Brooks S. Edwards

Circulating and Tissue Endothelin Immunoreactivity in Advanced Atherosclerosis

BACKGROUND Atherosclerosis is characterized by endothelial injury and the proliferation of arterial smooth-muscle cells. The latter may be a result of the release of growth factors from the vessel wall; such growth factors may include an endothelium-derived vasoconstrictor for peptide with mitogenic properties. We tested the hypothesis that plasma endothelin concentrations are elevated in persons with symptomatic atherosclerosis, independently of age. METHODS We measured plasma endothelin levels in 100 normal subjects and in 40 patients with atherosclerosis predominantly of the following types: aortic and peripheral vascular disease (14 patients), renovascular disease (9 patients) coronary artery disease (9 patients), and carotid disease (8 patients). We also performed immunohistochemical staining for endothelin in the walls of atherosclerotic vessels. RESULTS In the normal subjects, the mean (+/- SD) plasma endothelin concentration was 1.4 +/- 0.2 pmol per liter, with no correlation between age and plasma endothelin concentration (r = 0.13, P = 0.2). In the patients with symptomatic atherosclerosis, the mean plasma endothelin concentration was 3.2 +/- 1.2 pmol per liter (P less than 0.001), and there was a significant correlation between plasma endothelin and the number of sites of disease involvement (r = 0.89, P less than 0.001). In the immunohistochemical studies, endothelin-1-like immunoreactivity was observed in vascular smooth muscle as well as in endothelial cells. CONCLUSIONS Endothelin may be a marker for arterial vascular disease. Whether it participates in the atherogenic process or is merely released from damaged endothelial cells is unclear.

Effect of cyclosporine on plasma endothelin levels in humans after cardiac transplantation

Abstract Since the introduction of cyclosporine in 1980, the 1-year survival rate after cardiac transplantation is now in excess of 80%. 1 Despite the success experienced with cyclosporine, considerable morbidity remains associated with its use. Renal insufficiency characterized by renal vasoconstriction occurs frequently and limits the use of the drug. 2 Hypertension occurs in >90% of cyclosporine-treated cardiac transplant recipients. 3 In vitro cyclosporine damages endothelial cells, resulting in cell lysis and detachment. 4 Endothelin represents a newly recognized polypeptide produced by vascular endothelium. Exogenous administration of endothelin results in intense renal and systemic vasoconstriction. 5 Recently, investigators speculated that endothelin may mediate cyclosporine-induced hypertension and renal insufficiency. 6 Recent studies in the rat 7 using superpharmacologic doses of cyclosporine demonstrate cyclosporine-induced activation of plasma endothelin with an associated increase in renal vascular resistance. Administration of endothelin antisera reversed the renal vasoconstriction. The effect of clinically relevant doses of cyclosporine on the activation of circulating endothelin in humans has not been evaluated. The current study was designed to (1) investigate whether plasma endothelin is activated in cyclosporine- and non-cyclosporine-treated patients after cardiac transplantation, and (2) to determine if a correlation exists between plasma endothelin and systemic arterial pressure or serum creatinine after transplantation.

Effect of Neurologic Complications on Outcome After Heart Transplant

OBJECTIVE To study neurologic complications after heart transplant. DESIGN Retrospective cohort study. SETTING Cardiac transplant program at Mayo Clinic, Rochester, Minnesota. PATIENTS We retrospectively studied 313 patients who underwent heart transplant at Mayo Clinic Rochester from January 1, 1988, through October 31, 2006. MAIN OUTCOME MEASURES Neurologic symptoms, neurologic complications, score on the Glasgow Outcome Scale, and mortality. RESULTS Causes of end-stage heart failure were idiopathic dilated myopathy (34%), ischemic heart failure (29%), congenital disorders (12%), amyloidosis (11%), and miscellaneous (15%). Perioperative neurologic complications occurred in 23% of patients and included delirium or encephalopathy (9%), cerebrovascular complications (5%), and diseases of the peripheral nerves and muscles (4%); however, only perioperative cerebrovascular complications were associated with 1-year mortality (hazard ratio, 4.17; 95% confidence interval, 1.04-16.76; P = .04). Most of these cerebrovascular complications occurred after the second postoperative day and were related to mechanical support of the circulation. Over 18 years, the risk for neurologic complications was 81%: sleeping disorders, 32%; polyneuropathy, 26%; and cerebrovascular diseases, 14%. Cause of death was neurologic in 12 of 95 patients (13%), and the most common were cerebrovascular disease (n = 6) and central nervous system infectious diseases (n = 3). Adjusting for baseline predictors, central nervous system infection (hazard ratio, 4.29; 95% confidence interval, 1.69-10.91; P = .002), depression (hazard ratio, 1.81; 95% confidence interval, 1.06-3.09; P = .03), and seizures (hazard ratio, 3.44; 95% confidence interval, 1.33-8.85; P = .01) were predictive for mortality. CONCLUSIONS Perioperative neurologic complications are frequent in heart transplant recipients, but most are transient and inconsequential. However, perioperative stroke is the most important neurologic complication affecting survival in the first year after heart transplant. Infectious diseases of the central nervous system are associated with fatal outcome.

The Relationship Between Atrial Granularity and Circulating Atrial Natriuretic Peptide in Hamsters With Congestive Heart Failure

The BIO 14.6 strain of hamster is a model of familial cardiomyopathy complicated by congestive heart failure, sodium retention, and edema. In previous studies, bioassay techniques have demonstrated that the cardiac content of atrial natriuretic peptide (ANP) is reduced in these animals. On the basis of this observation, the syndrome of congestive heart failure has been hypothesized to be due to a deficiency in ANP. The current study was designed to correlate the cardiac content of ANP (determined by immunohistochemical techniques) with plasma circulating ANP (determined by radioimmunoassay). alpha-ANP antibodies were used for both determinations. The content of ANP in the atria was based on the degree of immunoreactive staining present (1 = lowest; 5 = highest), as graded by two observers. The mean granularity score of the cardiomyopathic hamsters was decreased (2.1 +/- 0.3) in comparison with that of age- and sex-matched control animals (3.5 +/- 0.5; P less than 0.05). In contrast, circulating immunoreactive ANP was higher in the hamsters with congestive heart failure than in the control animals--185.5 +/- 27.2 pg/ml versus 77.7 +/- 10.8 pg/ml (P less than 0.005). This study demonstrates that an inverse relationship exists between ANP content in the atria and circulating ANP. Furthermore, this study suggests that these hamsters with congestive heart failure are not deficient in ANP; rather, secretion of ANP is stimulated and storage of the peptide, represented by atrial granularity, is reduced.

Cardiac transplantation in patients with preexisting neoplastic diseases

Cardiac transplantation has traditionally been reserved for individuals with end-stage congestive heart failure (CHF) in whom there is no history of other life-threatening systemic disorders. In most transplant centers, patients with a history of malignancy and severe heart failure have not been considered acceptable candidates for cardiac transplantation. In the last 4 years at Stanford University Medical Center, 8 cardiac transplants have been performed in 7 patients with a history of neoplastic disease. Six of these patients had already received treatment for lymphoproliferative disorders and in 1 case, a patient underwent a transplant after treatment for adenocarcinoma of the colon. Six of the 7 patients were discharged from the hospital and in that group, the 1-year posttransplant survival rate was 71%. This was comparable to an overall 1-year survival rate of 80% for patients undergoing a cardiac transplant at our center during the same period of time. At follow-up averaging over 2 years, there has been 1 case of recurrent neoplasia. One patient with evidence of radiation-induced pulmonary damage died of respiratory failure 2 days after transplantation. One patient required retransplantation because of intractable rejection and subsequently died from infectious complications. Immunosuppressive therapy in these patients has not been associated with an increased risk for neoplastic recurrence or for the development of posttransplant lymphoproliferative disorders. The current study demonstrates that in a carefully selected group, previously treated neoplastic disease should not represent a contraindication to cardiac transplantation.

OKT3 neurotoxicity presenting as akinetic mutism

Background. Muromonab-CD3 (OKT3), a mouse monoclonal antibody directed against human T lymphocytes, is a potent immunosuppressive agent used to reverse and more recently to prevent allograft rejection, mostly in cardiac transplant recipients. Neurotoxicity from OKT3 usually manifests itself as a transient aseptic meningitis and remains uncommon. Methods. The authors describe a dramatic neurologic syndrome after orthotopic heart transplant characterized by akinetic mutism, blepharospasm, anomic aphasia, and delirium. Results. Magnetic resonance imaging (MRI) showed meningeal enhancement and single-photon emission computed tomography (SPECT) showed markedly reduced tracer uptake. Discontinuation of OKT3 resulted in resolution of this neuropsychiatric syndrome and reversal of abnormalities on neuroimaging that coincided with normalization of CD3+ lymphocyte count. Conclusions. In the initial posttransplant period, it remains difficult to attribute encephalopathic signs to toxicity of immunosuppressive drugs. However, MRI and cerebral perfusion studies may help support the diagnosis. More precise characterization of the prevalence of OKT3-associated encephalopathy could come from prospective SPECT studies.

The role of medical management for acute intravascular hemolysis in patients supported on axial flow LVAD.

Continuous flow left ventricular assist devices (LVADs) are used with good outcome. However, acute intravascular hemolysis due to thrombus in the pump remains a clinical challenge. We screened for LVAD-related intravascular hemolysis among 115 consecutive patients surviving HeartMateII implantation and investigated the role of medical therapy in resolving the hemolysis. Hemolytic events were identified in 7% of patients, 2–26 months after implant, manifested by peak lactate dehydrogenase (LDH) levels >6 times normal. With the institution of heparin and enhanced antiplatelet therapy, LDH levels receded rapidly reaching a stable trough level near baseline within 2 weeks with the resolution of clinical symptoms except in one patient who required additional therapy with tissue plasminogen activator (tPA). Complications included transient renal failure, one splenic infarct, and a cerebrovascular attack after tPA. The acute event of hemolysis resolved with medical therapy, and all were successfully discharged. However, recurrent hemolysis was common (6/8 patients over the next 1–7 months). At the end of follow-up, three patients were transplanted, one patient died refusing LVAD exchange for recurrent hemolysis, and 4 remained alive on LVAD support. Medical treatment with intensification of anticoagulation can be effective in resolving the acute hemolytic event. However, a definitive long-term strategy should be planned because the recurrence rate is high.

Total lymphoid irradiation: a novel and successful therapy for resistant cardiac allograft rejection.

Total lymphoid irradiation (TLI) is a novel type of adjuvant immunosuppression for patients who undergo cardiac transplantation and have refractory allograft rejection during standard immunosuppressive therapy. TLI consists of 6 to 10 fractions of 80 cGy (1 cGy = 1 rad) of irradiation to lymphatic tissues with use of the standard mantle and inverted Y fields. We have used TLI in six patients with biopsy-proven rejection that was refractory to standard treatments, including cyclosporine, azathioprine, antilymphocyte antibodies, and corticosteroids. In five patients, recalcitrant rejection was resolved after completion of TLI, and resolution persisted during long-term follow-up (17 to 30 months; mean, 22.2 months). In each patient, a substantial increase in the CD8 (suppressor T-lymphocyte) subset and elimination of B lymphocytes were demonstrated, findings that also persisted. Side effects were mild and primarily limited to transient leukopenia. In four patients, a readily treated cytomegalovirus reactivation was noted during TLI; thus, a causal relationship was suggested. In recipients of cardiac allografts who have refractory rejection, TLI provides long-lasting amelioration of the rejection profile. This result may be attributable to a relative enhancement of the suppressor T-cell subset and elimination of the B-lymphocyte line. Side effects are minimal, but monitoring for cytomegalovirus activation or reactivation is recommended.

Combined heart and liver transplantation: protection of the cardiac graft from antibody rejection by initial liver implantation.

A 50-year-old Caucasian female with arrhythmogenic right ventricular (RV) dysplasia presented with 2 years of progressive RV heart failure (New York Heart Association class IV), recurrent ascites, and peripheral edema in spite of optimal medical therapy. Liver biopsy demonstrated advanced liver cirrhosis. Left ventricular chamber size and systolic function were normal. Right heart catheterization was consistent with severe RV dysfunction (RV dP/dtG200 mm Hg/ms). The patient had had three pregnancies. Surgical history included surgical disarticulation of the right ventricle for recurrent syncope, and a cholecystectomy a few months before presentation, requiring transfusion of blood products. She was found to have a large number of antiYhuman leukocyte antigen (HLA) antibodies with very high titers (Fig. 1A). The cytotoxic panel reactive antibody (PRA) was positive at 98%. The ‘‘calculated’’ PRA based on existing antiHLA antibodies with levels above 8000 mean fluorescence intensity was 95%. She was blood group A, Rh positive. It was thought that an appropriate donor for cardiac transplantation was not likely and that usual desensitization protocols would be insufficient in the context of very high PRA and very high antibody titers. Based on our experience with renal transplantation in recipients with donor-specific antibody (DSA) (1, 2), we planned to proceed with liver followed by heart transplantation with the use of a single local donor (G200 miles) to minimize cardiac ischemic time and perform a prospective flow-mediated crossmatch accepting a positive T-cell crossmatch with a channel shift less than 350 or a positive complement-dependent cytotoxicity crossmatch up to a dilution of 1:8. The plan also consisted of performing preoperative plasmapheresis and intravenous eculizumab (3), intended to protect the heart until the liver had time to reduce the DSA levels. The donor was an 18-year-old African-American male who suffered a gunshot wound to the head. The heart and liver were felt suitable for transplantation. Donor and recipient HLA types are shown in Table S1 (see SDC, http://links.lww.com/TP/A739). DSA are shown in Figure 1B (pre-Tx). Prospective cytotoxic crossmatch was negative. Flow crossmatch was positive with channel shifts for B-cell FCXM 358 and T-cell FCXM 279. Preoperative plasmapheresis was performed, methylprednisolone (360 mg) was given intravenously, and the first dose of eculizumab (1200 mg) was administered after which DSA titers were rechecked (Fig. 1B, post-PP). To minimize cardiac ischemic time and to allow cardiopulmonary bypass to be initiated at the time of liver reperfusion, the initial step of the surgical procedure was median sternotomy and dissection of aorta and superior and inferior vena cava. The liver transplant team then performed the abdominal incision and dissection for the liver transplantation. Before reperfusion of the liver, heparin was administered, cannulas were placed in the vena cavas and ascending aorta, and cardiopulmonary bypass was initiated to reduce hepatic venous pressure for the liver (set at 2.4 L/min/m). The patient was cooled to 32-C, and mean systemic blood pressure was maintained at above 70 to 80 mm Hg to adequately perfuse the liver. After hepatic reperfusion, methylprednisolone (250 mg) was given and blood was drawn for repeat crossmatch (Fig. 1B, post-liver). A second dose of eculizumab (1200 mg) was administered. Cardiac dissection and cardiectomy were performed and cardiac implantation was performed in a standard fashion with bicaval anastomoses. The cardiac ischemic time was 4 hr 17 min. After weaning from cardiopulmonary bypass and giving protamine to reverse the heparin, methylprednisolone (500 mg) was administered followed 30 min later by rabbit anti-thymocyte globulin (110 mg; our standard immunosuppression for heart transplantation). A third dose of eculizumab (900 mg) was given 9 hr after the second dose and after the patient had arrived in the intensive care unit. Flow crossmatch was repeated with donor serum and blood was drawn from the recipient immediately after the transplantation and was negative for both B and T cells (channel shift G52 for B cells and G106 for T cells). Anti-HLA antibody titers were monitored daily, showing a significant decrease immediately after liver transplantation, and stabilization since then (Fig. 1B). Based on this, no additional doses of eculizumab were given and no additional plasmapheresis (just one time preoperatively) was performed. Immunosuppression was managed routinely with induction therapy using daily anti-thymocyte globulin (seven doses) until initiation of tacrolimus (based on renal function) and until therapeutic levels were achieved. The first cardiac biopsy was at the time of chest closure 2 days after transplantation and was negative for celland antibody-mediated rejection. In the 15 months after surgery, she has had more than 10 sequential cardiac biopsies that were all negative for cellor antibody-mediated rejection. Anti-HLA antibodies were monitored routinely twice a week and have remained stable (Fig. 1B). At 15 months after transplantation, she has done very well clinically with no other complications and regained normal functional status with no recurrent edema or ascites. LETTERS TO THE EDITOR

Prognostic Features in Patients With Congestive Heart Failure and Selection Criteria for Cardiac Transplantation

Cardiac transplantation can be a highly successful therapeutic option for patients with end-stage congestive heart failure. Successful results, however, depend on the appropriate selection of patients for the procedure. Patients whose survival or quality of life would be compromised without cardiac transplantation and who are likely to benefit from this intensive type of treatment are potential candidates. Each patient should undergo a thorough assessment to identify any medical or psychologic contraindications to cardiac transplantation. In this review, we discuss the important predictors of survival in patients with congestive heart failure: the cause of heart failure, the patients symptomatic and functional status, the hemodynamic and pathologic findings, the evaluation of neurohumoral activity, and the presence of cardiac arrhythmias. Once a patient with congestive heart failure has been identified as having a limited life expectancy and severely impaired quality of life, cardiac transplantation should be considered.