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Ann Thorac Surg 1997;63:806-813
© 1997 The Society of Thoracic Surgeons
Division of Cardiovascular and Thoracic Surgery, Department of Surgery, Duke University Medical Center, Durham, North Carolina
Accepted for publication October 28, 1996.
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Abstract |
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 TopFootnotes Abstract IntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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Methods. Animals underwent pulmonary artery catheterization to measure right heart pressures before and 8 weeks after injection of either 3 mg/kg of monocrotaline pyrrole (n = 8) or placebo (n = 8). Eight weeks after injection, hearts underwent instrumentation with an ultrasonic flow probe and micromanometers. Harmonic derivation of functional data was achieved with Fourier analysis.
Results. Significant increases in mean pulmonary artery pressure and pulmonary vascular resistance were observed after monocrotaline pyrrole injection. There was no significant difference in pulmonary blood flow. However, significant increases in input resistance and right ventricular hydraulic power with significant decreases in transpulmonary efficiency were observed.
Conclusions. Pulmonary hypertension causes significant alterations in pulmonary hemodynamics. Pulmonary blood flow is maintained by a significant increase in total power but with a significant decrease in transpulmonary efficiency. This adult canine model of pulmonary hypertension provides a useful means by which to evaluate surgical options of lung transplantation for improving pulmonary hemodynamics in the setting of chronic pulmonary hypertension.
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Introduction |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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Attempts to gain further understanding of both the short-term and long-term hemodynamic effects of the different surgical options for pulmonary hypertension in an experimental setting have been limited by lack of an appropriate large-animal model of chronic pulmonary hypertension. Further, assessment of pulmonary hemodynamics has traditionally been done with the measurement and comparison of pulmonary vascular resistance, which is reported to decrease after lung transplantation for chronic pulmonary hypertension. However, pulmonary vascular resistance is a general measure of resistance across the entire pulmonary circulation and does not give a quantitative profile of the vasculature at each level. This study was designed to characterize the changes in pulmonary hemodynamics occurring in the setting of chronic pulmonary hypertension using an adult canine model of monocrotaline pyrrole–induced chronic pulmonary hypertension [1] and Fourier analysis for assessment of the pulmonary vascular impedance spectrum.
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Material and Methods |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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Anesthesia, Hemodynamic Monitoring, and Monocrotaline Pyrrole Injection
All animals were anesthetized with 5 mg/kg of intravenous sodium thiopental (Gensia Laboratories, Irvine, CA) and 20 mg/kg of intramuscular ketamine sodium (Fort Dodge Laboratories, Fort Dodge, IA) before all studies, including drug injections and baseline and follow-up hemodynamic measurements. Each animal also received 900,000 units of penicillin G benzathine and penicillin G procaine (Fort Dodge Laboratories). All animals were intubated with a 9F endotracheal tube and mechanically ventilated with a Bear 1 ventilator (Inter Med; Bear Medical Systems, Inc, Riverside, CA). The tidal volume was set at 15 mL/kg, the fraction of inspired oxygen at 21%, and the rate at 10 breaths/min. Arterial blood samples were drawn from the right femoral artery and processed using a Gem-Stat blood gas analyzer (Mallinckrodt Sensor Systems, Ann Arbor, MI).
All hemodynamic measurements and drug injections were done under sterile conditions. For each animal, an 8.5F introducer sheath (Baxter Healthcare, Irvine, CA) was placed percutaneously into the external jugular vein using the Seldinger technique. A 5F Swan-Ganz catheter (Baxter Healthcare) was then advanced through the introducer sheath into the right atrium, the right ventricle, and the pulmonary artery for measuring right atrial, right ventricular, and pulmonary artery pressures, respectively. All pressures were measured by a Horizon 2000 hemodynamic monitor (Mennen Medical Inc, Clarence, NY). Hemodynamic measurements were done at baseline and 8 weeks after injection. Monocrotaline pyrrole or placebo was injected into the right atrium after measurement of baseline pulmonary hemodynamics.
After instrumentation and collection of functional data, all animals were euthanized with an overdose of thiopental and KCl.
Instrumentation for Assessment of Cardiopulmonary Function
A standard median sternotomy and an anterior pericardiotomy were performed to expose the heart in every animal. An ultrasonic flow probe (T208X; Transonic Systems Inc, Ithaca, NY) was placed around the pulmonary trunk to measure pulmonary blood flow. Micromanometers (MPC-500; Millar Instruments Inc, Houston, TX) were placed into the right ventricle, the pulmonary artery, and the left atrium for continuous pressure recording of right ventricular pressure, pulmonary artery pressure, and left atrial pressure, respectively (Fig 1
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Fourier Analysis
Calculation of the impedance spectrum of the pulmonary circulation from the collected raw data was done with Fourier analysis. Fourier analysis is based on the principle that all periodic waveforms can be broken down into a series of pure sine waves or harmonics [4]. Harmonics exist at frequencies that are multiples of the frequency of the original waveform ("the fundamental frequency") and are described in terms of an amplitude and phase. Each harmonic represents an oscillatory component of the original waveform at its respective frequency. The net effect of Fourier analysis is to transform a waveform from the time domain, ie, described as a function of time, to the frequency domain, where the waveform is described as a function of frequency.
The pulsatile waveforms of pulmonary artery pressure and flow can be treated as periodic waveforms possessing a fundamental frequency (ie, the heart rate). At each individual harmonic, division of the pressure amplitude by the flow amplitude gives the oscillatory counterpart of resistance, impedance, at that respective harmonic. The array of individually calculated impedance values from every harmonic represents the impedance spectrum. Input resistance (RIN) is the impedance calculated at the zeroth harmonic and is a measure of resistance to mean pulmonary blood flow. Characteristic impedance (Zo) is estimated as the mean impedance between 2 and 12 Hz and is a measure of resistance to pulsatile blood flow. In theoretic terms, Zo is an index of the overall distensibility or stiffness of the pulmonary vascular bed.
The product of the impedance amplitude, the square of the flow amplitude, and the cosine of the impedance phase angle for each individual harmonic gives the individual power at that particular harmonic. These products across all harmonics constitute the power spectrum, which represents the amount of energy, or hydraulic power, produced by the right ventricle necessary to maintain pulmonary blood flow, and are expressed as follows:
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where Qo presents the flow amplitude, Z represents the impedance amplitude, and 
represents the impedance phase angle. Hydraulic power can be divided into two components: steady power and oscillatory power. Steady power is the power obtained at the zeroth harmonic and represents the energy required to move blood forward at a steady rate. Oscillatory power is taken from the remainder of the power spectrum exclusive of the zeroth harmonic and reflects the energy wasted in oscillatory acceleration of the blood and eventually disseminating into the vessel walls.
Transpulmonary efficiency was defined as the ratio of mean pulmonary blood flow divided by right ventricular hydraulic power. Pulmonary vascular resistance was calculated by the standard formula applying mean pulmonary artery pressure, left atrial pressure, and cardiac output.
Lung Biopsies
Generous 1.5- to 2-g peripheral lung tissue samples were taken from the right upper lung lobe of all animals after instrumentation and later analyzed using light microscopy. Hematoxylin and eosin–stained sections were used to assess the pulmonary parenchyma in all biopsy samples. To calculate percent water content, additional pulmonary samples from each animal were weighed, placed in a 120°C oven, and dried for 24 hours. The dry weight of each tissue sample was weighed as well. Percent of tissue water content was calculated from the following equation: Percent water = (wet weight - dry weight) · 100%/wet weight
Humane Animal Care
All animals received humane care 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" published by the National Institutes of Health (NIH publication 85-23, revised 1985). The experiments were approved by the Duke University Institutional Animal Care and Use Committee (DUIACUC Assigned Registry No. A621-95-9R1).
Statistical Analysis
Statistical analysis was performed on a Dell personal computer using commercially available software (SigmaStat V1.0; Jandel Corp, San Rafael, CA). Data taken before and after injection of monocrotaline pyrrole within the MCTP group was analyzed with standard two-tailed paired Student's t tests. Unpaired Student's t tests were used to analyze data between the CTL and MCTP groups. The results are expressed as the mean ± the standard error of the mean. A difference was considered significant at a p value of less than 0.05.
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Results |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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Hemodynamic Changes Before and After Monocrotaline Pyrrole Injection
Significant increases in mean right ventricular pressure and mean pulmonary artery pressure were observed in the MCTP group after monocrotaline pyrrole treatment compared with baseline (8.25 ± 0.49 mm Hg to 13.08 ± 0.57 mm Hg and 9.71 ± 0.62 mm Hg to 20.08 ± 1.10 mm Hg, respectively; p < 0.0005). No significant differences in heart rate (96 ± 4 beats/min versus 85 ± 5 beats/min) or central venous pressure (3.75 ± 0.45 mm Hg versus 3.13 ± 0.35 mm Hg) were observed.
Eight weeks after injection, significant differences were observed in mean right ventricular pressure, mean pulmonary artery pressure, and left atrial pressure between the MCTP and CTL groups. In addition, there was a significant increase in pulmonary vascular resistance from 461 ± 37 dyne·s·cm-5 in the CTL group to 951 ± 129 dyne·s·cm-5 in the MCTP group (Fig 2). The hemodynamic differences between the two experimental groups after monocrotaline pyrrole injection are summarized in Table 1.
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). The Zo was slightly increased in the MCTP group compared with the CTL group, but this difference did not reach significance.
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). In addition, transpulmonary efficiency was significantly decreased in the MCTP group versus the CTL group. The changes in the right ventricular power analysis after monocrotaline pyrrole injection are summarized in Table 2.
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Comment |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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Initially, heart-lung transplantation was the surgical procedure of choice to treat all patients with end-stage pulmonary hypertension. Success rates were reasonable with 1-year survival rates ranging from 64% to 76% [8], and recurrence of pulmonary hypertension or right ventricular dysfunction was not observed for up to 10 years after transplantation [9]. Disadvantages of this technique include the limited supply of suitable donor heart-lung blocks, the complexity of the operation, the replacement of a heart that has been secondarily (and presumably reversibly) injured, and the occurrence of bronchiolitis obliterans, which limits long-term survival [7, 8].
As a result, favor has shifted away from heart-lung transplantation toward single-lung and bilateral lung transplantation. Single-lung transplantation has the advantages of increased donor organ availability, relative technical ease of the operation, and encouraging short-term results [10]. However, major concerns include poor functional reserve and increased basal ventilation/perfusion mismatch during acute rejection episodes as well as after the onset of bronchiolitis obliterans [11]. Currently the long-term outcome of patients with pulmonary hypertension having single-lung transplantation or bilateral lung transplantation remains unknown [12] because of insufficient long-term data available after single-lung transplantation [13] and paucity of reports examining bilateral lung transplantation.
It is clear that the indications for and the application of the various surgical procedures of lung transplantation in the treatment of adult pulmonary hypertension require further investigation. However, an appropriate large-animal model of experimental pulmonary hypertension has not previously existed as a means by which to examine the effects of single-lung, bilateral lung, and heart-lung transplantation on pulmonary hemodynamics in a laboratory setting. Single-lung transplantation has been studied in rats with pulmonary hypertension [14]; however, the small size of this species limits the accurate assessment of pulmonary hemodynamics in a lung transplantation model. More importantly, the pulmonary circulation of a rat is quite different from that of a human with respect to vessel ultrastructure, remodeling patterns, and pathologic reactions to hypoxia, making the rat a poor animal model for the study of human pulmonary hypertension [15].
Several previously well described large-animal models of chronic pulmonary hypertension exist as potential means to examine and compare the various surgical options of lung transplantation in the treatment of pulmonary hypertension. The methods used to induce pulmonary hypertension included embolization [16], banding of the pulmonary artery [17], and pulmonary venous constriction [18]. Although significant hemodynamic effects were achieved, they were accomplished acutely in each model, which does not accurately reflect the chronic nature of end-stage pulmonary hypertension. More importantly, the parenchymal changes noted clinically in association with end-stage pulmonary hypertension were not observed in these models. Thus, these models fail to accurately mimic the clinical picture of pulmonary hypertension as seen in the potential transplant population.
Monocrotaline is a pyrrolizidine alkaloid that induces a pulmonary vascular syndrome characterized by a proliferative pulmonary vasculitis and pulmonary hypertension [19]. After intravenous administration, monocrotaline undergoes hepatic metabolism from the action of the cytochrome P-450 monooxygenase system to form its reactive metabolite, monocrotaline pyrrole, which, in turn, circulates to the pulmonary vascular bed where lung injury is induced [19]. Remodeling of the pulmonary vascular bed in response to this initial injury is responsible for the rise in hemodynamic pressures observed clinically.
In this study, microscopic examination of the pulmonary parenchyma from animals treated with monocrotaline pyrrole revealed endothelial degeneration and hyperplasia as well as medial smooth muscle hypertrophy affecting both the small and medium-sized pulmonary arterioles. Perivascular connective tissue proliferation and alveolar septal widening were also observed. These microscopic findings are quite similar to the changes observed clinically in a particular pathologic subtype of primary pulmonary hypertension known as plexogenic pulmonary arteriopathy [20]. Thus, the model of pulmonary hypertension used in this report accurately reflects the clinical picture of end-stage pulmonary hypertension not only by virtue of its chronic nature, but also because the parenchymal changes produced from monocrotaline pyrrole treatment are similar to the microscopic findings seen in patients with this pathologic process.
Initial pulmonary vascular injury from monocrotaline pyrrole results in increased capillary permeability leading to interstitial and alveolar edema [19]. When we were first creating this model, two doses were originally tested, 5 mg/kg in a total of 4 animals and 3 mg/kg in 13 animals. Within 24 hours of that initial injection, all animals receiving 5 mg/kg of monocrotaline pyrrole and 5 animals receiving 3 mg/kg had died. At postmortem examination, the animals were found to have severe pulmonary edema; in addition, the animals treated with 5 mg/kg of monocrotaline pyrrole had large amounts of bilateral pleural effusions. At that point, it was decided to subject all subsequent animals to heavy diuresis for 24 to 48 hours after monocrotaline pyrrole injection. Since that time, there have been no deaths as a result of monocrotaline pyrrole treatment, making this an extremely reliable and reproducible model. Further, no deaths have ever occurred from the instrumentation procedures or surgical preparations described in this report. Because of the significant rise in pulmonary hemodynamics observed after injection of 3 mg/kg of monocrotaline pyrrole, no additional animals were treated with 5 mg/kg.
Aside from damage to the pulmonary vasculature, the other commonly reported outcome from monocrotaline pyrrole toxicity is liver injury [21]. Hepatic insult results from chronic exposure to extremely high doses of monocrotaline and is characterized by veno-occlusive disease, hepatic fibrosis, hepatocellular megalocytosis, and hepatocyte necrosis [21]. Human toxicity is due exclusively to accidental ingestion of the parent compound monocrotaline, as the pyrrole metabolites are highly unstable in an aqueous milieu, and has been a serious problem only in third world countries where plants containing this substance grow as weeds among food crops such as wheat or corn and are harvested with the grain [21]. Previous morphologic analysis using light and electron microscopy suggests that monocrotaline itself has no direct toxic effect on myocardial tissue [22].
The model of pulmonary hypertension described in this report is not the first application of monocrotaline pyrrole to induce chronic pulmonary hypertension in dogs. Okada and co-workers [23] also administered this substance to a canine species and produced significant alterations in pulmonary hemodynamics. In that study, a threefold increase in mean pulmonary artery pressure and pulmonary vascular resistance was observed 8 weeks after treatment with monocrotaline pyrrole.
The rise in pulmonary vascular hemodynamics after monocrotaline pyrrole injection in this report was not as high as the increases observed in the investigation by Okada and associates [23] or what is often observed clinically in the adult population with chronic pulmonary hypertension. One important distinction between the two studies, however, lies in the fact that the animals used by Okada and colleagues were 3-month old beagles, not adult animals. The pulmonary vasculature in the pediatric population is quite distinct from the adult pulmonary circulation. More specifically, the muscular arteries are thicker than in adulthood [24]. One of the primary characteristics of monocrotaline pyrrole–induced vascular pulmonary injury is vascular smooth muscle hypertrophy. Response to an agent such as monocrotaline pyrrole in a pediatric animal is therefore more pronounced and quite different from that in an adult animal [25]. A potential means of achieving a higher degree of pulmonary hypertension in our model would be to perform numerous injections of monocrotaline pyrrole at regularly spaced intervals. This theoretically would lead to repeated injury to the pulmonary circulation and produce greater scarring of the pulmonary vasculature, resulting in higher pulmonary pressures.
In addition, because of specific differences between the adult and pediatric pulmonary vasculatures, one would also expect any improvements or changes in pulmonary hemodynamics occurring in response to therapeutic measures, such as pharmacologic agents or lung transplantation, to be different in adult species compared with juveniles. The goals of both this model and the methods used to assess pulmonary hemodynamics are to further evaluate the surgical options of cardiopulmonary transplantation in the treatment of adult chronic pulmonary hypertension, and the use of pediatric animals would be inappropriate.
This study is unusual in that cardiopulmonary hemodynamics were characterized using Fourier analysis, therefore illustrating the feasibility of applying this technique in the setting of chronic pulmonary hypertension. Conventional steady-state hemodynamic measurements, including mean pulmonary artery pressure, pulmonary vascular resistance, and mean pulmonary artery blood flow, have traditionally been used to assess pulmonary hemodynamics; however, they do not fully characterize the nature of the pulmonary vasculature in terms of its physical state. The pulmonary circulation is a highly compliant, low-resistance vascular bed subject to pulsatile blood flow. Fourier analysis of pulmonary artery pressure and pulmonary blood flow separates these measurements into their respective steady-state and pulsatile components. This technique thus allows a complete and quantitative description of the pulmonary circulation in the form of vascular impedance and gives information regarding the physical state of the pulmonary vasculature. It has been suggested that energy and impedance describe more fundamental properties of the pulmonary circulation than resistance alone [26]. Furthermore, the application of Fourier analysis to biologic systems has been thoroughly investigated and validated for the pulmonary vascular systems in both dogs and humans [27].
In addition, the interactions of the right ventricle and its afterload, the pulmonary vasculature, and the left atrial pressure can also be assessed with Fourier analysis by measurements of pulmonary vascular energetics and their oscillatory nature using an ultrasonic flow probe and micromanometers. The impedance spectrum resulting from Fourier analysis precisely defines the external load against which the right ventricle must pump to move blood forward through the pulmonary circulation. This allows the determination of right ventricular hydraulic power and divides this power into its two components, steady power and oscillatory power.
In this investigation, right ventricular hydraulic power was significantly increased 8 weeks after injection of 3 mg/kg of monocrotaline pyrrole. In addition, there was no significant change in pulmonary blood flow, and there was a significant decrease in transpulmonary efficiency. The increase in right ventricular hydraulic power was due exclusively to a significant increase in the steady power, as no significant change was observed in the absolute value of the oscillatory component after monocrotaline pyrrole treatment. These findings indicate that vascular injury caused by monocrotaline pyrrole results in a situation where a significantly increased amount of energy is expended by the right ventricle to maintain the same level of pulmonary blood flow. Presumably, a greater amount of energy was necessary to sustain pulmonary blood flow because of a higher right ventricular afterload as represented by the significant increase in RIN as well as pulmonary vascular resistance observed after monocrotaline pyrrole injection. The right ventricle was able to adapt to the gradual increase in afterload without evidence of cardiac failure, a finding suggesting an important power reserve to sustain pulmonary blood flow in the setting of chronic pulmonary hypertension. However, across the entire pulmonary vascular bed, this blood flow is achieved at a significantly lower level of efficiency.
The normal ratio of oscillatory power to steady power has been measured at 30% to 35%:70% to 65% in both humans and dogs [28]. The results of this study are consistent with these previous findings, although after monocrotaline pyrrole treatment, the ratio of oscillatory power to steady power changed significantly to 20%:80%. This suggests that although total energy expenditure of the right ventricle was increased, a lower proportion of this total amount of energy was dissipated in the oscillatory movements of blood, and a higher proportion was converted to the forward motion of pulmonary blood flow.
The changes in pulmonary vascular mechanics, right ventricular power, and transpulmonary efficiency observed in this report may be the result of the parenchymal changes occurring in the pulmonary circulation as a result of monocrotaline pyrrole injection. In several instances, the medial smooth muscle hypertrophy and increased cellular hyperplasia observed in the small and medium-sized arterioles were so marked that the vessel lumen was at least partially, if not completely, occluded. These microscopic changes most likely led to a situation of decreased vessel compliance and increased right ventricular afterload and account for the observed increases in mean pulmonary artery pressure and input resistancy as well as the greater energy expenditure of the right ventricle required to maintain the same level of cardiac output compared with that before monocrotaline pyrrole treatment.
Although both the pulmonary vascular resistance and input resistance were significantly increased in the monocrotaline pyrrole–treated animals, one interesting finding was that the Zo was only slightly elevated 8 weeks after drug injection. Characteristic impedance, or Zo, represents an impedance value in the absence of reflected waves, dependent only on vascular elastic properties and dimensions, and is an index of the overall distensibility or stiffness of the vascular bed [29]. One would intuitively expect the pulmonary circulation to be less compliant (stiffer) given the increase in perivascular fibrosis after monocrotaline pyrrole injection and therefore Zo to be significantly elevated compared with the value seen prior to injection. However, because reflected waves occur at branching points in vessels in vivo, direct measurement of Zo is not possible. It can be estimated by various techniques and, in this report, was defined as the mean of the input impedance values from 2 to 12 Hz. However, the precision of the Zo estimate is inversely proportional to heart rate, and because measurements in all dogs were made only at their respective resting heart rates, this precision may have suffered, leading to a lack of significance.
No additional data were collected other than at 8 weeks after monocrotaline pyrrole injection. Such information would certainly be relevant, as hemodynamic changes after lung transplantation can be quite dynamic and can vary tremendously for a period after operation. Future studies should include examination of the changes in pulmonary hemodynamics occurring over multiple intervals during the development of pulmonary hypertension after monocrotaline pyrrole injection as well as after subsequent lung transplantation in a canine survival model.
In summary, pulmonary hemodynamics and blood flow were assessed in an adult canine model of chronic pulmonary hypertension using Fourier analysis. The results of this investigation demonstrate that significant alterations in pulmonary vascular mechanics occur in the setting of monocrotaline pyrrole–induced chronic pulmonary hypertension. Significant increases in pulmonary vascular resistance and RIN were observed 8 weeks after monocrotaline pyrrole injection. Pulmonary blood flow is maintained by a significantly larger amount of energy expenditure by the right ventricle, but it is achieved at a significantly lower level of efficiency. The insignificant difference in the pulmonary water content suggests that these hemodynamic changes were not the result of volume overload. This investigation demonstrates a potentially useful model for evaluating the different surgical options of lung transplantation for improving pulmonary hemodynamics in the setting of chronic pulmonary hypertension.
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Acknowledgments |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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We thank Robert A. Roth, PhD, and Kerry Ross for their invaluable assistance in the synthesis of monocrotaline pyrrole.
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Footnotes |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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Address reprint requests to Dr Chen, Department of Surgery, University of California, San Francisco, S-343, Box 0470, San Francisco, CA 94143.
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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This article has been cited by other articles:
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  Y. Takami and H. Ina Relation of intraoperative flow measurement with postoperative quantitative angiographic assessment of coronary artery bypass grafting Ann. Thorac. Surg., October 1, 2001; 72(4): 1270 - 1274. [Abstract] [Full Text] [PDF]
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E. P. Chen, S. A. Akhter, H. B. Bittner, W. J. Koch, R. D. Davis, and P. Van Trigt III Molecular and functional mechanisms of right ventricular adaptation in chronic pulmonary hypertension Ann. Thorac. Surg., April 1, 1999; 67(4): 1053 - 1058. [Abstract] [Full Text] [PDF]
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p < 0.01 versus CTL.)