Comments on “Temporal Relationship Between Visceral Fat and Inflammation, and Their Joint Effect on Cardiometabolic Diseases: Evidence from the China Health and Retirement Longitudinal Study (CHARLS)” [Response to Letter]

Between Visceral Fat and Inflammation, and Their Joint Effect on Cardiometabolic Diseases: Evidence from the China Health and Retirement Longitudinal Study.(CHARLS)". 1In our study, a total of 9559 participants, followed up to 9 years, were included.We found that visceral fat accumulation and inflammation were individually and jointly associated with cardiometabolic disease (CMD) risk.Individuals with concomitant high visceral fat accumulation and elevated inflammation have highest risk of hypertension, diabetes, heart disease, and stroke.There was a biological interaction between visceral fat and inflammation on the incident hypertension and diabetes.In addition, a unidirectional temporal relationship from baseline visceral fat to follow-up inflammation levels was observed.These indicated that combined assessment of both visceral fat and inflammation may improve risk stratification and primary prevention of CMD.We would like to address the valuable points raised by Zhang. 2 Based on potential mechanisms linking visceral fat and inflammation, this study was conducted to verify one of our hypotheses that there might be a bidirectional relationship between the two factors.A cross-lagged path analysis was performed to evaluate the bidirectional relationship between Chinese visceral adiposity index (CVAI) and high-sensitivity C-reactive protein (hs-CRP), including both directions (visceral fat inflammation, and inflammation visceral fat).As shown in Figure 3 (in the original paper), there were temporal relationships from baseline CVAI to follow-up hs-CRP, but not from baseline hs-CRP to follow-up CVAI, indicating a unidirectional relationship.Despite the theoretical possibility that inflammation influences visceral fat accumulation, our study found no statistical evidence for this reverse causal pathway.However, future research should account for potential variations in results due to heterogeneity in populations, disease types, and analytical models.We agree with Dr. Zhang's opinion that other statistical methods can be used to further verify the causal relationship.As described in the limitation section, we used a hs-CRP threshold of 1mg/L in the primary analyses given the number of groups and sample size, which was lower than that in some previous studies.It is noteworthy that even a lowgrade inflammation could increase CMD risk by interacting with visceral fat accumulation.Moreover, the stability of the main results was verified in sensitivity analyses using 1 or 3 as the threshold for hs-CRP, in which similar results were observed (Table S8 in the original paper).