Coronary Pressure-Function and Steady-State Pressure-Flow Relations During Autoregulation in the Unanesthetized Dog. John M. Canty Jr.

Transcription

1 2 oroary Pressure-Fuctio ad Steady-State Pressure-Flow Relatios Durig Autoregulatio i the Uaesthetized Dog Joh M. aty Jr. Dowloaded from by o September, 20 The preset study was iteded to defie the iterrelatio amog edocardial flow, edocardial fuctio, ad coroary arterial pressure durig spotaeous autoregulatio i the left vetricle of chroically istrumeted uaesthetized dogs. Steady-state soomkrometric measuremets of regioal fuctio ad epicardial coroary artery pressure were used to determie the lower pressure limit of edocardial autoregulatio while global idexes of myocardial demad remaied costat. Trasmural wall thickeig i the circumflex bed remaied uchaged (±% of cotrol values) util coroary pressure fell below 3 ±.6 (SD) mm Hg. Edocardial segmet shorteig was similarly costat util coroary pressure fell below 2 ± 7. mm Hg. There was o sigificat chage i edocardial flow as coroary pressure was reduced over the autoregulatory plateau from to mm Hg (.0-0. ml/mi/g, p=). Below the critical pressure limits, small additioal reductios i pressure were associated with marked reductios i both edocardial flow ad fuctio. The coroary pressure-fuctio relatio was liear as well as steep hi this rage for both wall thickeig (r=0. ±0.0) ad segmet shorteig (r=0.6 ±0.03). Although the relatio betwee edocardial flow ad fuctio showed more variability tha pressure-fuctio relatios at low pressures, wall thickeig reductios ad edocardial flow reductios related o a early oe-to-oe basis. The preset study establishes that the coroary pressure-fuctio relatio ca be used to defie the lower limit of edocardial autoregulatio. It also idicates that the lower pressure limit of edocardial autoregulatio is cosiderably less tha hi aesthetized aimals (0 vs. 70 mm Hg) ad that steady-state flow above this limit is cotrolled more tightly. Although these differeces may relate to systemic hemodyamics, it seems likely that geeral aesthesia ad/or acute surgical istrumetatio alter coroary autoregulatio uder at least some experimetal circumstaces. (irculatio Research ;63:2-36) oroary blood flow is autoregulated over a wide pressure rage as coroary artery pressure is reduced.'- 3 urret kowledge cocerig coroary autoregulatio is based etirely o studies coducted i aesthetized aimals. While the precise mechaisms resposible for autoregulatio are still cotroversial, several features i the From the Departmets of Medicie ad Physiology, State Uiversity of New York at Buffalo ad the Erie outy Medical eter, Buffalo, New York. Prelimiary reports of this work were preseted at the th ad 60th Aual Scietific Sessios of the America Heart Associatio, ad 7. Supported by grats from the Natioal Heart, Lug, ad Blood Istitute (RO-HL-3762, PO-HL-, ad KO- HL-06) ad the America Heart Associatio with fuds cotributed from the Wester New York Affiliate (3-77 ad 6-2). Address for correspodece: Joh M. aty Jr., MD, SUNY/ B liical eter, Room, Erie outy Medical eter, 62 Grider Street, Buffalo, NY 2. Received Jue, 7; accepted May 7,. coroary circulatio are oteworthy. First, there are sigificat trasmural variatios. Edocardial flow autoregulatio is lost whe mea coroary pressure falls below 70 mm Hg (diastolic pressure, below 0 mm Hg) i aesthetized aimals. 3-6 I cotrast, epicardial flow is autoregulated over a wider pressure rage. 3-6 Secod, there is a close couplig betwee edocardial flow ad fuctio below the lower autoregulatory limit. 7-0 I this rage, reductios i edocardial fuctio presumably reflect iadequate oxyge delivery. Previous studies have ot examied regioal flow, myocardial fuctio, ad coroary pressure simultaeously durig autoregulatio. Thus, the specific relatio betwee coroary pressure ad edocardial fuctio has ot bee established. Recet experimetal studies i aesthetized aimals have challeged the otio of "perfect" coroary autoregulatio (i.e., autoregulatio that is able to match flow to local vasodilator reserve

2 Dowloaded from by o September, irculatio Research Vol 63, No, October uder all circumstaces). It is ow well established that reductios i flow (ad i some studies, myocardial fuctio) occur at reduced coroary artery pressure i the presece of cosiderable vasodilator reserve, which is recruitable pharmacologically. - Other studies have demostrated that regioal oxyge cosumptio decreases cotiuously as coroary pressure is reduced despite costat hemodyamic determiats of oxyge cosumptio. 336 The potetial effects of these chages o edocardial flow or a sesitive idex of edocardia] fuctio have ot bee evaluated. Each such observatio raises the possibility that factors other tha local vasodilator reserve modulate coroary autoregulatio uder at least some experimetal circumstaces. Because acute istrumetatio ad geeral aesthesia have bee show to alter the relatio betwee edocardia] flow ad fuctio, - 0 it seems plausible that differeces i coroary autoregulatory resposes could also occur i these two experimetal settigs. The preset study was performed to defie iterrelatios amog coroary pressure, trasmural myocardial perfusio, ad edocardial fuctio i chroically istrumeted uaesthetized dogs. Specific aims were to ) determie whether the relatio betwee coroary pressure ad edocardial fuctio ca be used to defie the lower edocardial autoregulatory pressure limit; 2) quatify steadystate edocardial autoregulatio ad the degree to which regioal flow ad fuctio (a idirect idex of chages i edocardial oxyge cosumptio) may chage over the autoregulatory "plateau," ad 3) compare the relative sesitivity at comparable levels of regioal ischemia of edocardial flowfuctio relatios based o segmet shorteig ad trasmural wall thickeig. The fidigs cotrast with previous studies i aesthetized aimals idicatig both a sigificatly lower edocardial autoregulatory pressure limit ( 0 mm Hg) ad maitaied oxyge delivery ad fuctio util this lower autoregulatory limit is reached. Materials ad Methods Aimal Preparatio Studies were coducted i awake, chroically istrumeted dogs. All experimetal procedures were performed i accordace with istitutioal guidelies. A total of 22 adult mogrel dogs (27 ± 2.3 [SD] kg) were studied. Aesthesia was iduced by ijectio of sodium thiamylal (20 mg/kg i.v.). After edotracheal itubatio, a surgical plae of aesthesia was maitaied with a itrous oxide (~60%), oxyge ( 0%), ad halothae ( -2%) mixture durig mechaical vetilatio. Uder sterile coditios, a thoracotomy was performed i the fifth left itercostal space. The preparatio is illustrated i Figure. Tygo catheters (0.062 i. i.d., 0.2 i. o.d., 2 i. log) were placed ito the left atrium ad descedig thoracic aorta for microsphere ijectio ad referece blood samplig, respectively. Ascedig aortic pressure was measured with a Teflo agiocath (22 gauge) iserted through vessel wall ad coected to Tygo microbore tubig (0.02 i. i.d., 0.06 i. o.d., 2 i. log). The frequecy respose of this system whe coected to a Statham P23dB pressure trasducer ad flushed with degassed salie was flat to at least Hz ad therefore sufficiet to measure phasic variatios i pressure at the heart rates ecoutered. Left vetricular pressure was measured by a Koigsberg Model P6. micromaometer placed through a stab woud i the vetricular apex ad secured with a purse-strig suture. Pacig leads were sew oto the left atrial appedage. The left circumflex artery was dissected free for -2 cm proximal to the first margial brach. A fluid-filled hydraulic occluder was placed aroud the proximal circumflex artery. A Teflo agiocath was iserted ito the circumflex artery distal to the occluder with the tip facig dowstream for coroary arterial pressure measuremet, with care take to avoid eterig ay side braches. Edocardial fuctio was measured i the distal circumflex ad aterior descedig regio with piezoelectric crystals placed to measure both wall thickess ad segmet legth, as previously described. 7 ircumflex crystals were placed i the posterobasal free wall (above the mior axis), ad aterior descedig crystals were placed i the apical free wall regio (below the mior axis), with care take to avoid crystal placemet i the aterior or posterior papillary muscles. I the majority of aimals, segmet legth crystals spaed the same regio occupied by the edocardial wall thickess crystal ad, thus, assessed edocardial fuctio i a similar aatomic regio. Segmet legth crystals were orieted parallel to the estimated edocardial fiber orietatio. For the ier quarter of the heart, this LAD W»D Thlckata FIGURE. Schematic diagram of experimetal preparatio. L, left circumflex; LAD, left aterior descedig coroary artery; PL, left circumflex pressure; P Ao, aortic pressure; P LV, left vetricular pressure; LA, left atrium. (See text for discussio.)

3 aty Autoregulatio i the Uaesthetized Dog 23 agle (a) varies sigificatly with respect to the circumferetial plae (a- + 0 to +0, Figure, referece ). Because of these edocardial variatios i fiber orietatio with depth, the segmet legth crystals were iserted at a approximate agle of +30 to the circumferetial plae. The positio of the crystals was carefully examied at the time of ecropsy. Six segmet legth pairs ad two wall thickess pairs were excluded because they were ot appropriately positioed. The iermost edge of the edocardial wall thickess crystals spaed 2 ± % of the myocardium. Segmet legth pairs were located 0 ± 0% of the distace across the wall. At the coclusio of istrumetatio, the crystal wires ad catheters were tueled through idividual stab wouds i the 6th-7th left itercostal space. The chest was closed, ad the peumoothorax evacuated with a chest tube. Aimals were give streptomyci (300 mg i.m.) ad procaie peicilli (300,000 uits i.m.) for 3- days after surgery. atheters were flushed with sterile salie ad filled with hepari at -3-day itervals (0,000 uits/ml for the circumflex artery catheter ad,000 uits/ml for all other catheters). Eteric coated aspiri (32 mg p.o.) was begu o the fourth day after surgery ad admiistered daily thereafter. Trasmural oroary Autoregulatio Microsphere flow studies were coducted i 6 aimals ± days after istrumetatio. Most studies were coducted durig light sedatio with Iovar-Vet (fetayl 0. mg/ml ad droperidol 20 mg/ml, -3 ml i.m.). The use of this sedatio resulted i stable systemic hemodyamics for 2-3 hours with substatially less variability tha that ormally ecoutered i the usedated state. Although lightly sedated, the aimals were coscious ad easily excited by extraeous oise. Measuremets were obtaied with the aimals lyig quietly o their right side. All pressure trasducers (Statham P23dB) were adjusted to the same height ad refereced to the dorsal spie to closely approximate mid heart level. The micromaometer was calibrated at the begiig of each study by matchig the systolic pressure to that measured simulta- PAO (mm HQ 60 Dowloaded from by o September, 20 L Segmet Legth (mm) LAD Segmet Legth (mm) ED ES Occlusio Mea P _(; mmhg 7mmHg 36mmHg 30mmHg 2mmHg 26mmHg 23mmHg otrol FIGURE 2. Aalog recordigs at selected levels of coroary pressure i a idividual aimal. Each pael represets a sigle cardiac cycle durig a steady-state level of coroary pressure reductio. Mea coroary pressure correspodig to each measuremet is illustrated below each pael. Solid vertical lies draw o the recordigs of wall thickess ad segmet legth represet ed diastole (ED, oset of positive dp/dt) ad ed systole (ES, 20 msec before peak egative dpidt). Durig gradual pressure reductio produced by iflatig the hydraulic occluder, regioal circumflex fuctio remaied costat over a wide coroary pressure rage. Whe mea coroary pressure fell below 3 mm Hg (diastolic pressure, ~20 mm Hg), further reductios i pressure were associated with large reductios i both segmet shorteig ad wall thickeig over a relatively arrow pressure rage. After restoratio of coroary pressure (right pael), circumflex fuctio remaied depressed i a fashio similar to stued myocardium. P Ao, aortic pressure; P LV, left vetricular pressure; P L, left circumflex pressure; dpidt, first derivative of left vetricular pressure; L, left circumflex; LAD, left aterior descedig coroary artery. ir Ml a

4 2 irculatio Research Vol 63, No, October Dowloaded from by o September, 20 FLOW (mlml"' ( ') o.e f ENDOARDIAL O EPIARDIAL 20 0 eo 0 MEAN ORONARY PRESURE (mm Hg) FIGURE 3. Plot of edocardial ( ) versus epicardial (O) autoregulatio. Flows are show as fuctios of mea coroary pressure. Restig flow was higher i the edocardium tha i the epicardium. There was o sigificat chage i flow whe mea pressure fell to mm Hg. Edocardial flow bega to fall whe mea coroary pressure reached 37 mm Hg. I cotrast, epicardial flow remaied uchaged util mea coroary pressure reached 2 mm Hg. Values represet mea±sem. eously i the ascedig aorta ad matchig left vetricular ed-diastolic pressure to equal the peak atrial wave o the simultaeously measured left atrial pressure. Variatios i heart rate over the experimetal period were miimized by atrial pacig at a rate slightly more tha the spotaeous heart rate. After allowig 30 miutes for the aimal to adjust to the laboratory, measuremets of hemodyamics ad regioal fuctio were begu. Progressive reductios i distal circumflex pressure were produced by the hydraulic occluder. Before ijectig microspheres, each level of pressure reductio was held costat for at least miutes. Microsphere flow measuremets were performed uder cotrol circumstaces ad after coroary pressure reached ~0 mm Hg with maitaied regioal circumflex fuctio. Additioal microspheres were ijected durig steady-state reductios i coroary pressure, which resulted i measurable reductios i regioal circumflex fuctio below restig values. Regioal perfusio was quatified with the referece withdrawal techique. Up to eightflowmeasuremets were performed i idividual aimals with -/im microspheres labeled with the followig gamma-emittig uclides: l3 Gd, "o, I, ll3 S, '"Nb (New Eglad Nuclear, Bosto, Massachusetts) ad l r, "Sr, ^Sc (3M Icorporated). Microspheres were suspeded i 0% dextra ad 0.0% Twee 0. The suspesios were placed i a ultrasoicator for at least miutes ad vortex agitated before ijectio. Approximately 2- x 0 6 microspheres were ijected ito the left atrium over a 0--secod period ad flushed with warm arterial blood. Before microsphere ijectio, a referece arterial blood sample was started at a costat rate (0 ml/mi) from the descedig aortic catheter ad cotiued for 2 miutes. Aortic, left vetricular, ad coroary artery pressure as well as measuremets of regioal fuctio were moitored throughout the withdrawal period. Of 7 total microsphere ijectios, six were discarded because of abruptly altered hemodyamic coditios after microsphere ijectio. From two to seve ijectios were acceptable i each aimal { = l, oe dog; /i = 6, oe dog; =, three dogs; =, six dogs; = 3, three dogs; = 2, two dogs). After the experimets were completed, the aimals were killed with potassium chloride overdose durig deep barbiturate aesthesia. The hearts were removed ad placed i formali for several days to facilitate sectioig. The left vetricle was sliced ito four cocetric circumferetial rigs ad the apex discarded. Each rig was cut ito eight wedges otig the aatomic locatio of each wedge. Wedges were the divided ito four trasmural layers of approximately equal thickess. The papillary muscles were removed ad couted separately. The circumflex perfused core icluded wedges from the base of the heart surroudig the crystals. Flow i samples adjacet to this regio were aalyzed to esure that all selected myocardial samples were withi the perfused core. Each sample was weighed ad activity quatified with a Tracor-Northera sodium iodide detector. Activity of each isotope was determied with a least-squares radiouclide separatio techique. 20 Regioal myocardial blood flow was calculated as previously described. Normalizatio of regioal flow. Because of both temporal ad spatial heterogeeity of microsphere flow measuremets, 2-22 regioal flow resposes i the circumflex (L) regio were ormalized to flow resposes i the left aterior descedig (LAD) or cotrol regio. This L/LAD flow ratio reflected the relative reductio i circumflex flow uder each experimetal coditio i a fashio similar to that previously used by other ivestigators. 3-0 Uder cotrol coditios, the ratio of L/LAD flow i the edocardium varied amog aimals (mea,.0 ± 0.0; rage, 0.6 to.2). Because this was believed to reflect samplig variatio ad spatial heterogeeity, subsequet measuremets of the L/LAD flow ratio were divided by the cotrol ratio. This latter parameter was called the ormalized L/LAD edocardial flow ratio. Flow measuremets associated with a depressio i wall thickeig ad/or segmet shorteig below 0% of cotrol values were grouped by the level of ormalized edocardial flow reductio (7-0%, - 70%, 3-0%, <30%). To avoid bias, each dog was represeted i a give group oly oce. Multiple flow measuremets that fell withi the same group for a give dog were averaged alog with their correspodig hemodyamic parameters to obtai sigle values. I aimals i which coroary pressure was reduced but regioal fuctio uchaged (oischemic poits), closed-loop autoregulatory gai was calculated as previously described. 3

5 aty Autoregulatio i the Uaestbetized Dog 2 TABLE. Group (% otrol edo flow) Noischemic (i=0) Microspbere Flow Experimets: oroary Pressure ad Regioal Myocardlal Flow (ore Regio) S P Normalized L/LAD edo flow 0.03±0. (mm Hg) 0 7±0 ±7 PL mea (mm Hg) ±0 ± PL ed djas (mm Hg) 73± 33±6 PL mea dias (mm Hg) ±0 0±7 Edo 0.0 ± ±0.2 L flow (ml/mi/g) Epi 0 0.± ±0.23 Edo/epi 0.30 ± ± % d = ) S P S P S P 0.2 ± ± ±0.0 6±0 0±6 7 7±0 2± 2± 37± 7 73± 22±2 7 2± 27±3.02 ± ± ± ±0.2.3±0..±0. < % d = 7) 6 3± 3±3 73±7 ±2 ±6 22±2 7 0.± ±0.6 < ± ± ±0. 0.±0. 3-0% d = ) 2±0 ±7 7± 2± 72 ±2 7± <0.002 ± 20±l.± ± ± ±0..36 ± ±0.0 Dowloaded from by o September, 20 <30% d = ) s p 0.2 ±0.07 ±3 ±2 ±6 2± < ±3 ± < ± ±3 <0.002.±0. 0.3±0. 0.± ±0.22 <0.0.3±O.O 0.2±0.2 Values are mea±sd. L, circumflex regio; LAD, left aterior descedig regio; P^, mea aortic pressure; PL, distal circumflex pressure; ed dias, ed diastolic; mea dias, mea diastolic; Edo, edocardial flow; Epi, epicardial flow; Edo/epi, ratio of edocardial to epicardial flow; ormalized L/LAD edo flow, ormalized L/LAD edocardial flow ratio for total perfused regio calculated as described i the text; i, umber of measuremets i each group;, cotrol; S, steosis; p, statistical sigificace for two-tailed paired t test;, ot sigificat. Measuremets have bee grouped ito five levels of pressure ad flow reductio as described i the text. oroary Pressure-Fuctio Relatios Relatios betwee coroary pressure ad circumflex fuctio were examied i 6 dogs ±7 days after istrumetatio. otrol measuremets were performed after a 30-miute equilibratio period, after which coroary pressure was gradually reduced i 2- mm Hg icremets. At least 2 miutes were allowed for coroary pressure ad regioal fuctio to equilibrate before data samplig. Whe fuctio bega to fall, coroary pressure was reduced over smaller icremets (-2 mm Hg) util percet wall thickeig approached zero, after which pressure was restored. With this approach, 0- steadystate poits were available for aalysis i idividual aimals. Normalizatio of circumflex fuctio. To compare relative reductios i circumflex fuctio amog differet aimals, circumflex wall thickeig (%WT) ad segmet shorteig (%SS) were ormalized. Prelimiary studies idicated that regioal dysfuctio was ever observed at a coroary pressure more tha 0 mm Hg uder these hemodyamic coditios. Therefore, all measuremets of %WT ad %SS at mea coroary pressures more tha 0 mm Hg were averaged to obtai the cotrol value of circumflex fuctio for each idividual study. Each idividual measuremet of %WT ad %SS i a give experimet was the divided by this mea value ad expressed as a percet. Because of the small variability i cotrol fuctio with repeated measuremets (coefficiet of variatio, 3-%), sigificat reductios i fuctio were defied as those havig both a mea coroary pressure below 0 mm Hg as well as a value of ormalized fuctio less tha 0% of cotrol. Pressure-fuctio data fulfillig these criteria were fit to liear ad quadratic relatios. Pressures correspodig to 00%, 0%, ad 0% of cotrol fuctio were calculated with the coefficiets obtaied from the least-squares fit ad tabulated. To avoid errors related to extrapolatio, aimals were excluded from regressio aalysis if the degree of coroary pressure reductio did ot result i fuctio failig below 0% of cotrol values. I additio, studies i which the coefficiet of variatio for systemic hemodyamics ad/or cotrol fuctio exceeded 0% were excluded because hemodyamic istability could alter myocardial metabolic demad durig the study period. Data Aalysis Experimetal data were recorded o a eightchael Gould 200 W recorder at a paper speed of

6 26 irculatio Research Vol 63, No, October Dowloaded from by o September, 20 ENDOARDIAL FLOW > 20 * «t * ^ 0 l MEAN I-*H r-oh O UAN DIASTOLI A END DIASTOLI 0 SO ORONARY PRESSURE (mm Hg) FIGURE. Plot of relatio betwee ormalized edocardial flow ad coroary pressure. Edocardial flow remaied costat util mea coroary pressure ( ) fell below 0 mm Hg. orrespodig values of mea diastolic coroary pressure (O) ad ed-diastolic coroary pressure (A) were 30 ad 2 mm Hg, respectively. Pressure rage over which edocardial flow approached zero varied from ~20 mm Hg for mea coroary pressure to ~0 mm Hg for ed-diastolic coroary pressure. Edocardial autoregulatory relatio was shifted to the left whe flow was related to diastolic coroary pressure idexes as opposed to mea coroary pressure. Values are mea±sem. 00 mm/sec. All data were digitized at a samplig rate of 200 Hz with a Data Traslatio DT 20-A aalog-to-digital covertor (Marlborough, Massachusetts) iterfaced to a IBM P AT computer. Most experimets were digitized ad aalyzed olie; however, i some, aalog sigals were recorded o a Hewlett-Packard FM tape recorder (Palo Alto, aliforia) ad digitized off-lie. All data represet averages of a -secod samplig iterval comprisig at least 20 cardiac cycles. Sigals from the ultrasoic crystals were processed with a Trito Techology (Sa Diego, aliforia) soomicrometer. Left vetricular pressure was differetiated with a filter cutoff of 00 Hz. The first derivative of left vetricular pressure (dp/dt) was used to determie ed diastole (ED; oset of positive dp/dt) ad ed systole (ES; 20 msec before peak egative dp/dt). From these measuremets, NORMAUZED SEGMENT SHORTENING NDO O EP A T FLOW WALL THIKENING the systolic excursio for wall thickess (A WT) ad segmet legth (A SL) were calculated as follows: A WT = ESWT-EDWT ad A SL = EDSL-ESSL. Percet wall thickeig ad percet segmet shorteig were determied as follows: %WT = A WT/ EDWT ad %SS = A SL/EDSL. ostacy of systemic hemodyamics throughout each study was determied by measurig heart rate, mea aortic pressure, systolic ad eddiastolic left vetricular pressure, ad the first derivative of left vetricular pressure (peak + dp/dt ad peak -dp/dt). Several idexes of coroary drivig pressure were calculated from the digitized data. Mea coroary pressure was averaged over the etire cardiac cycle. Ed-diastolic coroary pressure was take at the oset of positive dp/dt. To calculate mea diastolic coroary pressure, diastole was defied as occurrig betwee the poit whe left vetricular pressure fell below coroary pressure util it exceeded it agai durig systole for each cardiac cycle. oroary pressure durig this period was the averaged. Statistical Aalysis All values represet the mea ± SD uless otherwise idicated. Data for microsphere flow measuremets were aalyzed with oe-way aalysis of variace. Sigificat differeces betwee each level of steosis ad the correspodig cotrol values were determied with a two-tailed paired t test. A value of p<0.0 was cosidered sigificat. Regressio aalyses of flow-fuctio ad pressurefuctio relatios were performed with a leastsquares liear fit. I some istaces, secod-order polyomials ad expoetial least-squares fits similar to previous studies were also determied. Statistical sigificace betwee differet regressio lies as well as betwee liear ad quadratic fits was determied with a aalysis of covariace. 23 Results Aalog recordigs from a idividual experimet are illustrated i Figure 2. Regioal circumflex wall thickeig ad segmet shorteig remaied co- too FLOW («otrol) FIGURE. Plots of the relatio betwee edocardial fuctio ad trasmural flow at selected levels of coroary steosis correspodig to data obtaied i microsphere flow experimets. otrol poits have bee elimiated for clarity., Lies of idetity (i.e., a oe-to-oe relatio betwee reductios iflow adfuctio). Reductios i both segmet shorteig ad wall thickeig were closely related to reductios i edocardial flow ( ). I cotrast, chages i edocardial fuctio were dissociated with epicardial flow (o). Values are mea±sem.

7 aty Autoregulatio i the Uaesthetized Dog 27 TABLE 2. Group (% otrol edo flow) Noischemic (=0) Mkrosphere Flow Experimets: Regioal L Fuctio S P Normalized L:LAD edo flow 0.03 ±0. %L WT (%) 2.±. 2.±.6 %LSS (%).±. 7.±. LED WT(mm).± <0.003 L ED SL (mm).±2..o±2.6 <0.003 LA WT (mm) 2. ±0. 2.7±.02 L ASL (mm) 2.6±0. 2. ±0. 7-0% («= ) S P 0.2± ± ±.2 < ±.7 < ± ± ± ±3.0 2.± ±0.6 < ±0.3.±0.30 <0.0-70% ( = 7) S P ± ±7. 7.±7.3.±.3 7.±6. < ± ±0. 3. ± ±0.6.7 ± ±0..3±.0 3-0% ( = ) S P 0.3 ± ±..±. < ±..0±6 <0.007.±.2.06±..2±2.O 6.3 ± ±0.7.0 ±0.2 < ± ±0.7 Dowloaded from by o September, 20 <30% d = ) 7 c s p 0.2 ± ±6.2 7.±. <0.0.3± < ±.30.± ± ± ± ±.02 < ± ±0.7 <0.06 Values are mea±sd. Normalized L: LAD edo flow, ormalized edocardial flow for total perfused regio (see text for details); %L WT, circumflex wall thickeig (%); % L SS, circumflex segmet shorteig (%); ED WT, ed-diastolic wall thickess; ED SL, ed-<liastolic segmet legth; A WT, ed-systolic mius ed-diastolic wall thickess; A SL, ed-diastolic mius ed-systolic segmet legth;, umber of measuremets i each group;, cotrol; S, steosis; p, statistical sigificace for two-tailed paired t test;, ot sigificat. Measuremets have bee grouped ito five levels of pressure ad flow reductio as described i the text. stat over a wide rage as coroary artery pressure was reduced. I this aimal, there were o chages i fuctio util coroary pressure fell below 3 mm Hg (ed-diastolic coroary pressure, 20 mm Hg). Below this critical pressure, reductios i coroary pressure were associated with proouced reductios i circumflex fuctio over a relatively arrow pressure rage. Despite the reductios i circumflex fuctio, there were o major chages i systemic hemodyamics. As oted i the extreme righthad pael of this figure, circumflex fuctio remaied depressed below cotrol after occlusio release. I 0 aimals, fuctio was compared before ad after determiatio of the autoregulatory relatio. O restoratio of coroary pressure after a average of ± (SD) miutes of ischemia, circumflex wall thickeig fell from 26. ±7.0% to 2.7±6.0% (p<0.002) ad segmet shorteig fell from.3 ±.% to 2.±.% (/>). There were o sigificat chages i aterior descedig fuctio. Thus, despite restoratio of coroary pressure ad presumably flow after the determiatio of the autoregulatory relatio, wall thickeig was depressed to ± 3% of cotrol ad segmet shorteig to 66 ± % of cotrol ad recovered over the subsequet 2-hour period. Trasmural oroary Autoregulatio Uder cotrol coditios for all aimals ( = 6), heart rate averaged 06 ± beats/mi. Aortic pressure was 0 ± mm Hg systolic ad 7 ±7 mm Hg diastolic. Left vetricular ed-diastolic pressure averaged.7 ±2. mm Hg. Left vetricular dp/dt^, was 3,06 ±606 mm Hg/sec ad dp/dt^,, was -2,6 ±3 mm Hg/sec. There were o sigificat differeces i systemic hemodyamics comparig cotrol with correspodig steosis measuremets except for heart rate, which icreased from 00 to 07 beats/mi whe circumflex flow fell to less tha 30% of cotrol (p<0.0). ircumflex zoe wall thickeig averaged 26.7 ± 0.%, ad segmet shorteig averaged 7. ±.%. I the aterior descedig or cotrol zoe, wall thickeig averaged 2.±.%, ad segmet shorteig averaged 2. ±.%. Arterial blood gases at the time of study were ph, 7. ±0.0; Pc^, 7 ±6 mm Hg; ad Pcch, 33 ± mm Hg. Hematocrit averaged 3 ±%. Regioal autoregulatory relatios at six selected levels of edocardial flow reductio are illustrated

8 2 irculatio Research Vol 63, No, October WALL THIKENING 0 00 EQMENT SHORTENING («otrol) 00-, ENDO FLOW FIGURE 6. Plots of the relatio betwee reductios i edocardial flow ad both wall thickeig reductios o the left ( ) ad segmet shorteig reductios o the right (O)for idividual flow-fuctio poits. Flow values have bee obtaied from the myocardium immediately surroudig the edocardial crystals. otrol microsphere flow poits have bee elimiated for clarity. Dashed lie o the left idicates the liear relatio betwee wall thickeig reductios (y) ad edocardial flow (x): y=0.6x+3., r=0.0. Relatio was improved by a secod-order polyomial (y=-0.003x x-33., r=0.3, solid lie o the left), but the deviatio from the liear fit was less tha 0% durig mild to moderate ischemia (i.e., edocardial flow, more tha 30% of cotrol). Solid lie o the right idicates the liear relatio betwee segmet shorteig reductios ad edocardialflow: y=.x-s, r=0.2. Slope of the liear flow-fuctio relatio for segmet shorteig was sigificatly differet from wall thickeig (p). Dowloaded from by o September, 20 i Figure 3. orrespodig hemodyamic ad regioal flow measuremets are summarized i Table. Uder cotrol coditios, circumflex edocardia] flow for all aimals averaged.06 ±0.22 ml/mi/g ad epicardial flow averaged 0.2 ±0.2 ml/mi/g (p). There were o sigificat differeces i flow betwee the circumflex or the aterior descedig regio uder restig coditios. Whe regioal fuctio was maitaied as coroary pressure was reduced from ± 0 to ± mm Hg, the reductio i absolute flow was 6% for the edocardium ad % for the epicardium (p = ). With the chages i absolute flow ad mea coroary pressure for these oischemic poits, closed-loop autoregulatory gai was 0.6 for the edocardium ad 0.0 for the epicardium. Edocardial flow bega to fall sigificatly whe coroary pressure reached 37 mm Hg (p vs. cotrol). This was associated with a correspodig fall i the edocardial-to-epicardial flow ratio from.3±0. to.±0. (p<0.00 vs. cotrol). I cotrast to the edocardium, autoregulatio of epicardial flow was maitaied util mea coroary pressure fell to 2 mm Hg (p<0.02 vs. correspodig cotrol measuremets). There were o sigificat chages i aterior descedig edocardial or epicardial flow durig circumflex ischemia. Normalized circumflex edocardial flow for each level of steosis is plotted versus mea, mea diastolic, ad ed-diastolic coroary pressure i Figure. The edocardial autoregulatory relatio was qualitatively similar for each idex of distal coroary pressure. The autoregulatory relatios with ed-diastolic ad mea diastolic coroary pressure were, however, shifted to the left of the autoregulatory relatio for mea coroary pressure. Furthermore, the rage of coroary pressure over which edocardial flow fell with diastolic pressure idexes was arrower. Flow-Fuctio Relatio Durig Autoregulatio Figure cotrasts edocardial ad epicardial variatios i flow relative to edocardial fuctio. Table 2 summarizes measuremets of regioal fuctio. Reductios i both segmet shorteig ad wall thickeig were closely related to reductios i edocardial flow. I cotrast, epicardial flow remaied uchaged util the most severe level of steosis, despite large reductios i edocardial fuctio. These data idicate a close couplig of edocardial flow with fuctio measured by wall thickeig or segmet shorteig. Furthermore, despite the fact that wall thickeig is a trasmural measuremet, its dissociatio with epicardial flow was similar to that of segmet shorteig. Regressio relatios for both wall thickeig ad segmet shorteig reductios are illustrated i Figure 6. Reductios i fuctio (percet of cotrol) were correlated with flow (percet of cotrol) i the edocardia] sample cotaiig the idividual crystals. Flow-fuctio relatios with the circumflex core regio flows were ot statistically differet. The relatio betwee wall thickeig reductios (y) ad edocardial flow (x) as a percet of cotrol was described by a liear equatio: y = 0.6x + 3., = 60, r=0.0. A quadratic equatio sigificatly improved the fit of the wall thickeig data: y=-0.003j X-33., r = 0.3, p versus liear fit by aalysis of covariace. A expoetial equatio failed to fit the data ad

9 aty Aatoregulatio i the Uaesthetized Dog 2 SEGMENT SHORTENING 00. 0/ -0 At?.if-.) WALL THIKENMQ eo f 37. ma ( it Hg «. * y - S.S2x r o 0.S7 Dowloaded from by o September, 20 WALL THIKENING FIGURE 7. Plot of the relatio betwee steady-state reductios i wall thickeig ad segmet shorteig for aimals i which both measuremets were available., Lie of idetity. Reductios i segmet shorteig exceeded wall thickeig reductios at all levels of ischemia. Relatio betwee them could be described as follows: y=36x-0, =30, r=0.. Segmet akiesis occurred at a time whe wall thickeig persisted (2 J% of iitial values). also failed to defie the cotrol poit (00% fuctio, 00% flow). Despite the improved quadratic fit over the etire rage of edocardial flow reductio, the liear fit was withi 0% of the quadratic fit at levels of flow above 30%. Thus, from a practical stadpoit, reductios i edocardial flow i this rage were related to reductios i wall thickeig o a early oe-to-oe basis. The relatio betwee reductios i segmet shorteig (y) ad edocardial flow (x) was also liear (Figure 6): y=l.lx-2j, = 3, r = 0.2. The fit was ot improved sigificatly by a quadratic equatio, ad a expoetial equatio did ot fit the data. As with wall thickeig, flow-fuctio relatios based o core regio flows were ot statistically differet. However, i compariso to wall thickeig, there were greater reductios i segmet shorteig at ay give level of flow reductio (p for the slope of the liear fits). Figure 7 depicts ormalized wall thickeig ad segmet shorteig reductios at comparable levels of ischemia i dogs i which both pairs of crystals were operatioal ad appropriately aliged. The relatio betwee segmet shorteig (v) ad wall thickeig (x) reductios as a percet of cotrol was described by the followig equatio: y =.36* - 0., = 30, r = 0.. Akiesis of segmet legth (y = 0%) occurred at a time whe wall thickeig persisted (x = 2.% of cotrol). Thus, these data corroborate the fidig that reductios i segmet shorteig exceed wall thickeig reductios durig steadystate circumflex ischemia. oroary Pressure-Fuctio Relatios oroary pressure-fuctio relatios were similar to edocardial autoregulatory relatios based o relative reductios i coroary flow. Figure illustrates typical pressure-fuctio relatios obtaied i a idividual aimal for both wall thickeig ad SEQUENT H0RTENIN eo eo SO MEAN ORONARY PRESURE (mm Hg) 3 mm Hg.. - ^ # y = e.70x r eo B0 MEAN ORONARY PRESSURE (mm Hg) FIGURE. Plots of pressure-fuctio relatios for wall thickeig ad segmet shorteig from a idividual aimal. Wall thickeig reductios occurred whe coroary pressure reached 37. mm Hg. Segmet shorteig reductios bega whe coroary pressure reached 3. mm Hg. Above the lower autoregulatory limit, there was little variatio i cotrol fuctio. Below the lower autoregulatory limit, reductios i fuctio were liearly related to coroary pressure. segmet shorteig. I each aimal, regioal fuctio remaied costat over a wide rage of coroary artery pressure. Below a critical pressure, reflectig the lower limit of edocardial autoregulatio, there was a liear fall i fuctio with pressure. The reproducibility of the pressure-fuctio relatio over time is show i Figure. Here, pressure-fuctio relatios were costructed o six differet days over a period of weeks i the same aimal. Heart rate ( ± beats/mi) ad systolic pressure (3± mm Hg) remaied withi fairly arrow limits over this time. The lowest pressure at which regioal fuctio was maitaied averaged.±3.3 mm Hg for wall thickeig ad.±3.2 mm Hg for segmet shorteig. The slope of the pressure-fuctio relatio below this lower pressure limit averaged. ±.%/mm Hg (r=0. ± 0.02) for wall thickeig ad.3 ±2.20%/ mm Hg (r = 0. ±0.0) for segmet shorteig. Thus, there was close correlatio of pressure ad fuctio throughout the duratio of the study with a lower autoregulatory limit that was reproducible withi arrow bouds. Pressure-fuctio regressio relatios for all aimals are summarized i Table 3, ad correspodig pressure-fuctio poits are plotted i

10 30 irculatio Research Vol 63, No, October *.v q^i g0 - WALL THIKENING <* ojiuofl 0 ' DAY FOLLOWING mtruu NTATtON Dowloaded from by o September, 20 SEGMENT HORTENINQ MEAN ORONARY PRESSURE /, // Jf/l lift II (»» H«> * * DAY FOLLOWING ITRUMENTATION #- 7 A J «0 0 ««O MEAN ORONARY PRESSURE <~i Ho) Figure 0. The stability of cotrol hemodyamics was ascertaied with the coefficiet of variatio (Table ). This raged from % to 6% for the differet variables examied idicatig that over the time period of the pressure-fuctio determiatio, global determiats of myocardial demad were essetially costat. Amog all aimals, the correlatio coefficiet for the regressio of mea coroary pressure ad fuctio averaged 0. ±0.0 for wall thickeig reductios ad 0.6 ±0.03 for segmet shorteig reductios. A quadratic relatio did ot improve the fits ad frequetly could ot be extrapolated back to 00% fuctio. Wall thickeig bega to fall (00% fuctio) below a mea coroary pressure of 3. ±.6 mm Hg, reachig a poit of akiesis (0% fuctio) at a pressure of 2. ±3. mm Hg. Segmet shorteig bega to fall at a mea coroary pressure of.7±7. mm Hg (p<0.06 vs. wall thickeig) ad reached a poit of akiesis at a mea coroary pressure of 26.2±3. mm Hg (/?<0.006 vs. wall thickeig). Usig diastolic idexes of coroary pressure, the pressurefuctio relatios were shifted to the left. Wall thickeig bega to fall at a mea diastolic pressure of 2.±.6 mm Hg ad at a ed-diastolic pressure of 22.0 ±2. mm Hg. Segmet shorteig FIGURE. Plots of reproducibility of the pressurefuctio relatio i a sigle aimal over weeks. Each lie ad symbol represets the pressurefuctio relatio o a give day. (See text for discussio). bega to fall whe mea diastolic pressure reached 3.±. mm Hg (p<0.062 vs. wall thickeig) ad ed-diastolic pressure reached 2. ±3.7 mm Hg (p<0.062 vs. wall thickeig). The slope of the pressure-fuctio relatio icreased whe mea diastolic pressure ad ed-diastolic pressure were used. This reflected the fact that the pressure rage over which fuctio fell from 00% to 0% of cotrol became arrower ( 0 mm Hg for eddiastolic coroary pressure). Discussio This study idicates that the coroary pressurefuctio relatio ca be used to defie the lower limit of edocardia] autoregulatio. I cotrast to aesthetized aimals, i which edocardial autoregulatory reserve is exhausted at coroary pressures of 70 mm Hg, edocardial flow ad fuctio remai costat i coscious aimals util coroary pressure falls to 0 mm Hg. As outlied below, this substatial shift i the lower autoregulatory limit is difficult to explai o the basis of differeces i hemodyamic factors ifluecig myocardial metabolic demad or vasodilator reserve. This raises the possibility that other factors may be resposible for modulatig coroary autoregulatio i the opechest aesthetized aimal.

11 - «aty Autoregulatio i the Uaesthetized Dog 3 TABLE 3. Pressure-Fuctio Experimets: oroary Pressure-Fuctio Relatios Normalized L WT («= ) Abscissa parameter 00% 0% 0% L pressure (mm Hg) Mea Mea diastolic Ed-diastolic L pressure (mm Hg) Mea Mea diastolic Ed-diastolic 3.±.6 2. ± ±2..7±7. 3.±. 2. ±3.7 3O.0± ±3.7 7.±2. Normalized L SS («= 2) 3.0±.7* 2.3±.* 20.0 ±2.* 2. ±3.. ± ±3.* * t Slope 6.36± ±2.7.3± ±3.6.23±3. 2.7±.27 Itercept -37±6O -06± -±6-203 ± -70±7 -± r 0. ± ± ± ± ± ±0.0 Values represet mea±sd. 00%, 0%, ad 0% idicate values of coroary pressure (mm Hg) that correspod to three selected levels of regioal fuctio reductio for ormalized wall thickeig (L WT) ad ormalized segmet shorteig (L SS). The slope (percet/mm Hg) ad itercept (%) represet the mea liear coefficiets from the pressure-fuctio relatio for each abscissa parameter ad r is the liear correlatio coefficiet. A total of 22 pressure-fuctio relatios were suitable for aalysis. I aimals i which multiple pressure-fuctio relatios were obtaied, the poits correspodig to 00%, 0%, ad 0% fuctio were determied for each relatio ad the averaged. I additio, the slope ad the itercept for each relatio were averaged to obtai oe value. */><0.0 vs. correspodig wall thickeig values; tp<0.0 vs. correspodig wall thickeig values. Dowloaded from by o September, 20 oroary Pressure-Fuctio Relatio I view of the close relatio betwee edocardial flow ad fuctio durig myocardial ischemia, it is ot surprisig that the relatio betwee edocardial fuctio ad coroary pressure is similar to the edocardial autoregulatory relatio betwee flow ad pressure. This correspodece permits the steady-state coroary pressure-fuctio relatio to be used to characterize edocardial autoregulatio at ay poit i time, as well as before ad after specific itervetios. Furthermore, uder experimetal circumstaces i which oxyge extractio icreases as coroary pressure is reduced, the WALL «H THIKENING (I otrol) SEGMENT SHORTEN! NO («ortrod pressure-fuctio relatio may allow more precise iterpretatio of flow chages i terms of the adequacy of edocardial oxyge delivery. Both edocardial segmet shorteig ad trasmural wall thickeig remaied costat over a wide rage of coroary pressure withi idividual aimals (coefficiet of variatio, 3-%). Below the lower autoregulatory limit, fuctio fell i a liear fashio with further reductios i coroary pressure (although a secod-order term occasioally improved the data fit, the secod-order fit deviated i a uphysiological fashio outside of the data rage). Reductios i fuctio correlated best with W 0to fto 00 to 0 K M W SO- 00- so- jf W 00 -ao- 0 0 M «0 00 to 0 to 0 00 MEAN MEAN HA3TOU END DiASTOU ORONARY PRESSURE FIGURE 0. Plots of regioal fuctio versus mea, mea diastolic, ad ed-diastolic coroary pressure. Poits represet data from pressure-fuctio relatio determiatios i 6 aimals. Arrows idicate pressures correspodig to the lower limit of autoregulatio (fuctio, 00% of cotrol) based o the pressure-fuctio relatios summarized i Table 3. Both wall thickeig (upper paels) ad segmet shorteig (lower paels) remaied costat over a wide pressure rage. Below a critical pressure, large chages i fuctio occurred over a arrow pressure rage. Pressure-fuctio relatios usig diastolic pressure idexes (middle ad right paels) were shifted to the left of the mea coroary pressure-fuctio relatio (left pael). ( Ho)

12 32 irculatio Research Vol 63, No, October TABLE. Pressure-Fuctio Experimets: Systemic Hemodyamks, Regioal Fuctio, ad oefficiets of Variatio Heart rate (beats/mi) Aortic pressure (mm Hg) LVEDP (mm Hg) Systolic Diastolic Mea Mea ±SD.0 oefficiet of variatio (mea±sd) 2.7±2.3% 2.+.%.±2.0% 3.6±.% * LV dp/dt (mm Hg/sec) Max Mi 3,0-2, ±2.6% -6.3±.% Dowloaded from by o September, 20 Regioal Fuctio (PL>0 mm Hg) L WT %WT (=) ED (mm) ES (mm) L SL % SS ( =) ED (mm) ES(mm) LAD WT% WT (=) ED (mm) ES (mm) LAD SL % SS ( =0) ED (mm) ES(mm) ±2.6% % 0.±0.% 2.±3.% 0. ±0.% 0. ±0.% 3.3±2.% 0.7 ±0.6% 0.±0.% 2.±2.%.0±0.7% 0. ±0.6% Values are mea±sd. LV, left vetricular; LVEDP, left vetricular ed-diastolic pressure; LV dp/dt, first derivative of LV pressure; L, left circumflex; LAD, left aterior descedig; WT, wall thickess; SL, segmet legth; %WT, wall thickeig (see text for calculatio); %SS, segmet shorteig (see text for calculatio); ED, ed diastole; ES, ed systole. *For LVEDP, the stadard deviatio of LVEDP withi a experimet averaged.±.3 mm Hg. mea coroary pressure (r = 0. for wall thickess, r=0.6 for segmet legth). They also correlated closely with mea diastolic ad ed-diastolic coroary pressure (r=0.0-0., Table 3). Although reductios i segmet shorteig appeared to begi at slightly higher coroary pressures tha reductios i wall thickeig (2 vs. 3 mm Hg), the level of sigificace of the diflferece was borderlie The temporal reproducibility of coroary autoregulatio is curretly ukow but has potetial importace i iterpretig studies examiig chages i coroary flow over time. I additio to variatios i heart rate, factors that alter systemic pressure, oxyge carryig capacity, or eural toe are likely to alter the overall autoregulatory relatio. I the preset study, i which heart rate ad systolic pressure remaied withi arrow bouds, there was miimal day-to-day variatio i the coroary pressure-fuctio relatio up to weeks after surgical istrumetatio. These results suggest fairly costat characteristics of edocardial autoregulatio over this time period. Reproducibility of the pressure-fuctio relatio i short-term studies is more problematic tha o a day-to-day basis. Pressure-fuctio relatios i the preset study were costructed with progressive reductios i coroary pressure. Although the experimetal procedure resulted i regioal dysfuctio ad ischemia for oly short periods, regioal fuctio remaied depressed below cotrol by 20-30% o restoratio of ormal coroary pressure. Regioal fuctio retured to cotrol levels withi 2 hours, ad gross evidece of myocardial ifarctio was ot observed. The depressio i fuctio appeared similar to the reversible postischemic dysfuctio reported after brief periods of total coroary occlusio 2 or prologed partial occlusio. 2 This fidig highlights a importat methodologic cosideratio i studyig autoregulatio ad/or the pressure-fuctio relatio o a repeated basis at a sigle settig, that is, effects of itervetios ca oly be evaluated after allowig a sufficiet time period for edocardial fuctio to recover after preitervetio data have bee collected. This issue may be germae to the iterpretatio of previous studies examiig the role of itervetios durig autoregulatio i aesthetized aimals haracteristics of autoregulatio i the postischemic or "stued" state may differ ad cotribute to the geeral lack of reproducibility of autoregulatio observed i idividual aesthetized aimals. 27 Two additioal factors eed to be addressed whe usig the coroary pressure-fuctio relatio

13 aty Autoregulatio i the Uaesthetized Dog 33 Dowloaded from by o September, 20 ENDOARDIAL FLOW (ml -ml* - g" ) L WALL THIKENING I-QH BH PfiESENT STUDY OQALLAQHER «t. itto MEAN ORONARY PREURE (mm Hg) FIGURE. Plots of compariso ofedocardial autoregulatory ad pressure-fuctio relatios i petobarbital aesthetized dogs (Gallagher et ap) with those i the preset study. To compare the studies, absolute values of edocardial flow ad fuctio have bee used. Systemic hemodyamic parameters were comparable as summarized i the text. Despite lower levels of restig edocardial flow i aesthetized aimals (O), reductios i flow ad wall thickeig occurred at higher coroary pressures tha i uaesthetized aimals ( ). The shift to the left of the edocardial autoregulatory relatio ad the pressure-fuctio relatio i the awake aimals suggests that aesthesia may modulate coroary autoregulatory resposes idepedetly of effects o heart rate, systolic pressure, ad cotractility. Values are mea±sem. to study edocardial autoregulatio. First, stable systemic hemodyamics are required for costacy of both myocardial metabolic demad ad coroary pressure at ay fixed level of coroary steosis. I aimals i which coefficiets of variatio for systemic hemodyamics exceeded 0%, correlatio coefficiets betwee reductios i fuctio ad coroary pressure were relatively poor (i.e., r<0.). Secod, after chages i the steosis severity, it is importat to delay observatios util fuctio ad pressure have reached a ew steady state. I the preset study, fuctio ad pressure typically stabilized withi miute after a icrease i degree of occlusio. While flow i the epicardial artery was ot measured, a previous study i aesthetized dogs from our laboratory idicated that the damped flow oscillatios after a sudde large step reductio i coroary pressure stabilize withi 0 secods." I respose to gradually icreasig steosis ad coroary pressure reductio, these oscillatios would be expected to be atteuated. Trasmural Variatios i Autoregulatio The results of this study are cosoat with previous studies i aesthetized aimals demostratig trasmural variatios i autoregulatio ad vulerability of the edocardium to ischemia. 3-6 They differ, however, i terms of the degree to which flow, oxyge delivery, ad fuctio remai costat above the lower edocardial autoregulatory pressure limit ad the level of coroary artery pressure at which autoregulatio is exhausted (as maifest by a declie i flow ad fuctio). Ivestigators from several laboratories have attempted to quatify the degree to which flow remais costat durig autoregulatio by calculatig the closed-loop autoregulatory gai. 3 I the preset study, the small variatios i absolute flow (6-%, p = ) observed whe coroary pressure was reduced from to mm Hg resulted i values of closed-loop gai (GJ of 0.6 for the edocardium ad 0.0 for the epicardium. Direct compariso with results from aesthetized studies is difficult because trasmural variatios i G c have ot bee reported. Available measuremets based o epicardial artery flow chages vary markedly, depedig o the coroary pressure rage examied Dole ad Nuo have also demostrated that icreases i heart rate from 0 to 20 beats/mi icrease G c sigificatly. I geeral, however, most aesthetized studies report cosiderably lower values of G c tha the preset study over a similar pressure rage (i.e., G c <0.). The compariso of the preset values of G c with previous results is further complicated by the fidig that myocardial oxyge cosumptio decreases as coroary pressure is reduced over the autoregulatory plateau i some aesthetized studies. 336 This variatio was origially described by Gregg 2 ad suggests that uder some circumstaces, coroary pressure ad/or flow appear to determie myocardial oxyge cosumptio. While oxyge cosumptio was ot measured i the preset study, the fact that both edocardial fuctio ad oxyge delivery remaied uchaged over a wide rage of distal coroary pressure argues agaist such a effect. Thus, the geerally higher values of G c i compariso to those i aesthetized aimals may reflect both a lower restig coroary veous Pc>2 (ad less reliace o ehaced oxyge extractio) as well as the absece of the Gregg effect as coroary pressure is reduced. The lower autoregulatory pressure limit has traditioally bee believed to reflect the critical pressure at which edocardial vasodilator reserve is exhausted. Reductios i the time available for edocardial perfusio with icreased rate ad icreases i myocardial metabolic demad both cause this limit to rise. 3 Recet studies have also demostrated reductios i flow durig autoregulatio i the presece of pharmacologically recruitable vasodilator reserve i aesthetized aimals.' '- Although the presece of pharmacological vasodilator reserve was ot examied i the preset study, it is difficult to attribute the lower edocardial autoregulatory pressure limit i the preset study (0 vs. 70 mm Hg mea pressure ad 2 vs.

14 3 irculatio Research Vol 63, No, October 00- A OO- WALL THIKENING SEGMENT SHORTENING i 0- / 0- LINEAR SO 00 SO I ENDO FLOW - LINE OF IDENTITY -PREENT STUDY -GALLAGHER et al.. VATNER FIGURE 2. Plots of compariso of flowfuctio relatios from the preset ad previous studies i uaesthetized aimals. All relatios have bee adjusted to reflect edocardial flow (x) ad fuctio (y) as a percet of cotrol. Pael A: ompares the liear relatios for wall thickeig from the preset study (y=0.6x+3., r=0.2) to that of Gallagher et al"> (y=.2x-, r=0.). Pael B: ompares the quadratic relatios for wall thickeig from the same two studies (y=-0.003x 2 +2Jx-33J, r=0.3, preset study, ady=-0.007x 2 +2.X-3, T=0.6, Gallagher et al' ). Pael : ompares the expoetial segmet shorteig relatio from Vater (y=00-6.6e-" M7(IO0 - x), r=0.2) to the liear relatio from the preset study (y=.x-2.7, r=0.2). (See text for further discussio.) Dowloaded from by o September, j ENDO FLOW 0 mm Hg 6 diastolic pressure) to differeces i restig flow ad/or edocardial vasodilator reserve betwee aesthetized ad uaesthetized aimals for several reasos. First, despite somewhat higher heart rates, values of restig edocardial flow i previous aesthetized studies are similar to those i the preset study (~ ml/mi/g). This may reflect a reductio i cotractility i the aesthetized state that couteracts the effects of icreased rate o myocardial demad. Secod, differeces i heart rate betwee the preset study ad previous studies are modest ( 00 vs. 0 beats/mi). 6 Autoregulatory reductios i flow at pressures as high as 70 mm Hg are difficult to recocile with measuremets of edocardial vasodilator reserve at a rate of 0 beats/mi demostratig flows of. ml/mi/g at a pressure of 0 mm Hg. 2 I additio, a prelimiary report from our laboratory i awake aimals has demostrated a lower autoregulatory limit of less tha 70 mm Hg i the face of a eve higher heart rate (200 beats/mi) ad higher restig flow (. ml/ mi/g). 30 Fially, i cotrast to edocardial flow, epicardial flow appears to be idepedet of heart rate durig maximum vasodilatio. 2 Nevertheless, the lower limit of epicardial autoregulatio is also higher i the aesthetized aimal (-0 mm Hg 3 ) as opposed to the preset study (2 mm Hg). Studies of autoregulatio i other vascular beds have demostrated atteuated autoregulatio i respose to aesthetic agets. It is therefore possible that effects of aesthesia ad/or acute surgical istrumetatio alter coroary autoregulatory resposes as they do the relatio betwee edocardial flow ad fuctio. 0 I this regard, the preset data are of particular iterest i compariso to the study of Gallagher et al 7 where coroary pressure ad wall thickeig were examied durig myocardial ischemia i aesthetized ope-chest dogs (Figure ). The experimetal preparatio was similar to the preset study. Systolic pressure levels were similar, but heart rate was slightly higher (30 vs. 00 beats/mi). Despite lower cotrol edocardial flows i the aesthetized aimals (0.62 vs..0 ml/ mi/g i the preset study), reductios i flow bega at sigificatly higher coroary pressures. A 20% reductio i edocardial flow occurred at a mea coroary pressure of versus 37 mm Hg i the preset study. Reductios i edocardial flow i each study were associated with cocomitat reductios i wall thickeig, eve though cotrol values of wall thickeig were lower i the aesthetized

15 Dowloaded from by o September, 20 aimals (.3% vs. 2.%). The shift to the left i both the edocardia! autoregulatory ad the pressurefuctio relatios i the preset study supports the hypothesis that factors other tha systemic hemodyamics produce differeces i coroary autoregulatio durig aesthesia. These differeces warrat further ivestigatio ad may bear importatly o the extrapolatio of data obtaied i aesthetized aimals to humas. Edocardial Flow-Fuctio Relatio It has bee appreciated sice the classic study of Teat ad Wiggers i 3 3 that myocardial performace is closely coupled to coroary flow. Although fuctio falls whe flow is reduced to a critical level, reported myocardial flow-fuctio relatios exhibit cosiderable variability While some of this variatio o doubt relates to aesthesia, differeces also exist betwee edocardial flowfuctio relatios obtaied i coscious aimals whe fuctio is assessed by trasmural wall thickeig 0 as opposed to segmet shorteig. Although beatto-beat variatios i wall thickeig ad segmet shorteig durig temporary total coroary occlusio have bee reported to follow a oe-to-oe relatio, 3 correlative studies durig steady-state ischemia have ot previously bee reported. Based o the preset results, there appear to be quatitative differeces betwee the magitude of wall thickeig ad segmet shorteig reductio at comparable levels of ischemia. Flow-fuctio relatios from the preset study are compared with two previous studies i coscious dogs i Figure 2. Wall thickeig ad edocardial flow were closely coupled i a fashio similar to that reported by Gallagher et al. 0 I each study, the flow-fuctio relatio was mildly curviliear ad better described by a secod-order polyomial tha a liear fit. Although the liear relatios differ modestly i slope (Figure 2A), the curviliear relatios from the two studies (Pael B) are quite similar. The liear differece may reflect the fact that relatively few measuremets were performed i the preset study durig severe ischemia. Whe edocardial flow was more tha 30% of cotrol, deviatios of quadratic from liear fits were small (<0%). Thus, durig mild to moderate ischemia, relative reductios i ormalized wall thickeig provide a useful idex of the relative reductio i edocardial flow o a early oe-to-oe basis. Although segmet shorteig reductios were also closely coupled to edocardial flow, the quatitative relatio betwee the two parameters i the preset study differed from that previously reported i coscious aimals by Vater (Figure 2). I the preset study, the relative magitude of segmet shorteig reductio exceeded that of edocardial flow reductio ad was liear (Figures ad 6). The previous study foud the flow-fuctio relatio to be expoetial, with a 0% reductio i flow resultig i oly a 20% reductio i segmet aty Autoregulatio i the Uaesthetized Dog 3 shorteig. This would seem to idicate a relative isesitivity of segmet shorteig reductios durig mild to moderate ischemia i cotrast to the preset fidigs. While it is difficult to recocile the differece i terms of methodology, regioal variatios i the edocardial flow-fuctio relatio may be resposible. Segmet shorteig i the preset study was measured i the posterobasal free wall (distal circumflex artery) as opposed to the ateroapical free wall (aterior descedig artery) i the earlier study. Observatios i aesthetized aimals idicate that relatios betwee epicardial segmet shorteig ad flow durig myocardial ischemia differ betwee the two regios. 33 * 36 A additioal differece betwee the studies may relate to the fact that restig coroary flow levels were somewhat higher i the earlier study, despite similar global determiats of myocardial oxyge demad. Thus, differeces i autoregulatory gai betwee the two studies could coceivably have altered the flowfuctio relatio, particularly if oxyge delivery at reduced flow were maitaied by icreasig extractio i the earlier study. Previous studies examiig relatios betwee regioal fuctio ad edocardial flow have ot compared simultaeous measuremets of wall thickeig ad edocardial segmet shorteig durig steady-state myocardial ischemia. The preset study idicates that the magitude of reductio i segmet shorteig is more tha that of wall thickeig durig steady-state circumflex ischemia. Akiesis (i.e., absece of systolic shorteig) occurred at a time whe wall thickeig, while sigificatly reduced, was still preset (Figure 7). I terms of detectig the oset of edocardial ischemia, segmet shorteig bega to fall at a slightly higher mea coroary pressure (2 vs. 3 mm Hg), but the differece was of borderlie sigificace (p<0.06). Thus, while the magitude of segmet shorteig impairmet is more tha wall thickeig at comparable levels of ischemia, there appears to be little differece betwee the measuremets i terms of detectig the lower autoregulatory pressure limit usig the coroary pressure-fuctio relatio. Summary The close relatio of both edocardial flow ad fuctio with coroary pressure demostrated i this study provides a basis for the use of the coroary pressure-fuctio relatio to characterize edocardial autoregulatio o a repeated basis i the uaesthetized aimal. The characteristics of trasmural coroary autoregulatio i the uaesthetized aimal appear to differ from the aesthetized aimal i several respects, with the mea coroary pressure at which edocardial flow begis to fall beig cosiderably lower (0 vs. 70 mm Hg). Although some of the disparity betwee coscious ad aesthetized aimals may reflect variatios i myocardial metabolic demad ad/or vasodilator reserve, factors modulatig the coroary autoregulatory mechaism durig

16 Dowloaded from by o September, irculatio Research Vol 63, No, October aesthesia seem likely to be operative. Future studies with pressure-fuctio as well as pressure-flow relatios should clarify the fuctioal sigificace of factors that ca modulate edocardial autoregulatio uder differet experimetal circumstaces. Ackowledgmets I would like to thak Dr. Fracis J. Klocke for his helpful suggestios ad guidace throughout this study. The techical assistace of Kathlee Harris, Kathlee Weibel, Ae oe, Joseph Giglia, Verl Harbiso, Amy Johso, ad Richard Kohlmeier ad the secretarial assistace of Kyle Nuget are greatly appreciated. Refereces. Mosher P, Ross J, McFate PA, Shaw RF: otrol of coroary blood flow by a autoregulatory mechaism. irc Res 6; : Beme RM, Rubio R: oroary circulatio, i Beme RM, Spcrelakis J, Geiger SR (eds): Hadbook of Physiology: The ardiovascular System, Volume I. Baltimore, Williams ad Wilkis o, 7, pp Dole, WP: Autoregulatio of the coroary circulatio. Prog ardiovasc Dis 7^: Johso P: Autoregulatio of blood flow. irc Res 6; :3-. Guyto RA, Mcleatha JH, Newma GE, Michaelis LL: Sigificace of subedocardial ST segmet elevatio caused by coroary steosis i the dog. Am J ardka 77;0: Rouleau J, Boerboom LE, Surjadhaa A, Hoffma JIE: The role of autoregulatio ad tissue diastolic pressures i the trasmural distributio of left vetricular blood flow i aesthetized dogs. irc Res 7;:0-7. Gallagher KP, KumadaT, Koziol JA, McKow MD, Kemper WS, Ross J Jr: Sigificace of regioal wall thickeig abormalities relative to trasmural myocardial perfusio i aesthetized dogs. irculatio 0;62: Weitraub WS, Hattori S, Agarwal JB, Bodeheimer MM, Baka VS, Helfat RH: The relatioship betwee myocardial blood flow ad cotractio by myocardial layer i the caie left vetricle durig ischemia. irc Res ;:30-3. Vater SF: orrelatio betwee acute reductios i myocardial blood flow ad fuctio i coscious dogs. irc Res 0;7: Gallagher KP, Matsuzaki M, Koziol JA, Kemper WS, Ross J Jr: Regioal myocardial perfusio ad wall thickeig durig ischemia i coscious dogs. Am J Physiol ;27: H727-H73. aty JM Jr, Klocke FJ: Reduced regioal myocardial perfusio i the presece of pharmacologic vasodilator reserve. irculatio ;7: Aversao T, Becker L: Persistece of coroary vasodilator reserve despite fuctioally sigificat flow reductio. Am J Physiol ;2:H03-H 3. Pately GA, Bristow JD, Sweso LJ, Ladley HD, Johso WB, Aseloe G: Icomplete coroary vasodilatio durig myocardial ischemia i swie. Am J Physiol ;2: H63-H67. Gratta MT, Haley FL, Steves MB, Hoffma JIE: Trasmural coroary flow reserve patters i dogs. Am J Physiol 6;20:H276-H23. Dole WP, Nuo DW: Myocardial oxyge tesio determies the degree ad pressure rage of coroary autoregulatio. irc Res 6^: YoekuraS,WataabeN,affrcyJL,GauglJF, Dowey HF: Mechaism of atteuated pressure-flow autoregulatio i right coroary circulatio i dogs. irc Res 7 ;60:33-7. aty JM, Klocke FJ: Reductios i regioal myocardial fuctio at rest i coscious dogs with chroically reduced regioal coroary artery pressure. irc Res 7;60(suppl II):U-07-II-6. Streeter DD Jr, Spotitz HM, Patel DP, Ross J Jr, Soeblick EH: Fiber orietatio i the caie left vetricle durig diastole ad systole. irc Res 6^: Heyma MA, Paye BD, Hoffma JIE, Rudolph AM: Blood flow measuremets with radiouclide-labeled particles. Prog ardiovasc Dis 77^0: Baer RW, Paye BD, Verrier ED, Vlahakes GJ, Molodowitch D, Uhlig PN, Hoffma JIE: Icreased umber of myocardial blood flow measuremets with radiouclidelabeled microspheres. Am J Physiol ;26:H-H3 2. Falsetti HL, arroll RJ, Marcus ML: Temporal heterogeeity of myocardial blood flow i aesthetized dogs. irculatio 7 2: Kig RB, Bassigthwaighte JB, Hales FRS, Rowell LB: Stability of heterogeeity of myocardial blood flow i ormal awake baboos. irc Res ^7: Sedecor GW, ochra WG: Statistical Methods. Ames, Iowa, Iowa State Uiversity Press, Heydrickx GR, Baig H, Nelles P, Leuse I, Fishbei M, Vater SF: Depressio of regioal blood flow ad wall thickeig after brief coroary occlusios. Am J Physiol 7;23:H63-H6 2. Matsuzaki M, Gallagher KP, Kemper WS, White F, Ross J Jr: Sustaied regioal dysfuctio produced by prologed coroary steosis: Gradual recovery after reperfusio. irculatio 3;6: Dole WP, Yamada N, Bishop VS, Olsso RA: Role of adeosie i coroary blood flow regulatio after reductios i perfusio pressure. irc Res ^6: Haley FL, Gratta MT, Steves MB, Hoffma JIE: Role of adeosie i coroary autoregulatio. Am J Physiol 6; 20:H-H66 2. Gregg DE: Effect of coroary perfusio pressure or coroary flow o oxyge usage of the myocardium. irc Res 63; 3: Bache RJ, obb FR: Effect of maximal coroary vasodilatio o trasmural myocardial perfusio durig tachycardia i the awake dog. irc Res 77;: aty JM, Giglia J, Kadath D, Klocke FJ: The effect of tachycardia o edocardial autoregulatio i the uaesthetized dog (abstract). irculatio 7;76(suppl IV):IV- 3. Teat R, Wiggers J: The effect of coroary occlusio o myocardial cotractio. Am J Physiol 3;2: Dowey JM: Myocardial cotractile force as a fuctio of coroary blood flow. Am J Physiol 76^30: Gallagher KP, Stirlig M, hoy M, Szpuar A, Gerre RA, Botham MJ, Lemmer JH: Dissociatio betwee epicardial ad trasmural fuctio durig acute myocardial ischemia. irculatio ;7: Roa PG, Buja LM, Izquierdo, Hashimi H, Saffer S, Willerso JT: Iterrelatioships betwee regioal left vetricular fuctio, coroary blood flow, ad myocellular ecrosis durig the iitial 2 hours ad week after experimetal coroary occlusio i awake, usedated dogs. irc Res ;: Sasayama S, Frakli D, Ross J Jr, Kemper WS, McKow D: Dyamic chages i left vetricular wall thickess ad their use i aalyzig cardiac fuctio i the coscious dog. Am J ardiol 76,3: Hattori S, Weitraub WS, Agarwal JB, Bodeheimer MM, Baka VS, Helfat RH: otrastig ischemic cotractio patters by zoe ad layer i caie myocardium. Am J Physiol 2;23:H2-H KEY WORDS pressure-fuctio relatio flow-fuctio relatio coroary autoregulatio trasmural flow regioal myocardial fuctio