Inflammation and the heart – prime time for new therapeutic approaches

Abstract

Introduction: Atherosclerosis remains one of the main causes of cardiovascular disease.

Areas covered: A brief overview of the work summarized by Berman et al. [Berman JP, Farkouh ME, Rosenson RS. Emerging anti-inflammatory drugs for atherosclerosis. Expert Opin Emerg Drugs 2013;18(2):193-205] on the development of anti-inflammatory drugs to tackle atherosclerosis is provided.

Expert opinion: Indeed, recent data from clinical trials on anti-inflammatory drugs in coronary artery disease highlight the potential of such therapies.

Keywords::

• anti-tumor necrosis factor-α
• atherosclerosis
• coronary artery disease
• inflammation
• interleukin-1 antagonists
• leukotriene
• P-selectin
• serpin

Atherosclerosis remains one of the main causes of cardiovascular disease, which in turn is the leading cause of death worldwide. Although atherosclerosis has long been considered a disease in which lipids are being passively deposited in the arterial wall [1], the emerging picture now demonstrates that atherosclerosis is the result of dynamic and complex processes involving multiple cell types, especially inflammatory cells as well as endothelial cells and smooth muscle cells [2-4]. The first step of this process consists of the recruitment and the migration of inflammatory cells, such as macrophages, in the arterial wall. Cholesterol deposits at the atherosclerotic site result in aberrant proliferation of smooth muscle cells and massive uptake of modified low-density lipoproteins by the accumulating macrophages. These progressive modifications lead to the formation of an atherothrombotic plaque in the arterial wall. Plaque progression results in lumen stenosis, myocardial ischemia and angina, as well as acute complications such as thrombosis leading to acute coronary syndromes and even heart failure and arrhythmia (including sudden death).

Given the crucial role of inflammation during the development and progression of atherosclerosis, many anti-inflammatory strategies have emerged as potential therapeutic approaches for atherosclerotic disease [4-6]. The JUPITER study was the first large-scale ‘proof-of-concept' trial targeting inflammation to tackle atherosclerosis [7], using rosuvastatin in high-risk patients with elevated highly sensitive C-reactive protein but without any extracardiac inflammatory disease. Statin therapy was shown to improve clinical outcomes in this population. This study suggested that an anti-inflammatory treatment on top of the available therapeutic armamentarium could potentially reduce the residual risk and improve cardiovascular outcomes [6,8,9]. Additionally, intense development of anti-inflammatory strategies to treat atherosclerosis and to target its complications paved the way for new innovative clinical trials [4,10].

In a review in the previous issue, Berman et al. [11] provide an excellent summary of the current data highlighting the role of inflammation in atherosclerosis and the current means to target inflammation and reduce cardiovascular events. They also highlight the fact that both clinical and surrogate endpoints could be used in the assessment of such new therapies. Indeed, although large clinical trials with clinical endpoints provide strong evidence, studies based on surrogate endpoints allow physiological assessment and offer rapidly informative results in smaller populations [12-14].

The authors provide an extensive review of the various anti-inflammatory agents, currently on the market or under development, including venerable drugs such as methotrexate (presently under study in clinical trials), or therapies used in clinical practice such as antibodies against tumor necrosis factor, a proinflammatory cytokine. Furthermore, they also present drugs under development, including antioxidants, inhibitors of phospholipase A2 or leukotrienes, interleukin-1 antagonists or modulators, inhibitors of chemoattractant molecules or inhibitors of pathways involved in inflammatory cell adhesion. Many of these molecules have been studied in basic research studies and in small clinical trials but few large clinical trials have been already completed. Promising results have been obtained for an inhibitor of the leukotriene pathway [15] (leukotrienes are known to exert various proinflammatory effects) and more recently for an inhibitor of P-selectin [16] (P-selectins are adhesion molecules involved in interactions among endothelial cells, platelets and leukocytes). If these and other approaches are further validated, they could offer the first tailored strategies targeting inflammatory processes involved in atherosclerosis.

Whether anti-inflammatory approaches will be effective on top of standard of care therapy remains to be seen. This field of research, both at the basic and translational levels, promises to be very active in the upcoming years: it is indeed prime time for the modulation of inflammation in atherosclerosis management.

Declaration of interest

This paper has been sponsored by the Montreal Heart Institute. F Roubille has received a research grant from Servier. J-C Tardif has received a research grant from Servier and Roche.