Andrea Mazza1, Sergio Valsecchi2, Umberto Riva2, Maria Grazia Bendini1 and Massimo Leggio3*
1Cardiology Division, Santa Maria della Stella Hospital, Orvieto, Italy
2Boston Scientific Italy, Milan, Italy
3Cardiovascular Department, Cardiac Rehabilitation Operative Unit, San Filippo Neri Hospital – Salus Infirmorum Clinic, Rome, Italy
Received: July 01, 2014; Accepted: August 02, 2014; Published: August 04, 2014
Massimo Leggio, M.D., Cardiovascular Department, Cardiac Rehabilitation Operative Unit, San Filippo Neri Hospital – Salus Infirmorum Clinic, Via della Lucchina 41, 00135 Rome, Italy, Tel: +3906302511; Fax: +390630811972; Email: firstname.lastname@example.org
Mazza A, Valsecchi S, Riva U, Bendini MG, Leggio M (2014) Cardiac Resynchronization Therapy in Heart Failure: Rationale, Results, Indications, Limits and Perspectives. J Cardiovasc Med Cardiol 1(1): 017-022. 10.17352/2455-2976.000004
© 2014 Mazza A. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Cardiac resynchronization therapy; Heart failure
Heart Failure is the result of heterogeneous structural heart diseases, especially ischemic disease, and is becoming increasingly common in all Western countries.
Many patients continue to be symptomatic in spite of progress in pharmacological therapy, and the risk of mortality remains high in the most advanced functional classes. Cardiac resynchronization therapy can be used as a therapeutic strategy for alleviating symptoms and reducing mortality in selected patients with heart failure.
Cardiac resynchronization therapy provides both immediate and medium/long-term results. The immediate results are the reduced QRS duration, the synchrony restoration between the ventricles and between the lateral and septal walls of the left ventricle, the reduced mitral regurgitation and the increased stroke volume. In the medium/long term, left ventricular reverse remodeling occurs and left ventricular ejection fraction is increased.
Several trials have documented both increased functional capacity and improvements in quality of life and New York Heart Association class. Moreover, cardiac resynchronization therapy has been seen to reduce HF hospitalizations and mortality and the total number of days of hospitalization.
In order to reduce the percentage of non-responders to cardiac resynchronization therapy, it is necessary to optimize the prognostic stratification of candidates for implantation through multi-parameter evaluations and to ensure correct device programming with periodic updates which are widely recommended but not so often performed.
Whether indications should be extended will need to be evaluated in view of the known complications mainly associated with lead implantation.
Heart Failure (HF) is the result of heterogeneous structural heart diseases, especially ischemic disease, and is becoming increasingly common in all Western countries. Indeed, over than 7 million individuals in Europe  and over than 4 million in the United States  are currently affected. Moreover, this prevalence is expected to double over the next 20 years , thus making HF the new cardiovascular epidemic .
Since 1986, numerous clinical trials focused on HF therapy have been conducted, ranging from the simple control of risk factors to the implementation of advanced treatment modalities for patients with HF refractory to conventional therapy .
However, many patients continue to be symptomatic in spite of progress in pharmacological therapy, and the risk of mortality remains high in the most advanced functional classes . Cardiac resynchronization therapy (CRT) can be used as a therapeutic strategy for alleviating symptoms and reducing mortality in a considerable percentage of HF patients.
It is well known that QRS duration is inversely correlated with survival in HF patients in functional classes II-IV, and patients with QRS ≥200 ms have a 5-fold higher risk of death than those with a narrow QRS . In particular, left bundle branch block (LBBB) usually delays activation of the posterior/lateral wall of the left ventricle, leading to asynchronous contraction between the septum and posterior-lateral wall and reducing the left ventricular ejection fraction (LVEF).
CRT can correct this asynchronous contraction through the pre-excitation of the posterior-lateral wall of the left ventricle, thereby improving systolic function [8,9]. Indeed, the dyssynchrony due to prolonged QRS duration involves the heterogeneous propagation of electrical activity in the ventricle, which determines various degrees of impaired coordination in filling and contraction . Consequently the contractile efficiency of the heart is compromised and the myocardial oxygen consumption increases, worsening the clinical course of HF.
It is therefore important to consider that 1/3 of HF patients have a QRS duration >120 ms , and that the incidence of LBBB is 10.9% in the first year of follow-up . In these patients, CRT enables synchronous stimulation of both ventricles, which reduces QRS duration and improves left ventricular systolic performance, although modestly increasing the myocardial oxygen consumption . The beneficial effects of CRT on left ventricular systolic function and on neurohormonal activation lead to clinical improvements in symptoms, exercise capability and quality of life, and reduce HF hospitalizations and mortality .
CRT provides both immediate and medium/long-term results in the so-called “positive responder patients”. The immediate results are the reduced QRS duration, the synchrony restoration between the ventricles and between the lateral and septal walls of the left ventricle, the reduced mitral regurgitation and the increased stroke volume. In the medium/long term, left ventricular reverse remodeling occurs, left ventricular end-systolic volume (LVEsV) is variably reduced and EF is increased. Standard criteria adopted for defining positive response to the therapy are a reduction of at least 15% in LVEsV and an increase of 5% in EF.
On the clinical side, several trials have documented both increased functional capacity, as evaluated by means of the 6-minute walking test and the VO2 peak, and improvements in quality of life and New York Heart Association (NYHA) class [15-23]. Moreover, CRT has been seen to reduce HF hospitalizations and mortality by 36% , and the total number of days of hospitalization by 77% . The COMPANION study  evaluated the efficacy of CRT, with or without an Implantable Cardioverter Defibrillator (ICD), versus medical therapy alone, in reducing the risk of death and hospitalizations in HF patients. In 1520 patients with advanced HF (LVEF ≤35%, left ventricular end-diastolic diameter (LVEdD) ≥60 mm, NYHA class III-IV) and intraventricular conduction delay (QRS ≥120 ms), both CRT with and without ICD reduced the primary end-point of mortality/hospitalization for HF by 20% in one year compared with optimal medical therapy. It was clearly demonstrated that CRT in addition to optimal medical therapy with beta-blockers [24,25], ACE-inhibitors [26,27] and mineralocorticoid antagonists , further reduced mortality in HF patients, and that this reduction reached a value of 36% in the long term .
The CARE-HF study  evaluated the effect of CRT on morbidity and mortality in 813 patients with advanced HF and a clinical and instrumental profile similar to that of the COMPANION study population. The primary end-point was the combination of all-cause death and hospitalization for major cardiovascular events over a mean follow-up of 29.4 months. In this study, CRT reduced the primary end-point by 37% compared with medical therapy (HR 0.63, 95% CI 0.51-0.77, P <0.0001) in subgroups that showed no statistically significant differences.
These exciting results led to further studies in which the benefits of CRT have been assessed in patients in lower functional classes. Specifically, in the REVERSE study  the long-term benefits of CRT were evaluated in 610 European patients in NYHA class II (83%) or I (previously symptomatic), with QRS ≥120 ms, LVEF ≤40%, LVEdD ≥55 mm, with or without indication for an ICD, and undergoing optimized medical therapy. Patients were randomized 2:1 to CRT-ON or CRT-OFF and followed up prospectively for 24 months. The end-points of the study were the combined clinical score of all-cause mortality, hospitalizations for HF, cross-over due to worsening HF and NYHA class, and LVEsV reduction. Echocardiography revealed a significant improvement in LVEsV, left ventricular end-diastolic volume (LVEdV) and LVEF (69.7 vs. 94.5 ml/m2, 103 vs. 132 ml/m2, 34.8% vs. 29.9%, CRT-ON vs. CRT-OFF, respectively). Clinically, a significant 62% reduction was reported in mortality and hospitalizations for HF at 24 months (11.7% vs. 24%, HR 0.38, 95% CI 0.20-0.73, P =0.003, CRT-ON vs. CRT-OFF).
Similarly, the MADIT-CRT study  enrolled 1820 patients in NYHA class I or II (85%) and with QRS ≥130 ms and LVEF ≤30%. Patients were randomized 3:2 to CRT with ICD or ICD alone and followed up for a mean of 2.4 years. The end-point of the study was the reduction in all-cause mortality and/or hospitalizations for HF. CRT with ICD showed a significant advantage over ICD alone with regard to the primary end-point (17.2% vs. 25.3%, HR 0.66, 95% CI 0.52-0.84, P =0.001), the reduction in left ventricular volume (LVEsV -57 ml vs. -18 ml, LVEdV -52 ml vs. -15 ml, P <0.01, CRT with ICD vs. ICD alone, respectively) and the increase in LVEF (+11% vs. + 3%, P <0.001, CRT with ICD vs. ICD alone). The MADIT-CRT results were largely confirmed by the RAFT study , which enrolled 1798 HF patients in NYHA class II (80%) and III, with QRS ≥130 ms, LVEF ≤ 30%, randomized to CRT with ICD or ICD alone and followed up for 40 months. The reduction in the primary end-point of all-cause mortality/hospitalizations for HF was 25% greater in the CRT with ICD group than in the ICD alone group (HR 0.75, 95% CI 0.64-0.87, P <0.001), with 29% reduction of the risk of mortality in the sub-group of patients in NYHA class II. The results of these three studies (REVERSE, MADIT-CRT and RAFT) encouraged CRT indications to be extended to all NYHA class II patients. Moreover, a recent meta-analysis of 5 randomized studies has shown that CRT provides greater benefits in patients with QRS >150 ms .
On the basis of the evidences collected, the main American and European scientific societies have modified CRT indications in the aim to include patients not only in NYHA classes III and IV, but also in NYHA class II with LBBB, in particular if with QRS >150 ms [33,34]. The benefit of CRT in patients in sinus rhythm with wide QRS but without LBBB is uncertain. In these patients, the indication for CRT is therefore less prescriptive.
Furthermore, in HF patients in permanent atrial fibrillation with wide QRS and left ventricular dysfunction, CRT is indicated only in an advanced NYHA class and on condition that 100% biventricular stimulation can be achieved, even through AV junction ablation if needed. Finally, there is indication to up-grade a conventional PMK or ICD to CRT or CRT with ICD in HF patients in an advanced NYHA class with left ventricular dysfunction and a high percentage of ventricular pacing.
As yet, in patients with mild-moderate left ventricular dysfunction in whom conventional pacing is indicated, the indication for “de novo” CRT implantation, in order to reduce the risk of HF worsening due to the high percentage of right apical pacing, is less established.
Because of its widespread involvement of clinical, instrumental, metabolic and endocrine factors, the response to CRT is not easy to precisely establish. Nevertheless, there is general agreement that patients in whom the LVEdV reduction in the medium/long term is less than 15% should be classed as non-responders. This is not a low percentage, mostly considering that these patients account for at least 30% of all undergoing implantations . The response to CRT may be sub-optimal for many reasons, ranging from the etiopathogenic and clinical heterogeneity of HF patients to the widespread and variable presence of co-morbidities or to the lack of optimization of medical therapy .
In the aim to increase the probability of response to CRT, it is important to ensure that left ventricular stimulation is concordant with the most delayed activation site, as identified by Tissue Doppler Imaging  or speckle-tracking  echocardiography. Moreover, the presence of large areas of fibrous scarring in the left ventricle can impair the CRT response , particularly if these are located in the posterior-lateral wall . By contrast, the presence of vital myocardium, as identified by means of echo-dobutamine  or nuclear medicine techniques [42,43], has a favorable prognostic significance in CRT candidates. Briefly, in order to reduce the percentage of non-responders to CRT, it is necessary to optimize the prognostic stratification of candidates for implantation through multi-parameter evaluations  and to ensure correct device programming, with periodic updates of the A-V and V-V intervals which are widely recommended but not so often performed .
At last, the recent diffusion of remote control systems for implanted devices has improved the assistance available to CRT patients through strict monitoring of numerous vital parameters during follow-up . Indeed, a strong association between remote monitoring and survival has been observed in CRT-ICD patients .
Alternative forms of CRT, including biventricular endocardial and multisite epicardial pacing, have been recently proposed. Left ventricular leads cannot be implanted in up to 10% of patients undergoing CRT implantation . These implant failures are not due to patient selection but rather challenges posed by anatomy leading to lead stability problems, phrenic nerve stimulation, and poor electrical measurements . The quadripolar leads recently made available in the market, allowing multiple pacing configurations, provide an opportunity to optimize the electrical performance and minimize phrenic nerve stimulation. Moreover, preliminary data suggest that simultaneous stimulation of multiple left ventricular sites using two or more pacing sites in a quadripolar lead could enhance the acute effectiveness of CRT . However, the results appear conflicting [51,52] and prospective follow-up studies are required to demonstrate clinical benefit.
During CRT device implantation, the pacing lead is usually positioned in the coronary sinus to stimulate the left ventricular epicardium. Transvenous left ventricular endocardial pacing via transeptal puncture has been proposed as an alternative method. Several experimental studies have demonstrated that endocardial pacing should elicit beneficial effects, allowing more homogeneous and rapid electric depolarization and repolarization [53,54]. In particular, pacing at an optimal individual endocardial site seems to yield enhanced left ventricular performance in comparison with conventional coronary sinus site stimulation . Thus, endocardial left ventricular pacing might provide an alternative approach to CRT, when coronary sinus pacing is not viable. However, the possibility of adverse effects of endocardial CRT (eg, the risk of thromboembolic complications and the induction of mitral valve dysfunction) should be considered and carefully addressed during the evaluation of risks and benefits of the procedure.
As previously reported, duration of QRS interval ≥120 or 130 ms was the inclusion criterion used in major CRT trials. However, sub-group analyses based on QRS morphology [30,31,56] and a meta-analysis  suggested that patients with complete LBBB showed a greater benefit on the composite of morbidity/mortality from CRT, compared with patients with non-specific intraventricular conduction delay or right bundle branch block. Based on this evidence, current class I recommendations were restricted to patients with complete LBBB. However, recent studies showed that fragmented QRS complexes in the electrocardiograms of patients with nonischemic dilated cardiomyopathy and narrow QRS complexes are associated with significant intraventricular dyssynchrony [58,59], and other studies suggested that fragmented QRS complexes might be useful in predicting response to CRT [60,61]. Ongoing studies are investigating the possibility of maximizing CRT benefits by refining ECG selection criteria .
Single-center studies suggested that echocardiographic parameters of mechanical dyssynchrony may improve patient selection for CRT. Moreover, since mechanical dyssynchrony may also be present in patients with normal QRS duration, potential benefits could be expected in this population, too.
In 2008, the PROSPECT study tested the performance of echocardiographic parameters to predict CRT response , and revealed that these parameters do not appear to have a clinically relevant impact on improving response rates.
Moreover, one randomized study that enrolled patients with QRS duration <130ms (the RethinQ trial) did not show any improvement in peak oxygen consumption on CRT . Similarly, in the LESSER-EARTH trial , which randomized patients with an LVEF ≤35%, symptoms of HF, and a QRS duration <120 milliseconds to active versus inactive CRT therapy, CRT did not result in an improvement in exercise capacity, symptoms, quality of life, or reverse LV remodeling. More recently, the EchoCRT study  showed that in patients with systolic heart failure and QRS duration of less than 130 msec, CRT does not reduce the rate of death or hospitalization for heart failure and may increase mortality.
Several studies have addressed the issue of the interventricular and left intraventricular dyssynchrony caused by right apical pacing. These studies have tested “de novo” CRT implantation in patients with a conventional pacing indication, both with preserved left ventricular systolic function [67-69] and with moderate-severe left ventricular dysfunction [70-72]. The results suggest that CRT plays a preventive role with regard to HF mortality/hospitalizations only in patients with left ventricular dysfunction (LVEF <40%). Indeed, left ventricular systolic dysfunction has recently been suggested as an independent predictor of the adverse clinical impact of pacing [73,74], even though the preventive impact of CRT on HF in these patients must be carefully evaluated considering the increase in complications due to the greater number of leads implanted (6.5% vs. 18%, conventional pacing vs. CRT in the BLOCK-HF study) .
An alternative strategy in these patients is to up-grade to CRT after first implanting a conventional PMK. This approach provides the same clinical benefit as “de novo” CRT implantation, but is however associated with a considerable percentage of complications .
Further evidence of the potential benefit of “de novo” CRT implantation in patients with conventional pacing indications in whom right apical stimulation cannot be avoided is expected from the BIOPACE trial (ClinicalTrials.gov Identifier: NCT00187278), while the on-going MIRACLE-EF study (ClinicalTrials.gov Identifier: NCT01735916) is testing the efficacy of CRT in patients with left ventricular dysfunction (LVEF 36%-50%) and LBBB but without indication for definitive pacing.
Finally, in patients with a prolonged PR interval, LBBB and left ventricular dysfunction, the REAL-CRT (Bivent Ricular pacing in prolongEd AV interval) study will evaluate the synergic effect of atrio-ventricular and inter-ventricular synchronization provided by CRT in patients with a minimum or intermittent indication for pacing (ClinicalTrials.gov Identifier: NCT02150538).
A large number of studies have already demonstrated that, compared with optimal medical therapy alone, CRT can reduce HF mortality and hospitalizations in selected HF patients in NYHA classes II-IV. Whether indications for CRT should be extended to patients with an indication for convention pacing, mild-moderate (or even no) left ventricular dysfunction and a high percentage of right apical pacing will need to be evaluated in view of the expected increase in complications due to the greater number of leads implanted.
Conflict of Interest
S.V. and U.R. are employees of Boston Scientific Italy; there are no other conflicts of interest.
- Nieminen MS, Harjola VP (2005) Definition and epidemiology of acute heart failure syndromes. Am J Cardiol 96: 5G-10G.
- Massie BM, Packer M (1990) Congestive heart failure: current controversies and future prospects. Am J Cardiol 66: 429-430.
- Heidenreich PA, Albert NM, Allen LA, Bluemke DA, Butler J, et al. (2013) Forecasting the impact of heart failure in the United States: a policy statement from the American Heart Association. Circ Heart Fail 6: 606-619.
- Anter E, Jessup M, Callans DJ (2009) Atrial fibrillation and heart failure: treatment considerations for a dual epidemic. Circulation 119: 2516-2525.
- Jessup M, Brozena S (2003) Heart failure. N Engl J Med 348: 2007-2018.
- Metra M, Ponikowski P, Dickstein K, McMurray JJ, Gavazzi A, et al. (2007) Advanced chronic heart failure: A position statement from the Study Group on Advanced Heart Failure of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail 9: 684-694.
- Gottipaty VK, Krelis SP, Lu F, Spencer EP, Shusterman V, et al. (1999) University of Pittsburgh, Pittsburgh PA, USA. The Resting Electrocardiogram Provides a Sensitive and Inexpensive Marker of Prognosis in Patients with Chronic Congestive Heart Failure. J Am Coll Cardiol 33:145A [Abstr. 847-4].
- Blanc JJ, Etienne Y, Gilard M, Mansourati J, Munier S, et al. (1997) Evaluation of different ventricular pacing sites in patients with severe heart failure: results of an acute hemodynamic study. Circulation 96: 3273-3277.
- Kass DA, Chen CH, Curry C, Talbot M, Berger R, et al. (1999) Improved left ventricular mechanics from acute VDD pacing in patients with dilated cardiomyopathy and ventricular conduction delay. Circulation 99: 1567-1573.
- Russell K, Smiseth OA, Gjesdal O, Qvigstad E, Norseng PA, et al. (2011) Mechanism of prolonged electromechanical delay in late activated myocardium during left bundle branch block. Am J Physiol Heart Circ Physiol 301: H2334-H2343.
- Lund LH, Jurga J, Edner M, Benson L, Dahlström U, et al. (2013) Prevalence, correlates, and prognostic significance of QRS prolongation in heart failure with reduced and preserved ejection fraction. Eur Heart J 34: 529-539.
- Clark AL, Goode K, Cleland JG (2008) The prevalence and incidence of left bundle branch block in ambulant patients with chronic heart failure. Eur J Heart Fail 10: 696-702.
- Kyriacou A, Pabari PA, Mayet J, Peters NS, Davies DW, et al. (2014) Cardiac resynchronization therapy and AV optimization increase myocardial oxygen consumption, but increase cardiac function more than proportionally. Int J Cardiol 171: 144-152.
- Freeman JV, Masoudi FA (2013) Effectiveness of implantable cardioverter defibrillators and cardiac resynchronization therapy in heart failure. Heart Fail Clin 9: 59-77.
- Gras D, Leclercq C, Tang AS, Bucknall C, Luttikhuis HO, et al. (2002) Cardiac resynchronization therapy in advanced heart failure the multicenter InSync clinical study. Eur J Heart Fail 4: 311-320.
- Kühlkamp V (2002) Initial experience with an implantable cardioverter-defibrillator incorporating cardiac resynchronization therapy. J Am Coll Cardiol 39: 790-797.
- Abraham WT, Fisher WG, Smith AL, Delurgio DB, Leon AR, et al. (2002) Cardiac resynchronization in chronic heart failure. N Engl J Med 346: 1845-1853.
- Young JB, Abraham WT, Smith AL, Leon AR, Lieberman R, et al. (2003) Combined cardiac resynchronization and implantable cardioversion defibrillation in advanced chronic heart failure: the MIRACLE ICD Trial. JAMA 289: 2685-2694.
- Cazeau S, Leclercq C, Lavergne T, Walker S, Varma C, et al. (2001) Effects of multisite biventricular pacing in patients with heart failure and intraventricular conduction delay. N Engl J Med 344: 873-880.
- Auricchio A, Stellbrink C, Sack S, Block M, Vogt J, et al. (2002) Long-term clinical effect of hemodynamically optimized cardiac resynchronization therapy in patients with heart failure and ventricular conduction delay. JAm Coll Cardiol 39: 2026-2033.
- Auricchio A, Stellbrink C, Butter C, Sack S, Vogt J, et al. (2003) Clinical efficacy of cardiac resynchronization therapy using left ventricular pacing in heart failure patients stratified by severity of ventricular conduction delay. J Am Coll Cardiol 42: 2109-2116.
- Bristow MR, Saxon LA, Boehmer J, Krueger S, Kass DA, et al. (2004) Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med 350: 2140-2150.
- Cleland JG, Daubert JC, Erdmann E, Freemantle N, Gras D, et al. (2005) The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med 352: 1539-1549.
- (1999) The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet 353: 9-13.
- Packer M, Fowler MB, Roecker EB, Coats AJ, Katus HA, et al. (2002) Effect of carvedilol on the morbidity of patients with severe chronic heart failure: results of the carvedilol prospective randomized cumulative survival (COPERNICUS) study. Circulation 106: 2194-2199.
- (1992) Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. The SOLVD Investigattors. N Engl J Med 327: 685-691.
- Kjekshus J, Swedberg K, Snapinn S (1992) Effects of enalapril on long-term mortality in severe congestive heart failure. CONSENSUS Trial Group. Am J Cardiol 69: 103-107.
- (1996) Effectiveness of spironolactone added to an angiotensin-converting enzyme inhibitor and a loop diuretic for severe chronic congestive heart failure (the Randomized Aldactone Evaluation Study [RALES]). Am J Cardiol 78: 902-907.
- Linde C, Abraham WT, Gold MR, St John Sutton M, Ghio S, et al. (2008) 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 52: 1834-1843.
- Moss AJ, Hall WJ, Cannom DS, Klein H, Brown MW, et al. (2009) Cardiac-resynchronization therapy for the prevention of heart-failure events. N Engl J Med 361: 1329-1338.
- Tang AS, Wells GA, Talajic M, Arnold MO, Sheldon R, et al. (2010) Cardiac-resynchronization therapy for mild-to-moderate heart failure. N Engl J Med 363: 2385-1395.
- Cleland JG, Abraham WT, Linde C, Gold MR, Young JB, et al. (2013) An individual patient meta-analysis of five randomized trials assessing the effects of cardiac resynchronization therapy on morbidity and mortality in patients with symptomatic heart failure. Eur Heart J 34: 3547-3556.
- Tracy CM, Epstein AE, Darbar D, Dimarco JP, Dunbar SB, et al. (2012) 2012 ACCF/AHA/HRS focused update of the 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 60: 1297-1313.
- Brignole M, Auricchio A, Baron-Esquivias G, Bordachar P, Boriani G, et al. (2013) 2013 ESC Guidelines on cardiac pacing and cardiac resynchronization therapy: the Task Force on cardiac pacing and resynchronization therapy of the European Society of Cardiology (ESC). Developed in collaboration with the European Heart Rhythm Association (EHRA). Eur Heart J 34: 2281-2329.
- Linde C, Ellenbogen K, McAlister FA (2012) Cardiac resynchronization therapy (CRT): clinical trials, guidelines, and target populations. Heart Rhythm 9: S3-S13.
- Mullens W, Grimm RA, Verga T, Dresing T, Starling RC, et al. (2009) Insights from a cardiac resynchronization optimization clinic as part of a heart failure disease management program. J Am Coll Cardiol 53: 765-773.
- Ansalone G, Giannantoni P, Ricci R, Trambaiolo P, Fedele F, et al. (2002) Doppler myocardial imaging to evaluate the effectiveness of pacing sites in patients receiving biventricular pacing. J Am Coll Cardiol 39: 489-499.
- Ypenburg C, van Bommel RJ, Delgado V, Mollema SA, Bleeker GB, et al. (2008) Optimal left ventricular lead position predicts reverse remodeling and survival after cardiac resynchronization therapy. J Am Coll Cardiol 52: 1402-1409.
- Ypenburg C, Roes SD, Bleeker GB, Kaandorp TA, de Roos A, et al. (2007) Effect of total scar burden on contrast-enhanced magnetic resonance imaging on response to cardiac resynchronization therapy. Am J Cardiol 99: 657-660.
- Bleeker GB, Kaandorp TA, Lamb HJ, Boersma E, Steendijk P, et al. (2006) Effect of posterolateral scar tissue on clinical and echocardiographic improvement after cardiac resynchronization therapy. Circulation 113: 969-976.
- Ypenburg C, Sieders A, Bleeker GB, Holman ER, van der Wall EE, et al. (2007) Myocardial contractile reserve predicts improvement in left ventricular function after cardiac resynchronization therapy. Am Heart J 154: 1160-1165.
- Ypenburg C, Schalij MJ, Bleeker GB, Steendijk P, Boersma E, et al. (2006) Extent of viability to predict response to cardiac resynchronization therapy in ischemic heart failure patients. J Nucl Med 47: 1565-1570.
- Ypenburg C, Schalij MJ, Bleeker GB, Steendijk P, Boersma E, et al. (2007) Impact of viability and scar tissue on response to cardiac resynchronization therapy in ischaemic heart failure patients. Eur Heart J 28: 33-41.
- Auricchio A, Prinzen FW (2011) Non-responders to cardiac resynchronization therapy: the magnitude of the problem and the issues. Circ J 75: 521-527.
- Burri H, Sunthorn H, Shah D, Lerch R (2006) Optimization of device programming for cardiac resynchronization therapy. Pacing Clin Electrophysiol 29: 1416-1425.
- Lazarus A (2007) Remote, wireless, ambulatory monitoring of implantable pacemakers, cardioverter defibrillators, and cardiac resynchronization therapy systems: analysis of a worldwide database. Pacing Clin Electrophysiol 30 Suppl 1: S2-S12.
- Saxon LA, Hayes DL, Gilliam FR, Heidenreich PA, Day J, et al. (2010) Long-term outcome after ICD and CRT implantation and influence of remote device follow-up: the ALTITUDE survival study. Circulation 122: 2359-2367.
- Dickstein K, Bogale N, Priori S, Auricchio A, Cleland JG, et al. (2009) The European cardiac resynchronization therapy survey. Eur Heart J 30: 2450-2460.
- Biffi M, Moschini C, Bertini M, Saporito D, Ziacchi M, et al. (2009) Phrenic stimulation: a challenge for cardiac resynchronization therapy. Circ Arrhythm Electrophysiol 2: 402-410.
- Pappone C, Ćalović Ž, Vicedomini G, Cuko A, McSpadden LC, et al. (2014) Multipoint left ventricular pacing improves acute hemodynamic response assessed with pressure-volume loops in cardiac resynchronization therapy patients. Heart Rhythm 11: 394-401.
- Padeletti L, Colella A, Michelucci A, Pieragnoli P, Ricciardi G, et al. (2008) Dual-site left ventricular cardiac resynchronization therapy. Am J Cardiol 102: 1687-1692.
- Shetty AK, Sohal M, Chen Z, Ginks MR, Bostock J, et al. (2014) A comparison of left ventricular endocardial, multisite, and multipolar epicardial cardiac resynchronization: an acute haemodynamic and electroanatomical study. Europace 16: 873-879.
- van Deursen C, van Geldorp IE, Rademakers LM, van Hunnik A, Kuiper M, et al. (2009) Left ventricular endocardial pacing improves resynchronization therapy in canine left bundle-branch hearts. Circ Arrhythm Electrophysiol 2: 580-587.
- Ginks MR, Lambiase PD, Duckett SG, Bostock J, Chinchapatnam P, et al. (2011) A simultaneous X-Ray/MRI and noncontact mapping study of the acute hemodynamic effect of left ventricular endocardial and epicardial cardiac resynchronization therapy in humans. Circ Heart Fail 4: 170-179.
- Padeletti L, Pieragnoli P, Ricciardi G, Perrotta L, Grifoni G, et al. (2012) Acute hemodynamic effect of left ventricular endocardial pacing in cardiac resynchronization therapy: assessment by pressure-volume loops. Circ Arrhythm Electrophysiol 5: 460-467.
- Zareba W, Klein H, Cygankiewicz I, Hall WJ, McNitt S, et al. (2011) Effectiveness of Cardiac Resynchronization Therapy by QRS Morphology in the Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy (MADIT-CRT). Circulation 123: 1061-1072.
- Sipahi I, Carrigan TP, Rowland DY, Stambler BS, Fang JC (2011) Impact of QRS duration on clinical event reduction with cardiac resynchronization therapy: meta-analysis of randomized controlled trials. Arch Intern Med 171: 1454-1462.
- Yusuf J, Agrawal DK, Mukhopadhyay S, Mehta V, Trehan V, et al. (2013) Fragmented narrow QRS complex: predictor of left ventricular dyssynchrony in non-ischemic dilated cardiomyopathy. Indian Heart J 65: 172-179.
- Tigen K, Karaahmet T, Gurel E, Cevik C, Nugent K, et al. (2009) The utility of fragmented QRS complexes to predict significant intraventricular dyssynchrony in nonischemic dilated cardiomyopathy patients with a narrow QRS interval. Can J Cardiol 25: 517-522.
- Celikyurt U, Agacdiken A, Sahin T, Al N, Vural A, et al. (2012) Relationship between fragmented QRS and response to cardiac resynchronization therapy. J Interv Card Electrophysiol 35: 337-342.
- Celikyurt U, Agacdiken A, Sahin T, Al N, Kozdag G, et al. (2013) Number of leads with fragmented QRS predicts response to cardiac resynchronization therapy. Clin Cardiol 36: 36-39.
- Stabile G, Bertaglia E, Botto G, Isola F, Mascioli G, et al. (2013) Cardiac Resynchronization Therapy MOdular REgistry: ECG and Rx predictors of response to cardiac resynchronization therapy (NCT01573091). J Cardiovasc Med (Hagerstown) 14: 886-893.
- Chung ES, Leon AR, Tavazzi L, Sun JP, Nihoyannopoulos P, et al. (2008) Results of the Predictors of Response to CRT (PROSPECT) trial. Circulation 117: 2608-2616.
- Beshai JF, Grimm RA, Nagueh SF, Baker JH 2nd, Beau SL, et al. (2007) Cardiac-resynchronization therapy in heart failure with narrow QRS complexes. N Engl J Med 357: 2461-2471.
- Thibault B, Harel F, Ducharme A, White M, Ellenbogen KA, et al. (2013) Cardiac resynchronization therapy in patients with heart failure and a QRS complex <120 milliseconds: the Evaluation of Resynchronization Therapy for Heart Failure (LESSER-EARTH) trial. Circulation 127: 873-881.
- Ruschitzka F, Abraham WT, Singh JP, Bax JJ, Borer JS, et al. (2013) Cardiac-resynchronization therapy in heart failure with a narrow QRS complex. N Engl J Med 369: 1395-1405.
- Albertsen AE, Nielsen JC, Poulsen SH, Mortensen PT, Pedersen AK, et al. (2008) Biventricular pacing preserves left ventricular performance in patients with high-grade atrio-ventricular block: a randomized comparison with DDD(R) pacing in 50 consecutive patients. Europace 10: 314-320.
- Chan JY, Fang F, Zhang Q, Fung JW, Razali O, et al. (2011) Biventricular pacing is superior to right ventricular pacing in bradycardia patients with preserved systolic function: 2-year results of the PACE trial. Eur Heart J 32: 2533-2540.
- Stockburger M, Gómez-Doblas JJ, Lamas G, Alzueta J, Fernández-Lozano I, et al. (2011) Preventing ventricular dysfunction in pacemaker patients without advanced heart failure: results from a multicentre international randomized trial (PREVENT-HF). Eur J Heart Fail 13: 633-641.
- Kindermann M, Hennen B, Jung J, Geisel J, Böhm M, et al. (2006) 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 47: 1927-1937.
- Martinelli Filho M, de Siqueira SF, Costa R, Greco OT, Moreira LF, et al. (2010) Conventional versus biventricular pacing in heart failure and bradyarrhythmia: the COMBAT study. J Card Fail 16: 293-300.
- Curtis AB, Worley SJ, Adamson PB, Chung ES, Niazi I, et al. (2013) Biventricular pacing for atrioventricular block and systolic dysfunction. N Engl J Med 368: 1585-1593.
- Mazza A, Bendini MG, Leggio M, Riva U, Ciardiello C, et al. (2013) Incidence and predictors of heart failure hospitalization and death in permanent pacemaker patients: a single-centre experience over medium-term follow-up. Europace 15: 1267-1272.
- De Sisti A, Márquez MF, Tonet J, Bonny A, Frank R, et al. (2012) Adverse effects of long-term right ventricular apical pacing and identification of patients at risk of atrial fibrillation and heart failure. Pacing Clin Electrophysiol 35: 1035-1043.
- Poole JE, Gleva MJ, Mela T, Chung MK, Uslan DZ, et al. (2010) Complication rates associated with pacemaker or implantable cardioverter-defibrillator generator replacements and upgrade procedures: results from the REPLACE registry. Circulation 122: 1553-1561.