Journal of Nuclear Medicine, published on December 12, 2011 as doi:10.2967/jnumed.111.095448 Impact of Myocardial Scarring on Outcomes of Cardiac Resynchronization Therapy: Extent or Location? Yi-Zhou Xu1, Yong-Mei Cha1–3, Dali Feng4, Brian D. Powell1, Heather J. Wiste5, Wei Hua3, and Panithaya Chareonthaitawee1 1Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota; 2Department of Cardiology, Hangzhou First People’s Hospital of Nanjing Medical University, Hangzhou, China; 3Cardiac Arrhythmia Center, Fu Wai Hospital of the Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; 4Metropolitan Heart and Vascular Institute, Minneapolis, Minnesota; and 5Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota Refining the criteria for patient selection for cardiac resynchro- Heart failure (HF) prevalence is estimated to be 1%– nization therapy (CRT) may improve its outcomes. The study 2% in Western countries, with an incidence of approxi- objective was to determine the effect of scar location, scar mately 5–10 per 1,000 persons per year. HF negatively burden, and left ventricular (LV) lead position on CRT outcomes. Methods: The study included 213 consecutive CRT recipients affects quality of life and survival and accounts for 1%– with radionuclide myocardial perfusion imaging before CRT be- 2% of all health-care expenditure in developed countries. tween January 2002 and December 2008. Scar localization and Left ventricular (LV) systolic function underlies the tradi- myocardial viability were analyzed using a 17-segment model tional HF paradigm and, despite significant advances in and a 5-point semiquantitative scale. New York Heart Associa- treatment, 5-y mortality still approaches 50% (1). Cardiac tion (NYHA) class and echocardiography were assessed before resynchronization therapy (CRT) is a treatment option for and after CRT. The anatomic LV lead location in the 17-segment model was assessed by review of fluoroscopic cinegrams in advanced HF despite optimal medical therapy, reduced LV right and left anterior oblique views. As in published studies, clinical ejection fraction (EF), and wide QRS complex. Random- response was defined as an absolute improvement in LV ejection ized studies have demonstrated that CRT can improve car- fraction of $5 percentage points after CRT. Results: A total of 651 diac function, clinical symptoms, quality of life, and even scar segments was identified in 213 patients. Eighty-three percent survival for patients with advanced HF (2–5). However, of scar segments were located in the LV anterior, posterior, septal, about one third of HF patients with reduced LVEF and wide and apical regions, whereas 84% of LV leads were in the lateral wall. Only 11% of LV leads were positioned in scar segments. The QRS do not clinically respond after CRT. The reasons are extent of scarring was significantly higher in nonresponders than in multifactorial, and predicting who will respond to CRT responders (18.0% vs. 6%, P 5 0.001). Compared with patients remains a challenge (2,6). The suboptimal selection of with scarring .22%, patients #70 y with scarring #22% of the left CRT candidates has been considered an important contrib- 6 ventricle had a greater increase in LV ejection fraction (10.1% utor to the less optimal response rate. Diverse strategies to 10.5% vs. 0.8% 6 6.1%; P , 0.001) and improvement in NYHA identify cardiac mechanical dyssynchrony and other predic- class (–0.9 6 0.7 vs. –0.5 6 0.8; P 5 0.02). Conclusion: LV leads were often located in viable myocardial regions. Less scar burden tors of benefit from CRT have been developed to improve was associated with a greater improvement in heart failure but only CRT patient selection (7,8). Over 25 echocardiographic in relatively younger CRT recipients. studies using LV dyssynchrony to predict CRT response Key Words: cardiac resynchronization therapy; heart failure; have been published, reporting a sensitivity of 24%– myocardial scarring; viability; imaging 100% and specificity of 55%–100% (7). Careful analysis J Nucl Med 2012; 53:1–8 of this literature reveals many limitations, including small DOI: 10.2967/jnumed.111.095448 sample sizes, single-center studies, lack of consensus in CRT-response assessment, and variable LV dyssynchrony measurements. Similarly, cardiac MRI studies of LV dys- synchrony to predict CRT response have been reported but also with variable results and similar limitations. A prom- Received Jul. 8, 2011; revision accepted Sep. 22, 2011. ising predictor is the measurement of myocardial scarring, For correspondence or reprints contact either of the following: Panithaya by either cardiac MRI or nuclear imaging; however, pub- Chareonthaitawee, Division of Cardiovascular Diseases, Mayo Clinic, 200 First St. SW, Rochester, MN 55905. lished studies also remain limited and inconclusive. Cardiac E-mail: [email protected] MRI studies suggest the role of scar location, scar burden, Wei Hua, Fu Wai Hospital and Cardiovascular Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, China. and scar transmurality in predicting CRT response, but E-mail: [email protected] most studies were small (8). Nuclear studies report higher Published online nnnn. COPYRIGHT ª 2012 by the Society of Nuclear Medicine, Inc. scar burden in CRT nonresponders than in responders but CARDIAC RESYNCHRONIZATION AND MYOCARDIAL SCARRING • Xu et al. 1 jnm095448-pm n 12/12/11 Copyright 2011 by Society of Nuclear Medicine. were limited similarly by their small sample size (9–12). validated in our nuclear cardiology laboratory and was found to Most studies did not assess lead position in relation to scar have a moderately high level of agreement. location. The purpose of this study was, therefore, to eval- Resting transthoracic 2-dimensional echocardiography was uate the relationships between myocardial scar distribution, performed before and at a median of 6.8 mo (interquartile range location, and burden by nuclear imaging, LV lead position, [IQR], 4.1–11.3 mo) after CRT implantation. Standard long-axis 2- and 4-chamber images and calculation of LV end-systolic and CRT clinical response and outcomes in a large cohort dimensions (LVESDs) and end-diastolic dimensions (LVEDDs) of patients with advanced HF and reduced LVEF. and LVEF were obtained using the Simpson biplane method. Mi- tral regurgitation (MR) severity was graded using standard tech- MATERIALS AND METHODS niques (0, none or trivial; 1, mild; 2, moderate; and 3, severe). From January 1, 2002, through December 31, 2008, 720 Right ventricular enlargement and systolic dysfunction (for both, consecutive patients with advanced HF received a CRT device at 0, normal; 1, mild; 2, moderate; and 3, severe) and pulmonary the Mayo Clinic. Of these, 213 patients had radionuclide artery systolic pressure were estimated from the transtricuspid myocardial perfusion imaging (MPI) within 1 y before CRT and maximal regurgitant flow velocity. were included. All patients met standard CRT criteria: New York Regarding CRT implantation and programming, commercially Heart Association (NYHA) functional class III or IV, LVEF # available leads and CRT devices were used. The lateral and 35%, and QRS duration $ 120 ms. Ischemic cardiomyopathy posterolateral cardiac veins were the target of LV lead placement, (ICM) was determined by coronary angiography as presence of as allowed by coronary venous anatomy, diaphragmatic stimula- coronary artery stenosis $ 70% in at least 1 major coronary artery tion, or pacing thresholds. The standard settings included DDD or or $ 50% in the left main (13). The study was approved by the DDDR mode and atrioventricular delay of 100 ms (sensed) and Mayo Clinic Institutional Review Board, and all patients con- 130 ms (paced). The device was programmed in VVIR mode when sented to participate in the study. chronic atrial fibrillation was present. Baseline clinical characteristics were obtained from medical Six-month follow-up was recommended after device implanta- records. Each subject was evaluated for symptom status, HF tion but actual follow-up time varied, with a median time of 6.8 etiology, NYHA functional class, and medication use. A 12-lead mo (IQR, 4.1–11.3 mo). NYHA status and echocardiography were electrocardiogram was performed at baseline; QRS duration and reassessed. As in prior studies, clinical response was defined as an morphology were assessed. The measurement of B-type natri- absolute improvement in LVEF of $5 percentage points after CRT uretic peptide (BNP) (14) was performed before and at 3 and 6 mo (6,20). Survival status as of May 2009 was obtained using a na- after CRT implantation. tional death and location database (Accurint; LexisNexis) (21). Before CRT implantation, 46 patients underwent PET MPI, and The median follow-up time was 3.2 y (IQR, 1.9–4.8 y). 167 patients underwent SPECT MPI. The anatomic lead locations in the 17-segment model were PET images were acquired with a PET Advance scanner assessed by review of fluoroscopic cinegrams in right and left (GE Healthcare) before CRT. After positioning in the scanner, anterior oblique views in available patients (22). The left ventricle a 4-min transmission scan was obtained to check optimal LV was divided into 3 levels (basal, mid, and apical). To match the MPI positioning in the field of view. A 10-min transmission scan was segments, the basal and mid levels were each divided further into 6 subsequently obtained for attenuation correction of the emission images. 13N-ammonia (370–740 MBq [10–20 mCi]; n 5 36) or TABLE 1 82 5 Rb (1,850–2,220 MBq [50–60 mCi]; n 7) was injected in- Baseline Demographics travenously at rest, followed immediately by the resting static emission acquisition. Variable Overall value SPECT images were acquired as described previously (15,16) 6 using either a 1-d low-dose rest 99mTc-sestamibi protocol (n 5 Age (y) 70.2 9.4 153) or a delayed 201Tl protocol (n 5 17).