Ege University, Medical School, Department of Cardiology, Izmir, Turkey
* Corresponding author. Meral Kayikcioglu, Gediz Cad. 11/2 Bornova, Izmir 35040, Turkey. Tel.: +90-532-4123489; fax: +90-232-3746618
E-mail address: mekay{at}med.ege.edu.tr
Received 17 March 2003; revised 24 July 2003; accepted 31 July 2003
Abstract
Aims The pathophysiological mechanism in cardiac syndrome-X (anginal chest pain, positive exercise test, and angiographically normal coronary arteries) has been suggested as an impairment in normal endothelial function of the coronary microvasculature, resulting in inadequate flow reserve. The aim of this study was to determine whether statins with proven beneficial effects on endothelium, have any effect on endothelial functions and exercise induced ischaemia in cardiac syndrome-X.
Methods and results Study population consisted of prospectively enrolled 40 patients with cardiac syndrome-X. Patients with left ventricular hypertrophy, hypertension, diabetes mellitus, and LDL levels 160mg/dl were excluded. Half of the patients received pravastatin (40mg/day) for 3 months irrespective of their lipid values, according to a single-blind, randomized, placebo-controlled design. Endothelial functions were assessed with high-resolution vascular ultrasound, which measured the brachial artery flow mediated dilatation (FMD). Lipid measurements, symptom limited exercise tests and vascular ultrasound images were obtained before and at the end of 3 months. After the treatment, FMD improved significantly in pravastatin group. Exercise duration, and time to 1mm-ST depression were significantly prolonged after statin therapy. Ischaemic symptoms and ECG findings during exercise test disappeared completely in 5 (26%) patients in the statin group. However, there were no significant changes in FMD and exercise parameters in placebo group.
Conclusions Statin therapy resulted in beneficial effects on both exercise induced ischaemia and FMD in cardiac syndrome-X. The mechanism of this beneficial effect is probably the result of improvement in endothelial functions.
Key Words: Endothelium Inflammation Cardiac syndrome-X Exercise Pravastatin
1. Introduction
The combination of typical anginal chest pain, noninvasive stress tests indicative of myocardial ischaemia, angiographically normal epicardial coronary arteries with no inducible coronary artery spasm, and no known associated cardiovascular disease is referred to as cardiac syndrome-X.1Despite the extensive studies, the pathophysiological mechanisms in syndrome-X remain unclear. Previous studies have demonstrated impairment in normal endothelial function of the coronary microvasculature, resulting in inadequate coronary flow reserve.2,3Recent data also suggest that these individuals have a generalized disorder of small vessels not confined to the intramyocardial vasculature with an unknown etiology.4,5
Previous studies have shown that statins can improve endothelial functions due to nonlipid lowering effects.6Starting out from this point, we aimed in this study, to determine whether statins have any beneficial effect on endothelium-dependent flow mediated dilatation (FMD) and exercise induced ischaemia in patients with cardiac syndrome-X.
2. Methods
2.1. Patient population
Study population consisted of 40 prospectively-enrolled consecutive patients with the diagnosis of cardiac syndrome-X. All were referred for diagnostic coronary angiography during a period of 2 years. The diagnosis of cardiac syndrome-X was based on the presence of typical exercise-induced angina pectoris, transient ischaemic ST-segment depression (>1mm) during exercise, and angiographically normal coronary arteries in the absence of coronary artery spasm (determined by hyperventilation), left ventricular hypertrophy and systemic hypertension. The exclusion criteria were previous myocardial infarction, congestive heart failure, diabetes mellitus, valvular heart disease including mitral valve prolapse, overt cardiomyopathy, sinus node dysfunction or conduction disturbance (including left bundle branch block), impaired renal or liver functions, hyperlipidaemia (LDL levels 160mg/dl or triglycerides >200mg/dl), and thyroid disease. In all patients, the extra-cardiac causes of chest pain including musculo-skeletal and oesophageal causes were ruled out. None of the patients were taking estrogen replacement therapy or lipid lowering agents. All patients were receiving antianginal treatment before entry into the study. The medication was withdrawn at least one week before the study. Only sublingual nitrates were allowed for the relief of chest pain during pharmacological wash-out period. At the end of wash-out period, all patients underwent both the brachial artery ultrasonographic examination for the measurement of endothelium dependent FMD and exercise stress test. Patients were not allowed to take sublingual nitroglycerine during the 24h before the brachial ultrasonographic examination and exercise tests.
After baseline determination of endothelial functions and response to exercise test, half of the patients received pravastatin (40mg daily) for 3 months irrespective of their lipid values, according to a single-blind, randomized, placebo-controlled design. At the end of the treatment period patients underwent exercise testing, and brachial ultrasonography for the evaluation of the effect of statin treatment. Study protocol was approved by local ethics committee and informed consent was obtained from all participants.
During the follow-up period groups did not receive any other drugs that can affect the lipid levels, and endothelial functions. Vitamin supplements were also not permitted throughout the study. Patients visited the clinics for lipid and laboratory safety evaluations at the end of 6th and 12th weeks. Total cholesterol, HDL cholesterol and triglycerides were assessed enzymatically by autoanalyser (Bayer Diagnostics Dax 48, Toshiba, Japan). LDL cholesterol was calculated by the Friedewald formula.7The apolipoprotein (Apo) A1 and Apo B levels and the C-reactive protein (CRP) concentrations were assayed on a Hitachi 704 automatic analyzer using a turbidimetric method (Boehringer Mannheim GmbH, Mannheim, Germany). Fibrinogen levels were measured according to the commonly used Clauss method. Complete data for fibrinogen levels were obtained in 31 patients (15 patients in placebo group and 16 patients in pravastatin group).
At each follow-up visit, physical examination, biometric measurements (height, weight, and waist and hip circumference), blood pressure reading, assessment of drug compliance (by pill count), and dietary and electrocardiographic evaluation were repeated, and patients were asked to report any ischaemic symptoms or adverse experience during the past 6 weeks. The frequency of angina pectoris, both during exercise and at rest, was recorded according to the CCS angina classification.8Patients subjective feelings of chest pain during the treatment periods were also recorded as improved, unchanged, or worsened in comparison with that before randomization. These interviewed findings were scored on an ordinal scale ranging from 0 (no angina) to 4 (serious chest pain atrest).
2.2. Cardiac catheterization
In each patient, cardiac catheterization including left ventricular and coronary angiography, was performed with standard Judkins method. All anti-anginal and anti-ischaemic medications, except sublingual nitroglycerin, were withheld for at least 1 week before the examination. All coronary angiograms were analysed by two experienced independent investigators. Only angiograms with visually smooth contours with no wall irregularities were accepted as normal. During coronary arteriography, to exclude the possibility of coronary artery vasospasm, all patients underwent hyperventilation test which was performed by asking the patients to breathe quickly and deeply for 5min.
2.3. Vascular assessment
The noninvasive determination of endothelial functions was performed according to the method described by Celermajer et al.9A high-resolution ultrasound machine (Hp-SONOS 2500, Andover, Massachusetts) equipped with a 7.5-MHz linear-array transducer was used to obtain B-mode scans of the right brachial artery 2-4cm above antecubital fossa. All ultrasound examinations were performed with a standard technique and appropriate environment as stated in the report of the International Brachial Artery Reactivity Task Force.10All vasoactive medications were withheld for 24h before the procedure. All ultrasound images were recorded on S-VHS videotape for subsequent blinded analysis. Records of both B-mode and pulsed Doppler spectral curve were taken at rest, during reactive hyperaemia (FMD), and after the sublingual application of 5mg isosorbide dinitrate (endothelium-independent vasodilatation). After baseline measurements, a sphygmomanometer cuff, placed around the right upper arm proximal to the imaged artery segment, was inflated to the pressure of 240mmHg for 4.5min. To verify that supra-systolic compression of the brachial artery caused adequate increases in blood flow, flow velocity was measured at rest and within 15s after cuff deflation. Blood flow was calculated by multiplying the velocity time integral of the Doppler flow signal by the heart rate and the vessel cross-sectional area (3.14xD2/4). Reactive hyperaemia was calculated as percent change in flow during hyperaemia compared with baseline. Blood flow and end-diastolic diameter were recorded at 30-s intervals for 300s after cuff release and at 6, 8 and 10min until recovery to baseline values. After re-establishing baseline conditions 15 to 20min later, measurements of arterial diameter and flow velocity were repeated, followed by sublingual isosorbide dinitrate at a dose of 5mg in order to assess endothelium-independent nitrate mediated vasodilatation (NMD). Four minutes later, measurements were repeated. The arterial diameter was measured in millimeters as the distance between the anterior wall media-adventitial interface (m line) and the posterior wall intima-lumen interface at end-diastole, coincident with the R wave on the continuously recorded electrocardiogram at two sites along the artery. The maximum FMD and NMD diameters were calculated as the average of the three consecutive maximum diameter measurements after hyperaemia and isosorbide dinitrate, respectively. The FMD and NMD were then calculated as the percent change in diameter compared with baseline resting diameters. NMD was evaluated after sublingual isosorbide dinitrate in only basal studies to verify the functional integrity of vascular smooth muscle. All images were analysed on two occasions by the same examiner throughout the study who was unaware of the subjects clinical details; intra-observer correlation (r) for maximum diameter was 0.93.
2.4. Exercise testing
All patients underwent standard exercise stress test using the modified Bruce protocol on two occasions: before randomization and at the end of 3rd month. Blood pressure, heart rate and 12-lead ECGs were recorded at rest, at one-minute intervals during exercise, at peak exercise, and for at least 8min in the recovery phase. The ECG and ST-segment depression were continuously displayed and measured automatically by a computer-assisted system (Q4500 treadmill, Quinton Instruments Co., Seattle, Wash.) in all 12 leads. The subjects were exercised until one of the end-points was reached: an age-specific target heart rate or the development of symptoms necessitating termination of the test. Patients were encouraged to perform their maximum effort and the symptoms developed during exercise test were recorded. The test was considered positive for ischaemia when more than 1mm of down-sloping or horizontal ST depression at 60 to 80ms after the J point occurred. Total exercise duration, total work load, and time to 1mm ST-segment depression during exercise testing were compared after treatment with pravastatin 40mg or placebo for 12 weeks.
2.5. Statistical analyses
SPSS (Chicago, Illinois) for Windows (Version 10.0) was used for all statistical analysis. Data are presented as percentages for discrete variables and as mean±SD for continuous variables. A P value of <0.05 (two-sided) was regarded as statistically significant without correction for multiplicity. The primary end-points were the percent changes observed in FMD, time to 1mm ST depression, and total exercise duration from baseline. The primary hypothesis was that the administration of pravastatin to patients with cardiac syndrome-X would result in a significantly greater improvement in FMD and time to 1mm ST depression during exercise test compared to placebo. This study was designed to have 85% power of detecting a difference in FMD measurement of 5% between the statin and placebo groups with an assumed SD of FMD measurement of 5%. The differences between demographic variables of the groups were assessed using the MannWhitney U test for continuous data and chi-square test for categorical data. Exercise test parameters including (total exercise duration, time to 1mm ST depression, and work load-METS), FMD, and serum levels of lipids and other biochemical variables were compared between groups with the MannWhitney U test. Wilcoxon Signed rank test was performed to compare these variables with pretreatment levels within the groups. The differences between the two groups observed changes from baseline for biochemical variables, FMD, and exercise test continuous variables were also examined by the MannWhitney U test. The chi-square test (or Fishers exact test when the contingency table has a cell with an expected frequency of less than 5) was used to compare the frequencies of chest pain during exercise, and anginal episodes between the treatment groups. Mc-Nemar test was used for the within-group comparison of the changes in the frequencies of chest pain during exercise, and anginal episodes before and after treatment. The correlation analyses were performed to investigate the association of changes observed in lipid levels, CRP and fibrinogen concentrations, FMD, and exercise parameters after treatment by using Pearson Correlation testing (or Spearman Correlation test when the data are not normally distributed or have ordered categoriescoefficient rs).
3. Results
Table 1outlines the demographic characteristics of the treatment groups. Thirty-eight of the 40 initially-enrolled patients completed the protocol: one patient who stopped smoking during the study in pravastatin group and one for his own personal reasons from the control group were lost to follow-up. The clinical characteristics did not differ statistically among the treatment groups at baseline. The use of antianginal drugs was similar between the two groups. Body weight did not vary significantly during the study. Mean dietary compliance did not change significantly in both groups during study. Compliance with the medication regimen was 100% for pravastatin group, and 95% for placebo group. Smoking habit in both groups remained unchanged.
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The comparison of the observed changes from baseline (percent changes) is shown in Table 3. The observed changes of biochemical parameters including total cholesterol, LDL cholesterol, Apo B, CRP and fibrinogen levels from baseline were significantly higher in the pravastatin group than the placebo group. Also the observed changes of the exercise parameters (total work, exercise duration, and time to 1mm ST depression) and FMD from baseline were significantly better in patients receiving pravastatin than the placebo group.
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4. Discussion
Despite the good prognosis of cardiac syndrome-X, the chronic, frequent nature of the persistent angina and the reduced exercise tolerance can significantly impair quality of life.11The pathophysiology of angina is not clear. A functional impairment in the coronary microvasculature causing an abnormal coronary flow reserve is the generally suspected mechanism.2,3There are several reports about elevated serum or coronary sinus levels of indirect markers of vascular dysfunction in cardiac syndrome-X.1214In patients with microvascular angina, an impaired forearm vasodilator response to ischaemia has been observed, suggesting that the vascular involvement is not confined to the coronary circulation but is part of a generalized vasomotor disturbance also involving the peripheral conduit arteries.4,5
On the other hand, the fact that endothelial dysfunction can be improved with the use of a statin, is beyond doubt.15There is substantial experimental evidence that improvement of the endothelial-dependent vasorelaxation with statins results from endothelial nitric-oxide (NO) activation.16,17In our study, we aimed to investigate whether statins have any beneficial effects in patients with cardiac syndrome-X. Our study is the first randomized, placebo-controlled study to investigate the effect of statins in normolipidemic patients with cardiac syndrome-X. Fabian et al had found simvastatin effective on both FMD and exercise induced ischaemia in hypercholesterolaemic patients with syndrome-X.18Their study included only 25 patients without any comparable control group. The results of our study showed a significant improvement in both FMD and exercise capacity in patients receiving pravastatin compared to the placebo group. This result is in agreement with Egashira et als finding of rapid improvement of defective endothelium-dependent vasodilatation of coronary microcirculation after supplementation of L-arginine19in cardiac syndrome-X. Both results probably are indicating anendothelial dysfunction in these patients resulting from defective synthesis or release of NO, or both.
In addition to their effect on NO, statins also affect endothelin20which is a vasoconstrictor substance and was shown to be elevated in patients with cardiac syndrome-X.12,13Statins decrease endothelin levels thereby, further shifting the balance toward vasodilatation. In vitro studies have also demonstrated a direct effect of statins on the susceptibility of LDL cholesterol to oxidation and a reduction in the expression of cellular adhesion molecules,21which were found to be elevated in cardiac syndrome-X.14Another mechanism that can explain the observed benefits of pravastatin might be inflammation. Pravastatin has been shown to inhibit the inflammatory and proliferative changes in the coronary vessels of rats independent of lipid lowering.22The significant decrease we observed in CRP levels with pravastatin in cardiac syndrome-X and the improvement of both FMD and exercise parameters might also indicate the presence of chronic inflammatory process in endothelium in patients with cardiac syndrome-X. The benefit we observed with pravastatin might also be due to a reduction in blood viscosity. Lipid lowering therapy with pravastatin has been shown to decrease the blood viscosity23,24which was also found to be elevated in patients suffering from cardiac syndrome-X.25Although we did not measure blood viscosity directly, afterpravastatin therapy we observed a significant decrease in fibrinogen concentration, which is an important determinant of blood viscosity. Finally, cellular anti-oxidative properties of statins, leading to decreased oxidative stress and restoration of NO bioactivity,26might have improved nitrate tolerance.27This may also be one of the beneficial effects of statins for cardiac syndrome-X. The evaluation of the endothelium-independent NMD after pravastatin therapy might be helpful to clarify such a mechanism. However, as this study was designed to observe the changes in endothelium-dependent FMD, NMD was assessed only at baseline pre-therapy to verify the functional integrity of vascular smooth muscles as an eligibility criterion for FMD testing. Despite thepravastatin treatment, angina pectoris developed during exercise in 21% of our patients. This may reflect the multi-factorial pathogenesis and heterogeneous nature of the cardiac syndrome-X.
5. Study limitations
The possibility of underlying coronary artery spasm was ruled out by hyperventilation test rather than ergonovine injection. As the specificity and the sensitivity of the hyperventilation test compared to ergonovine injection is lower, the use of hyperventilation might be a limitation of this study. However, we preferred hyperventilation test in our patients because of the possibility of persistent and severe, painful spasm with ergonovine. The lack of direct observation of the coronary endothelium dependent vasodilatation may also be accepted as a limitation. Although, a correlation exists between systemic andcoronary endothelial functions, direct evaluation of the coronary microvasculature might be a better way of studying these cases. Especially, the new guide wire-based Doppler flow velocimetry systems,28which were not available during the patient recruitment of this study, can be convenient for the evaluation of the coronary endothelial functions in cardiac syndrome-X. The other major limitations of this study were the lack of ischaemia documentation with either myocardial perfusion scintigraphy or Holter monitoring and the relatively small number of study population. However our patients were quite homogeneous with the limited number of risk factors.
6. Conclusions
Statin treatment reduces exercise-induced ischaemia in patients with cardiac syndrome-X, probably through direct modulation of coronary microvascular tone, which results in an increased myocardial oxygen supply. The results obtained in this study may also support the presence of chronic inflammation with involvement of the endothelium in patients with cardiac syndrome-X. Therefore, statins may be adjunctive to treatment in cardiac syndrome-X, based on pathophysiological endothelial dysfunction hypothesis.
Footnotes
1 The preliminary results of this study was presented at the 24th Congress of the European Society of Cardiology (Berlin, September 2002).
References
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