Cardiac Resynchronization Therapy for Heart Failure Patient Selection and Clinical Outcomes Edited by A kharazi M.D cardiac electrophysiologist

Heart Failure (HF) Definition A complex clinical syndrome in which the heart is incapable of maintaining a cardiac output adequate to accommodate metabolic requirements and the venous return.

Etiology of Heart Failure What causes heart failure? The loss of a critical quantity of functioning myocardial cells after injury to the heart due to: –Ischemic Heart Disease –Hypertension –Idiopathic Cardiomyopathy –Infections (e.g., viral myocarditis, Chagas’ disease) –Toxins (e.g., alcohol or cytotoxic drugs) –Valvular Disease –Prolonged Arrhythmias

Prevalence of HF by Age and Gender United States: Source: NHANES III ( ), CDC/NCHS and the American Heart Association

New York Heart Association Functional Classification Class I:No symptoms with ordinary activity Class II:Slight limitation of physical activity. Rest comfortable but ordinary physical activity results in fatigue, palpitation, dyspnea, or angina Class III:Marked limitation of physical activity. Comfortable at rest, but less than ordinary physical activity results in fatigue, palpitation, dyspnea, or anginal pain Class IV:Unable to carry out any physical activity without discomfort. Symptoms of cardiac insufficiency may be present even at rest

Poor Quality of Life for HF patients Hobbs FDR, et al. Eur Heart J 2002;23: Doug Smith:

MERIT-HF Study Group. Effect of Metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL randomized intervention trial in congestive heart failure (MERIT-HF). LANCET. 1999;353: Severity of Heart Failure Modes of Death 12% 24% 64% CHF Other Sudden Death n = 103 NYHA II 26% 15% 59% CHF Other Sudden Death n = 103 NYHA III 56% 11% 33% CHF Other Sudden Death n = 27 NYHA IV

VolumeOverloadPressureOverload Loss of MyocardiumImpairedContractility LV Dysfunction EF < 40%  Cardiac Output Hypoperfusion  End Systolic Volume  End Diastolic Volume Pulmonary Congestion Left Ventricular Dysfunction

Treatment Approach for the Patient with Heart Failure Stage A At high risk, no structural disease Stage B Structural heart disease, asymptomatic Stage D Refractory HF requiring specialized interventions Therapy Treat HypertensionTreat Hypertension Treat lipid disordersTreat lipid disorders Encourage regular exerciseEncourage regular exercise Discourage alcohol intakeDiscourage alcohol intake ACE inhibitionACE inhibitionTherapy All measures under stage AAll measures under stage A ACE inhibitors in appropriate patientsACE inhibitors in appropriate patients Beta-blockers in appropriate patientsBeta-blockers in appropriate patientsTherapy All measures under stage AAll measures under stage ADrugs: DiureticsDiuretics ACE inhibitorsACE inhibitors Beta-blockersBeta-blockers DigitalisDigitalis Dietary salt restrictionDietary salt restrictionTherapy All measures under stages A,B, and CAll measures under stages A,B, and C Mechanical assist devicesMechanical assist devices Heart transplantationHeart transplantation Continuous (not intermittent) IV inotropic infusions for palliationContinuous (not intermittent) IV inotropic infusions for palliation Hospice careHospice care Stage C Structural heart disease with prior/current symptoms of HF Hunt, SA, et al ACC/AHA Guidelines for the Evaluation and Management of Chronic Heart Failure in the Adult, 2001

Diuretics, ACE Inhibitors Reduce the number of sacks on the wagon

ß-Blockers Limit the donkey’s speed, thus saving energy

Digitalis Compounds Like the carrot placed in front of the donkey

Ventricular Dysynchrony Abnormal ventricular conduction resulting in a mechanical delay –Wide QRS (IVCD); typically LBBB morphology –Poor systolic function –Impaired diastolic function ECG depicting interventricular conduction delay

Prevalence of Ventricular Dyssynchrony in Heart Failure 1. Masoudi, et al. JACC 2003;41: Aaronson, et al. Circ 1997;95:2660-7

Elements of Cardiac Dyssynchrony Atrio- ventricular Inter- ventricular Intra- ventricular Cazeau, et al. PACE 2003; 26[Pt. II]: 137–143

Intra-ventricular Dyssynchrony Septal-Posterior Wall Motion Delay Difference in times from peak excursions of the septum and of the posterior wall at the papillary muscle level SPWMD  130 ms predicted response (LVEDVi) to CRT in study of 25 pts with QRS  140 ms 1 From parasternal short-axis view at papillary muscle level 1. Pitzalis M, et al. JACC 2002;40: septum Posterior wall Parasternal Long-axis View Shown

Animation – Ventricular Dysynchrony Click to Start/Stop

1 Tavazzi L. Eur Heart J 2000;21: Tavazzi L. Eur Heart J 2000;21: Shenkman et al. Circulation 2000; 102(18):Suppl II, abstract Etiology of Ventricular Dysynchrony What Causes Ventricular Dysynchrony? 1 –Inter- or intraventricular conduction delays usually manifested as left bundle branch block –Regional wall motion abnormalities with increased workload and stress—compromising ventricular mechanics –Disruption of myocardial collagen matrix impairing electrical conduction and mechanical efficiency Estimated that 15% of all HF patients have ventricular dysynchrony 2

Clinical Consequences of Ventricular Dysynchrony Abnormal interventricular septal wall motion 1 Reduced dP/dt 3 Reduced diastolic filling time 1,2 Prolonged MR duration 1,2 1 Grines CL, Bashore TM, Boudoulas H, et al. Circulation 1989;79: Grines CL, Bashore TM, Boudoulas H, et al. Circulation 1989;79: Xiao, HB, Lee CH, Gibson DG. Br Heart J 1991;66: Xiao, HB, Lee CH, Gibson DG. Br Heart J 1991;66: Xiao HB, Brecker SJD, Gibson DG. Br Heart J 1992;68: Xiao HB, Brecker SJD, Gibson DG. Br Heart J 1992;68: Click to Start/Stop

Deleterious Effects of Ventricular Dyssynchrony on Cardiac Function Reduced diastolic filling time 1 + Weakened contractility 2 + Protracted mitral regurgitation 2 + Post systolic regional contraction 3 = Diminished stroke volume 1. Grines CL, et al Circulation 1989;79: Xiao HB, et al Br Heart J 1991;66: Søgaard P, et al. J Am Coll Cardiol 2002;40:723–730 Courtesy of Ole-A. Breithardt, MD

Cardiac Resynchronization Therapy The therapeutic intent of atrial-synchronized, biventricular pacing is to restore ventricular synchrony Complements drug therapy

Cardiac Resynchronization Therapy Goals Improve hemodynamics Improve Quality of Life

Cardiac Resynchronization Therapy Cardiac resynchronization, in association with an optimized AV delay, improves hemodynamic performance by forcing the left ventricle to complete contraction and begin relaxation earlier, allowing an increase in ventricular filling time. Coordinate activation of the ventricles and septum. ECG depicting cardiac resynchronization ECG depicting IVCD

Cardiac Resynchronization Therapy Increase the donkey’s (heart) efficiency

Achieving Cardiac Resynchronization Goal: Atrial synchronous biventricular pacing Transvenous approach for left ventricular lead via coronary sinus Back-up epicardial approach Doug Smith: Right Atrial Lead Right Ventricular Lead Left Ventricular Lead

Transvenous Approach –Standard pacing leads in RA and RV –Specially designed left heart lead placed in a left ventricular cardiac vein via the coronary sinus Achieving Cardiac Resynchronization Mechanical Goal: Pace Right and Left Ventricles Cardiac Resynchronization System

Proposed Mechanisms of Cardiac Resynchronization Improved Contraction Pattern AV Interval Optimization Click to Start/Stop

LV Pacing Dobutamine Nelson et al. Circulation 2000;102: CRT Improves Cardiac Function at Diminished Energy Cost p< 0.05

CRT Improves Cardiac Function at 6 Months in Moderate to Severe Heart Failure LVEF Avg. Change (Absolute %) Data sources: MIRACLE: Circulation 2003;107: MIRACLE ICD:JAMA 2003;289: Contak CD: J Am Coll Cardiol 2003;2003;42:  Control  CRT MR Jet Area Avg. Change (cm 2 ) Not Reported

MR area LV End Systolic and Diastolic Volumes LV Reverse Remodeling after CRT PacingNo pacing N = 25 Yu CM, et al, Circulation 2002;105:

Mortality/Morbidity Comparison Risk reduction with CRT or CRT + ICD Study (n random.) Follow -up Treat- ment Mor- tality & Hosp. Mortal. & HF Hosp. Mor- tality HF Mort. HF Hosp. MIRACLE 1 (n=453) 6 MCRT 39% 27% 50% JAMA meta- analysis 2 (n=1634)* 3-6MCRT 23%51%29% P < 0.05 * Includes MIRACLE Date Sources: 1. Abraham WT, et al. N Engl J Med 2002;346: Bradley DJ, et al. JAMA 2003;289:

CRT Improves Submaximal Exercise Distance Walked in 6 Minutes Change from Baseline* Change from Baseline* Follow-up Period (Month) Meters 1 * Paired median change Error bars are 95% CI. P=0.004 P=0.003 P=0.005 Baseline (meters) 291 ± ± 85 Abraham WT, Fisher WG, Smith AL, et al. N Engl J Med 2002;346: Abraham WT, Fisher WG, Smith AL, et al. N Engl J Med 2002;346: CRT Control

CRT Improves Patients’ Quality of Life Minnesota Living with Heart Failure Questionnaire Baseline (score) 59 ± ± 20 Abraham WT, Fisher WG, Smith AL, et al. N Engl J Med 2002;346: Abraham WT, Fisher WG, Smith AL, et al. N Engl J Med 2002;346: * Paired median change Error bars are 95% CI. Change from Baseline* Follow-up Period (Month) Score Improvement (points) 1 P=0.001 P<0.001 P<0.001 CRT Control

CRT Improves NYHA Functional Class Number of Patients Improved 2 or more classes Improved 1 class No Change Worsened Control CRT 6% 32% 59% 4% 16% 52% 30% 2%P<0.001 Abraham WT, Fisher WG, Smith AL, et al. N Engl J Med 2002;346: Abraham WT, Fisher WG, Smith AL, et al. N Engl J Med 2002;346:

CRT Improves Exercise Capacity in Moderate to Severe Heart Failure 6 Min Walk Avg. Change (m) Data sources: MIRACLE: Circulation 2003;107: MUSTIC SR: NEJM 2001;344: MIRACLE ICD:JAMA 2003;289: Contak CD: J Am Coll Cardiol 2003;2003;42:  Control  CRT Peak VO 2 Avg. Change (mL/kg/min)

Optimizing VV Delay Based on Aortic VTI Obtain Pulsed Wave Doppler of LVOT with several different sequential ventricular paced intervals Select the setting yielding the largest VTI as the optimal paced interval CSA is assumed constant, therefore optimal delay is based on VTI alone LV first by 4 ms LV first by 20 ms RV first by 40 ms

Relative Cost of CRT Doug Smith:

CRT: Moderate to severe systolic heart failure with wide QRS Jessup M, Brozena S. Medical Progress--Heart Failure. N Eng J Med 2003; 348: Copyright 2002 Massachusetts Medical Society. All rights reserved.

Patient Indications CRT device: –Moderate to severe HF (NYHA Class III/IV) patients –Symptomatic despite optimal, medical therapy –QRS  130 msec –LVEF  35% CRT plus ICD: –Same as above with ICD indication Cardiac Resynchronization Therapy

–is safe and well tolerated –improves quality of life, functional class, and exercise capacity –Improves cardiac function and structure –improves heart failure composite response –may have a favorable effect on combined measures of morbidity and mortality In NYHA Class III and IV systolic heart failure patients with intraventricular conduction delays, cardiac resynchronization therapy: Abraham WT, Fisher WG, Smith AL, et al. N Engl J Med 2002;346: Abraham WT, Fisher WG, Smith AL, et al. N Engl J Med 2002;346: Conclusions

Summary Large number of patients studied in RCTs Concordant proof that CRT improves quality of life, exercise capacity, functional capacity –Improvements persist through 1 year CRT reduces the risk of mortality and heart failure due to worsening HF CRT + ICD reduces risk of mortality CRT improves cardiac function and structure