Targeted Anti‐Inflammatory Therapy in Cardiovascular Events: Challenges and Opportunities

ABSTRACT

Cardiovascular diseases (CVDs) remain the leading cause of morbidity and mortality globally. Emerging evidence suggests that inflammation plays a pivotal role in the pathogenesis of atherosclerosis and subsequent cardiovascular events. Traditional treatments primarily focus on lipid‐lowering and antithrombotic strategies; however, these approaches do not fully address the inflammatory component of CVD. Recent advancements have highlighted the potential of targeted anti‐inflammatory therapies in mitigating cardiovascular risk. This review explores the efficacy and safety of these novel therapeutic agents. Interleukin (IL)‐1β inhibitors, such as canakinumab, have shown promising results in reducing recurrent cardiovascular events in post‐myocardial infarction patients. By directly modulating inflammatory pathways, canakinumab significantly lowered the incidence of major adverse cardiovascular events (MACE) independent of lipid levels. Similarly, colchicine, an ancient anti‐inflammatory drug, has gained renewed interest due to its efficacy in reducing cardiovascular events in patients with chronic coronary disease and recent myocardial infarction. Furthermore, emerging therapies targeting other inflammatory mediators like IL‐6 and tumor necrosis factor‐α are under investigation, offering additional avenues for intervention. Despite these advancements, challenges such as identifying appropriate patient populations, long‐term safety, and cost‐effectiveness remain. Ongoing research aims to refine these therapies, ensuring a balance between risk reduction and adverse effects. In conclusion, targeted anti‐inflammatory therapy represents a promising adjunct to traditional CVD treatments, potentially revolutionizing the management of cardiovascular events. Future studies are essential to optimize these strategies and fully integrate them into clinical practice, enhancing outcomes for patients with CVD.

1. Introduction

Cardiovascular diseases (CVDs) encompass a range of conditions affecting the heart and blood vessels, including coronary artery disease, heart failure, and stroke. These diseases are the leading cause of morbidity and mortality worldwide, accounting for a significant portion of healthcare burden and economic costs [1]. Traditional treatment strategies have primarily focused on lipid‐lowering therapies, such as statins, and antithrombotic agents, including aspirin and anticoagulants [2]. These approaches aim to reduce cholesterol levels and prevent blood clots, respectively, thereby mitigating the risk of heart attacks and strokes [3, 4]. However, emerging evidence has underscored the critical role of inflammation in the pathogenesis of atherosclerosis (AS), a key underlying process in many cardiovascular events [5].

The disease starts with endothelial dysfunction, which increases adhesion molecules expression and the permeability that facilitates the retention of immune cells. Monocyte‐derived macrophages generate foam cells by taking up modified low‐density lipoproteins (LDLs) which accumulate, forming fatty streak lesions, and perpetuate inflammation by producing cytokines such as interleukin (IL)‐6 and tumor necrosis factor alpha (TNF‐α). In middle stages, various mediators induce a change in the phenotype of vascular smooth muscle cells (VSMCs), which become proinflammatory, migratory and proliferative and form the fibrous cap. The recruited T cells in lesions coordinate the adaptive immune response and exert diverse effects. Pro‐atherogenic T helper‐1 (Th‐1) are highly proinflammatory, Th‐2 is associated with secretion of anti‐inflammatory cytokines. Regulatory T (Treg) cells, a minor subpopulation of CD4+T lymphocytes, have anti‐inflammatory properties and suppress the activity of effector T cells. Th‐17, mostly associated with chronic inflammation, has been suggested to be pro‐atherogenic and a low Treg/Th‐17 cellular ratio promotes acute coronary syndrome.1 In later stages, proinflammatory cytokines TNF‐α, interferon‐γ (INF‐γ), and IL‐1 induce apoptosis in VSMCs and macrophages, destabilizing plaques. These processes lead to an unresolved inflammatory chronic state generating unstable plaque lesions, which are a key feature of ischemic events. Acute‐phase reactants, such as C‐reactive protein (CRP), increase in patients with coronary artery disease and are known to predict adverse outcomes [6, 7].

Despite the effectiveness of traditional treatments in addressing lipid levels and thrombotic risks, they do not fully target the inflammatory processes that are crucial in CVD development and progression [8]. In recent years, significant progress has been made in identifying and developing pharmacological agents that specifically target inflammatory pathways implicated in CVD [9]. Notably, IL‐1β inhibitors, exemplified by canakinumab, have demonstrated remarkable efficacy in reducing recurrent cardiovascular events [10]. Canakinumab's ability to lower the incidence of major adverse cardiovascular events (MACE) without altering lipid levels underscores the therapeutic potential of directly modulating inflammatory responses in post‐myocardial infarction patients [11, 12]. Additionally, colchicine, a long‐standing anti‐inflammatory drug traditionally used for gout, has garnered renewed interest for its cardiovascular benefits [13]. Clinical trials have illustrated colchicine's efficacy in decreasing cardiovascular events among patients with chronic coronary disease and recent myocardial infarction [14, 15]. These findings support the broader applicability of anti‐inflammatory strategies beyond traditional lipid‐lowering approaches [16]. Emerging therapies targeting other inflammatory mediators, including IL‐6 and TNF‐α, are currently under investigation, offering further potential for therapeutic intervention [17]. However, the integration of these therapies into clinical practice faces challenges, including the identification of suitable patient populations, evaluation of long‐term safety, and considerations of cost‐effectiveness [18].

This review aims to critically assess the current landscape of targeted anti‐inflammatory therapies in CVD, focusing on their efficacy, safety, and potential to complement existing treatment modalities. By exploring the advancements and ongoing research in this field, we seek to elucidate the promise and limitations of these innovative therapies in enhancing cardiovascular outcomes.

2. Rationale for Targeted Anti‐Inflammatory Therapy

2.1. Limitations of Traditional Therapies

The onset and progression of coronary atherosclerotic heart disease are believed to be linked to various risk factors, such as hypertension, hyperlipidemia, diabetes mellitus, and smoking, among others [19, 20]. Effective prevention and management of coronary heart disease (CHD) can be achieved through the stringent control of these risk factors [21]. CVD treatments, primarily focused on lipid‐lowering and antithrombotic strategies, have significantly reduced the incidence of major cardiovascular events. Statins and other lipid‐lowering agents effectively reduce cholesterol levels, while antithrombotic agents such as aspirin and anticoagulants prevent blood clot formation [22]. However, a previous study demonstrated that even among low‐risk populations lacking notable risk factors, a significant portion still developed coronary atherosclerotic heart disease [23]. Additionally, standard treatment following percutaneous coronary intervention (PCI) did not effectively halt the progression of non‐offending coronary plaque [24]. Consequently, the treatment of coronary artery disease requires further refinement.

Inflammation is pivotal in every stage of AS, from plaque formation to rupture. Conditions characterized by chronic inflammation, such as rheumatism and gout, are significantly more prone to coronary atherosclerotic heart disease [25]. Analyses of randomized human trials have shown that patients with coronary artery disease can gain additional benefits from lowering LDL cholesterol (LDL‐C) by also reducing inflammation risk [26, 27, 28]. However, traditional therapies often fail to target the underlying inflammatory processes that contribute to plaque instability and subsequent cardiovascular events. As a result, many patients continue to experience recurrent events despite optimal lipid control and antithrombotic therapy, highlighting a significant unmet need in the current treatment paradigm [29, 30]. Thus, researchers have conducted a series of clinical trials on inflammation and coronary artery disease. Anti‐inflammatory therapy might become an important tool for optimizing existing coronary drug therapy.

2.2. Emergence of Anti‐Inflammatory Strategies

The recognition of inflammation's central role in CVD has spurred the development of targeted anti‐inflammatory therapies. These strategies aim to directly modulate the inflammatory pathways involved in AS and cardiovascular events, offering a novel and complementary approach to existing treatments [31]. Recent clinical trials have provided compelling evidence for the efficacy of specific anti‐inflammatory agents in reducing cardiovascular risk. For example, IL‐1β inhibitors, such as canakinumab, have demonstrated significant reductions in recurrent cardiovascular events in post‐myocardial infarction patients [32]. This indicates that targeting inflammation can provide substantial cardiovascular benefits independent of lipid levels. Other anti‐inflammatory agents, like colchicine, have also shown promise. Traditionally used to treat gout, colchicine has been found to reduce cardiovascular events in patients with chronic coronary disease and those who have recently experienced a myocardial infarction. These findings highlight the therapeutic potential of repurposing existing anti‐inflammatory drugs for cardiovascular protection [33]. The emergence of these targeted anti‐inflammatory therapies represents a significant advancement in the management of CVD. By addressing the inflammatory component of AS, these treatments offer new avenues for reducing cardiovascular risk, particularly in patients who remain at a high risk despite optimal traditional therapy. As research continues, these strategies may become integral to comprehensive cardiovascular care, improving outcomes for millions of patients worldwide.

3. Key Anti‐Inflammatory Agents in CVD

3.1. IL‐1β Inhibitors

One of the most promising advancements in targeted anti‐inflammatory therapy for CVD involves the inhibition of IL‐1β, a pro‐inflammatory cytokine implicated in the pathogenesis of AS. Numerous studies have demonstrated the significant impact of IL‐1β on AS [34, 35]. First, both the protein and mRNA levels of IL‐1β are markedly elevated in patients with AS compared to healthy individuals, and these levels are positively correlated with disease severity [36, 37]. Additionally, the increased susceptibility to AS associated with clonal hematopoiesis in peripheral blood cells is regulated, at least in part, by the NLRP3/IL‐1β pathway [38, 39].

IL‐1β plays a critical role in all stages of AS [34, 40]. It induces an inflammatory response in endothelial cells, marked by increased expressions of adhesion factors and chemokines, promoting the accumulation and invasion of inflammatory cells into the vessel intima, a key event in the initiation of AS [41]. Adhesion molecules include intercellular inflammatory cytokines (ICAM‐1) and vascular cell adhesion molecule (VCAM‐1), while chemokines such as monocyte chemoattractant protein‐1 (MCP‐1) recruit mononuclear phagocytes and are closely linked to AS. IL‐1β also stimulates the proliferation and differentiation of VSMCs, activates monocytes and macrophages, and promotes the secretion of various inflammatory mediators [42]. It enhances the gene expression of several inflammatory mediators, creating a positive feedback loop with IL‐1 itself, induces cyclooxygenase‐2 (COX‐2) formation leading to prostaglandin production, and stimulates the production of IL‐6 and matrix metalloproteinases (MMPs) [43]. IL‐6 mediates the acute phase response, increasing acute‐phase reactants like CRP, fibrinogen, and plasminogen activator inhibitors, all closely associated with atherosclerotic thrombosis formation. MMP1, MMP8, and MMP13, known as collagenases, contribute to the rupture of atherosclerotic fibrous cap plaques by breaking down collagen [44]. Additionally, IL‐1β impairs myocardial contractility and exacerbates post‐infarction reperfusion injury [45]. It plays a crucial role in the progression of established atheromas. In experimental models, selective neutralization of IL‐1β has been shown to promote a switch of monocytes to a less inflammatory state, increase plasma levels of IL‐10, and reduce atherosclerotic plaque size without affecting compensatory outward remodeling of the artery [46].

The role of IL‐1β is closely linked to its signal transduction, so inhibiting this pathway may help alleviate AS. Several molecules can inhibit IL‐1β signal transduction [47]: (1) IL‐1Ra competitively binds to IL‐1R1, blocking IL‐1β or IL‐1α. While IL‐1Ra binds tightly to IL‐1R1, it cannot recruit IL‐1Racp (IL‐1R3) to form TIR dimers, thereby preventing intracellular signaling. (2) IL‐1R2 acts as a decoy receptor, binding to IL‐1α or IL‐1β and recruiting IL‐1R3. Structurally similar to IL‐1R1 but lacking an intracellular domain, IL‐1R2 cannot form TIR dimers and thus does not mediate intracellular signaling. (3) Soluble receptors can bind IL‐1β without mediating intracellular signaling. Although no mature bait receptor or soluble receptor is currently available, this remains a potential approach. Additionally, animal experiments and clinical trials have explored various drugs targeting IL‐1β for the treatment of AS, including Anakinra, monoclonal antibodies, vaccines, and rilonacept.

3.2. TNF‐α Inhibitors

TNF‐α antagonists were developed for the treatment of rheumatoid arthritis and there are five biological drugs that target TNF: infliximab, etanercept, adalimumab, certolizumab, and golimumab. Retrospective studies in rheumatoid arthritis patients under TNF‐α blocking therapies have provided support for considering these drugs as anti‐inflammatory agents for CVD [48].

Serious adverse effects have been shown for TNF‐α inhibitors, such as increases in total, LDL, and high‐density lipoprotein (HDL) cholesterol and triglycerides [49]. While long‐term infliximab therapy might be proatherogenic, etanercept and adalimumab can exert beneficial effects on lipid levels [50]. TNF‐α is a potent proinflammatory and proatherogenic cytokine, which, by binding to its receptor, activates NFκB and p38 mitogen‐activated protein kinases, inducing the transcription of proinflammatory genes in atheroma plaque cells, lymphocytes, macrophage, endothelial cells, and VSMCs [51]. TNF‐α can influence plaque vulnerability by promoting apoptosis of endothelial cells and proliferation of VSMCs [52]. In mouse models, treatment of apoE (‐/‐) mice with TNF‐α‐binding protein reduced plaque development and double deficiency in TNF‐α and apoE diminished atherosclerotic plaque formation [53]. Consistently, mice deficient in TNF receptors showed reduced vascular recruitment of immune cells and decreased AS in LDL receptor‐deficient mice [54].

Rheumatoid arthritis patients are at increased risk of the development of AS and have a two‐fold risk of myocardial infarction [55]. Observational cohort studies with patients showed that the incidence of CVD is lower in patients receiving anti‐TNF‐α therapy than in those receiving alternative treatments [56]. In psoriasis patients, treatment with anti‐TNF‐α inhibitors was associated with decreased intima‐media thickness (IMT) [57]. In rheumatoid arthritis patients, use of etanercept or adalimumab diminished aortic inflammation and inversely correlated with aortic stiffness [58]. Long‐term TNF‐α blockade decreased pulse wave velocity and carotid IMT in participants with inflammatory arthropathies and acute CVD in participants with rheumatoid arthritis [59]. A systematic review in participants with rheumatoid arthritis and psoriatic arthritis treated with TNF‐α antagonists showed decreased subclinical AS and arterial stiffness [60]. In in vitro studies, human serum from adalimumab‐treated rheumatoid arthritis participants improved cholesterol transport in THP1 macrophages, increased serum HDL levels, and increased scavenger receptor class B type I‐mediated cholesterol efflux, thereby showing anti‐atherosclerotic activity by preventing foam cell formation [61].

3.3. IL‐6 Inhibitors

IL‐6 is a key mediator of inflammation involved in many processes, including AS and rheumatic diseases and is a unique pleiotropic cytokine, exhibiting both pro‐ and anti‐inflammatory properties depending on the target cell type. Prospective studies have shown a detrimental effect of IL‐6 receptor (IL‐6R)‐dependent signaling on CVD. Thus, loss‐of‐function of IL‐6R polymorphisms results in reduced CVD [62]. IL‐6 blockade therapies, tocilizumab and sarilumab, tested in the MONARCH and MOBILITY rheumatoid arthritis clinical trials, reported efficacy as rheumatoid arthritis therapy in patients at a high risk of CVD [63].

Tocilizumab is a monoclonal antibody of IL‐6R approved for use in combination with other antirheumatic drugs or as monotherapy in patients with rheumatoid arthritis and other related diseases [64]. Tocilizumab blocks the binding of IL‐6 to the IL‐6R, preventing inflammatory manifestations of elevated IL‐6 and decreasing disease severity. Although tocilizumab causes significant perturbations in lipid and cholesterol homeostasis, such as increases in LDL and total cholesterol, it also displays beneficial effects on surrogate markers of vascular risk [65]. A recent multicenter population‐based cohort study showed no evidence of increased cardiovascular risk among rheumatoid arthritis patients treated with tocilizumab [66]. Other clinical trials with a large cohort of rheumatoid arthritis patients receiving tocilizumab in a post‐marketing setting have shown low rates of major adverse CVD [67].

3.4. Canakinumab: Mechanism and Effects

Canakinumab received approval from the U.S. Food and Drug Administration (FDA) in 2009 for the treatment of cryopyrin‐associated periodic syndromes (CAPS) [68]. Subsequently, in 2016, it was approved for three types of spontaneous inflammatory diseases: TNF receptor‐associated periodic syndrome (TRAPS), hyper immunoglobulin D syndrome (HIDS)/mevalonate kinase (MKD), and familial Mediterranean fever (FMF) [69].

Regarding clinical outcomes, Canakinumab Anti‐inflammatory Thrombosis Outcomes Study (CANTOS) trial, presented at the 2017 Annual Meeting of the European Association for Cardiology, provided confirmation of the inflammation hypothesis. In this trial, 10 061 volunteers with CRP levels > 2 mg/L after previous second‐line preventive treatment for myocardial infarction were randomly assigned to either a placebo group or canakinumab treatment groups at dosages of 50 , 150 , or 300 mg. Subcutaneous injections were administered once every 3 months. Patients treated with 150 mg of canakinumab experienced a 15% lower incidence of primary clinical endpoints, including non‐fatal myocardial infarction, non‐fatal stroke, and cardiovascular death, despite a slight increase in infections compared to those in the placebo group. In a pre‐specified secondary analysis of trial results, the compound primary endpoint was reduced by 25%, while all‐cause and cardiovascular mortality were reduced by 31% in patients treated with canakinumab [70].

CANTOS provided robust evidence for the cardiovascular benefits of IL‐1β inhibition. In this large, randomized, double‐blind, placebo‐controlled trial, canakinumab significantly reduced the incidence of MACE in post‐myocardial infarction patients. Importantly, these benefits were observed independently of changes in lipid levels, underscoring the unique anti‐inflammatory mechanism of canakinumab. The CANTOS trial marked a pivotal step in validating inflammation as a therapeutic target in CVD and highlighted the potential of IL‐1β inhibitors in reducing cardiovascular risk [70]. Unexpectedly, canakinumab demonstrated a reduction in inflammation but triggered the development of plaque instability in apoE (‐/‐) mice [71]. Despite the apparent protective effect of IL‐1β against AS in this context, several considerations need to be addressed. First, there often exist discrepancies between findings from animal experiments and outcomes of clinical trials for targeted drugs, owing to differences in physiological and pathological processes between animal models and human diseases. Experiments utilizing non‐high‐fat or restrictive high‐fat diets have frequently demonstrated that the IL‐1β signaling pathway could promote AS [72]. Second, insights from earlier animal experiments on IL‐1Ra suggest that IL‐1β plays a more crucial role in the early stages of AS, whereas the animal model in this instance represents a later stage. Thirdly, in this experiment, macrophages were observed to polarize toward the M2 phenotype. Additionally, when the SMC‐specific IL1r1 gene was knocked out, a reduction in atherosclerotic plaque occurred; however, it is inevitable for various cells to decrease during this process, and a reduction in smooth muscle cells (SMCs) is not necessarily indicative of adverse effects. Thus, the role of IL‐1β in AS is still believed to be detrimental in anti‐inflammatory treatment. Apart from CANTOS, other off‐target therapies have also been explored. For instance, statins, typically used to lower LDL‐C levels, have consistently shown to reduce vascular inflammation [73].

3.5. Colchicine: Historical Use and Renewed Interest

Colchicine, an ancient anti‐inflammatory drug traditionally used to treat gout, has gained renewed interest for its potential cardiovascular benefits [74]. Colchicine primarily accumulates in neutrophils, exerting its effects primarily by binding to tubulin monomers. This binding prevents the formation of heterodimers of microtubulin, crucial for cell division, signal transduction, regulation of gene expression, and migration [75]. Other anti‐inflammatory actions of colchicine include inhibiting monosodium urate (MSU)‐induced NLRP3 inflammasome activity in macrophages [76], altering adhesion molecule expression in endothelial cells and neutrophils [77], thereby reducing neutrophil adhesion and recruitment into inflamed joints, and inhibiting a characteristic protein tyrosine phosphorylation pattern induced when neutrophils are exposed to MSU crystals [78]. A key concern with colchicine is its narrow therapeutic index. Serum concentrations of colchicine poorly correlate with efficacy because its anti‐inflammatory effects primarily result from intracellular accumulation. Effective steady‐state plasma concentrations range from 0.5 to 3 µg/L, with toxic effects occurring at approximately 3 µg/L [79]. Excessive intake of colchicine can lead to severe, often fatal poisoning. Therefore, it is crucial for both health care providers and patients prescribed colchicine to understand the risks and ensure its safe storage and use [74].

Inflammation has emerged as a key player in AS and various other cardiovascular disorders, prompting the exploration of anti‐inflammatory therapies to enhance cardiovascular outcomes. Among these, colchicine, a well‐established treatment for conditions like gout and familial Mediterranean fever, has garnered attention as a promising novel anti‐inflammatory agent in the realm of CVDs [80]. Its ability to address both conventional risk factors and residual inflammatory risk signifies a notable advancement in cardiovascular prevention strategies, marking a new era in cardiovascular care. Moreover, its endorsement by major cardiovascular societies underscores its significance as the first targeted anti‐inflammatory therapy for CVD. Nonetheless, vigilant monitoring for potential drug interactions and adverse effects, especially concerning kidney and liver function, remains imperative for ensuring safe utilization [81]. The interest in colchicine as a cardiovascular therapy stems from its well‐established safety profile and its broad anti‐inflammatory effects, which could potentially mitigate AS‐related inflammation (Figure 1).

FIGURE 1.

Colchicine affects interleukin 1β/interleukin 6 pathway through NLRP3 inflammasome. Colchicine prevents assembly of NLRP3 inflammasome in cells by inhibiting the function of microtubules, thus reducing the maturation and release of IL‐1β and further reducing release of IL‐6 from various types of cells.

The Colchicine Cardiovascular Outcomes Trial (COLCOT) and the Low‐Dose Colchicine 2 (LoDoCo2) trial have provided significant evidence supporting the efficacy of colchicine in reducing cardiovascular events [82, 83]. In the COLCOT trial, low‐dose colchicine (0.5 mg daily) significantly reduced the incidence of MACE in patients who had recently experienced a myocardial infarction [84]. Similarly, the LoDoCo2 trial demonstrated that low‐dose colchicine reduced cardiovascular events in patients with chronic coronary disease [85]. Clinical evidence from studies such as the Low‐Dose Colchicine for Secondary Prevention of Cardiovascular Disease and the Colchicine Cardiovascular Outcomes Trial supports the efficacy of colchicine in reducing major cardiovascular events following acute coronary syndrome, although findings from some studies vary. While colchicine can induce transient gastrointestinal side effects, it is prescribed cautiously in patients with specific medical conditions. The recent FDA approval of a low dose of colchicine reaffirms its benefit in reducing cardiovascular risk. Furthermore, the cost‐effectiveness of colchicine products at doses of 0.5  and 0.6 mg is compared, suggesting that the generic 0.6 mg dose of colchicine serves as a viable alternative to branded formulations of the drug [86]. These trials highlight colchicine's potential as a cost‐effective and accessible anti‐inflammatory therapy for reducing cardiovascular risk.

In summary, both IL‐1β inhibitors like canakinumab and traditional anti‐inflammatory drugs like colchicine have shown substantial promise in reducing cardiovascular events through targeted anti‐inflammatory mechanisms. These agents represent important additions to the therapeutic arsenal for managing CVD, addressing the inflammatory component that traditional therapies often overlook.

4. Emerging Therapies and Targets

4.1. Other Inflammatory Mediators

As the role of inflammation in CVD becomes increasingly recognized, a variety of novel therapeutic targets and agents are being explored. Beyond IL‐1β and colchicine, other inflammatory mediators are under investigation, offering new avenues for intervention. IL‐6 is another cytokine that plays a critical role in the inflammatory process associated with AS.

In vascular biology, IL‐6 is released by macrophages, monocytes, and other cell types relevant to atherothrombosis, such as fibroblasts and endothelial cells, typically in response to IL‐1 stimulation [87, 88]. Interactions involving IL‐6 signaling are intricate and can manifest in one of three modalities [89]. Generally, therapeutic strategies targeting IL‐6 are categorized into three interlinked groups, progressing sequentially deeper into what has been termed a cytokine funnel [89]: direct inhibition of IL‐6, targeting receptors like IL‐6R or gp130, or focusing on downstream kinases or transcription factors within the JAK‐STAT (Janus kinase signal transducer and activator of transcription) pathway. These approaches have been harnessed using therapeutic monoclonal antibodies, currently applied in various immunologic conditions such as rheumatoid arthritis, systemic lupus erythematosus, ulcerative colitis, Crohn's disease, and psoriasis, all conditions associated with elevated rates of atherothrombotic disease. Elevated levels of IL‐6 are linked to increased cardiovascular risk. Targeting IL‐6 directly or its receptor has shown potential in reducing inflammation and improving cardiovascular outcomes.

In mice, IL‐6 exhibits various effects, including enhancing peripheral blood platelet counts, inducing thrombocytosis, modulating endothelial‐dependent relaxation, influencing vascular monocyte differentiation, and impacting obesity and metabolism. Additionally, IL‐6 can induce tissue factor surface expression on monocytes, resulting in enhanced monocyte procoagulant activity [90], which seems reversible upon IL‐6 elimination. Other procoagulant effects include the induction of plasminogen activator inhibitor type 1 (PAI‐1) as part of the acute phase response, as well as the inverse regulation of antithrombin and protein S, leading to a prothrombotic state. At the vessel wall, IL‐6 has been shown to upregulate cell adhesion molecules [91], potentiate vascular permeability, and cause sustained loss of endothelial barrier function [92].

In a related trial, a single dose of the IL‐6R antagonist tocilizumab administered before angiography in 117 non‐acute ST‐segment elevation myocardial infarction (NSTEMI) patients showed reduced area under the postischemia CRP curve, along with a modest reduction in PCI‐related troponin release [93]. A subsequent study of these patients using aptamer‐based proteomics revealed that tocilizumab modified five additional proteins associated with the acute phase response, monocyte chemoattraction, and neutrophil function [94]. In another study involving 400 individuals undergoing elective PCIs, preprocedural administration of colchicine attenuated the increase in IL‐6 and hsCRP but did not clearly reduce the risk of PCI‐related myocardial injury [95]. Inclacumab, a monoclonal antibody targeting P‐selectin, has also demonstrated modest efficacy in reducing post‐PCI troponin release [96].

Looking back, these non‐STEMI data expand on insightful clinical observations from the randomized FRISC trial (Fragmin and Fast Revascularisation During Instability in Coronary Artery Disease II trial) conducted in unstable angina 20 years ago, wherein individuals with elevated IL‐6 levels significantly benefited from an early invasive reperfusion strategy, leading to reduced mortality, while those with lower IL‐6 levels did not [97]. Preliminary studies suggest that tocilizumab may also reduce inflammatory markers and improve outcomes in patients with CVD. Ongoing trials are assessing its efficacy and safety in this new context.

TNF‐α is a pro‐inflammatory cytokine involved in systemic inflammation and has been implicated in AS. Sustained inflammation plays a crucial role in AS, as certain cytokines, notably TNF‐α and IL‐6, have been demonstrated to influence lipid levels, shifting them toward an atherogenic profile [98]. Additionally, other cytokines like IFN‐γ and TNF‐α can modulate the permeability of vascular endothelial cells to macromolecules such as LDL, while activated endothelial cells release chemokines and other cytokines to recruit immune cells, particularly monocytes and T‐lymphocytes, to the lesion site [99]. Furthermore, TNF‐α, IL‐4, and IL‐13 are known to promote LDL oxidation by monocytes/macrophages, and IFN‐γ stimulates macrophage foam cell formation by enhancing the uptake of modified LDL and reducing cholesterol efflux [100]. Various growth factors produced by macrophages, endothelial cells, and T‐cells regulate the migration and proliferation of SMCs. Additionally, other pro‐inflammatory cytokines such as IFN‐γ and TNF‐α influence plaque vulnerability by inducing the apoptosis of macrophages and SMCs. Lastly, certain pro‐inflammatory cytokines like TNF‐α and IL‐6 suppress natural anticoagulant mechanisms such as the protein C pathway, thereby favoring coagulation [98]. Inhibiting TNF‐α can potentially reduce the inflammatory burden in CVD. Etanercept and Infliximab TNF‐α inhibitors are primarily used to treat autoimmune conditions like rheumatoid arthritis and inflammatory bowel disease [101, 102]. Some studies indicate potential cardiovascular benefits, but their use in CVD is still under investigation. Safety concerns, particularly related to infection risk, need to be carefully evaluated.

Monocyte chemoattractant protein‐1 (MCP‐1), also known as CCL2, recruit's monocytes to sites of inflammation in the vascular wall, contributing to AS [103]. Bindarit is a drug that inhibits MCP‐1, reducing monocyte recruitment and subsequent inflammation [104]. Preclinical studies have shown promising results in reducing atherosclerotic lesions, and clinical trials are underway to evaluate its effectiveness in human subjects [105].

4.2. Novel Therapeutic Agents

The NLRP3 inflammasome, commonly activated by crystal or particle pathogen damage‐associated molecular patterns (PAMPs) and ischemic hypoxia danger‐associated molecular patterns (DAMPs), is known to promote the secretion of IL‐1β and IL‐18 [106]. Through these mechanisms, it contributes to the development of AS, CHDs, and heart ischemia‐reperfusion (I/R) injury [107]. Therefore, the NLRP3 inflammasome likely plays a crucial role in the pathophysiology of CVDs, acting as a proinflammatory mediator. Inhibiting the NLRP3 inflammasome has the potential to reduce inflammation at its source (Figure 2).

FIGURE 2.

Mechanisms of NLRP3 inflammasome activation.

Clinical trials have validated the potential of IL‐1β and its receptor antagonist for treating various CVDs [108, 109], while the commonly prescribed drug glyburide has demonstrated significant efficacy in CVD treatment by inhibiting the NLRP3 inflammasome [110]. Hence, research into the NLRP3 inflammasome promises to elucidate the pathogenesis of CVDs and offer crucial insights for identifying new targets in the development of clinical drugs for CVDs.

MCC950 is small‐molecule inhibitor targets the NLRP3 inflammasome, showing promise in preclinical models of AS. Clinical trials are needed to determine its efficacy and safety in patients with CVD [111, 112]. While primarily known for their antiplatelet effects, P2Y12 receptor antagonists also have anti‐inflammatory properties [113]. Ticagrelor, besides its role in platelet aggregation, has been found to reduce inflammatory markers. Its dual action makes it a promising candidate for reducing both thrombotic and inflammatory components of CVD [114, 115].

4.3. MicroRNAs and Gene Therapy

The progress in genetic manipulation techniques and their application in cardiovascular biology has revealed the pivotal role of small RNAs, particularly microRNAs (miRNAs), as dynamic regulators of disease pathogenesis. These molecules are recognized as central players in gene expression regulation through diverse mechanisms, offering opportunities for the development of biomarkers and therapeutic interventions for AS. Circulating miRNAs, enclosed within membrane‐surrounded vesicles originating from various subcellular compartments, are now emerging as novel regulators of intercellular communication. Both freely circulating and vesicle‐bound forms of miRNAs serve as valuable tools for diagnosing and monitoring CVDs, recently termed as “liquid biopsy” [116]. Modulating specific miRNAs presents a promising approach to mitigating inflammation. However, despite the recent advancements in miRNA‐based diagnostics and therapeutics, understanding how miRNAs can regulate AS is still crucial to achieving an effective intervention and reducing the disease burden (Figure 3).

FIGURE 3.

MiR‐based therapeutics and delivery strategies in cardiovascular disease. The manipulation of miRNAs can be achieved by using various methods. The expression of pathogenic miRNAs can be inhibited by using an antagomiR or through the expression of protective miRs that can be upregulated by using a miRNA‐mimic. Moreover, miRNA sponges can be used to occupy miRNA‐binding sites, whereas BlockmiR can be used to inhibit the target sites. Recently, some alternative miRNA‐therapeutics have been introduced, which demonstrated that “caged” antagomiRs, which can be activated by light, can be used to target therapeutic miRs and to heal vessels. Alternatively, therapeutic miRs can be conjugated to a cell‐specific aptamer or cell‐specific ligand, which increases cellular uptake and stability.

4.4. Gut Microbiota Modulation

The gut microbiota has the capacity to influence and be influenced by virtually all known cardiovascular risk factors. Patients with arterial hypertension often exhibit a lower diversity in their gut microbiota, with increased abundance of Clostridial and Bacteroides species observed in both male individuals and mouse models of hypertension [117]. In the Coronary Artery Risk Development in Young Adults (CARDIA) study, higher abundance of Robinsonville was inversely associated with systolic blood pressure [118]. Studies in germ‐free mice have demonstrated protection against angiotensin‐II‐induced hypertension and cardiac inflammation and remodeling [119]. Additionally, spontaneous hypertensive mice exhibit a high Firmicutes to Bacteroidetes ratio compared to chronic angiotensin‐II infusion mice models or healthy controls [120].

Moreover, the gut microbiota can influence plasma lipoprotein profiles by reducing cholesterol biosynthesis and plasma cholesterolemia through various mechanisms, such as incorporation into bacterial cell membranes, deconjugation of primary bile acids into secondary bile acids, conversion into coprostanol excreted in feces, and production of short‐chain fatty acids (SCFAs) [121, 122]. Specific bacterial products, like exopolysaccharides (EPSs) derived from Agaricus brasiliensis, exhibit cholesterol‐lowering effects in mice [123]. Additionally, gut microbiota can interact with dietary lipids, generating active compounds that regulate plasma lipoproteins. Among these compounds, conjugated linoleic acid has been shown to lower cholesterol, triglyceride, and lipoprotein levels in both in vivo and in vitro studies [124]. Modulating the composition and function of the gut microbiota through interventions such as probiotics, prebiotics, or dietary changes presents a novel strategy for reducing inflammation and cardiovascular risk.

The gut microbiota can influence cardiovascular risk through its pro‐inflammatory effects, which are mediated not only by its metabolites but also by the bacteria themselves, particularly in conditions of dysbiosis [125]. Accumulating scientific evidence over the past two decades suggests a role for lipopolysaccharide (LPS) in the development of AS, particularly in foam cell formation and cholesteryl ester accumulation from native LDLs. Additionally, LPS promotes the secretion of trimethylamine (TML), a precursor of trimethylamine‐N‐oxide (TMAO), and other pro‐inflammatory cytokines from monocytes‐macrophages. Elevated serum levels of LPS have been observed in individuals with coronary artery disease, suggesting its potential as a disease marker [126]. The correlation between gut microbiota and inflammation also involves platelet hyperactivation mediated by TMAO. Specifically, it has been demonstrated that plasma enriched with TMAO enhances human platelet reactivity not only to specific stimuli but also to multiple agonists, including adenosine diphosphate (ADP), thrombin, collagen, and arachidonic acid. TMAO interacts with platelet membrane phospholipids, promoting cellular activation in response to sub‐maximal agonist stimulation. This effect is mediated by the augmentation of agonist‐dependent release of calcium ions (Ca²⁺) from intracellular platelet stores and an increase in inositol‐1,4,5‐trisphosphate (IP3)‐related signaling [127].

Numerous non‐antibiotic medications have the potential to modulate the composition and function of the microbiota, thereby influencing health outcomes. Among the emerging class of sodium/glucose cotransporter 2 inhibitors (SGLT2i), empagliflozin stands out for its ability to enhance the richness and diversity of the gut microbiota, leading to improvements in inflammatory parameters. A recent study demonstrated that empagliflozin promotes the proliferation of SCFA‐producing bacteria, such as oseburia, Faecalibacterium, and Eubacterium, while inhibiting potentially harmful bacteria like Escherichia‐Shigella, Bilophila, and Hungatella [128].

In another investigation, a 28‐day treatment with dapagliflozin, another SGLT2i, significantly enhanced cardiac function in a non‐diabetic myocardial infarction mouse model, concurrently modifying the composition of the gut microbiota by increasing the abundance of beneficial bacteria such as Lactobacillaceae [129]. Following dapagliflozin treatment, Muribaculaceae and Lactobacillaceae were predominant members of the intestinal microbial community, contrasting with Muribaculaceae and Erysipelotrichaceae, which were associated with myocardial infarction.

Furthermore, antihypertensive medications, like the angiotensin‐converting enzyme inhibitor captopril, have demonstrated favorable effects on hypertension‐related gut pathology. Specifically, captopril has been shown to alleviate intestinal permeability, reduce the thickness of the muscularis layer, and increase villi length by 55% [130]. In essence, pharmacomicrobiomics underscores the significance of personalized medicine strategies that take into account the individual's microbiota profile.

In conclusion, the exploration of novel inflammatory mediators and therapeutic targets holds great promise for advancing the treatment of CVDs. These emerging therapies offer potential new strategies to complement existing treatments, addressing the inflammatory component of CVD and improving patient outcomes.

5. Implications for Clinical Practice

In considering the implications for clinical practice, the integration of anti‐inflammatory strategies into the management of CVDs emerges as a transformative avenue. The practical applications of these strategies, which is explored in this section, shed light on their potential to redefine how we approach CVDs treatment. As we navigate the intricacies of CVDs management, understanding the significance of incorporating anti‐inflammatory interventions into existing protocols becomes paramount [131]. This involves not only recognizing the specific clinical scenarios where such strategies prove most effective but also ensuring a seamless integration that aligns with the broader treatment landscape [132].

The discussion extends beyond general applications to delve into the realm of personalized medicine. Tailoring anti‐inflammatory interventions to the unique characteristics of individual patients represents a paradigm shift in clinical practice. By acknowledging patient‐specific considerations, such as comorbidities, genetic predispositions, and lifestyle factors, clinicians can optimize the efficacy of anti‐inflammatory strategies while minimizing potential risks. As we advance, these considerations forge a path toward a more patient‐centered approach in the realm of CVDs management, thus promising not only improved outcomes, but also a more tailored and compassionate form of cardiovascular care [133].

The ideal CVD target might be a patient with a large inflammatory burden. Extensive myocardial infarction, which are characterized by significant ischemic damage, release higher levels of inflammatory mediators, thereby leading to a more pronounced acute inflammatory response. These patients with extensive myocardial infarction, and consequently elevated inflammatory burden, might experience greater advantages from early anti‐inflammatory treatments. Thus, the selection of patients with STEMI rather than NSTEMI, or the selection of patients with elevated levels of cardiac troponins, might be a useful approach in terms of promptly identifying individuals with substantial CVD and identifying the most suitable surrogate markers for anti‐inflammatory therapy [134]. Additionally, the use of available biomarkers of inflammation (e.g., CRP and IL‐6) could further improve the identification of individuals with a large inflammatory burden post‐CVDs, who would benefit from anti‐inflammatory strategies. Finally, the ideal patient would benefit by the administration of anti‐inflammatory therapy at early stages after the acute event. Inflammatory response may be protective in the early stage of the myocardial infarction through stimulation of myocyte autophagy. Anti‐inflammatory treatment that is administered early after coronary occlusion may have an adverse effect [135]. A treatment plan aimed at addressing the initial stages of excessive and harmful post‐CVDs inflammation could potentially restrict further myocardial damage.

6. Challenges and Considerations

Implementing targeted anti‐inflammatory therapy in cardiovascular events presents several challenges and considerations that need to be addressed for its successful integration into clinical practice. Not all cardiovascular patients may benefit from anti‐inflammatory therapy. It is crucial to identify those with high residual inflammatory risk despite optimal traditional treatments. This requires advanced diagnostic tools and a deep understanding of individual patient profiles to ensure therapy is targeted effectively [136]. Ensuring the safety and sustained efficacy of anti‐inflammatory therapies is essential. Chronic use of these agents may lead to adverse effects like increased infection risk or unforeseen side effects. Long‐term monitoring and management strategies are necessary to mitigate these risks while maintaining therapeutic efficacy [137]. Successfully incorporating anti‐inflammatory therapies into routine cardiovascular care requires clear guidelines and protocols. Health care providers need education on the benefits, risks, and management of these therapies to ensure effective implementation. This includes knowing when to initiate treatment, how to monitor patients, and how to handle potential adverse effects [138]. Treatment of CVDs with anti‐inflammatory therapy can result in a wide variety of side effects. Soon after the introduction of the first anti‐inflammatory therapy to clinical practice, it was clear that although effective in treatment of pain and inflammation, had the potential to damage gastric mucosa. Since that time, formation of gastric ulcers has been the most feared complication of anti‐inflammatory therapy with a generally high perception of risk in the healthcare community. In addition, renal (hyperkalemia, interstitial nephritis, kidney failure, reduced glomerular filtration rate, sodium and water retention, and pitting edema), cardiovascular (increased blood pressure, congestive heart failure, palpitations, and thrombotic events), and central nervous system (headache, fatigue, insomnia, vertigo, seizures) are the most common reported adverse effects [139].

Ethical issues such as equitable access to new therapies and maintaining informed consent must be addressed. Navigating regulatory processes to gain approval for new drugs involves demonstrating safety, efficacy, and superiority or complementarity to existing treatments [140]. Continuous research is essential to refine existing therapies and discover new anti‐inflammatory agents. This includes further understanding the mechanisms of inflammation in AS, conducting large‐scale clinical trials to validate safety and efficacy, and navigating regulatory landscapes to gain approval for new drugs [141]. Addressing these challenges and considerations is crucial for optimizing the use of targeted anti‐inflammatory therapy in cardiovascular events. It requires a multidisciplinary approach involving healthcare providers, researchers, policymakers, and regulatory agencies to ensure safe, effective, and equitable access to these treatments for patients with CVDs.

7. Future Directions

Ongoing research aims to further elucidate the role of inflammation in CVDs and refine targeted anti‐inflammatory therapies. Clinical trials are evaluating the efficacy and safety of new agents, such as inhibitors targeting specific inflammatory pathways or novel approaches like gene therapy [142]. Deeper understanding of inflammatory pathways involved in AS will guide the development of more precise and effective therapies. Mechanistic studies are crucial for identifying new drug targets and optimizing treatment strategies. Continued efforts in drug development will focus on improving the potency, selectivity, and safety profiles of anti‐inflammatory agents. This includes exploring novel drug delivery systems and repurposing existing drugs for cardiovascular indications.

Clear guidelines and protocols are needed to standardize the use of targeted anti‐inflammatory therapy in clinical practice. These guidelines should provide evidence‐based recommendations for patient selection, dosing, monitoring, and management of adverse effects. Training programs for healthcare providers will ensure they are knowledgeable about the benefits, risks, and appropriate use of anti‐inflammatory therapies. This includes education on patient selection, treatment initiation, and long‐term management.

Improving patient outcomes requires a multifaceted approach that addresses not only inflammation but also other cardiovascular risk factors. Integrated care models that combine anti‐inflammatory therapy with lifestyle modifications, pharmacotherapy, and cardiovascular rehabilitation can optimize outcomes. Long‐term monitoring of patients receiving anti‐inflammatory therapy is essential to track treatment response, detect adverse effects early, and adjust therapy as needed. This includes regular assessment of inflammatory markers, cardiovascular risk factors, and medication adherence. In conclusion, future directions for targeted anti‐inflammatory therapy in CVDs involve advancing research, refining therapeutic strategies, integrating these therapies into clinical practice, and enhancing patient outcomes through evidence‐based care and patient‐centered approaches. Collaborative efforts among researchers, health care providers, policymakers, and patients are essential for realizing the full potential of anti‐inflammatory therapy in improving cardiovascular health.

8. Conclusion

CVDs continue to pose a significant global health burden, highlighting the urgent need for innovative therapeutic approaches. Emerging evidence underscores the pivotal role of inflammation in the pathogenesis of AS and subsequent cardiovascular events. While traditional treatments have primarily focused on lipid‐lowering and antithrombotic strategies, they often overlook the inflammatory component of CVD. Recent advancements in targeted anti‐inflammatory therapies offer promising avenues for mitigating cardiovascular risk. Agents like canakinumab and colchicine have shown efficacy in reducing recurrent cardiovascular events, independent of lipid levels. These therapies directly modulate inflammatory pathways, addressing a crucial aspect of CVD pathophysiology. Moreover, ongoing research is exploring novel targets and agents, such as inhibitors of IL‐6 and TNF‐α, further expanding the therapeutic landscape for inflammation‐driven CVD. Despite these advancements, challenges persist, including identifying appropriate patient populations, ensuring long‐term safety, and addressing cost‐effectiveness concerns. However, ongoing research endeavors aim to refine these therapies, striking a balance between risk reduction and adverse effects. In conclusion, targeted anti‐inflammatory therapy represents a promising adjunct to traditional CVD treatments, potentially revolutionizing the management of cardiovascular events. Future studies are crucial for optimizing these strategies and fully integrating them into clinical practice, ultimately enhancing outcomes for patients with CVD. Through collaborative efforts among researchers, health care providers, and policymakers, we can realize the full potential of anti‐inflammatory therapy in combating CVD and improving global cardiovascular health.

Author Contributions

Tianyi Ma and Feng Li conceived and directed the project, contributed to the discussion of content, and reviewed and edited the article. Ling Wang and Xiaorong Yan drafted the article. All authors reviewed and edited the article and contributed to the discussion of content.

Ethics Statement

The author have nothing to report.

Ma T., Wang L., Yan X., and Li F., “Targeted Anti‐Inflammatory Therapy in Cardiovascular Events: Challenges and Opportunities.” The Journal of Clinical Hypertension 27, no. 11 (2025): e70172. 10.1111/jch.70172