Response by Aparicio et al to Letter Regarding Article, "Temporal Trends in Ischemic Stroke Incidence in Younger Adults in the Framingham Study".

In Response: We thank Fuller-Thomson et al for their letter in response to our article Temporal Trends in Ischemic Stroke Incidence in Younger Adults in the Framingham Study. They describe their hypothesis that declining environmental lead exposure over time may contribute to declines in stroke incidence, possibly mediated by the association of lead with atherosclerosis and hypertension. Indeed, chronic exposure to heavy metals, including lead and cadmium, have been related to cardiovascular disease, cardiovascular mortality, and cognitive dysfunction. Data from population studies relating lead exposure to ischemic stroke is sparse. As Fuller-Thomson and colleagues mention, cumulative lead dose is best measured in bone samples, while lead concentration in whole blood has been the primary method used to monitor short-term exposure. Hair lead was measured in 1322 Framingham Original and Offspring Cohort participants, age ≥35 years, at Examination Cycles 20 to 21 and 4, respectively (years 1987–1992). We observed that median lead levels decreased with age group (age, 35–44 years, n=174, median, 4.46 μg/g; age, 45–54 years, n=299, median, 3.83 μg/g; age, 55–64 years, n=291, median, 3.80 μg/g; age, 65–74 years, n=315, median, 3.60 μg/g; age, ≥75 years, n=243, median, 3.19 μg/g). Median lead levels also differed by cohort (original, n=422, median 3.49 μg/g; offspring, n=900, median 3.82 μg/g). In ageand sex-adjusted regression models, there was no significant difference in log-transformed lead levels among age groups but there was a significant difference by cohort (P=0.012), with higher lead levels in the Offspring cohort. In exploratory analyses, we investigated the association of hair lead with stroke incidence in up to 10 years of follow-up. Lead levels were log-transformed and we used Cox regression models, adjusting for age and sex. There were 116 incident strokes in 10-year follow up. We did not observe an association between hair lead and incident stroke (hazard ratio, 1.06; P>0.10), and there was no interaction between cohort and hair lead in their effects on incident stroke. Limitations of using hair lead include the possibility of exogenous contamination (eg, lead in hair dye) despite the use of hair washing methods and the lack of a standardized reference range for normal levels. Of note, childhood lead exposure in the Original cohort would have been in the 1920s and in the Offspring cohort in the 1950s and 1960s, well before the phase-out of leaded gasoline in the 1970s. The hypothesis that hypertension mediates the observed association between lead and ischemic stroke risk is intriguing, and temporal trends toward lower blood pressure parallel observed decreases in stroke incidence. Pirkle et al used data from the second National Health and Nutrition Examination Survey (1976–1980) and found that blood lead levels are significantly related to blood pressure. However, the 37% decline in mean blood lead levels during the study period only predicted a 6.7% decrease in incident fatal and nonfatal strokes over 10 years, even assuming a direct causal relationship between lead and blood pressure. We observed a >50% decline in the risk of incident ischemic stroke in older adults over the 5 decades examined in our study. Unsurprisingly, other factors have likely contributed to the decline, including hypertension control with medications, statins, public health campaigns to reduce blood pressure and encourage smoking cessation, and reduced salt intake in recent years.