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CLINICAL STUDY: HEART FAILURE

Comparison of the prognostic value of cardiac iodine-123 metaiodobenzylguanidine imaging and heart rate variability in patients with chronic heart failure

A prospective study

Takahisa Yamada, MD^*,*, Tsuyoshi Shimonagata, MD^*, Masatake Fukunami, MD^*, Kazuaki Kumagai, MD^*, Hisakazu Ogita, MD, Akio Hirata, MD^*, Mitsutoshi Asai, MD^*, Nobuhiko Makino, MD^*, Hidetaka Kioka, MD^*, Hideo Kusuoka, MD, Masatsugu Hori, MD and Noritake Hoki, MD^*

^* Division of Cardiology, Osaka Prefectural General Hospital, Osaka, Japan
Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Osaka, Japan
Institute for Clinical Research, Osaka National Hospital, Osaka, Japan

Manuscript received April 19, 2002; revised manuscript received August 26, 2002, accepted September 13, 2002.

^* Reprint requests and correspondence: Dr. Takahisa Yamada, Division of Cardiology, Osaka Prefectural Hospital, 3-1-56, Mandai-Higashi, Sumiyoshi-ku, Osaka 558-8558, Japan.
tyamada{at}gh.pref.osaka.jp

	Abstract

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OBJECTIVES: We sought to prospectively compare the prognostic value of cardiac iodine-123 (I-123) metaiodobenzylguanidine (MIBG) imaging with that of heart rate variability (HRV) in patients with mild-to-moderate chronic heart failure (HF).

BACKGROUND: Cardiac I-123 MIBG imaging, which reflects cardiac adrenergic nerve activity, provides prognostic information on chronic HF patients. Reduced HRV, indicating derangement in cardiac autonomic control, was also reported to be associated with a poor prognosis in chronic HF patients.

METHODS: At study entry, I-123 MIBG imaging and 24-h Holter monitoring were performed in 65 chronic HF outpatients with a radionuclide left ventricular ejection fraction <40%. The cardiac MIBG heart to mediastinum ratio (H/M) and washout rate (WR) were obtained from MIBG imaging. The time and frequency domain parameters of HRV were calculated from 24-h Holter recordings.

RESULTS: At a mean follow-up of 34 ± 19 months, WR (p < 0.0001), H/M on the delayed image (p = 0.01), and normalized very-low-frequency power (n-VLFP) (p = 0.047) showed a significant association with the cardiac events (sudden death in 3 and hospitalization for worsening chronic HF in 10 patients) on univariate analysis. Multivariate analysis revealed that WR was the only independent predictor of cardiac events, although the predictive accuracy for the combination of abnormal WR and n-VLFP significantly increased, compared with that for abnormal WR (82% vs. 66%, p < 0.05).

CONCLUSIONS: Cardiac MIBG WR has a higher prognostic value than HRV parameters in patients with chronic HF. The combination of abnormal WR and n-VLFP would be useful to identify chronic HF patients at a higher risk of cardiac events.

Abbreviations and Acronyms   HF   heart failure   H/M   heart to mediastinum ratio   HRV   heart rate variability   I-123   iodine-123   LAD   left atrial dimension   LV   left ventricle, left ventricular   MIBG   metaiodobenzylguanidine   (n-)VLFP   (normalized) very-low-frequency power   R-LVEF   radionuclide left ventricular ejection fraction   ROI   region of interest   WR   washout rate

	Methods

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Study patients.   We studied 71 consecutive chronic HF outpatients in sinus rhythm, whose radionuclide left ventricular ejection fraction (R-LVEF) was <40%. Patients were required to be stable for at least three months by use of conventional therapy with angiotensin-converting enzyme inhibitors, diuretics, and digoxin. Patients were excluded from the study if they had atrial fibrillation, sinus node dysfunction, atrioventricular block, a permanent pacemaker, significant renal dysfunction, insulin-dependent diabetes mellitus, or autonomic neuropathy. None of the patients were receiving beta-blockers, calcium antagonists, or antiarrhythmic drugs, except for mexiletine (n = 10) and amiodarone (n = 3) at study enrollment. At study entry, all patients had cardiac MIBG imaging, 24-h ambulatory ECG monitoring, echocardiography, and a plasma noradrenaline assay. All patients gave written, informed consent for their participation in this study, which was approved by the Osaka Prefectural General Hospital’s Review Committee.

Radionuclide angiography for entry criteria
Before entering this study, patients underwent electrocardiography (ECG)-gated blood-pool scintigraphy at rest in the supine position, using a conventional rotating gamma camera (Prism 2000, Picker, Bedford, Ohio) equipped with a low-energy, high-resolution, parallel-hole collimator. Patients were given 740 MBq of technetium-99m–labeled human serum albumin (Nihon Medi-Physics, Nishinomia, Japan). The camera was positioned in the modified left anterior oblique projection to isolate the left ventricle (LV) from other cardiac structures, and data acquisition was then completed. The LVEF was calculated using a standard program (19).

Cardiac MIBG imaging
No patients were taking tricyclic antidepressant drugs, sympathomimetic agents, or other drugs known to interfere with MIBG uptake in the month preceding cardiac MIBG imaging.

Cardiac MIBG acquisition
All patients underwent myocardial imaging with I-123 MIBG (Daiichi Radioisotope Laboratory, Tokyo, Japan), using the same gamma camera as for the radionuclide angiography. Patients were placed in the supine position. A 111-MBq dose of I-123 MIBG was injected intravenously at rest after an overnight fast. Initial and delayed image acquisitions were performed in the anterior chest view 20 and 200 min after the isotope injection.

Image analysis
Two independent observers who were unaware of the clinical status of patients assessed cardiac MIBG uptake (Fig. 1). Left ventricular activity was recorded using a manually drawn region of interest (ROI) over the whole LV myocardium, and the mean heart counts per pixel were calculated. Another 7 x 7 pixel ROI was recorded over the upper mediastinal area, and the mean counts per pixel were calculated. Background subtraction was performed using the upper mediastinal ROI. The heart-to-mediastinum ratio (H/M) was then determined by dividing the mean counts per pixel in the LV by the mean counts per pixel in the mediastinum. After taking radioactive decay of I-123 into consideration, the cardiac MIBG washout rate (WR) was calculated from the initial and delayed images, as previously reported (15). Based on our previous study, abnormal WR was defined as more than 27% (15).

View larger version (84K): [in this window] [in a new window]   Figure 1 Iodine-123 metaiodobenzylguanidine (MIBG) imaging in a patient with chronic heart failure (HF). Heart (H) and mediastinum (M) were selected, as shown, to measure the H/M ratio. The cardiac MIBG washout rate (WR) was calculated from the initial (left) and delayed images (right).

Traditional measurements of HRV were analyzed using the HRV system, DSC-3100;MemCalc/Chiram (Nihon Koden Co. Ltd., Tokyo, Japan), according to the Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology (4). Time domain analysis of HRV included the mean RR (mean duration of all normal to normal [NN] intervals), SDNN (standard deviation of all NN intervals), SDANN (standard deviation of the averages of NN intervals in all 5-min segments), SDNN index (mean of the standard deviations of all NN intervals for all 5-min segments), rMSSD (square root of the mean of the sum of the squares of differences between adjacent NN intervals), pNN50 (number of NN intervals differing by more than 50 ms from the adjacent interval divided by the total number of NN intervals), and HRV triangular index. Spectral analysis was performed using the maximum entropy method (20). Power spectra were quantified by the area within the following frequency band: total power (0.0001 to 0.5 Hz), ultra-low-frequency power (ULFP: 0.0001 to 0.003 Hz), very-low-frequency power (VLFP: 0.003 to 0.04 Hz), low-frequency power (LFP: 0.04 to 0.15 Hz), and high-frequency power (HFP: 0.15 to 0.4 Hz). The LFP/HFP ratio was also calculated. The power within each band was also expressed as the percentage of the total power (normalized ULFP, VLFP, LFP, and HFP). We determined a control value for the HRV parameter in 20 persons (12 men and 8 women; mean age 55 ± 12 years) who had no history of heart disease, a normal physical examination, and normal ECG and chest X-ray findings. The mean value of normalized VLFP (n-VLFP) was 32.3 ± 5.1%. Therefore, we defined abnormal n-VLFP as <22%, which is the mean control value –2 SD.

Echocardiography
Two-dimensional echocardiography was performed with a Toshiba SSH-380A recorder equipped with a 2.5- or 3.75-MHz transducer. The standard technique was employed for sizing the LV and atrium (21). The LV dimension was measured at end-diastole on the R-wave of the ECG-derived QRS complex, just below the level of the mitral leaflets through the standard left parasternal window. The left atrial dimension (LAD) was measured as the distance from the leading edge of the posterior aortic wall to the leading edge of the posterior left atrial wall at end-systole.

Plasma noradrenaline concentration
Blood sampling for determination of the plasma noradrenaline concentration was done from an intravenous cannula after resting for at least 30 min in the supine position. The plasma noradrenaline concentration was determined in EDTA plasma by high-performance liquid chromatography (22) at Shionogi Biomedical Laboratories (Osaka, Japan). A duplicate determination in the laboratory showed a coefficient of variation of 0.4% to 5.5%.

Follow-up
All of the study patients were then followed up in our hospital at least once a month by clinicians who did not know the results of the cardiac MIBG imaging and HRV analysis. The end point of this study was when a patient died either suddenly or from other cardiac diseases, or hospital admission for worsening HF failure.

Statistical analysis
Data are presented as the mean value ± SD. The Student t test and a Fisher exact test were used to compare differences for continuous and discrete variables, respectively, in patients with and without cardiac events. The cardiac event–free rates in the two groups were calculated using the Kaplan-Meier method, and the difference between them was detected using the log-rank test. The Cox proportional hazards regression model was used to determine the significance of variables predictive of outcome by univariate analysis (p < 0.05) as independent predictors of cardiac events on multivariate analysis. The Fisher exact test was used to compare sensitivity, specificity, predictive accuracy, and positive and negative predictive values among the different criteria for prediction of cardiac events. All statistical analyses were carried out using the Stat-View statistical package, version 4.5. A p value <0.05 was considered statistically significant.

	Results

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Characteristics of patients.   Of 71 enrolled patients, six were excluded: five because of the presence of >15% ectopic beats or noise during 24-h ambulatory ECG monitoring and one because of the recording of <20 h of analyzable data. Thus, analysis of both HRV and cardiac MIBG imaging was possible in 65 patients. The mean age of the 65 patients was 63 ± 12 years (range 28 to 85). Fifty-one patients (79%) were men and 14 (21%) were women. Radionuclide LVEF was 28 ± 8%; 13 patients (20%) were in functional class I, 38 patients (58%) were in class II, and 14 patients (22%) were in functional class III. Heart failure was due to ischemic heart disease in 41 patients (63%) and due to idiopathic dilated cardiomyopathy in 24 patients (37%).

Follow-up outcome
All patients were followed up completely. The mean period of follow-up was 34 months (maximum 57 months). All patients were examined at least once a month in our hospital during a study period. During that period, 13 (20%) of 65 patients had cardiac events. Three patients died suddenly, 10 patients were admitted for worsening chronic HF, and one of these patients subsequently died of progressive pump failure.

Comparison of baseline characteristics between patients with and without cardiac events
The baseline characteristics of patients with and without cardiac events are listed in Table 1. There were no differences in age, gender, or functional class between the two groups. Although there were no significant differences in the 6-min walk distance, heart rate, blood pressure, R-LVEF, LV end-diastolic dimension, Lown’s grade, or presence of nonsustained ventricular tachycardia between the two groups, the LAD was significantly greater and the plasma noradrenaline concentration was significantly higher in patients with than in those without the cardiac events.

Figure 2 shows the results of cardiac MIBG imaging. Patients with cardiac events had a significantly lower H/M ratio on the delayed image (1.56 ± 0.29 vs. 1.77 ± 0.28, p = 0.02) and a higher WR (44.0 ± 14.7% vs. 25.6 ± 12.8%, p < 0.0001) than those without cardiac events, although there was no significant difference in H/M on the early image between the two groups (1.80 ± 0.30 vs. 1.85 ± 0.26). The results of HRV parameters in patients with and without cardiac events are listed in Table 2. Patients with cardiac events had significantly lower n-VLFP than did those without cardiac events, although other time and frequency domain parameters did not differ significantly between the groups.

View larger version (25K): [in this window] [in a new window]   Figure 2 Plots of data of cardiac metaiodobenzylguanidine (MIBG) imaging in patients with chronic heart failure with and without cardiac events. H/M(e) and H/M(d) denote the cardiac MIBG heart to mediastinum ratio (H/M) on the early and delayed images, respectively. Patients with cardiac events had a significantly lower H/M(d) and higher washout rate (WR) than did those without cardiac events, although there was no significant difference in H/M(e) between the two groups.

View larger version (16K): [in this window] [in a new window]   Figure 3 The cardiac event-free rate curves by Kaplan-Meier analysis in patients with chronic heart failure with and without an abnormal washout rate (WR) (>27%). The cardiac event-free rate was significantly lower in patients with an abnormal WR than in those without it.

View larger version (15K): [in this window] [in a new window]   Figure 4 The cardiac event-free rate curves by Kaplan-Meier analysis in patients with chronic heart failure with and without abnormal normalized very-low-frequency power (n-VLFP) (<22). The cardiac event-free rate was significantly lower in patients with abnormal n-VLFP than in those without it.

View larger version (15K): [in this window] [in a new window]   Figure 5 The cardiac event-free rate curves by Kaplan-Meier analysis in patients with chronic heart failure, according to a combination of abnormal washout rate (WR) and normalized very-low-frequency power (n-VLFP). The cardiac event-free rate was significantly lower in patients with both an abnormal WR and n-VLFP than in those with both a normal WR and n-VLFP.

	Discussion

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Prognostic value of MIBG and HRV in chronic HF.   An accurate noninvasive assessment of cardiac sympathetic nerve activity would be particularly important in the setting of chronic HF because of the association between high sympathetic activity in this condition and an adverse prognosis (2). Cardiac MIBG imaging provides direct information on the function and integrity of the presynaptic sympathetic nerve endings (10,24,25). On the other hand, HRV, which depends on postsynaptic signal transduction, reflects the end-organ response of the sinus node. In conditions characterized by marked, persistent sympathetic activation, which is often observed in chronic HF, the sinus node may drastically diminish its responsiveness to neural inputs. The HRV parameters, tending toward very low levels in chronic HF, might have a reduced dispersion, thus limiting their possible statistical power in the regression model. Furthermore, cardiac MIBG imaging may be useful in the assessment of cardiac sympathetic alteration in patients with a high incidence of ectopic activity, in whom HRV analysis cannot always be performed reliably. Therefore, in the present study, cardiac MIBG imaging had a higher prognostic value than HRV analysis in patients with chronic HF.

Cardiac MIBG WR
Uptake of MIBG in the myocardium decreases with time, and there is evidence that MIBG WR could be an index of noradrenaline spillover. There are conflicting data on the relative prognostic values of MIBG WR versus H/M on the delayed images (12-15). In the present study, multivariate analysis showed that only MIBG WR contributes to the estimation of clinical outcome, although H/M on the delayed image was significantly lower in patients with than in those without cardiac events. This result is inconsistent with previous studies showing that H/M has a powerful predictive value, whereas MIBG WR does not (12,13). Different results concerning the predictive value of WR may be due to differences in the method used to calculate WR (application of background subtraction) and the etiology of chronic HF. Metaiodobenzylguanidine WR could reflect adrenergic activity more accurately in patients with chronic HF, in whom denervation is suspected, because WR is independent of the amount of adrenergic neurons, whereas H/M is not. Therefore, in the present study, MIBG WR was superior to H/M with regard to the estimation of prognosis in patients with chronic HF.

Effect of beta-blockade by carvedilol on cardiac MIBG imaging
We assessed the effect of beta-blockade by carvedilol on the MIBG parameters in 21 study patients. The WR significantly decreased (30.8 ± 16.0% to 27.2 ± 17.1%, p = 0.008) and H/M on the delayed images increased (1.68 ± 0.28 to 1.74 ± 0.28, p = 0.02) one year after the administration of carvedilol, although there was no change in H/M on the early images (1.78 ± 0.20 to 1.79 ± 0.29). Furthermore, R-LVEF significantly increased one year after carvedilol therapy (30.1 ± 7.9% to 37.8 ± 11.8%, p < 0.0001). The degree of decrease in MIBG WR roughly correlated with the degree of increase in R-LVEF (r = –0.46, p < 0.05). These findings were similar to those reported in previous studies (26,27). These results suggest that carvedilol would improve cardiac adrenergic function by an increase in noradrenaline uptake and a reduction of the spillover in cardiac adrenergic terminals and that the improvement in LV function with carvedilol therapy might be accompanied by an attenuation of activation of cardiac adrenergic nerve function.

Heart rate variability in chronic HF
Previous studies showed that time domain measurements of HRV, especially SDNN, were independently associated with mortality (6-8). However, in the present study, none of the time domain measures of HRV were related to cardiac events. The discrepancy may derive from differences in the severity of chronic HF and the study end point, which we defined as not only cardiac death but also hospitalization for worsening chronic HF.

In the present study, on univariate analysis, n-VLFP showed a significant association with cardiac events. Bigger et al. (28) reported that VLFP after myocardial infarction was strongly associated with a poor prognosis, although the physiologic mechanism for this component has not been fully identified. Very-low-frequency power may be influenced by a number of factors other than autonomic balance, such as thermoregulation, the renin-angiotensin system, or peripheral chemoreceptors (29-31). Recently, it has been shown that breathing disorders increase the spectral power to the VLFP range in patients with chronic HF and confound the use of HRV analysis (32). In the present study, n-VLFP in patients with chronic HF was significantly lower than that in normal control subjects with normal breathing (27.9 ± 8.8% vs. 32.3 ± 5.1%, p < 0.05). Therefore, it appears that our study was not affected by this confounding effect.

Study limitations
There are several limitations of this study. First, medications used during follow-up may affect MIBG uptake, HRV measurements, and clinical outcome. There was a trend toward a decrease in the use of carvedilol in patients with cardiac events, although the difference was not statistically significant, which may be due to the small sample size in the present study. However, even if the Cox analysis were performed in the subgroups with and without carvedilol therapy separately, the same result—that MIBG WR was significantly associated with the cardiac events–was obtained (p = 0.035, hazard ratio 1.076 [95% CI 1.024 to 1.130] in subgroup with carvedilol therapy vs. p = 0.02, hazard ratio 1.074 [95% CI 1.010 to 1.142] in subgroup without therapy). Second, there may be a problem in quantifying the cardiac MIBG images. In the present study, 55 (85%) of 65 study patients had an exceedingly low H/M on the early images (<2.11, mean –2 SD of normal value: 2.43 ± 0.16). This may introduce errors when drawing the ROI manually on cardiac MIBG images of patients with chronic HF. In the present study, two independent observers drew the ROI. The interobserver variation in counts per pixel was within 1.2%. Thus, errors introduced by drawing the ROI manually on the cardiac MIBG images are likely to be subtle. Third, we excluded patients with atrial fibrillation, a pacemaker implant, frequent ectopic beats, or insulin-dependent diabetes mellitus. Some of these conditions could be associated with a worse prognosis and therefore could introduce a bias—namely, selecting a subgroup of patients with chronic HF with a lower event rate. Fourth, in this study, we studied only stable outpatients who had mild-to-moderate chronic HF. The results of our study should not be generalized to inpatients with severe chronic HF. Further study is needed to address this issue.

Conclusions
To the best of our knowledge, this is the first study to show that the prognostic value of cardiac MIBG imaging is more powerful than that of HRV analysis and that the combination of abnormal WR and n-VLFP would identify a higher-risk subset for cardiac events in patients with mild-to-moderate chronic HF.

	Acknowledgments

 
We thank Ms. Setsuko Ishida and Ms. Hiroko Maekawa for their technical assistance with Holter electrocardiography, and Ms. Yumiko Sugie, Ms. Yoshie Kimoto, and Ms. Yukie Tanesaka for caring for these patients.

	References

Top Abstract Methods Results Discussion References

 
1. Floras JS. Clinical aspects of sympathetic activation and parasympathetic withdrawal in heart failure. J Am Coll Cardiol. 1993;22(Suppl A):72–84A

2. Cohn JN, Levine BT, Olivari MT, et al. Plasma norepinephrine as a guide to prognosis in patients with chronic heart failure. N Engl J Med. 1984;311:819–823[Abstract]

3. Packer M. The neurohumoral hypothesis: a theory to explain the mechanism of disease progression in heart failure. J Am Coll Cardiol. 1992;20:248–254[Abstract]

4. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Heart rate variability: standard of measurement, physiological interpretation, and clinical use. Circulation. 1996;93:1043–1065[Free Full Text]

5. Brouwer J, Van Veldhuisen DJ, Man in’T Veld AJ, et al. Prognostic value of heart rate variability during long-term follow-up in patients with mild to moderate heart failure. J Am Coll Cardiol. 1996;28:1183–1189[Abstract]

6. Ponikowski P, Anker SD, Chua TP, et al. Depressed heart rate variability as an independent predictor of death in chronic congestive heart failure secondary to ischemic or idiopathic cardiomyopathy. Am J Cardiol. 1997;79:1645–1650[CrossRef][Medline]

7. Nolan J, Batin PD, Andrews R, et al. Prospective study of heart rate variability and mortality in chronic heart failure: results of the United Kingdom Heart Failure Evaluation Assessment of Risk trial. Circulation. 1998;98:1510–1516[Abstract/Free Full Text]

8. Fauchier L, Babuty D, Cosnay P, et al. Prognostic value of heart rate variability for sudden death and major arrhythmic events in patients with idiopathic dilated cardiomyopathy. J Am Coll Cardiol. 1999;33:1203–1207[Abstract/Free Full Text]

9. Bonaduce D, Petretta M, Marciano F, et al. Independent and incremental prognostic value of heart rate variability in patients with chronic heart failure. Am Heart J. 1999;138:273–284[CrossRef][Medline]

10. Wieland DM, Brown LE, Rogers WL, et al. Myocardial imaging with a radioiodinated norepinephrine storage analogue. J Nucl Med. 1981;22:22–31[Abstract/Free Full Text]

11. Henderson ES, Kahn JK, Corbett JR, et al. Abnormal I-123 metaiodobenzylguanidine myocardial washout and distribution may reflect myocardial adrenergic derangement in patients with congestive cardiomyopathy. Circulation. 1988;78:1192–1199[Abstract/Free Full Text]

12. Merlet P, Valette H, Dubois-Rande J-L, et al. Prognostic value of cardiac metaiodobenzylguanidine imaging in patients with heart failure. J Nucl Med. 1992;33:471–477[Abstract/Free Full Text]

13. Cohen-Solal A, Esanu Y, Logeart D, et al. Cardiac metaiodobenzylguanidine uptake in patients with moderate heart failure: relationship with peak oxygen uptake and prognosis. J Am Coll Cardiol. 1999;33:759–766[Abstract/Free Full Text]

14. Imamura Y, Fukuyama T, Mochizuki T, et al. Prognostic value of I-123 metaiodobenzylguanidine imaging and cardiac natriuretic peptide levels in patients with left ventricular dysfunction resulting from cardiomyopathy. Jpn Circ J. 2001;65:155–160[CrossRef][Medline]

15. Ogita H, Shimonagata T, Fukunami M, et al. Prognostic significance of cardiac I-123 metaiodobenzylguanidine imaging for mortality and morbidity in patients with chronic heart failure: a prospective study. Heart. 2001;86:656–660[Abstract/Free Full Text]

16. Somsen GA, Szabo BM, Van Veldhuisen DJ, de Milliano PAR, de Groot CA, Lie KI. Comparison between iodine-123 metaiodobenzylguanidine scintigraphy and heart rate variability for the assessment of cardiac sympathetic activity in mild to moderate heart failure. Am Heart J. 1997;134:456–458[CrossRef][Medline]

17. Kurata C, Shouda S, Mikami T, et al. Metaiodobenzylguanidine and heart rate variability in heart failure. Jpn Circ J. 1998;62:770–772[CrossRef][Medline]

18. Lotze U, Kober A, Kaepplinger S, Neubauer S, Gottschild D, Figulla HR. Cardiac sympathetic activity as measured by myocardial 123-I-metaiodobenzylguanidine uptake and heart rate variability in idiopathic dilated cardiomyopathy. Am J Cardiol. 1999;83:1548–1551[CrossRef][Medline]

19. Goris ML, McKillop JH, Brijandet PA. A fully automated determination of the left ventricular region of interest in nuclear angiography. Cardiovasc Intervent Radiol. 1981;4:117–123[Medline]

20. Ohtomo N, Terachi S, Tanaka Y, Tokiwano K, Kaneko N. New method of time series analysis and its application to Wolf’s sunspot number data. Jpn J Appl Physiol. 1994;33:2821–2831[CrossRef]

21. Sahn DJ, Demaria A, Kissio J, et al. Recommendations regarding quantification in M-mode echocardiography: result of a survey of echocardiographic measurements. Circulation. 1978;58:1072–1083[Abstract/Free Full Text]

22. Foti A, Kimura S, DeQuattro V, et al. Liquid-chromatographic measurement of catecholamines and metabolites in plasma and urine. Clin Chem. 1987;33:2209–2213[Abstract/Free Full Text]

23. Hasking GJ, Esler MD, Jennings GL, Burton DB, Johns JA, Korner PI. Norepinephrine spillover to plasma in congestive heart failure: evidence of increased cardiorenal and total sympathetic nerve activity. Circulation. 1986;73:615–621[Abstract/Free Full Text]

24. Shofer J, Spielmann R, Schuchert A, Weber K, Schluter M. Iodine-123 metaiodobenzylguanidine scintigraphy: a noninvasive method to demonstrate myocardial adrenergic nerve system disintegrity in patients with idiopathic dilated cardiomyopathy. J Am Coll Cardiol. 1988;12:1252–1258[Abstract]

25. Imamura Y, Ando H, Mitsuoka W, et al. Iodine-123 metaiodobenzylguanidine images reflect intense myocardial adrenergic nervous activity in congestive heart failure independent of underlying cause. J Am Coll Cardiol. 1995;26:1594–1599[Abstract]

26. Agostini D, Belin A, Amar MH, et al. Improvement of cardiac neuronal function after carvedilol treatment in dilated cardiomyopathy: a I-123 MIBG scintigraphic study. J Nucl Med. 2000;41:845–851[Abstract/Free Full Text]

27. Fujimura M, Yasumura Y, Ishida Y, et al. Improvement in left ventricular function in response to carvedilol is accompanied by attenuation of neurohumoral activation in patients with dilated cardiomyopathy. J Cardiac Fail. 2000;6:3–10[CrossRef][Medline]

28. Bigger JT, Fleiss JL, Steinman RC, Rolnitzky LM, Kleiger RE, Rottman JN. Frequency domain measures of heart rate variability and mortality after myocardial infarction. Circulation. 1992;85:164–171[Abstract/Free Full Text]

29. Malliani A, Pagani M, Lombardi F, Cerutti S. Cardiovascular neural regulation explored in the frequency domain. Circulation. 1991;84:482–492[Abstract/Free Full Text]

30. Parti G, Saul JP, Di Rieuzo M, Mancia G. Spectral analysis of blood pressure and heart rate variability in evaluating cardiovascular regulation: a critical appraisal. Hypertension. 1995;25:1276–1286[Abstract/Free Full Text]

31. Ponikowski P, Chua TP, Amadi AA, et al. Detection and significance of a discrete very low frequency rhythm in RR interval variability in chronic congestive heart failure. Am J Cardiol. 1996;77:1320–1326[CrossRef][Medline]

32. Morata A, Sleight P, Pinna GD, et al. Abnormal awake respiratory patterns are common in chronic heart failure and may prevent evaluation of autonomic tone by measures of heart rate variability. Circulation. 1997;96:246–252[Abstract/Free Full Text]

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