inflammation

The role of inflammation in coronary artery disease’s pathophysiology dates back to more than 100 years ago. By the end of the 18^th century, Virchow described atherosclerosis as “endarteritis deformans” for the first time. Since then, many studies at the cellular level have shown that lipid accumulation in blood vessels cannot justify the development and progression of the atherosclerosis process. Today, it is established that metabolic factors in conjunction with the inflammatory process lead to the initiation and progression of atherosclerosis. Still, the interaction of innate and adaptive immune systems for the development of atherosclerosis is not fully understood.

Despite significant progress in cardiovascular disease therapies, patients with cardiovascular disease are at high risk of adverse clinical outcomes. Current treatments have focused on lowering low-density lipoprotein-cholesterol concentration, inhibiting platelet activation and coagulation cascades, controlling blood pressure and glucose levels. None of these FDA-approved therapies have targeted the inflammatory pathways involved in atherosclerosis.

Clinical studies have emerged in the cardiovascular field to target inflammation in the past five years. Canakinumab, a monoclonal antibody targeting interleukin-1β, was one of the first anti-inflammatory medications shown to lower the risk of adverse cardiovascular events. In 2017, Ridker and colleagues¹ showed that canakinumab led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering among patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. Two years later, in 2019, Ridker and colleagues² published the efficacy of low-dose methotrexate to prevent atherosclerotic events. Unlike the Canakinumab Anti-Inflammatory Thrombosis Outcome Study (CANTOS), methotrexate-an antimetabolite medication indicated for the treatment of autoimmune diseases and a variety of cancers- not only failed to show any efficacy in lowering adverse cardiovascular events among patients with previous myocardial infarction or multivessel coronary disease but also resulted in elevations in liver enzyme levels, reductions in leukocyte counts, hematocrit levels, and a higher incidence of non–basal-cell skin cancers than placebo. The negative result implies the need for explicitly targeting the inflammatory pathways directly involved in atherosclerosis. In 2020, 2 studies evaluated the efficacy of colchicine in reducing atherosclerotic events. Both studies^{3, 4} showed that patients with chronic coronary artery disease who received colchicine 0.5mg daily had a lower risk of cardiovascular events compared who received placebo. Lastly, a double-blind, randomized, placebo-controlled phase 2 trial⁵ evaluated the efficacy of ziltivekimab-a human monoclonal IL-6 inhibitor- among chronic kidney disease patients with elevated high-sensitivity CRP. The study showed that ziltivekimab significantly reduced biomarkers of inflammation relevant to atherosclerosis. The study paves the way for conducting a large-scale cardiovascular outcomes trial to investigate the effect of ziltivekimab at high risk of cardiovascular events.

In today’s practice, monoclonal antibodies targeting interleukins are standard therapies in many medicine subspeciality like oncology (many cancers: lymphoma, leukemia), rheumatology (autoimmune disease: rheumatoid arthritis, gout), gastroenterology (Crohn’s disease), and infectious disease (COVID-19 treatment). In the cardiovascular field, although randomized trials are emerging about the efficacy of monoclonal antibodies targeting inflammatory pathways to reduce the cardiovascular risk in patients with atherosclerotic disease, still further evidence is needed. The role of inflammation in atherosclerosis is well-established, and cardiologists may need to better familiarize themselves with inflammatory pathways involved in atherosclerosis since many anti-inflammatory medications will probably be routinely prescribed in the near future to lower the elevated cardiovascular risk.

References:

Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, Fonseca F, Nicolau J, Koenig W, Anker SD, Kastelein JJP, Cornel JH, Pais P, Pella D, Genest J, Cifkova R, Lorenzatti A, Forster T, Kobalava Z, Vida-Simiti L, Flather M, Shimokawa H, Ogawa H, Dellborg M, Rossi PRF, Troquay RPT, Libby P, Glynn RJ and Group CT. Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. N Engl J Med. 2017;377:1119-1131.
Ridker PM, Everett BM, Pradhan A, MacFadyen JG, Solomon DH, Zaharris E, Mam V, Hasan A, Rosenberg Y, Iturriaga E, Gupta M, Tsigoulis M, Verma S, Clearfield M, Libby P, Goldhaber SZ, Seagle R, Ofori C, Saklayen M, Butman S, Singh N, Le May M, Bertrand O, Johnston J, Paynter NP, Glynn RJ and Investigators C. Low-Dose Methotrexate for the Prevention of Atherosclerotic Events. N Engl J Med. 2019;380:752-762.
Tardif JC, Kouz S, Waters DD, Bertrand OF, Diaz R, Maggioni AP, Pinto FJ, Ibrahim R, Gamra H, Kiwan GS, Berry C, Lopez-Sendon J, Ostadal P, Koenig W, Angoulvant D, Gregoire JC, Lavoie MA, Dube MP, Rhainds D, Provencher M, Blondeau L, Orfanos A, L’Allier PL, Guertin MC and Roubille F. Efficacy and Safety of Low-Dose Colchicine after Myocardial Infarction. N Engl J Med. 2019;381:2497-2505.
Nidorf SM, Fiolet ATL, Mosterd A, Eikelboom JW, Schut A, Opstal TSJ, The SHK, Xu XF, Ireland MA, Lenderink T, Latchem D, Hoogslag P, Jerzewski A, Nierop P, Whelan A, Hendriks R, Swart H, Schaap J, Kuijper AFM, van Hessen MWJ, Saklani P, Tan I, Thompson AG, Morton A, Judkins C, Bax WA, Dirksen M, Alings M, Hankey GJ, Budgeon CA, Tijssen JGP, Cornel JH, Thompson PL and LoDoCo2 Trial I. Colchicine in Patients with Chronic Coronary Disease. N Engl J Med. 2020;383:1838-1847.
Ridker PM, Devalaraja M, Baeres FMM, Engelmann MDM, Hovingh GK, Ivkovic M, Lo L, Kling D, Pergola P, Raj D, Libby P, Davidson M and Investigators R. IL-6 inhibition with ziltivekimab in patients at high atherosclerotic risk (RESCUE): a double-blind, randomized, placebo-controlled, phase 2 trial. Lancet. 2021;397:2060-2069.

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There has recently been a craze about using turmeric for a number of health-related issues. Are these claims valid? What is turmeric anyway? I mean, where did it come from and what is the mechanism of action if this root does indeed work for improving health? I intend to reveal here whether jumping on yellow wagon is worth the hype.

Being a rhizomatous, herbaceous perennial from the ginger family, this plant is native to the Indian subcontinent and Southeast Asia. To preserve these roots after harvest, the rhizomes are boiled, dried and ground into powder that can be used for cooking, coloring, and flavoring in many dishes such as curries. It is often used in Ayurvedic medicine because of the curcumin constituents that are thought to be therapeutic. However, curcumin makes up approximately 3% (with an average of 1.5%) of turmeric powder commercially sold including curcumin, demethoxycurcumin, and bisdemethoxycurcumin. Interesting!!! What about the essential oils, you may ask? There are about 34 oils, including tumerone, germacrone (antiviral isolate), atlantone, and zingiberene (the monocyclic sesquiterpene component of ginger comprising ~30% of the essential oils).

Traditionally, turmeric was used in traditional Siddha or Ayurveda medicine, generally place on the skin or adorned the body. For example, during the Haldi ceremony, Gaye holud (yellow on the body), turmeric is used in weddings. In Tamil Nadu and Andhra Pradesh, it is strung into a necklace, or in Marathi the tubers are tied by the couples to their wrists. However, because it is sold by weight, it is commonly adulterated by the addition of toxic powders such as lead oxide, changing the color from its native golden yellow to an orange-red color. Additionally, a compound known as acid yellow 36 is added for use in food products but is deemed illegal in some countries. Does this now make you want to read the label of the turmeric in your spice cabinet? However, in traditional medicine, curcumin has been used to alleviate respiratory conditions, anorexia, coryza, cough, and hepatic diseases.

Research is now supporting the medicinal uses for turmeric’s active ingredient, curcumin, because it has been demonstrated to reduce pro-inflammatory-induced chronic illnesses including cardiovascular, metabolic, pulmonary, auto immune and malignant diseases (Prasad et al). This group went on to suggest that inhibition of transcription factors nuclear factor-kappaB (NF-κB), Wnt/beta-catenin, and activates peroxisome proliferator-activated receptor-gamma and Nrf2 cell signaling pathways. Modulating these activities can potentially lead to downregulation of adipokines and upregulation of adiponectin and other gene products. Curcumin has also been shown to modulate not only cell survival proteins and inflammatory components on a biological level, but it has also been linked to histone acetylase, deacetylase, protein kinases and reductases, and glyoxalase I, as well as DNA, RNA, and metal ions. Needless to say, these are a vast number of pathways being acted upon by this compound.

A recent article by Dai et al suggest curcumin plays a role in alleviating collagen-induced inflammation by targeting the mTOR pathway. Although this study is focused on rheumatoid arthritis, the inflammatory markers that were explored play a vital role in vascular inflammation such as chemokines, cathepsin, matrix matalloproteinases, TNF-α, and IL-1 to breakdown the extracellular matrix and ultimately lead to vascular remodeling. Curcumin is considerably cheap and easily available, making it attractive to use in inflammation studies. Rapamycin (mTOR) role in cellular proliferation, differentiation, and apoptosis makes it an important player in cellular regulation. Using Wistar rats as their model, Dai et al suggest curcumin can potentially inhibit the mTOR pathway under collagen-induced inflammatory conditions when compared to the control group. Additionally, this group demonstrated a reduction in inflammatory cell infiltration in the treatment group alleviating the hyperplasia with curcumin therapy.

Promising results were demonstrated by Xiao et al with hemeoxygenase-1 (HO-1) with cytoprotective effects under some pathological conditions. This group used New Zealand white rabbits that were fed curcumin for four weeks. Once the acute vascular inflammation was induced, there was an increase in serum bilirubin and vascular, liver, and spleen HO-1 mRNA levels with curcumin treatment compared to control, as well as a decrease in vascular inflammation. Furthermore, with HO inhibition or HO-1 siRNA knock down, there was an amelioration of carotid artery HO-1, impeding vascular inflammation. Xiao et al went on to report treatment of human artery endothelial cells with curcumin lead to the activation of the Nrf2 and p38 MAPK signaling pathways.

Ultimately, the active compound in turmeric, curcumin, has been shown to contribute to the reduction of vascular inflammation in addition to rheumatoid arthritis-induced inflammation by decreasing the proinflammatory cytokines and chemokines. Additionally, antioxidant response elements are responsive in the presence of curcumin. The thing to remember here is, with all the positive results, curcumin is not readily bioavailable. To get a therapeutic amount, it should be formulated with delivery compounds such as capsaicin or hyaluronic acid (see image). Furthermore, the dose that is necessary to have an effect may be higher than the amount delivered if it is not correctly monitored. For example, it takes up to 90 mg orally to attenuate oxidative stress following a downhill run according to Kawanishi et al. This reduction was observed due to the increase in the blood’s antioxidant capabilities that utilize the TNF, cyclooxygenase-2, and iNOS to initiate anti-inflammatory mechanisms.

So the question, is it a good idea to jump on the yellow band wagon? Yes. However, some things to keep in mind is to read the labels to be sure the turmeric is pure or try to purchase the root in its native form and dry it to the powder at home. Do your research to make sure you are consuming enough to get the benefits from the product. Make sure you are mixing it with the right compounds. I have been utilizing turmeric for years before this band wagon came along, and I will continue to purchase turmeric roots from the farmer’s market and make powder by drying it out in a low temperature oven overnight (get to the powder by blending in the Ninja Blender). I do not think I will use the diatomaceous earth (silica) that was suggested in one of the recipes I saw online.

If you are interested in recipes using turmeric, there are a lot on @dashdiet1 www.AHA.org. I also post on my twitter.

Remember to follow me on Twitter @AnberithaT where I will keep you posted on #AHAMeetingsReports @AHA_Meetings and #VascularScience. See you in Hawaii for #ISC2019!

Inflammation: a missing target in coronary heart disease treatment

Role of Curcumin on Inflammation