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Limited prognostic value of cardiac metaiodobenzylguanidine in advanced heart failure
Research Correspondance VE/VCO2 slope added 25% to the predictive ability of the HFSS, increasing the chi-square from 20.1 to 26.2. Systolic blood pressure (SBP), expressed as a dichotomous variable (SBP ⱕ100 mm Hg),5 in combination with VE/VCO2 slope, was a better predictor than the HFSS, adding 18% to its predictive ability. Figure 1 shows the receiver-operator characteristic curve where VE/VCO2 slope was a more sensitive and specific determinant of death or urgent transplantation compared with the HFSS and peak VO2. Although the HFSS comparisons did not include the entire cohort of 399 patients, our sample of 62 patients was 25% that of the derivation population2 of the HFSS and, importantly, the HFSS is applied clinically to individual rather than population risk. Compared with our entire cohort, patients in our HFSS cohort were sicker (Table 1), especially when considering the VE/VCO2 slope and peak VO2 (Table 1). This difference may be explained by the clinical nature of this study: patients who were more ill had more testing performed. After 10 years, our event-free survival was 45%, which was higher than that of the HFSS derivation sample2 at both 1 (86% vs 76%) and 2 years (73% vs 63%). Our population may not exemplify contemporary therapy, as evidenced by the reduced rates of betablocker use. VE/VCO2 slope added significant predictive information above that provided by the HFSS alone. The HFSS is composed of 7 different variables, among them electrocardiography, blood laboratory studies, echocardiography and medical history, yet its predictive value was inferior to that obtained by 2 simple variables that are easily obtained during exercise testing: resting systolic blood pressure and VE/VCO2 slope. In conclusion, we have added to the body of evidence3 supporting the use of VE/VCO2 slope as a clinical prognostic tool in patients with heart failure.
Figure 1 Receiver-operator characteristic curve displaying the ability of VE/VCO2 slope, peak VO2 and the Heart Failure Survival Score to identify death or urgent transplantation in a sample of 62 patients.
591 Disclosure statement The authors have no conflicts of interest to disclose. Robert L. Bard, MSa Brenda W. Gillespie, PhDb David C. Lange, MDa John M. Nicklas, MDa a
Division of Cardiovascular Medicine Center for Statistical Consultation and Research University of Michigan Ann Arbor, Michigan
b
References 1. Hunt SA, Abraham WT, Chin MH, et al. 2009 Focused update incorporated into the ACC/AHA 2005 guidelines for the diagnosis and management of heart failure in adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines developed in collaboration with the International Society for Heart and Lung Transplantation. J Am Coll Cardiol 2009; 53:e1-90. 2. Aaronson KD, Schwartz JS, Chen TM, et al. Development and prospective validation of a clinical index to predict survival in ambulatory patients referred for cardiac transplant evaluation. Circulation 1997;95: 2660-7. 3. Arena R, Myers J, Guazzi M. The clinical and research applications of aerobic capacity and ventilatory efficiency in heart failure: an evidencebased review. Heart Fail Rev 2008;13:245-69. 4. Mehra MR, Kobashigawa J, Starling R, et al. Listing criteria for heart transplantation: International Society for Heart and Lung Transplantation guidelines for the care of cardiac transplant candidates—2006. J Heart Lung Transplant 2006;25:1024-42. 5. Bard RL, Gillespie BW, Clarke NS, et al. Determining the best ventilatory efficiency measure to predict mortality in patients with heart failure. J Heart Lung Transplant 2006;25:589-95.
Limited prognostic value of cardiac metaiodobenzylguanidine in advanced heart failure To the Editor: Cardiac sympathetic neuronal activity can be non-invasively assessed by the use of 123I-labeled metaiodobenzylguanidine (MIBG), an analog of norepinephrine. In mild to moderate heart failure, a prognostic value of MIBG has been forthcoming and appears incremental to heart rate variability (HRV).1,2 However, most studies have focused on moderate left ventricular dysfunction,3,4 whereas few data exist with regard to advanced heart failure.5 We sought to ascertain the prognostic value of MIBG in patients with advanced heart failure (AHF) awaiting heart transplantation and developed comparisons with other prognostic indices, including brain natriuretic peptide (BNP) and peak VO2. We prospectively studied 51 AHF patients (40 men, 11 women; NYHA Class III, n ⫽ 45; Class IV, n ⫽ 6) referred to our unit for cardiac transplant assessment. All patients underwent the following: MIBG scintigraphy; non-invasive hemodynamic examination; neuroendocrine measurements; and assessment of functional parameters (6-min. walk test, cardiopulmonary exercise test VO2). All patients provided informed consent for study participation.
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The Journal of Heart and Lung Transplantation, Vol 29, No 5, May 2010
The functional status was low (mean peak VO2: 13.0 ⫾ 0.6 ml/kg/min), and left ventricular ejection fraction (LVEF) was significantly decreased (21.3 ⫾ 1.1%), left ventricular end-diastolic diameter was increased (67.9 ⫾ 1.4 mm), and BNP was significantly elevated (1,000.4 ⫾ 147.1 pg/ml). All patients were followed completely by direct examination or by contact with the patient’s general practitioner, cardiologist or family. The date and cause of death were documented in every case. Because there is no consensus about the best way to consider heart transplantation in survival analyses, we used two methods of analysis: (1) using both death and transplantation as end-points (19 events); and (2) censoring patients who underwent cardiac transplantation at the time of intervention (considering them alive at this time) (10 events). After 494 days (median) of follow-up (range 15 to 1,426 days), 10 patients died before transplantation (7 died of worsening AHF, 3 died suddenly) and 9 underwent urgent heart transplantation. Patients who died or received transplants had significantly higher plasma BNP, lower peak VO2 and worse NYHA class than patients without events at the end of the study. There were no differences among patients with and without ischemic cardiomyopathy and there was no prognostic power of MIBG wash-out rate (WOR) in these 2 groups. By Kaplan–Meier analysis, BNP was predictive of event-free survival (cut-off median value: 672 pg/ml; chi-square ⫽ 11.27; p ⫽ 0.0008). Median peak oxygen consumption was predictive of eventfree survival (cut-off median value: 12 ml/min/kg; chisquare ⫽ 4.3; p ⬍ 0.04). The first-quartile WOR MIBG (36.63%) was predictive of event-free survival (chi-square ⫽ 4.6; p ⬍ 0.04), but the median WOR MIBG cut-off value of 51.70% was not. By univariate analysis, plasma BNP (p ⫽ 0.002), NYHA class (p ⫽ 0.003) and peak VO2 (p ⫽ 0.03) were predictive of death or heart transplantation. By multivariate analysis, only plasma BNP and NYHA remained as independent predictors of outcome. Finally, receiver-operator characteristic (ROC) curves (Figure 1) showed a greater area under the curve for plasma BNP than for peak VO2 and WOR MIBG. The combination of plasma
BNP median value and WOR (Youden index: 0.4; X2:4.45*, alpha ⱕ 0.05) did not increase the discrimination of patients with the highest risk than plasma BNP alone (Youden index: 0.66; X2:16.76*, alpha ⱕ 0.001). In conclusion, MIBG uptake and WOR reflect the morphologic and functional status of the cardiac adrenergic pathway but are modest prognostic parameters in AHF. These parameters are correlated with the severity of HF yet Scintigraphic MIBG parameters remain a less powerful prognostic index than clinical parameter, VO2 or BNP (ROC curves).
Disclosure statement We would like to acknowledge the help and support of Sandrine Mazon and LN Pharma (Laurence Negre-Pagès and Marina Aristin) for statistical support. We thank R. Cagnac and M. Alonso for technical support of MIBG exploration. Fabien Despas, PharmDa,b,c Emilie Guerriero, PharmDa,b,c Michel Galinier, MD, PhDb,d JeanMichel Senard, MD, PhDa,b,c Atul Pathak, MD, PhDa,b,c,d a
INSERM U858 équipe 8 F-31432 Toulouse, France b Institut de Médecine Moléculaire de Rangueil Université de Toulouse, UPS F-31432 Toulouse, France c Department of Clinical Pharmacology Toulouse University Hospital F-31432 Toulouse, France d Department of Cardiology Toulouse University Hospital F-31432 Toulouse, France
References
Figure 1 ROC curves. Solid blue line: MIBG ⬎36.63%; dotted green line: BNP ⬎672 pg/ml; dashed red line: peak VO2 ⬎12 ml/kg/min.
1. Yamada T, Shimonagata T, Fukunami M, et al. Comparison of the prognostic value of cardiac iodine-123 metaiodobenzylguanidine imaging and heart rate variability in patients with chronic heart failure: a prospective study. J Am Coll Cardiol 2003;41:231-8. 2. Anastasiou-Nana MI, Terrovitis JV, et al. Prognostic value of iodine123-metaiodobenzylguanidine myocardial uptake and heart rate variability in chronic congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol 2005;96:427-31. 3. Verberne HJ, Brewster LM, Somsen GA, et al. Prognostic value of myocardial 123I-metaiodobenzylguanidine (MIBG) parameters in patients with heart failure: a systematic review. Eur Heart J 2008;29:1147-59. 4. Ogita H, Shimonagata T, Fukunami M, et al. Prognostic significance of cardiac (123)I metaiodobenzylguanidine imaging for mortality and morbidity in patients with chronic heart failure: a prospective study. Heart 2001;86:656-60. 5. Lucreziotti S, Gavazzi A, Scelsi L, et al. Five-minute recording of heart rate variability in severe chronic heart failure: correlates with right ventricular function and prognostic implications. Am Heart J 2000;139:1088-95.
Figure 1 Receiver-operator characteristic curve displaying the ability of VE/VCO2 slope, peak VO2 and the Heart Failure Survival Score to identify death or urgent transplantation in a sample of 62 patients.
591 Disclosure statement The authors have no conflicts of interest to disclose. Robert L. Bard, MSa Brenda W. Gillespie, PhDb David C. Lange, MDa John M. Nicklas, MDa a
Division of Cardiovascular Medicine Center for Statistical Consultation and Research University of Michigan Ann Arbor, Michigan
b
References 1. Hunt SA, Abraham WT, Chin MH, et al. 2009 Focused update incorporated into the ACC/AHA 2005 guidelines for the diagnosis and management of heart failure in adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines developed in collaboration with the International Society for Heart and Lung Transplantation. J Am Coll Cardiol 2009; 53:e1-90. 2. Aaronson KD, Schwartz JS, Chen TM, et al. Development and prospective validation of a clinical index to predict survival in ambulatory patients referred for cardiac transplant evaluation. Circulation 1997;95: 2660-7. 3. Arena R, Myers J, Guazzi M. The clinical and research applications of aerobic capacity and ventilatory efficiency in heart failure: an evidencebased review. Heart Fail Rev 2008;13:245-69. 4. Mehra MR, Kobashigawa J, Starling R, et al. Listing criteria for heart transplantation: International Society for Heart and Lung Transplantation guidelines for the care of cardiac transplant candidates—2006. J Heart Lung Transplant 2006;25:1024-42. 5. Bard RL, Gillespie BW, Clarke NS, et al. Determining the best ventilatory efficiency measure to predict mortality in patients with heart failure. J Heart Lung Transplant 2006;25:589-95.
Limited prognostic value of cardiac metaiodobenzylguanidine in advanced heart failure To the Editor: Cardiac sympathetic neuronal activity can be non-invasively assessed by the use of 123I-labeled metaiodobenzylguanidine (MIBG), an analog of norepinephrine. In mild to moderate heart failure, a prognostic value of MIBG has been forthcoming and appears incremental to heart rate variability (HRV).1,2 However, most studies have focused on moderate left ventricular dysfunction,3,4 whereas few data exist with regard to advanced heart failure.5 We sought to ascertain the prognostic value of MIBG in patients with advanced heart failure (AHF) awaiting heart transplantation and developed comparisons with other prognostic indices, including brain natriuretic peptide (BNP) and peak VO2. We prospectively studied 51 AHF patients (40 men, 11 women; NYHA Class III, n ⫽ 45; Class IV, n ⫽ 6) referred to our unit for cardiac transplant assessment. All patients underwent the following: MIBG scintigraphy; non-invasive hemodynamic examination; neuroendocrine measurements; and assessment of functional parameters (6-min. walk test, cardiopulmonary exercise test VO2). All patients provided informed consent for study participation.
592
The Journal of Heart and Lung Transplantation, Vol 29, No 5, May 2010
The functional status was low (mean peak VO2: 13.0 ⫾ 0.6 ml/kg/min), and left ventricular ejection fraction (LVEF) was significantly decreased (21.3 ⫾ 1.1%), left ventricular end-diastolic diameter was increased (67.9 ⫾ 1.4 mm), and BNP was significantly elevated (1,000.4 ⫾ 147.1 pg/ml). All patients were followed completely by direct examination or by contact with the patient’s general practitioner, cardiologist or family. The date and cause of death were documented in every case. Because there is no consensus about the best way to consider heart transplantation in survival analyses, we used two methods of analysis: (1) using both death and transplantation as end-points (19 events); and (2) censoring patients who underwent cardiac transplantation at the time of intervention (considering them alive at this time) (10 events). After 494 days (median) of follow-up (range 15 to 1,426 days), 10 patients died before transplantation (7 died of worsening AHF, 3 died suddenly) and 9 underwent urgent heart transplantation. Patients who died or received transplants had significantly higher plasma BNP, lower peak VO2 and worse NYHA class than patients without events at the end of the study. There were no differences among patients with and without ischemic cardiomyopathy and there was no prognostic power of MIBG wash-out rate (WOR) in these 2 groups. By Kaplan–Meier analysis, BNP was predictive of event-free survival (cut-off median value: 672 pg/ml; chi-square ⫽ 11.27; p ⫽ 0.0008). Median peak oxygen consumption was predictive of eventfree survival (cut-off median value: 12 ml/min/kg; chisquare ⫽ 4.3; p ⬍ 0.04). The first-quartile WOR MIBG (36.63%) was predictive of event-free survival (chi-square ⫽ 4.6; p ⬍ 0.04), but the median WOR MIBG cut-off value of 51.70% was not. By univariate analysis, plasma BNP (p ⫽ 0.002), NYHA class (p ⫽ 0.003) and peak VO2 (p ⫽ 0.03) were predictive of death or heart transplantation. By multivariate analysis, only plasma BNP and NYHA remained as independent predictors of outcome. Finally, receiver-operator characteristic (ROC) curves (Figure 1) showed a greater area under the curve for plasma BNP than for peak VO2 and WOR MIBG. The combination of plasma
BNP median value and WOR (Youden index: 0.4; X2:4.45*, alpha ⱕ 0.05) did not increase the discrimination of patients with the highest risk than plasma BNP alone (Youden index: 0.66; X2:16.76*, alpha ⱕ 0.001). In conclusion, MIBG uptake and WOR reflect the morphologic and functional status of the cardiac adrenergic pathway but are modest prognostic parameters in AHF. These parameters are correlated with the severity of HF yet Scintigraphic MIBG parameters remain a less powerful prognostic index than clinical parameter, VO2 or BNP (ROC curves).
Disclosure statement We would like to acknowledge the help and support of Sandrine Mazon and LN Pharma (Laurence Negre-Pagès and Marina Aristin) for statistical support. We thank R. Cagnac and M. Alonso for technical support of MIBG exploration. Fabien Despas, PharmDa,b,c Emilie Guerriero, PharmDa,b,c Michel Galinier, MD, PhDb,d JeanMichel Senard, MD, PhDa,b,c Atul Pathak, MD, PhDa,b,c,d a
INSERM U858 équipe 8 F-31432 Toulouse, France b Institut de Médecine Moléculaire de Rangueil Université de Toulouse, UPS F-31432 Toulouse, France c Department of Clinical Pharmacology Toulouse University Hospital F-31432 Toulouse, France d Department of Cardiology Toulouse University Hospital F-31432 Toulouse, France
References
Figure 1 ROC curves. Solid blue line: MIBG ⬎36.63%; dotted green line: BNP ⬎672 pg/ml; dashed red line: peak VO2 ⬎12 ml/kg/min.
1. Yamada T, Shimonagata T, Fukunami M, et al. Comparison of the prognostic value of cardiac iodine-123 metaiodobenzylguanidine imaging and heart rate variability in patients with chronic heart failure: a prospective study. J Am Coll Cardiol 2003;41:231-8. 2. Anastasiou-Nana MI, Terrovitis JV, et al. Prognostic value of iodine123-metaiodobenzylguanidine myocardial uptake and heart rate variability in chronic congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol 2005;96:427-31. 3. Verberne HJ, Brewster LM, Somsen GA, et al. Prognostic value of myocardial 123I-metaiodobenzylguanidine (MIBG) parameters in patients with heart failure: a systematic review. Eur Heart J 2008;29:1147-59. 4. Ogita H, Shimonagata T, Fukunami M, et al. Prognostic significance of cardiac (123)I metaiodobenzylguanidine imaging for mortality and morbidity in patients with chronic heart failure: a prospective study. Heart 2001;86:656-60. 5. Lucreziotti S, Gavazzi A, Scelsi L, et al. Five-minute recording of heart rate variability in severe chronic heart failure: correlates with right ventricular function and prognostic implications. Am Heart J 2000;139:1088-95.