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Research Volume 121 | 2013

Environ Health Perspect; DOI:10.1289/ehp.1205197

Arsenic Exposure from Drinking Water and QT-Interval Prolongation: Results from the Health Effects of Arsenic Longitudinal Study

Yu Chen,1,2 Fen Wu,1,2 Faruque Parvez,3 Alauddin Ahmed,4 Mahbub Eunus,4 Tyler R. McClintock,5 Tazul Islam Patwary,4 Tariqul Islam,4 Anajan Kumar Ghosal,4 Shahidul Islam,4 Rabiul Hasan,4 Diane Levy,3 Golam Sarwar,4 Vesna Slavkovich,3 Alexander van Geen,6 Joseph H. Graziano,3 and Habibul Ahsan7

Author Affiliations open
1Department of Population Health, and 2Department of Environmental Medicine, New York University School of Medicine, New York University, New York, New York, USA; 3Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, New York, USA; 4U Chicago Research Bangladesh Ltd., Dhaka, Bangladesh; 5New York University School of Medicine, New York University, New York, New York, USA; 6Lamont-Doherty Earth Observatory of Columbia University, Palisades, New York, USA; 7Departments of Health Studies, Medicine and Human Genetics and Comprehensive Cancer Center, The University of Chicago, Chicago, Illinois, USA

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  • Background: Arsenic exposure from drinking water has been associated with heart disease; however, underlying mechanisms are uncertain.

    Objective: We evaluated the association between a history of arsenic exposure from drinking water and the prolongation of heart rate–corrected QT (QTc), PR, and QRS intervals.

    Method: We conducted a study of 1,715 participants enrolled at baseline from the Health Effects of Arsenic Longitudinal Study. We assessed the relationship of arsenic exposure in well water and urine samples at baseline with parameters of electrocardiogram (ECG) performed during 2005–2010, 5.9 years on average since baseline.

    Results: The adjusted odds ratio (OR) for QTc prolongation, defined as a QTc ≥ 450 msec in men and ≥ 460 msec in women, was 1.17 (95% CI: 1.01, 1.35) for a 1-SD increase in well-water arsenic (108.7 µg/L). The positive association appeared to be limited to women, with adjusted ORs of 1.24 (95% CI: 1.05, 1.47) and 1.24 (95% CI: 1.01, 1.53) for a 1-SD increase in baseline well-water and urinary arsenic, respectively, compared with 0.99 (95% CI: 0.73, 1.33) and 0.86 (95% CI: 0.49, 1.51) in men. There were no apparent associations of baseline well-water arsenic or urinary arsenic with PR or QRS prolongation in women or men.

    Conclusions: Long-term arsenic exposure from drinking water (average 95 µg/L; range, 0.1–790 µg/L) was associated with subsequent QT-interval prolongation in women. Future longitudinal studies with repeated ECG measurements would be valuable in assessing the influence of changes in exposure.

  • Citation: Chen Y, Wu F, Parvez F, Ahmed A, Eunus M, McClintock TR, Patwary TI, Islam T, Ghosal AK, Islam S, Hasan R, Levy D, Sarwar G, Slavkovich V, van Geen A, Graziano JH, Ahsan H. 2013. Arsenic Exposure from Drinking Water and QT-Interval Prolongation: Results from the Health Effects of Arsenic Longitudinal Study. Environ Health Perspect 121:427–432;

    Address correspondence to Y. Chen [New York University School of Medicine, Departments of Population Health and Environmental Medicine, 650 First Ave., New York, NY 10016 USA. Telephone: (212) 263-4839. E-mail:]

    This work was supported by grants R01ES017541, P42ES010349, P30ES000260, and R01CA107431 from the National Institutes of Health.

    The authors declare they have no actual or potential competing financial interests.

    Received: 11 March 2012
    Accepted: 31 January 2013
    Advance Publication: 5 February 2013
    Final Publication: 1 April 2013

  • PDF icon Supplemental Material (389 KB) PDF

Epidemiologic studies have linked arsenic exposure from drinking water to cardiovascular disease (CVD) (Chen CJ et al. 1996; Chen Y et al. 2011a; Chiou et al. 1997; Tseng et al. 2003) and to heart disease in particular (Chen CJ et al. 1996; Chen Y et al. 2011a; Tseng et al. 2003). However, the underlying mechanism by which arsenic may lead to heart disease is unclear.

The QT interval on an electrocardiogram (ECG) is defined as the time from the onset of the QRS complex to the end of the T wave. It represents the duration of ventricular electrical systole, including depolarization and repolarization. Its prolongation indicates nonuniform recovery of myocardial excitability and has been shown to lower the ventricular fibrillation threshold and increase susceptibility to ventricular arrhythmia and sudden cardiac death (Algra et al. 1991; Straus et al. 2006). QT-interval prolongation has been associated with an increased risk of cardiovascular and all-cause mortality in a broad range of clinical populations as well as in healthy subjects in population-based studies (Goldberg et al. 1991; Okin et al. 2000). Arsenic has been demonstrated to prolong the QT interval both in animal studies (Ficker et al. 2004; Sun et al. 2006) and in cases of acute arsenic poisoning (Chiang et al. 2002; Hall and Harruff 1989). Clinical studies consistently demonstrate that arsenic trioxide, used to treat acute promyelocytic leukemia, induces QT prolongation, torsades de pointes (a life-threatening polymorphic ventricular tachycardia), and sudden death (Ohnishi et al. 2000; Westervelt et al. 2001). Several studies have reported positive associations between arsenic exposure from drinking water and ECG abnormalities, including QT-interval prolongation and QT dispersion (Ahmad et al. 2006; Mordukhovich et al. 2009; Mumford et al. 2007; Wang et al. 2009; Yildiz et al. 2008). However, small sample sizes (Ahmad et al. 2006; Yildiz et al. 2008) and the use of ecological measures of exposure (Ahmad et al. 2006; Wang et al. 2009) have limited the interpretation of study results. In addition, all previous studies measured arsenic exposure at one point in time, without information on longitudinal exposure.

It has been estimated that 13 million Americans have been exposed to drinking water with arsenic concentrations of 10–50 µg/L (Gianfrancesco et al. 2003). In Bangladesh, an estimated 57 million people have been chronically exposed to arsensic from drinking groundwater with arsenic concentrations exceeding the World Health Organization standard (10 µg/L) (British Geological Survey 2007). In 2000, we established a large prospective cohort study of > 20,000 adults in Araihazar, Bangladesh, to evaluate the health effects of arsenic exposure. More than 90% of the cohort has been exposed to drinking water with arsenic concentrations of 0.1–300 µg/L (including > 47% exposed to 0.1–50 µg/L), providing us with a unique opportunity to study cardiovascular outcomes in a population exposed to arsenic at moderate levels. In the present study, we estimated associations between baseline arsenic exposure and subsequent ECG abnormalities, including prolongation of heart rate–corrected QT (QTc), PR, and QRS intervals in 1,715 cohort members.

Materials and Methods

Study population. The Health Effects of Arsenic Longitudinal Study (HEALS) is an ongoing population-based, prospective cohort study in Araihazar, Bangladesh. Details of the study methodologies have been presented elsewhere (Ahsan et al. 2006a). Briefly, we recruited 11,746 residents 18–75 years of age (original cohort) in 2000. HEALS was expanded to include an additional 8,287 participants (expansion cohort) in 2007–2008. The overall response rate was 97%. The cohort is being actively followed with personal visits at 2-year intervals, which include a physical examination, collection of urine samples, and a structured interview conducted by trained physicians following the same procedures used in the baseline interview. Interim health surveys have been conducted every 6 months between the biennial follow-up visits. A field clinic was established exclusively for the cohort participants to receive medical diagnoses and treatments and facilitate the follow-up (Ahsan et al. 2006a). Oral informed consent was provided by study participants, and study procedures were approved by the ethics committee of the Bangladesh Medical Research Council and the institutional review boards of Columbia University and the University of Chicago.

Measurements of arsenic exposure. Information on arsenic exposure was prospectively collected beginning with concentrations measured in drinking water and urine at baseline recruitment, and in follow-up urine samples collected every 2 years. At baseline, water samples from 10,971 contiguous wells were collected in 20 mL polyethylene scintillation vials, which were first rinsed several times with groundwater. The samples were acidified to 1% with high-purity Optima hydrochloric acid (Fisher Scientific, Pittsburgh, PA, USA) for at least 48 hr before analysis. Total arsenic concentration was analyzed by high-resolution inductively-coupled plasma mass spectrometry, with a detection limit of < 0.2 µg/L. Further details on field sampling and laboratory analysis procedures are described elsewhere (Cheng et al. 2004; Van Geen et al. 2005). The long-term reproducibility determined from consistency standards included with each run averaged 4% (1 σ) in the 40–500 µg/L range.

Spot urine samples were collected in 50 mL acid-washed tubes from 95.6%, 94.5%, and 91.2% of the original cohort participants at baseline and the first and second follow-up visits, respectively. Total arsenic concentration was measured by graphite furnace atomic absorption, using a PerkinElmer AAnalyst 600 graphite furnace system (PerkinElmer, Waltham, MA, USA) with a detection limit of 2 μg/L, as previously described (Nixon et al. 1991). Urinary creatinine was analyzed by a colorimetric Sigma diagnostics kit (Sigma, St. Louis, MO, USA) for adjustment of urinary total arsenic concentration (Slot 1965).

ECG measurements and evaluation. Participants in the present analysis were 1,715 cohort members referred for ECG examinations because of high blood pressure or symptoms of heart disease (including chest pain, shortness of breath, irregular heartbeat, and palpitations) identified during a biennial follow-up study visit, an interim health survey, or a visit to the field clinic for medical treatment. These participants were referred to one of three trained field clinic physicians, who were blinded to arsenic-exposure information, for further evaluation and diagnostic confirmation followed by treatment and referral to the only local hospital in the study area as appropriate. Standard 12-lead resting ECGs were performed using a Bionet Cardiocare 2000 device (Bionet America Inc., Tustin, CA, USA). All ECGs were processed using the Dalhousie ECG program (Rautaharju et al. 1990). The QT interval was measured from the beginning of the QRS complex to the end of the T wave, and was corrected for heart rate using the Bazzet formula (QTc = QT ÷ [60/heart rate]1/2) (Bazett 1920). The PR interval was measured from the beginning of the P wave to the beginning of the QRS complex, and the QRS interval was measured from the beginning of the QRS complex to the end of the QRS complex. Prolongation was defined as a QT interval ≥ 450 msec in men and ≥ 460 msec in women (Rautaharju et al. 2009), a PR interval > 200 msec (Cheng et al. 2009), and a QRS interval ≥ 120 msec (Dhar et al. 2008). ECGs were conducted between 2005 and 2010, with an average time since baseline of 5.9 years.

Statistical analyses. We first conducted descriptive analyses to compare arsenic exposure data and demographic and lifestyle characteristics between the present study population and the overall cohort, and between participants with and without QTc prolongation in the study population.

We used unconditional logistic regression to estimate the odds ratios (ORs) for QTc prolongation in relation to quartiles of baseline well-water and urinary arsenic. We first adjusted for sex and age (years) (model 1); we then additionally adjusted for educational attainment (years), baseline body mass index (BMI; kilograms per meter squared), and baseline smoking status (never, past, and current) (model 2) (Ahsan et al. 2006b; Argos et al. 2007). Data for the full cohort suggested little change in BMI, educational attainment, and smoking status over time; therefore, these variables were not measured again at the time of ECG evaluation. Because arsenic exposures may have changed from baseline levels in some participants, we adjusted the final model (model 3) for changes in urinary arsenic between visits. We assumed that urinary arsenic levels were unchanged from baseline among expansion cohort participants (n = 273) who did not have follow-up measurements because of the recency of their recruitment (1.8 years from baseline to ECG evaluation). For subjects in the original cohort, we adjusted for the difference in urinary arsenic between baseline and the first follow-up, and between the first and second follow-up, in 1,402 participants from the original cohort whose ECGs were performed after the second follow-up or within the 6 months before the second follow-up. For participants whose ECG was performed > 6 months before the second follow-up (n = 38), we adjusted for the difference between baseline and the first follow-up only. Separate dummy variables for changes in urinary arsenic were created for participants who did not have urine arsenic concentrations measured at the first (n = 15) or second follow-up visit (n = 28) under a “missing at random” assumption. Linear regression models were also conducted to estimate associations between arsenic exposure and QTc as a continuous dependent variable, with the same adjustments as in the logistic regression models.

The literature suggests that women have longer average QTc intervals compared with men, and therefore we conducted stratified analysis to estimate associations of arsenic exposure with prolongation of QTc, PR, and QRS intervals separately in men and women, similar to previous studies (Benoit et al. 2005; Fukui et al. 2003; Giunti et al. 2007). ORs for QTc, PR, and QRS prolongation in relation to 1-SD increases in baseline well-water and urinary arsenic were also estimated.

We examined the assumption of a linear effect of arsenic exposure by including higher-order polynomial terms for arsenic exposure variables in the models, but found no indication of any nonlinear relation based on the significance of the β coefficient for the terms (data not shown). Additional analyses were conducted, including analyses restricted to the subpopulation who had a more complete exposure history because they used their baseline wells for ≥ 5 years prior to baseline (n = 1,142), analyses of associations with urinary arsenic in the sample collected closest to the ECG measurement, analyses excluding those with QRS of ≥ 120 msec [because the increased QRS duration may contribute to prolongation of the QT interval (Rautaharju et al. 2009)], and analyses of associations with heart rate–adjusted PR interval [PRa = PR + 0.26 (heart rate – 70) for participants < 60 years of age and PRa = PR + 0.42 (heart rate – 70) for those ≥ 60 years of age], with PRa prolongation defined as PRa > 205 msec (Soliman and Rautaharju 2012). In addition, because adjustment for creatinine might influence the relation between urinary arsenic and disease outcomes related to creatinine (Gamble and Liu 2005; Steinmaus et al. 2009), we adjusted urinary total arsenic for specific gravity (SG) to account for dilution, instead of adjusting for creatinine. Adjustment for SG was shown to be less affected by body size, socioeconomic status, and arsenic exposure compared with creatinine adjustment in a study carried out in Matlab, Bangladesh (Nermell et al. 2008). Urinary arsenic was adjusted to the overall mean SG value of 1.013 g/mL (range, 1.00–1.03 g/mL) in the study population, such that SG-adjusted urinary arsenic = [urinary arsenic × (1.013 – 1)] ÷ measured SG – 1. All analyses were performed using the SPSS version 19.0 software (IBM, New York, NY, USA). p-Values for trend (ptrend) were estimated with arsenic exposure variables modeled as continuous variables. All tests were two sided, and p < 0.05 was considered significant.


Arsenic exposures and demographic and lifestyle characteristics were in general similar between the study population and the overall HEALS cohort, although the study population had a slightly higher proportion of women [see Supplemental Material, Table S1 (].

The QTc prolongation was observed among 13.9% of the overall study participants (16.7% of women, and 9.1% of men) (Table 1). There was no consistent relationship between age and QTc prolongation. The proportions of never smokers, those with BMI ≥ 25.0, and those with elevated systolic or diastolic blood pressure (≥ 140 and 90 mmHg, respectively) were higher among cases than noncases. Average baseline well-water and urinary arsenic concentrations were higher among those with QTc prolongation than in noncases (106.0 µg/L vs. 92.8 µg/L for well-water arsenic, and 280.8 µg/L vs. 263.8 µg/L for urinary arsenic, respectively). Among members of the original cohort, total urinary arsenic decreased from baseline to the first follow-up by an average of 64.7 and 70.6 µg/g creatinine in those with QTc prolongation and noncases, respectively, whereas concentrations were relatively stable from the first to second follow-up in both groups. Cases of QTc prolongation had a higher heart rate, QTc, and QRS interval and a lower PR interval compared with noncases.

Table 1 - See HTML link for full tableTable 1 – Demographic, baseline lifestyle, and arsenic-exposure variables by QTc prolongation status.a

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In the overall analysis, there was a positive association between continuous baseline well-water arsenic and QTc prolongation [model 3 OR = 1.17 (95% CI: 1.01, 1.35) for a 1-SD (108.7 µg/L) increase, ptrend = 0.04] (Table 2), but the categorical exposure model did not indicate a monotonic increase of ORs according to quartiles of well-water arsenic. The association with baseline urinary arsenic was similar [model 3 OR = 1.18 (95% CI: 0.97, 1.43) for a 1-SD (270.7 µg/g creatinine) increase], and the ORs increased monotonically with increasing quartiles of exposure; however, the trend p-value was not significant (ptrend = 0.10). In stratified analyses by sex, the prevalence of QTc prolongation was positively associated with baseline arsenic exposure in women, but not in men. The OR for QTc prolongation in association with the highest versus lowest quartile of baseline well-water arsenic (> 145 µg/L, mean 254.5 µg/L; and < 9 µg/L, mean 2.8 µg/L, respectively) was 1.61 (95% CI: 1.00, 2.58, model 3) in women and 0.76 (95% CI: 0.34, 1.69) in men. The adjusted ORs for a 1-SD increase in baseline well-water arsenic were 1.24 [(95% CI: 1.05, 1.47) in women; ptrend = 0.01], and 0.99 [(95% CI: 0.73, 1.33) in men; ptrend = 0.94]. The ORs for QTc prolongation comparing the highest and lowest quartiles of baseline urinary arsenic, and for continuous baseline urinary arsenic, were also positive in women (ptrend = 0.04), but not in men (ptrend = 0.60).

Table 2 - See HTML link for full tableTable 2 – Associations [OR (95% CI)] between baseline arsenic exposure variables and QTc prolongation measured during follow-up.

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Results from linear regression of QTc as a continuous dependent variable were consistent with the findings based on dichotomized QTc [see Supplemental Material, Table S2 (]. For example, a 1-SD increase in well-water arsenic was associated with a 2.2-msec (95% CI: 0.3, 4.0) increase in mean QTc in the total population, and with 3.0-msec (95% CI: 0.3, 5.7) and 0.7-msec (95% CI: –1.5, 2.9) increases in mean QTc in women and men, respectively.

Adjusted estimates based on SG-adjusted urinary arsenic were consistent with those for creatinine-adjusted urinary arsenic. For example, the OR for QTc prolongation in relation to a 1-SD increase in baseline urinary arsenic was 0.94 (95% CI: 0.61, 1.44) in men (ptrend = 0.76) and 1.21 (95% CI: 1.01, 1.45) in women (ptrend = 0.04), respectively [see Supplemental Material, Table S3 (]. Exclusion of participants with QRS ≥ 120 msec did not materially change the results (see Supplemental Material, Table S4). The positive associations remained similar in the subpopulation with ≥ 5 years of arsenic exposure (see Supplemental Material, Table S5). In the analyses of associations with urinary arsenic concentrations in the samples collected closest to the ECG measurement, effect estimates were consistent with, but weaker than, estimates from the main analysis (see Supplemental Material, Table S6). For instance, the adjusted OR for QTc prolongation in relation to a 1-SD increase in urinary arsenic concentration (216.8 µg/g creatinine) was 0.90 (95% CI: 0.60, 1.36) in men and 1.10 (95% CI: 0.97, 1.26) in women, respectively.

Prolongation of PR and QRS intervals was observed in 2.6% and 4.9% of the study population, respectively. There was no apparent association of either baseline well-water or baseline urinary arsenic with PR or QRS prolongation in the population as a whole (Table 3). Associations of baseline well-water and urinary arsenic with PR prolongation remained similar after excluding participants with QRS ≥ 120 msec (data not shown). Lastly, analyses of associations with prolonged heart rate–adjusted PR intervals generated very similar results (data not shown).

Table 3 - See HTML link for full tableTable 3 – Associations [OR (95%CI)] of 1-SD increases in baseline arsenic exposure variables with PR and QRS prolongation measured during follow-up.a

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In this study of arsenic exposure from drinking water and ECG abnormalities, we found a positive relationship between past arsenic exposure assessed at baseline and the QTc prolongation detected during follow-up. This association differed by sex and appeared to be present in women but not in men.

Several cross-sectional studies have assessed the association between arsenic exposure and QT interval. For instance, studies conducted in Bangladesh showed that the prevalence of prolonged QTc was significantly higher in arsenic-exposed individuals with skin lesions than in those without skin lesions or not exposed to arsenic (Ahmad et al. 2006). A study in Turkey found QTc intervals were longer in men (n = 40) chronically exposed to high levels of arsenic in drinking water (659 µg/L, range 422–1,066 µg/L) compared with men (n = 40) not exposed to arsenic (Yildiz et al. 2008). However, the sample size was small. A cross-sectional study of 300 adults (168 men and 145 women) in Inner Mongolia with well-water arsenic measured at the household level reported a monotonic relationship between well-water arsenic and QTc prolongation. However, the exposure categories were wide (≤ 21, 100–300, 430–690 μg/L) (Mumford et al. 2007). A recent study conducted in elderly men from the Normative Aging Study reported positive associations between toenail arsenic and QT duration (Mordukhovich et al. 2009). However, analyses were not conducted to assess effects of arsenic exposure on clinically significant levels of prolongation. More recently, a cross-sectional study of well-water arsenic measured at the village level in southwestern Taiwan reported a positive relationship and increased prevalence of QTc prolongation associated with arsenic concentrations > 700 µg/L in drinking water (Wang et al. 2009). Our prospective study, with the strengths of a large sample size (1,715 adults), a wide range of exposures (0.1–790 µg/L in drinking water, mean 95 µg/L), and exposure data at the individual level based on well-water arsenic and urinary arsenic concentrations at baseline and follow-up, adds to the weight of the evidence suggesting adverse effects of chronic arsenic exposure at moderate levels on QTc prolongation and that the effects were mostly limited to women. Total urinary arsenic has previously been shown to correlate well with well-water arsenic in our study population (with a correlation coefficient of > 0.70) (Ahsan et al. 2007). Associations with urinary arsenic in samples collected closest to the ECG measurement were weaker than associations with urinary arsenic concentrations at baseline that were adjusted for changes in concentrations during follow-up, whereas the analyses restricted to those with a more complete exposure history prior to baseline were similar to associations in the study population as a whole. Together, these data suggest that the effect on QTc prolongation was related to past and persistent arsenic exposure from drinking water measured at baseline. Future longitudinal studies with repeated ECG measurements would be valuable in assessing the influence of longitudinal changes in exposure on changes in QTc.

In our previous cohort analyses of CVD mortality, we observed a positive relationship between well-water arsenic and overall CVD mortality, with hazard ratios ranging from 1.22 to 1.92 for the three highest quartiles of well-water arsenic compared with the lowest quartile, and the association was similar in men and women (Chen Y et al. 2011b). However, in the present study, QTc prolongation was significantly associated with the highest quartile of exposure in women only [OR = 1.61 (95% CI: 1.00, 2.58)]. Given that CVD is a broad set of diseases and condition, QTc prolongation might not be a main driver of the overall CVD mortality. QTc prolongation may be a more critical intermediate endpoint for higher levels of exposure and for subtypes of CVD, such as coronary heart disease. The data on different end points support the idea that the cardiovascular effects of arsenic exposure may differ according to dose and subtypes of CVD, and may be increased in susceptible subsets of the population.

We found that the positive association between arsenic exposure and QTc prolongation was only present in women. Among men, the ORs were below the null for categorical exposures, but were imprecise and not significantly negative. Associations with arsenic as a continuous variable were consistent with the null, and overall, the findings for men did not support an effect of arsenic exposure on ECG abnormalities, in contrast with the findings for women. Data from the study in Inner Mongolia (Mumford et al. 2007) also indicated a potentially greater susceptibility in women. Several in vitro and in vivo studies have shown that female sex is a strong risk factor for drug-induced long QT interval and cardiac arrhythmias (Liu et al. 1998; Lu et al. 2001). It is well known that females have longer mean QT intervals than males (Schwartz 2000). Women are also more susceptible to develop torsades de pointes during administration of drugs that prolong QT (Lehmann et al. 1996; Makkar et al. 1993; Reinoehl et al. 1996; Zareba et al. 1995). Although the mechanisms for the differences in QT intervals in men and women are uncertain, previous studies suggest that sex hormones and differences in cardiac ionic channels or serum potassium levels may contribute to sex-specific differences in ventricular repolarization (Drici et al. 1996; Fukui et al. 2003; Liu et al. 1998). Future studies are needed to investigate the underlying mechanisms of the sex differences in arsenic-induced ECG abnormalities.

Potential mechanisms by which arsenic might induce QT-interval prolongation are also unclear. Arsenic may induce abnormalities of cardiac repolarization by increasing cardiac calcium currents and reducing surface expression of cardiac potassium channel genes such as hERG (human ether-a-go-go–related gene) and KCNQ1 (potassium voltage-gated channel, KQT-like subfamily, member 1) (Curran et al. 1995; Wang et al. 1996). Arsenic interferes with hERG trafficking to the cell surface by inhibiting hERG-chaperone complexes and increasing calcium currents as shown in a series of biochemical and electrophysiological experiments in vitro (Ficker et al. 2004). Other possible mechanisms of arsenic-induced QT prolongation include alterations in DNA repair and methylation, generation of reactive oxygen species, and induction of cardiomyocyte apoptosis (Flora et al. 2007; Zhao et al. 2008).

The study has several limitations. First, our study population consisted of relatively few overweight individuals, possessing a mean BMI of 20.8. Thus, the findings may not be generalizable to other populations with a different nutritional profile. However, our data were consistent with those of Mumford et al. (2007) from a population in Inner Mongolia with a completely different ethnic and cultural background and a better nutritional status (average BMI > 22.5), suggesting that the findings may be generalizable to other populations. Second, we did not evaluate potential effect modification by specific nutritional factors that may play a role in prevention of CVD, such as antioxidants (Palace et al. 1999; Willcox et al. 2008). However, no evidence of interaction between arsenic and antioxidant intake was found for QTc interval in the study of a U.S. general population (Mordukhovich et al. 2009). Third, the study was conducted in participants who were referred for ECG examinations because of potential health problems. However, because of our comprehensive follow-up mechanism, ECG was performed for individuals with and without risk of heart conditions. The distributions of lifestyle, demographic, and arsenic exposure variables suggest that the study population was similar to the overall cohort.


We found a positive association between past arsenic exposure in a population with long-term exposures at moderate levels and QT-interval prolongation measured on average 5.9 years after baseline and the association was present in women but not in men. Our finding may help explain the increased mortality from CVD in humans exposed to arsenic from drinking water. ECG analysis of the QT interval may be useful for early detection of cardiac toxicity induced by arsenic exposure and for evaluation of populations at high risk for cardiovascular events.


Ahmad SA, Khatun F, Sayed MH, Khan MH, Aziz R, Hossain MZ, et al. 2006. Electrocardiographic abnormalities among arsenic-exposed persons through groundwater in Bangladesh. J Health Popul Nutr 24:221–227.

Ahsan H, Chen Y, Kibriya MG, Slavkovich V, Parvez F, Jasmine F, et al. 2007. Arsenic metabolism, genetic susceptibility, and risk of premalignant skin lesions in Bangladesh. Cancer Epidemiol Biomarkers Prev 16:1270–1278.

Ahsan H, Chen Y, Parvez F, Argos M, Hussain AI, Momotaj H, et al. 2006a. Health Effects of Arsenic Longitudinal Study (HEALS): description of a multidisciplinary epidemiologic investigation. J Expo Sci Environ Epidemiol 16:191–205.

Ahsan H, Chen Y, Parvez F, Zablotska L, Argos M, Hussain I, et al. 2006b. Arsenic exposure from drinking water and risk of premalignant skin lesions in Bangladesh: baseline results from the Health Effects of Arsenic Longitudinal Study. Am J Epidemiol 163:1138–1148.

Algra A, Tijssen JG, Roelandt JR, Pool J, Lubsen J. 1991. QTc prolongation measured by standard 12-lead electrocardiography is an independent risk factor for sudden death due to cardiac arrest. Circulation 83:1888–1894.

Argos M, Parvez F, Chen Y, Hussain AZ, Momotaj H, Howe GR, et al. 2007. Socioeconomic status and risk for arsenic-related skin lesions in Bangladesh. Am J Public Health 97:825–831.

Bazett HC. 1920. The time relations of the blood-pressure changes after excision of the adrenal glands, with some observations on blood volume changes. J Physiol 53:320–339.

Benoit SR, Mendelsohn AB, Nourjah P, Staffa JA, Graham DJ. 2005. Risk factors for prolonged QTc among US adults: Third National Health and Nutrition Examination Survey. Eur J Cardiovasc Prev Rehabil 12:363–368.

British Geological Survey. 2007. Groundwater Studies for Arsenic Contamination in Bangladesh—Phase 1 Findings. Available:​r/health/arsenic/Bangladesh/home.html [accessed 7 May 2010].

Chen CJ, Chiou HY, Chiang MH, Lin LJ, Tai TY. 1996. Dose-response relationship between ischemic heart disease mortality and long-term arsenic exposure. Arterioscler Thromb Vasc Biol 16:504–510.

Chen Y, Graziano JH, Parvez F, Liu M, Slavkovich V, Kalra T, et al. 2011a. Arsenic exposure from drinking water and mortality from cardiovascular disease in Bangladesh: prospective cohort study. BMJ. 342. (d2431). [Onlne 5 May 2011].

Chen Y, Parvez F, Liu M, Pesola GR, Gamble MV, Slavkovich V, et al. 2011b. Association between arsenic exposure from drinking water and proteinuria: results from the Health Effects of Arsenic Longitudinal Study. Int J Epidemiol 40:828–835.

Cheng S, Keyes MJ, Larson MG, McCabe EL, Newton-Cheh C, Levy D, et al. 2009. Long-term outcomes in individuals with prolonged PR interval or first-degree atrioventricular block. JAMA 301:2571–2577.

Cheng Z, Zheng Y, Mortlock R, Van Geen A. 2004. Rapid multi-element analysis of groundwater by high-resolution inductively coupled plasma mass spectrometry. Anal Bioanal Chem 379:512–518.

Chiang CE, Luk HN, Wang TM, Ding PY. 2002. Prolongation of cardiac repolarization by arsenic trioxide. Blood 100:2249–2252.

Chiou HY, Huang WI, Su CL, Chang SF, Hsu YH, Chen CJ. 1997. Dose-response relationship between prevalence of cerebrovascular disease and ingested inorganic arsenic. Stroke 28:1717–1723.

Curran ME, Splawski I, Timothy KW, Vincent GM, Green ED, Keating MT. 1995. A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome. Cell 80:795–803.

Dhar R, Alsheikh-Ali AA, Estes NA III, Moss AJ, Zareba W, Daubert JP, et al. 2008. Association of prolonged QRS duration with ventricular tachyarrhythmias and sudden cardiac death in the Multicenter Automatic Defibrillator Implantation Trial II (MADIT-II). Heart Rhythm 5:807–813.

Drici MD, Burklow TR, Haridasse V, Glazer RI, Woosley RL. 1996. Sex hormones prolong the QT interval and downregulate potassium channel expression in the rabbit heart. Circulation 94:1471–1474.

Ficker E, Kuryshev YA, Dennis AT, Obejero-Paz C, Wang L, Hawryluk P, et al. 2004. Mechanisms of arsenic-induced prolongation of cardiac repolarization. Mol Pharmacol 66:33–44.

Flora SJ, Bhadauria S, Kannan GM, Singh N. 2007. Arsenic induced oxidative stress and the role of antioxidant supplementation during chelation: a review. J Environ Biol 28:333–347.

Fukui S, Katoh H, Tsuzuki N, Ishihara S, Otani N, Ooigawa H, et al. 2003. Multivariate analysis of risk factors for QT prolongation following subarachnoid hemorrhage. Crit Care 7:R7–R12.

Gamble MV, Liu X. 2005. Urinary creatinine and arsenic metabolism. Environ Health Perspect 113:A442..

Gianfrancesco F, Grogg A, Mahmoud R, Wang RH, Meletiche D. 2003. Differential effects of antipsychotic agents on the risk of development of type 2 diabetes mellitus in patients with mood disorders. Clin Ther 25:1150–1171.

Giunti S, Bruno G, Lillaz E, Gruden G, Lolli V, Chaturvedi N, et al. 2007. Incidence and risk factors of prolonged QTc interval in type 1 diabetes: the EURODIAB Prospective Complications Study. Diabetes Care 30:2057–2063.

Goldberg RJ, Bengtson J, Chen ZY, Anderson KM, Locati E, Levy D. 1991. Duration of the QT interval and total and cardiovascular mortality in healthy persons (the Framingham Heart Study experience). Am J Cardiol 67:55–58.

Hall JC, Harruff R. 1989. Fatal cardiac arrhythmia in a patient with interstitial myocarditis related to chronic arsenic poisoning. South Med J 82:1557–1560.

Lehmann MH, Hardy S, Archibald D, Quart B, MacNeil DJ. 1996. Sex difference in risk of torsade de pointes with d,l-sotalol. Circulation 94:2535–2541.

Liu XK, Katchman A, Drici MD, Ebert SN, Ducic I, Morad M, et al. 1998. Gender difference in the cycle length-dependent QT and potassium currents in rabbits. J Pharmacol Exp Ther 285:672–679.

Lu HR, Remeysen P, Somers K, Saels A, De Clerck F. 2001. Female gender is a risk factor for drug-induced long QT and cardiac arrhythmias in an in vivo rabbit model. J Cardiovasc Electrophysiol 12:538–545.

Makkar RR, Fromm BS, Steinman RT, Meissner MD, Lehmann MH. 1993. Female gender as a risk factor for torsades de pointes associated with cardiovascular drugs. JAMA 270:2590–2597.

Mordukhovich I, Wright RO, Amarasiriwardena C, Baja E, Baccarelli A, Suh H, et al. 2009. Association between low-level environmental arsenic exposure and QT interval duration in a general population study. Am J Epidemiol 170:739–746.

Mumford JL, Wu K, Xia Y, Kwok R, Yang Z, Foster J, et al. 2007. Chronic arsenic exposure and cardiac repolarization abnormalities with QT interval prolongation in a population-based study. Environ Health Perspect 115:690–694.

Nermell B, Lindberg AL, Rahman M, Berglund M, Persson LA, El Arifeen S, et al. 2008. Urinary arsenic concentration adjustment factors and malnutrition. Environ Res 106:212–218.

Nixon DE, Mussmann GV, Eckdahl SJ, Moyer TP. 1991. Total arsenic in urine: palladium-persulfate vs nickel as a matrix modifier for graphite furnace atomic absorption spectrophotometry. Clin Chem 37:1575–1579.

Ohnishi K, Yoshida H, Shigeno K, Nakamura S, Fujisawa S, Naito K, et al. 2000. Prolongation of the QT interval and ventricular tachycardia in patients treated with arsenic trioxide for acute promyelocytic leukemia. Ann Intern Med 133:881–885.

Okin PM, Devereux RB, Howard BV, Fabsitz RR, Lee ET, Welty TK. 2000. Assessment of QT interval and QT dispersion for prediction of all-cause and cardiovascular mortality in American Indians: the Strong Heart Study. Circulation 101:61–66.

Palace VP, Khaper N, Qin Q, Singal PK. 1999. Antioxidant potentials of vitamin A and carotenoids and their relevance to heart disease. Free Radic Biol Med 26:746–761.

Rautaharju PM, MacInnis PJ, Warren JW, Wolf HK, Rykers PM, Calhoun HP. 1990. Methodology of ECG interpretation in the Dalhousie program; NOVACODE ECG classification procedures for clinical trials and population health surveys. Methods Inf Med 29:362–374.

Rautaharju PM, Surawicz B, Gettes LS, Bailey JJ, Childers R, Deal BJ, et al. 2009. AHA/ACCF/HRS recommendations for the standardization and interpretation of the electrocardiogram: part IV: the ST segment, T and U waves, and the QT interval: a scientific statement from the American Heart Association Electrocardiography and Arrhythmias Committee, Council on Clinical Cardiology; the American College of Cardiology Foundation; and the Heart Rhythm Society: endorsed by the International Society for Computerized Electrocardiology. Circulation 119:e241–e250.

Reinoehl J, Frankovich D, Machado C, Kawasaki R, Baga JJ, Pires LA, et al. 1996. Probucol-associated tachyarrhythmic events and QT prolongation: importance of gender. Am Heart J 131:1184–1191.

Schwartz JB. 2000. The electrocardiographic QT interval and its prolongation in response to medications: differences between men and women. J Gend Specif Med 3:25–28.

Slot C. 1965. Plasma creatinine determination. A new and specific Jaffe reaction method. Scand J Clin Lab Invest 17:381–387.

Soliman EZ, Rautaharju PM. 2012. Heart rate adjustment of PR interval in middle-aged and older adults. J Electrocardiol 45:66–69.

Steinmaus C, Yuan Y, Liaw J, Smith AH. 2009. Low-level population exposure to inorganic arsenic in the United States and diabetes mellitus: a reanalysis. Epidemiology 20:807–815.

Straus SM, Kors JA, De Bruin ML, van der Hooft CS, Hofman A, Heeringa J, et al. 2006. Prolonged QTc interval and risk of sudden cardiac death in a population of older adults. J Am Coll Cardiol 47:362–367.

Sun HL, Chu WF, Dong DL, Liu Y, Bai YL, Wang XH, et al. 2006. Choline-modulated arsenic trioxide-induced prolongation of cardiac repolarization in Guinea pig. Basic Clin Pharmacol Toxicol 98:381–388.

Tseng CH, Chong CK, Tseng CP, Hsueh YM, Chiou HY, Tseng CC, et al. 2003. Long-term arsenic exposure and ischemic heart disease in arseniasis-hyperendemic villages in Taiwan. Toxicology letters 137:15–21.

Van Geen A, Cheng Z, Seddique AA, Hoque MA, Gelman A, Graziano JH, et al. 2005. Reliability of a commercial kit to test groundwater for arsenic in Bangladesh. Environ Sci Technol 39:299–303.

Wang CH, Chen CL, Hsiao CK, Chiang FT, Hsu LI, Chiou HY, et al. 2009. Increased risk of QT prolongation associated with atherosclerotic diseases in arseniasis-endemic area in southwestern coast of Taiwan. Toxicol Appl Pharmacol 239:320–324.

Wang Q, Curran ME, Splawski I, Burn TC, Millholland JM, VanRaay TJ, et al. 1996. Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias. Nat Genet 12:17–23.

Westervelt P, Brown RA, Adkins DR, Khoury H, Curtin P, Hurd D, et al. 2001. Sudden death among patients with acute promyelocytic leukemia treated with arsenic trioxide. Blood 98:266–271.

Willcox BJ, Curb JD, Rodriguez BL. 2008. Antioxidants in cardiovascular health and disease: key lessons from epidemiologic studies. Am J Cardiol 101:75D–86D.

Yildiz A, Karaca M, Biceroglu S, Nalbantcilar MT, Coskun U, Arik F, et al. 2008. Effect of chronic arsenic exposure from drinking waters on the QT interval and transmural dispersion of repolarization. J Int Med Res 36:471–478.

Zareba W, Moss AJ, le Cessie S, Locati EH, Robinson JL, Hall WJ, et al. 1995. Risk of cardiac events in family members of patients with long QT syndrome. J Am Coll Cardiol 26: 1685–1691.

Zhao XY, Li GY, Liu Y, Chai LM, Chen JX, Zhang Y, et al. 2008. Resveratrol protects against arsenic trioxide-induced cardiotoxicity in vitro and in vivo. Br J Pharmacol 154:105–113.

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