This review comprehensively explores the roles of noncoding RNAs (ncRNAs) in cardiovascular diseases (CVDs), highlighting their involvement in major pathological programs and cellular functions. The diverse types of ncRNAs, including microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs), and their mechanisms in regulating gene expression and cellular functions are reviewed. We also examine the potential of ncRNAs as diagnostic biomarkers and therapeutic targets, emphasizing recent advancements in delivery systems and clinical trials. Challenges such as achieving tissue-specific delivery, minimizing off-target effects, and ensuring long-term safety are addressed. By synthesizing current research and addressing translational challenges, this review aims to elucidate the transformative potential of ncRNAs in cardiovascular medicine, paving the way for innovative, targeted therapies
The natural process of aging in humans often increases one’s risk for a number of chronic diseases, including type 2 diabetes (T2D), dyslipidemia, hypertension, and cardiovascular disease (CVD). It is increasingly recognized that aging-related CVD in the absence of other confounding risk factors, such as obesity and T2D, has unique features. Although aging is accompanied by various molecular and physiological changes ultimately affecting whole-body homeostasis, alterations in myocardial energy metabolism are a common hallmark of CVD in elderly people. Under normal physiological conditions, the hearts of healthy individuals oxidize fatty acids, glucose, ketones, and amino acids to meet their energy demand. However, the relative contribution of these fuels for myocardial energy production changes during aging, including a decrease in fatty acid oxidation and an increase in overall glucose utilization (glucose uptake and glycolysis in particular). The heart is also associated with mitochondrial structural and functional abnormalities, resulting in the accumulation of reactive oxygen species and redox-regulated signaling that can exacerbate damage to oxidative phosphorylation capacity and aggravate cardiac dysfunction. We herein discuss the primary changes in myocardial energy metabolism and mitochondrial structure and function, as well as alterations in key molecular mediators that ensue during the physiological process of aging, while considering their potential impact on cardiac function. We have also highlighted the need for comprehensive clinical trials of potential lifestyle or established pharmacological interventions to attenuate myocardial energy metabolism and improve cardiac health in the setting of aging, which may lead to a healthy lifespan.
Cardiovascular aging is increasingly recognized as a mitochondrial-initiated systemic network dysfunction, a progressive, integrative failure driven by deteriorating mitochondrial quality and signaling. This review synthesizes emerging evidence linking comprehensive mitochondrial pathology to the erosion of cardiovascular resilience as a network-level dysfunction. Age-dependent remodeling of mitochondrial ultrastructure and component composition disrupts respiratory efficiency, positioning bioenergetic insufficiency as a central determinant of reduced stress tolerance across the cardiovascular system. Concurrently, defects in mitochondrial fission-fusion dynamics and impaired mitophagy propagate dysfunction within the mitochondrial network, amplifying the decline in energetic capacity. Beyond energy failure, the release of mitochondrial DNA, vesicles, and peptides activates innate immune sensors such as the cyclic guanosine monophosphate-adenosine monophosphate (GMP-AMP) synthase-stimulator of interferon genes (cGAS-STING) pathway, initiating chronic sterile inflammation that propagates maladaptive remodeling cascades throughout cardiovascular tissues and distal organs. We challenge the traditional view of mitochondria solely as energy producers, revealing that uncoupled perfusion and energy metabolism, together with nitric oxide imbalance, can serve as early indicators of diastolic dysfunction and ischemic susceptibility. Additionally, we introduce the concept of “mitochondrial age”, a composite measure that integrates respiratory function, imaging-based structural indices, and circulating mitochondrial biomarkers to quantify mitochondrial health. This metric may serve as a translational tool for assessing cardiovascular aging through mitochondrial network communication. Finally, we highlight rejuvenation strategies aimed at restoring mitochondrial youthfulness, ranging from behavioral interventions (exercise, time-restricted feeding) to metabolic and molecular therapies targeting nicotinamide adenine dinucleotide (NAD+) metabolism, mitophagy, and endothelial mitochondrial protection. Collectively, this review defines cardiovascular aging as a network-level mitochondrial disorder, offering new conceptual and therapeutic directions for preserving cardiac and vascular function.
Cardiac fibrosis is a hallmark of various cardiovascular diseases and is characterized by excessive extracellular matrix (ECM) deposition and progressive tissue stiffening. Emerging evidence suggests that ECM stiffening is not merely a mechanical consequence of fibrosis but also an active driver of pathological cellular responses. Among the mechanosensitive cells within the myocardium, macrophages play a central role in sensing and responding to mechanical cues. Through defined mechanotransduction pathways, macrophages undergo phenotypic and functional reprogramming that shapes inflammatory signaling and the progression of fibrosis. In this review, we summarize current knowledge on ECM stiffening in cardiac fibrosis and its impact on macrophage behavior. We also highlight key mechanosensors that mediate macrophage responses to biomechanical stress. Finally, we discuss emerging therapeutic strategies targeting macrophage mechanotransduction and ECM remodeling and explore their potential as antifibrotic interventions in cardiovascular disease.
Aim: Cancer and cardiovascular disease (CVD), although often perceived as distinct entities, are complexly interrelated and share numerous common risk factors. Despite increasing attention to deaths from cancer and CVD, studies on mortality trends due to concomitant CVD and cancer remain limited. Therefore, this study sought to assess trends in mortality with both cancer and CVD listed as causes of death in the United States across key demographic and state-level subgroups. Methods: The data used in this study was obtained from the Centers for Disease Control and Prevention Wide-ranging Online Data for Epidemiologic Research dataset and the US Census Bureau. The analysis included deaths occurring from 2000 to 2023 among persons aged 15 years or older with both cancer and CVD listed as causes of death. Results: From 2000 to 2015, age-adjusted mortality rate due to concomitant cancer and CVD decreased significantly, then declined at a slower and non-significant rate until 2018. After 2018, interestingly, a significant upward trend emerged. This pattern of falling first and then rising was consistent across most demographic subgroups, except for American Indian or Alaska Native and Asian or Pacific Islander population. Notably, the timing of the upward inflection point varied across subgroups, with the youngest individuals (aged 15-44 years) being the first to transition to an upward trend. Geographically, from 2000 to 2015, significant decreases occurred in 41 states (80%). In contrast, from 2015 to 2023, a significant increase was observed in 34 states(66%). Proportion analysis indicates that the observed increase in mortality due to concomitant cancer and CVD represents a true increase in the burden of death due to concomitant cancer and CVD rather than an artifact stemming solely from independent changes in mortality for each individual disease. Conclusion: These findings underscore the critical need for enhanced intervention strategies targeting mortality risk associated with comorbid due to concomitant cancer and CVD.
Aim: This study aimed to identify key ubiquitin-regulating molecules involved in cardiomyocyte survival under ischemic injury and to investigate the role of Josephin domain-containing protein 2 (JOSD2) in ischemic stress-induced cardiomyocyte death after myocardial infarction (MI). Methods: A ubiquitin-related single-guide RNA (sgRNA) library targeting 903 genes was screened in AC16 cells under oxygen-glucose deprivation (OGD), followed by sgRNA sequencing. Integrated analysis of multiple transcriptomic datasets was performed to identify JOSD2 as a candidate. Stable JOSD2 knockdown and overexpression cell models were established. Reverse transcription quantitative polymerase chain reaction (RT-qPCR), Western blot, flow cytometry, terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining, and Cell Counting Kit-8 (CCK-8) assays were performed to evaluate OGD-induced cardiomyocyte apoptosis and survival. Transcriptomic analysis, co-immunoprecipitation (co-IP), and deubiquitination assays were performed to explore the underlying mechanism. Adeno-associated virus 9 (AAV9)-mediated cardiomyocyte-specific JOSD2-overexpressing mice were used to evaluate cardiac remodeling and function after MI. Results: The CRISPR-Cas9 screen identified a series of ubiquitin-regulating candidate genes associated with cardiomyocyte survival under ischemic stress. Combined transcriptomic and experimental analyses showed that JOSD2 was significantly upregulated in cardiomyocytes and mouse hearts after ischemic injury. JOSD2 knockdown attenuated OGD-induced cardiomyocyte apoptosis, whereas JOSD2 overexpression increased apoptosis. Mechanistically, JOSD2 reduced K27-, K29-, K33-, and K63-linked polyubiquitin chains on liver kinase B1 (LKB1), suppressed its activity, and inhibited downstream AMPK (AMP-activated protein kinase) phosphorylation. In vivo , cardiomyocyte-specific JOSD2 overexpression promoted cardiomyocyte death and aggravated cardiac remodeling and dysfunction after MI. Conclusion: JOSD2 is upregulated in cardiomyocytes after MI and may promote post-infarction cell death and cardiac remodeling by suppressing the LKB1-AMPK pathway. Targeting JOSD2 may represent a potential therapeutic strategy for MI.
Introduction: Comparative data on long-term outcomes (> 5 years) between fulminant myocarditis (FM) and non-fulminant myocarditis (NFM) remain limited, particularly under contemporary treatment strategies in China. Aim: To compare long-term clinical outcomes between FM and NFM patients and to evaluate the prognostic value of persistent troponin I elevation. Methods and Results: In this multicenter prospective cohort study, 355 patients with myocarditis confirmed by endomyocardial biopsy or cardiac magnetic resonance were enrolled (181 FM, 174 NFM). The primary composite endpoint included cardiovascular death, heart transplantation, chronic heart failure, or cardiac structural abnormalities. The secondary outcome was persistent troponin I elevation (> 34.2 pg/mL at 1 month). Directed acyclic graphs guided covariate selection in Cox regression models. In the unadjusted analysis, FM was associated with a higher risk of the primary outcome compared with NFM [hazard ratio (HR) 1.52, 95% confidence interval (CI) 1.10-2.11; P = 0.011]. After adjustment for age, sex, and time from symptom onset to hospitalization, this association was attenuated and no longer statistically significant (HR 1.38, 95%CI 0.98-1.94; P = 0.062). Findings were consistent in propensity score-matched and age ≥ 15 years subgroups. FM patients had a higher likelihood of persistent troponin elevation [odds ratio (OR) 3.44, 95%CI 2.01-6.03; P < 0.001]. Persistent troponin elevation was positively associated with increased risk of the primary outcome. Conclusion: Under current treatment strategies in China, FM was not associated with a significantly higher long-term risk compared with NFM. However, limited statistical power may influence this finding. Persistent troponin elevation is associated with a worse prognosis.
Aim: To investigate the association between fluid input volume and long-term outcomes, including all-cause mortality, cardiac mortality, and in-hospital hypotension, in patients with right ventricular myocardial infarction (RVMI). Methods: This retrospective multicenter study included 1,561 patients with RVMI from four hospitals between 1 January 2013 and 30 June 2021. Fluid input volume was assessed on the first day and as the average over 3 and 7 days. Cox proportional hazards models were used to evaluate associations with all-cause mortality, cardiac mortality, and in-hospital hypotension. Results: The median follow-up was 4.8 years (interquartile range: 2.7-6.4). We found a significantly lower all-cause mortality risk with higher first-day fluid input (median tertile hazard ratio (HR): 0.64, 95% confidence interval (CI): 0.44-0.94; highest tertile HR: 0.66, 95%CI: 0.44-0.99) compared with the lowest input tertile. Similar reductions were observed for cardiac mortality (median tertile HR: 0.52, 95%CI: 0.31-0.85; highest tertile HR: 0.50, 95%CI: 0.30-0.85). However, average fluid input over three or seven days was not associated with long-term mortality risk. Higher first-day input was associated with reduced in-hospital hypotension risk (HR: 0.68, 95%CI: 0.46-1.00; P = 0.049) after confounder adjustment. Conclusion: Sufficient early fluid input is associated with improved long-term outcomes (all-cause and cardiac mortality) and lower in-hospital hypotension risk in patients with RVMI.
Aim: This study aimed to evaluate the bidirectional association between coronary artery disease (CAD) and epilepsy and to examine the modifying effect of genetic susceptibility. Methods: Using data from the UK Biobank, we conducted cross-sectional and longitudinal analyses. In the cross-sectional analysis (n = 502,359), logistic regression estimated odds ratios for the association between CAD and epilepsy. In Cohort 1 (n = 496,921 without baseline epilepsy), stratified Cox models assessed the risk of incident epilepsy by CAD status. In Cohort 2 (n = 475,130 without baseline CAD), the risk of incident CAD by epilepsy status was similarly evaluated. Polygenic risk scores for CAD and epilepsy were incorporated to assess genetic modification. Results: The median baseline age was 58.0 years, and 45.6% were male. Over a median follow-up of 13.8 years, 3,590 participants developed epilepsy and 39,223 developed CAD. CAD was significantly associated with epilepsy both cross-sectionally and longitudinally (hazard ratio (HR) 1.32; 95% confidence interval (CI): 1.15-1.51; P < 0.001). Conversely, epilepsy increased CAD risk (HR 1.31; 95%CI: 1.12-1.54; P < 0.001). These associations were consistent across age, sex, and body mass index (BMI) strata. CAD predicted epilepsy only in participants with low genetic risk, while epilepsy predicted CAD mainly in those with high genetic risk. Conclusions: Our findings indicate a bidirectional association between CAD and epilepsy. Additionally, this association exhibits heterogeneity across subgroups and may be influenced by genetic susceptibility. These results underscore the need for further studies to elucidate the underlying mechanisms and clinical implications.
Cardiac aging is accompanied by progressive alterations in myocardial structure and function that arise even in the absence of overt cardiovascular disease. Large population-based imaging studies demonstrate that healthy aging is typically characterized by concentric geometric remodeling, subtle impairment of diastolic performance, and preserved resting systolic function, alongside a gradual decline in cardiac functional reserve. These features indicate that age-related cardiac remodeling does not simply reflect pathological degeneration, but instead encompasses a range of adaptive responses with substantial inter-individual variability. Mechanistically, remodeling of the aging heart reflects coordinated changes across multiple regulatory layers. Alterations in intercellular communication, extracellular matrix organization, mitochondrial quality control, DNA damage responses, and epigenetic regulation collectively influence myocardial stiffness, energetic flexibility, and responsiveness to physiological stress. While many of these processes may initially support cardiac performance, their progressive dysregulation can reduce compensatory capacity and increase vulnerability to stress with advancing age. This review integrates current evidence on the structural, functional, and molecular features of cardiac remodeling during healthy aging, with an emphasis on biological aging mechanisms rather than disease-driven remodeling. We further discuss emerging strategies that prioritize preservation of functional reserve, modulation of extracellular matrix mechanics, and maintenance of mitochondrial and metabolic adaptability. Viewing cardiac aging through the lens of adaptive capacity provides a framework for understanding how physiological remodeling transitions toward functional limitation and for developing interventions aimed at sustaining cardiovascular healthspan rather than reversing established age-related structural changes.
Population aging is a critical global health challenge that drives a significant increase in the burden of aging-related chronic diseases. Vascular aging, defined as the progressive structural and functional degeneration of blood vessels, is a pivotal manifestation of systemic aging and a major contributor to cardiovascular morbidity and mortality. Recent advances have highlighted the gut microbiota and its metabolites as crucial modulators of host physiology and disease. This review synthesizes current knowledge on the "gut-vascular axis", focusing on the mechanistic roles of key gut-derived metabolites such as short-chain fatty acids, bile acids, and phenylalanine-derived metabolites in vascular aging. We provide a detailed analysis of how specific microbial metabolites influence these processes, discuss their implicated roles in aging-related vascular diseases, particularly atherosclerosis and aortic aneurysms, and illustrate their potential as both pathogenic drivers and therapeutic targets.
Aim: The protective effects of inorganic nitrate in hypertensive patients remain uncertain. Therefore, this study investigated the associations of urinary nitrate with blood pressure, the prevalence of cardiovascular disease (CVD), and cardiovascular mortality among the hypertensive population. Methods: A total of 6,130 hypertensive adults from the 2005-2014 NHANES (The National Health and Nutrition Examination Survey) were included. Piecewise linear regression, logistic regression, and Cox proportional hazards regression models were performed to evaluate the associations of urinary nitrate with blood pressure, CVD prevalence, and cardiovascular mortality, respectively. Mediation and subgroup analyses were further conducted to explore the potential mechanisms and the consistency of the association between urinary nitrate and cardiovascular mortality. Results: Within the range of 0-4.40 mg/dL, an inverse linear correlation between urinary nitrate and systolic blood pressure (SBP) was observed [β = -0.60; 95% confidence interval (95%CI): -0.99 to -0.21; P < 0.001]. Higher urinary nitrate levels were associated with a reduced prevalence of heart failure [odds ratio (OR): 0.942; 95%CI: 0.905 to 0.981; P = 0.004] and lower cardiovascular mortality [hazard ratio (HR): 0.921; 95%CI, 0.867 to 0.977; P = 0.006]. Mediation analyses indicated that neither SBP nor baseline heart failure mediated the association between urinary nitrate and cardiovascular mortality. Subgroup analyses showed that the inverse association between urinary nitrate and cardiovascular mortality was modified by the presence of coronary heart disease. Conclusion: Among hypertensive individuals, higher urinary nitrate levels were associated with lower SBP, heart failure prevalence, and cardiovascular mortality. These findings suggest that urinary nitrate may serve as a potential biomarker for cardiovascular risk stratification.
Proprotein convertase subtilisin/kexin type 9 (PCSK9), a crucial regulator of cholesterol metabolism, is gaining recognition for its broader involvement in aging-related disorders. Emerging evidence indicates that PCSK9 is closely linked to cardiovascular aging, neurodegenerative disorders, and metabolic dysfunction. This review synthesizes up-to-date understanding on PCSK9's multifaceted contributions, emphasizing its role in oxidative stress, inflammation, and cellular senescence, alongside potential therapeutic implications. PCSK9 inhibition not only confers cardiovascular benefits via low-density lipoprotein-dependent and independent pathways but also exhibits broader therapeutic potential. For instance, PCSK9 inhibitors show promise in cancer immunotherapy by and in attenuating inflammation through suppressing the Toll-like receptor 4/nuclear responses and the incomplete understanding of long-term systemic effects. Overall, this highlights the need for further mechanistic studies to guide its therapeutic application.
Selective autophagy, as a crucial form of cellular autophagy, plays a vital role in the degradation of specific substances or organelles in cells. Different from traditional autophagy mechanisms, it precisely identifies and removes damaged or superfluous cellular components, such as lipids, mitochondria, or endoplasmic reticulum, thereby maintaining cellular homeostasis. In recent years, research has revealed a close relationship between selective autophagy and cardiovascular diseases (CVDs). Dysfunction in selective autophagy may promote pathological damage or disease progression in various CVDs, including atherosclerosis, heart failure, ischemic heart disease, and metabolic cardiomyopathy. In this review, we focused on summarizing the mechanisms of specific selective autophagy pathways, including lipophagy, mitophagy, and reticulophagy in CVDs. Furthermore, we analyzed the potential applications and underlying mechanisms of small-molecule compounds, which could target selective autophagy for the treatment of CVDs. We aimed to provide a new theoretical foundation for the prevention and treatment of CVDs.
Background: Heart failure (HF) is a chronic disease with high morbidity and mortality among older populations. Chronic HF ultimately affects both the right (RV) and left (LV) ventricles and often presents with extra-cardiac outcomes including pulmonary hypertension (PH). Study of biventricular failure and its extra-cardiac consequences has been challenging in pre-clinical models, suggesting new models may be beneficial to uncover new mechanisms of disease. Potassium channels are implicit regulators of vascular tone and are strongly but independently associated with PH and LV dysfunction. Aim: We hypothesized that deletion of the potassium rectifier channel Kv1.5 would cause biventricular HF, thus representing a new model from which to understand ventricle-specific mechanisms of HF. Methods and Results: We used a model of global vasoconstriction by genetic deletion of potassium rectifier channel Kv1.5 (Kv1.5 KO). Male and female mice were studied at middle age (12-13 months) as this is when HF risk begins to increase with age. In response to Kv1.5 KO, both the LV and RV experienced elevated afterload. While Kv1.5 KO mice developed RV systolic dysfunction with hypertrophy and fibrosis, the LV developed mild hypertrophy and diastolic dysfunction. Consistent with biventricular remodeling, Kv1.5 KO mice also displayed higher liver and lung weights and exercise intolerance. Conclusion: Deletion of Kv1.5 causes systemic and pulmonary vasoconstriction with distinct outcomes in the LV and RV. This model of biventricular dysfunction may be useful for studying extra-cardiac consequences of HF and understanding ventricle-specific mechanisms of disease.
