V 77 no 2 2008 by Joanne Paterson

Volume 77 Number 2

Cardiovascular Issue

Contents FROM THE EDITORS Melanie Sproule Hall, Meds 2008, Amber Menezes, Meds 2009, Wendy Ng, Meds 2009, and Tiffany Kwok, Meds 2010

Profiles

DEPARTMENT ARTICLES Clinical Procedures Current Techniques in Carotid Artery Stenting: A Synopsis Paul Lau. Meds 2011

Thinking on your Feet

Diagnostic Review Innovations in Cardiac Computed Tomography: Cone Beam CTNolume CT and Dual Source CT Jaron Chong, Meds 2010 and Jason Essue, Meds 2011

Dr. Ri chard J. Novick on Gun s, Germs and Steel - Perspecti ves fro m a Cardio-Thoracic and Tran pl ant Surgeon Al) sia Zhou, Meds 2010

Atri al Septal Defects in Adults Todd Greenspoon, Meds 2010 and Aiman Alak, Meds 201 1

Zebra Files Commoti o cordi : an important cause of sudden cardiac death in yo un g athletes Ashley Brown, Meds 2011, Jenna Ashkanase, 40 Meds 2011 , and Tiffany Kwok, Meds 2010 7

FEATURE ARTICLES Ethics The Aprotinin Story: Lessons in Drug Regulation and Safety Adam Katchky, Meds 2010 and Christina Morgan, Meds 2011

An overview of using cost-effec ti ve measures in preventing cardiova cul ar disease Dinesh Bhayana, Meds 2010 43

Health Promotion Heart Health or Hype? Exploring the effect of diet trends on cardi ovascul ar di ease Jonathan Klein, Meds 2010 and Laura Hin z, Meds 2011

Health Canada Ban on Ephedrine- A Postban Asses ment of Effecti venes lshvinder S. Chattha, Meds 2011

Takotsubo Cardi omyopathy: A Review of Clinical Features, Pathophysiology and Ma nage ment Xian gning Fan , Meds 2010

Genetic Basis of Coronary Artery Disease Ma tthew Lanktree, Medicine I PhD 2012

Doe being "South A ian" increase the risk of CAD? Wajid Sayeed, Meds 2010

A Look at Cardi ac Myxo ma Ahraaz Wyne, Meds 2010

History of Medicine Hi story of the C ircul atory Sy tern : discovery of the basics Adam Garber, Meds 2010 and Michael 22 Livingston, Meds 2011

Medicine and the Internet Computer-assisted learning-teaching clinical skill s in cardiology Jordan Glicksman, Meds 2010 and Pencilla 25 Lang, Meds 2011

Medicine and the Law Medical Malpractice Liti gation: Myth or Growing Cri sis? Abdullah Alabousi, Meds 2011

ÂŠ 2008 UWOMJ

Editorial Staff EDITORIAL BOARD AND SUPPORT Editor-in-Chief

Melanie Sproule Hall , Meds 2008

Managerial Stream Senior A oc iate Editor Junior As ociate Ed itor

Amber Meneze , Med 2009 Wendy Ng, Med 2009 Tiffany Kwok, Meds 20 10

Contracts and A wards Stream Senior A oc iate Ed itor Junior Associate Ed itor

Renata Villela, Med 2009 Jean C hen, Med 20 I 0

IT Director Layout Editor

lshvinde r Chattha, Med 20 11 Stephen C hihrin . Med 2008

DEPARTMENTAL EDITORS Clinical Procedure Sr: Brent Mollon. Med 20 I 0 Jr: Paul Lau , Meds 20 1 1

Diagnostic Review Sr: Jaron Chong, Med 2010 Jr: Jason E ue, M eds 20 11

Ethics Sr: Adam Katchky, Med 20 10 Jr: Christina Morgan, Med 20 11

Health Promotion Sr: Jonath an Kl e in , Med 20 10 Jr: Laura Hinz, Med 20 11

History of Medicine Sr: Ada m Garber, Meds 20 I 0 Jr: Michael Livingston , Med 20 L I

Medicine and the Internet Sr: Jordan Glick man, Med 2010 J r: Penci II a Lang. Meds 20 11

Medicine and the Law Sr: Michae l Slatnik, Meds 20 10 Jr: Abdull ah Alabousi, M d 20 11

Profiles Sr: Alysia Zhou, Meds 20 10 Jr: Be n Turner, Meds 20 LI

Thinking on your Feet Sr: Todd Green poon , Meds 20 I 0 Jr: Aiman Alak, Med 路 20 11

Zebra Files Sr: Tiffany Kwok, Meds 2010 Jr: Jenna As hkanase, Meds 20 11 Ashl ey Brown , Meds 20 11

UWOMJ ADVISORY BOARD Dr. Dr. Dr. Dr. Dr.

Dougla Quan Loi s Champion Mic hae l Reider Ron Wex ler Ke lli e Le itch

Dr. Dr. Dr. Dr. Dr.

Dav id Co lby Fai al Rehman Jeffrey Ni . ker Jim Silcox Way ne Weston

PRINTER fnPrint Design: University Stude nts' Coun cil , Univer ity of Western Ontario

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COVER ART Front: Olga Wrezel, Meds 2009, "Normal Sinus Rhythm" Back: Azad Mashari, Meds 2008, "Vi sual conceptions of structure and function of the heart." The coll age assembles nine images from Europe, The Middl e Ea t and North America fro m the 14th century to present. With the exception of image [8] all source image are from the United States National Library of Medicine's (NLM) Historica l Anatomies on the Web (http://www.nlm.ruh.gov/ exhibiti on lhistoricalanatornies/ ho me.html) and the exhibit Dream Anatomy (http:// www.nJm.ruh.gov/ exhibitionldrea manato my/index .htm 1). Image [8) i from the NLM's Vi ible Huma n Project (http://www . nlm.nih.gov/ research/vi ible/ vi ible_ human.htrnl. All source image . a well as this collage, are in the Public Do main and may be freely hared and modified for any purpo e.

Legend [ 1)[2)[3] [4][5][6] [7][8][9] [1, 3] An anonymo us Per ian anatomica l illu tration. Iran or Paki tan ca. 1680-1750. [2] Man ur ibn Il ya (0 . ca. 1390). Ta hrih-i badan-i insan. [Anatomy of the Human Body], Folio 18a. Iran ca. 1390. 141 Sarlandiere. Jean-Bapti ste ( 1787 - 1838). Anatornie methodique. Pari : hez le libraires de medec ine. et chez l'a ute ur, 1829. Plate 9. [5] B ugle, Juli en ( 18681903 ). Le c rpu humai n et gra ndeur nature lle: planc he co loriee et uperpo ees, avec texte ex pli catif. Paris: .l. B. Bailliere et fil s, 1899. [6] Spiegel, Adri aan van ( 1578- 1625) and Ca seri. Giulio (ca. 1552- 16 16). De huma ni corpori s fabrica libri decem. Ve nice: Eva ngeli sta Deuc hin o, 1627. p.85. [7 , 91 Kats, Toviyah (ca. 16521729). Ma'a' ch Toviyah [The Works of T ob ias]. Venice, 1708. Woodcut. f8 j Cryosection throu 1:'oh the thorax of the human ma le. Nati onal Library of Medi cine' Vi 路ible Human Proj ec t.

From the Editors

Upcoming Issue: Infectious Disease The Univer ity of Western Ontario Medical Journal (UWOMJ ) is Canada's econd olde l student run medical journ al. Established in 1930, the UW OMJ prov ides a fo rum fo r original articles based on research or clinical medicine of topic or hi torical interest. It is a biannual publication with interdisciplinary reader hip that incl udes students, faculty members, residents a nd pecialists. At any given time during the academi c year, over 40 past and present current medical tudent Senior and Juni or Departmental Editors recruit, write, submit and edit articles. The UWOMJ has over 20 confirmed physician fac ulty reviewers for eac h is ue, ofte n affili ated with the Uni versity of We tern Ontario' Schulich School of Medicine and Denti stry, as well as hospital s in both London, Ontari o and Windsor, Ontario. Our Advisory Board includes both nationally known academic and community ph ys icians.

Melanie Sproule Hall, Medicine 2008, Amber Menezes, Medicine 2009, Wendy Ng, Medicine 2009, and Tiffany Kwok, Medicine 2010 Cardiovac ular health is of increasing importance in the Canadi an healthcare sy te m. With growing public awareness and medi a profiling of cardiovasc ular health , resea rch, and updates, we cho e to foc us thi issue on this cuttin g-edge and exciting area of medi cin e. Given expanding pati ent know ledge and interest, our contri butors stepped up to the ta k of writing on relevant, informati ve, and provocative topi c Thi issue includes a broad pectrum of articles appealin g to readers of all backgrounds and interests. Fro m the newe t surgical advances, diagnostic modalities and techniques, to bread-and-butter management guidelines, we hope that thi s issue will piqu e yo ur interest and draw your attenti on to thi s rapi dly ad vancin g and dynamic field. As editorial staff, we would like to extend a heartfelt thank yo u to o ur departmental editor and contributors, cover artists, fac ulty advi ors, fac ulty reviewers, the Hippocratic Council at the University of W estern Ontari o. This issue would not be possible without the help of Dr. Faisal Rehman and our Contracts and A ward team, Renata Villela and Jean Chen. We are grateful to Bristol-M yer Squibb for their genero us contribution towards fundin g thi s issue. As always, we thank yo u, our dedicated readers fo r yo ur continued support. Your feedback, co mments, idea , and questions are welco med at uwo mj @meds. uwo.ca. W e trust that yo u will enj oy this issue ! Your editorial staff,

Please visit us online at:

www.uwomeds.com/uwomj For informati on about writing for the UWOMJ, please fo ll ow the guidelines outlined on our web site. The UWOMJ is a fac ulty reviewed and peer-reviewed publicati on. All editorial matter in the UWOMJ represents the opinions o f the authors and not necessaril y th ose of the editorial staff and advisory board . The editorial staff and advisory council assume no responsibility or liability fo r damages arising from any error or omission or fro m use of any informati o n or advice contained in the UWOMJ.

Melanie Sproule Hall Editor-in-Chief

Amber Menezes Senior Editor: M anageri al Stream

W endy Ng Seni or Editor: Managerial Stream

Ti ffany Kwok Junior Editor: Managerial Stream

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Clinical Procedures Current Techniques in Carotid Artery Stenting: A Synopsis Paul Lau, Meds 2011 Reviewed by Dr. Stephen P. Lownie

Introduction Cardi ova cul ar di sea e and tro ke are the leadin g cau e of death in Canada. Approx imately 15,000 Canadians will di e o f troke every year and 300,000 peopl e w ill be li ving with its 1 effec ts. In the United States of Ame1ica, 30 % of all stro ke related death were associated with 2 carotid artery le ions, a tati tic likely imilar in Canada. The commone t carotid artery disease is teno i , where there i narrow ing of the carotid artery lumen. Becau e the carotid arteries are the principal blood uppl y to the brain , decrease o f fl ow as a result of stenos is can cause transient i c hemic attacks or in the ca e of complete occlu sion, cerebro va c ular accidents? The majority of carotid arte ry stenos is case are a re ult of atherosclerotic pl aque acc umul ati on in the wall of the arteri e . Therefore, a second ary ri k factor in carotid atherosc lerotic steno i is the di slodging of e mboli to the 3 cerebrovasculature. Indeed, the rupture or di lodgement of plaques cau ing down tream e mboli acco unt for the majority o f carotid artery stroke . Pati ent with carotid stenos is can be asymptomatic or present with a tran ient i chemi c attack or stro ke. 2 路3 Di ag nos is is made u ing several technique. . Upon ph y ical examin ati on, carotid au c ultati on may reveal a carotid bruit. o mputed tomograph y angiography, magneti c reso nance angiograph y or carotid dupl ex ultra o nograph y are vari ous im ag in g modaliti es u ed to di ag nose suspected 4 carotid steno is. Furtherm ore, these im ages permit the surgeon or interventi onali st to calcul ate the degree of teno is, an important con iderati on in tenn s of dec idin g between vari ou treatments. Several treatments have been approved for improving outco mes o f pati ents with carotid

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artery stenosis. Currentl y, endarterectomy or urgical removal of the narrowed carotid egment is the accepted and most widely used treatment for carotid teno i 5 ; however, carotid artery tenting ha ri sen a a non-invasive altern ative for orne patient with the aim of 4 restoring the carotid lumen. Thi s article will ex plore the procedural as pect of carotid stenting and pre ent the indi cati on and contraindication fo r thi interventi on.

Carotid Stenting Procedure The non-in va ive nature of carotid tenting permits the pati ent to be awake during the procedure. Thi allow the physician to monitor the patient's neuro logical tatus; 2 an important con ideration due to the po ibility of embolism to the cerebral ve e l . The procedure i performed in an angi graph y suite under the guidance o f flu oro copy. Co ntras t agent are constantl y admini tered to direct catheters and co nfirm po iti onin g of balloon and te nt . A needle is in serted into the common fe moral artery under local anaesthesia. A radioopaqu e guidewire i then threaded throu gh the needl e and advanced into the abdominal aorta.6 The needl e is ub. equ ntl y re moved and a heath i pl aced over the guidewire and advanced to the ao rta. At thi po int, the guidewire is al o re mo ved and the sheath act a a catheter by whi ch other catheter and wire can be pl aced and guided towards the tenos is?路6 Using catheter , a preliminary carotid angiogram i conducted to demonstrate the degree of teno is (ex pres ed a a percentage) and a e s for artery ize down stream of the le ion. Thi s allow the ph y ician to choose the appropriate Embolic Protection Device (EPD) and tent based on degree of steno is and ize f 2 the artery re pective ly. A ce re bral angiogram i

also perfonned to rule out any contraindication to carotid stenting. Appropriately, heparin is administered to prevent clotting and its effect is measured using the Activated Clotting Time (ACT). The ACT in thi s procedure should exceed 250 seconds. An EPD i a specially des igned umbrella haped device that is used to capture debri s and emboli as a result of either Percutaneous Transluminal Angioplasty (PTA) or the release of a stent compressing the artherosclerotic 7 plaque. Before the stent is placed, an EPD is deployed upstream with re pect to the site of stenosis. The use of an EPD has shown to reduce the ri k of ischemic attack 30 days post procedure to 2.2% from 5.3%? This has prompted the routine use of an EPD by many interventionalists. If the degree of con triction is too evere to safely allow an EPD through , PTA with a small balloon may be appropriate to allow for safe pa sage of the EPD. At thi s point, a sheath covered stent is introduced and directed towards the site of the lesion . The sheath is peeled and removed and the stent is positioned in the stenotic portion of the artery. 6 The stent is self expandable and will effectively reduce the degree of stenosis. Following stent deployment, an angiogram is obtained to confirm the increase in diameter of the artery. In severe cases of stenosis, the stent itself may only reduce the occlusion mildly? To combat the high degree of post procedure stenosis, a balloon catheter may be placed within the boundaries of the stent and expanded to allow for greater augmentation of the vessel diameter. Similarly, it i essential to confirm with an angiogram the degree of post procedure stenosis. Importantly, the placement of the balloon should not extend further then the margins of the stent. Damage resulting from inflation of exaggerated balloons may cau e damage to vessel walls and increase the ri sk of restenosis. Angiogram confirmation of arterial lumen expansion is followed by catheter 26 dependent removal of the EPD. 路 Results from a recent study proposed that because pre- and post-stent deployment balloon angioplasty may be the major cause of dislodged emboli in carotid stenting procedures, that

removal of the e step in carotid tenting wou ld elimin ate the need for EPDs.8 This study demonstrated that the u e of elf expanding stents alone provided moderate allev iation of teno i with increasi ng lumen diameter for up to one year. In co njuncti on, none of the patient in the study had a troke as a direct result of the proced ure. The implicati ons of this tud y are twofold . Firstly, PTA may be the majo r cau e of emboli related co mpli cations in carotid tenting and secondly, if PTA is not u ed within the procedure, EPDs may not be necessary. Effectively, the e modifications to the carotid stenting techniqu e may provide future intervention alists with a afer, qui cker, more cost efficient procedure.

Pre-procedure Considerations Carotid tenting is onl y advised over endarterectomy in a subset of patients. Currently, within the context of a randomized control trial, any symptomatic patient (tran sient ischemic attacks or stroke) with greater th an 60% carotid artery stenosis or asymptomatic patients with greater than 80% stenosis are eligible for carotid stenting? Additionally, individual deemed to be at a high ri sk for surgery or who have had a previous endarterectomy with recurrent stenosis are also eligible for stenting. Some exclusion criteria include individuals with torturou s aortic arches , unfavo urable anatomy, inaccess ible lesions and patients with contraindications to anticoagulation therapy. If approved for carotid artery stenting, patients should undergo a full neurological examination as well as a neurological angiogram 24 hours pre-procedure. Antiplatelet therapy should be given four day prior to the intervention ; however, patients who are over 80 years of age may require lon ger treatment periods. Acetylsalicylic acid and clopidogrel are administered once daily to the patient. 6 Post-Procedure Considerations Following the intervention , the patient' blood pressure should be kept under 160mm Hg and antiplatelet therapy continued for 6 weeks. Following these 6 weeks, the patient should be advised to continue acetyl salicylic ac id treatment for the duration of their life.

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Conclusion Although endarterecto my ha proven hi ghly ucce sful in the treatment of carotid artery steno i , carotid artery tenting has emerged a an altern ative. On the pati ent level, carotid tenting may prove to be a safer procedure for specific indi vidu al . However, stenting of the carotid artery is a technically challenging interventi on with numerous potenti al complicati on that make it un favo urable a a standard therapy when compared to 4 endarterectomy. Recent tudi e have hown the non-in fe rior nature of carotid artery tentin g compared to carotid endan erecto my in a tri al u ing asympto mati c pati ent w ith greater th an 80% teno is or ymptomati c pati ents with greater than 50% teno i .9 However, increa ed ri k of post procedu re co mplicati ons of tenting have been docum ented in a tri al co nsi ting of onl y y m ~ to m a ti c patient with greater th an 60 steno i . 1 These tudies demon trate th at in pecific pati ent populati ons stenting may be preferred but upport fo r carotid artery stentin g a a routine treatment for carotid stenos is is lacking.

References l.

6. 7.

A nnual Report [In ternet]. Heart and Stroke F undation of Ca nada ( anada); 2006 [cited 2007, Dec I]. We sti ll have much to do ; pg. l. Avail ab le: http://ww2. hearta ndstroke.ca/i mage I e ngli h/H SFC_AR_2006_e ng.pd f. Carotid Artery Ste nt Procedure [Internet] . O Rii ve (USA) ; 2005 [cited 2007, Dec l] . Ava il able fro m: http://www .or-li ve.com/ Stlo eph/ 13 17. Stolz E, 0 c hma nn P, Potz ch B, Kra us 1, Kaps M. T hrombocyte activati on increase. with the degree or carotid artery sten sis. 1 Stroke Cerebrovasc Dis 2002; I I (6):324-9. Meschi a 1F, Brott TG , Hobson RW . Di agno i Âˇ and in va ive management of caroti d atherosc leroti c tenos is. Mayo Cl in Proc 2007;82(7):85 1-8. E ka ndari MK. Car tid endarterec to my for tro ke preventi on rev isited. Ex pert Rev Ne urother 2007 ;7(8) :935-8. Stoc kx L. Techniques in caroti d artery steting. Eur 1 Rad io l 2006;60: I 1- 13. Whitl ow PL, Lylyk P, Lo ndero H, et al. Carotid artery tenting protec ted with an e mbo li co ntainme nt y te rn. Stroke 2002;33(5): 1308- 14. Low nie SP, Pe lz DM , Lee DH , et al. Efficacy of treatme nt of severe carotid bifurcati o n stenos i by usin g e lf-expanding ste nts witho ut de liberate use o f

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Ne uroradi ol J Am angiopl asty balloons. 2005 ;26: 124 1-48. 9. Yadav JS , Who ley MH , Kuntz RE, et a l. P~ote~t~~ carotid-artery ste nting versu endarterecto my m hâ€˘ g ri sk patient . N Engl J Med 2004;3 51: 1493- 1501. JL, C hatelli er G , Beysse n B , et al. 10. Ma Endarterecto my ver us te ntin g in patie nts with ymptomatic severe carotid steno is. N E ng l J M ed 2006; 355: 1660-7 1.

Diagnostic Review

Innovations in Cardiac Computed Tomography: Cone Beam CTN olume CT and Dual Source CT Jaron Chong, Medicine 2010 and Jason Essue, Medicine 2011 Re viewed by Dr. Ali Islam Two recent inno vati o ns in cardi ac Co mputed T omograph y (CT) o f Co ne Beam CT or Vo lume CT ( VCT ) and more recentl y, Dual-So urce CT (DSCT) o ffe r phys ic ians c linica ll y viabl e a ltern ati ve to in vas ive coronary angiography for the imag ing o f coronary artery ste noses. Performing the procedure termed CT angiography or Multi -Detector CT angiograph y, both techno log ies provide the neces ary pati al and te mpo ral re o luti o n, in additi on to a vari ety of o ther ad vantage to image the cardi ac patient. Both report improvements over co nve nti o na l CT with reduced acqui sitio n time, greater image quality, and with DSCT an ability to perform cardiac imag ing on tac hycardic patient a well as reduce radi ati o n dose, all witho ut co mpromi sin g image quality. Whil e o nl y being two exa mple of new tec hno logie in cardi ac imaging, VCT and DSCT represent the c urre nt and next steps, in wh at pro mi ses to be many excitin g developme nts to co me .

Introduction The field of Computed Tomography (CT) has realized many significant developments over the past four decades that have dramatically improved the clinical applicability of thi s 1 technology. CT became widely available in the 1970s with the introduction of ingle-detector CT canners that captured one slice per rotation . In 1992, the first Multi-Detector CT (MDCT) scanner was produced (CT-Twin, Elscint) capturing two slices per rotation. 2 Since then , the field has advanced to the point where modem MDCT scanners are routinely able to capture up to 64 slices per rotation. 3 The past decade has seen multiple generations of CT scanners emerge, and when 64-slice scanners first arrived, the ensitivity and specificity of detecting coronary artery stenosis via CT angiography began to approach that of 4 invasive angiography. In year pa t, what some in the press have dubbed the 'slice wars' between the four major vendors of GE, Siemens, Toshiba, and Phillip in the push for greater spatial and temporal resolution has evolved into a more complex marketplace with different 5 vendors pursuing different strategies. Toshiba has decided to pursue greater slice count to an industry record of 320 slices and coverage area up to 12cm. 6â€˘7 Phillips has taken efforts to increase the gantry rotation speed (i.e. the speed at which the X-ray sen ors rotate around the patient) which in conjunction with reconstruction algorithms provides a temporal resolution of

270ms. 8 However, for the purposes of this article, we will be reviewing in greater detail GE 's Volume CT (VCT) and Siemens' DualSource CT (DSCT) systems.

-~~

Figure 1: 30 Vo lume Re ndering of the Heart. 3

Cardiac CT Imaging With re pect to cardiac imaging, many efforts utilizing CT have focu sed on the imaging of coronary artery steno es, a technique tem1ed CT angiography or MDCT angiography (Figure 1). In comparison with the gold tandard of invasive conventional coronary angiography, noninvasive CT has the advantage of avoiding ri ks of arterial vascular complications such as arterial punctures, vessel damage, and dislodged aortic plaques causmg myocardial infarct or stroke. UWOMJ 77(2) 2008 7

Estimate place the total risk of an adverse event between 1.7-2.0% for all causes. 9- 11 In contrast, the major ri sks of CT angiography are a reaction to intravenous contrast and the radiation dose potentially cau ing cancer, both of which are equally present in traditional inva ive angiography. The risk of a severe or fatal anaphylactic reaction to contrast is estimated at 0.04% and the lifetime ri sk of dying from cancer due a CT angiography can is estimated to be le s than 0.1 %.9 With regards to the radiation dose, significant advance have been made to decrease the radiati on abso rbed while maintaining image quality and is the focus of much active re earch. Cardiac im aging poses th e very unique challenge of im aging a moving target, requiring any clinically effective scanner to compl ete an image acquisition during an akinetic end- y tolic or dia tolic period. 12· 13 A a natural co nsequence of thi , the faster a scanner can complete a rotation to avoid parts of the cardiac cycle with motion , the clearer the image will be, generall y speaking. Thi s quick scanning speed also prove advantageous during tachycardia without the need to use drugs like beta-blockers for heart rate control.

Cone Beam CT/Volume CT Conventional MDCT canners collect projection from a fan beam of x-ray . 14 • In compari on, Cone Beam CT or Volume CT (VCT), expand the x- ray beam from a fan to a pyramid or co ne (Fi gure 2). 3 ' 14 A computer algorithm then proces es the 20 cone-beam projections into a 3D image of a patients' X ·MAY COH£ UEAM

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Figure 2: Cone-Bea m CT concepl.

UWOMJ 77(2) 2008 8

anatomy. With the advent of scanners a?le to capture up to 64-slices per rotation, this has created the platform necessary for Volume CT to emerge. 3 One such scan ner is the LightSpeed VCT model introduced by General Electric (GE) in 2004. GE 's LightSpeed VCT canner features a 64-slice detector and rotation speed of 370 milli second with slice widths of 0.625millimeters, enabling the system to generate 64 sub-millimeter images totaling 40 millimeters of . coverage wtt . h a mg . 1e rotatiOn. . 14, ts GE anato mic attributes orne of the image acq uisition improvement to the development of a new detector technology named V-Res, which is able to acquire 64 channels of data while spinning at le th an 0.4 second per rotation .3 The combination of hi gh volume and high re olution demon trated by the LightSpeed VCT scanner translates into three major tangible clinical benefit : Dramatically reduced acquisition time: Scanning time i half that needed for conventional MDCT scanners. Static organ can be imaged in one econd , the lung in two econds, the heart and coronary arterie in fewer than five econds, and a whole body scan in les than 10 seconds. 3• 15 The quicker imaging process more comfortable for patients because it requires horter breath-holds, can be especially u eful for trauma patients when time i of the es ence, and may help to allevi ate lengthy queue for diagno tic imaging given that a hi gher volume of patient can be imaged on a given day. 3 Improved image quality: The characteri tic thin slicing capacity of the Volume CT allows for the generation of hi gh resoluti on image , which translates to better diagnostic accuracy. 16 • 17 In addition , multi-planar reformatting of images in any plane, including curved planes, i al o po ible. This improves the depiction of pathologic features paLticularly in cardiac imaging because s uch tructure do not lie in the tandard planes (x , y, z), which also improve diagnostic accuracy. 18•19 New diagnostic possibilities: Volume CT offers the po sibility to acquire a complete angiooram within five heartbeat (at 60 beat fmin approx im ately 5 seconds) making the procedur~ less u ceptible to irregular heartbeats, helping

phy ician rule out, or in, the three main causes of life-threatening ER chest pain (i.e. aortic dissection , pulmonary embolism, and coronary artery di ease) in one can, and en ure a more thorough troke work-up because the entire Circle of Willis can be dynamically acquired with high reso lution. 3 More recently in 2007, GE introduced the LightSpeed VCT XT scanner (an improved ver ion of their LightSpeed VCT canner) that operates on a new scanning platform called 'SnapShot Pulse', which claims to reduce radiation dosage by a much a 70-83 % when compared to conventional helical techniques without compromi ing image quality by pul ing the x-ray beam during akinetic portions of the cardiac cycle as orposed to continuously engaging the beam ?0-2

Dual-Source CT (DSCT) Dual-Source CT, a more recent development, innovates upon modem CT system by utilizing multiple X-ray source and detectors to reduce the length of time required to perform one canner pas . A of thi s writing, the only commercially DSCT sy tem available, known a the SOMATOM Definition, is manufactured by Siemens Medical Solution . Utilizing two X-ray tube sources and two corresponding detectors offset by 90·, the SOMATOM system yields significant gains in temporal reso lution making it ideal for cardiac application (Figure 3)?3 In a typical si ngle- ource CT canner, the length of time required to perform a scan i

limited by what is known a the 'gantry rotation time' which can range from 0.33s to 1.0 . Thi i the amount of time it phy ically takes to rotate the fan-shaped X -ray source and detector 180. through the field of view gathering the necessary images to re-con truct a slice or array of sli ces. By utili zing the second-so urce X-ray tube and detector array, the time taken i halved to 165m 5 while maintaining equivalent spatial resolution ? Steady Imaging Up To 100 BPM: The ability to image at this enhanced speed has numerou s implications for the cardiac imaging challenges mentioned earlier. DSCT allows for teady imaging of the heart irre pective of heart rate up to 100 beats/min whereas a ingle-source CT can only guarantee temporal re olution at 66 beats/min or lower (Figure 4)? 6 Thu , with single-source CT, stringent protocols are required duting Coronary CT Angiography (CCTA) to lower a patient' s heart rate to less than 65 beats/min using beta-blocker . Such compensations are optional with DSCT. 27 •28 Increased Pitch/Reduced Radiation Dose at High Heart Rates: Another advantage of DSCT is the ability to increase pitch (i.e. the speed at which the patient is advanced through the scanner) for any given heart rate thereby reducing the duration of time the patient is exposed to radiation, and hence, overall radiation dose. A study conducted by McCollough et al. examined the dose performance of the SOMATOM in comparison to traditional multi29 detector CT. The study noticed a dec rea e m radiation exposure when radiation do e 22(

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Heart rate in bpm Figure 3: Configuration of Dual-Source CT scanner with two X-ray tube sources and two corresponding detectors . 24 offset by 90 .

Figure 4: Comparison of ingle-source versu dual- ource CT. Note the preservation of temporal resolution despite increasi ng heart rate. 24

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o ptimization methods were used for patients with high heart rates close to a facto r of 2 (At >90 beats/min: 26.6mGy DSCT vs. 43.7mGy MDCT). However, this advantage is lost and almost co mpletely reversed when imagin g at very low heart rates (At <55 beats/min : 6 1.2mGy DSCT v . 28. 7mGy MDCT).29 路30 Consistent Image Quality: All of these advantage wo uld no t be particul arly useful if di agnostic quali ty were compro mi sed bu t DSCT maintain high standards in spite of hi gh heart rates. M att et al. managed to de monstrate no significant correlation between between mean heart rate and image qu ali ty in a populatio n of 80 patient that underwent DSCT, with heart rates ranging from 35 to 99 beat /mi n.31 In contras t, o ther studie with 64- li ce MDCT have hown a decrea e in image quality with inc reas ing heart rate.32,33

Conclusion Both Cone-Beam CT I Volume CT and Du alSource CT represent two example of recent developments in cardiac im aging. While vendo r have an interest to push the edge of techno logy to even greater height , re earchers, clinic ians, and policy makers have an equ ally impo rtant re ponsibili ty to evalu ate the e new techno logies w ith an eye toward efficacy, clinical benefi t, and pro per indications for u age. N umerous developments in CT scanners are cutTentl y 18 undergo ing clinical evalu ati o n, and research is being conducted into further strategies for bo th reducin g radiatio n do age whil e im provin g im age qu ali ty. Several ve ndo rs are alread y looki ng at d ual-energy CT that has the potenti al to improve characteri zation o f varyin g tiss ue 4 5 densiti es and minimi ze metal im age artifac ts? .3 It may be many years befo re we see w ide-s pread adopti on o f the e techno logies here in Canada, but there can be no do ubt a to the impo rtant im plicati o ns of wo rk like thi . T wo sources or o ne, 320-or 64-s lices, cardiac imaging is onl y just getting started .

References I.

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Jan;29(4):566-9. Ketelsleger E, Beers BEV. Urinary calc uli : i mpro~ed detectio n and characteri zati on with thw- hce multidetector CT. Euro pean radio logy. 2006 Jan;16( 1): 16 1-5. GE Hea lthcare. Volume CT: A GE Healthcare Publication-Volume 1 [Internet] ;. A vail abl e: http://www.gehealthcare.com/eue n/ct!products/ prod uctstechn ologies/docs/GEvo lumeCTmagazine049245B.pdf. Herzog C, Zangos S, Zwerner P, Coste ll o P, Yogi TJ, Schoepf UJ. CT of coronary artery disea e. Journal of thorac ic imagi ng. 2007 Feb;22( 1):40-8. Avail able: http://mela. wkhea lth.co rnlpt!pt-core/te mpl atejourna1/lwwgateway/mediallandingpage. htm?an=0000 5382-200702000-00007. Davis W . T he End of the Sli ce Wars? Hardl y!; 2006. Avail ab le: http://www. medicali magingmag.corn/ i ues/article /2006-0302.asp[cited January 14, 2008]. Casey B, Forrest W . Aqu ili onONE 320-slice CT canner pearhead Toshi ba RSNA launche ;. A vai lab le:http://www .aun tmi nnie.cornlindex.asp? Sec=rca& ub=r na2007 &Pag=dis&lte mld= 789 14& w f=2239 . Ko ndo C, Mori S, Endo M, Ku akabe K, Suzuki N, Hattori A, et al. Rea l-time vo lumetric imaging of hu man heart without e lectrocardiographic gating by 256-detector row co mputed to mography: initi al Comput A i t T omogr. experience. J 2005 ;29(5) :694-698 . Moe SM, O' Nei ll KD , Res lerova M , Fine berg N, Per ohn S, Meyer C . Natura l hi tory of va c ul ar calcification in dia ly is and tra n plant pati ent . Nephrol Dia l Transp lant. 2004; 19(9):23 7- 2393 . Pe lzel JM , Le ser JR. Knicke lbi ne T , Flyge nrin g B, Tadro G, chwartz RS. Multidetector CT coro nary angiography: where we are, a nd where we are go ing. Catheterization and card iovasc ul ar in terventi o ns: offic ial journal of the Society fo r Card iac ngiography & In terve ntio ns. 2007 Feb ;69(2): 15971. Budoff M, Ac he nbac h S, Duerinckx A. No n-In vas ive oronary Angiography: CT and MR Techniques. 2002 Aug ;p. 3 1. Avai lab le fro m: hup://www. newportbodyscan.corn!Down loads/CT A cri oEB vM DCT. htm. "' Carrozza J P. Comp licatio n of di ag nostic card iac ca theteri za tio n. UpToDate. 2008 Jan;p. 23. Garc ia M.J. No nin vasive coronary angiograph y: hype or new paradig m? J AM A. 2005 May;293(20):253 1-3. A va1l ab le: http://j ama.a ma-ass n.org/cgi/co nte nt!fu 111 293/20/253 1. Winter perger BJ, Nikolaou K, von Zieg ler F, John so n T , . R1 t C, Leber A, et a l. Image quality, moti o n art1facts, and reconstructi o n timjng of 64- li e coronary o mputed to mograph y angiograph y with 0.33-second rotat1 o n speed . In vestigati ve radi logy. 2006 May;4 1(5):436-42. Ava il ab le: http://meta. wkhealth.co m/pt!pt-corc/te mpl ate-j ournal/ lwwga teway/medi alla ndin gpage. htm ?a n=00004424-

200605000-00003. 14. BIR. Industri a l sy terns: Vo lume CT ; 2005 . Ava il abl e fro m: http ://w ww .bi o-imagin g.co rnN olume CT Scanning.a p. 15 . Harvey D. CT Evo luti o n. Radi o logy Today. 2004 Aug;5( 18):22-25. 16. Pate l S, Kazeroo ni EA, Cascade PN . Pulmo nary e mbo li m: optimi zati o n of small pulmo nary artery visuali zati o n at multi -detector ro w CT. Radi o logy. 2003 May;22 7(2):455-60. Ava il able: hllp :// radi o logy .rs naj nl s.org/cg i/co ntenllfull/22 7 /2/455 . 17. Re my-Jardin M , Baghaie F, Bo nne! F, Ma o n P, Duhame l A, Re my J. Thorac ic he li cal CT: influence o f subsecond ca n time and thin c llimati o n o n evaluatio n o f peripheral pulmo nary arteries. Eur Radi o!. 2000 ; 10(8): 1297- 1303. 18. Parrish FJ . Vo lume CT: tate-o f-th e-art reporting. AJR American j ournal of roe ntgeno logy. 2007 Sep;189(3):528-34. Available : http://www . ajronline.org/cg i/ content/full/1 89/3/5 28. 19. Rie ber J, Mooyaart E, Re ichardt B , Gupta R, Ho ffman U. Co mpariso n o f MDCT and the nove l flat pa ne l vo lume CT for the quantifi cati o n of coro nary calfic iati o n and vesse l dime nsio n. Circ ulati o n. 2006; 114:11 449. 20 . GE Hea lthcare. SnapSho t Pulse: Lo w-Dose Cardi ac Imagin g [Internet] ;. A vail abl e fro m: http://www .gehealthcare.co m/u e n/cllproduct /docs/ n ap hot pul e lo w do e. pdf. 2 1. GE Healthcare. CT Clarity: The Magazine of CT http://www .gehealthcare.co m [Internet] ;. A va iIabl e: /u e n/cLidocs/CTCi arity magazineFall07 .pdf. 22. GE Healthcare. Li ghtSpeed VCT XT;. Availabl e: http://w ww.in trume ntarium. cornlusen/ct/productsfl speed vctxt i ndex. html. 23. Ohnesorge B , Fl ohr T , Bec ker C , Kopp AF, Sc hoepf UJ , Baum U, et a l. Cardi ac imaging by means o f e lec trocardi ographi ca ll y gated multi ecti on spiral CT: injti al experie nce. Radi o logy. 2000;2 17(2): 564-571. 24. Fl ohr TG , McCo ll ough C H, Bruder H, Pe ter ilka M , Gruber K, s ·· uss C, et a l. First performance evaluati o n of a dua l-source CT (DSCT) sys te m. European 2006 Feb; 16(2):256-68. A va il able : radi ology. http://www. springerlink .co m/content/ 7858 1m264 k65567m. 25. Juergens KU , Grude M , Falle nberg EM , Opitz C, Wichter T , Heindel W , et al. Usin g ECG -gated multidetector CT to evaluate g loba l left ventri c ular myocardi al functi o n in patie nts with coro nar y artery di sease. AJR Am J Roe ntgeno l. 2002; 179(6): 15451550. 26. Ac he nbach S, Ul zhe imer S, B aum U, Kache lri es M, Roper D, Gi e ler T , et al. No nin va ive coronary angiograph y by retrospectively ECG -gated multi slice spiral CT. Circ ulati o n. 2000; 102(23):2823-2828. 27. Agatsto n AS , Jano witz WR , Hildner FJ, Zu mer NR, Vi a mo nte MJ, Detrano R. Quantificati o n o f coronary artery calcium using ultrafast computed to mography. J Am Co li Cardi o l. 1990 ;15(4): 827-832. 28. Sie me ns Medical So luti o ns. Sie me n Expands the

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SO MAT O M Definiti o n™ Line with World 's Fir t Adapti ve CT Scanne r;. Avail ab le fro m: http://www. medi ca l.sie me ns.com/webapp/wcs/storcs /servle LIPressRe lease View-qcata logld-e- 1-acatTree -e nulra langld-e. McColl o ugh C H, Primak AN, Saba 0 , Bruder H, Sti erstorfer K, Ra upac h R, et a l. Dose performance o f a 64-channel dual-source CT sca nner. Radi o logy. 2007 .lun ;243(3):775-84. Avail ab le: http:// rad io logy.rsnajnl .org/cg i/c nte nllfull/243/3/775. In: UJ S, editor. Sca n tec hniques for cardi ac and coro nary artery imag ing with multi sli ce CT . In: Schoepf U.l, ed . CT of th e heart: princ iple and applicati o n . To towa, N.l : Humana; 2005. p. 23-43. Co ll etti PM. Cardi ac imaging 2006. AJR Am J Roentgeno l. 2006; 186(6 S uppl 2):S337- 9. Matt D, Sc he ffel H, Le chka S, Fl ohr T G, Marincek B, Kaufmann PA, et al. Dua l-source CT coronary angiograph y: image quality, mean heart rate, a nd heart rate vari ability. AJR A merica n j o urnal of roentge no logy. 2007 Sep; I 89(3) :567- 73. Avail abl e: http ://www .ajro nline.org/cgi/ content/full/1 89/3/5 67 . Nie man K, O udkerk M, Re n in g BJ, va n Ooij e n P, Munne A, van Geun RJ, et al. Coro nary angiograph y with multi-sli ce co mputed to mograph y. Lancet. 2001 Feb;357(9256): 599-603. G E Hea lthcare. Dual Energy:. A vail abl e fro m: http://ww w.gehealthcare.co m/e ue n/radi ograph y/ product /appli cati o ns/dual-energy/index. html1 . Sieme ns Medi cal So lution . Sie me n Introduces New Dual Energy Appli cati o ns to SOMA TOM De finiti o n;. A va il abl e fro m: http ://ww w. medi ca l. sie me ns.co m/ webapp/wcs/sto res/serv le LIPress Re lease Vi e wq cata log Id-e- 1-acatTree-e 10001 I , 18301 , 13839. I 7705-a langlde- 1-apageld-e I 0002 1-astore Id-e 1000 l.htm.

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Ethics The Aprotinin Story: Lessons in Drug Regulation and Safety Adam Katchky, Medicine 2010 and Christina Morgan, Medicine 2011 Reviewed by Drs. Lois Champion and Mark Speechley Issues o f drug regul ati on and safety are a fami li ar co ncern within the pharmaceutical industry a nd ofte n do not emerge until several year after a drug ha been on the market. The antifibrino lyti c drug aprotinin (Trasylo l) was developed by Bayer Pharmaceutica l and approved to prevent excessive bleeding in patients undergoing coro nary artery bypass graftin g surgery. After evera l year o f widespread use o f the drug in cardiac proced ures, two ob ervational studies demo n trated a ri k of aprotinin for erious co mpli cati o ns such a renal failure and myocardial infarction . These observations led to a prol onged rev iew of the drug 's safety label by the Food and Drug Adrniru trati on and to the revelati on that Bayer had w ithhe ld the result o f a private ly co mmi s io ned observational study which demon strated these reported co mplicati ons. Thi s essay hi ghli ghts the ethica l iss ues rai sed by the aprotinin aga a nd di cu es the importance of transpare ncy, honesty , and clini ca l equipo ise in drug regul ati on and safety.

Timeline On December 30, 1993, the Food and Drug Admini stration (FDA ) announced it approval of the antifibrino lytic agent, aprotinin , developed by Bayer Pharm aceuticals and marketed under the trade name Trasylol for use in cardiac 1 urgery. Antifibrinolytics have long been a main stay of treatment to prevent excessive bleeding, a frequent cause of morbidity and mortality in patients undergoing on-pump coronary artery bypass grafting (CABG ) and other cardiac procedures. Traditional antifibrino lytic agents, including an1inocaproic ac id (ACA) and tranexamic acid (TXA), often take the form of lysine analogues that prevent bleeding by interfering with the activation of plasminogen to plasmin , a molecule re pon sible for the degrad ation of fibrin clot . Aprotinin is unique in that it promotes c lotting by inhibition of erine proteases, includin g pia min , thereby preventing the degrad ation of the pl as ma protein compri s ing fibrin c lots. The initial FDA approval was ba ed primarily on two randomized, placebo-controlled clinical trials. One study reported that 77 % of patients who rece ived no bleeding prevention therapy required at lea t one tran sfu sion dllling or after the operative procedure ; among patients who had received aproti nin , on ly 42% required the administration of blood products? The 3 second study showed similar result . However, the author also noted the possibility of all ergic reaction after chronic usage, as we ll as incidents of kidn ey toxicity. Although these adverse

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effects were sufficiently rare and manageable to permit drug approval, aprotmm was recommended for u e primarily m high risk patients. In the year following its approval, aprotinin gained acceptance into the practice of cardiac surgery. Over 70 tudie were conducted to e tabli sh and confirm the efficacy of aprotinin by measuring the blood product transfu ion requirements of patients undergoing cardiac bypa s procedures, with or without aproti nin. A placebo-controlled, double-blind study cond ucted by Bidstrup et al. , for example, demonstrated a significant reduction in blood unit required in a high do e aprotinin gro up following cardiopu lmonary bypas .4 While numerou studie uch a this confim1ed it e ffic acy, little hint of the ri sk of aproti nin was found beyond the initially reported side effect . Thi was due in large patt to the fact that the primary endpoint of the majority of the e studies, including that conducted by Bidstrup et al. , were transfu ion requirements , and the tudies were frequently not de igned or powered to detect mortality benefit or specific adverse outcomes. While donor blood requirements may be used a an indicator of blood loss the e studies failed to address ' patient im~ortant outcomes' such as morbidity or mortality. By 1998, the FDA had expanded the indications for aprotinin use to all CABG 4 patient and its use burgeoned as it became the mainstay of bleeding prevention therapy in cardiac urgery. Thi was aided largely by it

newly expanded recommendation, a well as a lack of other drugs indicated for thi s purpose, as the ly ine analogue antifibrinolytics such as TXA were initially developed to prevent bleeding in other procedures and condition .5 For everal years, the ri k of anaphylactic reaction with repeated admini stration remained one of the only ri sks identified with aprotinin use. The fir t study to rai se concerns regarding the safety of aprotinin was conducted by Karkouti et al at the University of Toronto, and wa published online ahead of print in This Transfusion on January 20, 2006.6 observational study employed a method known as propen ity scoring to compare risk-variable patients who received aprotinin or tranexamic acid. Propensity scoring i a statistical technique used to control for selection bias in observational studies where treatment allocation is not random, and involves detennining the probability, or propensity score, of receiving a particular treatment based on a number of background variables, or covariates, which may plausibly influence treatment as ignment. Whjle aprotinin and TXA were found to be quite similar in effectivene s with respect to transfusion requirements, the former was associated with a statistically significant increase in renal dysfunction within the first postoperative week, sometime requiring dialysis. 6 On January 26, 2006, a similar study conducted by Mangano et al. was published in the New England Journal of Medicine. 7 This multi-centre observational study examined nearly 4500 patients who were administered either aprotinin , aminocaproic acid, tranexamic acid , or no treatment. Through propensity scoring and multivariate analysis, they found that aprotinin was associated with a significantly increased risk of renal failure , myocardial infarction, heart failure, stroke and encephalopathy, while ACA and TXA were not 7 associated with these adverse effects. A subsequent follow-up tudy by Mangano et al. also demonstrated increa ed risk of long-term 8 mortality associated with aprotinin. These two studies prompted the FDA to initiate a year-long review of the safety of aprotinin, and to convene a meeting of it Advisory Cardiovascular and Renal Drug Commission on September 21 , 2006. The FDA

chose neither to amend the label on apro tinin nor to iss ue any additional safety warnin gs The urrounding potential adver e effect . primary outcome of the meeting was a reiteration of the initial recommendation that aprotinin be used only in high ri sk patients. In defending their deci sion, FDA committee representatives cited iss ues of tran sparency rel ated to an unwillingness to release data on the part of Mangano et al. 9 Mangano responded in a letter to NEJM, indicating that although their data release was initially offered with re trictions related to patient confidentiality and independent analysis, it was eventually offered without re triction prior to the committee meeting and following a lengthy delay in acknowledgment of their data or requests by the FDA . 10 He further indicated that, despite repeated requests, the FDA infonned him that a review of hi s data was unnecessary at that point. Six days following adjournment of the meetings, however, Bayer relea ed the troubling results of an observational study it had commissioned. These findings demonstrated that the use of aprotinin led to an increase in kidney damage, congestive heart failure, stroke, and mortality, and quickly triggered erious safety warning with re pect to the drug. 11 Following the revelation s regarding the safety of aprotinin, many sought to determine what had gone wrong. What they found , however, was even more di turbing than what had already tran spired and rai sed seriou issues with respect to manufacturer transparency and deception regarding adverse drug effects. Bayer hired a private contract research team to conduct their observational study on the postoperative complications of aprotinin use, and their findings were similar to those of Mangano et al. 12 Further inve tigation revealed that Bayer official were given the preliminary re ults before the FDA review meetings, yet neither the manufacturer nor the private contract team had shared thi information with the regulatory body. They explained that an internal mistake resulted in the delayed release of thi information . 13 However, investigation into the body of evidence which initially supported the efficacy of aprotinin revealed that Bayer repeatedly funded numerou s small trial which showed the drug to be

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effective, but were underpowered to show any rare but seriou s adverse effects. Meta-analysis later showed that on average these trials referenced only 20 % of the preceding reports; only 15 % referenced the largest trial , which is considered to be central to the evidence urrounding aprotinin. 14

Ethical Analysis The aprotinin ca e serve to hi ghli ght numerous ethical i sues with drug regulation and safety a they pertain to the pharmace utical indu. try. While public intere t and patient safety should be central pri oritie in all healthcare activiti es, these can be overlooked or ignored by pharmaceutical companies in favor of drug marketing. However, in this instance, ethical i ues are raised not only by Bayer's actions, but also by those of the FDA and the researchers who ounded the alarm . FDA: According to Man gano , the FDA did not respond to his repeated requests for data review prior to upholding the apro tinin label, citing it was unnecessary. In hi response to the FDA 's decision, Man gano stated, "The FDA and its Advisory Committee sho uld take a conservative, protective stance when independent ev idence regardin g dru g safety presents itself. In stead, they appear to be protecting the drug rather than 11 the patient. " While ethical discuss ion centered on dru g regulation most often foc uses on the behavior of pharmaceutical companies, the aforementi oned interacti ons between Mangano and the FDA call into question the prioriti e of the regulating body as well. Whil e the FDA did requ est the data from the Mangano study upon convenin g it Advisory Com mi ss ion, it appear as if the FDA did not make every effo rt to obtain the data via di scus ion with Mangano before judging the safety of the dru g. This raises questions a to the efforts of the FDA and the nature of the influence of ph arm aceuti cal co mpani es on their regulatory body. Mangano : While the researcher did offer the original . tudy data to the FDA, there appeared to be initial resistance to do so in th at data release was contingent upon several restnctJOns includin g pati ent confide nti ality and independent data analysis. This rai e the iss ue of tran sparency in research , and the situation in

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which researchers should be encouraged or obligated to share their data and their anal~tical methods. Methodological transparency IS . of particular importance in observational stud1es where treatment allocation is not randomly assigned and certain analytical s trat~gies are required in order to minimize known b1ases and approach a true evaluation of effect. Often these are the only means by which critical drug safety issues can be evalu ated . Thu s transparency becomes a central value in research ethics. However, the concept of transparency itself rai e further ethical i sues, as the obligation the release indi vidual-level data may conflict with the value of privacy and anonymity. Bayer: Bayer face the erious charge of withholding inform ation garnered from a privately conducted tudy at the time of the FDA co mmi sion. This goes beyond the concept of tran parency and encroaches on honesty, which mu t undoubtedl y be a central value in all research acti vities. It ha become clear that Baye r became aware of at least the preliminary resu It of the study , yet they did not di sclose thi s information to the FDA Advi ory Comrni ion in a timely manner. Dru g afety analy es are often an is ue because we rely on pharmaceutical companie to fund the tudie necessary to assess safety ; however, when they have a vested intere t in the lucrative s ucce of their product, it i difficult to expect them to fund or disclo e the re ult of tudi es that might disc redit their product or jeopardi ze it succe . Bayer' Finally, and most ubtly inve Li gation of the effectiveness of aprotmm remains in tark co ntrast with the principle of clinical eq uipoise. Thi principle tates that rando mi zed control trials can only be conducted ethi cally when tru e di agreement exi t as to the effectiveness of one treatment compared to another. In placebo-controlled studie , it is only ethical to admini ster no treatment (or a placebo) whe~ no proven treatment exi ts. Bayer contmued to fund placebo-controlled RCTs de pi~e. the prev iou literature supporting aprotmm as an effective treatment for decrea ino tran fu sion requirements. In hind ight, thi~ appear to have been done in order to build the body of evidence supporting thi s therapy, and to continue to show effectiveness without bein g

able to identify adverse effect a ociated with it admini tration. These tudie , while ufficiently powered to detect ignificance of efficacy, were for the mo t part too mall to have a high likelihood of howing serious and rare side effects. These actions further contributed to the skewed view of aprotinin held by both the public and the medical community, and to its longtime u e de pite its dangers.

Conclusion The protracted length of time between the approval of aprotinin for the prevention of exce ive bleeding during coronary artery bypa grafting and the revelation of drug afety concern indicates a need to refine the process of drug afety revtew . The ethical tssues highlighted by the action of Bayer Pharmaceutical , the Food and Drug Admini tration , and the drug researchers indicate that drug safety is not influenced olely by the philo ophies of pharmaceutical corporation , but instead it involves complex political and procedural interactions between the pharmaceutical companie , the regulating body, and drug inve tigators. We have indicated a fundamental requirement for transparency as it pertain to all studies asse sing dntg afety, particularly on the part of the pharmaceutical compante . As observational tudies are often the only mean s by which we can assess longterm drug safety, it i al o important that they be tran parent and sufficiently powered to detect long term morbidity and mortality. While the aprotinin aga repre ent a very recent example, other drugs including flecainide acetate (Tambocor) and ro iglitazone (Avandia) have rai ed imilar i sue in the past decade. Major change are required to refine the evaluation and monitoring of pharmaceutical products following regulatory approval and widespread use. These acti vi tie are critical to treatment effecti venes and patient safety.

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14. Fergu so n, D., Gla , K. C. , Hulton , B. , Shapiro, S. Rando mi zed contro lled trial s of aprotinin in cardi ac surgery: co uld c lini ca l eq uipo ise have stopped the bl eeding?. Clin Trial 2005 (2): 2 18-232.

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Health Promotion

Heart Health or Hype? Exploring the effect of diet trends on cardiovascular disease Jonathan Klein, Medicine 2010 and Laura Hinz, Medicine 2011 Reviewed by Dr. Lynn Bergin Certain foods have been touted a prov idi ng pecia l benefits in preve nting cardiova cul ar di. ease. We reviewed the literature upporting cardi oprotecti ve effec ts from cranberri es, choco late, dairy foods, and omega-3 fatty ac id 路 T o varying degrees, all fo ur of the e ca tegorie of food prov ide demonstra ted be nefi t for heart health . For each food in vesti ga ted, we prov ided insight into how they ca n be incorp orated into a hea lth y li fe ty le along w ith o rne caveats aga in t their overuse. A balanced, nutri tious diet including orne of the e food , combined with an acti ve life ty le, can provide proven benefi ts for cardiova cul ar hea lth .

Introduction The importance of eating a balanced di et and engaging in regul ar exerc i e for the maintenance of good health is generally accepted as common ense and is upported by ri go rou s sc ientifi c 1 in vesti gati on. Obe ity and inac tt vtty rate continue to ri e teadil y, however, bringing with them a ho t of di sorder such a diabetes mellitu and cardiova cul ar di ease (CVD). In the face of increa ed CVD incidence, many food have been touted as being espec iall y good for the heart. In thi article, we in ve ti gate the bi ochemi stry and ev idence fo r the cardi o protective effect of cranberries, choco late, dairy foods, and omega-3 fatty acid , whi ch have all received attenti on for their potenti all y heart health y pro perti es. Cranberries Evidence and Biochemistry: C ranberri es have been pro moted for putati ve wide-rangin g health benefits, o much o that the jo urn al Criti cal Reviews in Food Science and N utriti on devoted an entire 2002 iss ue to ex to lling the fruit 's 2 virtue . Fro m preventing urinary tract infecti ons to pro tectin g against gastri c ul cer 3 to reduc in g 4 th e ri sk of cardi ac events, cranberri es have been credited fo r providin g ignificant hea lth bene fit beyond th ose o f other fruit . Several large tudi es, including the 5 lNTERHEART tud y, have shown signifi cant health benefits from di et hi gh in fruits and 6 vegetables, such as th e Mediterranean Oi et. Though many mechani ms for the e re ults have been proposed, much attention has focu ed on a class of compounds called fl avonoid , whi ch are present in hi gh concentrati ons in cranberri es and

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other fruit .7 Flavo noid are a group of mo lecul es with a common diphenylpropane (C6C3-C6) mo iety, which contain two aromatic ring linked by a ix-member ring. There are ix different categories of fl avonoids characterized by variati on in the central ring. 8 Cranberries co ntain many different flavonoid classes inc luding fl avo nol , fl avan- 3-ols, and anthocyanin .9 Flavo noids have been identified as cardi o protecti ve co mpound due to their 11 antiox idant effect . Substantial ev idence has demon trated that ox idation of low den ity lipoprotein (LDL, the o-called "bad cho le tero l") co nttibute to atheroscl ero is, one o f the main predicti ve fac tors of heart attack 12 and troke .

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Oxidized LDL is preferentially taken up into macrophage and foam cells), which are major constituents of atherosclerotic plaques. 13 By reducing the oxidation of LDL, flavonoids help prevent this accumulation of plaque, decreasing morbidity and mortality from CV di sease. 14 It eems that only small amounts of fl avonoids are needed to achieve their beneficial effects, so even occasional consumption of cranberries may be cardioprotective. 15 Ruel and Couillard have also shown that there i so me evidence for cranberrie improving plasma lipid profiles, another strong predictor of cardiovascular disease. The evidence suggest that cranberries may be able to increase HDL and decrea e LDL levels in the blood, but some tudies have failed to show a change in serum lipid levels.7 Verdict: Cranberries seem to confer significant benefits on cardiovascular health, mostly through flavonoid-mediated inhibition of oxidation of LDL. Including fresh cranberries or cranberry juice in the diet can reduce the ri k of atherosclerosis and subsequent events such as troke or infarction. However, these benefits may not be exclusive to cranberries, as research has shown similar outcomes with diet high in other fruits and vegetables (such as the Mediterranean diet). Con umer should also be wary of the advertised benefits of cranberry juice. While these juices do contain flavonoids and other beneficial compounds, inve tigators exclu ively studied the benefits of low-calorie juices. Mo t commercial juices are high in sugar, which can contribute to obesity and other associated health problem . For an effective public-health campaign to be built around cranberry juice, it mu st be explicit th at fre h cranberries and low-calorie juices will confer the greatest health benefits. All in all, the data is strong suggesting that adding cranberrie to an already balanced di et may reduce the onset of cardiovascular symptoms.

Chocolate Evidence and Biochemistry: Many news outlets have publicized studies demonstrating the 16 18 benefits of chocolate consumption. - While the reports have been careful to warn against gorging on chocolate bars in an effort to stave off

atherosclerosis, many people may still be tempted to add large amount of chocolate to their diet, possibly believ ing that protecting their hearts is outweighs the ri sks of excessive junk food consumpti on. Studies on chocolate and cardiovasc ul ar di sease have focused on the effects of dark . . 19 Th e chocolate and cocoa consumptiOn protective mechanism is similar to that of cranberries, with fl avonoids acting as the primary cardioprotecti ve agent. Chocolate contains large amounts of catechin , which are flavan-3-ol fl avo noid compound , and 20 2 1 procyanidins, another ci a of flavonoids. The mech anism mimics that of cranberries, with an increa e in anti-oxidant effects inhibiting LDL oxidation and preventing formation of arterial plaques. Studies have also demonstrated that chocolate and cocoa consumption can raise levels of high den ity lipoproteins (HDL, the "good cholesterol"), which has been shown to 22 decreased susceptibility to cardi ac events. Increased HDL levels have been hypothesized to suppress LDL oxidation by one of several mechanisms including inhibition of monocyte chemotaxi leading to decreased 23 atherosclerosis and direct hydrolysis of lipid 4 peroxide? Some studie , however, have failed to demonstrate ignificant change in HDL:LDL ratios, o chocolate alone hould not be used to treat lipid disorders. An average increase in HDL level of 4% and 8% longer lag time in LDL oxidation were observed in patients on an average American diet supplemented with 16g of dark chocolate and 22g of cocoa powder per day. 19 Verdict: Medical consensus holds th at chocolate and cocoa can protect against cardiovascular di sease, likely via flavonoid-mediated LDL antioxidation and increased HDL levels. However, the observed effects on the serum lipids were relatively minor -hardly ufficient to counter the fact that chocolate i a high-fat, hi ghsugar food lacking the overall nuttition al value of other rich flavonoid sources such as fruits and vegetables. Expetimental studies focu sed only on dark chocolate and cocoa consumption (not other varieties, like milk chocolate) and were careful to study diet similar to a standard American diet

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in nutritional value and calori c intake. Thu s, adding chocolate to the diet without eliminating an equi valent source of calori es and maintainin g proper nutriti on has not been hown to improve health and intui tively seems likely to contribute to poor health th ro ugh increased weight and adi pose bu ild- up. Our recommendation is that dark chocolate or cocoa may be consumed to prevent heart di sease, but onl y a part of a balanced, nutritional diet. While (arguably) less enjoyable, it may be more beneficial to overall health to seek a differe nt so urce of fl avo noids, such a frui ts and vegetabl es.

Dairy Products Evidence: Milk con um ption has traditi onall y been associated with increased cardi ova c ular disease due to its high cho lestero l and satu rated fat content, 25 which have been cau all y linked to atherosclerosi . 12 However, everal epide miologic studi e have demonstrated reduced risk of athero clerosis with inc reased Further evidence fo r milk intake. 26 -27 cardi oprotecti ve effects of dairy foo ds co mes fro m the o-called "French paradox;" the typical diet in France is high in saturated fat and cholesterol, but the citizens tend to have a lower 28 incidence of heart disease. The e data suggest th at further co n ide rati on of dairy product a protective again st cardi ovascul ar d i ea e is warranted. One hypoth esis fo r milk ' s cardi oprotection is that it reduce su ceptibility to the metabolic syndro me, whi ch can lead to cardi ovascular di sease. 28 The World Health Organization defines metabo li c yndro me as glucose into lerance, im paired glucose to lerance or di abetes mellitus and/or in sulin re i Lance together with two or more of: blood pre . ure above 140/90, hi gh pl as ma tri glyceride and/or low HDL, central obesity and lb 29 m1 croa ummun a. Several studi es have hown in verse relati onships between dairy foo d consumpti on and all as pects of the metaboli c syndro me.30 -32 The e studies have shown that milk has a protecti ve effect in both men and wo men and across populati ons of differe nt ethniciti es and nati onaliti es. Th e incide nce of type II di abetes mellitus, one of the co mponents of the metaboli c 0

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syndrome and a di sease also characteri zed by insulin resistance, was demonstrated to decrease with hi gher dairy intake. The effect was even larger if the study participants consumed only 28 33 low-fa t dau y products. 路 . Dairy foo ds may also prevent weight gain, and might even promote loss of abdominal fat. 34 This would , in tum , reduce the risk of obesity leading to onset of metabolic syndrome, which wo ul d prevent the resultant cardiovascular disease. One explanatio n fo r this effect holds that dietary calcium may play a role in regulation of energy metabolism.28 Dairy foods can al o have antih ypertensive effect , as eating 35 or more ervin gs of dairy per week halved the 10-year ri k of developing hypertension as compared to eatin g 10 or fewe r serving in the CARDIA stud y. 30 Thi effect may result from peptide produced by lactic acid bacteri a present in milk product inhibiting ACE enzyme and endothelin re lease, two kn own anti"h ypertenstve agents. 35-36 Verdict: Even though dairy foo ds contain ignificant amount of CVD-pro moting fat and chole terol, the ev idence uggests that dairy products are actu ally cardi oprotecti ve. The dramati c re ult of the C ARDIA tud y how significant anti hypertensive effec ts, though it i unrealistic to ex pect peopl e who would not otherw i e do so to eat 35 or more ervings of dairy foo d per week. However, even moderately increas in g dairy co nsumpti on can be beneficial. Dairy food al o pl ay an important role in protecti on fro m metabolic syndrome and type II di abete . Low fa t and skim milk and yogurt seem to have the most pro nounced effects, and people wishing to increase their dairy con umption should foc u on the e foods. Though the evidence is stro ng for dairy products' benefits, it is important to re member that dairy foo ds will not pro tect against C VD in the ab ence of other interventi ons like a balanced diet and acti ve lifestyle. 0

Omega-3 fatty acids Evidence: Of all the dietary elements claimin bo cardiovascular benefit , few have garnered more attention than omega 3 fatty ac ids. Egg , bread, yog urt and other foods are fo rtif ied with the e compounds and display attention -grabbin g labels touting their hi gh levels of o mega-3. Di etar y

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HO Figure 2: Eicosapentanoic acid, an example of an omega-3 fatty acid. Note that the th ird-last carbon i invo l ved in a 39 double bond.

supplements containing omega-3 ' s are also bein g marketed with promises to deli ver improve ment in health .37 Omega-3 fatty acid are e ential fatty acid naturally present in fish, flaxseed, walnuts, canola oil , and soybean oil. They are o named because they are characteri zed by a double bond beginnin g at the third-last carbon atom in their chain , the third carbon from the "omega" end of the chain. The three main omega-3 fatty acids consumed are alpha-linolenic ac id, eicosapentaenoic acid and docosahexaenoic acid. 38 Omega-3 fatty acids have been demo nstrated to exert anti atherogenic, antithro mbotic, and anti arrh ythmic effects, all of which contribute to their preventi on of 40 cardiovascular disease . In vesti gatio ns using many different de igns have linked omega-3 fatty acid and fi sh consumptio n to reductions in cardiovascular disease. Epidemiologic studies include the Health Professional Follow Up 41 2 study and the Nurses Health Studl which fo llowed 45 ,722 and 76,283 subj ects for average follow up time of 14 and 10 years, res pecti vely. The Nurses Health Study showed a relati ve risk of fatal i chemic heart disease of 0.55 for the cohort with the hi ghest consumptio n of omega3' s versus the gro up with the lowe t consumption. Other studie and meta-analyse have demonstrated in verse relati on hip between omega-3 consumption and mortality, both allcause mortality and that from cardiova cular di sease (coronary artery di sease, MI, stroke, etc.).43-45 Given the benefit to heart health demonstrated by these studies, it is not surprising that omega-3' have received huge publi city and are potenti ally exploited by dubi ous companies and products. A search fo r "o mega 3" on the popular search-engine www .ask.com yi elded links to websites claiming extra benefits fo r such 46 products as Norwegian " virgin almon oil."

Other ites pro mote "clean" and " natural" omega-3 sources 47 and oils deri ved fro m "gently pressed" ources. 48 Such products typicall y co me in pill fo rm with reco mmended do es of up to 3 per day, ensurin g a hi gh cost fo r their co ntinu ed use. Verdict: A reso unding yes. The evidence is extremely strong that including fish and other o mega-3 sources in the di et, even in moderate amo unts, can prov ide maj or benefits in reducti o n of cardi ovascular disease. However, there is a potential for ex ploitation and fa l e claims to abound due to lack of public understanding. Claims of special efficacy fro m certain types or sources of o mega-3 and claims th at intuiti ve ly unhealth y foo ds like bacon are actually health y should be ignored. Nevertheless, fish and other omega-3 fo rtified foods like eggs and yogurt should be added to the diet of heart-conscious people. The Am erican Heart Associatio n and World Health Organi zation both recommend two servin g of fi sh per week, especially oily fi h like salmon , tuna, and trout. Diets such as the 49 are good sources of Mediterranean diet guidance for incorporating o mega-3 fatty acids into a health y di et.

Conclusion Diet plays a powerful role in cardi ovascular health , but this will not come as news to most people. However, certain foo ds seem to confer more benefit than others, whether by changin g lipid profiles, moderating the metaboli c syndrom e, anti-thro mbotic effects, or other mechanisms. Stro ng ev idence backs cranberrie , dairy foods, chocolate, and o mega-3 fatty acids as pro tecti ve against cardi ova cular disea e. A few studies received funding or other upport fro m corporations with interests in the . 1 f or b"1ase . reS u lts 3, 11 .30 w h"IC h create a potentia However, the vast maj ority of tudi es cited in this paper did not declare any competing interests and the evidence remains stro no b

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supporting the cardioprotecti ve effects of the aforementioned food . These effec ts demonstrate that what we eat can powerfull y impact the health of our hearts. However, it is important not to overstate the impacts that the e foods can deliver. After surveyin g the ev idence, a Starbucks Mocha Latte may seem to be a new "superfood"- after all, it contains choco late and caffeine fo r anti ox idants milk fo r calcium, and health y fa ts. Bu t tha~ doesn' t cancel out the sugar and unhealth y fa t assoc iated with tho e beneficial compound . No single food will prevent heart di ease nor i adherence to every new guideline required to be protected, but modem researc h continue to support Hippocrate ' idea that foo d ha the power to heal. Regular exerci e and a balanced diet incl uding so me of the food di scussed in thi s article will go a long way toward maintainin g a healthy heart.

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e ndo the lin- 1 by e nd olhe li a l cell s. Reg ul Pepl. 2004 Apr 15 ; 11 8(1 -2): 105-9. T sang G . Health Be ne fit s o f O mega 3 fa tty ac ids [interne t] . M ay 2007. [c ited Nov . 25, 2007]. Avail ab le fro m: http ://ww w.hea lthcastl e .co m/o mega3. hunl Omega-3 fatty ac ids [inte rne t]. Co ll ege Park (MD ): Uni ver ity of Ma ry la nd Medi ca l Ce nte r (UMMC);2007 . [ ited Nov. 25, 2007 ]. Avail ab le fro m: http://w ww .umm .edu/altmed/artic les/o mega-30003 l 6. htm . Omacor: The First a nd O nl y FDA-approved Pre c ripti o n O mega-3 Fatty Acid Produc t [inte rne t]. Eu-pharmagate . [c ited Ja n 3 , 200 8]. Ava il able at: http://w ww.e u-pharmaga te.com/new de ttagli oENG .asp ? rD=2 18&TAB = ultimi s ime. P o ta TL, Ge ba ue r S K, Kri -Ethe rto n P. Di e tary Omega-3 Fa tty Ac id Intake a nd Cardi ovasc ul ar Ri s k. Am Jo ur C ardi o. 2006 Aug 2 1 ;98( 1):3- 18. M ozaffari a n D , A c he ri o A , Hu F. B , Sta mpfe r M1 , Will e tt W C, Siscov ic k OS, Rimm EB. Interpl ay be twee n diffe re nt po lyun saturated fa tty ac ids a nd ri sk o f coro nary heart di ea e in me n. C irc ul ati o n. 2005 ; 111:157- 164. Fra nk B Hu , Meir J Sta mpfe r, JoA nn E Ma nso n, Eri c B Rirrun , Ali cj a W o lk , Graha m A Co lditz, C harles 1-1 He nne ke ns a nd W alte r C Will e tt . Di etary inta ke o f alino le nic ac id a nd ri s k o f fata l isc he mi c heart di sease a mo ng wo me n. Am Jo ur o f C lin Nutr. 1999 M ay;69(5 );890 -897 . Jaco bso n T A. B eyond lipid : the ro le o f o mega-3 fatty ac id s fro m fi s h o il in the preventi o n o f coro nary heart di ease. C urr Athe rosc le r Re p. 2007 A ug;9(2): 14 5-53 . Nordoy A, M a rc hi o li R, Arne e n 1-1, Vide baek J. n-3 a nd cardi ovascular po lyun saturated fatty ac id di seases. Lipids. 2001 ;36 Suppi :Sl 27-9. Bres lo w JL. N-3 fatty ac ids a nd cardi ovascul a r di sease. Am J Clin Nutr. 2006 1un ;83(6 S uppl ): 1477S1482S . Ultra marine Omega-3 Virgin Salmo n Oil Ge lcap l080mg/90 Ge lca ps [inte rne t]. Nu-Ge n Nutriti o n, Inc. [c ited Dec 6, 2007] . A va il able a t: http://www .ca ncerc ho ices.com!Me rc ha nt2/me rc ha n t. mvc?Screen= PROD&Sto re_Code=OOl & Produc t_Cod e= U0mega-3G e lca p &Category_Code= . Wh at Yo u Sho uld Kn o w A bo ut Omega-3 Fis h O il [inte rne t] . HWW Ente rpri se Gro up . [c ited Dec 6 , 2007] . Avail abl e at: http://ww w.o mega-3. us/ Omega 3 I DHA E te rs [inte rne t]. Xte nd Life. 2006 . [c ited Dec 6, 2006]. A va il abl e at: http://we llness.xte nd -li fe.co mlproduc t!Omega_3_ - _ DI-IA_E ters.aspx? id=7 38834.

49. M edite rra nean die t fo r heart health [inte rne t] . M ayo Fo und ati o n fo r M edical Educati o n. 2007 . [c ited Dec 6, 2007] . Ava il able at: http ://www .mayoc linic.co m/ healthlmedite rra nea n-di e t!C LOOO 11 .

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History of Medicine History of the Circulatory System: discovery of the basics Adam Garber, Medicine 2010 and Michael Livingston, Medicine 2011 Reviewed by Dr. Vi vian McAlister T oday, the fi eld of cardi ology i understood a a highl y evo l ved and mature pec ialty of medicine. H owever, the journey toward our current gr a p on the subject ha been a long one. T he discovery of the most basi c heart phy iology and anatomy ha a hi Lory of more than two mill enni a. T hi s paper d i cus e the development of the most fundamental principles of heart phy iology and anatomy whi le outli nin g the influential contex t of their ori gin .

The fie ld of cardi ology ha lo ng been perceived as a hi ghl y sophi ticated are na of understandin g wi th ph y iologically intri cate pro ble m and technologically advanced oluti ons. And though it i j u t that, it was not alway o. In the greater timeline, cardi ology a a medical pecialty i till in it in fa ncy. More o, cardi othoracic urgery remained a fie ld unborn until after World W ar II, making it the tardiest of urgical specialties by 1 twenty year . The stud y of the human heart in general ha had a much longer history with fa c in atin g accelerati on , tediou plateaus, and , at times, di appointing regressions. But the hi story that is di cus ed herein is the history of that part of cardi ology that most people, scie nti t or not, take for granted a obvious knowledge; this is the understanding of the most ba ic principl es of the circulatory system. I begin at the end o f thi s hi story by ummari zing its acco mpli shment. The heart i a pump. lt contain four chamber . The ri ght ide o f the heart pump bl ood to the lun g where it pi ck up oxygen and then enter the left ide of the heart. The oxygen-ri ch bl ood in the left side o f the heart i separated fro m the oxygen-poo r blood in the ri ght ide of th e heart by the interventri cul ar septum . The oxygen-ri c h blood is pumped throu gh the le ft ide o f heart to th e entire body by arteri es where it uppli es the di fferent ti s ues with oxygen. Oxygen exchange occurs in the small e t ve se ls called capillari es and oxygen poor bl ood ubsequ ently is carri ed 2 bac k to the ri ght side of the heart by vein . The mo t bas ic princ ipl es o f the circ ulatory system took thousands of year to uncover. An E gyptian papyru datin g back to l500BC correctl y correlated the character and

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frequency of the pul e with the patient's health status. Hippocrate (460-355BC) and his pupils also drew acc urate co nclusion regarding the nature of blood fl ow. One pupil described the perpetual movement of blood " with courses of ri ver returning to the ir ources after a passage through numerou channel ". 3 However, this concept of circul arity wo uld only be confirmed two millenni a later by William Harvey. It wa Ari totl e, the anato mi t, philo o pher, and knowit-all of the time who began the di ruption of cientific under tanding of the heart and its y tern. While orne of hi physiological ideas bore orne value, he al o committed the academic di ervice of attributing the eat of body intelligence' and the ource of body heat to 4 the herut . Such exaggeration of the heart's fun cti on in the body was mirrored by Erasistratu (c. 3 10-240BC) who first described the heart' val ve , and ex pla ined that air entered the heart fro m the lung where it was transformed into ' pneuma', the vital pirit, 'a most ubtle vapor' to be carri ed to the body by 1 arterie . Only ve in , he eiToneous ly conceived , contained blood. So, fo r a peri od of 500 year little advance was made in the under tandin co- of the c irculatory syste m. However, the under tanding o f our world and all thing in it was forever changed w ith the birth of Chri ti anity and it populari zation. Indeed, the nex t advance ment in circul atory ph ys iology came from Gale n (c. AD 130-200), whose work was viewed favo urably by the Church. Galen, though not Chri ti an, was monothei. tic and hi wor hip o f o ne god , Aesculaplll s, the god of medi cine, haped hi theories in uch a way th at they were compatible

with the vi ews of th e Church. The Church was, at the time, fi ghting Roman polythei m and so Galen' s worship of a si ngle God who created all things fo r a purpose was agreeable enough. 1 ln brief, Galen fo und th at arterie contained blood, in tead of air a had been the belief to that point. He conceived of two ystems: the venous system whi ch was nutritionally relevant, and the arteri al system, which was responsible fo r body heat. Included in his theories are the belief in the existence of pneuma, the vital spirit on which life depends as well a two other spirit , the ' animal pirit' and the ' natural spirits' . Galen falsely connected these two ystems of the ri ght and left heart by supposed pores in the interventri cular eptum. 1â€˘4 Galen' theories were more thorou gh and complex than detailed in this essay. His views were intricate enough for the critical scientist, compatible enough with the Church, and mystical such that it enre uraged the philo opher's under tanding of the heart as the seat of the soul. As a result, his views went largely unqu estioned fo r a staggering 1500 years ! The fir t ph ysician to question Galen ' views was Ibn An-Nafis (12 10-88), whose work made the first reference to the pulmonary circulation. However, thi s kn owledge was likely lo t until this same findin g was independently di covered three centuri es later by Servetu s, a Unitarian, who was rewarded for his science and his anti-Protestant beli ef by John Calvin in Geneva, who had him placed on a stake and 1 burnt to the core. The initi al anatomical understandin gs of the heart were dispersed, lo t, or destroyed purpo efully and, throu ghout the Dark Age , human dissecti on was either di sallowed or difficult to carry out due to certain 5 impo ed ecclesia ti cal edicts. Leonardo da Vinci (1452-151 9) took great interest in the anatomical structure and ph ysiological workings of the heart. He correctly drew the heart with four chambers and, through experiments, described the mechanism by whi ch the aortic valve closed. 6 Andreas Vesalius (151 4-64) also possessed a passion for dissection and partook in the illegal yet common , practice of bodysnatching. In his work, "De Humani Corpori Fabrica", he carefully, but strongly, questi oned

Galen's view , which were taught in the chools of medicine du ri ng his time. With Galen's views begi nnin g to turn obsolete, many ph ysiological questions of the heart were reopened. In 1574, Fabriciu of Aqu apendente (1537- 16 19), publi hed "De Venarum Osteolis" which examined the valves of veins. He aptl y de cri bed the valves a ' the little doors of the veins' and pro posed that they 'delay the blood and so prevent the whole of it 4 flowing to the feet. .. and collecting there' . But it was Willi am Harvey (15 78- 1657) who fin all y deconstructed the false views of the cardiovascular system. Hi s, "De Motu Cordis", a short book dedicated to King Charle I, compared the ' ki ng in hi s kingdom' to the heart 1 in the contex t of th e body. T his wise maneuver, which praised the Kin g whom he and many admired, perhaps aided in his avo idance of harm fo r hi s publication of contrary views. Th ro ugh his lectures and in his publication, he explained that blood pumps with ventricular contraction thro ugh the lungs back to the heart and th en through the body where it ' passe thro ugh pores in the flesh' and returns fro m the periphery through veins increasin g in size as they approach the h eart. ~ He specified that blood moves, ' as it were, in a circle' and ' th is is the only reason fo r 4 the motion and beat of th e heart' . He emphasized that the heart is no other thing but a pump as if to crush the spiritu alistic functions impo ed on the heart until th at time. Finally, Marcello Malpi ghi (1628- 1694), Jacob van Swammerdam (1637- 1680), and Anthony van Leeuwenhoek (1632 -1723) used the microscope to ex plain the shape of the red blood cell and the capillary networks that fo rm the connection between arterioles and venules.4 So, over a great many years the myth of the heart were dispelled and the truth came to be accepted like in mo t cases of di covery, slowly and with much dissent. Yet the heart remai ns an etern al symbol. A ubiquitous metaphori cal fo rce made reference to by the holiest of books and by the most lucrati ve of co mmercial recordin g artists. In Genes i 6:6 God i described a possessing a symbolic ' heart' when he decides that a great flood is in order, " And the LORD was orry that He had made man on the earth and He was gri eved in His heart" . 7 God who has'

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no other body part, but perh ap for a guiding ' hand ', must also pos e a ' heart', an enigmatic box of emotion. M ore comicall y, Tom W aits, the guttural crooner, explains that he has a "bad live r and a broken heaLt" .8 While cocktails and the like may have done the job on hi s li ver, it was an e motional cocktail of ort that hanned hi s heart. The li ver's pro blem i ph ys iological but the heart's is of a different nature. The ' heart' a a human-constructed ymbo l is an entity whi ch attempt to tran cend it physio logical function and to uch on the intangible a pects of what it i to be hu man. T hen is it so urprising that with all of this attac hed ymbo li sm, th e academi c uncoverin g of the function of the heart too k a long a it di d? It wa a lot to lose and yet, the ym bo l ha never been lost at all.

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References Richardson, Robert G. T he surgeon' s heart. Cox & Wyman Ltd. 1969. 2. Guyton AC, Hall JE. Textbook of medi cal phy iology: eleventh editi o n. Phil ade lphi a: 3. Elsevier Saunders; 2006. 4. Walker K. The tory of bl ood . Lo ndo n: Jenkin s; L958. 5. Hurt, R. T he hi tory of cardi othoracic surgery: from early time . New York: Parthe non 6. Publishing G roup ; 1996. 7. Aufder he ide AC. T he cie ntific tud y of mummies. Cambridge Uni ver ity Pre s; 2003 . 8. Shumacker Jr. HB. T he evoluti o n of cardi ac urgery. B loorrti ngton: Indiana Uni ver ity 9. Pre ; 1992. I 0. The Old Te tament. Gene is 6:6. II. Wai t T. Small C ha nge. Elektra/Asylum Records; 1976. I.

Medicine and the Internet

Computer-assisted learning-teaching clinical skills in cardiology Jordan Glicksman, Medicine 2010. Pencilla Lang, Medicine 2011, and Dr. Kevin Fung, Department of Otolaryngology Reviewed by Dr. David Masse/ Cardiology i a diver e and ever-expanding field of medicine. Medical trainees mu t master a wide variety of skill and knowledge in order to become proficient at managi ng patient with cardiovasc ul ar co nditi ons. Comp uter-assisted learnin g has the potential to enhance medical teac hing in card iol ogy by providing tudents with an enriching interactive learnin g environment.

During medical school , student are expected to develop a trong foundation of clinical skills. In many centers tandardized patients are used to teach and evaluate students as they have been hown to be an effective teaching method. Cardiology, like many areas of medicine, is a diverse and ever-expanding field. Advances in technology have made many tool available to clinician to diagnose and manage patients with cardiova cular conditions. Despite the availability of equipment such as electrocardiograms (ECG), echocardiograms (ECHO), physicians till rely heavily on basic clinical skills uch as history and physical exam 1 to determine the nature of a patient's illness â€˘ While traditional teaching method are helpful fo r teaching students basic eli nical skills, multimedia computer technologies provide students in the 21 t century with an opportunity to refine their talents.

The Current Use of Multimedia Teaching Tools Medical educators already ultilize multimedia computer technologies to provide students with increased exposure in their respective field . The Computer-Ass isted Learning in Pediatrics Program (CLIPP) has already been implemented to augment medical education in pediatric _2 CLIPP is a computer-assisted learning (CAL) program that provides students with a multimedia experience to case-based learning. Programs like CLIPP are gaining popularity, as they allow students to learn at their own pace. This can allow for tudents to learn at a time and

location that is convenient for them, as long as there is a co mputer available to work at.

Advantages of CAL in Cardiology Clinical Skills Teaching CAL application are of particular value 111 cardiology teaching due to their ability to provide students with information in an interactive manner. In a traditional teaching etting, students may be taught during a didactic teaching seminar (and subsequently memorize) that an aortic stenosis murmur is a sys tolic ere cendo-decrescendo murmur. This information may be reinforced in a clinical methods teaching seminar. However, without actually hearing the sound themselve , can tudents truly appreciate the sound of such a murmur? Furthem1ore, will students be able to apply this knowledge to a patient that present to them during their training or in their future practice? CAL allows students to learn in a truly enriched self-directed learning environment. Physical findings such as au cultation may be conveyed as they would naturally be ob erved by the student. Heart sound from patients with real findings may be recorded with electronic stethosco pes and then can be incorporated into the CAL program. Additionally, the programs may make use of other tools such as ECHO and ECG findings to allow the learner to correlate a patient's findings into a broader picture and help reinforce the content.

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Costs of Implementation While the multimedia approach that CAL offers is exciting, as with any new technology, cost can be concernin g. Nevertheless, widespread use of CAL modules can be very cost-effecti ve For example, in 2005 , the average development cost per CLIPP ca e session was approximately $6. 2 Thi s amount will decrea e as the number of students using the program increase . Replac ing traditi onal teac hing method with CAL has the potential to free up the time of medical school lecturer to teach in other capacities, such a small group ses ion . Furthermore, CAL has the potential to enhance teaching at di stant locati ons uch as satelli te campu es, rural setting and in developing nati ons.

CAL and Other Learning Methods Adult have been how n to learn optimally in self-directed learnin g enviro nments? As a result, there has been a shi ft away fro m traditi onal lecture and eminar-based teaching and towards the implementation of more elf-directed learning in medical school . In addition to the use of multimed ia modalities, CAL can help guide learning thro ugh other fea tures uch a qui zzes and learnin g game . In fac t, many in fo rmal fo rums fo r CAL have already been created by students and in structor . For example, it i po sible to find video in structi ons for various as pect of the clini cal examin ati on on YouTube 庐 and perso nal webpages. A more profes ional fo rum wo uld allow tudents to better capitali ze o n CAL's advantage . Currentl y, th ere i debate a to the effecti venes of CA L as a teachin g modality. Several studi e have co mpared the use of C AL to other modes of learn ing. So me of the e tudies how th al there i no significant di ffe rence in knowl edge and s!Ull retenti on between those taught didactica ll y or by seminar when co mpared to tho e taught by co mputer teaching modules, while so me tudi e ugge t that other fo m1 s of leac hin g (e.g. didactic Iecture ) are tt'll supen.or. 2 路 ,_(. 7

The Future of CAL While research continu es to asse s the effecti venes of CA L in medical educati on, this new learning tool is a ri sin g fo rm of medical teachin g. Th e Assoc iati o n of Am eri can Medi cal

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Co lleges (AAMC) has established MedEd Portal, a peer-reviewed collection of online teaching tools. This resource contains a database of learning resources that include tutorials, virtu al pati ent , and case-based learning among 8 other medical education resources. Not only does the MedEd Portal provide easy access to CAL modules, but it also provides incentive to acade mi c ph ysicians to create more CAL tools th ro ugh recogmt10n as a peer-reviewed publication. Initiatives such as thi s will likely increa e the productio n of CAL module . The u e of computer-based teaching in medicine has the potenti al to change the way medicine is taught to both current and future generations. Between the multimedi a capabilities of CAL, enh ancements over current learning modalities and increa ed recognition for publishing CAL modules there appears to be a bright future for co mputer-a sisted learning.

References 1.

Hata la S, I e nberg B, Kas e n G, Bacchu M, Scale e R. Assess ing the Re lati o nship between Cardiac Ph y ica l Exarrun ati o n Techruque and Acc urate Bedside Diagno i d urin g a n Objecti ve Structured C lini ca l Exarru natio n (OSCE). Acad Med 2007 . 82( I 0) : 26-S29. Fa ll L , Berman N. Srru th S, el al. Multi -instituti onal deve lopment and utili za ti on of a co mputer-a i ted learning program fo r the ped iatric c lerkship: the C LIPP project. Acad Med 2005. 0(9): 847-55. Kn ow le M . Self directed learn ing: a guide for learner and teachers. 1975, New York: A oc iati on Pres . Brandl M and Dav ies E. Vi ua l-spati a l ability, learning moda lity and urgica l kn ot ty ing. Can 1 Surg 2006. 49(6): 4 12-6. Carr M. Reznick R, and Brown D. Co mpari o n of co mputer-as isted in tructio n and e mi nar in tructi on to acq~ire psyc ho motor and cogniti ve kn o wl edge of ep1 tax 1 manageme nt. O tolaryngo l Head Nec k Sur<>0 1999. 12 1(4): 430-4 . Greenhalgh T. Computer a sisted learnin g in undergraduate medi cal educati o n. BMJ 2001 . 322(7277): 40-4 . Rogers D, Regehr G, Yeh K, and Ho wdi eshe ll T. Co mputer-a si ted learnin g versus a lecture and feedbac k se minar for leaching a ba ic suroical 0 techni ca l kill. Am 1 Surg 1998 . 175(6): 508- LO. Assoc iati o n of Ameri ca n Medi cal C li ege . MedEd Portal. 2007; Available at: www.aa mc.org/mededportal (acces ed Augu 1 2 1, 2007 ).

Medicine and the Law Medical Malpractice Litigation: Myth or Growing Crisis? Abdullah Alabousi, Medicine 2011 Reviewed by Dr. Mark Speechley One of the most ta lked about is ues in hea lth care, and one th at receives much media coverage and public attention, is medical malpractice liti gati on. Opinions on how well thi s liti gati o n sys te m functions differ, o metimes starkl y, depending on who is being asked. In o rder to full y apprec iate the exte nt a nd co mplex ity of medical malpractice liti gation this paper will con ider the de finiti o n of med ica l ma lpracti ce as well a the laws and proced ures followed in Canada. M oreover, tre nds in ma lpracti ce law uits for practi c ing ph y ic ian s in the field of Card io logy will be u ed a a ca e study. Hopefull y, by introduc ing the key orga ni zation and parti es in volved a nd the important tre nd s and indicator to watch, thi paper will help the reader be more informed as a co mpl ex debate unfo lds on the effec ti ve ness of the c urrent syste m.

One of the most talked about issues in health care, and one that receives much media coverage and public attention, is medical malpractice litigation. Broadly, litigation refers to the u e of the courts to enforce a right, and request a remedy, by one party against another. In the context of medical malpractice litigation, the legal 'right' being enforced is the right of the public to competent medical care - care that is free of medical errors that could rea onably have been avoided. 1 Opinions on how well thi sy tern functions to protect this right differ, sometime starkly, depending on who is being asked. For example, some physicians view such legal action "a random events that visit unwarranted expense and emotional pain on competent, hardworking practitioners". 1 Similarly, within the North American healthcare industry (the hospital sector and insurance providers) there is wide agreement that medical malpractice lawsuits have become more of a burden than a way to ensure patient safety and punish errors and carelessness. Even some observers from outside the medical system express their concern that medical malpractice cases have been altered into some form of a "lawsuit lottery" whereby a few patients receive hefty compensation, while no reimbursement is given to the majority of 1 patients injured by medical errors. Nonetheless, lawyers and the public, even with all the imperfections and equity problems, still view malpractice litigation as a way to regulate and control "a profession that is unaccustomed to

external policing". ' In fact, so me lawyers perceive them selve as "champions of patient afety" who are fighting battles with the healthcare system on behalf of patients. ' This complex and imperfect system of malpractice lawsuits has created a significant gap between the views of medical professionals and the views of their patients. While physicians believe they are being unfairly targeted, their patient hold the view that legal action is an effective way of policing their doctors. ' Legal questions that proceed to court inherently become adversarial, with lawyer for each side hired to defend the intere ts of those who have retained their ervice . The inherent adversarial nature of these legal contests cannot help but obscure the common goal of physicians and patients of improving patient ' health , which in tum may reinforce mi conceptions and di stru t and damage the doctor-patient relation ship that is o important to effective medical care. The United States ha 70 percent of the world' s lawyers, and five percent of the world 's population -- a supply of one lawyer for every 265 people? Social observers who note the way Canada is becoming more similar to the United States may see a cautionary tale with respect to increased litigiousness in Canada. In order to fully appreciate the extent and complexity of medical malpractice litigation it is important to consider the definition of medical malpractice as well as the laws and procedures followed in Canada. Moreover, trend in malpractice lawsuits for practicing physicians in

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the fi eld of Cardiology will be used a a ca e study.

What is Medical Malpractice? Although di cuss ions in volving malpractice li tigati on can in vo lve complex legal techni calities, there is a fairly inclusive and wide ly agreed upon defini tion for medi cal malpractice. M uch of th e d i crepancy in the views of the d iffe rent parties to the e di pu tes can then be understood as d isagree men t over which events and occ urre nce fa ll under this broad defin ition , and whi ch do no t. Medical malpractice can be defined as an act or an omission by a health care prov ider that deviates fro m accepted standard of prac tice in the medi cal fie ld and whi ch cau es injury or harm to the patient. 3 M alprac ti ce can result fro m negli gence, professional mi conduct, carele ne , and/or failure to u e adequate levels skill or diligence while cari ng for a patient. To determjne and e tabli sh an accepted standard of care, comparison is made to typical care offered by ph ysicians in the community; in other wo rds, compari son i made to standard applied within the same geographical area. Another matter th at fa ll s under the category of medical malpractice is failure to get a pati ent' info nned consent. A ph ysician mu st fully in fo nn the pati ent about th e nature of the diag no ed condi tion, the range of treatment o ptions, and the know n major ri k ? of each. It i interesti ng to note that when a doctor inform a pati ent of the risks associated with a procedure or a treatment, they don' t have to ex pl ain all the pos ibl e ri sk . T hey are onl y respon ibl e for ex pl ainin g those ri sks that a ' rea onabl e ' pati ent wo uld want to know before makin g the ir decis ion. In addi tion, even if the practiti oner does not prov ide the ir pati ent with all the inform ati on, the phy ic ian will not be li able if a ' reaso nable' person in the ir positi on wo uld have agreed to the pro posed treatment or procedure anyway, even if the phys ic ian had g iven them all 3 the informati on. Thi ex tensive and broad de finiti on of medical malprac tice leaves many issue open to the interpretati on o f judges, juries, and lawyers. Thi s leaves much roo m fo r inequ ality and incons istency in judgments and compensati on

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for patients. Ph ysici ans are taught to understand the considerable amount of uncertainty that accompanies diagnosis, and appropriate treatment but members of the public may not ' fully appreciate that medicine is not an exact cience and that doctors are not able to make the correct 'diagnosis every time. Doctors may order the appro pri ate te ts and procedures and follow the standard of care in a given location and still make either no diag nosis or, in some cases, the wro ng diagnosis. If a phy ician doe all that i in the ir power to help the patient, and still misdiagnoses a pati ent, are they liable, and is thi s cons idered malpractice? Depending on who interprets the law and the definitio n of malprac tice, a ph y ic ian may in some cases be till taken to court even after following the appro pri ate stand ards of care. It i imperfec tions such as the one menti oned above, which are a cause of concern fo r ph ysic ians and th e health care indu stry. It is very important to keep in mind that because of medi cal uncertainty, doctors cannot be guarantors of the ervice which they render with one hundred percent certainty. A physician is, however, legall y required to have the necessary know ledge and ex peri ence to perform the ervice in que ti on. Further, doctor mu t exercise the ki ll and care that other in the co mmunity u e when dealing w ith imilar itu ati ons.

The story in Canada T he medical malprac ti ce liti gati on c risi has not reac hed th e everity seen in the United State .4 The compl ex ity of the itu ati on there will be di cu ses later in the artic le. In th e meantime it is important to appreciate that takin bo- leo-al action b with re pect to medi cal ma lpractice cases is much more difficult in Canada whe n compared to the United State and even the United 4 Kingdom. In fac t, "Canadian judges tend both to be more reluctant to find breach of medical standard of care, and to require mo re exactin oproof of causati on". 4 o .. In . addition, defence of prac ti cing ph ys1c tan ~~ Canada is killfully managed and generously fm anced by the nonprofit Canadi an Medical Protective Associati on (CMPA), a mutu al defence a sociation o f phys icians. 5 The

CMPA, founded in 1901, is funded and operated on a not-for-profit bas i by ph ysicians. The organization has more th an 71 ,000 member co mprisin g about 95 per cent of the doctors licen ed to practise in Canada. 5 The CMPA will do all that is in its power and will in ves t heavily in defending any ph y ician action th at is in any way defen ible. The organization's main aim i to prevent the setting of medical malpractice precedents th at could cause irrever ible damage to the profess ional reputation of the medical profession as well as long term financial 4 burdens. The CMPA's contract with their member physicians is for unlimited coverage, with few exceptions. Some of the exclusions include cases involving ethical violati ons by a physician, uch a sex ual mi conduct; in such circumstances the CMP A will not cover the physician but will pro vide them with defence 4 counsel and advice. In term of medical malpractice litigation in Canada, there are a number of trends that need to be di scussed. These trends include the rate at which legal action is taken against practicin g physicians, and the cost of malpractice insurance in the country. On the positive side, the CMPA has made it clear that legal actions against ph ysici ans have declined over the past decade fro m about 26 per 1000 members in 1996 to 13 per 1000 members in 2006.6 In other words, practicing Canadian ph ysicians today are half as likely to be involved in medical malpractice lawsuits than they were 10 years ago. This maybe interpreted as resultin g from a growin g emphasis on pati ent safety and ri sk management by doctors, or it can be seen to have resulted from a more extreme approach of the CMPA in the pa t decade to preserve the profes ional reputation of medicine. However, while the rate of liti gation against Canadian doctors has been declining, there are other trends that are quite troubling. For ha instance, the cost of medical liability increased signi ficantly over the past decade, with annual damages and legal and ex pert administration costs rising from about $ 170 million in 1997 to more than $400 million by 2006. The median damage cost increa ed from about $30,000 in 1996 to nearly $ 100,000 in 2006.6

In addition, the CMPA has identified a trend of "increasin g intru sions on a physician' ri ght to due proce s in the name of patient safety".6 However, these claims are subj ective, may be bi ased , and are diffic ult to verify witho ut the in volvement of an independent entity that does not have special interest in the iss ue of med ical malpractice litigation and their outcome . Another tro ubling trend, which does not seem to be affected by the decline in legal action again t physician , i the rising cost of malpracti ce insurance in Canada. Over the past decade there has been a steep increase in the cost of malpractice insurance in the co un try that is begin nin g to have a ignificant effect on practici ng ph ysicians. It has been estimated that as of 2001 , average insurance rates in On tario had climbed by nearly 45 %, while rates in M anitoba, Saskatchewan, and Alberta had had a 7 more modest increase of 11 % by the same year. And , since Canada in general, and Ontario in particular, ha a worriso me physician shortage, the significant increase in malpractice insurance fees in so me provinces may put these jurisdi cti ons at a disadvantage when recruiting 7 and retaining doctors. Although most specialti es are being affected by the insurance fee hikes, some specialtie such as Orthopaedics, Neuros urgery, and Obstetrics have been more significantly influenced. 7 These figure clearl y upport the view th at there ha been an increase in malpractice insurance fees in Canada and the awards in malpractice court decision . However, contrary to popular belief and the selecti ve media report describin g the high-profile, high-cost cases, the perception th at Canadi an doctors are maki ng more mi takes and that they are more likely to get ued than in the pas t is false according to research conducted by the Canadi an Health Services Research Foundation (CHSRF).8 In reality, the number of medical malpractice lawsuits filed in Canada peaked at 1,4 15 in 1996, and has been on the decline since. 8 Furthermore, an increa in g percentage of lawsui ts that went to trial concluded with j udgments in favour of the physicians, fro m 73% in 1994 to 82% in 2004. 8

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Malpractice in Cardiology After considerin g the general concerns with medical malpractice litigation in Canada, we will now go on with a bri ef overview o f issues with medical malpractice in the fi eld of Cardiology. E ven though there is a plethora of informati on pertaining to medical malprac tice liti gati on in general, it wa very di fficult to find Canadi an data pertaining pecifi cally to the fi eld of Cardio logy. However, the A merican College of C ardio logy prov ides so me in fo rmation th at can be used to get a general idea about what is happening within thi s field of medicine in North America. Ju st as in other medi cal spec ialti es, medical malpractice liti gati on has been a key area of co ncern for Cardi o logists. Costs of medical malprac tice insurance have been increa in g rapidly, and the rates for doc tors in Cardi ology are co nsistent with those in oth er 9 high-ri k specialti es. This has had a significant effect on the li velihood of such ph y ic ian , and has even fo rced orne of them to leave th eir practice. Thi trend has been een in the United State , but presumably th e situati on is similar yet pro bably not as ex treme here in Canada. As for th e causes behind thi increase in premiums, th ey are pre umably simil ar to other pecialti e in that they include "fri volous laws uit and exaggerated monetary award ", in additi on to the exodu s o f o rne major insurance carri ers from the market. 9

Future Outlook At thi s point in time, the future outl ook for ph ys icians is bl eak at be t. Medi cal malprac ti ce ins urance pre mium s are still on the ri e, and monetary award in the cases where the rulin g i in favo ur o f the patient are rapidl y increas in g. The only bri ght side to all o f this is the fact th at there has been a decrease in the rates at whi ch physic ians are being sued. Howeve r, th at has not been e nough to slow dow n th e trend of inc reasin g in surance fees . The questi on that co me to mind at this point is wh o reall y is respons ible for the c ri si ? And if more th an one party is res ponsible, then will any of the m stand up and do so methin g about it? Sh ould the government attempt to

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reform the laws to better protect both doctors and patients? What is the evidence that patient safety is actually improved by the pre ent system? Should the medical profession cease to be regulated by the physici ans themselves? Should ph ysicians accept a greater role by the government in policin g the medical profession , in exchange fo r legal protecti on against frivolou s and unreasonable legal actions? What if anything can be learned from other countries? These are all complex questions, with no simple an wers. Hopefull y, by introducing the key organizations and parties in vo lved and the important trends and indicator to watch, this paper will help the reader be more informed as thi s complex debate unfo ld .

References I. 2.

6. 7. 8.

Studdert D M, Mell o M M, Bre nnan, T A. Medical Ma lpractice. N Engl J Med . 2004 Jan; 350(3): 283. National Lawyer Popul aLio n by State [Internet]. The America n Bar A oc iati o n; 2007 [cited 2008 Jan 5] . Ava il ab le from : http://www.abane t. org/market researc h/2007 _N atl _La wyer_ FIN ALo nepage. pdf Med ical Malpractice [Internet]. The Ca nadia n Bar Associati o n (B riti sh Co lu mbi a Bra nch); 2006 Dec [c ited 2008 Jan 5] . Avail able fro m: http://www.cba.org/BC/ publi c_media/health/420 .aspx Lim bert J. Medi cal Malpractice Liti gati on - Ca nadian Per pec ti e: T he Role of the Medica l Expert [Internet]. Internatio na l Medica l Liti gati on Consultant ; 2007 [c ited ~008 Ja n 5]. Avai lable from: http://www .medli t. in fo/g ue t /rnmpca nadi an/ medlit.ht m bout the MPA [Internet] . T he Ca nadi an Medica l Protec ti ve As oc iati o n (CMPA); 2007 [cited 2008 Jan va il ab le fro m: http://www .cmpa-acpm.ca/ 5] . c mpapd03/ pub_ index.c fm ?LAN G=E&URL=cmpa% 5Fdocs %2Fe ngli h%2Fco nte nt o2Fa bo ut%5Fc mpa ~ 2Fp u b li c % 2Fp ub ~ 5Fabout %5Fu %2De%2EhtmJ Jo nes D. Lega l a ti o n aga in st doctors dow n 5 0 ~ in past decade. CM AJ. 2007 Sept; 177(7): 7 10. Spurgeon D. Cos t o f ma lprac tice in surance e t to ri e in Ca nada. BMJ. 2000 March; 320(7235): 601. Sulli va n P. Re earchers cha lle nge Canada' "ma lprac tice myth " [Internet] . Ca nadi a n Medical A oc iati o n; 2006 Jul y fc ited ~008 Jan 5]. Ava ilable fro m: hllp ://www.c ma.ca/ index.c fm ?c i id= 10035209 &la_ id= l DeMari a A N. Medi ca l ma lpracti ce in urance a :ultifaceted pro bl e m. J ACC. 2003 Nov ; 42(9): 1683-

Profiles Dr. Richard J. Novick on Guns, Germs and Steel- Perspectives from a CardioThoracic and Transplant Surgeon Alysia Zhou, Medicine 20IO Reviewed by Dr. Richard Novick I was a medical tudent on surgery at the Royal Vic [in Montreal] o ne ni ght when I got a stat page to go dow n to emerg. In emerg there was a policeman who had bee n s hot down on Pee l St. at the j ewe lry store where he ca me across a robbery. The g uy wa lyi ng on the stretcher, hi eyes ro ll ed back, hi blood pressure wa 50, there was blood spurting o ut from his chest - it was a to tal ni gh tmare situation and I was the o nl y one there. So I said, " Get the s urg ical chi ef res ident; get the atte nding." I put an IV in thi s guy o I fe lt pro ud about that; th ey intubated him . The Chief re ide nt ca me a minute later, got o n the phone and sa id , "Get me an OR." We went up the e levator and in the meantime the police man arrested o we started CPR. As we e ntered the OR, I wa sitting with my knees on the bed and pumping o n hi s chest while blood was pouri ng o ut a ll over the pl ace. I was so tachycardic my pulse was throbbing in my ears. Paul (the C hi ef resident) opened the chest and the guy was sti ll fibrillating so he ope ned the pericardium and massaged and zapped him internall y. He came back but hi s BP wa just 50 and there wa black blood spurting from hi s ri ght ventric le. Paul aid, "G ive me a 2-0"; he took the 2-0 prol ene, put it into the RV and turned to me: " Novick take thi s driver." I wa ho ldin g thi s driver and shaking like a leaf and he said, "When I put thi s need le through, you grab the tip of the need le and you bring it thro ug h." So he put the need le through, I grabbed it and the policeman fibrillated agai n; we defibrillated and blood was still pouring out. The second need le came through , I grabbed it, Paul tied a knot and the bleeding stopped. Thi s wa a yo un g man who didn ' t have coro nary disease and all of a sudde n the BP was 78 , 80 ... So we stood there fo r about an hour irri gatin g and closing the policeman. after which we brought him to the unit. Of course he had every comp licatio n under the s un ; hi s kidneys failed and he needed dialysis but six weeks later he walked out of the ho -pital in excell ent shape. That was one of my first nights o n call in surgery and I wa there for hi s whole hospital stay .

Not short of an episode one would see on the television series E.R. , this was, however, a reallife pivotal experience for a young third year medical student and now Chief and Chair of Cardiac Surgery, Dr. Richard J. Novick. With a 42-page curriculum vitae detailing over 125 publications, numerous appointments, grants and awards, as well a knowing six languages, Dr. Novick is truly a renaissance man . Born and raised in Montreal, Quebec, hi s talents were fostered by a liberal arts philosophy instilled in him by his parents of the importance of having a broad education. He grew up in a "medical hou ehold" and hi s father still practices otolaryngology in Montreal at age 84. True to this broad education of philosophy, Dr. Novick took a path less traveled and pursued a degree in Philosophy at Brandeis University in Boston , with a minor in biology. His honors thesis wa an analysis of the original works of Jean-Paul Sartre's theory of existentialism.

Towards the end of the 3rd year of hi s undergraduate studies, Dr. Novick knew that deci sions had to be made about what to pursue after his Bachelor's degree. To keep his options open, Dr. Novick wrote the MCAT, LSAT and GMAT exams. After much personal reflection and di cus ion with his family , Dr. Novick decided medicine was hi s true callin g. Ironically, Dr. Novick started medical school at McGill Univer ity in the fall of 1976 in the same class as hi younger brother of 15 month , who pursued a pre-medical education at McGill and was focused on medicine at a young age:

I had the bare minimum of sciences, so the first few months of med school were torture for me: pretty much the only reason I survived was: 1) I worked very hard, and 2) my brother helped m.e. He had done anatomy, histology, and physiology the year before. When I looked under the microscope, I had no idea -.,vhat I was looking at. I had never looked under a microscope before in my life; even in biology in

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College it was all conceptual learning. By the middle of first year, however, everyone was ort of the sam.e in terms of their knowledge base so those of us from a non-science background caught up pretty quickly.

It was almost as if it was just a little scrape. So I 1 decided in the beginning of 4 h year that I wanted to be a surgeon. For m.e, it was undifferentiated initially, and then I only thought of cardiac surge1y later.

When asked on how he decided during medical chool that surgery was his pass ion, it often came down to the clinical ex perience , the teachers and mentors he encountered throu ghout hi s medical educati on, and keepin g an o pen mind throughout hi clerk hip year. For in tance, Dr. Nov ick came into medicin e con ide rin g psychi atry to be an area of intere t because of hi undergradu ate and volunteer ex perience related to psychology, a we ll as having a mentor in the fie ld. Durin g medical choo l, Dr. Nov ick excelled in variou fi eld of medi cine, inc luding winning the Franci William Pri ze for the hi ghe t achi evement in Intern al Medicine. Hi s clerkship year al o bro ught him into contact with Dr. L. D . Macl ean, Chi ef of Surgery at McGill, who became Dr. Novick's mentor throu gho ut hi urgery ro tati on. Thi , co mbined with e minal event that occ urred during hi urgery rotation at the Royal Vi ctori a Hospital, helped Dr. Nov ick narrow hi area of interest and " o after that ex peri ence psychi atry wa a negati ve and surgery, although intense, wa pretty pos iti ve." With electi ve time and the res idency matc h loo min g, Dr. Nov ick requ ested a cardi ac surgery e lecti ve and wa launched into another life-changin g ex peri ence:

Dr. Nov ick decided to apply to the US match becau e he wanted a broad and intense ex perience. He therefore applied to numerous American in tituti on , "including all the major kni fe and gun clubs." He subsequently matched to Bellev ue Ho pital and the New York U ni versity M edical Center. Moving to New York and embarking on what wa to be an "earth -shattering experience," Dr. Novick wa thru st into the full intensity of hi urgical intern hip from day one. In addition to the re pon ibiliti e o f being a newly minted MD, the ' 80 pro ved to be a high tre period for all healthcare worker a AIDS and HIV were ju t co mjng into the foray o f medical knowledge.

I had the good fo rtune to spend a month as a medical student on cardiac surgery. It was Dr. Tony Dobe/l who was the second surgeon to mentor me. He was Head of Ca rdiac Surgery at the time and a world-renowned pediatric surgeon. He also did a f air number of adult cases and he took m.e under his wing. Th e most amazing thing with Dr. Dobell was that no m.atter how bad things got he would always stay calm. For example, there could be a hole in the aorta with blood flying past his head and he would just put his fin ger on it and ·ay, "A lit1le bit of mild oozing here- maybe I'll take a 4-0 " and put the 4-0 through and solve the problem.

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Back then, the crime rate were dramatically higher in New York City than they are now. It was also a cra::_y time becau e people were starting to appea r with big lymph nodes and pnewnocysti pneumonia. AIDS wasn 't officially labeled until 19 4 o there were all these sick people coming to emerg coughing and hypoxemic and a week later they were dead ... It was a high ri k time across the board. There was no universal precaution and f rankly, we were lucky I to not have contra ted disease our elve /. I was on the I rauma service my first two months and on call one in two. During m • f ir t night, things got a bit quiet at midnight o I asked the ward nurse. " Where i the on call room ? " She started laughing and replied, "There's no on call room here ... You 're never going to get to bed. ·· " Well it 's quiet now and I want to go to bed " 1 responded. The beeper then rang and reported, '' Dr. Novick there's 23 patients f or you to asses in emerg. " There was no sleep; it wa total brutality .... You sta r~ed pre- rounds at 4:30am. the Chief Restdent came at 5:30am and expected you to take him. around ... There were patients on 5 or 6

different wards and severaL different ICUs and you had to draw the blood and measure cardiac outputs yourself, as weLL as know every patient's lab value. On your night off, you'd get out at 10 or 11pm, go to your apartment, have a Little bit of supper, crash for 3 hours and then the whole cycLe would reswne ... For exampLe, there were two days where I didn't eat anything. You 'd see a cart of muffins being pushed down the haLLway after rounds and Like a rabid anim.al, you would grab a donut because you hadn't eaten in 36 hours. There was no one Looking out for you. Drug trafficking and gang violence in the area would guarantee Dr. Novick and the hospital staff that on every Friday shift at 2:30 or 3am, they would have "3 or 4 people shot up very reliably" with some coming to emergency DOA. The pecking order of the resident would dictate who did what in case of multiple gunshot victims coming into the hospital:

There were a couple of times where we had three gunshot wounds staggered. So the first one I would resuscitate, put the !Vs in, intubate and get him. up to the OR and the R5 would be opening him. Another one would come in and the R3 would open him up so both ORs were in progress. And then a new gunshot victim would come in and then I had to do the resuscitation, sometimes a left thoracotomy to put a cLamp on the descending aorta if it was a major abdominal exsanguination. That would fairly reliably get the patient back but then you'd have to get him into the OR with an open chest and blood is dripping down the haLLways as you wheeled him to the OR. You've then got to prep, drape, open the belly, and by then the R5 would come over because som.eone else would be cLosing the first gunshot wound that came in. It was pretty catacLysmic. I did two months of training in trauma, and then I had rotations in neurosurge1y, cardiac and plastic surgery at NYU. I did orthopedics as well at Bellevue. It was a real rotating surgical internship and I saw everything. Most of the trauma populations were pretty unsavory people; they didn 't have a healthy

lifestyLe so I had concerns about getting serious disease myself. And then also the sheer intensity of it: with 160 hours in a week, I was in the hospital for 125 to 130 of those hours. My health held up but there were a coupLe of people in our group who didn't fare so well. We were 16 initiaLLy, but one guy took his own life and couldn 't handLe it. Another colleague of mine, and I was actuaLLy very Lucky, wanted to switch caLL with me so we switched on short notice. He left the hospital and got stabbed 14 times literally m.inutes after leaving and barely survived; I had just been talking to him severaL minutes previously. So I had severa L concerns about my personal safety. As Dr. Novick's intern hip was nearing an end, an "awkward week, ju t like a pivotal week when I decided to go to medical chool" helped him in deciding where to pursue hi residency training.

I had, for severaL months, doubts that I really wanted to stay in New York and I had just heard that there was an opening at the Royal Vic in Montreal. The Chief of Surgery. Dr. Maclean, had spoken to m.y dad, who still works there, asked how I was doing and mentioned that they had an opening for a second year surgical resident [equivalent to a PGY3 position] because of my experience in New York. I was by then engaged and my fiance (and subsequent wife) Terri was working in Montreal. In deciding to return to Canada, Dr. Novick turned down the offer of a Chief Resident position at Bellevue. During hi s re idency at McGill, Dr. Novick found time to also complete his Masters of Science degree in Experimental Surgery within cardiac urgery, ' and it was in that year that I decided ultimately I was intere ted in cardiac surgery." In fact, Dr. Novick started in the cardiac surgery program without even having a formal acceptance letter:

I remember very well Dr. Dobell, one of my mentors, walking dmvn to the Lab toward the end of my research year and said "Richard you've been doing great work, you've published a couple of papers already, and you 're going to

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be writing your Master's. Do you want to be a cardiac surgery resident in our program ?" I had been thinking about it for a few months and replied, " Well let me speak with my wife." Dr. Dobell replied, " Well if you want it it 's yours." "But don 't you have a selection committee ? Don 't I have to fill out an application ? Don 't I have to interview?" I asked. " Well here, shake my hand'' he responded. So I decided to go into cardiac surgery and in fact I never had any I'Vritten acceptance letter. But back then it was a different time. He gave tne his word, he shook my hand and told me I was in the program. Within a period of 4 years, Dr. Novick had written 12 fellow hip exam s which included Quebec, Canadian and American board exam in General Surgery, as well as Cardiac and Thoracic Surgery. It was al o a time of rapid change in the field of surgery with tran splantation starting to be offered a a treatment for conditions that previously proved fatal :

Those were early days of transplantation but at the Royal Vic there was a transplant progrmn and a very energetic transplant surgeon, Dr. Albert Guerraty ... We would do a transplant and I always peJformed the donor run to bring the heart back. Usually at the beginning Albert would sew it in; sometimes I would at the end. During the pivotal first f ew hours after transplant, we camped out with the patient and we took care of them 2417 f or 3 or 4 days. I would do two of the days, Albert would do one. It was a cataclysmic experience. We did 9 or 10 transplants during the time I was at the Royal Vic and all survived. To further develop hi s clinical and research interest in transplant urgery, Dr. Novick, with the help of hi s mentor Dr. Dobell, entered the tran splant fellowship program at Stanford University. Following hi s fellowship , Dr. Novick was offered a co nsultant position at th e Montreal General (a McGill-affiliated Hospital), but wanted to ee what other opportuniti e were availabl e.

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I sent a bunch of letters around to every centre in Canada. Dr. McKenzie from London responded and set me up for an interview. My youngest sister was a law student at Western so I stayed in her Cherryhill apartment. My interviews were arranged for the Monday morning with Dr. McKenzie, whom I met once at a meeting, as well as Dr. John Duff, who was Chair of Surgery. So I was at my sister's place and we went out .for supper on Sunday night when she told me, "I don 't feel so well." " What's the st01y, do you have food poisoning?" "No, no. I have pains. " She explained. I examined her and she had rebound in her right lower quadrant.. .So I scooped 1ny younger sister, who could barely stand up straight, into my rental car and brought her up to emerg at UH. The general surge1y resident cam.e and sure enough she had appendicitis and Dr. Duff was on call. I was supposed to have an interview with Dr. Duff at 7am on Monday morning and here we were past m.idnight on Sunday. All of a udden I wa n 't a surgeon anymore, but rather a family member in the waiting room.. So my sister got her appendix out and Dr. Duff came to m.e at 2am and said, " We found an inflamed appendix, eve rything 's good. " So I asked him. " Would you pref er to have the interview now? .. "No come back at seven. " I remember going back to her apartment and having a f ew hour of sleep before the interview. I was basically overwhelmed by what was available [in London] . First of all, I recognized that Dr. McKenzie would be an exceptional mentor, which he has been .for the past 19 years. The fo cus back then was transplantation - nwre transplants were being done here than in Montreal and it was all under one roof Even though I didn 't know a soul in London except for the people I had just met, I decided to com.e here and have never regretted that decision. When a ked about what factors influenced him to choose to become an academic cardiac urgeon:

Some people wish to be big volume cutters and they're better suited for community practice. There are others who place primacy on the academic m.ission. I also did a Graduate Certificate in Clinical Epidem.iology and Biostatistics and have always cultivated a wellrounded practice. I' ve done an intennediate volume of cardiac surgety cases but ha ve always had grants supporting laboratory or clinical research. The major difference benveen community and academic practice is that with the latter, 1) you have to be a teacher to medical students and residents. You spend a lot of time with the residents; they get to know us and we get to know them very well. 2) You have to make a valuable academic contribution. That makes for a very busy life professionally to the point where your career can be all-consuming. So balance, i it even pos ible?

If anyone in my position, for instance, with major academic, administrative, and clinical commitments tells you they've got a wellbalanced life, they're not being fully truthful. But you learn how to cope 路with innumerable demands and do the best you can. There are several ways to accomplish that and one is by delegating. My administrative assistant knows the way I approach issues, and handles administrative tasks in a proactive manner. In addition, my secretary has been employed by me since the onset of my practice in 1988 and runs a very efficient office. Furthennore, the residents and fellows work very hard. Academically, we have a clinical research associate who is very conunitted and knowledgeable.

Above and beyond the adm.inistrative, teaching, research and clinical work, many of us, myself included, have a larger responsibility to the field as a whole. I was the Associate Editor for the Annals of Thoracic Surgery for 10 years, which is one of the tvvo major publications in our field. Presently, I'm on the Royal College Cardiac Surgery exam. committee. You need to ha ve a supportive family, and that's not only a supportive spouse but also kids who understand. You need to have a lot of energy and be willing to wake up very early and be a rigorously efficient as you can with your tim.e. Even with highly capable people to delegate work to, it's still a scramble on a daily basis and you really don't have much free time. Complementing Dr. Novick' role as a leader, teacher, mentor and innovator i a clear recognition of teamwork and the contribution of others in helping the divi sion to succeed :

There's only so m.uch one individual can do so it's basically the team; cardiac surgery is the commensurate team sport. I'm very proud of our team. at all levels. We have state-of-the-art individuals including our bedside nurses, perfusionists, our residents who work vel)' hard, and of course my fellow faculty members, each one of whom has eve f)' rea on to be very proud of what they 've accomplished in their careers. Evetyone has m.ade a major contribution to this enterprise. For some the focus is clinical and technical excellence in surgery, for other it 's research, andfor other it 's teaching. Everyone has made a wondeJful contribution, 路which has made my job much easier. I'm very proud of the team.

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Thinking on Your Feet Atrial Septal Defects in Adults Todd Greenspoon, Medicine 2010 and Aiman Alak, Medicine 2011 Reviewed by Dr. Keith Finnie Atri al septa l defects (AS D ) are abn orma l co mmunica ti ons between the left and right atria all o wing mixin g o f the bl ood between the e two compartme nts. ASD are the econd mo t commo n conge njtal lesions in adults. Embryologicall y, the septum betwee n the atri a i made of eptum primum covering the ostium pri mum orfice, and the eptu m ec und um covering the ostium sec und um orfi ce. In 70 % of the popu latio n, these epta fu e. A pate nt fo rame n ovale ex i ts if the space is covered but the epta are not fu ed . An AS D exists whe n an open communicati o n exists between atri a. A large AS D can ca u e ex tra blood to acc umul ate in the ri ght atrium and ri ght ve ntri c le . Eventuall y, the hu nted fl ow causes ri ght ide di latati on, main pulmo nary artery enlarge ment, and increase in pulmo nary vascul ature . Most ASD are asy mptomati c in infancy a nd pre ent upon routi ne physical exa mi nati on. T he time it ta kes fo r symptom uc h a heart failure, genera lized edema, exerc i e in to lerance or dyspnea is in ver e ly re lated to the ize of the ASD. O n phy ical exami nation, the most co mmo n fi ndi ngs are a precord ia l bul ge, abnormal murmur , and ex traneo u heart so unds. T he most u e fultest in the identi fi ca ti on and q uanti fi catio n o f the AS D i an echocardi ogram (tran thorac ic or tran esophageal, with or witho ut Doppl er); ho wever, other in ve ti gati on includ ing ECG a nd chest radi ography may be uti li zed. Mechanical c losure i ind icated fo r pati e nt that develop sympto ms or have a large degree o f le ft-to-rig ht hun t. Hi tori ca ll y, surgical c los ure ha been the mainstrea m treatme nt, but recentl y percutaneou device have come to the fore front in the repair of ostium sec undum AS Ds because o f the ir excellent outcome and decrea ed peri operati ve morbid ity. T he tra nscatheter approach ha all owed e lderly patient and tho e wi th co- morbidities to undergo cl os ure o f their AS Ds and thri ve afterward .

Case A 19 year old tudent presented with an incidentally noted irregular heart beat. Pati ent worked out regul arly, but hi s aero bic endurance wa not th at great. He was not a smoker. He had no fa mily hi tory of congenital heart di sease. He did not take any medications, and had no all ergies. He had no pro blems w ith palpitati ons, li ght-headedne s, or yncope. He had no medical hi story. He weighed 76 kg. Hi blood press ure was 110170 mmHg. Hi s heart rale wa 62 beats per minute and reg ular. His seco nd heart ound was widely split and fi xed. Hi s murmur was described as a midsy tolic pulmonary ejecti on murmur. Che t x-ray revealed cardi omega ly du e to ri ght ventri c le enlargement. Echocardi ograph y revealed th at hi s ri ght atrium and ri ght ventri c le were moderately dil ated. Hi s ri ght ventricle had mildly reduced systo li c fun cti on, and co lor flow Doppler sugge ted left-tori ght shunting. Transesophageal ECG found a dilated ri ght atrium and ri ght ventricle, moderate ri ght ventricle global hypokinesis, and a 1 em o tium secundum atri al septal defect with left-to-ri ght shunting.

UWO M.I 77(2) 2008 36

Patient underwent a perc utaneou device closure. Arrangements were made fo r foll ow-up in 2 months.

Introduction Atrial eptal defects (ASDs) are the second most co mmon congenital lesio n in adults. A patent fo ramen ovale (PFO ) exi ts in 30-40 % of the normal adult po pul ation.' In an ASD, a defect in the in te ratrial eptum of the heart allow mi xing of the blood in the ri ght and left sides of the heart. The ex tent of he modyna mic and clinical signi ficance depends on the ex tent of shunting. Embryology: The moth er's placenta provides ox ygen for the foetus, o bl ood can bypa s the 2 lungs. In earl y weeks of ge tatio n, an orfice, o tium primum , exi ts between the atri a. Beginnin g in the 5th week, the septum prim um be~in s clos ing th_e orfice. Within thi s septum, an orftce call ed ostium secundum fo rms, which in tum beco mes clo ed by the eptum ecundum. The _septum ecundum does not co mpl ete ly seal, leavmg th e f~ram en ovale. The septum primum forms a fl exible fl op on the left side o f the foramen ovale. However, since the right atri al pressure i higher th an the left side, the fl exible

flap is pushed aside holding the foramen ovale open. At birth, expansion of the lungs and increase in systemic vasculature resistance reverses the atrial pressure gradient; the flap is held down and the interatrial hunt ceases. In approximately 70% of the population, the septa fuse after birth. A " probe patent" or " patent" foramen ovale (PFO) exists if the space is covered but the septa are not fused. A reversal of the interatrial pressure gradient or an intercardiac catheter can open the PFO. An ASD exists when an open communication exi ts between the atria.

Pathophysiology: Many types of ASD exist, but the pathophysiology is very similar? Normally, the left side of the heart has a higher pressure than the right side. A large ASD can cau e extra blood to accumulate in the right atrium and right ventricle. Pulmonary to systemic flow ratio can be as high as 8:1, while some patients can have a 5:1 ratio but be asymptomatic. Eventually, the shunted flow causes right size dilatation , main pulmonary artery dilation , and increase in pulmonary vasculature. Untreated, the inc rea es the size of the right ide of the heart can lead to heart failure. Any increase in the pressure in the left ventricle, such as by hypertension and coronary artery disease, worsens the left-to-right shunt. Overload of the right side of the heart, in tum, overloads the pulmonary vasculature, which leads to pulmonary hypertension. The pulmonary hypertension further overloads the right ventricle, called afterload, and results in the right ventricle to generate higher pressures to overcome the pulmonary hypertension. Potentially, the right ventricle fails or the pressure in the right side of the heart becomes higher than the left side. As the normal pressure differential between the right and left ides of the heart decreases, the hunting decreases. Eisenmenger' s syndrome describes the situation where severe fixed pulmonary hypertension caused by the shunt leads to elimination of the left to right shunt and bi-directional or right to left shunting leading to arterial desaturation and cyanOSIS. Types of ASDs: Many types of ASDs exist? Primum ASDs are typically associated with ventricular septal defects and/or A V valve malformations. Poor growth of the secundum

eptum or exce sive absorption of the primum septum is called secundum type ASD. Thi s type accounts for 70% of all ASDs, and i more common in female . It can be as ociated with other ASDs. Some patient have a family history of this defect. An abnormality in the insertion of the superior or inferior vena cava can form an interatrial communication outside the fo sa ovalis. This defect is called sinu s venosu ASD. When a part of the wall between the coronary sinus and left atrium is absent, the defect is called coronary inu ASD. A PFO is not a real ASD. It can be detected in 25 to 40% of normal adult hearts.3 PFO may be a famili al trait.

Management History and Physical Examination The vast majority of small ASDs are asymptomatic in infancy and childhood, and they are found secondary to hearing an incidental murmur upon auscultation of the chest. The minority of newborn s with small ASDs may present with mild cyanosis with right to left 4 shunting across the ASD. Typically small ASDs are not associated with a significant shunt and o may not be associated with a mUimur or any abnormal findings . Infants and children with larger ASDs may pre ent with hea11 failure , failure to thrive, or recurrent respiratory tract infections. 5 Patients with moderately ized ASD , if not corrected, will develop symptoms such as heart failure , hepatomegaly, generalized edema, atrial atTthymias, exerci e intolerance, or dyspnea later in life (usually before age 40) as the degree of left to right hunting increa es with age. 6 There are numerous physical findings associated with ASD . Children with an ASD may be small for their age, even in the absence of complications uch as heart failure . Upon palpation of the precordium there may be a precordial bulge, a right ventricular heave , or a palpable pulmonary artery at the second left interspace. During au sculatation of the heart commonly a widely spaced second left hear~ sound is present hypothesized to stem from the increase in pulmonary arterial flow and delayed closure of the pulmonic valve.7 This, however, is u ually absent in newborn because of a minimal left to right shunt. If the ASD is associated with

UWOMJ 77(2) 2008 37

pulmonary hypertension the pulmonary component of the second heart sound i louder than u ual. The u uall y split fir t heart sound mi ght be even more pronounced in patients with ASDs because of increa ed blood flow needed to occur across the valve. A variety of murmur may be associated with ASD primaril y or econdary to pulmonary hyperten ion.7 It is important to reali ze that the blood flow aero s the ASD contains in ufficient turbul ence to be au cultated. The prim ary murmur incl ude: a mid y tolic pulmonary ejection mu rmur becau e of increa ed fl ow thoro ugh the pulmonic valve, a mi d diastoli c mu rm ur econdary to increased flow across the tricu pid valve, a di asto li c murmur consi tent wi th pulmonary regurgitation becau ·e of pulmonary trunk dilatati on, and a y toli c ejecti on murmur be t heard over the lun g con i tent with increa ed flow th ro ugh the smaller pulmonary arteri es. Additi onall y, with pulmonary hypertension patient with ASDs may have additional murmur and ex traneous heart ounds. Other Investigations: In the evalu ati on of a patient with an ASD the most utili zed te t are the echocardi ogram, the electrocardi ograph , and the chest x-ray. Echocardi ograph y is the mo t useful te t fo r the di agnosis of ASD. Tran thorac ic echocardi ograph y is u uall y di agno tic; however, transe ophageal echocardiograph y can prov ide additi onal inform ati on regarding the ize of the defect and the other a sociated co ngenital anomali e . The vo lume of blood shunted, the shunt ratios, a we ll as pulmonary artery press ure can be mea ured with Doppler fl ow echocardi ograph y. Treatment: The two main indicati ons for surgical or percutaneou clo ure of the ASD are the development of sy mptom. or a large left to ri ght shunt. 4·8 The Ameri can Heart A ociati on reco mmends closure when the Qp/Qs i greater th an 1.5:19 , while the Canadi an Cardiac Soc iety recommends closure when the Qp/Q is greater than 2:1 , or greater th an 1.5:1 in addition to . Ie pu l monary hyperten .ton. 10 rever tb The traditi onal surgery performed for ASD repairs ha been a medi an sternotomy with Pericardi a! or Dacron patche , although a ri ght anterolateral ubmamm ary subpectoral approach

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may be preferred by women for cosmetic rea on . 11 • 12 There has been an increased use of minimally invasive urgery recently, as ~n alternative to surgery or percutaneou repa1r. Intraoperative tran esophageal echocardiography may be u ed to ensure proper closure of the defect. Po toperatively, beta blockers and anticoagulation reduce the ri k of atrial troke respecti vely. The fibrill ati on and perioperati ve mortality of such procedures approac he Om-;o. 13· 14· 15· 16 Over the long term, patients still have quite succe sful outcomes, e peciall y with ongoing medical therapy, with minor diffe rences in survival compared to the popul ati on, and minimal ri k of needing Minimally mva 1ve addi tional surgery. approache may reduce the perioperative morbidity and decrea ed hospital tay. Dr. K. Finnie add th at clo ure of the ASD does not reduce the incidence of recurrent atrial arrh ythmi a such a atri al fibrill ati on. (Personal co mmunicati on, 2008) The FDA ha approved two percutaneous devices, Ampl atzer Septal Occluder and the Cardi oSEAL eptal Occlu ion Sy tern th at may be u ed a an altern ati ve to treatment. 17 The benefit of a transcatheter clo ure are that the patient avo id cardiopulmonary bypa , thoracotomy, and atri oto my. The outcomes are exce llent and the tran catheter closure i largely replac ing surgical clo ure in orne center for the management of appro pri ate ASDs. Additionally th e peri operati ve morbidity, rate of co mplicati ons, and ho pita! tay may be reduced. The percutanou method of ASD clo ure will beco me the more preferred method of clo ure, e peciall y in elderl y patient or tho e with ignificant comorbiditie . 18•19 Thi nonoperative device clo ure onl y can be used in patient with o tium ec undum ASD (about 50-70 o of all A~Ds ) an~ i not u ed in pati ents with o tium pnmum, mu s veno u , or coron ary sinu atri al eptal defect . The ASD mu st al o be mall or moderately sized, ideally under 20 mm . Dr. K. Finnie adds th at defects up to 39 mm can now be repaired.(Per onal co mmunication, 2008). Conclusion Atri al septal . . defect (ASD ) are abnorm a1 co mmum catJOns between the left and ri ~:> ht atri a

allowing mixing of the blood between these two compartments. ASDs are the second most common congenital lesion in adult . Transcatheter closure of ASDs with the Amplatzer Septal Occluder and the CardioSEAL Septal Occlusion System are streamlining the way ASDs are man aged. Decreased hospital stay, decreased morbidity, and outcomes on par or better than with surgery are popularizing the minimally invasive procedure for the repair of pecific types of ASDs.

References 1.

4. 5.

We igers SE, Sutton MGJ. Pathoph ys iology and clinical features o f atri a l epta l defect in adults. UpToDate. 2007 Sep 2 1; 15.3. Sankaran VG , Brown OW . Co ngenital heart di ease. In: Lill y LS, editor. Pathophysio logy o f heart di sease. New York: Lippincott Willi ams & Wilkin s; 2007 . P. 37 1-396. Hagen PT, Scholz DG, Edwards WD. Inc ide nce and size of patent foramen ova le during the first 10 decades of life: An autopsy stud y of 965 normal hearts. Mayo Clin Proc 1984;59 :17 . We igers SE, Sutto n MGJ. Identifi cati o n of atri al septal defects in adults. UpToDate. 2007 Sep 2 1; 15.3. Andrew R, Tulloh R, Magee A, Anderson D. Atrial septal defect with fai lure to thri ve in infancy : Hidden pulmo nary vascular disease? Pedi atr Cardiol. 2002; 23:528. Rhee EK, Evangelista JK, Nigrin OJ , Erickson LC. Impact of anatomic c losure o n o matic growth among small , asy mpto mati c childre n with secundum atri al septal defect. Am J Cardi ol. 2000; 85:1472 . Muta H, Akagi T , Ega mi K, et al. Incide nce and clinical features of asy mpto mati c atri al eptal defect in school c hildren diag nosed by heart di sease screening. Circ J. 2003; 67: 11 2. Therrien J, DoreA, Gersony W , et al. CCS Consensus Conference 200 1 update: Reco mme ndati on for the manage me nt of adults wi th conge nital heart disease. Part I. Can J Cardio l. 200 1;17 :940 . Drisco ll D , Allen HD, Atkins DL, et al. Guide lines for eva luatio n and management of co mmo n congenita l

1O.

11 .

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19.

cardi ac prob lems in in fa nt , c hildren, a nd adolescents. A state me nt for healthcare pro fess iona ls from the Committee o n Congenital Card iac Defects of the Council o n Cardiovascul ar Di ease in the Yo ung, America n Heart Assoc iation . C irc ul ati o n. 1994; 90 :2 180. Vi ck GW UI. De fects o f the atri al septum inc ludin g atri oventri c ul ar septal defects. f n: Garso n A J r, Bric ker JT, Fishe r OJ, Ne ish SR, ed itors. Science a nd practi ce of pedi atri c cardi ology, 2nd ed . Wil li a m & Wilkin s: Ba ltimore; 1998, p. 11 4 1. Hopkins RA , Bert AA , Buc hh olz B, e t a l. S urg ica l patch closure of atri al septal defects. Ann Thorac S urg. 2004 ;77 :2 144. . Die tl CA, T orres AR, Fava loro RG . R1 ght subma mmari an thoracoto my in fema le pati e nts with atri al eptal defect and a no malo us pu lmo nary veno us connec ti o ns. Comparison between the transpectoral and subpectoral approaches. J Thorac Card iova c Surg. 1992 ; 104:723. Atti e F, Rosas M, Granado N, et a l. S urgica l treatme nt for ec undum atrial septal defect in patie nt >40 years o ld . A ra ndo mi zed c lini ca l trial. J Am Co li Cardiol. 200 1;38:2035 . Konsta ntinides S, Geibe l A, O lsc hewski M, et a l. A co mpariso n of urgical and medi cal therapy for atri a l septal de fec t in ad ults. N Engl J Med. 1995 ; 333:469 . Burke RP, Horvath K, La ndzberg M , et al. Lo ng-te rm fo ll ow-up after urg ical repair o f ostium primum atrial septa l defects in adults. J Am Co li Cardio l. 1996; 27:696. Fiore AC, Naunhe im KS , Kes ler KA , e t al. S urgical c losure of atrial septal defect in pati e nts older tha n 50 years of age . Arc h Surg. 1988 ; 123:965. Schwe tz BA. Co ngenita l heart defec t dev ices . From the Food and Drug Admini strati o n. JAMA. 2002 ; 287 :578 . Ingle is I, Landzberg MJ . lnte rve nti o nal catheteri zati o n in adult co nge nita l heart di ea e. Circ ul ati o n. 2007 ; 115 :1622. Du ZD, Hij azi ZM , Kle inman CS, et al. Compari o n urgica l c losure of betwee n tra n cathete r and ecundum atrial septal defect in childre n and ad ul t : Re ults o f a multicenter no nra ndo mi zed tri a l. J Am Co li Cardi ol. 2002; 39: 183.

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Zebra Files

Commotio cordis: an important cause of sudden cardiac death in young athletes Ashley Brown, Medicine 2011, ]erma Ashkanase, Medicine 2011, and Tiffany Kwok, Medicine 2010 Reviewed by Dr. Andrew Krahn Although a rare occ urre nce, co mmoti o cordis is the second most common cau e o f sudden cardiac death in young, hea lth y athlete . A slo w-moving proj ec tile (o ften a baseba ll or orne other sport eq uipment) trikes the co mpliant precordium of an affected pati ent immed iately be fore the T wave of the cardiac cyc le, ca using a premature ve ntricu lar con traction that induce vemri cul ar fibri ll atio n and cardiac arre t. Resusc itati on attempts are often unsucce sful and urviva l rate are o nl y 15 %. Thi revi ew outlines the path ophy io logy and epidemiol ogy associated with co mmo li o cordis, and addres es strategies that may help preve nt thi s lifethreatenin g occurrence.

Introduction Commotio cordi (CC), also termed "cardiac concussion" , i a rare but devastating event characterized by a eemingly inn oc uous blow to the chest followed by s udden death. 170 ca e have been reported in the U.S. Commotio Cordi Registry (USCCR) since 1996, almost all of whom are young male athlete with no pri or history of heart abnormaliti es or dy function. 1路2 Although it is relatively rare, the eriou sness of CC warrants investigation into it pathophys iology and ubseq uent indication for treatment and prevention.

Case Report Th e patient described by Maro n et. al. (2005 ) illustrates many key features present in pati ent affected by CC. A 22-year-o ld male who was not wearing any protective chest gear was struck directly over the precordium by a lacrosse ball. He was extre mely athletic, had no prev iou Iy reported health problems, and weighed 185 lb . After bein g stru ck, he stumb led two teps and fe ll to the ground . A trai ner immedi ately ran onto the fie ld, determined that a pu lse wa. absent, and initi ated cardi opulm onary res u. citati on (C PR ). A sports med icine physician quickly entered the scene with an automated ex tern al defibrillator (AED) which detected ventricular fibrill ation (VF). T he AED deli vered an appropriate defibrillation hock of 2001 within 2 minutes of the athlete's collap e. Thi s successfully terminated the VF and advised no further shocks, however th e man's pulse did not return , and CPR was continued by bystander

UWOMJ 77( 2) 2008 40

and 5 minutes later by paramedics. The man was later pronounced dead in the emergency department, approximately 1 hour after coll apse. A che t x-ray revealed no rib fracture or other injurie , and an echocardiogram revealed no tructural abnormalitie of the heart. 3 A in the preceding case, most ca es of CC in volve a yo ung male being truck in the chest during an athletic event, immediately initiating VF. Resuscitatio n i un uccessful m 4 the vast majority of case . A case of co mmoti o co rdi s wa een m London over 10 years ago. Attending phy ician Dr. Andrew Krahn recount , "a young healthy trucker, fat her of 2, [was] ti ghtening his load with a cheater bar (bi g teel ratc het like bar for the strap winch on a tran port truck)... at Wellin gton and the 401. [He uffered a] minor blow to the che t [with a] long delay to the ambul ance." Unfortunately, thi man ultimately suffered the arne fate as many commotio cordi pati ent and di ed befo re the ambulance reached 5 him.

Pathophysiology The pathophysiology of CC is not entirely understood, although M adi as et al. (2006) have dev ised a possible model to exp lai n it occurrence. It ha been widely ob e rved that key factors mu st ali gn in order to cause CC: a sufficient but not exce sive force mu t strike the precordium of a relatively compliant che t wall just prior to the peak of the T-wave of the . card tac eye le 1,2.6 ( ee p路tgure 1). The force strikin g the co mpli ant che t wall causes a rapid

increa e in pressure within the left ventricle. This tretches the myocardium and activate mechano-sensitive ion channel , re ulting in a rapid influx of potassium ions and consequently a premature depolarization of the myocardium. This alone would cause depolarization of a ingle beat, but would not be sufficient to cause a u tained arrhythmia. However, within a period a few milliseconds (15-30ms) before the peak of the T-wave, so me of the myocyte of the left ventricle can be depolarized , while others are till refractory and are therefore unable to be depolarized. Depolarization of only a portion of the left ventricular myocardium results in nonimultaneous excitation, and thus fibrillation, providing a 15ms window of vulnerability within 7 the cardiac cycle. When one is struck directly over the heart, the force i transmitted significantly within the chest cavity due to mechanical compliance of 7 their che t wall. If the impact is at exactly the rioht time within the cardiac cycle, non-uniform b depolarization of the myocardium occurs, re ulting in sustained VF and consequently sudden death. It i important to note that structural damage to the heart and urroundin g ti sues is not present in cases of CC due to the low velocity of impact8 ; the pressure wave that is transmitted to the left ventricle is the basis of the pathology. CC may occur in any healthy heart. 9 Athletes are more commonly affected because they are at greater risk than the average per on of sustaining a blow to the chest wall. Young people are more commonly affected due to increased compliance of their chest wall, transmitting the force to the left ventricle more easily than adults. Other than these two indirect risk factors, CC requires no predisposing features. It can theoretically happen to anyone, but it is rare because very specific factors mu st align within an extremely small window of opportunity.

Population at Risk

The specific factors that coalesce to tngger CC place a fairly narrow demographic at ri sk: commonly, young male athletes appear to be the most susceptible. Indeed, an analysis of 128

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ca e in the USCCR performed by Maron et al. (1999) reported that 62 % of the events occurred in male athletes of median age 14 years during sporting competitions. This finding may be due in part to sport' increased ri k of projectiles, especially those that are rigid and/or possess a den e core such as baseballs and hockey puck , hitting one's chest as well as the increased chest wall compliance of young athlete described above. 9 It is impottant to note that CC can occur in non-athletes a well. The USCCR has recorded cases in which CC wa induced fo llowing chest contact during uch seemingly harmless event a horse-play, being struck with a snow aucer, and a family pet colliding with a 8 ch ild 's chest. While these instances are thou ght to be uncommon , they emphasize the point that CC can affect almost anyone if all the etiological factors are present.

Strategies for Prevention Though cases of CC are considered to be rare overall, there has been an increased incidence of reports over the past two decades as recorded by 8 the USCCR. Survival rates are dismal at approximately 15%. In athlete this condition has become the seco nd mo t common cause of

UWOMJ 77(2) 2008 41

8 11

in tant death. ' Since several factors are in volved in the eti o logy of CC, everal meas ures may be taken to reduce the incide nce of thi s Both e mergency medical tragic occurre nce. techniques a nd porting apparatu s mu st be examined and improved upon to reduce the ri ks of deleterio us effect for athle tes. M edi cal profe ionals pre ent during sportin g event well trained in sho uld no t onl y be cardiopul mo nary re u citatio n and defibrillatio n techni que, bu t should al o be edu cated regarding the necessity of qui ck re po n e whe n CC is u pected. It is thought that as i tance within 3 of collapse may improve the minu te or le outco me fo r so me pati e nts altho ugh it i not a guarantee of succe s, as ev ide nced by the athl ete in theca e tud y. M ethods of alte rin g po rting equipme nt and protecti ve gear to reduce the ri k of CC fo r athlete have been uggested, most prominently fo r baseball and po rt requmn g c hest 8 The implementati o n of ofter pro tectors. ba eballs was proposed, but met with oppositi on fo llow ing tri al th at de mo nstrated alte red bo unce and velocity. B a eball of an inte rmedi ate den ity have been develo ped and are c un·entl y being evalu ated as a co mp ro mi e between afety and the integrity of the game. C he t protectors have fall e n unde r scrutin y fo r bo th th eir co mpo iti o n and the ir fun cti o nal capac ity. In a tud y conducted by Doere r et al. (2007 ) examining c hest protectors, 38% o f the affli cted athl etes were wearin g a pproved pro tecti ve c hest padding. It ha thus been suggested th at the dens ity and its distributio n within the protecti ve gear be alte red to prov ide additi o nal defense. 8 It 1 also relevant to note th at of th e athlete. wearin g ches t protectors, 25 o f 32 ex pe rie nced di pl aceme nt of the ches t pro tector during the 12 cour e o f game pl ay. A more effective mean of keeping the pro tecti ve gear over th e cardi ac silho ue tte ho uld be dev ised.

Conclusion Co mmo ti o cordi s, tho ugh rare, i a partic ul arl y deva tatin g cause of fa tality th at predo minantly affect health y yo un g male athle te . It is cau ed by a proj ectil e striking o ne's compli ant precordium mo ments be fo re the T wave and causes ve ntri c ular fibrill ati o n th at may not

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re pond to re uscitation . The ri sk of phy ical and projectile contact inherent to sporting compe tition enhance the likelihood of usceptibility in athle tes, but non-athletes may also be affected if the etiological factors converge. Althou gh CC is considered to be a relatively uncommon e ve nt, its ris ing incide nce and tragic consequence nece sitate increased awareness and preventive effort on several levels.

References Maro n, B .J ., Doerer. J.J., Haa , T.S ., Estes, N.A.M . III , & Link, M .S. (2006). Historica l observati o n on commoti o n cord i . Heart Rhythm , 3. 605-606 . 2. Va lani , R., Mi krog iana ki s, A., & Go ldma n, R.D . (2004 ). Cardiac conc u io n (co mmoti o cordis). Canadian Jou. rna l of Emergency Medicine, 6, 428-430 . 3. Maron, B.J ., We ntzel, D.C., Zenovic h, A.G ., E te , N.A.M . III , & Lin k. M . . (2005). Death in a young athl e te due to commo tio cordi de pile prompt ex ternal defibrill a ti on. Heart Rhythm, 2, 99 1-993 . 4. Maro n, B.J ., Gohma n, T.E., Ky le, .B ., Este , N .A. M . III, & Lin k, M. . (2002). C linical pro fil e a nd spectrum of co mmoti o cordis. Journal of the American Medical A sociation, 287, 11 42- 11 46. 5 . Krahn , A. Re: o mmoti o Cordi s Arti c le [Inte rne t, per o nal e-mai l]. Me age to: Tiffany Kwo k. 2008 Jan 29 . 6. McCrory. P. (200_)_ Commotio cord i : In tanta neou card iac arre t caused by a b low to the c he t de pe nd on the ti mi ng of the b low re la ti e to the cardi ac cyc le. British Journal of ports Medicin e, 36, 236-237. 7. Madi a . C. . Maro n. B.J .. We in stoc k, J ., E tes , N.A. M . Ill , & Link , M. . (2007). o mmoti o cordi s: Sudde n dea th with c hc ·t wa ll impact. Jou rnal of Cardio1•ascular Electrophy iology, 18, I 15- 122 . 8. M adi as C e t al. Commoti o Cordi . Indi a n Pac ing Ele trop hy io l. J. 2007 Oc t - Dec; 7(4) :235 -45. 9 . Maro n, B.J ., Lin k. M . ., W a ng. P.J ., & E tes, N .A. M . Ill. ( 1999). lin ical profi le of commo ti o cord i : n under ap preciated ca u c or · udde n death in the youn g dunng . port a nd o th er acti viti es. Journal of Ca rdwFascular Electrophysiology, 10. 11 4- 120 . 10 . Thomp o n, J .F. (2007) . Exam 1 RevieiV: Chapter 18: Cardw c cycle IWe bpage] . Re tri eved Decembe r 4 2007, fro ~ htt~ : //www . aps u .ed u/th o mp so nj / A na to my91 20&% 20P hy IOiogy/2020/2020%20Exam%20Rev iews/Exa m %2 0 I /Cl-1 18%20 ard iac %20Cyc le. htm II . Link . MS a nd_ E~te M . M echa ni ca ll y ind uced ventn c ul ar fi bnll all o n (c mmoti o cordi ). Heart Rh ythm . 2007 Apr: 4{4) : 529-32. 12. Doerer . J, e t al. Eva lua ti o n o f C hc t B arn·e r raor Protecti . o n Aga in t Sudde n D eath Due t o mmOti·O Cord1 . Am J Ca rdi o l. 2007 Ja n; 99 : 857-9 . I.

Feature Article An overview of using cost-effective measures in preventing cardiovascular disease Dinesh Bhayana, Medicine 2010 Reviewed by Dr. John Feightner Cardiovascular di ea e carries a worldwid e economi c burden hi gher than any other chronic di sea e. The ag in g populati on of developed nations have pl ayed a maj or ro le in the rapidl y increa ing the cost of deli verin g hea lthcar e. In order to continue providing public healthcare to all citi ze n , the Canadi an government mu t loo k beyo nd increas in g pending and focu on the appropriate alloca tion of available reso urces . Cost-ef fec ti ve meth ods o f hea lthcare deli very should be con idered as a mean o f reducin g the gro win g eco no mi c burden o f cardi ova cul ar di sea e and other chroni c di seases. Preventi o n of cardiovascu lar di ease has hown promi se as a co. t-e ffecti ve too l in the ex isting literature. Further investi gation is required to develop a clear pi cture o f the rol e that preventi on will pl ay in reducing co ts and delivering high quality healthcare to Canadian s. H owever, the exi stin g evidence should co mpel current and f uture phy ician to appreciate the increasingly important rol e that cost-effective analy es will pl ay in shaping the future o f our healthcare system.

Introduction Healthcare spending by the federal and provincial governments in Canada has come under crutiny in recent years. Public discontent and nation-wide anxiety have surfaced a the co t of delivering healthcare climbs higher. Once a solely economic and political issue dealt with by policy makers in Ottawa, the topic of healthcare pending is now seen in newspaper and magazines in homes acros the nation. It has long been recognized that among the reform s needed to revive public support of Canadian healthcare, control of spending must be a priority. To this end, health policy makers should systematically addres each determinant of government spending that can be manipulated. The three factors mo t influential in determining healthcare pending in Canada are provincial revenue, federal transfer , and the percentage of 1 the population over the age of 65. While provincial revenue and federal transfers can be controlled politically by manipulating fiscal policy, the aging population is of concern to the medical community. The mechanism by which the aging population exerts its effects on healthcare in developed nations, Canada included, is the increased economic burden of chronic disease? Thus, it is of utmost importance that medical practitioners understand the nature of chronic diseases and ubsequently apply government resources in a cost-effective manner.

In 2001 , the two leading causes of death and disability in developed nation were of cardiovascular origin. 3 Ischemic heart di ea e and cerebrovascular di ease ranked fir t and second among t a variety of chronic conditions that carry a large economic burden. The most recent report by the Public Health Agency of Canada estimated the economic burden of cardiovascular disease (CVD) in Canada to be over $18 billion in 1998, an increa e of nearly 4 12% since 1986. This escalating cost to healthcare and society includes direct cost from hospitals, physicians, procedures, and medications, as well as indirect costs from disability and premature mortality. Cardiovascular disease is a pnme example of the pre sure that chronic di ease places on healthcare spending. Patients may require immediate high-quality radiographic imaging, procedural intervention , and orne Furthennore, CVD length of hospital stay. patients often require chronic maintenance by a multi-drug regimen , routine follow-up including blood work, and an array of behavioural interventions aimed at reducing the ri k of recurrence. It has been established that the ri k factors implicated in CVD are modifiable prior to the on et of disease and can reduce the ri sk of ~ first . eve nt and the need for costly 5 ~ntervent~ons. Thus, prevention of CVD by mtervent10ns of proven efficacy, a outlined in 6 the literature , should decrease the overall burden

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of thi costl y di ease. This logic ha been pro moted by health professionals for some time bu t ha onl y recentl y begun to manife tin policy changes. Thi likely due to the fac t that preventi on strategies are, unlike curati ve trategies, characteri zed by immedi ate costs and delayed benefits.7 Using data fro m cost-effecti ve analyse to develop practice guideline i currently a complex undertakin g due to inherent li mitatio n in the publi hed li teratu re. The wide variation between studie in the in terventi on cho en, methodology and interpretation ha made it d iffic ult to im plement the ir recom mendations. However, by recogniz in g that eco no mically sound in terventi on exist, current medical tude nts and practi tioners can face govern ment pre sure to prov ide cost-effecti ve healthcare with innovati ve approache .

Overview of the evidence for cost-effective prevention Prim ary prevention i characteri zed by measures that decrea e the likelih ood of a fir t occ urrence of the di ease th ro ugh health pro motio n, c reening for ri k fac tors, and ri sk fac tor mod ification.7 A particular et of guideline for primary preventi on of C YD 6 li ts ri k facto rs that can be modified in several ways including health pro moti on, poli tical acti on, pharmaceuti cal intervention, and behavioural modi ficati o n. H yperlipidemi a, hyperten ion, and cigarette smokin g are modifi able ri sk factors with a variety of interventi ons th at are costeffecti ve if used approp riate ly. The most costeffecti ve ro ute of ac ti on is often attained by choo ing in terventi on ta rgeted at the ri k profil e of the ind ividu al patient in questi on. Therefore, know ledge of co t-effecti veness i imperati ve to th o e developin g and impl ementing appro priate preventi on guidelines. The reducti on of serum cholesterol leve ls thro ugh primary preventi on has been show n to reduce the ri sk of an adverse cardi ovasc ul ar event. 6 HMG -CoA reductase inhibitors (statin ) and di etary modi ficati on are effecti ve tool in lowering levels of erum low density lipopro tein (LDL) in many populati ons, but their roles as a cost-e ffective means of preventin g CVD vari e by ri sk subgroup. In a rev iew o f cost-effective analyses, autho rs fo und that tatin therapy is

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nearly 4 times more cost-effective in the primary prevention of CVD in men with elevated erum LDL and three other ri k factors than in men with serum LDL elevated to the same degree and no other risk factor present. Statin therapy in both these po pul ations of men was still considered cost-effecti ve, while initiating therapy in yo un ger women with erum LDL elevated to the ame degree and no ri sk factor 8 was not cons idered cost-effecti ve. The initiation of a low-fat, low-chole terol diet throu gh physician counseling and mass- media health pro moti on has al o been shown to be co teffecti ve in certain risk subgroup . In an evaJu ati on of guideline fo r LDL target , authors de termined th at employing dietary modification as a primary preventi on mea ure i co t-effective fo r nearl y all men regardless of ri sk subgroup and wo men over the age of 55 .9 Hyperten ion can harply increa e the ri k of C VD when multiple ri k factors are pre ent, hence the need fo r aggressive therapeutic target .6 In a large cost-effective analy i tud y of a number of diffe rent risk fac tor intervention , two hyperten ion the rapi es howed pro mi ing re ult . While deemed generally co t-effecti ve in multiple ubgroup of on particular tud y, initi atio n of a B-blocker and diuretic regimen wa fo und to be con iderabl y more co t-effecti ve in pati ents with a y tolic blood pre ure of greater than 160mmHg when co mpared to those with a ystoli c blood pre ure of 140 to 159 mmHg. A lso, the introducti on o f po pulation-wide legi lati on to decrea the alt co ntent in proces ed foo d proved to be extremely co t-effecti ve in reduc in g CYD-induced di abili ty re lated to hyperte n io n. 10 Although the adver e health effects o f cigarette smoking are le s spec ifi c to C YD than hyperlipide mi a and hypertension, moking ce.. ati ~n l s of hi gh ptiority in primary prev~n.t w n . In o ne tud y, moking ce ati o n by ph ysic ian counselin g wa fo und to be a mo re cost-effecti ve approac h to primary preventi on of C YD than therapy fo r hyperlipide mi a o r h . 8 yperte.n 10 11 . ~h e ma s medi a approach o f promotmg moking ce . ati on wa fo und to be less cost-effecti ve than ph y ician coun ' eli no to those pati ents with more th an one oth r ~i k factor. Al o, moking ce sati on wa found to be

le cost-effective than dietary modification m the overall prevention of CVD. 12

Discussion There exists a strong body of evidence for the cost-effectiveness of measures in CVD prevention. Despite the difficulties in clinically applying co t-effective analyses, the current body of literature ha provided a solid basis upon The which further investigation can build. overview provided here illustrates the importance of targeting groups of patient based on their risk profile and utilizing appropriate primary prevention measures to modify ri sk factors . While cost-effective tools for primary prevention should be used, each intervention has a threshold of risk subgroups outside of which it is no longer cost-effective. Thus, the use of a single prevention algorithm would result in overshooting prevention and wasted resources or under hooting prevention and increased disease burden. An adaptive and patient-centered approach i necessary to pro peri y apply preventive measures to the variable population of individuals at ri sk for CVD. While CVD currently accounts for the greatest economic burden to the healthcare system, a preventive revolution aimed at modifiable risk factors in the Canadian population will likely have widespread influence. The risk factors for CVD are implicated in a wide array of chronic di seases including respiratory, endocrine and hepatic conditions, as well as a number of malignancies. As the burden of these chronic diseases continues to put pressure on the healthcare ystem, the need for a strong preventive medicine agenda becomes increasingly apparent. The role of economics in understanding the effective use of prevention will continue to grow a challenges in modeling and investigation are overcome. Thus far, current and future practitioner should be aware that research supporting the cost-effectiveness of primary prevention in CVD exists and that studies in this field may soon move from balance sheet to bedside.

References I.

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11.

12.

Di Matteo L, Di Matteo R. Ev ide nce on the determina nts of Ca nadi an provincia l government hea lth ex pe nditures: 1965- 199 1. J Hea lth Econ 1998 ; 17:2 11 -228. Mathers C, Lo ncar D. Proj ecti o n o f glo bal mortality and burden o f di sease from 2002 to 2030 . Pl oS Med 2006; 3:e442. Lopez A, Mather C, Ezzati M, el. al. Gl o bal and regional burde n of di sea e and ri sk factors, 2001 : yste mati c ana lys is o f popul ati o n hea lth data. Lance t 2006 ; 367: 1747-57 . Public Health Agency o f Ca nada . Econo mi c Burden of Illness On-Line [Internet] . 200 I [upd ated 2003 Jun 11 ; c ited 2008 Jan 10] . Ava il able http://ebi c-fe mc. hcc.gc.ca. Grover S, Paquet S, Levinto n C, el. al. Estimating the benefits o f modifying ri sk factors o f cardi ova cul ar di sease. Arch Intern Med 1998; 158: 655-62. Pear on T, Blair S, Danie ls S, et. al. AH A g uide line for primary preventi on of cardi ova c ular di ea e and stroke: 2002 update. Circ 2002; I 06:388-9 1. Schwappach D, Boluarte T, Suhrc ke M . The econo mi c o f primary preventi o n of cardi ova cul ar ys te mati c revie w o f econo mi c di sea e - a evaluati o ns. Cos t-e ffec ti ve nes and Resource All ocati o n 2007 ; 5: 5- 18. Probstfi e ld J . How co t-effec ti ve are ne w preventi ve trategie for cardi ovascular di sease? Am J Cardi o 2003; 9 1(10):22-27. Pros er L, Stinnett A, Goldman P , et. al. Costeffective ness of cho le terol-lo werin g therapi es according to selec ted patie nt characteri tics. Ann Intern Med 2000 ; 132(10): 769-79. MuiTay C, Lauer J, Hutubes y R. Effecti ve ness a nd costs of interventi o ns to lo wer ystolic bl ood pressure and choles terol. La ncet 2003; 36 1: 717-25. World Health Organi zatio n. Di sability adjusted life years (DALY) [Internet] . [cited 2008 Jan 12]. Ava il abl e http ://www. who .int/healthinfo/boddaly/en/ Brunner E, Cohe n D, T oon L. Cost e ffec tive ne o f cardi o vascular disease pre ve nti o n strategie . Publi c Health Nutriti o n 2001 ; 4(2 B):711-J5 .

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Feature Article Health Canada Ban on Ephedrine - A Post-ban Assessment of Effectiveness Is/w inder S. Chattha, Medicine 2011 Reviewed by Dr. David Masse[ Ephedrine i the pharmacolog icall y active alkaloid found in extracts from the Ephedra genu of shrubs nati ve to Central A ia. It pharmaco log ica l propertie have been put to u e in variou weight-lo s products, athletic enhancer s, deconge tants and bronchodi lators. D ue to i t primaril y negati ve card iovasc ul ar effec t , an inco mpl ete ban ha bee n pl aced by Health Canada on ephedrine u age, whi ch i now restricted to use so lel y in nasal deconge ti ves and re tri cted to 8mg doses. Ephedri ne bans have been ucce sfu l i n reducing ephedrine ales, however it ha not bee n effecti ve in changing the widespread beliefs o f co ll ege tudent or eli mi nating ill egal ephedrine u age. T he ban also doe not take into accoun t the ynergi tic effect of ca f feine and ephedrin e. A dd iti onal re earch into the ynergi sti c effects of ca ffeine and ephedrine should be conducted in order to address the need o f a full ban in order to protect again t cardi ova cul ar co mplicati ons.

Introduction Governmental restnctiO n on the usage of pharmacologically ac ti ve ub tance can be tri ggered by newly uncovered scientific ev idence, increasing public awareness, politi cal moti vation , or a co mbination of these factor among others.u Post-re tricti on data JS co mmonl y lacking in regards to effecti venes o f po licie , implementation, and regul ati on. Thi article a esses the po t-re triction literature in regards to the 2001 Health Canada re tricti on on the usage of ephedrine to determine the effecti veness of the inco mpl ete ban. Ephedrine i the pharmacologicall y acti ve alkaloid found in ex tracts from the Ephed ra genu s of hrub nati ve to Central A ia. Ephedrine is a sym(1ath omimetic amine, whi ch exert it affects primaril y th ro ugh interacting with a - and ~ -adrenergic receptors which medi ate sympath eti c responses. It also stimul ate the release of endogenou catec ho lamine and inhibit there reuptake fro m the synapse. 3 Ephedrine' s ac ti on on the 路ympatheti c nervo us sy tern have been put to use in vari ous weightlo product , athl eti c enh ancers, concentrati on 4 aids, deconge tants and bronchodil ators. Several adverse cardi ac event have been docum ented from ephedrine usage: the mo t evere includin g myocardi al infarcti on, troke, and sudden death .5 In 200 l , after 60 adverse events were reported in Canada, Health Canada restri cted the sale and dosage limit of ephedrine products. Eph edrine is now authori zed for u e

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onl y as a na al decongestant and at a maximum dose of 8 mg with no more than 32 mg in a 24 hr pen.o d .6 It i important to a ess the change in ephedrine u age and ephedrine-related adver e events after th e re tricti on has been put in place in order to evalu ate the effectivene of uch legislati on as it is a co mmon form of prevention. This article look at the literature co ncerning ephedrine re lated adver e event and epidemiological data in order to asses the rati onale and effecti vene of Health Canada ' s inco mplete ban on eph edrine products.

Pharmacological Properties Ephedrine' ympatho mimetic effec t are medi ated th ro ugh interac tions with a - and ~ adrenergic receptor . It al o timulate the re lea e of endogenous catecho lamine from neuro ns through increasing the number of ve icle relea ed during each action potenti al and al o delays their reuptake fro m the synap e It affinity to ~ -receptor is greatest for ~1 followed by ~2 then ~3 recepto rs. 7 Ephedrine produces positi ve ionotro pi c e ffect and chronotropi c effects. It i a powerful vasocon trictor and i arrythmogenic. Ephedrine readil y eros e the blood-brain bani er produc in g central nervo us y te m effect resembling tho e o f a mphetamines. Ephedrine has an 85% bioavail ability, half life o f three to ix hours, and IS removed through renal excretion. 8

Adverse Effects Before ephedrine re triction were put in place in the US , The American Association on Poi on Control Centers, in 2003, reported that ephedrine related adverse events accounted for more th an one-half of all reported dietary supplement related adverse reaction while ephedrine product ales accounted for less than 1% of the 9 marketplace. This di sproportion highlights the concerns regarding ephedrine usage. The mo t common reported adverse event a ociated with e~hedrine usage is hypertension and tachycardia.' Ephedrine use has al o been associated with both i chemic and hemorrhagic stroke, cardiac arrhythmias including ventricular tachycardia, coronary vasospasm, acute myocardial infarction, tachycardia-induced cardiomyopathy, and udden death . 11 Effectiveness of Incomplete Ban Ephedrine products have seen increasing use in the past two decade for the unapproved purposes of weight loss and improved athletic performance. Ephedrine increase the rate of weight loss by 0.6 kg per month in comparison to placebo. When combined with caffeine, the rate increased to 1.0 kg per month greater lo 12 than with placebo. In the athletic arena, ephedrine and caffeine alone do not have significant effects on oxygen consumption, carbon dioxide production, or time to exhaustion in comparison to placebo. However, when taken in ~ombination, ephedrine and caffeine have shown to produce up to a 20% to 30% increa e m athletic performance as seen throu gh imr>rovements m run times and trengthtrai)1ing.1 3 Although Health Canada has limited the dopage of ephedrine, when taken in combination with caffeine, a low dose can produce effects mjmicking those of moderate (30-40 mg) to high 14 d~sages (70-80 mg) of ephedrine. This is of p,articular importance as ephedrine combined y;ith caffeine produces greater weight loss and fmproved athletic performance, the primary reason for u e among females and males, . 1y. 15 respective The protective action of the 8 mg per dose, 32 mg/day maximum dosage has been found to have limited value as The As ociation

of Food and Dru g Officials (AFDO) states that serious adver e effects to ephed rine products 16 may occur at do age of 24 mg per day. Lifethreatenin g adverse reaction s have been reported 17 to occur with doses of 1 to 5 mg. AFDO is also concerned that setting a dosage limit may fa lsely imply th at a safe dose exists. Several States in the US have issued a complete ban on ephedrine products. This legi lation res ulted in a significant reduction in methamphetamine usage (prod uced by ephedrine throu gh che mi cal reduction) a well a 18 methamphetamine related hospital admissions. Ephedrine ales through retail outlets have al o dropped si nce the ban. 19 In 1997, National Collegiate Athletic A sociation (NCAA) iss ued a ban on all ephedri ne co ntaining sub tance . Desp ite these bans, studies have shown an increasin g trend in ephedrine usage amongst college athletes. In 2001 , a study of NCAA athletes howed ephedrine usage at 3.9%. 20 Usage has been ri ing since 1991 , and continued 21 to rise even after the ban was put into place. A 2006 study by Bents and M ar h (22) showed th at among members of an NCAA hockey team, 59 .0% reported that the ephedrine ban would make them less likely to use the substance, while 40.3% reported that they would u e banned substances to play at hi gher level. De pite the restrictions placed on the usage of ephedrine, ephedrine products are easily obtainable throu gh products so ld a nasal decongestants or via the internet? 3 Federal authoritie are getting involved a ephedri ne can be chemically reduced to produce methamphetamines. During 2006, the most frequently smu ggled prec urso rs fro m other countries into Canada was ephedri ne. Approximate ly 33.8 million ton s of imported ephedrine is b in g used by manufacturer each year to create non-methamphetamine product for sale in Canada? 4

Conclusion With the negative cardiovasc ular effects of ephedrine use, there is a clear methodol ogy behind the ban of ephedrine substances. Although Canadian data do not currently ex ist, US data pre- and post-ban has hown th at although the legislation has not completely

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eliminated non-approved usage, it ha decreased its overall incidence however not among select popul ati on such as college athletes. As urvey re ults have shown, ephedrine u age most co mmonly begins during hi gh schoo1. 25 Further reducti ons in use may be attain able through educati on of the adverse effects ' bein 0u implemented at the high schoo l and college levels, targeting those e pec ially at risk fo r ephedrine usage: athletes and weight conscious individuals. The cardi ovascul ar co mplicati ons of ephedrine use in co mbin ation with caffein e, requi res further scientific research as few tudi es exist on thi s topic. If a synergi tic effect on producing cardiovascular compli cati ons is repeatedly fo und such as tho e shown by Persky et al. (26), the 8 mg per dose guideline hould be reconsidered. Cardiovascular events are bein g reported at do age lower th an 8 mg. The benefits of usi ng ephedrine in ph armaceutical products need to be weighed against the risks associated with its use, both pharmacological and no npharmacological, as over the counter medications are a source of ephedrin e use fo r 7 non-approved purposes ?

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Persky AM , Berry NS, Po ll ack GM, Brouwer KLR . Modelling the card iova c ul ar effec ts of ephedrine. Brit J Clin Pharrn . 2004; 57(5): 552- 62. 4 . C upp, MJ. Herba l remedi es: adverse e ffect and drug interacti ons Am Fam Ph ysic ian. 1999 Mar;59(5 ): 1239-44. 5. Woo ltorton E, Sibba ld B. Ephedra/ephedrine: card iovasc ul ar and CNS effec t . CMAJ . 2002 Mar; 166(5):633 . 6. Natural Hea lth Products Direc torate. Natura l hea lth products co mpli ance gui de. Ottawa (ON): Hea lth Canada; 2007 Jan. Report No.: 0-662-4403 1-5. 7. Per. ky AM, Berry NS, Po ll ack G M, Br uwer KLR . Modelling the card iovasc ul ar e ffec ts of ephedrine. Br J C lin Ph armaca l. 2004; 57(5): 552- 62. 8. Per ky AM , Berry NS, Po ll ack GM, Bro uwer KLR . Mode llin g the card iovasc ul ar effects of ephedrine. Br J Clin Ph armaca l. 2004; 57(5): 552-62.

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Bent S, Tiedt TN, Odden MC, Shlipak MG. The relati ve sa fety of ephedra compared with other herbal products. Ann Intern Med . 2003; 138:468-71. Dhar R, Stout W , Lin k MS, Houmo ud M K, Wei nstock .T, MarkEstc NA . Card iovascul ar toxic iti es o f pcrformance-e nh ancig s ubstances in sports. M ayo C lin Proc. 2005 Oct; 80( 10):1307- 15. Shekell e PG,hardy ML, Morton SC, Magli o ne M , Mojica W A, S uttorp, M.T , Rhode SI, Jungvig L, Gag ne J. Effi cacy and sa fety of ephedra fo r weight loss and athl eti c performance - a meta-anal ysis. .TAMA . 2003 Mar;28( 12): 1537-45. Shekell e PG. hard y ML, Morto n SC, Mag lio ne M , Moj ica W A, S uttorp, M.T , Rhode SI, Jungvig L Gag ne J. Effi cacy and safety of ephedra for we ight lo and athletic perfo rmance - a meta-a nalys is. JAMA . 2003 Mar;28(l2): 1537-45. Shekell e PG,hard y ML, Morto n SC, Mag li one M , Mojica WA, S uttorp, MJ , Rhodes Sl, Jungvig L, Gag ne J. Effi cacy and safety of ephedra for weight lo s and athl etic perfo rmance - a meta-ana lys is. JAMA. 2003 Mar;28( 12): 1537-45 . Persky AM, Berry NS , Po llac k GM , Brouwer KLR . Modelling the cardiova c ul ar effec ts of ephedrine. Br J C lin Pharmacal. 2004:57(5):552-62. Peters RJ, Ada m LF, Barnes JB , Hines LA, Jo nes DE. Krebs KMA, et al. Be liefs and ocia l norms about ephedra onset and perce ived add ic ti o n a mo na0 co lleae 0 male and fe male athl etes. Sub t Use Mi u e. 2005 Jan;40( I ): 125 -35. C upp , MJ . Herbal remed ie : adverse effect and drug interaction Am Fam Phys ic ian. 1999 Mar;59(5): 1239-44. Cupp, MJ. Herba l remed ie : adverse effects and dru 0o . . . mteracllons Am Fam Ph ysic ian. 1999 Mar;59(5): 1239-44. C unn ingham JK , Liu L. Impact of fede ral ephedrine and pseudoephedrine regulati o n on methamphetami ne-re lated hospital ad mi s io ns. Add iction. 2002 Aug;98: 1229-37. Drug Enfo rce me nt Ad mj ni strati o n. Establi shed A es ment of Annua l Need fo r the Li st I Che mj a l Ephedrine, Pseudoephedrine, and Phenylpropano lamj ne fo r 2008. Washington DC. 2007 Dec.72(247):7336 1-7. T he NCAA Co mmittee o n Co mpetiti ve Sa feauar ds and Medica l A pee ls of Sports. NCAA Study of Substance Use Habit o f Co llege Student-A thle tes. The Nati o nal Co llegiate Athl eti c Ass ciati o n; 200 1 Jun . The N AA Commjttee on Co mpetiti ve Sa feguard and Med1ca l Aspects o f Sport . NCAA Study of Substance Use Habit o f Co ll ege Student-Athl ete . The Nati ona l Co ll egiate Athle ti c Assoc iati n; 2001 Jun . B ~nts RT, M ~rs h E. Patterns o f epehedra and other stimul ant use Ill co lleg iate hoc key athl ete . ln t J ort Nutr Exer Met. 2006; 16:636-643. p Po~ ul ar Weight Loss Ingred ie nt has Cau cd So me Serr ou Hea lth Pro bl em. : C BC Marketpl ace; 1999

Nov 16 [c ited 2008 Jan 3]. Ava il abl e from : http://www.cbc.ca/cons umer /markeUfi les/hea lth/ephe drine/hea lthca n.htmJ . 24. Drug ava il ability Leerin g co rnm.ittee. Drug avai lab ility estimates in the Un ited Stale . Washin gto n DC. 2002 Dec. Report No.: N J 197 107 . 25. The NCAA Commillee on Competitive Safeg uards and Medi ca l Aspect of S ports. N AA S tud y o f Sub La nce U e Habits o f Co ll ege Stud ent-A thl ete .

The Nati o na l Co lleg iate Ath letic Associati n; 200 I Jun . 26. Persky AM, Berry NS, Po llack G M, Brouwer KLR . Mode lling the cardi ova c ul ar effects of ep hedrine. Br J Clin Pharmaco l. 2004;57(5):552- 62 . 27 . Po pular We ight Lo In gred ient has a uscd Some Serious Hea lth Prob le ms: CBC Marketpl ace: 1999 Nov 16 [c ited 2008 Jan 3] . Ava il ab le from : hnp ://www .c bc.ca/co ns umer /market/file. /health/ephe drine/healthcan.htmJ.

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Feature Article

Takotsubo Cardiomyopathy A Review of Clinical Features, Pathophysiology and Management Xiangning Fan. Medicine 2010 Reviewed by Dr. Patrick Teefy Takotsubo cardiomyo pathy i a recentl y described and poorl y recogni zed clinica l entity perhap best known for its nt e levati on myocard ial in fa rcti on (STEMI) and non-ST -seg me nt elevati o n myocardi al abi lity to mimic both ST-seome b . . . in farc ti on (NSTEM I), especia ll y in po t-me nopausa l women and fo ll ow ing stressful situati ons. Becau e of thi S, It IS an important co nsidera tio n in the d iffe renti al diag nos is fo r patients presentin g with sy mpto ms and signs consistent with ac ute coronary sy nd rome (ACS). Ap ical ba ll ooning of the left ve ntric le see n o n ec hocard iograph y or left ventri cul ogram with preserved motion or hyperki nesis of the ba al seg ment i the s ignature appearance o f thi co nditio n; however, a di ag nos is ca nnot be made until coronary artery d i ea. e is rul ed o ut with a ngiograph y. The pathophysio logy of thi co nd iti on ap pear to be re lated to tran ie nt myocardial tunnj ng econdary to hi gh level of circul ating catec holami nes. T hi s appears to be via a di ffere nt mec hani sm tha n th at seen in response to myocardial ischemia, but the exact mechani sm re mai ns un known. Although Takotsubo cardi o myopathy is thought to compri se 2% or less of all presentati ons of ACS, thi i thought to repre ent an underes timate of the true incide nce. Increasing aware ness of the cond itio n as well as the trend towards urge nt ang iography and primary PC I a the favo ured treatme nt o f ST EMI are expec ted to reveal prev iously undi agnosed or rni di agnosed case .

Background 1

In 1990 , Satoh and colleague described a unique cardiomyopath y whi ch has ince beco me known as "T akotsubo cardiomyo pathy," " transient apical ball ooning," "stres -induced cardiomyo path y," and "broken heart synd ro me." Classically, this co nditi on manifests itself as acute-on et retrostern al chest pain , shortness of breath , and EKG changes consistent with transmural anterior wall infarction, most commonl y ST- egment elevati on in the 2 4 appropri ate precordi al lead . - It is seen most comm onl y, but not exclu sively, in po tmenopau al wo men who have ex peri enced a udden ph ys ical or e moti onal tress, and is acco mpani ed by a characteri sti c appearance of the left ventricle on echocardi ograph y or left ventriculograph y and the absence of he modynamically igni ficant coronary artery di sease in the distribution of the left anteri or descendin g (LAD ) artery. 5路6 T akotsubo cardi o myopath y, th erefore, represents a di agnosti c diffi culty in that it mu st be rapidl y and acc urate ly di stin gui shed from anteri or STEMI in order to fac ilitate correct c linical dec ision-making regarding therapy for th e patient with ACS. S ince 1990 , the clini cal features of Takotsubo cardio myo path y have been described 7, and di agnosti c criteria established by

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vari ous groups 6 路8 - ; these invariably emphasize the tran ient and rever ible nature o f Takot ubo cardi omyopath y, and the ab ence of signifi cant coronary artery di ease, ruling out ischemic heart di ease as a cau e of ventri cular dysfun ction .

Clinical and Investigative Features Much of wh at i known about the clinical presentati on and course of Takotsubo cardi omyo path y deri ve from publi hed case reports. Since its initi al de cription in the literature in 1990 , Takot ubo cardi o myopath y has been reported with increasing freque ncy both in and outside of Japan. There is a mall rise in serum troponin and creatine kinase levels with imil ar kinetic to th at seen in Acs _2A路6 High plas ma catecho lamines are found in a maj ority of patient at presentati on; however, their role in the pathogenesi remains poorl y under tood and these are not generally measured unles there is concern about pheochromocyto ma. It i not clear whether eri al measurements are of value for clinical deci ion-making. '' -' 4 Pati ents with Takotsubo cardi omyo path y, because they do not have signi ficant co ron ary artery disease, are thought to have a more favo urable clinical course than the ir peers pre enting with MI. 15 At initial pre entation, it is o ften difficult to differenti ate T ako t ubo cardiomyo path y from

STEMI via electrocardiography, as ST- egment elevations in the appropriate precordial leads are een in electrocardiograms (EKG ) performed on both set of patient . 16路17 A the hyper-acute phase pas e , the EKG will evolve, often revealing deep T wave inversion s in the anterior lead and QT prolongation. 1 Much attention , therefore, ha been devoted to identifying and characterizing the sen itivity and specificity of EKG pattern which may suggest STEMI over Takotsubo cardiomyopathy, or vice versa. Ogura and colleagu ugge t that a con tellation of EKG findings -namely, absence of reciprocal change , absence of abnormal Q wave and a ratio of the ST egment elevations in leads V4-6 over elevations in Vl-3 > 1-may be highly pecific for Takotsubo cardiomyopathy when 19 the e exi t together. Inoue and colleague confirmed that the ab ence of reciprocal changes and abnormal Q waves on EKG may be helpful in differentiating between patient pre enting with Takot ubo cardiomyopathy and those with anterior MI secondary to occlusion of the 0 proximal LAD ? Bybee and colleagues ugge t that patients with Takotsubo cardiomyopathy typically pre ent with lower ST egment elevations than their peer who present with bona fide anterior MI seco ndary to occlu ion of the LAD. 15 However, a the electrocardiographic differences between Takotsubo cardiomyopathy and anterior STEMI are subtle and easily mi ssed and the clinical features of these two conditions overlap, urgent coronary angiography to rule out ignificant coronary artery disease and echocardiography or left ventriculography to demonstrate the characteristic apical ballooning remain necessary for diagno i . The characteristic appearance upon echocardiography or left ventriculography of the heart of a patient with Takot ubo cardiomyopathy i of dilation of the apex of the left ventricle with pre erved_ or ~~fer-contrac~ion of the ba e of the left ventncle.- The ventncle is said to re emble a Japane e octopu trap, from which the name derives. More recently, a variant form of Takotsubo cardiomyopathy ha been described in which the ventricular dilation occurs not at the apex of the left ventricle, but in 20 the mid-ventricular segment. Takotsubo

cardiom yopathy involving the right ventricle ha 21 also been re ported in the literature. An inverted pattern ha been de cribed m as ociation with central nervous y tern injury ?2.?4 and pheochromocytoma.- -

Pathophysiology In contrast to the clinical course of anterior MI, the impairment in left ventri cu lar function een in Takot ubo cardiomyopathy i transient, and typically recovers within 2 month s of initial pre entation . Tho ug h this tran sient left ventricular d ysfunc ti o n is thought to represent myocardial stunning of the affected portion of the left ventricle, wi th or witho ut transient myocardi al ischemi a, muc h remain unknown about the pathophysiology of Takot ubo cardiomyopathy. Recent attempt to exp lai n the pathophysiology have settled upon high levels of circulating catecholamines a the likely pathology underlying thi cardio myopathy. One explanation i that ystemic release of catecholamines following a stressful event result is suffici e nt to tun the myocardium. Du e to the high concentration of adre ne rgic receptor in the apex of the left ventricle, thi regio n is preferentially s usceptible to catecholamine2 induced tunning. A Circulating catecho lami ne are hypothesized to produce left ventric ular dysfunction via a mechani m differe nt from that 12 25 seen in ischemi a ' , altho ugh Takot ubo cardiomyopathy ha been een fo llowi ng 26 coronary artery va o pa m and tra n ie nt catecholamine-mediated vaso pa m may 4 contribute. Inte re ting ly, Takot ubo- like cardiomyopathy ha been reported with pheochromocytoma, thereby le ndin g credence to the ugge tion of catecholamine- induced . 1 dys f unction. . 2?-路-') 7 Mo re recently , Ako myocar d 1a and co lleague have noted imilarity between Takot ubo-like cardiomyopathy and left ventricular dy function following ac ute brain injury, thu rai ing the po ibility of a hared pathophysiology. 28 Alternatively, Iban ez has proposed that the phenomenon of Takot ubo cardiomyopath y can be better ex plained by occlu ion of the proximal or mid-segment of an exception ally long LAD which wrap around the apex of the

UWOMJ 77(2) 2008 51

left ve ntricle, res ul tin g in i chemjc myocardi al dysfunction, fo ll owed by pontaneous 29 -3 1 . h" h h . . reper f us1on ; t 1 ypot ests 1 not as we 11 accepted, but may explai n how Takot ubo cardiomyopathy may develop in patients without significantly elevated plasma catecho lamines. Impaired microvascular fu nction may al o be present and explain the anatom ic pattern of ventric ul ar dy function extendi ng beyond the territory of the LAD.32 A genetic contribu tio n to the etiology and/or usceptibi lity ha been recentl y ugge ted 33 , but ha yet to be conclu ively prove n.

Management There ho uld be a high index of su ptc io n fo r this disorder e peciall y in o lder fe males fo llowin g a recent emotio nal up et o r ph ys ical tress. Differentiatio n fro m ACS can be di fficult. If prompt acces to a cardi ac catheteri zati o n laboratory i available , it is the preferred approach to acc urately diag nose thi s di sorder and rul e o ut myocardi al in fa rcti o n. Understandabl y, if a catheteri zati o n laborato ry is not readil y available, o rne patients may be di ag nosed wi th STEMI, and, as a re ult, receive thrombolyti c therapy. Emergency echocardi ograph y may have a ro le in imagi ng the anato mic dy functio n characteristi c of Takotsubo cardi o myo path y. Initi al therapy is u uall y suppo rti ve in nature 4-6 , and con ist of a pirin , ACE inhibitor , beta blocker , and/or calcium channe l blocker 34 , tho ugh the ir use i o mewhat empiri . Anti coagul ati o n with heparin ( w itchin g t Coumadin) is often used give n concern about deve lopment of in tram ural th ro mbu s in the ball ooned apex. This can be sto pped o nce the ventric ul ar functi on norm ali zes in 1-2 month .

econdary to embolism of an extstmg apical 47 thro mbu s46 and left ventricular w all rupture. The mortality attributed to T akotsubo cardio myo path y i 1%? Although the o bserved rate of recurrence is low, it is impo rtant to note th at lo ng term fo llow-up of patients with Takot ubo cardio myopath y i limited ?

Summary T akot ubo cardiomyopathy is increasingly recogni zed a a cause of ac ute chest pain and dys pn ea mim icbng ACS . It is di tingui hed fro m anterior MI o n the basis of characteristic and/or ventriculographic echocardi ographic findin g , namely, left ventricle wall motion abno rmaliti e , in the absence of critical coronary arteri e teno e . The typical wall motio n abno rmality seen is octo pu -po t shaped dilation o f the apical and midpo rti o ns of the left ventric le, with normal mo tio n or hypercontrac tio n of the base of the left ventri cle, altho ugh variant fo rm A lthough the preci e have been de cribed. patho physiological mechani m which produces these changes in the ventric le i unknown, recent ugge tio n of tran ient myocardi al tunning secondary to hi gh level of circ ulating catecholamine appear con i tent with clini cal observatio n . O verall , pati ent w ith T akotsubo cardi o myopath y hav a favo urable prog no i , but related to may ex perience complicatio n tran ient left ventricular d y func ti o n whi ch require supportive care.

References I.

Complications

. I e dema35-37 , m1tra Pu I mo nary regurgitati on 38 , cardi ac dys rh ythmi as 35 ·39 ·40 and . gent.c . d card w s hoc k' 3641 · are recogmze complicati o n , espec iall y in elderly pati ents, and these life-threatenin g compli cati ons require 2 3 42 treatment as per u ual pro tocol. ' ' Addi tio na! noted sequelae of Tako tsubo cardi o myopath y 43 api cal thro mbu s include peri carditi s , 44 45 cerebrovascul ar acc ident fo rmatio n • ,

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lsojima K, OHtomi S, Yoshimoto N. A sociation of Takotsubo cardiomyopathy and long QT syndrome. Circ J 2006;70: 1220-1222. Nault MA , Baranchuk A, Simpson CS , Redfearn DP. Takotsubo cardiomyopathy : a novel "proarrhythmic" di sease. Anatol J Cardiol2007;7 Suppl 1: 101-103. de Vasconcelos JTP, Martins S, de Sousa JF, Portela A. Takotsubo cardiomyopathy : a rare cause of cardi ogenic sock imul ating acute myocardial infarction . Arq Bras Cardiol 2005 ;85: 128- 130. Sakai K, Ochiai H, Kataya ma N, Nakamura K, Arataki K, l(jdo T , Iwamoto H, Nakamura S, Naka nj shi T. A seriou clinical co ur e of a very e lderl y patient with Takotsubo cardiomyopathy. Heart and Vessels 2005 ;20: 77-8 1. Maruyama T , Hanaoka T, Nakajima H. Acute peri carditi s in the recovery phase of transient left ventri cular api ca l ball oorung syndrome (Takotsubo cardi o myopathy). Int Med 2007 ;46: 1857- 1860. Yoshida T, Hibino T, Fujimaki T , Oguri M, Kato K, Yajima K, Ohte N, Yo koi K, l(jmura G. Tako-t ubo cardi o myopathy complicated by apical thrombu formation : a case report. Int J Cardiol 2007:In press. Schmidt M , Herholz C, Block M. Apical thrombus in tako-t ubo cardiomyopathy. Heart 2007; 93 :1368. Grabowski A, l(jli a n J, Strank C, Cieslinsk G, Meyding-Lamade U. Takot ubo cardi omyopathy : a rare cau e of card ioembolic troke. Cerebrovasc Dis 2007 ;24: 146- 148. Aka hi YJ , Tej ima T , Sakurada H. Matsuda H, Suzuki K, Kawasaki K, Tsuchi ya K. Hashimoto N, Musha H, Sakakibara M, Nakazawa K, Miyake F. Le ft ve ntricul ar rupture assoc iated with Takot ubo cardi o myopath y. Mayo Clin Proc 2004;79:82 1-824 .

Feature Article Genetic Basis of Coronary Artery Disease Matthew Lanktree, Medicine I PhD 2012 Reviewed by Dr. Robert A. Hegele While fanuly history i a strong ri sk factor for coronary artery di ea. e (CAD), the actual molecular basis has not been chara terized in mot ca e. In 2007, four genome-wide a ociati on studi es (GWAS) reported strong as ociation (up to 22 p=l0- ) between a region of chromo orne 9p2 1 and CAD. The high ri k genotype was found in up to 30% of people, creating the potential for a clinica l genetic te t to a ist in the prediction of a patient' ri sk for CAD. However, the reported effect ize of the association is modest (odds rati o - 1.3) and incorporati on into a clinica l setting may be premature. Thi paper reviews the adva nce in human molec ular geneti c allowi ng for the production of GWAS , and a re ult of the four GWAS of CAD relea ed in 2007. In addition, these four GW AS are meta-analyzed and the pooled ignifica nce and effec t size e timate are ca lculated. A of yet, there is no explan ati n for th e basi s of the assoc iati on of thi s region of chromosome 9 with CAD. The consistency of the as ociati on aero populations sugge ts a biologica l mechani m i re ponsible. Perhaps the greate t co ntribution from the assoc iation i yet to come, a further studie identify the mechani tic ba is for the lrong assoc iati on, possibly lead ing to additional in ights into the progre ion, prevention , and treatment of CAD.

Completion of the sequencing of the human I 7 . genome wa a monumental ac h1evement. 路Molecular re earcher now take for granted the information provided by the seq uence, however the clinical application are not immediately obvious. A limitation of the Human Genome Project wa that it produced only a s ingle "reference" equence. But in order to identify new di sease causing mechanisms and cures for di ea e, we need to go beyond the " reference" and characterize the differences between our genomes, and in turn the effect that these differences have. The Human HapMap 3 consortium and recent genome-wide association studies (GW AS) have set out to capture the interindividual difference that are associated with di sease proce se , including coronary artery di sease (CAD).

Basics of Genetic Variation Every human nucleu contains 46 chromo omes organized into 23 homologou pair : 22 autosomes plu s a sex chromo orne inherited from the mother and 22 autosome plu s a ex chromosome inherited from the father. Chromo orne are made of DNA and can be divided into gene , which are area that are transcribed into mRNA then tran slated into proteins, and intergenic regions, which can contain tran cription regulating elements. Only -5% of the genome is thought to be tran lated

ultimately into protein ; the remainder i ilent. Mo t of the genomic sequence (-99.5 %), whether coding or silent, invariant between individual . The mam form of genomic difference between people is the s ingle nucleotide polymorphi sm (SNP, pronounced " nip"). A SNP is a ingle ba e pair change in the DNA sequence that, by convention, occurs in at least 5% of the population. With the human genome equence known, the location of any polymorphi sm can be preci ely determined. Each SNP i repre ented by two allele , together called a genotype, with one all ele re iding on each homologou chromosome. SNPs are the most ba ic and ea ily measured forn1 of genetic variation that might lead to inter-individual differences at the level of the phenotype. A gene can contain zero to many SNP : on average SNP occur about 1 in every 300 to 400 base pair , and gene range in size from le than a thou and to more than two mi ilion ba e pair .-1 DNA i replicated extremely effectively with very few error . Thu s, SNP are generally inherited from our parents rather than occurring pontaneou ly. Occasionally , a de novo meiotic mutation increa es in frequency in ucce ive generation to become a SNP, e pec ially if it confer a survival or fitne advantage. Because they are inherited , SNPs can give insight into the hi tory of the surrounding block of the

UWOMJ 77('2) 2008 55

chromosome. If an unknown sequence variant that alters disease risk resides within the same block of DNA a a SNP, known a a haplotype block, we can indirectly identify the ri k equence variant by examinin g the co egregation of the SNP with the disease. In associati on studie , researchers compare the prevalence of alleles of SNPs in cases and contro l to potentially identi fy a ri k block. Early in the twenty first century a new technology called "SNP chip ", also call ed arrays or o li gonucleotide microarrays, were SNP chips permit introduced. These si multaneous analysi of up to a million SNP genotypes aero the genome in a sin gle experiment for a single DNA sample. Le s than five year ago, u ing older technology a hi ghly motivated grad uate student might produce 400 genotypes in a day. Using SNP chips, large genetics centres can now perform GW AS to measure millions of variants in thou sands of case and controls in a few days. In 2007, SNP chips were co mbined with the GW AS approach to di cover new chromosomal regions that were as ociated with a range of common di sease including rheumatoid arthritis, Crohn 's di ea e, type 1 diabete , type 2 diabetes, and CAD.

Genomics of CAD CAD is the leadin g cause of death among North Americans. Smoking ce sation , weight and Publication date

Number of cases

He lgadotti r et al. 6

Jun e 2007

diabetes management, low-dose aspirin, hyperten ion control, and lipid-lowering therapy can substantially reduce the ri sk of CAD. Many rare single-gene di sorders have been discovered that substantially increase the ri sk of CAD but are only present in a small proportion of the population (eg. familial hypercholesterolemia due to point mutations found in 1 in 500 people). Heritability studie of CAD and myocardial in farc tion (MI) indicate th at common usceptibility gene va1iants (perhaps found in 3050% of people) are an important part of CAD n. k' . 5

Synthesis of large GWAS in CAD from 2007 Four GW AS from 2007 , performed in samples from several different populations, all howed th at a region on the hort arm of chromosome 9 (namely 9p21) was associated with increased CAD risk. The fo ur studies reviewed in this 6 paper will be referred to as Helgadottir , McPherson7 , WTCCC 8 and Samani 9 for the remainder of the paper. The chromosome 9p21 results from these four GW AS will be metaanalyzed. Study samples: Helgadottir tudied pati ent from Iceland, an isolated population, to ens ure genetic and controls. homogenei ty between case McPherson studied European Caucasian participants from the Ottawa Heart Study, African American and Cauca ian participants

4587

Numbe r of co ntro ls 12767

Icelandi c

Jun e 2007

3989

18808

Mi xed

WTCCC~

June 2007

1926

2938

Samani et a/.9

Aug. 2007

875

1644

Great Brita in Caucasian German Caucas ian

11 337

36 157

McPher on et al.

Combined

Popu lati on

Genotypi ng method Ulumina Hap300 array C ustom an路ay Affy metrix 500k array Affymetrix 500k array

Number of SNPs examined 305 953 75 000 2* 377 857t

272 602t

Table 1. Studi es described in thi s pape r. Ab bre viati o n - WTC C : We lco me Trust Ca e Contro l Con ortium路 SNP: Si ng le nuc leotide po lymorphi sm. *initial sa mpl e of 322 cases and 3 12 contro l , re pli cati o n o f re ulls p~0 .025 in 1.658 ca e ~ ~d 9380 controls, 2 9p2 l SN P performed in re mainin g . ubj ect . tS NPs tha t did not meet Hardy We mbcrg equ ll1 bnum, had a rrun or a ll ele freque ncy< l %, <98 9l S NP ca ll ra te, or were on X c hro mo orne were re moved .

UWOMJ 77(2) 2008 56

from the Athero clerosis Ri sk in Communitie Study, Dani h Cauca ian participants from the Coppenhagen City Heart Study, and a multi ethnic ample from the Dallas Heart Study. Control were carefully selected in order to ensure equal representation in case and control group . Samani cases and control were collected from a genetically homogenou region of Bavaria in outhern Germany . WTCCC exten ively te ted for difference in background allele frequencies due to the ethnicity of study subjects. Twelve regions from aero the genome were found to be heavily influenced by geographic variation and were thus removed from the WTCCC and Samani tudie . Study subj ects: All tudie included male and female . The Helgadottir ca es were diagno ed with aMI before the age of 70 in males and 75 in female . The McPher on ca es underwent coronary artery bypass grafting, coronary artery angiography, or care for acute MI before the age of 60. The WTCCC case had a documented history of MI or coronary revascularization before their 66th birthday. Finally, the Samani cases were diagnosed with a MI prior to the age of60. Statistics: The WTCCC and Samani studie reported odd ratios comparing individual with two ri sk alleles verse no ri k alleles and individual with one ri sk allele verses no ri k alleles (genotype odd ratio). The Helgadottir and McPher on studies reported odds ratio by comparing the number of the ri k alleles pre ent in cases to the number of risk alleles pre ent in controls (allelic odds ratio). It is poss ible to calculate allelic odds ratio from genotype odd ratio (each homozygote contributes two alleles and each heterozygote contribute one of each allele) but not vice ver a; hence, the current meta-analysi u es allelic odd ratio. The four GW AS did not assess the exact same SNPs due to different genotyping technologies, but all ignificantly a ociated SNP were located in the same haplotype block (Helgadottir, rs l0757 278 ; McPheron, rs l0757274; WTCCC, rs6475606 ; Meta-an alysis wa Samani , r 4977574). performed u ing the Mantel-Haenszel method, which create an estimate of the pooled odd ratio as uming a fixed effect model using the raw data from the individual studies. Haplotype

block tructure wa obtained from the HapMap International VIa Consortium 3 . 10 H ap Iov1ew. Synthesis findings: The odd ratio, confide nce interval and chi- quare p-value found for the SNP on chromo orne 9p21 are show n in figure 1. The Mantel-Haen ze l umm ary effect e timate aero all four tudie i an odds ratio of 1.30 (95% C.I. 1.25-1.36). Odds Ratio (95% Confidence Interval) 0 Helgadottir

0.5

1.5

P = lxl0路20

A vs 6

McPherson

=1xlo路 22

Avs B

WTCCC

p = 4xlo- 14

AA vs BB

Saman i AA vs BB

Combined

p = Sxlo路 7 p = 4xlo- 69

Avs B

Figure l. Fore t plot of odd ratio obta ined comparing 9p1 l SNPs with CAD from the four GW AS a nd the combined effect e timate u ing Ma ntel-Hae n ze l metaanalysi s. A vs. B indi ca tes alle li c odds rati o a nd AA vs. BB indi cates genotypi c odd. ratio.

Discussion Thi meta-analysis of 4 large GWAS empha izes the trength , significance, and replicability of the association on chromo orne 9p21 with CAD. The significance level from the combined analysis, p = 4xl0-69 , is a result rarely seen in statistical analysi of biological sy tern , and i approximately equivalent to the probability of flipping a non-loaded coin and obtaining head 227 time m a row. However, despite the overwhelming stati stical relationship, it i important to recall the difference between tati tical ignificance and clinical significance. The level of confidence that a differen ce ex ist between the allele frequencies in CAD case and controls implies little regarding the clinical implication of thi s difference. An odd ratio of 1.3 i hardly suffici ent for a clinician to introduce any new ri sk factor test or imaging

UWOMJ 77(2) '>OOR c;

method into hi /her deci ion making fo r a ing le patie nt. In compari on, smoking confe r an 11 increased ri k of MI with an odd rati o of 3.0 . Simpl y taki ng a famil y hi tory verbally and findin g out that a parent had heart disease under 12 age 60 confe rs a 2-fold inc reased ri k. It is ex tre mely di ffi c ult to plumb the impo rtance of a ri k of an odd rati o of 1.3 de ri ved fro m a SN Pbased assay on an indi vidu al pati e nt. So why is the geneti c finding important? Perhaps thi di covery will ultimate ly contribute to our under tandin g of the pathogene i of CAD. Wh at expl ains the inc redibl y tro ng tati ticall y ignificant assoc iati on o f the 9 p2 1 SNPs with C AD? The 9p2 1 haplotype block i in the middl e o f a tretch of DNA with no know n fun ctio n. The cl o e t genes to the re po rted SNPs are: 1) MTAP (meth ylthi oadeno in e phosphoryla e), whi ch is in volved in polya mine metaboli m and the alvage of ade nine and methio nine; 2) CDKN2A and CDKN2B (cyc lin dependent kin a e inhibitor 2A and B ), whi ch are tumour suppressor genes; 3) and DMRTA 1 (doublesex and mab-3 related tran c riptio n facto r like famil y A 1), whi ch i important in ex ual differe ntiati o n. However, these gene are approximately 45 ki lobase (kb ), 70 kb and 200 kb away fro m the stro ngest SNP ignal respecti vely. It is poss ible that vari ants at 9p2 1 co uld affect the e gene via regul atory ele ment , but this i diffic ult to determine usin g c urrent techno logie . Moreover, it i diffi c ult to even hypothes ize how the e gene c uld be in vo lved in CAD ri sk. C learl y, there is much more to learn and di scover. In conclu sion, fo ur GW AS publi shed in 2007 that e nro ll ed large and non-o ve rl appin g tud y popul ati o ns have identi fied a regio n o f 9p2 1 to be tro ng ly associated with C AD ri sk. The effect ize is too small fo r the results to be eas ily integrated into clini cal deci ion-mak ing for a sin gle pati ent, but the tre ngth of the associati o n suggests that there mu . t be a shared

UWO MJ 77(2) 2008 58

unde rl yin g biological mechanism, although the actu al mechani sm remains unclear at this time. Furthe r tudie to identify the reason for the trong as ociation may lead to additional insights into the progre sion , prevention, and treatment of CAD.

References I.

4. 5.

10.

I l.

12.

Lander ES , Linton LM , Birren B et a!. Initial eq uenci ng and analysis of the human ge nome. Nature 200 I; 409: 860-92. Venter J , Adams MD, Myers EW et al: The seq uence of the human ge n me. Sc ience (New York, y 2001 ; 29l: 1304- 135 1. Frazer KA, Ballin ger DG. ox DR et al: A econd generati n human hap lotype map o f over 3. 1 milli on SNP . Nature 2007: 449: 85 1- 6 1. Strac han T, Read, A: Human M lecul ar Genetic , 3rd ed n: Garland Sc ie nce, 2003 . Mayer B. Erdma nn J. chun kert H: Genetic and heri tabi lity of coronary artery di ea e and myocardial in farcti on. lin Re Cardi I 2007; 96: 1-7. Helgadottir A, Thorleif on G, Mano le cu A et al: A commo n variant on chromo orne 9p2 1 affect the ri sk of myocardial in farct ion. c ience (New York, NY 2007 ; 3 16: 149 1- 1493 . McPheron R, Pert em lid i A, Kavas lar N et al: A commo n all ele on chromosome 9 associated with coronary heart di ea e. Scie n e (New York, NY 2007 ; 3 16: 148 - 1491. We lcome Trust a e Co ntro l ons rtium : Genomewide assoc iati on tudy o f 14,000 ca es of eve n common di ease and 3,000 hared controls. Nature 2007:447 : 66 1-678. ama ni NJ, Erdma nn J, Hall et al: Ge nomewide a oc iatio n analy i of cor nary artery di ea e. The Ne England journal of med icine 2007; 357: 443-453. Barrell J , Fry B. Maller J, Daly MJ : Hap! view: analysis and visuali zati o n of LD and hapl otype maps. Bi in ~ rma ti cs (Oxford, England ) 2005; 2 1: 263-265. Teo KK, Ounpuu , Hawken et al: Tobacco u e and risk of myocardi al in fa rcti o n in 52 countri e in the INTERH E RT stud y: a case-control tud y. Lancet 2006: 3 8: 647-658. Ge net J, Frohli ch J, odor G. McPher on R: Recommendati on fo r the manaaement of dys li pide rnia and the preve nti on of c:rdi ovasc ul ar disease: summary o f the 2003 upd ate. CMAJ 2003; 169 :92 1-924.

Feature Article Does being "South Asian" increase the risk of CAD? Wajid Sayeed, Medicine 2010 Reviewed by Dr. Robert Hegele Since ma ny di sea e aeti o logies have a ge ne ti c contributi o n, the u e of e thni c categori es (or "geographi ca l ancestries") can be a useful way of integrating a ra nge of cultural and geneti c attributes in o rder to e luc idate the associatio n between uc h factors and disease usceptibility. "So uth A ia" is u ua ll y defined a the area e nco mpas ing Pakistan, Nepal , Bangladesh, India, and Sri Lanka. Numero us observatio na l tudi es have been done howi ng that So uth Asia n , both in itu in South Asia a nd in South Asian diaspora com muniti e , are at increa ed ri sk for cardi ovasc ular disease, especially coronary artery di sea e (CAD ), a findin g with major impli cati ons for c linical practice in co untri es s uc h a. Canada, where South Asian are the third most popul o u imrrugrant group . While not every South A ian may develop CAD-related morbidity, o ne approach to preventive medic ine is the applicati o n of interventi o ns in a n e ntire at-ri k population, rather tha n targeting interventi on to individuals o n a case-by-case ba is. S uch population-wide interventions rru ght, however, do more harm than good if their ri sks and costs outwe igh the ir be ne fits, and if they cau e the clinician or the pati e nt to neglect modifiabl e indepe nde nt ri k factors with a proven ca u ative ro le in disease aeti ology. We therefore pre e nt a critical look at literature suggesting the use of South Asian ethnic ity as an independe nt ri k factor in the development of CAD.

Epidemiology of CAD in South Asian Populations Unfortunately, there are no large multi-centre studies performed in regions of South Asia, and the national figure available from India are based on pooling of studies taken from different centres at different time points. More importantly, such data are not directly comparable with those from South Asian diaspora communities, for which disease prevalence estimates are so metimes more scarce and less reliable than mortality rates. World Heath Organization (WHO) data are typically expressed as DAL Ys, but thi s is a flawed measure of disease burden, and not nece sarily a good indicator of ri k. Mortality from CAD in India has been calculated to be 0.85 million in men and 0.74 million in women, totaling 1.59 1 million deaths in 2000. For an Indian population of 1.05 billion in 2000, this translates to a mortality rate of 151 CAD death 1100000 people. Global mortality from ischaemic heart disease, which correlate closely with symptomatic CAD, stands at 115 deaths/100,000? Like the DALY, mmtality is highly ubject to local socioeconomic conditions, and is therefore not a good indicator of risk.

Similar challenges exist in surveillance of South Asian populations outside of South Asia, though these are mitigated by smaller overall population size. For instance, in Canada, ischaemic heart disease mortality is roughly similar between South Asian men and European-origin men: approximately 320 deaths/100000 per year between 1979 and- 1993,3 but is increased for South Asian versus European-origin women: 145 versus 109.9 deaths per year between 1979 and 1993. The comparison is more valid than at the international level, given more uniform soc ial conditions within Canada. Furthermore, prevalence estimates within Canada between ethnic group were made in the Study of Health Assessment and Ri sk in Ethnic groups (S HARE), which showed a prevalence of 8.6% in the South Asian origin cohort compared to 4.9% in the European origin one. 4 Data in UK and US cohorts show similar trend 5-6

Is risk genetic? While the epidemiological data may support increased cardiovascular disease ri sk in South Asians versus other populations, this does not necessarily imply that genetic factors in the group described as "South Asians" are of primary importance. Culture - includin o- diet t> ' activity and social factor - while "heritable," is unlike the genome in th at the consequences of

uwo

77(?)?

cultural factor m determining ri sk mi ght be more amenable to modification through education and counseling. Some authors, however, assert th at the degree to which risk is increased among t South Asians is too high to be 7 acco unted fo r onl y by li fes tyle fac tor . Thi has led to considerable di scu sion of whether or not South Asian ori gin hould be considered an 8 independent ri sk factor fo r CVD di sease. The attempt to find bi oc hemical marker for genetically detem1ined risk i in its in fancy and has met mixed res ults. Some wo rk has been done as oc1atm g polymorphi sms in homocysteine metabolic pathways with carotid atherosclero i ,9 but a cau ati ve link has not been well-de cribed. Thus far, the only bi ochemi cal marker with a clear as oc iation with South A ian origin that i based in geneti cs, and not the environment, i a hi gh pla rn a level of Lipopro tein (a), which has been con idered as an emergi ng ri k fac tor by the U.S. Nati onal Cholesterol Educati on Program (NCEP). 10 Both . d ata ] ?- strong l y . . 111 and b as1.c sc1ence c l mica ugge t both that Lp(a) is under geneti c control and th at ex pression of particular alleles plays a causative role in atherosclerosis and the aeti ology of thrombogeni c conditions. Thi alone does not necessitate th at elevated plas ma Lp(a), or any other independent risk factor a sociated with South Asian origin , is primarily to blame fo r the increased prevalence and mortality of CAD in South A ians. The importance of environment and life tyle over geneti cs was hi ghli ghted in a stud y by Bhatn agar et al in the Lancet, th at howed signi ficant differences in cardiova c ular di sease ri sk fac tors between siblings of So uth Asian ori gin who lived in either West London or Punj ab state. While so me risk factors, such as Lp(a), were similar between the cohort , indi catin g a geneti c component, blood glucose, beta cell function, serum apo B, and body mass index (BMI) were 13 all appreciably worse in the UK coho rt. Since environment, and therefore lifes tyle, obvi ously contributes to th e growth of C AD amongst South A ians in Western countri es, research is required to detennine whether or not genetics, environment, or an interacti on between the m fundamentall y ex pl ains the increa ed ri sk. Un fo rtunately, to date no

UWOMJ 77(2) 2008 60

study claiming an increase in independent risk factor amongst South Asians has properly controlled for lifestyle factors - instead indirect bi ochemical or anthropometric surrogates such 14 as insulin sensitivity, dyslipidemia,7 or central 15 adiposity have been u ed to argue that South Asians are more susceptible to the effects of a sedentary li fes tyle, perhaps by virtue of genetics. Cultural attitudes towards diet and exercise are, however, heritable or perhaps learned, and could re ult in increased expo ure of South Asians to negati ve life tyle fac tors, explaining the increase in ri sk without the need to invoke genetics. Culture can and does have a profound impact upon how a group views health-related lifes tyle choices, uch as frequenc y of exercise or the content of the di et. On the question of exercise, a small tudy (n = 56) published by Lip 16 and coworkers showed South A ians presenting with ac ute MI were much less likely than their Cauca ian counterparts to have engaged in regular exerc i e. At lea t 12 other studie on the general po pulation of South A ian in the UK have been do ne. A systematic review revealed that British South Asians were generally le ph ysicall y acti ve than their "white" or "Eu ropean " co unterparts. 17 In the fi eld of di et and nutrition, the data leave much to be de ired in terms of inter-ethnic co mpari ons. Recent ev idence, however, shows th at Canadi an South Asian on average con ume a hi gher pro portion of calo rie as carbohydrate than Euro peans, Abori ginal , or Chinese 18 per ons. In the arne cohort, consumption of carbohydrate was in ver ely related to serum HDL, a potent pro tecti ve facto r against CAD. In prelimin ary data fro m sc hoo lchildren in the UK ' South Asian ' tudents consumed les fresh fruit and vegetable than white children did . 14 South Asian cookin g, particularl y fro m northern India and Paki tan does not typi cally in volve the use of raw vegetables, and there i a strong reli ance u~o n saturated fats for cooking, ev idenced by the Widespread use of ghee (clarifi ed butter) and khoya or mawa (precipitated who le milk) in traditional food.

The validity of the concept of "Ethnicity" The current literature does not recogni ze potential genetic heterogeneity amongst South Asians. Whil t thi s overall categori zation of "South Asian" may be useful "shorthand" that might simplify data collection, it is predi sposes studies to sampling error: there might be substrata in a ample labelled as being "South Asian' that have different ri sk than others so classified, but which would be falsely seen a respresentative of the whole population. India, Paki stan , Bangladesh, Nepal, and Sri Lanka each have genetically and culturally distinct ub-population , and cultural differences need not track with genetics. Even in the relatively confined space of Sri Lanka, 5 19 genetically distinct populations are discernible, and Tamil and Sinhale e, the two large t groups, both have the least in common , from a genetic per pective, with India's Veddah s, Gujaratis and Punjabis.20 Whether genetic or cultural, heterogeneity can be shown to manifest itself in different cardiovascular ri sks between population substrata. For in tance, Bangladeshi in the UK have been shown to have the highest cardiovascular risk of any South Asian group, both from biochemical data, and from selfreported lifestyle factors, with Pakistanis also 21 having demonstrably higher risk than Indians. These national groupings ("geopraphical may them selves be futher ancestries") misleading, given the significant cultural and genetic overlap between North India and Pakistan, as well as the over-representation of certain ethnic groups within tho e countries in the UK. Given the history and ethnology of the "South A ian" region, such use of generalized ethnic origin as a risk factor cannot be justified based upon the current evidence, which is as imprecise as studies in "Europeans" that have not differentiated between such diverse subpopulations as Italians, Finns Icelanders or Ashkenazim.

Conclusions Despite the volume of studies published, there is no definitive evidence that South Asian origin can be yet used as an independent risk factor

when considering a pati ent's CAD risk in order to plan interventions. A with most indi vidu al pati ent , bi ochemical an d bi o metric data may be useful a "red flags " fo r the ph ysician, and more precise indi cators o f ri k fo r the specific pati ent since they mo re directl y reflect potenti al underlying di sease proce es. C lini cians do no t treat po pulati on , they treat indi vidu als, and each ri sk profile i still related to individu al' behaviour, regardless of the geneti c contributi on. Since genetic risk facto rs are not amenable to modification, the sensible co urse of actio n is to base treatment strategies upon the indi vidual patient' hi story and circ umstances, and to make the same key recommendati o n to South Asian patients as i made to all other patients - the adoption of a healthy diet and regular exercise.

References 1.

Gupta, R. Burde n of Coronary Heart Disea e in Indi a. Indi an HeartJ. 2006 Jul ; l 24(1 ):15-22 . Anonymo us. Cardiova c ul ar Di ease: Preventi o n a nd Control [Internet]. World Health Orga ni zati o n. 2003 [cited 2008 01 25] . A vail abl e fro m http://www . who. intldie tph ys ica lacti vity/publicati o ns/f acts/cvd/e n/ She th T , Nair C , Nargundkar M , Ana nd S, Yu suf S . mortality a mo ng Cardi ovasc ular a nd cancern Canadi a n o f Europea n, o uth A ian, a nd C hinese ori gin fro m 1979 to 1993 : a n a nalys is o f 1. 2 milli o n death . CMAJ.l 999 Jul ; 16 1: 132-8. An a nd S, Yusuf S, Vuksan V, Devanese n S, Teo KK , Montag ue PA , Kele me n L, Yi C, Lonn E, Ge r tein H, Hege le RA, McQuee n M , SHARE ln ve ti ga tors. Differences in ri k fac tors. athero c le r si , and cardi ovasc ul ar di sea e be twee n e thni c groups in Canada: the Stud y o f Hea lth A es me nt and Ri k in Ethni c groups (SHARE) . The Lancet. 2000 Jul ; 365 :279-84 . Balaraj an R. Ethni c differe nce in mortality fro m i chaern.i c heart di sease a nd cerebrova c ular di sea e in Engla nd a nd Wales. BMJ. March 199 1; 302 :560 -4 . Mc Keigue PM, Mille r GJ , Marmot MG . Coro nary heart di sease in south A ia n overseas: review . J C lin Epide mi o l. Jun e 1989; 42:597- 609. Singh V, Deedwani a P . Dys lipi de mi a in Spec ia l Popul ati ons: Asian Indi a n , A fri ca n Ame rica ns, a nd Hi . pani cs. C urr. Athe rosc leros is Re p. 2006 ; 8 :32-40 . Gupta M, Brister S. I So uth As ian e thnic it y a n mdepe nde nt cardi ovas ul ar ri k factor? Ca n. J . Cardiol. 2006 Aug; 22(3): 193- 197. Kele me n LE, Ana nd SS , Hege1e RA , Sta mp fer MJ. Ros ner B, Willet WC , Montague PA , Lo nn E, Vuksa n V, Teo KK, De vanesen S, Yusuf S. Assoc iati ons o f plasma ho mocyste ine and the meth yle netetrah ydro folate reduc tase C677T

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po lymorphj sm with carotid intima media thic kness amo ng South Asian , Chinese a nd European Canadian . Atherosclero is. 2004 Jul y; 176: 36 1-370. Nati onal Cholesterol Education Progra m (NCEP) Ex pe rt Pane l o n Detecti o n, Eva lua ti o n, and Treatme nt of Hi g h Blood Cholesterol in Adults (Adult Treatme nt Pane l ill) (2002) Third Re po rt of the Nati o nal Chole te rol Education Progra m (NC EP) Ex pert Pane l on De tecti o n, Evaluati o n, a nd Treatment of Hi g h Bl ood C ho lesterol in Adult (Ad ult Treatme nt Panel III) final re po rt. C irc ul ati o n. I 06: 3 143- 342 1. Gazzaruso C, Buscag lia P, Garzaniti A, Falcone C , Mari otti S. Savi no S, Bo ne lli G , Finardi G , Geroldi D . A ociati o n of lipoprotei n(a) level a nd apolipopro te in(a) phenotype with coro nary heart di ea e in patie nt with e e nti al hyperte nsion. J Hyperte ns. 1997 M ar;15 (3):227-35. Ko chin ky ML. Lipoprotein(a) a nd atherosclerosis: new per pecti ve o n the mec hani sm of actio n of a n e ni gmatic lipo pro te in . C urr A the roscler Rep. 2005 Sep; 7(5):389-95. Bhatnagar D, Anand IS , Durring to n PN, Pate l OJ , W ander GS. M ackness MI , C reed F, T o me nso n B , Chandra he khar Y, Winterbo th a m M . Coronary ri s k factor in peopl e from the Indian subco ntine nt li vi ng in west Lo ndo n and the ir iblings in lndia. La ncet. 1995 Feb 18;345(8947):405-9. Wrunc up PH , Gilg JA , Papacosta 0 , Seymour C , Miller GJ , Alberti KG , Cook DG . Earl y ev ide nce of ethnic difference in cardi ovasc ular ri sk: cross ec ti o nal co mpari o n of British South Asian and white c hildre n. BMJ. 2002 Mar 16;324(7338):635 . Mc Keigue PM , Shah B, Marmo t MG . Re lati o n of central bes ity and in ulin res istance with hi gh di abetes prevalence a nd cardi ovasc ular ri sk in South Asian s. La ncet. 199 1 Feb 16 ;337(8738):382-6. Lip GY , Cader MZ, Lee F, Munir SM , Beevers DG . Ethni c differences in pre-admi s io n leve ls of physical admitted with myocardial actJ VJty 1n pati e nt infarcti o n. lnt. J . Cardio logy. 1996 June ; 56: 169- 175 . Fi sc hbac her CM , Hunt S, Alexander L.How physically acti ve are So uth Asia n in the United Kin gdo m? A lite rature review. J Publi c Hea lth (Ox f) . 2004 Sep ; 26(3) :250-8. Me rchant AT, Anand SS, Ke le me n LE, Yuk a n V, Jacobs R, Davis B, Teo K, Yus uf S, S HA RE a nd SHARE-AP investi gators. Carbo hydrate inta ke a nd HDL in a multi e thnic po pul ati o n. Am J C lin Nutr. 2007 Jan;85( 1):225 -30. Papiha SS, Mas tana SS , Jayasekara R. Genetic variation in Sri Lanka. Hum Bi o i. 1996 Oct; 68(5):707 -37. Kshatri ya GK. Genetic affiniti e o f Sri La nka n po pul ati o ns. Hum Bi o i. 1995 Dec ;67(6):843-66. Bhopal R, Unwin N, White M, Ya ll op J , Walke r L , Alberti KG , Harl a nd J, Pa te l S, Ahmad N, Turner C , Wa tso n B, Kaur D, Kulkarni A, La ke r M , T av rid o u A. He te rogene ity o f coro nar y heart di sease ri sk factors in Indi a n, Paki sta ni , B ang lade hi , and European o ri gin

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po pul a ti o n : cross sectio nal study. BMJ. 1999 Jul ; 3 19(7204 ):2 15-20 .

Feature Article A Look at Cardiac Myxoma Ahraaz Wyne, Medicine 2010 Reviewed by Dr. David Masse[ Cardiac M yxoma i the most common primary cardi ac tumor. It arises from the e nd ocardium as a lipidi c cell mas e mbedded in a va c ul ar myxo id stro ma. M o t myxo mas are sporadi c and the cau e is large ly unknown. Fami li a l variant with an autosoma l domi nant inheritance ex ist. Myxomas typically develop in female between the eco nd to sixth decade of life . C linica l manife tati o n ca n mimic many cardi ac conditi o ns and depend o n the natura l behaviour of the tumo r and its locati o n within the heart, ranging from co mpl ete ly a ymp LOmatic to causing udden death . Establishing a n early di agno is is esse nti al and requires imag ing techniques. 2D-Ec hocardi ography is the diagnostic modality o f c ho ice however, ultrafast CT or MRI may be required. The preferred treatment is urgica l re ectio n whi c h is curati ve and should be performed as early a possib le to avo id yste mic co mpli cati o ns s uc h a embo li. Patient with cardiac myxo ma ge nerall y have an exce ll ent prog nos is. Following surg ical re ecti o n, scree nin g for rec urre nce is prudent, especia ll y a mo ng th e famili a l varia nts, where the rec urre nce rates may be as hi gh a 20%. Myxomas, although rare, pre ent a vari ed c lini ca l picture and represe nt a diagnostic c ha ll e nge. Co n eq ue ntl y, physicians must have a high index of su pic io n, since pro mpt surgical removal improves quality of life and ex tends survival.

Introduction The fir t de cription of a left atrial myxoma is 1 accredited to King in 1845. A recent review of Carl Rokitansky' collection has revealed a 170year old perfectly con erved myxoma of the pulmonary valve; the patient died in 1833? Prior to 1951 the diagnosis was made primarily at postmortem examinations; in that year, an intracavitary left atrial tumor was diagnosed by angiography.3 The first succe sful excision of a 4 left atrial myxoma was performed in 1955. Primary tumors of the heart are rare clinical entities and studie estimate the incidence as being between 0.0017% and 0.19% at autopsy, among unselected patients. 5 Cardiac myxomas are the most common of the primary cardiac tumors comprising about 30-50%. Approximately 75 % are located in the left atrial cavity, 23% in the right atrial cavity, and about 46 2% in a ventricular cavity. â€˘ While extremely 6 rare, tumors may be found in multiple cavities. Cardiac myxomas have varied clinical presentations which primarily depend on the cardiac chamber where they occur and thu present a challenge for early diagnosi s. Epidemiology and Clinical Practice Epidemiology: Myxomas occur in all age group but are particularly frequent between the third and sixth decades of life. The youngest known

patient was a stillborn infant, and the oldest a 95year-old woman .4 The majority of myxoma are sporadic and tend to be single, atrial , and more typically in women. 1 Approximately 10% are familial , with an autosomal domin ant 7 inheritance. At pre ent, the Carney complex is used to describe an autosomal dominant trait that include cardiac myxomas, cutaneous myxomas, spotty pigmentation s on the skin, endocrinopathy, and both endoctine and nonendocrine tumors. 8 These patient are considerably younger at the time of diagnosis when compared to patient with sporadic myxomas.4 Pathology: Histological examination how atrial myxomas arising from the endocardium , commonl y attached at the border of the fossa ovalis in the left atrium. 4 The cells ari e from multipotential mesenchymal cells and are characterized as lipidic cell embedded in a 4 vascular myxoid stroma. Tumors vary in shape from round-oval to polygonal , and often show calcification, necrosis and/or hemorrhage (see 9 Figure 1). The expres ion of interleuk.in-6 (IL6) by atrial myxomas has been widely reported in the literature and is believed to aid tumor-cell proliferation and differentiation.'' In one series of 37 cases of myxoma, 74% howed expre sion 5 of IL-6. The malignant potential of cardiac

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Figure 1. Histo log ic section show ing polygonal lipidic cell s embedded in an ac id-rnucopo ly acc hari de va cul ar . 4 rna tnx.

myxo ma remains doubtful, although there have been reports of remote myxo matous growth that has emboli zed. 18 Clinical Presentation: While small myxo mas can be asymptomatic, the maj ority present with one or more of the tri ad of intracardiac o bstructi on, cardioemboli sm, and/or nonspecific constituti onal manifes tations; The clini cal presentation will vary depending upon the ph ysical behaviour of the tumor and its locati on within the heart. A. Physical Behaviour: Obstructi on of the circulati on th ro ugh the heart or heart valves commonly gives ri se to ymptom of left(dys pn ea, recurrent pulmonary ede ma, paroxys mal nocturnal dyspnea, orthopnea) or right-sided (peripheral edema, asc ite , fati gue, hepatomegaly) heart-failure, often mimicking mitral or tri cuspid stenosis. The severity of sympto m will depend upon th e ex tent of o bstruction and can vary with body po iti on. If the tumor is large, eas ily defonnable and has a long stalk, then temporary co mplete obstructi on of the mitral or tricuspid valve ori fice can occ ur, res ulting in syncope, di zziness (20 % o f pati ent. ) 4 or sudden death . Interference of the tumor with heart valve fun cti on may produce symptoms of valvular in uffi ciency. Thi s occ urs du e to movement of the mass back and forth between the atrium and ventricle (" wrecking ball" effect), hamperin g proper valve clos ure or damagin g the 4 A V-valve apparatus (e.g. chordal rupture). In vasion o f the myocardium can cause impaired contractility, supraventri c ular arrh ythmi as, heart

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block or pericardia! effu sion. If the myxoma in vades adj acent lung tissue, pulmonary symptom can manifest, often mimicking bronchogenic carcinoma. Emboli zati on, which occurs in 30-40% of 4 myxo mas, is usually syste mic but may also be pulmonary; it will depend on the tumor's chamber of origin . It is for this reason th at myxo ma should always be on the differential for pulmonary embolism, pulmonary hypertension , and embolic stroke . Constituti onal or ystemic symptom such as fa ti gue, fever, ras hes, joint pains and weight loss can also be seen. Laboratory abnonn alities are usually seen as elevated inflammatory markers (erythrocyte sedimentati on rate, serum C -reacti ve pro teins and globulin levels) as well as anemi a, 4 11 and hi gh serum interleukin-6 levels. 路 So metime , low grade but long-standing fever can be the onl y ymptom.9 B. Location: The maj ority (75 %) of atrial myxomas arise in the left atrium and up to 23 % percent in the ri ght atrium. Mo t arise from the inter-atri al septum at the border of the fos a ovalis, but they can al o originate, in de cending order of frequency, fro m the po terior atri al wall, the anteri or atrial wall , and the atri al appendage. ' .4 Tumors can also grow into the atri al lumen and cause ymptoms of blood flo w ob tructi on or create mitral in sufficiency, which are symptoms often assoc iated with commoner condition uch a mitral valve di ease, heart failure and/or econdary pulmonary hypertension. If the tumor moves within the atrium, depending on the length of its talk and ex tent of attachment to the eptum, symptomatic alterati on can occur with changes in body pos iti o n. M yxo mas can also e mbolize producing serious pulmonary and neuro logic equelae. Ph~sical Examination: Phy ical signs are highly van able and depend upon the clinical pre entati on and the ori ginating chamber of the myxo ma. For example, right atrial myxomas may manifest as elevated jugular venou pressure or a pro minent a wave. If the myxoma leads to v al~ular damage ( tenosi /regurgitation), then ys to hc or di as tolic murmurs may be au cultated. A loud S 1 will be heard if there i a delay in mitral valve closure due to tumor prolapse into the valve ori fice (mimicking mitral

stenosi ). The intensity of P2 may also be normal or increased, depending upon the presence of pulmonary hypertension. 4 In many ca es, an early dia tolic so und called a 'tumor plop' i heard, as the tumor impacts against the endocardial wall m left and right sided 8 10 myxoma . " Upon general examination, ystemic signs could include fever, cyanosis, clubbing, rash , or petechiae. Patients with familial or syndromic forms of myxoma may also have feature including skin pigmentations or endocrine abnormalities such as Cushing's Syndrome. 8

Diagnosis The goals of diagno is are three-fold: to ascertain whether a tumor exists, determine its location, and to characterize it. Diagnosis of myxoma require a high index of suspicion and, because of the non-specific nature of laboratory testing, require various imaging studies.'+ Echocardiography first successfully showed a 4 left atrial myxoma in 1959. Today, because of its wide availability and simplicity, 2Dechocardiography is an excellent noninvasive tool for initial evaluation. It typically show unimpeded images of the atria, septae and ventricles making it helpful in detecting tumor location (see Figure 2) and morphology (cysts, calcifications, necrotic foci, and hemorrhage). 4 Doppler techniques aid in determining degree of cardiac obstruction or valvular damage. In many situations a tran esophageal echocardiogram (TEE) is preferred as it provides superior images

Figure 2. One-dimensional echocardiogram 4 apical view of a biatrial myxoma.

showing characteristics of the tumor and location in relation to the interatrial eptum. Sometimes, newer imaging techniques such a cardiac MRI and ultrafast-CT may be required ; both provide noninvasive, high reso lution cross-sectional v1ews of cardiac structures. Cardiac MRI is generally preferred becau e of its hi gher resolution (Figure 3) and ability to reflect chemical microenvironments within a tumor by differential Tl- and T2weighting; however tumors must measure at 4 J? 13 lea t 0.5 em before they are detectable. 路 -路 CT scanning is u eful when MRI is unavailab le or contraindicated. Finally, contrast angiography ha al o been u ed in the diagnosis of myxoma however catheterization is more invasive and run the risk of embolizing tumor fragments. A study by Agostini et al. howed that positron emi ion tomography (PET) could also be used 13 in the diagnosis of myxoma, however PET remains widely unavailable in Canada and may not offer reso lutions comparable to MRI or CT.

Treatment The treatment of choice for myxoma is curative 4 surgical resection . After a review of the literature, there appears to be no known medical therapy for shrinking or preventing recurrence of myxoma and drugs are primarily used to manage symptoms, such as heart failure, or when trying to differentiate tumor from thrombu s (e.g. anticoagulants). Furthermore, there are no recommended dietary modifications and life tyle activities are permitted as tolerated. Once a presumptive diagnosis ha been made, most surgeon recommend prompt resection to avoid embolic complications uch as sudden 14 15 death. " Thi s include asymptomatic patients

Figure 3. A cardiac MRI showin g left atri al myxoma in the Transverse (left) and saggital (ri ght) plane .4

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who have had incidental findings of myxoma during routine echocardiography. Surgery entails performing a median ternotomy and ubsequent tumor excision with the use of mild general and deep topical hypothermia, cardioplegic cardiac arrest, and cardiopulmonary bypass .~ Care is taken to avoid intraoperative fragmentation a all chambers of the heart are in spected for multifocal disea e. If there is associated valvular damage, then thi s is corrected with annulopla ty, 16 17 repair or replacement. 路 The results of surgical re ection are generally very good with most series reporting operative mortality rates under 5 14 17 percent. - M ajor complications of the surgery include tumor embo lization, supraventric ular arrhythmias and requirement of permanent 4 cardiac pacing due to conduction di turbances. Alternative surgical approaches using endoscopic tumor re ection have also been used for their co metic advantage and faster recovery. Recurrence is low, close to 5% in pati ents with sporadic myxomas but can be a high as 20% 7 with the familial variant . As such , there is a need for careful follow-up and biannual 2-D echocardiograms would be reasonable. In rare ca e of freq uent recurrence , cardiac 17 tran plantation has also been performed.

Conclusion Although rare, myxoma IS the mo t common type of primary cardiac tumor and requires a high index of uspicion. For the patient' illness experience, myxoma ran ges from being completely asymptomat ic to causin g severe morbidity and sudden death , with symptom s suggestive of many card iac causes. Surgical removal offers curative treatment with excellent prognosis and recurrences are rare. Thi s paper has briefly provided an overv iew of cardiac myxom as as probably pre enting the most varied clinical picture of all card iac tumors. References l.

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