Article

Emerging Cardiac Resynchronisation Therapy Indications

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Abstract

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 ≥120ms, and left ventricular ejection fraction (LVEF) ≤35%, 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.

Keywords

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.

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Accepted:

DOI:https://doi.org/10.15420/ecr.2011.7.1.29

Correspondence Details:Charlotte Eitel, University of Leipzig, Heart Center, Department of Electrophysiology, Strümpellstrasse 39, 04289 Leipzig, Germany. E: charlotteeitel@gmx.de

Copyright Statement:

The copyright in this work belongs to Radcliffe Medical Media. Only articles clearly marked with the CC BY-NC logo are published with the Creative Commons by Attribution Licence. The CC BY-NC option was not available for Radcliffe journals before 1 January 2019. Articles marked ‘Open Access’ but not marked ‘CC BY-NC’ are made freely accessible at the time of publication but are subject to standard copyright law regarding reproduction and distribution. Permission is required for reuse of this content.

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–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 ≥120ms, and left ventricular ejection fraction (LVEF) ≤35% despite optimal pharmacological therapy.7–9

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.

New Cardiac Resynchronisation Therapy Indications within the European Society of Cardiology Guidelines

New evidence from clinical trials has recently led to an updated version (see Table 1) of the current ESC HF guidelines from 20087 and the cardiac pacing guidelines from 2007.9,10 In contrast to previous guidelines, these recommendations not only are based on the inclusion criteria of patients in randomised clinical trials, but also consider the characteristics and outcome of patients actually treated. With respect to evidence-based efficacy of CRT in patients with NYHA class III/IV, the recommendations have been adapted to no longer require left ventricular (LV) dilatation and to limit NYHA class IV to ambulatory patients. This had already been established in the US guidelines.8

Cardiac Resynchronisation Therapy in Patients with Mildly Symptomatic or Asymptomatic Heart Failure

The recent publication of two large randomised studies, the Multicentre automatic defibrillator implantation trial with cardiac resynchronisation therapy (MADIT-CRT)11,12 and the Resynchronisation reverses remodelling in systolic left ventricular dysfunction (REVERSE) trial,13,14 has led to the most substantial changes in current CRT guidelines. The results of these trials suggest that CRT reverses LV remodelling, resulting in a reduction of disease progression and HF-related adverse clinical events. While REVERSE failed to show a difference in the primary end-point (HF clinical composite response), the results indicate that CRT reverses LV remodelling and reduces the risk for HF hospitalisation.14 Results from the 24-month follow-up of the European cohort of REVERSE have shown less clinical disease progression and an improvement in LV function.13 With extended follow-up there was a significant reduction in the clinical composite end-point in the CRT group (19% worsened in the CRT-ON group compared with 34% in the CRT-OFF group; p<0.01), as well as a significant reduction in time to first HF hospitalisation or death in the CRT-ON group (hazard ratio [HR] 0.38; p<0.003). Correspondingly, over a follow-up of 2.5 years, MADIT-CRT showed that patients with CRT-D had a one-third lower risk for the primary end-point (death or other clinical HF events) compared with patients with regular ICDs.11 Separating the primary end-point, there was no significant difference in death, but CRT resulted in a 41% reduction in other clinical HF events.

Extending clinical follow-up of CRT patients with mildly symptomatic HF over five to 10 years seems likely to show an influence on overall mortality reduction according to our pathophysiological understanding and the current scientific data.15 That benefit, however, has yet to be proved. Therefore, CRT in mildly symptomatic HF patients (NYHA II, LVEF ≤35%) is currently recommended not to reduce mortality but rather to reduce morbidity and to prevent disease progression, and should be limited to patients with a high likelihood of CRT response (QRS ≥150ms; class I recommendation, level of evidence A).10

Patients with NYHA functional class I are excluded from this recommendation as such patients accounted for only a small proportion of the populations studied in MADIT-CRT (15%) and REVERSE (18%); in addition, these patients did not derive a demonstrable clinical benefit. For the same reason, the cut-off for QRS duration (≥150ms) was chosen because patients with wider QRS duration responded more favorably in MADIT-CRT and REVERSE.

In addition, women, especially those with left bundle branch block (LBBB), showed a better clinical response to device therapy in MADIT-CRT. Nevertheless, this is not considered in the guidelines as analysis by sex was not pre-specified. Contrary to the European guidelines, the US Food and Drug Administration (FDA) based its newly proposed recommendations solely on the MADIT-CRT trial, using the inclusion criteria rather than the actual treated patient cohorts. This led to extended indications also in ischemic NYHA I patients and in patients with LBBB QRS duration ≥130ms.

To further strengthen the evidence and to address the issue of potential mortality reduction, data from a large randomised study with longer follow-up of CRT in patients with mildly symptomatic HF are soon to be expected from the Resynchronisation/defibrillation in advanced heart failure trial (RAFT; ClinicalTrials.gov identifier NCT00251251).16 This study included 1,800 patients in SR or with atrial fibrillation (AF), LVEF ≤30%, and QRS ≥120ms, and randomised patients to either ICD or CRT-D in a 1:1 fashion. The follow-up is expected to cover 4.5 years.

Cardiac Resynchronisation Therapy in Patients with Atrial Fibrillation

The prevalence of AF in HF patients is high and increases with progressive heart disease to up to 50% in NYHA III/IV patients.17 Therefore, AF patients represent a relevant and important subgroup of patients. The main problem in patients with AF and CRT is the decreased percentage of effectively biventricular paced captured beats due to irregular spontaneous AF rhythm, which corresponds to increased mortality.18 Based on these observations, a consensus exists that complete ventricular capture is mandatory to maximise clinical benefit and improve the prognosis of patients with permanent AF and CRT.19 Besides the establishment of pharmacological rate control, complete atrioventricular (AV) block by AV nodal ablation may be required to assure adequate pacing. However, randomised studies on this issue are lacking and results from observational studies have yielded controversial results, with some studies proposing AV nodal ablation as a prerequisite for mortality reduction in AF patients undergoing CRT20,21 and others reporting similar prognostic and symptomatic benefits without AV nodal ablation.22,23

Data on catheter ablation in HF patients with AF are promising and indicate significant improvements in cardiac function, symptoms, exercise capacity, and quality of life.24 Furthermore, this approach has been shown to be superior to AV nodal ablation and consecutive CRT implantation with respect to LVEF, six-minute walking distance and quality of life.25 However, data are limited by small sample size, short follow-up, and generally controversial data on the benefit of rhythm control in HF patients.26

The updated ESC guidelines consider CRT for morbidity reduction in patients with permanent AF, highly impaired LVEF (≤35%), NYHA III/IV, and QRS ≥130ms, on the condition that complete ventricular capture (at least 95%)18 is facilitated, mostly through AV nodal ablation.10

Contrary to the CRT guidelines and based on expert consensus only (class IIb, level of evidence C), the new ESC guidelines on AF27 consider biventricular pacing after AV nodal ablation, even in patients with only mildly symptomatic HF, irrespective of QRS duration and with only mildly depressed LV function (LVEF <45%).

Further understanding of the effect of primary catheter ablation in CRT patients suffering from AF may result from currently ongoing trials such as the Atrial fibrillation management in congestive heart failure with ablation (AMICA; ClinicalTrials.gov identifier NCT00652522), which is comparing LV reverse remodelling after catheter ablation versus conventional medical therapy in AF patients with reduced LVEF (<35%) requiring an ICD or CRT-D.

Cardiac Resynchronisation Therapy in Patients with a Conventional Pacemaker Indication

Chronic right ventricular (RV) apical pacing has been shown to increase morbidity and mortality in patients with ICDs and impaired LV function.28 These adverse effects are attributed to the induction of delayed activation of lateral LV segments with consecutive intra- and inter-ventricular dyssynchrony. Additional placement of an LV lead might potentially correct this dyssynchrony and result in a better clinical outcome. In this way, biventricular pacing has been shown to be superior to conventional RV pacing with regard to LVEF, quality of life, and exercise capacity in patients with a conventional PM indication and pre-existing LV dysfunction.29,30

These results have recently been extended to patients with normal systolic function and a conventional PM indication.31 In a prospective, double-blind, multicentre trial, 177 patients were randomly assigned to biventricular or RV apical pacing.29 At 12 months, the mean LVEF was significantly lower in the RV pacing group than in the biventricular pacing group (55 versus 62%; p<0.001), whereas the LV end systolic volume was significantly higher in the RV pacing group than in the biventricular pacing group (36 versus 28ml; p<0.001). Correspondingly, studies of upgrading patients with RV apical pacing to biventricular pacing showed significant improvements in LV reverse remodelling, even after long-term RV apical pacing.32,33 Larger studies with a longer follow-up evaluating morbidity and mortality are needed before biventricular pacing can be recommended in patients with preserved LV function and an indication for permanent pacing.

Therefore, the updated ESC guidelines underline the importance of avoiding RV pacing and recommend consideration of CRT for morbidity reduction in patients with severely and mildly symptomatic HF with a permanent PM indication, irrespective of QRS duration, in the context of a significantly impaired LVEF (<35%; class IIb, level of evidence C).

In the future, two landmark trials will further address the effect of biventricular versus RV pacing on survival, quality of life, and functional capacity in patients with a bradycardia indication for ventricular pacing. The biventricular pacing for atrioventricular block to prevent cardiac desynchronisation (BioPace) trial34 and the Biventricular versus right ventricular pacing in heart failure patients with atrioventricular block (BLOCK HF; ClinicalTrials.gov identifier: NCT00267098) have included 1,800 and 1,600 patients, respectively, with each group having a wide range of LVEF values. Clinical follow-up is ongoing.

Emerging Indications
Cardiac Resynchronisation Therapy in Patients with Narrow QRS

Evidence for a clinical benefit of CRT has been proved in HF patients with prolonged QRS as a marker of ventricular dyssynchrony. The presence of mechanical dyssynchrony, however, has also been shown in about 30–40% of HF patients with a normal QRS duration.35–37 Therefore, several studies have explored the potential benefit of CRT in this subset of patients.

While small single-centre trials indicated improvements in LVEF and exercise capacity in HF patients with narrow QRS and baseline mechanical asynchrony,38–40 these results could not be replicated in two multicentre trials.41,42 Evaluation of screening techniques in electrically normal, mechanically dyssynchronous HF patients (ESTEEM-CRT) included 68 patients with NYHA III, narrow QRS (<120ms), LVEF ≤35%, and LV mechanical asynchrony as assessed by tissue Doppler imaging. Patients did not improve as measured by objective exercise performance or echocardiographic LV reverse remodelling. Subjective symptomatic improvement was attributed to bias or placebo.42 RethinQ, the first randomised study, enrolled 172 NYHA III patients with narrow QRS (<130ms), a standard ICD indication, and LV mechanical asynchrony assessed by tissue Doppler imaging. At six months, CRT did not result in an improvement of peak oxygen consumption as the primary end-point (CRT-ON group 46% versus CRT-OFF group 41%). In a pre-specified subgroup with a QRS ≥120ms, peak oxygen consumption increased in the CRT group (p=0.02) but was unchanged in the subgroup with QRS <120ms (p=0.45). HF events did not differ between treatment groups. Consequently, there is currently no evidence that CRT is indicated in HF patients with QRS <120ms. However, it should be emphasised that both multicentre trials included a small number of patients, had a limited follow-up (up to six months), and did not focus on rehospitalisation and long-term survival. From a principal pathophysiological viewpoint, the method of evaluation of mechanical asynchrony and its impact on optimal LV lead positioning represent further methodological limitations of these studies.

More data on these issues are expected from the ongoing Echocardiography-guided Cardiac resynchronisation therapy (EchoCRT) trial (ClinicalTrials.gov identifier: NCT00683696).43 This trial will randomise around 2,200 patients to CRT or no CRT. The presence of baseline LV mechanical dyssynchrony is being assessed by speckle tracking echocardiography and validated through a single echo core laboratory. The primary end-point is all-cause mortality or hospitalisation for cardiovascular events during long-term follow-up.

Conceptually, the optimal position of the LV lead may play a greater role in achieving a clinical CRT benefit in narrow-QRS patients. Further impact on the role of CRT among those patient cohorts may therefore be expected from therapy developments aiming at the description and achievement of individualised optimal LV pacing sites.

Cardiac Resynchronisation Therapy in Patients with New York Heart Association Class IV

The major experience with CRT derives from systolic HF patients with NYHA class III disease. Patients with NYHA class IV account for only 10% of all patients in clinical CRT trials and these patients were highly selected, ambulatory outpatients who were taking oral medications and had no history of recent hospitalisation.8,44 The two landmark trials, the Cardiac resynchronization–heart failure trial (CARE-HF) and the Comparison of medical therapy, pacing, and defibrillation in heart failure (COMPANION) trial, included only 50 and 217 NYHA IV patients, respectively. Patients requiring continuous intravenous therapy or admissions for HF during the last month were excluded. In the CARE-HF study, no significant differences in outcome between class III and IV patients were reported.6,45 Correspondingly, a recent post-hoc analysis of the COMPANION trial that examined the outcome of all enrolled patients in NYHA functional class IV demonstrated a significant improvement in time to all-cause mortality and hospitalisations in NYHA class IV patients, with a trend toward improved mortality. Total mortality rates at two years were 55 and 45% with CRT-D and CRT-P, respectively, compared with 62% in the control group.44

Based on these data, current US guidelines8 and the updated ESC guidelines10 recommend CRT to improve morbidity (but not mortality) in ambulatory class IV patients. Patients with more advanced HF receiving intravenous inotropic support with refractory fluid retention or progressive renal dysfunction are not included in this recommendation as these patients represent the highest-risk population for complications during any procedure and for early mortality after discharge.8 A few observational single-centre46,47 or retrospective studies48–50 have addressed these patients, and have controversial results. On the one hand, urgent CRT implantation in patients with severely decompensated HF seems to be feasible and associated with clincial improvement;46,50,51 on the other hand, a significant reduction of mortality has not been proved.47,48 In our experience, the concept of CRT represents a promising approach as a temporary treatment in patients with refractory cardiogenic shock and a lack of further treatment options. In our own series of 18 patients with cardiogenic shock and electrical (QRS ≥120 ms, LBBB) as well as mechanical dyssynchrony, temporary percutaneous LV stimulation was feasible and resulted in improved haemodynamics with weaning of catecholamines.52

Cardiac Resynchronisation Therapy in Patients with Mildly Impaired Ejection Fraction

Nearly 50% of hospitalised patients with HF have a preserved LVEF but reveal a similar mortality and rehospitalisation risk to patients with highly impaired LVEF.53,54 Current clincial guidelines recommending CRT implantation in patients with LVEF ≤35% are based on the entry criteria of landmark trials implementing this LVEF cut-off.5,6 However, two small single-centre studies55,56 as well as post-hoc analysis of the Predictors of response to CRT (PROSPECT) study57 suggest that patients with wide QRS and LVEF >35% might also benefit from CRT.

The only prospective study on this patient cohort included 15 patients with LVEF 35–45% and QRS >120ms. At three-month follow-up, significant LV reverse remodelling could be observed with reduced LV end systolic (86 to 70ml) and end diastolic (136 to 121ml) volumes and improved LVEF (39 to 44%).56 Correspondingly, significant clinical improvements (NYHA functional class, six-minute walking distance, and quality of life) were reported in 27 patients whose LVEF as assessed with cardiac magnetic resonance imaging was >35% (mean 44%).55 These observations were replicated in a recent post-hoc analysis of the PROSPECT study. Of 361 subjects with available data, 86 were found to have an LVEF >35% (mean 43%) when assessed by the core laboratory. These patients experienced similar clinical and structural benefits to patients with more impaired LVEF.57

The prevalence of electrical and mechanical dyssynchrony and the potential usefulness of conducting clinical trials on CRT in patients with HF and preserved LVEF is currently being investigated in the prospective, observational Karolinska-Rennes (KaRen) study.58 In general, current data are too limited to recommend CRT in this patient population.

Conclusion

CRT is an efficacious and cost-effective therapy in patients with highly symptomatic systolic HF and delayed ventricular conduction. However, one-third of patients undergoing CRT for current guideline-recommended indications do not derive a demonstrable benefit from CRT.59,60

This, as well as the higher complication rate of CRT-D implant procedures compared with single-chamber devices,61,62 shows that efforts should be made to better define patients who are likely to respond or to increase the responder rate by using better implantation strategies.

On the other hand, exploring new indications might extend the benefits of CRT to a broader HF population. The concept of an early CRT intervention to delay or prevent HF progression has driven recent trials in the mild HF population, ultimately resulting in an extension of the current recommendations. Whether this concept can be applied to patients with narrow QRS or mildly impaired LVEF still needs to be proved. The use of CRT in patients with severely advanced HF and recent cardiac decompensation represents a therapy extension on the other end of the clinical HF spectrum. Scientifc data and evaluation are limited by the naturally high mortality rate in this patient subgroup; therefore, clinical guidelines do not state this indication. However, the first clinical descriptions indicate a potential role of temporary CRT as an additional treatment option in pre-terminal HF patients.

References

  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;111:2146–50.
    Crossref | PubMed
  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;107:1985–90.
    Crossref | PubMed
  3. Ypenburg C, Lancellotti P, Tops LF, et al., Mechanism of improvement in mitral regurgitation after cardiac resynchronization therapy, Eur Heart J, 2008;29:757–65.
    Crossref | PubMed
  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;102:3053–9.
    Crossref | PubMed
  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;350:2140–50.
    Crossref | PubMed
  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;352:1539–49.
    Crossref | PubMed
  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;29:2388–2442.
    Crossref | PubMed
  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:e1–62.
    Crossref | PubMed
  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;28:2256–95.
    Crossref | PubMed
  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;31:2677–87.
    Crossref | PubMed
  11. Moss AJ, Hall WJ, Cannom DS, et al., Cardiac-resynchronization therapy for the prevention of heart-failure events, N Engl J Med, 2009;361:1329–38.
    Crossref | PubMed
  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;122:985–92.
    Crossref | PubMed
  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;54:1837–46.
    Crossref | PubMed
  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;52:1834–43.
    Crossref | PubMed
  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;112:1580–6.
    Crossref
  16. Tang AS, Wells GA, Arnold M, et al., Resynchronization/ defibrillation for ambulatory heart failure trial: rationale and trial design, Curr Opin Cardiol, 2009;24:1–8.
    Crossref | PubMed
  17. Maisel WH, Stevenson LW, Atrial fibrillation in heart failure: epidemiology, pathophysiology, and rationale for therapy, Am J Cardiol, 2003;91:2D–8D.
    Crossref | PubMed
  18. Koplan BA, Kaplan AJ, Weiner S, et al., Heart failure decompensation and all–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;53:355–60.
    Crossref | PubMed
  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;10:809–15.
    Crossref | PubMed
  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;48:734–43.
    Crossref | PubMed
  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;29:1644–52.
    Crossref | PubMed
  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;99:1252–7.
    Crossref | PubMed
  23. Khadjooi K, Foley PW, Chalil S, et al., Long-term effects of cardiac resynchronisation therapy in patients with atrial fibrillation, Heart, 2008;94:879–83.
    Crossref | PubMed
  24. Hsu LF, Jais P, Sanders P, et al., Catheter ablation for atrial fibrillation in congestive heart failure, N Engl J Med, 2004;351:2373–83.
    Crossref | PubMed
  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;359:1778–85.
    Crossref | PubMed
  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;358:2667–77.
    Crossref | PubMed
  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;31:2369–429.
    Crossref | PubMed
  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;288:3115–23.
    Crossref | PubMed
  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;47:1927–37.
    Crossref | PubMed
  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;16:293–300.
    Crossref | PubMed
  31. Yu CM, Chan JY, Zhang Q, et al, Biventricular pacing in patients with bradycardia and normal ejection fraction, N Engl J Med, 2009;361:2123–34.
    Crossref | PubMed
  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;31:1477–85.
    Crossref | PubMed
  33. Horwich T, Foster E, De MT, et al., Effects of resynchronization therapy on cardiac function in pacemaker patients “upgraded” to biventricular devices, J Cardiovasc Electrophysiol, 2004;15:1284–9.
    Crossref | PubMed
  34. Funck RC, Blanc JJ, Mueller HH, et al., Biventricular stimulation to prevent cardiac desynchronization: rationale, design, and endpoints of the ‘Biventricular Pacing for Atrioventricular Block to Prevent Cardiac Desynchronization (BioPace)’ study, Europace, 2006;8:629–35.
    Crossref | PubMed
  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;95:140–2.
    Crossref | PubMed
  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;25:571–8.
    Crossref | PubMed
  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;30:616–22.
    Crossref | PubMed
  38. Achilli A, Sassara M, Ficili S, et al., Long-term effectiveness of cardiac resynchronization therapy in patients with refractory heart failure and “narrow” QRS, J Am Coll Cardiol, 2003;42: 2117–24.
    Crossref | PubMed
  39. Bleeker GB, Holman ER, Steendijk P, et al., Cardiac resynchronization therapy in patients with a narrow QRS complex, J Am Coll Cardiol, 2006;48:2243–50.
    Crossref | PubMed
  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;48:2251–7.
    Crossref | PubMed
  41. Beshai JF, Grimm RA, Nagueh SF, et al., Cardiac-resynchronization therapy in heart failure with narrow QRS complexes, N Engl J Med, 2007;357:2461–71.
    Crossref | PubMed
  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;6:49–56.
    Crossref | PubMed
  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;115:204–12.
    Crossref | PubMed
  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;27:1928–32.
    Crossref | PubMed
  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;7:215–7.
    Crossref | PubMed
  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;106:59–62.
    Crossref | PubMed
  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: 1136–40.
    Crossref | PubMed
  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: 19–22.
    PubMed
  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;10:291–7.
    Crossref | PubMed
  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;100:90–3.
    Crossref | PubMed
  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.
  53. 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;50:768–77.
    Crossref | PubMed
  54. 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;47:76–84.
    Crossref | PubMed
  55. 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):S186–9.
    Crossref | PubMed
  56. 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: 1288–92.
    Crossref | PubMed
  57. 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;12:581–7.
    Crossref | PubMed
  58. 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;11:198–204.
    Crossref | PubMed
  59. Abraham WT, Fisher WG, Smith AL, et al., Cardiac resynchronization in chronic heart failure, N Engl J Med, 2002;346:1845–53.
    Crossref | PubMed
  60. Chung ES, Leon AR, Tavazzi L, et al., Results of the Predictors of Response to CRT (PROSPECT) trial, Circulation, 2008;117:2608–16.
    Crossref | PubMed
  61. Curtis JP, Luebbert JJ, Wang Y, et al., Association of physician certification and outcomes among patients receiving an implantable cardioverter-defibrillator, JAMA 2009;301:1661–70.
    Crossref | PubMed
  62. 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;55:774–82.
    Crossref | PubMed
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