Improved survival with statins, angiotensin receptor blockers, and steroid weaning after heart transplantation.

Various immunosuppressive and adjunctive pharmacological regimens exist for cardiac transplantation, though the associations between these regimens and long-term survival are unclear. We reviewed demographic, clinical, and pharmacological data from 220 consecutive adult heart transplant recipients between 1986 and 2003 who survived beyond 3 months. Immunosuppression was cyclosporine-based (n=94) or tacrolimus-based (n=126), and 104 patients were weaned off steroids (all receiving tacrolimus). Covariates of mortality were assessed in a Cox proportional hazards analysis. The mean age was 5.2+/-13 years. Survival was 96%, 88%, and 81% at 1, 3, and 5 years, respectively. Significant covariates associated with mortality included pretransplant diabetes mellitus (hazard ratio [HR] 2.83, 95% confidence interval [CI] 1.45 to 5.04), black race (HR 1.41, 95% CI 1.01 to 1.94), higher pretransplant creatinine clearance (HR 0.99, 95% CI 0.98 to 1.00), steroid withdrawal (HR 0.60, 95% CI 0.39 to 0.85), and exposure to a statin (HR 0.53, 95% CI 0.40 to 0.70) or an angiotensin receptor blocker (HR 0.50, 95% CI 0.20 to 0.95) after transplantation. Treatment with a statin, an angiotensin receptor blocker, and steroid withdrawal were each associated with improved survival in heart transplant recipients. These findings warrant prospective study, with specific emphasis on identifying the clinical effects of these medications in transplant recipients.

Can initial tacrolimus trough levels be predicted from clinical variables?

In eligible patients, cardiac transplantation has become the definitive treatment for end-stage heart failure. The initial posttransplantation course is marked by many potential difficulties, including renal insufficiency, hemodynamic instability, and perioperative bleeding. It is important to prevent early rejection; calcineurin inhibitors, such as tacrolimus or cyclosporine, are integral parts of such management. However, these drugs are associated with renal toxicity in some patients. Previous work suggests that limiting the increase in tacrolimus levels is associated with less renal insufficiency. The hypothesis of the current study was that a combination of clinical or laboratory variables could identify patients at risk for rapid changes in tacrolimus target levels. No single variable was strongly associated with high resultant trough levels following a standard 1-mg oral "test dose" of tacrolimus. However, the combination of 2 indices of liver metabolism (alanine aminotransferase and total bilirubin) along with serum creatinine did identify patients who tended toward elevated levels of tacrolimus (> or =4.5 ng/dL). Other variables, such as demographics, and even functional variables, such as right ventricular function by echocardiography, did not enhance the predictive value of this simple scoring system.

Refractory humoral cardiac allograft rejection successfully treated with a single dose of rituximab.

Despite improvements in immunosuppression over the last two decades, the risk of allograft rejection is still high in the early postoperative period. Cellular rejection accounts for the majority of these episodes. However, humoral rejection is a distinct phenomenon that carries a high rate of graft loss and mortality. The currently available treatments for this serious clinical problem include anti-lymphocyte antibodies, immune globulin infusions, as well as plasmapheresis, all of which have limitations. We describe a case of refractory humoral cardiac rejection successfully treated with a single dose of rituximab (375 mg/m2). No further episodes occurred with 2 years of follow-up.

Cardiac transplantation in the older recipient: excellent long-term survival based on pretransplant screening.

BACKGROUND: Cardiac transplantation has become the established treatment of choice for eligible patients with end-stage congestive heart failure. Older recipients (over the age of 60) are sometimes regarded as too high risk for transplant. Because chronological age is frequently disparate from physiologic age, we hypothesized that with careful selection after a comprehensive screening evaluation we would be able to achieve comparable survival and quality of life in an older population. METHODS: Between January 1989 and December 2002, 240 de novo adult cardiac transplants were performed for 74 female and 176 male patients. Prior to listing for cardiac transplantation, the patients were evaluated to exclude significant comorbidities that would limit survival or functional capacity postsurgery. In patients over the age of 60, particularly rigorous testing was conducted to eliminate significant extracardiac disease. RESULTS: The patients are divided in this analysis into three groups based on age at transplant (age 18 to 45, 46 to 59, and 60 years or older). Older recipients experienced similar rates of moderately severe cellular rejection (ISHLT grade 3A/ B). Survival as derived by Kaplan-Meier analysis was equivalent for all groups by Mantel-Cox logrank test (P = NS). The survival for patients older than age 60 was 83.1%, 73.7%, 67.7%, 57.4%, and 43.1% at 1,3, 5, 7, and 10 years posttransplant, respectively. CONCLUSION: We conclude that chronological age over 60 years old should not exclude a patient from the potential long-term benefit of cardiac transplant, ensuring added longevity and excellent quality of life.

Current practices: immunosuppression induction, maintenance, and rejection regimens in contemporary post-heart transplant patient treatment.

Cardiac transplantation is the definitive treatment for eligible patients with end-stage cardiomyopathy. Survival rates have improved dramatically during the last 10 years, especially since the advent of cyclosporine-A. Cardiac allograft rejection, previously considered a major cause of early mortality after transplantation, is no longer the limiting factor for early survival, with the use of newer and more specific immunosuppression regimens. Very few randomized, prospective trials, including comparisons between immunosuppression regimens, have been conducted in this area. Therefore, practices vary with physician and institutional experience. Most centers use a multipronged approach to immunosuppression, targeting multiple sites in the immune cascade that lead to allograft rejection. Multiple new agents in development are reviewed. Drugs such as sirolimus and its derivative, everolimus, act on specific intracellular receptors within lymphocytes, whereas other medications such as Daclizumab (Roche Laboratories, Nutley, NJ) block the interleukin-2 receptor on the surface of activated T cells. The immune response to foreign antigens is complex, with multiple redundant levels. Immunosuppression regimens continue to seek a fine balance between overimmunosuppression and insufficient protection, which may lead to allograft rejection or loss.

Tacrolimus monotherapy in adult cardiac transplant recipients: intermediate-term results.

BACKGROUND: Tacrolimus (FK506) is a macrolide antibiotic that inhibits T-cell activation and proliferation. To date, all published trials have used tacrolimus and steroids in combination with either azathioprine or mycophenolate mofetil. Previous experience with pediatric cardiac transplant patients at our institution suggested that use of tacrolimus alone provides an adequate level of immunosuppression and that withdrawal of steroids is readily achieved in most recipients. Between January 1, 1996, and July 7, 1999, we performed 77 adult cardiac transplants. Forty-three of these patients received tacrolimus and prednisone as primary immunosuppression, without azathioprine or mycophenolate mofetil. Thirty-two of the 43 patients started on tacrolimus have been weaned off steroids and are maintained on monotherapy. These latter patients form the basis of this report. The mean time for achieving monotherapy was 246 +/- 127 days (range, 106 to 730). Grade > or = 2 rejection occurred at 0.40 episodes per patient in the first 90 days (a combination of Grades 2 and 3A/3B rejections). The freedom from treated rejection (includes all 3A/3B and Grade 2 rejection in the first 90 days) was 69% at 90 days and 52% at 1 year. One patient (of 32) had documented cytomegalovirus infection (gastritis) diagnosed at 8 months post-transplant. We observed 1 case of transplant vasculopathy and 1 case of post-transplant lymphoproliferative disorder during the follow-up period. Our results show that use of tacrolimus alone after steroid weaning provides effective immunosuppression with low incidence of rejection, cytomegalovirus infection, transplant arteriopathy, or post-transplant lymphoproliferative disease.

New preexcitation following cardiac transplant.

Preexcitation developed post-operatively in a cardiac transplant recipient whose donor electrocardiogram was normal. An electrophysiology study revealed evidence of a mid-septal atrioventricular (AV) bypass tract. The patient is clinically well fourteen months after transplant and has intermittent preexcitation.

Cardiac troponin T: a noninvasive marker for heart transplant rejection?

BACKGROUND: Diagnosis of acute rejection remains a major concern in heart transplant recipients. Currently, endomyocardial biopsy is the gold standard for detecting rejection. Given the risks and cost of endomyocardial biopsy, a noninvasive marker for rejection would be ideal. Cardiac troponin T (cTnT) is an established marker of myocyte damage, and a rat transplantation model of heart transplant rejection has suggested that cTnT may be of value in detecting rejection. METHODS: The cTnT levels were measured in 90 transplant recipients (67 men and 23 women) at the time of endomyocardial biopsy. There were a total of 256 cTnT levels and 256 biopsy samples. The cTnT levels were compared by use of International Society of Heart and Lung Transplantation rejection grades. RESULTS: Only one of the 12 grade 3 biopsy specimens had a corresponding elevated cTnT level. Of the 29 biopsy specimens with myocyte necrosis (grade 2 or grade 3), three had a corresponding elevated cTnT. The cTnT levels were elevated during the first 1 to 2 months after transplantation. There was no correlation between ischemic time and cTnT levels. CONCLUSION: CTnT is an insensitive marker of acute rejection, both early and late after heart transplantation. Elevation of cTnT after transplantation does not seem to be directly related to ischemic time.

Dobutamine thallium 201 perfusion imaging in candidates for lung transplantation.

BACKGROUND: Thallium-201 stress imaging is the most often used noninvasive test for detection of coronary artery disease. Its utility in patients with end-stage lung disease has not been defined. METHODS: Feasibility, safety, and reliability of thallium 201 perfusion imaging was evaluated in 23 consecutive candidates for lung transplantation. All underwent graded dobutamine thallium 201 single photon emission computed tomography imaging. The perfusion imaging results were correlated with results of coronary angiography, radionuclide angiography, and right heart catheterization. RESULTS: The testing was completed without complications in all patients. No perfusion abnormality was detected in five patients, and none had evidence of coronary artery disease on coronary angiography. In 18 patients with abnormal thallium 201 imaging, coronary artery disease was detected in four patients only, and no angiographic data was available in three patients. Thus, in at least 11 of 23 patients, thallium 201 imaging was falsely positive. There was a trend toward lower left ventricular ejection fraction in patients with abnormal thallium 201 imaging. No correlation was found between thallium 201 results, pulmonary artery and right atrial pressures at rest. Possible noncoronary origin of the perfusion defects include the following (1) presence of sarcoid in the myocardium, (2) left ventricular attenuation by hypertrophied right ventricle, and (3) altered left ventricular anatomy, function, and coronary perfusion as a result of right ventricular pressure overload. CONCLUSIONS: Dobutamine thallium 201 stress test can be safely performed in lung transplant candidates. However, its specificity for detection of coronary artery disease is low. Selective use of coronary angiography in patients with multiple risk factors is likely a more cost-effective approach.