Low-density lipoprotein cholesterol (LDL-C) is a major risk factor for atherosclerotic cardiovascular disease (ASCVD), but relevant studies have shown that targeting LDL-C alone cannot completely prevent ASCVD, and inflammation, as an important source of residual risk of ASCVD, should also be of great concern. A large number of basic and clinical studies have confirmed that inflammation can be used as a therapeutic target for ASCVD. From March 28th to 31st, the 27th Interventional Cardiology Conference of the Chinese Medical Doctor Association and the 13th China Chest Pain Center Conference (CCIF&CCPCC2024) was held. On this occasion, Yimai Tongte invited Professor Huang Kai from Union Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology to conduct an exclusive interview to share the progress of inflammation mechanism and residual inflammation risk in the occurrence and development of atherosclerosis. Professor Huang said that inflammation plays a very important role in the development of atherosclerosis, but this role mainly depends on cholesterol. It makes no sense to talk about the pro-atherosclerotic effects of inflammation completely independent of hypercholesterolemia or high LDL-C levels.
Yimaitong: LDL-C is the main pathogenic risk factor for ASCVD, but relevant studies have shown that targeting LDL-C alone cannot completely prevent and treat ASCVD, and inflammation is an important source of residual ASCVD risk, which has attracted great attention. Inflammation is one of the important mechanisms for the occurrence and development of ASCVD. Could you please describe the inflammatory mechanisms involved in the development of atherosclerosis?
Professor Kai Huang
It is well known that cholesterol, especially LDL-C, plays a leading role in the development of atherosclerosis. And in this process, inflammation plays a very important driving role. For atherosclerosis, the increased oxidized low-density lipoprotein (Ox-LDL) in the blood is an important inflammatory factor: under the action of a variety of complex factors, LDL-C is oxidized to form ox-LDL-C, and then stimulates monocytes to activate and convert into macrophages through multiple pathways to engulf Ox-LDL, transform into foam cells and secrete a large number of pro-inflammatory cytokines, continuously strengthen the local inflammatory response, promote cholesterol deposition and accelerate cell death, and form the lipid core of atherosclerosis. In this case, the inflammation is further amplified to create a cascade effect, which promotes the development and worsening of the atherosclerotic plaque, which eventually leads to plaque rupture and an acute thrombotic event.
At the same time, during the occurrence and development of atherosclerosis, vascular smooth muscle cells will be activated by inflammation and transform into macrophage-like cells. Macrophage-like cells secrete various pro-inflammatory factors (eg, MFG-E8, MCP-1, calpain-1, matrix metalloproteinases) that contribute to the occurrence of "fibrocap instability" and exacerbate plaque instability and rupture.
It is worth noting that once the inflammation is activated, it will not completely resolve with the decrease of LDL-C and Ox-LDL, but will gradually become a "continuous self-strengthening process". Throughout the process, even if the upstream LDL-C falls to very low levels, if the inflammation is not well controlled, it can still promote plaque instability. Therefore, inflammation is an important component that constitutes a residual risk of atherosclerosis.
Yimaitong: With the release of the results of the CANTOS study in 2017, the benefit of anti-inflammatory therapy in ASCVD has been confirmed, providing strong evidence-based medical evidence for the "inflammation hypothesis". Can you tell us about some of the new developments in recent years in terms of inflammation and residual risk of ASCVD?
Professor Kai Huang
Currently, there has been more progress in inflammation and residual risk of ASCVD.
In terms of drugs that target inflammatory mechanisms, such as canakinumab (targeting IL-1β) and colchicine, studies have found that in patients with chronic coronary syndrome (CCS), stable coronary heart disease, or acute coronary syndrome (ACS), the addition of these drugs to statin therapy can further reduce the occurrence of events and can effectively control residual risk.
In the CANTOS study of canakinumab, the risk of cardiovascular events was reduced by 7%, 15%, and 14% in the primary endpoint of kanakinumab (50 mg, 150 mg, and 300 mg) compared with placebo, suggesting that canakinumab-targeted anti-inflammatory therapy alone significantly reduced the risk of cardiovascular disease due to atherosclerosis.
The 2019 COLCOT study found that colchicine reduced the composite endpoint of patients following recent myocardial infarction. A mean follow-up of 22.6 months showed a significant 23% reduction in the primary composite endpoint risk for patients in the colchicine group compared with the placebo group. In addition, the 2020 LoDoCo2 study found that the use of low-dose colchicine in the CCS population also reduced endpoint events by 31%.
These three studies provide evidence to support anti-inflammatory therapy by demonstrating that anti-inflammatory therapy can reduce the incidence of events in addition to statin therapy, particularly in patients with elevated C-reactive protein (CRP). It is expected that more and more effective drugs can be developed in the future that can antagonize a variety of pro-inflammatory factors.
IN APRIL 2023, THE LANCET PUBLISHED A META-ANALYSIS OF THREE STUDIES, INCLUDING PROMINENT, REDUCE-IT, AND STRENGTH, WHICH AIMED TO EXPLORE THE EFFECT OF RESIDUAL INFLAMMATION MEASURED BY HIGH-SENSITIVITY C-REACTIVE PROTEIN (HS-CRP) ON CARDIOVASCULAR RISK IN ASCVD PATIENTS RECEIVING STATIN THERAPY. The results of the three studies, which were divided into four groups according to the tetrartile method, showed that after adequate adjustment for LDL-C and residual cholesterol risk, residual inflammation was associated with a 30% increase in the relative risk of cardiovascular events and a more than 1-fold increase in the risk of cardiovascular death and all-cause death.
Therefore, whether it is CCS, stable coronary heart disease, or ACS patients, it is necessary to pay attention to people with high CRP and add anti-inflammatory therapy. Of course, evidence from larger cardiovascular outcome trials (COVTs) is needed.
Yimaitong: Do you think inflammation will be the next ASCVD management target?
Professor Kai Huang
Whether inflammation can be the next ASCVD management target depends on several factors:
First, in patients with high CPR levels, multiple studies have demonstrated benefit from the addition of anti-inflammatory therapies to those who reduce LDL-C levels with statins, PCSK9 inhibitors, Inclisiran, or ezetimibe. However, further studies are needed to confirm the benefits of anti-inflammatory therapy in patients with low CRP levels.
Second, based on the available evidence-based evidence, it is a false proposition to consider inflammation independent of LDL-C as the goal of ASCVD management. This is mainly because the contribution of the inflammatory response to atherosclerosis is dependent on LDL-C. First, ox-LDL-C is a powerful pro-inflammatory factor, and secondly, although inflammation can independently lead to plaque instability after LDL-C reduction, this is based on the occurrence of atherosclerotic plaques, and without the increase in LDL, atherosclerotic plaques will not form, which is the reason why most acute infectious diseases cannot directly lead to atherosclerosis.
In addition, in 2021, Professor Peter Libby explored the relationship between cholesterol lowering and inflammation in a review published in Nature. One of its core ideas is to merge the cholesterol theory of atherosclerosis with the theory of inflammation, arguing that one is indispensable. Current studies have also been conducted on the basis of statin therapy. Therefore, it makes no sense to talk about the pro-atherosclerotic effects of inflammation completely independent of hypercholesterolemia or high LDL-C levels.
Expert Profile
Professor Kai Huang
- He is currently the Vice President of Union Hospital Affiliated to Huazhong University of Science and Technology, Director of the Department of Cardiology, and Director of the Liyuan Cardiovascular Clinical Center of Tongji Medical College
- Director of Hubei Provincial Key Laboratory of Metabolic Abnormalities and Vascular Aging
- Director of Hubei Provincial Clinical Research Center for Metabolic Cardiovascular Disease
- Director of Hubei Provincial Center for Cardiovascular Disease Prevention and Control
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