Atherosclerosis is a chronic disease characterized by the accumulation of plaque in the lining of blood vessels and is a major underlying cause of cardiovascular disease. The development of atherosclerosis is associated with the accumulation of cholesterol and inflammation. Although lowering low-density lipoprotein cholesterol (LDL-C) levels is an effective therapy, some patients still experience cardiovascular events due to ongoing inflammation, known as residual inflammatory risk (RIR). Researchers have conducted laboratory and animal studies to investigate the measurement and targeting of the inflammatory cascade associated with atherosclerosis, with promising results. In addition to guideline-recommended lifestyle changes and optimal pharmacotherapy focused on reducing LDL-C levels, pharmacological interventions targeting inflammation may provide further assistance in preventing future cardiac events. This article summarizes ongoing research in this rapidly evolving area targeting inflammatory pathways, continues to identify potential new drugs and biomarkers, and will focus on known drugs and relevant prominent studies with significant clinical outcomes.
Author: Zheng Gang, TEDA International Cardiovascular Hospital
This article is authorized by the author to be published by Yimaitong, please do not reprint without authorization.
秋水仙碱（COLCHICINE）的作用机制
Colchicine can inhibit the vesicle secretion of inflammatory signals, prevent cholesterol crystals from activating NLRP3 inflammasomes, and reduce the release of interleukin IL-1β by hindering microtubule formation and inhibiting cytoskeletal reorganization[1]. In animal models, plasma C-reactive protein (CRP) levels in colchicine-treated patients were lower than those treated with atorvastatin. A preliminary study in 200 patients with clinically stable coronary artery disease (CAD) who had already received atorvastatin showed a 60% reduction in high-sensitivity CPR (HS-CRP) levels after 4 weeks of colchicine treatment [2].
The LoDoCo trial is a prospective, randomized, observer-blinded endpoint trial. A total of 532 patients with stable coronary artery disease treated with aspirin and/or clopidogrel and statins were randomized to receive colchicine 0.5 mg/day or placebo with a median follow-up of three years [3]. Primary outcomes were defined as composite event incidence of acute coronary syndrome (ACS), out-of-hospital cardiac arrest, or ischemic stroke. The primary outcome occurred in 5.3% of patients treated with colchicine and 16.0% in patients who did not receive colchicine. In a secondary analysis that excluded 32 patients who took colchicine within 30 days due to intestinal intolerance and seven patients who did not start treatment, the primary outcome was 4.5 versus 16.0 percent (p<0.001). The study concluded that taking 0.5 mg of colchicine daily in addition to statins and other standard secondary prevention therapies appears to be effective in preventing cardiovascular events in patients with stable coronary artery disease.
The LoDoCo2 study is an investigator-initiated, double-blind, placebo-controlled trial in which 5552 patients with chronic coronary syndrome (CCS) are randomized to receive either 0.5 mg colchicine or placebo per day [4]. The primary endpoint was defined as a composite event endpoint of cardiovascular death, myocardial infarction (MI), ischemic stroke, or ischemic coronary artery reconstruction. The median follow-up was approximately 30 months. The primary endpoint event occurred in 6.8% of patients in the colchicine group and 9.6% of patients in the placebo group (P<0.001). When the components of the primary endpoint were analysed separately, a consistent trend was shown across all endpoints, with significant reductions in the incidence of MI and ischemia-driven coronary revascularization in the colchicine group. In this study, more than 90% of patients tolerated colchicine with no significant side effects. The study concluded that colchicine may be a good option for long-term prevention of cardiovascular events in patients with CCS.
The COLCOT trial included a total of 4745 patients who had experienced MI in the past 30 days, who were randomized to either 0.5 mg colchicine or placebo (unlike the LoDoCo trial, patients with stable coronary artery disease were not included in COLCOT). The primary composite endpoint is defined as the time to first occurrence of one of the following events: cardiovascular death, cardiac arrest, MI, stroke, or emergency hospitalization for angina requiring coronary revascularization [5]. All patients received guideline-directed medical therapy and percutaneous coronary intervention (PCI) (if needed) prior to randomization. The follow-up was only 23 months. The incidence of the primary composite endpoint was significantly lower in the colchicine group than in the placebo group (5.1 versus 7.1 percent; P=0.004）。 With the exception of nausea, flatulence, and pneumonia, the rates of other adverse events were similar in both groups, with colchicine being significantly higher in the group. The study showed that colchicine was effective in reducing the risk of a first-time ischemic cardiovascular event compared to placebo. The results of a recently published pilot study of MACT focused only on ACS patients undergoing PCI. The results of the study suggest that stopping aspirin one day after PCI and taking low-dose colchicine with ticagrelor or prasugrel is not only safe, but also has beneficial effects on platelet function and inflammatory profile[6].
Interleukin and chemical factor inhibitors
1.卡那单抗（Canakinumab）
Canakinumab is a human anti-IL-1β monoclonal antibody whose mode of action is based on the neutralization of 1β signaling, thereby inhibiting inflammation. This medication is mainly used to treat autoimmune diseases. The CANTOS trial was the first study to demonstrate the benefits of targeted inflammation (published in 2017). The study evaluated the use of three different doses of canakinumab (50 mg, 150 mg, and 300 mg) compared to placebo; This medicine is injected under the skin every three months. The primary endpoints of cardiovascular events, defined as non-fatal MI, non-fatal stroke, and cardiovascular death, were assessed at 24 months. More than 17,000 patients from 39 countries were screened, of whom 10,061 were successfully randomized. At 24 months, hs-CRP values were significantly lower in all three canakinumab groups compared to baseline and placebo groups. Cardiovascular events were significantly reduced in the 150 mg and 300 mg groups compared to the placebo group. When the 150 mg and 300 mg groups were combined, patients treated with canakinumab had a 39% reduction in the relative risk of hs-CRP values and a 15% reduction in the primary endpoint relative risk compared with the placebo group. In addition, patients with higher hs-CPR levels at baseline benefited more.
A subanalysis of the study looked at a group of patients with CANTOS who had hs-CRP levels below 2 mg/L and compared them to subjects with smaller reductions [7]. The reduction of hs-CRP after a single dose of kanakinumab has been shown to be a strong predictor of kanakinumab efficacy. In patients with hs-CRP levels below 2 mg/L, the incidence of major events was significantly reduced by 25% (P<0.0001). This finding suggests that a target of less than 2 mg/L for hs-CRP is needed to adequately reduce RIR. The main side effect of kanakinumab in the CANTOS trial was a small increase in fatal infections. However, kanakinumab currently lacks a clear dose-response relationship, has an increased risk of fatal complications from infection, requires injections, and is costly.
Another interleukin inhibitor is anakinra, which is an IL-1 receptor antagonist. The VCU-ART3 trial is a randomized, placebo-controlled, double-blind clinical trial that included 99 patients with ST-elevation myocardial infarction (STEMI) [8]. Patients were randomly assigned to anakinra once-daily, anakinra twice-daily, or placebo. Patients treated with anakinra had significantly lower hs-CRP levels compared to the placebo group. The incidence of death or new-onset heart failure or death and hospitalization due to heart failure was significantly lower with anakinra compared with placebo (9.4 versus 25.7 percent; P = 0.046 and 0% vs 11.4%; P=0.011）。 The incidence of severe infections did not differ between the anakinra and placebo groups. Injection site reactions were more common in patients treated with anakinra placebo. The study suggests that anti-inflammatory drugs such as anakinra may reduce the inflammatory response in patients with STEMI, leading to better outcomes.
2.Ziltivekimab
Ziltivekimab is a novel human antibody against the IL-6 ligand. The RESCUE trial was a randomized, double-blind, phase 2 trial in participants (n = 264) with moderate to severe chronic kidney disease and hs-CRP levels of at least 2 mg/L. Participants were randomly assigned to either placebo or ziltivekimab (different doses) injected subcutaneously every 4 weeks for 24 weeks. The study compared changes in hs-CRP levels after 12 weeks of treatment as the primary outcome. At 12 weeks, median hs-CRP levels were reduced by 77% in the 7.5 mg group, 88% in the 15 mg group, and 92% in the 30 mg group, compared to 4% in the placebo group. A dose-dependent reduction in inflammatory markers was also observed. The drug was well tolerated and there were no serious side effects. The results of this study strongly demonstrate that ziltivekimab has a high potential to improve prognosis, suggesting that this IL-6 inhibitor may be as effective as kanakimab [9].
3.托珠单抗（Tocilizumab）和沙利鲁单抗（sarilumab）
Both tocilizumab and thalilumab are monoclonal antibodies that target the IL-6 receptor. Despite elevated LDL-C, tocilizumab improves endothelial function in patients at high risk of CAD. The ASSAIL-MI trial is a double-blind, placebo-controlled, randomized controlled study of patients with acute STEMI [10-11]. Participants were randomly assigned to receive either a single infusion of 280 mg tocilizumab or placebo. The primary endpoint is the myocardial salvage index, which is measured by magnetic resonance imaging 3-7 days after the event. The tocilizumab group had a higher score on the myocardial salvage index; There was a significant difference in the area under the CRP curve, with a median of 1.9 mg/L/hour in tocilizumab patients compared to 8.6 mg/L/hour in the placebo group (p<0.001). There was a 21% difference in final infarct size at 6 months between the tocilizumab and placebo groups, but this difference was not statistically significant (P = 0.08). There were no differences in serious events (MI, coronary artery bypass grafting, subarachnoid hemorrhage, ventricular fibrillation resuscitation, ventricular tachycardia, chest pain, and ischemic stroke) between the two groups (P=0.57). In a pilot study, neutralizing monoclonal antibodies against CCR2 resulted in a significant reduction in hs-CRP MLN1202 compared with placebo [12].
4.甲氨蝶呤（Methotrexate）
Inhibits lymphocyte proliferation and the production of inflammatory cytokines by adenosine binding to A2 receptors. The CIRT trial is a randomized, double-blind trial of 4786 patients with type 2 diabetes mellitus or metabolic syndrome with early-stage MI or multivessel coronary artery disease treated with low-dose (15~20 mg weekly) methotrexate or placebo [13]. This anti-inflammatory drug is available in a generic form and is considered safe at low doses. Compared to placebo, methotrexate had no effect on the primary endpoint of major adverse cardiovascular events. The same is true for the composite event and final outcome of non-fatal MI, non-fatal stroke, or cardiovascular death, but increases the incidence of hospitalizations for unstable angina pectoris, which in turn increases the incidence of emergency revascularization. In addition to this, methotrexate did not reduce CRP, IL-1β, or IL-6 levels. Low-dose methotrexate was associated with a higher mortality rate, either due to cardiovascular causes or all-cause deaths, which is why the trial was discontinued after a median follow-up of 2.3 years.
5.羟基氯喹（Hydroxychloroquine）、别嘌呤醇（Allopurinol）和水杨酸盐（Salicylates）
Hydroxychloroquine is used in inflammatory rheumatic diseases to alter lysosomal pH and reduce inflammation by inhibiting TLR7 and TLR989 [14]. Allopurinol treatment of hyperglycemia in patients with gout may reduce atherosclerosis-related inflammation in mice, but its clinical efficacy remains uncertain [15]. In the TINSAL-T2D and TINSAL-FMD trials, salicylate inhibited NF-κB activity but did not reduce inflammation in patients with atherosclerosis [16].
6. Other drugs under investigation
Dapansutrile, an NLRP3 inflammasome inhibitor, has no significant effect on CRP levels [17]. In a phase III trial, succinobucol did not reduce cardiovascular events [18]. Darapladib is an Lp-PLA2 inhibitor that has shown conflicting results in clinical studies[19]. Losmapimod (p38 inhibitor) and inclacumab (P-selectin inhibitor) are currently being studied. Due to the relationship between inflammation and thrombosis, antithrombotic agents in patients with CAD may provide additional benefits beyond their primary purpose [20].
Treatment strategies
The assessment and treatment of the presence of local and systemic inflammation in patients with atherosclerosis is well established. Targeted reduction of inflammation is essential to prevent cardiovascular events in patients who have already received optimal medical therapy.
Biomarkers can be used to detect and measure inflammatory processes, with hs-CRP being the most widely studied and available biomarker for this purpose. Several anti-inflammatory drugs, including colchicine, have improved inflammation and clinical outcomes in people with heart disease. Recently, colchicine has even been widely approved by the FDA for this purpose [21]. In order to effectively tailor a treatment plan, clinicians need to assess the patient's overall risk/benefit ratio. There are two main patient phenotypes: those who are at risk of residual cholesterol and elevated LDL-C levels despite drug therapy, and those with RIR. The first group of patients should receive additional treatment. LDL-C augmentation therapy is based on guidelines such as those recommended by the European Society of Cardiology (ESC) or the United States Society of Cardiology (ACC)/United States Heart Association (AHA) [22]. The second group consisted of patients who reached target levels of LDL-C but were still experiencing RIRs. Although ESC guidelines recommend lowering LDL-C to less than 40 mg/dL or adding colchicine to patients with recurrent cardiac events despite optimal medical therapy, these indications are primarily based on secondary prevention after the event.
The data presented here support the use of biomarkers to diagnose RIR and proactively treat inflammation before an event occurs. Non-invasive or invasive imaging techniques, such as coronary computed tomography (CTA), carotid ultrasound, positron emission tomography, intravascular ultrasound, near-infrared spectroscopy, and optical coherence tomography, can show atherosclerotic arteries, while risk scores can identify patients at high risk of atherosclerosis, even in the absence of visual evidence of plaque. Once the patient has reached the target LDL-C level, we suggest using biomarkers to assess the presence of RIRs rather than taking a watchful waiting approach for new events.
In multiple prospective epidemiological cohorts, hs-CRP levels have been shown to independently predict cardiovascular events (both new and recurrent). Over time, stable hs-CRP levels are typically below the commonly used cut-off of 2 mg/L, except for acute infection. If the patient has elevated hs-CRP levels under LDL-C control, anti-inflammatory drugs should be considered. While no drug has proven to be superior given previous research, experience, affordability, and recent FDA approvals [23], colchicine appears to be the best option. Therefore, we collectively recommend hs-CRP as the preferred biomarker and colchicine as the preferred agent [24]. However, to establish this protocol, several issues need to be addressed, such as the timing and frequency of hs-CRP testing after reaching target LDL-C levels, the management of patients with renal failure or gastrointestinal intolerance, the duration of colchicine prescription, and follow-up strategies after treatment of RIRs. In addition, the proposed regimen does not address the potential treatment of patients with low levels of hs-CRP and LDL-C.
Future prospects
The future of atherosclerosis and RIR treatment lies in personalized medicine and novel medicines. Ongoing research focuses on promising anti-inflammatory strategies and explores new possibilities for atherosclerotherapy [25]. An interesting pathway is to target efferent cytosis, which is a process by which macrophages remove apoptotic tissue from plaques.
Dysregulation of this process leads to an increase in inflammation and atherosclerosis. In addition, advances in nanotechnology offer potential breakthroughs by improving drug delivery, reducing systemic toxicity, and extending the cycle time of drugs, including water-insoluble drugs. In vitro and animal studies have evaluated nanotherapeutics against atherosclerosis. Personalized medicine represents a treatment that takes into account an individual's medical history, environmental factors, genetic background, and molecular defects. mRNA-based therapies are a promising therapeutic strategy that can precisely target specific genes and may bring great potential for future medical treatments.
To augment existing risk assessment methods, two key advancements worth considering are the use of updated models and integrated AI algorithms that incorporate the latest imaging techniques. In future trials related to colchicine for the treatment of ACS, emphasis will be placed on the inclusion of optical coherence tomography (OCT) guidance as a secondary endpoint, as well as cardiac noninvasive techniques such as cardiac magnetic resonance imaging, nuclear medicine, and sodium fluoride positron emission tomography/computed tomography [26-27]. In addition, the importance of integrating hs-CRP into existing and new cardiac risk algorithms must be emphasized.
In addition, several pivotal clinical trials are currently underway to examine the effects of different drugs on RIRs. For example, the ZEUS trial was designed to evaluate the effect of ziltivekimab on reducing cardiovascular events in patients with atherosclerotic cardiovascular disease, chronic kidney disease, and inflammation [28]. The CONVINCE trial was designed to investigate the efficacy of colchicine in adults with ischemic stroke or transient ischemic attack [29]. THE CLEAR SYNERGY TRIAL INVESTIGATED THE EFFICACY AND SAFETY OF COLCHICINE AND SPIRONOLACTONE IN PATIENTS WITH MI WHO UNDERWENT PRIMARY PCI [30]. FINALLY, THE GOLDILOX-TIMI 69 TRIAL IS A PHASE IIB STUDY DESIGNED TO EVALUATE THE ANTI-INFLAMMATORY POTENTIAL OF MONOCLONAL ANTIBODY MEDI6570 AND ITS IMPACT ON ATHEROSCLEROTIC AND HEART FAILURE EVENTS IN PATIENTS WITH A HISTORY OF MI [31]. These clinical trials represent an important effort in our understanding and treatment of atherosclerosis and RIRs.
Conclusion
A large body of data suggests that aggressive prevention of RIRs in atherosclerosis is key. Emphasizing the convergence of biological evidence for atherosclerotic inflammation, the availability of biomarkers, and the effectiveness of anti-inflammatory drugs demonstrated in clinical trials all require inclusion in future guidelines. We believe that the current evidence is sufficient to support or use the hs-CRP to evaluate patients with confirmed atherosclerosis and to add colchicine to their regimen as a preventive measure, rather than waiting for relapse to occur.
Expert Profile
Prof. Zheng Gang
•He is currently a distinguished expert of TEDA International Cardiovascular Hospital and vice president of Jixing Hospital
•Director of the Chinese Hypertension Alliance, member of the Chinese Heart Failure Society, deputy leader of the Tianjin Working Group of the Hypertension Branch of the Chinese Geriatrics Society, and member of the Hypertension Branch of the China Association for the Promotion of International Exchange in Health Care. He is a member of the Cardiovascular Disease Committee of Tianjin Medical Association and a member of the Standing Committee of the Geriatrics Professional Committee of Tianjin Medical Association. He is a member of the Standing Committee of the Hypertension Professional Committee of Tianjin Medical Doctor Association, a member of the Geriatric Professional Committee of Tianjin Medical Doctor Association, a member of the Heart Failure Professional Committee of Tianjin Medical Doctor Association, and a member of the Shuangxin Professional Committee of the Cardiovascular Physician Branch of Tianjin Medical Doctor Association. He is a member of the first committee of Tianjin Heart Rhythm Society, and a member of the Standing Committee of Tianjin Atrial Fibrillation Center Alliance. He is a member of the first cardiovascular professional committee of Tianjin Pharmaceutical Experts Association and a member of the Standing Committee of the Clinical Cardiovascular Pharmacology Professional Committee of Tianjin Pharmacological Society. Member of the Standing Committee of the Cardiovascular Disease Committee of Tianjin Association of Integrative Traditional and Western Medicine, Editorial Board Member of Chinese Journal of Geriatric Cardiovascular and Cerebrovascular Diseases, Invited Reviewer of Chinese Journal of Clinical Physicians (Electronic Edition), Reviewer of Chinese Journal of Diagnostics Electronic Journal, Deputy Editor-in-Chief of Chinese Medical Journal, Executive Editorial Board Member of Chinese Journal of Cardiovascular Diseases, Member of the Fourth Editorial Board of Chinese Journal of Cardiovascular Research, Editorial Board Member of World Journal of Clinical Medicine, Editorial Board Member of Medical Review Journal, Editorial Board Member of China Medical Herald Journal, and Modern Chinese Doctor Member of the editorial board of the journal, reviewer of the Journal of Cardiovascular Surgery (Electronic Edition) • I have published 948 articles in professional journals and cardiovascular networks, including 759 articles as the first author, and participated in 11 books, • I was awarded the title of "May Day Labor Medal and Award" in Tianjin in 2005 and "The Second Good Doctor with People's Satisfaction in Tianjin Health Industry".
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