The causal relationship between immune cells and heart failure risk and the mediating role of serum metabolites: A Mendelian randomization study_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

ZHU Yun ¹ , WEI Jiaming ¹ , LIN Ruifang ¹ , LIU Yongjun ¹ , LIU Yue ¹ , ZHANG Guohua ² ,  GUO Zhihua ^1,2,3,4

1. School of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, 410208, P. R. China;
2. First Clinical College of Chinese Medicine, Hunan University of Chinese Medicine, Changsha, 410208, P. R. China;
3. Hunan Key Laboratory of Colleges and Universities of Intelligent Traditional Chinese Medicine Diagnosis and Preventive Treatment of Chronic Diseases of Hunan Universities of Chinese Medicine, Changsha, 410208, P. R. China;
4. Internet+TCM Diagnosis and Treatment of Chronic Diseases and Intelligent Application of Health Care Joint Postgraduate Training Base, Changsha, 410208, P. R. China;

Corresponding author：

GUO Zhihua, Email: guozhihua112@163.com

Keywords：

Immune cells; serum metabolites; heart failure; Mendelian randomization; mediation

DOI：

10.7507/1007-4848.202410071

Video：

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Objective To explore the causal relationship between immune cells and heart failure (HF), and the mediating role of serum metabolites, in order to identify potential biomarkers and therapeutic targets. Methods We employed a two-sample Mendelian randomization (MR) analysis method based on genome-wide association study (GWAS) data, analyzing the direct and indirect effects of 731 types of immune cells and 1 400 metabolites on HF. We selected valid instrumental variables and conducted statistical analyses using R software. The primary analysis was performed using the inverse variance weighted method, supplemented by MR-Egger analysis and weighted median method. The stability of the results was assessed through tests such as Cochran’s Q. Results Our research found a negative causal relationship between PD-L1 on CD14⁻CD16⁺ and HF. Sensitivity analysis supported this result. The reverse MR analysis did not find an effect of HF on PD-L1 on CD14⁻CD16⁺, indicating that PD-L1 on CD14⁻CD16⁺ may play a unidirectional role in reducing the risk of HF. Further mediation MR analysis showed that PD-L1 on CD14⁻CD16⁺ might influence the risk of HF onset by regulating the levels of sphingomyelin (d17:1/14:0, d16:1/15:0), with a mediation effect ratio of 6.7%. Conclusion PD-L1 on CD14⁻CD16⁺ might reduce the risk of HF by elevating the levels of sphingomyelin (d17:1/14:0, d16:1/15:0), providing a new perspective for understanding the pathogenesis of HF.

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2.	Aimo A, Castiglione V, Borrelli C, et al. Oxidative stress and inflammation in the evolution of heart failure: From pathophysiology to therapeutic strategies. Eur J Prev Cardiol, 2020, 27(5): 494-510.
3.	Savarese G, Becher PM, Lund LH, et al. Global burden of heart failure: A comprehensive and updated review of epidemiology. Cardiovasc Res, 2023, 118(17): 3272-3287.
4.	Tahir S, Steffens S. Nonclassical monocytes in cardiovascular physiology and disease. Am J Physiol Cell Physiol, 2021, 320(5): C761-C770.
5.	Adamo L, Rocha-Resende C, Prabhu SD, et al. Reappraising the role of inflammation in heart failure. Nat Rev Cardiol, 2020, 17(5): 269-285.
6.	Zhou J, Bai W, Liu Q, et al. Intermittent hypoxia enhances THP-1 monocyte adhesion and chemotaxis and promotes M1 macrophage polarization via RAGE. Biomed Res Int, 2018, 2018: 1650456.
7.	Hanna A, Frangogiannis NG. Inflammatory cytokines and chemokines as therapeutic targets in heart failure. Cardiovasc Drugs Ther, 2020, 34(6): 849-863.
8.	Majmundar M, Kansara T, Park H, et al. Absolute lymphocyte count as a predictor of mortality and readmission in heart failure hospitalization. Int J Cardiol Heart Vasc, 2022, 39: 100981.
9.	Wang Z, Chen S, Zhu Q, et al. Using a two-sample mendelian randomization method in assessing the causal relationships between human blood metabolites and heart failure. Front Cardiovasc Med, 2021, 8: 695480.
10.	Capone F, Sotomayor-Flores C, Bode D, et al. Cardiac metabolism in HFpEF: From fuel to signalling. Cardiovasc Res, 2023, 118(18): 3556-3575.
11.	Pérez-Carrillo L, Giménez-Escamilla I, Martínez-Dolz L, et al. Implication of sphingolipid metabolism gene dysregulation and cardiac sphingosine-1-phosphate accumulation in heart failure. Biomedicines, 2022, 10(1): 135.
12.	Thorp EB, Karlstaedt A. Intersection of immunology and metabolism in myocardial disease. Circ Res, 2024, 134(12): 1824-1840.
13.	Trindade BC, Ceglia S, Berthelette A, et al. The cholesterol metabolite 25-hydroxycholesterol restrains the transcriptional regulator SREBP2 and limits intestinal IgA plasma cell differentiation. Immunity, 2021, 54(10): 2273-2287.
14.	Wang Q, Dai H, Hou T, et al. Dissecting causal relationships between gut microbiota, blood metabolites, and stroke: A Mendelian randomization study. J Stroke, 2023, 25(3): 350-360.
15.	Birney E. Mendelian randomization. Cold Spring Harb Perspect Med, 2022, 12(4): a041302.
16.	Orrù V, Steri M, Sidore C, et al. Complex genetic signatures in immune cells underlie autoimmunity and inform therapy. Nat Genet, 2020, 52(10): 1036-1045.
17.	Chen Y, Lu T, Pettersson-Kymmer U, et al. Genomic atlas of the plasma metabolome prioritizes metabolites implicated in human diseases. Nat Genet, 2023, 55(1): 44-53.
18.	Sun BB, Kurki MI, Foley CN, et al. Genetic associations of protein-coding variants in human disease. Nature, 2022, 603(7899): 95-102.
19.	Yu XH, Yang YQ, Cao RR, et al. The causal role of gut microbiota in development of osteoarthritis. Osteoarthritis Cartilage, 2021, 29(12): 1741-1750.
20.	Wang C, Zhu D, Zhang D, et al. Causal role of immune cells in schizophrenia: Mendelian randomization (MR) study. BMC Psychiatry, 2023, 23(1): 590.
21.	Guo MN, Hao XY, Tian J, et al. Human blood metabolites and lacunar stroke: A Mendelian randomization study. Int J Stroke, 2023, 18(1): 109-116.
22.	Ming R, Wu H, Liu H, et al. Causal effects and metabolites mediators between immune cell and risk of breast cancer: A Mendelian randomization study. Front Genet, 2024, 15: 1380249.
23.	Yuan J, Xiong X, Zhang B, et al. Genetically predicted C-reactive protein mediates the association between rheumatoid arthritis and atlantoaxial subluxation. Front Endocrinol (Lausanne), 2022, 13: 1054206.
24.	Li YS, Xia YG, Liu YL, et al. Metabolic-dysfunction associated steatotic liver disease-related diseases, cognition and dementia: A two-sample mendelian randomization study. PLoS One, 2024, 19(2): e0297883.
25.	Cheng ZX, Hua JL, Jie ZJ, et al. Genetic insights into the gut-lung axis: Mendelian Randomization analysis on gut microbiota, lung function, and COPD. Int J Chron Obstruct Pulmon Dis, 2024, 19: 643-653.
26.	Davies NM, Holmes MV, Davey Smith G. Reading Mendelian randomisation studies: A guide, glossary, and checklist for clinicians. BMJ, 2018, 362: k601.
27.	Huang YL, Zheng JM, Shi ZY, et al. Inflammatory proteins may mediate the causal relationship between gut microbiota and inflammatory bowel disease: A mediation and multivariable Mendelian randomization study. Medicine (Baltimore), 2024, 103(25): e38551.
28.	Burgess S, Thompson SG. Interpreting findings from Mendelian randomization using the MR-Egger method. Eur J Epidemiol, 2017, 32(5): 377-389.
29.	Verbanck M, Chen CY, Neale B, et al. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat Genet, 2018, 50(5): 693-698.
30.	Carter AR, Sanderson E, Hammerton G, et al. Mendelian randomisation for mediation analysis: current methods and challenges for implementation. Eur J Epidemiol, 2021, 36(5): 465-478.
31.	Oh ES, Na M, Rogers CJ. The association between monocyte subsets and cardiometabolic disorders/cardiovascular disease: A systematic review and meta-analysis. Front Cardiovasc Med, 2021, 8: 640124.
32.	Peng Q, Qiu X, Zhang Z, et al. PD-L1 on dendritic cells attenuates T cell activation and regulates response to immune checkpoint blockade. Nat Commun, 2020, 11(1): 4835.
33.	Ożańska A, Szymczak D, Rybka J. Pattern of human monocyte subpopulations in health and disease. Scand J Immunol, 2020, 92(1): e12883.
34.	Boyette LB, Macedo C, Hadi K, et al. Phenotype, function, and differentiation potential of human monocyte subsets. PLoS One, 2017, 12(4): e0176460.
35.	Bianchini M, Duchêne J, Santovito D, et al. PD-L1 expression on nonclassical monocytes reveals their origin and immunoregulatory function. Sci Immunol, 2019, 4(36): eaar3054.
36.	Ryan S, Arnaud C, Fitzpatrick SF, et al. Adipose tissue as a key player in obstructive sleep apnoea. Eur Respir Rev, 2019, 28(152): 190006.
37.	Miyazaki S, Fujisue K, Yamanaga K, et al. Prognostic significance of soluble PD-L1 on cardiovascular outcomes in patients with coronary artery disease. J Atheroscler Thromb, 2024, 31(4): 355-367.
38.	Kushnareva E, Kushnarev V, Artemyeva A, et al. Myocardial PD-L1 expression in patients with ischemic and non-ischemic heart failure. Front Cardiovasc Med, 2022, 8: 759972.
39.	Choudhary A, Brinkley DM, Besharati S, et al. PD-L1 (programmed death ligand 1) as a marker of acute cellular rejection after heart transplantation. Circ Heart Fail, 2021, 14(10): e008563.
40.	Mir FA, Ullah E, Mall R, et al. Dysregulated metabolic pathways in subjects with obesity and metabolic syndrome. Int J Mol Sci, 2022, 23(17): 9821.
41.	Borodzicz-Jażdżyk S, Jażdżyk P, Łysik W, et al. Sphingolipid metabolism and signaling in cardiovascular diseases. Front Cardiovasc Med, 2022, 9: 915961.
42.	Lemaitre RN, Jensen PN, Hoofnagle A, et al. Plasma ceramides and sphingomyelins in relation to heart failure risk. Circ Heart Fail, 2019, 12(7): e005708.
43.	Jozefczuk E, Guzik TJ, Siedlinski M. Significance of sphingosine-1-phosphate in cardiovascular physiology and pathology. Pharmacol Res, 2020, 156: 104793.
44.	Lemaitre RN, McKnight B, Sotoodehnia N, et al. Circulating very long-chain saturated fatty acids and heart failure: The cardiovascular health study. J Am Heart Assoc, 2018, 7(21): e010019.
45.	Stenemo M, Ganna A, Salihovic S, et al. The metabolites urobilin and sphingomyelin (30: 1) are associated with incident heart failure in the general population. ESC Heart Fail, 2019, 6(4): 764-773.
46.	Mueller-Hennessen M, Düngen HD, Lutz M, et al. A novel lipid biomarker panel for the detection of heart failure with reduced ejection fraction. Clin Chem, 2017, 63(1): 267-277.
47.	Lemaitre RN, Jensen PN, Hoofnagle A, et al. Plasma ceramides and sphingomyelins in relation to heart failure risk. Circ Heart Fail, 2019, 12(7): e005708.
48.	Peters L, Kuebler WM, Simmons S. Sphingolipids in atherosclerosis: Chimeras in structure and function. Int J Mol Sci, 2022, 23(19): 11948.
49.	Gaggini M, Fenizia S, Vassalle C. Sphingolipid levels and signaling via resveratrol and antioxidant actions in cardiometabolic risk and disease. Antioxidants (Basel), 2023, 12(5): 1102.

1. Groenewegen A, Rutten FH, Mosterd A, et al. Epidemiology of heart failure. Eur J Heart Fail, 2020, 22(8): 1342-1356.
2. Aimo A, Castiglione V, Borrelli C, et al. Oxidative stress and inflammation in the evolution of heart failure: From pathophysiology to therapeutic strategies. Eur J Prev Cardiol, 2020, 27(5): 494-510.
3. Savarese G, Becher PM, Lund LH, et al. Global burden of heart failure: A comprehensive and updated review of epidemiology. Cardiovasc Res, 2023, 118(17): 3272-3287.
4. Tahir S, Steffens S. Nonclassical monocytes in cardiovascular physiology and disease. Am J Physiol Cell Physiol, 2021, 320(5): C761-C770.
5. Adamo L, Rocha-Resende C, Prabhu SD, et al. Reappraising the role of inflammation in heart failure. Nat Rev Cardiol, 2020, 17(5): 269-285.
6. Zhou J, Bai W, Liu Q, et al. Intermittent hypoxia enhances THP-1 monocyte adhesion and chemotaxis and promotes M1 macrophage polarization via RAGE. Biomed Res Int, 2018, 2018: 1650456.
7. Hanna A, Frangogiannis NG. Inflammatory cytokines and chemokines as therapeutic targets in heart failure. Cardiovasc Drugs Ther, 2020, 34(6): 849-863.
8. Majmundar M, Kansara T, Park H, et al. Absolute lymphocyte count as a predictor of mortality and readmission in heart failure hospitalization. Int J Cardiol Heart Vasc, 2022, 39: 100981.
9. Wang Z, Chen S, Zhu Q, et al. Using a two-sample mendelian randomization method in assessing the causal relationships between human blood metabolites and heart failure. Front Cardiovasc Med, 2021, 8: 695480.
10. Capone F, Sotomayor-Flores C, Bode D, et al. Cardiac metabolism in HFpEF: From fuel to signalling. Cardiovasc Res, 2023, 118(18): 3556-3575.
11. Pérez-Carrillo L, Giménez-Escamilla I, Martínez-Dolz L, et al. Implication of sphingolipid metabolism gene dysregulation and cardiac sphingosine-1-phosphate accumulation in heart failure. Biomedicines, 2022, 10(1): 135.
12. Thorp EB, Karlstaedt A. Intersection of immunology and metabolism in myocardial disease. Circ Res, 2024, 134(12): 1824-1840.
13. Trindade BC, Ceglia S, Berthelette A, et al. The cholesterol metabolite 25-hydroxycholesterol restrains the transcriptional regulator SREBP2 and limits intestinal IgA plasma cell differentiation. Immunity, 2021, 54(10): 2273-2287.
14. Wang Q, Dai H, Hou T, et al. Dissecting causal relationships between gut microbiota, blood metabolites, and stroke: A Mendelian randomization study. J Stroke, 2023, 25(3): 350-360.
15. Birney E. Mendelian randomization. Cold Spring Harb Perspect Med, 2022, 12(4): a041302.
16. Orrù V, Steri M, Sidore C, et al. Complex genetic signatures in immune cells underlie autoimmunity and inform therapy. Nat Genet, 2020, 52(10): 1036-1045.
17. Chen Y, Lu T, Pettersson-Kymmer U, et al. Genomic atlas of the plasma metabolome prioritizes metabolites implicated in human diseases. Nat Genet, 2023, 55(1): 44-53.
18. Sun BB, Kurki MI, Foley CN, et al. Genetic associations of protein-coding variants in human disease. Nature, 2022, 603(7899): 95-102.
19. Yu XH, Yang YQ, Cao RR, et al. The causal role of gut microbiota in development of osteoarthritis. Osteoarthritis Cartilage, 2021, 29(12): 1741-1750.
20. Wang C, Zhu D, Zhang D, et al. Causal role of immune cells in schizophrenia: Mendelian randomization (MR) study. BMC Psychiatry, 2023, 23(1): 590.
21. Guo MN, Hao XY, Tian J, et al. Human blood metabolites and lacunar stroke: A Mendelian randomization study. Int J Stroke, 2023, 18(1): 109-116.
22. Ming R, Wu H, Liu H, et al. Causal effects and metabolites mediators between immune cell and risk of breast cancer: A Mendelian randomization study. Front Genet, 2024, 15: 1380249.
23. Yuan J, Xiong X, Zhang B, et al. Genetically predicted C-reactive protein mediates the association between rheumatoid arthritis and atlantoaxial subluxation. Front Endocrinol (Lausanne), 2022, 13: 1054206.
24. Li YS, Xia YG, Liu YL, et al. Metabolic-dysfunction associated steatotic liver disease-related diseases, cognition and dementia: A two-sample mendelian randomization study. PLoS One, 2024, 19(2): e0297883.
25. Cheng ZX, Hua JL, Jie ZJ, et al. Genetic insights into the gut-lung axis: Mendelian Randomization analysis on gut microbiota, lung function, and COPD. Int J Chron Obstruct Pulmon Dis, 2024, 19: 643-653.
26. Davies NM, Holmes MV, Davey Smith G. Reading Mendelian randomisation studies: A guide, glossary, and checklist for clinicians. BMJ, 2018, 362: k601.
27. Huang YL, Zheng JM, Shi ZY, et al. Inflammatory proteins may mediate the causal relationship between gut microbiota and inflammatory bowel disease: A mediation and multivariable Mendelian randomization study. Medicine (Baltimore), 2024, 103(25): e38551.
28. Burgess S, Thompson SG. Interpreting findings from Mendelian randomization using the MR-Egger method. Eur J Epidemiol, 2017, 32(5): 377-389.
29. Verbanck M, Chen CY, Neale B, et al. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat Genet, 2018, 50(5): 693-698.
30. Carter AR, Sanderson E, Hammerton G, et al. Mendelian randomisation for mediation analysis: current methods and challenges for implementation. Eur J Epidemiol, 2021, 36(5): 465-478.
31. Oh ES, Na M, Rogers CJ. The association between monocyte subsets and cardiometabolic disorders/cardiovascular disease: A systematic review and meta-analysis. Front Cardiovasc Med, 2021, 8: 640124.
32. Peng Q, Qiu X, Zhang Z, et al. PD-L1 on dendritic cells attenuates T cell activation and regulates response to immune checkpoint blockade. Nat Commun, 2020, 11(1): 4835.
33. Ożańska A, Szymczak D, Rybka J. Pattern of human monocyte subpopulations in health and disease. Scand J Immunol, 2020, 92(1): e12883.
34. Boyette LB, Macedo C, Hadi K, et al. Phenotype, function, and differentiation potential of human monocyte subsets. PLoS One, 2017, 12(4): e0176460.
35. Bianchini M, Duchêne J, Santovito D, et al. PD-L1 expression on nonclassical monocytes reveals their origin and immunoregulatory function. Sci Immunol, 2019, 4(36): eaar3054.
36. Ryan S, Arnaud C, Fitzpatrick SF, et al. Adipose tissue as a key player in obstructive sleep apnoea. Eur Respir Rev, 2019, 28(152): 190006.
37. Miyazaki S, Fujisue K, Yamanaga K, et al. Prognostic significance of soluble PD-L1 on cardiovascular outcomes in patients with coronary artery disease. J Atheroscler Thromb, 2024, 31(4): 355-367.
38. Kushnareva E, Kushnarev V, Artemyeva A, et al. Myocardial PD-L1 expression in patients with ischemic and non-ischemic heart failure. Front Cardiovasc Med, 2022, 8: 759972.
39. Choudhary A, Brinkley DM, Besharati S, et al. PD-L1 (programmed death ligand 1) as a marker of acute cellular rejection after heart transplantation. Circ Heart Fail, 2021, 14(10): e008563.
40. Mir FA, Ullah E, Mall R, et al. Dysregulated metabolic pathways in subjects with obesity and metabolic syndrome. Int J Mol Sci, 2022, 23(17): 9821.
41. Borodzicz-Jażdżyk S, Jażdżyk P, Łysik W, et al. Sphingolipid metabolism and signaling in cardiovascular diseases. Front Cardiovasc Med, 2022, 9: 915961.
42. Lemaitre RN, Jensen PN, Hoofnagle A, et al. Plasma ceramides and sphingomyelins in relation to heart failure risk. Circ Heart Fail, 2019, 12(7): e005708.
43. Jozefczuk E, Guzik TJ, Siedlinski M. Significance of sphingosine-1-phosphate in cardiovascular physiology and pathology. Pharmacol Res, 2020, 156: 104793.
44. Lemaitre RN, McKnight B, Sotoodehnia N, et al. Circulating very long-chain saturated fatty acids and heart failure: The cardiovascular health study. J Am Heart Assoc, 2018, 7(21): e010019.
45. Stenemo M, Ganna A, Salihovic S, et al. The metabolites urobilin and sphingomyelin (30: 1) are associated with incident heart failure in the general population. ESC Heart Fail, 2019, 6(4): 764-773.
46. Mueller-Hennessen M, Düngen HD, Lutz M, et al. A novel lipid biomarker panel for the detection of heart failure with reduced ejection fraction. Clin Chem, 2017, 63(1): 267-277.
47. Lemaitre RN, Jensen PN, Hoofnagle A, et al. Plasma ceramides and sphingomyelins in relation to heart failure risk. Circ Heart Fail, 2019, 12(7): e005708.
48. Peters L, Kuebler WM, Simmons S. Sphingolipids in atherosclerosis: Chimeras in structure and function. Int J Mol Sci, 2022, 23(19): 11948.
49. Gaggini M, Fenizia S, Vassalle C. Sphingolipid levels and signaling via resveratrol and antioxidant actions in cardiometabolic risk and disease. Antioxidants (Basel), 2023, 12(5): 1102.

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Latest ArticlesThe causal relationship between immune cells and heart failure risk and the mediating role of serum metabolites: A Mendelian randomization study

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