Syndrome X Jassim Al Suwaidi, MD Amir Lerman, MD Address Division of Cardiovascular Diseases and Department of Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. E-mail:
[email protected] Current Treatment Options in Cardiovascular Medicine 2000, 2:73–82 Current Science Inc. ISSN 1092-8464 Copyright © 2000 by Current Science Inc.
Opinion statement • Syndrome X, defined as typical angina with positive exercise test results and normal coronary angiographic findings, represents a multifactorial pathophysiologic state that may range from abnormalities in pain perception to abnormalities in endothelial- and nonendothelial-dependent coronary flow reserve associated with myocardial ischemia. Treatment begins with accurate diagnosis by means of a comprehensive coronary vascular reactivity evaluation. This may lay the groundwork for appropriate treatment. • The management of patients with syndrome X is challenging, and it may be necessary to attempt various medications depending on the patient’s response. We feel that the first step in the treatment is accurate diagnosis. This is done by performing a functional angiogram (assessment of endothelial-dependent and endothelialindependent coronary flow reserve). In those without evidence of coronary flow reserve abnormalities, reassurance might be curative; however, in those who continue to have symptoms, a trial of imipramine therapy at a dose of 50 mg/d may be attempted, provided other organic disorders (in particular gastrointestinal disorders) are excluded. • Those who demonstrate evidence of abnormal coronary vascular reactivity are approached as outlined in Figure 1. Patients are advised to avoid medications that may cause coronary “spasm.” We routinely refer our patients to the cardiovascular health clinic for risk factor management and an exercise program. • Our first choice of medications usually consists of slow-release calcium channel blockers. We tend to start with a once-a-day regimen, and based on the response, we occasionally change the regimen to twice a day. If the functional angiogram reveals concomitant epicardial disease, then nitrates are added to the medical regimen. Angiotensin-converting enzyme inhibitors are part of the treatment if the patient has hypertension or diabetes or if calcium channel blocker therapy fails. L-Arginine at an initial dosage of 1 g three times daily is added and may be increased to 3 g three times daily if no contraindications are present. Because there are no data regarding the effect of L-arginine, which may affect insulin secretion, in patients with diabetes, we use caution in this patient population [1]. There is no “gold standard” therapy for syndrome X, so each patient may respond differently to the initial medical therapy. Thus, we follow these patients closely to monitor their response to treatment.
Introduction Syndrome X is neither a pathogenic nor a clinical entity but is rather a collection of various diseases of different causes. Included in this category are patients with coro-
nary microvascular dysfunction, in whom angina may represent myocardial ischemia; this syndrome is frequently referred to as microvascular angina [2••].
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Other causes include esophageal motility disorders, gastroesophageal reflux disease, mitral valve prolapse, and abnormal pain perception. The chest pain in some patients may be atypical in that the pain may be uncharacteristically long, severe, and disabling. Despite evidence of nonsignificant obstructive coronary artery disease on diagnostic coronary angiography, patients usually continue to suffer from chest pain, require many physician consultations (including cardiologists, gastroenterologists, and psychiatrists), and report psychosocial disability [2••,3•,4]. Thus, these observations underscore the need for a more comprehensive approach to the diagnosis and treatment of this syndrome. The pathophysiologic abnormality observed most consistently (although not universally) in patients with angina-like chest pain and normal coronary angiographic findings is decreased endothelial-dependent or endothelial-independent coronary flow reserve. These abnormalities were shown to be associated with myocardial perfusion defects in patients with angina and nonobstructive coronary artery disease [5,6•]. Another potential mechanism is abnormal cardiac sensitivity, which was demonstrated in some of these patients. Cannon et al. [2••] suggested that patients with microvascular angina might represent the opposite end of the nociceptive spectrum from the subgroup of patients who have “silent ischemia.” Other potential causes of syndrome X include a significant reduction in coronary blood flow during esophageal acid stimulation, heightened sympathetic tone, and insulin resistance. All have been reported in syndrome X, which highlights the heterogeneous nature of this syndrome [7•]. The approach to these patients begins with an attempt to make an accurate diagnosis. An accurate history should be taken, including review of the patient’s medications, because some medications may induce coronary “spasm” (eg, ergot substances, sumatriptan, diet pills containing epinephrine, 5-fluorouracil, and some antiallergy medications). If there is a history of cocaine abuse, it must be elicited, especially in young adults. Although noninvasive functional imaging was suggested as a diagnostic study in patients with normal coronary angiographic findings [4], we and others [7•,8] found no correlation between abnormalities in noninvasive functional studies and coronary flow reserve. We evaluated the association between the two in 180 consecutive patients, who were divided into two
groups based on their coronary flow reserve (Table 1). The lack of association between objective evidence of ischemia as seen on noninvasive imaging studies and direct assessment of coronary flow reserve abnormalities in patients with normal coronary arteries does not exclude the presence of ischemia in these patients. It has been suggested that this may be related to patchy distribution of the microvascular dysfunction in the myocardium, which may have small and barely detectable metabolic and hemodynamic consequences [7•,8].
Figure 1. Our approach to patients presenting with angina-like chest pain and nonobstructive coronary artery disease. ACE—angiotensin-converting enzyme.
Table 1. Functional study results in angina-like chest pain with normal coronary angiographic findings
Positive exercise electrocardiographic results, % New reversible perfusion defects, %
Group 1*
Group 2†
21 49
33 36
*Group 1 has normal coronary flow reserve. † Group 2 has abnormal endothelial-dependent coronary flow reserve with or without endothelial-independent coronary flow reserve.
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Table 2. Studies of pharmacologic treatment of syndrome X Investigator
Sample size Medication
Nitrates
Lanza [9] Burgiardini [10]
18 16
ISDN ISDN
Beta-blockers
Fragasso [11] Burgiardini [12] Borghi [13] Romeo [14] Cannon [15] Cannon [15] Borghi [13] Montorsi [16] Burgiardini [12] Romeo [14] Kaski [17] Nalbantgil [18] Egashira [19] Lerman [20••] Emdin [21•] Elliott [22] Cannon [23•]
22 28 24 30 17 9 24 18 28 30 10 18 8 13 8 10 20
Atenolol Propranolol Propranolol Acebutolol Verapamil Nifedipine Verapamil Nifedipine Verapamil Verapamil Enalapril Cilazapril L-arginine L-arginine Aminophylline Aminophylline Imipramine
Calcium channel blockers
Angiotensin-converting enzyme inhibitors L-Arginine Aminophylline Antidepressants
Dosage 5 mg sublingually 10 mg sublingually/ 2 mg intracoronary 100 mg/d 120–160 mg/d 120–160 mg/d 400 mg/d 40–160 mg four times a day 10–30 mg four times a day 320–480 mg/d 10–20 mg four times a day 320 mg/d 80 mg four times a day 10 mg/d 5 mg/d 50 mg/min intracoronary 3 g orally three times a day 6 mg/kg intravenously 225 or 350 mg/d 50 mg/d
Result + + + +/+ + + + + + + + + + +
ISDN—isosorbide dinitrates.
Treatment • Treatment begins with an attempt to make an accurate diagnosis by means of comprehensive coronary vascular reactivity evaluation. • Patients without evidence of microvascular dysfunction are reassured that the origin of their symptoms may not be cardiac, and workup for other causes of chest pain (eg, gastrointestinal factors) is done. • Patients with evidence of microvascular dysfunction are informed about their disease, and appropriate treatment is initiated. • Cardiovascular risk factors are managed very aggressively because the risk factors for atherosclerosis are also associated with endothelial dysfunction. Smokers are encouraged to stop smoking, and hypercholesterolemia is managed with diet control and effective lipid-lowering therapy, with the target being a low-density lipoprotein level of less than 100 mg/dL. Estrogen supplementation is recommended for symptomatic postmenopausal women not receiving hormone replacement therapy.
Pharmacologic treatment • The pharmacologic treatment of patients with syndrome X is challenging because there is no consensus about the best treatment and there are limited data from studies, which enrolled only a small number of patients (Table 2). Furthermore, enrollment criteria and assessment of the effectiveness of therapy varied among studies.
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Coronary Artery Disease • Initially, we discuss the various medications previously studied and the available data; subsequently, we describe our approach to treating these patients at our institution.
Nitrates
Standard dosage Contraindications Main drug interactions Main side effects Special points Cost/cost effectiveness
The response to nitrates is unpredictable. They are commonly not effective in controlling symptoms. Lanza et al. [9] and Burgiardini et al. [10] studied the acute effects of sublingual isosorbide dinitrates in patients with syndrome X and demonstrated either failure to improve exercise tolerance or lowering of the ischemic threshold in association with worsening of coronary blood flow. This lack of response may be related to the mechanism of action of nitroglycerin, which causes dilation of coronary vessels greater than 200 mm in diameter but has no effect on smaller vessels [24•] and probably has no significant role in microvascular angina. Isosorbide mononitrate is given orally in an initial dose of 30 to 60 mg/d. This may be increased to 120 mg/d. Hypersensitivity or idiosyncratic reaction to nitrates. Additive hypotensive effects with hypotensive medications. Headache (>10%); dizziness, nausea, or vomiting (1% to 10%); pruritus or rash (< 1%). Tablets should not be chewed or crushed. Some nitrates are available in generic forms. The response to nitrates is variable and unpredictable. In a strength of 20 mg, 30 tablets of isosorbide mononitrate cost $18.86.
Beta-blocker therapy
Standard dosage Contraindications Main drug interactions Main side effects
Special points
Cost/cost effectiveness
The mechanism of action of beta-blockers is most likely limitation of the metabolic demands of the heart. Fragasso et al. [11] demonstrated that atenolol significantly reduced episodes of angina and completely prevented exercise-induced ST segment changes in 18 of 22 patients with syndrome X. Other investigators obtained similar results with propranolol [12,13]. Acebutolol was useful only in a subset of the patients studied [14]. Atenolol: 50 to 100 mg orally once daily. Pulmonary edema, cardiogenic shock, bradycardia, heart block, or uncompensated heart failure. Additive effect with other hypotensive agents. Nonsteroidal anti-inflammatory drugs decrease the hypotensive effect when used concomitantly. Bradycardia, hypotension, second- or third-degree atrioventricular block, dizziness, fatigue, lethargy, headaches, and, when the daily dosage exceeds 100 mg/d, wheezing and dyspnea. Use with caution in bronchospastic disease. Beta-blockers may potentiate hypoglycemia in a diabetic patient; they may also mask signs and symptoms of hypoglycemia. Beta-blockers are available in generic form and may be cost effective. In a strength of 50 mg, 100 tablets of atenolol cost $4.35.
Calcium channel blockers The mechanism of action of calcium channel blockers is probably smooth muscle relaxation and vasodilatation of both small and large vessels. In a randomized double-blind crossover trial in 26 patients, Cannon et al. [15] demonstrated that patients receiving calcium channel blockers recorded fewer episodes of angina and consumed fewer nitroglycerin tablets than those receiving placebo. Other investigators obtained similar results [14,16]; however, these results are not consistent in all studies [12,13]. Standard dosage Diltiazem extended-release tablets: 180 to 480 mg/d. Contraindications Severe hypotension, cardiogenic shock, sick sinus syndrome, second- or thirddegree heart block, acute myocardial infarction, and pulmonary congestion.
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Main drug interactions Cimetidine may increase the bioavailability of diltiazem. Beta-blockers may increase cardiac depressant effects on atrioventricular conduction. Use with diltiazem may increase carbamazepine levels, and use with cyclosporine may increase cyclosporine levels. Fentanyl may increase hypotension. Use with digitalis may increase digitalis levels, and use with quinidine may increase quinidine levels (causing hypotension and bradycardia). Use with theophylline may increase the pharmacologic actions of theophylline. Main side effects Headache (>10%). The following effects occur in 1% to 10% of patients: bradycardia, atrioventricular block (first-degree), edema, vasodilation, flushing, dizziness, asthenia, nausea, vomiting, and constipation (with verapamil). Special points Titrate doses with caution in those with impaired renal or hepatic function; use with caution in patients with congestive heart failure. Cost/cost effectiveness Some calcium channel blockers are available in generic form and are very cost effective. In a strength of 90 mg, 100 tablets of diltiazem cost $19.41.
Angiotensin-converting enzyme inhibitors
Standard dosage Contraindications Main drug interactions
Main side effects
Special points Cost/cost effectiveness
The beneficial effects of angiotensin-converting enzyme (ACE) inhibitors in patients with microvascular angina probably occur through a number of mechanisms, including inhibition of the degradation of bradykinin, inhibition of the conversion of angiotensin I to angiotensin II, stimulation of the production of other vasodilators (such as prostacyclin), and inhibition of endothelin-1. Kaski et al. [17] reported on a randomized, single-blind, crossover placebo-controlled study in 10 patients with microvascular angina and demonstrated significant prolongation of exercise duration and time to 1-mm ST depression with enalapril, 10 mg daily for 2 weeks. Similar results were obtained using cilazapril [18]. A potential role of ACE inhibitors is also supported by the Trial on Reversing ENdothelial Dysfunction (TREND) [25•], which demonstrated improvement in endothelial function in patients with coronary artery disease with use of ACE inhibitor therapy. Quinapril: 10 to 40 mg orally once daily. History of angioedema induced by other ACE inhibitors, renal artery stenosis. Concomitant diuretic use causes hypotension. Potassium-sparing diuretics and potassium supplements cause hyperkalemia. Tetracycline causes reduced absorption of quinapril. Use with lithium increases lithium levels. The following occur in 1% to 10% of patients: hypotension, dizziness, headache, fatigue, diarrhea, increased blood urea nitrogen and serum creatinine levels, upper respiratory symptoms, and cough. Use with caution in patients with renal impairment. Some ACE inhibitors are available in a generic form. Cost effectiveness is unknown. In a strength of 10 mg, 100 tablets of Accupril (Parke-Davis, Morris Plains, NJ) cost $95.01.
L-Arginine L-Arginine
is a precursor of endothelium-derived nitric oxide. Because endotheliumdependent dilation of the coronary microcirculation is impaired in patients with microvascular angina, supplementation with L-arginine may facilitate the production of nitric oxide and augment endothelium-dependent vasodilation. Egashira et al. [19] demonstrated improvement in endothelial function in patients with syndrome X with use of intracoronary L-arginine. We have recently reported a randomized controlled trial evaluating the effect of long-term oral L-arginine therapy [20••]. Twenty-six patients with chest pain and without significant coronary artery disease on angiography were blindly randomized to receive oral L-arginine, 3 g three times daily, or placebo. Endothelium-dependent coronary blood flow reserve in response to acetylcholine was assessed at baseline and after 6 months of therapy. Assessment of patients’ symptoms at follow-up was also obtained. In the subjects who were taking L-arginine for 6 months, there was a significant improvement in endothelial-dependent coronary flow reserve, which was associated with significant improvement in symptoms. Standard dosage 1 to 3 g orally three times daily.
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Coronary Artery Disease Contraindications Severe allergic reaction. Main drug interactions A drug-drug interaction can occur with potassium-sparing diuretics such as amiloride, spironolactone, and triamterene. These can cause severe hyperkalemia in combination with L-arginine. Main side effects Elevation of potassium levels with significant renal or hepatic failure and diabetes, tissue irritation with extravasation, mild drop in blood pressure (with large intravenous doses), headache, flushing, and nausea and vomiting (<3%). Special points The dosage mentioned here may require the ingestion of 18 500-mg capsules per day, which entails some inconvenience to the patient. Cooke [26] has recently developed a nutrient bar enriched with L-arginine (the HeartBar; Cooke Pharma Inc., Belmont, CA) that may be a palatable way for patients to incorporate this supplement into their diet. Cost/cost effectiveness Very cost effective. In powder form, 1000 g of L-arginine costs $98.00.
Aminophylline
Standard dosage Contraindications Main drug interactions
Main side effects Special points
Cost/cost effectiveness
It is hypothesized that there is heightened cardiac sensitivity to certain mediators, including adenosine, in some patients. Aminophylline is a competitive inhibitor of adenosine; thus, it has been suggested that it may play a role in the treatment of these patients. In a double-blind randomized study of intravenous aminophylline in patients with syndrome X, Emdin et al. [21•] demonstrated beneficial effects on exercise-induced chest pain and ischemia-like electrocardiographic changes. Elliot et al. [22] demonstrated similar results using oral aminophylline; however, 23% of patients reported side effects. Thus, the main limitations of theophylline are its narrow therapeutic window and the frequent development of side effects. Theophylline: 100 to 300 mg three or four times daily or in a sustainedrelease preparation. Uncontrolled arrhythmias, hypersensitivity to aminophylline or theophylline, hyperthyroidism. Change in diet may affect elimination of theophylline. Theophylline may decrease the effects of phenytoin, lithium, and neuromuscular blocking agents. It increases the excretion of lithium and may have synergistic toxicity with sympathomimetics. Cimetidine, allopurinol, propranolol, erythromycin, influenza virus vaccine, ciprofloxacin, oral contraceptives, amiodarone, troleandomycin, clindamycin, and lincomycin increase theophylline concentrations. Cigarette smoking, rifampin, phenobarbital, phenytoin, and aminoglutethimide may decrease theophylline concentrations. Palpitations, sinus tachycardia, insomnia, nausea, vomiting, and epigastric pain. The elderly and patients with severe respiratory problems or liver dysfunction are at greater risk of toxicity because of reduced drug clearance. Use with caution in patients with peptic ulcer disease. Although available in a generic form, the effectiveness of aminophylline is questioned, and it has a narrow therapeutic window. In a strength of 100 mg, 100 tablets of theophylline cost $4.80.
Management of cardiovascular risk factors • This is not limited to the factors listed here but also includes the management of other cardiovascular risk factors, including hypertension and smoking.
Lipid-lowering agents There are no available data regarding the role of lipid-lowering therapy in treating patients with syndrome X. There is, however, a growing body of evidence suggesting that hypercholesterolemia may lead to endothelial dysfunction and that lowering of cholesterol level improves endothelial function [27–29]. It is our practice to evaluate the lipid profile in all patients and to treat patients with hypercholesterolemia initially with diet modification. Those patients in whom nonpharmacologic therapy fails are started on statins to attempt to achieve a low-density lipoprotein level of less than 100 mg/dL.
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Standard dosage Simvastatin: 5 to 40 mg/d. Lovastatin: 10 to 80 mg/d. Contraindications Previous hypersensitivity to simvastatin or lovastatin or other hepatic hydroxymethyl glutaryl coenzyme A reductase inhibitors; active liver disease or unexplained increases in serum transaminase levels; or pregnancy or lactation. Main drug interactions Lipid-lowering agents increase the effect of warfarin. Rhabdomyolysis or acute renal failure can occur with concomitant use of immunosuppressive agents (eg, cyclosporine), gemfibrozil, nicotinic acid, erythromycin, or azole antifungals. Main side effects In 1% to 10% of patients, the following side effects may occur: headache, dizziness, rash, flatulence, abdominal cramps, diarrhea, constipation, nausea, dyspepsia, heartburn, myalgia, or increased creatine phosphokinase level. Special points In patients taking immunosuppressives concomitantly, simvastatin therapy should be started at 5 mg and should not exceed 10 mg/d. In patients with renal impairment, it is recommended that one start at a lower dose and that patients be followed up closely. Cost/cost effectiveness Cost effective. In a strength of 10 mg, 100 tablets of Zocor (Merck & Co., Inc., West Point, PA) cost $174.51.
Hormone replacement therapy
Standard dosage Contraindications Main drug interactions
Main side effects
Special points Cost/cost effectiveness
Not only is estrogen deficiency one of the mechanisms responsible for endothelial dysfunction, but also estrogen replacement therapy has been shown to improve endothelial function [30–32]. Hence, estrogen replacement therapy may be useful in postmenopausal women with syndrome X [33]. Conjugated estrogen: 0.625 to 1.25 mg/d orally. Undiagnosed vaginal bleeding, thrombophlebitis, liver disease, carcinoma of the breast, or estrogen-dependent tumor. Barbiturates may produce lower estrogen levels owing to increased hepatic metabolism. Hormone replacement therapy may result in an increase in the pharmacologic and toxicologic effect of corticosteroids. Hydantoins and rifamycins may cause increased metabolism of estrogen compounds. Hypertension, edema, thromboembolic disorders, depression, headache, vomiting, cholestatic jaundice, breast tenderness, change in menstrual flow, or hypercalcemia. Concomitant administration of progesterone is recommended if the uterus is intact. Very cost effective.
Pain management Imipramine Although the role of imipramine in patients with microvascular angina is unclear, it may play a role in patients with syndrome X without evidence of microvascular dysfunction. Cannon et al. [23•] evaluated the role of imipramine in patients with chest pain and normal coronary angiographic findings. Of the 60 patients studied, only 13 had ischemic-appearing electrocardiographic responses to exercise (syndrome X). In a randomized double-blind placebo-controlled 3-week trial, there was significant improvement of symptoms in the group receiving imipramine. The mechanism (ie, vascular or central neural) of improvement is not understood. Standard dosage 50 mg once daily. Contraindications Cross-sensitivity with other tricyclic antidepressants may occur. Contraindicated in patients who have received monoamine oxidase inhibitors within the past 14 days, those with narrow-angle glaucoma, and those in the acute recovery period after myocardial infarction. Main drug interactions May decrease or reverse effects of guanethidine and clonidine; may increase effects of central nervous system depressants, adrenergic agents, and anticholinergic agents. When used with monoamine oxidase inhibitors, hyperpyrexia, tachycardia, hypertension, seizures, and death may occur.
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Coronary Artery Disease Main side effects Arrhythmia, hypotension, hypertension, heart block, myocardial infarction, drowsiness, sedation, confusion, dizziness, weakness, fatigue, anxiety, nervousness, sleep disorders, seizures, rash, hypersensitivity, nausea, vomiting, constipation, dry mouth, hepatitis, blurred vision, increased intraocular pressure, urinary retention, hypersensitivity reactions, and blood dyscrasias. Special points Use with caution in elderly patients. Cost/cost effectiveness Imipramine may be cost effective; 100 tablets in a strength of 50 mg cost $3.69.
Interventional procedures Spinal cord stimulation
Standard procedure
Contraindications Complications
Special points Cost/cost effectiveness
Spinal cord stimulation (SCS) as a treatment for pain was initially introduced in 1967. Its success in the treatment of patients with intractable angina pectoris was first reported in 1987. It was also shown to be useful in certain patients who failed to respond to standard therapies, owing in part to its anti-ischemic properties. Because coronary arteries are innervated by the adrenergic and parasympathetic nerves and may mediate coronary vasoconstriction, SCS may elicit improvement in pain through an increase in coronary blood flow. Sympathetic stimulation (eg, anxiety or fear) can induce or worsen angina through this mechanism; SCS may reduce this sympathetic activity [34•,35–37]. The role of SCS in patients with syndrome X is as yet unclear. Randomized controlled trials assessing its role in this patient population are currently being conducted. The procedure is safe, quick, and minimally invasive. It involves the insertion of an electrode tip into the midline of the epidural space in the area that may produce the anginal pain. SCS is usually performed with the patient under monitored anesthesia care with infiltration of a local anesthetic. Infection at the site of epidural access, bleeding diathesis, or use of anticoagulants or antiplatelet agents. There are a few potential complications that occur rarely in the immediate postoperative period, including epidural bleeding, which must be identified and treated immediately. Superficial bleeding may or may not require additional surgical intervention. Superficial or deep (eg, epidural abscess) infections are also potential immediate complications. Long-term complications include lead migration, hardware failure, and infections. Lead migration occurs in 16% to 25% of patients; lead fracture occurs in up to 20% of patients; and a superficial infection occurs in 2% to 12% of patients. Because the therapy is still being studied, we do not yet recommend it except in one of the randomized studies currently being conducted. Unknown and awaiting the results of ongoing trials.
References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: • Of special interest •• Of outstanding interest Schmidt HHHW, Warner TD, Ishii K, et al.: Insulin secretion from pancreatic B cells caused by L-argininederived nitric oxide. Science 1992, 255:721–723. 2.•• Cannon RO III, Camici PG, Epstein SE: Pathophysiologic dilemma of syndrome X. Circulation 1992, 85:883–892. This article provides an excellent review of the pathogenesis of syndrome X. 1.
3.• Hasdai D, Holmes DR Jr, Higano ST, et al.: The prevalence of coronary blood flow reserve abnormalities among patients with non-obstructive coronary artery disease and chest pain. Mayo Clin Proc 1998, 73:1133–1141. This article describes the prevalence of coronary flow reserve abnormalities in patients with chest pain and normal coronary angiographic findings who underwent vascular reactivity evaluation at our institution.
Syndrome X Al Suwaidi and Lerman Cannon RO III: How to manage chest pain in patients with normal coronary angiograms. Cardiologia 1997, 42:21–29. 5. Hasdai D, Gibbons RJ, Holmes DR Jr, et al.: Coronary endothelial dysfunction in humans is associated with myocardial perfusion defects. Circulation 1997, 96:3390–3395. 6.• Zeiher AM, Krause T, Schachinger V, et al.: Impaired endothelium-dependent vasodilation of coronary resistance vessels is associated with exercise-induced ischemia. Circulation 1995, 91:2345–2352. This article was one of the first to describe an association between exercise-induced ischemia and endothelial dysfunction. 7.• Cianflone D, Lanza GA, Maseri A: Microvascular angina in patients with normal coronary arteries and with other ischaemic syndromes. Eur Heart J 1995, 16(suppl I):96–103. This article provides an excellent overall review of the disease. 8. Galassi AR, Crea F, Araujo LI, et al.: Comparison of regional myocardial blood flow in syndrome X and one vessel coronary artery disease. Am J Cardiol 1993, 72:134–139. 9. Lanza GA, Manzoli A, Bia E, et al.: Acute effects of nitrates in exercise testing in patients with syndrome X: clinical and pathophysiologic implications. Circulation 1994, 90:2695–2700. 10. Burgiardini R, Borghi A, Pozzati A, et al.: The paradox of nitrates in patients with angina pectoris and angiographically normal coronary arteries. Am J Cardiol 1993, 72:343–347. 11. Fragasso G, Chierchia SL, Pizzetti G, et al.: Impaired left ventricular filling dynamics in patients with angina and angiographically normal coronary arteries: effect of beta adrenergic blockade. Heart 1997, 77:32–39. 12. Burgiardini R, Borghi A, Biaggetti L, Puddu P: Comparison of verapamil versus propranolol therapy in syndrome X. Am J Cardiol 1989, 63:286–290. 13. Borghi A, Sassone B, Trevisani M, et al.: Long-term efficacy of beta-blockers in syndrome X [abstract]. Circulation 1991, 84:II732. 14. Romeo F, Gaspardone A, Ciavollela M, Gioffre P: Verapamil versus acebutolol for syndrome X. Am J Cardiol 1988, 62:312–313. 15. Cannon RO III, Watson RM, Rosing DR, Epstein SE: Efficacy of calcium channel blocker therapy for angina pectoris from small-vessel coronary artery disease and abnormal vasodilator reserve. Am J Cardiol 1985, 56:242–246. 16. Montorsi P, Cozzi S, Loaldi A, et al.: Acute coronary vasomotor effects of nifedipine and therapeutic correlates in syndrome X. Am J Cardiol 1990, 66:302–307. 17. Kaski JC, Rosano G, Gavrielides S, Chen L: Effects of angiotensin-converting enzyme inhibition on exercise-induced angina and ST segment depression in patients with microvascular angina. J Am Coll Cardiol 1994, 23:652–657. 18. Nalbantgil I, Onder R, Altintig A, et al.: Therapeutic benefits of cilazapril in patients with syndrome X. Cardiology 1998, 89:130–133. 4.
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Egashira K, Hirooka Y, Kuga T, et al.: Effects of L-arginine supplementation on endothelium-dependent coronary vasodilation in patients with angina pectoris and normal coronary arteriograms. Circulation 1996, 94:130–134. 20.••Lerman A, Burnett JC, Higano ST, et al.: Long-term L-arginine supplementation improves small-vessel coronary endothelial function in humans. Circulation 1998, 97:2123–2128. This randomized double-blind placebo-controlled trial of oral L-arginine reports clinical improvement in symptoms in patients with microvascular angina in association with improvement in endothelial function. 21.• Emdin M, Picano E, Lattanzi F, L’Abbate A: Improved exercise capacity with acute aminophylline administration in patients with syndrome X. J Am Coll Cardiol 1989, 14:1450–1453. A double-blind randomized study evaluating the role of aminophylline in syndrome X. 22. Elliot P, Krzyzowska-Dickinson K, Calvino R, et al.: Effect of oral aminophylline in patients with angina and normal coronary arteriograms (cardiac syndrome X). Heart 1997, 77:523–526. 23.• Cannon RO, Quyyumi AA, Mincemoyer R, et al.: Imipramine in patients with chest pain despite normal coronary angiograms. N Engl J Med 1994, 330:1411–1417. A randomized study describing the role of imipramine in patients with chest pain and normal coronary angiographic findings. 24.• Harrison DG, Bates JN: The nitrovasodilators. New ideas about old drugs. Circulation 1993, 87:1461–1467. This article provides an excellent review of nitrates and their mechanism of action. 25.• Mancini GBJ, Henry GC, Macaya C, et al.: Angiotensinconverting enzyme inhibition with quinapril improves endothelial vasomotor dysfunction in patients with coronary artery disease: the TREND study (Trial on Reversing Endothelial Dysfunction). Circulation 1996, 94:258–265. A randomized study demonstrating the benefits of angiotensin-converting enzyme inhibitors in improving endothelial function. 26. Cooke JP: Nutriceuticals for cardiovascular health. Am J Cardiol 1998, 82(10A):43S–45S. 27. Treasure CB, Klein JL, Weintraub WS, et al.: Beneficial effects of cholesterol-lowering therapy on the coronary endothelium in patients with coronary artery disease. N Engl J Med 1995, 332:481–487. 28. Huggins GS, Pasternak RC, Alpert NM, et al.: Effects of short-term coronary vasodilator function and myocardial perfusion in regions having substantial impairment of baseline dilator reserve. Circulation 1998, 98:1291–1296. 29. Vogel RA, Corretti MC, Gellman J: Cholesterol, cholesterol lowering and endothelial function. Prog Cardiovasc Dis 1998, 41:117–136. 30. Gerhard M, Walsh BW, Tawakol A, et al.: Estradiol therapy combined with progesterone and endothelium-dependent vasodilation in postmenopausal women. Circulation 1998, 98:1158–1163.
19.
82 31.
32.
33.
Coronary Artery Disease Collins P, Rosano GMC, Sarrell PM: 17-Estradiol attenuates acetylcholine-induced coronary arterial constriction in women but not men with coronary heart disease. Circulation 1995, 92:24–30. Lieberman EH, Gerhard MD, Uehata A, et al.: Estrogen improves endothelium-dependent flow mediated vasodilation in post-menopausal women. Ann Intern Med 1994, 121:936–941. β-Estradiol Rosano GM, Peters NS, Lefroy D, et al.: 17-β therapy lessens angina in postmenopausal women with syndrome X. J Am Coll Cardiol 1996, 28(6):1500–1505.
34.• Sanderson JE, Woo KS, Chung HK, et al.: The effect of transcutaneous electrical nerve stimulation on coronary and systemic haemodynamics in syndrome X. Coron Artery Dis 1996, 7(7):547–552. A study evaluating the role and effects of transcutaneous electrical stimulation in patients with syndrome X. 35. Bagger JP, Jensen BS, Johannsen G: Long-term outcome of spinal cord electrical stimulation in patients with refractory chest pain. Clin Cardiol 1998, 21(4):286–288. 36. Sanderson JE, Ibrahim B, Waterhouse D, Palmer RB: Spinal electrical stimulation for intractable angina— long-term clinical outcome and safety. Eur Heart J 1994, 15(6):810–814. 37. Anderson C, Hole P, Oxhoj H: Spinal cord stimulation as a pain treatment for angina pectoris. Pain Clin 1995, 4:333–339.
