Hemodynamic and Its Role in Shear Stress Atherosclerosis Adel M, Malek, MD, PhD ih L. Alper, MD, PhD igo laumno, MD [OR MORE THAN A CENTURY, HE- modynamic forces have been proposed as factors regulating blood vessel structure’ and in- fuencing development of vaseular pa- thology such as atherosclerosis," an- ceurysis," poststenotic dilatations,’ and arteriovenous malformations The flow of blood, by virtue of viscosity, engen- ders on the luminal vessel wall and en- dothelisl surface a frictional force per unitarea knowns hemodynamic shear stress." Shear stress has not only been shown to be a critical determinant of 8 hut hasalso been im- vessel caliber. plicated in vascular remodeling!" and pathobiology.” “Atherosclerosis, which remains the leading cause of death in the devel- oped world, is associated with genetic predisposition and multiple tisk fac- tors such as hypertension,” smok- sng.” hyperlipidemia,” diabetes melli- tus," social stress." sedentary lifestyle," viral infection, and possibly chla- mydial infection." Despite the sy temic nature ofits associated risk fac- tors, atherosclerosis isa geometrically focal disease that has a propensity to in- volve the outer edges of blood vessel bi- farcations.°2=* In these susceptible ar- cas, blood flow is slow and changes direction with the cardiac eycle,result- {ng in a weak net hemodynamic shear stress, In contrast, vessel regions that are exposed to steady blood flow and aa higher magnitude of shear stress re- ‘main comparatively disease-free."?* Recent animal, molecular, and cel- lular studies of the endothelium’s re ‘Atherosclerosis, the leading cause of death in the developed world and nearly the leading cause in the developing world, is associated with systemic risk factors including hypertension, smoking, hyperlipidemia, and diabetes mell tus, among others. Nonetheless, atherosclerosis remains a geometrically fo- cal disease, preferentially affecting the outer edges of vessel bifurcations. In these predisposed areas, hemodynamic shear stress, the frictional force acting on the endothel than in protected regions. Studies have identified hemodynamic shear stress as an important determinant of endothelial function and phenotype. Arterial- level shear stress (>15 dyne/cm’) induces endothelial quiescence and an atheroprotective gene expression profile, while low shear stress (<4 dyne/ ‘cm), which is prevalent at atherosclerosis-prone sites, stimulates an ath- ‘erogenic phenotype. The functional regulation of the endothelium by local hemodynamic shear stress provides a model for understanding the focal pro- pensity of atherosclerosis in the setting of systemic factors and may help guide future therapeutic strategies. ‘AN 1999;2822035-2002 ama com sponse to hemodynamic shear stress toblood flow viscosity, andinversely pro- have provided new insights into its pos-_ portional to the third power of the in- sible contribution to the pathogenesis ternal radius." Measurements us- ofatherosclerosis."°*"" In this article, ingdifferent modalities show that shear we review the recentadvances made in stress ranges from 1 to odyne/em? inthe understanding the regulation of endo- venous system and between 10nd 70 thelial cell function and gene expres- dyne/em inthearterial vascular network. sion by shear stress. The modulation of (Figure 1,B).lnnumerousexperiments, ‘endothelial phenotype by local hemo- shear stress has been shown to actively dynamic shear stress is postulated to influence vessel wallremodeling.'*” Spe- contribute to the focal geometric pro- cifically, chronic increases in blood flow, _gression of atherogenesis in the set- and consequently shear stress, such as Ling of local and systemic risk factors seen in the radial artery of dialysis pa- that enhance the thrombotic, prolifera- _tientsproximal totheirarteriovenous is- tive, and inflammatory components of this pathological process. ‘Author Aflitions: Neurosurgery, Bigham and Wor etcetera caren s Hospital ele) and ‘THE VESSEL WALL AND Departments of Neurosurgery (br Male) Medione HEMODYNAMIC FORCES (Ore Alper ane ume), and Cal Biogy (Or Ape. ‘Revd idedealsccl and Malcl Mnand Theluminal surface ofthe blood vessel Rel Unt(D: Abe, an Catbvasasrbuon Irmo), et se Beacons eda Cee Ba anditsendothelalsurlaceareconstantly {on Mis and Bvson af enesbon fesovae Exposed tobemodynamicshearstrse*™ cli fadogy, vert of Cairns at an Fak he “lio de ody hi al ‘isco, San Francisco (Dr Malek). The magnitude of the shear stress can Corresponding Author and Reprints: Adel M. beestimatedin mostotthe vasculature Malek, ND, PD, Newetgety. Brigham and , mens and Chidrens Hosta, Buger 3,300 byPoiscuilleslaw’ (FIGUREL,A),which [opgwood Ave. doston, MA 05915 Ce-mal states that shear stress is proportional ammulekObis buh.havard eat) (©1909 American Medical Association, All rights reserved, JAMA, December 1, 1999 Vol 202, No.2 2085 ‘Downloaded From: http:/jamanetwork.com/ by a Mexico | Access Provided by JAMA. User on 10/05/2017HEMODYNAMIC SHEAR STRESS Figure 1, Hemodynamic Shear Suess Peisulestaw +, ange of Wall Shar Stress Magrtude ‘Shear Sees, nae? 1 Gross-sacionalchematie agra ofa bod venl Husratng hemadyranie sea soe, the fchonal fecepr untae acng ote ne veel al and on he urate fhe endo ae of the iw ot vse Tabular agar dst te ange of shear sess agitudes encouered Ves aris, andin ow shear and high-searpabeoge tats, tula,*or in feeder arteries supplying ce- rebralarteriovenous malformations,lead toexpansion ofthe luminal adiussuch that mean shear stress is returned to its baseline level.'** Conversely, decreased shear stress resulting [rom lower flow or blood viscostty” induces a decrease {n internal vessel radius.” The net effect of these endothelial-mediated compen- salory responses is the maintenance fof mean arterial hemodynamic shear stress magnitude at approximately 15, to 20 dynefem."! This shear stress stabilising process is dependent on in- tact endothelial function nd is abolished by priorselective destruction of the en- dothelisl monolayer? SHEAR STRESS AND ‘THE LOCALIZATION OF ATHEROSCLEROTIC PLAQUES Atherosclerotic lesions long have been known to occur near vascular branch- {ng points.* Two contradictory hypoth- ceses were advanced in the 1070s to ex- plain this distribution of lesions, The first. Iinpplicated high shear stress (400 dyne/ em!) via direct endothelial injury and denudation, as suggested by experimen- tal exposure of endothelium to supra physiological shear stress (400 dyne/ em’). The second, proposed by Caro et al,' invoked low shear stress, Subse- {quent observations and studies made in the last 3 decades have validated the low- shear hypothesis of atherosclero- 2036 JAMA, December 1.1999 Vo 28, No.2 ‘Downloaded From: http:/jamanetwork.com/ by a Mexico | Access Provided by JAMA. User on 10/05/2017 sis 220 An explanatory mechanism for this association has recently begun to 353899 that ean serve to explain, the focal nature of the inflammatory and proliferative responses to injury that likely underlie atherogenesis.” Atherogenesis preferentially in- volves the outer walls of vessel bifur- cations and points of blood flow recit- ‘culation and stasis (FIGURE 2, A and B). In these geometrically predisposed lo- ceations, fluid shear stress on the ves- sel wall is significantly lower in mag- nitude and exhibits directional changes and flow separation, features absent from regions of the vascular tree gen- erally spared from atherosclerosis. Di- rect measurementsand fluid mechani- ‘eal models of these susceptible regions have revealed shear values on the or- der of 24 dyne/em* compared with ‘greater than 12 dynefem? in the pro- tected areas.*** This association sug- ‘gests that physiological or elevated lev- cls of shear stress might shield against atherosclerosis via effects on the endo- thelium, a hypothesis since confirmed in cholesterol-fed miniature swine.” evolve Atherosclerotic lesions co-localize with regions oflow shearstressthrough- ‘out the arterial tre, from the carotid ar- tery bifurcation’ ®"to the coronary," infrarenal, and femoral artery vaseula- tures." High-speed cinematography and iicroparticle low analystsin postmor- tem coronary arterial trees have corre lated subintimal thickening withthe low wallshearstress of bifurcations" ;incon- rast, pathologiclesions were absent from, the flow-dividers and inner wall where shear is higher. The local rates of ath- crosclerosis progression in patients with coronary artery disease were found by serial quantitative coronary angiography to correlate inversely with shear stress magnitude, even whencontrolled forsys- temicrisk factors suchas circulating lev- els of lipoproteins." Flow analysis and corresponding ea- rotid endarterectomy pathological see- tions showed greatest plaque thickness fn the outer wall of the carotid sinus where low shows stasis and shears low {in magnitude and exhibits direetion re- versal! (Figure 2). Gnasso eta” found that plaque-affected human carotid at- teries exhibited significantly lower wall shear stress than diel disease-free con- trols. The co-localization of atheroscle- rosis to low-shear arcas has also been confirmed inthe only location inthe hue rman body where 2 arteries join to form avascular confluence, atthe apex of the intracranial vertebrobasilar junction.” The localization of atherosclerosis to low shear regions has been further es- tablished in human abdominal aortas both at autopsy" and with noninvasive ‘magnetic resonance phase velocity map- ping." The same pattem of early plague localization is observed in young trauma patients,"*regardless of ethnic origin" or dictary habits Enface examination of endothelial surfaces in human thoracie aortas reveals leukocyte adhesion, aceue mulation of subendothelial macro- phages and lymphocytes, irregular en- dothelial morphology with denuded regions covered with platelets, and dic lated intercellular clefts in the outer walls but not in the inner walls or flow dic vider of bifurcations.’ Measurements of wall shear stress using echo-Doppler ul- ‘rasound in healthy young patients (aged 28-38 years) revealed a statistically sig- nificant inverse relationship between in- tima-media thickness in the carotid ar- tery and local wall shear stress. Similar localization of atherosclerotic lesions has been reproduced in prospective experi- ‘mental animal tudiesin the aorta" and (©1900 American Medical Association, All rights reserved,HEMODYNAMIC SHEAR STRESS carotidarteries.* These data together es senger RNA (mRNA), protein, and ac- _high-shear counterparts low-shear grafts tablish a clear correlation between low tivity in high-shear stressed aortas exhibited gr xersmooth muscle ell pro- wall shear stress and subintimal thick- compared with sham-operated con- liferation and higher levels of platelec cningand atherosclerosis initiation. They ols.” These increases were followed by derived growth factor-A protein and are consistent with the hypothesis that vessel structural expansion” similar to mRNA.” The connection between high low wal shear stress contributes impor- that seen in the canine model.! This shear stress and low intimal prolifera tantly to conditions that favor athero- structural increase in vascular lumen to tion has been further clarified in rodent genic transformation normalize shear was prevented inthe rat experiments showing that focal in. —————__________sxodel by inhibition of nitric oxide syn- creases in shear stress in the aorta te BIOLOGICAL RESPONSE OF THE ENDOTHELIUM, TO SHEAR STRESS in shear-mediated structural remodel- Shear stress has also been associated In Vivo Responses to Surgically ing wasconfirmed by Rudicetal” when, with the endothelial proliferative state Induced Alterations in Shear Stress in wid-iype mice, the common carotid sn anlimal studies, Endothelial cell pro- thase (NOS) with N-w-nitro-Larginine- sulted in corresponding decreases in an methylester." The central role of NOS giotensin-converting enzyme activity Additional insight into the importance artery responded to surgically induced liferation increased 18-fold within 48 of the endothelial response to hemody- decrease in flow by reducing caliber to hours of reduction in shear stress."* De namics has also been gained from ani- normal e shear stress to ils preapers- creasing shear stress was followed by en- mal experiments in which shear stress tvelevel, whereasit failed todosoinmu- dothelial cel loss and desquamation, has been acutely or chronically altered. tant mice that lacked the gene for eNOS.” altered morphology with decreased elon Ine ation, decrease in actin stress fibers, casing shear stress in the rat by sur- Ina baboon polytetrafluoroethylene graft gical construction ofan aortocaval shunt fistula model, elevated shear stress Was greater monocyteattachment to and mi results in increased cyclic gu anosine associated with increased expression of gration across the endothelial layer,"*and. 3/5'-monophosphate (presumably as a eNOS,alowerdegreeof neointimal and increased endothelial surface expres: result of increased nitric oxide rel sse)," smooth muscle proliferation, and even sion of vascular cell adhesion molecule and elevated shear inereased endothe- induced regression of previously estab- 1." The incre: sed endothelial cell loss lial nitric oxide synthase (eNOS) mes- lished neointima." In contrast with their in response to decreased shear has re- Figure 2. Localzaton of Aterostlerois Lesions aR A, Schamaiilatation ofthe fea nature of atheroscerosis ands tendeny to inv the ote wall of vascul {nda artery fo ders 8 Left tral cena caotdatenogam ina 7a-yearé man who Towngicsee athe outer was ofthe conenen carob ater btrcaton oth the interna carci ater (arowhaa) andthe exten CVelocty map of he cara bfueatio at endystle using computational ud dynamic modelng usrates the love! velocies sen at he ove tral eg, (Bie) The computed wa shear sess (tor) shows the Tea lw seat magietue atte outer was that cmespand cic to he athetosdeross prone tess orth ifucaton (compare wth ) ands in canvas wit the ss suscep net fees ofthe biftaton whet flow vlc and consequrly, heme Symamie shear sess atthe veel walls Rgher (yew aa ren) (Courtesy of Des Oa Salone and Lang-Der ou, Unversty of Cater, Bee). (©1909 American Medical Association, All rights reserved. JAMA, December 1, 1999 Vl 21 2037 ‘Downloaded From: http:/ljamanetwork.com/ by a Mexico | Access Provided by JAMA. User on 10/05/2017HEMODYNAMIC SHEAR STRESS ey cer siggested tobe the result of Figure 3, Transformaton of Endothelial Cel Morphology by Flug Shear tere spopuonts whieh semaine unabeted une Praag Area Tow Ma Ul the shear normalization has been re- Homedjnama Shear Stoss emai Shear Sos (ets ameter] (eens 0-4delen stored." These in vivo experiments ob- tained in various species using dillerent rcthods to alter hemodyrsamics help es- Lablish framework to understand the propensity for intimal hyperplasia and atherosclerosis initiation in areas oflow shear stress and the protective ellect of clevated shear stress in sheltered re- sions of the vasculature The correlations between hemody- namie factors and intimal hyperplasia fn humans and animal models! have led intensive study of the in viteo endothelial response to uid shear sess inthe past decade.!"2" Bovine sot endothelial ces exposed to physilogi shear ses (>15 dynele eft panel for 28 hous Blgn nthe crechon of bled flow whe tose exposed to lw shes sess at panel do nat (phase cor tras: orginal magnfeston 123). Se "Boog Responce of te Endothelium fo Shear Stes” sacton, Short-term Effects of Shear Stress ‘Table. Endothelial Response to Hemodynamic Shear Stress ‘on Endothelial Function Tanna ier Siew ———— Hemodynamic shear ates resling Sa en gt tomacenc sinc csc ar Pore MRP Gen int incense ection foe {415 dyne/om) (x= = 0-4 dyne/em) — tacyclin™ and nitric oxide,"" both of Tiuoniaed ———Tavalusigna” which hinder pile activation Ereothetal cal funtion attenuate smooth muscle prolifera Se thon and in ection cee. ow ‘igs allowing expert blloon Inry ie or TH inanima* Phytologist Vasoaiiatons (2 15dyne/em*) decreases in vitro endo- Teor se Low flea turnover by decreasing beth = Ea ISH te of apopot rom provth ator Ferenomedul Fgh Tow Uepleion, et a = in neces ets of Come High Low hydrogen peroxide exposure "via ioe va Tr — staonstakvandatonmedenpece Sor va Ta Pedited ling oats Control of Endothelial Gene Wow tow theres and Phenotype ee sitching by shear stress oe oh vow lib shear areas ansorma pogo: mae tacotletoneshpedendtieel cle MoP A Low High of random orientation into fusiform en- Clb clesliged nthe decom ow vs flow (FIGURE 3) Shea ses of pps Tipe ones High Low ological and elevated magnitudes de- rr retentive by dress a aR — fagbothprolertion” and pepo a Tag —— Increasing the production ef vaso Fr eee oer EE FRESE ESTE Sore Eoin paracrine growth inhibitors Sein Sate Ayes cea etesacioe ronolyses and anionidants eineauaatitnants Tes aca ra! qitanareeearsie’ et Sdsuppressing production of vasocon- Sticors™ paracrine growth promot. 2038 JAMA, December 1, 1999 Vo 252, No.2 (©1900 American Medical Association, All rights reserved, ‘Downloaded From: http:/jamanetwork.com/ by a Mexico | Access Provided by JAMA. User on 10/05/2017HEMODYNAMIC SHEAR STRESS rs" inflammatory mediators”and transients or suppress endothelin 1 Although extrapolation from in vitro adhesion molecules."*!©! These re mRNA." In vitro oscillatory shear data to the living organism may be dif- sponses contribute to functional switch- stress of low magnitude (25 dyne/ ficult, these findings suggest that el- ing of endothelial phenotype by shear cm") increases endothelial levels of su-_evated arterial-level shear stress (>15 stress from a quiescent atheroprotec- peroxide anion (O,") via activation of dyne/em*) induces a quiescent, anti tive phenotype under physiological and its biosynthetic enzyme, nicotinamide proliferative, antioxidant, and anti- clevated levels ofshear stress (>15dyne/ adenine dinucleotide (reduced form) _ thrombotic phenotype," em’) toanatherogenic phenotypeatlow oxidase,” and enhances monocyte ad- and direction-varying low shear stress shearstress(0-tdynefem®) with highen- hesion.* Oscillatory shear stress is a magnitude (<4 dyne/em’), as seen in dothelialturnover. Shearstressthusregu- weaker inducer of eNOS than steady regions prone to atherosclerosis," re- lates the endothelial phenotypeonatime shear stress," and creates greater en-_sulls in an aggressive and proliferative scale of hours to days by controlling the dothelial cell proliferation.” Simi- phenotype. expression of all its known majorfune- larly, turbulent shear stress, in con- tional product classes (TABLE). trast to steady laminar shear stress, A Model of Atherogenesis Based induces in vitro endothelial cell warm on the Endothelial Response to Detrimental Effects of Oscillatory over and fails to stimulate in vitro Shear Stress ‘while time- and Turbulent Shear Stress MRNA expression of eNOS, Mn! 4 su- Investigations of the cellular mecha- Oscillatory shear stress, unlike steady peroxide dismutase, and COX-2 nisms of atherosclerosis initiation and, shear stress, can fail to induce [Ca*I, genes.” progression have contributed to acon- Figure 4, Mosel of Atherogenesis Physcloge hea avail ‘Sheer Stess Shear Stross seme aced BS gg te e be L, vd ‘ whe od 3 = —— sais io ne aca ne ora TRSISNGE these IEE {egos HE cerns 8 aa vhs ee | treat, oa ieee ees Se allansco Mtmtoitanenje pe Ratet Aageoste ce Seas ip oant Myson of theater endatheal phenotypic such tom ateoprotectve (et pana fo atherogenic ight pane induced byte ocal low magnitude shea stress, (4:dypelen eondtons fund in seroseron prone repo of wsclrbfurcatons =” The sterogene endothell phenotype resulting om weak ll he Imodyninc shear see the vee! walling he lon shear mei erutment and activo of manocjes,nease pte aca, nteteedvsacon- Schon and pace growth simula of vse! wal constituents, mereased dan state, and ceased apooioss ad cellar trove gh para) Indetes Sear stress NO, nti oxide EC, endothelal cl; and NOS, endothell rate once thas, For ether bbrevaions, see foknte to Tate (©1909 American Medical Association, All rights reserved, JAMA, Decerer 1, 1999 Vol 292, No. 21-2089 ‘Downloaded From: http:/jamanetwork.com/ by a Mexico | Access Provided by JAMA. User on 10/05/2017HEMODYNAMIC SHEAR STRESS sistent model involving immune and in- flammatory responses perpetuated by self-reinforcing cycle of monocyte re- cruitment, lipid accumulation by mac- rophages, increased smooth muscle cell proliferation, increased oxidant activ- ity, and eventual plaque rupture and thromboembolic complications." The paradigm of endothelial fune- tional regulation by shear stress can ex- plain the focal propensity of the ath- cerosclerotic response to intimal injury (FIGURES 2 and 4 and Table) The shear-controlled gene expres- sion of endothelial cells likely has evolved to maintain global vascular structural and functional homeostasis through local control by transduction of hemodynamic shear. Shear stress of| physiological arterial magnitudes (>15 dynefem*) appears to produce an ath- ceroprotective endothelial phenotype (Pigures 3 and 4) that consists of de- creased expression of vasoconstric- tors, paracrine growth factors, inflam- matory mediators, adhesion molecules, oxidants, and elevated production of vasodilators, growth inhibitors, fibri- nolyties, antiplatelet factors, and anti- oxidants. The atheroprotective pheno- type is imparted by physiological and clevated shear and renders endothe- lium less susceptible to pathogenic stimuli of injury, cell adhesion, cell pro- liferation, and lipid uptake (Figure 4). In contrast, the outer walls of vessel ized by low. and oscillatory shear stress due to vas- cular network architectural con- straints (024 dyne/em*) and are prone to atherosclerosis, These focal areas manifest greater endothelial cell cy cling and vulnerability to systemic apoplogenic stimuli such as oxidized low-density lipoprotein and tumor ne- crosis factor (TNF) a. Endothelial cells under the hemodynamic conditions de- seribed in Figure 4 might preferen- ially activate circulating monocytes and encourage local adhesion and diapede- sis. Persistently low antioxidant levels likely actin synergy with reduced pro- duction of nitric oxide to potentiate the steady paracrine mitogenic stimula- tion of vessel wall constituents. High bifurcations are charac 2040 JAMA, December 1, 1999 Vo 282, No.2 ‘Downloaded From: http:/jamanetwork.com/ by a Mexico | Access Provided by JAMA. User on 10/05/2017 ‘endothelial production of vasoconstric- tor and mitogente substances such as ‘endothelin 1, angiotensin Il, and plate lev-derived growth factor Bacts to per petuate underlying smooth muscle and fibroblast proliferation. Inaddition, re duced production of hbrinolytictissue- type plasminogen activator, coupled ‘with low production of nitric oxide and prostacyclin, may foster focal platelet aggregation and fibrin deposition, ac- celerating plaque formation and in- creasing the risk of thromboembolic events, This hypothesis is compatible ‘with systemic effects of hyperlipid- ‘emia on blood viscosity," and with possible effects of low blood flow on increased platelet aggregation” and thrombosis." This model does not preclude the m= portant contributions of known sys- lemic cardiovascular risk factors. These deleterious systemic factors, stich as smoking, hyperlipidemia, hyperten- sion, oF infectious agents, although thought to act onall regions of the vas- cculature, may be particularly potent in accentuating the local atherogenic phe- notype of the endothelial cell in re- _glons of low shear stress. Similarly, the systemic benelits of exercise, such as the observed inerease in human NOS activity with cycle training," may induce local elevations of atheropro- lective shear stress at otherwise ath- erosclerosis-prone low-flow regions at bifurcations, Sufficient activity- related elevation of local shear stress might then shift endothelial pheno- typealong the continuum from athero- ‘genic toward atheroprotective, thus al- tenuating (and potentially reversing) this chronic disease process. ‘CONCLUSION Shear stress studies have altered our ‘concept of the endothelium from that of a passive, nonthrombogenic sur- face to that of a dynamically respon- sive vascular element producing auto- cerine and paracrine factors under the functional regulation of local hemody namic forces."°2°* These findings have underlined the importance of studying endothelial cell function wn- der flow conditions and have renewed ellorts to dently novel and known gene products that may be regulated by shear "© The molecular phenotypic switching of endothelium by shear stress olfers an integrated model to explain the focal nature of atheroscle- rosis, Future work will address thera- peutic approaches to thwart the local atherogenic phenotype of the endothe- lial cell in lesion-prone low-shear regions, without interfering with its ability to maintain global vascular ho- reostass, and should include studies of interactions of this regulation by clinically established cardiovascular risk factors. Fundng/Suppot_r ek wassupooted bya Na tol stttecot Heath NH Medel sents Tra IngProgiam grant, the Whitaker Feundabn, andthe Boson Neufsurgica Foundation. Dr Apes sup Ported by NI grant HLI5178 and by a grata From the Amertan Heat Asocstion, seaman Alper were tstablsnes Investigators ofthe Amercan Heart Assocation during the couse of hs resexch Acknowledgment: We apologize to those col- lesquer hore warkwar nt ced de fo space i= ‘atone RERENS 4. Kamiya A, Togawa T. Adaptive eguaton of wall Sear eso fow change nthe caine carob a tery Am JPhysel 1980255144021 2 Lange BLO Donne FReductonsin ateial Siete produced by conic decreases Blood Now ‘Meendethlum dependent Science. 1986231405 an 3. Fry DL. Certain histological and chemical - once ofthe vascular nec osc induced tmecnaieastes nthe aoa ofthe dog, Clee. 3652433108 4 Cao CG, Fa-Gerald IM, Setter RC. 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