The salient finding in the present study was that FABP4 was independently and negatively correlated with e’, which reflects LV relaxation and is known as one of the most sensitive indexes of LV diastolic function in a healthy population . LV diastolic dysfunction often precedes LV systolic dysfunction in heart diseases, and moderate diastolic dysfunction alone potentially induces heart failure, which is referred to as heart failure with preserved ejection fraction (HFpEF) . A recent study in which data from the Framingham cohort study were analyzed showed that age, diabetes mellitus, BMI, smoking and atrial fibrillation were predictors of HFpEF . It is notable that the correlation of FABP4 level with e’ was independent of age, BMI, HOMA-R and LV wall thickness (Table 4). These results suggest that serum FABP4 is a novel marker of LV diastolic dysfunction and potentially a predictor of HFpEF.
Previous studies using animal models indicated that FABP4 plays a significant role in several aspects of metabolic syndrome, including insulin resistance, type 2 diabetes and atherosclerosis, through its action at the interface of metabolic and inflammatory pathways in adipocytes and macrophages ,,-. Epicardial fat has been reported to directly influence cardiac function because of the absence of a fibrous fascial layer between fat and the underlying myocardium ,. FABP4 mRNA expression in epicardial adipose tissue was recently reported to be profoundly increased compared with its expression in paraaortic adipose tissue in patients with metabolic syndrome . Furthermore, it has recently been reported that exogenous FABP4 acutely suppresses shortening amplitude in cardiomyocytes by attenuating intracellular systolic peak Ca2+ level in a dose-dependent manner  and impairs the insulin-dependent nitric oxide pathway in vascular endothelial cells . Therefore, it is possible that either FABP4 secreted from epicardial fat tissue or circulating FABP4 released from subcutaneous and/or visceral adipose tissue or from macrophages may directly modulate cardiac function. In the heart, FABP3 known as heart-type FABP (H-FABP) is abundant and is rapidly released from cells into the circulation after onset of cardiomyocyte damage. Serum concentration of FABP3 has been characterized as an early biochemical marker of acute myocardial infarction and a sensitive marker of ongoing myocardial damage in patients with heart failure ,. Impact of circulating FABP3 is apparently different from that of FABP4.
Inflammation is an important factor in the pathogenesis and progression of heart failure. It has been shown that increased inflammatory cytokines produced by mononuclear cells including macrophages and/or damaged myocardium impaired myocardial function by inducing apoptosis, necrosis and hypertrophic response in cardiomyocytes . In the Framingham Heart Study, increased inflammatory markers, such as CRP, interleukin-6 and TNFα levels, were able to identify asymptomatic older subjects in the community who were at high risk for the future development of heart failure . In the present study, FABP4 was positively correlated with hsCRP, being consistent with the results of several previous studies ,. The macrophage is a critical site of FABP4 action, and macrophage-specific FABP4 deficiency leads to reduced activation of nuclear factor κ B (NF-κB) and c-Jun N-terminal kinase (JNK), resulting in reduced production of a cluster of inflammatory cytokines . Conversely, several inflammatory stimuli have been shown to cause significantly increased expression of FABP4 in macrophages . Local inflammation mediated by FABP4 in macrophages of the heart may participate in mediating cardiac dysfunction.
Up-regulation of FABP4 expression and other adipokines in heart failure has been demonstrated in recent studies -, indicating complex neurohormonal and metabolic abnormalities associated with heart failure. Of note, up-regulation of inflammatory cytokines, catecholamines and natriuretic peptides in heart failure is known to mediate increased lipolysis and insulin resistance . It has been reported that lipolysis is mediated in part through the interaction of FABP4 with hormone-sensitive lipase in adipocytes . A recent study also showed that FABP4 is secreted from adipocytes in a non-classical secretion pathway in relation to lipolysis . Although most of the recruited subjects in the present study were considered to be healthy, relatively high level of lipolytic stimuli, such as inflammatory cytokines, catecholamines and natriuretic peptides, in asymptomatic cardiac dysfunction may increase serum FABP4 concentration.
Circulating FABP4 level was associated with increased LV mass in overweight and obese women  and in patients with obstructive sleep apnea syndrome . Recent studies also showed an independent correlation of elevated serum FABP4 with NT-proBNP in heart failure patients  or deterioration of LV systolic function in non-obese patients hospitalized for acutely decompensated heart failure  and in patients with coronary artery disease . In contrast, there was no significant association between FABP4 level and concurrent  or subsequently developed  systolic dysfunction in subjects without obvious cardiac disease. In the present study using apparently healthy subjects with no medication, serum FABP4 level was weakly correlated with mean LV wall thickness but with LV mass index or LV ejection fraction. These findings suggest only a marginal contribution of FABP4 to development of the early phase of LV hypertrophy and systolic dysfunction.
Similar to our results, a very recent study by Baessler et al.  demonstrated that FABP4 level was independently correlated with e’ after adjustment of age, sex and adiposity in 96 obese subjects and 24 healthy normal weight control subjects, although the association of FABP4 levels with LV diastolic dysfunction was mainly observed in obese subjects with metabolic complications but not in metabolically healthy obese subjects. However, LV diastolic dysfunction in the previous study was defined by combination of several parameters, such as e’, E/e’, E/A, E-wave deceleration time and left atrial dimension. This definition may affect the results. Of note, we showed that FABP4 level was an independent predictor of e’, which is known as an index of LV relaxation and one of the most sensitive indicator of LV diastolic function compared with other indices, especially in a healthy population .
A genetic variant at the FABP4 locus associated with decreased FABP4 expression in adipose tissue has been reported to reduce the risk of cardiovascular disease in a population study . We and others previously showed that serum FABP4 level predicts long-term cardiovascular events -. Furthermore, a large-scale prospective study showed that concentration of FABP4 predicted the risk of heart failure during a median follow-up of 10.7 years . Accumulating evidence of a causative role of FABP4 in cardiac dysfunction would prove that FABP4 is a novel target for prevention of heart failure.
Since FABP4 is a low-molecular-weight protein and freely filtered at the glomerulus, a decrease in glomerular function was shown to result in an elevation of FABP4 concentration . In the present study, FABP4 was negatively correlated with eGFR but remained as an independent predictor of LV diastolic dysfunction even after adjusting for renal function. Besides eGFR, multivariate regression analysis demonstrated that the association of FABP4 level with LV diastolic dysfunction was independent of blood pressure, LV wall thickness and BNP, a well-known predictor of cardiac damage.
The present study has some limitations. Since it has been reported that several drugs, including statin, angiotensin II receptor blocker and peroxisome proliferator-activated receptor γ agonist, affect FABP4 concentrations -, we excluded subjects who had been treated with any drugs in the present study. Therefore, only a small number of subjects could be enrolled, and the statistical power was not large. Another limitation of this study is its cross-sectional design. Prospective longitudinal studies using larger numbers of subjects with no medication are necessary for determining whether FABP4 level is indeed a major determinant of subsequent development of cardiac dysfunction. In addition, the results of our study rely on correlation analyses. A direct relationship between FABP4 level and progression of LV diastolic dysfunction remains unclear. This issue warrants further investigation using an interventional approach.