Current Atherosclerosis Reports最新文献

Purpose of review: Plaque erosion is the second most frequent cause of acute coronary syndrome, yet the biological processes and biomarkers associated with erosion remain incompletely understood. This review aims to examine the current understanding of plaque erosion, with a focus on identifying potential biomarkers.

Recent findings: Recent studies have identified distinct pathophysiological characteristics associated with plaque erosion, including variations in inflammatory response and immune cell infiltration within the culprit lesions and thrombi. Additionally, differences in the expression patterns of specific molecules have been noted, suggesting unique underlying mechanisms that contribute to plaque erosion. Understanding the differential expression and role of immune cells and biomarkers in erosion may be crucial for developing targeted therapies. The identification of biomarkers may help in the early detection and treatment of erosion-prone plaques, potentially reducing the incidence of acute coronary events.

Purpose of review: Abdominal aortic aneurysm (AAA) is a life-threatening vascular disorder with high mortality upon rupture, yet effective pharmacotherapy remains lacking. This review synthesizes the pivotal roles of myeloid cells-key mediators of aortic inflammation and remodeling-in AAA pathogenesis, highlighting their therapeutic targeting potential.

Recent findings: Single-cell RNA sequencing has revealed myeloid diversity in AAA. Among these myeloid populations, macrophages (including interferon-responsive monocytes, pro- and anti-inflammatory subsets, and reparative populations) emerge as central regulators of AAA pathogenesis, influencing disease initiation, progression, and tissue repair processes. Neutrophils promote vascular injury via neutrophil extracellular traps, while dendritic cells bridge innate-adaptive immunity. Eosinophils and myeloid-derived suppressor cells exhibited protective effects by immunoregulation. Mechanistic studies identified transcriptional, metabolic, and epigenetic regulators of myeloid plasticity. Clonal hematopoiesis and trained immunity may serve as potential novel mechanisms of myeloid cells involved in AAA. These mechanistic insights have inspired therapeutic innovation, with nanoparticle-targeted myeloid cell therapies showing promising immunomodulatory effects in mitigating AAA progression. Myeloid cells play a pivotal role in AAA pathogenesis by driving inflammatory responses, extracellular matrix degradation, and maladaptive vascular remodeling. Their functional heterogeneity, encompassing both destructive and protective subsets, highlights the need for precisely targeted therapeutic approaches. While single-cell technologies have significantly advanced our understanding of myeloid diversity, clinical translation remains challenged by microenvironmental crosstalk and potential off-target effects. Future research should prioritize: (1) spatial multi-omics characterization of myeloid-vascular interactions, (2) development of precision therapies targeting clonal hematopoiesis-driven subpopulations, and (3) combinatorial strategies to reprogram pathogenic myeloid phenotypes. Addressing these critical gaps may lead to transformative therapies for aneurysm stabilization, ultimately fulfilling the urgent unmet needs in AAA clinical management.

Purpose of review: This review summarizes the current knowledge on the benefits of various exercise training modalities on subclinical atherosclerotic cardiovascular disease (ASCVD) risk factors (i.e., endothelial dysfunction, large artery stiffening, carotid artery intima-media thickening) across the adult lifespan and the moderating role of biological sex, with the goal of informing/being to inform research gaps and future research directions.

Recent findings: Regular exercise is an effective intervention to counter subclinical risk factors for ASCVD. However, sex-specific variation has been observed in exercise training benefits. For example, aerobic exercise improves large artery stiffening in both middle-aged/older men and women and enhances endothelial function in middle-aged/older men; however, similar exercise-mediated improvements in endothelial function are not consistently observed in postmenopausal women Sex differences in exercise benefits may be related to differences in the sex hormone environment across the adult lifespan that influence cellular-molecular mechanisms, disconnecting favorable signaling in the vasculature induced by exercise training. Moreover, differences could be explained by social and/or psychological factors that make women more susceptible, on average, to barriers to exercise training compared to age-matched men.

Purpose of review: This paper explores the diagnostic and management challenges associated with genetic lipodystrophy syndromes (LDs) and their implications for atherosclerosis and cardiovascular health.

Recent findings: Genetic LDs, such as familial partial lipodystrophy (FPLD) and congenital generalized lipodystrophy (CGL), are characterized by abnormal fat distribution and significant metabolic complications. FPLD patients are often misdiagnosed as having type 2 diabetes; CGL patients may die early from noncardiovascular causes, giving the impression that cardiovascular disease is not frequent. Actually, these syndromes are associated with increased cardiovascular risks and early-onset atherosclerosis. Cardiovascular disease is common in LD patients; a high level of suspicion is essential for early diagnosis and effective management of genetic LDs to mitigate associated cardiovascular risks. Continued research into innovative therapies and a better understanding of the underlying mechanisms are crucial for improving patient outcomes and alleviating the healthcare burden of these syndromes.

Purpose of review: Outcome benefits for HMG-CoA reductase inhibitor (statin) use in the prevention of atherosclerotic cardiovascular disease (ASCVD) are well established and yet, statins remain underutilized with only half of eligible individuals receiving them among certain vulnerable populations. This review critically examines available data to provide a summary of the current evidence for statin use in select populations.

Recent findings: Lipid management can be more complex in patients with chronic kidney disease (CKD), organ transplants, metabolic dysfunction associated with steatotic liver disease (MASLD), and human immunodeficiency virus (HIV). Statins are generally safe and effective to reduce the burden of ASCVD among these highly heterogeneous groups of patients and should be considered with careful attention to their concomitant disease state. Herein, we focus on appropriate statin use in these challenging to treat conditions, their relationship with increased ASCVD risk, and approaches to statin use for ASCVD risk reduction. Although further research is needed to define optimal therapy in select high risk groups for ASCVD prevention, statins are proven to be clinically efficacious, safe, and cost-effective for ASCVD prevention, warranting greater efforts to increase their use.

Purpose of review: Lowering low-density lipoprotein cholesterol (LDL-C) is a crucial step in reducing the risk of atherosclerotic cardiovascular disease. Inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9), an important regulator of circulating LDL-C levels, represent a modern approach for the treatment of hypercholesterolaemia. Approved approaches targeting PCSK9 to date include injectable biologics. Here, we provide an overview of the current state of research on the development of oral PCSK9 inhibitors.

Recent findings: Several small molecules have been developed in recent years. Enlicitide decanoate (formerly known as MK-0616) has been shown to significantly reduce LDL-C levels by a maximum of 66% from baseline with a good safety and tolerability profile. Its formulation with sodium caprate enabled a higher bioavailability. Several clinical trials are currently underway to evaluate the efficacy and safety of this drug, including an outcome trial. AZD0780 is another oral small molecule that lowers LDL-C levels by 52% and can be administered on top of a statin. Several other small molecules with the potential to inhibit PCSK9 have been identified, some of which have stopped the development. Oral PCSK9 inhibitors are showing promising results in early studies. If the results of the outcome studies will be positive, we will have a safe, effective and easy-to-use oral therapy. Oral PCSK9 inhibitors could provide a convenient alternative to injectable PCSK9 inhibitors and result in a greater number of patients receiving an effective LDL-C-lowering therapy.

Purpose of review: The prevalence of dyslipidemia in the pediatric population continues to rise, increasing the future risk of atherosclerotic cardiovascular disease (ASCVD) as these children transition to adulthood. Timely diagnosis and intervention, beginning at a young age, is important in reducing the risk of ASCVD and preventing premature mortality in this vulnerable population. Implementation of a heart-healthy lifestyle should be encouraged in all children, and, when appropriate, the role of medication discussed in those at-risk. The purpose of this review is to discuss the impact of non-lipid lowering medications which affect lipid and lipoprotein metabolism in children (< 18 years-of-age).

Recent findings: According to National Center of Health Statistics, there has been a steady rise of pediatric obesity and cardiovascular disease (CVD) risk amongst youth over the last 2 decades, with roughly 1 out of 5 children having a BMI > 95th percentile for their age and gender. Such a rise can contribute to an increase of CVD risk factors, which play a role in the development of atherosclerosis. Evidence of atherosclerosis appears as early as childhood, progresses throughout adolescences, and accelerates after 20 years-of-age. Although some children are genetically predisposed to dyslipidemia, many have elevated lipids and lipoproteins as a result of unhealthy lifestyles - high fat, high carbohydrate diets, lack of exercise, and use of medications for other health conditions. In a 2023 survey, it was predicted that approximately 40.1% of children < 17 years-of-age have had at least one medication prescribed for a short or long-term health condition within the past 12 months. Clinicians should be aware of health conditions and medications that can adversely affect lipid levels when evaluating and treating children with lipid disorders. With the increased prevalence of lipid disorders in the pediatric population, healthcare providers are searching for both primary and secondary causes including the influence of certain medications or drug classes known to cause lipid abnormalities in adults, identifying similar findings amongst children. These include but are not limited to corticosteroids, retinoid agents, beta blockers, oral contraceptives, chemotherapy agents, antiretroviral medications, androgenic steroids and behavioral medications.

Purpose of review: This review discusses new treatment approaches for familial chylomicronemia syndrome (FCS), a rare disorder affecting triglyceride metabolism. The focus is on antisense oligonucleotides (ASO) and small-interfering RNA (siRNA) therapies targeting APOC3 and angiopoietin-like protein 3 (ANGPTL3).

Recent findings: Volanesorsen, an ASO targeting APOC3, has shown effectiveness in managing FCS, multifactorial chylomicronemia, and familial partial lipodystrophy, but its use is limited by thrombocytopenia. Emerging therapies, Olezarsen (ASO anti-APOC3) and Plozasiran (siRNA anti-APOC3), both conjugated with GalNAc, show promise in reducing acute pancreatitis risk without platelet concerns. ANGPTL3 inhibition requires residual lipoprotein lipase (LPL) activity, with only siRNA-based therapies-zodasiran and solbinsiran-under investigation. Suppressing APOC3 expression and targeting ANGPTL3 via siRNA offer significant potential, but long-term studies are needed to confirm their efficacy and safety. Future research may explore gene-editing strategies using lipid nanoparticle-based CRISPR-Cas9 delivery for more durable treatment outcomes.

To evaluate the impact of statins on CHD prevention, role of CAC scoring and CCTA in guiding statin therapy for both primary and secondary prevention in ASCVD. Coronary artery calcium (CAC) scoring and coronary computed tomography angiography (CCTA) have emerged as vital non-invasive imaging tools for refining cardiovascular risk assessment and guiding statin therapy in patients with atherosclerotic cardiovascular disease (ASCVD). CAC scoring helps stratify patients based on subclinical atherosclerosis burden, while CCTA provides detailed insights into plaque composition and distribution. Multiple studies, including the Multi-Ethnic Study of Atherosclerosis (MESA) and the CONFIRM registry, have demonstrated the utility of CAC scoring in identifying individuals at risk of major adverse cardiovascular events (MACE) and guiding personalized statin therapy. CAC scores, categorized into risk-based thresholds, enable clinicians to determine when statins should be initiated or deferred. CCTA complements CAC scoring by assessing plaque characteristics, including non-calcified plaque (NCP), calcified plaque, and high-risk features such as low-attenuation plaques, spotty calcifications, and positive remodeling. Serial CCTA imaging has further highlighted the effect of high-intensity statin therapy on plaque progression, demonstrating reductions in NCP and stabilization through increased calcification. CAC scoring effectively identifies patients with subclinical atherosclerosis who would benefit from statin therapy, particularly those with CAC scores > 100 or in the ≥ 75th percentile for age and sex. Statin therapy has been shown to promote plaque stabilization by increasing calcified plaque volume while reducing the progression of non-calcified plaques, thereby mitigating the risk of plaque rupture. CCTA provides additional value by identifying vulnerable plaque features and monitoring the impact of statin therapy over time. Studies have demonstrated significant reductions in total plaque volume and low-attenuation plaques in patients undergoing intensive lipid-lowering therapy, reinforcing the role of CCTA in guiding statin decisions for patients with established ASCVD. CAC scoring serves as a powerful tool to refine risk stratification and guide statin therapy initiation, particularly in asymptomatic individuals. CCTA enhances this approach by providing comprehensive plaque assessment and monitoring the response to statin therapy. Integrating CAC scoring and CCTA into clinical practice allows for a personalized approach to ASCVD management, improving patient outcomes through optimized statin therapy and targeted risk reduction.

Purpose of review: Inflammation has become a major residual risk factor for atherosclerotic cardiovascular disease (ASCVD). Certain lipid mediators, known as specialized proresolving mediators (SPMs), are mainly derived from polyunsaturated fatty acids (PUFAs) and can promote inflammation resolution while maintaining host autoimmunity. This review investigates the synthesis and ligand action pathways of these lipid mediators, as well as their regulatory mechanisms in the microenvironment of atherosclerotic plaques. Furthermore, it explores their clinical therapeutic potential, aiming to offer new insights into novel anti-inflammatory drug targets for the treatment of ASCVD.

Recent findings: Reduced levels of SPMs are associated with the progression of atherosclerosis. SPMs inhibit inflammatory responses in the plaque microenvironment by limiting immune cell infiltration, reducing oxidative stress, and promoting the clearance of apoptotic cells, all of which contribute to plaque stabilization. Tyrosine-protein kinase Mer (MerTK), TRIF-related adaptor molecule (TRAM), and high mobility group box 1 (HMGB1) play crucial roles in the modulation of SPM production. Clinical use of ω-3 PUFAs has been shown to reduce the incidence of fatal cardiovascular events. Furthermore, aspirin not only initiates the synthesis of specific SPMs but also extends their activity within the body. The enhanced production of SPMs promotes inflammation resolution in the plaque microenvironment without inducing immunosuppression. This characteristic highlights MerTK, TRAM, and HMGB1 as potential targets for the development of anti-inflammatory drugs. Investigating targets and compounds that enhance the production of SPMs presents a promising strategy for developing future anti-inflammatory agents.