Reviews & Analysis

GPR15 is a chemoattractant-G protein-coupled receptor that mediates homing of T cells. Stoffers et al. present insights into how GPR15 mediates the recruitment of cytotoxic T cells to contain and clear coxsackievirus B3 from the heart and regulatory T cells to limit immune pathology.

Physical simulators of organs can have great impact on diagnostic and surgical training. A novel biohybrid platform to simulate the right ventricle of the heart with high fidelity has been developed and tested, demonstrating that this is a valid alternative to in vivo experimentation.

Timothy syndrome is a severe variant of long QT syndrome, but an accurate in vivo model to study the disease and identify treatments has been lacking. A knock-in swine model of Timothy syndrome now shows that CaMKII-mediated reduction in peak I_Na slows the cardiac impulse propagation and contributes to the severe arrhythmia in the disorder.

Xie et al. discuss the strengths and limitations of induced cardiomyocyte-like cell reprogramming, the progress made in the past decade, with a focus on single-cell '-omics' research, and the obstacles that remain to be overcome for clinical application.

Raposo-Gutiérrez et al. review the recent knowledge on adaptive immunity in atherosclerosis, the identity of antigens driving the immune response and how to exploit antigen specificity in possible immunomodulatory strategies, including vaccination.

A key consequence of increased and sustained vascular permeability in several inflammatory and cardiovascular disorders is the development of interstitial protein-rich proinflammatory edema. This response remains poorly understood mechanistically and its potential adverse effect on local and systemic diseases is often underestimated. To discuss current findings and identify crucial unresolved questions, a workshop was held in Berlin from 12–15 April 2023. Key topics that were discussed included regulation of endothelial cell junctions, neutrophil-dependent vascular leakage, resolution of edema, exemplar diseases, and anti-edema therapies. This report is a summary of the meeting.

Arrhythmogenic cardiomyopathy is a major cause of sudden death among young people. Three studies show that gene therapy to restore the desmosomal protein PKP2 holds promise in improving the prognosis of affected individuals.

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.

The molecular mechanisms that link propionyl-CoA metabolism and epigenetic regulation of gene expression are unclear, as are the implications for heart function. Now, new insights into the modulation of chromatin acylation and transcription by aberrant oxidation of propionyl-CoA are revealed in the dysfunctional hearts of mice with propionic acidemia.

Coronary artery calcification (CAC) is a strong predictor of coronary artery disease. A genome-wide association study of CAC in diverse populations, including 22,400 participants, identifies two previously unrecognized loci associated with CAC and provides insights into the underlying molecular mechanism of CAC.

Pregestational diabetes is linked to an increased risk of congenital disorders, including cardiac and craniofacial defects, but the underlying mechanisms are unclear. Using a hyperglycemic mouse model, Nishino et al. show that ectopic retinoic acid signaling in the anterior heart field causes aberrant tissue patterning and associated pathologies¹.

TREM2 was recently found to have crucial roles in microglia and adipose tissue macrophage function. Research now shows that genetic deletion of macrophage TREM2 modulates lipid uptake, cell death susceptibility and efferocytosis and ultimately reduces experimental atherosclerosis development.

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.

Ventricular arrhythmias are associated with aging and are a leading cause of sudden cardiac death. A new study shows that hyperactivation of p38γ/δ MAPKs is a key driver of stress-induced ventricular arrhythmias via increased phosphorylation of ryanodine receptor 2 at Ser2367 and impaired localization of potassium voltage-gated channel K_v4.3.

Effective pharmacological treatment options for abdominal aortic aneurysm (AAA) are missing. A study by Zhang et al. suggests that targeting the thrombo-inflammatory activity of platelets by blocking the intracellular accumulation of ceramides might limit AAA progression while not affecting hemostatic platelet function.

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.

Abraham and colleagues review the recent developments and future strategies to therapeutically target the endothelin pathway for a broad spectrum of cardiovascular diseases.

The key determinants of the passive mechanical properties of the heart have long been debated, but remain controversial. Research using a precision approach indicates that titin, microtubules, actin and the extracellular matrix each meaningfully contribute to myocardial passive stiffness in a highly context-dependent manner.

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.

BBLN, a protein with predominantly uncharted functions, serves as an instigator of CAMK2D autophosphorylation, leading to subsequent cardiac remodeling and failure in both humans and mice. The induction of BBLN is driven by hypoxia in TOF and/or pressure overload, as evidenced in mouse models.