Manual of Cardiovascular Medicine

I.Introduction. The prevalence of heart failure (HF) in the United States has increased considerably in the past two decades as a result of the aging population and better medical management of left ventricular dysfunction (LVD). Unfortunately, medical therapy is not completely effective in preventing or reversing the progression of HF, and as a result, patients with advanced HF have limited options. A subset of patients with systolic LVD who have associated ventricular conduction delay are at highest risk for HF progression and a poor overall outcome. Since the late 1970s, various investigators have shown that left bundle branch block (LBBB), right ventricular (RV) pacing, or intraventricular conduction delay (IVCD) is associated with a less favorable hemodynamic profile in those with LVD and even in normal subjects. The mechanism for this phenomenon is thought to be due to asynchronous and inefficient contraction of opposing areas of the ventricular myocardium. More importantly, restoring synchronization, either via simultaneous pacing of the RV apex and the left ventricular (LV) free wall or with timed LV free wall activation, can lead to a significant hemodynamic improvement. Starting in the 1990s, small observational studies suggested benefit from synchronous pacing. Larger randomized clinical trials confirmed these findings. Cardiac resynchronization therapy (CRT) was first approved for maximally medically managed patients with persistent New York Heart Association (NYHA) class III or IV HF symptoms because of severe LVD associated with prolonged QRS duration. Further randomized studies, powered for mortality, showed a significant survival benefit with CRT or the combination of CRT with a defibrillator (CRT-D). More recently, CRT has been shown to be beneficial in less symptomatic patients. Unfortunately, not all patients who are selected for CRT based on current guidelines appear to respond. The terms “responder” or “nonresponder” to CRT have been criticized by many who argue that the natural history of disease progression in any individual patient is not known hence some patients who appear to not have responded may have in fact done even worse if CRT was not employed. Complicating matters further is that there is no uniform definition of response.

II.Mechanism of LV Dyssynchrony. The normal pattern of electrical activation of the ventricular myocardium, once the impulse passes through the atrioventricular (AV) node, starts in the His bundle, followed by simultaneous activation of the right and left bundles of the Purkinje system and then by myocardial depolarization. The Purkinje system is electrically isolated from the rest of the myocardium until it reaches its exit points at the Purkinje–myocardial junctions. As a result, typical LV myocardial activation occurs from the apex to base, simultaneously in the septum and in the LV free wall, and is described as synchronous. Because of tight electromechanical coupling of the myocardium, synchronous ventricular activation is followed by synchronous ventricular contraction.

In the setting of conduction delay, the electromechanical coupling of the heart is disrupted, leading to dyssynchrony. Over time, electromechanical uncoupling leads to impaired stroke volume, worsened mitral insufficiency, prolonged LV isovolumetric events, and impaired diastolic filling. These effects contribute to adverse remodeling in the already impaired heart, creating a vicious cycle that perpetuates this process into more advanced HF. As a result, when comparing patients with similar degrees of LVD, those with conduction delay have a worse overall prognosis. CRT has been shown to reverse this deleterious process. Synchronized pacing has been shown to improve LV function without increasing oxygen demand, suggesting that the improvement is related to better efficiency of the LV chamber.

Interestingly, dyssynchronous activation and contraction have an undesirable effect in patients without LV systolic dysfunction also. When compared with normal controls, patients with LBBB have a lower ejection fraction (EF), are more likely to develop HF, and have a 10-fold greater cardiovascular morbidity and mortality risk. In some patients (patients with chronic LBBB, frequent premature ventricular contractions, or chronic RV pacing), the conduction delay in and of itself may cause deterioration in the EF. In this population, treatment with CRT can have profound effects potentially normalizing the LV function.

III.TYPES OF DYSSYNCHRONY

A.AV dyssynchrony. In the setting of PR or QRS prolongation, the atrial contribution to LV filling is abnormal. Atrial systole can occur too early with respect to ventricular diastole, leading to early truncation of passive LV filling. Early atrial systole also causes an early rise in diastolic ventricular pressure, leading to diastolic mitral regurgitation (MR). Compromised LV filling and MR cause lower cardiac output.

B.Interventricular dyssynchrony. Early RV activation present during LBBB, IVCD, or RV pacing leads to early RV contraction, creating a pressure gradient between the RV and LV that negatively affects LV filling, which translates to a decrease in LV preload and a subsequent decrease in cardiac output. In the early development of CRT, interventricular dyssynchrony was thought to be a major contributor to adverse events in patients with HF and conduction disease and hence the primary target for CRT. Whereas correction of interventricular dyssynchrony with CRT may improve hemodynamics, it is now thought that that correction of intraventricular dyssynchrony is far more important to improved outcomes with CRT.

C.Intraventricular dyssynchrony. In the presence of conduction delay, there is a substantial delay in the activation of certain LV segments compared with others, leading to an inefficient back-and-forth mechanical interaction that results in inefficient myocardial contraction. In the case of a native LBBB, for example, there is a significant delay in activation between the early activated septum and the late activated posterolateral wall, often resulting in profound delays between segments. Mitigation of intraventricular dyssynchrony is currently thought to be the primary mechanism of improved myocardial performance with CRT.

V.Role of CRT. The primary role of CRT is to improve systolic LV performance via an improvement in chamber efficiency, thereby leading to symptomatic improvements in patients with medication refractory HF. In clinical trials, the EF improved by an average of about 5% with a significant improvement in MR and was accompanied by symptomatic improvement, as evidenced by increased 6-minute walk time and quality of life index score (QOLS). The remodeling of the LV takes at least 3 or more months. On average, the LV systolic and diastolic dimensions decrease significantly following prolonged CRT. In studies in which biventricular (Bi-V) pacing was switched off after prolonged synchronized pacing, the systolic benefits disappeared rapidly; however, the LV dimensions were maintained for a longer period of time, suggesting that actual LV remodeling took place during CRT. There is also evidence that CRT may lead to electrical remodeling of the heart although this effect is less well studied. Evidence from randomized clinical trials powered for mortality, in addition to symptomatic improvement, supports the use of CRT alone or in combination with an implantable cardioverter defibrillator (ICD) in patients with ischemic and nonischemic etiologies of severe LVD.

VI.Summary of major clinical trials OF CRT. Most clinical trials evaluating CRT have addressed its role in patients in normal sinus rhythm (NSR) with severe LVD, and indirect evidence of mechanical dyssynchrony represented by prolonged QRS duration (on average, >120 ms). Early studies of CRT compared patients with CRT pacemaker (CRT-P) devices with optimal medical therapy alone and enrolled patients with NYHA class III–IV HF. Over the years, trials progressed to enrolling patients with minimally symptomatic HF and compared patients with CRT-D devices to those with an ICD alone.

A.PATH-CHF. A longitudinal crossover study of 41 patients evaluating CRT-P (Bi-V or LV pacing) versus no therapy. Primary end points of peak Vo₂, 6-minute walk, NYHA class, and QOLS significantly improved during CRT.

B.MUSTIC. A small prospective randomized trial powered for symptomatic improvement as measured by hospitalization, 6-minute walk, and QOLS in patients in NSR or with atrial fibrillation at the time of enrollment. The trial showed significant improvements with CRT-P, and the benefit was similar in NSR and atrial fibrillation.

C.MIRACLE. The MIRACLE trial, completed in late 2000, randomized 453 patients with advanced HF and a QRS duration ≥130 ms to CRT versus conventional therapy for HF. The trial revealed significant improvements in peak Vo₂ consumption, 6-minute hall walk, QOLSs, EF, NYHA class, and treadmill exercise times with CRT compared with controls. This trial led to the approval of CRT devices by the Food and Drug Administration.

D.MIRACLE-ICD. Very similar to MIRACLE, the MIRACLE-ICD trial was a moderate-sized prospective randomized trial evaluating the safety and efficacy of combining CRT with ICD therapy for a composite end point of mortality, hospitalization, and symptomatic improvement. At 6 months follow-up, the CRT-ICD arm had a significant improvement in the composite end point. Combining CRT with ICD was deemed safe. Of note, CRT-D devices were compared to optimal medical therapy alone in this trial (not to an ICD alone).

E.CARE-HF. The CARE-HF was a large, open-label randomized controlled trial powered to assess mortality comparing CRT-P to optimal medical therapy alone in patients with ischemic and nonischemic etiology of LVD. In addition to the conventional dyssynchrony criteria of QRS duration >150 ms, the trial was the first to implement echocardiographic markers of mechanical dyssynchrony in those patients with QRS duration between 120 and 150 ms. At 3 years of follow-up, the primary end point of all-cause mortality and hospitalization was significantly different in favor of the CRT group. Furthermore, the secondary end point of all-cause mortality reached statistical significance after 3 years of follow-up, and the survival curves continued to separate. The number needed to treat with CRT to save one life was estimated at nine patients.

F.COMPANION. A large, open-label randomized (1:2:2) prospective trial powered for mortality and hospitalization benefit in patients with ischemic and nonischemic etiologies of LVD comparing medical therapy versus CRT-P or CRT-D. In addition to conventional QRS criteria for CRT, patients also had to have had one episode of hospitalization for HF in the year prior to randomization. Both CRT-D and CRT-P were superior in terms of the primary end point of all-cause mortality and hospitalization compared with optimal medical therapy alone. The secondary end point of all-cause mortality was significantly different in the CRT-D group compared with optimal medical therapy alone. The CRT-P group showed a strong trend toward mortality benefit compared with optimal medical therapy alone that did not reach statistical significance. The trial was not powered to compare mortality benefits between the two device groups. In the CRT-D group, the mortality benefit was noticed shortly after the beginning of the trial, as compared with 6 to 12 months after study initiation in CARE-HF. The early mortality benefit in this trial was thought to be ICD related. The later benefits were attributed to both ICD and CRT therapies. The results of this trial led to approval of combined CRT-D therapy in the above population of patients.

G.ECHO-CRT. A large clinical multicenter trial examining the role of CRT pacing in patients with EF <35%, narrow QRS (<130 ms), and echocardiographic evidence of LV dyssynchrony. Dyssynchrony was defined by means of color-coded tissue Doppler imaging as an opposing-wall delay in the peak systolic velocity of 80 ms or more in apical four-chamber or apical long-axis views or by means of speckle-tracking radial strain as a delay in the anteroseptal-to-posterior wall of 130 ms or more in the mid-LV short-axis view. All patients underwent device implantation but were randomized to have CRT pacing on (404 patients) or off (405 patients in which device settings were set to minimize RV pacing). Mean QRS duration was 105 ms. The study was terminated because of futility where the CRT group had increased mortality (11.1% vs. 6.4%; hazard ratio [HR] 1.81; p = 0.02). This study suggested that implanting CRT in patients with a narrow QRS may be harmful.

H.BLOCK-HF. A randomized clinical trial examining the role of CRT pacing in patients with AV block and systolic dysfunction who require significant ventricular pacing. The trial enrolled patients with indications for pacing with AV block; NYHA class I, II, or III HF; and a left ventricular ejection fraction (LVEF) of 50% or less. They all got CRT devices and were randomized to biventricular pacing (349 patients) versus RV pacing (342 patients). Patients got ICD if they had an indication for one. The primary outcome was the time to death from any cause, an urgent care visit for HF that required intravenous therapy, or a 15% or more increase in the LV end-systolic volume (ESV) index. The primary outcome occurred less frequently in the biventricular pacing group (HR 0.74, confidence interval [CI], 0.6 to 0.9).

VII.MAJOR TRIALS OF CRT IN MINIMALLY SYMPTOMATIC HF

A.REVERSE. The REVERSE study, published in 2008, was a large randomized, double-blind trial designed to assess whether CRT in addition to medical therapy could delay progressive myocardial remodeling and/or prevent HF progression. The study enrolled 610 patients with a 2:1 enrollment design such that 419 patients received a CRT-D device and 191 patients received an ICD alone. Inclusion criteria for the study were NYHA class I or II symptoms, an LVEF ≤40%, an LV end-diastolic dimension ≥55 mm, NSR, and a QRS duration ≥120 ms. The primary end point of REVERSE was a novel clinical composite end point developed by Packer and colleagues, which rates patients as “improved,” “unchanged,” or “worsened” based on the combination of mortality status, hospitalizations because of HF, withdrawal of consent, and worsening NYHA class. The American arm of the study concluded at 12 months, with the European arm proceeding to 24 months. Although there was no difference in the primary end point at 12 months, patients in the CRT arm derived significantly greater reductions in the LV ESV index and the LV end-diastolic volume (EDV) index, respectively, and improvement in LVEF compared with those without CRT. During the 12-month follow-up period, there was no difference in mortality between the two groups; however, CRT significantly lowered HF hospitalizations. In the European arm of the trial in which follow-up was continued for an additional year, the benefit of CRT in inducing reductions in LV volumes and improvement in LVEF persisted at 24 months.

B.MADIT-CRT. MADIT-CRT, published in 2009, sought to determine the impact of CRT on HF hospitalizations and all-cause mortality in patients with NYHA class I or II HF symptoms. This multicenter, unblinded study randomized 1,820 patients in North America and Europe with an LVEF ≤30%, NYHA class I or II symptoms (patients with nonischemic cardiomyopathy and NYHA class I symptoms were excluded), NSR, and a QRS duration ≥130 ms to a CRT-D device or an ICD alone. The primary end point for the study was death from any cause or a nonfatal HF event. At a mean follow-up of 2.4 years, patients in the CRT arm had a significantly lower incidence of the primary end point compared with the ICD-alone arm. Similar to what was shown in REVERSE, patients in the CRT arm of MADIT-CRT realized significantly greater improvements in myocardial structure and function compared with those without CRT.

C.RAFT. The RAFT trial which began enrollment in 2003 was a large, double-blinded, randomized controlled trial of 1,798 patients with NYHA class II or III symptoms, an LVEF ≤30%, and a QRS duration ≥120 ms (or a paced QRS >200 ms), which compared therapy with CRT-D versus that with an ICD alone. Originally, the trial sought to determine whether CRT in addition to an ICD would improve survival in patients with class II and III symptoms. After publication of the CARE-HF trial and subsequent guideline changes, however, the protocol was altered in early 2006 to include only patients with NYHA class II symptoms. Of 894 patients receiving a CRT-D device in the RAFT trial, 79.2% had NYHA class II symptoms. For inclusion, patients had to either be in NSR or have rate-controlled permanent atrial fibrillation or flutter. The primary end point of all-cause death or HF hospitalization occurred in 33.2% of the CRT-D group and in 40.3% of the ICD-only group over a follow-up of 40 ± 20 months. In looking at only patients with NYHA class II symptoms, patients in the CRT arm had reductions in the primary end point as well as in both cardiovascular and all-cause mortality and hospitalizations because of HF.

VIII.Factors Associated with Improved Outcomes in CRT. Several factors have been associated with improved outcomes with CRT.

A.Women have continually derived improved outcomes in multiple studies compared with men. Although the reason for this has been debated, it is likely due to a lower LV mass at the same QRS duration (more relative dyssynchrony) compared with men.

B.Patients with nonischemic cardiomyopathy appear to be more likely to derive reverse ventricular remodeling than patients with ischemic cardiomyopathy.

C.Patients with LBBB either native or paced are far more likely to improve function with CRT compared with patients with a non-LBBB (right bundle branch block [RBBB] or IVCD).

D.Lastly patients with wide QRS durations (>150 ms) appear to have improved outcomes compared with patients with narrower QRS durations (120 to 149 ms). There is debate among experts as to the relative importance of QRS morphology compared to QRS duration. Whereas patients with LBBB have been shown to outperform patients with non-LBBB when it comes to CRT responsiveness, patients with LBBB also inherently have a wider QRS duration for the most part. Taking the literature into account, both QRS duration and morphology likely play a role.

E.Lead position is an important determinant of response. Apical lead positions are inferior to mid and basal positions. Septal locations such as pure anterior or posterior locations (in the great cardiac vein which parallels the LAD or the middle cardiac vein which parallels the posterior descending artery) are inferior to lateral locations although the data behind this is less robust.

IX.QLV and RV–LV Timing. Electrical delay or electrical dyssynchrony is a key factor when predicting response to CRT. Electrical delay can be easily measured in the electrophysiology lab at the time of CRT implant. The SMART-AV QLV substudy looked at the relationship between the intrinsic electrical delay of the LV and clinical end points. LV electrical delay was defined by the time interval from the first QRS deflection on surface electrocardiogram (ECG) to the local intrinsic activation at the LV stimulation site (QLV) as measured in the electrophysiology lab. The goal of optimizing CRT is to deliver electrical stimuli in an area that has the latest activation within the LV. The study found that when the observed QLV was >95 ms, HF patients had the best improvements in EF, ESV, EDV, and quality of life measurements at 6 months follow-up. Measuring the time between the RV and LV electrograms is a similar measure to QLV, with the advantage that this time is easily measurable through CRT devices. Whereas the utility of QLV and RV–LV timing in terms of selecting lead location and choosing pacing vectors has been encouraging, neither as of yet have been shown to be sensitive nor specific for predicting long-term outcomes.

X.Current guidelines and recommendations. Based on the inclusion criteria from the available large randomized trials at that time, the American Heart Association/American College of Cardiology 2012 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult gives CRT the following indications (see Table 52.1):

TABLE 52.1 Current Recommendations for the Use of CRT in Patients with HF
Recommendation	Class	Level of Evidence
Patients with ischemic or nonischemic etiology of depressed LV function, EF ≤35%, and NYHA class II, III, or ambulatory class IV, on GDMT, in sinus rhythm with an LBBB with a QRS complex ≥150 ms	I	A
Patients with ischemic or nonischemic etiology of depressed LV function, EF ≤35%, and NYHA class II, III, or ambulatory class IV, on GDMT who are in sinus rhythm with an LBBB QRS 120–149 ms	IIa	B
Patients with ischemic or nonischemic etiology of depressed LV function, EF ≤35%, and NYHA class II, III, or ambulatory class IV, on GDMT who are in sinus rhythm with a non-LBBB QRS ≥150 ms	IIa	A
Patients with depressed LV function, EF ≤35% and anticipated to require frequent ventricular pacing (>40%)	IIa	C
Patients with atrial fibrillation if ventricular pacing is required or QRS criteria above are met and rate control (including AV node ablation) will result in nearly 100% ventricular pacing	IIa	B
Patients with ischemic or nonischemic etiology of depressed LV function, EF ≤35%, on GDMT, and NYHA III or ambulatory class IV, with non-LBBB with QRS 120–149 ms	IIa	B
Patients with ischemic or nonischemic etiology of depressed LV function, EF ≤35%, on GDMT, and NYHA II with non-LBBB with QRS >150 ms	IIa	B
Patients with ischemic etiology of depressed LV function, EF ≤30%, sinus rhythm, NYHA class I on GDMT, and LBBB QRS ≥150 ms	IIa	C
CRT is not recommended in patients on inotropic support except in special cases when patients are listed for transplant or have LV assist device or in patients with less than 1 year survival	III	C
CRT is not recommended in patients with NYHA class I or II symptoms and non-LBBB pattern with QRS duration <150 ms	III	B

CRT, cardiac resynchronization therapy; EF, ejection fraction; GDMT, guideline-directed medical therapy; HF, heart failure; LBBB, left bundle branch block; LV, left ventricular; NYHA, New York Heart Association.

Adapted from the ACC/AHA/HRS 2008 guidelines for device-based therapy of cardiac rhythm; American Heart Association, Inc.

A.Class Ia (level of evidence A): In patients with ischemic or nonischemic etiology of depressed LV function, EF ≤ 35%, and NYHA class II, III, or ambulatory class IV, on guideline-directed medical therapy (GDMT) for ≥3 months or ≥40 days after MI, in sinus rhythm with an LBBB with a QRS complex ≥150 ms.

B.Class IIa: In patients with ischemic or nonischemic etiology of depressed LV function, EF ≤ 35%, and NYHA class II, III, or ambulatory class IV, on GDMT for ≥3 months or ≥40 days after MI who are in sinus rhythm with an LBBB QRS 120 to 149 ms (level of evidence B); sinus rhythm with non-LBBB QRS ≥150 ms (level of evidence A); patients anticipated to require frequent ventricular pacing (>40%) (level of evidence C); or atrial fibrillation if ventricular pacing is required or QRS criteria above are met and rate control (including AV node ablation) will result in nearly 100% ventricular pacing (level of evidence B).

C.Class IIb: Patients with ischemic or nonischemic etiology of depressed LV function, EF ≤ 35%, and NYHA class II, III, or ambulatory class IV, on GDMT for ≥3 months or ≥40 days after MI with non-LBBB QRS 120 to 149 ms and NYHA III/ambulatory IV on GDMT (level of evidence B); in patients with non-LBBB with QRS >150 ms and NYHA II on GDMT (level of evidence B); in patients with ischemic cardiomyopathy who have an EF <30%, LBBB QRS ≥150 ms (level of evidence C).

D.CRT is not recommended in patients on inotropic support except in special cases when patients are listed for transplant or have LV assist device or in patients with less than 1 year survival (level of evidence C); patients with NYHA class I or II symptoms and non-LBBB pattern with QRS duration <150 ms (level of evidence B).

XI.Implantation Procedure. Unlike conventional transvenous pacemaker or ICD implantation that requires lead placement in the right atrium and/or the right ventricle only, Bi-V pacing requires LV lead implantation. Initially, this was achieved via a thoracotomy; however, currently up to 98% of Bi-V devices are placed via a transvenous approach. Although now used infrequently, some patients are still referred for a thoracotomy after a failed transvenous approach.

The procedure is performed in an electrophysiology laboratory under sterile conditions. All patients receive preprocedural antibiotics at least 30 minutes before the procedure. A subcutaneous pocket is first prepared, making sure that appropriate hemostasis is achieved. Typically, a cephalic or axillary vein approach to venous access is used. The right atrial and RV leads are implanted in a fashion similar to a pacemaker or ICD implantation. The LV lead is placed through the coronary sinus (CS) into a CS branch on the lateral free wall of the left ventricle. Modern CRT systems have the availability of quadripolar LV pacing leads, which are desirable in terms of adding flexibility to programming options compared with older bipolar leads. Performing an occlusive CS venogram may help identify the appropriate vein. Various sheaths, catheters, and guidewires are available to cannulate the CS and advance the pacing lead into the appropriate vein. Although the optimal site for LV lead placement is controversial, many experts agree that septal positions (straight anterior or posterior) and apical positions are suboptimal. Once the lead is advanced, its location should be confirmed by fluoroscopy, typically in the left anterior oblique (LAO) view. The goal is to document base to mid-posterolateral LV lead placement and maximal LV–RV lead separation in the LAO view. A steep angulation in the LAO view tends to be most accurate. Pacing thresholds are acceptable if <3 V at 0.5 ms. Diaphragmatic capture is excluded by high-voltage pacing. If high pacing threshold or diaphragm capture occurs, the lead should be repositioned. CS trauma is occasionally noted during lead placement, and it may range from dissection to frank perforation. Because the pressure in the venous system is low, serious sequelae are unusual and cardiac tamponade rarely results. After adequate LV lead placement and confirmed appropriate LV lead function, care must be taken during guidewire, CS platform, and stylet removal, so as not to disrupt lead position. Lead dislodgement occurs in as many as 5% of implantations. The time frame for the majority of dislodgements is the first 24 to 48 hours postimplantation, when patients resume activity. For that same reason, patients are encouraged to ambulate while still in-house to prevent any out-of-hospital dislodgement, which may have more serious consequences.

XII.Programming and follow-up. Currently, multiple configurations for Bi-V pacing exist. The available pacing configurations vary by device manufacturer. Changing configurations for pacing can be very useful in cases of poor thresholds or diaphragmatic stimulation.

Ventricular pacing must be continuous during CRT in order to obtain maximal benefit. Typically, DDD mode with a short AV delay (80 to 110 ms) to prevent native conduction is typically employed. More recently, fusion pacing algorithms have been developed in which RV pacing is limited or completely omitted and the LV paced wave front fuses with intrinsic conduction.

Follow-up of CRT devices includes a 12-lead ECG to assess for Bi-V capture and device interrogation to assess pacing thresholds. Patents should have a posteroanterior and lateral chest ray to confirm lead position and to rule out pneumothorax. In those patients who are deemed nonresponders, echocardiography may be used to optimally time the AV delay based on Doppler mitral valve inflow patterns or Doppler aortic velocity time integral. Generally speaking, interventricular timing (V–V interval), although programmable, is not taken into consideration during CRT programming. Limited studies suggest that AV programming may lead to a better acute hemodynamic response to CRT in certain patients. The value of VV optimization is of considerable debate. In addition, specialized CRT clinics may help troubleshoot device issues, treat arrhythmias, maximize congestive heart failure (CHF) medications, and optimize the AV interval. Although such clinics are limited mostly to specialized centers, such clinics have shown improved outcomes in patients receiving CRT.

XIII.Future Directions. Although CRT has emerged as one of the most important advances in the treatment of LVD over the last 15 years, several important questions remain. Despite the myriad of parameters of mechanical dyssynchrony that are available, none has been shown to be a practical and reliable predictor of response. Developing a measure of dyssynchrony that predicts response accurately and can be used across multiple care settings remains a challenge. ECHO-CRT trial has made it clear that CRT does not benefit patients with narrow QRS even if they have echocardiographic evidence of dyssynchrony. Lastly, the role of CRT in patients without a native or RV-paced LBBB morphology is an area of considerable controversy. Patients with RBBB have early activation of the left ventricle and late activation of the right ventricle, calling into question the role of LV pacing for these patients. Still, most patients with RBBB have a wider QRS duration than would be expected from having a “pure” RBBB alone. This implies additional left-sided delay that may be mitigated by CRT. Although retrospective studies have certainly called into question the benefits of CRT in this population, currently, there is no prospective randomized trial to provide a more definitive answer. Patients with nonspecific IVCD are a heterogeneous population, likely with both right- and left-sided delay. In retrospective studies, the response rate of this population is more akin to those with RBBB than LBBB; however, the studies have been small.

XIV.Summary. CRT has emerged as an effective therapy in patients with LVD refractory to CHF medications and a wide QRS duration. Major clinical trials have proven significant morbidity and mortality benefits from CRT first in patients with advanced heart and more recently in those with minimal symptoms. The issue of nonresponse to CRT continues to be a major problem, and much ongoing research continues to be dedicated to predicting which patients will respond to this therapy. Although many studies have shown some predictive ability of various imaging modalities, none to date has been shown to be a reliable predictor of response that could be utilized across multiple centers. Although the response to CRT in patients with a native LBBB or RV-paced rhythm is well documented, the response in patients with RBBB or a nonspecific IVCD continues to be debated.

ACKNOWLEDGMENTS: The author wishes to acknowledge the contribution of Dr. Peter Borek to the previous edition of this chapter.

Key Reviews and Book Chapters

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Ellenbogen KA, Wilkoff BL, Kay GN, et al, eds. Clinical Cardiac Pacing, Defibrillation and Resynchronization Therapy. 4th ed. Philadelphia, PA: Saunders; 2011.

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McAlister FA, Ezekowitz J, Hooton N, et al. Cardiac resynchronization therapy for patients with left ventricular systolic dysfunction: a systematic review. JAMA. 2007;297:2502–2514.

Spragg DD, Kass DA. Pathobiology of left ventricular dyssynchrony and resynchronization. Prog Cardiovasc Dis. 2006;49:26–41.

Vardas PE, Auricchio A, Blanc JJ, et al. European Society of Cardiology; European Heart Rhythm Association. Guidelines for cardiac pacing and cardiac resynchronization therapy: the task force for cardiac pacing and cardiac resynchronization therapy of the European Society of Cardiology. Developed in collaboration with the European Heart Rhythm Association. Eur Heart J. 2007;28:2256–2295.