Abstract
Aim: People with high normal blood pressure (BP) have a higher risk of cardiovascular events than those with normal BP; therefore, progression to hypertension (HT) should be prevented. We aimed to assess the HT risk using central BP and carotid intima media thickness (CIMT) in people with high normal BP.
Methods: This prospective cohort study used the Tohoku Medical Megabank Community-Based Project Cohort Study (conducted from 2013 in Miyagi Prefecture in Japan). The participants had a high normal BP, defined as a systolic BP of 120–139 mmHg and diastolic BP ＜90 mmHg using brachial BP measurement during the baseline survey. The outcome was new-onset HT during the secondary survey, conducted four years after the baseline survey.
Results: Overall, 4,021 participants with high normal BP during the baseline survey, with an average age of 58.7 years, were included; 1,030 (26%) were diagnosed with new-onset HT during the secondary survey, 3.5±0.7 years after the baseline survey. The multivariable odds ratio (95% confidence interval) for HT in the highest versus lowest quartile of central BP was 1.7 (1.2–2.4, p=0.0030), and that of CIMT was 1.8 (1.4–2.4, p＜0.001). Subgroup analysis according to age (＜60 and ≥ 60 years) and sex revealed that the central BP was influential in groups with younger age and female individuals; CIMT was influential in all groups.
Conclusions: Higher central BP and thicker CIMT at the baseline were correlated with new-onset HT in individuals with high normal BP, independent of brachial systolic BP and other cardiovascular risk factors.
Introduction
Hypertension (HT) is a known risk factor for cardiovascular events, and therefore, appropriate management is important1-3). High normal blood pressure (BP) does not satisfy the criteria for either normal BP or HT, and its definition differs between guidelines1-3). For example, the International Society of Hypertension, European Society of Cardiology, and European Society of Hypertension define systolic BP (SBP) of 130–139 mmHg and/or diastolic heart pressure (DBP) of 85–89 mmHg as high normal BP1, 2). Conversely, cases with SBP of 120–129 mmHg and DBP ＜80 mmHg are defined as cases with high normal BP by the Japanese Hypertension Society3). A high normal BP, which is a status of pre-HT, incurs a higher risk of cardiovascular events than normal BP, and approximately half of the cardiovascular deaths are estimated to be attributed to BP beyond the normal limit4, 5).
According to the guidelines for HT, instead of medication, people with high normal BP are recommended to measure their BP at home and improve their lifestyles by adopting a low-sodium diet, involving in aerobic physical activity, and losing weight1-3, 6, 7). However, as improving lifestyle habits is left to the individuals’ desire, without appropriate management, the risk of cardiovascular events may remain. Low adherence to BP monitoring at home and dietary approaches diminishes the effects that prevent HT8, 9). Thus, it may be effective to screen individuals with a high HT incidence risk who require active management for better adherence to BP monitoring at home and better lifestyles to prevent HT onset and the consequent organ damage.
To screen participants who should be carefully followed up, easy, and noninvasive methods are necessary. This study focuses on central BP and carotid intima media thickness (CIMT). Although brachial BP measurements are widely used to diagnose HT, central BP can reflect the hemodynamic status more accurately, as it is not influenced by peripheral vascular resistance and is closer to the organs10, 11). A meta-analysis has demonstrated that central hemodynamic indices, such as central BP, central pulse pressure (PP), and augmentation index (AI), are independent predictors of future cardiovascular events11); additionally, CIMT has been reported to have a positive relationship with central BP12). Central BP directly affects the common carotid arteries, resulting in CIMT for a long duration13, 14). CIMT is also related to cardiovascular events15, 16).
Aim
This study aims to evaluate the association between central hemodynamic indices and CIMT with the occurrence of new-onset HT, independent of known risk factors, including brachial BP, to stratify the risk for HT development in participants with high normal BP, namely, pre-HT. Considering the different definitions indicated in the guidelines, brachial BP measurements of SBP 120–139 mmHg and DBP ＜90 mmHg are defined as high normal BP1-3). Further, we hypothesize that there was a positive relationship between these factors and new-onset HT and that we can demonstrate the effectiveness of additional measurements for hemodynamic indices and CIMT for screening participants at risk, requiring active management to prevent progression into HT.
Methods
Study Participants
This prospective cohort study used the Tohoku Medical Megabank Community-Based Project Cohort Study (TMM CommCohort Study), a community-based prospective cohort study conducted from 2013 in the Miyagi prefecture in Japan17). The baseline survey comprises two surveys: Survey 1 collected basic information, such as blood, and urine test data, questionnaire responses, and municipal health check-up data at the sites of the annual community health examination; Survey 2 was conducted at the TMM facility and included physical examination measurements, blood and urine tests, and detailed measurements, including central BP measurement, and carotid ultrasound imaging. The study included detailed measurements, such as hemodynamic indices and CIMT, in addition to brachial BP, and several studies aiming to prevent and manage HT were previously reported using this cohort18-21).
Almost the same examinations were carried out in the secondary survey, which was conducted approximately four years after the baseline survey. All participants provided written informed consent to participate in this study, which was approved by the institutional review board of the Tohoku Medical Megabank Organization (approval number: 2021-4-028).
The inclusion criteria included the following: participation in Survey 2 for the TMM CommCohort Study; a high normal BP, defined as SBP of 120–139 mmHg and DBP ＜90 mmHg using brachial BP measurement; no administration of antihypertensive drugs during the baseline survey; absence of medical history of stroke, myocardial infarction, aortic dissection, and atrial fibrillation; and participation in the secondary survey, conducted four years after the baseline survey.
Outcome of the Secondary Survey
Data from the baseline survey were extracted to assess cardiovascular risk factors at the baseline, and results of BP measurements and questionnaires regarding medication for HT during the secondary survey were used to assess new-onset HT, the outcome of this study (Fig.1).
New-onset HT was defined as satisfying at least one of the following two criteria: HT (SBP ≥ 140 mmHg and/or DBP ≥ 90 mmHg) using brachial BP measurement; and taking medication for HT according to the self-reported questionnaire22, 23). The participants who did not meet the definition of new-onset HT were defined as having non-new-onset HT.
Data Collection and Measurement during the Baseline Survey
Physical examination measurements included height, weight, body mass index (BMI), brachial SBP and DBP, and heart rate (HR) measurements. Blood test data, including γ-glutamyl transpeptidase (G-GTP), HbA1c, total cholesterol, low density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglyceride (TG), creatinine (Cr), and estimated glomerular filtration rate (eGFR), were extracted.
Lifestyle habits, such as smoking and drinking, and past medical history were defined according to the self-reported questionnaire responses. Smoking was defined as having smoked more than 100 cigarettes throughout their lives. The amount of alcohol intake per day was calculated according to self-report questionnaires. Dyslipidemia was defined when they were under treatment or satisfied the criteria of dyslipidemia (LDL ≥ 140 mg/dL, HDL ＜40 mg/dL, TG ≥ 150 mg/dL, and/or non-HDL ≥ 170 mg/dL)24). Diabetes mellitus was defined when they were under treatment or HbA1c ≥ 6.5%25).
Brachial BP was measured at our research center26). A trained nurse measured the research BP of the seated participants twice after they had rested for 1–2 min, using an HEM-9000AI electronic upper arm-cuff device (Omuron Corporation, Kyoto, Japan). The means of BP values were analyzed.
Hemodynamic indices, such as central BP, and AI, were measured using tonometry with a multielement probe that selects the best quality pressure wave, HEM-9000AI. The second systolic peak of the radial artery SBP (SBP2) was considered the central BP27). The AI value was calculated as the amplitude of the late systolic peak/the amplitude of the early systolic peak ＊100 (%), and the AI measurement was normalized to an HR of 75 bpm for the analysis28, 29). Central PP was defined as the SBP2 minus the brachial DBP, based on the observation that the DBP was consistent throughout any conduit artery from central to peripheral30, 31).
Carotid ultrasound imaging was measured by trained nurses using the GM-72P00A (Panasonic Healthcare Co., Kanagawa, Japan), equipped with an 8.5- MHz linear scan type B-mode probe, which was used in several previous studies32, 33). The left and right CIMTs were measured at a plaque-free site, 10 mm proximal to the carotid bifurcation. The bilateral CIMTs were measured twice, and the mean CIMT was the average of the four measurements. The images were measured in an automated analyzing system with automated settings based on ultrasound echo signal processing. Intraobserver and interobserver variability and producibility between systems (automated and conventional methods) were established in a previous study34), and we previously examined CIMT and related factors using this method35).
Statistical Analysis
The data are presented as means±standard deviations for normal distribution or medians (25–75 percentile) for skewed distribution and as numbers (percentages) for categorical variables. We used the t-test for normally-distributed data, Mann–Whitney U test for skewed data, and Chi-squared test for categorical variables to compare the characteristics of the participants, according to the central BP and CIMT. The participants were divided into two groups with lower and higher values using each median. Multivariable logistic regression models were used to obtain odds ratios (ORs) and 95% confidence intervals (CIs) to assess the relationship between baseline hemodynamic indices, such as central BP, AI, and central PP, and the mean CIMT with new-onset HT. Considering collinearity between the brachial BP and central BP, the correlation and variance inflation factor (VIF) in multivariable logistic regression analysis using brachial BP and central BP as continuous variables were assessed to construct the model. Subsequently, the central BP, CIMT, AI, and central PP were classified into quartiles from the lowest (Q1) to the highest (Q4) for analysis, with the lowest quartile of each serving considered the reference. The trends for new-onset HT according to the quartiles of these factors were also evaluated using logistic regression analysis. The models were adjusted for age, sex, BMI, brachial SBP, HR, eGFR, dyslipidemia, diabetes mellitus, smoking status, and alcohol intake. In the analysis of AI, HR was removed from this model, as AI measurement was normalized to an HR of 75 bpm. We also performed subgroup analysis according to age (＜60 and ≥ 60 years) and sex, as these factors were reported to have a significant influence on HT. We adopted the rounded-off average age as a cut-off value.
Although a previous study demonstrated the relationship between the central BP and
CIMT
12)
, we evaluated whether there was positive interaction between central BP and CIMT for new-onset brachial HT. To test our hypothesis, we used a combination of the two factors. Central BP and CIMT were classified based on each median, and participants were classified into four groups (lower central BP and lower CIMT; higher central BP and lower CIMT; lower central BP and higher CIMT; and higher central BP and higher CIMT); logistic regression analysis was performed with reference to the lower central BP and lower CIMT groups.
To compare the attribution of central BP and CIMT for new-onset HT, we calculated the area under the receiver operating characteristics curve (AUROC) and 95% CI. We compared the AUROCs of the basic model (age, sex, BMI, brachial SBP, HR, eGFR, dyslipidemia, diabetes mellitus, smoking status, and alcohol intake), brachial SBP only, brachial SBP with age and sex, and basic model with central BP and/or CIMT.
Further, we performed sensitivity analysis for the participants, excluding the participants under treatment for dyslipidemia and diabetes mellitus because their BPs were more likely to be monitored by their physicians. Two-tailed p-values ＜0.05 were considered statistically significant. All analyses were performed using the Statistical Analysis System software, version 9.4 for Windows (SAS Inc., Cary, NC, USA).
Results
Fig.2 shows the flow of participant selection. In total, 17,575 individuals participated in Survey 2. Among the 5,000 participants who satisfied the inclusion criteria at the baseline, 4,021 (80.4%) participants completed the secondary survey. The average age at baseline was 58.7±11.5 years (1,113 males, 27.7%). The characteristics of the participants are shown in Table 1. The average central BP was 120.1±8.2 mmHg, and CIMT was 0.60 mm (0.53–0.68).
Table 1. Baseline characteristics of participants with high normal blood pressure at the baseline survey (2013–2016) according to central BP and CIMT
|
Total N= 4,021 |
Central BP |
CIMT |
|
lower
n= 1,939
|
higher
n= 2,066
|
p-value
|
lower
n= 2,057
|
higher
n= 1,951
|
p-value
|
| Age (years) |
58.7±11.5 |
55.7±12.9 |
61.5±9.2 |
＜0.001 |
53.4±11.9 |
64.3±7.9 |
＜0.001 |
| Sex (male) (%) |
1113 (27.7) |
687 (35.4) |
424 (20.5) |
＜0.001 |
523 (25.4) |
586 (30.0) |
0.001 |
| BMI |
22.7±3.2 |
22.9±3.4 |
22.5±3.0 |
＜0.001 |
22.6±3.4 |
22.8±3.1 |
0.18 |
| HR (/min) |
67.1±9.7 |
69.8±9.9 |
64.6±8.7 |
＜0.001 |
68.2±9.9 |
66.0±9.3 |
＜0.001 |
| Brachial SBP (mmHg) |
127.5 |
123.5 |
132.0 |
＜0.001 |
126.0 |
130.0 |
＜0.001 |
| (123.0–132.5) |
(122.0–126.5) |
(128.0–135.5) |
|
(122.0–131.5) |
(125.5–135.0) |
|
| Brachial DBP (mmHg) |
78.5 |
78.0 |
80.0 |
＜0.001 |
80.0 |
77.0 |
＜0.001 |
| (73.5–83.0) |
(72.5–81.5) |
(75.0–84.0) |
|
(72.0–82.0) |
(75.0–84.5) |
|
| Central BP (mmHg) |
120.1±8.2 |
113.3±5.1 |
126.5±4.7 |
＜0.001 |
118.9±8.3 |
121.4±7.9 |
＜0.001 |
| CIMT (mm) |
0.60 |
0.58 |
0.61 |
＜0.001 |
0.53 |
0.68 |
＜0.001 |
| (0.53–0.68) |
(0.51–0.66) |
(0.55–0.70) |
|
(0.49–0.56) |
(0.64–0.75) |
|
| AI (%) |
83.0±12.1 |
76.5±11.4 |
89.0±9.3 |
＜0.001 |
82.1±12.7 |
83.9±11.3 |
＜0.001 |
| Central PP (mmHg) |
42.1±9.4 |
36.3±7.6 |
47.5±7.6 |
＜0.001 |
39.5±8.9 |
44.7±9.2 |
＜0.001 |
| HbA1c (%) |
5.5±0.44 |
5.48±0.47 |
5.51±0.39 |
0.009 |
5.43±0.40 |
5.56±0.47 |
＜0.001 |
| T-chol (mg/dL) |
215.2±35.0 |
211.9±35.7 |
218.2±34.1 |
＜0.001 |
212.1±34.7 |
218.6±34.9 |
＜0.001 |
| LDL (mg/dL) |
129.8±31.0 |
127.5±31.0 |
132.0±30.9 |
0.14 |
126.5±30.1 |
133.2±31.1 |
＜0.001 |
| HDL (mg/dL) |
65.1±16.6 |
63.5±16.2 |
66.5±16.9 |
＜0.001 |
65.5±16.5 |
64.6±16.8 |
0.12 |
| TG (mg/dL) |
87.0 |
86.5 |
88.0 |
0.97 |
84.0 |
90.0 |
＜0.001 |
| (64.0–123.0) |
(63.0–127.0) |
(65.0–121.0) |
|
(61.0–123.0) |
(68.0–124.0) |
|
| Cr (mg/dL) |
0.67±0.14 |
0.68±0.16 |
0.65±0.13 |
＜0.001 |
0.65±0.13 |
0.68±0.15 |
＜0.001 |
| eGFR |
79.3±15.0 |
80.7±15.7 |
77.9±14.2 |
＜0.001 |
82.6±15.6 |
75.8±13.6 |
＜0.001 |
| Alcohol intake (g/day) |
0.77 (0.0–0.89) |
0.91 (0.0–10.6) |
0.65 (0.0–7.4) |
0.006 |
0.91 (0.0–10.1) |
0.65 (0.0–7.6) |
0.007 |
| Smoke (%) |
1,265 (31.5) |
701 (36.2) |
561 (27.2) |
0.57 |
685 (33.4) |
577 (29.7) |
0.013 |
| Diabetes mellitus (%) |
192 (4.8) |
130 (4.3) |
62 (6.0) |
0.10 |
60 (2.9) |
132 (6.8) |
＜0.001 |
| Dyslipidemia (%) |
2,094 (52.1) |
951 (49.0) |
1,135 (54.9) |
＜0.001 |
949 (46.1) |
1,136 (58.2) |
＜0.001 |
AI, augmentation index; BMI, body mass index; BP, blood pressure; CIMT, carotid intima media thickness; Cr, creatinine; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; HT, hypertension; HDL, high density lipoprotein; HR, heart rate; LDL, low density lipoprotein; PP, pulse pressure; SBP, systolic blood pressure; T-chol, total cholesterol; TG: triglyceride
The baseline characteristics were compared according to the lower/higher central BP and CIMT (Table 1). The group with higher central BP and that with higher CIMT had similar properties except for sex and HR compared to the groups with lower values (i.e., older age, higher brachial BP, higher AI, higher PP, and higher prevalence of dyslipidemia and diabetes mellitus). CIMT was thicker in the group with higher central BP (0.61 [0.55–0.70] mm vs. 0.58 [0.51–0.66] mm; p＜0.001), and central BP was higher in the group with higher CIMT (121.4±7.9 vs. 118.9±8.3 mmHg; p＜0.001).
The secondary survey was performed 3.5±0.7 years after the baseline survey. Among 4,021 participants, 226 (5.6%) used antihypertensive drugs, whereas another 804 (20.0%) satisfied the BP measurement criteria for HT; thus, 1,030 (25.6%) participants were included in the new-onset HT group.
In the multivariable logistic regression analysis, the ORs (95% CIs) for new-onset HT were 1.06 (1.03–1.08) in brachial BP and 1.03 (1.01–1.04) in central BP. VIFs were adequately low to use the model, including the brachial SBP and central BP (2.8 in brachial SBP and 3.6 in central BP), although there was a positive correlation between the brachial SBP and central BP (r=0.73, 0.71–0.74).
The ORs (95% CIs) for new-onset HT according to the central BP, CIMT, AI, and central PP quartiles are shown in Table 2. In multivariable-adjusted analysis, as the quartile for central BP increased, the OR of the new-onset of HT also increased (p for trend=0.0030). In the highest quartile, the OR was 1.7 (95% CI: 1.2–2.4; p＜0.01) when the reference was a risk of new-onset HT in the lowest quartile. The same trend was observed for CIMT (p for trend ＜0.001), where the OR was 1.8 (95% CI: 1.4–2.4; p＜0.001). Otherwise, the ORs for AI, and central PP were 1.03 (95% CI: 0.82–1.3; p for trend=0.70) and 0.65 (95% CI: 0.47–0.90; p for trend=0.018), respectively.
Table 2. Odds ratios (95% CIs) for new-onset hypertension at the secondary survey according to quartiles of hemodynamic indexes and intima media thickness at the baseline survey
|
|
Q1 |
Q2 |
Q3 |
Q4 |
p for trend
|
| Central BP |
Cut-off |
＜114.5 |
114.5 ≤, ＜120 |
120 ≤, ＜126 |
126 ≤ |
|
| New-onset HT, n (%)
|
153/944 (16.2) |
212/995 (21.3) |
280/1,016 (27.6) |
380/1,050 (36.2) |
|
| Crude ORs (95% CIs) |
1 (reference) |
1.4 (1.1–1.8)＊＊
|
2.0 (1.6–2.5)＊＊＊
|
2.9 (2.4–3.6)＊＊＊
|
＜0.001 |
| Age- and sex- adjusted ORs |
1 (reference) |
1.3 (1.04–1.7)＊
|
1.8 (1.4–2.3)＊＊＊
|
2.6 (2.1–3.3)＊＊＊
|
＜0.001 |
| Multivariable adjusted ORs |
1 (reference) |
1.3 (0.97–1.6) |
1.5 (1.1–1.9)＊＊
|
1.7 (1.2–2.4)＊＊
|
0.0030 |
| CIMT |
Cut-off |
＜0.53 |
0.53 ≤, ＜0.60 |
0.60 ≤, ＜0.68 |
0.68 ≤ |
|
| New-onset HT, n (%)
|
183/982 (18.6) |
227/1,075 (21.1) |
267/951 (28.1) |
350/1,000 (35.0) |
|
| Crude ORs (95% CIs) |
1 (reference) |
1.2 (0.94–1.5) |
1.7 (1.4–2.1)＊＊＊
|
2.4 (1.9–2.9)＊＊＊
|
＜0.001 |
| Age- and sex- adjusted ORs |
1 (reference) |
1.1 (0.84–1.3) |
1.5 (1.2–1.9)＊＊
|
2.0 (1.6–2.6)＊＊＊
|
＜0.001 |
| Multivariable adjusted ORs |
1 (reference) |
1.0 (0.80–1.3) |
1.4 (1.1–1.8)＊＊
|
1.8 (1.4–2.4)＊＊＊
|
＜0.001 |
| AI |
Cut-off |
＜76 |
76 ≤, ＜84 |
84 ≤, ＜91 |
91 ≤ |
|
| New-onset HT, n (%)
|
214/946 (22.6) |
263/1,060 (24.8) |
274/1,016 (27.0) |
274/985 (27.8) |
|
| Crude ORs (95% CIs) |
1 (reference) |
1.1 (0.92–1.4) |
1.3 (1.01–1.6)＊
|
1.3 (1.07–1.6)＊＊
|
0.0087 |
| Age- and sex- adjusted ORs |
1 (reference) |
0.97 (0.78–1.2) |
1.1 (0.84–1.3) |
1.1 (0.86–1.4) |
0.33 |
| Multivariable adjusted ORs |
1 (reference) |
0.97 (0.77–1.2) |
1.00 (0.79–1.3) |
1.03 (0.82–1.3) |
0.70 |
| Central PP |
Cut-off |
＜36 |
36 ≤, ＜42 |
42 ≤, ＜49 |
49 ≤ |
|
| New-onset HT, n (%)
|
218/1,042 (20.9) |
221/935 (23.6) |
314/1,082 (29.0) |
272/945 (28.8) |
|
| Crude ORs (95% CIs) |
1 (reference) |
1.2 (0.94–1.4) |
1.5 (1.3–1.9)＊＊＊
|
1.5 (1.2–1.9)＊＊＊
|
＜0.001 |
| Age- and sex- adjusted ORs |
1 (reference) |
0.99 (0.79–1.2) |
1.2 (0.99–1.5) |
1.1 (0.89–1.4) |
0.12 |
| Multivariable adjusted ORs |
1 (reference) |
0.83 (0.65–1.06) |
0.86 (0.66–1.1) |
0.65 (0.47–0.90)＊＊
|
0.018 |
AI, augmentation index; BP, blood pressure; CIs, confidence intervals; CIMT, carotid intima media thickness; ORs, odds ratios; Q1, first quartile; Q2, second quartile; Q3, third quartile; Q4, fourth quartile
＊p＜0.05, ＊＊p＜0.01, ＊＊＊p＜0.001 with the first quartile as a reference
Covariates include age, sex, body mass index, brachial systolic blood pressure, heart rate, eGFR, dyslipidemia, diabetes mellitus, smoking, alcohol intake. In multivariable analysis of AI, the heart rate was removed.
In the subgroup analysis, participants were categorized into two groups according to age (＜60 and ≥ 60 years) and sex; thereafter, we analyzed the relationship between the central BP and new-onset HT, or CIMT and new-onset HT (Table 3). The same models were constructed for all analyses (Table 2). A thicker CIMT was significantly correlated with a higher risk of new-onset HT in all age and sex groups, and the ORs in the fourth quartile were higher in older and female individuals (older, OR: 2.0, 95% CI: 1.4–3.0; female, OR: 2.1, 95% CI: 1.6–2.8); however, a higher central BP was significantly associated with new-onset HT in the younger age group and that with female individuals (younger, OR: 3.0, 95% CI: 1.7–5.4; female, OR: 1.8, 95% CI: 1.2–2.8).
Table 3. Subgroup analysis for new-onset hypertension by age at the baseline survey
| Age (years) |
Q1 |
Q2 |
Q3 |
Q4 |
p for trend
|
| Central BP |
＜60 |
New-onset HT, n (%)
|
49/416 (11.8) |
78/404 (19.3) |
93/450 (20.7) |
163/453 (36 .0) |
|
|
ORs (95% CIs) |
1 (Reference) |
1.8 (1.2–2.7)＊＊
|
1.8 (1.2–2.9)＊＊
|
3.0 (1.7–5.4)＊＊＊
|
＜0.001 |
| ≥ 60 |
New-onset HT, n (%)
|
118/562 (21.0) |
138/535 (25.8) |
173/610 (28.4) |
213/575 (37.0) |
|
|
ORs (95% CIs) |
1 (Reference) |
1.1 (0.84–1.6) |
1.1 (0.76–1.5) |
1.2 (0.79–2.0) |
0.44 |
| Male |
New-onset HT, n (%)
|
44/265 (16.6) |
59/282 (20.9) |
69/274 (25.2) |
95/290 (32.8) |
|
|
ORs (95% CIs) |
1 (Reference) |
1.3 (0.84–2.1) |
1.4 (0.85–2.4) |
1.6 (0.90–3.0) |
0.11 |
| Female |
New-onset HT, n (%)
|
114/691 (16.5) |
161/732 (22.0) |
193/708 (27.3) |
290/763 (38.0) |
|
|
ORs (95% CIs) |
1 (Reference) |
1.3 (0.97–1.7) |
1.4 (0.98–1.9) |
1.8 (1.2–2.8)＊＊
|
0.0093 |
| CIMT |
＜60 |
New-onset HT, n (%)
|
138/760 (18) |
113/521 (22) |
84/276 (30) |
50/168 (30) |
|
|
ORs (95% CIs) |
1 (Reference) |
1.1 (0.77–1.4) |
1.5 (1.04–2.2)＊
|
1.4 (0.88–2.1) |
0.036 |
| ≥ 60 |
New-onset HT, n (%)
|
45/222 (20) |
114/554 (21) |
183/675 (27) |
300/832 (36) |
|
|
ORs (95% CIs) |
1 (Reference) |
0.99 (0.67–1.5) |
1.4 (0.96–2.1) |
2.0 (1.4–3.0)＊＊＊
|
＜0.001 |
| Male |
New-onset HT, n (%)
|
63/396 (15.9) |
97/455 (21.3) |
91/430 (21.2) |
134/444 (30.2) |
|
|
ORs (95% CIs) |
1 (Reference) |
1.2 (0.81–1.7) |
1.1 (0.74–1.7) |
1.6 (1.05–2.4)＊
|
0.032 |
| Female |
New-onset HT, n (%)
|
121/599 (20.2) |
133/521 (25.5) |
181/595 (30.4) |
207/568 (36.4) |
|
|
ORs (95% CIs) |
1 (Reference) |
1.3 (0.98–1.8) |
1.6 (1.2–2.1)＊＊
|
2.1 (1.6–2.8)＊＊＊
|
＜0.001 |
AI, augmentation index; BP, blood pressure; CIs, confidence intervals; CIMT, carotid intima media thickness; ORs, odds ratios; Q1, first quartile; Q2, second quartile; Q3, third quartile; Q4, fourth quartile
＊p＜0.05, ＊＊p＜0.01, ＊＊＊p＜0.001 with the first quartile as a reference
Covariates include age, sex, body mass index, brachial systolic blood pressure, heart rate, eGFR, dyslipidemia, diabetes mellitus, smoking, alcohol intake.
The combination of central BP and CIMT for new-onset HT was also evaluated (Table 4). Compared with the lower central BP and lower CIMT group, the multivariable-adjusted ORs (95% CIs) were as follows: 1.8 (1.3–2.3) for higher central BP and lower CIMT; 2.2 (1.7–2.9) for lower central BP and higher CIMT; and 2.3 (1.8–3.1) for higher central BP and higher CIMT. There was an offsetting effect between the central BP and CIMT on new-onset HT (p for interaction =0.0049), resulting in a small increase of OR in higher central BP and higher CIMT. A similar relationship was observed in groups aged ＜60 years and among females.
Table 4. Combination of central blood pressure and carotid intima media thickness for new-onset hypertension
|
Lower central BP and Lower CIMT |
Higher central BP and Lower CIMT |
Lower central BP and Higher CIMT |
Higher central BP and Higher CIMT |
p for interaction
|
| All |
1.0 (Reference) |
1.8 (1.3–2.3＊＊＊
|
2.2 (1.7–2.9)＊＊＊
|
2.3 (1.8–3.1)＊＊＊
|
0.0049 |
| Age ＜60 years |
1.0 (Reference) |
1.7 (1.1–2.7)＊
|
1.5 (0.99–2.3) |
2.2 (1.3–3.7)＊＊
|
0.016 |
| Age ≥ 60 years |
1.0 (Reference) |
1.4 (0.96–2.1) |
1.7 (1.2–2.3)＊＊
|
1.9 (1.2–3.0)＊＊
|
0.73 |
| Male |
1.0 (Reference) |
1.2 (0.69–2.1) |
1.2 (0.71–2.0) |
1.3 (0.68–2.4) |
0.23 |
| Female |
1.0 (Reference) |
1.5 (1.02–2.1)＊
|
1.6 (1.2–2.1)＊＊
|
2.3 (1.6–3.4)＊＊＊
|
0.0055 |
BP, blood pressure; CIMT, carotid intima media thickness
＊p＜0.05, ＊＊p＜0.01, ＊＊＊p＜0.001 with the first quartile as a reference
A higher central BP exceeded the median of 120 mmHg, while a higher CIMT exceeded the median of 0.60 mm. Covariates include age, sex, body mass index, brachial systolic blood pressure, heart rate, eGFR, dyslipidemia, diabetes mellitus, smoking, alcohol intake.
To assess the attribution of central BP and CIMT for new-onset HT, AUROCs were calculated, as presented in Table 5. The AUROC of the basic model was 0.660 and showed poor predictability. The addition of central BP and/or CIMT improved the predictability, and the AUROCs were 0.662 with central BP, 0.674 with CIMT, and 0.678 with both.
Table 5. Area under the receiver operating characteristics curve and 95% confidence interval for new-onset hypertension
| Models |
AUROCs (95% CIs) |
difference from basic model |
| Brachial SBP only |
0.638 (0.619–0.657) |
-0.022 |
| Brachial SBP＋Age＋Sex |
0.642 (0.623–0.661) |
-0.018 |
| Basic model＊
|
0.660 (0.641–0.678) |
0 |
| Basic model＋Central BP |
0.662 (0.644–0.681) |
+0.002 |
| Basic model＋CIMT |
0.674 (0.655–0.692) |
+0.014 |
| Basic model＋Central BP＋CIMT |
0.678 (0.659–0.696) |
+0.018 |
AUROC, area under the receiver operating characteristics curve; BP, blood pressure; CIs, confidence intervals; CIMT, carotid intima media thickness
＊Basic model includes age, sex, body mass index, brachial systolic blood pressure, heart rate, eGFR, dyslipidemia, diabetes mellitus,
smoking, alcohol intake.
Sensitivity analysis, excluding participants under treatment for dyslipidemia and diabetes mellitus, indicated the robustness of the results.
Discussion
This study assessed the association between hemodynamic indices and CIMT with new-onset HT in individuals with high normal BP to test the hypothesis that these factors increased the incidence of new-onset HT. As expected, higher central BP, and thicker CIMT showed positive associations with new-onset HT in multivariable analysis. This indicates that central BP and CIMT may be effective in accurately predicting HT in individuals with high normal BP. Other hemodynamic indices, including PP, and AI, did not show a significant relationship with new-onset HT. In older and male participants, CIMT may be more effective than central BP in predicting new-onset HT.
Although central hemodynamic indices were previously assessed to predict cardiovascular events, the relationship between central BP and new-onset HT was first evaluated in this study10, 11). Organs, such as the heart, kidney, and brain, are exposed to central BP rather than brachial BP. BP in peripheral arteries, including the brachial arteries, is affected by the branching structure and mechanical properties of the arterial system, increasing the BP in the peripheral arteries; therefore, this does not necessarily reflect central BP36). Previous studies suggest that although brachial BP and central BP have a strong correlation, there is a discrepancy between the two37, 38). The difference between the brachial BP and central BP, which is affected by arterial wall stiffness as reflected by AI, is larger in male than female individuals, and in the younger than in the older age group38). The mechanism of the discrepancy is unclear, and several explanations are speculated. One explanation is that a hyperkinetic heart in young individuals produces a high narrow systolic peak of the brachial wave, resulting in higher brachial BP39, 40); another explanation is that lower height and higher HR increase the wave reflection, resulting in higher central BP38). Although the Framingham Heart Study did not demonstrate that hemodynamic indices improved the model for predicting cardiovascular events41), as our study limited the study population depending on brachial BP measurement, central BP became a valuable measure owing to the discrepancy between the brachial BP and central BP.
The CIMT refers to the thick media layer of the arterial wall and the thin intima layer. HT causes large-artery remodeling and results in the thickening of CIMT42). Many previous studies demonstrate that the progression of CIMT increases the risk of cardiovascular diseases and mortality13, 15, 16, 43-48); the Atherosclerosis Risk in Communities Study has also revealed that CIMT is associated with the onset of HT, which represents an early change in cardiovascular disease status13); our findings are consistent with this result.
In subgroup analysis, high ORs were observed for the highest quartile of central BP in the younger age category. This may be because the previous report indicated that the difference between brachial BP and central BP was larger in the younger population38). Thicker CIMT was correlated with HT in both age categories, and the trend was clearer for individuals aged ≥ 60 years. CIMT was reported to increase at a rate of 7–10 µm/year13) and is thicker in older age. A possible explanation for our results is that individual differences in CIMT increase with aging.
The common carotid arteries are directly affected by central BP, and the thickening of the CIMT is a response to high BP at the common carotid arteries42). A previous study reported a positive relationship between central BP and CIMT12). Thickening of the CIMT slowly progresses13, 14), and a thick CIMT indicates that the common carotid arteries are exposed to a high BP for a long duration. Central BP and CIMT are closely related, and an offsetting effect is observed between them. The effect is small, and the highest OR is obtained in participants with higher central BP and higher CIMT in the combination analysis. It shows that each central BP and CIMT are related to new-onset HT. However, the effect size is different between the categories of age and sex.
This study is clinically important as the study population includes individuals with high normal BP, in which risk stratification is essential for the prevention of HT. Both central BP and CIMT can be measured noninvasively, and the results can be immediately obtained. Our results suggested that either central BP or CIMT should be measured, in addition to already known cardiovascular risk factors, to accurately predict new-onset HT in individuals with high normal BP. In people aged ＜60 years or female individuals, both central BP, and CIMT are effective; otherwise, CIMT is recommended for individuals aged ≥ 60 years or male individuals. To predict new-onset HT, CIMT may be better than the central BP in addition to known risk factors. This may be because central BP is correlated with brachial BP, which is an essential factor for HT, and the effect of central BP may reduce, even though central BP is an independent risk factor for HT. Accurate risk stratification can promote focused approaches, including home BP measurements, and lifestyle improvements in high-risk populations, which may prevent the onset of HT and cardiovascular events.
This study has several limitations. First, the outcome of this study was new-onset HT, defined as the use of antihypertensive drugs, or satisfying the HT criteria using brachial BP measurement, according to previous studies22, 23). The use of antihypertensive drugs was queried in the questionnaire; however, its accuracy was uncertain. Although it may cause misclassification, the results of the study may not change. Additionally, there were no data regarding cardiovascular events and mortality; thus, this study failed to assess the risks of major adverse cardiovascular events. This problem will be addressed in the future, as the participants of this cohort will be followed-up regarding cardiovascular events and mortality using mail surveys, medical record reviews, and medical statistics17). Furthermore, this community cohort study had a unique population; the mean age of participants was 58.7±11.5 years, and approximately 70% of the cohort was female. Although ORs for new-onset HT in males increased according to the quartiles of central BP, the relationship was not significant. We supposed that the sample size of male participants was too small to show significance. In the future, generalizability should be confirmed by further studies targeting different populations. Furthermore, although the results of this study indicate that central BP and CIMT may be independent markers of future HT development, future studies are needed to determine whether they can be used as prevention targets.
Conclusion
In conclusion, higher central BP and thicker CIMT are related to new-onset HT in participants with high normal BP, independent of brachial SBP, and cardiovascular risk factors. As the measurement of central BP and CIMT may be effective in assessing the risk of HT, it can enable focused management for the high-risk population.
Acknowledgements
This research was supported by the Japan Agency for Medical Research and Development, AMED under Grant Number JP21tm0124005.
This research used the super computer system provided by Tohoku Medical Megabank Project (founded by AMED under Grant Number JP21tm0424601).
The authors thank the members of the Tohoku Medical Megabank Organization, including the Genome Medical Research Coordinators and the office and administrative personnel for their assistance. A complete list of members is available at https://www.megabank.tohoku.ac.jp/english/a220901/.
Conflict of Interest
The authors do not have any conflicts of interest to disclose with respect to this manuscript.
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