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Cardiovascular Research 2001 52(2):174-177; doi:10.1016/S0008-6363(01)00457-6
© 2001 by European Society of Cardiology
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Copyright © 2001, European Society of Cardiology

The pathophysiology of cardiac syndrome X — a tale of paradigm shifts

Stuart D Rosen*

Department of Heart Function, National Heart and Lung Institute, Imperial College School of Science, Technology and Medicine, London, UK

* Correspondence address: Department of Cardiology, Ealing Hospital, Uxbridge Road, Middlesex UB1 3HW, UK. Tel.: +44-20-8967-5359; fax: +44-20-8967-5007 stuart.rosen{at}ic.ac.uk

Received 24 August 2001; accepted 30 August 2001

See article by Gulli et al. [18] (pages 208–216) in this issue.


   1. Introduction
Top
 1. Introduction
2. The sympathetic nervous...
 3. Studies of heart...
 4. Pain perception and...
 5. Conclusion
 References
 
The aetiology of cardiac syndrome X — the problem of the patient with chest pain of anginal quality, ischaemic-like changes on the stress electrocardiogram (ECG) but a normal coronary arteriogram — continues to fascinate many engaged in cardiovascular research. It is a field of endeavour which has gone through a number of ‘paradigm shifts’ during the 28 years since the term was coined by Harvey Kemp [1], commenting on the ‘Group X’ subset of patients in Arbogast and Bourassa’s seminal paper on patients with angina and ‘normal or near normal’ coronary angiograms [2].

The first and most obvious mechanism of chest pain to be indicated was that of true myocardial ischaemia, but since the epicardial vessels were normal by definition, the microcirculation seemed the likely site of impairment of flow (or flow reserve) [3]. In recent years, newer methods of measurement of myocardial blood flow, especially non-invasive techniques that have permitted comparison with true normal controls, have done much to undermine this notion [4]. This is because in the vast majority of syndrome X patients, coronary vasodilator reserve is within the normal range and besides this, no relationships have been demonstrable amongst coronary vasodilator reserve, pain perception and ECG changes [5]. In addition, the preservation of left ventricular function and the absence of unequivocal evidence of lactate release during stress, call into question whether ischaemia as it is usually understood has very much pathophysiological relevance [6–9]. It is should be acknowledged with admiration that in Arbogast and Bourassa’s original paper [2], almost all of these points are made explicitly. (Furthermore, in this author’s opinion, the position has not been altered to any significant extent by more recent explorations of other mediators of vascular tone such as oestrogen, endothelin or nitrous oxide.)


   2. The sympathetic nervous system and the aetiology of cardiac syndrome X
Top
 1. Introduction
 2. The sympathetic nervous...
3. Studies of heart...
 4. Pain perception and...
 5. Conclusion
 References
 
Not long after the ‘ischaemia paradigm’, the hypothesis was formulated that abnormal neural regulation of the heart was an important aetiological factor in cardiac syndrome X. In particular, it was suggested by several workers that enhanced sympathetic system activity might account for many of the clinical features of the disorder [2,8,10–12]. A practical problem is that there is no simple ‘gold standard’ by which to assess sympathetic activity and so the evidence considered suggestive of enhanced sympathetic system activation in syndrome X is varied. From the point of view of global cardiovascular function, hyperdynamic heart rate and blood pressure responses to exercise have been noted in syndrome X patients [2,8,10,11]. The exercise-induced curtailment of diastolic time (abnormally short diastolic time as a percentage of the cardiac cycle) noted by Spinelli and colleagues [12] is also consistent with this. In addition, a number of the metabolic responses to pacing stress in these patients (net production of pyruvate in the face of lactate extraction and reduced carbohydrate oxidation with a greater uptake and oxidation of lipids) have been shown to differ from normal and are consistent with a heightened sympathetic drive [8].

One potential effect of interest of such putative sympathetic activation would be coronary vasoconstriction, epicardial or microvascular. However, Galassi et al. showed that prazosin had no impact on exercise duration, rate-pressure product at 1 mm ST segment depression during exercise or the number of episodes of ST segment depression on ambulatory ECG monitoring [11]. Our own study of {alpha}1 blockade in syndrome X patients found that doxazosin made no difference to coronary vasodilator reserve [13]. Similarly, cold pressor stimulation (which can induce reflex {alpha}1 mediated vasoconstriction of the coronary microcirculation [14]) has been shown to have a similar effect in syndrome X patients and in normal controls [15].

In a recent study, Lanza et al. have reported a substantial reduction in regional and global cardiac uptake of meta-iodobenzylguanidine (MIBG), suggesting abnormal cardiac adrenergic nerve function in the majority of the syndrome X patients in their series of 12 patients [16]. In contrast, in an earlier study, using positron emission tomography (PET) with [11C]CGP-12177, a hydrophilic tracer with high affinity for membrane-bound β adrenoceptors [17] we found no difference in myocardial β-adrenoceptor density or in plasma catecholamines between syndrome X patients and matched normal controls, from which we inferred that myocardial tissue catecholamines were normal.

Despite all the foregoing studies of sympathetic activity in cardiac syndrome X, the most widely used tool in practice today for assessment of the sympathetic system is that of analysis of heart rate variability. We now turn to its application to this patient group.


   3. Studies of heart rate variability in cardiac syndrome X
Top
 1. Introduction
 2. The sympathetic nervous...
 3. Studies of heart...
4. Pain perception and...
 5. Conclusion
 References
 
In the present edition of Cardiovascular Research, Gulli et al. [18] have added a further piece to the jigsaw puzzle in the form of novel and significant data pointing to a role for parasympathetic impairment rather than an enhancement of sympathetic activity having an important role in the aetiology of cardiac syndrome X. Their patient group underwent heart rate variability (HRV) studies in the time and frequency domains, as well as spectral analysis of finger arterial pressure (SAP) and bedside autonomic function tests. The majority of syndrome X patients showed an absence of the low frequency (LF) and high frequency (HF) power spectral component responses to orthostatic challenge, despite the SAP analysis being effectively normal. A vagal impairment was found in several of that majority group of syndrome X patients who had absent HRV responses to orthostatic challenge.

Their findings should be considered in the light of a number of earlier studies. Historically, the first of these published was Rosano’s 1994 paper [19], which also contains heart rate variability data from a substantial population of syndrome X patients. In it, they observed that the standard deviation of RR intervals was lower in their patients and as a result, the absolute power of the spectral components was reduced in the patient group, although there was no difference in the circadian pattern of these quantities between the syndrome X patients and controls.

Meeder et al. [20] measured time domain parameters of HRV [mean NN, SD-NN, SDANN (S.D. of 5-min mean RR intervals), mean of all 5-min S.D.-values of RR intervals, pNN50, rmsRR] and their relationship with myocardial blood flow measured by positron emission tomography and 13NH3. In contrast with other studies, there were no differences between the syndrome X patients and normal controls with respect to the HRV parameters. There were however, some relationships between the latter and the coefficient of variation (S.D./mean) of myocardial perfusion.

A comparison of patients with positive versus negative stress ECGs, all of whom had angina and normal coronary arteriograms, was performed by Frobert et al. in 1995 [21]. Mean RR, the awake–asleep difference of mean RR, standard deviation (S.D.) and percentage of successive RR>6% (pNN6%) were measured. Intriguingly, whilst the patients with a negative exercise test showed shorter mean RR and reduced 24-h S.D. and a tendency to a lower awake–asleep difference of mean RR than normal controls, there were no differences in any of these parameters between the patients with a positive exercise ECG and the normal controls.

Our own group, using an autoregressive method akin to that of Gulli et al., also described autonomic dysregulation in syndrome X patients on the basis of power spectral analysis of the ECG [22]. Of relevance to Gulli et al.’s work, we also showed that overall in the 24-h period, mean RR, total RR variance and power of the LF and HF components were not significantly different between patients and controls, but there was a blunting of the normal modification of the spectral indices of sympathetic and parasympathetic modulation during the day–night cycle and in response to orthostatic challenge. We did not observe a greater LF and a reduced HF component in patients compared to controls, which would have indicated a shift of sympatho-vagal balance towards a stable sympathetic predominance. However, there was a lack of response of LF and HF to the stimulus of standing, a manoeuvre that increases activation of the sympathetic nervous system in normal subjects.

Ponikowski and colleagues at the Royal Brompton Hospital explored the relationship between the low and high frequency spectral components occurring within 30 min of episodes of transient ST segment depression on the ambulatory ECG [23]. When the episodes of ST segment depression were associated with an increase in heart rate, there was a prior reduction in HF spectral component and increase in the LF/HF ratio, although no change in absolute LF. There were no changes in the HRV parameters preceding the episodes of ST depression that were not accompanied by a heart rate increase. This study was an important one in drawing attention to the issue of parasympathetic withdrawal as a feature of the autonomic dysregulation in syndrome X. Similar findings were reported by Lee et al. 2 years later [24].

Autonomic regulation was explored further — to incorporate baroreflex sensitivity data as well as HRV parameters — by the Brompton group in 1998 [25]. Using the relationship between phenylephrine-induced increases in systolic blood pressure and changes in RR interval, it was found that compared to normal controls, baroreceptor sensitivity was reduced in syndrome X patients, associated with a reduction in pNN50, root mean square of adjacent RRs (rmsRR) and HF. The syndrome X patients’ results for these also tended to be lower than those in patients with angina caused by coronary artery disease.

Lanza et al. have recently related their report of reduced cardiac MIBG uptake in syndrome X with a reduction in rmsRR and HF [26].

A unique feature of Gulli et al.’s paper, however, is the systematic study of bedside clinical parameters of autonomic function in syndrome X patients and the relationship between those data and the HRV results. Without doubt, the renewed attention to the role of the parasympathetic system is welcome, because it might help explain a number of anomalies. For example, although the observation that the corrected QT interval (QTc) is prolonged in syndrome X patients has been interpreted as a marker of altered sympathovagal balance [27,28], the nature of the alteration discernible from the QTc data is unclear; it may represent sympathetic overactivity, parasympathetic withdrawal or both.

Gulli et al.’s findings also contribute to a conceptual bridge, one which relates study of the heart in patients with syndrome X to the one consistent observation in this patient group, namely abnormal pain perception.


   4. Pain perception and sympathetic activation in patients with syndrome X
Top
 1. Introduction
 2. The sympathetic nervous...
 3. Studies of heart...
 4. Pain perception and...
5. Conclusion
 References
 
Abnormal sensitivity to stimuli from the heart [29,30] is very common in syndrome X patients. Cardiac catheterisation, usually a painless procedure after introduction of the cardiac catheter into the arterial system, has been shown to cause pain either during inflation of a balloon in the right atrium or injection of the coronary arteries with contrast medium. Electrical pacing of the right atrium has been shown to have a similarly painful effect [30].

Another important experimentally-employed stimulus which provokes chest pain is administration of the adenosine deaminase inhibitor dipyridamole. Its mechanism of action is through an increase in local concentration of adenosine. Intracoronary or intravenous adenosine can provoke chest pain in all subjects [31,32], but it has been shown that syndrome X patients are more sensitive to this stimulus than normals [33] and are at least as sensitive as patients with coronary artery disease [34]. However, in the latter patient group, dipyridamole or adenosine produces frank myocardial ischaemia demonstrable as a regional wall motion abnormality. In contrast, in syndrome X patients, left ventricular function is entirely preserved or even enhanced [6] after dipyridamole.

Sylvén and colleagues [33] have expressed the view that the chest pain in syndrome X is "a sympathetic-maintained pain of neurogenic origin due to dysregulation in the complex cardiac nervous system". According to this view, during chest pain in syndrome X, abnormal central nervous handling of afferent pain signals would bring with it activation of the brain areas subserving autonomic outflow. Sympathetic activation in syndrome X would thus constitute an epiphenomenon, secondary to a primary central nervous system functional abnormality. In turn, sympathetic activation would contribute to the maintenance of a lowered threshold for the afferent pain.

Although it is increasingly being accepted that abnormalities of visceral pain perception are demonstrable in patients with syndrome X, the point along the afferent chain at which the pain threshold is reduced is unclear. It may be within the central nervous system, up to and including the cortical level and may involve the endogenous opioid system [35]. Certainly from the clinical, therapeutic point of view, interventions which target the central nervous system have been far more effective than ‘anti-anginal’ medication [36,37].

We have recently investigated the central neural substrate of the abnormal sensitivity to chest pain in syndrome X patients directly by PET scanning of the brain during episodes of chest pain [38]. It was demonstrated that in syndrome X, the percept of chest pain is accompanied by greater and more extensive cortical activation (particularly of the right anterior insula) than in angina due to coronary artery disease, despite there being no discernible myocardial pathology in syndrome X. In the latest paradigm shift, therefore, syndrome X might be thought of more as a cortical pain syndrome, a ‘top-down’ process, in contrast with the ‘bottom-up’ generation of a pain percept due to myocardial ischaemia in coronary artery disease.


   5. Conclusion
Top
 1. Introduction
 2. The sympathetic nervous...
 3. Studies of heart...
 4. Pain perception and...
 5. Conclusion
References
 
The conception of cardiac syndrome X has gradually evolved from a paradigm centred upon myocardial ischaemia to one based upon differences in pain perception. The bridge between these ideas has been that of abnormal autonomic neural regulation of the heart. Studies of heart rate variability in these patients, such as that of Gulli et al. in the present journal [18], have helped to establish the latter idea as a fact.


   References
Top
 1. Introduction
 2. The sympathetic nervous...
 3. Studies of heart...
 4. Pain perception and...
 5. Conclusion
 References
 

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