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Chronic arsenic exposure and cardiac repolarization abnormalities with QT interval prolongation in a population-based study.



BACKGROUND: Chronic arsenic exposure is associated with cardiovascular abnormalities. Prolongation of the QT (time between initial deflection of QRS complex QRS complex
n.
The principal deflection in the electrocardiogram, representing ventricular depolarization.



QRS complex, QRS wave
 to the end of T wave) interval and profound repolarization repolarization /re·po·lar·iza·tion/ (re-po?ler-i-za´shun) the reestablishment of polarity, especially the return of cell membrane potential to resting potential after depolarization.  changes on electrocardiogram electrocardiogram /elec·tro·car·dio·gram/ (-kahr´de-o-gram?) a graphic tracing of the variations in electrical potential caused by the excitation of the heart muscle and detected at the body surface.  (ECG ECG electrocardiogram.

ECG
abbr.
1. electrocardiogram

2. electrocardiograph


ECG
Also called an electrocardiogram, it records the electrical activity of the heart.
) have been reported in patients with acute promyelocytic leukemia acute pro·my·e·lo·cyt·ic leukemia
n.
A severe bleeding disorder that is a form of leukemia and is characterized by low concentrations of plasma fibrigen, defective coagulation, and infiltration of the bone marrow with abnormal promyelocytes and
 treated with arsenic trioxide arsenic trioxide Warning - Hazardous drug!

Trisenox

Pharmacologic class: Nonmetallic element, white arsenic

Therapeutic class: Antineoplastic

. This acquired form of long QT syndrome The long QT syndrome (LQTS) is a heart condition associated with prolongation of repolarisation (recovery) following depolarisation (excitation) of the cardiac ventricles. It is associated with syncope (fainting) and sudden death due to ventricular arrhythmias.  can result in life-threatening arrhythmias.

OBJECTIVE: The objective of this study was to assess the cardiac effects of arsenic by investigating QT interval QT interval

the portion of an electrocardiogram between the onset of the Q wave and the end of the T wave, representing the total time for ventricular depolarization and repolarization.
 alterations in a human population chronically exposed to arsenic.

METHODS: Residents in Ba Men, Inner Mongolia, have been chronically exposed to arsenic via consumption of water from artesian wells. A total of 313 Ba Men residents with the mean arsenic exposure of 15 years were divided into three arsenic exposure groups: low ([less than or equal to] 21 [micro]g/L), medium (100-300 [micro]g/L), and high (430-690 [micro]g/L). ECGs were obtained on all study subjects. The normal range for QTc (corrected QT) interval is 0.33-0.44 sec, and QTc [greater than or equal to] 0.45 sec was considered to be prolonged.

RESULTS: The prevalence rates of QT prolongation and water arsenic concentrations showed a dose-dependent relationship (p = 0.001). The prevalence rates of QTc prolongation were 3.9, 11.1, 20.6% for low, medium, and high arsenic exposure, respectively. QTc prolongation was also associated with sex (p < 0.0001) but not age (p = 0.486) or smoking (p = 0.1018). Females were more susceptible to QT prolongation than males.

CONCLUSIONS: We found significant association between chronic arsenic exposure and QT interval prolongation in a human population. QT interval may potentially be useful in the detection of early cardiac arsenic toxicity.

KEY WORDS: arsenic, cardiac repolarization, cardiovascular effects, drinking water drinking water

supply of water available to animals for drinking supplied via nipples, in troughs, dams, ponds and larger natural water sources; an insufficient supply leads to dehydration; it can be the source of infection, e.g. leptospirosis, salmonellosis, or of poisoning, e.g.
, nail, QT prolongation. Environ Health Perspect 115:690-694 (2007). doi:10.1289/ehp.9686 available via http://dx.doi.org/ [Online 14 February 2007]

**********

Arsenic is an element found in multiple compounds commonly encountered in the environment. Human exposure to inorganic and organic arsenicals may occur from a variety of sources including occupational, medical, and environmental (Lee and Fraumeni 1969; Watanabe et al. 2004; Westervelt et al. 2001). Whether from medical therapy (as with the use of arsenic trioxide in advanced malignancies) or malicious intent (as in acute poisoning), the cardiac effects of massive acute arsenic exposure are well documented (Hall and Harruff 1989; Little et al. 1990; Westervelt et al. 2001). Patients experiencing arsenic toxicity manifest profound abnormalities in repolarization of the heart, resulting in life-threatening malignant ventricular arrhythmias (Ohnishi et al. 2002; St. Petery et al. 1970). Although chronic arsenic exposure via drinking water with high arsenic concentrations has been associated with coronary disease, stroke, and peripheral vascular disease Peripheral Vascular Disease Definition

Peripheral vascular disease is a narrowing of blood vessels that restricts blood flow. It mostly occurs in the legs, but is sometimes seen in the arms.
 in humans (Navas-Acien et al. 2005; Wang et al. 2002), little is known about its effects on cardiac electrophysiologic properties in general populations experiencing chronic lower-dose arsenic exposure from environmental contamination.

The primary inorganic arsenic exposure in the human population is through ingestion ingestion /in·ges·tion/ (-chun) the taking of food, drugs, etc., into the body by mouth.

in·ges·tion
n.
1. The act of taking food and drink into the body by the mouth.

2.
 of contaminated drinking water. Arsenic is widely present in natural waters, in the form of inorganic arsenite ([As.sup.III]) and arsenate ar·se·nate
n.
A salt of arsenic acid.



arsenate

an uncommon garden pesticide, as lead arsenate, or as antifungal spray on fruit trees or cattle tick dip as sodium arsenate.
 ([As.sup.V]). After consumption, inorganic arsenic is converted to methylated meth·yl·ate  
n.
An organic compound in which the hydrogen of the hydroxyl group of methyl alcohol is replaced by a metal.

tr.v. meth·yl·at·ed, meth·yl·at·ing, meth·yl·ates
1.
 derivatives. Although methylation methylation,
n a phase-II detoxification pathway in the liver; methyl groups combine with toxins to rid the body of various substances.

methylation
(meth´
 of arsenic has been commonly considered a mechanism for detoxification Detoxification Definition

Detoxification is one of the more widely used treatments and concepts in alternative medicine. It is based on the principle that illnesses can be caused by the accumulation of toxic substances (toxins) in the body.
, recent studies have shown that methylated trivalent trivalent /tri·va·lent/ (tri-va´lent) having a valence of three.

tri·va·lent
adj.
Having valence 3.



tri·va
 arsenicals are more toxic than inorganic arsenic (DeMarini et al. 2003). There are no appropriate animal models available for investigating health effects of arsenic. In 2001, the U.S. Environmental Protection Agency Environmental Protection Agency (EPA), independent agency of the U.S. government, with headquarters in Washington, D.C. It was established in 1970 to reduce and control air and water pollution, noise pollution, and radiation and to ensure the safe handling and  (EPA EPA eicosapentaenoic acid.

EPA
abbr.
eicosapentaenoic acid


EPA,
n.pr See acid, eicosapentaenoic.

EPA,
n.
) adopted the maximum contaminant level Maximum Contaminant Levels are standards that are set by the United States Environmental Protection Agency (EPA) for drinking water quality. A Maximum Contaminant Level (MCL) is the legal threshold limit on the amount of a hazardous substance that is allowed in drinking water under  (MCL MCL - Macintosh Common LISP ) of 10 [micro]g/L for arsenic in drinking water (U.S. EPA 2001). Significant uncertainties remain regarding mechanisms by which arsenic exerts a deleterious affect on the cardiovascular system cardiovascular system: see circulatory system.
cardiovascular system

System of vessels that convey blood to and from tissues throughout the body, bringing nutrients and oxygen and removing wastes and carbon dioxide.
, especially at low exposure levels.

The QT (time between initial deflection of QRS complex to the end of T wave) interval on the electrocardiogram (ECG) represents the duration of ventricular electrical systole systole /sys·to·le/ (sis´to-le) the contraction, or period of contraction, of the heart, especially of the ventricles.systol´ic

aborted systole
 including depolarization depolarization /de·po·lar·iza·tion/ (de-po?lahr-i-za´shun)
1. the process or act of neutralizing polarity.

2. in electrophysiology, reversal of the resting potential in excitable cell membranes when stimulated.
 and repolarization. The QT interval varies with heart rate and is typically expressed in seconds or milliseconds in a corrected form (QTc). Several calculations have been used to correct the measurement based on heart rate, and the most commonly employed is the Bazett formula (Bazett 1920). The upper limit of normal for QTc is 0.44 sec (Surawicz and Knilans 2001). Women are known to have slightly longer average QTc intervals than men (0.41 sec for women vs. 0.39 sec for men) (Chou 1986). Prolongation of the QTc intervals [greater than or equal to] 0.45 sec is associated with increased risk of arrhythmia arrhythmia (ārĭth`mēə), disturbance in the rate or rhythm of the heartbeat. Various arrhythmias can be symptoms of serious heart disorders; however, they are usually of no medical significance except in the presence of  and mortality. Wu et al. (2003) reported that the mean of the normal QTc interval for Chinese is 0.41 sec (0.42 sec for females and 0.40 sec for males).

Inner Mongolia is an autonomous region in Northern China. The study site is in the Bayingnormen (Ba Men) region located in Western Inner Mongolia on the Hetao Plain, north of the Huang He River (Figure 1). Before installation of the artesian wells in 1980, Ba Men residents used the water from the large shallow wells containing low levels of arsenic for drinking water. Since 1980, > 300,000 Ba Men residents used artesian wells and have been chronically exposed by drinking arsenic-contaminated water. Arsenic occurs naturally in ground water in Ba Men, in levels ranging from nondetectable to 1.8 mg/L (Ma et al. 1999). The counties in Ba Men most affected by arsenicosis are Lin He, Wu Yuan, and Hangjin Hou (Figure 1). Health effects, including dermal dermal /der·mal/ (der´mal) pertaining to the dermis or to the skin.

der·mal or der·mic
adj.
Of or relating to the skin or dermis.
 (skin hyperkeratosis hyperkeratosis /hy·per·ker·a·to·sis/ (-ker?ah-to´sis)
1. hypertrophy of the stratum corneum of the skin, or any disease so characterized.

2. hypertrophy of the cornea.
, alterations in pigmentation pigmentation, name for the coloring matter found in certain plant and animal cells and for the color produced thereby. Pigmentation occurs in nearly all living organisms. , and cancer), neurologic, cardiovascular, and peripheral vascular diseases have been reported in this region (Ma et al. 1999). Ba Men residents have been exposed to a wide range of arsenic concentrations, and it is possible to assess individual exposure because most households (80%) have their own wells. This region is known for its abundance of agricultural products, including dairy and domestic animals for both commercial and personal consumption. In general, nutrition is not a problem among the residents. In Ba Men, drinking water is the main source of arsenic intake. Chinese investigations on arsenic contamination in Ba Men region have shown that the levels of arsenic in the irrigation irrigation, in agriculture, artificial watering of the land. Although used chiefly in regions with annual rainfall of less than 20 in. (51 cm), it is also used in wetter areas to grow certain crops, e.g., rice.  or surface water from Huang He River are below the U.S. standard for arsenic in drinking water, ranging from 2 to 9 [micro]g/L (Yu et al. 1995). Therefore, arsenic concentrations in grains, beans, poultry, vegetables, and fruits are low. Occasionally, the residents consume freshwater fish or shrimp, but most residents ([greater than or equal to] 60%) do not (Table 1). Thus, intake from diet in this population is not an important source of arsenic exposure. Because migration in this region is minimal among Ba Men residents, and for the reasons stated above, this population provided good opportunities for assessing cardiovascular effects of chronic arsenic exposure in humans. The objective of the study was to assess the effects of chronic exposure to arsenic on cardiac repolarization by investigating ECG QT intervals in a general population.

Materials and Methods

Study subjects. Because little information is available on the effects of chronic arsenic exposure via drinking water on QT interval in a general population, we conducted a range-finding study. Study subjects had been exposed to a wide range of arsenic levels (low, medium, and high with gaps among the groups), so we investigated at what levels, if any, arsenic exposure affected QT interval in this population. The study subjects included 313 residents of the Ba Men region exposed to different levels of arsenic concentrations via drinking water. One ECG was collected from each subject. Among the 313 ECGs, three manifested right bundle branch block right bundle branch block Cardiology A condition in which the electrical impulse from the bundle of His to the ventricles is delayed or fails to conduct along the right bundle branch, resulting in right ventricular depolarization by cell-to-cell conduction . These subjects were excluded from the data analysis of QT interval. The low-exposed subjects were from the village of Long Sheng sheng

(Chinese; “sage” or “saint”)

In Chinese belief, a mortal who attains extraordinary or supernatural powers by self-cultivation and serves as a model for others. Confucius used the term to refer to exemplary rulers of the past.
 in Lin He County, the medium-exposed from Gu Cheng in Lin He County and Yong Li in Wu Yuan County, and the high-exposed were from Fen Zi Di in Lin He County (Figure 1).

We obtained information regarding the consumption of artesian well water with arsenic contamination, tobacco smoking, alcohol consumption, sociodemographic characteristics, and past medical history through questionnaires (Table 1). This study was conducted according to the recommendations of the Declaration of Helsinki For the political accords, see .
. There is also another Declaration of Helsinki, dealing with the Information Society.[1] Introduction
The Declaration of Helsinki,[2] was developed by the World Medical Association[3]
 (World Medical Association 1989) for international health research. All subjects gave written informed consents to participate in this study. The research protocol met the requirements for protection of human subject certification and was approved by the U.S. EPA.

Arsenic exposure assessment. Water collection and arsenic analysis. Samples of drinking water were collected in acid-washed containers from the study subjects' homes, as previously described (Mo et al. 2006). Drinking-water samples from the storage tank for well water in each home were collected, stored at -20[degrees]C, and transported on ice via air to University of Alberta in Edmonton, Canada, for analysis. Total arsenic was determined using hydride generation atomic fluorescence spectrometry (HGAFS HGAFS Hydride Generation Atomic Fluorescence Spectrometry ) (Le and Ma 1998). The detection limit for HGAFS is 0.2 [micro]g/L.

Nail collection and analysis. Toenail toenail /toe·nail/ (to´nal) the nail on any of the digits of the foot.

ingrown toenail  see under nail.


toe·nail
n.
 arsenic has been reported to provide an integrated measure of internal arsenic exposure (Karagas et al. 1996). In this study, toenail samples were collected from each study subject as described previously and transported to the U.S. EPA laboratory in Research Triangle Park Research Triangle Park, research, business, medical, and educational complex situated in central North Carolina. It has an area of 6,900 acres (2,795 hectares) and is 8 × 2 mi (13 × 3 km) in size. Named for the triangle formed by Duke Univ. , North Carolina North Carolina, state in the SE United States. It is bordered by the Atlantic Ocean (E), South Carolina and Georgia (S), Tennessee (W), and Virginia (N). Facts and Figures


Area, 52,586 sq mi (136,198 sq km). Pop.
, for analysis (Schmitt et al. 2005). The nail samples were cleaned by sonification in HPLC-grade water and then acetone acetone (ăs`ĭtōn), dimethyl ketone (dīmĕth`əl kē`tōn), or 2-propanone (prō`pənōn), CH3COCH3  washed to remove debris from the nail surface. Toenails were analyzed for arsenic using Instrumental Neutron Activation Analysis Neutron Activation Analysis (NAA) is a nuclear process used for determining certain concentrations of elements in a vast amount of materials. NAA allows discrete sampling of elements as it disregards the chemical form of a sample, and focuses solely on its nucleus.  (INAA INAA Instrumental Neutron Activation Analysis
INAA Islamic National Accord Association
INAA Integrated Network Access Arrangement
INAA Intelligent Network Access Arrangement
) at North Carolina State University History

Main article: History of North Carolina State University
The North Carolina General Assembly founded NC State on March 7, 1887 as a land-grant college under the name North Carolina College of Agriculture and Mechanic Arts.
 Nuclear Services Department (Raleigh, NC, USA) (Heydorn 1984). The detection limit for INAA is 0.0012 [micro]g/g.

QT measurement and evaluation. The ECG QT interval defines the period of ventricular repolarization. The subjects were placed in a supine position. After 10 min of rest, an ECG tracing was recorded for 2 min. In this study, two cardiologists (W.E.S., J.F.) who are certified as electrophysiologists by the American Board of Internal Medicine The American Board of Internal Medicine (ABIM) is a non-profit, independent physician organization in the U.S. that certifies physicians who practice in internal medicine and its sub-specialties.  measured all QT intervals. Discrepancies in the measurement of QT interval between the two cardiologists who evaluated the ECGs were rare. In cases where the measurements were not the same, an average was used. Heart rate of each subject was also determined from the ECG. The physicians were blinded to subjects' arsenic level as well as the other physician's interpretation of the ECG. QT interval was corrected for heart rate using the Bazett formula (Bazett 1920). A QTc interval of [less than or equal to] 0.44 sec was considered normal.

Statistical analysis. Arsenic concentration was divided into three categories: low (< 21 [micro]g/L), medium (100-350 [micro]g/L), and high (430-690 [micro]g/L). Age was also divided into three categories: young (9-29 years), middle aged (30-50 years), and older (51-65 years). We assessed exposure by measuring arsenic concentrations in drinking water and nails. QTc interval was considered to be normal if it was [less than or equal to] 0.44 sec and abnormal if it was [greater than or equal to] 0.45 sec. We performed analysis of Spearman spear·man  
n.
A man, especially a soldier, armed with a spear.
 correlation coefficients to evaluate the association between arsenic concentrations in drinking water and nails. We compared heart rate and QTc interval measurements in subgroups using Student's t-test. We evaluated bivariate bi·var·i·ate  
adj.
Mathematics Having two variables: bivariate binomial distribution.

Adj. 1.
 associations between categorical variables using chi-square tests. We used a binary logistic regression model with the QTc interval as dependent outcome and arsenic concentration as the predictor of interest. After prior selection, we used age, sex, smoking status, body mass index (BMI BMI body mass index.

BMI
abbr.
body mass index


Body mass index (BMI)
A measurement that has replaced weight as the preferred determinant of obesity.
), and pesticide exposure as control covariates in the model. Also two-by-two interactions of the above six main effects are included in the model to control for possible interactions. We used the maximum likelihood estimation method to estimate the logistic model (Hosmer and Lemeshow 2000). The main effects model was fit with all the main effects including age, sex, smoking, BMI, and pesticide exposure. For the final model, we used backward selection with the main effects and all two-way interactions in the full model, eliminating the least significant terms at each iteration and including only the statistically significant variables (p < 0.05) in the final model. The final-selected variables maximize the likelihood of distribution of QTc interval outcome and thus significantly predict the QTc interval outcome. All statistical analyses were conducted using SAS (1) (SAS Institute Inc., Cary, NC, www.sas.com) A software company that specializes in data warehousing and decision support software based on the SAS System. Founded in 1976, SAS is one of the world's largest privately held software companies. See SAS System.  version 9.1 (SAS Institute Inc., Cary, NC, USA).

Results

Study subjects. Table 1 shows the characteristics of the study subjects. Most of the subjects were farmers with an average of 15 years of chronic arsenic exposure. There were a total of 168 males and 145 females with a mean age of 35 [+ or -] 14 years; among these subjects, 33% were smokers. Most subjects had at least a primary education. Diet included frequent meat, fruits, and vegetables. Vitamin use was rare ([less than or equal to] 2%). Most subjects did not consume seafood from fresh water, or if they did, it was infrequent.

Water and nail arsenic concentrations. Table 2 shows the nail arsenic concentrations in the low, medium, and high arsenic exposure groups. The mean arsenic concentrations in nails and drinking water in these study subjects showed a positive dose-dependent relationship. Arsenic concentrations in nails and water showed positive correlations in all three groups and also in all subjects.

QTc and arsenic exposure. Figure 2 shows the effects of arsenic, age, sex, and smoking on QTc interval. Significant dose-related prevalence rates of QT prolongation were seen in the subjects with increasing water arsenic concentrations (p = 0.001) and was most profound in the high-exposure group, with 20.6% of the subjects having marked cardiac repolarization abnormalities. Medium arsenic exposure resulted in 11.1% of subjects having QTc prolongation. The low arsenic exposure group had QTc abnormalities in 3.9% of study subjects. Using chi-square tests, we observed no statistically significant differences in the prevalence of QTc prolongation related to tobacco smoking (p = 0.1018) or age (p = 0.486). However, there was a significant difference due to sex (p = 0.0001). Females were more susceptible to QT interval prolongation than males.

Results from maximum likelihood estimation of logistic regression models, including main effects model and the final model are shown in Table 3. The main effects model controlled for arsenic exposure, age, sex, smoking, BMI, and pesticide exposure; the final model controlled for arsenic exposure, age, sex, BMI, and age-BMI interaction. The results from the main effects model showed that prolonged QTc was associated with arsenic exposure and sex, but not age, smoking, or pesticide exposure. This is consistent with the results from the chi-square tests shown above. Smoke and pesticide exposure were dropped out of the final model. Also dropped out of the final model were all other insignificant interactions except age-BMI interaction, which was statistically significant (p < 0.0020). For lower-level BMI, as age increased, the probability of prolonged QTc interval tends to decrease, and for upper-level BMI, as age increased the probability of prolonged QTc interval tends to increase. Both the main effects and the final model showed a dose-dependent relationship in increasing odds ratio (OR) between arsenic concentrations and prolonged QTc intervals (Table 4). In the final model, although all other covariates remain constant, the adjusted OR of prolonged QTc interval for the medium- versus low-exposure group was 3.829 [95% confidence interval confidence interval,
n a statistical device used to determine the range within which an acceptable datum would fall. Confidence intervals are usually expressed in percentages, typically 95% or 99%.
 (CI), 1.128-12.993] and the high- versus low-exposure group was 8.848 (95% CI, 2.723-28.748). Sex was also a significant predictor, with OR of 5.819 (95% CI, 2.486-13.621) for female versus male.

Heart rates and QTc. Table 5 shows the comparison of heart rate and QTc interval in the QTc prolonged and normal subjects. The individual withs prolonged QTc demonstrated a statistical significant increase in heart rate in the medium- and high-exposure groups, but not in the low-exposure group. Arsenic has known effects on the nervous system (Hindmarsh et al. 1977). In this study, the subjects with prolonged QTc had slightly higher normal baseline heart rates. This may reflect the arsenic effects on the autonomic nervous system autonomic nervous system: see nervous system.
autonomic nervous system

Part of the nervous system that is not under conscious control and that regulates the internal organs. It includes the sympathetic, parasympathetic, and enteric nervous systems.
 with withdrawal of parasympathetic parasympathetic /para·sym·pa·thet·ic/ (-sim?pah-thet´ik) see under system.

par·a·sym·pa·thet·ic
adj.
Of, relating to, or affecting the parasympathetic nervous system.
 tone to the sinus node sinus node
n.
See sinoatrial node.


sinus node Sinoatrial node, see there, SA node
. In Table 5, the mean QTc interval for the low-exposure group was 0.41 sec, which is consistent with the mean of the reported normal QTc for Chinese subjects (Wu et al. 2003). There were statistical differences in QTc measurements between the prolonged QTc and normal individuals.

Discussion

Chronic arsenic exposure has long been associated with carcinogenesis car·ci·no·gen·e·sis
n.
The production of cancer.



carcinogenesis

production of cancer.


biological carcinogenesis
viruses and some parasites are capable of initiating neoplasia.
 and atherogenesis atherogenesis /ath·ero·gen·e·sis/ (-jen´e-sis) formation of atheromatous lesions in arterial walls.atherogen´ic

ath·er·o·gen·e·sis
n.
, particularly peripheral vascular disease (Simeonova and Luster 2004; Yoshida et al. 2004). Increased mortality from cardiovascular events in individuals in Taiwan who were exposed to arsenic via artesian wells has been reported (Chen et al. 1996). Although Ahmad et al. (2006) reported a study conducted in Bangladesh showing significant difference in QTc interval between the arsenicosis and the non-arsenic-exposed group, cardiac repolarization abnormalities showing dose-dependent relationship with arsenic exposure has not been previously observed. In this study, we evaluated ECG changes in individuals exposed to arsenic via drinking water in Inner Mongolia and assessed the association of prolongation of QTc interval with environmental arsenic exposure. A dose-response relationship was observed, and the prevalence of prolonged QTc interval was significantly associated with arsenic exposure via drinking water in this general population in Inner Mongolia. This is in agreement with the clinical studies showing that arsenic trioxide used in the treatment of acute promyelocytic leukemia induced significant cardiac electrophysiologic abnormalities (QT prolongation) and ventricular arrhythmias (torsade de pointes tor·sade de pointes
n.
Paroxysms of ventricular tachycardia in which the electrocardiogram shows a steady undulation in the QRS axis in runs of 5 to 20 beats and with progressive changes in direction.
) (Westervelt et al. 2001). Similar cardiac electrical changes have been shown in acute arsenic poisoning (St. Petery et al. 1970).

The mechanisms by which arsenic induces QT interval prolongation are not completely understood. We hypothesize hy·poth·e·size  
v. hy·poth·e·sized, hy·poth·e·siz·ing, hy·poth·e·siz·es

v.tr.
To assert as a hypothesis.

v.intr.
To form a hypothesis.
 that this might be caused by the functional alterations in cardiac cell surface channels. Potassium-selective channels play a key role in maintaining the resting membrane potential membrane potential
n.
The potential inside a cell membrane measured relative to the fluid just outside; it is negative under resting conditions and becomes positive during an action potential.
 and repolarization of the action potential in excitable excitable /ex·ci·ta·ble/ (ek-sit´ah-b'l) irritable (1).

ex·cit·a·ble
adj.
1. Capable of reacting to a stimulus. Used of a tissue, cell, or cell membrane.

2.
 cardiac myocytes (Sanguinetti and Tristani-Firouzi 2006). Hereditary QT prolongation or long QT syndrome occurs in patients with mutations in the cardiac ion channel ion channel
n.
See channel.
 genes, particularly those involved in potassium ion flow (Keating and Sauguinetti 2001). Among the potassium channel genes, the most commonly observed inherited mutations are found in hERG (the human ether-a go-go-related gene) and KCNQ KCNQ Potassium Channel, Voltage-Gated, KQT-like subfamily 1 (Curran et al. 1995; Wang et al. 1996). These channelopathies result in significant alterations in cardiac repolarization and predispose pre·dis·pose
v.
To make susceptible, as to a disease.
 the affected individuals to arrhythmias and sudden cardiac death Sudden Cardiac Death Definition

Sudden cardiac death (SCD) is an unexpected death due to heart problems, which occurs within one hour from the start of any cardiac-related symptoms. SCD is sometimes called cardiac arrest.
 (Sanguinetti and Tristani-Firouzi 2006). hERG encodes the voltage-gated potassium channel Voltage-gated potassium channels are transmembrane channels specific for potassium and sensitive to voltage changes in the cell's membrane potential. They play a crucial role during action potentials in returning the depolarized cell to a resting state.  [alpha] subunit underlying [I.sub.kr] (rapidly activating potassium current) (Sanguinetti et al 1995). Potassium current change can result from blockade of the potassium channel, alterations of ion selectivity, or reduction of hERG protein expression. Proarrhythmia is observed in patients treated with drugs that block the hERG channel, including quinidine quinidine (kwĭn`ĭdēn'), heart muscle relaxant used to maintain regular heart rhythm patterns. It is an alkaloid chemically similar to quinine and, like quinine, occurs naturally in some species of cinchona trees. , dofetilide, antihistamines Antihistamines Definition

Antihistamines are drugs that block the action of histamine (a compound released in allergic inflammatory reactions) at the H1
, and antibiotics (Bednar et al. 2001; Redfern et al. 2003). In addition, the therapeutic use of arsenic trioxide in the treatment of acute promyelocytic leukemia has been hampered by its severe side effects Side effects

Effects of a proposed project on other parts of the firm.
, which include QT prolongation, malignant ventricular tachycardia (torsade de pointes), and sudden death (Unnikrishnan et al. 2001). Recently, arsenic trioxide has been shown to block [I.sub.kr] by inhibition of the processing of the hERG protein in the endoplasmic endoplasmic

pertaining to or arising from endoplasm.


endoplasmic ribosomes
small, cytoplasmic granules consisting of approximately 60% RNA and 40% protein.
 reticulum reticulum /re·tic·u·lum/ (re-tik´u-lum) pl. retic´ula   [L.]
1. a small network, especially a protoplasmic network in cells.

2. reticular tissue.
 (Ficker et al. 2004). In contrast to other drugs, which result in blockade via binding to specific sites within the channel, arsenic trioxide appears to produce hERG liability by inhibition of ion-channel trafficking resulting in reduced channel expression on the cell surface. The QT prolongation seen in our study is most probably the consequence of potassium ion channel alterations induced by arsenic, and may involve hERG trafficking defects.

In this study we observed that age and smoking were not important factors in QT prolongation. However, there was a significant difference related to sex. Women showed an increased sensitivity to toxic effects of arsenic with regard to QT prolongation. Women are known to exhibit average QT intervals slightly longer than those of men and are also more susceptible to the drugs that induce prolonged QT (Drici et al. 1998; Lehmann et al. 1996; Villareal et al. 2001). This may explain the higher frequency of QT interval prolongation in women exposed to arsenic. We are conducting a follow-up study with a larger sample size focusing on women and the sex-specific effects of arsenic as manifested by QT prolongation. Our finding that chronic inorganic arsenic ingestion in a general population can result in QT prolongation may help explain the increased cardiovascular mortality in humans exposed to contaminated drinking water. The risk of significant arrhythmia increases with an increasing QT interval, but is still present with minimal prolongation. In summary, we found significant association between chronic arsenic exposure and QT interval prolongation in a human population, and ECG analysis of the QT interval may be useful in detecting early cardiac arsenic toxicity and in evaluating populations at risk for cardiovascular events. In addition to a larger follow-up study investigating arsenic effects on QT prolongation, we are also conducting a study to investigate cardiac morbidity and mortality Morbidity and Mortality can refer to:
  • Morbidity & Mortality, a term used in medicine
  • Morbidity and Mortality Weekly Report, a medical publication
See also
  • Morbidity, a medical term
  • Mortality, a medical term
 in this population. The Chinese government recently has provided assistance in installing water systems in Ba Men to lower the arsenic levels in well water among the Ba Men residents. Reducing arsenic concentrations in drinking water to a safe level in this population would likely eliminate QT prolongation and the associated cardiac risk.

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Ahmad SA, Khatun F, Sayed MH, Khan MH, Aziz R, Hossain MZ, et al. 2006. Electrocardiographic electrocardiographic

emanating from or pertaining to electrocardiography.


electrocardiographic monitoring
maintenance of a more or less continuous surveillance of a patient's cardiac status by means of electrocardiography.
 abnormalities among arsenic-exposed persons through groundwater in Bangladesh. J Health Popul Nutr 24:221-227.

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Judy L. Mumford, (1) Kegong Wu, (2) Yajuan Xia, (2) Richard Kwok, (3) Zhihui Yang, (4) James Foster, (5) and William E. Sanders Jr. (6,7)

(1) U.S. Environmental Protection Agency, National Health and Environmental Effects Research Laboratory, Research Triangle Park, North Carolina, USA; (2) Inner Mongolia Center for Endemic Disease Control and Research, Huhhot, Inner Mongolia, China; (3) RTI International, Research Triangle Park, North Carolina, USA; (4) Ba Men Anti-Epidemic Station, Lin He, Inner Mongolia, China; (5) Wake Heart Associates, Raleigh, North Carolina For other uses of this name, see Raleigh.
Raleigh (IPA: /ˈrɑli/, ral-ee) is the capital of the State of North Carolina and the county seat of Wake County.
, USA; (6) Department of Medicine, and (7) Center for Environmental Medicine, Asthma and Lung Biology, University of North Carolina, Chapel Hill, North Carolina Chapel Hill is a town in North Carolina and the home of the University of North Carolina at Chapel Hill (UNC-CH), the oldest state-supported university in the United States. As of the 2000 census, it had a population of 48,715. As of 2004 its estimated population was 52,440. , USA

Address correspondence to J.L. Mumford, MD 58C, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 USA. Telephone: (919) 966-0651. Fax: (919) 966-0655. Email: mumford.judy@epa.gov

We thank I.I.H. Chen for his technical advice in preparing this manuscript, X.C. Le of the University of Alberta for analyzing water samples, S. Lassell of North Carolina State University for analyzing nail samples, Y. Li of RTI International for excellent assistance in statistical analysis, and also all the participating members of Inner Mongolia Center for Endemic Disease Control and Research and Ba Men Anti-epidemic Station.

This research has been reviewed by the U.S. EPA and approved for publication. Approval does not signify that the contents reflect views of the agency or endorse the trade names mentioned.

This study was conducted and funded by the U.S. EPA, partially funded by Cooperative Agreement R82952201 with the University of North Carolina at Chapel Hill The University of North Carolina at Chapel Hill is a public, coeducational, research university located in Chapel Hill, North Carolina, United States. Also known as The University of North Carolina, Carolina, North Carolina, or simply UNC , Center for Environmental Medicine, Asthma and Lung Biology; and Cooperative Agreement R82808401, Inner Mongolia Center for Endemic Disease Control and Research.

The authors declare they have no competing financial interests.

Received 6 September 2006; accepted 14 February 2007.
Table 1. Study subjects' information, by low, medium, and high levels of
arsenic.

                                                        Medium
                                   Low                  (100-300
Characteristic                     (BDL-21 [micro]g/L)  [micro]g/L)

No. of subjects                    103                  108
Sex [no. (male/female)]             53/50                57/51
Age [years (mean [+ or -] SD)]      35 [+ or -] 14       36 [+ or -] 14
Smoker (%)                          29                   41
Education (%)
  Illiterate                        13                   19
  Primary                           41                   49
  Middle                            39                   26
  High                               7                    6
Water arsenic concentration         10.7 [+ or -] 6.6   199.9 [+ or -]
  [[micro]g/L (mean [+ or -] SD)]                        55.7
Water consumption (L/day)            1.6 [+ or -] 1.0     1.9 [+ or -]
                                                          1.1
Years of arsenic exposure           17.0 [+ or -] 3.4    14.6 [+ or -]
  (mean [+ or -] SD)                                      3.5
Pesticide exposure within           60                   53
  previous 5 years (% yes)
Diet
  Meat [> 3 times/week (%)]        100                   97
  Fruit/vegetables [> 3 times/     100                   98
    week (%)]
  Seafood (%)
    Do not eat                      60                   72
    [less than or equal to] 1       40                   28
      time/week
    [greater than or equal to] 3     0                    0
      times/week
BMI (a)                             22.9 [+ or -] 3.7    22.7 [+ or -]
                                                          3.4
Alcohol consumption [> 2 times/     22                   15
  week (% yes)]

                                   High
Characteristic                     (430-690 [micro]g/L)

No. of subjects                    102
Sex [no. (male/female)]             58/44
Age [years (mean [+ or -] SD)]      34 [+ or -] 14
Smoker (%)                          30
Education (%)
  Illiterate                        18
  Primary                           42
  Middle                            37
  High                               3
Water arsenic concentration        568.3 [+ or -] 71.1
  [[micro]g/L (mean [+ or -] SD)]
Water consumption (L/day)            1.9 [+ or -] 1.2
Years of arsenic exposure           14.7 [+ or -] 3.3
  (mean [+ or -] SD)
Pesticide exposure within           50
  previous 5 years (% yes)
Diet
  Meat [> 3 times/week (%)]        100
  Fruit/vegetables [> 3 times/      98
    week (%)]
  Seafood (%)
    Do not eat                      60
    [less than or equal to] 1       38
      time/week
    [greater than or equal to] 3     2
      times/week
BMI (a)                             22.6 [+ or -] 3.1
Alcohol consumption [> 2 times/     12
  week (% yes)]

Abbreviations: BDL, below detection limit; BMI, body mass index.
(a) BMI was calculated as body weight (kg) divided by squared body
height ([m.sup.2]).

Table 2. Nail arsenic concentrations and correlations between toenails
and water arsenic concentrations.

                                   Nail arsenic
                                   concentration
                                   [[micro]g/g
                                   (mean [+ or -]
Water arsenic exposure    No.      SD)]            Spearman r  p-Value

All subjects              307 (a)  11.80 [+ or -]  0.9056      < 0.0001
                                   11.80
Low exposure (< 21        103       1.21 [+ or -]  0.3478        0.0003
  [micro]g/L)                       0.74
Medium exposure (100-300  102       9.79 [+ or -]  0.3547        0.0003
  [micro]g/L)                       4.77
High exposure (430-690    102      24.61 [+ or -]  0.3940      < 0.0001
  [micro]g/L)                      10.65

(a) Data were missing from six subjects.

Table 3. Analysis of maximum likelihood estimates from binary logistic
regression models.

Parameter                                  Estimate  SE       p-Value

Main effects model (a)
  Water arsenic (medium vs. low exposure)   1.1184   0.6083     0.0660
  Water arsenic (high vs. low exposure)     1.9706   0.5814     0.0007
  Age                                       0.00354  0.0168     0.8328
  Sex                                       1.5678   0.5311     0.0032
  Smoking                                   0.3363   0.5536     0.5436
  BMI                                      -0.0558   0.0652     0.3921
  Pesticide exposure                       -0.3462   0.4580     0.4498
  Constant                                 -2.9943   1.4464     0.0384

Final model (b)
  Water arsenic (medium vs. low exposure)   1.3426   0.6234     0.0313
  Water arsenic (high vs. low exposure)     2.1802   0.6012     0.0003
  Age                                      -0.2524   0.0835     0.0025
  Sex                                       1.7611   0.4340   < 0.0001
  BMI                                      -0.5237   0.1701     0.0021
  Age/BMI interaction                       0.0123   0.00398    0.0020
  Constant                                  6.0435   3.2398     0.0621

(a) Main effects model adjusting for arsenic, age, sex, tobacco smoking,
BMI, and pesticide exposure. (b) Final model adjusting for arsenic, age,
sex, BMI, and age/BMI interaction.

Table 4. Estimated ORs (95% CIs) for relationships between QTc intervals
and arsenic exposure.

Water arsenic exposure   Main effects model (a)  Final model (b)

Low exposure (reference  1.0                     1.0
  group)
Medium vs. low exposure  3.060 (0.929-10.081)    3.829 (1.128-12.993)
High vs. low exposure    7.175 (2.296-22.425)    8.848 (2.723-28.748)

(a) Main effects model adjusting for arsenic, age, sex, tobacco smoking,
BMI, and pesticide exposure. (b) Final model adjusting for arsenic, age,
sex, BMI, and age/BMI interaction.

Table 5. Heart rate and QTc among the subjects with prolonged QTc and
normal QTc subjects (mean [+ or -] SD).

Water arsenic    Heart rate
exposure         Subjects with QTc [less than or equal to] 0.44 sec (n)

Low exposure     66 [+ or -] 10 (99)
Medium exposure  68 [+ or -] 10 (96)
High exposure    68 [+ or -] 10 (81)
All Subjects     68 [+ or -] 10 (276)

                 Heart rate
                 Subjects with
Water arsenic    QTc [greater than or equal to] 0.45
exposure         sec (n)                              p-Value (a)

Low exposure     73 [+ or -] 13 (4)                     0.1910
Medium exposure  80 [+ or -] 15 (12)                    0.0194
High exposure    76 [+ or -] 10 (21)                    0.0018
All Subjects     77 [+ or -] 12 (37)                  < 0.0001

Water arsenic    QTc
exposure         Subjects with QTc [less than or equal to] 0.44 sec (n)

Low exposure     0.409 [+ or -] 0.021 (99)
Medium exposure  0.407 [+ or -] 0.021 (96)
High exposure    0.410 [+ or -] 0.023 (81)
All Subjects     0.409 [+ or -] 0.023 (276)

                 QTc
Water arsenic    Subjects with
exposure         QTc [greater than or equal to] 0.45 sec (n)  p-Value

Low exposure     0.467 [+ or -] 0.016 (4)                     < 0.0001
Medium exposure  0.456 [+ or -] 0.017 (12)                    < 0.0001
High exposure    0.459 [+ or -] 0.017 (21)                    < 0.0001
All Subjects     0.459 [+ or -] 0.017 (37)                    < 0.0001

(a) p-Values are from t-tests.
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Title Annotation:Research
Author:Mumford, Judy L.; Wu, Kegong; Xia, Yajuan; Kwok, Richard; Yang, Zhihui; Foster, James; Sanders, Will
Publication:Environmental Health Perspectives
Date:May 1, 2007
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