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.
This paper offers a theory of communication visibility based on a field study of the implementation of a new enterprise social networking site in a large financial services organization. The emerging ...theory suggests that once invisible communication occurring between others in the organization becomes visible for third parties, those third parties could improve their metaknowledge (i.e., knowledge of
who knows what
and
who knows whom
). Communication visibility, in this case made possible by the enterprise social networking site, leads to enhanced awareness of who knows what and whom through two interrelated mechanisms: message transparency and network translucence. Seeing the contents of other’s messages helps third-party observers make inferences about coworkers' knowledge. Tangentially, seeing the structure of coworkers' communication networks helps third-party observers make inferences about those with whom coworkers regularly communicate. The emerging theory further suggests that enhanced metaknowledge can lead to more innovative products and services and less knowledge duplication if employees learn to work in new ways. By learning vicariously rather than through experience, workers can more effectively recombine existing ideas into new ideas and avoid duplicating work. Moreover, they can begin to proactively aggregate information perceived daily rather than engaging in reactive search after confronting a problem. I discuss the important implications of this emerging theory of communication visibility for work in the knowledge economy.
The argument proffered in this paper is that use of enterprise social networking technologies can increase the accuracy of people’s metaknowledge (knowledge of “who knows what” and “who knows whom”) ...at work. The results of a quasi-natural field experiment in which only one of two matched-sample groups within a large financial services firm was given access to the enterprise social networking technology for six months revealed that by making people’s communications with specific partners visible to others in the organization, the technology enabled observers to become aware of the communications occurring amongst their coworkers and to make inferences about what and whom those coworkers knew based on the contents of the messages they sent and to whom they were sent. Consequently only individuals in the group that used the social networking technology for six months improved the accuracy of their metaknowledge (a 31% improvement in knowledge of who knows what and an 88% improvement in knowledge of who knows whom). There were no improvements in the other group over the same time period. Based on these findings, how technologically enabled “ambient awareness”—awareness of ambient communications occurring amongst others in the organization—can be an important antecedent for knowledge acquisition is discussed.
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.
Unelected Power Tucker, Paul
2019, 2018., 20180522, 2018, 2019-10-08, 2018-05-22
eBook
Guiding principles for ensuring that central bankers and other unelected policymakers remain stewards of the common good Central bankers have emerged from the financial crisis as the third great ...pillar of unelected power alongside the judiciary and the military. They pull the regulatory and financial levers of our economic well-being, yet unlike democratically elected leaders, their power does not come directly from the people. Unelected Power lays out the principles needed to ensure that central bankers, technocrats, regulators, and other agents of the administrative state remain stewards of the common good and do not become overmighty citizens. Paul Tucker draws on a wealth of personal experience from his many years in domestic and international policymaking to tackle the big issues raised by unelected power, and enriches his discussion with examples from the United States, Britain, France, Germany, and the European Union. Blending economics, political theory, and public law, Tucker explores the necessary conditions for delegated but politically insulated power to be legitimate in the eyes of constitutional democracy and the rule of law. He explains why the solution must fit with how real-world government is structured, and why technocrats and their political overseers need incentives to make the system work as intended. Tucker explains how the regulatory state need not be a fourth branch of government free to steer by its own lights, and how central bankers can emulate the best of judicial self-restraint and become models of dispersed power. Like it or not, unelected power has become a hallmark of modern government. This critically important book shows how to harness it to the people's purposes.
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