The term ‘cardiac syndrome X’ is used to define patients who have typical chest pain of myocardial ischemia and normal coronary arteriograms 1. The pathophysiological mechanism is still uncertain, but microvascular and endothelial dysfunction has been invoked 2 according to the results of the acetylcholine test 3. Although patients with cardiac syndrome X are not necessarily at high risk for events, the quality of life in a large proportion of patients is significantly impaired because of persistence or worsening of symptoms 4. In the past three decades, various treatment strategies, including anti-ischemic agents, analgesic therapy, hormone replacement therapy, and psychological intervention, have been used 2. Previous studies have reported that statins and calcium channel blockers might be beneficial in patients with cardiac syndrome X 5,6. However, the efficacy of the combination of statin and calcium channel blocker in patients with cardiac syndrome X was still unknown.
Therefore, the aim of this study was to determine whether a combination of fluvastatin and diltiazem has a superior effect on endothelial functions and exercise-induced ischemia than solo treatment in patients with cardiac syndrome X.
This study groups included 68 prospectively enrolled patients with the diagnosis of cardiac syndrome X at Jining First People’s Hospital. The diagnosis of cardiac syndrome X was made on the basis of the presence of typical angina chest pain, normal 12-lead ECG at rest, a positive exercise test response (>0.1 mV ST segment depression at 80 ms after the J point in two or more contiguous leads), and a complete normal coronary angiogram. Patients with myocardial infarction, valvular heart disease, left ventricular hypertrophy, hypertension, congestive heart failure, estrogen replacement therapy, and lipid-lowering agents were excluded from the study. The patients were divided randomly into three groups: fluvastatin-treated group (40 mg/day), diltiazem-treated group (90 mg/day), and fluvastatin (40 mg/day)+diltiazem (90 mg/day)-treated group. All of the patients were treated for 90 days.
All patients provided informed consent for the study and the study was approved by the Ethics Committee of Jining First People’s Hospital.
Routine coronary angiography, using Judkins’ technique, was performed in all patients.
Baseline clinical characteristics measurement
Information on demographic characteristics including age and sex was collected. Cigarette smoking was defined as smoking at least one cigarette per day for 1 year or more. Body weight and height were measured with the participant wearing light indoor clothing, but not shoes, using a standard protocol. BMI was defined as weight (kg)/height2 (m2). Obesity was defined as BMI of at least 30 according to the WHO criteria. Blood pressure was measured on the right arm using standard mercury sphygmomanometers. Three blood pressure readings were obtained after the participant had been sitting quietly for 5 min. Systolic blood pressure (SBP) or diastolic blood pressure (DBP) was calculated as the average of three SBP or DBP readings, respectively.
Blood samples were taken in the morning hours under overnight fasting conditions of more than 12 h at baseline (day 0) and at the end of the study (day 90) from the antecubital vein in all study patients. Blood samples were taken into evacuated lithium heparinized tubes and centrifuged within 1 h after collection at 4°C. Then, the samples were stored at −80°C until analysis. Serum total cholesterol (TC) and triglycerides (TG) levels were determined using enzymatic methods. The level of high-density lipoprotein cholesterol (HDL-C) was measured using the phosphotungstic acid/magnesium chloride precipitation method. The concentration of low-density lipoprotein cholesterol (LDL-C) was calculated using the formula LDL-C=TC−HDL-C−TG/5. Plasma nitric oxide (NO) levels were analyzed using commercial ELISA kits (#430310; Neogen Co. Ltd, Lansing, Michigan, USA) according to the manufacturer’s instructions. Plasma endothelin-1 (ET-1) concentrations were determined using an ET-1 enzyme immunoassay kit (Kemei dongya Bio-Technology Co. Ltd, Beijing, China).
Coronary flow reserve (CFR) was performed in all patients by echocardiography. Each measurement was analyzed by two experienced investigators. The examinations were performed using a Vivid digital ultrasound system (HP SONOS 5500; Hewlett-Packard Corporation, Palo Alto, California, USA) at rest and during dipyridamole infusion (0.14 mg/kg/min for 4 min). All patients underwent two-dimensional echocardiography. M-mode tracing and Doppler signals were recorded and the measurements were taken using standard methods. Using a frequency range of 2.5–4 MHz, the spectral Doppler signals at rest were first recorded in the distal portion of the left anterior descending artery. Echocardiographic images were obtained from the acoustic window around the mid-clavicular line in the fourth and fifth intercostal spaces in the left lateral decubitus position. From this position, the transducer was rotated anticlockwise until coronary blood flow in the interventricular groove was identified by color Doppler. The ultrasound beam direction was aligned with the distal left anterior descending artery flow as parallel as possible. Dipyridamole was administered (0.14 mg/kg/min) for 4 min to record spectral Doppler signals under hyperemic conditions. Mean diastolic velocities (MDVs) were measured at baseline and under peak hyperemic conditions. CFR was determined by the ratio of hyperemic MDV to basal MDV. Measurements were averaged over three cardiac cycles. Intraobserver and interobserver variabilities of Doppler measurements were assessed in 10 randomly selected patients. Intraobserver variability was calculated as the SD of the differences between the first and the second measurements (2-week interval) for a single observer. Interobserver variability was calculated as the SD of the differences between two observers. Both intraobserver and interobserver variabilities were described as a percent of the average value.
Exercise stress test
Tests were performed on the Marquette series 2000 model (GE Co. Ltd, Waukesha, Wisconsin, USA) according to the Bruce/Ellestad protocol in the morning hours. Predicted peak heart rate was calculated as [220−age (years)]. Individuals were encouraged to exercise until they experienced limiting symptoms, even if 85% of the maximum predicted heart rate was achieved. During each exercise stage and recovery stage, symptoms, blood pressure, and heart rate were recorded. Criteria for exercise termination were maximum heart rate greater than the age-predicted maximum, physical exhaustion, elevated DBP greater than 120 mmHg for normotensive patients and greater than 140 mmHg for hypertensive patients, elevated SBP greater than 260 mmHg, a sustained SBP decrease, clinical manifestation of intense chest pain, depression of the ST segment greater than 2 mm, serious arrhythmia, signs of left ventricular failure, or failure in the monitoring and/or recording systems. The test was considered positive when one of the following was observed: typical symptoms, a straight ST segment depression greater than 1.0 mm at 80 ms from the J point, or even an ST segment elevation greater than 1.0 mm. The exercise tests were performed, analyzed, and reported with a standard protocol utilizing a computerized database.
Statistical analysis was carried out using SPSS software for Windows (version 17.0; SPSS Inc., Chicago, Illinois, USA). Continuous variables were presented as mean±SD. Differences between groups at baseline were analyzed by one-way analysis of variance analysis. Student’s t-test was used to assess the differences at baseline and at the end of the study. The χ2-test was used to analyze the positive frequencies of exercise test among the treatment groups. A P value less than 0.05 was considered statistically significant.
A total of 68 patients were randomized at baseline. Two patients, from the fluvastatin-treated and the fluvastatin+diltiazem-treated groups, respectively, were lost to follow-up. A total of 66 patients completed the study and were eligible for the analyses. No serious side effects occurred during the 90-day follow-up period in the 66 individuals.
The main characteristics of the patients are shown in Table 1. No significant differences were found in age, sex distribution, smoking, lipid profiles, fasting plasma glucose, BMI, obesity, SBP, and DBP among the three groups.
Changes in lipid profiles
The lipid profile levels, including TC, TG, LDL-C, and HDL-C, were not statistically different among the three groups at baseline. Diltiazem treatment did not alter the lipid profile levels markedly. The levels of TC, TG, and LDL-C were significantly decreased in the fluvastatin-treated and fluvastatin+diltiazem-treated groups (all P<0.05). HDL-C levels were not statistically altered in the three groups. No significant differences were found in TC, TG, LDL-C, and HDL-C levels at the end of the study between the fluvastatin-treated group and the fluvastatin+diltiazem-treated group (Table 2).
Changes in coronary flow reserve
CFRs were not significantly different among the three groups at baseline. After 90 days of treatment, CFRs were improved in the three groups (fluvastatin-treated group: 23.2%; diltiazem-treated group: 12.4%; fluvastatin+diltiazem-treated group: 29.1%, all P<0.05). The improvement in CFR in the fluvastatin+diltiazem-treated group was more remarkable than that in the fluvastatin-treated group (0.83±0.07 vs. 0.61±0.05, P<0.05) or the diltiazem-treated group (0.83±0.07 vs. 0.31±0.03, P<0.001) (Table 3).
Intraobserver and interobserver variabilities for the value of MDV were 4.9 and 2.5%, respectively.
Changes in the exercise stress test
At baseline, the occurrence of greater than 1 mm ST segment depression and time to 1 mm ST segment depression were similar among the three groups. At the end of 90 days, the occurrence of greater than 1 mm ST segment depression decreased by 30.1% in the fluvastatin-treated group, 22.2% in the diltiazem-treated group, and 50.1% in the fluvastatin+diltiazem-treated group, respectively (all P<0.05). The time to 1 mm ST segment depression increased significantly in the fluvastatin-treated group (from 241±97 to 410±140 s, P<0.05), the diltiazem-treated group (from 258±91 to 392±124 s, P<0.05), and the fluvastatin+diltiazem-treated group (from 250±104 to 446±164 s, P<0.05) (Table 3).
Changes in nitric oxide and endothelin-1
The baseline NO and ET-1 levels among the three groups were not statistically different. At the end of the 90-day treatment, the levels of NO increased significantly in the fluvastatin-treated group (from 52.68±14.64 to 64.04±13.24 μmol/l, P<0.05) and the fluvastatin+diltiazem-treated group (from 53.54±17.18 to 72.59±15.24 μmol/l, P<0.05). In contrast, ET-1 levels decreased apparently in the fluvastatin-treated group (from 50.45±6.52 to 40.54±5.75 ng/l, P<0.05), the diltiazem-treated group (from 51.27±5.17 to 33.31±5.45 ng/l, P<0.05), and the fluvastatin+diltiazem-treated group (from 52.95±6.02 to 27.18±5.11 ng/l, P<0.01) compared with those of baseline. The increase in NO and decrease in ET-1 were much more remarkable in the fluvastatin+diltiazem-treated group than in the fluvastatin-treated and diltiazem-treated groups (Table 4).
To the best of our knowledge, this is the first study to compare the effect of combination therapy of statin and calcium channel blocker with monotherapy in patients with cardiac syndrome X. The major findings of the study were as follows. First, both fluvastatin and diltiazem induced an increase in exercise tolerance in patients with cardiac syndrome X. Second, combination treatment with fluvastatin and diltiazem may have a synergetic protective effect on exercise tolerance. Finally, the effect of fluvastatin and diltiazem may be related to the elevation of NO and reduction of ET-1.
Previous studies have shown that statins and calcium channel blockers were beneficial to patients with cardiac syndrome X, and our current findings confirmed these results 7,8. In our present study, the CFRs were elevated in both the fluvastatin-treated and diltiazem-treated groups, which indicated that both fluvastatin and diltiazem could improve coronary microcirculation. Moreover, our current results showed that both fluvastatin and diltiazem increased exercise tolerance, which was consistent with the previous reports 9,10.
The pathophysiology of cardiac syndrome X is uncertain 2. Endothelial dysfunction, which leads to an imbalance between vasodilator forces such as NO and vasoconstrictor forces such as ET-1, may partly explain the abnormal behavior of the coronary microvasculature in patients with cardiac syndrome X 11,12. Our present study found that the levels of NO increased significantly in the fluvastatin-treated group, but not in the diltiazem-treated group, suggesting that the improvement in CFR and exercise tolerance in the diltiazem-treated group may not be related to the NO level. However, both fluvastatin and diltiazem decreased the ET-1 levels. Taken together, the opposite effect on NO and ET-1 may improve the endothelial vasodilatation function. Although we failed to find a significant change of NO in the diltiazem-treated group, the ratio of NO/ET-1 increased significantly, which might be attributed to the improvement in endothelial function and exercise capacity.
Although our study showed that both fluvastatin and diltiazem were beneficial to patients with cardiac syndrome X, conditions such as CFR and exercise tolerance did not improve significantly in a large proportion of patients. Few researches have assessed the efficacy of combination therapy on cardiac syndrome X. Pizz et al. 13 reported that combination treatment with ramipril and atorvastatin was superior to placebo treatment in patients with cardiac syndrome X. Our present results showed that the time to 1 mm ST segment depression increased more apparently in the combination group compared with the fluvastatin-treated or the diltiazem-treated group. Similarly, the elevation in CFR was more significant in the combination group, accompanied by the more marked increase of NO and decrease of ET-1. Thus, the combination therapy of fluvastatin and diltiazem may have a synergetic effect on the microvascular function and exercise tolerance.
In conclusion, both fluvastatin and diltiazem treatment reduce exercise-induced ischemia in patients with cardiac syndrome X. Combination treatment of fluvastatin and diltiazem is more effective than solo treatment, probably through improvement of endothelial function by elevating NO and reducing ET-1.
Several limitations of this study should be considered. First, a major shortcoming is the lack of a control group to account for time-related variability. Second, the doses of the drugs were fixed; thus, we lacked information on dose dependency of the effects of therapy. Third, the levels of NO measured by peripheral blood samples might not be very accurate because of the unstable nature of NO.
This work was supported by a grant from the National Natural Science Foundation of China (No. 81100207).
Conflicts of interest
There are no conflicts of interest.
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