The Contribution of Declines in Blood Lead Levels to Reductions in Blood Pressure Levels: Longitudinal Evidence in the Strong Heart Family Study

Wil Lieberman‐Cribbin; Zheng Li; Michael Lewin; Patricia Ruiz; Jeffery M Jarrett; Shelley A Cole; Allison Kupsco; Marcia O'Leary; Gernot Pichler; Daichi Shimbo; Richard B Devereux; Jason G Umans; Ana Navas‐Acien; Anne E Nigra

doi:10.1161/JAHA.123.031256

. 2024 Jan 11;13(2):e031256. doi: 10.1161/JAHA.123.031256

The Contribution of Declines in Blood Lead Levels to Reductions in Blood Pressure Levels: Longitudinal Evidence in the Strong Heart Family Study

Wil Lieberman‐Cribbin ^1,^✉, Zheng Li ², Michael Lewin ³, Patricia Ruiz ⁴, Jeffery M Jarrett ⁵, Shelley A Cole ⁶, Allison Kupsco ¹, Marcia O'Leary ⁷, Gernot Pichler ⁸, Daichi Shimbo ⁹, Richard B Devereux ¹⁰, Jason G Umans ^11,¹², Ana Navas‐Acien ¹, Anne E Nigra ¹

PMCID: PMC10926826 PMID: 38205795

Abstract

Background

Chronic lead exposure is associated with both subclinical and clinical cardiovascular disease. We evaluated whether declines in blood lead were associated with changes in systolic and diastolic blood pressure in adult American Indian participants from the SHFS (Strong Heart Family Study).

Methods and Results

Lead in whole blood was measured in 285 SHFS participants in 1997 to 1999 and 2006 to 2009. Blood pressure and measures of cardiac geometry and function were obtained in 2001 to 2003 and 2006 to 2009. We used generalized estimating equations to evaluate the association of declines in blood lead with changes in blood pressure; cardiac function and geometry measures were considered secondary. Mean blood lead was 2.04 μg/dL at baseline. After ≈10 years, mean decline in blood lead was 0.67 μg/dL. In fully adjusted models, the mean difference in systolic blood pressure comparing the highest to lowest tertile of decline (>0.91 versus <0.27 μg/dL) in blood lead was −7.08 mm Hg (95% CI, −13.16 to −1.00). A significant nonlinear association between declines in blood lead and declines in systolic blood pressure was detected, with significant linear associations where blood lead decline was 0.1 μg/dL or higher. Declines in blood lead were nonsignificantly associated with declines in diastolic blood pressure and significantly associated with declines in interventricular septum thickness.

Conclusions

Declines in blood lead levels in American Indian adults, even when small (0.1–1.0 μg/dL), were associated with reductions in systolic blood pressure. These findings suggest the need to further study the cardiovascular impacts of reducing lead exposures and the importance of lead exposure prevention.

Keywords: American Indians, cardiovascular disease, lead, Strong Heart Study

Subject Categories: Epidemiology, Cardiovascular Disease, High Blood Pressure, Hypertension

Nonstandard Abbreviations and Acronyms

ATSDR: Agency for Toxic Substances and Disease Registry
NHANES: National Health and Nutrition Examination Survey
SHFS: Strong Heart Family Study
SHS: Strong Heart Study
TACT: Trial to Assess Chelation Therapy
TACT 2: Trial to Assess Chelation Therapy 2

Clinical Perspective.

What Is New?

Declines in blood lead levels, even at low blood lead concentrations, were associated with reductions in systolic blood pressure.
Declines in blood lead were associated with decreases in interventricular septum thickness, potentially reflecting regression of hypertension‐mediated cardiac damage.
The findings provide important evidence of the benefits of reducing blood lead even at these lower levels.

What Are the Clinical Implications?

Small reductions in blood lead likely result in improved subclinical and clinical cardiovascular outcomes.

Changes in US regulatory and public health policies, including banning lead in gasoline, residential paint, plumbing components, and food cans, as well as regulating lead in public drinking water and air emissions, have reduced lead exposures nationwide. ¹ , ² As a result, adult and child blood lead levels have decreased substantially, although lead remains ubiquitous in the United States, and major racial and ethnic inequities in lead exposure persist. ³ , ⁴ , ⁵ , ⁶

Lead is an independent risk factor for cardiovascular disease. ⁷ , ⁸ , ⁹ , ¹⁰ In the National Health and Nutrition Examination Survey (NHANES), declines in blood lead levels in the US population over several decades were associated with subsequent reductions in cardiovascular disease death. ⁹ Experimental models and epidemiologic studies also support the causal association of lead with higher blood pressure, through oxidative stress, altered vascular reactivity, angiotensin system dysfunction, and vasomodulator imbalance. ¹¹ , ¹² , ¹³ Lead exposure has also been associated with measures of left ventricular (LV) function and structure, including LV hypertrophy, independent of blood pressure. ¹⁰ , ¹⁴ Most studies on the associations of lead exposure with blood pressure and LV function and structure have been conducted at high blood lead levels (>20 μg/dL), and epidemiologic evidence at currently low blood lead levels (<3 μg/dL) is limited. ¹³

American Indian communities experience both a higher burden of cardiovascular disease and elevated chronic metal exposures compared with the general US population. ¹⁵ , ¹⁶ The SHS (Strong Heart Study) and the SHFS (Strong Heart Family Study; its family‐based cohort extension) are the largest epidemiologic cohorts of American Indian adults followed specifically to study cardiovascular disease. Using blood lead data available in a subset of SHFS participants from 2 study visits occurring from 1997 to 1999 and 2006 to 2009, ¹⁷ we recently estimated that mean within‐person blood lead declined by 23% over this period (mean, 2.5% yearly decline), ¹⁸ similar to population‐level declines estimated in NHANES. These data provide the opportunity to evaluate short‐term changes in blood pressure and LV function and structure in relation to declines in blood lead levels. If present, short‐term cardiovascular benefits of reduced lead exposure could explain at least part of the long‐term benefit on cardiovascular death observed in NHANES. ⁹

Our primary objective was to evaluate whether declines in blood lead concentrations, even at low levels, were associated with changes in systolic and diastolic blood pressure, and secondarily, metrics of cardiac geometry and function over time in the SHFS. Our primary outcomes were changes in systolic and diastolic blood pressure, with secondary analyses considering metrics of cardiac geometry and function measured via transthoracic echocardiograms. We hypothesized that declines in blood lead would be associated with declines in both systolic and diastolic blood pressure over time, and with improvements in measures of cardiac geometry and function.

Methods

Study Population

The data underlying this article cannot be shared publicly in an unrestricted manner due to limitations in the consent forms and in the agreements between the SHS tribal communities and the SHS investigators. The data can be shared with external investigators following the procedures established by the SHS (available at https://strongheartstudy.org/). The SHS is an ongoing, prospective, population‐based cohort of 4549 American Indian adults from >10 tribes and communities in Arizona, Oklahoma, North Dakota, and South Dakota, originally developed to evaluate cardiovascular disease and its risk factors. All adults aged 45 to 74 years at baseline were invited to participate in the phase 1 baseline exam (1989–1991). ¹⁵ , ¹⁹ The participation rate was 62%. ²⁰ Participants were reevaluated at phase 2 (1993–1995) and phase 3 (1997–1999) study visits. To extend the SHS into a multigenerational cohort derived from the original SHS families, the SHFS was initiated with a pilot study conducted during SHS phase 3 (1997–1999) and reevaluated at phase 4 (2001–2003) and phase 5 (2006–2009). Families were eligible if they had a core sibship consisting of 3 original SHS participants and at least 5 additional living family members. ²¹ Additional SHS cohort family members aged ≥15 years were enrolled during the first exclusively SHFS visit at phase 4 (2001–2003). The SHS protocol was approved by institutional review boards, participating tribes, and the respective area Indian Health Service institutional review boards. All participants provided informed consent. This analysis used the Strengthening the Reporting of Observational Studies in Epidemiology cohort reporting guidelines. ²²

In our current analysis, participants were eligible for inclusion if they had whole blood samples available during both phase 3 and phase 5 visits. In a substudy funded by a National Institute for Environmental Health Sciences pilot award at Columbia University, 150 participants with whole blood samples collected at both phase 3 and phase 5 were selected via blocked random sampling to ensure an approximately equal number of male and female participants from each study center. Because the remaining blood sample volume was inadequate for 25 samples collected during phase 3, only 125 of these 150 participants had blood lead measured in whole blood at phase 3. For an additional substudy conducted by the Centers for Disease Control and Prevention/Agency for Toxic Substances and Disease Registry (ATSDR), 2014 participants with sufficient volume of blood sample available at phase 3 were selected to study blood metals and cardiovascular disease. Among those, 176 participants also had blood samples with sufficient quantity at phase 5. We combined participants from both substudies (N=125 and N=176, with 16 overlapping participants who were included in both substudies), for a total of 285 participants with blood lead measurements from both phase 3 and phase 5 for the current analysis. The 16 participants with blood metals measured by both substudies allowed for direct measurement comparisons between both participating laboratories (ie, the Columbia University Trace Metals Core Laboratory and Centers for Disease Control and Prevention's National Center for Environmental Health Laboratory).

Blood Lead Measurements

In both substudies, whole blood samples from phase 3 and phase 5 were shipped from Medstar Health Research Institute in Hyattsville, Maryland, on dry ice to the respective laboratory, where samples were stored at −70 °C to −80 °C before analysis. Blood lead was measured at the Columbia University Laboratory using inductively coupled plasma–mass spectrometry with dynamic reaction cell and at the Centers for Disease Control and Prevention laboratory using inductively coupled plasma triple quadrupole mass spectrometry. ¹⁷ , ²³ The limit of detection was 0.04 μg/dL at the Columbia University Laboratory and 0.049 μg/dL at the Centers for Disease Control and Prevention laboratory, and no values were measured below the limit of detection at either laboratory. Using blood metal measurements for a total of 32 samples included in both substudies (N=16 participants), we evaluated agreement in measured blood lead concentrations between the 2 laboratories using linear regression, scatterplots, and Bland–Altman plots (Tukey mean difference). We found no evidence of systematic differences between the 2 laboratories (Bland–Altman bias=0.02 [95% CI, −0.16 to 0.20], regression coefficient 1.05 [95% CI, 0.87–1.23]; Figures S1 and S2) and proceeded by pooling all blood lead measurements together.

Blood Pressure Measures

Centrally trained SHS nurses and medical assistants measured systolic and diastolic blood pressure (mm Hg) during physical examinations, as previously described. ¹⁵ , ²¹ Specifically, 3 consecutive measurements of blood pressure (systolic and diastolic) were performed on seated participants after 5 minutes of rest. ¹⁵ Measurements were taken on each participant's right arm with a mercury sphygmomanometer. The mean of the last 2 measurements was used to estimate systolic and diastolic blood pressures. Various quality control measures were performed, including repeated measures, observation of data collection by supervisors, simultaneous Y‐tube observation by each technician, and a sphygmomanometer maintenance program. ¹⁵ Further, the SHS Coordinating Center reviewed blood pressure data and compared blood pressure measures across technicians and study centers. We defined hypertension as systolic blood pressure ≥140 mm Hg, diastolic blood pressure ≥90 mm Hg, or reported use of antihypertensive medication.

Echocardiographic Measures of Cardiac Geometry and Functioning

Expert sonographers performed transthoracic echocardiograms on participants during the phase 4 and phase 5 study visits, according to standardized and previously described methods. ²⁴ Briefly, echocardiograms were reviewed by 2 readers, and ≈97% of echocardiograms were finally interpreted by a single highly experienced investigator as recommended by the American Society of Echocardiography. ²⁵ Cardiac geometry and functioning were assessed by phased‐array echocardiographs with M‐mode, 2‐dimensional, and Doppler capabilities. At least 10 consecutive beats of 2‐dimensional and M‐mode recordings of cardiac geometry parameters were recorded in the parasternal acoustic window at or just below the tips of the mitral leaflets in both long‐ and short‐axis views. We used LV internal diameter as the parameter of cardiac geometry at the end of diastole, and in systole: interventricular septum, LV posterior wall thickness, and relative wall thickness. LV mass was calculated by a necropsy‐validated formula and normalized for body surface area. ²⁶ , ²⁷

Ejection fraction (calculated from LV linear dimensions ²⁸ ) was used to assess LV systolic function. We used the following parameters of cardiac diastolic function: transmitral early and late filling velocities (measured at the annular level), and early peak rapid filling velocity to peak atrial filling velocity (measured as the E/A ratio). Because of the small sample size, we did not assess categorical or binary outcomes (eg, LV hypertrophy, hypertension).

Other Variables

Centrally trained SHS nurses and medical assistants collected participant information from a standardized interview, physical examination, medication review, and biospecimen collection at each study visit. The measurements, protocols, central trainings, and operating procedures did not differ across study visits and were collected under a standardized methodology. ¹⁵ Sociodemographic and lifestyle information was collected from standardized SHS questionnaires, including age, sex, years of schooling/education, whether household income met needs (yes/no/unsure), exposure to secondhand smoke (hours per week), smoking status (never/former/current), and alcohol drinking status (never/former/current). Never smoking was defined as reporting never smoking regularly, or never smoking >100 cigarettes in lifetime; former smoking was defined as smoking at least 100 cigarettes in lifetime but not smoking currently; current smoking was defined as smoking at least 100 cigarettes in lifetime and currently smoking. Never drinking was defined as never consuming alcoholic beverages; former drinking was defined as previously consuming alcoholic beverages but not within the past 12 months; current drinking was defined as having consumed an alcoholic beverage in the past 12 months.

Detailed methods on the collection of anthropometric measurements and biospecimens (eg, blood, urine), and the laboratory measurements of relevant biomarkers in biospecimens have been described previously. ¹⁵ , ²¹ , ²⁹ We calculated estimated glomerular filtration rate using age, sex, and urinary creatinine (mg/dL) via the 2009 Chronic Kidney Disease—Epidemiology Collaboration formula. ³⁰ We defined dyslipidemia as total cholesterol ≥200 mg/dL, low‐density lipoprotein ≥130 mg/dL, high‐density lipoprotein ≤40 mg/dL, total triglycerides ≥150 mg/dL, or reported use of lipid‐lowering medication. Impaired fasting glucose was defined as fasting blood glucose ≥100 and <126 mg/dL; normal fasting glucose was defined as fasting blood glucose <100 mg/dL. Hypertension treatment was defined as taking antihypertensive drugs, diuretics, β blockers, or cardiac or vasodilators, and having a recorded history of hypertension.

Statistical Analysis

All analyses were conducted in R version 4.1.1 (R Foundation for Statistical Computing, Vienna, Austria). The decline in blood lead concentrations (phase 3 blood lead concentration minus phase 5 blood lead concentration) was normally distributed and modeled in the original scale (Figure S3). We first compared baseline (phase 3) participant characteristics overall and stratified by tertile of decline in blood lead. We then calculated the Spearman correlation coefficients between decline in blood lead (from phase 3 to phase 5) and change in systolic blood pressure, diastolic blood pressure, and other metrics of cardiac geometry and functioning (from phase 4 to phase 5). We next evaluated the mean change in systolic blood pressure and other metrics of cardiac geometry and functioning per decline in blood lead concentration corresponding to the interquartile range (0.94 μg/dL) in linear generalized estimating equation models to account for the clustering of participants within families. All model adjustment variables were measured at phase 3 (baseline) except education measured at phase 4. Model 1 was adjusted for age, sex, study center, body mass index, and education (<12 years/≥12 years). Model 2 was further adjusted for smoking status (never/former/current) and estimated glomerular filtration rate. Model 3 (the main model of interest) was further adjusted for baseline antihypertensive medication and systolic blood pressure (in models evaluating the change in diastolic blood pressure, we instead adjusted for baseline diastolic blood pressure). Finally, model 4 further adjusted for fasting glucose (continuous) and dyslipidemia (yes/no). To evaluate the potential dose–response relationship, we repeated these analyses evaluating the mean change in outcomes across tertiles of decline in blood lead (with the first tertile as the reference) using generalized estimating equation models. Finally, we used flexible natural cubic spline models to evaluate potential nonlinearity in the associations between decline in blood lead and blood pressure, cardiac geometry, and cardiac functioning. We included knots at the 50th (0.53 μg/dL) and 90th (1.87 μg/dL) percentiles of the decline in blood lead distribution, and set the reference to the 10th percentile (−0.43 μg/dL).

To further evaluate the impact of interlaboratory measurement agreement on our findings, we repeated our analysis of the mean difference in systolic and diastolic blood pressure per decline in blood lead corresponding to the interquartile range, restricted to blood lead measurements taken at Columbia University (N=125). We also repeated our flexible spline analyses evaluating the change in systolic and diastolic blood pressure measured from phase 3 to phase 5 (rather than from phase 4 to phase 5). We did not perform stratified subgroup analyses given the small sample size and exploratory nature of the substudies.

Results

A total of 285 participants had blood lead measured at both phase 3 and phase 5 and were included in our analyses. Participants included in our analytic sample were similar to all participants at phase 3 by sex (60.5% women versus 59.6% women), systolic blood pressure (mean 127.3 mm Hg versus 124.9 mm Hg), body mass index (mean 30.8 kg/m² versus 31.9 kg/m²), and smoking status (33.5% current smokers versus 34.5% current smokers). The mean (SD) age of participants was 51.5 (16.3) years, and all participants were >18 years old at phase 3. Participant characteristics overall and stratified by tertile of decline in blood lead are presented in Table 1. For all participants, mean blood lead was 2.04 μg/dL at phase 3 (baseline). Mean baseline blood lead concentrations were 1.33 μg/dL for participants in the lowest tertile of decline in blood lead and 3.21 μg/dL for participants in the highest tertile of decline in blood lead. Changes in blood lead from phase 3 to phase 5 ranged from a decline of 7.58 μg/dL (reported as a decline of 7.58 μg/dL) to an increase of 5.26 μg/dL (reported as a decline of −5.26 μg/dL, ie, an increase in blood lead). Those in the highest tertile of decline in blood lead (>0.91 μg/dL) experienced a mean decline of 1.78 μg/dL over time. At baseline, 32.9% of participants (n=93) had hypertension. Participants in the highest tertile of decline in blood lead were more likely to be men, less likely to have hypertension at baseline, and had lower fasting glucose levels at baseline. The Spearman correlation between decline in blood lead and change in outcomes was statistically significant for the change in systolic blood pressure (rho=−0.12; P<0.05; Figures S4 and S5).

Table 1.

Participant Characteristics at Phase 3 (1997–1999), Stratified by Tertile of Decline in Blood Lead (μg/dL) from Phase 3 (1997–1999) to Phase 5 (2006–2009) (N=285)

	Overall	Tertile 1	Tertile 2	Tertile 3	P value	N
	−5.26 to 7.58 μg/dL decline	<0.27 μg/dL decline	0.27−0.91 μg/dL decline	>0.91 μg/dL decline	P value	N
Blood lead at phase 3 (baseline), μg/dL mean (SD)	2.04 (1.32)	1.33 (0.64)	1.58 (0.65)	3.21 (1.52)
Decline in blood lead, μg/dL, mean (SD)	0.67 (1.19)	−0.33 (0.89)	0.55 (0.18)	1.78 (1.06)
N (%)	285 (100)	95 (33.3)	95 (33.3)	95 (33.3)
Center, n (%)
Arizona	39 (13.7)	16 (16.8)	15 (15.8)	8 (8.4)	0.398	285
Oklahoma	146 (51.2)	47 (49.5)	50 (52.6)	49 (51.6)
North and South Dakota	100 (35.1)	32 (33.7)	30 (31.6)	38 (40.0)
Sex, female, n (%)	170 (59.6)	69 (72.6)	58 (61.1)	43 (45.3)	<0.001	285
Age, y, mean (SD)	51.5 (16.3)	52.7 (17.2)	47.7 (16.1)	53.9 (15.2)	0.613	285
Education,^* y, n (%)
≥12	206 (73.6)	71 (77.2)	69 (74.2)	64 (69.6)	0.498	280
<12	74 (26.4)	21 (22.8)	24 (25.8)	28 (30.4)
Income met needs, n (%)
Yes	117 (73.6)	37 (69.8)	47 (75.8)	33 (75.0)	0.744	159
No/unsure	42 (26.4)	16 (30.2)	15 (24.2)	11 (25.0)
Smoking status, n (%)
Former	65 (23.0)	20 (21.3)	19 (20.0)	26 (27.6)	0.179	283
Never	123 (43.5)	49 (52.1)	40 (42.1)	34 (36.2)
Current	95 (33.5)	25 (26.6)	36 (37.9)	34 (36.2)
Secondhand smoke exposure, h/wk, mean (SD)	1.9 (3.5)	1.3 (2.4)	2.5 (4.4)	1.9 (3.3)	0.325	158
Alcohol consumption status, n (%)
Former	114 (40.3)	33 (35.1)	36 (37.9)	45 (47.9)	0.258	283
Never	49 (17.3)	21 (22.3)	14 (14.7)	14 (14.9)
Current	120 (42.4)	40 (42.6)	45 (47.4)	35 (37.2)
Body mass index, kg/m², mean (SD)	30.8 (6.8)	31.1 (6.4)	31.6 (8.1)	29.8 (5.4)	0.173	282
Hypertension, n (%)	93 (32.9)	41 (43.6)	24 (25.3)	28 (29.8)	0.020	283
Hypertension treatment, n (%)	64 (22.5)	32 (33.7)	17 (17.9)	15 (16.0)	0.006	284
Fasting glucose, mg/dL, mean (SD)	113.2 (48.2)	122.4 (56.9)	111.7 (49.2)	105.4 (34.6)	0.015	284
Impaired fasting glucose, n (%)	20 (8.7)	4 (6.1)	10 (12.2)	6 (7.3)	0.361	230
Dyslipidemia, n (%)	197 (78.2)	63 (78.8)	68 (76.4)	66 (79.5)	0.875	252
eGFR (CKD‐EPI), mean (SD)	106 (21.8)	103.5 (25.6)	109.5 (20)	105 (19)	0.660	284
Systolic blood pressure, mm Hg, mean (SD)	127.3 (16.2)	130 (16.5)	124.5 (14.8)	127.2 (16.8)	0.241	283
Diastolic blood pressure, mm Hg, mean (SD)	75 (8.7)	74.8 (9.3)	75.7 (8.5)	74.5 (8.2)	0.805	284

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Tertile 1 represents the smallest blood lead decline (<0.27 μg/dL decline), and tertile 3 represents the largest blood lead decline (>0.91 μg/dL decline). Negative values of the decline in blood lead represent increases in blood lead over time. CDK‐EPI indicates Chronic Kidney Disease Epidemiology Collaboration; and eGFR, estimated glomerular filtration rate.

Assessed at phase 4.

Declines in blood lead from phase 3 to phase 5 were associated with declines in systolic blood pressure from phase 4 to phase 5 (Table 2). In model 3, the mean difference in the change in systolic blood pressure comparing participants in the highest tertile of decline in blood lead (>0.91 μg/dL) to those in the lowest tertile (reference) of decline in blood lead (<0.27 μg/dL) was −7.08 mm Hg (95% CI, −13.16 to −1.00). The magnitude of this effect estimate slightly increased after further adjustment for baseline fasting glucose and dyslipidemia, although this change was not statistically significant (model 4, mean difference, −8.17 mm Hg [95% CI, −14.59 to −1.75). In linear models, a decline in blood lead corresponding to the interquartile range (0.94 μg/dL) was associated with a nonsignificant mean change in systolic blood pressure of −2.15 mm Hg (95% CI, −4.45 to 0.15) (model 3). However, declines in blood lead were not linearly associated with mean difference in systolic and diastolic blood pressure in flexible cubic spline models (Figure 1). There was no evidence of an association when there was no decline, and associations became apparent when declines in blood lead exceeded 0.1 μg/dL. Similar to our findings from tertile models, the association between decline in blood lead and the mean difference in systolic blood pressure was statistically significant and apparent in flexible spline models when declines in blood lead were >0.1 μg/dL. Flexible spline modeling decreases in blood lead and changes in diastolic pressure followed similar trends as for systolic blood pressure, but were not statistically significant. In sensitivity analyses restricted to blood lead measurements made at the Columbia University Laboratory, effect estimates were similar to those in our main analysis (Table S1). Associations were attenuated in sensitivity analyses considering changes in systolic blood pressure from phase 3 to phase 5, potentially reflecting differences in the half‐life of lead in bone (decades) versus blood (months), and the significant contribution of bone lead to blood lead levels (Figure S6). While declines in blood lead reflect declines in recent/ongoing exposures, declines in bone lead reflect declines in total body burden of lead, which may be more relevant for blood pressure. Changes in both blood lead and blood pressure outcomes across phase 3 and phase 5 relative to phase 3 concentrations are depicted in Figures S7 through S9. In sensitivity analyses restricted to participants without hypertension at baseline (n=192) and without adjustment for baseline hypertension treatment, we observed similar effect estimates of the association between declines in blood lead and changes in both systolic and diastolic blood pressure, although associations were not statistically significant (Table S2). In sensitivity analyses adjusting for income needs measured at baseline (n=154), we observed stronger effect estimates of the association between declines in blood lead and changes in both systolic and diastolic blood pressure, although sample size was limited (Table S3). In sensitivity analyses removing those with declines/increases in lead values >4 μg/dL (n=274), effect estimates of the association between declines in blood lead and changes in both systolic and diastolic blood pressure were similar to the main model (Table S4). In a sensitivity analysis, we added 10 mm Hg to systolic blood pressure values and 5 mm Hg to diastolic blood pressure values for those receiving hypertension treatment, as a way to correct for their lower levels because of treatment, following the approach of Balakrishnan et al ³¹ (Table S5). The strength and direction of relationships between changes in lead and blood pressure outcomes were similar to those observed in main models.

Table 2.

Mean Difference in the Change in Systolic and Diastolic Blood Pressure (mm Hg) From Phase 4 (2001–2003) to Phase 5 (2006–2009) Across Tertiles of Blood Lead Decline from Phase 3 (1997–1999) to Phase 5 (2006–2009) and by Decline in Blood Lead Corresponding to the IQR (N=278)

	Tertile 1	Tertile 2	Tertile 3	Per IQR decrease
	<0.27 μg/dL	0.27 to 0.91 μg/dL	>0.91 μg/dL	(0.94 μg/dL)
Systolic blood pressure
Model 1	Reference	−2.13 (−7.00 to 2.74)	−6.65 (−12.51 to −0.79)	−2.00 (−4.11 to 0.12)
Model 2	Reference	−1.78 (−6.68 to 3.11)	−6.44 (−12.30 to −0.58)	−2.07 (−4.25 to 0.11)
Model 3	Reference	−2.51 (−7.38 to 2.35)	−7.08 (−13.16 to −1.00)	−2.15 (−4.45 to 0.15)
Model 4	Reference	−2.48 (−7.66 to 2.70)	−8.17 (−14.59 to −1.75)	−2.28 (−4.72 to 0.16)
Diastolic blood pressure
Model 1	Reference	1.11 (−1.82 to 4.04)	−1.06 (−4.15 to 2.04)	−0.51 (−1.41 to 0.39)
Model 2	Reference	1.35 (−1.58 to 4.28)	−0.97 (−4.10 to 2.16)	−0.62 (−1.60 to 0.36)
Model 3	Reference	1.51 (−1.46 to 4.49)	−0.86 (−4.03 to 2.31)	−0.59 (−1.59 to 0.42)
Model 4	Reference	0.95 (−2.18 to 4.08)	−1.87 (−5.38 to 1.64)	−0.82 (−1.94 to 0.31)

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Negative values represent declines in blood pressure. Tertile 1 represents the smallest blood lead decline, and tertile 3 represents the largest blood lead decline. Model 1 was adjusted for sex, age, center, body mass index, and education (<12 years/≥12 years). Model 2 was further adjusted for smoking status (never/former/current) and estimated glomerular filtration rate (calculated via the Chronic Kidney Disease Epidemiology Collaboration formula). Model 3 was further adjusted for hypertension treatment/medication and baseline systolic blood pressure. Model 4 was further adjusted for fasting glucose and dyslipidemia. All model adjustment variables were measured at phase 3 (baseline) except for education measured at phase 4. Model 3 and model 4 considering diastolic blood pressure adjusted for diastolic blood pressure at baseline instead of systolic blood pressure. IQR indicates interquartile range.

Negative values represent declines in blood pressure. Analysis was restricted to N=278 participants without missing covariate data. Models are adjusted for sex, age, study center, body mass index, education (<12 years/≥12 years), smoking status (never/former/current), estimated glomerular filtration rate (calculated via the Chronic Kidney Disease Epidemiology Collaboration formula), hypertension medication/treatment, and baseline systolic blood pressure. All model adjustment variables were measured at phase 3 (baseline) except for education measured at phase 4. The reference is set to the 10th percentile of the change in decline in blood lead distribution (−0.43 μg/dL), with knots at the 50th and 90th percentiles. Diastolic blood pressure models adjusted for diastolic blood pressure at baseline instead of systolic blood pressure.

Flexible spline models of the mean difference in other metrics of cardiac function and geometry per decline in blood lead are presented in Figures 2 and 3. Declines in blood lead were significantly associated with decreases in interventricular septum thickness (Figure 2). Declines in blood lead were also associated with increases in transmitral early filing velocity (Figure 3), but only at the highest ends of the decline in blood lead distribution, where the sample size was very small.

Models are adjusted for sex, age, study center, body mass index, education (<12 years/≥12 years), smoking status (never/former/current), estimated glomerular filtration rate (calculated via the Chronic Kidney Disease Epidemiology Collaboration formula), hypertension medication/treatment, and baseline systolic blood pressure. All model adjustment variables were measured at phase 3 (baseline) except for education measured at phase 4. The reference is set to the 10th percentile of the change in blood lead distribution (−0.43 μg/dL), with knots at the 50th and 90th percentiles. LV mass was measured in grams and other cardiac geometry measures were measured in cm. LV indicates left ventricular; and Pb, lead.

Discussion

This study evaluates the impact of blood lead declines over time on blood pressure and measures of LV geometry and function. It is one of the few longitudinal studies of changes in blood pressure related to declines in low levels of blood lead. Declines in blood lead in this sample of adults from the SHFS were associated with decreases in systolic blood pressure, while associations for decreases in diastolic blood pressure were not significant. The reductions in systolic blood pressure were observed with lead declines >0.1 μg/dL. Declines in blood lead were associated with nonlinear changes in measures of cardiac geometry and function, including a statistically significant decrease in interventricular septum thickness. These associations and the reductions in lead exposure observed in our population could help explain improvements in cardiovascular morbidity and death reported across the entire SHS. ³²

In this study, blood lead levels were similar in magnitude to those reported for the general US population. ³³ Across NHANES data, the geometric mean of blood lead levels declined from 2.76 μg/dL in 1988 to 1994 to 1.64 μg/dL in 1999 to 2002, ³⁴ and to 1.12 μg/dL (1.10–1.14) in 2009 to 2010. ³⁵ The decline in blood lead levels in the SHFS is likely for similar reasons as in the general US population, including bans of lead in gasoline in the 1970s, the phasing out of lead‐based paint products, and specific policy to reduce exposures to consumer products (including use of lead soldering in canned foods, which are commonly consumed in American Indian reservations) and from plumbing within the home. ³⁶ , ³⁷ , ³⁸ , ³⁹ These coordinated public health efforts and policies and their long‐term impacts are likely responsible for the substantial declines in blood lead observed for SHFS participants during the time frame of this study. Despite the decline observed in the SHFS, lead exposure remains an important concern in American Indian communities. ⁴⁰ Prior research in the SHS identified that participants in North Dakota/South Dakota have higher blood lead levels compared with Arizona and Oklahoma. ¹⁷ Persistent lead exposure has also been documented in both private and public water systems. ⁴¹ Other relevant sources of exposure include herbal supplements, spices, tobacco products, and other products, similar to other US communities. ⁴² , ⁴³ , ⁴⁴ , ⁴⁵

The current study complements available evidence on the relationships between blood lead and blood pressure reported in the general U.S. population. In NHANES‐II (1976 to 1980), blood lead (mean ~15 μg/dL) was positively associated with systolic and diastolic blood pressure in men after adjustment. ⁴⁶ , ⁴⁷ In NHANES 1999 to 2016, where mean blood lead levels were <5 μg/dL, higher blood lead levels were also associated with higher risk of hypertension. ³⁵ The findings reported here at mean blood lead concentrations of ~2 μg/dL provide important evidence of the benefits of reducing blood lead even at these lower levels. Future work should consider additionally evaluating bone lead, which reflects cumulative exposure ⁴⁸ and contributes substantially to blood lead levels, ⁴⁹ for studying long‐term reductions in blood pressure.

The present study also identified a reduction in interventricular septum thickness, which is a surrogate for LV hypertrophy as well as for heart failure with preserved ejection fraction. An increased interventricular septum thickness can indicate hypertension‐mediated target‐organ damage in the heart, and is a commonly reported outcome in clinical practice. ⁵⁰ , ⁵¹ The European Society of Cardiology/European Society of Hypertension recommends the assessment of interventricular septum thickness in patients with hypertension, as a reduction in blood pressure levels leads to a regression of interventricular septum thickness and LV hypertrophy, with a consecutive decrease in cardiovascular disease risk. ⁵² In the current analysis, the extensive reduction in systolic blood pressure could help explain the significant decrease in interventricular septum thickness; however, the decrease in interventricular septum thickness appears to be independent of blood pressure or antihypertensive medication (Figure 2). We did not observe a significant association between LV mass index and blood lead declines, and this study is likely underpowered to detect a significant association.

This study builds on prior research on metals exposure and cardiovascular disease from across the broader literature and within the SHS. Findings from the general US population using NHANES data have reported associations between increasing blood lead and subclinical myocardial injury. ⁵³ Various studies performed in occupationally exposed populations have also identified a variety of cardiovascular measures associated with blood lead, ¹⁰ including increased prevalence of LV hypertrophy, ⁵⁴ higher left ventricular mass, and lower ejection fraction. ⁵⁵ Previous findings from the SHFS identified the association of higher urinary arsenic levels with higher levels of LV wall thickness and LV hypertrophy. ⁵⁶ The current article additionally focuses on evaluating the impact of reducing blood lead levels on blood pressure levels, with potential long‐term implications for cardiovascular health. In the TACT (Trial to Assess Chelation Therapy), repeated infusions with disodium edeate, a chelating agent that primarily removes lead from the body, found a marked benefit in preventing clinical cardiovascular outcomes among participants with a prior myocardial infarction (hazard ratio [HR], 0.82 [95% CI, 0.69–0.99]), with a stronger benefit for those who also had diabetes (HR, 0.59 [95% CI, 0.44–0.79]). ⁵⁷ , ⁵⁸ , ⁵⁹ To further investigate the impact of chelation on cardiac events among patients with diabetes, TACT2 (Trial to Assess Chelation Therapy 2) is currently ongoing, and will provide more information about the effects of lead removal from bone. ⁶⁰ Blood pressure end points were not assessed in TACT; however, the potential cardiovascular benefits of lead removal from bone merits further consideration, both in populations with diabetes where managing hypertension is paramount and in the general population.

The main limitation of this analysis is the relatively small sample of SHFS participants with blood lead measured (N=285). Studies with larger sample sizes could better define the dose–response relationship between declines in blood lead and blood pressure across the entire SHFS, in particular by evaluating associations across subgroups by study center, sex, age groups, diabetes status, glycemic control, and other characteristics. Previous studies have also reported nonsignificant associations between declines in blood lead and diastolic blood pressure; larger sample sizes are likely needed to detect a statistically significant association. ¹⁰ , ⁶¹ , ⁶² , ⁶³ In the SHFS, declines in blood lead and changes in blood pressure over time could be related to differences in access to health care, which is not well captured in SHFS data. Changes in blood lead and blood pressures were both weakly correlated with their initial values, which could affect the model between blood lead and blood pressure changes, although this would be better evaluated with larger sample sizes. Further, there are many factors that influence the distribution of lead in the body ⁶⁴ that could not be captured with available SHFS data but could partially explain observed declines in blood lead over time, including calcium deficiency, pregnancy, and menopause. It is also possible that participants who initiated hypertensive treatment after the baseline visit experienced larger declines in blood pressure over time. In this analysis, there were 135 participants with hypertension treatment (47.4%) at visit 5. However, our main models of interest adjusted for both baseline blood pressure and baseline hypertensive medication use, and we also observed consistent but nonsignificant associations between declines in blood lead and blood pressure in sensitivity analyses restricted to participants free from hypertension at baseline.

Conclusions

In a sample of SHFS participants, declines in blood lead levels occurring between 1997 to 1999 and 2006 to 2009 were associated with marked reductions in systolic blood pressure levels and decreases in interventricular septum thickness. These results were obtained at a time when lead exposure was already relatively low in the SHFS and are consistent with other US populations. Together, these findings further highlight the important cardiovascular benefits of further reducing lead exposure, the importance of assessing clinical interventions and secondary prevention measures, and the critical need for further assessing this relationship in other subgroups of the US population with higher blood lead levels.

Sources of Funding

Drs Navas‐Acien and Nigra are supported by R01ES021367, R01ES025216, P42ES033719, and P30ES009089. Wil Lieberman‐Cribbin was supported by 5T32ES007322. This study was supported by cooperative agreement grants U01‐HL41642, U01‐HL41652, U01‐HL41654, U01‐HL65520, and U01‐HL65521, and research grants R01‐HL109315, R01HL109301, R01HL109284, R01HL109282, and R01HL109319 from the National Heart, Lung, and Blood Institute, Bethesda, Maryland. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention/Agency for Toxic Substances and Disease Registry.

Disclosures

None.

Supporting information

Tables S1–S5

Figures S1–S9

JAH3-13-e031256-s001.pdf^{(1.1MB, pdf)}

This manuscript was sent to Tochukwu M. Okwuosa, DO, Associate Editor, for review by expert referees, editorial decision, and final disposition.

Supplemental Material is available at https://www.ahajournals.org/doi/suppl/10.1161/JAHA.123.031256

For Sources of Funding and Disclosures, see page 10.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Tables S1–S5

Figures S1–S9

JAH3-13-e031256-s001.pdf^{(1.1MB, pdf)}

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PERMALINK

The Contribution of Declines in Blood Lead Levels to Reductions in Blood Pressure Levels: Longitudinal Evidence in the Strong Heart Family Study

Wil Lieberman‐Cribbin, MPH

Zheng Li, PhD

Michael Lewin, MS

Patricia Ruiz, PhD

Jeffery M Jarrett, MS

Shelley A Cole, PhD

Allison Kupsco, PhD

Marcia O'Leary, RN

Gernot Pichler, MD, PhD

Daichi Shimbo, MD

Richard B Devereux, MD

Jason G Umans, MD, PhD

Ana Navas‐Acien, MD, PhD

Anne E Nigra, ScM, PhD

Abstract

Background

Methods and Results

Conclusions

Nonstandard Abbreviations and Acronyms

Clinical Perspective.

What Is New?

What Are the Clinical Implications?

Methods

Study Population

Blood Lead Measurements

Blood Pressure Measures

Echocardiographic Measures of Cardiac Geometry and Functioning

Other Variables

Statistical Analysis

Results

Table 1.

Table 2.

Figure 1. Restricted cubic spline models of the mean difference in the change in systolic and diastolic blood pressure (mm Hg) from phase 4 (2001–2003) to phase 5 (2006–2009) by declines in blood lead from phase 3 (1997–1999) to phase 5 (2006–2009) (N=278).

Figure 2. Restricted cubic spline models of the mean difference in the change in cardiac geometry measures from phase 4 (2001–2003) to phase 5 (2006–2009) by declines in blood lead from phase 3 (1997–1999) to phase 5 (2006–2009) (N=278).

Figure 3. Restricted cubic spline models of the mean difference in the change in cardiac function measures from phase 4 (2001–2003) to phase 5 (2006–2009) by declines in blood lead from phase 3 (1997–1999) to phase 5 (2006–2009) (N=278).

Discussion

Conclusions

Sources of Funding

Disclosures

Supporting information

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

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