Letters

In a retrospective cohort study examining the comparative effectiveness of diabetes drugs in adults at moderate risk for cardiovascular disease, GLP-1 receptor agonists and SGLT2 inhibitors reduced the risk of cardiovascular events compared to DPP4 inhibitors, whereas sulfonylureas increased the risk.

Piollet, Porsch et al. report that the myeloid receptor TREM2 limits necrotic core formation in atherosclerosis and controls key atherosclerosis-related functions of macrophages, such as efferocytosis, lipid uptake and foam cell survival.

Gustafsson, Lampa et al. used proteomics, metabolomics and clinical factors in a case–cohort study to identify biomarkers of imminent myocardial infarction and devise a prediction model for imminent myocardial infarction, which can be clinically used in the general population.

Shetty et al. report that individuals of African ancestry harboring a high-proportion spliced-in titin truncating variant have a similar increase in the risk of atrial fibrillation, dilated cardiomyopathy and heart failure as individuals of European ancestry.

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.

C-C chemokine receptor type 2 (CCR2) is expressed on inflammatory populations of monocytes and macrophages that contribute to heart failure. In this study, Lavine et al. establish the feasibility of CCR2 imaging in patients who have had a myocardial infarction.

A single-center, observational cohort study assessing the mitochondrial bioenergetics of left ventricular tissue from patients undergoing coronary artery bypass grafting surgery suggests that viable myocardium has global alterations in bioenergetics and transcriptome without large regional differences between areas with or without inducible ischemia.

Perez-Bermejo et al. performed an in-depth study on a variant in the BAG3 gene that has been previously associated with lowered incidence of heart failure and show that, in induced pluripotent stem cell-derived cardiomyocytes engineered to express such BAG3 variant, the interactome of the corresponding BAG3 protein has changed, rendering the engineered cardiomyocytes more resistant to a well-known cardiotoxic drug.

Seront et al. report a case of successful management of high-risk cervicofacial fetal lymphatic malformations in utero via sirolimus taken orally by the mother from the 22nd week of pregnancy until 2 weeks before planned delivery.

The bone morphogenetic protein (BMP) 9/10 receptor, ALK1, was recently shown to mediate LDL entry and transcytosis in endothelial cells. Here, Lee et al. show that genetic ablation of arterial endothelial ALK1 in mice limits atherosclerosis without affecting cholesterol or triglyceride levels and that a monoclonal antibody binding ALK1 efficiently blocks LDL transcytosis, but not BMP9 signaling, leading to a reduction in plaque burden.

Lenaeus et al. use a combination of mutagenesis, electrophysiology and cryogenic electron microscopy to define the interaction of the antianginal and antiarrhythmic ranolazine, with the sodium channel Na_V1.5 at high resolution, thus revealing the binding pose and distinct molecular interactions underlying the favorable pharmacological characteristics of this drug, which present fewer proarrhythmic effects than class I antiarrhythmic drugs.

In a phase II, randomized, placebo-controlled, double-blind cross-over trial, Jama et al. show that delivery of short-chain fatty acids via acetylated and butyrylated high-amylose maize starch (HAMSAB) supplementation result in a clinically relevant reduction in 24-hour systolic blood pressure in patients with essential hypertension.

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.

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.

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.

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.

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

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.