Reviews & Analysis

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.

The incidence of acute cardiovascular events, including myocardial infarction and ischemic stroke, is increased in individuals with COVID-19. A study shows that SARS-CoV-2 can directly infect macrophages and foam cells in atherosclerotic plaques and contribute to plaque instability.

Right ventricular failure is a major cause of morbidity and mortality in pulmonary hypertension. Transcriptomic profiling of adaptive and maladaptive right ventricular remodeling in humans adds to our basic knowledge of myocardial remodeling and identifies molecular subgroups and biomarkers.

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that coordinates cellular responses to environmental stimuli. Two recent Nature papers show that endothelial AHR is responsive to dietary micronutrients, triggering a signaling cascade that supports tissue homeostasis and responses to infection.

Reduced expression of smooth muscle α-actin (αSMA), a crucial piece of the vascular smooth muscle cell cytoplasmic contractile apparatus, contributes to these cells’ dysfunction in vascular diseases. αSMA is now shown to localize in the nucleus and bind chromatin-remodeling complexes to regulate smooth muscle contractile gene expression.

Inflammatory monocytes and macrophages in the heart express C-C chemokine receptor 2 (CCR2) on their cell surface and contribute to heart failure pathogenesis. This study established the feasibility of imaging CCR2⁺ cells by positron emission tomography in patients with myocardial infarction.

Spatially resolved multiomics is an emerging approach for profiling gene expression at the cellular level while maintaining the spatial organization of tissues. Its application in healthy human hearts provides insight into ion channels and regulatory signaling in the cardiac conduction system, cardiac cellular niches and drug–cell interactions.

A method to identify and analyze clonal hematopoiesis in clinical blood samples at single-cell resolution reveals cell-intrinsic and paracrine effects of DNMT3A mutations in circulating monocytes, T cells and natural killer cells in the setting of heart failure.

Lipid remodeling, from fatty acid transport and de novo lipid synthesis, is necessary for megakaryocyte differentiation and platelet production. Dietary saturated fatty acids, impaired fatty acid transport and/or dysfunction in lipid biogenesis can contribute to low platelet counts.

Wang, Brady, et al. review the current knowledge on how ECM mechanics regulate vascular homeostasis and dysfunction and the approaches available to examine ECM mechanisms at tissue and cellular levels and to model pathological cell–ECM mechanical interactions for therapeutic applications.

Patients with chronic ischemic heart disease — an important cause of heart failure — show altered myocardial bioenergetics with metabolomic and transcriptomic changes that seem to occur at a global, rather than regional, level in human hearts.

We established a mouse model that recapitulates the clinical symptoms of Takotsubo syndrome (‘broken heart syndrome’) and revealed a causal relationship between calcineurin-dependent cardiac inflammation and disease severity. Inhibition of calcineurin as a therapeutic approach is now entering a multi-center clinical trial.

We outline protein interaction networks for 13 ion channels isolated from mouse hearts and show that several protein components are shared between ion channel networks. Multi-omic data integration couples these findings to features of the human heart electrocardiogram and we evaluate the functional effect of ten network proteins on cardiac electrophysiology.

Vascular inflammation is an established risk factor for atherosclerosis progression and associated outcomes. Single-cell RNA sequencing of carotid atherosclerotic plaques identifies a population of lipid-associated macrophages that may contribute to plaque inflammation and clinical events.

Genome-wide association studies have correlated a common allelic block with reduced incidence of heart failure, but the causal mechanism remains unclear. New research suggests that the C151R coding variant in the BAG3 gene is involved in the cardioprotective effect of the haplotype block by increasing cardiomyocyte protection from stress.

Structural determination of the ABCC4 transporter is a major first step in providing crucial molecular insights into the transport of platelet substrates into granules, as well as drug transport from platelets. The findings provide a framework for understanding platelet interactions and potential design of specific platelet antagonists.