Primary Motility  Disorders of the  Esophagus
 The Esophageal
 Esophagogastric  Junction

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Volume: Primary Motility Disorders of the Esophagus
Chapter: Pseudoanginal pains of esophageal origin

Microvascular angina: its diagnosis, pathophysiology and treatment

R.O. Cannon (Bethesda)

Claims for etiologies of chest pain in patients with angiographically normal coronary arteries have been reported by cardiology, gastroenterology, and psychiatry investigators. Thus, it appears likely that this represents a heterogenous population.

The usual approach towards such a patient is reassurance of an excellent prognosis, regardless of the cause for that individual's chest pain syndrome [1, 3]. Unfortunately, many patients are « reassurance resistant», continue to have chest discomfort, and utilize health care resources [4, 5]. Published reports 20 years ago suggested that some of these patients indeed had a cardiac basis for pain [6, 7] although in more recent years emphasis has shifted to noncardiac causes, primarily gastrointestinal [8] (esophageal motility disorders, acid reflux) and psychiatric [9, 10] (psychosomatic disorders, panic attacks, anxiety neurosis). A noncardiac cause for chest pain symptoms in these patients is appealing to cardiologists, because it allows the clinician to direct the patient's attention away from the heart and towards interested specialists.

On occasion, ischemia may be a consequence of undiagnosed valvular, congenital, or cardiomyopathic (especially hypertrophic or hypertensive) heart disease. Mitral valve prolapse is another etiology that has waxed and waned in credibility over the years. Having excluded these considerations by echocardiography and catheterization hemodynamics, we and others have demonstrated in a subset of patients with anginal chest pain responses to pacing stress and to potent coronary arteriolar vasodilators such as dipyridamole, abnormal coronary vascular responses to exercise and nifedipine, and ischemic-appearing ST segment changes during exercise and daily activities [11, 21]. On the other hand, other studies have concluded that there is no evidence for myocardial ischemia in these patients [22, 24]. These studies, however, differed in patient inclusion criteria and study design, as well as in the interpretation of the results. Even the name « Syndrome X » has taken on different meanings to investigators, generally resulting in an unsatisfactory diagnosis for the clinician to make, and for the patient to receive.

We initially separated patients with chest pain despite angiographically normal coronary arteries based on whether or not the stress of rapid atrial pacing provoked the pain described to us upon entry into our study [12, 15, 17]. With pacing to a heart rate of 150, those who experienced their typical chest pain had less of an increase in coronary flow and less of a decrease in coronary vascular resistance compared to those patients experiencing no pain or a non characteristic pain. However, a feature we believe of major importance to our studies, and which distinguishes our work from others, has been the re-assessment of coronary blood

flow and the metabolic response to pacing at the same heart rate following ergonovine administration. After ergonovine 0.15 to 0.3 mg was administered intravenously, repeat atrial pacing was associated with even less of an increase in coronary flow in the patients experiencing chest pain (three-quarters of all patients studied by us) compared to pacing prior to ergonovine.

Further, the absolute differences in flow and coronary resistance, and the metabolic and hemodynamic responses to pacing were more convincing than pacing prior to ergonovine.

Of interest was the observation that coronary resistance during pacing actually increased after ergonovine administration, indicating coronary vasoconstriction in the chest pain group. To our initial surprise, repeat coronary angiography showed only minimal changes in epicardial artery dimensions, too insignificant to explain the resistance changes indicated by our measurements. Thus, we concluded that vasoconstriction must have occurred in vessels too small to be reliably imaged angiographically [25]. We subsequently assessed pharmacologic flow reserve with dipyridamole and found that those patients with ergonovine-provoked chest pain and microvascular constriction also had limited coronary vasodilatation in response to this potent arteriolar vasodilator [17]. We have suggested that « microvascular angina » might be an appropriate name for this syndrome [26].

We subsequently found that patients with microvascular angina, even in the absence of hypertension (present in one-third of our patients), have blunted hyperemic forearm blood flow responses to ischemia compared to normal age and gender-matched controls [27]. Further, the severity of flow limitation in the forearm to ischemic stress correlated directly with the severity of coronary flow limitation to pharmacologic vasodilatation after dipyridamole. Thus, limitation in vasodilator responses appears to co-exist in the coronary and systemic circulations, suggesting abnormal function of vascular smooth muscle. The observation that many patients with microvascular angina also have evidence of esophageal motility dysfunction [28], most commonly «nutcracker esophagus», and methacholine provoked increases in airflow resistance [29], a response similar to asthmatics, has led us to consider a hypothesis of a generalized abnormality of both vascular and non-vascular smooth muscle in some patients. The cause of smooth muscle dysfunction is not known at present, but may be heightened sensitivity to vasoconstrictor stimuli, either neural or humoral, abnormal endothelial-smooth muscle interactions or increased intrinsic tension development in smooth muscle, with inappropriate relaxation in response to vasodilating stimuli.

Approximately one-third of our patient population with microvascular angina have convincingly ischemic ECG changes during treadmill exercise. Thus, although abnormal ECG responses to treadmill exercise might identify patients with micro-vascular angina, the absence of ischemic ST segment changes does not eliminate this diagnosis. We have found instead that a more sensitive and specific noninvasive test for microvascular angina is the left ventricular ejection fraction response to exercise measured by radionuclide angiography. Two-thirds of the patients we studied had either limited (less than 5 %) increase in ejection fraction with exercise, or an actual decrease in ejection fraction during exercise, often associated with wall

motion abnormalities [30]. The absence of convincingly ischemic ECG changes during exercise treadmill testing may relate to the generalized microvascular dysfunction and relative mildness of ischemia in this syndrome. This is in contrast to coronary artery disease, in which flow limitation is more focal and severe. Although the coronary flow reserve studies performed in our catheterization laboratory are impractical for most clinicians, noninvasive techniques are currently being investigated for assessment of coronary flow and may prove useful in the future (e.g., assessment of coronary flow reserve by positron emission tomography before and after dipyridamole).

A recent observation made by Shapiro et al. [31], and confirmed and expanded in our laboratory [32], is of interest, and potentially of clinical importance. Patients with chest pain and normal coronary arteries have a painful sensitivity to catheter manipulation within the heart, a response rarely seen in patients with coronary artery disease or valvular heart disease, and clearly occurring on a nonischemic basis. Further, we have noted that inflation of a balloon within the esophagus commonly provoked chest pain in patients undergoing esophageal manometry, irrespective of whether or not they had any evidence of esophageal motility dysfunction or acid reflux [28].

These observations suggest that a fundamental problem in patients with chest pain and normal coronary arteries may be abnormal afferent sensory receptor activation and nociception, with a painful perception of visceral sensations that would otherwise go unnoted in most individuals. Certainly, some patients within this broad group do have organic dysfunction of the esophagus, or microvascular angina, or both. However, abnormal sensory nerve function and pain perception may explain why high esophageal pressures alone (e.g., nutcracker esophagus), or mild myocardial ischemia (microvascular angina) may cause frequent, severe, prolonged and disabling pain. Either of these conditions in an individual with normal visceral sensory nerve function would probably go unnoted. Further, the anxiety commonly seen in these patients may be a pathogenetic component of this syndrome.

The patient determined in the catheterization laboratory to have angiographically normal coronary arteries, with no evidence of coronary spasm following ergonovine challenge, deserves reassurance, and repeat hospitalizations for chest pain should be discouraged. We do not believe at present that a diagnosis of microvascular angina should be made without demonstration of limited coronary flow reserve response to pacing or pharmacologic stimulation. However, if noninvasive testing suggests myocardial ischemia, associated with the patient's typical chest pain during exercise stress, a cardiac etiology would be supported and an empiric trial of anti-ischemic medications should be considered. We have found most patients to respond to nitrates and calcium channel blockers [33], although a significant minority do not, possibly explained by the recent observation of the inability of nifedipine to dilate coronary arteries of some patients [20].

Also under investigation at our institution is the role of drugs that affect neural pain pathways and processing. Other centers have found beta blockers to be of benefit [34], possibly by reducing myocardial oxygen demands. Recently, Emdin and co-workers have demonstrated improvement in effort duration, pressure-rate

product achieved, and symptom response during bicycle exercise with the abolition of ischemic-appearing ST segment responses, following aminophylline infusion [35]. Whether oral aminophylline preparations will provide the same benefit, while avoiding side effects and toxicity, remains to be determined.

If this treatment trial is ineffective, or if noninvasive testing is normal, the patient should be referred for esophageal testing, including motility testing and 24-hour pH monitoring. An esophageal etiology for pain would be supported by abnormal motility or acid reflux associated with the patient's typical symptoms. If anxiety, depression, or panic attacks appear to be a component of chest pain episodes, consideration should be made for the use of anxiolytic or antidepressant therapy.


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2. Bemiller CR et al. (1973) Long-term observation in patients with angina and normal coronary arteriograms. Circulation 47 : 36.

3. Kemp HG et al. (1986) Seven year survival of patients with normal or near normal coronary arteriograms : A CASS registry study. J Am Coll Cardiol 7 : 479.

4. Isner JM et al. (1981) Long-term clinical course of patients with normal coronary angiography: Follow-up study of 121 patients with normal or nearly normal coronary arteriograms. Am Heart J 102:645.

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6. Kemp HG et al. (1967) The anginal syndrome with normal coronary arteriography. Trans Assoc Am Physicians 80 : 59.

7. Likoff W et al. (1967) Paradox of normal selective coronary arteriograms in patients considered to have unmistakable coronary heart disease. N Engl J Med 276: 1063.

8. Richter JE et al. (1989) Esophageal chest pain: Current controversies in pathogenesis, diagnosis, and therapy. Ann Intern Med 110 : 66.

9. Weiglosz AT et al. (1984) Unimproved chest pain in patients with minimal or no coronary disease : A behavioral phenomenon. Am Heart J 108 : 67.

10. Lantinga LJ et al. (1988) One-year psychosocial follow-up of patients with chest pain and angiographically normal coronary arteries. Am J Cardiol 62 : 209.

11. Opherk D et al. (1981) Reduced coronary dilatory capacity and ultrastructural changes of the myocardium in patients with angina pectoris but normal coronary arteriograms. Circulation 63 : 817.

12. Cannon RO et al. (1983) Angina caused by reduced vasodilator reserve of the small coronary arteries. J Am Coll Cardiol 1 : 1359.

13. Schmidt HL et al. (1984) Ergonovine/dipyridamole-induced changes in regional myocardial perfusion in patients with angina and normal coronary arteries (abstract). Circulation 70: 11-274.

14. Virtanen KS (1984) Evidence of myocardial ischemia in patients with chest pain syndromes and normal coronary angiograms. Acta Med Scand (Suppl.) 694 : 58.

15. Cannon RO et al. (1985) Chest pain and « normal » coronary arteries : role of small coronary arteries. Am J Cardiol 55 : 50B.

16. Legrand V et al. (1985) Abnormal coronary flow reserve and abnormal radionuclide exercice test results in patients with normal coronary angiograms. J Am Coll Cardiol 6 : 1245.

17. Cannon RO et al. (1987) Limited coronary flow reserve after dipyridamole in patients with ergonovine-induced coronary vasoconstriction. Circulation 75 : 163.

18. Greenberg MA et al. (1987) Impaired coronary vasodilator responsiveness as a cause of lactate production during pacing-induced ischemia in patients with angina pectoris and normal coronary arteries. J Am Coll Cardiol 9 : 743.

19. Bortone et al. (1989) Abnormal coronary vasomotion during exercise in patients with normal coronary arteries and reduced coronary flow reserve. Circulation 79 : 516.

20. Montorsi et al. (1989) Comparison of coronary vasomotor responses to nifedipine in Syndrome X and in Prinzmetal's angina pectoris. Am J Cardiol 63 : 1198.

21. Kaski JC et al. (1986) Transient myocardial ischemia during daily life in patients with Syndrome X. Am J Cardiol 58: 1242.

22. Arbogast R, Bourassa MG (1973) Myocardial function during atrial pacing in patients with angina pectoris and normal coronary arteriograms. Am J Cardiol 32: 257.

23. Levy RD et al. (1986) Syndrome X : The hemodynamic significance of ST segment depression. Br Heart J 56 : 353.

24. Crake et al. (1988) Continuous recording of coronary sinus oxygen saturation during atrial pacing in patients with coronary artery disease or with Syndrome X. Br Heart 59 : 31.

25. Epstein SE, Cannon RO (1986) Site of increased resistance to coronary flow in patients with angina pectoris and normal epicardial coronary arteries. J Am Coll Cardiol 8 : 459.

26. Cannon RO, Epstein SE (1988) « Microvascular angina » as a cause of chest pain with angiographically normal coronary arteries. Am J Cardiol 61 : 1338-1343.

27. Sax FL et al. (1987) Impaired forearm vasodilator reserve in patients with microvascular angina: Evidence of generalized disorder of vascular function ? N Engl J Med 317 : 1366-1370.

28. Cannon RO et al. Coronary flow reserve, esophageal motility and chest pain in patients with « normal » coronary arteries. Am J Med 88 : 217-990.

29. Cannon RO et al. Airway hyper-responsiveness in patients with microvascular angina. Circulation 1990 (in press).

30. Cannon RO et al. (1985) Left ventricular dysfunction in patients with angina pectoris, normal epicardial coronary arteries, and abnormal vasodilator reserve. Circulation 71 : 218.

31. Shapiro LM et al. (1988) Is altered cardiac sensation responsible for chest pain in patients with normal coronary arteries ? Br Med J 296 : 170.

32. Cannon RO et al. Abnormal cardiac sensitivity in patients with chest pain and normal coronary arteries. J Am Coll Cardiol 1990 (in press).

33. Cannon RO (1985) Efficacy of calcium channel blocker therapy in patients with angina pectoris due to small coronary disease with abnormal vasodilator reserve. Am J Cardiol 56 : 242.

34. Romeo F et al. (1988) Verapamil versus acebutolol for Syndrome X. Am J Cardiol 62: 312.

35. Endim et al. (1989) Improved exercise capacity with acute aminophylline administration in patients with Syndrome X. J Am Coll Cardiol 14 : 1450.

Publication date: May 1991 OESO©2015