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.

Cardiovascular diseases (CVD), with approximately 17.9 million fatalities annually, account for 32% of all deaths worldwide, as reported by the World Health Organization (WHO).¹ Atherosclerosis is a leading contributor to this staggering mortality rate, acting as the primary pathology underpinning many forms of CVD such as coronary artery disease, cerebrovascular incidents, and peripheral artery diseases. This complex disease is characterized by lipid metabolism disorders, inflammatory cell infiltration, thrombosis, and fibroplasia, leading to progressive arterial blockage.²⁻⁴ The progression of atherosclerosis typically follows a sequence of stages that begins with early lipid accumulation, advancing to fibrous plaque formation, developing into complex atheromatous plaques, and potentially culminating in acute cardiovascular events when critical arteries are obstructed.⁵

Historically, the perception of atherosclerosis has undergone significant transformations. Initially considered a mere consequence of lipid accumulation within arterial walls, it is now understood as a multifactorial disease involving intricate interactions between metabolic, genetic, and environmental factors.⁶⁻⁸ This evolving understanding has paralleled advancements in medical interventions, ranging from surgical revascularization techniques developed in the mid-20th century to recent pharmacological innovations aimed at lipid reduction and inflammation modulation. Notable among these are statins, ezetimibe, and PCSK9 inhibitors, which, despite their efficacy in lowering lipid levels and conforming to clinical guidelines, are associated with a reduction in adverse cardiovascular events by less than 50%.⁹ This residual risk highlights the incomplete nature of current treatment paradigms and underscores the imperative for more efficacious strategies.

Contemporary research on atherosclerosis is rich and varied, reflecting a spectrum of theories concerning its pathogenesis. While no single theory unifies the underlying mechanisms of atherosclerosis, the recognition of its complexity has spurred diverse investigative approaches, focusing on aspects such as lipid deposition, inflammatory responses, and genetic predispositions.¹⁰ This has paved the way for emerging therapies that aim to address not only the lipid-related aspects of atherosclerosis but also its inflammatory and genetic dimensions. Innovations such as targeted anti-inflammatory drugs, immunotherapies, nucleic acid-based treatments, and precision medicine strategies are increasingly being researched for their potential to revolutionize the management of atherosclerosis.

This review seeks to explore the detailed pathophysiological processes of atherosclerosis and the array of both established and novel treatment strategies. By delving into the traditional pharmacological and surgical interventions and evaluating cutting-edge advances, this review aims to lay the groundwork for integrating these novel therapeutic approaches into clinical practice to more effectively combat the global challenge of atherosclerosis.

1. Pathogenesis of Atherosclerosis

The formation of atherosclerotic plaques is a dynamic and multifaceted process, influenced by a range of cellular activities and biochemical pathways, progressing through distinct early and late stages, as shown in Figure 1. Initially, the local vascular microenvironment is compromised by various toxic substances, such as nicotine and alcohol, alongside dyslipidemia and dysglycemia. These factors are often exacerbated by maladaptive lifestyle choices and are further aggravated by hemodynamic disturbances like hypertension. Such conditions disrupt endothelial tight junctions and impair endothelial barrier function, setting the stage for advanced pathological changes.¹¹

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.

Endothelial dysfunction is pivotal, as it increases the permeability of the vascular wall to macromolecules, including lipoproteins. This dysfunction triggers endothelial cells to initiate signal transduction processes that lead to the secretion of various adhesion molecules and chemotactic factors, such as intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), monocyte chemoattractant protein-1 (MCP-1), and P-selectin.¹²⁻¹⁴ These molecules facilitate the adhesion and migration of monocytes from the bloodstream into the subendothelial space, where they differentiate into macrophages.^15,16

Within the subendothelial space, low-density lipoprotein (LDL) is a key player.¹⁷ Normally, macrophages clear LDL via LDL receptors (LDL-R) through a regulated process that prevents overload and cytotoxicity. However, in the atherosclerotic environment, excessive LDL leads to its modification into oxidized LDL (ox-LDL), a process catalyzed by reactive oxygen species (ROS) produced by the macrophages themselves.¹⁸ Unlike native LDL, ox-LDL is not recognized by traditional LDL-R but by specialized receptors such as scavenger receptor A (SR-A), oxidized low-density LDL receptor 1 (LOX-1), and CD36,¹⁹⁻²² which do not have the negative feedback mechanisms typical of LDL-R, leading to uncontrolled uptake of ox-LDL and subsequent cholesterol accumulation. This accumulation results in the transformation of macrophages into foam cells, which are lipid-laden and pro-inflammatory.^23,24 These cells, along with necrotic cells and other immune components, release cytokines like interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β), which further recruit and activate more immune cells and vascular smooth muscle cells (VSMCs).²⁵ The VSMCs migrate from the tunica media to the intima, where they proliferate and also ingest ox-LDL, contributing to the foam cell population and exacerbating plaque complexity. Moreover, these cells can produce extracellular traps that promote plaque progression and destabilization.²⁶⁻²⁸

As the plaque matures, macrophage- and VSMC-derived foam cells accumulate to form large lipid cores covered by thin fibrous caps. These unstable plaques are prone to rupture, which exposes their thrombogenic contents to the bloodstream, leading to platelet adhesion, aggregation, and thrombosis. Such events are the precipitants of acute clinical manifestations, including myocardial infarction and stroke, marking the catastrophic end stages of atherosclerosis, as shown in Figure 2.²⁹⁻³¹

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.

2. Traditional Pharmacological Treatments

Atherosclerosis is primarily managed through a variety of pharmacological treatments aimed at mitigating the disease’s primary risk factors and preventing the progression to serious cardiovascular events. These treatments target different aspects of the disease’s complex pathophysiology, including lipid accumulation, platelet aggregation, hypertension, and diabetes-related complications. Each category of drugs plays a specific role in stabilizing plaques, improving blood flow, and reducing the likelihood of plaque rupture and thrombosis. This section explores the traditional pharmacological approaches to atherosclerosis management, namely lipid management therapies, antiplatelet therapies, hypertensive management therapies, and diabetes mellitus management therapies. By detailing the mechanisms, benefits, and limitations of each treatment, we aim to provide a comprehensive overview of how these interventions contribute to the overall therapeutic strategy for atherosclerosis.

2.1. Lipid Management Therapies

Lipid management is foundational in the treatment of atherosclerosis, primarily addressing disorders in cholesterol metabolism that underpin the disease. The strategic reduction of total plasma cholesterol and LDL cholesterol is crucial, as these lipids are central to the development of atherosclerotic plaques. Cholesterol in the body originates from two main sources: exogenous cholesterol, obtained through dietary intake, and endogenous cholesterol, synthesized within the body itself.³² Exogenous cholesterol is absorbed in the intestinal tract via the Niemann-Pick C1-Like 1 (NPC1L1) protein located on the epithelial cells of the intestinal mucosa. Once inside the body, it combines with triglycerides and apolipoprotein B-48 to form chylomicrons, which transport the absorbed lipids to the liver for further metabolism. The triglycerides in these chylomicrons are then hydrolyzed for use by peripheral tissues. Endogenously, cholesterol is primarily synthesized in the liver, the major site for its biosynthesis. This process involves the conversion of acetyl-CoA into cholesterol through several enzymatic steps, with hydroxymethylglutaryl coenzyme A reductase (HMGCR) playing a pivotal role.³³ The cholesterol thus produced is packaged into very low-density lipoprotein (VLDL), along with triglycerides and apolipoprotein B-100. VLDL is subsequently converted into LDL, the principal carrier of cholesterol in the bloodstream.³⁴ Once in the circulation, cholesterol’s impact on vascular health becomes evident when the endothelial barrier is compromised, allowing LDL to infiltrate the subendothelial space where it is prone to oxidation and uptake by macrophages.^28,35,36 This initiates a cascade of pathophysiological changes leading to plaque formation.

To counteract the deleterious effects of excessive cholesterol accumulation in macrophages, several mechanisms are critical, as shown in Figure 3. Cholesterol efflux is facilitated through simple diffusion, SR-B1-promoted diffusion, and active transport mechanisms mediated by ATP-binding cassette transporters A1 (ABCA1) and G1 (ABCG1). The expression of these transporters is intricately regulated by liver X receptors (LXRs), which play a crucial role in maintaining cellular cholesterol balance.³⁷⁻³⁹ Under normal physiological conditions, cholesterol efflux is primarily managed by simple diffusion, driven by the concentration gradient of cholesterol across the cell membrane. However, in conditions where macrophages are overloaded with cholesterol, ABCA1 and ABCG1 become essential in effectively removing excess cholesterol. High-density lipoprotein (HDL) particles in the bloodstream are integral to this regulatory mechanism. They receive cholesterol effluxed from macrophages and transport it back to the liver for reprocessing. Additionally, hepatocytes contribute to systemic cholesterol regulation by up-taking LDL from the bloodstream via LDL-R on their surface. Once internalized, the cholesterol from LDL is converted into bile acids within the liver, then excreted into the intestinal lumen through a series of biochemical transformations, ensuring maintenance of cholesterol homeostasis.⁴⁰

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.

Among the pharmacological strategies for managing lipid levels, statins are notably prevalent. These medications function as competitive inhibitors of HMGCR, the enzyme critical for intracellular cholesterol synthesis.⁴¹ By inhibiting this enzyme, statins not only reduce the synthesis of cholesterol but also enhance the clearance of LDL from the bloodstream via up-regulation of LDL-R on hepatocytes.^42,43 This dual action helps significantly lower blood cholesterol levels, directly impacting the progression of atherosclerosis. The effectiveness of statins was highlighted in one of the first long-term clinical trials, the Scandinavian Simvastatin Survival Study (4S), which demonstrated that statin therapy significantly improves survival rates and reduces the need for revascularization procedures in patients with coronary heart disease.⁴⁴ Moreover, data from the United States show a high usage rate of statins, particularly in the primary prevention of cardiovascular diseases among older adults over 75, emphasizing their vital role in managing atherosclerosis risk.⁴⁵ Given their proven benefits, it is recommended that statin therapy be initiated promptly for high-risk patients with atherosclerosis who do not present contraindications to the drug. This proactive approach aims to mitigate the risk factors associated with cardiovascular events and improve long-term health outcomes, irrespective of the patients’ initial cholesterol levels.⁴⁶

Ezetimibe is a unique intestinal cholesterol absorption inhibitor that operates by interacting with the NPC1L1 protein on the epithelial cells of the intestinal mucosa.⁴⁷ This interaction specifically blocks the uptake of cholesterol without impacting the absorption of triglycerides and fat-soluble vitamins. Additionally, ezetimibe has been shown to enhance the expression of LDL-R on the liver, which in turn increases the clearance of LDL cholesterol (LDL-C) from the bloodstream.^48,49 Due to these effects, ezetimibe is frequently used in combination with statins, which together provide a more comprehensive approach to lowering plasma cholesterol levels. Clinical evidence supporting the effectiveness of this combination comes from a double-blind randomized ctrial, which demonstrated that adding ezetimibe to statin therapy reduced cardiovascular end points by 6.4% (P = 0.016) compared with statin therapy alone.⁵⁰ This significant finding underscores the potential of combined lipid-lowering therapy to more effectively delay the progression of cardiovascular diseases and suggests that integrating ezetimibe with statins could enhance overall treatment outcomes for patients with elevated cholesterol levels.

The PCSK9 gene encodes a serine protease produced in the liver, which plays a critical role in cholesterol regulation by binding to LDL-R on hepatocytes, leading to their degradation. This process elevates plasma LDL-C levels.⁵¹⁻⁵³ PCSK9 inhibitors, such as alirocumab and evolocumab, are humanized monoclonal antibodies that block this interaction, significantly increasing hepatic LDL-R availability. As a result, they effectively lower plasma LDL-C levels and reduce the risk of major adverse cardiovascular events.^54,55 In recognition of their therapeutic potential, the U.S. Food and Drug Administration (FDA) approved these agents in 2015 as new lipid-lowering therapies. They are especially beneficial for patients who either cannot tolerate statins or do not achieve sufficient LDL-C reduction with maximum tolerated doses of statins in combination with ezetimibe. However, the practical use of PCSK9 inhibitors is often constrained by their need for frequent injections due to a short half-life and high cost. Consequently, these treatments are typically reserved for high-risk patients or those with familial hypercholesterolemia.

2.2. Antiplatelet therapy

Platelets play a fundamental role in hemostasis, where they respond to injury by adhering and aggregating at the site to form clots. This process involves the conversion of soluble fibrinogen in plasma into insoluble fibrin by thrombin, intertwining with the platelet clots to form a stable thrombus and consolidating the hemostatic response. However, in the context of atherosclerosis, platelets contribute not only to thrombus formation but also to the progression and complications of atherosclerotic lesions. At sites of atherosclerotic plaque rupture, platelets amplify thrombotic pathways, leading to the formation of a more robust thrombus that can occlude vessels and precipitate acute cardiovascular events such as myocardial infarction and stroke. Given these critical implications, antiplatelet therapy is paramount in managing atherosclerosis.⁵⁶ It serves as a cornerstone of both acute treatment and secondary prevention for ischemic stroke and coronary heart disease. Antiplatelet agents work by inhibiting the platelet activation and aggregation processes, thereby reducing the risk of thrombus formation at sites of arterial injury. This therapeutic approach is essential not only for managing acute episodes but also for preventing the recurrence of these life-threatening events. By effectively interrupting the pathways that lead to thrombus stabilization and vessel occlusion, antiplatelet medications play a vital role in the comprehensive treatment and secondary prevention strategies for patients with atherosclerotic cardiovascular disease.⁵⁷⁻⁵⁹

Aspirin forms the backbone of antiplatelet drug therapy by irreversibly inhibiting the cyclooxygenase-1 (COX-1) enzyme in platelets, thus blocking platelet aggregation.⁶⁰ This action makes aspirin crucial in preventing thrombus formation, particularly after percutaneous coronary intervention (PCI), where it is commonly used in combination with P2Y₁₂ receptor antagonists. The combination therapy significantly enhances thrombotic prevention compared to either agent alone and is standard care for patients undergoing PCI.⁶¹ Clopidogrel, a second-generation antiplatelet drug, acts as a potent inhibitor of the platelet P2Y₁₂ receptor. It blocks the binding of adenosine diphosphate to its receptor, effectively preventing the abnormal aggregation of platelets that is often induced by various agonists. This mechanism not only helps to manage the severity of atherosclerosis but also provides an alternative for patients who are intolerant to aspirin. The COMMIT study underscores the effectiveness of combining clopidogrel with aspirin in patients with ST-segment elevation myocardial infarction (STEMI). This combination was shown to significantly reduce the incidence of composite end points such as death, reischemia, and stroke, without a statistically significant increase in bleeding rates.⁶²

Nevertheless, existing antiplatelet therapies primarily focus on inhibiting the action of platelet surface receptors to mitigate cardiovascular events triggered by thrombosis following the rupture of vulnerable atherosclerotic plaques. These therapies typically target specific receptors like COX-1 and P2Y₁₂ to prevent platelet aggregation. However, the involvement of multiple platelet receptors and complex signaling pathways necessitates a careful consideration of treatment strategies, particularly in terms of potential adverse effects such as prolonged bleeding times. The rational combination of these therapies with other drugs to enhance efficacy while minimizing risks remains an important area of clinical research. Moreover, the systemic administration of antiplatelet drugs can lead to side effects associated with thrombophilic conditions, prompting researchers to explore more targeted approaches. The development of drug delivery systems that concentrate the therapeutic agents at the site of the lesions—thereby sparing other tissues—could revolutionize the treatment of cardiovascular diseases. This targeted delivery not only aims to enhance the efficacy of the drugs but also to reduce side effects by limiting systemic exposure. Research into such targeted therapies may provide significant advancements in the management of atherosclerosis and its associated complications.

2.3. Hypertensive Management Therapies

Hypertension is a significant risk factor for the development of atherosclerosis and subsequent CVD, and it is also the leading cause of premature death worldwide.⁶³ Hypertension contributes to endothelial cell dysfunction, exacerbating the formation of atherosclerotic plaques and decreasing their stability, thereby increasing the risk of cardiovascular events.⁶⁴ Effective management of hypertension is crucial in mitigating these risks. Current clinical guidelines recommend a diverse array of antihypertensive drugs, categorized into four major classes: β-blockers, calcium channel blockers, renin-angiotensin-aldosterone system (RAAS) blockers, and thiazide diuretics. Each class targets hypertension through different mechanisms: β-blockers reduce sympathetic nervous system activity, calcium channel blockers relax vascular smooth muscle, RAAS blockers decrease vascular resistance, and thiazide diuretics lower plasma volume.

A comprehensive meta-analysis has shown that all major classes of antihypertensive medications generally provide comparable effects on major cardiovascular outcomes.⁶⁵ However, the choice of medication must be carefully considered based on individual patient histories to avoid potential contraindications. For example, nonselective β-blockers are not suitable for patients with a history of asthma due to their respiratory system effects. Furthermore, research indicates that even a modest reduction in systolic blood pressure, by as little as 5 mmHg, can significantly decrease the risk of adverse cardiac events by up to 10%.⁶⁶ This underscores the importance of effective hypertension management in reducing cardiovascular risks and improving overall patient outcomes in those with atherosclerosis.

2.4. Diabetes Mellitus Management Therapies

Diabetes mellitus, a rapidly growing global health issue, is a chronic systemic metabolic disease influenced by both genetic predispositions and environmental factors, primarily characterized by elevated blood glucose levels.^67,68 Hyperglycemia, the hallmark of diabetes, contributes significantly to endothelial dysfunction. This dysfunction exacerbates the vulnerability of the arterial walls to further damage from hyperglycemia and other risk factors such as hypertension and dyslipidemia, compounding the harm to both the function and structure of the arterial system.⁶⁹ The link between diabetes and cardiovascular disease is well-established, with diabetic patients exhibiting a significantly increased risk of developing atherosclerotic cardiovascular diseases. For instance, a 20-year study of the Framingham cohort revealed that individuals with diabetes had a two- to 3-fold higher risk of developing clinical atherosclerotic conditions and subsequent cardiovascular events.⁷⁰

Currently, the FDA has approved a wide array of nearly 60 drugs for the management of type 2 diabetes mellitus (T2DM), alongside insulin therapies for type 1 diabetes mellitus (T1DM). These treatments span several classes, including biguanides, sulfonylureas, glinides, alpha-glucosidase inhibitors, thiazolidinediones, and sodium-glucose cotransporter-2 (SGLT2) inhibitors, each with unique mechanisms of action. These mechanisms range from reducing glucose absorption in the small intestine and inhibiting hepatic glucose production, to enhancing insulin sensitivity and secretion, and even decreasing renal glucose reabsorption.⁷¹

Recent Cardiovascular Outcomes Trials (CVOTs) and other studies have demonstrated that advances in managing both T1DM and T2DM have progressively led to a reduction in major cardiovascular events.⁷²⁻⁷⁴ Therefore, effective management of diabetes is crucial not only for controlling blood sugar but also as an integral part of cardiovascular disease prevention, especially in patients with coexisting atherosclerosis. In such cases, a combined approach involving both antiatherosclerosis therapy and comprehensive diabetes management is essential to effectively reduce the compounded risk of cardiovascular complications.

3. Revascularization Intervention

Aside from pharmacological treatments for risk factors involved with atherosclerosis, surgical interventions such as percutaneous coronary artery stenting (PCI), coronary artery bypass grafting (CABG), and carotid artery endarterectomy are widely available to treat atherosclerosis, which have the advantages of being convenient to perform, less hazardous, with shorter postoperative recovery time, and capable of rapid revascularization and restoration of blood flow during an acute attack of coronary AS.⁷⁵⁻⁷⁸

3.1. Percutaneous Coronary Artery Stenting

Percutaneous coronary artery stenting, widely known as PCI, stands as a pivotal surgical intervention in the management of atherosclerosis, especially critical during episodes of acute coronary syndromes. This minimally invasive procedure was originally based on balloon angioplasty techniques, where a balloon catheter was used to dilate the artery at the site of blockage to restore essential blood flow. While effective in reopening the artery, balloon angioplasty often led to significant complications such as acute arterial closure, thrombosis, and a high rate of restenosis where the artery narrows again.^79,80

To combat these drawbacks, medical technology advanced with the introduction of bare metal stents (BMS), which provided a scaffold that kept the artery open after angioplasty.⁸¹ However, even with the support of BMS, many patients experienced aggressive neointimal hyperplasia, leading to restenosis within months after the procedure. This necessitated the development of drug-eluting stents (DES), which are coated with medication that slowly releases into the arterial wall to prevent the proliferation of vascular smooth muscle cells that contribute to restenosis.⁸²

DES dramatically improved the long-term success of PCI by reducing the likelihood of the artery renarrowing, thus enhancing patient outcomes. However, despite these improvements, the risk of in-stent thrombosis (ST), a dangerous complication where a blood clot forms at the stent site, remained. In-stent thrombosis is particularly hazardous as it can lead to myocardial infarction in 60–70% of cases and has been associated with an increased mortality rate of 20–25%.⁸³ To address this, newer generations of DES have been engineered with biocompatible or bioabsorbable polymers that further reduce the risk of thrombosis and enhance endothelialization, the process where the endothelium heals over the stent.

Moreover, the procedure itself has been refined with better preprocedural imaging techniques and postprocedural care strategies that help personalize treatment to the patient’s specific arterial anatomy and health condition.⁸⁴ This tailored approach helps to optimize outcomes and minimize complications. Advanced imaging and pressure wire assessments during PCI allow for more precise stent placement and the ability to assess the functional significance of arterial blockages before stent deployment.

Today, PCI with the latest generation of DES remains the cornerstone of interventional cardiology, offering patients suffering from coronary artery disease a highly effective option to relieve symptoms, improve quality of life, and reduce adverse cardiac events. As research continues and technology evolves, further improvements in stent design and antirestenotic therapies are expected, which will continue to enhance the safety and efficacy of this essential cardiac procedure.^85,86

3.2. Coronary Artery Bypass Grafting

CABG is a vital surgical intervention for patients suffering from severe coronary artery disease, especially those who are not ideal candidates for percutaneous coronary interventions like stenting. CABG is used extensively in individuals with multivessel coronary disease or highly complex arterial lesions that do not respond well to less invasive treatments.^87,88 The procedure involves grafting one or more blood vessels from other parts of the body—often the saphenous vein in the leg or the internal mammary artery in the chest—to the coronary arteries. This allows the surgeon to create new pathways for oxygen-rich blood to bypass the narrowed or blocked segments of the coronary arteries and reach the heart muscle.

The strategic choice of graft depends on various factors including the specific needs of the patient, the severity of arterial blockage, and overall heart function. CABG is particularly beneficial for providing symptom relief, reducing the need for further interventional procedures, and enhancing overall cardiac function. Studies have shown that CABG can significantly improve long-term survival rates and quality of life for patients with advanced coronary artery disease, making it a preferred treatment for complex cases.⁸⁹

The effectiveness of CABG has been well-documented through long-term clinical studies. These studies underscore CABG’s superiority over medical therapy alone in reducing symptoms of angina, preventing myocardial infarctions, and enhancing survival in specific patient populations. The procedure’s success has made it a mainstay of coronary artery disease management, with hundreds of thousands of surgeries performed annually. In 2014 alone, approximately 371,000 CABG procedures were conducted in the United States, reflecting its critical role in cardiovascular surgery.⁹⁰

Moreover, advancements in surgical techniques, such as off-pump CABG (where the heart is not stopped during the surgery) and minimally invasive direct coronary artery bypass (MIDCAB), have further refined the procedure, reducing risks and improving recovery times. These innovations allow for a broader range of patients to benefit from CABG, including those who might have been considered too high-risk for traditional open-heart surgery.⁹¹

CABG remains a cornerstone of therapeutic strategies for managing severe coronary artery disease.⁹² Its ability to effectively restore coronary blood flow and improve cardiac function is invaluable, particularly for those with extensive coronary blockages and those who have not had success with or are not suitable for other forms of treatment. As technology and techniques continue to evolve, CABG is likely to remain a vital tool in the fight against coronary artery disease, providing life-saving treatment to those in need.

3.3. Carotid Artery Endarterectomy

Carotid artery endarterectomy is a critical surgical procedure aimed at preventing strokes by meticulously removing atherosclerotic plaque from the carotid arteries.⁹³ This operation is particularly recommended for patients who have shown symptoms of carotid artery stenosis, which can include transient ischemic attacks (TIAs), minor strokes, or other neurological symptoms indicative of reduced cerebral blood flow.⁹⁴ These symptoms often signal the presence of significant obstructions in the carotid arteries, which are major blood vessels in the neck that supply blood to the brain.

The procedure is performed under general or sometimes local anesthesia and begins with a carefully placed incision along the side of the neck.⁹⁵ The surgeon then exposes the affected carotid artery and temporarily clamps it to prevent blood flow during the plaque removal process. The artery is opened, and the plaque is meticulously cleared from the artery walls. Once the plaque is removed, the artery is sutured back together to restore normal blood flow to the brain. This direct method of removing plaque is considered highly effective in reducing the risk of stroke, particularly in patients who have already experienced symptoms of cerebral blood flow interruption.

Long-term studies and clinical trials have consistently shown that carotid endarterectomy significantly reduces the risk of future strokes in patients with symptomatic carotid stenosis.⁹³ The procedure‘s efficacy in preventing stroke is comparable to, and sometimes surpasses, that of carotid artery stenting, especially in older adults or those with certain medical conditions where stenting poses higher risks.⁹⁶

The decision to perform a carotid endarterectomy involves careful consideration of various factors, including the severity of artery stenosis, the patient’s overall health, and the presence of other medical conditions. The procedure’s benefits must clearly outweigh the risks, which can include complications such as stroke, heart attack, or cranial nerve injuries during surgery.⁹⁷

In 2014, approximately 86,000 carotid artery endarterectomies were performed in the United States,⁹⁰ underscoring the procedure’s role as a prevalent and effective intervention for reducing the incidence of serious cerebral events among patients with significant carotid artery disease. As surgical techniques and perioperative care continue to advance, carotid artery endarterectomy remains a cornerstone in the management of patients at high risk of stroke, providing a lifesaving option for those vulnerable to the debilitating effects of cerebrovascular accidents.

4. Emerging Anti-Atherosclerosis Therapies

Advancements in medical research have significantly enriched our arsenal against atherosclerosis. Although traditional therapies, including systemic medications for managing cardiovascular disease (CVD) risk factors and revascularization interventions to restore blood flow postplaque formation, have made substantial contributions to patient care, they often fall short due to issues related to drug stability, targeting accuracy, toxicity, and production complexities, as shown in Table 1. In response, a wave of innovative therapeutic targets and strategies is currently being explored in preclinical studies and undergoing evaluation in large-scale clinical trials, promising to enhance the efficacy and safety of atherosclerosis management, as shown in Figure 4.

Table 1. Comparison of Traditional and Emerging Atherosclerosis Treatments.

methods		mechanism of therapy	advantages	disadvantages	expenditurea
Traditional pharmacological treatments	Statins	Competitive inhibition of 3-hydroxy-3-methylglutaryl CoA reductase (rate-limiting enzyme for cholesterol biosynthesis).42 Upregulates LDL-R(mediates increased uptake of LDL cholesterol by liver cells). Stimulates the expression of scavenger receptor SR-B1 (promotes the selective uptake of cholesterol esters by HDL molecules). Reduces the expression of various proinflammatory mediators.43	Low cost. First-line drug for As treatment.	Poor tolerance. Allergies, muscle pain, myopathy, rhabdomyolysis, hepatotoxicity, and new-onset diabetes.	*
	Fibrates	Stimulation of nuclear receptor peroxisome proliferators activates receptor α (PPARα). Up-regulated SR-B1 and ABCA1 expression. Reduced production of lipoprotein lipase (LPL) inhibitor ApoC-III, resulting in lower serum triglyceride levels. Antioxidant, anti-inflammatory and antithrombotic.34	Relatively well tolerated. As a monotherapy or combination therapy to treat patients with hypercholesterolemia and hyperlipidemia.	Gastrointestinal side effects and rashes.	*
	Ezetimibe	Inhibits the intestinal NPC1L1 transporter to inhibit cholesterol absorption. Significant curative effects of single drug and combined treatment.47,48	The curative effects of single drug and combined treatment were significant.	Myopathy and rhabdomyolysis.49 More research about effect needed.	*
	PCSK9 Inhibitors	Inhibits LDL-R endocytosis and degradation, thereby promoting cholesterol uptake by liver cells.51,52	Reduced adverse cardiovascular outcomes. More effective than other monotherapies.	Neurocognitive adverse events (such as dementia delirium and mental impairment problems).53	***
	Antiplatelet therapy	Inhibits platelet thrombosis.	AS a first-line preventive drug for AS, it can reduce the occurrence of adverse cardiovascular events.	Gastrointestinal reaction.	*
	Hypertensive management therapies	Reduces the damage of endothelial barrier function and prevent or delay the progression of AS.	Reduce the incidence of adverse cardiovascular outcomes of AS.	Large individual differences. Target organ damage.	*
	Diabetes mellitus management therapies
Revascularization invention	PCI	Balloon catheters and stents are used to dilate the artery at the blocked site to restore necessary blood flow.80	For acute coronary syndromes. Performed simultaneously with coronary angiography.	Invasive surgery, tent thrombosis. restenosis.	****
	CABG	One or more blood vessels from another part of the body (usually the saphenous vein in the leg or the internal mammary artery in the chest) are grafted onto the coronary artery.87	Superior to drug therapy in alleviating angina symptoms, preventing myocardial infarction and improving survival rate of certain patients.88	Complicated and invasive operation. Large trauma and long recovery time.	******
	Endarterectomy	Removes carotid plaque restores blood flow continuity to prevent stroke.95	Reduces the risk of stroke effectively.	Strict surgical indications, multiple complications: stroke, multiple complications.	****
Emerging antiatherosclerosis therapies	Anti-inflammation therapies	Atherosclerosis involves chronic vascular inflammation influenced by various risk factors. Targeting this inflammation could stabilize plaque and mitigate disease progression.99	Anti-inflammatory treatments can reduce cardiovascular events in patients, even when LDL levels are controlled.	Not all anti-inflammatory interventions are beneficial; some may cause adverse effects, indicating a need for personalized treatment approaches..	N/A
	Nucleic acid-based therapies	Target mRNA sequences to inhibit protein translation involved in atherosclerosis.	Highly specific, can reduce cardiovascular risks by targeting multiple pathways.108	Target selection challenging; often requires combination with other therapies.107	N/A
	Immunomodulating therapies	Modulates immune responses to target the inflammation in atherosclerotic plaques.118	Reduces reliance on drugs and surgery; may prevent worsening of cardiovascular conditions.	Complex vaccine development; potential for adverse reactions postvaccination.	N/A
	Nanotechnology-based therapies	Utilizes nanoparticles’ small size and targeting capabilities for efficient atherosclerosis treatment.	Enables delivery of diverse therapeutic agents, offering flexible and potent treatment combinations.	Regulatory challenges due to complex characterization needs; requires thorough safety and efficacy evaluations for clinical use.135	N/A

^aThe number of asterisks represents the cost of treatment.

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.

4.1. Anti-Inflammation Therapies

In the realm of atherosclerosis, the role of cholesterol as a primary contributor is well-recognized. However, clinical observations highlight that up to half of all adverse cardiovascular events occur in individuals without traditional risk factors such as smoking, obesity, and dyslipidemia.⁹⁸ This discrepancy has brought attention to the residual risk that persists even with effective lipid-lowering therapies, suggesting that other pathological mechanisms, such as inflammation, play a critical role in the progression of atherosclerotic cardiovascular disease. Emerging evidence from large-scale cohort studies has revealed a strong association between elevated levels of inflammatory biomarkers, such as C-reactive protein (CRP) and IL-6, and the risk of myocardial infarction and ischemic stroke.⁹⁹ These markers have not only been linked to the initial occurrence of cardiovascular events but also to their recurrence, underscoring the profound impact of systemic inflammation on cardiovascular health. The inflammatory response is intricately linked with lipid metabolism and other cardiovascular risk factors, forming a complex network that promotes the development of atherosclerosis.¹⁰⁰ As a result, targeting inflammation has emerged as a pivotal therapeutic strategy.

In recent years, the pursuit of innovative anti-inflammatory treatments for atherosclerosis has led to several promising clinical trials. These studies have begun to illustrate the potential benefits and challenges of targeting inflammation in cardiovascular disease management. One of the noteworthy trials is the Low Dose Colchicine 2 (LoDoCo2) trial, which investigated the effects of colchicine, a drug traditionally used to treat gout, on cardiovascular health. The trial demonstrated that a daily dose of 0.5 mg of colchicine significantly reduced the risk of adverse cardiac events in patients with chronic coronary disease, both in those with and without a history of acute coronary syndromes.¹⁰¹ This outcome suggests that colchicine’s anti-inflammatory properties can play a crucial role in stabilizing atherosclerotic plaques and preventing cardiac complications.

Furthermore, an additional study involving colchicine focused on its effects on atherosclerotic plaques using computed tomography coronary artery imaging. This trial provided visual evidence of colchicine’s impact, showing a reduction in the volume of low-density plaque and CRP levels after one year of treatment.¹⁰² These findings reinforce the potential of colchicine not only to reduce systemic inflammation but also to directly influence the characteristics of atherosclerotic plaques, potentially leading to improved cardiovascular outcomes.

Another significant study, the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS), explored the effects of Canakinumab, a monoclonal antibody that targets IL-1β. While the treatment did not affect lipid levels, it successfully reduced levels of CRP and subsequently lowered the incidence of recurrent cardiovascular events.¹⁰³ However, the study also highlighted a critical concern: patients receiving Canakinumab experienced an increased risk of fatal infections, underscoring the challenges of systemic immunosuppression and indicating a need for more precisely targeted therapies that do not broadly compromise immune function.

As a potent anti-inflammatory cytokine, interleukin-10 (IL-10) also plays a critical role in the regulation of the immune system. Produced by various types of inflammatory cells, including macrophages and regulatory T cells, IL-10 serves to limit the immune response to pathogens, thereby preventing unnecessary damage to the host and helping to maintain tissue homeostasis. Its functions are particularly relevant in the context of atherosclerosis, where excessive inflammation can lead to the progression of the disease. Studies have shown that IL-10 levels are significantly reduced in patients with atherosclerotic plaques prone to rupture compared to healthy controls. This reduction highlights the protective role of IL-10 in cardiovascular health.¹⁰⁴ Despite its beneficial effects, the therapeutic use of IL-10 is limited by its short systemic half-life, which complicates its delivery and effectiveness. To overcome this challenge, researchers have encapsulated IL-10 in biodegradable polymers such as poly(d-lactic acid) (PLA) and poly(lactic-co-glycolic acid) (PLGA). These polymers form nanoparticles that can encapsulate and protect IL-10 from rapid degradation in the bloodstream, enhancing its local availability and therapeutic efficacy, as shown in Figure 5.¹⁰⁵

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.

4.2. Nucleic Acid-based Therapies

Nucleic acid-based therapeutics, recently developed for various diseases, have shown considerable promise in targeting the molecular underpinnings of atherosclerosis. RNA-based therapies such as small interfering RNA (siRNA) function by specifically binding to complementary mRNA sequences, leading to targeted mRNA degradation. This process, known as RNA interference (RNAi), allows for the precise knockdown of genes involved in disease pathways. Antisense oligonucleotides (ASOs) are single-stranded molecules that prevent mRNA from being translated into protein, thus offering another layer of gene expression control.^106,107 These molecules can be chemically modified, such as with N-acetylgalactosamine (GalNAc), to enhance liver-specific uptake, highlighting making them particularly effective in targeting hepatic genes involved in lipid metabolism.¹⁰⁸

At present, RNA-based inhibitors targeting PCSK9, Lp(a), APOCIII, and Angptl3 have successfully progressed through phase II–III clinical trials. Additionally, various microRNAs (miRNAs) and long noncoding RNAs have been shown to mitigate atherosclerosis formation in preclinical animal models.¹⁰⁹ Regarding PCSK9, an attractive target for lowering cholesterol levels in atherosclerosis, a range of approaches including small RNA have been explored.¹¹⁰ Inclisiran, a GalNAc-coupled siRNA against PCSK9, is currently under investigation in multiple phase III trials to assess its impact on cardiovascular outcomes and familial hypercholesterolemia. In phase II trials, inclisiran was administered to patients with elevated LDL cholesterol and a high cardiovascular risk, resulting in a dose-dependent reduction of PCSK9 and LDL levels. After 180 days, LDL levels were reduced by 27.9% to 41.9% following a single administration, and by 35.5% to 52.6% after two administrations. Importantly, PCSK9 siRNA was well-tolerated and did not cause significant side effects over the course of the trial.¹¹¹

Angiopoietin-like protein 3 (Angptl3) plays a crucial role in inhibiting lipoproteins and endothelial lipase, subsequently elevating LDL, triglycerides, and high-density lipoprotein (HDL) levels. An ASO targeting Angptl3 has been shown to reduce triglyceride levels by up to 63% in humans.¹¹² This GalNAc-coupled ASO, known as Ionis-Angptl3-LRx, has demonstrated a favorable safety profile, with no serious adverse effects reported. A phase II study is currently ongoing, involving patients with hypertriglyceridemia, type 2 diabetes, and nonalcoholic fatty liver disease.

In addition to these therapies targeting cholesterol metabolism, siRNA targeting ox-LDL receptors such as SR-A, LOX-1, and CD36 on the surface of macrophages could also serve as potential strategies for inhibiting atherosclerotic plaque formation and progression. siRNA has been shown to regulate the expression of macrophage scavenger receptors, thus influencing the development of atherosclerosis.¹¹³ Furthermore, reverse cholesterol transport in macrophages presents an intriguing target, with several miRNA-regulated steroid transcription factors, such as ABCA1 and ABCG1, mediating the transfer of free cholesterol to low-fat apolipoprotein A1 (ApoA1) to form de novo or recycled high-density lipoprotein particles.^114,115

4.3. Immunomodulating Therapies

Atherosclerosis is increasingly recognized as not merely a lipid disorder but a chronic inflammatory disease involving intricate interactions between cholesterol homeostasis and the immune system. Advances in immunology and preclinical models have illuminated the pivotal roles of both innate and adaptive immune systems in the pathogenesis of atherosclerosis.^116−118

The innate immune response in atherosclerosis is characterized by the activation of monocytes and macrophages, and the recruitment of neutrophils to the arterial wall.¹¹⁹ These cells recognize and respond to ox-LDL and other damage-associated molecular patterns (DAMPs), which accumulate within arterial plaques. Macrophages, in particular, play a dual role by phagocytosing ox-LDL and secreting inflammatory cytokines that further propagate local inflammation and plaque instability. Conversely, adaptive immunity contributes through the involvement of T cells and B cells within atherosclerotic lesions.¹²⁰ T cells, along with cells expressing major histocompatibility complex class II (MHC-II), are prevalent in atherosclerosis plaques, laying the groundwork for adaptive immunity within the atherosclerotic environment. Specifically, dendritic cells (DCs) located within the plaques act as first responders. These cells recognize disease-associated molecular patterns, such as the aberrant deposition of ox-LDL in the arterial wall, initiating an immune response.¹²¹ DCs, together with macrophages, process and present these antigens to T-cells, effectively phagocytosing ox-LDL as a defense mechanism. Epitopes presented on MHC-I and MHC-II molecules then facilitate the activation of CD8⁺ cytotoxic T cells and CD4⁺ helper T cells, which are pivotal in generating ox-LDL-specific T cells. Furthermore, B cells contribute to the humoral response by producing antibodies against ox-LDL, which may have both protective and pathogenic roles in atherosclerosis.¹²²

In the realm of immunotherapy for atherosclerosis, strategies are divided into passive and active approaches.¹²³ Passive immunotherapy involves the administration of therapeutic antibodies targeting key molecules implicated in atherosclerosis progression, such as targeting PCSK9. Aliclutumumab and eloxacinumab are examples of antibodies that neutralize PCSK9, thereby enhancing liver clearance of LDL and reducing plasma cholesterol levels.¹²⁴ However, these therapies are costly and require repeated administration, posing significant economic challenges for widespread use. In contrast, active immunotherapy aims to modulate the immune system more fundamentally by inducing tolerance to atherosclerosis-associated antigens. Tolerogenic vaccines are designed to induce regulatory T cells that suppress pro-inflammatory responses against self-antigens, thus preventing the chronic inflammation that drives plaque formation.¹²⁵ The development of these vaccines involves creating antigen-carrying particles that target dendritic cells, encouraging them to foster a regulatory rather than an inflammatory T cell response.

Despite rapid advances in preclinical vaccine development for atherosclerosis, successful translation into clinical trials remains elusive. The major challenges include achieving immune tolerance to autoantigens and preventing target-specific immunotoxicity.^126,127 With ongoing advancements in understanding the underlying biology and improvements in technological platforms, such as nanotechnology delivery systems and adjuvants, this field is poised for significant clinical breakthroughs. The future of atherosclerosis treatment through immunomodulation looks promising, with potential vaccine platforms that cater specifically to the unique needs of treating this complex disease.

4.4. Nanotechnology-Based Therapies

Recent advancements in nanotechnology have opened new horizons in the treatment of atherosclerosis by enhancing the efficacy and precision of therapeutic delivery systems. Nanomedicine, leveraging nanoscale materials, offers significant advantages over traditional drug delivery methods by enhancing pharmacokinetics and pharmacodynamics, thereby improving the therapeutic index of drugs.^128,129 Moreover, nanomedicine provides a versatile platform for delivering water-insoluble drugs and enables the codelivery of multiple therapeutic agents, optimizing treatment efficacy and minimizing adverse effects. Nanomedicine also excels in facilitating the intracellular delivery of a broad spectrum of therapeutic molecules, such as small molecules, peptides, proteins, and nucleic acids, including siRNA and mRNA therapies.^130,131 A diverse array of materials, including liposomes, polymers, and organic and inorganic biomimetic materials, are employed to formulate nanomedicines.^5,132 These materials are crafted into nanoplatforms with specialized functions such as therapeutic delivery systems, imaging contrast agents, and theranostics—integrating diagnosis and therapy into a single system.^133−135

The use of biocompatible materials like liposomes and polymers in nanoparticle construction minimizes the immune system’s response and reduces the potential toxicity of traditional therapies. Liposomes, particularly, have been utilized to encapsulate and deliver lipophilic statins directly to plaques, thereby enhancing drug retention at the site of action and reducing systemic side effects. This approach not only improves patient compliance but also the overall safety profile of the treatment. For instance, researchers have developed stable simvastatin-loaded liposomes that have demonstrated remarkable efficacy in promoting cholesterol efflux and exhibiting anti-inflammatory properties.¹³⁶ Similarly, biomimetic nanoparticles, which mimic biological structures, are another exciting area of nanomedicine. These nanoparticles can evade the immune system and selectively bind to atherosclerotic plaque due to their surface characteristics, which can be modified to mimic those of natural cells involved in atherosclerosis, such as macrophages or endothelial cells. An innovative example includes a macrophage membrane-coated nanoparticle containing rapamycin (RAPNPs), designed with a PLGA-based nanodelivery platform. This platform targets atherosclerotic plaques effectively, with a high drug loading rate and has shown to reduce plaque area significantly more effectively than free rapamycin, as shown in Figure 6.¹³⁷

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.

Additionally, inspired by various inorganic nanomaterials, photodynamic therapy, acoustodynamic therapy, and gas therapy have been explored as novel therapeutic approaches in the treatment of atherosclerosis. These methods leverage the unique properties of nanomaterials to activate therapeutic effects through light, sound, or gas-mediated mechanisms, offering innovative and potentially more effective treatments for atherosclerosis. As nanomedicine continues to evolve, the landscape of atherosclerosis treatment is expected to be transformed by the integration of these advanced technologies. The ongoing development and clinical integration of nanomedicines promise not only more effective therapeutic strategies but also a broader array of tools for clinicians to combat atherosclerosis and improve patient outcomes.

5. Digital Health Innovations in Atherosclerosis Management

In recent years, digital health technologies have emerged as a transformative force in the management and treatment of atherosclerosis, offering novel approaches to enhance patient care and clinical outcomes. Wearable devices, for instance, are increasingly utilized to monitor physiological parameters such as heart rate, blood pressure, and physical activity levels in real time. These devices enable continuous patient monitoring, which can help in early detection of cardiovascular anomalies potentially linked to atherosclerosis progression. Moreover, mobile health applications have revolutionized patient engagement and compliance by providing personalized diet and exercise recommendations, medication reminders, and easy access to health information, thereby facilitating lifestyle modifications that are crucial for atherosclerosis management. Telemedicine platforms further augment this landscape by allowing for remote consultations and follow-ups, which are particularly beneficial for patients in underserved areas or those requiring frequent monitoring. Collectively, these technologies not only improve the efficiency of healthcare delivery but also empower patients to take an active role in managing their health, potentially leading to better disease outcomes and reduced healthcare costs. The integration of these digital tools into clinical practice is poised to significantly impact the therapeutic strategies for atherosclerosis, making healthcare more proactive, personalized, and patient-centered.

6. Conclusion

Atherosclerosis remains a complex and multifaceted disease characterized by chronic inflammation and disruptions in lipid metabolism. Despite significant advances in understanding its pathophysiology and treatment, challenges persist in fully addressing this pervasive condition. The past decade has seen substantial progress in the managing atherosclerotic complications, extending life expectancy for many patients. However, current therapies often provide only symptomatic relief and fail to address the underlying disease mechanisms.

Looking to the future, gene therapy emerges as a particularly promising avenue for revolutionizing atherosclerosis treatment. By targeting the genetic underpinnings of the disease, these therapies aims not only to alleviate symptoms but also to halt or even reverse disease progression. Additionally, ongoing research into novel pharmacological targets continues to reveal potential pathways for innovative treatments. These include new classes of lipid-regulating drugs, advanced anti-inflammatory agents, and cutting-edge strategies that leverage the body’s immune response to combat plaque formation.

The successful integration of these emerging research findings into clinical practice is vital for the evolution of atherosclerosis management. However, several barriers must be overcome to achieve this integration. These includes the complexities of regulatory approvals, the high costs associated with drug development, and the necessity for extensive clinical trials to verify long-term safety and efficacy. Addressing these challenges demands a collaborative effort among researchers, clinicians, regulatory authorities, and the pharmaceutical industry to ensure that promising treatments transition from discovery to delivery efficiently.

Furthermore, the field of nanomedicine and precision medicine are set to play a crucial role in personalizing atherosclerosis treatment. These technologies offer the potential to enhance the delivery and efficacy of therapies and to tailor treatments to the individual genetic profiles and disease phenotypes of patients. Embracing such innovations could substantially improve outcomes for individuals affected by atherosclerosis.

In conclusion, while the journey toward fully understanding and treating atherosclerosis continues, the ongoing advancements in medical research and technology offer considerable hope. With a sustained commitment to research and development and a focused effort to surmount implementation hurdles, the coming decade could see transformative breakthroughs in combating this formidable disease.

Author Contributions

^§ Y.L. and K.L. contributed equally. The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

The authors declare no competing financial interest.