M.S. Avila

Circulating miR-1 as a potential biomarker of doxorubicin-induced cardiotoxicity in breast cancer patients

Cardiotoxicity is associated with the chronic use of doxorubicin leading to cardiomyopathy and heart failure. Identification of cardiotoxicity-specific miRNA biomarkers could provide clinicians with a valuable prognostic tool. The aim of the study was to evaluate circulating levels of miRNAs in breast cancer patients receiving doxorubicin treatment and to correlate with cardiac function. This is an ancillary study from “Carvedilol Effect on Chemotherapy-induced Cardiotoxicity” (CECCY trial), which included 56 female patients (49.9±3.3 years of age) from the placebo arm. Enrolled patients were treated with doxorubicin followed by taxanes. cTnI, LVEF, and miRNAs were measured periodically. Circulating levels of miR-1, -133b, -146a, and -423-5p increased during the treatment whereas miR-208a and -208b were undetectable. cTnI increased from 6.6±0.3 to 46.7±5.5 pg/mL (p<0.001), while overall LVEF tended to decrease from 65.3±0.5 to 63.8±0.9 (p=0.053) over 12 months. Ten patients (17.9%) developed cardiotoxicity showing a decrease in LVEF from 67.2±1.0 to 58.8±2.7 (p=0.005). miR-1 was associated with changes in LVEF (r=-0.531, p<0.001). In a ROC curve analysis miR-1 showed an AUC greater than cTnI to discriminate between patients who did and did not develop cardiotoxicity (AUC = 0.851 and 0.544, p= 0.0016). Our data suggest that circulating miR-1 might be a potential new biomarker of doxorubicin-induced cardiotoxicity in breast cancer patients.

Recovery of Renal Function in Heart Transplantation Patients After Conversion From a Calcineurin Inhibitor-Based Therapy to Sirolimus

BACKGROUND Renal failure is the most important comorbidity in patients with heart transplantation, it is associated with increased mortality. The major cause of renal dysfunction is the toxic effects of calcineurin inhibitors (CNI). Sirolimus, a proliferation signal inhibitor, is an imunossupressant recently introduced in cardiac transplantation. Its nonnephrotoxic properties make it an attractive immunosuppressive agent for patients with renal dysfunction. In this study, we evaluated the improvement in renal function after switching the CNI to sirolimus among patients with new-onset kidney dysfunction after heart transplantation. METHODS The study included orthotopic cardiac transplant (OHT) patients who required discontinuation of CNI due to worsening renal function (creatinine clearance < 50 mL/min). We excluded subjects who had another indication for initiation of sirolimus, that is, rejection, malignancy, or allograft vasculopathy. The patients were followed for 6 months. The creatinine clearance (CrCl) was estimated according to the Cockcroft-Gault equation using the baseline weight and the serum creatinine at the time of introduction of sirolimus and 6 months there after. Nine patients were included, 7 (78%) were males and the overall mean age was 60.1 +/- 12.3 years and time since transplantation 8.7 +/- 6.1 years. The allograft was beyond 1 year in all patients. There was a significant improvement in the serum creatinine (2.98 +/- 0.9 to 1.69 +/- 0.5 mg/dL, P = .01) and CrCl (24.9 +/- 6.5 to 45.7 +/- 17.2 mL/min, P = .005) at 6 months follow-up. CONCLUSION The replacement of CNI by sirolimus for imunosuppressive therapy for patients with renal failure after OHT was associated with a significant improvement in renal function after 6 months.

The first cardiac transplant experience in a patient with mucopolysaccharidosis

Hunter syndrome (MPSII) is a rare X-linked lysosomal storage disorder that can affect multiple systems but primarily affects the heart. We report the case of a previously asymptomatic 23-year-old patient who had an attenuated form of MPSII and presented with refractory heart failure that required a heart transplant. The diagnosis was confirmed by detection of an increase in urinary excretion of glycosaminoglycans, a deficiency in enzymatic activity, and molecular analysis. A myocardial biopsy revealed hypertrophic cardiomyocytes, mild fibrosis, and lysosomal storage in interstitial cells. Molecular analysis identified a novel mutation in the iduronate-2-sulfatase gene. Although the clinical outcome was not favorable, we believe that this approach may be valid in end-stage heart failure.

Left ventricular assist device followed by heart transplantation.

Heart failure (HF) is the major cause of cardiovascular hospitalization in Brazil1. It is estimated that approximately 1%–2% of the population present with HF and 50% of these individuals have a decreased ejection fraction2. In the last 30 years, despite the substantial improvement in the treatment of chronic HF, the quality of life and survival rates of affected patients are limited. In addition, most of these patients are refractory to standard treatment and hospitalization, and rates of death or rehospitalization within 6 months are approximately 50%2. Heart transplantation (HT) is considered the standard treatment in patients with advanced or refractory HF. However, this procedure is limited by the number of available donors and possible contraindications, such as pulmonary hypertension (PH) secondary to HF3. Since 1994, after the approval of the use of implantable ventricular assist devices (VADs) for long-term therapy in patients with advanced HF in the United States, there has been an increased interest in these devices. Technological improvement of VADs has resulted in the improved survival and quality of life in patients undergoing implantation, and the limitations of HT render these devices as an important tool for the treatment of advanced HF4,5. In Brazil, VAD therapy for patients with HF is still nascent. Here we report, to the best of our knowledge, the first case of hospital discharge after VAD implantation and subsequent HT.

Case 4--77-year-old female patient with heart failure, normal left ventricular systolic function and signs of restrictive cardiopathy.

Section Editor: Alfredo José Mansur (ajmansur@incor.usp.br) Associated Editors: Desidério Favarato (dclfavarato@incor.usp.br) Vera Demarchi Aiello (anpvera@incor.usp.br) The laboratory assessment on June 2008 showed: total cholesterol 157 mg/dl, HDL-cholesterol 34 mg/dl, LDLcholesterol 107 mg/dl, triglycerides 83 mg/dl, TSH 0.595 mUI/ml, blood glucose 92 mg/dl, aspartate aminotransferase (AST) 29 UI/l and alanine-aminotransferase (ALT) 28 UI/l.