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Background Increased myocardial fibrosis may play a key role in heart failure with preserved ejection fraction (HFpEF) pathophysiology. The study aim was to evaluate the presence, associations, and prognostic significance of diffuse fibrosis in HFpEF patients compared to age- and sex-matched controls. Methods We prospectively included 118 consecutive HFpEF patients. Diffuse myocardial fibrosis was estimated by extracellular volume (ECV) quantified by cardiovascular magnetic resonance with the modified Look-Locker inversion recovery sequence. We determined an ECV age- and sex-adjusted cutoff value (33%) in 26 controls. Results Mean ECV was significantly higher in HFpEF patients versus healthy controls (32.9 ± 4.8% vs 28.2 ± 2.4%, P  <  0.001). Multivariate logistic regression showed that body mass index (BMI) (odds ratio (OR) =0.92 [0.86–0.98], P  = 0.011), diabetes (OR = 2.62 [1.11–6.18], P  = 0.028), and transmitral peak E wave velocity (OR = 1.02 [1.00–1.03], P  = 0.022) were significantly associated with abnormal ECV value. During a median follow-up of 11 ± 6 months, the primary outcome (all-cause mortality or first heart failure hospitalization) occurred in 38 patients. In multivariate Cox regression analysis, diabetes (hazard ratio (HR) =1.98 [1.04; 3.76], P  = 0.038) and hemoglobin level (HR = 0.81 [0.67; 0.98], P  = 0.028) were significant predictors of composite outcome. The ECV ability to improve this model added significant prognostic information. We then developed a risk score including diabetes, hemoglobin and ECV > 33% demonstrating significant prediction of risk and validated this score in a validation cohort of 53 patients. Kaplan–Meier curves showed a significant difference according to tertiles of the probability score ( P  <  0.001). Conclusion Among HFpEF patients, high ECV, likely reflecting abnormal diffuse myocardial fibrosis, was associated with a higher rate of all-cause death and first HF hospitalization in short term follow up. Trial registration Characterization of Heart Failure With Preserved Ejection Fraction. Trial registration number: NCT03197350 . Date of registration: 20/06/2017. This trial was retrospectively registered.

Myocardial T1, T2 and T2* imaging techniques become increasingly used in clinical practice. While normal values for T1, T2 and T2* times are well established for 1.5 Tesla (T) cardiovascular magnetic resonance (CMR), data for 3T remain scarce. Therefore we sought to determine normal reference values relative to gender and age and day to day reproducibility for native T1, T2, T2* mapping and extracellular volume (ECV) at 3T in healthy subjects. After careful exclusion of cardiovascular abnormality, 75 healthy subjects aged 20 to 90 years old (mean 56 ± 19 years, 47% women) underwent left-ventricular T1 (3-(3)-3-(3)-5 MOLLI)), T2 (8 echo- spin echo-imaging) and T2 * (8 echo gradient echo imaging) mapping at 3T CMR (Philips Ingenia 3T and computation of extracellular volume after administration of 0.2 mmol/kg Gadovist). Inter- and intra-observer reproducibility was estimated by intraclass correlation coefficient (ICC). Day to day reproducibility was assessed in 10 other volunteers. Mean myocardial T1 at 3T was 1122 ± 57 ms, T2 52 ± 6 ms, T2* 24 ± 5 ms and ECV 26.6 ± 3.2%. T1 (1139 ± 37 vs 1109 ± 73 ms, p < 0.05) and ECV (28 ± 3 vs 25 ± 2%, p < 0.001), but not T2 (53 ± 8 vs 51 ± 4, p = NS) were significantly greater in age matched women than in men. T1 (r = 0.40, p < 0.001) and ECV (r = 0.37, p = 0.001) increased, while T2 decreased significantly (r = −0.25, p < 0.05) with increasing age. T2* was not influenced by either gender or age. Intra and inter-observer reproducibility was high (ICC ranging between 0.81-0.99), and day to day coefficient of variation was low (6.2% for T1, 7% for T2, 11% for T2* and 11.5% for ECV). We provide normal myocardial T2, T2*,T1 and ECV reference values for 3T CMR which are significantly different from those reported at 1.5 Tesla CMR. Myocardial T1 and ECV values are gender and age dependent. Measurement had high inter and intra-observer reproducibility and good day-to-day reproducibility.

Background Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome, with several underlying etiologic and pathophysiologic factors. The presence of diabetes might identify an important phenotype, with implications for therapeutic strategies. While diabetes is associated with worse prognosis in HFpEF, the prognostic impact of glycemic control is yet unknown. Hence, we investigated phenotypic differences between diabetic and non-diabetic HFpEF patients (pts), and the prognostic impact of glycated hemoglobin (HbA1C). Methods We prospectively enrolled 183 pts with HFpEF (78 ± 9 years, 38% men), including 70 (38%) diabetics (type 2 diabetes only). They underwent 2D echocardiography (n = 183), cardiac magnetic resonance (CMR) (n = 150), and were followed for a combined outcome of all-cause mortality and first HF hospitalization. The prognostic impact of diabetes and glycemic control were determined with Cox proportional hazard models, and illustrated by adjusted Kaplan Meier curves. Results Diabetic HFpEF pts were younger (76 ± 9 vs 80 ± 8 years, p = 0.002), more obese (BMI 31 ± 6 vs 27 ± 6 kg/m 2 , p = 0.001) and suffered more frequently from sleep apnea (18% vs 7%, p = 0.032). Atrial fibrillation, however, was more frequent in non-diabetic pts (69% vs 53%, p = 0.028). Although no echocardiographic difference could be detected, CMR analysis revealed a trend towards higher LV mass (66 ± 18 vs 71 ± 14 g/m 2 , p = 0.07) and higher levels of fibrosis (53% vs 36% of patients had ECV by T1 mapping > 33%, p = 0.05) in diabetic patients. Over 25 ± 12 months, 111 HFpEF pts (63%) reached the combined outcome (24 deaths and 87 HF hospitalizations). Diabetes was a significant predictor of mortality and hospitalization for heart failure (HR: 1.72 [1.1–2.6], p = 0.011, adjusted for age, BMI, NYHA class and renal function). In diabetic patients, lower levels of glycated hemoglobin (HbA1C < 7%) were associated with worse prognosis (HR: 2.07 [1.1–4.0], p = 0.028 adjusted for age, BMI, hemoglobin and NT-proBNP levels). Conclusion Our study highlights phenotypic features characterizing diabetic patients with HFpEF. Notably, they are younger and more obese than their non-diabetic counterpart, but suffer less from atrial fibrillation. Although diabetes is a predictor of poor outcome in HFpEF, intensive glycemic control (HbA1C < 7%) in diabetic patients is associated with worse prognosis.

Background Heart failure (HF) with preserved ejection fraction (HFpEF) is increasingly prevalent worldwide due to aging and comorbidities. Epicardial adipose tissue (EAT), favored by diabetes and obesity, was shown to contribute to HFpEF pathophysiology and is an emerging therapeutic target. This study explored the relationship between ventricular EAT measured by cardiovascular magnetic resonance (CMR), metabolic factors, and imaging characteristics in controls, pre-HF patients, and HFpEF patients. Methods Patients from a Belgian cohort enrolled from December 2015 to June 2017 were categorized by HF stage: pre-HF (n = 16), HFpEF (n = 104) and compared to matched controls (n = 26) and to pre-HF (n = 191) from the Beta3-LVH cohort. Biventricular EAT volume was measured in end-diastolic short-axis cine stacks. In the Belgian cohort, associations between EAT, HF stage, and various biological and imaging markers were explored. The clinical endpoint was a composite of mortality or first HF hospitalization in the HFpEF group. Results EAT significantly differed between groups, with higher values in HFpEF patients compared to pre-HF and controls (72.4 ± 20.8ml/m 2 vs. 55.0 ± 11.8ml/m 2 and 48 ± 8.9ml/m 2 , p < 0.001) from the Belgian cohort and to pre-HF (52.0 ± 15.0 ml/m 2 , p < 0.001) from the Beta3-LVH cohort. Subsequent analyses focused on the Belgian cohort. In contrast to atrial fibrillation, diabetes prevalence and body mass index (BMI) did not differ between pre-HF and HFpEF patients. Multivariable logistic regression and random forest classification identified EAT, N-terminal pro-B-type natriuretic peptide (NT-proBNP), and H 2 FPEF score as strong markers of HFpEF status. EAT was significantly correlated with H 2 FPEF score (r = 0.41, p = 0.003), BMI (r = 0.30, p < 0.001), high‐sensitive troponin T (r = 0.41, p < 0.001), NT-proBNP (r = 0.37, p < 0.001), soluble suppression of tumorigenicity-2 (sST2) (r = 0.30, p < 0.001), E/e’ ratio (r = 0.33, p < 0.001), and left ventricular global longitudinal strain (r = 0.35, p < 0.001). In HFpEF patients, diabetes, ischemic cardiomyopathy, and elevated sST2 were independently associated with elevated EAT. In contrast with diabetes and BMI, increased EAT was not associated with prognosis. Conclusions EAT assessed by CMR was significantly higher in HFpEF patients compared to controls and pre-HF patients, irrespective of diabetes and BMI. EAT was moderately associated with HFpEF status. HFpEF patients with elevated EAT exhibited a marked diabetic, ischemic, and inflammatory profile, highlighting the potential role of drugs targeting EAT. Trial registration Characterization of Heart Failure With Preserved Ejection Fraction; Assessment of Efficacy of Mirabegron, a New beta3-adrenergic Receptor in the Prevention of Heart Failure (Beta3_LVH). Trial registration number ClinicalTrials.gov. Identifier: NCT03197350; NCT02599480. Graphical abstract

Aims Heart failure (HF) with preserved ejection fraction (HFpEF) is a disease associated with high morbidity and mortality, for which it is difficult to identify patients with the poorest prognosis in routine clinical practice. Carbohydrate antigen 125 (CA 125) has been shown to be a potential marker of congestion and prognosis in HF. We sought to better characterize HFpEF patients with high CA 125 levels by using a multimodal approach. Methods and results We prospectively enrolled 139 HFpEF patients (78 ± 8 years; 60% females) and 25 controls matched for age and sex (77 ± 5 years; 60% females). They underwent two‐dimensional echocardiography, cardiac magnetic resonance with late gadolinium enhancement [including extracellular volume (ECV) measurement], and serum measurements of CA 125 level. The primary endpoint of the study was a composite of all‐cause mortality or first HF hospitalization. The prognostic impact of CA 125 was determined using Cox proportional hazard models. Median CA 125 levels were significantly higher in HFpEF patients compared with controls [CA 125: 23.5 (14.5–44.7) vs. 14.6 (10.3–21.0) U/mL, P = 0.004]. CA 125 levels were positively correlated with a congestion marker [N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) levels, Pearson's r = 0.37, P < 0.001] and markers of cardiac fibrosis estimated by both ECV (Pearson's r = 0.26, P = 0.003) and fibroblast growth factor 23 levels (Pearson's r = 0.50, P < 0.001). Over a median follow‐up of 49 (22–64) months, 97 HFpEF patients reached the composite endpoint. Even after adjustment for the Meta‐Analysis Global Group in Chronic risk score, a CA 125 level ≥35 U/mL was still a significant predictor of the composite endpoint [hazard ratio (HR): 1.58 (1.04–2.41), P = 0.032] and more particularly of HF hospitalization [HR: 1.81 (1.13–2.92), P = 0.014]. In contrast, NT‐proBNP levels were not an independent predictor. Conclusions CA 125 levels were significantly higher in HFpEF patients compared with controls matched for age and sex and were associated with markers of congestion and cardiac fibrosis. CA 125 levels were a strong and independent predictor of HF hospitalization in HFpEF patients. These data suggest a potential value of CA 125 as a biomarker for staging and risk prediction in HFpEF.

Aims Besides regulating calcium‐phosphate metabolism, fibroblast growth factor 23 (FGF‐23) has been associated with incident heart failure (HF) and left ventricular hypertrophy. However, data about FGF‐23 in HF and preserved ejection fraction (HFpEF) remain limited. The aim of this study was to assess the association between FGF‐23 levels, clinical and imaging characteristics, particularly diffuse myocardial fibrosis, and prognosis in HFpEF patients. Methods and results We prospectively included 143 consecutive HFpEF patients (78 ± 8 years, 61% female patients) and 31 controls of similar age and gender (75 ± 6 years, 61% female patients). All subjects underwent a complete two‐dimensional echocardiography and cardiac magnetic resonance with extracellular volume (ECV) assessment by T1 mapping. FGF‐23 was measured at baseline. Among the patients, differences in clinical and imaging characteristics across tertiles of FGF‐23 levels were analysed with a trend test across the ordered groups. Patients were followed over time for a primary endpoint of all‐cause mortality and first HF hospitalization and a secondary endpoint of all‐cause mortality. Median FGF‐23 was significantly higher in HFpEF patients compared with controls of similar age and gender (247 [115; 548] RU/mL vs. 61 [51; 68] RU/mL, P < 0.001). Among HFpEF patients, higher FGF‐23 levels were associated with female sex, higher incidence of atrial fibrillation, lower haemoglobin, worse renal function, and higher N terminal pro brain natriuretic peptide levels (P for trend < 0.05 for all). Regarding imaging characteristics, patients with higher FGF‐23 levels had greater left atrial volumes, worse right ventricular systolic function, and more fibrosis estimated by ECV (P for trend < 0.05 for all). FGF‐23 was moderately correlated with ECV (r = 0.46, P < 0.001). Over a mean follow‐up of 30 ± 8 months, 43 patients (31%) died and 69 patients (49%) were hospitalized for HF. A total of 87 patients (62%) reached the primary composite endpoint of all‐cause mortality and/or first HF hospitalization. In multivariate Cox regression analysis for the primary endpoint, FGF‐23 (HR: 3.44 [2.01; 5.90], P < 0.001) and E wave velocities (HR: 1.01 [1.00; 1.02], P = 0.034) were independent predictors of the primary composite endpoint. In multivariate Cox regression analysis for the secondary endpoint, ferritin (HR: 1.02 [1.01; 1.03], P < 0.001), FGF‐23 (HR: 2.85 [1.26; 6.44], P = 0.012), and ECV (HR: 1.26 [1.03; 1.23], P = 0.008) were independent predictors of all‐cause mortality. Conclusions Fibroblast growth factor 23 (FGF‐23) levels were significantly higher in HFpEF patients compared with controls of similar age and gender. FGF‐23 was correlated with fibrosis evaluated by ECV. High levels of FGF‐23 were significantly associated with signs of disease severity such as worse renal function, larger left atrial volumes, and right ventricular dysfunction. Moreover, FGF‐23 was a strong predictor of poor outcome (mortality and first HF hospitalization).

Huntington’s disease (HD) is caused by a CAG repeat expansion in the HTT gene, leading to altered gene expression. However, the mechanisms leading to disrupted RNA processing in HD remain unclear. Here we identify TDP-43 and the N6-methyladenosine (m6A) writer protein METTL3 to be upstream regulators of exon skipping in multiple HD systems. Disrupted nuclear localization of TDP-43 and cytoplasmic accumulation of phosphorylated TDP-43 occurs in HD mouse and human brains, with TDP-43 also co-localizing with HTT nuclear aggregate-like bodies distinct from mutant HTT inclusions. The binding of TDP-43 onto RNAs encoding HD-associated differentially expressed and aberrantly spliced genes is decreased. Finally, m6A RNA modification is reduced on RNAs abnormally expressed in the striatum of HD R6/2 mouse brain, including at clustered sites adjacent to TDP-43 binding sites. Our evidence supports TDP-43 loss of function coupled with altered m6A modification as a mechanism underlying alternative splicing in HD. Nguyen et al. identify TDP-43 and METTL3 as key regulators of disrupted RNA splicing in Huntington’s disease, offering insight into how TDP-43 mislocalization and aberrant m6A RNA modification and localization relate to disease pathogenesis.

Background This study aimed to compare the short- and long-term outcomes of robotic (RRC-IA) versus laparoscopic (LRC-IA) right colectomy with intracorporeal anastomosis using a propensity score matching (PSM) analysis based on a large European multicentric cohort of patients with nonmetastatic right colon cancer. Methods Elective curative-intent RRC-IA and LRC-IA performed between 2014 and 2020 were selected from the MERCY Study Group database. The two PSM-groups were compared for operative and postoperative outcomes, and survival rates. Results Initially, 596 patients were selected, including 194 RRC-IA and 402 LRC-IA patients. After PSM, 298 patients (149 per group) were compared. There was no statistically significant difference between RRC-IA and LRC-IA in terms of operative time, intraoperative complication rate, conversion to open surgery, postoperative morbidity (19.5% in RRC-IA vs. 26.8% in LRC-IA; p = 0.17), or 5-yr survival (80.5% for RRC-IA and 74.7% for LRC-IA; p = 0.94). R0 resection was obtained in all patients, and > 12 lymph nodes were harvested in 92.3% of patients, without group-related differences. RRC-IA procedures were associated with a significantly higher use of indocyanine green fluorescence than LRC-IA (36.9% vs. 14.1%; OR: 3.56; 95%CI 2.02–6.29; p < 0.0001). Conclusion Within the limitation of the present analyses, there is no statistically significant difference between RRC-IA and LRC-IA performed for right colon cancer in terms of short- and long-term outcomes.

Background Trisomy 21 (T21) is associated with intellectual disability that ranges from mild to profound with an average intellectual quotient of around 50. Furthermore, T21 patients have a high risk of developing Alzheimer’s disease (AD) early in life, characterized by the presence of senile plaques of amyloid protein and neurofibrillary tangles, leading to neuronal loss and cognitive decline. We postulate that epigenetic factors contribute to the observed variability in intellectual disability, as well as at the level of neurodegeneration seen in T21 individuals. Materials and Methods A genome-wide DNA methylation study was performed using Illumina Infinium® MethylationEPIC BeadChips on whole blood DNA of 3 male T21 patients with low IQ, 8 T21 patients with high IQ (4 males and 4 females), and 21 age- and sex-matched control samples (12 males and 9 females) in order to determine whether DNA methylation alterations could help explain variation in cognitive impairment between individuals with T21. In view of the increased risk of developing AD in T21 individuals, we additionally investigated the T21-associated sites in published blood DNA methylation data from the AgeCoDe cohort (German study on Ageing, Cognition, and Dementia). AgeCoDe represents a prospective longitudinal study including non-demented individuals at baseline of which a part develops AD dementia at follow-up. Results Two thousand seven hundred sixteen differentially methylated sites and regions discriminating T21 and healthy individuals were identified. In the T21 high and low IQ comparison, a single CpG located in the promoter of PELI1 was differentially methylated after multiple testing adjustment. For the same contrast, 69 differentially methylated regions were identified. Performing a targeted association analysis for the significant T21-associated CpG sites in the AgeCoDe cohort, we found that 9 showed significant methylation differences related to AD dementia, including one in the ADAM10 gene. This gene has previously been shown to play a role in the prevention of amyloid plaque formation in the brain. Conclusion The differentially methylated regions may help understand the interaction between methylation alterations and cognitive function. In addition, ADAM10 might be a valuable blood-based biomarker for at least the early detection of AD.

Huntington's disease (HD) is a neurodegenerative disorder caused by a CAG repeat expansion in the first exon of the gene encoding huntingtin. Prior reports have established a correlation between CAG expanded and altered gene expression. However, the mechanisms leading to disruption of RNA processing in HD remain unclear. Here, our analysis of the reported HTT protein interactome identifies interactions with known RNA-binding proteins (RBPs). Total, long-read sequencing and targeted RASL-seq of RNAs from cortex and striatum of the HD mouse model R6/2 reveals increased exon skipping which is confirmed in Q150 and Q175 knock-in mice and in HD human brain. We identify the RBP TDP-43 and the N6-methyladenosine (m6A) writer protein methyltransferase 3 (METTL3) to be upstream regulators of exon skipping in HD. Along with this novel mechanistic insight, we observe decreased nuclear localization of TDP-43 and cytoplasmic accumulation of phosphorylated TDP-43 in HD mice and human brain. In addition, TDP-43 co-localizes with HTT in human HD brain forming novel nuclear aggregate-like bodies distinct from mutant HTT inclusions or previously observed TDP-43 pathologies. Binding of TDP-43 onto RNAs encoding HD-associated differentially expressed and aberrantly spliced genes is decreased. Finally, m6A RNA modification is reduced on RNAs abnormally expressed in striatum from HD R6/2 mouse brain, including at clustered sites adjacent to TDP-43 binding sites. Our evidence supports TDP-43 loss of function coupled with altered m6A modification as a novel mechanism underlying alternative splicing/unannotated exon usage in HD and highlights the critical nature of TDP-43 function across multiple neurodegenerative diseases.