Research articles

Snellings et al. show that an identical PIK3CA mutation is found in both developmental venous anomalies (DVAs) and associated cerebral cavernous malformations (CCMs). However, an activating MAP3K3 mutation appears only in CCMs, supporting a mechanism where DVAs develop as the result of a PIK3CA mutation.

Jarr and colleagues show that statins augment efferocytosis by inhibiting the nuclear translocation of NF-κB1 p50 and suppressing the expression of the key ‘don’t-eat-me’ molecule CD47, which in part explains the pleiotropic effects of statins and provides a basis for future translational efforts.

Sun and Li propose and validate a model for cholesterol engagement and transport via the ATP-binding cassette transporter ABCA1, via generating and comparing high-resolution cryo-EM structures of three distinct states of the transporter: with and without ATP and a mutant form unable to export cholesterol that is relevant to human pathology

In a multicenter research program coordinated by the International Mouse Phenotyping Consortium, Spielmann et al. analyze the cardiac function and structure in ~4,000 monogenic mutant mice and identify 705 mouse genes involved in cardiac function, 75% of which have not been previously linked to cardiac heritable disease in humans. Using the UK Biobank human data, the authors validate the link between cardiovascular disease and some of the newly identified genes to illustrate the resource value and potential of their mutant mouse collection.

Song and colleagues show that FDA-approved cough suppressant dextromethorphan could be used as an agonist of sigma non-opioid intracellular receptor 1 (SIGMAR1) to normalize the action potential in human cellular models and a mouse model of Timothy syndrome, a congenital disease with no available treatment. The researchers also show that dextromethorphan normalizes the action potential in human cellular models of two additional inherited cardiac arrhythmias: long QT syndrome types 1 and 2, which are caused by mutations in different genes.

Using large-scale single-nucleus transcriptomics, Nicin et al. report insights into human cardiac hypertrophy, caused by pressure overload, at single-cell resolution. The authors show that intercellular communication, particularly via the Eph receptor tyrosine kinase EPHB1, is impaired in human cardiomyopathy.

Honigberg and colleagues analyzed the frequency of depressed mood in conjunction with polygenic risk scores for coronary artery disease (CAD), type 2 diabetes (T2D) and atrial fibrillation in the UK Biobank and showed that depressed mood was independently associated with a lower risk of CAD and T2D across the cardiometabolic polygenic risk spectrum.

Cerebral venous thrombosis (CVT) is a rare life-threatening disease of unknown etiology. Stegner et al. show that aberrant platelet activation through cooperative signaling of CLEC-2 and GPIIb/IIIa receptors triggers foudroyant CVT in mice and shed light on the molecular pathways of the disease pathogenesis.

In this epidemiological analysis, Marcus et al. show that acute alcohol consumption is associated with a higher risk of discrete atrial fibrillation episodes, as well as for new-onset (incident) atrial fibrillation, in the general population.

Hernandez et al. show that aortic intima resident macrophages (Mac^AIR) seed the mouse aorta at birth, self-replicate and line the aortic lumen together with the endothelium, protecting the aorta from clot formation in regions of disturbed flow by clearing fibrin deposits and blunting thrombin activity.

Koplev et al. apply interactive system analyses to infer and characterize gene-regulatory networks (GRNs) active within and across tissues that cause cardiometabolic disease and coronary artery disease (CAD). By including GWAS in the integrative analysis, the provided multiorgan framework of GRNs is suggested to explain significantly more heritability of CAD than what has been achieved by analyzing GWAS alone.

Borlaug et al. show that, among patients where heart failure was excluded, an increasing H₂FPEF score was associated with greater left atrial dilation, left ventricular hypertrophy and more severe diastolic dysfunction.

Sustained cardiac function depends on circadian REV-ERBs. Here, Dierickx et al. show that circadian nuclear receptors REV-ERBα and β are indispensable to establish the transcriptional program that controls cardiac metabolism and NAD⁺ production. Deregulation of REV-ERBs leads to dilated cardiomyopathy and premature death.

Sick heart and vessels skew hematopoiesis toward inflammatory myeloid cells. Rhode et al. show that hypertension, atherosclerosis and myocardial infarction cause endothelial dysfunction in bone marrow (BM), which in return causes overproduction of inflammatory myeloid cells and systemic leukocytosis in mice. This process is mediated by VEGF signaling, IL-6 and versican production by the BM endothelium.