Skip to main content
Top
Published in: Cardiovascular Drugs and Therapy 5-6/2017

01-12-2017 | REVIEW ARTICLE

Chelation Therapy as a Cardiovascular Therapeutic Strategy: the Rationale and the Data in Review

Authors: Roy O. Mathew, Joshua Schulman-Marcus, Elizabeth L. Nichols, Jonathan D. Newman, Sripal Bangalore, Michael Farkouh, Mandeep S. Sidhu

Published in: Cardiovascular Drugs and Therapy | Issue 5-6/2017

Login to get access

Abstract

Chelation therapy, typically used to remove heavy metal toxins, has also been controversially used as a treatment for coronary artery disease. The first Trial to Assess Chelation Therapy (TACT) aimed to provide evidence on chelation therapy’s potential for benefit or harm. Although TACT had some significant results, the trial does not provide enough evidence to recommend routine chelation therapy and has limitations. The second TACT was recently funded reigniting a discussion about the value of chelation therapy, its efficacy, and allocation of research resources. Despite limited evidence, patients continue to pursue chelation therapy as a treatment for coronary artery disease. As the medical community has a responsibility to understand all treatments patients pursue, it is important to comprehensively appraise chelation therapy for cardiovascular disease. Understanding the background of heavy metal toxicity, the putative target of chelation therapy, on the cardiovascular system is important to contextualize the role of chelation therapy in cardiovascular disease prevention. We review the clinical evidence of heavy metal toxicity and cardiovascular disease, and available clinical trial data on use of chelation therapy to minimize the cardiovascular burden of heavy metal toxicity.
Literature
1.
go back to reference Clarke TC, Black LI, Stussman BJ, Barnes PM, Nahin RL. Trends in the use of complementary health approaches among adults: United States, 2002–2012. National health statistics reports. 2015;(79):1–16. Clarke TC, Black LI, Stussman BJ, Barnes PM, Nahin RL. Trends in the use of complementary health approaches among adults: United States, 2002–2012. National health statistics reports. 2015;(79):1–16.
2.
go back to reference Lamas GA, Goertz C, Boineau R, Mark DB, Rozema T, Nahin RL, et al. Effect of disodium EDTA chelation regimen on cardiovascular events in patients with previous myocardial infarction: the TACT randomized trial. JAMA J Am Med Assoc. 2013;309(12):1241–50.CrossRef Lamas GA, Goertz C, Boineau R, Mark DB, Rozema T, Nahin RL, et al. Effect of disodium EDTA chelation regimen on cardiovascular events in patients with previous myocardial infarction: the TACT randomized trial. JAMA J Am Med Assoc. 2013;309(12):1241–50.CrossRef
3.
go back to reference Borne Y, Barregard L, Persson M, Hedblad B, Fagerberg B, Engstrom G. Cadmium exposure and incidence of heart failure and atrial fibrillation: a population-based prospective cohort study. BMJ Open. 2015;5(6):e007366.CrossRefPubMedPubMedCentral Borne Y, Barregard L, Persson M, Hedblad B, Fagerberg B, Engstrom G. Cadmium exposure and incidence of heart failure and atrial fibrillation: a population-based prospective cohort study. BMJ Open. 2015;5(6):e007366.CrossRefPubMedPubMedCentral
4.
go back to reference Jain NB, Potula V, Schwartz J, Vokonas PS, Sparrow D, Wright RO, 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(6):871–5.CrossRefPubMedPubMedCentral Jain NB, Potula V, Schwartz J, Vokonas PS, Sparrow D, Wright RO, 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(6):871–5.CrossRefPubMedPubMedCentral
5.
go back to reference Knudtson ML, Wyse DG, Galbraith PD, Brant R, Hildebrand K, Paterson D, et al. Chelation therapy for ischemic heart disease: a randomized controlled trial. JAMA J Am Med Assoc. 2002;287(4):481–6.CrossRef Knudtson ML, Wyse DG, Galbraith PD, Brant R, Hildebrand K, Paterson D, et al. Chelation therapy for ischemic heart disease: a randomized controlled trial. JAMA J Am Med Assoc. 2002;287(4):481–6.CrossRef
6.
go back to reference Ernst E. Chelation therapy for peripheral arterial occlusive disease: a systematic review. Circulation. 1997;96(3):1031–3.CrossRefPubMed Ernst E. Chelation therapy for peripheral arterial occlusive disease: a systematic review. Circulation. 1997;96(3):1031–3.CrossRefPubMed
7.
go back to reference Berg JM, Tymoczko J, Stryer L. Biochemistry. 6th ed. New York: W.H. Freeman; 2006. Berg JM, Tymoczko J, Stryer L. Biochemistry. 6th ed. New York: W.H. Freeman; 2006.
8.
go back to reference Clarke CN, Clarke NE, Mosher RE. Treatment of angina pectoris with disodium ethylene diamine tetraacetic acid. Am J Med Sci. 1956;232(6):654–66.CrossRefPubMed Clarke CN, Clarke NE, Mosher RE. Treatment of angina pectoris with disodium ethylene diamine tetraacetic acid. Am J Med Sci. 1956;232(6):654–66.CrossRefPubMed
9.
go back to reference Barnes PM, Bloom B, Nahin RL. Complementary and alternative medicine use among adults and children: United States, 2007. National health statistics reports. 2008;(12):1–23. Barnes PM, Bloom B, Nahin RL. Complementary and alternative medicine use among adults and children: United States, 2007. National health statistics reports. 2008;(12):1–23.
10.
go back to reference Nissen SE. Concerns about reliability in the Trial to Assess Chelation Therapy (TACT). JAMA J Am Med Assoc. 2013;309(12):1293–4.CrossRef Nissen SE. Concerns about reliability in the Trial to Assess Chelation Therapy (TACT). JAMA J Am Med Assoc. 2013;309(12):1293–4.CrossRef
11.
go back to reference Messner B, Bernhard D. Cadmium and cardiovascular diseases: cell biology, pathophysiology, and epidemiological relevance. Biometals. 2010;23(5):811–22.CrossRefPubMed Messner B, Bernhard D. Cadmium and cardiovascular diseases: cell biology, pathophysiology, and epidemiological relevance. Biometals. 2010;23(5):811–22.CrossRefPubMed
12.
go back to reference Zhang R, Witkowska K, Afonso Guerra-Assuncao J, Ren M, Ng FL, Mauro C, et al. A blood pressure-associated variant of the SLC39A8 gene influences cellular cadmium accumulation and toxicity. Hum Mol Genet. 2016. Zhang R, Witkowska K, Afonso Guerra-Assuncao J, Ren M, Ng FL, Mauro C, et al. A blood pressure-associated variant of the SLC39A8 gene influences cellular cadmium accumulation and toxicity. Hum Mol Genet. 2016.
13.
go back to reference Zhang H, Li L, Wang Y, Dong F, Chen X, Liu F, et al. NF-kappaB signaling maintains the survival of cadmium-exposed human renal glomerular endothelial cells. Int J Mol Med. 2016;38(2):417–22.CrossRefPubMedPubMedCentral Zhang H, Li L, Wang Y, Dong F, Chen X, Liu F, et al. NF-kappaB signaling maintains the survival of cadmium-exposed human renal glomerular endothelial cells. Int J Mol Med. 2016;38(2):417–22.CrossRefPubMedPubMedCentral
14.
go back to reference Olszowski T, Baranowska-Bosiacka I, Gutowska I, Piotrowska K, Mierzejewska K, Korbecki J, et al. The effects of cadmium at low environmental concentrations on THP-1 macrophage apoptosis. Int J Mol Sci. 2015;16(9):21410.CrossRefPubMedPubMedCentral Olszowski T, Baranowska-Bosiacka I, Gutowska I, Piotrowska K, Mierzejewska K, Korbecki J, et al. The effects of cadmium at low environmental concentrations on THP-1 macrophage apoptosis. Int J Mol Sci. 2015;16(9):21410.CrossRefPubMedPubMedCentral
15.
go back to reference Evis MJ, Kane KA, Moore MR, Parratt JR. The effects of ethanol and lead, alone and in combination, on the severity of arrhythmias induced by coronary artery occlusion, and by noradrenaline, in anaesthetised rats. Arch Toxicol. 1986;59(1):56–60.CrossRefPubMed Evis MJ, Kane KA, Moore MR, Parratt JR. The effects of ethanol and lead, alone and in combination, on the severity of arrhythmias induced by coronary artery occlusion, and by noradrenaline, in anaesthetised rats. Arch Toxicol. 1986;59(1):56–60.CrossRefPubMed
16.
go back to reference Goncalves-Rizzi VH, Nascimento RA, Possomato-Vieira JS, Dias-Junior CA. Sodium nitrite prevents both reductions in circulating nitric oxide and hypertension in 7-day lead-treated rats. Basic Clin Pharmacol Toxicol. 2016;118(3):225–30.CrossRefPubMed Goncalves-Rizzi VH, Nascimento RA, Possomato-Vieira JS, Dias-Junior CA. Sodium nitrite prevents both reductions in circulating nitric oxide and hypertension in 7-day lead-treated rats. Basic Clin Pharmacol Toxicol. 2016;118(3):225–30.CrossRefPubMed
17.
go back to reference Wildemann TM, Siciliano SD, Weber LP. The mechanisms associated with the development of hypertension after exposure to lead, mercury species or their mixtures differs with the metal and the mixture ratio. Toxicology. 2016;339:1–8.CrossRefPubMed Wildemann TM, Siciliano SD, Weber LP. The mechanisms associated with the development of hypertension after exposure to lead, mercury species or their mixtures differs with the metal and the mixture ratio. Toxicology. 2016;339:1–8.CrossRefPubMed
18.
go back to reference Silva MA, de Oliveira TF, Almenara CC, Broseghini-Filho GB, Vassallo DV, Padilha AS, et al. Exposure to a low lead concentration impairs contractile machinery in rat cardiac muscle. Biol Trace Elem Res. 2015;167(2):280–7.CrossRefPubMed Silva MA, de Oliveira TF, Almenara CC, Broseghini-Filho GB, Vassallo DV, Padilha AS, et al. Exposure to a low lead concentration impairs contractile machinery in rat cardiac muscle. Biol Trace Elem Res. 2015;167(2):280–7.CrossRefPubMed
19.
go back to reference Tellez-Plaza M, Guallar E, Fabsitz RR, Howard BV, Umans JG, Francesconi KA, et al. Cadmium exposure and incident peripheral arterial disease. Circ Cardiovasc Qual Outcomes. 2013;6(6):626–33.CrossRefPubMedPubMedCentral Tellez-Plaza M, Guallar E, Fabsitz RR, Howard BV, Umans JG, Francesconi KA, et al. Cadmium exposure and incident peripheral arterial disease. Circ Cardiovasc Qual Outcomes. 2013;6(6):626–33.CrossRefPubMedPubMedCentral
20.
go back to reference 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(6):671–81.CrossRefPubMedPubMedCentral 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(6):671–81.CrossRefPubMedPubMedCentral
21.
go back to reference Franceschini N, Fry RC, Balakrishnan P, Navas-Acien A, Oliver-Williams C, Howard AG, et al. Cadmium body burden and increased blood pressure in middle-aged American Indians: the Strong Heart Study. J Hum Hypertens. 2017;31(3):225–30.CrossRefPubMed Franceschini N, Fry RC, Balakrishnan P, Navas-Acien A, Oliver-Williams C, Howard AG, et al. Cadmium body burden and increased blood pressure in middle-aged American Indians: the Strong Heart Study. J Hum Hypertens. 2017;31(3):225–30.CrossRefPubMed
22.
go back to reference 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(25):3196–201.CrossRefPubMed 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(25):3196–201.CrossRefPubMed
23.
go back to reference Han SJ, Ha KH, Jeon JY, Kim HJ, Lee KW, Kim DJ. Impact of cadmium exposure on the association between lipopolysaccharide and metabolic syndrome. Int J Environ Res Public Health. 2015;12(9):11396–409.CrossRefPubMedPubMedCentral Han SJ, Ha KH, Jeon JY, Kim HJ, Lee KW, Kim DJ. Impact of cadmium exposure on the association between lipopolysaccharide and metabolic syndrome. Int J Environ Res Public Health. 2015;12(9):11396–409.CrossRefPubMedPubMedCentral
24.
go back to reference Den Hond E, Nawrot T, Staessen JA. The relationship between blood pressure and blood lead in NHANES III. National Health and Nutritional Examination Survey. J Hum Hypertens. 2002;16(8):563–8.CrossRef Den Hond E, Nawrot T, Staessen JA. The relationship between blood pressure and blood lead in NHANES III. National Health and Nutritional Examination Survey. J Hum Hypertens. 2002;16(8):563–8.CrossRef
25.
go back to reference Staessen JA, Bulpitt CJ, Fagard R, Lauwerys RR, Roels H, Thijs L, et al. Hypertension caused by low-level lead exposure: myth or fact? J Cardiovasc Risk. 1994;1(1):87–97.PubMed Staessen JA, Bulpitt CJ, Fagard R, Lauwerys RR, Roels H, Thijs L, et al. Hypertension caused by low-level lead exposure: myth or fact? J Cardiovasc Risk. 1994;1(1):87–97.PubMed
26.
go back to reference Jhun MA, Hu H, Schwartz J, Weisskopf MG, Nie LH, Sparrow D et al. Effect modification by vitamin D receptor genetic polymorphisms in the association between cumulative lead exposure and pulse pressure: a longitudinal study. Environ Health Glob Access Sci Sour. 2015;14:5. Jhun MA, Hu H, Schwartz J, Weisskopf MG, Nie LH, Sparrow D et al. Effect modification by vitamin D receptor genetic polymorphisms in the association between cumulative lead exposure and pulse pressure: a longitudinal study. Environ Health Glob Access Sci Sour. 2015;14:5.
27.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
28.
go back to reference Navas-Acien A, Guallar E, Silbergeld EK, Rothenberg SJ. Lead exposure and cardiovascular disease—a systematic review. Environ Health Perspect. 2007;115(3):472–82.CrossRefPubMed Navas-Acien A, Guallar E, Silbergeld EK, Rothenberg SJ. Lead exposure and cardiovascular disease—a systematic review. Environ Health Perspect. 2007;115(3):472–82.CrossRefPubMed
29.
go back to reference Weisskopf MG, Jain N, Nie H, Sparrow D, Vokonas P, Schwartz J, 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(12):1056–64.CrossRefPubMedPubMedCentral Weisskopf MG, Jain N, Nie H, Sparrow D, Vokonas P, Schwartz J, 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(12):1056–64.CrossRefPubMedPubMedCentral
30.
go back to reference Milton Prabu S, Muthumani M, Shagirtha K. Quercetin potentially attenuates cadmium induced oxidative stress mediated cardiotoxicity and dyslipidemia in rats. Eur Rev Med Pharmacol Sci. 2013;17(5):582–95.PubMed Milton Prabu S, Muthumani M, Shagirtha K. Quercetin potentially attenuates cadmium induced oxidative stress mediated cardiotoxicity and dyslipidemia in rats. Eur Rev Med Pharmacol Sci. 2013;17(5):582–95.PubMed
31.
go back to reference Nascimento RA, Mendes G, Possomato-Vieira JS, Goncalves-Rizzi VH, Kushima H, Delella FK, et al. Metalloproteinase inhibition protects against reductions in circulating adrenomedullin during lead-induced acute hypertension. Basic Clin Pharmacol Toxicol. 2015;116(6):508–15.CrossRefPubMed Nascimento RA, Mendes G, Possomato-Vieira JS, Goncalves-Rizzi VH, Kushima H, Delella FK, et al. Metalloproteinase inhibition protects against reductions in circulating adrenomedullin during lead-induced acute hypertension. Basic Clin Pharmacol Toxicol. 2015;116(6):508–15.CrossRefPubMed
32.
go back to reference Guldager B, Jelnes R, Jorgensen SJ, Nielsen JS, Klaerke A, Mogensen K, et al. EDTA treatment of intermittent claudication—a double-blind, placebo-controlled study. J Intern Med. 1992;231(3):261–7.CrossRefPubMed Guldager B, Jelnes R, Jorgensen SJ, Nielsen JS, Klaerke A, Mogensen K, et al. EDTA treatment of intermittent claudication—a double-blind, placebo-controlled study. J Intern Med. 1992;231(3):261–7.CrossRefPubMed
33.
go back to reference van Rij AM, Solomon C, Packer SG, Hopkins WG. Chelation therapy for intermittent claudication. A double-blind, randomized, controlled trial. Circulation. 1994;90(3):1194–9.CrossRefPubMed van Rij AM, Solomon C, Packer SG, Hopkins WG. Chelation therapy for intermittent claudication. A double-blind, randomized, controlled trial. Circulation. 1994;90(3):1194–9.CrossRefPubMed
34.
go back to reference Lin JL, Lin-Tan DT, Hsu KH, Yu CC. Environmental lead exposure and progression of chronic renal diseases in patients without diabetes. N Engl J Med. 2003;348(4):277–86.CrossRefPubMed Lin JL, Lin-Tan DT, Hsu KH, Yu CC. Environmental lead exposure and progression of chronic renal diseases in patients without diabetes. N Engl J Med. 2003;348(4):277–86.CrossRefPubMed
35.
go back to reference Chen KH, Lin JL, Lin-Tan DT, Hsu HH, Hsu CW, Hsu KH, et al. Effect of chelation therapy on progressive diabetic nephropathy in patients with type 2 diabetes and high-normal body lead burdens. Am J Kidney Dis Off J Natl Kidney Found. 2012;60(4):530–8.CrossRef Chen KH, Lin JL, Lin-Tan DT, Hsu HH, Hsu CW, Hsu KH, et al. Effect of chelation therapy on progressive diabetic nephropathy in patients with type 2 diabetes and high-normal body lead burdens. Am J Kidney Dis Off J Natl Kidney Found. 2012;60(4):530–8.CrossRef
36.
go back to reference Ernst E. Chelation therapy for coronary heart disease: an overview of all clinical investigations. Am Heart J. 2000;140(1):139–41.CrossRefPubMed Ernst E. Chelation therapy for coronary heart disease: an overview of all clinical investigations. Am Heart J. 2000;140(1):139–41.CrossRefPubMed
37.
go back to reference Lamas GA, Ackermann A. Clinical evaluation of chelation therapy: is there any wheat amidst the chaff? Am Heart J. 2000;140(1):4–5.CrossRefPubMed Lamas GA, Ackermann A. Clinical evaluation of chelation therapy: is there any wheat amidst the chaff? Am Heart J. 2000;140(1):4–5.CrossRefPubMed
38.
go back to reference Lamas GA, Goertz C, Boineau R, Mark DB, Rozema T, Nahin RL, et al. Design of the Trial to Assess Chelation Therapy (TACT). Am Heart J. 2012;163(1):7–12.CrossRefPubMedPubMedCentral Lamas GA, Goertz C, Boineau R, Mark DB, Rozema T, Nahin RL, et al. Design of the Trial to Assess Chelation Therapy (TACT). Am Heart J. 2012;163(1):7–12.CrossRefPubMedPubMedCentral
39.
go back to reference Mark DB, Anstrom KJ, Clapp-Channing NE, Knight JD, Boineau R, Goertz C, et al. Quality-of-life outcomes with a disodium EDTA chelation regimen for coronary disease: results from the trial to assess chelation therapy randomized trial. Circ Cardiovasc Qual Outcomes. 2014;7(4):508–16.CrossRefPubMedPubMedCentral Mark DB, Anstrom KJ, Clapp-Channing NE, Knight JD, Boineau R, Goertz C, et al. Quality-of-life outcomes with a disodium EDTA chelation regimen for coronary disease: results from the trial to assess chelation therapy randomized trial. Circ Cardiovasc Qual Outcomes. 2014;7(4):508–16.CrossRefPubMedPubMedCentral
40.
go back to reference Escolar E, Lamas GA, Mark DB, Boineau R, Goertz C, Rosenberg Y, et al. The effect of an EDTA-based chelation regimen on patients with diabetes mellitus and prior myocardial infarction in the Trial to Assess Chelation Therapy (TACT). Circ Cardiovasc Qual Outcomes. 2014;7(1):15–24.CrossRefPubMed Escolar E, Lamas GA, Mark DB, Boineau R, Goertz C, Rosenberg Y, et al. The effect of an EDTA-based chelation regimen on patients with diabetes mellitus and prior myocardial infarction in the Trial to Assess Chelation Therapy (TACT). Circ Cardiovasc Qual Outcomes. 2014;7(1):15–24.CrossRefPubMed
41.
go back to reference 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(1):5–7.CrossRefPubMed 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(1):5–7.CrossRefPubMed
42.
go back to reference Lamas GA, Navas-Acien A, Mark DB, Lee KL. Heavy metals, cardiovascular disease, and the unexpected benefits of chelation therapy. J Am Coll Cardiol. 2016;67(20):2411–8.CrossRefPubMedPubMedCentral Lamas GA, Navas-Acien A, Mark DB, Lee KL. Heavy metals, cardiovascular disease, and the unexpected benefits of chelation therapy. J Am Coll Cardiol. 2016;67(20):2411–8.CrossRefPubMedPubMedCentral
Metadata
Title
Chelation Therapy as a Cardiovascular Therapeutic Strategy: the Rationale and the Data in Review
Authors
Roy O. Mathew
Joshua Schulman-Marcus
Elizabeth L. Nichols
Jonathan D. Newman
Sripal Bangalore
Michael Farkouh
Mandeep S. Sidhu
Publication date
01-12-2017
Publisher
Springer US
Published in
Cardiovascular Drugs and Therapy / Issue 5-6/2017
Print ISSN: 0920-3206
Electronic ISSN: 1573-7241
DOI
https://doi.org/10.1007/s10557-017-6759-5

Other articles of this Issue 5-6/2017

Cardiovascular Drugs and Therapy 5-6/2017 Go to the issue