Volume 3 Issue 3, March 2024

The cellular microenvironment and interplay between cell types are essential for cardiac renewal. Combined single-cell and single-nucleus sequencing, spatial transcriptomics and loss-of-function experiments in constitutively YAP-expressing infarcted hearts reveal a cellular triad and complement signaling that evoke renewal of heart muscle.

Myocarditis, an inflammatory heart disease, causes cardiomyocyte loss leading to heart failure. Research now shows that BMP4 is crucial for cardiac tissue homeostasis, and targeted neutralization of BMP inhibitors GREM1 and GREM2 mitigates T cell-induced myocardial inflammation and maintains cardiomyocyte integrity.

Older men with loss of the Y chromosome are more susceptible to heart failure but the responsible genes have not been identified. A study now shows that loss of a single Y chromosome gene in bone marrow cells induces heart failure by switching cardiac macrophages from an inflammatory to a fibrogenic pattern of gene activity.

Recent analyses of observational data from 340,000 UK Biobank participants indicate that people with a higher biological age than their same-aged peers have an increased risk of developing cardiometabolic diseases. By contrast, the ability of accelerated biological aging to predict multimorbidity progression is relatively limited.

Hepatocytes are recognized as having a primary role in production and clearance of apolipoprotein B100-containing lipoproteins. A new study finds that Kupffer cells can respond to the initial atherogenic dyslipidemia and regulate levels of circulating lipoprotein.

Inhibition of MEIS1–HOXB13 activity by the aminoglycosides neomycin and paromomycin facilitates cardiomyocyte proliferation and heart regeneration.

Motivated by a CRISPR screen, in vitro and in vivo studies identified an essential role for the bromodomain and extraterminal domain (BET) family member BRD4 in the differentiation of second heart field progenitors into cardiomyocytes. Single-cell transcriptomic studies showed that BRD4 deficiency affects a specific subset of cardiac progenitor cells.

Cardiometabolic multimorbidity — the coexistence of type 2 diabetes, ischemic heart disease or stroke — is a growing clinical and public health challenge. Accelerated biological aging, measured by clinical traits, provides innovative clues into subclinical prevention of cardiometabolic multimorbidity and mortality among older adults.

Piollet, Porsch et al. report that the myeloid receptor TREM2 limits necrotic core formation in atherosclerosis and controls key atherosclerosis-related functions of macrophages, such as efferocytosis, lipid uptake and foam cell survival.

Using single-cell RNA sequencing, spatial transcriptomics and genetic experiments, Li et al. report that the close interaction of a specific cardiomyocyte subtype (aCM2), fibroblasts expressing the complement C3 and macrophages expressing C3ar1 was observed in pro-renewal conditions, such as regenerative neonatal hearts and hearts of adult mice overexpressing an active form of YAP in cardiomyocytes.

Perez-Shibayama et al. report that BMP4 signaling is downregulated in autoimmune myocarditis. Restoring BMP4 levels with antibodies that neutralize the BMP inhibitors gremlin-1 and gremlin-2 can ameliorate cardiac inflammation and improve function in mouse models.

By performing a genome-wide CRISPR screen in human induced pluripotent stem cells, Padmanabhan et al. identify the acetyl-lysine reader protein BRD4 as a regulator of cardiomyocyte differentiation, and they validate in vivo that BRD4 is required during development for the fate determination of a subset of secondary heart field cardiac progenitor cells.

A multistate analysis of 341,159 adults from the UK Biobank shows that the development and mortality of cardiometabolic multimorbidity are associated with biological aging, as measured by the Klemera–Doubal Method Biological Age and PhenoAge algorithms.

Horitani, Chavkin et al. report that the loss of the Y chromosome in macrophages from failing human hearts correlates with cardiac fibroblast activation and that the deficiency of a single Y chromosome gene, Uty, triggers an epigenetic rewiring in macrophages toward a profibrotic phenotype and increases cardiac fibrosis and dysfunction that can be prevented by TGFβ-neutralizing antibodies.

Using two complementary approaches to induce hypercholesterolemia in mice, Di Nunzio, Hellberg, Zhang, Ahmed et al. identified liver macrophages as key cells that organize the systemic responses to lipoproteins during the initial phases of atherosclerosis pathogenesis.

Ahmed, Nguyen et al. show that two FDA-approved antibiotics, paromomycin and neomycin, promote cardiomyocyte proliferation and improve cardiac function after myocardial infarction in mice and pigs by interfering with the cell division inhibiting function of transcription factors Meis1 and Hoxb13.

Vargas Aguilar et al. report that the PD-1–PD-L1 checkpoint-inhibitor pathway is highly active in heart-resident and circulating immune cells of newborn mice and disruption of this pathway led to increased inflammation and pathogenic T cell activity, impairing regeneration.