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Journal of the American College of Cardiology Vol. 47, No. 5, 2006© 2006 by the American College of Cardiology Foundation ISSN 0735-1097/06/$32.00P

arly Inflammation and Risk ofong-Term Development of Heart Failure andortality in Survivors of Acute Myocardial Infarction

redictive Role of C-Reactive Proteinahmoud Suleiman, MD,* Rania Khatib,* Yoram Agmon, MD,* Riad Mahamid, MD,*onther Boulos, MD,† Michael Kapeliovich, MD, PHD,* Yishai Levy, MD,† Rafael Beyar, MD, DSC,*alter Markiewicz, MD,* Haim Hammerman, MD,* Doron Aronson, MD*

aifa, Israel

OBJECTIVES We aimed to study the relationship between C-reactive-protein (CRP), obtained within 12to 24 h of symptoms onset, and long-term risk of death and heart failure (HF) in survivorsof acute myocardial infarction (MI).

BACKGROUND A robust inflammatory response is an integral component of the response to tissue injuryduring MI. The magnitude of the early inflammatory response to ischemic injury might bean important determinant of long-term outcome.

METHODS We prospectively studied 1,044 patients admitted with acute MI and discharged fromhospital in stable condition.

RESULTS During a median follow-up of 23 months (range, 6 to 42 months), 113 patients died and 112developed HF. In a multivariable Cox regression model adjusting for clinical variables andpredischarge ejection fraction, compared with patients in the first CRP quartile, the adjustedhazard ratios (HRs) for death progressively increased with higher quartiles of CRP (secondquartile 1.4 [95% confidence interval (CI) 0.6 to 2.9]; third quartile 2.3 [95% CI 1.2 to 4.6];fourth quartile 3.0 [95% CI 1.5 to 5.7]; for trend, p � 0.0002). Compared with patients inthe first CRP quartile, the adjusted HRs for HF were: second quartile, 1.1 (95% CI 0.5 to2.3); third quartile, 1.9 (95% CI 1.0 to 3.6); and fourth quartile, 2.1 (95% CI 1.2 to 3.9) (fortrend, p � 0.005).

CONCLUSIONS C-reactive-protein is a marker of long-term development of HF and mortality in patientswith acute MI and provides prognostic information beyond that provided by conventional riskfactors and the degree of left ventricular systolic dysfunction. (J Am Coll Cardiol 2006;47:

ublished by Elsevier Inc. doi:10.1016/j.jacc.2005.10.055

962–8) © 2006 by the American College of Cardiology Foundation

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robust inflammatory response is an integral component ofhe response to tissue injury and plays a particularly activeole after myocardial infarction (MI). Proinflammatoryytokines are elaborated soon after myocardial ischemicnjury and mediate tissue repair and adaptation; however,here is evidence that an exaggerated inflammatory responseight also promote tissue injury. Therefore, the degree of

he inflammatory response might be an important determi-ant of outcome by leading to chronic cardiac dilatation,eart failure (HF), and death (1).C-reactive protein (CRP) has emerged as a simple tool

or detecting low-level systemic inflammation that portendsoronary events in apparently healthy subjects (2,3) and inatients with a recent coronary event (4). In this setting,RP levels might reflect inflammation in the vascular bedr an intensification of focal inflammatory processes thatestabilize vulnerable plaques (5). By contrast, in the acutehase of MI, CRP levels are likely to be dominated by thenflammatory response to myocardial necrosis rather than byhronic vascular inflammation (6–8). The CRP levels in the

From the Departments of *Cardiology and †Internal Medicine D, Rambamedical Center and the Bruce Rappaport faculty of medicine, Haifa, Israel.

wManuscript received July 25, 2005; revised manuscript received October 6, 2005,

ccepted October 17, 2005.

arly phase of MI might be a simple marker for the magni-ude of the inflammatory response to myocardial necrosis,otentially providing prognostic information regarding theisk of death and HF (9,10).

Despite the pathophysiological link between inflamma-ion and HF (11), previous studies that addressed therognostic values of CRP after MI seldom included HF asn outcome, and most of the prognostic information wasontributed by early in-hospital events (9,12,13); however,he end point of HF is important because of the contribu-ion of MI survivors to the epidemic of HF (14,15) andecause inflammation might antedate the development ofF in patients without prior MI (11). Therefore, the

urpose of the present prospective study was to test theypothesis that early determination of CRP, a potentialarker of the intensity of inflammatory response to isch-

mic injury, might predict the long-term development ofF and death in patients who survived their index

nfarction.

ETHODS

atients. All patients presenting to the intensive coronaryare unit of the Rambam Medical Center with acute MI

ere eligible for entry into the study. The investigational

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963JACC Vol. 47, No. 5, 2006 Suleiman et al.March 7, 2006:962–8 CRP and Long-Term Outcome After MI

eview committee on human research approved the studyrotocol.Myocardial infarction was diagnosed according to the

oint European Society of Cardiology/American College ofardiology criteria (16). Exclusion criteria were knownalignancy, known inflammatory disease, surgery, trauma,

r MI in the previous month. Patients admitted at �24 hrom symptoms onset were also excluded. Patients withT-segment elevation of �0.1 mV in two contiguouslectrocardiographic leads received thrombolytic therapytissue plasminogen activator or streptokinase) or underwentrimary angioplasty.Left ventricular ejection fraction (LVEF) was measured

y echocardiography in 895 patients and by contrast leftentriculograms in the remaining 149 patients. Computer-ssisted analysis of the traced left ventriculograms at endiastole and at end systole provided the LVEF.lood sampling procedure and CRP assay. Venous blood

amples for CRP were obtained within 12 to 24 h ofymptom onset. Blood samples were collected in citrate-reated tubes, centrifuged for at least 5 min, and stored at

70°C. High-sensitivity CRP was measured with latex-nhanced immunonephelometry on a Behring BN-ProSpecephelometer (Dade Behring, Marburg, Germany). The

ssay has a detection limit of 0.175 mg/l. The intra-assayoefficient of variation for CRP was 3.3% and the inter-ssay coefficient of variation was 3.2%. The CRP levels werenalyzed by laboratory personnel who were not involved inatient care. Test results were not available to the attendinghysicians.tudy end points. The primary end points of the studyere: 1) all-cause mortality, and 2) development of HF,efined as readmission to hospital for the management ofF (defined by the presence of new symptoms of dyspnea or

dema with one or more concurrent signs, including ven-ricular gallop rhythm, bilateral post-tussive rales in at leasthe lower third of the lung fields, elevated venous pressure,r pulmonary venous congestion on X-ray with interstitialr alveolar edema). The diagnosis of HF was confirmedith hospital records and discharge summaries. The sec-ndary end point was the combined end point of death andF. After hospital discharge, clinical end point informationas acquired by reviewing the national death registry and by

Abbreviations and AcronymsBNP � B-type natriuretic peptideCI � confidence intervalCK � creatine kinaseCRP � C-reactive proteinEF � ejection fractionHF � heart failureHR � hazard ratioLV � left ventricle/ventricularMI � myocardial infarction

ontacting each patient individually and independently re- w

iewing the hospital course for major clinical events if theatient had been re-hospitalized.tatistical analysis. Data are expressed as mean � SD oredian and interquartile range. Baseline characteristics of the

roups were compared with analysis of variance (ANOVA) forontinuous variables and by the chi-square statistic for non-ontinuous variables. When continuous data was not normallyistributed or had unequal variance, groups were comparedith the nonparametric one-way ANOVA (Kruskal-Wallis

est).Event-free survival was estimated by the Kaplan–Meierethod, and curves were compared with the log-rank test.nivariate and multivariate Cox proportional hazard anal-

ses were performed to determine the relation between CRPnd mortality. The following baseline clinical characteristicsere considered in the multivariate procedure: age, gender,aseline creatinine, history of congestive HF, history ofrior HF, history of diabetes, history of hypertension,moking status, Killip class �I on admission, hypotensionsystolic blood pressure �100 mm Hg) and tachycardiaheart rate �100 beats/min) on admission, anterior locationf infarction, ST-segment elevation infarction, peak creat-ne kinase (CK), reperfusion therapy with either thrombo-ytics or primary angioplasty, and predischarge LVEF strat-fied as above or below 45%. Only variables with p � 0.2 inhe univariate Cox regression analyses were used in theultivariate model.Cox proportional hazards modeling was also used to

etermine the relationship between quartiles of CRP anddmission for the treatment of HF. Known predictors of theevelopment of HF in survivors of MI (15) were forced intohe model (age, LVEF, baseline heart rate, Killip class atdmission, history of hypertension and diabetes, previousnfarction). In addition, other potential predictors wereonsidered (gender, previous HF, anterior infarction, ST-egment elevation infarction, peak CK, and use of reperfu-ion therapy) if they demonstrated association with HF onnivariate analysis (p � 0.2). Because recurrent MI in-reases the risk for HF (15) and is associated with greateregrees of HF, we performed two separate analyses for thisnd point: Model 1, including recurrent MI as a time-ependent covariate in the Cox model; and Model 2, inhich only HF events occurring without a preceding recur-

ent MI were considered (i.e., HF that can be attributed tohe index infarction).

We performed supplementary analyses for the combinednd point of death and HF after dividing the studyarticipants into 12 groups on the basis of CRP quartilesnd three categories incorporating clinical evidence of HFuring admission or reduced LV systolic function, as fol-

ows: 1) Killip class I on admission and preserved (�45%)redischarge LVEF; 2) Killip class II to IV on admission oreduced (�45%) predischarge LVEF; and 3) Killip class IIo IV on admission and reduced predischarge LVEF.

All models were also developed after excluding patients

ith previous history of HF (n � 48). These models were

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964 Suleiman et al. JACC Vol. 47, No. 5, 2006CRP and Long-Term Outcome After MI March 7, 2006:962–8

ot appreciably different with regard to the relation betweenRP and the primary end points. Therefore, only analysesased on the whole study population are presented in detail.ifferences were considered statistically significant at the

wo-sided p � 0.05 level. All statistical analyses wereerformed with the SPSS statistical software (version 11.5,PSS Inc., Chicago, Illinois).

ESULTS

etween July 2001 and June 2004, a total of 1,196 patientsresenting with acute MI were enrolled. Of these, 1,044urvived their index event and were discharged from hospi-al in stable condition. Median CRP level of these patientsas 13.6 mg/l (interquartile range 5.0 to 38.1 mg/l).The clinical characteristics of patients according to the

uartiles of CRP are shown in Table 1. Patients with CRPn the upper quartiles were older and had higher baselinereatinine and more history of previous HF; they presentedith higher heart rates and higher Killip class and had lowerF. They were less likely to receive reperfusion therapy. Atischarge, use of statins was less frequent in patients withlevated CRP.

ortality. The median duration of follow-up after hospitalischarge was 23 months (range, 6 to 42 months). Duringhe follow-up period 113 patients (10.8%) died. MedianRP levels were significantly higher among patients whoied than among patients who survived (31.6 mg/l inter-

able 1. Baseline Patient Characteristics According to CRP Qua

Variable

Quartil

1st (n � 261)(<5.0)

2nd ((5.

ge (yrs) 59 � 11 60ale gender 217 (84) 20

erum creatinine (mg/dl)* 1.0 � 0.4 1.0rior myocardial infarction 58 (22) 4rior heart failure 5 (2)iabetes 61 (23) 7

moking habit 43 (17) 3ypertension 127 (49) 13

T-segment elevation infarction 183 (70) 19nterior infarction 108 (42) 10illip class on admission 1.2 � 0.5 1.2eart rate on admission (beats/min) 75 � 17 77

ystolic blood pressure onadmission (mm Hg)

134 � 28 135

eak CK (IU/l)† 779 [281, 1,735] 994 [4jection fraction (%) 50ny reperfusion therapy‡ 126 (48) 12edications at dischargeAntiplatelet agents 256 (98) 25ACE inhibitors or ARBs 204 (78) 21Beta-blockers 220 (84) 22Statins 177 (68) 17

ontinuous variables were compared using analysis of variance except for peak creatinere compared by the chi-square statistic. *To convert from mg/dl to �mol/l, mult

ngioplasty.ACE � angiotensin-converting enzyme; ARB � angiotensin II receptor blocker

uartile range [13.8 to 96.7] vs. 12.6 mg/l interquartile i

ange [4.7 to 32.8], p � 0.0001). Kaplan-Meier analysishowed an increased probability of death during follow-upith increasing quartiles of CRP (Fig. 1). The Kaplan-eier survival curves for CRP quartiles separated early,

ielding a statistically significant difference in mortality at0 days after hospital discharge (log-rank p � 0.005). Theeparation of the curves continued throughout the follow-uperiod (log-rank p � 0.0001), with mortality rates of 4.4%12 patients), 6.1% (16 patients), 12.3% (32 patients), and0.3% (53 patients) in the respective quartiles.In a multivariable Cox proportional hazards model adjust-

ng for other potential clinical predictors of mortality andor EF, increasing quartiles of CRP independently contrib-ted to the prediction of post-discharge death (Table 2).djusting for LVEF as a continuous variable gave similar

esults. Compared with patients in the first CRP quartile,he adjusted HRs for death were 1.3 for patients in theecond quartile (95% confidence interval [CI], 0.6 to 2.7;� 0.7); 1.9 for patients in the third quartile (95% CI, 1.0

o 3.8; p � 0.05); and 2.6 for patients in the fourth quartile95% CI, 1.4 to 5.1; p � 0.004). Additional adjustments foroncomitant cardiovascular medications at discharge had noiscernible effect on these estimates.ost-discharge HF. During follow-up 112 patients (10.7%)ere admitted for the treatment of HF. Median CRP levelsere significantly higher among patients who developed HF

han among patients who did not develop HF (27.0 mg/l,

-Reactive Protein (Range, mg/l)

p Value261)5)

3rd (n � 261)(13.6–37.8)

4th (n � 261)(>37.9)

3 60 � 13 64 � 13 �0.0001) 203 (78) 203 (78) 0.32.4 1.1 � 0.9 1.2 � 0.8 0.001) 61 (23) 59 (23) 0.38

12 (5) 22 (8) 0.003) 79 (30) 85 (33) 0.12) 41 (16) 46 (18) 0.05) 129 (49) 150 (57) 0.18) 194 (74) 172 (66) 0.16) 126 (48) 114 (44) 0.13.6 1.4 � 0.7 1.6 � 1.0 �0.00016 78 � 18 82 � 20 �0.00014 132 � 28 132 � 26 0.32

,039] 1,127 [441, 2,663] 1,201 [583, 2,250] �0.000144 41 �0.0001

) 138 (53) 100 (38) 0.007

) 249 (95) 248 (95) 0.11) 222 (85) 204 (78) 0.14) 213 (82) 207 (80) 0.23) 150 (58) 151 (58) 0.02

se (CK), which was compared with the Kruskal-Wallis test. Noncontinuous variables88.4. †To convert U/l to �kat/l, divide by 60. ‡Thrombolytic therapy or primary

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965JACC Vol. 47, No. 5, 2006 Suleiman et al.March 7, 2006:962–8 CRP and Long-Term Outcome After MI

ange [4.8 to 33.8], p � 0.0001). Recurrent infarctionccurred more frequently in patients who developed HFhan in patients who did not develop HF (15.2% vs. 6.0%,� 0.0001). The risk of subsequent death was significantly

reater in patients with HF developing during follow-upompared with patients without HF (27.7% vs. 8.8%, p �.0001).Kaplan-Meier analysis showed a graded increased prob-

bility for HF during follow-up with increasing quartiles ofRP (Fig. 2). Table 3 displays the results of multivariate

nalyses examining the relationship between CRP levels andisk of HF. C-reactive protein added prognostic informa-ion above and beyond that provided by known clinicalredictors of HF, pre-discharge EF, and recurrent infarc-ion during follow-up (Table 3, Model 1). Other significantredictors of HF included age (HR 1.4 per 10 years; 95% CI.2 to 1.7, p � 0.0001), Killip class above I at admissionHR 2.0; 95% CI 1.3 to 3.0, p � 0.002), reduced LVEFHR 2.4; 95% CI 1.5 to 3.7, p � 0.0001), peak CK (HR 1.3er quartile, 95% CI 1.1 to 1.6, p � 0.003) and recurrentI (HR 2.5; 95% CI 1.3 to 4.8, p � 0.008).The relationship between CRP and HF was also exam-

ned in patients in whom development of HF could bettributed to the index infarction, by excluding HF events

igure 1. Kaplan-Meier plot showing the crude cumulative incidence of deor the overall comparison among the groups.

able 2. Unadjusted and Adjusted Cox Proportional Hazards Mo

CRPQuartile n Events (%)

Unadjusted

HR (95% CI) p Value p Trend

1st 261 12 (4.6) 1.0 — �0.00012nd 261 16 (6.1) 1.3 (0.6–2.8) 0.443rd 261 32 (12.3) 2.8 (1.5–5.5) 0.0024th 261 53 (20.3) 5.5 (2.9–10.2) �0.0001

he final model adjusted for age, gender, baseline creatinine, previous heart failure, his

eart rate and blood pressure on admission, use of reperfusion therapy, and left ventricular

CI � confidence interval; CRP � C-reative protein; HR � hazard ratio.

hat occurred in patients with recurrent infarction (n � 17).he effect of increasing CRP was particularly striking after

xcluding these events, with an adjusted HR for HF of 2.8n the upper CRP quartile (Table 3, Model 2). Adjusting forVEF as a continuous variable resulted in an adjusted HRf 2.8 in patients in the fourth CRP quartile compared withatients in the first CRP quartile (95% CI 1.3 to 5.9; p �.007). No significant differences were found when thenalyses in Table 3 were repeated after exclusion of patientsn � 48) with prior HF.

C-reactive protein levels were not predictive of theevelopment of recurrent MI (16, 21, 20, and 20 recurrentnfarctions occurring in patients in the first, second, third,nd fourth CRP quartile, respectively; p � 0.84).ombined end point of death and HF. For the combined

nd point of death and HF, 23 (8.8%), 27 (10.3%), 5822.2%), and 86 (33.0%) events occurred in the first, second,hird, and fourth CRP quartile, respectively (p � 0.0001).ompared with patients in the first CRP quartile, the

djusted HRs for the combined end point of death and HFere as follows: second quartile, 1.2 (95% CI, 0.6 to 2.1; p �.60); third quartile, 1.9 (95% CI, 1.1 to 3.2; p � 0.02); andourth quartile, 2.5 (95% CI, 1.5 to 4.1; p � 0.0001).

cording to quartiles of C-reactive protein. p � 0.0001 by the log-rank test

or All-Cause Mortality According to Quartiles of CRP

justed for Clinical VariablesAdjusted for Clinical Variables

and LVEF

(95% CI) p Value p Trend HR (95% CI) p Value p Trend

1.0 — �0.0001 1.0 — 0.0002(0.7–2.9) 0.40 1.4 (0.6–2.9) 0.40(1.3–4.9) 0.007 2.3 (1.2–4.6) 0.01(1.7–6.3) 0.0003 3.0 (1.5–5.7) 0.001

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966 Suleiman et al. JACC Vol. 47, No. 5, 2006CRP and Long-Term Outcome After MI March 7, 2006:962–8

We further estimated the HRs for the combined endoint of death or HF after dividing the study participantsnto 12 groups on the basis of CRP quartiles and clinicalvidence of HF during admission or reduced LV systolicunction. As shown in Figure 3, after adjustment to otherlinical risk factors, CRP added prognostic informationith regard to the risk of death and HF even in the low-riskroup of patients with no evidence of HF during admissionnd preserved predischarge EF (adjusted HR 2.7; 95% CI.2 to 6.4, p � 0.02 for patients in the fourth compared withhe first CRP quartile). Similarly, CRP added prognosticnformation for post-discharge death of HF in the high-riskubgroup of patients with both clinical evidence of HFuring admission and reduced LV systolic function (ad-

usted HR 2.8; 95% CI 1.1 to 7.4, p � 0.04 for patients inhe fourth compared with the first CRP quartile).

igure 2. Kaplan-Meier plot showing the crude cumulative incidence of arotein. p � 0.0001 by the log-rank test for the overall comparison amon

able 3. Unadjusted and Adjusted Cox Proportional Hazards Mo

CRPQuartile n Events (%)

Unadjusted

HR (95% CI) p Value p Trend

odel 1*1st 261 13 (5.0) 1.0 — �0.00012nd 261 16 (6.1) 1.2 (0.6–2.6) 0.563rd 261 35 (13.4) 2.8 (1.5–5.3) 0.0024th 261 48 (18.4) 4.3 (2.3–7.9) �0.0001odel 2†1st 261 9 (3.4) 1.0 — �0.00012nd 261 13 (5.0) 1.5 (0.6–3.4) 0.393rd 261 28 (10.7) 3.2 (1.5–6.8) 0.0024th 261 45 (17.2) 5.7 (2.8–11.6) �0.0001

he final model adjusted for age, gender, serum creatinine, peak creatine kinase, previillip class on admission, heart rate on admission, blood pressure on admission, an

ncludes only HF events occurring without a preceding recurrent myocardial infarction.Abbreviations as in Table 1.

ISCUSSION

he present prospective study demonstrates a strong, pos-tive, graded association between CRP obtained within 12o 24 h from symptoms onset and long-term developmentf HF and death in survivors of acute MI. The associationetween CRP and the development of HF was maintainedfter adjusting for the occurrence of recurrent MI duringollow-up. The relationship between elevated CRP anddverse outcome remained robust even when assessed inpparently low-risk patients (preserved predischarge LVEFnd Killip class I during admission) as well as in high-riskatients (reduced EF and clinical evidence for HF atdmission).RP and outcomes in acute coronary syndromes. Theechanism for CRP elevation and its predictive value for

ifferent outcomes in patients with acute coronary syn-

ion for the treatment of heart failure according to quartiles of C-reactivegroups.

or Admission for HF According to Quartiles of CRP

djusted for Clinical VariablesAdjusted for Clinical Variables

and LVEF

(95% CI) p Value p Trend HR (95% CI) p Value p Trend

1.0 — 0.001 1.0 — 0.005(0.5–2.2) 0.93 1.1 (0.5–2.3) 0.89(1.1–3.9) 0.03 1.9 (1.0–3.6) 0.05(1.3–4.6) 0.005 2.1 (1.2–3.9) 0.02

1.0 — �0.0001 1.0 — 0.006(0.5–2.6) 0.90 1.1 (0.5–2.7) 0.74(1.1–5.0) 0.03 2.1 (1.0–4.6) 0.49(1.6–7.0) 0.001 2.8 (1.4–5.9) 0.005

art failure (HF), history of hypertension, diabetes, smoking habit, anterior infarction,F. *Model adjusting for recurrent infarction as a time-dependent variable; †model

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967JACC Vol. 47, No. 5, 2006 Suleiman et al.March 7, 2006:962–8 CRP and Long-Term Outcome After MI

romes depends critically on the clinical setting and time ofeasurement. The low-grade CRP elevation in the chronic

hase of atherosclerosis is associated with future coronaryvents among apparently healthy individuals (2,3).-reactive protein levels might further increase in patientsith unstable angina, owing to widespread vascular inflam-ation (17), and are associated with recurrent clinical

nstability and recurrent infarctions (18); however, in unsta-le coronary disease the rise in CRP and other markers ofnflammation such as interleukin-6 occurs almost exclu-ively in patients with evidence of myocardial necrosis7,8). Thus myocardial necrosis seems to elicit a moreronounced activation of CRP that is superimposed onhe low-grade, vascular-mediated inflammation (6,8).ecause the extent of CRP elevation in patients with MI

s dominated by the inflammatory response to myocardialnjury rather than vascular inflammation, it has beenssociated with mortality but not with recurrent infarc-ions (9,12,19,20).

The finding that elevated CRP in the early phase of MIredicts long-term development of HF also supports theoncept that at this time point CRP levels mainly reflectngoing myocardial inflammation. These results are in keep-ng with previous studies showing that elevated peak CRP iselated to early mechanical complications such as cardiacupture, ventricular aneurysmal formation, and thrombus for-ation (21).The acute phase response shown by CRP during the

cute phase of MI is highly dynamic, with levels beginningo rise within a few hours after symptoms onset, peaking atto 4 days (6,8,12). Importantly, the relationship betweenRP elevation and HF or death is present only if CRP

evels are obtained early in the course of MI (6–8). Thecute inflammatory response associated with myocardialecrosis subsides within 4 to 6 weeks, with CRP levels

igure 3. Adjusted hazard ratios (HRs) for mortality or admission for heartailure (HF) after hospital discharge according to quartiles of C-reactiverotein (CRP) and left ventricular ejection fraction (LVEF), clinicalvidence for heart failure on admission, and left ventricular systolicunction. The percent of events in each group is given above each bar.

eturning to baseline values (8,12). At this time, elevated p

RP levels again reflect the degree of vascular inflammationnd are predictive of future coronary events (4).RP and HF. The development of late HF in patients

fter MI is particularly ominous because these patients haveseveral-fold increase in the risk of death when comparedith other MI survivors (14,15,22). In a recent study, MI

urvivors who developed HF had a 10-fold risk of deathompared with patients who did not develop HF (15). Ourata indicates that inflammatory markers might be useful indentifying patients at high risk for HF despite apparentlinical stability. Late development of HF in MI survivors isrobably related to several mechanisms, including progres-ive remodeling (23,24), recurrent infarction, and subclinicalschemia; however, CRP was predictive for HF events afterxcluding patients who developed HF in the context ofecurrent infarction. Taken together, these findings suggesthat CRP in the early phase of infarction might be indica-ive of an intense inflammatory state that contributes torogressive postinfarction ventricular remodeling. Impor-antly, CRP in not only a marker of inflammation butppears to actively participate in myocardial damage viaocal complement activation (25,26).

The mechanisms relating elevated CRP to future devel-pment of HF are unclear, although accumulating evidenceuggests that inflammatory responses, primarily mediated byytokines, play a key role in the process of healing andemodeling after MI. During infarction, cytokines are elab-rated by immune, vascular, and interstitial tissue to regu-ate important biological processes of cell growth, migra-ion, repair, and fibrosis (1).

In rodent models of MI, a robust up-regulation ofntra-myocardial cytokines occurs within the first hours to 1ay after the infarct. The messenger ribonucleic acid expres-ion of cytokines such as tumor necrosis factor-alpha,nterleukin-6, and interleukin-1-beta increases dramatically inhe infarct area (up to 50-fold). Cytokine expression is notonfined to the infarct zone, because its expression is alsop-regulated in cardiac myocytes in the noninfarcted myo-ardium (up to 15-fold) (1,27,28). On the basis of experi-ental studies, it has been postulated that the early inflam-atory response might have long-term consequences in

erms of ventricular function and remodeling (1).Cytokines originating from the myocardium or infiltrat-

ng inflammatory cells (particularly interleukin-6, the chieftimulator of the production of CRP in the liver) contributeo the raised CRP concentrations observed in patients withcute MI (9,21). Thus, in patients with acute MI, CRPight be a simple marker for the intensity of the inflam-atory response within the myocardium.

tudy limitations. The inflammatory reaction to ischemicnjury entails the elaboration of multiple inflammatory

ediators (1,13,27,28). We measured only one globalarker of inflammation but other markers might prove to

e more useful for risk stratification. The inflammatoryeaction to ischemic injury begins within several hours and

eaks after several days. We measured CRP levels at one

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968 Suleiman et al. JACC Vol. 47, No. 5, 2006CRP and Long-Term Outcome After MI March 7, 2006:962–8

ime point within 12 to 24 h from symptoms onset;owever, CRP levels at other time points, particularly peakRP levels, might better reflect the magnitude of the

nflammatory response to myocardial necrosis.Cardiac natriuretic peptides reflect ventricular impair-ent and the severity of hemodynamic decompensation in

eart disease. Elevated plasma B-type natriuretic peptideBNP) levels are associated with increased risk of adversevents in patient with acute coronary syndromes (29). Perti-ent to the present study is the recent demonstration thatNP taken early after the onset of symptoms improves risk

tratification for mortality and readmission to hospital forF, beyond clinical risk factors and LVEF (30). Thus, the

nclusion of both CRP and BNP in our analysis might havemproved risk prediction, because these biomarkers haveeen shown to provide additive prognostic information inatients with acute coronary syndromes (31).Finally, diagnosis of HF was defined as admission for theanagement of HF. Thus, milder forms of HF that could

e managed on an outpatient basis were not considered.onclusions. The results of the present study indicate thatRP level obtained early in the acute phase of acute MI ispowerful independent marker for long-term mortality and

he development of HF. Beyond the use of CRP forrognostic purposes, these results support the concept thathe magnitude of the early inflammatory response to infarc-ion affects long-term outcome.

eprint requests and correspondence: Dr. Doron Aronson, De-artment of Cardiology, Rambam Medical Center, PO Box 9602,aifa 31096, Israel. E-mail: d_aronson@rambam.health.gov.il.

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