approach to the patient with chest pain and nonobstructive coronary artery disease

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atients with chest pain and nonobstructive coro-ary artery disease (NOCAD) utilize a significantart of our health care resources. Their diagnosisnd treatment can often be difficult and time con-uming. A simple classification system and step-ise diagnostic approach may help to reduce un-ecessary testing. Also, utilization of a chest painlinic may be beneficial for these patients.

2004 Elsevier Inc. All rights reserved.

n the United States, chest pain results in over 5million visits to emergency departments, 2 mil-

ion admissions, and multiple outpatient consul-ations every year. Together, these generate a costf over $8 billion.1 A large number of these pa-ients will eventually undergo coronary angiogra-hy and depending on the population studied, aignificant number (20% to 30%) will have nor-al-appearing coronary arteries.2,3 Indeed, 10%

o 15% of all patients undergoing angiography inur catheterization laboratory have normal coro-ary arteries and another 10% to 15% have angio-rams showing lesions of less than 30% stenosis.he treatment and diagnosis of chest pain in pa-

ients with nonobstructive coronary artery diseaseNOCAD) continues to represent a major chal-enge to contemporary cardiology. When evaluat-ng these patients, a revisit of the history and phys-cal examination helps to narrow the extensive listf pathologic conditions in the differential diag-osis (Table 1) and focus further investigation. It

s important to develop a logical, step-wise ap-roach so as to limit unnecessary testing, expense,nd patient discomfort.

The evaluation of patients with chest pain andOCAD should allow classification of patients

nto 1 of 3 main groups. The first group includes

rogress in Cardiovascular Diseases, Vol. 46, No. 5, (March/Apr

atients with chest pain and a flow-limiting coro-ary lesion that is not detected on angiographyut may be detected after physiologic evaluation.he second group includes patients without sig-ificant atherosclerotic epicardial disease, butith evidence of epicardial or microvascular reac-

ivity abnormalities that may lead to myocardialschemia. The third group consists of patientsithout evidence of epicardial or microvascular

bnormalities after extensive coronary and physi-logic assessment. This group will need furthervaluation and assessment for a noncoronary oroncardiac etiology. The current review focusesn the mechanism, diagnosis, and treatment ofatients with NOCAD. Moreover, the potentialeed for specialized chest pain clinics will be dis-ussed.

Epicardial Atherosclerotic Cause forIschemia

t should be emphasized that physiologically sig-ificant coronary stenosis may not be readily ap-arent on angiography.4 A review of the angio-ram and/or further assessment with fractionalow reserve or intravascular ultrasound may beecessary to ensure there is no significant epicar-ial coronary lesion.5,6

From the Center for Coronary Physiology and Imaging,ivision of Cardiovascular Diseases and Department of

nternal Medicine, Mayo Clinic Rochester, Rochester,N.Address reprint requests to Amir Lerman, Mayo Clinic

ivision of Cardiovascular Diseases, 200 First St SW,ochester, MN 55905. E-mail: [email protected]/$ - see front matter© 2004 Elsevier Inc. All rights reserved.
doi:10.1016/j.pcad.2003.12.003
453il) 2004: pp 453-464

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454 HALLIGAN AND LERMAN

Epicardial or Microvascular Causesfor Ischemia

nce a flow-limiting lesion has been ruled out as aontributing factor for chest pain, other coronarybnormalities must be considered, including epi-ardial spasm, myocardial bridging, coronary dis-ection, or abnormalities in the microvasculature.yocardial bridging and dissection should be

eadily apparent on the angiogram; however, epi-ardial vasoconstriction and abnormalities of theicrovasculature will require further investiga-

Table 1. Etiology of Chest Pain

. Coronary causesA. Epicardial coronary etiology

1. Obstructive epicardial disease2. Epicardial spasm3. Epicardial bridging4. Coronary dissection5. Epicardial endothelial dysfunction

B. Microvascular etiology1. Microvascular endothelial dysfunction2. Microvascular abnormalities secondary to

valvular heart disease3. Microvascular abnormalities secondary to

infiltrative disease4. Microvascular abnormalities secondary to

hypertension5. Microvascular abnormalities secondary to

cardiomyopathyI. Noncoronary causes

A. Cardiac1. Pericarditis2. Myocarditis

B. Gastrointestinal1. Biliary colic2. GERD3. PUD4. Pancreatitis5. Esophageal dysmotility

C. Pulmonary1. Spontaneous pneumothorax2. Pulmonary embolus3. Pneumonia4. Pleuritis

D. Musculoskeletal1. Costochondritis/Tietze syndrome

E. Vascular1. Aortic dissection2. Vasculitis

F. Endocrine diseaseG. Drug-induced (cocaine)H. Enhanced pain perception/psychogenic

Abbreviations: GERD, gastroesophageal reflux disease;UD, peptic ulcer disease.

ive and provocative procedures. c

picardial Coronary Spasm

picardial coronary spasm was first described byrinzmetal in 1959 and although relatively rare,hould be considered in all patients with chestain and NOCAD.7 It affects approximately 4 outf 100,000 people (approximately 2% of patientsomplaining of angina).8 The epicardial coronaryrteries can exhibit significant vasoactivity andatients with or without coronary atherosclerosisay have spontaneous increases in coronary va-

omotor tone, resulting in myocardial ischemia.atients often complain of nocturnal or earlyorning chest pain that typically occurs at rest

nd less so with exertion. In fact, they often main-ain good exercise tolerance. This atypical presen-ation of epicardial spasm may lead to chest painymptoms being erroneously dismissed as or-anic. Certain triggers can exacerbate coronarypasm, such as exposure to cold, emotional stress,lcohol, vasoconstricting medications, cocaine, orobacco, and these should be avoided. Further-ore, coronary vasospasm can lead to cardiac ar-

hythmias, including ventricular tachycardia/fi-rillation, heart block, acute infarction, or suddeneath.9 The clinical history aids in the diagnosis oforonary vasospasm and noninvasive modalitiesuch as ambulatory Holter monitoring, docu-enting ST-segment elevation, or provocative

chocardiography have been used in diagnosingasospasm.10 If noninvasive testing is equivocal,hen provocative testing with methylergonovineften demonstrates the presence of coronarypasm in these patients.11,12 Although normal va-oconstriction can result in as much as a 20%hange in lumen diameter, coronary spasm is con-idered to be present when a reduction in lumenaliber �50% occurs during a provocative test andeversal is achieved with intracoronary nitroglyc-rin.13 Treatment typically consists of medicalherapy with calcium channel blockers and/or ni-rates.14 �-Blockers should be used with cautions patients may experience a worsening of theirymptoms due to unopposed alpha stimulation.15

he long-term prognosis of patients with variantngina is generally good if the patient is treatednd avoids certain provocative stimuli.16,17

icrovascular Abnormalities

atients with chest pain and/or evidence of myo-
ardial ischemia and NOCAD and no other obvi-

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455APPROACH TO PATIENTS WITH CHEST PAIN AND NOCAD

us epicardial etiology should undergo evaluationor abnormalities in the coronary microcircula-ion. With an increase in myocardial oxygen de-and, there is an increase in coronary blood flow

CBF). The ability to increase coronary blood flown response to vasoactive stimuli is termed coro-ary flow reserve (CFR). CFR is determined by theatio of maximal CBF to the resting CBF.18 Theajor epicardial coronary arteries only contribute

bout 5% to the total coronary vascular resistance.he majority of coronary vascular resistance orig-

nates in the coronary arterioles, typically lesshan 300 �m. Changes in the microcirculationay result in dramatic alterations in CBF andFR, which may provoke ischemia. Cannon andpstein proposed the term microvascular angina in985 for the symptoms of angina pectoris and aositive stress test in the setting of no significantpicardial stenosis.19 In the presence of normalpicardial arteries and normal microvasculature,he CFR is normal. However, severe flow-limitingpicardial stenosis or microvascular pathologictates of the coronary arterioles results in the dim-nution of CFR.

Fig 1. Role of the microcirculation in the

Several pathologic entities are known to affect

he coronary microcirculation. All can lead toome abnormality in CBF through endothelial-ependent or -independent mechanisms. There-ore, patients with chest pain and NOCAD shouldndergo assessment of endothelial dependent and

ndependent abnormalities of the microcircula-ion, especially in the setting of disease statesnown to affect the microcirculation. We willriefly discuss the role of the endothelium in theaintenance of a healthy coronary circulation and

hen describe several disease states that can lead toicrovascular abnormalities, which may lead to

hest pain in patients with NOCAD.

ndothelial Dysfunction

he endothelium plays a pivotal role in coronaryomeostasis. It regulates vascular tone and coro-ary blood flow by releasing endothelial derivedasodilating factors such as nitric oxide (NO) andndothelial derived vasoconstrictors such as en-othelin-120 (Fig 1). It also plays a role in manyhysiologic processes such as inflammation,hrombosis, and platelet activation.21

al heart. Abbreviation: NO, nitric oxide.

Acetylcholine (Ach) stimulates the release of

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O from normal endothelium, which then acti-ates guanylate cyclase leading to an increasedroduction of cyclic guanosine monophosphatend a reduction in intracellular calcium. It is ap-arent that NO is a key factor in vascular physiol-gy and its bioavailability is vital in the mainte-ance of endothelial health. The degradation ofO is enhanced by reactive oxidant species such

s superoxide anion and oxidized low-density li-oprotein (LDL) cholesterol and this reduction inhe bioavailability of NO can lead to abnormaloronary physiology.22

Both invasive (with intracoronary Ach) andoninvasive (reactive hyperemia using brachialrtery ultrasound) assessments of endothelialunction have been reported.23,24 In coronary ar-eries with normal endothelium, the response tontracoronary Ach is epicardial and microvascularilation resulting in an increase in coronary bloodow. However, when the endothelial lining is dis-upted, intracoronary Ach induces vasoconstric-ion and a decrease in coronary blood flow. Thisndothelial-dependent response to Ach may serves a marker for the bioavailability of NO. More-ver, the abnormal coronary constriction re-ponse to Ach suggests a lack of NO bioavailabilitynd denotes endothelial dysfunction.

The fact that the epicardial arteries may be an-iographically free of disease does not precludendothelial dysfunction; atherosclerosis may note evident secondary to remodeling, diffuse dis-ase, or may in fact be absent, as endothelialysfunction is considered an early stage of athero-clerosis.25 Moreover, several studies have dem-nstrated that endothelial dysfunction is not just aisk factor and marker for developing atheroscle-osis, but that inducible ischemia has beenemonstrated in patients with nonobstructiveoronary arteries and abnormal endothelial test-ng.26-28 We and others have demonstrated thatbnormal endothelial function serves as a prog-ostic indicator to future cardiac events.29,30

Treatment for endothelial dysfunction can behallenging and should always include risk factorodification with diet, exercise, tobacco cessa-

ion, blood pressure control, glucose control, andipid management. Several studies have demon-trated abnormal coronary flow reserve in hy-ercholesterolemic or diabetic patients withOCAD.31-34 Statins may have a significant bene-
t in patients with endothelial dysfunction by im- o
roving lipid profiles and possibly through otherechanisms such as reduction of inflammation.-reactive protein (CRP) is a marker of systemic

nflammation that has been shown to correlateith future cardiac events.35 It has also been sug-ested that elevated CRP is associated with theevelopment of endothelial dysfunction.36 Fich-lscherer et al37 demonstrated blunted endothelialunction in patients with elevated CRP. More re-ently, Cosin-Sales et al38 reported on patientsith chest pain and normal coronary arteries and

ound that CRP levels correlated with symptomsnd electrocardiographic markers of myocardialschemia. A number of studies have demonstratedhat CRP levels can be lowered with statin ther-py.39,40 It is plausible that statins may improvendothelial function by reducing or preventingnflammation.41

Other therapies, such as angiotensin-convert-ng enzyme (ACE) inhibition and anti-oxidantsave also shown some benefit in endothelial dys-

unction.42 We have shown that oral L-arginine (arecursor to NO) improves endothelial functionnd symptoms at 6 months43 (Table 2).

It is important to assess secondary conditionsssociated with chest pain and abnormal CFR,uch as, hypertension, valve disease, cardiomyop-thy, and amyloidosis.

ypertension

icrocirculatory abnormalities secondary to hy-ertension may be one of the most frequent andnderdiagnosed causes of chest pain in patientsith NOCAD. In fact, �35% of patients with hy-ertension will complain of some chest pain.44

ypertension increases left ventricular stress,hich leads to an increase in myocardial oxygenemand and not infrequently to subendocardialschemia. Furthermore, during exercise a com-romise to diastolic coronary filling can occur sec-

Table 2. Treatment Options for EndothelialDysfunction

ACE inhibitionCalcium channel blockersCholesterol-lowering medicationsAntioxidantsL-arginineFish oil

ndary to tachycardia, which can lead to further

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eductions in myocardial oxygen delivery. Severaltudies have demonstrated that patients with hy-ertension have a decrease in coronary flow re-erve.45-47 Optimizing therapy in patients withhest pain, NOCAD and hypertension will notnly lower their long-term cardiac event rate butill likely reduce their chest pain symptoms.

alvular Heart Disease

everal types of valvular disease are associatedith chest pain despite NOCAD. Aortic stenosis,

ortic regurgitation, and mitral valve regurgita-ion have all been associated with a decrease inoronary flow reserve.48-50

The incidence of chest pain in patients withortic stenosis has been reported to be 30% to0%, despite the absence of significant coronarytherosclerosis.51,52 The mechanism of chest pains not clear but may be related to impaired coro-ary flow reserve and left ventricular hypertrophy

eading to myocardial oxygen supply–demandismatch.53 Indeed, Julius et al54 noted that 50%

f all patients with severe aortic stenosis had chestain, which was associated with left ventricularypertrophy, increased wall stress, and reducedoronary flow reserve. Moreover, it has been dem-nstrated that patients with aortic stenosis andbnormal CFR have long-term improvement inFR after aortic valve replacement.55

Chest pain has also been described in patientsith aortic regurgitation and NOCAD. Nitenberg

t al49 demonstrated a significant reduction inFR in 8 patients with chronic aortic regurgita-

ion. Furthermore, left ventricular dilation, whichften accompanies aortic regurgitation, can leado subendocardial ischemia.56

Another controversial cause of chest pain inatients with NOCAD is mitral regurgitation.kasaka et al50 studied 31 patients with nonrheu-atic chronic mitral regurgitation and found a

ecrease in CFR compared to controls (2.1 vs..3). Moreover, CFR improved with mitral valveeconstructive surgery. The reduction in CFR ap-ears to be secondary to elevations in baselineverage peak velocity (APV), as hyperemic APVas not significantly different. Another possibleechanism for chest pain in patients with mitral

egurgitation is papillary muscle tension leadingo ischemia.57

All patients with unexplained chest pain and d

OCAD should undergo evaluation for valvularisease and assessment for coronary microvascu-ar abnormalities.

ardiomyopathy

ngina can occur with all types of cardiomyopa-hy, but is most commonly seen in the hypertro-hic and dilated cardiomyopathies.Anginal chest pain without angiographically

etectable coronary artery lesions has been foundn up to 50% of patients with dilated cardiomyop-thy.58 There have been several postulated mech-nisms including external vascular compressionfrom elevated left ventricular filling pressure, en-arged cardiac chamber, or intramyocardial fibro-is), dynamic limitation of vasodilatation, and en-othelial dysfunction.59 All of these mechanismsan lead to abnormal microvascular function, as isvident by the fact that impaired CFR has beenemonstrated in most patients with dilated car-iomyopathy.60

Chest pain is also commonly reported in pa-ients with hypertrophic cardiomyopathy (HCM).

yocardial ischemia has been repeatedly demon-trated in both the obstructive and nonobstructiveorms.61,62 The exact cause of the ischemia is notntirely clear, although it may be related to small-essel disease, septal perforator artery compres-ion, myocardial bridging, decreased coronaryerfusion pressure, obstruction to left ventricularutflow, or impaired relaxation leading to im-aired coronary filling.63 Furthermore, Krams etl64 demonstrated changes in the coronary micro-irculation of patients with HCM leading to ab-ormal coronary reserve.

myloidosis

myloidosis is a rare cause of chest pain in pa-ients with NOCAD. Amyloidosis represents aeterogeneous group of disorders that result fromxtracellular deposition of amyloid fibrils. Theost common form in the western world is immu-oglobulin light-chain–related or primary amy-

oidosis.65 Although the cardiac manifestation isypically heart failure, it can present as anginalhest pain. The mechanism for ischemia may beelated to direct involvement of the microcircula-ion with amyloid depositions. Amyloid deposi-ion in the coronary microcirculation has been
escribed in autopsy studies and endomyocardial

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iopsy studies.66,67 The vascular amyloid deposi-ion initially occurs in the media; with increasingeverity, amyloid infiltrates the adventitia and in-ima, resulting in complete or near-complete lu-inal obliteration of the intramyocardial arteries.he epicardial arteries are usually spared.

iagnosis

hen evaluating patients with chest pain, the rolef the cardiologist is to determine if symptoms areelated to a cardiac etiology. It is important toealize that patients with NOCAD may needurther testing after angiography and echocardi-graphy. The assessment of both endothelial-de-endent and -independent epicardial and micro-ascular abnormalities can often lead to a cardiaciagnosis that may have otherwise been missed.his in turn allows appropriate treatment options

o be initiated and better outcomes for patients. Inur catheterization laboratory, we have used theerm functional angiogram to denote assessment ofhe endothelium and microvascular circulation.

hysiologic Angiography

he regulation of coronary vascular tone involvesndothelial as well as nonendothelial factors. Inhe catheterization laboratory there are a numberf available drugs to help assess endothelial and/oronendothelial function (Table 3).The following protocol is a comprehensive

unctional angiogram to detect any abnormality inFR (Figure 2). Cardioactive medications areithheld at least 24 hours prior to and nitroglyc-

rin is not administered prior to diagnostic an-iography. A guiding catheter is used to engagehe left coronary ostium and a Doppler wire isdvanced into the mid left anterior descendingrtery through an infusion catheter, and intrave-

Table 3. Coronary Va

Endothelium-Dependent

Epicardial Micr

cetylcholine ��denosine �/�itroglycerin �itroprusside �

Abbreviations: Ach, acetylcholine; �, has an effect on;

ous heparin is given. We assess nonendothelial- i

ependent CFR with intracoronary boluses ofdenosine (18 to 42 �g) until maximal hyperemias achieved. After velocities return to baseline, thendothelial-dependent CFR is assessed by admin-stration of the vasodilator, acetylcholine (10�6

, 10�5 M, 10�4 M). Symptoms, hemodynamicata, electrocardiographic data, and Doppler ve-ocities are recorded at the end of each infusion.ollowing Ach infusion, intracoronary nitroglyc-rin (100 to 200 �g) is given.

CBF is calculated by using the formula D2 �PV/8, with D representing the coronary diameternd APV representing the average peak velocityrom the Doppler tracing.

In this way, we are able to evaluate both endo-helial-dependent (Ach) and endothelial-inde-endent (adenosine) changes (Table 4). An in-rease of �50% in CBF above the baseline inesponse to Ach and a CFR �2.5 in response todenosine are considered normal responses.68

If the functional angiogram is normal, the causeor chest pain falls into our third classification,amely, those patients without any evidence ofpicardial or microvascular abnormalities.

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Nonepicardial, NonmicrovascularCauses for Chest Pain

his group is the largest and most diverse of thehree groups. It includes all other disease statesot related to epicardial or microvascular disease.t is important to realize that these patients maytill have a cardiac etiology for their pain, such asericarditis.An in-depth discussion of each of the patholo-

ies that fall into this classification (Table 1) iseyond the scope of this review; however, theyhould all be kept in mind when evaluating thetiology of chest pain in a patient with NOCAD.oreover, if the epicardial and microvascular as-

essments are normal, than consultation withther specialists is important to help define thetiology of the chest pain.

ericarditis

ericardial and/or myocardial inflammation canimic ischemic chest pain. Typically, the pain is

escribed as sharp, retrosternal, and is aggravatedy lying flat and improved by sitting up. The phys-cal exam may reveal a pericardial friction rub orericardial knock. The electrocardiogram usuallyemonstrates diffuse ST-segment elevation. How-ver, the upward concavity of the ST segment,bsence of Q-waves and T-wave inversions, helpo distinguish pericarditis from acute coronaryyndromes. Pericarditis often responds well toonsteroidal anti-inflammatory agents.69

ascular

horacic aortic dissection is the most commonatastrophe of the aorta, 2 to 3 times more com-

Table 4. Interpretation of the FunctionalAngiogram

cetylcholineesponse

AdenosineResponse Diagnosis

ntact Intact Normalmpaired Intact Endothelial dysfunctionntact Impaired Nonedothelial

microvasculardysfunction

mpaired Impaired Both endothelial andnonendothelialdysfunction

on than rupture of the abdominal aorta. When i

eft untreated, about 35% of patients die withinhe first 24 hours, and �50% die within 48 hours.he pathologic features of aortic dissection con-ist of a tear in the intimal layer, followed by for-ation and propagation of a subintimal hema-

oma. If the pericardial space is involved in theissection, cardiac tamponade may result. Chestain is the most common presenting complaint inatients. The pain usually is described as rippingr tearing; however, this description is not univer-al, and some patients present with only mildain. Patients may present with ischemic pain andlectrocardiographic changes, if the coronary ar-eries are involved with the dissection. Smokingnd hypertension are the most common risk fac-ors associated with dissection.

Although aortic dissection or penetrating aorticlcers are unlikely to cause intermittent pain overeveral weeks, they should be considered in allatients complaining of acute, sudden, and severehest pain that is maximal at onset. Diagnosis isest obtained with computed tomography orransesophageal echocardiography.70

astrointestinal

ir William Osler first described the esophagus assource of episodic chest pain in 1892.71 Esoph-

geal abnormalities represent a significant per-entage of patients with noncardiac chest pain15% to 60%) and although gastroesophageal re-ux disease and esophageal spasm are the mostommon causes for chest pain originating fromhe gastrointestinal (GI) tract, one should alsoonsider biliary colic, cholecystitis, and peptic ul-er disease.72 It is not inconceivable that esopha-eal abnormalities produce similar symptoms asardiac ischemia because the distal esophagus andhe heart have a common afferent nerve supply.istory is often not helpful in discerning cardiac

rom esophageal chest pain because both can in-uce pressure or burning chest discomfort, whichs exertional in nature. Response to nitroglycerins not a helpful clue either; nitroglycerin can re-ieve the discomfort produced by esophagealpasm by relaxing smooth muscle or via placeboffect. Also, patients with cardiac and esophagealain often have similar risk factors, namely, to-acco use and obesity.Endoscopy, manometry, and 24-hour pH mon-

toring have all been advocated in the work up of

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atients with chest pain and NOCAD. However,andak et al73 found a short course of protonump inhibition to be more sensitive and specificor determining the cause of chest pain than en-oscopy, manometry, or 24-hour pH monitoring.t may be reasonable to consider acid suppressionherapy in patients prior to an extensive GI work-p.If the cardiac work-up is unremarkable, all pa-

ients with chest pain and NOCAD should be care-ully screened for the occurrence of esophagealisorders. Referral to a gastroenterologist may berudent.

ulmonary

everal pathologies in the pulmonary system mayead to chest pain and should be considered inatients with chest pain and NOCAD. Importantnes to rule out are pneumonia, pneumothorax,nd pulmonary embolism (PE). The first 2 shoulde readily apparent with history, physical exam,nd radiographs; however, PE frequently goes un-iagnosed and leads to significant morbidity andortality. It is estimated that PE leads to 50,000 to

00,000 deaths annually in the United States. Theost common symptoms reported in PE include

yspnea, chest pain, and cough. Patients oftenevelop tachypnea, rales, and/or tachycardia.owever, chronic PEs can lead to less dramatic

ymptoms and patients may present with pulmo-ary hypertension. Diagnosis is best obtainedith computed tomography or pulmonary an-iography. Therapy consists of anticoagulation.74

usculoskeletal

ietze syndrome is characterized by benign, local-zed, painful, swelling of an upper costochondralrea, without any evidence of overlying disease.he cause is unknown and the syndrome usuallyccurs in the second through fourth decades ofife. Tietze syndrome likely represents a small seg-

ent of the chest pain population. Epstein et al75

ound that only 10% of patients seen for chest painad a costochondral syndrome. Although it can beebilitating and associated with significant pain, its typically self-limiting and patients often obtainelief with nonsteroidal anti-inflammatory drugs.
p
nhanced Pain Perception/Psychogenic Pain

sychological factors have been suspected as aause of noncardiac chest pain for more than aentury. Fleet et al76 found that 1 in 4 patientsonsulting an ambulatory emergency depart-ent for chest pain suffer from panic disorder.nhanced pain perception has also been dem-nstrated in patients with chest pain andOCAD. Chauhan et al77 showed that intracar-iac catheter manipulation produced typicalhest pain in 34 of 36 patients with NOCAD, inhe absence of any changes in CBF, and that theame stimulus caused chest pain in only a smallroportion of patients with coronary artery dis-ase. A lower threshold for pain perceptionould explain the occurrence of chest pain inhese patients without involving an ischemicechanism.Treatment and diagnosis of chest pain second-

ry to enhanced pain perception or psychiatricbnormalities can be difficult and many patientsay not accept this explanation. Most patients

enefit from counseling, which helps in reducingurther health care utilization. Medical therapyften consists of tricyclic antidepressants such asmipramine or benzodiazepines.78 Nonpharmaco-ogic therapies may include biotherapy or spinalord stimulators.79-81 Spinal cord stimulation haseen shown to reduce symptoms and increase ex-rcise capacity in patients with chest pain andOCAD.82

Prognosis

verall, once life threatening diseases are ex-luded (dissection, PE, etc.), patients with chestain and NOCAD have an excellent long-termrognosis despite continued symptoms.83 In a

arge number of patients with chest pain and nor-al coronary angiograms, Kemp et al3 found that

he survival after a 7-year follow-up was 96%.bout one third of the deaths, however, were car-iovascular in origin. As noted, several studiesave shown that patients with endothelial dys-

unction are at risk for subsequent cardiac eventsnd it is this subpopulation that may contribute tohe cardiac mortality seen in patients with chest
ain and NOCAD.

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Chest Pain Clinic

he difficulty and extensive resource utilizationn diagnosing and treating patients with chest painnd NOCAD has led many institutions to developspecialized chest pain clinic, which utilizes aultidisciplinary approach to patient care. This

llows thorough investigation, patient education,nd frequent follow-up. Patients undergo lifestyleodification counseling and meet with dieticians

nd tobacco cessation specialists as needed. Pa-ients with NOCAD and chest pain often havengoing symptoms and may require frequent fol-ow-up to avoid further hospitalizations and un-ecessary evaluations. This can be accomplishedith the utilization of a chest pain clinic. In to-ay’s era of the informed patient, reassurance issually not adequate and patients will want anxplanation as to why they have chest pain. With-ut a sincere attempt to make a diagnosis, mostatients remain frustrated and return to seek med-

cal care. In our own institution, we have seen aecrease in the number of emergency room visitsnd coronary angiograms in patients with chestain and NOCAD after undergoing functional an-iography (Figure 3).

Educational opportunities, multidisciplinaryersonnel, and regular follow-up are key benefitsf a chest pain clinic that may reduce health caretilization and improve patient satisfaction.

Conclusions

he diagnosis and treatment of patients with chest

ig 3. Health care utilization. Abbreviations: ER,mergency room; Pre, prior to functional angiogra-hy; Post, after functional angiography.

ain and NOCAD can be a complex and time-

onsuming responsibility. A logical classificationnd step-wise approach is needed to avoid signif-cant expense and unnecessary testing. The prog-osis for these patients, with few excepted diag-oses, is quite good and reassurance, education,nd follow-up are important in their management.

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