B GIO DC V O TO B Y T TRNG I HC Y H NI =========== TRN XUN THY TổNG QUAN Về CHẩN ĐOáN Và ĐIềU TRị BệNH ĐộNG MạCH CHI DƯớI Ngi hng dn khoa hc: PGS.TS inh Th Thu Hng Cho ti: Giỏ tr ca ch s ABI v vai trũ ca Ticagrelor bnh nhõn b bnh ng mch chi di Chuyờn ngnh Mó s : Tim Mch : 62720141 TIU LUN TNG QUAN H NI 2016 MC LC T VN Bnh ng mch chi di mn tớnh (BMCDMT) l tỡnh trng hp mt phn hay tc hon ton lũng ng mch chi di kộo di, nguyờn nhõn x va ng mch, dn n gim lng mỏu ti phn chi ng mch chi phi Bnh ng mch chi di thng u sau tui 40 v tng dn thao tui Nghiờn cu NHANES iu tra ti Hoa k t nm 1999 -2000 cho thy: t l BMCDMT nhúm tui 40 49 l 0,9%; nhúm tui t 50 -59 l 2,5%; t 60 69 l 4,7%; v t l ny tng lờn 14,5% nhúm bnh nhõn > 70 tui Tớnh chung thỡ t l bnh qun th dõn s > 40 tui l 4,3% Vi t l bnh ny, ngi ta c lng cú khong triu ngi mc bnh trờn ton nc M, mt s cao hn so vi nhúm bnh ng mch vnh v t qu nhi mỏu nóo V n nm 2020 s c lng cú th lờn ti triu ngi[1] Din bin ca BMCDMT thng õm thm nhiu nm, triu chng khụng in hỡnh dn n b sút nhiu trng hp bnh Trong ú i cựng vi s tin trin mch chi di thỡ bnh lý x va mch cng tin trin cỏc mch mỏu quan khỏc nh mch vnh, mch cnh, v cú th gõy nhng bin c tim mch nng n T vong bnh nhõn b bnh ng mch chi di ch yu cỏc bin c tim mch Nghiờn cu cho thy sau nm theo dừi nhúm bnh nhõn au cỏch hi cú 20% bnh nhõn b NMCT v t qu khụng gõy t vong, v 10 15% bnh nhõn b t vong (trong s ny t vong tim mch chm 75%)[2] Chớnh vỡ lý trờn m chn oỏn, v iu tr sm bnh l quan trng Trong tiu lun tng quan, chỳng tụi trỡnh by tng quan v chn oỏn v iu tr bnh lý ny NI DUNG 1.1 T l bnh, yu t nguy c, v din bin t nhiờn c bnh ng mch chi di 1.1.1 T l bnh Bnh ng mch chi di thng u sau tui 40 v t l tng dn theo tui: t l bnh nhúm tui 40 -49 tui l 0,9%; 50 -59 tui l 2,5%; 60 -69 tui l 4,7%; trờn 70 tui l 14,5%, v trờn 80 tui l 23,2% Nm 19992000, khong triu ngi M b bnh lý ny, v s c tớnh s t khong triu vo nm 2020 T l BMCDMT nc M cũn cao hn c bnh lý suy tim, t qu, v cng cao hn c bnh nhi mỏu c tim [1] Theo Norgren L, Hiatt WR: nm 2007 c lng cú khong 27 triu ngi b bnh ng mch chi di chõu u v Bc M[3] Theo nghiờn cu PARTNERS thỡ t l bnh nhng ngi cú nguy c tim mch cao (nhng ngi 50 - 69 tui cú ỏi thỏo ng hoc tin s hỳt thuc trờn 10 bao nm, hoc nhng ngi trờn 70 tui) l 29% Trong s ny 13% cú bnh ng mch chi di n thun, v 16% cú kt hp vi bnh ng mch vnh[4] 1.1.2 Yu t nguy c Hỳt thuc lỏ: Hỳt thuc lỏ l yu t nguy c gõy bnh ng mch chi di cũn mnh m hn i vi bnh ng mch vnh Theo nghiờn cu Edinburgh Artery Study thỡ hỳt thuc lm tng nguy c bnh ng mch chi di 2,72 ln (95% CI: 1.13-6.53), v bnh mch vnh 1,62 ln (95% CI: 0.91-2.85)[5] Theo nghiờn cu NHANES thỡ hỳt thuc lỏ lm tng nguy c bnh ng mch chi di vi OR= 3.39 (95% CI: 2.58-4.46) [1] Tng huyt ỏp: Tng huyt ỏp l yu t nguy c chớnh ca cỏc bnh x va ng mch Nghiờn cu cho thy t l THA nhúm bnh nhõn cú ch s ABI mmol/l cú nguy c b au cỏch hi gp ln so vi ngi bỡnh thng[7] Nghiờn cu Physicians Health Study cho thy t s gia cholesterol ton phn/ HDL cholesterol l mt yờỳ t d bỏo c lp cho bnh ng mch chi di[11] iu tr ri lon lipid mỏu lm gim tin trin ca bnh ng mch chi di v lm gim t l au cỏch hi Trong nghiờn cu Heart protection study, iu tr h cholesterol mỏu bng statin lm t vong chung 12%, v gim t vong tim mch 7%[12] Hi chng chuyn húa Hi chng chuyn húa (cú tiờu chun: bộo phỡ, tng huyt ỏp, tng triglycerid mỏu, gim HDl cholesterol mỏu, ri lon dung np glucose mỏu- khỏng insulin) lm tng nguy c tim mch Trong mt nghiờn cu ct ngang cho thy 60% bnh nhõn b bnh ng mch chi di cú hi chng chuyn húa, nhng mc nng ca hi chng chuyn húa khụng tng quan vi mc nng ca bnh ng mch chi di[13] Mt nghiờn cu thun theo dừi 27 111 ph n ban u khụng cú cỏc bnh tim v mch mỏu, thi gian theo giừi trung bỡnh l 13,3 nm cho thy: ph n b hi chng chun húa cú nguy c bnh ng mch chi di 62% cao hn so vi ngi khụng cú hi chng chuyn húa[14] Tng homocystein mỏu Theo nghiờn cu thun ca Asfar S, Safar HA thỡ: nng homocystein mỏu cao lm phỏt trin sm mng x va 41% bnh nhõn b bnh ng mch chi di[15] Homocystein c cho l lm tng sinh t bo c trn, thỳc y viờm thnh mch mỏu, lm tng nng ca cht c ch hot húa plasminogen, v c ch gii phúng nitro oxid t t bo ni mch Tng homocystein mỏu lm tng dy thnh mch, tng to huyt v hp mch mỏu[16] Mc dự tng homocystein mỏu lm tng nguy c v y nhanh tin trin ca bnh ng mch chi di[17], nhng cha cú nghiờn cu no cho thy cỏc liu phỏp lm h homocystein mỏu lm chm tin trin v ci thin bin c nhng bnh nhõn ny 1.1.3 Tin trin t nhiờn ca bnh ng mch chi di[3] 1.1.3.1 Din bin ti ch Ti thi im chn oỏn BMCD cú khong: 20 -50% bnh nhõn khụng cú triu chng, 10 -35% bnh nhõn cú au cỏch hi in hỡnh, 30- 40% bnh nhõn au khụng in hỡnh, v 10 15% bnh nhõn cú biu hin thiu mỏu trm trng nhúm bnh nhõn khụng cú triu chng, au khụng in hỡnh, v au cỏch hi thỡ sau nm theo giừi thy: triu chng n nh hoc thuyờn gim chim 70%, tng triu chng chim 10 -20%, v tin trin nng phi ct ct l: 5-10% nhúm bnh nhõn thiu mỏu chi trm trng thỡ sau nm theo dừi cú ti 30% bnh nhõn b ct ct chi, v ch cú 45% bnh nhõn cũn sng m khụng phi ct ct 1.1.3.2 Din bin ton thõn nhúm bnh nhõn thiu mỏu chi trm trng sau nm cú ti 25% bnh nhõn t vong, v nguyờn nhõn ch yu l cỏc bin c mch mỏu cỏc nhúm bnh nhõn cũn li, sau nm thao giừi thy: 20% bnh nhõn b nhi mỏu c tim hoc t qu khụng gõy t vong; 10 -15% bnh nhõn t vong: s t vong ny cú ti 75% l t vong nguyờn nhõn tim mch 1.2 Cỏc phng phỏp chn oỏn bnh ng mch chi di 1.2.1 Ch s huyt ỏp tõm thu c chõn cỏnh tay (ch s ABI) 1.2.1.1 Khuyn cỏo Hi tim mch v trng mụn tim mch hc Hoa K[18] khuyn cỏo sng lc BMCD bng o ch s ABI nhng tng sau: - Ngi < 50 tui b bnh T cú kốm theo mt yu t nguy c tim mch khỏc (hỳt thuc lỏ, ri lon lipid mỏu, THA, tng homocystein mỏu) - Ngi t 50 69 tui cú hỳt thuc lỏ hoc T - Nhng ngi 70 tui - Cú triu chng gng sc (gi ý au cỏch hi), hoc triu chng au ngh - Khỏm phỏt hin bt thng mch chi di - Cú bnh x va nhng mch khỏc: Mch vnh, mch cnh, mch thn 1.2.1.2 Din gii kt qu - ABI ln hn 1,3: M quỏ cng (ỏi thỏo ng, suy thn, tui cao) - 0,90 ABI < 1,30: h M bỡnh thng hoc tn thng M cha gõy thay i huyt ng - 0,75 ABI < 0,90: chng t cú BMCDMT Tuy nhiờn tun hon bng h bự tr tt - 0,4 ABI < 0,75: tỡnh trng bự tr mc trung bỡnh, ỏp lc xa ch m bo ti mỏu cho nhu cu chuyn hoỏ lỳc ngh - ABI < 0,4 hoc huyt ỏp c chõn di 50mmHg: tn thng gõy nh hng huyt ng nghiờm trng, bnh nng 1.2.1.3 Giỏ tr chn oỏn ca ch s ABI Theo nghiờn cu ca Lijmer JG v CS[19]: s dng im cut off l 0,9 thỡ nhy v c hiu ca ch s ABI l 79% - 95 % v 96% tng ng Din tớch di ng cong ROC ca ch s ny l 95%, lũng mch hp trờn 50% Vi giỏ tr ABI < 0,8 hoc giỏ tr trung bỡnh ln o < 0,9 thỡ giỏ tr chn oỏn dng tớnh lờn ti trờn 95% Khi ABI > 1,1 hoc giỏ tr trung bỡnh ln o >1 thỡ giỏ tr chn oỏn õm tớnh l > 99%[20] Giỏ tr ca ABI cú mi tng quan vi mc nng ca bnh Theo Baker JD v cs[21]: vi ch s ABI< 0,5 thỡ bnh nhõn cú nguy c cao phi ct ct, v s thay i ch s ny > 0,15 sau tỏi to mch chng t cú suy gim ti mỏu chi hoc l ti mỏu c ci thin sau tỏi to mch Cỏc nghiờn cu ca Vog, Newman v cng s cho thy giỏ tr ca ch s ABI 0,9 cú tng quan cht vi nguy c cao b bnh ng mch vnh, t qu nóo, cn thiu mỏu nóo cc b thong qua, v t vong mi nguyờn nhõn [22] 1.2.2 Siờu õm mch mỏu 1.2.2.1 Gii thiu Siờu õm mch mỏu l mt thm dũ khụng chy mỏu dựng chựm tia siờu õm chn oỏn bnh ng mch chi di Hin chn oỏn BMCD ngi ta dựng k thut siờu õm triplex K thut ny l s kt hp ca c k thut siờu õm cựng mt h thng, bao gm: siờu õm hai chiu, siờu õm Doppler mu, v siờu õm Doppler xung Siờu õm mch mỏu cú vai trũ quan trng chn oỏn bnh mch mỏu chi di Khụng nhng cung cp nhng hỡnh nh v gii phu nh: v trớ, mc v hỡnh thỏi tn thng; m siờu õm cũn cung cp nhng thụng tin quan trng v dũng chy v huyt ng ca ng mch T ú giỳp hng dn iu tr, v ỏnh giỏ kt qu tỏi ti mỏu Nhiu phõn tớch gp so sỏnh siờu õm mch vi chp mch cn quang cho cho thy nhy v c hiu ca siờu õm phỏt hin hp mch > 50% lũng mch l 85-90% v > 96% tng ng[23][24] Khụng cú s khỏc bit v giỏ tr chn oỏn ca siờu õm mch gia tn thng on ng mch trờn v di khoeo [25] 1.2.2.2 Hỡnh nh siờu õm ca bnh ng mch chi di[26][27][28][29] Hỡnh nh siờu õm ca hp ng mch chi di Hỡnh nh siờu õm 2D v doppler mu: 10 Siờu õm 2D: Mt s liờn tc v nhn u ca thnh mch, thay vo ú l cu trỳc li vo lũng mch Nguyờn nhõn cú th mng x va, cc huyt bỏm thnh Cú th xỏc nh c v trớ, o c kớch thc, ỏnh giỏ tỡnh trng b mt v cu trỳc õm ca mng x va o ng kớnh lũng mch, tớnh c t l % hp so vi on bỡnh thng Siờu õm Doppler mu: S lp y mu hp hn so vi vựng k cn Ti vựng hp mu sỏng hn (hoc o mu) Cú th thy hỡnh khm mu sau ch hp dũng ri Hỡnh nh siờu õm Doppler xung: Hỡnh nh trc tip: - Tng tc v phõn tỏn ca ph Doppler ti v tr trớ hp: tng tc tõm thu ti a l du hiu u tiờn ca hp ng mch S gia tng tc ti a ph thuc vo mc hp ca lũng mch Theo quy c, tc tõm thu ti a ln hn hoc bng 2m/s tng ng vi mc hp lũng mch trờn 70% Tuy nhiờn hp trờn 70% lũng mch thỡ cú s chuyn hng theo chiu ngc li gim lu lng tun hon - Tớn hiu õm ti v trớ hp cú dng ting rớt sc nhn Hỡnh nh giỏn tip: - Du hiu sau ch hp (h lu): Trong hp nh di 50% lũng ng mch: cha nh hng ti tun hon phớa h lu Hp va t 50% - 70%: gim tc tõm thu ti a h lu gim lu lng tun, ch s mch p gim Trong hp khớt trờn 70% lũng ng mch, du hiu giỏn tip l: ph Doppler dng mt pha sau hp cú dng vũm, Vmax tõm trng rt gim, thi gian tõm thu ti a kộo di, súng phn hi u tõm trng mt, hoc thay th bi mt ph dng ca súng tõm trng - Tớn hiu Doppler phớa trc v trớ hp l hin tng tng sc cn ngoi vi: ch s sc cn v ch s mch p tng 27 Tựy theo c im ca tn thng m bnh nhõn s c u tiờn tỏi ti mỏu bng phu thut bỏc cu ni hay l can thip ni mch Tuy nhiờn c im tn thng mch mỏu bnh nhõn b thiu mỏu chi trm trng l thng cú tn thng ng mch chy, tn thng nhiu tng, v tn thng a mch mỏu nờn phõn loi TASC II khụng thc s hiu qu hng dn tỏi ti mỏu nhúm bnh nhõn ny Nghiờn cu BASIL(bypass versus angioplasty in severe ischemia of the leg) trờn 450 bnh nhõn thiu mỏu chi trm trng b tn thng di dõy chng bn xỏc nh xem nờn u tiờn phu thut trc hay hay can thip trc[73] Da trờn nghiờn cu ny thỡ AHA/ACC ó khuyn cỏo nh sau [18]: - Vi nhng bnh nhõn cú trin vng sng di nm, khụng cú tnh mch tt lm cu ni, thỡ can thip mch qua da c ch nh cho mt s bnh nhõn cú tn thng phự hp ci thin lng mỏu n chi di - Vi nhng bnh nhõn cú trin vng sụng trờn nm v cú tnh mch tt bỏc cu ni thỡ phu thut bỏc cu ni c ch nh trc Can thip ng mch qua da: Vi bnh nhõn b bnh lý kt hp tn thng ng vo v tn thng ng thỡ can thip tn thng ng vo trc Nu cú bnh lý c ng vo v ng ó c can thip ng vo m cũn triu chng thiu mỏu nng thỡ tin hnh can thip ng Trong trng hp khụng rừ tn thng ng vo cú gõy thay i huyt ng cú ý ngha hay khụng thỡ phi o huyt ỏp lũng ng mch qua u tn thng trờn cung ựi trc v sau dựng cht gión mch xỏc nh Phu thut bỏc cu ni Vi bnh nhõn b bnh c ng vo v ng thỡ phu thut ng vo trc Nu tn thng c ng vo v ng ó c phu thut ng vo m cũn triu chng thiu mỏu nng thỡ tin hnh phu thut 28 hoc can thip ng Khụng cú ch nh phu thut cho nhng bnh nhõn cú suy gim ti mỏu trm trng (VD: ABI< 0.4), nhng khụng cú triu chng lõm sng ca thiu mỏu Cỏc phng phỏp phu thut: Tựy theo v trớ, tớnh cht cỏc tn thng m cú th ỏp dng cỏc phng phỏp phu thut khỏc bng mch t thõn hoc vt liu nhõn to Cỏc loi phu thut nh: cu ni ch chu, cu ni ng mch chu ựi, cu ni ng mch nỏch ng mch ựi, cu ni ựi khoeo Hiu qu mt s loi cu ni: - Phu thut cu ni ch ựi: c ch nh bnh nhõn b bnh lý ng mch ch chu vi nguy c phu thut thp T l t vong chu phu khong 5% Mt nghiờn cu trờn 285 bnh nhõn bỏc cu ni ch ựi c theo giừi 19 nm thy t l cu ni thụng sau v 10 nm l 96% v 95% tng ng, t l ct ct l 4.5%[74] - Phu thut cu ni nỏch ựi hai bờn: l phu thut thay th phu thut bỏc cu ch ựi cho nhng bnh nhõn nguy c phu thut cao Phu thut khụng nh hng ti hụ hp, khoang bng ca bnh nhõn, v ch phi gõy tờ ti ch T l cu ni cũn thụng sau nm l khong 50% [75] - Cu ni ựi ựi: ch nh cho bnh nhõn b tn thng mt bờn ng mch chõu, ng mch ch v ng mch chu bờn i din bỡnh thng bnh nhõn ch phi gõy tờ ti ch, thc hin c bnh nhõn nguy c phu thut cao T l cu cũn thụng sau nm l 70 80%[76] - Cu ni ựi khoeo: c ch nh tc ng mch ựi nụng hoc on gn ng mch khoeo T l cu ni cũn thụng nhng bnh nhõn dựng tnh mch t thõn lm cu ni sau v nm l 84% v 69% T l ny nhúm bnh nhõn dựng cu ni nhõn to bng polytetrafluoroetylene l 84% v 69% [77] 29 - Cu ni xa: cu ni xa n ng mch di khoeo ch c ch nh cu ni ựi khoeo khụng th thc hin c, hoc cu ni ựi khoeo khụng cho dũng chy tt ti cỏc ng mch phớa xa T l cu ni bng tnh mch cũn thụng sau v nm l 77% v 62% T l ny nhúm s dng mch nhõn to l 68% v 48%[77] 1.3.4.4 Ct ct chi bnh nhõn b bnh ng mch chi di mn tớnh cú thiu mỏu chi trm trng cú khong 25% bnh nhõn phi ct ct chi tring vũng nm Lý phi ct ct chi bao gm: - Hoi t ln bn chõn, hoi t gõy co kộo gõy bin dng khụng th sa cha c, hoi t gõy nhim khun huyt - Lit chi - Trin vng sng ngn vỡ cỏc bnh lý phi hp khỏc 30 KT LUN Cỏc phng phỏp chn oỏn bnh ng mch chi di Ch s huyt ỏp tõm thu c chõn cỏnh tay (ch s ABI) l phng phỏp n gin, nhng cú nhy cao, giỳp sng lc, chn oỏn v ỏnh giỏ nng ca bnh ng mch chi di Cỏc phng phỏp chn oỏn hỡnh nh khỏc nh : siờu õm mch mỏu, chp MSCT mch mỏu, chp cng hng t mch mỏu cú giỏ tr cao chn oỏn ; cung cp nhng thụng tin quan trng v gii phu, huyt ng hng dn chin lc iu tr tỏi ti mỏu Chp ng mch chi di qua da cú bm thuc cn quang ng mch l tiờu chun vng chn oỏn Phng phỏp ny thng c ch nh v thc hin cựng vi th thut can thip ng mch chi di, bnh nhõn cú ch nh tỏi ti mỏu chi di bng phng phỏp can thip mch mỏu 1.1 iu tr bnh ng mch chi di Mc tiờu iu tr bnh ng mch chi di mn tớnh gm: - Ngn nga s tin trin ca bnh lý x va h thng ng mch v phũng nga cỏc bin c tim mch ton thõn - Ci thin triu chng c nng chi, nõng cao cht lng cuc sng, v phũng nga bin c phi ct ct chi Gim thiu cỏc yu t nguy c v phũng nga bin c tim mch: - iu tr THA, T, RLLP mỏu, ngng hỳt thuc - Khỏng kt tiu cu bng aspirin 75 mg 325 mg/ ngy, hoc clopidogrel 75 mg/ngy Khụng cú ch nh liu phỏp khỏng kt tiu cu kộp iu tr triu chng au: 31 - Vi bnh nhõn au cỏch hi: iu tr gim au bng cilostazol, v phc hi chc nng bng phng phỏp luyn i b c khuyn cỏo - Vi bnh nhõn thiu mỏu chi trm trng: ch nh truyn prostaglandin E1 ci thin triu chng v gim nguy c ct ct chi iu tr tỏi ti mỏu - iu tr tỏi ti mỏu c ch nh nhng bnh nhõn thiu mỏu chi trm trng, hoc nhng bnh nhõn au cỏch hi mc nng khụng ỏp ng vi iu tr ni khoa - Tựy theo bi cnh lõm sng, c im gii phu tn thng m la chn tỏi ti mỏu bng can thip qua da hay phu thut bỏc cu ni - Ch nh ct ct chi mt s trng hp nh: hoi t ln bn chõn, hoi t gõy co kộo gõy bin dng khụng th sa cha c, hoi t gõy nhim khun huyt, hoc trờn bnh nhõn cú trin vng sng ngn vỡ cỏc bnh lý phi hp khỏc TI LIU THAM KHO Selvin E, Erlinger TP (2004) Prevalence of and risk factors for peripheral arterial disease in the United States: results from the National Health and Nutrition Examination Survey, 1999-2000 Circulation; 110:738 Hirsch AT, Criqui MH, Treat-Jacobson D, et al (2001) Peripheral arterial disease detection, awareness, and treatment in primary care JAMA; 286:1317 Norgren L, Hiatt WR, Dormandy JA, et al (2007) Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II) J Vasc Surg; 45 Suppl S:S5 Hirsch AT, Criqui MH, Treat-Jacobson D, et al (2001) Peripheral arterial disease detection, awareness, and treatment in primary care JAMA; 286:1317 Price JF, Mowbray PI, Lee AJ, et al (1999) Relationship between smoking and cardiovascular risk factors in the development of peripheral arterial disease and coronary artery disease: Edinburgh Artery Study Eur Heart J; 20:344 Meijer WT, Hoes AW, Rutgers D, et al (1998) Peripheral arterial disease in the elderly: The Rotterdam Study Arterioscler Thromb Vasc Biol; 18:185 Murabito JM, D'Agostino RB, Silbershatz H, Wilson WF (1997) Intermittent claudication A risk profile from The Framingham Heart Study Circulation; 96:44 Leibson CL, Ransom JE, Olson W, et al (2004) Peripheral arterial disease, diabetes, and mortality Diabetes Care; 27:2843 Selvin E, Marinopoulos S, Berkenblit G, et al (2004) Meta-analysis: glycosylated hemoglobin and cardiovascular disease in diabetes mellitus Ann Intern Med; 141:421 10 Greenhalgh RM, Rosengarten DS, Mervart I, et al (1971) Serum lipids and lipoproteins in peripheral vascular disease Lancet; 2:947 11 Ridker PM, Stampfer MJ, Rifai N (2001) Novel risk factors for systemic atherosclerosis: a comparison of C-reactive protein, fibrinogen, homocysteine, lipoprotein(a), and standard cholesterol screening as predictors of peripheral arterial disease JAMA; 285:2481 12 Heart Protection Study Collaborative Group (2002) MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20,536 high-risk individuals: a randomised placebo-controlled trial Lancet; 360:23 13 Maksimovic M, Vlajinac H, Radak D, et al (2009) Relationship between peripheral arterial disease and metabolic syndrome Angiology; 60:546 14 Conen D, Rexrode KM, Creager MA, et al (2009) Metabolic syndrome, inflammation, and risk of symptomatic peripheral artery disease in women: a prospective study Circulation; 120:1041 Asfar S, Safar HA (2007) Homocysteine levels and peripheral arterial 15 occlusive disease: a prospective cohort study and review of the literature J Cardiovasc Surg (Torino); 48:601 Cacciapuoti F (2011) Hyper-homocysteinemia: a novel risk factor or a 16 powerful marker for cardiovascular diseases? 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