Community-dwelling individuals at high cardiovascular risk are clinically heterogeneous, but whether distinct clinical-metabolic phenotypes differ in carotid plaque burden remains unclear.

From 4191 participants in a community-based screening project conducted in two communities in Guangzhou, 1015 individuals in the high-cardiovascular-risk stage with nonmissing high-plaque-burden status were included. All 1015 participants underwent exploratory clustering using 17 clinical, metabolic, lifestyle-related, and disease-history variables. High plaque burden was defined as bilateral carotid plaques, multiple plaques, or maximum plaque thickness at or above the 75th percentile among plaque-positive participants. Logistic regression examined associations between phenotypes and high plaque burden.

Among the 1015 participants included in the clustering analysis, 329 (32.4%) met the definition of high plaque burden. Four phenotypes were identified: relatively low metabolic burden, older age-ASCVD burden, smoking-low HDL-C, and blood pressure-loaded phenotypes. The corresponding prevalences of high plaque burden were 15.9%, 44.4%, 49.7%, and 33.2%. After adjustment for age and sex, all three non-reference phenotypes showed higher odds of high plaque burden. In sensitivity analysis excluding age and prior ASCVD from clustering, the blood pressure-loaded phenotype remained associated with high plaque burden.

Four exploratory clinical-metabolic phenotypes showed different levels of carotid plaque burden among community-dwelling individuals at high cardiovascular risk. The blood pressure-loaded and smoking-low HDL-C phenotypes were associated with greater plaque burden and may provide an exploratory framework for describing heterogeneity within high-risk populations.

The long-term prognosis of left ventricular noncompaction (LVNC) compared to dilated cardiomyopathy (DCM) remains inconclusive, as prior studies have frequently failed to adequately adjust for heart failure severity. We conducted a single-center, retrospective, comparative study enrolling 96 patients with dilated LVNC (dLVNC) and 437 patients with DCM diagnosed at Peking Union Medical College Hospital between January 2010 and December 2022. dLVNC was defined as meeting the Jenni criteria, with left ventricular ejection fraction (LVEF) ≤45% and increased left ventricular end-diastolic diameter (LVEDD). A 1:1 propensity score matching (PSM) was performed, with matching variables including sex, age, history of heart failure (HF) hospitalization, arrhythmia, LVEF, and LVEDD, resulting in 96 matched pairs. The primary endpoint was major adverse cardiovascular events (MACEs), comprising cardiovascular death or heart transplantation, HF hospitalization or cardiac resynchronization therapy implantation, severe arrhythmias, and systemic embolism. After a median follow-up of 5.46 (2.14-8.62) years in the dLVNC group and 5.26 (2.47-8.50) years in the DCM group, the Kaplan-Meier survival curves between the groups were highly overlapping and revealed no significant differences in MACEs (log-rank p = 0.88), all-cause mortality (log-rank p = 0.84), and individual components of MACEs. After adjusting for heart failure severity, dLVNC and DCM exhibit no substantial difference in long-term prognosis, and the morphological feature of excessive trabeculation itself does not independently increase the risk of adverse events.

Recently, adhesion G-protein-coupled receptors (aGPCRs) gained recognition for their essential roles in embryonic development. However, for the majority of them, their exact functions and underlying signaling mechanisms remain poorly understood. Here, we summarize the existing literature on aGPCRs in the context of kidney development, physiology, and disease. We compile available aGPCR expression profiles, discuss their validation statuses, and describe the knockout phenotypes. For instance, Celsr1/Adgrc1 is expressed early in metanephric development, and its deletion results in aberrant oriented cell division and simplified ureteric trees. Furthermore, GPR116/ADGRF5 is important for the integrity of the glomerular filtration barrier and regulation of renal acid secretion. Several aGPCRs are also implicated in kidney diseases, e.g., deletion of Gpr56/Adgrg1 ameliorates diabetic kidney disease. On the other hand, upregulation of GPR97/ADGRG3 exacerbates acute kidney injury and hypertensive nephropathy. Notably, for around two-thirds of the aGPCRs expressed in the kidney, no function has been proposed. For such aGPCRs, we draw hypotheses for potential functions based on their role in other tissues. Our goal is to shed light on how aGPCRs potentially contribute to the complex and highly regulated orchestration of cellular and molecular mechanisms underlying disease and development of a highly specialized organ such as the kidney.

The adult heart relies on fatty acid β-oxidation for energy, and cardiomyocyte lipid droplets (CLDs) are central to myocardial lipid homeostasis. CLDs are now recognized to protect cardiomyocytes against lipotoxicity, endoplasmic reticulum (ER) stress, oxidative stress, and nutrient deprivation. Moreover, accumulating evidence suggests that CLDs within the same cardiomyocyte are not uniform but may exhibit heterogeneity in size, subcellular localization, protein composition, and metabolism. Here, we propose a conceptual framework that classifies CLD heterogeneity along three dimensions: morphology, organelle connectivity, and molecular composition. We first define the biological characteristics of CLDs and categorize their heterogeneity. We then discuss the molecular pathways maintaining this heterogeneity, their roles in the healthy heart, and their dysregulation in cardiovascular diseases. Finally, we review preclinical strategies targeting CLD heterogeneity and outline challenges and future directions for clinical translation. This framework integrates current evidence while acknowledging that direct molecular validation awaits future single-droplet omics technologies.

The cardiovascular actions of testosterone remain controversial, particularly regarding the safety of testosterone replacement therapy (TTh) in hypogonadal men. We investigated the effects of sustained supraphysiological testosterone exposure on aortic atherogenesis and cardiac remodelling in the testicular feminised (Tfm) mouse, a model of functional androgen receptor (AR) deficiency. Male Tfm mice and AR-intact XY littermate controls were fed a cholesterol-enriched diet for 28 weeks and received fortnightly intramuscular injections of saline or supraphysiological testosterone, alone or in combination with fulvestrant (oestrogen receptor antagonist) or anastrozole (aromatase inhibitor). Aortic lipid deposition was quantified by Oil Red O staining, while cardiac remodelling was assessed by heart weight, cardiomyocyte cross-sectional area and myocardial gene expression. Supraphysiological testosterone significantly reduced aortic fatty streak formation in Tfm mice compared with saline-treated controls (1.25 ± 0.36% vs. 2.85 ± 0.37%, p < 0.01), an effect preserved following fulvestrant or anastrozole treatment, consistent with mechanisms that do not require classical AR or oestrogen receptor signalling. No additional reduction in aortic lipid deposition was observed in AR-intact XY littermates. In contrast, supraphysiological testosterone increased heart weight, cardiomyocyte size and expression of hypertrophic markers exclusively in XY mice, with no evidence of cardiac remodelling in Tfm mice. Collectively, these findings demonstrate divergent tissue-specific cardiovascular actions of testosterone, whereby supraphysiological exposure promotes AR-dependent cardiac remodelling without conferring additional vascular benefit, supporting maintenance of physiological testosterone concentrations during TTh.

Acute cerebrovascular events once dominated efforts to protect the brain from cardiovascular disease. As stroke prevention and treatment have advanced, attention has broadened to the more continuous vascular processes that contribute to cognitive decline across later life. This review organizes cardiovascular brain injury by route, direct structural injury versus indirect mediated pathways, and tempo, acute events versus chronic processes, with vessel caliber determining lesion topography.

Vascular and Alzheimer pathology commonly coexist in older adults with cognitive impairment, and their relationship appears bidirectional but asymmetric: Alzheimer pathology can directly injure the cerebral vasculature, while vascular dysfunction may facilitate Alzheimer pathology and, more clearly, accumulated vascular injury lowers the threshold at which Alzheimer pathology becomes clinically expressed. Covert infarction, microbleeds, white matter disease, and blood-brain barrier disruption accumulate into a cumulative vascular substrate that erodes cognition over decades without requiring a recognized clinical event, and the clinical syndrome follows the lesion, with the subcortical dysexecutive phenotype the modal presentation. Evidence from SPRINT MIND, FINGER, US POINTER, BRAIN-AF, LACI-2, CREST-2, and Mendelian randomization identifies blood pressure control as the best-established intervention, uses discordant and null findings to refine presumed mechanisms, and frames the emerging dilemma of anti-amyloid therapy in patients with substantial vascular disease. In the mixed vascular and Alzheimer disease that dominates late-life dementia, the vascular component is often the more modifiable, and cardiovascular risk management remains among the most actionable strategies for preserving cognition.

Cardiovascular disease progression is shaped by a close interaction between metabolic adaptation and inflammatory signaling. In injured cardiac and vascular tissues, ischemia, pressure overload, lipid stress and metabolic excess reshape how cardiomyocytes, endothelial cells, immune cells and fibroblasts sense damage and communicate with their microenvironment. Cardiovascular inflammation follows a staged tissue response, from danger-signal sensing and nuclear factor-κB-related priming to inflammasome activation, cytokine amplification, leukocyte recruitment, efferocytosis and chronic remodeling. Metabolic reprogramming shapes this sequence by altering substrate use, redox control, biosynthetic routing and metabolite signaling. A major challenge is that glycolysis, fatty acid oxidation and amino-acid metabolism do not carry fixed biological meanings; their effects depend on the cell type, measurement layer and disease phase in which they occur. This review examines metabolism-inflammation crosstalk in cardiovascular disease by linking core inflammatory pathways with metabolic sensors, immune-cell metabolic reprogramming and signaling metabolites, then comparing disease-specific mechanisms in myocardial infarction/ischemia-reperfusion injury, heart failure, atherosclerosis, hypertrophic remodeling and myocardial fibrosis. We emphasize how apparently similar metabolic shifts can represent adaptive repair, inflammatory amplification or maladaptive remodeling in different compartments. The therapeutic discussion separates pathway activity from targetability and uses anti-inflammatory trials and metabolic interventions to define when patient selection, pathway engagement and safety considerations support targeted treatment.

Myocardial ischemia-reperfusion injury (MIRI) is a significant factor in the development of cardiac dysfunction following an acute myocardial infarction (AMI). Ferroptosis, a type of regulated cell death driven by iron and marked by lipid peroxidation, has attracted increasing attention for its pivotal role in the pathogenesis of MIRI. It has been reported that acyl-CoA synthetase long chain family member 1 (ACSL1), a ferroptosis promoter, could mediate ferroptosis of myocardial cells during AMI. However, the specific function and mechanism of ACSL1 in AMI are still unclear. Differentially expressed genes in AMI were identified from the Gene Expression Omnibus (GEO) databases (GSE166780 and GSE97320), and ferroptosis-related genes were acquired from the PathCards database. Through integrated analysis of the two genomes, ferroptosis-related genes in AMI were identified. Then, the identified genes were subjected to cross-validation using three machine learning algorithms (LASSO, SVM-RFE, and RF), ultimately identifying characteristic genes. ACSL1, Forkhead box protein O4 (FOXO4), tripartite motif-containing protein 25 (TRIM25), and GPX4 protein levels were detected using western blot. Cell viability and apoptosis were Cell Counting Kit-8 (CCK-8) and flow cytometry. Interleukin-6 (IL-6) and tumor necrosis factor α (TNF-α) levels were analyzed using enzyme-linked immunosorbent assay (ELISA). Fe2+ level, lipid reactive oxygen species (ROS) level, and GSH level were examined using commercial kits. Flow cytometric analysis of mitochondrial membrane potential using JC-1. Binding between FOXO4 and ACSL1 promoter was predicted by JASPAR and verified using dual-luciferase reporter and ChIP assays. The stability of ACSL1 was assessed by CHX assay. Interaction between TRIM25 and ACSL1 was verified using Co-immunoprecipitation (CoIP) assay. The effect of ACSL1 on myocardial injury was detected using a mouse MIR model. After screening and identification, ferroptosis-related gene ACSL1 in AMI was selected for this study. ACSL1 expression was increased in AMI patients and Ischemia/Reperfusion (H/R)-treated AC16 cells. H/R-triggered AC16 cell viability inhibition, and apoptosis, inflammatory response, ferroptosis, and mitochondrial dysfunction promotion were partly abolished by ACSL1 silencing. Mechanistically, FOXO4 activated ACSL1 transcription by binding to its promoter region. TRIM25 facilitated ACSL1 ubiquitination and decreased its protein stability. ACSL1 downregulation could relieve myocardial damage in vivo. ACSL1 was identified as a key ferroptosis-related gene in AMI. Furthermore, FOXO4-activated transcription and TRIM25-mediated ubiquitination-dependent degradation of ACSL1 could affect H/R-induced cardiomyocyte damage and ferroptosis, providing a promising therapeutic target for MIRI treatment.

Facial fillers are widely regarded as a safe and effective method for cosmetic enhancement, with common adverse effects including bruising, swelling, and tenderness. Rarely, however, vascular complications can occur, resulting in severe outcomes such as sudden blindness. The classic theory posits that a retrograde column of filler is injected into a vessel and reaches the take-off of the central retinal artery, yet several biomechanical and clinical inconsistencies challenge this mechanism. We propose an alternative theory in which filler emboli enter a vessel and follow anterograde flow to reach the central retinal artery. This model better accounts for the rapid and sometimes simultaneous distribution of emboli observed clinically. Understanding the underlying pathophysiology is essential, as prevention strategies may differ depending on the mechanism.

Left ventricular wall thickening may result from disease such as hypertrophic cardiomyopathy (HCM) or infiltrative cardiomyopathies such as transthyretin amyloidosis (ATTR). When features of both conditions coexist, distinguishing the dominant pathology can be challenging and may influence management.

A 72-year-old man presented with progressive exertional dyspnea and syncope. He was found to have severe left ventricular outflow tract obstruction with systolic anterior motion of the mitral valve. He experienced marked symptomatic improvement after initiation of mavacamten for presumed HCM. Genetic testing later revealed a pathogenic TTR p.Val50Met variant, and technetium-99m pyrophosphate scintigraphy demonstrated grade 3 myocardial uptake consistent with hereditary ATTR cardiomyopathy. Persistent symptoms led to septal myectomy, which demonstrated marked myocyte hypertrophy and moderate myocardial amyloid deposition but insufficient infiltration to explain the hypertrophy.

This case highlights the diagnostic complexity of coexisting HCM and hereditary ATTR cardiomyopathy and underscores the importance of multimodality imaging, genetic testing, and pathologic correlation.

Dynamic left ventricular outflow tract obstruction does not exclude cardiac amyloidosis. Dual cardiomyopathies should be considered when clinical, imaging, and genetic findings appear discordant.