Skip to main content

Advertisement

Log in

Moderate consumption of a soluble green/roasted coffee rich in caffeoylquinic acids reduces cardiovascular risk markers: results from a randomized, cross-over, controlled trial in healthy and hypercholesterolemic subjects

  • Original Contribution
  • Published:
European Journal of Nutrition Aims and scope Submit manuscript

Abstract

Purpose

Coffee is rich in bioactive compounds with health beneficial properties, with green coffee presenting higher phenol content than roasted. We evaluated the effects of regularly consuming realistic amounts of a green/roasted coffee blend on cardiovascular health-related biomarkers.

Methods

A randomized, cross-over, controlled study was carried out in 25 normocholesterolemic [total cholesterol (TC) < 200 mg/dL] and 27 hypercholesterolemic (TC 200–240 mg/dL) subjects. During 8 weeks, volunteers consumed 6 g/day of soluble green/roasted (35:65) coffee or a control beverage (water or an isotonic drink). Blood pressure, heart rate and body weight were monitored at the end of each intervention, and serum lipids [TC, HDL-C, LDL-C, VLDL-C, triglycerides and phospholipids], cytokines and chemokines (IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-10, IL-12, IL-13, IL-17, G-CSF, GM-CSF, MCP-1, MIP-1β, TNF-α, INF-γ), adhesion molecules (ICAM-1, VCAM-1), and C-reactive protein were measured. Plasma antioxidant capacity (FRAP, ORAC and ABTS methods), and lipid (malondialdehyde, MDA) and protein (carbonyl groups, CG) oxidation were also determined.

Results

Attending to the general lineal model of variance for repeated measures, after the green/roasted coffee intervention significant reductions in TC, LDL-C, VLDL-C and triglycerides levels (p = 0.006, 0.001, 0.003 and 0.017, respectively), and a significant group effect were observed (0.001, < 0.001, 0.019 and 0.027, respectively). Only within the hypercholesterolemic group, attending to the Bonferroni test, the aforementioned lipid parameters were significantly lower after regular green/roasted coffee intake compared to baseline values. Moreover, after the coffee stage, plasma antioxidant capacity improved, according to the increase in ORAC and FRAP values (p < 0.001 and p < 0.001, respectively) and decrease of MDA (p = 0.015) and CG (p < 0.001) levels, without differences between groups. Systolic (p = 0.001) and diastolic (p < 0.001) blood pressure, heart rate (p = 0.035), and body weight (p = 0.017) were reduced in both normo- and hypercholesterolemic groups.

Conclusion

Regular consumption of moderate amounts of a soluble green/roasted (35:65) coffee blend may contribute to improve cardiovascular health in moderately hypercholesterolemic people, as reducing serum lipids, blood pressure and body weight effects, as well as increasing plasma antioxidant capacity, have been observed. Moreover, positive influences on blood pressure, body weight, and plasma antioxidant capacity were obtained in the healthy group. Therefore, incorporation of green coffee beans into the coffee brew can be recommended as part of a dietary strategy to protect from cardiovascular disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

Abbreviations

ABTS:

2,2′-Azino-bis(3-ethylbenzothiazoline-6-sulphonic acid)

BMI:

Body mass index

BP:

Blood pressure

CG:

Carbonyl groups

CQAs:

Caffeoylquinic acids

CRP:

C-reactive protein

DBP:

Diastolic blood pressure

FRAP:

Ferric reducing/antioxidant power

G-CSF:

Granulocyte colony-stimulating factor

ICAM-1:

Intercellular cell adhesion molecule-1

IFNγ:

Interferon gamma

IL:

Interleukin

LC-MS:

Liquid chromatography–mass spectrometry

MCP-1:

Monocyte chemoattractant protein-1

MDA:

Malondialdehyde

MIP-1β:

Macrophage inflammatory protein-1 beta

ORAC:

Oxygen radical absorbance capacity

RCT:

Randomized clinical trial

SBP:

Systolic blood pressure

TC:

Total cholesterol

TG:

Triglycerides

TNF-α:

Tumor necrosis factor alpha

VCAM-1:

Vascular cell adhesion molecule-1

References

  1. Farah A (2012) Coffee constituents. In: Chu YF (ed) Coffee: emerging health effects and disease prevention. Blackwell Publishing Ltd, Oxford, pp 21–58

    Chapter  Google Scholar 

  2. Jaiswal R, Matei MF, Subedi P, Kuhnert N (2014) Does roasted coffee contain chlorogenic acid lactones or/and cinnamoylshikimate esters? Food Res Int 61:214–227

    Article  CAS  Google Scholar 

  3. Alonso-Salces RM, Serra F, Reniero F, Heberger K (2009) Botanical and geographical characterization of green coffee (Coffea arabica and Coffea canephora): chemometric evaluation of phenolic and methylxanthine contents. J Agric Food Chem 57:4224–4235

    Article  CAS  PubMed  Google Scholar 

  4. Baeza G, Sarriá B, Bravo L, Mateos R (2016) Exhaustive qualitative LC-DAD-MSn analysis of Arabica green coffee beans: cinnamoyl-glycosides and cinnamolyshikimic acids as new polyphenols in green coffee. J Agric Food Chem 64:9663–9674

    Article  CAS  PubMed  Google Scholar 

  5. Morales FJ, Somoza V, Fogliano V (2012) Physiological relevance of dietary melanoidins. Amino Acids 42:1097–1109

    Article  CAS  PubMed  Google Scholar 

  6. Ochiai R, Chikama A, Kataoka K, Tokimitsu I, Maekawa Y, Ohishi M, Rakugi M, Mikami H (2009) Effects of hydroxyhydroquinone-reduced coffee on vasoreactivity and blood pressure. Hypertens Res 32:969–974

    Article  CAS  Google Scholar 

  7. Bakuradze T, Boehm N, Janzowski C, Lang R, Hofmann T, Stockis JP, Albert FW, Stiebitz H, Bytof G, Lantz I et al (2011) Antioxidant-rich coffee reduces DNA damage, elevates glutathione status and contributes to weight control: results from an intervention study. Mol Nutr Food Res 55:793–797

    Article  CAS  PubMed  Google Scholar 

  8. Lopez-Garcia E, Guallar-Castillon P, Leon-Muñoz L, Graciani A, Rodriguez-Artalejo F (2014) Coffee consumption and health-related quality of life. Clin Nutr 33:143–149

    Article  CAS  PubMed  Google Scholar 

  9. Ohnaka K, Ikeda M, Maki T, Okada T, Shimazoe T, Adachi M, Nomura M, Takayanagi R, Kono S (2012) Effects of 16-week consumption of caffeinated and decaffeinated instant coffee on glucose metabolism in a randomized controlled trial. J Nutr Metab 207426

  10. Sarriá B, Martínez-López S, Sierra-Cinos JL, García-Diz L, Mateos R, Bravo L (2016) Regularly consuming a green/roasted coffee blend reduces the risk of metabolic syndrome. Eur J Nutr. https://doi.org/10.1007/s00394-016-1316-8

    Article  PubMed  Google Scholar 

  11. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE, Drazner MH, Fonarow GC, Gerazi SA, Horwich T, Januzzi JL et al (2013) ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation 128:e240–e327

    PubMed  Google Scholar 

  12. Bravo L, Mateos R, Sarriá B (2017) Preventive effect of coffee against cardiovascular diseases. In: Farah A (ed) Coffee: chemistry, quality and health implications. Royal Society of Chemistry, Oxford

    Google Scholar 

  13. Jee SH, He J, Appel LJ, Whelton PK, Suh I, Klag MJ (2001) Coffee consumption and serum lipids: a meta-analysis of randomized controlled clinical trials. Am J Epidemiol 153:353–362

    Article  CAS  PubMed  Google Scholar 

  14. Cai L, Ma D, Zhang Y, Liu Z, Wang P (2012) The effect of coffee consumption on serum lipids: a meta-analysis of randomized controlled trials. Eur J Clin Nutr 66:872–877

    Article  CAS  PubMed  Google Scholar 

  15. Jee SH, He J, Whelton PK, Suh I, Klag MJ (1999) The effect of chronic coffee drinking on blood pressure. A meta-analysis of controlled clinical trials. Hypertension 33:647–652

    Article  CAS  PubMed  Google Scholar 

  16. Noordzij M, Uiterwaal CS, Arends LR, Kok FJ, Grobbee DE, Geleijnse JM (2005) Blood pressure response to chronic intake of coffee and caffeine: a meta-analysis of randomized controlled trials. J Hypertens 23:921–928

    Article  CAS  PubMed  Google Scholar 

  17. Nurminen M-L, Niittyenen L, Korpela R, Vapaatalo V (1999) Coffee, caffeine and blood pressure: a critical review. Eur J Clin Nutr 53:831–839

    Article  CAS  Google Scholar 

  18. Mesas AE, Leon-Muñoz LM, Rodriguez-Artalejo F, Lopez-Garcia E (2011) The effect of coffee on blood pressure and cardiovascular disease in hypertensive individuals: a systematic review and meta-analysis. Am J Clin Nutr 94:1113–1126

    Article  CAS  PubMed  Google Scholar 

  19. Steffen M, Kuhle C, Hensrud D, Erwin PJ, Murad MH (2012) The effect of coffee consumption on blood pressure and the development of hypertension: a systematic review and meta-analysis. J Hypertens 30:2245–2254

    Article  CAS  PubMed  Google Scholar 

  20. Zhang Z, Hu G, Caballero B, Apple L, Chen L (2011) Habitual coffee consumption and risk of hypertension: a systematic review and meta-analysis of prospective observational studies. Am J Clin Nutr 93:1212–1219

    Article  CAS  PubMed  Google Scholar 

  21. Karatzis E, Papaioannou TG, Aznaouridis K, Karatzi K, Stamatelopoulos K, Zampelas A, Papamichael C, Lekakis J, Mavrikakis M (2005) Acute effects of caffeine on blood pressure and wave reflections in healthy subjects: should we consider monitoring central blood pressure? Int J Cardiol 98:425–430

    Article  PubMed  Google Scholar 

  22. Papamichael CM, Aznaouridis KA, Karatzis EN, Karatzi KN, Stamatelopoulos KS, Vamvakou G, Lekakis JP, Mavrikakis ME (2005) Effect of coffee on endothelial function in healthy subjects: the role of caffeine. Clin Sci 109:55–60

    Article  CAS  PubMed  Google Scholar 

  23. Buscemi S, Verga S, Batsis JA, Donatelli M, Tranchina MR, Belmonte S, Mattina A, Re A, Cerasola G (2010) Acute effects of coffee on endothelial function in healthy subjects. Eur J Clin Nutr 64:483–489

    Article  CAS  PubMed  Google Scholar 

  24. Ochiai R, Sugiura Y, Otsuka K, Katsuragi Y, Hashiguchi T (2014) Coffee polyphenols improve peripheral endothelial function after glucose loading in healthy male adults. Nutr Res 34:155–159

    Article  CAS  PubMed  Google Scholar 

  25. Ludwig IA, Clifford MN, Lean ME, Ashihara H, Crozier A (2014) Coffee: biochemistry and potential impact on health. Food Funct 5:1695–1717

    Article  CAS  PubMed  Google Scholar 

  26. Cho AS, Jeon SM, Kim MJ, Yeo J, Seo KI, Choi MS, Lee MK (2010) Chlorogenic acid exhibits anti-obesity property and improves lipid metabolism in high-fat diet-induce-obese mice. Food Chem Toxicol 48:937–943

    Article  CAS  PubMed  Google Scholar 

  27. Vinson JA, Burnham BR, Nagendran MV (2012) Randomized, double-blind, placebo-controlled, linear dose, crossover study to evaluate the efficacy and safety of a green coffee bean extract in overweight subjects. Diabetes Metab Syndr Obes Target Ther 5:21–27

    Article  CAS  Google Scholar 

  28. Agudelo-Ochoa GM, Pulgarín-Zapata IC, Velásquez-Rodríguez CM, Duqye-Ramírez M, Naranjo-Cano M, Quintero-Ortiz MM, Lara-Guzmán OJ, Muñoz-Durango K (2016) Coffee consumption increases the antioxidant capacity of plasma and has no effect on the lipid profile or vascular function in healthy adults in a randomized controlled trial. J Nutr 146:524–531

    Article  CAS  PubMed  Google Scholar 

  29. Meng S, Cao J, Feng Q, Peng J, Hu Y (2013) Roles of chlorogenic acid on regulating glucose and lipids metabolism: a review. Evid Based Complem Alt Med 2013:801457

    Google Scholar 

  30. Kozuma K, Tsuchiya S, Kohori J, Hase T, Tokimitsu I (2005) Antihypertensive effect of green coffee bean extract on mildly hypertensive subjects. Hypertens Res 28:711–718

    Article  CAS  PubMed  Google Scholar 

  31. Watanabe T, Arai Y, Mitsui Y, Kusaura T, Okawa W, Kajihara Y, Saito I (2006) The blood pressure-lowering effect and safety of chlorogenic acid from green coffee bean extract in essential hypertension. Clin Exper Hypert 28:439–449

    Article  CAS  Google Scholar 

  32. Revuelta-Iniesta R, Al-Dujaili EAS (2014) Consumption of green coffee reduces blood pressure and body composition by influencing 11β-HSD1 enzyme activity in healthy individuals: a pilot crossover study using green and black coffee. Bio Med Res Int 482704

  33. Ochiai R, Jokura H, Suzuki A, Tokimitsu I, Ohishi M, Komai N, Rakugi H, Ogihara T (2004) Green coffee bean extract improves human vasoreactivity. Hypertens Res 27:731–737

    Article  CAS  PubMed  Google Scholar 

  34. Ward NC, Hodgson JM, Woodman RJ, Zimmermann D, Poquet L, Leveques A, Actis-Goretta L, Puddey IB, Croft KD (2016) Acute effects of chlorogenic acids on endothelial function and blood pressure in healthy men and women. Food Funct 7:2197–2203

    Article  CAS  PubMed  Google Scholar 

  35. Sarriá B, Martínez-López S, Mateos R, Bravo L (2016) Long-term consumption of a green/roasted coffee blend positively affects glucose and insulin resistance in humans. Food Res Int 89:1023–1028

    Article  CAS  Google Scholar 

  36. Martinez-Lopez S, Sarria B, Baeza G, Mateos R, Bravo-Clemente L (2014) Theobromine, caffeine, and theophylline metabolites in human plasma and urine after consumption of soluble cocoa products with different methylxanthine contents. Food Res Int 63:446–455

    Article  CAS  Google Scholar 

  37. Olthof MR, Hollman PC, Zock PL, Katan MK (2001) Consumption of high doses of chlorogenic acid, present in coffee, or of black tea increases plasma total homocysteine concentrations in humans. Am J Clin Nutr 73:532–538

    Article  CAS  Google Scholar 

  38. Kempf K, Kolb H, Gärtner B, Bytof G, Stiebitz H, Lantz I, Lang R, Hofmann T, Martin S (2015) Cardiometabolic effects of two coffee blends differing in content form major constituents in overweight adults: a randomized controlled trial. Eur J Nutr 54:845–854

    Article  CAS  PubMed  Google Scholar 

  39. Hoelzl C, Knasmüller S, Wagner KH, Elbling L, Huber W, Kager N, Ferk F, Ehrlich V, Nersesyan A, Neubauer O et al (2010) Instant coffee with high chlorogenic acid levels protects humans against oxidative damage of macromolecules. Mol Nutr Food Res 54:1722–1733

    Article  CAS  PubMed  Google Scholar 

  40. Re R, Pellegrini N, Proteggente A, Pannala A, Yang M, Rice-Evans C (1999) Antioxidant activity applying an improved ABTS radical cation decolorization assay. Free Radical Bio Med 26:1231–1237

    Article  CAS  Google Scholar 

  41. Huang D, Ou B, Hampsch-Woodill M, Flanagan JA, Prior RL (2002) High-throughput assay of oxygen radical absorbance capacity (ORAC) using a multichannel liquid handling system coupled with a microplate fluorescence reader in 96-well format. J Agric Food Chem 50:4437–4444

    Article  CAS  Google Scholar 

  42. Pulido R, Bravo L, Saura-Calixto F (2000) Antioxidant activity of dietary polyphenols as determined by a modified FRAP assay. J Agric Food Chem 48:3396–3402

    Article  CAS  Google Scholar 

  43. Mateos R, Lecumberri E, Ramos S, Goya L, Bravo L (2005) Determination of malondialdehyde (MDA) by high-performance liquid chromatography in serum and liver as a biomarker for oxidative stress. Application to a rat model for hypercholesterolemia and evaluation of the effect of diets rich in phenolic antioxidants from fruits. J Chrom B 827:76–82

    Article  CAS  Google Scholar 

  44. Ritcher S, Wehr NB, Stadtman ER, Levine RL (2002) Assessment of skin carbonyl content as a noninvasive measure of biological age. Arch Biochem Biophys 397:430–432

    Article  CAS  Google Scholar 

  45. Moreiras O, Carbajal A, Cabrera L, Cuadrado C (2016) Ingestas diarias recomendadas de energía y nutrientes para la población española. Tablas de Composición de Alimentos. Ed. Pirámide (Grupo Anaya, SA), 18th edn. Madrid

  46. FAO/WHO/UNU (1985) Expert Consultation Report. Energy and Protein Requirements. Technical Report Series 724. WHO, Geneva

    Google Scholar 

  47. Greenberg JA, Boozer CN, Geliebter A (2006) Coffee, diabetes, and weight control. Am J Clin Nutr 84:682–693

    Article  CAS  PubMed  Google Scholar 

  48. Riksen NP, Rongen GA, Smits P (2009) Acute and long-term cardiovascular effects of coffee: implications for coronary heart disease. Pharmacol Ther 121:185–191

    Article  CAS  PubMed  Google Scholar 

  49. Mubarak A, Bondonno CP, Liu AH, Considine MJ, Rich L, Mas E, Croft KD, Hodgson JM (2012) Acute effects of chlorogenic acid on nitric oxide status, endothelial function, and blood pressure in healthy volunteers: a randomized trial. J Agric Food Chem 60:9130–9136

    Article  CAS  PubMed  Google Scholar 

  50. Kempf K, Herder C, Erlund I, Kolb H, Martin S, Cartensen M, Koenig W, Sundvall J, Bidel S, Kuha S, Tuomilehto J (2010) Effects of coffee consumption on subclinical inflammation and other risk factors for type 2 diabetes: a clinical trial. Am J Clin Nutr 91:950–957

    Article  CAS  PubMed  Google Scholar 

  51. Koh KK, Quon MJ, Han SH, Chung W-J, Ahn JY, Seo Y-H, Kang MH, Ahn TH, Choi IS, Shin EK (2004) Additive beneficial effects of losartan combined with simvastatin in the treatment of hypercholesterolemic, hypertensive patients. Circulation 110:3687–3692

    Article  CAS  PubMed  Google Scholar 

  52. Panahi Y, Hosseini MS, Khalili N, Naimi E, Simental.Mendia LE, Majeed M, Sahebkar A (2016) Effects of curcumin on serum cytokine concentrations in subjects with metabolic syndrome: a post-hoc analysis of a randomized controlled trial. Biomed Pharmacother 82:578–582

    Article  CAS  PubMed  Google Scholar 

  53. Correa TAF, Rogero MM, Mioto BM, Tarasoutchi D, Tuda VL, Cesar LAM, Torres EAFS. (2013) Paper-filtered coffee increases cholesterol and inflammation biomarkers independent of roasting degree: a clinical trial. Nutrition 29:977–981

    Article  CAS  PubMed  Google Scholar 

  54. Therkelsen SP, Hetland G, Lyberg T, Lygren I, Johnson E (2016) Cytokine levels after consumption of a medicinal Agaricus blazei Murill-based mushroom extract, AndoSanTM, in patients with Chron’s disease and ulcerative colitis in a randomized single-blinded placebo-controlled study. Human Immunol 84:323–331

    CAS  Google Scholar 

  55. Chang WC, Chen CH, Lee MF, Chang T, Yu YM (2010) Chlorogenic acid attenuates adhesion molecules up-regulation in IL-1β-treated endothelial cells. Eur J Nutr 49:267–275

    Article  CAS  PubMed  Google Scholar 

  56. Hwang SJ, Kim Y-W, Park Y, Lee H-J, Kim K-W (2014) Anti-inflammatory effects of chlorogenic acid in lipopolysaccharide-stimulated RWA 264.7 cells. Inflamm Res 63:81–90

    Article  CAS  Google Scholar 

  57. Lee E-S, Park S-H, Kim MS, Han S-Y, Kim H-S, Kang Y-H (2012) Caffeic acid disturbs monocyte adhesion onto cultured endothelial cells stimulated by adipokine resistin. J Agric Food Chem 60:2730–2739

    Article  CAS  PubMed  Google Scholar 

  58. Ma Z-C, Hong Q, Wang Y-G, Tan H-L, Xiao C-R, Liang Q-D, Cai S-H, Gao Y (2010) Ferulic acid attenuates adhesion molecule expression in gamma-radiated human umbilical vascular endothelial cells. Biol Pharm Bull 33:752–758

    Article  PubMed  Google Scholar 

  59. Pellegrini N, Serafini M, Colombi B, Del Rio D, Salvatore S, Bianchi M, Brighenti F (2003) Total antioxidant capacity of plant foods, beverages and oils consumed in Italy assessed by three different in vitro assays. J Nutr 133:2812–2819

    Article  CAS  PubMed  Google Scholar 

  60. Svilaas A, Sakhi AK, Andersen LF, Svilaas T, Ström EC, Jacobs DR, Ose L, Bloomhoff R (2004) Intakes of antioxidants in coffee, wine, and vegetables are correlated with plasma carotenoids in humans. J Nutr 134:562–567

    Article  CAS  PubMed  Google Scholar 

  61. Baeza G, Amigo-Benavent M, Sarria B, Goya L, Mateos R, Bravo L (2014) Green coffee hydroxycinnamic acids but not caffeine protect human HepG2 cells against oxidative stress. Food Res Int 62:1038–1046

    Article  CAS  Google Scholar 

  62. Gómez-Juaristi M, Martínez-López S, Sarria B, Bravo L, Mateos R (2018) Bioavailability of hydroxycinnamates in an instant green/roasted coffee blend in humans. Identification of novel colonic metabolites. Food Funct 9:313–334

    Article  Google Scholar 

Download references

Acknowledgements

The financial support of projects AGL2010-18269 and AGL2015-69986-R from the Spanish Ministry of Economy, Industry and Competitivity is acknowledged. We want to thank the volunteers who participated in the study, J. L. Sierra Cinos and L. García-Diz for their assistance in anthropometric measurements, M. Jimenez and L. T. Cayuelas for their assistance in dietary records analysis and M. Barba and C. Oeo for their assistance in lab analysis. Nestle, S. A. provided and packed the soluble coffee product for free. S. M.-L. thanks the Spanish National Research Council for her pre-doctoral fellowship under the JAE-Pre programme co-funded by CSIC and the European Social Fund. L.B. designed the trial and has the primary responsibility for final content. B.S. and S.M.-L carried out the statistical analysis of data. B.S., R.M. and S.M.-L. conducted the research and interpreted the results. S.M.-L wrote the initial draft and all authors revised and approved the final version of the manuscript.

Funding

This study was funded by Projects AGL2010-18269 and AGL2015-69986-R from the Spanish Ministry of Economy and Competitivity and approved by Ethical Committee Hospital Puerta de Hierro (Majadahonda, Madrid).

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Beatriz Sarriá or Laura Bravo-Clemente.

Ethics declarations

Conflict of interest

The authors declare no conflicts of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Martínez-López, S., Sarriá, B., Mateos, R. et al. Moderate consumption of a soluble green/roasted coffee rich in caffeoylquinic acids reduces cardiovascular risk markers: results from a randomized, cross-over, controlled trial in healthy and hypercholesterolemic subjects. Eur J Nutr 58, 865–878 (2019). https://doi.org/10.1007/s00394-018-1726-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00394-018-1726-x

Keywords

Navigation