A narrative review of inherited arrhythmogenic syndromes in young population: role of genetic diagnosis in exercise recommendations

Sudden cardiac death is a rare but socially devastating event, especially if occurs in young people. Usually, this unexpected lethal event occurs during or just after exercise. One of the leading causes of sudden cardiac death is inherited arrhythmogenic syndromes, a group of genetic entities characterised by incomplete penetrance and variable expressivity. Exercise can be the trigger for malignant arrhythmias and even syncope in population with a genetic predisposition, being sudden cardiac death as the first symptom. Due to genetic origin, family members must be clinically assessed and genetically analysed after diagnosis or suspected diagnosis of a cardiac channelopathy. Early identification and adoption of personalised preventive measures is crucial to reduce risk of arrhythmias and avoid new lethal episodes. Despite exercise being recommended by the global population due to its beneficial effects on health, particular recommendations for these patients should be adopted considering the sport practised, level of demand, age, gender, arrhythmogenic syndrome diagnosed but also genetic diagnosis. Our review focuses on the role of genetic background in sudden cardiac death during exercise in child and young population

Weight loss in obese patients with heart failure

BACKGROUND: In heart failure (HF), weight loss (WL) has been associated with an adverse prognosis whereas obesity has been linked to lower mortality (the obesity paradox). The impact of WL in obese patients with HF is incompletely understood. Our objective was to explore the prevalence of WL and its impact on long-term mortality, with an emphasis on obese patients, in a cohort of patients with chronic HF. METHODS AND RESULTS: Weight at first visit and the 1-year follow-up and vital status after 3 years were assessed in 1000 consecutive ambulatory, chronic HF patients (72.7% men; mean age 65.8±12.1 years). Significant WL was defined as a loss of ≥5% weight between baseline and 1 year. Obesity was defined as body mass index ≥30 kg/m(2) (N=272). Of the 1000 patients included, 170 experienced significant WL during the first year of follow-up. Mortality was significantly higher in patients with significant WL (27.6% versus 15.3%, P 0.001). In univariable Cox regression analysis, patients with significant WL had 2-fold higher mortality (hazard ratio 1.95 [95% CI 1.39-2.72], P 0.001). In multivariable analysis, adjusting for age, sex, body mass index, New York Heart Association functional class, left ventricular ejection fraction, HF duration, ischemic etiology, diabetes, and treatment, significant WL remained independently associated with higher mortality (hazard ratio 1.89 [95% CI 1.32-2.68], P 0.001). Among obese patients with HF, significant WL was associated with an even more ominous prognosis (adjusted hazard ratio for death of 2.38 [95% CI 1.31-4.32], P=0.004) than that observed in nonobese patients (adjusted hazard ratio 1.83 [95% CI 1.16-2.89], P=0.01). CONCLUSIONS: Weight loss ≥5% in patients with chronic HF was associated with high long-term mortality, particularly among obese patients with HF

Thirty-day outcomes in frail older patients discharged home from the emergency department with acute heart failure: effects of high-risk criteria identified by the DEED FRAIL-AHF trial

Objectives: To study the effect of high-risk criteria on 30-day outcomes in frail older patients with acute heart failure (AHF) discharged from an emergency department (ED) or an ED's observation and short-stay areas. Material and methods: Secondary analysis of discharge records in the Older AHF Key Data registry. We selected frail patients (aged > 70 years) discharged with AHF from EDs. Risk factors were categorized as modifiable or nonmodifiable. The outcomes were a composite endpoint for a cardiovascular event (revisits for AHF, hospitalization for AHF, or cardiovascular death) and the number of days alive out-of-hospital (DAOH) within 30 days of discharge. Results: We included 380 patients with a mean (SD) age of 86 (5.5) years (61.2% women). Modifiable risk factors were identified in 65.1%, nonmodifiable ones in 47.8%, and both types in 81.6%. The 30-day cardiovascular composite endpoint occurred in 83 patients (21.8%). The mean 30-day DAOH observed was 27.6 (6.1) days. Highrisk factors were present more often in patients who developed the cardiovascular event composite endpoint: the rates for patients with modifiable, nonmodifiable, or both types of risk were, respectively, as follows in comparison with patients not at high risk: 25.0% vs 17.2%, P = .092; 27.6% vs 16.7%, P = .010; and 24.7% vs 15.2%, P = .098). The 30-day DAOH outcome was also lower for at-risk patients, according to type of risk factor present: modifiable, 26.9 (7.0) vs 28.4 (4.4) days, P = .011; nonmodifiable, 27.1 (7.0) vs 28.0 (5.0) days, P = .127; and both, 27.1 (6.7) vs 28.8 (3.4) days, P = .005). After multivariate analysis, modifiable risk remained independently associated with fewer days alive (adjusted absolute difference in 30-day DAOH, -1.3 days (95% CI, -2.7 to -0.1 days). Nonmodifiable factors were associated with increased risk for the 30-day cardiovascular composite endpoint (adjusted absolute difference, 10.4%; 95% CI, -2.1% to 18.7%). Conclusion: Risk factors are common in frail elderly patients with AHF discharged home from hospital ED areas. Their presence is associated with a worse 30-day prognosis

Soluble Transferrin Receptor as Iron Deficiency Biomarker: Impact on Exercise Capacity in Heart Failure Patients

The soluble transferrin receptor (sTfR) is a marker of tissue iron status, which could indicate an increased iron demand at the tissue level. The impact of sTfR levels on functional capacity and quality of life (QoL) in non-anemic heart failure (HF) patients with otherwise normal systemic iron status has not been evaluated. We conducted an observational, prospective, cohort study of 1236 patients with chronic HF. We selected patients with normal hemoglobin levels and normal systemic iron status. Tissue iron deficiency (ID) was defined as levels of sTfR > 75th percentile (1.63 mg per L). The primary endpoints were the distance walked in the 6 min walking test (6MWT) and the overall summary score (OSS) of the Minnesota Living with Heart Failure Questionnaire (MLHFQ). The final study cohort consisted of 215 patients. Overall QoL was significantly worse (51 +/- 27 vs. 39 +/- 20, p-value = 0.006, respectively), and the 6 MWT distance was significantly worse in patients with tissue ID when compared to patients without tissue ID (206 +/- 179 m vs. 314 +/- 155, p-value < 0.0001, respectively). Higher sTfR levels, indicating increased iron demand, were associated with a shorter distance in the 6 MWT (standardized beta = -0.249, p < 0.001) and a higher MLHFQ OSS (standardized fi = 0.183, p-value = 0.008). In this study, we show that in patients with normal systemic iron parameters, higher levels of sTfR are strongly associated with an impaired submaximal exercise capacity and with worse QoL

Derechas, historia y memoria: Teoría y praxis de las dictaduras en el poder

Acción financiada por la Comunidad de Madrid a través del Convenio Plurianual con la Universidad Autónoma de Madrid en su línea de actuación estímulo a la investigación de jóvenes doctores, en el marco del V PRICIT (V Plan Regional de Investigación Científica e Innovación Tecnológica). Referencia SI1/PJI/2019-0025

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Solving patients with rare diseases through programmatic reanalysis of genome-phenome data.

Funder: EC | EC Seventh Framework Programm | FP7 Health (FP7-HEALTH - Specific Programme "Cooperation": Health); doi: https://doi.org/10.13039/100011272; Grant(s): 305444, 305444Funder: Ministerio de Economía y Competitividad (Ministry of Economy and Competitiveness); doi: https://doi.org/10.13039/501100003329Funder: Generalitat de Catalunya (Government of Catalonia); doi: https://doi.org/10.13039/501100002809Funder: EC | European Regional Development Fund (Europski Fond za Regionalni Razvoj); doi: https://doi.org/10.13039/501100008530Funder: Instituto Nacional de Bioinformática ELIXIR Implementation Studies Centro de Excelencia Severo OchoaFunder: EC | EC Seventh Framework Programm | FP7 Health (FP7-HEALTH - Specific Programme "Cooperation": Health)Reanalysis of inconclusive exome/genome sequencing data increases the diagnosis yield of patients with rare diseases. However, the cost and efforts required for reanalysis prevent its routine implementation in research and clinical environments. The Solve-RD project aims to reveal the molecular causes underlying undiagnosed rare diseases. One of the goals is to implement innovative approaches to reanalyse the exomes and genomes from thousands of well-studied undiagnosed cases. The raw genomic data is submitted to Solve-RD through the RD-Connect Genome-Phenome Analysis Platform (GPAP) together with standardised phenotypic and pedigree data. We have developed a programmatic workflow to reanalyse genome-phenome data. It uses the RD-Connect GPAP's Application Programming Interface (API) and relies on the big-data technologies upon which the system is built. We have applied the workflow to prioritise rare known pathogenic variants from 4411 undiagnosed cases. The queries returned an average of 1.45 variants per case, which first were evaluated in bulk by a panel of disease experts and afterwards specifically by the submitter of each case. A total of 120 index cases (21.2% of prioritised cases, 2.7% of all exome/genome-negative samples) have already been solved, with others being under investigation. The implementation of solutions as the one described here provide the technical framework to enable periodic case-level data re-evaluation in clinical settings, as recommended by the American College of Medical Genetics

Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

Prognostic role of tissue iron deficiency measured by sTfR levels in heart failure patients without systemic iron deficiency or anemia

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