Download Carvedilol's Effect on Cardiac Adrenergic Function in Dilated Cardiomyopathy Patients with and more Study notes Nuclear medicine in PDF only on Docsity!
al-receptor blockade (5). A small trial of carvedilol sug gested that this agent was well tolerated and improved exercise tolerance and left ventricular (LV) function (6). In several controlled trials of carvedilol (6—8),patients with heart failure caused by ischemic or idiopathic cardiomyopa thies improved in New York Hospital Association (NYHA) functional class assessment, exercise tolerance, LV ejection fraction (LVEF), quality oflife, and survival times (9). In congestive heart failure the sympathetic nervous sys tem is activated, as reflected by the increase in the concentra tion of plasma norepinephrine (NE). In addition, in the failing myocardium, neuronal uptake of noradrenaline is impaired (10,11). Both the enhanced release of noradrena line and the altered cardiac neuronal uptake may be respon sible for the observed downregulation of adrenoreceptors in patients with heart failure (12). We applied a scintigraphic method of assessing cardiac
adrenergic innervation in chronic heart failure. ‘23I-meta
iodobenzylguanidine (MIBG), an analog of NE, concen trates in adrenergic nerve endings in various regions includ ing the heart (13—15).It is possible to assess myocardial presynaptic adrenergic uptake in heart diseases (myocardial infarction [16], idiopathic dilated cardiomyopathy [DCM] [17,18], pheochromocytoma[19], acute myocarditis [20], and ventricular arrhythmia [21]). A report from our labora tory showed that exercise rehabilitation can improve cardiac neuronal function without negative effects on systolic func tion in patients with ischemic cardiomyopathy and DCM (22). Fukuoka et al. (23) showed that regional myocardial assessment using MIBG SPECT imaging can predict the functional improvement of LVEF in patients with DCM treated with metoprolol for 1 mo. In addition, Suwa et al. (24) showed that cardiac MIBG uptake provided a useful index of whether patients with DCM could respond to bisoprolol therapy. Carvedilol (a third-generation @3-blocker), then, might induce changes in the sympathetic nervous system in patients with heart failure caused by idiopathic DCM. The aim ofthe study was to assess noninvasively the effect of 6 mo of carvedilol treatment on cardiac adrenergic func tion in patients with DCM, using ‘23I-MIBGscintigraphy.
Carvedilolcaninduceimportantclinicalandhemodynamicim
provements in patients with chronic heart failure resulting from
severeleftventricular(LV)dysfunction.Thisstudyexaminesthe
impact of carvedilol on cardiac neuronal function using 1@l@
metaiodobenzylguanidine(MIBG)scintigraphyindilatedcardio
myopathy. Methods: Twenty-two patients with chronic heart failure (19 men, 3 women; mean age, 54 y; age range, 34—64y)
assessedasNewYorkHospitalAssociation(NYHA)classIIorIll
and with initial restingradionuclideLVejectionfractions(LVEF)< 0.40 were enrolled in the study. Patients had long histories of symptomaticLVdysfunctiondespiteoptimal diureticsand angio tensin-convertingenzyme inhibitor treatment. Over a 6-mo pe nod, 50 mg/day carvedilol was administered to these patients. Planar1@l-MlBGscintigraphyprovidedmeasurementsof cardiac
neuronaluptake(as heart-to-mediastinumcountactivityratio
[HMR]),4h after intravenousinjectionof 185 MBq MIBG. Hemo dynamic, clinical, radionuclide LVEF and HMR data measured at the outset and after 6 mo of carvedilol were compared. Results: Restingheartratedecreasedfrom81 ±13 to 71 ± 9 bpm (P = 0.003). After carvedilol therapy NYHA functional classificationfor these patientsimprovedfrom 2.6 ±0.5 to 2.3 ± 0.5 (P = 0.04), LVEFimprovedfrom 22% ±9% to 30% ±13% (P = 0.005), and HMR improvedfrom 145% ±23% to 170% ± 25% (P = 0.0001). Conclusion: Carvedilolinducesimprove ments of clinical symptoms and cardiac neuronal and systolic functions in patients with dilated cardiomyopathy and chronic optimaltreatment.
KeyWords:carvedilol;cardiacneuronalfunction;dilatedcardio
myopathy;metaiodobenzylguanidine;scintigraphy J NucI Med 2000; 41:845—
drenergic activation in chronic heart failure appears to have adverse effects on myocardial function (1). n-blockers may improve hemodynamic function in patients with heart failure caused by idiopathic cardiomyopathy (2—4). Carvedilol is a potent, mildly @3l-se1ective @3-blocking agent with vasodilator and antioxidant properties related to
ReceivedMay10,1999;revIsionacceptedSep.14,1999. Forcorrespondenceor reprintscontact:DenisAgostini,MD,Servicede MédecineNucléaire,CHU COte de Nacre, F-14 000 Caen, France.
CARVEDILOL AND Ci@iwi@C NEURONAL FUNCTION •Agostini et al. 845
Improvement of Cardiac Neuronal Function After
Carvedilol Treatment in Dilated Cardiomyopathy:
A 1231.-MIBGScintigraphic Study
Denis Agostini, Annette Belin, Michel Henry Amar, Yves Darlas, Martial Hamon, Gilles Grollier, Jean Claude Potier, and Gerard Bouvard
Services de MédecineNucléaire,RéadaptationCardiaque, Recherche Clinique, Cardiologie, Centre Hospitalier Universitaire Côtede Nacre, Caen; Center FrançoisBaclesse, Caen, France
During the final week of the fixed-dose maintenance period, noninvasive isotopic variables were measured again.
MIBG Imaging Procedure Radiopharmaceuticals. The pharmacologic precursor,metaiodo benzyl guanidium sulfate, was obtained commercially (CIS Bioin ternational, Gif/Yvette, France). The specific activity of MIBG was
37 MBq/mL.Theradiochemicalpurityof theradioisotopewas
guaranteed to exceed 99.8% by the manufacturer at the time of delivery. Thin-layer chromatography showed that the radiopharma ceutical purity of each dose exceeded 90%. Planar Imaging Protocol. All sympathomimetic medicines that could potentially interfere with the uptake ofMIBG were discontin ued for at least 5 half-lives before the scintigraphic examination. In addition, patients with diabetes and chronic renal failure were excluded because of possible interference with cardiac MIBG uptake (26,27). Patients were pretreated with 30 drops of Lugol's solution in a cup of water 2 d before and 4 d after administration of the radiopharmaceutical. There was no pretreatment wih clonidine. One hundred eighty-five MBq ‘231-MIBGwere administrated. Scanning was performed 4 h later for evaluation of cardiac MIBG uptake (18,22). Energy discrimination was provided by a 20% window centered on the l59-keV photopeak of 1231.An anterior @ thoracic view using a camera equipped with a low-energy, all-purpose, large-field-of-view, parallel-hole collimator. Images were acquired using a dedicated nuclear medicine computer. The anterior view acquisition lasted for 10 mm. The uptake of MIBG to the heart was semiquantified with a
regionof interest(ROI)automaticallydrawnin each subject.The
ROt wasplacedin the cardiacarea,and an ROl of the samesize was placed over the upper mediastinum to standardize cardiac uptake, as previously described (18,22). The mediastinum ROl was placed in the middle of the top of the lungs. The ROl was 24 X 24 pixels and the matrix frame 128 X 128. When there was cardiac inhomogeneous uptake, the ROl was placed using chest radiogra phy. In addition, a similar amount of activity of MIBG was injected (185 ±8MBq)attOandt6. A control value of cardiac MIBG uptake was determined in 10 healthy volunteers matched in age (mean age, 46 ±11 y) with the group of patients. The healthy volunteers showed no sign of cardiac disease after clinical, electrocardiographic, and echocardiographic examinations.
RadionuclideLVEFImaging
After in vivo red-blood-cell labeling with 925 MBq @“Tc,gated blood-pool scans were acquired with the same -ycamera in the left anterior oblique 30°—50°view and 5°—l0°caudal tilt to provide the best separation between both ventricles and atria. The cardiac cycle was divided into 24 segments. The matrix size format was 64 X 64. Five million counts per view were collected. Data were stored on a magnetic disk for subsequent analysis. LVEF was measured with semiautomatic edge detection, and counts technique was measured with a varying ROl. Fourier phase and amplitude images were generated to help trace ROIs. MIBG imaging was performed 48 h after the LVEF imaging.
Assessmentof Reproducibility
We determined the interobserver and intraobserver reproducibili ties of cardiac MIBG scintigraphic data. The time between the 2 evaluations was 1 wk.
846 THE JOURNALOF NUCLEARMEDICINE •Vol. 41 •No. 5 •May 2000
MATERIALS AND METHODS
StudyDesign
The study was approved by the local Research Ethics Commit tee and compared patients with DCM and congestive heart failure at 2 times: baseline (tO)and after 6 mo (t6) of carvedilol treatment. The nuclear physicians conducting the scintigraphic protocol were unaware of the clinical status of the patients and also unaware of the imaging sequence. Procedure of Carvedilol Therapy Inclusion of Patients. Patients 18—80y old were eligible for inclusion in the study if they had symptomatic but stable heart failure (NYHA functional class II [n 10] or Ill [n = 12]) caused by DCM (as evidenced by normal coronary arteriography and endomyocardial biopsy) and a radionuclide LVEF < 0.40. Patients had histories of heart failure averaging 16 mo (range, 6—24mo). Twenty-two consecutive patients (19 men, 3 women; mean age, 54 y; age range, 34-64 y) gave their informed consent for participation in this study. Patients were excluded if they had valvular heart disease as the cause of LV dysfunction, active myocarditis, active angina. a documented history of sustained ventricular tachycardia, symptomatic nonsustained ventricular tachycardia not adequately controlled by antiarrhythmic drugs, or second- or third-degree atrioventricular block unless equipped with a permanent pace maker. Patients with symptomatic peripheral vascular disease, chronic obstructive lung disease, bronchial asthma, diabetes melli tus, long-term alcohol or drug abuse, or chronic renal, hepatic, hematologic, neurologic, or collagen vascular disease were cx cluded. Medications that could interfere with myocardial MIBG uptake, such as @3-blockers,digoxin, calcium channel blockers, monoamine oxidase inhibitors, tricyclic antidepressant agents, @3-agonists,reserpine, guanethidine, and antihypertensive medica tions were excluded (25). Concomitant Medications. Permissible concomitant medica tions included diuretic drugs (furosemide, n = 22), angiotensin converting enzyme (ACE) inhibitors (n = 22), anticoagulant agents (n = 4), antiplatelet agents (n = 10), nitrates (n = 4), and amiodarone (n = 6). Adjustment of cardiac medication doses was not permiued during the screening or baseline phases but was permitted when clinically indicated during the remainder of the study. All patients had optimal but tolerated doses of furosemide and ACE inhibitors within the period of 6 mo. Therefore, no significant changes in body water space that could affect the volume of distribution of MIBG occurred during the period of medication. Other noncardiac medications were administrated when appropriate.
TreatmentPhaseswithCarvedilol
Based on the different studies described in the literature (7—9), medication was initiated in Hospital of Trouville-sur-mer at a dose equivalent to 6.25 mg orally every 12 h. Each time dosages were changed, vital signs were monitored for at least 2 h after the first dose was administrated. At each weekly clinic visit, patients were evaluated for symptoms and signs of worsening heart failure, hypotension, or other adverse effects possibly related to @3-blocker therapy. If no adverse effects were observed, doses of carvedilol were then titrated upward at weekly intervals until either a maximal tolerated dose or the maximal allowed dose was reached. The maximal allowed dose was 25 mg twice a day for 20 patients weighing <75 kg and 50 mg twice a day for 2 patients weighing >75 kg. The maximal attained dose of study medication was then continued for a fixed-dose maintenance period of 6 mo.
A (^) .-s-@ .@
FiGURE 1. (A) Planar scintigraphicim age of anterior view of chest of 54-y-old
man4 h after‘@l-MlBGintravenousinjec
lion and beforecarvedilol(tO).Heart(H) and mediastinum(M)were selectedas shownto
measureheart-to-mediastinumratioactivity
(HMR).HMRwasevaluatedas 111%.(B)
Planarscintigraphicimageofanteriorview
of chest4 h after‘@l-MlBGintravenous
Injection after carvedilol (16). Significant in crease in cardiac MIBG uptake was ob served(HMR = 162%).
848 THEJoui@.Niu.OFNucLEARMEDICINE•Vol. 41 •No. 5 •May 2000
and our patient populations were younger than 65 y, and the decrease ofcardiac MIBG uptake is the result ofheart failure and not related to the age of patients. In patients with DCM, assessment of the myocardial distribution of ‘23I-MIBGmight be used as a relatively noninvasive means of evaluating the severity of altered adrenergic innervation in the heart (30). The myocardial kinetics of ‘23I-MIBGcan be classified into adrenergic neuronal compartments (intravesicular accumulation) and extraneuronal compartments (extravesicular accumulation) (31). One studyhassuggestedthat the extraneuronaluptake does not play a role in the human heart, because there is no accumulation of ‘23I-MIBGon either early or delayed images in the transplanted heart (32). Meredith et al. (28) suggested that the marked increase in NE spillover from the heart in heart failure results largely from an increase in sympathetic nerve firing and neuronal release of NE and not from a failure to recapture NE. The ‘231-MIBGmyocardial concentration, especially the heart-to-mediastinum ratio count activity, has been shown to correlate with myocardial NE concentration and LVEF (17). Because MIBG shares many transport properties with NE,
‘23IMIBGcan be used to assess cardiacadrenergicnervous
system disintegrity in human heart failure (32). Imamura et
a!. (30) have shown that the heart-to-mediastinum activity ratio of ‘23I-MIBGdecreases in severe heart failure, and myocardial washout of ‘23I-MIBGis accelerated in propor tion to the severity of heart failure. In heart failure, reduction of cardiac MIBG uptake may result from several causes. Increased circulating cate cholamines may be competing at the NE uptake sites for MIBG in patients with heart failure (31). Several authors showed that in patients with DCM, heart-to-mediastinum
MIBG ratio decreased with increasing plasma catechol
amine levels (17, 18). Indeed, in patients with pheochromo cytoma, Nakajo et a!. (33) found that the cardiac MIBG accumulation at 24 and 48 h after injection was inversely related to plasma concentrations and urinary excretion rate of catecholamine. In our study, plasma catecholamine con centrations were not determined. Plasma NE did not reflect cardiac sympathetic activity, because cardiac NE spillover accounts for less than 3% of total body NE release (34). Merlet et al. (18) showed that MIBG uptake decreased with normal circulating NE concentrations in patients with mod crate heart failure. This finding suggested that an increase of circulating NE concentrations was not the only factor involved in the decrease of cardiac MIBG uptake. Others causes of nonvisualization of the heart may be
drugs such as labetalol or propranolol that interfere with the
uptake of ‘231-MIBGin the heart (25). No patient was taking medications that might have interfered with cardiac MIBG uptake (other @3-blockers,such as atenolol or metoprolol). Myocardial MIBG uptake was measured within a long period of time without any change in the clinical situation and treatment of each patient. Therefore, it can be assumed
that the condition under which MIBG uptake was measured remained the same during the course of the study.
Carvedilol and Cardiac MIBG Uptake in DCM Carvedilol induces a significant improvement in cardiac neuronal function assessed by MIBG scintigraphy. Chizzola et al. (35) showed in the preliminary and randomized double-blind study that carvedilol improved cardiac adrener gic function and LVEF in patients with DCM as assessed at early (3 mo) and late (6 mo) follow-up. Different mecha nisms can be involved in this finding. Carvedilol may improve cardiac neuronal uptake of NE by increasing the ratio of NE uptake to release or increasing uptake and reducing release. However, the metabolic path way is not well defined and remains unclear. This local effect may result in a reduced exposure of the myocytes to NE and a subsequent upregulation of the myocardial @3adrenorecep tors in patients with chronic heart failure. No isotopic method using monophotonic tracers can really evaluate directly and noninvasively both cardiac parasympathetic and sympathetic systems. Few PET studies have quantitated cardiac presynaptic activity (36,37). In fact, PET is probably the optimal way that the effect of carvedilol on regional myocardial sympathetic function can be evaluated. MIBG delivery to the myocardium is largely flow limited,
as is the case for several of the PET NE analogs. Improved
myocardial blood flow, as a result of improved cardiac output from the carvedilol, improved ventricular function. The fact that these subjects had no coronary artery disease eliminated the possibility of differential regional delivery which might confound the issue. Also, data suggest that endothelial function in DCM is abnormal and may account for altered delivery globally. However, it is difficult to explore in vivo the endothelial function in humans. More
studies are needed to address the impact of carvedilol on the
presynaptic cardiac neuronal function. It might be anticipated that myocardial MIBG uptake in fibrotic areas is lower than in normal myocardium because of sympathetic denervation. However, the current method does not assess segmental cardiac MIBG uptake and instead
assesses global neuronal uptake.
These data suggest that cardiac planar MIBG scintigraphy can be used as a noninvasive method to assess changes in cardiac sympathetic neuronal function caused by carvedilol treatment in chronic heart failure, even in instances in which the variation of MIBG uptake was moderate.
CarvedilolandHemodynamicandSystolicFunctions
Metra et al. (6) randomly assigned 40 patients with
NYHA class II or ifi heart failure and LVEF < 35% to
carvediol or placebo. Compared with placebo, 3 mo of
carvedilol produced improvement in pulmonary artery and
pulmonary capillary wedge pressures, stroke volume, and stroke volume indices; submaximal exercise capacity; quality of-life score; and NYHA functional class. Carvedilol also improved resting LVEF from 20% to 30%. In addition,
CARVEDILOL AND Ciiwi@C NEURONAL FUNCTION Agostini et al. 849
double-blind, randomized study of bucindolol versus placebo. Am J Med. 1990:88:223—229.
5. Strein K, Sponer G, Muller-Beckmann B, Bartsch W. Pharmacological profile of carvedilol, a compound with @-b1ockingand vasodilating properties. I Cardiovasc Pharmacol. 1987:10(suppl ll):S11—S41. 6. Metra M, Nardi M, Giubbini R, Del Cas L Effects of short- and long-term carvedilol administration on rest and exercise hemodynamic variables, exercise capacity and clinical conditions in patients with idiopathic dilated cardiomyopa thy. JAm Coil CardioL 1994:24:1678—1687. 7. Olsen S. Gilbert EM, Renlund DO, Taylor DO, Yanowitz FD. Bristow MR. Carvedilol improves left ventricular function and symptoms in chronic heart failure: a double-blind randomized study. JAm ColiCardiol. 1995:25:1225—1231. 8. Packer M, Bristow MR. Cohn JN, et al. The effect ofcarvedilol on morbidity and mortality in patients with chronic heart failure. N Engi J Med. 1996:334:1349—
9. Bristow MR. Gilbert EM, Abraham WT, et al. Carvedilol produces dose-related improvements in left ventricular function and survival in subjects with chronic heart failure. Circulation. 1996:94:2807—2816. 10. Petch MC, Nayler WG. Uptake of catecholamines by human cardiac muscles in vitro. Br Heart J. 1979:41:336—339. 11. Bohm M, La Rosee K, Schwinger RHG, Erdmann E. Evidence for reduction of norepinephrine uptake sites in the falling human heart. J Am Coil Cardioi. 1995:25:146—153. 12. Lefkowitz Ri, Caron MG, Stiles GL Mechanisms of membrane-receptor regulation. N Engi J Med. 1994:310:1570-1579. 13. Wieland DM, Brown LE, Les Rogers W, et al. Myocardial imaging with radioiodinated norepinephrine storage analog. J Nuci Med. 1981:22:22—31. 14. Kline RC, Swanson DP, Wieland DM, Thrall JH, Cross MD, Pin B. Myocardial imaging in man with 1-123 metaiobenzylguanidine. J Nuci Med. 1981:24:1194—
15. Sisson JC, Wieland DM, Sherman P. Mangner MC, Tobes MC, Jacques S. Metaiodobenzylguanidine as an index of adrenergic nervous system integrity and **function.JNucl Med. 1987:28:1620—1624.
- Dae MW, Herre JM, O'Connell 3W, Botvinick EH, Newman D, Munoz L.** Scintigraphic assessment of sympathetic innervation after transmural versus nontransmural myocardial infarction. JAm CoilCardiol 1991:17:1416-1423.
- Schofer J, Spielmann R, Schubert A, Weber K, Schiuter M. lodine-123 mets iobenzylguanidine scintigraphy: a noninvasive method to demonstrate myocardial adrenergic nervous system disintegrity in patients with idiopathic dilated cardio **myopathy. JAm Coil Cardiol. 1988:12:1252—1258.
- Merlet P, Valette H, Dubois-RandéIL, et al. Prognostic value of cardiac** metaiodobenzylguanidine imaging in patients with heart failure. J Nucl Med. 1992:33:471—477. 19. Agostini D, Scanu P. Babatasi 0, et al. Pheochromocytoma with catecholamine induced impairment of cardiac neuronal function. Am Heart J. 1995:130:1128— **1130.
- Agostim D, Babatasi G, Manrique A, et al. Impairment of cardiac neuronal** function in acute myocarditis: iodine-123-metaiodobenzylguanidine scintigraphy study.JNuclMed. 1998:39:1841—1844. 21. Wichter Th, Hindricks G, Lerch H, et al. Regional myocardial sympathetic dysinnervation in arrhythmogenic tight ventricular cardiomyopathy: an analysis using ‘@I-metaiodobenzylguanidinescintigraphy. Circulation. 1994:84:667-683.
- Agostim D, Lecluse E, Belin A, et al. Impact of exercise rehabilitation on cardiac neuronal function in heart failure: an iodine-l23-metaiodobenzylguanidine scm tigraphy study. EurJ Nuci Med. 1998:25:235—241. 23. Fukuoka S. Hayashida K, Hirose Y, Ishida Y, Kakuchi H, Eto T. Use of iodine-123-metaiodobenzylguanidine myocardial imaging to predict the effective
ness of n-blocker therapy in patients with dilated cardiomyopathy. Eur I Nuci Med@1997:24:523—529.
24. Suwa M, Yoshiaki 0, Moriguchi A, et al. Iodine-l23-metaiodobenzylguanidine myocardial scintigraphy for prediction of response to @-b1ockertherapy in **patients with dilated cardiomyopathy. Am Heartf. 1997:133:353—358.
- Huguet F, Fagret D, Caillet M, Piriou A, Besnard JC, Guilloteau D. Interaction of** metaiodobenzylguanidine with cardioactive drugs: an in vitro study. Eur J Nuci **Med. 1996:23:546—549.
- Mantysaari M, Kuikka J, Mustonen J, et al. Noninvasive detection of cardiac** sympathetic nervous dysfunction in diabetes patients using [‘DI]metaiodobenzyl guanidine. Diabetes. 1992:41:1069—1075.
- Miyanaga H, Yoneyama S. Kamitani T, Kawasaki 5, Takahashi T, Kunishige H. Abnormal myocardial uptake and clearance of ‘@I-labeledmetaiodobenzylguani dine in patients with chronic renal failure and autonomic dysfunction. I Nuci Cardiol. 1996:3:508—515. 28. Meredith IT, Eisenhofer 0, Lambert GW, Dewar EM, Jennings OL, Esler MD. Cardiac sympathetic nervous activity in congestive heart failure: evidence for increased neuronal norepinephrine release and preserved neuronal uptake. Circu lation. 1993:88:136—145. 29. Estorch M, Carrio I, Berna L et al. Myocardial iodine-labeled metaiodobenzylgua **nidine-123 uptake relates to age. J Nuci Cardiol. 1995:2:126-132.
- Imamura Y. Ando H, Mitsuoka W, Masaki H, Ashihara T, Fukuyama T.** Iodine-123-metaiodobenzylguanidine images reflect intense myocardial adrener gic nervous activity in congestive heart failure independent of underlying cause. J **Am CoilCardioL1995:26:1594—1599.
- Nakajo M, Shimabukuro K, Yoshimura H, et al. Iodine-131 metaiodobenzylguani** dine intra- and extravesicular accumulation in the rat heart. J Nuci Med. 1986:27:84—89.
- Dae MW, De Marco T, Botvinick EH, et al. Scintigraphic assessment of MIBG uptake in globally denervated human and canine hearts: implications for clinical studies. JNuciMed. 1992:33:1444—1450. 33. Nakajo M, Shapiro B, Glowniack J, Sisson JC, Beirwaltes WH. Inverse relationship between cardiac accumulation of metaiodobenzylguanidine and circulating catecholamines in suspected pheochromocytoma. JNuclMed. 1983:24: **1127—1134.
- Esler MB, Jennings GL, Korner P. et al Assessment of human sympathetic** nervous system activity from measurements ofnorepinephrine turnover. Hyperten sion. 1988:11:3—20. 35. Chizzola PR, Marinho NVS, Moraes RF, et al. The beneficial effects of carvedilol on heart failure is associated to changes in adrenergic neuronal functional. Preliminary results ofa randomized double-blind study (Caribe Study) [abstract]. Circulation. 1998:17:11917. 36. Melon P. Schwaiger M. Imaging of metabolism and autonomic innervation of the heart by positron emission tomography. EurJ NucIMed@ 1992:19:453—464.
- Valette H, Loc'h C, Mardon K, et al. Br-76 metabromobenzylguanidine: a PET radiotracer for mapping sympathetic nerves of the heart. J Nuci Med. 1993:34: 1739—1744. 38. Vesalainen RK, Pietila M, Tahvanainen KUO, et al. Cardiac positron emission tomography imaging with [“C]hydroxyephedrine,a specific tracer for sympa thetic nerve endings, and its functional correlates in congestive heart failure. Am I CardioL 1999;84:568—574. 39. Somsen GA, Vlies B, de Milliano PAR, et al. Increased myocardial metaiodoben zylguanidine uptake afterenalapril treatment in patients with chronic heart failure. Heart 1996:76:218—222.
- Takeishi Y, Atsumi H, Fujiwara 5, Takajashi K, Tomoike H. ACE inhibition reduces cardiac iodine-123-MIBG release in heart failure. I Nuci Med. 1997:38: 1085—1089.
CARVEDILOL @r@rCiwi@C NEURONAL FUNCTION •Agostini et a!. 851
