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Stoffers, Wolf et al. report that, in virus-mediated myocarditis, GPR15 deficiency delays the recruitment of T cells into cardiac tissue, which impairs viral elimination and leads to delayed but also prolonged inflammation and, thus, adverse cardiac outcomes.
Lhoste et al. show that cardiometabolic and renal traits of the US population have shifted from phenotypes with high blood pressure and high cholesterol toward poor kidney function, hyperglycemia and severe obesity.
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 PKP2c.2013delC/WT induced pluripotent stem cell-derived cardiomyocytes and heterozygous Pkp2c.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.
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.
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.
By single-cell mass cytometry and adoptive transfer of B cell subtypes in mice, Pattarabanjird et al. show that human CD24hi circulating marginal zone B cells produce IgM to atherosclerosis antigens and confer atheroprotection. Blocking CD24 increased vascular inflammation in hyperlipidemic humanized mice.
Patterson, Firulyova, et al. report that TREM2 is a key regulator of foamy macrophage differentiation. Myeloid-specific deletion of Trem2 caused increased macrophage susceptibility to cholesterol-mediated toxicity and cell death and significantly attenuated atherosclerotic plaque progression in mice.
Abd Alla et al. identify bublin coiled-coil protein (BBLN) as a factor upregulated in unrepaired hearts of patients with tetralogy of Fallot, and show that this protein binds to and controls the function of calcium/calmodulin-dependent protein kinase II delta (CAMK2D). Overexpression of BBLN in mice induced pathological cardiac remodeling, which was precluded when the interaction of BBLN with CAMK2D was prevented or upon CAMK2D downregulation.
The results of EMPATROPISM-FE, a post hoc analysis of the EMPA-TROPISM trial performed by Angermann et al., suggest that the beneficial effects of empagliflozin treatment in heart failure populations may be related to changes in iron metabolism.
Loescher, Freundt et al. investigated the contribution of each cytoskeletal filament to passive myocardial stiffness by using a mouse model that allows for specific cleavage of titin; they show that titin is a major cytoskeletal filament controlling myocardial elastic forces, whereas viscous forces are controlled by titin, the microtubules and actin.
Xie et al. characterize the translational dynamics of fibroblast conversion into induced cardiomyocytes (iCMs) and identify the protein Ybx1 as a critical barrier to iCM transdifferentiation. Ybx1 protein removal in mice with myocardial infarction enhanced iCM conversion and rescued cardiac dysfunction.
Sweat, Cao et al. used different genetic and epigenetic approaches to show that Tbx5 is essential for the maintenance of atrial identity in postnatal cardiomyocytes by binding atrial-specific enhancers and maintaining the atrial-specific chromatin architecture, in a dose-dependent manner.
Kwartler et al. show that α-smooth muscle actin functions in the nucleus by associating with chromatin remodeling complexes and the promoters of smooth muscle-specific genes, but this nuclear activity is reduced in ACTA2 p.Arg179 pathogenic variants, resulting in impaired smooth muscle differentiation and increased plasticity.
Khassafi et al. identify molecular subgroups of right ventricular (RV) dysfunction using transcriptomic analysis of RV samples from individuals with compensated RV hypertrophy or decompensated RV failure and two rat models of RV dysfunction. Several extracellular matrix genes found to be deregulated in decompensated RV subgroups were validated at the protein level in two independent cohorts of individuals with pulmonary arterial hypertension, revealing their predictive biomarker potential in maladaptive RV development.
Eberhardt et al. show that SARS-CoV-2 infects human coronary lesions where it preferentially targets plaque macrophages, triggering plaque inflammation and potentially leading to acute cardiovascular complications and long-term cardiovascular risks in patients with COVID-19.
Abplanalp et al. define the transcriptome of cells carrying mutations in a specific gene at a single-cell level (MutDetect-Seq) and apply it to reveal the cell-intrinsic effects of mutations in DNMT3A associated with clonal hematopoiesis in patients with heart failure.