Association between cumulative blood pressure in early adulthood and right ventricular structure and function in middle age: The CARDIA study

Abstract Objective Cumulative blood pressure (BP) exposure is a known risk factor for cardiovascular disease. This study sought to investigate the association between cumulative BP from early adulthood to middle age and right ventricular (RV) structure and function in middle age. Methods We included 2844 participants from the CARDIA study (Coronary Artery Risk Development in Young Adults). Cumulative BP over the 30‐years follow‐up was defined as the sum of the product of mean BP for each pair of consecutive examinations and the time interval between these two consecutive examinations in years. RV structure and function were assessed by echocardiography. The main analyses utilized logistic and linear regression models. Results In fully adjusted models, higher cumulative systolic BP was independently associated with lower tricuspid annular plane systolic excursion (TAPSE), right ventricular peak systolic velocity (RVS′), right ventricular early diastolic velocity (RVe′), and higher pulmonary arterial systolic pressure. Higher cumulative diastolic BP was independently associated with smaller RV basal diameter, lower TAPSE, RVS′, and RVe′. For categorical analyses of RV dysfunction, cumulative systolic BP was not related to systolic dysfunction. Per 1‐SD increase in cumulative systolic BP was associated with a higher risk of diastolic dysfunction, while an increase in cumulative diastolic BP was associated with a higher risk of systolic dysfunction and diastolic dysfunction. Conclusions Cumulative exposure to increased BP from early adulthood to middle age was associated with incipient RV systolic and diastolic dysfunction in middle age. Exposure to higher diastolic BP levels from early adulthood to middle age was associated with a smaller RV basal diameter in middle age.


| INTRODUCTION
High blood pressure (BP) is a known risk factor for cardiovascular disease (CVD). 1,2 To date, CVD risk prediction algorithms have predominantly focused on BP at a single time measurement, and do not consider the potential effect of long-term BP exposure. 3,4 Cumulative BP exposure, a measure which incorporates both BP level and exposure time, has provided incremental prognostic value and improvement in CVD risk classification. 5,6 In recent years, with the advent of reliable and reproducible echocardiographic measures of RV function, right ventricular dysfunction is being increasingly recognized in hypertension 7,8 and found to be an independent predictor of adverse cardiovascular outcome. 9,10 Previous studies suggested that subclinical RV dysfunction may be observed early in the course of arterial hypertension. [11][12][13][14] However, these studies have been limited by either their small sample size or cross-sectional nature. The association of cumulative BP exposure from early adulthood onwards with RV structure and function in later life has not been studied.
Using longitudinal data from the Coronary Artery Risk Development in Young Adults (CARDIA) study, we aimed to evaluate the association of cumulative BP exposure starting during early adulthood (ages 18-30 years) with several echocardiographic indices of RV myocardial structure and function in later life.

| Study population
The CARDIA study is a longitudinal cohort that was designed to study determinants of subclinical and overt CVD in 5115 black and white young adults initially aged 18-30 years in 1985-1986 across four cities (Birmingham, AL; Chicago, IL; Minneapolis, MN; and Oakland, CA). Detailed descriptions of the design, recruitment, and protocol for examinations have been described previously. 15   RV systolic and diastolic dysfunctions as follows: RVS' < 9.5 cm/s or TAPSE < 17 mm/s and RVe′ < 7.8 cm/s. 16

| COVARIATES
Standardized protocols were used for the collection of height, weight, glucose levels, lipid levels, lung function, and education level at each visit. Demographic characteristics, smoking status, and physical activity levels were self-reported. Body mass index (BMI) was calculated as weight (kg) divided by height in meters squared. Lung function measurements included FVC (forced vital capacity) and FEV1 (forced expiratory volume in one second).

| STATISTICAL ANALYSIS
Normally distributed continuous variables were presented as mean (SD), while non-normal data were presented as the median and interquartile range. Categorical variables were presented as counts (percentages). Differences between groups were tested by the χ 2 test for categorical data, and the independent Student t test and Mann-Whitney U were used for normally and nonnormally distributed continuous variables, respectively. Multivariable linear regression models were used to assess the association between cumulative BP over 30 years and echocardiographic parameters For categorical analyses of clinically significant RV dysfunction, binary logistic regression models were performed to estimate the association between cumulative BP over 30 years and clinically relevant RV dysfunction at Year 30. In multivariate logistic regressions, we adjusted for similar covariates, reporting odds ratios (ORs) and 95% confidence intervals (CIs). Potential effect modification by race and sex was assessed.
All analyses were performed using R 3.6.2 software and a p < .05 was considered as statistically significant.

| RESULTS
Overall, the study cohort included a total of 2844 participants (mean age: 55.1 ± 3.6 years, 56.8% female, 53.1% White). Table 1 presents the characteristics of the study participants by grouped by sex. Mean values for conventional echocardiographic parameters were within the normal range in mid-age (43-55 years). Females were more likely to have higher BMI, LDL-cholesterol, and HDL-cholesterol and lower systolic blood pressure (SBP), diastolic blood pressure (DBP), cumulative SBP, cumulative DBP, physical activity, FVC, and FEV1. A higher portion of males were current smokers. Table 2 shows the results for linear regression models examining the association between cumulative BP exposure and echocardiographic RV parameters. In the fully adjusted model, higher cumulative systolic BP was independently associated with lower TAPSE (β = −.21, Results from the binary logistic regression models to examine the association between cumulative BP exposure and RV dysfunction are summarized in Table 3

| DISCUSSION
In this large population-based study of generally healthy young adults followed over 30 years, several important findings were observed. First, higher cumulative BP exposure from early adulthood was associated with RV dysfunction in middle age. Second, cumulative diastolic BP was more strongly associated with worse RV function parameters compared with cumulative systolic BP. A recent paper from CARDIA study reports longitudinal associations of fitness and obesity with RV function, showing that obesity and decline of physical activity were associated with RV dysfunction. 17 In our study, after adjusting for obesity and physical activity in the multivariable regression models, cumulative BP is still associated with RV dysfunction, suggesting an independent association beyond obesity and physical activity. Studies investigating the associations between cumulative BP and RV structure have shown inconsistent results. Tadic et al. 18 found that there was no difference in RV basal diameter between controls and untreated hypertensive patients with a mean age of 50 years old. However, Akintude et al. 12 found that RV end-diastolic dimensions were lower in hypertensive subjects (age, 57.5 ± 13.33 years) compared with controls (age, 55.9 ± 11.33 years). 12 In another large study from the Multi-Ethnic Study of Atherosclerosis, higher BP was associated with smaller RV volumes and lower RV mass in an adult sample without clinical evaluated the RV functional capacity by 2D conventional echocardiography, speckle tracking, and 3D analysis. They found that RV systolic and diastolic strain rates were reduced in hypertensive participants, whereas 3D EF was decreased in patients with uncontrolled hypertension. In our study, we used M-mode derived TAPSE and tissue Doppler-derived RVS′ to assess RV systolic function and tissue Doppler-derived RVe′ to assess RV diastolic function and found that both cumulative systolic and diastolic BP, even at levels below the hypertension threshold, was associated with RV systolic and diastolic dysfunction in middle age. Furthermore, we observed that both cumulative systolic and diastolic BP were associated with higher PASP on follow-up. Previous studies reported increased PASP in some patients with early-stage hypertension, with normal LV filling pressure. 26,27 This suggests that the activation of common signal pathways may contribute to an increase in both systemic BP and PASP. 27 To the best of our knowledge, the current study represents the first report on the effect of cumulative BP on RV function. We also found T A B L E 2 Relationship of cumulative exposure to BP over 30 years to RV functional parameters

| CONCLUSION
Cumulative exposure to higher systolic and diastolic BP over 30 years from early adulthood to middle age is associated with incipient RV systolic and diastolic dysfunction in middle age. Exposure to higher diastolic BP levels from young adulthood to midlife is associated with a smaller RV basal diameter in midlife.