptomatic till late adulthood [75, 80]. The condition is characterized by gross changes in the MV components, including thickening, enlargement and hooding of the leaflets, annular dilation, and elongated and/or ruptured chordae [86, 122]. The underlying pathology of MVP is myxomatous degeneration, which is defined by the abnormal accumulation of mucopolysaccharides. The pathology engulfs a number of processes, including diminishing of the fibrosa and thickening of the spongiosa layer of the leaflets, increased cellularity in the spongiosa, deposition of randomly orientated collagens, accumulation of GAG- and proteoglycan-rich myxomatous material in the leaflets and chordae, fragmentation of collagen and elastic fibers, and production of abundant matrix metalloproteases [80, 86, 123, 124]. These changes in the histoarchitecture and constitution lead to the biomechanical weakening of the MV components, which ultimately leads to mitral regurgitation, thromboembolism, heart failure and atrial fibrillation [75, 80]. Myxomatous MVs have been reported to demonstrate a lower strength, increased extensibility and decreased modulus compared to normal MVs in both the leaflets and chordae [86, 125, 126]. Myxomatous degeneration has also been reported to affect the biomechanical integrity of the chordae more that it does in the case of the leaflets [125, 126]. This finding is in accord with clinical reports that have indicated that most cases of myxomatous mitral regurgitation involve chordal elongation and/or rupture rather than isolated leaflet prolapse due to annular dilation [86, 122]. In terms of constitution, human myxomatous MV leaflets and chordae have been reported to contain 3–9% more water and 2.4–7% more collagen compared to the normal tissues. In addition, the myxomatous leaflets and chordae contained 30–150% more GAGs compared to the normal tissues, with chordae from unileaflet prolapsing valves demonstrating 62% more GAGs than chordae from bileaflet ones [86]. The alteration in the histoarchitecture and biochemical constitution is an attribute of the altered biosynthetic response of the VICs [80]. This leads to the pathological remodeling of the myxomatous valves, which coupled with their normal wear induced during the cyclic loading, leads to the deterioration of their mechanical integrity. As discussed above, abnormalities in histoarchitecture and constitution cause alterations in the mechanical loading generated in the heart valves and, thus, abnormal VIC mechanotransduction. Indeed, VICs have been shown to respond to mechanical strain *in vitro* and modulate their biosynthetic and ECM-degradation activity. Under cyclic straining, VICs, isolated from porcine MV leaflets and chordae, produced upregulation of GAGs, with chordal VICs responding more rapidly to the cyclic strain than leaflet VICs [127, 128]. Moreover, studies with human MV explants have reported that during MVP development, healthy quiescent VICs undergo a phenotypic activation though the upregulation of the BMP4-mediated pathway [75, 129, 130]. BMP4 is an osteogenic morphogen that, together with BMP2, have been shown to be present in ossified valves [131]. BMP4 is also a potent inducer of collagen and proteoglycan synthesis, and matrix mineralization [75].

## **Acknowledgements**

of the initial diagnosis, and require immediate AV replacement [115]. Accumulating evidence suggests that apart from the upregulation of certain cellular pathways that can activate VIC transdifferentiation into osteogenic phenotype and promote osteogenic ECM remodeling, several non-cellular mechanisms, such as epitaxial calcification, can also induce calcium deposition in heart valves [116]. Calcific deposits in CAVD typically occur in regions of high stress concentration [117], highlighting the importance of mechanical factors in valve calcification, and initiate on the outflow surface of the leaflets [80, 106, 118]. It has been hypothesized that valvular ECs may regulate VIC function, and that the initiation of calcific deposits on the outflow, rather than the inflow, surface of the leaflets is due to differences in the hemodynamic microenvironment on the two sides of the leaflet. Elaborating, the different hemodynamic environments generate different mechanical forces that induce different phenotypic modulations on the ECs on the opposing sides. This, in turn, causes variations in the regulation of VIC function [80, 119]. Moreover, accumulating evidence suggests that CAVD shares common features with atherosclerosis, particularly the early accumulation of low-density lipoproteins (LDL), possibly by proteoglycan retention, and the attraction of inflammatory cells by hyaluronic acid, in the early stages of both pathologies [84]. These commonalities have led to the suggestion that there might be an regulatory mechanism of CAVD, similar to that in arterial atherosclerosis [84, 106, 120]. It has been suggested that a potential mediator of the hemodynamics-induced differential EC modulation might be Kruppel-like factor 2 (KLF2) [80]. KLF2 is a shear-stress-regulated transcription factor that is selectively induced in ECs localized in arterial regions that are protected from atherosclerosis [121]. Along these lines, ECs exposed to the same shear stress as the inflow surface of the aortic valve leaflets, demonstrated upregulation of KLF2 relatively to ECs exposed to shear stress levels equivalent to the outflow surface the aortic leaflets [80]. Moreover, it has also been suggested that the initiation of calcific deposits on the outflow surface of the leaflets might be due to the presence

26 Structural Insufficiency Anomalies in Cardiac Valves

of nucleation sites, which provide the starting point for calcium nodule formation [75].

MVP is another common form of congenital valve disease that affects more than 2% of the general population, and it is the most common indication for surgical MV repair or replacement. MVP refers to the displacement of one (unileaflet MVP) or both (bileaflet MVP) MV leaflets into the left atrium during systole [80]. MVP is not apparent at birth and it usually remains asymptomatic till late adulthood [75, 80]. The condition is characterized by gross changes in the MV components, including thickening, enlargement and hooding of the leaflets, annular dilation, and elongated and/or ruptured chordae [86, 122]. The underlying pathology of MVP is myxomatous degeneration, which is defined by the abnormal accumulation of mucopolysaccharides. The pathology engulfs a number of processes, including diminishing of the fibrosa and thickening of the spongiosa layer of the leaflets, increased cellularity in the spongiosa, deposition of randomly orientated collagens, accumulation of GAG- and proteoglycan-rich myxomatous material in the leaflets and chordae, fragmentation of collagen and elastic fibers, and production of abundant matrix metalloproteases [80, 86, 123, 124]. These changes in the histoarchitecture and constitution lead to the biomechanical weakening of the MV components, which ultimately leads to mitral regurgitation, thromboembolism, heart failure and atrial fibrillation [75, 80]. Myxomatous MVs have been reported to demonstrate a lower strength, increased extensibility and decreased modulus compared to normal MVs in both the leaflets and chordae [86, 125, 126]. Myxomatous degeneration has also been reported to affect the biomechanical integrity of the chordae more that it does in the case of the leaflets [125, 126]. This finding is in accord with clinical reports that have indicated that most cases of myxomatous mitral regurgitation This work was supported by the People Programme (Marie Curie Actions) of the EU 7th Framework Programme FP7/2007–2013/ under the REA Grant Agreement Number 317512, and the German Research Foundation through the Cluster of Excellence REBIRTH (From Regenerative Biology to Reconstructive Therapy; EXC 62). The author is also funded by the German Centre for Lung Research (DZL) BREATH (Biomedical Research in End-stage and Obstructive Lung Disease Hannover) (DZL: 82DZL00201), and the German Research Foundation through a Project Grant (348028075).
