Heart retransplantation.

Retransplants comprise only a small minority (3-4%) of heart transplants, however outcome following retransplantation is compromised. Risk factors for a poor outcome following retransplantation include retransplantation early (<6 months) after primary transplant, retransplantation for acute rejection or early allograft failure, and retransplantation in an earlier era. The incidence of rejection and infection is similar following primary transplant and retransplantation. The compromised outcomes and risk factors for a poor outcome are similar in adult and pediatric heart retransplantation. However, due to the short half-life of the transplanted heart, it is an expectation that patients transplanted in childhood may require retransplantation. Based on the data available and the opinion of the working group, indications for heart retransplantation are (i) chronic severe cardiac allograft vasculopathy with symptoms of ischemia or heart failure (should be considered) or asymptomatic moderate or severe left ventricular dysfunction (may be considered) or (ii) chronic graft dysfunction with symptoms of progressive heart failure in the absence of active rejection. Patients with graft failure due to acute rejection with hemodynamic compromise, especially <6 months post-transplant, are inappropriate candidates for retransplantation. In addition, guidelines established for primary transplant candidacy should be strictly followed.

Contemporary concepts in prevention and treatment of cardiac allograft vasculopathy.

Cardiac allograft vasculopathy (CAV), is characterized by heterogeneous proliferative thickening of the vascular intima of the cardiac allograft vasculature. Since its presentation is commonly clinically silent, early diagnosis and preventative therapy are critical. Preventative therapy including optimization of immunosuppressive therapy and treatment of comorbidities associated with CAV progression must be initiated early since most of the intimal thickening occurs during the first year posttransplant. Long-term use of calcineurin inhibitors is associated with a high incidence of chronic renal disease and also contributes to hyperlipidemia and hypertension, all of which may exacerbate CAV. In addition, statins, antihypertensive agents and anti-CMV agents all have demonstrated benefits in reducing CAV. Once established, the limited treatment options include nonpharmacologic interventions such as retransplantation, percutaneous coronary interventions, coronary artery bypass grafting, transmyocardial laser revascularization and heparin-induced/mediated extracorporeal LDL plasmapheresis (HELP). As the use of new assessment tools increases our understanding of this disease, better preventative and treatment strategies are evolving.

Mycophenolate mofetil reduces intimal thickness by intravascular ultrasound after heart transplant: reanalysis of the multicenter trial.

UNLABELLED: The mycophenolate mofetil (MMF) trial involved 650 heart transplant patients from 28 centers who received MMF or azathioprine (AZA), both in combination with cyclosporine and corticosteroids. Baseline and 1-year intravascular ultrasound (IVUS) were performed in 196 patients (102 MMF and 94 AZA) with no differences between groups in IVUS results analyzed by morphometric analysis (average of 10 evenly spaced sites, without matching sites between studies). Baseline to first-year IVUS data can also be analyzed by site-to-site analysis (matching sites between studies), which has been reported to be more clinically relevant. Therefore, we used site-to-site analysis to reanalyze the multicenter MMF IVUS data. RESULTS: IVUS images were reviewed and interpretable in 190 patients (99 MMF and 91 AZA) from the multicenter randomized trial. The AZA group compared to the MMF group had a larger number of patients with first-year maximal intimal thickness (MIT)>or=0.3 mm (43% vs. 23%, p=0.005), a greater decrease in the mean lumen area (p=0.02) and a decrease in the mean vessel area (the area actually increased in the MMF group, p=0.03). CONCLUSION: MMF-treated heart transplant patients compared to AZA-treated patients, both concurrently on cyclosporine and corticosteroids, in this study have significantly less progression of first-year intimal thickening.

Noninvasive discrimination of rejection in cardiac allograft recipients using gene expression profiling.

Rejection diagnosis by endomyocardial biopsy (EMB) is invasive, expensive and variable. We investigated gene expression profiling of peripheral blood mononuclear cells (PBMC) to discriminate ISHLT grade 0 rejection (quiescence) from moderate/severe rejection (ISHLT > or = 3A). Patients were followed prospectively with blood sampling at post-transplant visits. Biopsies were graded by ISHLT criteria locally and by three independent pathologists blinded to clinical data. Known alloimmune pathways and leukocyte microarrays identified 252 candidate genes for which real-time PCR assays were developed. An 11 gene real-time PCR test was derived from a training set (n = 145 samples, 107 patients) using linear discriminant analysis (LDA), converted into a score (0-40), and validated prospectively in an independent set (n = 63 samples, 63 patients). The test distinguished biopsy-defined moderate/severe rejection from quiescence (p = 0.0018) in the validation set, and had agreement of 84% (95% CI 66% C94%) with grade ISHLT > or = 3A rejection. Patients >1 year post-transplant with scores below 30 (approximately 68% of the study population) are very unlikely to have grade > or = 3A rejection (NPV = 99.6%). Gene expression testing can detect absence of moderate/severe rejection, thus avoiding biopsy in certain clinical settings. Additional clinical experience is needed to establish the role of molecular testing for clinical event prediction and immunosuppression management.

Metaanalysis of statins and survival in de novo cardiac transplantation.

BACKGROUND: The use of HMG CoA reductase inhibitors (statins) after cardiac transplantation has been suggested to decrease the incidence of severe rejection and improve survival. Individual investigations that have led to this suggestion are randomized (but not placebo-controlled) studies, including small patient numbers that have (and thus underpowered) and enrolling heterogeneous subjects (including retransplant recipients). The purpose of this pooled analysis was to quantify the benefit of statins on survival in de novo cardiac transplant recipients. METHODS: Medline (1966 to 2003) was queried using the keywords statin, HMG CoA reductase inhibitors, cardiac transplantation, transplant, cholesterol, atorvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin. In addition, we searched the cited literature and previously published systematic reviews. Of 36 articles retrieved, 3 randomized controlled studies met our population inclusion criteria; namely age >18 years, de novo heart transplant recipients, statin therapy within 3 months, and > or = 1-year follow-up. Pooled data were metaanalyzed by Mantel-Haenszel tests using a random effects model that included tests for heterogeneity. RESULTS: The three pooled studies included 246 patients (statin, n = 129; no statin, n = 117) and 27 events (11%). The pooled analysis demonstrated a significant reduction in mortality with statin use (RR 0.31; 95% CI 0.13 to 0.7; P = .006) without significant heterogeneity (P = .7) among the studies. Two of the three studies reported allograft rejection with hemodynamic compromise. The pooled analysis demonstrated a significant benefit on this endpoint (RR 0.22, 95% CI 0.08 to 0.63; P = .004). CONCLUSION: This meta-analysis demonstrates that statin therapy decreases rejection episodes with hemodynamic consequences and improves 1-year heart transplant survival.

Ventricular-vascular uncoupling increases expression of B-type natriuretic peptide in heart transplantation.

BACKGROUND: Allograft adaptation to a foreign circulation is imperfect as noted from persistent limitations to stress. Effective arterial elastance (Ea), a measure of afterload, provides an estimate of aortic impedance. End systolic elastance (Ees) is a load-independent measure of ventricular performance as well as its interaction in the periphery. The ratio (Ea to Ees) characterizes ventricular-vascular coupling; a value close to unity signifies poor mechanical efficiency. The purpose of this investigation was to correlate mechanical efficiency of work with expression of B-type natriuretic peptide BNP, a specific marker of ventricular stress and strain. METHODS: We measured BNP levels in 40 consecutive stable heart transplant recipients free from rejection. In addition, echocardiography was performed to obtain Ea, Ees, and their ratio (Ea to Ees) by the single-beat method. We examined correlates of BNP expression by assessing Ea to Ees, while correcting for mean arterial pressure, body mass index, left ventricular mass index, ejection fraction, and serum creatinine. RESULTS: BNP levels were significantly and positively correlated (r=0.38, P=.05) with an increased Ea to Ees ratio. By multivariable analysis, this relationship persisted independently (t=2.1, P=.04), while the five other measures were insignificant predictors. CONCLUSION: This investigation indicated that the transplanted heart demonstrates poor contractile efficiency and operates at maximal left ventricular work. This is paralleled by a tandem increase in BNP, suggesting that elevation in this stress peptide is at least partly explained by ventriculo-vascular uncoupling in heart transplantation, independent of alterations in blood pressure.

Corticosteroid weaning in the tacrolimus and mycophenolate era in heart transplantation: clinical and neurohormonal benefits.

BACKGROUND: Compared with cyclosporine, tacrolimus-based immunosuppression yields improved metabolic outcomes in heart transplantation. Whether corticosteroid freedom provides incremental metabolic benefits in tacrolimus and mycophenolate mofetil immunoprophylaxis remains uncertain. METHODS: In a prospective trial, 41 heart transplant patients treated with tacrolimus and mycophenolate mofetil underwent steroid weaning immediately after transplantation until weaning was complete. Weaning was interrupted only for treated rejection with or without hemodynamic compromise. Benefits of steroid weaning assessed following the first year included B-type natriuretic peptide (BNP), late infections, lipids, blood pressure, hyperglycemia, and body mass index (BMI). RESULTS: Of this 41 patient cohort (age 53 +/- 9 years, 50% black American, 35% women) followed for a total of 47 +/- 5 months, 25 had corticosteroids discontinued (62%) by an average of 20 +/- 11 months. No differences between the two groups were noted in baseline characteristics. Significant predictors of failure to wean steroids included higher rejection, BNP, and lower dose of mycophenolate mofetil. No significant benefits of steroid weaning were noted on lipids, blood pressure, hyperglycemia, and BMI. However, late infections (after 1 year) requiring hospitalizations were more frequent in the failure to wean group (0.60.4 vs 0 infections/patient/y, P <.001). INFERENCES: Unlike known metabolic benefits of steroid withdrawal with cyclosporine, heart transplant recipients treated with tacrolimus and mycophenolate mofetil demonstrate no incremental metabolic benefits, but instead experience benefits of decreased serious late infections. Furthermore, failure to discontinue corticosteroids in this series is predicted by early allograft rejection, use of lower doses of mycophenolate mofetil, and higher BNP levels suggesting poor cardiac adaptation.

Comparison of the efficacy and safety of pravastatin and simvastatin in heart transplantation.

AIMS: Data on the safety and efficacy of HMG CoA reductase inhibitors in managing dyslipidemia in heart transplant recipients is inadequate. We undertook this study to evaluate the comparative safety and efficacy of simvastatin and pravastatin in lowering lipids in heart transplant recipients. METHODOLOGY: Forty eight patients (38 males) who received heart transplantation between 1995 and 1997, and who had no contraindications to statin therapy or history of myopathy were randomized to receive either pravastatin (n=24) or simvastatin (n=24) for six months. Detailed fasting lipid profiles, hepatic function tests, and serum creatinine phosphokinase were obtained regularly. Baseline and six month characteristics were compared using the unpaired student t test for continuous variables and Chi-square analysis or Fisher's exact test, as appropriate. RESULTS: Baseline total cholesterol levels, LDL cholesterol levels, HDL cholesterol levels, and triglyceride levels were similar in the two groups. At six months, the total cholesterol, LDL cholesterol, and triglyceride levels were greatly reduced in both groups, with greater reductions in the simvastatin group than in the pravastatin group. Only modest increases were noted in HDL cholesterol levels in the two groups. No significant adverse effects were noted, and no complications with drug withdrawals occurred. Patient compliance exceeded 97%. CONCLUSION: Simvastatin and pravastatin are safe and very effective in total cholesterol and LDL cholesterol lowering in heart transplant recipients, with simvastatin being more efficacious than pravastatin in lipid lowering in this group of patients.

The dilemma of late-stage heart failure. Rationale for chronic parenteral inotropic support.

The available evidence suggests that while chronic inotropic support likely exerts a long-term deleterious effect on survival, their use is accompanied by short-term enhancements in symptomatology and decreases in medical resource use, thereby curtailing the overall medical costs. The decision to use chronic parenteral inotropic support should not be made lightly and must be considered only after all evidence based therapeutic options has been investigated thoroughly and tried (Fig. 1). This should include not only hemodynamic monitoring-based drug therapy but [figure: see text] also appropriate consideration for options such as heart transplantation or patient enrollment into large-scale drug trials that seek to answer pertinent issues relating to various aspects of advanced heart failure therapeutics. The use of parenteral inotropic support as a chronic bridge to transplantation is accepted widely but remains controversial in other scenarios. For instance, when refractory congestion or hypoperfusion is exhibited in the absence of any definitive medical or mechanical option, it may be wise to contemplate inotropic support after appropriate informed consent has been obtained from the patient. Lastly, it is of great importance to continually seek ways to transit the patient from this approach to a definitive therapeutic end point, such as with transition to oral beta-blockade, which may be better tolerated in the patient with advanced heart failure using an inotropic umbrella.

Treatment of heart failure according to William Stokes: the enchanted mercury.

BACKGROUND: It was not until 1919 that the diuretic properties of mercury were observed in patients with syphilis; in the same year the beneficial effects of mercurial diuretics were shown in a patient with severe rheumatic heart disease and anasarca. However, mercury had been used much earlier for the treatment of dropsy without clear guidelines. In this article we describe William Stokes' insights into the treatment of heart failure, focusing on the beneficial diuretic properties of mercury. METHODS: We reviewed the chapter "Treatment of the Weak and Probably Dilated Heart in Connexion With Enlargement of the Liver and Pulmonary Disease" in William Stokes' famous treatise The Diseases of the Heart and the Aorta. CONCLUSIONS: Stokes makes several important clinical observations. First, he provides precise guidelines on when and how to use mercury in these patients. Second, he realizes the importance of mercury for the treatment of decompensated heart failure. Stokes recognizes the cyclical nature of frequent decompensation in congestive heart failure, the relationship of clinical deterioration and reduced urine output, and the importance of reestablishing urinary flow to ameliorate dyspnea. Third, he attempts to define the mechanism of action "... if any of the characteristic action of mercury can be perceived unless we include diuresis." Finally, he gives interesting guidelines on the dosage and side effects of mercury. These observations on the treatment of "congestive" heart failure are an important contribution to the understanding of heart failure pathophysiology and the design of prescription regimens for this disease.

Desperate diseases, desperate measures: tackling malignant hypertension in the 1950s.

BACKGROUND: The conquest of malignant hypertension is one of the most important medical achievements of the second half of the 20th century. As we enter the new millennium, it is critical to examine the efforts that have led to our ability to treat this once incurable disease. METHODS: Review was performed of the literature from 1900 to the 1950s regarding the etiology, clinical evaluation, and treatment of hypertension, focusing on malignant hypertension. RESULTS: Fifty years ago, in a time of sparse treatment options, the occurrence of malignant hypertension was a dreaded event that taxed the aptitude of the clinician. Confronted with an "extreme disease," physicians chose to use "extreme methods of cure" in conformity with the teaching of Hippocrates. In the 1950s malignant hypertension was treated with such drastic measures as rice diet, sympathectomy, and intravenous pyrogens. CONCLUSIONS: In the practice of medicine today, while work is being done to reassert biomolecular mechanisms, we still face patients who have reached the end stages of failure and manifest devastating morbidity. These patients are subjected to "extreme therapies" reminiscent of those that surrounded malignant hypertension in the past. In an era when adequate treatment of hypertension has become a reality for so many patients, it is appropriate to give credit to those who paved the way to such great progress.