Foam cell formation is a hallmark of atherosclerosis, yet the cellular complexity within foam cells in human plaques remains unexplored. Here, we integrate published single-cell RNA-sequencing, spatial transcriptomic, and chromatin accessibility sequencing datasets of human atherosclerotic lesions across eight distinct studies. Through this large-scale integration of patient-derived information, we identified foamy macrophages enriched for genes characteristic of the foamy signature. We further re-clustered the foamy macrophages into five unique subsets with distinct potential functions: (i) pro-foamy macrophages, exhibiting relatively high inflammatory and adhesive properties; (ii) phagocytic foamy macrophages, specialized in efferocytosis; (iii) high-efflux foamy macrophages marked by high NR1H3 expression; (iv) mature foamy macrophages prone to programmed cell death; and (v) synthetic subset. Trajectory analysis elucidated a bifurcated differentiation cell fate from pro-foam macrophages toward either the programmed death (iv) or synthetic (v) phenotype. The existence of these foamy macrophage subsets was validated by immunostaining. Moreover, these foamy macrophage subsets exhibited strong potential ligand–receptor interactions. Finally, we conducted Mendelian randomization analyses to identify a possible causal relationship between key regulatory genes along the programmed death pathway in foamy macrophages and atherosclerotic diseases. This study provides a high-resolution map of foam cell diversity and a set of potential key regulatory genes in atherosclerotic plaques, offering novel insights into the multifaceted pathophysiology underlying human atherosclerosis.

Mechanical force is the basis of cardiovascular development, homeostasis, and diseases. The perception and response of mechanical force by the cardiovascular system are crucial. However, the molecular mechanisms mediating mechanotransduction in the cardiovascular system are not yet understood. PIEZO1, a novel transmembrane mechanosensitive cation channel known for its regulation of touch sensation, has been found to be widely expressed in the mammalian cardiovascular system. In this review, we elucidate the role and mechanism of PIEZO1 as a mechanical sensor in cardiovascular development, homeostasis, and disease processes, including embryo survival, angiogenesis, cardiac development repair, vascular inflammation, lymphangiogenesis, blood pressure regulation, cardiac hypertrophy, cardiac fibrosis, ventricular remodeling, and heart failure. We further summarize chemical molecules targeting PIEZO1 for potential translational applications. Finally, we address the controversies surrounding emergent concepts and challenges in future applications.

EphrinB2, a membrane-tethered ligand preferentially binding to its receptor EphB4, is ubiquitously expressed in all mammals. Through the particular bidirectional signaling, EphrinB2 plays a critical role during the development of cardiovascular system, postnatal angiogenesis physiologically and pathologically, and cardiac remodeling after injuries as an emerging role. This review highlights the pivotal involvement of EphrinB2 in heart, from developmental cardiogenesis to pathological cardiac remodeling process. Further potential translational therapies will be discussed in targeting EphrinB2 signaling, to better understand the prevention and treatment of cardiovascular diseases.

Thyroid dysfunction and inflammation are individually implicated in the increased risk of heart failure. Given the regulatory role of thyroid hormones on immune cells, this study aimed to investigate their joint association in heart failure. Patients with pre-existing heart failure were enrolled when hospitalized between July 2019 and September 2021. Thyroid function and inflammatory markers were measured at the enrollment. The composite of all-cause mortality or rehospitalization for heart failure were studied in the following year. Among 451 participants (mean age 66.1 years, 69.4% male), 141 incident primary endpoints were observed during a median follow-up of 289 days. TT3 and FT3 levels were negatively correlated with BNP levels (r: −0.40, p < 0.001; r: −0.40, p < 0.001, respectively) and NT-proBNP levels (r: −0.39, p < 0.001; r: −0.39, p < 0.001). Multivariate COX regression analysis revealed that FT3 (adjusted HR: 0.677, 95% CI: 0.551–0.832) and NLR (adjusted HR: 1.073, 95% CI: 1.036–1.111) were associated with adverse event, and similar results for TT3 (adjusted HR: 0.320, 95% CI: 0.181–0.565) and NLR (adjusted HR: 1.072, 95% CI: 1.035–1.110). Restricted cubic splines analysis indicated a linear relationship between T3 level and adverse events. Mechanistically, primary cardiomyocytes showed strong resistance to TNF-α induced apoptosis under optimal T3 concentrations, as evidenced by TUNEL staining, flow cytometry analysis, and LDH release assay as well as increased expression of Bcl-2. Thyroid dysfunction and inflammation are independently associated with cardiovascular risk in heart failure patients, which may concurrently contribute to the ongoing cardiomyocyte loss in the disease progression.

The excessive deposition of extracellular matrix (ECM) components in cardiac tissue increases myocardial stiffness, contributing to diastolic dysfunction and arrhythmia risk. While this clinical association is established, the underlying electromechanical mechanisms remain elusive. Using human and neonatal rat cardiomyocytes cultured on tunable 3D PDMS substrates replicating infarcted rat heart decellularized ECM (dECM) stiffness, we systematically investigated how ECM-mediated mechanical changes alter action potentials and sodium current dynamics, as well as Nav1.5 expression. 3D PDMS substrates were fabricated with stiffness values spanning the mechanical range of infarcted rat heart dECM (Young's modulus: ∼20-400 kPa; elastic modulus: ∼5-30 pN/nm). Human induced pluripotent stem cell-derived cardiomyocytes (15-day culture), neonatal rat cardiomyocytes (3-day culture) and human embryonic kidney 293 (24-h culture) cells stably expressing human Nav1.5 were cultured on the these PDMS substrates. Stiffness-dependent cellular electrophysiological effects were assessed using patch-clamp recordings. The gene and protein level changes were assessed by real-time quantitative polymerase chain reaction and immune blot. We found that evaluated substrate stiffness levels progressively reduced the AP upstroke slope, resulted in proarrhythmic AP morphologies characterized by increased AP instability and triangulation. Electrophysiological analysis revealed this mechanical modulation occurred through distinct sodium channel kinetic alterations: (1) a significant rightward-shifted voltage-dependent activation curve, and (2) a faster transition from a closed state to inactivation occurred, while maintaining unchanged current density, steady-state inactivation properties, and recovery time across stiffness conditions. This effect may arise from a conformation change in Nav1.5, since the expression and distribution of Nav1.5 has not altered across three PDMS groups. In summary, substrate stiffening impaired cardiomyocyte depolarization and promoted conduction abnormalities via Nav1.5 dysfunction, suggesting a mechanoelectrical mechanism in ECM deposition related arrhythmogenesis.