Electrical Muscle Stimulation in Heart Failure Patients: A Mini Review
Main Article Content
Abstract
This review serves as a synopsis of current knowledge about electrical muscle stimulation in patients with heart failure. It summarizes actual data, emphasizes the beneficial effects of electrical muscle stimulation in heart failure and tries to characterize a target population. Improvements of functional capacity and quality of life are knowingly achieved by variable stimulation protocols to the lower extremities. The population most likely to benefit from this therapy is of older age, has relevant comorbidities or reduced left ventricular ejection fraction. While short-term outcomes are mostly positive, there are few data on long-term outcomes that should be further investigated. Overall, electrical muscle stimulation can be considered a safe and efficacious therapy alternative to conventional physical exercise in patients with heart failure. Despite promising and increasing evidence for over two decades of scientific research on this topic, there are no recommendations in recent published guidelines concerning the use of electrical muscle stimulation in heart failure patients.
Article Details
How to Cite
VÖGELI, Benjamin et al.
Electrical Muscle Stimulation in Heart Failure Patients: A Mini Review.
Medical Research Archives, [S.l.], v. 10, n. 12, dec. 2022.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/3369>. Date accessed: 21 nov. 2024.
doi: https://doi.org/10.18103/mra.v10i12.3369.
Section
Review Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. McDonagh TA, Metra M, Adamo M, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: Developed by the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) With the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2021;42(36):3599-3726. doi:10.1093/eurheartj/ehab368
2. Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2022;145(18):e895-e1032. doi:10.1161/CIR.0000000000001063
3. Arenja N, Mueller C, Tomilovskaya E, Koryak Y, Poltavskaya M, Saner H. Real-world experience of feasibility and efficacy of electrical muscle stimulation in elderly patients with acute heart failure: A randomized controlled study. Int J Cardiol. 2021;344:113-119. doi:10.1016/j.ijcard.2021.09.062
4. Dirks ML, Hansen D, Van Assche A, Dendale P, Van Loon LJC. Neuromuscular electrical stimulation prevents muscle wasting in critically ill comatose patients. Clin Sci Lond Engl 1979. 2015;128(6):357-365. doi:10.1042/CS20140447
5. Forestieri P, Bolzan DW, Santos VB, et al. Neuromuscular electrical stimulation improves exercise tolerance in patients with advanced heart failure on continuous intravenous inotropic support use-randomized controlled trial. Clin Rehabil. 2018;32(1):66-74. doi:10.1177/0269215517715762
6. Groehs RV, Antunes-Correa LM, Nobre TS, et al. Muscle electrical stimulation improves neurovascular control and exercise tolerance in hospitalised advanced heart failure patients. Eur J Prev Cardiol. 2016;23(15):1599-1608. doi:10.1177/2047487316654025
7. Smart NA, Dieberg G, Giallauria F. Functional electrical stimulation for chronic heart failure: a meta-analysis. Int J Cardiol. 2013;167(1):80-86. doi:10.1016/j.ijcard.2011.12.019
8. Poltavskaya M, Sviridenko V, Giverts I, et al. In-hospital electrical muscle stimulation for patients early after heart failure decompensation: results from a prospective randomised controlled pilot trial. Open Heart. 2022;9(2):e001965. doi:10.1136/openhrt-2022-001965
9. Tanaka S, Kamiya K, Matsue Y, et al. Efficacy and Safety of Acute Phase Intensive Electrical Muscle Stimulation in Frail Older Patients with Acute Heart Failure: Results from the ACTIVE-EMS Trial. J Cardiovasc Dev Dis. 2022;9(4). doi:10.3390/jcdd9040099
10. Hao Y, Zhang L, Zhang Z, Chen L, He N, Zhu S. Tai Chi exercise and functional electrical stimulation of lower limb muscles for rehabilitation in older adults with chronic systolic heart failure: a non-randomized clinical trial. Braz J Med Biol Res Rev Bras Pesqui Medicas E Biol. 2019;52(12):e8786. doi:10.1590/1414-431X20198786
11. Gomes Neto M, Oliveira FA, Reis HFCD, de Sousa Rodrigues- EJ, Bittencourt HS, Oliveira Carvalho V. Effects of Neuromuscular Electrical Stimulation on Physiologic and Functional Measurements in Patients With Heart Failure: A SYSTEMATIC REVIEW WITH META-ANALYSIS. J Cardiopulm Rehabil Prev. 2016;36(3):157-166. doi:10.1097/HCR.0000000000000151
12. Banerjee P, Clark A, Witte K, Crowe L, Caulfield B. Electrical stimulation of unloaded muscles causes cardiovascular exercise by increasing oxygen demand. Eur J Cardiovasc Prev Rehabil Off J Eur Soc Cardiol Work Groups Epidemiol Prev Card Rehabil Exerc Physiol. 2005;12(5):503-508. doi:10.1097/01.hjr.0000169188.84184.23
13. Banerjee P, Caulfield B, Crowe L, Clark AL. Prolonged electrical muscle stimulation exercise improves strength, peak VO2, and exercise capacity in patients with stable chronic heart failure. J Card Fail. 2009;15(4):319-326. doi:10.1016/j.cardfail.2008.11.005
14. Dobsák P, Nováková M, Siegelová J, et al. Low-frequency electrical stimulation increases muscle strength and improves blood supply in patients with chronic heart failure. Circ J Off J Jpn Circ Soc. 2006;70(1):75-82. doi:10.1253/circj.70.75
15. Karavidas A, Driva M, Parissis JT, et al. Functional electrical stimulation of peripheral muscles improves endothelial function and clinical and emotional status in heart failure patients with preserved left ventricular ejection fraction. Am Heart J. 2013;166(4):760-767. doi:10.1016/j.ahj.2013.06.021
16. Nuhr MJ, Pette D, Berger R, et al. Beneficial effects of chronic low-frequency stimulation of thigh muscles in patients with advanced chronic heart failure. Eur Heart J. 2004;25(2):136-143. doi:10.1016/j.ehj.2003.09.027
17. Quittan M, Wiesinger GF, Sturm B, et al. Improvement of thigh muscles by neuromuscular electrical stimulation in patients with refractory heart failure: a single-blind, randomized, controlled trial. Am J Phys Med Rehabil. 2001;80(3):206-214; quiz 215-216, 224. doi:10.1097/00002060-200103000-00011
18. Harris S, LeMaitre JP, Mackenzie G, Fox KAA, Denvir MA. A randomised study of home-based electrical stimulation of the legs and conventional bicycle exercise training for patients with chronic heart failure. Eur Heart J. 2003;24(9):871-878. doi:10.1016/s0195-668x(02)00822-9
19. Parissis J, Karavidas A, Farmakis D, et al. Efficacy and safety of functional electrical stimulation of lower limb muscles in elderly patients with chronic heart failure: A pilot study. Eur J Prev Cardiol. 2015;22(7):831-836. doi:10.1177/2047487314540546
20. Sbruzzi G, Ribeiro RA, Schaan BD, et al. Functional electrical stimulation in the treatment of patients with chronic heart failure: a meta-analysis of randomized controlled trials. Eur J Cardiovasc Prev Rehabil Off J Eur Soc Cardiol Work Groups Epidemiol Prev Card Rehabil Exerc Physiol. 2010;17(3):254-260. doi:10.1097/HJR.0b013e328339b5a2
21. Jones S, Man WDC, Gao W, Higginson IJ, Wilcock A, Maddocks M. Neuromuscular electrical stimulation for muscle weakness in adults with advanced disease. Cochrane Database Syst Rev. 2016;10(10):CD009419. doi:10.1002/14651858.CD009419.pub3
22. Poltavskaya M, Sviridenko V, Kozlovskaya I, et al. Comparison of the Efficacy of Neuromuscular Electrostimulation and Interval Exercise Training in Early Rehabilitation of Patients Hospitalized with Decompensation of Chronic Heart Failure. Hum Physiol. 2018;44:663-672. doi:10.1134/S0362119718060087
23. Kondo T, Yamada S, Tanimura D, et al. Neuromuscular electrical stimulation is feasible in patients with acute heart failure. ESC Heart Fail. 2019;6(5):975-982. doi:10.1002/ehf2.12504
24. Ennis S, McGregor G, Hamborg T, et al. Randomised feasibility trial into the effects of low-frequency electrical muscle stimulation in advanced heart failure patients. BMJ Open. 2017;7(8):e016148. doi:10.1136/bmjopen-2017-016148
25. de Araújo CJS, Gonçalves FS, Bittencourt HS, et al. Effects of neuromuscular electrostimulation in patients with heart failure admitted to ward. J Cardiothorac Surg. 2012;7(1):124. doi:10.1186/1749-8090-7-124
26. Soska V, Dobsak P, Pohanka M, et al. Exercise training combined with electromyostimulation in the rehabilitation of patients with chronic heart failure: A randomized trial. Biomed Pap Med Fac Univ Palacky Olomouc Czechoslov. 2014;158(1):98-106. doi:10.5507/bp.2012.096
27. Iliou MC, Vergès-Patois B, Pavy B, et al. Effects of combined exercise training and electromyostimulation treatments in chronic heart failure: A prospective multicentre study. Eur J Prev Cardiol. 2017;24(12):1274-1282. doi:10.1177/2047487317712601
28. Wang HY, Chen YH, Kuan YC, Huang SW, Lin LF, Chen HC. The effectiveness of functional electrical stimulation of the legs in patients with heart failure: A systematic review and meta-analysis of randomized controlled trials. Clin Rehabil. 2022;36(3):303-316. doi:10.1177/02692155211056999
29. Ploesteanu RL, Nechita AC, Turcu D, Manolescu BN, Stamate SC, Berteanu M. Effects of neuromuscular electrical stimulation in patients with heart failure - review. J Med Life. 2018;11(2):107-118.
30. Kadoglou NP, Mandila C, Karavidas A, et al. Effect of functional electrical stimulation on cardiovascular outcomes in patients with chronic heart failure. Eur J Prev Cardiol. 2017;24(8):833-839. doi:10.1177/2047487316687428
31. Palau P, Domínguez E, López L, et al. Inspiratory Muscle Training and Functional Electrical Stimulation for Treatment of Heart Failure With Preserved Ejection Fraction: The TRAINING-HF Trial. Rev Espanola Cardiol Engl Ed. 2019;72(4):288-297. doi:10.1016/j.rec.2018.01.010
32. Kimura T, Kameda N, Moritani T. Impact of phase difference between cardiac systole and skeletal muscle contraction on hemodynamic response during electrically-induced muscle contractions. J Electromyogr Kinesiol Off J Int Soc Electrophysiol Kinesiol. 2010;20(4):572-579. doi:10.1016/j.jelekin.2010.03.004
33. Kondo T, Yamada S, Asai C, Okumura T, Tanimura D, Murohara T. Skeletal Muscle Pump Function Is Associated With Exercise Capacity in Patients With Heart Failure. Circ J Off J Jpn Circ Soc. 2018;82(4):1033-1040. doi:10.1253/circj.CJ-17-0927
34. Nägele H, Azizi M. Inappropriate ICD discharge induced by electrical interference from a physio-therapeutic muscle stimulation device. Herzschrittmachertherapie Elektrophysiologie. 2006;17(3):137-139. doi:10.1007/s00399-006-0527-8
35. Shenoy A, Sharma A, Achamyeleh F. Inappropriate ICD Discharge Related to Electrical Muscle Stimulation in Chiropractic Therapy: A Case Report. Cardiol Ther. 2017;6(1):139-143. doi:10.1007/s40119-017-0086-6
36. Kamiya K, Satoh A, Niwano S, et al. Safety of neuromuscular electrical stimulation in patients implanted with cardioverter defibrillators. J Electrocardiol. 2016;49(1):99-101. doi:10.1016/j.jelectrocard.2015.11.006
37. Badger J, Taylor P, Swain I. The safety of electrical stimulation in patients with pacemakers and implantable cardioverter defibrillators: A systematic review. J Rehabil Assist Technol Eng. 2017;4:2055668317745498. doi:10.1177/2055668317745498
38. Cenik F, Schoberwalter D, Keilani M, et al. Neuromuscular electrical stimulation of the thighs in cardiac patients with implantable cardioverter defibrillators. Wien Klin Wochenschr. 2016;128(21-22):802-808. doi:10.1007/s00508-016-1045-2
39. Tanaka SC and FP in CR. Current and Future Perspectives in Cardiac Rehabilitation. J Pers Med. 2022;12(9). doi:10.3390/jpm12091510
40. Sasaki K ichiro, Matsuse H, Akimoto R, et al. Cardiac cycle-synchronized electrical muscle stimulator for lower limb training with the potential to reduce the heart’s pumping workload. PLOS ONE. 2017;12(11):e0187395. doi:10.1371/journal.pone.0187395
2. Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2022;145(18):e895-e1032. doi:10.1161/CIR.0000000000001063
3. Arenja N, Mueller C, Tomilovskaya E, Koryak Y, Poltavskaya M, Saner H. Real-world experience of feasibility and efficacy of electrical muscle stimulation in elderly patients with acute heart failure: A randomized controlled study. Int J Cardiol. 2021;344:113-119. doi:10.1016/j.ijcard.2021.09.062
4. Dirks ML, Hansen D, Van Assche A, Dendale P, Van Loon LJC. Neuromuscular electrical stimulation prevents muscle wasting in critically ill comatose patients. Clin Sci Lond Engl 1979. 2015;128(6):357-365. doi:10.1042/CS20140447
5. Forestieri P, Bolzan DW, Santos VB, et al. Neuromuscular electrical stimulation improves exercise tolerance in patients with advanced heart failure on continuous intravenous inotropic support use-randomized controlled trial. Clin Rehabil. 2018;32(1):66-74. doi:10.1177/0269215517715762
6. Groehs RV, Antunes-Correa LM, Nobre TS, et al. Muscle electrical stimulation improves neurovascular control and exercise tolerance in hospitalised advanced heart failure patients. Eur J Prev Cardiol. 2016;23(15):1599-1608. doi:10.1177/2047487316654025
7. Smart NA, Dieberg G, Giallauria F. Functional electrical stimulation for chronic heart failure: a meta-analysis. Int J Cardiol. 2013;167(1):80-86. doi:10.1016/j.ijcard.2011.12.019
8. Poltavskaya M, Sviridenko V, Giverts I, et al. In-hospital electrical muscle stimulation for patients early after heart failure decompensation: results from a prospective randomised controlled pilot trial. Open Heart. 2022;9(2):e001965. doi:10.1136/openhrt-2022-001965
9. Tanaka S, Kamiya K, Matsue Y, et al. Efficacy and Safety of Acute Phase Intensive Electrical Muscle Stimulation in Frail Older Patients with Acute Heart Failure: Results from the ACTIVE-EMS Trial. J Cardiovasc Dev Dis. 2022;9(4). doi:10.3390/jcdd9040099
10. Hao Y, Zhang L, Zhang Z, Chen L, He N, Zhu S. Tai Chi exercise and functional electrical stimulation of lower limb muscles for rehabilitation in older adults with chronic systolic heart failure: a non-randomized clinical trial. Braz J Med Biol Res Rev Bras Pesqui Medicas E Biol. 2019;52(12):e8786. doi:10.1590/1414-431X20198786
11. Gomes Neto M, Oliveira FA, Reis HFCD, de Sousa Rodrigues- EJ, Bittencourt HS, Oliveira Carvalho V. Effects of Neuromuscular Electrical Stimulation on Physiologic and Functional Measurements in Patients With Heart Failure: A SYSTEMATIC REVIEW WITH META-ANALYSIS. J Cardiopulm Rehabil Prev. 2016;36(3):157-166. doi:10.1097/HCR.0000000000000151
12. Banerjee P, Clark A, Witte K, Crowe L, Caulfield B. Electrical stimulation of unloaded muscles causes cardiovascular exercise by increasing oxygen demand. Eur J Cardiovasc Prev Rehabil Off J Eur Soc Cardiol Work Groups Epidemiol Prev Card Rehabil Exerc Physiol. 2005;12(5):503-508. doi:10.1097/01.hjr.0000169188.84184.23
13. Banerjee P, Caulfield B, Crowe L, Clark AL. Prolonged electrical muscle stimulation exercise improves strength, peak VO2, and exercise capacity in patients with stable chronic heart failure. J Card Fail. 2009;15(4):319-326. doi:10.1016/j.cardfail.2008.11.005
14. Dobsák P, Nováková M, Siegelová J, et al. Low-frequency electrical stimulation increases muscle strength and improves blood supply in patients with chronic heart failure. Circ J Off J Jpn Circ Soc. 2006;70(1):75-82. doi:10.1253/circj.70.75
15. Karavidas A, Driva M, Parissis JT, et al. Functional electrical stimulation of peripheral muscles improves endothelial function and clinical and emotional status in heart failure patients with preserved left ventricular ejection fraction. Am Heart J. 2013;166(4):760-767. doi:10.1016/j.ahj.2013.06.021
16. Nuhr MJ, Pette D, Berger R, et al. Beneficial effects of chronic low-frequency stimulation of thigh muscles in patients with advanced chronic heart failure. Eur Heart J. 2004;25(2):136-143. doi:10.1016/j.ehj.2003.09.027
17. Quittan M, Wiesinger GF, Sturm B, et al. Improvement of thigh muscles by neuromuscular electrical stimulation in patients with refractory heart failure: a single-blind, randomized, controlled trial. Am J Phys Med Rehabil. 2001;80(3):206-214; quiz 215-216, 224. doi:10.1097/00002060-200103000-00011
18. Harris S, LeMaitre JP, Mackenzie G, Fox KAA, Denvir MA. A randomised study of home-based electrical stimulation of the legs and conventional bicycle exercise training for patients with chronic heart failure. Eur Heart J. 2003;24(9):871-878. doi:10.1016/s0195-668x(02)00822-9
19. Parissis J, Karavidas A, Farmakis D, et al. Efficacy and safety of functional electrical stimulation of lower limb muscles in elderly patients with chronic heart failure: A pilot study. Eur J Prev Cardiol. 2015;22(7):831-836. doi:10.1177/2047487314540546
20. Sbruzzi G, Ribeiro RA, Schaan BD, et al. Functional electrical stimulation in the treatment of patients with chronic heart failure: a meta-analysis of randomized controlled trials. Eur J Cardiovasc Prev Rehabil Off J Eur Soc Cardiol Work Groups Epidemiol Prev Card Rehabil Exerc Physiol. 2010;17(3):254-260. doi:10.1097/HJR.0b013e328339b5a2
21. Jones S, Man WDC, Gao W, Higginson IJ, Wilcock A, Maddocks M. Neuromuscular electrical stimulation for muscle weakness in adults with advanced disease. Cochrane Database Syst Rev. 2016;10(10):CD009419. doi:10.1002/14651858.CD009419.pub3
22. Poltavskaya M, Sviridenko V, Kozlovskaya I, et al. Comparison of the Efficacy of Neuromuscular Electrostimulation and Interval Exercise Training in Early Rehabilitation of Patients Hospitalized with Decompensation of Chronic Heart Failure. Hum Physiol. 2018;44:663-672. doi:10.1134/S0362119718060087
23. Kondo T, Yamada S, Tanimura D, et al. Neuromuscular electrical stimulation is feasible in patients with acute heart failure. ESC Heart Fail. 2019;6(5):975-982. doi:10.1002/ehf2.12504
24. Ennis S, McGregor G, Hamborg T, et al. Randomised feasibility trial into the effects of low-frequency electrical muscle stimulation in advanced heart failure patients. BMJ Open. 2017;7(8):e016148. doi:10.1136/bmjopen-2017-016148
25. de Araújo CJS, Gonçalves FS, Bittencourt HS, et al. Effects of neuromuscular electrostimulation in patients with heart failure admitted to ward. J Cardiothorac Surg. 2012;7(1):124. doi:10.1186/1749-8090-7-124
26. Soska V, Dobsak P, Pohanka M, et al. Exercise training combined with electromyostimulation in the rehabilitation of patients with chronic heart failure: A randomized trial. Biomed Pap Med Fac Univ Palacky Olomouc Czechoslov. 2014;158(1):98-106. doi:10.5507/bp.2012.096
27. Iliou MC, Vergès-Patois B, Pavy B, et al. Effects of combined exercise training and electromyostimulation treatments in chronic heart failure: A prospective multicentre study. Eur J Prev Cardiol. 2017;24(12):1274-1282. doi:10.1177/2047487317712601
28. Wang HY, Chen YH, Kuan YC, Huang SW, Lin LF, Chen HC. The effectiveness of functional electrical stimulation of the legs in patients with heart failure: A systematic review and meta-analysis of randomized controlled trials. Clin Rehabil. 2022;36(3):303-316. doi:10.1177/02692155211056999
29. Ploesteanu RL, Nechita AC, Turcu D, Manolescu BN, Stamate SC, Berteanu M. Effects of neuromuscular electrical stimulation in patients with heart failure - review. J Med Life. 2018;11(2):107-118.
30. Kadoglou NP, Mandila C, Karavidas A, et al. Effect of functional electrical stimulation on cardiovascular outcomes in patients with chronic heart failure. Eur J Prev Cardiol. 2017;24(8):833-839. doi:10.1177/2047487316687428
31. Palau P, Domínguez E, López L, et al. Inspiratory Muscle Training and Functional Electrical Stimulation for Treatment of Heart Failure With Preserved Ejection Fraction: The TRAINING-HF Trial. Rev Espanola Cardiol Engl Ed. 2019;72(4):288-297. doi:10.1016/j.rec.2018.01.010
32. Kimura T, Kameda N, Moritani T. Impact of phase difference between cardiac systole and skeletal muscle contraction on hemodynamic response during electrically-induced muscle contractions. J Electromyogr Kinesiol Off J Int Soc Electrophysiol Kinesiol. 2010;20(4):572-579. doi:10.1016/j.jelekin.2010.03.004
33. Kondo T, Yamada S, Asai C, Okumura T, Tanimura D, Murohara T. Skeletal Muscle Pump Function Is Associated With Exercise Capacity in Patients With Heart Failure. Circ J Off J Jpn Circ Soc. 2018;82(4):1033-1040. doi:10.1253/circj.CJ-17-0927
34. Nägele H, Azizi M. Inappropriate ICD discharge induced by electrical interference from a physio-therapeutic muscle stimulation device. Herzschrittmachertherapie Elektrophysiologie. 2006;17(3):137-139. doi:10.1007/s00399-006-0527-8
35. Shenoy A, Sharma A, Achamyeleh F. Inappropriate ICD Discharge Related to Electrical Muscle Stimulation in Chiropractic Therapy: A Case Report. Cardiol Ther. 2017;6(1):139-143. doi:10.1007/s40119-017-0086-6
36. Kamiya K, Satoh A, Niwano S, et al. Safety of neuromuscular electrical stimulation in patients implanted with cardioverter defibrillators. J Electrocardiol. 2016;49(1):99-101. doi:10.1016/j.jelectrocard.2015.11.006
37. Badger J, Taylor P, Swain I. The safety of electrical stimulation in patients with pacemakers and implantable cardioverter defibrillators: A systematic review. J Rehabil Assist Technol Eng. 2017;4:2055668317745498. doi:10.1177/2055668317745498
38. Cenik F, Schoberwalter D, Keilani M, et al. Neuromuscular electrical stimulation of the thighs in cardiac patients with implantable cardioverter defibrillators. Wien Klin Wochenschr. 2016;128(21-22):802-808. doi:10.1007/s00508-016-1045-2
39. Tanaka SC and FP in CR. Current and Future Perspectives in Cardiac Rehabilitation. J Pers Med. 2022;12(9). doi:10.3390/jpm12091510
40. Sasaki K ichiro, Matsuse H, Akimoto R, et al. Cardiac cycle-synchronized electrical muscle stimulator for lower limb training with the potential to reduce the heart’s pumping workload. PLOS ONE. 2017;12(11):e0187395. doi:10.1371/journal.pone.0187395