Lead Accumulation in Shin Bone Tied to Resistant Hypertension

Batya Swift Yasgur MA, LSW

November 06, 2018

Lead accumulation in the tibia is associated with treatment-resistant hypertension, new research shows.

Investigators tested lead levels in the blood, tibias, and patellae of 475 adult men, 97 with resistant hypertension.

After adjusting for demographics, lifestyle, and socioeconomic factors, the team found that the risk for resistant hypertension was 19% higher with every 15 μg/g increase in tibia lead levels — an association not found in the blood or patella

"We found that lead measured in the tibia, the shin bone, is associated with a higher risk of resistant hypertension, and this association was independent of important risk factors for hypertension," lead author Sung Kyun Park, ScD, MPH, associate professor of epidemiology and environmental health sciences, University of Michigan School of Public Health, Ann Arbor, told theheart.org | Medscape Cardiology.

"Our study suggests that physicians may also want to ask patients about past lead exposure," he said.

The study was published online October 24 in the Journal of the American Heart Association.

Interference With Vasculature

"Lead has been studied for its potential role in elevated and volatile blood pressure," the authors write.

Prolonged exposure to lead has been found to predict the development of hypertension, and cohort studies have linked blood lead levels to increased blood pressure (BP) and hypertensive risk.

"Lead has been shown to interfere with the function of vasculature and endothelial cells through increases in the RAS [rennin–angiotensin system] and vasoconstricting prostanoids, in combination with decreases in the potent vasodilator nitric oxide," Park explained.

"Low levels of lead can lead to marked decrease in nitric oxide availability, and lead can upregulate the RAS activity via increased angiotensin-converting enzyme and angiotensin II receptor type 1, which results in arterial contraction," he continued.

He recounted that the motivation of the study was to understand "why some patients need more drugs to control high blood pressure than others, [which is] poorly understood."

Given the connection between hypertension and lead exposure, "we were curious of whether lead exposure is also associated with drug-resistant hypertension," he said.

In light of the interference that lead can have on vascular regulation, atherosclerotic progression, and BP, the researchers hypothesized "that the lead level in bone as a marker of cumulative lead exposure is an independent variable influencing the development of resistant hypertension."

To investigate the question, the researchers studied male, predominantly white volunteers who were participating in the Veterans Affairs Normative Aging Study (NAS), a longitudinal study of 2280 volunteers, ranging from 21 to 81 years of age, based out of the Boston Veterans Affairs Healthcare system in 1963.

Participants were seen in clinic every 3 to 5 years for a complete history and physical exam, which included measurement of BP and tracking of antihypertensive medical management, when relevant.

From 1991 on, bone and blood lead measurements were collected from participants who agreed to have their levels recorded.

Subjects were initially chosen if they were taking any medication for BP control or had elevated BP (SDP/DBP ≥ 140/90 mm Hg).

Demographic and socioeconomic factors included age, race, educational attainment, income level, body mass index, cigarette smoking, and family history of hypertension.

Resistant hypertension was defined as "inadequate BP control on ≥3 antihypertensive medications of different classes…or adequate control on ≥4 antihypertensive medications."

Lead levels were measured at the mid-tibia shaft and patella using K x-ray fluorescence, a noninvasive method that evaluates lead in bone by  measuring x-ray traits that correlate with fluorescent atoms of targeted elements.

Novel Marker

Participants (n = 475) ranged in age from 48 to 93 years (mean, 68.2 years), with median lead levels of 20.0 μg/g (IQR, 13.0 - 28.5 μg/g) for the tibia, and 27.0 μg/g (IQR 18.0 - 40.0 μg/g) for the patella.

Tibia and patella lead were found to be strongly correlated (= 0.78; 95% CI, 0.75 - 0.82; P < .001).

Median blood lead levels (5.0 μg/dL; IQR, 3.36 - 8.00 μg/dL]) were moderately associated with tibia lead levels (r = 0.38; 95% CI, 0.30 - 0.46; P < .001) and patella lead levels (r = 0.43; 95% CI, 0.35 - 0.50; P < .001).

Age, smoking (pack-years), education, and race were all significantly associated with high tibia lead levels; and age, smoking (pack-years), education, and race were significantly associated with higher patella lead levels (< .05 for both).

Associated bone lead measurements identified 97 cases (19.8%) of resistant hypertension in the 475 study participants.

Among these cases of resistant hypertension, median tibia lead was 20.0 μg/g and median patella lead was 25.0 μg/g, compared with participants without resistant hypertension, who had a median tibia lead level of 20.0 μg/g and median patella lead level of 27.5 μg/g.

However, the final adjusted models accounting for family history of hypertension showed significance in the relation between tibia and resistant hypertension (RR, 1.19; 95% CI, 1.01 - 1.41; P = .04).

No similar association was found between patella and resistant hypertension.

Sensitivity analysis for smoking status did not significantly alter the relation between tibia or patella lead and resistant hypertension.

Blood lead was not found to be significantly associated with resistant hypertension.

"In adults, the bone contains more than 90% of body burden of lead, so once lead enters the body, it is very difficult to remove it and it stays in your hard bones — such as the shin bone — for several decades," Park said.

"When you get old and your bones get weak, lead can be released into the bloodstream and then move to target organs," he continued.

He called lead level in the tibia "an indicator of retained cumulative lead dose," adding that the study "suggests that tibia lead is a novel biomarker for the risk of resistant hypertension and may offer greater insight into how low-level lead impedes pharmacologic management of hypertension."

Be Alert to Potential Exposure

Commenting on the study for theheart.org | Medscape Cardiology, Ana Navas-Acien, MD, MPH, PhD, professor of environmental health sciences, Columbia University Mailman School of Public Health, New York City, who was not involved with the study, said that the findings "highlight once more the enormous damage that lead exposure causes to the cardiovascular system and identifies an important outcome — resistant hypertension — which can ultimately contribute to serious clinical events, such as MI [myocardial infarction] or stroke."

The study has important implications, she said.

"For practicing clinicians, it is important to be alert on potential lead exposure — for instance, if children have been diagnosed with lead poisoning, the whole family should be monitored, including the adults in the family."

She noted that an ongoing study, the Trial to Assess Chelation Therapy (TACT2), is investigating whether repeated chelation can protect patients with MI from having another cardiac event.

"If TACT2 confirms the findings from the previous trial, which showed cardiovascular benefits of metal chelation, this could provide an additional therapeutic tool for patients with chronic lead exposure at high risk of cardiovascular disease," she said.

Park added, "Long-term exposure to lead may be an unrecognized risk factor for resistant hypertension; therefore, the most important clinical and public health implication of our study is to prevent lead exposure early in life."

Moreover, "new knowledge on the health implications of low-level exposure can help motivate exposure removal via infrastructure investment from a public health standpoint," the authors add.

The National Institute of Environmental Health Sciences, the Centers for Disease Control and Prevention, the National Institute for Occupational Safety and Health, the Department of Veterans Affairs, and the Massachusetts Veterans Epidemiology Research and Information Center funded the study. Park, the study coauthors, and Navas-Acien disclose on conflicts of interest.

J Am Heart Assoc. Published online October 24, 2018. Article

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