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Cadmium level and severity of peripheral artery disease in patients with

coronary artery disease

Article  in  European Journal of Preventive Cardiology · August 2018

DOI: 10.1177/2047487318796585

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Francisco Ujueta Denisse Diaz

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Columbia University Mount Sinai Medical Center of Florida
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Research letter
Cadmium level and severity of peripheral
artery disease in patients with coronary
artery disease
Francisco Ujueta1, Ivan A Arenas2, Denisse Diaz2,
Timothy Yates3, Robert Beasley3, Ana Navas-Acien4 and
Gervasio A Lamas1,2
Coronary artery disease (CAD) and peripheral artery
disease (PAD) both share similar risk factor profiles,
representing a high disease burden and cost worldwide.
Yet the preferential development of CAD, PAD, or
both in individual patients is not fully understood. As
part of a study of toxic metals in patients with vascular
disease, we explored toxic metal profiles in three prin-
cipal diagnoses: CAD, PAD, and PAD with critical
limb ischemia (CLI). CLI is the most advanced form
of PAD and carries a high (up to 55%) one-year risk of
major vascular events.1 The principal target of this
investigation was cadmium, a toxic atherogenic transi-
tion metal of which the principal environmental sources
are smoking and diet.
Methods
This is a cross-sectional study of individuals without an
occupational history to toxic metals. Eligible patients
participated in studies of toxic metals in vascular dis-
ease, and had a serum creatinine of 2.0 mg/ml or less.
CAD was defined as evidence of a prior myocardial
infarction; simple PAD as history of claudication with
confirmed evidence of obstruction in the affected leg(s)
by an imaging modality. CLI was defined as Rutherford
4 or 5 stages; essentially minimal arterial circulation
with rest pain or early gangrene. Toxic metals were mea-
sured in overnight urine and after an ethylenediamine
tetraacetic acid (EDTA)-based chelation infusion as
previously described.2,3 Categorical variables were com-
pared with Chi-Square or Fisher’s exact tests and con-
tinuous variables using analysis of variance (ANOVA).
Results
The study included 43 patients (Table 1). Cadmium was
detected in the urine of all participants. Chelation with
EDTA was associated with an average 408% increase
in cadmium urinary excretion. Baseline urinary
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cadmium levels were lowest in CAD patients without
evidence of PAD, higher in CAD-PAD (no CLI), and
highest in the CLI subgroup, who had a 4-fold
increase in urine cadmium levels compared to coronary
patients without PAD (0.37  0.19, 0.56  0.34,
1.56  2.33, p ¼ 0.009, Figure 1). A similar pattern in
urinary cadmium levels was observed in post-edetate
disodium infusion urine samples (2.33  1.42,
4.06  1.68, 4.1  2.40; p ¼ 0.01, Figure 1). The associ-
ation between urinary cadmium and PAD status
remained significant after adjustment for age and
prior smoking status. In an analysis including only
patients with diabetes, urine cadmium levels were high-
est in patients with CLI.
Discussion
Ambient air pollution has multiple adverse effects on
human health,4–6 as do ingested environmental pollu-
tants. In this group of CAD patients without an occu-
pational history of exposure to toxic metals, the
severity of PAD was associated with higher cadmium
levels in both spontaneous and stimulated (post-chela-
tion) urine. Urine cadmium reflects total body cad-
mium burden. Epidemiologic studies have shown that
higher cadmium is associated with higher prevalence of
PAD in the general US population.7–9 This small study,
1
Department of Internal Medicine, Mount Sinai Medical Center, USA
2
Columbia University Division of Cardiology, Mount Sinai Medical Center,
USA
3
Vascular and Interventional Radiology, Mount Sinai Medical Center, USA
4
Department of Environmental Health Sciences, Columbia University
Mailman School of Public Health, USA
Corresponding author:
Gervasio Lamas, Columbia University Division of Cardiology, Mount Sinai
Medical Center, 4300 Alton Road, Suite #2070A, Miami Beach, FL 33140,
USA.
Email: gervasio.lamas@msmc.com
2 European Journal of Preventive Cardiology 0(00)

Table 1. Baseline characteristics.

Patients (n ¼ 43) PAD (n ¼ 22) No PAD (n ¼ 21) p-Value

Age 67.3 (10) 70.9 (10.2) 63.5 (8.4) 0.52

Baseline creatinine (mg/dl) 0.99 (0.33) 1.03 (0.36) 0.94 (0.29) 0.119
Sex (male) 38 (88%) 17 (77%) 21 (100%) 0.027
Hypertension 28 (65%) 15 (68%) 13 (62%) 0.62
Myocardial infarction 37 (86%) 16 (73%) 21 (100%) 0.12
Diabetes mellitus 30 (70%) 20 (91%) 10 (48%) 0.002
Chronic kidney disease 10 (23%) 4 (18%) 6 (29%) 0.328
Smoking history 22 (51%) 13 (59%) 9 (43%) 0.177
PAD: peripheral artery disease.
Categorical variables are described as n (%) and continuous variable in mean (standard deviation).

p = 0.01

p = 0.01

4.5
4.06 4.1
4

3.5
p = 0.009
Urinary Cd (µg/g creatinine)

2.5 p = 0.048 2.33

2
1.56
1.5

1
0.56
0.5 0.37

0
Baseline Post-edetate disodium

CAD, no PAD PAD + CAD (no CLI) CAD + CLI

Figure 1. Urinary cadmium (Cd) in coronary artery disease (CAD) patients with and without peripheral artery disease (PAD).
Individual p-values within groups of CAD with no PAD, CAD+PAD (no critical limb ischemia (CLI)) or CADþCLI for urinary Cd were
significantly higher as disease severity increased for baseline and post-edetate disodium. The association between urinary Cd and PAD
status remained after adjustment for age and smoking status.

however, suggests that PAD patients have greater body
cadmium levels compared with patients that have vas-
cular disease, but not PAD. This extends epidemiologic
studies of healthy populations.
In conclusion, the present study suggests that cad-
mium accumulation may be a quantitative risk factor
for graded development of symptomatic disease of the
lower extremities, from low cadmium burden in CAD
only, intermediate cadmium burden in CADþsimple
PAD, and highest cadmium burden in the most severe
form of PAD – CLI. The present study suggests poten-
tial lines for future research into cadmium as a bio-
marker for severity of PAD, and as a therapeutic
target in patients with CLI. A pilot study focusing on
the latter question is currently in progress.
Declaration of conflicting interests
The authors declared no potential conflicts of interest with
respect to the research, authorship, and/or publication of this
article.
 Ujueta et al.
Funding
The authors received no financial support for the research,
authorship, and/or publication of this article.
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