This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lanza, G. A. Articles by Maseri, A. Search for Related Content PubMed PubMed Citation Articles by Lanza, G. A. Articles by Maseri, A.

(Circulation. 1997;96:821-826.)
© 1997 American Heart Association, Inc.

Articles

Abnormal Cardiac Adrenergic Nerve Function in Patients With Syndrome X Detected By [¹²³I]Metaiodobenzylguanidine Myocardial Scintigraphy

Gaetano Antonio Lanza, MD; Alessandro Giordano, MD; Christian Pristipino, MD; Maria Lucia Calcagni, MD; Guido Meduri, MD; Carlo Trani, MD; Rodolfo Franceschini, MD; Filippo Crea, MD; Luigi Troncone, MD; ; Attilio Maseri, MD

From the Istituto di Cardiologia (G.A.L., C.P., C.T., F.C., A.M.) and Istituto di Medicina Nucleare (A.G., M.L.C., G.M., L.T.), Università Cattolica del Sacro Cuore, Rome, and Sorin Biomedia Diagnostics (R.F.), Saluggia, Italy.

Correspondence to Gaetano A. Lanza, MD, Istituto di Cardiologia, Università Cattolica del Sacro Cuore, L.go A. Gemelli, 8, 00168 Roma, Italy.

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Background Previous studies have suggested that an abnormal cardiac adrenergic tone may have a pathophysiological role in syndrome X (effort angina, positive exercise testing, angiographically normal coronary arteries).

Methods and Results To evaluate cardiac adrenergic nerve function, we performed [¹²³I]metaiodobenzylguanidine (MIBG) myocardial scintigraphy in 12 patients with syndrome X and 10 control subjects. Cardiac MIBG uptake was assessed by the heart/mediastinum (H/M) ratio and by an MIBG uptake defect score (higher values=lower uptake). In syndrome X patients, we also correlated MIBG scintigraphic findings with stress myocardial perfusion as assessed by ²⁰¹Tl scintigraphy. An inferior MIBG defect was observed in only 1 control subject, whereas 9 patients (P<.01) showed MIBG defects. The heart was totally or almost totally invisible on MIBG images in 5 patients, and predominantly regional defects were observed in 4. The H/M ratio was lower (1.70±0.6 versus 2.2±0.3, P=.03) and MIBG uptake defect score higher (35±31 versus 4±2, P=.003) in syndrome X patients. Reversible stress thallium perfusion defects were found in 62% of patients with MIBG defects but in no patient with normal MIBG uptake. MIBG defects persisted unchanged in 7 patients at a 5±3-month follow-up study.

Conclusions In this study, obvious defects in global and/or regional cardiac MIBG uptake, indicating an abnormal cardiac adrenergic nerve function, were detected in 75% of patients with syndrome X. These findings strongly support the cardiac origin of chest pain in syndrome X, although the mechanisms and the pathophysiological meaning of the abnormal cardiac MIBG uptake in these patients deserve further investigation.

Key Words: syndrome X • nervous system, adrenergic • scintigraphy

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
Patients with anginal pain typical and severe enough to warrant coronary angiography and found to have a normal coronary angiogram are classified as having syndrome X.^{1 2} Such patients probably represent a heterogeneous group, but the appearance of ischemialike ST-segment depression associated with chest pain suggests a cardiac origin of their symptoms.³ In such patients, evidence for a dysfunction of small coronary arteries has been repeatedly reported,^{4 5 6 7 8 9} although the ischemic (and also cardiac) origin of the syndrome has been questioned because of the frequent lack of convincing evidence of myocardial ischemia^{10 11 12 13} and the excellent long-term prognosis.¹⁴

Previous studies have suggested that a predominance of sympathetic activity may contribute to the pathogenesis of syndrome X.^{15 16 17 18 19} In particular, an abnormal adrenergic function could increase microvascular tone and sensitize small coronary arteries to vasoconstrictor stimuli.^{20 21 22 23} In this study, we investigated cardiac sympathetic nerve function in patients with syndrome X by performing myocardial scintigraphy with MIBG, a guanethidine analogue compound sharing the same uptake, storage, and release mechanisms of norepinephrine at sympathetic nerve endings.^{24 25} At the same time, in syndrome X patients, we also assessed the relationship between the results of MIBG studies and those of perfusional stress ²⁰¹Tl myocardial scintigraphy.

	Methods

Top Abstract Introduction Methods Results Discussion References

 
Study Groups
Twelve patients who fulfilled strict diagnostic criteria for syndrome X (7 women; age, 52±9 years) participated in this study. All patients had a history of effort-related anginal pain, both ST-segment depression and anginal pain induced on the qualifying exercise test, totally normal coronary arteries at angiography, and negative ergonovine test. The standard 12-lead ECG was normal in all patients, and none had any evidence, by full clinical and laboratory investigations, of other cardiac or noncardiac diseases, including definite hypertension (blood pressure 160/95 mm Hg), diabetes, and glucose intolerance. Both echocardiographic study and ventricular angiography showed normal global and regional left ventricular function in all patients. Left ventricular ejection fraction, calculated on a Philips DCI system from standard biplane left ventricular angiographic views (30° right and 60° left anterior oblique views) by the area-length method, was 74±7% (range, 65% to 85%). All investigations in these patients were carried out after appropriate washout of all medications; ß-blockers, in particular, were withdrawn at least 15 days before each test. No patients were taking any other drug known or suspected to interfere with MIBG uptake.²⁶ Sublingual nitrates were allowed to relieve chest pain, but tests were always performed at least 12 hours after the last nitrate consumption.

A control group of 10 normal volunteers matched for sex and age to patients (6 women; age, 53±5 years) was studied. All subjects had no history of any type of chest pain or evidence of heart or systemic diseases. They also had normal ECGs, echocardiographic studies, and symptom-limited exercise testing and were not taking any type of drugs.

Study Investigations
The following laboratory investigations were performed in patients and control subjects after written informed consent had been obtained for their participation in the study.

Basal Investigations
Both patients and control subjects underwent symptom-limited exercise testing according to a standard Bruce protocol and 24-hour Holter monitoring.

The exercise test was terminated when one of the following end points was reached: physical exhaustion, progressive angina, ST-segment depression 3 mm, or occurrence of clinically harmful conditions. Horizontal or downsloping ST-segment depression >1 mm at 0.08 second after the J-point was considered to be significant.

Holter recordings were obtained with Oxford Medilog MR-45 two-channel tape recorders monitoring the CM₅ and CM₃ leads. Transient ST-segment depression was defined as a horizontal or downsloping ST shift >1 mm 0.08 second after the J-point lasting at least 1 minute.

MIBG Scintigraphy
To assess cardiac adrenergic innervation, both syndrome X patients and control subjects underwent the following scintigraphic procedure.²⁷ Five millicuries (185 MBq) of high-specific-activity MIBG (3.7 MBq/µg, supplied by Sorin Biomedica) was injected intravenously in 1 minute through an indwelling catheter with the patient in a fasting state and after at least 1 hour of rest. Planar scintigraphic images of the chest were obtained by a single-head gamma camera (Elscint 409 ECT) with a 40-cm field of view, equipped with a low-energy general-purpose parallel-hole collimator. Images were recorded in the anterior view 0.5, 1, 2, 3, and 18 hours after the injection, with an acquisition time of 5 minutes, matrix size 256x256, and zoom factor x1. Energy discrimination was achieved by a 20% window centered over the 159-keV peak of ^I23I. After the planar scan, a SPECT acquisition was performed by rotating the camera by 6° increments, collecting 30 views for 30 seconds each, with zoom factor x1.2 and acquisition matrix 64x64. Image reconstruction was done by filtered back-projection with a Butterworth filter with a cutoff frequency of 0.35 cycle per pixel and a power factor of 5. No attenuation correction was performed.

For the purposes of the study, only data for MIBG uptake at 3 hours after injection were analyzed, because earlier time points have been shown to be less reliable for the assessment of adrenergic cardiac function by MIBG uptake.²⁸ The H/M ratio, which is considered an index of global cardiac MIBG uptake,²⁹ was calculated on planar MIBG images by use of ROIs positioned around the heart and on the mediastinal area. When the heart silhouette was not clearly identifiable, an ROI was centered in the anatomic site of the heart. To evaluate whether abnormalities in MIBG uptake were confined to the heart or were also present in other organs, MIBG uptake was also measured in the lungs, and the L/M ratio was calculated for both patients and control subjects. The ROIs used to calculate heart, mediastinum, and lung MIBG counts are shown in Fig 1A. Moreover, as a further evaluation of extracardiac adrenergic function, we also assessed MIBG uptake of salivary glands, which are richly innervated by adrenergic fibers.³⁰ To this aim, a planar scintigraphic image of the neck and upper chest was acquired at 3 hours after tracer injection. Uptake by salivary glands was qualitatively graded by two independent observers blinded to scintigraphic cardiac results according to a three-class score (0=normal uptake; 1=mild uptake reduction; 2=severe uptake reduction), with disagreements being resolved by consensus.

View larger version (23K): [in this window] [in a new window]   Figure 1. A, Schematic showing regions of interest for assessment of MIBG uptake in heart (H), lungs (L), and mediastinum (M). B, Schematic showing 24 cardiac segments considered to evaluate regional MIBG uptake on SPECT scintigrams.

Transverse cardiac tomographic images were reoriented on the short axis and on the vertical/horizontal long axis of the left ventricle. Slice thickness was normalized to 1 cm. For purposes of analysis, five short-axis slices (from the most proximal to the most distal but excluding the apex) and the midventricular vertical and horizontal slices were selected. To evaluate regional tracer uptake, the left ventricle was divided into 24 anatomic segments according to the model illustrated in Fig 1B. Semiquantitative MIBG uptake for each segment was obtained by a threshold method based on an eight-level color scale, each level corresponding to 12.5% of the maximal pixel value. Segments were scored as follows: 0=normal (tracer uptake >87.5% of maximum); 1=mild defect (uptake >75% to 87.5%); 2=moderate defect (uptake 50% to 75%); and 3=severe defect (uptake <50%). A global MIBG uptake defect score was obtained as the sum of all segmental scores for each patient. To investigate the reproducibility of results, the MIBG study was repeated in 7 syndrome X patients at a follow-up of 5.1±3.3 months (range, 1 to 10 months).

²⁰¹Tl Scintigraphy
Eleven syndrome X patients underwent SPECT ²⁰¹Tl stress-redistribution study 1 week after MIBG scintigraphy. The test was not performed in the remaining patient for logistic reasons. Bicycle exercise testing (25-W increments every 2 minutes) was performed in 10 patients, with exercise end points identical to those described for treadmill exercise testing (see above). When an end point was approached, 3 mCi (111 MBq) of ²⁰¹Tl chloride was injected intravenously, and the exercise was continued for at least 1 minute. Dipyridamole stress testing (0.56 mg/kg IV) was performed in a woman who was unable to pedal, with the same dose of ²⁰¹Tl being injected 2 minutes after the end of dipyridamole infusion. Image acquisition was started within 10 minutes of the injection of thallium. The same gamma-camera configuration and SPECT procedure as described above for MIBG studies were used, but energy discrimination was achieved by a 25% window centered over the 69-keV x-ray peak of ²⁰¹Tl, and collection time was 30 seconds for stress images and 45 seconds for redistribution images acquired 3 to 4 hours later. Short-axis and vertical/horizontal long-axis tomographic images of the left ventricle were evaluated qualitatively for the presence and location of perfusion defects. Defects were considered "ischemic" if perfusion normalization was observed on redistribution images.

Because myocardial perfusion at rest appeared normal in all patients, no correction of MIBG for perfusion was attempted in this study.

Catecholamines
Twenty-four–hour catecholamine urinary excretion was measured in 8 syndrome X patients (4 men) and 7 control subjects (2 men). Samples were collected in a container and acidified with 6N HCl. Column chromatography was used for catecholamine extraction and fluorimetric detection for dosing.

Statistics
Comparisons of continuous variables were performed by t test or Mann-Whitney U test, as indicated. Paired Wilcoxon test and Spearman rank correlation analysis were applied to evaluate the reproducibility of MIBG results. Proportions were compared by Fisher's exact test. Values are reported as mean±SD. A value of P<.05 was always considered statistically significant.

	Results

Top Abstract Introduction Methods Results Discussion References

 
The main findings and results of syndrome X patients and control subjects are shown in Table 1. Resting heart rate and blood pressure were similar in the two groups. As an inclusion criterion, all patients had ST-segment depression and anginal pain on exercise testing. The duration of the test was longer and heart rate and double product at peak exercise were higher in control subjects. Exercise testing was stopped because of fatigue in all control subjects and in 5 syndrome X patients. In the other 7 patients, exercise was stopped because of worsening angina in 5 and ST-segment depression >3 mm in 2. Fifty-eight episodes of ST-segment depression were detected on Holter monitoring in 6 patients with syndrome X (50%) (range, 1 to 24 episodes per patient), only 10% of which were associated with anginal pain. No significant ST-segment changes were found in control subjects. Urinary catecholamine excretion was similar in the two groups (Table 1).

View this table: [in this window] [in a new window]   Table 1. Main Clinical Findings and Results in Patients With Syndrome X and Healthy Control Subjects

MIBG Study
On visual inspection, cardiac MIBG images appeared normal in all but 1 of the control subjects (10%), who showed a mild regional inferior defect. Conversely, 9 syndrome X patients (75%, P<.01) showed abnormalities in cardiac MIBG uptake. In 5 patients, MIBG uptake was so impaired that the heart was totally (in 4 patients) or almost totally (in 1 patient) invisible on scintigraphic images (Figs 2 and 3), whereas the other 4 patients showed inhomogeneous cardiac tracer uptake, with obvious regional defects (Table 2).

View larger version (64K): [in this window] [in a new window]   Figure 2. Left, Planar MIBG scintigram in control subject showing normal uptake in region of heart. Right, Planar MIBG scintigram in patient with syndrome X showing total absence of radionuclide activity in region of heart. This pattern was confirmed in a follow-up study performed after 6 months. Note presence of normal MIBG uptake in lungs and liver of this patient.

View larger version (68K): [in this window] [in a new window]   Figure 3. Twelve short-axis slices of left ventricle obtained with 201Tl (A, stress; B, redistribution) and MIBG (C) myocardial scintigraphic studies in patient with syndrome X (patient 5 in Table 2) who had only a regional defect in MIBG uptake. Inferior defect is evident in both stress thallium and MIBG images. Thallium defect shows substantial normalization in redistribution images.

View this table: [in this window] [in a new window]   Table 2. Main Results of SPECT Stress 201Tl and SPECT MIBG Cardiac Scintigraphy in Patients With Syndrome X

Quantitative analysis confirmed these findings. The H/M ratio was lower (1.70±0.6 versus 2.19±0.3, P=.03) and cardiac MIBG uptake defect score strikingly higher (36.7±31 versus 4.0±2.5, P=.003) in syndrome X patients. Eight patients had an H/M ratio lower than the lowest value (1.84) found in control subjects, and 9 had an MIBG score higher than the highest value (8.0) observed in control subjects (Fig 3). There was no correlation in syndrome X patients between duration of symptoms and both H/M ratio (r=.16, P=.61) and MIBG score (r=-.22, P=.49).

The L/M ratio of MIBG uptake was similar in the two groups (1.36±0.2 versus 1.35±0.2), and MIBG uptake by salivary glands was totally normal (score=0) in both patients and control subjects, thus suggesting that the abnormal cardiac MIBG findings in syndrome X patients were confined to the heart.

²⁰¹Tl Scintigraphy
The results of stress thallium and MIBG SPECT studies are compared in Table 2. Reversible perfusion defects were found in 5 of 11 syndrome X patients (45%); all 5 also had abnormal MIBG scintigrams, whereas all 3 patients with normal MIBG scintigraphy also had normal thallium images. MIBG alterations appeared much more striking and extensive than thallium defects. Two patients with inferolateral and 1 with anterolateral reversible thallium defects showed no significant cardiac MIBG uptake. The last 2 patients with positive thallium scintigraphy showed a good regional correlation between MIBG and thallium defects (Fig 4). Of the 6 patients with normal thallium scintigraphy, 1 had no MIBG uptake, 2 had regional MIBG defects, and 3 had normal MIBG studies.

View larger version (9K): [in this window] [in a new window]   Figure 4. Distribution of individual values of H/M ratio and MIBG score in patients with syndrome X and control subjects.

Reproducibility of MIBG Results
In the 7 syndrome X patients who underwent a follow-up MIBG study, H/M ratio was 1.63±0.54 on the first and 1.50±0.50 on the second test (P=NS), and MIBG uptake defect score was 38.6±32.5 and 38.6±32.6 (P=NS), respectively. Correlation analysis revealed a high reproducibility of both H/M ratio (r=.96, P=.01, Fig 5) and MIBG score (r=.99, P<.0001), as well as of the regional distribution of MIBG defects.

View larger version (10K): [in this window] [in a new window]   Figure 5. Reproducibility of H/M ratio at follow-up (5±3 months) in 7 patients with syndrome X.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
MIBG is a guanethidine analogue compound that shares the same uptake/retention mechanisms as norepinephrine at sympathetic nerve terminals,^{24 25} and myocardial MIBG scintigraphy can be used to assess the adrenergic innervation of the heart.^{29 31 32}

In this study, for the first time, we demonstrate obvious global and/or regional abnormalities in cardiac MIBG scintigraphy in a high proportion (75%) of patients with syndrome X, whereas only one control subject exhibited a mild inferior defect. Of note, cardiac MIBG uptake was totally or almost totally absent in 42% of patients, and MIBG results were highly reproducible in all patients who underwent a follow-up study. These findings indicate the presence of an abnormal function of efferent cardiac sympathetic nerve endings and support the cardiac origin of chest pain in these patients. The abnormalities of adrenergic activity in our patients seemed to be localized predominantly in the heart, rather than being systemic, as suggested by the absence of differences between patients and control subjects in the L/M ratio of MIBG uptake, salivary gland MIBG uptake, urinary catecholamine excretion, and the finding of regional rather than global MIBG defects observed in some patients.

The lack of detectable abnormalities in cardiac MIBG scan in 25% of our patients is compatible with two alternative explanations. First, it may suggest that the impaired adrenergic nerve function is a mere consequence of the primary causes of the syndrome and occurs in most but not all patients. Second, it may indicate that the mechanisms of recurrent anginal pain and of transient ischemialike ST-segment changes are not necessarily the same in all syndrome X patients, even when they are selected according to strict inclusion criteria.^{3 10}

Interpretations of MIBG Defects
There are several possible mechanisms to explain the MIBG abnormalities detected in this study. Experimental work^{33 34} has demonstrated that cardiac MIBG defects may reflect sympathetic denervation, and clinical studies in patients with myocardial necrosis^{35 36 37 38 39} or heart transplantation⁴⁰ have suggested that this condition can also occur in humans. However, it seems unlikely that cardiac MIBG defects are caused by sympathetic denervation in patients with syndrome X.

MIBG abnormalities in our patients can most likely be accounted for by functional mechanisms, such as, in particular, an increased cardiac spillover of norepinephrine,^{28 41} resulting in antagonistic competition with MIBG for uptake at nerve terminals. In fact, the increased norepinephrine spillover could help explain both the enhanced adrenergic drive^{15 16 17 18 19} and, by determining microvascular constriction,^{20 21 22} the reduction of coronary flow reserve^{4 5 6 7 8 9 23} and the heterogeneity of myocardial perfusion^{15 19} previously reported in these patients. In fact, in our study, reversible myocardial defects on stress thallium scintigraphy were observed in a sizable proportion (ie, 62%) of patients with defective MIBG uptake but in none of those with normal MIBG scan, suggesting that the abnormal adrenergic function can result in heterogeneous myocardial perfusion under stress in most patients.

Alternatively, the detection of stress thallium defects among patients with MIBG alterations may suggest that cardiac MIBG defects in our patients could be consequent to a primary microvascular dysfunction, resulting in functional abnormalities of efferent adrenergic nerve endings, such as an impairment of either uptake-1 function or of the storage system. Indeed, regional defects in cardiac MIBG uptake consequent to myocardial ischemia have been described previously in patients with coronary artery disease^{37 42 43 44} and have been reported as persisting for several days after the resolution of ischemia.^{42 43}

The discrepancy in the extension of MIBG and stress thallium scintigraphic defects in our study does not necessarily exclude this mechanism. Indeed, thallium scintigraphy may fail to reveal alterations in myocardial perfusion caused by a mild diffuse or patchy distributed coronary flow disturbance,^{2 6 19} whereas such alterations could be sufficient to cause a detectable dysfunction of cardiac nerve fibers. Indeed, the latter have been shown experimentally to have greater sensitivity than myocardial cells to ischemia,³⁴ and MIBG defects are usually wider than thallium defects in ischemic territories of patients with coronary artery disease,^{35 36 37 38 39 42 43 44} suggesting that in these patients as well, there may be "peri-ischemic" areas with coronary flow reduction sufficient to cause adrenergic nerve suffering in the absence of any detectable evidence of myocardial ischemia.

	Selected Abbreviations and Acronyms

 

H/M = heart/mediastinum L/M = lung/mediastinum MIBG = [123I]metaiodobenzylguanidine ROI = region of interest SPECT = single photon emission computed tomography

	Acknowledgments

 
We are grateful to Sorin Biomedica Diagnostics, Unità di Business, Saluggia (VC), for providing high-specific-activity MIBG for this study. We are indebted to Dr Italiana Liberale for analysis of urinary catecholamines. We also gratefully acknowledge Vanessa Perrin for the revision and correction of the manuscript.

Received November 12, 1996; revision received February 26, 1997; accepted February 28, 1997.

	References

Top Abstract Introduction Methods Results Discussion References

 
1. Kemp HG, Vokonas PS, Cohn PF, Gorlin R. The anginal syndrome associated with normal coronary arteriograms. Am J Cardiol. 1973;54:735-742.

2. Maseri A, Crea F, Kaski JC, Crake T. Mechanisms of angina pectoris in syndrome X. J Am Coll Cardiol. 1991;17:499-506.

3. Maseri A. Syndrome X and microvascular angina. In: Maseri A, ed. Ischemic Heart Disease: A Rational Basis for Clinical Practise and Clinical Research. New York, NY: Churchill Livingstone; 1995:507-532.

4. Opherk D, Zebe H, Schuler G, Weihe E, Mall G, Kubler W. Reduced coronary dilator capacity and ultrastructural changes of the myocardium in patients with angina pectoris but normal coronary arteriograms. Circulation. 1981;63:817-825.

5. Cannon RO, Epstein SE. `Microvascular angina' as a cause of chest pain with angiographically normal coronary arteries. Am J Cardiol. 1988;61:1338-1343.

6. Galassi AR, Crea F, Araujo LI, Lammertsma AA, Pupita G, Yamamoto Y, Rechavia E, Jones T, Kaski JC, Maseri A, Taylor C, Lewington G. Comparison of regional myocardial blood flow in syndrome X and one-vessel coronary artery disease. Am J Cardiol. 1993;72:134-139.

7. Chauhan A, Mullins PA, Petch MC, Schofield PM. Effect of hyperventilation and mental stress on coronary blood flow in syndrome X. Br Heart J. 1993;69:516-524.

8. Egashira K, Inou T, Hirooka Y, Yamada A, Urabe Y, Takeshita A. Evidence of impaired endothelium-dependent coronary vasodilation in patients with angina pectoris and normal coronary angiograms. N Engl J Med. 1993;328:1659-1664.

9. Chauhan A, Mullins PA, Petch MC, Schofield PM. Is coronary flow reserve in response to papaverine really abnormal in syndrome X? Circulation. 1994;89:1998-2004.

10. Cannon RO, Camici PG, Epstein SE. Pathophysiological dilemma of syndrome X. Circulation. 1992;85:883-892.

11. Nihoyannopoulos P, Kaski JC, Crake T, Maseri A. Absence of myocardial dysfunction during stress in patients with syndrome X. J Am Coll Cardiol. 1991;18:1463-1470.

12. Picano E, Lattanzi F, Masini M, Distante A, L'Abbate A. Usefulness of a high-dose dipyridamole-echocardiography test for diagnosis of syndrome X. Am J Cardiol. 1987;60:508-512.

13. Rosen SD, Uren NG, Kaski JC, Tousoulis D, Davies GJ, Camici PG. Coronary vasodilator reserve, pain perception, and sex in patients with syndrome X. Circulation. 1994;90:50-60.

14. Kaski JC, Rosano GMC, Collins P, Nihoyannopoulos P, Maseri A, Poole-Wilson PA. Cardiac syndrome X: clinical characteristics and left ventricular function: long-term follow-up study. J Am Coll Cardiol. 1995;25:807-814.

15. Galassi AR, Kaski JC, Crea F, Pupita G, Gavrielides S, Tousoullis D, Maseri A. Heart rate response during exercise testing and ambulatory ECG monitoring in patients with syndrome X. Am Heart J. 1991;122:458-463.

16. Montorsi P, Fabbiocchi F, Loaldi A, Fabbiocchi P, Polese A, De Cesare N, Guazzi MD. Coronary adrenergic hyperreactivity in patients with syndrome X and abnormal electrocardiogram at rest. Am J Cardiol. 1991;68:1698-1703.

17. Rosano GMC, Ponikowski P, Adamopoulos S, Collins P, Poole-Wilson PA, Coats AJS, Kaski JC. Abnormal autonomic control of the cardiovascular system in syndrome X. Am J Cardiol. 1994;73:1174-1179.

18. Rosen SD, Dritsas A, Bourdillon PJ, Camici PG. Analysis of the electrocardiographic QT interval in patients with syndrome X. Am J Cardiol. 1994;73:971-972.

19. Meeder JG, Blanksma PK, Crijns HGJM, Anthonio RL, Pruim J, Brouwer J, de Jong RM, van der Wall EE, Vaalburg W, Lie KI. Mechanisms of angina pectoris in syndrome X assessed by myocardial perfusion dynamics and heart rate variability. Eur Heart J. 1995;16:1571-1577.

20. Feigl EO. Adrenergic control of transmural coronary blood flow. Basic Res Cardiol. 1990;85(suppl I):167-175.

21. Krajcar M, Heusch G. Local and neurohumoral control of coronary blood flow. Basic Res Cardiol. 1990;85(suppl I):25-42.

22. Cordero DL, Cagin NA, Natelson BH. Neurocardiology update: role of the nervous system in coronary vasomotion. Cardiovasc Res. 1995;29:319-328.

23. Camici PG, Marracini P, Gistri R, Salvadori PA, Sorace O, L'Abbate A. Adrenergically mediated coronary vasoconstriction in patients with syndrome X. Cardiovasc Drugs Ther. 1994;8:221-226.

24. Sisson JC, Shapiro B, Meyers L, Mallette S, Mangner TJ, Wieland TM, Glowniak JV, Sherman P, Beierwaltes WH. Metaiodobenzylguanidine to map scintigraphically the adrenergic nervous system in man. J Nucl Med. 1987;28:1625-1636.

25. Wafelman AR, Hoefnagel CA, Maes RAA, Beijnen JH. Radioiodinated metaiodobenzylguanidine: a review of its biodistribution and pharmacokinetics, drug interactions and dosimetry. Eur J Nucl Med. 1994;21:545-559.

26. Solanki KK, Bomanji J, Moyes J, Mather SJ, Trainer PJ, Britton KE. A pharmacological guide to medicines which interfere with the biodistribution of radiolabelled meta-iodo benzylguanidine (MIBG). Nucl Med Commun. 1992;13:513-521.

27. Giordano A, Calcagni ML, Rufini V, Colivicchi F, Melina D, Melina G, Pristipino C, Nori S, Trani C, Santarelli P, Troncone L. Use of [¹²³I]MIBG to assess cardiac adrenergic innervation: experience in hypertensive cardiopathy and left ventricular aneurysm. Q J Nucl Med. 1995;39(suppl 1):44-48.

28. Nakajo M, Shimabukuro K, Yoshimura H, Yonekura R, Nakabeppu Y, Tanoue P, Shinohara S. Iodine-131 metaiodobenzylguanidine intra- and extravascular accumulation in the rat heart. J Nucl Med. 1986;27:84-89.

29. Merlet P, Valette H, Randé JD, Moyse D, Duboc D, Dove P, Bourguignon MH, Benvenuti C, Duval AM, Agostini D, Loisance D, Castaigne A, Syrota A. Prognostic value of cardiac metaiodobenzylguanidine imaging in patients with heart failure. J Nucl Med. 1992;33:471-477.

30. Glowniak JV, Turner FE, Gray LL, Palac RT, Lagunas-Solar MC, Woodward WR. Iodine-123 metaiodobenzylguanidine imaging of the heart in idiopathic congestive cardiomyopathy and cardiac transplants. J Nucl Med. 1989;30:1182-1191.

31. Kline RC, Swanson DP, Wieland DM, Thrall JH, Gross MD, Pitt B, Beierwaltes W. Myocardial imaging in man with I-123 meta-iodobenzylguanidine. J Nucl Med. 1981;22:129-132.

32. Wieland TM, Brown LE, Rogers L, Worthington KC, Wu J, Clinthorne NH, Otto CA, Swanson DP, Beierwaltes WH. Myocardial imaging with a radioiodinated norepinephrine storage analog. J Nucl Med. 1981;22:22-31.

33. Minardo JD, Tuli MM, Mock BH, Weiner RE, Pride HP, Wellman HN, Zipes DP. Scintigraphic and electrophysiological evidence of canine myocardial sympathetic denervation and reinnervation produced by myocardial infarction or phenol application. Circulation. 1988;78:1008-1019.

34. Iwasaki T, Suzuki T, Tateno M, Sasaki Y, Oshima S, Imai S. Dual-tracer autoradiography with thallium-201 and iodine-125-metaiodobenzylguanidine in experimental myocardial infarction of rat. J Nucl Med. 1996;37:680-684.

35. McGhie AI, Corbett JR, Akers MS, Kulkarni P, Sills MN, Kremers M, Buja M, Durant-Reville M, Parkey RW, Willerson TJ. Regional cardiac adrenergic function using I-123 meta-iodobenzylguanidine tomographic imaging after acute myocardial infarction. Am J Cardiol. 1991;67:236-242.

36. Dae MW, Herre JM, O'Connell JW, Botvinick EH, Newman D, Munoz L. Scintigraphic assessment of sympathetic innervation after transmural versus nontransmural myocardial infarction. J Am Coll Cardiol. 1991;17:1416-1423.

37. Tomoda H, Yoshioka K, Shiina Y, Tagawa R, Ide M, Suzuki Y. Regional sympathetic denervation detected by iodine 123 metaiodobenzylguanidine in non-Q-wave myocardial infarction and unstable angina. Am Heart J. 1994;128:452-458.

38. Hartikainen J, Mantysaari M, Kuikka J, Lansimies E, Pyorala K. Extent of cardiac autonomic denervation in relation to angina on exercise test in patients with recent acute myocardial infarction. Am J Cardiol. 1994;74:760-763.

39. Hartikainen J, Kuikka J, Mantysaari M, Lansimies E, Pyorala K. Sympathetic reinnervation after acute myocardial infarction. Am J Cardiol. 1996;77:5-9.

40. De Marco T, Dae M, Yuen-Gree MSF, Kumar S, Sudhir K, Keith F, Amidon TM, Rifkin C, Klinski C, Lau D, Botvinick EH, Chatterjee K. Iodine-123 metaiodobenzylguanidine scintigraphic assessment of the transplanted human heart: evidence for late reinnervation. J Am Coll Cardiol. 1995;25:927-931.

41. Imamura Y, Ando H, Mitsuoka W, Egashira S, Masaki H, Ashihara T, Fukuyama T. 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.

42. Tsutsui H, Ando S, Fukai T, Kuroiwa M, Egashira K, Sasaki M, Kuwabara Y, Koyanagi S, Takeshita A. Detection of angina-provoking coronary stenosis by resting iodine 123 metaiodobenzylguanidine scintigraphy in patients with unstable angina pectoris. Am Heart J. 1995;129:708-715.

43. Nakata T, Nagao K, Tsuchihashi K, Hashimoto A, Tanaka S, Iimura O. Regional cardiac sympathetic nerve dysfunction and the diagnostic efficacy of metaiodobenzylguanidine in stable coronary artery disease. Am J Cardiol. 1996;78:292-297.

44. Takano H, Nakamura T, Satou T, Umetani K, Watanabe A, Ishihara T, Mochizuchi S, Kimura H, Honma H, Ikeda Y, Koizumi K, Arbab AS, Tamura K. Regional myocardial sympathetic dysinnervation in patients with coronary vasospasm. Am J Cardiol. 1995;75:324-329.

This article has been cited by other articles:

				F. Crea, P. G. Camici, R. De Caterina, and G. A. Lanza CHAPTER 17 Chronic Ischaemic Heart Disease ESC Textbook of Cardiovascular Medicine, January 1, 2009; 2(1): med-9780199566990-chapter - med-9780199566990-chapter. [Abstract] [Full Text] [PDF]

				G. A. Lanza, A. Buffon, A. Sestito, L. Natale, G. A. Sgueglia, L. Galiuto, F. Infusino, L. Mariani, A. Centola, and F. Crea Relation between stress-induced myocardial perfusion defects on cardiovascular magnetic resonance and coronary microvascular dysfunction in patients with cardiac syndrome X. J. Am. Coll. Cardiol., January 29, 2008; 51(4): 466 - 472. [Abstract] [Full Text] [PDF]

				M. Yazici, S. Demircan, K. Durna, and M. Sahin The Role of Adrenergic Activity in Slow Coronary Flow and Its Relationship to TIMI Frame Count Angiology, September 1, 2007; 58(4): 393 - 400. [Abstract] [PDF]

				G. Angelo Sgueglia, A. Sestito, A. Spinelli, B. Cioni, F. Infusino, F. Papacci, F. Bellocci, M. Meglio, F. Crea, and G. Antonio Lanza Long-term follow-up of patients with cardiac syndrome X treated by spinal cord stimulation Heart, May 1, 2007; 93(5): 591 - 597. [Abstract] [Full Text] [PDF]

				J. Madaric, J. Bartunek, K. Verhamme, M. Penicka, E. Van Schuerbeeck, P. Nellens, G. R. Heyndrickx, W. Wijns, M. Vanderheyden, and B. De Bruyne Hyperdynamic Myocardial Response to Beta-Adrenergic Stimulation in Patients With Chest Pain and Normal Coronary Arteries J. Am. Coll. Cardiol., October 4, 2005; 46(7): 1270 - 1275. [Abstract] [Full Text] [PDF]

				G. A. Lanza, A. Sestito, G. A. Sgueglia, F. Infusino, F. Papacci, M. Visocchi, C. Ierardi, M. Meglio, F. Bellocci, and F. Crea Effect of spinal cord stimulation on spontaneous and stress-induced angina and 'ischemia-like' ST-segment depression in patients with cardiac syndrome X Eur. Heart J., May 2, 2005; 26(10): 983 - 989. [Abstract] [Full Text] [PDF]

				M. Valeriani, A. Sestito, D. L. Pera, L. D. Armas, F. Infusino, T. Maiese, G. A. Sgueglia, P. A. Tonali, F. Crea, D. Restuccia, et al. Abnormal cortical pain processing in patients with cardiac syndrome X Eur. Heart J., May 2, 2005; 26(10): 975 - 982. [Abstract] [Full Text] [PDF]

				K. Senen, M. Ileri, A. Alper, F. Yetkin, R. Atak, I. Hisar, E. Yetkin, H. Turhan, H. Bardakci, and D. Demirkan Increased Levels of Soluble Adhesion Molecules E-Selectin and P-Selectin in Patients with Cardiac Syndrome X Angiology, May 1, 2005; 56(3): 273 - 277. [Abstract] [PDF]

				F. Crea and G. A Lanza Angina pectoris and normal coronary arteries: cardiac syndrome X Heart, April 1, 2004; 90(4): 457 - 463. [Full Text] [PDF]

				A. Maseri and Endorsed by the American College of Cardiology Fou Women's Ischemic Syndrome Evaluation: Current Status and Future Research Directions: Report of the National Heart, Lung and Blood Institute Workshop: October 2-4, 2002: Perspective: New Frontiers in Detection of Ischemic Heart Disease in Women Circulation, February 17, 2004; 109 (6): e62 - e63. [Full Text] [PDF]

				J. C. Kaski Pathophysiology and Management of Patients With Chest Pain and Normal Coronary Arteriograms (Cardiac Syndrome X) Circulation, February 10, 2004; 109(5): 568 - 572. [Full Text] [PDF]

				G. A. Lanza, A. Sestito, S. Iacovella, L. Morlacchi, E. Romagnoli, G. Schiavoni, F. Crea, A. Maseri, and F. Andreotti Relation Between Platelet Response to Exercise and Coronary Angiographic Findings in Patients With Effort Angina Circulation, March 18, 2003; 107(10): 1378 - 1382. [Abstract] [Full Text] [PDF]

				G A Lanza and F Crea The complex link between brain and heart in cardiac syndrome X Heart, October 1, 2002; 88(4): 328 - 330. [Full Text] [PDF]

				J. R. Panting, P. D. Gatehouse, G.-Z. Yang, F. Grothues, D. N. Firmin, P. Collins, and D. J. Pennell Abnormal Subendocardial Perfusion in Cardiac Syndrome X Detected by Cardiovascular Magnetic Resonance Imaging N. Engl. J. Med., June 20, 2002; 346(25): 1948 - 1953. [Abstract] [Full Text] [PDF]

				K Shimizu, K Chin, T Nakamura, H Masuzaki, Y Ogawa, R Hosokawa, A Niimi, N Hattori, R Nohara, S Sasayama, et al. Plasma leptin levels and cardiac sympathetic function in patients with obstructive sleep apnoea-hypopnoea syndrome Thorax, May 1, 2002; 57(5): 429 - 434. [Abstract] [Full Text] [PDF]

				S. D Rosen The pathophysiology of cardiac syndrome X -- a tale of paradigm shifts Cardiovasc Res, November 1, 2001; 52(2): 174 - 177. [Full Text] [PDF]

				G. Gulli, R. Cemin, P. Pancera, G. Menegatti, C. Vassanelli, and A. Cevese Evidence of parasympathetic impairment in some patients with cardiac syndrome X Cardiovasc Res, November 1, 2001; 52(2): 208 - 216. [Abstract] [Full Text] [PDF]

				G.A. Lanza, F. Andreotti, A. Sestito, A. Sciahbasi, F. Crea, and A. Maseri Platelet aggregability in cardiac syndrome X Eur. Heart J., October 2, 2001; 22(20): 1924 - 1930. [Abstract] [PDF]

				P. K. Goel, S. K. Gupta, A. Agarwal, and A. Kapoor Slow Coronary Flow: A Distinct Angiographic Subgroup in Syndrome X Angiology, August 1, 2001; 52(8): 507 - 514. [Abstract] [PDF]

				E.N Simantirakis, V.K Prassopoulos, S.I Chrysostomakis, G.E Kochiadakis, S.I Koukouraki, J.P Lekakis, N.S Karkavitsas, and P.E Vardas Effects of asynchronous ventricular activation on myocardial adrenergic innervation in patients with permanent dual-chamber pacemakers. An I123-metaiodobenzylguanidine cardiac scintigraphic study Eur. Heart J., February 2, 2001; 22(4): 323 - 332. [Abstract] [PDF]

				A. Buffon, S. Rigattieri, S. A. Santini, V. Ramazzotti, F. Crea, B. Giardina, and A. Maseri Myocardial ischemia-reperfusion damage after pacing-induced tachycardia in patients with cardiac syndrome X Am J Physiol Heart Circ Physiol, December 1, 2000; 279(6): H2627 - H2633. [Abstract] [Full Text] [PDF]

				A. Gaspardone, C. Ferri, F. Crea, F. Versaci, F. Tomai, A. Santucci, L. Chiariello, and P. A. Gioffre Enhanced activity of sodium-lithium countertransport in patients with cardiac syndrome X: A potential link between cardiac and metabolic syndrome X J. Am. Coll. Cardiol., December 1, 1998; 32(7): 2031 - 2034. [Abstract] [Full Text] [PDF]

This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lanza, G. A. Articles by Maseri, A. Search for Related Content PubMed PubMed Citation Articles by Lanza, G. A. Articles by Maseri, A.