Calcific Aortic Valve Disease: Not Simply a Degenerative Process
2011; Lippincott Williams & Wilkins; Volume: 124; Issue: 16 Linguagem: Inglês
10.1161/circulationaha.110.006767
ISSN1524-4539
AutoresNalini M. Rajamannan, F.J. Evans, Elena Aïkawa, K. Jane Grande‐Allen, Linda L. Demer, Donald D. Heistad, Craig A. Simmons, Kristyn S. Masters, Patrick Mathieu, Kevin D. O’Brien, Frederick J. Schoen, Dwight A. Towler, Ajit P. Yoganathan, Catherine M Otto,
Tópico(s)Aortic Disease and Treatment Approaches
ResumoHomeCirculationVol. 124, No. 16Calcific Aortic Valve Disease: Not Simply a Degenerative Process Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBCalcific Aortic Valve Disease: Not Simply a Degenerative ProcessA Review and Agenda for Research From the National Heart and Lung and Blood Institute Aortic Stenosis Working Group Nalini M. Rajamannan, MD, Frank J. Evans, PhD, Elena Aikawa, MD, PhD, K. Jane Grande-Allen, PhD, Linda L. Demer, MD, PhD, Donald D. Heistad, MD, Craig A. Simmons, PhD, Kristyn S. Masters, PhD, Patrick Mathieu, MD, Kevin D. O'Brien, MD, Frederick J. Schoen, MD, PhD, Dwight A. Towler, MD, PhD, Ajit P. Yoganathan, PhD and Catherine M. Otto, MD Nalini M. RajamannanNalini M. Rajamannan From the Division of Cardiology and Pathology: Feinberg School of Medicine, Chicago IL (N.M.R.); National Heart, Lung, and Blood Institute of the National Institutes of Health, Bethesda MD (F.J.E.); Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (E.A.); Rice University, Houston TX (K.J.G.-A.); David Geffen School of Medicine at UCLA, Los Angeles, CA (L.L.D.); Cardiovascular Center and Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA (D.D.H.); Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON, Canada (C.A.S.); Department of Biomedical Engineering, University of Wisconsin, Madison, WI (K.S.M.); Institut Universitaire de Cardiologie et de Pneumologie de Québec, QC, Canada (P.M.); University of Washington, Seattle, WA (K.D.O., C.M.O.); Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (F.J.S.); Department of Medicine, Washington University, St Louis, MO (D.A.T.); and Georgia Institute of Technology, Atlanta, GA (A.P.Y.). , Frank J. EvansFrank J. Evans From the Division of Cardiology and Pathology: Feinberg School of Medicine, Chicago IL (N.M.R.); National Heart, Lung, and Blood Institute of the National Institutes of Health, Bethesda MD (F.J.E.); Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (E.A.); Rice University, Houston TX (K.J.G.-A.); David Geffen School of Medicine at UCLA, Los Angeles, CA (L.L.D.); Cardiovascular Center and Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA (D.D.H.); Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON, Canada (C.A.S.); Department of Biomedical Engineering, University of Wisconsin, Madison, WI (K.S.M.); Institut Universitaire de Cardiologie et de Pneumologie de Québec, QC, Canada (P.M.); University of Washington, Seattle, WA (K.D.O., C.M.O.); Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (F.J.S.); Department of Medicine, Washington University, St Louis, MO (D.A.T.); and Georgia Institute of Technology, Atlanta, GA (A.P.Y.). , Elena AikawaElena Aikawa From the Division of Cardiology and Pathology: Feinberg School of Medicine, Chicago IL (N.M.R.); National Heart, Lung, and Blood Institute of the National Institutes of Health, Bethesda MD (F.J.E.); Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (E.A.); Rice University, Houston TX (K.J.G.-A.); David Geffen School of Medicine at UCLA, Los Angeles, CA (L.L.D.); Cardiovascular Center and Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA (D.D.H.); Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON, Canada (C.A.S.); Department of Biomedical Engineering, University of Wisconsin, Madison, WI (K.S.M.); Institut Universitaire de Cardiologie et de Pneumologie de Québec, QC, Canada (P.M.); University of Washington, Seattle, WA (K.D.O., C.M.O.); Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (F.J.S.); Department of Medicine, Washington University, St Louis, MO (D.A.T.); and Georgia Institute of Technology, Atlanta, GA (A.P.Y.). , K. Jane Grande-AllenK. Jane Grande-Allen From the Division of Cardiology and Pathology: Feinberg School of Medicine, Chicago IL (N.M.R.); National Heart, Lung, and Blood Institute of the National Institutes of Health, Bethesda MD (F.J.E.); Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (E.A.); Rice University, Houston TX (K.J.G.-A.); David Geffen School of Medicine at UCLA, Los Angeles, CA (L.L.D.); Cardiovascular Center and Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA (D.D.H.); Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON, Canada (C.A.S.); Department of Biomedical Engineering, University of Wisconsin, Madison, WI (K.S.M.); Institut Universitaire de Cardiologie et de Pneumologie de Québec, QC, Canada (P.M.); University of Washington, Seattle, WA (K.D.O., C.M.O.); Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (F.J.S.); Department of Medicine, Washington University, St Louis, MO (D.A.T.); and Georgia Institute of Technology, Atlanta, GA (A.P.Y.). , Linda L. DemerLinda L. Demer From the Division of Cardiology and Pathology: Feinberg School of Medicine, Chicago IL (N.M.R.); National Heart, Lung, and Blood Institute of the National Institutes of Health, Bethesda MD (F.J.E.); Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (E.A.); Rice University, Houston TX (K.J.G.-A.); David Geffen School of Medicine at UCLA, Los Angeles, CA (L.L.D.); Cardiovascular Center and Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA (D.D.H.); Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON, Canada (C.A.S.); Department of Biomedical Engineering, University of Wisconsin, Madison, WI (K.S.M.); Institut Universitaire de Cardiologie et de Pneumologie de Québec, QC, Canada (P.M.); University of Washington, Seattle, WA (K.D.O., C.M.O.); Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (F.J.S.); Department of Medicine, Washington University, St Louis, MO (D.A.T.); and Georgia Institute of Technology, Atlanta, GA (A.P.Y.). , Donald D. HeistadDonald D. Heistad From the Division of Cardiology and Pathology: Feinberg School of Medicine, Chicago IL (N.M.R.); National Heart, Lung, and Blood Institute of the National Institutes of Health, Bethesda MD (F.J.E.); Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (E.A.); Rice University, Houston TX (K.J.G.-A.); David Geffen School of Medicine at UCLA, Los Angeles, CA (L.L.D.); Cardiovascular Center and Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA (D.D.H.); Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON, Canada (C.A.S.); Department of Biomedical Engineering, University of Wisconsin, Madison, WI (K.S.M.); Institut Universitaire de Cardiologie et de Pneumologie de Québec, QC, Canada (P.M.); University of Washington, Seattle, WA (K.D.O., C.M.O.); Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (F.J.S.); Department of Medicine, Washington University, St Louis, MO (D.A.T.); and Georgia Institute of Technology, Atlanta, GA (A.P.Y.). , Craig A. SimmonsCraig A. Simmons From the Division of Cardiology and Pathology: Feinberg School of Medicine, Chicago IL (N.M.R.); National Heart, Lung, and Blood Institute of the National Institutes of Health, Bethesda MD (F.J.E.); Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (E.A.); Rice University, Houston TX (K.J.G.-A.); David Geffen School of Medicine at UCLA, Los Angeles, CA (L.L.D.); Cardiovascular Center and Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA (D.D.H.); Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON, Canada (C.A.S.); Department of Biomedical Engineering, University of Wisconsin, Madison, WI (K.S.M.); Institut Universitaire de Cardiologie et de Pneumologie de Québec, QC, Canada (P.M.); University of Washington, Seattle, WA (K.D.O., C.M.O.); Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (F.J.S.); Department of Medicine, Washington University, St Louis, MO (D.A.T.); and Georgia Institute of Technology, Atlanta, GA (A.P.Y.). , Kristyn S. MastersKristyn S. Masters From the Division of Cardiology and Pathology: Feinberg School of Medicine, Chicago IL (N.M.R.); National Heart, Lung, and Blood Institute of the National Institutes of Health, Bethesda MD (F.J.E.); Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (E.A.); Rice University, Houston TX (K.J.G.-A.); David Geffen School of Medicine at UCLA, Los Angeles, CA (L.L.D.); Cardiovascular Center and Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA (D.D.H.); Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON, Canada (C.A.S.); Department of Biomedical Engineering, University of Wisconsin, Madison, WI (K.S.M.); Institut Universitaire de Cardiologie et de Pneumologie de Québec, QC, Canada (P.M.); University of Washington, Seattle, WA (K.D.O., C.M.O.); Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (F.J.S.); Department of Medicine, Washington University, St Louis, MO (D.A.T.); and Georgia Institute of Technology, Atlanta, GA (A.P.Y.). , Patrick MathieuPatrick Mathieu From the Division of Cardiology and Pathology: Feinberg School of Medicine, Chicago IL (N.M.R.); National Heart, Lung, and Blood Institute of the National Institutes of Health, Bethesda MD (F.J.E.); Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (E.A.); Rice University, Houston TX (K.J.G.-A.); David Geffen School of Medicine at UCLA, Los Angeles, CA (L.L.D.); Cardiovascular Center and Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA (D.D.H.); Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON, Canada (C.A.S.); Department of Biomedical Engineering, University of Wisconsin, Madison, WI (K.S.M.); Institut Universitaire de Cardiologie et de Pneumologie de Québec, QC, Canada (P.M.); University of Washington, Seattle, WA (K.D.O., C.M.O.); Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (F.J.S.); Department of Medicine, Washington University, St Louis, MO (D.A.T.); and Georgia Institute of Technology, Atlanta, GA (A.P.Y.). , Kevin D. O'BrienKevin D. O'Brien From the Division of Cardiology and Pathology: Feinberg School of Medicine, Chicago IL (N.M.R.); National Heart, Lung, and Blood Institute of the National Institutes of Health, Bethesda MD (F.J.E.); Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (E.A.); Rice University, Houston TX (K.J.G.-A.); David Geffen School of Medicine at UCLA, Los Angeles, CA (L.L.D.); Cardiovascular Center and Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA (D.D.H.); Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON, Canada (C.A.S.); Department of Biomedical Engineering, University of Wisconsin, Madison, WI (K.S.M.); Institut Universitaire de Cardiologie et de Pneumologie de Québec, QC, Canada (P.M.); University of Washington, Seattle, WA (K.D.O., C.M.O.); Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (F.J.S.); Department of Medicine, Washington University, St Louis, MO (D.A.T.); and Georgia Institute of Technology, Atlanta, GA (A.P.Y.). , Frederick J. SchoenFrederick J. Schoen From the Division of Cardiology and Pathology: Feinberg School of Medicine, Chicago IL (N.M.R.); National Heart, Lung, and Blood Institute of the National Institutes of Health, Bethesda MD (F.J.E.); Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (E.A.); Rice University, Houston TX (K.J.G.-A.); David Geffen School of Medicine at UCLA, Los Angeles, CA (L.L.D.); Cardiovascular Center and Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA (D.D.H.); Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON, Canada (C.A.S.); Department of Biomedical Engineering, University of Wisconsin, Madison, WI (K.S.M.); Institut Universitaire de Cardiologie et de Pneumologie de Québec, QC, Canada (P.M.); University of Washington, Seattle, WA (K.D.O., C.M.O.); Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (F.J.S.); Department of Medicine, Washington University, St Louis, MO (D.A.T.); and Georgia Institute of Technology, Atlanta, GA (A.P.Y.). , Dwight A. TowlerDwight A. Towler From the Division of Cardiology and Pathology: Feinberg School of Medicine, Chicago IL (N.M.R.); National Heart, Lung, and Blood Institute of the National Institutes of Health, Bethesda MD (F.J.E.); Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (E.A.); Rice University, Houston TX (K.J.G.-A.); David Geffen School of Medicine at UCLA, Los Angeles, CA (L.L.D.); Cardiovascular Center and Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA (D.D.H.); Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON, Canada (C.A.S.); Department of Biomedical Engineering, University of Wisconsin, Madison, WI (K.S.M.); Institut Universitaire de Cardiologie et de Pneumologie de Québec, QC, Canada (P.M.); University of Washington, Seattle, WA (K.D.O., C.M.O.); Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (F.J.S.); Department of Medicine, Washington University, St Louis, MO (D.A.T.); and Georgia Institute of Technology, Atlanta, GA (A.P.Y.). , Ajit P. YoganathanAjit P. Yoganathan From the Division of Cardiology and Pathology: Feinberg School of Medicine, Chicago IL (N.M.R.); National Heart, Lung, and Blood Institute of the National Institutes of Health, Bethesda MD (F.J.E.); Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (E.A.); Rice University, Houston TX (K.J.G.-A.); David Geffen School of Medicine at UCLA, Los Angeles, CA (L.L.D.); Cardiovascular Center and Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA (D.D.H.); Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON, Canada (C.A.S.); Department of Biomedical Engineering, University of Wisconsin, Madison, WI (K.S.M.); Institut Universitaire de Cardiologie et de Pneumologie de Québec, QC, Canada (P.M.); University of Washington, Seattle, WA (K.D.O., C.M.O.); Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (F.J.S.); Department of Medicine, Washington University, St Louis, MO (D.A.T.); and Georgia Institute of Technology, Atlanta, GA (A.P.Y.). and Catherine M. OttoCatherine M. Otto From the Division of Cardiology and Pathology: Feinberg School of Medicine, Chicago IL (N.M.R.); National Heart, Lung, and Blood Institute of the National Institutes of Health, Bethesda MD (F.J.E.); Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (E.A.); Rice University, Houston TX (K.J.G.-A.); David Geffen School of Medicine at UCLA, Los Angeles, CA (L.L.D.); Cardiovascular Center and Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA (D.D.H.); Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON, Canada (C.A.S.); Department of Biomedical Engineering, University of Wisconsin, Madison, WI (K.S.M.); Institut Universitaire de Cardiologie et de Pneumologie de Québec, QC, Canada (P.M.); University of Washington, Seattle, WA (K.D.O., C.M.O.); Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (F.J.S.); Department of Medicine, Washington University, St Louis, MO (D.A.T.); and Georgia Institute of Technology, Atlanta, GA (A.P.Y.). Originally published18 Oct 2011https://doi.org/10.1161/CIRCULATIONAHA.110.006767Circulation. 2011;124:1783–1791IntroductionCalcific aortic valve disease (CAVD) encompasses the range of disease from initial alterations in the cell biology of the leaflets to end-stage calcification resulting in left ventricular outflow obstruction. The first detectable macroscopic changes in the leaflets, seen as calcification, or focal leaflet thickening with normal valve function, is termed aortic valve sclerosis, but it is likely that the initiating events in the disease process occur much earlier. Disease progression is characterized by a process of thickening of the valve leaflets and the formation of calcium nodules—often including the formation of actual bone—and new blood vessels, which are concentrated near the aortic surface. End-stage disease, eg, calcific aortic stenosis, is characterized pathologically by large nodular calcific masses within the aortic cusps that protrude along the aortic surface into the sinuses of Valsalva, interfering with opening of the cusps. There is no disease along the ventricular surface. For decades, this disease was thought to be a passive process in which the valve degenerates with age in association with calcium accumulation. Moreover, although CAVD is more common with age, it is not an inevitable consequence of aging. Instead, CAVD appears to be an actively regulated disease process that cannot be characterized exclusively as senile or degenerative.The National Heart, Lung, and Blood Institute convened a group of scientists from different fields of study, including cardiac imaging, molecular biology, cardiovascular pathology, epidemiology, cell biology, endocrinology, bioengineering, and clinical outcomes, to review the scientific studies from the past decade in the field of CAVD. The purpose was to develop a consensus statement on the current state of translational research related to CAVD. Herein, we summarize recent scientific studies and define future directions for research to diagnose, treat, and potentially prevent this complex disease process.Normal Aortic Valve Anatomy and FunctionKey Structure-Function CorrelationsHeart valves permit unobstructed, unidirectional forward flow through the circulation. Valve components must accomplish the second-to-second movements necessitated by the cardiac cycle and must maintain sufficient strength and durability to withstand repetitive and substantial mechanical stress and strain over many years. The functional requirements of the heart valves are accomplished by a specialized set of cells and heterogeneous extracellular matrix, arrayed in a spatially specific and differentiated tissue structure, that are temporally dynamic and highly responsive to the external biomechanical environment.1The aortic valve (AV) provides a paradigm for valvular structural specialization and tissue dynamics, as viewed by echocardiography and bioreactor models (Figure 1A). The direction of flow during systole allows the valve cusps to open as the blood flows across the open AV leaflets. The inflow surface is located along the direction of flow, as indicated in Figure 1A. The outflow surface is demonstrated in the diastole as the valves are closed, and there is end-diastolic pressure closing the valve leaflets along the outflow surface. Individual AV cusps attach to the aortic wall in a semilunar fashion, ascending to the commissures and descending to the basal attachment of each cusp. In the closed phase, under the backpressure from the blood in the aorta, the AV cusps stretch and coapt and, thereby, occlude the orifice. Pulmonary valve structure is analogous to the structure of the AV, consistent with the lower-pressure environment. During diastole, the tissue of the cusps is stretched via a backpressure; during systole, the cuspal tissue becomes relaxed and shortens owing to the recoil of elastin, which was elongated and taut during diastole.Download figureDownload PowerPointFigure 1. A, Echocardiographic and bioengineering and hemodynamic force perspective of the diastole and systole in the aortic root affecting aortic valve leaflet cell and function. B, Demonstration of the cellular architecture of a normal aortic valve. C, Demonstration of the osteogenic phenotype of the calcified aortic valve along the aortic surface. CAVD indicates calcific aortic valve disease; VIC, valvular interstitial cell.All 4 cardiac valves have a similarly layered architectural pattern composed of cells, including the valvular endothelial cells (VECs) at the blood-contacting surfaces, the deep valvular interstitial cells (VICs), and valvular extracellular matrix (VECM), including collagen, elastin, and amorphous extracellular matrix (predominantly glycosaminoglycans). The AV has a dense collagenous layer close to the outflow surface and continuous with valvular supporting structures, which provide strength: the fibrosa, a central core of loose connective tissue; the spongiosai, rich in glycosaminoglycans; and a layer rich in elastin below the inflow surface, the ventricularis, as shown in Figure 1B. The glycosaminoglycan-rich spongiosa facilitates the relative rearrangements of the collagenous and elastic layers during the cardiac cycle. Moreover, the diverse characteristics of the cell phenotype, such as smooth muscle α-actin, are associated with distinct locations within the valve leaflet in situ.2 In vitro, this heterogeneity of phenotype is consistently demonstrated in primary cultures of VICs. Only recently, however, has it become possible to identify and characterize the behavior of discrete subpopulations of valvular cells using methods such as cloning3 and subculturing based on differential adhesion.4 These approaches have been used to demonstrate that discrete valvular cell subpopulations have unique morphological characteristics, synthesis of extracellular matrix, potential for calcification and ossification, and potential for promoting angiogenesis.5 These latter 2 characteristics are particularly relevant to calcific valve disease, and hence these methods offer the potential for determining whether selected groups of cells within the entire population undergo specific pathological changes that drive valve remodeling and mediate the progression of disease, which is the calcified valve leaflet as depicted in Figure 1C.Cardiac Valve Cell Types: Valvular Interstitial CellsVICs are abundant in all layers of the heart valves, and are crucial to function. VICs synthesize VECM and express matrix-degrading enzymes (including matrix metalloproteinases and their inhibitors) that mediate and regulate remodeling of collagen and other matrix components. VICs comprise a diverse, dynamic, and highly plastic population of resident cells.6 They modulate function among phenotypes in response to changes in stimulation by the mechanical environment or by certain chemicals during valvular homeostasis, adaptation, and pathology. Adult heart valve VICs in situ have characteristics of resting fibroblasts; they are quiescent, without synthetic or destructive activity for extracellular matrix. VICs are activated during intrauterine valvular maturation, by abrupt changes in the mechanical stress state of valves, and in disease states, and VICs continuously repair a low level of injury to the VECM that occurs during physiological functional remodeling of AV tissue.7 The Table6 demonstrates the phenotypic transitions of the VIC cells, which are critical for normal development, homeostasis, and function of the AV, and likely mediate the development of valve calcification. Once activated, VICs can differentiate into a variety of other cell types,3 including myofibroblasts and osteoblasts, although valve osteoblasts may respond to cellular signals differently than skeletal osteoblasts.Table. In Vitro Valvular Interstitial Cell PhenotypesCell TypeLocationFunctionEmbryonic progenitor endothelial/mesenchymal cellsEmbryonic cardiac cushionsGive rise to resident qVICs, possibly through an activated stage. EMT can be detected by the loss of endothelial and the gain of mesenchymal markersqVICsHeart valve leafletMaintain physiological valve structure and function and inhibit angiogenesis in the leafletspVICsBone marrow, circulation, and/or heart valve leafletEnter valve or are resident in valve to provide aVICs to repair the heart valve, may be CD34-, CD133-, and/or S100-positiveaVICsHeart valve leafleta-SMA-containing VICs with activated cellular repair processes including proliferation, migration, and matrix remodeling. Respond to valve injury attributable to pathological conditions and abnormal hemodynamic/ mechanical forcesobVICsHeart valve leafletCalcification, chondrogenesis, and osteogenesis in the heart valve. Secrete alkaline phosphatase, osteocalcin, osteopontin, bone sialoproteinVIC indicates valvular interstitial cell; EMT, endothelial-mesenchymal transition; α-SMA, smooth muscle actin.Reprinted from Liu et al,6 with permission from the publisher. Copyright © Elsevier, 2007.Valvular Endothelial CellsVECs resemble endothelial cells elsewhere in the circulation in some respects. However, they are phenotypically different from VECs in the adjacent aorta and elsewhere in the circulation.8 VECs probably interact with VICs to maintain the integrity of valve tissues and potentially mediate disease. Evidence indicates that different transcriptional profiles are expressed by VECs on the opposite (ie, aortic and ventricular) faces of a normal adult pig AV, and some investigators have hypothesized that these differences may contribute to the typical localization of early pathological AV calcification, predominantly near the outflow surface secondary to inhibitors along the inflow surface.9 Studies indicate that abnormal hemodynamic forces (such as hypertension,10 elevated stretch,11 or shear stresses11) experienced by the valve leaflets can cause tissue remodeling and inflammation, which may lead to calcification, stenosis, and ultimate valve failure.Normal Cardiac Valve DevelopmentVIC and VEC phenotypes, critical for maintaining valve function, change throughout life in response to environmental stimuli, as demonstrated in recent studies using quantitative histological assessment of human semilunar valves obtained from fetuses, neonates, children, and adults.7,12 VECs express an activated phenotype throughout fetal development (eg, vascular cellular adhesion molecular-1, intercellular adhesion molecule-1). Numerous signaling pathways have been proposed and tested in the critical pathways that promote endothelial-mesenchymal transition in the valves.12 In addition, VIC density, proliferation, and apoptosis are significantly higher in fetal than adult valves. A trilaminar architecture appears by 36 weeks of gestation, but remains rudimentary in comparison with that of adult valves. These data of the natural history of cell and matrix changes in valve development extend the paradigm that cardiac valves can adapt to pathological conditions, which suggests similar molecular mechanisms in physiological and pathological cell activation.Pathobiology of CAVDCalcific AV stenosis has characteristic pathological features of an osteoblast phenotype.13 The calcific process begins deep in the valvular tissue, near the margins of attachment. In advanced disease, the nodules extend through the outflow surfaces of the cusps and are nearly transmural. An early morphological stage of the calcification process is called AV sclerosis. In the later stage, AV stenosis, the functional valve area is decreased sufficiently to cause measurable obstruction to outflow and a significant gradient from the left ventricle to the aorta.Lipids also play an important initiating role in the cell signaling of vascular and valvular calcification.14 Surgical pathological studies have shown the presence of oxidized low-density lipoprotein (LDL) in calcified valves.15,16 Patients with homozygous familial hypercholesterolemia provide an opportunity to test the hypothesis that lipids play a role in the development of calcific aortic stenosis, because these patients have extremely elevated levels of LDL cholesterol without other traditional risk factors for coronary artery disease.17–20Renin-Angiotensin Signaling PathwayAngiotensin-converting enzyme is expressed and colocalizes with LDL in calcified AVs.21 In addition, an observational study showed the slowing of progression of AV disease in patients taking angiotensin-converting enzyme inhibitors in comparison with those not taking this therapy.22 This study is the first to demonstrate this novel signaling pathway in CAVD, which is still preliminary and somewhat controversial, but it is promising for the future potential to target this pathway with angiotensin-converting enzyme inhibitors and angiotensin receptor blockade in the early stages of the disease.Initiating Events: Oxidative StressIn the presence of cardiovascular risk factors, similar to vascular atherosclerosis, an early event is the presence of abnormalities in oxidative stress. This has been demonstrated in abnormal endothelial nitric oxide synthase function, which decr
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