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Combined effects of carotid plaques and hypertension on the risk of cardiovascular disease and all‐cause mortality

Abstract Background Both hypertension and atherosclerotic plaques are risk factors for cardiovascular disease (CVD). Hypothesis This study aimed to investigate whether the combined effects of carotid plaques and hypertension increase the risks of CVD and all‐cause mortality. Methods Patients from the stroke and elderly cohorts of the Kailuan study in China who completed a carotid sonography examination were included in the study. Participants in both cohorts underwent physical examinations between 2010 and 2011 and were divided into four groups: no carotid plaques with normal blood pressure (n = 2227), hypertension only (n = 1290), carotid plaques only (n = 1128), and hypertension with carotid plaques (n = 1862). The outcomes included the first occurrence of CVD and all‐cause mortality. Results Among the 6507 participants (mean age, 58.1 ± 11.8 years, 61% males), 157 cardiovascular events, and 210 deaths occurred after average follow‐ups of 4.5 and 4.9 years, respectively. After adjusting for covariates, carotid plaques only and hypertension with carotid plaques were associated with excess risk (hazard ratio [HR]; confidence interval [CI]) for the first occurrence of CVD (HR = 1.85; 95% CI, 1.01‐3.44; and HR = 2.97; 95% CI, 1.66‐5.29, respectively), cerebral infarction (HR = 2.66; 95% CI, 1.16‐6.15; and HR = 4.15; 95% CI, 1.87‐9.19, respectively), and all‐cause mortality (HR = 1.96; 95% CI, 1.16‐3.31; and HR = 1.85; 95% CI, 1.09‐3.13, respectively). Conclusions The combination of hypertension and atherosclerotic plaques may increase the risk of CVD events and all‐cause mortality, especially cerebral infarction, compared with participants without those factors.


| INTRODUCTION
Cardiovascular diseases (CVDs) encompass a number of vascular conditions such as coronary heart disease (CHD), cerebrovascular disease, peripheral artery disease, rheumatic heart disease, congenital heart disease, deep vein thrombosis, and pulmonary embolism. 1 CVDs are the leading causes of death worldwide, with an estimated 17.9 million deaths in 2016, or 31% of all global deaths. 1 One of every three deaths in the United States is attributable to CVDs, 2,3 and the prevalence of CVDs in China is continuously increasing because of changes in lifestyle, urbanization, and the aging population. 4 Currently, one in five Chinese adults are afflicted with CVDs, which account for >40% of deaths from all causes in China. 5 Therefore, the burden of CVDs is substantial and has become a serious public health issue. Most CVDs can be prevented using proper lifestyle interventions. 1 Hypertension is a primary risk factor for CVD and all-cause mortality. [6][7][8] People with hypertension (blood pressure ≥140/90 mm Hg or treatment with antihypertensive medications) have a significant lifetime risk of overall CVD by 30 years of age. 9 Given a systolic blood pressure (SBP) of 115 mm Hg and diastolic blood pressure (DBP) of 75 mm Hg, each 20 mm Hg increase in SBP (or an equivalent of a 10 mm Hg DBP increase) is associated with more than a twofold risk of CVD and death. 10 More than half of all cases of CVDs are associated with hypertension in China, 4 and the risk of all-cause mortality from CHD and stroke is expected to increase from 14% to 95% and 290% among individuals with hypertension. 11 Atherosclerosis is the main cause of many CVDs. The formation of an atherosclerotic plaque is the hallmark of atherosclerosis, and vascular occlusion caused by plaque rupture is an important pathophysiological mechanism in the development of ischemic CVD. 12 The risk of CVD among individuals with atherosclerotic plaques is 1.3 to 2.8 times higher than that of individuals without plaques, as reported by several large cohort studies. [13][14][15][16] Therefore, the formation of atherosclerotic plaques is a major risk factor for the development of

CVD. The 2016 European Guidelines on CVD Prevention in Clinical
Practice recommended the use of carotid artery scanning for atherosclerotic plaque screening as part of CVD risk assessments. 17 After the addition of atherosclerotic plaques to the Framingham Risk Factor Model, the ability to predict CVD events increased by 2% to 5%, which was reported in several large cohort studies. 18 Therefore, the presence of atherosclerotic plaque has become an important measure of the level of risk in clinical studies.
In theory, because hypertension and atherosclerotic plaques are both independent risk factors for CVD, patients with these two factors may be at even higher risk for CVD events compared with patients with only one of these factors, but there are no scientific reports or empirical data on the effects of the relationships among hypertension, atherosclerotic plaques, and CVD, and their effects on all-cause mortality. To address this knowledge gap, data collected as part of the Kailuan study were analyzed to examine whether the combined risk factors of hypertension and atherosclerotic plaques could be associated with an increase in CVD events and all-cause mortality.

| Study design and population
The study population consisted of the stroke and elderly cohorts from the Kailuan cohort study, an ongoing prospective study, which has been described previously. 19 The study was initiated in 2006 by the Kailuan (Group) Co., Ltd. in Tangshan

| Data collection
Data on demographic characteristics, including age, sex, household income, education, lifestyle, and related variables, were collected using standardized questionnaires by trained investigators. Smoking was recorded as "yes" or "no" based on participants' self-reports.
Drinking was defined as alcohol consumption ≥100 mL/day for more than 1 year. Hypertension was defined as the presence or history of hypertension or the use of antihypertensive medication or a SBP ≥140 mm Hg or a DBP ≥90 mm Hg. Diabetes mellitus was defined as the presence or history of diabetes mellitus or current treatment with insulin or oral hypoglycemic agents or a fasting blood glucose (FBG) level ≥126 mg/dL. Dyslipidemia was defined as the presence or history of dyslipidemia, or the current use of lipid-lowering medication, or total cholesterol (TC) ≥220 mg/dL, triglyceride ≥150 mg/dL, or low-density lipoprotein cholesterol (LDL-C) ≥140 mg/dL.

| Assessment of cranial-carotid plaques
All study participants underwent a bilateral carotid duplex ultrasound (Philips iU-22 Ultrasound System, Philips Medical Systems, Bothell, Washington) to determine the presence of carotid plaques. Carotid artery plaque is defined as a focal structure that encroaches into the arterial lumen at least 0.5 mm or 50% of the surrounding IMT value or demonstrates a thickness >1.5 mm, as measured from the mediaadventitia interface to the intima-lumen interface. 20

| Follow-up and outcomes
Participants were followed using face-to-face interviews during routine medical examinations every 2 years until December 31, 2015, the occurrence of an event of interest, or death. The outcome information for patients who could not complete the face-to-face follow-up interviews was obtained by checking medical records from the hospital and the patient's medical insurance. The study endpoints included the first occurrence of a CVD event (stroke or MI) and all-cause mortality.
The diagnosis of stroke was confirmed by brain-computed tomography (CT) or magnetic resonance imaging (MRI) and classified into two main types: cerebral infarction and hemorrhagic stroke. MI was defined in accordance with the 2007 universal definition. 21 Deaths were confirmed by checking the death certificates from the provincial vital statistics offices. All outcomes were approved by the Data Safety Monitoring Board and the Arbitration Committee for Clinical Outcomes.

| Statistical analyses
Continuous variables were reported as means ± standard deviations, and compared using analysis of variance with the SNK or Dunnett T3 post hoc test. Categorical variables were reported as percentages, and analyzed using the chi-square test. Cox proportional hazards regression was used to estimate the risks of events by calculating the hazard ratios (HR) and 95% confidence intervals (CI). Other relevant risk factors were adjusted in the regression analysis. The rates of events were estimated using the Kaplan-Meier method and compared across groups using the log-rank test. All statistical tests were two-tailed, and the significance level was set to 0.05. Statistical analyses were performed using SAS 9.3 (SAS Institute, Cary, North Carolina).

| Baseline characteristics of the study population
The data from 6507 participants (mean age, 58.1 ± 11.8 years, 61% of males) were analyzed. The baseline characteristics of the entire cohort are presented in Table 1. Significant differences among the groups were found for age, sex, smoking habits, drinking habits, FBG, TC, LDL-C levels, carotid intima-media thickness, and follow-up.

| CVD events and all-cause mortality
After a mean follow-up of 4.5 ± 0.7 years, 157 CVD events occurred.
Among the overall study population, 44 participants had MIs, and 113 had strokes, including 105 cerebral ischemic strokes, and 8 cerebral hemorrhagic strokes. The incidence of CVDs was 53.91 per 10 000 person years. A total of 210 deaths occurred after a mean follow-up of 4.9 ± 0.6 years. The incidence of all-cause mortality was 65.54 per 10 000 person years ( Table 2).

| HRs for CVD and all-cause mortality by group
The results of the multivariable Cox proportional hazards regression analysis are shown in Table 3. After adjusting for all covariates, the hypertension only group did not show an increased risk for all-cause mortality or CVD, but the risk of cerebral ischemic stroke was 2.25 times higher (95% CI, 1.01-5.24). The groups with carotid plaques only and hypertension with carotid plaques were both associated with excess risks for the occurrence of CVD

| Sensitivity analysis results
Sensitivity analysis was performed after removing the lipid-lowering drug, and the results were consistent with the above results (Table S1).     39,40 used this method. The sample size of this study is large, and the participants did not move, resulting in minimal loss to follow-up.

| Survival analysis
The results still provide a scientific basis for the prevention and treatment of cardiovascular and cerebrovascular diseases.

| CONCLUSIONS
In conclusion, we can improve our evaluations of levels of risk for CVD and all-cause mortality, especially for stroke, with the use of ultrasound measurements in patients with combined hypertension and carotid plaques. This combined analysis was more sensitive to risk evaluations of CVD and all-cause mortality than any single indicator.