Advancements in the Treatment of Atherosclerosis: From Conventional Therapies to Cutting-Edge Innovations

Abstract

Atherosclerosis is a leading cause of morbidity and mortality worldwide, driven by a complex interplay of lipid dysregulation, inflammation, and vascular pathology. Despite advancements in understanding the multifactorial nature of atherosclerosis and improvements in clinical management, existing therapies often fall short in reversing the disease, focusing instead on symptom alleviation and risk reduction. This review highlights recent strides in identifying genetic markers, elucidating inflammatory pathways, and understanding environmental contributors to atherosclerosis. It also evaluates the efficacy and limitations of current pharmacological treatments, revascularization techniques, and the impact of these interventions on patient outcomes. Furthermore, we explore innovative therapeutic strategies, including the promising fields of nanomedicine, nucleic acid-based therapies, and immunomodulation, which offer potential for targeted and effective treatment modalities. However, integrating these advances into clinical practice is challenged by regulatory, economic, and logistical barriers. This review synthesizes the latest research and clinical advancements to provide a comprehensive roadmap for future therapeutic strategies and emphasize the critical need for innovative approaches to fundamentally change the course of atherosclerosis management.

Figure 1

Atherosclerosis progression mechanism. This illustration details the sequential events in the progression of atherosclerosis. The process begins with the disruption of the endothelial barrier, which allows low-density lipoprotein (LDL) to deposit within the arterial wall. Monocytes infiltrate the intima, differentiating into macrophages that phagocytize modified lipoproteins, which results in foam cell formation. These macrophage-derived foam cells stimulate the migration and phenotypic transformation of smooth muscle cells (SMCs) from the media to the intima, which contributes to plaque development. Initially, the lesion is stable, characterized by a small necrotic core encapsulated by a robust fibrous cap composed of SMCs and extracellular matrix. Over time, macrophages release matrix metalloproteinases, thereby degrading collagen within the cap and thinning it while also secreting pro-inflammatory cytokines that promote apoptosis. These changes gradually transform stable lesions into larger, unstable plaques, which increase the risk of acute cardiovascular events such as thrombosis, as depicted in the upper right of the illustration.

Figure 2

Atherosclerosis risk factors and disease progression. This diagram illustrates both traditional and emerging risk factors for atherosclerosis, along with the sequential phases of disease progression. Atherosclerosis, a chronic inflammatory condition, is initiated by cholesterol-rich lipoproteins and exacerbated by various risk factors such as smoking, diabetes, and hypertension, with genetics also playing a crucial role. The disease progression is depicted through four main stages: the asymptomatic phase, the fatty streak phase, the fibrous plaque phase, and the plaque rupture phase. Each stage is visually represented to show the gradual development from a healthy vessel to significant arterial blockage that can lead to critical outcomes like stroke, coronary artery disease, and kidney disease.

Figure 3

Mechanisms of cholesterol-lowering interventions in atherosclerosis. This diagram illustrates the multifaceted approaches to reducing cholesterol levels and their impact on atherosclerosis progression. Statins work by inhibiting HMGCR, which effectively decreases the synthesis of cholesterol within the liver. Ezetimibe targets the intestinal absorption of cholesterol by blocking the NPC1L1 protein, thereby reducing dietary cholesterol contribution to plasma levels. PCSK9 inhibitors, by reducing the degradation of low-density lipoprotein receptors (LDLRs), enhance the clearance of LDL-C from the bloodstream. Together, these interventions significantly lower plasma LDL-C levels to address the fundamental drivers of atherosclerosis development. The diagram traces the path from dietary cholesterol intake through to the formation of atherosclerotic plaques, highlighting the points of action of each therapeutic agent and their combined effect on preventing foam cell formation and subsequent plaque development.

Figure 4

Overview of current and emerging anti-atherosclerosis therapies. This diagram categorizes the broad spectrum of therapies used in the management of atherosclerosis. The primary clinical approach involves lifestyle modifications aimed at reducing risk factors that elevate serum LDL levels, such as poor diet, smoking, and lack of exercise. Pharmacologically, statins are the mainstay that reduce LDL-C levels by inhibiting the enzyme hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase, which is critical in cholesterol biosynthesis. Adjacent to these, revascularization procedures, such as CABG, PCI, and endarterectomy, are illustrated, thereby highlighting their role in physically managing obstructed arteries. Emerging therapeutic strategies, including anti-inflammation, nucleic acid-based therapies, immunomodulation, and nanotechnology, represent a shift toward personalized and targeted therapies promising to refine and enhance the efficacy of atherosclerosis management.

Figure 5

Nanoparticle-mediated anti-inflammatory therapy in atherosclerosis. (A) Schematic representation of PLGA-loaded IL-10 nanoparticles designed to stabilize atherosclerotic lesions by increasing fibrous cap thickness and reducing the necrotic core in advanced lesions. (B) Biophysicochemical properties of collagen type IV (Col-IV) IL-10 nanoparticles displaying hydrodynamic size (DLS measurements), actual size (TEM measurements), zeta potential, encapsulation efficiency (% EE), and drug loading (% Loading). Data shown as mean ± SD. (C,D) Release kinetics and TNF-alpha suppression activity of IL-10 from selected Col-IV IL-10 nanoparticles over time. (E) Confocal laser scanning microscopy (CLSM) images showing the impact of Col-IV IL-10 NP (NP22) on IL-1β release compared to controls. Visualization markers: Hoechst (blue) for nuclei, α-tubulin (green) for cytoskeleton, and IL-1β (red) for inflammation. Scale bar = 20 μm. (F–H) Hematoxylin and eosin (HE) staining demonstrating reduced necrosis in LDL receptor-deficient (Ldlr^–/–) mice treated with Col-IV IL-10 nanoparticles. The images include DAPI-stained aortic root sections highlighting NP22 in pink and nuclei in blue. Scale bar = 50 μm. (I) Detailed view of an atherosclerotic lesion outlined by a white dotted box with the white scale bar representing 50 μm. (J–L) Aortic root sections stained with picrosirius red to assess collagen content indicating increased subendothelial collagen in Ldlr^–/– mice treated with Col-IV IL-10 nanoparticles, thereby demonstrating the therapeutic efficacy in reinforcing vascular structure. Reproduced with permission from ref (105). Copyright 2016 American Chemical Society.

Figure 6

Efficacy of macrophage membrane-coated nanoparticles in atherosclerosis therapy. (A) Schematic illustration of macrophage membrane-coated rapamycin nanoparticles (MM/RAPNPs) designed for targeted atherosclerosis (AS) therapy. (B) Transmission electron microscopy (TEM) images showing the structure of rapamycin nanoparticles (RAPNPs) and MM/RAPNPs. Scale bar = 100 nm. (C) Confocal laser scanning microscopy (CLSM) images demonstrating the uptake of DiD-labeled nanoparticles (DiDNPs) and MM/DiDNPs by RAW264.7 macrophage cells over time. Scale bar = 10 μm. (D) CLSM images comparing the cellular uptake of DiDNPs and MM/DiDNPs by human umbilical vein endothelial cells (HUVECs), both nonactivated and activated with TNF-α, highlighting the enhanced uptake in activated endothelial cells (Acti-ECs). Scale bar = 20 μm. (E) Graph showing the relative fluorescence intensity of DiDNPs and MM/DiDNPs in the bloodstream over time, which indicates prolonged circulation of MM/DiDNPs. (F) Ex vivo fluorescence imaging of MM/DiDNPs distribution in atherosclerotic models. (G) CLSM images showing the localization of MM/DiDNPs within atherosclerotic plaques in the aortic root sections of ApoE–/– mice, delineated by a white dashed line. Scale bar = 60 μm. (H) Photographs of en face preparations of aortas stained with Oil Red O (ORO) to visualize lipid-rich atherosclerotic lesions. (I) Quantitative analysis of lesion areas, comparing controls, free RAP, RAPNPs, and MM/RAPNPs (n = 5, mean ± SD). Statistical significance noted as **p < 0.01, ***p < 0.001, ns (no significance). (J) ORO-stained cross sections of aortic roots highlighting areas of lipid deposition. Scale bar = 500 μm. (K) Quantitative analysis of lipid deposition areas within aortic root cross sections (n = 5, mean ± SD). (L) Toluidine blue staining of the necrotic core areas within the aortic root cross sections. Scale bar = 500 μm. (M) Quantitative assessment of the necrotic core areas in plaque lesions demonstrating significant reduction in MM/RAPNPs treated groups compared to controls (n = 5, mean ± SD). Reproduced with permission from ref (137). Available under a CC-BY 4.0 license. Copyright 2021 The Authors.