Impaired collateral blood flow reserve early after nontransmural myocardial infarction in conscious dogs

EXPERIMENTAL STUDIES

Impaired Collateral Blood Flow Reserve Early After Nontransmural Myocardial Infarction in Conscious Dogs RANDOLPH E. PATTERSON, MD, BEVERLY A. JONES-COLLINS, ROGER AAMODT,

MD, and

PhD

The purpose of this study was to determine the adequacy of collateral blood flow reserve of surviving myocardlum 3 to 4 days after coronary occlusion in dogs. The proximal circumflex coronary artery was occluded in 9 conscious dogs, and In 7 of these the mid-left anterior descending coronary artery was also occluded. Three to 4 days after myocardial infarction, studies were performed under control conditions and during rlght ventricular pacing at the maximal heart rate that did not decrease aortic pressure. Pacing increased the heart rate from 110 to 222 beats/min, caused no change In mean aortic pressure (112 to 118 mm Hg), and increased left atrial pressure marginally (13.5 to 18.0 mm Hg) (0.05

0.18 to 0.02 m~min-i*g-l/lOO mm Hg (0.05

Gradual coronary occlusion over days to weeks in the dog usually does not cause myocardial infarction and leads to a substantial increase in coronary collateral function so that myocardial blood flow approaches normal values at rest.‘-:{ After gradual coronary occlusion, collateral flow reserve during stress has been reported to be either normal4 or slightly subnormal”-7 during stress in dogs.

In contrast to the gradual occlusion in the aforementioned studies, sudden coronary occlusion regularly causes myocardial infarction. A few hours to days after infarction, transmural mean blood flow to collateraldependent myocardium is subnormal under resting conditions,R-‘0 and the limited collateral flow that is available is redistributed from necrotic to surviving tissue.s This results in near-normal myocardial blood flow at rest in surviving tissue, an adaptation that might be expected to limit the development of additional ischemia. However, assessment of the reserve capacity to augment collateral myocardial blood flow is required to clarify the potential susceptibility of surviving myocardium to develop ischemia during stress.

From the Cardiology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland. Manuscript received August 25. 1981; revised manuscript received April 12, 1982, accepted April 16, 1982. Address for repints: Randolph E. Patterson, MD. Cardiology Branch, National Heart, Lung, and Blood Institute. Building 10. Room 7B-15, National Institutes of Health, Bethesda, Maryland 20205.

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1982

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Relatively little is known about collateral blood flow reserve after myocardial infarction. Recently, Hess and Bachell studied dogs 2 weeks after sudden occlusion of a single coronary artery. They found collateral myocardial blood flow during submaximal treadmill exercise to be 80% of normal in the tissue that contained minimal (1 to 25%) necrotic tissue, whereas flow was only 11% of normal in tissue that contained 75 to 100% necrotic tissue. These data indicate good collateral flow reserve during exercise in tissue with little or no necrosis 2 weeks after single vessel coronary occlusion. The aforementioned studyll was not designed to assess collateral flow reserve either early after myocardial infarction or in the presence of multivessel coronary disease. Because complications occur more frequently in patients in the first days after infarction12 and in patients with multivessel coronary disease,13 the purpose of the present study was to assess collateral blood flow reserve 3 to 4 days after myocardial infarction in dogs with occlusion of 2 coronary arteries. We also assessed factors that might influence collateral flow and its response to stress. The experimental model of 2 vessel coronary occlusion used in the present study was extremely difficult because of the high death rate, but it may offer some unique features with potential relevance to human acute myocardial infarction. Met hods Experimental preparation: We anesthetized 41 foxhound dogs with sodium amytal, nitrous oxide, and halothane. Under sterile conditions, a thoracotomy was performed in the fourth left intercostal space and a polyethylene catheter was placed into the left internal mammary artery. We next opened the pericardium and dissected the left circumflex coronary artery

1

ET AL

near its origin (before any major ventricular branches), and the left anterior descending coronary artery in its mid-portion (after the second or third left ventricular branches). A deflated balloon occluder (Brunswick Manufacturing, Quincy, Massachusetts) was positioned around the circumflex coronary artery and snares (1-O silk inside a plastic catheter) were placed around both coronary arterial branches. Great care was taken to anchor the balloon and snare occlusive devices so that they would not cause coronary occlusion until the desired time. A polyethylene catheter was then inserted through a stab wound in the left atria1 appendage and secured in the left atrium. Finally, a 3-pronged electrode plate was secured by sutures on the epicardial surface of the outflow tract of the right ventricle. The connectors from all of the implanted instruments were tunneled under the skin to a subcutaneous pouch at the base of the neck. The catheters were filled with heparin, 1,000 U/ml, sealed by a knot and a heat-seal at the tip, and the chest was closed in layers. The dogs were trained to lie on their right side in a quiet, dimly lit room during the period of recovery from surgery. Protocol: After recovery from surgery for 1 to 3 weeks, each dog received morphine, 1 mg/kg, and local anesthesia with lidocaine to exteriorize the connectors from the subcutaneous pouch. The catheters were connected to Statham P23Db transducers to measure continually aortic and left atria1 pressure, along with an electrocardiogram on a Sanborn model 350 physiologic recorder. Each dog received lidocaine, 1 mg/kg, as an intravenous bolus and a 2 to 3 mg/min continuous infusion before inflation of the pneumatic occluder on the circumflex coronary artery. The occluder was inflated with saline solution to one fourth of the volume that had been required at the time of surgery to cause coronary occlusion. Every 15 minutes an additional one fourth of this volume was injected into the occluder until the circumflex coronary artery was totally occluded (45 minutes after the beginning of balloon inflation). The circumflex artery snare was pulled and secured to ensure total permanent. occlusion as soon as the last volume

Saline

NormalZone Samples

FIGURE 1. Diagram of postmortem methods to identify ischemic zone and myocardiai infarction. Left, diagram of a dog heart showing how the circumflex and left anterior descending coronary arteries were perfused by cannuias inserted distal to the points of occlusion. These arteries were perfused with Evans blue dye at the same pressure as the other unoccluded coronary arteries, which were perfused with fiuorosine through the aortic root. The left ventricle was cut into 4 to 5 mm thick doughnut-shaped slices, one of which is shown in the diagram al the right. The blue-stained ischemic zone was marked on both sides of each slice by a careful incision at the border between blue and fiuorosine dye, and each slice was incubated in triphenyl tetrazolium to stain the surviving tissue red. Each slice was photographed on both sides for integration of areas of the normal, ischemic (IZ), and myocardial infarction zones. The average area of normal zone, ischemic zone, and myocardiai infarotion, for both sides of each slice was multiplied by the weight of each slice to give the total mass of normal, ischemic, and myocardiai infarction zones for the entire ventricle. Samples were dissected from normal and ischemic zones, as shown, to count microsphere radioactivity for myocardial blood flow. ischemic zone samples were at least 10 mm inside the blue-stained border to avoid normal zone contamination, and samples were divided into transmural thirds from subendocardium. mid-myocardium, and subepicardium.

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of saline solution had been injected into the balloon. Five minutes after circumflex artery occlusion, we pulled and secured the left anterior descending snare in all dogs in which mean left atria1 pressure had not increased above 15 mm Hg. The dogs were monitored and received lidocaine for 3 to 5 hours after coronary occlusion. We began coronary occlusion on 41 dogs, and 27 died within the first day after occlusion. Thus 14 dogs survived 3 to 4 days. The pacemaker electrodes did not work in 2 of these dogs, and 2 died from ventricular fibrillation during right ventricular pacing (200 to 240/min). One dog did not receive radionuclide-labeled microspheres because of left atria1 catheter failure, so 9 dogs were studied. Of these 9 dogs, 7 had 2 vessels occluded, and 2 had circumflex artery occlusion alone because left atria1 pressure had been over 15 mm Hg 5 minutes after circumflex artery occlusion. Myocardial blood flow measurements: These 9 dogs received morphine, 1 mg/kg, 3 to 4 days after coronary occlusion, and their catheters and right ventricular pacing wires were exteriorized. Thirty minutes after beginning continuous electrocardiographic and pressure monitoring we injected 2 million 15 /*m diameter microspheres labeled with one of the following radionuclides: iodine-125, cerium-141, chromium-51, strontium-85, niobium-95, or scandium-46 (3M, St. Paul, Minnesota). A reference sample of aortic blood was withdrawn at 15.2 ml/min beginning before and continuing for 90 seconds after microsphere injection. The reference blood sample was not collected adequately during either the control or pacing period in 4 dogs. Criteria for inadequate collection were failure to turn on the aortic blood withdrawal pump before microsphere injection (n = 2) and having the blood withdrawal stop within the first 60 seconds after microsphere injection because of clotting in the aortic catheter (n = 2). Thus, in these dogs only relative blood flow to different regions of the heart (ischemic zone versus normal zone) could be measured. This ratio of blood flows is useful because it relates the blood supply to the ischemic region to the normal region where patent coronary arteries allow autoregulation to match blood supply to metabolic demands.lJ Two of these 4 dogs were the dogs with single vessel occlusion. After the control measurements, we paced each dog’s right ventricle to 200/min and increased pacing by 20lmin every 15 to 30 seconds until there was a decreasing mean aortic pressure. We waited 15 minutes and resumed pacing at 20/min slower than the maximum. After 2 minutes of pacing, we measured pressures and injected microspheres labeled with a different radionuclide. Pacing was continued 1 to 2 minutes after microsphere injection to allow microspheres to distribute to tissues. The dogs were euthanized with an overdose of pentobarbital. Postmortem analyses: We cannulated each occluded coronary artery distal to the site of its occusion and the aorta 1 to 2 cm above the coronary ostia (Fig. 1). The dye reservoirs were positioned high above the heart to perfuse the coronary arteries at the same pressure as the aorta (100 mm Hg), delivering fluorosine into the aorta and Evans blue dye into the coronary arteries distal to their sites of occlusion.l* Thus, the regions supplied by the occluded arteries and therefore dependent on collateral flow and potentially ischemic, were identified by blue stain. Myocardium supplied by patent arteries was identified by the fluorosine stain. After removing the atria and right ventricle, we cut each heart into 8 to 10 doughnut-shaped slices, 4 to 5 mm thick, from apex to base (Fig. 1). Each slice was carefully dissected to make an incision along the irregularly shaped boundary between blue and fluorosine stains on both sides of each slice. We incubated each slice in triphenyl tetrazolium for 1 hour at 37°C to stain

FLOW RESERVE AFTER MYOCARDIAL

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noninfarcted tissue red. The heart slices were preserved in 10% buffered formalin for 24 hours and then each side was individually photographed. The photographic slides were projected to trace the outlines of the total left ventricular slice, potentially ischemic zone (marked by previous incisions), and the tetrazolium-negative region of myocardial infarction (Fig. 1). The areas of each region were integrated for each side of the heart slice, averaged, and multiplied by the weight of each slice to yield the masses (g) of the left ventricular slice, ischemic zone, and myocardial infarction region for each slice. The total masses of each region were summed for all slices to yield the total masses of the left ventricular ischemic zone and myocardial infarction. Finally, we dissected samples from the normal zone remote from the ischemic zone, and from the center of the circumflex-dependent ischemic zone at least 1 cm inside the incision that marked the boundary between the ischemic and normal zones. These samples for microsphere radioactivity counting were divided into subendocardial, mid-myocardial, and subepicardial layers. The samples were weighed and counted in appropriate energy windows. Counts were corrected for crossover activity from other radionuclides by a decontamination matrix of simultaneous linear equations, as previously described.‘” Myocardial blood flow was calculated by the following formula: (tissue counts).(sample weight)-‘-(refer-

NS P<.ool

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32 -

280 -

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Heart Rate

4-

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Pace SAP

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FIGURE 2. Effects of pacing-tachycardia on systemic hemodynamics 3 to 4 days after myocardial infarction. These 3 graphs show values for heart rate (beats.min-‘), mean aortic or-temic arterial pressure (SAP, mm Hg), and mean left atriil pressure (LAP, mm Hg). Data for the same dog are shown by closed circles and connected by lines from the control (Cont) value on the left to the value during pacing (Pace) on the right in each of the 3 graphs. The mean values of each variable during each condition are shown by the open circles beside each bar. The p values shown above each graph resulted from paired Student’s t tests (n = 9).

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ence blood sample counts)-l+ate of withdrawal of the reference blood sample).16Because the major focus of the present study was on the measurements made a few minutes before the animals’ death, we did not attempt to calculate microsphere loss in these studies.15 Data analysis: We tested the significance of changes in variables between control and pacing periods by Students’ t test for paired data. The best fit equation (least squares linear regression) was calculated, as was the correlation coefficient (r).17 P values less than 0.05 were considered significant, and p values less than 0.1 but greater than 0.05 were reported as marginally significant.

and its reserve capacity to increase during pacing stress, 3 to 4 days after infarction. The fraction of the ischemic zone that developed myocardial infarction correlated closely with resting subendocardial flow (r = 0.87), but not with resting subepicardial flow (r = 0.43) (Fig. 4). These correlations indicate that 3 to 4 days after infarction collateral blood flow in the infarcted subendocardium is related closely to the extent of infarction. In contrast, collateral blood flow to the surviving subepicardial layer is nearly normal and relatively independent of the extent of infarction. Pacing tends to decrease the relative distribution of flow to the ischemic zone for any given extent of infarction, although the correlations between flow (ischemic zone/normal zone)

Results Sizes of ischemic and infarct zones: The mass of the ischemic zone averaged 56% of the left ventricle (range 38 to 69), the mass of the myocardial infarction averaged 21% of the left ventricle (range 4 to 41), and the mass of the infarct averaged 32% of the ischemic zone (range 7 to 74). Gross examination of specimens stained by tetrazolium before microsphere counting revealed some myocardial infarction in all samples from the subendocardium and in some samples from the mid-myocardium, but in no samples from the subepicardium. Hemodynamics: Figure 2 shows heart rate, mean aortic pressure, and left atria1 pressure during control and pacing periods 3 to 4 days after myocardial infarction. Right ventricular pacing increased the heart rate twofold, caused no change in mean aortic pressure, and caused a marginal increase in left atria1 pressure (0.05

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The American Journal of CARDKXDGY

NS 3.0 -

2

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FIGURE 3. Effects of pacing-tachycardia on coronary vascular conductance 3 to 4 days after rnyocardial infarction. Top, data for the normal zone and bottom, data for the ischemic zone. Coronary vascular conductance was calculated as myocardial blood flow divided by mean aortic pressure, (ml~min-i~g-l/lOO mm Hg). Data are shown for the following samples: transmural mean, subendocardial (subendo), midmyocardial (mldmyo), and subepiwdtal (subepi). The clear bars show the control (Cont) values and the shaded bare the values during pacing (Pace). The p values resulted from paired Student’s t tests. The brackets show 1 standard error of the difference (n = 5 because of problems with collecting reference arterial blood samples in 4 of 9 dogs).

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a Subendo

r = -0.87

Y = -1.49(X1 + 0.97 f 0.25

ISEEI

0 Subepi

r = -0.43

Y = -1.48(X)

(SEEI

+0.18

f0.94

FLOW RESERVE AFTER MYOCARDIAL

INFARCTION-PATTERSON

ET AL.

0 1.6

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FIGURE 4. Relations between the myocardial blood flow (MBF) ratio, ischemic zone/normal zone (lZ/NZ), and the fraction of the ischemic zone that is infarcted (MVIZ) 3 to 4 days after infarction. Left, during control conditions, and right, during pacing-tachycardia (n = 9). Left, the closed circles represent data for the subendocardium, and the open circles, diamond-shaped symbols for the subepicardium. The boxed area shows the correlation coefficients (r) and equations for the linear regression lines, f the standard error of the estimate (SEE).Right, the symbols are shown in the box. Note that the best correlation between blood flow (IZ/NZ) and the fraction of the ischemic zone that undergoes infarction (MVIZ) is found for the subendocardium under control conditions (f = -0.87). Subepicardial samples (which had no gross evidence of infarction) have more blood flow for any given percent infarction during control or pacing conditions (n = 9).

and size of myocardial infarction (myocardial infarction mass/ischemic zone mass) are not strong (r = -0.55 for subendocardium and r = 0.64 for subepicardium). Figure 5 shows a fair correlation between collateral flow 5 minutes after coronary occlusion versus 3 to 4 days after occlusion during pacing (r = 0.73), suggesting that collateral flow reserve 3 to 4 days after myocardial infarction depends in part on preexisting collateral flow. The initial collateral flow 5 minutes after coronary occlusion does not permit quantitative prediction of collateral flow reserve 3 to 4 days after acute myocardial infarction. Figure 6 shows the lack of relation between the left atria1 pressure and subepicardial collateral flow during control (r = 0.44) and pacing (r = 0.29). Discussion The major objective of the present study was to determine whether the coronary vascular conductance to surviving myocardium has the reserve capacity to increase during pacing tachycardia 3 to 4 days after acute myocardial infarction. We also examined factors that might influence collateral flow reserve 3 to 4 days after infarction. The design of the present study differs from most previous reports in that the dogs had myocardial infarction before collateral blood flow reserve was tested. Most physiologic studies of coronary collateral function have been designed to avoid myocardial infarction.* CollateraI reserve after myocardial infarction and multivessel coronary occlusion was studied because inadequate collateral blood flow reserve in surviving myocardium might predispose the heart to further

ischemia and infarct extension after the initial acute myocardial infarction. This relation might be expected because myocardial infarction size has been found related to the collateral myocardial blood flow available a few minutes after coronary occlusion.si0J8 One previous study by Hess and Bathe” found only a moderate reduction in collateral blood flow to regions with minimal myocardial infarction during exercise in dogs 2 weeks after acute occlusion of a single coronary vessel. The present study design differed from the previous study in 2 major ways: Collateral blood flow reserve was assessed earlier (3 to 4 days) after acute coronary occlusion, and 2 major coronary vessels were occluded in 7 of the 9 animals studied. The experimental model of multivessel coronary disease 3 to 4 days after myocardial infarction seems relevant to the patients in whom complications of myocardial infarction are most likely to develop in the clinical situation,12Js but the exceedingly high death rate of these dogs limits the number of animals that can realistically be entered into a study. Coronary vascular conductance at rest and during pacing tachycardia: The results of the present investigation indicate that coronary vascular conductance at rest in collateral-dependent myocardium 3 to 4 days after acute coronary occlusion is reduced in subendocardial and mid-myocardial layers. These regions contain grossly visible infarcted tissue. Pacing stress led to a further decrease in vascular conductance in these deep layers. In contrast, collateral conductance at rest returned to values equal to that in the normal

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Subepi cardium

2.8 r

2.4

3-4 Days Pacing @ 1r =

Subepicardium

+ .73 1 y =.72(X)+

,677 k .63 (SEE)

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r=

Pacing 0

r= +29 y= .03(X) + 540

]

+ .A4

y = .06(XI + 225 f .61 ISEEl f .62lSEE)

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MBF (IZINZ)

FIGURE 5. Relation between the myocardial blood flow (MBF) ratio, ischemic zone/normal zone (WNZ) in the noninfarcted subepicardium 5 minutes after coronary occlusion versus 3 to 4 days later, after myocardial infarction, during pacing-tachycardia . Other symbols and abbreviations as in Figure 4 (n = 9). Note that the index of collateral blood flow reserve (IZ/NZ during pacing) 3 to 4 days after myocardial infarction correlates moderately well with the initial collateral blood flow available 5 minutes after coronary occlusion (r = 0.73). The initial collateral flow ratio does not allow quantitative prediction of subsequent collateral flow reserve.

zone in the subepicardial layers. Nonetheless, vascular conductance did not increase in the surviving collateral-dependent subepicardial layers during pacing to the same extent that it did in normal myocardium that lay outside the collateral-dependent zone. The potential functional significance of this finding will be discussed after a critique of our methods. Methodology: Several methodologic considerations are important to consider. First, dogs were studied in the awake state to avoid the effects of anesthesia and acute surgical trauma. Second, we defined the presence or absence of myocardial infarction by examination of both surfaces of heart slices 4 to 5 mm thick after staining with triphenyl tetrazolium. The ability of this staining technique to distinguish necrotic from surviving tissue within the vascular distribution of the occluded coronary artery has been validated in this laboratory by histopathologic examination.14 Some myocardial infarction was found in all of the subendocardial samples and most mid-myocardial samples that were used for microsphere measurements of blood flow. In contrast, none of the subepicardial samples mani-

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1982

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Journal of CARDIOLOGY

0

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FIGURE 6. Relation between the myocardial blood flow ratio (ischemic zone/normal zone) and mean left atrial pressure during control (closed circles) versus pacing (x Inside circles) conditions, 3 to 4 days after infarction. Note that there is no particular relation between the changes in blood flow and left atrial pressure during either control or pacing periods, 3 to 4 days after infarction. Other symbols and abbreviations as in Figures 4 and 5 (n = 9).

fested any evidence of infarction. Although large regions of myocardial infarction could be excluded by the method employed, it is possible that a small amount of necrotic tissue existed in the subepicardial samples. Even if these samples contained up to 10% necrotic tissue with zero blood flow, this would cause our microsphere blood flow measurements to underestimate true collateral myocardial blood flow by only 10%. Thus, it is unlikely that our conclusion that subepicardial collateral vascular conductance does not increase normally 3 to 4 days after myocardial infarction is due to an artifact resulting from the presence of necrotic tissue in the samples. Third, if the samples of supposedly ischemic myocardium used for collateral flow measurements had included some overlapping tissue dependent on an unoccluded coronary artery, then our measurement of

apparent collateral blood flow might be increased artifactually. This artifactual increase in collateral myocardial blood flow is most serious during interventions that increase blood flow through normally patent coronary arteries.lg In the present study we minimized the likelihood of this artifact influencing our results by injecting dye into the coronary arteries distal to their sites of occlusion and dissecting samples from at least 10 mm inside the dye-stained border. In other studies using

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similar dye injection methods and a microsphere technique to label tissue supplied by normally patent arteries, the overlapping normal tissue was located primarily in the subendocardium20 and was less than 5 mm from the lateral border of the dye-stained zone.8’20,21Further, the increase in normal zone blood flow in the present study were not large enough to cause a large artifactual increase in apparent collateral blood flow. These considerations indicate that no significant contribution to subepicardial collateral blood flow would be expected from overlapping normal zone tissue in the present study. Fourth, right ventricular pacing does not stimulate a maximal increase in coronary blood flow. Studies in man22 and dog7 have indicated that exercise causes a greater increase in coronary blood flow than does pacing to the same heart rate. However, after adjusting the increase in coronary blood flow for the increased aortic pressure during exercise, exercise appears to cause only a 30 to 50% greater increase in coronary vascular conductance than does pacing to the same heart rate.7r22 Thus, the failure of collateral blood flow to increase in surviving subepicardial tissue during pacing does not appear to be an artifact of an inadequate stimulus to collateral blood flow. The tachycardia-stress employed in the present study is a stress that frequently occurs in patients with tachyarrhythmias 3 to 4 days after myocardial infarction.12 Fifth, pacing was performed for 2 minutes before and 1 to 2 minutes after microsphere injection to ensure tissue distribution. No major hemodynamic changes were noted during pacing probably because the rate had been selected from previous tests in the same dog to ensure stable mean arterial pressure. Left atrial pressure increased in 4 dogs by more than 3 mm Hg, decreased by 3 mm Hg in 2 dogs, and did not change in 3 dogs (Fig. 2). Changes in left atria1 pressure were not related to changes in heart rate, aortic pressure, collateral myocardial blood flow (Fig. 6), or myocardial infarction size. Sixth, the present study measured blood flow reserve in collateral-dependent myocardium 3 to 4 days after acute myocardial infarction, but we did not measure an index of ischemic injury during pacing stress. Thus, the conclusions are related specifically to collateral blood flow reserve-a major determinant of the potential for ischemia-rather than to the severity of ischemia itself. We did express collateral blood flow reserve as a fraction of the flow reserve measured simultaneously in the regions of the left ventricle supplied by patent coronary arteries. These normal regions of the heart should show autoregulatory changes in blood flow to reflect the level of myocardial oxygen demand at the time of collateral blood flow measurements.4 Mechanisms influencing collateral flow: Several mechanisms probably contribute to limited collateral myocardial blood flow reserve after myocardial infarction. First, occlusion near the origin of the circumflex and the mid-portion of the left anterior descending coronary arteries rendered 56% of the left ventricle ischemic in the present study. Occlusion of 2 of 3 vessels

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deprives the heart of 1 of its 2 potential sources of collateral vessels that would be available after single vessel occlusion. This effect contributes to the observation that collateral myocardial blood flow decreases as a larger fraction of the left ventricle is rendered ischemic by coronary occlusion. 23~24 Multivessel occlusion in 7 of 9 dogs in the present study must have contributed to the fact that we observed lower collateral flow reserve than have others.” Also, the dogs’ individual variability in collateral development probably influences collateral flow reserve 3 to 4 days after infarction. This is suggested by Figure 5, which indicates a reasonable correlation between collateral flow reserve 3 to 4 days after infarction and the initial collateral flow 5 minutes after coronary occlusion (r = 0.73). Second, 3 to 4 days after acute coronary occlusion the coronary collateral vessels would be in only an early stage of their growth transformation process, which usually takes 4 to 6 months. 2,$The early days of collateral development appear to be associated with less flow reserve than is found later.2-7 Thus, the brief time available for collateral development undoubtedly contributed to the more severe impairment of subepicardial blood flow reserve observed in the present study compared with the moderate impairment reported by others 2 weeks after acute occlusion.” Third, the 9 dogs studied were selected from 14 survivors of multivessel occlusion. Most of the 41 dogs subjected to these coronary occlusions in the awake, sedated state died within a few hours. The relatively high blood flow to normal zone myocardium after occlusion of 2 coronary arteries probably reflects reflex stimulation of the heart to maintain the circulation after the large myocardial infarction. Thus, the surviving dogs selected for study may differ from the general population of dogs in ways that could influence their subepicardial blood flow reserve measured after infarction. It seems most likely that the selection process would have favored dogs with better collateral flow reserve, again making our results conservative in estimating the severity of the flow deficit. Fourth, impaired collateral flow reserve in the surviving subepicardium may be explained in part by the decreased diastolic time per minute during pacing, because collateral coronary flow occurs primarily during diastole.25,26 The level of left atria1 pressure during pacing (16 mm Hg) did not appear to inhibit subepicardial collateral flow, as indicated by the poor correlations between left atria1 pressure and its changes and subepicardial collateral flow (ischemic zone/normal zone, r = 0.29 during pacing). This lack of effect of left ventricular filling pressure on subepicardial collateral flow reserve is not surprising because left ventricular diastolic pressure exerts its major inhibitory effect on collateral blood flow in the subendocardium.27-“0 Clinical implications: The validity of extrapolating from animal studies to human disease is always uncertain. Man may have less potential for collateral vessel development than does the dog, which suggests that the present animal study may be conservative in that it estimates better coronary collateral flow than is present

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in patients 3 to 4 days after acute myocardial infarction.31 It is likely that there is overlap between the status of collateral flow development in individual patients and animals. If this is so, then the results of this study suggest that some patients with multivessel coronary disease have inadequate collateral blood flow reserve capacity 3 to 4 days after myocardial infarction. The present study should not be interpreted as evidence that early mobilization of patients with an uncomplicated clinical course after acute myocardial infarction is necessarily dangerous. Rather, these data in animals support a “common sense approach” to early mobilization.s2 If early mobilization caused a large increase in heart rate, most cardiologists would advise a decrease in the level of physical activity.“” Further clinical data suggest the feasibility of discharging carefully selected patients 1 week after myocardial infarction34 or of treadmill stress testing 2 to 4 weeks after myocardial infarction.35t3s These clinical practices have been restricted to carefully selected subgroups of patients,“2-ss who probably differ from these animals with multivessel disease 3 to 4 days after a large myocardial infarction. Further, the demonstration of impaired collateral flow reserve in the present study may be relevant to the mechanism of positive stress tests after acute myocardial infarction.s5vss Acknowledgment We thank Stephen E. Epstein, MD, for his advice and encouragement; William Parker and Kenneth Steadman; and John Bather, DVM, and his staff in the Surgical Section, Veterinary Resources Branch, Division of Research Services, National Institutes of Health, for their invaluable assistance. We especially thank June Moon for her expert preparation of the manuscript. References 1. 2. 3. 4. 5.

6. 7. a.

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BockorLC,

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9. RtvaaF,DobbFR,BacheRF,~ JC Jr. Relatiwhip between blood flow to ischemic regions and extent of my-dial infarcticn. Serial measuremants of blood flow to ischemic regions in dogs. Circ Res 1976;38: 439-447. IO. Bishop SP, White FC, 8100( CM. Regional myocardial blood flow during ~;~~443mgyocardial infarction in the conscious dog. Circ Res 1976;38: 11. Hess DS,‘Bache RJ. Regiil myocardial bbod flow dui gaded treadmill exercise followi circumflex coronary artery occlusion in the dog. Circ Res 1980;47:59- 9 8. 12. Kllllp T, Klrnball JT. Treatment of myocardtal infarction in a coronary care unit. A 2 year experience with 250 patients. Am J Cardiol 1967;20:457466. 13. Herman MV, Gorlln R. In vivo angiographic patho-anatomy of the acute syndromes coronary heart disease. Trans Assoc Am Physicians 1971; 85:231-239. 14. Eunow RO, LIpron LC, Sheahan FH. Capurro ML, lsner JM, Roberts WC, Gokfsteln RE, Eprtrkt SE. Lack of effect of aspirin on myocardial infarct size in the Am J Cardlol 1981;47:258-264. 15. Capurro ML, ?? ofdstrln RE, Aamodt R, Sntfth JR. Eprtdn SE. Loss of microspheres from ischemic canine cardiac tissue: an important technical limitation. Circ Res 1979;44:223-227. 16. Hrymann Mt. Payne BD, Hoffman JIE, Ruddph AM. Blood flow measurements wrth radionuclkfa-labelled particles. Prog Cardiovasc Dis 1977;20:55-79. 17. Bnedacer GW, C_ocfuan WG. Statistical Methods, 6th ed. Ames. IA: Iowa State Unlversity Press, 1967:91-119, 135-198. 16. lrwh RG, Cobb FR. RelationsMp between epicardial STsegnent elevation, regional myocardial blood flow and extent of myocardtal infarction in awdte dogs. Circutation 1977:55:825-832. 19. Patterson RE, Kirk ES. Apparent improvement in canine collateral myocardial blood flow during vasodilation depends on criteria used to identify ischemic m ocardia. Circ Res 1980;47:108-116. 29. Pattarsmt R i , Welntraub WS, H&ash DA, Mfao J, Rogen JR, KupamntKh J. Spatial distribution of [“C #docaine and blood flow in transmual and lateral border zones of isc bemic canine myocardium. Am J Cardlol 1980;50:63-73. 21. Patterron RE, Klrk ES. Coronary collaterals in pi s: physiol ic and anatomic charactarizatlon (abstrl. Circufation 1978: B8:SuooI lll:ll “B-87. 22. Holnhrg S. Tha lnflosnce of exercise and of p&ir&duced tachycardia on coronary blood flow arxi myocardtal oxygen consumptkn. In: Maseri A, ed. Myocardial Blood Flow in Man: Methods and Si ificance in Coronary Disease. Turin, Italy: Minerva Msdica. 1972:489-4 $ 6. 23. BcJtaPer W. Experimental coronary artery occlusion. Ill. The determinants of collateral blood flow in acute coronary occlusion. Basic Res Cardiol 1978;73:584-594. 24. Juadutt Bt. Hutchlns GM, Eulkky BH. Beckr LC. Myocardial infarction inthaccftscious~: three dimerislonal mapping of infarct, collateral flow ard reolon at risk. lrculatlon 1979:6&l 141-1150. 25. Brown-BG, Gundaf WD, Gett VL, C&l JW. Coronary collateral flow following acute coronary occlusion: a diastolic p henomeoon. Cardlovasc Res 1974;8:621-631. 26. Downe JM Klrk ES. Distribution of the coronary blood flow across the canine & wall during systole. Circ Res 1974;34:251-257. 27. KjeMnts JK. Mechanism for flow distribution in normal and ischemic myocardium during increased ventricular preload in the dog. Circ Res 1973;33:489-497. 26. Mofr TW. Subecdocardtal distribution of coronary blood flow and the effect of antianglnal drqs. Circ Res 1972;30:621-627. 29. Downey , Ktrk E . Inhibition of coronary blood flow by a vascular waterfall mechanism. Circ Res 1975;36:753-760. 30. Beme RM, Rublo R. Coronarycirculaticn. In: Berne RM. Sperlakis S. eds. Handbook of Physiology, The Cardiovascular System. Vol 1. The Heart. Washington, DC: American Physiological Society, 1979:873-952. 31. Gorlln R. Coronary artery disease. In: Smith LH Jr, ed. Manor Problems in Internal Medicine. Vol 2. Philadelphia: WB Saunders, 197 6 :59-70. 32. Hurst JW. Early ambulation after myocardial infarction. N Engl J Med 1975;292:746-747. 33. Wengsr NK, Glfbert CA. Rehabilitation of the myocardial infarction patient. In: Hust JW. Logue RB. Scftlant RC. Wenger NK. eds. The Heart, Arteries and Veins. 4th ed. New York: McGraw-Hill. 1978:1303-1311. 34. McRser JF. Wallace AC, Wagner GS, Stanner CF, Rosatl RA. The cause Of acute myocardial infarction: feasibility of early discharge of the uncomplicated patient. Circuiation 1975;51:410-416. 35. Saml M, Kraemer H, DeBosk RF. The prognostic significance of serial exercise testing after myocardial infarction. Circulatron 1979;60: 12381246. 36. llmrarx P, Waters W, Hatphen C, DebaMsu x X. M@ala HR. Frognostic value of exercise testing soon after myocardial infarction. N Engl J Med 1979;301:341-345.

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