Emerging Cardiac Resynchronisation Therapy Indications


Cardiac resynchronisation therapy (CRT) is an efficacious and cost-effective therapy in patients with highly symptomatic systolic heart failure and delayed ventricular conduction. Current guidelines recommend CRT as a class I indication for patients with sinus rhythm, New York Heart Association (NYHA) functional class III or ambulatory class IV, a QRS duration ├óÔÇ░─ä120ms, and left ventricular ejection fraction (LVEF) ├óÔÇ░┬ñ35%, despite optimal pharmacological therapy. Recent trials resulted in an extension of current recommendations to patients with mild heart failure, patients with atrial fibrillation, and patients with an indication for permanent right ventricular pacing with the aim of morbidity reduction. The effectiveness of CRT in patients with narrow QRS, patients with end-stage heart failure and cardiogenic shock, and patients with an LVEF >35% still needs to be proved. This article reviews current evidence and clinical applications of CRT in heart failure and provides an outlook on future developments.

Cardiac resynchronisation therapy, heart failure, biventricular pacemaker, cardiomyopathy, indications

Disclosure: Charlotte Eitel has no conflicts of interest to declare. Gerhard Hindricks has received modest lecture honoraria from St Jude Medical, Biotronik, Medtronic, and Biosense and is a member of the St Jude Medical and Biosense advisory boards. Christopher Piorkowski has received modest lecture honoraria from St Jude Medical and Biotronik and is a member of the St Jude Medical advisory board.
Received: 12 November 2010 Accepted: 8 February 2011 Citation: Eurpoean Cardiology, 2011;7(1):29├óÔé¼ÔÇ£33
Correspondence: Charlotte Eitel, University of Leipzig, Heart Center, Department of Electrophysiology, Str─é─¢mpellstrasse 39, 04289 Leipzig, Germany. E: charlotteeitel@gmx.de



Cardiac resynchronisation therapy (CRT) is an established therapy for patients with drug-refractory, highly symptomatic systolic heart failure (HF) and delayed ventricular conduction.1 CRT devices are designed to synchronise the mechanical activity within the left ventricle, between the left and the right ventricle and between the atria and ventricles. Resynchronisation induces reverse remodelling and reduces mitral regurgitation.2,3 This has been shown to improve cardiac function, resulting in an enhanced functional capacity and improved quality of life.4 Finally, large randomised trials have shown significant reductions in all-cause mortality and hospital admissions with CRT versus usual care.5,6 Thus, current guidelines recommend CRT combined with a pacemaker (PM; CRT-P) or implantable cardioverter├óÔé¼ÔÇ£defibrillator (ICD; CRT-D) as a class I indication for patients with sinus rhythm (SR), New York Heart Association (NYHA) functional class III or ambulatory IV, a QRS duration ├óÔÇ░─ä120ms, and left ventricular ejection fraction (LVEF) ├óÔÇ░┬ñ35% despite optimal pharmacological therapy.7├óÔé¼ÔÇ£9

Given the high morbidity and mortality in chronic HF, efforts are being made to explore new indications with the aim of extending the beneficial effects of CRT to selected subgroups of patients who do not fulfill current selection criteria. Nevertheless, the high number of patients not deriving any demonstrable benefit despite fulfilling current guidelines should be kept in mind, requiring careful assessment of evidence.

Data from multicentre clinical trials have recently been published and resulted in an update of the European Society of Cardiology (ESC) guidelines, further extending CRT indications to selected patients. The aim of this article is to give an overview of these recent trials and the respective changes to the guidelines. Furthermore, emerging indications and ongoing trials are reported and discussed.


  1. Strickberger SA, Conti J, Daoud EG, et al., Patient selection for cardiac resynchronization therapy: from the Council on Clinical Cardiology Subcommittee on Electrocardiography and Arrhythmias and the Quality of Care and Outcomes Research Interdisciplinary Working Group, in collaboration with the Heart Rhythm Society, Circulation, 2005;111:2146├óÔé¼ÔÇ£50.
  2. St John Sutton MG, Plappert T, Abraham WT, et al., Effect of cardiac resynchronization therapy on left ventricular size and function in chronic heart failure, Circulation, 2003;107:1985├óÔé¼ÔÇ£90.
  3. Ypenburg C, Lancellotti P, Tops LF, et al., Mechanism of improvement in mitral regurgitation after cardiac resynchronization therapy, Eur Heart J, 2008;29:757├óÔé¼ÔÇ£65.
  4. Nelson GS, Berger RD, Fetics BJ, et al., Left ventricular or biventricular pacing improves cardiac function at diminished energy cost in patients with dilated cardiomyopathy and left bundle-branch block, Circulation, 2000;102:3053├óÔé¼ÔÇ£9.
  5. Bristow MR, Saxon LA, Boehmer J, et al., Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure, N Engl J Med, 2004;350:2140├óÔé¼ÔÇ£50.
  6. Cleland JG, Daubert JC, Erdmann E, et al., The effect of cardiac resynchronization on morbidity and mortality in heart failure, N Engl J Med, 2005;352:1539├óÔé¼ÔÇ£49.
  7. Dickstein K, Cohen-Solal A, Filippatos G, et al., ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2008: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2008 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association of the ESC (HFA) and endorsed by the European Society of Intensive Care Medicine (ESICM), Eur Heart J, 2008;29:2388├óÔé¼ÔÇ£2442.
  8. Epstein AE, DiMarco JP, Ellenbogen KA, et al., ACC/AHA/HRS 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices) developed in collaboration with the American Association for Thoracic Surgery and Society of Thoracic Surgeons, J Am Coll Cardiol, 2008;51:e1├óÔé¼ÔÇ£62.
  9. Vardas PE, Auricchio A, Blanc JJ, et al., Guidelines for cardiac pacing and cardiac resynchronization therapy: The Task Force for Cardiac Pacing and Cardiac Resynchronization Therapy of the European Society of Cardiology. Developed in collaboration with the European Heart Rhythm Association, Eur Heart J, 2007;28:2256├óÔé¼ÔÇ£95.
  10. Dickstein K, Vardas PE, Auricchio A, et al., 2010 Focused Update of ESC guidelines on device therapy in heart failure: An update of the 2008 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure and the 2007 ESC guidelines for cardiac and resynchronization therapy Developed with the special contribution of the Heart Failure Association and the European Heart Rhythm Association, Eur Heart J, 2010;31:2677├óÔé¼ÔÇ£87.
  11. Moss AJ, Hall WJ, Cannom DS, et al., Cardiac-resynchronization therapy for the prevention of heart-failure events, N Engl J Med, 2009;361:1329├óÔé¼ÔÇ£38.
  12. Solomon SD, Foster E, Bourgoun M, et al., Effect of cardiac resynchronization therapy on reverse remodeling and relation to outcome: multicenter automatic defibrillator implantation trial: cardiac resynchronization therapy. Circulation, 2010;122:985├óÔé¼ÔÇ£92.
  13. . Daubert C, Gold MR, Abraham WT, et al., Prevention of disease progression by cardiac resynchronization therapy in patients with asymptomatic or mildly symptomatic left ventricular dysfunction: insights from the European cohort of the REVERSE (Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction) trial, J Am Coll Cardiol, 2009;54:1837├óÔé¼ÔÇ£46.
  14. Linde C, Abraham WT, Gold MR, et al., Randomized trial of cardiac resynchronization in mildly symptomatic heart failure patients and in asymptomatic patients with left ventricular dysfunction and previous heart failure symptoms, J Am Coll Cardiol, 2008;52:1834├óÔé¼ÔÇ£43.
  15. Yu CM, Bleeker GB, Fung JW, et al., Left ventricular reverse remodeling but not clinical improvement predicts long-term survival after cardiac resynchronization therapy, Circulation, 2005;112:1580├óÔé¼ÔÇ£6.
  16. Tang AS, Wells GA, Arnold M, et al., Resynchronization/ defibrillation for ambulatory heart failure trial: rationale and trial design, Curr Opin Cardiol, 2009;24:1├óÔé¼ÔÇ£8.
  17. Maisel WH, Stevenson LW, Atrial fibrillation in heart failure: epidemiology, pathophysiology, and rationale for therapy, Am J Cardiol, 2003;91:2D├óÔé¼ÔÇ£8D.
  18. Koplan BA, Kaplan AJ, Weiner S, et al., Heart failure decompensation and all├óÔé¼ÔÇ£cause mortality in relation to percent biventricular pacing in patients with heart failure: is a goal of 100% biventricular pacing necessary?, J Am Coll Cardiol, 2009;53:355├óÔé¼ÔÇ£60.
  19. Ferreira AM, Adragao P, Cavaco DM, et al., Benefit of cardiac resynchronization therapy in atrial fibrillation patients vs. patients in sinus rhythm: the role of atrioventricular junction ablation, Europace, 2008;10:809├óÔé¼ÔÇ£15.
  20. Gasparini M, Auricchio A, Regoli F, et al., Four-year efficacy of cardiac resynchronization therapy on exercise tolerance and disease progression: the importance of performing atrioventricular junction ablation in patients with atrial fibrillation, J Am Coll Cardiol, 2006;48:734├óÔé¼ÔÇ£43.
  21. Gasparini M, Auricchio A, Metra M, et al., Long-term survival in patients undergoing cardiac resynchronization therapy: the importance of performing atrio-ventricular junction ablation in patients with permanent atrial fibrillation, Eur Heart J, 2008;29:1644├óÔé¼ÔÇ£52.
  22. Delnoy PP, Ottervanger JP, Luttikhuis HO, et al., Comparison of usefulness of cardiac resynchronization therapy in patients with atrial fibrillation and heart failure versus patients with sinus rhythm and heart failure, Am J Cardiol, 2007;99:1252├óÔé¼ÔÇ£7.
  23. Khadjooi K, Foley PW, Chalil S, et al., Long-term effects of cardiac resynchronisation therapy in patients with atrial fibrillation, Heart, 2008;94:879├óÔé¼ÔÇ£83.
  24. Hsu LF, Jais P, Sanders P, et al., Catheter ablation for atrial fibrillation in congestive heart failure, N Engl J Med, 2004;351:2373├óÔé¼ÔÇ£83.
  25. Khan MN, Jais P, Cummings J, et al., Pulmonary-vein isolation for atrial fibrillation in patients with heart failure, N Engl J Med, 2008;359:1778├óÔé¼ÔÇ£85.
  26. Roy D, Talajic M, Nattel S, et al., Rhythm control versus rate control for atrial fibrillation and heart failure, N Engl J Med, 2008;358:2667├óÔé¼ÔÇ£77.
  27. Camm AJ, Kirchhof P, Lip GY, et al., Guidelines for the management of atrial fibrillation: The Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC), Eur Heart J, 2010;31:2369├óÔé¼ÔÇ£429.
  28. Wilkoff BL, Cook JR, Epstein AE, et al., Dual-chamber pacing or ventricular backup pacing in patients with an implantable defibrillator: the Dual Chamber and VVI Implantable Defibrillator (DAVID) Trial, JAMA, 2002;288:3115├óÔé¼ÔÇ£23.
  29. Kindermann M, Hennen B, Jung J, et al., Biventricular versus conventional right ventricular stimulation for patients with standard pacing indication and left ventricular dysfunction: the Homburg Biventricular Pacing Evaluation (HOBIPACE), J Am Coll Cardiol, 2006;47:1927├óÔé¼ÔÇ£37.
  30. . Martinelli FM, de Siqueira SF, Costa R, et al., Conventional versus biventricular pacing in heart failure and bradyarrhythmia: the COMBAT study, J Card Fail, 2010;16:293├óÔé¼ÔÇ£300.
  31. Yu CM, Chan JY, Zhang Q, et al, Biventricular pacing in patients with bradycardia and normal ejection fraction, N Engl J Med, 2009;361:2123├óÔé¼ÔÇ£34.
  32. Frohlich G, Steffel J, Hurlimann D, et al., Upgrading to resynchronization therapy after chronic right ventricular pacing improves left ventricular remodelling, Eur Heart J, 2010;31:1477├óÔé¼ÔÇ£85.
  33. Horwich T, Foster E, De MT, et al., Effects of resynchronization therapy on cardiac function in pacemaker patients ├óÔé¼┼øupgraded├óÔé¼┼Ñ to biventricular devices, J Cardiovasc Electrophysiol, 2004;15:1284├óÔé¼ÔÇ£9.
  34. Funck RC, Blanc JJ, Mueller HH, et al., Biventricular stimulation to prevent cardiac desynchronization: rationale, design, and endpoints of the ├óÔé¼´åİBiventricular Pacing for Atrioventricular Block to Prevent Cardiac Desynchronization (BioPace)™ study, Europace, 2006;8:629├óÔé¼ÔÇ£35.
  35. Bleeker GB, Schalij MJ, Molhoek SG, et al., Frequency of left ventricular dyssynchrony in patients with heart failure and a narrow QRS complex, Am J Cardiol, 2005;95:140├óÔé¼ÔÇ£2.
  36. Ghio S, Constantin C, Klersy C, et al., Interventricular and intraventricular dyssynchrony are common in heart failure patients, regardless of QRS duration, Eur Heart J, 2004;25:571├óÔé¼ÔÇ£8.
  37. Haghjoo M, Bagherzadeh A, Fazelifar AF, et al., Prevalence of mechanical dyssynchrony in heart failure patients with different QRS durations, Pacing Clin Electrophysiol, 2007;30:616├óÔé¼ÔÇ£22.
  38. Achilli A, Sassara M, Ficili S, et al., Long-term effectiveness of cardiac resynchronization therapy in patients with refractory heart failure and ├óÔé¼┼ønarrow├óÔé¼┼Ñ QRS, J Am Coll Cardiol, 2003;42: 2117├óÔé¼ÔÇ£24.
  39. Bleeker GB, Holman ER, Steendijk P, et al., Cardiac resynchronization therapy in patients with a narrow QRS complex, J Am Coll Cardiol, 2006;48:2243├óÔé¼ÔÇ£50.
  40. Yu CM, Chan YS, Zhang Q, et al., Benefits of cardiac resynchronization therapy for heart failure patients with narrow QRS complexes and coexisting systolic asynchrony by echocardiography, J Am Coll Cardiol, 2006;48:2251├óÔé¼ÔÇ£7.
  41. Beshai JF, Grimm RA, Nagueh SF, et al., Cardiac-resynchronization therapy in heart failure with narrow QRS complexes, N Engl J Med, 2007;357:2461├óÔé¼ÔÇ£71.
  42. Leon AR, Niazi I, Herrmann, Ket al., Chronic evaluation of CRT in narrow QRS patients with mechanicaldyssynchrony from a multicenter study: ESTEEM-CRT. Paper presented at Heart Rhythm Society Congress, San Francisco, CA, US, May 15, 2008.
  43. Holzmeister J, Hurlimann D, Steffel J, Ruschitzka F, Cardiac resynchronization therapy in patients with a narrow QRS, Curr Heart Fail Rep, 2009;6:49├óÔé¼ÔÇ£56.
  44. . Lindenfeld J, Feldman AM, Saxon L, et al., Effects of cardiac resynchronization therapy with or without a defibrillator on survival and hospitalizations in patients with New York Heart Association class IV heart failure, Circulation, 2007;115:204├óÔé¼ÔÇ£12.
  45. Cleland JG, Daubert JC, Erdmann E, et al., Longer-term effects of cardiac resynchronization therapy on mortality in heart failure [the CArdiac REsynchronization-Heart Failure (CARE-HF) trial extension phase], Eur Heart J, 2006;27:1928├óÔé¼ÔÇ£32.
  46. Cowburn PJ, Patel H, Jolliffe RE, et al., Cardiac resynchronization therapy: an option for inotrope-supported patients with end-stage heart failure?, Eur J Heart Fail, 2005;7:215├óÔé¼ÔÇ£7.
  47. Konstantino Y, Iakobishvili Z, Arad O, et al., Urgent cardiac resynchronization therapy in patients with decompensated chronic heart failure receiving inotropic therapy. A case series, Cardiology, 2006;106:59├óÔé¼ÔÇ£62.
  48. Castel MA, Magnani S, Mont L, et al., Survival in New York Heart Association class IV heart failure patients treated with cardiac resynchronization therapy compared with patients on optimal pharmacological treatment, Europace, 2010;12: 1136├óÔé¼ÔÇ£40.
  49. James KB, Militello M, Barbara G, Wilkoff BL, Biventricular pacing for heart failure patients on inotropic support: a review of 38 consecutive cases, Tex Heart Inst J, 2006;33: 19├óÔé¼ÔÇ£22.
  50. Milliez P, Thomas O, Haggui A, et al., Cardiac resynchronisation as a rescue therapy in patients with catecholamine-dependent overt heart failure: results from a short and mid-term study, Eur J Heart Fail, 2008;10:291├óÔé¼ÔÇ£7.
  51. Herweg B, Ilercil A, Cutro R, et al., Cardiac resynchronization therapy in patients with end-stage inotrope-dependent class IV heart failure, Am J Cardiol, 2007;100:90├óÔé¼ÔÇ£3. 52. Staab C, Piorkowski C, Grebe E, et al., Abstract 5925: Temporary Percutaneus Left Ventricular Stimulation in Patients with Cardiogenic Shock and Asynchronous Left Ventricular Contraction, Circulation, 2008;118:S_1031.
  52. Fonarow GC, Stough WG, Abraham WT, et al., Characteristics, treatments, and outcomes of patients with preserved systolic function hospitalized for heart failure: a report from the OPTIMIZE-HF Registry, J Am Coll Cardiol, 2007;50:768├óÔé¼ÔÇ£77.
  53. Yancy CW, Lopatin M, Stevenson LW, et al., Clinical presentation, management, and in-hospital outcomes of patients admitted with acute decompensated heart failure with preserved systolic function: a report from the Acute Decompensated Heart Failure National Registry (ADHERE) Database, J Am Coll Cardiol, 2006;47:76├óÔé¼ÔÇ£84.
  54. Foley PW, Stegemann B, Smith RE, et al., Cardiac resynchronization therapy in patients with mildly impaired left ventricular function, Pacing Clin Electrophysiol, 2009;32(Suppl. 1):S186├óÔé¼ÔÇ£9.
  55. Fung JW, Zhang Q, Yip GW, et al., Effect of cardiac resynchronization therapy in patients with moderate left ventricular systolic dysfunction and wide QRS complex: a prospective study, J Cardiovasc Electrophysiol, 2006;17: 1288├óÔé¼ÔÇ£92.
  56. Chung ES, Katra RP, Ghio S, et al., Cardiac resynchronization therapy may benefit patients with left ventricular ejection fraction >35%: a PROSPECT trial substudy, Eur J Heart Fail, 2010;12:581├óÔé¼ÔÇ£7.
  57. Donal E, Lund LH, Linde C, et al., Rationale and design of the Karolinska-Rennes (KaRen) prospective study of dyssynchrony in heart failure with preserved ejection fraction, Eur J Heart Fail, 2009;11:198├óÔé¼ÔÇ£204.
  58. Abraham WT, Fisher WG, Smith AL, et al., Cardiac resynchronization in chronic heart failure, N Engl J Med, 2002;346:1845├óÔé¼ÔÇ£53.
  59. Chung ES, Leon AR, Tavazzi L, et al., Results of the Predictors of Response to CRT (PROSPECT) trial, Circulation, 2008;117:2608├óÔé¼ÔÇ£16.
  60. Curtis JP, Luebbert JJ, Wang Y, et al., Association of physician certification and outcomes among patients receiving an implantable cardioverter-defibrillator, JAMA 2009;301:1661├óÔé¼ÔÇ£70.
  61. Lee DS, Krahn AD, Healey JS, et al., Evaluation of early complications related to De Novo cardioverter defibrillator implantation insights from the Ontario ICD database, J Am Coll Cardiol, 2010;55:774├óÔé¼ÔÇ£82.