Volume 2 Issue 12, December 2023

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

de Vries, Conomos, Singh and Nicholson et al. identify two additional loci associated with coronary artery calcification (ARSE and MMP16) via a genome-wide association study in 22,400 participants from multiple ancestral groups and prove that ARSE is a mediator of vascular smooth muscle cell calcification and phenotype switching.

Zhang et al. report that alkaline ceramidase 1–mediated ceramide degradation in platelets alleviated platelet-involved vascular inflammation and abdominal aortic aneurysm formation but without affecting hemostasis and thrombosis.

Nishino et al. show how maternal diabetes leads to epigenetic changes in cardiac and pharyngeal progenitor subsets with anteroposterior patterning and retinoic acid signaling dysregulation, revealing how environmental factors can cause birth defects.

Romero-Becerra et al. report that stress kinases p38γ and p38δ are activated in ventricles of old mice and in arrhythmogenic conditions, and they demonstrate that p38γ/δ -driven phosphorylation of RyR2 and SAP97 is a trigger for ventricular fibrillation.

Metabolism can influence gene expression through histone modifications. Using a mouse model of the inborn error of metabolism propionic acidaemia, Park et al. show how raised propionate levels produce epigenetic actions that impact cardiac function.

Bradford, Zhang and colleagues generate a mouse model harboring a mutation that impacts PKP2 splicing and show that one-time administration of AAV-PKP2 in neonatal mice could restore PKP2 and prevent the onset of key pathological features of arrhythmogenic right ventricular cardiomyopathy, and one-time administration in adult mice could rescue the phenotype and prevent sudden death up to 4 months post treatment.

Kyriakopoulou et al. report that adeno-associated virus-mediated delivery of PKP2 in PKP2^{c.2013delC/WT} induced pluripotent stem cell-derived cardiomyocytes and heterozygous Pkp2^c.1755delA knock-in mice restores cardiomyocyte junctions, enhances cardiac function and mitigates arrhythmogenic substrates leading to arrhythmogenic cardiomyopathy.

Zhang et al. show that bone marrow fatty acid metabolism fuels expanded leukocyte production after myocardial infarction and, based on mouse, pig and human data, suggest that lipolysis in marrow adipocytes provides fatty acids to hematopoietic stem cells.

Porta-Sanchez et al. developed a pig model for Timothy syndrome (TS), which mirrors the severe heart condition seen in children with TS and also uncovers novel triggers of these life-threatening cardiac arrhythmias, illustrating the suitability of the new TS animal model for exploring new therapies.

Singh et al. developed a soft robotic model that can mimic the right ventricular motion and hemodynamics in healthy and pathological conditions and can be used as an in vitro simulator for tricuspid valve repair and replacement.