CLINICAL STUDIES
Elevated endothelin concentrations are associated with reduced coronary vasomotor responses in patients with chest pain and normal coronary arteriograms
Ian D. Cox, MRCP*,
Hans E. Bøtker, MD ,
Jens P. Bagger, MD ,
Helle S. Sonne, MD,
Bent Ø Kristensen, MD and
Juan Carlos Kaski, MD, FACC*
* Department of Cardiological Sciences, St. George’s Hospital Medical School, London, United Kingdom
Department of Cardiology, Skejby University Hospital, Aarhus, Denmark
Department of Cardiology, Hammersmith Hospital, London, United Kingdom
Manuscript received August 13, 1998;
revised manuscript received March 17, 1999,
accepted April 22, 1999.
Reprint requests and correspondence: Dr. J.C. Kaski, Department of Cardiological Sciences, St. George’s Hospital Medical School, Cranmer Terrace, London, SW17 0RE, United Kingdom
jkaski{at}sghms.ac.uk
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Abstract
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OBJECTIVES
The purpose of this study was to investigate the relationship between arterial and coronary sinus endothelin (ET) concentrations and coronary vasomotor responses during rapid atrial pacing in patients with chest pain and normal coronary arteriograms (CPNA).
BACKGROUND
Plasma ET concentrations are significantly higher in CPNA patients than in healthy control subjects.
METHODS
We investigated 19 carefully characterized CPNA patients (14 women; mean age 53 ± 9 years) of whom 10 had positive electrocardiographic responses to exercise. The percentage fall in coronary vascular resistance (%d.CVR) after 10 min of rapid atrial pacing was determined using a thermodilution pacing catheter. Plasma ET concentrations were measured by radioimmunoassay on simultaneously drawn arterial and coronary sinus samples.
RESULTS
No significant differences in ET concentrations were observed between men and women, but a strong statistical trend suggested that %d.CVR was lower in women than men (27[23 to 31]% vs. 34[29 to 45]%—median[interquartile range]; p = 0.07). Simple regression analysis including only the women (n = 14) suggested a significant relationship between baseline arterial ET concentrations and %d.CVR (R2 = 0.34; p = 0.06). Furthermore, stepwise multivariate regression analysis of the group as a whole indicated that both gender (p = 0.03) and baseline arterial ET concentration (p = 0.02) were independently predictive of %d.CVR (R2 = 0.44; overall p = 0.02); this relationship predicts that women with high ET levels would have the lowest %d.CVR during pacing.
CONCLUSIONS
These data support the hypothesis that elevated ET activity may be associated with reduced coronary flow responses during rapid atrial pacing in CPNA patients.
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Abbreviations and Acronyms
| | CPNA | = chest pain with normal coronary arteriogram | | CSBF | = coronary sinus blood flow | | eECG | = exercise electrocardiogram | | ET | = endothelin | | %d.CVR | = percentage fall in coronary vascular resistance during pacing |
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Coronary microvascular dysfunction can be demonstrated in a proportion of patients with chest pain and normal coronary arteriograms (CPNA) (1). The pathogenesis of such microvascular dysfunction remains poorly understood, but previous studies (2–5) have demonstrated evidence of coronary endothelial dysfunction. Endothelin (ET) is a potent vasoconstrictor peptide produced by vascular endothelium which appears to play an important role in cardiovascular regulation and pathophysiology (6–8). Recent studies (9,10) have indicated that peripheral immunoreactive ET concentrations are elevated in CPNA patients (in particular, those with positive exercise electrocardiogram [eECG], left bundle branch block or a history of myocardial infarction) compared with healthy control subjects (10). Most recently, Newby et al. (11) have demonstrated reduced sensitivity of peripheral resistance vessels to exogenous ET in CPNA patients with positive eECG compared with healthy age- and gender-matched control subjects. They concluded that their findings were consistent with increased ET production and down-regulation of the ETA receptor. A preliminary report by Huelmos et al. (12) has also recently described an inverse correlation between scintigraphically determined myocardial perfusion reserve and plasma ET levels in a group of patients with cardiovascular risk factors. These data support the hypothesis that elevated ET levels may have pathophysiologic significance in the CPNA patient group. In this article, we report for the first time a study examining the relationship between arterial and coronary sinus ET levels and coronary sinus blood flow responses during rapid atrial pacing in a group of carefully characterized CPNA patients.
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Methods
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Patients.
We studied 19 patients (14 women) with chest pain and completely normal coronary arteriograms. All patients had typical exertional angina, and none gave a history suggesting coronary vasospasm (pain occurring primarily at rest, preserved exercise tolerance and/or episodes of pain associated with acute ST segment elevation). Hyperventilation testing (13) was also negative in all cases. No significant valvular abnormality or left ventricular dysfunction was detected by echocardiography in any of the study patients. None of the patients had a history of hypertension or concomitant metabolic abnormalities. Ischemic ST segment changes (>0.1 mV depression at 80 ms after the J point) during bicycle eECG were present in 10 of the 19 study patients.
Invasive assessment.
The study was approved by the Local Research Ethics Committee, and all patients provided fully informed consent before participation. Antianginal medication, except for sublingual nitroglycerin, was stopped one week before invasive assessment. No sedative or analgesic medications other than local analgesic (lidocaine) were administered before invasive assessment. After an overnight fast, a 7-F Wilton-Webster thermodilution pacing catheter (Webster Labs., Baldwin Park, California) was advanced from the left antecubital vein to a midposition in the coronary sinus. Coronary sinus blood flow (CSBF) measurements were performed by continuous infusion of cold saline solution (36 ml/min) for 20 to 25 s. A Teflon catheter for arterial blood sampling and pressure measurements was also inserted into the distal aorta via the femoral artery. The catheters were kept patent by intermittent infusion of sodium chloride solution (154 mmol/liter), to which a maximum of 300 IU of heparin was added. Electrocardiographic monitoring was performed continuously during the procedure.
After an equilibration period of 15 min, baseline arterial and coronary sinus blood samples were drawn in triplicate with simultaneous measurements of hemodynamic variables (heart rate, blood pressure and CSBF). Atrial pacing was then performed at a constant rate of 150 beats/min for a period of 10 min. Intravenous atropine (0.25 mg) was given just before pacing to prevent pacing-induced atrioventricular block. During the last minute of pacing, two sets of arterial and coronary sinus blood samples were drawn with simultaneous measurements of hemodynamic variables. The stability of the coronary sinus electrode position during pacing was confirmed by fluoroscopic control. The presence of chest pain during pacing and postpacing ST segment depression were noted.
Analysis of blood samples.
Blood samples were transferred to the laboratory on ice for immediate centrifugation, and the plasma was decanted and stored at –20°C until analysis. Plasma ET concentrations were measured by radioimmunoassay (Nichols Institute, Diagnostic B.V., Wichen, The Netherlands). The cross-reactivity of the assay was 100% with ET-1, 52% with ET-2, 96% for ET-3 and 7% for big ET. Cross-reactivity with atrial natriuretic peptide, angiotensin II, adrenocorticotropic hormone and vasopressin was <0.1%. The interassay variability was <10%. Lactate concentration was measured in whole blood as previously described (14).
Statistical analysis.
Endothelin data are expressed as mean ± SD, and a two-tailed t test was used for pairwise comparisons between groups. Fractional myocardial substrate extraction (ET and lactate) was calculated as the arteriocoronary sinus difference divided by the arterial concentration and expressed as a percentage. Coronary vascular resistance was calculated as mean arterial pressure divided by CSBF (mm Hg/ml·min–1), and from these data the percentage fall in coronary vascular resistance during pacing (%d.CVR) was calculated. This value has two important advantages: 1) by calculating a statistic for resistance from the coronary sinus flow rate and mean arterial pressure, the confounding influence of any change in blood pressure during pacing is taken into account; and 2) the comparison of absolute values for coronary sinus flow and CVR calculated by the thermodilution method is subject to criticism because these values may be influenced by anatomic factors and variations in the exact placement of the thermodilution catheter within the coronary sinus during testing. The %d.CVR data are presented as median [interquartile range] in the text; pairwise comparison of %d.CVR data between groups was performed by the Mann-Whitney U test. Correlation between %d.CVR and other parameters was assessed by Pearson’s correlation coefficient. A p value of less than 0.05 was considered statistically significant. Multiple regression analysis was performed using a computer software package (SSPS version 6, SPSS Inc., Chicago, Illinois).
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Results
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Baseline characteristics of study groups.
The baseline characteristics of the study group divided according to gender are presented in Table 1. The proportion of patients with a positive eECG was higher in the women than in the men (64% vs. 20%, respectively; p = 0.14) and exercise test duration was also less in women than in men (8.3 ± 1.0 vs. 13.6 ± 3.0 min, respectively; p = 0.02).
Immunoreactive et concentrations.
As shown in Table 2, there was no significant difference between baseline arterial ET concentrations in men and women (1.99 ± 0.75 pg/ml vs. 1.67 ± 0.58 pg/ml, respectively; p = 0.36). Furthermore, there was no significant correlation (R = 0.14; p = 0.68) between baseline arterial ET and serum estradiol concentration in the women. In the study group as a whole, arterial ET levels did not change significantly between baseline and pacing (1.76 ± 0.63 pg/ml vs. 1.59 ± 0.46 pg/ml, respectively; p = 0.19). No significant differences in the coronary sinus ET concentrations or ET extraction were detected between the men and women. Net lactate extraction was present in both groups at rest and during pacing, and no significant changes in lactate handling were detected between rest and pacing in either group.
Relationship between ET levels and coronary vasomotor responses.
A strong statistical trend suggested that %d.CVR was lower in women than men (27[23 to 31]% vs. 34[29 to 45]%—median[interquartile range]; p = 0.07). Simple correlation analysis indicated statistical trends suggesting possible correlations between %d.CVR and both patient gender (R = 0.35; p = 0.14) and baseline arterial ET (R = 0.41; p = 0.11). Correlation analysis of the relationship between %d.CVR and baseline arterial ET levels in the women alone was even more suggestive that a significant relationship might exist between these variables (R2 = 0.34; p = 0.06). Therefore, backward stepwise regression analysis was performed including %d.CVR as the outcome variable and baseline arterial ET concentration, exercise test positivity, patient gender and age as the initial predictor variables. After exclusion of exercise test positivity and patient age (p > 0.6, in both cases), the resulting multivariate regression model for %d.CVR indicated a significant relationship (R2 = 0.44; overall p = 0.02) with both baseline arterial ET concentration (p = 0.02) and patient gender (p = 0.03) (Fig. 1, Table 3). Although univariate analysis indicated that the %d.CVR was significantly lower in the eECG+ compared with the eECG– group (27[22 to 29]% vs. 34[29 to 45]%; p = 0.02), a relationship between eECG positivity and %d.CVR was not substantiated by the multivariate regression analysis. This may have arisen as a result of the confounding influence of gender and the fact that the baseline arterial ET concentration was significantly higher in the eECG+ group than the eECG– group (2.24 ± 0.56 pg/ml vs. 1.40 ± 0.40 pg/ml, respectively; p = 0.003; see Table 2). There was also no significant correlation (R = 0.1; p = 0.69) between %d.CVR and serum estradiol concentration in the female patients.
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Figure 1 Scattergram illustrating the relationship between baseline arterial endothelin (ET) concentration and percentage fall in coronary vascular resistance during rapid atrial pacing in men and women; dashed lines represent simple regression plots for women (circles) (R2 = 0.34; p = 0.06) and men (squares) (R2 = 0.62; p = 0.11).
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Discussion
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Quyyumi et al. (4) have previously demonstrated abnormalities in coronary sinus blood flow responses to both acetylcholine and atrial pacing in CPNA patients. They further demonstrated that there was a strong correlation between the flow responses observed with the two stimuli and concluded that microvascular endothelial dysfunction may contribute to the reduced vasodilator reserve with atrial pacing in these patients (4). In this study, we used the same methodology as Quyyumi et al. (4) to assess the relationship between the coronary vasomotor responses during rapid atrial pacing and coronary ET concentrations in a CPNA patient group.
Relationship between gender, baseline arterial ET concentration and coronary vascular responses in CPNA patients.
Our findings indicated that both female gender and baseline arterial ET concentration were independently predictive of %d.CVR. This inverse relationship is intriguing, because it predicts that women with high ET levels would have the lowest %d.CVR during pacing. Our findings are consistent with those of Huelmos et al. (12), who have also reported an inverse correlation (R = –0.59; p < 0.05) between plasma ET levels and scintigraphically determined myocardial perfusion reserve in a group of patients with cardiovascular risk factors. These data further support the hypothesis that increased ET activity may contribute to microvascular endothelial dysfunction in CPNA patients. Our findings regarding female gender must also be considered in the context that most series of CPNA patients have been dominated by post- and perimenopausal women (15,16). The hypothesis that estrogen deficiency is associated with coronary endothelial dysfunction and abnormal vasomotor control in such women has been supported by evidence from a variety of studies (17,18), although the underlying mechanisms are not clearly understood. However, in the present study, serum estradiol concentrations did not correlate with either plasma ET concentration or %d.CVR in the female patients; therefore, this sole factor cannot explain the observed differences.
Pathophysiologic significance of ET in CPNA patients.
Endogenous production of ET, a potent vasoconstrictor peptide (7), contributes to the balanced opposition between vasodilator and vasoconstrictor mediators involved in endothelial regulation of vascular tone (6–8). Therefore, it seems reasonable to speculate that increased levels of a potent vasoconstrictor peptide such as ET in certain patients might contribute to reduced vasodilatory responses, and the data presented in our study support the existence of such a relationship. Nonetheless, a similar relationship between %d.CVR and either the arterial ET concentration during pacing or the net ET balance (extraction or production) across the coronary circulation might have provided more compelling evidence in this context. However, one must remember that ET produced by the vascular endothelium functions primarily as a paracrine mediator, with up to 75% of ET from cultured endothelial cells being secreted in the abluminal direction, that is, toward the vascular smooth muscle cells (19). The mechanisms responsible for and controlling ET extraction across the coronary vascular bed are also not well understood. Consequently, variations in local endothelial ET production and effects on vascular smooth muscle may not be reflected in a simple relationship by changes in plasma ET concentrations. Therefore, we do not believe that these data can be discounted simply because they do not conform to a simple model. The consistency of our observations with recent findings by Huelmos et al. (12) and Newby et al. (11) supports this view.
The relationship between endothelial microvascular dysfunction, coronary flow abnormalities and myocardial ischemia in CPNA patients.
The relationship between endothelial microvascular dysfunction, coronary flow abnormalities and myocardial ischemia in CPNA patients remains uncertain (20). A high incidence of scintigraphic perfusion defects has been reported in CPNA patients (21,22), and an association between scintigraphic perfusion defects and impaired regional endothelium-dependent vasodilation of the coronary microcirculation has now also been demonstrated in this group (23,24). Such perfusion abnormalities may be attributed to inhomogeneity of blood flow between different myocardial regions without absolute reductions in blood flow (20). In this context, Meeder et al. (25) have demonstrated increased heterogeneity of myocardial perfusion in CPNA patients compared with healthy volunteers using positron emission tomography. Maseri et al. (26) have proposed that "patchy" constriction of prearteriolar vessels due to increased sympathetic tone or focal release of vasoactive mediators in CPNA patients may lead to heterogeneity of blood flow and small ischemic foci. The existence of an ischemic mechanism has also been supported by recent preliminary findings indicating the presence of increased intracardiac oxidative stress in CPNA patients (27). Animal studies (28) have also suggested that ET may have algogenic properties and, consequently, elevated ET levels in CPNA patients might contribute to both the evolution of an ischemic stimulus and its "amplification" through an algogenic mechanism (29).
Increased coronary sinus lactate concentrations during pacing stress have been demonstrated in CPNA patients in some studies (3,30,31), but others (30,32) which excluded patients with hypertension and left bundle branch block have failed to demonstrate lactate production during pacing stress in similar patient groups. However, the absence of lactate production as in the present study does not necessarily exclude an ischemic mechanism, because lactate exchange may be an insensitive marker of myocardial ischemia. This assertion is supported by the results of other studies (33) which have failed to detect lactate production during stress in patients with significant macrovascular coronary stenoses. It is also possible that lactate efflux from small areas of focal ischemia in CPNA patients may be obscured due to dilution by blood draining from neighboring, normally perfused areas. Even in the absence of lactate production, significant differences in the pattern of myocardial substrate metabolism during atrial pacing have been reported in CPNA patients (22).
Conclusions.
The data presented in this study lend further support to the hypothesis that increased ET activity may be associated with coronary microvascular dysfunction in CPNA patients.
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Footnotes
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Dr. Ian D. Cox is supported by a Fellowship Grant from the British Heart Foundation.
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References
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Abstract
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