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Eur J Cardiothorac Surg 2001;19:74-81
© 2001 Elsevier Science NL

Comparison of myocardial oxygen consumption using 11C acetate positron emission tomography scanning in a working and non-working heart transplant model

Kenton J. Zehra, Ching Y. Wongb, Bennet Chinb, Hayden T. Raverta, Robert F. Dannalsb, Ralph H. Hrubanc, Dean F. Wongb, William A. Baumgartnera

a Department of Cardiac Surgery, Johns Hopkins Medical Institution, Baltimore, MD 21287, USA
b Department of Nuclear Medicine, Johns Hopkins Medical Institution, Baltimore, MD 21287, USA
c Department of Pathology, Johns Hopkins Medical Institution, Baltimore, MD 21287, USA

Received 12 January 2000; received in revised form 2 October 2000; accepted 30 October 2000.

Corresponding author. Division of Thoracic and Cardiovascular Surgery, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. Tel.: +1-507-255-2034; fax: +1-507-255-7378
e-mail: zehr.kenton{at}mayo.edu


   Abstract
Top
 Abstract
1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 References
 
Objective: In acute cardiac rejection, changes in myocardial oxygen consumption occur; non-invasive detection of these metabolic changes would have obvious clinical utility. In the classic cervical, heterotopic, canine, transplant model, the heart is non-working. It has a low myocardial oxygen consumption. Creation of a working model with normal myocardial oxygen consumption would enhance validity of non-human studies. Methods: Clearance of 11C acetate was determined by positron emission tomography (PET) scanning and compared with myocardial oxygen consumption in normal and transplanted canine hearts. Donor hearts from mongrel dogs (2.5–3 kg; n=4) were transplanted into the neck of adult beagles (12–15 kg; n=4), no immunosuppression was given. Two non-working hearts were modified to eject only coronary flow via the right ventricle. In two hearts, a novel working model was created with aortic regurgitation to load the left ventricle. Working and non-working hearts underwent PET scanning on post-operative days 2 and 4. Normal dog hearts (n=2) and native hearts of transplanted dogs (n=3) were used to validate the scanning technique. Coronary sinus and aortic oxygen saturation data along with myocardial blood flow (radiolabeled microspheres) confirmed that clearance of 11C acetate in normal and transplanted hearts followed a bi-exponential model. Results: Myocardial oxygen consumption was correlated with the rate constant of 11C acetate rapid phase clearance (r=0.91) in normal and transplanted hearts. The working hearts had increased myocardial oxygen consumption compared to non-working hearts. Conclusions: This study (1) introduces a model of a working heterotopic cardiac transplantation with near-normal oxygen consumption; and (2) demonstrates that regional myocardial oxygen consumption in transplanted hearts can be detected by 11C acetate PET.

Key Words: Positron emission tomography scan • Cardiac transplantation • Myocardial oxygen consumption • Acute rejection


   1. Introduction
Top
 Abstract
 1. Introduction
2. Materials and methods
 3. Results
 4. Discussion
 References
 
In acute cardiac rejection, certain metabolic abnormalities are present. Non-invasive detection of these changes would have obvious clinical utility. Early reproducible decreases in the phosphocreatine to inorganic phosphate ratio been demonstrated using nuclear magnetic resonance imaging (NMR) [1,2]. NMR 31P has been shown to be a reproducible and sensitive way of in vivo evaluation of the global energy state [3,4]. This technique is limited because intermediate molecules of glycolysis and the tricarboxylic acid (TCA) cycle lack high concentrations of phosphorylated compounds. It is in these pathways that metabolic changes associated with graft ischemia and rejection are thought to first occur. Use of 13C NMR can give information of glucose supported flux through the TCA cycle but cannot differentiate aerobic and anaerobic metabolism [5–7]. Metabolism in the TCA cycle is closely associated with oxidative metabolism in myocardium. The positron emitting isotope 11C acetate can be used to trace TCA cycle flux with close correlation to oxygen consumption over varying physiological conditions regardless of substrate [8–10]. PET may provide a non-invasive means of measuring regional myocardial oxygen consumption (MVO2) to more precisely determine and localize metabolic derangements associated with rejection. These early changes may or may not be detectable by histological analysis.

Several models have been developed to study rejection in the myocardium. Most notable is the heterotopic intraabdominal or cervical rat heart transplant [11]. This model does minimal work resulting in non-physiological energy metabolism. Experimental, orthotopic, cardiac, transplant models have limitations of difficult operative and post-operative management. Interference from chest wall musculature precludes accurate data analysis in the case of NMR and left ventricular biopsy. The canine heterotopic cervical model described by Carrel has been valuable in providing a readily accessible, superficial, transplanted heart. This non-working model proved valuable in detailing global metabolic changes in phosphorus metabolism using NMR. A working heart model is necessary to accurately detail oxygen consumption changes in rejecting myocardium.

The objectives of this study were (1) to introduce a model of a working, heterotopic, canine heart transplant by modification of Carrel's model; (2) to measure myocardial oxygen consumption (MVO2) non-invasively using 11C acetate positron emission tomography (PET) scanning under varying physiological conditions in normal and transplanted hearts.


   2. Materials and methods
Top
 Abstract
 1. Introduction
 2. Materials and methods
3. Results
 4. Discussion
 References
 
2.1. Surgical procedure
The experimental animal models used were two modifications of the heterotopic canine cardiac transplant as described by Carrel. Mongrel outbred puppy hearts (animal weight 3–4 kg) were placed in a cervical subplatysmal position of adult beagles (12–15 kg). In the non-working model (NW) (n=2) the superior and inferior vena cavae and pulmonary veins were ligated. The mitral valve was rendered incompetent by cutting the chordae tendineae and an atrial septostomy was performed. Blood flow to the heart was via the coronary arteries with subsequent drainage into the right atrium via the coronary sinus and eventual ejection through the pulmonary artery (Fig. 1a). In the working model (W) (n=2) the non-coronary cusp of the aortic valve was made incompetent by perforation. A small cruciate incision (3x3 mm) was made in the center of the cusp with an 11-blade. This allowed the left ventricle to fill. The mitral valve and atrial septum were left intact and the inflow vessels to the right and left atria were ligated (Fig. 1b). These modifications of the NW were made to allow myocardial oxygen consumption and substrate utilization of the left ventricle to approach normality.



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  		Fig. 1. (a) Drawing of the heterotopic non working heart model. Note the adaptation by disruption of the chordae tendineae of the mitral valve and creation of an atrial septostomy. The vena cavae and pulmonary veins are ligated. The aortic root is oversewn. The tricuspid valve remains intact. (b) Drawing of the heterotopic working heart model. Note the adaptation by creation of a 3 mm hole in the non-coronary cusp of the aortic valve. The vena cava and pulmonary veins are ligated. The aortic root is oversewn. The tricuspid and mitral valves remain intact.

 
General anesthesia was induced in donors and recipients with sodium pentobarbital (15–20 mg/kg i.v.). Ventilation was supported by a volume cycle ventilator (20 cm3/kg). A median sternotomy was performed and the donor heparinized (150 units/kg). The donor heart was arrested by infusion of cold (4°C) potassium cardioplegic solution (15 ml/kg) into the aortic root. The heart was excised and the above modifications made. The aorta was oversewn distal to the innominate artery and a silastic catheter inserted into the coronary sinus through the right atrial appendage for blood sampling. The heart was kept cold by 4°C topical saline until reperfusion.

The recipient's left neck vessels were isolated and the dog heparinized (150 units/kg). The donor heart was transplanted into the recipient by anastomosis of the donor innominate artery to the recipient carotid artery in an end-to-side fashion and the donor pulmonary artery to the recipient external jugular vein in an end-to-end fashion. After reperfusion and defibrillation, hemostasis was obtained and the skin flap closed over the graft.

Prior to scanning, each dog was anesthetized, intubated, and ventilated (20 ml/kg) at an FiO2 of 1. Femoral arterial and venous cannulation were performed for monitoring and blood sampling. A left ventricular pigtail catheter and a coronary sinus catheter were placed percutaneously under fluoroscopic guidance. After scanning, the dogs were sacrificed and transplanted and native hearts harvested. Animals used were treated in accordance 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 (NIH publication 86–23, revised 1985).

2.2. Experimental and PET scanning procedure
As previously described, 11C acetate was prepared by the 14N (p,a) reaction [12]. Confirmation of radioactive purity was determined by high phase liquid chromatography and >98% purity was achieved. PET scanning was performed with the dogs in a supine position cradled in a plexiglass trough inserted within the circular rings of detectors in a General Electric 4096 (+) PET tomograph. Seven slices were simultaneously acquired over a total axial field of 11 cm using circularly arrayed detectors. Attenuation of radiation within the animal’s chest was evaluated with a ring source of germanium-68. Serial tomograms were obtained every minute for 40 min after injection. Six half-lives were allowed for 11C acetate decay between scans.

PET scan studies (n=12 scans) following injection of 1.0–1.5 mCi/kg 11C acetate were done in five normal hearts under resting (three) or stress (two) physiologic conditions; four non-immunosuppressed heterotopic transplants (2 W and 2 NW on PODs 2 and 4); and three recipient native hearts (Table 1). Stress conditions were produced by titration of dobutamine or norepinephrine to a target systolic blood pressure of 200 mmHg.


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  		Table 1. MVO2, Kr, and flow dataa

 
Polygonal regions of interest (ROI) were used to generate counts/min from the PET images in ventricular slices of mid-ventricle, septum, apex and lateral wall. Bi-exponential curve fitting was done by computer using Marquardt’s non-linear least squares algorithms from the decay-corrected data. Corrections for partial volume effect, spillover, and metabolites were not performed. Previous validation studies have shown good correlations of Kr with oxygen consumption without these corrections [9]. The general formula is: f(t)=alxexp (-11xt)+a2xexp (l2xt). The rapid phase rate constants, Kr=max (l1l2), were used to correlate with MVO2.

Blood pressure and heart rate were monitored throughout the scanning phase by arterial line and telemetry, respectively. The rate pressure product (RPP)=systolic blood pressurexheart rate. To insure steady state conditions, pre-scan and post-scan blood gases were obtained from the coronary sinus, central venous catheter, and left ventricle. Calculation of oxygen consumption (MVO2 in mmolxmin/g) was done using the methods of Steveringhaus et al. [13] from direct measurement of PaO2 in mmHg with correction for Hgb, pH, and temperature. Oxygen consumption was calculated: MVO2=flowxO2 content (a-v).

CO2 efflux was measured in two studies as described previously [8]. Simultaneous blood samples were collected from the left ventricle and coronary sinus simultaneously at 10, 20, 40, 60, 90, and 120 s, then at 1 min intervals for 14 min, then at 2 min intervals to the end of the scan at 40 min. The samples were divided in two and treated with either isopropyl alcohol and HCl, or NaHCO3 and NaOH. Each sample was heated in an ultrasonic bath (85°C) for 10 min. Activity was assessed in a gamma well counter with correction for decay. Activity of 11C CO2=total-non-CO2 (activity in NaOH treated-activity in HCI treated).

Cardiac blood flow was measured by standard radionuclide microsphere technique [14]. Injection into the left ventricle of 153Gd and 113Sn 15 micron microspheres took place just prior to each scan and blood withdrawn by Harvard pump from the femoral artery at a rate of 2 ml/min for 6 min. Blood flow was calculated as flow (ml/min per g of myocardium)=2 ml/minxmyocardial activity, activity in Harvard pumpxg weight with correction for down-scatter. Activity and consequently flow were determined in lateral, anterior, posterior, and septal walls of the left ventricle in 1 cm sections from base to apex. Activity was measured in a multichannel well counter.


   3. Results
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
4. Discussion
 References
 
3.1. Overall
The rapid phase rate constants (Kr) of clearance of 11C acetate for all hearts pooled together was correlated (r=0.91) with measured myocardial oxygen consumption (MVO2) (Fig. 2). A mid-ventricular slice was used for this correlation. When Kr from lateral, septal, and apical left ventricular regions were plotted with MVO2 corresponding to the same region, the r-value was 0.78 (Fig. 3).



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  		Fig. 2. Correlation between measured MVO2 and rate constant (Kr) of the rapid phase of 11C acetate myocardial turnover. This midventricular slice data represents global oxygen consumption.

 


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  		Fig. 3. Correlation between measured MVO2 and rate constant (Kr) of the rapid phase of 11C acetate myocardial turnover using regional data from apex, septum, and lateral wall of the left ventricle.

 
3.2. Normal and native hearts at rest (n=3)
The MVO2 of intrathoracic hearts from both normal and transplanted dogs ranged from 0.82±0.03 to 1.83±0.014 mmol/g per min.

3.3. Normal hearts under stress conditions (n=2)
The stress conditions using dobutamine (n=1) and norepinephrine (n=1) resulted in mean RPP's of 24 000 mmHg/beats per min and 18 500 mm/Hg.beats per min, respectively. This resulted in a marked increase in MVO2 to 4.36 and 5.47 mmol/g/min (Figs. 2 and 3).

3.4. Non-working transplants on post-operative days 2 (n=1) and 4 (n=1)
The non-working transplants were found to have similar MVO2 and Kr values compared to hearts at rest (Figs. 2 and 3).

3.5. Working transplants on post-operative days 2 (n=1) and 4 (n=1)
Surgical modifications to load the left ventricle resulted in a marked increase in measured MVO2. Augmentation of the arterial pressure tracing by the cervical heterotopic heart as measured by a femoral arterial line was observed. MVO2 was 2.26 mmol/g/min on POD 2 and 3.34 mmol/g/min on POD 4, Kr correlated with measured MVO2 both regionally and using mid-ventricular slice representation (Figs. 2 and 3). The working transplant model PET scan appearance was similar to the pattern of MVO2 of the intrathoracic hearts (Fig. 4).



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  		Fig. 4. PET scan of midsection of working transplanted heart in the cervical location post-operative day 2. MVO2 increases from red to yellow to white.

 
3.6. Histology
At POD 2 rejection (ISHLT scale 0–4) was grade 4 in the NW heart and 1B in the W heart in all evaluated regions (right ventricle, septum, mid, and lateral free wall of the left ventricle). The grade 4 dog had significant global ischemic changes, which created confusion in determination of rejection. Because there were no regional variations, correlation with PET data was uninformative. In the POD 4 transplants, there were variations in the histologic rejection grades from 1B to 3B in the NW heart and from 2 to 3B in the working heart. Kr from right and left ventricle regions were correlated by Spearman rank testing with corresponding histologic rejection grade on POD 4 (r=0.95, P=0.01) (Table 2). Higher rejection grade was associated with decreased MVO2 within the same allograft.


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  		Table 2. Rejection grade versus Kr on postoperative day 4a

 
3.7. CO2 efflux
CO2 efflux was measured in one normal dog at baseline conditions to provide additional confirmation that peak efflux was associated with the time of maximal decline in the myocardial radioactivity. The efflux declined in a mono-exponential fashion as a function of time and the rate constant was estimated by least squares analysis. Peak efflux was at approximately 5 min post injection of 11C acetate (Fig. 5). Correlation between the rate constant of CO2 efflux and Kr was close.



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  		Fig. 5. Measured CO2 efflux.

 
3.8. Flow analysis
Regional flow measured by radiolabeled microsphere technique was within expected physiological values. Coronary blood flow compromise was not observed in any region (Table 1).

3.9. Rate-pressure products
RPP's correlated (r=0.88) with Kr in normal and native hearts (Fig. 6). RPP's could not be determined in transplants because the pressure generated to open the aortic valve is unknown due to beat to beat temporal variability in relation to the heart rate of the recipient dogs.



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  		Fig. 6. Correlation between rate-pressure products and Kr.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
References
 
Use is made of 11C acetate as a tracer for myocardial oxygen consumption. It is readily taken up by myocardium and cleared bi-exponentially. Brown et al. [8] and Henes et al. [17] have shown increased tissue clearance in increased workload conditions. The Kr have been shown to be decreased in ischemic conditions and in infarcted areas of myocardium [9,15,16]. Metabolism of acetyl CoA is tightly coupled with oxygen utilization in the TCA cycle. Glycolytic flux as well as lactate metabolism drive the cycle via pyruvate and fatty acid metabolism via acyl CoA with nearly identical mole ratios of O2 utilized per acetyl CoA. There is only a 4% difference in mole ratios between these substrates. The conversion of pyruvate to acetyl CoA is essentially irreversible and only 1% of acetyl CoA is incorporated into fatty acids by de novo synthesis or chain elongation. Thus, following 11C acetate within the TCA cycle closely correlates with mitochondrial oxidative flux. Brown et al. [10] tested this hypothesis by infusion of either glucose or Intralipid to alter substrate utilization in normal canines. They found estimates of MVO2 by 11C acetate PET scanning were valid despite these substrate variations.

One of the goals of this study was to validate the technique of MVO2 determination by comparison of clearance of 11C acetate with the measured MVO2 in transplanted hearts. There was a correlation between invasive and non-invasive measurements of MVO2 under various physiological conditions (r=0.91) in normal and transplanted hearts. The data points were measured over a variety of physiological conditions, resting versus stress and working versus non-working transplants. This wide range of oxygen utilization improved the correlation. Without the data from the stressed hearts, the correlation would have been less. Despite the trend, without more data points, the Kr values can not conclusively discriminate the difference between the working and non-working hearts and variations in regional MVO2. However, our results corroborate those by Brown et al. [9] in normal canines and Armbrecht et al. [18] in normal humans. Those studies found similar bi-exponential curves of 11C acetate clearance with close correlation of the rapid phase constant to MVO2 (r=0.95 and 0.90, respectively). Regional variations in MVO2 consumption also paralleled Kr measured in the same areas. Brown et al. [8] measured regional changes with close correlation. Rate pressure products have been found to closely parallel MVO2. We found this to be additional confirmatory data in normal and native hearts (r=0.88). Rate pressure products were not calculated in heart transplants because of the inability to estimate the pressure generated at the aortic valve.

This study shows that the correlation between Kr and measured MVO2 was similar for the transplanted hearts. Regional Kr variations were more marked within the transplanted hearts than either native or normal hearts. The range was most pronounced in the working hearts. The wider regional differences in the Kr of the transplanted hearts and particularly the working model hearts could be explained by heterogeneous rejection. However, the transplanted hearts were protected by crystalloid cardioplegia and topical cold during the transplantation procedure. It is well known that quality of protection varies depending on adequacy of cardioplegia perfusion and homogeneous application of the topical cold. The variations in Kr could be explained by areas of ischemia caused by incomplete myocardial protection. Both explanations would explain our results. In the NW POD 2 dog (Table 1) the Kr and MVO2 is low despite having supraphysiologic coronary blood flow.

The regional variations were not as pronounced by directly measured MVO2. These regional values were derived by extrapolation from global myocardial MVO2 utilizing regional flow as a dependent variable. This results in shifting the lower and higher oxygen utilization regions toward the mean. Thus directly measured 11C acetate clearance is likely more sensitive in depicting regional differences.

We speculate that acutely rejecting regions shift toward anaerobic metabolism and production of lactate while non-rejecting areas increase oxygen consumption compensate for their increased work load. There was a rank association between worse acute rejection by histological grade at POD 4 and decreased Kr within the same region. However, the data are too few to make any definitive statement. Duboc et al. [19] and Abastado et al. [20] showed a lower rate of NADH re-oxidation in mitochondria in rat allografts vs. isografts on POD 6 after a brief ischemic stress. This was done in a heterotopic non-working model. This suggested either decreased oxygen delivery or decreased utilization at a mitochondrial level. Salomon et al. [21] and Reemstma et al. [22] showed coronary blood flow is relatively stable over the course of acute rejection and parallels cardiac output. These studies were confirmed by quantitative PET studies by Krivokapich et al. [23] We also found no significant changes in regional flow. Thus, the metabolic changes likely account for the regional variations in oxygen utilization.

Fraser et al. [1] showed early measurable decreases in high energy phosphate stores in canine allografts. The mean ratios of PCr/Pi and PCr/b-ATP decreased steadily with a >25% reduction by POD 2 and >50% reduction by day 3. Canby et al. [4] found similar differences with high energy to low energy phosphate ratios remaining stable in isografts whereas in allografts these ratios manifested significant changes starting at post-transplantation day 4 compared to day 2. They also noted a shift toward intracellular acidosis in allografts implying anaerobic metabolism in postoperative day 4 hearts.

The goal to modify the Carrel model by creating an aortic regurgitant lesion to load the left ventricle was realized in this study. The working transplanted hearts consumed more O2 than heterotopic non-working transplants. They also had greater MVO2 than normal and native hearts and higher Krs. In this model, the small transplanted hearts eject blood into an adult beagle's carotid artery. In fact, the ejection can be observed as an augmented pressure bump on the femoral artery pressure trace of the recipient animals. The increased afterload is likely responsible for the high MVO2 observed. Altering the size of the regurgitant lesion in the non-coronary aortic valve cusp would result in varying workloads on the left ventricle. These hearts could be readily assessable to NMR imaging because of the lack of interfering overlying musculature. This would allow for 31P NMR correlative studies. Repeated biopsies under direct vision can be obtained by opening the cervical skin flap. This model may prove useful for analysis of the metabolic flux of other substrates during acute rejection.

This study confirms that 11C acetate PET scanning can be used to noninvasively assess MVO2 in an experimental cardiac transplantation model. Clearance of 11C acetate followed bi-exponential kinetics under a wide range of conditions in normal and transplanted hearts, both working and non-working. Further studies using serial PET scanning in larger experimental groups are necessary.


   References
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 References
 

  1. Fraser C.D., Jr., Chacko V.P., Jacobus W.E., Soulen R.L., Hutchins G.M., Reitz B.A., Baumgartner W.A. Metabolic changes preceding functional and morphologic indices of rejection in heterotopic cardiac allografts. Transplantation 1988;46:346-351.[Medline]
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  19. Duboc D., Abastado P., Muffat-Joly M., Perrier P., Toussaint M., Marsac C., Francois D., Lavergne T., Pocidalo J.J., Guerin F. Evidence of mitochondrial impairment during cardiac allograft rejection. Transplantation 1990;50:751-755.[Medline]
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