In congestive heart failure, the main goal of treatment is

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1 Left Ventricular Assist System as a Bridge to Myocardial Recovery O. H. Frazier, MD, and Timothy J. Myers, BS Texas Heart Institute at St. Luke s Episcopal Hospital, Houston, Texas Background. Despite recent advances in medical therapy, heart transplantation, and mechanical circulatory support, the mortality of patients with congestive heart failure remains high. Methods. Retrospective data on 5 patients were obtained from our hospital s medical records. Each patient was supported by a left ventricular assist system (LVAS) because of severe congestive heart failure. The duration of LVAS support averaged 229 days (range, 46 to 447 days). In 3 patients, the LVAS was removed electively after the patient showed recovery of myocardial function. In the other 2, it was removed because of a malfunction. Results. In response to LVAS support, hemodynamic variables were significantly improved. The mean cardiac index increased from 1.45 to 2.69 L min 1 m 2 (p < 0.001) and the mean left ventricular ejection fraction increased from to (p < 0.025). All patients were in New York Heart Association functional class IV at LVAS implantation and class I at its explantation. One patient died of noncardiac-related causes 10 days after LVAS removal. The remaining 4 patients are alive and well 35, 33, 14, and 2 months after LVAS removal. Conclusions. In select patients with severe congestive heart failure, mechanical unloading with an LVAS can result in recovery of myocardial function. These patients can return to a normal physical status, thereby avoiding heart transplantation. More research is required to determine optimal modes of LVAS support, to predict which patients are likely to recover, and to assess long-term outcomes. (Ann Thorac Surg 1999;68:734 41) 1999 by The Society of Thoracic Surgeons The heart, like any other diseased organ, improves with rest. George Burch, 1966 [2] In congestive heart failure, the main goal of treatment is to reduce myocardial work and thereby stabilize, or even improve, myocyte function. One possible way to achieve this goal is prolonged bed rest, which was formerly the mainstay of treatment for congestive heart failure [1, 2]. Bed rest reduces heart rate, blood pressure, cardiac output, and cardiac size, thus promoting recovery of myocardial function [2]. In the 1940s and 1950s, Burch and DePasquale [2] quantitatively demonstrated the potential for recovery in patients with congestive heart failure who underwent long-term bed rest. This approach was useful in some cases but was not uniformly beneficial. Newer methods of allowing the heart to rest involve the pharmacologic reduction of cardiac work with angiotensin-converting enzyme inhibitors and -blockers. Because of improved pharmacologic therapy, the mortality resulting from heart failure has recently been stabilized [3]. Nevertheless, for many patients with end-stage congestive heart failure, pharmacologic therapy is insufficient. Revascularization and other surgical procedures are usually only palliative and do not greatly reduce the Presented at the Fourth International Conference on Circulatory Support Devices for Severe Cardiac Failure, The Society of Thoracic Surgeons, Houston, TX, Oct 3 5, Address reprint requests to Dr Frazier, Texas Heart Institute, PO Box 20345, Houston, TX ; mmallia@heart.thi.tmc.edu. overall ultimate mortality [4]. Ventricular reduction, introduced by Batista and colleagues [5] as a means of enhancing ventricular function, is beneficial in some instances but carries a high operative risk and seems less effective in the United States than in Brazil, Batista s homeland. For patients with end-stage heart failure, acute decompensation of an already compromised heart entails a very high mortality. These patients may be candidates for mechanical circulatory support as a bridge to heart transplantation. However, the overall applicability of heart transplantation is limited by a severe shortage of suitable donors. In addition, the longevity of transplanted hearts is limited, with an annual recipient mortality rate of 4% 5%. Implantable left ventricular assist systems (LVASs) are being used with greater frequency and for longer periods to provide circulatory support until transplantation can be achieved. Since the mid-1980s, three LVASs the HeartMate (Thermo Cardiosystems, Inc, Woburn, MA), the Novacor (Baxter Healthcare Corp, Oakland, CA), and the Thoratec (Thoratec Laboratories Corp, Berkeley, CA) have been used as long-term bridges to heart transplantation. As the transplant waiting time has increased, the duration of mechanical support has also increased. In most cases, the LVAS has extended the patient s life and improved its quality, both during mechanical support and after heart transplantation. Patients who are supported by an LVAS for longer than 1 month typically show substantial improvement in end-organ function [6, 7]. Along with 1999 by The Society of Thoracic Surgeons /99/$20.00 Published by Elsevier Science Inc PII S (99)0801-2

2 Ann Thorac Surg CIRCULATORY SUPPORT FRAZIER AND MYERS 1999;68: LVAS AS BRIDGE TO MYOCARDIAL RECOVERY 735 Table 1. Summary of Data on Patients Receiving Left Ventricular Assist Systems Patient No. Age (y) Diagnosis LVAS Type Duration of LVAS Support (days) Time Since LVAS Removal (mos) 1 42 Idiopathic cardiomyopathy VE LVAS Peripartum cardiomyopathy VE LVAS Idiopathic cardiomyopathy VE LVAS Peripartum cardiomyopathy IP LVAS Idiopathic cardiomyopathy Thoratec VAS 46 2 IP LVAS implantable pneumatic left ventricular assist system; VE LVAS vented electric left ventricular assist system; VAS ventricular assist system. ventricular unloading, such improvement creates an optimal environment for myocardial recovery. Measurable clinical recovery after prolonged left ventricular support was reported in 1994 by our center [8]. The patient, a 33-year-old man, was the first to undergo long-term support by an untethered LVAS. By the time of his death from stroke, after 505 days of mechanical support, his ventricular function had improved markedly, both physiologically and anatomically. Numerous other reports [9 13] have documented similar LVAS related improvement. Here we present our recent experience with LVAS support as a bridge to recovery in 5 young patients with severe heart failure. We also review the transition from clinical to scientific observations that validate this approach. Material and Methods Five patients with severe heart failure who were referred from outlying hospitals for mechanical circulatory support or for evaluation for heart transplantation were included (Table 1). The average age of the 3 women and 2 men was 29 years (range, 22 to 42 years). After the patients were approved for heart transplantation, LVAS support was initiated when intraaortic balloon pump and pharmacologic support failed to stabilize them. Echocardiography was performed preoperatively, intraoperatively, and then serially during LVAS support to assess changes in cardiac function. The first patient had been awaiting heart transplantation when the LVAS malfunctioned after 13 months of implantation. The remaining 4 patients were considered poor candidates for heart transplantation, and LVAS implantation thus was focused more toward myocardial recovery. After the patients were rehabilitated to New York Heart Association (NYHA) class I status, the LVAS was turned off or run at minimal settings, and the degree of myocardial recovery was assessed by a stress dobutamine hydrochloride study. Three patients were supported with a HeartMate vented electric (VE) LVAS, 1 patient had a HeartMate implantable pneumatic LVAS, and 1, a Thoratec ventricular assist system (LVAS). Standard implantation techniques and perioperative care were used in each patient. Physiologic data were evaluated for differences using Student s paired t test. Results The average duration of LVAS support was 229 days (range, 46 to 447 days). Compared with preimplantation values, hemodynamic variables were significantly improved with LVAS support (Fig 1). The mean cardiac index increased from 1.45 to 2.69 L min 1 m 2 ( p 0.001), and the mean pulmonary capillary wedge pressure decreased from 27.6 to 12.8 mm Hg ( p 0.01). The mean left ventricular ejection fraction increased from to ( p 0.025). During LVAS support, the status of all 5 patients improved from NYHA class IV to class I. The device was electively explanted in 3 patients, and in 2 patients, it was removed because of a malfunction. At the time of LVAS removal, a left ventricular reduction procedure was also performed. The hemodynamic improvement observed during LVAS support was sustained after the device was removed (see Fig 1). Myocardial tissue obtained at the time of LVAS implantation and at the time of explantation showed a dramatic improvement in myocyte structure. The mean myocyte diameter decreased from to m (p ). One patient died of noncardiac-related causes after LVAS removal. The remaining 4 patients were discharged from the hospital and as of this writing are alive and well 35, 33, 14, and 2 months after device removal. The hospital course of each patient was unique and is presented in the following case reports. Patient 1 A 42-year-old man was initially diagnosed with idiopathic cardiomyopathy in 1992 after a viral illness. For 3 years he had only mild symptoms of heart failure, which were treated medically. By March 1995, the severity and frequency of these symptoms had increased substantially. The left ventricular end-diastolic dimension enlarged to 9 cm on echocardiography. On March 17, 1995, the patient was admitted to the hospital because of severe heart failure, which required treatment with multiple inotropic agents, diuretics, angiotensin-converting enzyme inhibitors, and intraaortic balloon pump support. Because of the patient s cardiac deterioration despite inotropic therapy and intraaortic balloon pump support, a HeartMate VE LVAS was implanted on day 47 of

3 736 CIRCULATORY SUPPORT FRAZIER AND MYERS Ann Thorac Surg LVAS AS BRIDGE TO MYOCARDIAL RECOVERY 1999;68: life-style. He was seen in the outpatient clinic weekly, as required by Food and Drug Administration protocol. The patient had few complaints, but 8 to 9 months after implantation, it was noted that VE LVAS flow was increasing steadily. The flow rate peaked at 9.0 L/min, which resulted in a pump flow index of 3.90 L min 1 m -2. The VE LVAS pump rate was then set to a fixedrate mode to achieve a constant pump flow of 7.5 L/min. The patient required diuretic therapy as a result of excessive weight gain and fluid retention. After 422 days of VE LVAS support, he was admitted to the hospital for evaluation of worsening hemolysis, renal dysfunction, and increasingly frequent complaints of malaise. Echocardiographic studies revealed continuous flow in both the inflow and outflow conduits of the device. In addition, the left ventricular dimensions, which had previously shown reductions in size during LVAS support, had increased slightly. After 447 days of VE LVAS support, the pump was explanted, and a left ventricular reduction procedure was performed. Thirty-one days later, the patient was discharged from the hospital and, at this time, 35 months after the operation, continues to do well. Six months after LVAS removal, his heart size was significantly reduced (Fig 2), and he has not experienced any symptoms of congestive heart failure. Fig 1. Hemodynamic changes: before implantation of left ventricular assist system (LVAS) (pre-lvas), during LVAS support (LVAS), and after LVAS removal (post-lvas). Pulmonary capillary wedge pressure, left ventricular ejection fraction, and cardiac index improved significantly during support, and these improvements were sustained after LVAS removal. hospitalization. The patient s size (body surface area, 2.34 m 2 ) severely limited donor-heart availability and led to long-term support with the VE LVAS. The implantation procedure and the postoperative recovery were uncomplicated. Thirty days after the operation, the patient left the hospital on a day pass. Five days later, he was discharged home, where he maintained a fairly active Patient 2 A 24-year-old woman had the first evidence of heart failure in Her condition deteriorated, and she was transferred in extremis to our service. Our concern was that she was an extremely ill woman whose small body habitus would make implantation of a left ventricular assist device difficult. Nevertheless, LVAS implantation was elected and performed in March Although the patient was gravely ill for a prolonged period, her condition gradually improved. She underwent multiple operations for bleeding and other complications. Forty-four days after LVAS implantation, she became ambulatory. However, a colonization of methicillin-resistant Staphylococcus bacteria developed. The panel-reactive antibodies were also very high, which limited her ability to undergo transplantation. The infection persisted, and removal of the device was thought necessary. During this period, we had noted a progressive improvement in cardiac function. To document this improvement, a stress dobutamine study was performed in the catheterization laboratory with the LVAS turned off (Fig 3). The test, done in September 1996, showed a nearly normal response. As a result, we were able to remove the device and perform left ventricular reduction, which allowed the infection to resolve. The patient s postoperative course was gratifying, and progressive improvement was noted. She was discharged from the hospital in November She has had a stable postoperative course and has maintained NYHA class I status. Although the echocardiographic improvement was not as dramatic as that in patient 1, patient 2 can climb three flights of stairs without difficulty and can carry out her usual day-to-day activities without cardiac

4 Ann Thorac Surg CIRCULATORY SUPPORT FRAZIER AND MYERS 1999;68: LVAS AS BRIDGE TO MYOCARDIAL RECOVERY 737 Fig 3. (Patient 2.) Results of stress dobutamine study performed after 5 months of vented electric left ventricular assist system support. The rate of rise of left ventricular pressure (dp/dt) and the cardiac index rose to normal levels with increasing doses of dobutamine. Fig 2. (Patient 1.) Chest roentgenograms (A) during left ventricular assist system (LVAS) support and (B) 6 months after LVAS removal. Cardiomegaly seen early during LVAS support normalized before removal of the device and remained normal at the 6-month follow-up. symptoms. She has not been hospitalized since her discharge for cardiac symptoms. Patient 3 A 22-year-old man underwent mitral valve repair for dilated cardiomyopathy at a hospital near his home in Puerto Rico in August In December, a viral illness was diagnosed, but worsening dyspnea and orthopnea led to further evaluation, and the subsequent diagnosis was congestive heart failure. His condition deteriorated during December, and he was transferred to our service on February 22, 1997, to be evaluated for heart transplantation. On admission, he was in NYHA class IV, had stable vital signs, and had mild pulmonary edema. Over the next several days, his condition worsened, and intraaortic balloon pump placement and increasing doses of inotropic agents were necessary. On hospitalization day 39, he received a HeartMate VE LVAS. Coagulopathy and excessive bleeding, pneumonia, and then gastrointestinal bleeding complicated the postoperative course, and multiple reexplorations were performed for persistent postoperative bleeding. The patient eventually recovered satisfactorily from these events and was discharged from the hospital 105 days after implantation of the VE LVAS. After 6 months of LVAS support, he underwent a stress dobutamine study with the pump turned off (Fig 4). Although he initially responded well to the dobutamine, he was unable to maintain a high cardiac output at increased dobutamine doses. On day 309 after VE LVAS implantation, he noted an unusual swishing sound and blood leaving the vent tube of the blood pump. He was immediately taken to the hospital; on arrival, he was alert but anemic, and the blood pressure was unstable. In the operating room, an echocardiographic study and hemodynamic measurements with the VE LVAS turned off indicated adequate cardiac function. The blood pressure was 110/65 mm Hg, and the cardiac index was 2.9 L min 1 m 2. The VE LVAS was removed and left ventricular reduction, performed. Fig 4. (Patient 3.) Results of stress dobutamine study performed after 6 months of vented electric left ventricular assist system support. The rate of rise of left ventricular pressure (dp/dt) and the cardiac index increased to normal levels at a dose of 20 g kg 1 min 1. Cardiac index, however, decreased at 30 and 40 g kg 1 min 1.

5 738 CIRCULATORY SUPPORT FRAZIER AND MYERS Ann Thorac Surg LVAS AS BRIDGE TO MYOCARDIAL RECOVERY 1999;68: Fig 6. (Patient 4.) Results of stress dobutamine study performed after 5.5 months of support with implantable pneumatic left ventricular assist system. The rate of rise of left ventricular pressure (dp/dt) and the cardiac index rose to normal levels with increasing doses of dobutamine. Fig 5. (Patient 3.) Representative histologic findings at time of implantation of left ventricular assist system (LVAS) and at LVAS removal 14 months later. The myocyte diameter decreased from 41.6 m to 30.6 m. When the patient was weaned from cardiopulmonary bypass, left ventricular function improved, and he maintained adequate blood pressure. Because of severe coagulopathy, the patient received multiple transfusions of blood products and was taken to the recovery room in critical condition. The continuing coagulopathy required multiple blood transfusions and administration of numerous inotropic agents. Cardiac function appeared adequate, but renal, hepatic, pulmonary, and neurologic functions worsened over the next several days. Ten days after VE LVAS removal, the patient died of overwhelming sepsis and purpura fulminans. Histologic comparison of myocardial tissue obtained at the time of LVAS implantation and removal showed evidence of myocyte recovery (Fig 5). Patient 4 A 25-year-old woman experienced symptoms that included frequent episodes of shortness of breath 3 months after delivering her third child. Over a period of 6 months, she was admitted to an outlying hospital on multiple occasions because of dyspnea, nausea, and vomiting. A chest roentgenogram revealed a markedly dilated heart. Nine months after the patient had given birth, congestive heart failure was diagnosed. She was then referred to our service for evaluation for heart transplantation. On admission, the patient, who was receiving maximal medical therapy, was in cardiogenic shock. An intraaortic balloon pump was inserted, and her condition stabilized. Over the next week, however, her condition deteriorated with worsening renal, hepatic, and pulmonary functions. Eight days after hospital admission, she received a HeartMate implantable pneumatic LVAS. The postoperative course was complicated by excessive bleeding and renal failure. She remained ventilator dependent and in the intensive care unit for approximately 3 months. Aggressive physical rehabilitation was required, after which she eventually became ambulatory and achieved NYHA class I status. Cardiac catheterization and echocardiographic studies revealed persistent pulmonary hypertension, but native cardiac function improved. Because of elevated (90%) panel-reactive antibodies and methicillin-resistant Staphylococcus bacteria, it was thought that transplantation was virtually impossible. A stress dobutamine study was performed to further assess native heart function, and the response to increasing doses of dobutamine was positive (Fig 6); the echocardiogram showed normal cardiac dimensions. After 187 days of implantable pneumatic LVAS support, the device was removed, and a left ventricular reduction procedure performed. Postoperatively, the patient bled excessively, and severe coagulopathy developed; cardiac function, however, remained stable. The patient again experienced multipleorgan dysfunction requiring dialysis and mechanical ventilation. An echocardiogram 4 months after device removal revealed normal cardiac function and dimensions. At discharge from the hospital nearly 1 year after admission, the patient was in NYHA class I.

6 Ann Thorac Surg CIRCULATORY SUPPORT FRAZIER AND MYERS 1999;68: LVAS AS BRIDGE TO MYOCARDIAL RECOVERY 739 Patient 5 A 32-year-old woman initially complained of flulike symptoms with loss of appetite and vomiting in late February The patient sought emergency medical care at a local hospital because of persistent dizziness, nausea, dyspnea, and chest pain. An echocardiogram demonstrated severely depressed myocardial function with a left ventricular ejection fraction of less than She was transferred to our service for further evaluation of the severe heart failure. Another echocardiogram revealed a left ventricular ejection fraction of 0.05, and a chest roentgenogram showed bilateral alveolar infiltrates, a right pleural effusion, and normal cardiac size. The patient was febrile with leukocytosis and had moderate thrombocytopenia. The clinical diagnosis of acute myocarditis was made; however, peripartum cardiomyopathy was also considered as a possible diagnosis. Intraaortic balloon pump support with dopamine hydrochloride was initiated, but the patient remained in hemodynamically unstable condition, with worsening hypoxemia and oliguria. Severe hypoxemia necessitated endotracheal intubation and mechanical ventilation. Because of the unstable condition and the continued deterioration of the patient, a Thoratec LVAS was inserted on hospitalization day 10. Postoperatively, she was in stable condition with good hemodynamics, adequate urine output, and a normalized coagulogram. On postoperative day 15, the patient began walking and continued with aggressive physical rehabilitation. Serial echocardiographic studies over the duration of VAS support showed dramatic improvement in left ventricular function (Fig 7). Approximately 4 weeks after initiation of VAS support, renal, hepatic, and pulmonary functions had normalized, and the patient had an NYHA functional class I status. After 40 days of VAS support, a stress dobutamine study was performed with right ventricular catheterization and the VAS set to 2 L/min. The results demonstrated that the patient s own heart could respond well to an increased cardiac output demand (Fig 8). On day 46 of device support, the Thoratec VAS was removed, and ventricular reduction was performed. The patient recovered without problems and currently remains in NYHA functional class I. She was discharged from the hospital 14 days after the VAS was removed. Comment This report summarizes our experience with LVAS in patients with chronic heart failure who were eventually weaned from mechanical support without undergoing heart transplantation. Each patient had unique variables that necessitated removal of the device. Patient 1, who had severe cardiomegaly and chronic left heart failure, was supported by the LVAS for more than a year. Device removal was necessary because the inlet and outlet valve malfunctioned. Patient 5, the most recent, was exceptional in that from the start, we actively pursued the goal of device explantation. This patient s ventricular recovery was quite remarkable; after initial severe impairment, Fig 7. (Patient 5.) Serial echocardiograms demonstrated marked improvements in left ventricular dimensions and function during left ventricular assist system support. These improvements were sustained after device removal. normal left ventricular function was attained. By the time of device removal, the ejection fraction had increased from 0.05 to The LVAS was first approved for bridging to transplantation under a protocol that anticipated only 30 days of device use. The systems tested were developed under the auspices of the National Heart, Lung, and Blood Institute s program for providing prolonged or permanent assistance for the failing heart, without regard for usage as bridges to transplantation. The first three instances of bridging to transplantation (involving two total artificial hearts and one LVAS) were performed at our institution. After undergoing subsequent transplantation, all 3 patients died of infectious complications. In the early 1980s, patients having transplantation benefited from the introduction of cyclosporine, a more forgiving immunosuppressant than earlier agents. This drug promoted the successful clinical use of the LVAS without increasing posttransplantation complications. Over the years, the waiting time for transplantation lengthened, which

7 740 CIRCULATORY SUPPORT FRAZIER AND MYERS Ann Thorac Surg LVAS AS BRIDGE TO MYOCARDIAL RECOVERY 1999;68: Torre-Amione and associates (Guillermo Torre-Amione: personal communication; Baylor College of Medicine and the University of Texas, Houston, TX). Improved glucose transport and energy utilization has been noted by Taegtmeyer and co-workers (Henrik Taegtmeyer: personal communication; Baylor College of Medicine and the University of Texas, Houston, TX). The heart failure related changes in gene expression that involve an increase in ventricular expression of atrial natriuretic factor and a decrease in sarcoplasmic reticulum Ca. ATPase have also shown improvement after left ventricular unloading [16]. Improvements in -adrenergic density and the contractility of cardiac muscle in response to isoproterenol hydrochloride stimulation have likewise been noted after ventricular unloading [17]. As clinical and scientific data concerning myocardial recovery after left ventricular unloading accumulate, questions arise as to how this knowledge is to be practically applied. Which mode of support (partial or full unloading) will be the most effective for recovery? Which etiologies are more likely to be associated with reversible disease? What degree of myocardial recovery will allow safe weaning from circulatory support, and how is this degree of recovery to be measured? To date, enough clinical and experimental data document that myocardial unloading with an LVAS results in long-term recovery from chronic heart failure (as first documented by Burch and DePasquale [2] in their bed-rest program) [6, 9 11, 13 15, 16 19]. The data now justify prospective application of these devices by centers involved in the programs. Meanwhile, the preliminary results raise the hope that heart transplantation can be delayed or even avoided altogether in many young patients with terminal heart failure. We thank the section of Scientific Publications at Texas Heart Institute for editorial assistance in the preparation of this manuscript. Fig 8. (Patient 5.) Results of stress dobutamine study performed after 40 days of left-sided support with a Thoratec ventricular assist system. Left ventricular dimensions and function improved to normal levels with increasing doses of dobutamine. meant longer periods of LVAS use. As recipients of long-term mechanical support underwent transplantation, improvement in native heart function became apparent. This evidence was confirmed initially by anatomic and physiologic findings as well as histologically by comparing tissue samples on LVAS implantation with samples taken at device removal at transplantation [14]. The samples were studied for changes at the cellular and subcellular levels. Normalization of the deranged calcium transport characteristic of advanced heart failure was reported by our group [15] in Recent data confirming improvement in tumor necrosis factor have been documented by our References 1. Levine S. Clinical heart disease. 3rd ed. Philadelphia: WB Saunders, 1945: Burch GE, DePasquale NP. On resting the human heart. Am Heart J 1966;71: Deaths from heart failure: United States, Atlanta, GA: Centers for Disease Control and Prevention, July 7, 1998; fact sheets. 4. Frazier OH, Myers TJ. Surgical therapy for severe heart failure. Curr Probl Cardiol 1998;23: Batista RJV, Santos JLV, Takeshita N, Bocchino L, Lima PN, Cunha MA. Partial left ventriculectomy to improve left ventricular function in end-stage heart disease. J Cardiac Surg 1996;11: Farrar DJ, Hill JD. Recovery of major organ function in patients awaiting heart transplantation with Thoratec ventricular assist devices. J Heart Lung Transplant 1994;13: Burnett CM, Duncan JM, Frazier OH, Sweeney MS, Vega JD, Radovancevic B. Improved multiorgan function after prolonged univentricular support. Ann Thorac Surg 1993;55: Frazier OH. First use of an untethered, vented electric left

8 Ann Thorac Surg CIRCULATORY SUPPORT FRAZIER AND MYERS 1999;68: LVAS AS BRIDGE TO MYOCARDIAL RECOVERY 741 ventricular assist device for long-term support. Circulation 1994;89: McCarthy PM, Nakatani S, Vargo R, et al. Structural and left ventricular histologic changes after implantable LVAD insertion. Ann Thorac Surg 1995;59: Loebe M, Weng Y, Muller J, et al. Successful mechanical circulatory support for more than two years with a left ventricular assist device in a patient with dilated cardiomyopathy. J Heart Lung Transplant 1997;16: Holman WL, Bourge RC, Kirklin JK. Case report: circulatory support for seventy days with resolution of acute heart failure [Letter]. J Thorac Cardiovasc Surg 1991;102: Frazier OH, Radovancevic B, Abou-Awdi NL, et al. Ventricular remodeling after prolonged ventricular unloading heart rest: experience with the HeartMate left ventricular assist device [Abstract]. J Heart Lung Transplant 1994;13:S Frazier OH, Benedict CR, Radovancevic B, et al. Improved left ventricular function after chronic left ventricular unloading. Ann Thorac Surg 1996;62: Scheinin SA, Capek P, Radovancevic B, Duncan JM, McAllister HA, Jr, Frazier OH. The effect of prolonged left ventricular support on myocardial histopathology in patients with end-stage cardiomyopathy. ASAIO J 1992;38:M Bick RJ, Poindexter BJ, Buja LM, Taegtmeyer H, Radovancevic B, Frazier OH. Improved sarcoplasmic reticulum function after mechanical left ventricular unloading. Cardiovasc Pathobiol 1998;2: Dilulio NA, DiPaola NR, Smedira NG, McCarthy PM, Moravec CS. Reversal of the heart failure phenotype by mechanical unloading [Abstract]. J Heart Lung Transplant 1999;18: Ogletree-Hughes ML, Barrett-Stull L, Smedira NG, Mc- Carthy PM, Moravec CS. Mechanical unloading restores beta-adrenergic responsiveness in the failing human heart [Abstract]. J Heart Lung Transplant 1999;18: Hunt SA, Frazier OH. Mechanical circulatory support and cardiac transplantation. Circulation 1998;97: Mueller J Weng Y, Dandel M, et al. Long-term results of weaning from LVAD it does work [Abstract]. ASAIO J 1999;45:153.