prognostic value of htfabps

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Journal of Cardiac Failure Vol. 11 No. 1 2005

Prognostic Value of Elevated Circulating Heart-Type

Fatty Acid Binding Protein in Patients With Congestive

Heart Failure

TAKANORI ARIMOTO, MD,1 YASUCHIKA TAKEISHI, MD,1 RYOKO SHIGA, MD,1 AKIO FUKUI, MD,1

HIDETADA TACHIBANA, MD,1 NAOKI NOZAKI, MD,1 OSAMU HIRONO, MD,1 JOJI NITOBE, MD,1

TAKUYA MIYAMOTO, MD,1 BRIAN D. HOIT, MD,2 AND ISAO KUBOTA, MD1

Yamagata, Japan; Cleveland, Ohio

ABSTRACT

Background: Heart-type fatty acid binding protein (H-FABP) is released into the circulation when the

myocardium is injured and is a novel marker for the diagnosis of acute myocardial infarction. The purpose of

the present study was to examine the clinical significance of increased serum H-FABP levels in patients

with congestive heart failure.

Methods and Results: Serum levels of H-FABP were measured in 179 patients admitted with congestive

heart failure and 20 age-matched normal controls by using a sandwich enzyme-linked immunosorbent

assay. Patients were prospectively followed during a mean follow-up period of 20 months with the end

points of cardiac death and progressive heart failure requiring rehospitalization. Serum levels of H-FABP

were higher in patients with congestive heart failure than in control subjects (5.7 4.8 ng/mL versus

2.7 0.8 ng/mL, P .01) and increased with advancing NYHA class (P .01). The cardiac event rate

was markedly higher in patients with elevated H-FABP levels than in those with normal levels (43%

versus 7%, P .0001). Furthermore, the Cox multivariate proportional hazard analysis revealed that the

elevated H-FABP level was the only independent predictor for cardiac events (2 7.397, P .01).

Conclusions: Elevation of H-FABP indicates latent and ongoing cardiomyocyte damage and identifies

patients at high risk for future cardiac events in congestive heart failure.

Key Words: H-FABP, heart failure, prognosis.

The heart uses free long-chain fatty acids as an energy

source under normal aerobic conditions.13 Fatty acid binding

proteins are small cytosolic proteins that bind long-chain

fatty acids and function as the principle transporter of long-

chain fatty acids in the cardiomyocyte.46 Heart-type fatty

acid binding protein (H-FABP) is present abundantly in

From the 1First Department of Internal Medicine, Yamagata UniversitySchool of Medicine, Yamagata, Japan, and 2Department of Medicine, Case

Western Reserve University and University Hospitals of Cleveland,

Cleveland, Ohio.

Manuscript received August 25, 2003; revised manuscript received Feb-ruary 3, 2004; revised manuscript accepted March 23, 2004.

Reprint requests: Yasuchika Takeishi, MD, First Department of InternalMedicine, Yamagata University School of Medicine, 2-2-2 Iida-Nishi, Ya-magata, Japan 990-9585.

Supportedin partby a grant-in-aid for Scientific Research(No. 14570635)from the Ministry of Education, Science, Sports and Culture, Japan andgrants from Japan Foundation of Cardiovascular Research and The JapanHeart Foundation Research Grant.

1071-9164/$ - see front matter 2005 Elsevier Inc. All rights reserved.

doi:10.1016/j.cardfail.2004.03.005

56

the myocardium and is released into the circulation when the

myocardium is injured. Recent studies have demonstrated

that H-FABP is a highly sensitive and specific biochemical

marker for the diagnosis of acute myocardial infarction.7,8

Leakage of cytosolic proteins and myofibrillar compo-

nents from cardiomyocytes implies latent myocardial damage

in patients with hypertrophic cardiomyopathy and in those

with severe congestive heart failure.911 In the present study,

we tested the hypothesis that H-FABP is detectable in the

circulation of patients with congestive heart failure and is

related with the disease severity and outcome.

Methods

Patients

We measured serum levels of H-FABP in 179 patients (110 men

and 69 women, mean age of 67 13 years) who were admitted

to the Yamagata University Hospital for the treatment of congestive

heart failure. Twenty age-matched normal subjects (10 men and

10 women, age 62 5 years) composed the control group. The


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H-FABP in Congestive Heart Failure Arimoto et al 57

etiologies of congestive heart failure included idiopathic dilated

cardiomyopathy (n 53), ischemic cardiomyopathy (n 49), val-

vular heart disease (n 28), tachycardia-induced cardiomyopathy

(n 23), hypertensive heart disease (n 21), and others (n 5).

No patients had clinical symptoms or signs suggestive of acute

myocardial infarction, unstable angina, or acute myocarditis in

the 3 months preceding admission. Patients with renal insufficiency

characterized by a serum creatinine level 1.8 mg/dL were ex-

cluded from the present study. There were 49 patients with New

York Heart Association (NYHA) functional class I, 58 patients

with class II, 57 patients with class III, and 15 patients with class IV.

H-FABP Assay

A sample of venous blood was obtained from the study popula-

tion on the day of admission. Serum H-FABP levels were deter-

mined by a sandwich enzyme-linked immunosorbent assay8 using

2 distinct murine anti-human H-FABP specific monoclonal antibod-

ies (Markit-M H-FABP, Dainippon Pharmaceutical Co Ltd, Tokyo,

Japan). H-FABP in the test sample was bound to a monoclonal

antiH-FABP antibody coated on microplate wells, and enzyme

labeled antiH-FABP antibody was added to the wells to forma sandwich immune complex. Substrate was added to start the

enzymatic reaction, and absorbance was measured at 492 nm in a

microplate reader.8

Plasmalevels of creatine kinase (CK), CK-MB, and lactate dehy-

drogenase (LDH) were measured using commercially available

kits (VITROS dry CK, Ortho-Clinical Diagnostics, Tokyo, Japan;

Dimension flex cartridge mass CKMB MMB, Dade Behring Inc,

Tokyo, Japan; and VITROS dry LDH, Ortho-Clinical Diagnostics,

Tokyo, Japan, respectively). Plasma levels of norepinephrine were

also measured by an automated high-performance liquid chroma-

tography analyzer (Tosoh Co, Tokyo, Japan).

Diagnostic Studies

Echocardiography was performed on the day of admission. Two-

dimensionally directed M-mode echocardiography measured left

ventricular dimensions at end-diastole (EDD) and end-systole

(ESD), and left ventricular fractional shortening was calculated as

[(EDD-ESD)/EDD] 100 (%). Pulse-wave Doppler echocardiogra-

phy measured early (E) and late (A) transmitral flow velocities, and

the E/A ratio wascalculated. Pulmonary artery pressure, pulmonary

capillary wedge pressure, and cardiac index were obtained by right

heart catheterization within 1 week after admission.

Endpoints and Follow-Up

Patients were prospectively followed for a mean period of 20

months. The end points were (1) cardiac death, defined as deathfrom progressive heart failure or sudden cardiac death, and (2)

progressive heart failure requiring rehospitalization. Sudden car-

diac death was defined as death without definite premonitory symp-

toms or signs and was established by the attending physician. Only

the first events were counted for the analysis.

Statistics

All values are expressed as mean standard deviation. Data

were analyzed by a Mann-Whitney U test or Kruskal-Wallis rank

test. A P value less than .05 was considered statistically significant.

Kaplan-Meier survival curves determined the time-dependent cu-

mulative cardiac event free rates in patients stratified into 2 groups

based on the levels of H-FABP, and were analyzed by a log rank

test. Statistical potentials of independent predictors in univariate

analysis were determined using the Cox proportional hazard model,

and statistical significance was analyzed by the 2 test.

Results

Serum levels of H-FABP ranged from 0.3 to 38.5 ng/mL(median 4.5 ng/mL) in all study subjects. Serum levels of

H-FABP were higher in patients with congestive heart failure

than in control subjects (5.7 4.8 ng/mL versus 2.7 0.8

ng/mL, P .01). The relationship between the levels of

serum H-FABP and the severity of heart failure was exam-

ined (Fig. 1). As the severity of NYHA functional class

advanced, H-FABP levels increased (control, NYHA class I,

II, III, and IV: 2.7 0.8, 3.3 1.5, 4.2 2.6, 7.5 4.8

[P .001 versus control and NYHA I and II] and 11.9

9.3 ng/mL [P .001 versus control and NYHA I and II,

P .01 versus NYHA III]. When patients with serum creati-

nine levels 1.0 mg/dL were excluded, H-FABP levels alsoincreased in advanced heart failure (control, NYHA class I,

II, III, and IV: 2.7 0.8, 3.4 1.5, 3.6 1.8, 5.8 2.7

[P .05 versus control and NYHA I] and 12.1 10.5

ng/mL [P .001 versus control and NYHA I, II, and III].

When patients with ischemic cardiomyopathy were ex-

cluded, H-FABP levels similarly increased with advancing

NYHA class (control, NYHA class I, II, III, and IV: 2.7

0.8, 3.1 1.4, 4.3 2.7, 7.7 5.3 [P .001 versus control

and NYHA I and II] and 12.3 9.9 ng/mL [P .001 versus

control and NYHA I and II, P .05 versus NYHA III].

From the values of 20 normal control subjects, the normal

upper limit of H-FABP was determined as 4.3 ng/mL

(mean 2 SD value of 20 normal control subjects). Of 179

patients with heart failure, there were 88 patients with nor-

mal H-FABP levels (4.3 ng/mL, group 1) and 91 patients

Fig. 1. Serum levels of heart-type fatty acid binding protein in study

population. *P .001 versus control, New York Heart Association

(NYHA) classification I, and II. #P .01 versus NYHA III.


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58 Journal of Cardiac Failure Vol. 11 No. 1 February 2005

Table 1. Serum Levels of H-FABP and Clinical Backgroundsin Heart Failure Patients

Group 1 Group 2(n 88) (n 91)

Age (y) 62 12 72 12*Sex (men/women) 56/32 54/37Etiology of congestive

heart failureDilated cardiomyopathy 25 28Ischemic cardiomyopathy 25 24Valvular heart disease 14 14Tachycardia-induced 11 12

cardiomyopathyHypertensive heart failure 9 12Others 4 1

New York Heart Associationfunctional class

I 39 (44%) 10 (11%)II 33 (38%) 25 (28%)III 14 (16%) 43 (47%)IV 2 (2%) 13 (14%)*

H-FABP, heart type fatty acid binding protein.Group 1: patients with normal H-FABP levels (4.3 ng/mL).Group 2: patients with abnormal H-FABP levels (4.3 ng/mL).*P .01.

with abnormally elevated H-FABP levels (4.3 ng/mL,

group 2).

Clinical, enzymatic, echocardiographic, and hemody-

namic data were compared between patients in groups 1

and 2 (Tables 1 and 2). Patients in group 2 were older

(P .01), had higher levels of plasma CK and LDH levels

(P .0001), lower fractional shortening (P .05), and more

advanced heart failure than those in group 1. Elevated

H-FABP levels were present in 10 of 49 patients (20%) withNYHA class I, in 25 of 58 patients (43%) with NYHA class

II, 43 of 57 patients (75%) with NYHA class III, and 13 of

15 patients (87%) with NYHA class IV (P .01). The

Table 2. Serum Levels of H-FABP and Severity of Congestive Heart Failure

Group 1 Group 2(n 88) (n 91) P value

Enzymes and norepinephrineCK (U/L) 87 47 122 81 .006

CK-MB (U/L) 1.3 1.2 1.8 1.3 .0752LDH (U/L) 327 69 417 138 .001Norepinephrine (pg/mL) 522 418 613 457 .2995

EchocardiographyLVEDD (mm) 52 10 53 10 .5837FS (%) 30 12 25 13 .0257E/A 0.85 0.47 0.79 0.37 .6351

HemodynamicsMean PA (mm Hg) 18 7 19 8 .7245Mean PCW (mm Hg) 10 6 10 6 .9122CI (Lminm2) 2.6 0.6 2.5 0.8 .3308

H-FABP, heart type fatty acid binding protein; CK, creatine kinase; LDH, lactate dehydrogenase; LVEDD, left ventricular dimension at end-diastole; FS,fractional shortening; E/A, ratio of the velocity of E wave to A wave; PA, pulmonary artery pressure; PCW, pulmonary capillary wedge pressure; CI,cardiac index.

Group 1: patients with normal H-FABP levels (4.3 ng/mL).Group 2: patients with abnormal H-FABP levels (4.3 ng/mL).

remaining parameters did not differ statistically between

the 2 groups.

The correlations between serum H-FABP levels and

plasma CK, CK-MB, LDH, and norepinephrine levels were

examined. Serum H-FABP was weakly but significantly

correlated with CK (r .214, P .02), CK-MB (r .336,

P .01), LDH (r .459, P .0001), and norepinephrine

(r .433, P .001).During a mean follow-up period of 20 months (range 1

to 104 months), cardiac events were observed in 45 of 179

patients (25%). These included 4 cardiac deaths (3 by theprogression of heart failure, 1 sudden) and 41 rehospitaliza-

tions resulting from worsening heart failure.

Patients were stratified into 2 groups based on their H-

FABP values (ie, groups 1 and 2). Cumulative event free

curves were constructed by the Kaplan-Meier method, asshown in Fig. 2. The cardiac event rate (43% versus 7%,

P .001) was markedly higher in patients with elevated

H-FABP levels (4.3 ng/mL, group 2) than in those

with normal levels (4.3 ng/mL, group 1). When patients

with renal insufficiency, determined by serum creatinine

levels1.0 mg/dL, were excluded, the cardiac event rate wasalso higher in patients with elevated H-FABP levels than in

those with normal levels (42% versus 6%, P .001).

When patients with ischemic cardiomyopathy were ex-

cluded, the cardiac event rate was similarly higher in patients

with elevated H-FABP levels than in those with normallevels (43% versus 7%, P .001).

H-FABP levels and variables that differed between groups

1 and 2 by univariate analysis (age, NYHA functional

class, plasma levels of CK and LDH, and fractional shorten-ing) were entered into the multivariate Cox proportional

hazard model. As shown in Table 3, the Cox regressionanalysis revealed that the elevated H-FABP level was theonly independent predictor for cardiac events (2 7.397,

P .01). Thus age, NYHA functional class, plasma levels
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H-FABP in Congestive Heart Failure Arimoto et al 59

Fig. 2. Serum levels of heart-type fatty acid binding protein and

prognosis of patients with congestive heart failure. Survival curves

were created by a Kaplan-Meier method and analyzed by a log

rank test.

of CK, LDH, and fractional shortening were not significantly

associated with a risk of subsequent cardiac events.

Patients were divided into those with mild (NYHA class

I and II, n 107) and severe (NYHA class III and IV,

n 72) heart failure. In the mild heart failure group, there

were 72 patients with normal H-FABP levels (4.3 ng/mL)

and 35 patients with elevated H-FABP levels (4.3

ng/dL). Importantly, in the mild heart failure group, patients

with elevated H-FABP levels had markedly higher cardiac

event rate than those with normal levels (34% versus 4%,

P .001, Fig. 3).

Discussion

The present study confirms that the increased serum levels

of H-FABP are detected in patients with advanced heart

failure and, for the first time, demonstrates that elevated

circulating levels of H-FABP provide important independent

prognostic information in patients with congestive heart

failure.

During the development of cardiac hypertrophy and fail-

ure, a transition of energy substrate utilization occurs with

reduced fatty acid oxidation and increased glucose utiliza-

tion.13,12,13 The H-FABP plays a critical role for the uptake

Table 3. Results of the Cox Proportional Hazards Analysis

Variable Chi-square P value

H-FABP 7.397 .0065NYHA functional class 2.631 .1048Fractional shortening (%) 1.404 .236CK (U/L) 1.072 .3005Age (y) 0.872 .3505LDH (U/L) 0.435 .5095

H-FABP, heart type fatty acid binding protein; NYHA, New York HeartAssociation; CK, creatine kinase; LDH, lactate dehydrogenase.

Fig. 3. Heart-type fatty acid binding protein levels and patient

outcome: comparisons between mild and severe congestive heart

failure (CHF).

and transport of long-chain fatty acid in the cardiomyo-

cyte; thus, both cellular uptake and lipid oxidation of long-

chain fatty acids are severely depressed in H-FABP knockout

mice.14 Changes in expression of H-FABP in the myocar-

dium have not been rigorously examined in heart failure.

H-FABP is rapidly released into the circulation when the

myocardium is injured.46 In that regard, H-FABP has been

used recently as a biochemical marker for acute myocardial

infarction.6,7 It has been reported that H-FABP is more sensi-

tive and more specific than both myoglobin and CK-MB

for detecting acute myocardial infarction within 12 hours

after the onset.8

Several studies reported that myofibrillar components leakfrom cardiomyocytes in patients with severe heart failure.9,10

Although the precise mechanism of escape has not yet been

established, this phenomenon may reflect ongoing myocar-

dial damage in patients with severe heart failure. In the

present study, no patients with suspected acute coronary

syndrome were included. Our study suggests that, although

levels vary directly with severity, H-FABP is released at

each stage of heart failure. When we excluded heart failure

patients with ischemic cardiomyopathy, similar results

were obtained. These data are consistent with those of Set-

suta et al, who recently reported an association between

troponin T and H-FABP in patients with chronic heart fail-ure.15 However, their study population was smaller (n 56)

and the follow-up period was shorter (average 16 months)

than the present study.

Our findings also suggest that an elevated circulating level

of H-FABP is not only a highly sensitive and specific marker

of myocardial damage, but also an important prognostic

determinant in patients with congestive heart failure. Thus,

although cardiac event rates were markedly higher in pa-

tients with elevated H-FABP levels than in those with normal

levels, the Cox proportional hazard analysis revealed that

H-FABP was the only independent variable associated with

high risk of subsequent cardiac events. Furthermore, it is


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60 Journal of Cardiac Failure Vol. 11 No. 1 February 2005

especially noteworthy that in patients with mild heart failure

(NYHA functional class I and II), the cardiac event rate was

markedly higher in patients with elevated H-FABPlevels than

in those with normal levels (34% versus 4%, P .001, Fig.

3). These data suggest that H-FABP can identify those with

mild heart failure who are at increased risk of cardiac events

and who may warrant more aggressive therapy.

Conclusions

In conclusion, serum levels of H-FABP are increased in

patients with heart failure, are related to the severity of heart

failure, and provide novel, independent prognostic informa-

tion irrespective of functional class. H-FABP is a new marker

of potentially latent and ongoing cardiomyocyte damage and

may identify patients at high risk for future cardiac events.

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prognostic value of htfabps

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