CARDIOVASCULAR disease remains the leading cause of morbidity and mortality both worldwide and in Australia.
Atherosclerosis, which is a major cause of cardiovascular disease, is mainly triggered by a maladaptive response to cholesterol deposits within the blood vessel wall which leads to the activation of endothelial cells, leucocytes and smooth muscle cells and subsequent plaque formation. Atherosclerotic plaque within the coronary vasculature can lead to a reduction of myocardial blood flow due to coronary artery luminal narrowing or alternatively, superimposed thrombosis from plaque surface disruption leading to an acute coronary syndrome (ACS).
ACS forms a significant proportion of cardiovascular disease which requires inpatient hospital management and encompasses a spectrum of clinical disorders of myocardial ischaemia or infarction, presenting as unstable angina, non-ST segment elevation myocardial infarction (NSTEMI) or ST-segment elevation myocardial infarction (STEMI).
There is increasing clinical and experimental data supporting the role of inflammation in atherogenesis and atherothrombosis (here and here). Cytokines, which are immunomodulatory molecules, such as interleukin-1b (IL-1b) and interleukin-6 (IL-6) have been shown to be predictive of coronary artery disease independent of traditional cardiovascular risk factors (here and here). Increased IL-1b levels result in increased leucocyte adhesion to vascular endothelial cells, which form the lining of blood vessels, allowing migration into the subintimal layer of the blood vessel wall and the development of plaque formation. Subsequent generation of IL-6 leads to an elevation in downstream inflammatory biomarkers such as high-sensitivity C-reactive protein (hsCRP).
hsCRP, which is synthesised in the liver, is a robust marker of systemic inflammation and strongly correlates with prognosis in atherosclerotic cardiovascular disease. While not being specific for vascular disease, hsCRP levels enable clinicians to estimate vascular risk and thus better risk-stratify patients at intermediate cardiovascular risk. This had led to hsCRP being incorporated into clinical scoring systems such as the Reynold’s risk score. It is also important to note that patients with ACS are particularly vulnerable in the period just after their index events, due to a global pro-inflammatory process affecting the “stability” of other atherosclerotic plaque. This instability and subsequent plaque rupture leads to superimposed blood clot formation within the blood vessel and is the triggering event that leads to most heart attacks.
The innate immune system is the first line of defence against foreign insults such as infections but also plays a significant role in atherosclerosis. Neutrophils, which are the most abundant white blood cell in humans, have been shown to be involved in atherothrombosis, low density lipoprotein (LDL) oxidation and plaque erosion and destabilisation via generation of reactive oxygen species. Cytokines generated from pro-inflammatory plaque contents such as oxidised LDL attract circulating monocytes into the plaque, where they differentiate into macrophages. The macrophages attempt to “clean up” the oxidised LDL by taking it up using scavenger receptors. Eventually though, the macrophage cellular cholesterol processing capacity is exhausted, and they become overloaded with cholesteryl esters and subsequently become foam cells. These foam cells undergo both necrosis and apoptosis and form a necrotic core within the plaque. The size of these necrotic cores has been shown to correlate with plaque instability and rupture and worse outcomes in atherosclerotic cardiovascular disease (ASCVD).
The current mainstay of management of ASCVD includes lipid-lowering therapy, statin and aspirin use as well as screening and modification of risk factors such as metabolic syndrome, regular exercise, smoking cessation, and glycaemic and blood pressure control. Insulin resistance and obesity — known risk factors for atherosclerosis — are also associated with a state of chronic inflammation. There is also a well known association between pro-inflammatory states in autoimmune conditions such as rheumatoid arthritis with an elevated risk for cardiovascular disease.
The current issue is that even with optimal medical therapy in keeping with national and international guidelines, which include aspirin, statins, b-blockers and angiotensin-converting enzyme inhibitors, the recurrence rate of adverse cardiovascular events in patients with ACS remains as high as 20%. In addition, there is also a significant subset of patients who have coronary events in the absence of the traditional risk factors and this population has been shown to have a higher rate of in-hospital mortality. One possible explanation for this is unidentified genetic or environmental factors that lead to a pro-inflammatory state.
This highlights a clear gap in the current management of patients with ASCVD and given the increasing evidence supporting the role of inflammation, it is only logical to investigate new therapeutic agents to target these immune pathways in patients with atherosclerosis and manage the issue of systemic inflammation.
Statins, which are a current mainstay in patients with ACS, are known to have anti-inflammatory properties in addition to their effects on lipid levels. The JUPITER (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) trial showed the benefits of statin treatment in patients with a high inflammatory risk even without significant hypercholesterolaemia.
There are several immunomodulatory drugs currently under investigation for use in atherosclerotic cardiovascular disease, including microtubule inhibitors; antimetabolites; leukotriene inhibitors; inhibitors of pro-inflammatory cytokines, such as IL-1b, IL-6 and TNF-a; phospholipase A2 inhibitors; and antioxidants. Of these, colchicine and IL-1b modulation therapy have shown the most promising results in large randomised clinical outcome trials.
The 2017 CANTOS (Canakinumab Antiinflammatory Thrombosis Outcome Study) study was the obvious standout clinical cardiovascular immunotherapy trial that consolidated the inflammatory hypothesis of atherosclerosis. The trial showed a reduction in adverse cardiac outcomes in post-myocardial infarction patients with elevated hsCRP levels who were treated with canakinumab — a IL-1b antagonist — in addition to current standard medical therapy.
Our group has an interest in the use of colchicine — which is well known for its use in gout and familial Mediterranean fever — for atheroprotective use in patients with ASCVD. Colchicine is an irreversible tubulin inhibitor and prevents microtubule polymerisation. It has been shown to be effective for secondary prevention in patients with stable coronary artery disease, and data from our group have shown its effects on blocking inflammasome-mediated release of IL-1b, reducing inflammatory cytokines in patients with ACS, as well as stabilisation of coronary plaque on coronary computed tomography angiography. There is a plethora of ongoing clinical trials assessing the use of colchicine in various clinical subsets of patients with ASCVD, including patients with STEMI, ACS or stable coronary disease and patients undergoing percutaneous coronary intervention.
These are indeed exciting times and hopefully, in the next few years, we will be able to add to our understanding of atheroinflammation and have new research results to provide further guidance and newer therapeutic options in the fight to reduce atherosclerotic cardiovascular disease.
Dr Rahul Kurup is a consultant cardiologist based in New South Wales and is currently undertaking a PhD with the Heart Research Institute and Royal Prince Alfred Hospital, looking at the role of inflammation in heart disease. He is passionate about lifestyle medicine and can be found on Twitter @elninokurup.
Associate Professor Sanjay Patel is a Staff Interventional Cardiologist at Royal Prince Alfred Hospital, Group Leader at the Heart Research Institute and Senior Lecturer at the Sydney Medical School. His research encompasses expertise in interventional and clinical cardiology, animal models of atherosclerosis and basic vascular biology.
The statements or opinions expressed in this article reflect the views of the authors and do not represent the official policy of the AMA, the MJA or MJA InSight unless that is so stated.
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