What Are The Structures That Makeup The Human Heart And How Are They Organized
Annu Rev Physiol. Author manuscript; available in PMC 2014 Oct 27.
Published in last edited class equally:
PMCID: PMC4209403
NIHMSID: NIHMS555772
Centre Valve Structure and Office in Development and Disease
Robert B. Hinton
1Sectionalization of Cardiology, the Center Establish, Cincinnati Children's Infirmary Medical Middle, 240 Albert Sabin Way ML7020, Cincinnati, OH 45229
Katherine E. Yutzey
2Division of Molecular Cardiovascular Biology, the Heart Institute, Cincinnati Children'due south Infirmary Medical Center, 240 Albert Sabin Way ML7020, Cincinnati, OH 45229
Abstruse
The mature heart valves are made up of highly organized extracellular matrix (ECM) and valve interstitial cells (VIC) surrounded by an endothelial cell layer. The ECM of the valves is stratified into elastin-, proteoglycan- and collagen-rich layers that confer distinct biomechanical properties to the leaflets and supporting structures. Signaling pathways have critical functions in primary valvulogenesis as well as maintenance of valve construction and function over time. Animal models provide powerful tools to study valve development and disease processes. Valve disease is a meaning public health problem and increasing evidence implicates abnormal developmental mechanisms underlying pathogenesis. Further studies are necessary to determine regulatory pathway interactions underlying pathogenesis in order to generate new avenues for novel therapeutics.
Keywords: middle, cardiac development, animal models, valve disease
INTRODUCTION
Heart valves function to promote coordinated forward blood flow during the cardiac cycle. Valves are highly organized connective tissue structures populated with dynamic cell populations (1). Valvulogenesis occurs after the initial stages of cardiogenesis equally a result of endocardial cushion formation and all-encompassing remodeling of the extracellular matrix (ECM) (2, 3). The valve ECM is stratified, and the localized distribution of elastin, collagen, and proteoglycan underlies the biomechanical properties of the mature valve (4). Valve disease (stenosis or regurgitation) is a meaning public wellness problem (5, 6). At that place are distinct types of valve malformations and disease that are characterized past ECM dysregulation, cellular disarray and often calcification. Any one of the iv middle valves can be afflicted; nonetheless, the aortic valve is the about mutual site of disease (7). Aortic valve malformation, including bicuspid aortic valve (BAV), is present in i–2% of the general population suggesting a developmental origin (8). Increasing evidence implicates aberrant developmental signaling pathways underlying valve disease pathogenesis (1–three). Faulty regulation of these interacting pathways results in maladaptive ECM remodeling, subtle malformation and ultimately disease.
VALVE ANATOMY AND STRUCTURE
Valve beefcake is circuitous (Figure 1). The mitral and tricuspid atrioventricular (AV) valves separate the atria from the ventricles, while the aortic and pulmonary semilunar (SL) valves separate the ventricles from the bully arteries. AV valves have leaflets and SL valves have cusps. At that place is a specialized support construction specific to AV valves, while the distinct shape of SL valves creates a unique self-contained support construction within the arterial roots (9, 10). In contrast to the aorta, the aortic root is made up of the fibrous valve annulus region and the arterial tissue inside the sinuses of Valsalva. The AV valves are characterized by large asymmetric leaflets hinged to ring shaped annuli on the secured end and tethered to the ventricles by an elaborate apparatus made up of the chordae tendineae and papillary muscles on the mobile end. The fibrous skeleton of the middle is continuous with the annulus fibrosa that constitutes the interconnected gristly cartilage-like back up appliance of the tricuspid, mitral, and aortic valves. The annulus fibrosa is connected to the muscle of the heart in a manner that is analogous to the attachment of tendon to skeletal muscle (11, 12). The pulmonary valve is separated from the other valves past a muscular sleeve and has a poorly divers, less substantial annulus structure. The annuli of the AV valves are ring-shaped; however, the annulus of the aortic valve is crown-shaped resulting in the "semilunar" shape of the private cusps (thirteen, 14).
SL and AV valves with distinct structural and functional features are present in the homo middle (A). The mitral valve (MV) is an AV valve and connects the left atrium (LA) to the left ventricle (LV). The MV consists of an annulus (A, bluish line), leaflets and chordae tendineae (CT) that insert into papillary muscles (PM) in the myocardial wall. The aortic valve (AoV) is a SL valve and connects the LV to the aorta (Ao). The AoV consists of an annulus (A, red line) and cusps anchored within the aortic root (Root). Pentachrome staining shows valve ECM structure and composition in human (B,C) and mouse (D,E) aortic valves. At low magnification, SL valve tissue demonstrates cusp and annulus regions in human being and mouse (B,D). At high magnification, aortic valve cusp architecture demonstrates similar ECM arrangement in human and mouse (C,East). The collagen-rich fibrosa layer (F) is oriented on the arterial aspect of the cusp, while the elastin-rich ventricularis layer (5) is oriented on the ventricular aspect of the cusp. The proteoglycan-rich spongiosa layer (S) interconnects the collagen and elastin fibers. IVS interventricular septum. (Console A from reference (115), with permission.)
The mitral valve is composed of two leaflets, the inductive (or aortic) and posterior leaflets. The supporting tendinous cords (chordae tendineae) on the ventricular aspect of the valve leaflets insert into two well-defined papillary muscles that are continuous with the left ventricular myocardium. The posterior leaflet dominates the majority of the mitral valve annulus circumference, but the anterior leaflet is larger and makes upward a greater surface area. Conversely, the tricuspid valve is composed of three leaflets, the anterior, posterior and septal leaflets, which attach to the ventricles via chordae tendineae to a big and variable number of seemingly unorganized papillary muscles inside the trabecular right ventricle (nine). The aortic valve is composed of three cusps, the left coronary, right coronary and non-coronary cusps, named for their relationship to the coronary arteries (xv). The pulmonary valve is situated anterior and leftward relative to the aortic valve, and the mirror image "facing" cusps of the pulmonary valve are aligned in an orthogonal plane (xiii). Human valve thickness varies past valve and valve region, just in all valves is normally less than 1mm (16, 17). The AV valves are slightly thicker than the SL valves, and the left-sided valves are slightly thicker than the right-sided valves. The base and tip of the valves tend to exist thicker, peculiarly in the SL valves. The anterior leaflet of the mitral valve is in directly continuity with the aortic valve unlike the tricuspid valve, which is separated by muscular tissue from the pulmonary valve. Despite the mutual functional requirements of all heart valves, each valve is structurally different, and in that location is emerging molecular bear witness that individual cusps and leaflets maintain distinct structural and biomechanical characteristics, potentially related to different intrinsic vulnerabilities to disease.
VALVE DEVELOPMENT
Valve morphogenesis
During embryonic development, the heart is the starting time organ to office, and it forms initially as a primitive tube composed of a myocardial cell layer surrounding an endocardial endothelial cell layer (iii). The first indication of valve development during vertebrate embryogenesis is the formation of endocardial cushions in the outflow tract (OFT) and atrioventricular (AV) canal regions of the primitive eye tube (reviewed in (eighteen)). Endocardial absorber formation is initiated when signaling factors emanating from the myocardium induce an epithelial to mesenchymal transition (EMT) of adjacent endocardial endothelial cells (19). This EMT generates mesenchymal progenitor cells that contribute to valvuloseptal structures and developed valve interstitial cells (20, 21). Initially the mesenchymal cells of the endocardial cushions are highly proliferative, and they are embedded in a loosely organized extracellular matrix (22). The endocardial cushion swellings in the OFT and AV canal function as valves to bulldoze unidirectional blood flow in the archaic heart tube (23). Valve primordia corresponding to the singled-out leaflets of the 4 valves arise with septation of the Oft and fusion of the AV canal cushions. Valve leaflet formation is characterized by thinning and elongation of the valve primordia, as well as remodeling of the ECM into layers rich in elastin (atrialis of AV valves/ventricularis of SL valves), fibrillar collagen (fibrosa), and proteoglycans (spongiosa) (18, 24). Likewise valve jail cell proliferation decreases during remodeling, and there is little to no proliferation of adult VICs (24, 25).
Embryonic origins of valve precursor cells
Heart valve cells come from multiple sources in the developing embryo. The endothelial cells that environs the valve leaflets course a continuous epithelial cell layer with the endocardium (two). In the Often, both the endocardial and myocardial precursors arise from the secondary heart field (26). During the early on stages of endocardial cushion germination, the mesenchymal cells of the AV and OFT cushions are derived from endothelial cells, as adamant by Tie2-Cre;ROSA26R reporter lineage tracing in mice (27). In the mature AV valves, the VICs as well are derived primarily, if not entirely, from Tie2-Cre expressing endothelial cells (xx, 21). In mice, there is little if any contribution of VICs in the AV valves from epicardially-derived cells, as indicated past Wilms Tumor 1 (WT1)-Cre lineage assay (28). However, chick-quail bubble studies in avian embryos take reported pregnant contributions of epicardium-derived cells in the developing AV valves (27, 29). In the developing OFT cushions, in that location are pregnant numbers of neural crest-derived cells, as demonstrated past Wnt1-Cre lineage studies in mice (27). In the mature SL valves, the cells of neural crest origin persist and are concentrated in individual cusps of the pulmonary and aortic valves (xxx)(Mead and Yutzey, unpublished). Overall, lineage tracing studies in mice demonstrate that the majority of VICs arise from endothelially-derived progenitors in the endocardial cushions. However, at that place is increasing bear witness that specific subpopulations in individual valve leaflets arise from distinct embryonic sources. Information technology is non known if these cells from diverse embryonic origins stand for different subpopulations of VICs with specific contributions to mature valve construction and function.
Molecular regulation of valvulogenesis
Several developmentally important signaling pathways take critical functions in endocardial cushion consecration and EMT. BMP2 signaling from the myocardium to the endocardium in the OFT and AV canal is required for the initial consecration of EMT (31). Canonical Wnt signaling, besides as TGF-beta signaling, besides are required for EMT and proliferation of mesenchymal endocardial cushion cells (19, 32, 33). Notch signaling in the endocardium regulates the repression of endothelial jail cell gene expression and also is required for EMT (34). The mesenchymal cells of the endocardial cushions are highly proliferative and express Twist1 and Msx transcription factors, characteristic of mesenchymal progenitor populations of many organ systems (18, 35). Twist1, along with Tbx20, promotes jail cell proliferation, migration and primitive ECM gene expression in the endocardial cushions and subsequently is down-regulated during valve remodeling (36, 37). Together, the valve progenitor cells of the endocardial cushions express many of the genes and cellular properties of mesenchymal jail cell types involved in development and regeneration, every bit well as tumor metastasis.
The generation of ECM compartments of the stratified valve leaflets is controlled by regulatory interactions shared with related connective tissue types (Figure ii) (12, 18). The transition from endocardial cushion to remodeling valve requires the transcription gene NFATc1, that promotes the expression of the ECM remodeling enzyme gene cathepsinK in valve endothelial cells, besides as osteoclasts in remodeling bone (38–40). Research over the past few years has demonstrated striking parallels in the interactions among signaling molecules, transcription factors, and structural proteins that control differentiation of connective tissues, such as cartilage, tendon, and os, and as well regulate compartmentalized ECM factor expression in the developing valves (12). For example, BMP2 signaling activates the Sox9 transcription factor and aggrecan factor expression in cartilage precursors as well as valve progenitors (41, 42). In add-on, FGF4 signaling activates Scleraxis and tenascin in developing tendons also as in the remodeling valves (41, 42). Wnt signaling, agile in the developing valves and critical for early os formation, promotes expression of genes characteristic of the collagen-rich fibrosa layer in cultured valve interstitial cells (43). The initiation and maintenance of valve leaflet stratification are likely affected by hemodynamics and biomechanical forces acting on the valves during the cardiac bike (44). Still, the molecular ground for the integration of valve function and cardiovascular physiology with ECM compartmentalization during development and later in life has not been elucidated.
Regulatory interactions of signaling pathways and transcription factors in heart valve development. Signaling pathways including Notch, Transforming growth factor (TGF), Bone morphogenetic protein (BMP), and Wnt, with transcription factors including Twist1, Tbx20 and Msx1/2 are involved in endocardial absorber (EC) germination during early on valvulogenesis. NFATc1 signaling contributes to elongation and remodeling of the EC. During valve maturation, BMP signaling induces cartilage-associated genes Sox9 and aggrecan. Fibroblast growth factor (FGF) signaling promotes expression of scleraxis and tenascin, which are characteristic of tendon cell lineages. These genes and pathways involved in valve evolution also are active in adult valve disease.
VALVE Limerick AND FUNCTION
ECM composition and arrangement in the developing and mature valves
Normal valve function requires coordinated activity of complex structures. Gross and Kugel systematically described the histology of the human being heart valves in 1931, and the proposed nomenclature for valve tissue organization is at present established (45). The mature valve structure is made upwards of highly organized ECM that is compartmentalized into three layers, the fibrosa, spongiosa, and either the ventricularis of the SL valves or the atrialis of the AV valves (Figure 1). The fibrosa, which is situated on the ventricular aspect of AV valves and the arterial aspect of SL valves, is equanimous predominantly of fibrillar collagens (types I and Three) that are circumferentially oriented and provide tensile stiffness (46–49). The atrialis layer of the AV valves and the ventricularis layer of the SL valves are equanimous primarily of radially-oriented filamentous rubberband fibers that facilitate tissue motion (fifty, 51). Elastic fibers extend from the valve hinge to the closing or coapting edge and therefore do not run the entire length of a valve. The atrialis/ventricularis layer facilitates valve tissue motion past allowing extension and recoil of the valve during the cardiac bicycle. The spongiosa makes upwards the center area and is composed primarily of proteoglycans with interspersed collagen fibers. Proteoglycans are present throughout the valve thickness, but are the predominant matrix component of the middle layer and serve as an interface between the orthogonally arranged fibrosa and atrialis/ventricularis layers to provide tissue compressibility and integrity. The annulus, equanimous primarily of fibrous collagen, provides a buttress for dispersion of forces, and tethering of the cusp/leaflet complimentary edges is required for tissue stabilization. In the AV valves, leaflets are connected to the ventricular myocardium by chordae tendineae, while in the SL valves, cusps are anchored directly to the arterial roots. There is redundant tissue at the tips of both AV and SL valves that provides functional valve closure or coaptation of the valve leaflets/cusps and ultimately competence when the valve is airtight. There has to be a precise balance between stiffness and flexibility. Therefore the stoichiometry and distribution of ECM components is critical to proper valve office.
Mice lacking specific ECM proteins have developmental defects in valve formation and function (Tabular array 1). In dissimilarity to the highly structured stratified ECM layers of the mature valve, the ECM of the endocardial cushions is initially composed primarily of hyaluronan, and the mesenchymal cells generate a loosely organized collagen network permissive for cell migration (22). Mice lacking the hyaluronan synthetic enzyme Has2 exhibit loss of endocardial cushion swelling and lack of EMT (52). Loss of the proteoglycans perlecan or versican also leads to OFT cushion abnormalities and embryonic lethality (53, 54). Likewise loss of cartilage link protein1 (Crtl1), that interacts with hyaluronan and versican, also leads to valvuloseptal defects (55). Elastin cistron expression is initiated in the remodeling valves during tardily embryonic and neonatal stages (24). Mice lacking elastin do non survive subsequently nativity due to vascular obstruction, and elastin heterozygous mice have aortic valve abnormalities in both construction and function in machismo (56–58). Periostin regulates collagen fibrillogenesis in a diversity of connective tissues, and loss of periostin in mice leads to aberrant valve morphogenesis and collagen system (59, 60). Similarly, loss of the crosslinking collagens 5a1 and 11a1 leads to thickening of the SL and AV valves, with altered ratios of fibrillar collagens 1 and 3 indicative of remodeling defects (61). Together these studies demonstrate that the expression and system of various ECM components is essential to the morphogenesis and structural integrity of the valves during development and consequently afterwards birth.
Table one
Mouse mutations in ECM genes associated with heart valve abnormalities
| ECM | Genotype | Phenotype | Ref. |
|---|---|---|---|
| Proteoglycan-related | |||
| Hyaluronan | Has2−/− | Lethal E9.5a; Lack endocardial cushions | (52) |
| Versican | hdf | Lethal E10.5; Lack endocardial cushions; Oft defects | (53) |
| Perlecan | Perlecan−/− | Lethal E10-P0; Ofttimes cushion defects; other middle defects | (104) |
| Cartilage Link Protein | Crtl1−/− | Lethal P0; valvuloseptal defects and other abnormalities | (55) |
| ADAMTS9 | Adamts9+/− | Aortic valve cusp and annulus malformations | (98) |
| Elastic fiber-related | |||
| Elastin | Eln−/− | P0 death from vascular obstruction | (56) |
| Eln+/− | Aortic valve cusp and annulus malformations | (58) | |
| Fibrillin-1 | Fbn1−/− | Lethality by P14 from vascular complications | (105) |
| Fbn1+/− | Mitral valve prolapse | (94) | |
| Fibulin-4 | Fibulin4-R/R | Adult thickened aortic valves and vascular defects | (106) |
| Fibrillar collagen-related | |||
| Periostin | Postn−/− | Spectrum of lethal and not-lethal valve defects | (59) |
| Collagen 1a1 | OIM | Thickening of adult semilunar valves | (Yutzey, unpublished) |
| Collagen 3a1 | Col3a1−/− | Aortic aneurysm; valves not examined | (95) |
| Collagen 11 | Col11a1−/− | P0 lethality; Thickened heart valves | (61, 107) |
The ECM limerick of the mature valves is dependent on the synthetic activeness of the valve interstitial cells (VIC). During valve remodeling, the VICs express genes that encode fibrillar collagens, chondroitin sulfate proteoglycans, and elastin, associated with the stratified ECM of the valve leaflets (24, 25). The localized expression of specific ECM proteins characteristic of dissimilar connective tissue cell types suggests that at that place are different subpopulations of VICs in the stratified valves, but this has not yet been definitively demonstrated. Boosted ECM remodeling enzymes such equally matrix metalloproteases (MMPs), tissue inhibitors of matrix metalloproteases (TIMPS), and cathepsins too are expressed during valve maturation (17, 25). VICs from remodeling valves are highly synthetic, and cell proliferation is reduced relative to the endocardial absorber cells (21, 24). In normal developed valves, the VICs are largely quiescent with little or no cell proliferation and maintain baseline levels of ECM gene expression necessary for valve homeostasis (25).
Biomechanics and hemodynamics
Valve structure-function relationships provide important insight in understanding mechanisms of valve homeostasis every bit well as developmental and disease processes. The middle valves function essentially to maintain unobstructed unidirectional blood catamenia. The hemodynamics of the normal mature heart are well established (62). Blood flows from low pressure atria to higher force per unit area ventricles, which in turn supply the great arteries. The left side of the center maintains significantly higher pressures than the correct side. Every bit a consequence, the impact of various physiologic forces depends on the position and hemodynamic surroundings of the valve. Valve composition and biomechanics reflect underlying hemodynamics. There are three basic loading states that affect valve tissue during the cardiac bicycle: flexure, shear and tension. Flexure occurs when the valve is actively opening or closing, shear occurs when blood is passing through the open valve, and tension occurs when the valve is closed (4, 63). Shear, compressive, and longitudinal stresses contribute to valve deformation, or deportation of the valve tissue during the constant motility of the cardiac cycle (64). Valve tissue has uncommonly loftier strain considering the tissue cycles to a completely unloaded state with each heart beat (49). These deformation forces result in a compensatory rest in cell matrix composition. For example, comparison of porcine aortic and pulmonary valves demonstrates that the left sided aortic valve is thicker, predominantly every bit a result of increased collagen expression and increased thickness of the fibrosa layer (Alfieri, Carruthers, Yutzey, and Sacks, unpublished data). The heart beats more than than 100,000 times per day treatment approximately v liters of blood per minute. Over the average lifetime, there are greater than iii billion heart beats, or cardiac cycles. Valve failure may upshot from an underlying predisposing genotype and valve malformation that alters the response to physiologic stresses. The long held appreciation of age-related degeneration ("wear and tear") and latent valve affliction may in fact represent subtle defects in valve tissue maintenance as regulated by developmental pathways.
VALVE MALFORMATION AND Illness
Valve disease is a public health problem
Valve disease results in approximately 20,000 deaths annually (65). The prevalence of aortic valve disease is 2.v% in the The states, corrected for age (66). Aortic valve sclerosis, a marker of valve disease and cardiovascular risk, is present in more than 25% of the aged (67). The actual direct cost for valve disease in the United States lonely has been estimated at 1 billion dollars per twelvemonth (68). Taken together, the public health affect of valve disease and burden to society is underappreciated. Valve disease may manifest as stenosis, an obstacle to outflow, or regurgitation, a defective closure resulting in backward period. Valve disease tends to progress. Ultimately, ventricular office can be compromised. Aortic valve stenosis is the almost common grade of valve illness and classically manifests as angina, syncope and center failure. The diagnosis can be fabricated clinically and confirmed past echocardiography, which quantifies the severity, and, over time, the progression of disease (62). The majority of valve disease at whatever age has an underlying valve malformation suggesting a genetic footing (8).
Built heart valve malformations occur in approximately ii% of live births, and the incidence is idea to be significantly college since many cases remain subclinical and therefore unidentified. The 2 most common types of valve malformation are bicuspid aortic valve (BAV), an aortic valve with ii rather than three cusps, and mitral valve prolapse (MVP), a mitral valve with redundant and billowing leaflets that prolapse into the left atrium. BAV has been estimated in upward to 2% and MVP in up to 5% of the general population (v). In improver, valve defects occur in approximately 30% of cardiovascular malformations (CVM), including complex defects where valve disease is one component of the diagnosis, east.g. aortic valve stenosis is function of hypoplastic left middle syndrome and pulmonary valve stenosis is part of tetralogy of Fallot (69). There is considerable prove that congenital valve malformations have a genetic basis and therefore stand for abnormalities in development (69). BAV and MVP are common findings in patients with gene mutations that impact connective tissue homeostasis (Table 2). In nonsyndromic families, mutations in NOTCH1 have been identified in cases of BAV and calcific aortic valve disease (70). Family unit based linkage studies have identified affliction loci on chromosomes 18q, 13q and 5q for BAV and 16p, 11p and 13q for MVP, however no genes have been identified (71–74). Importantly, these linkage studies stand for a significant proportion of cases and therefore likely harbor the causes of malformation and illness. Pedigree assay is consistent with complex inheritance, and in the context of reduced penetrance and variable expressivity, valve malformation may exist the result of multiple predisposing genotypes. Taken together, valve malformation is a subtle and viable genetic defect that unremarkably manifests as significant disease afterward in life.
Table ii
Human mutations in ECM genes associated with heart valve abnormalities
| Factor | Syndrome | Valve phenotype | Ref. |
|---|---|---|---|
| FIBRILLIN-1 (FBN1) | Marfan | Aortic root dilation, BAVa, MVP | (108) |
| ELASTIN (ELN) | Williams | SVAS, BAV, MVP | (109) |
| TGFβReceptor-1 (TGFBR1) | Loeys-Dietz | Aortic aneurism, MVP | (110) |
| COLLAGEN-one (COL1A1) | Osteogenesis Imperfecta | Aortic valve prolapse, MVP | (96) |
| COLLAGEN-three (COL3A1) | Ehlers-Danlos | Aortic root dilation, BAV, MVP | (111) |
| NOTCH-1 | BAV, CAVD, CVM | (seventy) | |
| ACTA-2 | Aortic aneurism, BAV | (112) | |
| MYH-11 | Aortic aneurism, BAV | (113) | |
| FLN-A | BAV, MVP | (114) |
Valve malformation underlies valve illness
Although valve disease has been recognized as a meaning cause of morbidity and mortality for a long fourth dimension, it was not until the 1950s that isolated aortic valve disease in the context of valve malformation was appreciated. Consequently, the idea emerged that latent affliction has its origins in subtle developmental abnormalities (75, 76). Afterwards, large scale studies have shown that at all ages, including avant-garde age, the majority of valve disease cases have a malformed valve (8, 77–80), suggesting valve affliction is attributable to aberrant developmental mechanisms (81). In this context, valve disease may develop as a outcome of predisposing genotypes in combination with maladaptive valve tissue maintenance, that over time leads to valve affliction. In addition to the clan betwixt valve disease and more severe congenital CVM, valve illness may as well be associated with other "acquired" CVM. For example, approximately twenty% of patients with aortic valve malformation also have aortopathy, raising fundamental questions virtually both etiology and therapy. In add-on to abnormalities in the aorta, de Sa et al. demonstrated that patients with aortic valve malformation had histologic abnormalities in the pulmonary artery, supporting the thought that developmental abnormalities have multiple furnishings that may be clinically relevant (82). Every bit more is learned well-nigh the pathogenesis of associated diseases, a molecular taxonomy will emerge that volition facilitate clinical decision-making.
Valve histopathology identifies ii basic affliction processes
Valve histopathology tends to suit to one of ii patterns, myxomatous modify or fibrotic change. Myomatous degeneration is characterized past proteoglycan accumulation, collagen deposition, and elastic fiber fragmentation. These changes consequence in a "floppy" valve that is prone to prolapse and regurgitation. Conversely, fibrosis is characterized past collagen aggregating, proteoglycan degradation, and elastic fiber fragmentation. These changes result in a "stiff" valve that is prone to restricted movement and stenosis. Aortic valve stenosis is typically characterized by sclerosis ("hardening") and progressive fibrosis with advanced disease marked by calcification. Calcification is a common late finding. The etiology of calcification is poorly understood; however, this attribute of valve illness has generated substantial interest every bit a potential avenue to develop new therapeutics. Ane benefit to studying pediatric valve illness is that the histopathology identified is non confounded by the common comorbidities of adulthood, namely coronary avenue illness and hypertension. Since aortic valve disease often occurs in the context of coronary artery disease, there is considerable interest in applying coronary artery illness treatment paradigms to valve disease. For instance, statin therapy is hypothetically appealing and showed early in vitro evidence of positive bear upon; unfortunately, a large clinical trial demonstrated that statin therapy does not appear to touch on aortic valve illness incidence or progression (83). Elucidating the genetic and molecular basis of valve malformation will provide opportunities for the development of new therapies.
At the cellular level, heart valve illness is characterized past VIC activation, too as increased ECM and remodeling enzyme gene expression (Effigy 3)(24, 84, 85). VIC activation is apparent in increased jail cell proliferation and induction of myofibroblast markers, such as vimentin, MMP-13, smooth muscle α-actin (SMA), and embryonic nonmuscle myosin heavy concatenation (SMemb) (84). These markers also are expressed in valve progenitor cells during development, supporting the thought that activated VICs in diseased valves correspond a developmental phenotype. This is supported by the observation that the transcription factor Twist1, critical in endocardial cushion mesenchyme, also is expressed in human diseased heart valves (Chakraborty, Wirrig, Hinton, and Yutzey, unpublished). During human aortic valve calcification, expression of several genes associated with osteogenesis, including Sox9, Runx2, osteocalcin, osteopontin, alkaline phophatase, and os sialoprotein, is induced (86, 87). There is increasing prove that calcific valve disease recapitulates factor regulatory interactions feature of osteogenesis.
Valve interstitial cell (VIC) phenotype relates to maladaptive and pathologic signaling pathways. Quiescent VICs prove petty proliferation or gene expression, while activated VICs demonstrate increased proliferation and increased myofibroblast-associated gene expression. VIC activation may be adaptive or maladaptive, and patterns of signaling pathway factor expression may distinguish these features. Some maladaptive VIC activation and induction of genes associated with bone formation are credible in valve tissue calcification. SMA smooth musculus α-actin; MMP matrix metalloprotease; OCN osteocalcin; BSP bone sialoprotein; ALP alkaline phosphatase.
The origins and inductive mechanisms of activated VICs in valve disease have not been identified. There is initial show from primary jail cell cultures that the interaction of VICs with the surrounding ECM contributes to VIC activation and osteogenic factor consecration (88). Some VICs have been shown to be dynamic and play an active role in ECM maintenance (85, 89). It is possible that activated VICs arise from quiescent VICs resident in the valve leaflets. Alternatively, immature valve progenitors arising during development could remain in the adult valves as potential effectors of regeneration and repair. The presence of an exogenous stem jail cell population that is recruited to the valves during affliction is supported past reports of hematopoietic stalk jail cell derivatives in adult eye valves (90, 91). Further studies are necessary to determine the regenerative potential or pathologic mechanisms associated with VIC activation in valve illness.
Genetic syndromes and creature models of valve disease
Normal heart valve part is dependent on the biomechanical backdrop of the stratified ECM, and mutations in a variety of ECM genes are associated with man heart valve disease (Table ii). Several genetic syndromes characterized by connective tissue disorders include valve malformations and progressive valve dysfunction. Marfan syndrome, caused by mutations in FIBRILLIN-i, is characterized by thickening of the mitral and aortic valves in addition to the characteristic aortic root and skeletal anomalies (92). Similarly, Williams syndrome, associated with heterozygous ELASTIN mutations, includes arteriopathy manifested every bit supravalvar aortic stenosis as well as aortic valve illness (93). Many valve phenotypes in human genetic syndromes are recapitulated by targeted mutagenesis fauna models (Table i). Fibrillin-i insufficient mice develop mitral valve prolapse like to that seen in humans (94). Likewise, heterozygous elastin (eln +/−) mice develop progressive aortic valve malformation and latent aortic valve affliction, similar to humans with degenerative aortic valve affliction (56–58). Interestingly, these mice have both valve disease and aortopathy with the annulus region implicated in disease manifestation. These findings raise fundamental questions virtually both the origin and functional capacity of the aortic valve and aortic root.
Ehlers-Danlos syndrome is acquired by a variety of collagen and tenascin factor mutations that affect connective tissue structure and office in multiple organs, including the heart valves (reviewed in (12)). There is currently non a mouse model for valve abnormalities related to Ehlers-Danlos syndrome, but mice lacking collagen 3a1 restate the aortic rupture phenotype (95). In the futurity, it would exist of involvement to determine if these mice also have valve abnormalities and dysfunction associated with human Ehlers-Danlos syndrome. Mutations in COL1A1 are associated with the homo bone condition ostegenesis imperfecta, and prolapse of aortic and mitral valves can occur in this patient population (96). A mouse model has been generated with a targeted Col1a1 oim mutation, and these animals develop progressive thickening of the semilunar valves with increased proteoglycan deposition as adults (97)(Wirrig, Cheek and Yutzey, unpublished). It is interesting to notation that man valve disease related to proteoglycan cistron mutations has not been reported. However, mice heterozygous for the versican-degrading protease factor Adamts9 take thickening of the semilunar valves and chondrogenic nodules in the annulus region (98). Mutations in additional isolated ECM genes are associated with human aortic and mitral valve malformations and disease, while dysregulation of the valve leaflet ECM organization and degradation is a full general feature of valve affliction regardless of etiology.
There is increasing bear witness that disruption of the valve ECM induces signaling pathways that lead to maladaptive ECM remodeling and ultimately valve affliction. The aortic and mitral valve phenotypes of Marfan syndrome are associated with increased TGF-beta signaling that contributes to the overall collagen dysregulation and loss of matrix integrity of these structures in animal models (94). Strikingly, inhibition of TGF-beta signaling via Losartan treatment reduces pathology in a mouse model of Marfan syndrome, and efficacy in humans as well has been demonstrated (99, 100). Likewise in adult mice, heterozygous loss of elastin or homozygous loss of periostin, affects TGF-beta signaling associated with aortic valve degeneration and dysfunction (Table i) (58, 59). Notch and Wnt signaling likewise have been reported to be altered in animal models of aortic valve affliction, as well equally in human patients, but the mechanisms of induction take not nonetheless been defined (70, 101). TGF-beta, Notch and Wnt signaling all are required for normal center valve evolution during embryogenesis, and there is increasing evidence that these pathways, in clan with ECM dysregulation, contribute to progressive valve pathogenesis resulting in a variety of disease phenotypes later in life.
Valve affliction handling
The treatment of valve illness remains primarily surgical. Any one of the iv heart valves can exist afflicted; nevertheless, the aortic valve is the nigh mutual site of disease (seven). Indications for valve replacement include clinical symptoms, ventricular dysfunction or exercise intolerance in asymptomatic patients. Aortic valve replacement is the second most mutual cardiothoracic procedure, and the demand for reintervention is common. Nigh 100,000 valve replacement procedures are performed in the U.s.a. annually, and the majority of these are aortic valve replacement procedures (six). Bioprosthetic valve replacement has become increasingly popular, yet continues to suffer from longevity issues. At that place have been exciting advances in interventional cardiac catheterization, including percutaneous insertion of the pulmonary valve (102). This arroyo was approved in January 2010 by the Nutrient and Drug Assistants under the Humanitarian Device Exemption program (world wide web.fda.gov/NewsEvents/ucm198597.htm) and delays the need for open middle surgery. Information technology may too be an appealing alternative in high take a chance cases. In add-on, transcatheter aortic valve implantation using either a trans-femoral retrograde or trans-apical antegrade approach is under investigation in humans, primarily in Europe, and shows early promise (103). Once feasibility is established, clinical trials will be organized.
To improve the care of patients with valve disease, markers of future disease and illness progression need to exist identified. Early identification of disease will allow early intervention and potentially preventive approaches to valve affliction. Current medical therapy for valve disease treats the symptoms of cardiovascular disease. For example, some medicines are directed at the important symptoms that event from congestive heart failure, only exercise not impact the underlying crusade or the primary trouble, valve disease. As the genetic and developmental ground of valve malformation and disease is elucidated, opportunities for novel medical therapies will emerge and potentially preclude or filibuster the need for surgery. Defining regulation of valve tissue maintenance and homeostasis will provide heady opportunities for prison cell-based or molecular therapies for valve disease.
CONCLUSIONS
The mature valve structure, consisting of highly organized ECM and dynamic VICs, maintains valve part. Together, the stratified ECM and VIC homeostatic mechanisms underlie valve structure and role and coordinate maintenance of valve tissue throughout a lifetime. Heart valve illness is characterized by dysregulation of ECM system and VIC activation with consecration of regulatory pathways active in valve development. Valve disease pathogenesis is existence elucidated through study of animal models, and a better understanding of these mechanisms volition allow the development of novel therapeutics.
Acknowledgements
We thank Elaine Wirrig for critical reading of the manuscript and advice on figure preparation. We thank Christina Alfieri, Christopher Carruthers, Santanu Chakraborty, Jonathan Cheek, Timothy Mead, Michael Sacks, and Elaine Wirrig for communication of results prior to publication. R.B.H. is supported past the Cincinnati Children's Research Foundation and NIH HL085122. Enquiry in K.Due east.Y.'s laboratory is supported by the American Heart Clan and NIH HL094319 and HL082716.
List of acronyms
| AV | Atrioventricular |
| AVR | Aortic valve replacement |
| BAV | Bicuspid aortic valve |
| CVM | Cardiovascular malformation |
| ECM | Extracellular matrix |
| EMT | Epithelial to mesenchymal transition |
| MVP | Mitral valve prolapse |
| Oftentimes | Outflow tract |
| SL | Semilunar |
| VIC | Valve interstitial jail cell |
Footnotes
Disclosure Statement
The authors are not aware of any affiliations, memberships, funding or financial holdings that might be perceived as affecting the objectivity of this review.
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Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4209403/
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