Lamas GA, Goertz C, Boineau R, et al. Effect of disodium EDTA chelation regimen on cardiovascular events in patients with previous myocardial infarction: the TACT randomized trial. JAMA. 2013;309:1241–50. Main results of the Trial to Assess Chelation Therapy.
Escolar E, Lamas GA, Mark DB, et al. Clinical benefit of EDTA chelation therapy in patients with diabetes in the trial to assess chelation therapy (TACT). Circulation 2013;128. Prespecified subgroup analysis showed that post-myocardial infarction patients with diabetes demonstrated that chelation was associated with 61 % reduction in hazard ratio for the primary endpoint of death, reinfarction, stroke, coronary revascularization, or hospitalization for angina. No benefit was evident in the patients without diabetes.
Nissen SE. Concerns about reliability in the Trial to Assess Chelation Therapy (TACT). JAMA. 2013;309:1293–4.
Kaul S. Are concerns about reliability in the trial to assess chelation therapy fair grounds for a hasty dismissal? An alternative perspective. Circ Cardiovasc Qual Outcomes. 2014;7:5–7.
Lamas GA, Boineau R, Goertz C, et al. EDTA chelation therapy alone and in combination with oral high-dose multivitamins and minerals for coronary disease: the factorial group results of the Trial to Assess Chelation Therapy. Am Heart J. 2014;168:37–44.e5.
Maron DJ, Hlatky MA. Trial to Assess Chelation Therapy (TACT) and equipoise: when evidence conflicts with beliefs. Am Heart J. 2014;168:4–5.
Brownlee M. The pathobiology of diabetic complications: a unifying mechanism. Diabetes. 2005;54:1615–25.
Selvin E, Halushka MK, Rawlings AM, et al. sRAGE and risk of diabetes, cardiovascular disease, and death. Diabetes. 2013;62:2116–21. Advanced glycation end products (AGEs) are produced in excess in diabetes due to the irreversible reaction of glucose with proteins. AGE binds to various ligands, especially the receptor for AGE (RAGE) which triggers NF-kB-mediated inflammatory signaling. Soluble circulating RAGE (sRAGE) may counteract the effects of RAGE. This study of stored samples from the Atherosclerosis Risk in Communities cohort showed an inverse relationship of sRAGE levels with future diabetes, coronary heart disease, and mortality.
Du XL, Edelstein D, Rossetti L, et al. Hyperglycemia-induced mitochondrial superoxide overproduction activates the hexosamine pathway and induces plasminogen activator inhibitor-1 expression by increasing Sp1 glycosylation. Proc Natl Acad Sci U S A. 2000;97:12222–6.
Pitocco D, Tesauro M, Alessandro R, Ghirlanda G, Cardillo C. Oxidative stress in diabetes: implications for vascular and other complications. Int J Mol Sci. 2013;14:21525–50. Detailed review of oxidative stress and the effect of reactive oxygen species (ROS) on the pancreatic beta cells and in the development of insulin resistance and diabetes. The role of ROS in the development of diabetic complications is discussed.
Gupta S, Chough E, Daley J, et al. Hyperglycemia increases endothelial superoxide that impairs smooth muscle cell Na+−K+−ATPase activity. Am J Physiol Cell Physiol. 2002;282:C560–6.
Hink U, Li H, Mollnau H, et al. Mechanisms underlying endothelial dysfunction in diabetes mellitus. Circ Res. 2001;88:E14–22.
Mullarkey CJ, Edelstein D, Brownlee M. Free radical generation by early glycation products: a mechanism for accelerated atherogenesis in diabetes. Biochem Biophys Res Commun. 1990;173:932–9.
Furukawa S, Fujita T, Shimabukuro M, et al. Increased oxidative stress in obesity and its impact on metabolic syndrome. J Clin Invest. 2004;114:1752–61.
Aronson D. Hyperglycemia and the pathobiology of diabetic complications. Adv Cardiol. 2008;45:1–16.
Anderson EJ, Lustig ME, Boyle KE, et al. Mitochondrial H2O2 emission and cellular redox state link excess fat intake to insulin resistance in both rodents and humans. J Clin Invest. 2009;119:573–81.
Houstis N, Rosen ED, Lander ES. Reactive oxygen species have a causal role in multiple forms of insulin resistance. Nature. 2006;440:944–8.
Anderson RA, Evans ML, Ellis GR, et al. The relationships between post-prandial lipaemia, endothelial function and oxidative stress in healthy individuals and patients with type 2 diabetes. Atherosclerosis. 2001;154:475–83.
Montgomery MK, Turner N. Mitochondrial dysfunction and insulin resistance: an update. Endocr Connect. 2015;4:R1–15.
Pennathur S, Wagner JD, Leeuwenburgh C, Litwak KN, Heinecke JW. A hydroxyl radical-like species oxidizes cynomolgus monkey artery wall proteins in early diabetic vascular disease. J Clin Invest. 2001;107:853–60.
Zheng Y, Li XK, Wang Y, Cai L. The role of zinc, copper and iron in the pathogenesis of diabetes and diabetic complications: therapeutic effects by chelators. Hemoglobin. 2008;32:135–45.
Krishnamurti C, Saryan LA, Petering DH. Effects of ethylenediaminetetraacetic acid and 1,10-phenanthroline on cell proliferation and DNA synthesis of Ehrlich ascites cells. Cancer Res. 1980;40:4092–9.
Hansen JB, Moen IW, Mandrup-Poulsen T. Iron: the hard player in diabetes pathophysiology. Acta Physiol. 2014;210:717–32.
Cooksey RC, Jouihan HA, Ajioka RS, et al. Oxidative stress, beta-cell apoptosis, and decreased insulin secretory capacity in mouse models of hemochromatosis. Endocrinology. 2004;145:5305–12.
Kakhlon O, Cabantchik ZI. The labile iron pool: characterization, measurement, and participation in cellular processes(1). Free Radic Biol Med. 2002;33:1037–46.
Lee DH, Liu DY, Jacobs Jr DR, et al. Common presence of non-transferrin-bound iron among patients with type 2 diabetes. Diabetes Care. 2006;29:1090–5.
Stack AG, Mutwali AI, Nguyen HT, Cronin CJ, Casserly LF, Ferguson J. Transferrin saturation ratio and risk of total and cardiovascular mortality in the general population. QJM. 2014;107:623–33.
Lapice E, Masulli M, Vaccaro O. Iron deficiency and cardiovascular disease: an updated review of the evidence. Curr Atheroscler Rep. 2013;15:358.
Haidari M, Javadi E, Sanati A, Hajilooi M, Ghanbili J. Association of increased ferritin with premature coronary stenosis in men. Clin Chem. 2001;47:1666–72.
You SA, Wang Q. Ferritin in atherosclerosis. Clin Chim Acta. 2005;357:1–16.
Nagai R, Ikeda K, Higashi T, et al. Hydroxyl radical mediates N epsilon-(carboxymethyl)lysine formation from Amadori product. Biochem Biophys Res Commun. 1997;234:167–72.
Zacharski LR, Chow BK, Howes PS, et al. Reduction of iron stores and cardiovascular outcomes in patients with peripheral arterial disease: a randomized controlled trial. JAMA. 2007;297:603–10.
Valko M, Morris H, Cronin MTD. Metals, toxicity and oxidative stress. Curr Med Chem. 2005;12:1161–208.
Cai L, Li XK, Song Y, Cherian MG. Essentiality, toxicology and chelation therapy of zinc and copper. Curr Med Chem. 2005;12:2753–63.
Cai L, Koropatnick J, Cherian MG. Metallothionein protects DNA from copper-induced but not iron-induced cleavage in vitro. Chem Biol Interact. 1995;96:143–55.
Rae TD, Schmidt PJ, Pufahl RA, Culotta VC, O’Halloran TV. Undetectable intracellular free copper: the requirement of a copper chaperone for superoxide dismutase. Science. 1999;284:805–8.
Uriu-Adams JY, Keen CL. Copper, oxidative stress, and human health. Mol Asp Med. 2005;26:268–98.
Cunningham J, Leffell M, Mearkle P, Harmatz P. Elevated plasma ceruloplasmin in insulin-dependent diabetes mellitus: evidence for increased oxidative stress as a variable complication. Metab Clin Exp. 1995;44:996–9.
Grammer TB, Kleber ME, Silbernagel G, et al. Copper, ceruloplasmin, and long-term cardiovascular and total mortality (the Ludwigshafen Risk and Cardiovascular Health Study). Free Radic Res. 2014;48:706–15. Analysis of the association between copper and ceruloplasmin concentrations and cardiovascular and all-cause mortality in 3253 participants of the LURIC study. This showed a hazard ratio for death of 2.23 for copper and 2.63 for ceruloplasmin when comparing highest to lowest quartiles. This significant association persisted after adjustments for risk factors.
Lee MJ, Jung CH, Hwang JY, et al. Association between serum ceruloplasmin levels and arterial stiffness in Korean men with type 2 diabetes mellitus. Diabetes Technol Ther. 2012;14:1091–7.
Hellman NE, Gitlin JD. Ceruloplasmin metabolism and function. Annu Rev Nutr. 2002;22:439–58.
Cooper GJ, Young AA, Gamble GD, et al. A copper(II)-selective chelator ameliorates left-ventricular hypertrophy in type 2 diabetic patients: a randomised placebo-controlled study. Diabetologia. 2009;52:715–22.
Cooper GJ, Phillips AR, Choong SY, et al. Regeneration of the heart in diabetes by selective copper chelation. Diabetes. 2004;53:2501–8.
Genuth S, Sun W, Cleary P, et al. Glycation and carboxymethyllysine levels in skin collagen predict the risk of future 10-year progression of diabetic retinopathy and nephropathy in the diabetes control and complications trial and epidemiology of diabetes interventions and complications participants with type 1 diabetes. Diabetes. 2005;54:3103–11.
Peppa M, Vlassara H. Advanced glycation end products and diabetic complications: a general overview. Hormones. 2005;4:28–37.
Semba RD, Ferrucci L, Sun K, et al. Advanced glycation end products and their circulating receptors predict cardiovascular disease mortality in older community-dwelling women. Aging Clin Exp Res. 2009;21:182–90.
Wolff SP, Dean RT. Glucose autoxidation and protein modification. The potential role of ‘autoxidative glycosylation’ in diabetes. Biochem J. 1987;245:243–50.
Brings S, Zhang S, Choong YS, et al. Diabetes-induced alterations in tissue collagen and carboxymethyllysine in rat kidneys: association with increased collagen-degrading proteinases and amelioration by Cu(II)-selective chelation. Biochim Biophys Acta. 1852;2015:1610–8.
Uchiki T, Weikel KA, Jiao W, et al. Glycation-altered proteolysis as a pathobiologic mechanism that links dietary glycemic index, aging, and age-related disease (in nondiabetics). Aging Cell. 2012;11:1–13.
Menke A, Muntner P, Batuman V, Silbergeld EK, Guallar E. Blood lead below 0.48 micromol/L (10 microg/dL) and mortality among US adults. Circulation. 2006;114:1388–94.
Navas-Acien A, Guallar E, Silbergeld EK, Rothenberg SJ. Lead exposure and cardiovascular disease--a systematic review. Environ Health Perspect. 2007;115:472–82.
Tellez-Plaza M, Guallar E, Howard BV, et al. Cadmium exposure and incident cardiovascular disease. Epidemiology. 2013;24:421–9.
Tellez-Plaza M, Jones MR, Dominguez-Lucas A, Guallar E, Navas-Acien A. Cadmium exposure and clinical cardiovascular disease: a systematic review. Curr Atheroscler Rep. 2013;15:356. Systematic review of epidemiologic studies evaluating the association between cadmium exposure and cardiovascular disease.
Tellez-Plaza M, Navas-Acien A, Menke A, Crainiceanu CM, Pastor-Barriuso R, Guallar E. Cadmium exposure and all-cause and cardiovascular mortality in the U.S. general population. Environ Health Perspect. 2012;120:1017–22.
Toxicological profile for cadmium. In: Services. US Department of Health and Human Services, editor. Atlanta, GA: US Department of Health and Human Services: Public Health Service. 1999.
Waters RS, Bryden NA, Patterson KY, Veillon C, Anderson RA. EDTA chelation effects on urinary losses of cadmium, calcium, chromium, cobalt, copper, lead, magnesium, and zinc. Biol Trace Elem Res. 2001;83:207–21.
Blanusa M, Varnai VM, Piasek M, Kostial K. Chelators as antidotes of metal toxicity: therapeutic and experimental aspects. Curr Med Chem. 2005;12:2771–94.
Jarup L, Berglund M, Elinder CG, Nordberg G, Vahter M. Health effects of cadmium exposure- a review of the literature and a risk estimate. Scand J Work Environ Health. 1998;24:1–51.
Nordberg GF, Nogawa K, Nordberg M, Friberg LT. Cadmium. In: Nordberg GF, Fowler BF, Nordberg M, Friberg LT, editors. Handbook on the toxicology of metals. 3rd ed. Amsterdam: Elsevier; 2007. p. 446–86.
Guallar E, Sanz-Gallardo MI, van’t Veer P, et al. Mercury, fish oils, and the risk of myocardial infarction. N Engl J Med. 2002;347:1747–54.
Navas-Acien A, Silbergeld EK, Sharrett R, Calderon-Aranda E, Selvin E, Guallar E. Metals in urine and peripheral arterial disease. Environ Health Perspect. 2005;113:164–9.
Solenkova NV, Newman JD, Berger JS, Thurston G, Hochman JS, Lamas GA. Metal pollutants and cardiovascular disease: mechanisms and consequences of exposure. Am Heart J. 2014;168:812–22.
Lalor GC. Review of cadmium transfers from soil to humans and its health effects in the Jamaican environment. Sci Total Environ. 2008;400:162–72.
Messner B, Bernhard D. Cadmium and cardiovascular diseases: cell biology, pathophysiology, and epidemiological relevance. Biometals. 2010;23:811–22.
Cuypers A, Plusquin M, Remans T, et al. Cadmium stress: an oxidative challenge. Biometals. 2010;23:927–40.
Ruiz-Hernandez A, Kuo CC, Rentero-Garrido P, et al. Environmental chemicals and DNA methylation in adults: a systematic review of the epidemiologic evidence. Clin Epigenetics. 2015;7:55.
Martin-Nunez E, Donate-Correa J, Muros-de-Fuentes M, Mora-Fernandez C, Navarro-Gonzalez JF. Implications of Klotho in vascular health and disease. World J Cardiol. 2014;6:1262–9.
Flegal AR, Smith DR. Lead levels in preindustrial humans. N Engl J Med. 1992;326:1293–4.
Blood lead levels - United States, 199902002. MMWR Morb Mortal Wkly Rep. 2005;54:513–6.
Apostolou A, Garcia-Esquinas E, Fadrowski JJ, McLain P, Weaver VM, Navas-Acien A. Secondhand tobacco smoke: a source of lead exposure in US children and adolescents. Am J Public Health. 2012;102:714–22.
Hu H, Rabinowitz M, Smith D. Bone lead as a biological marker in epidemiologic studies of chronic toxicity: conceptual paradigms. Environ Health Perspect. 1998;106:1–8.
Hu H, Rothenberg SJ, Schwartz BS. The epidemiology of lead toxicity in adults: measuring dose and consideration of other methodologic issues. Environ Health Perspect. 2007;115:455–62.
Barbosa FJ, Tanus-Santos JE, Gerlach RF, Parsons PJ. A critical review of biomarkers used for monitoring human exposure to lead: advantages, limitations and future needs. Environ Health Perspect. 2005;113:1669–74.
Vaziri ND. Mechanisms of lead-induced hypertension and cardiovascular disease. Am J Physiol Heart Circ Physiol. 2008;295:H454–65.
Kern M, Audesirk G. Stimulatory and inhibitory effects of inorganic lead on calcineurin. Toxicology. 2000;150:171–8.
Tellez-Plaza M, Navas-Acien A, Crainiceanu CM, Sharrett AR, Guallar E. Cadmium and peripheral arterial disease: gender differences in the 1999–2004 US National Health and Nutrition Examination Survey. Am J Epidemiol. 2010;172:671–81.
Navas-Acien A, Selvin E, Sharrett AR, Calderon-Aranda E, Silbergeld E, Guallar E. Lead, cadmium, smoking, and increased risk of peripheral arterial disease. Circulation. 2004;109:3196–201.
Fagerberg B, Bergstrom G, Boren J, Barregard L. Cadmium exposure, intercellular adhesion molecule-1 and peripheral artery disease: a cohort and an experimental study. BMJ Open. 2013;3.
Bergstrom G, Fagerberg B, Sallsten G, Lundh T, Barregard L. Is cadmium exposure associated with the burden, vulnerability and rupture of human atherosclerotic plaques? PLoS One. 2015;10:e0121240.
Tellez-Plaza M, Navas-Acien A, Crainiceanu CM, Guallar E. Cadmium exposure and hypertension in the 1999–2004 National Health and Nutrition Examination Survey (NHANES). Environ Health Perspect. 2008;116:51–6.
Peters JL, Fabian MP, Levy JI. Combined impact of lead, cadmium, polychlorinated biphenyls and non-chemical risk factors on blood pressure in NHANES. Environ Res. 2014;132:93–9.
Navas-Acien A, Tellez-Plaza M, Guallar E, et al. Blood cadmium and lead and chronic kidney disease in US adults: a joint analysis. Am J Epidemiol. 2009;170:1156–64.
Sangartit W, Kukongviriyapan U, Donpunha W, et al. Tetrahydrocurcumin protects against cadmium-induced hypertension, raised arterial stiffness and vascular remodeling in mice. PLoS One. 2014;9:e114908.
Daniel S, Limson JL, Dairam A, Watkins GM, Daya S. Through metal binding, curcumin protects against lead- and cadmium-induced lipid peroxidation in rat brain homogenates and against lead-induced tissue damage in rat brain. J Inorg Biochem. 2004;98:266–75.
Kukongviriyapan U, Pannangpetch P, Kukongviriyapan V, Donpunha W, Sompamit K, Surawattanawan P. Curcumin protects against cadmium-induced vascular dysfunction, hypertension and tissue cadmium accumulation in mice. Nutrients. 2014;6:1194–208.
Jiao Y, Wilkinson J, Di X, et al. Curcumin, a cancer chemopreventive and chemotherapeutic agent, is a biologically active iron chelator. Blood. 2009;113:462–9.
Muntner P, Menke A, DeSalvo KB, Rabito FA, Batuman V. Continued decline in blood lead levels among adults in the United States: the National Health and Nutrition Examination Surveys. Arch Intern Med. 2005;165:2155–61.
Jain NB, Potula V, Schwartz J, et al. Lead levels and ischemic heart disease in a prospective study of middle-aged and elderly men: the VA Normative Aging Study. Environ Health Perspect. 2007;115:871–5.
Weisskopf MG, Jain N, Nie H, et al. A prospective study of bone lead concentration and death from all causes, cardiovascular diseases, and cancer in the Department of Veterans Affairs Normative Aging Study. Circulation. 2009;120:1056–64.
Forbes JM, Cooper ME, Thallas V, et al. Reduction of the accumulation of advanced glycation end products by ACE inhibition in experimental diabetic nephropathy. Diabetes. 2002;51:3274–82.
Miyata T, van Ypersele de Strihou C, Ueda Y, et al. Angiotensin II receptor antagonists and angiotensin-converting enzyme inhibitors lower in vitro the formation of advanced glycation end products: biochemical mechanisms. J Am Soc Nephrol. 2002;13:2478–87.
Nagai R, Murray DB, Metz TO, Baynes JW. Chelation: a fundamental mechanism of action of AGE inhibitors, AGE breakers, and other inhibitors of diabetes complications. Diabetes. 2012;61:549–59. Hypothesis-generating article that details the drugs commonly prescribed for patients with diabetes and heart disease, such as angiotensinogen-converting enzyme inhibitor (ACEI), chelates metal at low concentration. The article provokes thought that their clinical effectiveness, which is especially marked in patients with diabetes, may be due in part to their chelating properties.
Gustafsson I, Torp-Pedersen C, Kober L, Gustafsson F, Hildebrandt P. Effect of the angiotensin-converting enzyme inhibitor trandolapril on mortality and morbidity in diabetic patients with left ventricular dysfunction after acute myocardial infarction. Trace Study Group. J Am Coll Cardiol. 1999;34:83–9.
Logie L, Harthill J, Patel K, et al. Cellular responses to the metal-binding properties of metformin. Diabetes. 2012;61:1423–33. Metformin, a biguanide, is recommended as the initial oral hypoglycemic agent for treatment of type 2 diabetes not controlled with diet and exercise. The mechanism by which metformin inhibits gluconeogenesis is complex, with several putative targets. This well-done in vitro study documents that metformin complexes with copper to initiate the cascade which produces its pharmacologic effect.