New Study Identifies 12 Proteins Linking Cholesterol and Inflammation in Ischemic Heart Disease, Pointing to Dual-Target Therapies
核心洞察
Oxford Population Health (搜索) researchers identified 12 proteins causally linked to ischemic heart disease (搜索) using proteomic and genetic analyses of 9,500 proteins in Chinese adults.
Eight proteins were lipid-related, one was hypertension-related, and three were linked to chronic inflammation, supporting dual targeting of lipids and inflammation beyond statin therapy.
The study used samples from the China Kadoorie Biobank comparing 1,976 IHD cases with 2,001 controls, with findings partially replicated in European ancestry populations.
A new study from Oxford Population Health (搜索) has identified 12 key proteins with likely causal roles in ischemic heart disease (搜索) (IHD), providing fresh evidence that effective treatment strategies must address both cholesterol and inflammation. The findings, published in the Journal of the American College of Cardiology (JACC), come at a time when cardiologists are increasingly recognizing that lipid-lowering alone leaves substantial residual risk in patients with cardiovascular disease.
The research team used high-throughput proteomic assays — employing both Olink and SomaScan platforms — to measure levels of 9,500 proteins in blood samples from participants in the China Kadoorie Biobank (CKB). The CKB study, jointly coordinated by Oxford Population Health (搜索) in the UK and Peking University in China, recruited 512,000 adults from 10 diverse areas of China between 2004 and 2008. For this analysis, researchers compared samples from 1,976 participants who subsequently developed IHD with those from 2,001 participants who remained free of IHD during follow-up.
Twelve Proteins with Causal Links to IHD
Among the 12 proteins identified as likely linked to IHD, eight were lipid-related, one was hypertension-related, and three were related to chronic inflammation — a lesser-known but increasingly recognized driver of conditions that cause heart attack and stroke. The researchers then used advanced genetic analyses to examine the likely causal associations of these proteins with IHD risk.
"Chronic inflammation in the walls of the arteries supplying the heart occurs in response to damage to the inner lining of the artery walls caused by higher levels of blood pressure or cholesterol," the researchers explained. "Ongoing inflammation results in blockage of the coronary arteries and reduced blood flow to the heart."
Professor Robert Clarke, Emeritus Professor at Oxford Population Health (搜索) and joint senior author of the paper, stated: "The findings provide support for evaluation of new drugs to lower blood levels of both lipids and inflammation for improved treatment of IHD, beyond statin therapy."
The Dual-Target Imperative
The study underscores a growing consensus in cardiology: while statin treatment is highly effective at lowering blood cholesterol and reducing the risk of heart attacks and stroke, up to 50% of residual cardiovascular risk in patients treated with statins may be attributable to inflammation. The Oxford findings suggest that combinations of drugs targeting lipids such as LDL-C (搜索) and inflammation simultaneously should be prioritized for development and evaluation in clinical trials.
This dual-target approach aligns with recent advances in coronary imaging that now allow clinicians to detect inflammation in and around coronary arteries. Researchers from the University of Oxford previously developed an artificial intelligence-enhanced form of coronary computed tomography angiography (CCTA) showing that people with inflamed arteries had dramatically elevated risk: one inflamed artery increased mortality risk by 13-fold, and three inflamed arteries increased the risk by 30-fold.
Cross-Ancestry Validation and Limitations
The researchers performed identical analyses for similar proteins in blood samples from people of European ancestry and reported similar, albeit not identical, results for certain protein biomarkers. This partial replication highlights the need for further studies involving multiple ancestries to better understand the genetic architecture of proteins in diverse populations.
The team also compared their findings with those reported in previous studies that used less robust analytic approaches and identified a number of weaknesses, including a lack of replication in different populations.
Clinical Implications and the Therapeutic Pipeline
The only drug currently approved by the US Food and Drug Administration to reduce cardiovascular inflammation is colchicine (Lodoco), authorized in 2023. However, not all clinical trials have shown that colchicine reduces the risk of major adverse cardiovascular events (MACE), and its side-effect profile — including diarrhea, nausea, cramping and muscle pain — has limited cardiology community adoption.
More advanced therapies targeting inflammatory pathways are now in development. Novo Nordisk's ziltivekimab, a monoclonal antibody directed against the inflammatory cytokine IL-6, has phase 3 trial results expected later this year. Other companies pursuing IL-6 targeting include Novartis and CSL Behring. Additionally, at least five early-stage trials are underway targeting the NLRP3 inflammasome (搜索), a multi-protein sensor that triggers production of IL-1β, IL-18 and IL-6 in response to danger signals such as modified cholesterol.
Professor Zhengming Chen, Principal Investigator for CKB in the UK and a senior author of the study, commented on the significance of the findings, noting that East Asia, particularly China, has witnessed some of the largest increases in IHD prevalence and deaths in recent decades, highlighting the need for improved treatment and prevention strategies. Heart disease caused by blockage of the coronary arteries accounts for about 9 million deaths annually worldwide.