Persistent myocardial ischemia following chronic hyperoxia in conscious dogs

J

THoRAc CARDIOVASC SURG

86:710-717,1983

Persistent myocardial ischemia following chronic hyperoxia in conscious dogs Following acute occlusion of the proximal left anterior descending (LAD) coronary artery, dogs were exposed continuously for 4 days in an environmental chamber to either 21 % or 40% oxygen. Regional transmural myocardial blood flow was then determined by means of radioactive microspheres (8 to 10 IJ.D) while each animal breathed room air (~21 % oxygen). Blood flows in the anterolateral and apical regions of the left ventricle in normoxic animals (n = 5) averaged 0.95 ± 0.03 and 0.69 ± 0.13 mlfmin . gm:', respectively. In hyperoxic dogs (n = 5), blood flows in these regions were significantly lower, averaging 0.71 ± 0.07 and 0.28 ± 0.08 mlfmin . gm:', respectively in the anterolateral free wall, the greatest disparity in perfusion between experimental groups occurred in the subendocardial layers, and macroscopic evidence of necrosis was more widespread after hyperoxia.

J. F. Borgia, Ph.D., S. M. Horvath, Ph.D., and R. A. Sorich, Ph.D.,· Santa Barbara. Calif.

Although arterial hypoxemia is commonly encountered and routinely treated in patients with acute myocardial infarction,'? the risk or benefit of oxygen administration relative to the eventual severity of ischemic myocardial injury remains controversial. Increasing the fraction of inspired oxygen (Fl o2) above the level necessary to optimize arterial oxyhemoglobin saturation (95% to 100% oxyhemoglobin), is thought to augment molecular oxygen in the peri-infarcted region and thereby lessen the extent of necrosis and the likelihood of pathological sequelae.t' This concept is not supported, however, by evidence of reduced morbidity or mortality in prospective clinical trials/-" Moreover, the theoretical advantage gained either by elevating arterial oxygen tension (Pao 2) above 100 torr or nominally increasing plasma oxygen content (physically dissolved oxygen) may be offset by dysfunctional hemodynamic From the Institute of Environmental Stress, University of California, Santa Barbara, Santa Barbara, Calif. Supported in part by the Air Force Office of Scientific Research, Grant 78-3534, by the William H. Joyce Jr. Fund, by the L. H. and F. M. Chrisman Memorial Fund, by the Biomedical Sciences Research Support Grant NIH RRO 7099, and by the Santa Barbara County Chapter of the American Heart Association. Received for publication Jan. 17, 1983. Accepted for publication Feb. 21, 1983. Address for reprints: Dr. Steven M. Horvath, Director, Institute of Environmental Stress, University of California, Santa Barbara, Santa Barbara, Calif. 93106. *Present address: Research and Development Division, Boehringer Mannheim Corporation, 2742 Dow Ave., Tustin, Calif. 92680.

710

or

metabolic

effects

that

occur

under

these

circumstances.t" Since innate coronary collateral blood flow in the area bordering an infarct is a principal determinant of oxygen availability and tissue viability,6.15.16 acute or chronic therapeutic interventions which either promote or retard innate perfusion or influence subsequent collateral development may have a deciding effect on the ultimate extent of injury.":" In the present study, the effect of respiring 40% oxygen on regional and transmural myocardial blood flow was ascertained in dogs 4 days after acute coronary artery occlusion. It was anticipated that the bulk of irreversible injury would be resolved by this time and that the efficacy of this treatment modality could be assessed by quantitating the degree of reperfusion in the ischemic myocardium.

Methods Adult male mongrel dogs, ranging in weight between 15 and 30 kg, were studied." Animals were maintained on a 12 hour light/dark cycle and allowed free access to open-air runs for 6 hours daily. For 2 to 3 weeks prior to study each dog was gradually conditioned to stand quietly in a webbed harness, for periods of I hour, with a rigid (clear plastic) hood enclosing the head and secured loosely at the shoulders. Air (21 % oxygen, balance *In conducting this research, the investigators adhered to the "Guide for Laboratory Animal Facilities and Care" as promulgated by the Committee for Laboratory Animal Facilities and Care, of the Institute of Animal Laboratory Resources, National Academy of Sciences, National Research Council.

Volume 86 Number 5 November, 1983

nitrogen) from a pressurized gas cylinder was admitted to the hood at a rate of 15 L/min and allowed to exhaust freely from around the base of the neck. After the dogs were trained, anesthesia was induced with pentobarbital sodium (25 mg/kg, intravenously) and mechanical ventilation was maintained (Model 607A respirator, Harvard Apparatus Co., Inc., S. Natick, Mass.) via a cuffed endotracheal tube. A left lateral thoracotomy was performed (third or fourth intercostal space) and the heart was suspended in a pericardial cradle. Polyvinyl chloride catheters (3 mm outer diameter and 1 mm inner diameter) were introduced into the aortic arch and left atrium by way of the left internal mammary artery and left atrial appendage, respectively,and secured in position with silk ligatures at each site of entry. The catheters were tunneled subcutaneously from the base of the neck and exteriorized through a carbonized skin capsule (General Atomic Co., San Diego, Calif.). The left anterior descending (LAD) coronary artery was dissected free of surrounding tissue at a point immediately distal to the first visible epicardial diagonal branch, and silk ligatures were loosely positioned around the vessel. An arterial blood sample was obtained through the aortic catheter in a heparinized glass syringe, and partial pressures of oxygen (Po2) and carbon dioxide (Pco.) were measured along with blood pH (CABl-l, Radiometer A/S, Copenhagen, Denmark). Sample syringes were stored at 4° C between multiple determinations. Minute ventilation was adjusted as necessary to maintain P3.02 between 75 and 85 torr, Paco 2 between 35 and 40 torr, and pH between 7.3 and 7.4. A 15 minute equilibration period was allowed before further manipulation. Regional myocardial blood flow was determined by injecting tracer microspheres (3M Co., St. Paul, Minn.) 8 to 10 fJ. in diameter which were labeled with 141Ce, 85Sr, or 95Nb. Each aliquot of microspheres contained 2.0 mCi of total activity (10 mCi/g specific activity) presuspended in 40 ml of 10% dextran and 0.05% surfactant (Tween-80). For 30 minutes prior to injection, microspheres were alternately' sonicated (Branson Model B52) and physically agitated (Vortex Genie). A 0.5 ml volume of the suspension containing approximately 5 X 106 microspheres was injected into the left atrium, and the catheter was flushed with 8 ml of warm (34° to 37° C) physiological saline. Commencing with the injection and continuing for 90 seconds, a reference blood sample was drawn from the aorta at a constant rate into a heparinized syringe by means of a mechanical pump (Harvard Model 941). (Heart rates, obtained from continuous electrocardiographic recordings, were not altered by this procedure.) The withdrawal syringe

Persistent myocardial ischemia 7 1 1

was mechanically rotated for 30 minutes and four 3 ml reference blood samples were pipetted into separate counting vials. The LAD coronary artery was then ligated. The pericardiotomy and thoracatomy were repaired and ventilatory support was gradually withdrawn. Catheters were flushed with heparinized saline (30,000 units/L) and sealed, and the dog was fitted with a protective vest (Alice King Chatham, Medical Arts, Los Angeles, Calif.). Within 10 minutes after resumption of voluntary ventilation, the animal was placed in a holding cage and housed in an environmental chamber (internal dimensions 2.5 by 3 by 3 m). Chamber oxygen concentration was maintained at either 21% or 40% oxygen (balance, nitrogen) at flow rates sufficient to keep carbon dioxide accumulation below 0.5%. Oxygen concentration was continuously monitored with an oxygen analyzer with remote sensor (Model 407, Instrumentation Laboratories, Inc., Lexington, Mass.) and samples of chamber exhaust were collected daily and analyzed for carbon dioxide content by gas chromatography (Model H-3, Quintron Instruments, Seattle, Wash.). Chamber temperature and relative humidity were held between 21 ° and 23° C and 65% and 75%, respectively. Food and water were provided ad libitum and the chamber was opened to room air (=:.:21 % oxygen) for approximately 1 hour daily to facilitate animal care and general maintenance. After 96 hours of chamber confinement, each dog was removed to a noise-controlled room and placed in the retention harness and hood (elapsed time < 10 minutes). Either 21% or 40% oxygen (balance, nitrogen) from premixed pressurized cylinders was administered (corresponding in each animal to the chamber oxygen concentration to which it had been exposed) and a 30 minute equilibration period was allowed. An aortic blood sample was then obtained for determination of blood gases and pH. Regional myocardial perfusion was measured by microsphere injection. The hood was removed and after an additional 30 minutes, during which all animals respired room air (:;::;:21% oxygen), blood flow was again determined by microsphere technique. The order of injection of each nuclide label was randomized in consecutive experiments. Each animal was administered an overdose of pentobarbitol sodium and the heart was removed, washed in cold saline, and weighed. The left common coronary artery was dissected free and cannulated via the aorta with a polyethylene catheter. Methylene blue (methylthionine chloride) was injected into the coronary system under low pressure «50 torr) to assist in differentiating ischemic (karyolytic areas) and nonischemic tissues.

The Journal of Thoracic and Cardiovascular Surgery

712 Borgia, Horvath, Sorich

Table I. Comparisons between hyperoxic and normoxic groups Group

Body weight (kg)

LV weight (gm)

Normoxic (n = 5) Hyperoxic (n = 5)

23.4 ± 2.3 21.0 ± 1.7

115.6 ± 11.1

119.0 ± 13.2

Pao} (torr)

79 ± 2].

146 ± 7

Index of injury

3].

15 ± 34 ± 2

Legend: Values are means ± standard error. Arterial oxygen tensions (Pao,) obtained in awake animals 4 days after infarction while normoxic group breathed 21% oxygen and hyperoxic group breathed 40% oxygen. The Index of injury represents the average number of tissue sites (of a total of 75 obtained from the left ventricle in each animal) which demonstrated visible evidence of surface injury. LV, Left ventricular. 'Statistically significant difference between groups (p

< 0.05).

Retrograde perfusion of the LAD artery by epicardial collaterals was observed in all hearts and serially photographed. The atria, right ventricle, and major blood vessels were dissected from the left ventricle. The left ventricle was weighed and sectioned, parallel to the mitral anulus, into four slices of approximately equal thickness. The upper three slices or rings (starting from the base of the heart) were divided into circumferential areas corresponding to the anterolateral, posterior, and septal regions of the intact ventricle, and contiguous transverse sections were obtained from each area. Each section was subdivided into three equal transmural layers (0.5 to 2.0 gm each) representing the epicardial, mid-myocardial, and endocardial regions, designated as areas 1, 2, and 3, respectively. The outermost layer of the septal region, corresponding to the endocardium of the right ventricle, was labeled as layer 1. The apical slice was sectioned into four equal tissue blocks, and each block was subdivided into transmural layers. The entire anterolateral and apical regions of each ventricle were obtained for study, and the combined tissue weight of all samples in each heart ranged from 60% to 80% of the total left ventricular mass. Without prior knowledge of tissue identification, each sample was evaluated independently by two investigators relative to the presence or absence of necrosis. Each tissue section was then weighed (Model H20T, Mettler Instrument Corp., Hightstown, N. J.). and placed in a counting vial. Tissue and reference blood activity was determined with an automatic gamma scintillation system (Model 4233, Nuclear Chicago, Chicago, Ill.) at window settings corresponding to the peak energy emitted by each radioactive isotope. All data were processed by a computer (Itel ASJ6) by means of resident programs derived from standard formulas. t5 Background and crossover activity were corrected for each sample, and blood flow was calculated per gram of tissue for each microsphere injection. Within each area of the left ventricle, average perfusion was determined for each transmural layer and mean regional perfusion was obtained by averaging blood flow values from all three layers. The ratio of endocardial to epicardial blood flow (mean blood flow in layer 3 divided by that in layer 1) was also calculated for each region.

Coronary artery ligation was performed on 16 animals. Two dogs died of early fibrillation «17 minutes after LAD occlusion), and one animal died suddenly after 94 hours in 49% oxygen. Data from three dogs were excluded from analysis because of technical or procedural problems (e.g., blocked catheters). Satisfactory studies were completed on five dogs exposed for 4 days to 40% oxygen (hyperoxic group) and five animals exposed for the same time to 21% oxygen (normoxic control group). Analysis of variance techniques were used to determine if significant differences in mean regional or transmural blood flow were present between groups." A Tukey HSD multiple comparison test was applied a posteriori when a significant F was obtained." Mean values for other variables were compared by means of Student's t test for unpaired data. A value of p < 0.05 was regarded as significant in all statistical evaluations. Data are presented as means ± standard error. Results As shown in Table I, mean body weights (measured prior to operation) did not differ significantly between experimental groups. Weight loss during chamber confinement averaged 0.64 ± 0.31 and 0.50 ± 0.14 kg, respectively, in normoxic and hyperoxic animals. Breathing 40% oxygen by hood increased Paoz in hyperoxic dogs by an average of 67 torr above that of control animals respiring 21% oxygen (balance, nitrogen). Arterial Pco, and pH were not significantly altered. Left ventricular weights ranged from 80 to 154 grn in normoxic animals and 79 to 140 gm in hyperoxic dogs. Macroscopic evidence of ischemic injury was more extensive in animals exposed to 40% oxygen for 4 days (Table I). Although the extent of damage was not quantitated in each tissue sample, it was noteworthy that visible injury in normoxic dogs was limited to sites in the anterolateral and apical regions. However, global left ventricular involvement (anterior, lateral, posterior, and septal) was present in all hyperoxic animals. In the latter group, 24% of the posterior and 69% of the septal samples had evidence of necrosis or karyolysis, and the incidence of similar changes in the anterolateral region

Volume 86 Number 5 November, 1983

Persistent myocardial ischemia

7 13

Table II. Regional myocardial blood flow immediately preceding and 4 days following coronary artery occlusion

Cardiac region

Group

Anterolateral LV

Normoxia(l80) Hyperoxia(l80) Normoxia (90) Hyperoxia (90) Normoxia (45) Hyperoxia (45) Normoxia (60) Hyperoxia (60) Normoxia (15) Hyperoxia (15)

Posterior LV Septum Apex of LV RV free wall

Preinfarct blood flow (:::::.21% O2)

0.99 ± 0.86 ± 1.20 ± 1.04 ± 1.16 ± 0.95 ± 0.79 ± 0.79 ± 0.82 ± 0.78 ±

Postinfarct blood flow :::::.21%

0.03 0.05 0.02 0.06 0.03 0.06 0.09 0.03

0d

0.96 ± 0.02

I

40% O2

0.78 ± 0.08] * 1.39 ± 0.12 1.22 ± 0.06 1.29 ± 0.09 1.05 ± 0.10 0.75 ± 0.14 0.36 ± 0.11 ] *

om

0.81 ± 0.02

0.02

0.78 ± 0.01

[

:::::.21 % O2

0.95 ± 0.71 ± 1.23 ± 1.22 ± 1.22 ± 0.97 ± 0.69 ± 0.28 ± 0.73 ± 0.71 ±

0.03] * 0.07 0.06 0.05 0.08 0.11 0.13 ] * 0.08 0.02 0.01

Legend: Blood flow values are means ± SE of layers J, 2, and 3, expressed as mljmin . gm ". LV, Left ventricle. RV, Right ventricle. Number of tissue samples used to calculate blood flow are in parentheses. The first postinfarction blood flow was measured when normoxic animals breathed 2 J% oxygen and hyperoxic animals breathed 40% oxygen. 'Statistically significant differences between groups (p

< 0.(5).

m. Transmural distribution of blood flow in the left ventricle 4 days after coronary artery occlusion while both experimental groups breathed room air (~21 % oxygen)

Table

Cardiac region

Group

Anterolateral

Normoxia Hyperoxia Normoxia Hyperoxia Normoxia Hyperoxia Normoxia Hyperoxia

Posterior Septum Apex

Layer I: Epicardium

1.00 ± 0.85 ± 1.09 ± 1.12 ± 1.11 ± 0.92 ± 0.94 ± 0.43 ±

0.15 0.07 0.17 0.14 0.18 0.10 0.12] * 0.09

Layer 2: Myocardium

0.94 ± 0.70 ± 1.29 ± 1.31 ± 1.22 ± 0.97 ± 0.54 ± 0.22 ±

0.14] * 0.07 0.26 0.15 0.16 0.09 0.14] * 0.08

Layer 3: Endocardium

0.90 ± 0.13 ] * 0.57 ± 0.06 1.32 ± 0.29 1.22 ± 0.12 1.32 ± 0.25 1.00 ± 0.05 0.59±0.14]* 0.18 ± 0.08

Legend: Blood flow values are means ± SE, expressed as m1jmin . gm ". 'Statistically significant differences between groups (p

< 0.(5).

was twice that observed in normoxic animals. The incidence of tissue involvement in the apex was similar in the two groups (80% to 90%). Regional myocardial perfusion preceding LAD ligation (anesthetized, open-chest preparation) and after infarction (awake, lightly restrained animals) is shown in Table II. Four days after the operative intervention, blood flows in the anterolateral and apical regions of hyperoxic animals breathing 40% oxygen were significantly lower than in control animals receiving 21% oxygen. These differences persisted when blood flows were measured again after the hyperoxic animals had been switched to room air (~21 % oxygen) for 30 minutes. However, only blood flow in the apical region of the hyperoxic group (0.36 ± 0.11 and 0.28 ± 0.08 ml/rnin . gm") differed significantly from the preocclusion value (0.79 ± 0.03 ml/min . grrr'). Postinfarction comparisons of regional transmural perfusion and endocardial/epicardial blood flow ratios obtained while both groups breathed room air are presented in Tables III and IV, respectively. After

chronic hyperoxia, blood flow values in the endocardial and mid-myocardial layers of the anterolateral region and in all layers of the apical region were significantly less than in control animals. Except for the middle layer of the anterolateral area, blood flows in these layers were also significantly lower than those measured in the hyperoxic group prior to infarction. As shown in Table IV, the subendocardium in the anterolateral region was underperfused relative to the epicardium after hyperoxic therapy. Significantly, transmural blood flow and endocardial/epicardial ratios in hyperoxic dogs were not altered in any region when Floz was reduced from 40% to :;;;;21 %. Transmural blood flow following infarction in the posterior and septal regions of the hyperoxic group (and in all regions in the normoxic group) did not differ significantly from the levels measured in these regions prior to coronary occlusion.

Discussion The present data suggest that administrations of 40% oxygen promotes myocardial injury in the conscious dog,

The Journal of Thoracic and Cardiovascular Surgery

7 14 Borgia, Horvath, Sorich

Table IV. Regional endocardial/epicardial blood flow ratios prior to infarction and during respiration of room air 4 days after coronary artery occlusion Cardiac region Anterolateral

Posterior Septum Apex

Endocardial/epicardial ratio Group

Before

Normoxia Hyperoxia

0.96 ± 0.10 1.03 ± 0.09

Normoxia Hyperoxia Normoxia Hyperoxia Normoxia Hyperoxia

1.07 1.09 0.96 1.02 0.72 0.83

I

After 0.92 ± 0.Q7 ] 0.67 ± 0.04

*

L........I

± ± ± ± ± ±

0.11 0.07 0.05 0.07 0.10 0.07

1.20 1.11 1.18 1.10 0.60 0.36

L........I

± ± ± ± ± ±

0.15 0.09 0.09 0.09 0.15 0.10

Legend: Values are means ± SE. Endocardial/epicardial now ratios were obtained by dividing blood values (ml/rnin . grn") in layer 3 by those in layer I. 'Significant differences between groups or within groups (p < 0.05).

as indicated by the sustained reductions in blood flow in those regions of the left ventricle that were initially rendered ischemic by acute LAD coronary artery ligation. This finding is in direct conflict with a report by Maroko and associates,' who postulated that hyperoxia reduced the extent of infarction in dogs by diverting blood flow to the ischemic myocardium from better perfused regions of the heart. Their conclusions were derived from observations that epicardial ST-segment elevation, myocardial creatine kinase (CK) depletion, and histologic evidence of tissue injury were significantly reduced by administration of either 40% or 100% oxygen during the initial 24 hours after coronary artery occlusion. Although ST-segment changes obtained from epicardial electrocardiograms have been reported to correlate well with decreased myocardial P0 221 and tissue CK activity,22.23 other investigators have questioned these associations or have shown that summated ST-segment elevations in dogs often underestimate the severity of myocardial injury.":" Irvin and Cobb" found that ST-segment alterations correlated poorly with regional coronary blood flow (measured by microspheres) 15 minutes and 2 hours after coronary artery occlusion, and that 39% of tissue samples with blood flow reductions greater than 50% failed to demonstrate significant ST-segment elevation. Moreover, ST-segment changes may not be observed if ischemic injury is limited to the subendocardium." Heng and associates" reported that neither tissue blood flow, measured 15 minutes and 24 hours after LAD occlusion, nor CK depletion, deter-

mined after 24 hours, paralleled ST-segment changes, but a close correlation existed between blood flow and myocardial CP activity. Thus although epicardial STsegment mapping apparently is not a reliable method of quantifying the extent of myocardial injury, the effects of hyperoxia reported by Maroko and colleagues' on myocardial CK depletion and tissue histology cannot be easily reconciled with the current results. It should be noted, however, that (1) Maroko and co-workers' ligated either the LAD coronary artery or one of its' diagonal branches and it is probable, therefore, that ischemic involvement was more extensive in the present study, (2) although 40% oxygen was used in both investigations, average Pa01 in the previous study was 25 to 45 torr higher, and (3) histologic evaluation of reversible and irreversible myocardial injury within the initial 24 hours after acute coronary occlusion is imprecise." There are several limitations in the present study which must be noted. The sample populations were modest in size, and blood flow comparisons were not obtained immediately following coronary occlusion. It is unlikely, however, that the results were due to chance occurrence in one group of several animals with greater or lesser degrees of ischemia. Extensive contiguous sampling of areas of probable ischemic involvement demonstrated a surprising degree of homogeneity within each group with regard to both the geographic limits of damage and the average number of sites evidencing necrosis (Table I). For example, posterior wall ischemic injury was found in all hyperoxic animals but was not present in any of the normoxic dogs. Although this additional injury may be due to nonspecific processes induced by oxygen therapy rather than reduced blood flow, the proximity of damage (posterior apical region) to the expected zone of necrosis as well as the modest increment in ambient oxygen concentration would argue against this. Further histologic studies are planned, however, to investigate this finding. Finally, it should be noted that the vascular geometry of the canine coronary collateral network differs significantly from that of man, 17. IUS and the response to hyperoxia in animals is unaffected by cumulative cardiac disease or diffuse obstructive vascular disease. Rivas and associates" studied the relationship between myocardial blood flow, measured by microsphere technique between 45 seconds and 24 hours after acute left circumflex artery occlusion, and histologic evidence of necrosis, evaluated 6 days after infarction. Tissue perfusion was inversely related to the extent of necrosis in each transmural layer, and damage in endocardial tissues exceeded that in epicardial sites

Volume 86 Number 5 November, 1983

when samples with similar blood flow values were compared. Significantly, mean blood flow in ischemic regions increased by 112% (from 0.25 to 0.53 mlj min . gnr') within 24 hours after coronary ligation. This increase indicates that the association between tissue injury and perfusion was a function of the time after occlusion before blood flow was determined. A principal assumption in the present study was that reperfusion of the ischemic zones would be complete 4 days after occlusion; thus sustained reductions in regional blood flow, under standard hemodynamic and metabolic conditions, would represent the extent of irreversible injury. The data presented here indicate that in normoxic animals mean regional blood flow in ischemic zones returns to normal (preocclusion) levels within 4 days after acute LAD ligation (Table 11). The presumed mechanism is an enhancement of coronary collateral perfusion. However, within the anterolateral and apical regions of all normoxic dogs, tissues sections were present which evidenced necrosis and sustained ischemia (blood flow values <0.50 mljmin . gm "). This finding indicated that reperfusion was not sufficiently rapid to preclude irreversible damage. In addition, since mean blood flows in these regions were essentially normal following infarction, it is apparent that undamaged tissues were overperfused relative to the preocclusion condition. This may have resulted from a compensatory increase in metabolic activity in unaffected tissue or a failure to intrinsically autoregulate collateral perfusion. Notwithstanding the latter possibility, the significantly lower regional and transmural blood flows found in the anterolateral and apical regions of the hyperoxic group, as well as the extensive evidence of necrosis observed in all ventricular regions, indicated that chronic exposure to 40% oxygen aggravated myocardial injury. It would appear that the bulk of additional damage caused by hyperoxia resulted from underperfusion of the subendocardium relative to its metabolic requirements." It is important to emphasize, however, that the determinants of infarct size are complex and the persistent ischemia seen here mayor may not be related to the effect of hyperoxia on the collateral circulation. Hyperoxia may operate through several mechanisms to influence positively or negatively the balance between myocardial oxygen delivery and utilization. Elevating Flo2 in normal adults'P" and in patients with acute myocardial infarction I. 10.14.32 can significantly increase systemic vascular resistance and arterial blood pressures. In the ischemic heart, this may lead to improved coronary perfusion 16. 29 or the rise in cardiac afterload (mean arterial pressure) may contribute to cellular

Persistent myocardial ischemia 7 1 5

hypoxia by augmenting cardiac work and myocardial oxygen demand. Although stroke volume and cardiac output reportedly decrease during oxygen therapy, I. 8.14.32 calculated left ventricular work in cardiac patients has been shown to increase," decrease, or remain unchanged."! despite concomitant elevations in systemic pressures. On the other hand, mean arterial blood pressure is often unaltered during acute hyperoxia in normal adults," cardiac patients,1.12.34 and dogs," 35 and some question remains as to the long-term effects of oxygen therapy on peripheral hemodynamics. Although the maximum duration of experimental hyperoxia in the aforementioned studies was I hour, mean arterial blood pressure in dogs tends to decrease by as much as 20 torr after 6 hours of continuous exposure to 40% oxygen.' This may be significant since coronary blood flow is highly pressure dependent when the coronary bed is maximally dilated." The affinity of hemoglobin for oxygen in coronary sinus blood has been shown to increase in patients with known or suspected heart disease,36.37 and a recent report indicates that similar changes occur in venous blood of normal men after respiring 95% oxygen for 20 minutes." Although the latter results were obtained by reconstructing oxyhemoglobin dissociation curves by means of a somewhat controversial technique," it remains to be determined if routine oxygen therapy in cardiac patients contributes to disorders of hemoglobinoxygen release. Although hyperoxia increases coronary vascular resistance and decreases coronary blood flow in man'" 41 and dogs,9.35.42.43 it is uncertain whether this is secondary to a reduction in myocardial oxygen demand or if Paa2 induces coronary vasoconstriction by acting on an intrinsic component in the arterial wall. Ganz and associates," using coronary sinus blood flow (measured by thermodilution) as an indicator of left coronary inflow, found that administration of 100% oxygen decreased coronary blood flow and myocardial oxygen consumption (calculated from hemoglobin saturation) in subjects with normal coronary arteries and in individuals with prior histories of infarction and angiographically confirmed coronary artery disease. They suggested that coronary blood flow decreased in response to an initial reduction in oxygen demand, but a cause and effect relationship was not shown. Using anesthetized open-chest dogs, Ishikawa, Lee, and Ganz" partially occluded the LAD coronary artery, initially reducing blood flow to 70% of control, and measured changes in myocardial blood flow (using electromagnetic flowmeters) and cardiac contractile force (from epicardial strain gauges) during administration of 100% oxygen.

7 16

The Journal of Thoracic and Cardiovascular Surgery

Borgia, Horvath, Sorich

Coronary blood flow and myocardial oxygen consumption decreased significantly which they postulated were secondary to a reduction in cardiac contractility-an effect also observed in cardiac patients during oxygen inhalation." However, Daniell and Bagwell? found, in anesthetized open-chest dogs, that reductions in coronary blood flow during exposure to 100% oxygen were not entirely dependent on cardiac mechanical activity or myocardial oxygen consumption, since oxygen-induced changes in myocardial perfusion always preceded decreases in cardiac contractile force. Furthermore, when myocardial blood flow and oxygen delivery were held constant by mechanical perfusion of the left common coronary artery, inhalation of 100% oxygen decreased developed tension by a similar amount. Maim and associates, II using a thermographic technique to estimate infarct dimensions in dogs within 2 hours of coronary ligation, reported that the cool area (infarcted zone) increased in size during inhalation of 100% oxygen and decreased during normoxic ventilation. Elevating Pao2 was thought to constrict precapillary sphincters in the ischemic regions or prevent dilation of coronary collateral vessels. A similar view was recently advanced by Rivas and colleagues." They compared the effect of 100% oxygen with that of room air on regional myocardial blood flow (measured by microspheres), in awake dogs, 45 seconds after complete occlusion of the left circumflex coronary artery. Perfusion was significantly lower during hyperoxia in ischemic and nonischemic regions, and transmural blood flow in all layers was uniformly reduced. In addition to a reduction in oxygen availability in the ischemic myocardium, they noted that hyperoxia had the potential to increase irreversible injury by retarding substrate delivery4S.46 and impeding the removal of the metabolic by-products that could further aggravate cellular damage." Although oxygen-induced vasoconstriction of coronary arteries or innate collateral channels appears to be a plausible explanation for our findings, alterations in regional or transmural perfusion were not observed when hyperoxic animals were switched from 40% oxygen to room air. It is possible, however, that this mechanism becomes attenuated after prolonged hyperoxia, or that the effects of Pao 2 on vascular tone persist for some time interval after the hyperoxic stimulus is removed. Although definitive conclusions cannot be drawn from these data regarding the clinical strategy of routinely providing supplemental oxygen to patients with acute myocardial infarction, they strongly suggest that additional studies are necessary to define the precise

role that elevated Pao2 exerts on the ischemic myocardium. REFERENCES 1 Davidson RM, Ramo BW, Wallace AG, Whalen RE, Starmer CF: Blood-gas and hemodynamic responses to acute myocardial infarction. Circulation 47:704-711, 1973 2 Fillmore SJ, Shapiro M, Killip T: Arterial oxygen tension in acute myocardial infarction. Serial analysis of clinical state and blood gas changes. Am Heart J 79:620-629, 1970 3 Valencia A, Burgess JH: Arterial hypoxemia following acute myocardial. infarction. Circulation 52:360-368, 1975 4 Madias JE, Madias NE, Hood WB: Precordial STsegment mapping. II. Effects of oxygen inhalation on ischemic injury in patients with acute myocardial infarction. Circulation 53:411-417,1976 5 Maroko PR, Radvany P, Braunwald E, Hale SL: Reduction of infarct size by oxygen inhalation following acute coronary occlusion. Circulation 52:360-368, 1975 6 Thurston JGB, Greenwood TW, Berling MR, Connor H, Curwen MP: A controlled investigation into the effects of hyperbaric oxygen on mortality following acute myocardial infarction. Q J Med 42:751-770,1973 7 Rawles JM, Kenmure, ACF: Controlled trial of oxygen in uncomplicated myocardial infarction. Br Med J 1:11211123, 1976 8 Bourassa MG, Campeau L, Bois MA, Rico 0: The effects of inhalation of 100 percent oxygen on myocardial lactate metabolism in coronary heart disease. Am J Cardiol 24:172-177, 1969 9 Daniell HB, Bagwell EE: Effects of high oxygen on coronary flow and heart force. Am J Physiol 214:14541459,1968 10 MacKenzie GJ, Taylor SH, Flenley DC, McDonald AH, Staunton HP, Donald KW: Circulatory and respiratory studies in myocardial infarction and cardiogenic shock. Lancet 2:825-832, 1964 II Maim A, Arborelius M, Bornmyr S, Lilja B, Gill RL: Effects of oxygen on acute myocardial infarction. A thermographic study in the dog. Cardiovasc Res 11:512518, 1977 12 Neill W A: Effects of arterial hypoxemia and hyperoxia on oxygen availability for myocardial metabolism. Am J Cardiol 24: 166-171, 1969 13 Rivas F, Rembert JC, Bache RJ, Cobb FR, Greenfield JC: Effects of hyperoxia on regional blood flow after coronary occlusion in awake dogs. Am J Physiol 238:H244-H248, 1980 14 Thomas M, Malmcrona R, Shillingford J: Haemodynamic effects of oxygen in patients with acute myocardial infarction. Br Heart J 27:401-407, 1965 15 Rivas F, Cobb FR, Bache RJ, Greenfield JC Jr: Relationship between blood flow to ischemic regions and extent of

Volume 86 Number 5

Persistent myocardial ischemia 7 1 7

November. 1983

myocardial infarction. Serial measurements of blood flow to ischemic regions in dogs. Circ Res 38:439-447, 1976 16 Saltzman HA: Efficacy of oxygen enriched gas mixtures in the treatment of acute myocardial infarction. Circulation 52:357-359, 1975 17 Bloor CM, White FC: Functional development of the coronary collateral circulation during coronary artery occlusion in the conscious dog. Am J Pathol 67:483-500, 1972 18 Bloor CM: Functional significance of the coronary collateral circulation. Am J Pathol 76:562-586, 1974 19 Winer BJ: Statistical Principles in Experimental Design, New York, 1971, McGraw-Hill Book Company, Inc., pp 191-195 20 Kirk RE: Experimental Design: Procedures for the Behavioral Sciences, Monterey, Calif., 1968, Brooks/Cole Publishing Co., pp 88-90 21 Sayen JJ, Sheldon WF, Pierce G, Kuo PT: Polarographic oxygen, the epicardial electrocardiogram and muscle contraction in experimental acute regional ischemia of the left ventricle. Circ Res 6:779-798, 1958 22 Kjeckshus JK, Maroko PR, Sobel BE: Distribution of myocardial injury and its relation to epicardial STsegment changes after coronary artery occlusion in the dog, Cardiovasc Res 6:490-499, 1972 23 Maroko PR, Kjekshus JK, Sobel BE, Watanabe T, Covell JW, Ross J Jr, Braunwald E: Factors influencing infarct size following experimental coronary artery occlusion. Circulation 43:67-82, 1971 24 Heng MK, Sing BH, Norris RM, John MB, Elliott R: Relationship between epicardial ST-segment elevation and myocardial ischemic damage after experimental coronary artery occlusion in dogs. J Clin Invest 58:1317-1326, 1976 25 Irvin RG, Cobb FR: Relationship between epicardial ST-segment elevation, regional myocardial blood flow,and extent of myocardial infarction in awake dogs. Circulation 55:825-832, 1977 E, Kiil F: Relationship 26 Lekven J, I1ebekk A, F~nstelien between ST-segment elevation and local tissue flow during myocardial ischemia in dogs. Cardiovasc Res 9:627-633, 1975 27 Moss AJ, Johnson J: Effects of oxygen inhalation on intramyocardial oxygen tension. Cardiovasc Res 4:436440, 1970 28 Gregg DE: The natural history of coronary collateral development. Circ Res 35:335-344, 1974 2? Hoffman JIE: Determinants and prediction of transmural myocardial perfusion. Circulation 58:381-391, 1978 30 Bird AD, Telfer ABM: The effects of oxygen at 1 and 2 atmospheres on resting forearm blood flow: Surg Gynecol Obstet 123:260-268, 1966 31 Daly WJ, Bondurant S: Effects of oxygen breathing on the heart rate, blood pressure, and cardiac index of normal men-resting, with reactive hyperemia and after atropine. J Clin Invest 41:126-132, 1962 32 Loeb HS, Chuquimia R, Sinno MZ, Rahimtoola A,

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

Rosen K, Gunnar RM: Effects of low-flowoxygen on the hemodynamics and left ventricular function in patients with uncomplicated acute myocardial infarction. Chest 60:352-355, 1971 Ekblom B, Huot R, Stein EM, Thortensson AT: Effect of charges in arterial oxygen content on circulation and physical performance. J Appl Physiol 39:71-75, 1975 Horvat M, Yoshida S, Prakash R, Marcus HS, Swan HJC, Ganz W: Effects of oxygen breathing on pacinginduced angina pectoris and other manifestations of coronary insufficiency. Circulation 45:837-844, 1972 Weglicki WB, Rubenstein CJ, Entman ML, Thompson HK Jr, McIntosh HD: Effects of hyperbaric oxygenation on myocardial blood flow and myocardial metabolism in the dog. Am J Physiol 216:1219-1225, 1969 Guy CR, Salany JM, Eliot RS: Disorders of hemoglobinoxygen release in ischemic heart disease. Am Heart J 82:824-832, 1971 Neville JR, Clemmer T: Hemoglobin-oxygen affinity in organic heart disease. Adv Exp Med Bioi 94:443-449, 1977 Ivanov LA, Chebotarev ND: Effects of hyperoxia on oxygen transport properties of blood. Kosm Bioi Aviakosm Med 1:39-42, 1980 Hahn CEW, Foex P, Raynor CM: A development of the oxyhemoglobin dissociation curve analyzer. J Appl Physiol 41:259-267, 1976 Ganz W, Donoso R, Marcus H, Swan HJC: Coronary hemodynamics and myocardial oxygen metabolism during oxygen breathing in patients with and without coronary artery disease. Circulation 45:763-768, 1972 Kenmure ACF, Beatson JM, Cameron AJV, Horton PW: Effects of oxygen on myocardial blood flow and metabolism. Cardiovasc Res 5:483-489, 1971 Ishikawa K, Lee T, Ganz W: Effects of oxygen on perfusion and metabolism of the ischemic myocardium. J Appl Physiol 36:56-59, 1974 Sobol BJ, Wanlass SA, Joseph EB, Azarshahy I: Alterations of coronary blood flow in the dog by inhalation of 100 percent oxygen. Circ Res 11:797-802, 1962 Ishikawa K, Sarma R, Getzen JH, McNair JD, Cosby RS, Buggs H, Johnson JL, Bing RJ: Reduction of myocardial contractility by 100% oxygen in patients with coronary disease. Proc Soc Exp Bioi Med 145:99-102, 1974 Jennings RB: Myocardial ischemia. Observations, definitions, and speculations. J Mol Cell Cardiol 1:345-349, 1970 Rovetto MJ, Whitmer JT, Neely JR: Comparison of the effects of anoxia and whole heart ischemia on carbohydrate utilization in isolated working rat hearts. Circ Res 32:699-711, 1973 Williamson JR, Shaffer SW, Ford C, Safer B: The cellular basis of ischemia and infarction. Contribution of tissue acidosis to ischemic injury in the perfused rat heart. Circulation 53:Suppl 1:3-14, 1976