Atherosclerosis: Open Access
Open Access

Atherosclerosis; Chronic inflammatory disease; Cholesterol; Cardiovascular disease; Statins; PCSK9 inhibitors; Inflammation; Endothelial dysfunction; Clinical trials

Introduction

Atherosclerosis stands as the primary culprit behind the development of cardiovascular disease (CVD), a leading global cause of morbidity and mortality. CVD encompasses a range of conditions affecting the heart and blood vessels, including coronary artery disease, stroke, and peripheral arterial disease [1,2]. Among these conditions, ischemic heart disease (IHD), commonly known as coronary artery disease, remains a significant contributor to cardiovascular-related morbidity and mortality. Atherosclerosis is a complex and insidious disease process characterized by the gradual accumulation of lipids, inflammatory cells, and fibrous tissue within the walls of large and medium-sized arteries. The process typically begins in childhood and slowly progresses throughout life, eventually leading to the formation of atherosclerotic plaques [3]. These plaques are the hallmark feature of atherosclerosis and represent localized areas of thickening and hardening of arterial walls. The key players in atherosclerosis development are lipids, particularly low-density lipoprotein (LDL) cholesterol, and inflammatory cells, such as macrophages and T lymphocytes. The arterial endothelium, which lines the inner surface of blood vessels, plays a pivotal role in regulating lipid transport and inflammatory processes within the arterial wall. The development of atherosclerotic plaques starts with endothelial dysfunction, triggered by various risk factors like hypertension, smoking, hypercholesterolemia, and diabetes [4-7]. In this dysfunctional state, the endothelium loses its ability to maintain a healthy vascular environment, allowing LDL cholesterol particles to penetrate the arterial intima, the innermost layer of the arterial wall. Once inside the arterial intima, LDL cholesterol undergoes oxidative modifications, rendering it highly reactive and pro-inflammatory. These oxidized LDL particles attract circulating monocytes, which migrate into the arterial wall and differentiate into macrophages. Within the intima, macrophages internalize the oxidized LDL cholesterol and become engorged, transforming into lipid-laden foam cells. The accumulation of foam cells within the arterial wall leads to the formation of fatty streaks, the earliest visible manifestations of atherosclerosis [8]. Over time, the fatty streaks evolve into more complex atherosclerotic plaques, characterized by the deposition of fibrous tissue, smooth muscle cells, and additional inflammatory cells. The interplay between inflammation and lipid metabolism plays a central role in the pathogenesis of atherosclerosis. Inflammatory mediators released by macrophages and other immune cells further propagate the inflammatory response, leading to increased oxidative stress and promoting further plaque progression. As the atherosclerotic plaques grow, they can eventually obstruct blood flow through the affected arteries. In some cases, these plaques can rupture, leading to the exposure of prothrombotic substances within the plaque’s core. This exposure triggers the formation of blood clots, or thrombi, which can partially or completely block blood flow downstream, resulting in ischemic events. If a thrombus forms within a coronary artery, it can cause a myocardial infarction (heart attack). When a thrombus develops within an artery supplying the brain, it can lead to an ischemic stroke. Peripheral vascular disease occurs when atherosclerosis affects arteries in the limbs, causing reduced blood flow and potentially leading to pain, tissue damage, and even limb loss. In conclusion, atherosclerosis is a multifaceted and chronic disease process that plays a central role in the development of cardiovascular disease. The progressive accumulation of lipids and inflammatory cells within arterial walls leads to the formation of atherosclerotic plaques, which can ultimately obstruct blood flow or rupture, causing severe cardiovascular complications. Understanding the complex interplay between inflammation and lipid metabolism in atherosclerosis is critical for developing effective prevention and treatment strategies to mitigate the burden of cardiovascular disease worldwide. Continued research and advancements in medical therapies hold the promise of improving patient outcomes and reducing the global impact of atherosclerosis and its associated cardiovascular events.

Atherosclerosis and inflammation: Atherosclerosis, once considered solely a lipid storage disorder, is now increasingly recognized as a chronic inflammatory disease. The early stages of atherosclerosis involve endothelial dysfunction, a process initiated by various risk factors, such as hypertension, smoking, hypercholesterolemia, diabetes, and other conditions that promote oxidative stress. The endothelium, a thin layer of cells that lines the inner surface of blood vessels, plays a crucial role in maintaining vascular homeostasis [9]. Under normal circumstances, the endothelium regulates vascular tone, inhibits platelet aggregation, promotes vasodilation, and prevents the adherence of circulating immune cells and LDL cholesterol particles to the arterial wall. However, when exposed to risk factors like hypertension or excessive oxidative stress, the endothelium’s functionality becomes impaired. Endothelial dysfunction allows circulating LDL cholesterol particles to penetrate the normally impermeable endothelial barrier and infiltrate the arterial intima, the innermost layer of the arterial wall. Once inside the arterial intima, LDL cholesterol particles undergo oxidative modifications. Oxidized LDL (oxLDL) is highly reactive and triggers an immune response, recruiting inflammatory cells to the site of arterial injury. Notably, monocytes and T lymphocytes play a pivotal role in the inflammatory response within the arterial wall. Monocytes are white blood cells that migrate from the bloodstream into the arterial intima in response to chemotactic signals produced by endothelial cells and macrophages. Once within the arterial wall, these monocytes differentiate into macrophages [10,11]. Macrophages play a central role in atherosclerosis development by taking up and storing the oxLDL cholesterol, thus becoming lipid-laden foam cells. Accumulation of foam cells and the release of pro-inflammatory cytokines by activated macrophages further amplify the inflammatory response within the arterial wall. The cytokines released by these immune cells include interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factoralpha (TNF-α). These pro-inflammatory cytokines contribute to endothelial dysfunction, enhance the recruitment of more immune cells, and promote smooth muscle cell proliferation, exacerbating the progression of atherosclerosis. As the inflammatory response intensifies, the immune cells and lipids form a lipid-rich core surrounded by a fibrous cap within the atherosclerotic plaque. The fibrous cap consists of smooth muscle cells, collagen, and other extracellular matrix components [12]. This structure is inherently unstable and prone to rupture. When an atherosclerotic plaque ruptures, its lipid-rich core is exposed to the bloodstream, triggering the formation of a blood clot or thrombus. The formation of a thrombus can further obstruct blood flow in the affected artery or embolize to other vessels, causing lifethreatening events such as myocardial infarctions or strokes.

Role of LDL cholesterol in atherosclerosis

Elevated levels of LDL cholesterol have long been identified as a major risk factor for atherosclerosis. LDL cholesterol is responsible for transporting cholesterol from the liver to peripheral tissues, including the arterial wall. When LDL cholesterol accumulates within the arterial intima, it undergoes oxidative modifications, becoming highly atherogenic. As discussed earlier, oxLDL cholesterol plays a critical role in the initiation and propagation of the inflammatory response in the arterial wall. The infiltration of oxLDL and its subsequent uptake by macrophages lead to foam cell formation, which is a hallmark of early atherosclerotic lesions known as fatty streaks. The accumulation of foam cells within the arterial wall initiates the formation of atherosclerotic plaques. As these plaques grow, they can obstruct blood flow and produce ischemic conditions in the affected organs. Moreover, the rupture of these plaques exposes their lipidrich core to the bloodstream, setting the stage for thrombotic events. Reducing LDL cholesterol levels has emerged as a key therapeutic strategy for preventing and managing atherosclerosis and its associated cardiovascular complications [13]. Statins, the most widely prescribed drugs for managing cholesterol, act by inhibiting HMG-CoA reductase, a crucial enzyme in the cholesterol synthesis pathway. By reducing hepatic cholesterol production, statins effectively lower LDL cholesterol levels in the bloodstream, thus mitigating the risk of atherosclerosis and its associated adverse cardiovascular events. In recent years, the development of PCSK9 inhibitors has provided a novel and potent approach for LDL cholesterol management. PCSK9 inhibitors are monoclonal antibodies that target proprotein convertase subtilisin/ kexin type 9 (PCSK9), a protein that regulates the degradation of LDL receptors. Inhibition of PCSK9 leads to increased LDL receptor expression on hepatocytes, resulting in enhanced LDL clearance from the bloodstream and a dramatic reduction in LDL cholesterol levels [14]. In conclusion, atherosclerosis is increasingly recognized as a chronic inflammatory disease in which endothelial dysfunction, oxidative stress, and inflammatory cells play pivotal roles. Elevated LDL cholesterol levels, especially when oxidatively modified, contribute significantly to atherosclerotic plaque formation and progression. Thus, targeting LDL cholesterol through interventions like statins and PCSK9 inhibitors represents a crucial therapeutic strategy for preventing and managing atherosclerosis and reducing the burden of associated cardiovascular complications. Continued research and advancements in these areas hold the potential to revolutionize the management of atherosclerosis and improve patient outcomes worldwide.

Statins as LDL cholesterol-lowering agents: Statins, also known as HMG-CoA reductase inhibitors, are a well-established class of drugs widely used for managing elevated LDL cholesterol levels. LDL cholesterol, often referred to as “bad cholesterol,” is a major contributor to atherosclerosis, making it a prime target for therapeutic intervention in cardiovascular disease management. The primary mechanism of action of statins lies in their ability to inhibit HMG-CoA reductase, an essential enzyme involved in the early stages of cholesterol synthesis. By inhibiting this enzyme in the liver, statins decrease the production of cholesterol within hepatocytes, the liver cells. As a result, the liver takes up more LDL cholesterol from the bloodstream to compensate for the reduced cholesterol synthesis, leading to a significant decrease in circulating LDL cholesterol levels [15]. Beyond their potent LDL cholesterol-lowering effects, statins have been found to exhibit pleiotropic effects, meaning they have additional beneficial actions beyond cholesterol reduction. Some of these pleiotropic effects include anti-inflammatory properties and improvements in endothelial function. Chronic inflammation plays a critical role in atherosclerosis development, contributing to plaque progression and instability. Statins have been shown to dampen inflammatory processes within the arterial wall, reducing the production of pro-inflammatory cytokines and the recruitment of inflammatory cells. By mitigating the inflammatory response, statins help stabilize atherosclerotic plaques, reducing the risk of plaque rupture and thrombotic events. Moreover, statins have been found to enhance endothelial function, improving the endothelium’s ability to regulate vascular tone, inhibit platelet aggregation, and promote vasodilation. These endothelial benefits contribute to better vascular health and reduced risk of endothelial dysfunction, which is a key early step in atherosclerosis development. The pleiotropic effects of statins, combined with their potent LDL cholesterol-lowering capabilities, contribute to their overall cardiovascular benefits. These benefits extend beyond simply reducing cholesterol levels and encompass improved plaque stability, decreased inflammation, and enhanced endothelial function, all of which contribute to a reduced risk of major adverse cardiovascular events (MACE).

PCSK9 inhibitors and LDL cholesterol management: PCSK9 inhibitors represent a relatively newer class of drugs that have shown tremendous promise in managing LDL cholesterol levels. PCSK9, short for proprotein convertase subtilisin/kexin type 9, is a protein that plays a crucial role in regulating LDL receptor recycling on the surface of hepatocytes. LDL receptors on hepatocytes are responsible for removing LDL cholesterol from the bloodstream by endocytosis. However, PCSK9 binds to these receptors and induces their degradation, reducing the number of LDL receptors available for LDL clearance. This process leads to elevated LDL cholesterol levels in the bloodstream, contributing to atherosclerosis development. PCSK9 inhibitors work by blocking PCSK9’s function and preventing it from interacting with LDL receptors. As a result, more LDL receptors remain available on the hepatocyte surface, leading to increased uptake and clearance of LDL cholesterol from the bloodstream. By enhancing LDL receptor recycling and reducing LDL cholesterol levels, PCSK9 inhibitors offer a potent means of managing hypercholesterolemia. Clinical trials evaluating PCSK9 inhibitors have consistently demonstrated their efficacy in significantly lowering LDL cholesterol levels. When used as an adjunct to statin therapy in individuals with familial hypercholesterolemia or high cardiovascular risk, PCSK9 inhibitors have shown impressive results in achieving LDL cholesterol reductions beyond what statins alone can achieve. Furthermore, the profound reduction in LDL cholesterol levels achieved with PCSK9 inhibitors has translated into notable cardiovascular benefits in clinical studies. These benefits include a substantial reduction in major adverse cardiovascular events (MACE), such as myocardial infarctions (heart attacks), strokes, and cardiovascular mortality.

Clinical evidences: Numerous clinical trials have been conducted to assess the efficacy and safety of both statins and PCSK9 inhibitors in managing LDL cholesterol levels and reducing MACE. Statin trials, such as the landmark HPS (Heart Protection Study) and PROVE-IT TIMI 22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy- Thrombolysis In Myocardial Infarction 22) trials, have consistently shown that statin therapy significantly lowers LDL cholesterol levels and leads to a reduction in cardiovascular events. These trials have been instrumental in establishing statins as a cornerstone of cardiovascular disease management. Similarly, clinical trials evaluating PCSK9 inhibitors, such as FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk), have demonstrated the efficacy of PCSK9 inhibitors in further reducing LDL cholesterol levels and reducing MACE in patients at high cardiovascular risk. The combination of statins and PCSK9 inhibitors has shown even more potent LDL cholesterol-lowering effects and cardiovascular benefits. These therapies have revolutionized the management of hypercholesterolemia and have proven to be valuable additions to the armamentarium of cardiovascular disease management strategies. In conclusion, both statins and PCSK9 inhibitors have emerged as effective and vital therapies for managing LDL cholesterol levels and reducing major adverse cardiovascular events. Statins act by inhibiting HMGCoA reductase and reducing hepatic cholesterol production, while PCSK9 inhibitors target PCSK9 to enhance LDL receptor recycling and enhance LDL cholesterol clearance. The combination of their LDL cholesterol-lowering effects and pleiotropic benefits makes these therapeutic approaches indispensable in preventing and managing atherosclerosis and its associated cardiovascular complications, ultimately improving patient outcomes.

Discussion

Atherosclerosis stands as a complex and chronic inflammatory disease that lies at the heart of cardiovascular disease progression. Elevated LDL cholesterol plays a pivotal role in the pathogenesis of atherosclerosis, emphasizing its significance as a crucial therapeutic target in managing cardiovascular risk. The therapeutic approaches of statins and PCSK9 inhibitors have demonstrated remarkable efficacy in reducing LDL cholesterol levels and mitigating major adverse cardiovascular events, marking significant advancements in atherosclerosis management. Statins’ pleiotropic effects, including anti-inflammatory properties and endothelial function improvement, complement their LDL cholesterol-lowering abilities, contributing to their overall cardiovascular benefits. Furthermore, PCSK9 inhibitors offer a promising avenue for achieving profound reductions in LDL cholesterol levels by targeting the PCSK9-LDL receptor axis, providing an innovative approach to combating hypercholesterolemia and its associated complications. However, the journey towards optimal atherosclerosis management does not end here. Continued research and clinical trials are imperative to deepen our understanding of the long-term safety and efficacy of these therapeutic agents. By gaining further insights into potential side effects and identifying patient populations that would benefit most from these treatments, we can refine our therapeutic approaches and maximize patient outcomes.

Moreover, the pursuit of novel targets and interventions holds great promise for advancing atherosclerosis management in the future. Precision medicine and personalized therapies may offer tailored approaches to address the diverse manifestations and risk profiles of patients with atherosclerosis.

Conclusion

In summary, atherosclerosis remains a major global health challenge, necessitating relentless efforts to uncover new insights and therapeutic strategies. By focusing on reducing elevated LDL cholesterol levels through agents like statins and PCSK9 inhibitors, medical practitioners can forge a path towards improved treatment outcomes and enhanced cardiovascular risk reduction. Through continued research, we aspire to make significant strides in combating atherosclerosis, reducing its burden on individuals and societies, and ultimately, promoting heart health and well-being worldwide.

Acknowledgement:

Not applicable.

Conflict of Interest:

Author declares no conflict of interest.

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