A 61-year-old man decided to enroll in a clinical trial because his history matched the description in an advertisement for the study. He had an acute myocardial infarction three years previously.
His medications included atorvastatin, aspirin, clopidogrel, captopril and metoprolol. He gave up smoking after his "heart attack". His LDL cholesterol was 77 mg/dl, arterial pressure 142/87, plasma glucose 111 mg/dl, and C-reactive protein 6.3 mg/l.
The statin drug had reduced his low density lipoprotein down to a reasonably well controlled level. Atherosclerosis occurs as these lipoprotein particles cross the endothelium of an artery, are oxidized, and engulfed by macrophages. As this process continues, it forms a plaque that can nearly occlude the artery and becomes the site where a clot can form that can precipitate a myocardial infarction.
(Captopril is an ACE inhibitor and metoprolol is a beta blocker. Both are used in heart failure and as anti-hypertensives. Aspirin and clopidogrel reduce platelet activation and thus blood clotting that might produce a further infarction.)
Current interventions to reduce the progress of atherosclerosis are focused almost entirely on reducing plasma cholesterol. But there are various indications that reducing inflammation might also be effective, quite apart from the plasma cholesterol. This is tested in the study by giving the patients canakinumab, an antibody which targets interleukin-1-alpha. This drug was developed for treating rheumatoid arthritis and is approved for use in rheumatological (mainly immune) disorders.
Patients were eligible for enrollment if they had a history of myocardial infarction and had a blood level of C-reactive protein of 2 mg or more per liter despite the use of aggressive secondary prevention strategies. Patients with chronic infections and inflammatory diseases were excluded.
QUESTION: Why is an elevated C-reactive protein level important for this study?
QUESTION: Where is C-reactive protein released, what causes its release and what is its normal function?
QUESTION: What is the usual, most common source of IL-1?.
QUESTION: Do statin drugs have effects other than blocking a key enzyme in the synthesis of cholesterol in the liver?
QUESTION: What is the likely source of the oxygen radicals that oxidize molecular components of a lipoprotein?
QUESTION: How is canakinumab given?
After three years, the results were published in the New England Journal of Medicine (NEJM) on August 27, 2017.
After four months, the C-reactive protein levels of the subjects receiving the intermediate dose of canakinumab were 37% lower than those receiving the placebo. The effect on IL-6 levels was similar. However, LDL and HDL were unchanged relative to the placebo group.
At the end of the study, the incidence of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular mortal was 4.50 events per 100 person years for the placebo. But for the group receiving the intermediate dose of canakinumab, the incidence was 3.86 events per 100 person years, giving a hazard ratio of 0.85 (P=.02). All cause mortality was similar for both the placebo and canakinumab groups.
Neutropenia and more cases of sepsis were found in the canakinumab group. Also, there were significantly fewer reports of arthritis, gout and osteoarthritis in the canakinumab group.
QUESTION: Based on what you know at this point, what might be an action of IL-1 that could increase growth of an atherosclerotic plaque?
QUESTION: A group of pigs was fed a high cholesterol diet. What would you predict would happen if some were injected with IL-1?
QUESTION: What is neutropenia?
QUESTION: Sepsis is defined as the presence of pathogenic bacteria or their toxins in in the blood or other tissues. Why might this have increased in the study?
QUESTION: Severe sepsis can cause severe circulatory problems called septic shock. This is dangerous and involves poor circulatory perfusion of vital organs. Can you identify one macrophage action that, while normally protective, might be a factor for this dangerous condition?