Person:

Sparrow, David

Background: Cumulative exposure to lead has been shown to be associated with depression of electrocardiographic conduction, such as QT interval (time from start of the Q wave to end of the T wave). Because iron can enhance the oxidative effects of lead, we examined whether polymorphisms in iron metabolism genes [hemochromatosis ((HFE)), transferrin ((TF)) C2, and heme oxygenase-1 ((HMOX-1))] increase susceptibility to the effects of lead on QT interval in 613 community-dwelling older men. Methods: We used standard 12-lead electrocardiograms, K-shell X-ray fluorescence, and graphite furnace atomic absorption spectrometry to measure QT interval, bone lead, and blood lead levels, respectively. Results: A one-interquartile-range increase in tibia lead level (13 μg/g) was associated with a 11.35-msec [95% confidence interval (CI), 4.05–18.65 msec] and a 6.81-msec (95% CI, 1.67–11.95 msec) increase in the heart-rate–corrected QT interval among persons carrying long (HMOX-1) alleles and at least one copy of an (HFE) variant, respectively, but had no effect in persons with short and middle (HMOX-1) alleles and the wild-type HFE genotype. The lengthening of the heart-rate–corrected QT interval with higher tibia lead and blood lead became more pronounced as the total number (0 vs. 1 vs. ≥2) of gene variants increased (tibia, (p)-trend = 0.01; blood, (p)-trend = 0.04). This synergy seems to be driven by a joint effect between (HFE) variant and (HMOX-1) L alleles. Conclusion: We found evidence that gene variants related to iron metabolism increase the impacts of low-level lead exposure on the prolonged QT interval. This is the first such report, so these results should be interpreted cautiously and need to be independently verified.

Background and Objectives: We have previously shown that reduced defenses against oxidative stress due to glutathione S-transferase M1 (GSTM1) deletion modify the effects of PM[2.5] (fine-particulate air pollution of < 2.5 μm in aerodynamic diameter) on heart rate variability (HRV) in a cross-sectional analysis of the Normative Aging Study, an elderly cohort. We have extended this to include a longitudinal analysis with more subjects and examination of the GT short tandem repeat polymorphism in the heme oxygenase-1 (HMOX-1) promoter. Methods: HRV measurements were taken on 539 subjects. Linear mixed effects models were fit for the logarithm of HRV metrics—including standard deviation of normal-to-normal intervals (SDNN), high frequency (HF), and low frequency (LF)—and PM2.5 concentrations in the 48 hr preceding HRV measurement, controlling for confounders and a random subject effect. Results: PM2.5 was significantly associated with SDNN (p = 0.04) and HF (p = 0.03) in all subjects. There was no association in subjects with GSTM1, whereas there was a significant association with SDNN, HF, and LF in subjects with the deletion. Similarly, there was no association with any HRV measure in subjects with the short repeat variant of HMOX-1, and significant associations in subjects with any long repeat. We found a significant three-way interaction of PM[2.5] with GSTM1 and HMOX-1 determining SDNN (p = 0.008), HF (p = 0.01) and LF (p = 0.04). In subjects with the GSTM1 deletion and the HMOX-1 long repeat, SDNN decreased by 13% [95% confidence interval (CI), −21% to −4%], HF decreased by 28% (95% CI, −43% to −9%), and LF decreased by 20% (95% CI, −35% to −3%) per 10 μg/m3 increase in PM. Conclusions: Oxidative stress is an important pathway for the autonomic effects of particles.

Background: Cumulative lead exposure is associated with a widened pulse pressure (PP; the difference between systolic and diastolic blood pressure), a marker of arterial stiffness and a predictor of cardiovascular disease. Polymorphisms in the hemochromatosis gene (HFE) have been shown to modify the impact of cumulative lead exposure on measures of adult cognition and cardiac function. Objectives: We examined whether the HFE mutations modify the impact of lead on PP in community-dwelling older men. Methods: We examined 619 participants with a total of 1,148 observations of PP from a substudy of bone lead levels (a measure of cumulative exposure, measured by in vivo K-shell X-ray fluorescence) and health in the Normative Aging Study between 1991 and 2001. Linear mixed-effects regression models with random intercepts were constructed. Results: Of the 619 subjects, 138 and 72 carried the HFE H63D and C282Y variants, respectively. After adjusting for age; education; alcohol intake; smoking; daily intakes of calcium, sodium, and potassium; total calories; family history of hypertension; diabetes; height; heart rate; high-density lipoprotein (HDL); total cholesterol:HDL ratio; and waist circumference, baseline bone lead levels were associated with steeper increases in PP in men with at least one H63D allele (p-interaction = 0.03 for tibia and 0.02 for patella) compared with men with only the wild types or C282Y variant. Conclusions: The HFE H63D polymorphism, but not the C282Y mutation, appears to enhance susceptibility to the deleterious impact of cumulative lead on PP, possibly via prooxidative or pro-inflammatory mechanisms.

In this study we investigated whether a known delta-aminolevulinic acid dehydratase (ALAD) exon 4 polymorphism has a modifying effect on the association of blood or bone lead level with uricemia and indices of renal function among middle-aged and elderly men. We performed a cross-sectional study of subjects who participated between 1991 and 1995 in the Department of Veterans Affairs Normative Aging Study. Information on blood lead levels, bone lead levels (measured by K-shell X-ray fluorescence), serum uric acid, serum creatinine, estimated creatinine clearance, and ALAD polymorphism status was available in 709 subjects. Regression models were constructed to examine the relationships of serum uric acid, serum creatinine, and estimated creatinine clearance to blood or bone lead level, stratified by genotype. We also adjusted for age, body mass index, blood pressure, smoking, alcohol consumption, and ingestion of analgesic medications (n = 638). Of the 709 subjects, 7 (1%) and 107 (15%) were homozygous and heterozygous for the variant (ALAD-2) allele, respectively. The mean (range) serum uric acid and creatinine levels were 6.5 (2.9-10.6) and 1.2 (0.6-2.5) mg/dL. No significant differences were found in serum uric acid, serum creatinine, or estimated creatinine clearance by ALAD genotype. However, after adjusting for other potential confounders, we found a significant linear relationship between serum uric acid and patella bone lead (p = 0.040) among the ALAD 1-2/2-2 genotype individuals above a threshold patellar lead level of 15 micro g/g. In contrast, among the wild-type (ALAD 1-1) individuals, there was a suggestion of a significant linear relationship of serum uric acid with patella bone lead (p = 0.141), but only after a threshold of 101 micro g/g. There was evidence of a significant (p = 0.025) interaction of tibia lead with genotype (ALAD 1-1 vs. ALAD 1-2/2-2) regarding serum creatinine as an outcome, but in the same linear regression model tibia lead alone was not a significant predictor of serum creatinine. Conversely, for estimated creatinine clearance, patella lead, but not the interaction of patella lead with genotype, was a significantly independent predictor (p = 0.026). Our findings suggest that ALAD genotype may modify the effect of lead on the renal excretion of uric acid as well as overall renal function among middle-aged and elderly men who had community (nonoccupational) exposures to lead. Additional research is needed to ascertain whether this constitutes a true gene-environment interaction and, if so, its clinical impact.

Background: Pulse pressure increases with age in industrialized societies as a manifestation of arterial stiffening. Lead accumulates in the vasculature and is associated with vascular oxidative stress, which can promote functional and structural vascular disease. Objectives: We tested the hypothesis that cumulative community-level lead exposure, measured with K-X-ray fluorescence, is associated with pulse pressure in a cohort of adult men. Methods and results: In a cross-sectional analysis of 593 men not treated with antihypertensive medication, tibia lead was positively associated with pulse pressure (p < 0.001). Adjusting for age, race, diabetes, family history of hypertension, education, waist circumference, alcohol intake, smoking history, height, heart rate, fasting glucose, and total cholesterol-to-HDL ratio, increasing quintiles of tibia lead remained associated with increased pulse pressure (ptrend = 0.02). Men with tibia lead above the median (19.0 μg/g) had, on average, a 4.2-mmHg (95% confidence interval, 1.9–6.5) higher pulse pressure than men with tibia lead level below the median. In contrast, blood lead level was not associated with pulse pressure. Conclusions: These data indicate that lead exposure may contribute to the observed increase in pulse pressure that occurs with aging in industrialized societies. Lead accumulation may contribute to arterial aging, perhaps providing mechanistic insight into the observed association of low-level lead exposure with cardiovascular mortality.

Reduced heart rate variability (HRV), a marker of poor cardiac autonomic function, has been associated with air pollution, especially fine particulate matter [< 2.5 μm in aerodynamic diameter (PM({2.5}))]. We examined the relationship between HRV [standard deviation of normal-to-normal intervals (SDNN), power in high frequency (HF) and low frequency (LF), and LF:HF ratio] and ambient air pollutants in 497 men from the Normative Aging Study in greater Boston, Massachusetts, seen between November 2000 and October 2003. We examined 4-hr, 24-hr, and 48-hr moving averages of air pollution (PM({2.5}), particle number concentration, black carbon, ozone, nitrogen dioxide, sulfur dioxide, carbon monoxide). Controlling for potential confounders, HF decreased 20.8% [95% confidence interval (CI), 4.6–34.2%] and LF:HF ratio increased 18.6% (95% CI, 4.1–35.2%) per SD (8 μg/m(^3)) increase in 48-hr PM({2.5}). LF was reduced by 11.5% (95% CI, 0.4–21.3%) per SD (13 ppb) increment in 4-hr O(3). The associations between HRV and PM({2.5}) and O(3) were stronger in people with ischemic heart disease (IHD) and hypertension. The associations observed between SDNN and LF and PM({2.5}) were stronger in people with diabetes. People using calcium-channel blockers and beta-blockers had lower associations between O(3) and PM({2.5}) with LF. No effect modification by other cardiac medications was found. Exposures to PM({2.5}) and O(_3) are associated with decreased HRV, and history of IHD, hypertension, and diabetes may confer susceptibility to autonomic dysfunction by air pollution.

In this prospective study, we examined changes in renal function during 6 years of follow-up in relation to baseline lead levels, diabetes, and hypertension among 448 middle-age and elderly men, a subsample of the Normative Aging Study. Lead levels were generally low at baseline, with mean blood lead, patella lead, and tibia lead values of 6.5 μg/dL, 32.4 μg/g, and 21.5 μg/g, respectively. Six percent and 26% of subjects had diabetes and hypertension at baseline, respectively. In multivariate-adjusted regression analyses, longitudinal increases in serum creatinine (SCr) were associated with higher baseline lead levels but these associations were not statistically significant. However, we observed significant interactions of blood lead and tibia lead with diabetes in predicting annual change in SCr. For example, increasing the tibia lead level from the midpoints of the lowest to the highest quartiles (9–34 μg/g) was associated with an increase in the rate of rise in SCr that was 17.6-fold greater in diabetics than in nondiabetics (1.08 mg/dL/10 years vs. 0.062 mg/dL/10 years; p < 0.01). We also observed significant interactions of blood lead and tibia lead with diabetes in relation to baseline SCr levels (tibia lead only) and follow-up SCr levels. A significant interaction of tibia lead with hypertensive status in predicting annual change in SCr was also observed. We conclude that longitudinal decline of renal function among middle-age and elderly individuals appears to depend on both long-term lead stores and circulating lead, with an effect that is most pronounced among diabetics and hypertensives, subjects who likely represent particularly susceptible groups.

Background: Exposure to lead is known to have adverse effects on cognition in several different populations. Little is known about the underlying structural and functional correlates of such exposure in humans. Objectives: We assessed the association between cumulative exposure to lead and levels of different brain metabolite ratios in vivo using magnetic resonance spectroscopy (MRS). Methods: We performed MRS on 15 men selected from the lowest quintile of patella bone lead within the Department of Veterans Affairs’ Normative Aging Study (NAS) and 16 from the highest to assess in the hippocampal levels of the metabolites N-acetylaspartate, myoinositol, and choline, each expressed as a ratio with creatine. Bone lead concentrations—indicators of cumulative lead exposure—were previously measured using K-X-ray fluorescence spectroscopy. MRS was performed on the men from 2002 to 2004. Results: A 20-μg/g bone and 15-μg/g bone higher patella and tibia bone lead concentration—the respective interquartile ranges within the whole NAS—were associated with a 0.04 [95% confidence interval (CI), 0.00–0.08; p = 0.04] and 0.04 (95% CI, 0.00–0.08; p = 0.07) higher myoinositol-to-creatine ratio in the hippocampus. After accounting for patella bone lead declines over time, analyses adjusted for age showed that the effect of a 20-μg/g bone higher patella bone lead level doubled (0.09; 95% CI, 0.01–0.17; p = 0.03). Conclusions: Cumulative lead exposure is associated with an increase in the myinositol-to-creatine ratio. These data suggest that, as assessed with MRS, glial effects may be more sensitive than neuronal effects as an indicator of cumulative exposure to lead in adults.

Background: Associations between ambient temperature and cardiovascular mortality are well established. This study investigated whether inflammation could be part of the mechanism leading to temperature-related cardiovascular deaths. Methods: The study population consisted of a cohort of 673 men with mean age of 74.6 years, living in the greater Boston area. They were seen for examination roughly every 4 years, and blood samples for inflammation marker analyses were drawn in 2000-2008 (total of 1254 visits). We used a mixed effects model to estimate the associations between ambient temperature and a variety of inflammation markers (C-reactive protein, white blood cell count, soluble Vascular Cell Adhesion Molecule-1, soluble Intercellular Adhesion Molecule-1, tumor necrosis factor alpha, and interleukins -1β, -6 and -8). Random intercept for each subject and several possible confounders, including combustion-related air pollution and ozone, were used in the models. Results: We found a 0 to 1 day lagged and up to 4 weeks cumulative responses in C-reactive protein in association with temperature. We observed a 24.9% increase [95% Confidence interval (CI): 7.36, 45.2] in C-reactive protein for a 5°C decrease in the 4 weeks' moving average of temperature. We observed similar associations also between temperature and soluble Intercellular Adhesion Molecule-1 (4.52%, 95% CI: 1.05, 8.10, over 4 weeks' moving average), and between temperature and soluble Vascular Cell Adhesion Molecule-1 (6.60%, 95% CI: 1.31, 12.2 over 4 weeks' moving average). Penalized spline models showed no deviation from linearity. There were no associations between temperature and other inflammation markers. Conclusions: Cumulative exposure to decreased temperature is associated with an increase in inflammation marker levels among elderly men. This suggests that inflammation markers are part of intermediate processes, which may lead to cold-, but not heat-, related cardiovascular deaths.

Background: Altered heart rate variability (HRV), a marker of poor cardiac autonomic function, has been associated with sudden cardiac death and heart failure. Objective: We examined the association of low-level lead exposure measured in bone by K-X-ray fluorescence with alterations in HRV, and whether metabolic syndrome (MetS) or its individual components modify those associations. Methods: HRV measures [power in high-frequency (HF({norm})) and low-frequency (LF({norm})) in normalized units, and LF/HF] were taken among 413 elderly men from the Normative Aging Study. MetS was defined as subjects having three or more of the following criteria: abdominal obesity, hypertriglyceridemia, low high-density lipoprotein, high blood pressure, and high fasting glucose. Results: Of the subjects, 32% were identified as having MetS. Inverse but nonstatistically significant associations of both tibia and patella lead levels with HF({norm}) and nonstatistically significant positive relations with LF({norm}) and LF/HF were found in the entire cohort. There was a graded, statistically significant reduction in HF({norm}) and increases in LF({norm}) and LF/HF in association with an increase in patella lead as the number of metabolic abnormalities increased. We also observed that higher patella lead was consistently associated with lower HFnorm and higher LF(_{norm}) and LF/HF among subjects with MetS or its individual components. No statistically significant interaction between MetS and tibia lead was observed. Conclusion: The results suggest that elderly men with MetS were more susceptible to autonomic dysfunction in association with chronic lead exposure as measured in patella. The modification by MetS is consistent with a role for oxidative stress in lead toxicity on the cardiovascular system.