Thallium Redistribution in Dogs with Severe Coronary Artery Stenosis of Fixed Caliber

Transcription

1 Thallum Redstrbuton n Dogs wth Severe Coronary Artery Stenoss of Fxed Calber 439 GERALD M. POHOST, ROBERT D. OKADA, DENNIS D. O'KEEFE, HENRY GEWIRTZ, GEORGE BELLER, H. WILLIAM STRAUSS, JOHN S. CHAFFIN, JEFFREY LEPPO, AND WlLLARD M. DAGGETT SUMMARY Patents wth severe coronary artery dsease may have defects on ntal rest myocardal thallum-20 (Tl-20) mages whch fll n over tme. To study the tme course and mechansm for ths defect dsappearance, a canne model of persstent reducton n regonal myocardal blood flow was created usng partal left anteror descendng coronary occluson wth a balloon cuff. Radolabeled mcrospheres to determne regonal myocardal blood flow and Tl-20 were admnstered mnutes after constrcton, and one group of dogs (n = 7) was klled 0 mnutes, another group (n = )2 hours, and a thrd group (n = 6) 4 hours ater Tl-20 admnstraton. Mcrospheres also were gven mmedately pror to death n the 2- and 4-hour groups and demonstrated no sgnfcant change n regonal myocardal blood flow compared to 0 mnutes. In the regons wth 20-00% of normal flow, a lnear correlaton was demonstrated between 0-mnute blood flow and Tl-20 actvty at 0 mnutes (r = 0.9; P < 0.00), 2 hours (r = 0.79; P < 0.00), and 4 hours (r = 0.66; P < 0.0) after Tl-20 admnstraton. The slopes of the regresson lnes (Tl-20 vs. flow) became progressvely lower between 0 mnutes, 2 hours, and 4 hours, wth a Tl-20 excess relatve to flow n the schemc flow zone. Ths was consstent wth a relatve ncrease n Tl-20 actvty n the schemc zone compared to the nonschemc zone and resoluton of Tl-20 defects observed clncally. To determne the change n absolute myocardal actvty of Tl-20, dogs n the 4-hour group also had transmural myocardal drll bopses of both schemc anteror and nonschemc posteror wall at 0 mnutes after Tl-20 admnstraton and mmedately pror to death. These bopses demonstrated that development of the Tl-20 excess relatve to flow was sgnfcantly related to both release of Tl-20 from the nonschemc zone and accumulaton of Tl-20 n the schemc zone. These data show that the defct of Tl-20 n an underperfused zone dstal to a persstent severe coronary artery stenoss slowly resolves over tme and that ths resoluton does not requre restoraton of normal blood flow. Both accumulaton of Tl-20 n the schemc zone and release from the nonschemc zone account for resoluton of an ntal Tl-20 defct. Crc Res 48: , 98 DISAPPEARANCE of ntal myocardal defects noted after njecton of thallum-20 (Tl-20) has been observed durng seral magng after excercse stress (Pohost et al., 976, 977; Blood et al., 978) or after an epsode of varant angna (Maser et al., 976). Prevous reports usng anmal models have studed ths phenomenon whch has become known as "Tl-20 redstrbuton," and demonstrated ts tme course when occluson was followed shortly thereafter by reflow. (Pohost et al., 977; Schwartz et al., 978). More recently, defect resoluton has been observed n clncal stuatons where myocardal blood flow s persstently reduced durng the seral mag- From the Cardac Unt, Department of Medcne, and Departments of Radology and Surgery, Massachusetts General Hosptal and Harvard Medcal School, Boston, Massachusetts. Supported n part by U.S. Publc Health Servce Grants HL-2075, HL-2777, HL-2322, and HL Dr. Pohost s an Establshed Investgator of the Amercan Heart Assocaton. Dr. Beller's current address s: The Unversty of Vrgna, Charlottesvlle, Vrgna. Address for reprnts: Gerald M. Pohost, M.D., Cardac Unt, Massachusetts General Hosptal, Boston, Massachusetts 024. Receved October 5, 979; accepted for publcaton September 9, 980. ng nterval: () n patents wth severe coronary artery dsease and angna pectors n the absence of clncal evdence of actve schema and wth presumed reductons n restng myocardal blood flow dstal to severe stenoses (Gewrtz et al., 979; Berger et al., 979), (2) n patents wth unstable angna even durng pan-free ntervals (Wackers et al., 978), and (3) n patents wth acute myocardal nfarcton (Smtherman et al., 978). In ths latter group, Tl-20 defects were reported to dmnsh n sze nward from the perphery, and ths was thought to be due to fllng n of an schemc pernfarcton area. The present study was performed n dogs () to demonstrate that resoluton of Tl-20 defcts does not depend on reflow, (2) to defne the tme course for the resoluton of such Tl-20 defects and, (3) to determne the role of Tl-20 release from nonschemc myocardum and accumulaton of Tl- 20 n the schemc zone n relaton to defect resoluton. Methods Twenty adult mongrel dogs (mean weght 24 kg) were anesthetzed wth chloralose (40 mg/kg,v) and urethane (400 mg/kg, v), ntubated and ven-

2 440 CIRCULATION RESEARCH VOL. 48, No. 3, MARCH 98 tlated wth an Emerson resprator wth 5 cm H 2 O of postve end expratory pressure (PEEP) and 00% oxygen. The heart was exposed va a left thoracotomy and then suspended n a percardal cradle. A 20-cm vnyl catheter was nserted nto the left atrum for njectng mcrospheres. A #7 NIH catheter was placed n the brachal artery and postoned n the aortc arch to obtan specmens of blood for determnaton of arteral ph, Pco 2, and P02. A 20-cm vnyl catheter was advanced from the opposte brachal artery to the aortc arch and attached to a Holter pump to obtan reference samples for mcrosphere determnaton of regonal myocardal blood flow. A large bore cannula was nserted nto the femoral ven for admnstraton of fluds and blood. Both femoral arteres were cannulated and connected to a reservor overflow column to mantan mean arteral pressure at 00 mm Hg. Blood from a donor dog was used to transfuse the study dog f pressure fell beneath 00 mm Hg. The left anteror descendng coronary artery was dssected free just above the orgn of the second dagonal branch and a balloon cuff postoned, but not nflated (Fg. ). A short catheter was placed retrograde nto a dagonal branch of the left anteror descendng coronary artery dstal to the occluder ste for montorng dstal pressure. Electrocardographc lead II, systemc arteral pressure, and left atra pressure (Statham P23Db transducers) were 2 fr 7/ 46 Sc Spheres LA 85 Sr Spheres '"'Tl LA Sacrfce, T = 7 dogs 20-30mm IV ^y 0 mm Sacrfce, n = 7dogs 4hr 46 Sc Spheres LA Socnfce,n=6 dogs FIGURE Outlne of expermental protocol. On the left s the canne heart wth a balloon occluder around the left anteror descendng artery (LAD). Mean arteral pressure was kept constant at 00 mm Hg and dstal LAD pressure at mm Hg. Twenty to 30 mnutes after LAD occluson, ^Sr mcrospheres were gven va the left atrum followed by ntravenously. Seven dogs were klled after 0 mnutes, seven dogs after 2 hours, and sx dogs after 4 hours. 46 Sc-mcrospheres were gven va the left atrum pror to sacrfce n the 2-hour and 4-hour dogs. montored contnuously throughout the experment and recorded on paper wth a Hewlett-Packard recorder (model #7788A). Specmens of arteral blood were obtaned at frequent ntervals to assess ph, Po 2, and Pco 2 and approprate adjustments made to mantan these parameters n the physologcal range (ph 7.35 to 7.45 and PCO2 30 to 40 mm Hg). Arteral Po 2 was mantaned above 00 mm Hg throughout the experment. Fgure demonstrates the expermental protocol. After baselne steady-state hemodynamc measurements were obtaned, the balloon cuff was nflated untl the pressure n the dstal left anteror descendng coronary artery was mm Hg, and adjusted for the duraton of the expermental protocol to mantan the dstal left anteror descendng coronary artery pressure, and thus the schemc arteral bed pressure, at the same level acheved ntally. Small adjustments n the balloon cuff nflaton pressure generally were requred every 5-30 mnutes to mantan a constant dstal pressure. After the cuff had been nflated, a 20- to 30-mnute perod was allowed for stablzaton of the preparaton. Approxmately two mllon 8-0 jam mcrospheres labeled wth Strontum-85 (Sr-85) were njected nto the left atrum and, shortly thereafter,.0-.5 mc of thallous chlorde (Tl-20) were admnstered ntravenously. The spheres were thoroughly suspended n 2 ml of normal salne and 0.0% Tween- 80 by agtatng them for 5 mnutes n a Vortex mxer just before admnstraton. Seven of the dogs were klled 0 mnutes after Tl-20 admnstraton. Seven dogs were klled 2 hours after Tl-20 admnstraton and, n these, a second dose of mcrospheres labeled wth Scandum-46 (Sc-46) was njected nto the left atrum just pror to death. The total number, mean sze, and total radoactvty of the Sc-46 mcrospheres were the same as for the Sr- 85 mcrospheres. The remanng sx dogs were klled 4 hours after Tl-20 admnstraton. In these dogs, the second dose of mcrospheres labeled wth Sc-46 was njected mmedately pror to death. In addton, these dogs had transmural myocardal drll bopses from the schemc and non-schemc zones performed at 0 mnutes and mmedately pror to death at 4 hours. These bopses were obtaned wth a trephne needle (2 mm n dameter) attached to a hgh speed drll as prevously descrbed (Gewrtz et al., 978). At the termnaton of the experment, the heart was removed and the left ventrcular free wall was dssected nto an schemc and a nonschemc zone. The schemc zone was determned by dssectng along the branches of the left anteror descendng coronary artery whch was constrcted by the occluder. Ths was subdvded nto three sectons basal, mddle, and apcal. The nonschemc zone was dvded nto basal and mddle segments. Both zones were subdvded nto nner, mddle, and outer segments. Each sample weghed -3 g.

3 THALLIUM REDISTRIBUTION WITH FIXED CORONARY STENOSIS/Pohost et al. 44 Thallum Actvty n Bopses The bopsy samples were placed n prevously weghed glass bottles. The bottles contanng the sample then were weghed n order to determne the weght of the sample. The materal was counted n a y scntllaton well counter for 5 mnutes usng a kev wndow-wdth settng. The actvty n each bopsy was then expressed as counts/5 mn per mg. In these specmens, whch were counted wthn 24 hours, Sr-85 and Sc-46 actvtes were found to comprse less than % of the counts n the Tl-20 wndow. The actvty n the schemc bopsy was expressed as a percent of the actvty n the normal bopsy taken at the same tme. Regonal Myocardal Blood Flow and Regonal Thallum Actvty The schemc zone and nonschemc zone samples were counted 3-7 days later after the Tl-20 actvty had delayed enough to permt accurate countng. The samples were counted n a well counter for 5 mnutes to collect at least 0,000 counts for each sotope. The Tl-20 was counted at kev, Sr- 85 at kev, and the Sc-46 at kev. A computer program was used to correct for actvty spllng from one wndow nto another. Regonal myocardal blood flow was calculated by the computer from the sample actvty and actvty n reference blood samples obtaned smultaneously wth the admnstraton of each sotope (Domenach et al., 969). Tl-20 actvty and mcrosphere flow n each schemc sample were expressed as a percent of the average of the normal samples for nner, mddle, or outer layer, respectvely. Statstcal Methods All results are expressed as mean ± SEM. The sgnfcance of a dfference between means was assessed usng Student's t-test. The sgnfcance of correlatons between Tl-20 actvty and regonal myocardal blood flow was determned by usng lnear regresson analyss. Dfferences n regresson lnes were determned usng an analyss of varance for dfferences between slopes. Results Hemodynamc Data The mean heart rate, mean left atral pressure, and dstal left anteror descendng coronary pressure dd not dffer sgnfcantly between study groups and dd not change sgnfcantly durng the study. Mean heart rates ntally, and at 2 and 4 hours, were 85 ± 6.2, 96 ± 7.2, and 84 ± 23.0 beats/mn, respectvely. Mean left atral pressures ntally, and at 2 and 4 hours, were 6.5 ± 0.6, 7.0 ± 0.8, and 8. ± 0.9 mm Hg, respectvely. Mean dstal left anteror descendng coronary artery pressures ntally, and at 2 and 4 hours, were 34.2 ± 0.9, 34.5 ±., and 3.2 ±.7 mm Hg, respectvely. Mean arteral pressure was mantaned at 00 mm Hg throughout the experment for all dogs. Relatonshp of Tl-20 to Mcrosphere- Determned Regonal Myocardal Blood Flow Fgures 2, 3, and 4 show plots of Tl-20 actvty (% ntal nonschemc) aganst ntal Sr-85 mcrosphere-determned regonal myocardal blood flow n the schemc zone for dogs klled 0 mnutes, 2 hours, and 4 hours, respectvely, after Tl-20 admnstraton. Each data pont represents Tl-20 actvty vs. mcrosphere flow values for each myocardal sample from the schemc zone expressed as a percent of the average nonschemc posteror wall value for the partcular layer (endocardal, mddle, or epcardal). The wde range of blood flows demonstrated n Fgures 2, 3, and 4 s due prmarly to dfferent flow reductons n ndvdual dogs rather than to wde varatons between dogs. Lnear regresson plots were restrcted to flows between 20 and 00% of nonschemc flow for two reasons. () There were no ponts n the 2-hour studes less than 20% nonschemc flow. (2) The relatonshp between flow and Tl-20 n the 4-hour studes appears to 00 I Mnutes I. A,* '- * V-'/ 20 - ^ol Tl]=O.80[ 85 Sr] + 6 '' / r = 0.9l p< 0.00 / / , Sr MICROSPHERE DETERMINED BLOOD FLOW (% Nonschemc) FIGURE 2 Relatonshp between actvty (% nonschemc) and ^Sr mcrosphere-determned blood flow (% nonschemc) n the schemc zone from dogs klled 0 mnutes after 2m Tl admnstraton. The heavy sold lne represents the lne of regresson between 20 and 00% of nonschemc flow and the lght dashed lne represents lne of dentty. The regresson lne was extrapolated to zero flow as a dashed porton to remnd the reader that t was not ncluded n the regresson analyss. Lnear regresson analyss was performed only on the 20-00% flow range so that t could be compared to the 2-hour data (Fg. 3) n whch there were no ponts under 20% nonschemc flow and the 4-hour data (Fg. 4) n whch the data clearly were not lnear under 20% nonschemc flow.

4 442 CIRCULATION RESEARCH VOL. 48, No. 3, MARCH OI TlJ =0.58[ 85 Sr] + 40 = 0.79 p<o.0oi Sr MICROSPHERE DETERMINED BLOOD FLOW ( % Nonschemc) FIGURE 3 Relatonshp between actvty (% nonschemc) and ntal 85 Sr determned blood flow (% nonschemc) n the schemc zone from dogs klled 2 hours after 20 Tl admnstraton. The sold lne represents the lne of regresson for blood flow between 20% and 00% nonschemc flow and the dashed lne represents the lne of dentty. The sold regresson lne has been extrapolated to zero flow as a dashed porton. become nonlnear at flows less than 20%. There was a sgnfcant lnear relatonshp between Tl-20 actvty and ntal Sr-85-determned regonal myocardal blood flow n the 20 to 00% of nonschemc 00 ] + 52 p< blood flow range at the end of each of the three study ntervals wth r = 0.9 (P < 0.00) at 0 mnutes, r = 0.79 (P < 0.00) at 2 hours, and r = 0.66 (P 0.00) at 4 hours. Fgure 5 demonstrates all three regresson lnes for Tl-20 actvty vs. Sr-85- determned regonal myocardal blood flow for dogs klled 0 mnutes, 2 hours, and 4 hours after Tl-20 admnstraton. The slopes and y-ntercepts of each of these lnes were sgnfcantly dfferent from the others; the 2-hour and 4-hour slopes were sgnfcantly less than the 0-mnute slope (P < 0.00) and the 4-hour slope was sgnfcantly less than the 2-hour slope (P = 0.05). The y ntercepts ncreased sgnfcantly between 0 mnutes, 2 hours, and 4 hours. These observatons are consstent wth the tme-dependent resoluton of schemc zone defects observed clncally. The Tl-20 actvty n the less than 20% nonschemc flow range has not yet been consdered, although data are present n the 0-mnute and 4- hour studes. It s evdent by nspecton of Fgure 4 that the relatonshp between flow and Tl-20 dstrbuton 4 hours after thallum admnstraton s not lnear. In the range between 20% and 00% nonschemc flow, lnear regresson analyss was employed to evaluate tme-dependent dfferences between Tl dstrbuton (Fg. 5). To evaluate further the dfferences n Tl-20 content between 0 mnutes and 4 hours, mean values for Tl-20 actvty were calculated n the 0-20%, 2-40%, 4-60%, 6-80%, and 8-00% ntal flow ranges. Table summarzes these mean Tl-20 actvtes. For samples wth ntal blood flows 0-20% of nonschemc, there was no sgnfcant dfference n mean Tl-20 actvty relatve to nonschemc zone Tl-20 actvty com I K Mnutes 85, Sr MICR0SPHERE DETERMINED BLOOD FLOW (% Nonschemc) FIGURE 4 Relatonshp between 20 Tl actvty (% nonschemc) and ntal ^Sr determned blood flow (% nonschemc) n the schemc zone from dogs klled 4 hours after 20l Tl admnstraton. The regresson lne (sold lne) s demonstrated for schemc flows 20-00% of nonschemc flow. The lne has been extrapolated to zero flow (dashed porton). The lght dashed lne represents the lne of dentty. _L Sr MICROSPHERE DETERMINED BLOOD FLOW (% Nonschemc) FIGURE 5 Regresson lnes for 20 Tl actvty vs. ^Srdetermned regonal myocardal blood flow for dogs klled 0 mnutes, 2 hours, and 4 hours after thallum admnstraton wthn the range of flow between 20 and 00% of normal. These were extrapolated to zero flow for comparson (dashed portons of each of the lnes).

5 THALLIUM REDISTRIBUTION WITH FIXED CORONARY STENOSIS/Pohost et al. 443 TABLE Mean Tl-20 Actvty (% Nonschemc) n the 0-Mnute and 4-Hour Study Groups as a Functon of Ranges of Intal ^Sr Mcrosphere-Determned Blood Flows ^Sr mcrosphere-determned blood flow (% nonschemc) 0-20% 2-40% 4-60% 6-80% 8-00% 0-Mnute group 30.0 ± 2.5% (n = 8) 39.2 ± 3.0% (n = 2) 55.8 ± 2.5% (n = 3) 73.7 ± 2.7% (n = ) 87. ± 2.8% (n = 7) 4-Hour group 36.3 ± 3.8% (n = 5) 57.9 ± 4.5% (n = 3) 75.4 ± 3.0% (n = 7) 76.9 ± 2.9% (n = 0) 88.6 ± 3.6% (n = 5) P NS <0.005 <0.00 NS NS parng the 0-mnute and 4-hour studes. However, for samples wth ntal blood flows 2-40% and 4-60% of nonschemc, Tl-20 relatve to nonschemc zone Tl-20 actvty was sgnfcantly hgher at 4 hours compared to 0 mnutes. In the 6-80% and 8-00% of nonschemc flow range there was agan no sgnfcant dfference n Tl-20 actvty between 0 mnutes and 4 hours. Regonal Myocardal Blood Flow over Tme There was no sgnfcant change n schemc zone endocardal, mddle, or epcardal layer blood flow durng the 2- or 4-hour study ntervals (pared t- test). Fgure 6 demonstrates regonal myocardal blood flow ntally and at the termnaton of the 2- hour study. Mean schemc zone ntal and fnal mcrosphere-determned blood flows n the 4-hour studes were 0.4 ± 0.03 and 0.4 ± 0.03 ml/g per mn for the endocardum; 0.52 ± 0.03 and 0.48 ± 0.03 ml/g per mn for the mddle layer, and 0.80 ± 0.03 and 0.75 ± 0.03 ml/g per mn for the epcardal layer. There was an ncrease n mcrosphere-determned blood flow n the nonschemc zone n each of the three layers n both the 2- and 4-hour studes, although ths dd not acheve statstcal sgnfcance for the 2-hour study. Mean nonschemc zone ntal 5!.2.0 I -S 0.8 k \ 0.6 S 0.4 I 2 0 H Intal wth 20l TI( 85 Sr) m 2hrAfter 20 TI( 46 Sc) r Endocardum Mddle Epcardum FIGURE 6 Mcrosphere-determned blood flow ntally and 2 hours after admnstraton for endocardal, mddle, and epcardal layers of myocardum. and 2-hour blood flows were.23 ± 0.0 and.43 ± 0.4 ml/g per mn for the endocardum,.6 ± 0.07 and.36 ± 0.4 ml/g per mn for the mddle layer, and.27 ± 0.0 and.52 ± 0.9 ml/g per mn for the epcardum. Mean nonschemc zone ntal and 4-hour blood flows were 0.85 ± 0.07 and.27 ± 0. ml/g per mn for the endocardum (P < 0.02), 0.83 ± 0.06 and.26 ± 0.3 ml/g per mn for the mddle layer (P < 0.0), and.00 ± 0.08 and.34 ± 0.08 ml/g per mn for the epcardum (P < 0.05). Changes n Transmural Tl-20 Actvty between 0 Mnutes and 4 Hours after Tl-20 Admnstraton as Determned by Needle Bopsy Fgure 7 demonstrates the relatonshp between Tl-20 actvty expressed as a percent of ntal ^ 60 : Bx l l MINUTES AFTER m TI Bx FIGURE 7 The relatonshp between actvty (% nonschemc) and tme followng njecton for the sx dogs that had needle bopses 0 mnutes and 4 hour after thallum admnstraton. The sold lne represents change n thallum actvty n the nonschemc zones of the sx dogs. The heavly dashed lne represents change n thallum actvty n the schemc zone of two dogs wth mld reducton n myocardal blood flow. The lghtly dashed lne represents change n thallum actvty n the schemc zone of four dogs wth moderate to severe reducton n myocardal blood flow.

6 444 CIRCULATION RESEARCH VOL. 48, No. 3, MARCH 98 nonschemc actvty and tme followng njecton for the sx dogs n the 4-hour group whch had needle bopses at 0 mnutes and 4 hours after Tl- 20 admnstraton. At 4 hours, Tl-20 actvty n the nonschemc zone decreased to 64.5 ± 5.3% (P < 0.0). In two dogs n whch the schemc zone bopsy demonstrated ntal myocardal Tl-20 actvty to be only mldly reduced (60-80% of nonschemc Tl-20 at 0 mnutes), mean Tl-20 actvty (% ntal nonschemc) decreased from 77.2 ± 2.0% at 0 mnutes to 63.2 ±.0% at 4 hours after Tl-20 admnstraton (P = NS). In four dogs n whch the 0-mnute schemc zone bopsy demonstrated myocardal Tl-20 actvty to be moderately to severely reduced (<60% of nonschemc Tl-20 actvty), mean Tl-20 ncreased from 38.2 ± 7.% at 0 mnutes to 57.3 ± 6.% at 4 hours after Tl-20 admnstraton (P < 0.0). When expressed as a percent of nonschemc zone actvty, Tl-20 ncreased from 38.2% at 0 mnutes to 88.8% at 4 hours n the moderately to severely schemc studes consstent wth nearly total resoluton of a Tl-20 defect by 4 hours of seral magng. Dscusson The dsappearance of ntal defects durng seral magng, after njecton of Tl-20 at rest, has been observed n several clncal stuatons. Gewrtz n our laboratory found that defects on early rest Tl- 20 mages also could be present n patents wthout evdence of myocardal scar or acute schema, but wth severe coronary artery stenoses (Gewrtz et al., 979). These Tl-20 defects were thought to be related to a restng reducton n regonal coronary blood flow due to severe coronary arteral stenoses wthout clncal schema. Cannon et al. (975) and Klocke (976) have observed reducton n regonal coronary blood flow at rest wthout other evdence of schema usng Xenon washout. Gewrtz et al. (979) also demonstrated that these restng Tl-20 defects related to underperfuson tended to resolve n later mages obtaned over a 2- to 4-hour perod whle defects related to prevous nfarcton tended to persst. Thus, underperfused myocardal zones appeared to attan a Tl-20 concentraton equal to that of zones suppled by vessels wthout angographcally apparent dsease over a perod of mnutes to hours. Wackers et al. (978) also observed transent Tl-20 defects on seral Tl-20 mages n patents wth severe coronary artery dsease and unstable angna, but who were asymptomatc at the tme of Tl-20 admnstraton. Fnally, Smtherman et al. (978) demonstrated a reducton n ntal Tl- 20 defect sze n patents wth acute myocardal nfarcton durng seral magng. The reducton n defect sze was thought to be due to delayed Tl-20 uptake n the schemc per-nfarcton zone. The results of the present study demonstrate the tme course and the mechansm for Tl-20 defect resoluton n myocardum wth persstently reduced regonal blood flow. Thallum Uptake n the Ischemc Zone Relatve to the Nonschemc Zone The present study demonstrates that early Tl- 20 dstrbuton s strongly dependent on perfuson (Fg. 2). There s, however, a slght offset of the 0- mnute regresson lne above the lne of dentty wth a Tl-20 excess at low flow, not present at normal flows. A smlar correlaton between early Tl-20 dstrbuton and regonal myocardal perfuson was reported by Strauss et al. (975). A relatve excess of Tl-20 n regons wth low flow, as determned by mcrospheres, s thought to be related to more effcent tssue extracton wth more prolonged exposure (Sangren and Sheppard, 953). A sgnfcant lnear relatonshp also exsts between ntal mcrosphere-determned blood flow and Tl-20 actvty at 2 hours (r = 0.79) and 4 hours (r = 0.66) after Tl-20 njecton (Fgs. 3 and 4) n the 20-00% of nonschemc flow regons. Thallum- 20 content n underperfused zones tends to normalze over tme. Ths s reflected by a progressve ncrease n the y ntercepts of the Tl-20 vs. flow plots (6% at 0 mnutes, 40% at 2 hours, 52% at 4 hours). Thus, the present study demonstrates that Tl-20 actvty ncreases n schemc relatve to nonschemc myocardum between 0 mnutes, 2 hours, and 4 hours n dogs wth persstent reducton n coronary blood flow; the fndngs are consstent wth resoluton of ntal defects n myocardal mages at rest. Ths ncrease n Tl-20 actvty n the schemc relatve to the nonschemc zone occurred wthout change n schemc zone blood flow durng the 4-hour expermental perod and despte an ncrease n blood flow to the nonschemc zone. Thallum Accumulaton n Severely Ischemc Zones Snce there were no samples wth flows below 20% of normal n the 2-hour studes, the relatonshp between Tl-20 actvty and ntal mcrosphere-determned blood flow were compared for blood flows <20% of nonschemc only at 0 mnutes and 4 hours. Ths severely schemc zone dd not appear to dsplay the excess n Tl-20 over flow at 4 hours. It s reasonable to consder that ths severely schemc myocardum became rreversbly njured durng 4 hours of nsult. Ingwall and assocates have demonstrated n vtro, n the flow-ndependent fetal mouse heart organ culture model, that Tl-20 accumulaton becomes mpared followng an schemc-lke nsult when rreversble damage occurs (Ingwall et al., 979). Thus, the nablty of the severely schemc zone to mantan an excess of Tl- 20 relatve to flow probably s related to the dmnshed capacty of ths zone to accumulate Tl- 20 due to loss of vable myocardal mass. Relatve Contrbuton of Washout from Normal and Accumulaton nto Underperfused Zones The relatve contrbuton of release of Tl-20 from the nonschemc zone and accumulaton n the

7 THALLIUM REDISTRIBUTION WITH FIXED CORONARY STENOSIS/Pohost et al 445 schemc zone was defned n the 4-hour studes by transmural needle punch bopses n the schemc and nonschemc zones at 0 mnutes and 4 hours. Values for the nonschemc zone decreased to 64.5 ± 5.3% of the 0-mnute level by 4 hours after Tl- 20 admnstraton. Ths value s consstent wth prevously reported determnatons of Tl-20 washout from normal myocardum (Schelbert et al., 977; Beller et al., 980). The data were analyzed separately for the two dogs wth mldly reduced 0- mnute transmural Tl-20 actvty (60-80% nonschemc actvty), and the four dogs wth moderate to severely reduced 0-mnute transmural Tl-20 actvty (<60% nonschemc actvty). There was no sgnfcant change n schemc zone Tl-20 actvty over the 4-hour perod n the group wth only mldly depressed ntal values for Tl-20, whereas n the group wth moderately to severely reduced ntal actvty, mean schemc zone Tl-20 actvty ncreased sgnfcantly (38.2 ± 7.% to 57.3 ± 6.% of ntal nonschemc zone actvty). It appears that both net accumulaton of Tl-20 actvty nto schemc zones and net release of Tl-20 from nonschemc zones account for resoluton of ntal defcts of Tl-20 n the presence of severe coronary stenoss when Tl-20 s admnstered n the restng state. At 4 hours after sotope njecton, Tl-20 actvty n the moderately to severely schemc zone was 88.8% of that n the nonschemc zone. Ths s comparable to our prevous fndngs when tracer was admnstered durng a 20-mnute perod of coronary occluson and reflow was nsttuted for 00 mnutes (Pohost, 977). Mean Tl-20 actvty ncreased to 77 ± 6% of nonschemc zone actvty. Thus, despte an ntal rapd ncrease n actvty after release of the coronary lgature, the Tl-20 actvty (% nonschemc) tends to normalze n a comparable tme n dogs subjected to reperfuson and n dogs wth a persstent stenoss. Although the basc mechansm for slow accumulaton of Tl-20 n the persstently schemc zone has not been defned precsely, t would seem reasonable to speculate that the mechansm s related to Tl + gradents between blood and myocardal cells. Ingwall et al. (979) have suggested that the rate of Tl-20 uptake by the myocardal cells of the cultured fetal mouse heart s not compromsed untl a severe schemc-lke nsult produces rreversble damage. Accordngly, the vable myocardal cells n the present canne model of persstent underperfuson would be antcpated to contnue extractng Tl- 20 at a normal rate untl a membrane determned gradent s acheved. Snce blood Tl-20 levels drop rapdly after ntravenous admnstraton (Beller et al., 980), the myocardal zones that are normally perfused acheve ther maxmal level of Tl uptake rapdly and then begn to release Tl-20. The cells n the underperfused zone, havng been exposed to less Tl-20 early, must contnue to extract the tracer from the very low level n the blood pool untl they acheve a peak. The more severe the underperfuson, the later the peak. The peak myocardal cellular level s probably related to the ablty of the cell to extract the Tl-20 (a functon of cellular ntegrty) and the level of Tl-20 n the blood. Our data suggest that the appearance of fllng-n of an ntal Tl-20 defect on seral mages appears to be related to both release of the agent from the normally perfused zone and uptake of the agent nto the underperfused zone. Clncal Implcatons Defects on Tl-20 magng after njecton at rest have been demonstrated prevously n vable zones suppled by severely stenotc coronary vessels (Gewrtz et al. 979). The present study corroborates these fndngs n an anmal model. Furthermore, the ablty to determne drectonal changes n schemc zone Tl-20 actvty through the development of relable quanttatve approaches could help dfferentate between nonschemc, mldly schemc, and moderate to severely schemc myocardum. Moderately to severely schemc zones accumulate Tl-20 whle nonschemc zones release the tracer. Mldly schemc zones show no net Tl-20 change. In concluson, thallum-20 redstrbuton occurs n myocardum suppled by a fxed coronary stenoss despte persstent reducton n blood flow. Ths ncrease n actvty wth tme n schemc relatve to normal zones accounts for fllng n of early defects on rest Tl-20 scans and s related to two processes occurrng smultaneously. Frst, actual net accumulaton of Tl-20 leads to ncreasng Tl- 20 actvty n the moderately to severely underperfused myocardum. Second, net release of Tl-20 leads to decreasng actvty that s most marked n the normally perfused regons. Mldly underperfused segments demonstrate no net change n Tl- 20 actvty. Acknowledgments We wsh to thank Sandra Jodre, Eleen Ftzgerald, and Betty LaMarca for ther secretaral assstance n the preparaton of ths manuscrpt. References Beller GA, Watson DD, Ackell P, Pohost GM (980) Tme course of thallum-20 redstrbuton after transent myocardal schema. Crculaton 6: Berger BC, Watson DD, Burwell LR, Crosby IK, Wellons HA, Teates CD, Beller GA (979) Stable and unstable angna and the effect of coronary artery bypass surgery n patents wth coronary artery dsease. Crculaton 60: 4-25 Blood DK, McCarthy DM, Scacca RR, Cannon PJ (978) Comparson of sngle-dose and double-dose thallum-20 myocardal perfson scntgraphy for the detecton of coronary artery dsease and pror myocardal nfarcton. Crculaton 58: Cannon PJ, Schmdt DH, Wess MB, Fowler DL, Scacca RR, Ells K, Casarella WJ (975) The relatonshp between regonal myocardal perfuson at rest and arterographc lesons n patents wth coronary atheroscleross. J Cln Invest 56: Domenach RJ, Hoffman JIE, Noble MIN, Saunders KA, Henson, JR, Subjanto S (969) Total and regonal coronary blood flow measured by radoactve mcrospheres n conscous and anesthetzed dogs. Crc Res 25:

8 446 CIRCULATION RESEARCH VOL. 48, No. 3, MARCH 98 Gewrtz H, O'Keefe DD, Pohost GM, Strauss HW, Mcllduff JB, Daggett WM (978) The effects of schema on thallum-20 clearance from the myocardum. Crculaton 58: Gewrtz H, Beller GA, Strauss HW, Dnsmore RE, Zr LM, McKusck KA, Pohost GM (979) Transent defects of restng thallum scans n patents wth coronary artery dsease. Crculaton 59: Ingwall J, Kramer M, Kloner RA, Alpert NM, Newell JB, Pohost GM (979) Thallum accumulaton: Dfferentaton between reversble and rreversble myocardal njury. Crculaton (suppl II): 73 Klocke FJ (976) Coronary blood flow n man. Progr Cardovasc Ds 9: 7-66 Maser A, Parod O, Sever S, Pesola A (976) Transent transmural reducton of myocardal blood flow, demonstrated by thallum-20 scntgraphy as a cause of varant angna. Crculaton 54: Pohost GM, Beller GA, Moore RH, McKusck KA, Zr LM (976) Redstrbuton of thallum-20 followng transent myocardal schema (abstr). Cln Res 24: 235A Pohost GM, Zr LM, Moore RH, McKusck KA, Guney TE, Beller GA (977) Dfferentaton of transently schemc from nfarcted myocardum by seral magng after a sngle dose of thallum-20. Crculaton 55: Sangren WC, Sheppard CW (953) A mathematcal dervaton of the extracton of a labeled substance between a lqud flowng n a vessel and an external compartment. Bull Math Bophys 5: Schelbert H, Schuler G, Ashburn W, Covell J (977) Tme course of redstrbuton of Tl-20 after transent schema (abstr). J Nucl Med 8:598 Schwartz JS, Ponto R, Carlyle P, Forstrom L, Cohn JN (978) Early redstrbuton of thallum-20 after temporary schema. Crculaton 57: Smtherman TC, Osborn RC, Narahara KA (978) Seral myocardal scntgraphy after a sngle dose of thallum-20 n men after acute myocardal nfarcton. Am J Cardol 42: Strauss HW, Harrson K, Langan JK, Lebowtz E, Ptt B (975) Thallum-20 for myocardal magng: Relatonshp of thallum-20 to regonal myocardal perfuson. Crculaton 5: Wackers FJ, Le KI, Lem KL, Sokole EB, Samson G, Schoot JB, Durrer D (978) Thallum-20 scntgraphy n unstable angna pectors. Crculaton 57: