cardial coronary artery dilation (stretch) followed by severe

Transcription

1 Evidence for ltered Epicrdil Coronry rtery utoregultion s Cuse of Distl Coronry Vsoconstriction fter Successful Percutneous Trnsluminl Coronry ngioplsty Tim. Fischell, Kurt N. Busbck, nd Thoms V. McDonld Division ofcrdiology, Stnford University Medicl Center, Stnford, Cliforni 9435 bstrct To determine whether vsoconstriction distl to the site of successful percutneous trnsluminl coronry ngioplsty (PTC) is result of ltered utoregultion in hypoperfused coronry rtery, we exmined the ssocition of this distl vsoconstriction with lesion severity in 2 ptients. Lesion severity ws clssified s moderte, severe or criticl (> 1.,.5-1., nd <.5 mm, respectively). Quntittive coronry mesurements were mde t 3, 15, nd 3 min fter PTC, nd then fter intrcoronry (IC) nitroglycerin, in coronry segments distl to the dilted lesion (distl) nd in nonmnipulted vessel (control). Coronry vsoconstriction in the Distl segment fter PIC correlted with lesion severity, with 14±4%, 28±2%, nd 41±5% vsoconstriction (vs. IC nitroglycerin, 3 min fter PTC) in the moderte, severe nd criticl lesion severity subgroups, respectively (P <.1 for criticl or severe vs. moderte). This vsoconstriction ws significntly greter thn tht observed in the corresponding control segment for ptients with severe (P <-.1), nd criticl (P <.1) lesions. These findings suggest tht hypoperfused humn epicrdil coronry rteries "reset" their utoregultory responsiveness nd tht distl vsoconstriction fter PIC is the result of this ltered utoregultion. These findings hve clinicl implictions concerning the etiology, prophylxis nd tretment of coronry spsm fter PTC nd coronry bypss surgery. (J. Clin. Invest : ) Key words: epicrdil. coronry rtery * vsoconstriction * ngioplsty * utoregultion Introduction In 192 Byliss first described the observtion tht rpid increses in intrluminl rteril pressure were cpble of provoking profound vsoconstriction in both denervted rteries in vivo, nd in excised rteril segments (1). This phenomenon ws ttributed to stretch-dependent reflex of rteril smooth muscle, nd hs been elborted s the "myogenic hypothesis" of rteril tone regultion (2, 3). In the dog rpid increse in blood pressure induced by methoxmine initilly cuses epi- ddress reprint requests to Dr. Fischell, Flk Crdiovsculr Reserch Center, Stnford University, Medicl Center, 3 Psteur Drive, Stnford, C Received for publiction 25 September 1989 nd in revised form 13 Mrch 199. J. Clin. Invest. The mericn Society for Clinicl Investigtion, Inc /9/8/575/1 $2. Volume 86, ugust 199, crdil coronry rtery diltion (stretch) followed by severe vsoconstriction (4). lthough these dt hve been interpreted s drenergic medited vsoconstriction, the time course of this response my be more consistent with stretch/ pressure-dependent form of epicrdil coronry vsoconstriction. The importnce ofthis myogenic reflex in the utoregultion of humn epicrdil coronry rtery tone is suggested by the finding tht coronry tone is essentilly independent of utonomic or humorl input (5). Recent observtions hve suggested tht chronic hypoperfusion my predispose to severe rteril spsm fter bypss grfting of totlly occluded coronry rteries (6). Given these observtions, we hypothesied tht the distl vsoconstriction which hs been observed fter percutneous trnsluminl coronry ngioplsty (PTC)' (7) my result from rpid post-ptc increse in perfusion pressure cusing pressure/stretch-dependent vsoconstriction in hypoperfused epicrdil coronry rteries with ltered (reset) utoregultion. If this hypothesis were correct one would expect to see much greter distl vsoconstriction fter successful dilttion of criticl/subtotl stenosis with its lrge ssocited resting trnsstenotic pressure grdient (hypoperfused) thn fter dilttion of moderte lesion with virtully no ssocited trnsstenotic pressure grdient t physiologic coronry blood flow(s) (not hypoperfused) (8). The purpose of this study ws to test this hypothesis by exmining whether or not the severity ofthis post-ptc distl vsoconstriction ws correlted with lesion severity nd/or qulittive ssessment of coronry blood flow before PTC. ccordingly, we prospectively studied, using quntittive rteriogrphy, the spontneous post-ptc vsoconstrictor responses in the coronry segment distl to the dilted lesion nd in nonmnipulted (control) segment in 2 ptients with vrying lesion severity who underwent uncomplicted single vessel PTC. Methods Ptients. 2 ptients scheduled for elective single vessel PTC of focl stenoses were prospectively entered into the study. ll ptients hd ngin pectoris despite medicl therpy. Exclusion criteri included concurrent nitroglycerin therpy, recent (< 2 wk) myocrdil infrction, length of lesion to be dilted greter thn 1 mm, grde 3 collterl filling of the trget vessel before PTC (9, 1), requirement for intrcoronry nitroglycerin during the PTC, greter thn 5% residul stenosis nd/or less thn thrombolysis in myocrdil infrction (TIMI) grde 3 coronry blood flow ( 11) fter PTC, refusl to prticipte in the study nd/or techniclly indequte coronry rteriogrphy. ttempts were mde to enroll ptients with left coronry rtery 1. bbrevitions used in this pper: CS, cross-sectionl re; EDRF, endothelium-derived relxing fctor; IC, intrcoronry; PTC, percutneous trnsluminl coronry ngioplsty; TIMI, thrombolysis in myocrdil infrction. Coronry Vsoconstriction fter Percutneous Trnsluminl Coronry ngioplsty 575

2 lesions so tht the nonmnipulted left coronry vessel (e.g., left circumflex when left nterior descending ws dilted) could be used for control mesurements. Procedure. The bsic protocol for study hs been described in detil previously (7). ll ptients greed to proceed with the PTC nd study procedures fter being informed of the potentil risks nd complictions, s outlined in protocol pproved by the Institutionl Review Bord of the Stnford University Medicl Center. ll ptients took their usul orl medictions including spirin nd clcium chnnel blockers on the dy of the procedure. fter premediction with diepm nd locl nesthesi with.25% bupivicine femorl rteril (8 Fr) nd femorl venous (7 Fr) sheths were plced vi single wll entry technique. 5 U i.v. of heprin ws given. In those ptients undergoing PTC of the right coronry rtery, bipolr temporry pcing ctheter ws plced in the right ventriculr pex. Selective coronry rteriogrphy of the vessel to be dilted ws performed in multiple projections, including t lest one pir of orthogonl views, using the 4-5-in imge CsI intensifier mode nd Renogrfin 76" t cine rte of 3 frmes per s. The precise ngle of ech projection ws recorded so tht the projection tht best demonstrted the stenosis to be dilted with miniml foreshortening could be replicted. ll contrst injections throughout given study were performed by the sme opertor in order to minimie vribility in ngiogrphic technique. fter second bolus of 5, U i.v. ofheprin coronry ngioplsty ws performed using either n over the wire blloon ctheter system ( 16 ptients) or fixed wire blloon ctheter system (4 ptients). Blloon sies were chosen to pproximte the dimeter of the "norml" coronry segment djcent to the segment to be dilted. t lest two blloon infltions were performed in ech cse, with dditionl infltions performed s needed until the coronry stenosis hd been dilted dequtely using ngiogrphic nd/or hemodynmic criteri. s soon s ws fesible fter the finl blloon infltion (verge 3 min, rnge 2-5 min) the blloon ctheter nd guidewire were withdrwn nd selective coronry rteriogrphy, in the previously selected projection tht best demonstrted the stenosis, ws performed. This ngiogrm ws designted post-ptc. The coronry guiding ctheter ws then withdrwn nd replced with n 8 Fr right or left coronry rtery Judkin's "mrket" ctheter, to be used s reference for coronry quntifiction (see below). Coronry rteriogrms (sme projection) were repeted t 15 nd 3 min fter finl blloon infltion, nd gin 3 min fter the dministrtion of 3 fig ofic nitroglycerin given immeditely fter the 3-min ngiogrm (33 min fter finl blloon infltion). This dose of IC nitroglycerin ws chosen to provide ner mximl vsodilting effect. Blood pressure nd hert rtes were recorded immeditely preceding ech rteriogrm (pre-ptc, post- PTC, 15 min, 3 min, fter IC nitroglycerin). Coronry rteriogrphic nlysis. ll films were nlyed by quntittive rteriogrphic techniques. This system utilies utomted computer ssisted edge detection of digitied cinengiogrphic imge, s hs been described in detil in prior reports (7, 12). Wellopcified end-distolic cine frmes were selected s described, nd mgnified (X3.5) with the pproprite coronry segment centered in the imge field. The imge ws digitied (model 5524; Den Systems, Fremont, C) with the video processor controlled by n 21 computer (Hewlett Pckrd, Plo lto, C). The digitied imge ws displyed on grphics computer terminl linked to light pen. Mgnifiction correction ws chieved using cylindricl tntlum mrker ofknown dimeter tht is ttched to the tip ofthe coronry ctheter in the field of view. fter the segment length ws designted on the computer terminl, the light pen ws used to mnully trce the mrgins of the pproprite vessel segment, nd to indicte the fiducil point. The mximum derivtive ofthe density profile perpendiculr to these mnully defined mrgins re defined s the computer generted vsculr boundries. Using these computer generted vsculr boundries, the minimum, mximum, nd men dimeters of the vessel segment were clculted. The resolution of this system hs been demonstrted to be ±.6 mm (12). Three coronry segments were nlyed in ptients undergoing PTC in the left coronry rtery system, s illustrted in Fig. 1. Segment 1 (Distl segment) ws chosen to be clerly identifible 5-mm long segment distl to the dilted segment nd not mnipulted by the blloon ctheter. Segment 2 (ngioplsty segment) ws defined s the 5-mm long segment centered on the nrrowest point of the coronry stenosis s viewed in the pre-ptc rteriogrm. Segment 3 (Control segment) ws defined s clerly identifible 5-mm long segment in the left coronry rtery tht ws not mnipulted by guide wire or blloon ctheter (e.g., left circumflex when PTC ws performed in the left nterior descending coronry rtery). For the three ptients undergoing right coronry rtery PTC, only segments 1 nd 2 could be nlyed since there ws no equivlent Control segment (see Fig. 1 B). One of the two designted film reders nlyed the men nd minimum segmentl dimeters in ech of three consecutive end-distolic frmes (mrked utomticlly on the cine film by n ECG mrker) for ech 5-mm long segment, t ech time/condition. The finl segmentl vessel dimeter (men nd minimum) t ech time ws defined s the men of the three end-distolic mesurements. Bsed upon mesurements of miniml lesion dimeter using quntittive coronry rteriogrphy in orthogonl projections prior to PTC, the ptients were divided into moderte (n = 7), severe (n = 6), nd criticl (n = 7) lesion severity subgroups (miniml lesion dimeters of > 1.,.5-1., nd <.5 mm, respectively). Miniml lesion cross-sectionl re (CS) ws clculted ssuming n ellipticl model where Dl = miniml lesion dimeter in one orthogonl projection, nd D2 = miniml lesion dimeter in the second orthogonl projection (13): CS = 7r(DI X D2)/4. For the purposes of determining percent (%) 5mm -mm B 5mm Figure 1. Digrm of coronry rtery segments nlyed by quntittive coronry rteriogrphy in the left () nd right (B) coronry rteries. Segment 1 (Distl segment) ws defined s clerly identifible 5-mm long segment distl to the dilted lesion. Segment 2 (ngioplsty segment) ws defined s 5-mm long segment centered in the nrrowest point of the coronry stenosis to be dilted. Segment 3 (Control segment) ws defined s 5-mm long segment in the left coronry rtery not mnipulted by the guidewire or blloon ctheter. OM, obtuse mrginl brnch; Dl nd D2, first nd second digonl brnches, respectively. (Reproduced from Circultion (6): , with permission from the mericn Hert ssocition.) 576 T.. Fischell, K. N. Busbck, nd T. V. McDonld

3 vsoconstriction, the segmentl vessel dimeters mesured from the post-ic nitroglycerin ngiogrm were defined s the mximlly vsodilted stte such tht: % Vsoconstriction (t) = Dimeter fter NTG - Dimeter t Time t/dimeter fter nitroglycerin. The coronry blood flow of the treted vessel in the pre-ptc nd immedite post-ptc rteriogrms ws grded ccording to TIMI clssifiction (i.e., grdes -3) ( 11) by two film reders before quntittive rteriogrphic nlysis of the films. Coronry collterl flow before PTC ws grded on -3 point scle s described by Rentrop (9) nd Fujit (1). Sttistics. Dt re presented s the men±stndrd error (SEM) unless otherwise stted. The comprisons of percent vsoconstriction between segments t given time were performed using Student's pired t test. Comprisons ofpercent vsoconstriction in ech segment for ech condition in the vrious lesion severity subgroups, nd ptient nd procedurl vribles were nlyed by one-wy nlysis of vrince, using repeted mesures (Fisher PLSD). nlysis of scttergrm plots of percent vsoconstriction vs. miniml lesion dimeter nd cross-sectionl re ws performed using polynomil regression pproch. P vlue of <.5 ws considered sttisticlly significnt. Drugs. Nitroglycerin for intrcoronry nd intrvenous dministrtion ws prepred by the ddition of 25 mg of nitroglycerin (TridilR, DuPont Phrmceuticls, Wilmington, DE) to 25 ml of norml sline, yielding finl concentrtion of 1 Jg/ml. Immeditely fter the 3-min rteriogrm, 3 ml of this solution ws dministered s n intrcoronry injection vi the right or left coronry rtery dignostic ctheter. Results The ptient nd PTC procedurl dt (n = 2) re shown in Tble I for ptients in ech of the lesion severity subgroups (moderte [n = 7], severe [n = 6], nd criticl [n = 7]). There were no significnt differences in the historicl vribles between the groups. 16 of the 2 ptients were tking orlly dministered clcium chnnel blockers (either diltiem [n = 12] or nifedipine [n = 4]), nd 15 of 2 ptients were treted with spirin (> 2 wk) t the time of entry into the study (see Tble I). ll ptients received their usul orl doses of these medictions before their PTC. There were no sttisticlly significnt differences between groups in the type or dosge of medictions dministered before the study. The criticl lesion severity subgroup hd significntly lower TIMI flow prior to PTC thn either the severe or moderte lesion severity subgroups (Tble I). The lesion severity before PTC, for ech subgroup, is lso shown in Tble I. Primry ngiogrphic success, defined s reduction in stenosis dimeter to less thn 5% nd TIMI grde 3 flow, ws chieved in ll 2 ptients. There ws no significnt difference in the post-ptc luminl dimeters in the dilted segment between the criticl, severe nd moderte lesion subgroups (Tble I). There ws modest nd nerly equl reduction in systolic blood pressure fter intrcoronry nitroglycerin in ll three subgroups (12, 1, nd 1 mmhg reductions in the moderte, severe, nd criticl lesion subgroups, respectively; P <.5 vs. 3 min fter PTC) without ny significnt chnge in blood pressure from before PTC to 3 min fter PTC in ny group. There were no sttisticlly significnt differences in systolic, distolic or men blood pressures between subgroups t ny time. There were no mjor complictions ssocited with ny of these procedures (i.e., no MI, deth, or need for coronry rtery bypss surgery). Tble I. Ptient nd Procedurl Dt Lesion severity: Moderte (> 1. mm) Severe (.5-1. mm) Criticl (<.5 mm) Ptients (n) ge (men±sem, yr), gender 57±1.9, 7 mle 61±5.4, 5 mle, 1 femle 61±1.6, 7 mle Vessel dilted 2 LD, 4 Cx., I RC 3 LD, 2 Cx., 1 RC 4 LD, 2 Cx., 1 RC Blloon sie (men, mm) Blloon sie: reference seg. (men±sem) 1.6±.7.96±.1.93±.12 Number of infltions (men, n) Mximl infltion pressure (men, tm) TIMI flow pre-ptc (men±sem) 3±. 2.3±.4 1.3±.3* Grde 1 (n) /7 1/6 5/7 Grde 2 (n) /7 1/6 2/7 Grde 3 (n) 7/7 4/6 /7 Lesion dimeter 1.31± ±.23 lpre-ptc (men±sem, mm) post-ptc (men±sem, mm).64±.4t 1.91±.32.43±.1* 1.82±.25 Distl segment dimeter fter nitroglycerin (men±sem, mm) 2.28±.2 2.1±.8 2.4±.23 Medictions: Diltiem 3/7 ptients 4/6 ptients 5/7 ptients Nifedipine 2/7 ptients 1/6 ptients 1/7 ptients spirin 4/7 ptients 6/6 ptients 5/7 ptients Dipyridmole 1/7 ptients 1/6 ptients /7 ptients Bet blockers 1/7 ptients 1/6 ptients 2/7 ptients Cx., left circumflex rtery; LD, left nterior descending coronry rtery; RC, right coronry rtery; * P <.1 for criticl vs. severe nd moderte subgroups. t P <.1 for severe vs. moderte subgroup. Coronry Vsoconstriction fter Percutneous Trnsluminl Coronry ngioplsty 577

4 -DCO t 1X: Distl coronry vsoconstriction fter PTC. The severity of vsoconstriction in the Distl versus the Control segment t 3 min fter successful PTC for ptients in the moderte, severe nd criticl lesion severity subgroups is illustrted in Fig. 2. s shown, the degree of vsoconstriction ws closely ssocited with lesion severity before PTC. There ws no significnt difference in percent vsoconstriction (t 3 min) between the Control vs. Distl segment vsoconstriction in the moderte lesion subgroup (12±1% vs. 14+2%, respectively, P = NS). The severe nd criticl lesion subgroups demonstrted significntly greter distl vsoconstriction thn the moderte lesion subgroup (28±2% nd 41±5% vs. 14±2%, respectively, P vlues s shown). Similrly (Fig. 2 B) there ws significntly greter vsoconstriction in the Distl segment in those ptients with impired trnslesionl blood flow before PTC (TIMI grde < 3 subgroup, n = 1) thn in those with qulittively norml epicrdil blood flow (TIMI grde 3 subgroup, n = 1) (36±3% vs. 16±2%, respectively, P <.5). In Fig. 3, percent vsoconstriction t 3 min fter PTC is plotted s function of miniml lesion dimeter (, C, nd E), nd lesion crosssectionl re (B, D, nd F) before PTC for the Distl, ngioplsty, nd Control segments. Using polynomil regression nlysis of the scttergrm plots, there ws significnt correltion (P <.1) between lesion severity, s judged by either miniml lesion dimeter or cross-sectionl re, nd percent vsoconstriction for the Distl segment. In contrst, there ws no ssocition between lesion severity nd post- PTC vsoconstriction in the Control segment or in the ngioplsty segment (R2 =.12, R2 =.1 1, P = NS, for Control nd ngioplsty segments, respectively). Fig. 4 shows n exmple of severe post-ptc vsoconstriction observed distl to subtotl occlusion compred to the modest nd stble degree of coronry tone in the nonmnipulted left coronry rtery (Control) of the sme ptient. Time course of distl vsoconstriction. The time course of the distl vsoconstriction observed in the severe nd criticl lesion severity subgroups (grouped together s Distl segment (s), n = 13) is illustrted in Fig. 5. The Distl segment in both the severe/criticl nd the moderte lesion severity (distl segment (m), n = 7) groups demonstrted norml "resting" tone before PTC (1±2% nd 12±2%, respectively). There ws minor increse in Distl vsoconstriction noted in the immedite post-ptc ngiogrm in the severe/criticl group but not in the moderte lesion (14±3% vs. 8±3%, respectively). t 15 nd 3 min fter PTC there ws mrked vsoconstriction in the Distl segment ofthe severe/criticl group but not in the moderte lesion or Control groups (31±4% nd 33±3%, vs. 12±2% nd 14±2%, nd 14±2% nd 12±1% for the severe/ criticl, moderte nd Control, respectively). The increse in percent vsoconstriction from pre-ptc to 3 min fter PTC ws lso significntly greter for the severe (21±3%) nd criticl (27±6%) lesion severity subgroups thn for the moderte (2±2%) lesion group (P vlues <.1 for severe or criticl vs. moderte). These dt suggest tht the mximl vsoconstriction in the Distl segment occurs within 15-3 min fter successful PTC. Vsoconstriction in ngioplsty segment. s previously reported (7) we gin observed progressive vsoconstriction in the dilted (ngioplsty) segment fter PTC with 2+2%, 24±2% nd 28±1% vsoconstriction (vs. IC nitroglycerin dimeter) t 3 (post-ptc), 15, nd 3 min fter PTC, respectively (Fig. 5). The degree of vsoconstriction observed 15 nd 3 min fter PTC in the dilted segment ws significntly greter thn tht seen immeditely post-ptc (P <.1), nd ws significntly greter thn the vsoconstriction of the Control segment t 15 nd 3 min (P vlues <.5). Discussion Coronry rtery vsoconstriction distl to the site of blloon dilttion hs been observed fter successful PTC, nd hs been previously ttributed to the relese of pltelet-derived vsoctive substnces t the proximl site of blloon-induced rteril injury (7). This study demonstrtes tht the severity of this distl vsoconstriction is significntly correlted with lesion severity before PTC. These findings suggest tht humn epicrdil coronry rteries reset their utoregultory response in the setting of chronic hypoperfusion nd tht this distl vsoconstriction is the result of mldptive constrictor response to incresed perfusion pressure fter successful PTC. The regultion of rteril smooth muscle tone is complex nd involves n interply between humorl, neurogenic, myogenic, nd endothelium-derived fctors (14). fter successful PTC the distl coronry rtery bed my be subjected to 5 P<O 5-5 B Figure 2. Br grphs demonstrting the degree of vsocon- Z l l D<5< striction in the Control (blck) nd Distl (stippled) seg ments 3 min fter PTC s function of lesion severity l () lnd i 4TIMI flow prior to PTC (B). Verticl brs repre- E sent percent vsoconstriction (men±sem, vs. intrcoronry, IC, nitroglycerin dimeter, see text). () Percent v- ~~~~~~~~~~~~~~~~~~~~soconstrictiont 3 min fter PTC is shown for the Dis-.:... tl nd Control segments s function of lesion severity 1~~~~~~~~~~~~~~~~1 for ptients ith miniml leion dimeters of> 1. (m o 1- = * F Eli:... erte lesion subgroup, n = 6),.5-1. mm (severe lesion TIMI-.._..._ subgroup, n = 6), nd <.5 mm (criticl lesion subgroup, > <.5.. TIMIl3.... TIMI < 3 n = 7) (P vlues s shown). There ws no significnt differ- Miniml Lesion Dimeter (mm) TIMI Flow Prior to PTC ence in vsoconstriction in the Control segments between the three groups nor between the Control nd Distl segment for the moderte lesion subgroup. (B) Percent vsoconstriction t 3 min fter PTC is shown for the Distl nd Control segments for ptients with norml coronry blood flow ("TIMI 3," n = 1) nd for ptients with impired coronry blood flow ("TIMI < 3," n = 1) prior to PTC. There ws significntly greter vsoconstriction in the Distl segment for the subgroup with impired coronry blood flow compred to the subgroup with norml flow (P vlue s shown). There ws no significnt difference in vsoconstriction in the Control segments in the two groups. 578 T.. Fischell, K. N. Busbck, nd T. V. McDonld

5 e:> 6-5 ;.2 4 E C 8 co o Distl Segment CP \ m1 5 R2 =.836 p =.1 I I I I I I --I Miniml Lesion Dimeter (mm) U Distl Segment -N o R2 =.832 p = Lesion Cross-Sectionl re (mm2) B -: ngioplsty Segment 6- C R2 =. 5- ngioplsty Segment R2 =.11 D c 4- i: 3 CF r o 1- n L 4 3- L ft S Miniml Lesion Dimeter (mm) Lesion Cross-Sectionl re (mm2) Control Segment R2 =.16 E 6 1 Control Segment 5 - R2 =.12 F c 4 : C%.o 3-8 o 1-8 ~~~~ --% ffi -- n_ O v W ~ 9 o Miniml Lesion Dimeter (mm) Lesion Cross-Sectionl re (nm2) Figure 3. Scttergrm plots showing the reltionship between lesion severity nd the degree of vsoconstriction in the Distl, ngioplsty, nd Control segments 3 min fter PTC. (-C) The reltionship between miniml lesion dimeter nd the severity of vsoconstriction in the Distl (n = 2), ngioplsty (n = 2), nd Control (n = 17) segments, respectively. (B, D, nd F) The reltionship between clculted lesion crosssectionl re nd the severity of vsoconstriction in the Distl (n = 2), ngioplsty (n = 2), nd Control (n = 17) segments, respectively. The severity of vsoconstriction in the Distl segment incresed exponentilly s the miniml lesion dimeter nd lesion cross-sectionl re decresed (R2 vlues nd P vlues s shown). In comprison, there ws no significnt ssocition between lesion severity nd the severity of vsoconstriction in the Control or ngioplsty segments (R2 vlues s shown). Coronry Vsoconstriction fter Percutneous Trnsluminl Coronry ngioplsty 579

6 LL w : C') -J I- I- LUw Cn -mli en I < 1) 58 T. Fischell, K. N. Busbck, nd T. V. McDonld

7 C._- U L n w * Control Segment (N=17) O Distl Segment (m) (N=7) * Distl Segment (s) (N=13) E3 ngioplsty Segment (N=2Q Pre-PTC Post-PTC 15 Minutes 3 Minutes Time Figure 5. Br grph showing the time course of spontneous vsoconstrictor responses fter PTC in the Control (n = 17), Distl (see below), nd ngioplsty (n = 2) segments. Verticl brs represent percent vsoconstriction (men±sem, see text for definition) for ech segment t ech time: before PTC (pre-ptc), < 5 min fter PTC (post-ptc), 15 nd 3 min fter PTC. The Distl segment group is divided into two subgroups: those with moderte pre-ptc lesion severity (Distl segment (m), n = 7), nd those with severe or criticl lesion severity (Distl segment (s), n = 13). Vsoconstriction in the Distl segment of the severe/criticl subgroup ws significntly greter t 15 nd 3 min fter PTC thn post-ptc, nd compred to the vsoconstriction in the Control nd Distl (m) segment t 15 nd 3 min (**Ps <.1 for ll comprisons). In contrst, vsoconstriction in the Distl segment (m) subgroup ws not significntly chnged during the first 3 min fter PTC nd did not differ from the Control segment t ny time. The degree of vsoconstriction in the ngioplsty segment t 15 nd 3 min fter PTC ws significntly greter thn tht seen in the post-ptc rteriogrms (**P <.1). N, not pplicble. number of stimuli tht could lter epicrdil coronry rtery tone Ḟirst, the distl coronry rtery could be exposed to incresed concentrtions of vsoctive substnces, such s serotonin or thromboxne, relesed from pltelets ggregting t the site of blloon injury (15, 16). The hypothesis tht there ws greter vessel trum fter ngioplsty of the more severely nrrowed segments, leding to incresed pltelet deposition nd greter distl vsoconstriction from pltelet-derived vsoctive substnces, however, is inconsistent with severl observtions from this study. One difficulty with this hypothesis is the lck of evidence tht there ws significntly greter vessel trum fter PTC of the criticl or severe lesions compred to the moderte lesions. The blloon sie, rtio of inflted blloon dimeter to dimeter of djcent norml rtery, totl number of blloon infltions, totl durtion of infltions nd post-ptc incidence of ngiogrphic intiml dissection were not significntly different for the three lesion severity subgroups. number of studies hve demonstrted tht the severity of rteril trum fter blloon ngioplsty, s judged by the incidence of intiml dissection nd cute closure fter PTC (15-17) or determined histologiclly fter in situ ngioplsty (18) or fter ngioplsty in the cholesterol fed rbbit model (19) is not necessrily relted to the severity ofthe lesion being dilted. Severe vessel injury, for exmple, is often observed fter blloon dilttion of moderte lesions (19). If, despite the bove considertions, one ssumes tht there ws substntilly greter injury nd pltelet deposition in the more severely nrrowed segments, one would expect to see n ssocition between lesion severity nd (pltelet-medited) vsoconstriction in the dilted segment prlleling the chnges seen in the distl segment. However, there ws no correltion between lesion severity nd vsoconstriction in the dilted segment. Moreover, if one ccepts this pltelet-meditor hypothesis, the bsence of distl vsoconstriction in ptients with moderte lesions would led to the unlikely conclusion tht pltelets ggregte minimlly or not t ll following blloon ngioplsty of modertely severe coronry lesions (2, 21). dditionlly, studies of blloon ngioplsty in therosclerotic rbbits hve shown tht the potent serotonin ntgonist LY53857 inhibits the spsm observed t the site of blloon injury but does not ffect the severity of distl vsoconstriction (22), which gin suggests tht distl vsoconstriction fter ngioplsty is not pltelet medited. Similrly, the finding tht there re no detectble increses in coronry sinus thromboxne concentrtions fter successful PTC (23) mkes it unlikely tht distl vsoconstriction is medited by in thromboxne. ll of these considertions suggest tht the significnt correltion between pre-ptc lesion severity nd the degree of vsoconstriction observed in the distl segment is not esily explined by the relese of pltelet-derived vsoctive substnces t the site of blloon injury. Increses in coronry blood flow fter successful PTC my lso ffect coronry rtery tone. In norml epicrdil coronry rteries of both dogs (24, 25) nd humns (26, 27), increses in blood flow cuse vsodilttion. This flow-medited vsodilttion ppers to be endothelium dependent nd my be the result of endothelium-derived relxing fctor(s) (EDRF) relese (26, 27). In contrst to ptients with norml coronry rteries, flow-medited epicrdil coronry rtery vsodilttion ppers to be blunted or lost in ptients with therosclerotic coronry rtery disese (27). Since ll of the ptients in the current study hd coronry rtery disese, it is likely tht their flow-medited vsodiltory responses were either blunted or bsent. Such loss of flow-medited vsodilttion could predispose these subjects to exggerted increses in perfusion pressure nd unopposed vsoconstriction in the setting of incresed coronry blood flow fter PTC. The coronry segment distl to the lesion being dilted my lso be exposed to minor trum from guidewire mnipultion, which could theoreticlly provoke coronry vsocon- Figure 4. Seril coronry rteriogrms demonstrting the vsoconstrictor responses of the Distl nd Control segment of study ptient in the criticl lesion subgroup (minimum lesion dimeter =.42 mm, TIMI grde 1 flow prior to PTC). ll imges re end-distolic frmes viewed in the sme projection nd mgnifiction nd shown fter computeried edge-detection imge processing. Imges of the Distl segment nd the Control segment re shown before PTC (pre-ptc), 3 min fter PTC (3 min), nd 3 min fter the dministrtion intrcoronry nitroglycerin (fter NTG). Mrked vsoconstriction is seen in the Distl segment 3 min fter PTC compred to the pre-ptc dimeter with mrked (56%) vsodiltory response to nitroglycerin. The Control segment demonstrted modest (8%) vsodilttion fter nitroglycerin nd no spontneous vsoconstrictor response during the sme time period. Coronry Vsoconstriction fter Percutneous Trnsluminl Coronry ngioplsty 581

8 striction vi endothelil cell injury with secondry pltelet ggregtion. lthough we cnnot totlly exclude guidewire trum s cuse of Distl segment vsoconstriction, this mechnism would not dequtely explin the ssocition between pre-ptc lesion severity nd Distl vsoconstriction or the lck of vsoconstriction observed in the Distl segment of the moderte lesion severity subgroup. In ddition, the vsoconstriction observed in the coronry rtery distl to the dilted lesion ws diffuse nd not limited to the prt of the vessel mnipulted by the guidewire (see Fig. 4.). Finlly, depending upon the severity of the lesion being dilted, there my be rpid increse in perfusion pressure in the epicrdil coronry rtery distl to the dilted lesion fter successful PTC (28). lthough one would expect pssive epicrdil coronry rtery dilttion from n increse in perfusion (distending) pressure fter PTC we observed either no chnge (moderte lesion subgroup) or pronounced decrese in coronry dimeter (severe nd criticl lesion severity subgroups) distl to the dilted segment fter successful PTC. Prdoxiclly, those vessels with presumbly the lowest resting perfusion pressure (TIMI grde 1 flow, distl to ner-totl occlusion) demonstrted the gretest loss of dimeter fter PTC, suggesting tht hypoperfusion predisposes to vsoconstriction fter PTC (see Fig. 4.). The spontneous loss of dimeter in the distl segment of the severe nd criticl lesion subgroups cnnot be explined by hemodynmic fctors, since blood pressure ws essentilly constnt during the seril rteriogrms nd the Control segment showed no similr loss of dimeter. The fct tht this progressive loss ofdimeter cnnot be explined by the expected or observed chnges in blood pressure, coronry perfusion pressure or coronry blood flow, nd ws reversed fter n intrcoronry injection of nitroglycerin suggests tht the loss of dimeter distl to the dilted lesion ws the result of ctive vsoconstriction. The mgnitude of the increse in perfusion pressure (stretch stimulus) fter successful PTC is directly relted to the severity of the resting pressure grdient cross the stenosis to be dilted. The reltionship between lesion severity nd trnsstenotic pressure grdient cross typicl high-grde humn coronry stenosis cn be pproximted by the formul PpPd = 1.8 Qs/dmin Qs2/dmin' s described by Brown et l. (8). In this formul Pp - Pd represents the pressure drop (mmhg) cross the stenosis, Qs the stenosis flow (ml/s) nd dmin the miniml lumen dimeter (mm). ssuming norml rnge of resting coronry blood flow for medium sied epicrdil coronry rteries ( ml/s) (29) one cn estimte, using this formul, tht the verge resting trnsstenotic pressure grdients in our three groups of ptients would be 3-6, 25-87, nd 1 ->2 mmhg for the moderte, severe, nd criticl lesion subgroups, respectively. It should be recognied, however, tht the flow-limiting nture of the most criticl lesions my result in n overestimtion of the trnsstenotic pressure grdients when one clcultes this grdient bsed upon norml resting coronry blood flow. The expected increse in perfusion pressure in the distl coronry bed fter successful PTC should be proportionl to these resting grdients (28). The ctul increse in perfusion pressure fter PTC will lso be ffected by the degree of collterl blood flow nd the dequcy of the PTC result. Despite these limittions, the observtion tht the degree of distl vsoconstriction closely prllels the estimted increse in perfusion pressure fter successful PTC provides good evidence tht humn epicrdil coronry rteries my reset their utoregultory response in the setting of chronic hypoperfusion. Reflex vsoconstriction my then occur when the distl vessel is suddenly exposed to higher thn usul (pre-ptc) perfusion pressure. s discussed, it ppers most likely tht distl vsoconstriction fter ngioplsty of high grde coronry stenoses is the result of pressure/stretch-medited stimulus. The vsoconstriction observed fter rpid rteril stretching hs clssiclly been considered to be intrinsic to the smooth muscle, or myogenic (1-3), nd therefore endothelium independent. However, recent studies by Hrder (3), Osol (31), Vnhoutte (32-34), nd Fischell (35) suggest tht some forms of stretch or pressure-induced myogenic tone, including utoregultion to blood pressure chnges in cerebrl rteries (3, 33), re endothelium dependent. In number of mmmlin species such s rts (31), rbbits (35), cts (3), dogs (33, 34), nd pigs (36) vsculr endothelil cells pper cpble of functioning s "mechnotrnsducers" (36), such tht mechnicl stimulus (e.g., incresed luminl pressure or stretch) my stimulte the relese of vsoctive substnce(s) (endothelium-derived contrctile fctor[s]) cpble of ctivting clcium-dependent smooth muscle contrction (3, 33, 35, 37, 38). lthough specultive, it is possible tht the vsoconstriction observed in the distl segment fter PTC of severe nd criticl stenoses is medited by such n endothelium-dependent process. We cnnot exclude, however, the possibility tht the distl vsoconstriction is myogenic. Implictions. The presumptive finding of ltered utoregultion s cuse of vsoconstriction in hypoperfused epicrdil coronry rteries hs severl clinicl implictions. Severl investigtors hve found bnormlly depressed coronry flow reserve in 5% of ptients who undergo successful PTC (39-41). This depressed coronry blood flow reserve is independent of ngiogrphic or hemodynmic prmeters of successful revsculrition nd eventully normlies in ll ptients who do not develop restenosis (39). Wilson et l. speculted tht prolonged hypoperfusion distl to n epicrdil coronry stenosis my "[lter] the bility of the rteriolr vsculture to utoregulte in response to sudden restortion of norml perfusion pressure" (39). If the ltertion in coronry utoregultion tht we observed in epicrdil vessels were generlied to the coronry rterioles, this might explin the finding of trnsient depression of coronry flow reserve fter successful PTC. second importnt clinicl finding of this study is the bility of intrcoronry nitroglycerin to reverse this coronry vsoconstriction. We hve previously reported tht intrvenous nitroglycerin dministered t doses tht reduce the systolic blood pressure by 2 mmhg is cpble of preventing vsospsm in both the Distl nd ngioplsty segments (7). Bsed on these observtions nd the findings tht orlly dministered clcium chnnel blockers nd spirin do not prevent vsoconstriction in the ngioplsty or Distl segments, we routinely dminister reltively high-dose systemic nitroglycerin therpy during, nd for t lest 24 h fter PTC. Finlly, in extreme cses this vsospsm my provoke ischemi nd/or myocrdil infrction fter PTC or coronry rtery bypss grfting surgery (6). In one prticulrly illustrtive cse occlusive coronry rtery spsm leding to myocrdil infrction occurred fter bypss grfting of chroniclly occluded left nterior descending coronry rtery, with no evidence of spsm in grfted obtuse mrginl coronry rtery 582 T.. Fischell, K. N. Busbck, nd T. V. McDonld

9 with moderte (6%) stenosis. Myocrdil infrction secondry to severe coronry rtery spsm fter coronry bypss grfting of chroniclly hypoperfused vessels could explin, in prt, the intriguing observtion tht mjority of postopertive myocrdil infrctions re ssocited with widely ptent bypss grfts t utopsy or rteriogrphy (42, 43). Limittions ofthe study. Despite the cre tken to control for confounding clinicl vribles there re severl potentil limittions of this study. It is recognied tht collterl blood flow my increse the coronry perfusion pressure distl to severe or criticl stenoses. To minimie the effects of well-developed coronry collterls on the trnsstenotic pressure drop we excluded from entry ptients with well-developed collterls supplying the vessel to be dilted (> grde 2 collterls) ( 12). Idelly, trnsstenotic pressure grdients should hve been used to correlte ltertions in epicrdil utoregultion with chronic hypoperfusion. lthough these pressure grdients cn be mesured using blloon ctheters before nd fter PTC, these mesurements re often inccurte nd my be erroneously ffected by vessel tortuosity, blloon ctheter sie, nd chnges in coronry blood flow (28, 44). For these resons we elected to use primrily ngiogrphic mesures of lesion severity to ssess the reltionship between hypoperfusion nd distl vsoconstriction fter PTC. Finlly, our methodolology does not llow us to comment upon the ltency period required to reset or redjust utoregultion in the setting of hypoperfusion, nor the durtion of ltered utoregultion fter the restortion of norml coronry blood flow. Summry. The severity ofcoronry rtery vsoconstriction distl to the site of successful PTC is closely correlted with lesion severity before PTC. This distl vsoconstriction begins shortly fter successful revsculrition nd ppers to pek t 15-3 min fter PTC. These observtions re consistent with the hypothesis tht humn epicrdil coronry rteries cn reset their utoregultory responsiveness in the settingofchronic hypoperfusion such tht restortion of more norml levels of perfusion pressure fter successful PTC my provoke reflex vsoconstriction. It is likely tht this vsospsm is medited by either n endothelium-dependent or myogenic mechnism. These findings hve importnt physiologic implictions concerning the dynmics nd plsticity of humn coronry rtery blood flow regultion s well s clinicl implictions regrding the etiology nd prophylxis of coronry rtery spsm fter PTC nd coronry rtery bypss grft surgery. cknowledments We thnk Dr. Dvid Clrk nd Dr. Mrc Grdmn for their ssistnce in ptient recruitment nd prticiption in the study protocol, nd Robert Kernoff for his ssistnce with photogrphy. Dr. Fischell is Clinicl Investigtor of the Ntionl Hert, Lung, nd Blood Institute (grnt HL-21-1). This pper ws ccepted for finlist presenttion, Young Investigtors wrd Competition, mericn College of Crdiology, 19 Mrch 199. References 1. Byliss, W. M On the locl rections ofthe rteril wll to chnges of internl pressure. J. Physiol. (Lond.). 28: Koch,. R Some mthemticl forms of utoregulting models. Circ. Res. 15(Suppl. 1): Bevn, J Vsculr myogenic or stretch-dependent tone. J. Crdiovsc. Phrm. 7(Suppl. 3):S Vtner, S. F., M. Pgni, W. T. Mnders, nd. D. Psipoulrides lph drenergic vsoconstriction nd nitroglycerin vsodiltion of lrge coronry rteries in the conscious dog. J. Clin. Invest. 45: Hodgson, J. M., M. D. Cohen, S. Senpetery, nd M. D. Thmes Effects of regionl lph- nd bet-blockde on resting nd hyperemic coronry blood flow in conscious, unstressed humns. Circultion. 79(4): Fischell, T.., T. V. McDonld, M. T. Grttn, D. C. Mille, nd M. L. Stdius Occlusive coronry-rtery spsm s cuse of cute myocrdil infrction fter coronry-rtery bypss grfting. N. Engl. J. Med. 32(6): Fischell, T.., G. Derby, T. M. Tse, nd M. L. Stdius Coronry rtery vsoconstriction routinely occurs fter percutneous trnsluminl coronry ngioplsty: quntittive rteriogrphic nlysis. Circultion. 78(6): Brown, B. G., E. L. Bolson, nd H. T. Dodge Dynmic mechnisms in humn coronry stenosis Circultion. 7(6): Rentrop, K. P., M. Cohen, H. Blnke, nd R.. Phillips Chnges in collterl chnnel filling immeditely fter controlled coronry rtery occlusion by n ngioplsty blloon in humn subjects. J. m. Coll. Crdiol. 5: Fujit, M., S. Ssym, H. snoi, H. Nkjim,. Ski, nd. Ohno Improvement of tredmill cpcity nd collterl circultion s result of exercise with heprin pretretment in ptients with effort ngin. Circultion. 77(5): Pssmni, E., nd the TIMI Study Group The thrombolysis in myocrdil infrction (TIMI) tril. N. Engl. J. Med. 312(14): ldermn, E. L., L. E. Berte, D. C. Hrrison, nd W. 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10 21. Lm, J. Y. T., J. H. Cheseboro, nd V. Fuster Pltelets, vsoconstriction, nd nitroglycerin during rteril wll injury: new ntithrombolytic role for n old drug. Circultion. 78: Sigl, S. L., I. J. Srembock, P. J. LVeu, T. L. Yng, nd M. D. Eekowit specific serotonin receptor ntgonist prevents proximl but not distl spsm following blloon ngioplsty. Circultion. (Suppl. II):I Peterson, M. B., V. Mchj, P. C. Block, I. Plcios, D. Philbin, nd W. D. Wtkins Thromboxne relese during percutneous trnsluminl coronry ngioplsty. m. Hert J. 11 (1); Inoue, T., H. Tomoike, K. Hisno, nd M. Nkmur Endothelium determines flow-dependent diltion ofthe epicrdil coronry rtery in dogs. J. m. Col. Crdiol. 11: Hinte, T. H., nd S. F. Vtner Rective diltion oflrge coronry rteries in conscious dogs. Circ. Res. 54: Drexler, H.,. Zeiher, H. Wollschlger, nd T. Bonel Flow-dependent coronry diltion in mn. Circultion. (Suppl. II):II Cox, D.., J.. Vit, C. B. Tresure, R. D. Fish, R. W. lexnder, P. Gn, nd. P. Selwyn therosclerosis impirs, flow-medited diltion of coronry rteries in humns. Clin. Res. 8: Serruys, P. W., W. Wijns, J. H. C. Reiber, P. de Feyter, M. Vn den Brnd, F. Piscione, nd P. G. Hugenholt Vlues nd limittions of trnsstenotic pressure grdients mesured during percutneous trnsluminl coronry ngioplsty. Her. 1(6): Gn, W., K. Kmur, H. S. Mrcus, S. Donoso, S. Yshid, nd H. J. C. Swn Mesurements of coronry sinus blood flow by continuous thermodilution in mn. Circultion. 44: Hrder, D. R Pressure-induced myogenic ctivtion of ct cerebrl rteries is dependent on intct endothelium. Circ. Res. 6: Osol, G., R. Osol, nd W. Hlpern Pressure-dependent modultion of myogenic tone by cerebrl endothelium (bstrct). Circultion. 76(Suppl. IV):IV Vnhoutte, P. M Endothelium-dependent contrctions in rteries nd veins. Blood Vessels. 24: Ktusic, Z. S., J. T. Shepherd, nd P. M. Vnhoutte Endothelium-dependent contrction to stretch in cnine bsilr rteries. m. J. Physiol. 252:H Ktusic, Z. S., J. T. Shepherd, nd P. M. Vnhoutte Endothelium-dependent contrction to stretch in cnine bsilr rteries (bstrct). Fed. Proc. 45: Fischell, T.., U. Nellessen, D. E. Johnson, nd R. Ginsburg Endothelium-dependent rteril vsoconstriction fter blloon ngioplsty. Circultion. 79: Lnsmn, J. B., T. J. Hllm, nd T. J. Rink Single stretch-ctivted ion chnnels in vsculr endothelil cells s mechnotrnsducers. Nture (Lond.). 325: Hickey, K.., G. Rubnyi, R. J. Pul, nd R. F. Highsmith Chrcterition of coronry vsoconstrictor produced by cultured endothelil cells. m. J. Physiol. 248:C Gillespie, M. N., J.. Owsoyo, I. F. McMurty, nd R. F. O'Brien Sustined coronry vsoconstriction provoked by peptidergic substnce relesed from endothelil cells in culture. J. Phrmcol. Exp. Ther. 236: Wilson, R. F., M. R. Johnson, M. L. Mrcus, P. E. ylwrd, D. J. Skorton, S. Collins, nd C. W. White The effect of coronry ngioplsty on coronry flow reserve. Circultion. 77: Hodgson, J. M., R. S. Riley,. S. Most, nd D.. Willims ssessment of coronry flow reserve using digitl ngiogrphy before nd fter successful percutneous trnsluminl ngioplsty. m. J. Crdiol. 6: Btes, E. R., F. M. ueron, V. Legrnd, M. T. Le Free, G. B. Mncini, J. M. Hodgson, nd R.. Vogel Comprtive longterm effects of coronry rtery bypss grft surgery nd percutneous trnsluminl ngioplsty on regionl coronry flow reserve. Circultion. 72: Lemmer, J. H., nd M. M. Kirsh Coronry rtery spsm following coronry rtery surgery. nn. Thorc. Surg. 46: Bulkley, B. H., nd G, M. Hutchins Myocrdil consequences of coronry rtery bypss grft surgery: the prdox of necrosis in res of revsculrition. Circultion. 56: Feldmn, R. C., nd D. J. nderson Grdients t PTC: physiologicl or rtifctul? J. m. Coll. Crdiol. 5: T.. Fischell, K. N. Busbck, nd T. V. McDonld