Sleep is recognized in Life's Essential 8™ as an important behavioral factor for improving and maintaining cardiovascular health. While sleep duration is currently the focus in Life's Essential 8™, sleep health is multidimensional and encompasses regularity, satisfaction, next-day alertness, timing, efficiency, and duration. In addition to sleep, circadian factors have also been implicated in cardiovascular health. For example, shift work, which results in significant circadian misalignment, is associated with poor cardiovascular health. This review will describe methods for measuring, analyzing, and interpreting sleep and circadian rhythms in humans. Subjective and objective measurements of sleep are not always concordant and may reflect distinct constructs. Therefore, both subjective and objective sleep measurements are discussed. Assessment of the circadian system in humans typically relies on the measurement of circadian biomarkers (i.e., melatonin, core body temperature, and/or cortisol) during rigorous and burdensome research protocols. However, novel approaches are being developed to estimate circadian parameters with lower cost and participant burden. This review aims to inform cardiovascular scientists and clinicians of common practices in the assessment of sleep and circadian rhythms.

This review provides a framework for understanding autonomic neural regulation of cardiac function and dysfunction, highlighting the anatomical and functional organization of the autonomic nervous system, from intrinsic cardiac neurons to central cortical control centers. We review pathways leading to autonomic dysregulation in heart failure (HF) and cardiomyopathy (CMY), and we discuss the potential for precision neuromodulation informed by biomarkers and neuroimaging.

We synthesize emerging insights into the molecular, inflammatory, and psychological mechanisms contributing to autonomic dysregulation in HF, and examine the clinical implications of impaired reflex arcs and persistent neurohormonal activation. Recent advances in neuromodulation, including vagus nerve stimulation, baroreflex activation therapy, spinal cord stimulation, cardiac sympathetic denervation and cortical neuromodulation demonstrate the potential to restore autonomic balance and improve HF outcomes. Autonomic imbalance, characterized by sympathetic overactivation and parasympathetic withdrawal, is a hallmark of HF and CMY, contributing to disease progression and adverse outcomes. While traditional pharmacotherapies target downstream neurohormonal pathways, neuromodulation offers the opportunity to intervene upstream, directly at pathophysiological nexus points. Ultimately, a shift toward personalized, circuit-specific neuromodulation strategies may offer new opportunities for treating autonomic dysregulation in HF and CMY.

Chromatin structure plays a central role in regulating gene expression and maintaining cellular identity, yet the structural factors driving these processes in cardiac disease remain poorly defined. To investigate whether these factors can distinguish healthy from diseased cardiac cell populations, we generated a comprehensive list of chromatin structural genes based on an extensive literature review. Applying this list to a published single-nuclei RNA sequencing dataset from human hearts with and without dilated cardiomyopathy (DCM), we found that chromatin structural gene expression effectively stratified cardiomyocyte and fibroblast populations by disease status. Diseased cardiomyocytes exhibited reduced expression of contractile genes and increased expression of cardiomyopathy markers, while fibroblasts showed enhanced activation signatures. Among these factors, HMGN3 emerged as a candidate of interest, showing consistent downregulation in cardiomyocytes from DCM human patients, as well as in mouse (pressure overload) and pig (myocardial infarction) models of heart failure. Functional studies in AC16 cells revealed that HMGN3 depletion promoted apoptosis, induced significant changes in gene expression, and reorganized chromatin structure by altering the distribution of the H3K27ac histone mark. These findings identify HMGN3 as a potential regulator of chromatin architecture in diseased cardiomyocytes, highlight the utility of chromatin structural changes in distinguishing pathological cardiac states, and reinforce the role of chromatin organization in shaping the cardiac phenotype.

As air pollution intensifies, the health risks associated with PM2.5 have gained increasing global attention. Previous research has established a link between PM2.5 exposure and increased risk of cardiovascular diseases (CVDs), yet the underlying mechanisms remain unclear. In this study, we demonstrate that PM2.5 induces ferroptosis in myocardial cells both in vitro and in vivo. We also show that PM2.5 exposure increases lipid peroxidation levels and cellular iron content while depleting glutathione (GSH). Notable alterations in the expression of transferrin receptor protein 1 (TfR1), ferritin light chain (FTL), and ferritin heavy chain (FTH) suggest that the dysfunction in iron uptake and storage plays a pivotal role in ferroptosis. Moreover, we observed that PM2.5 exposure upregulates p53 expression, which transcriptionally regulates TfR1 synthesis. This leads to increased iron influx into cells, causing iron overload and ultimately contributing to ferroptosis and myocardial injury. In conclusion, our findings suggest that PM2.5 promotes ferroptosis in the myocardium via the p53/TfR1 pathway.

Significance: Hydrogen sulfide (H₂S) is an important signaling molecule involved in cardiovascular diseases (CVDs). Although it is important, the precise mechanisms underlying the diverse functions of H₂S in CVDs are not known and need to be elucidated. Recent Advances: Studies have shown the importance of different programmed cell death (PCD) modalities, such as NETosis, apoptosis, necroptosis, pyroptosis, ferroptosis, and cuproptosis, in the pathogenesis of CVDs. An overview of the role of H₂S in regulating PCD in diabetic cardiomyopathy (DCM), cardiac hypertrophy and fibrosis, hypertension, heart failure, atherosclerosis and myocardial ischemia/reperfusion injury, might provide a better understanding of the cardiovascular effects of H₂S. Critical Issues: The mechanisms by which H₂S modulates each type of PCD in CVD patients need to be elucidated. The differences in the effects of H₂S on PCD modalities in different cardiovascular cell types, such as cardiomyocytes, endothelial cells, smooth muscle cells, and immune cells, require further evidence. Future Directions: Future studies should focus on the mechanism by which H₂S affects distinct PCD pathways. Whether H₂S acts as a switch between different PCD pathways under stress or disease conditions needs to be determined. H₂S might regulate the temporal and spatial overlapping PCD pathways in CVDs. Single-cell RNA sequences, spatial transcriptomics, and live-cell imaging are needed to map PCD events regulated by H₂S. Innovation: In this review, we summarized the regulatory effects of H₂S on signaling pathways related to PCD in patients with CVDs. Understanding these mechanisms is crucial for elucidating the pathophysiological roles of H₂S in CVDs. Antioxid. Redox Signal. 43, 637-690.

Diabetes is a metabolic disorder primarily characterized by hyperglycemia, posing a substantial global health concern. Insulin resistance significantly contributes to the pathogenesis of type 2 diabetes and its associated complications, such as cardiovascular diseases and dyslipidemia. MicroRNAs (miRNAs), critical regulators of gene expression, have emerged as essential mediators in diabetes and its related pathological conditions. Among these, miR-126 is particularly important for vascular homeostasis and endothelial function. Dysregulated expression of miR-126 is closely associated with impaired angiogenesis, endothelial dysfunction, and the accelerated progression of diabetic complications. This review comprehensively examines the diverse roles of miR-126 in diabetes and its microvascular complications, emphasizing the mechanisms by which miR-126 modulates pivotal signaling pathways implicated in the pathophysiology of diabetes. By integrating miRNA-mRNA interactions with protein-protein interaction networks in diabetic microvascular complications, this study highlights the central role of miR-126 in gene regulation and associated pathophysiological events. The “AGE-RAGE signaling pathway in diabetic complications” emerged as the most significantly enriched pathway, with AKT1, BCL2, MAPK1, TP53, and SIRT1 identified as critical common target genes involved in these processes. Collectively, these insights underscore the therapeutic potential of miR-126 in managing and treating diabetes and associated complications.

Cardiac remodeling underlies many cardiovascular diseases and is characterized by cardiomyocyte hypertrophy, apoptosis, and interstitial fibrosis, leading to structural and functional deterioration of the heart. Angiotensin II (Ang II), a component of the renin-angiotensin system, drives pathological remodeling through hypertrophy and fibrosis. La-related protein 1 (LARP1), an RNA-binding protein involved in post-transcriptional regulation, has been implicated in cancer biology but its role in cardiovascular disease is largely unexplored. This study investigates the role of LARP1 in regulating Ang II-induced cardiac remodeling and its interaction with ATP2A2, a gene essential for calcium homeostasis.

Human cardiac tissues from hypertrophic cardiomyopathy patients and healthy controls were analyzed for LARP1 mRNA and protein expression. A murine model of Ang II-induced cardiac hypertrophy was established, and LARP1 expression was modulated using adeno-associated virus serotype 9 (AAV9)-LARP1 and gene-deficient mice. Primary cardiomyocytes and cardiac fibroblasts were treated with Ang II to study LARP1 function in vitro. RNA immunoprecipitation, RNA pull-down, and actinomycin D assays were performed to investigate the interaction between ATP2A2 mRNA and LARP1 protein. Cardiac function, hypertrophy, and fibrosis were evaluated through echocardiography, histological staining, and molecular analyses.

LARP1 mRNA and protein expression were significantly downregulated in hypertrophic human and murine cardiac tissues and in Ang II-treated cardiomyocytes. LARP1 overexpression alleviated Ang II-induced cardiac remodeling, as evidenced by reduced cardiomyocyte size, fibrosis, and normalized expression of hypertrophy markers. In vivo, LARP1 overexpression improved cardiac function and reduced pathological changes in Ang II-treated mice. ATP2A2 was identified as a downstream target of LARP1, with LARP1 overexpression enhancing ATP2A2 mRNA stability and expression. Furthermore, ATP2A2 overexpression reversed hypertrophic and fibrotic changes in LARP1-deficient cardiomyocytes and mice, underscoring its critical role in mediating LARP1 protective effects.

LARP1 alleviates Ang II-induced cardiac remodeling in vivo and in vitro, potentially by stabilizing ATP2A2 mRNA and enhancing its expression, thereby reducing pathological remodeling. These findings establish LARP1 as a promising therapeutic target for preventing cardiac remodeling and highlight ATP2A2 as a key mediator of its protective effects. Future studies should explore the therapeutic potential of LARP1-based interventions in cardiovascular disease.

Septic cardiomyopathy (SCM) is a prevalent and severe complication associated with sepsis. This study explores the effects of sevoflurane and pentobarbital on lipopolysaccharide (LPS) -induced SCM and elucidates underlying mechanisms. The SCM model was established using an intraperitoneal injection of 10 mg/kg LPS. Pentobarbital and sevoflurane were administered thirty minutes post-model establishment. Following the echocardiographic assessment, mice were euthanized 24 h after the modeling, and cardiac samples were collected. Gene sequencing and western blot were utilized to identify potential hub genes and signaling pathways. Sevoflurane markedly reduced LPS-induced myocardial injury and cardiac dysfunction compared to the pentobarbital intervention. Transcriptome sequencing revealed that numerous genes exhibited differential expression following intervention with sevoflurane and pentobarbital, with predominant enrichment in the signaling pathways, such as the extracellular region and matrix, tumor necrosis factor (TNF), and p53 signaling. Sevoflurane significantly induced TATA-box binding protein-associated factor, RNA polymerase I subunit D (TAF1D) expression and attenuated cardiomyocyte death, oxidative stress, and the secretion of IL-6 and TNF-α compared to the pentobarbital group (p < 0.05). Furthermore, oe-TAF1D significantly exacerbated cardiomyocyte death, oxidative stress, and inflammatory responses, which were alleviated with si-TAF1D (p < 0.05). Sevoflurane mitigates sepsis-induced cell death, oxidative stress, and inflammatory responses by up-regulating TAF1D, consequently diminishing cardiac injury and preserving cardiac function.

A large proportion of disease variants is found in non-coding RNAs (ncRNAs), gene loci that have been identified as key regulatory elements. However, for most ncRNAs, their targets are unknown, hindering our ability to understand complex diseases. Here, we found that allele-specific ncRNAs were enriched nearby allelic protein-coding genes (pcGenes), suggesting that the allele-specific information could be used to predict cis-acting ncRNA-targets. We translated this concept into the Allelome.LINK framework and applied it to the major mouse organs, revealing 397 events where the allele-specific expression (ASE) of a ncRNA correlated or anticorrelated with the ASE of a nearby pcGene, suggesting either enhancing or repressive regulatory interactions. Integration of H3K27ac heart ChIP-seq enabled the linkage of putative allelic enhancers to allele-specific gene loci and provided insight into ncRNA- versus DNA-mediated regulatory effects. Next, we applied our strategy to the largest human dataset including tissues from nearly 1000 individuals. Given the high genetic diversity across humans, each individual allows for the discovery of novel ASE correlation events. We uncovered 2291 ncRNA-mRNA ASE events along with their mechanisms, which we benchmarked against sample-matched eQTLs, yielding a high validation rate of 77.47%. Further GWAS integration assigned variants overlapping informative ncRNA to their pcGene targets. As more sequencing data and risk variants become available, this strategy has the potential to decode the entire cis-acting landscape of the non-coding genome.

Ischemic heart disease (IHD) continues to rank among the leading global causes of mortality, consistently linked to long-term exposure to fine particulate matter (PM_2.5). Despite a declining trend in the annual average PM_2.5 concentration in Seoul, they still fail to meet the air quality standards set by the Korean Ministry of Environment (15 µg/m³). We aim to estimate the IHD mortality attributable to PM_2.5 and the health benefits derived from reducing PM_2.5 concentration in Seoul, South Korea, between 2016 and 2020.

We utilized machine-learning-based PM_2.5 data, Global Exposure Mortality Model, mortality data, and population data to estimate the burden of IHD mortality attributed to PM_2.5 and the benefits in IHD mortality associated with reductions in PM_2.5 concentration in Seoul between 2016 and 2020. We also estimated the health benefits by considering the reference concentration in three reduction scenarios.

During the study period, the average PM_2.5 concentration was 23.5 µg/m³, with 10,971 IHD deaths among individuals aged ≥ 25 years. We estimated 2,861 excess IHD deaths (aged ≥ 25 years) attributable to PM_2.5 exposure between 2016 and 2020. Under the PM_2.5 reduction scenario, achieving a PM_2.5 concentration of 15 µg/m³ corresponds to an avoidable mortality rate of approximately 8%.

Our study assessed the burden of IHD mortality attributable to ambient PM_2.5 and the potential health benefits associated with its reduction in Seoul between 2016 and 2020. The findings suggest that continued efforts to reduce PM_2.5 concentrations could significantly mitigate IHD mortality, particularly in the context of an aging population.