Association between healthy vascular aging and the risk of the first stroke in a community-based Chinese cohort

Study participants

From January 1, 2010 to December 31, 2016, brachial-ankle pulse wave velocity (baPWV) measurements were made in 30,772 participants in the Kailuan cohort. Among them, 13,280 were older than 50 years. After excluding participants for whom blood pressure data was lacking (N=1112) and those with a history of cerebrovascular diseases before the baPWV measurement (N=694), a total of 11,474 participants were included in the study (Figure 1). Among that group, 3003 (26.2%) exhibited HVA at baseline, whereas the remaining 8471 (73.8%) did not. A comparison of demographic and clinical information between the HVA and Non-HVA groups is shown in Table 1.

The prevalence and determinants of HVA

The prevalence of HVA was 36.0% among participants aged 50 to 59 years, 18.2% among participants aged 60 to 69 years, and 4.7% among those aged ≥70 years (Figure 2). Using a multivariable analysis, we found that younger age, female sex, lower body mass index (BMI), lower high-sensitive C-reactive protein (hs-CRP), lower fasting blood glucose (FBG), higher education level, active physical activity, absence of current alcohol drinking, and the absence of diabetes mellitus and hyperlipidemia were significantly associated with HVA (p<0.05) (Table 2).

Association between HVA and the risk of first-ever stroke

The follow-up times were similar in the two groups (HVA group, 3.37 ± 2.25 years; Non-HVA group, 3.29 ± 2.31 years). During a median follow-up of 3.3 years, first stroke occurred in 0.5% (15/3003) of participants in HVA group, as compared to 2.6% (217/8471) of those in the Non-HVA group (p<0.001). First ischemic stroke occurred in 0.5% (14/3003) of participants in the HVA group, as compared to 2.3% (198/8471) of those in the Non-HVA group (p<0.001) (Table 3). Participants with HVA had considerably lower age and sex-adjusted (model 1) risk of stroke (hazard ratio (HR), 0.21; 95% confidence intervals (CI), 0.12-0.36) and ischemic stroke (HR, 0.22; 95% CI, 0.12-0.37) as compared to participants in the Non-HVA group (Table 4). After adjusting for other cardiovascular risk factors (including BMI, smoking, alcohol consumption, physical activity, history of diabetes, history of hyperlipidemia) (model 2), HVA was associated with a 0.23-fold (95% CI, 0.13–0.39) lower risk of stroke and a 0.23-fold lower risk (95% CI, 0.14–0.41) of ischemic stroke. After further adjusting for monthly income, education level, FBG, total cholesterol (TC), low-density lipoprotein cholesterol (LDL), hs-CRP, and use of anti-diabetic and lipid-lowering medications (model 3), HVA was associated with a 0.23-fold (95% CI, 0.14-0.40) lower risk of stroke and a 0.24-fold lower risk (95% CI, 0.14–0.42) of ischemic stroke. After additionally adjusting for systolic blood pressure (model 4), HVA was associated with a 0.32-fold (95% CI, 0.18-0.56) lower risk of stroke and a 0.32-fold lower risk (95% CI, 0.18-0.58) of ischemic stroke (Figure 3).

Study participants

The Kailuan cohort is an ongoing prospective cohort based in the Kailuan community in Tangshan City in the north of China [30, 31]. All employees (≥ 18 years) of the Kailuan Group, a coal energy and chemical enterprise, were enrolled with the aim of investigating the risk factors of various diseases (e.g., stroke and cancers). As of December 31, 2016, 171,414 participants were included in the Kailuan cohort. The study’s protocol was approved by the participating hospitals’ ethics committees. All participants provided written informed consent. All participants underwent questionnaire assessments, clinical examinations and laboratory tests at the 11 hospitals responsible for healthcare in the Kailuan community.

To capture a distinct sample of individuals with HVA, in the present study we considered only participants in late middle age or older (aged ≥ 50 years), and we only enrolled participants who underwent baPWV measurement between 2010 and 2016. We excluded participants for whom blood pressure data was lacking as well as those with a history of cerebrovascular diseases before the baPWV measurement.

Assessment of baPWV

BaPWV was measured using a BP-203 RPE III networked arteriosclerosis detection device produced by Omron Health Medical Co., LTD (China) [30, 31]. Participants received baPWV assessment after 5 min of rest in a supine position. Cuffs were applied to both arms and ankles. The lower edge of the arm cuff was positioned 2-3 cm above the cubital fossa transverse striation, and the lower edge of the ankle cuff was positioned 1-2 cm above the medial malleolus. The heartbeat monitor was placed at the left edge of the sternum, and electrocardiogram electrodes were placed on both wrists. BaPWV was calculated as the distance between the two sites divided by the pulse transit time (defined as the time interval between the wave fronts of the brachial and ankle waveforms). The distance between the sampling points was calculated automatically according to the subject’s height. The maximum value of the bilateral baPWV was used in our study. Using the detection device, we were able to read the baPWV value directly. The methodology for baPWV measurement was the same for all participants.

Baseline data on demographics and cardiovascular risk factors were collected through face-face interviews when baPWV was measured. The collected data included age, sex, BMI, smoking, alcohol consumption, physical activity, history of diabetes, history of hyperlipidemia, monthly income, education level, FBG, TC, LDL, hs-CRP, use of antidiabetic or lipid-lowering drugs. Physical activity was evaluated from responses to questions about the type and frequency of physical activity at work and during leisure time. Inactive physical activity was defined as no physical activity or less than 30 minutes every week.

Assessment of HVA

We defined HVA for participants aged ≥ 50 years as follows [12]: 1) absence of hypertension, which was defined as a systolic blood pressure < 140 mmHg, a diastolic blood pressure < 90 mmHg (blood pressure was measured at least twice at different occasions), and an absence of antihypertensive drugs; 2) baPWV < mean + 2 standard deviations (SD), which was determined from a reference sample of healthy participants aged 18-30 years with no cardiovascular risk factors (e.g., hypertension, diabetes, smoking, hyperlipidemia) and without a history of myocardial infarction, stroke, and other cardiovascular disease. To obtain the reference value for baPWV, we enrolled 595 healthy participants aged < 30 years from the Kailuan study (Figure 4). The results showed that the reference value for baPWV was 11.90 ± 1.65 m/s. Thus, HVA was defined as a normotensive blood pressure and baPWV < 15.20 m/s. Based on these data, participants were classified into HVA and Non-HVA groups.

Outcome assessment and follow-up

The participants were followed up by face-to-face interviews at every two-year routine medical examination until December 31, 2017 or to death. The outcome information for the participants without face-to-face follow-up was obtained by referring to death certificates from provincial vital statistics offices, discharge summaries from the 11 hospitals, and medical records from medical insurance. The follow-ups were performed by hospital physicians, research physicians, and research nurses who were blinded to the baseline data. All stroke records were reviewed by two independent stroke specialists. If there were instances of disagreement in a single case, the final evaluation was made by the event adjudication committee.

The primary outcome was the first occurrence of stroke (both ischemic and hemorrhagic). These included the first nonfatal stroke event or stroke death without a preceding nonfatal event. Stroke was diagnosed according to the World Health Organization criteria [32] combined with brain computed tomography (CT) or magnetic resonance (MR) imaging for confirmation. The secondary outcome was the first occurrence of ischemic stroke. All study outcomes were validated by the Data Safety Monitoring Board and the Arbitration Committee for Clinical Outcomes.

Statistical analysis

Continuous variables are presented as the mean ± SD or median with interquartile range, while categorical variables are presented as frequencies with percentages. The nonparametric Wilcoxon or t tests were used to compare group differences for continuous variables and χ² tests were used for categorical variables.

The association between baseline characteristics and HVA was investigated using multivariate backward logistic regression, and variables with p values < 0.05 were selected as confounding variables. Odds ratios (ORs) with the 95% CI were reported. We also examined associations between HVA and first stroke or ischemic stroke using Cox proportional hazards regression models. For each outcome, 4 multivariable models were performed. In model 1, we only adjusted for age and sex. In model 2, we additionally adjusted for other cardiovascular risk factors (including BMI, smoking, alcohol consumption, physical activity, history of diabetes, history of hyperlipidemia). In model 3, we further adjusted for monthly income, education level, FBG, TC, LDL, hs-CRP, and use of antidiabetic or lipid-lowering medications. In model 4, we further adjusted for systolic blood pressure. Life table methods were used to calculate the cumulative rate of stroke-free survival, and a curve was generated.

Two-sided p values < 0.05 were considered significant. All analyses were performed using SAS 9.4 (SAS Institute, Cary, North Carolina).