News & Views in 2022

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.

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.

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.

Transiently inducing proliferation of adult cardiomyocytes is a long-sought goal in the cardiac regeneration field. A new study shows that genetic deletion of calcineurin B1 and treatment with FK506 (tacrolimus, an FDA-approved inhibitor of calcineurin) induce cardiomyocyte proliferation in adult mice.

Viral infections and cardiovascular disease (CVD) share a two-way connection: viral infection can raise CVD risk, and people with CVD are more prone to severe viral infection. Zhao et al. now detail a molecular mechanism whereby macrophages from patients with CVD inhibit antiviral T cell responses via immune checkpoint activation.

A mouse model of spontaneous arrhythmia in awake mice enables researchers to study how immune cells contribute to this process. The authors find opposing effects of the immune compartment, with neutrophils favoring arrhythmias by increasing oxidative stress and macrophages protecting against it via their phagocytic activity.

The stretch-activated ion channel Piezo1 senses biomechanical stress and provides calcium for transcriptional activation and cardiac growth. In turn, the high amplitude of calcium determines specific signaling through the CaMKII–HDAC–MEF2 pathway as opposed to the calcineurin–NFAT pathway.

A prospective observational case-report study now shows that thalidomide can be a well-tolerated, efficacious treatment for complications such as pain, bleeding and ulceration from extracranial arteriovenous malformation.

Clonal hematopoiesis is a risk factor for hematological cancers, cardiovascular diseases and death. Two papers now use new experimental and mathematical tools to quantify changes in the clonal composition of human blood over time, and the results have implications for the risk of cardiovascular diseases.

Rupture or dissection of the aorta is often fatal. Tcheandjieu and colleagues now identify key pathways underlying aortic dilatation, a common prelude to acute aortic events, and assess the utility of a polygenic risk score to identify those at highest risk of aortic death in whom prophylactic surgical repair may be beneficial.

Blood vessels are thought to form either by de novo vasculogenesis or by angiogenesis from pre-existing blood vessels. Research now finds that anal fin blood vessels form by endothelial transdifferentiation from lymphatic vessels.

Dysregulation of voltage-gated cardiac Na channels can be arrhythmogenic. A new study shows that splice variants of fibroblast growth factor homologous factors (FHFs) can either promote or suppress arrhythmogenic late Na current, and the peptide inhibitor FixR could represent a therapeutic strategy to treat cardiac arrhythmias.

Blood vascular leakage in conjunction with stroke causes edema and a worsened outcome. Through augmented and selective tyrosine phosphatase activity, endothelial junctions can be sealed, resulting in reduced stroke volume and improved survival.

Apelin is a multifunctional peptide that stimulates angiogenesis in a VEGF-A-dependent manner. A study now shows that apelin produced by intestinal endothelium drives VEGF-A-independent angiogenesis in intestinal crypts and is needed for the homeostasis of crypt-resident stem or progenitor cells.

Loss of transcription factor SMAD3 changes the smooth muscle cell (SMC) to a unique remodeling SMC phenotype and points to a potential role for SMAD3 in the inhibition of macrophage recruitment and outward remodeling of the aortic wall.

Genome-wide association studies of magnetic resonance imaging (MRI) of diastolic heart function shed light on the underlying molecular mechanisms and support a causal role of diastolic function for the development of heart failure.

A combined imaging–clinical risk prediction model with the use of deep learning seems a promising approach for predicting sudden cardiac death in patients with ischemic cardiomyopathies. Deep-learning-guided clinical trials will be needed to translate this model into clinical practice.

ABCA1 promotes the efflux of cholesterol from cells to HDL and has anti-atherogenic activities. Sun and Li present cryo-EM structures of ABCA1 in the ATP-free and ATP-bound states, which reveal bound cholesterol molecules and suggest a transmembrane cholesterol-transport mechanism.

Statins continue to make a difference and are here to stay. A new study provides further evidence that statins can function beyond inhibition of cholesterol synthesis by increasing the rate of macrophage efferocytosis, via a reduction in the ‘don’t eat me’ signal CD47, thereby decreasing the atherosclerotic plaque burden.