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Once considered unconventional cellular structures, membraneless organelles (MLOs), cellular substructures involved in biological processes or pathways under physiological conditions, have emerged as central players in cellular dynamics and function. MLOs can be formed through liquid-liquid phase separation (LLPS), resulting in the creation of condensates. From neurodegenerative disorders, cardiovascular diseases, aging, and metabolism to cancer, the influence of MLOs on human health and disease extends widely. This review discusses the underlying mechanisms of LLPS, the biophysical properties that drive MLO formation, and their implications for cellular function. We highlight recent advances in understanding how the physicochemical environment, molecular interactions, and post-translational modifications regulate LLPS and MLO dynamics. This review offers an overview of the discovery and current understanding of MLOs and biomolecular condensate in physiological conditions and diseases. This article aims to deliver the latest insights on MLOs and LLPS by analyzing current research, highlighting their critical role in cellular organization. The discussion also covers the role of membrane-associated condensates in cell signaling, including those involving T-cell receptors, stress granules linked to lysosomes, and biomolecular condensates within the Golgi apparatus. Additionally, the potential of targeting LLPS in clinical settings is explored, highlighting promising avenues for future research and therapeutic interventions., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a ubiquitous neurotrophic factor that exhibits a variety of physiological functions and plays a critical role in the exploitation of therapeutic potential across a range of diseases, including cardiovascular disorders, nervous system diseases, metabolic imbalances, and cancers. In the context of cardiac diseases, MANF significantly promotes cardiomyocyte survival and improves cardiac functionality. Furthermore, MANF not only provides neuroprotection by shielding neurons from damage and promoting nerve regeneration in neurological disorders, but also involves in insulin resistance, lipid metabolism disturbances and fat-containing liver lesions. However, the oncogenic or tumor suppressive function of MANF in cancer remains unclear, requiring further investigation to elucidate its precise role in the process of cancer initiation and progression. This review aims to summarize the latest advancements in understanding the molecular pathways, intricate mechanisms, and therapeutic potential of MANF in the prevention and treatment of various diseases, emphasizing its multifaceted contributions to health and disease management., Competing Interests: Declarations Ethics approval Not applicable. Competing interests The authors declare no competing interests. Institutional review board statement Not applicable. Informed consent statement Not applicable. Disclosure of potential conflicts of interest The authors declare that they have no conflict of interest., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Na + /K + -ATPase (NKA) is a plasma membrane ion-transporting protein involved in the generation and maintenance of Na + and K + gradients across the cell membrane, which can produce a driving force for the secondary transport of metabolic substrates. NKA also regulates intracellular calcium that is responsible for modulating numerous cellular processes, while it interacts with many other proteins and functions as a signal transducer, with several signaling pathways being involved. Thus, NKA has become an important target for the treatment of human diseases. Cardiac glycosides are well-known NKA inhibitors, of which (+)-digoxin or digoxin has been long used for the treatment of congestive heart failure. Also, digoxin has exhibited potential antitumor activity, by targeting directly HIF-1α, NKA, and NF-κB. Thus, the function of NKA in human cardiovascular diseases and cancer and the therapeutic effects of digoxin on these diseases are summarized in the present review, with the correlations among digoxin, NKA, cardiovascular diseases, and cancer being discussed. Presented herein are also the antitumor potential of monosaccharide cardiac glycoside analogues of digoxin, including (-)-cryptanoside A, (-)-oleandrin, (-)-ouabain, and (+)-strebloside. It is hoped that this contribution will provide some helpful information for the design and discovery of new cardiac glycoside-type therapeutic agents for the treatment of cardiovascular diseases and cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Vitamin D deficiency (VDD) is a widespread global health issue, affecting nearly a billion individuals worldwide, and mounting evidence links it to an increased risk of cardiovascular diseases like hypertension, atherosclerosis, and heart failure. The discovery of vitamin D receptors and metabolizing enzymes in cardiac and vascular cells, coupled with experimental studies, underscores the complex relationship between vitamin D and cardiovascular health. This review aims to synthesize and critically evaluate the preclinical evidence elucidating the role of vitamin D in cardiovascular health. We examined diverse preclinical in vitro (cardiomyocyte cell line) models and in vivo models, including knockout mice, diet-induced deficiency, and disease-specific animal models (hypertension, hypertrophy and myocardial infarction). These studies reveal that vitamin D modulates vascular tone, and prevents fibrosis and hypertrophy through effects on major signal transduction pathways (NF-kB, Nrf2, PI3K/AKT/mTOR, Calcineurin/NFAT, TGF-β/Smad, AMPK) and influences epigenetic mechanisms governing inflammation, oxidative stress, and pathological remodeling. In vitro studies elucidate vitamin D's capacity to promote cardiomyocyte differentiation and inhibit pathological remodeling. In vivo studies further uncovered detrimental cardiac effects of VDD, while supplementation with vitamin D in cardiovascular disease (CVD) models demonstrated its protective effects by decreasing inflammation, attenuating hypertrophy, reduction in plaque formation, and improving cardiac function. Hence, this comprehensive review emphasizes the critical role of vitamin D in cardiovascular health and its potential as a preventive/therapeutic strategy in CVDs. However, further research is needed to translate these findings into clinical applications as there are discrepancies between preclinical and clinical studies., Competing Interests: Declaration of competing interest The authors have no relevant interests to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Cardiovascular diseases (CVD) are the leading cause of death worldwide, and advanced age is a main contributor to the prevalence of CVD. Cellular senescence is an irreversible state of cell cycle arrest that occurs in old age or after cells encounter various stresses. Senescent cells not only result in the reduction of cellular function, but also produce senescence-associated secretory phenotype (SASP) to affect surrounding cells and tissue microenvironment. There is increasing evidence that the gradual accumulation of senescent cardiomyocytes is causally involved in the decline of cardiovascular system function. To highlight the role of senescent cardiomyocytes in the pathophysiology of age-related CVD, we first introduced that senescent cardiomyoyctes can be identified by structural changes and several senescence-associated biomarkers. We subsequently provided a comprehensive summary of existing knowledge, outlining the compelling evidence on the relationship between senescent cardiomyocytes and age-related CVD phenotypes. In addition, we discussed that the significant therapeutic potential represented by the prevention of accelerated senescent cardiomyocytes, and the current status of some existing geroprotectors in the prevention and treatment of age-related CVD. Together, the review summarized the role of cardiomyocyte senescence in CVD, and explored the molecular knowledge of senescent cardiomyocytes and their potential clinical significance in developing senescent-based therapies, thereby providing important insights into their biology and potential therapeutic exploration., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared toinfluence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Cardiovascular diseases (CVDs) represent a significant public health concern because of their associations with inflammation, oxidative stress, and abnormal remodeling of the heart and blood vessels. In this review, we discuss the intricate interplay between mitochondria-associated membranes (MAMs) and cardiovascular inflammation, highlighting their role in key cellular processes such as calcium homeostasis, lipid metabolism, oxidative stress management, and ERS. We explored how these functions impact the pathogenesis and progression of various CVDs, including myocardial ischemia-reperfusion injury, atherosclerosis, diabetic cardiomyopathy, cardiovascular aging, heart failure, and pulmonary hypertension. Additionally, we examined current therapeutic strategies targeting MAM-related pathways and proteins, emphasizing the potential of MAMs as therapeutic targets. Our review aims to provide new insights into the mechanisms of cardiovascular inflammation and propose novel therapeutic approaches to improve cardiovascular health outcomes., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: Obesity is a complex, diverse and multifactorial disease that has become a major public health concern in the last decades. The current classification systems relies on anthropometric measurements, such as BMI, that are unable to capture the physiopathological diversity of this disease. The aim of this study was to redefine the classification of obesity based on the different H-NMR metabolomics profiles found in individuals with obesity to better assess the risk of future development of cardiometabolic disease., Materials and Methods: Serum samples of a subset of the Di@bet.es cohort consisting of 1387 individuals with obesity were analyzed by H-NMR. A K-means algorithm was deployed to define different H-NMR metabolomics-based clusters. Then, the association of these clusters with future development of cardiometabolic disease was evaluated using different univariate and multivariate statistical approaches. Moreover, machine learning-based models were built to predict the development of future cardiometabolic disease using BMI and waist-to-hip circumference ratio measures in combination with H-NMR metabolomics., Results: Three clusters with no differences in BMI nor in waist-to-hip circumference ratio but with very different metabolomics profiles were obtained. The first cluster showed a metabolically healthy profile, whereas atherogenic dyslipidemia and hypercholesterolemia were predominant in the second and third clusters, respectively. Individuals within the cluster of atherogenic dyslipidemia were found to be at a higher risk of developing type 2 DM in a 8 years follow-up. On the other hand, individuals within the cluster of hypercholesterolemia showed a higher risk of suffering a cardiovascular event in the follow-up. The individuals with a metabolically healthy profile displayed a lower association with future cardiometabolic disease, even though some association with future development of type 2 DM was still observed. In addition, H-NMR metabolomics improved the prediction of future cardiometabolic disease in comparison with models relying on just anthropometric measures., Conclusions: This study demonstrated the benefits of using precision techniques like H-NMR to better assess the risk of obesity-derived cardiometabolic disease., (© 2024. The Author(s).)

To maintain homeostasis in the heart, endothelial cells and cardiomyocytes engage in dynamic cross-talk through paracrine signals that regulate both cardiac development and function. Here, we review the paracrine signals that endothelial cells release to regulate cardiomyocyte growth, hypertrophy and contractility, and the factors that cardiomyocytes release to influence angiogenesis and vascular tone. Dysregulated communication between these cell types can drive pathophysiology of disease, as seen in ischemia-reperfusion injury, diabetes, maladaptive hypertrophy, and chemotherapy-induced cardiotoxicity. Investingating the role of cross-talk is critical in developing an understanding of tissue homeostasis, regeneration, and disease pathogenesis, with the potential to identify novel targets for diagnostic and therapeutic purposes., (© 2024 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Obesity significantly contributes to the progression of cardiovascular diseases (CVDs) and elevates the risk of cardiovascular mortality. Atherosclerosis, the primary pathogenic process underlying CVDs, initiates with vascular endothelial dysfunction, serving as the cornerstone of vascular lesions. Adipokines, bioactive molecules secreted by adipose tissue that regulate metabolic and endocrine functions, play a pivotal role in modulating endothelial function during atherosclerosis. This review comprehensively examines the distinct roles of various adipokines in regulating endothelial function in atherosclerosis. We categorize these adipokines into two main groups: protective adipokines, including adiponectin, FGF21, CTRP9, PGRN, Omentin, and Vaspin, and detrimental adipokines such as leptin, Chemerin, Resistin, FABP4, among others. Targeting specific adipokines holds promise for novel clinical interventions in the management of atherosclerosis-related CVDs, thereby providing a theoretical foundation for cardiovascular disease treatment strategies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Yan, Wang, Zhong, Wen and Liu.)

This comprehensive review discusses the crucial role of copper in human health and disease as an essential trace mineral. It emphasizes the significance of copper while addressing potential risks from imbalances in copper levels, be it excessive or inadequate. The review outlines various challenges in copper research, including toxicity concerns, data limitations, metabolic complexities, genetic influences, nutrient interactions, and resource constraints. Despite these challenges, the review identifies specific research areas needing exploration, such as copper homeostasis regulation, transport mechanisms, gut microbiome interactions, immune function, neurodegenerative diseases, cardiovascular health, cancer, fertility, and reproductive health. The purpose of this review is to explore the important role of copper in human health and disease, which highlights the delicate balance required to avoid deficiency or toxicity. For the researchers and scientists, it provides the gaps in the research, so it aims to provide insights that could advance diagnostic and therapeutic strategies across various medical disciplines., (© 2024 Wiley Periodicals LLC.)

Secreted proteins have gained more and more attentions, since they can become therapeutic targets, drugs and biomarkers for prevention, diagnosis and treatment of disease and aging. In 2014, Metrnl (also named Meteorin-like, Cometin, Subfatin, Interleukin-39, Interleukin-41, Meteorin-β, and Metrn-β/Metrnβ), as a novel secreted protein released from a certain tissue, was reported by us and others. During the past decade, the number of articles on Metrnl has continued to increase. Different sources of Metrnl have been described with different functions, including Metrnl as an adipokine for insulin sensitization, a cardiokine against cardiac hypertrophy and dysfunction, an endothelium-derived factor against endothelial dysfunction and atherosclerosis, etc. Especially, we show that endothelial Metrnl is a major source for circulating Metrnl levels. Meanwhile, lots of clinical studies have investigated the relationship between blood Metrnl levels and metabolic, inflammatory and cardiovascular diseases. Metrnl appears a protective factor and a promising therapeutic target and/or drug against these diseases, given the relatively consistent conclusion from the preclinical studies. In addition to graphically demonstrating the role of Metrnl in various organs and diseases, this review will mainly describe the discovery of Metrnl, summarize the role of Metrnl in cardiovascular system that is a recently major progress in Metrnl research, and highlight several perspectives for future basic and translational research. Also, we suggest using one name Metrnl instead of other multiple names for the same protein., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest, financial or otherwise in this article., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Cardiovascular disease (CVD) remains the leading cause of global morbidity and mortality. Extensive efforts have been invested to explicate mechanisms implicated in the onset and progression of CVD. Besides the usual suspects as risk factors (obesity, diabetes, and others), the gut microbiome has emerged as a prominent and essential factor in the pathogenesis of CVD. With its endocrine-like effects, the microbiome modulates many physiologic processes. As such, it is not surprising that dysbiosis-by generating metabolites, inciting inflammation, and altering secondary bile acid signaling- could predispose to or aggravate CVD. Nevertheless, various natural and synthetic compounds have been shown to modulate the microbiome. Prime among these molecules are flavonoids, which are natural polyphenols mainly present in fruits and vegetables. Accumulating evidence supports the potential of flavonoids in attenuating the development of CVD. The ascribed mechanisms of these compounds appear to involve mitigation of inflammation, alteration of the microbiome composition, enhancement of barrier integrity, induction of reverse cholesterol transport, and activation of farnesoid X receptor signaling. In this review, we critically appraise the methods by which the gut microbiome, despite being essential to the human body, predisposes to CVD. Moreover, we dissect the mechanisms and pathways underlying the cardioprotective effects of flavonoids., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

By disturbing the prooxidant-antioxidant balance in the cell, a condition called oxidative stress is created, causing severe damage to the nucleic acid, protein, and lipid of the host cell, and as a result, endangers the viability of the host cell. A relationship between oxidative stress and several different diseases such as cardiovascular diseases, cancer, and obesity has been reported. Therefore, maintaining this prooxidant-antioxidant balance is vital for the cell. Probiotics as one of the potent antioxidants have recently received attention. Many health-promoting and beneficial effects of probiotics are known, and it has been found that the consumption of certain strains of probiotics alone or in combination with food exerts antioxidant efficacy and reduces oxidative damage. Studies have reported that certain probiotic strains implement their antioxidant effects by producing metabolites and antioxidant enzymes, increasing the antioxidant capacity, and reducing host oxidant metabolites. Therefore, we aimed to review and summarize the latest anti-oxidative activity of probiotics and its efficacy in aging, cardiovascular diseases, cancer, and obesity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Histone deacetylases (HDACs) play critical roles in cardiovascular diseases (CVDs). In addition, reactive oxygen species (ROS) produced by NADPH oxidases (NOXs) exert damaging effects due to oxidative stress on heart and blood vessels. Although NOX-dependent ROS production is implicated in pathogenesis, the relationship between HDACs and NOXs in CVDs remains to be elucidated. Here, we present an overview of the regulatory effects and interconnected signaling pathways of HDACs and NOXs in CVDs. Improved insights into these relationships will facilitate the discovery of novel therapeutic agents that target HDACs, oxidase stress pathways, and the interactions between these systems which may be highly effective in the prevention and treatment of cardiovascular disorders., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Psychological stress during early development and adolescence may increase the risk of psychiatric and cardiometabolic comorbidities in adulthood. The gut microbiota has been associated with mental health problems such as depression and anxiety and with cardiometabolic disease, but the potential role of the gut microbiota in their comorbidity is not well understood. We investigated the effects and mode of action of the intestinal bacterium Christensenella minuta DSM 32891 on stress-induced mental health and cardiometabolic disturbances in a mouse model of social defeat stress. We demonstrate that administered C. minuta alleviates chronic stress-induced depressive, anxiogenic and antisocial behavior. These effects are attributed to the bacterium's ability to modulate the hypothalamic-pituitary-adrenal axis, which mediates the stress response. This included the oversecretion of corticosterone and the overexpression of its receptors, as well as the metabolism of dopamine (DA) and the expression of its receptors (D1, D2L and D2S). Additionally, C. minuta administration reduced chronically induced inflammation in plasma, spleen and some brain areas, which likely contribute to the recovery of physical and behavioral function. Furthermore, C. minuta administration prevented chronic stress-induced cardiovascular damage by regulating key enzymes mediating liver fibrosis and oxidative stress. Finally, C. minuta increased the abundance of bacteria associated with mental health. Overall, our study highlights the potential of microbiota-directed interventions to alleviate both the physical and mental effects of chronic stress., Competing Interests: Declaration of Competing Interest The authors Agusti A, Molina-Mendoza G., Cenit MC, Gómez Del Pulgar EM, Sanz Y are co-inventors of a patent on Christensenella minuta. Conflicts of interest The authors Y.S, A.A, G.M., MC.C, EM.G. are co-inventors of a patent on C. minuta., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Cardiovascular disease (CVD) remains a leading cause of mortality worldwide, with hypercholesterolemia being a major risk factor. Although various lipid-lowering therapies exist, many patients fail to achieve optimal cholesterol control, highlighting the need for novel therapeutic approaches. ASGR1 (asialoglycoprotein receptor 1), predominantly expressed on hepatocytes, has emerged as a key regulator of cholesterol metabolism and low-density lipoprotein (LDL) clearance. This receptor's ability to regulate lipid homeostasis positions it as a promising target for therapeutic intervention in hypercholesterolemia and related cardiovascular diseases. This review critically examines the biological functions and regulatory mechanisms of ASGR1 in cholesterol metabolism, with a focus on its potential as a therapeutic target for hypercholesterolemia and related cardiovascular diseases. By analyzing recent advances in ASGR1 research, this article explores its role in liver-specific pathways, the implications of ASGR1 variants in CVD risk, and the prospects for developing ASGR1-targeted therapies. This review aims to provide a foundation for future research and clinical applications in hypercholesterolemia management., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Aging is one of the most significant factors affecting cardiovascular health, with cellular senescence being a central hallmark. Senescent cells (SCs) secrete a specific set of signaling molecules known as the senescence-associated secretory phenotype (SASP). The SASP has a remarkable impact on age-associated diseases, particularly cardiovascular diseases (CVD). Targeting SCs through anti-aging therapies represents a novel strategy to effectively retard senescence and attenuate disease progression. Accumulating evidence demonstrates that the flavonoids, widely presented in fruits and vegetables worldwide, can delay or treat CVD via selectively eliminating SCs (senolytics) and modulating SASPs (senomorphics). Nevertheless, only sporadic research has illustrated the application of flavonoids in targeting SCs for CVD, which requires further exploration. This review recapitulates the hallmarks and key molecular mechanisms involved in cellular senescence, then summarizes senescence of different types of cardiac cells and describes the mechanisms by which cellular senescence affects CVD development. The discussion culminates with the potential use of flavonoids via exerting their biological effects on cellular senescence to reduce CVD incidence. This summary will provide valuable insights for cardiovascular drug design, development and clinical applications leveraging flavonoids., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Valosin-containing protein (VCP), also known as p97, plays a crucial role in various cellular processes, including protein degradation, endoplasmic reticulum-associated degradation, and cell cycle regulation. While extensive research has been focused on VCP's involvement in protein homeostasis and its implications in neurodegenerative diseases, emerging evidence suggests a potential link between VCP and cardiovascular health. VCP is a key regulator of mitochondrial function, and its overexpression or mutations lead to pathogenic diseases and cellular stress responses. The present review explores VCP's roles in numerous cardiovascular disorders including myocardial ischemia/reperfusion injury, cardiac hypertrophy, and heart failure. The review dwells on the roles of VCP in modifying mitochondrial activity, promoting S-nitrosylation, regulating mTOR signalling and demonstrating cardioprotective effects. Further research into VCP might lead to novel interventions for cardiovascular disease, particularly those involving ischemia/reperfusion injury and hypertrophy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Copper, a vital trace element, is indispensable for the maintenance of physiological functioning, particularly in the cardiac system. Unlike other forms of cell death such as iron death and apoptosis, copper‑induced cell death has gained increasing recognition as a significant process influencing the development of cardiovascular diseases. The present review highlights the significance of maintaining copper homeostasis in addressing cardiovascular diseases. This review delves into the crucial roles of copper in physiology, including the metabolic pathways and its absorption, transport and excretion. It provides detailed insights into the mechanisms underlying cardiovascular diseases resulting from both excess and deficient copper levels. Additionally, it summarizes strategies for treating copper imbalances through approaches such as copper chelators and ion carriers while discussing their limitations and future prospects.

Nitric oxide (NO) plays a crucial role as a messenger or effector in the body, yet it presents a dual impact on cardio-cerebrovascular health. Under normal physiological conditions, NO exhibits vasodilatory effects, regulates blood pressure, inhibits platelet aggregation, and offers neuroprotective actions. However, in pathological situations, excessive NO production contributes to or worsens inflammation within the body. Moreover, NO may combine with reactive oxygen species (ROS), generating harmful substances that intensify physical harm. This paper succinctly reviews pertinent literature to clarify the in vivo and in vitro origins of NO, its regulatory function in the cardio-cerebrovascular system, and the advantages and disadvantages associated with NO donor drugs, NO delivery systems, and vascular stent materials for treating cardio-cerebrovascular disease. The findings provide a theoretical foundation for the application of NO in cardio-cerebrovascular diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Cardiovascular disease (CVD) is a leading cause of death worldwide, and the number of patients with CVD continues to increase despite extensive research and developments in this field. Chronic inflammation is a pivotal pathological component of CVD, and unveiling new proinflammatory factors will help devise novel preventive and therapeutic strategies. The extracellular matrix (ECM) not only provides structural support between cells but also contributes to cellular functions. Secreted protein acidic and rich in cysteine (SPARC) is a collagen-binding matricellular protein that is particularly induced during development and tissue remodeling. A proinflammatory role for SPARC has been demonstrated in various animal models, such as in the lipopolysaccharide-induced footpad model and dextran sodium sulfate-induced colitis model. Recent clinical studies reported a positive correlation between elevated plasma SPARC levels and hypertension, obesity, and the inflammatory marker high-sensitive C-reactive protein. In addition, SPARC gene deletion attenuates the cardiac injury induced by aging, myocardial infarction, and pressure load, suggesting that SPARC has deleterious effects on CVD. This review summarizes the regulatory and proinflammatory mechanisms of SPARC on CVD, chronic kidney disease (CKD), and cerebrovascular disease and discusses the rationale behind measuring SPARC as a biomarker of CVD and the effects of inhibition of SPARC in the prevention and treatment of CVD.

Regulation of energy metabolism is pivotal in the development of cardiovascular diseases. Dysregulation in mitochondrial fatty acid oxidation has been linked to cardiac lipid accumulation and diabetic cardiomyopathy. Sirtuin 1 (SIRT1) is a deacetylase that regulates the acetylation of various proteins involved in mitochondrial energy metabolism. SIRT1 mediates energy metabolism by directly and indirectly affecting multiple aspects of mitochondrial processes, such as mitochondrial biogenesis. SIRT1 interacts with essential mitochondrial energy regulators such as peroxisome proliferator-activated receptor-α (PPARα), PPARγ coactivator-1α, estrogen-related receptor-α, and their downstream targets. Apart from that, SIRT1 regulates additional proteins, including forkhead box protein O1 and AMP-activated protein kinase in cardiac disease. Interestingly, studies have also shown that the expression of SIRT1 plays a dual-edged role in energy metabolism. Depending on the physiological state, SIRT1 expression can be detrimental or protective. This review focuses on the molecular pathways through which SIRT1 regulates energy metabolism in cardiovascular diseases. We will review SIRT1 and discuss its role in cardiac energy metabolism and its benefits and detrimental effects in heart disease.

A unique interplay between body and environment embeds and reflects host-microbiome interactions that contribute to sex-differential disease susceptibility, symptomatology, and treatment outcomes. These differences derive from individual biological factors, such as sex hormone action, sex-divergent immune processes, X-linked gene dosage effects, and epigenetics, as well as from their interaction across the lifespan. The gut microbiome is increasingly recognized as a moderator of several body systems that are thus impacted by its function and composition. In humans, biological sex components further interact with gender-specific exposures such as dietary preferences, stressors, and life experiences to form a complex whole, requiring innovative methodologies to disentangle. Here, we summarize current knowledge of the interactions among sex hormones, gut microbiota, immune system, and vascular health and their relevance for sex-differential epidemiology of cardiovascular diseases. We outline clinical implications, identify knowledge gaps, and place emphasis on required future studies to address these gaps. In addition, we provide an overview of the caveats associated with conducting cardiovascular research that require consideration of sex/gender differences. While previous work has inspected several of these components separately, here we call attention to further translational utility of a combined perspective from cardiovascular translational research, gender medicine, and microbiome systems biology., (© 2024 The Author(s). Acta Physiologica published by John Wiley & Sons Ltd on behalf of Scandinavian Physiological Society.)

The mutual regulation between hydrogen sulfide (H 2 S) and microRNA (miRNA) is involved in the development of many diseases, including cancer, cardiovascular disease, inflammatory disease, and high-risk pregnancy. Abnormal expressions of endogenous H 2 S-producing enzyme and miRNA in tissues and cells often indicate the occurrence of diseases, so the maintenance of their normal levels in the body can mitigate damages caused by various factors. Many studies have found that H 2 S can promote the migration, invasion, and proliferation of cancer cells by regulating the expression of miRNA, while many H 2 S donors can inhibit cancer progression by interfering with the proliferation, apoptosis, cell cycle, metastasis, and angiogenesis of cancer cells. Furthermore, the mutual regulation between H 2 S and miRNA can also prevent cell injury in cardiovascular disease and inflammatory disease through anti-inflammation, anti-oxidation, anti-apoptosis, and pro-autophagy. In addition, H 2 S can promote angiogenesis and relieve vasoconstriction by regulating the expression of miRNA, thereby improving fetal growth in high-risk pregnancy. In this review, we discuss the mechanism of mutual regulation between H 2 S and miRNA in various diseases, which may provide reliable therapeutic targets for these diseases., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Cardiovascular disease is the deadly disease that can result in sudden death, and inflammation plays an important role in its onset and progression. High mobility group box 1 (HMGB1) is a nuclear protein that regulates transcription, DNA replication, repair, and nucleosome assembly. HMGB1 is released passively by necrotic tissues and actively secreted by stressed cells. Extracellular HMGB1 functions as a damage associated molecular patterns molecule, producing numerous redox forms that induce a range of cellular responses by binding to distinct receptors and interactors, including tissue inflammation and regeneration. Extracellular HMGB1 inhibition reduces inflammation and is protective in experimental models of myocardial ischemia/reperfusion damage, myocarditis, cardiomyopathies caused by mechanical stress, diabetes, bacterial infection, or chemotherapeutic drugs. HMGB1 administration following a myocardial infarction followed by permanent coronary artery ligation improves cardiac function by stimulating tissue regeneration. HMGB1 inhibits contractility and produces hypertrophy and death in cardiomyocytes, while also stimulating cardiac fibroblast activity and promoting cardiac stem cell proliferation and differentiation. Maintaining normal nuclear HMGB1 levels, interestingly, protects cardiomyocytes from apoptosis by limiting DNA oxidative stress, and mice with HMGB1cardiomyocyte-specific overexpression are partially protected from cardiac injury. Finally, elevated levels of circulating HMGB1 have been linked to human heart disease. As a result, following cardiac damage, HMGB1 elicits both detrimental and helpful responses, which may be due to the formation and stability of the various redox forms, the particular activities of which in this context are mostly unknown. This review covers recent findings in HMGB1 biology and cardiac dysfunction., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Sirtuins, as NAD + -dependent deacetylases, are widely found in eubacteria, archaea, and eukaryotes, and they play key roles in regulating cellular functions. Among these, SIRT7 stands out as a member discovered relatively late and studied less extensively. It is localized within the nucleus and displays enzymatic activity as an NAD + -dependent deacetylase, targeting a diverse array of acyl groups. The role of SIRT7 in important cellular processes like gene transcription, cellular metabolism, cellular stress responses, and DNA damage repair has been documented in a number of studies conducted recently. These studies have also highlighted SIRT7's strong correlation with human diseases like aging, cancer, neurological disorders, and cardiovascular diseases. In addition, a variety of inhibitors against SIRT7 have been reported, indicating that targeting SIRT7 may be a promising strategy for inhibiting tumor growth. The purpose of this review is to thoroughly look into the structure and function of SIRT7 and to explore its potential value in clinical applications, offering an essential reference for research in related domains., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Transgender identity is often associated with gender dysphoria and minority stress. Gender-affirming hormone treatment (GAHT) includes masculinising or feminising treatment and is expected to be lifelong in most cases. Sex and sex hormones have a differential effect on metabolism and CVD in cisgender people, and sex hormone replacement in hypogonadism is associated with higher vascular risk, especially in ageing individuals. Using narrative review methods, we present evidence regarding metabolic and cardiovascular outcomes during GAHT and propose recommendations for follow-up and monitoring of metabolic and cardiovascular risk markers during GAHT. Available data show no increased risk for type 2 diabetes in transgender cohorts, but masculinising GAHT increases lean body mass and feminising GAHT is associated with higher fat mass and insulin resistance. The risk of CVD is increased in transgender cohorts, especially during feminising GAHT. Masculinising GAHT is associated with a more adverse lipid profile, higher haematocrit and increased BP, while feminising GAHT is associated with pro-coagulant changes and lower HDL-cholesterol. Assigned male sex at birth, higher age at initiation of GAHT and use of cyproterone acetate are separate risk factors for adverse CVD markers. Metabolic and CVD outcomes may improve during gender-affirming care due to a reduction in minority stress, improved lifestyle and closer surveillance leading to optimised preventive medication (e.g. statins). GAHT should be individualised according to individual risk factors (i.e. drug, dose and form of administration); furthermore, doctors need to discuss lifestyle and preventive medications in order to modify metabolic and CVD risk during GAHT. Follow-up programmes must address the usual cardiovascular risk markers but should consider that biological age and sex may influence individual risk profiling including mental health, lifestyle and novel cardiovascular risk markers during GAHT., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The morbidity and mortality rates of cardiovascular diseases (CVDs) are increasing; thus, they impose substantial health and economic burdens worldwide, and effective interventions are needed for immediate resolution of this issue. Recent studies have suggested that noncoding RNAs (ncRNAs) play critical roles in the occurrence and development of CVDs and are potential therapeutic targets and novel biomarkers for these diseases. Newly discovered modes of cell death, including necroptosis, pyroptosis, apoptosis, autophagy-dependent cell death and ferroptosis, also play key roles in CVD progression. However, ferroptosis, which differs from the other aforementioned forms of regulated cell death in terms of cell morphology, biochemistry and inhereditability, is a unique iron-dependent mode of nonapoptotic cell death induced by abnormal iron metabolism and excessive accumulation of iron-dependent lipid peroxides and reactive oxygen species (ROS). Increasing evidence has confirmed that ncRNA-mediated ferroptosis is involved in regulating tissue homeostasis and CVD-related pathophysiological conditions, such as cardiac ischemia/reperfusion (I/R) injury, myocardial infarction (MI), atrial fibrillation (AF), cardiomyopathy and heart failure (HF). In this review, we summarize the underlying mechanism of ferroptosis, discuss the pathophysiological effects of ncRNA-mediated ferroptosis in CVDs and provide ideas for effective therapeutic strategies., (© 2023. The Author(s).)

Background: Autophagy is an evolutionarily conserved turnover process for intracellular substances in eukaryotes, relying on lysosomal (in animals) or vacuolar (in yeast and plants) mechanisms. In the past two decades, emerging evidence suggests that, under specific conditions, autophagy can target particular macromolecules or organelles for degradation, a process termed selective autophagy. Recently, accumulating studies have demonstrated that the abnormality of selective autophagy is closely associated with the occurrence and progression of many human diseases, including neurodegenerative diseases, cancers, metabolic diseases, and cardiovascular diseases., Aim of Review: This review aims at systematically and comprehensively introducing selective autophagy and its role in various diseases, while unravelling the molecular mechanisms of selective autophagy. By providing a theoretical basis for the development of related small-molecule drugs as well as treating related human diseases, this review seeks to contribute to the understanding of selective autophagy and its therapeutic potential., Key Scientific Concepts of Review: In this review, we systematically introduce and dissect the major categories of selective autophagy that have been discovered. We also focus on recent advances in understanding the molecular mechanisms underlying both classical and non-classical selective autophagy. Moreover, the current situation of small-molecule drugs targeting different types of selective autophagy is further summarized, providing valuable insights into the discovery of more candidate small-molecule drugs targeting selective autophagy in the future. On the other hand, we also reveal clinically relevant implementations that are potentially related to selective autophagy, such as predictive approaches and treatments tailored to individual patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Production and hosting by Elsevier B.V.)

Importance: The recent change in terminology from nonalcoholic fatty liver disease (NAFLD) to metabolic dysfunction-associated fatty liver disease (MAFLD) and metabolic dysfunction-associated steatotic liver disease (MASLD) highlights the link between hepatic steatosis and metabolic dysfunction, taking out the stigmata of alcohol., Objective: We compared the effects of NAFLD and MAFLD definitions on the risk of overall and cardiovascular (CV) mortality, liver-related events (LRE), nonfatal CV events (CVE), chronic kidney disease (CKD), and extra-hepatic cancers (EHC)., Data Sources and Study Selection: We systematically searched four large electronic databases for cohort studies (published through August 2023) that simultaneously used NAFLD and MAFLD definitions for examining the risk of mortality and adverse CV, renal, or oncological outcomes associated with both definitions. In total, 21 eligible cohort studies were identified. Meta-analysis was performed using random-effects modelling., Results: Compared with those with NAFLD, individuals with MAFLD had significantly higher rates of overall mortality (random-effect OR 1.12, 95% CI 1.04-1.21, p = .004) and CV mortality (random-effect OR 1.15, 95% CI 1.04-1.26, p = .004), and a marginal trend towards higher rates of developing CKD (random-effect OR 1.06, 95% CI 1.00-1.12, p = .058) and EHC events (random-effect OR 1.11, 95% CI 1.00-1.23, p = .052). We found no significant differences in the risk LREs and nonfatal CVE between MAFLD and NAFLD. Meta-regression analyses identified male sex and metabolic comorbidities as the strongest risk factors related to the risk of adverse clinical outcomes in MAFLD compared to NAFLD., Conclusions and Relevance: Individuals with MAFLD have higher rates of overall and CV mortality and higher rates of developing CKD and EHC events than those with NAFLD, possibly due to the dysmetabolic risk profile related to MAFLD., (© 2024 The Author(s). Liver International published by John Wiley & Sons Ltd.)

Non-coding RNAs (ncRNAs) have key roles in the etiology of many illnesses, including heart failure, myocardial infarction, stroke, and in physiological processes like angiogenesis. In transcriptional regulatory circuits that control heart growth, signaling, and stress response, as well as remodeling in cardiac disease, ncRNAs have become important players. Studies on ncRNAs and cardiovascular disease have made great progress recently. Here, we go through the functions of non-coding RNAs (ncRNAs) like circular RNAs (circRNAs), and microRNAs (miRNAs) as well as long non-coding RNAs (lncRNAs) in modulating cardiovascular disorders., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Despite advancements in managing traditional cardiovascular risk factors, many cardiovascular diseases (CVDs) persist. Fibroblast growth factors (FGFs) have emerged as potential diagnostic markers and therapeutic targets for CVDs. FGF1, FGF2, and FGF4 are primarily used for therapeutic angiogenesis. Clinical applications are being explored based on animal studies using approaches such as recombinant protein administration and adenovirus-mediated gene delivery, targeting patients with coronary artery disease and lower extremity arterial disease. Although promising results have been observed in animal models and early-stage clinical trials, further studies are required to assess their therapeutic potential. The FGF19 subfamily, consisting of FGF19, FGF21, and FGF23, act via endocrine signaling in various organs. FGF19, primarily expressed in the small intestine, plays important roles in glucose, lipid, and bile acid metabolism and has therapeutic potential for metabolic disorders. FGF21, found in various tissues, improves glucose metabolism and insulin sensitivity, suggesting potential for treating obesity and diabetes. FGF23, primarily secreted by osteocytes, regulates vitamin D and phosphate metabolism and serves as an important biomarker for chronic kidney disease and CVDs. Thus, FGFs holds promise for both therapeutic and diagnostic applications in metabolic and cardiovascular diseases. Understanding the mechanisms of FGF may pave the way for novel strategies to prevent and manage CVDs, potentially addressing the limitations of current treatments. This review explores the roles of FGF1, FGF2, FGF4, and the FGF19 subfamily in maintaining cardiovascular health. Further research and clinical trials are crucial to fully understand the therapeutic potential of FGFs in managing cardiovascular health.

Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. Morag J Young reports financial support was provided by Baker Trustees and Baker HDI. Viet Q.Ho reports a relationship with Monash University that includes: funding grants. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Irisin, a product of the post-translational processing of fibronectin type III domain-containing protein 5 (FNDC5), is a novel myokine which is upregulated during exercise. This hormone not only promotes the transformation of white adipose tissue into a brown-fat-like phenotype but also enhances energy expenditure and mitigates fat accumulation. Its role is crucial in the management of certain metabolic disorders such as diabetes and heart disease. Of note, the type of exercise performed significantly affects blood irisin levels, indicating the critical role of physical activity in regulating this hormone. This article aims to summarize the current scientific understanding of the role of irisin and the mechanisms through which it mediates cardiovascular protection through exercise. Moreover, this article aims to establish irisin as a potential target for preventing and treating cardiovascular diseases., Competing Interests: The authors declare that they have no competing interests., (© 2024 Guo et al.)

Cardiovascular diseases (CVDs) are a leading cause of morbidity and mortality worldwide. Metabolic imbalances and pathological stress often contribute to increased mortality. Sestrin2 (Sesn2) is a stress-inducible protein crucial in maintaining cardiac energy and metabolic homeostasis under pathological conditions. Sesn2 is upregulated in response to various stressors, including oxidative stress, hypoxia, and energy depletion, and mediates multiple cellular pathways to enhance antioxidant defenses, promote autophagy, and inhibit inflammation. This review explores the mechanisms through which Sesn2 regulates these pathways, focusing on the AMPK-mTORC1, Sesn2-Nrf2, and HIF1α-Sesn2 pathways, among others. We can identify the potential therapeutic targets for treating CVDs and related metabolic disorders by comprehending these complex mechanisms. Sesn2's unique ability to respond thoroughly to metabolic challenges, oxidative stress, and inflammation makes it a promising prospect for enhancing cardiac health and resilience against pathological stress., (© 2024 Federation of American Societies for Experimental Biology.)

Cardiovascular disease (CVD) remains a global economic burden even in the 21st century with 85% of deaths resulting from heart attacks. Despite efforts in reducing the risk factors, and enhancing pharmacotherapeutic strategies, challenges persist in early identification of disease progression and functional recovery of damaged hearts. Targeting mitochondrial dysfunction, a key player in the pathogenesis of CVD has been less successful due to its role in other coexisting diseases. Additionally, it is the only organelle with an agathokakological function that is a remedy and a poison for the cell. In this review, we describe the origins of cardiac mitochondria and the role of heteroplasmy and mitochondrial subpopulations namely the interfibrillar, subsarcolemmal, perinuclear, and intranuclear mitochondria in maintaining cardiac function and in disease-associated remodeling. The cumulative evidence of mitochondrial retrograde communication with the nucleus is addressed, highlighting the need to study the genotype-phenotype relationships of specific organelle functions with CVD by using approaches like genome-wide association study (GWAS). Finally, we discuss the practicality of computational methods combined with single-cell sequencing technologies to address the challenges of genetic screening in the identification of heteroplasmy and contributory genes towards CVD., (© 2024. The Author(s).)

Background: Rheumatoid arthritis (RA) is a chronic inflammatory disease that affects not only the joints but also has significant cardiovascular (CV) manifestations. The mechanistic interplay between RA and cardiovascular complications is not yet well understood due to the lack of relevant in vitro models. In this study, we established RA cardiac microtisses (cMTs) from iPSC-derived cardiomyocytes (CMs), endothelial cells (ECs) and cardiac fibroblasts (CFs) to investigate whether this fully human 3D multicellular system could serve as a platform to elucidate the connection between RA and CV disorders., Methods: PBMC and FLS from healthy and RA donors were reprogrammed to hiPSCs with Sendai vectors. hiPSCs pluripotency was assessed by IF, FACS, spontaneous embryoid bodies formation and teratoma assay. hiPSCs were differentiated to cardiac derivatives such as CMs, ECs and CFs, followed by cell markers characterizations (IF, FACS, qRT-PCR) and functional assessments. 3D cMTs were generated by aggregation of 70% CMs, 15% ECs and 15% CFs. After 21 days in culture, structural and metabolic properties of 3D cMTs were examined by IF, qRT-PCR and Seahorse bioanalyzer., Results: hiPSCs demonstrated typical colony-like morphology, normal karyotype, presence of pluripotency markers, and ability to differentiate into cells originating from all three germ layers. hiPSC-CMs showed spontaneous beating and expression of cardiac markers (cTnT, MYL7, NKX2.5, MYH7). hiPSC-ECs formed sprouting spheres and tubes and expressed CD31 and CD144. hiPSC-CFs presented spindle-shaped morphology and expression of vimentin, collagen 1 and DDR2. Self-aggregation of CMs/ECs/CFs allowed development of contracting 3D cMTs, demonstrating spherical organization of the cells, which partially resembled the cardiac muscle, both in structure and function. IF analysis confirmed the expression of cTnT, CD31, CD144 and DDR2 in generated 3D cMTs. RA cMTs exhibited significantly greater formation of capillary-like structures, mimicking enhanced vascularization-key RA feature-compared to control cMTs. Seahorse examination of cMTs revealed changes in mitochondrial and glycolytic rates in the presence of metabolic substrates and inhibitors., Conclusions: The cMTs model may represent an advanced human stem cell-based platform for modeling CV complications in RA. The highly developed capillary-like structures observed within RA cMTs highlight a critical feature of inflammation-induced CV dysfunction in chronic inflammatory diseases., (© 2024. The Author(s).)

Background: As the predominant leisure-time sedentary behavior, television viewing was documented to increase cardiovascular diseases in observational studies, yet the causal relationship and potential mechanisms remain to be determined., Objectives: To systematically investigate the causal relationship between television viewing time, cardiovascular diseases, and potential mechanisms., Methods: We conducted a two-sample Mendelian randomization (MR) analysis to estimate causal associations with cardiovascular diseases and biomarkers of cardiometabolic risk. The random inverse-variance weighted method was used as the primary estimate. To account for multiple comparisons, a Bonferroni correction p value for cardiovascular diseases and biomarkers of cardiometabolic risk was 0.0045 and 0.0024, respectively., Results: Genetically instrumented television viewing time was associated with higher risks of type 2 diabetes (odd ratio [OR]=2.51; 95% confidence interval [CI]: 1.89-3.33; p<0.00001), hypertension (OR=2.11; 95% CI: 1.67-2.66; p<0.00001), coronary heart disease (OR=1.53; 95% CI: 1.23-1.91; p=0.00015), and heart failure (OR=1.42; 95% CI: 1.18-1.70; p=0.00017). Suggestive evidence of harmful associations was also observed for peripheral artery disease (OR=1.58; 95% CI: 1.07-2.34; p=0.02253) and ischemic stroke (OR=1.34; 95% CI: 1.10-1.63; p=0.00328). Biomarkers of cardiometabolic risk, including interleukin 10, leptin, visceral adipose, abdominal subcutaneous adipose, liver fat, body mass index, waist circumference, triglycerides, and C-reactive protein, were increased. Systolic blood pressure, heart rate, low-density lipoprotein, and total cholesterol were potentially increased while high-density lipoprotein was decreased. However, television viewing time had no effect on venous thromboembolism or pulmonary embolism., Conclusion: Television viewing time was causally associated with increased risks of cardiovascular diseases, which may be explained by metabolic and inflammatory mechanisms., Background: An overview of the effect of television viewing time on cardiovascular diseases and biomarkers of cardiometabolic risk.

Lipoproteins and apolipoproteins are crucial in lipid metabolism, functioning as essential mediators in the transport of cholesterol and triglycerides and being closely related to the pathogenesis of multiple systems, including cardiovascular. Lipoproteins a (Lp(a)), as a unique subclass of lipoproteins, is a low-density lipoprotein(LDL)-like particle with pro-atherosclerotic and pro-inflammatory properties, displaying high heritability. More and more strong evidence points to a possible link between high amounts of Lp(a) and cardiac conditions like atherosclerotic cardiovascular disease (ASCVD) and aortic stenosis (AS), making it a risk factor for heart diseases. In recent years, Lp(a)'s role in other diseases, including neurological disorders and cancer, has been increasingly recognized. Although therapies aimed at low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) have achieved significant success, elevated Lp(a) levels remain a significant clinical management problem. Despite the limited efficacy of current lipid-lowering therapies, major clinical advances in new Lp(a)-lowering therapies have significantly advanced the field. This review, grounded in the pathophysiology of lipoproteins, seeks to summarize the wide-ranging connections between lipoproteins (such as LDL-C and HDL-C) and various diseases, alongside the latest clinical developments, special emphasis is placed on the pivotal role of Lp(a) in cardiovascular disease, while also examining its future potential and mechanisms in other conditions. Furthermore, this review discusses Lp(a)-lowering therapies and highlights significant recent advances in emerging treatments, advocates for further exploration into Lp(a)'s pathogenic mechanisms and its potential as a therapeutic target, proposing new secondary prevention strategies for high-risk individuals., (© 2024. The Author(s).)

Cardiovascular disease (CVD) is the leading cause of mortality, disability, and healthcare costs, with a significant impact on the elderly and contributing to premature deaths across various age groups, including those below age 70. Despite decades of transformative discoveries and clinical efforts, the challenges of diagnosis, prevention, and treatment of CVD persist on a massive scale. This study aimed to unravel potential CVD-associated biomarkers and establish a machine learning model for the risk assessment of CVD. Untargeted metabolic assay with ultra-high performance liquid chromatography-tandem mass spectrometry and routine clinical biochemistry test were undertaken on the fasting venous blood specimens from 57 subjects. Four relevant clinical traits and 164 CVD-associated metabolites were identified, especially those related to glycerophospholipid metabolism and biosynthesis of unsaturated fatty acids. The machine learning model achieved from an integrated biomarker panel of palmitic amide, oleic acid, 138-pos (the 138th detected metabolomic feature in positive ion mode), phosphatidylcholine, linoleic acid, age, direct bilirubin, and inorganic phosphate, was able to improve the accuracy of CVD risk assessment up to a high satisfactory value of 0.91. The findings indicate that disorders in the metabolic processes of biological membranes and energy are significantly associated with increased risk of vascular damage in CVD patients. With machine learning methods, the pivotal metabolites and clinical biomarkers offer a promising potential for the efficient risk assessment and diagnosis of CVD., (© 2024. The Author(s).)

Reactive oxygen species (ROS) contribute to endothelial dysfunction, platelet activation, and coagulation abnormalities, promoting thrombus formation. Given the growing interest in non-pharmacological approaches to modulate oxidative stress, we examine the potential of various dietary interventions and antioxidant supplementation in reducing oxidative damage and preventing thrombotic events. Key dietary patterns, such as the Mediterranean, Dietary Approaches to Stop Hypertension (DASH), and ketogenic diets, as well as antioxidant-rich supplements like curcumin, selenium, and polyphenols, demonstrate promising effects in improving oxidative stress markers, lipid profiles, and inflammatory responses. This review highlights recent advances in the field, drawing from in vitro, ex vivo, and clinical studies, and underscores the importance of integrating dietary strategies into preventive and therapeutic approaches for managing thrombosis and cardiovascular health. Further research is needed to better understand long-term effects and personalize these interventions for optimizing patient outcomes.

Voltage-gated ion channels (VGICs) are central to cellular excitation, orchestrating skeletal and cardiac muscle contractions and enabling neural signal transduction. Among these, voltage-gated potassium (Kv) channels are particularly significant in cardiac electrophysiology, especially during the repolarization phase of the cardiac action potential. In cardiac myocytes, Kv channels are integral to a multitude of sophisticated functions, including electrical conduction. Despite their importance, research on Kv channels in the context of cardiovascular diseases is limited. This review offers a comprehensive summary of the structural complexities of Kv channels, delineating the regulatory mechanisms involved in channel gating, expression, and membrane localization. Additionally, we examine the role of different Kv α-subunits in modulating Kv channels and their impact on cardiac remodeling, and assess the potential of targeting Kv channels for the development of anti-arrhythmic therapies.

A state of hypoxia (lack of oxygen) persists in the initial and later phases of healing in cardiovascular diseases, which can alter the tissue's repair or regeneration, ultimately affecting the structure and functionality of the related organ. Consequently, this results in a cascade of events, leading to metabolic stress and the production of reactive oxygen species (ROS) and autophagy. This unwanted situation not only limits the oxygen supply to the needy tissues but also creates an inflammatory state, limiting the exchange of nutrients and other supplements. Consequently, biomaterials have gained considerable attention to alleviate hypoxia and oxidative stress in cardiovascular diseases. Numerous oxygen releasing and antioxidant biomaterials have been developed and proven to alleviate hypoxia and oxidative stress. This review article summarizes the mechanisms involved in cardiovascular pathologies due to hypoxia and oxidative stress, as well as the treatment modalities currently in practice. The applications, benefits and possible shortcomings of these approaches have been discussed. Additionally, the review explores the role of novel biomaterials in combating the limitations of existing approaches, primarily focusing on the development of oxygen-releasing and antioxidant biomaterials for cardiac repair and regeneration. It also directs attention to various other potential applications with critical insights for further advancement in this area.

Cancer patients, especially long cancer survivors, are exposed to several cardio-metabolic diseases, including diabetes, heart failure, and atherosclerosis, which increase their risk of cardiovascular mortality. Therapy with glucagon-like peptide 1 (GLP1) receptor agonists demonstrated several beneficial cardiovascular effects, including atherosclerosis and heart failure prevention. Cardiovascular outcome trials (CVOTs) suggest that GLP-1 RA could exert cardiorenal benefits and systemic anti-inflammatory effects in patients with type-2 diabetes through the activation of cAMP and PI3K/AkT pathways and the inhibition of NLRP-3 and MyD88. In this narrative review, we highlight the biochemical properties of GLP-1 RA through a deep analysis of the clinical and preclinical evidence of the primary prevention of cardiomyopathies. The overall picture of this review encourages the study of GLP-1 RA in cancer patients with type-2 diabetes, as a potential primary prevention strategy against heart failure and atherosclerosis.

Background: Dapagliflozin (DPG) is a sodium-glucose cotransporter-2 inhibitor and is used in the treatment of diabetes. In this study, we aimed to investigate the effect of DPG on cardiotoxicity caused by systemic inflammation via endoplasmic reticulum (ER) stress and autophagy., Methods and Results: Four groups of thirty-two Wistar Albino rats were created: Control (1 ml oral physiological saline for five days and intraperitoneal saline on the 5th day), LPS (1 ml oral physiological saline for five days and intraperitoneal 5 mg/kg of LPS on the 5th day), LPS + DPG (10 mg/kg of DPG orally for five days and 5 mg/kg of LPS intraperitoneally on the 5th day), and DPG (10 mg/kg of DPG orally for five days and 5 mg/kg of SF intraperitoneally on the 5th day). Histopathological and immunohistochemical analyses were performed on heart and aorta tissues. ER stress and autophagy gene markers in heart tissues were evaluated by RT-qPCR. Oxidative stress in heart tissues and serum cardiac enzymes were analyzed by spectrophotometric method. The heart and aortic tissues of the LPS group showed increased expressions of Tumor Necrosis Factor-α (TNF-α) and Caspase-3 (Cas-3), along with mild hyperemia, slight inflammatory cell infiltrations, and myocardial cell damage. The heart tissues also showed genetically increased expressions of include binding immunoglobulin protein (BiP/ GRP78), protein kinase RNA-like ER Kinase (PERK), inositol-requiring enzyme 1 (IRE-1), activating transcription factors 4 (ATF-4), activating transcription factors 4 (ATF6), C/EBP homologous protein (CHOP), and BECLIN 1. Furthermore, Creatine kinase-MB (CK-MB) and Lactate dehydrogenase (LDH) levels in blood tissue significantly increased, according to biochemical analysis. With DPG therapy, all of these findings were reversed., Conclusion: In conclusion, DPG protects against the cardiotoxic effect of systemic inflammation with its antioxidant and anti-inflammatory properties by regulating ER stress and autophagy pathways., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Inositol 1,4,5-trisphosphate receptors (IP 3 Rs) play a crucial role in maintaining intracellular/cytosolic calcium ion (Ca 2+ i ) homeostasis. The release of Ca 2+ from IP 3 Rs serves as a second messenger and a modulatory factor influencing various intracellular and interorganelle communications during both physiological and pathological processes. Accumulating evidence from in vitro, in vivo, and clinical studies supports the notion that the overactivation of IP 3 Rs is linked to the pathogenesis of various cardiac conditions. The overactivation of IP 3 Rs results in the dysregulation of Ca 2+ concentration ([Ca 2+ ]) within cytosolic, mitochondrial, and nucleoplasmic cellular compartments. In cardiovascular pathologies, two isoforms of IP 3 Rs, i.e., IP 3 R1 and IP 3 R2, have been identified. Notably, IP 3 R1 plays a pivotal role in cardiac ischemia and diabetes-induced arrhythmias, while IP 3 R2 is implicated in sepsis-induced cardiomyopathy and cardiac hypertrophy. Furthermore, IP 3 Rs have been reported to be involved in various programmed cell death (PCD) pathways, such as apoptosis, pyroptosis, and ferroptosis underscoring their multifaceted roles in cardiac pathophysiology. Based on these findings, it is evident that exploring potential therapeutic avenues becomes crucial. Both genetic ablation and pharmacological intervention using IP 3 R antagonists have emerged as promising strategies against IP 3 R-related pathologies suggesting their potential therapeutic potency. This review summarizes the roles of IP 3 Rs in cardiac physiology and pathology and establishes a foundational understanding with a particular focus on their involvement in the various PCD pathways within the context of cardiovascular diseases.

Adverse Childhood Experiences (ACEs) refer to early life stress events, including abuse, neglect, and other psychosocial childhood traumas that can have long-lasting effects on a wide range of physiological functions. ACEs provoke sex-specific effects, whereas women have been shown to display a strong positive correlation with obesity and cardiometabolic disease. Notably, rodent models of chronic behavioral stress during postnatal life recapitulate several effects of ACEs in a sex-specific fashion. In this review, we will discuss the potential mechanisms uncovered by models of early life stress that may explain the greater susceptibility of females to obesity and metabolic risk compared with their male counterparts. We highlight the early life stress-induced neuroendocrine shaping of the adrenal-adipose tissue axis as a primary event conferring sex-dependent heightened sensitivity to obesity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Turner, Dalmasso and Loria.)

Vascular aging encompasses structural and functional changes in the vasculature, significantly contributing to cardiovascular diseases, which are the leading cause of death globally. The incidence and prevalence of these diseases increase with age, with most morbidity and mortality attributed to myocardial infarction and stroke. Diagnosing and intervening in vascular aging while understanding the mechanisms behind age-induced vascular phenotypic and pathophysiological alterations offers the potential for delaying and preventing cardiovascular mortality in an aging population. This review delves into various aspects of vascular aging by examining age-related changes in arterial health at the cellular level, including endothelial dysfunction, cellular senescence, and vascular smooth muscle cell transdifferentiation, as well as at the structural level, including arterial stiffness and changes in wall thickness and diameter. We also explore aging-related changes in perivascular adipose tissue deposition, arterial collateralization, and calcification, providing insights into the physiological and pathological implications. Overall, aging induces phenotypic changes that augment the vascular system's susceptibility to disease, even in the absence of traditional risk factors, such as hypertension, diabetes, obesity, and smoking. Overall, age-related modifications in cellular phenotype and molecular homeostasis increase the vulnerability of the arterial vasculature to structural and functional alterations, thereby accelerating cardiovascular risk. Increasing our understanding of these modifications is crucial for success in delaying or preventing cardiovascular diseases. Non-invasive techniques, such as measuring carotid intima-media thickness, pulse wave velocity, and flow-mediated dilation, as well as detecting vascular calcifications, can be used for the early detection of vascular aging. Targeting specific pathological mechanisms, such as cellular senescence and enhancing angiogenesis, holds promise for innovative therapeutic approaches.

Ankyrin repeat domain 1 (Ankrd1) is an acute response protein that belongs to the muscle ankyrin repeat protein (MARP) family. Accumulating evidence has revealed that Ankrd1 plays a crucial role in a wide range of biological processes and diseases. This review consolidates current knowledge on Ankrd1's functions in myocardium and skeletal muscle development, neurogenesis, cancer, bone formation, angiogenesis, wound healing, fibrosis, apoptosis, inflammation, and infection. The comprehensive profile of Ankrd1 in cardiovascular diseases, myopathy, and its potential as a candidate prognostic and diagnostic biomarker are also discussed. In the future, more studies of Ankrd1 are warranted to clarify its role in diseases and assess its potential as a therapeutic target., (© 2024. The Author(s).)

The interaction between macrophages and cardiomyocytes plays an important role not only in maintaining cardiac homeostasis, but also in the development of many cardiovascular diseases (CVDs), such as myocardial infarction (MI) and heart failure (HF). In addition to supporting cardiomyocytes, macrophages and cardiomyocytes have a close and complex relationship. By studying their cross-talk, we can better understand novel mechanisms and target pathogenic mechanisms, and improve the treatment of CVDs. We review macrophage-cardiomyocyte communication through connexin 43 (Cx43)-containing gap junctions (GJs) directly, secreted protein factors indirectly, and discuss the implications of these interactions in cardiac homeostasis and the development of various CVDs, including MI, HF, arrhythmia, cardiac fibrosis and myocarditis. In this section, we review various drugs that work by modulating cytokines or other proteins to reduce inflammation in CVDs. The clinical findings from targeting inflammation in CVDs are also discussed. Additionally, we examine the challenges and opportunities for improving our understanding of macrophage-cardiomyocyte coupling as it relates to pathophysiological disease processes, extending our research scope, and helping identify new molecular targets and improve the effectiveness of existing therapies., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)