The role of inflammatory response in the development of atherosclerosis, myocardial infarction, and remodeling

INTRODUCTION

Atherosclerotic, a chronic inflammatory disease affecting large and medium-sized arteries, is a significant contributor to cardiovascular morbidity and mortality worldwide. Despite the importance of controlling risk factors like hypertension, diabetes, dyslipidemia, and cigarette smoking, it is crucial to understand and investigate the pathophysiology behind atherosclerosis. This chronic inflammatory process primarily affects coronary, cerebral, and peripheral vessels. The importance of inflammation in atherosclerosis is further highlighted by the fact that patients with inflammatory conditions such as rheumatoid and other inflammatory arthritis are at significantly higher risk of developing cardiovascular disease^[1]. Traditionally, atherosclerosis was viewed as a process of lipid accumulation, mainly driven by low-density lipoprotein (LDL) in the arterial intima^[2]. However, recent evidence from the last 25 years suggests that atherogenesis is an active inflammatory response involving both innate and adaptive immune responses, rather than a passive cholesterol accumulation process^[3]. The initiation of atherosclerosis is controversial, with theories proposing lipid deposition followed by oxidation and leukocyte recruitment, or leukocyte attachment to inflamed endothelial cells, leading to lipid accumulation and macrophage foam cell formation^[4,5]. Macrophage foam cells not only serve as a reservoir, but also as a source of proinflammatory and inflammatory mediators such as interleukins (IL) and tumor necrosis factor-α (TNF-α), which promote atherosclerotic plaque progression, mineralization and rupture^[6].

This atherosclerotic process progresses over years and patients are usually asymptomatic during this phase. When the plaque size exceeds the capacity of the artery to accommodate outwards, the arterial lumen becomes narrow, leading to flow restriction and/or potential complications such as acute coronary syndrome due to plaque rupture or erosion. Matrix metalloproteinases secreted by macrophages cause the destruction of the extracellular matrix within the plaque, resulting in a weak fibrous cap that is prone to rupture^[7]. Additionally, T-cell-mediated interferon gamma (IFN-γ) secretion from within the plaque inhibits collagen synthesis, further predisposing plaques to rupture. In several studies, toll-like receptor 2 (TLR-2) signaling has been implicated in plaque erosion by altering endothelial function^[8,9].

In addition to the role of inflammation in atherosclerosis and myocardial infarction (MI), inflammation plays a crucial role in cardiac remodeling. As a result of myocardial ischemia, apoptotic and necrotic myocardial cells activate immune cells to repair damaged tissue, leading to an initial inflammatory response followed by a healing phase characterized by fibroblast activation and the release of anti-inflammatory mediators to promote tissue repair and scar formation^[10]. This reparative phase is characterized by fibroblast activation and proliferation in addition to the release of inhibitory mediators such as IL-10 and transforming growth factor (TGF) to suppress inflammation and promote a profibrotic environment^[11]. Understanding the complex interplay between inflammation, immune responses, and plaque stability is crucial in developing targeted therapies to prevent atherosclerotic plaque progression and reduce the risk of acute cardiovascular events like MI. Further research into the molecular and cellular mechanisms underlying atherosclerosis initiation, progression, and plaque destabilization is essential for advancing preventive and therapeutic strategies in cardiovascular medicine. This review will delve into the pivotal role of inflammatory responses in the development of atherosclerosis, myocardial infarction, and cardiac remodeling.

ATHEROSCLEROSIS, INFLAMMATION, AND THE ROLE OF THE IMMUNE RESPONSE

Atherosclerotic cardiovascular disease has a complex and incompletely understood pathogenesis, which extends beyond mere cholesterol accumulation in arterial intima^[12-14]. Recent research indicates that chronic vascular inflammation, coupled with both innate and adaptive immune responses, contributes to the development of this disease^[15]. A hallmark of atherosclerosis is leukocyte recruitment and penetration of endothelial cells (EC), mainly macrophages and monocytes, through leucocyte adhesion molecules (LAM) on the surface of the EC^[16] such as vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1). This recruitment and invasion process has its roots in a complicated chain of biological responses. Oxidation of LDL secondary to hypertension, diabetes, or smoking, in combination with endothelial activation, triggers an immune response resulting in upregulation of these LAM, attracting more macrophages and monocytes to take up oxidized LDL and become foam cells^[17]. This process is mediated by scavenger receptors, particularly scavenger receptor A (SR-A) and CD36, which recognize and internalize oxidized LDL^[18]. This is followed by the secretion of chemokines and growth factors by both the ECs and macrophages to induce proliferation in the smooth muscle cells (SMC), which stimulates the formation of atheroma. Activated SMCs become fibroblasts, fibro-myocytes, and osteoblast-like cells^[19]. These cells receive stimuli from platelet-derived growth factor and TGF-β secreted by T cells for collagen production, which contributes to fibrous cap formation. Furthermore, neutrophils increase tissue damage and enhance plaque vulnerability by initiating SMC lysis and death^[20]. Cytokines, specifically TNF-α, IL-1B, IL-6, and IFN-γ, are not mere bystanders in this process. They play an integral role in every stage of atherogenesis - from the initial endothelial activation phase all through to plaque rupture. This underlines the importance of these small protein molecules in inflammation and immune responses, signifying them as potential therapeutic targets for combating atherosclerotic disease^[17].

INFLAMMATION AND MYOCARDIAL INFARCTION

Acute coronary syndrome is often a consequence of a plaque rupture or ulceration within the coronary vessels. Studies have identified specific features of vulnerable plaques that predispose them to rupture, such as a necrotic core exceeding 30% of the plaque, a thin fibrous cap (< 65 µm), and significant infiltration of inflammatory cells like lymphocytes and macrophages^[21].

The enlarged necrotic core is due to a lack of collagen with an accumulation of cholesterol in the center, likely due to the death of foam cells and release of the large lipid content. Necrotic cells leak intracellular components, which triggers an inflammatory response; one of these components is high-mobility group box 1 (HMGB1) molecules^[22]. These molecules bind to TLR2 and TLR4, stimulating macrophages to release proinflammatory cytokines such as IL-1α, IL-1β, IL-6, and TNF-α, which in return causes more necrosis^[23,24]. The stability of the plaque is dependent on a balance between the formation and degradation of the fibrous cap; if the breakdown of the ECM and collagen exceeds their formation, a thin fibrous cap is formed, which has a higher chance of rupture^[19].

Thrombosis is activated upon fibrous cap rupture, superficial erosion, and coronary vasospasm. Fibrous cap rupture is the most common and accounts for 76% of men and 55% of women with fatal MI^[25]. When plaque disruption occurs, thrombogenic substances will be exposed, triggering thrombus formation on the affected area^[26]. It can be silent if the thrombosis is not occlusive; however, completely occlusive thrombi leads to myocardial injury in the area supplied by the occluded artery.

Moreover, studies suggest a link between sympathetic nervous system activation and myocardial infarction, with beta-adrenergic stimulation promoting emergency hematopoiesis, leucocyte migration, and mobilization, thereby contributing to the inflammatory response and myocardial healing^[27,28]. In addition, it increases leucocyte migration and mobilization from medullary and extramedullary reservoirs. This emergency hematopoiesis will participate in the inflammatory response caused by myocardial ischemia and also aid in myocardial healing. This intricate interplay between inflammation, plaque vulnerability, and thrombosis underscores the multifaceted pathophysiology of myocardial infarction.

INFLAMMATION AND REMODELING

Cardiac remodeling post MI is a multifaceted process extending over months or even years that can significantly alter the structure and functionality of the heart^[29]. This process has substantial prognostic implications due to its close association with heart failure. Inflammation is an essential component of tissue healing but has also been linked to pathological remodeling and the development of structural and functional changes.

Immediately after MI, ischemia leads to a rapid buildup of intracellular calcium, sodium, and hydrogen, resulting in tissue acidosis. This induces energy depletion through mitochondrial damage and triggers the release of proapoptotic signals to initiate and maintain the inflammatory process that later aids in the remodeling process^[30].

Repair post MI can be categorized into three overlapping phases: the inflammatory phase, the proliferative phase, and the maturation phase^[31]. During the inflammatory phase, apoptotic and necrotic cells, along with the damaged extracellular matrix, initiate an inflammatory cascade reaction, leading to the release of cytokines and chemokines^[32]. Subsequently, more leucocytes get attracted to the inflammatory site to aid in the clearing dead cells and digesting extracellular matrix tissue. During the proliferative phase, macrophages and fibroblasts secrete extracellular matrix proteins to restore structural integrity and start scar formation. Switching from the activation to the suppression of inflammatory signals is not a passive process; it likely requires the intervention of inhibitory molecules that activate suppressive pathways^[33]. Finally, during the maturation phase, scar maturation takes place due to the deactivation of reparative cells and the withdrawal of the fibrogenic growth factors.

Prolonged inflammation or defective suppression can have catastrophic consequences, such as loss of myocyte contractility, leading to chamber dilation, which can subsequently progress to heart failure^[31]. The fibrotic response after MI can be divided into two types: replacement and reactive fibrosis. Although initial reparative fibrosis is important for preventing myocardial wall rupture, exaggerated or reactive fibrosis due to excessive deposition of extracellular matrix (ECM) can result in organ distortion and disruption of cardiac function^[34]. This is defined as pathological remodeling, in which the ECM expansion leads to hypertrophy of cardiac myocytes as a trial to compensate for the increased workload by increasing in size to improve myocardial function and decrease ventricular wall tension^[35].

CARDIOVASCULAR TREATMENT FOR INFLAMMATION AND FUTURE DIRECTIONS

It is currently an ongoing challenge to overcome the adverse effects of pathological remodeling post MI. Medications like angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and aldosterone antagonists are used in clinical practice for the treatment of the chronic phase of remodeling^[36]. However, little is known regarding therapies targeting the acute phase of remodeling. Recently, colchicine has emerged as a potential treatment (due to its anti-inflammatory properties) to reduce cardiovascular events in patients with chronic coronary and acute coronary syndromes^[37-39]. The 2023 AHA/ACC/ACCP/ASPC/NLA/PCNA Guideline for the Management of Patients with Chronic Coronary Disease suggests that in patients with chronic coronary disease, the addition of colchicine for secondary prevention may be considered to reduce recurrent cardiovascular events^[40,41]. Another novel anti-inflammatory agent, Ziltivekimab, a monoclonal antibody that targets interleukin-6, is being tested in the Specifying the Anti-inflammatory Effects of Ziltivekimab (SPIDER) trial [ClinicalTrials.gov ID - NCT06263244]. Many studies propose gene therapy for the prevention and treatment of cardiac remodeling, such as B-type natriuretic peptide gene delivery, which has been used to prevent cardiac remodeling in rats^[42]. Other therapies such as glucagon-like peptide and insulin-like growth factor were shown to exert anti-remodeling effects in animal models^[43,44].

Recent advancements in nanomedicine research have brought to light significant progress in nanoparticle drug delivery systems, particularly in the realm of diagnosing and treating atherosclerosis. The evolution of imaging technologies has broadened the scope of research from merely identifying existing atherosclerotic plaque in symptomatic patients to characterizing asymptomatic vulnerable plaque. Nanotechnology is proving to be instrumental in the field of cardiovascular disease by facilitating the targeted accumulation of nanoparticles within atherosclerotic lesions, thereby enabling a meticulous molecular-level analysis of delicate markers and the early detection of vulnerable plaque^[45].

Drug nanocarriers are commonly employed, either encapsulating drugs within their structures or on their surfaces. Various imaging nanoparticles (NPs) such as iron oxide, perfluorocarbon, gadolinium, and gold nanoparticles offer diagnostic capabilities for diverse cardiovascular conditions^[46]. Beyond their diagnostic utilities, NPs hold immense potential for therapeutic applications. For instance, the successful integration of Rapamycin into leukosome nanoplatforms has demonstrated a significant reduction in proinflammatory cytokine levels and the inhibition of macrophage proliferation, thereby reshaping plaque morphology in mouse models^[47,48]. Moreover, in contexts beyond atherosclerosis, certain NPs like cerium oxide have shown efficacy in mitigating oxidative stress post-myocardial infarction in murine models, thereby reducing the incidence of post-MI remodeling^[49]. The constant progress in nanotechnology and nanomedicine heralds a promising future for the landscape of clinical treatments, ushering in new prospects for personalized and targeted healthcare interventions.

CONCLUSION

This review article illuminates the role of inflammation in atherosclerosis, myocardial injury, necrosis, and cardiac remodeling. The multifaceted pathophysiology of myocardial infarction underscores the intertwined roles of inflammation, plaque vulnerability, and thrombosis. Insights into the role of the immune response in atherosclerosis and inflammation highlight potential therapeutics for combating atherosclerotic disease. A meticulous understanding of post-MI cardiac remodeling processes can guide prognostic implications and the management of heart failure. Although chronic inflammatory disease indeed presents a complex and formidable challenge, it also suggests a broad and promising field for the development of innovative and efficient treatments.