American journal of physiology. Heart and circulatory physiology最新文献

The most fatal side effect associated with revolutionary immune checkpoint inhibitor (ICI) cancer therapies is myocarditis, a rare and devastating complication with a mortality rate approaching 40%. This review comprehensively examines the limited knowledge surrounding this recently recognized condition, emphasizing the absence of evidence-based therapeutic strategies, diagnostic modalities, and reliable biomarkers that hinder effective management. It explores advancements in preclinical models that are uncovering disease mechanisms and enabling the identification of therapeutic targets. These efforts have informed the design of early clinical trials aimed at reducing mortality. With the growing prevalence of ICI therapies in oncology, addressing critical gaps-such as long-term outcomes and risk stratification-has become increasingly urgent. By synthesizing current evidence, this work seeks to enhance understanding and guide the development of strategies to improve patient outcomes and ensure the continued safe use of ICIs in cancer care.

TREM2 (Triggering Receptor Expressed on Myeloid Cells 2) is a transmembrane protein expressed on myeloid cells, including macrophages and microglia, and is involved in modulating inflammation and lipid metabolism. Elevated plasma levels of soluble TREM2 (sTREM2) have been associated with heart failure (HF) and neurodegenerative diseases such as Alzheimer's disease (AD). This post-hoc analysis explored the association of plasma sTREM2 with cognition and mortality in the Cognition.Matters-HF cohort of 148 chronic HF patients. Plasma sTREM2 levels were measured using a bead-based immunoassay, and the cohort was split into high and low sTREM2 groups based on a median concentration of 16.6 ng/ml. Higher sTREM2 levels were associated with worse cognitive performance, particularly in working memory (T = -2.67, p = 0.009) and visual/verbal memory (T = -2.16, p = 0.032), but not with cardiac function. In univariate cox regression, a higher plasma sTREM2 concentration was linked to increased mortality (HR = 1.28, 95% CI 1.05-1.57, p = 0.015), although this association did not remain significant after adjusting for age and heart failure severity (adjusted HR = 0.95, 95% CI 0.70-1.28, p = 0.720). These findings suggest that plasma sTREM2 reflects cognitive impairment more than cardiac dysfunction in HF, highlighting its potential as a biomarker for neuroinflammation in HF patients.

Sustained stress, assessed as a high allostatic load score (ALS), is an independent cardiovascular disease (CVD) risk factor in older adults but its associations in young people are undefined. Since neurological maturation impacts stress adaptation and CVD risk, we assessed the relationship of ALS with CVD profile using a tiered approach stratified by age (emerging adults 20-24y, EA vs. young adults 25-30y, YA) and ALS (high vs. low). In 1054 healthy African-PREDICT participants, we determined: 1) ALS in EA vs. YA; 2) the relationship between ALS with cardiovascular health; and 3) the odds of high ALS>4 to identify masked hypertension and prediabetes as cardiometabolic outcomes. A 9-component four-domain ALS was compiled: neuro-endocrine (dehydroepiandrosterone, cortisol), inflammatory (interleukin-6, C-reactive protein), cardiovascular (systolic and diastolic-blood pressure), and metabolic (total cholesterol, HDL-cholesterol, body mass index). Retinal vessel caliber, pulse wave velocity (PWV), cardiac structure and function were assessed. Median ALS was 3 (range:1-9). A high-ALS>4 was more common in YA vs. EA (47%vs.35%, P=0.032). Higher ALS associated with narrower retinal arteries (P<0.01), greater PWV (P=<0.01), lower diastolic (P<0.01) and left ventricular function (P<0.01). High-ALS increased the odds of having masked hypertension, prediabetes, narrower retinal arteries, higher LV mass, poorer diastolic and ventricular function (all P≤0.01) in EA and YA independent of traditional CVD risk factors. The composite ALS identified early stress dysregulation in cardiometabolic health and higher odds for prediabetes and masked hypertension in young adults. Cumulative stress may be a modifiable independent cardiometabolic risk factor in younger populations that needs further investigation.

This review comprehensively examines the diverse roles of non-coding RNAs (ncRNAs) in the pathogenesis and treatment of cardiovascular disease (CVD), focusing on microRNA (miRNA), long non-coding RNA (lncRNA), piwi-interacting RNA (piRNA), small interfering RNA (siRNA), circular RNA (circRNA), and vesicle-associated RNAs. These ncRNAs are integral regulators of key cellular processes, including gene expression, inflammation, and fibrosis, and they hold great potential as both diagnostic biomarkers and therapeutic targets. The review highlights novel insights into how these RNA species, particularly miRNAs, lncRNAs, and piRNAs, contribute to various CVDs such as hypertension, atherosclerosis, and myocardial infarction. Additionally, it explores the emerging role of extracellular vesicles (EVs) in intercellular communication and their therapeutic potential in cardiovascular health. The review underscores the need for continued research into ncRNAs and RNA-based therapies, with a focus on advancing delivery systems and expanding personalized medicine approaches to improve cardiovascular outcomes.

Kawasaki disease (KD) is an acute vasculitis that mostly affects children and is characterized by inflammation of medium-sized arteries, particularly the coronary arteries. The absent in melanoma 2 (AIM2) inflammasome senses cytosolic dsDNA and regulates IL-1β-driven inflammation. We investigated the role of AIM2 in Candida albicans water-soluble fraction (CAWS)-induced vasculitis in a murine model mimicking KD. Aim2^-/- mice exhibited reduced vasculitis, inflammatory cell infiltration, and vascular fibrosis in the aorta and coronary arteries. In addition, dsDNA damage was detected in Dectin-2⁺ cells infiltrating vasculitis areas. In vitro experiments showed that CAWS induced dsDNA damage in Dectin-2⁺ bone marrow-derived dendritic cells (BMDC) isolated from wild-type (WT) and Aim2^-/- mice. Furthermore, CAWS induces nuclear membrane deformation and DNA leakage into the cytosol, leading to AIM2 inflammasome activation and subsequent IL-1β production in WT BMDC. These findings suggest that AIM2 inflammasome activation in dendritic cells, triggered by dsDNA damage and leakage, contributes to the development of CAWS-induced vasculitis, and provides important insights into the inflammatory mechanisms underlying KD.

Osteogenesis imperfecta (OI) is a heritable connective tissue disorder with marked skeletal fragility and increased recognition as a pleiotropic type I collagenopathy. The impact of OI-causing gene variants on cardiac health and lifespan is just beginning to be understood. To begin to investigate cardiac manifestations of OI-causing type I collagen variants, we utilized the osteogenesis imperfecta murine (oim/oim) model to examine survival with increased age, as well as cardiac function and collagen expression at 4 and 18 months of age. We determined male oim/oim mice had 50% decreased survival by 18 months of age compared to wildtype (Wt) littermates. Cardiac magnetic resonance imaging and echocardiography revealed 18-month-old male oim/oim mice had increased left ventricular end-diastolic and end-systolic volumes concomitant with decreased function, as well as the presence of aortic stenosis in a subset of 4- and 18- month-old male oim/oim mice compared to Wt littermates. Female oim/oim survival and cardiac function were equivalent to their Wt counterparts. Cardiac evaluations of an adult OI patient cohort corroborated increased incidences of valvular dysfunction in the OI patient population with much of the male cohort also presenting with altered left ventricular function. Little is known concerning the impact of OI causing variants on patient cardiac health and the influence of sex and age. Using an OI mouse model, we determined that 18-month-old male oim/oim mice have cardiac dysfunction with decreased lifespan, confirming the need for further investigations to understand pleiotropic extra-skeletal manifestations and disease progression in osteogenesis imperfecta.

Despite the advancements and release of new therapeutics in the past few years, cardiovascular diseases (CVDs) have remained the number one cause of death worldwide. Genetic variation of a 9p21.3 genomic locus has been identified as the most significant and robust genetic CVD risk marker on the population level, with the strongest association with coronary artery disease (CAD) and other diseases, including diabetes and cancer. Several mechanisms of 9p21.3 in CVDs have been proposed, but their effects on CVDs have remained elusive. Moreover, most of the single nucleotide polymorphisms (SNPs) associated with CAD are located on a sequence of a long noncoding RNA (lncRNA) called ANRIL. ANRIL has several linear and circular splicing isoforms, which seem to have different effects and implications for CVDs. The mechanisms of the 9p21.3 locus and the interplay of its coding and noncoding transcripts in different diseases require further research. Circular RNAs have generally raised interest due to their beneficial features as biomarkers and therapeutic molecules. Here, we review the literature of 9p21.3 from its identification in 2007 and draw the current knowledge on its function, implications in CVDs, and therapeutic potential.

Autonomic dysfunction is associated with cardiovascular and neurological diseases, including hypertension, heart failure, anxiety, and stress-related disorders. Prior studies demonstrated that late gestation exposure to dexamethasone (DEX) resulted in female-biased increases in stress-responsive mean arterial pressure (MAP) and heart rate (HR), suggesting a role for glucocorticoid-mediated programming of autonomic dysfunction. The present study investigated the influence of sympathetic (SYM) or parasympathetic (PS) blockade on cardiovascular function in male and female rat offspring of mothers injected with DEX in utero [gestation days (GD) 18-21]. At 11-12-wk of age, MAP, HR, and heart rate variability (HRV) were evaluated at baseline and in response to SYM antagonists (α₁-adrenoceptor + β₁-adrenoceptor), a PS (muscarinic) antagonist, or saline (SAL). To assess stress-responsive function, rats were exposed to acute restraint. Tyrosine hydroxylase was measured in the adrenals and left ventricle, and expression of the β₁ adrenergic receptor, choline acetyltransferase, and acetylcholinesterase were measured in the left ventricle. Maternal DEX injection reduced basal HRV in male and female offspring. SYM blockade attenuated increases in stress-responsive HR and MAP. PS blockade elevated stress-responsive HR and MAP to a greater extent in vehicle females. SYM and PS blockade produced equivalent effects on HR and MAP responses in male offspring, regardless of maternal treatment. Based on these findings, we suggest that maternal DEX injection disrupted autonomic regulation of cardiovascular function in females, resulting in a shift toward greater SYM input and less input from PS. Future studies will investigate whether changes in autonomic function are mediated by changes in central autonomic circuitry.NEW & NOTEWORTHY Pharmacological antagonists are used to characterize the nature of the autonomic dysregulation induced in female offspring exposed to dexamethasone, in utero. The female offspring of dams injected with dexamethasone in late gestation show a reduction in vulnerability to parasympathetic blockade and an increase in responses to acute restraint stress even in the presence of sympathetic blockade. This suggests that late gestation dexamethasone disrupts the normal development of the autonomic function in females, shifting sympathovagal balance.