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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).

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).

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.

 

References:

  1. 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.
  2. 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.
  3. 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.
  4. 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.

 

“The views, opinions and positions expressed within this blog are those of the author(s) alone and do not represent those of the American Heart Association. The accuracy, completeness and validity of any statements made within this article are not guaranteed. We accept no liability for any errors, omissions or representations. The copyright of this content belongs to the author and any liability with regards to infringement of intellectual property rights remains with them. The Early Career Voice blog is not intended to provide medical advice or treatment. Only your healthcare provider can provide that. The American Heart Association recommends that you consult your healthcare provider regarding your personal health matters. If you think you are having a heart attack, stroke or another emergency, please call 911 immediately.”

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Modifiable Factors Influence Non-modifiable Factors for Cardiovascular Health?

The scientific community continues its full force swing at reducing cardiovascular disease risk. In the Scientific Session titled “Microbiome in Cardiovascular Disease,” the complexity of accounting for human variation was the theme. The important difference and interactions between non-modifiable (genetics) and modifiable (diet, exercise, smoking, etc..) factors were presented. Dr. Katherine Tucker opened up the session by highlighting work from Thanassoulis et. al., 2012, which identified 13 single nucleotide polymorphisms (SNPs) to generate a genetic risk score (GRS) to predict cardiovascular events and coronary artery calcium (CAC). Single nucleotide polymorphisms are the most common type of genetic variation among people and are used to help quantify the variation in individuals (1). The CAC score comes from a test that quantifies the amount of calcium accumulation in the walls of the coronary arteries. A lower score represents a greater risk and a lower score relates to a lower risk of heart disease. Dr. Tucker went on to explain the genetic risk is influenced by individual environmental factors (i.e. smoking, exercise, and diet) (2). Recent data from the CARDIA study supports this in reporting that, “low-carbohydrate diets at a younger age is associated with an increased risk of subsequent CAC progression, particularly when animal protein or fat are chosen to replace carbohydrates. (3).”

Figure 1 source: https://doi.org/10.1093/nutrit/nux001

The changes in macronutrient content in a diet is related to what happens in the gut. Within the gut, there are trillions of bacteria that make up a microbiome. An individual microbiome modulates the immune system and metabolic processes. The microbiome influence on human health is so pronounced in that it actively reprograms the genome in response to the environment, changing the bacteria phyla ratios that lead to down-stream effects that could influence cardiovascular health (Figure 1) (2). Dietary fiber and prebiotic consumption are two components that modulate the composition of the gut microbiome (Figure 2) (4). Also, there is some great news for you Kombucha fans out there! Fermented foods have some benefits for the gut.

Figure 2. Source: https://doi.org/10.1093/nutrit/nux062

Bhat and Kapila 2017 further highlight diet in a review stating “The composition of the gut microbiota has a tremendous influence on host metabolism.” Perhaps specific dietary interventions can reduce the risk of cardiovascular disease with the focus on obtaining an optimal microbiota composition. Zhang et. al., 2020, showed how detrimental diets with contain highly processed foods can be the bacteria in our gut (Figure 3) (5).

Figure 3. Source: https://doi.org/10.1093/ajcn/nqaa276

To further highlight how much people differ from one another, Dr. Tang from the Cleveland Clinic explained only 37% of the gut is actually shared between twins. In addition, there are significant diurnal variations in response to meals consumed among people. The work presented the relationship between microbiota and trimethylamine (TMA)/trimethylamine–N-oxide(TMAO) generation. Elevated TMAO levels predict major adverse cardiac events like death, myocardial infarction (MI), and stroke (Figure 4) (6). Dr. Tang explained that risk is highest with people who displayed the highest baseline levels of two TMAO precursors choline or L-carnitine, while some may show no risk with higher levels. Dr. Tang emphasized the variation again among individuals.

Figure 4. Source: Tang, W. W., & Hazen, S. L. (2014)

We are only scratching the surface with the modifiable risk factors for heart disease. Specifically, the gut shows an area rich for investigation. The gut microbiota contributes to human physiology and diseases and it is something to be excited about for biomedical researchers.

 

References:

  1. Thanassoulis G, Peloso GM, Pencina MJ, Hoffmann U, Fox CS, Cupples LA, Levy D, D’Agostino RB, Hwang SJ, O’Donnell CJ. A genetic risk score is associated with incident cardiovascular disease and coronary artery calcium: the Framingham Heart Study. Circ Cardiovasc Genet. 2012 Feb 1;5(1):113-21. doi: 10.1161/CIRCGENETICS.111.961342. Epub 2012 Jan 10.
  2. Mohd Iqbal Bhat, Rajeev Kapila, Dietary metabolites derived from gut microbiota: critical modulators of epigenetic changes in mammals, Nutrition Reviews, Volume 75, Issue 5, May 2017, Pages 374–389, https://doi.org/10.1093/nutrit/nux001
  3. Gao, J. W., Hao, Q. Y., Zhang, H. F., Li, X. Z., Yuan, Z. M., Guo, Y., … & Liu, P. M. (2020). Low-Carbohydrate Diet Score and Coronary Artery Calcium Progression: Results From the CARDIA Study. Arteriosclerosis, Thrombosis, and Vascular Biology, ATVBAHA-120.
  4. Genelle R Healey, Rinki Murphy, Louise Brough, Christine A Butts, Jane Coad, Interindividual variability in gut microbiota and host response to dietary interventions, Nutrition Reviews, Volume 75, Issue 12, December 2017, Pages 1059–1080, https://doi.org/10.1093/nutrit/nux062
  5. Zefeng Zhang, Sandra L Jackson, Euridice Martinez, Cathleen Gillespie, Quanhe Yang, Association between ultraprocessed food intake and cardiovascular health in US adults: a cross-sectional analysis of the NHANES 2011–2016, The American Journal of Clinical Nutrition, https://doi.org/10.1093/ajcn/nqaa276
  6. Tang, W. W., & Hazen, S. L. (2014). The contributory role of gut microbiota in cardiovascular disease. The Journal of clinical investigation, 124(10), 4204-4211.

 

“The views, opinions and positions expressed within this blog are those of the author(s) alone and do not represent those of the American Heart Association. The accuracy, completeness and validity of any statements made within this article are not guaranteed. We accept no liability for any errors, omissions or representations. The copyright of this content belongs to the author and any liability with regards to infringement of intellectual property rights remains with them. The Early Career Voice blog is not intended to provide medical advice or treatment. Only your healthcare provider can provide that. The American Heart Association recommends that you consult your healthcare provider regarding your personal health matters. If you think you are having a heart attack, stroke or another emergency, please call 911 immediately.”