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.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Aburto, N.J., Ziolkovska, A., Hooper, L., Elliott, P., Cappuccio, F.P., and Meerpohl, J.J. (2013). Effect of lower sodium intake on health: systematic review and meta-analyses. BMJ 346, f1326.
Balafa, O., and Kalaitzidis, R.G. (2021). Salt sensitivity and hypertension. J Hum Hypertens 35, 184–192.
Bowden, J., Spiller, W., Del Greco M.F., Sheehan, N., Thompson, J., Minelli, C., and Davey Smith, G. (2018). Improving the visualization, interpretation and analysis of two-sample summary data Mendelian randomization via the Radial plot and Radial regression. Int J Epidemiol 47, 1264–1278.
Brial, F., Alzaid, F., Sonomura, K., Kamatani, Y., Meneyrol, K., Le Lay, A., Péan, N., Hedjazi, L., Sato, T.A., Venteclef, N., et al. (2020). The natural metabolite 4-cresol improves glucose homeostasis and enhances β-cell function. Cell Rep 30, 2306–2320.e5.
Brion, M.J.A., Shakhbazov, K., and Visscher, P.M. (2013). Calculating statistical power in Mendelian randomization studies. Int J Epidemiol 42, 1497–1501.
Burgess, S., Daniel, R.M., Butterworth, A.S., and Thompson, S.G. (2015). Network Mendelian randomization: using genetic variants as instrumental variables to investigate mediation in causal pathways. Int J Epidemiol 44, 484–495.
Chaudhary, P., Velkoska, E., and Wainford, R.D. (2021). An exploratory analysis of comparative plasma metabolomic and lipidomic profiling in salt-sensitive and salt-resistant individuals from The Dietary Approaches to Stop Hypertension Sodium Trial. J Hypertens 39, 1972–1981.
Chen, J. (2010). Sodium sensitivity of blood pressure in Chinese populations. Curr Hypertens Rep 12, 127–134.
Chen, J., Gu, D., Huang, J., Rao, D.C., Jaquish, C.E., Hixson, J.E., Chen, C.S., Chen, J., Lu, F., Hu, D., et al. (2009). Metabolic syndrome and salt sensitivity of blood pressure in non-diabetic people in China: a dietary intervention study. Lancet 373, 829–835.
Cheng, Y., Song, H., Pan, X., Xue, H., Wan, Y., Wang, T., Tian, Z., Hou, E., Lanza, I.R., Liu, P., et al. (2018). Urinary metabolites associated with blood pressure on a low- or high-sodium diet. Theranostics 8, 1468–1480.
D’Elia, L., Galletti, F., La Fata, E., Sabino, P., Strazzullo, P. (2018). Effect of dietary sodium restriction on arterial stiffness: systematic review and meta-analysis of the randomized controlled trials. J Hypertens 36, 734–743.
Derkach, A., Sampson, J., Joseph, J., Playdon, M.C., and Stolzenberg-Solomon, R.Z. (2017). Effects of dietary sodium on metabolites: the Dietary Approaches to Stop Hypertension (DASH)–Sodium Feeding Study. Am J Clin Nutr 106, 1131–1141.
Elijovich, F., Weinberger, M.H., Anderson, C.A.M., Appel, L.J., Bursztyn, M., Cook, N. R., Dart, R.A., Newton-Cheh, C.H., Sacks, F.M., and Laffer, C.L. (2016). Salt sensitivity of blood pressure. Hypertension 68, e7.
GenSalt Collaborative Research, G. (2007). GenSalt: rationale, design, methods and baseline characteristics of study participants. Journal of Human Hypertension 21, 639–646.
Global Burden of Disease. (2022). Global burden of disease.
He, F.J., Li, J., and MacGregor, G.A. (2013a). Effect of longer term modest salt reduction on blood pressure: cochrane systematic review and meta-analysis of randomised trials. BMJ 346, f1325.
He, J., Huang, J.F., Li, C., Chen, J., Lu, X., Chen, J.C., He, H., Li, J.X., Cao, J., Chen, C.S., et al. (2021). Sodium sensitivity, sodium resistance, and incidence of hypertension: a longitudinal follow-up study of dietary sodium intervention. Hypertension 78, 155–164.
He, J., Kelly, T.N., Zhao, Q., Li, H., Huang, J., Wang, L., Jaquish, C.E., Sung, Y.J., Shimmin, L.C., Lu, F., et al. (2013b). Genome-wide association study identifies 8 novel loci associated with blood pressure responses to interventions in Han Chinese. Circ Cardiovasc Genet 6, 598–607.
Kawasaki, T., Delea, C.S., Bartter, F.C., and Smith, H. (1978). The effect of high-sodium and low-sodium intakes on blood pressure and other related variables in human subjects with idiopathic hypertension. Am J Med 64, 193–198.
Lu, X., Liu, Z., Cui, Q., Liu, F., Li, J., Niu, X., Shen, C., Hu, D., Huang, K., Chen, J., et al. (2022). A polygenic risk score improves risk stratification of coronary artery disease: a large-scale prospective Chinese cohort study. Eur Heart J 43, 1702–1711.
Lu, X., Wang, L., Lin, X., Huang, J., Charles Gu, C., He, M., Shen, H., He, J., Zhu, J., Li, H., et al. (2015). Genome-wide association study in Chinese identifies novel loci for blood pressure and hypertension. Hum Mol Genet 24, 865–874.
Meneton, P., Jeunemaitre, X., de Wardener, H.E., and Macgregor, G.A. (2005). Links between dietary salt intake, renal salt handling, blood pressure, and cardiovascular diseases. Physiol Rev 85, 679–715.
Najmanová, I., Pourová, J., Mladěnka, P. (2020). A mixture of phenolic metabolites of quercetin can decrease elevated blood pressure of spontaneously hypertensive rats even in low doses. Nutrients 12, 213.
Pinto, P.R., Yoshinaga, M.Y., Del Bianco, V., Bochi, A.P., Ferreira, G.S., Pinto, I.F.D., Rodrigues, L.G., Nakandakare, E.R., Okamoto, M.M., Machado, U.F., et al. (2021). Dietary sodium restriction alters muscle lipidomics that relates to insulin resistance in mice. J Biol Chem 296, 100344.
Ruan, Z., Li, J., Liu, F., Cao, J., Chen, S., Chen, J., Huang, K., Wang, Y., Li, H., Wang, Y., et al. (2021). Study design, general characteristics of participants, and preliminary findings from the metabolome, microbiome, and dietary salt intervention study (MetaSalt). Chronic Dis Transl Med 7, 227–234.
Sakaue, S., Kanai, M., Tanigawa, Y., Karjalainen, J., Kurki, M., Koshiba, S., Narita, A., Konuma, T., Yamamoto, K., Akiyama, M., et al. (2021). A cross-population atlas of genetic associations for 220 human phenotypes. Nat Genet 53, 1415–1424.
Shi, M., He, J., Li, C., Lu, X., He, W.J., Cao, J., Chen, J., Chen, J.C., Bazzano, L.A., Li, J. X., et al. (2022). Metabolomics study of blood pressure salt-sensitivity and hypertension. Nutr Metab Cardiovasc Dis 32, 1681–1692.
Verbanck, M., Chen, C.Y., Neale, B., and Do, R. (2018). Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat Genet 50, 693–698.
Wang, T., Malone, J., Fu, H., Heilmann, C., Qu, Y., and Huster, W.J. (2016). Crossover design and its application in late-phase diabetes studies. J Diabetes 8, 610–618.
Wilck, N., Matus, M.G., Kearney, S.M., Olesen, S.W., Forslund, K., Bartolomaeus, H., Haase, S., Mähler, A., Balogh, A., Markó, L., et al. (2017). Salt-responsive gut commensal modulates TH17 axis and disease. Nature 551, 585–589.
Yan, X., Jin, J., Su, X., Yin, X., Gao, J., Wang, X., Zhang, S., Bu, P., Wang, M., Zhang, Y., et al. (2020). Intestinal flora modulates blood pressure by regulating the synthesis of intestinal-derived corticosterone in high salt-induced hypertension. Circ Res 126, 839–853.
Yang, J., Lee, S.H., Goddard, M.E., and Visscher, P.M. (2011). GCTA: a tool for genome-wide complex trait analysis. Am J Hum Genet 88, 76–82.
Zárate, R., el Jaber-Vazdekis, N., Tejera, N., Pérez, J.A., and Rodríguez, C. (2017). Significance of long chain polyunsaturated fatty acids in human health. Clin Transl Med 6, 25.
Zhang, F., Xie, Y., Yang, X., Peng, W., Qi, H., Li, B., Wen, F., Li, P., Sun, Y., Zhang, L. (2023). Association of serum metabolites and salt sensitivity of blood pressure in chinese population: the EpiSS study. Nutrients 15, 690.
Acknowledgement
The authors are grateful to all study staff and participants at each center of the MetaSalt study, and we thank the Biobank Japan project for access to GWAS summary statistics.
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
The authors declare that they have no conflict of Interest. This study was approved by the Institutional Review Board at Fuwai Hospital in Beijing, China.
Supporting Information
11427_2023_2507_MOESM1_ESM.pdf
Metabolomics signature of blood pressure salt sensitivity and its link to cardiovascular disease: A dietary salt-intervention trial
Rights and permissions
About this article
Cite this article
Lin, Z., Li, J., Liu, F. et al. Metabolomics signature of blood pressure salt sensitivity and its link to cardiovascular disease: A dietary salt-intervention trial. Sci. China Life Sci. (2024). https://doi.org/10.1007/s11427-023-2507-9
Received:
Accepted:
Published:
DOI: https://doi.org/10.1007/s11427-023-2507-9