Research articles

Through a combination of transcriptomic and proteomic profiling of human right ventricle tissue with plasma proteome profiling in a Canadian cohort of patients with pulmonary arterial hypertension (PAH), Bonnet et al. discovered new circulating proteins associated with right ventricular dysfunction in the setting of PAH.

Su, Chen et al. show that sepsis-derived S100A8/A9 induces GSDMD-dependent platelet pyroptosis via the TLR4/ROS/NLRP3/caspase 1 pathway, leading to the release of ox-mtDNA contributing to neutrophil extracellular traps (NET) formation. NET in turn release S100A8/A9 and accelerate platelet pyroptosis, forming a positive feedback loop, thereby amplifying the production of proinflammatory cytokines. GSDMD deficiency in platelets or pharmacological inhibition of S100A9 using Paquinimod can break this detrimental feedback loop, thus ameliorating excessive NET-mediated inflammation in mouse models of severe sepsis.

Using data from the MONICA/KORA registry, Chen et al. show that the risk of heat-related non-fatal myocardial infarction was significantly elevated in patients receiving anti-platelet medication and beta-receptor blockers compared with non-users, and the effect of the medications was stronger in younger patients, with lower prevalence of pre-existing cardiovascular disease, compared with older patients.

Lam et al. show that conditional deletion of calcineurin B1 in cardiomyocytes and its inhibition using the US Food and Drug Administration-approved drug, FK506, promotes cardiomyocyte cell-cycle re-entry and increases cardiomyocyte numbers in adult mice

Zhao et al. show that, in patients with coronary artery disease, CD4⁺ T cells present a blunted response to SARS-CoV-2 and Epstein–Barr viral antigens, due to the overexpression of the immune checkpoint CD155 in macrophages, primed by the exposure to low-density lipoprotein and its oxidized form. The experiments show that CD155 overexpression is due to stabilizing post-translational modifications mediated by the mRNA methylase MTTL3.

Grune et al. show that hypokalemic mice develop spontaneous ventricular tachycardia after myocardial infarction, and they use this model to dissect the role of immune cells in arrhythmia: neutrophils increase ventricular tachycardia, partly by promoting reactive oxygen species production, whereas efferocytic macrophages play a protective role.

Using rat and mouse models of pulmonary hypertension and patients’ data, Shu, Liu, Zhou et al. show that the concomitant increase in immunoglobulin E (IgE) and mast cells expressing the effector receptor FcεRIα has an important role in pulmonary vascular remodeling, and genetic and pharmacological inhibition of the IgE–FcεRIα signaling alleviated the progression of pulmonary hypertension in animal models.

Fractional flow reserve (FFR) is the current gold standard method to quantify coronary blood flow (CBF) changes in coronary artery disease. In a large comparative study on 203 diseased arteries, Aubiniere-Robb et al. analyzed the degree of concordance between fractional and absolute CBF reduction and identified the FFR areas with high discordance. Patients with those FFR values may benefit from the additional absolute CBF measures.

Pianca and Sacchi et al. unveil an important role for glucocorticoids and their receptor (GR) in cardiomyocyte cytoarchitectural/metabolic maturation, cell cycle exit and loss of regenerative ability, and they propose GR antagonization as a strategy for heart regeneration.

Yu et al. show that Piezo1 is the stretch-activated mechanosensor that provides the calcium source to activate TRPM4 and the downstream CaMKII-HDAC4-MEF2 pathway, a key mediator in the cardiomyocytes’ hypertrophic response in pressure overload models.

Boon et al. show that thalidomide appears to be efficacious in the management of chronic pain, bleeding and ulceration in 18 patients with severely symptomatic arteriovenous malformations refractory to conventional therapies.

Hansmann et al. show that serial intravascular infusions of conditioned media produced by allogenic umbilical cord mesenchymal stem cells markedly improved the clinical features of a young child with severe pulmonary arterial hypertension. The multi-omic approach analyzing the transcriptome and the proteome of these stem cells isolated from four donors provides initial insight into their beneficial paracrine function.

Using high-resolution confocal images and computational surface mapping, Esteban et al. provide a detailed pseudodynamic atlas of early heart tube development (E7.5–E8.5), develop a morphometric staging system based on landmark curves and distances in the surface of the tissues and identify parameters that can be used for precise embryo staging across different labs. This morphometric analysis reveals early signs of left–right asymmetry, before the cardiac looping stage, which is regulated by the Nodal signaling pathway.

Increased late sodium current due to the disruption of voltage-gated sodium channel inactivation is a common pathogenic mechanism in different arrhythmogenic syndromes. Chakouri et al. show that fibroblast growth factor homologous factors (FHFs) modulate pathogenic late sodium current in an isoform-specific way, and leverage this observation to design and test a prototype of inhibitor peptide based on a protein domain from an inhibitory FHF isoform.

Bernier-Latmani et al. report a mechanism for maintaining colon cancer-associated vasculature, in which colon endothelial apelin signaling promotes migration of distant venous endothelial cells toward the tumor progenitor cell niche to sustain VEGFA-independent vascular expansion and a normoxic microenvironment.

Corti et al. show that the proteoglycan Syndecan-2 (Sdc2) regulates the interaction between phosphatase DEP1 and the vascular endothelial growth factor receptor VEGFR2. Depletion or antibody-mediated inhibition of Sdc2 causes compromised internalization of DEP1, and excessive expression of DEP1 in the membrane results in large dephosphorylation specifically of VEGFR2 Y951 residue, leading to reduced VEGF-mediated permeabilization without affecting other VEGF-mediated functions, with beneficial effects in animal models of skin edema and brain focal stroke.

Atherosclerosis is accompanied by an autoimmune response that includes CD4 T cells recognizing epitopes in apolipoprotein B (APOB). Saigusa et al. analyzed the transcriptomes and T cell receptors of APOB-specific CD4 T cells by single-cell RNA sequencing using MHC-II tetramers in women with atherosclerosis, and showed that APOB-specific regulatory T cells switch to a more memory-like phenotype in atherosclerosis.

Wang et al. analyze the metabolome and lipidome of heart and plasma samples from patients with HCM and healthy individuals and identify panels of metabolites that can be used as diagnostic biomarkers of HCM or predictors of HCM patient survival; patients are stratified into three groups with distinct cardiac function and survival and identify metabolic pathways that are greatly affected in patients with HCM, suggesting that targeting the pentose phosphate pathway and oxidative stress may represent effective ways to treat HCM.

Despite an emerging role for cerebrovascular endothelial cells in a range of neurological pathologies, AAV vector development to date has focused on tools designed to target neurons or astrocytes. Here, Krolak et al. describe a specific variant of AAV (AAV-BI30), with high specificity and efficacy for transduction of endothelial cells across the central nervous system.

Huang et al. show that myocardial infarction (MI)-associated vasculature is structurally and functionally abnormal, impeding vessel function and cardiac repair in mice. Analyses of the transcriptome of the cardiac endothelium after MI identify a PDGF–NF-κB–HIF-1α Snail axis responsible for mesenchymal transformation of endothelial cells and show that genetic ablation or targeted disruption of PDGF signaling normalizes vasculature and improves cardiac function recovery after MI.