NAC Treatment and Outcomes in Patients With Advanced Atherosclerosis and DM

Summary

Atherosclerosis and diabetes are related to coronary artery disease and peripheral artery disease. The mechanisms are related to increased reactive oxygen species (ROS) formation and inflammatory cytokine secretion. However, simply using antioxidant or anti-inflammatory therapies has no optimal outcomes. On the other hand, N-acetylcysteine (NAC) which has both antioxidant and anti-inflammatory effects could effectively attenuate ROS production and reduce vascular inflammation. Hence, we will investigate the effect of NAC treatment on the outcomes in patients with advanced atherosclerotic heart diseases and patients with diabetes combined with significant peripheral artery disease.

Timeline

Start

2021-10-15

Primary completion

2021-10-15

Completion

2021-10-15

Publications

• Background Virani SS, Alonso A, Benjamin EJ, Bittencourt MS, Callaway CW, Carson AP, Chamberlain AM, Chang AR, Cheng S, Delling FN, Djousse L, Elkind MSV, Ferguson JF, Fornage M, Khan SS, Kissela BM, Knutson KL, Kwan TW, Lackland DT, Lewis TT, Lichtman JH, Longenecker CT, Loop MS, Lutsey PL, Martin SS, Matsushita K, Moran AE, Mussolino ME, Perak AM, Rosamond WD, Roth GA, Sampson UKA, Satou GM, Schroeder EB, Shah SH, Shay CM, Spartano NL, Stokes A, Tirschwell DL, VanWagner LB, Tsao CW; American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee. Heart Disease and Stroke Statistics-2020 Update: A Report From the American Heart Association. Circulation. 2020 Mar 3;141(9):e139-e596. doi: 10.1161/CIR.0000000000000757. Epub 2020 Jan 29.
• Background Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C. Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis. JAMA. 2007 Feb 28;297(8):842-57. doi: 10.1001/jama.297.8.842.
• Background Thompson PL, Nidorf SM. Colchicine: an affordable anti-inflammatory agent for atherosclerosis. Curr Opin Lipidol. 2018 Dec;29(6):467-473. doi: 10.1097/MOL.0000000000000552.
• Background 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; CANTOS Trial Group. Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. N Engl J Med. 2017 Sep 21;377(12):1119-1131. doi: 10.1056/NEJMoa1707914. Epub 2017 Aug 27.
• Background 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; LoDoCo2 Trial Investigators. Colchicine in Patients with Chronic Coronary Disease. N Engl J Med. 2020 Nov 5;383(19):1838-1847. doi: 10.1056/NEJMoa2021372. Epub 2020 Aug 31.
• Background Salamon S, Kramar B, Marolt TP, Poljsak B, Milisav I. Medical and Dietary Uses of N-Acetylcysteine. Antioxidants (Basel). 2019 Apr 28;8(5):111. doi: 10.3390/antiox8050111.
• Background Voghel G, Thorin-Trescases N, Farhat N, Mamarbachi AM, Villeneuve L, Fortier A, Perrault LP, Carrier M, Thorin E. Chronic treatment with N-acetyl-cystein delays cellular senescence in endothelial cells isolated from a subgroup of atherosclerotic patients. Mech Ageing Dev. 2008 May;129(5):261-70. doi: 10.1016/j.mad.2008.01.004. Epub 2008 Jan 20.
• Background Sung HJ, Kim J, Kim Y, Jang SW, Ko J. N-acetyl cysteine suppresses the foam cell formation that is induced by oxidized low density lipoprotein via regulation of gene expression. Mol Biol Rep. 2012 Mar;39(3):3001-7. doi: 10.1007/s11033-011-1062-1. Epub 2011 Jun 17.
• Background Anderson JL, Halperin JL, Albert NM, Bozkurt B, Brindis RG, Curtis LH, DeMets D, Guyton RA, Hochman JS, Kovacs RJ, Ohman EM, Pressler SJ, Sellke FW, Shen WK. Management of patients with peripheral artery disease (compilation of 2005 and 2011 ACCF/AHA guideline recommendations): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2013 Apr 2;127(13):1425-43. doi: 10.1161/CIR.0b013e31828b82aa. Epub 2013 Mar 1. No abstract available.
• Background Hoffstad O, Mitra N, Walsh J, Margolis DJ. Diabetes, lower-extremity amputation, and death. Diabetes Care. 2015 Oct;38(10):1852-7. doi: 10.2337/dc15-0536. Epub 2015 Jul 22.
• Background Geiss LS, Li Y, Hora I, Albright A, Rolka D, Gregg EW. Resurgence of Diabetes-Related Nontraumatic Lower-Extremity Amputation in the Young and Middle-Aged Adult U.S. Population. Diabetes Care. 2019 Jan;42(1):50-54. doi: 10.2337/dc18-1380. Epub 2018 Nov 8.
• Background Malik RA, Tesfaye S, Ziegler D. Medical strategies to reduce amputation in patients with type 2 diabetes. Diabet Med. 2013 Aug;30(8):893-900. doi: 10.1111/dme.12169.
• Background Howangyin KY, Silvestre JS. Diabetes mellitus and ischemic diseases: molecular mechanisms of vascular repair dysfunction. Arterioscler Thromb Vasc Biol. 2014 Jun;34(6):1126-35. doi: 10.1161/ATVBAHA.114.303090. Epub 2014 Mar 27.
• Background Forrester SJ, Kikuchi DS, Hernandes MS, Xu Q, Griendling KK. Reactive Oxygen Species in Metabolic and Inflammatory Signaling. Circ Res. 2018 Mar 16;122(6):877-902. doi: 10.1161/CIRCRESAHA.117.311401.
• Background Giacco F, Brownlee M. Oxidative stress and diabetic complications. Circ Res. 2010 Oct 29;107(9):1058-70. doi: 10.1161/CIRCRESAHA.110.223545.
• Background Singh DK, Winocour P, Farrington K. Oxidative stress in early diabetic nephropathy: fueling the fire. Nat Rev Endocrinol. 2011 Mar;7(3):176-84. doi: 10.1038/nrendo.2010.212. Epub 2010 Dec 14.
• Background Arden GB, Sivaprasad S. Hypoxia and oxidative stress in the causation of diabetic retinopathy. Curr Diabetes Rev. 2011 Sep;7(5):291-304. doi: 10.2174/157339911797415620.
• Background Frey RS, Ushio-Fukai M, Malik AB. NADPH oxidase-dependent signaling in endothelial cells: role in physiology and pathophysiology. Antioxid Redox Signal. 2009 Apr;11(4):791-810. doi: 10.1089/ars.2008.2220.
• Background Incalza MA, D'Oria R, Natalicchio A, Perrini S, Laviola L, Giorgino F. Oxidative stress and reactive oxygen species in endothelial dysfunction associated with cardiovascular and metabolic diseases. Vascul Pharmacol. 2018 Jan;100:1-19. doi: 10.1016/j.vph.2017.05.005. Epub 2017 Jun 1.
• Background Liemburg-Apers DC, Willems PH, Koopman WJ, Grefte S. Interactions between mitochondrial reactive oxygen species and cellular glucose metabolism. Arch Toxicol. 2015 Aug;89(8):1209-26. doi: 10.1007/s00204-015-1520-y. Epub 2015 Jun 6.
• Background Kunkemoeller B, Kyriakides TR. Redox Signaling in Diabetic Wound Healing Regulates Extracellular Matrix Deposition. Antioxid Redox Signal. 2017 Oct 20;27(12):823-838. doi: 10.1089/ars.2017.7263. Epub 2017 Aug 10.

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Indications