IL-10 indirectly modulates functional activity of CD4+CD28null T-lymphocytes through LFA-3 and HLA class II inhibition.

Expansion of CD4+CD28null T-lymphocytes is common in chronic heart failure (CHF) patients. Its ability to produce high levels of proinflammatory cytokines is probably the key role of these cells in CHF. IL-10 is a candidate for limiting CD4+CD28null T-lymphocyte responses, whereas tumour necrosis factor (TNF) is the cytokine most closely involved in the loss of CD28 expression. Serum levels of TNF and IL-10 were measured in 65 CHF patients (mean age, 65.2 ± 13.84 years). Patients with an IL-10/TNF ratio ≥1 had significantly lower levels of CD4+CD28null T-lymphocytes than those with a ratio <1. In vitro, IL-10 reduced the frequency of proliferative CD4+CD28null T-lymphocytes stimulated with anti-CD3. Pre-treatment with IL-10 before anti-CD3 stimulation was required for the cytokine to inhibit TNF production by CD4+CD28null T-lymphocytes. In addition to the previously described effect of IL-10 on HLA-DR and ICAM-1 expression, LFA-3 protein and mRNA levels were reduced in the presence of the cytokine in monocytes. IL-10 inhibition on CD4+CD28null T-lymphocytes may be mediated by a reduction in HLA class II and LFA-3 expression because blocking interactions with these costimulators has similar effects to those of IL-10 treatment. Moreover, costimulation through CD2/LFA-3 interaction is enough to induce proliferation and cytokine production in CD4+CD28null T-lymphocytes.

More intensive CMV-infection in chronic heart failure patients contributes to higher T-lymphocyte differentiation degree.

Immunosenescence in chronic heart failure (CHF) is characterized by a high frequency of differentiated T-lymphocytes, contributing to an inflammatory status and a deficient ability to generate immunocompetent responses. CMV is the best known inducer of T-lymphocyte differentiation, and is associated with the phenomenon of immunosenescence. In this study, we included 58 elderly chronic heart failure patients (ECHF), 60 healthy elderly controls (HEC), 40 young chronic heart failure patients (YCHF) and 40 healthy young controls (HYC). High differentiation of CD8+ T-lymphocytes was found in CMV-seropositive patients; however, the differentiation of CD4+ T-lymphocytes was increased in CMV-seropositive but also in CHF patients. Anti-CMV antibody titers showed positive correlation with more differentiated CD4+ and CD8+ subsets and inverse correlation with CD4/CD8 ratio. Immunosenescence found in CHF patients is mainly due to the dynamics of CMV-infection, since the differentiation of T-lymphocyte subsets is related not only to CMV-infection, but also to anti-CMV antibody titers.

CMV Infection Is Directly Related to the Inflammatory Status in Chronic Heart Failure Patients.

High levels of inflammation play an important role in chronic heart failure (CHF). Patients with CHF have elevated levels of pro-inflammatory cytokines circulating systemically, mainly TNF and IL-6. However, there are almost no studies that relate these levels to the functional status of patients in CHF, much less to their CMV serostatus. In this study, patients with CHF (n=40; age=54.9 ± 6.3; New York Heart Association functional classification (NYHA, I-III) and healthy controls (n=40; age=53.5 ± 7.1) were analyzed. The serum concentrations of nine pro- and anti-inflammatory cytokines were measured by Luminex® xMap Technology and the basal level of mRNA expression of some immune molecules was quantified by TaqMan™ Array in CD4+ T-lymphocytes. The concentration of these cytokines in culture supernatants in response to anti-CD3 and LPS was also measured. The percentage of CD28null T-cells was determined, as well as the antibody titer against CMV. We found a higher concentration of all cytokines studied in CHF serum compared to healthy controls, as well as a direct correlation between functional status in CHF patients and levels of inflammatory cytokines. Moreover, the highest cytokine concentrations were found in patients with higher concentrations of lymphocytes lacking CD28 molecule. The cytokine production was much higher in CMV+ patients, and the production of these cytokines was found mainly in the T-lymphocytes of CMV+ patients in response to anti-CD3. Anti-CMV antibody levels were positively correlated with cytokine levels. The baseline expression of specific mRNA of the main molecules involved in the Th1 response, as well as molecules related to the CD4+CD28 null subset was higher in CMV+ patients. The cytokine concentrations are higher in CHF CMV+ patients and these concentrations are related to the production of antibodies against CMV. These high levels of cytokines are also associated with the more differentiated CD28null lymphocyte populations. All this, together with the dynamics of the pathology itself, makes CMV+ patients present a worse functional status and possibly a worse evolution of the pathology.

Validation of the usefulness of 2-dimensional strain parameters to exclude acute rejection after heart transplantation: a multicenter study.

INTRODUCTION AND OBJECTIVES: Two-dimensional speckle-tracking echocardiography has emerged as a promising alternative to endomyocardial biopsy to rule out acute cellular rejection after orthotopic heart transplantation (OHT) in single center studies. In an original cohort, 15.5% and 17% of cutoff points for left ventricular global longitudinal strain (LVGLS) and free-wall right ventricular longitudinal strain, respectively, achieved 100% negative predictive value to exclude moderate or severe acute cellular rejection (ACR ≥ 2R). Our objective was to demonstrate the usefulness of speckle-tracking and validate these cutoff points in an external cohort. METHODS: A prospective, multicenter study that included patients who were monitored during their first year after OHT was conducted. Echocardiographic studies analyzed by local investigators were compared with simultaneous paired endomyocardial biopsies samples. RESULTS: A total of 501 endomyocardial biopsy-echocardiographic studies were included in 99 patients. ACR≥2R was present in 7.4% of samples. LVGLS and free-wall right ventricular longitudinal strain were significantly reduced during ACR≥2R on univariate analysis. On multivariate analysis, LVGLS was independently associated with the presence of ACR≥2R. The original cutoff points demonstrated a negative predictive value of 94.3% to exclude ACR≥2R. CONCLUSIONS: This study maintained a strong negative predictive value to exclude ACR≥2R after OHT and LVGLS was independently associated with the presence of ACR≥2R. We propose the use of speckle-tracking, especially LVGLS, as part of the noninvasive diagnosis and management of ACR.

Early Everolimus Initiation Fails to Counteract the Cytotoxic Response Mediated by CD8+ T and NK Cells in Heart Transplant Patients.

The positive long-term effects of conversion to everolimus (EVL) after heart transplantation (HT) have been evaluated in several studies. However, the timing of EVL initiation, the best way to combine it with other immunosuppressive treatments, and the impact of these combinations on the immune response are poorly understood aspects. Here, we analyzed the immune phenotype and function of HT patients (n = 56) at short and long terms (prospective and retrospective cohorts), taking into account the time of EVL initiation: early (3 months post-transplant, EVL-E group) or late (>1 year post-transplant, EVL-L group) compared with mycophenolate mofetil treatment (MMF group). We show that early EVL conversion from MMF allows the increase of cytotoxic (CD56dim CD16+) NK and effector-memory (EM, CD45RA- CCR7-) CD8+ T cell subsets, which show a significantly higher level of expression of cytotoxic molecules, IFN-γ production and degranulation ability under activation. NK cell expansion is accompanied by an altered balance of receptor expression, increasing the activation state, and lytic activity of those cells. Those changes are detected after as little as 1 month after EVL conversion in association with the expansion of regulatory T cells and the decrease in B cell frequency. However, no changes in the immune cells subsets were observed after late EVL initiation (EVL-L) compared with the MMF group. Our results imply that only early EVL conversion induces key changes in the post-transplant immune response, preserving an efficient anti-viral response, but simultaneously showing a limited ability to counteract the cytotoxic response to the allograft.

Efficacy and Safety of de Novo and Early Use of Extended-release Tacrolimus in Heart Transplantation.

INTRODUCTION AND OBJECTIVES: The extended-release formulation of tacrolimus (ERT) allows once-daily dosage, thus simplifying the immunosuppressive regimen. This study aimed to describe the safety and efficacy of the de novo and early use of ERT in heart transplantation. METHODS: This was an observational, retrospective, multicenter study comparing the safety and efficacy of the de novo use of ERT (ERT group [n=94]), standard-release tacrolimus (SRT group [n=42]) and early conversion (EC) from SRT to ERT (EC group [n=44]). Extended-release tacrolimus was used between 2007 and 2012. One-year incidence rates of acute rejection, infection, and cytomegalovirus infection were analyzed. Safety parameters were also evaluated. RESULTS: There were no significant between-group differences in the daily dose or trough levels of tacrolimus during the first year after transplantation. The rejection incidence rates were 1.05 (95%CI, 0.51-1.54), 1.39 (95%CI, 1.00-1.78), and 1.11 (95%CI, 0.58-1.65) episodes per patient-years in the SRT group, ERT group, and EC group, respectively (P=.48). The infection incidence rates were 0.75 (95%CI, 0.60-0.86), 0.62 (95%CI, 0.52-0.71), and 0.55 (95%CI, 0.40-0.68) in the SRT group, ERT group, and EC group, respectively (P=.46). Cytomegalovirus infection occurred in 23.8%, 20.2%, and 18.2% of the patients, respectively (P=.86). No significant between-group differences were found in laboratory tests or in allograft function. There was 1 death in the SRT group and 2 in the ERT group. CONCLUSIONS: Both de novo and early use of ERT seem to have similar safety and efficacy profiles to conventional SRT-based immunosuppression.

Update for 2014 on clinical cardiology, geriatric cardiology, and heart failure and transplantation.

In the present article, we review publications from the previous year in the following 3 areas: clinical cardiology, geriatric cardiology, and heart failure and transplantation. Among the new developments in clinical cardiology are several contributions from Spanish groups on tricuspid and aortic regurgitation, developments in atrial fibrillation, syncope, and the clinical characteristics of heart disease, as well as various studies on familial heart disease and chronic ischemic heart disease. In geriatric cardiology, the most relevant studies published in 2014 involve heart failure, degenerative aortic stenosis, and data on atrial fibrillation in the geriatric population. In heart failure and transplantation, the most noteworthy developments concern the importance of multidisciplinary units and patients with preserved systolic function. Other notable publications were those related to iron deficiency, new drugs, and new devices and biomarkers. Finally, we review studies on acute heart failure and transplantation, such as inotropic drugs and ventricular assist devices.

2013 update on congenital heart disease, clinical cardiology, heart failure, and heart transplant.

This article presents the most relevant developments in 2013 in 3 key areas of cardiology: congenital heart disease, clinical cardiology, and heart failure and transplant. Within the area of congenital heart disease, we reviewed contributions related to sudden death in adult congenital heart disease, the importance of specific echocardiographic parameters in assessing the systemic right ventricle, problems in patients with repaired tetralogy of Fallot and indication for pulmonary valve replacement, and confirmation of the role of specific factors in the selection of candidates for Fontan surgery. The most recent publications in clinical cardiology include a study by a European working group on correct diagnostic work-up in cardiomyopathies, studies on the cost-effectiveness of percutaneous aortic valve implantation, a consensus document on the management of type B aortic dissection, and guidelines on aortic valve and ascending aortic disease. The most noteworthy developments in heart failure and transplantation include new American guidelines on heart failure, therapeutic advances in acute heart failure (serelaxin), the management of comorbidities such as iron deficiency, risk assessment using new biomarkers, and advances in ventricular assist devices.

Withdrawal of proliferation signal inhibitors due to adverse events in the maintenance phase of heart transplantation.

BACKGROUND: The increasing use of proliferation signal inhibitors (PSIs) has raised the issue of their risk profile. We sought to determine the causes, incidence, risk factors, and consequences of withdrawal due to adverse events of PSIs in maintenance heart transplantation. METHODS: This was a retrospective study from 9 centers of the Spanish Registry for Heart Transplantation. Demographic, clinical, analytic, and evolution data were obtained for patients in whom a PSI (sirolimus or everolimus) was used between October 2001 and March 2009. RESULTS: In the first year, 16% of 548 patients could not tolerate PSIs. This incidence rate stabilized to 3% to 4% per year thereafter. The most frequent causes for discontinuation were edema (4.7%), gastrointestinal toxicity (3.8%), pneumonitis (3.3%), and hematologic toxicity (2.0%). In multivariate analysis, withdrawal of PSI was related to the absence of statin therapy (p = 0.006), concomitant treatment with anti-metabolites (p = 0.006), a poor baseline renal function (p = 0.026), and multiple indications for PSI use (p = 0.04). Drug discontinuation was associated with a decline in renal function (p = 0.045) but not with an excess in mortality (p = 0.42). CONCLUSIONS: In this large cohort of maintenance heart transplant recipients taking a PSI, 16% withdrew treatment in the first year, and 25% had stopped PSI due to severe adverse events by the fourth year. This high rate of toxicity-related PSI withdrawal could limit the clinical utility of this otherwise novel class of immunosuppressive agents.