This document discusses the history and evidence for cardiac resynchronization therapy (CRT). It notes that approximately 25% of heart failure patients have intraventricular conduction delays that cause dyssynchronous contraction. CRT aims to resynchronize contraction by pacing both ventricles simultaneously. Randomized controlled trials found CRT improves symptoms, exercise capacity, and survival in patients with low ejection fraction and wide QRS. Guidelines recommend CRT for class III/IV heart failure patients with LBBB morphology and QRS >120ms. Some evidence also supports benefit in milder heart failure. Response can vary and not all patients respond equally.

1. CARDIAC RESYNCHRONIZATION

2. Wiggers CJ (1925) The muscular reactions of mammalian ventricles to artificial surface stimuli. Am J Physiol 73:346–378 Cardiac Resynchronization History: Adverse Effects of Dyssynchrony

3. Background Approx 25% of patients with CHF have intraventricular conduction delay; commonly LBBB Electrical activation of lateral aspect of LV can be delayed in relation to that of RV and/or interventricular septum This results in Dyssynchronous electrical activation & contraction Unequal distribution of myocardial workload Altered myocardial blood flow & metabolism Patients with conducting disease have worse prognosis from CHF Patients with a paced RV end up having an artificially induced interventricular conducting delay and overall systolic function is poorer

4. Lateral X-ray view of the first fully transvenous cardiac resynchronization therapy system (University Hospital of Rennes, August 1994). Ritter P et al. Eur Heart J Suppl 2007;9:I107-I112 Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2007.For Permissions, please e-mail: journals.permissions@oxfordjournals.org Note RV lead in RVOT, 2 Leads in CS, one for LA pacing

5. Cardiac Resynchronization Simultaneous pacing of RV & LV = Biventricular pacing RA, RV & LV LV paced via coronary sinus

7. Randomized Controlled Trials Of CRT MIRACLE (453) MUSTIC SR (58) MUSTIC AF (43) PATH CHF (41) MIRACLE ICD (369) CONTAK CD (490) COMPANION (1520) PATH CHF II (89) MIRACLE ICD II (186) CARE HF (814) Studies (n randomized): CRT Improves: NYHA Class Quality of Life Score Exercise Capacity (6 MW, Peak VO2) LV Function (EF, degree of MR) Reverse Remodeling (LVEDV) Hospitalization Mortality

8. Recommendations for Cardiac Resynchronization Therapy in Patients With Severe Systolic Heart Failure (ACC/AHA/HRS 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities) Class I 1. For patients who have LVEF less than or equal to 35%, a QRS duration greater than or equal to 0.12 seconds, and sinus rhythm, CRT with or without an ICD is indicated for the treatment of NYHA functional Class III or ambulatory Class IV heart failure symptoms with optimal recommended medical therapy. (Level of Evidence: A) Class IIa 1. For patients who have LVEF less than or equal to 35%, a QRS duration greater than or equal to 0.12 seconds, and AF, CRT with or without an ICD is reasonable for the treatment of NYHA functional Class III or ambulatory Class IV heart failure symptoms on optimal recommended medical therapy. (Level of Evidence: B) 2. For patients with LVEF less than or equal to 35% with NYHA functional Class III or ambulatory Class IV symptoms who are receiving optimal recommended medical therapy and who have frequent dependence on ventricular pacing, CRT is reasonable. (Level of Evidence: C) Class IIb 1. For patients with LVEF less than or equal to 35% with NYHA functional Class I or II symptoms who are receiving optimal recommended medical therapy and who are undergoing implantation of a permanent pacemaker and/or ICD with anticipated frequent ventricular pacing, CRT may be considered. (Level of Evidence: C) See subsequent slide, ? In patients with better EF’s. Class III 1. CRT is not indicated for asymptomatic patients with reduced LVEF in the absence of other indications for pacing. (Level of Evidence: B) See subsequent slide. In patients with LBBB, EF less than 35%, and Class I and II CHF, who are undergoing prophylactic AICD implantation. Based on MADIT CRT trial, FDA approved resynchronization in this class of patients in October 2010. GUIDELINES OUTDATED. 2. CRT is not indicated for patients whose functional status and life expectancy are limited predominantly by chronic noncardiac conditions. (Level of Evidence: C) Note: “ambulatory” class IV for CRT therapy. Also note in section on indications for defibrillator implantation: ICD therapy is NOT indicated for NYHA Class IV patients with drug-refractory congestive heart failure who are NOT candidates for cardiac transplantation or CRT-D . (Level of Evidence: C)

9. Benefit of CRT in Patients with LV Dysfunction, LBBB, and Mild or Minimal CHF (Class I, II) Linde C, et al. Randomized trial of cardiac resynchronization in mildly symptomatic heart failure patients and in asymptomatic patients with left ventricular dysfunction and previous heart failure symptoms (REVERSE Trial) J Am Coll Cardiol 2008;52:1834-43 Moss AJ et al. for the MADIT-CRT Trial Investigators. Cardiac-Resynchronization Therapy for the Prevention of Heart-Failure Events. N ENGL J MED 2009;361:1329-1338. Tang ASL et al. for the RAFT Investigators. Cardiac-Resynchronization Therapy for Mild-to-Moderate Heart Failure. N ENGL J MED 2010;363:2385-2395. Adabag S, Moss AJ et al. Cardiac Resynchronization Therapy in Patients With Minimal Heart Failure: A Systematic Review and Meta-Analysis. Journal of the American College of Cardiology 58(9) 23 August 2011:935-941. Benefits Include: Reduction in CHF Events Reduction in CHF Hospitalization Reduction in Mortality Increase in LVEF, Decrease in LV Volumes

10. CRT: Special Situations (all involve RV only pacing, which induces dyssynchrony) AV junctional ablation ( Cardiac resynchronization therapy in patients undergoing atrioventricular junction ablation for permanent atrial fibrillation: a randomized trial. Eur Heart J. 2011; 32(19):2420-9 , found the beneficial effects of CRT were consistent in patients who had ejection fraction ≤35%, New York Heart Association Class ≥III and QRS width ≥120 and in those who did not. At multi-variable Cox regression, only CRT mode remained an independent predictor of absence of clinical failure during the follow-up) Congenital complete heart block Acquired AV block Atrial fibrillation where pacing expected ? With reduction in LVEF ? With normal LVEF Large body of evidence that RV pacing very adverse in defibrillator population with LV dysfunction

11. CRT: What Is It Good For (and probably Not Good For) Good evidence: broader the QRS complex with LBBB, the greater the benefit (several studies). Electrical dyssynchrony the BEST indicator of response. Good evidence: RV-only pacing-induced dyssynchrony Good evidence: non-ischemic cardiomyopathies respond better than ischemic cardiomyopathies. Poor evidence: Narrow QRS complex Poor evidence: RBBB patients

12. Right bundle branch block patients do not respond to CRT Fact or Myth?

13. Small Numbers of RBBB Patients included in RCTs Uncertain benefit of CRT in patients with right bundle branch block (RBBB) ACC/AHA HF Guidelines: “…only a small number of patients with ‘pure’ (RBBB) have been enrolled in CRT trials. The effect of CRT in these patients is currently unknown.” 1 Presumption that pre-excitation of left ventricle will not benefit patients with a right bundle branch block. 1. J Am Coll Cardiol, 2008; 51:2085-2105

14. COMPANION Subgroup Analysis COMPANION study 1 year duration Randomized CRT-P, CRT-D, OMT in 2:2:1 ratio Subgroup analysis LBBB: 215 OMT and 426 CRT-P patients Other includes RBBB and IVCD: 93 OMT and 190 CRT-P patients LBBB Other Favors CRT Bristow M, et al. N Engl J Med 2004; 350:2140-50. [COMPANION sponsored by Guidant]

15. Sub-analyses of RBBB from Other Randomized Controlled Studies MIRACLE 1 313 patients with LBBB, 43 with RBBB With CRT, RBBB patients improved NYHA class compared to control With CRT, RBBB patients’ improvements in exercise time and peak VO 2 did not reach statistical significance Pooled data from MIRACLE and Contak CD studies 2 61 patients with RBBB (34 CRT, 27 Control) CRT improved NYHA Class compared to control Trends toward improved QoL, 6 minute walk distance, norepinephrine (NE) with CRT compared to baseline, but with no difference compared to control 1. Aranda J, et al. Clin Cardiol 2004;27: 678–82. [MIRACLE was sponsored by Medtronic] 2. Egoavil CA, et al. Heart Rhythm 2005;2:611–615. [Contak CD was sponsored by Guidant]

16. Do RBBB Patients Respond? Small number of RBBB patients in randomized controlled trials precludes definitive conclusions about efficacy of CRT. 1 Masked LBBB may be present in significant proportion of patients identified as having RBBB. 2,3 Not sufficient evidence to withhold therapy from this group 1. J Am Coll Cardiol, 2008; 51:2085-2105 2. Fantoni C, et al. J Cardiovasc Electrophysiol 200516:112-119 3. Aranda J, et al. Clin Cardiol 2004;27: 678–82.

17. Use Of Resynchronization Pacemaker Elderly patient, poor quality of life and/or frequent CHF hospitalizations, LBBB, low EF Implant resynchronization PACER, NOT AICD Goal is quality of life, not prevention of sudden cardiac death CARE-HF (sub-population patients ≥70): Reduction in all cause mortality Reduction in CHF/CV hospitalization Improvement in Quality of Life Improvement in LVEF/LVESV Mabo P et al. Circulation 2008;118:S949 Abstract 8450, Laviolle et al. Circulation 2008;118:S950b Abstract 48540, Leclercq C et al. Circulation 2008;118:S619b Abstract 826 MIRACLE (sub-population 174 patients >75) Significant reduction in NYHA Class Significant improvement in LVEF/LVESV Kron et al. J Interv Card Electrophysiol:2009 Jan 19

18. Variable Response to Cardiac Resynchronization Non-responders (approx. 30% in various studies). Etiologies may include poor LV lead position, need for adjustment of AV or VV intervals, LV scar, poor position of RV lead, not enough bi-V pacing, Bi-V worse, or just that may not work in some patients no matter what. Hyper-responders or super-responders (dramatic clinical improvement with marked increase in EF, approx. 10% of patients) Steffel, J et al. Characteristics and long-term outcome of echocardiographic super-responders to cardiac resynchronization therapy: 'real world' experience from a single tertiary care centre. Heart. 97(20):1668-1674, October 15, 2011.

19. Mullens, W. et al. J Am Coll Cardiol 2009;53:765-773 Potential Reasons for Suboptimal Response Cleveland Clinic Nonresponders Clinic

20. Echo Techniques in Cardiac Resynchronization Can echo techniques looking at dyssynchrony (including tissue doppler imaging, strain imaging, speckle tracking) be used to predict response to LV lead implantation? Can echo techniques be used to optimally adjust A-V and V-V intervals? ?

24. Studies of the use of echo to predict response to resynchronization and to optimize AV and VV delays Conclusion: total confusion, ? Possibly use AV and VV optimization in non-responders FLEMING LM et al. Use of Echocardiography to Manage Cardiac Resynchronization Therapy. Innovations in Cardiac Rhythm Management, Sept 2011

25. Procedure Sequence (a lot of steps) Incision over deltopectoral groove Wire into cephalic vein Possibly make pocket (vs. later in case) Trendelenberg, feet on wedge Axillary vein stick under fluoro using wire in cephalic as guide Introducer to cephalic, double wire Introducer to cephalic, RV lead (septum preferred) Sew in RV lead Introducer to cephalic, RA lead 9F sheath to axillary vein, double wire to retain, advance sheath over one guidewire Medtronic Attain Extended hook sheath and glidewire to access CS, use of RAO view, may need other sheaths, R-sided sheath, Mariner catheter Sheath advanced, prefer DISTAL and FORCEFUL venogram, allows occlusion and visualization of all branches and connections Selection of lead Use of .014” guidewire, sometimes use of guide/inner catheter Testing of lead, configurations, phrenic Remove 9F sheath Cut away long sheath (R hand completely steady, must pull sheath in line with cutter) Hemostatic suture and sew in LV lead Remove sheath around atrial lead in cephalic, hemostatic suture, sew in atrial lead Connect device, test, close

26. Power of Negative Thinking; Things That Can Go Wrong Access difficult, no or small cephalic, difficult axillary or subclavian Persistent L SVC Leads moving one another unless separate sticks RV and RA leads not to be underestimated, but I place first Complete heart block (these patients have LBBB) Back bleeding in CHF patient Cannulation of CS Dissection of CS Very tortuous CS, valve in CS (sheath can’t advance) Absent CS No good veins (too tortuous, small, too large, stenosis, phrenic, threshold) Lead keeps dislodging/moving, during peel away or subsequently Phrenic capture (general anesthesia with paralysis) High threshold Infection Pneumothorax Tamponade Dye reactions Air embolus Hematoma Complications of anesthesia (long cases) Pro-arrhythmia related to LV pacing

27. Coronary Sinus Anatomy Anterior Interventricular Vein Posterior Cardiac Vein- Often Has Lateral Extension

28. © 2011 American Heart Association, Inc. Left ventricular lead position and clinical outcome in the multicenter automatic defibrillator implantation trial-cardiac resynchronization therapy (MADIT-CRT) trial. 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 Circulation. 123(11):1159-66, 2011 Mar 22. Figure 1 . Angiographic classification of left ventricular lead position. A, Right anterior oblique (RAO) view representative of the long axis of the heart. This view enables segmentation of the heart into basal, midventricular (MID), and apical segments. B, Left anterior oblique (LAO) view used to divide the left ventricular wall along the short axis of the heart into 5 equal parts; anterior, anterolateral, lateral, posterolateral, and posterior. For the analysis, the anterolateral, lateral, and posterolateral segments were grouped together as the lateral wall. AIV indicates anterior interventricular vein; CS, coronary sinus; and MCV, middle cardiac vein. Conclusion: Apical Placement Worse Outcomes

29. ACCESSING THE CORONARY SINUS

30. ACCESSING THE CORONARY SINUS

31. Coronary Sinus Venogram

32. Tips on Coronary Sinus Venogram Access CS with glidewire to avoid dissection Fill balloon wedge catheter with dye prior to placing in sheath so can see exit end of sheath (otherwise can be pushed too far/hard, dissection) Before advancing wedge catheter, and then before blowing up balloon, puff of dye; so don’t advance down small branch, Vein of Marshall, dissection. If resistance to balloon inflation, stop, puff Inflate balloon. Puff dye to make sure occlusive. Can double inflate (vein). DISTAL venogram, very forceful injection to fill entire CS, visualize branches proximal to balloon and detail branches (esp. sub branches for small leads) If dissection, can usually proceed, esp. in prior cardiac surgical patient

33. Advancing Lead over 0.014” Guidewire

34. Short 90º 5mm reduction distal to the tip Aids advancement in small, tortuous anatomy Extended 90º & Extended 130º 8mm extension distal to the tip Provides additional reach for sub-selection All Attain Select II catheters can deliver a 5.3 Fr lead or smaller (up to 5.6 Fr electrode tip) Attain Select ® II Shapes Short 90º Extended 90º Extended 130º 130º 90º

35. Placement of 4 Fr Lead Via Attain Select Attain outer catheter Chronic pace/sense lead

36. Medtronic Starfix Lead Issues: Unipolar EXTRACTION

37. Attain StarFix ® Deployment

38. Electronic Repositioning

39. New Technology: St. Jude's Quadrapolar Lead Four Narrow Electrodes Quadripolar lead enables greater pacing flexibility than unipolar or bipolar leads and provides more options for pacing complication avoidance. Optim™ Lead Insulation Optim insulation is a hybrid insulation material–the first of its kind, developed specifically for cardiac lead use. It blends the biostability and flexibility of high-performance silicone rubber with the strength, tear resistance and abrasion resistance of polyurethane. This insulation allows for an abrasion-resistant, thin diameter lead. Low Profile Entire lead body: 4,7 F Lead tip: 4,0 F Steerable Tip Distal tip angle can be controlled to manoeuvre the lead through venous anatomy. Over-the-wire or Stylet-approach Compatibility Specially designed leads give the implanting physician the option of using either approach during the same procedure. Fast-Pass™ Lubricious Coating Enables multiple leads to easily slide against one another, possibly reducing inadvertent dislodgement. S-shaped for Stability The S-curve shape is designed to provide enhanced lead stability in a wide variety of vein sizes. Suture Sleeve The suture sleeve has been designed with silicone ridges to secure a thin lead body. Titanium Nitride (TiN) Coating TiN coating on the tip and ring electrodes has been shown to improve stimulation efficiency and lower polarisation. Steroid Elution Steroid elution minimizes inflammatory reaction at the electrode-tissue interface and provides lower acute and chronic thresholds than nonsteroid-eluting leads.

40. LV Only Pacing From Coronary Sinus Twelve-lead ECG showing monochamber LV pacing from the coronary venous system. There is typical right bundle branch pattern and right axis deviation. Note the dominant R wave from V1 to V6 consistent with basal LV pacing. LV pacing from the traditional site for resynchronization produces a RBBB pattern in lead V1 virtually without exception. When lead V1 shows a negative QRS complex during LV pacing, one should consider incorrect ECG lead placement (lead V1 too high) or location in the middle or great (anterior) cardiac vein S. Serge Barold et al. Diagnostic Value of the 12-lead ECG During Conventional and Biventricular Pacing for Cardiac Resynchronization. Cardiology Clinics 24(3), August 2006:471-490.

41. R-wave in V1 with RV apical pacing Diagram showing evaluation of a dominant R wave in lead V1 during uncomplicated RV pacing. When a dominant R wave occurs when V1 is recorded one or two ICS too high, a negative QRS complex will often be recorded in the fourth ICS which is the correct site for V1. If the dominant R wave persists or is initially recorded in the fourth ICS, a negative QRS complex will be recorded one ICS lower in the fifth ICS. Never see R-wave in V1 with uncomplicated RVOT pacing S. Serge Barold et al. Diagnostic Value of the 12-lead ECG During Conventional and Biventricular Pacing for Cardiac Resynchronization. Cardiology Clinics 24(3), August 2006:471-490.

42. RV Outflow Tract Pacing Combined With LV Pacing Biventricular pacing with the RV lead in the outflow tract. There was a very prominent R wave in lead V1 during monochamber LV pacing. Note the typical absence of a dominant R wave in lead V1, and the presence of right axis deviation, an uncommon finding during biventricular pacing with the RV lead at the apex. S. Serge Barold et al. Diagnostic Value of the 12-lead ECG During Conventional and Biventricular Pacing for Cardiac Resynchronization. Cardiology Clinics 24(3), August 2006:471-490.

43. Conclusion: ECG Patterns in V1 With LV only pacing, always see positive QRS complex in V1 (unless lead placed too high) Sometimes with RV pacing only, see positive QRS complex in V1 (falsely suggesting LV capture), but change lead position lower should become negative Given above, place V1 in low position, positive QRS denotes LV capture If lead known to be in RVOT and biventricular paced QRS positive in V1, definitely have LV capture (RVOT pacing never neg. in V1) Can have negative QRS complex in V1 with biventricular capture if RV lead in RVOT (lack of positive QRS does not mean loss of LV capture)

44. Frontal Plane Axis With Various Pacing Configurations Diagram showing the usual direction of the mean frontal plane axis during apical RV pacing, RV outflow tract pacing, LV pacing from the coronary venous system, and biventricular pacing with LV from the coronary venous system + RV from the apex. The axis during biventricular pacing from the LV from the coronary sinus + RV outflow tract usually points to the right inferior quadrant (right axis) as with monochamber LV pacing. S. Serge Barold et al. Diagnostic Value of the 12-lead ECG During Conventional and Biventricular Pacing for Cardiac Resynchronization. Cardiology Clinics 24(3), August 2006:471-490.

45. Q Wave in I Georger and colleagues observed a q wave in lead I in 17 of 18 patients during biventricular pacing As indicated previously, a q wave in lead I during uncomplicated RV apical pacing is rare, and these workers observed it in only one patient. Loss of the q wave in lead I was 100% predictive of loss of LV capture. It therefore appears that analysis of the Q/q wave or a QS complex in lead I may be a reliable way to assess LV capture during biventricular pacing. Georger F, et al. Specific electrocardiographic patterns may assess left ventricular capture during biventricular pacing. PACE ; 25 (2002), p. 56 [abstract].