Narrative Review: Alternative Causes for Elevated Cardiac TroponinLevels when Acute Coronary Syndromes Are ExcludedAllen Jeremias, MD, and C. Michael Gibson, MS, MD

Current guidelines for the diagnosis of non-ST -segment elevation

myocardial infarction are largely based on an elevated troponin

level. While this rapid and sensitive blood test is certainly valu-

able in the appropriate setting, its widespread use in a variety of

clinical scenarios may lead to the detection of troponin elevation

in the absence of thrombotic acute coronary syndromes. Manydiseases, such as sepsis, hypovolemia, atrial fibrillation, conges-

tive heart failure, pulmonary embolism, myocarditis, myocardial

contusion, and renal failure, can be associated with an increase in

troponin level. These elevations may arise from various causes

other than thrombotic coronary artery occlusion. Given the lack of

any supportive data at present, patients with non thrombotic tro-

ponin elevation should not be treated with antithrom'botic and

antiplatelet agents. Rather, the underlying cause of the troponinelevation should be targeted. However, troponin elevation in theabsence of thrombotic acute coronary syndromes still retains prog-

nostic value. Thus, cardiac troponin elevations are common innumerous disease states and do not necessarily indicate the pres-ence of a thrombotic acute coronary syndrome. While troponin is

a sensitive biomarker to "rule out" non-ST -segment elevation

myocardial infarction, it is less useful to "rule in" this eventbecause it may lack specificity for acute coronary syndromes.

Ann Intern Med. 2005;142:786-791. www.annals.org

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dial infarction should therefore be diagnosed in conjunc-tion with other supportive evidence.

The implementation of these new guidelines in clinicalpractice has led to a substantial increase in the frequency ofmyocardial infarction diagnosis. For example, among 2181patients presenting with chest pain to an inner-city tertiarycare center, diagnoses of myocardial infarction based oncardiac troponin level increased up to 195% as comparedwith diagnoses made according to creatine kinase-MB cri-teria (4). Mortality at 30 days was significantly higheramong patients with elevated troponin levels at presenta-tion than among patients with no biomarkers detected, butit was not as high as among patients with elevated creatinekinase-MB levds. In several studies of acute coronary syn-dromes, troponin elevation has likewise been associatedwith a worse prognosis (5). FUrthermore, the risk for sub-sequent death appears to be rdated to the degree of tropo-nin elevation: There is a statistically significant increase inmortality with increasing levels of troponin, and the rela-tive risk for death is 7.8 in the group with the highesttroponin levels (6). While the presence of thrombus andimpaired epicardial blood flow are both associated withtroponin elevation (7, 8), impaired myocardial perfusion isa more robust and independent predictor of trQPonin ele-vation .among patients with acute coronary syndromes (9).

Among patients with a high pretest probability or clin-ical suspicion of thrombotic coronary artery disease, thediagnostic and prognostic value of troponin is clear. How-ever, troponin testing is now also being used as a screeningtool among patients with a low pretest probability of

I n September 2000, the Joint European Society of Cardi-ology/American College of Cardiology (ESC/ACC)

Committee proposed a new definition of myocardial in~farction based predominantly on the detection of the car-diospecific biomarkers troponin T and troponin I in theappropriate clinical setting (1). The rationale of includingtroponin assays in the diagnostic pathway was based on theassumption that myocardial necrosis, regardless of its mag~nitUde, should be characterized as a myocardial infarction.Contemporary troponin assays are quite sensitive and candetect even very small episodes of myocardial necrosis « 1 g).The Committee's recommendation for the diagnosis ofmyocardial infarction based on troponin elevation catego~rizes a cohort of patients whose values exceed the 99thpercentile of a reference control group with an acceptableimprecision (coefficient of variation) of 10% or less. Un-fortUnately, few assays in current clinical use meet thisstandard. It has therefore been proposed that an increase incardiac troponin levds above the 10% coefficient of varia~tion be considered indicative of myocardial injury (2).Given that numerous tropo~in assays are commerciallyavailable and in clinical use, each individual laboratoryshould confirm the range of reference values in their spe-cific setting and define the value that is considered a "sig-nificant" troponin devation.

The ESC/ACC Committee consensuS document statesthat "any amount of myocardial damage. ..implies animpaired clinical outcOme for the patient" and there is "nodiscernible threshold below which an elevated value of car-diac troponin would be deemed harmless" (1). This view isalso reflected in the updated 2002 ACC/ American HeartAssociation (AHA) practice guidelines for the managementof patients with unstable angina and non-ST ~segment el-evation myocardial infarction (3). However, the ACC/AHA guiddines do indicate that the myocardial necrosissignified by troponin elevation may not necessarily be dueto atherosclerotic coronary artery disease and that myocar-

786\ @ 2005 American CoUege of Physicians

Alternative Causes for Elevated Catdiac Troponin Levels REVIEW

thrombotic coronary artery disease. Given the high sensi-tivity of cardiac troponin for detecting even minimal myo-cardial-cell necrosis, these markers may become "positive"even in the absence of thrombotic acute coronary syn-dromes. This may occasionally be related to a spurioustroponin elevation (usually easily detectable by obtaining asecond sample) but may also be due to several nonthrom-botic cardiac and systemic diseases. In many instances,these troponin devations may arise from demand ischemia,with or even without significant coronary artery disease ormicrocirculatory dysfunction, rather than "supply-side"thrombotic ischemia. For example, among 1000 consecu-tive patients presenting to the emergency department of alarge urban hospital, troponin I level was elevated on ad-mission in 112 patients, and 45% of these patients had afinal diagnosis other than acute coronary syndrome (10).Given the high sensitivity but low specificiry among thesepatients with a low pretest probability of disease, the de-tection of even minimal troponin devation may divert at-tention from the true underlying clinical problem and maylead to unnecessary cardiac evaluation, including invasivetesting. The goal of this article is to review potential causesof troponin elevation that are unrelated to coronary throm-bosis (Table) and to provide guidance on the evaluationand management of patients with non thrombotic troponinelevation.

Table. Nonthrombotic Causes and Presumed Mechanism for

Elevated Cardiac Troponln Level

Mechanism

Myocardial depression/supply-demand mismatch

Decreased perfusion pressureDecreased filling pressure/output

Supply-demand mismatch

Subendocardial ischemia

Prolonged ischemia with myonecrosisImbalance of autonomic nervous

systemDirect adrenergic effeCts

Diagnosis

Demand ischemia

Sepsis/systemic inflammatoryresponse syndrome

Hypotension

HypovolemiaSupraventricular tachycardia!

atrial fibrillation

Left ventricular hypertrophy

Myocardial Ischemia

Coronary vasospasmIntracranial hemorrhage or

strokeIngestion of

sympathomimetic agents

Direct myocardial damage

Cardiac contusionDirect current cardioversion

Cardiac infiltrative disorders

ChemotherapyMyocarditisPericarditisCardiac transplantation

Myocardial strainCongestive heart failure

Pulmonary embolism

Pulmonary hypertension or

emphysemaStrenuous exercise

Traumatic

Traumatic

Myocyte compressionCardiac toxicity

InflammatoryInflammatory

Inflammatory/immune-mediated

Myocardial wall stretch

Right ventricular stretchRight ventricular stretch

Ventricular stretch

Chronic renal insufficiency UnknownCARDIAC TROPONINS

Cardiac troponins are regulatory proteins that controlthe calcium-mediated interaction of actin and myosin. Thetroponin complex consists of 3 subunits: troponin T,which binds to tropomyosin and facilitates contraction;troponin I, which binds to actin and inhibits actin-myosininteractions; and troponin C, which binds to calcium ions(11). The amino acid sequences of the skeletal and cardiacisoforms of cardiac troponin T and troponin I are suffi-ciently dissimilar and therefore detectable by monoclonalantibody-based assays (3). Troponin C is not used clini-cally because both cardiac and smooth muscle share tropo-nin C isoforms. The release of cardiac troponin from themyocyte to the blood can be due to reversible or irrevers-ible cell damage. In prolonged ischemia, cells are irrevers-ibly damaged as the cell membrane degrades, followed bythe gradual release of myofibril-bound cytosolic complexes(11). However, the notion that troponin is increased onlyafter irreversible myocardial necrosis has recently beenchallenged by the observation that some patients with un-stable angina have only transient troponin elevations, withvalues returning to baseline within a few hours (12). Thispattern of troponin increase may not be consistent withpermanent myocardial damage. It is, therefore, conceivablethat myocardial troponin can also be released in the settingof increased membrane permeability. For example, it isthought that myocardial depressive factors (released in thesetting of sepsis and other inflammatory states) cause deg-

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radation of free troponin in sitU to lower-molecular-weightfragments (13). With increased membrane permeability,those smaller troponin fragments could be released into thesystemic circulation. In this setting, myocyte damage maynot be permanent, and thus cell necrosis does not occur.This notion is also supported by the clinical observationt;hat myocardial depression during sepsis is a fully reversibleprocess in most surviving patients (14).

NONTHROMBOTIC MECHANISMS OF TROPONIN

ELEVATION

Demand IschemiaThe concept of "demand ischemia" without significant

coronary artery disease refers to a mismatch bet:.veen myo-cardial oxygen demand and supply in the absence of flow-limiting epicardial stenosis. Although theoretically thesame pathophysiologic principle may be valid in the pres-ence of coronary artery disease, it may be more difficult toidentify the predominant mechanism that accounts formyocardial ischemia in that clinical scenario. Myocardialoxygen demand frequently increases in the setting of sepsisor septic shock and the systemic inflammatory responsesyndrome (15-17), hypotension or hypovolemia (18), and

3 May 2005 \ Annals of Internal Medicine \ Volumc 142 0 Number 91787

atrial fibrillation or other tachyarrhythmias (19, 20). All ofthese clinical scenarios are either due to or can lead totachycardia with various loading conditions on the heart.This increases myocardial oxygen demand while decreasing

myocardial oxygen supply by shortening diastolic time, aperiod during which the majority of the myocardial perfu-sion occurs. In addition, sepsis and other systemic inflam-matory processes may lead to myocardial depression,greatly increased oxygen consumption, reduced perfusionpressure, and decreased oxygen delivery to the heart, ulti-mately resulting in the release of troponin into the systemiccirculation (16). Among 20 septic patients treated in anintensive care unit, 85% were noted to have elevated tro-ponin levels (16). The majority (59%) had no evidence ofsignificant coronary artery disease. Similarly, Guest andcolleagues found that elevated cardiac troponin level is acommon finding among critically ill patients and is associ-ated with a significant increase in mortality (15). In a morerecent study, Ammann and colleagues evaluated 58 pa-tients who were admitted to the intensive care unit fordiagnoses other than acute coronary syndromes (17).Among the 55% of patients with elevated troponin levels,tumor necrosis factor-a, interleukin-6, and C-reactive pro-tein levels were significantly higher than among patientswith undetectable troponin, and mortality was fourfoldhigher in the troponin-positive group. Of note, significantcoronary artery disease was excluded in 72% of troponin-positive patients. Thus, troponin elevation among patientswith sepsis and the systemic inflammatory response syn-drome with or without shock in the intensive care unitsetting is common and largely affects patients without sig-nificant coronary artery disease. Troponin elevation is as-sociated with a worse prognosis, but whether any cardio-vascular intervention could improve outcomes amongthese patients is unclear. Although a causal relationship hasyet to be established, inflammatory mediators in conjunc-tion with a myocardial oxygen demand-supply mismatchmay be likely explanations for this phenomenon.

Other potential causes of "demand ischemia" in theabsence of obstructive coronary artery disease includetachycardia and several tachyarrhythmias. In reviewing thecauses of elevated troponin levels in 21 patients with anormal coronary angiogram, Bakshi and colleagues foundthat tachycardia was the culprit in 28%, pericarditis in10%, congestive heart failure in 5%, and strenuous exercisein 10%; no precipitating event was identified for 47% ofpatients (19). Likewise, Zellweger and associates reportedon 4 patients with supraventricular tachycardia who werefound to have elevated troponin levels without evidence ofepicardial coronary stenoses (20). These reports illustratethat myocardial troponin can be released as a consequenceof tachycardia alone in the absence of myodepressive fac-tors, infla1Jlmatory mediators, and coronary artery disease.

Cardiac troponin elevation also has been described inthe context of left ventricular hypertrophy. Among 74 pa-tients without clinical evidence of active myocardial isch-

78813 May 20051 Annals ofIntcrnal Medicine I Volume 142. Number 9

emia, almost one third in the tertile with the greatest leftventricular mass had elevated troponin levels, as opposedto no patients in the lowest tertile of left ventricular mass(21). It is well recognized that left ventricular hypertrophycan lead to occult subendocardial ischemia via increasedoxygen demand from increased muscle mass, coupled withdecreased flow reserve due to remodeled coronary micro-circulation. Similar observations have been made in thesetting of aortic valve disease, in which elevated troponinlevel was associated with greater left ventricular wall thick-ness and higher pulmonary artery systolic pressures (22).

Myocardial Ischemia in the Absence of FixedObstructive Coronary Artery Disease

In the absence of acute coronary syndromes withthrombus formation and total vessel occlusion or distalembolization, myocardial ischemia can be caused by vaso-spasm (Prinzmetal angina). Among 93 patients with sus-pected myocardial ischemia and a subsequent diagnosis ofinsignificant coronary artery disease, 25% had elevated tro-ponin levels (23). Subsequent ergonovine provocation test-ing explained 74% of elevated troponin levels in these pa-tients, suggesting that vasospasm may lead to prolongedischemia and myonecrosis.

Elevated cardiac troponin levels along with ischemicchanges on the electrocardiogram are frequently observedin the setting of acute stroke or intracranial hemorrhage.Up to 27% of patients with acute stroke symptoms (24)and 20% of patients with a diagnosis of subarachnoidhemorrhage (25) were found to have increased troponinlevels. The most likely explanation of troponin elevationand myocardial damage in this setting is an imbalance ofthe autonomic nervous system, with resulting excess ofsympathetic activity and increased catecholamine effect onthe myocardial cells, rather thail preexisting coronary arterydisease (26). Similar effects can be observed after the inges-tion of sympathomimetics, not infrequently leading tomyocardial damage and troponin elevation.

Direct Myocardial DamageTroponin elevation can occur in the presence of struc-

tural heart disease. The mechanisms of troponin release inthese circumstances include cell injury by traumatic or in-flammatory processes. Velmahos and colleagues' recentstudy of 333 consecutive patients with significant bluntthoracic trauma showed the value of tropon~n testing inthe detection of cardiac contusion (27). The positive andnegative predictive values of an elevated troponin levelwere 21% and 94%, making troponin testing a valuabletool in excluding significant myocardial injury aftertrauma. Other reasons for traumatic troponin elevation in-clude implantable cardioverter defibrillator shocks (28) andinfiltrative disorders such as amyloidosis (29). It has beenpostulated that extracellular amyloid deposition may leadto myocyte compreSsion injury, leading to myocardialdamage and troponin release. Troponin measurementsmay also aid in the assessment of the cardiotoxic effects of

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Alternative Causes for Elevated Cardiac Troponin Levds REVIEW

high-dose chemotherapy and predict the development offuture left ventricular dysfunction in this population (30).

Inflammatory disorders leading to troponin elevationinclude acute pericarditis (31), myocarditis (32), and animmune response after heart transplantation. In fact,chronically elevated troponin levels after cardiac transplan-tation may be associated with a poorer prognosis. In aprospective cohort stUdy of 110 consecutive patients aftercardiac transplantation, troponin levels remained persis-tently elevated in 51 % of patients and were associated withmore fibrin deposition in the microvasculature and amongmyocytes, as well as a significant increase in the risk forcoronary artery disease and graft failure (33).

may be related to an increase in myocardial strain during

exercise, although catecholamineMinduced vasospasm hasalso been invoked as an explanation (11).

Cardiopulmonary Disease and Right-Heart Strain

Similarly, patients with right-heart strain are fre-quently found to have elevated troponin levels. The re-ported incidence of tloponin elevation among patientswith acute pulmonary embolism varies from 16% to 50%,and elevated levels are associated with a significant increasein mortality (40). Among patients with chronic pulmonaryhypertension, troponin was detectable in 14% of cases andwas associated with higher heart rates, lower mixed venousoxygen satUration, and higher levels of B-type natriureticpeptide, as well as significantly worse cumulative survival at2 years (81% vs. 29%) (41). Exacerbation of chronic ob-structive pulmonary disease can also increase troponin lev-els and has been identified as an independent predictor of

in-hospital mortality (42).

Myocardial StrainVolume and pressure overload of both the right and

left ventricle, as in congestive heart failure, can lead to therelease of cardiac troponin in the absence of myocardialischemia. This may be due to excessive wall tension or"myocardial strain," with resulting myofibrillary damage.Myocardial strain may be defined as the percentage changeof a structure from its initial length with the application ofstress (22). Support for the "strain" theory comes frommultiple studies that demonstrate a close correlation be-tween troponin and B-type natriuretic peptide (34), amarker of right and left ventricular wall strain. Further-more, in vitro experiments with myocytes established a linkbetween myocardial wall stretch and programmed celldeath (35), and troponin degradation has been demon-strated as a result of increased preload independendy frommyocardial ischemia in isolated rat hearts (36). It has alsobeen hypothesized that increased myocardial wall stressmay lead to decreased subendocardial perfusion, with re-sulting troponin elevation and decline in left ventricularsystolic function (37). In the setting of acute or chroniccongestive heart failure, additional factors, including theactivation of the renin-angiotensin system, sympatheticstimulation, and inflammatory mediators, may be partiallyresponsible for myocyte injury and cell death. Progressivemyocyte loss is now thought to playa prominent role inthe progression of cardiac dysfunction; it may explain theominous prognosis of patients with congestive heart failureand elevated troponin levels. In fact, several small studiesdocumented troponin elevation in the presence of conges-tive heart failure without evidence of an acute coronarysyndrome. They have also established a relationship be-tween troponin elevation and increased mortaliry duringfollow-up. Of 238 patients with advanced heart failurewho were referred for cardiac transplantation evaluation,49% were found to have elevated cardiac troponin levels(37). Patients with detectable troponin had significandyhigher B-type natriuretic peptide levels, higher pulmonarywedge pressures, lower cardiac indices, and a twofold in-crease in mortality.

Many reports have described troponin elevation innormal persons after ultraendurance exercise (38, 39). This

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Cardiac Troponin In Chronic Renal InsufficiencyPersistently elevated cardiac troponin is frequently ob-

served among patients with end-stage renal disease (43-45). Therefore, a higher troponin threshold was proposedfor the diagnosis of myocardial ischemia in patients withchronic renal insufficiency (46). Despite these permanentelevations, troponin was found to be an independent pre-dictor of death or myocardial infatction across the entirespectrum of renal function in a recent analysis of 7033patients with acute coronary syndrome in the GUSTO IV(Globa,i Use of Strategies to Open Occluded Coronary Ar-teries IV) trial (47).

The prevalence of increased troponin values amongp~tients with chronic renal failure in the absence of clini-cally suspected ischemia may be as high as 53% (45). Thismay be the result of small areas of clinically silent myocat-dial necrosis, but other causes, such as increased left ven-tricular mass and impaired renal troponin excretion, havealso been proposed. Although the exact mechanism of tro-ponin elimination is unknown, it is believed to be clearedby the reticuloendothelial system given the relatively largemoleculat size of troponin (45). However, recent evidencedemonstrates that troponin T is fragmented into moleculessmall enough to be renally excreted; this may explain thehigh prevalence of troponin elevation in patients with se-vere renal failure (48). IrrespeCtive of the cause, detectabletroponin among stable patients with end-stage renal diseaseappeats to be a powerful predictor of incr~ased intermedi-ate-term mortality (44) and may be an even stronger riskfactor in conjunction with elevated C-reactive protein lev-els (43). Of note, multivessel coronary artery disease wasmore prevalent across progressively higher quartiles of tr6-ponin T, suggesting an ischemic mechanism for the tropo-nin increase in this patient population (43).

3 May ZOO5 I Annals of Internal Mcdicincjv°lumc 14ZoNumbcr 91789

REVIEW Alternative Cause.s for Elevated Cardiac Troponin Levds

no means always, caused by thrombotic obstruction andimpaired myocardial perfusion in the context of an acutecoronary syndrome. This marker is frequendy "positive" inother disease states in the absence of thrombotic acute cor-onary syndromes. Therefore, while troponin is a sensitivebiomarker to "rule out" non-ST -segment elevation myo-cardial infarction, it is less useful to "rule in" this eventbecause it is not specific for acute coronary syndromes. Asa result, if troponin testing is applied indiscriminately inbroad populations that have a low pretest probability ofthrombotic disease, the positive predictive value of themarker is greatly diminished. While troponin devation in apatient with suspected acute coronary syndrome may guidemanagement decisions, such as the need for antithrom-botic, antiplatelet, and interventional therapies, no datasupport the role of these therapies in the management ofpatients with a nonthrombotic syndrome. Treatmentshould be aimed at the underlying disorder. However, tro-ponin elevation in the absence of thrombotic acute coro-nary syndromes still retains prognostic value, and screeningmay be justified on this basis. .

From Berh Israel Deaconess Medical Center and Harvard MedicalSchool, Boston, Massachusetts.

Potential Financial Conflicts of Interest: None disclosed.

Requests for Single Reprints: Allen Jeremias, MD, Division of Cardi-ology, Beth Israd Deaconess Medical Center, One Deaconess Road,Baker 4, Boston, MA 02215; e-mail, ajeremia@bidmc.harvard.edu.

Current author addresses are available at www.annals.org.

SIGNIFICANCE OF TROPONIN ELEVATION IN THE

ABSENCE OF ACUTE CORONARY SYNDROMES AND

POTENTIAL TREATMENT STRATEGIES

Both short- and long-term survival are impairedamong patients with troponin elevation in many differentclinical settings, including congestive heart failure, sepsis,pulmonary disease, acute pulmonary embolism, and renalinsufficiency. The reasons for this increase in mortality arecurrently poorly understood but may be related to myocar-dial necrosis with myocyte loss or underlying quiescentcoronary artery disease. However, another possibility isthat increased troponin merely reflects a more fulminantdisease process. Given this substantially increased risk foradverse outcomes, patients with troponin elevation in gen-eral require appropriate diagnostic evaluation and therapyaimed at the underlying disorder.

The assessment of whether a troponin elevation isthrombotic or nonthrombotic in origin can be challenging.Ischemic electrocardiogram changes, chest pain, wall-motion abnormalities on echocardiography, and the pres-ence of atherosclerotic risk factors may be associated with athrombotic origin of the troponin elevation and shouldguide the use of further cardiovascular evaluation, includ-ing early risk stratification (3). On the other hand, patientswith a low pretest probability of coronary artery diseasewill most likely not derive any benefit from a treatmentstrategy aimed at coronary thrombosis. In this population,the main goal is to identify the underlying cause of thetroponin elevation, which frequently becomes evident aftera thorough history and physi!::al examination (in conditionssuch as myocarditis, pericarditis, cardiac contusion, sepsis,pulmonary embolism, and congestive heart failure). Ther-apy in these circumstances should target the underlyingcause rather than the "troponin leak" itself.

No data from randomized, controlled trials are avail-able to assess the efficacy of therapies aimed at reducing therisk for adverse events among patients with troponin ele-vations in the absence of an acute coronary syndrome. Asoutlined in this review, cardiac troponin elevations arecommon in numerous disease states and do not necessarilyin,dicate the presence of a thrombotic acute coronary syn-drome. Therefore, in the absence of any supportive data atpresent, in our practice, patients with nonthrombotic tro-ponin elevation are generally not treated with antithrom-botic and antiplatelet agents. Likewise, no current datasupport an early invasive mechanical revascularizationstrategy among these patients, in whom the suspicion ofthrombotic coronary artery disease is low. Unless aspirin iscontraindicated, we frequently recommend the use of thisdrug, which appears to be relatively safe in most clinicalcircumstances .

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CONCLUSIONS

Troponin is a highly sensitive biomarker that aids inthe detection of myocardial cell damage. It is often, but by

79°13 May 200SIAnna!s of In..,nal Meciieine I Volume 142. Number 9 www.annals.oti

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3 May 200S I Annals of Internal Medicine!Volume 142 "Number 91791www.annals.org

Current Author Addresses: Drs. Jeremias and Gibson: Division of Car-diology, Beth Israel Deaconess Medical Center, One Deaconess Road,Baker 4, Boston, MA 02215.

W'18613 May 2005 \ Annals of Incernal Medicine I Volume 142'Number 9 YNIW.annals.org