Low-Level Cadmium Exposure and Atherosclerosis.

PURPOSE OF REVIEW: Cadmium has been recognized as a potential risk factor for cardiovascular disease (CVD). We present a review of cadmium toxicity, its effect on cellular activities, and a summary of reported association between environmental cadmium exposure and CVD. We also discuss the possible therapeutic benefit of cadmium chelation. RECENT FINDINGS: Experimental data suggest that cadmium affects several signaling pathways which may lead to endothelial dysfunction and vascular tissue damage, promoting atherosclerosis. This is further supported by epidemiological studies that have shown an association of even low-level cadmium exposure with an increased risk of clinical cardiovascular events. The Trial to Assess Chelation Therapy (TACT) provided inferential evidence for the cardiovascular benefit of treating toxic metal burden. However, at the present time, there is no direct evidence, but suggestive findings from clinical trials indicating that removal of cadmium from body stores may be associated with improved cardiovascular outcomes. An evolving body of evidence supports environmental cadmium exposure as a pro-atherosclerosis risk factor in CVD; however, the mechanisms for the proatherogenic effect of cadmium are still not completely understood. Further studies in translational toxicology are needed to fill the knowledge gaps regarding the molecular mechanisms of cadmium toxicity and the promotion of atherosclerosis.

The effect of EDTA-based chelation on patients with diabetes and peripheral artery disease in the Trial to Assess Chelation Therapy (TACT).

OBJECTIVE: Approximately 1 in 7 US adults have diabetes; and over 60% of deaths in patients with diabetes have cardiac disease as a principal or contributing cause. Both coronary and peripheral artery disease (PAD) identify high-risk cohorts among patients with diabetes. We have previously demonstrated improved cardiovascular outcomes with edetate disodium-based chelation in post-MI patients with diabetes, enrolled in the Trial to Assess Chelation Therapy (TACT). In these analyses we further studied the effect size of patients with diabetes and severe disease in 2 vascular beds; coronaries, and lower extremity arteries. We questioned whether greater atherosclerotic burden would attenuate the observed beneficial effect of edetate disodium infusions. RESEARCH DESIGN AND METHODS: The multicenter TACT used a double blind, placebo controlled, 2 × 2 factorial design with 1708 participants, randomly assigned to receive edetate disodium-based chelation, or placebo and high dose oral vitamins or placebo. There were 162 (9.5% of 1708) post-MI patients with a diagnosis of diabetes mellitus and PAD for this post hoc analysis. Patients received up to 40 double-blind intravenous infusions of edetate disodium-based chelation, or placebo. The composite primary endpoint of TACT consisted of death from any cause, myocardial infarction, stroke, coronary revascularization and hospitalization for angina. RESULTS: The median age was 66 years, 15% female, 5% non-Caucasian, and BMI was 31. Insulin was used by 32% of patients. Active infusions significantly reduced the primary endpoint compared with placebo infusions (HR, 0.52; 95% CI, 0.30-0.92; P = 0.0069), with a 30% absolute risk reduction in the primary endpoint. There was a marked reduction in total mortality from 24% to 11%, although of borderline significance (P = 0.052). CONCLUSION: Atherosclerotic disease in multiple vascular beds did not attenuate the beneficial effect of edetate disodium infusions in post MI patients with diabetes. Studies now in progress will prospectively test this post hoc finding.

Potential Role of Metal Chelation to Prevent the Cardiovascular Complications of Diabetes.

CONTEXT: For decades, there has been epidemiologic evidence linking chronic toxic metal exposure with cardiovascular disease, suggesting a therapeutic role for metal chelation. Given the lack of compelling scientific evidence, however, the indications for metal chelation were never clearly defined. To determine the safety and efficacy of chelation therapy, the National Institutes of Health funded the Trial to Assess Chelation Therapy (TACT). TACT was the first double-blind, randomized, controlled trial to demonstrate an improvement in cardiovascular outcomes with edetate disodium therapy in patients with prior myocardial infarction. The therapeutic benefit was striking among the prespecified subgroup of patients with diabetes. DESIGN: We review the published literature focusing on the atherogenic nature of diabetes, as well as available evidence from clinical trials, complete and in progress, of metal chelation with edetate disodium therapy in patients with diabetes. RESULTS: The TACT results support the concept that ubiquitous toxic metals such as lead and cadmium may be modifiable risk factors for cardiovascular disease, particularly in patients with diabetes. CONCLUSIONS: The purpose of this review is to discuss the potential mechanisms unifying the pathogenesis of atherogenic factors in diabetes with toxic metal exposure, and the potential role of metal chelation.

Limb Preservation Using Edetate Disodium-based Chelation in Patients with Diabetes and Critical Limb Ischemia: An Open-label Pilot Study.

Background In 2015, there were 30.3 million patients with diabetes in the US, including 25.2% of people ages 65 or older and 108,000 hospitalizations for non-traumatic amputations. Severe diabetic limb disease includes critical limb ischemia (CLI ) due to an infrapopliteal disease with foot pain and ischemic ulcerations including gangrene. Environmentally acquired toxic metals, such as lead and cadmium, have been associated with cardiovascular disease. Thus, we designed the present unblinded pilot study to determine whether there was a signal of benefit for edetate disodium-based infusions in patients with critical limb ischemia. Methods This was an open-label pilot study in 10 patients with diabetes and critical limb ischemia. Each patient received up to 50 edetate disodium-based infusions and was assessed for safety, clinical efficacy, metal excretion, and quality of life. The primary endpoint was to assess the effect of edetate disodium-based therapy plus vitamins in patients with diabetes and infra-popliteal peripheral artery disease presenting with severe CLI and determine if there were improvements in vascular flow parameters. Results We enrolled 10 (60% male) predominantly Caucasian (90%) subjects. The mean age was 75.3 (8.0) years. Smoking was reported by 30%. There were 70% with coronary artery disease (30% had prior coronary artery bypass grafting) and 50% had a prior lower-extremity amputation, three having previous minor amputations and two major amputations. There were no major adverse cardiovascular events during the infusion phase through the one-year follow-up. Patients completing 40 infusions demonstrated complete wound healing and improvement in the quality of life. Conclusion Patients with diabetes and CLI treated with a regimen of edetate disodium-based infusions demonstrated a potential signal of benefit and preliminary evidence of safety. The Trial to Assess Chelation Therapy in Critical Limb Ischemia (TACT3a), a randomized double-blind, placebo-controlled clinical trial now in progress, will further test these findings.

Chelation therapy to prevent diabetes-associated cardiovascular events.

PURPOSE OF REVIEW: For over 60 years, chelation therapy with disodium ethylene diamine tetraacetic acid (EDTA, edetate) had been used for the treatment of cardiovascular disease (CVD) despite lack of scientific evidence for efficacy and safety. The Trial to Assess Chelation Therapy (TACT) was developed and received funding from the National Institutes of Health (NIH) to ascertain the safety and efficacy of chelation therapy in patients with CVD. RECENT FINDINGS: This pivotal trial demonstrated an improvement in outcomes in postmyocardial infarction (MI) patients. Interestingly, it also showed a particularly large reduction in CVD events and all-cause mortality in the prespecified subgroup of patients with diabetes. The TACT results may support the concept of metal chelation to reduce metal-catalyzed oxidation reactions that promote the formation of advanced glycation end products, a precursor of diabetic atherosclerosis. SUMMARY: In this review, we summarize the epidemiological and basic evidence linking toxic metal accumulation and diabetes-related CVD, supported by the salutary effects of chelation in TACT. If the ongoing NIH-funded TACT2, in diabetic post-MI patients, proves positive, this unique therapy will enter the armamentarium of endocrinologists and cardiologists seeking to reduce the atherosclerotic risk of their diabetic patients.