Associations of blood pressure components with risks of cardiovascular events and all‐cause death in a Chinese population: A Prospective Study

Abstract The associations of blood pressure components with cardiovascular risks and death remain unclear, and the definition of wide pulse pressure (PP) is still controversial. Using data from 1257 participants without a history of cardiovascular disease, who were followed for 4.84 years, we performed multivariable Cox regression analyses to assess how systolic blood pressure (SBP), diastolic blood pressure (DBP), and PP contribute to risks of cardiovascular events and all‐cause death. Among all participants, SBP and PP were significantly associated with the risks of cardiovascular events and all‐cause death (all p < .05). DBP was not significantly associated with the risk of all‐cause death; rather, it was only associated with a marginally significant 1% increased risk for cardiovascular events (p = 0.051). In participants aged < 65 years, DBP was significantly associated with a 3% increased risk for cardiovascular events (hazard ratio [HR]: 1.03, 95% confidence interval [95% CI]: 1.01–1.06). The association between PP and cardiovascular events appeared to be J‐shaped in comparison to participants with the lowest‐risk PP (50–60 mmHg), with adjusted HRs of 1.71 (95% CI: 1.03–2.85), 1.63 (95% CI: 1.00–2.68), and 2.13 (95% CI: 1.32–3.43) in the <50, 60.0–72.5, and ≥72.5 mmHg subgroups, respectively. The optimal cutoff points of a wide PP for predicting the risks of cardiovascular events and all‐cause death were 70.25 and 76.25 mmHg, respectively. SBP and PP had a greater effect on cardiovascular risk, whereas DBP independently influenced cardiovascular events in middle‐aged participants. Considerable PP alterations should be avoided in antihypertensive treatment.


INTRODUCTION
Hypertension remains one of the most important contributors to cardiovascular events and deaths worldwide. 1 Robust evidence from clinical trials has shown the benefit of antihypertensive medication in reducing adverse health outcomes in patients with hypertension. [2][3][4] However, previous studies investigating the effects of blood pressure components (systolic blood pressure [SBP], diastolic blood pressure [DBP], and pulse pressure [PP]) on cardiovascular risks and death provided equivocal results. 5,6 Some studies reported that SBP levels could be used to better predict cardiovascular events compared to other blood pressure components; 6,7 in contrast, other studies reported that DBP levels showed a J-curve 8,9 or were not associated with the prediction of cardiovascular events. 10,11 PP remains a poorly studied parameter receiving less attention in clinical trials. 12 Current hypertension guidelines do not include a target PP, [13][14][15] and the definition of wide PP remains controversial, [16][17][18] which may subject patients to an independent risk factor, leading to poor outcomes.
Equivocal results of different blood pressure components on cardiovascular risks and death might be explained by age differences.
Middle-aged individuals commonly have a higher DBP in the early stage of hypertension. With aging and progressing arterial stiffening, older people are prone to having a higher SBP, a lower DBP, and a wide PP. Previous studies found that the relative importance of blood pressure components to coronary heart disease 19 and stroke 20 risks changed with aging in Framingham Heart Study and the MOnica, Risk, Genetics, Archiving, and Monograph Project. However, the question of which blood pressure components predict cardiovascular events across age ranges has not been fully evaluated in the Chinese population.
Therefore, this study aimed to explore the associations of blood pressure components with cardiovascular events and all-cause death in different age groups. We performed a prospective cohort study using data from the Beijing Longitudinal Study of Aging (BLSA), a longitudinal study on middle-aged and older community-dwelling individuals in Beijing, China. The present study findings may have clinical health implications for the prevention of cardiovascular events in middle-aged and elderly people.

METHODS
The data of the current study were collected from the BLSA, which was designed to investigate the health status and cardiovascular risk factors of the Chinese middle-aged and elderly population. Details on the design and implementation of the BLSA whose data were used in this study have been reported previously. [21][22][23] Briefly, Beijing consists of 18 administrative districts that are classified into the following three categories according to their degree of urbanization and economic status: eight main cities, five suburbs, and five extended suburbs in 1992.
First, the following three districts were selected by stratificationrandom-clustering sampling from each category: Xuanwu District (urban), Daxing County (suburb), and Huairou County (extended sub-urb). Secondly, specific communities/villages were randomly selected from these districts based on demographic characteristics and the

Definitions and laboratory examinations
PP was calculated as the difference between SBP and DBP. Wide PP was defined as either ≥60 24 or ≥100 mmHg. 12 Hypertension was defined as an SBP of ≥140 mmHg and/or a DBP of ≥90 mmHg and/or use of antihypertensive medication in the past 2 weeks. 25  14 mmol/L. 26 Furthermore, diabetes mellitus was defined by a fasting plasma glucose level of ≥7.0 mmol/L, the use of antidiabetic medication, or a history of diabetes mellitus. 26 Smoking and drinking were subcategorized as former, current, and never. Former smokers/drinkers were those who had a history of smoking/drinking and had stopped for at least 2 years; current smokers/drinkers were defined as those who were still smoking/drinking frequently or occasionally till the time of the investigation, and participants with no history of smoking/drinking were identified as never smokers/drinkers.
In this report, we defined smokers/drinkers as former or current smokers/drinkers. 21 High-sensitivity C-reactive protein (hs-CRP) levels were measured using a high-sensitivity nephelometric assay with the Behring Nephelometer II system (Dade Behring, Marburg, Germany). Fasting glucose levels were determined using the glucose oxidase-peroxidase assay.
High-density and low-density lipoprotein cholesterol levels were measured using the direct assay. Total cholesterol, triglycerides, and creatinine levels were determined with the standard enzymatic method using the Hitachi Clinical Analyzer (Hitachi 7600, Hitachi, Tokyo, Japan

Participants' baseline information
Baseline characteristics of the participants in the entire study population (1257 participants) and in both age subgroups are shown in Additionally, the hsCRP, total cholesterol, and triglycerides levels were significantly higher in older participants than in younger participants (all p < .05), whereas the proportion of smokers was significantly lower in older participants (p = .012). Figure 1 shows the relationship between SBP and DBP measurements in all participants, as well as in those in the two age groups. In all participants, the prevalence rates of a wide PP defined as ≥60 or ≥100 mmHg were 49.96% (628/1257) and 3.66% (46/1257), respectively.
When wide PP was defined as ≥60 mmHg, the prevalence of a wide PP was significantly higher in older participants than in younger participants (58.11% vs. 36.27%, p < .001). Similar results were obtained when a wide PP was defined as ≥100 mmHg; older participants had a significantly higher prevalence rate than younger participants (4.93% vs. 1.50%, p = .002; Figure 2).

F I G U R E 1
Relationship between systolic blood pressure and diastolic blood pressure in all participants (A), participants <65 years of age (B), and participants ≧65 years (C)

Blood pressure and outcomes in the two age groups
The results of Cox regression analyses evaluating the effects of blood pressure parameters on cardiovascular events and all-cause death by age are shown in Table 3. As shown in Figure 2, the prevalence of a wide PP defined as ≥100 mmHg was low, especially in participants aged <65 years. Considering this finding, we assessed the associations of SBP, DBP, PP, and wide PP (≥60 mmHg) with cardiovascular events and allcause death in both age groups. In participants aged <65 years, DBP was significantly associated with a 3% increased risk for cardiovascular events (HR: 1.03, 95% CI: 1.01-1.06) in the fully adjusted model.

ROC analysis
Next, PP levels were analyzed to determine the ROC curves for obtaining optimal cutoff points that predict the risks of cardiovascular events and all-cause death during the 4.84-year follow-up (Figures 4 and 5).
The optimal cutoff points of PP for predicting the risk of cardiovascu-

DISCUSSION
We found that in community-dwelling individuals without a history of cardiovascular disease, SBP and PP were predictors of cardiovascular   Our findings do not confirm the results of previous studies, which described a J-curve phenomenon 8,9 between DBP and cardiovascular risk. A J-curve, that is, an increase in cardiovascular risk below or above a certain DBP, has been described in patients with coronary artery disease 8,9 and in high-risk populations. 33 Additionally, a DBP of <60 mmHg was associated with incident coronary heart dis-ease, but not with stroke, in the Atherosclerosis Risk in Communities (ARIC) cohort. 34 Importantly, these studies were conducted in highrisk cardiovascular populations and did not find a J-shaped relationship between DBP and stroke. Notably, our community cohort had no cardiovascular disease history and had a higher incidence of stroke than coronary event, consistent with the findings of a previous report. 15 A direct J-curve of DBP may be of greater importance in patients with limitations to coronary perfusion 8 or in those with conditions involving end-organ microcirculatory abnormalities. 5 As also demonstrated in the ARIC cohort, low DBP levels might harm the myocardium and are associated with subsequent coronary artery disease. 34 PP, an indicator of diffuse vascular stiffening and vascular aging, has been reported to be independently associated with adverse cardiovascular outcomes and mortality in patients with hypertension 24 and coronary artery disease, 9 patients with heart failure with reduced 35 and preserved ejection fraction, 36  Nevertheless, our study also has certain strengths. We performed a prospective cohort study to explore the association between blood pressure components and adverse outcomes. This study was under strict quality control, and potential confounding risk factors were determined and adjusted for as covariables in the multivariate Cox regression analysis. Oscillometric devices were used in this study to obtain valid blood pressure measurements, which may have reduced human errors associated with auscultatory measurements. 40

CONCLUSIONS
In conclusion, this prospective cohort study shows that SBP and PP are associated with cardiovascular events and death in community-

CONFLICT OF INTEREST
The authors have no competing interests to declare.

AUTHOR CONTRIBUTIONS
Zhongying Zhang, Zhe Tang, and Xianghua Fang contributed to the study concept and design. Zhongying Zhang, Xiang Gu, Shaochen Guan, Hongjun Liu, and Yan Zhao contributed to data collection. Zhongying Zhang and Xiaoguang Wu analyzed and interpreted the data. Zhongying Zhang drafted and revised the manuscript. All authors reviewed and approved the final manuscript.

ETHICS APPROVAL STATEMENT
The Ethics Committee of Xuanwu Hospital, Capital Medical University, Beijing, China, approved this study (No.2018-038). This study was performed in accordance with the Declaration of Helsinki.

PATIENT CONSENT STATEMENT
All participants provided written informed consent.

SOURCES
The paper does not reproduce material from other sources.