The NLRP3-inflammasome inhibitor MCC950 improves cardiac function in a HFpEF mouse model.

Heart failure with preserved ejection fraction (HFpEF) is posing a significant medical challenge due to its growing prevalence, high hospitalization rates and limited response to current treatment options. Accumulating evidence suggests that a comorbidity-driven systemic pro-inflammatory state, including activation of the NLRP3 inflammasome, contributes to the pathogenesis of HFpEF. This study aimed to investigate the potential cardiac protective effects of the selective NLRP3 inhibitor MCC950, in a mouse model of HFpEF.

Reassessing the Mechanisms of PLN-R14del Cardiomyopathy: From Calcium Dysregulation to S/ER Malformation.

The phospholamban (PLN) pathogenic gene variant, p.Arg14del (PLN-R14del), can lead to dilated and arrhythmogenic cardiomyopathy, resulting in heart failure. PLN-R14del cardiomyopathy has been conceptualized as a disease caused by sarco/endoplasmic reticulum calcium adenosine triphosphatase 2a (SERCA2a) superinhibition.

Sparing of the Heart Facilitates Recovery From Cardiopulmonary Side Effects After Thoracic Irradiation.

Purpose: When irradiating thoracic tumors, dose to the heart or lung has been associated with survival. We previously showed in a rat model that in addition to known side effects such as pericarditis, pneumonitis and fibrosis, heart and/or lung irradiation also impaired diastolic function and increased pulmonary artery pressure. Simultaneous irradiation of both organs strongly intensified these effects.

Hallmarks of cancer in patients with heart failure: data from BIOSTAT-CHF.

Background: Within cardio-oncology, emerging epidemiologic studies have demonstrated a bi-directional relationship between heart failure (HF) and cancer. In the current study, we aimed to further explore this relationship and investigate the underlying pathophysiological pathways that connect these two disease entities.

Methods: We conducted a post-hoc analysis in which we identified 24 Gene Ontology (GO) processes associated with the hallmarks of cancer based on 92 biomarkers in 1960 patients with HF.

Heart failure-induced microbial dysbiosis contributes to colonic tumour formation in mice.

Aims: Heart failure (HF) and cancer are the leading causes of death worldwide. Epidemiological studies revealed that HF patients are prone to develop cancer. Preclinical studies provided some insights into this connection, but the exact mechanisms remain elusive.

Deletion of DWORF does not affect cardiac function in aging and in PLN-R14del cardiomyopathy.

The phospholamban () pathogenic gene variant p.Arg14del causes cardiomyopathy, which is characterized by perinuclear PLN protein clustering and can lead to severe heart failure (HF). Elevated expression of dwarf open reading frame (DWORF), a protein counteracting the function of PLN in the sarcoplasmic reticulum (SR), can delay disease progression in a PLN-R14del mouse model.

Early consequences of the phospholamban mutation PLN-R14del in a transgenic mouse model.

Aims: The heterozygous phospholamban (PLN) mutation R14del (PLN R14del ) is associated with a severe arrhythmogenic cardiomyopathy (ACM) developing in the adult. "Superinhibition" of SERCA2a by PLN R14del is widely assumed to underlie the pathogenesis, but alternative mechanisms such abnormal energy metabolism have also been reported. This work aims to (1) to evaluate Ca dynamics and energy metabolism in a transgenic (TG) mouse model of the mutation prior to cardiomyopathy development; (2) to test whether they are causally connected.

The Cardioprotective Effects of Semaglutide Exceed Those of Dietary Weight Loss in Mice With HFpEF.

Obesity-related heart failure with preserved ejection fraction (HFpEF) has become a well-recognized HFpEF subphenotype. Targeting the unfavorable cardiometabolic profile may represent a rational treatment strategy. This study investigated semaglutide, a glucagon-like peptide-1 receptor agonist that induces significant weight loss in patients with obesity and/or type 2 diabetes mellitus and has been associated with improved cardiovascular outcomes.

DWORF Extends Life Span in a PLN-R14del Cardiomyopathy Mouse Model by Reducing Abnormal Sarcoplasmic Reticulum Clusters.

Background: The p.Arg14del variant of the (phospholamban) gene causes cardiomyopathy, leading to severe heart failure. Calcium handling defects and perinuclear PLN aggregation have both been suggested as pathological drivers of this disease.

A Kinase Interacting Protein 1 regulates mitochondrial protein levels in energy metabolism and promotes mitochondrial turnover after exercise.

A Kinase Interacting Protein 1 (AKIP1) is a signalling adaptor that promotes mitochondrial respiration and attenuates mitochondrial oxidative stress in cultured cardiomyocytes. We sought to determine whether AKIP1 influences mitochondrial function and the mitochondrial adaptation in response to exercise in vivo. We assessed mitochondrial respiratory capacity, as well as electron microscopy and mitochondrial targeted-proteomics in hearts from mice with cardiomyocyte-specific overexpression of AKIP1 (AKIP1-TG) and their wild type (WT) littermates.

Fibrotic Marker Galectin-3 Identifies Males at Risk of Developing Cancer and Heart Failure.

Background: Cancer and heart failure (HF) are the leading causes of death in the Western world. Shared mechanisms such as fibrosis may underlie either disease entity, furthermore it is unknown whether this relationship is sex-specific.

Objectives: We sought to investigate how fibrosis-related biomarker galectin-3 (gal-3) aids in identifying individuals at risk for new-onset cancer and HF, and how this differs between sexes.

Evaluation of Senescence and Its Prevention in Doxorubicin-Induced Cardiotoxicity Using Dynamic Engineered Heart Tissues.

Background: Doxorubicin is an essential cancer treatment, but its usefulness is hampered by the occurrence of cardiotoxicity. Nevertheless, the pathophysiology underlying doxorubicin-induced cardiotoxicity and the respective molecular mechanisms are poorly understood. Recent studies have suggested involvement of cellular senescence.

Circulating immune checkpoints predict heart failure outcomes.

Aims: There are limited data examining the role of immune checkpoint (IC) ligands in the pathophysiology of heart failure (HF). Therefore, we explore this in three HF animal models and in three different human cohorts (healthy, stable, and worsening HF).

Methods And Results: Transcriptomic analyses of cardiac tissue of three different HF mouse models revealed differentially expressed IC receptors and their ligands compared with control mice.

Galectin-3 and Blood Group: Binding Properties, Effects on Plasma Levels, and Consequences for Prognostic Performance.

Previous studies have reported an association between ABO type blood group and cardiovascular (CV) events and outcomes. The precise mechanisms underpinning this striking observation remain unknown, although differences in von Willebrand factor (VWF) plasma levels have been proposed as an explanation. Recently, galectin-3 was identified as an endogenous ligand of VWF and red blood cells (RBCs) and, therefore, we aimed to explore the role of galectin-3 in different blood groups.

A Kinase Interacting Protein 1 (AKIP1) promotes cardiomyocyte elongation and physiological cardiac remodelling.

A Kinase Interacting Protein 1 (AKIP1) is a signalling adaptor that promotes physiological hypertrophy in vitro. The purpose of this study is to determine if AKIP1 promotes physiological cardiomyocyte hypertrophy in vivo. Therefore, adult male mice with cardiomyocyte-specific overexpression of AKIP1 (AKIP1-TG) and wild type (WT) littermates were caged individually for four weeks in the presence or absence of a running wheel.

Multi-omics analyses identify molecular signatures with prognostic values in different heart failure aetiologies.

Background: Heart failure (HF) is the leading cause of morbidity and mortality worldwide, and there is an urgent need for more global studies and data mining approaches to uncover its underlying mechanisms. Multiple omics techniques provide a more holistic molecular perspective to study pathophysiological events involved in the development of HF.

Methods: In this study, we used a label-free whole myocardium multi-omics characterization from three commonly used mouse HF models: transverse aortic constriction (TAC), myocardial infarction (MI), and homozygous Phospholamban-R14del (PLN-R14).

Clonal haematopoiesis of indeterminate potential: associations with heart failure incidence, clinical parameters and biomarkers.

Aim: We aimed to analyse the association of clonal haematopoiesis of indeterminate potential (CHIP) with incident heart failure (HF) in a European population cohort.

Methods And Results: From the prospective Prevention of Renal and Vascular End-stage Disease (PREVEND) cohort, we included all 374 participants with incident HF and selected 1:1 age- and sex-matched control subjects. Peripheral blood samples of 705 individuals were successfully analysed by error-corrected next generation sequencing for acquired mutations at a variant allele frequency ≥2% in 27 CHIP driver genes.

Towards a Better Understanding of Genotype-Phenotype Correlations and Therapeutic Targets for Cardiocutaneous Genes: The Importance of Functional Studies above Prediction.

Genetic variants in gene-encoding proteins involved in cell−cell connecting structures, such as desmosomes and gap junctions, may cause a skin and/or cardiac phenotype, of which the combination is called cardiocutaneous syndrome. The cardiac phenotype is characterized by cardiomyopathy and/or arrhythmias, while the skin particularly displays phenotypes such as keratoderma, hair abnormalities and skin fragility. The reported variants associated with cardiocutaneous syndrome, in genes DSP, JUP, DSC2, KLHL24, GJA1, are classified by interpretation guidelines from the American College of Medical Genetics and Genomics.