Objective: To investigate the central neural contribution to chest pain perception in cardiac syndrome X (angina-like pain, ECG changes during stress, angiographically normal coronary arteriogram).
Subjects: Eight syndrome X patients and eight healthy volunteers.
Methods: Dobutamine stress using echocardiography to assess myocardial function, and positron emission tomography to measure changes in regional cerebral blood flow, as an index of neuronal activity.
Results: During similar doses of dobutamine, syndrome X patients and controls showed comparable regional cerebral blood flow changes in the hypothalamus, thalami, right orbito-frontal cortex, and anterior temporal poles, associated with the sensation of a fast or powerful heart beat. In patients, but not controls, the stress also generated severe chest pain associated with increased activity in the right anterior insula/Frontal operculum junction. There were ischaemia-like ECG changes in the syndrome X patients, but no left ventricular dysfunction on echocardiography. Activation of the right insula during chest pain clearly distinguished the syndrome X patients from a group of patients with known coronary disease.
Conclusions: Chest pain and ECG changes were not accompanied by demonstrable myocardial dysfunction in syndrome X patients, but altered central neural handling of afferent signals may contribute to the abnormal pain perception in these patients.
It is obvious that pain is an important issue in all branches of clinical medicine. However, the management of pain in general, and chest pain in particular, remains suboptimal in many instances. Improved understanding of the mechanisms of pain would be welcome. In particular, the role of central nervous system abnormalities in maintaining chronic pain syndromes deserves greater attention. (1)
We have previously studied angina pectoris as a model of visceral pain, by employing functional brain imaging with positron emission tomography (PET) and oxygen-15 labelled water ([H.sup.15.sub.2]O), measuring regional cerebral blood flow as an index of regional synaptic activity during pharmacologically induced myocardial ischaemia. (2) Using this approach, we were able to "map" the neural systems involved in the perception of anginal pain in patients with coronary artery disease. (3) Subsequently, the technique was applied to investigate the difference between painful and silent myocardial ischaemia in patients with coronary artery disease. (4) As the distinguishing feature between these two populations was cortical activation rather than any demonstrable differences in the heart or in the lower neuroaxis, we concluded that abnormal central nervous system handling of afferent signals might determine the perception of cardiac pain for comparable levels of afferent input. A corollary of this was our hypothesi s that abnormal central nervous system handling of afferent signals might on its own produce a syndrome characterised by cardiac chest pain.
Cardiac syndrome X is characterised by angina-like chest pain and ST segment depression on the ECG during stress, although angiographically the coronary arteries appear normal. The quality of the pain and the ECG findings led earlier workers to hypothesise that myocardial ischaemia might account for the features of syndrome X. (5) However, the aetiology of chest pain in cardiac syndrome X remains unclear. (6) Some studies have shown that myocardial blood flow (7) and left ventricular function (8) can be within normal limits in this condition, regardless of chest pain or ECG changes, therefore casting doubts on the ischaemic origin of the pain. Additionally, abnormal visceral pain perception has been demonstrated consistently in most syndrome X patients, both in invasive studies (9 10) and during pharmacological stress. (11) While there is some evidence of autonomic dysfunction in syndrome X, (12-14) whether abnormal handling of afferent stimuli by the central nervous system is involved in the perception of chest pain in these patients has not been investigated.
Our aim in the present study was thus to determine whether cardiac syndrome X patients have a distinct pattern of cortical activation during chest pain. To do this, we measured regional cerebral blood flow at rest and during dobutamine induced chest pain in a group of patients with syndrome X and an equal number of matched normal volunteers. The results were also compared with data from patients with known coronary artery disease.
Syndrome X patients
Eight right handed patients (six women, two men; mean (SD) age, 59 (9) years) were recruited consecutively from our clinic over a period of one year. They were normotensive and had a history of typical angina (15) on exertion in all cases; three patients also experienced pain at rest. Physical examination was normal in all cases, as were the resting ECG findings. All patients developed > 0.1 mV rectilinear or downsloping ST segment depression on the exercise ECG. Cardiac catheterisation showed angiographically smooth normal coronary arteries. We employed strict exclusion criteria for other cardiac or systemic pathology. (7)
Eight normal subjects (five women, three men; age 56 (11) years; p = NS v the syndrome X patients) were also studied. None had a history of cardiac or pulmonary disease, or risk factors for coronary artery disease. All had normal resting and stress ECGs and normal effort tolerance.
A few days before PET scanning, patients underwent stress echocardiography with intravenous dipyridamole (0.56 to 0.84 mg/kg). The stress echocardiograms were performed outside the scanner suite under ideal conditions, and normal or enhanced ventricular function was found in all the syndrome X patients. During the PET scanning session, adequate views were obtained to exclude wall motion abnormalities at rest and during dobutamine Stress.
PET scanning protocol
Patients refrained from any drug treatment for 24 hours before the scan; [beta] blockers were stopped at least a week before. As we have described previously, (3 4) six regional cerebral blood flow measurements were made for each patient using dynamic PET with [H.sub.2][O.sup.15] (regional cerebral blood flow is a reliable index of cerebral glucose consumption, which increases when a given cerebral …