Research Briefing

The mechanisms by which stroke and myocardial infarction trigger lymphocyte loss remain poorly defined. This study shows that the release of neutrophil extracellular traps (NETs) after stroke and myocardial infarction triggers B cell apoptosis and reduces the number of IgA-producing plasma cells. Therapeutic targeting of NETs is immunoprotective in mice and humans.

Motivated by a CRISPR screen, in vitro and in vivo studies identified an essential role for the bromodomain and extraterminal domain (BET) family member BRD4 in the differentiation of second heart field progenitors into cardiomyocytes. Single-cell transcriptomic studies showed that BRD4 deficiency affects a specific subset of cardiac progenitor cells.

Cardiometabolic multimorbidity — the coexistence of type 2 diabetes, ischemic heart disease or stroke — is a growing clinical and public health challenge. Accelerated biological aging, measured by clinical traits, provides innovative clues into subclinical prevention of cardiometabolic multimorbidity and mortality among older adults.

Myocardial infarction causes endoplasmic reticulum (ER) stress, thereby triggering the release of a set of poorly defined growth factors. A study shows that the growth factor CRELD2 is secreted in response to ER stress and is required for preserving heart function after myocardial infarction in mice.

Environmental factors can contribute to congenital disorders, including heart defects and craniofacial malformations. Single-cell multi-omic analyses in mouse embryos from diabetic mothers (with high intrauterine glucose levels) revealed epigenetic changes in specific sub-populations of cardiac and craniofacial progenitors. These changes affected retinoic acid signaling and axial patterning, contributing to the observed developmental anomalies.

We show how a build-up of propionyl-CoA in a mouse model of propionic acidaemia produces histone modifications in the heart. The transcriptional responses included genes implicated in contractile dysfunction. Notably, female mice are more severely affected, owing to a protective effect of β-alanine in males, a therapeutically important finding.

BBLN, a protein with largely unknown function, was found to be upregulated in damaged hearts of children with tetralogy of Fallot, one of the most frequent congenital heart defects. Transgenic mice and in vitro studies showed that elevated BBLN levels triggered heart damage by activation of the protein CAMK2D.

Passive stiffness measurements in heart samples of a ‘titin-cleavage’ mouse model reveal the elastic and viscous force contributions of individual myocardial components. Titin is the principal contributor to elastic forces, whereas the microtubules and titin, followed by actin, dominate the viscous force contributions; the extracellular matrix contributes at high strain.

Right ventricular failure is a major cause of morbidity and mortality in pulmonary hypertension. Transcriptomic profiling of adaptive and maladaptive right ventricular remodeling in humans adds to our basic knowledge of myocardial remodeling and identifies molecular subgroups and biomarkers.

Inflammatory monocytes and macrophages in the heart express C-C chemokine receptor 2 (CCR2) on their cell surface and contribute to heart failure pathogenesis. This study established the feasibility of imaging CCR2⁺ cells by positron emission tomography in patients with myocardial infarction.

Patients with chronic ischemic heart disease — an important cause of heart failure — show altered myocardial bioenergetics with metabolomic and transcriptomic changes that seem to occur at a global, rather than regional, level in human hearts.

We established a mouse model that recapitulates the clinical symptoms of Takotsubo syndrome (‘broken heart syndrome’) and revealed a causal relationship between calcineurin-dependent cardiac inflammation and disease severity. Inhibition of calcineurin as a therapeutic approach is now entering a multi-center clinical trial.

We outline protein interaction networks for 13 ion channels isolated from mouse hearts and show that several protein components are shared between ion channel networks. Multi-omic data integration couples these findings to features of the human heart electrocardiogram and we evaluate the functional effect of ten network proteins on cardiac electrophysiology.

Modeling complex immune responses to decipher and target the underlying inflammatory mechanisms of atherosclerotic cardiovascular disease (ASCVD) in humans has been challenging. By combining systems immunology-driven drug repurposing with drug functional screens directly in human samples, we identified a new anti-atherosclerotic use for the dual kinase inhibitor saracatinib.

Targeting the Notch ligand DLL4 in adult liver vessels induced transcriptional states associated with endothelial cell (EC) proliferation and sprouting. However, genetic and pharmacological inhibition of these angiogenic cell states did not prevent an abnormal vasculature and pathology in the liver, suggesting that transcriptional states do not always inform on the vascular phenotype and related pathophysiology.

Our study demonstrates that statins improve endothelial function and vascular health by inhibiting the epigenetic activation of the YAP–SOX9 signaling axis and subsequently preventing endothelial-to-mesenchymal transition in conditions associated with an increased risk of cardiovascular disease, such as type 2 diabetes.

Our work defines three-dimensional atlases that illustrate the morphological and molecular heterogeneity of the mouse nasal vasculature and lymphatic system. The unique features of these vessels offer insights into their associations with nasal inflammation, infection and aging.

We report an intronic variant of the endothelial angiopoietin receptor TIE2 that is associated with increased gene expression and decreased risk of coronary artery disease. Genetic deletion of Tie2 in hypercholesterolemic mice shows that the Tie2 receptor protects from atherosclerosis by controlling inflammation in the arterial wall.

Variants in the alpha kinase 3 (ALPK3) gene cause cardiomyopathy, but we have little understanding of the mechanisms at play. We demonstrate that ALPK3 forms a critical signaling node that links contractile proteins to protein quality control machinery. These findings may open new therapeutic approaches to treat cardiomyopathies.

We report a new non-invasive approach to track neutrophils in both mice and humans by directing multimodal fluorine-loaded nanotracers equipped with specific binding peptides to neutrophil surface markers to enable background-free readout by in vivo ¹⁹F MRI.