Faculty Bibliography

BACKGROUND: Preformed anti-HLA antibodies reacting specifically with donor lymphocytes have been associated with acute vascular rejection and early cardiac allograft failure. However, the effect of preformed anti-HLA antibodies directed against allogeneic major histocompatibility complex (MHC) class I or II antigens of a donor panel on heart transplantation outcome has not been extensively studied. METHODS AND RESULTS: The study group consisted of 68 patients who received cardiac transplants between 1989 and 1996 and who were at high risk for developing anti-HLA antibodies before transplantation. The effect of preformed antibodies against allogeneic MHC class I or class II antigens on the development of early high-grade cellular rejection and on cumulative annual rejection frequency was determined. Both patients with left ventricular assist devices and retransplantation candidates had a similar increase in the frequency of IgG anti-MHC class II antibodies (IgG anti-II) compared with control subjects (P<0.0001), whereas the frequency of IgG anti-MHC class I antibodies (IgG anti-I) was elevated only in patients with left ventricular assist devices. Pretransplantation IgG anti-II predicted early development of high-grade cellular rejection (P=0.006) and higher cumulative annual rejection frequency (P<0.001) in both of these sensitized patient groups. Among retransplantation recipients, a match between donors 1 and 2 at HLA-A additionally predicted an earlier time to a high-grade cellular rejection. CONCLUSIONS: These results emphasize the importance of specifically screening heart transplantation candidates for the presence of IgG antibodies directed against MHC class II molecules and suggest that strategies aimed at their reduction may have an impact on the onset and frequency of high-grade cellular rejections after transplantation.

BACKGROUND: Left ventricular assist devices have been reported previously to reverse ventricular remodeling in patients with dilated cardiomyopathy. In patients with prolonged mechanical support, structural failure of the left ventricular assist device inflow valve can cause regurgitation into the left ventricle, which may affect adversely this process. METHODS: Left ventricular end-diastolic pressure-volume relation of hearts explanted from 8 patients with left ventricular assist device and 8 control subjects with idiopathic cardiomyopathy was determined ex vivo at the time of transplantation. RESULTS: Duration of mechanical support ranged from 210 to 276 days (mean +/- standard deviation = 283 +/- 76 days) in 3 patients with inflow valve regurgitation versus 100 to 155 days (132 +/- 22 days) in 5 patients without (p = 0.005). The end-diastolic pressure-volume relation of all hearts supported mechanically was shifted to the left toward normal controls. This effect was markedly attenuated in patients with inflow valve regurgitation. CONCLUSIONS: Mechanical assistance can cause reverse remodeling in patients with dilated cardiomyopathy as evidenced by the shift in the end-diastolic pressure-volume relation curve to the left. Inflow valve failure, associated with prolonged support, can attenuate changes in left ventricular structure and dimension. Ineffective pressure and volume unloading may explain these observations.

The risk of development of breast lesions in patients on chronic immunosuppression is unknown. In order to assess this risk, a retrospective review was performed of the records of 87 women between the ages of 12 and 47 years who received thoracic organ transplant from 1987 to 1996 at our institution. Inclusion criteria consisted of patients who were premenopausal, had no previous history of breast disease, and survived for at least 1 year posttransplantation. All patients were on a triple immunosuppressive regimen consisting of cyclosporine, steroids, and azathioprine. Mean follow-up was 4 +/- 1.2 years with a range of 1-6 years. During this period, 21 patients (24%) with a mean age of 38 +/- 10 years had screening or diagnostic mammography. The remainder of patients with a mean age of 24 +/- 9 years were followed clinically. Overall, 10 patients (11%) developed a total of 17 palpable, solid lesions at 33 to 72 months posttransplantation. Fifteen of these lesions were surgically excised. Five of the patients had multiple lesions. Pathological examination of the specimens revealed fibroadenoma in nine, fibrocystic disease in four, low grade phylloides tumor in one, and T-cell lymphoma in one case. None of the patients have developed primary breast cancer during follow-up. In conclusion, short-term immunosuppression does not increase the risk of the development of benign breast lesions in young women after thoracic organ transplantation, but rather the distribution of benign lesions is similar in an age-matched population. There were several cases of multiple fibroadenomas in the transplant population, but mammography revealed no malignant disease in this age group and does not need to be utilized in this population beyond what is considered standard for immunocompetent patients. The long-term effect ofimmunosuppressive therapy on the developmentof breast cancer in this group remains to be defined.

BACKGROUND: Mechanical cardiac assistance has recently emerged as a tenable option in the treatment of end-stage heart failure. In spite of recent technical improvements that have reduced the incidence of life-threatening complications, the reported frequency of infections in these patients has remained high. METHODS: Over a 5-year period, 60 patients underwent insertion of a left ventricular assist device (LVAD) at our institution. Detailed medical records were kept prospectively for all patients, and a variety of endpoints were analyzed, including the incidence, nature, and sequelae of infections before and after LVAD implantation and after transplantation. RESULTS: Twenty-nine of 60 patients (48%) undergoing LVAD insertion subsequently had development of infections. The most frequent sites of infection were blood, LVAD drivelines, and central venous catheters, representing 61% of all infections. At the time of LVAD implantation, 13 of 60 patients (22%) had culture-proven infections. In spite of an increased incidence of subsequent infection (77% vs 40%), there were no differences in rates of mortality (31% vs 26%), LVAD endocarditis, (23% vs 11%) and eventual transplantation (62% vs 57%) between these patients and those without periimplantation infections. Although the overall mortality rate was not influenced by infections during LVAD support (28% vs 26%), the development of LVAD endocarditis was associated with a high mortality rate. Finally, although patients with infections during LVAD support had significantly longer median support times than those who remained infection free (101 vs 49 days, respectively), there was no difference in the rate of successful transplantation (59% vs 58%) or in the rate of infection after transplantation (35% vs 28%). CONCLUSIONS: Infections are common in patients undergoing LVAD support, but they do not adversely affect survival, the rate of successful transplantation, or the incidence of posttransplantation infection. Periimplantation infections may increase the risk of subsequent infections, but they also do not influence survival or transplantability. Patients with development of LVAD endocarditis are at increased risk for morbidity and death and require early and aggressive therapy, potentially including device explantation.

The incidence of clinically significant thromboembolic events is reported to be as high as 25% in patients with left ventricular assist devices (LVAD). Clinically detectable neurologic deficits resulting from thromboembolic events are reported to occur at a frequency of 0.0056% per patient-month with the Thermo Cardiosystems Heartmate 1000 (Woburn, MA) intraperitoneal LVAD (TCI). To date, the occurrence of asymptomatic cerebral microemboli in patients with this device has not been characterized. Transcranial doppler (TCD) monitorings were used for evaluation of the incidence of cerebral microembolism in 14 patients with the TCI LVAD. Studies were performed after LVAD support ranging from 7 to 305 days. Overall, 35 studies were obtained from the left middle cerebral artery for a duration of 30 minutes per study and the number of high intensity transient signals (HITS) were recorded. In one patient with a fatal stroke, an average of 0.86 HITS per study period (0.03/min) was observed. In 13 patients without any symptoms, an average of 0.46 HITS per study (0.016/min) was observed. Overall, no HITS were determined in 74% of the studies. Although the clinical significance or the nature of these microemboli is unknown, the data support that microembolism with the TCI LVAD is a rare event despite absence of anticoagulation. Long-term detailed neurocognitive testing and hematologic assessment is needed to establish the clinical relevance of these microemboli in patients with detected signals.

BACKGROUND: Elevated tumor necrosis factor serum levels have been reported in patients with severe congestive heart failure. This study was designed to characterize the cytokine profile in patients with acute circulatory collapse. METHODS: Blood drawn from 14 consecutive patients within 24 hours before undergoing left ventricular assist device placement and after at least 30 days of mechanical assistance or before transplantation was assayed for levels of interleukin 6, interleukin 8, and tumor necrosis factor-alpha. RESULTS: Interleukin 6 level was elevated in 11 (79%), interleukin 8 in 10 (71%), and tumor necrosis factor in 2 (14%) of the 14 patients. After hemodynamic recovery, interleukin 6 levels decreased from 33.6 +/- 9 pg/mL to 11.3 +/- 4 pg/mL (p = 0.05) and interleukin 8 levels decreased from 122 +/- 34 pg/mL to 19.7 +/- 8 pg/mL (p = 0.005). Tumor necrosis factor-alpha levels did not vary significantly; they were associated with infection in 2 left ventricular assist device recipients and normalized after left ventricular assist device support. All patients had resolution of circulatory shock after mechanical support and had improvement in parameters of end-organ function. CONCLUSIONS: Circulatory shock treated with left ventricular assist device placement is associated with a proinflammatory response similar to that seen in septic shock. The decrease in cytokine serum levels that follows hemodynamic recovery suggests that these cytokines may be markers of tissue damage and may modulate cardiac dysfunction.

BACKGROUND: Lung volume reduction surgery has shown early promise as a palliative therapy in severe emphysema. Selection of potential candidates has been based on certain functional and anatomic criteria, and a variety of operative contraindications have been proposed. METHODS: Over 15 months, we performed lung volume reduction surgery in 85 patients selected on the basis of severe hyperinflation with air trapping, diaphragmatic dysfunction, and disease heterogeneity. Patients were not excluded on the basis of severe hypercapnia, steroid dependence, profound pulmonary dysfunction, or inability to complete preoperative rehabilitation. RESULTS: We observed significant improvements in pulmonary function, exercise capacity, and dyspnea, with an acceptable 30-day perioperative mortality of 7% and actuarial survival of 90% and 83% at 6 and 12 months, respectively. In each "high-risk" group, perioperative mortality, actuarial survival to 1 year, and functional results were equivalent, and in some cases superior, to those in the corresponding "low-risk" patients. CONCLUSIONS: Severe hypercapnia, steroid dependence, profound pulmonary dysfunction, and inability to complete preoperative rehabilitation do not preclude successful lung volume reduction surgery and should not be regarded as absolute exclusionary criteria.