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Institutes of 1 Cardiology, 2 Biochemistry, and 3 Chemistry and Clinical Chemistry, Università Cattolica del Sacro Cuore, Rome 00168, Italy
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The presence of myocardial ischemia in syndrome X (chest pain, "ischemia-like" electrocardiogram changes, and normal coronary angiograms) is uncertain possibly because, when focally distributed, it may not cause contractile dysfunction or lactate production. We measured lipid hydroperoxides (ROOHs) and conjugated dienes (CDs), two sensitive, independent markers of ischemia-reperfusion oxidative stress, in paired aortic and great cardiac vein blood samples before and after pacing-induced tachycardia in nine patients with syndrome X. Diagnostic ischemic S-T segment changes during pacing were followed by a consistent increase in ROOH and CD levels in the great cardiac vein (from 4.83 ± 1.18 µmol/l at baseline to 7.88 ± 1.12 µmol/l and from 0.038 ± 0.002 to 0.051 ± 0.003 arbitrary units, respectively, P < 0.01). In controls, ROOH and CD levels did not change after pacing. The large postpacing cardiac release of lipid peroxidation products, consistently observed in all patients and similar to that previously observed after ischemia caused by percutaneous transluminal coronary angioplasty, is consistent with an ischemic origin of syndrome X.
myocardial microcirculation; focal ischemia; free radicals; angina
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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AMONG PATIENTS SUBJECTED TO coronary angiography, 10-30% are found to have normal coronary arteries (23), and those with recurrent angina pectoris are commonly labeled "syndrome X" (SX) patients. This term was coined by Kemp (24) in 1973 in an editorial on the puzzling finding of ischemia-like electrocardiographic (ECG) changes and angina induced by atrial pacing in patients with chronic stable angina and normal coronary angiography. Included in this broad definition, a subgroup of patients can be identified in whom anginal pain is associated with ECG ischemic changes during stress test or Holter monitoring (26) or with regional defects on effort myocardial scintigraphy (42). Although in such patients the assumption of a cardiac origin of their angina seems reasonable, an ischemic origin is regarded with skepticism by several investigators (6, 7, 11, 34, 39, 40). Indeed, also in this more precisely defined subgroup, several studies failed to show metabolic evidence of myocardial ischemia (6, 11, 39) or transient wall motion abnormalities during angina and ischemia-like ECG changes (2, 7, 34). More consistent data are available on the presence of a reduced coronary flow reserve and of an impaired endothelial function in SX patients (12, 27, 36); however, most of these authors do not believe that a minor reduction of microvascular dilation capacity could be sufficient to cause myocardial ischemia in the presence of a transient increase in oxygen demand (7, 34). Other researchers have proposed that angina in SX is not necessarily of ischemic origin but might be due to enhanced cardiac pain perception or metabolic myocardial abnormalities (40, 44).
Multiple small foci of ischemia, caused by a patchily distributed microvascular dysfunction (30), may not cause detectable lactate production, because low blood flow drains ischemic areas and high flow drains normally perfused myocardium (18) and because lactate production stops as soon an ischemia is interrupted. Intracoronary embolization with moderate amounts of obstructive microspheres (28 µm diameter) in animals is associated with an increase in myocardial blood flow without detectable signs of ischemia (35). Patchily distributed foci of ischemia may not cause detectable contractile dysfunction, inasmuch as myocardial contraction is not detectably impaired until global flow to subendocardium is reduced by ~20% (43). Moreover, lactate has been shown to be a specific, but relatively insensitive, marker of myocardial ischemia in clinical settings (18, 29).
We reasoned that the measurements of markers of ischemia-reperfusion-induced oxidative stress in cardiac venous blood could have a greater sensitivity for detecting sparse foci of ischemia. Lipid peroxides could be a better marker for ischemia than lactate because of the magnitude and timing of their release in a reoxygenated tissue. Indeed, at the end of ischemia, while flow and lactate extraction rapidly normalize, a large and sustained production of lipid peroxides has been consistently demonstrated by several experimental and clinical studies (1, 9, 15, 37, 20, 33, 38). Malondialdehyde, a well-known marker of oxidative stress, has been demonstrated to be a sensitive marker of transient myocardial ischemia in several clinical models of transient myocardial ischemia. In particular, Coghlan et al. (9) showed, in the coronary venous blood after a brief episode of myocardial ischemia during coronary angioplasty, a large increase in malondialdehyde, which was detectable even in a subgroup of patients with minor and not significant changes in myocardial lactate extraction.
Lipid hydroperoxides (ROOHs) and conjugated dienes (CDs) have been
shown to be even more accurate oxidative markers than malondialdehyde (10, 32). ROOHs and CDs are intermediate and reactive
compounds in the lipid peroxidation cascade, in which lipids and
proteins continuously interact, causing a prolonged and self-maintained generation of peroxides in the reoxygenated tissue as well as in the
surrounding normooxygenated myocardial regions; conversely, lactate is
rapidly extracted by normooxygenated surrounding endothelial and
myocardial cells. We recently demonstrated, after brief (2-min) episodes of myocardial ischemia during coronary angioplasty, a large
and sustained release of ROOHs and CDs, two independent indexes of
lipid peroxidation, in the coronary venous blood lasting up to 15 min
after reperfusion (4, 37) (Fig.
1).
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Therefore, to investigate whether typical chest pain and ischemia-like ECG changes induced by atrial pacing in patients with SX are followed by cardiac release of lipid peroxidation products, compatible with an ischemic origin, we measured sequentially myocardial production of ROOHs and CDs in a group of SX patients and in controls after atrial pacing. In these patients the increased myocardial demand induced by pacing may cause focal ischemia distal to those microvessels with a limited coronary flow reserve.
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METHODS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Study Population
The study population consisted of two groups of patients.SX.
Nine patients (4 women and 5 men, 54 ± 8 yr) with typical effort
chest pain, smooth coronary arteries in multiple angiographic views,
and ECG evidence of myocardial ischemia on atrial pacing (horizontal or downsloping S-T segment depression 
0.1 mV) were studied. Seven patients also had a positive exercise ECG stress test,
and five showed a reversible perfusion defect on 201Tl
myocardial scintigraphy; three patients with predominantly rest angina
also had a negative ergometrine test. None had a history of diabetes,
but two patients were insulin resistant. None had systemic
hypertension, echocardiographic evidence of ventricular hypertrophy, or
abnormal resting ECG.
Controls. The control group consisted of five patients (3 women and 2 men, 52 ± 17 yr) undergoing cardiac catheterization because of mild-to-moderate mitral valve disease with normal ECG and normal coronary angiogram. Left ventricular volume and wall thickness were normal in all patients. All controls had normal ECG at rest, and none had a history of chest pain.
Study Protocol
The study was approved by the local ethics committee, and written informed consent was obtained from each patient after the study protocol was explained. All subjects were studied in the fasting state after medication with diazepam (10 mg). Through femoral access, a 5-F multipurpose catheter was advanced into the great cardiac vein (GCV), and a 5-F Judkins catheter was positioned into the aortic root. Blood samples (10 ml) were simultaneously drawn by needle puncture from the femoral vein and through the arterial and GCV catheters [baseline (t0)].Atrial pacing.
A pacing electrode was inserted into the right atrium, and heart rate
was progressively increased by 10 beats/min at 30-s intervals up to 160 beats/min or until the development of ischemic S-T segment depression.
Atropine sulfate (0.5 mg iv) was administered when second-degree
atrioventricular block developed. Maximum heart rate was maintained for
3 min. A 12-lead ECG was recorded every 30 s during atrial pacing
and recovery. The pacing test was considered positive when the ECG
showed a horizontal or downsloping S-T segment depression of 1 mm
(0.1 mV) at 0.08 s after the J point in at least one lead. Paired
blood samples were simultaneously drawn from the aorta and GCV 30 s before (tmax) and 1 (t1), 5 (t5), and 15 min
(t15) after pacing interruption.
80°C, and analyzed within 1 mo.
Analysis of lipid peroxidation products. The investigators responsible for the biochemical analysis were unaware of the patients' identity and of the clinical protocol. Plasma lipids were extracted by a modification of the method of Folch et al. (13). CDs were measured by second-derivative spectrophotometry and are expressed in arbitrary units (AU) (10). Intra-assay coefficient of variation for this method was 7.5%. ROOHs were determined with the FOX2 version assay (32, 41). They were determined as a function of the mean absorbance difference of samples with and without elimination of ROOHs by triphenylphosphine. Intra-assay coefficient of variation for this method was 5.0%.
Statistical Analysis
Continuous variables were normally distributed and are reported as means ± SD. Cardiac release of lipid peroxidation products was calculated as plasma GCV minus aortic levels. Student's t-test, ANOVA for repeated measures, and Newman-Keuls test were used to evaluate the statistical significance of the difference within and between groups. P < 0.05 was considered significant.| |
RESULTS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Clinical features of patients and controls are reported in Table
1. The individual results are presented
in Table 2. Baseline aortic and femoral
vein ROOH and CD levels were not statistically different, indicating
that the measurements were unaffected by catheter sampling. The levels
of both markers were not significantly different in aortic blood
samples taken at t0, t1,
t5, and t15 in SX
patients and controls. The coefficients of variation of the four aortic
sample measurements in SX patients and in controls were 27 and 23%,
respectively, for ROOHs and 10 and 10%, respectively, for CDs; these
values are larger than the intra-assay variability but indicate that,
in arterial blood, both lipid peroxidation indexes were quite stable
and reproducible.
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In SX patients, but not in controls, baseline ROOH and CD levels were slightly higher in the GCV than in the aorta or femoral vein (4.83 ± 1.18 vs. 2.44 ± 0.52 and 2.07 ± 0.74 µmol/l, P < 0.01, respectively; 0.039 ± 0.002 vs. 0.031 ± 0.003 and 0.031 ± 0.003 AU, respectively, P < 0.01).
Atrial Pacing
In all SX patients, atrial pacing caused ischemic S-T segment depression (0.17 ± 0.07 mV) in association with the usual chest pain in all but one patient (Table 3). None of the controls had chest pain or ischemic ECG changes. Heart rate, mean arterial pressure, rate-pressure product, and total pacing time in SX patients and controls were not significantly different; oxygen saturation in the GCV did not change throughout the study in the two groups.
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GCV Lipid Peroxidation Levels
In SX, at peak pacing (tmax), GCV, ROOH, and CD levels remained similar to levels at t0 (4.98 ± 1.61 vs. 4.83 ± 1.18 µmol/l and 0.038 ± 0.001 vs. 0.039 ± 0.002 AU, respectively, not significant), but they increased significantly at t1 (7.21 ± 1.00 µmol/l and 0.048 ± 0.001 AU, respectively, P < 0.01 vs. t0) and t5 (7.88 ± 1.12 µmol/l and 0.051 ± 0.003 AU, respectively, P < 0.01 vs. t0) and remained elevated at t15 (5.80 ± 1.02 µmol/l and 0.043 ± 0.005 AU, respectively; Table 2). In controls, GCV, ROOH, and CD levels did not change at any time after pacing interruption (Table 2). The increase occurred in all SX patients, ranging from 11 to 93% for ROOHs and from 12 to 40% for CDs at t1 and from 25 to 144% for ROOHs and from 10 to 46% for CDs at t5. Accordingly, in SX patients, but not in controls, the calculated coronary arteriovenous difference of ROOHs and CDs increased significantly at t1 [4.76 ± 1.04 vs. 2.76 ± 1.36 µmol/l at t0 for ROOHs (P < 0.01) and 0.017 ± 0.003 vs. 0.007 ± 0.004 AU at t0 for CDs (P < 0.05)] and t5 (5.41 ± 1.58 µmol/l and 0.016 ± 0.02 AU, respectively, P < 0.01 vs. t0) and remained higher than baseline at t15 (3.17 ± 1.45 µmol/l and 0.013 ± 0.006 AU, respectively), indicating a significant cardiac release of lipid peroxidation products immediately after pacing-induced ischemic ECG changes and angina (Fig. 2).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The results of our study demonstrate a large release of two independent, very sensitive markers of lipid peroxidation in blood samples taken in the GCV 1 and 5 min after the end of pacing-induced ischemic ECG changes in all nine patients with SX included in the study but in none of the controls. The time course of the cardiac release of lipid peroxidation products immediately after pacing interruption strongly suggests an ischemia-reperfusion mechanism (1, 4, 15, 37).
Our SX patients were selected according to commonly used criteria: history of typical anginal pain and evidence of a cardiac origin of pain derived from scintigraphic or ECG diagnostic signs of myocardial ischemia. Four SX patients also had a positive 24-h Holter recording. All the patients developed diagnostic ischemic S-T segment changes during pacing that were associated with their typical anginal pain in all but one patient. These findings suggest that the development of angina and ischemic S-T segment changes during pacing in these patients is most likely due to myocardial ischemia.
The development of diagnostic S-T segment changes during pacing may explain the consistent evidence of ischemia in all our patients compared with only 20% of women studied by myocardial 31P NMR spectroscopy (a sensitive method for detecting ischemia through a decrease in the myocardial phosphocreatine-to-ATP ratio) in whom handgrip failed to produce ischemic ECG changes (3).
Significance of Cardiac Lipid Peroxidation Product Release
A transient, marked increase in cardiac oxidative stress, detectable immediately after episodes of myocardial ischemia, has been consistently demonstrated by several studies after ischemia-reperfusion injury (1, 9, 15, 20, 33, 38). Ischemia is associated with depletion of endogenous antioxidants, and reoxygenation of an ischemic tissue causes a rapid release of reactive oxygen species that results in blood lipid and protein peroxidation product release in the effluent blood, with a peak during the first 1-5 min of reperfusion and a decline after 2-5 min (15). This time course of cardiac lipid peroxidation has been consistently observed in several clinical studies, regardless of whether the ischemic mechanism was a transient reduction of coronary flow (9, 38) or an increased oxygen demand in the presence of a fixed coronary stenosis (19, 33). Moreover, the pattern of cardiac venous ROOH and CD release was remarkably similar to that recently observed after a 2-min left anterior descending coronary occlusion in patients undergoing percutaneous transluminal coronary angioplasty (4, 37) (Fig. 1). Indeed, no evidence of oxidative stress was detected at the end of atrial pacing, after 3 min of ischemic S-T segment changes. The large and persistent release up to 15 min (Fig. 2) is explained by the already documented higher sensitivity of the methods used in the present study for the measurement of oxidative stress in blood (4, 10, 32, 37). As hypothesized in the introduction, the assessment of postischemic oxidative injury appears theoretically much more suitable for the detection of sparse microvascular foci of ischemia because of the persistence and the self-amplification of oxidative injury in the early minutes of reperfusion (1, 15). This time course is different from that of lactate release, which rapidly normalizes as soon as adequate flow is restored in the ischemic regions (18, 29).This is the first study in SX that demonstrates a consistent individual
response compatible with ischemia-reperfusion episodes in all
patients enrolled. The mechanism of microvascular dysfunction responsible for the reduction of coronary flow reserve dysfunction, sufficiently severe to produce sparse foci of myocardial ischemia during pacing, may be multiple and cannot be deduced by our study. Increased local production of endothelin (27, 28),
defective production of nitric oxide (12, 36), increased
nervous 
-adrenergic (14, 25) or neuropeptide Y
(8) stimulation, enhanced vascular reactivity to
constrictor stimuli (17), or structural changes in the
coronary microvasculature (31) represent plausible
mechanisms of coronary microvascular dysfunction, each of which can
operate in some patients but not in others. Also a primary production of oxygen free radicals may cause vascular alterations, including inhibition of nitric oxide production (21), hyperresponse
to constrictor stimuli (22), and leukocyte-endothelial
adhesion (16), which, in turn, may increase the
microvascular response to constrictor stimuli, thus setting the stage
for potential vasoconstrictor vicious cycles.
The baseline elevation of lipid peroxidation markers in the coronary venous blood found in this study was also observed in a previous study in patients with stable and unstable angina and flow-limiting stenosis (5). Recurring ischemia-reperfusion episodes (which are typically detectable in patients with SX and in those with multivessel disease at 24-h Holter monitoring) and/or a chronic reduction of antioxidant defenses might be the causes of these findings.
Patients with obstructive coronary stenosis undergoing atrial pacing could have been an important positive control group in our study. There is, however, a large body of evidence in the literature showing that transient ischemia causes coronary release of lipid peroxides in patients with obstructive coronary atherosclerosis, whether ischemia is caused by a reduced coronary flow (9, 38) or an increased cardiac oxygen demand (19, 33).
Conclusions
Our results, for the first time, demonstrate a consistent pattern of response in all patients with SX who developed pacing-induced angina and/or S-T segment depression. The pattern of lipid peroxidation product release into the GCV at the end of pacing is remarkably similar to that observed after a 2-min left anterior descending coronary occlusion during percutaneous transluminal coronary angioplasty and, therefore, is consistent with an ischemic origin of angina and ECG changes in SX. This observation was made possible 1) by the choice to assess markers of ischemia-reperfusion injury at the end of the ischemic period, which theoretically should have a greater sensitivity for the detection of small foci of myocardial ischemia than myocardial lactate production during ischemia, and 2) by the use of two independent, very sensitive methods to measure lipid peroxide production that are unaffected by catheter sampling.Measurements of markers of ischemia-reperfusion injury may open new areas of research on the causes of SX for the development of diagnostic methods and of effective, rational forms of treatment.
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FOOTNOTES |
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Address for reprint requests and other correspondence: A. Buffon, Istituto di Cardiologia, Università Cattolica del Sacro Cuore, Largo Gemelli 8, 00168 Rome, Italy (E-mail: abuffon{at}mail.omnitel.it).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 6 July 2000; accepted in final form 23 August 2000.
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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