2) Massachusetts General Hospital, 55 Fruit St, Boston, MA 02114 Journal of Nuclear Cardiology | Official Journal of the American Society of Nuclear Cardiology Assessment of Dyssynchrony by Gated Myocardial Perfusion Imaging Does Not Improve Patient Management   Ran Lee, MD (1), Ravi V. Shah, MD (2) and Venkatesh L. Murthy, MD, PhD (1) 1) Frankel Cardiovascular Center, University of Michigan, 1500 E. Medical Center Dr, Ann Arbor, MI 48109-5873 2) Massachusetts General Hospital, 55 Fruit St, Boston, MA 02114 Copyright American Society of Nuclear Cardiology

Journal of Nuclear Cardiology | Official Journal of the American Society of Nuclear Cardiology BACKGROUND Heart failure is the most common cause for hospitalization in patients older than 65 years old Despite optimal medical therapy, morbidity and mortality remain high Mechanical dyssynchrony is prevalent and leads to worsening symptoms and poorer prognosis Copyright American Society of Nuclear Cardiology

Journal of Nuclear Cardiology | Official Journal of the American Society of Nuclear Cardiology Results Several trials demonstrate benefit of cardiac resynchronization, leading to guidelines supporting its use in patients with QRS ≥ 150 ms, LBBB morphology, NYHA II-IV symptoms and LVEF ≤ 35% on guideline-directed medical therapy There are several methods by which to measure dyssynchrony, including electrocardiographic, echocardiographic, and nuclear Several large randomized echo trials (PROSPECT, EchoCRT) to date have not supported routine use of echocardiographic methods of dyssynchrony imaging in patient selection or decision to implant resynchronization devices To date, using gated SPECT imaging, phase standard deviation and histogram bandwidth have been used to assess patients who may respond to CRT, in addition to being measures that may be related to hard outcomes such as mortality or arrhythmias ERNA has been used as well to assess for response to CRT therapy Copyright American Society of Nuclear Cardiology

Journal of Nuclear Cardiology | Official Journal of the American Society of Nuclear Cardiology Figures Figure 1: Pressure-Volume Loop with and without Mechanical Dyssynchrony11,12. Right ventricular free wall pacing was used to induce dyssynchrony 12. Atrial pacing was used as a control. In the setting of induced dyssynchrony, stroke volume decreases and end-systolic volume increases while the end-systolic pressure-volume relationship (ESPVR) shifts to the right11. 11. Cheng A, Helm RH, Abraham TP. Pathophysiological mechanisms underlying ventricular dyssynchrony. Europace. 2009; 11: v10-v14.   12. Park RC, Little WC, O'Rourke RA. Effect of alteration of left ventricular activation sequence on the left ventricular end-systolic pressure-volume relation in closed-chest dogs. Circ Res. 1985;57:706-17. Copyright American Society of Nuclear Cardiology

Journal of Nuclear Cardiology | Official Journal of the American Society of Nuclear Cardiology Table Study Question Patients (n) Inclusion Criteria Therapy Primary End Point P value MUSTIC-SR (NEJM 2001)34 CRT benefit in HFrEF 58 NYHA III LVEF <35% QRS > 150 ms LVEDd ≥ 60 mm Active vs. Inactive CRT after implant 6 min walk <0.001c MIRACLE (NEJM 2002)8 453 NYHA III-IV LVEF ≤ 35% QRS ≥ 130 ms LVEDd ≥ 55 mm 6MW ≤ 450 m NYHA, QOL score, 6 min walk <0.001a 0.001b 0.005c MIRACLE-ICD (JAMA 2003)35 CRT-D benefit in HFrEF 369 0.007a 0.02b 0.36c CARE-HF (NEJM 2005)9 814 QRS ≥ 120 ms LVEDd ≥ 30 mm CRT vs. optimal medical therapy Death or hospitalization HR 0.63; CI 0.51-0.77; p<0.001 REVERSE (JACC 2008)22 610 NYHA I-II LVEF ≤ 40% HF clinical composite response, hospitalization 0.10d HR 0.47e p=0.03e MADIT-CRT (NEJM 2009)23 1820 LVEF ≤ 30% CRT-D vs. ICD alone Death or non-fatal HF event HR 0.66, CI 0.52-0.84, p=0.001 RAFT (NEJM 2010)36 1798 NYHA II-III Death, hospitalization for CHF HR 0.75, CI 0.62-0.91, p=0.003 8. Abraham WT, Fisher WG, Smith AT, et al. on behalf of the MIRACLE Study Group. Cardiac resynchronization in chronic heart failure. N Engl J Med. 2002;346:1845-53. 9. Cleland JG, Daubert JC, Erdmann E, et al. on behalf of the Cardiac Resynchronization-Heart Failure (CARE-HF) Study Investigators. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med. 2005; 352:1539-49. 22. Daubert C, Gold MR, Abraham WT, et al., on behalf of the REVERSE Study Group. Prevention of disease progression by cardiac resynchronization therapy in patients with asymptomatic or mildly symptomatic left ventricular dysfunction: insights from the European cohort of the REVERSE trial. J Am Coll Cardiol. 2009; 54:1837-46. 23. Moss AJ, Hall WJ, Cannom DS, et al., on behalf of the MADIT-CRT Trial Investigators. Cardiac-resynchronization therapy for the prevention of heart-failure events. N Engl J Med. 2009; 361:1328038. 34. Cazeau S, Leclercq C, Lavergne T, et al. Effects of multisite biventricular pacing in patients with heart failure and intraventricular conduction delay, on behalf of the MUSTIC Study Investigators. New Engl J Med. 2001; 344(12):873-80. 35. Young JB, Abraham WT, Smith AL, et al. Combined cardiac resynchronization and implantable cardioversion defibrillation in advanced chronic heart failure: the MIRACLE ICD Trial. JAMA. 2003; 289(20):2685-94. 36. Tang AS, Wells GA, Talajic M, et al. Cardiac-resynchronization therapy for mild-to-moderate heart failure, on behalf of the RAFT Trial Investigators. N Engl J Med. 2010; 363(25):2385-95. aNYHA Class Improvement bQOL or Quality of Life Score Improvement c6-minute Walk Improvement dHF clinical composite response eTime to first hospitalization Copyright American Society of Nuclear Cardiology

Journal of Nuclear Cardiology | Official Journal of the American Society of Nuclear Cardiology CONCLUSIONS Although imaging methods of dyssynchrony assessment may be useful in research, their clinical role remains unproven Despite favorable small, single-center studies assessing these techniques, there are no existing high-quality data supporting the use of noninvasive methods of dyssynchrony assessment in patient selection for cardiac resynchronization therapy Copyright American Society of Nuclear Cardiology