ReviewCombating Inflammation in Cardiovascular Disease
Introduction
Cardiovascular diseases including ischaemic heart disease, cerebrovascular disease and peripheral vascular disease are the leading causes of death in Australia, with a total of 29,442 deaths in 2018 [1]. Many people suffer cardiovascular events despite control of traditional cardiovascular risk factors such as smoking, hypertension and diabetes, and nearly 40% of the general population with normal cholesterol levels die from ischaemic heart disease [2]. Hence, atherosclerosis can no longer be considered solely due to lipoprotein accumulation in the arterial wall, but rather inflammation is increasingly thought to play an important part in the initiation and progression of atherosclerosis [3]. Many recent trials have provided proof of this concept with the most noteworthy study being Anti-inflammatory Therapy with Canakinumab for Atherosclerotic Disease (CANTOS) trial, which showed that in patients with controlled lipids but residual inflammatory risk, the anti-inflammatory agent canakinumab provided additional cardiovascular benefit in proportion to the degree of reduction in inflammation [4]. The most well studied biomarker for assessing inflammation and the most used in research and clinical practice is high sensitivity C-reactive protein (HsCRP)—although upstream biomarkers of inflammation such as interleukin 1 (IL-1), interleukin 18 (IL-18) interleukin 6 (IL-6) and tumour necrosis factor alpha (TNFα) have also been investigated but are less clinically available [3]. The association between elevated CRP and cardiovascular risk persists even after adjustment for age and other traditional cardiovascular risk factors [5]. Several studies have also shown an association between elevated CRP and the prevalence of underlying atherosclerosis, the incidence of first cardiovascular events and the risk of recurrent cardiovascular events amongst patients with established disease [[6], [7], [8], [9], [10], [11]]. A recently proposed strategy for targeting residual cardiovascular risk incorporates measurement of HsCRP so that an individualised treatment plan to lower cardiovascular risk in patients can be made [12]. As therapies targeting different aspects of the immune system emerge, it will be important to balance the benefit of lowering inflammation with its cost and side effect profile, especially the increased predisposition for infections and malignancy [4]. This review aims to summarise important aspects pertaining to inflammation in cardiovascular disease which opens new avenues in cardiovascular therapeutics. It will highlight the pathophysiological pathways leading to inflammation and subsequent atherogenesis, the utility of HsCRP as a downstream biomarker of this inflammatory cascade and explore different drug classes for targeting this inflammation.
Section snippets
Pathophysiology of Inflammation in Cardiovascular Disease
The process of atherogenesis involves components of both the innate immune system and adaptive immune system [13]. The innate immune system provides an immediate and non-specific first line of host defence. Specialised cytokines known as chemokines attract mononuclear phagocytes and facilitate its migration into the intima via leukocyte adhesion molecules [13]. Maturation of these monocytes into macrophages and subsequent foam cell formation leads to plaque generation. The adaptive immune
HsCRP as a Biomarker of Inflammation
The association between CRP and cardiovascular disease was reported more than 20 years ago [18]. Due to its long half-life, HsCRP is the most useful biomarker for use in clinical practice, with IL-1 and IL-6 mainly reserved for research purposes.
Higher levels of HsCRP have been seen in people with established atherosclerotic plaques, as well as those with risk factors for accelerated atherosclerosis such as metabolic syndrome, obesity and insulin resistance. In particular, adipose tissue is a
Therapeutic Options to Treat Inflammation in Cardiovascular Disease
Outlined below is the evidence for different treatment modalities that target inflammation, utilising HsCRP as a surrogate marker of inflammation. Lifestyle factors such as a healthy diet, exercise and smoking cessation also reduce inflammation and cardiovascular disease and should be recommended in conjunction with any pharmacological therapies.
Statins
Statins reduce LDL cholesterol, CRP and cardiovascular events when used in primary prevention such as after an acute coronary [9,[32], [33], [34], [35]]. The observation that statins reduce CRP and that CRP is correlated with cardiovascular disease raised the possibility that the risk reduction with statin therapy may be at least partly attributed to its anti-inflammatory effects. These pleiotropic effects of statins are mediated by modulating various signalling pathways in endothelial cells
Anti-Inflammatory Drugs
A summary of anti-inflammatory medications, their actions and effect on C-reactive protein is provided in Table 2.
Conclusion
The CANTOS and COLCOT trials strongly support the concept that decreasing inflammation reduces the risk of cardiovascular disease. However, the fact the methotrexate (a nonspecific immune modulator) had no effect in reducing inflammation and cardiovascular endpoints suggests that specific pathways need to be targeted to achieve a desirable risk reduction. Colchicine targeted the NLRP3 inflammasome and canakinumab targeted the IL-1 pathway and both decreased inflammation and cardiovascular risk.
Conflicts of Interest
There are no conflicts of interest to disclose.
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