Elena García-Romero

Memory/effector T cells help control CMV through responses to IE-1 and pp65 antigens and the IFN-γ ELISpot assay enables the detection of CMV-reactive T cells and prediction of infection risk (3). CMV-specific cellular immunity (CMI) can identify higher-risk kidney transplant recipients who are more likely to develop CMV infection, while preserved CMV-CMI responses confer protection against post-transplant replication and disease (4,5). Recent multicenter trials have further supported the role of immunoguided prophylaxis in solid-organ transplantation. In kidney and liver transplant recipients, immune monitoring based on CMV-specific T-cell responses safely reduced antiviral exposure without increasing infection rates (6), whereas in lung transplantation, CMV-CMI-guided prophylaxis proved non-inferior to standard strategies while minimizing antiviral toxicity and adverse events (7).However, most studies assessing CMV-specific cellular immunity have been conducted in kidney transplantation, and their findings may not be fully extrapolable to heart transplant recipients, who face higher perioperative morbidity and mortality (5).Current Spanish and international guidelines for heart transplantation provide only low-level evidence, and CMV-CMI monitoring is still recommended based solely on expert opinion, particularly in seropositive (R+) recipients (8,9).Preventive strategies currently rely on universal prophylaxis with valgancicloviror PCR-guided preemptive therapy. While effective, both have limitations such as toxicity, late-onset infections, and viral resistance (8,10).The ELISPOT-TC trial will address this gap by evaluating whether prophylaxis guided by CMVspecific CMI, assessed by IFN-γ ELISpot (T-SPOT.CMV), is non-inferior to universal valganciclovir prophylaxis in seropositive heart transplant recipients.It will be a phase IV, multicenter, open-label, randomized (2:1), non-inferiority clinical trial conducted across 11 Spanish transplant centers. A total of 188 adult CMV-seropositive recipients will be enrolled (125 experimental, 63 control).Patients will be randomly assigned by a centralized computer system to either:-Group 1: CMI-guided prevention based on T-SPOT.CMV results, or -Group 2: Standard universal valganciclovir prophylaxis for 3 months.Randomized will be centralized and stratified by center. The assigned preventive strategy will not be masked to investigators or participants.Eligible participants will be adult (≥18 years) CMV-seropositive recipients able to provide informed consent. All patients will undergo T-SPOT.CMV testing at day 10 and at month 3 posttransplant,Viral load monitoring by quantitative nucleic acid testing (QNAT) will be performed throughout follow-up according to a standardized schedule.In the experimental arm, T-SPOT.CMV testing at day 10 post-transplant will classify patients as high or low risk, guiding either initiation of antiviral prophylaxis in those without CMV-specific cellular immunity (high-risk) or a pre-emptive strategy in those with preserved immunity (low-risk).Patients will be followed for 48 weeks with scheduled visits to monitor outcomes.The primary endpoint will be the cumulative incidence of CMV infection at one year. Secondary endpoints will include the classification of CMV infection into clinically significant and no-clinically significant categories (according to standardized, consensus-based viral load thresholds uniformly applied across centers and the presence of CMV-related symptoms or disease) as well as CMV disease, graft rejection, opportunistic infections, hematological adverse events, mortality, and cost-effectiveness.Analysis is planned both per-protocol and by intention-to-treat. Comparisons between groups will use standard tests for continuous and categorical variables, Cox proportional hazards models for time-to-event analyses, and Kaplan-Meier survival curves. Non-inferiority will be assessed with a 10% margin. The trial will comply with the Declaration of Helsinki and Spanish legislation and has received approval from the national regulatory authority and local ethics committees. It has been registered at ClinicalTrials.gov (NCT04278547). This study will represent the first randomized multicenter trial in heart transplantation to use a validated and commercially available IFN-γ ELISpot assay (T-SPOT.CMV) for guiding CMV prevention.As a randomized clinical trial, the study design will ensure strong internal validity and methodological robustness, while stratification by center will enhance the generalizability of the results across diverse clinical settings. By prospectively integrating immunological monitoring into a clinical decision algorithm, this trial takes an essential step toward individualized prevention. The trial will not only examines efficacy and safety but will also address the economic impact, including both direct antiviral costs and indirect healthcare-related costs.Universal valganciclovir prophylaxis is effective but costly and associated with frequent adverse events such as leukopenia and neutropenia. A CMI-guided approach has the potential to reduce unnecessary drug exposure, minimize toxicity, and lower costs while maintaining protection. This aligns with the broader movement toward precision medicine in transplantation (8,9). Certain limitations should be acknowledged: variability among participating laboratories may influence CMV DNAemia quantification despite standardized procedures; the exact proportion of patients who will ultimately receive valganciclovir prophylaxis versus preemptive therapy cannot be determined in advance; and the 48-week follow-up period will be insufficient to fully assess indirect CMV effects such as cardiac allograft vasculopathy, which has traditionally been one of the main arguments supporting universal prophylaxis. Despite these challenges, the ELISPOT-TC trial could support a paradigm shift in CMV prevention. Instead of exposing all...

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used in the management of type 2 diabetes and obesity due to their metabolic benefits. Beyond weight loss and glycemic control, emerging evidence suggests they may also exert cardioprotective effects. In the context of heart failure (HF), particularly HF with preserved ejection fraction (HFpEF), GLP-1RAs have been associated with improvement in symptoms, physical capacity, biomarkers, and structural cardiac remodeling. These benefits appear to be independent of weight loss, suggesting additional mechanisms including anti-inflammatory effects, improved myocardial metabolism or modulation of epicardial adipose tissue. However, current data largely come from non-HF dedicated trials, with limited standardization of the HF phenotype. Results are overall inconsistent and may suggest potential harm in some cases, particularly in HF with reduced ejection fraction (HFrEF). This review aims to summarize the current evidence on the role of GLP-1RAs in heart failure, explore possible underlying mechanisms and highlight key gaps in knowledge.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used in the man-agement of type 2 diabetes and obesity due to their metabolic benefits. Beyond weight loss and glycemic control, emerging evidence suggests they may also exert cardiopro-tective effects. In the context of heart failure (HF), particularly HF with preserved ejection fraction (HFpEF), GLP-1RAs have been associated with improvement in symptoms, physical capacity, biomarkers and structural cardiac remodeling. These benefits appear to be independent of weight loss, suggesting additional mechanisms including an-ti-inflammatory effects, improved myocardial metabolism or modulation of epicardial adipose tissue. However, current data largely come from non-HF dedicated trials, with limited standardization of HF phenotype. Results are overall inconsistent and may suggest potential harm in some cases, particularly in HF with reduced ejection fraction (HFrEF). This review aims to summarize the current evidence on the role of GLP-1RAs in heart failure, explore possible underlying mechanisms and highlight key gaps in knowledge.

Background. Iron deficiency (ID) is a significant, high-prevalence comorbidity in chronic heart failure (HF) that represents an independent predictor of a worse prognosis. However, a clear-cut diagnosis of ID in HF patients is not assured. The soluble transferrin receptor (sTfR) is a marker that reflects tissue-level iron demand and may be an early marker of ID. However, the impact of sTfR levels on clinical outcomes in non-anemic HF patients with a normal systemic iron status has never been evaluated. Methods. This is a post hoc analysis of an observational, prospective cohort study of 1236 patients with chronic HF of which only those with normal hemoglobin levels and a normal systemic iron status were studied. The final cohort consisted of 215 patients. Tissue ID was defined as levels of sTfR > 75th percentile (1.65 mg/L). Our aim was to describe the association between sTfR and clinical outcomes (all-cause death and HF hospitalization) and to explore its association with a wide array of serum biomarkers. Results. The sTfR level (HR 1.48, 95% CI 1.13–1.96, p = 0.005) and tissue ID (HR 2.14, 95% CI 1.22–3.75, p = 0.008) was associated with all-cause death. However, we found no association between sTfR levels and the risk of HF hospitalization. Furthermore, high sTfR levels were associated with a worse biomarker profile indicating myocardial damage (troponin and NT-proBNP), systemic inflammation (CRP and albumin), and impaired erythropoiesis (erythropoietin). Conclusions. In this cohort, the presence of tissue ID defined by sTfR levels is an independent factor for all-cause death in patients with normal systemic iron parameters.

Introduction and objectives: The Index for Mortality Prediction After Cardiac Transplantation (IMPACT) score was derived and validated as a predictor of mortality after heart transplantation (HT). The primary objective of this work is to externally validate the IMPACT score in a contemporary Spanish cohort.Methods: Spanish Heart Transplant Registry data were used to identify adult (>16 years) HT patients between January 2000 and December 2015. Retransplantation, multiorgan transplantation and patients in whom at least one of the variables required to calculate the IMPACT score was missing were excluded from the analysis (N = 2810).Results: Median value of the IMPACT score was five points (IQR: 3, 8). Overall, 1‐year survival rate was 79.1%. Kaplan‐Meier 1‐year survival rates by IMPACT score categories (0–2, 3–5, 6–9, 10–14, ≥15) were 84.4%, 81.5%, 79.3%, 77.3%, and 58.5%, respectively (Log‐Rank test:p < .001). Performance analysis showed a good calibration (Hosmer‐Lemeshow chi‐square for 1 year was 7.56;p = .47) and poor discrimination ability (AUC‐ROC .59) of the IMPACT score as a predictive model.Conclusions: In a contemporary Spanish cohort, the IMPACT score failed to accurately predict the risk of death after HT.

Aims: Non-ischaemic dilated cardiomyopathy (NIDCM) is characterized by left ventricular (LV) chamber enlargement and systolic dysfunction in the absence of coronary artery disease. Left ventricular reverse remodelling (LVRR) is the ability of a dilated ventricle to restore its normal size, shape and function. We sought to determine the frequency, clinical predictors and prognostic implications of LVRR, in a cohort of heart failure (HF) patients with NIDCM. Methods: We conducted a multicentre observational, retrospective cohort study of patients with NIDCM, with prospective serial echocardiography evaluations. LVRR was defined as an increase of ≥15% in left ventricular ejection fraction (LVEF) or as a LVEF increase ≥ 10% plus reduction of LV end-systolic diameter index ≥ 20%. We used multivariable logistic regression analyses to identify the baseline clinical predictors of LVRR and evaluate the prognostic impact of LVRR. Results: LVRR was achieved in 42.5% of 527 patients with NIDCM during the first year of follow-up (median LVEF 49%, median change +22%), Alcoholic aetiology, HF duration, baseline LVEF and the absence of LBBB (plus NT-proBNP levels when in the model), were the strongest predictors of LVRR. During a median follow-up of 47 months, 134 patients died (25.4%) and 7 patients (1.3%) received a heart transplant. Patients with LVRR presented better outcomes, regardless of other clinical conditions. Conclusions: In patients with NIDCM, LVRR was frequent and was associated with improved prognosis. Major clinical predictors of LVRR were alcoholic cardiomyopathy, absence of LBBB, shorter HF duration, and lower baseline LVEF and NT-proBNP levels. Our study advocates for clinical phenotyping of non-ischaemic dilated cardiomyopathy and intense gold-standard treatment optimization of patients according to current guidelines and recommendations in specialized HF units.

Background: Iron deficiency is a common disorder in patients with heart failure and is related with adverse outcomes and poor quality of life. Previous experimental studies have shown biological connections between iron homeostasis, mitochondrial metabolism, and myocardial function. However, the mechanisms involved in this crosstalk are yet to be unfolded. Methods: The present research attempts to investigate the intrinsic biological mechanisms between heart failure and iron deficiency and to identify potential prognostic biomarkers by determining the gene expression pattern in the blood of heart failure patients, using whole transcriptome and targeted TaqMan^® low-density array analyses. Results: We performed a stepwise cross-sectional longitudinal study in a cohort of chronic heart failure patients with and without systemic iron deficiency. First, the full transcriptome was performed in a nested case-control exploratory cohort of 7 paired patients and underscored 1128 differentially expressed transcripts according to iron status (cohort1#). Later, we analyzed the messenger RNA levels of 22 genes selected by their statistical significance and pathophysiological relevance, in a validation cohort of 71 patients (cohort 2#). Patients with systemic iron deficiency presented lower mRNA levels of mitochondrial ferritin, sirtuin-7, small integral membrane protein 20, adrenomedullin and endothelin converting enzyme-1. An intermediate mitochondrial ferritin gene expression and an intermediate or low sirtuin7 and small integral membrane protein 20 mRNA levels were associated with an increased risk of all-cause mortality and heart failure admission ((HR 2.40, 95% CI 1.04–5.50, p-value = 0.039), (HR 5.49, 95% CI 1.78–16.92, p-value = 0.003), (HR 9.51, 95% CI 2.69–33.53, p-value < 0.001), respectively). Conclusions: Patients with chronic heart failure present different patterns of blood gene expression depending on systemic iron status that affect pivotal genes involved in iron regulation, mitochondrial metabolism, endothelial function and cardiovascular physiology, and correlate with adverse clinical outcomes.