“…Common examples of leaflet function include activation of myocyte and fibroblast differentiation during inflammatory response to calcification 50 , as well as ongoing adjustment of biomechanical properties through fibroblast-driven tissue remodeling in response to the hemodynamic forces constantly imparted over the three billion repetitive systole and diastole cycles of a human lifespan 23 , 48 , 49 . These adaptive structural and functional responses are made possible by communication between valvular endothelial cells (VECs) and valvular interstitial cells (VICs), which results in tissue remodeling and the synthesis of a valvular extracellular matrix (VECM), collagen and elastin 7 , 11 , 12 , 14 , 23 , 24 , 48 , 49 , 51 – 53 . Figure 3 Physiological context and vertical histological cryosection of aortic valve leaflets.…”
Section: Resultsmentioning
confidence: 99%
“…3 d): (1) a fibrosa layer on the aortic side (45% of leaflet thickness) that contains a mixed population of VICs and Type I collagen fibers 55 – 57 for support against circumferential hemodynamic stresses and tensile forces imparted by aortic backflow during diastole; (2) a middle spongiosa layer (35% of leaflet thickness) with a microvascular system that permits interstitial cells to absorb shear forces during the cardiac cycle, an extracellular matrix that produces high concentrations of proteoglycan and glycosaminoglycan (GAG) and a high hydrous content for gliding of the layers during the cardiac cycles; and (3) a lowermost ventricularis layer (20% of leaflet thickness) that contains densely laminated and radially aligned elastin fibers that provide tissue structural flexibility, enhanced radial stretch and elastic recoil during systole. However, upon calcification and initiation of inflammatory responses, leaflets undergo complex modifications and remodeling 14 .…”
Section: Resultsmentioning
confidence: 99%
“…As a result, original leaflet tissue permeability may be sufficient to permit the ongoing normally occurring infiltration of saturated lipid-rich serum-derived solutions that are capable of in vivo calcification. In addition to these permeating fluids, ACP-rich vesicles and lipids may also be delivered inside the leaflet tissues via microvasculature 14 .…”
Section: Discussionmentioning
confidence: 99%
“…Since 1975, several comprehensive reviews 12 , 13 , 15 , 25 refer to four basic research studies 26 – 29 that have identified ACP as the primary agent of aortic valve and arterial calcification by combining electron diffraction, standard microscopy and microprobe analyses with optical microscopy on unstained histological cryosections. Now, a half century later, rigorous examination specifically targeting the role of ACP in cardiovascular calcification remains to be completed 12 , 14 , 25 , 29 . This is in sharp contrast to long-running recognition of the fundamental importance of ACP biomineralization in bone, teeth and kidney stones 4 , 30 – 32 , as well as a wide variety of other bioengineering applications that have used multiple nano- and micro-scale analytical techniques to characterize ACP 3 , 32 – 34 .…”
Calcification of aortic valve leaflets is a growing mortality threat for the 18 million human lives claimed globally each year by heart disease. Extensive research has focused on the cellular and molecular pathophysiology associated with calcification, yet the detailed composition, structure, distribution and etiological history of mineral deposition remains unknown. Here transdisciplinary geology, biology and medicine (GeoBioMed) approaches prove that leaflet calcification is driven by amorphous calcium phosphate (ACP), ACP at the threshold of transformation toward hydroxyapatite (HAP) and cholesterol biomineralization. A paragenetic sequence of events is observed that includes: (1) original formation of unaltered leaflet tissues: (2) individual and coalescing 100’s nm- to 1 μm-scale ACP spherules and cholesterol crystals biomineralizing collagen fibers and smooth muscle cell myofilaments; (3) osteopontin coatings that stabilize ACP and collagen containment of nodules preventing exposure to the solution chemistry and water content of pumping blood, which combine to slow transformation to HAP; (4) mm-scale nodule growth via ACP spherule coalescence, diagenetic incorporation of altered collagen and aggregation with other ACP nodules; and (5) leaflet diastole and systole flexure causing nodules to twist, fold their encasing collagen fibers and increase stiffness. These in vivo mechanisms combine to slow leaflet calcification and establish previously unexplored hypotheses for testing novel drug therapies and clinical interventions as viable alternatives to current reliance on surgical/percutaneous valve implants.
“…Common examples of leaflet function include activation of myocyte and fibroblast differentiation during inflammatory response to calcification 50 , as well as ongoing adjustment of biomechanical properties through fibroblast-driven tissue remodeling in response to the hemodynamic forces constantly imparted over the three billion repetitive systole and diastole cycles of a human lifespan 23 , 48 , 49 . These adaptive structural and functional responses are made possible by communication between valvular endothelial cells (VECs) and valvular interstitial cells (VICs), which results in tissue remodeling and the synthesis of a valvular extracellular matrix (VECM), collagen and elastin 7 , 11 , 12 , 14 , 23 , 24 , 48 , 49 , 51 – 53 . Figure 3 Physiological context and vertical histological cryosection of aortic valve leaflets.…”
Section: Resultsmentioning
confidence: 99%
“…3 d): (1) a fibrosa layer on the aortic side (45% of leaflet thickness) that contains a mixed population of VICs and Type I collagen fibers 55 – 57 for support against circumferential hemodynamic stresses and tensile forces imparted by aortic backflow during diastole; (2) a middle spongiosa layer (35% of leaflet thickness) with a microvascular system that permits interstitial cells to absorb shear forces during the cardiac cycle, an extracellular matrix that produces high concentrations of proteoglycan and glycosaminoglycan (GAG) and a high hydrous content for gliding of the layers during the cardiac cycles; and (3) a lowermost ventricularis layer (20% of leaflet thickness) that contains densely laminated and radially aligned elastin fibers that provide tissue structural flexibility, enhanced radial stretch and elastic recoil during systole. However, upon calcification and initiation of inflammatory responses, leaflets undergo complex modifications and remodeling 14 .…”
Section: Resultsmentioning
confidence: 99%
“…As a result, original leaflet tissue permeability may be sufficient to permit the ongoing normally occurring infiltration of saturated lipid-rich serum-derived solutions that are capable of in vivo calcification. In addition to these permeating fluids, ACP-rich vesicles and lipids may also be delivered inside the leaflet tissues via microvasculature 14 .…”
Section: Discussionmentioning
confidence: 99%
“…Since 1975, several comprehensive reviews 12 , 13 , 15 , 25 refer to four basic research studies 26 – 29 that have identified ACP as the primary agent of aortic valve and arterial calcification by combining electron diffraction, standard microscopy and microprobe analyses with optical microscopy on unstained histological cryosections. Now, a half century later, rigorous examination specifically targeting the role of ACP in cardiovascular calcification remains to be completed 12 , 14 , 25 , 29 . This is in sharp contrast to long-running recognition of the fundamental importance of ACP biomineralization in bone, teeth and kidney stones 4 , 30 – 32 , as well as a wide variety of other bioengineering applications that have used multiple nano- and micro-scale analytical techniques to characterize ACP 3 , 32 – 34 .…”
Calcification of aortic valve leaflets is a growing mortality threat for the 18 million human lives claimed globally each year by heart disease. Extensive research has focused on the cellular and molecular pathophysiology associated with calcification, yet the detailed composition, structure, distribution and etiological history of mineral deposition remains unknown. Here transdisciplinary geology, biology and medicine (GeoBioMed) approaches prove that leaflet calcification is driven by amorphous calcium phosphate (ACP), ACP at the threshold of transformation toward hydroxyapatite (HAP) and cholesterol biomineralization. A paragenetic sequence of events is observed that includes: (1) original formation of unaltered leaflet tissues: (2) individual and coalescing 100’s nm- to 1 μm-scale ACP spherules and cholesterol crystals biomineralizing collagen fibers and smooth muscle cell myofilaments; (3) osteopontin coatings that stabilize ACP and collagen containment of nodules preventing exposure to the solution chemistry and water content of pumping blood, which combine to slow transformation to HAP; (4) mm-scale nodule growth via ACP spherule coalescence, diagenetic incorporation of altered collagen and aggregation with other ACP nodules; and (5) leaflet diastole and systole flexure causing nodules to twist, fold their encasing collagen fibers and increase stiffness. These in vivo mechanisms combine to slow leaflet calcification and establish previously unexplored hypotheses for testing novel drug therapies and clinical interventions as viable alternatives to current reliance on surgical/percutaneous valve implants.
“…Increased oxidative stress promotes the formation of oxidized LDL, which triggers the vascular and valve inflammatory response, activating local macrophages, CD4+, CD8+ lymphocytes, T lymphocytes, and mast cells (16). After the inflammatory phase, the propagation stage will predominantly be in the valve tissue, in which cytokines secreted by immune cells promote the differentiation of valve interstitial cells into myofibroblasts and osteoblastic phenotypes, and this process will finally cause the diffuse release of calcium in the valve tissue (16,17) .…”
Aortic stenosis is associated with aortic plaques in up to 85% of cases because they share risk factors and pathogenic pathways. Intrinsically, complex aortic plaques carry a high risk of stroke, which has also been demonstrated in the context of aortic stenosis, especially in patients who underwent percutaneous or surgical replacement. Transesophageal echocardiography (TEE) is the imaging test of choice to detect plaques in the thoracic aorta and classify them as complex plaques. Furthermore, the 3D modality allows us to better specify its dimensions and anatomical characteristics, such as added thrombi or the presence of ulcers inside. This review aims to evaluate the use of TEE to detect complex aortic plaques in patients with an indication for percutaneous or surgical aortic valve replacement. To highlight the association between aortic stenosis and complex aortic plaques, we attached to the review some TEE studies from our experience.
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