Editor's Corner | Hippocrates, Black Bile and the CANTOS Trial

Long, long ago, in a galaxy far, far away called Harvard Medical School, the first question on a pathology exam was this: Inflammation is a salutary phenomenon — Discuss.

In that exam, as the initial anxiety abated, some of us guessed the correct definition of “salutary,” but that did not really help. What, then, to write? We had heard lectures on acute infection, the body’s responses and the mechanisms involved. Thus, most of us dutifully recited the benefits of inflammation: white cell mobilization, fever, increased transudation through the vascular basement membrane near an inflammatory site, etc.

But there were the brightest few who took another tack. “Not so fast!” they wrote. “Though inflammation is, in general, a salutary phenomenon, it is not always so. Inflammation can occasionally be an example of how Mother Nature’s responses can go awry. An inflammatory response, unchecked, in the wrong organ can lead to disaster.” They went on to cite examples: the pathology of glomerulonephritis, acute rheumatic fever with its sequelae, and Stevens-Johnson Syndrome. And, they left the rest of us in their academic wake. Today they could include atherosclerosis and all its sequelae as an example of Mother Nature’s response gone bad. They got it right.

So did Hippocrates, 2500 years ago. He had less biomedical information, but nonetheless espoused the theory of the four humours (blood, phlegm, yellow bile and black bile). A balance of these four humours, present in the bloodstream in varying amounts and the purity of them, he thought, were essential to the maintenance of health. These humours were also associated with subtle vapors, which pervade the entire body. He got that right as well.

And so did John Burns, a surgeon in Scotland who wrote in his Dissertations on Inflammation in 1812: “...inflammation is to be considered only as a disturbed state of parts, which requires a new mode of action to restore them to that state.” Indeed, there is nothing new under the sun.

Fast forward to 2018 and our cover story for this edition of Cardiology: Interventions which showcases the CANTOS trial and Interleukin 1 (IL-1). To honor Hippocrates, let’s call IL-1 “black bile” for short. Too much black bile can induce potentially pathogenic functions of vascular endothelial cells. More than 30 years ago, in 1986, Libby and colleagues reported their experiments that showed the accumulation of black bile beta mRNA in adult human vascular endothelial cells exposed to endotoxin.1 The endothelial cells not only accumulated, but also released biologically active black bile. The authors concluded: “Because bloodborne agents must traverse the endothelium before entering tissues, endothelial IL-1 production induced by microbial products or other injurious stimuli could initiate local responses to invasion. Endothelial cells are both a source of, and target for IL-1; accordingly, this novel autocrine mechanism might play an early role in the pathogenesis of vasculitis, allograft rejection, and arteriosclerosis.” Peter Libby would have gotten an “A” on that pathology test.

Back in 1986 few outside of translational biology took notice — certainly not interventional cardiologists, who were occupied with the outcomes of balloon angioplasty and the emerging transcatheter treatments of acute myocardial infarction and mitral stenosis. The irony of that sentence should not be lost on us. We knew even then that plasma levels of high sensitivity C-reactive protein (hsCRP), an inflammatory marker, could predict vascular risk. In fact, levels of hsCRP were as good a predictor as LDL-C levels.

But twenty years later, despite the emergence of lots of evidence that lowering cholesterol levels was directly associated with better outcomes, randomized trials targeting hsCRP did not show a decrease in major adverse coronary events (MACE). However, those trials did uncover the so-called pleiotropic anti-inflammatory effects of statins. Surely something was afoot, but what exactly was going on?

The trials were a bust for hsCRP. There were a lot more scoffers than believers. It took a while, but the concept that hsCRP is a “downstream” surrogate biomarker for active upstream IL-1β activity moved the therapeutic target from CRP to IL-1 (our friend black bile). That finally provided a new therapeutic possibility — inhibition of the IL-1β-producing NLRP3 inflammasome.

Long, long ago, in a galaxy far, far away called Harvard Medical School, the first question on a pathology exam was this: Inflammation is a salutary phenomenon — Discuss.

Enter the human monoclonal antibody canakinumab and CANTOS.2 Canakinumab, by inhibiting the NLRP3 inflammasome, reduces plasma levels of hsCRP. It does not affect atherogenic lipids. Those diligent researchers of inflammation, in CANTOS, finally showed that a drug targeting an inflammatory molecule could reduce the risk of cardiovascular events in patients with a previous myocardial infarction and signs of excess inflammation. The benefit of the treatment was independent of lipid lowering. The short version of the outcomes of CANTOS is that in the 150-mg arm, the primary MACE endpoint (nonfatal MI, nonfatal stroke and cardiovascular death) was reduced by 15 percent after almost 4 years. Need for revascularization was reduced 30 percent. Finally!

Canakinumab has been approved since 2009 for rare, “orphan” disorders characterized by over-production of IL-1 (Necrosis Factor Receptor-Associated Periodic Syndrome (TRAPS), Hyperimmunoglobulin D Syndrome (HIDS)/Mevalonate Kinase Deficiency (MKD) and Familial Mediterranean Fever). That is all good news. Unfortunately, the cost of canakinumab is akin to the current high cost of PCSK9 inhibitors. Unless this is reduced, therapy for large numbers of patients will be prohibitively expensive. Let us hope Novartis (the drug manufacturer) will be able to lower the cost if it is approved for its anti-atherogenic properties.

What is it about the CANTOS trial makes its outcomes important for the interventional cardiologist? After all, this may be just another way to reduce risk of atherogenic events in the general population. It may be important for general cardiologists and preventive cardiologists, but interventionalists? Well… exactly. CANTOS opens up a new avenue for the treatment of post-MI patients. These are the patients who have interventions for coronary syndromes of all types. If they have evidence of a high inflammatory milieu by virtue of a high hsCRP, we now have another tool for patient-specific therapy.

Inflammatory molecules that are produced by Mother Nature’s responses to noxious stimuli (IL-6, IL-1 or black bile, the NLRP3 inflammasome) surely are there for some salutary reason. But their effect runs amok inside the vascular system and incites atherogenesis. Counteraction reduces MACE. The CANTOS results have alerted us to another risk factor we need to measure, think about and probably treat, if indicated, in every patient we have seen for an acute coronary syndrome. CANTOS has finally opened the window to shine therapeutic light on the dark side of supposed salutary inflammatory reactions. Inhibition of the NLRP3 inflammasome by canakinumab can apparently counter the negative effects of inflammation that my classmates wrote about and thereby reduce atherogenic MACE events. We are all getting smarter. Hippocrates would probably say: “I told you so.”


Peter C. Block, MD, FACC, is a professor of medicine and cardiology at Emory University Hospital and School of Medicine in Atlanta, GA.

References

  1. Libby P, Ordovas JM, Auger KR, et al. Am J Pathol 1986;124:179-85.
  2. Ridker PM, Everett BM, Thuren T, et al. N Engl J Med 2017;377:1119-31.

Clinical Topics: Acute Coronary Syndromes, Dyslipidemia, Invasive Cardiovascular Angiography and Intervention, Valvular Heart Disease, Vascular Medicine, ACS and Cardiac Biomarkers, Lipid Metabolism, Nonstatins, Novel Agents, Statins, Interventions and ACS, Interventions and Structural Heart Disease, Interventions and Vascular Medicine

Keywords: ACC Publications, Cardiology Interventions, Acute Coronary Syndrome, Allografts, Angioplasty, Balloon, Antibodies, Monoclonal, Anxiety, Atherosclerosis, Basement Membrane, Bile, Biological Markers, Burns, Cholesterol, C-Reactive Protein, Drug Delivery Systems, Endothelial Cells, Endothelium, Endotoxins, Familial Mediterranean Fever, Glomerulonephritis, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Inflammasomes, Inflammation, Interleukin-1, Interleukin-6, Lipids, Mevalonate Kinase Deficiency, Mitral Valve Stenosis, Myocardial Infarction, omega-Chloroacetophenone, Research Personnel, Rheumatic Fever, Risk Factors, RNA, Messenger, Schools, Medical, Stevens-Johnson Syndrome, Stroke, Surgeons, Vasculitis, Virtues


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