Prehypertension during Young Adulthood and Coronary Calcium Later in Life

Context The long-term effects of prehypertension in young adults are not well defined. Contribution These investigators found that young adults with systolic prehypertension were more likely than those without prehypertension to have coronary artery calcium. Caution Not all patients with coronary artery calcium develop clinically significant cardiovascular disease. Implication Prehypertension in young adulthood is associated with coronary artery calcium in middle age. The Editors High blood pressure in middle-age and older populations is a strong risk factor for cardiovascular disease (1). Among adults age 40 years or older, each 20mm Hg increase in systolic blood pressure is associated with an approximate doubling in the short-term risk (within 5 years) of a cardiovascular disease event (2, 3). Clinical trials show that lowering blood pressure with antihypertensive medications reduces this short-term risk (4), but damage from blood pressure elevation seems to accumulate over time, such that damage from past exposure may not be completely reversible with treatment later in life. Cohort studies in elderly persons show that blood pressure elevation even 20 to 30 years in the past is associated with cardiovascular events (5, 6) and atherosclerosis (7) independent of current blood pressure. Less is known about the effects of blood pressure elevation during young adulthood. Although hypertension (systolic blood pressure >140 mm Hg or diastolic blood pressure >90 mm Hg) is rare before age 40 years, prehypertension (systolic blood pressure of 120 to 139 mm Hg, or diastolic blood pressure of 80 to 89 mm Hg [1]) is more common (8, 9). Current guidelines recommend lifestyle modification without pharmacotherapy for persons with prehypertension to reduce the risk for hypertension (1, 10), but whether prehypertension during young adulthood may itself cause vascular damage that persists later in life is unclear. In practice, suboptimal blood pressure that remains below 140/90 mm Hg are often ignored in young adults (8). The CARDIA (Coronary Artery Risk Development in Young Adults) Study provides a unique opportunity to evaluate the consequences of prehypertension during young adulthood. Using CARDIA's repeated measures of blood pressure starting at the outset of adulthood and continuing over 20 years of follow-up, we identified participants exposed to prehypertension between age 20 and 35 years, estimated cumulative exposure in mm Hgyears (similar to pack-years of tobacco exposure), and observed associations with coronary calcium levels measured later in life. Methods Study Design and Sample Population The CARDIA Study is a longitudinal cohort of 5115 black and white women and men recruited in 1985 from 4 U.S. cities. The participants were 18 to 30 years old and healthy at enrollment (11, 12). The participants underwent a baseline examination and follow-up examinations at years 2, 5, 7, 10, 15, and 20. For our investigation, we identified all CARDIA participants who had cardiac computed tomography for coronary calcium in either the 15-year or 20-year follow-up examination and excluded participants who developed hypertension (systolic blood pressure 140 mm Hg, diastolic blood pressure 90 mm Hg, or taking a blood pressure medication) before the age of 35 years. Blood Pressure At each CARDIA examination, research staff measured right-arm blood pressure 3 times after the participant had been sitting in a quiet room for 5 minutes. We used the average of the second and third readings. Members of the CARDIA research staff took measurements by using a Hawksley random-zero sphygmomanometer (Hawksley, Sussex, United Kingdom) until the last examination at year 20, when concerns about mercury contained in the apparatus required a switch to the OmROn HEM907XL sphygmomanometer (Omron Corporation, Kyoto, Japan). Dual measurement on a subgroup of participants was used to calibrate the new measurements and assure comparability. Estimating Systolic Blood Pressure Trajectories and Cumulative Exposure We used mixed models to estimate a blood pressure trajectory (systolic and diastolic) for each participant from age 20 years up to the time of his or her coronary calcium measurement. We assumed that the trajectory for each participant had a constant slope within each decade of life (age 20 to 30 years, 30 to 40 years, and 40 to 50 years), so we allowed each participant a different random intercept and 3 random slopes, modeled as deviations from race- and sex-specific mean trajectories. (See the Appendix for details.) Using these individual blood pressure trajectories, we then calculated an integrated, cumulative measure of years of exposure to blood pressure elevation for each participant, measured in mm Hgyears, by calculating the area under the trajectory for each participant in the blood pressure range of interest. We considered the area under the blood pressure trajectory before the age of 35 years and in the prehypertension range (systolic blood pressure of 120 to 139 mm Hg, or diastolic blood pressure of 80 to 89 mm Hg) to be the primary predictor for this analysis and referred to this measurement as the cumulative exposure to prehypertension during young adulthood. We used the area under the blood pressure trajectory after age 35 years as a covariate in the multivariable analysis. Coronary Calcium Consenting CARDIA participants had cardiac computed tomography, with an electron-beam or multidetector electrocardiographically gated cardiac computed tomography scanner, at year 15 and year 20 to measure coronary calcium level, which represents calcified plaque in the coronary arteries (13, 14). Technicians obtained 2 sequential coronary calcium scans by using a standard phantom with known concentrations of calcium hydroxyapatite for calibration and performed imaging by using prospective gating in late diastole, a slice thickness of 2.5 to 3.0 mm, a reconstruction into a 35-cm field of view, and a temporal resolution of 100 to 520 ms (year 15 examination) and 100 to 250 ms (year 20 examination). Experienced image analysts who were blinded to participant information and the paired scan identified calcified plaque in the epicardial coronary arteries and calculated a total coronary calcium score by using a modified Agatston method to account for slice thickness (15), a minimum lesion size of 4 adjacent pixels (an area 1.87 mm2), and a density greater than 130 Hounsfield units. An expert physician in cardiovascular imaging reviewed all scans that were discordant (1 with and 1 without coronary calcium), had a score greater than 200, had a change in calcium status between year 15 and year 20, had a possible surgical intervention (pacemaker, valve replacement, coronary stent, or bypass surgery), or had a concern identified by the reviewer. Other articles describe the accuracy, comparability, reproducibility, and robustness of calcium score measurement by using these methods (16, 17). For this analysis, we used the last nonmissing coronary calcium measurement (that is, the scan from year 20 if available; otherwise, the scan from year 15). Other Measurements Research staff obtained information on sex, race (black or white), date of birth, serum cotinine levels, and family history of premature coronary heart disease (defined by a mother or father with myocardial infarction before age 60 years) at baseline. We used levels of fasting plasma glucose (and diabetes status), low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol, and triglycerides, as well as smoking habits, from all CARDIA examinations. We took other covariates, including educational grade attained and income (self-reported), body mass index and waist circumference (directly measured), and physical activity (self-reported on a scale of 1 to 5) from the time of the coronary calcium scan (18). We estimated the cumulative exposure to LDL and HDL cholesterol, triglycerides, and fasting glucose (without partition by age or level) by the same method used for blood pressure. Statistical Analysis We described persons with and without prehypertension (systolic or diastolic) before age 35 years and compared characteristics by using t tests (for continuous variables) and chi-square tests (for dichotomous variables). To estimate independent cross-sectional associations of various demographic factors with prehypertension before age 35 years, we constructed a multivariable logistic regression model, regressing prehypertension before age 35 years on age, sex, and all incomeeducation combinations (3 education and 4 income categories for a total of 12 combined incomeeducation categories). Cumulative blood pressure exposure variables, including the primary predictor, were right-skewed with most participants having zero exposure, and the relationships between these continuous cumulative exposure measures and coronary calcium prevalence were closer to linear after log transformation of the cumulative exposure measure (adding 1 mm Hgyear before the log-transformation). Therefore, we presented our main adjusted results by using these log-transformed cumulative exposure measures as continuous predictors. Results are also presented by using categorized cumulative exposure measures. We calculated trends across categories and trend interactions by using adjusted Wald tests of linear combinations of regression coefficients. We used logistic regression to analyze the association between blood pressure elevation and the presence or absence of coronary calcium. We first analyzed the association of coronary calcium with categories of systolic and diastolic prehypertension, with simple adjustment or stratification for age, sex, race, and current blood pressure. We then fit models for our primary predictor (cumulative exposure to prehypertension before age 35 years), adjusting for a priorispecified potential confounders modeled flexibly with spline knots where suggested by linearity plots. These includ