The relationship between inflammation and atherosclerotic cardiovascular disease (ASCVD) has been increasingly recognized and paid attention to by clinicians
According to the China Cardiovascular Health and Disease Report 2022, there are currently 330 million people with cardiovascular diseases in mainland China, of which about 61% of the cardiovascular disease burden is caused by ASCVD [1]. Previous studies have suggested that lipid accumulation is an important pathogenesis of ASCVD, but with the deepening of research, more evidence suggests that inflammation is a driving factor in the development and development of ASCVD.
A variety of immune cells, such as T cells, B cells, dendritic cells, and monocytes, are involved in the inflammatory process by producing inflammatory cytokines. Inflammatory factors can play an important role in plaque rupture leading to thrombosis by inducing collagen degradation and leading to increased plaque instability[2]. In recent years, large clinical studies such as the CANTOS study [3], the COLCOT study [4], and the LoDoCo2 study [5] have confirmed that anti-inflammatory therapy can significantly reduce the risk of cardiovascular death, providing a solid evidence-based basis for the theory of atherosclerotic inflammation. So far, the "inflammation theory" of ASCVD has gradually gained recognition and attention from the academic community.
What is the current status of anti-inflammatory treatment for cardiovascular disease? What are the clear and promising therapeutic targets? How should anti-inflammatory therapy evolve in the future? On May 15, 2024, Professor Tang Yida from Peking University Third Hospital and Professor Lale Tokgözoğlu from Hasiedpe University in Turkey were invited to share their experience on topics related to "inflammation and ASCVD" and had an in-depth discussion with the online audience.
Photo: Professor Tang Yida presided over the meeting
Inflammation, a new therapeutic target for ASCVD
Under the chairmanship of Prof. Yida Tang, Prof. Lale Tokgözoğlu gave a wonderful speech on the topic of "Inflammation and ASCVD". Professor Lale Tokgözoğlu first introduced the possible mechanism of inflammation in the occurrence and development of ASCVD, and pointed out that the level of related inflammatory factors (such as IL-6, etc.) is closely related to cardiovascular prognosis, and targeted inflammatory treatments, such as inhibition of NLRP3 inflammasome and its downstream inflammatory factors, can significantly reduce the risk of cardiovascular disease.
Photo: Professor Lale Tokgözoğlu giving a speech
The inflammasome pathway is an important target for the management of ASCVD
Professor Lale Tokgözoğlu said that there is still a high residual risk of ASCVD after treatment of existing risk factors in ASCVD patients, and inflammation may be a new therapeutic target for ASCVD. Previous studies have found that patients with chronic inflammatory diseases, such as autoimmune diseases and gout, can promote the formation of atherosclerosis [6]. In terms of specific mechanism, it is believed that NLRP3 inflammasome plays an important role in the occurrence and development of atherosclerotic inflammation. NLRP3 inflammasome is a complex composed of multiple proteins that promote the production and release of IL-1β and IL-18 when activated. These cytokines stimulate various inflammatory cells and produce IL-6, which leads to the production of C-reactive protein (CRP) in the liver and amplifies the inflammatory cascade within the blood vessel wall [7]. Therefore, the current anti-inflammatory treatment of ASCVD mostly revolves around this pathway.
Figure: Inflammasome pathway and its role[7]
PAI-1:纤溶酶原激活物抑制因子1;SREBP2:固醇调节元件结合蛋白2;CRP:C反应蛋白;iNOS:一氧化氮合酶;Caspase-1:含半胱氨酸的天冬氨酸蛋白水解酶1
hs-CRP is recommended as a predictor of cardiovascular risk
In terms of inflammatory markers, higher levels of high-sensitivity C-reactive protein (hs-CRP) are significantly associated with an increased risk of major adverse cardiovascular events (MACE). In patients with ASCVD who are at risk for residual inflammation, hs-CRP is superior to low-density lipoprotein cholesterol (LDL-C) in predicting MACE and all-cause mortality [8]. These results suggest that hs-CRP may be an ideal predictor of cardiovascular events.
Professor Lale Tokgözoğlu noted that hs-CRP (≥2.0 mg/L) has been recommended by guidelines in the United States and Canada as a predictor of cardiovascular disease risk [9,10]. In the primary prevention of ASCVD, hs-CRP is helpful in guiding clinical evaluation and treatment; In the secondary prevention of patients with acute coronary syndrome (ACS) or chronic coronary syndrome (CCS), hs-CRP can be used as an independent predictor of the prognosis of relapsing events.
Targeted intervention of inflammasomes
Significantly reduces the risk of cardiovascular disease
How can subclinical inflammation be effectively treated to reduce cardiovascular risk? Professor Lale Tokgözoğlu says that a healthy diet, such as the Mediterranean diet, is the first step in treatment. In terms of drug intervention, targeted inhibition of NLRP3 inflammasome and its downstream inflammatory factors can significantly reduce the levels of hs-CRP and IL-6, and significantly improve the prognosis of patients. Current clinical studies have shown that canakinumab and colchicine are drugs with the potential to reduce cardiovascular risk.
Canakinumab is a monoclonal antibody to IL-1β, which can neutralize IL-1β in the body, affect the NLRP3 inflammasome pathway, and reduce the release of IL-6. The CANTOS study [3] demonstrated that canakinumab reduced hs-CRP and IL-6 levels by approximately 35% to 40% and reduced the risk of MACE by up to 15% compared with placebo in patients with prior myocardial infarction and systemic inflammation (P=0.007). In addition, subgroup analysis showed a 36% reduction in the risk of MACE in patients who achieved IL-6 below the median of the trial (1.65 ng/L) with canakinumab at the third month of the study (P<0.0001). Unfortunately, kanakinumab has not been approved by the US Food and Drug Administration (FDA) for anti-inflammatory indications in the cardiovascular field because it reduces the risk of cardiovascular events while increasing the risk of infection and infection-related death.
Colchicine affects the NLRP3 inflammasome by inhibiting microtubule polymerization, further reducing the production of downstream inflammatory cytomes such as IL-1β, IL-6 and CRP. The COLCOT study [4] and the LoDoCo2 study [5] found that low-dose colchicine significantly reduced the risk of MACE in patients with coronary heart disease. A meta-analysis of five randomized controlled trials (RCTs) also showed that low-dose colchicine reduced the risk of MACE, myocardial infarction, and stroke, as well as the need for coronary revascularization in patients with coronary artery disease [11]. Based on this, the FDA approved low-dose colchicine for anti-inflammatory therapy in patients with cardiovascular disease. In the 2021 Guidelines for the Clinical Prevention of Cardiovascular Diseases issued by the European Society of Cardiology (ESC) [12], low-dose colchicine was recommended for the secondary prevention of cardiovascular diseases (IIb,A), which marked the official entry of cardiovascular anti-inflammatory therapy into clinical practice.
In addition, Prof. Lale Tokgözoğlu introduced Ziltivekimab, a monoclonal antibody against IL-6 ligands. The RESCUE study [13] found that Ziltivekimab reduced hs-CRP levels in patients with chronic kidney disease (CKD) in a dose-dependent manner. Another ongoing ZEUS study may provide additional evidence for the cardiovascular benefit of ziltivekimab in patients with ASCVD and elevated CKD and hs-CRP. Professor Lale Tokgözoğlu also pointed out that there are currently a number of ongoing studies on anti-inflammatory targets in ASCVD, and it is expected that more innovative drugs will be applied in clinical practice to provide patients with better treatment options.
Panel Discussion: Cardiovascular inflammation management
In the following discussion session, Prof. Tang Yida had a lively discussion with Prof. Lale Tokgözoğlu on ASCVD anti-inflammatory treatment and other related issues.
Figure: Discussion session of the meeting
Q: Could you please comment on the anti-inflammatory effect of colchicine and share your clinical experience with colchicine?
Lale Tokgozoglu 教授
Colchicine has been clinically used to treat gout, pericarditis and other diseases for many years. Current studies have shown that anti-inflammatory therapy with colchicine significantly reduces cardiovascular risk in some patients with subclinical inflammation, such as those with atherosclerosis. Large clinical studies such as the LoDoCo2 study have confirmed that low-dose colchicine can significantly reduce the risk of MACE in patients with coronary heart disease. Therefore, anti-inflammatory therapy with colchicine is recommended for patients with ACS or CCS to reduce the risk of cardiovascular death. Colchicine anti-inflammatory therapy has also been recommended by guidelines. May be considered in patients with elevated hs-CRP and persistent inflammatory states. It should be noted that colchicine is currently mainly used for the secondary prevention of cardiovascular diseases.
Professor Tang Yida
When using colchicine, it is also necessary to pay attention to its adverse effects and contraindications. The main adverse effects of colchicine are gastrointestinal symptoms such as abdominal pain, diarrhoea and vomiting. In addition, it needs to be used with caution in patients with renal insufficiency.
Lale Tokgozoglu 教授
I agree with you that patients with clinical renal insufficiency often have inflammation, and for this part of the patient, we need to choose other anti-inflammatory drugs for treatment. In addition, colchicine should be used in combination with other drugs to avoid drug-drug interactions.
Q: In addition to the current recommendation of hs-CRP as an inflammatory marker, what other inflammatory markers do you think can be used as risk predictors to guide clinical evaluation and treatment?
Lale Tokgozoglu 教授
Clinically, IL-1, IL-6 and hs-CRP are all good inflammatory markers, and I personally believe that IL-6 may be the most ideal inflammatory marker at present. As a marker downstream of the inflammasome pathway, CRP can well reflect the level of inflammation, and at the same time, it is convenient to detect, reliable in results, and low in cost, so it is widely used in clinical practice and has been recommended by relevant guidelines in the United States and Canada.
Professor Tang Yida
Agree with you. Inflammatory markers can help doctors better understand a patient's overall disease risk and guide treatment decisions. Among the inflammatory markers commonly used in clinical practice, hs-CRP has been recognized by clinicians because of its convenient detection and stable results. It is hoped that basic research and clinical trials will lead to the discovery of new inflammatory markers that better reflect the level of inflammation and predictive value.
Q: How long do you think ASCVD anti-inflammatory therapy typically lasts? Do I need to take medication for life?
Lale Tokgozoglu 教授
There are no clinical trial results to answer this question, and the duration of anti-inflammatory may vary for patients with ACS and CCS. We need to wait for the results of relevant clinical trials. At the same time, it is important to observe and assess whether anti-inflammatory therapy has a cumulative effect like statin therapy, and the longer it is maintained, the greater the benefit. At this time, from personal clinical experience, continued medication may need to be considered.
Professor Tang Yida
We are still exploring how long anti-inflammatory therapy lasts in clinical practice, whether and when to stop the drug, and whether there are risks after stopping the drug, so we cannot give an accurate answer. Lifelong anti-inflammatory therapy may be a reasonable strategy, but it should also be tailored to the patient's situation.
Q: What do you think is the basis for setting hs-CRP≥2.0mg/L as the cut-off value for anti-inflammatory therapy in clinical practice?
Lale Tokgozoglu 教授
The cut-off value for anti-inflammatory therapy for hs-CRP is currently controversial. Data from the US study suggest that setting hs-CRP ≥ 2.0 mg/L as a cut-off value can observe differences in the incidence of CVD in patients, reflecting a subclinical inflammatory state, which may be reasonable as a cut-off value for treatment, and is also recommended by US and Canadian guidelines. Patients may benefit more from treatment if the hs-CRP cut-off is set high, but a high hs-CRP sometimes means that the patient may have other infections.
Professor Tang Yida
According to my personal observation, in the Asian or Chinese population, many patients with cardiovascular diseases have low hs-CRP levels, often between 1.5mg/L ~ 1.8mg/L. Do these patients need to be treated with low-dose colchicine?
Lale Tokgozoglu 教授
The questions you ask may need to be answered by designing clinical studies for different populations. In addition, it is important to consider the differences in colchicine efficacy and metabolism between different populations, which can affect the effectiveness of treatment.
Q: Studies have shown that novel drugs such as glucagon-like peptide-1 receptor agonists (GLP-1RA) also have anti-inflammatory effects, do you think GLP-1RA can be used for ASCVD anti-inflammatory treatment?
Lale Tokgozoglu 教授
Yes, GLP-1RA has been found to have anti-inflammatory effects and can reduce hs-CRP levels. However, GLP-1RA does not target inflammasomes, and its anti-inflammatory mechanism still needs to be further studied and elucidated. In clinical practice, the reduction of hs-CRP will be greater with drugs targeting inflammasomes, such as kanakimab and colchicine.
Professor Tang Yida
Agree with you. Anti-inflammatory therapy also requires individualized treatment. In certain populations, such as obese patients, GLP-1RA reduces the risk of residual inflammation while reducing weight.
Lale Tokgozoglu 教授
Yes, a lot of our research is based on standardised treatments. However, in clinical practice, we need to develop individualized therapies based on the specific situation of the patient. Personally, I believe that inflammation is a very important field, and I predict that in the next five years, the research results in the field of inflammation will show explosive growth. It is believed that the emergence of some new drugs or therapies can bring more choices to patients in treatment, and is also conducive to individualized treatment.
Professor Tang Yida
Thank you very much Prof. Tokgözoğlu for your excellent presentation and presentation. For the anti-inflammatory treatment of ASCVD patients, we can choose from non-targeted drugs such as statin and GLP-1RA, as well as carakinumab and colchicine, which target inflammasomes. At the same time, we also look forward to the emergence of more new drugs to bring better long-term benefits to patients.
brief summary
Inflammation plays a key role in the formation and progression of atherosclerosis and is one of the clinically intervenable targets. Scientific assessment and management of inflammation is of great significance for reducing adverse cardiovascular events in patients with ASCVD. Drug therapy targeting the inflammasome pathway and its downstream inflammatory factors has shown encouraging efficacy, providing new ideas and directions for the prevention and treatment of ASCVD in the future. With the release of evidence-based results on cardiovascular anti-inflammatory targets, more new anti-inflammatory drugs are available to address the unmet clinical needs.
Bibliography:
[1]. Chinese Cardiovascular Health and Disease Report Writing Group. Summary of the 2022 China Cardiovascular Health and Disease Report[J]. Chinese Journal of Circulation,2023,38(6):583-612.
[2]. Peter Libby. The changing landscape of atherosclerosis. Nature. 2021 Apr; 592(7855): 524-533.
[3]. Ridker PM, et al. Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. N Engl J Med. 2017; 377(12):1119-1131.
[4]. Jean-Claude Tardif, et al. Efficacy and Safety of Low-Dose Colchicine after Myocardial Infarction.2019 Dec 26; 381(26):2497-2505.
[5]. Stefan M Nidorf, et al. Colchicine in Patients with Chronic Coronary Disease.N Engl J Med. 2020 Nov 5; 383(19):1838-1847.
[6]. Justin C Mason , Peter Libby. Cardiovascular disease in patients with chronic inflammation: mechanisms underlying premature cardiovascular events in rheumatologic conditions. Eur Heart J. 2015 Feb 21; 36(8):482-9c.
[7]. Paul M Ridker. From C-Reactive Protein to Interleukin-6 to Interleukin-1: Moving Upstream To Identify Novel Targets for Atheroprotection. Circ Res. 2016 Jan 8; 118(1):145-56.
[8]. Paul M Ridker, et al. Inflammation and cholesterol as predictors of cardiovascular events among patients receiving statin therapy: a collaborative analysis of three randomised trials. Lancet. 2023 Apr 15; 401(10384):1293-1301.
[9]. Scott M Grundy, et al. 2018 AHA/ACCGuideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019 Jun 18; 139(25):e1082-e1143.
[10]. Glen J Pearson, et al. 2021 Canadian Cardiovascular Society Guidelines for the Management of Dyslipidemia for the Prevention of Cardiovascular Disease in Adults.Can J Cardiol. 2021 Aug; 37(8):1129-1150.
[11]. Aernoud T L Fiolet, et al. Efficacy and safety of low-dose colchicine in patients with coronary disease: a systematic review and meta-analysis of randomized trials. Eur Heart J. 2021 Jul 21; 42(28):2765-2775.
[12]. Frank L J Visseren, et al. 2021 ESC Guidelines on cardiovascular disease prevention in clinical practice. Eur Heart J. 2021 Sep 7; 42(34):3227-3337.
[13]. Paul M Ridker, et al. IL-6 inhibition with ziltivekimab in patients at high atherosclerotic risk (RESCUE): a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet. 2021 May 29; 397(10289):2060-2069.