Increased cardiovascular risk in rheumatoid arthritis: mechanisms and implications

In compiling their extensive review England et al.(1) cast a rather narrow net, using only “the MeSH terms ‘rheumatoid arthritis’ and ‘cardiovascular disease’ or ‘cardiovascular system’”. Considering the common denominator that emerged as a major focus, namely, “shared inflammatory mediators”, and the fact that so many other widespread and devastating diseases such as diabetes and cancer are linked to inflammation, it would seem that looking upstream for causes of inflammation rather than downstream toward specific sequelae and treatment regimens for RA and CVD might be more fruitful in identifying common threads and hopefully, better prevention and treatment strategies.

In particular, the simple amino acid glycine is emerging as a key endogenous regulator of inflammation, via direct action on the plasma membranes of macrophages and other effector cells. These glycine receptors are actually glycine-gated chloride channels, by which glycine allows for chloride influx, stabilizing membrane resting potential, and thus raising the threshold for activation to produce an impressive array of poisons necessary to repel a microbial infection. The resulting inflammatory response, when exaggerated and chronic, seems to lie at the root of the chronic diseases under consideration here.

The critical importance of glycine in regulating macrophages—the chief cellular mediators of inflammation—was presaged by of the Thurman group at UNC Chapel Hill back in 1999 (2). They established the presence of classical glycine receptors on different types of macrophages. They reported that Glycine concentrations up to 1 mM in the culture medium blunted—but did not abolish--the exaggerated macrophage response activation to bacterial lipopolysaccharide (2) This was demonstrated to be due to the glycine-mediated influx of chloride ions, which inhibits the depolarization of the membrane that initiates macrophage activation. In 2001 the Thurman group established the role of glycine—acting via the glycine receptor—in preventing disease in a standard rodent model of rheumatoid arthritis (3). Hence, a deficiency in glycine (i.e., levels below the range of approximately 0.5 – 1 mM (2), even though the normal range of plasma glycine is typically 0.1 – 0.4 mM) may predispose macrophages to exaggerated inflammatory responses to stimuli, and thus to the onset of a multiplicity of diseases rooted in chronic inflammation. More recently, the widespread availability of metabolomics has generated many studies showing an inverse relationship between plasma glycine concentration and prediabetes and diabetes (4), cardiovascular disease (5,6) and cancer (7). With regard to cardiovascular disease in particular, note that glycine receptors have also been identified in vascular endothelial cells, platelets (aggregation of which is inhibited by glycine), and cardiomyocites (in which glycine improved survival after reperfusion injury in an experimental rat model(8)).

More recently, I have detailed (9) how glycine levels tend to be historically low due to the typical omnivorous diet that is high in(methionine-rich) muscle meats, to the exclusion of the glycine-rich collagen of bone and connective tissue. Thus, while the intake of all amino acids—including glycine—is historically high, the relative depletion of plasma glycine (which is needed for the clearance of excess methionine) among meat-eaters, was recently demonstrated in an Oxford arm of the EPIC study (10).

Since glycine is a simple bulk nutrient, it would seem that investigation of its potential in the prevention and reversal of arthritis and cardiovascular disease, as well as other inflammatory conditions, may provide safer and more cost effective solutions than traditional pharmacological approaches.

Correspondence to: joelbrind@yahoo.com

References cited

1.England BR, Thiele GM, Anderson DR, Mikuls TR. Increased cardiovascular risk in rheumatoid arthritis: mechanisms and implications. BMJ 2018;361:k1036.

2.Wheeler MD, Ikejema K, Enomoto N, et al. Glycine: a new anti-inflammatory immunonutrient (Review). Cell Mol Life Sci 1999;56:843–856

3.Li X, Bradford BU, Wheeler MD, et al. Dietary glycine prevents peptidoglycan polysaccharide-induced
reactive arthritis in the rat: role for glycine-gated chloride channel. Infect Immun 2001;69:5883–5891. DOI: 10.1128/IAI.69.9.5883–5891.2001

4.Guasch-Ferré M, Hruby A,Toledo E, et al. Metabolomics in Prediabetes and Diabetes: A Systematic Review
and Meta-analysis. Diabetes Care 2016;39:833–846. DOI: 10.2337/dc15-2251

5.Ding Y, Svingen GFT, Pedersen ER, et al. Plasma glycine and risk of acute myocardial infarction in patients with suspected stable angina pectoris. J Am Heart Assoc. 2016;5:
e002621 doi: 10.1161/JAHA.115.002621

6.Hartiala JA, Tang WHW, Wang Z, et al. Genome-wide association study and targeted metabolomics identifies sex-specific association of CPS1 with coronary artery disease. Nature Comm 2016; DOI: 10.1038/ncomms10558

7.Osman D,, Ali O, Obada M., et al. Chromatographic determination of some biomarkers of liver cirrhosis and hepatocellular carcinoma in Egyptian patients Biomed Chromatogr.2017;31. doi: 10.1002/bmc.3893. Epub 2016 Dec 28.

8.McCarty MJ, DiNicolantonio JJ. The cardiometabolic benefits of glycine: Is glycine an ‘antidote’ to dietary fructose? Open Heart 2014;1:e000103. doi:10.1136/openhrt-2014-000103

9.Brind J. Re: Cancer risk associated with chronic diseases and disease markers: prospective cohort study. BMJ 2018;360:k134

10.Schmidt JA, Rinaldi S, Scalbert A, et al. Plasma concentrations and intakes of amino acids in male meat-eaters, fish-eaters, vegetarians and vegans: a cross-sectional analysis in the EPIC-Oxford cohort. Eur J Clin Nutrition 2016;70:306–12. doi:10.1038/ejcn.2015.144