Reviews & Analysis

Myocardial ischemia–reperfusion injury is more severe during the sleep-to-wake transition period of the day. A new study shows that timed administration of digoxin, a cardiac glycoside approved by the US Food and Drug Administration, prevents experimental myocardial ischemia–reperfusion injury by controlling proteostasis of the circadian-clock regulator Rev-Erbα.

Mutations in Kir2.1 resulting in defects in trafficking to the cardiomyocyte sarcolemma promote arrhythmia in Anderson–Tawil syndrome. Macias and colleagues provide a dual mechanism underlying cardiac arrhythmia that involves chaperoning of voltage-gated Na⁺ channels and a unique population of intracellular Kir2.1 channels that regulate Ca²⁺ cycling at the sarcoplasmic reticulum.

Little is known about the maintenance of endothelial cell fate in adults. We show that deletion of Erg and Fli1 in endothelial cells of adult mice causes loss of endothelial cell fate and vascular collapse. Overexpression of ERG and FLI1 in non-vascular cells activates an endothelial cell program, confirming their regulation of endothelial cell identity.

Late fetal liver hematopoiesis was thought to primarily rely on hematopoietic stem cells (HSCs). Using new genetic-tracing tools, a study shows that EVI1-positive HSCs mainly undergo expansion in the fetal liver, while differentiated blood cell production depends on HSC-independent intermediate hematopoietic progenitors.

A recent study by the GIGASTROKE consortium combines genetic discovery, fine-mapping and proteomic data to identify causal genes and variants related to disease. Results reveal known and new targets for prevention or treatment of stroke, and highlight the importance of genomics for drug discovery and development.

We explored age-dependent patterns in sex differences for a wide range of cardiometabolic disease risk factors and observed widespread and divergent patterns for different risk-factor groups. These findings highlight the importance of taking both age and sex into account when assessing a person’s risk of developing cardiometabolic disease.

Changes in gene regulatory networks leading to species-specific variations in cardiac structure and function remain to be fully investigated. A new study presents a repertoire of human-gained (absent in mice) cis-regulatory elements, some of which appear to be involved in the acquisition of human-specific cardiac features.

Sex–age disparities in disease risk have been a neglected topic in cardiometabolic disease research. Zhernakova et al. demonstrate that risk factors and metabolic predictors covary with both sex and age: that is, men and women are different, and these differences are not static but change with age.

In this Review, the authors provide an overview of the critical studies reporting Cre and CreER toxicity in the cardiovascular system, discuss the mechanisms proposed to underlie Cre toxicity and highlight the need to understand, eliminate and control for Cre/CreER toxicity in each experimental model.

Heart failure is marked by metabolic insufficiency, but detailed understanding of the underlying metabolic rewiring has been limited. By applying state-of-the-art mass spectrometry to a large pool of human hearts in end-stage heart failure, we unveil numerous metabolic aberrations in human heart failure.

Recent developments in high-throughput, in-depth sequencing platforms are providing opportunities to improve our understanding of biology and disease. Here, Kuppe et al. use a combinatorial approach to relate transcriptional changes to translational and functional implications for the heart in response to myocardial infarction.

A landscape view of metabolic remodeling in end-stage human failing hearts generated by multiomics analysis confirms main changes in cardiac energy metabolism and challenges several widely held mechanisms derived from animal models. Further validation in non-end-stage heart failure and metabolic flux analysis will be necessary to move the field forward.

LTBP-2 expression is increased in the right ventricle and plasma of patients with pulmonary arterial hypertension. Circulating levels of LTBP-2 correlate with right ventricular function and predict long-term survival in two independent cohorts of patients with pulmonary arterial hypertension.

Collateral arteries may act as natural bypasses that reduce hypoperfusion after a coronary blockage. 3D imaging of neonatal and adult mouse hearts, plus human fetal and diseased adult hearts, is now used to computationally predict flow within the heart, and understand the cardioprotective role of collateral arteries in vivo.

The replacement of damaged cardiomyocytes by extracellular matrix-producing fibroblasts underpins adverse remodeling in the failing heart. New research finds that MHC class II-dependent fibroblast–CD4⁺ T cell interactions in the myocardium lead to fibroblast activation and exacerbate fibrotic remodeling of the myocardium.

Goerlich et al. review the history of cardiac allo- and xenotransplants, the progress in immunomodulation to prevent rejection, the regulatory requirements for clinical application and the lessons learned from the first genetically modified pig-to-human heart xenotransplantation.

Sepsis-derived S100A8/A9 induces GSDMD-dependent platelet pyroptosis via the TLR4–ROS–NLRP3–caspase 1 pathway, leading to the release of oxidized mitochondrial DNA that contributes to the formation of neutrophil extracellular traps (NETs). NETs in turn release S100A8/A9 and accelerate platelet pyroptosis, forming a positive feedback loop and thereby amplifying the production of proinflammatory cytokines.

In this Review, the authors provide an overview of the pathogenic effects of somatic activating PIK3CA mutations in congenital disorders and discuss how the interplay between genetics, cell identity and the environment explains the onset, progression and severity of these disorders with a special focus on the vasculature.

Thrombocytopenia is common in severe sepsis and is associated with an increased risk of mortality. A new study shows that platelet pyroptosis initiated during infection promotes a feedforward loop of neutrophil-mediated inflammation that worsens outcomes during sepsis.

In patients with coronary artery disease, stabilizing post-translational modifications to the mRNA of the immune-checkpoint inhibitor CD155 result in an immunosuppressive macrophage phenotype and impair activation of T cells in response to viral infection.