No surprise, all inflammation is not created equal as it relates to cardiovascular disease

That atherosclerotic cardiovascular disease (ASCVD) has an important inflammatory component has become the paradigm within the cardiovascular community.¹ The well-described histopathology of the atherosclerotic plaque containing proinflammatory macrophages and other assorted cells along the inflammatory continuum has long suggested that this is the case. Recognition of the pathology was followed by studies defining the interactions within atherosclerotic plaque of immune cells and mediators with oxidized low-density lipoprotein cholesterol, endothelium, and platelet-dependent thrombotic pathways. The fact that the serum C-reactive protein (CRP), a hepatocyte-derived protein that is a component of the systemic inflammatory acute phase response, is elevated in many patients with ASCVD further supported the generalized inflammation concept, and CRP, measured using sensitive assays, has become an accepted biomarker in cardiovascular risk assessment. The demonstration that some anti-inflammatory drugs can be effective in the secondary prevention of cardiovascular events has seemingly cemented the expectation that control of inflammation will ultimately be part of our multipronged therapeutic approach to ASCVD.

But all is not straightforward. The effect size in inflammation-directed interventional studies has not been uniformly large (or even always positive), and the “off-target” effects of some anti-inflammatory drugs may be sufficient to counteract their potential cardiovascular benefits. Consider the cardiovascular concerns with the use of nonsteroidal anti-inflammatory drugs and corticosteroids. Use of corticosteroids, our most potent and pleiotropic anti-inflammatory and immunosuppressive medication, is a recognized risk factor for ASCVD. The exact mechanisms by which different therapeutics impact the development or progression of ASCVD are still incompletely understood.

I think that we still have a way to go before we hit the right inflammatory target in ASCVD. CRP is a reasonable marker of the systemic inflammatory response, which may include adipocyte activation, but it may not adequately reflect all the inflammatory pathways at play in cardiovascular disease. Interleukin (IL) 1 and IL-6 increase synthesis of CRP, as these cytokines drive the acute phase response. Inhibition of IL-1 activity using the monoclonal anti–IL-1 antibody canakinumab in CANTOS (Canakinumab Anti-Inflammatory Thrombosis Outcome Study)² did indeed reduce cardiovascular events in patients with known ASCVD who already had therapeutically lowered levels of low-density lipoprotein cholesterol. This supported a role of IL-1 in ASCVD, but the effect was modest, and demonstrating that a drop in the CRP level is associated with benefit is not conclusive evidence that the IL-1 pathway should be our ultimate target. In the rheumatology clinic, there is an imperfect relationship between CRP diminution and clinical response to specific therapies in the treatment of inflammation, including IL-1–directed therapies. All the components of the proatherosclerotic inflammatory response in vulnerable plaque are not necessarily strongly linked with pathways that impact the level of systemic markers of inflammation like CRP.

In CIRT (Cardiovascular Inflammation Reduction Trial),³ methotrexate at 15 mg weekly failed to reduce the number of (secondary) cardiovascular events. Methotrexate 15 mg weekly is not a high dose, many patients with rheumatoid arthritis do not respond to this dose, and in CIRT, it did not lower the CRP level. Thus, 15 mg weekly may have been too low of a dose. Alternatively, it just may not be the right drug to treat ASCVD. Methotrexate is quite effective at treating rheumatoid arthritis, but it has limited efficacy in treating spondylitis or crystal-associated arthritis. All inflammation is not the same.

Singh et al⁴ in this issue of the Journal discuss the data supporting the potential role of colchicine in treating patients with ASCVD. Initial observational studies⁵ and then randomized interventional trials in patients with chronic coronary artery disease⁶ demonstrated a beneficial effect of low-dose daily colchicine in reducing cardiovascular events, at approximately the same dose that we use for prophylaxis against gout flares. These trials resulted in the US Food and Drug Administration approving colchicine for reducing the risk of cardiovascular events. A subsequent large trial failed to reproduce the beneficial effect.⁷ Foibles in the collection of trial data due to the COVID epidemic have been proposed as an explanation, and I do not have a good alternative mechanistic explanation for the discrepant results.

The beneficial effect of colchicine in experimental and clinical studies⁶ raises the question as to its mechanism of action in patients with ASCVD. Why should a drug with demonstrated efficacy in treating and preventing acute neutrophilic inflammation of gout be effective in a condition characterized by vessel wall infiltration with lipid-laden macrophages, endothelial activation, and platelet-driven thrombosis? Colchicine inhibits microtubule polymerization, which can affect oriented cell migration (chemotaxis) as well as intracellular endosome transport. It has been proposed, with support from some in vitro data and recent murine studies,⁸ that colchicine inhibits leukocyte adhesion and extravascular migration. But if this was its major effect, it would seemingly be effective in many more clinical conditions than are currently recognized and likely would be associated with more tissue infections.

Additionally, in a very simple decades-old study in a rabbit model of acute gout, intravenous colchicine markedly decreased neutrophil influx into the knee joint of rabbits following intra-articular injection of urate crystals, but had no effect on neutrophil influx following intra-articular injection of a neutrophil-directed chemotactic factor.⁹ This suggested that colchicine in some situations has a greater effect on mediator generation than on the cellular response to inflammatory mediators.

Low-dose colchicine alters intracellular molecular and endosome transport, disrupting the organization of macromolecular structures, including the NLRP3 inflammasome that activates IL-1beta and IL-18, as well as (perhaps) selectively inhibiting transcription factor migration to the nucleus. Interestingly, colchicine has been shown to reduce tissue macrophage polarization to a proinflammatory M1 state¹⁰ via its impact on metabolic pathways that include AMP-activated kinase (the same pathway impacted by the glucagon-like peptide 1 receptor agonists). Colchicine has also been shown to modulate leukocyte-platelet interactions¹¹ but not affect platelet-platelet interactions. It should be noted that the cellular effects of colchicine in the laboratory are very dependent on concentration and duration of exposure.

Low-dose colchicine has been shown to decrease macrophage cholesterol uptake, at least in part by decreasing the expression of oxidized low-density lipoprotein–uptake receptors on the macrophage surface.¹² The same investigators also reaffirmed its inhibitory effect on inflammasome activation in vitro. Both of these effects occurred without major disruption of microtubule polymerization. In a murine model of atherosclerosis, low-dose colchicine increased the thickness of the plaque’s fibrous cap, a marker of plaque stability.¹² Colchicine’s beneficial effects on fibrous cap thickness and plaque stability, including decreased plaque rupture, were confirmed in humans using intracoronary optical coherence tomography in a controlled study of a small group of patients after myocardial infarction.¹³ A critical conclusion from this study was that prolonged treatment (> 16 months) was necessary before the benefit could be demonstrated. This has significant implications for the design of future clinical trials and the interpretation of previous ones.

A more complete understanding of how colchicine exerts beneficial effects on reducing cardiovascular events may help identify specific targets for pharmacologic attack. At present, based on clinicians’ prescribing behavior, the medical community has yet to fully embrace colchicine as part of the routine management of patients with ASCVD.¹⁴

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