Distinct Mediating Roles of Hypertension in Arterial Stiffness Mechanisms Associated with Cardiovascular Disease Risk: A Community-Based Cohort Study

BACKGROUND: Arterial stiffness (AS), a key cardiovascular disease (CVD) risk factor, arises from structural stiffening due to arterial remodeling and load-dependent stiffening from elevated blood pressure (BP). However, their contributions to CVD risk and the mediating role of hypertension remain uncertain. We aimed to quantify the associations of AS components with incident CVD and assess hypertension's mediating effects. METHODS: Among 12,684 Kailuan cohort participants, AS (measured via brachial-ankle pulse wave velocity [baPWV]) and hypertension were assessed at baseline (2010-2014). The exposures were four AS components: measured, total, structural, and load-dependent stiffness. Total stiffness was derived from measured baPWV and concurrent BP. Structural stiffness was calculated by adjusting total stiffness to a reference BP (120/80 mmHg) using participant-specific models, with load-dependent stiffness defined as the residual. Cox models evaluated associations between AS components and incident CVD. Mediation analysis decomposed each component's total effect into direct and hypertension- mediated indirect effects. RESULTS: Over a median follow-up of 11.35 years, 803 CVD events occurred. Each 1-SD increase in AS components was associated with higher CVD risk, with adjusted hazard ratios (95% CIs) of 1.21 (1.14, 1.29) for measured, 1.20 (1.13, 1.28) for total, 1.17 (1.10, 1.25) for structural, and 1.20 (1.11, 1.30) for load-dependent stiffness. Hypertension mediated 48.7%, 50.6%, 24.0%, 75.9% of these associations for measured, total, structural, and load-dependent stiffness, respectively. CONCLUSIONS: Load-dependent stiffness appears to act mainly via hypertension, whereas structural stiffness may reflect BP-independent vascular damage. Thus, combining BP control with vascular protection strategies may help prevent CVD.