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• W53682016 abstract "Ectopic calcification is defined as inappropriate biomineralization occurring in soft tissues.1Cotran RS Kumare V Robbins SL Cellular injury and cellular death.in: Robbins SL Pathological Basis of Disease. 5th ed. WB Saunders, Philadelphia1994: 1-35Google Scholar Ectopic calcifications are typically composed of calcium phosphate salts, including hydroxyapatite, but can also consist of calcium oxalates and octacalcium phosphate as seen in kidney stones.2Pak CYC Etiology and treatment of urolithiasis.Am J Kidney Dis. 1991; 18: 624-637PubMed Scopus (119) Google Scholar In uremic patients, a systemic mineral imbalance is associated with widespread ectopic calcification, referred to as metastatic calcification.3Block GA Hulbert-Shearon TE Association of serum phosphorus and calcium X phosphate product with mortality risk in chronic hemodialysis patients: a national study.Am J Kidney Dis. 1998; 31: 607-617Abstract Full Text Full Text PDF PubMed Scopus (2099) Google Scholar In the absence of a systemic mineral imbalance, ectopic calcification is typically termed dystrophic calcification. Often, these sites show evidence of tissue alteration and/or necrosis. Dystrophic mineralization is commonly observed in soft tissues as a result of injury, disease, and aging. Although most soft tissues can undergo calcification, skin, kidney, tendons, and cardiovascular tissues appear particularly prone to developing this pathology.4Anderson HC Morris DC Mineralization.in: Mundy GR Martin TJ Physiology and Pharmacology of Bone. Springer-Verlag, New York1993: 267-298Crossref Google Scholar In addition, a number of prosthetic devices are prone to ectopic calcification, as discussed below. Recent insights into the mechanisms regulating ectopic calcification have come from studies of cardiovascular calcification, including that by Kim et al5Kim MK Herrera GA Batarbee HD The role of glutaraldehyde in calcification of porcine aortic valve fibroblasts.Am J Pathol. 1999; 154: 843-852Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar in this issue of the Journal, and thus will be the major focus of this article. The reader is referred to other reviews for information about additional tissue-specific ectopic calcifications.2Pak CYC Etiology and treatment of urolithiasis.Am J Kidney Dis. 1991; 18: 624-637PubMed Scopus (119) Google Scholar, 6Uhtoff HK Calcifying tendinitis.Ann Chir Gynaecol. 1996; 85: 111-115PubMed Google Scholar, 7Walsh JS Fairley JA Calcifying disorders of the skin.J Am Acad Dermatol. 1995; 33: 693-706Abstract Full Text PDF PubMed Scopus (273) Google ScholarEctopic calcification can lead to clinical symptoms when it occurs in cardiovascular tissues, particularly arteries and heart valves. In arteries, calcification is correlated with atherosclerotic plaque burden and increased risk of myocardial infarction,8Beadenkopf WG Daoud AS Love BM Calcification in the coronary arteries and its relationship to arteriosclerosis and myocardial infarction.Am J Roentgenol. 1964; 92: 865-871Google Scholar, 9Locker TH Schwartz RS Cotta CW Hickman JR Fluoroscopic coronary artery calcification and associated coronary disease in asymptomatic young men.J Am Coll Cardiol. 1992; 19: 1167-1172Abstract Full Text PDF PubMed Scopus (119) Google Scholar, 10Puentes G Detrano R Tang W Wong N French W Narahara K Brundage B Baksheshi H Estimation of coronary calcium mass using electron beam computed tomography: a promising approach for predicting coronary events?.(abstr) Circulation. 1995; 92: I313Google Scholar increased ischemic episodes in peripheral vascular disease,11Niskanen LK Suhonen M Siitonen O Lehtinen JM Uusitupa MI Aortic and lower limb artery calcification in type II (non-insulin-dependent) diabetic patients and non-diabetic control subjects: a five year follow-up study.Atherosclerosis. 1990; 84: 61-71Abstract Full Text PDF PubMed Scopus (65) Google Scholar and increased risk of dissection following angioplasty.12Fitzgerald PJ Ports TA Yock PG Contribution of localized calcium deposits to dissection after angioplasty: an observational study using intravascular ultrasound.Circulation. 1992; 86: 64-70Crossref PubMed Scopus (465) Google Scholar Medial arterial calcification is also a strong independent marker of future cardiovascular events in diabetic patients.13Lehto S Niskanen L Suhonen L Ronnemaa T Laakso M Medial artery calcification: a neglected harbinger of cardiovascular complications in non-insulin-dependent diabetes mellitus.Arterioscler Thromb Vasc Biol. 1996; 16: 978-983Crossref PubMed Scopus (479) Google Scholar In the heart, valves are particularly prone to calcification. Degenerative calcific aortic stenosis is currently the most common valvular lesion encountered in clinical cardiology and one of the most difficult to manage.14O'Keefe JH Lavie CJ Nishimura RA Edwards WD Degenerative aortic stenosis: one effect of the graying of America.Postgrad Med. 1991; 89: 143-154PubMed Google Scholar It is estimated that approximately 1–2% of the elderly population suffer from this pathology, which is characterized by encrustation of aortic valve leaflets with apatitic mineral deposits and subsequent stiffening, tearing, and mechanical failure. Congenital anomalies, inflammatory changes such as those seen in rheumatic fever, renal disease, and age are all risk factors for aortic valve stenosis.14O'Keefe JH Lavie CJ Nishimura RA Edwards WD Degenerative aortic stenosis: one effect of the graying of America.Postgrad Med. 1991; 89: 143-154PubMed Google ScholarThe definitive treatment for severe symptomatic aortic stenosis is aortic valve replacement. This treatment was put into clinical practice in the 1960s and has resulted in dramatic improvement in longevity and symptoms of patients with valve disease, but problems persist. More than 40,000 patients undergo valve replacement each year in the United States.15Schoen FJ Levy RJ Piehler HR Pathological considerations in replacement cardiac valves.Cardiovasc Pathol. 1992; 1: 29-52Abstract Full Text PDF Scopus (121) Google Scholar Two types of prosthetic valves are commonly used: mechanical valves and tissue bioprosthetic valves. Mechanical valves are typically made of materials such as pure titanium, cobalt-chromium alloys, and pyrolytic carbon. These implants offer excellent long-term durability but are procoagulant and prothrombotic, thus necessitating chronic anticoagulation therapy and limiting their use in many patients (eg, women of child-bearing age and children). The major bioprosthetic tissue valves used clinically include valves fabricated from chemically cross-linked animal tissues, such as porcine aortic valves. In addition, non-cross-linked human aortic valve allografts are used, but usually in limited supply. Although tissue bioprosthetic valves have superior hemodynamic and thromboresistant properties compared to mechanical valves, those fabricated from porcine aortic valves or bovine pericardium have a higher rate of failure. Failure is most often attributed, again, to calcification of the tissue prosthetic valve. In fact, by 10 years, one third of bioprosthetic valves require replacement, increasing to two thirds by 15 years. In addition, failure in children often occurs within 2 to 5 years, and is increased substantially in hemodialysis patients.3Block GA Hulbert-Shearon TE Association of serum phosphorus and calcium X phosphate product with mortality risk in chronic hemodialysis patients: a national study.Am J Kidney Dis. 1998; 31: 607-617Abstract Full Text Full Text PDF PubMed Scopus (2099) Google Scholar, 15Schoen FJ Levy RJ Piehler HR Pathological considerations in replacement cardiac valves.Cardiovasc Pathol. 1992; 1: 29-52Abstract Full Text PDF Scopus (121) Google Scholar, 16Kopf GS Geha AS Hellenbrand WE Kleinman CS Fate of left-sided cardiac bioprosthesis in children.Arch Surg. 1986; 121: 488-490Crossref PubMed Scopus (26) Google Scholar, 17Edmunds LH Mckinlay S Anderson JM Callahan TH Chesebro JH Geiser EA Makanani DM McIntire LV Meeder WQ Naughton GK Panza JA Schoen FJ Didisheim P Directions for improvement of substitute heart valves: National Heart, Lung, and Blood Institutes working group report on heart valves.J Biomed Mater Res. 1997; 38: 263-266Crossref PubMed Scopus (35) Google Scholar, 18Salgueira M Jarava C Alba RM Arma JR Areste N Palma A Milan JA Valvular heart calcifications in hemodialysis patients: an analysis of predisposed factors.Nefrologia. 1998; 18: 221-226Google ScholarThe need for improvements in tissue bioprosthetic valves aimed at minimizing valve failure and patient reoperation rates has driven research in this area and provided much of the current information on mechanisms of ectopic calcification. These studies have led to an excellent understanding of the morphology, ultrastructure, and crystal chemistry of bioprosthetic valve mineralization. Morphologically, nearly all explanted bioprosthetic valves display loss of cuspal connective tissue cells and endothelium, valve calcification particularly in the spongiosa and at the commissures, and very little inflammation.19Fishbein MC Gissen SA Collins JJ Barsamian EM Cohn LH Pathological findins after cardiac valve replacement with glutaraldehyde-fixed porcine valves.Am J Cardiol. 1977; 40: 331-337Abstract Full Text PDF PubMed Scopus (114) Google Scholar, 20Spray TL Roberts WC Structural changes in porcine xenografts used as substitute cardiac valves.Am J Cardiol. 1977; 40: 319-330Abstract Full Text PDF PubMed Scopus (141) Google Scholar, 21Ferrans VJ Boyce SW Billingham ME Jones M Ishihara T Roberts WC Calcific deposits in porcine bioprostheses: structure and pathogenesis.Am J Cardiol. 1980; 46: 721-734Abstract Full Text PDF PubMed Scopus (191) Google Scholar, 22Schoen FJ Pathological findings in explanted clinical bioprosthetic valves fabricated from photooxidized bovine pericardium.J Heart Valve Dis. 1998; 7: 174-179PubMed Google Scholar Using transmission electron microscopy, several studies have shown that explanted porcine xenografts contain intracytoplasmic and interstitial calcospherulae, calcified collagen fibrils, and platelike calcium deposits on amorphous material.23Ferrans VJ Spray TL Billingham ME Roberts WC Structural changes in glutaraldehyde-treated porcine heterografts used as substitute cardiac valves.Am J Cardiol. 1978; 41: 1159-1184Abstract Full Text PDF PubMed Scopus (268) Google Scholar, 24Valente M Bortolotti U Thiene G Ultrastructural substrates of dystrophic calcification in porcine bioprosthetic failure.Am J Pathol. 1985; 119: 12-21PubMed Google Scholar The calcified deposits were identified by X-ray diffraction as apatitic in nature,24Valente M Bortolotti U Thiene G Ultrastructural substrates of dystrophic calcification in porcine bioprosthetic failure.Am J Pathol. 1985; 119: 12-21PubMed Google Scholar similar but not identical to those observed in natural heart valve calcification.25Tomazic BB Edwards WD Schoen FJ Physiochemical characterization of natural and bioprosthetic heart valve calcific deposits: implications for prevention.Ann Thorac Surg. 1995; 60: S322-327Abstract Full Text PDF PubMed Scopus (22) Google Scholar In addition, a number of animal models have been developed to study bioprosthetic valve calcification, including subcutaneous implantation in rats26Levy RJ Schoen FJ Levy JT Nelson AC Howard SL Oshry LJ Biologic determinants of dystrophic calcification and osteocalcin deposition in glutaraldehyde-preserved porcine aortic valve leaflets implanted subcutaneously in rats.Am J Pathol. 1983; 113: 143-155PubMed Google Scholar, 27Schoen FJ Levy RJ Nelson AC Bernard WF Nashef A Hawley M Onset and progression of experimental bioprosthetic heart valve calcification.Lab Invest. 1985; 52: 523-532PubMed Google Scholar and rabbits,28Fishbein MC Levy RJ Ferrans VJ Dearden LC Nashef A Goodman AP Carpentier A Calcification of cardiac valve bioprostheses: biochemical, histologic, and ultrastructural observations in a subcutaneous implantation model system.J Thorac Surg. 1982; 83: 602-609Google Scholar as well as valve replacement in sheep or calves.27Schoen FJ Levy RJ Nelson AC Bernard WF Nashef A Hawley M Onset and progression of experimental bioprosthetic heart valve calcification.Lab Invest. 1985; 52: 523-532PubMed Google Scholar Using these models, biological determinants of cardiac valve calcification have been identified and include host factors (eg, young age, uremia, hyperparathyroidism), tissue fixation conditions (eg, aldehyde cross-linking), and mechanical stress.15Schoen FJ Levy RJ Piehler HR Pathological considerations in replacement cardiac valves.Cardiovasc Pathol. 1992; 1: 29-52Abstract Full Text PDF Scopus (121) Google Scholar, 29Vyavahare NR Chen W Joshi RR Lee C Hirsch D Levy J Schoen FJ Levy RJ Current progress in anticalcification for bioprosthetic and polymeric heart valves.Cardiovasc Pathol. 1997; 6: 219-229Abstract Full Text Full Text PDF Scopus (40) Google Scholar These animal models have also been used to test various anticalcification therapies.29Vyavahare NR Chen W Joshi RR Lee C Hirsch D Levy J Schoen FJ Levy RJ Current progress in anticalcification for bioprosthetic and polymeric heart valves.Cardiovasc Pathol. 1997; 6: 219-229Abstract Full Text Full Text PDF Scopus (40) Google Scholar Despite these considerable achievements, lack of knowledge of the underlying mechanisms controlling abnormal biomineralizations has hampered the development of clinically effective anticalcification strategies.Though mammalian extracellular fluids are metastable with respect to hydroxyapatite, this crystal does not spontaneously precipitate. Thus, bone and tooth mineral, as well as ectopic calcifications, exist in disequilibrium with the blood.30Scarpace PJ Neuman WF The blood-bone disequilibrium.Calcif Tiss Res. 1976; 20: 137-149Crossref Scopus (33) Google Scholar This paradox has led to the concept of heterogeneous nucleation, whereby biomolecules (termed “nucleators”) may serve as substrates for initial crystal formation.31Neuman WF Neuman MW Mechanisms of calcification.in: The Chemical Dynamics of Bone. Univ of Chicago Press, Chicago1958: 169-187Google Scholar In bone and teeth, nucleators are thought to be generated by active processes in osteogenic cells as part of their normal physiological function. However, bioprosthetic implants are devoid of live cells. Thus, a key question is how bioprosthetic valve calcification is initiated, ie, what are the nucleators?Important observations have led to several mechanistic theories. First, aldehyde fixation appears to be a prerequisite for bioprosthetic valve mineralization. Animal studies have shown that nonfixed or alternatively processed (eg, by photo-oxidation) valves do not mineralize following subcutaneous implantation, and processed but non-glutaraldehyde-fixed human allografts show much less mineralization than aldehyde-fixed valves.26Levy RJ Schoen FJ Levy JT Nelson AC Howard SL Oshry LJ Biologic determinants of dystrophic calcification and osteocalcin deposition in glutaraldehyde-preserved porcine aortic valve leaflets implanted subcutaneously in rats.Am J Pathol. 1983; 113: 143-155PubMed Google Scholar, 32Gong G Ling Z Seifter E Factor SM Frater RWM Aldehyde tanning: the villain in bioprosthetic calcification.Eur J Cardiothorac Surg. 1991; 5: 288-293Crossref PubMed Scopus (55) Google Scholar, 33Golomb G Schoen FJ MSS Linden J Dixon M Levy RJ The role of glutaraldehyde-induced crosslinks in calcification of bovine pericardium used in cardiac valve bioprostheses.Am J Pathol. 1987; 127: 122-130PubMed Google Scholar, 34Moore MA Pericardial tissue stabilized by dye-mediated photooxidation: a review article.J Heart Valve Dis. 1997; 6: 521-526PubMed Google Scholar Therefore, it has been proposed that aldehyde cross-linking may create specific nucleation sites in valve extracellular matrix that are highly susceptible to nucleation. Furthermore, residual glutaraldehyde may leach out of fixed valves and induce surrounding tissue injury, thus promoting mineralization (glutaraldehyde toxicity).35Huang-Lee LLH Cheung DT Nimni ME Biochemical changes and cytotoxicity associated with the degradation of polymeric glutaraldehyde derived crosslinks.J Biomed Mater Res. 1990; 24: 1185-1201Crossref PubMed Scopus (301) Google Scholar, 36Grimm M Eybl E Grabenwoger M Spreitzer H Jager W Grimm G Bock P Muller MM Wolner E Glutaraldehyde affects biocompatibility of bioprosthetic heart valves.Surgery. 1992; 111: 74-78PubMed Google Scholar, 37Gendler E Gendler S Nimni ME Toxic reactions evoked by glutaraldehyde-fixed pericardium and cardiac valve tissue bioprosthesis.J Biomed Mater Res. 1984; 18: 727-736Crossref PubMed Scopus (160) Google Scholar Second, devitalization of aldehyde-treated prosthetic valves has been proposed to alter membrane permeability and calcium influx,38Schoen FJ Tsao JW Levy RJ Calcification of bovine pericardium used in cardiac valve bioprostheses.Am J Pathol. 1986; 123: 134-145PubMed Google Scholar, 39Kim KM Apoptosis and calcification.Scanning Microsc. 1995; 9: 1137-1178PubMed Google Scholar thus bringing high concentrations of calcium into contact with high phosphate levels in membrane-bound intracellular compartments and achieving [Ca+2] × [PO4−3] products high enough for precipitation. Finally, mechanical stress is proposed to exacerbate mineralization, because regions of valves with the greatest stresses correlate with the highest degree of mineralization.23Ferrans VJ Spray TL Billingham ME Roberts WC Structural changes in glutaraldehyde-treated porcine heterografts used as substitute cardiac valves.Am J Cardiol. 1978; 41: 1159-1184Abstract Full Text PDF PubMed Scopus (268) Google Scholar, 24Valente M Bortolotti U Thiene G Ultrastructural substrates of dystrophic calcification in porcine bioprosthetic failure.Am J Pathol. 1985; 119: 12-21PubMed Google Scholar However, studies showing that bioprosthetic valves mineralize in noncirculatory in vivo models indicate that mechanical stress is not required for calcification to occur.26Levy RJ Schoen FJ Levy JT Nelson AC Howard SL Oshry LJ Biologic determinants of dystrophic calcification and osteocalcin deposition in glutaraldehyde-preserved porcine aortic valve leaflets implanted subcutaneously in rats.Am J Pathol. 1983; 113: 143-155PubMed Google Scholar, 27Schoen FJ Levy RJ Nelson AC Bernard WF Nashef A Hawley M Onset and progression of experimental bioprosthetic heart valve calcification.Lab Invest. 1985; 52: 523-532PubMed Google Scholar, 28Fishbein MC Levy RJ Ferrans VJ Dearden LC Nashef A Goodman AP Carpentier A Calcification of cardiac valve bioprostheses: biochemical, histologic, and ultrastructural observations in a subcutaneous implantation model system.J Thorac Surg. 1982; 83: 602-609Google ScholarConversely, several potential mechanisms have been ruled out by the experimental data. While some recent studies on ectopic mineralization suggest that host mesenchymal cells may contribute to mineralization (see below), this is apparently not required in bioprosthetic valve mineralization because fixed valve leaflets implanted within millipore diffusion chambers go on to mineralize.26Levy RJ Schoen FJ Levy JT Nelson AC Howard SL Oshry LJ Biologic determinants of dystrophic calcification and osteocalcin deposition in glutaraldehyde-preserved porcine aortic valve leaflets implanted subcutaneously in rats.Am J Pathol. 1983; 113: 143-155PubMed Google Scholar, 40Nimni ME Biochemistry of bone induction and dystrophic calcification.Clin Plast Surg. 1994; 21: 419-427PubMed Google Scholar Likewise, a role for nonspecific inflammation or specific immunity as causes of mineralization appears unlikely, because both fixed and nonfixed tissue valves show a foreign body response consisting of predominantly mononuclear infiltrates following implantation, yet only fixed valves mineralize.41Levy RJ Qu X Underwood T Trachy J Schoen FJ Calcification of valved aortic allografts in rats: effects of age, crosslinking, and inhibitors.J Biomed Mater Res. 1995; 29: 217-226Crossref PubMed Scopus (32) Google Scholar In addition, valve tissues implanted in congenitally athymic, T cell-deficient (nude) mice calcify to the same extent as implants in immunocompetent mice.42Levy RJ Schoen FJ Howard SL Mechanism of calcification of porcine bioprosthetic aortic valve cusps: role of T-lymphocytes.Am J Pathol. 1983; 52: 629-631Scopus (71) Google Scholar Thus, graft rejection is not thought to play a major role in bioprosthetic valve mineralization.The study by Kim and colleagues5Kim MK Herrera GA Batarbee HD The role of glutaraldehyde in calcification of porcine aortic valve fibroblasts.Am J Pathol. 1999; 154: 843-852Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar in this issue of the Journal provides hard data supporting the calcium influx theory and simultaneously provides a provocative idea about the role of aldehyde fixation in bioprosthetic valve mineralization. Porcine aortic valve fibroblasts were isolated and glutaraldehyde-fixed. Using calcium-sensitive dyes, an immediate and sustained increase in cytosolic Ca2+ was measured in fixed cells compared to live cells. In 0.6% glutaraldehyde-treated valve fibroblasts, intracellular concentrations of calcium reached ∼1.5 mmol/L, a million times greater than calcium levels seen in unfixed fibroblasts. Furthermore, a severalfold increase in Pi was also noted within the fixed valve cells, bringing the Pi concentrations to ∼35 mmol/L, and greatly elevating the [Ca+2] X [PO4−3] product. With time, the glutaradehyde-fixed cells progressively depleted the media of Ca2+ and inorganic phosphate, and mineralization of the cultures was observed. The phenomenon relied on the presence extracellular Ca2+ and was shown to depend on the concentration of glutaraldehyde. Thus, these are the first studies to experimentally measure increased intracellular Ca2+ and inorganic phosphate levels following glutaraldehyde fixation, and to correlate these changes to valve cell mineralization, thus substantiating the calcium influx theory.The study by Kim et al5Kim MK Herrera GA Batarbee HD The role of glutaraldehyde in calcification of porcine aortic valve fibroblasts.Am J Pathol. 1999; 154: 843-852Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar additionally provides insights into a possible mechanism of glutaradehyde-induced mineralization. The investigators noted cellular blebbing following glutaraldehyde fixation, and an increase in calcein fluorescence intensity in these membranous structures increased as these structures calcified. Ultrastructural analyses found that calcium crystals were contained in the blebs, either in close association with the inner surface of the plasma membrane or in swollen mitochondria. With time, the entire valve fibroblast cell was observed to contain mineral deposits. Thus, the authors propose that following glutaraldehyde-induced calcium influx, cell blebbing is induced and serves to isolate the overloaded calcium, and that it is in these structures that nucleation of apatite first occurs. Temporal studies in experimental bioprosthetic valve calcification are consistent with this possibility because calcification is observed first in devitalized cells and cell fragments, and only later in matrix collagen fibers.27Schoen FJ Levy RJ Nelson AC Bernard WF Nashef A Hawley M Onset and progression of experimental bioprosthetic heart valve calcification.Lab Invest. 1985; 52: 523-532PubMed Google Scholar Importantly, ultrastructural analysis of failed porcine xenografts provides clinical evidence for the initial calcification in cellular debris and membrane fragments of porcine cusp cells.24Valente M Bortolotti U Thiene G Ultrastructural substrates of dystrophic calcification in porcine bioprosthetic failure.Am J Pathol. 1985; 119: 12-21PubMed Google Scholar Furthermore, physiological mineralization of bone and cartilage is thought to proceed, at least in part, via nucleation in matrix vesicles and cell derived membranous vesicles, either actively released by live cells or resulting from apoptosis.43Anderson HC Matrix vesicle calcification: review and update.in: Peck WA Bone and Mineral Research. Vol. 3. Elsevier Science Publishers, Chicago1985: 109-149Google Scholar Mineralization of matrix vesicles and cell degeneration products have also been observed in diseased aortic valves in addition to calcified atherosclerotic plaques.44Kim KM Calcification of matrix vesicles in human aortic valve and aortic media.Fed Proc. 1976; 35: 156-162PubMed Google Scholar Whether the membrane blebs observed in the studies by Kim et al5Kim MK Herrera GA Batarbee HD The role of glutaraldehyde in calcification of porcine aortic valve fibroblasts.Am J Pathol. 1999; 154: 843-852Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar are analogous to matrix vesicles either in derivation or function, however, is not yet known. Likewise, whether glutaraldehyde might induce apoptotic cell death is unclear. Finally, it should be stressed that although nucleation in cell-derived membranes following glutaraldehyde fixation appears to be the most important mechanism early in bioprosthetic valve mineralization, it is impossible to rule out a potential contribution of cross-linked valve tissue matrix to nucleation of apatite, especially late in bioprosthetic valve calcification.Despite the overwhelming in vitro and in vivo data supporting the calcium influx theory of bioprosthetic valve calcification, this hypothesis does not predict the delayed onset of calcification-related problems observed in human patients and experimental models of bioprosthetic valve calcification. This may be explained, in part, by the fact that glutaraldehyde fixation of heterografts is usually performed in the absence of Ca2+, perhaps limiting bleb formation and subsequent mineralization. However, it is also likely that natural inhibitors of calcification are present in the host, and that it is only when these inhibitory mechanisms are overcome that calcium crystals precipitate and proliferate.The idea that natural inhibitors of mineralization exist has long been recognized by investigators in the hard tissue field,4Anderson HC Morris DC Mineralization.in: Mundy GR Martin TJ Physiology and Pharmacology of Bone. Springer-Verlag, New York1993: 267-298Crossref Google Scholar, 45Boskey AL Matrix proteins and mineralization: an overview.Connect Tissue Res. 1996; 35: 357-363Crossref PubMed Scopus (171) Google Scholar, 46Gorski JP Acidic phosphoproteins from bone matrix: a structural rationalization of their role in biomineralization.Calcif Tissue Int. 1992; 50: 391-396Crossref PubMed Scopus (205) Google Scholar but only recently have definitive data for systemic or local inhibitors of cardiovascular calcification been obtained. Using gene knockout technology, mice null for the matrix gla protein (MGP) gene were created and found to have extensive cardiovascular calcification, in addition to abnormal cartilage calcification. In fact, MGP-null mice die within the first 2 months of age due to arterial rupture and heart failure as a result of extensive calcification of the large elastic and muscular arteries and heart valves.47Luo GDP McKee MD Pinero GJ Loyer E Behringer RR Karsenty G Spontaneous calcification of arteries and cartilage in mice lacking matrix GLA protein.Nature. 1997; 386: 78-81Crossref PubMed Scopus (1732) Google Scholar In wild-type mice, MGP is normally expressed at high levels in cartilage and blood vessels.48Shanahan CM Cary NR Metcalfe JC Weissberg PL High expression of genes for calcification-regulating proteins in human atherosclerotic plaques.J Clin Invest. 1994; 93: 2393-2402Crossref PubMed Scopus (558) Google Scholar Likewise, osteoprotegerin-null mice were recently shown to develop arterial calcification in addition to osteoporosis.49Bucay N Sarosi I Dunstan CR Morony S Tarpley J Capparelli C Scully S Tan HL Xu W Lacey DL Boyle WJ Simonet WS Osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification.Genes Dev. 1998; 12: 1260-1268Crossref PubMed Scopus (2111) Google Scholar Osteoprotegerin is a soluble member of the TGF receptor super family, and known to regulate osteoclast differentiation. In addition to expression in bone, osteoprotegerin is also normally expressed in blood vessels.49Bucay N Sarosi I Dunstan CR Morony S Tarpley J Capparelli C Scully S Tan HL Xu W Lacey DL Boyle WJ Simonet WS Osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification.Genes Dev. 1998; 12: 1260-1268Crossref PubMed Scopus (2111) Google Scholar Other genes whose mutation leads to enhanced cardiovascular calcification have been reported and include glucosidase,50Kuroo M Matsamura Y Aizawa H Kawaguchi H Suga T Utsugi T Ohyama Y Kurabayashi M Kaname T Kume E Iwasaki H Iida A Shiraki-Iida T Nishikawa S Nagai R Nabeshima Y Mutation of the mouse klotho gene leads to a syndrome resembling ageing.Nature. 1997; 390: 45-51Crossref PubMed Scopus (2730) Google Scholar desmin,51Thornell LE Carlsson L Li Z Mericskay M Paulin D Null mutation in the desmin gene gives rise to cardiomyopathy.J Mol Cell Cardiol. 1997; 29: 2107-2124Abstract Full Text PDF PubMed Scopus (168) Google Scholar and carbonic anhydrase II.52Spicer SS Lewis SE Tashian RE Schulte BA Mice carrying a CAR-2 null allele lack carbonic anhydrase II immunohistochemically and show vascular calcification.Am J Pathol. 1989; 134: 947-954PubMed Google Scholar The mechanisms by which loss of these genes leads to enhanced susceptibility of cardiovascular calcification is not yet known, but represent important areas for further research. Finally, osteopontin, an acidic phosphoprotein found at high levels in calcified vascular tissues (see below) was recently shown to be a" @default.
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• W53682016 title "Ectopic Calcification" @default.
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