Reviews & Analysis

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.

In lung tissues of pulmonary hypertension rodent models, B cell activation and immunoglobulin E (IgE) production lead to mast cell activation and release of the cytokines IL-6 and IL-13, which result in remodeling of vascular smooth muscle cells. Blockade of IgE with omalizumab, a clinically approved monoclonal antibody against IgE, alleviated the progression of experimental pulmonary hypertension.

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.

Libby and Tokgözoğlu discuss the management of atherogenic lipoproteins, notably low-density lipoprotein, with an emphasis on the role of strategies that target PCSK9.

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.

In a prospective experimental observational study of 18 individuals with severe, recurrent extracranial arteriovenous malformations, thalidomide was effective in reducing pain, healing ulceration, stopping bleeding and resolving cardiac failure.

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.