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Plasma metabolomic profiles associated with hypertension and blood pressure in response to thiazide diuretics

Hypertension Research volume 45, pages 464–473 (2022)Cite this article

A Comment to this article was published on 14 January 2022

Abstract

This study aimed to identify the metabolomic alterations associated with hypertension (HTN) and the response of blood pressure (BP) to thiazide diuretics. A total of 50 participants previously untreated for HTN were prospectively recruited. After a 2-week lifestyle adjustment, 30 participants with systolic BP ≥ 140 mmHg and/or diastolic BP ≥ 90 mmHg were classified into the HTN group and prescribed hydrochlorothiazide (HCTZ) at 50 mg per day for 2 weeks. The remaining 20 participants, who had relatively normal BP, were assigned to the normotension group. Metabolomic profiles related to the response of BP to thiazide diuretics were analyzed. A total of 73 differential metabolites were found to be associated with HTN, and 27 metabolites were significantly changed upon HCTZ treatment (HCTZ-sensitive metabolites). Among the identified metabolites, 7 (aspartate, histidine, C5-DC, C5-M-DC, C14:1, phosphatidylcholine ae C34:1, and phosphatidylcholine ae C34:3) were positively associated with HTN and decreased in abundance upon HCTZ treatment (HCTZ-reduced/HTN-associated metabolites). Moreover, multivariate analysis of 20 metabolites whose baseline levels were associated with the response of BP revealed that aspartate, glutamate, lysophosphatidylcholine C16:0, lysophosphatidylcholine C20:3, and sphingomyelin C24:1 were independently related to systolic BP reduction, and lysophosphatidylcholine C20:3 was independently associated with diastolic BP reduction. In conclusion, we identified 5 metabolites independently related to BP changes with HCTZ treatment. An advanced biomarker profile of thiazide-induced metabolomic changes may provide a clue with which to further explore the complex and mixed effects of thiazide treatment in a clinical setting.

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References

  1. Yusuf S, Joseph P, Rangarajan S, Islam S, Mente A, Hystad P, et al. Modifiable risk factors, cardiovascular disease, and mortality in 155 722 individuals from 21 high-income, middle-income, and low-income countries (PURE): a prospective cohort study. Lancet. 2020;395:795–808.

    Article  Google Scholar 

  2. Zhou B, Danaei G, Stevens GA, Bixby H, Taddei C, Carrillo-Larco RM, et al. Long-term and recent trends in hypertension awareness, treatment, and control in 12 high-income countries: an analysis of 123 nationally representative surveys. Lancet. 2019;394:639–51.

    Article  Google Scholar 

  3. Obermüller N, Bernstein P, Velázquez H, Reilly R, Moser D, Ellison DH, et al. Expression of the thiazide-sensitive Na-Cl cotransporter in rat and human kidney. Am J Physiol. 1995;269:F900–F910.

    PubMed  Google Scholar 

  4. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002;288:2981–97.

    Article  Google Scholar 

  5. Psaty BM, Lumley T, Furberg CD, Schellenbaum G, Pahor M, Alderman MH, et al. Health outcomes associated with various antihypertensive therapies used as first-line agents: a network meta-analysis. JAMA. 2003;289:2534–44.

    Article  CAS  Google Scholar 

  6. Suchard MA, Schuemie MJ, Krumholz HM, You SC, Chen R, Pratt N, et al. Comprehensive comparative effectiveness and safety of first-line antihypertensive drug classes: a systematic, multinational, large-scale analysis. Lancet. 2019;394:1816–26.

    Article  Google Scholar 

  7. Whelton PK, Carey RM, Aronow WS, Casey DE Jr, Collins KJ, Dennison Himmelfarb C, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the american college of cardiology/american heart association task force on clinical practice guidelines. Hypertension. 2018;71:e13–e115.

    CAS  PubMed  Google Scholar 

  8. Williams B, Mancia G, Spiering W, Agabiti Rosei E, Azizi M, Burnier M, et al. 2018 ESC/ESH Guidelines for the management of arterial hypertension. Eur Heart J. 2018;39:3021–104.

    Article  Google Scholar 

  9. Carey RM, Calhoun DA, Bakris GL, Brook RD, Daugherty SL, Dennison-Himmelfarb CR, et al. Resistant hypertension: detection, evaluation, and management: a scientific statement from the American heart association. Hypertension. 2018;72:e53–e90.

    Article  CAS  Google Scholar 

  10. Turner ST, Schwartz GL, Chapman AB, Boerwinkle E. WNK1 kinase polymorphism and blood pressure response to a thiazide diuretic. Hypertension. 2005;46:758–65.

    Article  CAS  Google Scholar 

  11. Turner ST, Bailey KR, Fridley BL, Chapman AB, Schwartz GL, Chai HS, et al. Genomic association analysis suggests chromosome 12 locus influencing antihypertensive response to thiazide diuretic. Hypertension. 2008;52:359–65.

    Article  CAS  Google Scholar 

  12. Salvi E, Wang Z, Rizzi F, Gong Y, McDonough CW, Padmanabhan S, et al. Genome-wide and gene-based meta-analyses identify novel loci influencing blood pressure response to hydrochlorothiazide. Hypertension. 2017;69:51–59.

    Article  CAS  Google Scholar 

  13. Shahin MH, Sá AC, Webb A, Gong Y, Langaee T, McDonough CW, et al. Genome-wide prioritization and transcriptomics reveal novel signatures associated with thiazide diuretics blood pressure response. Circ Cardiovasc Genet. 2017;10:e001404.

    Article  CAS  Google Scholar 

  14. Sá ACC, Webb A, Gong Y, McDonough CW, Shahin MH, Datta S, et al. Blood pressure signature genes and blood pressure response to thiazide diuretics: results from the PEAR and PEAR-2 studies. BMC Med Genomics. 2018;11:55.

    Article  Google Scholar 

  15. Singh S, McDonough CW, Gong Y, Bailey KR, Boerwinkle E, Chapman AB, et al. Genome wide analysis approach suggests chromosome 2 locus to be associated with thiazide and thiazide like-diuretics blood Pressure Response. Sci Rep. 2019;9:17323.

    Article  CAS  Google Scholar 

  16. Huang CC, Chung CM, Hung SI, Leu HB, Wu TC, Huang PH, et al. Genetic variation in renin predicts the effects of thiazide diuretics. Eur J Clin Invest. 2011;41:828–35.

    Article  CAS  Google Scholar 

  17. Shahin MH, Gong Y, McDonough CW, Rotroff DM, Beitelshees AL, Garrett TJ, et al. A genetic response score for hydrochlorothiazide use: insights from genomics and metabolomics integration. Hypertension. 2016;68:621–9.

    Article  CAS  Google Scholar 

  18. Shahin MH, Gong Y, Frye RF, Rotroff DM, Beitelshees AL, Baillie RA, et al. Sphingolipid metabolic pathway impacts thiazide diuretics blood pressure response: insights from genomics, metabolomics, and lipidomics. J Am Heart Assoc. 2017;7:e006656.

    PubMed  PubMed Central  Google Scholar 

  19. Trabado S, Al-Salameh A, Croixmarie V, Masson P, Corruble E, Fève B, et al. The human plasma-metabolome: Reference values in 800 French healthy volunteers; impact of cholesterol, gender and age. PLoS One. 2017;12:e0173615.

    Article  Google Scholar 

  20. Varma VR, Oommen AM, Varma S, Casanova R, An Y, Andrews RM, et al. Brain and blood metabolite signatures of pathology and progression in Alzheimer disease: a targeted metabolomics study. PLoS Med. 2018;15:e1002482.

    Article  Google Scholar 

  21. Goïta Y, Chao de la Barca JM, Keïta A, Diarra MB, Dembélé KC, Chabrun F, et al. Sexual dimorphism of metabolomic profile in arterial hypertension. Sci Rep. 2020;10:7517.

    Article  Google Scholar 

  22. Dietrich S, Floegel A, Weikert C, Prehn C, Adamski J, Pischon T, et al. Identification of serum metabolites associated with incident hypertension in the european prospective investigation into cancer and nutrition-potsdam study. Hypertension. 2016;68:471–7.

    Article  CAS  Google Scholar 

  23. Lin YT, Salihovic S, Fall T, Hammar U, Ingelsson E, Ärnlöv J, et al. Global Plasma metabolomics to identify potential biomarkers of blood pressure progression. Arterioscler Thromb Vasc Biol. 2020;40:e227–e237.

    Article  CAS  Google Scholar 

  24. Hiltunen TP, Rimpelä JM, Mohney RP, Stirdivant SM, Kontula KK. Effects of four different antihypertensive drugs on plasma metabolomic profiles in patients with essential hypertension. PLoS One. 2017;12:e0187729.

    Article  Google Scholar 

  25. Rotroff DM, Shahin MH, Gurley SB, Zhu H, Motsinger-Reif A, Meisner M, et al. Pharmacometabolomic assessments of atenolol and hydrochlorothiazide treatment reveal novel drug response phenotypes. CPT Pharmacomet Syst Pharm. 2015;4:669–79.

    Article  CAS  Google Scholar 

  26. Kim M, Jung S, Kim SY, Lee SH, Lee JH. Prehypertension-associated elevation in circulating lysophosphatidlycholines, Lp-PLA2 activity, and oxidative stress. PLoS One. 2014;9:e96735.

    Article  Google Scholar 

  27. Jiang H, Nie L, Li Y, Xie J. Application of ultra-performance liquid chromatography coupled with mass spectrometry to metabonomic study on spontaneously hypertensive rats and intervention effects of Ping Gan prescription. J Sep Sci. 2012;35:483–9.

    Article  CAS  Google Scholar 

  28. Kim JY, Kim OY, Paik JK, Kwon DY, Kim HJ, Lee JH. Association of age-related changes in circulating intermediary lipid metabolites, inflammatory and oxidative stress markers, and arterial stiffness in middle-aged men. Age (Dordr). 2013;35:1507–19.

    Article  CAS  Google Scholar 

  29. Hoover RS, Poch E, Monroy A, Vázquez N, Nishio T, Gamba G, et al. N-Glycosylation at two sites critically alters thiazide binding and activity of the rat thiazide-sensitive Na(+):Cl(-) cotransporter. J Am Soc Nephrol. 2003;14:271–82.

    Article  CAS  Google Scholar 

  30. Li AP, Yang L, Cui T, Zhang LC, Liu YT, Yan Y, et al. Uncovering the mechanism of Astragali Radix against nephrotic syndrome by intergrating lipidomics and network pharmacology. Phytomedicine. 2020;77:153274.

    Article  CAS  Google Scholar 

  31. Luo H, Beaumont K, Vaughn DA, Fanestil DD. Solubilization of thiazide diuretic receptors from rat kidney membranes. Biochim Biophys Acta. 1990;1052:119–22.

    Article  CAS  Google Scholar 

  32. Welker P, Böhlick A, Mutig K, Salanova M, Kahl T, Schlüter H, et al. Renal Na+-K+-Cl- cotransporter activity and vasopressin-induced trafficking are lipid raft-dependent. Am J Physiol Ren Physiol. 2008;295:F789–F802.

    Article  CAS  Google Scholar 

  33. Ke C, Zhu X, Zhang Y, Shen Y. Metabolomic characterization of hypertension and dyslipidemia. Metabolomics. 2018;14:117.

    Article  Google Scholar 

  34. Zhao JV, Kwok MK, Schooling CM. Effect of glutamate and aspartate on ischemic heart disease, blood pressure, and diabetes: a Mendelian randomization study. Am J Clin Nutr. 2019;109:1197–206.

    Article  Google Scholar 

  35. Hou E, Sun N, Zhang F, Zhao C, Usa K, Liang M, et al. Malate and aspartate increase L-arginine and nitric oxide and attenuate hypertension. Cell Rep. 2017;19:1631–9.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Jie-Ling Li for her excellent technical support. This work was supported by research grants VGHUST108-G1-3-1, VGHUST108-G1-3-2, VGHUST108-G1-3-3, and V110C-058 from Taipei Veterans General Hospital, Taipei, Taiwan, and by research grants NSC 100-2314-B-075-055, MOST108-2314-B-075-062-MY3, and MOST 109-2311-B-010-003 from the Ministry of Science and Technology, Taiwan. The funders had no role in the study design, the data collection and analysis, the decision to publish, or the preparation of the manuscript.

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Authors and Affiliations

  1. Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan

    Chin-Chou Huang & Jaw-Wen Chen

  2. School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan

    Chin-Chou Huang

  3. Institute of Pharmacology, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan

    Chin-Chou Huang & Jaw-Wen Chen

  4. Cardiovascular Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan

    Chin-Chou Huang & Jaw-Wen Chen

  5. Department of Life Sciences and Institute of Genome Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan

    Yi-Long Huang & Chao-Hsiung Lin

  6. Aging and Health Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan

    Yi-Long Huang & Chao-Hsiung Lin

  7. Healthcare and Services Center, Taipei Veterans General Hospital, Taipei, Taiwan

    Jaw-Wen Chen

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  1. Chin-Chou Huang
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Correspondence to Chin-Chou Huang or Chao-Hsiung Lin.

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Huang, CC., Huang, YL., Lin, CH. et al. Plasma metabolomic profiles associated with hypertension and blood pressure in response to thiazide diuretics. Hypertens Res 45, 464–473 (2022). https://doi.org/10.1038/s41440-021-00825-9

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