Special Report Gaining New Insights into Early Abdominal Aortic Aneurysm Disease

Transcription

1 vilble online: Originl rticle Specil Report Gining New Insights into Erly Abdominl Aortic Aneurysm Disese Julie J White Ronld L Dlmn, MD, FACS, FAHA Abstrct Abdominl ortic neurysm (AAA) disese is prevlent nd highly morbid condition mong older people in the US. There re currently no proven methods for reducing or eliminting enlrgement in smller preclinicl neurysms. Given their reltively slow increse in dimeter (typiclly <0.4 cm/yer), these smller neurysms offer vluble window into the underlying pthophysiology of AAA disese. Through Vsculr Remodeling Specilized Center of Cliniclly Oriented Reserch progrm funded by the Ntionl Institutes of Helth, we hve estblished, in conjunction with Northern Cliforni Kiser Permnente, multidisciplinry reserch effort to efficiently identify nd hndicp suppressive therpeutic strtegies for erly AAA disese. Bckground Abdominl ortic neurysm (AAA) disese is prevlent nd highly morbid condition mong older people in the US. The ort normlly elongtes nd diltes with ge, but when the dimeter distl to the renl rteries exceeds 3 cm, it is considered neurysml. In the US, AAA disese ffects pproximtely 6% of men nd 1% of women older thn 60 yers, nd more thn 30,000 people die becuse of ruptured neurysms or complictions relted to surgicl repir of the ort ech yer. 1 Tody AAAs re most commonly identified s incidentl findings during bdominl imging exmintions. Smll AAAs generlly enlrge t predictble rte, 2 so ptients in whom AAA hs just been dignosed usully enter wtchful witing period before surgicl intervention. There re no proven medicl therpies for ptients with erly disese. The lck of nonsurgicl therpies to prevent progression of erly-stge disese nd the bsence of vlidted biomrkers or imging prmeters to monitor disese dvncement present mjor clinicl chllenges in the mngement of smll neurysm disese. 3 5 We im to nswer these clinicl chllenges through our study: AAA Disese: Mechnism, Strtifiction nd Tretment, recently funded by the Ntionl Hert, Lung, nd Blood Institute (NHLBI). The pthophysiology of AAA disese is defined by trnsmurl inflmmtion, smooth muscle cell poptosis, nd impired extrcellulr remodeling. These events led to progressive ortic enlrgement nd eventul rupture. The risk of rupture nd sudden deth is most closely relted to neurysm dimeter. Surgicl intervention through open or endovsculr repir is presently the only effective method of tretment. At 5.5 cm in men, the risk of surgicl repir is outweighed by the risk of neurysm rupture or neurysm-relted deth. For women, the guidelines re less well defined repir is generlly recommended t dimeter between 4.5 nd 5.0 cm. 6 There re currently no proven methods for reducing or eliminting enlrgement in smller preclinicl neurysms. Given their reltively slow increse in dimeter (typiclly <0.4 cm/yer), these smller neurysms offer vluble window into the underlying pthophysiology of AAA disese. Although AAA ws once reltively obscure nd uncommon premortl dignosis, AAA wreness mong ptients nd physicins hs incresed significntly since 2004, mening tht ptients who re otherwise quite helthy re becoming wre of their erly AAA disese t reltively younger ges thn ever before. In 2004 the Wll Street Journl received Pulitzer Prize for its reporting on the growing helth risks of AAA disese nd its incresing impct on the ging bby-boom demogrphic. 7 Shortly therefter, the United Sttes Preven- Julie J White, (left) is the Reserch Progrm Director for the Stnford Ntionl Institutes of Helth (NIH) SCCOR Progrm Project Grnt on bdominl ortic neurysms in Stnford, CA. E-mil: juliejohnsonwhite@stnford.edu. Ronld L Dlmn, MD, FACS, FAHA, (right) is Professor nd Chief of the Division of Vsculr nd Endovsculr Surgery t Stnford University Medicl Center in Stnford, CA. Dr Dlmn is the Progrm Director nd Principl Investigtor of the Stnford Ntionl Institutes of Helth (NIH) SCCOR Progrm Project Grnt on bdominl ortic neurysms. E-mil: rld@stnford.edu. 10 The Permnente Journl/ Spring 2008/ Volume 12 No. 2

2 Gining New Insights into Erly Abdominl Aortic Aneurysm Disese ORIGINAL Article ttive Services Tsk Force reported tht screening reduced AAA-relted mortlity by 43% in men 65 to 75 yers of ge. 8 Additionlly, in Jnury 2007, the Screening Abdominl Aortic Aneurysms Very Efficiently (SAAAVE) Amendment went into effect. It provides one-time ultrsound screening exmintion for AAA disese to qulifying Medicre beneficiries s prt of their Welcome to Medicre physicl exmintion when they rech ge 65 yers (for more informtion, see www. vsculrweb.org/ptients/medicrescreening/index.html). Ninety percent of AAAs detected through screening progrms fll below the 5.5- or 4.5-cm threshold currently recommended for elective surgery eligibility for men nd women, respectively. In the bsence of clerly defined tretment guidelines for smll AAA, the obvious question for mny of these ptients nd their physicins is Wht s next? Figure 1. Custom softwre ws used to convert mgnetic resonnce dt (left) to three-dimensionl geometric model of the flow domin (center left). The three-dimensionl model, in combintion with ptient-specific blood flow informtion, ws used to simulte blood flow in n neurysm during rest nd exercise. During resting conditions, res of low flow nd flow stgntion exist within the neurysm even t pek systole (center right); these regions re decresed during simulted exercise (right). Current Reserch The NHLBI initited AAA-specific reserch effort in 1999, funding 11 collbortive R0-1 reserch grnts in seven different institutions, including Stnford University. 9 Although initilly limited to bsic cellulr, niml modeling, nd genetic linkge studies, these progrms proved quite productive in defining the mechnisms responsible for AAA pthogenesis nd outlining potentil trnsltionl reserch strtegies This ws followed in 2004 by n NHLBI Request for Applictions (RFA) for Specilized Centers of Cliniclly Oriented Reserch (SC- COR) progrms in vsculr injury, repir, nd remodeling, which specificlly solicited proposls to move AAA reserch squrely into clinicl frmework. With the help of resources obtined through the Vsculr Remodeling SCCOR, we hve estblished, in conjunction with Kiser Permnente Northern Cliforni (KPNC), multidisciplinry reserch effort to efficiently identify nd hndicp suppressive therpeutic strtegies for erly AAA disese. Our progrm, AAA Disese: Mechnism, Strtifiction nd Tretment, includes 28 investigtors or coinvestigtors, including Brdley B Hill, MD, Chief of Vsculr Surgery t the Snt Clr Medicl Center, nd sttisticins, study coordintors, engineers, physicins, exercise physiologists, technicins, nd medicl science grdute students. Together, our multidisciplinry tem will develop n integrted pproch to nlysis, strtifiction, nd tretment of AAA disese. Our progrm includes three relted projects nd four support cores. The first project uses proteomic tools to improve dignosis of erly AAA disese, to identify disese-specific predictors of expnsion, nd to monitor response to potentil medicl therpies. The second project nlyzes the influence of hemodynmic vribility on AAA pthophysiology nd disese progression. The third project exmines the reltionship between physicl ctivity nd AAA disese risk, including both the nlysis of lifetime physicl ctivity vis-à-vis ortic dimeter nd rndomized clinicl tril testing the bility of supervised exercise trining to modify AAA disese progression. The support cores provide histology, bioimging, nd clinicl skills development trining, s well s dministrtive support. The exercise tril described bove nchors nd connects the projects nd supportive core units of this comprehensive trnsltionl reserch progrm. Substntil evidence links sedentry existence nd resulting proinflmmtory ortic conditions to the pthogenesis of AAA disese. 16,17 For this cross-sectionl correltion study to determine whether lifetime physicl ctivity nd mesured exercise cpcity represent independent risk fctors for AAA disese, 1400 prticipnts will be recruited. In ddition, subset of 340 study subjects with smll AAAs will prticipte in prospective, rndomized, controlled longitudinl tril of exercise to suppress smll AAA progression. The impct of exercise trining will be monitored by ultrsound imging surveillnce Substntil evidence links sedentry existence nd resulting proinflmmtory ortic conditions to the pthogenesis of AAA disese. 16,17 The Permnente Journl/ Spring 2008/ Volume 12 No. 2 11

3 Originl rticle Gining New Insights into Erly Abdominl Aortic Aneurysm Disese nd surrogte serum mrkers. Defining the exct nture of those surrogte serum mrkers is the purpose of the proteomic project. In view of similr observtions of ptients with therosclerotic occlusive disese, it is likely tht AAAs produce unique signture profiles of proteins tht include spects of inflmmtion, poptosis (progrmmed cell deth), extrcellulr mtrix brekdown, nd thrombosis. In this project, trnscriptionl profiling of humn AAA tissue, dtbse mining for ptterns of protein expression nd serum multimrker ssessment of experimentl models will be used to develop proteomic profiles (simultneous expression of disese-specific meditor proteins in serum) of AAA disese. Our expecttion is tht these proteomic profiles would not only provide insight into the AAA disese process but lso enble serologic monitoring of neurysm expnsion nd response to novel therpies. 18,19 Aneurysm expnsion nd rupture re dynmic processes driven by luminl pressure, wll sher, nd strin forces. The hemodynmic project will employ novel imging nd computer modeling techniques to quntify the biomechnicl forces cting in AAAs during resting nd Tble 1. Protocol for specific im 1 1. Telephone or in-person screening consent, followed by the reserch consent. 2. Collection of medicl history informtion from medicl records, including current medictions. 3. Directed physicl exmintion. 4. Completion of two questionnires regrding lifetime physicl ctivity nd helth history questionnire. 5. Abdominl ultrsound imging to mesure ortic dimeter. 6. Blood drw for lipid pnel, hs-crp, MMP-9, fsting insulin nd glucose levels, nd protein profiles. 7. Urine smple for cotinine nlysis. A prospective cross-sectionl study of lifetime physicl ctivity s n independent risk fctor for bdominl ortic neurysm disese. hs-crp = high-sensitivity C-rective protein; MMP-9 = mtrix metlloproteinse-9. exercise conditions. After refining our bility to quntify bdominl ortic blood flow t rest nd during exercise, we will develop nd vlidte computtionl methods to model blood flow, pressure, nd wll motion in ptient-specific reproductions of the bdominl ort 20 (Figure 1). This project will imge nd model blood flow in pproximtely 100 ptients from the sustined exercise or usul ctivity rms of the clinicl tril. In ddition to KPNC, Stnford University is collborting with the Plo Alto Institute for Reserch nd Eduction nd the Veterns Affirs Plo Alto Helth Cre System (VAP- AHCS) through consortium greements on this study. The progrm ws initited in My 2006, with humn subjects pprovl through Stnford University, VAPAHCS, KP, nd the NHLBI Dt Sfety Monitoring Bord finlized in November Recruitment begn in lte November 2006 for the prospective cross-sectionl correltion study to determine whether lifetime physicl ctivity nd mesured exercise cpcity represent independent AAA risk fctors. For this specific im 1 (SA 1), prospective cross-sectionl study of lifetime physicl ctivity s n independent risk fctor for AAA disese, study subjects with smll AAAs (<5.5 cm) complete the protocol shown in Tble 1. After initil screening, the prticipnt completes these procedures Tble 2. Protocol for specific im 2 exercise group 1. Assessment of mximum exercise cpcity, performed t the beginning of the study s well s every six months until completion. HR, BP, electrocrdiogrms, nd exercise tolernce re monitored throughout the test by medicl personnel. 2. Supervised outptient exercise trining three dys per week for prticipnts living within 15 miles of the VAPAHCS. Exercise sessions include five-minute wrm-ups nd cool-downs nd minutes of continuous erobic exercise (tredmill wlking, cycle ergometry, step bench). Electrocrdiogrphic, HR, nd BP responses re monitored throughout the test period. Study subjects living >15 miles from the VAPAHCS re provided with detiled exercise prescription nd wer HR- nd ctivity-trcking devices while exercising for monitoring purposes. Prticipnts return monthly for downloding of HR nd ctivity dt. Reserch stff routinely contct study subjects nd monitor progress. 3. In ddition to being prescribed exercise regimens, ll study subjects re encourged to increse dily exercise levels nd will wer pedometer every dy nd GPS/HR monitor twice month. 4. Prticipnts with AAAs of <4 cm undergo bdominl ultrsound imging, blood drw (for lipid pnel, hs-crp level, MMP- 9 protein profiles, nd fsting insulin nd glucose levels), nd urine smple (cotinine nlysis) nnully. 5. Prticipnts with AAAs 4 cm undergo bdominl ultrsound imging nd blood drws (lipid pnel, hs-crp level, MMP-9 protein profiles, fsting insulin nd glucose levels) nd provide urine smple (cotinine nlysis) binnully. Prospective evlution of the bility of exercise trining to reduce AAA progression. AAA = bdominl ortic neurysm; BP = blood pressure; HR = hert rte; hs-crp = high-sensitivity C-rective protein; MMP-9 = mtrix metlloproteinse-9; VAPAHCS = Veterns Affirs Plo Alto Helth Cre System (in Cliforni). 12 The Permnente Journl/ Spring 2008/ Volume 12 No. 2

4 Gining New Insights into Erly Abdominl Aortic Aneurysm Disese ORIGINAL Article Tble 3. Protocol for specific im 2 usul ctivity group 1. Wer pedometers nd continue usul level of ctivity. 2. Prticipnts with AAA <4 cm undergo bdominl ultrsound imging nd blood drw (lipid pnel, hs-crp level, MMP-9 protein profiles, fsting insulin nd glucose levels) nd provide urine smple (cotinine nlysis) nnully. 3. Prticipnts with AAA 4 cm undergo bdominl ultrsound imging nd blood drws (lipid pnel, hs-crp level, MMP-9 protein profiles, fsting insulin nd glucose levels) nd provide urine smples (cotinine nlysis) binnully. 4. Ptients re sked bout level of ctivity every 6 12 months when they undergo blood drws. Prospective evlution of the bility of exercise trining to reduce AAA progression. AAA = bdominl ortic neurysm; hs-crp = high-sensitivity C-rective protein; MMP-9 = mtrix metlloproteinse-9. during hlf-dy visit to the VAP- AHCS exercise physiology lbortory. When this rticle ws written, we hd screened nd enrolled 146 ptients into this im, t n verge of 25 per month. Currently, there re no dditionl study requirements necessry for prticiption in SA 1; plns re underwy, however, to modify the protocol to include one dditionl one-hlf dy visit for ultrsound nd serum mrker testing t the end of the study. A subset of ptients with smll neurysms identified in SA 1, who qulify nd re interested in prticipting, hve the opportunity to enroll in the prospective evlution of the bility of exercise trining to reduce AAA progression (SA 2). Prticiption in SA 2 is clerly limited to highly motivted individuls with the highest level of commitment to the study. By the end of the second yer of the study, we hope to rndomize 170 ptients to the exercise group nd 170 to usul ctivity. Ptients ssigned to the exercise group prticipte in three-yer protocol outlined in Tble 2. At the time of the bseline exercise test visit, study subjects re counseled regrding the identifiction of signs nd symptoms of exertionl intolernce nd the need for medicl ttention. Ptient progress, symptoms experienced, nd complince re monitored closely throughout the course of the study. Study subjects in the home progrm re lso sked to return to the hospitl monthly for mintennce counseling, to updte questionnires on physicl ctivity ptterns, nd to downlod ccelerometer ( device to mesure displcement ctivity) dt. Mximl exercise testing is repeted fter the initil two months nd t six-month intervls therefter, providing mple opportunity to monitor trining effects, ensure ptients medicl stbility, nd updte the exercise prescription (Figures 2 nd 3). Ptients rndomly ssigned to the usul ctivity group complete the protocol in Tble 3 over threeyer period. Forty-two ptients hve enrolled in SA 2. As noted bove, prticiption is limited to highly motivted study subjects who re committed to completing the entire period of the study. One ptient remrked tht the opportunity to prticipte in n exercise progrm hs been delightful nd hving the results contribute to useful medicl knowledge is bonus. I m n 80- yer-old widower who hd been degenerting physiclly from simple lck of mbition nd motivtion. This opportunity to lern proper exercise nd enjoy some socil life with fellow prticipnts hs been enjoyble. This ptient represents one of the motivted individuls who hs successfully integrted this study into his routine nd benefited gretly. Recruitment for both ims is ongoing through vsculr nd primry cre clinics throughout the consortium hospitls, including ll 14 KPNC fcilities. We hve lso recently dded significnt resources to our KP ffilition by upgrding nd expnding our contrct with the KP Division of Reserch (DOR) in Oklnd, CA. DOR personnel, led by Aln Go, MD, nd Crlos Iribrren, MD, MPH, PhD, re collborting on the scientific direction of the study nd helping ctlyze its successful completion. Severl thousnd KPNC ptients re lredy wre tht they hve smll AAAs nd will ultimtely need surgicl repir. Mny, if not most, of those ptients my be interested in lerning more bout their disese through prticiption in this importnt study, which is clled Abdominl Aortic Aneurysms: Simple Tretment or Prevention (AAA: STOP). Should the opportunity rise, plese consider mentioning AAA: STOP to your ptients who hve smll neurysms. Study personnel from Stnford re vilble to provide onsite eduction progrms bout AAA disese nd current mngement options, s well s study-relted informtion. Study contct inform- Figure 2. A study prticipnt, supervised by stff member, is exercising on n irdyne bicycle, which llows prticipnts to get both n upper- nd lower-body workout. I m n 80-yerold widower who hd been degenerting physiclly from simple lck of mbition nd motivtion. This opportunity to lern proper exercise nd enjoy some socil life with fellow prticipnts hs been enjoyble. The Permnente Journl/ Spring 2008/ Volume 12 No. 2 13

5 Originl rticle Gining New Insights into Erly Abdominl Aortic Aneurysm Disese Figure 3. A study prticipnt exercises on tredmill t the lb in the Veterns Affirs Plo Alto Hospitl. tion nd dditionl AAA resource mterils for helth cre providers re vilble on our Web site ( stop.stnford.edu) or through the Vsculr SCCOR offices in the Division of Vsculr Surgery t Stnford University: Cll or e-mil juliejohnsonwhite@stnford. edu. Ptients who re interested in study prticiption re encourged to visit our study Web site. Reserch Outcomes Ultimtely, we hope tht when ptients in Northern Cliforni sk the question Wht s next? the nswer will be n introduction to AAA: STOP by their primry cre physicin or vsculr surgeon. In the ner future, we nticipte tht the nswer will include specific tretment recommendtion enbled by the nturl history informtion collected from this importnt study. v Disclosure Sttement The uthor(s) hve no conflicts of interest to disclose. Acknowledgment Kthrine O Moore-Klopf of KOK Edit provided editoril ssistnce. References 1. Kent KC, Zwolk RM, Jff MR, et l; Society for Vsculr Surgery; Americn Assocition of Vsculr Surgery; Society for Vsculr Medicine nd Biology. Screening for bdominl ortic neurysm: consensus sttement. J Vsc Surg 2004 Jn;39(1): Brdy AR, Thompson SG, Greenhlgh RM, Powell JT; UK Smll Aneurysm Tril Prticipnts. Crdiovsculr risk fctors nd bdominl ortic neurysm expnsion: only smoking counts. Abstrct. Br J Surg 2003;90: Golledge J, Muller J, Dugherty A, Normn P. Abdominl ortic neurysm: pthogenesis nd implictions for mngement. Arterioscler Thromb Vsc Biol 2006 Dec;26(12): Golledge J, Powell JT. Medicl mngement of bdominl ortic neurysm. Eur J Vsc Endovsc Surg 2007 Sep;34(3): Powell JT, Brdy AR. Detection, mngement, nd prospects for the medicl mngement of smll bdominl ortic neurysms. Arterioscler Thromb Vsc Biol 2004 Feb;24(2): Normn PE, Powell JT. Abdominl ortic neurysm: the prognosis in women is worse thn in men. Circultion 2007 Jun 5;115(22): Helliker K, Burton TM. Medicl ignornce contributes to toll from ortic illness: mny doctors don t relize neurysms re tretble; pucity of specilists. The Wll Street Journl [seril on the Internet] Nov 4 [cited 2007 Sep 12]. Avilble from: 8. Fleming C, Whitlock EP, Beil TL, Lederle FA. Screening for bdominl ortic neurysm: best-evidence systemtic review for the US Preventive Services Tsk Force. Ann Intern Med 2005 Feb 1;142(3): Wssef M, Bxter BT, Chisholm R, et l. Pthogenesis of bdominl ortic neurysms: multidisciplinry reserch progrm supported by the Ntionl Hert, Lung nd Blood Institute. J Vsc Surg 2001 Oct;34(4): Nkhshi TK, Hoshin K, Krwowski JK, et l. Flow loding induces mcrophge heme oxygense 1 expression in experimentl neurysms. Arterioscler Thromb Vsc Biol 2002 Dec 1;22(12): Hoshin K, Sho E, Sho M, Nkhshi TK, Dlmn RL. Wll sher stress nd strin modulte experimentl neurysm cellulrity. J Vsc Surg 2003 My;37(5): Sho E, Sho M, Hoshin K, Kimur H, Nkhshi TK, Dlmn RL. Hemodynmic forces regulte murl mcrophge infiltrtion in experimentl ortic neurysms. Exp Mol Pthol 2004 Apr;76(2): Sho E, Chu J, Sho M, et l. Continuous retroperitonel infusion improves doxycycline efficcy in experimentl ortic neurysms. J Vsc Surg 2004 Jun;39(6): Sho E, Sho M, Nnjo H, Kwmur K, Msud H, Dlmn RL. Hemodynmic regultion of CD34+ cell locliztion nd differentition in experimentl neurysms. Arterioscler Thromb Vsc Biol 2004 Oct;24(10): Sho E, Sho M, Nnjo H, Kwmur K, Msud H, Dlmn RL. Comprison of cell-type-specific vs trnsmurl ortic gene expression in experimentl neurysms. J Vsc Surg 2005 My;41(5): Myers J, Lee M. Fitness, physicl ctivity, nd inflmmtory mrkers for crdiovsculr disese. ACSM s Certified News [seril on the Internet] 2006 Apr Jun [cited 2007 Sep 12];16(2):5 7. Avilble from cfm?section=acsm_s_certified_ne ws&contentid=4869&template=/ CM/ContentDisply.cfm. 17. Myers J, Kykh A, George S, et l. Fitness versus physicl ctivity ptterns in predicting mortlity in men. Am J Med 2004 Dec 15;117(12): Ardigo D, Assimes T, Fortmnn SP, et l. Circulting chemokines ccurtely identify individuls with cliniclly significnt therosclerotic hert disese. Physiol Genomics 2007 Nov 14;31(3): Tbibizr R, Wgner RA, Ashley EA, et l. Signture ptterns of gene expression in mouse therosclerosis nd their correltion to humn coronry disese. Physiol Genomics 2005 Jul 14;22(2): Tylor CA, Drney MT. Experimentl nd computtionl methods in crdiovsculr fluid mechnics. Annul Review of Fluid Mechnics 2004 Jn;36: The Permnente Journl/ Spring 2008/ Volume 12 No. 2