Exercise-induced intra-ventricular gradients as a frequent potential cause of myocardial ischemia in cardiac syndrome X patients

BioMed Cen al Page 1 o 7 (page numbe no o ci a ion pu poses) Ca dio ascula Ul asound Open Access Resea ch Exe cise-induced in a- en icula g adien s as a equen po en ial cause o myoca dial ischemia in ca diac synd ome X pa ien s Ca los Co im*1,3, Ana G Almeida2 and Manuel Ca age a1,2,3 Add ess: 1Ca diology Depa men , Ga cia de O a Hospi al, Almada, Po ugal, 2Ca diology Depa men , San a Ma ia Hospi al, Lisboa, Po ugal and 3Lisboa Uni e si y Medical School, Lisboa, Po ugal Email: Ca los Co im* - ca losad[email p o ec ed]; Ana G Almeida - anagalme[email p o ec ed]; Manuel Ca age a - mca age a@mail. elepac.p * Co esponding au ho Abs ac Backg ound: The de elopmen o in a- en icula g adien s (IVG) du ing dobu amine o exe cise s ess is no in equen , and can be associa ed o symp oms du ing s ess. The pu pose o his s udy was o assess he occu ence o IVG du ing exe cise s ess echoca diog aphy in ca diac synd ome X pa ien s. Me hods: We p ospec i ely e alua ed 91 pa ien s (p s) mean aged 51 ± 12 yea s (age anged 20 o 75 yea s old), 44 o whom we e women. All p s had angina, posi i e exe cise ECG eadmill es ing, no mal es echoca diog am and no co ona y a e y disease on co ona y angiog am (ca diac X synd ome). A e comple e Dopple echoca diog aphic e alua ion wi h de e mina ion o le en icula ou low ac index (LVOTi), ela i e le en icula wall hickness (RLVWT) and le en icula end-dias olic olume index (LVDVi), all pa ien s unde wen s ess echoca diog aphy wi h wo-dimensional and Dopple echog aphic e alua ion du ing and a e eadmill exe cise. Resul s: Fo analysis pu pose pa ien s we e di ided in 2 g oups, acco ding o he de elopmen o IVG. Dopple e idence o IVG was ound in 33 (36%) o he pa ien s (G oup A), wi h mean age 47 ± 14 yea s old (age anged 20 o 72 yea s) and wi h a mean end-sys olic peak g adien o 86 ± 34 mmHg ( anging om 30 o 165 mmHg). The IVG de elopmen was accompanied by SAM o he mi al al e in 23 p s. Th ee o hese p s expe ienced symp oma ic hypo ension. Ten we e women (30% p s). 58 p s in g oup B, 34 o whom we e women (59%) (p = 0,01 s g oup A), mean aged 53,5 ± 10,9 yea s old (age anged 34 o 75 yea s) (p = 0,03 s g oup A), did no de elop IVG. LVOTi was 10,29 ± 0,9 mm/m2 in g oup A and 11,4 ± 1 mm/m2 in g oup B (p < 0,000); RLVWT was 0,36 ± 0,068 in g oup A and 0,33 ± 0,046 in g oup B (p < 0,01); LVDVi was 44,8 ± 10 ml/m2 in g oup A and 56 ± 11,6 ml/m2 in g oup B (p = 0,000). Conclusion: 1. A signi ican numbe o pa ien s wi h ca diac X synd ome de eloped IVG du ing up igh exe cise in eadmill. These p s (g oup A) a e mainly males and younge han hose who did no de elop IVG. 2. The de elopmen o IVG and mi al al e SAM on exe ion seems o be associa ed wi h ST segmen downsloping du ing s ess es ing in pa ien s wi hou epica dial co ona y disease. 3. The de elopmen o IVG and mi al al e SAM seems o be associa ed wi h lowe LVOTi, lowe LVDVi and highe RLVWT. Published: 14 Janua y 2008 Ca dio ascula Ul asound 2008, 6:3 doi:10.1186/1476-7120-6-3 Recei ed: 10 Decembe 2007 Accep ed: 14 Janua y 2008 This a icle is a ailable om: h p://www.ca dio ascula ul asound.com/con en /6/1/3 © 2008 Co im e al; licensee BioMed Cen al L d. This is an Open Access a icle dis ibu ed unde he e ms o he C ea i e Commons A ibu ion License (h p://c ea i ecommons.o g/licenses/by/2.0), which pe mi s un es ic ed use, dis ibu ion, and ep oduc ion in any medium, p o ided he o iginal wo k is p ope ly ci ed. Ca dio ascula Ul asound 2008, 6:3 h p://www.ca dio ascula ul asound.com/con en /6/1/3 Page 2 o 7 (page numbe no o ci a ion pu poses) Backg ound The de elopmen o IVG du ing DSE has been la gely epo ed and his ac is commonly associa ed wi h symp- oms du ing he s ess s udy [1,2]. The occu ence o IVG du ing he ESE is a ely ind [3]. In a g oup o 10 pa ien s who de eloped IVG du ing DSE, we pe o med ESE and we ound a small IVG in only one o hem [4]. In a 23 yea s old male, wi h a posi i e eadmill es , a s uc u al no mal hea , no mal co ona y angiog aphies, an ESE was pe o med and du ing he s udy we unexpec edly de ec a 102 mmHg in a- en icula g adien [5] and sys olic an e io mo emen o mi al al e (SAM). A simila case has been epo ed p e iously by Lau [6] and was ea ed success ully wi h β blocke s. The aim o his s udy was o p esen he esul s o sea ch o in a- en icula g adien s du ing exe cise s ess echoca diog aphy in pa ien s wi h angina, posi i e s ess elec oca diog aphy, no mal co ona y a e ies, and no - mal echoca diog am (ca diac X synd ome). Me hods This s udy includes 91 (p s) mean aged 51 ± 12 yea s (age anged 20 o 75 yea s old), 44 o whom we e women. All p s had angina, posi i e exe cise ECG eadmill es ing ( ou pa ien s had only ischemia in a myoca dial pe - usion s udy), no mal es echoca diog am – no le en- icula hype ophy – and no co ona y a e y disease on co ona y angiog am. Diabe es melli us o uncon olled hype ension in he las yea we e mo i es o exclusion. Twen y ou pa ien s (26%) a e cu en smoke s and hi y h ee p s (36%) had hype choles e olemia. A he momen o inclusion in he s udy, 47 (51%) pa ien s we e ea ed wi h ni a es, 10 (11%) wi h calcium an agonis s, 18 p s (20%) on β blocke s, 12 p s (13%) wi h angio ensin II ecep o blocke s o angio ensin-con- e ing enzyme inhibi o s, 7 p s (8%) wi h diu e ics. All pa ien s ga e in o med consen o he s udy. Exe cise s ess echoca diog aphy A e comple e echoca diog aphic e alua ion which also includes de e mina ion o le en icula ou low ac index (LVOTi), ela i e le en icula wall hickness (RLVWT) and le en icula end-dias olic olume index (LVDVi), all pa ien s unde wen s ess echoca diog aphy wi h wo-dimensional and Dopple echog aphic e alua- ion. We also measu ed he dis ance D1 in he end o dias- ole, in sho axis iew, as showed in Figu e 1. Exe cise s ess echoca diog aphy as pe o med by he au ho s [7] includes e alua ion du ing all he exe cise in eadmill, o con ac ili y, and in his g oup o pa ien s also pulsed, con inuous and colou Dopple om apical window (Addi ional Files 1 and 2). Mi al al e mo ion was also assessed, o he de elopmen o SAM (Addi ional ile 3 and Figu e 2). The exam was o ally s o ed in ideo ape and pa ially in op ical disk. A signi ican in a en icula g adien , was conside ed an inc ease in he in a en icu- la low eloci y o o g ea e han 2.5 m/s a he end o sys ole ( elesys olic peak)(Figu e 3) and i s occu ence sepa a ed he pa ien s in wo g oups. S a is ical analysis The esul s a e exp essed as mean ± SD o con inuous a - iables, and equency pe cen age o ca ego ical a iables. The a iables we e compa ed be ween g oups wi h he s u- den T es . The X2 es was used o quali a i e a iables. Resul s o s a is ic es s we e conside ed signi ican i he obse ed p alue was less han 0.05. Resul s A ypical example o s ess elec oca diog aphy (Figu e 4), and angiog aphic (Figu e 5) indings is showed. F om he all g oup, 33 pa ien s (36%) de elop IVG (g oup A) and 58 p s (64%) did no de elop in a en icula g a- dien (G oup B) as de ined by he au ho s. In g oup A he IVG a peak exe cise was 86 ± 34 mmHg ( anging om 30 o 165 mmHg). In all bu 11 pa ien s, 85% o p edic ed maximum heo- e ical hea a e o age was eached. Clinical and demo- A line ha o igina es a he poin whe e he in e io wall begins, di ides he le en icle in hal sFigu e 1 A line ha o igina es a he poin whe e he in e io wall begins, di ides he le en icle in hal s. The D1 dis ance is he dis ance be ween ha line and he pos e o in e nal papil- la y muscle (a ow) a he poin whe e i encoun e s he in e io wall. Ca dio ascula Ul asound 2008, 6:3 h p://www.ca dio ascula ul asound.com/con en /6/1/3 Page 3 o 7 (page numbe no o ci a ion pu poses) g aphic da a is p esen ed in Table 1, de ails o he exe cise es a e depic ed in Table 2, and de ails o echoca diog am in Table 3, 4, and 5. In g oup A 23 p s (70%) de elop SAM (Figu e 2, Addi- ional ile 3) du ing exe cise, associa ed wi h IVG (Figu e 3, Addi ional ile 2). No one pa ien de eloped segmen al wall abno mali ies. Mul i a ia e Analysis A logis ic eg ession model was cons uc ed wi h he ol- lowing a iables: age, sex, e o angina, le en icula ou low ac index, le en icula dias olic olume index, ela i e wall hickness, le en icula mass index, D1 dis ance. F om he a iables included a ained s a is i- cal signi icance (p < 0.05) he con ibu ion o e o angina, D1 dis ance, LVDVi, LVOTi and sex, o appea - ance o IVG as we can see in Table 6. Discussion Pa ien s wi h a posi i e eadmill exe cise es , and no mal co ona y angiog aphy ha e long been ecognised as an impo an p oblem in clinical p ac ice [8-10]. These ea ly s udies iden i ied many o he cha ac e is ics o wha was subsequen ly cha ac e ized as synd ome X [10]. The same denomina ion was also applied o a synd ome, cha ac e - ized by insulin esis ance, hype insulinemia, and diabe- es, ha is associa ed wi h dyslipidemia, hype ension, and abdominal obesi y. Hence a mo e speci ic e minol- ogy comes in use: angina wi h no mal co ona y a e iog- aphy [11]. Pa ien s wi h his en i y, p edominan ly women [12], complain o pain ha is equen ly a ypical. I may be p ecipi a ed by exe ion, al hough he h eshold o p ecipi a ing pain is highly a iable [13]. I s du a ion may be uncha ac e is ically long, and i may be unusually se e e and is a ely associa ed wi h symp oms such as dia- pho esis. Pe usion abno mali ies ha e been obse ed commonly in pa ien s wi h ches pain and no mal co o- na y a e iog ams, bu no consis en co ela ion could be made among he ex en o he de ec , he posi i i y o he exe cise es , and exe cise ole ance [14]. Thus in many o his pa ien s he e is e idence o pe usion abno mali ies ha a e a ibu ed o abno mali ies in he mic o ascula- u e [15]. Howe e s ess echoca diog aphy allways ailled o demons a e segmen al wall abno mali ies e en show- ing hype dinamic en icles[16]. The esul s o ou s udy, in which 33 (36%) o 91 pa ien s wi h no mal co ona y angiog am and posi i e eadmill exe cise es de eloped in a en icula g adien , sugges ha ST-segmen dep ession may be ela ed wi h he de el- opmen o IVG du ing exe cise which is possibly in ol ed in he genesis o elec oca diog aphic changes. The possi- ble associa ion be ween ca díac X synd ome and he de elopmen o IVG du ing exe cise was desc ibed be o e [17,18] howe e some o he pa ien s om hese s udies ha e a e ial hype ension, and le en icula hype o- phy ha by de ini ion o X Synd ome [19] we ha e excluded and ha mo e equen ly de eloped IVG [3]. The low ob ained a ha momen wi h con inuous Dopple Figu e 3 The low ob ained a ha momen wi h con inuous Dopple . In his apical ou chambe iew ob ained nea peak exe cise (be o e s oping) we can clea ly see sys olic an e io mo e-men o mi al al eFigu e 2 In his apical ou chambe iew ob ained nea peak exe cise (be o e s oping) we can clea ly see sys olic an e io mo e- men o mi al al e. Ca dio ascula Ul asound 2008, 6:3 h p://www.ca dio ascula ul asound.com/con en /6/1/3 Page 4 o 7 (page numbe no o ci a ion pu poses) The appea ance o IVG in ou s udy was associa ed wi h mo phological de e minan s like educed LVOTi, educed le en icula dias olic olume, a educed dis ance D1, and inc eased ela i e le en icula wall hickness. All hese inding ansla e a p opo ional small hea ha he mul i a ia e model con i ms. The educed D1 in G oup A means an an e io "displace- men " o he pos e o in e nal papilla y muscle ha may be in ol ed in he de elopmen o IVG and SAM o he mi al al e [20,21] as desc ibed by o he au ho s. We can admi ha his phenomenon is e en ually caused by he sub le changes in le en icle geome ic shape and dimensions wi h mo e an e io papilla y muscles implan- a ion [20,21], ha du ing exe cise, induce and submi he co dae and mi al al e o an abno mal sys olic an e io mo ion and o papilla y muscle ischemia. The obs uc ion o he ou low in le en icle wi h he inc ease in he in a en icula p essu e ha i causes may con ibu e, o le en icula s ain and ST-dep ession in his pa ien s. The de elopmen o in a en icula g adien du ing exe - cise may possibly explain he ST changes in a subg oup o pa ien s who ha e eadmill posi i e es and no mal co - ona y a e ies. The pa ien s wi h IVG du ing exe cise had mo e angina du ing exe cise and we e p edominan ly male, and his may explain why hese pa ien s we e submi ed o co o- na y angiog aphy much ea ly, a e he beginning o he symp ons, han pa ien s in G oup B. F om he all s udy g oup 42 pa ien s (46%) ep oduced symp oms du ing ESE, howe e his ac occu ed mo e equen ly (22 p s om 33 in g oup A s 20 om 58 p s in g oup B – p = 0.002) in g oup A, a ou ing he po encial pa icipa ion o in a en icula g adien in he occu ence o symp- oms. Summa y o a posi i e exe cise s ess es in one pa ien om he s udyFigu e 4 Summa y o a posi i e exe cise s ess es in one pa ien om he s udy. Ca dio ascula Ul asound 2008, 6:3 h p://www.ca dio ascula ul asound.com/con en /6/1/3 Page 5 o 7 (page numbe no o ci a ion pu poses) In ou s udy popula ion, we ound a g ea numbe o pa ien s ha de elop SAM o he mi al al e in associa- ion wi h IVG con a ily o o he au ho s [17,18]. We hink ha we de ec SAM in a g ea e numbe o pa ien s because we do echo du ing all he exe cise in eadmill (Addi ional ile 2 and 4) [7]. The magni ude o he IVG ha we ha e de ec ed in ou pa ien s is also g ea e o he same mo i e (Figu e 3). Fou o he 33 pa ien s ha de eloped in a en icula g adien a e a hle es [22] and we should p obably s udy his phenomenon in his speci ic popula ion and, i his Table 1: Clinical and demog aphic da a G oup A G oup B p Age, yea s 47,70 ± 13,36 53,53 ± 10,89 0,026 Sex, emale (%) 10/33 (30%) 34/58 (59%) 0,008 BSA m21,8 ± 0,16 1,73 ± 0,13 0,022 E o Angina 28/33 (85%) 33/58 (56%) 0,006 E o less Angina 9/33 (27%) 35/58 (57%) 0,002 Du a ion o symp oms be o e ca h. (mon hs) 15 ± 10 46 ± 40 0,000 Time o FLW (mon hs) 36,4 ± 17,9 39,1 ± 19,5 0,55 E en s in FLW 6/33 (18%) 8/56 (14%) 0,31 ACS in FLW 1/33 (3%) 7/56 (13%) 0,24 β Bloq. 7/33 (21%) 11/58 (19%) 0,798 CCB 4/33 (12%) 7/58 (12%) 0,666 Ni a es 16/33 (48%) 31/58 (53%) 0,769 IECA/ARAII 5/33 (15%) 7/58 (12%) 0,680 Diu e ics 2/33 (6%) 5/58 (9%) 0,663 β Bloq. FLW 20/33 (60%) 17/56 (30%) 0,003 CCB FLW 4/33(12%) 19/56 (34%) 0,530 Ni a es FLW 9/33 (27%) 33/56 (59%) 0,006 IECA/ARAII FLW 9/33 (27%) 8/56 (14%) 0,068 Diu e ics FLW 4/33(12%) 4/56 (7%) 0,403 BSA – body su ace a ea; ACS – Acu e co ona y Synd ome; CCB – Calcium chanell blocke s; FLW – ollow-up No mal angiog aphy o co ona y a e ies in he same pa ien Figu e 5 No mal angiog aphy o co ona y a e ies in he same pa ien . Ca dio ascula Ul asound 2008, 6:3 h p://www.ca dio ascula ul asound.com/con en /6/1/3 Page 6 o 7 (page numbe no o ci a ion pu poses) occu s, also in es iga e he possible p ognos ic implica- ions o his e en in his pa icula popula ion [23]. The esul s o ESE ha e p obably in luenced he ea men o he pa ien s once a he end o ollow-up a g ea e pe - cen age o pa ien s a e ea ed wi h β blocke s [24,25] in g oup A han in g oup B (Table 1). The p incipal limi a ions o his s udy a e: 1) no one pa ien has done a es o p o oca ion o co ona y spasm a ca h. labo a o y e en no pa ien included in he s udy had segmen al wall abno mali ies wi h exe cise 2) The p esence o absence o ischemia was only e alua ed by ESE wi hou use o scin ig aphic s udies. 3) We excluded all pa ien s wi h le en icula hype ophy and uncon- oled a e ial hype ension ha cons i u es a g ea numbe o pa ien in he eal wo ld o clinical p ac ice and ha should be s udied in he u u e wi h he same p o o- col. Conclusion We can conclude ha a ele an numbe o pa ien s wi h ca diac X synd ome de elop signi ican in a en icula g adien du ing exe cise and also ha mo phological a - iables a e in ol ed in is pa hophysiology. The au ho s belie e ha his phenomenon may cons i u e a new en i y ha joins o he he e ogeneous g oup o pa ien s wi h angina, ST-dep ession du ing eadmill exe cise es and no mal co ona y a e iog aphy. Table 6: Mul i a ia e analysis Va iable -2 Log Likelihood Loss Func ion (p) Age 114,1548 ,071918 Sex 109,0601 ,023868 LVOTi (mm/m2) 91,70272 ,000031 LVDVi ml/m281,35754 ,001299 RLVWT 78,80142 ,109878 LVMi g/m278,73733 ,800141 D1 dis ance 64,62039 ,000172 E o Angina 52,25502 ,000438 LVOTi; LVDVi; RLVWT; LVMi; D1 – as p e iously de ined Table 4: De ails o wo-dimensional echoca diog am G oup A G oup B p LVOTi (mm/m2) 10,29 ± 0,9 11,4 ± 1 0,000 EF (%) 67,94 ± 5,4 66,90 ± 4,5 0,333 LVDVi ml/m244,8 ± 10 56 ± 11,6 0,000 D1 (mm) 10,72 ± 3,11 13,75 ± 2,98 0,000 LVOTi – le en icula ou low ac index; EF – ejec ion ac ion, LVDVi – le en icula dias olic olume index; D1 – dis ance D1 measu ed as explained in igu e 1. Table 2: Exe cise es da a G oup A G oup B p HR Baseline 70 ± 10,5 70 ± 11 0,769 HR Peak 163 ± 14 151 ± 17 0,001 Sys . BP Baseline 133 ± 13 135 ± 15 0,575 Sys . BP Peak 175 ± 21 173 ± 27 0,640 % heo e ical MHR 95 ± 7 91 ± 9 0,02 Du a ion seconds 659 ± 159 503 ± 175 0,000 Time eco e y HR 254 ± 99 260 ± 151 0,832 Double p oduc 28760 ± 4493 26232 ± 4760 0,015 Angina du ing ESE 22/33 (66%) 20/58(34%) 0,002 HR – hea a e; BP – blood p essu e; MHR – maxymal hea a e. Table 3: De ails o echoca diog am M Mode G oup A G oup B p LVEDDi (mm/m2) 25,3 ± 2,8 28 ± 2,7 0,000 LVESDi 15,6 ± 2,4 17,4 ± 2,3 0,0002 FS (%) 38,9 ± 5,4 37,5 ± 4,9 0,219 IVSi (mm/m2) 5,2 ± 0,9 5,1 ± 0,8 0,62 PWi (mm/m2) 4,55 ± 0,7 4,59 ± 0,6 0,75 LVMi g/m273,9 ± 13,1 80,6 ± 13,9 0,028 LA (mm) 37,1 ± 3,2 37,8 ± 2,7 0,279 RLVWT 0,36 ± 0,068 0,33 ± 0,046 0,01 LVEDDi – le en icle eledias olic diame e index; LVESDi – le en icle elesys olic diame e index; FS – accional sho ening; IVSi – in e en icula sep um index; PWi – pos e io wall index; LVMi – le en icula mass index; LA – le a ium; RLVWT – ela i e le en icula wall hickness Table 5: De ails o echoca diog am (Dopple ) G oup A G oup B p CiLLD ml/m22086 ± 561 2235 ± 495 0,198 CWmáxLLD cms130 ± 15,8 120,6 ± 12,5 0,002 CWmáxO ho cms117 ± 14 111 ± 12 0,027 CWmáx 3 182 ± 15 158 ± 15 0,000 E cms85 ± 14 85 ± 16 0,963 A cms68 ± 19 67 ± 13 0,772 Dec. ime sec. 170 ± 34 175 ± 44 0,614 IVRT 85,9 ± 15 88,9 ± 11 0,286 PV 50 ± 12,8 47,9 ± 9,8 0,314 CiLLD – ca diac index in le la e al decubi us be o e de s a o he exam; CWmáxLLD – máximal eloci y o low ob ained a apical i e chambe iew wi h con inuous Dopple o ien ed h ough LVOT o he ao a in le la e al decubi us; CwmáxO ho – máximal eloci y o low ob ained a apical i e chambe iew wi h con inuous Dopple o ien ed h ough LVOT o he ao a in o hos a ic posi ion; CWmáx3-máximal eloci y o low ob ained a apical i e chambe iew wi h con inuous Dopple o ien ed h ough LVOT o he ao a; E- maximal eloci y o E wa e o mi al low; A – maximal eloci y o E wa e o mi al low; Dec. Time sec.- decele a ion ime in seconds; IRVT – iso olumic elaxa ion ime; PV p opaga ion o eloci y e alua ed wi h M Mode colo . Ca dio ascula Ul asound 2008, 6:3 h p://www.ca dio ascula ul asound.com/con en /6/1/3 Page 7 o 7 (page numbe no o ci a ion pu poses) As as consequence o ou esul s, exe cise s ess echoca di- og aphy should be pa o new diagnos ic algo i hm whene e we suspec ha ou pa ien s wi h angina may ha e ca diac X synd ome. Addi ional ma e ial Re e ences 1. Scandu a S, A cidiacono S, Felis S, Ba bagallo G, Des e W, D ago A, Cal i V, Giu ida G: Dynamic obs uc ion o le en icula ou low du ing dobu amine s ess echoca diog aphy: The p obable mechanisms and clinical implica ions. Ca diologia 1998, 43:1201-8. 2. Pellikka PA, Oh JK, Bailey KR, Nichols BA, Monahan KH, Tajik AJ: Dynamic in a en icula obs uc ion du ing dobu amine s ess echoca diog aphy: a new obse a ion. Ci cula ion 1992, 86:1429-2. 3. Pe ei o J, Monse a L, Cas o-Bei as A: Labil subao ic obs uc- ion, du ing exe cise s ess echoca diog aphy. Am J Ca diol 84(9):1119-23. 1999 No 1; A10-1. 4. Co im C, Osó io P, João I, Vic o AR, Co dei o P, Fazendas P, de Oli ei a LM, Ca age a M: Do pa ien s wi h in a en icula g a- dien s du ing dobu amine s ess echoca diog aphy ha e in a en icula g adien s du ing exe cise es ing. Re Po Ca diol 2002, 21(12):1461-5. 5. Co im C, João I, Vic o AR, Fazendas P, Co dei o P, Sequei a A, Hen iksson I, de Oli ei a LM, Ca age a M: Exe cise induced en- icula g adien in a young pa ien wi h posi i e eadmill es and no mal co ona y a e ies. Re Po Ca diol 2002, 21:331-5. 6. Lau TK, Na a ijo J, S ainback RF: Pseudo-False-Posi i e exe cise eadmill es ing. Tex Hea Ins J 2001, 28:308-1. 7. Co im C, Ca age a M: S ess-exe cise echoca diog aphy. Re Po Ca diol 2000, 19(3):345-0. 8. Liko W, Segal BL, Kaspa ian H: Pa adox o no mal selec i e co - ona y angiog ams in pa ien s conside ed o ha e unmis aka- ble co ona y hea disease. N Engl J Med 1967, 276:1063-6. 9. Kemp HG, Ellio WC, Go lin R: The anginal synd ome wi h no - mal co ona y a e iog aphy. T ans Assoc Am Physicians 1967, 80:59-70. 10. Kemp GH: Le en icula unc ion in pa ien s wi h he angi- nal synd ome and no mal co ona y a e iog ams. Am J Ca diol 1973, 32:375-6. 11. Kaplan MN: Synd omes X: Two oo many. J Am Coll Ca diol 1992, 69:1643-4. 12. João I, Co im C, Fazendas P, Ma ins C, Osó io P, Hen iksson I, Dua e JA, Pe ei a H, Oli ei a LM, Ca age a M: Changes in egional con ac il y induced by e o in women wi h no - mal co ona y angiog aphy – epo o a clinical case. Re Po Ca diol 2001, 20(2):183-6. 13. Pupi a G, Mase i A, Kaski JC, Galassi AR, Ga ielides S, Da ies G, C ea F: Myoca dial ischemia caused by dis al co ona y a e y cons ic ion in s able angina pec o is. N Engl J Med 1990, 323:514-0. 14. Tweddel AC, Ma in W, Hu on I: Thallium scans in synd ome X. B Hea J 1992, 68:48-0. 15. Eps ein SE, Cannon RO: Si e o inc eased esis ance o co o- na y low in pa ien s wi h angina pec o is and no mal epica - dial co ona y a e ies. J Am Coll Ca diol 1986, 8:459-1. 16. Picano E, La anzi F, Masini M, Alessand o D, L'abba e A: Use ulness o high-dose dipy idamole-echoca diog aphy es o diagno- sis o synd ome X. Am J Ca diol 1987, 60:508-2. 17. Bueno FC, Bailón IR, Salgue o RL, Doblas JJG, Cabeza AP, He nández JP, F anco AD, Hidalgo LM, Gal án ET: Obs ucción dinámica in a en icua izquie da inducida po es ue zo. Re Esp Ca - diol 2004, 57(12):1179-87. 18. Bueno FC, Doblas JJ, Ga cia AM, Pinilla JMG, Na a o MJ, Gal án ET: E o angina, no mal co ona y angiog am and dynamic le en icula obs uc ion. J Am Soc Echoca diog 2007, 20:415-0. 19. Kaski JC: Ca diac synd ome X and mic o ascula angina. In Ches pain wi h no mal co ona y angiog am: Pa hogenesis, Diagnosis and Managemen Edi ed by: Kaski JC. London, UK: Kluwe Academic Pub- lishe s; 1999:1-12. 20. Robe Le ine A, Gus Vlahakes J, Le eb e Xa ie , Luis Gue e o J, Edwa d Cape G, Aji Yogana han P, A hu Weyman E: Weyman. Papilla y muscle displacemen causes sys olic an e io mo ion o he mi al al e. Expe imen al alida ion and insigh s in o he mechanism o subao ic obs uc ion. Ci cula- ion 1995:1189-5. 21. Quei oz e Melo J, Canada M, Ne es J, Fe ei a MM, de Sousa JS, Rebo- cho MJ, de San os JC, Seab a-Gomes R: Anomalous inse ion o mi al papilla y muscles in obs uc i e hype ophic myo- ca diopa hy. Repo o 2 cases. Re Po Ca diol 1996, 15(6):499-3. 22. Co im C, Lou ei o MJ, Simões O, Co dei o P, Hen iksson I, Vinhas H, Almeida A, Ca age a M: In a en icula g adien du ing e o in a P o essional socce playe . Clinical signi icance. Re Po Ca diol 2005, 24(11):1395-1. 23. Co im C, Almeida AG, Ca age a M: Clinical signi icance o in a en icula g adien du ing e o in an adolescen ka a e playe . Ca dio ascula Ul asound 2007, 5:39. 24. Bueno FC, Pinilla JMG, Doblas JJG, T ujillo AM, Baílon IR, Gal an ET: Be a-blocke he apy o dynamic le en icula ou low ac obs uc ion induced by exe cise. In e na ional Jou nal o Ca diology 2007, 25:117(2):222-6. 25. Almeida S, Co im C, B andão L, Mi anda R, Lou ei o MJ, Simões O, Lopes L, Ca age a M: Exe cise-Induced le en icula ou low ac obs uc ion. A po en ial cause o symp oms in he eld- e ly. Re Po Ca diol 2007, 26(3):257-2. Addi ional ile 1 Echoca diog aphic images ob ained du ing exe cise. Apical ou and i e chambe iew ob ained in apical window du ing exe cise con aining wo dimensional and Dopple da a. Click he e o ile [h p://www.biomedcen al.com/con en /supplemen a y/1476- 7120-6-3-S1.wm ] Addi ional ile 2 Images ob ained du ing exe cise es in he i s pa ien wi h IVG. Images ob ained du ing he exam ha we epea ed, a e in o med consen was ob ained, in he i s pa ien included in he s udy. IVG is easily obse ed du ing exe cise echo. Click he e o ile [h p://www.biomedcen al.com/con en /supplemen a y/1476- 7120-6-3-S2.MPG] Addi ional ile 3 Images ob ained du ing exe cise es in he i s pa ien wi h IVG and SAM. Images ob ained du ing he exam ha we epea ed, a e in o med consen was ob ained, in he i s pa ien included in he s udy. SAM o mi al al e is easily obse ed du ing exe cise echo. Click he e o ile [h p://www.biomedcen al.com/con en /supplemen a y/1476- 7120-6-3-S3.MPG] Addi ional ile 4 Images ob ained du ing exe cise es . Images ob ained du ing exe cise es showing he posi ion o ope a o wi h he cubi al bo de o he igh hand a a ched o he pa ien ches wall. Click he e o ile [h p://www.biomedcen al.com/con en /supplemen a y/1476- 7120-6-3-S4.wm ]