13
Although the dominant mid–20th century paradigm viewed atherosclerosis primarily as an obstructive disease caused by the deposition of cholesterol and proliferation of smooth muscle cells in the artery wall, the inflammatory nature of atherosclerosis is not a new concept.1 Even the great 19th century pathologist Rudolf Virchow, who first described atherosclerosis, once wrote that “the softening manifests itself even in the arteries not as the consequence of a really fatty process, but as a direct product of inflammation.”2 But it was not until the 1990s that modern medical scientists began to fully appreciate the active role of the arterial wall in atherosclerosis. Atherosclerosis is not merely a passive cholesterol storage disease but an active inflammatory process involving hormone-like molecules called cytokines that recruit white blood cells and scavenger cells called macrophages that try to clear cholesterol and calcium deposits from the plaque but instead get trapped inside and contribute to its growth.3 Some plaques become very fibrous, with calcium deposits and thick caps that contain this material within the plaque. These fibrous plaques rarely cause heart attacks. But others contain abundant cholesterol and soft inflammatory cellular debris and have thin fragile caps. When the cap is breeched, the plaque contents spill into the artery lumen and attract clot-forming platelet cells, blocking the flow of blood through the artery. In a coronary artery, this causes a heart attack; in a cerebral artery, this causes a stroke. The detailed biology of inflammation is complex and beyond the scope of this book. Here we will focus only on how our new understanding of atherosclerosis as a dynamic inflammatory process has led us to explore the potential role of anti-inflammatory drugs in the prevention of heart attacks.
An important catalyst of the paradigm shift in our understanding of atherosclerosis was the recognition of circulating biological markers that signaled the presence of active inflammation somewhere in the body. One of the oldest of these nonspecific inflammatory biomarkers (but by no means the only one) is C-reactive protein (CRP), which was discovered in the 1930s and is elevated in diverse inflammatory diseases, ranging from rheumatoid arthritis to tuberculosis.4 In the 1990s, the development of a high-sensitivity CRP assay let to the realization that modest elevations of CRP, heretofore considered within the “normal range,” were associated with atherosclerotic cardiovascular disease, independently of the conventional cardiovascular risk factors enumerated in Chapter 2.5 A later study, which included a review of CRP analyses on stored samples from several statin trials confirmed this result.6 However, while it appeared that CRP and other known markers of inflammation were moderate predictors of future heart attacks and strokes, it was not clear whether these molecules were active agents or mere bystanders in the inflammatory process and whether inflammation itself was a cause or effect of atherosclerosis. Therefore, the 2009 U.S. Preventive Services Task Force did not recommend routine screening for CRP levels.7
The interest in CRP as a cardiovascular risk factor was further piqued by the results of a large statin trial called JUPITER (Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin) in 2008.8 This 17,802-patient randomized trial was unique in that it specifically targeted healthy volunteers with elevated CRP (> 2.0 mg/L) but not elevated LDL cholesterol levels. JUPITER participants were randomized to receive the highly potent statin rosuvastatin (Crestor) or a placebo. The trial was stopped early after 1.9 years of treatment because of a highly significant 44% reduction in the combined incidence of MI, stroke, revascularization, unstable angina, and death from cardiovascular causes (the prespecified primary outcome). While the outcome could readily be attributed to the 50% mean reduction in LDL cholesterol in the rosuvastatin group, rosuvastatin also reduced CRP levels by 37%. Further analysis showed that reductions in CRP were as predictive of a favorable outcome as reductions in LDL cholesterol.9 Participants who experienced large reductions in both LDL and CRP had fewer adverse cardiovascular outcomes than those who experienced large reductions in only one of these two risk factors, who in turn experienced fewer adverse cardiovascular outcomes than those whose LDL and CRP responded minimally to rosuvastatin. These results prompted medical scientists to look at statins not merely as potent cholesterol-lowering drugs but also as anti-inflammatory drugs that could spearhead a two-pronged attack on atherosclerotic cardiovascular disease. Two years later, the FDA extended their indications for rosuvastatin to include healthy persons with normal LDL cholesterol but increased risk based on a combination of age, CRP, and at least one other risk factor.10 The 2018 ACC/AHA Guideline on the Management of High Blood Cholesterol has also incorporated CRP as a risk factor to consider in primary prevention.11
The post–JUPITER controversy about whether to put inflammatory markers like CRP on an equal footing with conventional cardiovascular risk factors like LDL cholesterol led to a push, spearheaded by lead JUPITER investigator Paul Ridker, to test the “inflammation hypothesis” in a randomized clinical trial using an anti-inflammatory drug with no measurable effect on LDL cholesterol or other risk factors that might affect outcomes. This rules out statins and aspirin (which has both anti-inflammatory and anti-thrombotic activity). Two such trials have recently been completed. The four-armed Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS) randomized 10,161 patients with a prior MI and a CRP > 2 mg/L to receive 0 (placebo), 50, 150, or 300 mg subcutaneous dose of canakinumab, a monoclonal antibody targeting interleukin-1β (an inflammatory cytokine), at 3-month intervals.12 The 150 mg dose (but not the other two doses) brought about a significant reduction in the combined incidence of nonfatal MI, stroke, and cardiovascular death (the primary outcome). Total mortality was not reduced. An increase in fatal infections in the combined treated groups relative to placebo was offset by an equal decrease in cancer deaths. While the CANTOS results were promising, their clinical application is uncertain due the small absolute reduction in cardiovascular outcomes and uncertain adverse risks of canakinumab.13
However, the results of the second large trial, the NHLBI-sponsored Cardiovascular Inflammation Reduction Trial (CIRT), were disappointing. In this trial, 4786 patients with stable coronary artery disease were randomized to receive an established anti-inflammatory drug—low-dose methotrexate—or placebo.14 There was no difference in the combined incidence of MI, stroke, cardiovascular death, or hospitalization for unstable angina leading to urgent PCI (the primary outcome). Surprisingly, methotrexate treatment did not reduce mean levels of inflammatory markers like CRP, interleukin-1β, or interleukin-2 in CIRT participants, although it is a proven anti-inflammatory drug for treating rheumatoid arthritis. So the CIRT results do not disprove the “inflammation hypothesis” but merely leave us back at square one.
Impact of Anti–Inflammatory Treatment on Decline in Heart Attack Mortality
While it is possible that the anti-inflammatory properties of statins and aspirin have contributed to the decline in heart attacks since 1980, such effects have been inadvertent and unquantifiable. The deliberate use of specific anti-inflammatory drugs to quell atherosclerosis and prevent cardiovascular deaths is in its infancy. Such treatments have not yet been proven effective and are not in wide use but may hold promise for the future.
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11. SM Grundy, NJ Stone, AL Bailey, C Beam, KK Birtcher, RS Blumenthal, LT Braun, S de Ferranti, J Faiella-Tommasino, DE Forman, R Goldberg, PA Heidenreich, MA Hlatky, DW Jones, D Lloyd-Jones, N Lopez-Pajares, CE Ndumele, CE Orringer, CA Peralta, JJ Saseen, SC Smith, L Sperling, SS Virani, J Yeboah. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation 2019; 139:e1082-e1143. https://www.ahajournals.org/doi/10.1161/CIR.0000000000000625
12. PM Ridker, BM Everett, T Thuren, JG MacFayden, WH Chang, C Ballantyne, F Fonseca, J Nicolau, W Koenig, SD Anker, JJP Kastelein, JH Cornel, P Pais, D Pella, J Genest, R Cifkova, A Lorenzatti, T Forster, Z Kobalava, L Vida-Smith, M Flather, H Shimokawa, H Ogawa, M Dellborg, PRF Ross, RPT Troquay, P Libby, RJ Glynn, for the CANTOS Trial Group. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med 2017; 377:1119–1131. DOI: 10.1056/NEJMoa170791.
13. RA Herrington. Targeting inflammation in cardiovascular disease. N Engl J Med 2017; 377:1197–1198. DOI: 10.1056/NEJMe1709904.
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