ADR 12089 No of Pages 27 Advanced Drug Delivery Reviews xxx 2011 xxx xxx Contents lists available at ScienceDirect Advanced Drug Delivery Reviews j o u r n a l h o m e p a g e w w w e l s ev i e r c o m l o c a t e a d d r Aortic valve disease and treatment The need for naturally engineered solutions Jonathan T Butcher Gretchen J Mahler Laura A Hockaday Department of Biomedical Engineering Cornell University Ithaca NY USA a r t i c l e i n f o a b s t r a c t The aortic valve regulates unidirectional ow of oxygenated blood to the myocardium and arterial system The natural anatomical geometry and microstructural complexity ensures biomechanically and hemodynamically ef cient function The compliant cusps are populated with unique cell phenotypes that continually remodel tissue for long term durability within an extremely demanding mechanical environment Alteration from normal valve homeostasis arises from genetic and microenvironmental mechanical sources which lead to congenital and or premature structural degeneration Aortic valve stenosis pathobiology shares some features of atherosclerosis but its nal calci cation endpoint is distinct Despite its broad and signi cant clinical signi cance very little is known about the mechanisms of normal valve mechanobiology and mechanisms of disease This is re ected in the paucity of predictive diagnostic tools early stage interventional strategies and stagnation in regenerative medicine innovation Tissue engineering has unique potential for aortic valve disease therapy but overcoming current design pitfalls will require even more multidisciplinary effort This review summarizes the latest advancements in aortic valve research and highlights important future directions 2011 Published by Elsevier B V Article history Received 12 November 2010 Accepted 14 January 2011 Available online xxxx Keywords Atherosclerosis Stenosis Calci cation Risk factors Heterogeneous Biomarkers Congenital heart defects Genetic mutations Animal models Tissue engineering Biomechanics Endothelial Interstitial Clinical trials Drug discovery Contents 1 2 Introduction Aortic valve structure and physiology 2 1 Root structure 2 2 Valve cusp structure 2 3 Coordinated function 2 4 In vivo kinematics 0 0 0 0 0 0 Abbreviations 2D two dimensional 3D three dimensional 5 HT serotonin 5 HTT serotonin transporter SMA Alpha smooth muscle actin ACE angiotensin converting enzymes ADHD attention de cit hyperactivity disorder ANF atrial natriuretic factor ANGII angiotensin II APOE Apolipoprotein E ARB angiotensin receptor blocker AT1 angiotensin II Type 1 AVD Aortic valve disorders B1 and B2 bradykinin receptors BAV bicuspid aortic valve BK bradykinin BMP bone morphogenic protein BMSC bone marrow derived mesenchymal stem cells BPV bioprosthetic valve CAD computer aided design CAVD calci c aortic valve disease CHD congenital heart defect CVD cardiovascular disease COL collagen CX40 connexin 40 DGEA collagen derived peptide motif EC endothelial cells ECM extracellular matrix EDMP Endocardial derived mesenchymal progenitors EDS Ehlers Danlos syndrome EDTA Ethylenediaminetetraacetic acid ELN elastin EMT endothelial to mesenchymal transformation eNOS endothelial nitric oxide synthase FBN1 brillin FDA Federal Drug Administration FZD frizzled receptors GAG glycosaminoglycans HMG CoA 3 hydroxy 3 methylglutaryl coenzyme A HVD heart valve disease KKS kallikrein kinin system LDL low density lipoprotein LDLr low density lipoprotein receptor LPS lipopolysaccharide MDA N demethylated metabolite 3 4 methylenedioxyamphetamine MDMA 3 4 methylenedioxymetham phetamine MGP matrix gla protein MMP matrix metalloproteases MPV mechanical prosthetic valves NADPH nicotinamide adenine dinucleotide phosphate oxidase NF B nuclear factor kappa B OPG osteoprotegerin OPN osteopontin P4HB poly 4 hydroxybutyrate PEG DA poly ethylene glycol diacrylate PGA polyglycolic acid PHO polyhydroxyalkanoate PLGA poly lactic co glycolic acid PLLA poly L lactic acid RANK receptor activator of nuclear factor kappa B RANKL receptor activator of nuclear factor kappa B ligand RAS renin angiotensin system RGDS bronectin derived peptide motif ROS reactive oxygen species RVD rheumatic valve disease SDS sodium dodecyl sulfate SMM smooth muscle myosin SPARC secreted protein acidic and rich in cysteine TEHV tissue engineered aortic heart valves TGF transforming growth factor beta TIMP tissue inhibitor of metalloproteinases TNX tenascin x TLR toll like receptors VEC valve endothelial cells VEGF vascular endothelial growth factor VIC valve interstitial cells YIGSR laminin derived peptide motif This review is part of the Advanced Drug Delivery Reviews theme issue on From Tissue Engineering To Regenerative Medicine The Potential And The Pitfalls Corresponding author at 304 Weill Hall Ithaca NY 14853 USA Tel 1 607 255 3575 fax 1 607 255 7330 E mail address jtb47 cornell edu J T Butcher 0169 409X see front matter 2011 Published by Elsevier B V doi 10 1016 j addr 2011 01 008 Please cite this article as J T Butcher et al Aortic valve disease and treatment The need for naturally engineered solutions Adv Drug Deliv Rev 2011 doi 10 1016 j addr 2011 01 008 2 J T Butcher et al Advanced Drug Delivery Reviews xxx 2011 xxx xxx 2 5 Cusp tissue biomechanics 2 6 Aortic root tissue biomechanics 2 7 Relationship to tissue microstructure 3 Normal aortic valve biology 3 1 Aortic valve endothelial cells 3 1 1 Shear stress and endothelial function 3 1 2 Side speci c VEC behaviors 3 2 Aortic valve interstitial cells 3 2 1 Mechanical stress and VIC phenotype 3 3 Intercellular crosstalk 4 Clinical and societal burden of aortic valve disease 4 1 Diagnosis and monitoring of AVD progression 4 1 1 Echocardiography 4 1 2 AVD biomarkers 4 2 Treatment of valve disease 4 2 1 Valve replacement 4 2 2 Pharmacological treatment 5 Animal models of aortic valve disease 5 1 Spontaneously occurring 5 2 Diet induced 5 3 Chemically induced 5 4 Transgenic models 5 5 Surgical models 6 Mechanisms of calci c aortic valve disease 6 1 Distinguishing pathobiology 6 2 Genetic predispositions to CAVD 6 2 1 Bicuspid aortic valve BAV 6 2 2 Marfan syndrome 6 2 3 Williams syndrome 6 2 4 Collagen mutations 6 2 5 22q11 deletion 6 2 6 Holt Oran syndrome 6 2 7 Noonan syndrome 6 2 8 Down s syndrome 6 2 9 Caveat 6 3 Other causes of aortic valve disease 6 3 1 Rheumatic fever 6 3 2 Infective endocarditis 6 4 Cellular and molecular mechanisms of CAVD 6 4 1 Endothelial dysfunction 6 4 2 Interstitial cell
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