Papers by The Journal of Cardiovascular Aging
The Journal of Cardiovascular Aging, 2025
This review aims to summarize the current landscape of cardiac arrhythmia therapeutics and highli... more This review aims to summarize the current landscape of cardiac arrhythmia therapeutics and highlight recent advances in nanoparticle-based strategies for the treatment of various human cardiac arrhythmias. A comprehensive literature review was conducted to curate and synthesize recent preclinical developments in nanoparticle-mediated therapies targeting cardiac arrhythmias. Cardiac arrhythmias represent one of the most prevalent and challenging forms of cardiovascular disease worldwide. Conventional treatments, including antiarrhythmic drugs, are often limited by suboptimal efficacy, high recurrence rates, and significant off-target toxicities. While catheter-based ablation techniques have emerged as alternative interventions, their long-term success remains inconsistent, as highlighted by outcomes from large trials such as the CABANA trial. In response to these limitations, nanoparticle-based interventions have emerged as a promising class of therapeutics. These strategies offer potential advantages, including site-specific drug delivery, reduced systemic toxicity, and novel approaches to both pharmacologic and ablative therapy. This review presents an overview of the emerging nanoparticle-based strategies for the treatment of atrial fibrillation and other cardiac arrhythmias. It also discusses recent proof-of-concept studies, evaluates the benefits and limitations of various nanoparticle formulations, and outlines key challenges and future directions for translating these technologies into clinical practice.
The Journal of Cardiovascular Aging, 2025
Hypertrophic cardiomyopathy (HCM) is a highly common cardiomyopathy and is characterized by left ... more Hypertrophic cardiomyopathy (HCM) is a highly common cardiomyopathy and is characterized by left ventricular hypertrophy and diastolic dysfunction. In half of the cases, HCM is associated with mutations in genes encoding sarcomere proteins, while the remaining cases occur without identifiable genetic mutations. Disrupted bioenergetic homeostasis has increasingly been recognized as a key feature of HCM pathophysiology. In this review, we summarize and critically evaluate studies addressing cardiometabolic alterations in HCM, with a particular focus on human-based research. These include non-invasive imaging studies, blood-based analyses, and molecular and functional assays of myocardial tissue. We also explore the therapeutic potential of targeting metabolic pathways in HCM and highlight promising directions for future studies.
The Journal of Cardiovascular Aging, 2025
Aging alters the immune system, leading to immunosenescence characterized by impaired T cell func... more Aging alters the immune system, leading to immunosenescence characterized by impaired T cell functions. The balance between regulatory T cells and type 17 helper T (Th17) cells is crucial for maintaining peripheral immune homeostasis. Aging disrupts this balance, contributing to a systemic chronic proinflammatory environment that increases the prevalence of age-related diseases. The Treg/Th17 imbalance compromises self-tolerance, promoting autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis. Furthermore, chronic inflammation driven by aberrant T cell responses is a significant risk factor for the progression of cardiovascular diseases (CVD), including hypertension, atherosclerosis, myocardial infarction, and myocarditis. Autoimmune disorders further exacerbate the risk of CVD, which remains the leading cause of mortality among patients with autoimmune diseases. This review provides an in-depth analysis of the mechanisms driving Treg/Th17 imbalance during aging, highlighting its impact on immune homeostasis, autoimmunity, and cardiovascular health. It explores how inflammaging and T cell dysfunction contribute to diseases such as rheumatoid arthritis, systemic lupus erythematosus, atherosclerosis, and myocardial infarction, emphasizing shared pathways and therapeutic strategies to restore immune balance and mitigate chronic inflammation. Understanding these immune pathways highlights the therapeutic potential of restoring Treg/Th17 balance to restore immune tolerance and reduce chronic inflammation, thereby mitigating the onset and progression of these age-related conditions.
The Journal of Cardiovascular Aging, 2025
Cardiovascular aging underpins the development of age-related diseases, including heart failure a... more Cardiovascular aging underpins the development of age-related diseases, including heart failure and vascular dysfunction, and is driven by molecular and cellular mechanisms described in the hallmarks of aging. Plasminogen activator inhibitor-1 (PAI-1), a key regulator of fibrinolysis, also mediates processes like vascular stiffness, cellular senescence, and immune evasion. This review highlights PAI-1's role in cardiovascular aging with a special emphasis on senescence, a key hallmark of aging. It further explores PAI-1's therapeutic potential, with a focus on its contribution to ECM remodeling, senescence signaling, and immune checkpoint regulation. Targeting PAI-1 could provide a promising strategy to mitigate age-related cardiovascular disease.
The Journal of Cardiovascular Aging, 2025
Introduction: The link between low-density lipoprotein/high-density lipoprotein (LDL/HDL ratio, L... more Introduction: The link between low-density lipoprotein/high-density lipoprotein (LDL/HDL ratio, LHR) and the prevalence of hypertension in large populations, especially among individuals aged 20 and older, has not been extensively explored. This research aims to examine whether LHR is associated with hypertension prevalence. Methods: This retrospective cohort analysis drew on cross-sectional data from a health checkup database located in China. Hypertension is classified as a systolic blood pressure (SBP) of ≥ 140 mmHg or a diastolic blood pressure (DBP) of ≥ 90 mmHg. Multivariable logistic regression was used to examine the association between LHR and hypertension prevalence. Furthermore, a subgroup analysis was performed to assess how this association varied across different demographic categories. Results: The cross-sectional evaluation encompassed 113,912 participants. After adjusting for confounding variables, every unit rise in LHR correlated with an 11% increase in the prevalence of hypertension (Odds Ratio [OR] = 1.11, 95% Confidence Interval [CI]: 1.06, 1.16). Our findings indicated a nonlinear relationship between LHR and hypertension prevalence, with an inflection point at 2.28. Below this level, each unit increase in LHR was linked to a 168% heightened risk of hypertension, while above this point, the correlation became insignificant. The subgroup analysis indicated that females, older adults, non-smokers, and individuals with lower body mass index (BMI) exhibited a particularly high prevalence of hypertension associated with higher LHR levels. Conclusion: The findings suggest that a higher LHR serves as a notable predictor of hypertension and elevated blood pressure among Chinese adults aged 20 and older. The identified nonlinear relationship and threshold effect highlight the importance of LHR in hypertension screening and management.
The Journal of Cardiovascular Aging, 2025
Cardiovascular diseases (CVD) remain the leading cause of death worldwide, with advancing age bei... more Cardiovascular diseases (CVD) remain the leading cause of death worldwide, with advancing age being the primary, nonmodifiable risk factor. Vascular dysfunction, namely arterial stiffening and endothelial dysfunction, is the key antecedent to the development of clinical CVD with aging. Fundamental aging macro-mechanistic processes that drive vascular aging include excess oxidative stress, chronic inflammation, and declines in the will highlight the systemic effects of vascular senescent cell suppression on other tissues and organs, given the integrative role of the vasculature in physiology. Together, this review will underscore the imperative role of cellular senescence in vascular dysfunction and the need for a deeper understanding of the translational use of cellular senescence and SASP targeting therapies in groups with high senescent cell burden.
The Journal of Cardiovascular Aging, 2025
With the increase in life expectancy globally, the challenge of dealing with aging becomes more p... more With the increase in life expectancy globally, the challenge of dealing with aging becomes more prominent. Aging is a risk factor for several diseases, including cardiovascular disease. Mitochondria, which have long been studied in relation to aging, play a crucial role in maintaining cellular homeostasis. However, there is a limitation in interorganellar communication as organisms age. The unfolded protein response in mitochondria (UPR mt) is activated during stress to maintain mitochondrial homeostasis and prevent the accumulation of damaged mitochondria. This response involves signaling from the mitochondria to the nucleus, leading to transcriptional changes. In the context of aging heart, this review explores the role of mitochondria in terms of function and morphology. It also discusses the impact of UPR mt on cardiac diseases such as heart failure, acute myocardial infarction, and dilated cardiomyopathy. The review also highlights the potential role of mitochondria-endoplasmic reticulum contact sites (MERCs) in modulating UPR mt during aging. Finally, it provides an update on molecules that induce UPR mt activity, potentially benefiting the aging heart with cardiac disease.
The Journal of Cardiovascular Aging, 2025
Aging is a primary driver of atrial remodeling and dysfunction, and contributes to the increasing... more Aging is a primary driver of atrial remodeling and dysfunction, and contributes to the increasing prevalence of atrial myopathy in the aging population. Atrial myopathy, characterized by structural, functional, and electrophysiological abnormalities of the atria, is a key pathological process underlying adverse cardiovascular outcomes such as atrial fibrillation (AF), heart failure with preserved ejection fraction (HFpEF), and ischemic stroke. Although these outcomes are often treated as distinct clinical entities, emerging evidence suggests that they may represent symptomatic manifestations of an underlying atrial disease process. Aging promotes atrial myopathy through multiple mechanisms, including inflammation, extracellular matrix remodeling, electrophysiological alterations, cellular senescence, epigenetic modifications, and non-coding RNA regulation. These changes collectively lead to atrial fibrosis, impaired mechanical function, conduction abnormalities, and a prothrombotic state. Despite its clinical significance, atrial myopathy remains an underrecognized entity, with current management strategies primarily focusing on treating its downstream complications rather than the underlying disease. Advances in imaging techniques, biomarker discovery, and molecular research have the potential to improve the early detection and risk stratification of atrial myopathy, paving the way for novel therapeutic strategies. In this review, we discuss the structural, mechanical, electrophysiological, and metabolic changes that occur in the aging atrium, explore the cellular and molecular mechanisms that drive these changes, and highlight recent advances in diagnostic and therapeutic approaches. By shifting the focus from managing AF and HFpEF to targeting the underlying atrial myopathy, we can unlock new avenues for prevention and treatment, ultimately improving cardiovascular health in the aging population.
The Journal of Cardiovascular Aging, 2025
Aging leads to structural and functional deterioration of the heart, reducing its capacity to wit... more Aging leads to structural and functional deterioration of the heart, reducing its capacity to withstand internal and external stressors and consequently increasing the risk of heart failure. Exercise is a potent modulator of cardiovascular and metabolic health, offering numerous physiological benefits that can persist throughout the aging process. Studies suggest that exercise can decelerate age-related cardiac deterioration and mitigate the risk of heart failure. In this review, we discuss recent advances in our understanding of exercise-mediated molecular and cellular adaptations that could serve as therapeutic targets for age-related cardiac remodeling and functional decline. We also explore how exercise-induced changes may enhance cardiac resilience with age, examine sex differences in cardiac aging and response to exercise, and highlight the value of murine exercise models as research tools for identifying novel therapeutic targets and strategies to combat heart failure.
The Journal of Cardiovascular Aging, 2025
Introduction: Aging is a multifaceted biological process characterized by a progressive decline i... more Introduction: Aging is a multifaceted biological process characterized by a progressive decline in cellular and tissue function. It significantly impacts the cardiovascular system and contributes to the onset of cardiovascular diseases. The mitochondria (mt) and the endoplasmic reticulum (ER) play synergistic roles in maintaining cellular homeostasis and energy production in the heart. Nevertheless, their response to cardiac aging is not well known. Aim: This study explores mt and ER stress responses and their associated factors, such as metabolic, cellular, and autophagic stress, in cardiac aging. Methods and Results: We utilized 10-and 25-month-old CBA/CaJ mice to evaluate mt, ER, and their associated factors, such as metabolic, cellular, and autophagic stress responses. We studied the gene expression for mitochondrial biogenesis, mt and ER stress response, autophagy and metabolic markers, and activating transcription factors that mediate cellular stress responses. We found no significant difference in mtDNA content and the mRNA expression of the mt transcription factor, Tfam; however, selective mtDNA genes, such as mt-Cytb and mt-Co2, showed significant induction in 25-month-aged compared to 10-month-young hearts. Interestingly, genes of several mitochondrial stress response proteases and their components, including Lonp1, Yme1l1, Afg3l2, and Spg7, were significantly induced, with a substantial induction of Clpp and Clpx. However, age-associated differences were not observed in the induction of mt chaperones (Hspa9 and Hspd1), but significant induction of Dnaja2, a mitochondrial co-chaperone, was observed. The ER stress transcription factors Xbp1 and Atf6 were markedly induced in aged hearts, accompanied by decreased expression of ER stress chaperone Hsp90b with no change in Hspa5 and Dnajb9 chaperones. However, induction of Dnm1l was significant, whereas Mfn1 and Fis1 were downregulated in contrast to Mfn2, suggesting dysregulated mitochondrial dynamics in the aged heart with no change in autophagy and metabolic stress regulators observed. Furthermore, aged hearts showed significantly increased oxidative damage as evidenced by elevated lipid peroxidation (4-HNE) levels. Conclusion: These findings demonstrate that aging triggers mt, ER, and oxidative stress in the heart, which over time leads to the accumulation of oxidative damage, causing cellular impairment, highlighting these pathways as potential therapeutic targets for mitigating age-related cardiac dysfunction.
The Journal of Cardiovascular Aging, 2025
Age is a major risk factor for heart failure, but one that has been historically viewed as non-mo... more Age is a major risk factor for heart failure, but one that has been historically viewed as non-modifiable. Emerging evidence suggests that the biology of aging is malleable, and can potentially be intervened upon to treat ageassociated chronic diseases, such as heart failure. While aging biology represents a new frontier for therapeutic target discovery in heart failure, the challenges of translating Geroscience research to the clinic are multifold. In this review, we propose a strategy that prioritizes initial target discovery in human biology. We review the rationale for starting with human omics, which has generated important insights into the shared (patho)biology of human aging and heart failure. We then discuss how this knowledge can be leveraged to identify the mechanisms of aging biology most relevant to heart failure. Lastly, we provide examples of how this human-first Geroscience approach, when paired with rigorous functional assessments in preclinical models, is leading to early-stage clinical development of gerotherapeutic approaches for heart failure.
The Journal of Cardiovascular Aging, 2025
Background: Immune checkpoint inhibitors (ICIs) have changed the landscape in oncology, providing... more Background: Immune checkpoint inhibitors (ICIs) have changed the landscape in oncology, providing effective cancer management for a growing population. However, by promoting an immunological attack on cancer cells, healthy cells may be harmed in the process. Increased awareness of ICI-associated myocarditis (ICIMy) as one of the most fatal immune-related adverse events has led to efforts to improve the diagnosis and treatment of this condition. The purpose of this review is to summarize the current state of knowledge regarding ICIMy. Methods: We performed a literature search in Pubmed and Scopus with the relevant keywords, screened the titles and abstracts of the results, and reviewed the selected publications using pre-established criteria. Main findings: Although ICIMy’s cumulative incidence is below 0.5% in clinical trials, real-world data reveal a higher incidence of up to 4%. Underlying pathophysiologic mechanisms include T cell clonal expansion, molecular mimicry, and increased inflammatory cytokine signaling pathways leading to ICIMy. The clinical presentation can vary from asymptomatic to fulminant cardiac death and is often accompanied by musculoskeletal adverse events. Emerging diagnostic tools with prognostic value include global longitudinal strain assessment and multiple PET-CT modalities. The mainstay of treatment includes holding the immunotherapy, prompt high-dose methylprednisolone, and close cardiovascular observation. Fulminant and refractory cases benefit from additional immunomodulatory therapies. Principal conclusions: Although ICIMy is a rare adverse event, its non-specific presentation warrants a high level of suspicion. Once ICIMy is considered a likely diagnosis, immunomodulatory therapies should be initiated promptly.
The Journal of Cardiovascular Aging, 2024
The Journal of Cardiovascular Aging, 2024
The Journal of Cardiovascular Aging, 2024
The Journal of Cardiovascular Aging, 2024
Patients with prior autoimmune diseases such as sarcoidosis require special care when treated wit... more Patients with prior autoimmune diseases such as sarcoidosis require special care when treated with checkpoint inhibitors (CPIs), given the risk for reactivation of inflammation. Here, we address the clinical dilemma of initiating CPIs for recurrent metastatic carcinoma in a patient with extensive sarcoidosis, controlled after prolonged immunosuppressive therapy when the tumor recurrence was detected. To achieve the best possible outcome, the case was discussed by an interdisciplinary team comprising specialists in rheumatology, oncology, and CPI-related myocarditis. Literature on this topic was very limited. Based on the pharmacodynamics of CPIs and the pathophysiology of CPI-related autoimmune diseases, we concluded that initiating CPIs alongside low-dose prednisolone would effectively suppress any reactivation of sarcoidosis without interfering with CPIs in a relevant way.
The Journal of Cardiovascular Aging, 2024
The age-related decline in diastolic function can result in heart failure with a preserved ejecti... more The age-related decline in diastolic function can result in heart failure with a preserved ejection fraction (HFpEF) and atrial fibrillation (AF), which are comorbid conditions that are increasingly prevalent and have a high socioeconomic burden. In humans, diastolic dysfunction results from structural and functional changes that increasingly impede diastolic filling after midlife. Comorbidities and pathomechanisms that lead to additional increases in cardiac filling pressures accelerate the age-related deterioration in diastolic function. It is, therefore, that targeting the accelerators of diastolic dysfunction holds the most promise in reducing the risk for HFpEF and AF.
The Journal of Cardiovascular Aging, 2024
Acetyltransferases are enzymes that catalyze the transfer of an acetyl group to a substrate, a mo... more Acetyltransferases are enzymes that catalyze the transfer of an acetyl group to a substrate, a modification referred to as acetylation. Loss-of-function variants in genes encoding acetyltransferases can lead to congenital disorders, often characterized by intellectual disability and heart and muscle defects. Their activity is influenced by dietary nutrients that alter acetyl coenzyme A levels, a key cofactor. Cardiovascular diseases, including ischemic, hypertensive, and diabetic heart diseases-leading causes of mortality in the elderly-are largely attributed to prolonged lifespan and the growing prevalence of metabolic syndrome. Acetyltransferases thus serve as a crucial link between lifestyle modifications, cardiometabolic disease, and aging through both epigenomic and nonepigenomic mechanisms. In this review, we discuss the roles and relevance of acetyltransferases. While the sirtuin family of deacetylases has been extensively studied in longevity, particularly through fasting-mediated NAD + metabolism, recent research has brought attention to the essential roles of acetyltransferases in health and agingrelated pathways, including cell proliferation, DNA damage response, mitochondrial function, inflammation, and senescence. We begin with an overview of acetyltransferases, classifying them by domain structure, including canonical and non-canonical lysine acetyltransferases, N-terminal acetyltransferases, and sialic acid O-acetyltransferases. We then discuss recent advances in understanding acetyltransferase-related pathologies, particularly focusing on cardiovascular disease and aging, and explore their potential therapeutic applications for promoting health in older individuals.
The Journal of Cardiovascular Aging, 2024
This review discusses the pathophysiological changes associated with cardiac aging and the potent... more This review discusses the pathophysiological changes associated with cardiac aging and the potential therapeutic role of the anti-aging protein Klotho. It highlights key contributors to heart failure, such as arterial stiffening, myocardial fibrosis, and impaired cardiac relaxation, all of which lead to the declining function of the aging heart. This review also explores the regulation of Klotho expression, its various forms, and its impact on cardiac health, emphasizing its protective roles against oxidative stress, inflammation, and cardiac remodeling. Klotho's potential as a therapeutic target for mitigating cardiac aging and improving cardiovascular health in the elderly is a central theme, making it a promising candidate for future interventions aimed at enhancing cardiac function and longevity.
The Journal of Cardiovascular Aging, 2024
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Papers by The Journal of Cardiovascular Aging