| Background:Stroke is the leading cause of death in China and the second leading cause of death in the world.[I]Primary prevention is regarded as the best option to reduce the population burden of stroke because about 77%of strokes are first events.[2]Hypertension is a well-recognized major modifiable risk factor of stroke.[3]According to the latest American Heart Association/American Stroke Association guidelines for the Primary Prevention of Stroke,[4]treatment of hypertension is among the most effective strategies for preventing both ischemic and hemorrhagic stroke.Little is known,however,about the role of pulse wave velocity(PWV),a marker of arterial stiffness,in the primary prevention of stroke.There is a growing recognition that PWV may affect BP and the response to anti-hypertension treatment.Large arterial stiffness and wave-reflection intensity have both been associated with isolated systolic hypertension(ISH).[5]Several studies have established important relationships between PWV(either carotid-femoral PWV(cfPWV)or brachial-ankle PWV(baPWV))and BP progression.[6-8]Our previous study showed that baPWV was an independent determinant of individual response to anti-hypertensive treatment.191 Particularly relevant to this report,recent longitudinal studies have demonstrated that increased baPWV levels predict cardiovascular mortality and morbidity among high-risk patients and the general population.[10-13]In their current guidelines for the management of arterial hypertension,the European Society of Hypertension included PWV as a potential consideration in managing middle-aged hypertensive patients with increased aortic stiffness.[14].However,none of the current stroke prevention guidelines have considered PWV due to limited data.This study sought to investigate whether baPWV can,independently and jointly with hypertension control,affect the risk of incident stroke using data from the China Stroke Primary Prevention Trial(the CSPPT).[15]This longitudinal analysis examined the independent and joint effect of brachial-ankle PWV(baPWV)with hypertension control on the risk of first stroke.Methods:Study Participants and DesignAll participants were part of the China Stroke Primary Prevention Trial(CSPPT,clinicaltrials.gov identifier:NCT00794885).The CSPPT was approved by the ethics committee of the Institute of Biomedicine,Anhui Medical University,Hefei,China(FWA assurance number FWA00001263).All participants provided written informed consent.A detailed description of the CSPPT can be found in a recent publication.[15]Briefly,the CSPPT was a multi-community,randomized,double-blind,controlled trial conducted from May 2008 to August 2013 in two study centers in China(Jiangsu and Anhui provinces).It was designed to evaluate whether a combined therapy of enalapril plus folic acid is more effective than enalapril alone in reducing the risk of stroke in hypertensive patients.Eligible participants were men and women aged 45 to 75 years old who had hypertension,defined as seated resting systolic blood pressure(BP)?140 mmHg or diastolic BP?90 mmHg at both the screening and recruitment visit,or were those on anti-hypertensive medications.The major exclusion criteria included history of physician-diagnosed stroke,myocardial infarction(MI),heart failure,post-coronary revascularization,or congenital heart disease.Participants were scheduled for the first visit after a 3-week run-in treatment period,and then were followed-up every 3 months until completion of the trial.Each visit involved recording BPs,pulse,treatment compliance,concomitant use of other medications,adverse events,and study outcome events.Laboratory testsOvernight fasting venous blood samples were collected at the baseline.The laboratory tests were performed at the core lab of the National Clinical Research Center for Kidney Disease(Nanfang Hospital,Guangzhou,China).Fasting glucose(FG),fasting lipids(serum total cholesterol,low density lipoprotein,high density lipoprotein-HDL-C,and triglycerides)and serum homocysteine were measured using automatic clinical analyzers(Beckman Coulter).An ABI Prism 7900HT sequence detection system(Life Technologies)was used to detect MTHFR C677T polymorphisms.Serum folate and vitamin B12 were measured at baseline by a commercial laboratory using a chemiluminescent immunoassay(New Industrial).BaPWV measurementsBaPWV,calculated as the ratio of transmission distance from the brachium to the ankle divided by the transit time,was used in this study.Participants were asked to remain in the supine position for at least five minutes after which baseline baPWV was measured using an automatic waveform analyzer(form PWV/ABI,BP-203RPE;Omron-Colin.Japan)according to published guidelines.[9,17]Examinations were performed on both left and right sides.Four oscillometric cuffs were applied to bilateral brachia and ankles,and electrocardiogram electrodes were placed on bilateral wrists.The cuffs were connected to a plethysmographic sensor that determines volume pulse-form and an oscillometric pressure sensor that measures blood pressure.Both cuffs were simultaneously pressurized to approximate the patient's diastolic pressure while the pulse volume waveforms were recorded using semiconductor pressure sensors.The distance between sampling points of baPWV was calculated automatically according to the height of the patient.The path length from the suprasternal notch to the ankle(La)was obtained using the following equation:La=0.8129×height(in cm)+12.328.The path length from the suprasternal notch to the brachium(Lb)was obtained using the following equation:Lb=0.2195 xheight-2.0734.The baPWV was calculated according to the following formula:baPWV=(La-Lb)/Tba,where Tba was the time interval between the wave front of the brachial waveform and that of the ankle waveform.Two readings of baPWV were measured bilaterally at the same time,and the maximum readings were used for the analysis.BaPWV was analyzed as quartiles and dichotomized:Q1-Q3 vs.Q4,in accordance with previous literature.[18]Blood pressure(BP)measurementsSystolic and diastolic BP(SBP/DBP mmHg)was measured at the baseline and each follow-up visit in the sitting position using a mercury sphygmomanometer with an appropriate cuff size after the subject rested for more than five minutes.Three consecutive measurements were obtained on the right arm,with one-minute intervals between each,and the mean value was calculated.Subjects were grouped according to whether hypertension was controlled:yes(mean SBP<140 and DBP<90mmHg)or no(mean SBP?140 and/or DBP?90mmHg).Outcome AssessmentThe primary outcome of interest was first incident nonfatal or fatal stroke(ischemic or hemorrhagic)occurring between baseline and follow-up(a median of 4.5 years),excluding subarachnoid hemorrhage and silent stroke.As detailed in a recent report,[15]all stroke cases were adjudicated by experts of the Endpoint Adjudication Committee using predefined criteria.More details on stroke definition and event adjudication can be found in the online Appendix:(http://iama.jamanetwork.com/data/Journals/JAMA/933696/.JOI150028suppl prod.pdf)Statistical analysisData were analyzed using the statistical package R(http://www.r-project.org)and Empower(R)(www.empowerstats.com,X&Y Solutions,Inc.Boston,MA).Data are presented as meanąstandard deviation(SD)for continuous variables and as frequency(%)for categorical variables.In all analyses,variables with a non-normal distribution were log-transformed before analysis.The population characteristics of the different groups were compared using two-sample t-tests,signed rank tests,or chi-square tests,accordingly.The effects of baPWV and hypertension control status on first stroke were evaluated using the Kaplan-Meier curves(log rank test)and Cox proportional hazard model(hazard ratio(HR)and 95%confidence interval(CI))with adjustment for major covariables including age,sex,study center,study treatment group,body mass index,smoking,alcohol consumption,baseline SBP and DBP,total cholesterol,high-density lipoprotein cholesterol,triglycerides,fasting glucose,creatinine,B12,folate,homocysteine,and MTHFR C677T polymorphism.A number of sensitivity tests were performed by including various sets of covariates in the models based on published literature and biological plausibility as well as evidence of co-linearity.A two-tailed p-value of<0.05 was considered to be statistically significant.The majority of the CSPPT participants had eGFR within the normal range(>90 mL/min/1.73m2)at the baseline.There was a small fraction of participants with eGFR<60,but none had a history of dialysis.When we performed additional analyses by adjusting either creatinine or eGFR,the results were very similar to those found without adjusting for eGFR and creatinine.Results:The present study included 3,310 participants,a subset of the CSPPT with baPWV measured at baseline.The mean(SD)age of the participants was 59.6(7.5)years;1456 were male(44%).Mean baseline baPWV was 18.76(ąSD 3.82)m/s.Compared to participants with baPWV in the lower quartiles(Q1-Q3),participants with baPWV in the 4th quartile had a higher mean age and higher levels of fasting plasma glucose(FPG),total cholesterol(TC),HDL-C levels,homocysteine,and BP at baseline and over the treatment period,and lower body mass index(BMI).No significant differences were found between the two groups in terms of creatinine,MTHFR genotype distribution,alcohol intake,smoking,or treatment group.Interestingly,we identified a moderate inverse relationship between BMI and baPWV,which may be due to the characteristics of our study participants:the majority of them(-80%)were farmers.We suspect that BMI in this population may reflect muscle mass and physical activity rather than adiposity.Compared to participants with adequate hypertension control(SBP<140 and DBP<90 mmHg)over the treatment period,participants with inadequately controlled hypertension(SBP?140 and/or DBP?90 mmHg)had higher levels of BMI,FPG,triglycerides(TG),baPWV,and SBP/DBP at baseline and over the follow-up period.During a median follow-up of 4.5 years,there were 111 total incident strokes including 96 ischemic strokes and 15 hemorrhagic strokes.The risk of stroke was higher among participants with a baPWV in the highest quartile compared to those with levels in the lower quartiles(6.3%vs.2.4%);and a similar pattern(5.1%vs.1.8%)was found among participants with inadequate hypertension control compared to those with adequate control(mean SBP<140 and DBP<90mmHg).Cox regression analysis was used to estimate the individual effect of baPWV and hypertension control on incident stroke risk.Higher baPWV(in the 4th quartile)was associated with a greater risk of incident stroke compared to lower baPWV(in Q1-Q3):the HR was 2.72(95%CI,1.87-3.94,p<0.001)in the crude model,and 1.52(95%CI,0.964-2.40,p=0.071)in the multivariate model with adjustment for age,sex,center,study treatment regimen,BMI,smoking,alcohol consumption,baseline SBP and DBP,total cholesterol,high-density lipoprotein cholesterol,triglycerides,fasting glucose,creatinine,B12,folate,homocysteine,and MTHFR C677T polymorphism.There were no significant interactions between baPWV and any of these covariates(P>0.05 for all interactions;data not shown).When baPWV and hypertension control were examined together,the Kaplan-Meyer curves showed that the cumulative hazard of stroke significantly differed among the four groups defined by baPWV and hypertension control categories(Log-rank P<0.001).Within each stratum of hypertension control,there was a positive relationship between quartiles of baPWV and risk of stroke.However,the overall risk was higher among the stratum of inadequate hypertension control.The Cox proportional hazard regression analyses estimated that the highest risk of stroke was in the group with high baPWV and inadequate hypertension control,with an HR of 3.6 and 95%CI:1.9,6.8,p<0.001,after adjusting for pertinent demographic and cardiovascular risk factors.The analyses revealed an additive effect of increased baPWV and inadequate hypertension control on stroke risk.The independent effect of high baPWV on stroke was clearly seen among participants with adequate hypertension control(HR=2.3,95%CI:1.1,4.8,p=0.029).Conclusion:Among hypertensive patients,baPWV and hypertension control were demonstrated to independently and jointly affect the risk of first stroke.Participants with high baPWV and inadequate hypertension control had the highest risk of stroke compared to other groups.The study raises the possibility that baPWV may serve as a simple and noninvasive measurement to identify hypertensive adults at high-risk of developing stroke and a novel therapeutic target to further reduce stroke risk.Clinical Implications:In their current guidelines for the management of arterial hypertension,the European Society of Hypertension included PWV as a potential consideration in managing middle-aged hypertensive patients with increased aortic stiffness.However,none of the current stroke prevention guidelines have considered PWV due to limited data.This is the first study in Chinese hypertensive adults to demonstrate that baPWV and hypertension control can independently and jointly affect the risk of incident stroke.While additional studies are needed,this study raises a possibility that baPWV may serve as a simple noninvasive screening tool in clinical or community settings to identify hypertensive adults at high-risk of stroke.It may also offer a novel therapeutic target to further reduce stroke risk beyond conventional management. |
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