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Right ventricular dysfunction in cirrhosis: A speckle-tracking echocardiography study

Year 2020, , 1036 - 1040, 01.11.2020
https://doi.org/10.28982/josam.818638

Abstract

Aim: The majority of studies on cardiac dysfunction in patients with cirrhosis are associated with left ventricular (LV) myocardial dysfunction, with fewer studies on right ventricular (RV) function. The aims of this study were to evaluate biventricular function, particularly RV function, in patients with cirrhosis and investigate its relationship with disease severity.
Methods: We included 50 hospitalized and ambulatory patients with cirrhosis and 33 healthy controls. Echocardiographic evaluation was performed with speckle-tracking analysis. Liver disease was graded according to Child-Pugh and Model for End-Stage Liver Disease (MELD) scores.
Results: In our study, the most prevalent etiology of cirrhosis was viral hepatitis (60%), followed by non-alcoholic fatty liver disease (24%). RV-global longitudinal strain (GLS) and LV ejection fraction (EF) values were lower in patients with cirrhosis compared to the control group (both, P=0.001). LVEF was <55% in 19 (38%) patients. Decreases in RV-GLS and LVEF values were more common in patients with ascites (both, P=0.001). However, measurements of RV-GLS and LVEF did not distinguish the degree of severity of liver disease on the basis of Child-Pugh and MELD scores. LV-GLS values between patients with cirrhosis and the control group were similar (P=0.896).
Conclusions: This study showed that RV function was impaired in patients with cirrhosis and more commonly, in patients with ascites. However, values of RV-GLS did not distinguish the degree of severity of liver disease. In addition, the LVEF was low and LV-GLS was normal in patients with cirrhosis.

References

  • 1. Møller S, Henriksen JH. Cirrhotic cardiomyopathy. J Hepatol. 2010;53(1):179-90. doi: 10.1016/j.jhep.2010.02.023
  • 2. Wong F. Cirrhotic cardiomyopathy. Hepatol Int. 2009;3(1):294-304. doi: 10.1007/s12072-008-9109-7
  • 3. Lee RF, Glenn TK, Lee SS. Cardiac dysfunction in cirrhosis. Best Pract Res Clin Gastroenterol. 2007;21(1):125-40. doi: 10.1016/j.bpg.2006.06.003
  • 4. Izzy M, VanWagner LB, Lin G, Altieri M, Findlay JY, Oh JK, et al. Redefining Cirrhotic Cardiomyopathy for the Modern Era. Hepatology. 2020 Jan;71(1):334-45. doi: 10.1002/hep.30875
  • 5. Wong F, Girgrah N, Graba J, Allidina Y, Liu P, Blendis L. The cardiac response to exercise in cirrhosis.Gut. 2001 Aug;49(2):268-75. doi: 10.1136/gut.49.2.268
  • 6. Sampaio F, Pimenta J, Bettencourt N, Fontes-Carvalho R, Silva AP, Valente J, et al. Systolic and diastolic dysfunction in cirrhosis: a tissue-Doppler and speckle tracking echocardiography study. Liver Int. 2013 Sep;33(8):1158-65. doi: 10.1111/liv.12187
  • 7. Rigolin VH, Robiolio PA, Wilson JS, Harrison JK, Bashore TM. The forgotten chamber: The importance of the right ventricle. Cathet Cardiovasc Diagn. 1995;35(1):18-28. doi: 10.1002/ccd.1810350105
  • 8. Chen Y, Chan AC, Chan SC, Chok SH, Sharr W, Fung J, et al. A detailed evaluation of cardiac function in cirrhotic patients and its alteration with or without liver transplantation.J Cardiol. 2016 Feb;67(2):140-6. doi: 10.1016/j.jjcc.2015.08.001
  • 9. Marmor A, Geltman EM, Biello DR, Sobel BE, Siegel BA, Roberts R. Functional response of the right ventricle to myocardial infarction: dependence of the site of left ventricular infarction. Circulation. 1981;64(5):1005-11. doi: 10.1161/01.cir.64.5.1005
  • 10. Yiu KH, Schouffoer AA, Marsan NA, Ninaber MK, Stolk J, Vlieland TV, et al. Left ventricular dysfunction assessed by speckle-tracking strain analysis in patients with systemic sclerosis: relationship to functional capacity and ventricular arrhythmias. Arthritis Rheum 2011;63:3969–78. doi: 10.1111/ajt.12385
  • 11. Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg 1973;60:646-9.
  • 12. Kamath PS, Wiesner RH, Malinchoc M, Kremers W, Therneau TM, Kosberg CL, et al. A model to predict survival in patients with end-stage liver disease. Hepatology. 2001;33:464-70. doi: 10.1053/jhep.2001.22172
  • 13. Merli M, Calicchia A, Ruffa A, Pellicori P, Riggio O, Giusto M, et al. Cardiac dysfunction in cirrhosis is not associated with the severity of liver disease. European Journal of Internal Medicine. 2013;24:172–6. doi: 10.1016/j.ejim.2012.08.007
  • 14. Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L, et al. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr. 2015;28:233-70.
  • 15. Foley TA, Mankad SV, Anavekar NS, Bonnichsen CR, Morris MF, Miller TD, et al. Measuring Left Ventricular Ejection Fraction - Techniques and Potential Pitfalls. European Cardiology. 2012;8(2):108-14. doi:10.15420/ecr.2012.8.2.108
  • 16. Voigt JU, Pedrizzetti G, Lysyansky P, Marwick TH, Houle H, Baumann R, et al. Definitions for a common standard for 2D speckle tracking echocardiography: consensus document of the EACVI/ASE/Industry Task Force to standardize deformation imaging. J Am Soc Echocardiogr. 2015 Feb;28(2):183-93. doi: 10.1016/j.echo.2014.11.003
  • 17. Kia L, Shah SJ, Wang E, Sharma D, Selvaraj S, Medina C, et al. Role of pretransplant echocardiographic evaluation in predicting outcomes following liver transplantation. Am J Transplant. 2013 Sep;13(9):2395-401. doi: 10.1111/ajt.12385
  • 18. Møller S, Henriksen JH. Cirrhotic cardiomyopathy: a pathophysiological review of circulatory dysfunction in liver disease. Heart. 2002 Jan;87(1):9-15. doi: 10.1136/heart.87.1.9
  • 19. Zhang Kun, Braun A, von Koeckritz F, Schmuck RB, Teegen EM, Cuspidi C, et al. Right Heart Remodeling in Patients with End-Stage Alcoholic Liver Cirrhosis: Speckle Tracking Point of View. J Clin Med. 2019 Sep;8(9):1285. doi: 10.3390/jcm8091285
  • 20. Bansal M, Sengupta PP. Longitudinal and Circumferential Strain in Patients with Regional LV Dysfunction. Curr Cardiol Rep. 2013 Mar;15(3):339. doi: 10.1007/s11886-012-0339-x
  • 21. Zakia ER, Baha El Deenb NM. Relation of right ventricular dysfunction to the severity of hepatic cirrhosis by different echo modalities using speckle-tracking echocardiography. Al-Azhar Assiut Med J. 2017;15:7–14. doi: 10.4103/1687-1693.213588
  • 22. Nazar A, Guevara M, Sitges M, et al. LEFT ventricular function assessed by echocardiography in cirrhosis: relationship to systemic hemodynamics and renal dysfunction. J Hepatol. 2013;58:51–7.
  • 23. Grose RD, Nolan J, Dillon JF, Errington M, Hannan WJ, Bouchier IA, Hayes PC. Exercise-induced left ventricular dysfunction in alcoholic and non-alcoholic cirrhosis. J Hepatol. 1995 Mar;22(3):326-32. doi: 10.1016/0168-8278(95)80286-x
  • 24. Kelbaek H, Rabøl A, Brynjolf I, Eriksen J, Bonnevie O, Godtfredsen J, et al. Haemodynamic response to exercise in patients with alcoholic liver cirrhosis. Clin Physiol. 1987 Feb;7(1):35-41. doi: 10.1111/j.1475-097x.1987.tb00631.x
  • 25. Laffi G, Barletta G, La Villa G, Del Bene R, Riccardi D, Ticalin P, et al. Altered cardiovascular responsiveness to active tilting in nonalcoholic cirrhosis. Gastroenterology. 1997 Sep;113(3):891-8. doi: 10.1016/s0016-5085(97)70184-7
  • 26. Wong F, Liu P, Lilly L, Bomzon A, Blendis L. Role of cardiac structural and functional abnormalities in the pathogenesis of hyperdynamic circulation and renal sodium retention in cirrhosis. Clinical Science. 1999;97(3):259–67.
  • 27. Pozzi M, Carugo S, Boari G, Pecci V, de Ceglia S, Maggiolini S, et al. Evidence of functional and structural cardiac abnormalities in cirrhotic patients with and without ascites. Hepatology. 1997 Nov;26(5):1131-7. doi: 10.1002/hep.510260507
  • 28. Papastergiou V, Skorda L, Lisgos P, Papakonstantinou N, Giakoumakis T, Ntousikos K, et al. Ultrasonographic Prevalence and Factors Predicting Left Ventricular Diastolic Dysfunction in Patients with Liver Cirrhosis: Is There a Correlation between the Grade of Diastolic Dysfunction and the Grade of Liver Disease? The Scientific World Journal. 2012;615057. doi:10.1100/2012/615057
  • 29. Sampaio F, Pimenta J. Left ventricular function assessment in cirrhosis: Current methods and future directions. World J Gastroenterol. Jan 7, 2016;22(1):112-125. doi: 10.3748/wjg.v22.i1.112
  • 30. McMurray JJ, Adamopoulos S, Anker SD, Auricchio A, Böhm M, Dickstein K, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2012;33:1787-847. doi: 10.1093/eurheartj/ehs104

Sirozda sağ ventrikül disfonksiyonu: Speckle-tracking ekokardiyografi çalışması

Year 2020, , 1036 - 1040, 01.11.2020
https://doi.org/10.28982/josam.818638

Abstract

Amaç: Sirozlu hastalarda kardiyak disfonksiyon üzerine yapılan çalışmaların çoğu, sol ventriküler (LV) miyokardiyal disfonksiyon ile ilişkilidir ve sağ ventrikül (RV) fonksiyonu üzerine daha az çalışma vardır. Bu çalışmanın amacı sirozlu hastalarda özellikle RV fonksiyonu olmak üzere, biventriküler fonksiyonu değerlendirmek ve hastalık şiddeti ile ilişkisini araştırmaktır.
Yöntemler: Hastanede yatan ve ayakta tedavi gören 50 siroz hastası ve 33 sağlıklı kontrol çalışmamıza dahil edildi. Ekokardiyografik değerlendirme speckle-tracking analizi ile yapıldı. Karaciğer hastalığı Child-Pugh ve Son Evre Karaciğer Hastalığı Modeli (MELD) puanlarına göre derecelendirildi.
Bulgular: Çalışmamızda sirozun en yaygın etiyolojisi viral hepatit (%60), ardından non-alkolik yağlı karaciğer hastalığı (%24) idi. Sirozlu hastalarda RV-global longitudinal strain (GLS) ve LV ejeksiyon fraksiyonu (EF) değerleri kontrol grubuna göre daha düşüktü (her ikisi de P=0.001). LVEF, 19 (% 38) hastada < %55 idi. Asitli hastalarda RV-GLS ve LVEF değerlerindeki düşüşler daha sıktı (her ikisi de, P=0,001). Bununla birlikte, RV-GLS ve LVEF ölçümleri, Child-Pugh ve MELD skorlarına göre karaciğer hastalığının şiddet derecesini ayırt etmedi. Sirozlu hastalar ile kontrol grubu arasındaki LV-GLS değerleri benzerdi (P=0.896).
Sonuç: Bu çalışma, RV fonksiyonunun sirozlu hastalarda ve daha sık olarak asitli hastalarda bozulduğunu göstermiştir. Bununla birlikte, RV-GLS değerleri, karaciğer hastalığının şiddet derecesini ayırt etmedi. Ayrıca sirozlu hastalarda LVEF düşüktü ve LV-GLS normaldi.

References

  • 1. Møller S, Henriksen JH. Cirrhotic cardiomyopathy. J Hepatol. 2010;53(1):179-90. doi: 10.1016/j.jhep.2010.02.023
  • 2. Wong F. Cirrhotic cardiomyopathy. Hepatol Int. 2009;3(1):294-304. doi: 10.1007/s12072-008-9109-7
  • 3. Lee RF, Glenn TK, Lee SS. Cardiac dysfunction in cirrhosis. Best Pract Res Clin Gastroenterol. 2007;21(1):125-40. doi: 10.1016/j.bpg.2006.06.003
  • 4. Izzy M, VanWagner LB, Lin G, Altieri M, Findlay JY, Oh JK, et al. Redefining Cirrhotic Cardiomyopathy for the Modern Era. Hepatology. 2020 Jan;71(1):334-45. doi: 10.1002/hep.30875
  • 5. Wong F, Girgrah N, Graba J, Allidina Y, Liu P, Blendis L. The cardiac response to exercise in cirrhosis.Gut. 2001 Aug;49(2):268-75. doi: 10.1136/gut.49.2.268
  • 6. Sampaio F, Pimenta J, Bettencourt N, Fontes-Carvalho R, Silva AP, Valente J, et al. Systolic and diastolic dysfunction in cirrhosis: a tissue-Doppler and speckle tracking echocardiography study. Liver Int. 2013 Sep;33(8):1158-65. doi: 10.1111/liv.12187
  • 7. Rigolin VH, Robiolio PA, Wilson JS, Harrison JK, Bashore TM. The forgotten chamber: The importance of the right ventricle. Cathet Cardiovasc Diagn. 1995;35(1):18-28. doi: 10.1002/ccd.1810350105
  • 8. Chen Y, Chan AC, Chan SC, Chok SH, Sharr W, Fung J, et al. A detailed evaluation of cardiac function in cirrhotic patients and its alteration with or without liver transplantation.J Cardiol. 2016 Feb;67(2):140-6. doi: 10.1016/j.jjcc.2015.08.001
  • 9. Marmor A, Geltman EM, Biello DR, Sobel BE, Siegel BA, Roberts R. Functional response of the right ventricle to myocardial infarction: dependence of the site of left ventricular infarction. Circulation. 1981;64(5):1005-11. doi: 10.1161/01.cir.64.5.1005
  • 10. Yiu KH, Schouffoer AA, Marsan NA, Ninaber MK, Stolk J, Vlieland TV, et al. Left ventricular dysfunction assessed by speckle-tracking strain analysis in patients with systemic sclerosis: relationship to functional capacity and ventricular arrhythmias. Arthritis Rheum 2011;63:3969–78. doi: 10.1111/ajt.12385
  • 11. Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg 1973;60:646-9.
  • 12. Kamath PS, Wiesner RH, Malinchoc M, Kremers W, Therneau TM, Kosberg CL, et al. A model to predict survival in patients with end-stage liver disease. Hepatology. 2001;33:464-70. doi: 10.1053/jhep.2001.22172
  • 13. Merli M, Calicchia A, Ruffa A, Pellicori P, Riggio O, Giusto M, et al. Cardiac dysfunction in cirrhosis is not associated with the severity of liver disease. European Journal of Internal Medicine. 2013;24:172–6. doi: 10.1016/j.ejim.2012.08.007
  • 14. Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L, et al. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr. 2015;28:233-70.
  • 15. Foley TA, Mankad SV, Anavekar NS, Bonnichsen CR, Morris MF, Miller TD, et al. Measuring Left Ventricular Ejection Fraction - Techniques and Potential Pitfalls. European Cardiology. 2012;8(2):108-14. doi:10.15420/ecr.2012.8.2.108
  • 16. Voigt JU, Pedrizzetti G, Lysyansky P, Marwick TH, Houle H, Baumann R, et al. Definitions for a common standard for 2D speckle tracking echocardiography: consensus document of the EACVI/ASE/Industry Task Force to standardize deformation imaging. J Am Soc Echocardiogr. 2015 Feb;28(2):183-93. doi: 10.1016/j.echo.2014.11.003
  • 17. Kia L, Shah SJ, Wang E, Sharma D, Selvaraj S, Medina C, et al. Role of pretransplant echocardiographic evaluation in predicting outcomes following liver transplantation. Am J Transplant. 2013 Sep;13(9):2395-401. doi: 10.1111/ajt.12385
  • 18. Møller S, Henriksen JH. Cirrhotic cardiomyopathy: a pathophysiological review of circulatory dysfunction in liver disease. Heart. 2002 Jan;87(1):9-15. doi: 10.1136/heart.87.1.9
  • 19. Zhang Kun, Braun A, von Koeckritz F, Schmuck RB, Teegen EM, Cuspidi C, et al. Right Heart Remodeling in Patients with End-Stage Alcoholic Liver Cirrhosis: Speckle Tracking Point of View. J Clin Med. 2019 Sep;8(9):1285. doi: 10.3390/jcm8091285
  • 20. Bansal M, Sengupta PP. Longitudinal and Circumferential Strain in Patients with Regional LV Dysfunction. Curr Cardiol Rep. 2013 Mar;15(3):339. doi: 10.1007/s11886-012-0339-x
  • 21. Zakia ER, Baha El Deenb NM. Relation of right ventricular dysfunction to the severity of hepatic cirrhosis by different echo modalities using speckle-tracking echocardiography. Al-Azhar Assiut Med J. 2017;15:7–14. doi: 10.4103/1687-1693.213588
  • 22. Nazar A, Guevara M, Sitges M, et al. LEFT ventricular function assessed by echocardiography in cirrhosis: relationship to systemic hemodynamics and renal dysfunction. J Hepatol. 2013;58:51–7.
  • 23. Grose RD, Nolan J, Dillon JF, Errington M, Hannan WJ, Bouchier IA, Hayes PC. Exercise-induced left ventricular dysfunction in alcoholic and non-alcoholic cirrhosis. J Hepatol. 1995 Mar;22(3):326-32. doi: 10.1016/0168-8278(95)80286-x
  • 24. Kelbaek H, Rabøl A, Brynjolf I, Eriksen J, Bonnevie O, Godtfredsen J, et al. Haemodynamic response to exercise in patients with alcoholic liver cirrhosis. Clin Physiol. 1987 Feb;7(1):35-41. doi: 10.1111/j.1475-097x.1987.tb00631.x
  • 25. Laffi G, Barletta G, La Villa G, Del Bene R, Riccardi D, Ticalin P, et al. Altered cardiovascular responsiveness to active tilting in nonalcoholic cirrhosis. Gastroenterology. 1997 Sep;113(3):891-8. doi: 10.1016/s0016-5085(97)70184-7
  • 26. Wong F, Liu P, Lilly L, Bomzon A, Blendis L. Role of cardiac structural and functional abnormalities in the pathogenesis of hyperdynamic circulation and renal sodium retention in cirrhosis. Clinical Science. 1999;97(3):259–67.
  • 27. Pozzi M, Carugo S, Boari G, Pecci V, de Ceglia S, Maggiolini S, et al. Evidence of functional and structural cardiac abnormalities in cirrhotic patients with and without ascites. Hepatology. 1997 Nov;26(5):1131-7. doi: 10.1002/hep.510260507
  • 28. Papastergiou V, Skorda L, Lisgos P, Papakonstantinou N, Giakoumakis T, Ntousikos K, et al. Ultrasonographic Prevalence and Factors Predicting Left Ventricular Diastolic Dysfunction in Patients with Liver Cirrhosis: Is There a Correlation between the Grade of Diastolic Dysfunction and the Grade of Liver Disease? The Scientific World Journal. 2012;615057. doi:10.1100/2012/615057
  • 29. Sampaio F, Pimenta J. Left ventricular function assessment in cirrhosis: Current methods and future directions. World J Gastroenterol. Jan 7, 2016;22(1):112-125. doi: 10.3748/wjg.v22.i1.112
  • 30. McMurray JJ, Adamopoulos S, Anker SD, Auricchio A, Böhm M, Dickstein K, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2012;33:1787-847. doi: 10.1093/eurheartj/ehs104
There are 30 citations in total.

Details

Primary Language English
Subjects Cardiovascular Surgery, Gastroenterology and Hepatology
Journal Section Research article
Authors

Deniz Ogutmen Koc 0000-0003-2738-625X

Tayfun Şahin 0000-0002-0851-2946

Sila Oksuz This is me 0000-0003-4721-0585

Hulya Cebe This is me 0000-0003-1954-406X

Ali Erkan Duman 0000-0002-7093-2503

Yasemin Gökden 0000-0001-6767-3072

Ugur Korkmaz 0000-0002-1103-5343

Tanyeli Güneyligil 0000-0002-4191-1244

Publication Date November 1, 2020
Published in Issue Year 2020

Cite

APA Ogutmen Koc, D., Şahin, T., Oksuz, S., Cebe, H., et al. (2020). Right ventricular dysfunction in cirrhosis: A speckle-tracking echocardiography study. Journal of Surgery and Medicine, 4(11), 1036-1040. https://doi.org/10.28982/josam.818638
AMA Ogutmen Koc D, Şahin T, Oksuz S, Cebe H, Duman AE, Gökden Y, Korkmaz U, Güneyligil T. Right ventricular dysfunction in cirrhosis: A speckle-tracking echocardiography study. J Surg Med. November 2020;4(11):1036-1040. doi:10.28982/josam.818638
Chicago Ogutmen Koc, Deniz, Tayfun Şahin, Sila Oksuz, Hulya Cebe, Ali Erkan Duman, Yasemin Gökden, Ugur Korkmaz, and Tanyeli Güneyligil. “Right Ventricular Dysfunction in Cirrhosis: A Speckle-Tracking Echocardiography Study”. Journal of Surgery and Medicine 4, no. 11 (November 2020): 1036-40. https://doi.org/10.28982/josam.818638.
EndNote Ogutmen Koc D, Şahin T, Oksuz S, Cebe H, Duman AE, Gökden Y, Korkmaz U, Güneyligil T (November 1, 2020) Right ventricular dysfunction in cirrhosis: A speckle-tracking echocardiography study. Journal of Surgery and Medicine 4 11 1036–1040.
IEEE D. Ogutmen Koc, T. Şahin, S. Oksuz, H. Cebe, A. E. Duman, Y. Gökden, U. Korkmaz, and T. Güneyligil, “Right ventricular dysfunction in cirrhosis: A speckle-tracking echocardiography study”, J Surg Med, vol. 4, no. 11, pp. 1036–1040, 2020, doi: 10.28982/josam.818638.
ISNAD Ogutmen Koc, Deniz et al. “Right Ventricular Dysfunction in Cirrhosis: A Speckle-Tracking Echocardiography Study”. Journal of Surgery and Medicine 4/11 (November 2020), 1036-1040. https://doi.org/10.28982/josam.818638.
JAMA Ogutmen Koc D, Şahin T, Oksuz S, Cebe H, Duman AE, Gökden Y, Korkmaz U, Güneyligil T. Right ventricular dysfunction in cirrhosis: A speckle-tracking echocardiography study. J Surg Med. 2020;4:1036–1040.
MLA Ogutmen Koc, Deniz et al. “Right Ventricular Dysfunction in Cirrhosis: A Speckle-Tracking Echocardiography Study”. Journal of Surgery and Medicine, vol. 4, no. 11, 2020, pp. 1036-40, doi:10.28982/josam.818638.
Vancouver Ogutmen Koc D, Şahin T, Oksuz S, Cebe H, Duman AE, Gökden Y, Korkmaz U, Güneyligil T. Right ventricular dysfunction in cirrhosis: A speckle-tracking echocardiography study. J Surg Med. 2020;4(11):1036-40.