BioMed Research International

BioMed Research International / 2019 / Article

Research Article | Open Access

Volume 2019 |Article ID 5274097 | 15 pages | https://doi.org/10.1155/2019/5274097

Short-Term and Long-Term Blood Pressure Changes and the Risk of All-Cause and Cardiovascular Mortality

Academic Editor: Yoshinari Uehara
Received17 Apr 2019
Revised02 Jul 2019
Accepted07 Jul 2019
Published06 Aug 2019

Abstract

Background. Few studies compared the effects of BP changes in short- and long-terms on all-cause mortality and CVD mortality. Methods. We performed a 12.5-year follow-up study to examine the association between short- (2008 to 2010) and long-term [baseline (2004-2006) to 2010] BP changes and the risk of mortality (2010 to 2017) in the Fuxin prospective cohort study. The Cox proportional hazards model was used for this study, and the average BP was stratified according to the Seven Joint National Committee (JNC7). Results. We identified 1496 (805 CVD deaths) and 2138 deaths (1222 CVD deaths) in short- and long-term study. Compared with BP maintainer, in short-term BP changes, for participants from normotension or prehypertension to hypertension, the hazards ratios (HRs) and 95% confidence intervals (CIs) of all-cause mortality were 1.948 (1.118-3.392) and 1.439 (1.218-1.700), respectively, while for participants from hypertension to prehypertension, the HRs (95% CIs) were 0.766 (0.638-0.899) for all-cause mortality and 0.729 (0.585-0.908) for CVD mortality, respectively. In long-term BP changes, for participants from normotension or prehypertension to hypertension, the HRs (95% CIs) of all-cause mortality were 1.738 (1.099-2.749) and 1.203 (1.023-1.414), and they were 2.351 (1.049-5.269) and 1.323 (1.047-1.672) for CVD mortality, respectively. In addition, the effects of short-term BP changes on all-cause and CVD mortality, measured as regression coefficients (β), were significantly greater than those in long-term change (all P<0.05). Conclusions. Our study emphasizes that short-term changes in BP have a greater impact on all-cause and CVD mortality than long-term changes and assess the cut-off value of the changes in blood pressure elevation.

1. Introduction

In 2017, the global adult mortality rate has declined slowly; not only that, but in some cases, the mortality rate is still rising [1]. Noncommunicable diseases accounted for 73% of the total number of deaths worldwide, more than half of which were attributed to only four risk factors, and hypertension was one of them [2]. The relationship between blood pressure (BP) level and mortality (all-cause or cardiovascular disease (CVD)) has been investigated in numerous studies [37]. It is well known that BP is an ever-changing variable in individuals during follow-up [8]. Therefore, office BP at a single point in time did not accurately predict all-cause mortality and researchers have begun to pay attention to the relationship between BP changes and death risk in recent years. For example, Fan JH et al. [9] found that, relative to stable BP of normotension, having a rise in BP from normotension or prehypertension to hypertension both conferred an increased risk of total and CVD and stroke mortality. Susanne M et al. [10] identified 4 BP trajectories and found that ten-year BP trajectories were the strongest predictors, among different BP measures, of CVD and all-cause mortality. In Kim MK’s study [11], they found that the risk of cardiovascular outcomes was increased with greater variability in systolic blood pressure (SBP) and greater BP variability leads to greater cardiac and vascular damage [12]. However, these studies focus on the impact of BP on outcomes at the same period, without considering both short- and long-term BP changes in one study. Short- and long-term BP changes may have different effects on mortality and it is unclear whether short- and long-term changes in BP categories are differentially associated with mortality risk.

In our study, we focused more on the changes in BP, a particularly compelling and underreported putative all-cause mortality risk factor, and to evaluate the relationship between changes in BP categories and all-cause and CVD mortality in a representative natural population.

2. Methods

2.1. Study Population and Study Design

This is a large-scale epidemiological follow-up study. From 2004 to 2006, a multistage, random cluster sampling design was performed to select a representative sample of the rural population aged 35 years and older from Fuxin County of Liaoning Province. The detailed methodology was described elsewhere [13]. From January to July 2008 (follow-up 1), from July to December 2010 (follow-up 2), and from March to December 2017 (follow-up 3), investigators were invited to participate in the follow-up study. Of the 45,925 participants at baseline, 3,883 subjects missed contact information or refused to attend the follow-up, and 42,042 participants were eligible to attend the follow-up. Of these, 846 participants who were missing SBP, diastolic blood pressure (DBP), or other key variables (demographics, lifestyle, CVD disease history, and history of disease associated with stroke) at baseline were excluded. For short-term changes analyses, subjects with missing SBP, DBP, and other key variables and missing body mass index (BMI), current smoking, and current drinking at the follow-up 1 (n=10,219) and missing SBP and DBP at the follow-up 2 (n=6776) and who died before the follow-up 2 (n=197) were excluded, leaving 24,004 participants for analysis. For long-term changes, subjects with missing SBP, DBP, and other key variables at the follow-up 2 (n=10,402) and who died before the follow-up 2 (n=288) were excluded leaving 30,506 participants for analyses (Figure 1). The procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation of China Medical University, and written informed consent of all subjects or their agents was obtained.

We aim to compare the association between short- and long-term BP changes and all-cause and CVD mortality (Figure 2). Long-term BP changes were between baseline and follow-up 2, and short-term BP changes were between follow-up 1 and follow-up 2. Data on events were all collected from 2010 to follow-up 2.

2.2. Baseline Measurement

Data on demographic variables (age, sex, and race), current drinking [14], current smoking, physical activity, history of disease (stroke, coronary heart disease (CHD), family history of hypertension, diabetes, and hyperlipemia), and information on antihypertensive medications were obtained by interview with a standard epidemiological questionnaire.

Details of the BP measurements have been described elsewhere [13]. In this study, based on the Seven Joint National Committee (JNC7) [15], we divided BP into normotension, prehypertension, and hypertension (SBP / DBP<120 / <80 mmHg, 120-129/80-89, ≥ 140 / 90 mmHg or receiving antihypertensive medications). Next, we classified the participants according to changes in BP: group 1, maintained at normotension; group 2, from normotension to prehypertension; group 3, from normotension to hypertension; group 4, from prehypertension to normotension; group 5, maintained at prehypertension; group 6, from prehypertension to hypertension; group 7, from hypertension to normotension; group 8, from hypertension to prehypertension; group 9, maintained at hypertension; the population was divided into 9 groups.

2.3. Follow-Up

All subjects were invited to attend the follow-up. A total of 42,242 patients finished at least one time follow-up (follow-up rate 91.5%). At each visit, we collected the information on clinical end points and concurrent medication use. During each visit, three BP measurements were taken according to a standard protocol identical to that of the baseline examination. The mean value of three BP measurements was used for each participant. We then evaluated the risk of study outcomes according to BP.

2.4. Study Outcomes

Our results included all-cause and CVD mortality. Deaths were confirmed through hospital records and direct contact with their families. We confirmed that death from CVD on the basis of autopsy reports, death certificates, medical record abstract, or information obtained from family members [16]. All materials were independently reviewed by the end-point assessment committee which included the certified neurologists, cardiologists, and others.

2.5. Statistical Analysis

Continuous variables were reported as means and standard deviations (SD), and categorical variables were expressed as frequency and percentage. The rates of events were presented as the number of events per 1000 person-years. We used multivariable Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations between BP categories and mortality. We calculated the risk of events for participants with altered BP levels, with reference to those with unchanged BP categories. Next, we calculated the events risk of participants with changes in BP levels and made normotension BP as a reference.

We adjusted for sex, age, race, BMI, SBP, DBP, current smoking, current drinking, education level, physical activity, antihypertensive treatment, family history of hypertension, and history of diabetes, hyperlipidemia, and CVD. Beyond that, we compared the predictive power of short-term changes and long-term changes using Fisher Z test [17]. A 2-sided P value <0.05 was deemed significant. Moreover, receiver operating characteristic (ROC) curves were constructed, and the area under the curve (AUC) was calculated to assess the cut-off value of the SBP changes in BP elevation. All analyses were performed with SPSS statistical software version 20.0 (SPSS Inc., Chicago, Illinois, USA). A P value less than 0.05 was accepted as indicating statistical significance.

3. Results

There were 24,004 participants in short-term analysis and 30,506 participants in long-term analysis, of which 49.4% and 51.1% were women, and the mean age was 51.9 (SD, 10.8) years and 50.2 (SD, 11.0) years, respectively. Table 1 presents the baseline characteristics of participants with short- and long-term changes in BP. For short-term, the mean (SD) of SBP and that of DBP were 131.1 (14.7) mmHg and 81.4 (10.0) mmHg, respectively. 12.7% were normotension, 54.7% were prehypertensive, and 32.6% were hypertensive. Of the long-term changes subjects, the mean BP was 133.5 (22.1)/82.3 (12.5) mmHg. The three BP categories accounted for 18.1%, 45.6%, and 36.3%, respectively.


CharacteristicsStudy population 1 
(n=24004)
Study Population 2 
(n=30506)

Female, n (%)11866(49.4)15577(51.1)
Age (year)51.9(10.8)50.2(11.0)
Race, n (%)
Han18553(77.3)23617(77.4)
Mongolian5126(21.4)6487(21.3)
Others325(1.4)402(1.3)
BMI (kg/m2)23.6 (2.5)23.2 (28)
SBP (mmHg)131.1(14.7)133.5(22.1)
DBP (mmHg)81.4(10.0)82.3 (12.5)
Education level, n (%)
Never or Less than 5 years9696(40.4)13048(42.8)
Primary school12871(53.6)15612(51.2)
Tertiary high school or higher education1437(6.0)1846(6.1)
Physical activity, n (%)
Low6147(25.6)8351(27.4)
Moderate11011(45.9)13824(45.3)
High6846(28.5)8331(27.3)
Current drinking, n (%)7434(31.0)9591(31.4)
Current smoking, n (%)8512(35.5)12669(41.5)
BP categories
Normal, n (%)3038(12.7)5520(18.1)
Prehypertension, n (%)13140(54.7)13912(45.6)
Hypertension, n (%)7826(32.6)11074(36.3)
Family history of hypertension, n (%)2852(11.9)3994(13.1)
Antihypertensive treatment, n (%)2186(9.1)2537(8.3)
History of diabetes, n (%)86(0.4)137(0.4)
History of hyperlipidemia, n (%)595(2.5)1053(3.5)
History of CVD, n (%)639(2.7)1107(3.6)

Values are expressed as mean (standard deviation) or number (percentage).
BMI: body mass index; BP: blood pressure; SBP: systolic blood pressure; DBP: diastolic blood pressure; BP categories according to JNC7; study population 1: participants with short-term (2008-2010) BP category changes; Study population 2: participants with long-term (2004-2006 to 2010) BP category changes.

Figure 3 shows the number of cases of all-cause mortality (Figure 3(a)) and CVD mortality (Figure 3(b)) per 1000 person-years by BP categories change. In the short-term BP changes study, 1496 deaths (including 805 from CVD deaths) were identified, and the overall incidence of all-cause mortality was 6.97 per 1000 person-years (CVD mortality was 3.75 per 1000 person-years). For the long-term BP changes analysis, there were 2138 all-cause mortality (1222 CVD mortality), and the total incidences of all-cause mortality and CVD mortality were 7.83/1000 person-years and 4.47/1000 person-years, respectively.

Table 2 shows HRs (95%CI) for the associations between BP changes and risk of all-cause and CVD mortality. In the multivariate adjusted Cox model for all-cause mortality, compared with BP maintainers, in short-term BP analysis, we found a significant decreasing risk of BP from hypertension to prehypertension, and the HRs (95%CI) were 0.766 (0.638-0.899) for all-cause mortality and 0.729 (0.585-0.908) for CVD mortality, respectively. And the results of women were the same; the HRs (95%CIs) were 0.606 (0.448-0.822) for all-cause mortality and 0.610 (0.418-0.889) for CVD mortality, respectively. In contrast, there were significant increasing risks of BP categories changes, and participants with BP from normotension or prehypertension to hypertension had HRs (95% CI) of 1.948 (1.118-3.392) and 1.439 (1.218-1.700) for all-cause mortality. Among men, the HRs (95% CIs) were 2.374 (1.059-5.323) and 1.672 (1.366-2.047) for all-cause mortality. The difference was a significant increasing risk of BP from prehypertension to hypertension in men, and the HR (95%CIs) was 1.401 (1.041-1.884). In long-term changes, the HRs (95% CI) of participants from normotension or prehypertension to hypertension were 1.738 (1.099-2.749) and 1.203 (1.023-1.414) for all-cause mortality, and they were 2.001 (1.041-3.838) and 1.241 (1.023-1.505) for all-cause mortality in men. BP from normotension to prehypertension had HR (95% CIs) of 2.351 (1.049-5.269) for CVD mortality. And from prehypertension to hypertension HRs (95% CIs) were 1.323 (1.047-1.672) in total and 1.354 (1.019-1.798) in men for CVD mortality. The results of nondiabetics are shown in Supplementary Appendix 1.


BP Category at BaselineBP Category at Follow-upnumberShort-term changes in blood pressurenumberLong-term changes in blood pressureP values#
Hazard Ratio (95%CI)P ValuesβHazard Ratio (95%CI)P Valuesβ

Total
All-cause mortality
NormotensionNormotension11131.000 (Ref.)13241.000 (Ref.)
Prehypertension15851.256(0.793-1.990)0.3320.22830561.379(0.895-2.125)0.1460.321
Hypertension3401.948(1.118-3.392)0.0190.66711401.738(1.099-2.749)0.0180.5530.0033
PrehypertensionNormotension18761.057(0.818-1.366)0.6720.05519320.930(0.704-1.228)0.607-0.073
Prehypertension84161.000 (Ref.)82111.000 (Ref.)
Hypertension28481.439(1.218-1.700)<0.0010.36437691.203(1.023-1.414)0.0250.185<0.001
HypertensionNormotension4860.826(0.549-1.244)0.361-0.1916411.157(0.884-1.516)0.2880.146
Prehypertension30950.766(0.638-0.899)0.002-0.26738190.894(0.782-1.021)0.097-0.112<0.001
Hypertension42451.000 (Ref.)66141.000 (Ref.)
CVD mortality
NormotensionNormotension11131.000 (Ref.)13241.000 (Ref.)
Prehypertension15850.789(0.360-1.730)0.554-0.23730562.351(1.049-5.269)0.0380.855<0.001
Hypertension3401.626(0.666-3.969)0.2860.48611401.834(0.765-4.397)0.1740.606
PrehypertensionNormotension18760.946(0.643-1.391)0.777-0.05619320.975(0.646-1.473)0.906-0.025
Prehypertension84161.000 (Ref.)82111.000 (Ref.)
Hypertension28481.227(0.963-1.563)0.0980.20437691.323(1.047-1.672)0.0190.2800.0012
HypertensionNormotension4860.639(0.355-1.147)0.133-0.4496411.105(0.778-1.568)0.5780.099
Prehypertension30950.729(0.585-0.908)0.005-0.31638190.902(0.765-1.064)0.222-0.103<0.001
Hypertension42451.000 (Ref.)66141.000 (Ref.)
Men
All-cause mortality
NormotensionNormotension2711.000 (Ref.)3201.000 (Ref.)
Prehypertension5781.428(0.732-2.784)0.2960.35612631.427(0.763-2.667)0.2650.355
Hypertension1172.374(1.059-5.323)0.0360.8655252.001(1.041-3.838)0.0370.694<0.001
PrehypertensionNormotension6821.111(0.795-1.552)0.5380.1057071.036(0.722-1.486)0.8470.036
Prehypertension46451.000 (Ref.)47071.000 (Ref.)
Hypertension14981.672(1.366-2.047)<0.0010.51421821.241(1.023-1.505)0.0290.216<0.001
HypertensionNormotension1650.812(0.442-1.490)0.501-0.2082111.154(0.789-1.687)0.4600.143
Prehypertension17230.853(0.692-1.052)0.138-0.15917980.881(0.738-1.051)0.160-0.127
Hypertension24591.000 (Ref.)32161.000 (Ref.)
CVD mortality
NormotensionNormotension2711.000 (Ref.)3201.000 (Ref.)
Prehypertension5780.438(0.139-1.378)0.158-0.82512632.927(0.888-9.643)0.0781.074
Hypertension1174.738(0.508-5.946)0.3790.5535253.008(0.870-10.403)0.0821.101
PrehypertensionNormotension6821.009(0.611-1.669)0.9710.0097071.297(0.783-2.147)0.3130.260
Prehypertension46451.000 (Ref.)47071.000 (Ref.)
Hypertension14981.401(1.041-1.884)0.0260.33721821.354(1.019-1.798)0.0370.3030.2585
HypertensionNormotension1650.354(0.113-1.113)0.076-1.0382110.869(0.496-1.522)0.624-0.140
Prehypertension17230.792(0.603-1.041)0.095-0.23317980.907(0.726-1.131)0.385-0.098
Hypertension24591.000 (Ref.)32161.000 (Ref.)
Women
All-cause mortality
NormotensionNormotension8421.000 (Ref.)10041.000 (Ref.)
Prehypertension10071.032(0.525-2.028)0.9280.03117931.255(0.684-2.303)0.4640.227
Hypertension2231.515(0.675-3.401)0.3140.4166151.289(0.656-2.531)0.4610.254
PrehypertensionNormotension11941.033(0.691-1.545)0.8730.03312250.851(0.549-1.321)0.472-0.161
Prehypertension37711.000 (Ref.)35041.000 (Ref.)
Hypertension13501.095(0.814-1.472)0.5500.09015871.162(0.862-1.567)0.3240.150
HypertensionNormotension3210.775(0.435-1.379)0.386-0.2554301.155(0.786-1.698)0.4640.144
Prehypertension13720.606(0.448-0.822)0.001-0.50020210.901(0.743-1.105)0.318-0.104<0.001
Hypertension17861.000 (Ref.)33981.000 (Ref.)
CVD mortality
NormotensionNormotension8421.000 (Ref.)10041.000 (Ref.)
Prehypertension10071.032(0.331-3.220)0.9560.03217931.765(0.572-5.448)0.3230.568
Hypertension2231.343(0.350-5.156)0.6670.2956150.549(0.119-2.543)0.444-0.599
PrehypertensionNormotension11940.894(0.486-1.645)0.719-0.11212250.697(0.340-1.426)0.323-0.362
Prehypertension37711.000 (Ref.)35041.000 (Ref.)
Hypertension13500.992(0.651-1.512)0.970-0.00815871.343(0.887-2.032)0.1630.295
HypertensionNormotension3210.811(0.393-1.677)0.573-0.2094301.330(0.844-2.094)0.2190.285
Prehypertension13720.610(0.418-0.889)0.010-0.49420210.882(0.686-1.133)0.324-0.126<0.001
Hypertension17861.000 (Ref.)33981.000 (Ref.)

Abbreviations: normotension: subjects with blood pressure (BP) <120/80 mmHg; prehypertension: subjects with BP of 120-139/80-89 mmHg; hypertension: subjects with BP≥140/90mmHg or antihypertensive treatment. Adjusted age, gender, ethnicity, SBP, DBP, BMI, education level, physical activity, current drinking, current smoking, family history of hypertension, history of CVD diseases, history of diabetes, history of hyperlipidemia, and antihypertensive treatment.
#comparison of β.

We also compared the effects of short- and long-term BP changes, measured as regression coefficients (β), and they were significantly greater in short-term changes than in long-term for all-cause mortality (total: β=0.667 VS β=0.553, P=0.0033; men: β=0.865 VS β=0.694, P<0.001) for participants from normotension to hypertension. The same result also occurs in the prehypertension to hypertension (total: β=0.364 VS β=0.185, P<0.001; men: β=0.514 VS β=0.216, P<0.001). Similarly, from hypertension to prehypertension, the results were reversed (total: β=-0.267 VS β=-0.112, P<0.001; women: β=-0.500 VS β=-0.104, P<0.001). When analyzing CVD mortality, we also found that short-term and long-term changes are different, from normotension to prehypertension (total: β=-0.237 VS β=0.855, P<0.001), prehypertension to hypertension (total: β=0.204 VS β=0.280, P=0.0012), and hypertension to prehypertension (total: β=-0.316 VS β=-0.103, P<0.001; women: β=-0.494 VS β=-0.126, P<0.001).

In Table 3, we compared all the other 8 groups with the group 1 as reference. In short-term changes, from normotension to hypertension increased significantly for all-cause mortality, the HRs (95% CI) were 1.846 (1.092-3.181). In long-term changes, there were more interesting results. For participants from normotension to hypertension the HRs (95% CIs) of all-cause mortality were 1.759 (1.129-2.742) in total and 1.892 (1.005-2.737) in men, respectively. For participants from hypertension to normotension, the HRs (95% CIs) of all-cause mortality were 1.725 (1.073-2.772). There were significant increased risks of BP categories changes normotension to prehypertension (HRs 2.409; 95%CI:1.090-5.328) and prehypertension to hypertension (HRs 2.441; 95%CI:1.136-5.244) for CVD mortality. For participants from hypertension to normotension or to prehypertension or that maintain hypertension, the HRs (95% CIs) of CVD mortality were 2.924 (1.276-6.700), 2.345 (1.083-5.081), and 2.591 (1.197-5.609), respectively. There was also a significant increased risk of BP from hypertension to normotension (HR: 3.330; 95%CIs: 1.107-10.023) for CVD mortality in women. The results of nondiabetics are shown in Supplementary Appendix 2.


BP Category ChangeShort-term changes in blood pressureLong-term changes in blood pressure
NumberHazard Ratios (95% CI)P ValuesNumberHazard Ratio (95%CI)P Values

Total
All-cause mortality
Normotension to Normotension11131.000 (Ref.)13241.000 (Ref.)
Normotension to Prehypertension15851.179(0.759-1.832)0.46330561.367(0.894-2.090)0.150
Normotension to Hypertension3401.846(1.092-3.181)0.02311401.759(1.129-2.742)0.012
Prehypertension to Normotension18760.943(0.613-1.451)0.79019321.137(0.718-1.799)0.592
Prehypertension to Prehypertension84160.861(0.588-1.262)0.44482111.223(0.823-1.819)0.317
Prehypertension to Hypertension28481.211(0.818-1.793)0.33937691.464(0.979-2.189)0.064
Hypertension to Normotension4860.726(0.415-1.272)0.2636411.725(1.073-2.772)0.022
Hypertension to Prehypertension30950.672(0.437-1.032)0.07038191.323(0.873-2.007)0.179
Hypertension to Hypertension42450.893(0.581-1.372)0.60466141.488(0.982-2.255)0.052
CVD mortality
Normotension to Normotension11131.000 (Ref.)13241.000 (Ref.)
Normotension to Prehypertension15850.755(0.359-1.590)0.46030562.409(1.090-5.328)0.030
Normotension to Hypertension3401.568(0.669-3.675)0.30111401.922(0.820-4.505)0.127
Prehypertension to Normotension18760.940(0.486-1.817)0.85519321.774(0.770-4.085)0.179
Prehypertension to Prehypertension84160.988(0.553-1.764)0.96682111.803(0.842-3.863)0.126
Prehypertension to Hypertension28481.200(0.661-2.177)0.54937692.441(1.136-5.244)0.022
Hypertension to Normotension4860.727(0.319-1.657)0.4496412.924(1.276-6.700)0.010
Hypertension to Prehypertension30950.819(0.435-1.542)0.53738192.345(1.083-5.081)0.028
Hypertension to Hypertension42451.127(0.599-2.119)0.71166142.591(1.197-5.609)0.013
Men
All-cause mortality
Normotension to Normotension2711.000 (Ref.)3201.000 (Ref.)
Normotension to Prehypertension5781.179(0.629-2.208)0.60712631.381(0.745-2.084)0.306
Normotension to Hypertension1171.912(0.882-4.144)0.1015251.892(1.005-2.737)0.048
Prehypertension to Normotension6820.909(0.490-1.686)0.7627071.238(0.639-1.802)0.527
Prehypertension to Prehypertension46450.775(0.445-1.349)0.36747071.214(0.677-1.807)0.515
Prehypertension to Hypertension14981.221(0.695-2.145)0.48821821.476(0.818-2.154)0.197
Hypertension to Normotension1650.617(0.271-1.406)0.2502111.745(0.874-2.655)0.114
Hypertension to Prehypertension17230.675(0.370-1.233)0.20117981.327(0.721-1.997)0.363
Hypertension to Hypertension24590.822(0.450-1.505)0.52632161.523(0.829-2.229)0.175
CVD mortality
Normotension to Normotension2711.000 (Ref.)3201.000 (Ref.)
Normotension to Prehypertension5780.438(0.147-1.309)0.13912632.77(0.849-9.0360)0.091
Normotension to Hypertension1171.552(0.491-4.907)0.4545252.725(0.805-9.221)0.107
Prehypertension to Normotension6820.735(0.303-1.782)0.4957072.277(0.668-7.759)0.188
Prehypertension to Prehypertension46450.704(0.322-1.538)0.37947071.810(0.572-5.726)0.313
Prehypertension to Hypertension14980.945(0.426-2.096)0.88921822.438(0.768-7.741)0.130
Hypertension to Normotension1650.267(0.067-1.071)0.0622112.334(0.655-8.320)0.191
Hypertension to Prehypertension17230.612(0.265-1.415)0.25117982.388(0.743-7.676)0.144
Hypertension to Hypertension24590.779(0.337-1.802)0.55932162.634(0.821-8.455)0.104
Women
All-cause mortality
Normotension to Normotension8421.000 (Ref.)10041.000 (Ref.)
Normotension to Prehypertension10071.064(0.565-2.001)0.84817931.316(0.723-2.394)0.368
Normotension to Hypertension2231.633(0.773-3.453)0.1996151.514(0.789-2.908)0.212
Prehypertension to Normotension11940.922(0.500-1.701)0.79612251.008(0.528-1.924)0.981
Prehypertension to Prehypertension37710.920(0.537-1.574)0.76035041.174(0.677-2.033)0.568
Prehypertension to Hypertension13501.023(0.581-1.802)0.93715871.374(0.783-2.410)0.268
Hypertension to Normotension3210.749(0.342-1.641)0.4714301.604(0.829-3.103)0.161
Hypertension to Prehypertension13720.535(0.280-1.020)0.05820211.218(0.684-2.170)0.504
Hypertension to Hypertension17860.864(0.457-1.632)0.65233981.368(0.767-2.439)0.289
CVD mortality
Normotension to Normotension8421.000 (Ref.)10041.000 (Ref.)
Normotension to Prehypertension10071.083(0.383-3.064)0.88017931.878(0.623-5.664)0.263
Normotension to Hypertension2231.430(0.400-5.121)0.5826150.693(0.155-3.102)0.632
Prehypertension to Normotension11941.157(0.429-3.116)0.77312251.240(0.380-4.048)0.721
Prehypertension to Prehypertension37711.376(0.576-3.291)0.47335041.775(0.636-4.954)0.273
Prehypertension to Hypertension13501.363(0.549-3.385)0.50415872.449(0.874-6.859)0.088
Hypertension to Normotension3211.489(0.482-4.596)0.4894303.330(1.107-10.023)0.032
Hypertension to Prehypertension13720.987(0.370-2.634)0.97920212.147(0.759-6.070)0.150
Hypertension to Hypertension17861.608(0.609-4.245)0.33833982.453(0.868-6.929)0.090

Abbreviations: normotension: subjects with blood pressure (BP) <120/80 mmHg; prehypertension: subjects with BP of 120-139/80-89 mmHg; hypertension: subjects with BP≥140/90mmHg or antihypertensive treatment. Adjusted age, gender, ethnicity, SBP, DBP, BMI, education level, physical activity, current drinking, current smoking, history of CVD diseases, family history of hypertension, history of diabetes, history of hyperlipidemia, and antihypertensive treatment.

For participants with elevated SBP, the cut-off value of SBP changes was evaluated by using the ROC curve to predict mortality (Figure 4). In short-term analysis (Figure 4(a)), the optimal cut-off value of SBP changes for the diagnosis of all-cause mortality was 11.5 mmHg in total, and the AUC (95% CIs) was 0.538 (0.517-0.559). And the cut-off value was 13.5 mmHg for CVD mortality; the AUC (95% CIs) was 0.543 (0.513-0.573). Among men, the cut-off values of all-cause and CVD mortality were 18.5 mmHg and 13.5 mmHg, and the AUC (95% CIs) were 0.543 (0.516-0.570) and 0.548 (0.510-0.586). Among women, for all-cause mortality, the cut-off value was 11.5 mmHg, and the AUC (95% CIs) was 0.548 (0.512-0.583). For CVD mortality, the cut-off value was 12.5 mmHg, and the AUC (95% CIs) was 0.549 (0.500-0.598). In long-term analysis, the cut-off values of all-cause mortality were 18.5 mmHg (AUC: 0.529; 95% CIs: 0.509-0.548) and they were 19.5 mmHg (AUC:0.538; 95% CIs:0.511-0.564) of CVD mortality for total. Among men, the cut-off values of all-cause and CVD mortality were 19.5 mmHg (AUC:0.538; 95% CIs:0.514-0.563) and 21.5 mmHg (AUC:0.562; 95% CIs: 0.530-0.595), respectively. The results of nondiabetics are shown in Supplementary Appendix 3.

4. Discussion

The main findings of the present study were the positive association between short- and long-term BP changes and the risk of all-cause and CVD mortality in rural areas of China. Overall, our data showed that, compared with people who maintain the BP status, participants with elevated BP had a high risk of all-cause and CVD mortality, and participants with reduced BP had a lower risk of all-cause and CVD mortality, both in short- and long-term changes analysis. In addition, the difference between short-term and long-term changes is statistically significant.

Our study confirmed the findings for positive associations between BP changes and all-cause mortality, which was comparable with previous studies [1821]. Two studies were performed on hypertensive patients and untreated hypertensive patients at the IPC Center in Paris, and changes in individual long-term BP are independent predictors of all-cause mortality in hypertensive patients [18]. Data from the Minnesota Business and Professional Men Study (n=261) and the Zutphen Study were shown, and the 10-year BP trajectory was the strongest predictor of cardiovascular mortality and all-cause mortality in Minnesota [19]. Cardiovascular health studies concluded that long-term visit-to-visit SBP variability was independently associated with a higher risk of subsequent mortality and a meta-analysis of 13 cohort studies in Japan also presented that adjusted mortality increased with increasing BP [20, 21]. These studies found that BP changes are a powerful predictor of cardiovascular events independently of mean SBP or DBP, which is more common in previous studies. And we also got the same conclusion when studying CVD and all-cause mortality. In addition, we explored the relationship between BP changes in the longitudinal pattern over time and the risk of subsequent mortality. What is more, we used BP short- and long-term changes to explore the relationship between BP and mortality, and this research was still very scarce in China.

We believe that short- and long-term changes in BP are an independent risk factor of mortality. And the impact of short- and long-term changes on outcomes is different. BP changes are indeed the result of a complex interaction between external environmental stimuli and the response of several cardiovascular control mechanisms [22]. There is evidence that short-term BP changes predict terminal organ damage and cardiovascular events [2325]. However, the individual biologic mechanisms by which long-term BP changes may affect risk of mortality CVD or all-cause mortality are yet unclear. This impact might be due to changes in BP that cause significant changes in vasculature exposure to pressure load over a long period of time [26]. These would affect the potential health of vascular tissue, thereby affecting the development or severity of CVD [27, 28]. Therefore, one hypothesis is that short- and long-term changes are different for vascular pressure states. Further studies are warranted to test for this hypothesis. We detected that the same changes in BP occur, and the shorter change time seems to affect mortality more. The content of the appeal reminds us that if only one baseline BP measurement is used, the impact of hypertension on the outcome of the event will be overestimated or underestimated! Therefore, pay special attention to sudden changes in BP. Only in this way can we better help prevent cardiovascular and all-cause mortality.

Interestingly, a declining BP in hypertensive patients increases the risk of all-cause mortality, compared with maintaining normotension, especially for CVD mortality. Some studies showed that a low DBP was associated with an increased all-cause mortality risk [29, 30]. In post hoc analyses of the Systolic Hypertension in the Elderly Program (SHEP), after fully adjusting the functional status and other confounding factors, the drop in BP is still accompanied by an increase in mortality. It is also possible that lower BP in the elderly may increase the risk of adverse outcomes [31]. In assessing the prevalence of BP decline in the elderly and its relationship to subsequent outcomes, Satish S et al. [32] found that a drop in BP may be a predictor of higher mortality risk in the elderly. This result appeared more in the elderly as shown in previous studies, but the reason is unclear.

4.1. Strengths and Limitations

Our study had several important strengths, which include the relatively large sample size and large number of adverse events accrued, thereby increasing the statistical power of our analyses. Moreover, in this study, information about BP was derived from the mean BP of follow-up, which helped determine the relationship between BP and adverse outcomes. Finally, in addition to looking at the effect of changes in BP Categories on death, we used the ROC curve to find the cut-off value of SBP in patients with elevated BP. Our study also had several limitations. First, the BP in this study is the average of three measurements in a day, so we might not account more for the effects of individual BP fluctuations. Secondly, our research sample only included participants in rural areas of China, and we could expect different results from more people of different ethnicity. Thirdly, we did not have enough laboratory measurements, such as cholesterol, blood glucose, and inflammatory biomarkers to control these covariates. This is why we have the low frequency off diabetes in baseline characteristics. Finally, it is also worth noting that the classification of BP changes may mask some of the individual variabilities of BP in terms of time variation and may lead to attenuation.

5. Conclusions

In our study, using the Cox proportional hazard models with short-term BP changes and long-term BP changes entered in the same model, BP changes provided more information on risk of all-cause and cardiovascular mortality than BP at a single point in time. Our research suggests that short-term BP changes have a greater effect on mortality. And individuals who are able to maintain their BP to normal BP levels have the lowest risk for CVD and all-cause mortality. The importance of hypertension management should be widely accepted in public health practice. Prevention efforts should continue to emphasize the importance of lowering BP and maintaining normotension to reduce the mortality.

Data Availability

The data used to support the findings of this study are available from the corresponding author upon request.

Disclosure

There are no relationships with industry.

Conflicts of Interest

All authors approved the manuscript and there are no conflicts of interest.

Authors’ Contributions

All authors should have made substantial contributions to all of the following: Yanxia Xie, Jia Zheng, Rongrong Guo, Zhaoqing Sun, Xingang Zhang, and Liying Xing were responsible for conception and design of the study, or acquisition of data, or analysis and interpretation of data. Yue Dai and Yali Wang drafted the article or revised it critically for important intellectual content. Liqiang Zheng and Yingxian Sun approved the version to be submitted and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Acknowledgments

The authors would like to express their gratitude to all those who helped them during the writing of this paper. This work was supported by funds from National Nature Science Foundation of China (No. 81773510) and National Key R&D Program of China (Grant #2017YFC1307600, #2018YFC1311600).

Supplementary Materials

Supplementary Appendix 1 shows HRs (95%CI) for the associations between BP changes and risk of all-cause and CVD mortality in nondiabetics. In short-term BP analysis, we found a significant decreasing risk of BP from hypertension to prehypertension, and the HRs (95%CI) were 0.768 (0.646-0.912) for all-cause mortality and 0.729 (0.584-0.909) for CVD mortality, respectively. In contrast, there were significant increasing risks of BP categories changes, and participants with BP from normotension or prehypertension to hypertension had HRs (95% CI) of 1.948 (1.118-3.392) and 1.437 (1.216-1.699) for all-cause mortality. In long-term changes, the HRs (95% CI) of participants from normotension or prehypertension to hypertension were 1.740 (1.000-2.751) and 1.194 (1.015-1.405) for all-cause mortality. BP from normotension to prehypertension had HR (95% CIs) of 2.351 (1.049-5.269) for CVD mortality. And from prehypertension to hypertension, HRs (95% CIs) were 1.326 (1.048-1.677) for CVD mortality. The effects of short- and long-term BP changes, measured as regression coefficients (β), were significantly greater in short-term changes than in long-term for all-cause mortality (β=0.667 VS β=0.554, P<0.001) for participants from normotension to hypertension. The same result also occurs in the prehypertension to hypertension (β=0.363 VS β=0.178, P<0.001). Similarly, from hypertension to prehypertension, the results were reversed (β=-0.264 VS β=-0.104, P<0.001). When analyzing CVD mortality, we also found that short-term and long-term changes are different, from normotension to prehypertension (β=-0.237 VS β=0.855, P<0.001), prehypertension to hypertension (β=0.211 VS β=0.282, P=0.0024), and hypertension to prehypertension (β=-0.317 VS β=-0.093, P<0.001). In Supplementary Appendix 2, in short-term changes, from normotension to hypertension increased significantly for all-cause mortality, the HRs (95% CI) were 1.848 (1.083-3.154). In long-term changes, for participants from normotension to hypertension the HRs (95% CIs) of all-cause mortality were 1.755 (1.125-2.737). For participants from hypertension to normotension, the HRs (95% CIs) of all-cause mortality were 1.646 (1.020-2.655). There were significant increased risks of BP categories changes normotension to prehypertension (HRs 2.403; 95%CI: 1.087-5.313) and prehypertension to hypertension (HRs 2.407; 95%CI: 1.120-5.173) for CVD mortality. For participants from hypertension to normotension or to prehypertension or that maintain hypertension, the HRs (95% CIs) of CVD mortality were 2.880 (1.255-6.612), 2.339 (1.079-5.070), and 2.563 (1.183-5.551), respectively. In Supplementary Appendix 3, in short-term analysis, the optimal cut-off value of SBP changes for the diagnosis of all-cause mortality was 12.5 mmHg, and the AUC (95% CIs) was 0.537 (0.515-0.558). And the cut-off value was 13.5 mmHg for CVD mortality; the AUC (95% CIs) was 0.542 (0.512-0.572). In long-term analysis, the cut-off values of all-cause mortality were 18.5 mmHg (AUC: 0.530; 95% CIs: 0.510-0.550), and they were 19.5 mmHg (AUC: 0.542; 95% CIs: 0.516-0.569) of CVD mortality. (Supplementary Materials)

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