Much remains to be discovered about the role of inflammation in atherosclerosis

For more than twenty years, attention has been paid to the interplay between inflammation and atherosclerosis, also in patients with kidney damage. “Still, there is still an incredible amount to figure out and win in this area,” said Willem Bax.

According to Willem Bax, internist-nephrologist and vascular physician at Noordwest Hospital Group in Alkmaar, most medical specialists interested in cardiovascular disease know a lot about the well-known, traditional risk factors for cardiovascular disease, such as blood pressure, cholesterol and lifestyle, but still little about the influence of inflammation. “The role of inflammation in the development of cardiovascular problems is still unknown,” said Bax.

And that while there have been enormous developments in this area in the past twenty years. Bax says Harvard professor Paul Ridker is the one who put the subject on the map. “Just before the turn of the century, his research was the first to show that elevated high-sensitivity C-reactive protein (hsCRP) and interleukin-6 (IL-6) levels in healthy subjects are important risk factors for atherosclerotic events, such as myocardial infarction, stroke and cardiovascular death. . In addition, around 2005, Ridker and his colleagues found that statins have important anti-inflammatory properties; they appear to be effective in lowering not only cholesterol but also hsCRP.”

Later, in 2017, Ridker will present the first results of the double-blind, randomized CANTOS trial comparing canakinumab, a monoclonal antibody targeting IL-1β, with placebo in patients with cardiovascular disease and elevated hsCRP. In the canakunimab group, 15% fewer cardiovascular events occurred. The effect of this proof-of-concept study is clear: reducing inflammation helps to prevent atherosclerotic events. But when Ridker conducts a similar study with the cheaper and more readily available methotrexate, it turns out to have no effect. So it is not the case that every anti-inflammatory will work.

“Comparable positive results were also found in the Netherlands for the anti-inflammatory agent colcichin in the LoDoCo2 study,” explains Bax (see box). “There were 31% fewer atherosclerotic events in the colcichine group compared to placebo. Because it is still unclear how we can explain these results, we are now looking for the mechanism behind the action of colcichin in follow-up research. We now know that this must be sought in the neutrophil granonulocyte and that IL-6 reduction occurs.”

Bax expects many more agents in the near future that can attack different targets in the inflammatory pathways and thus remove the effect of inflammation. “We are currently still doing this with monoclonal antibodies, but for the huge patient population with cardiovascular disease, that is not feasible because it is an extremely expensive therapy. Fortunately, there are probably other options as well. For example, in addition to statins, some diabetes drugs such as the GLP1 agonist semaglutide have been shown to lower CRP and also to be effective in preventing atherosclerotic events. The ultimate goal is to find or develop drugs – preferably oral and affordable – that specifically target certain parts of the complicated inflammatory pathway.”

Inflammation and Atherosclerosis: Mechanisms

In recent decades it has become clear that atherosclerosis is much more than simply an accumulation of lipids in the artery wall. For example, we now know that in atherosclerosis there is a chronic inflammatory reaction locally in the vessel wall. The number of white blood cells (such as monocytes and macrophages) is proportional to the size of the atherosclerotic lesion, but the inflammatory effects are not limited to the plaque. Also systemically, the production of monocytes increases and the circulating monocytes change their phenotype.

In kidney patients, atherosclerosis develops even earlier and faster than in people without kidney problems. That’s because chronic kidney damage (as well as several other cardiovascular risk factors) causes systemic, chronic, low-grade inflammation, resulting in atherosclerotic lesions, vascular calcification and aging, myocardial fibrosis, and heart valve calcification. This makes chronic kidney damage an independent risk factor for cardiovascular disease.

De Low-Dose Colchicine in Coronary Disease (LoDoCo) studie

Colchicine is an old and inexpensive generic anti-inflammatory that works well for gout and pericarditis. In patients taking colchicine for gout, it also appears to protect against heart attacks, possibly by inhibiting inflammation in the artery wall. A small Australian study – the first LoDoCo study – showed that a low dose (0.5 mg, once daily) of colchicine does indeed significantly reduce the risk of a heart attack or stroke.

To confirm the findings from the first LoDoCo study, the larger LoDoCo2 study was conducted between 2016 and 2018 in patients with stable coronary artery disease. The study involved cardiologists from thirty Dutch and nine Australian hospitals and randomized 5,522 patients to treatment with colcichine or placebo, both in addition to lipid-lowering and antithrombotic therapy. After a median follow-up of 29 months, colchicine was shown to reduce the risk of the primary composite endpoint (cardiovascular death, myocardial infarction, ischemic stroke, or ischemia-driven coronary revascularization) by 31% compared to placebo.

The Dutch branch of the LoDoCo2 study is led by Prof. Dr. Jan-Hein Cornel, cardiologist at Noordwest Hospital Group (Alkmaar) and Radboudumc (Nijmegen) and Dr. Arend Mosterd, cardiologist at the Meander Medical Center (Amersfoort).

New studies in kidney patients: CANTOS and ZEUS

Until now, little is known about the treatment of inflammation to prevent atherosclerotic events in kidney patients, but that will soon change. In early April, new results of the CANTOS study will be presented at the annual meeting of the American College of Cardiology (ACC). In these secondary analyses, the risk of atherosclerosis due to inflammation was also examined in relation to chronic kidney damage.

In addition, the international ZEUS study was recently started in various nephrological centers in the Netherlands. This phase III trial from Novo Nordisk is investigating the effect of inhibiting inflammation with ziltivekimab on atherosclerosis and renal function, also in patients with advanced chronic kidney disease with an eGFR between 15 and 60 ml/min/1.73m2† Bax: “The idea is that the link between inflammation and atherosclerosis plays an even greater role in patients with kidney damage. In addition, the nice thing about the ZEUS study is that ziltivekimab is a monoclonal antibody that intervenes in the inflammatory pathway in a different place; namely on IL-6.”

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