Syndrome X

Patients with a chronic stable pattern of mixed angina, "ischemic" ST-segment depression, and/or myocardial perfusion defects during stress test, but angiographically normal coronary arteries are classified as having syndrome X. In these patients, angina also predominantly occurs on exertion, typically with a variable ischemic threshold and occasionally at rest, but very seldom at night. Although the location and radiation of pain are often indistinguishable from those of patients with flow-limiting stenosis, some distinct features raise the suspicion of syndrome X:

(1) patients usually report persistence of angina for several minutes after the interruption of exertion, and many report attacks lasting over 30 mm;

(2) they have a poor response to sublingual nitrates, which were also shown to worsen exercise tolerance, in sharp contrast with their established beneficial effect in patients with flow-limiting stenosis (Fig. 209-1);

(3) they show a variable individual response to prophylactic long-acting nitrates, calcium antagonists, and beta blockers, possibly because of differences in the underlying causes of microvascular dysfunction;

(4) they develop their typical pain (often with transient ischemic ECG changes) during dipyridamole test but without development of left ventricular contractile abnormalities ;

(5) they often have an enhanced response to painful stimuli, which contributes to explain the paradox of severe angina in the absence of detectable myocardial contractile dysfunction (Fig. 209-2); and

(6) Holter monitoring demonstrates that some episodes of chest pam and ST-segment depression are not associated with tachycardia, and it may show episodes of transient ST-segment depression in patients with a negative exercise test, suggestive of possible episodic occurrence of microvascular constriction.

The diagnosis of syndrome X is confirmed by
(1) the evidence of a cardiac origin of pain because of its consistent association with transient ischemic ECG changes and/or myocardial perfusion defects during exercise test or by diagnostic ECG changes on Holter monitoring (cardsynX-fig1.gif);
(2) normal coronary angiogram and
(3) the exclusion of epicardial coronary spasm on the basis of distinct clinical history, absence of transient episodes of ST-segment elevation, and failure to induce coronary spasm by provocative tests.

Maseri,A. and Others, Coronary Blood Flo w and Myocardial Ischemia ,THE HEART,Hurst's,Volume 1 10th edition ,pp.1124-1125.

 

CardsynX-fig1.gif
(http://www.hosppract.com/issues/2000/02/kaski.htm)

The Microvasculature and Coronary Ischemia

The recognition of the likely importance of the coronary microvascular resistance vessels in the pathogenesis of angina pectoris resulted from studies of patients with angina-like chest pain and angiographically normal epicardial coronary arteries.

The coronary etiology of the chest pain is supported by the frequent but not universal evidence of ischemia in these patients during exercise testing; many were found to have abnormal vasodilator reserve. Specifically, in patients with angina and angiographically normal coronary arteries, endothelial-dependent vasodilatation of the resistance arteries, as reflected in the responses of CBF (coronary blood flow) to infusion of the endothelial-dependent vasodilator acetylcholine, was diminished relative to controls (cardsynX.fig2-gif and cardsynX.fig3-gif).

 

 

mricardsyn.Fig4gif. Measurements of Myocardial Perfusion Index in Controls and in Patients with Syndrome X.

Panel A shows the myocardial perfusion index at rest and during stress. Panel B shows the ratio of subendocardial to subepicardial myocardial-perfusion reserve index.

 

mricardsynX.Fig5-gif. Images of Myocardium at Peak Myocardial Enhancement during the First Pass of Gadolinium in a Control Subject at Rest (Panel A) and during Stress (Panel B), Showing Uniform Myocardial Signal Enhancement.

 

mricardsynX.Fig6-gif. Images of Myocardium at Peak Myocardial Enhancement during the First Pass of Gadolinium in a Patient with Syndrome X at Rest (Panel A) and during Stress (Panel B), Showing a Ring of Delayed Subendocardial Enhancement (Arrows in Panel B).

In patients with syndrome X, cardiovascular magnetic resonance imaging demonstrates subendocardial hypoperfusion during the intravenous administration of adenosine, which is associated with intense chest pain. These data support the notion that the chest pain may have an ischemic cause.

In the controls, the myocardial perfusion index increased in both myocardial layers with adenosine (in the subendocardium, from a mean [±SD] of 0.12±0.03 to 0.16±0.03 [P=0.02]; in the subepicardium, from 0.11±0.02 to 0.17±0.05 [P=0.002]); in patients with syndrome X, the myocardial perfusion index did not change significantly in the subendocardium (0.13±0.02 vs. 0.14±0.03, P=0.11; P=0.09 as compared with controls) but increased in the subepicardium (from 0.11±0.02 to 0.20±0.04, P<0.001; P=0.11 for the comparison with controls). Adenosine provoked chest pain in 95 percent of patients with syndrome X and 40 percent of controls (P<0.001). See mricardsynX.fig4-gif, mricardsynX.Fig5-gif, and mricardsynX.Fig6-gif.

Although values for the transmural myocardial perfusion index at base line and under stress were equivalent between the groups, in the patients with syndrome X the subendocardial myocardial perfusion index did not increase with adenosine; in the controls, in contrast, a normal increase was seen. There was also a significant reduction in the subendocardial myocardial perfusion index normalized to heart rate in the patients with syndrome X, which was not seen in the control group. The responses in the subepicardium were similar in both groups. Thus, the ratio of subendocardial to subepicardial myocardial-perfusion reserve index was significantly lower in patients with syndrome X. There was consistent evidence in patients with syndrome X of an abnormality of myocardial perfusion limited to the subendocardium. These results could be obtained because transmural resolution is higher with cardiovascular magnetic resonance imaging than with other techniques.

The above results show that patients with syndrome X have a reduction in subendocardial myocardial perfusion index normalized to heart rate during stress and a reduction in the ratio of subendocardial to subepicardial myocardial-perfusion reserve index. These findings, combined with the occurrence of chest pain during stress in patients with syndrome X, support the hypothesis that subendocardial ischemia is the cause of the angina symptoms in these patients. However, whether there is an actual absolute reduction in subendocardial perfusion with stress in patients with syndrome X is unresolved.

http://content.nejm.org/cgi/content/full/346/25/1948

Abnormal Subendocardial Perfusion in Cardiac Syndrome X Detected by Cardiovascular Magnetic Resonance Imaging
Jonathan R. Panting, M.B., M.R.C.P., Peter D. Gatehouse, Ph.D., Guang-Zhong Yang, Ph.D., Frank Grothues, M.D., David N. Firmin, Ph.D., Peter Collins, M.D., and Dudley J. Pennell, M.D.

 

CardsynX-fig2-3.gif

In contrast, the flow responses to the non-endothelial-dependent dilators, isosorbide dinitrate and papaverine were no different between patients and controls, suggesting that the intrinsic vasodilator capacity of the resistance arteries was not defective. Similar defects in endothelial-dependent increases in CBF have been observed in LV hypertrophy associated with hypertension, another condition that may be associated with angina pectoris with angiographically normal epicardial coronary arteries.

The histopathology of biopsy specimens from patients with normal epicardial coronaries but with anginal syndromes has demonstrated capillary narrowing with swollen endothelium encroaching on the lumen as well as decreased capillary density. Thus the coronary microvasculature can develop dysfunction of vasomotor control mechanisms and of endothelial-dependent vasodilation that may become clinically significant in the setting of increased demand or MV02. In this situation, the loss of vasodilator reserve and/or the actual constriction of resistance arterioles may induce ischemia and chest pain.

O'Rourke,R. and others,Diagnosis and Management of Patients with Chronic Ischemic Heart Disease,Hurst's THE HEART,Vol.1,Page1217,10th Edition.

 

In view of the syndrome's good prognosis, therapeutic goals should be to control the patient's chest pain and improve quality of life.

 

Treatment

As the mechanisms underlying chest pain in syndrome X probably vary in different subgroups, there is no standard, off-the-shelf therapeutic protocol. Instead, various types of drugs and therapeutic approaches have been tested.

Antianginals

Standard antianginal agents are often used on an empiric basis rather than clear scientific evidence.

Calcium antagonists appear to be beneficial in a proportion of patients. Nifedipine has been shown to improve angina and ST-changes as well as to have positive effects on coronary vasomotor tone, but mainly in patients without increased sympathetic drive.

Diltiazem is also widely used and is an effective antianginal agent in syndrome X.

Nitrates, which are extremely effective in patients with coronary artery disease (CAD), appear to be beneficial in approximately 40% to 50% of syndrome X patients.

Beta-blockers have been shown to reduce the number of episodes of chest pain and improve exercise tolerance mainly in syndrome X patients who have increased sympathetic activity.

Angiotensin converting-enzyme (ACE) inhibitors have been tested against the syndrome based on the notion that the renin-angiotensin system plays an important role in the regulation of coronary vasomotion and may thus be a pathogenetic factor. It has been showed that ACE inhibition improved exercise-induced angina and ECG changes in a small group of patients with microvascular angina.

Other Agents

Among other treatments to control chest pain that appear to be effective in some cases, imipramine, a tricyclic anti-depressant used for management of chronic pain disorders, has been shown to significantly reduce the number of chest pain episodes in patients with angina and normal coronary arteries. However, imipramine is associated with a high incidence of side effects that may impair the patient's quality of life.

A similar situation may arise with aminophylline, a competitive blocker of adenosine purinergic receptors that has been shown to reduce the magnitude of chest pain and ST-segment changes in syndrome X patients.

Finally, transdermal administration of 17-beta-estradiol in women with syndrome X reduces the number of episodes of chest pain during daily activities.But its use has to be balanced against side effects long term.