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Original Research: Pulmonary Vascular Disease |

Prognostic Value of Plasma Heart-Type Fatty Acid-Binding Protein in Patients With Acute Pulmonary EmbolismHeart-Type Fatty Acid-Binding Protein: A Meta-analysis FREE TO VIEW

Li Bo Ruan, MS; Liang He, MS, MM; Shan Zhao, MS; Ping Zhu, BS; Wei Yuan Li, BS
Author and Funding Information

From the Department of Cadre’s Ward (Drs Ruan and Li) and the Department of Respiratory Medicine (Dr Zhao), the First People’s Hospital of Yunnan Province; the Department of Anesthesiology (Dr He), Yan’an Hospital of Kunming City; and the Policy and Information Research Center (Ms Zhu), Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming, China.

CORRESPONDENCE TO: Liang He, MS, MM, Department of Anesthesiology, Yan’an Hospital of Kunming City, No.245, Renmin Rd (E), Kunming, 650051, China; e-mail: hauliang@163.com


FUNDING/SUPPORT: The authors have reported to CHEST that no funding was received for this study.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2014;146(6):1462-1467. doi:10.1378/chest.13-1008
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BACKGROUND:  Several studies have described heart-type fatty acid-binding protein (H-FABP) from early blood samples as a predictor of outcome in acute pulmonary embolism (PE). This systematic review is designed to determine the prognostic value of H-FABP aimed for use in patients with acute PE.

METHODS:  Studies published prior to January 2013 in PubMed, Ovid, and Embase were reviewed, and the relationship between H-FABP and the risk of acute PE-related death or serious complications was evaluated. A summary estimate was calculated using the bivariate random-effects approach, and covariate analysis was used to examine sources of heterogeneity among studies.

RESULTS:  A systematic search revealed six studies containing a total of 618 patients. Elevated H-FABP level was significantly associated with short-term death (within 30 days of embolism) (OR, 40.78; 95% CI, 11.87-140.09) and with complicated clinical events (OR, 32.71; 95% CI, 11.98-89.26). The prevalence of serious complications and death in acute PE was 51% (95% CI, 43%-59%) and 31% (95% CI, 24% -39%), respectively. The combined sensitivity and specificity for the prediction of death and serious complications was 98% and 86%, respectively.

CONCLUSIONS:  H-FABP is associated with an increased risk of mortality or complicated clinical events in patients with acute PE across different studies with a high degree of clinical and methodologic diversity. The result suggests that H-FABP has significant prognostic value for acute PE.

Figures in this Article

Acute pulmonary embolism (PE) is a serious condition with a poor prognosis that places a significant burden on the health-care system.1 Timely classification of patients with acute PE may positively impact patient-management decisions: Patients identified as having a low risk of complications may be eligible for outpatient management, whereas high-risk patients may benefit from more aggressive treatment.2 Several cardiac biomarkers have emerged as indicators of right ventricular dysfunction and predictors of clinical outcome in patients with acute PE.311 A number of studies in unselected patients with acute PE suggest that heart-type fatty acid-binding protein (H-FABP) levels upon hospital admission may more sensitively and specifically predict early adverse clinical outcomes than do cardiac troponins or natriuretic peptides.4,812 H-FABP is an early, highly sensitive marker of myocardial injury and has been evaluated for emergency triage of patients with acute coronary syndromes.13 Fatty acid-binding proteins are relatively small cytoplasmic proteins (12-15 kDa) and are abundant in tissues with active fatty acid metabolism, including the heart.14 After myocardial cell damage, H-FABP diffuses much more rapidly through the interstitial space than do troponins and appears in the circulation as early as 90 min after symptom onset, reaching its peak within 6 h.13 Moreover, Cox regression analysis revealed a hazard ratio of 1.10 (95% CI, 1.04-1.18) for each 1 ng/mL increase in H-FABP level, and the continuous increase in H-FABP is an independent predictor of adverse outcome by multivariable analysis in chronic thromboembolic pulmonary hypertension.15 Given the early release of H-FABP, the availability of H-FABP testing,16 and the current lack of a prognostic marker with good performance in acute PE, we carried out this systematic review and meta-analysis to estimate the prognostic value of increased H-FABP levels as a cardiac biomarker in stratifying the risk of mortality or serious complications in patients with acute PE.

Literature Search

We performed a systematic electronic search of the PubMed, Ovid, and Embase databases for original articles published before January 1, 2013. In PubMed, the search terms used were “pulmonary embolism” AND “heart-type fatty acid-binding protein,” which yielded 11 results. In Ovid, we used the following strategy: (1) heart type fatty acid binding protein.mp. [mp = ti, ab, tx, ct, mc, st, or, tn, ps, ds, cb, rn, sq, mq, ge, tm, mi, sh, hw, bc, bo, bt, cc, gl, gn, ot, rw, nm, rs, an, ui] (752 results); (2) pulmonary embolism.mp. [mp = ti, ab, tx, ct, mc, st, or, tn, ps, ds, cb, rn, sq, mq, ge, tm, mi, sh, hw, bc, bo, bt, cc, gl, gn, ot, rw, nm, rs, an, ui] (88,551 results); (3) 1 and 2 (54 results). In Embase, we used the following strategy: (1) pulmonary AND “embolism”/exp; (2) “heart”/exp OR heart AND type AND fatty AND (“acid”/exp OR acid) AND binding AND (“protein”/exp OR protein); and (3) 1 and 2 (20 results).

Selection of Publications

We screened the titles and abstracts of all publications for relevancy. Full-text publications were retrieved for relevant articles without language limitation. Studies were selected on the basis of whether (1) patients had an acute PE confirmed by guidelines, (2) the primary end point of the study was death or serious complications (thrombolysis, cardiopulmonary resuscitation, IV vasopressors) in relation to H-FABP testing; and (3) the completeness of the data (availability of absolute numbers of true-positive, false-positive, true-negative, and false-negative H-FABP results to allow reconstruction of the diagnostic 2 × 2 table).

Assessment of Study Methods and Data Extraction

Information on the study characteristics (design and quality), the number and type of participants, the types of diagnostic test used, the methods by which the test was executed, and the test results were collected using a standardized data extraction form. Three reviewers (L. B. R., L. H., and P. Z.) reviewed the lists of titles and abstracts independently and used the inclusion criteria to mark potentially relevant articles for full review. Each study that was selected as potentially relevant in the search process was read and abstracted independently by four reviewers (L. B. R., L. H., S. Z., and P. Z.). Besides extracting summary statistics from the published literature for survival end points, the timing of the blood draw was a factor we considered. The reasons for excluding particular studies are presented in Figure 1.

For each study, information was collected on (1) the use of a valid reference standard in accordance with international PE guidelines; (2) the design of the study (prospective or retrospective, single center or multicenter); (3) the treatment (number of patients who received thrombolytic therapy, underwent cardiopulmonary resuscitation, needed IV vasopressors or pulmonary embolectomy); (4) mortality; and (5) the full description of the H-FABP test and manufacturer, and the method and cutoff value for assays of other biologic markers (Table 1). The reasons for excluding particular studies are presented in Figure 1.

Table Graphic Jump Location
TABLE 1 ]  Characteristics of Studies and H-FABP Assays Evaluating the H-FABP in Patients With Acute Pulmonary Embolism

CCE = complicated clinical event; ELISA = enzyme-linked immunosorbent assay; H-FABP = heart-type fatty acid-binding protein; ICA = immunochromatographic assay; Mort = mortality related to acute pulmonary embolism; NA = not applicable.

a 

Mo.

Data Analysis

Categorical variables from individual studies were presented as a percentage value (n/N), and continuous variables were presented as mean values. Measures of ORs and diagnostic performance were reported as point estimates with 95% CI. The main analysis was performed on the prognostic value of H-FABP testing in predicting death, whereas the available complicated clinical events (CCEs) data were analyzed using forest plots. The pooled sensitivity, specificity, and unconditional positive and negative predictive values were estimated for comparative purposes. We combined individual statistics using a random-effects model. The statistical heterogeneity was assessed using the Cochran Q χ2 test and the I2 test. A P value < .001 indicated significant difference. We used Stata v11 (StataCorp LP) and Review Manager 5.2 (The Cochrane Collaboration) software for meta-analytical analysis.

Six hundred eighteen patients from six studies were extracted from a list of 85 potentially relevant studies that met the criteria for inclusion (Fig 1). Five studies (including 472 patients) evaluated the prevalence of CCEs and 30-day mortality resulting from acute PE,812 three studies (including 373 patients) assessed long-term survival (from 90 to 500 days),4,8,11 and five studies (including 618 patients) analyzed the value of multiple biomarkers as prognostic markers for serious complications and/or death.4,812

In the six studies, the proportion of patients who developed serious complications ranged from 7% to 44%, and the mortality due to acute PE varied from 3% to 18%. The 30-day mortality resulting from acute PE ranged from 5% to 18%, and rates of CCE were 7% to 44% in the included studies. The rates of 30-day death from acute PE were 14% to 57% in patients with increased H-FABP (greater than cutoff) and 0% to 3% in patients without increased H-FABP. CCEs occurred in 28% to 86% of patients with increased H-FABP, and in 0% to 23% of patients without increased H-FABP. Elevated plasma H-FABP was significantly associated with 30-day mortality from acute PE (OR, 40.78; 95% CI, 11.87-140.09) (Fig 2) and with CCEs (OR, 32.71; 95% CI, 11.98-89.26) (Fig 3).

Figure Jump LinkFigure 2 –  Prognostic value of heart-type fatty acid-binding protein for 30-d mortality in patients with acute pulmonary embolism. The outcome was 30-d mortality for all studies, except for the 90-d mortality. df = degrees of freedom; M-H = Mantel-Haenszel.Grahic Jump Location
Figure Jump LinkFigure 3 –  Prognostic value of heart-type fatty acid-binding protein for 30-d complicated clinical event in patients with acute pulmonary embolism. The outcome was 30-d complicated clinical event (CCE) for all studies, except for the 90-d CCE. See Figure 2 legend for expansion of other abbreviations.Grahic Jump Location

To our knowledge, this is the first time that a systematic review and meta-analysis have been performed to determine the prognostic value of the early and novel cardiac biomarker, plasma H-FABP, to stratify patient risk for acute PE. H-FABP is potentially a reliable marker of myocardial injury and was identified recently as a predictor of outcome in acute PE. Using a bivariate random-effects approach, the sensitivity and specificity of the test in predicting 30-day mortality related to acute PE were 98% and 77%, respectively. In predicting the occurrence of a serious complication, the sensitivity and specificity of the test were 86% and 82%, respectively. This suggests that the use of H-FABP as a prognostic marker would lead to false-negative test results in 2% of patients with acute PE, and false-positive test results in 23% of patients without acute PE. Because PE is a potentially fatal condition, this percentage of missed patients is too high, but may be improved by combining H-FABP with other prognostic markers. The positive predictive value for death is 31%, indicating that in a hospital setting, a large number of patients with false-positive results may be unnecessarily subjected to aggressive thrombolytic therapy, which carries associated risks. The negative predictive value is 99%. Highly sensitive H-FABP assays have become available and are showing higher prognostic accuracy than are the currently used standard of troponin and other assays. Adopting a method in which H-FABP is used in combination with other prognostic markers for PE may facilitate an earlier and more accurate prediction of serious complications in acute PE.

Limitations

The major limitation of the current analysis was the lack of individual data and the fact that few studies were specifically designed to answer our research questions. Therefore, our pooled estimates of prognostic performance are not adjusted for conventional risk factors such as age, sex, hemodynamics, methodologies, or history of heart dysfunction or failure. However, most of the included studies performed multivariate analyses confirming the increased risk of death and serious complications in patients with elevated H-FABP levels. Surprisingly, only small differences between adjusted and nonadjusted estimates were found. In fact, the OR appeared greater after adjustment in most studies, suggesting that our estimates may be conservative and may slightly underestimate the true increase in the risk of adverse outcomes associated with elevated H-FABP levels.

This systematic review and meta-analysis suggest that elevated plasma H-FABP is associated with an increased risk of death within 30 days of onset and CCEs in patients with acute PE (Table 2). It has the potential to be a novel prognostic marker that can help optimize patient management strategies and risk-stratification algorithms in the population of patients with acute PE, which has been a difficult task, thus far. Despite clinical and methodologic diversity among the included studies, all showed a similar increase in OR. Sound prospective studies, with definitions of acute PE under international guidelines, as well as the determination of plasma levels of multivariate cardiac biomarkers, are required to further increase confidence in the value of this new prognostic marker.

Table Graphic Jump Location
TABLE 2 ]  Pooled Summary Results of the Prognostic Value of Elevated H-FABP in Acute Pulmonary Embolism

NPV = negative predictive value; PPV = positive predictive value. See Table 1 legend for expansion of other abbreviations.

a 

Death related to acute pulmonary embolism.

Author contributions: L. H. had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. L. B. R., L. H., and P. Z. contributed to the independent review of the lists of titles and abstracts and to the use of the inclusion criteria to mark potentially relevant articles for full review; L. B. R., L. H., S. Z., and P. Z. contributed to the selection of potentially relevant papers; L. H. contributed to the design of the study, statistical analysis, and revision of the manuscript; and L. B. R., L. H., S, Z., P. Z., and W. Y. L. contributed to reading and approval of the final manuscript.

Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

CCE

complicated clinical event

H-FABP

heart-type fatty acid-binding protein

PE

pulmonary embolism

Konstantinides S, Goldhaber SZ. Pulmonary embolism: risk assessment and management. Eur Heart J. 2012;33(24):3014-3022. [CrossRef] [PubMed]
 
Torbicki A, Perrier A, Konstantinides S, et al; ESC Committee for Practice Guidelines (CPG). Guidelines on the diagnosis and management of acute pulmonary embolism: the Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC). Eur Heart J. 2008;29(18):2276-2315. [CrossRef] [PubMed]
 
Lankeit M, Friesen D, Aschoff J, et al. Highly sensitive troponin T assay in normotensive patients with acute pulmonary embolism. Eur Heart J. 2010;31(15):1836-1844. [CrossRef] [PubMed]
 
Vuilleumier N, Le Gal G, Verschuren F, et al. Cardiac biomarkers for risk stratification in non-massive pulmonary embolism: a multicenter prospective study. J Thromb Haemost. 2009;7(3):391-398. [CrossRef] [PubMed]
 
Becattini C, Vedovati MC, Agnelli G. Prognostic value of troponins in acute pulmonary embolism: a meta-analysis. Circulation. 2007;116(4):427-433. [CrossRef] [PubMed]
 
Cavallazzi R, Nair A, Vasu T, Marik PE. Natriuretic peptides in acute pulmonary embolism: a systematic review. Intensive Care Med. 2008;34(12):2147-2156. [CrossRef] [PubMed]
 
Kostrubiec M, Pruszczyk P, Bochowicz A, et al. Biomarker-based risk assessment model in acute pulmonary embolism. Eur Heart J. 2005;26(20):2166-2172. [CrossRef] [PubMed]
 
Boscheri A, Wunderlich C, Langer M, et al. Correlation of heart-type fatty acid-binding protein with mortality and echocardiographic data in patients with pulmonary embolism at intermediate risk. Am Heart J. 2010;160(2):294-300. [CrossRef] [PubMed]
 
Kaczyñska A, Pelsers MM, Bochowicz A, Kostrubiec M, Glatz JF, Pruszczyk P. Plasma heart-type fatty acid binding protein is superior to troponin and myoglobin for rapid risk stratification in acute pulmonary embolism. Clin Chim Acta. 2006;371(1-2):117-123. [CrossRef] [PubMed]
 
Puls M, Dellas C, Lankeit M, et al. Heart-type fatty acid-binding protein permits early risk stratification of pulmonary embolism. Eur Heart J. 2007;28(2):224-229. [CrossRef] [PubMed]
 
Dellas C, Puls M, Lankeit M, et al. Elevated heart-type fatty acid-binding protein levels on admission predict an adverse outcome in normotensive patients with acute pulmonary embolism. J Am Coll Cardiol. 2010;55(19):2150-2157. [CrossRef] [PubMed]
 
Gül EE, Can I, Güler I, et al. Association of pulmonary artery obstruction index with elevated heart-type fatty acid binding protein and short-term mortality in patients with pulmonary embolism at intermediate risk. Diagn Interv Radiol. 2012;18(6):531-536. [PubMed]
 
Alhadi HA, Fox KA. Do we need additional markers of myocyte necrosis: the potential value of heart fatty-acid-binding protein. QJM. 2004;97(4):187-198. [CrossRef] [PubMed]
 
Storch J, Thumser AE. The fatty acid transport function of fatty acid-binding proteins. Biochim Biophys Acta. 2000;1486(1):28-44. [CrossRef] [PubMed]
 
Lankeit M, Dellas C, Panzenböck A, et al. Heart-type fatty acid-binding protein for risk assessment of chronic thromboembolic pulmonary hypertension. Eur Respir J. 2008;31(5):1024-1029. [CrossRef] [PubMed]
 
Dellas C, Tschepe M, Seeber V, et al. A novel H-FABP assay and a fast prognostic score for risk assessment of normotensive pulmonary embolism. Thromb Haemost. 2014;111(5):996-1003. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 2 –  Prognostic value of heart-type fatty acid-binding protein for 30-d mortality in patients with acute pulmonary embolism. The outcome was 30-d mortality for all studies, except for the 90-d mortality. df = degrees of freedom; M-H = Mantel-Haenszel.Grahic Jump Location
Figure Jump LinkFigure 3 –  Prognostic value of heart-type fatty acid-binding protein for 30-d complicated clinical event in patients with acute pulmonary embolism. The outcome was 30-d complicated clinical event (CCE) for all studies, except for the 90-d CCE. See Figure 2 legend for expansion of other abbreviations.Grahic Jump Location

Tables

Table Graphic Jump Location
TABLE 1 ]  Characteristics of Studies and H-FABP Assays Evaluating the H-FABP in Patients With Acute Pulmonary Embolism

CCE = complicated clinical event; ELISA = enzyme-linked immunosorbent assay; H-FABP = heart-type fatty acid-binding protein; ICA = immunochromatographic assay; Mort = mortality related to acute pulmonary embolism; NA = not applicable.

a 

Mo.

Table Graphic Jump Location
TABLE 2 ]  Pooled Summary Results of the Prognostic Value of Elevated H-FABP in Acute Pulmonary Embolism

NPV = negative predictive value; PPV = positive predictive value. See Table 1 legend for expansion of other abbreviations.

a 

Death related to acute pulmonary embolism.

References

Konstantinides S, Goldhaber SZ. Pulmonary embolism: risk assessment and management. Eur Heart J. 2012;33(24):3014-3022. [CrossRef] [PubMed]
 
Torbicki A, Perrier A, Konstantinides S, et al; ESC Committee for Practice Guidelines (CPG). Guidelines on the diagnosis and management of acute pulmonary embolism: the Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC). Eur Heart J. 2008;29(18):2276-2315. [CrossRef] [PubMed]
 
Lankeit M, Friesen D, Aschoff J, et al. Highly sensitive troponin T assay in normotensive patients with acute pulmonary embolism. Eur Heart J. 2010;31(15):1836-1844. [CrossRef] [PubMed]
 
Vuilleumier N, Le Gal G, Verschuren F, et al. Cardiac biomarkers for risk stratification in non-massive pulmonary embolism: a multicenter prospective study. J Thromb Haemost. 2009;7(3):391-398. [CrossRef] [PubMed]
 
Becattini C, Vedovati MC, Agnelli G. Prognostic value of troponins in acute pulmonary embolism: a meta-analysis. Circulation. 2007;116(4):427-433. [CrossRef] [PubMed]
 
Cavallazzi R, Nair A, Vasu T, Marik PE. Natriuretic peptides in acute pulmonary embolism: a systematic review. Intensive Care Med. 2008;34(12):2147-2156. [CrossRef] [PubMed]
 
Kostrubiec M, Pruszczyk P, Bochowicz A, et al. Biomarker-based risk assessment model in acute pulmonary embolism. Eur Heart J. 2005;26(20):2166-2172. [CrossRef] [PubMed]
 
Boscheri A, Wunderlich C, Langer M, et al. Correlation of heart-type fatty acid-binding protein with mortality and echocardiographic data in patients with pulmonary embolism at intermediate risk. Am Heart J. 2010;160(2):294-300. [CrossRef] [PubMed]
 
Kaczyñska A, Pelsers MM, Bochowicz A, Kostrubiec M, Glatz JF, Pruszczyk P. Plasma heart-type fatty acid binding protein is superior to troponin and myoglobin for rapid risk stratification in acute pulmonary embolism. Clin Chim Acta. 2006;371(1-2):117-123. [CrossRef] [PubMed]
 
Puls M, Dellas C, Lankeit M, et al. Heart-type fatty acid-binding protein permits early risk stratification of pulmonary embolism. Eur Heart J. 2007;28(2):224-229. [CrossRef] [PubMed]
 
Dellas C, Puls M, Lankeit M, et al. Elevated heart-type fatty acid-binding protein levels on admission predict an adverse outcome in normotensive patients with acute pulmonary embolism. J Am Coll Cardiol. 2010;55(19):2150-2157. [CrossRef] [PubMed]
 
Gül EE, Can I, Güler I, et al. Association of pulmonary artery obstruction index with elevated heart-type fatty acid binding protein and short-term mortality in patients with pulmonary embolism at intermediate risk. Diagn Interv Radiol. 2012;18(6):531-536. [PubMed]
 
Alhadi HA, Fox KA. Do we need additional markers of myocyte necrosis: the potential value of heart fatty-acid-binding protein. QJM. 2004;97(4):187-198. [CrossRef] [PubMed]
 
Storch J, Thumser AE. The fatty acid transport function of fatty acid-binding proteins. Biochim Biophys Acta. 2000;1486(1):28-44. [CrossRef] [PubMed]
 
Lankeit M, Dellas C, Panzenböck A, et al. Heart-type fatty acid-binding protein for risk assessment of chronic thromboembolic pulmonary hypertension. Eur Respir J. 2008;31(5):1024-1029. [CrossRef] [PubMed]
 
Dellas C, Tschepe M, Seeber V, et al. A novel H-FABP assay and a fast prognostic score for risk assessment of normotensive pulmonary embolism. Thromb Haemost. 2014;111(5):996-1003. [CrossRef] [PubMed]
 
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