| Background and ObjectiveHypertension is the most common chronic disease in China,affecting 270 million Chinese,and is a major contributor to the leading causes of morbidity and mortality in China,including stroke,myocardial infarction,and renal failure.Despite past 20 year intervention effort,hypertension induced end organ morbidity and mortality such as stroke continue to rise rapidly in China.Compared to adults with normal blood pressure(BP),hypertension may result in a three to four-fold risk increase for stroke,and two to three-fold risk increase for myocardial infarction,heart failure and kidney disease increased.Diseases related to hypertension are among the most burdensome and costly,and in particular,hypertension is the major risk factor for stroke in China.The main goal of treating hypertension is to minimize the overall risk of cardiovascular and cerebrovascular complications and associated mortality.Early identification and intervention of all reversible cardiovascular risk factors(such as dyslipidemia,smoking,etc.)and subclinical target organ damage is of great significance for public health.Meanwhile,it has been indicated that,in China,hypertension has a different effect on the risk of cardiovascular disease from that of western populations.Also,diverse therapeutic methods should be considered for different populations due to significant dissimilarities in ethnicity,environment,nutritional status,and lifestyle.In the past decades,epidemiological data indicates that inadequate folate intake is very prevalent in China.The CSPPT found that reduction in plasma homocysteine by folate treatment is significantly reduced the risk of first stroke and progression of CKD by 21%.It is noteworthy that apart from folate,there has been interest in evaluating possible role of various nutrients,including vitamin D,in prevention of varies disease and improve longevity.Vitamin D deficiency has been recognized as a public health problem.More and more studies suggested that vitamin D deficiency or insufficiency is associated with many non-skeletal disorders,such as hypertension,diabetes mellitus,cardiovascular disease(CVD),cancer,as well as total and cause-specific mortality.Moreover,most of previous studies were conducted in North American and European countries,few studies have been conducted in Asian.Furthermore,in addition to identifying modifiable risk factors,antihypertensive treatment itself is the most crucial strategies in the primary prevention of hypertension associated complications.However,the optimal BP target that is protective against organ damage and associated mortality risk remains controversial.The exploration of the most appropriate blood pressure target has become an important and pressing public-health task world-wide.Randomized control trial(RCT)is the highest level of evidence for clinical practice guidelines,it is necessary,and of great interest to find a intermediate that can be effectively and safely managed according to the intensive antihypertensive treatment.The intima-media thickness and plaque has been regarded as an useful biomarker of asymptomatic target organ damage and intermediate of CVD.Blood pressure was the independent risk factor of atherosclerosis which was traditionally represented by the intima-media thickness measured by 2D ultrasound.Previous studies found that use of antihypertensive medication can reduce carotid intima-media thickening,however,the effects of antihypertensive treatment on carotid plaques are unknown.Therefore,we aimed to test two hypotheses as follows:Study 1:We aimed to examine the prospective association of plasma 25(OH)-hydroxyvitamin D[25(OH)D]concentrations with all-cause and cause-specific mortality risk,and to examine possible effect modifiers.Study 2:The current analysis,based on the feasibility study of the CSPPT2(Effects of intensive blood-pressure control in general hypertensive adults:A prospective randomized open-label blinded-endpoint trial),was to investigate the efficacy of different targeted blood pressures among elderly Chinese hypertensive participants and used the progression of total plaque volume(TPV)measured by 3D ultrasound as the surrogate endpoint.MethodsStudy 1:Using data from the CSPPT,we conducted a nested case-control study of 622 cases that died during the 4.5(median)year follow up,and 622 matched controls who were still living.Controls were matched by age(±1year),sex,treatment group and study site with cases on a 1:1 ratio.For the current analysis,after excluding 5 individuals with missing 25(OH)D data and 5 individuals not paired,a total of 617 paired subjects were included.Study 2:We randomly assigned 105 hypertensive participants without cardiovascular or cerebrovascular diseases,aged over 60 years old to one of three groups of different systolic blood-pressure targets:Standard-BP control group:140～<150 mmHg;Moderate-BP control group:130～<140 mmHg;and Intensive-BP control group:less than 130mmHg.All participants agreed to undergo a 3D ultrasound procedure to measure TPV at baseline and again after 6 months of blood-pressure lowering treatment.The primary outcome of interest was the progression of TPV measured by 3D ultrasound,defined as(exit TPV-baseline TPV)/baseline TPV.ResultsStudy 1:The prevalence of plasma 25(OH)D<10(serve deficiency),20 ng/mL(deficiency)and 30 ng/mL(insufficiency)was 8.8%,48.5%and 84.6%,respectively.During a median length of 4 years of follow-up,a reverse J-shaped association between plasma 25(OH)D and mortality was observed.A plasma 25(OH)D level of 30-35 ng/mL was associated with the lowest mortality risk.Compared to 30-35 ng/mL,the adjusted Odds ratios(95%confidence intervals)of all-cause mortality at 25(OH)D level<20,20-<25,25-<30 and≥35 ng/mL were 1.46(95%CI:0.89-2.40),1.76(95%CI:1.05-2.50),2.00(95%CI:1.22-3.29)and 1.53(95%CI:0.80-2.95),respectively.Similar but not statistically significant trend toward higher CVD mortality and cancer mortality were also observed.Furthermore,the increased risk of all-cause mortality associated with low 25(OH)D levels was particularly evident among individuals with low serum folate levels(<6.0 vs.≥6.0 ng/dL,P for interaction=0.057)and whose blood sample was drawn in winter or spring(summer/fall vs.winter/spring,P for interaction=0.018).Study 2:There were a total of 97 patients with 3D ultrasound data at baseline among whom 95 participants underwent a second 3D ultrasound measurement at 6 months.After excluding one patient with unqualified data,94 participants with complete ultrasound data were included in the final analysis.At 6 months,the mean systolic blood pressure was in Intensive-BP control group,Moderate-BP control group and Standard-BP control group was 142.2(SD,6.3)mmHg,139.9(SD,6.5)mmHg and 135.5(SD,7.3)mmHg,respectively.After 6-months of blood-pressure lowering treatment,Progression of TPV in Intensive-BP control group,Moderate-BP control group and Standard-BP control group was 0.071(SD,0.425),0.107(SD,0.518)and 0.196(SD,0.258),respectively.The multivariate analysis showed that compared to Standard-BP control group or Moderate-BP control group,participants in Intensive-BP control group experienced a significantly slower progression of TPV(Intensive-BP control vs.Standard-BP control,β:-0.306,95%CI:-0.543 to-0.069,P=0.014).ConclusionsStudy 1:There was a reverse "J-shaped" association between plasma 25(OH)D concentrations and risk of all-cause mortality in Chinese hypertensive adults.indicating not only a lower limit but also an upper limit.The lowest mortality risk was at 30-35 ng/mL.Further studies are needed to confirm our findings and elucidate a possible causal relationship between 25(OH)D levels,especially higher levels,and mortality.Study 2:Among elderly hypertensive patients aged over 60 years old without cardiovascular or cerebrovascular diseases,a target systolic blood pressure of less than 130 mm Hg,compared to 140～<150 mmHg or 130～<140 mmHg,resulted in a slower progression of TPV as measured by 3D ultrasound.TPV is sensitive to anti-hypertensive treatment and could be an intermediate outcome in future clinical trials. |
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