Background
Cardiac syndrome X (CSX) is characterized by typical angina and abnormal exercise test results, with normal coronary arteries. Cardiovascular magnetic resonance imaging has shown subendocardial hypoperfusion in patients with CSX after adenosine. The aim of this study was to investigate the contribution of separate myocardial layers to global function under stress in women with CSX.
Methods
Twenty-two postmenopausal women with CSX were studied and compared with 20 healthy women matched for age and body mass index. All subjects underwent clinical evaluations and exercise echocardiography. Left ventricular systolic and diastolic parameters were evaluated at rest and at peak exercise. Layer-specific global longitudinal strain (GLS) and strain rate (SR) were assessed from the endocardium, midmyocardium, and epicardium using two-dimensional speckle-tracking echocardiography.
Results
All subjects showed normal contractile function at rest and at peak exercise. Significant increases in GLS and SR in all myocardial layers were observed at peak exercise in the control group, whereas patients with CSX showed significantly lower increases in endocardial GLS and SR compared with the control group (endocardial ΔSR, 0.17 ± 0.19 vs 0.33 ± 0.13 [ P < .01]; endocardial ΔGLS, 1.33 ± 2.93 vs 6.64 ± 2.62 [ P < .001]). Moreover, significantly impaired diastolic function (ΔE′, 1.1 ± 3.3 vs 4.0 ± 2.03) was observed in patients with CSX.
Conclusions
The results of this study show subendocardial impairment of contractile function during exercise in patients with CSX, confirming the existence of reduced myocardial perfusion reserve in patients with CSX and suggesting layer-targeted exercise echocardiography as a sensitive diagnostic tool in the assessment of suspected CSX.
Between 10% and 20% of patients who undergo coronary angiography for the evaluation of chest pain are found to have normal or near normal coronary arteries. A subgroup of these patients, who also have classic typical chest pain and transient ischemic ST-segment changes during exercise, are classified as having cardiac syndrome X (CSX).
Interest in this syndrome has recently been renewed because of the appearance for the first time of angina with “normal” coronary arteries and its diagnosis in the European guidelines for the management of stable coronary artery disease.
Most patients with CSX are women; a recent review found a pooled relative frequency of women of 56%. These patients have a survival rate comparable with that of the normal population. Nevertheless, they continue to report symptoms over an extended follow-up period, and about half of these patients are disabled because of chest pain. The exact pathophysiology underlying this condition is not yet well understood, and many mechanisms have been suggested to account for symptoms of chest pain.
Noninvasive imaging techniques to determine the presence of ischemia in patients with CSX have been used. In particular, studies based on stress echocardiography, associated with dipyridamole or with physical exertion, have revealed no ventricular wall motion abnormalities in patients with CSX despite the occurrence of ST-segment depression and the onset of angina. This lack of consistent findings in previous studies was attributed to the low sensitivity of the available tests in detecting ischemia limited to the subendocardial region. Thallium-201 myocardial perfusion studies in patients with CSX have reported abnormal results in an extremely variable proportion of patients. Moreover, positron emission tomography (PET) has shown abnormal heterogeneity in perfusion in several studies, whereas others have shown no abnormalities.
In contrast and more recently, cardiac magnetic resonance imaging (MRI) has clearly demonstrated the presence of subendocardial hypoperfusion associated with intense chest pains in patients with CSX during intravenous administration of adenosine.
Strain rate (SR) imaging is a recently developed echocardiographic procedure that allows the quantitative assessment of regional myocardial wall motion. Speckle-tracking echocardiography is a relatively new technique used to assess myocardial function and to measure strain and SR by tracking groups of intramyocardial speckles in the imaging plane. Longitudinal left ventricular (LV) mechanics, which are governed mainly by the subendocardial layer, are the most vulnerable and sensitive to the presence of myocardial diseases. Echocardiography has been shown to be able to differentiate the three layers of the myocardium for SR analysis. Moreover, strain and SR appear sensitive enough to selectively evaluate subendocardial function. Because endocardial function is more affected in patients with significant coronary artery disease compared with epicardial function, the assessment of layer-specific strain by two-dimensional speckle-tracking echocardiography has recently proved to be able to identify patients with non–ST-segment elevation acute coronary syndromes and significant coronary artery disease. Moreover, transmural myocardial strain gradient has been shown to be able to identify subtle regional differences in wall function.
It was therefore hypothesized that selective strain and SR analysis of the different myocardial layers at rest and after exercise could identify nontransmural ischemia in patients with CSX. For this purpose, a population of women with CSX (as well as a control group) was assessed for contractile function at rest and at peak exercise. New echocardiographic modalities based on speckle-tracking were used to distinguish and quantify systolic function at both subendocardial and subepicardial levels.
Methods
Study Population
Twenty-two postmenopausal women with CSX (mean age, 56 ± 6.4 years), recruited from the Cardiology Outpatient Clinic at the University Hospital of Cagliari, were enrolled in this study. CSX diagnosis was formulated on the basis of a typical history of angina from effort, abnormal effort electrocardiographic findings (0.1-mV horizontal or down-sloping ST-segment depression 80 msec after the J point), and normal results on coronary angiography performed <2 years before study enrollment.
Twenty women who showed no structural heart defects or evidence of coronary heart disease, matched for age (mean, 52 ± 5.5 years) and body mass index, represented the control group.
Other inclusion criteria for both patients and controls were normal hepatic and renal function (bilirubin ≤ 1.5 mg/dL, creatinine ≤ 2.0 mg/dL), echocardiographic LV ejection fraction ≥ 55%, and absence of echocardiographic wall motion abnormalities at rest. Exclusion criteria were arterial hypertension with LV hypertrophy (LV mass > 104 g/m 2 on echocardiography), moderate to severe heart valve disease, atrial fibrillation or severe arrhythmias, or disabilities that prevented exercise testing.
Most patients with CSX were treated with multiple anti-ischemic medications. The controls were all healthy, with no histories of chest pain or other cardiovascular symptoms. The profiles of patients and controls with respect to cardiovascular risk factors are listed in Table 1 . None of the controls had undergone coronary angiography. The study was approved by the ethics committee of the University Hospital at the University of Cagliari. Written informed consent was obtained from all patients involved. All medications were discontinued ≥12 hours before testing.
| Variable | Patients with CSX ( n = 18) | Controls ( n = 18) | P |
|---|---|---|---|
| Age (y) | 55 ± 6.2 | 52 ± 5.3 | NS |
| BMI (kg/m 2 ) | 24.5 ± 2.5 | 25.6 ± 3.2 | NS |
| Weight (kg) | 62.8 ± 13.1 | 64.9 ± 7.95 | NS |
| HR (beats/min) | NS | ||
| Resting | 78 ± 10 | 75 ± 13 | |
| Peak | 146 ± 12 | 144 ± 14 | |
| Systolic BP (mm Hg) | NS | ||
| Resting | 132 ± 14 | 128 ± 11 | |
| Peak | 202 ± 23 | 193 ± 18 | |
| Diastolic BP (mm Hg) | NS | ||
| Resting | 77 ± 7 | 82 ± 5 | |
| Peak | 94 ± 8 | 90 ± 4 | |
| CV risk factors | |||
| Family history | 2 (11%) | 3 (17%) | NS |
| Diabetes | 1 (6%) | 0 (0%) | NS |
| Hypertension | 3 (17 %) | 3 (17 %) | NS |
| Smoking habit | 5 (28%) | 3 (17 %) | NS |
| Dyslipidemia | 5 (28%) | 4 (22%) | NS |
Study Protocol
At enrollment, all subjects underwent physical examinations, 12-lead electrocardiography, and basal and exercise echocardiography with the acquisition of raw data for speckle-tracking analysis.
Conventional Echocardiography and Doppler Tissue Imaging
Echocardiographic images were obtained using a system equipped with speckle-tracking and raw data acquisition (Toshiba Artida; Toshiba Corporation, Tochigi, Japan). Standard two-dimensional measurements (end-diastolic and end-systolic dimensions, ventricular septal and posterior wall thickness, left atrial volume index, LV mass index, and LV outflow tract) were taken at baseline before the stress test. LV ejection fraction was obtained from the apical four-chamber and two-chamber views according to Simpson’s rule. Pulsed-wave Doppler was performed in the apical four-chamber view, with the sample volume placed between the mitral leaflet tips, and the early (E) and late (A) diastolic peak velocities were determined. Deceleration time was measured, and the E/A ratio was derived. Longitudinal function was assessed using tissue Doppler spectral analysis of the mitral annulus, placing the sample volume at the septal and lateral wall corner from the apical four-chamber view. Peak velocities in systole (S′), and early (E′) and late (A′) diastole were measured. The mitral inflow peak velocity E/E′ ratio was calculated to evaluate LV filling pressure.
Exercise Stress Echocardiography
Stress echocardiography was performed using a symptom-limited, multistage supine stress test with a variable-load bicycle ergometer (Ergoline Inc). The bed ergometer was rotated to the left by 20° to 30°. Briefly, after obtaining the images at rest, patients cycled at a constant speed, starting at a workload of 25 W and adding an incremental workload of 25 W every 2 min. From the apical window, mitral inflow velocities were traced, and early mitral peak velocity (E) and late velocity (A) readings were obtained. Mitral annular velocity was measured using tissue Doppler spectral analysis. The measurements were accompanied by simultaneous electrocardiography at a speed of 50 mm/sec. Each measurement was performed at baseline, at each stage of exercise, and during recovery. Because of the high incidence of fusion of E′ and A′ during exercise at workloads > 50 W, the diastolic functional parameters were assessed at baseline and at 50 W. Moreover, ΔE′ and ΔS′, defined as the differences from exercise peak to baseline, were calculated.
Two-dimensional echocardiographic images were recorded at rest and at each stage of exercise, and the raw data were digitally stored for SR analysis. Patients with more than two nonevaluable segments were excluded from the study analysis. Five cycles were acquired, and the best three cardiac cycles were selected for offline measurements. Longitudinal SR values were averaged over the three cardiac cycles. All offline measurements were performed by a single investigator blinded to the clinical condition of the study patients. Intraobserver variability was then calculated.
Speckle-Tracking Echocardiography
Longitudinal ventricular function at baseline and after exercise was calculated offline using raw data. Global longitudinal strain (GLS) and global longitudinal SR measurements were obtained as averages from the two-chamber and four-chamber values. Exercise contractile reserve was assessed as the increases in systolic parameters (S′, GLS, and SR) from baseline to peak exercise. The LV wall was automatically divided into three layers: the inner third (endocardial), the middle third (midmyocardial), and the outer third (epicardial) ( Figure 1 ). GLS and SR measurements were automatically obtained from each layer using echocardiographic software (Toshiba Corporation). ΔSR and ΔGLS were calculated as the differences between exercise peak and baseline for each layer.
Statistical Analysis
Continuous variables were assessed using one-way analysis of variance, and categorical variables were compared using Fisher’s exact test. Two-tailed P values < .05 were considered statistically significant.
Results
Characteristics of the Study Population
Four patients and two controls were excluded from the study analysis because of suboptimal exercise test LV images, which resulted in more than two nonevaluable segments. Anthropometric and laboratory information for both patients with CSX and healthy matched controls are summarized in Table 1 . No differences between the two groups of women with respect to physical characteristics or in terms of cardiovascular risk factors, such as family history, smoking habit, hypertension, and dyslipidemia, were observed. Resting heart rate and blood pressure were within the normal ranges for both groups.
Echocardiographic Parameters
Normal LV mass and dimensions, as well as normal LV ejection fractions, were observed in all patients and controls when examined under baseline conditions. After observing diastolic function indices, diastolic impairment in patients with CSX was noted: E/A ratio, 0.92 ± 0.32 versus 0.99 ± 0.25 ( P < .05), and E/E′ ratio, 9.86 ± 5.1 versus 8.52 ± 3.19 ( P < .05) ( Table 2 ). S′-wave readings at rest were within the normal range for both patients with CSX and controls ( Table 2 ).
| Variable | Patients with CSX | Controls | P |
|---|---|---|---|
| EDV (mL) | 71.5 ± 15.4 | 67.9 ± 11.2 | NS |
| LV mass (g/m 2 ) | 72.6 ± 17.2 | 74.3 ± 20.6 | NS |
| Systolic function | |||
| LVEF (%) | 65.3 ± 4.7 | 66.8 ± 9.2 | NS |
| S′ (cm/sec) | 5.1 ± 1.39 | 4.7 ± 0.71 | NS |
| Diastolic function | |||
| E/A ratio | 0.92 ± 0.32 | 0.99 ± 0.25 | <.05 |
| DT (msec) | 0.236 ± 0.096 | 0.213 ± 0.078 | NS |
| E/E′ ratio | 9.86 ± 5.1 | 8.52 ± 3.19 | <.05 |
Exercise Echocardiography
Workload obtained during exercise was not significantly different between the groups. During exercise on the bicycle bed ergometer, heart rate and blood pressure increased, as expected. All patients and controls reached 85% of maximal predicted heart rate. No wall motion abnormalities were observed in patients with CSX or controls ( Table 3 ). Chest pain during exercise was experienced by 13 patients with CSX (72%) but by no controls. All patients with CSX exhibited repolarization abnormalities, such as inverted T waves (33%) and ST-segment depression (78%), on exercise electrocardiography. As expected, all controls had completely normal electrocardiographic findings during exercise.
| Variable | Patients with CSX | Controls | P |
|---|---|---|---|
| Work (W) | 108.3 ± 12 | 104.2 ± 15 | NS |
| DTI echocardiography | |||
| E′ (cm/sec) | |||
| Basal | 6.1 ± 1.65 | 5.1 ± 2.1 | NS |
| Stress | 7.3 ± 3.7 | 9 ± 2.1 | NS |
| ΔE′ | 1.1 ± 3.3 | 4.0 ± 2.03 | <.05 |
| S′ | |||
| Basal | 5.1 ± 1.39 | 4.7 ± 0.71 | NS |
| Stress | 7.8 ± 1.72 | 7.3 ± 1.71 | NS |
| ΔS′ | 2.7 ± 1.48 | 2.6 ± 1.25 | NS |
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