Plasma levels of the inflammatory biomarker high-sensitivity C-reactive protein (hsCRP) predict vascular risk with an effect estimate as large as that of total or high-density lipoprotein ...cholesterol. Further, randomized trial data addressing hsCRP have been central to understanding the anti-inflammatory effects of statin therapy and have consistently demonstrated on-treatment hsCRP levels to be as powerful a predictor of residual cardiovascular risk as on-treatment levels of low-density lipoprotein cholesterol. Yet, although hsCRP is clinically useful as a biomarker for risk prediction, most mechanistic studies suggest that CRP itself is unlikely to be a target for intervention. Moving upstream in the inflammatory cascade from CRP to interleukin (IL)-6 to IL-1 provides novel therapeutic opportunities for atheroprotection that focus on the central IL-6 signaling system and ultimately on inhibition of the IL-1β-producing NOD-like receptor family pyrin domain containing 3 inflammasome. Cholesterol crystals, neutrophil extracellular traps, atheroprone flow, and local tissue hypoxia activate the NOD-like receptor family pyrin domain containing 3 inflammasome. As such, a unifying concept of hsCRP as a downstream surrogate biomarker for upstream IL-1β activity has emerged. From a therapeutic perspective, small ischemia studies show reductions in acute-phase hsCRP production with the IL-1 receptor antagonist anakinra and the IL-6 receptor blocker tocilizumab. A phase IIb study conducted among diabetic patients at high vascular risk indicates that canakinumab, a human monoclonal antibody that targets IL-1β, markedly reduces plasma levels of IL-6, hsCRP, and fibrinogen with little change in atherogenic lipids. Canakinumab in now being tested as a method to prevent recurrent cardiovascular events in a randomized trial of 10 065 post-myocardial infarction patients with elevated hsCRP that is fully enrolled and due to complete in 2017. Clinical trials using alternative anti-inflammatory agents active against the CRP/IL-6/IL-1 axis, including low-dose methotrexate and colchicine, are being explored. If successful, these trials will close the loop on the inflammatory hypothesis of atherosclerosis and serve as examples of how fundamental biologic principles can be translated into personalized medical practice.
IL (interleukin)-6 is a pivotal cytokine of innate immunity, which enacts a broad set of physiological functions traditionally associated with host defense, immune cell regulation, proliferation, and ...differentiation. Following recognition of innate immune pathways leading from the NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3) inflammasome to IL-1 to IL-6 and on to the hepatically derived clinical biomarker CRP (C-reactive protein), an expanding literature has led to understanding of the proatherogenic role for IL-6 in cardiovascular disease and thus the potential for IL-6 inhibition as a novel method for vascular protection. In this review, we provide an overview of the mechanisms by which IL-6 signaling occurs and how that impacts upon pharmacological inhibition; describe murine models of IL-6 and atherogenesis; summarize human epidemiological data outlining the utility of IL-6 as a biomarker of vascular risk; outline genetic data suggesting a causal role for IL-6 in systemic atherothrombosis and aneurysm formation; and then detail the potential role of IL-6 inhibition in stable coronary disease, acute coronary syndromes, heart failure, and the atherothrombotic complications associated with chronic kidney disease and end-stage renal failure. Finally, we review anti-inflammatory and antithrombotic findings for ziltivekimab, a novel IL-6 ligand inhibitor being developed specifically for use in atherosclerotic disease and poised to be tested formally in a large-scale cardiovascular outcomes trial focused on individuals with chronic kidney disease and elevated levels of CRP, a population at high residual atherothrombotic risk, high residual inflammatory risk, and considerable unmet clinical need.
The recognition that atherosclerosis is a complex chronic inflammatory disorder mediated through both adaptive and innate immunity has led to the hypothesis that anticytokine therapies targeting ...specific IL (interleukin) signaling pathways could serve as powerful adjuncts to lipid lowering in the prevention and treatment of cardiovascular disease. Cytokines involved in human atherosclerosis can be broadly classified as proinflammatory and proatherogenic (such as IL-1, IL-6, and TNF tumor necrosis factor) or as anti-inflammatory and antiatherogenic (such as IL-10 and IL-1rA). The recent CANTOS (Canakinumab Anti-Inflammatory Thrombosis Outcomes Study) has shown that specific targeting of IL-1β can significantly reduce cardiovascular event rates without lipid or blood pressure lowering. In CANTOS, the magnitude of benefit of this cytokine-targeted approach to atherosclerosis treatment was associated to the magnitude of reduction of the central signaling cytokine IL-6 and the downstream clinical biomarker high-sensitivity CRP (C-reactive protein). By contrast, in the recent CIRT (Cardiovascular Inflammation Reduction Trial), low-dose methotrexate neither reduced IL-1β, IL-6, or high-sensitivity CRP nor lowered cardiovascular event rates. Taken together, these 2 contemporary trials provide proof of principle that focused cytokine inhibition, not broad-spectrum anti-inflammatory therapy, is likely to be crucial for atheroprotection. This review provides an overview of cytokines in atherosclerosis, the potential benefits and risks associated with targeted anticytokine therapies, and a look to the future of clinical practices addressing residual inflammatory risk.
The inflammatory biomarker high-sensitivity C-reactive protein (hsCRP) adds prognostic information on cardiovascular risk comparable to blood pressure or cholesterol. Values <1, 1 to 3, and >3 mg/l ...indicate lower, average, or higher relative cardiovascular risk, respectively. Global risk algorithms that include hsCRP outperform those solely using Framingham covariates. Although diet, exercise, and smoking cessation are first steps for patients with a proinflammatory response, JUPITER (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) trial data demonstrate that statins reduce by 47% the rate of first myocardial infarction, stroke, or confirmed cardiovascular death when given to patients with low-density lipoprotein-C levels of <130 mg/dl and hsCRP of >2 mg/l (hazard ratio: 0.53; 95% confidence interval: 0.40 to 0.69; p < 0.00001). In current U.S. guidelines, hsCRP carries a class IIb assessment and is most appropriate in primary prevention when clinical decisions to initiate statin therapy are uncertain. Ongoing multinational trials are pursuing whether reducing inflammation will decrease vascular event rates.
Life-threatening cardiovascular events occur despite control of conventional risk factors. Inflammation, as measured by high-sensitivity C-reactive protein (hsCRP) concentration, is associated with ...future vascular events in both primary and secondary prevention, independent of usual risk markers. Statins are powerful lipid-lowering agents with clinically relevant anti-inflammatory effects. Recent data support targeting the interleukin (IL)-1-to-IL-6-to-CRP signaling pathway as an adjunctive method for atheroprotection. The CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study) trial showed that reducing inflammation through IL-1β inhibition significantly reduced vascular risk, beyond that achievable with lipid lowering. CANTOS further demonstrated a 31% reduction in cardiovascular mortality and all-cause mortality among patients treated with canakinumab who achieved the largest reductions in hsCRP, as well as efficacy in high-risk patients with chronic kidney disease and diabetes. This review outlines the clinical implications of CANTOS for patients with "residual inflammatory risk," the potential benefits and risks associated with anti-inflammatory therapy, and the importance of CANTOS for future drug development.
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