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. Author manuscript; available in PMC: 2022 Oct 25.
Published in final edited form as: Eur J Prev Cardiol. 2021 Oct 25;28(13):1445–1451. doi: 10.1177/2047487320915342

Long-term cumulative blood pressure in young adults and incident heart failure, coronary heart disease, stroke, and cardiovascular disease: The CARDIA study

Chike C Nwabuo 1, Duke Appiah 2, Henrique T Moreira 1, Henrique D Vasconcellos 1, Yuichiro Yano 3, Jared P Reis 4, Ravi V Shah 5, Venkatesh L Murthy 6, Norrina B Allen 7, Stephen Sidney 8, Paul Muntner 9, Cora E Lewis 9, Donald M Lloyd-Jones 7, Pamela J Schreiner 10, Samuel S Gidding 11, João AC Lima 1,*
PMCID: PMC8653578  NIHMSID: NIHMS1756394  PMID: 34695218

Abstract

Aims

Cumulative blood pressure (BP) is a measure that incorporates the severity and duration of BP exposure. The prognostic significance of cumulative BP in young adults for cardiovascular diseases (CVDs) in comparison to BP severity alone is, however, unclear.

Methods and results

We investigated 3667 Coronary Artery Risk Development in Young Adults participants who attended six visits over 15 years (year-0 (1985–1986), year-2, year-5, year-7, year-l0, and year-15 exams). Cumulative BP was calculated as the area under the curve (mmHg × years) from year 0 through year 15. Cox models assessed the association between cumulative BP (year 0 through year 15), current BP (year 15), and BP change (year 0 and year 15) and CVD outcomes. Mean (standard deviation) age at year 15 was 40.2 (3.6) years, 44.1% were men, and 44.1% were African-American. Over a median follow-up of 16 years, there were 47 heart failure (HF), 103 coronary heart disease (CHD), 71 stroke, and 191 CVD events. Cumulative systolic BP (SBP) was associated with HF (hazard ratio (HR) = 2.14 (1.58–2.90)), CHD (HR = 1.49 (1.19–1.87)), stroke (HR = 1.81 (1.38–2.37)), and CVD (HR = 1.73 (1.47–2.05)). For CVD, the C-statistic for SBP (year 15) was 0.69 (0.65–0.73) and change in C-statistic with the inclusion of SBP change and cumulative SBP was 0.60 (0.56–0.65) and 0.72 (0.69–0.76), respectively. For CVD, using year-15 SBP as a reference, the net reclassification index (NRI) for cumulative SBP was 0.40 (p < 0.0001) and the NRI for SBP change was 0.22 (p = 0.001).

Conclusions

Cumulative BP in young adults was associated with the subsequent risk of HF, CHD, stroke, and CVD. Cumulative BP provided incremental prognostic value and improved risk reclassification for CVD, when compared to single BP assessments or changes in BP.

Keywords: Hypertension, cardiovascular disease, heart failure, stroke, coronary heart disease

Introduction

High blood pressure (BP) is a leading cause of morbidity and mortality worldwide. Based on the prevailing definition of hypertension (systolic BP ≥130 mmHg or diastolic BP ≥80 mmHg), one out of four adults aged 20 to 44 years in the US already have high BP and the cumulative lifetime risk for hypertension exceeds 75%.1,2

Higher BP levels at the time of risk assessment are associated with an increased risk of cardiovascular disease (CVD).1,3–6 However, rather than being a fixed exposure that remains unchanged after a single assessment, BP is a dynamic risk factor that changes over time. Beyond temporal changes in the severity of BP, the duration of hypertension also plays a contributory role.7 Recent evidence underscores ongoing difficulty in achieving guideline-directed BP targets,8 likely resulting in greater long-term exposure to high BP levels.

In this context, cumulative BP has emerged as a marker of interest that allows an integrated assessment of long-term severity and duration of BP exposure. Cumulative BP is derived from the area under the curve (mmHg × years) from multiple BP assessments over time. In prior studies of middle-aged to elder participants, cumulative BP was a strong predictor of CVD events.9,10 However, whether cumulative BP in young adults is associated with the risk of clinical outcomes is uncertain. It is also unclear whether cumulative BP has any incremental predictive value for CVD over the assessment of single time-point or temporal changes in BP, more so in young adulthood – a crucial time period for BP-lowering strategies that may forestall the development of CVD in later life.11 We, therefore, investigated the association between cumulative BP in young adults and the subsequent risk of heart failure (HF), stroke, coronary heart disease (CHD), and CVD, and made comparisons with BP at a single time-point and longitudinal changes in BP.

Methods

Study design and participant selection

The Coronary Artery Risk Development in Young Adults (CARDIA) study design and participant selection has been previously reported.12 In brief, CARDIA is a biracial prospective cohort study that enlisted 5115 White and African-American men and women from four field sites located in Birmingham, Alabama; Oakland, California; Chicago, Illinois; and Minneapolis, Minnesota. Participants in the overall cohort were aged 18 to 30 years at the year-0 exam (1985–1986) and were subsequently followed up in eight examination cycles over three decades. Follow-up examinations were conducted at 2, 5, 7, 10, 15, 20, 25, and 30 years after baseline, with response rates of 91%, 86%, 81%, 79%, 74%, 72%, 72%, and 71% of the surviving cohort, respectively. The analytic sample for the present study included 3667 African-American and White participants of both sexes who had BP readings available across six visits from year 0 to year 15 (year 0, year 2, year 5, year 7, year 10, and year 15) and who had no CVD outcomes prior to year 15. In compliance with the Declaration of Helsinki, all study participants gave written informed consent and the study’s protocol was approved by the institutional review board of each participating institution.

BP assessment

BP was assessed using standardized protocols across all study visits in the analytic sample. BP was recorded in a quiet room after subjects had been seated for five minutes. Trained staff obtained three readings from the brachial artery at one-minute intervals using a random-zero sphygmomanometer. Cumulative BP from year-0 to year-15 visits was derived by calculating the means of BP values from each pair of consecutive examinations and multiplying each mean value by the number of years between the consecutive visits.9,13 The unit of cumulative BP was expressed as mmHg-years. BP components assessed included systolic BP, diastolic BP, and pulse pressure (PP). We selected a 15-year interval from year 0 to year 15 to provide data for the early adult life span.9

Covariate assessment

Covariates included in the present analysis were obtained from standardized questionnaires, clinical, and laboratory data that have been previously described.14,15 In summary, participants were instructed to fast before each study visit and to avoid smoking or engaging in heavy physical activity for at least two hours prior to exam. Weight and height were measured following a standardized protocol. A physical activity score (exercise units) derived from a modified version of the Minnesota leisure time physical activity questionnaire was utilized to capture moderate to vigorous physical activity. The details of the laboratory assessment of plasma total cholesterol, high-density lipoprotein cholesterol, triglycerides, fasting (≥8 hours) glucose have been reported.16 Plasma cholesterol was obtained using enzymatic assays by Northwest Lipids Research Laboratory (Seattle, Washington).

Clinical outcomes

Trained research staff collected information on hospitalization and outpatient medical procedures with standardized questionnaires administered during exams and semi-annual contacts. During their scheduled study examinations and yearly telephone interviews, each participant or their designated proxy was asked about interim hospital admissions, outpatient procedures, and deaths. Medical records were requested for each participant that had been hospitalized or received an outpatient revascularization procedure. Two physician members of the CARDIA Endpoints Committee independently reviewed medical records to adjudicate each possible CVD event. If disagreement occurred between the primary reviewers, the case was further reviewed by a full committee. HF diagnosis required both a final diagnosis of HF by a physician, and medical treatment for HF during hospitalization (use of a diuretic and either digitalis or an afterload reducer such as nitroglycerin, hydralazine, angiotensin-converting enzyme inhibitor, or angiotensin receptor blocker). CHD included hospitalization for myocardial infarction, acute coronary syndrome with or without evidence of myocardial necrosis, coronary artery revascularization, or CHD death. CVD included CHD, and hospitalization for HF, stroke, or peripheral artery disease. Participants were followed up until August 2017.

Statistical analysis

Population characteristics were presented as mean ± standard deviation (SD) for continuous variables and frequencies and proportions for categorical variables. The Kaplan–Meier method was used to illustrate the cumulative incidence of CVD among participants by tertile of cumulative systolic and diastolic BP. Cox models assessed the association between cumulative BP (year 0 through year 15), current BP (year 15), and BP change (year 0 and year 15) measures as explanatory variables and HF, CHD, stroke, and CVD. To account for possible confounding, Cox models were adjusted for age, sex, race, education, body mass index, BP medication use (year 0 to year 15), smoking, high-density lipoprotein cholesterol, total cholesterol, physical activity, and fasting glucose. Interactions by race and by sex were tested. The C-statistic, net reclassification index (NRI), and integrated discrimination improvement (IDI) were assessed. All analyses were performed using STATA version 15.1, and a two-tailed p-value of <0.05 was considered significant.

Results

Population characteristics

Mean (SD) age at the year-15 exam was 40.2 (3.6) years, 44.2% of participants were men, and 47.1% were African-American (Table 1). There was a mean decrease in PP from year 0 (41.7± 9.6 mmHg) to year 15 (38.7± 9.65 mmHg). The distributions of cumulative systolic and diastolic BP in the analytical sample are illustrated in Figure 1. Cumulative systolic BP ranged from 1272.5 to 2639 mmHg-years, while cumulative diastolic BP ranged from 708 to 1668 mmHg-years. Persons in the highest tertile of cumulative systolic BP were more likely to be men, African-Americans, current smokers, and have a higher body mass index.

Table 1.

Population characteristics at the CARDIA year-15 exam, by tertile of cumulative systolic blood pressure.

Characteristics Tertile of cumulative systolic blood pressure
 p-value
Low
1273–1568
(n = 1227)		 Intermediate
1569–1692
(n = 1221)		 High
1693–2639
(n = 1219)
Age, years 40.1 ± 3.7 40.1 ± 3.6 40.3 ± 3.6   0.35
Men, n (%) 259 (21.1) 568 (46.5) 792 (65) <0.001
African-American, n (%) 417 (34) 586 (48) 724 (59.4) <0.001
SBP, mmHg 101.6 ± 7.6 111.9 ± 8.8 126.3 ± 15 <0.001
DBP, mmHg 67.5 ± 8.1 73.7 ± 8.9 82.3 ± 12.2 <0.001
PP, mmHg 34.1 ± 6.9 38.2 ± 7.7 44.0 ± 11.2 <0.001
Years of education 15.4 ± 2.5 15.0 ± 2.5 14.3 ± 2.5 <0.001
Body mass index, kg/m2 26.5 ± 5.9 28.8 ± 6.3 31.0 ± 7.4 <0.001
Total cholesterol, mg/dL 180.9 ± 33 184.3 ± 35.9 188.8 ± 37.8 <0.001
HDL cholesterol, mg/dL 54.1 ± 14.2 50.6 ± 14.5 47.4 ± 14.2 <0.001
Current smoker, n (%) 221 (18) 250 (20.5) 334 (27.5) <0.001
BP medication, n (%) 9 (0.7) 51 (4.2) 230 (18.9) <0.001
Diabetes mellitus, n (%) 63 (5.1) 51 (4.2) 96 (7.9)   0.001
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BP: blood pressure; SBP: systolic BP; DBP: diastolic BP; HDL: high-density lipoprotein; CVD: cardiovascular disease; kg/m2; kilogram per meters squared; mg: milligram; dL: deciliters.

Cumulative systolic blood pressure is reported in mmHg-years. Population characteristics are presented as mean ± standard deviation for continuous variables, and frequencies and proportions for categorical variables. P-value represents multiple-comparison tests for between-group differences.

Figure 1.

Figure 1

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Histogram showing the distribution of cumulative systolic and diastolic blood pressure in the analytical sample.

Cumulative BP and clinical outcomes

Over a median follow-up of 16 years, there were 47 HF, 103 CHD, 71 stroke, and 191 CVD events. As shown in Figure 2, the cumulative incidence of CVD was highest in participants in the highest tertile of cumulative systolic or diastolic BP. Table 2 shows the association between cumulative BP measures and clinical outcomes. In adjusted Cox models (per 1-SD), cumulative systolic BP was positively associated with HF (hazard ratio (HR) = 2.14 (1.58–2.90)), CHD (HR = 1.49 (1.19–1.87)), stroke (HR = 1.81 (1.38–2.37)), and CVD (HR = 1.73 (1.47–2.05)). Current systolic BP (year 15), systolic BP change, and cumulative diastolic BP were positively related to clinical outcomes, albeit with lower magnitudes of association when compared to cumulative systolic BP. There were no sex or race differences observed in the association of cumulative BP measures and outcomes (p for interaction >0.05).

Figure 2.

Figure 2

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Cumulative incidence of CVD among participants by tertile of cumulative systolic and diastolic BP. The cumulative probability of CVD events by tertile of cumulative BP was calculated using the Kaplan–Meier method. The log-rank test was used to calculate the p-value (<0.001).

Table 2.

Blood pressure measures and the risk of clinical outcomes.

HF
HR (95% CI)		 CHD
HR (95% CI)		 Stroke
HR (95% CI)		 CVD
HR (95% CI)
Systolic BP measures
 Year-15 systolic BP 1.68 (1.35–2.09) 1.35 (1.13–1.62) 1.69 (1.37–2.07) 1.56 (1.36–1.78)
 Systolic BP change 1.49 (1.21–1.84) 1.14 (0.95–1.36) 1.62 (1.34–1.96) 1.38 (1.21–1.57)
 Cumulative systolic BP 2.14 (1.58–2.90) 1.49 (1.19–1.87) 1.81 (1.38–2.37) 1.73 (1.47–2.05)
Diastolic BP measures
 Year-15 diastolic BP 1.55 (1.21–1.98) 1.23 (1.00–1.51) 1.58 (1.30–1.93) 1.43 (1.25–1.65)
 Diastolic BP change 1.40 (1.06–1.84) 1.11 (0.91–1.37) 1.61 (1.30–1.99) 1.35 (1.16–1.57)
 Cumulative diastolic BP 1.76 (1.23–2.52) 1.29 (1.01–1.64) 1.72 (1.30–2.28) 1.49 (1.25–1.78)
Pulse pressure measures
 Year-15 pulse pressure 1.51 (1.19–1.92) 1.23 (1.04–1.46) 1.24 (1.01–1.52) 1.28 (1.12–1.45)
 Pulse pressure change 1.45 (1.11–1.90) 1.07 (0.89–1.30) 1.22 (0.97–1.53) 1.15 (1.00–1.33)
 Cumulative pulse pressure 1.65 (1.26–2.15) 1.28 (1.05–1.56) 1.24 (0.98–1.57) 1.36 (1.18–1.56)
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HR: hazard ratio; CI: confidence interval.

Cox models assessing the association between systolic blood pressure (BP), diastolic BP, and pulse pressure measures for heart failure (HF), coronary heart disease (CHD), stroke, and cardiovascular disease (CVD).

Estimated relative hazards are per 1 standard deviation increment at time of risk assessment (year 15).

Models were adjusted for age, sex, race, education, body mass index, BP medication use (year 0 to year 15), smoking status, high-density lipoprotein cholesterol, total cholesterol, physical activity, and fasting plasma glucose.

Predictive and discriminatory model performance

Table 3 shows the discriminatory model performance for BP measures and CVD risk. For CVD, the C-statistic for year-15 systolic BP was 0.69 (0.65–0.73) and the inclusion of cumulative systolic BP resulted in a significant increase in C-statistic to 0.72 (0.69–0.76). In contrast, the inclusion of systolic BP change to year-15 systolic BP models did not result in a significant improvement in the C-statistic (0.60 (0.56–0.65)). As also shown in Table 3, using systolic BP at year 15 as reference, there was a significant improvement in NRI for cumulative systolic BP (0.40, p < 0.0001), whereas NRI for change in systolic BP was 0.22 (p =0.001) and IDI was non-significant.

Table 3.

Predictive and discriminatory performance of blood pressure measures for cardiovascular disease.

Cardiovascular disease events C-statistic (95% CI) Category-free NRI (SE) IDI (SE)
Systolic BP
 Year-15 systolic BP 0.69 (0.65–0.73) Reference Reference
 Systolic BP change 0.60 (0.56–0.65) 0.22, p = 0.001 0.001, p = 0.40
 Cumulative systolic BP 0.72 (0.69–0.76) 0.40, p < 0.0001 0.02, p = 0.002
Diastolic BP
 Year-15 diastolic BP 0.66 (0.62–0.70) Reference Reference
 Diastolic BP change 0.58 (0.53–0.62) 0.10, p = 0.15 0.001, p = 0.35
 Cumulative diastolic BP 0.70 (0.66–0.74) 0.29, p < 0.0001 0.02, p < 0.0001
Pulse Pressure
 Year-15 pulse pressure 0.59 (0.56–0.4) Reference Reference
 Pulse pressure change 0.56 (0.51–0.60) 0.05, p = 0.48 0.0001, p = 0.87
 Cumulative pulse pressure 0.59 (0.55–0.63) 0.08, p = 0.22 0.002, p = 0.11
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CI: confidence interval; SE: standard error; BP: blood pressure; NRI: net reclassification index; IDI: integrated discrimination improvement.

Discussion

In this prospective cohort of young adults transitioning into middle age, cumulative systolic and diastolic BP was associated with incident HF, CHD, stroke, and CVD in middle age. Cumulative BP provided incremental prognostic value and improvement in CVD risk classification, when compared to single time-point BP or to longitudinal changes in BP.

Our study findings underscore the incremental prognostic and discriminatory value of using cumulative BP measures – which incorporate the severity and duration of BP exposure – for risk assessment in the community. To our knowledge, this is the first study to investigate the prognostic significance of long-term cumulative BP in early adulthood – an important time period where community and primary care interventions may facilitate longitudinal declines in BP and, thus, mitigate the deleterious impact of high BP in later life.11,17 In a prior study of participants aged 45–65 years, the inclusion of cumulative systolic BP in the atherosclerotic CVD risk score equation resulted in improved CVD risk reclassification.9 Our study results are consistent with this report, but importantly extend to the early adult life span and include a broader range of outcomes that have been shown to be related to high BP.

In adults younger than 50 years, diastolic BP at a single time-point is generally perceived to be a stronger predictor of CVD,18 with possible race differences.19 In the current study of adults aged <45 years, cumulative systolic BP had stronger risk prediction performance than cumulative diastolic BP with no significant race interaction. The natural history of BP tracking in human life involves aging-associated changes, where in steeper systolic BP increases and a marked decrease in diastolic BP occur in later life in the setting of impaired vasoreactivity of the elastic conduit arteries and arterial remodeling.18,20 It may be reasonable to surmise that cumulative hemodynamic load is more representative of the risks of CVD that are increasingly driven by elevations in systolic BP, as adults transition into middle age.

In our analysis, PP had lower magnitudes of association for clinical outcomes when compared to systolic and diastolic BP. Weaker associations between PP and adverse outcomes occurred in the context of a small 15-year decrease in PP in the present study. These changes parallel the previously reported declining trajectory of PP before the onset of middle age.21 Our study observations are supported by prior reports of associations between long-term BP and atherosclerosis,22 arterial remodeling,23–25 myocardial fibrosis,26 left atrial and left ventricular structural and functional alterations,13,27 chronic kidney disease,28 and cognitive dysunction.29 Further studies are needed to examine the usefulness of cumulative BP in various clinical and research settings.

Strengths and limitations

Our observations are strengthened by the use of standardized protocols for BP assessment in a contemporary biracial community-based cohort; good cohort retention; and long-term outcome ascertainment. There may be fluctuations in BP during periods between study visits. Diurnal or nocturnal BP variability was not assessed. Ambulatory BP readings were not utilized, which may limit the generalizability of our findings to exposures obtained in this setting. Hypertension treatment may influence BP variations, but BP medication use in this young cohort was only 7.9% and study findings remained significant even after accounting for time-varying antihypertensive medication use. Although absolute events were not high, they are consistent with expected incidence rates for young adults in the community.1,30 Despite the relatively small number of events, which can serve as a conservative bias, cumulative BP remained a strong predictor of adverse outcomes.

Conclusions

Cumulative BP from young adulthood to middle age was associated with incident HF, CHD, stroke, and CVD, and provided incremental predictive and discriminatory value when compared to single time-point BP or long-term changes in BP. Our study findings underscore the prognostic value of using cumulative BP measures, which incorporate BP duration and intensity, for risk assessment in the community.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The CARDIA study was supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with the University of Alabama at Birmingham (HHSN268201800005I and HHSN268201800007I), Northwestern University (HHSN268201800003I), University of Minnesota (HHSN268201800006I), and Kaiser Foundation Research Institute (HHSN268201800004I). VL Murthy was supported by 1R01HL136685 from the NHLBI and 1R01AG059729 from the National Institute on Aging.

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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