Työterveyslääkäri

Inflammation: reviewing current evidence

Työterveyslääkäri
2024;42(2):44-47
Andrew Agbaje

It is common knowledge that disease initiation, progression, manifestation, and regression have an inflammatory path. There are several inflammatory markers targeted at specific disease conditions but one so largely studied is the C-reactive protein (CRP).

In the last three decades, high levels of CRP have been associated with an increased risk of metabolic and cardiovascular disease. Earlier there was inconclusive evidence about CRP's causal role in disease formation, but emerging studies suggest that CRP might be a causal risk factor for premature vascular damage such as worsening arteriosclerosis and subclinical atherosclerosis (Figure 1 «»1). Arteriosclerosis which refers to the stiffening of arteries has been established as an independent risk factor of cardiovascular mortality. This recent study in the young population raises the question about the earliest point when cardiovascular alterations induced by elevated CRP begin.

A well-articulated review recently summarized existing evidence on the role of CRP in cardiovascular diseases. The review found similarities between animal experiment results and Mendelian randomization studies which concluded that CRP may not be causally associated with cardiovascular diseases. The challenge with animal studies is the inability to directly extrapolate the findings to humans, in addition to unexplained inconsistencies in the findings from animal experiments. Mendelian randomization assumes that genetic variants of CRP associated with altered CRP levels should also be associated with cardiovascular disease risks. This assumption is not as prone to confounding and reverse causation bias as observational studies. However, a meta-analysis of several Mendelian randomization studies also concluded that CRP is not causally associated with cardiovascular diseases.

On the other hand, observational studies and clinical trials seem to show a positive association between CRP and cardiovascular diseases but have been unable to prove causality. This is partly due to the confounding bias of observational studies and the short-term duration of clinical trials. Clinical trials are also not designed to prove the causal relationships between CRP and cardiovascular diseases. A few randomized, double-blind, placebo-controlled clinical trials (JUPITER – Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin, CANTOS – Canakinumab Antiinflammatory Thrombosis Outcome Study, and CIRT – Cardiovascular Inflammation Reduction Trial studies) have shown some effect of anti-inflammatory treatments on cardiovascular disease and CRP. Unfortunately, these randomized clinical trials used diverse anti-inflammatory treatments unspecific to reducing CRP levels, thus making the causal conclusion on CRP lowering and reduced risk of cardiovascular diseases quite difficult.

An emerging inflammatory marker in the last decade

Another inflammatory marker recently identified is the nuclear magnetic resonance (NMR)-derived measure of glycoprotein acetylation (GlycA). This novel biomarker of systemic inflammation integrates the concentration and glycosylation of numerous acute-phase proteins (such as alpha-1-acid glycoprotein, haptoglobin, and alpha-1-antitrypsin). Among old adults GlycA predicts the risk of incident type 2 diabetes and cardiovascular diseases independently of CRP. GlycA appears to be more stable over a long period and reflects the burden of chronic disease processes when compared to the sensitivity of CRP to an acute state. The challenge with GlycA is the heterogeneous nature of its constituting acute phase proteins, exemplified by two individuals with the same GlycA level having different concentrations and/or glycosylation patterns in underlying proteins. These interindividual disparities may affect or limit the diagnostic potential of GlycA when compared with CRP.

A higher level of GlycA has been associated with higher odds of depression in a study involving nine cohorts from the Netherlands comprising 10 145 control participants and 5 283 persons with depression. Depression was established with diagnostic interviews or questionnaires and a proton nuclear magnetic resonance metabolomics platform was used in assessing GlycA and other metabolites. This large cross-cohort study findings may potentially open new prevention or treatment avenues for depression but further studies are needed.

Preventing old and new inflammatory markers with exercise

As clinicians and health workers, we are keen on providing effective counsel and management advice to clients but there are several gaps in knowledge that limits available options. What role could exercise play in lowering inflammatory markers either old (CRP) or new (GlycA)? The effect of regular exercise on GlycA was examined across seven studies with 14 exercise interventions and 1 568 individuals. Nuclear magnetic resonance spectroscopy, specifically signal amplitudes originating from the N-acetyl methyl group protons of the N-acetylglucosamine residues on the glycan branches of glycoproteins, was used to quantify GlycA concentrations. The authors concluded that regular exercise significantly reduced plasma GlycA across 14 different exercise interventions irrespective of exercise programs and study population differences although the mechanism supporting the result is not fully clear.

An increase in sedentary time from 6 hours/day in childhood to 9 hours/day in adulthood is an independent risk factor for increased CRP. Generally adults spend more hours sedentary > 10 hours/day which significantly increases their risk of high CRP. Thus, sedentariness appears to be a predictor of high CRP and its attendant consequences. Importantly, engaging in 3–4 hours/day of light-intensity physical activity like walking the dog, gardening, and playing with kids at the park, etc, seems effective in reversing elevated CRP induced by sedentariness (Figure 2). Since inflammation has been positively associated with the risk of type 2 diabetes, cardiovascular diseases, and depression, and sedentariness is an independent risk factor for inflammation, it is essential to encourage clients to significantly reduce sedentariness. It is hoped that while not all mechanistic explanations on the role of inflammation and disease formation have been discovered to date we could proactively limit inflammation by engaging in exercise as a daily lifestyle.

Honorary Research Fellow, Children's Health and Exercise Research Centre, Public Health and Sports Sciences Department, Faculty of Health and Life Sciences, University of Exeter, Exeter, UK. Email: a.agbaje@exeter.ac.uk

Andrew Agbaje
MD, MPH, PhD, FESC, FAHA, Cert. Clinical Researcher (Harvard)
Docent in Clinical Epidemiology and Child Health, principal Investigator of urFIT-child research group
Institute of Public Health and Clinical Nutrition, School of Medicine, Faculty of Health Sciences
University of Eastern Finland, Kuopio, Finland
andrew.agbaje@uef.fi

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