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Sodium-glucose cotransporter 2 inhibitors (SGLT-2i) have demonstrated efficacy in reducing cardiovascular events and potentially improving kidney function in diabetic patients. This investigation analyzes the TriNetX database to assess the efficacy of SGLT-2i in diabetic kidney transplant recipients (KTR) concerning all-cause mortality, major adverse cardiac events (MACE), and major adverse kidney events (MAKE). The study includes type 2 diabetic patients over 18 who underwent kidney transplants between June 1, 2015, and June 1, 2023, with a focus on SGLT-2i use within the first three months post-transplant. After propensity score matching, the study compares 1970 SGLT-2i users with matched non-users. With a median follow-up of 3.4 years, SGLT-2i users showed significantly lower rates of all-cause mortality (adjusted hazard ratio [aHR]: 0.32), MACE (aHR: 0.48), and MAKE (aHR: 0.52). These findings indicate that SGLT-2i significantly reduces mortality and adverse events in diabetic KTR, underscoring its potential to improve post-transplant outcomes., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Poor adherence to chronic cardiovascular treatments can impede targeted clinical outcomes. This study estimates the potential benefits of improving adherence among patients with cardiovascular disease requiring secondary prevention in Mexico, Thailand, and China., Methods and Results: We performed Markov model simulation for patients with cardiovascular disease in 3 countries from health care and societal perspectives over a lifetime horizon. Two scenarios were compared: (1) optimal adherence based on a meta-analysis of 51 randomized controlled trials and (2) status quo. The association between adherence and cardiovascular disease outcomes derives from a dose-response meta-analysis of 4 051 338 patients. Outcomes include the accumulated number of cardiovascular events and associated costs in 2022 US dollars, life years, and quality-adjusted life years. Optimal adherence could prevent 42 (95% credible interval [CrI], 29-56) cardiovascular events in Mexico, 34 (95% CrI, 24-50) in Thailand, and 63 (95% CrI, 43-89) in China per 1000 patients over a lifetime. Incremental effectiveness per patient was 0.60 (95% CrI, 0.47-0.74) life-years in Mexico, 0.68 (95% CrI, 0.37-0.94) quality-adjusted life years in Thailand, and 0.93 (95% CrI, 0.44-1.27) quality-adjusted life years in China. Cost savings from societal perspective amounted to $412 (95% CrI, $211-$723), $316 (95% CrI, $187-$541), and $700 (95% CrI, $355-$1144) per patient for Mexico, Thailand, and China, respectively. Findings remained cost saving in deterministic and probabilistic sensitivity analyses., Conclusions: Achieving optimal adherence in patients with cardiovascular disease requiring lipid-lowering therapy saves costs and improves health outcomes in Mexico, Thailand, and China. These findings support national health care systems implementing strategies to improve adherence in these countries.

Context: Thyroid-stimulating hormone (TSH) trajectory classification represents a novel approach to defining the adequacy of levothyroxine (LT4) treatment for hypothyroidism over time., Objective: This is a proof of principle study that uses longitudinal clinical data, including thyroid hormone levels from a large prospective study to define classes of TSH trajectories and examine changes in cardiovascular (CV) health markers over the study period., Methods: Growth mixture modeling (GMM), including latent class growth analysis (LCGA), was used to classify LT4-treated individuals participating in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) based on serial TSH levels. Repeated measure analyses were then utilized to assess within-class changes in blood pressure, lipid levels, hemoglobin A1c, and CV-related medication utilization., Results: From the 621 LT4-treated study participants, the best-fit GMM approach identified 4 TSH trajectory classes, as defined by their relationship to the normal TSH range: (1) high-high normal TSH, (2) normal TSH, (3) normal to low TSH, and (4) low to normal TSH. Notably, the average baseline LT4 dose was lowest in the high-high normal TSH group (77.7 µg, P < .001). There were no significant differences in CV health markers between the classes at baseline. At least 1 significant difference in CV markers occurred in all classes, highlighted by the low to normal class, in which total and high-density lipoprotein cholesterol, triglycerides, and A1c all increased significantly (P = .049, P < .001, P < .001, and P = .001, respectively). Utilization of antihypertensive, antihyperlipidemic, and antidiabetes medications increased in all classes., Conclusion: GMM/LCGA represents a viable approach to define and examine LT4 treatment by TSH trajectory. More comprehensive datasets should allow for more complex trajectory modeling and analysis of clinical outcome differences between trajectory classes., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Little is known about the long-term effectiveness of risk-based treat-to-target cholesterol-lowering interventions on cardiovascular risk. Here, we show the emulated effectiveness of guideline-recommended low-density and non-high-density lipoprotein cholesterol-lowering interventions using the absolute risk reduction (ARR) and the restricted mean event-free time-based number needed to treat (NNT). With 5,375 participants, the 29-year risks for cardiovascular disease (CVD), all-cause mortality, and atherosclerotic CVD were 18.6%, 25.6%, and 17.7%, respectively. Long-term treat-to-target interventions showed significant reductions in CVD (ARR -2.3%, 95%CI -3.4% to -0.8%; NNT 115), all-cause mortality (-3.0%, -4.3% to -1.8%; 95), and atherosclerotic CVD (-2.6%, -3.5% to -1.2%; 104). Such effects appear more pronounced in women, smokers, and those with body mass index < 24 kg/m² or higher adherence rates., Competing Interests: Competing interests The Authors declare no competing interests., (© 2024. The Author(s).)

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.)

Ethnic Pharmacological Relevance: Panax ginseng is a traditional Chinese herbal medicine used to treat cardiovascular diseases (CVDs), and it is still widely used to improve the clinical symptoms of various CVDs. However, there is currently a lack of summary and analysis on the mechanism of Panax ginseng exerts its cardiovascular protective effects. This article provides a review of in vivo and in vitro pharmacological studies on Panax ginseng and its active ingredients in reducing CVDs damage., Aim of This Review: This review summarized the latest literature on Panax ginseng and its active ingredients in CVDs research, aiming to have a comprehensive and in-depth understanding of the cardiovascular protection mechanism of Panax ginseng, and to provide new ideas for the treatment of CVDs, as well as to optimize the clinical application of Panax ginseng., Methods: Enrichment of pathways and biological terms using the traditional Chinese medicine molecular mechanism bioinformatics analysis tool (BATMAN-TCM). The literature search is based on electronic databases such as PubMed, ScienceDirect, Scopus, CNKI, with a search period of 2002-2023. The search terms include Panax ginseng, Panax ginseng ingredients, ginsenosides, ginseng polysaccharides, ginseng glycoproteins, ginseng volatile oil, CVDs, heart, and cardiac., Results: 132 articles were ultimately included in the review. The ingredients in Panax ginseng that manifested cardiovascular protective effects are mainly ginsenosides (especially ginsenoside Rb 1 ). Ginsenosides protected against CVDs such as ischemic reperfusion injury, atherosclerosis and heart failure mainly through improving energy metabolism, inhibiting hyper-autophagy, antioxidant, anti-inflammatory and promoting secretion of exosomes., Conclusion: Panax ginseng and its active ingredients have a particularly prominent effect on improving myocardial energy metabolism remodeling in protecting against CVDs. The AMPK and PPAR signaling pathways are the key targets through which Panax ginseng produces multiple mechanisms of cardiovascular protection. Extracellular vesicles and nanoparticles as carriers are potential delivery ways for optimizing the bioavailability of Panax ginseng and its active ingredients., Competing Interests: Declaration of Competing interest The authors declare no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Statins are the gold standard in the treatment of dyslipidemia, significantly reducing the risk of cardiovascular disease., Objective: To systematically review the efficacy and safety of Moderate-intensity Rosuvastatin Plus Ezetimibe compared with High-intensity Rosuvastatin in treating Composite Cardiovascular Events., Methods: PubMed, Embase, Cochrane Library, CINAHL, Web of Science, China Knowledge Network, China Biological Literature Database, Wan Fang Database, and Weipu Database were searched to retrieve randomized controlled trials assessing the safety and efficacy of the two therapies from the time of construction to December 2023. The Jadad scale assessment tool was used to evaluate the quality of the included literature, and Review Manager 5.4 software was used for meta-analysis. The heterogeneity of outcomes was estimated by the I2 test, where we applied risk ratios (RR) and 95% confidence intervals (CI) to assess dichotomous outcomes and mean difference (MD) and 95% CI to present continuous outcomes. We used funnel plots to assess study publication bias and sensitivity analysis was used to address significant clinical heterogeneity., Results: The meta-analysis described 21 RCTs involving 24592 participants. The findings indicated that moderate-intensity statin combination therapy improved low-density lipoprotein cholesterol (LDL-C) (MD -8.06, 95% CI [-9.48, -6.64] p < 0.05), total cholesterol (TG) (MD -5.66, 95% CI [-8.51, -2.82] p < 0.05), and non-high-density lipoprotein cholesterol (non-HDL-C) (MD -17.04, 95% CI [-29.55, -4.54] p < 0.05) to a greater extent and superior in achieving LDL-C <70 (RR1.26, 95% CI [1.22, 1.29] p < 0.05) and LDL-C <55 (RR1.66, 95% CI [1.56, 1.77] p < 0.05) ratios and in the incidence of adverse events than the high-intensity Rosuvastatin monotherapy group. However, there was no statistical difference between the two in improving HDL-C, total cholesterol (TC), and preventing long-term composite adverse cardiovascular events (ACE). Funnel plots indicated publication bias. Sensitivity analysis suggested instability in long-term composite cardiovascular events, HDL-C, and TC results., Conclusions: Moderate-intensity statin plus ezetimibe with combination therapy had better efficacy and safety than high-intensity statins. Future validation is needed with more long-term high-quality large samples., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Liu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Cardiovascular disease (CVD) represents a significant global health challenge, remaining the leading cause of illness and mortality worldwide. The adult heart's limited regenerative capacity poses a major obstacle in repairing extensive damage caused by conditions like myocardial infarction. In response to these challenges, nanomedicine has emerged as a promising field aimed at improving treatment outcomes through innovative drug delivery strategies. Nanocarriers, such as nanoparticles (NPs), offer a revolutionary approach by facilitating targeted delivery of therapeutic agents directly to the heart. This precise delivery system holds immense potential for treating various cardiac conditions by addressing underlying mechanisms such as inflammation, oxidative stress, cell death, extracellular matrix remodeling, prosurvival signaling, and angiogenic pathways associated with ischemia-reperfusion injury. In this review, we provide a concise summary of the fundamental mechanisms involved in cardiac remodeling and regeneration. We explore how nanoparticle-based drug delivery systems can effectively target the afore-mentioned mechanisms. Furthermore, we discuss clinical trials that have utilized nanoparticle-based drug delivery systems specifically designed for cardiac applications. These trials demonstrate the potential of nanomedicine in clinical settings, paving the way for future advancements in cardiac therapeutics through precise and efficient drug delivery. Overall, nanomedicine holds promise in revolutionizing the treatment landscape of cardiovascular diseases by offering targeted and effective therapeutic strategies that address the complex pathophysiology of cardiac injuries., 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.)

Objective: To investigate the role of glucagon-like peptide 1 (GLP-1) in myocardial perfusion, focusing on its effects on coronary microcirculation and cardiovascular outcomes., Methods: Review of foundational research and large-scale clinical trials, including Cardiovascular Outcome Trials (CVOTs), examining the cardiovascular effects of GLP-1. Systematic analysis of trial data to assess the impact of GLP-1 therapy on myocardial infarction, composite cardiovascular events, and stroke incidence., Results: GLP-1 therapy was found to significantly reduce myocardial infarction and composite cardiovascular events. Additionally, GLP-1 receptor agonists were observed to reduce stroke incidence, suggesting systemic effects on panvascular diseases. While direct protective effects on coronary microvasculature have been less studied, growing evidence supports GLP-1's role in comprehensive myocardial perfusion., Conclusion: GLP-1 is a promising therapeutic agent for improving myocardial perfusion and reducing cardiovascular events. Its protection is likely associated with comprehensive improvements in myocardial perfusion, including effects on coronary microcirculation. Further research is needed to fully elucidate its mechanisms of action and potential clinical applications., (© 2024 John Wiley & Sons Ltd.)

Introduction: Mixed hyperlipidemia represents a substantial public health issue and a considerable burden on healthcare systems. Although the introduction of statins and LDL-cholesterol lowering agents have significantly reduced the incidence of atherosclerotic cardiovascular diseases (ASCVD), a significant portion of the population continues to exhibit ASCVD progression due to elevated triglyceride-rich lipoprotein (TRL) levels. This persistent risk has catalyzed the development of novel pharmacological interventions targeting these lipoproteins., Areas Covered: Our special report commenced with a targeted PubMed search using keywords such as 'plozasiran,' 'zodasiran,' and terms related to APOC3 and ANGPTL3. As the review progressed, emergent research questions guided further searches, allowing for the inclusion of additional relevant articles to comprehensively illustrate the linkage between TRLs and cardiovascular disease, discuss the roles of APOC3, ANGPTL3, and the pharmaceutical agents that target these proteins, and provide a comparison on the ARCHES-2 and MUIR trials., Expert Opinion: The ARCHES-2 and MUIR trials demonstrated effective triglyceride reduction by these therapies, yet it is uncertain if this correlates with significant clinical benefits. Advances in antisense oligonucleotide technology, especially the GalNAc delivery platform, show promise for personalized lipid management, though challenges such as cost and safety concerns remain.

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.)

Background: Ponatinib (Iclusig) is an oral tyrosine kinase BCR-ABL inhibitor for treating patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL) and chronic myeloid leukemia (CML) who are resistant to the therapies with other tyrosine kinase inhibitors. However, adverse cardiovascular events caused by Ponatinib are a serious issue that affects patients' survival rates. Thus, it is necessary to search for candidate drugs to reduce the cardiovascular toxicity of Ponatinib., Purpose: To investigate the effects of Aspirin on Ponatinib-induced cardiovascular toxicity in zebrafish., Methods: AB strain of wild type zebrafish (Danio rerio), Tg (cmlc2: GFP) transgenic zebrafish, and Tg (gata1: dsRed) transgenic zebrafish were used as in vivo models to assess survival, blood flow, cardiac morphology, and function. Thrombus formation was detected using O-dianisidine staining. The transcriptome of zebrafish larvae treated with Ponatinib was assessed using RNA sequencing., Results: Ponatinib not only reduced survival rate but also caused cardiovascular toxic events such as pericardial edema, abnormal heart structure, low heart rate, and thrombosis. In addition, whole-body transcriptome analysis showed that Ponatinib up-regulated the expression of cyclooxygenase-1 (COX-1). Compared with other antithrombotic drugs, a COX-1 inhibitor Aspirin more effectively reduced ponatinib-induced cardiovascular toxicity events and improved the survival rate of zebrafish larvae., Conclusion: Our findings suggest that Aspirin exhibits the potential to reduce Ponatinib-induced cardiovascular toxicity., 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.)

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.)

Drug repurposing is defined as the use of approved therapeutic drugs for indications different from those for which they were originally designed. Repositioning diminishes both the time and cost for drug development by omitting the discovery stage, the analysis of absorption, distribution, metabolism, and excretion routes, as well as the studies of the biochemical and physiological effects of a new compound. Besides, drug repurposing takes advantage of the increased bioinformatics knowledge and availability of big data biology. There are many examples of drugs with repurposed indications evaluated in in vitro studies, and in pharmacological, preclinical, or retrospective clinical analyses. Here, we briefly review some of the experimental strategies and technical advances that may improve translational research in cardiovascular diseases. We also describe exhaustive research from basic science to clinical studies that culminated in the final approval of new drugs and provide examples of successful drug repurposing in the field of cardiology., (© 2024 Deutsche Pharmazeutische Gesellschaft.)

Purpose of Review: After decades of relying on the control of hypertension and treatment with renin angiotensin system inhibitors as the only evidence-based interventions to slow the progression of chronic kidney disease (CKD), we have entered an era when multiple effective treatment options are available. This review considers the mechanisms and benefits of these novel treatments as well as the challenges associated with achieving optimal combination therapy., Recent Findings: Over the past 5 years, large clinical trials have provided robust evidence that, when added to renin angiotensin system inhibitors, treatment with sodium glucose cotransporter 2 inhibitors reduces the rate of CKD progression and the risk of cardiovascular events in people with CKD with or without diabetes and with or without albuminuria; nonsteroidal mineralocorticoid antagonists and glucagon-like peptide-1 receptor agonists afford similar benefits in people with type 2 diabetes and CKD. The mechanisms of actions of these novel therapies suggest that combination therapy will produce additive benefits, though specific evidence is sparse., Summary: Further trials are warranted to investigate the benefits of combination therapy with novel treatments in people with CKD. Clinical implementation of optimal combination therapy will require reorganization of services to ensure that patients receive adequate education, support and monitoring., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Atherosclerotic cardiovascular disease (ASCVD), a leading cause of mortality and morbidity, is associated with a substantial healthcare and economic burden. Reduction of low-density lipoprotein cholesterol (LDL-C) to guideline-recommended goals is crucial in the prevention or management of ASCVD, particularly in those at high risk. Despite the availability of several effective lipid-lowering therapies (LLTs), up to 80% of patients with ASCVD do not reach evidence-based LDL-C goals. This nonattainment may be due to poor adherence to, and lack of timely utilization of, LLTs driven by a range of variables, including polypharmacy, side effects, clinical inertia, costs, and access issues. Inclisiran was approved by the US Food and Drug Administration in 2021 as a novel, twice-yearly, healthcare provider (HCP)-administered LLT. In-office administration allows HCPs more control of drug acquisition, administration, and reimbursement, and may allow for more timely care and increased patient monitoring. In the USA, in-office administered drugs are considered a Medical Benefit and can be acquired and reimbursed using the "buy-and-bill" process. Buy-and-bill is a standard system for medication administration already established in multiple therapeutic areas, including oncology, vaccines, and allergy/immunology. Initiating in-office administration will involve new considerations for clinicians in the cardiovascular specialty, such as the implementation of new infrastructure and processes; however, it could ultimately increase treatment adherence and improve cardiovascular outcomes for patients with ASCVD. This article discusses the potential implications of buy-and-bill for the cardiology specialty and provides a practical guide to implementing HCP-administered specialty drugs in US clinical practice., (© 2024. 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.)

Peptides exhibit significant specificity and effective interaction with therapeutic targets, positioning themselves as key players in the global pharmaceutical market. They offer potential treatments for a wide range of diseases, including those that pose significant challenges. Notably, the peptide trofinetide (Daybue) marked a groundbreaking achievement by providing the first-ever cure for Rett syndrome, and several peptides have secured FDA approval as first-in-class medications. Furthermore, peptides are expanding their presence in areas traditionally dominated by either small or large molecules. A noteworthy example is the FDA approval of motixafortide (Aphexda) as the first peptide-based chemokine antagonist. Here, the focus will be on the analysis of FDA-approved peptides, particularly those targeting cardiovascular diseases, human immunodeficiency, central nervous system diseases, and various other intriguing classes addressing conditions such as osteoporosis, thrombocytopenia, Cushing's disease, and hypoglycemia, among others. The review will explore the chemical structures of the peptides, their indications and modes of action, the developmental trajectory, and potential adverse effects., (© 2024 The Author(s). Journal of Peptide Science published by European Peptide Society and John Wiley & Sons Ltd.)

Metformin has been recommended as first-line pharmacological therapy in type‑2 diabetes (T2D) since 1998. It was the first medication that demonstrated cardiovascular benefits in obese subjects with T2D. Efficacy and safety of metformin have since been demonstrated in further studies and in real-world data on its use in practice. The recommendation of metformin as baseline therapy has reached wide acceptance internationally. During the period 2015-2021, large cardiovascular safety trials showed superiority for cardiovascular morbidity and partly also mortality outcomes for most substances of the novel antidiabetic substance classes of GLP‑1 receptor agonists and SGLT‑2 inhibitors in people with T2D and very high cardiovascular risk or preexisting cardiovascular disease. The evidence for these two substance classes is now broader than for metformin. Therefore, the question arises as to whether it is still justified to recommend metformin generally as first-line therapy in T2D. This article provides an overview of the study data as well as an overview of the evidence-based guidelines. The status and position of metformin in the treatment of T2D are discussed., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Obesity and overweight affect almost one third of the European population. Obesity and its associated conditions, including type 2 diabetes, significantly impact healthcare systems, life expectancy and quality of life. The emergence of glucagon-like peptide-1 (GLP-1) receptor agonists for the treatment of obesity, with or without diabetes, has provided an effective alternative to metabolic surgery and dietary interventions. We are now beginning to understand their pleiotropic effects beyond weight loss, such as their favourable impact on cardiovascular profiles. The aim of this review is to summarize available preclinical and clinical data on the beneficial effects of GLP-1 receptor agonists on atherosclerosis and cardiovascular disease which has the potential to substantially broaden the scope of their clinical applications., Competing Interests: Declaration of competing interest No., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Diabetes mellitus is a metabolic disease with an escalating global prevalence. Despite the abundance and relative efficacies of current therapeutic approaches, they primarily focus on attaining the intended glycaemic targets, but patients ultimately still suffer from various diabetes-associated complications such as retinopathy, nephropathy, cardiomyopathy, and atherosclerosis. There is a need to explore innovative and effective diabetic treatment strategies that not only address the condition itself but also combat its complications. One promising option is the reproductive hormone relaxin, an endogenous ligand of the RXFP1 receptor. Relaxin is known to exert beneficial actions on the cardiovascular system through its vasoprotective, anti-inflammatory and anti-fibrotic effects. Nevertheless, the native relaxin peptide exhibits a short biological half-life, limiting its therapeutic potential. Recently, several relaxin mimetics and innovative delivery technologies have been developed to extend its biological half-life and efficacy. The current review provides a comprehensive landscape of the cardiovascular effects of relaxin, focusing on its potential therapeutic applications in managing complications associated with diabetes. The latest advancements in the development of relaxin mimetics and delivery methods for the treatment of cardiometabolic disorders are also discussed., 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.)

Type 2 diabetes mellitus (T2DM) is associated with a heightened risk of cardiovascular and renal complications. While glycemic control remains essential, newer therapeutic options, such as SGLT2 inhibitors, offer additional benefits beyond glucose reduction. This review delves into the mechanisms underlying the cardio-renal protective effects of SGLT2 inhibitors. By inducing relative hypoglycemia, these agents promote ketogenesis, optimize myocardial energy metabolism, and reduce lipotoxicity. Additionally, SGLT2 inhibitors exert renoprotective actions by enhancing renal perfusion, attenuating inflammation, and improving iron metabolism. These pleiotropic effects, including modulation of blood pressure, reduction of uric acid, and improved endothelial function, collectively contribute to the cardiovascular and renal benefits observed with SGLT2 inhibitor therapy. This review will provide clinicians with essential knowledge, understanding, and a clear recollection of this pharmacological group's mechanism of action., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Herbal medicines (HMs) have deciphered indispensable therapeutic effects against cardiovascular disease (CVD) (the predominant cause of death worldwide). The conventional CVD therapy approaches have not been efficient and need alternative medicines. The objective of this study was a review of herbal bioactive compound efficacy for CVD therapy based on computational and in silico studies. HM bioactive compounds with potential anti-CVD traits include campesterol, naringenin, quercetin, stigmasterol, tanshinaldehyde, Bryophyllin A, Bryophyllin B, beta-sitosterol, punicalagin, butein, eriodyctiol, butin, luteolin, and kaempferol discovered using computational studies. Some of the bioactive compounds have exhibited therapeutic effects, as followed by in vitro (tanshinaldehyde, punicalagin, butein, eriodyctiol, and butin), in vivo (gallogen, luteolin, chebulic acid, butein, eriodyctiol, and butin), and clinical trials (quercetin, campesterol, and naringenin). The main mechanisms of action of bioactive compounds for CVD healing include cell signaling and inhibition of inflammation and oxidative stress, decrease of lipid accumulation, and regulation of metabolism and immune cells. Further experimental studies are required to verify the anti-CVD effects of herbal bioactive compounds and their pharmacokinetic/pharmacodynamic features., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Elham Zarenezhad et al.)

Introduction: Hydroxychloroquine (HCQ) exerts a large reduction of cardiovascular risk in patients with inflammatory diseases, but the mechanisms are not fully known. The aim of this study was to study potential mechanisms for this., Methods: This interventional study (EudraCT 2014-005418-45) in 30 patients (23 with rheumatoid arthritis, 7 with systemic lupus erythematosus) investigates the effects of HCQ on cardiovascular risk factors and arterial stiffness in patients with inflammatory disease. Blood lipids, blood pressure, blood glucose, glycated haemoglobin (HbA1c) and arterial stiffness was assessed at initiation, after four weeks of treatment and after eight weeks of treatment with 200 mg HCQ daily., Results: After four weeks of treatment with HCQ, total cholesterol had decreased from 5.4 mmol/L to 5.1 mmol/L (p<0.001), low-density lipoproteins from 3,0 mmol/L to 2.7 mmol/L (p<0.001) and apolipoprotein B from 0.96 g/L to 0.90 g/L (p<0.01). Those levels remained unchanged after eight weeks of treatment with HCQ. Levels of triglycerides, high-density lipoproteins and apolipoprotein A1 remained unchanged during the study. HbA1c decreased in most patients, especially in patients with high levels at start of HCQ, but increased HbA1c was seen in patients with low levels at start of treatment with HCQ. No significant effect was seen on blood pressure or any measure of arterial stiffness., Conclusion: This study does not identify the mechanisms of cardiovascular risk reduction from HCQ. Arterial stiffness is not affected by HCQ. The impact of HCQ on HbA1c and blood lipids is rapid, but of modest magnitude, and these effects do not fully explain the reduced risk of cardiovascular disease seen in observational studies. The mechanisms of cardiovascular risk reduction from HCQ are yet not completely known., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Wahlin et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Eugenol, a phenylpropanoid compound, is found in various dietary resources and medicinal plants. From a historical perspective, eugenol is widely employed as a flavoring agent in the food and fragrance industries. Here, this review mainly focuses on recent advances in eugenol with respect to its versatile physiological roles in health and disease and discusses the mechanisms. Emerging evidence has highlighted that eugenol exhibits multiple biological activities in cancer, diabetes, obesity, cardiovascular diseases, and neurodegenerative diseases. It also has analgesic, anti-inflammatory, and antioxidant qualities and has lethal or inhibiting effects on various viruses, bacteria, fungi, and parasites. The manuscript also contains some patents that have been filed thus far regarding the production and application of eugenol. Overall, these benefits make eugenol a promising nutritional supplement which fulfils its historical function as a flavoring agent, opening up new possibilities for the creation of therapeutic agents for the treatment of disease.

Type 2 diabetes (T2D) affects millions of individuals worldwide and is a well-documented risk factor for cardiovascular (CV) disease and chronic kidney disease, both of which are leading causes of mortality. Racial and ethnic minority groups in the US, including but not limited to Hispanic/Latino, non-Hispanic Black, and Southeast Asian individuals, are disproportionately burdened by both T2D and its adverse outcomes. In recent years, there have been numerous cardiovascular outcomes trials (CVOTs) on novel antidiabetic therapies, including the dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists (RAs), and sodium-glucose cotransporter-2 (SGLT2) inhibitors. CVOTs's initial aim was to demonstrate the cardiovascular safety of these drugs. Unexpected CV and kidney protective effects were found, specifically among the GLP-1 RAs and the SGLT2 inhibitors. These benefits informed the new paradigm of the management of patients with T2D. However, some experts argued that the lack of racial and ethnic minority group representation in these trials represented a challenge. While the downstream effects of this lack of representation must be further elucidated, it is clear and recognized that efforts need to be made to include a more representative sample in future CVOTs, specifically including individuals from those groups most burdened by T2D and its complications, if clinicians are to have an accurate picture of the benefits and potential pitfalls of utilizing these drugs in a real-world setting. In this comprehensive review, we briefly summarize the significant findings from the CVOTs, report the lack of representation of Hispanic/Latino, non-Hispanic Black, and Southeast Asian individuals in the CVOTs, investigate the barriers to recruiting racial and ethnic minority groups into clinical trials, and suggest potential solutions to overcome these obstacles at the patient-, provider-, and sponsor/system-level in future trials., Competing Interests: CJD reports consultancy with United Health Group and the National Committee for Quality Assurance. The remaining 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 Sinclair, Ardehali, Diamantidis and Corsino.)

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.)

Resveratrol (RES) is a polyphenol with natural anti-inflammatory and antioxidant properties. It is found in abundance in plants, i.e., grapes and mulberry fruit. In addition, synthetic forms of RES exist. Since the discovery of its specific biological properties, RES has emerged as a candidate substance not only with modeling effects on the immune response but also as an important factor in preventing the onset and progression of cardiovascular disease (CVD). Previous research provided strong evidence of the effects of RES on platelets, mitochondria, cardiomyocytes, and vascular endothelial function. In addition, RES positively affects the coagulation system and vasodilatory function and improves blood flow. Not only in humans but also in veterinary medicine, cardiovascular diseases have one of the highest incidence rates. Canine and human species co-evolved and share recent evolutionary selection processes, and interestingly, numerous pathologies of companion dogs have a human counterpart. Knowledge of the impact of RES on the cardiovascular system of dogs is becoming clearer in the literature. Dogs have long been recognized as valuable animal models for the study of various human diseases as they share many physiological and genetic similarities with humans. In this review, we aim to shed light on the pleiotropic effects of resveratrol on cardiovascular health in dogs as a translational model for human cardiovascular diseases.

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.)

Nitric oxide (NO) from endothelial NO synthase importantly contributes to vascular homeostasis. Reduced NO production or increased scavenging during disease conditions with oxidative stress contribute to endothelial dysfunction and NO deficiency. In addition to the classical enzymatic NO synthases (NOS) system, NO can also be generated via the nitrate-nitrite-NO pathway. Dietary and pharmacological approaches aimed at increasing NO bioactivity, especially in the cardiovascular system, have been the focus of much research since the discovery of this small gaseous signaling molecule. Despite wide appreciation of the biological role of NOS/NO signaling, questions still remain about the chemical nature of NOS-derived bioactivity. Recent studies show that NO-like bioactivity can be efficiently transduced by mobile NO-ferroheme species, which can transfer between proteins, partition into a hydrophobic phase, and directly activate the soluble guanylyl cyclase-cGMP-protein kinase G pathway without intermediacy of free NO. Moreover, interaction between red blood cells and the endothelium in the regulation of vascular NO homeostasis have gained much attention, especially in conditions with cardiometabolic disease. In this review we discuss both classical and nonclassical pathways for NO generation in the cardiovascular system and how these can be modulated for therapeutic purposes. SIGNIFICANCE STATEMENT: After four decades of intensive research, questions persist about the transduction and control of nitric oxide (NO) synthase bioactivity. Here we discuss NO signaling in cardiovascular health and disease, highlighting new findings, such as the important role of red blood cells in cardiovascular NO homeostasis. Nonclassical signaling modes, like the nitrate-nitrite-NO pathway, and therapeutic opportunities related to the NO system are discussed. Existing and potential pharmacological treatments/strategies, as well as dietary components influencing NO generation and signaling are covered., (Copyright © 2024 by The American Society for Pharmacology and Experimental Therapeutics.)

Cardiovascular diseases (CVDs) have a high mortality rate, and despite the several available therapeutic targets, non-response to antihypertensives remains a common problem. Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are important classes of drugs recommended as first-line therapy for several CVDs. However, response to ACEIs and ARBs varies among treated patients. Pharmacogenomics assesses how an individual's genetic characteristics affect their likely response to drug therapy. Currently, numerous studies suggest that genetic polymorphisms may contribute to variability in drug response. Moreover, further studies evaluating gene-gene interactions within signaling pathways in response to antihypertensives might help to unravel potential genetic predictors for antihypertensive response. This review summarizes the pharmacogenetic data for ACEIs and ARBs in patients with CVD, and discusses the potential pharmacogenetics of these classes of antihypertensives in clinical practice. However, replication studies in different populations are needed. In addition, studies that evaluate gene-gene interactions that share signaling pathways in the response to antihypertensive drugs might facilitate the discovery of genetic predictors for antihypertensive response., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Nothing to declare. 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., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction: Cardiovascular diseases (CVD) are the leading cause of death globally. This burden of disease is particularly high among healthcare workers (HCW). However, adherence to treatment of well-known cardiovascular risk conditions (CRC) still represents a challenge, even among healthcare workers (HCW). Since the identification of modifiable related factors is a prerequisite for developing effective public health interventions, the purpose of this study was to develop a predictive model for adherence to pharmacological treatment (APT) for CRC in HCW, using psychological variables related to CVD mortality, such as the type A behavior pattern, perceived stress, depression, anxiety and attitudes toward treatment adherence., Methods: An anonymous online survey was completed by a non-probabilistic sample of 1,377 Mexican HCW from tertiary public hospitals, with a diagnosis of only one of the following CRC: ischemic heart disease, diabetes, high blood pressure or dyslipidemia. Sociodemographic questionnaires and self-reported measures were used to collect data: PSS-14 for perceived stress, Type A Behavior Pattern Withdrawal Scale, HADS for anxiety and depression symptoms, the Attitudes toward Medication Scale and the Therapeutics Adherence Scale for Patients with Chronic Diseases., Results: Anxiety and depression symptoms were higher in the group with risk for non-adherence, while perceived stress and positive attitudes toward medication were higher in the group with likelihood of adherence ( p  ≤ 0.05). The Type A behavior pattern and sociodemographic variables did not differ between groups. In a regression model, positive attitudes toward medication and perceived stress doubled APT (OR = 2.04, CI95% = 1.39-2.97; OR = 2.02, CI95% = 1.71-2,39, respectively) whereas depression decreased its likelihood (OR = 0.61, CI95% = 0.58-0.73)., Discussion: In conclusion, psychoeducation for patients with CRC should include information on the advantages of medication for treating their condition, even if they are HCW. Promoting adaptative coping skills to handle daily stressful events, including their CRC, could reduce the level of stress that could increase their APT but also their cardiovascular risk. Moreover, our data provide evidence regarding the importance of identifying and treating depressive symptoms as part of the standard care of this population., 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 Flores-Mendoza, Robles García, García-Méndez and Rodríguez-Argüelles.)

Glycemic variability (GV), independently of glycemic control, has emerged as a prognostic marker in patients with type 2 diabetes mellitus (DM). In this study, we assessed the prognostic value of long-term GV for predicting major adverse cardiovascular events (MACE) in our local population. We also assessed its prognostic value for diabetic microvascular complications (DMC) and its relationships with antidiabetic medications. This was a retrospective cohort study that recruited 680 patients with type 2 DM across 2015-2017. MACE were defined as: the composite of; total death, myocardial infarction (MI), stroke, hospitalization due to heart failure, and revascularization. GV was calculated for two glycemic control markers: glycated hemoglobin (G-Hb) and fasting blood sugar (FBS); via three metrics- standard deviation (SD), coefficient of variation (CV), and variability independent from the mean (VIM). Cox proportional hazard models and Kruskal-Wallis tests were used in the statistical analysis. 105 events classified as MACE were identified in 86 patients and 104 DMC in 98 patients in an average follow-up period of 78.43 months. Long-term GV was found to be an independent predictor of MACE, particularly for FBS-CV but not a predictor of DMC. FBS-CV ≥ 17.51% as compared with < 17.51% was a significant and independent predictor of MACE, with HR 1.589 (95% CI; 1.022, 2.472) (P = 0.040). DMC were predicted mainly by the duration of type 2 DM, and by the glycemic control; similarly represented by G-Hb and FBS. Patients on metformin, and dipeptidyl peptidase (DPP) 4 inhibitors, had the lowest GV, as compared with patients whose treatments included insulin/sulphonylureas (P < 0.001). In our population, long-term GV predicted MACE: with FBS-CV superior to the "gold standard" glycemic control marker G-Hb. Further, GV may be explained, partially at least, by the choice of antidiabetic medications: this finding might contribute to the cardiovascular protection attributed to one class rather than another., (© 2024. The Author(s).)

Endothelial cells (ECs) are pivotal in maintaining vascular health, regulating hemodynamics, and modulating inflammatory responses. Nanocarriers hold transformative potential for precise drug delivery within the vascular system, particularly targeting ECs for therapeutic purposes. However, the complex interactions between vascular ECs and nanocarriers present significant challenges for the development and clinical translation of nanotherapeutics. This review assesses recent advancements and key strategies in employing nanocarriers for drug delivery to vascular ECs. It suggested that through precise physicochemical design and surface modifications, nanocarriers can enhance targeting specificity and improve drug internalization efficiency in ECs. Additionally, we elaborated on the applications of nanocarriers specifically designed for targeting ECs in the treatment of cardiovascular diseases, cancer metastasis, and inflammatory disorders. Despite these advancements, safety concerns, the complexity of in vivo processes, and the challenge of achieving subcellular drug delivery remain significant obstacles to the effective targeting of ECs with nanocarriers. A comprehensive understanding of endothelial cell biology and its interaction with nanocarriers is crucial for realizing the full potential of targeted drug delivery systems., (© 2024. The Author(s).)

Cardiovascular disease (CVD) remains the major cause of morbidity and mortality around the world. Transcription factor EB (TFEB) is a master regulator of lysosome biogenesis and autophagy. Emerging studies revealed that TFEB also mediates cellular adaptation responses to various stimuli, such as mitochondrial dysfunction, pathogen infection and metabolic toxin. Based on its significant capability to modulate the autophagy-lysosome process (ALP), TFEB plays a critical role in the development of CVD. In this review, we briefly summarize that TFEB regulates cardiac dysfunction mainly through ameliorating lysosomal and mitochondrial dysfunction and reducing inflammation., Competing Interests: The authors declare there are no competing interests., (©2024 Yan et al.)

Atherosclerosis is a key etiological event in the development of cardiovascular diseases (CVDs), strongly linked to the formation of foam cells. This study explored the effects of two blue mussel-derived bioactive peptides (BAPs), PIISVYWK (P1) and FSVVPSPK (P2), on inhibiting foam cell formation and mitigating inflammation in oxLDL-treated RAW264.7 macrophages. Both peptides significantly suppressed intracellular lipid accumulation and cholesterol levels while promoting cholesterol efflux by downregulating cluster of differentiation 36 (CD36) and class A1 scavenger receptors (SR-A1) and upregulating ATP binding cassette subfamily A member 1 (ABCA-1) and ATP binding cassette subfamily G member 1 (ABCG-1) expressions. The increased expression of peroxisome proliferator-activated receptor-gamma (PPAR-γ) and liver X receptor-alpha (LXR-α) further validated their role in enhancing cholesterol efflux. Additionally, P1 and P2 inhibited foam cell formation in oxLDL-treated human aortic smooth muscle cells and exerted anti-inflammatory effects by reducing pro-inflammatory cytokines, nitric oxide (NO), prostaglandin E 2 (PGE 2 ), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2), primarily through inhibiting NF-κB activation. Furthermore, P1 and P2 alleviated oxidative stress by activating the Nrf2/HO-1 pathway. Our findings demonstrate that P1 and P2 have significant potential in reducing foam cell formation and inflammation, both critical factors in atherosclerosis development. These peptides may serve as promising therapeutic agents for the prevention and treatment of CVDs associated with oxidative stress and inflammation.

Suppressor of cytokine signaling 2 (SOCS2), an E3 ubiquitin ligase, regulates the JAK/STAT signaling pathway, essential for cytokine signaling and immune responses. Its dysregulation contributes to cardiovascular diseases (CVDs) by promoting abnormal cell growth, inflammation, and resistance to cell death. This study aimed to elucidate the molecular mechanisms underlying the interactions between Lumbricus -derived proteins and peptides and SOCS2, with a focus on identifying potential therapeutic candidates for CVDs. Utilizing a multifaceted approach, advanced computational methodologies, including 3D structure modeling, protein-protein docking, 100 ns molecular dynamics (MD) simulations, and MM/PBSA calculations, were employed to assess the binding affinities and functional implications of Lumbricus -derived proteins on SOCS2 activity. The findings revealed that certain proteins, such as Lumbricin, Chemoattractive glycoprotein ES20, and Lumbrokinase-7T1, exhibited similar activities to standard antagonists in modulating SOCS2 activity. Furthermore, MM/PBSA calculations were employed to assess the binding free energies of these proteins with SOCS2. Specifically, Lumbricin exhibited an average ΔG binding of -59.25 kcal/mol, Chemoattractive glycoprotein ES20 showed -55.02 kcal/mol, and Lumbrokinase-7T1 displayed -69.28 kcal/mol. These values suggest strong binding affinities between these proteins and SOCS2, reinforcing their potential therapeutic efficacy in cardiovascular diseases. Further in vitro and animal studies are recommended to validate these findings and explore broader applications of Lumbricus -derived proteins.

Clopidogrel, a prescription drug to reduce ischemic events in cardiovascular patients, has been extensively studied in mostly European individuals but not among Caribbean Hispanics. This study evaluated the low abundance and reduced activity of paraoxonase-1 (PON1) in clopidogrel-resistant patients as a predictive risk biomarker of poor responders and disease severity in this population. Thirty-six patients on clopidogrel (cases divided into poor and normal responders) were enrolled, along with 11 cardiovascular patients with no clopidogrel indications (positive control) and 13 healthy volunteers (negative control). Residual on-treatment platelet reactivity unit (PRU), PON1 abundance by Western blotting, and PON1 activity by enzymatic assays were measured. PON1 genotyping and computational haplotype phasing were performed on 512 DNA specimens for two genetic loci (rs662 and rs854560). No statistical differences in mean relative PON1 abundance were found among the groups ( p > 0.05). However, a significantly lower enzymatic activity was found in poor responders (10.57 ± 6.79 µU/mL) when compared to controls (22.66 ± 8.30 µU/mL and 22.21 ± 9.66 µU/mL; p = 0.004). PON1 activity among carriers of the most prevalent PON1 haplotype (AA|AA) was significantly lower than in wild types (7.90 µU/mL vs. 22.03 µU/mL; p = 0.005). Our findings suggested that PON1 is a potential biomarker of cardiovascular disease severity in Caribbean Hispanics.

Background: Chronic Rapid eye movement (REM) sleep deprivation has been associated with various cardiovascular alterations, including disruptions in antioxidant defense mechanisms, lipid metabolism, and inflammatory responses. This study investigates the therapeutic potential of green tea extract (GTE) in mitigating these adverse effects., Methods: A total of 24 male Wistar albino rats were used in this study and divided into the control group (n = 8), Chronic-REM Sleep Deprivation (CRSD) Group (n = 8) and Chronic-REM SD + Green Tea 200 (CRSD + GTE200) Group (n = 8). After 21 days, a comprehensive analysis of paraoxonase (PON1), arylesterase (ARE), malondialdehyde (MDA), glutathione (GSH), nitric oxide (NOx), proinflammatory cytokines, and lipid profiles in aortic tissue, heart tissue, and serum was conducted in a sleep-deprived rat model., Results: Chronic REM sleep deprivation led to a significant reduction in PON1 and ARE levels in aortic (p = 0.046, p = 0.035 respectively) and heart tissues (p = 0.020, p = 0.019 respectively), indicative of compromised antioxidant defenses. MDA levels increased, and NOx levels decreased, suggesting oxidative stress and impaired vascular function. Lipid profile alterations, including increased triglycerides and total cholesterol, were observed in serum. Elevated levels of inflammatory cytokines (IL-6 and TNF-alpha) further indicated an inflammatory response (p = 0.007, p = 0.018 respectively). GTE administration demonstrated a protective role, restoring antioxidant enzyme levels, suppressing lipid peroxidation, and improving NOx levels., Conclusion: These findings suggest the therapeutic potential of GTE in alleviating the cardiovascular impairments of chronic REM sleep deprivation, emphasizing its candidacy for further clinical exploration as a natural intervention in sleep-related disorders and associated cardiovascular risks., (© 2024. The Author(s).)

Melatonin, N-acetyl-5-methoxytryptamine, is a neuroendocrine hormone secreted by the pineal gland. This pleiotropic indoleamine possesses amphiphilic properties, allowing it to penetrate most biological barriers and exert its effects at the subcellular level. Importantly, melatonin also plays a crucial role in regulating the body's response to circadian rhythms, adapting to internal and external environmental cues. Melatonin functions as a powerful antioxidant and free radical scavenger, protecting cells from oxidative damage. Its diverse physiological roles include maintaining the functional integrity of endothelial cells, thereby preventing atherosclerosis, a major contributor to cardiovascular disease. Additionally, melatonin exhibits antioxidant and free radical scavenging properties, potentially improving metabolic disorders. These combined effects suggest a unique adjunctive therapeutic potential for melatonin in treating cardiovascular diseases. This review aims to explore the mechanisms by which melatonin interacts with the cardiovascular system and investigates its potential use as an adjunctive therapeutic agent in managing cardiovascular disease., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective: This study aimed to evaluate the association between tumor necrosis factor-α inhibitor (TNFi) therapy and cardiovascular (CV) outcomes, as well as all-cause mortality, in patients with ankylosing spondylitis (AS)., Patients and Methods: This retrospective cohort study included 24,986 patients newly diagnosed with AS between 2010-2019 without a history of CV diseases, using data from the Korean National Health Insurance Service. CV events were observed through the end of 2021. After exposure density sampling (1:1), we investigated the association among use of TNFi, duration of TNFi use, and risk of the composite CV outcome (ischemic stroke, heart failure, ischemic heart disease, or CV death) and all-cause mortality., Results: Overall, TNFi users (N = 8,650) and non-users (N = 8,580) had a comparable risk of the composite CV outcome. However, prolonged TNFi use (≥ 1 year) was associated with a significantly lower risk of the composite CV outcome [adjusted hazard ratio (aHR): 0.72, 95% CI: 0.55-0.93, p = 0.012] and all-cause mortality (aHR: 0.37, 95% CI: 0.21-0.66, p < 0.001) compared to discontinued TNFi use (< 1 year), with adjustments made for age, sex, disease duration, hypertension, diabetes, hyperlipidemia, chronic kidney disease, non-steroidal anti-inflammatory drug (NSAID) use, body mass index (BMI), and smoking status., Conclusions: TNFi therapy did not reduce CV events in AS patients. However, long-term TNFi therapy is likely to be beneficial in reducing CV events and all-cause mortality compared to discontinuing TNFi therapy in patients with AS.

Introduction: Nattokinase (NK) is the primary ingredient of natto, a traditional Asian food made from fermented soybean by Bacillus subtilis natto . Studies have shown that natto reduces the risk of cardiovascular disease (CVD) mortality due to its fibrinolytic and antithrombotic properties. A new field of studies also demonstrates that NK can mitigate molecular pathways related to inflammation and oxidative stress and can be considered an adjuvant strategy for use in many non-communicable diseases (NCDs). This paper is a narrative review of the literature. A search was conducted in PubMed and ScienceDirect up to July 2024., Areas Covered: This review discusses the possible effects of NK on mitigating the common complications of NCDs, such as inflammation and oxidative stress. In addition, it provides an update on the most addressed areas related to NK's fibrinolytic and antithrombotic activities., Expert Opinion: Due to the fibrinolytic and antithrombotic activity of nattokinase, and more recently added to the anti-inflammatory and antioxidant effects, this enzyme can be used as a new adjuvant therapeutic strategy to mitigate inflammation and oxidative stress in NCDs, including CVD.

Asthma and cardiovascular disease (CVD) often co-exist. When a patient has both conditions, management requires an approach that addresses the unique challenges of each condition separately, while also considering their potential interactions. However, specific guidance on the management of asthma in patients with CVD and on the management of CVD in patients with asthma is still lacking. Nevertheless, health care providers need to adopt a comprehensive approach that includes both respiratory and CVD health. The management of CVD in patients with asthma requires a delicate balance between controlling respiratory symptoms and minimising potential cardiovascular (CV) risks. In the absence of specific guidelines for the management of patients with both conditions, the most prudent approach would be to follow established guidelines for each condition independently. Careful selection of asthma medications is essential to avoid exacerbation of CV symptoms. In addition, optimal management of CV risk factors is essential. However, close monitoring of these patients is important as there is evidence that some asthma medications may have adverse effects on CVD and, conversely, that some CVD medications may worsen asthma symptoms. On the other hand, there is also increasing evidence of the potential beneficial effects of asthma medications on CVD and, conversely, that some CVD medications may reduce the severity of asthma symptoms. We aim to elucidate the potential risks and benefits associated with the use of asthma medications in patients with CVD, and the potential pulmonary risks and benefits for patients with asthma who are prescribed CVD medications., (© 2024. The Author(s).)

Introduction: Cholesteryl ester transfer protein (CETP) plays an important role in lipid metabolism. Early interest in the development of CETP inhibitors proved to be disappointing. Recent interest has focused on the potential for CETP inhibition to reduce cardiovascular risk by lowering levels of low-density lipoprotein cholesterol (LDL-C)., Areas Covered: The data suggesting that low CETP activity may associate with lower levels of cardiovascular risk and early experience with CETP inhibitors focused on raising HDL-C levels. More recent data that suggests that any potential to reduce cardiovascular risk by inhibition of CETP is more likely to result from lowering levels of atherogenic lipid parameters. The development of obicetrapib, a potent CETP inhibitor, with robust lowering of apoB and LDL-C, will be summarized as a potential approach to the prevention of cardiovascular disease., Expert Opinion: Obicetrapib is a potent CETP inhibitor, with a demonstrated ability to lower levels of apoB and LDL-C as monotherapy and in addition to high intensity statin therapy. The ultimate impact of obicetrapib on cardiovascular events will be evaluated by ongoing clinical trials.