By Richard E. Kerber and Francois M. Abboud

Transcription

1 Effect f Alteratins f Arterial Bld Pressure and Heart Rate n Segmental Dyskinesis during Acute Mycardial Ischemia and fllwing Crnary Reperfusin By Richard E. Kerber and Francis M. Abbud ABSTRACT The effect f alteratins f bld pressure and heart rate n segmental dyskinesis induced by crnary artery ligatin and the influence f such manipulatins n the magnitude f recvery f the dyskinetic segment during subsequent crnary artery reperfusin were evaluated in 77 pen-chest dgs. Wall mtin was recrded by ultrasund reflected directly frm the ischemic mycardial segment. Acute ischemia prduced characteristic reginal abnrmalities in wall mtin: aneurysmal bulging ccurred during ismetric cntractin and wall velcity was markedly reduced during ventricular ejectin. During f ischemia, a cntrl grup f dgs underwent n interventins and shwed n further changes in wall mtin. Tachycardia induced by atrial pacing during ischemia had n significant effect. Arterial hypertensin during ischemia caused a marked reductin in wall velcity when methxamine was used: 14 ± 2 (SE) mm/sec (ischemia alne) t 6 ± 1 mm/sec (ischemia + drug). In cntrast, nrepinephrine imprved wall velcity: 11 ± 2 mm/sec (ischemia alne) t 25 ± 4 mm/ sec (ischemia + drug). Hypertensin caused by infusin f phenylephrine gave intermediate results, as did hyptensin induced by either nitrprusside r hemrrhage during the ischemic perid. After the drugs were stpped, the crnary ligatin released, and the ischemic mycardium reperfused. The relative rder f imprvement f wall velcity with reperfusin was 11 ± 2 mm/sec (ischemia alne) t 24 ± 3 mm/sec (reperfusin) in the grup that received nrepinephrine, 12 ± 3 mm/sec t 20 ± 3 mm/ sec in the cntrl grup with n interventin during ischemia, 13 ± 2 mm/sec t 20 ± 1 mm/sec in the nitrprusside grup, 9 ± 1 mm/sec t 9 ± 2 mm/sec in the phenylephrine grup, and 14 ± 2 mm/sec t 12 ± 1 mm/sec in the methxamine grup. The aneurysmal bulging during ismetric cntractin als was reduced t a greater degree by reperfusin in the grup that received nrepinephrine during the ischemic perid than it was in the grups underging ther interventins during ischemia. We cnclude that drug-induced elevatins in arterial bld pressure can have different effects n the dyskinetic mtin f acutely ischemic mycardium and n the degree f recvery fllwing reperfusin depending n the particular agent used. A reductin in bld pressure r an increase in heart rate during the perid f ischemia has n significant beneficial effect n the recvery f the dyskinesis tward cntrl levels after reperfusin. Hwever, it remains pssible that such manipulatins ver a brader range f pressure and rate r fr a lnger perid f ischemia may have mre nticeable effects. KEY WORDS psterir wall velcity mycardial infarctin aneurysm ventricular diameter artcrnary bypass graft ultrasund vasdilatr agents vaspressr agents dgs Acute crnary artery cclusin prduces ischemia in the area f mycardium deprived f its bld supply. In at least a part f this ischemic Frm the Divisin f Cardivascular Diseases, Department f Internal Medicine, University f Iwa Cllege f Medicine, and the Veterans Administratin Hspitals, Iwa City, Iwa This investigatin was supprted by Grant 73-G-23 frm the Iwa Heart Assciatin and U. S. Public Health Service Grant HL frm the Natinal Heart and Lung Institute. Please address reprint requests t Dr. Richard E. Kerber, Cardivascular Divisin, University f Iwa Hspitals, Iwa City, Iwa Received March 28, Accepted fr publicatin Octber 4, mycardium, prgressin t frank infarctin can be prevented if the mycardial xygen supply is increased r the demand reduced (1). Recently, attentin has been directed particularly at the size f the experimental mycardial infarctin as a useful parameter in assessing the effect f varius therapeutic interventins. Using epicardial S-T segment mapping and intramycardial creatinine phsphkinase assay techniques, it has been shwn that increases in crnary perfusin pressure by pharmaclgic agents r artic cunterpulsatin reduce infarct size and that decreases in crnary perfusin pressure increase infarct size (2, 3). Similarly, crnary artery reperfusin reduces the amunt f necrsis prduced by crnary artery cclusin (4). 145

2 146 In cnsidering the prblem f the salvage f ischemic mycardium, it seems clear that attentin must be paid nt nly t the size f the ultimate infarctin but als t the functin r the mtin f the jepardized mycardium; the aim f any therapeutic interventin is bth t minimize the size f the infarctin and simultaneusly t preserve r restre nrmal mycardial functin in the ischemic area. Factrs that benefit ne f these parameters can cnceivably have a detrimental effect n the ther. Utilizing an ultrasund technique in an experimental canine mdel, the aim f the present study was t assess the respnse f the reginal wall mtin abnrmalities f acutely ischemic mycardium t alteratins f arterial bld pressure and heart rate during the perid f acute ischemia and t determine the effect f such manipulatins n the respnse t subsequent crnary artery reperfusin. Methds Seventy-seven adult mngrel dgs weighing kg were anesthetized with sdium pentbarbital (25 mg/ kg, iv). Ventilatin was maintained with a Harvard respiratr via a cuffed endtracheal tube; peridic hyperinflatin was perfrmed t prevent atelectasis. The heart was expsed via a midsternal thractmy and lifted slightly in a pericardial sling. Systemic anticagulatin was achieved by administering heparin intravenusly. Artic and left ventricular pressures were recrded using n. 8 French plyurethane catheters attached t Statham P23 strain gauges. Left ventricular dp/dt was determined frm the left ventricular pressure tracing by a resistance-capacitance differentiating circuit; the catheters were flushed with 5 ml f heparinized saline befre each recrding. Cardiac utput (minus crnary bld flw) was determined with an EKG A PRESSURE IV SEPTUM ECHO POSTERIOR WALL ECHO LV PRESSURE KERBER, ABBOUD electrmagnetic flw prbe placed arund the ascending arta. Recrdings were made utilizing an Electrnicsfr-Medicine DR-12 multichannel phtgraphic recrder that had been mdified t display the ultrasund as well as the analgue pressure and electrcardigram (ECG) signals. An ultrasund transducer was placed lightly n the expsed anterir surface f the heart, usually resting n the interventricular grve. The ultrasund beam was directed t recrd the characteristic signal frm the left ventricular psterir wall caudad t the mitral valve ech, and it was fixed in place by a statinary arm. Verificatin f the ech identificatins was achieved by rapid injectin f 5 ml f nrmal saline slutin thrugh the left ventricular catheter; this maneuver prduces a "clud" f eches utlining the endcardialbld interfaces brdering the ventricular cavity (5). The echcardigraphic registratin f the psterir left ventricular wall mtin was measured accrding t the cnventins intrduced by Kraunz and Kennedy (6) (Fig. 1). Pint B, the psterir wall psitin at enddiastle, is apprximately simultaneus with the R wave f the ECG. During ismetric cntractin, the wall mves slightly psterirly frm pint B t pint C. The anterir mtin frm pint C t pint D is cincident with ventricular ejectin, and the mtin frm pint D t pint E reflects ismetric relaxatin. The mean psterir wall velcity (mm/sec) during ejectin is the slpe f the line drawn frm the nset (pint C) t the end (pint D) f ventricular ejectin. Psterir wall excursin (mm) is the amplitude f psterir wall mtin measured by the vertical distance frm pint C t pint D. The end-diastlic diameter (mm) is measured as the distance between the interventricular septum and the psterir wall at pint B. Fllwing cntrl hemdynamic and echcardigraphic measurements, acute ischemia f the true psterir wall was prduced by cclusin f the psterir descending crnary artery and ther psterir branches f the circumflex crnary artery. The ultrasund beam then struck the center f the ischemic area, CONTROL ISCHEMIA REPERFUSION FIGURE 1 Echcardigraphic recrdings befre and after crnary artery ligatin and after I hur f reperfusin in a typical dg. Vertical lines shw 0.5-secnd time intervals. IV = interventricular, A = artic, LV = left ventricular, PWV = psterir wall velcity, PWE = psterir wall excursin, and EKG = electrcardigram. See text fr explanatin f pints B, C, D, and E.

3 PRESSURE-RATE ALTERATIONS AND SEGMENT AL DYSKINESIS 147 resulting in a characteristic alteratin f the echcardigraphic wall mtin seen nly when the ultrasund beam is reflected ff ischemic rather than nrmal mycardium (7). Further evidence that the beam was actually striking the ischemic area was btained at the cnclusin f the experiment by passing a metal prbe thrugh the heart alngside the ultrasund transducer and bserving the site f penetratin f the left ventricular psterir wall. In all f the dgs in this study, the characteristic mtin abnrmalities were present n ech recrdings after cclusin, and the prbe intersected the psterir wall in an area supplied by the ccluded crnary artery. Hemdynamic and echcardigraphic recrdings were made 5 minutes after crnary artery cclusin and the prductin f acute ischemia. The dgs were then divided int fur grups. The cntrl grup (11 dgs) underwent n therapeutic interventin during the ischemic perid, which lasted 1 hur. A secnd grup f 10 dgs underwent right atrial pacing during the hur f ischemia t increase heart rate t % f the pstligatin rate; the average increase achieved was 50 beats/min (range 32 t 77 beats/min). In a third grup, drugs were administered t raise artic systlic pressure t % f the pstligatin level. We attempted t maintain the systlic pressure at this level fr the 1 hur f ischemia, althugh in sme dgs the arterial pressure tended t fall smewhat despite increases in the rate f drug infusin. Dgs in this grup received either methxamine ( mg/min) (12 dgs), phenylephrine ( mg/min) (9 dgs), r nrepinephrine (1-4 ^ug/min) (12 dgs). In the furth grup f dgs, artic systlic pressure was lwered during ischemia t 50-75% f the pstligatin level by either the administratin f sdium nitrprusside ( mg/ min) (15 dgs) r the withdrawal f ml f bld (8 dgs). After 1 hur f ischemia, the interventins were ended by discntinuing the drug infusins, stpping the atrial pacing, r rapidly reinfusing the warmed bld previusly withdrawn. The crnary artery cclusin was then released in all f the dgs, and the ischemic area was thereby reperfused. Dgs that develped ventricular irritability during the perid f crnary artery ligatin r reperfusin were treated with small amunts f lidcaine administered intravenusly. A number f dgs develped ventricular fibrillatin, especially after release f the crnary artery ligature; n attempt was made t defibrillate these dgs, and data frm them are nt included in the results. Recrdings were again made 1 hur after the start f the reperfusin perid. The dgs were then killed by an intravenus injectin f ptassium chlride, and a metal prbe was passed thrugh the heart alngside the ultrasund prbe t determine the path f the ultrasund beam and verify that the beam was striking the infarcted area. In additin, the crnary artery that had been temprarily ccluded during the experiment was pened and inspected t ensure that the arterial lumen was free f clts r intimal damage that might have interfered with reperfusin after release f the ligature. Statistical analysis was perfrmed with Student's paired /-test, cmparing data btained 5 minutes after ligatin (befre interventin) with thse btained frm the same dg after ligatin (at the end f each interventin) and after the initiatin f reperfusin. In additin, the data btained after 60 minutes f reperfusin were cmpared with cntrl preligatin data. In cmparing the effects f the different interventins, an unpaired t-test was used. Results IMMEDIATE EFFECTS OF CORONARY ARTERY LIGATION Hemdynamic changes and ultrasund-registered dyskinesis prduced by acute ischemia in each f the grups f dgs studied were similar t thse previusly reprted by us (7) (Table 1, Fig. 1). In the cntrl dgs, a significant increase in the B-C amplitude (psterir displacement f the psterir heart wall during ismetric cntractin) ccurred after crnary artery ligatin; this increase represents aneurysmal bulging f the ischemic mycardium during ismetric cntractin. Significant reductins in psterir wall velcity and excursin were als seen. During ismetric relaxatin, the ischemic mycardium mved abruptly frward (D-E perid), indicating reciling f the stretched and bulging mycardium as the interventricular pressure rapidly fell. The end-diastlic diameter increased significantly with ischemia. These mtin abnrmalities remained cnstant during 1 hur f ischemia withut further interventin in the cntrl dgs. EFFECTS OF INTERVENTIONS DURING THE ISCHEMIC PERIOD Increased Heart Rate. End-diastlic diameter fell, but there were n ther significant ultrasund r hemdynamic changes in respnse t an increase in heart rate (Table 1). Elevated Arterial Bld Pressure. Elevatin f bld pressure t apprximately equal levels by administratin f pharmaclgic agents prduced variable effects (Table 2). Methxamine prduced large falls in psterir wall velcity and excursin; the B-C amplitude (aneurysmal bulging) was als reduced, and there was a marked increase in enddiastlic diameter. Phenylephrine administratin prduced significant rises in psterir wall velcity and excursin. End-diastlic diameter fell, but this change was nt statistically significant, and there was n change in B-C amplitude. With the nrepinephrine infusin, psterir wall velcity and excursin shwed striking rises, but end-diastlic diameter declined. An increase in aneurysmal bulging (B-C amplitude) als ccurred, but it was nt statistically significant. Reduced Arterial Bld Pressure. Hyptensive interventins during ischemia als prduced variable effects (Table 3). Nitrprusside administratin

4 148 KERBER, ABBOUD TABLE 1 Effects f Crnary Reperfusin after N Interventin and after Atrial Pacing during Ischemia Reperfusin alne (11 dgs) Reperfusin after atrial pacing during ischemia (10 dgs) Cntrl 5 minutes Reperfusin: Cntrl 5 minutes Ischemia + atrial pacing: Reperfusin: PWV (mm/sec) B-C (mm) PWE (mm) EDD (mm) Heart rate (beats/min) Artic systlic pressure Artic diastlic pressure LV end-diastlic pressure LV dp/dt (mm Hg/sec) Cardiac utput (liters/ min) 27 ± ± ± ± ± ± 6 74 ± 4 5± ± ±3 4.8± ± ± ±4 99 ±6 69 ±5 6± ± ±2 4.2 ± ± ± ±6 89 ± 5t 62 ±6 5± ± ±3*t 2.5 ±0.4* 2.0 ± 0.4t 13.7± 1.1* 162 ±6 90 ± 7t 64 ± 6t 3± l*t 1135± 112t 31 ± ± ± ± ± ± 6 90 ± 5 7± ± ± ± ± ± ± ± ± 5 86 ± 6 9± ± ± ± 2 2.8± ± ±3.1t 194 ±7t ±5 9± ± ± ± 2*t 2.7±0.2t 2.6±0.3t 21.0 ±2.8* 154 ± 7* 99±3t 78±3t 7± 1* 1360± ± 0.3 All values are means ± SE. PWV = psterir wall velcity, PWE = psterir wall excursin, B-C = B-C amplitude (see text), EDD = end-diastlic diameter, and LV = left ventricular. *P < 0.05, reperfusin vs. ischemia at 5 minutes. tp < 0.05, reperfusin vs. cntrl. tp < 0.05, ischemia at 5 minutes vs. ischemia at r vs. atrial pacing. caused a mderate increase in psterir wall velcity as end-diastlic diameter fell. Acute hemrrhage prduced initial declines in bld pressure equivalent t thse resulting frm nitrprusside administratin, but a cmpensatry vascnstrictin partially reelevated the pressures; by the end f the 60-minute ischemic perid the net declines were small (Table 3). Nevertheless, psterir wall velcity shwed a slightly greater increase with this interventin. End-diastlic diameter fell. Reductins in aneurysmal bulging (B-C amplitude) ccurred during bth hyptensive interventins, althugh the decrease was nt statistically significant in either case. Table 4 summarizes the cmparative percent recvery (i.e., return tward cntrl levels) fr the ultrasund parameters f psterir wall velcity and B-C amplitude in respnse t alteratins f heart rate and bld pressure during ischemia. The percent change in psterir wall velcity during ischemia was calculated fr each individual dg as (value at f ischemia value at beginning f ischemia) / (cntrl value - value at beginning f ischemia). The percent imprvement in B-C amplitude during ischemia was calculated fr each dg as (value at beginning f ischemia value at f ischemia) / (value at beginning f ischemia cntrl value). This table indicates that nrepinephrine was the interventin which restred psterir wall velcity mst tward cntrl (preischemic levels) and that methxamine restred it least. Nrepinephrine als increased velcity significantly mre than did nitrprusside r phenylephrine. Cnversely, nrepinephrine mst exacerbated the aneurysmal bulging during ismetric cntractin, and methxamine mst reduced it. EFFECTS OF CORONARY ARTERY REPERFUSION Crnary artery reperfusin was perfrmed after 1 hur f ischemia alne r 1 hur f ischemia plus interventin; measurements were made after 1 hur f reperfusin. In the grup f dgs underging n interventin during ischemia (Table 1), crnary reperfusin fr 1 hur resulted in significant restratin f psterir wall velcity cmpared with pstligatin (ischemia) levels (Figs. 1 and 2). The B-C amplitude (aneurysmal bulging during ismetric cntractin) and the end-diastlic diameter als imprved significantly with reperfusin (Fig. 3). Psterir wall velcity did nt return t the cntrl preligatin levels after 1 hur f reperfusin, althugh B-C amplitude and end-diastlic diameter did. After cessatin f atrial pacing during ischemia and 1 hur f reperfusin, there was a significant

5 Ischemia + nrepinephrine: 25+4* ±0.4* 17.7± 1.6* 168 ± 9* 131± 12* 105 ± ± ± 249* 2.2 ±0.3 Reperfusin: 24+3t$ 2.5 ±0.2$ tt tt 157 ±7 101± lit ±1$ 1567 ± ±0.3tt PRESSURE-RATE ALTER/ H CO > (A m O >m YTA r- O W * z m (0 < TABLE 2 Effects f Crnary Reperfusin after Elevatin f Arterial Bld Pressure during Ischemia Methxamine (12 dgs) Phenylephrine (9 dgs) Nrepinephrine (12 dgs) Cntrl Ischemia + imethxamine: 5 minutes Reperfusin: Cntrl 5 minutes Ischemia + phenylephrine: Reperfusin: Cntrl 5 minutes PWV (mm/sec) B-C (mm) PWE (mm) EDD (mm) Heart rate (beats/min) Artic systlic pressure Artic diastlic pressure LV end-diastlic pressure LV dp/dt (mm Hg/sec) Cardiac utput (liters/ min) 29 ± ± ± ± ±9 99 ±8 76 ±7 9±2 1171± ± ± ± ± ± ± 9 94 ±6 76 ± 5 8± ± ± 1* 2.7 ± 0.7* 1.1 ±0.1* 28.8 ± 1.6* 135 ± 6* 124 ±8* 105 ± 7* 16 ±2* 1056 ± ±0.3* 12: ±lt 2.8± 0.2tt 1.5± 0.2t 20.6 ± 2.3t 153 ± : 7t 94 ± 8 76 ± 7 10 ± ± 1.9± 57tt 0.2tt 24 ±2 2.0 ± ± ±9 108 ± 8 82 ±8 8± ± ±0.1 9± ± ± ± ± ± 9 81 ± 9 8± ± ± ± 2* 3.3 ± ± 0.2* 16.2 ± ± ± 8* 106 ± 9* 10± ± 1.8± * 9± 2t 2.3 ± 0.4$ 1.7± 0.3t 14.5 ± ± : lot 75 ± :9tt 53 ±7tt 8± ± i26n 1.3 i: 0.3tt 34 ±3 2.7 ± ± ± ± ± ± 10 8± ± ±0.2 11± ± ± ± ± 8 118± 9 93 ±9 9±1 1564± ±0.2 All values are means± SE. Abbreviatins are the same as they are in Table 1. *P < 0.05, ischemia at 5 minutes vs. ischemia + drug at. tp < 0.05, reperfusin vs. cntrl. $P < 0.05, reperfusin vs. ischemia at 5 minutes.

6 150 KERBER, ABBOUD TABLE 3 Effects f Crnary Reperfusin after Reductin f Arterial'Bld Pressure during Ischemia Nitrprusside (15 dgs) Hemrrhage (8; dgs) Cntrl 5 minutes Ischemia + nitrprusside: Reperfusin: Cntrl Ischemia + hemrrhage: Reperfusin: 5 minutes PWV (mm/sec) 29±1 13± * 20±m 28±3 10±2 17+3* 18±2+t B-C (mm) 2.3 ± ± ± ± ± ± 0.4+ PWE (mm) 3.2 ± ± ± t 3.7 ± ± * 2.2 ±0.2+} EDD (mm) 19.6 ± ± ±1.3* t ± ±1.4+ Heart rate (beats/min) 169 ± ± ±7 184± ± ±9 Artic systlic pressure ±4* 96+ 5t 111 ±9 106 ± ±6 Artic diastlic pressure 83 ±5 80 ±6 59 ±4* 74±5t 83 ±8 81 ± ± 6 LV end-diastlic pressure 7+1 8±1 6±1* 6± ±1 6±1 8±1 LV dp/dt (mm Hg/sec) 1388 ± ± ±90* 1078 ± 73+i 1810 ± ± Cardiac utput (liter/min) 2.6 ± ± ± ± ± ± * 2.4±0.2 All values are means ± SE. Abbreviatins are the same as they are in Table 1. *P < 0.05, ischemia at 5 minutes vs. ischemia + interventin at. tp < 0.05, reperfusin vs. ischemia at 5 minutes. XP < 0.05, reperfusin vs. cntrl. increase in psterir wall velcity and a fall in enddiastlic diameter cmpared with ischemic levels. End-diastlic diameter returned t cntrl levels, but psterir wall velcity remained significantly less than cntrl. Reperfusin after the administratin f hypertensive agents prduced variable results (Fig. 4). After cessatin f methxamine administratin TABLE 4 and 1 hur f reperfusin, psterir wall velcity and excursin, which had been very depressed during the drug administratin, rse t ischemic levels but remained well belw the cntrl preischemic state. The aneurysmal bulging als persisted despite reperfusin (Table 2). The end-diastlic diameter fell but did nt return t the levels seen during ischemia alne; it remained much Cmparative Percent Recvery f Tw Ultrasund Parameters in Respnse t Alteratins f Bld Pressure and Heart Rate during Ischemia B-C amplitude (aneurysmal bulging) Interventin Methxamine Cntrl (n interventin) Atrial pacing Nitrprusside Hemrrhage Phenylephrine Nrepinephrine % Recvery * ± 35* 11 ± t Nrepinephrine Nitrprusside Atrial pacing Hemrrhage Phenylephrine Cntrl (n interventin) Methxamine Psterir wall velcity Interventin 85 ± ± 9* ± ± 10* 5±9-67 ± 20*t Recvery Percent recvery values are means ± SE. Interventins are listed in descending rder f effectiveness with thse abve the cntrl value representing a beneficial trend and thse belw a detrimental trend. See text fr methd f calculatin. The methxamine-induced reductin f aneurysmal bulging during ischemia reflects the marked dilatin f the left ventricle which limited further stretch f the ischemic mycardium during systle. *P < 0.05 cmpared with the nrepinephrine grup. *P < 0.05 cmpared with the cntrl grup.

7 PRESSURE-RATE ALTERATIONS AND SEGMENT AL DYSKINESIS 151 <u '^ 0 in -IO Ischemi FIGURE 2 Reperfusin Effect f reperfusin alne n psterir wall velcity in individual dgs. larger than the cntrl value. After phenylephrine administratin, reperfusin similarly caused nly sme imprvement in the segmental mtin abnrmalities; significant dyskinesis remained cmpared with the cntrl state. End-diastlic diameter returned t cntrl level. After nrepinephrine administratin, n the ther hand, reperfusin imprved psterir wall velcity and excursin t a degree exceeding that seen in the dgs underging reperfusin after n interventin. End-diastlic diameter shwed a small further decline. This imprvement in segmental dyskinesis n reperfusin after nrepinephrine administratin was significantly greater than that n reperfusin after administratin f the ther tw pressr agents (Table 5). Reperfusin after hyptensive interventins during ischemia shwed that the segmental dyskinesis imprved t an intermediate degree. After bth nitrprusside administratin and hemrrhage, psterir wall velcity and excursin imprved with reperfusin but remained significantly belw cntrl levels; B-C amplitude (aneurysmal bulging) was n lnger significantly different frm the cntrl state after reperfusin. End-diastlic diameter was belw the cntrl levels in bth grups after reperfusin. Table 5 presents cmparative intergrup data fr the ultrasund parameters f psterir wall velc- ity and B-C amplitude. The percent recvery f psterir wall velcity after reperfusin was calculated fr each individual dg by the fllwing frmula- (value at f reperfusin - ischemic value)/(cntrl value - ischemic value). The percent recvery f B-C amplitude after reperfusin was calculated fr each dg by the fllwing frmula: (ischemic value - value at f reperfusin)/(ischemic value - cntrl value). This table indicates that fr bth f the ultrasund parameters, B-C amplitude and psterir wall velcity, dgs that had received nrepinephrine shwed the mst return f ischemia-induced dyskinesis tward nrmal with reperfusin and that dgs that had received methxamine shwed the least return. Because f the cnsiderable interanimal variatin nne f the grups subjected t an interventin was significantly different frm the grup that was nt subjected t an interventin fr the parameter f B-C amplitude. Hwever, fr psterir wall velcity the recvery after methxamine interventin was significantly less than that f the grup that was nt subjected t an interventin. Cmparisn with the nrepinephrine-treated grup indicated that this grup shwed significantly greater psterir wall velcity recvery than 8 E 6 3 Q. E 4 i m Ischemia FIGURE 3 \ Reperfusin Effect f reperfusin alne n B-C amplitude (aneurysmal bulging during ismetric cntractin) in individual dgs.

8 152 KERBER, ABBOUD 40 r E = I I.S t E FIGURE 4 Effect f reperfusin n psterir wall velcity after elevatins f bld pressure during ischemia with methxamine (left), phenylephrine (center), and nrepinephrine (right). the grups receiving nitrprusside, phenylephrine, r methxamine, althugh the recvery was nt significantly greater than that f the grup that was nt subjected t an interventin. Discussin This study indicates that after a limited perid f ischemia crnary artery reperfusin had beneficial effects n segmental mycardial dyskinesis in that it partially restred the wall mtin abnrmalities tward their cntrl preischemic state; hwever, reperfusin was nt evaluated after lnger perids f ischemia when the beneficial effects might be less. Mrever, the respnse f TABU 5 Cmparative Percent Recvery f the Tw Ultrasund Parameters after Reperfusin B-C amplitude (aneurysmal bulging) Interventin Reperfusin after nrepinephrine Reperfusin alne (n interventin) Reperfusin after phenylephrine Reperfusin after methxamine Reperfusin after atrial pacing Reperfusin after hemrrhage Reperfusin after nitrprusside 7c Recvery 112 ± ± ± ± ± ± ±36 ther species with different crnary cllaterals cannt be predicted. The varius heart rate and bld pressure manipulatins perfrmed during the perid f ischemia had different effects n the respnse t subsequent reperfusin. Nrepinephrine infusin increased wall velcity while it was being administered during ischemia and als imprved the respnse f the dyskinetic mtin t later reperfusin. The ther hyper- and hyptensive interventins and atrial pacing depressed t varius degrees the respnse t reperfusin despite the fact that sme appeared t have beneficial effects n wall mtin when they were given during ischemia. Methxamine and phenylephrine had particularly deleterius effects n the later recvery f wall velcity. These changes cannt be explained simply by the relatively small and incnstant differences in heart rate and bld pressure between the different grups f dgs. Especially when cnsidering the deleterius effects f methxamine n the later respnse t reperfusin, it might be argued that the betareceptr blckade this agent induces was affecting reginal wall mtin abnrmalities by virtue f a prlnged generalized depressant effect n generalized cardiac perfrmance (8). Hwever, the heart rate and bld pressure 1 hur after cessatin f methxamine infusin were nt significantly different frm the predrug (ischemia) values. Mrever, when we administered methxamine t several additinal dgs in whm crnary artery ligatin was nt perfrmed, heart rate, bld pressure, psterir wall velcities, and end-diastlic diameter returned t cntrl values within 1 hur after the drug was stpped. Previus investigatins have shwn that the size Psterir wall velcity Interventin Reperfusin after nrepinephrine Reperfusin alne (n interventin) Reperfusin after hemrrhage Reperfusin after nitrprusside Reperfusin after atrial pacing Reperfusin after phenylephrine Reperfusin after methxamine % Recvery 62 ± ± ± ±6* 26 ± 11* 6± 19* * + Percent recvery values are means ± SE. Interventins are listed in descending rder f effectiveness with thse listed abve the values fr reperfusin alne representing a beneficial effect and thse listed belw a detrimental effect. See text fr methd f calculatin. *P < 0.05 cmpared with reperfusin after nrepinephrine administratin. +P < 0.05 cmpared with reperfusin alne.

9 PRESSURE-RATE ALTERATIONS AND SEGMENTAL DYSKINESIS 153 f an experimental mycardial infarctin is reduced by an elevatin in arterial bld pressure and increased by a reductin in arterial bld pressure and als by tachycardia (2). This study indicates that the segmental dyskinesis f an area f ischemic mycardium respnds differently t these interventins. Why des this difference exist? Fllwing crnary artery cclusin, ne encunters histlgically an area f central necrsis surrunded by a zne f ischemic but viable tissue (9). Estimatins f infarct size prbably measure alteratins in the size f this zne f brderline r jepardized mycardium, which wuld be significantly affected by the extent f cllateral flw and, therefre, by alteratins in crnary perfusin pressure (2, 10). Hwever, in the echcardigraphic technique used in this study, an ultrasund beam is reflected frm the center f the acutely ischemic area, an area which after 1 hur prbably cnsists mainly f "blighted" tissue (1) likely t prgress t ultimate necrsis regardless f therapeutic interventins. Elevatins in crnary perfusin pressure and cllateral flw, althugh they affect the periphery f the ischemic area, may have less r n effect n the degree f ischemia and dyskinesis in this central regin (10). Furthermre, mycardial energy utilizatin depends n wall tensin during systle, which in turn is related t intraventricular pressure and ventricular diameter (11, 12). If the w "20 c E a* N Rx MX* PE NE* AP" NP H p<0.05 interventin vs ischemia FIGURE S Effect f ischemia and varius interventins during ischemia n left ventricular end-diastlic diameter. Values are pltted as the percent change in diameter during the ischemic perid cmparing the value at f ischemia with the value at the nset f ischemia. N Rx = n interventin during ischemia, Mx = methxamine, PE = phenylephrine, NE = nrepinephrine, AP = atrial pacing, NP = nitrprusside, and H = hemrrhage. An asterisk indicates a significant (P < 0.05) difference between the interventin level and the initial ischemic (preinterventin) level. rise in bld pressure is assciated with increased ventricular diameter (as it is with methxamine) (Fig. 5), the central cre f the ischemic area may have an increased xygen demand and energy utilizatin in additin t a decreased delivery because f mechanical cmpressin f vessels as mycardial wall tensin increases. The result wuld be an imbalance between xygen demand and delivery which wuld then be cnsistent with the bservatins made in this study, which indicated that administratin f methxamine and phenylephrine during the ischemic perid interfered significantly with the subsequent beneficial effects f crnary artery reperfusin n restring cardiac wall mtin frm dyskinetic t nrmal despite the fact that arterial bld pressure was elevated and the size f the ischemic area presumably reduced (2). The ppsite beneficial results f nrepinephrine infusin may als be explained by these cnsideratins. Unlike methxamine and phenylephrine, nrepinephrine has significant psitive intrpic effects which resulted in the bserved sharp increase in psterir wall velcity and the significant reductin in end-diastlic ventricular diameter during the infusin f this agent. The reductin in ventricular diameter wuld tend t lwer mycardial xygen requirements in the ischemic area and minimize the cmpressin f crnary vessels and thereby diminish the amunt f necrsis by reducing the imbalance between xygen supply and demand (13). Subsequent reperfusin wuld then be mre successful in restring cardiac wall mtin tward nrmal. T sme degree the beneficial effects f the reductin in ventricular diameter and wall tensin prbably are cunterbalanced by the increase in xygen requirements assciated with nrepinephrine-induced augmentatin f cardiac cntractility; isprterenl, uabain, and glucagn have all been shwn t increase the severity and the extent f ischemic injury, presumably via this mechanism (2). The effect f atrial pacing, nitrprusside, and hemrrhage n the respnse t subsequent reperfusin als prbably depends n the balance f a number f variables. With all f these interventins, ventricular diameter fell; the resultant decrease in wall tensin wuld tend t reduce mycardial xygen requirements in the ischemic area. Cunterbalancing this beneficial effect wuld be the hyptensin and the tachycardia seen during these interventins, which wuld increase xygen requirements and reduce crnary perfusin and cllateral flw (2). The net result f all f these

10 154 KERBER, ABBOUD interventins was t mderately depress the recvery f the dyskinetic area. The respnse t crnary artery reperfusin shwed interanimal variatin. In a minrity f the dgs, reperfusin accentuated the dyskinesis prduced riginally by acute ischemia (Fig. 6). These dgs presumably sustained a mre severe r a larger mycardial insult after the riginal crnary artery ligatin. Other investigatrs have fund that after prlnged crnary artery cclusin revascularizatin may be fllwed by decreases in strain gauge-measured tensin f bth central and brder znes f ischemia (14) and by mycardial hemrrhage (15). Pstmrtem grss inspectin ften revealed extensive epicardial hemrrhage in this subgrup f dgs, a finding we seldm encuntered in the dgs that shwed imprvement in dyskinesis after reperfusin. Ludbrk et al. (16) have shwn that echcardigraphically measured psterir wall velcity des nt crrelate well with ther accepted indexes f ttal left ventricular perfrmance. Thrughut this discussin we have taken the ultrasund parameters f aneurysmal bulging during ismetric cntractin and wall velcity during ventricular ejectin t reflect lcalized wall mtin abnrmalities f the ischemic area. Sme f the bserved changes in these parameters during the varius interventins may cnceivably evlve frm alteratins in cntractility and mtin in surrunding nnischemic mycardium, resulting in passive changes in the dyskinesis f the central ischemic zne. Hwever, because f the glbular shape f the A EKG PRESSURE IV SEPTUM ECHO POSTERIOR WALL ECHO ventricle the surrunding nnischemic mycardium shuld mve mre r less perpendicularly t the ultrasund beam. Only net mtin directly tward r away frm the transducer is registered, thereby minimizing such effects n the mtin f the ischemic area. Additinal supprt fr the cncept that the bserved aneurysmal bulging and wall velcity changes primarily reflect lcalized ischemic wall mtin changes cmes frm current studies in ur labratry relating these ultrasund measurements t mycardial perfusin determined by a labeled (radiactive) micrsphere technique; preliminary data indicate that changes in the ech parameter crrelate well with alteratins in mycardial perfusin in the ischemic area. We cnclude that elevatin f arterial bld pressure, which reduces the size f an experimental mycardial infarctin, may simultaneusly wrsen the segmental dyskinesis f the ischemic mycardium and have deleterius effects n the subsequent respnse t reperfusin depending n the pressr agent used. Reductin f arterial bld pressure and tachycardia have sme beneficial effects n ischemic wall velcity, but they are nt maintained after later reperfusin. In particular, this study suggests that if elevatin f arterial bld pressure is cntemplated in an effrt t increase crnary r systemic perfusin, nrepinephrine may have a substantial advantage ver ther pressr agents such as phenylephrine r methxamine in that it increases wall velcity during ischemia and imprves the subsequent respnse f the ischemic area t reperfusin. LV PRESSURE CONTROL ISCHEMIA I hr REPERFUSION FIGURE 6 Echcardigraphic recrdings befre and after crnary ligatin and after 1 hur f reperfusin. Segmental dyskinesis is wrsened by reperfusin. Cmpare with Figure 1; abbreviatins are the same as they are in Figure 1.

11 PRESSURE-RATE ALTERATIONS AND SEGMENTAL DYSKINESIS 155 Acknwledgment We gratefully acknwledge the technical assistance f David Panther and Margaret Schrader. References 1. SOBEL BE, SHELL WE: Jepardized, blighted and necrtic mycardium. Circulatin 47: , MAROKO PR, KJEKSHUS JK, SOBEL BE, WATANABE T, COVELL JW, Rss J JR, BRAUNWALD E: Factrs influencing infarct size fllwing experimental crnary artery cclusins. Circulatin 43:67-82, MAROKO PR, BERNSTEIN EF, LIBBY P, DELARIA GA, COVELL JW, Rss J JR, BRAUNWALD E: Effects f intraartic balln cunterpulsatin n the severity f mycardial ischemic injury fllwing acute crnary cclusin. Circulatin 45: , MAROKO PR, LIBBY P, GINKS WR, BLOOR CM, SHELL WE, Rss J JR: Crnary artery reperfusin: I. Early effects n lcal mycardial functin and the extent f mycardial necrsis. J Clin Invest 51: , FEIGENBAUM H, STONE J, LEE DA, NASSER WK, CHANG S: Identificatin f ultrasund eches frm the left ventricle by use f intracardiac injectins f indcyanine green. Circulatin 41: , KRAUNZ RF, KENNEDY JW: Ultrasnic determinatin f left ventricular wall mtin in nrmal man: Studies at rest and after exercise. Am Heart J 79:36-43, KERBER RE, ABBOUD FM: Echcardigraphic detectin f reginal mycardial infarctin: An experimental study. Circulatin 47: , KERBER RE, ABBOUD FM, MARCUS ML, ECKBERG DE: Effect f intrpic agents n the lcalized dyskinesis f acutely ischemic mycardium. Circulatin 49: , Cx JL, MCLAUGHLIN VW, FLOWERS NC, HORAN L: Ischemic zne surrunding acute mycardial infarctin: Its mrphlgy as detected by dehydrgenase staining. Am Heart J 76: , HOOD WR: Salvage f mycardium in acute ischemia. Circulatin 43:11-13, SANDLER H, DODGE HJ: Left ventricular tensin and stress in man. Circ Res 13:91-102, COHN JN: Bld pressure and cardiac perfrmance. Am J Med 55: , WATANABE T, COVELL JW, MAROKO PR, BRAUNWALD E, Rss J JR: Effects f increased arterial pressure and psitive intrpic agents n the severity f mycardial ischemia in the acutely depressed heart. Am J Cardil 30: , BANKA VS, CHADDA KD, MEISTER SG, HELFANT RH: Limitatins f mycardial revascularizatin in restratin f reginal cntractin abnrmalities prduced by crnary cclusin (abstr). Am J Cardil 31:118, BRESNAHAN GF, SHELL WE, Rss J, ROBERTS R, SOBEL BE: Deleterius effects f reperfusin in evlving mycardial infarctin (abstr). Circulatin 45(suppl II):II- 13, LUDBROOK P, KARLINER JS, LONDON A, PETERSON KL, LEOPOLD GR, O'ROURKE RA: Psterir wall velcity: Unreliable index f ttal left ventricular perfrmance in patients with crnary artery disease. Am J Cardil 33: , 1974