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Effects of Heart Transplantation on Cerebral Metabolic Abnormalities in Patients With Congestive Heart Failure
THE BEAUTY OF BREVITY
Effects of Heart Transplantation on Cerebral Metabolic Abnormalities in Patients With Congestive Heart Failure Cheol Whan Lee, MD,a Jung Hee Lee, PhD,b Hyun Suk Yang, MD,a Keun Ho Lim, MS,a Jung-Min Ahn, MD,a Myeong-Ki Hong, MD,a Seong-Wook Park, MD, PhD,a Seung-Jung Park, MD, PhD,a Myeong-Geun Song, MD, PhD,c and Jae-Joong Kim, MD, PhDa We investigated the serial changes in cerebral metabolites in 34 patients with congestive heart failure before and 2 and 12 months after heart transplantation, using proton magnetic resonance spectroscopy. Regional differences were detected in the recovery of cerebral metabolites after the heart transplantation procedure. J Heart Lung Transplant 2006;25:353–5. Copyright © 2006 by the International Society for Heart and Lung Transplantation.
Heart transplantation is a definitive therapy for patients with advanced congestive heart failure (CHF). Despite the excellent clinical outcomes associated with this procedure, there are questions related to the resulting quality of life.1 Cognitive function is a major determinant of quality of life and cerebral metabolism is increasingly used as an objective measure of cognitive performance in various diseases.2– 4 Cerebral metabolism has been reported to be abnormal in CHF,3 but it is not known if heart transplantation leads to improvement in these abnormalities. We evaluated the effects of successful heart transplantation on cerebral metabolism in CHF patients. METHODS The study population consisted of patients with advanced CHF who received heart transplants between January 1999 and June 2002 at our institution. Thirtyseven consecutive patients were enrolled in this study, but 3 were excluded because of inadequate quality of spectroscopic images (n ⫽ 1) and post-operative stroke or death (n ⫽ 1 each). All 34 remaining subjects provided written informed consent, and the protocol was approved by the institutional review committee. Patients were treated with standard medications and
followed-up for at least 12 months. Cyclosporine was given to a target trough level of 300 to 400 g/liter for the first 6 months and to 200 to 300 g/liter thereafter. Localized in vivo 1H magnetic resonance spectroscopy (MRS) was performed on a GE 1.5-T Signa system (General Electric Medical Systems, Milwaukee, WI), as previously described in detail.5 Image-guided watersuppressed spectra were obtained in 2 locations (voxel volume 7 to 9 ml), consisting of mostly parietal white matter (PWM) and occipital gray matter (OGM). Average spectral acquisition parameters were TR ⫽ 3.0 seconds, TE ⫽ 30 milliseconds and NS ⫽ 36 in the stimulated echo-acquisition mode sequence incorporated into PROBE (proton brain examination). Peaks were identified with known chemical shifts: 2.02 ppm for N-acetylaspartate; 3.03 ppm for creatine; 3.22 ppm for choline; and 3.56 ppm for myoinositol. The absolute concentrations of the cerebral metabolites were calculated from the PROBE data using the brain water signal as an internal reference, and expressed as millimoles per kilogram wet weight. All data are expressed as mean ⫾ SD. Continuous variables were compared using Student’s t-test, and categoric variables by the chi-square test. Repeated measures analysis of variance (ANOVA) was used to Table 1. Baseline Characteristics
From the aDepartment of Medicine, bAsan Institute for Life Science, and cDepartment of Thoracic and Cardiovascular Surgery, Asan Medical Center, University of Ulsan, Seoul, Korea. Submitted April 18, 2005; revised July 23, 2005; accepted September 11, 2005. Supported by a grant from the Asan Institute for Life Science (#2004 –217). Reprint requests: Jae-Joong Kim, MD, Department of Medicine, University of Ulsan, Asan Medical Center, 388-1 Poongnap-dong, Songpa-gu, Seoul 138-736, Korea. Telephone: 82-2-3010-3150. Fax: 82-2-486-5918. E-mail: [email protected] Copyright © 2006 by the International Society for Heart and Lung Transplantation. 1053-2498/06/$–see front matter. doi:10.1016/ j.healun.2005.09.012
Characteristic Age (years) Gender (male/female) NYHA class Etiology Dilated cardiomyopathy Ischemic cardiomyopathy Others Atrial fibrillation Left ventricular ejection fraction (%) Urgent transplantation
38.1 ⫾ 11.9 29/5 3.3 ⫾ 0.5 27 (79.4%) 1 (2.9%) 6 (17.7%) 9 (26.5%) 20.7 ⫾ 5.2 14 (41.2%)
NYHA, New York Heart Association.
353
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Lee et al.
The Journal of Heart and Lung Transplantation March 2006
Figure 1. Representative 1H MR spectra from a 31-old-male patient with heart failure before and 2 months and 12 months after heart transplantation. The choline and creatine peaks in occipital gray matter (OGM) improved at 2-month and 12-month follow-up, whereas the peaks in parietal white matter (PWM) showed early improvement with a late decrease. Cho, choline; Cr, creatine; mI, myoinositol; NAA, N-acetylaspartate.
compare serial changes of cerebral metabolites, and Pearson’s correlation coefficients were used to correlate the measured variables. p ⬍ 0.05 was considered statistically significant. RESULTS Baseline characteristics are summarized in Table 1. Compared with pre-transplant values, all patients showed significant improvements in New York Heart Association (NYHA) functional status (3.3 ⫾ 0.5 vs 1.1 ⫾ 0.2, p ⬍ 0.01) and left ventricular ejection fraction (20.7 ⫾ 5.2
vs 62.0 ⫾ 3.3%, p ⬍ 0.01) at 12-month follow-up. Body mass index (22.9 ⫾ 3.5 vs 24.3 ⫾ 3.4 kg/m2, p ⬍ 0.01), blood levels of creatine (1.16 ⫾ 0.34 vs 1.46 ⫾ 0.48 mg/dl, p ⬍ 0.01) and systolic blood pressure (102.6 ⫾ 16.7 vs 128.7 ⫾ 12.5 mm Hg, p ⬍ 0.01) were also elevated 12 months after heart transplantation. Figure 1 shows representative 1H MR spectra obtained from a patient with heart transplantation. Serial changes in levels of metabolites are shown in Table 2. In the OGM, the levels of creatine, choline and myoinositol gradually improved, and the level of N-acetylas-
Table 2. Changes in Levels of Cerebral Metabolites After Heart Transplantation Cerebral metabolites (mmol/kg) Occipital gray matter Choline Creatine Myoinositol N-acetylaspartate Parietal white matter Choline Creatine Myoinositol N-acetylaspartate a
Pre-transplant
Post-transplant 2 months
Post-transplant 12 months
1.37 ⫾ 0.24 7.34 ⫾ 0.95 5.12 ⫾ 1.35 9.41 ⫾ 1.00
1.53 ⫾ 0.27a 7.87 ⫾ 1.00b 5.37 ⫾ 1.10 9.27 ⫾ 1.48
1.54 ⫾ 0.27b 8.42 ⫾ 1.24b 6.07 ⫾ 1.13b 10.13 ⫾ 2.27
1.62 ⫾ 0.28 6.20 ⫾ 0.84 4.99 ⫾ 1.51 9.01 ⫾ 1.02
2.00 ⫾ 0.36b 6.91 ⫾ 0.91a 5.41 ⫾ 1.26 9.04 ⫾ 1.43
1.89 ⫾ 0.25b 6.56 ⫾ 0.69 5.67 ⫾ 1.17a 8.66 ⫾ 1.02
p ⬍ 0.05, bp ⬍ 0.01 compared with pre-transplant.
The Journal of Heart and Lung Transplantation Volume 25, Number 3
partate showed a tendency to increase at 12-month follow-up compared with baseline (9.41 ⫾ 1.00 vs 10.13 ⫾ 2.27 mmol/kg, p ⫽ 0.078). In the PWM, the level of myoinositol showed a similar pattern of recovery, whereas the choline level was highest at 2 months, but approached normal at 12 months. In contrast, the parietal N-acetylaspartate level tended to decline at 12-month follow-up compared with baseline, whereas the creatine level initially improved but later decreased. These changes were unrelated to the cumulative dose or mean blood levels of cyclosporine (p ⫽ NS). DISCUSSION In this study, we found that metabolites in the OGM and PWM showed different patterns of recovery after heart transplantation, and that these changes were unrelated to cyclosporine levels. Cerebral blood flow was markedly reduced in patients with CHF but recovered after heart transplantation.6 We previously reported that cerebral metabolism in CHF was abnormal, with regional differences, reflecting the severity of disease.5 It is therefore likely that cerebral metabolic abnormalities are ameliorated after successful heart transplantation. As expected, metabolites in the OGM were substantially improved 12 months after transplantation. N-acetylaspartate has been regarded as a putative neuronal marker, with loss of N-acetylaspartate generally believed to accompany neuronal loss.7 It remains uncertain whether loss of N-acetylaspartate is reversible relative to disease activity. Interestingly, we found that N-acetylaspartate levels tended to increase after heart transplantation, suggesting that it may be reversible in some patients, depending on their clinical situation. In the PWM, the levels of choline and myoinositol also improved after heart transplantation. Despite persistent hemodynamic improvement, however, the levels of N-acetylaspartate and creatine in this region failed to improve. Although we thought that this failure was caused by cyclosporine, we found that levels of cyclosporine within the therapeutic range were not correlated with changes in these metabolites. Although the mechanisms underlying these metabolic processes remain unknown, individual and regional susceptibility to cyclosporine toxicity may be contributing factors.
Lee et al.
355
These findings suggest that metabolites in the OGM may be less sensitive to cyclosporine toxicity than metabolites in the PWM. Improved surgical and medical management in heart transplantation has led to excellent short- and long-term outcomes. However, cognitive performance may have a major impact on quality of life of the transplant recipient. Our results suggest that 1H MRS can be used as a new tool for objective evaluation of cognitive performance in these patients and may help the clinician identify patients for early intervention. Neuropsychologic tests were not performed, however, and the specific relationship between cerebral metabolites and cognitive functioning remains unknown. Furthermore, open heart surgery and intensive or late care quality may affect cerebral metabolism. Further studies are needed to better understand these issues. REFERENCES 1. Schall RR, Petrucci RJ, Brozena SC, Cavarocchi NC, Jessup M. Cognitive function in patients with symptomatic dilated cardiomyopathy before and after cardiac transplantation. JAMA 1989;14:1666 –72. 2. Gruber S, Frey R, Mlynarik V, et al. Quantification of metabolic differences in the frontal brain of depressive patients and controls obtained by 1H-MRS at 3 Tesla. Invest Radiol 2003;38:403– 8. 3. Hass HG, Nagele T, Seeger U, et al. Detection of subclinical and overt hepatic encephalopathy and treatment control after L-ornithine-L-aspartate medication by magnetic resonance spectroscopy (1H-MRS). Z Gastroenterol 2005;43: 373– 8. 4. Hancu I, Zimmerman EA, Sailasuta N, et al. 1H MR spectroscopy using TE averaged PRESS: a more sensitive technique to detect neurodegeneration associated with Alzheimer’s disease. Magn Reson Med 2005;53:777– 82. 5. Lee CW, Lee JH, Kim JJ, et al. Cerebral metabolic abnormalities in congestive heart failure detected by proton magnetic resonance spectroscopy. JAMA 1999;33:1196 –202. 6. Gruhn N, Larsen FS, Boesgaard S, et al. Cerebral blood flow in patients with chronic heart failure before and after heart transplantation. Stroke 2001;32:2530 –3. 7. Ross B, Kreis R, Ernst T. Clinical tools for the 90s: magnetic resonance spectroscopy and metabolite imaging. Eur J Radiol 1992;14:128 – 40.
Effects of Heart Transplantation on Cerebral Metabolic Abnormalities in Patients With Congestive Heart Failure Cheol Whan Lee, MD,a Jung Hee Lee, PhD,b Hyun Suk Yang, MD,a Keun Ho Lim, MS,a Jung-Min Ahn, MD,a Myeong-Ki Hong, MD,a Seong-Wook Park, MD, PhD,a Seung-Jung Park, MD, PhD,a Myeong-Geun Song, MD, PhD,c and Jae-Joong Kim, MD, PhDa We investigated the serial changes in cerebral metabolites in 34 patients with congestive heart failure before and 2 and 12 months after heart transplantation, using proton magnetic resonance spectroscopy. Regional differences were detected in the recovery of cerebral metabolites after the heart transplantation procedure. J Heart Lung Transplant 2006;25:353–5. Copyright © 2006 by the International Society for Heart and Lung Transplantation.
Heart transplantation is a definitive therapy for patients with advanced congestive heart failure (CHF). Despite the excellent clinical outcomes associated with this procedure, there are questions related to the resulting quality of life.1 Cognitive function is a major determinant of quality of life and cerebral metabolism is increasingly used as an objective measure of cognitive performance in various diseases.2– 4 Cerebral metabolism has been reported to be abnormal in CHF,3 but it is not known if heart transplantation leads to improvement in these abnormalities. We evaluated the effects of successful heart transplantation on cerebral metabolism in CHF patients. METHODS The study population consisted of patients with advanced CHF who received heart transplants between January 1999 and June 2002 at our institution. Thirtyseven consecutive patients were enrolled in this study, but 3 were excluded because of inadequate quality of spectroscopic images (n ⫽ 1) and post-operative stroke or death (n ⫽ 1 each). All 34 remaining subjects provided written informed consent, and the protocol was approved by the institutional review committee. Patients were treated with standard medications and
followed-up for at least 12 months. Cyclosporine was given to a target trough level of 300 to 400 g/liter for the first 6 months and to 200 to 300 g/liter thereafter. Localized in vivo 1H magnetic resonance spectroscopy (MRS) was performed on a GE 1.5-T Signa system (General Electric Medical Systems, Milwaukee, WI), as previously described in detail.5 Image-guided watersuppressed spectra were obtained in 2 locations (voxel volume 7 to 9 ml), consisting of mostly parietal white matter (PWM) and occipital gray matter (OGM). Average spectral acquisition parameters were TR ⫽ 3.0 seconds, TE ⫽ 30 milliseconds and NS ⫽ 36 in the stimulated echo-acquisition mode sequence incorporated into PROBE (proton brain examination). Peaks were identified with known chemical shifts: 2.02 ppm for N-acetylaspartate; 3.03 ppm for creatine; 3.22 ppm for choline; and 3.56 ppm for myoinositol. The absolute concentrations of the cerebral metabolites were calculated from the PROBE data using the brain water signal as an internal reference, and expressed as millimoles per kilogram wet weight. All data are expressed as mean ⫾ SD. Continuous variables were compared using Student’s t-test, and categoric variables by the chi-square test. Repeated measures analysis of variance (ANOVA) was used to Table 1. Baseline Characteristics
From the aDepartment of Medicine, bAsan Institute for Life Science, and cDepartment of Thoracic and Cardiovascular Surgery, Asan Medical Center, University of Ulsan, Seoul, Korea. Submitted April 18, 2005; revised July 23, 2005; accepted September 11, 2005. Supported by a grant from the Asan Institute for Life Science (#2004 –217). Reprint requests: Jae-Joong Kim, MD, Department of Medicine, University of Ulsan, Asan Medical Center, 388-1 Poongnap-dong, Songpa-gu, Seoul 138-736, Korea. Telephone: 82-2-3010-3150. Fax: 82-2-486-5918. E-mail: [email protected] Copyright © 2006 by the International Society for Heart and Lung Transplantation. 1053-2498/06/$–see front matter. doi:10.1016/ j.healun.2005.09.012
Characteristic Age (years) Gender (male/female) NYHA class Etiology Dilated cardiomyopathy Ischemic cardiomyopathy Others Atrial fibrillation Left ventricular ejection fraction (%) Urgent transplantation
38.1 ⫾ 11.9 29/5 3.3 ⫾ 0.5 27 (79.4%) 1 (2.9%) 6 (17.7%) 9 (26.5%) 20.7 ⫾ 5.2 14 (41.2%)
NYHA, New York Heart Association.
353
354
Lee et al.
The Journal of Heart and Lung Transplantation March 2006
Figure 1. Representative 1H MR spectra from a 31-old-male patient with heart failure before and 2 months and 12 months after heart transplantation. The choline and creatine peaks in occipital gray matter (OGM) improved at 2-month and 12-month follow-up, whereas the peaks in parietal white matter (PWM) showed early improvement with a late decrease. Cho, choline; Cr, creatine; mI, myoinositol; NAA, N-acetylaspartate.
compare serial changes of cerebral metabolites, and Pearson’s correlation coefficients were used to correlate the measured variables. p ⬍ 0.05 was considered statistically significant. RESULTS Baseline characteristics are summarized in Table 1. Compared with pre-transplant values, all patients showed significant improvements in New York Heart Association (NYHA) functional status (3.3 ⫾ 0.5 vs 1.1 ⫾ 0.2, p ⬍ 0.01) and left ventricular ejection fraction (20.7 ⫾ 5.2
vs 62.0 ⫾ 3.3%, p ⬍ 0.01) at 12-month follow-up. Body mass index (22.9 ⫾ 3.5 vs 24.3 ⫾ 3.4 kg/m2, p ⬍ 0.01), blood levels of creatine (1.16 ⫾ 0.34 vs 1.46 ⫾ 0.48 mg/dl, p ⬍ 0.01) and systolic blood pressure (102.6 ⫾ 16.7 vs 128.7 ⫾ 12.5 mm Hg, p ⬍ 0.01) were also elevated 12 months after heart transplantation. Figure 1 shows representative 1H MR spectra obtained from a patient with heart transplantation. Serial changes in levels of metabolites are shown in Table 2. In the OGM, the levels of creatine, choline and myoinositol gradually improved, and the level of N-acetylas-
Table 2. Changes in Levels of Cerebral Metabolites After Heart Transplantation Cerebral metabolites (mmol/kg) Occipital gray matter Choline Creatine Myoinositol N-acetylaspartate Parietal white matter Choline Creatine Myoinositol N-acetylaspartate a
Pre-transplant
Post-transplant 2 months
Post-transplant 12 months
1.37 ⫾ 0.24 7.34 ⫾ 0.95 5.12 ⫾ 1.35 9.41 ⫾ 1.00
1.53 ⫾ 0.27a 7.87 ⫾ 1.00b 5.37 ⫾ 1.10 9.27 ⫾ 1.48
1.54 ⫾ 0.27b 8.42 ⫾ 1.24b 6.07 ⫾ 1.13b 10.13 ⫾ 2.27
1.62 ⫾ 0.28 6.20 ⫾ 0.84 4.99 ⫾ 1.51 9.01 ⫾ 1.02
2.00 ⫾ 0.36b 6.91 ⫾ 0.91a 5.41 ⫾ 1.26 9.04 ⫾ 1.43
1.89 ⫾ 0.25b 6.56 ⫾ 0.69 5.67 ⫾ 1.17a 8.66 ⫾ 1.02
p ⬍ 0.05, bp ⬍ 0.01 compared with pre-transplant.
The Journal of Heart and Lung Transplantation Volume 25, Number 3
partate showed a tendency to increase at 12-month follow-up compared with baseline (9.41 ⫾ 1.00 vs 10.13 ⫾ 2.27 mmol/kg, p ⫽ 0.078). In the PWM, the level of myoinositol showed a similar pattern of recovery, whereas the choline level was highest at 2 months, but approached normal at 12 months. In contrast, the parietal N-acetylaspartate level tended to decline at 12-month follow-up compared with baseline, whereas the creatine level initially improved but later decreased. These changes were unrelated to the cumulative dose or mean blood levels of cyclosporine (p ⫽ NS). DISCUSSION In this study, we found that metabolites in the OGM and PWM showed different patterns of recovery after heart transplantation, and that these changes were unrelated to cyclosporine levels. Cerebral blood flow was markedly reduced in patients with CHF but recovered after heart transplantation.6 We previously reported that cerebral metabolism in CHF was abnormal, with regional differences, reflecting the severity of disease.5 It is therefore likely that cerebral metabolic abnormalities are ameliorated after successful heart transplantation. As expected, metabolites in the OGM were substantially improved 12 months after transplantation. N-acetylaspartate has been regarded as a putative neuronal marker, with loss of N-acetylaspartate generally believed to accompany neuronal loss.7 It remains uncertain whether loss of N-acetylaspartate is reversible relative to disease activity. Interestingly, we found that N-acetylaspartate levels tended to increase after heart transplantation, suggesting that it may be reversible in some patients, depending on their clinical situation. In the PWM, the levels of choline and myoinositol also improved after heart transplantation. Despite persistent hemodynamic improvement, however, the levels of N-acetylaspartate and creatine in this region failed to improve. Although we thought that this failure was caused by cyclosporine, we found that levels of cyclosporine within the therapeutic range were not correlated with changes in these metabolites. Although the mechanisms underlying these metabolic processes remain unknown, individual and regional susceptibility to cyclosporine toxicity may be contributing factors.
Lee et al.
355
These findings suggest that metabolites in the OGM may be less sensitive to cyclosporine toxicity than metabolites in the PWM. Improved surgical and medical management in heart transplantation has led to excellent short- and long-term outcomes. However, cognitive performance may have a major impact on quality of life of the transplant recipient. Our results suggest that 1H MRS can be used as a new tool for objective evaluation of cognitive performance in these patients and may help the clinician identify patients for early intervention. Neuropsychologic tests were not performed, however, and the specific relationship between cerebral metabolites and cognitive functioning remains unknown. Furthermore, open heart surgery and intensive or late care quality may affect cerebral metabolism. Further studies are needed to better understand these issues. REFERENCES 1. Schall RR, Petrucci RJ, Brozena SC, Cavarocchi NC, Jessup M. Cognitive function in patients with symptomatic dilated cardiomyopathy before and after cardiac transplantation. JAMA 1989;14:1666 –72. 2. Gruber S, Frey R, Mlynarik V, et al. Quantification of metabolic differences in the frontal brain of depressive patients and controls obtained by 1H-MRS at 3 Tesla. Invest Radiol 2003;38:403– 8. 3. Hass HG, Nagele T, Seeger U, et al. Detection of subclinical and overt hepatic encephalopathy and treatment control after L-ornithine-L-aspartate medication by magnetic resonance spectroscopy (1H-MRS). Z Gastroenterol 2005;43: 373– 8. 4. Hancu I, Zimmerman EA, Sailasuta N, et al. 1H MR spectroscopy using TE averaged PRESS: a more sensitive technique to detect neurodegeneration associated with Alzheimer’s disease. Magn Reson Med 2005;53:777– 82. 5. Lee CW, Lee JH, Kim JJ, et al. Cerebral metabolic abnormalities in congestive heart failure detected by proton magnetic resonance spectroscopy. JAMA 1999;33:1196 –202. 6. Gruhn N, Larsen FS, Boesgaard S, et al. Cerebral blood flow in patients with chronic heart failure before and after heart transplantation. Stroke 2001;32:2530 –3. 7. Ross B, Kreis R, Ernst T. Clinical tools for the 90s: magnetic resonance spectroscopy and metabolite imaging. Eur J Radiol 1992;14:128 – 40.