Fatty Acid Binding Protein‐4 and Risk of Cardiovascular Disease: The Cardiovascular Health Study

FABP‐4 is a lipid chaperone in adipocytes and has been associated with prognosis in selected clinical populations. We investigated the associations between circulating FABP‐4, risk of incident cardiovascular disease (CVD) and risk of CVD mortality.

Originally published 6 Apr 2020 | https://doi.org/10.1161/JAHA.119.014070 | Journal of the American Heart Association. 2020;9:e014070

Cells binding

Abstract

Background

FABP‐4 (fatty acid binding protein‐4) is a lipid chaperone in adipocytes and has been associated with prognosis in selected clinical populations. We investigated the associations between circulating FABP‐4, risk of incident cardiovascular disease (CVD), and risk of CVD mortality among older adults with and without established CVD.

Methods and Results

In the Cardiovascular Health Study, we measured FABP4 levels in stored specimens from the 1992–993 visit and followed participants for incident CVD if they were free of prevalent CVD at baseline and for CVD mortality through June 2015. We used Cox regression to estimate hazard ratios for incident CVD and CVD mortality per doubling in serum FABP‐4 adjusted for age, sex, race, field center, waist circumference, blood pressure, lipids, fasting glucose, and C‐reactive protein. Among 4026 participants free of CVD and 681 with prevalent CVD, we documented 1878 cases of incident CVD and 331 CVD deaths, respectively. In adjusted analyses, FABP‐4 was modestly associated with risk of incident CVD (mean, 34.24; SD, 18.90; HR, 1.10 per doubling in FABP‐4, 95% CI, 1.00–1.21). In contrast, FABP‐4 was more clearly associated with risk of CVD mortality among participants without (HR hazard ratio 1.24, 95% CI, 1.10–1.40) or with prevalent CVD (HR hazard ratio 1.57, 95% CI, 1.24–1.98). These associations were not significantly modified by sex, age and waist circumference.

Conclusions

Serum FABP‐4 is modestly associated with risk of incident CVD even after adjustment for standard risk factors, but more strongly associated with CVD mortality among older adults with and without established CVD.

Nonstandard Abbreviations and Acronyms

ACS: acute coronary syndrome

aP2: adipocyte P2

BMI: body mass index

BP: blood pressure

CAD: coronary artery disease

CHS: Cardiovascular Health Study

CRP: C‐reactive protein

CV: coefficients of variation

CVD: cardiovascular disease

eGFR: estimated glomerular filtration rate

FABP‐4: fatty acid binding protein‐4

GRACE: Global Registry of Acute Coronary Events

HDL: high‐density lipoprotein

HR: hazard ratio

LDL: low‐density Lipoprotein

LLC: limited liability corporation

VEGF: vascular‐endothelial growth factor

Clinical Perspective

What Is New?

  • Obesity has been clearly associated with a higher risk of cardiovascular disease but adipocyte‐derived products have not consistently been associated with risk of cardiovascular disease and cardiovascular disease mortality in populations.

  • FABP‐4 (fatty acid binding protein‐4), an adipocyte derived product, is strongly associated with cardiovascular disease mortality and may serve as a useful measure of metabolically adverse obesity.

What Are the Clinical Implications?

  • Pharmacologic inhibition of FABP‐4 may present a viable therapeutic target for reducing obesity‐related cardiovascular mortality among older adults.

Although obesity is clearly associated with a higher risk of cardiovascular disease (CVD),1 and several promising physiological pathways have been implicated in this relationship,1 adipocyte‐derived products have not consistently been associated with risk of CVD and CVD mortality in populations.2 For example, initial reports related higher plasma adiponectin to a lower incidence of coronary heart disease in predominantly healthy middle‐aged men,34 but other studies have demonstrated contrasting findings in various cohorts, including the CHS (Cardiovascular Health Study) and Dallas Heart Study.5678 The adipokine, resistin, has been associated with risk in diabetic patients of European ancestry9 and in elderly, nondiabetic chronic kidney disease patients,10 but a recent meta‐analysis demonstrated significant heterogeneity in results from prospective cohort studies, only 10% of which accounted for participant age.11

FABP‐4 (fatty acid binding protein‐4), also known as aP2 (adipocyte P2),12 is the adipose‐specific isoform of the family of fatty‐acid–binding proteins and makes up around 6% of the total protein of adipocytes. It is also present in dendritic cells, macrophages, and in the bloodstream (after release from adipocytes).1213141516 As a lipid chaperone, FABP‐4 orchestrates intracellular pathways that lead to inflammatory activation, development of atherosclerosis,1314 insulin resistance, and adipokine secretion in adipocytes,171819including reduced adiponectin production.20

FABP‐4 promotes development and progression of atherosclerosis in some animal models.1821222324 In one, a small‐molecule inhibitor of FABP‐4 reduced development of diabetes mellitus and atherosclerosis.24 A variant in the gene encoding FABP‐4 has been associated with a lower risk for coronary heart disease in 2 parallel cohorts.23 A cross‐sectional study of Chinese adults found that FABP‐4 levels were associated with carotid plaque, but only in women,25 but a study of diabetic patients in Spain found no such association.26

In people with known coronary artery disease, FABP‐4 has been associated with complex coronary lesions,27 left ventricular hypertrophy, systolic dysfunction,12 myocardial perfusion abnormality, clinical heart failure,15 and adverse events in patients with stable coronary artery disease,2829 as well as after acute coronary syndrome.30

To determine whether an association exists between FABP‐4 and risk of CVD and CVD mortality, we assessed levels of circulating FABP‐4 in the CHS, a prospective, population‐based study of nearly 6000 older adults recruited from 4 field centers across the United States, who have been followed for approximately 30 years.

Methods

Requests to access the data set by qualified researchers trained in human subject confidentiality protocols may be sent to “The Cardiovascular Health Study” by contacting the CHS research coordinator, Erika Enright (phone: +1‐206‐897‐1922), and/or e‐mail to: [email protected]

Study Designs and Populations

The CHS is a prospective study of 5888 men and women aged ≥65 years who were recruited from randomly generated Medicare‐eligibility lists in Pittsburgh, Pennsylvania; Forsyth County, North Carolina; Sacramento, California; and Washington County, Maryland. Participants were not institutionalized or wheelchair dependent, did not require a proxy for consent, were not under treatment for cancer at the time of enrollment, and were expected to remain in their respective regions for at least 3 years. In 1989–1990, 5201 participants were recruited and examined (the original cohort); in 1992–1993, an additional 687 predominantly black participants were recruited and examined. The institutional review board at each participating center approved the study, and each participant gave informed consent.

The CHS study design and objectives have been published previously.31 The baseline examination included standardized medical history questionnaires, physical examination, resting ECG, and laboratory examination. Follow‐up contact has occurred every 6 months, alternating between telephone calls and clinic visits for the first decade of follow‐up and by telephone calls since. For this analysis, the 1992–1993 CHS clinic visit served as the baseline examination for follow‐up of CVD; most of the procedures performed at the original 1989–1990 baseline were repeated in 1992–1993. Participants were excluded from these analyses if they did not participate in (n=288) or had died before the 1992–1993 visit (n=335) or did not have sufficient stored plasma for FABP‐4 measurement (n=558).

Measurement of FABP‐4 and Other Biomarkers

FABP‐4 was measured from plasma collected at the 1992–1993 visit and subsequently stored at −80°F or below at the CHS Central Laboratory at the University of Vermont (Colchester, VT). As previously described,32 technicians at the Central Laboratory measured plasma FABP‐4 using standard ELISA kits (BioVendor, LLC, Asheville, NC). Interassay coefficients of variation were 2.61% to 5.32%, with a detectable range of 5 to 250 ng/mL.

The Central Laboratory also measured standard cardiovascular risk factors from samples collected in 1992–1993, including fasting glucose, lipids, and high‐sensitivity C‐reactive protein.33

Determination of Incident CVD and CVD Mortality

Details of the CHS protocols for confirmation of prevalent and incident cardiovascular events, including the algorithms used for classification, have been published.3435 Participants reported incident CVD at annual clinic visits and interim telephone interviews when questioned regarding hospitalizations and other acute events. Discharge summaries and diagnoses were obtained for all hospitalizations. For all potential incident events, additional information, including history of chest pain, cardiac enzyme levels, and serial ECGs, was collected. The CHS Cardiovascular Events Committee reviewed and classified all potential CVD events. In addition, the CHS Events Committee reviewed all deaths and classified these as cardiovascular or noncardiovascular. For these analyses, we used a primary composite outcome of incident CVD that included incident myocardial infarction (nonfatal and fatal), stroke, and CVD mortality, among participants free of prevalent CVD at baseline; we also examined these components separately. Our primary outcome among participants with prevalent CVD at baseline was CVD mortality.

Statistical Analysis

Our study included 4707 eligible CHS participants who had available FABP‐4 measures. For analysis of incident CVD, 4026 participants who were free from any CVD at baseline were included. The analysis of CVD mortality included 681 participants who had a known diagnosis of CVD at baseline. Missing covariate data were replaced by previously measured values, if available, or values estimated through imputation.36 We conducted a descriptive analysis of both of the study populations stratified according to baseline FABP‐4 quartiles, calculating mean and SD for continuous variables and frequencies for categorical variables. Time to event was calculated as the interval between the baseline examination in 1992–1993 to the earliest date of event of interest (myocardial infarction, stroke), date of CVD death, or date of last follow‐up (up until June 2015). Cox proportional hazard regression models were used to estimate hazard ratios for incident CVD and CVD mortality. We created initial models that included age, sex, race, field center, and waist circumference and a more extensively adjusted model that further included systolic blood pressure, use of antihypertensive medications, high‐density lipoprotein‐cholesterol, low‐density lipoprotein‐cholesterol, triglycerides, fasting glucose, use of medications for control of blood glucose, and C‐reactive protein. We modeled FABP‐4 concentrations in 2 ways—as quartiles within each population and per doubling of FABP‐4 concentration (using a logarithmic transformation to base 2). We used generalized additive model plots to evaluate the associations of transformed FABP‐4 with outcome with no meaningful departures from linearity. To assess subgroups in which FABP‐4 concentrations might be differentially associated with outcome, we created multiplicative interaction terms of FABP‐4 with age, sex, and waist circumference; of note, FABP‐4 was most strongly associated with risk of diabetes mellitus among lean men in previous analyses from the CHS.32 Statistical analyses were performed using Stata aoftware (version 14.2; StataCorp LP, College Station, TX). All P values were 2‐tailed.

Results

Baseline characteristics of participants free of CVD are summarized in Table 1 and those of participants with prevalent CVD in Table S1. Women tended to have higher FABP4 levels than men. As expected, mean levels of cardiometabolic predictors (including body mass index, waist circumference, systolic blood pressure, low‐density lipoprotein‐cholesterol, triglycerides, and C‐reactive protein) were higher in ascending FABP‐4 quartiles.

Table 1. Characteristics of CHS Participants Free of CVD at 1992–1993 Examination, by FABP‐4

T01



Table 2. Hazard Ratios (95% CIs) of Cardiovascular Outcomes Associated With Circulating Levels of FABP‐4

Table 02


Table 3.Hazard Ratios (95% CIs) of CVD Mortalitya Associated With Circulating Levels of FABP‐4 Among Participants With Prevalent CVD

Table 03

Discussion

Our prospective, population‐based, cohort study provides evidence for the association of circulating FABP‐4 with CVD mortality among older adults. Circulating FABP‐4 concentrations were not associated with incident nonfatal CVD among older adults without previous CVD, but were more clearly associated with CVD mortality among individuals without or with known CVD, even beyond traditional CVD risk factors.

Our results mirror those of selected previous studies, particularly in the strong association of FABP‐4 with CVD mortality in the clinical population of patients with previous CVD. In one 10‐year prospective study among German adults, circulating FABP‐4 levels were associated with prognosis among patients with coronary heart disease.29 Chow et al demonstrated that circulating FABP‐4 levels predicted development of CVD after adjustment for traditional risk factors in a community‐based Chinese cohort. FABP‐4 has also been associated with left ventricular hypertrophy, systolic and diastolic cardiac dysfunction,12 clinical heart failure,37 coronary atherosclerotic burden, number and complexity of stenotic coronary arteries,27 increased carotid intima‐media thickness, and ischemic stroke.14152538394041 In patients with established coronary artery disease, FABP‐4 has been reported to be associated with subsequent adverse cardiovascular events13272830 with a similar prognostic performance as the GRACE (Global Registry of Acute Coronary Events) in‐hospital risk score.30 Interestingly, FABP‐4 was not associated with subsequent adverse cardiovascular events in the subset of asymptomatic participants with CAD.30 Liu et al42 also demonstrated an association between circulating FABP‐4 levels and CVD mortality in men with type 2 diabetes mellitus.

The relationship of FABP‐4 with outcomes was attenuated after adjustment for lipids, blood pressure, glucose, and C‐reactive protein. This may suggest that part of the pathogenic effect of circulating FABP‐4 (and adipose mass, from which FABP‐4 derives) is, in part, mediated through these other traditional risk factors, although formal analyses will require cohorts in which all of these factors are measured repeatedly over time. Blood pressure, hyperglycemia, and inflammation, in particular, have been strongly associated with risk of CVD in CHS.4344454647

FABP‐4 is expressed in macrophages and dendritic cells and therefore may contribute to inflammation‐related alteration, resulting in progression of atherosclerosis and cardiac dysfunction. Beyond the metabolic risks, other pathogenic effects of FABP‐4 have been proposed. As a lipid chaperone involved in lipid oxidation, signaling, and trafficking, FABP‐4 has been correlated with adiposity4849 and, in particular, with epicardial fat deposition.50 FABP‐4 produced by epicardial fat may contribute to development of coronary atherosclerosis.51 FABP‐4 levels in atherosclerotic plaques are also associated with an unstable plaque phenotype.52 In samples from human endarterectomies, increased FABP‐4 expression in macrophages has been linked to unstable carotid plaques.53However, we cannot exclude the possibility of any confounding factors in these associations.

To our knowledge, there are no available literature to explain the differential associations of FABP‐4 levels with incident CVD and CVD mortality. We hypothesize that FABP‐4 levels may more closely reflect the downstream pathological processes that occur after development of CVD compared with its influence on development and progression of atherosclerosis. One intriguing speculation is that circulating FABP‐4 levels may partly reflect levels in vascular endothelium, where FABP‐4 is under direct control of VEGF (vascular endothelial growth factor) by VEGF receptor‐2.54If so, then FABP‐4 levels may reflect conditions in which this pathway is active, such as ischemia. This speculation requires further investigation.

Strengths and Limitations

For our analysis, we utilized a single snapshot measurement of serum FABP‐4 concentration. Regardless, our preliminary results suggest its association with incident CVD and CVD death. This finding suggests that future studies utilizing longitudinal measures of serum FABP‐4 concentration might show even stronger associations. Our study population included exclusively older adults. Older‐aged individuals have a higher risk of adverse CVD outcomes. We do not know how serum FABP‐4 concentrations would perform in middle‐aged adults at lower risk for CVD. As an observational study, we cannot exclude the possibility of residual or unmeasured confounding as an alternative explanation of observed associations. However, we included multiple covariates to minimize confounding. Other strengths of our study include a reproducible method for measuring FABP‐4, long‐term follow‐up, and standardized adjudication of CVD and mortality.

Conclusions

FABP‐4, a lipid chaperone and major protein constituent of adipocytes, is modestly associated with development of CVD in older adults, but is considerably more strongly associated with CVD mortality and may serve as a useful measure of metabolically adverse obesity. Although some studies support the association of FABP‐4 with cardiac dysfunction, obesity‐related CVD, and adverse cardiovascular events, the role of pharmacological inhibition of FABP‐4 has not been fully explored. Strategies that are centered on reducing or suppressing the effect of circulating FABP‐4 may be viable therapeutic targets for reducing obesity‐related cardiovascular mortality among older adults.

Sources of Funding

This research was supported by contracts HHSN268201200036C, HHSN268200800007C, HHSN268201800001C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, and N01HC85086 and grants U01HL080295, R01HL094555, and U01HL130114 from the National Heart, Lung, and Blood Institute (NHLBI), with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided by R01AG023629 and R01AG053325 from the National Institute on Aging (NIA).

Disclosures

None.

Acknowledgments

A full list of principal CHS investigators and institutions can be found at CHS‐NHLBI.org. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Footnotes

*Correspondence to: Obiora Egbuche, MD, MPH, Division of Cardiovascular Disease, Morehouse School of Medicine, 720 Westview Dr, Atlanta, GA 30310. E‐mail: [email protected]

References

  • Mandviwala T, Khalid U, Deswal A. Obesity and cardiovascular disease: a risk factor or a risk marker?Curr Atheroscler Rep. 2016; 18:21.Crossref | Medline | Google Scholar
  • Lavie CJ, De Schutter A, Parto P, Jahangir E, Kokkinos P, Ortega FB, Arena R, Milani RV. Obesity and prevalence of cardiovascular diseases and prognosis‐the obesity paradox updated. Prog Cardiovasc Dis. 2016; 58:537–547.Crossref | Medline | Google Scholar
  • Kizer JR. Adiponectin, cardiovascular disease, and mortality: parsing the dual prognostic implications of a complex adipokine. Metab, Clin Exp. 2014; 63:1079–1083.Crossref | Medline | Google Scholar
  • Zhang H, Mo X, Hao Y, Huang J, Lu X, Cao J, Gu D. Adiponectin levels and risk of coronary heart disease: a meta‐analysis of prospective studies. Am J Med Sci. 2013; 345:455–461.Crossref | Medline | Google Scholar
  • Kizer JR, Barzilay JI, Kuller LH, Gottdiener JS. Adiponectin and risk of coronary heart disease in older men and women. J Clin Endocrinol Metab. 2008; 93:3357–3364.Crossref | Medline | Google Scholar
  • Wu ZJ, Cheng YJ, Gu WJ, Aung LH. Adiponectin is associated with increased mortality in patients with already established cardiovascular disease: a systematic review and meta‐analysis. Metab Clin Exp. 2014; 63:1157–1166.Crossref | Medline | Google Scholar
  • Dekker JM, Funahashi T, Nijpels G, Pilz S, Stehouwer CD, Snijder MB, Bouter LM, Matsuzawa Y, Shimomura I, Heine RJ. Prognostic value of adiponectin for cardiovascular disease and mortality. J Clin Endocrinol Metab. 2008; 93:1489–1496.Crossref | Medline | Google Scholar
  • Witberg G, Ayers CR, Turer AT, Lev E, Kornowski R, de Lemos J, Neeland IJ. Relation of adiponectin to all‐cause mortality, cardiovascular mortality, and major adverse cardiovascular events (from the Dallas Heart Study). Am J Cardiol. 2016; 117:574–579.Crossref | Medline | Google Scholar
  • Menzaghi C, Bacci S, Salvemini L, Mendonca C, Palladino G, Fontana A, De Bonis C, Marucci A, Goheen E, Prudente S, et al. Serum resistin, cardiovascular disease and all‐cause mortality in patients with type 2 diabetes. PLoS One. 2014; 8:e64729.Crossref | Medline | Google Scholar
  • 10 Marouga A, Dalamaga M, Kastania AN, Kroupis C, Lagiou M, Saounatsou K, Dimas K, Vlahakos DV. Circulating resistin is a significant predictor of mortality independently from cardiovascular comorbidities in elderly, non‐diabetic subjects with chronic kidney disease. Biomarkers. 2016; 21:73–79.Crossref | Medline | Google Scholar
  • 11 Fontana A, Spadaro S, Copetti M, Spoto B, Salvemini L, Pizzini P, Frittitta L, Mallamaci F, Pellegrini F, Trischitta V, et al. Association between resistin levels and all‐cause and cardiovascular mortality: a new study and a systematic review and meta‐analysis. PLoS One. 2015; 10:e0120419.Crossref | Medline | Google Scholar
  • 12 Rodriguez‐Calvo R, Girona J, Alegret JM, Bosquet A, Ibarretxe D, Masana L. Role of the fatty acid‐binding protein 4 in heart failure and cardiovascular disease. J Endocrinol. 2017; 233:R173–R184. Crossref | Medline | Google Scholar
  • 13 Takagi W, Miyoshi T, Doi M, Okawa K, Nosaka K, Nishibe T, Matsuo N, Hirohata S, Ito H. Circulating adipocyte fatty acid‐binding protein is a predictor of cardiovascular events in patients with stable angina undergoing percutaneous coronary intervention. BMC Cardiovasc Disord. 2017; 17:258. Crossref | Medline | Google Scholar
  • 14 Miyoshi T, Onoue G, Hirohata A, Hirohata S, Usui S, Hina K, Kawamura H, Doi M, Kusano KF, Kusachi S, et al. Serum adipocyte fatty acid‐binding protein is independently associated with coronary atherosclerotic burden measured by intravascular ultrasound. Atherosclerosis. 2010; 211:164–169.Crossref | Google Scholar
  • 15 Huang CL, Wu YW, Wu CC, Lin L, Wu YC, Hsu PY, Jong YS, Yang WS. Association between serum adipocyte fatty‐acid binding protein concentrations, left ventricular function and myocardial perfusion abnormalities in patients with coronary artery disease. Cardiovasc Diabetol. 2013; 12:105.Crossref | Medline | Google Scholar
  • 16 Tso AW, Xu A, Sham PC, Wat NM, Wang Y, Fong CH, Cheung BM, Janus ED, Lam KS. Serum adipocyte fatty acid binding protein as a new biomarker predicting the development of type 2 diabetes: a 10‐year prospective study in a Chinese cohort. Diabetes Care. 2007; 30:2667–72.Crossref | Medline | Google Scholar
  • 17 Baar RA, Dingfelder CS, Smith LA, Bernlohr DA, Wu C, Lange AJ, Parks EJ. Investigation of in vivo fatty acid metabolism in AFABP/aP2(‐/‐) mice. Am J Physiol Endocrinol Metab. 2005; 288:E187–E193.Crossref | Medline | Google Scholar
  • 18 Makowski L, Brittingham KC, Reynolds JM, Suttles J, Hotamisligil GS. The fatty acid‐binding protein, aP2, coordinates macrophage cholesterol trafficking and inflammatory activity. Macrophage expression of aP2 impacts peroxisome proliferator‐activated receptor gamma and IkappaB kinase activities. J Biol Chem. 2005; 280:12888–12895.Crossref | Medline | Google Scholar
  • 19 Shaughnessy S, Smith ER, Kodukula S, Storch J, Fried SK. Adipocyte metabolism in adipocyte fatty acid binding protein knockout mice (aP2‐/‐) after short‐term high‐fat feeding: functional compensation by the keratinocyte [correction of keritinocyte] fatty acid binding protein. Diabetes. 2000; 49:904–911.Crossref | Medline | Google Scholar
  • 20 Hertzel AV, Smith LA, Berg AH, Cline GW, Shulman GI, Scherer PE, Bernlohr DA. Lipid metabolism and adipokine levels in fatty acid‐binding protein null and transgenic mice. Am J Physiol Endocrinol Metab. 2006; 290:E814–E823.Crossref | Medline | Google Scholar
  • 21 Makowski L, Boord JB, Maeda K, Babaev VR, Uysal KT, Morgan MA, Parker RA, Suttles J, Fazio S, Hotamisligil GS, et al. Lack of macrophage fatty‐acid‐binding protein aP2 protects mice deficient in apolipoprotein E against atherosclerosis. Nat Med. 2001; 7:699–705.Crossref | Medline | Google Scholar
  • 22 Boord JB, Maeda K, Makowski L, Babaev VR, Fazio S, Linton MF, Hotamisligil GS. Adipocyte fatty acid‐binding protein, aP2, alters late atherosclerotic lesion formation in severe hypercholesterolemia. Arterioscler Thromb Vasc Biol. 2002; 22:1686–1691.Link | Google Scholar
  • 23 Tuncman G, Erbay E, Hom X, De Vivo I, Campos H, Rimm EB, Hotamisligil GS. A genetic variant at the fatty acid‐binding protein aP2 locus reduces the risk for hypertriglyceridemia, type 2 diabetes, and cardiovascular disease. Proc Natl Acad Sci U S A. 2006; 103:6970–6975.Crossref | Medline | Google Scholar
  • 24 Furuhashi M, Tuncman G, Gorgun CZ, Makowski L, Atsumi G, Vaillancourt E, Kono K, Babaev VR, Fazio S, Linton MF, et al. Treatment of diabetes and atherosclerosis by inhibiting fatty‐acid‐binding protein aP2. Nature. 2007; 447:959–965.Crossref | Medline | Google Scholar
  • 25 Yeung DC, Xu A, Cheung CW, Wat NM, Yau MH, Fong CH, Chau MT, Lam KS. Serum adipocyte fatty acid‐binding protein levels were independently associated with carotid atherosclerosis. Arterioscler Thromb Vasc Biol. 2007; 27:1796–1802.Link | Google Scholar
  • 26 Cabre A, Lazaro I, Girona J, Manzanares JM, Marimon F, Plana N, Heras M, Masana L. Fatty acid binding protein 4 is increased in metabolic syndrome and with thiazolidinedione treatment in diabetic patients. Atherosclerosis. 2007; 195:e150–e158.Crossref | Medline | Google Scholar
  • 27 Kajiya M, Miyoshi T, Doi M, Usui S, Iwamoto M, Takeda K, Nosaka K, Nakayama R, Hirohata S, Kusachi S, et al. Serum adipocyte fatty acid‐binding protein is independently associated with complex coronary lesions in patients with stable coronary artery disease. Heart Vessels. 2013; 28:696–703. Crossref | Medline | Google Scholar
  • 28 Huang IC, Hsu BG, Chang CC, Lee CJ, Wang JH. High levels of serum adipocyte fatty acid‐binding protein predict cardiovascular events in coronary artery disease patients. Int J Med Sci. 2018; 15:1268–1274.Crossref | Medline | Google Scholar
  • 29 von Eynatten M, Breitling LP, Roos M, Baumann M, Rothenbacher D, Brenner H. Circulating adipocyte fatty acid‐binding protein levels and cardiovascular morbidity and mortality in patients with coronary heart disease: a 10‐year prospective study. Arterioscler Thromb Vasc Biol. 2012; 32:2327–2335. Link | Google Scholar
  • 30 Reiser H, Klingenberg R, Hof D, Cooksley‐Decasper S, Fuchs N, Akhmedov A, Zoller S, Marques‐Vidal P, Marti Soler H, Heg D, et al. Circulating FABP4 is a prognostic biomarker in patients with acute coronary syndrome but not in asymptomatic individuals. Arterioscler Thromb Vasc Biol. 2015; 35:1872–1879.Link | Google Scholar
  • 31 Fried LP, Borhani NO, Enright P, Furberg CD, Gardin JM, Kronmal RA, Kuller LH, Manolio TA, Mittelmark MB, Newman A, et al. The Cardiovascular Health Study: design and rationale. Ann Epidemiol. 1991; 1:263–276.Crossref | Medline | Google Scholar
  • 32 Djousse L, Khawaja O, Bartz TM, Biggs ML, Ix JH, Zieman SJ, Kizer JR, Tracy RP, Siscovick DS, Mukamal KJ. Plasma fatty acid‐binding protein 4, nonesterified fatty acids, and incident diabetes in older adults. Diabetes Care. 2012; 35:1701–1707.Crossref | Medline | Google Scholar
  • 33 Cushman M, Cornell ES, Howard PR, Bovill EG, Tracy RP. Laboratory methods and quality assurance in the Cardiovascular Health Study. Clin Chem. 1995; 41:264–270.Crossref | Medline | Google Scholar
  • 34 Psaty BM, Kuller LH, Bild D, Burke GL, Kittner SJ, Mittelmark M, Price TR, Rautaharju PM, Robbins J. Methods of assessing prevalent cardiovascular disease in the Cardiovascular Health Study. Ann Epidemiol. 1995; 5:270–7.Crossref | Medline | Google Scholar
  • 35 Ives DG, Fitzpatrick AL, Bild DE, Psaty BM, Kuller LH, Crowley PM, Cruise RG, Theroux S. Surveillance and ascertainment of cardiovascular events. The Cardiovascular Health Study. Ann Epidemiol. 1995; 5:278–85.Crossref | Medline | Google Scholar
  • 36 Arnold AM, Kronmal RA. Multiple imputation of baseline data in the Cardiovascular Health Study. Am J Epidemiol. 2003; 157:74–84.Crossref | Medline | Google Scholar
  • 37 Liu M, Zhou M, Bao Y, Xu Z, Li H, Zhang H, Zhu W, Zhang J, Xu A, Wei M, et al. Circulating adipocyte fatty acid‐binding protein levels are independently associated with heart failure. Clin Sci. 2013; 124:115–122.Crossref | Medline | Google Scholar
  • 38 Bao Y, Lu Z, Zhou M, Li H, Wang Y, Gao M, Wei M, Jia W. Serum levels of adipocyte fatty acid‐binding protein are associated with the severity of coronary artery disease in Chinese women. PLoS One. 2011; 6:e19115.Crossref | Medline | Google Scholar
  • 39 Xu A, Wang Y, Lam KS, Vanhoutte PM. Vascular actions of adipokines molecular mechanisms and therapeutic implications. Adv Pharmacol. 2010; 60:229–255.Crossref | Medline | Google Scholar
  • 40 Doi M, Miyoshi T, Hirohata S, Nakamura K, Usui S, Takeda K, Iwamoto M, Kusachi S, Kusano K, Ito H. Association of increased plasma adipocyte fatty acid‐binding protein with coronary artery disease in non‐elderly men. Cardiovasc Diabetol. 2011; 10:44.Crossref | Medline | Google Scholar
  • 41 Tso AW, Lam TK, Xu A, Yiu KH, Tse HF, Li LS, Law LS, Cheung BM, Cheung RT, Lam KS. Serum adipocyte fatty acid‐binding protein associated with ischemic stroke and early death. Neurology. 2011; 76:1968–1975.Crossref | Medline | Google Scholar
  • 42 Liu G, Ding M, Chiuve SE, Rimm EB, Franks PW, Meigs JB, Hu FB, Sun Q. Plasma levels of fatty acid‐binding protein 4, retinol‐binding protein 4, high‐molecular‐weight adiponectin, and cardiovascular mortality among men with type 2 diabetes: a 22‐year prospective study. Arterioscler Thromb Vasc Biol. 2016; 36:2259–2267.Link | Google Scholar
  • 43 Psaty BM, Furberg CD, Kuller LH, Cushman M, Savage PJ, Levine D, O'Leary DH, Bryan RN, Anderson M, Lumley T. Association between blood pressure level and the risk of myocardial infarction, stroke, and total mortality: the Cardiovascular Health Study. Arch Intern Med. 2001; 161:1183–1192.Crossref | Medline | Google Scholar
  • 44 Tracy RP, Lemaitre RN, Psaty BM, Ives DG, Evans RW, Cushman M, Meilahn EN, Kuller LH. Relationship of C‐reactive protein to risk of cardiovascular disease in the elderly. Results from the Cardiovascular Health Study and the Rural Health Promotion Project. Arterioscler Thromb Vasc Biol. 1997; 17:1121–1127.Crossref | Medline | Google Scholar
  • 45 Smith NL, Barzilay JI, Shaffer D, Savage PJ, Heckbert SR, Kuller LH, Kronmal RA, Resnick HE, Psaty BM. Fasting and 2‐hour postchallenge serum glucose measures and risk of incident cardiovascular events in the elderly: the Cardiovascular Health Study. Arch Intern Med. 2002; 162:209–216.Crossref | Medline | Google Scholar
  • 46 Voulgari C, Tentolouris N, Dilaveris P, Tousoulis D, Katsilambros N, Stefanadis C. Increased heart failure risk in normal‐weight people with metabolic syndrome compared with metabolically healthy obese individuals. J Am Coll Cardiol. 2011; 58:1343–50.Crossref | Medline | Google Scholar
  • 47 Bahrami H, Bluemke DA, Kronmal R, Bertoni AG, Lloyd‐Jones DM, Shahar E, Szklo M, Lima JA. Novel metabolic risk factors for incident heart failure and their relationship with obesity: the MESA (Multi‐Ethnic Study of Atherosclerosis) study. J Am Coll Cardiol. 2008; 51:1775–83.Crossref | Medline | Google Scholar
  • 48 Ishimura S, Furuhashi M, Watanabe Y, Hoshina K, Fuseya T, Mita T, Okazaki Y, Koyama M, Tanaka M, Akasaka H, et al. Circulating levels of fatty acid‐binding protein family and metabolic phenotype in the general population. PLoS One. 2013; 8:e81318.Crossref | Medline | Google Scholar
  • 49 Xu A, Wang Y, Xu JY, Stejskal D, Tam S, Zhang J, Wat NM, Wong WK, Lam KS. Adipocyte fatty acid‐binding protein is a plasma biomarker closely associated with obesity and metabolic syndrome. Clin Chem. 2006; 52:405–13.Crossref | Medline | Google Scholar
  • 50 Sovova E, Sova M, Zapletalova J, Stejskal D, Sovova M, Kaletova M, Svobodova G, Kuca I, Janak M, Kaminek M. Possitive correlation between adipocyte fatty acid‐binding protein and epicardial fat in patients with a family history of cardiovascular disesase. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2017; 161:174–178.Crossref | Medline | Google Scholar
  • 51 Furuhashi M, Fuseya T, Murata M, Hoshina K, Ishimura S, Mita T, Watanabe Y, Omori A, Matsumoto M, Sugaya T, et al. Local production of fatty acid‐binding protein 4 in epicardial/perivascular fat and macrophages is linked to coronary atherosclerosis. Arterioscler Thromb Vasc Biol. 2016; 36:825–834.Link | Google Scholar
  • 52 Lee K, Santibanez‐Koref M, Polvikoski T, Birchall D, Mendelow AD, Keavney B. Increased expression of fatty acid binding protein 4 and leptin in resident macrophages characterises atherosclerotic plaque rupture. Atherosclerosis. 2013; 226:74–81.Crossref | Medline | Google Scholar
  • 53 Agardh HE, Folkersen L, Ekstrand J, Marcus D, Swedenborg J, Hedin U, Gabrielsen A, Paulsson‐Berne G. Expression of fatty acid‐binding protein 4/aP2 is correlated with plaque instability in carotid atherosclerosis. J Intern Med. 2011; 269:200–210.Crossref | Medline | Google Scholar
  • 54 Elmasri H, Karaaslan C, Teper Y, Ghelfi E, Weng M, Ince TA, Kozakewich H, Bischoff J, Cataltepe S. Fatty acid binding protein 4 is a target of VEGF and a regulator of cell proliferation in endothelial cells. FASEB J. 2009; 23:3865–3873.Crossref | Medline | Google Scholar