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Cardiovascular Research 2002 53(3):620-626; doi:10.1016/S0008-6363(01)00460-6
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Copyright © 2002, European Society of Cardiology

Overview of gender aspects of cardiac syndrome X

Juan Carlos Kaski*

Coronary Artery Disease Research Unit, Department of Cardiological Sciences, St. George's Hospital Medical School, Cranmer Terrace, London SW17 0RE, UK

jkaski{at}sghms.ac.uk

* Tel.: +44-181-725-5901; fax: +44-181-725-3328

Received 20 June 2001; accepted 17 September 2001


   Abstract
Top
 Abstract
1. Introduction
 2. Myocardial ischaemia in...
 3. Oestrogen therapy for...
 4. Arguments against myocardial...
 5. Summary
 References
 
Cardiac syndrome X, a condition defined by the presence of angina-like chest pain, a positive response to stress testing and normal coronary arteriograms, has been shown to occur in approximately 20–30% of angina patients undergoing coronary arteriography. The prevalence of syndrome X is significantly higher in women compared to men. In the majority of patients with chest pain and normal coronary arteriograms, symptoms are likely to be non-cardiac in origin. However, myocardial ischaemia may be the pathogenic mechanism in a proportion of syndrome X patients. Indeed, the clinical characteristics, the ischaemic electrocardiographic findings and the presence of myocardial perfusion defects during stress testing are similar in syndrome X and coronary artery disease patients. Moreover, coronary sinus oxygen saturation abnormalities and pH changes, as well as myocardial lactate production and alterations of cardiac high energy phosphate are seen during stress testing in patients with syndrome X and appear to endorse an ischaemic origin of symptoms in at least a proportion of these individuals. Patients with chest pain and normal coronary arteries have abnormal vasodilatory coronary blood flow responses and an increased sensitivity of the coronary microcirculation to vasoconstrictor stimuli (microvascular angina). Microvascular endothelial dysfunction appears to be responsible for these coronary microcirculation abnormalities. Given the high prevalence of peri- and post-menopausal women in cardiac syndrome X, it has been hypothesized that oestrogen deficiency may play a major role in the pathogenesis of this condition. Oestrogen vasoactive properties involve endothelium-dependent effects and, in postmenopausal women, forearm vasodilatation induced by acetylcholine is potentiated by the acute local administration of intravenous oestradiol. This suggests that endothelium-dependent responses in the peripheral circulation may be modulated by steroid hormones. Impairment of endothelial function in post-menopausal women with syndrome X has been reported by various groups and it could be hypothesized that oestrogen deficiency may contribute to the development of microvascular angina through endothelial dysfunction and that exogenous oestrogen administration may have a beneficial effect in syndrome X patients. This article reviews current knowledge regarding the role of oestrogen deficiency in the pathogenesis of syndrome X and the potential therapeutic role of oestrogen replacement therapy in women with chest pain and normal coronary arteriograms

KEYWORDS Coronary disease; Gender; Hormones; Microcirculation


   1. Introduction
Top
 Abstract
 1. Introduction
2. Myocardial ischaemia in...
 3. Oestrogen therapy for...
 4. Arguments against myocardial...
 5. Summary
 References
 
Cardiac syndrome X is a heterogeneous condition that encompasses a variety of pathogenic mechanisms. The diagnosis of cardiac syndrome X is based on the presence of typical exercise-induced angina pectoris, transient ischaemic ST-segment depression (>1 mm) (ECG) during exercise, or at rest, and angiographically normal coronary arteries. Patients with coronary artery spasm, systemic hypertension, left ventricular hypertrophy and valve heart disease, are usually excluded from the diagnosis of syndrome X. Characteristically, cardiac syndrome X is more common in women than in men and the observation that women with syndrome X are often menopausal and suffer from symptoms of ovarian insufficiency is intriguing. It has been postulated that oestrogen deficiency may play a pathogenic role in syndrome X and that the exogenous administration of oestrogen may have therapeutic implications in women with cardiac syndrome X. This article reviews the clinical characteristics of syndrome X — a term first used by Kemp in 1973 [1] to define a condition characterised by typical anginal chest pain and ECG changes suggestive of myocardial ischaemia despite the presence of angiographically normal coronary arteries. This review also addresses the potential pathogenic, and therapeutic, role of oestrogen in women with angina-like chest pain and normal coronary arteriograms.

1.1. Clinical characteristics of patients with syndrome X — female prevalence
Normal or nearly normal (minor irregularities <20% lumen diameter reduction) coronary arteries are found in approximately 20% of patients who undergo coronary arteriography for the assessment of angina pectoris [2]. Many of these patients have valve heart disease, left ventricular hypertrophy, uncontrolled hypertension, coronary artery spasm or other non-cardiac mechanisms, which provide a reasonable explanation for their symptoms. In approximately 30% of patients, however, there is no identifiable cause, whether cardiac or non-cardiac, for their chest pains and ECG abnormalities. Given the typical features of the chest pain and the ST segment changes observed in ‘syndrome X’ patients, the search for myocardial ischaemia is an unavoidable mission for the treating physician. Interestingly, the majority of these patients — approximately 70% — are peri- or post-menopausal women [3–10]. Chest pain in patients with syndrome X occurs on exertion but may develop also at rest. Despite the typical features of chest pain in most syndrome X patients, atypical features such as a prolonged duration and a lack of response to the administration of sublingual nitrate are also commonly seen in syndrome X patients. Prognosis in syndrome X is good despite the ischaemic pain and the typical ST segment shifts. However, quality of life is poor in a large proportion of patients, particularly in those with frequent, prolonged and severe anginal episodes. Understandably, these patients fail to be reassured by the finding of a normal coronary arteriogram and a thorough characterisation of the mechanisms responsible for their symptoms is required.

A few years ago we reported the clinical and gynaecological features of women with syndrome X — defined as typical exertional angina pectoris, positive exercise-ECG test responses and completely normal coronary arteriograms [11]. Musculo-skeletal and oesophageal causes of chest pain, as well as coronary artery spasm were excluded. Briefly, 107 women from a cohort of 134 patients with syndrome X were assessed from the clinical and gynaecological points of view. Clinical presentation, risk factors of coronary artery disease and ECG findings were recorded, together with the menstrual history, onset of menopause (natural or surgical), type of menopausal symptoms and type and dosage of hormone replacement therapy. Eight women were on hormone replacement therapy at study entry but all had evidence of inadequate dosing as assessed by plasma oestradiol and FSH levels. Over 30% of patients (n=37) had symptoms of vasomotor instability such as hot flushes, and 20% had migraine. Interestingly, these symptoms were commonly associated with chest pain episodes suggestive of myocardial ischaemia. Moreover, in 43 of the 45 patients whose menopause was surgical in origin, ischaemia-like chest pain appeared to parallel the development of oestrogen deficiency. In the younger women chest pain started approximately 3 years after hysterectomy. These findings suggest that oestrogen deficiency may be associated with chest pain in women with syndrome X.


   2. Myocardial ischaemia in women with syndrome X — the role of oestrogen deficiency
Top
 Abstract
 1. Introduction
 2. Myocardial ischaemia in...
3. Oestrogen therapy for...
 4. Arguments against myocardial...
 5. Summary
 References
 
Since the original description of the syndrome of angina and normal coronary arteriograms over 30 years ago [3], the search to establish an ischaemic origin of this condition has never ceased.

Syndrome X patients have typical angina-like chest pain, transient ischaemic ST segment changes during effort and, often, abnormal myocardial perfusion stress tests. These are findings similar to those seen in patients with coronary artery disease (CAD) [8]. Studies have also shown that patients with syndrome X have ventricular dysfunction during stress testing, as assessed by radionuclide techniques [12,13]. In a small study by Crake et al. [14], patients with typical exertional chest pain despite normal coronary arteries were shown to have a reduced oxygen saturation of the coronary sinus blood during chest pain thus suggesting the presence of abnormal myocardial perfusion. Moreover, myocardial lactate production, an objective metabolic marker of myocardial ischaemia, has been shown to occur during stress testing in patients with cardiac syndrome X [15]. In a recent study from our group [16], three out of 11 (27%) syndrome X patients showed changes in coronary sinus pH during episodes of stress-induced chest pain, a finding compatible with myocardial ischaemia. Of importance, the pH changes observed in these patients were indistinguishable from those seen in a subgroup of patients with documented CAD who also took part in the study [16]. A finding in this study, which may contradict the suggestion that pH changes represented myocardial ischaemia, is that lactate production was not observed in these patients. However, whilst the finding of lactate production is confirmatory of ischaemia, failure in documenting its presence during chest pain does not necessarily deny the occurrence of ischaemia, particularly in the presence of pH changes and a drop in coronary sinus oxygen saturation. Techniques used for the assessment of myocardial lactate production are not without limitations. Our data are consistent with previous reports, which suggest that myocardial ischaemia may be the mechanism responsible for chest pain in approximately 20–25% of syndrome X patients [8]. These observations, albeit based on small numbers of patients and sometimes, heterogeneous patient groups, have been further endorsed by a recent report by Buchthal et al. [17]. Using nuclear magnetic resonance (NMR) techniques, they demonstrated transient myocardial ischaemia in seven of 35 (20%) syndrome X women. These authors compared findings in women with chest pain and normal coronary arteries, age- and weight-matched control women and patients with CAD. Myocardial high-energy phosphates were measured using 31P-NMR spectroscopy before, during and after handgrip stress testing and the ratio of phosphocreatine to ATP was considered to represent a sensitive and objective marker of myocardial ischaemia. During handgrip, seven of the 35 women (20%) with syndrome X had decreases in the phosphocreatine to ATP ratio thus documenting the presence of myocardial ischaemia [17].

2.1. Pathogenesis of myocardial ischaemia in cardiac syndrome X
It is established that a large proportion of patients with chest pain and normal coronary arteries have both abnormal vasodilatory coronary blood flow responses and increased sensitivity of the coronary microcirculation to vasoconstrictor stimuli (‘microvascular angina’). These findings led Cannon and Epstein [10] to suggest that ‘microvascular angina’ was a common pathogenic mechanism of syndrome X. The presence of microvascular angina has been confirmed by several studies, which showed that syndrome X patients have a reduced coronary flow reserve in response to atrial pacing and the administration of dipyridamole [10,18,19]. The precise reason for this abnormality is not known; however, endothelial dysfunction may play a role. Microvascular endothelial dysfunction has been shown to be responsible for at least some of the abnormalities detected in the coronary circulation of cardiac syndrome X patients [18]. The endothelium produces diverse vasoactive substances (i.e. the potent endogenous vasodilator nitric oxide and constrictor substances such as endothelin) and the balanced opposition of these substances determines the so-called vascular tone. Endothelins (ET) are a family of potent vasoconstrictor peptides that includes ET-1, ET-2 and ET-3. ET-1 is synthesised by endothelial cells and is mainly released towards the abluminal side of the vessels, causing smooth muscle cell vasoconstriction. Endothelin plays an important role in the regulation of vascular tone and we have hypothesised that this peptide may, at least in part, be responsible for coronary flow abnormalities in microvascular angina [20]. This hypothesis is substantiated by the findings of Kaski et al. [21] who showed that plasma levels of ET-1 are significantly raised in patients with chest pain and normal coronary arteries, compared to normal controls. More recently, Cox et al. [22] observed a significant relationship between baseline ET-1 levels and abnormal coronary vascular responses in patients with syndrome X. The latter studies have further endorsed the hypothesis that endothelial dysfunction may be at least one of the possibly several mechanisms leading to microvascular angina in patients with syndrome X. Endothelial dysfunction in syndrome X is likely to be multifactorial. Cardiac risk factors present in patients with syndrome X, such as hypertension, hypercholesterolaemia and smoking can contribute to the development of endothelial dysfunction. Relevant to the subject of this article, oestrogen deficiency is a recognized cause of endothelial dysfunction. Indeed, the menopause is a major milestone in women and studies in healthy women have shown a significant change in endothelial function at the time of the menopause [23]. As mentioned before in this article, most of the women with syndrome X are post-menopausal and it has been also shown that estradiol-17β deficiency is associated with vasomotor instability and decreased arterial blood flow velocity in humans [24,25]. The administration of exogenous oestradiol increases peripheral blood flow in otherwise normal postmenopausal women [26]. Furthermore, studies have shown that the acute administration of oestradiol-17β improves endothelial function in menopausal women with syndrome X [27]. In relation to the observation that abnormal ET-1 levels correlate with microvascular angina in menopausal women with syndrome X, it is interesting that Webb et al. [28] have shown that short-term oestradiol administration decreases coronary ET-1 levels in postmenopausal women with coronary artery disease. Of interest however, no changes in vasomotor function were observed in this study [28], despite reduced ET-1 levels. It has been also reported that myocardial ischaemia is reduced by oestrogen administration in women with coronary artery disease [29–31].


   3. Oestrogen therapy for cardiac syndrome X
Top
 Abstract
 1. Introduction
 2. Myocardial ischaemia in...
 3. Oestrogen therapy for...
4. Arguments against myocardial...
 5. Summary
 References
 
Given the observed association between oestrogen deficiency and microvascular dysfunction [32], the possibility that acute [27] and chronic [33] administration of oestrogen may be helpful in the treatment of syndrome X has also been entertained. Rosano et al. [33] studied 25 postmenopausal patients with syndrome X who completed a double-blind placebo controlled study of the effect of oestradiol-17β cutaneous patches (100 µg/24 h) on the frequency of chest pain and on exercise tolerance. Patients were randomized to receive either placebo or oestradiol-17β patches for 8 weeks, after which they crossed over to the other treatment. During the placebo phase, patients had a mean of 7.3 episodes of chest pain/10 days. A reduction of 3.6 episodes/10 days was observed during the oestradiol-17β phase (P<0.05). No significant differences between oestradiol-17β and placebo were observed in exercise duration. The observation in this study that a significant reduction in the frequency of chest pain was obtained in oestrogen-deficient women with syndrome X when treated with oestradiol-17β, supports the hypothesis that oestrogen deficiency may have a role in the pathogenesis of syndrome X [33]. The dissociation of effects on chest pain compared with exercise tolerance and ST segment changes may indicate that syndrome X is likely to be heterogeneous with multiple pathogenic mechanisms. It may therefore be speculated that the chest pain in such patients may not be necessarily due to myocardial ischaemia.

In a study by Albertsson et al. [34] of 15 postmenopausal women (mean age 58±6 years) with clinical syndrome X it was shown that a 24-h treatment with 100 µg 17β-oestradiol patch improved exercise time to angina, time to 1 mm ST-segment depression and total exercise time. The discrepancies between these two studies [33,34] could be reconciled if one considers the possibility that in the latter [34] the majority of the patients did have true myocardial ischaemia as a cause of their chest pain, which was improved by oestradiol.

How can the beneficial effects of oestradiol be explained in the context of cardiac syndrome X? It is accepted that oestrogens have vasoactive properties [35–42]. Oestrogen deficiency is known to be associated with vasomotor instability [24,41,42] and oestrogen replacement therapy has been shown to restore the impaired vasodilator response in women with syndrome X [27,34]. Coronary vasodilatation by 17β-oestradiol may also relieve myocardial ischaemia in the subset of patients in whom this mechanism is responsible for the symptoms. Oestrogen vasoactive properties involve endothelium-dependent and endothelium-independent effects [43–46]. Both these effects may be relevant in syndrome X patients in whom coronary flow reserve may be altered by endothelium and non-endothelium dependent mechanisms [47]. Recently, Mendelsohn and Karas [48] reviewed the cardiovascular effects of oestrogen. Oestrogen receptors are expressed in the cardiovascular cells, which are targets for both endogenous and exogenous oestrogen. Among many other effects, oestrogen-oestrogen receptor complexes modulate vasomotor tone [48]. Two major vascular responses have been observed in relation to oestrogen: (1) a rapid vasodilator effect, which occurs within minutes of estrogen stimulation and is independent of gene expression [48]; and (2) longer term effects on vessels, which are dependent on gene expression [48]. In postmenopausal women, forearm vasodilatation induced by acetylcholine is potentiated by the acute local administration of intravenous oestradiol [47], which suggests that endothelium-dependent responses in the peripheral circulation may be modulated by steroid hormones in these women. Impairment of endothelial function in syndrome X has been reported by various groups [18,27,47] and it is also common in post-menopausal women without chest pain [32]. It could therefore be hypothesized that oestrogen deficiency may contribute to the development of microvascular angina through endothelial dysfunction. Thus oestrogen replacement therapy may have beneficial effects on the cardiovascular system acting via both endothelium-dependent and -independent mechanisms [49]. The subject of oestrogen therapy for management of microvascular angina in patients with syndrome X is somehow linked to the controversial issue of CAD prevention using oestrogen preparations.

Although beyond the scope of this article, the question of whether oestrogen should be administered for primary and secondary prevention of ischaemic heart disease, is the subject of heated debate at present. Recent prospective secondary prevention studies have failed to demonstrate a beneficial effect of chronic oestrogen therapy in postmenopausal women with coronary heart disease. The Heart and Estrogen/Progestin Replacement Study (HERS) [50] showed that after an average follow-up of 4.1 years there was no significant difference in the incidence of cardiac events in women receiving hormonal therapy and those on placebo. A sub-analysis of HERS showed an increased incidence of events (52%) during the first 2 years of follow-up in women receiving hormonal treatment which was followed by an improvement in serious events thereafter. The Estrogen Replacement and Atherosclerosis Trial (ERA) [51] in postmenopausal women with CAD confirmed the HERS findings. The results of these studies are in sharp contrast with previous observational studies [52,53]. Whilst recommendations can be issued, based on prospective studies, regarding secondary prevention with oestrogens, data are not available to guide decisions regarding primary prevention [35]. In relation to the specific topic of this review, whether oestrogen administration will constitute effective therapy for syndrome X, as suggested by a few pilot studies, needs to be confirmed by larger trials. Understanding the molecular basis of the effects of oestrogen on the cardiovascular system may prove vital to plan rational therapeutic and preventative strategies using oestrogen replacement therapy. It has been postulated that oestrogens may have a pro-inflammatory action, as suggested by the observation that C-reactive protein (CRP) levels increase in response to oestrogen administration [54]. This notion has been used to explain some of the negative results of HERS. However, our group has recently suggested that oestrogen may induce CRP production by non-inflammatory mechanisms [55]. Moreover, current evidence regarding the effects of oestrogen on the inflammatory cascade points towards a prevailing anti-inflammatory effect [55]. Although the focus of this section has been on endothelial-dependent impairment of vascular tone and the role of oestrogen deficiency, it has been also shown that endothelium-independent coronary blood flow reserve may be altered in post-menopausal women [56,57] and this may be an important therapeutic target.


   4. Arguments against myocardial ischaemia in syndrome X — the role of abnormal pain perception in the pathogenesis of the syndrome
Top
 Abstract
 1. Introduction
 2. Myocardial ischaemia in...
 3. Oestrogen therapy for...
 4. Arguments against myocardial...
5. Summary
 References
 
Several investigators have questioned the existence of myocardial ischaemia in patients with cardiac syndrome X. Their arguments are mainly based on the fact that prognosis is good in these patients and that studies with stress echocardiography have consistently failed to show the presence of regional wall motion abnormalities during stress [58], even in patients with typical ischaemic ECG changes. It is certainly true, that the majority of syndrome X patients do not appear to have myocardial ischaemia. The presence of chest pain in these patients can be explained by an increased pain perception [4,59–62], psychological abnormalities [63], oesophageal dysmotility [64,65] and other mechanisms. Approximately 20–25% of syndrome X patients appear to have metabolic evidence of ischaemia. However, they have normal stress echocardiography responses. Whether stress echocardiography should be considered the gold standard for the assessment of myocardial ischaemia in patients with syndrome X is debatable. Ischaemia in these patients may be patchy, limited to the subendocardium and/or of a small magnitude and may, therefore, escape detection by echocardiography.

Oestrogen administration has been shown to improve chest pain in syndrome X patients, as shown by small studies [33,34]. There are a number of speculative mechanisms for the alleviation of chest pain by oestrogen, without invoking anti-ischaemic actions. These include relief of pre-arteriolar vasoconstriction and augmentation of adenosine-induced A2 receptor-mediated vasodilatation by a direct action on the vascular smooth muscle cells [62]. Adenosine is a known algogen, excessive release of which, or sensitivity to which, is suggested as being the painful stimulus in syndrome X, resulting in exaggerated cardiac sensitivity to non-ischemic stimuli [60,62]. The improvement in chest pain observed in clinical studies with 17β-oestradiol [33,34], in the absence of improvement in cardiac testing, might, therefore, result from attenuation of adenosine production or by altering the balance or sensitivity of adenosine receptors [59,60]. Heterogeneity of adenosine receptors or sensitivity may account for regional myocardial perfusion abnormalities [13,62]

The symptomatic benefits of 17β-oestradiol in women with syndrome X may involve analgesic properties of oestrogen. Recent animal data have shown female/male differences in pain sensitivity [66]. These differences were abolished by ovariectomy and re-established after oestrogen replacement therapy. These data suggest that oestrogen may have analgesic properties, which may in turn contribute to the results observed in this study. The results of recent studies by Cannon et al. [67] and by Cox et al. [68] suggest that imipramine, a tricyclic antidepressant agent known to have visceral analgesic properties, reduces chest pain without any objective changes on cardiovascular variables including the ECG response to stress testing. Psychosomatic symptoms and panic disorders [63] and a general reduction in pain threshold [4,69] have been found to be associated with chest pain and, possibly, the ST segment changes observed in patients with syndrome X [70]. Thus, the effects of 17β-oestradiol in menopausal patients with syndrome X may be multifactorial and may include vascular and non-vascular actions, which may improve quality of life in these patients.


   5. Summary
Top
 Abstract
 1. Introduction
 2. Myocardial ischaemia in...
 3. Oestrogen therapy for...
 4. Arguments against myocardial...
 5. Summary
References
 
Syndrome X occurs more commonly in postmenopausal women, who are oestrogen deficient. Oestrogen deficiency may be a trigger for the syndrome in susceptible women with endothelial dysfunction and/or abnormal pain perception. Oestrogen replacement therapy in some of these women may be useful for the prevention of chest pain. The mechanisms whereby oestrogen replacement appears to improve symptoms in patients with syndrome X are speculative. In view of the disappointing results of large secondary prevention studies using oestrogen replacement therapy, and given the fact that beneficial effects of oestrogen have been reported by very small studies of patients with syndrome X, we eagerly await the results of large, ongoing primary prevention trials. These will be instrumental in helping physicians to decide whether oestrogen therapy can be safely and successfully used in women with cardiac syndrome X. I therefore believe that until more definitive information is available, our use of hormone replacement therapy should be guided by the recently published recommendations of the American Heart Association [35].

Time for primary review 33 days.


   References
Top
 Abstract
 1. Introduction
 2. Myocardial ischaemia in...
 3. Oestrogen therapy for...
 4. Arguments against myocardial...
 5. Summary
 References
 

  1. Kemp H.G. Jr. Left ventricular function in patients with anginal syndrome and normal coronary arteriograms. Am J Cardiol (1973) 32:375–376.[CrossRef][ISI][Medline]
  2. Phibbs B., Fleming T., Ewy G.A., et al. Frequency of normal coronary arteriograms in three academic medical centers and one community hospital. Am J Cardiol (1988) 62:472–474.[CrossRef][ISI][Medline]
  3. Likoff W., Segal B.L., Kasparian H. Paradox of normal selective coronary arteriograms in patients considered to have unmistakable coronary heart disease. N Engl J Med (1967) 276:1063–1066.[ISI][Medline]
  4. Turiel M., Galassi A.R., Glazier J.J., Kaski J.C., Maseri A. Pain threshold and tolerance in women with syndrome X and women with stable angina pectoris. Am J Cardiol (1987) 60:503–507.[CrossRef][ISI][Medline]
  5. Galassi A.R., Kaski J.C., Crea F., et al. Heart rate response during exercise testing and ambulatory ECG monitoring in patients with syndrome X. Am Heart J (1991) 122:458–463.[CrossRef][ISI][Medline]
  6. Pupita G., Kaski J.C., Galassi A.R., Vejar M., Crea F., Maseri A. Long-term variability of angina pectoris and electrocardiographic signs of ischemia in syndrome X. Am J Cardiol (1989) 64:139–143.[CrossRef][ISI][Medline]
  7. Kaski J.C., Crea F., Nihoyannopoulos P., Hackett D., Maseri A. Transient myocardial ischemia during daily life in patients with syndrome X. Am J Cardiol (1986) 58:1242–1247.[CrossRef][ISI][Medline]
  8. Kaski J.C., Rosano G.M.C., Collins P., Nihoyannopoulos P., Maseri A., Poole-Wilson P.A. Cardiac syndrome X: clinical characteristics and left ventricular function. Long term follow-up study. J Am Coll Cardiol (1995) 25:807–814.[Abstract]
  9. Cannon R.O., Schenke W.H., Leon M.B., Rosing D.R., Urqhart J., Epstein S.E. Limited coronary flow reserve after dipyridamole in patients with ergonovine-induced coronary vasoconstriction. Circulation (1987) 75:163–174.[Abstract/Free Full Text]
  10. Cannon R.O., Epstein S.E. ‘Microvascular angina’ as a cause of chest pain with angiographically normal coronary arteries. Am J Cardiol (1988) 61:1338–1343.[CrossRef][ISI][Medline]
  11. Rosano G.M.C., Collins P., Kaski J.C., Lindsay D.C., Sarrel P.M., Poole-Wilson P.A. Syndrome X in women is associated with oestrogen deficiency. Eur Heart J (1995) 16:610–614.[Abstract/Free Full Text]
  12. Cannon R.O. III, Bonow R.O., Bacharach S.L., et al. Left ventricular dysfunction in patients with angina pectoris, normal epicardial coronary arteries, and abnormal vasodilator reserve. Circulation (1985) 71:218–226.[Abstract/Free Full Text]
  13. Yoshio H., Shimizu M., Kita Y., Ino H., Taki J., Takeda R. Left ventricular functional reserve in patients with syndrome X: evaluation by continuous ventricular function monitoring. J Am Coll Cardiol (1993) 22:1465–1469.[Abstract]
  14. Crake T., Canepa-Anson R., Shapiro L., Poole-Wilson P.A. Continuous reading of coronary sinus oxygen saturation during atrial pacing in patients with coronary artery disease or syndrome X. Br Heart J (1988) 59:31–38.[Abstract/Free Full Text]
  15. Hutchison S.J., Poole-Wilson P.A., Henderson A.H. Angina with normal coronary arteries: A review. Q J Med (1989) 72:677–688.[ISI][Medline]
  16. Rosano G.M., Kaski J.C., Arie S., et al. Failure to demonstrate myocardial ischaemia in patients with angina and normal coronary arteries. Evaluation by continuous coronary sinus pH monitoring and lactate metabolism. Eur Heart J (1996) 17:1175–1180.[Abstract/Free Full Text]
  17. Buchthal S.D., denHollander J.A., Merz C.N., et al. Abnormal myocardial phosphorus-31 nuclear magnetic resonance spectroscopy in women with chest pain but normal coronary angiograms. N Engl J Med (2000) 23(342):829–835.
  18. Egashira K., Inoue T., Hirooka Y., Yamada A., Urabe Y., Takeshita A. Evidence of impaired endothelium-dependent coronary vasodilatation in patients with angina pectoris and normal coronary angiograms. N Engl J Med (1993) 328:1659–1664.[Abstract/Free Full Text]
  19. Opherk D., Zebe H., Weihe E., et al. Reduced coronary dilatory capacity and ultrastructural changes of the myocardium in patients with angina pectoris but normal coronary arteriograms. Circulation (1981) 63:817–825.[Abstract/Free Full Text]
  20. Kaski J.C., Elliott P.M., Salomone O., et al. Concentration of circulating plasma endothelin in patients with angina and normal coronary angiograms. Br Heart J (1995) 74:620–624.[Abstract/Free Full Text]
  21. Kaski J.C., Cox I.D., Crook J.R., et al. Differential plasma endothelin levels in subgroups of patients with angina and angiographically normal coronary arteries. Am Heart J (1998) 136(3):412–417.[CrossRef][ISI][Medline]
  22. Cox I.D., Botker H.E., Bagger J.P., Sonne H.S., Kristensen B.O., Kaski J.C. Elevated endothelin concentrations are associated with reduced coronary vasomotor responses in patients with chest pain and normal coronary arteriograms. J Am Coll Cardiol (1999) 34:455–460.[Abstract/Free Full Text]
  23. Hayward C.S., Kelly R.P., Collins P. The roles of gender, the menopause and hormone replacement on cardiovascular function. Cardiovasc Res (2000) 46:28–49.[Free Full Text]
  24. Kronenberg F., Cote L.J., Linkie D.M., Dyrenfurth I., Downey J.A. Menopausal hot flushes: thermoregulatory, cardiovascular and circulating catecholamine and LH changes. Maturitas (1984) 6:31–43.[CrossRef][ISI][Medline]
  25. Ginsburg J., Hardiman P. The circulation in the female. Ginsburg J., ed. (1989) Lancashire, UK: Carnforth. 99–115.
  26. Volterrani M., Rosano G.M.C., Coats A., Beale C., Collins P. Oestrogen acutely increases peripheral blood flow in postmenopausal women. Am J Med (1995) 99:119–122.[CrossRef][ISI][Medline]
  27. Roque M., Heras M., Roig E., et al. Short-term effects of transdermal oestrogen replacement therapy on coronary vascular reactivity in postmenopausal women with angina pectoris and normal results on coronary angiograms. J Am Coll Cardiol (1998) 31:139–143.[Abstract/Free Full Text]
  28. Webb C.M., Ghatei M.A., McNeill J.G., Collins P. 17 beta-estradiol decreases endothelin-1 levels in the coronary circulation of postmenopausal women with coronary artery disease. Circulation (2000) 102:1617–1622.[Abstract/Free Full Text]
  29. Alpasian M., Shimokawa H., Kuroiwa-Matsumoto M., Harasawa Y., Takeshita A. Short-term oestrogen administration ameliorates dobutamine-induced myocardial ischemia in postmenopausal women with coronary artery disease. J Am Coll Cardiol (1997) 30:1466–1471.[Abstract]
  30. Webb C.M., Rosano G.M.C., Collins P. Oestrogen improves exercise-induced myocardial ischaemia in women. Lancet (1998) 351:1556–1557.[CrossRef][ISI][Medline]
  31. Rosano G.M.C., Sarrel P.M., Poole-Wilson P.A., Collins P. Beneficial effect of oestrogen on exercise-induced myocardial ischaemia in women with coronary artery disease. Lancet (1993) 342:133–136.[CrossRef][ISI][Medline]
  32. Lieberman E.H., Gerhard M.D., Uehata A., et al. Oestrogen improves endothelium-dependent, flow-mediated vasodilation in postmenopausal women. Ann Intern Med (1994) 12:936–941.
  33. Rosano G.M.C., Peters N.S., Lefroy D.C., et al. 17-beta-estradiol therapy lessens angina in postmenopausal women with syndrome X. J Am Coll Cardiol (1996) 28:1500–1505.[Abstract]
  34. Albertsson P.A., Emanuelsson H., Milsom I. Beneficial effect of treatment with transdermal estradiol-17-beta on exercise-induced angina and ST segment depression in syndrome X. Int J Cardiol (1996) 54:13–20.[CrossRef][ISI][Medline]
  35. Mosca L., Collins P., Herrington M.D., et al. Hormone replacement therapy and cardiovascular disease. A statement for Healthcare Professional from the American Heart Association. Circulation (2001) 104:499–503.[Free Full Text]
  36. Mugge A., Riedel M., Barton M., Kuhn M., Lichten P.R. Endothelium independent relaxation of human coronary arteries by 17beta-estradiol in vitro. Cardiovasc Res (1993) 27:1939–1942.[Abstract/Free Full Text]
  37. Sarrel P.M., Lindsay D.C., Rosano G.M.C., Poole-Wilson P.A. Angina and normal coronary arteries in women. Gynecologic findings. Am J Obstet Gynecol (1992) 167:467–471.[ISI][Medline]
  38. Jiang C., Sarrel P.M., Lindsay D.C., Poole-Wilson P.A., Collins P. Endothelium-independent relaxation of rabbit coronary artery by 17β-estradiol in vitro. Br J Pharmacol (1991) 104:1033–1037.[ISI][Medline]
  39. Gilligan D.M., Quyyumi A.A., Cannon R.O. III. Effects of physiological levels of oestrogen on coronary vasomotor function in postmenopausal women. Circulation (1994) 89:2545–2551.[Abstract/Free Full Text]
  40. Reis S.E., Gloth S.T., Blumenthal R.S., Resar J.R., Zacur H.A., Gerstenblith G., Brinker J.A. Ethinyl estradiol acutely attenuates abnormal coronary vasomotor responses to acetylcholine in postmenopausal women. Circulation (1994) 89:52–60.[Abstract/Free Full Text]
  41. Williams J.K., Adams M.R., Herrington D.M., Clarkson T.B. Short-term administration of oestrogen and vascular responses of atherosclerotic coronary arteries. J Am Coll Cardiol (1992) 20:452–457.[Abstract]
  42. Magness R.R., Rosenfeld C.R. Local and systemic estradiol-17 beta: effects on uterine and systemic vasodilation. Am J Physiol (1989) 256:E536–E542.[ISI][Medline]
  43. Gilligan D.M., Badar D.M., Panza J.A., Quyyumi A.A., Cannon R.O. III. Acute vascular effects of oestrogen in postmenopausal women. Circulation (1994) 90:787–791.
  44. Collins P. Angina pectoris with normal coronary arteries: Syndrome X. Kaski J.C., ed. (1994) Norwell, Massachusetts: Kluwer. 237–247.
  45. Chester A.H., Jiang C., Borland J.A., Yacoub M.H., Collins P. Oestrogen relaxes human epicardial coronary arteries through non-endothelium-dependent mechanisms. Cor Art Dis (1995) 6:417–422.
  46. Collins P., Rosano G.M.C., Sarrel P.M., et al. Estradiol-17β attenuates acetylcholine-induced coronary arterial constriction in women but not men with coronary heart disease. Circulation (1995) 92:24–30.[Abstract/Free Full Text]
  47. Bottcher M., Botker H.E., Sonne H., Nielsen T.T., Czernin J. Endothelium-dependent and -independent perfusion reserve and the effect of L-arginine on myocardial perfusion in patients with syndrome X. Circulation (1999) 99:1795–1801.[Abstract/Free Full Text]
  48. Mendelsohn M.E., Karas R.H. The protective effects of estrogen on the cardiovascular system. N Engl J Med (1999) 340:1801–1811.[Free Full Text]
  49. Collins P., Rosano G.M.C., Jiang C., Lindsay D., Sarrel P.M., Poole-Wilson P.A. Hypothesis: Cardiovascular protection by oestrogen-a calcium antagonist effect? Lancet (1993) 341:1264–1265.[CrossRef][ISI][Medline]
  50. Hulley S., Grady D., Bush T., et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary artery disease in post-menopausal women: Heart and Estrogen/Progestin Replacement Study (HERS) Research Group. J Am Med Assoc (1998) 280:605–613.[Abstract/Free Full Text]
  51. Herrington D.M., Reboussin D.M., Brosniham K.B., et al. Effects of estrogen replacement on the progression of coronary artery atherosclerosis. N Engl J Med (2000) 343:522–529.[Abstract/Free Full Text]
  52. Mosca L. The role of hormone replacement therapy in the prevention of postmenopausal heart disease. Arch Intern Med (2000) 160:2263–2272.[Abstract/Free Full Text]
  53. Pettiti D.B. Hormone replacement therapy and heart disease prevention: experimentation trumps observation. J Am Med Assoc (1998) 280:650–652.[Free Full Text]
  54. Cushman M., Lagault C., Barrett-Connor E., et al. Effects of postmenopausal hormones on inflammation-sensitive proteins: the Post Menopausal Estrogen/Progestin Interventions (PEPI) Study. Circulation (1999) 100:717–722.[Abstract/Free Full Text]
  55. Garcia-Moll X., Zouridakis E., Cole D., Kaski J.C. C-reactive protein in patients with chronic stable angina: differences in baseline serum concentration between women and men. Eur Heart J (2000) 21:1598–1606.[Abstract/Free Full Text]
  56. Reis S.E., Holubkov R., Lee J.S., et al. Coronary flow velocity response to adenosine characterizes coronary microvascular function in women with chest pain and no obstructive coronary disease. Results from the pilot phase of the Women's Ischemia Syndrome Evaluation (WISE) study. J Am Coll Cardiol (1999) 33:1469–1475.[Abstract/Free Full Text]
  57. Schachinger V., Britten M.B., Elsner M., Walter D.H., Scharrer I., Zeiher A.M. A positive family history of premature coronary artery disease is associated with impaired endothelium-dependent coronary blood flow regulation. Circulation (1999) 100:1502–1508.[Abstract/Free Full Text]
  58. Panza J.A., Laurienzo J.M., Curiel R.V., et al. Investigation of the mechanism of chest pain in patients with angiographically normal coronary arteries using transesophageal dobutamine stress echocardiography. J Am Coll Cardiol (1997) 29:293–301.[Abstract]
  59. Cannon R.O. III, Quyyumi A.A., Schenke W.H., et al. Abnormal cardiac sensitivity in patients with chest pain and normal coronary arteries. J Am Coll Cardiol (1990) 16:1359–1366.[Abstract]
  60. Lagerqvist B., Sylven C., Waldenström A. Lower threshold for adenosine-induced chest pain in patients with angina and normal coronary arteriograms. Br Heart J (1992) 68:282–285.[Abstract/Free Full Text]
  61. Shapiro L.M., Crake T., Poole-Wilson P.A. Is altered cardiac sensation responsible for chest pain in patients with normal coronary arteries? Clinical observation during cardiac catheterisation. Br Med J (1988) 296:170–171.[ISI][Medline]
  62. Rosano G.M.C., Lindsay D.C., Poole-Wilson P.A. Syndrome X: a hypothesis for cardiac pain without ischaemia. Cardiologia (1991) 36:885–895.[Medline]
  63. Bass C., Chambers J.B., Kiff P., et al. Panic anxiety and hyperventilation in patients with chest pain: a controlled study. Q J Med (1988) 260:949–959.
  64. Dart A.M., Davies H.A., Dalal J., Ruttley M., Henderson A.H. ‘Angina’ and normal coronary arteriograms: a follow-up study. Eur Heart J (1980) 1:97–100.[Abstract/Free Full Text]
  65. De Caestecker J.S. Chest pain with normal coronary angiograms. Kaski J.C., ed. (1999) 1st ed. Massachusetts: Kluwer Publishers. 33–47.
  66. Mogil J.S., Sternberg W.F., Kest B., Marek P., Liebeskind J.C. Sex differences in the antagonism of stress-induced analgesia: effects of gonadectomy and oestrogen replacement. Pain (1993) 53:17–25.[CrossRef][ISI][Medline]
  67. Cannon R.O. III, Quyyumi A.A., Mincemoyer R., et al. Imipramine in patients with chest pain despite normal coronary angiograms. N Engl J Med (1994) 330:1411–1417.[Abstract/Free Full Text]
  68. Cox I.D., Hann M., Kaski J.C. Low dose imipramine improves chest pain but not quality of life in patients with angina and normal coronary angiograms. Eur Heart J (1998) 19:250–254.[Abstract/Free Full Text]
  69. Maseri A., Crea F., Kaski J.C., Crake T. Mechanisms of angina pectoris in syndrome X. J Am Coll Cardiol (1991) 17(2):499–506.[ISI][Medline]
  70. Botker H.E., Sonne H.S., Frobert O., Andreasen F. Enhanced exercise-induced hyperkalemia in patients with syndrome X. J Am Coll Cardiol (1999) 33:1056–1061.[Abstract/Free Full Text]

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