Elevated lactate dehydrogenase activity and increased cardiovascular mortality in the arsenic-endemic areas of southwestern Taiwan

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Abstract

Arsenic ingestion has been linked to increasing global prevalence of and mortality from cardiovascular disease (CVD); arsenic can be removed from drinking water to reduce related health effects. Lactate dehydrogenase (LDH) is used for the evaluation of acute arsenic toxicity in vivo and in vitro, but it is not validated for the evaluation of long-term, chronic arsenic exposure. The present study examined the long-term effect of chronic arsenic exposure on CVD and serum LDH levels, after consideration of arsenic metabolism capacity. A total of 380 subjects from an arseniasis-endemic area and 303 from a non-endemic area of southwestern Taiwan were recruited in 2002. Various urinary arsenic species were analyzed using high-performance liquid chromatography (HPLC) and hydride generation systems. Fasting serum was used for quantitative determination of the total LDH activity. A significant dose–response relationship was observed between arsenic exposure and LDH elevation, independent of urinary arsenic profiles (P < 0.001). Furthermore, abnormal LDH elevation was associated with CVD mortality after adjustment for Framingham risk scores for 10-year CVD and arsenic exposure (hazard ratio, 3.98; 95% confidence interval, 1.07–14.81). LDH was elevated in subjects with arsenic exposure in a dose-dependent manner. LDH is a marker of arsenic toxicity associated with CVD mortality. Results of this study have important implications for use in ascertaining long-term arsenic exposure risk of CVD.

Highlights

► We showed that arsenic exposure was correlated with LDH elevation. ► LDH elevation was related to arsenic methylation capacity. ► Abnormal LDH elevation can be a marker of susceptibility to CVD mortality.

Introduction

Arsenic is a potent but modifiable environmental pollutant that has been linked to the increasing prevalence of cardiovascular disease (CVD), a major cause of excess mortality worldwide (Navas-Acien et al., 2005); arsenic can be removed from drinking water to reduce related health effects. Nonetheless, little was known about the excess mortality from arsenic when genetic factors were considered, notwithstanding individual susceptibility to arsenic toxicity (NRC, 1999) due to differences in age, sex, and arsenic metabolism (Vahter, 2000, Watanabe et al., 2001). Inter-individual differences in the speciation and amounts of arsenic metabolites are reported among subjects chronically exposed to arsenic (Loffredo et al., 2003). Arsenic-induced CVD may result from the inter-correlations between environmental and toxicological mechanisms.

The total level of plasma lactate dehydrogenase (LDH), which measures all five isoforms (LDH1 to LDH5) present in the blood, is usually used in the diagnosis and treatment of acute tissue damage, cardiac diseases such as acute myocardial infarction (Galen et al., 1975), tumors of the lung (Turan et al., 2007), and liver diseases such as acute viral hepatitis, cirrhosis, and metastatic carcinoma of the liver or kidneys (Chu et al., 2002). In addition, LDH test has also been shown to predict in-hospital mortality among subjects with severe underlying physical illness (Davis et al., 1995). Furthermore, LDH has also been widely used for the evaluation of acute arsenic toxicity in vivo and in vitro (Peraza et al., 2003, Petrick et al., 2000, Saad et al., 2006, Tajima et al., 2010); but the association between chronic arsenic exposure and the level of serum LDH remains unclear.

One recent cross-sectional study showed that the total LDH level in the plasma correlated positively with the concentration of arsenic in drinking water (Karim et al., 2010). Therefore, in conjunction with the role of LDH in cardiovascular evaluation, we suggest a link between arsenic-related LDH elevation and the mortality of CVD. The present study examined the long-term effect of chronic arsenic exposure and serum LDH levels on CVD after consideration of urinary arsenic metabolites. Our results are beneficial to the identification of a biomarker for long-term arsenic exposure risk assessment.

Section snippets

Study areas

The study included a community-based cohort comparing the population from a previously arseniasis-endemic area in southwestern Taiwan to a non-exposed population recruited from a documented non-endemic area in the same county. The subjects shared similar ages, genders, and ecological statuses at the time of data collection. The arseniasis-endemic area of Homei, Fusin, and Hsinming villages in Putai Township on the southwestern coast of Taiwan were described previously (Chen et al., 1985, Chen

Descriptive statistics of study participants

The average characteristics of the study populations are summarized in Table 1. The numbers of study subjects in endemic and non-endemic areas were 380 and 296, respectively. Demographic data showed that there was no significant difference in the age and gender profiles between the two areas. However, the percentage of subjects who smoked cigarettes was significantly higher in the endemic area. The average LDH levels for the non-endemic and endemic areas were 295.06 IU/L and 408.43 IU/L,

Discussion

The present study examined the association between chronic arsenic exposure and LDH elevation. Previously, Brancaccio et al. (2008) reported that factors associated with LDH levels included age, gender, race, muscle mass, physical activity, and climatic conditions. Our study further demonstrated that urinary arsenic species were associated with LDH elevation, especially As(III) and MMA, after adjustment for the reported conventional risk factors. We also examined the sum of iAs and MMA, both of

Conflict of interest

The authors have no competing interests or financial disclosures.

Acknowledgments

This work was supported by the National Health Research Institute (grants EO-094-PP-11, EO-095-PP-07, and EO-096-PP-07), National Taiwan University (grant 100R0001) and National Science Council (NSC98-2314-B-400-001-MY3), Taiwan. We thank the clinicians and nurses at Hsin-Ying Branch Hospital, Beimen, Tainan, for their support with the health examinations of the study subjects. We are also deeply indebted to all members of the Blackfoot Disease Team for their assistance in data collection and

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