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Chin Med J (Taipei) 1997;60:177-83.
Division of Cardiology, Department of Medicine, Veterans General Hospital-1Taipei and 2Taichung; and
3National Yang-Ming University School of Medicine,
Taipei, Taiwan, R.O.C.
The term "syndrome X" is now widely used to specify a group of patients with anginal chest pain, ischemia-like electrocardiogram, normal coronary angiograms, and no evidence of coronary spasm. Though chest pain and exercise-induced myocardial ischemia may both be present in patients with syndrome X and those with coronary artery disease, the underlying pathogenesis of these two disease entities is different. In patients with syndrome X, the causes of angina and myocardial ischemia are multifarious while coronary angiograms are normal. Coronary microvascular function has been shown to be impaired in these patients. However, the presentation of myocardial ischemia may be varied and even subclinical, suggesting dynamic characteristics and regional distribution of coronary microvascular insufficiency in them. Recently, there is increasing evidence that chest pain may develop without detectable myocardial ischemia and has been attributed to abnormal pain perception in at least some of the patients. Thus, there is a heterogeneous group of patients with syndrome X. The rational patient management should be related to individual clinical presentation and depend upon the proper identification of the underlying mechanisms of anginal chest pain or myocardial ischemia or both in these patients.
[Chin Med J (Taipei) 1997;60:177-83.]
Keywords: chest pain, coronary micro-vascular dysfunction, microvascular angina, syndrome X
Received: May 5, 1997.
Accepted: September 4, 1997.
Address reprint requests to: Jaw-Wen Chen, MD, Division of Cardiology, Department of Medicine, Veterans General Hospital-Taipei, No. 201, Section 2, Shih-Pai Road, Taipei, Taiwan, R.O.C.
Up to 30% of the patients who underwent coronary angiography to evaluate the causes of chest pain have angiographically normal coronary arteries. In these patients, chest pain may occur and myocardial ischemia may persist for years even after the coronary angiograms reveal normal [1]. The term "syndrome X", first raised by Kemp in 1973 to describe a group of patients with typical angina and normal coronary angiograms [2], is now widely used to specify patients with angina-like chest pain, ischemia-like electrocardiogram (ECG), normal coronary angiograms, and no evidence of coronary spasm [3,4]. Although the definition of syndrome X has not been unified, the exclusion of extra-cardiac and cardiac causes of chest pain with normal coronary angiograms such as left ventricular hypertrophy, systemic hypertension, coronary spasm, cardiomyopathy, and valvular heart disease is usually required for the diagnosis of syndrome X. Recently, a metabolic entity characterized by hyperlipidemia, insulin resistance, hypertension, and coronary atherosclerosis was also termed "syndrome X" by Reaven [5]. However, this new metabolic syndrome X is clinically different from the cardiac syndrome X though there is evidence of insulin resistance in some cardiac syndrome X patients [6].
Angina Pectoris in Syndrome X
Chest pain in patients with syndrome X is usually exertional and similar in character to that in patients with coronary artery disease [7]. However, resting and atypical angina may also be present in > 40% of these patients [1]. The causes of angina might be multifarious in patients with syndrome X [3,7], including myocardial ischemia itself [8], increased cardiac pain perception to external mechanical stimulation [9,10] or intrinsic adenosine production [7], abnormal central pain perception [11], and altered cardiac metabolism [4]. Recently, there is increasing evidence that in patients with syndrome X, chest pain may develop without clinical myocardial ischemia showing up either on an ECG or in metabolic studies [3,7]. It seems that chest pain may be mainly due to abnormal pain perception rather than myocardial ischemia at least in some of patients with syndrome X [9-11].
On the other hand, chest pain may also be induced by either clinically significant or insignificant myocardial ischemia. The term "microvascular angina", first suggested by Cannon, is used to describe coronary microvascular dysfunction as the cause of typical angina in patients with normal coronary angiograms [1,2]. Though the results of a treadmill exercise test are not necessarily positive, coronary flow reserve (CFR), defined as the ratio of maximum coronary blood flow after pacing or pharmacological stimulation to that at baseline, has been suggested as an indicator of coronary microvascular function and shown to be impaired in these patients [3,4,12]. In patients with syndrome X, anginal chest pain could also be attributed to regional and/or patchy distribution of myocardial ischemia resulting from coronary microvascular dysfunction [3,7].
Evidence of Myocardial Ischemia in Syndrome X
The objective evidence of myocardial ischemia in patients with syndrome X could be shown noninvasively by the presence of an ischemia-like ECG in a treadmill exercise test or a 24-hour Holter's ECG monitoring, and transient left ventricular dysfunction during exercise [13-15]. It can also be shown invasively by measuring the lactate production in coronary sinus blood during atrial pacing [4]. The treadmill exercise test has been widely used to identify the existence of myocardial ischemia in patients with syndrome X [16,17]. Though factors other than coronary microvascular dysfunction such as abnormal interstitial release of potassium may theoretically produce the ischemia-like changes in exercise ECG [18,19], we recently demonstrated the association between impaired CFR and ischemia-like ECG during exercise in patients with chest pain and normal coronary angiograms [20]. On the other hand, only 10-40% of our syndrome X patients developed transient ischemic episodes, mostly silent, on 24-hour Holter's ECG monitoring (our unpublished data). However, the presentation of myocardial ischemia might be varied and subclinical in patients with syndrome X [1].
The most reliable way to evaluate myocardial perfusion in these patients is to measure coronary blood flow, either invasively by coronary sinus catheter, intracoronary Doppler catheter/wire or noninvasively by echocardiography or a positron emission tomography (PET), both at baseline and after variable physiological and pharmacological stimulation [21-25]. Several recent studies showed a varied distribution of regional myocardial blood flow both at baseline and after the administration of coronary vasodilators such as papaverine, dipyridamole or adenosine, suggesting the existence of focal myocardial ischemia in patients with syndrome X [26-28]. While the epicardial coronary arteries are patent, coronary microvascular dysfunction is considered to be the major cause of myocardial ischemia in patients with either microvascular angina or syndrome X [16,17]. However, the dynamic characteristics of angina as well as ischemic episodes suggest a dynamic dysfunction of coronary microvascular tone in patients with syndrome X [3,7]. In some circumstances, myocardial ischemia may even coexist with airway hypersensitivity [29], esophageal dysmotility [30], or impaired forearm vasodilatory reserve [31], suggesting a generalized smooth muscle dysfunction in these patients.
Coronary Microvascular Insufficiency as the Cause of Myocardial Ischemia in Syndrome X
It has been suggested that, in patients with syndrome X, exercise-induced myocardial ischemia is caused by coronary microvascular dysfunction with or without structural changes of the small coronary arteries [3,32,33]. The conflicting data about the structural changes of coronary microvasculatures also give a rationale for the different stages and mechanisms of coronary microvascular insufficiency in syndrome X patients.
Clinically, coronary microvascular insufficiency may be associated with either the attenuation of vasodilator capacity to variable physiological and pharmacological stimuli or the enhancement of vasoconstriction activity at rest, or both [34]. Several possible mechanisms have been linked to the abnormal coronary microvascular tone in syndrome X patients. They include endothelial dysfunction [35,36], extravascular compression [37], increased thromboxane A2 from platelet aggregation [38], functional change of vascular smooth muscle cells, increased sympathetic activities [39] and insulin resistance [6]. Recently, we and other investigators have demonstrated the presence of parasympathetic withdrawal and abnormal sympathetic activities both during persistent and just preceeding the onset of myocardial ischemia, suggesting the important role of cardiac autonomic dysfunction in the development of myocardial ischemia in patients with syndrome X [40,41]. Besides, endothelial dependent vasodilatation of coronary microvasculatures was shown to be impaired with relatively normal endothelial independent vasodilatation in patients with chest pain and normal coronary angiograms [35,36]. It seems that either endothelial dysfunction or abnormal cardiac autonomic activities or both may directly contribute to coronary microvascular insufficiency and clinical ischemic episodes in syndrome X patients. On the other hand, the deficiency of estrogen has been related to the presence of myocardial ischemia in peri- or postmenopausal female patients with syndrome X [42,43], suggesting the possible difference in the pathogenesis of coronary microvascular insufficiency is gender based. Thus, there is a heterogeneous group, both in clinical presentation and underlying etiology, of patients with syndrome X.
Prognosis of Syndrome X Patients
Though angina pectoris may persist, blood pressure may be elevated, and left ventricular function may progressively deteriorate in some patients with syndrome X [44], the prognosis is generally good in long-term follow-up [1]. Recently, Kaski et al. reported that in a group of 99 syndrome X patients, there were no cardiac death and only one with left ventricular dysfunction during a follow-up period of 7 +/- 4 years [1]. They found that the anginal chest pain lessened in 11, was variable or unchanged in 64 and worsened in 24 patients, suggesting the poor response to conventional antianginal and anti-ischemic treatments. The results indicated that most of the patients with syndrome X remained symptomatic throughout the follow-up and some were even disabled because of persistent chest pain [1]. On the other hand, the prognosis of syndrome X patients might become poor with the progression of heart failure within 4 years if they have left bundle-branch block, either at rest or during exercise, at initial diagnosis [45]. Therefore, it is important to treat anginal chest pain and follow up left ventricular function regularly though long-term survival is not adversely affected in patients with syndrome X.
Potential Treatment of Syndrome X Patients
While the symptoms of chest pain and the signs of myocardial ischemia may exist seperately with probably different underlying mechanisms, the treatment of syndrome X patients should be considered individually in these two different entities.
It has been shown that conventional antianginal treatment such as sublingual nitroglycerin was ineffective in relieving chest pain in more than 50% of the syndrome X patients [1]. Considering the high incidence of co-existence of non-cardiac chest pain in these patients, one can always evaluate the esophagus for reflux esophagitis and esophageal motility disorder at first [30]. A recent study showed that imipramine, an antidepressant, could effectively relieve chest pain, probably by increasing the cardiac pain threshold, in a large portion of patients with syndrome X [46]. Aminophylline, an antagonist to adenosine, was also suggested to lessen angina as well as myocardial ischemia in these patients [3,7].
On the other hand, myocardial ischemia due to coronary microvascular insufficiency is suggested to account for both angina pectoris and left ventricular dysfunction in patients with syndrome X. Medications that could improve coronary microvascular function may theoretically lessen myocardial ischemia, reduce anginal attack and prevent possible left ventricular dysfunction. However, the anti-ischemic effects of oral nitrates [47] and calcium channel blockers [48-50] were insignificant in syndrome X patients. There were also conflicting data about the effects of a-sympathetic antagonists [51,52]. Recently, Kaski et al. showed that short-term oral administration of enalapril, an angiotensin-converting enzyme inhibitor, could improve exercise tolerance and ischemic threshold during exercise in a small group of patients with syndrome X [53]. We also found that 2-week treatment of nicorandil, a nitrate-potassium channel opener, has the similar anti-ischemic effect in patients with microvascular angina [54]. These effects were suggested to be related to the improvement of coronary microvascular insufficiency either by restoring endothelial function with angiotensin-converting enzyme inhibition [53] or by a direct hyperpolarization effect via potassium channel opening on vascular smooth muscle cells [54]. The results of other studies indicated that sympathetic antagonists could improve myocardial ischemia in particular patients with clinical evidence of increased sympathetic tone such as ventricular hypercontractility and relatively increased heart rate [55]. The supplement of estrogen to postmenopausal female patients with syndrome X may improve their myocardial ischemia as well as angina pectoris [56]. It is unknown whether this treatment is also effective in male patients.
Conclusions
It has been more than 20 years since the term, syndrome X, was first raised by Kemp in 1973. The various definitions and wide-ranged clinical presentations make it impossible to conclude syndrome X patients have a common pathogenesis. Therefore, a multi-approach is necessary to evaluate and manage these patients. While the pathogenesis is heterogeneous, rational treatment should depend upon the proper identification of the underlying mechanisms of chest pain or myocardial ischemia, or both, in patients with syndrome X.
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Copyright: 1997, Chinese Medical Association (Taipei)