Cardiac Resynchronization Therapy Dr Nithin P G 16/4/2013

Abnormal Electrical Activation of Heart Prolonged AV delay Interventricular delay Intraventricular delay Intramural delay

Resynchronization Term “resynchronization” introduced by ‘Cazeau et al’ Rationale BBB/IVCD V. Dysynchrony Regional loading disparity Efficiency of contraction LV preexcitation may correct inter and intra ventricular conduction delays & permit optimization of left sided AV delay Improved ventricular pumping function [+dP/dt]

Mechanism of resynchronization Contractile function- greater coordination of global contraction Myocardial effec. Improved Normal increase in dP/dt at HR Trials Comments CARE HF Median LVEF ~25% baseline LVEF in CRT vs. no CRT [3.7% in 3 m, 6.9% in 18 m] increased dP/dt, SBP ; reduced BNP MIRACLE 6m LVEF [increase by 3.6%]

Mechanism of resynchronization Reverse LV remodeling LV EDV ESV Mass ? Molecular changes- homogenous activation of stress kinases & reduced apoptosis CARE –HF, MIRACLE, CONTAK CD, PATH-CHF, VIGOR-CHF Trials Comments Circulation 2005; 112:1580 [n=141; f/up 2 yrs] Responders [>10% decrease in LV ESV] 62 % responders  reduction in all cause mortality (7vs31); reduction in CV mortality (2.3 vs. 24); reduction in HF events (12 vs. 33)

Mechanism of resynchronization Reduction in functional MR Imbalance between the closing and tethering forces that act on mitral leaflets Tethering force- V. dilatation and increased chamber sphericity increase the distance b/w the papillary muscles to the enlarged mitral annulus as well as to each other, restricting leaflet motion and increasing the force needed for effective mitral valve closure. Closing force- determined by the systolic LV-LA pressure difference (transmitral pressure gradient) MR orifice area will be largely determined by the phasic changes in transmitral pressure. [Increasing the transmitral pressure can reduce the EROA] CRT Acute MR [quantitatively related to an increase in LV + DP/dt max and transmitral pressure] Chronic MR due to reduced LV dimensions from remodeling Ameliorates delayed sequential activation of papillary muscles due to intraventricular delay.

Mechanism of resynchronization Other mechanisms Increase in cardiac index and reduced PCWP Tolerate more aggressive medical therapies [ beta blockers] Improved diastolic functions Improvement in heart rate variability

Implantation Type of implantation LV Epicardial Vein [Trans-venous] LV Epicardial lead [Surgically planted] LV Endocardial lead [ Trans-septal puncture] Trans venous- Directional sheath into CS on a coronary catheter or deflective EPS catheter balloon occlusion Animation

Implantation Cannulation of the coronary sinus using a coronary guide catheter and an over-the-wire technique. A: The guidewire has been directed into the coronary sinus by the sheath in the right atrium. The sheath is advanced over the wire. Note LV lead delivery sheath within main body of coronary sinus. B: The guidewire is withdrawn into the sheath.

Limitations & Complications Inability to cannulate C.S. and implant the LV pacing lead successfully Coronary venous anatomy Absent / inaccessible target vein Coronary venous tortuosity High LV stimulation threshold  Scar burden Phrenic nerve stimulation

Coronary venous anatomy Retrograde coronary venogram. A: With the balloon occlusive catheter in the distal coronary sinus there appear to be no satisfactory lateral veins for lead placement. B: Repeat venogram with the balloon proximal in the coronary sinus partially fills a more proximal branch missed on the distal injection.

Coronary venous anatomy “Shepherd’s Crook” take-off of lateral marginal vein Absence of lateral marginal or posterior cardiac veins serving the LV free wall Multiple diminutive lateral marginal veins

Phrenic nerve stimulation A: LV lead positioned in lateral marginal vein. This site was rejected due to phrenic nerve stimulation. B: Repositioning of a larger diameter LV lead more proximally in the same vein eliminated phrenic nerve stimulation.

High LV stimulation threshold A good lead position does not guarantee a good response Scar burden- presence, location and/or extent of left ventricular scar may impact response to CRT Articles Comments Circulation 2006; 113:969. [n= 40, Cardiac MRI] 14 had transmural posterolateral scar  lower response rate to CRT Am Heart J 2007; 153:105 [n=50, SPECT imaging] Global scar burden, number of severely scarred segments and scar burden near the LV lead were all inversely correlated with increase in LVEF after CRT

Other complications C.S. or Coronary vein trauma Pneumothorax Diaphragmatic/ phrenic nerve pacing Infection Prolonged radiation risk Articles Comments JAMA 2007; 297:2502 54 studies (n=6123) of CRT-alone devices [implantation unsuccessful- 7%, death during implantation-0.3%] [Median 6 months f/up 5% devices malfunctioned and 2% hospitalized for infections in the implant site] [Median 11 months f/up 7% lead problems]

Optimal LV lead placement Varies b/w patients Venous anatomy Regional and global LV mechanical function Myocardial substrate Characterization of electrical activation Success depends on pacing from a site which causes a change in activation sequence improvement in cardiac function Systolic improvement and mechanical resynchronization does not always require electrical synchronization

Optimal LV lead placement PATH-CHF II trial ‘Activating a later activated region produced a larger response becos’ it more efficiently restores regional activation synchrony’ ‘Best site yielded greater improvements in +dP/dt max than pacing the coronary sinus, the lateral LV wall, or the latest activated LV wall as determined by echocardiography’ Anterior pacing- Worsened acute hemodynamics Lateral pacing- Increased LV +dP/dt & pulse pressure

Hardware Leads

Hardware PG 1. DDD A V RV LV Ventricular double counting loss of CRT Pacemaker inhibited if LV lead slips into CS with sensing of atrial activity

Hardware 2. Multisite pacing

Hardware Pacing chamber Biventricular Univentricular Uneasiness about long term LV lead performance If LV lead displaces into atrium bradycardia Some pts respond only to BiV pacing ICD systems require RV pacing [sensing, high voltage therapies, long record of safety and reliability Univentricular Uncertainty abt requirement of RV stimulation Equally efficacious

Hardware Trials Comments DECREASE-HF [N=306, NYHA III or IV, LVEF ≤35%, QRS ≥150 ms] Randomly assigned to simultaneous BiV pacing, sequential BiV pacing (ie, LV activation preceding RV by 20 to 80 ms) or LV pacing.). At 6m, all groups had a significant improvement in LVEF and LV volumes (standard BiV pacing had the greatest improvement in ESV) B-LEFT HF [N=176, NYHA III or IV, LVEF ≤35%,QRS ≥130 ms] randomized to BiV or LV. At 6m, LV pacing non inferior (improvement in NYHA class, reverse remodeling, improvement in HF composite score, and reduction in LV ESV of at least 10%). GREATER-EARTH [N=121, LVEF ≤35%, QRS ≥120 ms] randomized to LV followed by BiV pacing or vice versa for consecutive 6m periods Reverse remodeling (≥15 percent reduction in LV ESV) was observed in 47% LV pacing and 55% BiV. Clinical response (≥20% increase in exercise duration) to LV and BiV pacing was similar (48 and 55 percent). 17% of BiV nonresponders improved with LV pacing and 31% vice versa.

Programming Modes For maximum benefit pacing must be continuous DDD AV synchrony preserved V pacing with all atrial events But increases possibility of atrial pacing and alter left AV timing relations due to interatrial conduction & atrial pacing latency A port LV and V port RV – LV paced before RV and protects against LV lead displacement & Brady VDD No atrial pacing A sense V pace But if sinus rate below lower prog rate limit VVI mode AV synchrony lost

Ventricular double counting I generation CRT Ventricular double counting causes loss of V pacing and CRT Produced by prolonged PVARP, ameliorated by reducing PVARP In CRT-D it can be mistaken for VT and shocked I generation CRT Ventricular double counting causes loss of V pacing and CRT Produced by prolonged PVARP, ameliorated by reducing PVARP In CRT-D it can be mistaken for VT and shocked

Atrioventricular optimization Not essential but for maximal hemodynamic response to CRT (Ventricular function can be improved by CRT in AF) AV optimization can result in 15-40% improvement and small changes in AV delay can nullify the hemodynamic effect of CRT

Responders vs. non-responders Non-responders not properly defined 18-30% pts fail to respond clinically Reasons Delayed ventricular activation may not produce mechanical dysynchrony Technical limitation ( no good site for pacing) MIRACLE study up to 57% patients had suboptimal lead positioning QRSd >150, LV +dP/dt <700 mmHg/sec greatest predictor of acute hemodynamic response to CRT

Responders vs. non-responders Specificity curve indicates that 80% of nonresponders have QRSd< 150ms Sensitivity curve indicates that 80% of responders have QRSd>150 ms CRT response is defined as greater than 5% acute increase in LV + dP/dt Drawbacks In some cases of LBBB, RV activation may be more prolonged than LV LBBB with no mechanical dysynchrony

Responders vs. non-responders Delay between the max. posterior displacement of septum and max. displacement of the LV posterior wall- [mean 192 ms to 14ms after 1m of CRT; responder 15% improvement in LV sys volume index] Tissue doppler imaging [currently the most widely studied method for direct measurement of dysynchrony] Baseline contractile function indexed by LV +dP/dt max inversely correlate with improvement after CRT Cardiac MRI (CMR)

Responders vs. non-responders Myocardial strain imaging Electrical activation patterns assessed by electrophysiological mapping Multicenter, prospective, nonrandomized study (PROSPECT) (n= 498) 12 echo dysynchrony measures (including 7 TDI parameters) offered only modest sensitivity (9 to 77 percent) and specificity (31 to 93 percent) to predict clinical composite score response; large variability in the analysis of the dysynchrony parameters. Therefore, no single echocardiographic measure of dysynchrony can be recommended to improve patient selection for CRT

Responders vs. non-responders Ischemic vs. non ischemic Males vs. females RBBB vs. LBBB Avoid RA pacing with DDD Interruption of CRT- atrial arrhythmias( MC), loss of LV capture

Clinical trials NYHA class III-IV Trials Comments Meta analysis [CARE-HF, COMPANION, MIRACLE and MIRACLE ICD, MUSTIC-SR and MUSTIC-AF, PATH-CHF, VENTAK CHF/CONTAK CD HOBIPACE] 14 trials, n=4420. Improving at least one NYHA class (59 versus 37 percent, relative risk [RR] 1.6, 95% CI 1.3-1.9), improvements in 6 min walk distance (mean difference 24 meters). Reduced rate of HF hospitalizations (RR 0.63, 95% CI 0.43-0.93). Reduced all-cause mortality (RR 0.78, 95% CI 0.67-0.91) COMPANION [CRT +ICD n= 1520, NYHA class III or IV, QRSd ≥120 ms LVEF ≤35%] OMT, CRT or CRT-D. All-cause mortality and all-cause hospitalization both CRT arms vs. OMT(56 and 56 versus 68 percent, HR 0.80, 95% CI 0.68-0.95) mortality benefit CRT-D vs. 8m in CRT alone CARE-HF [n=813 NYHA III or IV HF, LVEF ≤35 percent QRSd >160ms or QRSd 120-149 + echo LV dysynchrony] CRT vs. OMT. All cause mortality, hospitalization for CV disease, improv in SCD, LVEF, Functional class, LV remodeling

Clinical trials Trials Comments CRT-D [CARE-HF, COMPANION, RAFT (NYHA II or III & LVEF ≤35%)] [REVERSE & MADIT-CRT(NYHA I or II, QRS ≥120-150&LVEF≤30-40%)] CRT plus ICD showed an almost significant trend toward lower all-cause mortality compared to CRT alone in patients with NYHA III or IV Reduce risk of rehospitalization, HF events and remodeling in patients with NYHA I or II NYHA II Meta-analysis (NYHA I to II, LVEF ≤40%)(MIRACLE ICD-II, REVERSE, MADIT-CRT, NYHA II pts from RAFT) CRT decreased mortality (OR 0.78, 95% CI 0.63 to 0.97) and HF events (OR 0.63, 95% CI 0.52 to 0.76), induced significant LV reverse remodeling, and reduced the progression of HF symptoms (OR for worsening NYHA functional class 0.54; 95% CI 0.31 to 0.93) MADIT-CRT [n=1820, LVEF ≤30%, QRS ≥130 ms & NYHA class I (15%) or II (85%) randomized to CRT-D or ICD alone, f/up 29m] Death from any cause or a nonfatal HF event decreased in CRT-D vs. ICD alone (17 versus 25 percent), 41% reduction in HF events. CRT induced reverse remodeling in QRS duration >150 ms

Indications 2008 ACC/AHA/HRS guidelines for device-based therapy of rhythm abnormalities, the 2005 ACC/AHA HF guidelines with 2009 focused update patients with LVEF ≤35 percent, a QRS duration ≥120 ms, SR, NYHA functional class III or ambulatory class IV symptoms with optimal medical therapy [1A] Patients with LVEF ≤35 percent, a QRS duration ≥120 ms, AF, NYHA functional class III or ambulatory class IV symptoms with optimal medical therapy [11a, B]

ESC Guidelines for HF 2012

MCQ 1 Complications of CRT implantation include all except- Pneumothorax Infection Phrenic nerve stimulation Sustained VT

MCQ 2 Which of the following is false? Increased LV Scarring is associated with increased LV stimulation threshold Phrenic nerve stimulation in the immediate post CRT period may require repositioning of the leads CRT may allow patients to discontinue beta blockers Epicardial leads are surgically implanted in the region of OM arteries

MCQ 3 Most common cause of CRT interruption is Loss of LV capture Atrial arrhythmias Amiodarone therapy Lead perforation

MCQ 4 Which of the following statements is false Activating a later activated region produced a larger response in LVEF ‘Best site pacing’ yielded greater improvements in +dP/dt max than pacing the latest activated LV wall as determined by echocardiography Pacing of LV anterior wall is better than Lateral wall Systolic improvement and mechanical resynchronization does not always require electrical synchronization

MCQ 5 Which of the following statements is true? CRT-D preferentially uses LV pacing alone BiV pacing has been found to be superior to LV pacing alone RA pacing with DDD mode improves LV function additionally by 15% Some patients respond only to BiV pacing

MCQ 6 Least chance of response to CRT among the following QRSd 160ms dP/dt 600mmHg/s Ischemic CMP LBBB pattern

MCQ 7 False statement- 80% of nonresponders have QRSd< 150ms 80% of responders have QRSd>150 ms Tissue doppler imaging is the most widely studied method for direct measurement of dysynchrony As baseline LV +dP/dt increases the response to CRT improves

MCQ 8 False statement about Ventricular double counting - Ventricular double counting is a cause for interruption of CRT. More common in the first generation devices Improved by prolonging PVARP Mistaken for VT in CRT-D

MCQ 9 False regarding AV optimization- Atrioventricular optimization is not absolutely essential for CRT AV delay kept longer than normal AV conduction Diastolic MR can occur in prolonged AV delay Small changes in AV delay can sometimes nullify the effects of CRT

MCQ 10 Which of the following is not a contra indication for CRT Poor survival expected (<1 year) Sinus rhythm LVEF 40% RBBB QRS 120ms

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