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Open research questions in Atherosclerosis and Cardiovascular Diseases

34 unresolved questions extracted from the limitations and future-work sections of 189 Atherosclerosis and Cardiovascular Diseases papers in our library. Each links back to the study that raised it.

What the literature leaves open

  • Although these processes have been extensively investigated, their integration into a unified mechanistic framework and their translational relevance for biomarker-guided precision medicine remain insufficiently addressed.

    The Redox–Inflammation Axis in Atherosclerosis and Ischemic Stroke: Mechanisms, Biomarkers, and Translational Challenges · 2026 · DOI

  • AIMChemokine signaling contributes to vascular inflammation and dysfunction in hypertension, yet the intracellular mechanisms linking CCL5/CCR5 activation to vascular impairment remain unclear.

    CCR5/CCL5 Links Mitochondrial Dysfunction to Angiotensin II Vascular Injury · 2026 · DOI

  • While current PCSK9-targeted therapies, including monoclonal antibodies and siRNA-based agents, have demonstrated robust efficacy in lowering lipid levels and reducing cardiovascular risk, their direct effects on endothelial PCSK9 signaling remain unclear.

    PCSK9 as a Potential Regulator of Endothelial Dysfunction: Mechanistic Insights and Future Directions · 2026 · DOI

  • It remains to be investigated whether other cytokines released from monocytes/macrophages such as TNFα and/or IL-6 are also contributing to the enhanced endothelial VCAM-1 and ICAM-1 upregulation.

    Arginase-2 enhances monocyte-endothelial interaction through regulation of integrin and membrane receptor expression: role in atherogenesis · 2026 · DOI

  • BackgroundHormone therapy (HT) has not consistently reduced atherosclerotic cardiovascular disease (ASCVD) events in post-menopausal women, yet the underlying mechanisms remain poorly understood.

    Cardiovascular Benefits of Menopause Hormone Treatment is Age-Dependent · 2026 · DOI

  • Nanomedicine has emerged as a promising strategy for improving the treatment of atherosclerosis through targeted drug delivery and controlled release of therapeutic agents (Chen et al., 2020; Duivenvoorden et al., 2019; Talev and Kanwar, 2020). Nanoparticles possess several advantages over conventional drug formulations, including increased bioavailability, prolonged circulation time, and enhanced accumulation at sites of vascular inflammation (Aili et al., 2024; Gu et al., 2024; Panda et al., 2019; Shi et al., 2024; Wang et al., 2018). Surface modification with targeting ligands, peptides, or cell membranes enables nanoparticles to selectively bind to molecules expressed in inflamed endothelium, such as VCAM-1, thereby improving drug localization within atherosclerotic plaques (Gu et al., 2024; Lameijer et al., 2018). In addition, biomimetic nanoparticle systems derived from monocyte or macrophage membranes have been developed to enhance immune evasion and facilitate targeted delivery to inflamed vascular tissues (Gu et al., 2024; Li et al., 2023; Sha et al., 2022; Yaman et al., 2020). Experimental studies have demonstrated that nanoparticle-encapsulated drugs can inhibit foam cell formation, reduce plaque inflammation, and improve plaque stability while reducing systemic toxicity (Fredman et al., 2015; Gu et al., 2024; Karami et al., 2023; Tao et al., 2020; Tomaszewska et al., 2025). Despite these promising findings, several limitations currently hinder the clinical translation of nanoparticle-based therapies (Chen et al., 2023; Guo et al., 2021). First, the majority of studies remain at the preclinical stage, with relatively few nanomedicine formulations evaluated in human clinical trials. To date, only a limited number of nanoparticle-based systems – such as liposomal prednisolone or paclitaxel-associated nanoemulsions – have entered early-phase clinical testing (Cheng et al., 2023). Second, concerns remain regarding the long-term safety of nanoparticles, including potential cardiotoxicity, oxidative stress induction, mitochondrial dysfunction, and inflammatory responses (Guo et al., 2021; Niżnik et 38 Myśliwiec et al. / J Appl Biomed al., 2024). These toxicological mechanisms may lead to myocardial damage or vascular dysfunction if nanoparticle formulations are not carefully optimized (Guo et al., 2021; Herrera-Rodríguez et al. 2023). Additional barriers to clinical implementation include variability in nanoparticle physicochemical properties, difficulties in large-scale manufacturing, regulatory challenges, and incomplete understanding of nanoparticle interactions with biological systems.

    Emerging biomedical and pharmaceutical strategies for the treatment of atherosclerosis: from conventional lipid-lowering therapy to nanomedicine · 2026 · DOI

  • While Perilla frutescens exhibits well-documented anti-inflammatory properties, the precise molecular targeting within the atherosclerotic plaque microenvironment and the regulatory mechanisms governing intercellular communication networks remain poorly elucidated.

    Unveiling anti-atherosclerotic targets of Perilla frutescens through a multi-scale computational framework integrating network pharmacology, single-cell analysis, machine learning, and molecular dynamics · 2026 · DOI

  • Peripheral blood (PB) is the predominant source of regulatory T cells (Tregs) for clinical applications, yet PB Tregs have not been systematically compared with tissue Tregs and their defining properties remain poorly understood.

    Low-self-reactive, circulation-biased blood regulatory T cells sense danger-associated nucleotides to restrain atherosclerosis · 2026 · DOI

  • Cigarette smoking has well-established detrimental effects on cardiovascular health, with a p a r t i c u l a r f o c u s o n a t h e r o s c l e r o s i s a n d atherothrombosis. This comprehensive review has highlighted the intricate mechanisms by which smoking contributes to such life-threatening conditions, including endothelial dysfunction, inflammation, and atherothrombotic effects. In summary, endothelial dysfunction, characterized by reduced NO bioavailability and increased superoxide anion production, is one of the earliest manifestations of smoking-induced atherosclerosis. Smoking-induced inflammation is a central pathogenic factor in smoking-induced atherosclerosis, with some involvement in inflammatory response mediated by Advance Publication Journal of Atherosclerosis and Thrombosis Accepted for publication: December 1, 2023 Published online: January 14, 2024 Smoking and Atherosclerosis PRRs and DAMPs. These mechanisms induce chronic vascular wall inflammation and contribute to atherosclerotic progression. Furthermore, cigarette smoke exerts a direct influence on atherothrombosis by enhancing platelet activation, adhesion, and aggregation as well as perturbing the coagulation cascade and fibrinolysis balance. MMPs further c o n t r i b u t e t o p l a q u e v u l n e r a b i l i t y a n d atherothrombotic events. Endothelial dysfunction, inflammation, and atherothrombosis are correlated and mutually exacerbate each other. Considering the significant public health burden posed by cardiovascular diseases, particularly in smoking populations, it is necessary to highlight the urgent need for smoking cessation. Understanding these multifaceted mechanisms at the intersection of endothelial function, inflammation, and thrombosis emphasizes the importance of anti-smoking initiatives and therapies for the preservation of cardiovascular health. Future research should continue to explore the specific molecular pathways and potential therapeutic interventions targeting these mechanisms, ultimately providing more effective strategies for mitigating cardiovascular risks associated with cigarette smoking.

    Cigarette Smoking and Atherosclerotic Cardiovascular Disease · 2024 · DOI

  • Astragalus polysaccharide (APS) has been widely used for treating diabetic vascular diseases, but its mechanisms of action have not been fully elucidated.

    Astragalus polysaccharide ameliorates vascular endothelial dysfunction by stimulating macrophage M2 polarization via potentiating Nrf2/HO-1 signaling pathway · 2023 · DOI

  • Besides the regulation of LDL-receptor expression, significant clinical importance is assigned to oxidized LDL (ox-LDL) and small dense LDL (sdLDL) that are generated through intravascular remodeling of triglyceride-rich lipoproteins, while the exact role of anti-oxLDL antibodies in atherosclerosis propagation and their clinical significance still remain unclear.

    Lipids and atherosclerosis · 2006 · DOI

  • Yet, due to the multi-factorial nature of dental infection and CVD, confirming a causal association is difficult, and the published results are conflicting.

    O<scp>ral</scp> H<scp>ealth</scp>, A<scp>therosclerosis</scp>, <scp>and</scp> C<scp>ardiovascular</scp> D<scp>isease</scp> · 2004 · DOI

  • Abstract Introduction E-cigarettes (ECs) are increasingly used by youth and young adults, but their long-term health risks remain unclear due to limited clinical data.

    Inflammatory Monocyte Responses and Endothelial Stress in Young Adult E-Cigarette Users 2253631 · 2026 · DOI

  • Apolipoprotein H (APOH), a circulating glycoprotein implicated in lipid metabolism, has not been studied in AD.

    Circulating APOH promotes aortic dissection by activating the vascular smooth muscle cell NR5A1-PPARγ pathway. · 2026 · DOI

  • Although micro- and nanoplastics have been detected in human atherosclerotic plaques, their mechanistic contribution to disease pathogenesis remains poorly defined.

    Chronic Polystyrene Nanoplastics Exposure Reprograms Gene Expression, Alternative Splicing, and Disrupts Host Microbiome Metabolic Networks to Promote Atherosclerosis in LDLr- Knockout Mice · 2026 · DOI

  • Abstract Aims Atherosclerosis is currently evaluated by imaging, but scalable circulating biomarkers to detect its presence and quantify overall burden are lacking.

    Proteomic signatures as biomarkers of atherosclerosis burden · 2026 · DOI

Most-cited papers in Atherosclerosis and Cardiovascular Diseases

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34 open questions have been extracted from the limitations and future-work passages of 189 Atherosclerosis and Cardiovascular Diseases papers in our library. Each one below links back to the study that raised it, so you can read the original claim in context.

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