News & Views

Genome-wide association studies (GWAS) in coronary artery disease have revealed gene variants highly expressed in vascular smooth muscles cells (SMCs). Research now suggests that loss of one, Prdm16, drives a switch toward a synthetic SMC phenotype, with robust, potentially protective extracellular matrix production and fibrous cap formation.

Anthrax toxin receptor 1 (ANTXR1), an integrin-like transmembrane protein, is a docking platform for anthrax toxin and mediates cell–extracellular matrix interactions. New work shows that ANTXR1 stabilizes transforming growth factor-β receptors on cardiac fibroblasts, leading to profibrotic signaling and pathological remodeling of the heart.

Physical activity lowers the risk of cardiovascular disease and overall mortality. Research now shows that women may derive greater cardiovascular benefit from exercise than men.

Cardiac dysfunction in diabetes is linked to metabolic stress, lipid overload and fibrosis. A study now demonstrates impaired glycogen clearance as a central disease mechanism, in which failed glycophagy drives glycogen accumulation and creates a metabolic ‘sugar trap’ that can be targeted therapeutically.

Massively parallel reporter assays (MRPAs) are used in vascular smooth muscle cells to measure the functional effects of over 25,000 variants associated with coronary artery disease. This approach identifies regulatory variants in moderate linkage to disease-associated loci, implicating a broader spectrum of causal variants.

Upregulation of PGC-1α in the mouse heart during exercise training maintains mitochondrial homeostasis and promotes physiological hypertrophy by suppressing the stress-induced production of GDF15 in cardiomyocytes independently of its circulating levels. Identification of this cell-autonomous signaling circuit provides novel insights into the functional role of GDF15 in health and diseases. Future studies are warranted to investigate the interaction of PGC-1α and GDF15 in other stress conditions and in human subjects.

The lymphatic vasculature has emerged as a key component of the heart’s response to injury, influencing both regeneration and maladaptive remodeling. Research now highlights the role of lymphatic clearance in shaping the composition of tissue-resident macrophages within the neonatal heart.

Increased intraocular pressure due to decreased outflow of aqueous humor from the anterior chamber of the eye is a major risk factor for the development of glaucoma, a leading cause of blindness. A new bioengineered device models ocular fluid outflow on a chip to advance discovery in the pathogenesis and treatment of glaucoma.

The blood–brain barrier is an important therapeutic target in the development of drugs to treat stroke. A recent study finds that inhibiting SKI-1 protects blood–brain barrier integrity and improves neurological recovery in mouse and rabbit models of stroke.

Targeting inflammation has emerged as a promising strategy to reduce residual cardiovascular risk. A study now uses human genetics to show that IL-6 inhibition is associated with a lower risk of cardiovascular disease with no increase in infection, supporting the use of pharmacological treatments that target IL-6 rather than its receptor.

Septic cardiomyopathy arises from complex molecular dysfunctions including cytopathic hypoxia that impair cardiac performance. Research shows that LPS-induced phospholipid metabolism stabilizes HIF-1α in cardiomyocytes, suppressing mitochondrial function and contractility, and identifies promising targets for sepsis-related cardiac dysfunction.

Ryanodine receptor (RyR2) phosphorylation was thought to regulate cardiac calcium handling and contractility. Research now shows that preventing RyR2 phosphorylation has no effect on heart rate or contractile function in response to catecholamines and instead drives an electrogenic process that can trigger lethal arrhythmia.

Protease-activated receptor 1 (PAR1) allows platelets and blood endothelial cells to respond to coagulation. Research in mouse models has uncovered a new role for PAR1 — enabling pulmonary collecting lymphatics to transform their intercellular junctions from ‘zippers’ into ‘buttons’ for additional interstitial fluid drainage during acute lung injury.

AAV-based gene therapies hold promise for treating disease, but their long-lasting gene expression limits their use in regenerative medicine. A study now presents DreAM, a drug-inducible AAV system that enables tunable tissue-specific gene activation via the splicing modulator risdiplam, and its potential application in myocardial infarction.

Finding phenotypic variance that results from gene interactions (epistasis) has been a longstanding challenge in human genetics. The combination of a new machine learning framework with functional genomics now provides evidence that cardiac hypertrophy is regulated by non-additive genetic interactions.

Immunomodulatory approaches have gained momentum in cardiology. A report now highlights how low-dose interleukin-2 treatment expands regulatory T cells, reducing inflammation, in patients with acute coronary syndrome, shedding light on T cell antigen specificity and differentiation in cardiovascular disease.

A multi-omics study in the Health for Life in Singapore (HELIOS) study uncovered novel associations among rs10488763, FDX1, the reverse cholesterol-transport pathway, and atheroprotection. This elegant functional genomics study illustrates the potential of integrated ‘-omics’ to uncover novel pathways and potential therapeutic targets.

A systematic biology approach identifies an RNA-binding protein, ARID5A, as a regulator of inflammation and fibrosis in the aging human heart. Inhibition of ARID5A reduced inflammation and fibrosis and improved cardiac function in old mice.

The discovery of plaque tertiary lymphoid organs (PTLOs) within human atherosclerotic plaques provides insights into the role of the immune system in atherosclerosis. The findings highlight the cellular and molecular features of PTLOs, and suggest a potential role of PTLOs in driving plaque instability by activating adaptive immune responses.

Oak-leaf, puzzle-like shapes and discontinuous cell–cell junctions are defining features of lymphatic capillary endothelial cells. A study by Schoofs et al. provides insights into the molecular mechanisms and functional significance of this unique organization.