High arrhythmic risk in antero-septal acute myocardial ischemia is explained by increased transmural reentry occurrence

1 Scien i ic RepoR S | (2019) 9:16803 | h ps://doi.o g/10.1038/s41598-019-53221-2 www.na u e.com/scien i ic epo s High a hy hmic isk in an e o- sep al acu e myoca dial ischemia is explained by inc eased ansmu al een y occu ence Hec o Ma inez-na a o, Ana Mincholé, Al onso Bueno-o o io & Blanca Rod iguez* Acu e myoca dial ischemia is a p ecu so o sudden a hy hmic dea h. Va iabili y in i s mani es a ion hampe s unde s anding o a hy hmia mechanisms and challenges isk s a i ica ion. Ou aim is o un a el he mechanisms unde lying how size, ansmu al ex en and loca ion o ischemia de e mine a hy hmia ulne abili y and ecG al e a ions. High pe o mance compu ing simula ions using a human o so/bi en icula biophysically-de ailed model we e conduc ed o quan i y he impac o a ying ischemic egion p ope ies, including loca ion (LAD/LcX occlusion), ansmu al/subendoca dial ischemia, size, and no mal/slow myoca dial p opaga ion. ecG bioma ke s and ulne abili y window o een y we e compu ed in o e 400 simula ions o 18 cases e alua ed. Two dis inc mechanisms explained la ge ulne abili y o een y in ansmu al e sus subendoca dial ischemia. Mac o- een y a ound he ischemic egion was he p ima y mechanism inc easing a hy hmic isk in ansmu al e sus subendoca dial ischemia, o bo h LAD and LcX occlusion. ansmu al mic o- een y a he ischemic bo de zone explained a hy hmic ulne abili y in subendoca dial ischemia, especially in LAD occlusion, as een ies we e a ou ed by he ischemic egion in e sec ing he sep o-apical egion. S ele a ion e lec ed ischemic ex en in ansmu al ischemia o LCX and LAD occlusion bu no in subendoca dial ischemia (associa ed wi h mild S dep ession). he echnology and esul s p esen ed can in o m sa e y and e icacy e alua ion o an i-a hy hmic he apy in acu e myoca dial ischemia. Acu e myoca dial ischemia is s ill one o he leading causes o sudden ca diac dea h wo ldwide1. I a ises om a misma ch be ween supply and consump ion o oxygen and nu ien s, and poo was e emo al, o en due o na owing o a co ona y a e y. One o he clinical challenges in he managemen o pa ien s su e ing om acu e myoca dial ischemia is i s highly a iable mani es a ion, due o di e ences in loca ion, ex en and se e i y o a ec ed myoca dium. Some pa ien s exhibi ma ked ECG abno mali ies, and speci ically ST ele a ion, whe eas o he s su e almos unno iceable changes on hei ECG2. I is also unclea how ischemia-induced ECG abno - mali ies can be used e ec i ely o a hy hmia isk s a i ica ion. The i s 10–15 minu es, o phase 1 A, o acu e myoca dial ischemia a e pa icula ly p o-a hy hmic3 due o inc eased he e ogenei y o epola isa ion and conduc ion a ound he ischemic egion in he human en icles4. These elec ophysiological he e ogenei ies es ablish he p o-a hy hmic subs a e o een an wa es5, po en ially b eaking in o en icula ib illa ion6,7. Compu e simula ions using human en icula models ha e been able o ep oduce exis ing knowledge on acu e ischemia-induced elec ophysiological al e a ions and he es ablishmen o igu e-o -eigh een an dynamics a ound ischemic egions5. This s udy aims o in es iga e how he size, ansmu al ex en and loca ion o he ischemic egion mod- ula e p o-a hy hmic mechanisms o een an dynamics in he human en icles. We hypo hesize ha mac o- een an pa e ns (such as igu e-o -eigh ) a e mo e likely o occu a ound la ge and ully ansmu al ischemic egions, whe eas subendoca dial ischemia sus ains ansmu al een an pa e ns, especially in he ana omically-complex sep al egion ollowing LAD occlusion. This esea ch ques ion has no been add essed so a 8–11, due o se e e me hodological challenges. Fi s ly, expe imen s in human whole- en icles a e challenging due o e hical and p ac ical limi a ions, and he spa io empo al dynamics o acu e egional ischemia con inu- ously change he subs a e. Secondly, compu a ionally, he in es iga ions equi e mul iscale ana omically-based Depa men o Compu e Science, B i ish Hea Founda ion Cen e o Resea ch Excellence, Uni e si y o Ox o d, Pa ks Rd., OX13QD, Ox o d, UK. *email: [email p o ec ed] open 2 Scien i ic RepoR S | (2019) 9:16803 | h ps://doi.o g/10.1038/s41598-019-53221-2 www.na u e.com/scien i ic epo s www.na u e.com/scien i ic epo s/ human o so/ en icula models, which a e e y cos ly and equi e high pe o mance compu ing. In his s udy, we exploi high esolu ion da ase s ob ained om high pe o mance compu ing simula ions using a human o so/ bi en icula elec ophysiology model, cons uc ed and e alua ed using ex ensi e expe imen al and clinical da a om ionic dynamics o he ECG. Elec ophysiological changes in phase 1A ischemia a e di e en om hose obse ed in o he s ages pos -occlusion, such as phase 1B ischemia o in a c ion, which ha e been he ocus o p e ious in es iga ions12,13. Me hods Human o so/bi en icula elec ophysiological model in acu e ischemia. A human bi en icula model embedded in a o so was used o simula e elec ophysiological ac i i y om ionic dynamics o body su - ace po en ials (Fig.1A, le )14. Elec ophysiological al e a ions in he ischemic egion we e modelled as in p e- ious s udies15,16, including ischemic co e zone (ICZ), la e al bo de zone (BZ) and endoca dial BZ. Memb ane Figu e 1. Human o so/bi en icula elec ophysiology model in acu e egional ischemia o ECG and a hy hmia simula ions. (A) Human o so/bi en icula elec ophysiology model in acu e egional ischemia, wi h he 12-lead ECG elec ode loca ions (wi h colou ed sphe es ep esen ing) using s anda d Eu opean colou -coding (le , ep oduced om14 unde open access license); schema ic ep esen a ion o LCX/LAD occlusion and ansmu al/subendoca dial ischemia ( igh ). (B) Compa ison be ween simula ed ECG signal in he p eco dial leads in ansmu al ischemia (le column, solid line) and clinical eco ding om a STAFF III da abase pa ien unde going a LAD co ona y balloon occlusion ( igh column, solid line). (C) Compa ison be ween simula ed ECG signal in he p eco dial leads in subendoca dial ischemia ( op, solid line) and clinical ECG om he Long-Te m ST Da abase du ing ansien ischemia episode (bo om, solid line). Dashed lines o ECG in con ol/p e-ischemia. 3 Scien i ic RepoR S | (2019) 9:16803 | h ps://doi.o g/10.1038/s41598-019-53221-2 www.na u e.com/scien i ic epo s www.na u e.com/scien i ic epo s/ dynamics we e ep esen ed by he modi ied O’Ha a-Rudy model17,18, as desc ibed in Supplemen a y Ma e ials EM.1. Elec ophysiological e ec s o acu e ischemia, caused by hype kalemia, hypoxia and acidosis we e in oduced o ep oduce he he e ogeneous changes in e ac o iness and conduc ion eloci y in human ischemic issue17. In o al, 18 scena ios we e simula ed, including 16 cases o acu e egional ischemia co esponding o combina ions o wo di e en sizes, wo ansmu al ex en s (subendoca dial and ansmu al ischemia), and wo loca ions ( ep- esen ing LCX and LAD occlusion, espec i ely) (Fig.1A and Supplemen a y Ma e ials EM.2). In addi ion, as acu e ischemia o en occu s in pa ien s wi h a diseased ca diac subs a e, we in es iga ed he impac o slow elec- ical p opaga ion (by 25%) h oughou he en icles o all combina ions. Fu he de ails on he cons uc ion and e alua ion o he compu a ional model a e p o ided in Supplemen a y Ma e ials EM.1 and EM.2. ecG simula ions and compa ison o clinical eco dings. The 12-lead ECG was calcula ed a s anda d clinical elec ode posi ions on he o so (Fig.1A, le ). ST de ia ion and QRS slopes we e compu ed, as impo an indica o s o ischemia-induced elec ophysiological abno mali ies19,20. The change in QRS downslopes in com- pa ison o con ol (ΔQRSDS) was quan i ied, wi h posi i e alues indica ing la e slopes in ischemia. Simula ed ECGs and measu ed bioma ke s we e compa ed wi h clinical eco dings om he Physione eposi o y (h ps:// physione .o g/), and speci ically he STAFF da abase, collec ed wi h Ins i u ional Re iew Boa d app o al21. Addi ional de ails a e p o ided in Supplemen a y Ma e ial EM.3. S imula ion p o ocols. Sinus hy hm was simula ed using a ealis ic ac i a ion sequence by applying endo- ca dial s imula ion14 o 3 bea s (S1) wi h a cycle leng h o 600 ms. To e alua e een y ulne abili y, ec opic s im- ula ion (S2) was applied ansmu ally a he BZ. This was based on he expe imen al e idence om22 epo ing ha he ea lies ac i i y o p ema u e bea s in acu e myoca dial ischemia was ound o occu in he no mal myo- ca dium adjacen o he ischemic egion, and ha no impo an ime di e ences we e ound be ween endo- and epica dium. S2 was applied a a ying coupling in e als (CI, i.e. ime di e ence be ween he las S1 and S2) and o each CI, simula ed elec ical ac i i y was analysed o iden i y een y occu ence. The ulne abili y window (VW) was quan i ied as he ange o CIs o which S2 esul ed in a leas wo een an cycles. As he ela i e loca ion o he ec opic s imula ion in he ischemic BZ wi h espec o en icula ana omy and ischemic egion may in luence he VW, we conside ed six S2 loca ions equally spaced a ound he BZ. Simula ions we e conduc ed using he nume ical sol e CHASTE23. By combining mul iple scena ios, CIs and ec opic loca ions, we conduc ed a compu a ionally-expensi e s udy o mo e han 400 simula ions o 3–11 hou s on 720 CPUs. Da a s a emen . The nume ical sol e CHASTE is eely a ailable as Open Sou ce a [h p://www.cs.ox. ac.uk/chas e/download.h ml]. Meshes, models, and sc ip s o eplica e simula ion ou pu s can be ound a [h ps://doi.o g/10.5287/bodleian:9RxJPo9po]. Resul s c edibili y o human o so- en icula model o ecG and een y ulne abili y in es iga ions in con ol and acu e ischemia. Simula ion esul s wi h he human o so-bi en icula model in acu e ischemia we e i s e alua ed h ough compa ison wi h expe imen al and clinical eco dings. Fi s ly, as demon- s a ed in ou p e ious s udy17 and in Supplemen a y TablesST1 and ST2, he elec ophysiological consequences o acu e myoca dial ischemia a ionic, cellula and issue le el a e ep oduced in he simula ions wi h he human en icula issue model, in ag eemen wi h expe imen al eco dings3,4,17,24,25. Speci ically, in he simula ions, ischemic issue exhibi s human en icula ac ion po en ial du a ion sho ening, ele a ion o es ing po en ial, p olonged pos - epola iza ion e ac o iness and dec eased conduc ion eloci y (see Supplemen a y TablesST1 and ST2) as shown in p e ious expe imen al, clinical and compu a ional eco dings3,4,17,24–28. These a e he key elec ophysiological p ope ies ele an o e alua ion o een an dynamics and ECG changes in acu e ischemia. Fu he mo e, as desc ibed in ou p e ious s udy14, he endoca dial ac i a ion model imposed o simula e sinus hy hm yields ac i a ion sequence and QRS complex in he 12-lead ECG, consis en wi h expe imen al and clinical eco dings29–31. This is u he illus a ed in Supplemen a y Fig.SF2, which shows he ag eemen o simula ed ECG in heal hy condi ions compa ed o a clinical eco ding om a heal hy olun ee om he PTB da abase32, bo h in e ms o QRS complex and T wa e mo phology. In oduc ion o acu e egional ischemia in he human o so/bi en icula model causes QRS al e a ions and ST de ia ions in ag eemen wi h clinical eco dings o bo h ansmu al and subendoca dial ischemia (Fig.1B,C, espec i ely). ST ele a ion alues ob ained in simula ed ansmu al ischemia (274 o 319 µV, leads V2, V3 and V4; Fig.1B, le ) a e wi hin he ange ob ained clinically du ing co ona y balloon LAD occlusion (200 o 500 µV in leads V2, V3 and V4, Fig.1B, igh )21. Figu e1C con i ms ag eemen be ween simula ed and clinical ECGs unde subendoca dial ischemia, displaying mild ST dep ession (simula ions: 28 µV in lead V2; −6.3 µV in lead V3; −25 µV in lead V4) in ange wi h maximal dep ession o up o −85 µV in clinical ansien ischemic ECGs33. Thus, he consis ency o simula ion esul s wi h expe imen al and clinical eco dings o ionic, cellula , issue, whole- en icula and ECG p ope ies yields c edibili y o he indings p esen ed below. impac o loca ion, ansmu al ex en and size o acu e egional ischemia on ecG bioma ke s. Figu e2 shows simula ed ECGs o he 16 ischemic scena ios o leads V6 (LCX occlusion, cases A-H) and V3 (LAD occlusion, cases I-P), chosen due o he spa ial p oximi y o hose leads o he la e al and an e io myoca dial walls, espec i ely. Values o ST de ia ion and a ia ion in maximum QRS downslope (ΔQRSDS) a e p o ided. O e all, ECG al e a ions we e mo e se e e o LAD (Fig.2, igh ) han o LCX occlusion (Fig.2, le ). T ansmu al ischemia caused ma ked ST ele a ion (Fig.2A–D,I–L), whe eas subendoca dial ischemia p ima ily esul ed in mild ST dep ession (Fig.2E–H,M–P). Slow myoca dial p opaga ion (Fig.2, g ey shade scena ios) mildly p olonged he QRS in e al wi h negligible e ec s on he ST segmen . 4 Scien i ic RepoR S | (2019) 9:16803 | h ps://doi.o g/10.1038/s41598-019-53221-2 www.na u e.com/scien i ic epo s www.na u e.com/scien i ic epo s/ Figu e3 p o ides u he quan i ica ion o ΔQRSDS and ST de ia ion as a unc ion o pe cen age o ischemic myoca dium ( op and bo om, espec i ely), o ansmu al (ci cles) and subendoca dial (squa es) ischemia. ΔQRSDS posi i ely co ela es wi h he olume o ischemic myoca dium o LAD occlusion (Fig.3, op igh panel), bu no o LCX occlusion (Fig.3, op le panel). Fo bo h LAD and LCX occlusion, ST ele a ion posi i ely Figu e 2. ECG al e a ions caused by acu ely-ischemic egions, o LCX e sus LAD occlusion (A–H and I–P, espec i ely), ansmu al (A–D and I–L) e sus subendoca dial (E–H and M–P) ischemia, small e sus la ge ischemic egion diame e s (∅ = 3 and 6 cm, espec i ely), and no mal e sus educed p opaga ion in emo e myoca dium ( ull colou and g ayscale, espec i ely). Dashed line indica es he ECG unde con ol/p e- ischemia. Leads V6 o LCX and V3 o LAD occlusions a e shown wi h ST de ia ion and change in maximum QRS downslope. 5 Scien i ic RepoR S | (2019) 9:16803 | h ps://doi.o g/10.1038/s41598-019-53221-2 www.na u e.com/scien i ic epo s www.na u e.com/scien i ic epo s/ co ela es wi h he size o he ansmu al ischemic egion (ci cles, solid lines). Howe e , subendoca dial ischemia (squa es) esul s in low o negligible ST dep ession in all cases ega dless o loca ion o size (dashed lines). Di e ences in wa eleng h o een y explain he e ec o ischemic egion size and myoca dial conduc ion eloci y on a hy hmic isk. Figu e4 displays he esul s o he VWs ob ained o he 16 di e en ischemia scena ios wi h p ema u e s imulus S2 in he ischemic BZ in he LV mid-ca i y o bo h LAD and LCX occlusion. No een y was induced wi hou ischemia wi h he same p o ocol. Consis en wi h he he- o y on een an ci cui s, slow myoca dial p opaga ion (as imposed in he g ey-colou ed cases in Figs2 and 4) acili a es een y by educing he wa eleng h o ca diac impulse (i.e. conduc ion eloci y mul iplied by e ac o y pe iod). This is demons a ed in Fig.4 by he wide VWs epo ed in each g ey-colou ed scena io wi h slow con- duc ion eloci y e sus hei co esponden case wi h no mal conduc ion eloci y in he emo e myoca dium. Addi ionally, la ge ICZ we e always mo e a hy hmogenic han smalle ones (Fig.4). The mechanisms a e illus a ed in Fig.5, o la ge e sus small ischemic egions (Fig.5A,B, espec i ely), and no mal e sus slow myoca dial p opaga ion o small ischemic egions (Fig.5B,C, espec i ely). In ag eemen wi h p e ious s udies5,15, p opaga ion ollowing he ec opic s imulus is blocked in he s ill e ac o y ischemic egion ( ed c oss, 382 ms), bu ci cles a ound i owa ds he RV h ough base and apex (whi e a ows, 382 ms). The la ge pa hway h ough he la ge ischemic egion (Fig.5A) allows enough ime, i s ly, o ischemic issue o eco e and o allow e og ade p opaga ion h ough he la ge ischemic egion (Fig.5A, 424 ms), and secondly, o he no mal issue o eco e once p opaga ion has a e sed he ischemic egion, ensu ing he con inua ion o he een y (Fig.5A, 544 ms). In con as , he small ischemic egion (Fig.5B) does no allow enough ime o he eco e y o ischemic issue, p e en ing e og ade p opaga ion and leading o bidi ec ional conduc ion block (Fig.5B, 424 ms), and no een- y es ablished (Fig.5B, 544 ms). Reducing conduc ion eloci y p omo es he o ma ion o een an ci cui s by delaying p opaga ion a ound he ischemic egion (Fig.5C, 382 ms), allowing he eco e y o he ischemic issue and ensu ing e og ade p opaga ion and een y (Fig.5C, 424, 544 ms), e en wi h small ischemic egion. A hy hmia ulne abili y in subendo ca dial LAD occlusion is explained by sep o-apical ans- mu al mic o een an pa hways. We hen in es iga ed he mechanisms explaining how he e ec o loca ion and ansmu al ex en o he ischemic egion may modula e a hy hmic isk. We hypo hesized ha he in e sec ion o he ischemic bo de zone wi h he sep um, as in LAD occlusion, p omo es he es ablishmen o ansmu al mic o- een an pa hways. In he in es iga ion o di e ences be ween LAD and LCX occlusion, Figu e 3. Ischemia-induced al e a ions in ECG bioma ke s e sus pe cen age o ischemic myoca dium ( op: change in maximum QRS downslope; bo om: ST segmen de ia ion), o LCX occlusion (le column, blue sca e poin s) and LAD occlusion ( igh column, ed sca e poin s). Coe icien s o de e mina ion (R2) a e anno a ed o each bioma ke . Smalle symbols co espond o slow p opaga ion condi ions. 6 Scien i ic RepoR S | (2019) 9:16803 | h ps://doi.o g/10.1038/s41598-019-53221-2 www.na u e.com/scien i ic epo s www.na u e.com/scien i ic epo s/ he loca ion o he ec opic s imulus wi h espec o he LV ana omy is likely o modula e a hy hmic isk. We he e o e compu ed he VWs o six di e en S2 loca ions a ound he BZ, o la ge ansmu al and subendoca - dial ischemic a eas in LAD e sus LCX occlusion (Fig.6). O e all, mo e een ies a e induced in LAD e sus LCX occlusion (54 e sus 33 een ies o CIs = 225–300 ms), conside ing bo h ansmu al and subendoca dial ischemia, o he condi ions es ed. Fu he mo e, mo e een ies a e es ablished in ansmu al e sus subendo- ca dial ischemia: 27 e sus 6 een ies, espec i ely, in LCX occlusion, and 35 e sus 19 een ies, espec i ely, in LAD occlusion (Fig.6). Mac o- een y a ound he ischemic egion, as desc ibed in Fig.5 and in p e ious s udies5,15, was es ablished in ansmu al ischemia, o bo h LCX and LAD occlusions and mos S2 loca ions (Fig.6, ligh g ey boxes). As epo ed by Janse e al.5, an addi ional mechanism consis ing o ansmu al mic o- een y was iden i ied (Fig.6, da k g ey boxes), o bo h LAD and LCX occlusion. E en hough ansmu al mic o- een ies occu ed bo h in ansmu al and subendoca dial ischemia, hey we e he key mechanism explaining ulne abili y o een- y in subendoca dial ischemia (Fig.6). Figu e7 demons a es he di e ences in een an pa e ns in ansmu al e sus subendoca dial ischemia. As in Figs5A,C, 7A illus a es he di e en s ages o mac o- een y, wi h unidi- ec ional conduc ion block in he ICZ, ollowed by p opaga ion a ound he BZ (400 ms) p oceeding e og adely in o he ICZ (480 ms) and inally een e ing in o he NZ (620 ms). The een an wa e con inues (710 ms), sus- aining he mac o- een y a ound he ICZ. Howe e , in subendoca dial ischemia (Fig.7B), he epica dial iew shows ha he ec opic s imulus p op- aga es h ough he en icles (260 o 480 ms), wi h subsequen eco e y (620 ms) un il a b eak h ough occu s (710 ms). In con as , in amu al dynamics a e e y di e en as shown in he ansmu al iew h ough he sep um in Fig.7C. Following he ec opic s imulus (260 ms), p opaga ion is blocked unidi ec ionally ( ed c oss) in he subendoca dial ischemic egion (400 ms) bu p oceeds owa ds he base and also su ounds he ischemic egion h ough he LV wall owa ds he apex (whi e a ows). P opaga ion con inues o su ound he BZ (480 ms, 550 ms), blocked in he ischemic egion due o e ac o iness ( ed c oss), bu een e ing h ough no mal issue owa ds he apex (whi e a ows, 620 ms). I is hen ha a spi al wa e is es ablished, ancho ed in he BZ in he sep o-apical Figu e 4. Vulne abili y windows o een y (da k g ey boxes) in acu e egional ischemia o LCX e sus LAD occlusion (A–H and I–P, espec i ely), ansmu al (A–D and I–L) e sus subendoca dial (E–H and M–P) ischemia, small e sus la ge ischemic egion diame e s, and no mal e sus educed p opaga ion in emo e myoca dium ( ull colou and g ayscale, espec i ely). Ec opic s imulus applied a CI = 245 o 285 ms in ischemic bo de zone in LV mid-ca i y (S2.b in Fig.6). 7 Scien i ic RepoR S | (2019) 9:16803 | h ps://doi.o g/10.1038/s41598-019-53221-2 www.na u e.com/scien i ic epo s www.na u e.com/scien i ic epo s/ egion (Fig.7C, 620 ms–802 ms). Figu e7D demons a es he exis ence o a s able I- ype ilamen in he sep o-apical egion. Simula ed elec oca diog aphic signal in lead V3 o bo h een ies analysed in Fig.7A,B/C/D a e shown in 7E, associa ing mac o een ies wi h la ge wa e ampli ude han ansmu al mic o- een ies (~1.3 e sus ~0.5 mV). The mechanisms unde lying he smalle numbe o een ies in subendoca dial e sus ansmu al ischemia pos -LCX occlusion a e illus a ed in Fig.8A,B. Mac o- een y a ound he ansmu al ischemic egion is es ablished in Fig.8A, simila ly o he pa e ns shown in Fig.7A. Howe e , he subendoca dial ischemic egion is no able o sus ain he condi ions o een y es ablishmen , as shown in Fig.8B. Figu e8C shows he elec oca diog am signal Figu e 6. Vulne abili y windows o een y o he mos p o-a hy hmic condi ions, in LAD e sus LCX occlusion and ansmu al e sus subendoca dial ischemic egion o 6 equally-spaced p ema u e s imulus loca ions a ound he ischemic egion. Mac o- een y (ligh g ey boxes), ansmu al mic o- een y (da k g ey boxes) and no een y (whi e boxes) a e indica ed o CI = 235 o 300 ms. Figu e 5. E ec s o slow myoca dial p opaga ion and ischemic egion size on mac o- een y o ma ion. (A) Figu e-o -eigh mac o- een y pa e n induced a ound la ge ansmu al ischemic egion in LAD occlusion. (B) No een y o small ansmu al ischemic egion in LAD occlusion. (C) Simila case as in B, bu mac o- een y is enabled due o slow myoca dial p opaga ion. CI = 260 ms in all cases. 8 Scien i ic RepoR S | (2019) 9:16803 | h ps://doi.o g/10.1038/s41598-019-53221-2 www.na u e.com/scien i ic epo s www.na u e.com/scien i ic epo s/ simula ed in lead V6 o he cases displayed in Fig.8A,B. Mo e de ails abou he o ma ion o een ies can be ound in he Supplemen a y Videos (SV1–SV4). Discussion In his simula ion s udy, he human en icles a ec ed by acu e egional ischemia a e shown o sus ain wo key ypes o een an pa e ns ha de e mine di e ences in a hy hmic isk wi h a ying ischemic egion loca ion, ansmu ali y and size using high pe o mance simula ions. Mac o- een y a ound he ischemic egion occu s p ima ily o la ge ully- ansmu al ischemic egions leading o ST ele a ion, o bo h LAD and LCX occlu- sion. La ge ischemic egions and slow myoca dial p opaga ion a ou ed he es ablishmen o mac o- een ies. Fu he mo e, ansmu al mic o- een y a he ischemic bo de zone was iden i ied as c i ical o explain a hy h- mic isk, pa icula ly o subendoca dial ischemic egions, associa ed wi h mild ST dep ession. Figu e 7. Two dis inc mechanisms o een y in acu e egional ischemia. (A) Mac o- een y in ansmu al ischemia by LAD occlusion. (B) T ansmu al mic o- een y in subendoca dial ischemia ollowing LAD occlusion, epica dial iew. (C) Same case as B, ansmu al iew h ough he sep um displaying he een an ci cui . (D) Same case as B and C, isualiza ion o he s able I- ype ilamen loca ed in he sep o-apical egion. (E) Elec oca diog am compu ed o bo h cases A and B/C/D. CI = 265 ms in A, CI = 260 ms in B/C/D. 9 Scien i ic RepoR S | (2019) 9:16803 | h ps://doi.o g/10.1038/s41598-019-53221-2 www.na u e.com/scien i ic epo s www.na u e.com/scien i ic epo s/ Ou simula ion esul s also show a highe a hy hmic isk in LAD e sus LCX pos -occlusion, o he condi- ions es ed, in ag eemen wi h clinical epo s34. Simula ions e eal ha his is due o a highe p opensi y o he es ablishmen o ansmu al een an ci cui s a he in e sec ion o ischemic egion and sep o-apical egion in LAD occlusion, a he han in he LV o LCX occlusion8,11. Fu he mo e, simula ions show ha QRS downslopes may p o ide use ul in o ma ion on ischemic ex en o subendoca dial ischemia, whe eas ST ele a ion is an indi- ca o o size o ully- ansmu al ischemic egions19,35. The c edibili y o he indings is suppo ed by he consis ency o he simula ion esul s wi h expe imen al and clinical eco dings a he di e en scales in ol ed, as p oposed by Ca usi e al.36. Fi s ly, ischemic issue displays key elec ophysiological al e a ions known o de e mine ECG bioma ke s and een an pa e ns pos -occlusion, and speci ically p olonged pos - epola iza ion e ac o iness and slow conduc ion eloci y3,4,16,24,25. This also includes elec ophysiological g adien s in he ischemic bo de zone, as in ou p e ious s udies15,26,28. Fu he mo e, he ac i a ion sequence used o simula e sinus hy hm has also been shown o be consis en wi h expe imen al eco dings29. Finally, ECG pa e ns in con ol and in acu e ischemia a e in ag eemen wi h clinical 12-lead ECGs eco dings21,32,33. This is bo h in e ms o QRS complex p og ession be ween p eco dial leads (Supplemen a y Fig.SF2) and ischemia-induced al e a ions in QRS slopes and ST ele a ion (Fig.2), shown o be in he ange wi h alues epo ed in clinical s udies35,37. The simula ions wi h he human en icula acu ely-ischemic model also ep oduce he igu e-o -eigh een- an pa e ns a ound he ischemic egion, as epo ed expe imen ally by5,15. These mac o- een ies a e a ou ed by la ge ansmu al ischemic egions, and hei likelihood is explained by he wa eleng h o een y. Simula ions also e eal mic o- een ies, also epo ed expe imen ally5, which a e acili a ed by slow in amu al conduc ion close o he BZ. Whe eas hey also occu in ansmu al ischemia, mic o- een ies a e he only obse ed mecha- nism o een y in subendoca dial ischemia. Pos -LAD occlusion, he in e sec ion o he BZ and he sep o-apical egion a ou s he es ablishmen o mic o- een y by p o iding la ge in amu al pa hways han in he LV ee wall. This can explain he highe a hy hmic isk in LAD e sus LCX occlusion8,11,38. The exis ence o wo p o-a hy hmic mechanisms o een y in acu e ischemia de e mined by he ansmu ali y and loca ion o he ischemic egion may o e oppo uni ies o a ge ed an i-a hy hmic ea men s. Slow p opaga ion in he emo e myoca dium had a subs an ial e ec on a hy hmic isk in ou simula ions, e en hough wi h negligible ECG e ec s (Fig.4). Fib osis39, diabe es40, o hype ophy41 a e main isk ac o s po en ially a ec ing cell coupling and consequen ly dec easing myoca dial conduc ion, albei wi h unclea ECG signa u e42. In ou simula ions, slow conduc ion p omo ed een y in acu e egional ischemia. This is in close co - espondence wi h ex- i o s udies linking he occu ence o ansmu al een ies o conduc ion delays p oduced by ib o ic issue43. I could also explain ha pa ien s su e ing om ib osis as a consequence o pa hologies like hype ophic ca diomyopa hy44 o diabe es melli us45 a e a highe isk unde ischemic condi ions. Mo eo e , subendoca dial ischemia was associa ed wi h sligh ST dep ession in ou simula ions, as in Wilhelms e al.46, bu also wi h high a hy hmia ulne abili y, o LAD occlusion. The signi icance o po en ial isk p edic o s in silen myoca dial ischemia emains an open discussion47,48. Signi ican ST ele a ion as main clinical ma ke o acu e ischemia se e i y48 was only co ela ed in ou esul s wi h ully- ansmu al scena ios sup- po ing mac o- een y (Fig.3). Con e sely, changes in QRS downslope19 accu a ely ep esen ed he p opo ion o a ec ed issue and a hy hmic isk o LAD occlusion. Figu e 8. Reen an mechanisms in LCX occlusion. (A) Mac o- een y in ansmu al ischemia by LCX occlusion. (B) No een y in subendoca dial ischemia by LCX occlusion. (C) Elec oca diog am compu ed o bo h cases A and B. CI = 265 ms in A and B.