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Segmental pattern of myocardial sympathetic denervation in idiopathic dilated cardiomyopathy: Relationship to regional wall motion and myocardial perfusion abnormalities
Segmental pattern of myocardial sympathetic denervation in idiopathic dilated cardiomyopathy: Relationship to regional wall motion and myocardial perfusion abnormalities F. I. Parthenakis, MD,a V. K. Prassopoulos, MD,b S. I. Koukouraki, MD,b E. A. Zacharis, MD,a G. F. Diakakis, MD,a N. K. Karkavitsas, MD,b and P. E. Vardas, MD, PhD, FESC, FACCa Background. Iodine 123–labeled metaiodobenzylguanidine (MIBG) has been used to study cardiac adrenergic nerve activity. Cardiac MIBG uptake is diminished in patients with heart failure. However, it is not known how this reduction is related to regional abnormalities of myocardial wall motion or perfusion. Methods and Results. We studied 24 patients with idiopathic dilated cardiomyopathy (ejection fraction <45%) and 15 healthy control subjects using I-123 MIBG cardiac imaging, echocardiographic assessment of wall motion abnormalities, technetium 99m sestamibi perfusion scintigraphy, and hemodynamic assessment. Cardiac MIBG was significantly correlated with ejection fraction (r = 0.67), cardiac index (r = 0.57), left ventricular wall motion score index (r = –0.68), and systolic wall stress (r = –0.61). MIBG was lower in patients than in control subjects (1.43 ± 0.19 vs 2.05 ± 0.02; P < .01), whereas the washout rate was higher (P < .01). Moreover, a significant correlation was found between the reduction in MIBG uptake and the severity of echocardiographic wall motion abnormalities in the anterior wall (r = 0.543), apex (r = 0.530), and septum (r = 0.675), as well as with the severity of decrease in resting myocardial perfusion in the anterior wall (r = 0.480) and septum (r = 0.580). Conclusions. Patients with idiopathic dilated cardiomyopathy show not only global but also regional abnormalities of cardiac sympathetic innervation. The severity of these changes is partially correlated with abnormalities of regional wall motion and myocardial perfusion. (J Nucl Cardiol 2002;9:15-22.) Key Words: Iodine 123–labeled metaiodobenzylguanidine • idiopathic dilated cardiomyopathy • wall motion • myocardial perfusion
See related editorial, p 127 Idiopathic dilated cardiomyopathy (IDC) is a primary myocardial disease of unknown origin, with a major defect in myocardial contractility that leads to progressive enlargement of the cardiac chambers.1 Although diffused hypokinetic ventricular wall motion (in the left ventricle) is thought to be more charFrom the Cardiology Departmenta and Department of Nuclear Medicine,b University Hospital of Heraklion, Crete, Greece. Received for publication Jan 26, 2001; final revision accepted June 25, 2001. Reprint requests: P. E. Vardas, MD, PhD, Cardiology Department, Heraklion University Hospital, PO Box 1352, Stavrakia, Heraklion, Crete, Greece; [email protected]. Copyright © 2002 by the American Society of Nuclear Cardiology. 1071-3581/2002/$35.00 + 0 43/1/118239 doi:10.1067/mnc.2002.118239
acteristic of IDC,2,3 segmental wall motion abnormalities (WMAs) have been noted in several studies.4,5 Endocardial or myocardial scarring, mural thrombus, geometric factors, and increased left ventricular (LV) wall stress have been implicated in these WMAs.6-8 Recent studies have shown that myocardial perfusion abnormalities occur in IDC and endothelial function is impaired.9,10 However, it is not clear if there is a correlation between regional motion abnormalities and myocardial perfusion defects. Neurohormonal activation is a common finding in patients with congestive heart failure.11-13 All alterations of the cardiac sympathoadrenergic system result in a reduction in cardiac responsiveness to β-adrenergic stimulation.14 Iodine 123–labeled metaiodobenzylguanidine (MIBG), a transmitter analog of norepinephrine15 that shares the same re-uptake pathway within the cardiac 15
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20 mg daily; 7 received enalapril, 10-20 mg; 6 received perindopril, 4 mg; and 4 received captopril, 25-50 mg. No patients were taking spironolactone, tricyclic antidepressants known to affect myocardial MIBG uptake, β-blockers, or β-agonists. The severity of congestive heart failure was assessed by scoring the functional class according to the NYHA classification. Our institution’s ethics committee approved the study protocol, and written, informed consent was obtained from all patients and control subjects before they entered the study.
Analysis of LV Wall Motion
Figure 1. Schema of polar map areas and corresponding LV regions provided from the echocardiographic 16-segment model. 1, 2, 7, and 8, Anterior; 3 and 9, lateral; 4 and 10, inferior; 5, 6, 11, and 12, interventricular septum; 13, 14, 15, and 16, apex.
synapse,16 was developed to visualize sympathetic innervation and has recently been used to study myocardial adrenergic nerve activity.17 Cardiac MIBG uptake has been reported to be reduced in patients with congestive heart failure.18 Global reduction and regional reduction have been demonstrated, the degree of each being positively correlated to markers of severity of heart failure.19 However, there is no study to correlate the regional pattern of MIBG with regional WMAs or myocardial perfusion. In this study we aimed to assess the regional pattern of cardiac adrenergic innervation using MIBG as a marker for presynaptic neuronal uptake activity and to address its relationship with both echocardiographic WMAs and myocardial perfusion using technetium 99m sestamibi scintigraphy in patients with IDC. METHODS Study Population We studied 24 patients with IDC and stabilized congestive heart failure, New York Heart Association (NYHA) class II to IV, and ejection fraction less than 45%, of whom 16 were men (mean age, 55.5 ± 13 years; range, 23-72 years). Fifteen healthy, age-matched volunteers showing no sign of cardiac disease after clinical, electrocardiographic, and echocardiographic examinations comprised the control group. IDC was diagnosed in the absence of coronary artery disease on coronary arteriography. Patients with valvular heart disease, a history of diabetes mellitus, left branch bifascicular block, or any kind of secondary cardiomyopathy were excluded from the study. Medical treatment of all patients consisted of diuretics, digoxin, and angiotensinconverting enzyme inhibitors—7 patients received quinapril, 10-
Cross-sectional echocardiography recording views were obtained with a Hewlett-Packard Sonos 2500 device (Andover, Mass) equipped with a 2.5- to 3.78-MHz transducer. The recordings were stored on a video recorder and on half-inch VHS tape for subsequent analysis. Regional systolic wall thickening was assessed according to the recommendations of the American Society of Echocardiography,20 with a 16-segment model. For each segment, systolic wall thickening is visually graded with a quantitation scoring system in which 1 is normal, 2 is hypokinetic, 3 is akinetic, and 4 is dyskinetic. For the purposes of the study the left ventricle was divided into 5 regional areas (Figure 1), in order to obtain complete correlation with the other methods, as mentioned below. A regional systolic wall thickening score was quantified for each patient by totaling the grades of the segments of each region and dividing by the total number of segments analyzed in that region. Two independent observers analyzed the LV WMAs.
Measurement of LV Systolic Wall Stress LV systolic wall stress21 was evaluated echocardiographically with the following equation (in dynes per centimeter squared): σ = (0.33 · P[LVESD])/(PW [1 + PW/LVESD]) where P is the mean of duplicate cuff arterial systolic pressure, LVESD is the LV systolic internal diameter, and PW is the systolic posterior wall thickness at the time of systole. LV internal diameter and wall thickness were obtained from M-mode tracing in the plane of the mitral valve during 2-dimensional echocardiography. Data were analyzed as the mean of 3 cardiac cycles.
I-123 MIBG Scintigraphy On the day of MIBG scintigraphy, all patients and control subjects were instructed to fast for 6 hours. One milliliter of Lugol’s solution was given orally 2 hours before the slow intravenous injection of I-123 MIBG (5 mCi) (Mallinckrodt Inc, St Louis, Mo; specific activity, 74 MBq/mg). At 10 minutes and 4 hours after tracer injection, a 10-minute anterior-view static acquisition was performed with a General Millenium large-field-of-view, single-head gamma camera (GE Medical Systems, Milwaukee, Wis) fitted with a low-energy, all-purpose, parallel-hole collimator. A 20% energy window centered on 157 keV and a 128 × 128
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matrix size were used. After the delayed planar image was obtained, single photon emission computed tomography (SPECT) was performed with a dual-head gamma camera (GE Medical Systems). Thirty-two projections (50 seconds each) were obtained over a 180° arc, starting at the left posterior oblique position, and images were stored by means of a 64 × 64 matrix. Transaxial, sagittal, and oblique tomograms were obtained through use of a nuclear medicine computer. Cardiac uptake was quantified in all planar views. A 7 × 7pixel region of interest was drawn over the cardiac region and another 7 × 7 region of interest over the upper mediastinum area. The cardiac region of interest was positioned over the heart in the anterior view and was the same in all patients and control subjects. The heart to mediastinum (H/M) activity ratio, introduced by Merlet et al,22 was then computed to quantify cardiac MIBG accumulation. Two independent observers measured the H/M ratio twice, and the mean of the 2 measurements was taken as the datum. The clearance rate from the myocardium (washout rate) was calculated as follows: (Initial myocardial MIBG uptake – Delayed myocardial MIBG uptake)/(Initial MIBG uptake) × 100. MIBG scintigrams were examined by 2 independent experts who had no knowledge of the clinical and angiographic results. To evaluate regional adrenergic dysfunction on SPECT imaging, the left ventricle was divided according to the 5segment model as in the echocardiographic study, and a 4point scoring system was used to determine a defect score for visual interpretation of I-123 MIBG uptake in the 5 regions of LV myocardium as follows: 1, normal radioisotope uptake (>75% of peak activity); 2, mildly reduced uptake (50%-75% of peak activity); 3, moderately reduced uptake (25%-50% of peak activity); and 4, absence of detectable tracer in a segment or severe reduction in radioisotope uptake (<25% of peak activity).
Myocardial Perfusion Imaging All patients underwent a treadmill stress test, and at peak exercise they were injected with Tc-99m sestamibi (10 mCi). Thirty to sixty minutes after the injection, tomographic images were obtained with a GE Optima tomographic dual-head gamma camera (GE Medical Systems) fitted with 2 lowenergy, general-purpose collimators. A 20% energy window was centered on the 140-keV photopeak of Tc-99m. A stepand-shoot mode rotation was used from the 45° right anterior oblique view to the 129° left posterior oblique view, with 32 projections at 40 seconds each. For computer acquisition a 64 × 64 matrix was used and a 3-dimensional image of the heart was created by means of a filtered backprojection technique. Four hours later, each patient was injected with Tc-99m sestamibi (20 mCi) at rest, and SPECT images were taken 30 to 60 minutes later. Image reconstruction was performed and vertical long-axis, horizontal long-axis, and short-axis images were obtained. For interpretation of myocardial perfusion, the same 5-segment model was used, and a semiqualitative 4-point scoring system was used for the evaluation of myocardial perfusion as follows: 1, normal; 2, markedly reduced; 3, definitely reduced; and 4, absent.
17
Cardiac Catheterization and Coronary Angiography Cardiac catheterization and selective coronary angiography were performed by means of standard techniques, and ejection fraction and cardiac index were evaluated. Significant coronary artery stenosis was defined as a 50% or greater reduction in the internal diameter of the main coronary artery or a 70% or greater reduction in the internal diameter of one of the large epicardial arteries.
Statistical Analysis The Pearson correlation coefficient was used to evaluate the association of 10-minute MIBG, 4-hour MIBG, and washout with ejection fraction, cardiac index, NYHA functional class, wall stress, and wall motion score index. Multiple stepwise regression analysis was used to determine which of the above parameters were independently associated with MIBG at 4 hours. Comparisons between 10-minute and 4-hour MIBG uptake in patients and control subjects, as well as in patients with reversible or nonreversible perfusion defects on SPECT imaging, were performed with t tests. The regional distribution of WMAs, MIBG uptake, and myocardial perfusion was assessed. The strength of association and the degree of agreement among the 3 methods were calculated with the Spearman correlation coefficient and Cohen’s kappa index, respectively. P values less than .05 were considered significant.
RESULTS Baseline Values The baseline characteristics of the patient and control groups are summarized in Table 1. Nine patients were in NYHA functional class II, 11 were in class III, and 4 were in class IV. The wall motion score index was 2.25 ± 0.5, the systolic wall stress was 171.5 ± 16.5 dyne/cm2, and the cardiac index was 2.5 ± 0.7 L/min/kg. The MIBG H/M uptake ratio was 1.6 ± 0.18 in the patient group during the first few minutes of the 10-minute phase, whereas it was 2.08 ± 0.20 in the control group (P < .001). At 4 hours, the MIBG H/M uptake was 1.43 ± 0.19 in the patient group, whereas it was 2.05 ± 0.02 in the control group (P < .001). The washout rate was significantly greater in the patient group compared with that in the control group (Figure 2). None of the patients had significant coronary artery stenosis on coronary angiography. MIBG Uptake: Relation to Hemodynamic and Stress Variables MIBG uptake at 4 hours correlated with LV ejection fraction (r = 0.67, P < .01), wall motion score index (r = –0.68, P < .01), and washout (r = –0.58, P < .01), as shown in Figure 3. Significant correlation was also found between MIBG uptake at 4 hours and cardiac index (r =
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Figure 2. MIBG uptake in the patient (1) and control (2) groups at 10 minutes and 4 hours.
0.57, P < .01), NYHA class (r = –0.507, P < .05), and systolic wall stress (r = –0.61, P < .01). Multivariate analysis showed that wall motion score index was the sole parameter that was independently correlated with MIBG at 4 hours (P < .01). Ten-minute MIBG uptake also correlated with ejection fraction (r = 0.62, P < .01) and wall motion score index (r = –0.39, P < .05), whereas washout MIBG rate correlated significantly with ejection fraction (r = –0.54, P < .05) but not with other hemodynamic variables. Fifteen patients showed reversibility in at least 1 of the 5 LV regions on myocardial perfusion SPECT, whereas 9 patients did not. The MIBG uptake values at 4 hours in the 2 groups were 1.45 ± 0.2 and 1.39 ± 0.16, respectively. Patients with reversible defects showed a tendency toward higher MIBG values as opposed to those with no reversible defects, which indicates that ischemia may play a role in MIBG uptake abnormalities. However, these values were not statistically significant (P = .26). Regional Pattern of MIBG Uptake The left ventricle was divided into 5 regions as shown in Figure 1. Of the 120 regions analyzed, 14 (11.7%) were classified as having normal wall motion on echocardiographic examination, 77 (64.1%) were hypokinetic, 28 (23.3%) were akinetic, and 1 was dyskinetic (0.83%). Qualitative analysis of the cardiac MIBG study
Figure 3. Correlation between MIBG uptake at 4 hours and ejection fraction (EF), wall motion score index (WMSI), and washout.
revealed normal uptake in 11 regions (9.2%); mildly reduced uptake in 75 regions (62.5%), moderately reduced uptake in 33 regions (27.5%), and an absence of detectable tracer in 1 region (0.8%). Figure 4 shows a comparison between a normal MIBG image and a typical image from a patient with regions of reduced MIBG uptake. On rest Tc-99m sestamibi SPECT analysis, 25 regions (20.8%) showed normal activity, 82 (68.3%) showed
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Figure 4. Cardiac MIBG image with normal distribution (right) and regional abnormalities (left).
Table 1. Baseline data from patients and control subjects
Patients (n = 24) Age (y) Sex (M/F) AF (n) EF (%) HR (beats/min) LVEDD (mm) LVESD (mm) SBP (mm Hg) SWS (dyne/cm2)
55.5 ± 16/8 3 32.7 ± 75 ± 69 ± 57 ± 125 ± 171.5 ±
P value
Control subjects (n = 15)
13
50 ± 9/6 0 67 ± 70 ± 42 ± 36 ± 120 ± 108 ±
6.2 16.2 9 9 10 16.5 × 103
14
NS NS NS <.001 NS <.001 <.001 NS <.001
5.4 11.4 6 8 10 11 × 103
AF, Atrial fibrillation; EF, LV ejection fraction; HR, heart rate; LVEDD, LV end-diastolic diameter; LVESD, LV end-systolic diameter; SPB, systolic blood pressure; SWS, systolic wall stress; NS, not significant.
markedly reduced activity, and 13 (10.9%) showed definitely reduced activity. None of the segments showed absolutely no perfusion activity. The control subjects showed no echocardiographic WMAs or perfusion defects on SPECT imaging, nor any regional reduction in MIBG uptake. The severity of WMAs and the decrease in MIBG uptake at 4 hours were significantly correlated in the septum (r = 0.675, P < .01), anterior wall (r = 0.543, P < .01), and apex (r = 0.530, P < .01), but not in the lateral and inferior wall. Following the use of the statistical agreement method, the severity of the WMAs and MIBG in the same regions matched quite well (Table 2). A good correlation was also found between MIBG uptake and the magnitude of resting myocardial perfusion in the septum (r = 0.58, P < .01) and in the anterior wall (r = 0.48, P < .01), with good agreement in the anterior wall (Table 3).
Table 2. Degree of agreement between severity of echocardiographic wall motion disturbances and reduced MIBG uptake in the same LV regions
Echocardiography/ MIBG Septum Anterior Inferior Lateral Apex
Agreement (%)
Cohen’s κ index
70 79 62 45 72
0.47 0.55 0.31 –0.37 0.5
When the severity of WMAs and resting myocardial perfusion were compared, a good correlation was found in the anterior (r = 0.475, P < .05) and inferior (r = 0.510, P < .01) walls, with good agreement in the anterior wall (75%).
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Table 3. Agreement between severity of regional alteration of MIBG uptake and myocardial perfusion
MIBG/SPECT Septum Anterior Inferior Lateral Apex
Agreement (%) 50 79 50 38 50
Cohen’s κ index 0.21 0.42 0.149 –0.001 0.23
DISCUSSION Several alterations of the cardiac sympathoadrenergic system have been reported in congestive heart failure, all of which resulted in a reduction in cardiac responsiveness to β-adrenergic stimulation.23,24 Postsynaptic β1-adrenoreceptor density is reduced, and the concentration of inhibiting Gi-α proteins is elevated.25,26 The chronically raised noradrenaline concentration in these patients could partially cause these findings.13 In addition, cardiac noradrenaline turnover is increased. Sympathetic activation in chronic congestive heart failure may lead to increased noradrenaline release with increased spillover to plasma and subsequent tissue depletion.27 Imaging of cardiac sympathetic innervation was first carried out in the 1980s by means of I-123 MIBG and single emission computed tomography techniques. Previous studies have shown that the non-neural myocardial uptake of MIBG mainly contributes to the early images and disappears rapidly, whereas the neural uptake contributes to the delayed images.28,29 These findings indicate that the delayed image represents adrenergic nervous system function more faithfully than does the early image. For these reasons, we mainly evaluated delayed MIBG uptake in our study. Patients with IDC demonstrated a significant reduction in MIBG uptake, but also showed a regional pattern of retention abnormalities that was correlated with the severity of the WMAs as evaluated by echocardiography, especially in the anterior wall, septum, and apex. Although there was a correlation between resting myocardial perfusion and MIBG uptake in the areas of the septum and anterior wall, significant agreement was only found in the anterior wall, indicating that the MIBG uptake was partially dependent on myocardial perfusion assessed by SPECT Tc-99m sestamibi. However, MIBG uptake correlated significantly with heart failure severity markers (ie, ejection fraction, NYHA functional class, and wall motion score index).
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The regional abnormalities of cardiac sympathetic tracer uptake in IDC could be explained in several ways. A decrease in myocardial perfusion alone may decrease planar MIBG uptake. Although in IDC the large epicardial coronary arteries are normal, studies have shown that regional myocardial ischemia may occur in patients with IDC.9 In our study, resting myocardial perfusion showed a regional correlation with MIBG uptake, especially in the septum and LV anterior wall. In these regions there was also greater agreement between severity of WMAs and Tc-99m sestamibi uptake, indicating a partial relationship among the 3 methods with regard to the severity of the parameters studied. The severity of WMAs, as determined by echocardiography, can be used as an index of regional reductions in MIBG uptake. Segmental WMAs were correlated with thallium 201 perfusion abnormalities in a similar way to that reported by Yamaguchi et al.30 Competitive inhibition of MIBG uptake due to raised noradrenaline concentration may be one reason. Previous studies31,32 reported that MIBG uptake was significantly correlated with the myocardial content of adrenaline and with increased contractility of the myocardium induced by intracoronary β-adrenergic stimulation. Metabolic abnormalities, because of the increased wall stress of the dilated ventricle, may lead to decreased activity of highly energy-dependent uptake-1 function and vesicular storage mechanism. The subsequent decrease in neuronal reuptake with a lack of activation of noradrenaline in the synaptic cleft may play a key role in changes of the sympathetic signal transduction pathway in heart failure. In our study a significant correlation was found between LV systolic wall stress and MIBG uptake. Finally, reduced MIBG retention may indicate loss of neuronal tissue, damaged by a mechanism of the underlying disease process. Histologic changes in the myocardium, LV-localized fibrosis in IDC, may cause a loss or potentially reversible functional disturbances of sympathetic neurons. This could explain the regional relationship we found between WMAs and LV sympathetic denervation. The 3 methods used showed good agreement in the anterior wall, septum, and apex. Differences in wall stress that may be present in the septum, especially in a distorted left ventricle,30 and the tendency for overestimation of perfusion defects in the inferior wall could explain why we did not reach powerful agreements among the 3 methods in these areas. This is the first study correlating the regional pattern of myocardial sympathetic denervation with WMAs and Tc-99m sestamibi myocardial perfusion in patients with IDC. Although this study presents new data, parts of our
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findings confirm existing knowledge.19 The prognostic implications of sympathoadrenergic dysfunction in these patients did not form part of the main aim of this study. However, because MIBG myocardial scintigraphy has the potential to mirror the whole myocardial adrenergic pathway disintegrity, it has been found to be an independent prognostic marker in patients with cardiomyopathy of different origins.22 Several studies have shown the relationship between MIBG uptake and cardiac hemodynamics,16 as well as cardiopulmonary exercise performance.33 The presence of regional myocardial sympathetic denervation has been correlated to arrhythmia development in post–myocardial infarction patients34 and in patients with ventricular tachycardia without coronary artery disease.35 Inhomogeneity of electrophysiological properties, caused by an upregulation of β-receptors in the denervated regions, could be a possible mechanism for the development of arrhythmias.
21
We have neither Holter data for arrhythmias nor measurements of neurohormonal plasma levels. Although MIBG uptake was been found to correlate with myocardial norepinephrine concentration31 in the study of Hartmann et al,19 no correlation was found between plasma concentration of norepinephrine and a newly developed synthetic catecholamine analog, carbon 11 hydroxyephedrine, which has been used as a marker of cardiac innervation. The MIBG uptake is more specific evidence of cardiac adrenergic dysfunction than that derived from measurements of plasma noradrenaline, which reflects the systemic adrenergic activity.37 We excluded patients with left bundle branch block because of difficulties in assessment of WMAs and falsepositive perfusion scintigraphic imaging results. We did not use therapeutic interventions such as β-blockers to determine whether WMAs or MIBG uptake could be improved with treatment. Further studies with larger sample sizes should therefore be undertaken. Conclusions
Clinical Implications In IDC, sympathoadrenergic imaging with I-123 MIBG has been evaluated as a diagnostic tool to assess the severity of heart failure and to provide prognostic information. Application of MIBG scintigraphy offers advantages in the assessment of not only global but also regional alterations in the cardiac adrenergic system. The regional pattern of adrenergic denervation in patients with IDC may be responsible for severe ventricular arrhythmias in these patients. MIBG imaging could also be used for monitoring β-blocker treatment in patients with IDC and could be useful in identifying the timing and functional improvement when this treatment is given.36 Patients with severe heart failure may be treated with carvedilol, as Lahiri and Senior37 and the COPERNICUS (Carvedilol Prospective Randomized Cumulative Survival Trial) study38 have demonstrated. These studies have proved that carvedilol treatment in these patients was associated with a reduction in mortality, even among patients who conventionally would not have been considered, by many, for β-blocker therapy. MIBG cardiac uptake can be used to monitor the functional improvement. Limitations The marked decrease in MIBG activity in patients with severe IDC created difficulties in image reconstruction. The regional interpretation of MIBG uptake depends on the experience of the observers. This subjective assessment could be considered the main limitation.
In this study of I-123 MIBG in patients with IDC, global reduction, as well as regional abnormalities of cardiac sympathetic integrity, was demonstrated. The magnitude of reduction is partially correlated with regional wall motion and resting myocardial perfusion abnormalities, especially in the LV apex and anterior wall. However, this reduction is positively correlated with indices of the severity of heart failure. The pathogenetic cause that produces the regional differences and the clinical and prognostic significance remain to be defined. Acknowledgment The authors have indicated they have no financial conflicts of interest.
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systolic wall stress: validation of the method and clinical implications. Circulation 1982;65:99-108. Merlet P, Valette H, Dubois-Rande JL, Moyse D, Duba D, Dove P, et al. Prognostic value of cardiac metaiodobenzylguanidine imaging in patients with heart failure. J Nucl Med 1992;33:471-7. Hasking GJ, Esler MD, Jennings GL, Burton D, Johns JA, Korner PI. Norepinephrine spillover to plasma in patients with congestive heart failure: evidence of increased overall and cardiorenal sympathetic nervous activity. Circulation 1986;73:615-21. Brodde OE. Beta 1- and beta 2-adrenoceptors in the human heart: properties, function and alterations in chronic heart failure. Pharmacol Rev 1991;43:203-42. Bristow MR, Hershberger RE, Port JD, Gilbert EM, Sandoval A, Rasmussen R, et al. Beta-adrenergic pathways in no failing and failing human ventricular myocardium. Circulation 1990;82(2 Suppl):I12-25. Bristow MR, Feldman AM. Changes in the receptor-G protein-adenylyl cyclase system in heart failure from various types of heart muscle disease. Basic Res Cardiol 1992;87:15-35. Meredith IT, Eisenhofer G, Lambert GW, Dewar EM, Jennings GL, Esler MD. Cardiac sympathetic nervous activity in congestive heart failure: evidence for increased neuronal norepinephrine release and preserved neuronal uptake. Circulation 1993;88:136-45. Dae MW, De Marco T, Botvinick EH, O’Connell JW, Hattner RS, Huberty JP, et al. Scintigraphic assessment of MIBG uptake in globally denervated human and canine hearts—implications for clinical studies. J Nucl Med 1992;33:1444-50. Yamakado K, Takeda K, Kitano T, Nakagawa T, Futagami Y, Konishi T, et al. Serial change of iodine-123 metaiodobenzylguanidine myocardial concentration in patients with dilated cardiomyopathy. Eur J Nucl Med 1992;19:265-70. Yamaguchi S, Tsuiki K, Hayasaka M, Yasui S. Segmental wall motion abnormalities in dilated cardiomyopathy: hemodynamic characteristics and comparison with thallium-201 myocardial scintigraphy. Am Heart J 1987;113:1123-8. Simmons W, Freeman M, Grima E, Hsia T, Armstrong PW. Abnormalities of cardiac sympathetic function in pacing-induced heart failure as assessed by [123I]metaiodobenzylguanidine scintigraphy. Circulation 1994;89:2843-51. Dubois-Rande JL, Merlet P, Roudot F, Benvenuti C, Adnot S, Hittinger L, et al. Beta-adrenergic contractile reserve as a predictor of clinical outcome in patients with IDC. Am Heart J 1992;124:679-85. Cohen-Solal A, Esanu Y, Logeart D, Pessione F, Dubois C, Dreyfus G, et al. Cardiac metaiodobenzylguanidine uptake in patients with moderate chronic heart failure: relationship with peak oxygen uptake and prognosis. J Am Coll Cardiol 1999;33:759-66. Zipes DP. Influence of myocardial ischemia and infarction on autonomic innervation of the heart. Circulation 1990;82:1095-105. Mitrani RD, Klein LS, Miles WM, Hackett FK, Burt RW, Wellman HN, et al. Regional cardiac sympathetic denervation in patients with ventricular tachycardia in the absence of coronary artery disease. J Am Coll Cardiol 1993;22:1344-53. Kakuchi H, Sasaki T, Ishida Y, Komamura K, Miyatake K. Clinical usefulness of 123I meta-iodobenzylguanidine imaging in predicting the effectiveness of beta blockers for patients with IDC before and soon after treatment. Heart 1999;81:148-52. Lahiri A, Senior R. Evolving therapeutic concepts and imaging in ischemic cardiomyopathy. J Nucl Cardiol 1998;5:598-608. Witte K, Thackray S, Clark AL, Cooklin M, Cleland JGF. Clinical trials update: IMPROVEMENT-HF, COPERNICUS, MUSTIC, ASPECT-II, APRICOT and HEART. Eur J Heart Fail 2000;2:455-60.
See related editorial, p 127 Idiopathic dilated cardiomyopathy (IDC) is a primary myocardial disease of unknown origin, with a major defect in myocardial contractility that leads to progressive enlargement of the cardiac chambers.1 Although diffused hypokinetic ventricular wall motion (in the left ventricle) is thought to be more charFrom the Cardiology Departmenta and Department of Nuclear Medicine,b University Hospital of Heraklion, Crete, Greece. Received for publication Jan 26, 2001; final revision accepted June 25, 2001. Reprint requests: P. E. Vardas, MD, PhD, Cardiology Department, Heraklion University Hospital, PO Box 1352, Stavrakia, Heraklion, Crete, Greece; [email protected]. Copyright © 2002 by the American Society of Nuclear Cardiology. 1071-3581/2002/$35.00 + 0 43/1/118239 doi:10.1067/mnc.2002.118239
acteristic of IDC,2,3 segmental wall motion abnormalities (WMAs) have been noted in several studies.4,5 Endocardial or myocardial scarring, mural thrombus, geometric factors, and increased left ventricular (LV) wall stress have been implicated in these WMAs.6-8 Recent studies have shown that myocardial perfusion abnormalities occur in IDC and endothelial function is impaired.9,10 However, it is not clear if there is a correlation between regional motion abnormalities and myocardial perfusion defects. Neurohormonal activation is a common finding in patients with congestive heart failure.11-13 All alterations of the cardiac sympathoadrenergic system result in a reduction in cardiac responsiveness to β-adrenergic stimulation.14 Iodine 123–labeled metaiodobenzylguanidine (MIBG), a transmitter analog of norepinephrine15 that shares the same re-uptake pathway within the cardiac 15
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20 mg daily; 7 received enalapril, 10-20 mg; 6 received perindopril, 4 mg; and 4 received captopril, 25-50 mg. No patients were taking spironolactone, tricyclic antidepressants known to affect myocardial MIBG uptake, β-blockers, or β-agonists. The severity of congestive heart failure was assessed by scoring the functional class according to the NYHA classification. Our institution’s ethics committee approved the study protocol, and written, informed consent was obtained from all patients and control subjects before they entered the study.
Analysis of LV Wall Motion
Figure 1. Schema of polar map areas and corresponding LV regions provided from the echocardiographic 16-segment model. 1, 2, 7, and 8, Anterior; 3 and 9, lateral; 4 and 10, inferior; 5, 6, 11, and 12, interventricular septum; 13, 14, 15, and 16, apex.
synapse,16 was developed to visualize sympathetic innervation and has recently been used to study myocardial adrenergic nerve activity.17 Cardiac MIBG uptake has been reported to be reduced in patients with congestive heart failure.18 Global reduction and regional reduction have been demonstrated, the degree of each being positively correlated to markers of severity of heart failure.19 However, there is no study to correlate the regional pattern of MIBG with regional WMAs or myocardial perfusion. In this study we aimed to assess the regional pattern of cardiac adrenergic innervation using MIBG as a marker for presynaptic neuronal uptake activity and to address its relationship with both echocardiographic WMAs and myocardial perfusion using technetium 99m sestamibi scintigraphy in patients with IDC. METHODS Study Population We studied 24 patients with IDC and stabilized congestive heart failure, New York Heart Association (NYHA) class II to IV, and ejection fraction less than 45%, of whom 16 were men (mean age, 55.5 ± 13 years; range, 23-72 years). Fifteen healthy, age-matched volunteers showing no sign of cardiac disease after clinical, electrocardiographic, and echocardiographic examinations comprised the control group. IDC was diagnosed in the absence of coronary artery disease on coronary arteriography. Patients with valvular heart disease, a history of diabetes mellitus, left branch bifascicular block, or any kind of secondary cardiomyopathy were excluded from the study. Medical treatment of all patients consisted of diuretics, digoxin, and angiotensinconverting enzyme inhibitors—7 patients received quinapril, 10-
Cross-sectional echocardiography recording views were obtained with a Hewlett-Packard Sonos 2500 device (Andover, Mass) equipped with a 2.5- to 3.78-MHz transducer. The recordings were stored on a video recorder and on half-inch VHS tape for subsequent analysis. Regional systolic wall thickening was assessed according to the recommendations of the American Society of Echocardiography,20 with a 16-segment model. For each segment, systolic wall thickening is visually graded with a quantitation scoring system in which 1 is normal, 2 is hypokinetic, 3 is akinetic, and 4 is dyskinetic. For the purposes of the study the left ventricle was divided into 5 regional areas (Figure 1), in order to obtain complete correlation with the other methods, as mentioned below. A regional systolic wall thickening score was quantified for each patient by totaling the grades of the segments of each region and dividing by the total number of segments analyzed in that region. Two independent observers analyzed the LV WMAs.
Measurement of LV Systolic Wall Stress LV systolic wall stress21 was evaluated echocardiographically with the following equation (in dynes per centimeter squared): σ = (0.33 · P[LVESD])/(PW [1 + PW/LVESD]) where P is the mean of duplicate cuff arterial systolic pressure, LVESD is the LV systolic internal diameter, and PW is the systolic posterior wall thickness at the time of systole. LV internal diameter and wall thickness were obtained from M-mode tracing in the plane of the mitral valve during 2-dimensional echocardiography. Data were analyzed as the mean of 3 cardiac cycles.
I-123 MIBG Scintigraphy On the day of MIBG scintigraphy, all patients and control subjects were instructed to fast for 6 hours. One milliliter of Lugol’s solution was given orally 2 hours before the slow intravenous injection of I-123 MIBG (5 mCi) (Mallinckrodt Inc, St Louis, Mo; specific activity, 74 MBq/mg). At 10 minutes and 4 hours after tracer injection, a 10-minute anterior-view static acquisition was performed with a General Millenium large-field-of-view, single-head gamma camera (GE Medical Systems, Milwaukee, Wis) fitted with a low-energy, all-purpose, parallel-hole collimator. A 20% energy window centered on 157 keV and a 128 × 128
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matrix size were used. After the delayed planar image was obtained, single photon emission computed tomography (SPECT) was performed with a dual-head gamma camera (GE Medical Systems). Thirty-two projections (50 seconds each) were obtained over a 180° arc, starting at the left posterior oblique position, and images were stored by means of a 64 × 64 matrix. Transaxial, sagittal, and oblique tomograms were obtained through use of a nuclear medicine computer. Cardiac uptake was quantified in all planar views. A 7 × 7pixel region of interest was drawn over the cardiac region and another 7 × 7 region of interest over the upper mediastinum area. The cardiac region of interest was positioned over the heart in the anterior view and was the same in all patients and control subjects. The heart to mediastinum (H/M) activity ratio, introduced by Merlet et al,22 was then computed to quantify cardiac MIBG accumulation. Two independent observers measured the H/M ratio twice, and the mean of the 2 measurements was taken as the datum. The clearance rate from the myocardium (washout rate) was calculated as follows: (Initial myocardial MIBG uptake – Delayed myocardial MIBG uptake)/(Initial MIBG uptake) × 100. MIBG scintigrams were examined by 2 independent experts who had no knowledge of the clinical and angiographic results. To evaluate regional adrenergic dysfunction on SPECT imaging, the left ventricle was divided according to the 5segment model as in the echocardiographic study, and a 4point scoring system was used to determine a defect score for visual interpretation of I-123 MIBG uptake in the 5 regions of LV myocardium as follows: 1, normal radioisotope uptake (>75% of peak activity); 2, mildly reduced uptake (50%-75% of peak activity); 3, moderately reduced uptake (25%-50% of peak activity); and 4, absence of detectable tracer in a segment or severe reduction in radioisotope uptake (<25% of peak activity).
Myocardial Perfusion Imaging All patients underwent a treadmill stress test, and at peak exercise they were injected with Tc-99m sestamibi (10 mCi). Thirty to sixty minutes after the injection, tomographic images were obtained with a GE Optima tomographic dual-head gamma camera (GE Medical Systems) fitted with 2 lowenergy, general-purpose collimators. A 20% energy window was centered on the 140-keV photopeak of Tc-99m. A stepand-shoot mode rotation was used from the 45° right anterior oblique view to the 129° left posterior oblique view, with 32 projections at 40 seconds each. For computer acquisition a 64 × 64 matrix was used and a 3-dimensional image of the heart was created by means of a filtered backprojection technique. Four hours later, each patient was injected with Tc-99m sestamibi (20 mCi) at rest, and SPECT images were taken 30 to 60 minutes later. Image reconstruction was performed and vertical long-axis, horizontal long-axis, and short-axis images were obtained. For interpretation of myocardial perfusion, the same 5-segment model was used, and a semiqualitative 4-point scoring system was used for the evaluation of myocardial perfusion as follows: 1, normal; 2, markedly reduced; 3, definitely reduced; and 4, absent.
17
Cardiac Catheterization and Coronary Angiography Cardiac catheterization and selective coronary angiography were performed by means of standard techniques, and ejection fraction and cardiac index were evaluated. Significant coronary artery stenosis was defined as a 50% or greater reduction in the internal diameter of the main coronary artery or a 70% or greater reduction in the internal diameter of one of the large epicardial arteries.
Statistical Analysis The Pearson correlation coefficient was used to evaluate the association of 10-minute MIBG, 4-hour MIBG, and washout with ejection fraction, cardiac index, NYHA functional class, wall stress, and wall motion score index. Multiple stepwise regression analysis was used to determine which of the above parameters were independently associated with MIBG at 4 hours. Comparisons between 10-minute and 4-hour MIBG uptake in patients and control subjects, as well as in patients with reversible or nonreversible perfusion defects on SPECT imaging, were performed with t tests. The regional distribution of WMAs, MIBG uptake, and myocardial perfusion was assessed. The strength of association and the degree of agreement among the 3 methods were calculated with the Spearman correlation coefficient and Cohen’s kappa index, respectively. P values less than .05 were considered significant.
RESULTS Baseline Values The baseline characteristics of the patient and control groups are summarized in Table 1. Nine patients were in NYHA functional class II, 11 were in class III, and 4 were in class IV. The wall motion score index was 2.25 ± 0.5, the systolic wall stress was 171.5 ± 16.5 dyne/cm2, and the cardiac index was 2.5 ± 0.7 L/min/kg. The MIBG H/M uptake ratio was 1.6 ± 0.18 in the patient group during the first few minutes of the 10-minute phase, whereas it was 2.08 ± 0.20 in the control group (P < .001). At 4 hours, the MIBG H/M uptake was 1.43 ± 0.19 in the patient group, whereas it was 2.05 ± 0.02 in the control group (P < .001). The washout rate was significantly greater in the patient group compared with that in the control group (Figure 2). None of the patients had significant coronary artery stenosis on coronary angiography. MIBG Uptake: Relation to Hemodynamic and Stress Variables MIBG uptake at 4 hours correlated with LV ejection fraction (r = 0.67, P < .01), wall motion score index (r = –0.68, P < .01), and washout (r = –0.58, P < .01), as shown in Figure 3. Significant correlation was also found between MIBG uptake at 4 hours and cardiac index (r =
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Figure 2. MIBG uptake in the patient (1) and control (2) groups at 10 minutes and 4 hours.
0.57, P < .01), NYHA class (r = –0.507, P < .05), and systolic wall stress (r = –0.61, P < .01). Multivariate analysis showed that wall motion score index was the sole parameter that was independently correlated with MIBG at 4 hours (P < .01). Ten-minute MIBG uptake also correlated with ejection fraction (r = 0.62, P < .01) and wall motion score index (r = –0.39, P < .05), whereas washout MIBG rate correlated significantly with ejection fraction (r = –0.54, P < .05) but not with other hemodynamic variables. Fifteen patients showed reversibility in at least 1 of the 5 LV regions on myocardial perfusion SPECT, whereas 9 patients did not. The MIBG uptake values at 4 hours in the 2 groups were 1.45 ± 0.2 and 1.39 ± 0.16, respectively. Patients with reversible defects showed a tendency toward higher MIBG values as opposed to those with no reversible defects, which indicates that ischemia may play a role in MIBG uptake abnormalities. However, these values were not statistically significant (P = .26). Regional Pattern of MIBG Uptake The left ventricle was divided into 5 regions as shown in Figure 1. Of the 120 regions analyzed, 14 (11.7%) were classified as having normal wall motion on echocardiographic examination, 77 (64.1%) were hypokinetic, 28 (23.3%) were akinetic, and 1 was dyskinetic (0.83%). Qualitative analysis of the cardiac MIBG study
Figure 3. Correlation between MIBG uptake at 4 hours and ejection fraction (EF), wall motion score index (WMSI), and washout.
revealed normal uptake in 11 regions (9.2%); mildly reduced uptake in 75 regions (62.5%), moderately reduced uptake in 33 regions (27.5%), and an absence of detectable tracer in 1 region (0.8%). Figure 4 shows a comparison between a normal MIBG image and a typical image from a patient with regions of reduced MIBG uptake. On rest Tc-99m sestamibi SPECT analysis, 25 regions (20.8%) showed normal activity, 82 (68.3%) showed
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19
Figure 4. Cardiac MIBG image with normal distribution (right) and regional abnormalities (left).
Table 1. Baseline data from patients and control subjects
Patients (n = 24) Age (y) Sex (M/F) AF (n) EF (%) HR (beats/min) LVEDD (mm) LVESD (mm) SBP (mm Hg) SWS (dyne/cm2)
55.5 ± 16/8 3 32.7 ± 75 ± 69 ± 57 ± 125 ± 171.5 ±
P value
Control subjects (n = 15)
13
50 ± 9/6 0 67 ± 70 ± 42 ± 36 ± 120 ± 108 ±
6.2 16.2 9 9 10 16.5 × 103
14
NS NS NS <.001 NS <.001 <.001 NS <.001
5.4 11.4 6 8 10 11 × 103
AF, Atrial fibrillation; EF, LV ejection fraction; HR, heart rate; LVEDD, LV end-diastolic diameter; LVESD, LV end-systolic diameter; SPB, systolic blood pressure; SWS, systolic wall stress; NS, not significant.
markedly reduced activity, and 13 (10.9%) showed definitely reduced activity. None of the segments showed absolutely no perfusion activity. The control subjects showed no echocardiographic WMAs or perfusion defects on SPECT imaging, nor any regional reduction in MIBG uptake. The severity of WMAs and the decrease in MIBG uptake at 4 hours were significantly correlated in the septum (r = 0.675, P < .01), anterior wall (r = 0.543, P < .01), and apex (r = 0.530, P < .01), but not in the lateral and inferior wall. Following the use of the statistical agreement method, the severity of the WMAs and MIBG in the same regions matched quite well (Table 2). A good correlation was also found between MIBG uptake and the magnitude of resting myocardial perfusion in the septum (r = 0.58, P < .01) and in the anterior wall (r = 0.48, P < .01), with good agreement in the anterior wall (Table 3).
Table 2. Degree of agreement between severity of echocardiographic wall motion disturbances and reduced MIBG uptake in the same LV regions
Echocardiography/ MIBG Septum Anterior Inferior Lateral Apex
Agreement (%)
Cohen’s κ index
70 79 62 45 72
0.47 0.55 0.31 –0.37 0.5
When the severity of WMAs and resting myocardial perfusion were compared, a good correlation was found in the anterior (r = 0.475, P < .05) and inferior (r = 0.510, P < .01) walls, with good agreement in the anterior wall (75%).
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Table 3. Agreement between severity of regional alteration of MIBG uptake and myocardial perfusion
MIBG/SPECT Septum Anterior Inferior Lateral Apex
Agreement (%) 50 79 50 38 50
Cohen’s κ index 0.21 0.42 0.149 –0.001 0.23
DISCUSSION Several alterations of the cardiac sympathoadrenergic system have been reported in congestive heart failure, all of which resulted in a reduction in cardiac responsiveness to β-adrenergic stimulation.23,24 Postsynaptic β1-adrenoreceptor density is reduced, and the concentration of inhibiting Gi-α proteins is elevated.25,26 The chronically raised noradrenaline concentration in these patients could partially cause these findings.13 In addition, cardiac noradrenaline turnover is increased. Sympathetic activation in chronic congestive heart failure may lead to increased noradrenaline release with increased spillover to plasma and subsequent tissue depletion.27 Imaging of cardiac sympathetic innervation was first carried out in the 1980s by means of I-123 MIBG and single emission computed tomography techniques. Previous studies have shown that the non-neural myocardial uptake of MIBG mainly contributes to the early images and disappears rapidly, whereas the neural uptake contributes to the delayed images.28,29 These findings indicate that the delayed image represents adrenergic nervous system function more faithfully than does the early image. For these reasons, we mainly evaluated delayed MIBG uptake in our study. Patients with IDC demonstrated a significant reduction in MIBG uptake, but also showed a regional pattern of retention abnormalities that was correlated with the severity of the WMAs as evaluated by echocardiography, especially in the anterior wall, septum, and apex. Although there was a correlation between resting myocardial perfusion and MIBG uptake in the areas of the septum and anterior wall, significant agreement was only found in the anterior wall, indicating that the MIBG uptake was partially dependent on myocardial perfusion assessed by SPECT Tc-99m sestamibi. However, MIBG uptake correlated significantly with heart failure severity markers (ie, ejection fraction, NYHA functional class, and wall motion score index).
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The regional abnormalities of cardiac sympathetic tracer uptake in IDC could be explained in several ways. A decrease in myocardial perfusion alone may decrease planar MIBG uptake. Although in IDC the large epicardial coronary arteries are normal, studies have shown that regional myocardial ischemia may occur in patients with IDC.9 In our study, resting myocardial perfusion showed a regional correlation with MIBG uptake, especially in the septum and LV anterior wall. In these regions there was also greater agreement between severity of WMAs and Tc-99m sestamibi uptake, indicating a partial relationship among the 3 methods with regard to the severity of the parameters studied. The severity of WMAs, as determined by echocardiography, can be used as an index of regional reductions in MIBG uptake. Segmental WMAs were correlated with thallium 201 perfusion abnormalities in a similar way to that reported by Yamaguchi et al.30 Competitive inhibition of MIBG uptake due to raised noradrenaline concentration may be one reason. Previous studies31,32 reported that MIBG uptake was significantly correlated with the myocardial content of adrenaline and with increased contractility of the myocardium induced by intracoronary β-adrenergic stimulation. Metabolic abnormalities, because of the increased wall stress of the dilated ventricle, may lead to decreased activity of highly energy-dependent uptake-1 function and vesicular storage mechanism. The subsequent decrease in neuronal reuptake with a lack of activation of noradrenaline in the synaptic cleft may play a key role in changes of the sympathetic signal transduction pathway in heart failure. In our study a significant correlation was found between LV systolic wall stress and MIBG uptake. Finally, reduced MIBG retention may indicate loss of neuronal tissue, damaged by a mechanism of the underlying disease process. Histologic changes in the myocardium, LV-localized fibrosis in IDC, may cause a loss or potentially reversible functional disturbances of sympathetic neurons. This could explain the regional relationship we found between WMAs and LV sympathetic denervation. The 3 methods used showed good agreement in the anterior wall, septum, and apex. Differences in wall stress that may be present in the septum, especially in a distorted left ventricle,30 and the tendency for overestimation of perfusion defects in the inferior wall could explain why we did not reach powerful agreements among the 3 methods in these areas. This is the first study correlating the regional pattern of myocardial sympathetic denervation with WMAs and Tc-99m sestamibi myocardial perfusion in patients with IDC. Although this study presents new data, parts of our
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findings confirm existing knowledge.19 The prognostic implications of sympathoadrenergic dysfunction in these patients did not form part of the main aim of this study. However, because MIBG myocardial scintigraphy has the potential to mirror the whole myocardial adrenergic pathway disintegrity, it has been found to be an independent prognostic marker in patients with cardiomyopathy of different origins.22 Several studies have shown the relationship between MIBG uptake and cardiac hemodynamics,16 as well as cardiopulmonary exercise performance.33 The presence of regional myocardial sympathetic denervation has been correlated to arrhythmia development in post–myocardial infarction patients34 and in patients with ventricular tachycardia without coronary artery disease.35 Inhomogeneity of electrophysiological properties, caused by an upregulation of β-receptors in the denervated regions, could be a possible mechanism for the development of arrhythmias.
21
We have neither Holter data for arrhythmias nor measurements of neurohormonal plasma levels. Although MIBG uptake was been found to correlate with myocardial norepinephrine concentration31 in the study of Hartmann et al,19 no correlation was found between plasma concentration of norepinephrine and a newly developed synthetic catecholamine analog, carbon 11 hydroxyephedrine, which has been used as a marker of cardiac innervation. The MIBG uptake is more specific evidence of cardiac adrenergic dysfunction than that derived from measurements of plasma noradrenaline, which reflects the systemic adrenergic activity.37 We excluded patients with left bundle branch block because of difficulties in assessment of WMAs and falsepositive perfusion scintigraphic imaging results. We did not use therapeutic interventions such as β-blockers to determine whether WMAs or MIBG uptake could be improved with treatment. Further studies with larger sample sizes should therefore be undertaken. Conclusions
Clinical Implications In IDC, sympathoadrenergic imaging with I-123 MIBG has been evaluated as a diagnostic tool to assess the severity of heart failure and to provide prognostic information. Application of MIBG scintigraphy offers advantages in the assessment of not only global but also regional alterations in the cardiac adrenergic system. The regional pattern of adrenergic denervation in patients with IDC may be responsible for severe ventricular arrhythmias in these patients. MIBG imaging could also be used for monitoring β-blocker treatment in patients with IDC and could be useful in identifying the timing and functional improvement when this treatment is given.36 Patients with severe heart failure may be treated with carvedilol, as Lahiri and Senior37 and the COPERNICUS (Carvedilol Prospective Randomized Cumulative Survival Trial) study38 have demonstrated. These studies have proved that carvedilol treatment in these patients was associated with a reduction in mortality, even among patients who conventionally would not have been considered, by many, for β-blocker therapy. MIBG cardiac uptake can be used to monitor the functional improvement. Limitations The marked decrease in MIBG activity in patients with severe IDC created difficulties in image reconstruction. The regional interpretation of MIBG uptake depends on the experience of the observers. This subjective assessment could be considered the main limitation.
In this study of I-123 MIBG in patients with IDC, global reduction, as well as regional abnormalities of cardiac sympathetic integrity, was demonstrated. The magnitude of reduction is partially correlated with regional wall motion and resting myocardial perfusion abnormalities, especially in the LV apex and anterior wall. However, this reduction is positively correlated with indices of the severity of heart failure. The pathogenetic cause that produces the regional differences and the clinical and prognostic significance remain to be defined. Acknowledgment The authors have indicated they have no financial conflicts of interest.
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