Color Atlas and Synopsis of Electrophysiology, 1st Ed.

70. CARDIAC RESYNCHRONIZATION THERAPY

Daniel J. Friedman, MD, and Jagmeet P. Singh, MD, DPhil

CASE PRESENTATION

A 63-year-old man with diabetes, hypertension, and ischemic cardioyopathy presented to the emergency department with orthopnea, paroxysmal nocturnal dyspnea, and increased lower extremity edema over the past 2 weeks. He underwent placement of a cardiac resynchronization therapy device with defibrillator 8 months prior when he was noted to have an ejection fraction of 24% and NYHA class III symptoms despite maximal medical therapy. Exam demonstrated 86% room air saturation, mild respiratory distress, an irregularly irregular heart rhythm, bilateral rales, and 2+ pitting edema. An ECG demonstrated atrial fibrillation with multiple QRS morphologies: paced and native IVCD with left axis deviation (Figure 70-1). A PA and lateral radiograph demonstrated bilateral interstitial edema and an implanted device with three leads in the heart. The coronary sinus (left ventricular) lead was located in the apical region (Figure 70-2). The patient was admitted and diuresed. He was started on anticoagulation and underwent cardioversion with restoration of sinus rhythm after transesophageal echocardiogram excluded left atrial appendage thrombus. Transthoracic echocardiogram demonstrated a diffusely hypokinetic left ventricle with a 21% ejection fraction, and he subsequently underwent echocardiogram guided AV and VV optimization. At the time of discharge, the patient continued to experience NYHA class III symptoms.

Images

FIGURE 70-1 An ECG demonstrating atrial fibrillation with multiple QRS morphologies: biventricular paced and native IVCD with left axis deviation. Note the paced beats, marked with “Images” on the V1rhythm strip, are characterized by prominent R wave in V1 and a narrower QRS compared to the native QRS.

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FIGURE 70-2 A posteroanterior and lateral radiograph demonstrating bilateral intersitial edema, cardiomegaly, and a standard 3-lead CRT device, with leads pacing the right atrium, right ventricle, and left ventricle. The LV lead is located in the coronary sinus, and the lead tip is position in the LV apex.

CRT: THE BASICS

CRT is an advanced pacing strategy able to restore electrical synchrony of both the atria and ventricles leading to improved chamber filling and pump function. Typical CRT systems include a right atrial lead, right ventricular lead, and left ventricular lead (Figure 70-2). The LV lead is typically implanted transvenously via the coronary sinus but can also be implanted epicardially via lateral thoracotomy. The 3-lead system allows for restoration of the AV and VV synchrony that is commonly lost in severe systolic heart failure with advanced conduction disease. Thus, CRT is more than simply biventricular pacing. CRT may be implanted with or without a defibrillator.

CRT has represented a significant advance in the treatment of severe symptomatic systolic heart failure with electrical dyssynchrony as evidenced by a prolonged QRS on the surface electrocardiogram. CRT has been associated with a significant reduction in heart failure symptoms, heart failure hospitalizations, and mortality1-4 and has become a widely accepted device therapy for a variety of indications. It has additionally been associated with improvements in exercise capacity, oxygen consumption, NYHA symptom class, and quality of life. While CRT is currently approved by the United States Food and Drug Administration for patients with EF <35% and either 1) QRS >120 ms and NYHA class III/IV symptoms or 2) QRS >130 ms, LBBB, and NYHA II symptoms, major society guidelines define additional appropriate patient subsets in whom the use of CRT is thought to be of benefit.5 These subsets are largely dictated by the width of the QRS interval and morphology of the conduction defect. In most situations, CRT is considered appropriate for patients with a LBBB and a QRS width ≥120 ms, while in patients with a non-LBBB morphology, the QRS width should ideally be ≥150 ms.

IMPACT ON MYOCARDIAL STRUCTURE AND FUNCTION

CRT has been clearly linked to favorable changes in myocardial structural and functional parameters, termed reverse remodeling. Ongoing therapy has been associated with increased ejection fraction, reduced mitral regurgitation, and decreased chamber size, including LV dimension and volume. Patients manifesting these changes are often referred to as echocardiographic responders. Notably, some degree of echocardiographic response often occurs immediately after initiation of CRT, though the maximal extent of response typically requires approximately 6 months of therapy. Echocardiographic response is tightly linked to improvements in clinical outcomes and is felt to be an important mechanism underlying the clinical improvements afforded by CRT.6

IMPACT ON ELECTRICAL FUNCTION AND DYSFUNCTION

The initiation of CRT is associated with a number of changes in electrical activation, function, and stability. Simultaneous or near simultaneous depolarization of the ventricles via biventricular pacing decreases the electrical dyssnchrony associated with ventricular conduction delay, leading to an increasingly synchronous mechanical contraction. Favorable change in the ventricular activation sequence may be manifested by a narrowing of the QRS interval with biventricular pacing. CRT additionally involves optimization of the AV interval, allowing for improvements in diastolic filling with a reduction in diastolic mitral regurgitation. AV optimization often involves programming to reduce the AV interval, which is frequently prolonged in the context of cardiomyopathy.

Initial reports suggested that CRT might be associated with an increase in ventricular arrhythmias. Multiple mechanisms were postulated, including epicardial pacing leading to a reversal of the transmural gradient with increased heterogeneity of repolarization, functional reentry, and torsades de pointes, and biventricular pacing causing a collision of multiple wavefronts in close proximity to a susceptible anatomic substrate. While these mechanisms may lead to arrhythmogenesis in a minority of CRT patients, antiarrhythmic mechanisms typically predominate, outweighing the theoretical deleterious effects. The antiarrhythmic effects of CRT are likely related to favorable changes in wall tension, LV size, neurohormonal activation, LV mass, and oxygen consumption, which are likely important for arrhythmogenesis. CRT additionally decreases pauses and conduction delays, which are important mechanisms for pause dependent and macroreentrant arrhythmias, respectively. Thus, while CRT may exert a number of pro- and antiarrhythmic effects on the myocardium, it is now well accepted that the net effect of CRT is a reduction of ventricular arrhythmias and sudden death. Improvements in electrical stability have been linked with echocardiographic response. Some have suggested that the antiarrhyhmic effect of CRT is sufficient to preclude benefit from concomitant ICD implantation, though this remains controversial, and most CRT patients typically receive an ICD.

FOLLOW-UP AND MONITORING RESPONSE TO THERAPY

The relation between echocardiographic response and improved clinical outcomes has led clinicians to assess routinely response to CRT with an echocardiogram at approximately 6 months after implant, as a supplement to history, physical, and NYHA class assessment. By 6 months, approximately two-thirds of patients experience an improvement in EF, a decrease in LV end systolic volume, and/or class improvement in NYHA symptom class. Those who do not demonstrate improvement based on one or more of these metrics are referred to as nonresponders. Of note, although the term “nonresponder” is a frequently used classification in clinical practice and research, there is not a single agreed upon definition. The patient described in the clinical vignette would be considered a nonresponder based on lack of symptomatic improvement and decrement in EF. Though heterogeneity in the definitions of responder and nonresponder exist, it remains a clinically useful concept as changes in EF, LV end systolic volume, and symptom class provide important prognostic information regarding the success of CRT. Based on this, all patients should undergo complete assessment including echocardiogram and NYHA symptom class assessment at baseline and 6 months after implantation to assess responder status. It should be noted that more frequent clinical and echocardiographic assessment might be warranted for early detection of patients who are at risk of nonresponse.

The identification of CRT nonresponse should prompt a comprehensive evaluation for reversible causes. CRT nonresponse may be due to one or more of a number of factors, including suboptimal AV and/or VV optimization, anemia, arrhythmia, insufficient biventricular pacing, suboptimal lead positioning, suboptimal medical therapy, narrow QRS, and patient noncompliance. A comprehensive examination should include device interrogation, ECG, basic laboratory tests, PA and lateral chest x-ray, and echocardiogram with a trial of different AV and VV device settings. Multidisciplinary evaluation from electrophysiology, heart failure, and cardiac imaging perspectives should strongly be considered for all nonresponders.7,8 Therapy for nonresponders may include medication adjustment, device optimization, lead revision, catheter ablation, antiarrhythmic drugs, and cardioversion.

DETERMINANTS OF RESPONSE

Despite ongoing advances in CRT, nearly one-third of patients are nonresponders due to patient selection and/or device related issues. Characteristics commonly associated with increased risk of nonresponse include male sex, ischemic cardiomyopathy, non-LBBB morphology, narrow QRS, atrial fibrillation, low percentage of biventricular pacing, and suboptimal lead position.

QRS Duration

Although advanced conduction disease is typically associated with worsened cardiovascular disease and worsened outcomes in many populations, a prolonged QRS interval is associated with improved outcomes among those undergoing CRT.9 This seemingly paradoxical finding is related to the fact that those with heart failure and a prolonged QRS frequently have heart failure at least in part due to conduction disease and resultant electrical dyssynchrony. Thus, a prolonged QRS represents an “electrical problem” that has the capacity to be treated by an electrical therapy (eg, CRT). Conversely, patients with severe heart failure and a narrower QRS are less likely to have an “electrical problem” underpinning pump dysfunction, and thus are less likely to respond to this pacing therapy.10,11

Bundle Branch Morphology

Though QRS duration has emerged as an important determinant of response, a number of recent studies have strongly suggested that QRS morphology is at least as important.12-14 Studies have demonstrated that patients with underlying LBBB prior to CRT are much more likely to respond to CRT than those with an RBBB or IVCD. This association is related to the fact that CRT predominantly resynchronizes the left ventricle, and those with RBBB and IVCD often have a substantial burden of right-sided conduction disease underlying clinical heart failure. Patients with an underlying paced rhythm have generally been excluded from major CRT trials and thus less thoroughly studied; however, outcomes after CRT appear to be nearly commensurate with LBBB patients. The findings regarding the impact of QRS duration and morphology have strongly informed the current CRT appropriate use guidelines (Table 70-1).

TABLE 70-1 Summary of Appropriate Use Criteria for Heart Failure Patients with an Ejection Fraction of Less Than 35%.

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Cardiomyopathy Etiology

Ischemic cardiomyopathy has been associated with worsened outcomes in CRT.12 This relation is likely related to the way scar is distributed across the myocardium in ischemic versus nonischemic cardiomyopathy. Ischemia-mediated cardiomopathy is often associated with dense transmural scar in areas corresponding to prior infarction. Areas of dense infarct often lead to poor lead capture and slowed conduction, precluding optimal ventricular resynchronization. This notion has been supported by research demonstrating that posterolateral scar (eg, scar in the preferred LV lead location) is associated with particularly poor outcomes.15 Though the nonischemic cardiomyopathies represent a heterogeneous group of diseases, they are typically characterized by scar that is comparatively more diffuse and less likely to be transmural.

Atrial Fibrillation

Atrial fibrillation has been associated with decreased benefit from CRT. This finding is related to the fact that atrial fibrillation (particularly with rapid rates) can favor a higher incidence of native conduction compared to paced complexes and that being in atrial fibrillation also precludes the optimal use of AV optimization. Given the improved outcomes associated with normal sinus rhythm, physicians often opt for a rhythm control strategy when possible. Initial reports suggested that the presence of atrial fibrillation may preclude benefit from CRT. However, patients with atrial fibrillation appear to derive similar benefit from CRT as long as there is a high percentage of biventricular pacing.16,17 Of note, CRT response has been associated with decreased atrial fibrillation burden,18 decrease in new onset atrial fibrillation,19 and reversion to sinus rhythm in certain individuals.20

Percent Biventricular Pacing

Optimal resynchronization of the left ventricular requires a high percentage of biventricular pacing. While it is generally thought that 90% biventricular pacing is sufficient to derive benefit from CRT, it has been suggested that optimal response may require as much as 98.5% biventricular pacing.21 Decreased biventricular pacing may be related to intrinsic AV conduction, premature ventricular beats, suboptimal device programming, and pacemaker dysfunction. Shortening of the programmed AV interval to less than the intrinsic AV conduction is essential to ensure a high percent of biventricular pacing. Intrinsic AV conduction may occur despite optimal device programming in the context of atrial fibrillation and other atrial arrhythmias; for this reason, adequate nodal blockade is essential. AV nodal ablation is being used with increasing frequency in CRT patients to improve biventricular pacing. Pacemaker dysfunction, including lead dislodgement and oversensing, represents an important consideration when evaluating a patient with a reduced percentage of biventricular pacing. It should be noted that contemporary CRT devices tend to overestimate the percentage of true biventricular pacing because of difficulty in discriminating among true biventricular pacing, fusions beats, and pseudofusion.22 Fusion complexes result when intrinsic and pacemaker induced wavefronts both contribute to a ventricular depolarization; these beats typically register as biventricular pacing on device counters, though they can be substantially more dyssynchronous than true biventricular pacing. Pseudofusion results when a pacemaker spike falls on an intrinsic QRS, giving the appearance of a fusion complex (Figure 70-3). As a result, Holter monitoring may be required for a full evaluation of nonresponders in whom fusion and pseudofusion is possible. A newer pacing strategy, termed “trigger pacing,” has been used to increase biventricular synchrony in instances of intrinsic ventricular depolarizations (either via AV conduction or ventricular ectopy). In trigger pacing, an intrinsic ventricular deplorization is recognized by one of the ventricular leads, prompting a simultaneous pacemaker-induced depolarization by the other ventricular lead. This results in a fusion of the wavefronts from the intrinsic depolarization and the paced depolarization, improving ventricular synchrony.

Images

FIGURE 70-3 Pseudofusion with a premature ventricular beat between two biventricular paced complexes in lead V1.

Lead Position

Anatomic left ventricular lead location has emerged as a key determinant of outcomes in CRT.23 Anatomic lead position is best defined using a validated 15-segment approach where the LV long axis is divided in the apical, midventricular, and basal segments, and the short axis is divided into anterior, anterolateral, lateral, posterolateral, and posterior segments24,25 (Figure 70-4). LV leads located in the basal or midventricular position along the long axis and the posterolateral segment along the short axis are generally associated with superior outcomes compared to other segments.24,25 While LV lead implantation should target an optimal anatomic location, options are sometimes limited by constraints of coronary venous anatomy, phrenic nerve stimulation, and the presence of focal scar precluding adequate capture.23

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FIGURE 70-4 Angiographic classification of left ventricular lead position observed during intraprocedural coronary sinus venography demonstrating the validated 15-segment approach for defining LV lead position. (A) A right anterior oblique (RAO) view enables segmentation of the heart along the long axis into basal, midventricular (MID), and apical segments. (B) The left anterior oblique (LAO) view enables segmentation of the heart along the short axis into anterior, anterolateral, lateral, posterolateral, and posterior segments. Abbreviations: AIV, anterior interventricular vein; CS, coronary sinus; MCV, middle cardiac vein. (Reproduced with permission from Singh JP, Klein HU, Huang DT, Reek S, Kuniss M, Quesada A, Barsheshet A, Cannom D, Goldenberg I, McNitt S, Daubert JP, Zareba W, Moss AJ. Left ventricular lead position and clinical outcome in the multicenter automatic defibrillator implantation trial-cardiac resynchronization therapy (madit-crt) trial. Circulation. 2011;Mar 22;123(11):1159-1166.)

Lead position can additionally be defined by its electrical location by measuring the time between onset of the native QRS on the surface electrocardiogram and the sensed signal on the LV lead during intrinsic conduction. When this value is indexed for (eg, divided by) the native QRS duration, it is termed left ventricular lead electrical delay (LVLED); when this value is not indexed, it is termed “QLV.” Longer delays are associated with enhanced CRT response and superior clinical outcomes, suggesting that intraprocedural assessment of electrical location may be useful during coronary sinus branch selection.26,27 Finally, it should be noted that electrical lead location assessment provides prognostic information that is complementary to traditional anatomic assessment, and as such, both can be considered during implantation.27,28

Case Vignette

The patient in the case described at the beginning of the case possesses many risk factors for nonresponse. These factors include ischemic cardiomyopathy etiology, atrial fibrillation, non-LBBB morphology, decreased biventricular pacing, and suboptimal lead positioning. While many risk factors for nonresponse are not modifiable, it is prudent to attempt to correct all options that can be performed noninvasively. This would include attempts at rhythm control and device reprogramming with consideration for lead revision if noninvasive strategies fail.

MULTIDISCIPLINARY APPROACH TO THE CARE OF THE CRT PATIENT

The patients undergoing CRT represent some of the most complex cardiovascular patients and demand a deliberate and coordinated approach for ongoing care. Multidisciplinary care involving structured follow-up integrating heart failure, echocardiography, and electrophysiology care (Figure 70-5) may have the potential to improve outcomes in CRT. This approach incorporates frequent assessment of changes in symptom and functional status and in changes in cardiac structure and function as assessed by echocardiography. It allows for early identification of nonresponders and frequent device optimization (often with echocardiogram guidance), medication titration, and arrhythmia management when needed.

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FIGURE 70-5 A diagram depicting a structured multidisciplinary care delivery strategy, integrating heart failure (HF), echocardiography (echo), and electrophysiology care during the first 6 months after device implantation. MLWHFQ indicates Minnesota Living with Heart Failure Questionnaire. (Reproduced with permission from Altman RK, Parks KA, Schlett CL, Orencole M, Park MY, Truong QA, Deeprasertkul P, Moore SA, Barrett CD, Lewis GD, Das S, Upadhyay GA, Heist EK, Picard MH, Singh JP. Multidisciplinary care of patients receiving cardiac resynchronization therapy is associated with improved clinical outcomes. Eur Heart J. 2012;Sep;33(17):2181-2188.)

An important component of multidisciplinary care of the CRT patient involves optimization of the AV interval. Optimal AV duration is important to maximize coordination of the atria and ventricles, maximize left ventricular filling time, increase cardiac output, and facilitate ventricular synchrony. AV optimization can occur via proprietary device-based algorithms or via echocardiogram guidance utilizing one of many different approaches. One of the more popular methods for echocardiogram-based optimization involves optimization of the mitral inflow pattern using an iterative approach. With this approach, AV delay is initially increased until biventricular capture is lost. The AV delay is then decreased in 10 to 30 ms intervals until an optimal mitral inflow pattern (eg, optimal diastolic filling) is achieved (Figure 70-6).

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FIGURE 70-6 Mitral inflow pattern changes after successive decrements in programmed AV interval. The AV interval was progressively shortened from 300 ms to 80 ms until the E/A wave demonstrated an optimized mitral inflow profile at an AV interval of 80 ms. Representative inflow patterns using Doppler echocardiography with programmed AV intervals of (A) 300 ms, (B) 200 ms, (C) 100 ms, and (D) 80 ms.

Altman and colleagues7 demonstrated that multidisciplinary care was associated with a 30% reduction in event-free survival at 2 years, compared to conventional care. A multidisciplinary approach has also been associated with a high rate of success in the evaluation and management of CRT nonresponders.8 Despite intensive management, a certain proportion of patients will demonstrate progressive worsening despite CRT. In these cases, a multidisciplinary approach will afford a more seamless transition to consideration for advanced therapies including mechanical support (eg, left ventricular assist device) and cardiac transplantation.

SUMMARY

CRT is an advanced pacing therapy associated with a reduction in mortality and heart failure hospitalizations and improvements in functional status, quality of life, and cardiac function. Although CRT has been associated with improvement in most patients, a significant minority (approximately one-third) does not respond to this therapy. New implantation and optimization strategies, coupled with improved care coordination are needed to improve response rates and outcomes.

REFERENCES

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7. Altman RK, Parks KA, Schlett CL, et al. Multidisciplinary care of patients receiving cardiac resynchronization therapy is associated with improved clinical outcomes. Eur Heart J. 2012.

8. Mullens W, Grimm RA, Verga T, et al. Insights from a cardiac resynchronization optimization clinic as part of a heart failure disease management program. J Am Coll Cardiol. 2009;53:765-773.

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10. Thibault B, Harel F, Ducharme A, et al; Lesser Earth Investigators. Cardiac resynchronization therapy in patients with heart failure and a QRS complex <120 milliseconds: the Evaluation of Resynchronization Therapy for Heart Failure (LESSER-EARTH) trial. Circulation. 2013;127:873-881.

11. Beshai JF, Grimm RA, Nagueh SF, et al. Cardiac-resynchronization therapy in heart failure with narrow QRS complexes. N Engl J Med. 2007;357:2461-2471.

12. Dupont M, Rickard J, Baranowski B, et al. Differential response to cardiac resynchronization therapy and clinical outcomes according to QRS morphology and QRS duration. J Am Coll Cardiol. 2012;60:592-598.

13. Gold MR, Thebault C, Linde C, et al. Effect of QRS duration and morphology on cardiac resynchronization therapy outcomes in mild heart failure: results from the resynchronization reverses remodeling in systolic left ventricular dysfunction (reverse) study. Circulation. 2012;126:822-829.

14. Zareba W, Klein H, Cygankiewicz I, et al; MADIT-CRT Investigators. 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.

15. Bleeker GB, Kaandorp TA, Lamb HJ, et al. Effect of posterolateral scar tissue on clinical and echocardiographic improvement after cardiac resynchronization therapy. Circulation. 2006;113:969-976.

16. Heist EK, Mansour M, Ruskin JN. Rate control in atrial fibrillation: targets, methods, resynchronization considerations. Circulation. 2011;124:2746-2755.

17. Upadhyay GA, Steinberg JS. Managing atrial fibrillation in the CRT patient: controversy or consensus? Heart Rhythm. 2012;9:S51-59.

18. Lellouche N, De Diego C, Vaseghi M, et al. Cardiac resynchronization therapy response is associated with shorter duration of atrial fibrillation. Pacing Clin Electrophysiol. 2007;30:1363-1368.

19. Brenyo A, Link MS, Barsheshet A, et al. Cardiac resynchronization therapy reduces left atrial volume and the risk of atrial tachyarrhythmias in MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy). J Am Coll Cardiol. 2011;58:1682-1689.

20. Gasparini M, Steinberg JS, Arshad A, et al. Resumption of sinus rhythm in patients with heart failure and permanent atrial fibrillation undergoing cardiac resynchronization therapy: a longitudinal observational study. Eur Heart J. 2010;31:976-983.

21. Hayes DL, Boehmer JP, Day JD, et al. Cardiac resynchronization therapy and the relationship of percent biventricular pacing to symptoms and survival. Heart Rhythm. 2011;8:1469-1475.

22. Kamath GS, Cotiga D, Koneru JN, et al. The utility of 12-lead holter monitoring in patients with permanent atrial fibrillation for the identification of nonresponders after cardiac resynchronization therapy.J Am Coll Cardiol. 2009;53:1050-1055.

23. Blendea D, Singh JP. Lead positioning strategies to enhance response to cardiac resynchronization therapy. Heart Failure Rev. 2011;16:291-303.

24. Merchant FM, Heist EK, McCarty D, et al. Impact of segmental left ventricle lead position on cardiac resynchronization therapy outcomes. Heart Rhythm. 2010;7:639-644.

25. Singh JP, Klein HU, Huang DT, et al. Left ventricular lead position and clinical outcome in the Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy (MADIT-CRT) trial. Circulation. 2011;123:1159-1166.

26. Gold MR, Birgersdotter-Green U, Singh JP, et al. The relationship between ventricular electrical delay and left ventricular remodelling with cardiac resynchronization therapy. Eur Heart J. 2011;32:2516-2524.

27. Singh JP, Fan D, Heist EK, et al. Left ventricular lead electrical delay predicts response to cardiac resynchronization therapy. Heart Rhythm. 2006;3:1285-1292.

28. Friedman DJ, Upadhyay GA, Altman RK, et al. The anatomic and electrical location of the left ventricular lead predicts ventricular arrhythmia in cardiac resynchronization therapy. Heart Rhythm. 2012.