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Circulation. 1995;91:186-191

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(Circulation. 1995;91:186-191.)
© 1995 American Heart Association, Inc.

Impact of Acute Pulmonary Rejection on Cardiac Function

Allison J. McLarty, MD; Christopher G. A. McGregor, MB, FRCS; N. H. Shu, MD, PhD; Virginia M. Miller, PhD; Erik L. Ritman, MD, PhD

From the Department of Physiology and Biophysics and Department of Surgery, Mayo Clinic and Foundation, Rochester, Minn.

Correspondence to Erik L. Ritman, MD, PhD, Mayo Medical School, 200 First St SW, Rochester, MN 55905.


*    Abstract
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Background Experiments were designed to define cardiac function in dogs with single lung allografts during acute rejection of the allografted lung.

Methods and Results Left lungs were either autotransplanted (n=4) or allotransplanted (n=8) in adult male mongrel dogs. All allotransplanted animals were maintained on triple-drug immunosuppression (cyclosporine, azathioprine, and steroids) for 5 days after the operation. In 4 allotransplanted animals, treatment was discontinued, allowing the animals to reject (usually after a further 3 days; rejecting group); 4 other allotransplanted animals were maintained on immunosuppression for an additional 3 days (immunosuppressed group). Another group of dogs were not operated on but were maintained on the same immunosuppression as the rejecting group (controls). All experimental animals underwent fast computed tomographic scanning with measurement of left ventricular pressure and calculation of ventricular chamber volumes, cross-sectional areas of coronary arteries, myocardial perfusion, and intramyocardial blood volume. Neither cardiac output, left ventricular mass, left ventricular pressure, nor myocardial oxygen consumption was altered during acute rejection of lung allografts. However, left ventricular contractility (systolic elastance, Emax) and ejection fraction were depressed to approximately one half (P<.05) in acutely rejecting animals compared with other groups. The cross-sectional area of the coronary arteries was less in autotransplanted and allotransplanted treated animals than in animals that were not operated on. Cross-sectional area of the coronary arteries was decreased by an additional 30% in the rejecting group (P<.05).

Conclusions The results of this study indicate that acute rejection of a single lung allograft decreases cardiac performance and reduces diameter of coronary arteries in the recipient. Alterations of circulating humoral factors and activated leukocytes may contribute to these changes.


Key Words: tomography • arteries • elasticity • myocardium


*    Introduction
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Single lung transplantation is now recognized as an acceptable form of therapy for selected patients with end-stage pulmonary vascular and parenchymal disease.1 2 Acute rejection continues to be a significant problem in this group of patients despite improved immunosuppressive therapy. During acute rejection, patients suffer from unspecific symptoms such as malaise, fever, and general discomfort. These symptoms may not be related only to the malfunction of the transplanted organ. Indeed, circulating mononuclear cells activated by the rejection process3 4 5 6 and circulating cytokines7 8 may directly affect the function of organs native to the transplant recipient. Little is known of such potential systemic effects of acute pulmonary rejection. Therefore, the purpose of this study was to assess, using a canine model, cardiac function during acute rejection of lung allografts. A high-speed volume computed tomographic scanner, the dynamic spatial reconstructor (DSR), was used for these experiments.9 This method allowed for concurrent quantification of arterial geometry and estimation of myocardial perfusion and left ventricular function in dogs with minimal surgical invasion.10 11 12


*    Methods
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Experimental Design
Adult mongrel dogs of either sex matched for size and weight (22.1±1.6 kg) were used. Animal care was in compliance with the "Principles of Laboratory Animal Care" formulated by the National Society for Medical Research and the "Guide for the Care and Use of Laboratory Animals" prepared by the National Academy of Sciences and published by the National Institutes of Health (NIH publication No. 86-23, revised 1985).

The following groups of animals were studied: (1) left lung allotransplants allowed to reject (n=4; rejecting group); (2) left lung allotransplants maintained on immunosuppressive drugs (n=4; immunosuppressed group): this group served as a control for the surgical procedure and immunological responses; (3) left lung autotransplants (n=4; autotransplant group): this group served as a control for the surgical procedures without the complicating effects of immunosuppressive treatment and immunological responses; and (4) nonoperated dogs maintained on the same immunosuppression as the rejecting group (n=3; unoperated, medicated group): this group served as control for residual effects of the immunosuppressive drugs. In some experiments, unoperated, unmedicated dogs were also tested. The responses of these animals were not statistically different from the medicated control dogs, and the data were combined with this group as additional control animals (control group).

Left Lung Autotransplantation and Allotransplantation
Operative techniques have been described in detail elsewhere.13 14 University of Wisconsin solution (60 mL/kg) was used for pulmoplegia.

Immunosuppression consisted of intravenous cyclosporine (1 to 3 mg · kg-1 · d-1) to maintain plasma concentrations of 250 to 500 ng/mL (radioimmunoassay for parent compound plus metabolites) and administration of azathioprine (2.5 mg · kg-1 · d-1) beginning after induction of anesthesia. Methylprednisolone (50 mg IV) was given at 8-hour intervals for 24 hours, reduced to 0.5 mg · kg-1 · d-1 by day 3, and maintained at this dose until day 5. In the postoperative period, all dogs received gentamicin (40 mg IV) and clindamycin (300 mg IV) and benzylpenicillin (1.2 million U IM) before the operation. The gentamicin and clindamycin were repeated every 12 hours after the operation for 3 days. Animals subsequently received Bactrim DS (160 mg trimethoprim and 800 mg sulfamethoxazole) orally twice a day until the end of the experiment. All intravenous drugs were administered through a catheter placed in the jugular vein the day of operation. Chest radiography was performed at postoperative day 5. Clearing of the chest radiograph indicated resolution of the reimplantation response. At this time, immunosuppression was discontinued in animals assigned to the rejecting group. When rejection was suspected (in this group) from clinical signs, a second chest radiograph was obtained. If opacification of the transplanted lung was observed, the dogs were used for experiments (postoperative day 8). Chest radiographs were obtained in allotransplanted, immunosuppressed, and autotransplanted animals the day of the experiment (postoperative day 8). Postmortem histological confirmation of rejection was obtained and graded according to the standard Working Formulation for the Standardization of Nomenclature in the diagnosis of heart and lung rejection developed by the Lung Rejection Study Group of the International Society of Heart Transplantation.15

Dynamic Spatial Reconstructor
Details of the DSR scanner have been described elsewhere.9 Briefly, the DSR scanner consists of a rotatable cylindrical gantry housing 14 x-ray sources positioned in a semicircle. Each DSR scan involves sequential pulsing of all 14 x-ray sources within 11 milliseconds, and this sequence of exposures is repeated 60 times per second. Fourteen video cameras are arranged on the semicircle opposite the x-ray tubes. These cameras digitally record the x-ray projection images and provide input for a stack of tomographic images of parallel transverse sections at approximately 1.2-mm intervals over the full cephalocaudal extent of the thorax. All operated/treated animals were scanned on day 8 after operation or day 3 after treatment.

Scanning Technique
After induction of anesthesia with pentobarbital (90 mg) and Innovar-vet (Pitman-Moore Co) (3 mL; fentanyl 0.4 and droperidol 20 mg/mL) IV, the animal was intubated and the lungs were ventilated with a 2:1 N2O-O2 gas mixture using a constant-volume respirator (model 607, Harvard Apparatus).

Three cardiac catheters were placed intravenously: a right atrial catheter for injection of nonionic contrast agent, a coronary sinus catheter for pacing of the heart and sampling blood oxygen content, and a pulmonary artery catheter for measurement of pulmonary arterial pressures. In addition, a Millar catheter-tip transducer was positioned in the left ventricle via the left carotid artery and a catheter placed in the aortic root via the right carotid artery for the injection of contrast agent for coronary arteriography and for sampling blood to measure oxygen content. The animal was supported supine in a molded cast and positioned within the scanner so that the entire thorax could be scanned simultaneously by the DSR. The heart was paced at a rate of 112 beats per minute to eliminate the effect of different heart rates in separate scans. Each DSR study involved two scans. The first, an 18-second scan sequence, was performed during apnea with the airway open to atmosphere; 1 mL/kg of contrast was injected into the aortic root for a 3-second period beginning 4 seconds after onset of the scan sequence. The second, again of 18 seconds' duration, was initiated 4 seconds before onset of injection of 30 mL contrast medium into the right atrium over 2 seconds. The scan covered the dextro and levo phases of that angiogram. The ECG and left ventricular pressure (LVP) were recorded synchronously with the x-ray image data.

On completion of the DSR study, the animals were killed with an intravenous injection of 1000 mg pentobarbital. The left ventricle was weighed, this information being necessary for subsequent calculations. The left ventricle and both lungs were then perfused with 10% buffered formalin and fixed for at least 24 hours in preparation for histological analysis.

DSR Data Analysis and Statistical Evaluation
Evaluation of Cardiac Stroke Volume, Ejection Fraction, and Pressure-Volume Loops
The left ventricular chamber volumes at end diastole and end systole were derived by use of the reconstructed images of the left ventricular phases during the right atrial injection.16 The method of Hoffman and Ritman17 was used to estimate left ventricular stroke volume, ejection fraction, and cardiac output (CO). These data were also used to compute the pressure-volume loops of the left ventricle.12 Myocardial oxygen consumption was calculated as the difference between aortic and coronary sinus blood oxygen content multiplied by total left ventricular (LV) myocardial blood flow [(flow, mL · g-1 · min-1)xLV mass].

Evaluation of Coronary Arterial Lumen Dimensions
The image data of the aortic root injection were used to calculate myocardial perfusion,11 intramyocardial blood volume,18 and coronary artery anatomy.10 Quantification of coronary artery anatomy involved measuring the cross-sectional area (CSA) of the opacified coronary arteries at 1-mm intervals along segments of the arteries between major branches. From these data, the average CSAs were obtained for the proximal three interbranch segments of the left anterior descending and left circumflex coronary arteries. The length of each of these segments was measured. These measurements were made coincident with peak systolic pressure.

Statistical Evaluation
The mean and SEM of the measurements in each group were computed. Comparison of the intervention groups was by Student's t test, and statistical significance was noted if P<.05. Hemodynamic parameters were compared between transplant (no rejection) and control and between transplant (rejection) and transplant (no rejection). Coronary artery CSA of each artery segment was compared with spatially comparable segment of the control group with significance determined for P<.05.


*    Results
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All animals that received transplants were clinically well at postoperative day 5, with clear chest radiographs. On postoperative day 8, all animals in the rejecting group had radiographic opacification of the transplanted lung. Histologically, three animals in the rejecting group had grade 3 rejection (borderline severe) and one, grade 4 rejection (severe). In the immunosuppressed group, chest radiographs were clear on postoperative day 8. However, one animal had histological grade 3 rejection, two had grade 2 (mild), and one had grade 0 (no rejection). All animals in the autotransplant group—unoperated, medicated control, and controls—had clear chest radiographs and were negative for pulmonary pathology. The weight of the animals did not differ significantly among groups (range, 20 to 30 kg). Arterial blood oxygen content and percent saturation were not statistically different for the groups relative to control. Myocardial perfusion and oxygen consumption (mO2) also were not statistically different among groups. Experimental results from each animal are summarized in Tables 1Down and 2Down.


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  		Table 1. Indexes of Left Ventricular Function


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  		Table 2. Geometry of Proximal Epicardial Coronary Arteries

Left Ventricular Performance
Left ventricular performance was measured by LVP, CO, left ventricular ejection fraction (LVEF), and contractility by means of systolic elastance (Emax). Neither ventricular mass, CO, nor LVPs (systolic and diastolic) were altered significantly with rejection of lung allografts. However, LVEF and Emax were decreased significantly with autotransplantation (Fig 1Down). With rejection, these parameters were reduced further to approximately half the control value (Fig 1Down). There were no statistically significant differences in any of the parameters measured between autotransplanted animals and allotransplanted, nonrejecting animals.



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  		Figure 1. Bar graph showing summary of ventricular function data. Control group includes unoperated dogs with and without antirejection medication. Transplant group includes autotransplanted and immunosuppressed allotransplanted animals. Rejection group includes the allotransplanted dogs that were allowed to reject. Emax indicates left ventricular systolic elastance; CO, cardiac output; LVEF, left ventricular ejection fraction; and LVP, LV systolic pressure. P value between indicated bar and the preceding bar.

Coronary Arterial Size
The CSAs of three sequential segments in each of the left anterior descending and left circumflex coronary arteries are summarized in Table 2Up.

CSAs of both left anterior descending and circumflex coronary arteries decreased with increasing distance from the aorta in all groups (Fig 2Down). With both autotransplantation and allotransplantation in the absence of rejection, CSA was reduced significantly compared with animals that did not receive transplants. Rejection caused an additional and significant decrease in CSA of left anterior descending and circumflex arterial segments (Fig 2Down).



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  		Figure 2. Graph showing that coronary artery cross-sectional area (CSA) decreases stepwise with each bifurcation (ie, distance) from the aortic origin. This CSA-to-distance relation is depressed with transplantation without ejection and is further depressed with transplant rejection. LAD indicates left anterior descending coronary artery; LCX, left circumflex artery.


*    Discussion
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*Discussion
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The results of the present study identify functional changes of an organ not directly undergoing rejection, that is, the heart of the lung transplant recipient. Nonrejecting, and more so, rejecting, allotransplantation of a single lung results in decrease of LVEF and of left ventricular Emax. Since no decrease in myocardial perfusion was observed with transplantation or rejection, the cause of the depressed myocardial function could be insufficient oxygen delivery (ie, flowxvol% oxygen) due to the depressed arterial oxygen pressure and content. If the myocardium functioned normally, hypoxemia would result in increased coronary flow so that oxygen delivery would remain at the normal level. This increased coronary flow would result from intramyocardial microvascular vasodilation. Such vasodilation should result in increased intramyocardial blood volume ({rho}), but this was not observed; in fact, a decrease in {rho} was observed. There is also the possibility that the epicardial vessels restrict flow to the myocardium. This is very unlikely because major epicardial vessels decreased their CSAs by an amount (to {approx}70% of control) that is not likely to restrict the increased blood flow needed to maintain adequate oxygen delivery. Such restriction of flow would be expected to occur only when cross-sectional narrowing to <50% is present. Consequently, we are left with the conclusion that the observed decrease in intramyocardial blood volume represents a primary decrease of CSA of the microcirculatory vessels in the myocardium and/or a decrease in myocardial demand for oxygen. That the microcirculation behaves abnormally, and thus may be the causal agent in the depressed ventricular function, is suggested by the observation that the normal relation of intramyocardial blood volume ({rho}) to flow (F) is altered. Thus, in the unoperated group, the relation {rho}=10.4F1/2 is observed, which is consistent with the previously observed18 normal relation of {rho}=9.5F1/2. In the nonrejecting transplanted animals, this becomes {rho}=7.4F1/2, and in the rejecting transplant group, it becomes {rho}=5.8F1/2. Thus, we can conclude that, secondary to the restricted microvascular vessel size, less oxygen (and blood flow) reaches the myocardium than would normally be expected and this, in turn, could result in depressed myocardial function. The myocardium may, in addition, be depressed independent of the microvascular component, but our experimental measurements cannot answer this question.

Interruption or damage to autonomic innervation to the heart during the lung transplant procedure may contribute in part to the changes in ventricular and coronary arterial function. This conclusion is supported by the observations that the parameters were decreased in both autotransplanted and immunosuppressed, allotransplanted animals compared with animals that had not been operated on. However, during acute rejection, there was a further decrease in ventricular function and cross section of the coronary arteries. These results suggest that in addition to denervation, humoral factors associated with the rejection process contribute to the changes in cardiac function. For example, circulating leukocytes activated by the rejection process can damage endothelial cells,7 19 possibly through increased production of oxygen-derived free radicals20 or other cytokines, including endothelin, which has cardiac effects.19 21 22 23 24 25 26 Oxygen-derived radicals can cause contraction of arteries through mechanisms that may be endothelium-dependent, including inactivation of endothelium-derived relaxing factors.27 28

The lung is important in metabolism of biologically active substances.29 30 Therefore, an alternative cause of the changes in cardiac function may reflect the loss of the metabolic capacity of the rejecting lung. During rejection, circulating levels of angiotensin-converting enzyme are decreased.13 The origin of circulating converting enzyme and the biological significance of this observation are not clear at this time. However, the observation supports the conclusion that a rejecting lung could result in alterations of systemic organs indirectly through changes in blood chemistry.

Immunosuppressive therapy alone may alter vascular and cardiac function. Cyclosporine may reduce endothelium-dependent relaxations,31 32 33 stimulate production of endothelin-1,34 alter expression of receptors for endothelin on cardiac myocytes,35 and alter cardiac contractility directly and indirectly through changes in endothelin.36 Steroids may inhibit induction of the inducible form of nitric oxide synthase.37 38 CSA of the coronary arteries and ventricular function were the same between autotransplanted animals and allotransplanted animals maintained on immunosuppression. Comparison of these groups controls for the effects of immunosuppression and suggests that the immunosuppressive therapy was not a causal factor in the functional changes observed. The immunosuppressed group still showed histological signs of rejection despite clear chest radiographs. These data suggest that histological assessment of rejection may not reflect functional activation of the infiltrating cells.

In conclusion, the results of this study suggest that circulating factors associated with rejection have the potential to alter function of organs native to the transplant recipient.

Received April 28, 1994; accepted July 31, 1994.


*    References
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 up arrowIntroduction
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*References
 

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