Cardiovascular complications, particularly diabetic cardiomyopathy (DCM), are the primary causes of morbidity and mortality among individuals with diabetes. Hyperglycemia associated with diabetes leads to cardiomyocyte hypertrophy, apoptosis, and myocardial fibrosis, culminating in heart failure (HF). Diabetic patients face a 2-4 times greater risk of developing HF compared to those without diabetes. Consequently, there is a growing interest in exploring the molecular mechanisms that contribute to the development of DCM. microRNAs (miRNAs) are short, single-stranded, non-coding RNA molecules that participate in the maintenance of physiological homeostasis through the regulation of essential processes such as metabolism, cell proliferation, and apoptosis. At the post-transcriptional level, miRNAs modulate gene expression by binding directly to genes´ mRNAs. Multiple cardiac-enriched miRNAs were reported to be dysregulated under diabetic conditions. Different studies revealed the role of specific miRNAs in the pathogenesis of diabetes and related cardiovascular complications, including cardiomyocyte hypertrophy and fibrosis, mitochondrial dysfunction, metabolic impairment, inflammatory response, or cardiomyocyte death. Circulating miRNAs have been shown to represent the potential biomarkers for early detection of diabetic heart injury. A deeper understanding of miRNAs and their role in diabetes-related pathophysiological processes could lead to new therapeutic strategies for addressing cardiac complications associated with diabetes.

The contribution of microRNAs remain poorly understood in the context of hypertensive cardiac pathology. The role of miR-146a-5p, miR-155-5p, and miR-29b-5p in cardiac hypertrophy and dysfunction was investigated in spontaneously hypertensive rats (SHR). Seven-month-old SHR (n=7 male, n=9 female), and normotensive Wistar Kyoto rats (WKY; n=7 male, n=9 female) underwent echocardiography. Plasma concentrations of inflammatory markers were measured by ELISA. Interstitial and perivascular fibrosis and percentage macrophage infiltration were determined by histology. LV mRNA expressions of cardiac remodelling markers and miRNA expressions were determined by RT-PCR. Circulating VCAM-1, macrophages infiltration, interstitial and perivascular fibrosis, RWT, E/e', and LV mRNA expression of and were greater in SHR. MidFS, e' and a' were lower in SHR. Expression of ratio, circulating CRP, IL-6, and TNF-α, and RWT were greater in females. No difference in miR-29b-5p expression was noted. MiR-155-5p expression was lower in female and associated with stroke volume and absolute heart and LV masses. MiR-146a-5p expression was greater in SHR and associated with SBP, circulating VCAM-1, macrophage infiltration, interstitial fibrosis, normalised heart and LV masses, RWT and a'. MiR-146a-5p was also associated with circulating VCAM-1 after adjustments for SBP. In addition, greater expression of miRNA-146a-5p reversed the relationship between circulating VCAM-1 and macrophage infiltration. Changes in expression of miR-155-5p may be involved with a cardiac phenotype related to sexual dimorphism. Conversely, upregulation of miR-146a-5p expression may act as a counter-mechanism induced by myocardial inflammation in the setting of reactive fibrosis, established LV hypertrophy and impaired diastolic function.

Women with endometriosis, an inflammatory disease, are at increased risk of cardiovascular disease and demonstrate impaired microvascular endothelial function, characterized by reduced nitric oxide (NO)-mediated vasodilation. In some clinical cohorts, nuclear factor-kappaB (NFκB) inhibition with salsalate improves endothelial function. We hypothesized that salsalate would improve cutaneous microvascular endothelial function in women with endometriosis. Following placebo or salsalate (3,000 mg/day 5 days), four intradermal microdialysis probes were placed in 11 women (33 ± 7 years) with endometriosis. Local heating units (set to 33°C) and laser-Doppler flowmetry (red blood cell flux) probes were placed over the probes. Increasing doses of acetylcholine (ACh; dissolved in lactated Ringer's) were perfused, alone (control) or co-perfused with: -nitro-L-arginine methyl ester (L-NAME), atorvastatin (statin), or L-NAME + statin (combo). Maximal vasodilation was then induced (local heat 43ºC + sodium nitroprusside perfusion). Data were normalized as percent of maximal cutaneous vascular conductance (CVC red blood cell flux/mean arterial pressure). To measure macrovascular endothelial function, flow-mediated dilation (FMD) was additionally performed. During Placebo, co-perfusion with statin did not impact the CVC ACh dose-response (p = 0.93). Oral salsalate attenuated the CVC response to ACh perfusion alone (p < 0.01), but did not impact the L-NAME site (p = 0.09). Salsalate significantly augmented the CVC response of the statin site (p < 0.01), but did not affect the combo site response (p = 1.00). FMD was not different between treatments (p=0.79). Salsalate treatment impairs vasodilation in the cutaneous microcirculation in women with endometriosis through non-NO-dependent mechanisms.

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 water-soluble fraction (CAWS)-induced vasculitis in a murine model mimicking KD. 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 (BMDCs) isolated from wild-type (WT) and 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. The AIM2 inflammasome in dendritic cells is a significant component of the murine model of Kawasaki disease-like vasculitis induced by CAWS injection. The AIM2 deficiency reduces vasculitis via reduced inflammatory cell infiltration and vascular fibrosis in CAWS-induced vasculitis. CAWS induces the damage and leakage of nuclear DNA in dendritic cells, which triggers AIM2 inflammasome activation, leading to an IL-1β-driven inflammatory response.

Cardiovascular disease remains the number one cause of death worldwide. Across the spectrum of cardiovascular pathologies, all are accompanied by changes in gene expression profiles spanning a variety of cellular components of the myocardium. Alterations in gene expression are regulated by small non-coding RNAs (sncRNAs), with Piwi-interacting RNAs (piRNAs) being the most abundant of the sncRNAs in the human genome. Composed of 21 - 35 nucleotides in length with a protective methyl group at the 3' end, piRNAs complex with highly conserved RNA-binding proteins termed PIWI proteins to recruit enzymes used for histone, DNA, RNA and protein modifications. Thus, specific piRNA expression patterns can be exploited for early clinical diagnosis of cardiovascular disease and the development of novel RNA therapeutics that may improve cardiac health outcomes. This review summarizes the latest progress made on understanding how piRNAs regulate cardiovascular health and disease progression, including discussion of their potential in the development of biomarkers and therapeutics.

This review comprehensively examines the diverse roles of noncoding RNAs (ncRNAs) in the pathogenesis and treatment of cardiovascular disease (CVD), focusing on microRNA (miRNA), long noncoding 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. In addition, 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.

Triggering receptor expressed on myeloid cells 2 (TREM2) 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 patients with chronic HF. 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 ( = -2.67, = 0.009) and visual/verbal memory ( = -2.16, = 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, = 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, = 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 patients with HF. This study establishes a significant association between elevated plasma sTREM2 levels and cognitive impairment in chronic patients with heart failure (HF), particularly in working memory and attention. Although higher sTREM2 levels correlated with worse survival in unadjusted analyses, they did not emerge as independent predictors of mortality once adjustments had been made for age and heart failure severity. These findings suggest that plasma sTREM2 may serve as a valuable biomarker for detecting HF-related mild cognitive impairment.

Preterm infants exposed to supplemental oxygen (hyperoxia) are at risk for developing heart failure later in life. Exposing rodents in early postnatal life to hyperoxia causes heart failure that resembles cardiac disease seen in adult humans who were born preterm. Neonatal hyperoxia exposure affects the left atrium and left ventricle differently, inhibiting the proliferation and survival of atrial cardiomyocytes while enhancing cardiomyocyte differentiation in the ventricle. In this study, whole genome transcriptomics revealed the left atria of neonatal mice are more responsive to hyperoxia than the left ventricle, with the expression of 4,285 genes affected in the atrium and 1,743 in the ventricle. While hyperoxia activated p53 target genes in both chambers, it caused greater DNA damage, phosphorylation of the DNA damage responsive ataxia telangiectasia mutated (ATM) kinase, mitochondrial stress, and apoptosis in the atrium. In contrast, hyperoxia induced the expression of genes involved in DNA repair and stress granules in the ventricle. Atrial cells also showed a greater loss of extracellular matrix and superoxide dismutase 3 (SOD3) expression, possibly contributing to the enlargement of the left atrium and reduced velocity of blood flow across the mitral valve seen in mice exposed to hyperoxia. Diastolic dysfunction and heart failure in hyperoxia exposed mice may thus stem from its effects on the left atrium, suggesting chamber-specific therapies may be needed to address diastolic dysfunction and heart failure in people who were born preterm.

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 by using a tiered approach stratified by age [emerging adults (EA) aged 20-24 yr vs. young adults (YA) aged 25-30 yr] and ALS (high vs. low). In 1,054 healthy participants of the African Prospective Study on Early Detection and Identification of Cardiovascular Disease and Hypertension (African-PREDICT), we determined: ) ALS in EA versus YA; ) the relationship between ALS and cardiovascular (CV) health, and ) the odds of high ALS > 4 to identify masked hypertension (HT) and prediabetes as cardiometabolic outcomes. A nine-component, four-domain ALS was compiled: neuroendocrine [dehydroepiandrosterone (DHEA), cortisol], inflammatory [interleukin-6 (IL-6), C-reactive protein (CRP)], cardiovascular [systolic blood pressure (SBP) and diastolic blood pressure (DBP)], and metabolic [total cholesterol, high density lipoprotein cholesterol (HDL-cholesterol), body mass index (BMI)]. Retinal vessel caliber, pulse wave velocity (PWV), and cardiac structure and function were assessed. Median ALS was 3 (range: 1-9). A high-ALS > 4 was more common in YA versus EA (47 vs. 35%, = 0.032). Higher ALS associated with narrower retinal arteries ( < 0.01), greater PWV ( 0.01), lower diastolic function ( < 0.01), and left ventricular (LV) function ( < 0.01). High-ALS increased the odds of having masked hypertension, prediabetes, narrower retinal arteries, higher LV mass, poorer diastolic and ventricular functions (all ≤ 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 masked hypertension and prediabetes in young adults. Cumulative stress may be a modifiable, independent cardiometabolic risk factor in younger populations that needs further investigation. This is the first study to assess the effect of stress, as a composite allostatic load score, on micro-, macrovascular, and central cardiac features in healthy emerging and young adults, independent of traditional cardiovascular risk markers. It exemplifies independent stress-induced changes throughout the cardiovascular tree, which may increase the risk of cardiometabolic complications, masked hypertension, and prediabetes. Sustained stress may be a key etiological factor in cardiometabolic disease development in a young population.

Increased arterial wave reflections can increase left ventricular wasted pressure effort (WPE) and cardiovascular disease risk. Naturally menstruating women experience fluctuations in sex hormones with known cardioprotective effects. We sought to determine whether hormonal fluctuations alter arterial hemodynamics or wave reflections, and thereby WPE, or contribute to sex differences. We hypothesized that premenopausal women would have favorable wave reflection changes and reduced WPE during high- versus low-hormone cycle phases and compared with men. We tested 13 women (28 ± 7 yr) during the early follicular (EF,  ± ), late follicular (LF,  ± ), and mid-luteal (ML,  ± ) phases. Eleven men (28 ± 3 yr) underwent time-matched visits. Sex hormones and arterial hemodynamics were measured at all visits. Wave reflection indices and WPE were assessed via aortic pressure-flow analyses. We observed sex-by-visit interactions for WPE and total peripheral resistance (TPR; both < 0.01). Women showed favorable reductions in WPE (EF: 2,758 ± 966 and LF: 2,489 ± 1,230 vs. ML: 1,954 ± 1,085 mmHg·ms, both < 0.05) and TPR (EF: 1,885 ± 271 vs. ML: 1,699 ± 255 dyn·s·cm, = 0.01) from low- to high-hormone phases. These reductions were not observed in men and were not paralleled in classic wave reflection indices ( > 0.05). Increased estradiol predicted a reduction in TPR ( = 0.45, < 0.001), whereas TPR, reflected wave amplitude, and timing of wave reflection predicted reductions in WPE ( = 0.71, < 0.001). These data implicate a role of estradiol on the peripheral vasculature, leading to reduced left ventricular WPE, suggesting a need to consider cycle phases when assessing ventricular load in naturally menstruating women. Using aortic pressure-flow analyses, we demonstrate favorable reductions in left ventricular wasted pressure effort across menstrual cycle phases in healthy premenopausal women, but not across time-matched visits in men. Increases in estradiol were related to changes in total peripheral resistance, which, along with reflected wave amplitude and timing, leads to a reduced wasted pressure effort. Our findings suggest a need to consider sex hormones and cycle phases when assessing ventricular load in naturally menstruating women.

Long COVID has been associated with significant cardiovascular complications, including fibrosis, functional impairment, and chronic inflammatory and immune responses. However, the underlying mechanisms driving these cardiac pathologies following COVID-19 infection remain understudied. Previously, we characterized a mouse model of long COVID and observed enhanced expression of kinin B1 receptor (B1R) in the infected animals. Here, we investigated the role of B1R in mediating long-COVID-induced cardiac pathologies. K18-hACE2 transgenic mice were infected intranasally with SARS-CoV-2 and evaluated at 28 days postinfection (dpi) to model long COVID and the effects of pharmacological blockade of B1R were evaluated. Persistent upregulation of B1R expression was accompanied by apoptosis, disrupted cardiomyocyte architecture, fibrosis, impaired gap junction integrity, and sustained inflammation and immune cell infiltration. B1R blockade restored gap junction integrity, reduced fibrosis and apoptosis, and mitigated inflammation and immune activation. Together, these data indicate that B1R plays a critical role in long-COVID-induced cardiac remodeling and damage, highlighting its potential as a target for treating long-lasting cardiovascular complications following SARS-CoV-2 infection. We are the first to report that elevated B1R expression may drive the long-lasting cardiovascular effects associated with recovery from COVID-19 infection. We have also collected novel evidence showing that blockade of B1R can reduce the cardiac complications associated with long COVID and may serve as a novel therapeutic target to mitigate SARS-CoV-2-induced long-term cardiac damage in affected individuals.

Altered hemodynamics is a key factor for atherosclerosis. For decades, endothelial cell (EC) responses to fluid-generated wall shear stress have been the central focus for atherogenesis. However, circulating blood is not a cell-free fluid, it contains mechanosensitive red blood cells (RBCs) that are also subjected to altered hemodynamics and release a large amount of ATP, but their impact on atherosclerosis has been overlooked. The focus of this study is the role of shear stress (SS)-induced RBC-released ATP in atherosclerosis. Hypercholesterolemic mouse models with and without RBC-Pannexin 1 deletion were used for the study. Results showed that SS-induced release of ATP from RBCs was at μM concentrations, three-orders of magnitude higher than that from other cell types. Suppression of RBC-released ATP via deletion of Pannexin 1, a mechanosensitive ATP-permeable channel, reduced high fat diet-induced aortic plaque burden by 40-60%. Importantly, the location and the extent of aortic atherosclerotic lesions spatially matched with the ATP deposition profile at aortic wall predicted by a computational fluid dynamic (CFD) model. Furthermore, hypercholesterolemia increases EC susceptibility to ATP with potentiated increase in [Ca], an initial signaling for aortic EC barrier dysfunction, and an essential cause for lipid accumulation and inflammatory cell infiltration. The computational prediction also provides a physics-based explanation for RBC-released ATP-induced sex disparities in atherosclerosis. Our study reveals an important role of RBC-released ATP in the initiation and progression of atherosclerosis. These novel findings provide a more comprehensive view of how altered hemodynamics and systemic risk factors synergistically contribute to atherosclerosis.

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.

Endothelial dysfunction has emerged as a risk factor for many age-related diseases such as cardiovascular disease and Alzheimer's disease and related dementias. T-lymphocytes (T-cells) have been identified as important regulators of endothelial function in multiple murine models, and pro-inflammatory and senescent T-cell subsets have been associated with endothelial dysfunction in middle-aged adults with hypertension. However, there is little data on the relationships between T-cell subsets and endothelial function in large, multi-ethnic, population-based cohorts free from cardiovascular diseases. Therefore, the purpose of this study was to determine whether T-cell subsets were associated with endothelial function in participants of the Multi-Ethnic Study of Atherosclerosis (MESA). Endothelial function was assessed using flow-mediated dilation (FMD) of the brachial artery by duplex ultrasound at the baseline exam. Baseline peripheral blood T-cell subsets were measured using flow cytometry (N=968). Two analyses were employed. The primary analysis examined associations of Th1 (CD4 interferon-γ (IFN-γ)) and CD4CD28CD57 T-cells, specified as a priori hypotheses, with FMD using multivariable linear regression. Secondary analyses examined associations between 27 additional immune cell populations with FMD. Th1 and CD4CD28CD57 T-cells were not associated with FMD. In secondary analyses, a 1-SD higher value of pan CD4 and pan CD8 T-cells were associated with lower and higher FMD, respectively. These results may suggest regulation of endothelial function by T-cells in pre-clinical models is conserved in humans. The findings warrant additional longitudinal human studies with greater T-cell phenotyping to further understand the influence of CD4 and CD8 T-cell balance on endothelial function.

Nearly 70 years after studies first showed that the offspring of vitamin A (retinol, ROL) -deficient rats exhibit structural cardiac defects and over 20 years since the role of vitamin A's potent bioactive metabolite hormone, all-trans retinoic acid (ATRA), was elucidated in embryonic cardiac development, the role of the Vitamin A metabolites, or retinoids, in adult heart physiology as well as heart and vascular disease, remains poorly understood. Studies have shown that low serum levels of retinoic acid correlate with higher all-cause and cardiovascular mortality, though the relationship between circulating retinol and ATRA levels, cardiac tissue ATRA levels, and intracellular cardiac ATRA signaling in the context of heart and vascular disease has only begun to be addressed. We have recently shown that patients with idiopathic dilated cardiomyopathy show a nearly 40% decline of in situ cardiac ATRA levels, despite adequate local stores of retinol. Moreover, we and others have shown that the administration of ATRA forestalls the development of heart failure (HF) in rodent models. In this review, we summarize key facets of retinoid metabolism and signaling and discuss mechanisms by which impaired ATRA signaling contributes to several HF hallmarks including hypertrophy, contractile dysfunction, poor calcium handling, redox imbalance, and fibrosis. We highlight unresolved issues in cardiac ATRA metabolism whose pursuit will help refine therapeutic strategies aimed at restoring ATRA homeostasis.

The incidence of HFpEF in women significantly increases following menopause. This trend cannot solely be attributed to chronological aging, as evidenced by the more gradual increase in prevalence among men, suggesting that menopause is a provocative event for HFpEF. However, the underlying mechanisms remain elusive and challenging to investigate in human subjects; moreover, an attempt to create HFpEF in ovariectomized (OVX) mice was unsuccessful. In this study, we created an animal model that resembles HFpEF in women undergoing natural menopause.

In spite of ongoing efforts to probe the metabolic signatures of stable (SA) from unstable (US) angina, it is concerning that to date there are no clinically validated circulatory biochemical signatures against the intrinsic anatomical changes that are screened by invasive coronary angiography. Hence the aim of this study is to generate precise biochemical fingerprints using filtered serum-based metabolomics and high-throughput NMR spectroscopy to accurately distinguish the metabolic signatures of patients suffering with SA or US angina. The study includes 118 filtered serum samples from patients suffering with US (n = 50) and SA (n = 68). High-resolution NMR spectroscopy was used to assess the metabolic remodelling in these cohorts. Subsequently, principle component analysis (PCA), orthogonal partial least square discriminant analysis (OPLS-DA) and artificial neural network (ANN) analysis was adapted to engender a precise prediction model. Analysis of the receiver operating characteristic (ROC) curve was conducted to determine the clinical usefulness of metabolic markers. The outcome revealed that the metabolic profile for the underlying disease is characterized by altered metabolite levels in UA relative to SA. Creatinine, 3-OH butyrate, and aspartate level could differentiate 100% of UA from SA with 100% sensitivity and specificity. To monitor and determine UA from SA patients, H NMR-based filtered serum metabolic profiling seems to be a promising, less invasive, and faster investigative approach.

The prevalence and incidence of diabetes in pediatrics have dramatically increased over the last three decades. Comparatively, pediatric diabetes has faster pancreatic β-cells decline and early progression to complications compared to adult diabetes. Therefore, diabetic complications are a major concern in children and adolescents with diabetes. Diabetes has detrimental effects on the macro- and micro-vascular systems, resulting in cardiovascular diseases, leading causes of morbidity and mortality in youth with diabetes. Oxidative stress plays a critical role in developing cardiovascular complications in the context of pediatric diabetes. In pediatric patients with diabetes, several factors can contribute to the development of excess reactive oxygen species and oxidative stress, including nutritional deficiencies, puberty, environmental exposures, and metabolic disorders such as obesity and high blood pressure. The present study aims to raise awareness of diabetic cardiovascular complications in children and adolescents with diabetes and the role of oxidative stress and their molecular mechanisms in the pathogenesis of cardiovascular complications. In addition, some novel therapeutic strategies for the treatment and prevention of diabetic cardiovascular complications in the pediatric populations are highlighted. In summary, children and adolescent with diabetes no matter T1D or T2D, they have many features similar to those in adults with same kinds of diabetes, but also have many their own features distinct from adults. By developing targeted therapies and preventive measures, healthcare providers can better address the rising incidence of diabetes-related complications in children and adolescents.

Non-coding RNAs (ncRNAs) are critical regulators of mitochondrial function in cardiovascular diseases. Several studies have explored the manipulation of ncRNAs in mitochondrial dysfunction in different cardiovascular disease contexts, however, there is a dearth of information on the exploration of these non-coding RNAs as actual therapeutics to ameliorate cardiovascular diseases. This systematic review examines the roles of various ncRNAs in modulating mitochondrial dysfunction across major cardiovascular diseases and how they can be targeted to the mitochondria. A comprehensive literature search was conducted using Web of Science and Scopus databases, following the PRISMA guidelines. Original research articles in the English language, focusing on ncRNAs and mitochondrial dysfunction in specific cardiovascular diseases, were eligible for inclusion. A total of 76 studies were included in the systematic review with up to 100 ncRNAs identified as therapeutic biomarkers. The identified ncRNAs participate in regulating mitochondrial processes including oxidative phosphorylation, fission/fusion dynamics, apoptosis, and calcium handling in cardiovascular diseases. Mitochondrial targeting moieties including mitochondrial targeting cell-penetrating peptides, mitochondrial targeting liposomes, and aptamers can be conjugated to ncRNAs and delivered to the heart via various injection routes including the pericardium or the myocardium. However, significant challenges remain in developing effective delivery methods to modulate these ncRNAs .

Aortic disease encompasses life-threatening conditions such as aortic aneurysm and dissection, which are associated with high prevalence, morbidity, and mortality. The complement system, a key component of innate immunity, not only defends against pathogens but also maintains tissue homeostasis. Recent discoveries have expanded its role beyond immunity, linking complement dysregulation to numerous diseases and positioning it as a target for pharmacotherapy. Complement-based treatments for precision medicine are emerging, with several pharmaceuticals either already approved or under investigation. In aortic disease, complement activation and dysregulation have unveiled novel mechanisms and clinical implications. Human and experimental studies suggest that all three complement pathways contribute to disease pathophysiology. The complement system induces direct cellular damage via the membrane attack complex, as well as matrix metalloproteinase (MMP)-associated tissue damage by promoting MMP-2 and MMP-9 expression. The anaphylatoxins C3a and C5a exacerbate disease by recruiting immune cells and triggering pro-inflammatory responses. Examples include neutrophil extracellular trap formation and cytokine release by polymorphonuclear neutrophils. These findings highlight the complement system as a promising novel diagnostic and therapeutic target in aortic disease with potential for individualized treatment. However, gaps remain, emphasizing the need for standardized multisite preclinical studies to improve reproducibility and translation. Biomarker studies must also be validated across diverse patient cohorts for clinical applicability. This review examines current knowledge regarding complement in aortic disease, aiming to evaluate its potential for innovative diagnostic and personalized treatment strategies.