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Abstract Heart failure is a devastating syndrome affecting an increasingly high number of patients worldwide. Its aetiology and pathogenesis are complex with the involvement of factors ranging from the genetic material through valvular dysfunctions to numerous organs beyond the entire cardiovascular system. Based on continuous efforts of the heart failure scientific community we have witnessed major advances in many related disciplines during the last year. For example, epidemiological aspects—paving the road for improved risk prevention—have been thoroughly analysed for various geographical regions. Additionally, evidence‐based approaches now allow the introduction of novel guideline recommended medical therapies (i.e. sodium‐glucose transporter 2 inhibitors, and iron supplementation) while basic and translational research aim to explore additional molecular targets for future heart failure diagnostics and medications. All above aspects are addressed in this article, where a selection of articles published in the ESC Heart Failure journal in 2023 are highlighted. The editors are confident that the scientific contributions of ESC Heart Failure effectively served a highly relevant area of cardiovascular research last year.

Zinc Finger DNA-binding domain-containing proteins are the most populous family among eukaryotic transcription factors. Among these, members of the BTB domain-containing ZBTB sub-family are mostly known for their transcriptional repressive functions. In this Viewpoint article, we explore molecular mechanisms that potentially diversify the function of ZBTB proteins based on their homo and heterodimerization, alternative splicing and post-translational modifications. We describe how the BTB domain is as much a scaffold for the assembly of co-repressors, as a domain that regulates protein stability. We highlight another mechanism that regulates ZBTB protein stability: phosphorylation in the zinc finger domain. We explore the non-transcriptional, structural roles of ZBTB proteins and highlight novel findings that describe the ability of ZBTB proteins to associate with poly adenosine ribose in the nucleus during the DNA damage response. Herein, we discuss the contribution of BTB domain scaffolds to the formation of transcriptional repressive complexes, to chromosome compartmentalization and their non-transcriptional, purely structural functions in the nucleus.

Background and aimsDespite different etiopathogenesis, Fabry Disease cardiomyopathy (FDc) and sarcomeric hypertrophic cardiomyopathy (HCM) share a similar hypertrophic phenotype, including anomalies of the mitral valve apparatus (AMVA). Some of these anomalies have also been described in the pre-hypertrophic stage of both diseases. This cardiovascular magnetic resonance (CMR) study aimed to: (i) compare AMVA between FDc and HCM with a similar degree of left ventricular hypertrophy (LVH), to add new insights into differential diagnosis; (ii) assess whether AMVA represent an early and progressive alteration in FDc; (iii) propose simple and potentially reproducible measurements of AMVA.MethodsThis observational, retrospective study enrolled: (i) 80 Fabry patients, divided into three groups with increasing severity of cardiac phenotype (20 patients LVH-/normal T1, 20 patients LVH-/low T1 and 40 patients LVH+), and (ii) 40 patients with HCM. All patients underwent CMR. The LVH + FDc and the HCM groups were matched for age, sex, body surface area and left ventricular (LV) mass. The following AMVA were measured on cine images: papillary muscles (PMs) hypertrophy (maximal diameter (Dmax) of anterolateral (Al) and posteromedial (Pm) PM), apical displacement, anteriorization of Al PM and anterior mitral valve leaflet (AMVL) elongation. Reference values for defining AMVA were derived from a matched healthy control group (n = 40).ResultsBoth HCM and FDc LVH + patients showed PMs hypertrophy, with a greater degree in the FDc LVH + group [Dmax Al PM 16 ± 3.4 vs. 15 ± 3.1 mm, p 0.017; Dmax Pm PM 14 ± 4.0 vs.12 mm (10.0–14.0), p 0.039] As compared to controls, both HCM and FDc LVH + patients showed PMs apical displacement (HCM 83% vs. healthy volunteers 8%, p

Abstract Background Since the beginning of the anti-COVID-19 vaccination campaign, it has become evident that vaccinated subjects exhibit considerable inter-individual variability in the response to the vaccine that could be partly explained by host genetic factors. A recent study reported that the immune response elicited by the Oxford-AstraZeneca vaccine in individuals from the United Kingdom was influenced by a specific allele of the human leukocyte antigen gene HLA-DQB1. Methods We carried out a genome-wide association study to investigate the genetic determinants of the antibody response to the Pfizer-BioNTech vaccine in an Italian cohort of 1351 subjects recruited in three centers. Linear regressions between normalized antibody levels and genotypes of more than 7 million variants was performed, using sex, age, centers, days between vaccination boost and serological test, and five principal components as covariates. We also analyzed the association between normalized antibody levels and 204 HLA alleles, with the same covariates as above. Results Our study confirms the involvement of the HLA locus and shows significant associations with variants in HLA-A, HLA-DQA1, and HLA-DQB1 genes. In particular, the HLA-A*03:01 allele is the most significantly associated with serum levels of anti-SARS-CoV-2 antibodies. Other alleles, from both major histocompatibility complex class I and II are significantly associated with antibody levels. Conclusions These results support the hypothesis that HLA genes modulate the response to Pfizer-BioNTech vaccine and highlight the need for genetic studies in diverse populations and for functional studies aimed to elucidate the relationship between HLA-A*03:01 and CD8+ cell response upon Pfizer-BioNTech vaccination.

BackgroundA sex-based evaluation of prognosis in heart failure (HF) is lacking.Methods and resultsWe analyzed the Metabolic Exercise test data combined with Cardiac and Kidney Indexes (MECKI) score registry, which includes HF with reduced ejection fraction (HFrEF) patients. A cross-validation procedure was performed to estimate weights separately for men and women of all MECKI score parameters: left ventricular ejection fraction (LVEF), hemoglobin, kidney function assessed by Modification of Diet in Renal Disease, blood sodium level, ventilation vs. carbon dioxide production slope, and peak oxygen consumption (peakVO2). The primary outcomes were the composite of all-cause mortality, urgent heart transplant, and implant of a left ventricle assist device. The difference in predictive ability between the native and sex recalibrated MECKI (S-MECKI) was calculated using a receiver operating characteristic (ROC) curve at 2 years and a calibration plot. We retrospectively analyzed 7,900 HFrEF patients included in the MECKI score registry (mean age 61 ± 13 years, 6,456 men/1,444 women, mean LVEF 33% ± 10%, mean peakVO2 56.2% ± 17.6% of predicted) with a median follow-up of 4.05 years (range 1.72–7.47). Our results revealed an unadjusted risk of events that was doubled in men compared to women (9.7 vs. 4.1) and a significant difference in weight between the sexes of most of the parameters included in the MECKI score. S-MECKI showed improved risk classification and accuracy (area under the ROC curve: 0.7893 vs. 0.7799, p = 0.02) due to prognostication improvement in the high-risk settings in both sexes (MECKI score >10 in men and >5 in women).ConclusionsS-MECKI, i.e., the recalibrated MECKI according to sex-specific differences, constitutes a further step in the prognostic assessment of patients with severe HFrEF.

Little is known either about either physical activity patterns, or other lifestyle-related prevention measures in heart transplantation (HTx) recipients. The history of HTx started more than 50 years ago but there are still no guidelines or position papers highlighting the features of prevention and rehabilitation after HTx. The aims of this scientific statement are (i) to explain the importance of prevention and rehabilitation after HTx, and (ii) to promote the factors (modifiable/non-modifiable) that should be addressed after HTx to improve patients’ physical capacity, quality of life and survival. All HTx team members have their role to play in the care of these patients and multidisciplinary prevention and rehabilitation programmes designed for transplant recipients. HTx recipients are clearly not healthy disease-free subjects yet they also significantly differ from heart failure patients or those who are supported with mechanical circulatory support. Therefore, prevention and rehabilitation after HTx both need to be specifically tailored to this patient population and be multidisciplinary in nature. Prevention and rehabilitation programmes should be initiated early after HTx and continued during the entire post-transplant journey. This clinical consensus statement focuses on the importance and the characteristics of prevention and rehabilitation designed for HTx recipients.

The BTB domain is an oligomerization domain found in over 300 proteins encoded in the human genome. In the family of BTB domain and zinc finger-containing (ZBTB) transcription factors, 49 members share the same protein architecture. The N-terminal BTB domain is structurally conserved among the family members and serves as the dimerization site, whereas the C-terminal zinc finger motifs mediate DNA binding. The available BTB domain structures from this family reveal a natural inclination for homodimerization. In this study, we investigated the potential for heterodimer formation in the cellular environment. We selected five BTB homodimers and four heterodimer structures. We performed cell-based binding assays with fluorescent protein-BTB domain fusions to assess dimer formation. We tested the binding of several BTB pairs, and we were able to confirm the heterodimeric physical interaction between the BTB domains of PATZ1 and PATZ2, previously reported only in an interactome mapping experiment. We also found this pair to be co-expressed in several immune system cell types. Finally, we used the available structures of BTB domain dimers and newly constructed models in extended molecular dynamics simulations (500 ns) to understand the energetic determinants of homo- and heterodimer formation. We conclude that heterodimer formation, although frequently described as less preferred than homodimers, is a possible mechanism to increase the combinatorial specificity of this transcription factor family.

Abstract Background It is known from recent studies that more than 90% of human multi-exon genes are subject to Alternative Splicing (AS), a key molecular mechanism in which multiple transcripts may be generated from a single gene. It is widely recognized that a breakdown in AS mechanisms plays an important role in cellular differentiation and pathologies. Polymerase Chain Reactions, microarrays and sequencing technologies have been applied to the study of transcript diversity arising from alternative expression. Last generation Affymetrix GeneChip Human Exon 1.0 ST Arrays offer a more detailed view of the gene expression profile providing information on the AS patterns. The exon array technology, with more than five million data points, can detect approximately one million exons, and it allows performing analyses at both gene and exon level. In this paper we describe BEAT, an integrated user-friendly bioinformatics framework to store, analyze and visualize exon arrays datasets. It combines a data warehouse approach with some rigorous statistical methods for assessing the AS of genes involved in diseases. Meta statistics are proposed as a novel approach to explore the analysis results. BEAT is available at http://beat.ba.itb.cnr.it. Results BEAT is a web tool which allows uploading and analyzing exon array datasets using standard statistical methods and an easy-to-use graphical web front-end. BEAT has been tested on a dataset with 173 samples and tuned using new datasets of exon array experiments from 28 colorectal cancer and 26 renal cell cancer samples produced at the Medical Genetics Unit of IRCCS Casa Sollievo della Sofferenza. To highlight all possible AS events, alternative names, accession Ids, Gene Ontology terms and biochemical pathways annotations are integrated with exon and gene level expression plots. The user can customize the results choosing custom thresholds for the statistical parameters and exploiting the available clinical data of the samples for a multivariate AS analysis. Conclusions Despite exon array chips being widely used for transcriptomics studies, there is a lack of analysis tools offering advanced statistical features and requiring no programming knowledge. BEAT provides a user-friendly platform for a comprehensive study of AS events in human diseases, displaying the analysis results with easily interpretable and interactive tables and graphics.

AimsImprovement in exercise capacity is the primary goal of physical activity programmes for patients with heart failure (HF). Although activity programmes are effective for some patients, others do not benefit. Identifying factors related to a lack of improvement in submaximal exercise capacity may help us interpret findings and design new interventions. The aim of this study is to identify factors contributing to a lack of improvement in submaximal exercise capacity 3 months after physical activity advice or an exergame intervention in patients with HF. Additionally, we aimed to assess differences in lack of improvement in submaximal exercise capacity of patients whose baseline exercise capacity predicted a worse compared with better prognosis of HF.Methods and resultsThis secondary analysis of the HF-Wii study analysed baseline and 3 month data of the 6 min walk test (6MWT) from 480 patients (mean age 67 years, 72% male). Data were analysed separately in patients with a pre-defined 6 min walking distance at baseline of

Abstract We witnessed major advances in the management of heart failure (HF) in 2022. Results of recent clinical and preclinical investigations aid preventive strategies, diagnostic efforts, and therapeutic interventions, and collectively, they hold promises for a more effective HF care for the near future. Accordingly, currently available information extends the 2021 European Society of Cardiology guidelines and provides a solid background for the introduction of improved clinical approaches in the number of HF‐related cases. Elaboration on the relationships between epidemiological data and risk factors lead to better understanding of the pathophysiology of HF with reduced ejection fraction and HF with preserved ejection fraction. The clinical consequences of valvular dysfunctions are increasingly interpreted not only in their haemodynamic consequences but also in association with their pathogenetic factors and modern corrective treatment possibilities. The influence of coronavirus disease 2019 pandemic on the clinical care of HF appeared to be less intense in 2022 than before; hence, this period allowed to refine coronavirus disease 2019 management options for HF patients. Moreover, cardio‐oncology emerges as a new subdiscipline providing significant improvements in clinical outcomes for oncology patients. Furthermore, the introduction of state‐of‐the‐art molecular biologic methods, multi‐omic approaches forecast improved phenotyping and precision medicine for HF. All above aspects are addressed in this article that highlights a selection of papers published in ESC Heart Failure in 2022.

Abstract Background The malignant transformation of precancerous colorectal lesions involves progressive alterations at both the molecular and morphologic levels, the latter consisting of increases in size and in the degree of cellular atypia. Analyzing preinvasive tumors of different sizes can therefore shed light on the sequence of these alterations. Methods We used a molecular pathway-based approach to analyze transcriptomic profiles of 59 colorectal tumors representing early and late preinvasive stages and the invasive stage of tumorigenesis. Random set analysis was used to identify biological pathways enriched for genes differentially regulated in tumors (compared with 59 samples of normal mucosa). Results Of the 880 canonical pathways we investigated, 112 displayed significant tumor-related upregulation or downregulation at one or more stages of tumorigenesis. This allowed us to distinguish between pathways whose dysregulation is probably necessary throughout tumorigenesis and those whose involvement specifically drives progression from one stage to the next. We were also able to pinpoint specific changes within each gene set that seem to play key roles at each transition. The early preinvasive stage was characterized by cell-cycle checkpoint activation triggered by DNA replication stress and dramatic downregulation of basic transmembrane signaling processes that maintain epithelial/stromal homeostasis in the normal mucosa. In late preinvasive lesions, there was also downregulation of signal transduction pathways (e.g., those mediated by G proteins and nuclear hormone receptors) involved in cell differentiation and upregulation of pathways governing nuclear envelope dynamics and the G2>M transition in the cell cycle. The main features of the invasive stage were activation of the G1>S transition in the cell cycle, upregulated expression of tumor-promoting microenvironmental factors, and profound dysregulation of metabolic pathways (e.g., increased aerobic glycolysis, downregulation of pathways that metabolize drugs and xenobiotics). Conclusions Our analysis revealed specific pathways whose dysregulation might play a role in each transition of the transformation process. This is the first study in which such an approach has been used to gain further insights into colorectal tumorigenesis. Therefore, these data provide a launchpad for further exploration of the molecular characterization of colorectal tumorigenesis using systems biology approaches.

Pathological processes associated with ageing increase the risk of cognitive deficits and dementia. Frailty syndrome, also known as weakness or reserve depletion syndrome, may significantly accelerate these pathological processes in the elderly population. Frailty syndrome is characterized by decreased physiological function and neuropsychiatric symptoms, including cognitive decline and depressive states. In people with cardiovascular disease, the risk of frailty is 3 times higher. Frailty syndrome is particularly prevalent in severe heart failure, which increases the risk of mortality, increases hospital readmission, and reduces patients’ quality of life. In addition, co-occurrence of cognitive impairment and frailty syndrome significantly increases the risk of dementia and other adverse outcomes, including mortality, in the heart failure population.

Abstract Background Aberrant DNA methylation of CpG islands of cancer-related genes is among the earliest and most frequent alterations in cancerogenesis and might be of value for either diagnosing cancer or evaluating recurrent disease. This mechanism usually leads to inactivation of tumour-suppressor genes. We have designed the current study to validate our previous microarray data and to identify novel hypermethylated gene promoters. Methods The validation assay was performed in a different set of 8 patients with colorectal cancer (CRC) by means quantitative reverse-transcriptase polymerase chain reaction analysis. The differential RNA expression profiles of three CRC cell lines before and after 5-aza-2'-deoxycytidine treatment were compared to identify the hypermethylated genes. The DNA methylation status of these genes was evaluated by means of bisulphite genomic sequencing and methylation-specific polymerase chain reaction (MSP) in the 3 cell lines and in tumour tissues from 30 patients with CRC. Results Data from our previous genome search have received confirmation in the new set of 8 patients with CRC. In this validation set six genes showed a high induction after drug treatment in at least two of three CRC cell lines. Among them, the N-myc downstream-regulated gene 2 (NDRG2) promoter was found methylated in all CRC cell lines. NDRG2 hypermethylation was also detected in 8 out of 30 (27%) primary CRC tissues and was significantly associated with advanced AJCC stage IV. Normal colon tissues were not methylated. Conclusion The findings highlight the usefulness of combining gene expression patterns and epigenetic data to identify tumour biomarkers, and suggest that NDRG2 silencing might bear influence on tumour invasiveness, being associated with a more advanced stage.

The co-occurrence of cancer and heart failure (HF) represents a significant clinical drawback as each disease interferes with the treatment of the other. In addition to shared risk factors, a growing body of experimental and clinical evidence reveals numerous commonalities in the biology underlying both pathologies. Inflammation emerges as a common hallmark for both diseases as it contributes to the initiation and progression of both HF and cancer. Under stress, malignant and cardiac cells change their metabolic preferences to survive, which makes these metabolic derangements a great basis to develop intersection strategies and therapies to combat both diseases. Furthermore, genetic predisposition and clonal haematopoiesis are common drivers for both conditions and they hold great clinical relevance in the context of personalized medicine. Additionally, altered angiogenesis is a common hallmark for failing hearts and tumours and represents a promising substrate to target in both diseases. Cardiac cells and malignant cells interact with their surrounding environment called stroma. This interaction mediates the progression of the two pathologies and understanding the structure and function of each stromal component may pave the way for innovative therapeutic strategies and improved outcomes in patients. The interdisciplinary collaboration between cardiologists and oncologists is essential to establish unified guidelines. To this aim, pre-clinical models that mimic the human situation, where both pathologies coexist, are needed to understand all the aspects of the bidirectional relationship between cancer and HF. Finally, adequately powered clinical studies, including patients from all ages, and men and women, with proper adjudication of both cancer and cardiovascular endpoints, are essential to accurately study these two pathologies at the same time.

Abstract Background In this paper we present a method for the statistical assessment of cancer predictors which make use of gene expression profiles. The methodology is applied to a new data set of microarray gene expression data collected in Casa Sollievo della Sofferenza Hospital, Foggia – Italy. The data set is made up of normal (22) and tumor (25) specimens extracted from 25 patients affected by colon cancer. We propose to give answers to some questions which are relevant for the automatic diagnosis of cancer such as: Is the size of the available data set sufficient to build accurate classifiers? What is the statistical significance of the associated error rates? In what ways can accuracy be considered dependant on the adopted classification scheme? How many genes are correlated with the pathology and how many are sufficient for an accurate colon cancer classification? The method we propose answers these questions whilst avoiding the potential pitfalls hidden in the analysis and interpretation of microarray data. Results We estimate the generalization error, evaluated through the Leave-K-Out Cross Validation error, for three different classification schemes by varying the number of training examples and the number of the genes used. The statistical significance of the error rate is measured by using a permutation test. We provide a statistical analysis in terms of the frequencies of the genes involved in the classification. Using the whole set of genes, we found that the Weighted Voting Algorithm (WVA) classifier learns the distinction between normal and tumor specimens with 25 training examples, providing e = 21% (p = 0.045) as an error rate. This remains constant even when the number of examples increases. Moreover, Regularized Least Squares (RLS) and Support Vector Machines (SVM) classifiers can learn with only 15 training examples, with an error rate of e = 19% (p = 0.035) and e = 18% (p = 0.037) respectively. Moreover, the error rate decreases as the training set size increases, reaching its best performances with 35 training examples. In this case, RLS and SVM have error rates of e = 14% (p = 0.027) and e = 11% (p = 0.019). Concerning the number of genes, we found about 6000 genes (p < 0.05) correlated with the pathology, resulting from the signal-to-noise statistic. Moreover the performances of RLS and SVM classifiers do not change when 74% of genes is used. They progressively reduce up to e = 16% (p < 0.05) when only 2 genes are employed. The biological relevance of a set of genes determined by our statistical analysis and the major roles they play in colorectal tumorigenesis is discussed. Conclusions The method proposed provides statistically significant answers to precise questions relevant for the diagnosis and prognosis of cancer. We found that, with as few as 15 examples, it is possible to train statistically significant classifiers for colon cancer diagnosis. As for the definition of the number of genes sufficient for a reliable classification of colon cancer, our results suggest that it depends on the accuracy required.

IntroductionInverted Internal Limiting Membrane (ILM)-flap technique demonstrated its effectiveness, in terms of anatomical closure rate and visual acuity recovery for high myopic macular holes. We evaluated macular function after a successful inverted ILM-flap for macular holes in high myopic eyes (hMMH) using microperimetry to predict visual prognosis.MethodsA retrospective study on 23 eyes of 23 patients after surgical closure of hMMH, was performed. All patients underwent inverted ILM-flap and gas tamponade. Cataract surgery was performed in phakic eyes. Study outcomes including best-corrected visual acuity (BCVA), retinal sensitivity (RS) at central 12°, central retinal sensitivity (CRS) at central 4° and mean deviation (MD), and fixation behavior as bivariate contour ellipse area (BCEA, degrees2) measured by microperimetry, were evaluated over 6 months. A mixed-effects model was used to evaluate and compare the repeated measurements of outcomes between phakic and pseudophakic eyes. A regression model was performed to assess the relationship between BCVA at 6 months and independent variables.ResultsOverall mean BCVA improved from 0.98 ± 0.21 logMAR at baseline to 0.47 ± 0.31 logMAR at the last follow-up (p

PATZ1 is a ubiquitously expressed transcriptional repressor belonging to the ZBTB family that is functionally expressed in T lymphocytes. PATZ1 targets the CD8 gene in lymphocyte development and interacts with the p53 protein to control genes that are important in proliferation and in the DNA-damage response. PATZ1 exerts its activity through an N-terminal BTB domain that mediates dimerization and co-repressor interactions and a C-terminal zinc-finger motif-containing domain that mediates DNA binding. Here, the crystal structures of the murine and zebrafish PATZ1 BTB domains are reported at 2.3 and 1.8 Å resolution, respectively. The structures revealed that the PATZ1 BTB domain forms a stable homodimer with a lateral surface groove, as in other ZBTB structures. Analysis of the lateral groove revealed a large acidic patch in this region, which contrasts with the previously resolved basic co-repressor binding interface of BCL6. A large 30-amino-acid glycine- and alanine-rich central loop, which is unique to mammalian PATZ1 amongst all ZBTB proteins, could not be resolved, probably owing to its flexibility. Molecular-dynamics simulations suggest a contribution of this loop to modulation of the mammalian BTB dimerization interface.

Abstract In the last years, major progress occurred in heart failure (HF) management. Quadruple therapy is now mandatory for all the patients with HF with reduced ejection fraction. Whilst verciguat is becoming available across several countries, omecamtiv mecarbil is waiting to be released for clinical use. Concurrent use of potassium‐lowering agents may counteract hyperkalaemia and facilitate renin–angiotensin–aldosterone system inhibitor implementations. The results of the EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Preserved Ejection Fraction (EMPEROR‐Preserved) trial were confirmed by the Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction (DELIVER) trial, and we now have, for the first time, evidence for treatment of also patients with HF with preserved ejection fraction. In a pre‐specified meta‐analysis of major randomized controlled trials, sodium–glucose co‐transporter‐2 inhibitors reduced all‐cause mortality, cardiovascular (CV) mortality, and HF hospitalization in the patients with HF regardless of left ventricular ejection fraction. Other steps forward have occurred in the treatment of decompensated HF. Acetazolamide in Acute Decompensated Heart Failure with Volume Overload (ADVOR) trial showed that the addition of intravenous acetazolamide to loop diuretics leads to greater decongestion vs. placebo. The addition of hydrochlorothiazide to loop diuretics was evaluated in the CLOROTIC trial. Torasemide did not change outcomes, compared with furosemide, in TRANSFORM‐HF. Ferric derisomaltose had an effect on the primary outcome of CV mortality or HF rehospitalizations in IRONMAN (rate ratio 0.82; 95% confidence interval 0.66–1.02; P = 0.070). Further options for the treatment of HF, including device therapies, cardiac contractility modulation, and percutaneous treatment of valvulopathies, are summarized in this article.

BackgroundPrevious systematic reviews have indicated that exercise-based cardiac rehabilitation (ExCR) for patients with heart failure (HF) has a beneficial effect on health-related quality-of-life (HRQoL) and exercise capacity. However, there is uncertainty regarding potential differential effects of ExCR across HF patient subgroups.ObjectivesThe authors sought to undertake an individual participant data (IPD) meta-analysis to: 1) assess the impact of ExCR on HRQoL and exercise capacity in patients with HF; and 2) investigate differential effects of ExCR according to a range of patient characteristics: age, sex, ethnicity, New York Heart Association functional class, ischemic etiology, ejection fraction, and exercise capacity.MethodsA single dataset was produced, comprising randomized trials where ExCR (delivered for 3 weeks or more) was compared with a no exercise control group. Each trial provided IPD on HRQoL or exercise capacity (or both), with follow-up of 6 months or more. One- and 2-stage meta-analysis models were used to investigate the effect of ExCR overall and the interactions between ExCR and participant characteristics.ResultsIPD was obtained from 13 trials for 3,990 patients, predominantly (97%) with reduced ejection fraction HF. Compared with the control group, there was a statistically significant difference in favor of ExCR for HRQoL and exercise capacity. At 12-month follow-up, improvements were seen in 6-min walk test (mean 21.0 m; 95% confidence interval: 1.57 to 40.4 m; p = 0.034) and Minnesota Living With HF score (mean improvement 5.9; 95% confidence interval: 1.0 to 10.9; p = 0.018). No consistent evidence was found of differential intervention effects across patient subgroups.ConclusionsThese results, based on an IPD meta-analysis of randomized trials, confirm the benefit of ExCR on HRQoL and exercise capacity and support the Class I recommendation of current international clinical guidelines that ExCR should be offered to all HF patients. (Exercise Training for Chronic Heart Failure [ExTraMATCH II]: protocol for an individual participant data meta-analysis; PROSPERO: international database of systematic reviews CRD42014007170).

AimsTo undertake an individual patient data (IPD) meta-analysis to assess the impact of exercise-based cardiac rehabilitation (ExCR) in patients with heart failure (HF) on mortality and hospitalisation, and differential effects of ExCR according to patient characteristics: age, sex, ethnicity, New York Heart Association functional class, ischaemic aetiology, ejection fraction, and exercise capacity.Methods and resultsRandomised trials of exercise training for at least 3 weeks compared with no exercise control with 6-month follow-up or longer, providing IPD time to event on mortality or hospitalisation (all-cause or HF-specific). IPD were combined into a single dataset. We used Cox proportional hazards models to investigate the effect of ExCR and the interactions between ExCR and participant characteristics. We used both two-stage random effects and one-stage fixed effect models. IPD were obtained from 18 trials including 3912 patients with HF with reduced ejection fraction. Compared to control, there was no statistically significant difference in pooled time to event estimates in favour of ExCR although confidence intervals (CIs) were wide [all-cause mortality: hazard ratio (HR) 0.83, 95% CI 0.67-1.04; HF-specific mortality: HR 0.84, 95% CI 0.49-1.46; all-cause hospitalisation: HR 0.90, 95% CI 0.76-1.06; and HF-specific hospitalisation: HR 0.98, 95% CI 0.72-1.35]. No strong evidence was found of differential intervention effects across patient characteristics.ConclusionExercise-based cardiac rehabilitation did not have a significant effect on the risk of mortality and hospitalisation in HF with reduced ejection fraction. However, uncertainty around effect estimates precludes drawing definitive conclusions.

Aims: To update the European Society of Cardiology (ESC) quality indicators (QIs) for the evaluation of the care and outcomes of adults with heart failure. Methods and results: The Working Group comprised experts in heart failure including members of the ESC Clinical Practice Guidelines Task Force for heart failure, members of the Heart Failure Association, and a patient representative. We followed the ESC methodology for QI development. The 2023 focused guideline update was reviewed to assess the suitability of the recommendations with strongest association with benefit and harm against the ESC criteria for QIs. All the new proposed QIs were individually graded by each panellist via online questionnaires for both validity and feasibility. The existing heart failure QIs also underwent voting to 'keep', 'remove' or 'modify'. Five domains of care for the management of heart failure were identified: (1) structural QIs, (2) patient assessment, (3) initial treatment, (4) therapy optimization, and (5) patient health‐related quality of life. In total, 14 'main' and 3 'secondary' QIs were selected across the five domains. Conclusion: This document provides an update of the previously published ESC QIs for heart failure to ensure that these measures are aligned with contemporary evidence. The QIs may be used to quantify adherence to clinical practice as recommended in guidelines to improve the care and outcomes of patients with heart failure. [ABSTRACT FROM AUTHOR]

The association between type 2 diabetes mellitus (T2DM) and heart failure (HF) has been firmly established; however, the entity of diabetic myocardial disorder (previously called diabetic cardiomyopathy) remains a matter of debate. Diabetic myocardial disorder was originally described as the occurrence of myocardial structural/functional abnormalities associated with T2DM in the absence of coronary heart disease, hypertension and/or obesity. However, supporting evidence has been derived from experimental and small clinical studies. Only a minority of T2DM patients are recognized as having this condition in the absence of contributing factors, thereby limiting its clinical utility. Therefore, this concept is increasingly being viewed along the evolving HF trajectory, where patients with T2DM and asymptomatic structural/functional cardiac abnormalities could be considered as having pre‐HF. The importance of recognizing this stage has gained interest due to the potential for current treatments to halt or delay the progression to overt HF in some patients. This document is an expert consensus statement of the Heart Failure Association of the ESC and the ESC Working Group on Myocardial & Pericardial Diseases. It summarizes contemporary understanding of the association between T2DM and HF and discuses current knowledge and uncertainties about diabetic myocardial disorder that deserve future research. It also proposes a new definition, whereby diabetic myocardial disorder is defined as systolic and/or diastolic myocardial dysfunction in the presence of diabetes. Diabetes is rarely exclusively responsible for myocardial dysfunction, but usually acts in association with obesity, arterial hypertension, chronic kidney disease and/or coronary artery disease, causing additive myocardial impairment. [ABSTRACT FROM AUTHOR]

PRKAG2 cardiomyopathy is a rare genetic disorder that manifests early in life with an autosomal dominant inheritance pattern. It harbors left ventricular hypertrophy (LVH), ventricular pre-excitation and progressively worsening conduction system defects. Its estimated prevalence among patients with LVH ranges from 0.23 to about 1%, but it is likely an underdiagnosed condition. We report the association of the PRKAG2 missense variant c.1006G>A p. (Val336Ile) with LVH, conduction abnormalities (short PR interval and incomplete right bundle branch bock) and early-onset arterial hypertension (AH) in a 44-year-old Caucasian patient. While cardiac magnetic resonance (CMR) showed a mild hypertrophic phenotype with maximal wall thickness of 17 mm in absence of tissue alterations, the electric phenotype was relevant including brady–tachy syndrome and recurrent syncope. The same variant has been detected in the patient's sister and daughter, with LVH + early-onset AH and electrocardiographic (ECG) alterations + lipothymic episodes, respectively. Paying close attention to the coexistence of LVH and ECG alterations in the proband has been helpful in directing genetic tests to exclude primary cardiomyopathy. Hence, identifying the genetic basis in the patient allowed for familial screening as well as a proper follow-up and therapeutic management of the affected members. A review of the PRKAG2 cardiomyopathy literature is provided alongside the case report. [ABSTRACT FROM AUTHOR]