The Pathophysiology of Coronary Artery Disease

Abstract

Cardiovascular disease is among the most prevalent and morbid conditions worldwide. Coronary artery disease (CAD) is an important cause of cardiovascular disease and can range from mild to fatal conditions. There have been advancements within the field of cardiology to help serve patients and improve outcomes related to CAD. A key aspect of this is a fundamental understanding of the pathophysiology of CAD and applying it in multiple disciplines. Clinicians are better equipped to manage their patients and come up with focused treatment plans once they have a solid foundation of the disease. In this review, we aim to highlight the important pathophysiological mechanisms behind CAD to help aid clinician decision-making and foster future advancements to continue to improve outcomes.

Scientific knowledge of atherosclerosis has significantly evolved. Early 20th-century experiments established a critical association between cholesterol and fatty arterial lesions in arterial walls, while mid-century discoveries confirmed that lipids are central to the pathogenesis of atherosclerosis. ^{1 2}

Further advances have been made in understanding atherosclerotic disease progression, which can occur asymptomatically over decades, yet manifest as acute events, such as myocardial infarctions or cerebrovascular accidents. As researchers continue to identify these factors, the efficacy of primary prevention strategies is steadily improving. ³

A deep understanding of the pathophysiology underpinning atherosclerosis is crucial for clinicians. This review explores the microanatomy of arterial structures, cellular dynamics, and pathophysiological processes relevant to CAD.

Layers of the Coronary Arteries

Coronary arteries are composed of specialized trilaminar structures essential for maintaining continuous blood flow to the myocardium's high metabolic demands, each of which is further discussed below. ⁴

The Adventitia

The adventitia is the outermost layer of the arterial wall and is recognized for its role in arterial homeostasis and vascular pathology. The adventitia has a lower cellular density, primarily consisting of fibroblasts and mast cells. Furthermore, it often contains aggregates of lymphocytes known as tertiary lymphoid organs, which may play a role in localized periarterial immune responses. ^{5 6}

The Tunica Media

The tunica media, located between the intima and adventitia, serves as a key structural and functional layer of the arterial wall. In large elastic arteries, such as the aorta, the media consists of concentric layers of smooth muscle cells (SMCs) interspersed with an elastin-rich extracellular matrix (ECM), allowing for effective dampening of the pulsatile output of the heart. Under physiological conditions, medial SMCs exhibit low rates of proliferation and apoptosis, contributing to vascular stability. ECM turnover is similarly balanced, maintaining homeostasis. The tunica media is delineated from the adventitia by the external elastic lamina, which serves as a structural boundary between both layers.

The Tunica Intima

The tunica intima, the innermost layer of the arterial wall, is generally thin at birth. With advancing age, the intima becomes progressively thickened through the incorporation of SMCs and fibrillar collagens, primarily types I and III. These intimal SMCs contribute to ECM production, leading to diffuse intimal thickening. The proximal segment of the left anterior descending (LAD) coronary artery is particularly predisposed to developing a pronounced intimal layer, often referred to as an “intimal cushion.” This is evident even in the absence of a significant atherosclerotic burden. ⁷

Specialized Cell Types Essential for Maintaining Arterial Integrity and Function

Endothelial Cells

Endothelial cells (ECs) lining the arterial intima form a critical interface between circulating blood and the vessel wall. The endothelial surface is capable of sustaining blood in a fluid state during prolonged contact due to expression of heparan sulfate proteoglycans on the endothelial surface, which serve as cofactors for antithrombin III. ECs bind thrombin and promote its anticoagulant activity by activating proteins C and S. In the event of thrombus formation, the endothelium contributes to fibrinolysis through the localized production of tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator. Although ECs share a common developmental origin, they exhibit substantial heterogeneity in phenotype and function across different vascular beds. ^{8 9 10}

Smooth Muscle Cells

SMCs are essential for vascular tone regulation, structural integrity, and pathological remodeling. SMCs regulate regional blood flow, particularly at the level of muscular arterioles. In larger arteries affected by atherosclerosis, abnormal SMC contraction may contribute to vasospasm and compromised perfusion. SMCs can proliferate, migrate, and contribute to intimal hyperplasia. Conversely, SMC apoptosis or necrosis may destabilize atheromatous plaques or promote remodeling, thereby contributing to aneurysm formation. ¹¹

The predilection for atherosclerosis and maladaptive remodeling in specific regions, such as the proximal LAD coronary artery, or medial degeneration in conditions like Marfan syndrome, may reflect intrinsic differences in SMC lineage. Notably, SMC plasticity has been shown in murine models to extend to phenotypic transitions in which these cells acquire macrophage-like characteristics within atherosclerotic plaques. ^{12 13 14}

The Role of Low-Density Lipoprotein, High-Density Lipoprotein, and Triglycerides: The Importance of the Reverse Cholesterol Transport Pathway

Cholesterol is synthesized in the liver via the mevalonate pathway, with the rate-limiting step being Hydroxymethylglutaryl-CoA (HMG-CoA) reductase. Cholesterol eventually forms high-density lipoprotein (HDL) and low-density lipoprotein (LDL). ¹⁵

The relationship between blood cholesterol levels and CAD has been extensively studied. Data from the Framingham Study demonstrated a significant increase in the risk of CAD among patients with elevated cholesterol. ¹⁶ Subsequent studies highlighted the importance of specific cholesterol ratios, the atheroprotective effects of HDL, the atherogenic effects of LDL, and the clinical implications for patients. ¹⁷

The atheroprotective role of HDL is largely attributed to the reverse cholesterol transport pathway (RCTP), a critical mechanism for cholesterol homeostasis. The efflux of excess cholesterol from foam cells is facilitated by ATP-binding cassette (ABC) transporters. ATP-binding cassette transporter A1 (ABCA1) mediates cholesterol transfer to lipid-poor apolipoprotein A-I, while ATP-binding cassette transporter G1 (ABCG1) promotes further efflux of cholesterol and phospholipids into the bloodstream, forming nascent HDL particles. In the plasma, free cholesterol within nascent HDL is esterified by the enzyme lecithin:cholesterol acyltransferase, generating cholesteryl esters and eventual maturation of HDL. These cholesteryl esters are then delivered to the liver via two main mechanisms: Direct uptake of the cholesteryl esters from the mature HDL into the liver via the protein scavenger receptor class B type I (SR-B1) or transfer to apolipoprotein B (ApoB)-containing lipoproteins via the cholesteryl ester transfer protein (CETP). The RCTP results in a reduction of cholesterol accumulation in macrophages, thus mitigating the creation of foam cells and limiting inflammation ( Fig. 1 ). For every 1 mg/dL increase in HDL, there is a 2 to 3% decrease in cardiovascular risk, thus providing a key role in maintaining cholesterol homeostasis. ^{18 19}

Fig. 1.

Visual representation highlighting the atheroprotective role of HDL and the reverse cholesterol transport pathway. ApoB, apolipoprotein B; CETP, cholesteryl ester transfer protein; HDL, high-density lipoprotein; LCAT, lecithin:cholesterol acyltransferase; SR-B1, scavenger receptor class B type I.

In contrast, LDL promotes atherogenesis. LDL particles are derived from very low-density lipoproteins (VLDLs), which are synthesized in the liver and contain triglycerides (TGs), cholesterol, phospholipids, and apolipoproteins. Once in circulation, VLDL undergoes hydrolysis by lipoprotein lipase, generating intermediate-density lipoprotein, which is subsequently converted into LDL via the action of hepatic lipase. LDL particles present in excess can penetrate the endothelial barrier, become oxidized, and trigger a cascade of proinflammatory and proatherogenic changes ( Fig. 2 ). ²⁰ The pathophysiological implications of LDL in atherosclerosis are discussed in more detail in subsequent sections.

Fig. 2.

Visual representation of the generation of mature LDL from VLDL, which eventually will become oxidized in order to form highly atherogenic oxLDL. LDL, low-density lipoprotein; oxLDL, oxidized low-density lipoprotein; VLDL, very low-density lipoprotein.

TGs play a contributory role in atherogenesis. TGs are exchanged between VLDL and both HDL and LDL particles via CETP, resulting in TG-enriched HDL and LDL. These modified lipoproteins are subsequently hydrolyzed by hepatic TG lipase, generating small dense HDL (sdHDL) and small dense LDL (sdLDL). These sdHDL particles exhibit diminished capacity for cholesterol efflux, thereby impairing the efficiency of the RCTP. Likewise, sdLDL particles are prone to oxidation, thereby increasing atherogenic potential and accelerating plaque development. ^{15 20}

Inflammation as the Key Mediator to Atheroma Formation and the Importance of Oxidized Low-Density Lipoprotein

Inflammation plays a central role in atherogenesis and, therefore, it is important to understand the mechanisms contributing to the development of inflammation and the subsequent pathophysiology of CAD. ^{21 22}

The initial step in atheroma formation typically involves endothelial dysfunction. Risk factors include inflammation, oxidative stress, hyperlipidemia, and hypertension. ^{21 22} Endothelial dysfunction is characterized by an imbalance of vasodilators (e.g., nitric oxide and prostaglandin) and vasoconstrictors (e.g., endothelin). ^{23 24 25} The net effect is a diminished ability to regulate vascular tone, which may increase blood pressure and vascular resistance. ²² An example is the overproduction of reactive oxygen species (ROS), causing damage to ECs, diminishing the bioavailability of nitric oxide, and impairing the vasodilating properties of the endothelium.

A damaged endothelium releases inflammatory cytokines and adhesion molecules such as vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1), increasing permeability and allowing LDL to pass from the vascular lumen to the vascular intima. ^{23 24 25} In the intima, LDL undergoes oxidation via ROS produced from ECs. This produces a highly atherogenic molecule called oxidized low-density lipoprotein (oxLDL). OxLDL upregulates proinflammatory transcription factors, such as the nuclear factor kappa B (NF-kB) and mitogen-activated protein kinase (MAPK) pathways, which play an integral role in the inflammatory response ( Fig. 3 ). ²⁵ Monocytes migrate into the intima via monocyte chemoattractant protein-1 (MCP-1), undergoing differentiation into macrophages.

Fig. 3.

Visual representation showing the major steps involving atheroma formation, including initial endothelial dysfunction, proinflammatory cytokines, and oxidation of LDL. LDL, low-density lipoprotein; ROS, reactive oxygen species.

Macrophages ingest oxLDL, becoming foam cells that further secrete proinflammatory cytokines and matrix metalloproteinases (MMPs). ^{26 27 28 29} An accumulation of foam cells within the intima can result in the formation of fatty streaks, often the earliest visible sign of atherosclerosis.

In the intima, foam cells increase vascular SMC proliferation and help synthesize ECM components such as collagen and elastin. ^{23 24 25} The net effect is increased plaque growth and complexity. ²⁴ This causes a circular loop of increasing inflammation and endothelial dysfunction, facilitating accelerated atherosclerotic plaque formation.

B Cells and the Relationship with Atheroma Formation: A Complex Relationship That Continues to Require Further Study

The development of atherosclerotic plaques involves B cells, which play a complex role through antigen-specific adaptive immunity. B cells appear to have both proatherogenic and atheroprotective effects, depending on the type of B cell, and thus appear to be key regulators in the size and stability of plaques. ^{30 31 32 33}

B2 cells (follicular B cells) promote atherogenesis by differentiating into plasma cells that produce pathogenic IgG antibodies and proinflammatory cytokines such as TNF-alpha and IL-6. ^{30 31 32 33 34} This further activates ECs and macrophages, enhancing inflammatory cell recruitment and resulting in a perpetuating cycle of increasing inflammation. ³⁵ The mechanism involved in this process is achieved by B2 cells presenting ApoB peptides to CD4+ cells via the MHC-II. ^{36 37} B2 cells also form immune complexes with oxLDL, which bind to receptors on macrophages and monocytes, leading to activation and release of proinflammatory cytokines. ³⁷ This again exemplifies the positive feedback loop of inflammation.

In contrast, B1 cells (regulatory B cells) are considered to have an atheroprotective role by producing IgM antibodies that help scavenge oxLDL and apoptotic cells, mitigating foam cell formation. ^{31 32 33} Furthermore, they produce anti-inflammatory cytokines such as IL-10 and TGF-beta, which attenuate atherosclerotic progression. B1 cells also offer an atheroprotective role via clearance of apoptotic cells (efferocytosis), thereby limiting further inflammation within the plaque. ³⁸ B1 cells bind to apoptotic cells and necrotic debris, promoting phagocytosis and reducing the size of the necrotic core within plaques. ³³

Given this information, the key to plaque stability may be related to the balance between the proatherogenic and atheroprotective properties of B cells.

Factors and Mechanisms Related to Atherosclerotic Plaque Stability

The stability of atherosclerotic plaques is influenced by a complex interplay of inflammatory mediators, SMC migration/proliferation, oxLDL, and B cells. ^{28 33} An atherosclerotic plaque is composed of a lipid and/or necrotic core, covered by a fibrous cap of varying thickness. The composition and integrity of this fibrous cap are critical determinants of plaque vulnerability. Stable plaques are characterized by a thick, collagen-rich cap, while thin-capped atheroma are more prone to rupture and thrombotic events. ^{34 39}

As endothelial dysfunction progresses, there is a positive feedback loop of inflammation as described above. Monocyte maturation into macrophages behaves in either a proinflammatory (M1) or an anti-inflammatory (M2) manner. The ratio of M1 to M2 macrophages is associated with increased inflammation, thus leading to a more vulnerable fibrous cap. As macrophages phagocytose cellular components, they transform into foam cells, thus contributing to the lipid pool and necrotic core. ⁴⁰

Atherogenesis is a multifactorial process involving activated Th1 cells, which produce interferon-gamma, thus inhibiting SMC-mediated synthesis of collagen. Th1 cells additionally express a CD40 ligand that attaches to the CD40 receptor on M1 macrophages, stimulating increased production of MMPs. These MMPs degrade collagen and contribute to fibrous cap thinning. ^{23 39} Furthermore, SMCs demonstrate senescence, and as the cells die, the necrotic core grows and extends, resulting in further thinning of the fibrous cap. ⁴⁰

In contrast, Th2 cells and M2 macrophages promote fibrous cap stability. Activated Th2 cells secrete IL-4 and IL-13, stimulating M2 macrophages to secrete anti-inflammatory cytokines and profibrotic factors, including IL-10, TGF-beta, fibronectin, and IGF-1. These factors augment the production of interstitial collagens and stimulate SMCs to synthesize ECM components. Despite the promotion of tissue and plaque stabilization, some studies demonstrate increased cellular apoptosis and calcification, which increases plaque rupture risk. ^{23 39 40}

OxLDLs induce expression of ICAM-1 and VCAM-1, promoting adhesion and mitogenesis of macrophages. OxLDL is cytotoxic, resulting in SMC and foam cell apoptosis, and promotes necrotic core growth. As cellular debris increases, it becomes more difficult to clear, causing secondary necrosis. This chain reaction promotes inflammation and thinning of the fibrous cap, leading to plaque vulnerability. ^{29 32 39}

In summary, the stability of atherosclerotic plaques is multifactorial and determined by a meticulous balance of key contributing factors. Understanding these mechanisms and how they interact with each other is integral to developing targeted therapies that augment plaque stability and mitigate acute coronary events.

Pathophysiological Mechanisms Contributing to Rupture of an Atherosclerotic Plaque Resulting in Acute Coronary Events

The most pronounced stressor to the fibrous cap is considered to be circumferential stress from elevated blood pressure. The complex interaction between physiology, hemodynamics, vessel geometry, and plaque morphology leads to either maintenance or rupture of the fibrous cap. ⁴⁰ Thin fibrous caps are more likely to rupture, as they are less able to tolerate the aforementioned stressors, leading to acute coronary syndrome (ACS) and posing grave consequences for a patient. ⁴¹

Vascular calcification is an active deposition process that adds additional stresses to plaque stability. Calcium and phosphate are crystallized into hydroxyapatite, which deposits in the ECM of the arterial wall. Vascular calcification generally falls into one of two categories: Mönckeberg calcification and atherosclerotic calcification. Mönckeberg calcification typically involves the media and occurs in peripheral vessels, secondary to osteoblast-like cell activity from altered intracellular signaling pathways and calcium-sensing receptors. Atherosclerotic calcification occurs in the intimal layer and is driven by dysmorphic calcium precipitation in the setting of an inflammatory cascade, resulting in arterial remodeling. This causes endothelial dysfunction and abnormal vascular repair, which augments the necrotic core. ^{20 42}

Fibrous cap thinning involves excessive ECM degradation in the setting of proinflammatory mediators, causing a loss of tensile strength of the cap. ⁴⁰ The presence of microcalcifications can induce focal areas of mechanical stress, weakening fibrous cap stability further. ^{40 41 43}

The physiological mechanisms leading to thrombosis following rupture of an atherosclerotic plaque involve a series of complex interactions between exposed plaque, the coagulation cascade, and platelet aggregation. Atherosclerotic plaque rupture exposes the highly thrombogenic necrotic core to the bloodstream. Prothrombotic factors, including tissue factors and lipid debris, are released, triggering platelet activation and aggregation. Platelets bind to integrins, most notably glycoprotein IIb/IIIa, allowing further binding to fibrinogen and von Willebrand factor, promoting platelet cross-linking and thrombus formation. ³⁵ Platelets are activated and release their storage granule contents, including thromboxane A ₂ and ADP. Thromboxane A ₂ causes vasoconstriction and amplifies platelet recruitment and activation. ADP promotes platelet aggregation via the stimulation of G-protein coupled receptors, specifically the P2Y ¹ and P2Y ¹² receptors. This exposes glycoprotein IIb/IIIa-binding sites, further potentiating platelet aggregation. This sequence results in the formation of a platelet plug at the site of endothelial damage. ^{44 45}

Simultaneously, tissue factor initiates the coagulation cascade by acting on the extrinsic pathway. It binds to factor VIIa and converts factor X to Xa, eventually forming thrombin. ⁴⁴ Thrombin converts fibrinogen to fibrin, forming a mesh that stabilizes a growing thrombus. When thrombosis outpaces fibrinolysis, this can lead to obstruction and result in ACS.

Pharmaceuticals have already provided pharmacologic agents such as aspirin (inhibiting thromboxane A ₂ production), P2Y ₁₂ inhibitors (limiting ADP-induced platelet aggregation), and various antithrombotics. Further study is required to generate novel approaches that can improve patient outcomes.

Exceptional Cases of Rapid or Irregular Progression of Arterial Atherosclerosis

Cardiac Allograft Vasculopathy

Cardiac allograft vasculopathy (CAV) is a rapidly progressive fibroproliferative disease affecting the vasculature of transplanted hearts typically within the first year posttransplant. It is characterized by SMC proliferation, inflammatory cell accumulation, and lipid deposition, leading to circumferential intimal thickening. Resultant vascular inflammation, endothelial injury, and fibroproliferative responses trigger excessive tissue repair mechanisms, including vascular cell proliferation, fibrosis, and constrictive remodeling. Luminal narrowing occurs, with plaque composition evolving from early fibrous and fibrofatty tissue to an atheromatous necrotic core. CAV is diffuse and affects both epicardial and intramural vessels. ^{46 47}

The pathophysiology of CAV involves a complex interaction between immune and non-immune factors. Allograft ECs express foreign human leukocyte antigens (HLA) that are recognized by recipient T lymphocytes. Activated T lymphocytes secrete cytokines, stimulating T-lymphocyte proliferation and upregulating endothelial adhesion molecules, which leads to EC activation and inflammatory cell recruitment. Macrophages in the intima secrete cytokines and growth factors, causing SMC migration, proliferation, and ECM deposition. ⁴⁸ Studies have suggested that circulating HLA antibodies are associated with increased rejection and CAV development. ^{49 50 51}

Non-immune factors predisposing to CAV include vasculopathic risk factors, such as those described above. Cytomegalovirus (CMV) infection generates a proatherogenic environment by increasing asymmetric dimethylarginine, a competitive nitric oxide synthase inhibitor, which impairs endothelial nitric oxide synthase-mediated coronary. Furthermore, CMV molecular mimicry of EC surface molecules leads to immune-mediated endothelial injury. ^{52 53 54 55}

Currently, immunosuppressive medical therapy serves as the cornerstone for mitigating disease progression. Owing to the high baseline risk of myocardial ischemia in these patients, the threshold for invasive evaluation is notably low.

The advent of intravascular ultrasound (IVUS) and optical coherence tomography (OCT) has provided a more objective method for assessing the necessity for intervention in this select population. Both guide interventional approaches, with OCT emerging as a more reliable tool because of the comprehensive data it provides. ⁵⁶

Coronary Artery Aneurysms

Coronary artery aneurysms (CAAs) are rare anomalies characterized by a localized dilation of a coronary artery segment exceeding 1.5 times the diameter of adjacent segments. ⁵⁷ The reported incidence of coronary aneurysms ranges from 0.3 to 5%, with a predilection for men and proximal segments of the coronary bed. ⁵⁸ These are classified based on morphology and vessel wall structure using IVUS. ⁵⁹ While the exact mechanisms underlying the pathogenesis of CAA are not well-understood, evidence links risk factors such as coronary atherosclerotic disease, genetic predispositions, inflammatory disorders, and connective tissue disorders. ^{60 61 62} Previous studies have highlighted the critical role of pathological atherogenic alterations within the arterial walls, particularly in the intima. ⁶³ These changes trigger nitric oxide release, which promotes vasodilation, decreases coronary resistance to intraluminal pressure, and increases the artery's susceptibility to dilation and subsequent CAA formation. In conclusion, while CAAs are primarily associated with atherosclerosis, their low prevalence in this patient population highlights the possibility of alternative risk factors. Understanding these complexities is essential to optimizing management and care.

Coronary Artery Disease in Chronic Inflammatory States

The complex interplay between the immune system and inflammatory processes is crucial in the development of CAD. Once monocytes are recruited, they transform into macrophages and eventually evolve into foam cells. ⁶⁴ These inflammatory syndromes exhibit heterogeneous presentations of atherosclerotic disease, due to unique inflammation patterns. ^{65 66} Some of the most frequently encountered chronic inflammatory conditions by health care providers are listed.

1. Rheumatologic Diseases : Inflammatory arthritis syndromes (including rheumatoid arthritis, psoriatic arthritis, and spondyloarthritis) mediate systemic inflammatory effects through similar pathways, occurring from dysregulation of the innate and/or adaptive immune system. Additionally, those with spondyloarthritis are also prone to aortic root and valve involvement. ^{67 68 69 70} Systemic lupus erythematosus is historically known for its wide range of tissue involvement, leading to valvular, myocardial, pericardial, and vascular involvement in the heart. These processes ultimately result in accelerated atherosclerosis, microvascular disease, valvular heart disease, myocarditis, and pericarditis. ^{70 71 72}

2. Inflammatory Bowel Disease : The pathogenesis of atherosclerotic heart disease associated with inflammatory bowel disease (IBD) occurs through various mechanisms, complicating the clinical management of affected patients. IBD induces endothelial dysfunction via a cascade of inflammatory cytokines which promote EC apoptosis, elevate tissue factor and superoxide radical levels, and activate the complement cascade, resulting in impaired endothelial-dependent vasodilation and a prothrombotic state. IBD also promotes a hypercoagulable state via three primary mechanisms. First, IBD impairs fibrinolysis, as evidenced by decreased plasma t-PA and altered levels of plasminogen activators in the colonic mucosa. Second, it activates the coagulation cascade, driven by proinflammatory cytokines and increased tissue factors. Third, IBD leads to abnormal platelet function, characterized by reactive thrombocytosis, formation of platelet–leukocyte aggregates, and increased CD40 ligand levels on activated platelets. Together, these interconnected pathways create a proinflammatory and prothrombotic environment that increases the risk of venous and arterial thrombotic events. ⁷³

   Additionally, IBD-associated conditions, such as malnutrition, malabsorption, altered intestinal transit, and systemic inflammation, trigger significant lipid alterations. These are characterized by a decrease in HDL and an increase in LDL. The reduction in HDL levels is linked to decreased apolipoprotein-AI levels. Concurrently, increased LDL cholesterol levels are exacerbated by decreased LDL receptor levels and increased cholesterol synthesis by hepatocytes, collectively promoting atherosclerosis. ⁷³

3. Human Immunodeficiency Virus : Advancements in antiretroviral therapy (ART) have markedly improved the life expectancy of individuals living with human immunodeficiency virus (HIV). As longevity has increased, there has been a corresponding increase in the demand for cardiovascular care within this population and a deeper understanding of the complex immunopathogenic mechanisms inherent in HIV-associated cardiovascular disease. HIV induces endothelial dysfunction through various intricate mechanisms, such as increasing levels of circulating ROS, which directly damage ECs and reduce vasodilatory mediators, such as nitric oxide. ⁷⁴ Endothelial integrity is further compromised due to direct injury from an elevated burden of proinflammatory cytokines. Active viral replication has also been linked to a prothrombotic state, believed to occur due to abnormal platelet reactivity in association with high concentrations of circulating fibrinogen, factor VII, von Willebrand factor, and tissue factors. ⁷⁵ The introduction of ART has also led to dysregulated lipid metabolism by decreasing adiponectin and glucose uptake, which translates to insulin resistance, dyslipidemia, and inflammation. ^{74 75}

Conclusion

Understanding the intricate mechanisms underlying CAD is essential for advancing both preventive and therapeutic strategies. This review has explored the multifaceted biology of atherosclerosis, including lipid metabolism, inflammation, immune system contributions, and the structural dynamics that govern plaque formation, stability, and rupture. Central to disease progression is a complex interplay between endothelial dysfunction, oxidized lipoproteins, inflammatory cytokines, SMC phenotype switching, and immune cell recruitment. These processes drive the transformation from stable plaques to vulnerable ones, which can lead to ACS events through rupture and thrombosis. Additionally, the role of adaptive immunity—especially B-cell subtypes—highlights novel areas for targeted therapy. Moving forward, deeper insights into the molecular and cellular players involved in CAD will guide the development of the next generation of therapeutic interventions. These interventions include targeted anti-inflammatory therapies, lipid-lowering agents tailored to individual risk profiles, and immunomodulatory strategies. Continued research in both native and transplant-associated coronary disease is essential to reduce cardiovascular morbidity and mortality globally.