第一部分：基于交叉滞后模型的动脉硬化和收缩压变化的先后关系

分析

研究背景: 收缩压（systolic blood pressure, SBP）升高和动脉硬化是心血管疾病（cardiovascular disease, CVD）风险的两个主要独立预测指标。血压和动脉僵硬度都随着年龄的增长而增加，导致了巨大的心血管疾病社会和经济负担。目前动脉硬化和SBP变化的先后关系存在争议，且动脉硬化和SBP变化的时间先后关系是否受到血压控制的影响暂不清楚。本研究基于中国老年高血压患者降压靶目标的干预策略研究（Strategy of blood pressure intervention in the Elderly hypertensive Patients, STEP）数据，分别在接受强化降压治疗（110≤SBP＜130 mmHg）和标准降压治疗（130≤SBP＜150 mmHg）的高血压患者中探究动脉硬化与SBP变化的先后关系。

研究方法: 本项研究基于STEP研究中基线和随访时baPWV数据完整的共计5369名患者。STEP研究是一项随机对照试验，研究在中国42个临床中心的8511例高血压患者中比较了强化降压治疗相比于标准降压治疗对心血管结局的影响。动脉硬化情况通过臂踝脉搏波传导速度（brachial ankle pulse wave velocity, baPWV）进行评估，动脉硬化定义为baPWV≥1800 cm/s，非动脉硬化定义为baPWV＜1800 cm/s。交叉滞后模型（cross-lagged panel model, CLPM）是一种用于探究因果关系的纵向研究模型。研究使用交叉滞后模型评估baPWV和SBP变化的先后关系，分析分别在纳入的全部患者，接受强化降压治疗和标准降压治疗的患者中进行。

研究结果: 研究纳入STEP研究中共5369例患者（平均年龄为66.01±4.69岁，其中54.07%为女性）。结果表明在强化降压治疗组和标准降压治疗组中，基线动脉硬化患者的SBP达标率明显低于非动脉硬化的患者，其中在强化降压治疗组中，基线动脉硬化及非动脉硬化患者SBP达标率分别为65.17%以及76.91%，P＜0.05；在标准降压治疗组中基线动脉硬化及非动脉硬化患者SBP达标率分别为97.33%以及98.96%，P＜0.05。交叉滞后模型分析表明，校正潜在混杂因素后，从基线baPWV到随访SBP的标准化回归系数为0.05（95%置信区间[confidence interval, CI] 0.02 - 0.08, P＜0.001），从基线SBP到随访baPWV的标准化回归系数不显著，为−0.007（95% CI −0.03 - 0.02; P=0.62）。强化降压治疗组和标准降压治疗组的中患者的baPWV与SBP变化的先后关系相似，强化降压组和标准降压组中患者从基线baPWV到随访SBP的标准化回归系数分别为0.04（95% CI, 0.0003 - 0.08; P＜0.05）和0.07（95% CI, 0.03 - 0.11; P＜0.05），从基线SBP到随访baPWV的标准化回归系数均不显著，分别为强化降压组β=−0.01（95% CI −0.05 - 0.03; P = 0.62），标准降压组β=−0.003（95% CI−0.04 - 0.03; P=0.15）。

研究结论：无论是在强化降压组还是标准降压组，患者动脉硬化的变化始终发生在SBP升高之前，相比于非动脉硬化的患者，动脉硬化的患者更难以达到SBP的目标值，尤其是在强化降压组。

第二部分：基线动脉硬化对强化降压干预效果的影响

研究背景：动脉硬化是血管老化的特征，也是高血压患者脑卒中、冠状动脉粥样硬化性心脏病和全因死亡的独立危险因素。动脉硬化和高血压两种疾病在老年患者中经常同时发生。目前越来越多的研究证据表明强化降压治疗对高血压患者心血管预后有益，然而在动脉硬化和非动脉硬化患者中，强化降压治疗相对于标准降压治疗的心血管获益是否存在差异尚不清楚。本研究的目的是探究基线动脉硬化情况和不同的血压干预方式对心血管终点事件影响的交互作用。

研究方法: 本研究基于中国老年高血压患者降压靶目标的干预策略研究（Strategy of blood pressure intervention in the Elderly hypertensive Patients, STEP）的数据，研究共纳入了6865名STEP研究中基线臂踝脉搏波传导速度（brachial ankle pulse wave velocity, baPWV）数据完整的患者。根据基线baPWV的数值将患者分为动脉硬化组及非动脉硬化组（动脉硬化定义为baPWV≥1800 cm/s；非动脉硬化定义为baPWV＜1800 cm/s）。研究的主要研究终点是心血管事件的复合终点，包括首次发生的脑卒中、急性冠脉综合征（acute coronary syndrome，ACS）、急性失代偿性心力衰竭、冠状动脉血管重建术、心房颤动或心血管导致的死亡。次要结局为脑卒中、ACS、主要心血管不良事件（major cardiovascular events, MACE）和全因死亡。Fine-Gray竞争风险模型分别计算动脉硬化组和非动脉硬化组中强化降压治疗组与标准降压治疗组之间主要终点事件和次要终点事件的95%置信区间（confidence interval, CI）的风险比（hazard ratio, HR）。Cox比例风险回归模型分别计算动脉硬化组中和非动脉硬化组中强化降压治疗组与标准降压治疗组之间全因死亡的95% CI的HR。交互作用P值用于计算基线动脉硬化情况和不同的血压干预方式对终点事件影响的交互作用。

研究结果：研究共纳入的6865名患者，平均年龄为66.14±4.75岁，其中女性患者占53.55%。在2.69年的随访期间，共计发生248例主要终点事件和81例全因死亡事件。主要终点事件在动脉硬化组和非动脉硬化组的HR分别为0.76（95%CI，0.54 - 1.09）和0.63（95% CI, 0.43 - 0.92），交互作用P值= 0.43；动脉硬化组和非动脉硬化组中患者脑卒中的HR分别为0.58（95% CI, 0.33 - 1.02）和0.48（95% CI, 0.23 - 0.99），交互作用P值=0.68。在动脉硬化和非动脉硬化的患者中，强化降压治疗对全因死亡和安全性终点的影响也是相似的（交互作用P值均＞0.05）。

研究结论：在60到80岁的老年高血压患者中，相比于标准降压治疗（130≤SBP＜150 mmHg），强化降压治疗（110≤SBP＜130 mmHg）带来的心血管获益在基线动脉硬化人群及非动脉硬化人群中是相似的。

Part I: Temporal relationship between arterial stiffness and systolic blood pressure: a cross-lagged analysis

Background: Systolic blood pressure (SBP) and arterial stiffness (AS) are two major independent predictors of cardiovascular disease (CVD). Both blood pressure (BP) and AS increase with advancing age and contribute to the substantial societal and economic burden of CVD. The temporal relationship between AS and SBP is controversial, and whether or not the temporal relationship between AS and SBP is affected by how strictly SBP is controlled has been unclear. In this study, we analyzed data from the STEP (Strategy of Blood Pressure Intervention in the Elderly Hypertensive Patients) trial to determine the temporal relationship between AS and SBP according to whether SBP control was intensive or standard (intensive, 110 ≤ SBP < 130 mmHg; standard, 130 ≤ SBP <150 mmHg).

Methods: This study included 5369 participants in the STEP trial for whom baseline and follow-up brachial-ankle pulse wave velocity (baPWV) data were complete. STEP was a randomized controlled trial that compared the effects of intensive and standard SBP control on cardiovascular outcomes in 8511 patients with hypertension at 42 clinical centers in China. Arterial stiffness was assessed by baPWV, patients were categorized by baseline baPWV (AS, baPWV ≥ 1800 cm/s; non-AS, baPWV < 1800 cm/s). Cross-lagged panel model (CLPM) is a longitudinal data statistics model used to explore the causal relationship. The temporal relationship between baPWV and SBP was assessed using a cross-lagged panel model. CLPM were performed in all patients and in those with intensive or standard SBP control respectively.

Results: Data were analyzed for 5369 patients (mean age 66.01±4.69 years; 54.07% women). Patients with AS at baseline were significantly less likely to achieve their target SBP than those without arterial stiffening in the intensive and standard treatment groups (65.17% vs 76.91% and 97.33% vs 98.96%, respectively, both P<0.05). The standardized regression coefficient from baseline baPWV to follow-up SBP was 0.05 (95% confidence interval [CI] 0.02–0.08, P<0.001) and that from baseline SBP to follow-up baPWV was insignificant from zero (β=−0.007, 95% CI −0.03 to 0.02; P=0.62) after adjustment for confounders. The findings were similar in the intensive and standard treatment groups. The standard regression coefficient from baseline baPWV to follow-up SBP was 0.04 (95% CI, 0.0003–0.08; P<0.05) in the intensive treatment group and 0.07 (95% CI, 0.03–0.11) in the standard treatment group and that from baseline SBP to follow-up baPWV was insignificant from zero in both groups (intensive, β=−0.01 [95% CI, −0.05 to 0.03]; P=0.62; standard, β=−0.003 [95% CI, −0.04 to 0.03]; P=0.15) after adjustment for confounders.

Conclusions: Arterial stiffening consistently preceded SBP in the intensive and standard groups, and compared with patients in non-AS group at baseline, patients with AS had difficulty in reaching of target SBP, particularly in the intensive treatment group.

Part II: Influence of baseline arterial stiffness on effects of intensive compared with standard blood pressure control

Background: Arterial stiffness (AS), a characteristic feature of aging arteries, is an independent age-related risk factor for stroke, coronary heart disease, and all-cause death in patients with hypertension. AS and hypertension frequently coexist, particularly in older patients. Emerging evidence has proven the benefit of intensive systolic blood pressure (SBP) control among patients with hypertension, however, whether the benefit effect of intensive versus standard SBP treatment (intensive, 110 ≤ SBP <130 mmHg; standard, 130 ≤ SBP <150 mmHg) is different in patients with and without AS is unclear. This study aims to investigate the interaction between the baseline AS and SBP treatments on cardiovascular outcomes.

Methods: This study based on the Strategy of Blood Pressure Intervention in the Elderly Hypertensive Patients (STEP) trial. We involved 6865 participants with complete data regarding baseline brachial-ankle pulse wave velocity (baPWV). Patients were categorized by baseline AS status (AS, baPWV ≥ 1800 cm/s; non-AS, baPWV < 1800 cm/s). The primary outcome was a composite of the first occurrence of stroke, acute coronary syndrome (ACS), acute decompensated heart failure, coronary revascularization, atrial fibrillation, or death of cardiovascular causes. The secondary outcomes were stroke, ACS, major cardiovascular events (MACE), and all-cause death. Cox regression was used to calculate hazard ratios for the outcomes. The Fine–Gray subdistribution hazard model was used to calculate the hazard ratios for the primary outcome and secondary outcomes associated with intensive SBP treatment versus standard SBP treatment (reference) among participants in the AS or non-AS group. Cox regression model was used to calculate the hazard ratios for all-cause death. P for interaction was used to investigate the interaction effect of the SBP treatment group in patients with AS and non-AS.

Results: A total of 6865 patients were included in this study (mean age, 66.14 ± 4.75 years; 53.55% female). During a mean follow-up of 2.69 years, 248 primary outcome events and 81 all-cause deaths occurred. The hazard ratios for the primary outcome were 0.76 (95% confidence interval (CI), 0.54–1.09) and 0.63 (95% CI, 0.43–0.92) in the AS and non-AS groups, respectively (P for interaction = 0.43), and that for stroke was 0.58 (95% CI, 0.33–1.02) and 0.48 (95% CI, 0.23–0.99) in the AS and non-AS groups, respectively (P for interaction = 0.68). Effects of intensive SBP treatment on all-cause death and safety outcomes were also similar in the two groups (P for interaction > 0.05 for all).

Conclusions: Among patients at 60 to 80 years of age with hypertension, the beneficial effects of an intensive SBP target of 110 to 130 mmHg compared with a standard SBP target of 130 to 150 mm Hg on cardiovascular events were similar among those in AS group and non-AS group.