Ann Thorac Surg 1997;64:1682-1685
© 1997 The Society of Thoracic Surgeons
Original Articles: Cardiovascular
Adjustable Model of Chronic Left Ventricular Dysfunction
Robert R. Waterford, MD,
Joseph R. Van Camp, MD,
Marsha A. Gallagher,
Michael T. Anderson,
Steven F. Bolling, MD,
Louis A. Brunsting, III, MD
Section of Thoracic Surgery, The University of Michigan Medical Center, Ann Arbor, Michigan
Accepted for publication May 16, 1997.
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Abstract
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Background. As an adjunct to the development of skeletal muscle-powered left ventricular assist devices, an adjustable model of chronic left ventricular failure was developed.
Methods. Implantation of a left ventricular balloon to induce heart failure was accomplished via left thoracotomy. Upon recovery, left ventricular failure was simulated by manipulation of left ventricular balloon volume to chronically raise left atrial pressure.
Results. Left atrial pressure increased from a baseline of 9.3 ± 0.7 mm Hg to 18.5 ± 1.2 mm Hg, 20.2 ± 1.8 mm Hg, and 26.0 ± 1.2 mm Hg by the 2nd, 6th, and 10th postoperative week, respectively. Cardiac index declined from a baseline of 4.4 ± 0.3 L • min-1 • m-2, reaching stability by the 8th postoperative week at 3.0 ± 0.4 L • min-1 • m-2. Stroke volume index declined from 1.12 ± 0.1 mL • kg-1 • beat-1 to 0.60 ± 0.1 mL • kg-1 • beat-1 by the 10th postoperative week. Mean survival was 75 ± 7 days. Causes of death included left ventricular failure, thromboembolism, and euthanasia.
Conclusions. This method of simulating chronic left ventricular dysfunction proved to be stable and adjustable and has been useful in the development of ventricular assist systems.
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Introduction
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Congestive heart failure (CHF) continues to be a major cause of morbidity and mortality worldwide [1]. Despite significant advances in the medical management of CHF, the mortality rate continues to be in excess of 50% within 5 years of diagnosis [2, 3]. After medical therapeutic options have been exhausted, surgical alternatives to inexorable progression and death include cardiac transplantation and mechanical assist devices. However, donor availability, side effects of immunosuppression, and thromboembolism limit these techniques, prompting investigation of skeletal muscle for circulatory assist [4, 5]. Critical to the development of such a ventricular assist system is the availability of a suitable model of ventricular dysfunction. A variety of methods for inducing experimental heart failure have been described, based on pressure overload, volume overload, myocardial infarction, chemical cardiomyopathy, or rapid ventricular pacing [6–9]. These methods have inherent limitations including nonstability, nonpredictability of damage, and nonadjustability, which either fail to simulate the clinical scenario or hamper the development of a ventricular assist system in the laboratory setting. To circumvent this limitation, we developed an adjustable method of simulating left ventricular failure in large animals [10], which has now been extended to the chronic setting.
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Material and Methods
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Anesthesia was induced with thiopental in 6 adult male goats (25 to 50 kg), the animals were endotracheally intubated, and anesthesia was maintained with an inhalation anesthetic agent (0.5% halothane). After procainamide administration as prophylaxis against arrhythmias (20 mg/kg bolus, then 1 mg/min intravenously), a left thoracotomy was performed and an ultrasonic perivascular flow probe (model 16S852D; Transonic Systems, Ithaca, NY) was placed around the ascending aorta. After systemic heparinization (100 U/kg intravenously), a chronic left atrial catheter fashioned from an implantable vascular access port (model GPV-5H-14; Access Technologies, Skokie, IL) was placed in the left atrial appendage (Fig 1
). Baseline measurements of heart rate, left atrial pressure (LAP), and cardiac output were obtained. An implantable, adjustable left ventricular (LV) balloon-tipped catheter (Cardiac Systems, Conshohocken, PA) was then placed in the LV apex via an apical left ventriculotomy. The LV balloon (LVB) was inflated with 15 mL of saline solution, the chest was closed after a brief period of thoracostomy tube drainage, and the chronic access ports of the left atrial and LV catheters were secured in the subcutaneous space adjacent to the thoracic spine. The flow probe transcutaneous adapter was secured and exteriorized. The LVB volume was adjusted to achieve an immediate postoperative LAP of approximately 15 mm Hg. The animals were then allowed to recover from general anesthesia.
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Fig 1. . Instrumentation involved in this method of simulating left ventricular (LV) dysfunction. Depicted are the left atrial (LA) monitoring line, aortic flow probe, and LV balloon-tipped catheter. The inset reveals the configuration of the LV balloon-tipped catheter, with an inflatable balloon on one end and a subcutaneous access port at the other end. (RV = right ventricle.)
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Postoperatively, the animals received anticoagulation in the form of daily aspirin alone (325 mg, first 5) or in combination with low-dose warfarin, to keep the prothrombin time at 15 to 18 seconds (international normalized ratio = 1.5 to 2.0). The LVB volume was adjusted over time such that the LAP would progress from 15 up to 25 mm Hg. Hemodynamic data were collected in the awake, fully conscious animals every other day for 90 days or until death, and included measurements of body weight, heart rate, LAP, and cardiac output. Cardiac output was normalized for total body surface area to yield cardiac index (CI). Stroke volume was computed by dividing cardiac output by heart rate, and then normalized for body weight, yielding a stroke volume index (SVI). Serum blood laboratory studies, including renal and liver function tests, complete blood counts, and measurements of prothrombin time, were performed weekly. At 90 days, a terminal study was performed, with hemodynamic measurements in the awake animal, followed by repeat hemodynamic assessment with the addition of peripheral arterial and pulmonary artery catheters while under general anesthesia. Afterwards, the animals were euthanized with potassium chloride while still under general anesthesia. Complete autopsies were then performed.
Values reported are means ± standard deviation. Statistical analysis of data was performed by repeated-measures analysis of variance. A p value less than 0.05 was considered significant.
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" prepared by the National Academy of Sciences and published by the National Institutes of Health (NIH publication 85-23, revised 1985).
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Results
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Six goats were instrumented and followed up with serial hemodynamic and laboratory data collection as described in Material and Methods. Mean survival was 75 ± 7 days. Significant LV failure developed in all animals. Two animals suffered thromboembolic complications on the 62nd and the 86th postoperative day and were euthanized before the end of the 90-day study period.
Hemodynamic data for the entire group are presented in Table 1. Baseline LAP after balloon insertion into the LV but before inflation was 9.3 ± 0.7 mm Hg. Baseline CI was 4.4 ± 0.3 L • min-1 • m-2 and baseline SVI was 1.1 ± 0.1 mL • kg-1 • beat-1. Upon inflation of the LVB to a mean volume of 21 ± 5 mL, mean LAP increased to 16.0 ± 1.0 mm Hg, while cardiac index and stroke volume index were preserved at 4.2 ± 0.2 L • min-1 • m-2 and 0.9 ± 0.1 mL • kg-1 • beat-1, respectively (p = not significant for both) (Fig 2). The hemodynamics were slowly decreased by adjustment of LVB volume (mean LVB volume at 8th week = 29 ± 5 mL). By the 10th postoperative week, LAP was 26.0 ± 1.2 mm Hg and CI and SVI had declined to 2.8 ± 0.3 L • min-1 • m-2 and 0.6 ± 0.1 mL • kg-1 • beat-1, respectively. Two animals succumbed to progressive CHF in the 11th week (in 1 of them the balloon could not be adjusted downward), and a thrombotic complication developed in 1 animal at 12 weeks.
At final evaluation and autopsy, 1 animal had gained 9.2 kg of weight, mostly of ascites. This animal was the only one that had evidence of right heart failure. Postmortem study revealed no thromboembolic events. A second had elevations in serum creatinine level, from a baseline of 0.9 mg/dL to a peak of 1.7 mg/dL, and experienced a sudden death episode on the 86th day. Postmortem study revealed a thrombus on the LV balloon. Multiple renal and cerebral infarcts were noted. The third and fourth animals' postmortem examinations revealed no evidence of thromboembolism. The fifth subject's postmortem examination revealed a torn LVB with minor thrombus and peripheral embolism. The sixth subject received low-dose warfarin in addition to daily aspirin therapy. The animal died of CHF on the 77th day. Postmortem examination revealed no evidence of thrombus or embolism. All of the animals had an increase in LV mass (20%) as well as LV cavity size on echocardiography and at postmortem examination (Fig 3). No animal had elevation of liver enzyme levels or hemolysis.
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Fig 3. . Heart from autopsy. The left ventricle (LV) has been opened via the anterior wall. Note is made of the LV balloon occupying a substantial portion of the LV cavity.
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Comment
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Left ventricular dysfunction is an inability to pump blood to adequately meet the metabolic requirements of the tissues, or the requirement of an increased filling pressure to adequately do so. It is further characterized by a variety of hemodynamic and clinical derangements, with various compensatory responses. Experimental models of CHF have relied on the induction of pressure loads, volume loads, myocardial infarctions, or toxic myocyte dysfunction. These models in turn have been used in the testing and development of numerous therapeutic modalities for CHF involving both pharmacologic and mechanical support. One of the major shortcomings of virtually all of these models has been the difficulty in consistently reproducing the same degree of CHF. Furthermore, most of these methods suffered additionally from the blunting of compensatory reflexes and the inability to adjust or modulate the degree of LV failure once established.
The method of simulating LV failure presented here is based on the insertion of an adjustable balloon-tipped catheter into the LV cavity and has several attractive features. Although it requires a thoracotomy, it is relatively simple to perform. It does not blunt or abolish the usual compensatory reflexes, thus facilitating attempts at in vivo therapeutic maneuvers. Furthermore, as shown, it readily allows for titration of LV failure by manipulating LV balloon volume as desired. The model does not mimic a specific disease entity and probably simulates LV failure by several mechanisms, including volume displacement and subsequent compensatory LV enlargement, a mild pressure load depending on the degree of LV balloon inflation with subsequent LV hypertrophy, and LV apical hypokinesis secondary to the apical left ventriculotomy required for LV balloon placement.
The model's major limitations initially included thromboembolism. A major thromboembolic event occurred in 1 of the first 5 animals studied, despite aspirin therapy and the selection of the goat, an animal with a relatively low thrombogenic tendency. We believe that this potential problem has been minimized by the addition of low-dose warfarin therapy, with preliminary data supporting this supposition. The problem of severe and progressive LV failure refractory to even LV balloon reduction was observed in 2 of the 6 subjects. Statistical analyses revealed that the animals tolerated moderate elevations in LAP (20 to 25 mm Hg) and mild reductions in CI and SVI, but further changes were associated with irreversible and progressive LV failure, culminating in death shortly thereafter. This fatal progression was aborted in 1 animal by reduction of LVB volume upon observing a worsening CI and SVI in the setting of elevated and rising LAP. Such timely adjustment of LVB volume resulted in gradual partial recovery of LV function. Subsequently, LVB volume was readjusted and the animal was maintained in moderate LV dysfunction for the entire study period.
In conclusion, this model has proved to be simple, adjustable, and reliable in both an acute and chronic study. Preliminary data suggest that thromboembolism can be minimized by mild anticoagulation. This method of simulating LV dysfunction may prove useful in the development of pharmacologic and mechanical ventricular assist systems.
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Acknowledgments
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This investigation was supported in part by American Heart Association research grant 93009680.
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Footnotes
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Address reprint requests to Dr Bolling, Section of Thoracic Surgery, The University of Michigan Hospitals, 2120D Taubman Center, Box 0344, 1500 E Medical Center Dr, Ann Arbor, MI 48109-0344 (e-mail: sbolling{at}umich.edu).
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Abstract
Introduction
