Metabolomics signature of blood pressure salt sensitivity and its link to cardiovascular disease: A dietary salt-intervention trial

Zhennan Lin; Jianxin Li; Fangchao Liu; Jie Cao; Shufeng Chen; Jichun Chen; Keyong Huang; Yaqin Wang; Hongfan Li; Yan Wang; Jianfeng Huang; Dongfeng Gu; Xiangfeng Lu

doi:10.1007/s11427-023-2507-9

Metabolomics signature of blood pressure salt sensitivity and its link to cardiovascular disease: A dietary salt-intervention trial

Sci China Life Sci. 2024 May 9. doi: 10.1007/s11427-023-2507-9. Online ahead of print.

Authors

Zhennan Lin¹, Jianxin Li¹, Fangchao Liu¹, Jie Cao¹, Shufeng Chen¹, Jichun Chen¹, Keyong Huang¹, Yaqin Wang¹, Hongfan Li¹, Yan Wang¹, Jianfeng Huang¹, Dongfeng Gu^{2

3}, Xiangfeng Lu⁴

Affiliations

¹ Key Laboratory of Cardiovascular Epidemiology, Department of Epidemiology, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College/National Center for Cardiovascular Diseases, Beijing, 100037, China.
² Key Laboratory of Cardiovascular Epidemiology, Department of Epidemiology, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College/National Center for Cardiovascular Diseases, Beijing, 100037, China. gudongfeng@cashq.ac.cn.
³ Medical School, Southern University of Science and Technology, Shenzhen, 518055, China. gudongfeng@cashq.ac.cn.
⁴ Key Laboratory of Cardiovascular Epidemiology, Department of Epidemiology, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College/National Center for Cardiovascular Diseases, Beijing, 100037, China. luxf@pumc.edu.cn.

PMID: 38739172
DOI: 10.1007/s11427-023-2507-9

Abstract

Individuals with a high degree of salt sensitivity (SS) have a greater risk of cardiovascular disease (CVD), but whether SS fosters CVD by influencing metabolomics homeostasis remains unclear. This study aimed to reveal the role of the SS-related metabolomics signature in the development of CVDs, based on the MetaSalt study, which was a dietary salt-intervention trial conducted at four centers in China in 2019. A total of 528 participants were recruited and underwent 3 days of baseline observations, a 10-day low-salt intervention, and a 10-day high-salt intervention. Plasma untargeted metabolomics, lipidomics, and BP measurements were scheduled at each stage. Participants were grouped into extreme SS, moderate SS, and salt-resistant (SR) individuals according to their BP responses to salt. Linear mixed models were used to identify SS-related metabolites and determine the relationship between the SS-related metabolomics signature and arterial stiffness. Mendelian randomization (MR) analyses were applied to establish the causal pathways among the SS-related metabolites, BP, and CVDs. Among the 713 metabolites, 467 were significantly changed after the high-salt intervention. Among them, the changes in 30 metabolites from the low-salt to the high-salt intervention differed among the SS groups. Of the remaining nonsalt-related metabolites, the baseline levels of 11 metabolites were related to SS. These 41 metabolites explained 23% of the variance in SS. Moreover, SS and its metabolomics signature were positively correlated with arterial stiffness. MR analyses demonstrated that the SS-related metabolites may affect CVD risk by altering BP, indicating that the increase in BP was the consequence of the changes in SS-related metabolites rather than the cause. Our study revealed that the metabolomics signature of SS individuals differs from that of SR individuals and that the changes in SS-related metabolites may increase arterial stiffness and foster CVDs. This study provides insight into understanding the biology and targets of SS and its role in CVDs.

Keywords: Mendelian randomization; cardiovascular disease; dietary salt intake; metabolomics; salt sensitivity.