Gene expression profiling for monitoring graft rejection in heart transplant recipients

Outcomes[Abstract] Heart transplantation is a life-prolonging therapy for many patients with stage D heart failure and other forms of advanced heart disease. However, graft rejection and/or immunosuppression-related side effects are major causes of morbidity and death among heart transplant patients. Graft rejection monitoring remains a challenge. It would be desirable to be able to detect rejection early enough and specifically enough to prevent allograft dysfunction without unnecessary overimmunosuppression. Hitherto, the main technique employed in monitoring the rejection status of a transplanted heart has been endomyocardial biopsy (EMB), which allows rejection to be screened for and monitored on the basis of the extent and distribution of lymphocytic infiltrates and associated myocardial damage. However, EMB has significant limitations: it is invasive, its sensitivity is limited by sampling efficacy, and it suffers from considerable between-observer variability. Although many noninvasive techniques have been investigated, none so far has proved able to match the performance of EMB. Currently, a multiparametric approach is employed that comprises clinical examination for signs or symptoms of heart failure, EMBs, drug level monitoring, allograft function tests (mainly echocardiographic studies), and screening for allograft vasculopathy. Gene expression profiling may be a promising tool for this purpose

Glucocorticoid receptor changes its cellular location with breast cancer development.

Glucocorticoids play a major role in attenuation of the inflammatory response and they are useful in the primary combination chemotherapy of breast cancer, since in vitro studies have demonstrated an antiproliferative effect in human breast cancer cells. In contrast, it was recently shown that glucocorticoids protect against apoptotic signals evoked by cytokines, cAMP, tumour suppressors, and death genes in mammary gland epithelia. Their actions are mediated by intracellular receptor (GR) that functions as a hormone-dependent transcription factor; however, no previous studies have been focused on GR expression in different pathologies of the human breast, and the possible relationship with that of mineralocorticoid receptor (MR) and COX-2. Also, the role of these proteins on tumoral breast epithelial cells remains unclear. Therefore, we examined GR, MR and COX-2 expression by immunohistochemistry and Western blot techniques in 142 samples of human breast obtained by total or partial mastectomy. We found that the percentage of positive patients presenting nuclear immunoreaction to GR decreased with tumor development, while all samples analyzed showed cytoplasmic immunoreactions to MR. All positive samples to COX-2 antibody showed cytoplasmic location, a higher immunoreaction being observed in benign breast diseases than in carcinomatous lesions. Thus, breast cancer progression is associated with the accumulation of GR in the cytoplasm of tumoral cells and the decrease of COX-2 expression

¿La distrofinopatía de Becker es una contraindicación para el trasplante cardiaco?: experiencia de un centro

Scientific lette

Mitochondrial DNA haplogroup H as a risk factor for idiopathic dilated cardiomyopathy in Spanish population

[Abstract] Idiopathic dilated cardiomyopathy (IDC) is a structural heart disease with strong genetic background. The different single nucleotide polymorphisms (SNPs) that constitute mitochondrial haplogroups could play an important role in IDC progression. The aim of this study was to test frequencies of mitochondrial haplogroups in healthy controls (n = 422) and IDC patients (n = 304) of a Caucasian Spanish population. To achieve this, ten major European haplogroups were identified. Frequencies and Odds Ratios for the association between IDC and haplogroups were calculated in both groups. We found that compared to healthy controls, the prevalence of haplogroup H was significantly higher in IDC patients (40.0% vs 50.7%, p-value = 0.040).Instituto de Salud Carlos III; PS09/0084

Mitochondrial haplogroups H and J: risk and protective factors for ischemic cardiomyopathy

[Abstract] Background. Since mitochondria are the principal source of reactive oxygen species (ROS), these organelles may play an important role in ischemic cardiomyopathy (IC) development. The mitochondrial genome may influence this disease. The aim of the present study was to test the relationship between IC development and the impact of single nucleotide polymorphisms (SNPs) in mitochondrial DNA (mtDNA) defining the mitochondrial haplogroups in a population study. Methodology and principal findings. Ten major European haplogroups were identified by using the single base extension technique and by polymerase chain reaction-restriction fragment length polymorphism. Frequencies and Odds Ratios for the association between IC patients (n = 358) and healthy controls (n = 423) were calculated. No convincing associations between classical risk factors for ischemic cardiomyopathy development and haplogroups were found. However, compared to healthy controls, the prevalence of haplogroup H was significantly higher in IC patients (40.0% vs 50.0%, p-value  = 0.039) while the frequency of haplogroup J was significantly lower (11.1% vs 5.6%, p-value  = 0.048). The analysis of the SNPs characterizing the European mtDNA haplogroups showed that the m.7028C allele (40.0% vs 50.0%, p-value  = 0.005) and m.14766C allele (43.0% vs 54.2%, p-value  = 0.002) were overrepresented in IC patients, meanwhile the m.10398G allele (19.8% vs 13.1%, p-value  = 0.015) and m.4216C allele (22.2% vs 16.5%, p-value  = 0.044) were found as protective factors against IC. Conclusions and significance. Our results showed that the haplogroups H and J were found as a risk and protective factors for ischemic cardiomyopathy development, respectively.Instituto de Salud Carlos III; PS09/0084

Renal dysfunction after orthotopic heart transplantation: incidence, natural history, and risk factors

[Abstract] Background. Renal dysfunction is a common complication after orthotopic heart transplantation (HT). The importance of factors other than exposure to immunosuppressive drugs is unclear. The purpose of this study was to determine the incidence and natural history of renal dysfunction following heart transplantation, and to evaluate a number of variables as risk factors for this condition. Methods. We examined the creatinine levels at 1, 6, 12, 24, and 60 months in 262 consecutive heart transplant patients who survived at least 1 year. The potential risk factors included pre- and posttransplantation diabetes mellitus, arterial hypertension, and drugs used to control arterial hypertension. Results. 17.2% of patients showed mild renal dysfunction (creatinine 1.5-2.5 mg/dL) and 1.9% moderate dysfunction (creatinine >2.5 mg/dL) at 1 month; 29.8% showed mild and 1.1% moderate dysfunction at 6 months; 33.2% showed mild and 1.9% moderate dysfunction at 1 year; 40% showed mild, 0.9% moderate and 0.4% severe dysfunction (requiring dialysis or renal transplantation) at 2 years; and 43.6% showed mild, 1.7% moderate and 0.9% severe dysfunction at 5 years. None of the conditions analyzed as possible risk factors showed a significant association with renal dysfunction except the use of diuretics. Conclusion. The incidence of renal dysfunction after orthotopic heart transplantation was 33.6% within the first year after transplant and 44% within the first five years, although more than 95% of cases were mild. The incidence increased with time after transplantation. Renal dysfunction seems likely to be multifactorial in origin, but no individual risk factors were identified

Safety of statins when response is carefully monitored: a study of 336 heart recipients

[Abstract] Background. Statins are used as first-line drugs against hypercholesterolemia after heart transplantation. Randomized clinical trials have shown that they reduce cholesterol levels, and the incidence of rejection and coronary vasculopathy. Adverse effects have been related to the use of certain statins, high statin dosages, comorbidities, and coadministration with cyclosporine. However, estimation of the risk of adverse effects for a given patient is difficult. The aims of this study were to determine the incidence of various kinds of adverse effect of statins; to evaluate certain potential risk factors; and to assess the efficacy of early response to signs of adverse effects. Methods. Between April 1991 and December 2003, we retrospectively evaluated 336 heart transplant patients (including 55 women) with regard to the occurrence of possible adverse effects of statins (rhabdomyolysis, myalgia, hepatotoxicity, high CK without muscle symptoms, and others). Resolution on reduction of dosage or discontinuance and/or change of statin were deemed to constitute confirmation of cause. Relations were sought between adverse effects and age, sex, immunosuppressive therapy, kidney failure, body mass index (BMI), arterial hypertension, and diabetes mellitus. Results. Possible adverse events of statins were suffered by 60 patients, all of them men. The causal role of statins was confirmed in 41 (12.2% of all 336): hepatotoxicity was suffered by 13, high CK without muscle ache or weakness by 18, rhabdomyolysis by 5, myalgia by 3, and other effects by 2. The incidence of confirmed statin-related complications was higher among patients with BMI >29 kg/m2 than among those with lower BMI (P = .055). None of the patients with confirmed statin-related complications needed dialysis, none died, and permanent suspension of statin treatment was only necessary in 13 cases (3.9% of the 336). Conclusions. Some 10% to 20% of HT patients appear to suffer adverse side effects of initial statin therapy. However, early detection of such effects through diligent clinical and analytical monitoring allows the therapy to be modified in time to minimize the appearance of severe complications. In only a minority of cases permanent suspension of statin therapy is necessary

Human pregnane X receptor is expressed in breast carcinomas, potential heterodimers formation between hPXR and RXR-alpha.

The human pregnane X receptor (hPXR) is an orphan nuclear receptor that induces transcription of response elements present in steroid-inducible cytochrome P 450 gene promoters. This activation requires the participation of retinoid X receptors (RXRs), needed partners of hPXR to form heterodimers. We have investigated the expression of hPXR and RXRs in normal, premalignant, and malignant breast tissues, in order to det. whether their expression profile in localized infiltrative breast cancer is assocd. with an increased risk of recurrent disease. Methods: Breast samples from 99 patients including benign breast diseases, in situ and infiltrative carcinomas were processed for immunohistochem. and Western-blot anal. Results: Cancer cells from patients that developed recurrent disease showed a high cytoplasmic location of both hPXR isoforms. Only the infiltrative carcinomas that relapsed before 48 mo showed nuclear location of hPXR isoform 2. This location was assocd. with the nuclear immunoexpression of RXR-alpha. Conclusion: Breast cancer cells can express both variants 1 and 2 of hPXR. Infiltrative carcinomas that recurred showed a nuclear location of both hPXR and RXR-alpha; therefore, the overexpression and the subcellular location changes of hPXR could be considered as a potential new prognostic indicator