A key role for nuclear cardiac imaging in evaluating and managing patients with heart failure

Mark I. Travin 0 FASNC 0 1 2 Gayathri Kamalakkannan 0 MD 0 1 2 0 From the Division of Nuclear Medicine, Department of Radiology 1 Montefiore Medical Center, Albert Einstein College of Medicine , Bronx, NY . Reprint requests: Mark I. Travin, MD , FASNC, Division of Nuclear Medicine, Department of Radiology, Montefiore Medical Center, Albert Einstein College of Medicine , 111 E. 210th Street, Bronx, NY 10467-2490 2 Division of Cardiology, Department of Medicine Congestive heart failure (CHF, HF) is a major health problem in the United States and much of the western world. More than 6 million Americans over age 20 have HF, with 1/5 people over 40 likely to develop HF sometime during their lives.1 Despite significant advancements in evaluation and management, the death rate remains high, with about 50% of HF patients dying in 5 years, and HF mentioned as a contributing factor in 1/9 death certificates.2,3 A variety of methods are used to assess patients with HF, including standard clinical techniques, i.e., history, physical examination, and laboratory measurements; a variety of non-invasive imaging procedures that include chest x-ray, echocardiography, equilibrium radionuclide angiography (ERNA), myocardial perfusion imaging with ECG-gated SPECT, cardiac CT methods, cardiac magnetic resonance imaging, and invasive procedures such as right and left heart catheterization, and coronary angiography. These methods diagnose HF, determine a likely etiology, classify its severity, identify additional contributing factors, and guide patient management in terms of remedying reversible causes, improving symptoms and patient well-being, and preventing additional adverse events ranging from frequent recurrent HF hospitalizations to dangerous cardiac arrhythmias to death. Recent American College of Cardiology Foundation/American Heart Association (ACCF/AHA) Heart Failure guidelines - recommend comprehensive pharmacologic regimens, and describe when advanced mechanical device therapies such as biventricular pacemakers for cardiac resynchronization therapy (CRT), left ventricular assist devices (LVAD), and implantable cardiac defibrillators (ICD) should be considered, as well as when cardiac transplantation is the preferred option.4 Nevertheless, much remains unclear regarding the approach to patients with HF, a condition expected to increase in prevalence in coming years as the population ages.5 In particular, many of the beneficial advanced mechanical device therapies are costly and have risks. It is important to wisely select which patients should receive them. An issue of particular focus is who should get an ICD. Based on several multicenter, prospective randomized clinical trials, the ACCF/AHA HF guidelines assign a Class IA recommendation for implantation of an ICD as primary prevention of sudden cardiac death (SCD) in patients with New York Heart Association (NYHA) Class II-III symptoms and a left ventricular ejection fraction (LVEF) B35%.4,6-8 At the same time, while trials report significant reductions in mortality with ICDs, the absolute decrease in death is relatively small, from about 5.6%7 to 7.2%,6 with 117 to 146 patients needing to receive an ICD to save 1 life.9 There are risks associated with an ICD, including a 4% postprocedural complication rate,10 infections, device malfunction, worsened quality of life, psychiatric problems, and life style restrictions.11,12 ICDs are expensive, about $28,000 per device, not including ICD follow-up costs.13 Thus, current methods for choosing which patients receive an ICD have limitations,14 and using LVEF as a major deciding parameter appears flawed.15 A key way to identify patients who are best managed with advanced mechanical therapies such as an ICD, and/or who should be referred for cardiac transplant, is effective risk stratification, better if one can adjust predicted outcomes for clinical status changes, including when a device is added. Using databases from multiple large HF studies, survival scores have been developed incorporating combinations of clinical variables. One such model, the Seattle Heart Failure Model (SHFM), uses routinely collected demographic, imaging, laboratory, and therapeutic parameters to generate a score that determines the likely 1-5-year mortality,16,17 predicts the mode of death, i.e., SCD versus progressive HF,18 and measures potential improved survival with mechanical devices.19 In response to demonstration by SCD-HEFT (SCD in HF)6 of improved survival with an ICD in Class II-III NYHA patients with LVEF B 35%, a modified version of the model, i.e., SHFM-D was developed.20 In particular, SHFM-D can identify not only subgroups of patients for whom ICD placement is most beneficial but also a subgroup that, while at high risk overall mortality, is so unlikely to have SCD that an ICD has no benefit. SHFM-D appears better than LVEFbased current approaches for deciding on an ICD. Another technique consistently found to effectively risk stratify patients with advanced HF is cardiac imaging with 123I-mIBG (metaiodobenzylguanidine), a radionuclide analogue of norepinephrine that provides information on the health of cardiac sympathetic innervation.21,22 Most commonly, global cardiac uptake is measured on delayed planar images, expressed as a ratio of cardiac activity to background, i.e., the heart-tomediastinal ratio (H/M). Among the first to recognize 123I-mIBG imaging as a potentially useful risk stratifying tool for patients with HF was Merlet et al,23 finding that H/M was independent of and superior to cardiac size on chest x-ray, echocardiographic end-diastolic diameter, and LVEF in predicting survival in patients with NYHA Class II-III symptoms and LVEF \ 45%. Subsequently, various small single-center studies reported the potential value of cardiac 123I-mIBG imaging in HF patients, followed by a 290 patient multicenter retrospective reanalysis study24 and a 1,755 patient meta-analysis25 that strengthened the belief by many that 123I-mIBG imaging provides prognostic and therapeutic guiding value beyond standard clinical and laboratory parameters. These efforts culminated in the AdreView Myocardial Imaging for Risk Evaluation in Heart Failure (ADMIRE-HF) trial, a prospective, multicenter, international study of 961 patients with NYHA Class II-III HF and LVEF B 35%.26 At 17 months, an H/M\1.6 more than doubled (from 15% to 37%) the incidence of worsening CHF, life-threatening arrhythmias, and cardiac death. Subsequent multivariate analysis showed that H/M was a predictor of cardiac and all-cause deaths independent of other clinical and image variables, including age, LVEF, and brain natriuretic peptide (BNP).27 In the manuscript by Ketchum et al28 appearing in this issue of the journal, the investigators examine enhancement of the risk stratification power of the SHFM-D model by the addition of 123I-mIBG parameters for patients enrolled in ADMIRE-HF. In this cohort, SHFM-D was again a significan (...truncated)