A ccording to recently reported meta-analyses, hyperuricemia is an independent risk factor for the development of hypertension, 1,2 although the underlying mechanisms have not yet been fully clarified. Hyperuricemia has also been reported to be associated with the early stages of development of some risk factors for hypertension, such as arterial stiffness, 3 renal function decline, 4 and inflammation. 5 Thus, we attempted to verify the possibility of involvement of these risk factors in the risk of development of hypertension associated with hyperuricemia. 6 Although an observational study would be needed for such an objective, conventional observational studies, in which the relevant assessments are conducted at 2 observational points, have the limitation that they exclude the effects of timevarying confounding variables.7 However, analysis of repeated measures data by mixed model linear (MML) regression analysis and general estimated equation (GEE) analysis may be useful to minimize the effects of time-varying confounders. In the present prospective observational study conducted in Japanese men without hypertension at the study baseline, we analyzed repeated measures data by MML regression analysis and GEE analysis to clarify the longitudinal associations of hyperuricemia with the above-mentioned risk factors for the development of hypertension, and then to examine the longitudinal associations of these risk factors with the development of hypertension. MethodsThe data, analytical methods, and study materials will not be made available to other researchers for the purpose of reproducing the results or replicating the procedure. Design and SubjectsThe present study was conducted in the same cohort as that used in a previously reported prospective observational study. 8,9 The cohort consisted of employees working at the headquarters of a single large Japanese construction company located in downtown Tokyo. According to the Occupational Health and Safety Law in Japan, it is mandatory for all company employees to undergo annual health checkups. Informed consent for participation in this study was obtained from all of the study participants before their enrollment in this study. The study was Correspondence to Hirofumi Tomiyama, Department of Cardiology, Tokyo Medical University, 6-7-1 Nishi-Shinjuku, Tokyo 160-0023, Japan. Email tomiyama@tokyo-med.ac.jp See Editorial Commentary, pp 582-584Abstract-This study analyzed repeated measurement data to clarify the longitudinal associations between hyperuricemia and the risk factors for the development of hypertension (ie, increased arterial stiffness, renal dysfunction, and inflammation), and then examined whether these risk factors show longitudinal associations with the development of hypertension. In 3274 Japanese men without hypertension, the brachial-ankle pulse wave velocity, blood pressure, estimated glomerular filtration rate, and serum uric acid and CRP (C-reactive protein) levels were measured annually over an 8-year period. Of these, 474 subjects developed hy...

BackgroundWe conducted analyses of repeated‐measures data to examine whether pressure wave reflection acts additively or synergistically with arterial stiffness in the pathogenesis of hypertension.Methods and ResultsIn 3172 middle‐aged (42±9 years) healthy Japanese men without hypertension at the study baseline, systolic and diastolic blood pressures, brachial–ankle pulse wave velocity, and radial augmentation index were measured annually during a 9‐year study period. Of these, 474 participants (15%) developed hypertension by the end of the study period. Binary logistic regression analysis demonstrated significant individual odds ratios for both baseline brachial–ankle pulse wave velocity and radial augmentation index for the development of hypertension. The rate of onset of hypertension during the study period was highest in the participant group with high values for both brachial–ankle pulse wave velocity and radial augmentation index at study baseline (262 of 965 participants: 27%). The generalized estimating equation analysis revealed that both radial augmentation index (estimate=0.06, SE=0.03, P=0.05) and brachial–ankle pulse wave velocity (estimate=0.07×10−1, SE=0.02×10−1, P<0.01) showed significant longitudinal association with new onset of hypertension, with no significant interaction.ConclusionsIn Japanese men, abnormal wave reflection and increased arterial stiffness may be additively associated with the risk of new onset of hypertension. Abnormal wave reflection and elevated central blood pressure may be longitudinally associated with increase in arterial stiffness, and this longitudinal association may be a mechanism underlying the additive effect of these 2 variables on the risk of new onset of hypertension.

BackgroundIt remains to be clarified whether liver stiffness is a direct risk factor for heart failure (HF) or whether its association with HF is mediated by vascular damage. We conducted cross-sectional and prospective longitudinal studies to examine whether fibrosis 4 score (FIB-4 score) is directly associated with the serum NT-pro-BNP levels or the association is mediated by arterial stiffness and/or abnormal central hemodynamics.Methods and resultsIn 3040 health Japanese subjects with serum NT-pro-BNP levels < 125 pg/ml, the FIB-4 score was calculated, and the serum NT-pro-BNP levels, brachial-ankle pulse wave (baPWV) velocity and radial augmentation index (rAI) were measured. These parameters were measured again after a 3-year interval in 2135 subjects. Multivariate linear regression analysis demonstrated a significant cross-sectional association of the FIB-4 scores with the log-transformed the serum NT-pro-BNP levels (beta = 0.08, p < 0.01), but not with the baPWV or rAI. The change of serum NT-pro BNP levels during the study period was significantly higher in subjects with increase of the FIB-4 score during the study period (8.2 ± 22.5 pg/ml) than that in those with decrease/no change (5.4 ± 22.3 pg/ml) (p < 0.05).ConclusionLiver stiffness may have a significant direct association with the development of HF from the early stage, without the mediation of arterial stiffness and/or abnormal central hemodynamics. Therefore, the FIB-4 score appears to serve as a direct risk factor for HF from the early stage, and its association with HF may not be mediated by vascular damages.

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Objectives: This prospective study was conducted to clarify the significance of augmented pressure wave reflection without accompanying increased arterial stiffness in the development of isolated diastolic hypertension (IDHT). Methods: A total of 3022 Japanese men without hypertension at the start of this study were included in the analyses. The blood pressure, brachial--ankle pulse wave velocity (brachial-ankle PWV), and radial augmentation index (rAI) were measured annually from year 2007 through year 2015. Results: At the end of the study period, 129 participants were diagnosed as having systolic/diastolic hypertension (SDHT), 112 as having isolated systolic hypertension (ISHT), and 74 as having IDHT. Both the brachial--ankle PWV and rAI showed significant individual odds ratios for new onset of SDHT and new onset of ISHT. However, only rAI, but not the brachial--ankle PWV, showed a significant odds ratio (1.44, P < 0.01) for new onset of IDHT. This association was significant in participants without elevated brachial--ankle PWV values at the start of the study, but not in those with elevated brachial--ankle PWV at the start of the study. Generalized estimating equation analyses demonstrated a significant longitudinal association of the rAI, but not brachial--ankle PWV, with the development of IDHT. Conclusion: Although increased arterial stiffness and augmented pressure wave reflection present concomitantly may be associated with the development of SDHT and ISHT, augmented pressure wave reflection alone, which may be related to isolated peripheral vascular damage, in the absence of accompanying increase of the arterial stiffness, may be a significant factor in the development of IDHT.