The Final Day (5/5) of AHA Scientific Sessions “Step on the Gas, so you can Hit the Breaks”
In the scientific session titled “Beyond Biomarkers: Inflammation and CVD across the Translational Spectrum”, inflammation was the topic of interest. It is important to note that inflammation has been established as a focus for the development of complications for cardiovascular diseases for some time now. The changes in inflammatory markers have been shown to be predictive of future cardiovascular events. But, do we know what exactly inflammation is? Are the markers we use precise enough to provide meaningful guidance for specific targeted therapies?
Dr. Russell Tracy from the University of Vermont was given the challenging opportunity to open the session in explaining how inflammation in cardiovascular disease works. He starts off by highlighting not just the amount of cells to consider, but all the different types and subtypes. There’s a multitude of pathways linked to inflammation and atherosclerosis. He proposed to focus on the pathophysiology that plays a role over the lifespan. Interestingly, the concept of trained immunity was highlighted as an influencer to the chronic inflammation that is signaled through adipose tissue. Dr. Tracy goes on to share that the inflammatory process could be related to input from multiple small pathways and that adaptative immunity impacts the inflammation research is attempting to characterize (Figure 1).
Dr. Peter Libby from the Brigham and Women’s Hospital took a shot at addressing why some anti-inflammatory therapies work and then why some do not. He highlighted three studies to keep in mind for attendees: 1) the Canakinumab Anti-inflammatory Thrombosis Outcomes Study or “CANTOS”, 2) the Cardiovascular Inflammation Reduction Trial “CIRT”, and 3) the Colchicine Cardiovascular Outcomes Trial or “COLCOT. CANTOS focused on interleukin-1ß (IL-1ß) and its role in the reduction of rates of recurrent myocardial infarction, stroke, and cardiovascular death among stable patients with coronary artery disease who remain at high vascular risk (1). Canakinumab at a dose of 150 mg every 3 months led to a lower rate of recurrent cardiovascular events (1).
CIRT addressed low-dose methotrexate use among patients with stable coronary artery disease (CAD). The investigation showed low-dose methotrexate does not reduce inflammatory markers or cardiovascular events (2). Dr. Libby quickly pointed out the difference in baseline inflammation between the two populations. Where the CANTOS study already showed some residual inflammation as compared to CIRT.
He went on stating,
“You have to step on the gas to press the breaks.”
The baseline level of inflammation is a characteristic to be more aware of when designing and evaluating drug studies like CIRT.
COLCOT involved the use of Colchicine to decrease the migrations of neutrophils, a white blood cell type that is essential for the resolution of inflammation. Neutrophils are a marker used for cardiovascular risk (4). Colchicine at a dose of 0.5 mg daily showed a significantly lower risk of ischemic cardiovascular events. Dr. Libby summed the presented work up with the slide below addressing residual inflammatory risk (Figure 2).
He left the attendees with Winston Churchill’s famous quote from London’s Mansion House, just after the British routed Rommel’s forces at Alamein, driving German troops out of Egypt,
“This is not the end. It is not even the beginning of the end. But it is, perhaps, the end of the beginning.”
Referring to the development of targeted anti-cytokine therapies for the treatment of atherothrombosis.
Overall it seems there is an oversimplification of inflammation at times, thus inaccurately conveying the heterogeneity of the processes involved. It is a challenge to accurately assess the mechanisms underlying CVD risk in each patient. More work around specific anti-inflammatory pathway is vital to characterize inflammation and develop targeted therapies that provide a cardiovascular benefit.
- Ridker PM, Thuren T, Zalewski A, Libby P. Interleukin-1β inhibition and the prevention of recurrent cardiovascular events: rationale and design of the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS). Am Heart J. 2011 Oct;162(4):597-605. doi: 10.1016/j.ahj.2011.06.012. Epub 2011 Sep 14. PMID: 21982649.
- 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; CIRT Investigators. Low-Dose Methotrexate for the Prevention of Atherosclerotic Events. N Engl J Med. 2019 Feb 21;380(8):752-762. doi: 10.1056/NEJMoa1809798. Epub 2018 Nov 10. PMID: 30415610; PMCID: PMC6587584.
- Tardif JC, Kouz S, Waters DD, Bertrand OF, Diaz R, Maggioni AP, Pinto FJ, Ibrahim R, Gamra H, Kiwan GS, Berry C, López-Sendón J, Ostadal P, Koenig W, Angoulvant D, Grégoire JC, Lavoie MA, Dubé MP, Rhainds D, Provencher M, Blondeau L, Orfanos A, L’Allier PL, Guertin MC, Roubille F. Efficacy and Safety of Low-Dose Colchicine after Myocardial Infarction. N Engl J Med. 2019 Dec 26;381(26):2497-2505. doi: 10.1056/NEJMoa1912388. Epub 2019 Nov 16. PMID: 31733140.
- Kain V, Halade GV. Role of neutrophils in ischemic heart failure. Pharmacol Ther. 2020 Jan;205:107424. doi: 10.1016/j.pharmthera.2019.107424. Epub 2019 Oct 16. PMID: 31629005; PMCID: PMC6981275.
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