Volume 2 Issue 11, November 2023

The key determinants of the passive mechanical properties of the heart have long been debated, but remain controversial. Research using a precision approach indicates that titin, microtubules, actin and the extracellular matrix each meaningfully contribute to myocardial passive stiffness in a highly context-dependent manner.

BBLN, a protein with predominantly uncharted functions, serves as an instigator of CAMK2D autophosphorylation, leading to subsequent cardiac remodeling and failure in both humans and mice. The induction of BBLN is driven by hypoxia in TOF and/or pressure overload, as evidenced in mouse models.

The incidence of acute cardiovascular events, including myocardial infarction and ischemic stroke, is increased in individuals with COVID-19. A study shows that SARS-CoV-2 can directly infect macrophages and foam cells in atherosclerotic plaques and contribute to plaque instability.

Passive stiffness measurements in heart samples of a ‘titin-cleavage’ mouse model reveal the elastic and viscous force contributions of individual myocardial components. Titin is the principal contributor to elastic forces, whereas the microtubules and titin, followed by actin, dominate the viscous force contributions; the extracellular matrix contributes at high strain.

BBLN, a protein with largely unknown function, was found to be upregulated in damaged hearts of children with tetralogy of Fallot, one of the most frequent congenital heart defects. Transgenic mice and in vitro studies showed that elevated BBLN levels triggered heart damage by activation of the protein CAMK2D.

Abraham and colleagues review the recent developments and future strategies to therapeutically target the endothelin pathway for a broad spectrum of cardiovascular diseases.

Loescher, Freundt et al. investigated the contribution of each cytoskeletal filament to passive myocardial stiffness by using a mouse model that allows for specific cleavage of titin; they show that titin is a major cytoskeletal filament controlling myocardial elastic forces, whereas viscous forces are controlled by titin, the microtubules and actin.

By single-cell mass cytometry and adoptive transfer of B cell subtypes in mice, Pattarabanjird et al. show that human CD24^hi circulating marginal zone B cells produce IgM to atherosclerosis antigens and confer atheroprotection. Blocking CD24 increased vascular inflammation in hyperlipidemic humanized mice.

Patterson, Firulyova, et al. report that TREM2 is a key regulator of foamy macrophage differentiation. Myeloid-specific deletion of Trem2 caused increased macrophage susceptibility to cholesterol-mediated toxicity and cell death and significantly attenuated atherosclerotic plaque progression in mice.

The results of EMPATROPISM-FE, a post hoc analysis of the EMPA-TROPISM trial performed by Angermann et al., suggest that the beneficial effects of empagliflozin treatment in heart failure populations may be related to changes in iron metabolism.

Abd Alla et al. identify bublin coiled-coil protein (BBLN) as a factor upregulated in unrepaired hearts of patients with tetralogy of Fallot, and show that this protein binds to and controls the function of calcium/calmodulin-dependent protein kinase II delta (CAMK2D). Overexpression of BBLN in mice induced pathological cardiac remodeling, which was precluded when the interaction of BBLN with CAMK2D was prevented or upon CAMK2D downregulation.

Xie et al. characterize the translational dynamics of fibroblast conversion into induced cardiomyocytes (iCMs) and identify the protein Ybx1 as a critical barrier to iCM transdifferentiation. Ybx1 protein removal in mice with myocardial infarction enhanced iCM conversion and rescued cardiac dysfunction.

Lipov et al. performed a meta-analysis of biallelic genotypes in cardiomyopathy patients and the UK Biobank. Using rare variant association analysis, they identified 18 genes with robust evidence for recessive inheritance and revealed a complex spectrum of dominance and recessiveness.