A New Biomarker for Faster Assessment of Cardiovascular Risk

December 31, 2006

Rapid, accurate diagnosisof acute myocardialinfarction(MI) in patientswith chest pain isa formidable challenge.

Rapid, accurate diagnosisof acute myocardialinfarction(MI) in patientswith chest pain isa formidable challenge.Three principal tools arenow used to evaluate thesepatients:

  • History of the event.
  • 12-Lead ECG.
  • Cardiac serum markers.

All 3 tools lack diagnosticpower in this setting,especially early in thecourse of the event. In particular,the serum markerscreatine kinase MB (CKMB),troponin, and myoglobinare less likely to demonstratea positive value earlyin the course of acute MI.Certainly, a new serum biomarkerthat could reliablydetect acute MI earlier inthe presentation would behighly useful.
Moreover, many patientswho present to theemergency department(ED) with chest pain willhave a major adverse cardiacevent several weeksor months later.

1,2

Betterpredictors of future eventsare also needed.

A NEW BIOMARKERBrennan and colleagues3recently investigatedserum myeloperoxidaseas a marker for plaque instabilityin ED patients withchest pain. Myeloperoxidaseis a leukocyte enzymethat is released (along withother inflammatory markers)when white blood cellsare activated as part of theinflammatory response. Inflammationhas been linkedto the development of coronaryartery disease (CAD),and the inflammatory responseplays a key role inthe pathophysiologic cascadeof the acute coronarysyndrome (ACS) especiallyin patients who presentwith plaque rupture.
Several laboratorystudies have demonstratedthat leukocytes can alterthe integrity of plaque inACS. Many of the mechanismsby which the conditionand overall stability of plaque are adversely affectedmay be mediatedby myeloperoxidase. Examplesinclude:

  • Growth of less densecoronary plaques.
  • Activation of variousthrombogenic proteases.
  • Production of prothrombogenicand cytotoxiclipids.
  • The depletion of nitricoxide, which results invasoconstriction.

Myeloperoxidase levelsare increased in patientswith CAD and inthose with active coronarylesions.

Study design.

Brennanand associates

3

studied604 sequential ED patientswith chest pain of less than24 hours duration in whomACS was suspected. ACS was defined as either unstableangina (angina at restor with a sudden increasein frequency, ST segmentdepression, or T wave inversion)or acute MI (as evidencedby elevated troponinT levels). The meanduration of chest discomfortwas 4 hours. Final diagnosesincluded acute MI(24%), unstable angina(17%), suspected coronarysyndrome (38%), and noncoronarychest pain (22%).
Outcomes at 1 and 6months were also noted.These included MI, reinfarction,need for revascularization,and death.
The investigators measuredmyeloperoxidase levelswith an enzyme-linkedimmunosorbent assay; theydetermined the normalrange of myeloperoxidaseby measuring levels in 115healthy participants who did not have a history orclinical evidence of CAD.

Results.

Serummyeloperoxidase levels inthe normal controls weremarkedly lower (median,120 pM, with a range of97 to 146 pM) than in thestudy participants (median,198 pM, with a range of119 to 394 pM). Myeloperoxidaselevels were higherin patients with acute MI(320 pM) than in thosewithout MI (178 pM). Moreover, the incidenceof acute MI increased withincreasing myeloperoxidasevalues from 14% inpatients with myeloperoxidaselevels less than 119pM to 38% in patients withmyeloperoxidase levelsgreater than 394 pM.
Elevated initial myeloperoxidaselevels also predictedincreased riskat 1 and 6 months of recurrentMI, urgent need forrevascularization, and death. In particular, initial myeloperoxidaselevels weremarkedly higher in patientswho died within 6 months(270 pM) than in those whosurvived (194 pM). Elevatedmyeloperoxidase levelspredicted risk at 1 and 6months even in patients withnormal serum troponin valuesregardless of whetherthey initially had acute MI.

HOWMYELOPEROXIDASECOMPARES WITHOTHER CARDIACMARKERS
Myeloperoxidase levelswere elevated (291 pM)as early as 2 hours after theonset of chest pain. Moreover these early elevationsaccurately predicted acuteMI; thus, myeloperoxidasemeasurement provided asignificant improvementover existing laboratorystudies (Table).
Serum troponin andCK MB levels althoughreasonably sensitive foracute MI at 8 to 12 hoursafter chest pain onset arenot elevated for the first 3to 6 hours.4-14 Thus, theyprovide little useful informationearly in the patientscourse. (In this study,myeloperoxidase levels didcorrelate with serum troponinvalues but weakly;the mean value in patientswith elevated troponin levelswas 353 pM, comparedwith 309 pM in those withnormal troponin levels.) Ofthe serum markers currentlyused to evaluate potentialACS, serum myoglobinexhibits the most impressivesensitivity for MIearly in the course of illnessvalues are elevatedas early as 2 hours after theonset of chest pain; however,this marker is nonspecificfor acute MI.
In addition, myeloperoxidasepredicted futurerisk of cardiovascular complicationsmore accuratelythan existing serum markersof cardiac injury andsystemic inflammation.
FUTUREIMPLICATIONSBrennan and colleaguesdescribe a potentiallyuseful diagnostic andprognostic tool. If their resultscan be reproduced,measurement of myelopermyeloperoxidaselevels representsa signficant improvementover existing laboratorytests used in patients withchest pain. However, thesample size was small,and additional work in largerpopulations will be requiredto validate the conclusionsof the investigators.Furthermore, therange of values demonstratedsignificant overlap betweenpatients with ACSand those without, whichlessens the significance ofany individual value.

References:

REFERENCES:


1.

Aufderheide TP, Hendley GE, WooJ, et al. A prospective evaluation ofprehospital 12-lead ECG application inchest pain patients. J

Electrocardiol.

1992;24(suppl):8-13.

2.

Aufderheide TP, Keelan MH,Hendley GE, et al. Milwaukee PrehospitalChest Pain Project-phase I:feasibility and accuracy of prehospitalthrombolytic candidate selection.

Am J Cardiol.

1992;69:991-996.

3.

Brennan ML, Penn MS, Van LenteF, et al. Prognostic value of myeloperoxidasein patients with chest pain.

N Engl J Med.

2003;349:1595-1604.

4.

deFilippi CR, Tocchi M, ParmarRJ, et al. Cardiac troponin T in chestpain unit patients without ischemicelectrocardiographic changes: angiographiccorrelates and long-term clinicaloutcomes.

J Am Coll Cardiol.

2000;35:1827-1834.

5.

Lindahl B, Toss H, Siegbahn A,et al. Markers of myocardial damageand inflammation in relation to longtermmortality in unstable coronaryartery disease.

N Engl J Med.

2000;343:1139-1147.

6.

Apple FS, Murakami MM, PearceLA, Herzog CA. Predictive valueof cardiac troponin I and T for subsequentdeath in end-stage renal disease.

Circulation.

2002;106:2941-2945.

7.

Balk EM, Ioannidis JP, Salem D,et al. Accuracy of biomarkers to diagnoseacute cardiac ischemia in theemergency department: a meta-analysis.

Ann Emerg Med.

2001;37:478-494.

8.

Marin MM, Teichman SL. Use ofrapid serial sampling of creatine kinaseMB for very early detection ofmyocardial infarction in patients withacute chest pain.

Am Heart J.

1992;123:354-361.

9.

Hamm CW, Goldmann BU, HeeschenC, et al. Emergency room triageof patients with acute chest pain bymeans of rapid testing for cardiac troponin troponinT or troponin I.

N Engl J Med.

1997;337:1648-1653.

10.

Antman EM, Tanasijevic MJ,Thompson B, et al. Cardiac-specifictroponin I levels to predict the risk ofmortality in patients with acute coronarysyndromes.

N Engl J Med.

1996;335:1342-1349.

11.

Ohman EM, Armstrong PW,Christenson RH, et al. Cardiac troponinT levels for risk stratification inacute myocardial ischemia.

N Engl JMed.

1996;335:1333-1341.

12.

Green GB, Skarbek-BorowskiGW, Chan DW, Kelen GD. Myoglobinfor early risk stratification of emergencydepartment patients with possiblemyocardial ischemia.

Acad EmergMed.

2000;7:625-636.

13.

Zimmerman J, Fromm R, MeyerD, et al. Diagnostic marker cooperativestudy for the diagnosis of myocardialinfarction.

Circulation.

1999;99:1671-1677.

14.

Panteghini M, Apple FS, ChristensonRH, et al. Use of biochemicalmarkers in acute coronary syndromes.IFCC Scientific Division,Committee on Standardization ofMarkers of Cardiac Damage.

ClinChem Lab Med.

1999;37:687-693.