Recent studies have revealed that several diseases that comprise the leading causes of illness and mortality globally may be sustained by systemic chronic inflammation. The underlying reasons for this inflammation are not always clear but may be linked to lifestyle, environment, social or genetic factors. 

Inflammation is associated with conditions such as cardiovascular disease, cancer, diabetes, chronic kidney disease, non-alcoholic fatty liver disease and autoimmune and neurodegenerative disorders.

Taking a closer look at cardiovascular disease (CVD), new research is increasingly examining the role of inflammation in its development and as a basis for potential therapeutic strategies.

CVD is an umbrella term that includes coronary artery diseases such as angina, heart attack and heart failure, as well as stroke, peripheral artery disease and aortic aneurysm. The underlying mechanisms vary depending on the disease but usually involve atherosclerosis - the buildup of fats, cholesterol and other substances in artery walls, known as plaque, which can restrict blood flow.

Many researchers agree that inflammation is a central process in the development of CVD. However, exactly what role it plays is currently unclear. Currently we do know that plaque in blood vessels is perceived by the immune system as foreign and possibly dangerous. The result is that plaque is "walled off" from the flowing blood. 

If the plaque ruptures, it comes into contact with blood and a blood clot can form, leading to a heart attack if an artery to the heart is blocked, or an ischemic stroke if an artery in or leading to the brain is blocked.

It is also well-established that biomarkers of inflammation are associated with CVD risk. A number of these mediators of inflammation have been studied, both as indicators of disease and as likely causal agents.

Proteins in the blood that are established markers of inflammation include Interleukin-6. cytokines, serum amyloid A, fibrinogen, and high-sensitivity C-reactive protein (hsCRP). In terms of CVD risk prediction, only high-sensitivity CRP is routinely used in clinical practice.

The first evidence that hsCRP predicts an individual's risk independently of traditional factors appeared 20 years ago. More recently, in an analysis of data from more than 160,000 people across 54 long-term prospective studies, higher levels of circulating CRP were associated with an increase in risk for both coronary heart disease and CVD mortality.

In the primary prevention setting, measurement of hsCRP adds as much to risk prediction as does evaluation of HDL or total cholesterol, both of which are recommended in current prevention guidelines.

A 2009 study known as the JUPITER trial made it clear that people with levels of hsCRP higher than 2 milligrams per litre benefit from statin therapy even in the absence of raised blood cholesterol.

A number of other mediators involved in the inflammatory process are involved in the interaction between the immune system and the development of atherosclerosis. The link is complex, involving specialized immune responses at several stages in the progression of plaque formation. 

Helper T cells have been shown to be critical in atherosclerosis. When activated by antigens in the blood vessel wall, they trigger an inflammatory cascade of immune cells, ultimately leading to plaque formation and progression.

Paul M. Ridker MD, at Brigham and Women’s Hospital, Boston, MA, believes, "In addition to high blood cholesterol, inflammation is intimately related to atherosclerosis, the process of the inflammation in the heart itself. Targeting inflammation - as a way to lower heart attack risk - might be a new treatment for this disease."

His team used CRP as a marker of inflammation and found it predicted future heart attack and stroke. They also showed that the benefits of aspirin were greater in the presence of high inflammation.

"Even if your cholesterol level is low, if your CRP is high you have higher than anticipated risk of a future heart attack or stroke," he concludes.

A further biomarker for systemic inflammation that has received attention recently is GlycA. It is currently being investigated as a potential biomarker to be used in CVD risk assessment.

In terms of statin therapy, multiple trials have now shown that as well as lowering lipids, statins may be effective in the primary and secondary prevention of CVD partly through their anti-inflammatory effect.

In addition to statins, several other drugs targeting specific inflammatory proteins or pathways are showing benefits in CVD trials. 

The CANTOS trial, in 2017, showed that targeting innate immunity with the monoclonal antibody canakinumab significantly lowers recurrent rates of heart attack and cardiovascular death among patients already on high intensity statins. The drug - approved for clinical use in rheumatologic disorders - reduced inflammation without reducing LDL cholesterol.

Another trial examined the common gout medication, colchicine, a long-standing treatment for inflammation which inhibits several inflammatory pathways, including those relating to atherosclerosis.

It was tested by a team led by Dr Mark Nidorf of GenesisCare, a major heart disease treatment provider in Australia. They gave 5,552 coronary artery disease patients either colchicine or placebo, alongside lipid lowering and antithrombotic therapy.

After a follow up of 30 months, the drug was found to significantly reduce cardiovascular death, myocardial infarction, ischaemic stroke, and ischaemia-driven coronary revascularisation. 

Findings were presented at the European Society of Cardiology Congress 2020, held online. Dr Nidorf said, “Over a decade, more than one in three heart patients will have another heart attack or stroke, or die from heart disease, despite taking preventive medication. Our study shows that this could be reduced to one in four with the addition of low-dose colchicine."

Another recent study looked at the popular supplement glucosamine, a dietary supplement used to treat osteoarthritis. Previous work indicated that it may play a role in preventing CVD and lowering mortality. So researchers analysed figures from people taking glucosamine supplements to help relieve the symptoms of osteoarthritis and joint pain.

Professor Lu Qi of Tulane University, New Orleans, USA, and colleagues used information on 466,039 men and women followed for 6 to 10 years. Once many risk factors were taken into account, use of glucosamine was linked to a 15% lower risk of cardiovascular events, a 22% lower risk of cardiovascular death, an 18% lower risk of coronary heart disease, and a 9% lower risk of stroke.

The scientists suggest that the effects are due to the ant-inflammatory action of glucosamine. "These findings suggest that glucosamine might have a preventive role in the development of CVD," they write in the BMJ.

The concept of CVD, and atherosclerosis in particular, as an inflammatory process, while seemingly relatively recent, is rooted in very early pathological observations. But the role of inflammatory mediators has only been clearly identified in the last few decades and the characterization of CVD as a chronic low-grade inflammatory condition is now largely accepted. 

With these advances in our understanding of the inflammation, as well as the cumulative findings from previous clinical trials, the use of safe, cost-effective anti-inflammatory therapies for treating patients with CVD has the potential to greatly improve patient care and public health.

References and Resources

1. https://www.nature.com/articles/s41591-019-0675-0 Furman, D. et al. Chronic inflammation in the etiology of disease across the life span. Nature Medicine 5 December 2019 doi: 10.1038/s41591-019-0675-0
2. https://pubmed.ncbi.nlm.nih.gov/25037581/ Golia, E. et al. Inflammation and cardiovascular disease: from pathogenesis to therapeutic target. Cardiovascular Disease and Stroke 19 July 2014 doi: 10.1007/s11883-014-0435-z
3. https://pubmed.ncbi.nlm.nih.gov/29930142/ Geovanini, G. R. et al. Atherosclerosis and inflammation: overview and updates. Clinical Science 29 June 2018 doi: 10.1042/CS20180306
4. https://academic.oup.com/eurheartj/article/39/46/4109/5173734 Ridker, P. M. et al. Has the time finally come to measure hsCRP universally in primary and secondary cardiovascular prevention? European Heart Journal 19 November 2018 doi: 10.1093/eurheartj/ehy723 
5. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4892833/  Paquissi, F. C. The role of inflammation in cardiovascular diseases: the predictive value of neutrophil–lymphocyte ratio as a marker in peripheral arterial disease. Therapeutics and Clinical Risk Management. 27 May 2016 doi: 10.2147/TCRM.S107635
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7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5488800/ Lopez-Candales, A. et al. Journal of Nature and Science. April 2017 
8. http://www.bmj.com/content/365/bmj.l1628 Ma, H. et al. Association of habitual glucosamine use with risk of cardiovascular disease: prospective study in UK Biobank. BMJ 15 May 2019 doi: 10.1136/bmj.l1628
9. https://pubmed.ncbi.nlm.nih.gov/33461451/ Muhammad, K. et al. Vascular inflammation in cardiovascular disease: Is Immune system protective or bystander. Current Pharmaceutical Design 18 January 2021 doi: 10.2174/1381612827666210118121952
10. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60447-5/fulltext Danielson, E. et al. Reduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin: a prospective study of the JUPITER trial. The Lancet 29 March 2009 doi: 10.1016/S0140-6736(09)60447-5
11. https://www.nejm.org/doi/full/10.1056/nejmoa1707914 Ridker, P. M. et al. Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. The New England Journal of Medicine 21 September 2017 doi: 10.1056/NEJMoa1707914
12. https://www.escardio.org/Congresses-&-Events/ESC-Congress/Congress-resources/Congress-news/hot-line-low-dose-colchicine-for-secondary-prevention-of-cvd-does-it-work Abstract title: Low-dose colchicine in patients with stable coronary artery disease. Presented at ESC Congress 2020 on Monday 31 August 2020

About the Author

Jane Collingwood is a medical journalist with 17 years experience reporting on all areas of medical research for online and print publications. Jane has also worked on a range of medical studies funded by the UK National Health Service within the University of Bristol in the South West of England. Jane has an academic background in psychology and has authored books on stress management and respiratory infections. Currently she is combining journalism with a national coordinating role on the UK's largest surgical research trial.