Decreased systolic wall thickening in myocardium adjacent to ischemic zones in conscious swine during brief coronary artery occlusion

Decreased systolic wall thickening in myocardium adjacent to ischemic zones in conscious swine during brief coronary artery occlusion The purpose of this study was to examine wall thickening in normally perfused myocardium adjacent to acutely ischemic zones. Regional wall thickening (%WT), internal minor axis diameter, and hemodynamics were monitored In nine conscious swine during temporary occlusion of the left circumflex coronary artery (LCCA). Animals were chronically instrumented with ultrasonic dimension gauges for measuring left ventricular (LV) wall thickness and minor axis, catheters in the left atrium and aorta, and a pneumatic occluder around the proximal LCCA. During a 2-minute occlusion of the LCCA, radiolabeled tracer microspheres (10 Am) were injected into the left atrium to determine regional myocardial blood flow (RMBF). Within the ischemic zone, reduction of %WT was related linearly (Y = 24.9 X -4.1, p < 0.001) to reduced RMBF and endocardial/epicardial blood flow ratio was reduced from 1.30 + 0.12 (mean + SE) to 0.87 * 0.11 (p < 0.01). In zones adjacent to the ischemic zones RMBF was unchanged by LCCA occlusion. RMBF and %WT were poorly correlated (r = 0.38) and endocardial/epicardial blood flow ratio was unchanged from preocclusion values. Therefore, myocardium adjacent to ischemic zones may have reduced thickening despite no apparent blood flow changes. We conclude that such dysfunction may be due to either mechanical tethering effects or a reduction of global LV function due to the presence of an acutely ischemic zone. (AM HEART J 107:458, 1984.)

Brian D. Guth, Ph.D., Francis C. White, Colin M. Bloor, M.D. La Jolla, Calif.

M.S., Kim P. Gallagher,

An accurate assessment of myocardial damage is essential to determine the prognosis of patients with myocardial infarction. The measurement of left ventricular (LV) function by echocardiography and radionuclide angiography is of great clinical use in localizing and evaluating the extent of infarcts in these patients. However, there is frequently an overestimation of infarct size with the use of these methodologies when the size of dysfunctional areas is compared to the size of areas with altered regional myocardial blood flow (RMBF) or histologic infarct.‘m4 Although some methodologic problems are involved,5 experimental studies of regional myocardial performance during acute coronary artery From the Departments University of California

of Pathology at San Diego.

and

Medicine,

School

of Medicine,

Supported by the Ischemic Heart Disease SCOR Heart, Lung, and Blood Institute (Grant HL-1’7682),

grant of the National Bethesda, Md.

Received accepted

for publication Nov. 2, 1982.

received

Reprint University 92093.

requests: Brian of California

458

Aug.

15, 1982;

revision

D. Guth, Department at San Diego School

Oct.

1, 1982;

of Pathology (M-012), of Medicine, La Jolla, CA

Ph.D., and

occlusion have suggested that the error may not be entirely artifactual.1,5,6 The effect of acute coronary artery occlusion on regional LV function has been recognized since the observations of Tennant and Wiggers.7 Numerous investigators have confirmed their findings that an acute reduction of myocardial perfusion quickly results in hypokinesia and eventual systolic bulging (dyskinesia) in the dependent myocardium.4p 7** While some controversy exists in regard to the exact mathematical relationship between blood flow and function in such ischemic zones, it is clearly a direct correlation.g,‘o Less agreement is found concerning the contractile performance of zones adjacent to and distant from the ischemic zone/* 6,g,I13I2 Previous studies have suggested that myocardium adjacent to ischemic tissue or an infarct may contract abnormally, although adequate perfusion exists.‘*‘j This poor correlation between myocardial blood flow and function in “adjacent zones” may account for the overestimation of infarct size encountered when the extent of wall motion abnormalities (measured with LV imaging techniques) is

Volume Number

107 3

Nonischemic

myocardial

dysfunction

during

coronary

occlusion 459

compared to histologically confirmed infarct.5 Possible mechanisms for this phenomenon include transient local ischemia of the “adjacent zone,” the presence of small islands of infarct, or mechanical tethering of the zone adjacent to the infarct.’ The first possibility attributes dysfunction in “adjacent zones” to persistent dysfunction following transient ischemia and reperfusion. Reperfusion after a 15 minute coronary occlusion results in a prolonged period of reduced RMBF and depressed regional wall thickening. l3 The second possibility involves the presence of small areas of necrotic tissue in primarily normal myocardium. Grossly normalappearing myocardium close to the border of an infarct may contain up to 10% infarct in the form of interdigitating islands of necrotic tissue.‘*14 Both of these explanations suggest that “adjacent zones” are subject to

initial

ischemic episodes resulting

in

prolonged regional dysfunction with or without the development of necrosis. The third alternative attributes reduced regional myocardial function in “adjacent zones” to a mechanical tethering effect. In vitro, a hypoxic muscle in series with a normal muscle causes asynergy of contraction and relaxation of both muscles.15 Wyatt et al.,6 in their “parallel fiber hypothesis,” suggest that an ischemic muscle in parallel with a normal muscle functions as a parallel resistance, thus transmitting to the adjacent normal muscle some of its own abnormal contractile properties. Of the three possibilities suggested, only this last

hypothesis does not involve a reduction in RMBF to the “adjacent zone” during an initial ischemic event. Our study was designed to measure regional myocardial function and blood flow in zones adjacent to zones that become ischemic during brief coronary artery occlusion in the conscious swine. We have previously used the conscious swine model in our laboratory to study acute myocardial ischemia.‘O Swine have coronary artery anatomy,“j coronary collateral circulation,‘? and heart weight to body weight ratio18 more similar to humans than do dogs; thus, swine may be an appropriate model of acute myocardial ischemia for comparison to humans having few collaterals.17 METHODS

We chose for our study the chronically Preparation. instrumented, consciousswine. Nine animals of either sex (30 to 40 kg) underwent aseptic left lateral thoracotomy for implanting instrumentation (Fig. 1). Anesthesia was induced with ketamine (1 mg/kg intramuscularly) and surital (20 mg/kg intravenously). After intubation, anesthesia was maintained with a combination of 0.5% halothane with oxygen and intravenous succinylcholine (300

Fig. 1. Diagram of experimental preparation showingthe positions of the ultrasonic dimension gaugesfor measuring LV wall thickness and internal diameter.

mg/L at 7 ml/min) while ventilation was maintained by a Bird Mark IV respirator. Thoracotomy in the fourth intercostal spaceexposedthe pericardium, which wasthen opened. Silicone rubber catheters (0.4 inch internal diameter) were placed in the descendingthoracic aorta (for the withdrawal of blood samplesduring microsphere injection), in the left ventricle via the apex (to monitor end-diastolic and peak systolic LV pressures),and in the left atrium (for microsphereinjection). In five animals,an electromagneticflow probe (18 mm, Biotronix) wasplaced around the ascendingaorta. All swine had an inflatable occlusive cuff placed around the left circumflex coronary artery (LCCA) near its origin. A temporary occlusion of the LCCA delineated its dependent perfusion bed for the positioning of ultrasonic dimensiongauges(Schuesslerand Associates,model 401) to measurewall thickness changesI One pair of crystals was implanted across the lateral free wall within the potentially ischemiczone, another acrossthe anterior wall near the septum, and the third pair was placed in an intermediate position (Fig. 1). The subendocardialtransducers were implanted by meansof a small Teflon tube surrounding the lead wires.Crystals were held at the tip of the tube and advanced diagonally to a site close to the endocardium through a narrow tract created by an 18gaugeneedle.Withdrawal of the tubing left the transducer near the endocardium facing the epicardium. Epicardial transducers were sutured in place directly acrossthe LV wall from the endocardial crystal at the point of least distance between the crystals, which was determined by monitoring the signals with an oscilloscope.This technique allowscrystal placement acrossthe LV wall without damaging the intervening tissue.19All crystal placements

March,

460

Guth et al.

American

CONTROL

LCCA

Table

0ccLusloN

I. Hemodynamics

/\: 100;

/ .A+J*

Heart rate (bpm) Cardiac output (L/min) Stroke volume (ml) End-diastolic LV pressure (mm Hg) Peak systolic LV pressure (mm Hg)

:-.\ ‘?--L-

.-/- -_

FLOW

\L-

*p < tp <

13

0.05; 0.05;

106 2.36 20 12

? k + +

1984

Journal

occlusion

Preocclusion

/

AORTIC

after LCCA

Heart

8 0.30 4 1

112 i 19

2 min 133 1.86 15 25

t + * f

19* 0.40t 3t 4*

95 +- 21

paired t test; n = 9. paired t test; n = 5.

ISCNEYIC 11

i1,

.

.-.

-_

_,- ---

124 ADJACENT

If,

0-l

“,,,,

‘L -

__

Fig. 2. Representative tracings from a swine before (control) and during a brief occlusion of the left circumflex coronary artery (LCCA) showing left ventricular pressure (LIT, mm Hg), aortic flow, ischemic zone wall thickness (mm), internal diameter (mm), and adjacent zone wall thickness (mm).

and wall thicknesses were confirmed at autopsy. A similar pair of ultrasonic crystals was placed across the LV cavity to measure internal diameter. One crystal was implanted on the interventricular septum with the other crystal on the lateral free wall (Fig. 1). The septal crystal was pulled through the LV free wall with a large needle. The crystal was left within the LV cavity while the lead wires were pulled out through the septum and right ventricle. The opposing crystal was placed at the endocardium of the lateral wall through the tract created by the needle. All catheters, crystal wires, the flow probe cable, and occlusive cuff were run subcutaneously to the animals’ backs where they were exteriorized. LV pressure was measured with Elema-Schiinander transducers calibrated with a mercury manometer. Measurements of LV pressure, aortic flow, and LV dimensions were recorded on an ElemaSchiinander Mingograph 81 ink jet recorder. Myocardial function. Regional myocardial function was assessed by the continuous measurement of ventricular wall thickness. Wall thickening (% WT) during ventricular ejection was defined as EEWT-PEWT/PEWT X 100, where EEWT is end-ejection wall thickness corresponding to the cessation of aortic flow and PEWT is preejection wall thickness, defined as the opening of the aortic valve as indicated by the aortic flow tracing (Fig. 2). Global LV function was measured by means of changes in internal

diameter. The percentage of change of internal diameter (% A) was defined as PED-EED/PED x 100, where PED and EED are preejection and end-ejection internal diameters, respectively. Regional myocardial blood flow. The tracer microsphere technique used in this study is similar to that used previously by this laboratory10~‘7~2” and follows the guidelines of Heymann et a1.21 RMBF was determined by injecting carbonized microspheres (10 f 2 pm; New England Nuclear, Boston, Mass.) labeled with one of the gamma-emitting nuclides (Gd-153, Cr-51, Sn-113, Ru-103, Nb-95, Co-57, or SC-46) into the left atrium. Microspheres were suspended in 0.01% Tween solution (10% dextran). Before injection, they were agitated by a vortex shaker to ensure dispersion of the spheres. The microsphere suspension was injected into the left atrium and then flushed with 10 ml of sterile saline solution. Each injection contained approximately 6 x lo6 microspheres and the order of radioisotopes used was randomized. A reference sample of arterial blood from the aortic catheter was withdrawn at the rate of 7.5 ml/min beginning 10 seconds before microsphere injection and continued for 1.5 minutes. By using this reference blood sample, myocardial blood flow was calculated by the “reference withdrawal method,“22 so that blood flows are expressed in ml/min/gm tissue (wet weight). Transmural tissue blocks were cut to contain both endo- and epicardial crystals as well as all intervening tissue. These were divided into three sections so that endocardial and epicardial blood flows could be differentiated. Wet weights of samples averaged 1.5 gm and were never less than 1 gm to ensure sufficient microsphere content in each sample. The tissue was minced and dried to facilitate its placement in tubes of the gamma counter. Microsphere content was analyzed by means of a Packard-Autogamma spectrometer (model 5912) equipped with a multichannel analyzer. Radioactivity per gram of tissue and myocardial blood flow were calculated with a Hewlett-Packard 9825A programmable calculator using standard techniques.*’ The analysis of the energy spectra was performed according to the matrix inversion method of Schosser et aLZ3 Standard samples, each containing one pure nuclide, were counted to obtain the overlap matrix. Unknown amounts of the nuclides in tissue samples were obtained by solving a system of simultaneous linear equations. Validity checks were made

Volume Number

107 3

Table

Nonischemic

myocardial

dysfunction

during

coronary

occlusion

461

Ii. Regional wall thickening and myocardial blood flow after LCCA occlusion Adjacent Preocclusion

PEWT (mm) % WT

RMBF (ml/min/gm) endo/epi

zone

(n = 7) Occlusion

Ischemic p

Preocclusion

zone

(n = 17) Occlusion

10.73 + 1.04 18.81 zk 1.49 1.03 rt 0.07

10.42 k 1.04 9.61 i 3.49 1.05 i 0.07

0.165 0.031* -

10.31 * 0.66 19.31 k 1.95 0.92 * 0.04

9.43 k 0.66 -0.68 i 1.95 0.16 r 0.04

1.20 * 0.15

1.26 c 0.15

0.690

1.30 k 0.12

0.97 k 0.12

Posterior P

septum

Preocclusion

(n = 9)

Occlusion

p

-

1.99 x 10-s* 2.89 x lo-‘* 1.60 X lo-“*

0.98 f 0.10

1.01 ? 0.10

0.572

6.40 x lo-‘*

1.34 ? 0.09

1.21 + 0.09

0.189

Abbreviations: PEWT = preejection LV wall thickness; % WT = percentage of wall thickening during ejection; RMBF = regional myocardial blood flow; endo/epi = ratio of endocardial to epicardial blood flow measured before (preocclusion) and during occlusion of the LCCA in ischemic zones, in zones adjacent to the ischemic zone, and in the distant posterior septum. Values of probability (p) are derived from paired t tests. *p < 0.05.

by counting sealed nuclide samplesseparately and then comparing them together in a single sample.All nuclides had lessthan a 3% error with the use of this validation procedure. Experimental protocol. Swine were studied 1 week postoperatively when they were eating normally and were afebrile. Throughout the protocol they were confined to a iidlessbox (2 ft x 4 ft) to restrict their movements, but it allowed accessto catheters and wires from above. Myocardial dimensions,aortic flow, and LV pressurewere continuously monitored while microsphereswere being injected for measurementof myocardial blood flow. After control recordingsand the microsphereinjection were completed, the occlusive cuff around the LCCA was inflated to eliminate antegrade blood flow to the lateral wall of the left ventricle. Once LV function had stabilized (as monitored by the ultrasonic dimension gauges)another injection of microsphereswas made with the use of a different radionuclide. Use of the various radionuclide labels was randomized throughout the study. Total occlusion time wasapproximately 3 minutes, at which time the occlusive cuff was released to restore blood flow. Following the experimental protocol, the swine were sedated and killed with intravenous KCl. The hearts were removed with the instrumentation intact so that crystal orientations could be confirmed and tissue samplesobtained. In addition to the three crystal location samples,myocardial blood flow wasdetermined in the posterior septum, a location chosen becauseof its distance from the LCCA perfusion bed. Statistical analysis. To determine the effect of LCCA occlusion on RMBF or function, each variable was compared to its preocclusion control by meansof a paired t test; p < 0.05 wasconsideredsignificant.24One-way analysis of variance was used to compare different sampling locations.24Correlation between regional function and blood flow was done by meansof linear regressionanalysis.2”Data are presented as mean rf: standard errors. RESULTS

All nine animals survived the surgical procedure

and were fully

conscious and mobile

during

the

experimental protocol. Of the 27 dimension gauges

implanted to measure wall thickness, 24 were functional on the day of the experiment. An example of the wave forms obtained from the ultrasonic dimension gauges in one animal is shown in Fig. 2. Wall

thickness data were categorized on the basis of the effect of LCCA occlusion on the RMBF to that site. One group (“ischemic” wall thickness) was characterized by a reduction in regional transmural blood flow and a reduced endocardial/epicardial

RMBF

ratio during LCCA occlusion. The remaining sites (“adjacent zone” wall thickness) were characterized by maintenance of transmural blood flow during LCCA occlusion. Hemodynamlcs and global LV function. The effect of LCCA occlusion on LV function and hemodynamics is summarized in Table I. Heart rate was significantly increased (27 bpm above control) while cardiac output was decreased (21% below control). Stroke volume decreased and end- diastolic pressure increased significantly. Peak systolic LV pressure also decreased but the change was not statistically significant.

Preejection LV diameter was 45.84 f

2.00 mm before the occlusion. Diameter at the end of ejection was 37.52 + 2.22 mm resulting in %A of 21.6 f 2.54%. During the LCCA occlusion, PED and EDD increased to 48.07 f 2.00 mm (p < 0.05) and 41.46 ? 2.22 mm (p < O.OOl), respectively. Percentage of change in diameter was reduced significantly to 13.76. f 2.54% (p < 0.005). RMBF vs function of ischemic zone. Values obtained for PEWT,

% WT, RMBF,

and endocardial/epicar-

dial ratio in the ischemic zones are presented in Table II. Occlusion of the LCCA resulted in significant reductions in all four measurements in ischemic zones. LV wall thickness before ejection was reduced from 10.31 + 0.66 mm to 9.43 -t 0.66 mm (p < 0.001) while wall thickening was replaced by wall thinning during ventricular ejection. This functional impairment was associated with a reduction

462

Guth et al.

American

Tram-mural

Bloodflow

March, 1984 Heart Journal

(ml/min/g)

Fig. 3. Effect of LCCA occlusion on RMBF (mean + SEM) and wall thickening (mean f SEM) in ischemic (circles) and adjacent zones (triangles). Negative value for function represents systolic wall thinning. Open symbols represent preocclusionvalues.

of transmural blood flow from 0.92 + 0.04 to 0.16 &

0.04 (p < 0.001). We observed a significant linear relationship between transmural blood flow and regional function in the ischemic zone (Y = 24.9, X = - 4.1, r = 0.81). RMBF vs function of adjacent zone. Data from seven ultrasonic dimension gauges were included in the group of adjacent zone wall thickness. All were located in the anterior wall of the left ventricle. In

LCCA occlusion. However, % WT was significantly reduced from 18.81 ? 1.49 to 9.61 +- 3.49 (p < 0.05). The relationship between regional transmural myocardial blood flow and function (% WT) in both adjacent zones and ischemic zones is illustrated in Fig. 3. We observed no significant linear relationship between transmural blood flow and function in the adjacent zone.

two animals, no crystal pairs were included in the

DISCUSSION

adjacent zone group; one because of unsatisfactory orientation across the ventricular wall and the other because it was located in myocardium rendered ischemic by LCCA occlusion. Crystals located in tissue that had less than 90% of the blood flow to the posterior septum (distant myocardium) were judged to be ischemic and were excluded from the adjacent zone group. Therefore, while only seven animals had an adjacent zone crystal, all nine animals had at least one ischemic zone crystal. The effect of LCCA occlusion on RMBF and function in the adjacent zone is summarized in Table II. Myocardial blood flow to those zones during LCCA occlusion (1.05 f 0.07 ml/min/gm) was unchanged from preocclusion values and it was no different from RMBF in the posterior septum before or during LCCA occlusion (Table II). In addition, the endocardial/epicardial ratio of blood flow in adjacent zones was not affected by the occlusion. No change in PEWT was detected during

Ultrasonic crystal location. The results of this study indicate that myocardial zones adjacent to ischemic tissue may contract abnormally despite apparently normal perfusion. During brief occlusion of the LCCA, we found that % WT in adjacent zone crystals was significantly reduced while RMBF was unchanged. Maintenance of transmural blood flow in the adjacent zones was predetermined, since inclusion of an ultrasonic crystal site into the group was based on the amount of RMBF during LCCA occlusion. Although all adjacent zone crystals were located on the anterior wall, they were at varying distances (1 to 2 cm) from the LCCA perfusion bed. This may account for the wide range of % WT values obtained for adjacent zones during LCCA occlusion. Variations in the configuration of the LCCA perfusion bed made the standardization of the dimension gauge sites, in relationship to the bed, difficult. As mentioned previously, one crystal pair located on the anterior wall near the septum had to be included

Volume Number

107 3

Nonischemic

in the ischemic zone group because of reduced blood flow during LCCA occlusion. RMBF was determined in tissue samples from the posterior septum because of its distance from the potentially ischemic myocardium. The posterior septum is typically perfused by branches of the right coronary artery. There is also a contribution from the left anterior descending artery in some cases.2o Therefore, RMBF to these zones is not directly affected by LCCA occlusion. Thus, it is of interest that the perfusion of the adjacent zone group was no different from that to the posterior septum. Hemodynamic effect of LCCA occlusion. Occlusion of the LCAA in this experimental model led to acute LV failure. The occlusive cuff was positioned very near the origin of the LCCA as it emerges from the left main coronary artery in the atrioventricular sulcus. Thus, inflation of the cuff affected nearly the entire perfusion bed which is approximately 30% of the left ventricle.zo End-diastolic LV pressure and PED were both significantly increased during the brief LCCA occlusion, whereas both cardiac output and stroke volume were significantly decreased. A decreased cardiac output was found despite a significant increase in heart rate during the occlusion. We observed an increase in PED despite the increase in heart rate that normally reduces ventricular diameter. This can be explained by the significant elevation of LV end-diastolic pressure. Nonischemic myocardial function. The behavior of myocardium distant to ischemic myocardium during a coronary artery occlusion is important in determining the adequacy of overall LV performance. Maintenance of hemodynamic stability, despite regional dysfunction, has been attributed to hyperfunction in uninvolved tissue.10~25-27Because of the placement of dimension gauges in this study, the regional performance of the distant myocardium was not measured. However, in a similar preparation, we observed both increased RMBF and function in distant myocardium.*O In that model, the region of myocardium affected by coronary artery occlusion was smaller (10% of LV) and overall LV function was affected minimally. Our failure to observe a compensating hyperemia in the posterior septum may be a result of the acute LV failure caused by the large ischemic zone. lschemic myocardial function. Within the ischemic myocardium, the direct relationship between RMBF and function is similar to that described previously by this laboratory and others38 lo*25*28A linear equation was adequate to describe the relationship between mean transmural blood flow and wall thick-

myocardial

dysfunction

during

coronary

occlusion

463

ening in this study. However, an exponential relationship between subendocardial blood flow and function was observed by Vatnerg in conscious dogs. In addition, the importance of transmural distribution of myocardial blood flow on regional wall thickening has been described by Gallagher et alzs We observed no reduction in RMBF or endocardiai/ epicardial blood flow ratio in the adjacent zone during LCCA occlusion to account for reduced % WT. The important finding of this study is that no perfusion abnormalities were detected to account for the dysfunction of adjacent zones. Conclusions. Three hypotheses were suggested to explain the overestimation of infarct size using clinical methodologies of LV imaging.’ We have suggested that such overestimation may be related to dysfunction in adjacent zones during acute coronary occlusion, as observed by Wyatt et al6 By using the conscious swine to study the affect of LCCA occlusion on adjacent zones, we may eliminate two of the hypotheses to account for adjacent zone dysfunction. One hypothesis attributed adjacent zone dysfunction to focal necrosis; in the model used in this study, no necrosis was present before LCCA occlusion. Furthermore, since the occlusions were of short duration, no necrosis resulted from the experimental protocol. The second hypothesis attributed regional dysfunction in adjacent zones to prolonged mild ischemia following reperfusion. This explanation cannot account for adjacent zone dysfunction in our model, since only an initial ischemic event is considered and no ischemia was detected in these zones by the radiolabeled microsphere technique. Thus, we conclude that in our study, the only hypothesis that can explain abnormal wall thickening in adjacent zones is a mechanical tethering between normal and ischemic myocardium. Our experimental model precludes the existence of ischemia or necrosis before the LCCA occlusion. Tyberg et all5 showed that the contractile performance of an isolated cat papillary muscle is affected by another when attached in series. When one muscle was made hypoxic, it functioned as an added passive series elastic element for the normoxic muscle. In a similar manner, the “parallel fiber hypothesis” proposed by Wyatt et a1.,6 to explain adjacent zone dysfunction, involves mechanical interactions between neighboring muscle fibers. How this relates to overall LV geometry in the intact heart is unclear. We measured significant increases in both PED and EED suggesting ventricular dilation. However, the reciprocal decrease in wall thickness was only detected in ischemic zones; PEWT in adjacent zones

464

Guth

et al.

American

was unaffected by LCCA occlusion. This suggests an asymmetric deformation of the left ventricle during acute regional ischemia. Thus, mechanical tethering in the intact ventricle may be the result of acutely altered geometry and increased wall stress in areas adjacent to ischemic tissue. Further two-dimensional analysis of ventricular geometry during acute ischemia is needed to resolve the issue. We thank this study.

.J. .J. Wright

for technical

assistance

in performing

REFERENCES I.

2.

3.

4.

.5.

6.

7. 8. 9.

10.

11.

1”.

Lieberman AN, Weiss JL, Jugdutt BI, Becker LC, Bulkley BH. Garrison JG, Hutchins GM, Kallman DA, Wiesfeldt ML: Two-dimensional echocardiography and infarct size: Relationship of regional wall motion and thickening to the extent of myocardial infarction in the dog. Circulation 63:739, 1981. Herg MK, Lang TW, Toshimitsu T, Meerbaum D, Wyatt HL, Lee SS, Davidson R, Corday E: Quantification of myocardial ischemic damage by two-dimensional echocardiography Circulation !%(suppl 111):125, 1977. (abstr.) Weyman AE, Franklin TD, Egeres KM, Green D: Correlation hetween the extent of abnormal regional wall motion and myocardial infarct size in chronically infarcted dogs. Circulation 55(suppl III):72, 1977. (abstr.) Kerher RE, Marcus ML, Erhardt J, Wilson R, Abboud FM: Correlation between echocardiographically demonstrated segmental dyskinesis and regional myocardial perfusion. Circulation 52:1097, 1975. Falsetti HL, Marcus ML, Kerber RE, Skorton DJ: Quantification of myocardial ischemia and infarction by left ventricular imaging. Circulation 63:747, 1981. (Editorial.) Wyatt HL, Forrester JS, daLuz PL, Diamond GA, Chagrasulis R, Swan HJC: Functional abnormalities in nonoccluded regions of myocardium after experimental coronary occlusion. Am d Cardiol 37:336, 1976. Tennant R, Wiggers CJ: The effect of coronary occlusion on myocardial contraction. Am J Physiol 112:351, 1935. Tatoules CJ, Randall WC: Local ventricular bulging after acute coronary occlusion. Am J Physiol 201:451, 1961. Vatner SF: Correlation between acute reduction in myocardial blood flow and function in conscious dogs. Circ Res 47:201, 1980. Savage RM, Guth B, White FC, Hagan AD, Bloor CM: Correlation of regional myocardial blood flow and function with mvocardial infarct size during acute myocardial ischemia in the conscious pig. Circulation 64:699, 1981. Theroux P. Ross J Jr. Franklin D. Cove11 J. Bloor CM, Sasayama S: Regional myocardial function and dimensions early and late after myocardial infarction in the unanesthetized dog. Circ Res 40~158, 1977. Daughters GT, Ingels NB, Alderman EL, Stenson EB: Does augmented contraction of normal myocardium compensate for hypokinetic ischemic regions? (abstrf. Fed Proc 40:485, 1981.

March, 1984 Heart Journal

13. Heyndrickx GR, Baig H, Neller P, Leussen I, Fishbein MC, Vatner SF: Depression of regional blood flow and wall thickening after brief coronary occlusions. Am J Physiol 234:H653, 1978. 14. Jugdutt BI, Hutchins GM, Bulkley BH, Becker LC: Myocardial infarction in the conscious dog: Three dimensional mapping of infarct, collateral flow, and region at risk. Circulation 60:1141, 1979. JV, Parmley WW, Sonnenblick EH: In vitro studies 15. Tyherg of myocardial asynchrony and regional hypoxia. Circ Res 25:569, 1969. 16. Lumb GD, Hardy LB: Collateral circulation and survival related to gradual occlusion of the right coronary artery in the pig. Circulation 27:717, 1963. 17. Sanders M, White FC, Peterson TM, Bloor CM: Effects of endurance exercise on coronary collateral blood flow in miniature swine. Am J Physiol 234:H614, 1978. W: The collateral circulation of the heart. Amster18. Schaper dam, 1971, North-Holland Publishing Company. 19. Sasayama S, Franklin D, Ross J, Kemper WS, McKown D: Dynamic changes in left ventricular wall thickness and their use in analyzing cardiac function in the conscious dog. A study based on modified ultrasonic technique. Am J Cardiol 38:870, 1976. FC, Bloor CM: Coronary collateral circulation in the 20. White pig: Correlation of collateral flow with coronary bed size. Basic Res Cardiol 76:189, 1981. 31. Heymann MA, Payne BD, Hoffman JIE, Rudoloph AM: Blood flow measurements with radionuclide labeled particles. Prog Cardiovasc Dis 30:55, 1977. 22. Domenech RJ, Hoffman JIE, Noble NIM, Saunders KB, Henson JR, Subijanto S: Total and regional coronary blood flow measured by radioactive microspheres in conscious and anesthetized dogs. Circ Res 24:581, 1969. 23. Schosser R, Arfos KE, Messmer K: Mic-11-a program for the determination of cardiac output, arterio-venous shunt, and regional blood flow using the radio microsphere method. Comput Programs Biomed 10:19, 1979. 24. Snedecor GW, Cochran WG: Statistical methods. Ames, 1973. Iowa State University Press. 25. Kerber RE, Marcus ML, Wilson R, Ehrhardt J, Abboud FM: Effects of acute coronary occlusion on the motion and perfusion of the normal and ischemic interventricular septum. Circulation 54:928, 1976. 26. Corva BC. Rasmussen S. Knoebel SB. Feinenbaum H: Echocardiography in acute myocardial infarction. Am J Cardiol 36:1, 27.

28.

29.

1975.

Stowe DF, Detlef GM, Moores WV, Glantz SA, Townsend RM, Kabra P, Chatterjee K, Parmley WW, Tyberg JV: Segment stroke work and metabolism depend on coronary blood flow in the pig. Am J Physiol 234:H597, 1978. Ross d, Franklin, D: Analysis of regional myocardial function, dimension, and wall thickness in the characterization of myocardial ischemia and infarction. Circulation 53:88. 1976. Gallagher KP, Kumada T, Koziol JA, McKown DM, Kemper WS, Ross J: Significance of regional wall thickening abnormalities relative to transmural myocardial perfusion in anesthetized dogs. Circulation 62:1266, 1980.