Cardiac Resynchronization Therapy: The Remaining Challenges

DOI: 10.19102/icrm.2012.030406

ERNEST W. LAU, MD

Department of Cardiology, Royal Victoria Hospital, Belfast, UK

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KEYWORDS. anodal capture, cardiac contractility modulation, cardiac resynchronization therapy, mechanical dyssynchrony, multisite left ventricular pacing.

The author reports no conflict of interest for the published content.
Manuscript received December 1, 2011, final version accepted December 19, 2011.

Address correspondence to: Dr. Ernest W. Lau, Department of Cardiology, Royal Victoria Hospital, Grosvenor Road, Belfast BT12 6BA, UK. E-mail: ernest.lau@btinternet.com

Introduction

Cardiac resynchronization therapy (CRT) has come a long way from its inception as a last-ditch attempt to salvage intractable heart failure (HF) in patients with demonstrated electrical dyssynchronies^1–3 to its current status as a routine mainstream therapy recommended for moderate and even mild HF.⁴ The increase in popularity of CRT is due to two main factors: large-scale randomized clinical trials demonstrating symptomatic, morbidity, and mortality benefits,^5–11 and better tools (catheters, leads and pulse generators) that facilitate therapy delivery. Despite the great advances which have been made, CRT still has several major remaining challenges. CRT requires left ventricular (LV) pacing, which is currently most commonly achieved by lead placement within a side branch of the coronary sinus (CS). This is not always successful and often suboptimal due to phrenic nerve stimulation, high LV capture threshold, or lead dislodgement.¹² Even when CS lead placement is successful, ≈30% of CRT recipients do not “respond” by either clinical or echocardiographic parameters.^13–15 Different strategies have been used and explored to improve the clinical and echocardiographic response to CRT, including better patient selection, A-V and V-V delay adjustment, LV pacing site selection, multisite LV and RV pacing, and LV pacing configurations. Although originally developed for use in the presence of electrical dyssynchrony, CRT has been extended to patients with narrow QRS complexes but demonstrated mechanical dyssynchrony, with conflicting results. Finally, the effects of cardiac stimulation by electrical impulses may not be confined to the generation of activation wavefronts and extend to modulation of myocardial contractility. These topics will be reviewed in this article.

Patient selection

Patient selection for CRT is intimately intertwined with therapy optimization: Is non-response a fixed characteristic of the patient or a variable consequence of therapy delivery? In the early days of CRT, the scope for therapy optimization was limited and hence the emphasis was on patient selection. Improved technologies and increased clinical experience have shifted the research focus more towards therapy optimization.

The published guidelines base patient selection for CRT on four basic criteria: 1) New York Heart Association (NYHA) function class; 2) QRS duration and morphology; 3) LV ejection fraction (EF); and 4) optimal medical therapy. Of the four criteria, NYHA class and QRS duration and morphology have seen most refinements in the light of recent clinical trial data. The EF is a crude way of assessing the LV. “Optimal medical therapy” is not precisely defined and subjective.

New York Heart Association function class

CRT is now indicated for NYHA class II as well as NYHA class III–IV HF⁴ due to the morbidity, mortality and LV remodeling benefits from early intervention with CRT in NYHA class II patients demonstrated in randomized clinical trials.^9,10,16–18

QRS duration and morphology

An increased QRS duration on the surface electrocardiogram (ECG) is the most commonly used criterion of electrical dyssynchrony, probably because it is simple, readily accessible and cheap. However, the QRS duration may vary in a patient (e.g. depending on the prevailing ventricular rate) and differ when assessed by a machine and a human observer. The QRA duration qualifying for CRT varies from ≥120 ms for NYHA class III–IV to ≥150 ms for NYHA class II, an inverse relationship between HF and electrical dyssynchrony severity.⁴ Patients with broader QRS complexes (≥150 ms) benefited more from CRT than patients with less broad QRS complexes (120–150 ms) in randomized clinical trials,^9,10 but a QRS complex duration of ≥150 ms alone does not guarantee clinical or echocardiographic response.^19,20

In the context of CRT, broad QRS complexes can be classified into four major patterns: left bundle branch block (LBBB), right bundle branch block (RBBB), non-specific intraventricular conduction delay (IVCD), and RV-only pacing. Patients with LBBB benefit most from CRT, whereas patients without LBBB (i.e. RBBB, IVCD, and RV-only pacing) benefit little if at all, in terms of morbidity, mortality, LV remodeling and ventricular arrhythmia reduction in randomized clinical trials.^10,21 However, patients with RBBB and left intraventricular mechanical dyssynchrony may still benefit from CRT.²² Despite its impact on clinical response, QRS morphology classification is not a selection criterion for CRT in the latest guidelines. Patients with advanced HF (NYHA class III–IV) needing pacing are still recommended to receive CRT (level of evidence I–IIa).⁴

Left ventricular assessment

In a simplistic model, CRT improves clinical outcomes by reducing electrical and hence mechanical dyssynchrony within the heart. Mechanical dyssynchrony should thus predispose to or may even be a prerequisite for response to CRT, and many imaging modalities have been used to assess its presence and extent. Even though there are different forms of mechanical dyssynchrony involving all the heart chambers (interatrial, atrioventricular, interventricular, LV intraventricular, and intramural),¹⁵ investigation has focused on the LV as it is the major pumping chamber of the heart. LVEF is a measure of global rather than regional LV systolic function and does not predict response to CRT. Structural abnormalities within the LV myocardium (scarring, fibrosis, infiltration) can cause systolic and diastolic dysfunction and affect response to CRT.

Echocardiography is the most popular imaging modality for investigating the heart for CRT. The methods which have been used for this purpose include M-mode,^23–26 Doppler,^8,27 pulsed-wave²⁸ and color-coded^13,29,30 tissue Doppler, longitudinal^31,32 and radial³³ strain and strain rate, speckle (two-dimensional-derived strain) tracking,^34–37 and real-time three-dimensional mode.^38–40 Numerous indices based on these methods have been devised, with different cut-off values for separating responders from non-responders, but none has emerged as clearly superior. When 12 echocardiographic conventional and tissue Doppler parameters were tested in a multicenter clinical trial, they showed only modest interobserver concordance and predictive power for response to CRT.⁴¹

Cardiac magnetic resonance imaging (MRI) can assess cardiac dimensions, velocities in all orientations,^42–44 strain rate (through tagging),^45,46 and tissue viability (through gadolinium contrast uptake),^47,48 making it extremely suitable for evaluation of mechanical dyssynchrony and myocardial scarring.⁴⁹ Apart from mechanical dyssynchrony, the site and extent (burden) of myocardial scarring may also determine response to CRT.^50,51 However, MRI may not be safely performed in the presence of foreign metal objects, including cardiovascular implantable electronic devices (CIEDs), in the body. This used to mean that patients considered for CRT could only be assessed with MRI before but not after device implantation. MRI-compatible pacemakers are now commercially available,⁵² and it is only a matter of time before MRI-compatible technologies are extended to CRT devices. However, MRI compatibility may be restricted to certain magnetic field strengths (e.g. 1.5 tesla) for the scanner. MRI-compatible CIEDs still cast significant artifacts in the MR image depending on the physical sizes and ferromagnetic contents of the components (Figure 1).

Radionuclide angiography^53,54 and ECG-gated single photon emission computed tomography (SPECT) myocardial perfusion imaging⁵⁵ have also been explored for use in assessing LV dyssynchrony.

A-V and V-V delays adjustment

The A-V and V-V delays are programmable parameters in a CRT device and provide a possible means of non-invasively improving response to CRT through their adjustment.^56,57 Two major approaches are currently used to guide their adjustment: echocardiography and intracardiac electrograms (IEGMs). Echocardiography-directed adjustment can be by many different methods (e.g. the Ritter's formula, the iterative technique),^58,59 but LV outflow tract velocity–time integral (VTI) (a surrogate measure of stroke measure) maximization is probably the most popular in practice.^60,61 IEGM-directed adjustment is by proprietary algorithms developed by different CIED manufacturers recommending values for the A-V and V-V delays on the basis of the intracardiac atrial, RV and LV signals.^62–64

Delays adjustment by echocardiography can be very time-consuming and operator dependent. Delays adjustment by IEGM methods depends critically on the validity of the algorithms used, which were derived empirically from observed clinical data without any underlying physiological bases.^62–64 The A-V and V-V delays “optimal” by whatever criteria vary with the prevailing atrial rate (such as with exercise)^65,66 and over time,^67–69 which means delays adjustment should be repeated periodically.⁷⁰ This largely precludes the use of invasive hemodynamic measurement (e.g. LV dP/dt) for this purpose.⁷¹ In contrast, intracardiac impedance may provide a new approach to delays adjustment,⁷² with the potential of being incorporated into future generations of CIEDs as an automated feature. “Optimal” values by different methods do not always agree.^73,74 Improvement of the surrogate measures used for guiding delays adjustment may not translate into enhanced echocardiographic or clinical response to CRT.^70,75 Patients with atrial fibrillation cannot be programmed to have the LV paced ahead of the RV unless intrinsic conduction through the atrioventricular node is suppressed by a high lower rate setting on the device, drugs, or ablation.

Left ventricular pacing site selection

The “optimal” site for LV pacing can be chosen on several theoretical bases: latest electrical activation;⁷⁶ avoidance of slow electrical conduction areas;⁷⁷ latest mechanical activation;^78–82 avoidance of myocardial scars;^50,78,83 and maximum or minimum hemodynamic parameters (e.g. cardiac output; stroke work, LV dP/dt, LVEF).⁸⁴

With conventional transvenous epicardial CS lead placement, selection of the LV pacing site is heavily constrained by the CS venous anatomy. A lead may not be placed at a desired site because of lack of a suitable side branch, high LV capture threshold, repeat lead dislodgement, or phrenic nerve stimulation.¹² In practice, some degree of CS lead placement site selection is still possible. The longest local LV electrical delay (compared to the surface QRS complex)⁷⁶ or maximum hemodynamic enhancement (e.g. on pressure–volume loop analyses)⁸⁴ can be assessed intraoperatively and are more suitable for this purpose than correlating the CS venous anatomy revealed intraoperatively by retrograde venography⁸⁵ or preoperatively by multislice computed tomography^86,87 with a desired pacing site identified preoperatively by echocardiography or cardiac MRI, which can be at best only approximate.

Surgical epicardial LV lead placement offers more choices on the pacing site than transvenous epicardial CS lead placement, but is inevitably more invasive^88–93 and hence used mainly as a second-line option. Correlating the lead placement site intraoperatively with a desired site identified preoperatively with an imaging modality will still be difficult, but invasive intraoperative hemodynamic assessment can be used to guide lead placement.⁹⁴ Implanting a pacing lead on a moving target that is the epicardial surface of a beating heart can be technically challenging if the pericardial sac is opened or the desired site is on the posterior surface. Epicardial fat may obscure the underlying cardiac anatomy. Surgically placed epicardial pacing leads have a much higher failure rate than transvenously placed leads,⁹⁵ and extraction and replacement will require repeat open chest surgery.

Endocardial LV lead placement has emerged as an alternative technique for achieving LV pacing in CRT.¹² Enodcardial LV lead placement can be achieved transvenously through a transseptal puncture (Figure 2),^96–105 or surgically through a LV apical puncture from the epicardial surface.^106–108 The transseptal approach is less invasive than the transapical approach. Even when the transapical puncture is performed percutaneously under echocardiographic guidance, hemostasis around the puncture site and fixation of the lead to the epicardial surface still require open chest surgical access.¹⁰⁸ Regardless of the approach, endocardial LV lead placement carries the risk of systemic thromboembolism (including stroke) and the need for long-term oral anticoagulation. The transseptal approach requires the endocardial LV lead crossing the mitral valve, with the potential of causing valvular stenosis, regurgitation, leaflet perforation, chordal rupture, or infective endocarditis. However, the pacing lead can theoretically be placed anywhere on the endocardial surface of the LV cavity, opening up the opportunity of “optimization” such as guided by hemodynamic parameters.^109–111 Endocardial LV pacing is more physiological and hemodynamically effective, and should be less pro-arrhythmic, than epicardial LV pacing.^112–115

Multisite left and right ventricular pacing

Multisite (≥3) ventricular pacing has been explored as a means of enhancing response to CRT. The combinations which have been tried include (2 RV sites + 1 LV site) and (1 RV site + ≥2 LV sites).

The (2 RV sites + 1 LV site) combination has two leads in the RV (at the apex and in the outflow tract) and one lead in the CS, and has been shown to be beneficial in some patients,¹¹⁶ especially with enlarged LV diastolic volume.¹¹⁷

The (1 RV site + ≥2 LV sites) combination has one lead in the RV and one or two leads in the CS. The two LV pacing sites can be radially separated (2 CS leads into 2 separate side branches – usually one posterior-lateral and one anterior-lateral) or longitudinally separated (the different poles of a quadripolar lead in one CS side branch). The (1 RV lead + 2 CS leads in 2 different side branches) combination did not demonstrate consistent benefits in previous clinical studies,^118,119 but a larger scale study is ongoing.¹²⁰ The (1 RV lead + 2 pacing sites on 1 quadripolar CS lead) combination may offer some minor extra hemodynamic benefits in patients with posterior-lateral LV scar compared with conventional (1 RV lead + 1 pacing site on 1 CS lead) combination in an electromechanical biophysical model of the human heart,¹²¹ but generally speaking does not produce as significant hemodynamic changes as two radially separated LV pacing sites.^122,123 On the other hand, there are data suggesting that LV only pacing with one lead may not be inferior to conventional RV + LV pacing.¹²⁴

Left ventricular pacing configurations

Experimentally, the myocardium can be electrically activated either during (make) or after (break) a cathodal (negative) or an anodal (positive) impulse delivered from a single electrode.¹²⁵ The impulse generates a “dog-bone” shape area of identical polarity across the direction of myocardial fibers in the immediate vicinity of the physical electrode, and two areas of opposite polarity within the concavities of the dog-bone shape along the direction of the myocardial fibers further away from the physical electrode. These areas of identical and opposite polarities are larger than the physical size of the actual electrode and give rise to “virtual electrodes” (Figure 3).¹²⁶ For “make” stimulation, the virtual cathode initiates wavefront activation whereas the virtual anode impedes wavefront propagation. For “break” stimulation, the virtual anode initiates wavefront activation whereas the virtual cathode impedes wavefront propagation. The higher the impulse amplitude, the larger the sizes of these virtual electrodes, and the further away from the physical electrode electrical activation starts. Activation wavefronts propagate faster along than across the direction of myocardial fibers. Based on these principles, anodal “make” stimulation will be more effective than conventional cathodal “make” stimulation in initiating wider and faster myocardial activation – there will be two simultaneous activation wavefronts starting further away from the physical electrodes and propagating faster along the direction of myocardial fibers. Cathodal “break” stimulation theoretically generates an activation pattern similar to that of anodal “make” stimulation, but “break” stimulation is not useful in practice as the impulse has to be delivered at a time when the myocardium is refractory (to avoid “make” stimulation) and generally requires a higher current density, with the potential of myocardial damage and localized hydrolysis around the physical electrode. Interestingly, apart from a higher pacing output and faster myocardial conduction velocities, anodal pacing was also associated with increased myocardial contractility compared to cathodal pacing in animal studies.^127,128

Clinically, increasing the output of LV cathodal pacing shortens the QRS duration and LV–RV interventricular delay, but this might be due to RV anodal capture in some cases.^129,130 Deliberate anodal pacing increased the LV outflow tract VTI by around 15% compared with cathodal pacing, regardless of whether it was LV only, unipolar (indifferent electrode at the skin), or extended bipolar (indifferent electrode at the RV coil).¹³¹ Gradual increases in the LV pacing output from a true bipolar CS lead attached to a CRT device caused abrupt changes in the QRS morphology, shortening of the QRS duration and LV–RV interventricular delay, and lengthening of the QTc and JTc, possibly as a result of reaching the anodal capture threshold.¹³² These effects were more marked for CS leads with longer tip-ring electrode spacing, and less likely to occur for leads with a bigger ring electrode area (and lower anodal current density).

While the electromechanical benefits of LV anodal capture are worth exploring, the costs of a higher pacing output (and hence reduced battery longevity) and the pro-arrhythmic effects of a longer QTc need to be borne in mind. It is unclear whether LV anodal capture from the endocardial surface will be substantially different from the epicardial surface. RV anodal capture has been associated with non-response to CRT, but that could be the reflection of a suboptimal LV placement site necessitating the use of a the RV coil or ring electrode as part of the LV pacing circuit.¹³³

Patients with narrow QRS complexes

LV mechanical systolic and diastolic dyssynchrony by tissue Doppler imaging was found in 51% and 46% respectively of HF patients with narrow QRS complexes, compared with 73% and 69% respectively of HF patients with wide QRS complexes, in one study.¹³⁴ This and other similar studies^135,136 spurred interest in extending the indications of CRT to HF patients with narrow QRS complexes (and hence no evidence of electrical dyssynchrony) but evidence of mechanical dyssynchrony on echocardiography. While some observational studies showed benefits of CRT in such patients,^137–140 this was not supported by randomized clinical trials.¹⁴¹ At the moment, the role of CRT in patients with narrow QRS complexes but mechanical dyssynchrony is unclear. Mechanical dyssynchrony in the absence of electrical dyssynchrony implies intramural not electrical dyssynchrony. Biventricular pacing is not so much “resynchronizing” the electrical activation heart as “pre-exciting” areas of the myocardium with long electromechanical activation delays. LV pacing site selection by intraoperative hemodynamic measurement may improve the response to CRT in HF patients with mechanical dyssynchrony and narrow QRS complexes.¹⁴²

Effects of cardiac stimulation by electrical impulses

Originally, CRT or biventricular pacing was developed to reverse electrical dyssynchrony, which presumably caused mechanical dyssynchrony, and hence reduced cardiac efficiency and hence failure. Biventricular pacing in HF patients with narrow QRS complexes and mechanical dyssynchrony is mechanical resynchronization through deliberate electrical dyssynchronization. However, the effects of cardiac stimulation with an electric impulse may not be confined to the production of one or more activation wavefronts propagating through the myocardium. Anodal stimulation increases myocardial contractility and conduction compared with cathodal pacing,^127,128 suggesting an electrical impulse may affect myocardial contractility in ways independent of its electrical activation. Non-excitatory electrical impulses delivered to the myocardium during its refractory period can improve its contractiliy, a concept called cardiac contractility modulation (CCM).¹⁴³ The inotropic effects on CMM have been demonstrated in HF patients,^144–146 and are associated with LV remodeling and systolic improvement unrelated to LV diastolic function or mechanical dyssynchrony¹⁴⁷ without increases in myocardial oxygen consumption or metabolic demands.^148,149 However, the high electrical stimulus output (around 5.8–7.7-V output at 20-ms pulse width) required to achieve CCM means the responsible pulse generator needs to be recharged with energy frequently through induction, which forms a major barrier to the widespread utilization of the treatment. Although there was no excess hospitalization or mortality, long-term CCM did not improve the ventilatory anaerobic threshold in a large-scale clinical study except in a retrospectively identified subgroup.^150–152

Conclusions

CRT straddles three different cardiac subspecialties: HF, electrophysiology, and imaging, which adds to the complexity of its study and refinement. Even though CRT is an established clinical treatment, there are still many aspects around it which have not been completely elucidated and are under active investigation. Better coordination of research efforts into larger scale, multicenter randomized prospective clinical studies will help clarify the conflicting data around many of these issues and more effectively guide clinical practice. The non-excitatory physiologic effects of electrical stimulation of the heart may be used to enhance myocardial contractility, extending the scope of cardiac stimulation (in contradistinction to just resynchronization) therapy even further to include patients with failing myocardium but neither electrical nor mechanical dyssynchrony.

References

1. Cazeau S, Ritter P, Bakdach S, Lazarus A, Limousin M, Henao L, et al. Four chamber pacing in dilated cardiomyopathy. Pacing Clin Electrophysiol 1994; 17:1974–1979. [CrossRef] [PubMed]
2. Cazeau S, Ritter P, Lazarus A, Gras D, Backdach H, Mundler O, et al. Multisite pacing for end-stage heart failure: early experience. Pacing Clin Electrophysiol 1996; 19:1748–1757. [CrossRef] [PubMed]
3. Bakker PF, Meijburg HW, de Vries JW, Mower MM, Thomas AC, Hull ML, et al. Biventricular pacing in end-stage heart failure improves functional capacity and left ventricular function. J Interv Card Electrophysiol 2000; 4:395–404. [CrossRef] [PubMed]
4. Dickstein K, Vardas PE, Auricchio A, Daubert JC, Linde C, McMurray J, 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; 31:2677–2687. [CrossRef] [PubMed]
5. Cazeau S, Leclercq C, Lavergne T, Walker S, Varma C, Linde C, et al. Effects of multisite biventricular pacing in patients with heart failure and intraventricular conduction delay. N Engl J Med 2001; 344:873–880. [CrossRef] [PubMed]
6. Abraham WT, Fisher WG, Smith AL, Delurgio DB, Leon AR, Loh E, et al. Cardiac resynchronization in chronic heart failure. N Engl J Med 2002; 346:1845–1853. [CrossRef] [PubMed]
7. Bristow MR, Saxon LA, Boehmer J, Krueger S, Kass DA, De MT, et al. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med 2004; 350:2140–2150. [CrossRef] [PubMed]
8. Cleland JG, Daubert JC, Erdmann E, Freemantle N, Gras D, et al. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med 2005; 352:1539–1549. [CrossRef] [PubMed]
9. Moss AJ, Hall WJ, Cannom DS, Klein H, Brown MW, Daubert JP, et al. Cardiac-resynchronization therapy for the prevention of heart-failure events. N Engl J Med 2009; 361:1329–1338. [CrossRef] [PubMed]
10. Tang AS, Wells GA, Talajic M, Arnold MO, Sheldon R, Connolly S, et al. Cardiac-resynchronization therapy for mild-to-moderate heart failure. N Engl J Med 2010; 363:2385–2395. [CrossRef] [PubMed]
11. Wells G, Parkash R, Healey JS, Talajic M, Arnold JM, Sullivan S, et al. Cardiac resynchronization therapy: a meta-analysis of randomized controlled trials. CMAJ 2011; 183:421–429. [CrossRef] [PubMed]
12. Lau EW. Achieving permanent left ventricular pacing-options and choice. Pacing Clin Electrophysiol 2009; 32:1466–1477. [CrossRef] [PubMed]
13. Bax JJ, Bleeker GB, Marwick TH, Molhoek SG, Boersma E, Steendijk P, et al. Left ventricular dyssynchrony predicts response and prognosis after cardiac resynchronization therapy. J Am Coll Cardiol 2004; 44:1834–1840. [CrossRef] [PubMed]
14. Bax JJ, Abraham T, Barold SS, Breithardt OA, Fung JW, Garrigue S, et al. Cardiac resynchronization therapy: Part 1—issues before device implantation. J Am Coll Cardiol 2005; 46:2153–2167. [CrossRef] [PubMed]
15. Ypenburg C, Westenberg JJ, Bleeker GB, Van de Veire N, Marsan NA, Henneman MM, et al. Noninvasive imaging in cardiac resynchronization therapy—part 1: selection of patients. Pacing Clin Electrophysiol 2008; 31:1475–1499. [CrossRef] [PubMed]
16. Linde C, Abraham WT, Gold MR, St John SM, Ghio S, Daubert C. 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; 52:1834–1843. [CrossRef] [PubMed]
17. St John SM, Ghio S, Plappert T, Tavazzi L, Scelsi L, Daubert C, et al. Cardiac resynchronization induces major structural and functional reverse remodeling in patients with New York Heart Association class I/II heart failure. Circulation 2009; 120:1858–1865. [CrossRef] [PubMed]
18. Daubert C, Gold MR, Abraham WT, Ghio S, Hassager C, Goode G, 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; 54:1837–1846. [CrossRef] [PubMed]
19. Kashani A, Barold SS. Significance of QRS complex duration in patients with heart failure. J Am Coll Cardiol 2005; 46:2183–2192. [CrossRef] [PubMed]
20. Mollema SA, Bleeker GB, van der Wall EE, Schalij MJ, Bax JJ. Usefulness of QRS duration to predict response to cardiac resynchronization therapy in patients with end-stage heart failure. Am J Cardiol 2007; 100:1665–1670. [CrossRef] [PubMed]
21. Zareba W, Klein H, Cygankiewicz I, Hall WJ, McNitt S, Brown M, et al. Effectiveness of cardiac resynchronization therapy by QRS morphology in the Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy (MADIT-CRT). Circulation 2011; 123:1061–1072. [CrossRef] [PubMed]
22. Garrigue S, Reuter S, Labeque JN, Jais P, Hocini M, Shah DC, et al. Usefulness of biventricular pacing in patients with congestive heart failure and right bundle branch block. Am J Cardiol 2011; 88:1436–41, A8. [CrossRef] [PubMed]
23. Pitzalis MV, Iacoviello M, Romito R, Massari F, Rizzon B, Luzzi G, et al. Cardiac resynchronization therapy tailored by echocardiographic evaluation of ventricular asynchrony. J Am Coll Cardiol 2002; 40:1615–1622. [CrossRef] [PubMed]
24. Pitzalis MV, Iacoviello M, Romito R, Guida P, De TE, Luzzi G, et al. Ventricular asynchrony predicts a better outcome in patients with chronic heart failure receiving cardiac resynchronization therapy. J Am Coll Cardiol 2005; 45: 65–69. [CrossRef] [PubMed]
25. Marcus GM, Rose E, Viloria EM, Schafer J, De MT, Saxon LA, et al. Septal to posterior wall motion delay fails to predict reverse remodeling or clinical improvement in patients undergoing cardiac resynchronization therapy. J Am Coll Cardiol 2005; 46:2208–2214. [CrossRef] [PubMed]
26. Diaz-Infante E, Sitges M, Vidal B, Mont L, Delgado V, Marigliano A, et al. Usefulness of ventricular dyssynchrony measured using M-mode echocardiography to predict response to resynchronization therapy. Am J Cardiol 2007; 100:84–89. [CrossRef] [PubMed]
27. Cazeau S, Bordachar P, Jauvert G, Lazarus A, Alonso C, Vandrell MC, et al. Echocardiographic modeling of cardiac dyssynchrony before and during multisite stimulation: a prospective study. Pacing Clin Electrophysiol 2003; 26: 137–143. [CrossRef] [PubMed]
28. Penicka M, Bartunek J, De BB, Vanderheyden M, Goethals M, De ZM, et al. Improvement of left ventricular function after cardiac resynchronization therapy is predicted by tissue Doppler imaging echocardiography. Circulation 2004; 109:978–983. [CrossRef] [PubMed]
29. Yu CM, Chau E, Sanderson JE, Fan K, Tang MO, Fung WH, et al. Tissue Doppler echocardiographic evidence of reverse remodeling and improved synchronicity by simultaneously delaying regional contraction after biventricular pacing therapy in heart failure. Circulation 2002; 105:438–445. [CrossRef] [PubMed]
30. Notabartolo D, Merlino JD, Smith AL, Delurgio DB, Vera FV, Easley KA, et al. Usefulness of the peak velocity difference by tissue Doppler imaging technique as an effective predictor of response to cardiac resynchronization therapy. Am J Cardiol 2004; 94:817–820. [CrossRef] [PubMed]
31. Popovic ZB, Grimm RA, Perlic G, Chinchoy E, Geraci M, Sun JP, et al. Noninvasive assessment of cardiac resynchronization therapy for congestive heart failure using myocardial strain and left ventricular peak power as parameters of myocardial synchrony and function. J Cardiovasc Electrophysiol 2002; 13:1203–1208. [CrossRef] [PubMed]
32. Yu CM, Zhang Q, Chan YS, Chan CK, Yip GW, Kum LC, et al. Tissue Doppler velocity is superior to displacement and strain mapping in predicting left ventricular reverse remodelling response after cardiac resynchronisation therapy. Heart 2006; 92:1452–1456. [CrossRef] [PubMed]
33. Dohi K, Suffoletto MS, Schwartzman D, Ganz L, Pinsky MR, Gorcsan J, III. Utility of echocardiographic radial strain imaging to quantify left ventricular dyssynchrony and predict acute response to cardiac resynchronization therapy. Am J Cardiol 2005; 96:112–116. [CrossRef] [PubMed]
34. Becker M, Bilke E, Kuhl H, Katoh M, Kramann R, Franke A, et al. Analysis of myocardial deformation based on pixel tracking in two dimensional echocardiographic images enables quantitative assessment of regional left ventricular function. Heart 2006; 92:1102–1108. [CrossRef] [PubMed]
35. Suffoletto MS, Dohi K, Cannesson M, Saba S, Gorcsan J, III. Novel speckle-tracking radial strain from routine black-and-white echocardiographic images to quantify dyssynchrony and predict response to cardiac resynchronization therapy. Circulation 2006; 113:960–968. [CrossRef] [PubMed]
36. Gorcsan J, III, Tanabe M, Bleeker GB, Suffoletto MS, Thomas NC, Saba S, et al. Combined longitudinal and radial dyssynchrony predicts ventricular response after resynchronization therapy. J Am Coll Cardiol 2007; 50:1476–1483. [CrossRef] [PubMed]
37. Delgado V, Ypenburg C, van Bommel RJ, Tops LF, Mollema SA, Marsan NA, et al. Assessment of left ventricular dyssynchrony by speckle tracking strain imaging comparison between longitudinal, circumferential, and radial strain in cardiac resynchronization therapy. J Am Coll Cardiol 2008; 51: 1944–1952. [CrossRef] [PubMed]
38. Kapetanakis S, Kearney MT, Siva A, Gall N, Cooklin M, Monaghan MJ. Real-time three-dimensional echocardiography: a novel technique to quantify global left ventricular mechanical dyssynchrony. Circulation 2005; 112:992–1000. [CrossRef] [PubMed]
39. Marsan NA, Henneman MM, Chen J, Ypenburg C, Dibbets P, Ghio S, et al. Real-time three-dimensional echocardiography as a novel approach to quantify left ventricular dyssynchrony: a comparison study with phase analysis of gated myocardial perfusion single photon emission computed tomography. J Am Soc Echocardiogr 2008; 21:801–807. [CrossRef] [PubMed]
40. Marsan NA, Bleeker GB, Ypenburg C, Ghio S, van de Veire NR, Holman ER, et al. Real-time three-dimensional echocardiography permits quantification of left ventricular mechanical dyssynchrony and predicts acute response to cardiac resynchronization therapy. J Cardiovasc Electrophysiol 2008; 19:392–399. [CrossRef] [PubMed]
41. Chung ES, Leon AR, Tavazzi L, Sun JP, Nihoyannopoulos P, Merlino J, et al. Results of the Predictors of Response to CRT (PROSPECT) trial. Circulation 2008; 117:2608–2616. [CrossRef] [PubMed]
42. Markl M, Schneider B, Hennig J. Fast phase contrast cardiac magnetic resonance imaging: improved assessment and analysis of left ventricular wall motion. J Magn Reson Imaging 2002; 15:642–653. [CrossRef] [PubMed]
43. Westenberg JJ, Lamb HJ, van der Geest RJ, Bleeker GB, Holman ER, Schalij MJ, et al. Assessment of left ventricular dyssynchrony in patients with conduction delay and idiopathic dilated cardiomyopathy: head-to-head comparison between tissue Doppler imaging and velocity-encoded magnetic resonance imaging. J Am Coll Cardiol 2006; 47:2042–2048. [CrossRef] [PubMed]
44. Delfino JG, Bhasin M, Cole R, Eisner RL, Merlino J, Leon AR, et al. Comparison of myocardial velocities obtained with magnetic resonance phase velocity mapping and tissue Doppler imaging in normal subjects and patients with left ventricular dyssynchrony. J Magn Reson Imaging 2006; 24:304–311. [CrossRef] [PubMed]
45. Zwanenburg JJ, Gotte MJ, Marcus JT, Kuijer JP, Knaapen P, Heethaar RM, et al. Propagation of onset and peak time of myocardial shortening in time of myocardial shortening in ischemic versus nonischemic cardiomyopathy: assessment by magnetic resonance imaging myocardial tagging. J Am Coll Cardiol 2005; 46:2215–2222. [CrossRef] [PubMed]
46. Zwanenburg JJ, Gotte MJ, Kuijer JP, Heethaar RM, van Rossum AC, Marcus JT. Timing of cardiac contraction in humans mapped by high-temporal-resolution MRI tagging: early onset and late peak of shortening in lateral wall. Am J Physiol Heart Circ Physiol 2004; 286:H1872–H1880. [CrossRef] [PubMed]
47. Kim RJ, Fieno DS, Parrish TB, Harris K, Chen EL, Simonetti O, et al. Relationship of MRI delayed contrast enhancement to irreversible injury, infarct age, and contractile function. Circulation 1999; 100:1992–2002. [CrossRef] [PubMed]
48. Kaandorp TA, Lamb HJ, van der Wall EE, de RA, Bax JJ. Cardiovascular MR to access myocardial viability in chronic ischaemic LV dysfunction. Heart 2005; 91: 1359–1365. [CrossRef] [PubMed]
49. Lardo AC, Abraham TP, Kass DA. Magnetic resonance imaging assessment of ventricular dyssynchrony: current and emerging concepts. J Am Coll Cardiol 2005; 46:2223–2228. [CrossRef] [PubMed]
50. Bleeker GB, Kaandorp TA, Lamb HJ, Boersma E, Steendijk P, de RA, et al. Effect of posterolateral scar tissue on clinical and echocardiographic improvement after cardiac resynchronization therapy. Circulation 2006; 113:969–976. [CrossRef] [PubMed]
51. Ypenburg C, Roes SD, Bleeker GB, Kaandorp TA, de RA, Schalij MJ, et al. Effect of total scar burden on contrast-enhanced magnetic resonance imaging on response to cardiac resynchronization therapy. Am J Cardiol 2007; 99:657–660. [CrossRef] [PubMed]
52. Shinbane JS, Colletti PM, Shellock FG. Magnetic resonance imaging in patients with cardiac pacemakers: era of “MR Conditional” designs. J Cardiovasc Magn Reson 2011; 13:63.:63. [CrossRef] [PubMed]
53. Kerwin WF, Botvinick EH, O'Connell JW, Merrick SH, DeMarco T, Chatterjee K, et al. Ventricular contraction abnormalities in dilated cardiomyopathy: effect of biventricular pacing to correct interventricular dyssynchrony. J Am Coll Cardiol 2000; 35:1221–1227. [CrossRef] [PubMed]
54. O'Connell JW, Schreck C, Moles M, Badwar N, DeMarco T, Olgin J, et al. A unique method by which to quantitate synchrony with equilibrium radionuclide angiography. J Nucl Cardiol 2005; 12:441–450. [CrossRef] [PubMed]
55. Chen J, Garcia EV, Bax JJ, Iskandrian AE, Borges-Neto S, Soman P. SPECT myocardial perfusion imaging for the assessment of left ventricular mechanical dyssynchrony. J Nucl Cardiol 2011; 18:685–694. [CrossRef] [PubMed]
56. Auricchio A, Stellbrink C, Block M, Sack S, Vogt J, Bakker P, et al. Effect of pacing chamber and atrioventricular delay on acute systolic function of paced patients with congestive heart failure. The Pacing Therapies for Congestive Heart Failure Study Group. The Guidant Congestive Heart Failure Research Group. Circulation 1999; 99:2993–3001. [CrossRef] [PubMed]
57. Auricchio A, Ding J, Spinelli JC, Kramer AP, Salo RW, Hoersch W, et al. Cardiac resynchronization therapy restores optimal atrioventricular mechanical timing in heart failure patients with ventricular conduction delay. J Am Coll Cardiol 2002; 39:1163–1169. [CrossRef] [PubMed]
58. Ritter P, Daubert C, Mabo P, Descaves C, Gouffault J. Haemodynamic benefit of a rate-adapted A-V delay in dual chamber pacing. Eur Heart J 1989; 10:637–646. [CrossRef] [PubMed]
59. Lane RE, Chow AW, Chin D, Mayet J. Selection and optimisation of biventricular pacing: the role of echocardiography. Heart 2004; 90(Suppl 6):vi10–16. [CrossRef] [PubMed]
60. Riedlbauchova L, Kautzner J, Fridl P. Influence of different atrioventricular and interventricular delays on cardiac output during cardiac resynchronization therapy. Pacing Clin Electrophysiol 2005; 28(Suppl 1):S19–23. [CrossRef] [PubMed]
61. Jansen AH, Bracke FA, van Dantzig JM, Meijer A, van der Voort PH, Aarnoudse W, et al. Correlation of echo-Doppler optimization of atrioventricular delay in cardiac resynchronization therapy with invasive hemodynamics in patients with heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol 2006; 97:552–557. [CrossRef] [PubMed]
62. Baker JH, McKenzie J, III, Beau S, Greer GS, Porterfield J, Fedor M, et al. Acute evaluation of programmer-guided AV/PV and VV delay optimization comparing an IEGM method and echocardiogram for cardiac resynchronization therapy in heart failure patients and dual-chamber ICD implants. J Cardiovasc Electrophysiol 2007; 18:185–191. [CrossRef] [PubMed]
63. Min X, Meine M, Baker JH, Pires LA, Turk KT, Horn EM, et al. Estimation of the optimal VV delay by an IEGM-based method in cardiac resynchronization therapy. Pacing Clin Electrophysiol 2007; 30 (Suppl 1): S19–22. [CrossRef] [PubMed]
64. Gold MR, Niazi I, Giudici M, Leman RB, Sturdivant JL, Kim MH, et al. A prospective comparison of AV delay programming methods for hemodynamic optimization during cardiac resynchronization therapy. J Cardiovasc Electro-physiol 2007; 18:490–496. [CrossRef] [PubMed]
65. Bordachar P, Lafitte S, Reuter S, Serri K, Garrigue S, Laborderie J, et al. Echocardiographic assessment during exercise of heart failure patients with cardiac resynchronization therapy. Am J Cardiol 2006; 97:1622–1625. [CrossRef] [PubMed]
66. Golovchiner G, Dorian P, Mangat I, Korley V, Ahmad K, Sharef K, et al. Electrogram-based optimal atrioventricular and interventricular delays of cardiac resynchronization change individually during exercise. Can J Cardiol 2011; 27:351–357. [CrossRef] [PubMed]
67. O'Donnell D, Nadurata V, Hamer A, Kertes P, Mohamed U. Long-term variations in optimal programming of cardiac resynchronization therapy devices. Pacing Clin Electrophysiol 2005; 28(Suppl 1):S24–26. [CrossRef] [PubMed]
68. Zhang Q, Fung JW, Chan YS, Chan HC, Lin H, Chan S, et al. The role of repeating optimization of atrioventricular interval during interim and long-term follow-up after cardiac resynchronization therapy. Int J Cardiol 2008; 124:211–217. [CrossRef] [PubMed]
69. Porciani MC, Dondina C, Macioce R, Demarchi G, Cappelli F, Lilli A, et al. Temporal variation in optimal atrioventricular and interventricular delay during cardiac resynchronization therapy. J Card Fail 2006; 12:715–719. [CrossRef] [PubMed]
70. Abraham WT, Gras D, Yu CM, Guzzo L, Gupta MS. Rationale and design of a randomized clinical trial to assess the safety and efficacy of frequent optimization of cardiac resynchronization therapy: the Frequent Optimization Study Using the QuickOpt Method (FREEDOM) trial. Am Heart J 2010; 159:944–948. [CrossRef] [PubMed]
71. van Gelder BM, Bracke FA, Meijer A, Lakerveld LJ, Pijls NH. Effect of optimizing the VV interval on left ventricular contractility in cardiac resynchronization therapy. Am J Cardiol 2004; 93:1500–1503. [CrossRef] [PubMed]
72. Bocchiardo M, Meyer zu Vilsendorf D, Militello C, Lippert M, Czygan G, Schauerte P, et al. Resynchronization therapy optimization by intracardiac impedance. Europace 2010; 12:1589–1595. [CrossRef] [PubMed]
73. van Gelder BM, Meijer A, Bracke FA. The optimized V-V interval determined by interventricular conduction times versus invasive measurement by LVdP/dtMAX. J Cardiovasc Electrophysiol 2008; 19:939–944. [CrossRef] [PubMed]
74. Kamdar R, Frain E, Warburton F, Richmond L, Mullan V, Berriman T, et al. A prospective comparison of echocardiography and device algorithms for atrioventricular and interventricular interval optimization in cardiac resynchronization therapy. Europace 2010; 12:84–91. [CrossRef] [PubMed]
75. Ellenbogen KA, Gold MR, Meyer TE, Fernndez Lozano I, Mittal S, Waggoner AD, et al. Primary results from the SmartDelay determined AV optimization: a comparison to other AV delay methods used in cardiac resynchronization therapy (SMART-AV) trial: a randomized trial comparing empirical, echocardiography-guided, and algorithmic atrioventricular delay programming in cardiac resynchronization therapy. Circulation 2010; 122:2660–2668. [CrossRef] [PubMed]
76. Singh JP, Fan D, Heist EK, Alabiad CR, Taub C, Reddy V, et al. Left ventricular lead electrical delay predicts response to cardiac resynchronization therapy. Heart Rhythm 2006; 3:1285–1292. [CrossRef] [PubMed]
77. Lambiase PD, Rinaldi A, Hauck J, Mobb M, Elliott D, Mohammad S, et al. Non-contact left ventricular endocardial mapping in cardiac resynchronisation therapy. Heart 2004; 90:44–51. [CrossRef] [PubMed]
78. Delgado V, van Bommel RJ, Bertini M, Borleffs CJ, Marsan NA, Arnold CT, et al. Relative merits of left ventricular dyssynchrony, left ventricular lead position, and myocardial scar to predict long-term survival of ischemic heart failure patients undergoing cardiac resynchronization therapy. Circulation 2011; 123:70–78. [CrossRef] [PubMed]
79. Becker M, Kramann R, Franke A, Breithardt OA, Heussen N, Knackstedt C, et al. Impact of left ventricular lead position in cardiac resynchronization therapy on left ventricular remodelling. A circumferential strain analysis based on 2D echocardiography. Eur Heart J 2007; 28:1211–1220. [CrossRef] [PubMed]
80. Becker M, Franke A, Breithardt OA, Ocklenburg C, Kaminski T, Kramann R, et al. Impact of left ventricular lead position on the efficacy of cardiac resynchronisation therapy: a two-dimensional strain echocardiography study. Heart 2007; 93:1197–1203. [CrossRef] [PubMed]
81. Becker M, Hoffmann R, Schmitz F, Hundemer A, Kuhl H, Schauerte P, et al. Relation of optimal lead positioning as defined by three-dimensional echocardiography to long-term benefit of cardiac resynchronization. Am J Cardiol 2007; 100:1671–1676. [CrossRef] [PubMed]
82. van Bommel RJ, Ypenburg C, Mollema SA, Borleffs CJ, Delgado V, Bertini M, et al. Site of latest activation in patients eligible for cardiac resynchronization therapy: patterns of dyssynchrony among different QRS configurations and impact of heart failure etiology. Am Heart J 2011; 161:1060–1066. [CrossRef] [PubMed]
83. Leyva F, Foley PW, Chalil S, Ratib K, Smith RE, Prinzen F, et al. Cardiac resynchronization therapy guided by late gadolinium-enhancement cardiovascular magnetic resonance. J Cardiovasc Magn Reson 2011; 13:29.:29. [CrossRef] [PubMed]
84. Delnoy PP, Ottervanger JP, Luttikhuis HO, Vos DH, Elvan A, Ramdat Misier AR, et al. Pressure-volume loop analysis during implantation of biventricular pacemaker/cardiac resynchronization therapy device to optimize right and left ventricular pacing sites. Eur Heart J 2009; 30:797–804. [CrossRef] [PubMed]
85. Meisel E, Pfeiffer D, Engelmann L, Tebbenjohanns J, Schubert B, Hahn S, et al. Investigation of coronary venous anatomy by retrograde venography in patients with malignant ventricular tachycardia. Circulation 2001; 104:442–447. [CrossRef] [PubMed]
86. Jongbloed MR, Lamb HJ, Bax JJ, Schuijf JD, de RA, van der Wall EE, et al. Noninvasive visualization of the cardiac venous system using multislice computed tomography. J Am Coll Cardiol 2005; 45:749–753. [CrossRef] [PubMed]
87. van de Veire NR, Marsan NA, Schuijf JD, Bleeker GB, Wijffels MC, van EL, et al. Noninvasive imaging of cardiac venous anatomy with 64-slice multi-slice computed tomography and noninvasive assessment of left ventricular dyssynchrony by 3-dimensional tissue synchronization imaging in patients with heart failure scheduled for cardiac resynchronization therapy. Am J Cardiol 2008; 101:1023–1029. [CrossRef] [PubMed]
88. Mair H, Jansens JL, Lattouf OM, Reichart B, Dabritz S. Epicardial lead implantation techniques for biventricular pacing via left lateral mini-thoracotomy, video-assisted thoracoscopy, and robotic approach. Heart Surg Forum 2003; 6:412–417. [CrossRef] [PubMed]
89. Mair H, Sachweh J, Meuris B, Nollert G, Schmoeckel M, Schuetz A, et al. Surgical epicardial left ventricular lead versus coronary sinus lead placement in biventricular pacing. Eur J Cardiothorac Surg 2005; 27:235–242. [CrossRef] [PubMed]
90. Navia JL, Atik FA, Grimm RA, Garcia M, Vega PR, Myhre U, et al. Minimally invasive left ventricular epicardial lead placement: surgical techniques for heart failure resynchronization therapy. Ann Thorac Surg 2005; 79:1536–1544. [CrossRef] [PubMed]
91. Gabor S, Prenner G, Wasler A, Schweiger M, Tscheliessnigg KH, Smolle-Juttner FM. A simplified technique for implantation of left ventricular epicardial leads for biventricular re-synchronization using video-assisted thoracoscopy (VATS). Eur J Cardiothorac Surg 2005; 28:797–800. [CrossRef] [PubMed]
92. Doll N, Piorkowski C, Czesla M, Kallenbach M, Rastan AJ, Arya A, et al. Epicardial versus transvenous left ventricular lead placement in patients receiving cardiac resynchronization therapy: results from a randomized prospective study. Thorac Cardiovasc Surg 2008; 56:256–261. [CrossRef] [PubMed]
93. Jutley RS, Waller DA, Loke I, Skehan D, Ng A, Stafford P, et al. Video-assisted thoracoscopic implantation of the left ventricular pacing lead for cardiac resynchronization therapy. Pacing Clin Electrophysiol 2008; 31:812–818. [CrossRef] [PubMed]
94. Dekker AL, Phelps B, Dijkman B, van der Nagel T, van der Veen FH, Geskes GG, et al. Epicardial left ventricular lead placement for cardiac resynchronization therapy: optimal pace site selection with pressure-volume loops. J Thorac Cardiovasc Surg 2004; 127:1641–1647. [CrossRef] [PubMed]
95. Tomaske M, Gerritse B, Kretzers L, Pretre R, Dodge-Khatami A, Rahn M, et al. A 12-year experience of bipolar steroid-eluting epicardial pacing leads in children. Ann Thorac Surg 2008; 85:1704–1711. [CrossRef] [PubMed]
96. Jais P, Douard H, Shah DC, Barold S, Barat JL, Clementy J. Endocardial biventricular pacing. Pacing Clin Electrophysiol 1998; 21:2128–2131. [CrossRef] [PubMed]
97. Jais P, Takahashi A, Garrigue S, Yamane T, Hocini M, Shah DC, et al. Mid-term follow-up of endocardial biventricular pacing. Pacing Clin Electro-physiol 2000; 23:1744–1747. [CrossRef] [PubMed]
98. Leclercq F, Hager FX, Macia JC, Mariottini CJ, Pasquie JL, Grolleau R. Left ventricular lead insertion using a modified transseptal catheterization technique: A totally endocardial approach for permanent biventricular pacing in end-stage heart failure. Pacing Clin Electrophysiol 1999; 22:1570–1575. [CrossRef] [PubMed]
99. Ji S, Cesario DA, Swerdlow CD, Shivkumar K. Left ventricular endocardial lead placement using a modified transseptal approach. J Cardiovasc Electrophysiol 2004; 15:234–236. [CrossRef] [PubMed]
100. Pasquie JL, Massin F, Macia JC, Gervasoni R, Bortone A, Cayla G, et al. Long-term follow-up of biventricular pacing using a totally endocardial approach in patients with end-stage cardiac failure. Pacing Clin Electrophysiol 2007; 30 (Suppl 1):S31–33. [CrossRef] [PubMed]
101. van Gelder BM, Scheffer MG, Meijer A, Bracke FA. Transseptal endocardial left ventricular pacing: an alternative technique for coronary sinus lead placement in cardiac resynchronization therapy. Heart Rhythm 2007; 4:454–460. [CrossRef] [PubMed]
102. Nuta B, Lines I, MacIntyre I, Haywood GA. Biventricular ICD implant using endocardial LV lead placement from the left subclavian vein approach and transseptal puncture via the transfemoral route. Europace 2007; 9:1038–1040. [CrossRef] [PubMed]
103. Lau EW. Yoked catheter positioning in transseptal endocardial left ventricular lead placement. Pacing Clin Electrophysiol 2011; 34:884–893. [CrossRef] [PubMed]
104. Morgan JM, Scott PA, Turner NG, Yue AM, Roberts PR. Targeted left ventricular endocardial pacing using a steerable introducing guide catheter and active fixation pacing lead. Europace 2009; 11:502–506. [CrossRef] [PubMed]
105. van Gelder BM, Houthuizen P, Bracke FA. Transseptal left ventricular endocardial pacing: preliminary experience from a femoral approach with subclavian pull-through. Europace 2011; 13:1454–1458. [CrossRef] [PubMed]
106. Kassai I, Foldesi C, Szekely A, Szili-Torok T. New method for cardiac resynchronization therapy: transapical endocardial lead implantation for left ventricular free wall pacing. Europace 2008; 10:882–883. [CrossRef] [PubMed]
107. Kassai I, Mihalcz A, Foldesi C, Kardos A, Szili-Torok T. A novel approach for endocardial resynchronization therapy: initial experience with transapical implantation of the left ventricular lead. Heart Surg Forum 2009; 12:E137–E140. [CrossRef] [PubMed]
108. Kassai I, Friedrich O, Ratnatunga C, Betts TR, Mihalcz A, Szili-Torok T. Feasibility of percutaneous implantation of transapical endocardial left ventricular pacing electrode for cardiac resynchronization therapy. Europace 2011; 13:1653–1657. [CrossRef] [PubMed]
109. Bracke FA, Houthuizen P, Rahel BM, van Gelder BM. Left ventricular endocardial pacing improves the clinical efficacy in a non-responder to cardiac resynchronization therapy: role of acute haemodynamic testing. Europace 2010; 12:1032–1034. [CrossRef] [PubMed]
110. Spragg DD, Dong J, Fetics BJ, Helm R, Marine JE, Cheng A, et al. Optimal left ventricular endocardial pacing sites for cardiac resynchronization therapy in patients with ischemic cardiomyopathy. J Am Coll Cardiol 2010; 56: 774–781. [CrossRef] [PubMed]
111. Derval N, Steendijk P, Gula LJ, Deplagne A, Laborderie J, Sacher F, et al. Optimizing hemodynamics in heart failure patients by systematic screening of left ventricular pacing sites: the lateral left ventricular wall and the coronary sinus are rarely the best sites. J Am Coll Cardiol 2010; 55:566–575. [CrossRef] [PubMed]
112. Fish JM, Di Diego JM, Nesterenko V, Antzelevitch C. Epicardial activation of left ventricular wall prolongs QT interval and transmural dispersion of repolarization: implications for biventricular pacing. Circulation 2004; 109:2136–2142. [CrossRef] [PubMed]
113. Garrigue S, Jais P, Espil G, Labeque JN, Hocini M, Shah DC, et al. Comparison of chronic biventricular pacing between epicardial and endocardial left ventricular stimulation using Doppler tissue imaging in patients with heart failure. Am J Cardiol 2001; 88:858–862. [CrossRef] [PubMed]
114. Mykytsey A, Maheshwari P, Dhar G, Razminia M, Zheutlin T, Wang T, et al. Ventricular tachycardia induced by biventricular pacing in patient with severe ischemic cardiomyopathy. J Cardiovasc Electrophysiol 2005; 16:655–658. [CrossRef] [PubMed]
115. Nayak HM, Verdino RJ, Russo AM, Gerstenfeld EP, Hsia HH, Lin D, et al. Ventricular tachycardia storm after initiation of biventricular pacing: incidence, clinical characteristics, management, and outcome. J Cardiovasc Electrophysiol 2008; 19:708–715. [CrossRef] [PubMed]
116. Yoshida K, Seo Y, Yamasaki H, Tanoue K, Murakoshi N, Ishizu T, et al. Effect of triangle ventricular pacing on haemodynamics and dyssynchrony in patients with advanced heart failure: a comparison study with conventional bi-ventricular pacing therapy. Eur Heart J 2007; 28:2610–2619. [CrossRef] [PubMed]
117. Yamasaki H, Seo Y, Tada H, Sekiguchi Y, Arimoto T, Igarashi M, et al. Clinical and procedural characteristics of acute hemodynamic responders undergoing triple-site ventricular pacing for advanced heart failure. Am J Cardiol 2011; 108:1297–1304. [CrossRef] [PubMed]
118. Leclercq C, Gadler F, Kranig W, Ellery S, Gras D, Lazarus A, et al. A randomized comparison of triple-site versus dual-site ventricular stimulation in patients with congestive heart failure. J Am Coll Cardiol 2008; 51:1455–1462. [CrossRef] [PubMed]
119. Padeletti L, Colella A, Michelucci A, Pieragnoli P, Ricciardi G, Porciani MC, et al. Dual-site left ventricular cardiac resynchronization therapy. Am J Cardiol 2008; 102:1687–1692. [CrossRef] [PubMed]
120. Bordachar P, Alonso C, Anselme F, Boveda S, Defaye P, Garrigue S, et al. Addition of a second LV pacing site in CRT nonresponders rationale and design of the multicenter randomized V(3) trial. J Card Fail 2010; 16:709–713. [CrossRef] [PubMed]
121. Niederer SA, Shetty AK, Plank G, Bostock J, Razavi R, Smith NP, et al. Biophysical Modeling to Simulate the Response to Multisite Left Ventricular Stimulation Using a Quadripolar Pacing Lead. Pacing Clin Electrophysiol 2011; 10–8159. [CrossRef] [PubMed]
122. Shetty AK, Mehta P, Bostock J, Rinaldi CA. Quad-site pacing using a quadripolar left ventricular pacing lead. Pacing Clin Electrophysiol 2011; 10–8159. [CrossRef] [PubMed]
123. Shetty AK, Duckett SG, Liang Y, Kapetanakis S, Ginks M, Bostock J, et al. The acute hemodynamic response to LV pacing within individual branches of the coronary sinus using a quadripolar lead. Pacing Clin Electrophysiol 2011; 10–8159. [CrossRef] [PubMed]
124. Boriani G, Kranig W, Donal E, Calo L, Casella M, Delarche N, et al. A randomized double-blind comparison of biventricular versus left ventricular stimulation for cardiac resynchronization therapy: the Biventricular versus Left Univentricular Pacing with ICD Back-up in Heart Failure Patients (B-LEFT HF) trial. Am Heart J 2010; 159:1052–1058. [CrossRef] [PubMed]
125. Dekker E. Direct current make and break thresholds for pacemaker electrodes on the canine ventricle. Circ Res 1970; 27:811–823. [CrossRef] [PubMed]
126. Wikswo JP, Jr., Lin SF, Abbas RA. Virtual electrodes in cardiac tissue: a common mechanism for anodal and cathodal stimulation. Biophys J 1995; 69:2195–2210. [CrossRef] [PubMed]
127. Thakor NV, Ranjan R, Rajasekhar S, Mower MM. Effect of varying pacing waveform shapes on propagation and hemodynamics in the rabbit heart. Am J Cardiol 1997; 79:36–43. [CrossRef] [PubMed]
128. Thakral A, Stein LH, Shenai M, Gramatikov BI, Thakor NV. Effects of anodal vs. cathodal pacing on the mechanical performance of the isolated rabbit heart. J Appl Physiol 2000; 89:1159–1164. [CrossRef] [PubMed]
129. Sauer WH, Sussman JS, Verdino RJ, Cooper JM. Increasing left ventricular pacing output decreases interventricular conduction time in patients with biventricular pacing systems. Pacing Clin Electrophysiol 2006; 29:569–573. [CrossRef] [PubMed]
130. Tedrow UB, Stevenson WG, Wood MA, Shepard RK, Hall K, Pellegrini CP, et al. Activation sequence modification during cardiac resynchronization by manipulation of left ventricular epicardial pacing stimulus strength. Pacing Clin Electrophysiol 2007; 30:65–69. [CrossRef] [PubMed]
131. Lloyd MS, Heeke S, Lerakis S, Langberg JJ. Reverse polarity pacing: the hemodynamic benefit of anodal currents at lead tips for cardiac resynchronization therapy. J Cardiovasc Electrophysiol 2007; 18:1167–1171. [CrossRef] [PubMed]
132. Theis C, Bavikati VV, Langberg JJ, Lloyd MS. The relationship of bipolar left ventricular pacing stimulus intensity to cardiac depolarization and repolarization in humans with cardiac resynchronization devices. J Cardiovasc Electrophysiol 2009; 20:645–649. [CrossRef] [PubMed]
133. Dendy KF, Powell BD, Cha YM, Espinosa RE, Friedman PA, Rea RF, et al. Anodal stimulation: an underrecognized cause of nonresponders to cardiac resynchronization therapy. Indian Pacing Electrophysiol J 2011; 11:64–72. [CrossRef] [PubMed]
134. Yu CM, Lin H, Zhang Q, Sanderson JE. High prevalence of left ventricular systolic and diastolic asynchrony in patients with congestive heart failure and normal QRS duration. Heart 2003; 89:54–60. [CrossRef] [PubMed]
135. Bleeker GB, Schalij MJ, Molhoek SG, Holman ER, Verwey HF, Steendijk P, et al. Frequency of left ventricular dyssynchrony in patients with heart failure and a narrow QRS complex. Am J Cardiol 2005; 95:140–142. [CrossRef] [PubMed]
136. Bleeker GB, Schalij MJ, Molhoek SG, Verwey HF, Holman ER, Boersma E, et al. Relationship between QRS duration and left ventricular dyssynchrony in patients with end-stage heart failure. J Cardiovasc Electro-physiol 2004; 15:544–549. [CrossRef] [PubMed]
137. Achilli A, Sassara M, Ficili S, Pontillo D, Achilli P, Alessi C, et al. Long-term effectiveness of cardiac resynchronization therapy in patients with refractory heart failure and “narrow” QRS. J Am Coll Cardiol 2003; 42:2117–2124. [CrossRef] [PubMed]
138. van Bommel RJ, Gorcsan J, III, Chung ES, Abraham WT, Gjestvang FT, Leclercq C, et al. Effects of cardiac resynchronisation therapy in patients with heart failure having a narrow QRS Complex enrolled in PROSPECT. Heart 2010; 96:1107–1113. [CrossRef] [PubMed]
139. van Bommel RJ, Tanaka H, Delgado V, Bertini M, Borleffs CJ, Ajmone MN, et al. Association of intraventricular mechanical dyssynchrony with response to cardiac resynchronization therapy in heart failure patients with a narrow QRS complex. Eur Heart J 2010; 31:3054–3062. [CrossRef] [PubMed]
140. Bleeker GB, Holman ER, Steendijk P, Boersma E, van der Wall EE, Schalij MJ, et al. Cardiac resynchronization therapy in patients with a narrow QRS complex. J Am Coll Cardiol 2006; 48:2243–2250. [CrossRef] [PubMed]
141. Beshai JF, Grimm RA, Nagueh SF, Baker JH, Beau SL, Greenberg SM, et al. Cardiac-resynchronization therapy in heart failure with narrow QRS complexes. N Engl J Med 2007; 357:2461–2471. [CrossRef] [PubMed]
142. de Roest GJ, Allaart CP, de Haan S, Hendriks ML, Bronzwaer JG, van Rossum AC, et al. Effects of QRS duration and pacing location on pressure-volume loop evaluation of cardiac resynchronization therapy in end-stage heart failure. Am J Cardiol 2011; 108:1581–1588. [CrossRef] [PubMed]
143. Morita H, Suzuki G, Haddad W, Mika Y, Tanhehco EJ, Sharov VG, et al. Cardiac contractility modulation with nonexcitatory electric signals improves left ventricular function in dogs with chronic heart failure. J Card Fail 2003; 9:69–75. [CrossRef] [PubMed]
144. Pappone C, Augello G, Rosanio S, Vicedomini G, Santinelli V, Romano M, et al. First human chronic experience with cardiac contractility modulation by nonexcitatory electrical currents for treating systolic heart failure: mid-term safety and efficacy results from a multicenter study. J Cardiovasc Electrophysiol 2004; 15:418–427. [CrossRef] [PubMed]
145. Neelagaru SB, Sanchez JE, Lau SK, Greenberg SM, Raval NY, Worley S, et al. Nonexcitatory, cardiac contractility modulation electrical impulses: feasibility study for advanced heart failure in patients with normal QRS duration. Heart Rhythm 2006; 3:1140–1147. [CrossRef] [PubMed]
146. Borggrefe MM, Lawo T, Butter C, Schmidinger H, Lunati M, Pieske B, et al. Randomized, double blind study of non-excitatory, cardiac contractility modulation electrical impulses for symptomatic heart failure. Eur Heart J 2008; 29:1019–1028. [CrossRef] [PubMed]
147. Yu CM, Chan JY, Zhang Q, Yip GW, Lam YY, Chan A, et al. Impact of cardiac contractility modulation on left ventricular global and regional function and remodeling. JACC Cardiovasc Imaging 2009; 2:1341–1349. [CrossRef] [PubMed]
148. Butter C, Wellnhofer E, Schlegl M, Winbeck G, Fleck E, Sabbah HN. Enhanced inotropic state of the failing left ventricle by cardiac contractility modulation electrical signals is not associated with increased myocardial oxygen consumption. J Card Fail 2007; 13:137–142. [CrossRef] [PubMed]
149. Goliasch G, Khorsand A, Schutz M, Karanikas G, Khazen C, Sochor H, et al. The effect of device-based cardiac contractility modulation therapy on myocardial efficiency and oxidative metabolism in patients with heart failure. Eur J Nucl Med Mol Imaging 2011. [CrossRef] [PubMed]
150. Kadish A, Nademanee K, Volosin K, Krueger S, Neelagaru S, Raval N, et al. A randomized controlled trial evaluating the safety and efficacy of cardiac contractility modulation in advanced heart failure. Am Heart J 2011; 161:329–337. [CrossRef] [PubMed]
151. Abraham WT, Nademanee K, Volosin K, Krueger S, Neelagaru S, Raval N, et al. Subgroup analysis of a randomized controlled trial evaluating the safety and efficacy of cardiac contractility modulation in advanced heart failure. J Card Fail 2011; 17:710–717. [CrossRef] [PubMed]
152. Schau T, Seifert M, Meyhofer J, Neuss M, Butter C. Long-term outcome of cardiac contractility modulation in patients with severe congestive heart failure. Europace 2011; 13:1436–1444. [CrossRef] [PubMed]