Patients with cardiac syndrome X (CSX) have an excellent long-term prognosis, but a significant number show worsening angina over time. Previous studies have found a significant impairment of cardiac uptake of iodine-123-meta-iodobenzylguanidine (MIBG) on myocardial scintigraphy, indicating abnormal function of cardiac adrenergic nerve fibers. The aim of this study was to assess whether cardiac MIBG results can predict symptomatic outcome in patients with CSX. Cardiac MIBG scintigraphy was performed in 40 patients with CSX (mean age 58 ± 5 years, 14 men). Cardiac MIBG uptake was measured by the heart/mediastinum uptake ratio and a single photon-emission computed tomographic regional uptake score (higher values reflected lower uptake). Clinical findings, exercise stress test parameters, sestamibi stress myocardial scintigraphy, and C-reactive protein serum levels were also assessed. At an average follow-up of 79 months (range 36 to 144), no patient had died or developed acute myocardial infarction. Cardiac MIBG defect score was significantly lower in patients with worsening versus those without worsening of angina status (13 ± 7 vs 38 ± 28, p = 0.001), in those with versus those without hospital readmission because of recurrent chest pain (15 ± 9 vs 35 ± 29, p = 0.01), and in those who underwent versus those who did not undergo repeat coronary angiography (11 ± 7 vs 36 ± 27, p = 0.001). Significant correlations were found between quality of life (as assessed by the EuroQoL scale) and heart/mediastinum ratio (r = 0.48, p = 0.002) and cardiac MIBG uptake score (r = −0.69, p <0.001). No other clinical or laboratory variable showed a significant association with clinical end points. In conclusion, in patients with CSX, abnormal function of cardiac adrenergic nerve fibers, as assessed by an impairment of cardiac MIBG uptake, identifies those with worse symptomatic clinical outcomes.
Cardiac syndrome X (CSX) is typically characterized by predominantly effort-induced angina, ST-segment depression during spontaneous or provoked angina, normal coronary arteries on angiography, absence of spontaneous or provoked epicardial coronary artery spasm, and absence of cardiac (e.g., valvular, myocardial) or systemic diseases. Coronary microvascular dysfunction has been documented in most patients with CSX and is believed to play a major role in its pathogenesis. Data have suggested that abnormal cardiac adrenergic tone may play a significant pathogenetic role in this anginal syndrome. In particular, in most of these patients, we previously found a severe impairment of cardiac uptake of iodine-123-meta-iodobenzylguanidine (MIBG), an analogue of norepinephrine, on myocardial scintigraphy, suggesting a dysfunction of cardiac adrenergic nerve fibers. Patients with CSX have an excellent long-term prognosis, but a significant number show persistence or worsening of symptoms, which can significantly impair their quality of life. Importantly, it is not clear whether the symptomatic state at follow-up can be predicted by clinical and/or laboratory findings. Some studies have suggested that coronary microvascular impairment and the inflammatory state can predict anginal outcome, but this was not confirmed by other studies. In this study, we aimed to assess whether in patients with CSX abnormalities of cardiac adrenergic nerve fibers can predict symptomatic clinical outcomes.
Methods
We performed clinical follow-up of 40 patients with CSX who had been studied with MIBG scintigraphy to assess the function of cardiac sympathetic nerve fibers and were included in previous reports. All patients had effort-related anginal pain, ST-segment depression and anginal pain induced by exercise stress testing, totally normal coronary arteries on angiography, and no evidence of spontaneous or provoked epicardial coronary artery spasm. Standard 12-lead electrocardiographic results were normal in all patients, and none had any evidence, by full clinical and laboratory investigations, of any other cardiac or noncardiac disease. In all patients, clinical histories were obtained including careful assessments of cardiovascular risk factors. At the time of MIBG scintigraphy, patients also underwent electrocardiographic exercise stress tests, perfusion stress technetium-99m sestamibi myocardial scintigraphy. and evaluation of inflammatory state by measurement of C-reactive protein (CRP) serum levels.
All investigations in these patients were carried out after appropriate washout of all medications; β blockers, in particular, were withdrawn ≥15 days before performing the study protocol. Sublingual nitrates were allowed to relieve chest pain in patients with CSX, but the tests were always performed ≥24 hours after the last nitrate consumption.
The methods for MIBG myocardial scintigraphy have been described in detail elsewhere. Briefly, 5 mCi (185 MBq) of high-specific-activity MIBG (3.7 MBq/μg) was injected intravenously in 1 minute through an indwelling catheter with the patient in a fasting state and after ≥1 hour of rest. Planar scintigraphic images of the chest were obtained by a single-head (Elscint SP4; Elscint Ltd., Haifa, Israel) or dual-head (e.cam; Siemens Medical Systems, Erlangen, Germany) gamma camera with a 40- or 55-cm field of view, equipped with low-energy general-purpose parallel-hole collimators. Images were recorded in the anterior view 20 to 30 minutes and 3 to 4 hours after the injection, with an acquisition time of 5 minutes, matrix size of 256 × 256, and zoom factor of 1×. Energy discrimination was achieved by a 20% window centered over the 159-keV peak of iodine-123. After the planar scan, a single photon-emission computed tomographic (SPECT) acquisition was performed by rotating the camera in 6° increments, collecting 30 or 32 views for 30 seconds each, with a zoom factor of 1.2× and an acquisition matrix of 64 × 64 when using the single-head camera and a zoom factor of 1× and a matrix size of 128 × 128 when using the dual-head camera. Image reconstruction was done by filtered back projection with a Butterworth filter with a cut-off frequency of 0.35 cycles/pixel and a power factor of 5. No attenuation correction was performed. For the purposes of the study, only data of MIBG uptake at 3 to 4 hours after injection were analyzed. The heart/mediastinum (H/M) ratio of MIBG uptake was calculated on planar MIBG images, as an index of global cardiac MIBG uptake, by use of regions of interest positioned around the heart and on the mediastinal area (normal value in our laboratory 2.2 ± 0.3). When the heart silhouette was not clearly identifiable, a region of interest was centered in the anatomic site of the heart. For SPECT image analyses, 5 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, as previously described. Semiquantitative MIBG uptake for each segment was obtained by a threshold method based on an 8-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 (normal value in our laboratory ≤8) was obtained for each patient as the sum of all segmental scores.
All patients performed symptom-limited treadmill exercise stress tests in the morning, in a fasting state, according to the Bruce protocol. Leads II, V 2 , and V 5 were monitored continuously; a 12-lead electrocardiogram was printed at the end of each stage or when clinically indicated and at 1-minute intervals in the recovery phase. Blood pressure was measured at baseline, during peak exercise, and during the last minute of each stage. The test was stopped in case of (1) physical exhaustion, (2) limiting angina, or (3) potentially harmful clinical events (e.g., hypotension, arrhythmias). ST-segment depression was considered significant if it was horizontal or downsloping and >1 mm at 0.08 seconds from the J point.
Patients underwent bicycle exercise stress testing (25-W increments every 2 minutes) under continuous heart rate, blood pressure, and electrocardiographic monitoring. A dose of technetium-99m sestamibi (370 MBq) was injected intravenously at peak exercise, and perfusion scintigraphic images were acquired 30 minutes after injection (stress SPECT imaging). After the administration of sublingual isosorbide dinitrate (5 mg), a second dose of technetium-99m sestamibi (1,110 MBq) was administered 2 hours after the first injection, and scintigraphic images were acquired 1 to 2 hours later (rest SPECT imaging). Short- and 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 improvement or normalization was observed on redistribution images.
Venous blood samples were collected before electrocardiographic exercise stress test and ultrasonographic investigation in all patients, and serum samples were frozen at −80°C until assayed. CRP levels, as a marker of subclinical inflammation, were assessed with a high-sensitivity nephelometric method (Behring Nephelometric 100 Analyzer; Dade Behring, Scoppito, Italy) with a detection limit of 0.05 mg/L.
Clinical follow-up of patients was performed through an ambulatory clinical visit. Patients were asked in detail about clinical events occurring during the period of follow-up, and documentation of events was carefully checked. Clinical end points were readmissions and repetition of coronary angiography for recurrent angina and quality of life, assessed by the validated EuroQoL visual analogue scale, which ranges from 0 (worst) to 100 (best). Furthermore, patients were also asked to indicate whether their angina symptoms had reduced, worsened, or remained substantially unchanged overtime.
The distribution of variables was assessed using the Kolmogorov-Smirnov test, and continuous variables were compared using unpaired Student’s t tests or Mann-Whitney U tests as indicated. Fisher’s exact test was used to compare categorical variables. Data are reported as mean ± SD or as proportions. A 2-tailed p value <0.05 was considered statistically significant. Data were analyzed using SPSS version 17.0 (SPSS Italia, Inc., Florence, Italy).
Results
At a mean follow-up time of 79 ± 47 months from the cardiac MIBG study (range 36 to 144), no patient had died or developed nonfatal acute myocardial infarction. Hospital readmission for recurrent chest pain, characterized by worsening exertional angina and/or rest angina, was reported by 27 patients (67.5%), and 25 patients (62.5%) underwent ≥1 new coronary angiographic study. Chest pain was judged to have reduced over time by 17 patients (42.5%), whereas 23 patients (57.5%) reported worsening of angina status.
The relations of clinical and laboratory variables with categorical clinical end points are listed in Tables 1 and 2 . None of the classic cardiovascular risk factors showed significant associations with end points. Furthermore, exercise variables and CRP serum levels were similar in patients with or without clinical end points.
| Variable | ≥1 Readmissions for Recurrent Angina | Coronary Angiography for Recurrent Angina | Worsened Angina | ||||||
|---|---|---|---|---|---|---|---|---|---|
| Yes (n = 27) | No (n = 13) | p Value | Yes (n = 25) | No (n = 15) | P Value | Yes (n = 23) | No (n = 17) | p Value | |
| BP ≥140/90 mm Hg | 37% | 46.2% | 0.73 | 32% | 53.3% | 0.20 | 34.8% | 47.1% | 0.52 |
| Glucose intolerance | 3.7% | 7.7% | 1.00 | 4% | 6.7% | 1.00 | 4.3% | 5.9% | 1.00 |
| Blood cholesterol >200 mg/dl | 44.4% | 30.8% | 0.50 | 40% | 40% | 1.00 | 43.5% | 35.5% | 0.74 |
| Active smoking | 7.4% | 7.7% | 1.00 | — | 20% | 0.05 | — | 17.6% | 0.07 |
| Drug therapy at follow-up | |||||||||
| β blockers | 51.9% | 61.5% | 0.73 | 60% | 46.7% | 0.52 | 65.2% | 41.2% | 0.20 |
| ACE inhibitors | 44.4% | 38.5% | 1.00 | 40% | 46.7% | 0.75 | 39.1% | 47.1% | 0.75 |
| Statins | 44.4% | 30.8% | 0.50 | 44% | 33.3% | 0.74 | 47.8% | 29.4% | 0.33 |
| Calcium channel blockers | 29.6% | 53.8% | 0.17 | 32% | 46.7% | 0.50 | 34.8% | 41.2% | 0.75 |
| Nitrates | 29.6% | 61.5% | 0.09 | 32% | 53.3% | 0.20 | 30.4% | 52.9% | 0.19 |
| Aspirin | 59.3% | 84.6% | 1.57 | 68% | 66.7% | 1.00 | 69.6% | 64.7% | 1.00 |
| Inflammatory state CRP (mg/L) | 4.31 ± 3.2 | 3.41 ± 2.8 | 0.50 | 3.88 ± 3.2 | 3.70 ± 2.8 | 0.85 | 3.82 ± 3.3 | 3.80 ± 2.7 | 0.98 |
| Exercise stress testing | |||||||||
| Peak RPP | 19,265 ± 4,416 | 21,598 ± 5,631 | 0.15 | 19,590 ± 4,623 | 21,211 ± 5,599 | 0.33 | 19,095 ± 4,319 | 21,690 ± 5,591 | 0.10 |
| RPP at 1-mm ST depression | 19,908 ± 5,325 | 18,654 ± 4,192 | 0.42 | 19,690 ± 5,223 | 18,685 ± 4,180 | 0.50 | 20,049 ± 5,055 | 18,332 ± 4,119 | 0.24 |
| ST depression (mm) | 1.6 ± 0.8 | 1.5 ± 0.7 | 0.76 | 1.43 ± 0.42 | 1.78 ± 1.19 | 0.18 | 1.38 ± 0.41 | 1.80 ± 1.11 | 0.09 |
| Time to 1-mm ST depression (seconds) | 321 ± 165 | 362 ± 162 | 0.44 | 350 ± 172 | 316 ± 150 | 0.53 | 331 ± 166 | 346 ± 164 | 0.78 |
| Exercise duration (seconds) | 200 ± 117 | 138 ± 96 | 0.61 | 413 ± 136 | 418 ± 165 | 0.92 | 399 ± 133 | 436 ± 163 | 0.44 |
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