Positive correlation of serum adipocyte fatty acid binding protein levels with carotid–femoral pulse wave velocity in geriatric population

Vessel stiffness is one of the multiple characteristics of cardiovascular (CV) disease, including abnormalities like, the thickening of the vessel wall, formation of fatty streaks, atherosclerotic plaques, and coronary artery calcification [1]. Arterial stiffness is being increasingly recognized as a surrogate end point for CV diseases [2]. The mechanism of arterial stiffness most often involves, degradation of elastin fibers, collagen accumulation, re-organization of cellular elements, and low-grade inflammation with increased expression of tumor necrosis factor-alpha, interleukin-6 and high-sensitivity C-reactive protein [3, 4]. Arterial stiffness reflects sub-clinical organ damage and is considered an important predictor of CV disease. The carotid-femoral pulse wave velocity (cfPWV) is a recommended measure to determine arterial stiffness [5]. A systematic review showed that aortic PWV is a strong predictor of future CV events and all-cause mortality, and has a predictive value independent of classic potential CV risk factors [2].

Aberrant production of the adipokines, due to adiposopathy (fat dysfunction), is an important risk factor for the development of obesity-related CV diseases. Adipocyte fatty acid binding protein (A-FABP), a polypeptide with 132 amino acids and a molecular mass of 14.6 kDa, is one of the most abundant proteins in mature adipocytes, accounting for about 6 % of their total cellular protein content [6]. A-FABP mRNA and protein production are elevated in subcutaneous adipose tissue, as compared to the visceral depot in lean and obese individuals [7]. A-FABP overproduction is believed to play a central role in obesity-related CV disease and endothelial dysfunction by increasing cholesterol and triglyceride accumulation, leading to foam cell development and induction of pro-inflammatory genes. This will in turn promote insulin resistance, atherosclerosis, and potentiate lipid-induced impairment in the activation of endothelial nitric oxide synthase (eNOS) [8].

Previously, we had reported that A-FABP was associated with metabolic syndrome in patients with coronary artery disease and in hemodialysis patients [9, 10]. In addition, arterial stiffness was reported to increase with age. The low prevalence of atherosclerosis in East Asian populations, suggests that the stiffness of arteries was an inevitable consequence of aging [11]. Since CV diseases are a major cause of mortality in the geriatric population, with adipokines playing an important role, we conducted this study to exclude the influences of aging on arterial stiffness. The present study examined the various risk factors in the development of arterial stiffness and evaluated the correlation between the serum concentration of A-FABP and arterial stiffness in geriatric adults.

Demographic, biochemical, and clinical characteristics of the 87 geriatric adults are shown in Tables 1 and 2. The medical histories of the geriatric adults included DM (n = 34 [39.1 %]), and HTN (n = 42 [48.3 %]). The medications prescribed to the geriatric adults included angiotensin-converting enzyme inhibitors (ACEi; n = 13 [14.9 %]), angiotensin receptor blockers (ARB; n = 30 [34.5 %]), β-blockers (n = 24 [27.6 %]), calcium channel blockers (CCB; n = 22 [25.3 %]), statins (n = 28 [32.2 %]), and fibrate (n = 10 [11.5 %]). Forty-two geriatric adults (48.3 %) belonged to the high arterial stiffness group, and when compared to the geriatric adults in the low arterial stiffness group, they had a higher incidence of DM (31.1 % vs. 52.4 %, P = 0.044) or HTN (37.8 % vs. 59.5 %, P = 0.043). There was no statistically significant difference between the high and low arterial stiffness groups, based on, gender, ACEi, ARB, β-blocker, CCB, statins, or fibrate use.

Body weight (67.37 ± 10.91 kg vs. 62.40 ± 9.69 kg, P = 0.027), waist circumference (93.79 ± 11.99 cm vs. 88.91 ± 9.10 cm, P = 0.035), BMI (26.63 ± 3.83 kg/m²vs. 24.04 ± 3.21 kg/m², P = 0.001), SBP (137.40 ± 18.68 mmHg vs. 126.69 ± 15.77 mmHg, P = 0.005), DBP (73.26 ± 7.71 mmHg vs. 69.53 ± 9.27 mmHg, P = 0.045), pulse pressure (64.14 ± 16.54 mmHg vs. 57.16 ± 14.42 mmHg, P = 0.038) were higher in the high arterial stiffness group, as compared to the low arterial stiffness group. Moreover, serum A-FABP was also elevated in the high arterial stiffness group than in the low arterial stiffness group (28.13 ± 13.86 ng/ml vs. 17.69 ± 11.01 ng/ml, P < 0.001; Table 3).

Multivariate logistic regression analysis of the factors significantly associated with arterial stiffness (DM, HTN, body weight, waist circumference, BMI, SBP, DBP, pulse pressure, and A-FABP) revealed that A-FABP (odds ratio: 1.833, 95 % confidence interval (CI): 1.123–2.993, P = 0.015) was an independent predictor of arterial stiffness in geriatric adults (Table 4).

The current results reveal that the fasting A-FABP levels were higher in the high arterial stiffness group than in the low arterial stiffness group, and A-FABP is an independent predictor for the development of arterial stiffness in the geriatric population.

A systematic review had shown that BP was independently associated with PWV in approximately 90 % of the studies [16]. Cecelja et al. found a dissociation of cfPWV with classic factors, such as gender, smoke, or lipids other than HTN, and they suggested that aortic stiffing might be driven by an alternative pathology, which depended on mechanical stretch of the arterial wall [16]. The pathophysiological correlation between arterial stiffness and HTN is that the increased arterial stiffness reduces the lumen diameter, for a given smooth muscle tone and blood pressure, leading to a premature return of the reflected wave in late systole, thereby increasing the central pulse pressure and SBP, and decreasing DBP [17]. On the other hand, aortic stiffness may affect aortic function, reduce baroreceptor responsiveness, and increase systolic pressure, making arterial stiffness one of the leading causes of increased blood pressure [4]. Meta-analysis of studies in the field have demonstrated that an increase in aortic PWV by 1 m/s corresponded to an age-, sex-, and risk factor-adjusted increase in total CV events, CV mortality, and all-cause mortality by 14, 15, and 15 %, respectively [2]. In addition, another meta-analysis found that greater arterial stiffness correlated with cerebral small vessel diseases [18], and Zhang et al. supposed that measuring cfPWV was beneficial to the elderly regarding the cardiovascular and cerebrovascular diseases, including atherosclerosis, cognitive dysfunction and mortality [19]. Therefore, arterial stiffness could serve as an independent predictor of coronary events and adverse CV diseases.

Studies had shown that there is a crosstalk between CV diseases and adipokines, such as, adiponectin, leptin, and A-FABP [20‐23]. Makowski and colleagues reported that apolipoprotein E deficient mice with A-FABP +/+ adipocytes and A-FABP −/− macrophages, showed a comparable reduction in atherosclerotic lesions to those with total A-FABP deficiency, indicating an independent role for macrophage A-FABP in atherogenesis [24]. Lee et al. had shown an enhanced expression of A-FABP on aortic endothelium of apolipoprotein E deficient mice and in cultured human microvascular endothelial cells. This lipid-induced A-FABP expression was associated with reduced phosphorylated eNOS and NO production, and was reversed by A-FABP inhibitor [8]. So, the pro-atherogenic potential of A-FABP on the vasculature is possibly mediated by the pro-inflammatory effects, independent of lipid metabolism and insulin sensitivity. Further, it contributes to the endothelial dysfunction by potentiating lipid-induced impairment in eNOS activation, and thus endothelium-dependent vasodilatation.

Clinical reports reveal a significant correlation of baseline serum A-FABP with BMI, homeostasis model of insulin resistance, and cardio-ankle vascular index, which is a marker of arterial stiffness [25, 26]. In addition to the associated metabolic risk factors, A-FABP levels were positively correlated with coronary plaque volume burden as well, and may serve as a biomarker for the detection of coronary artery disease [22, 23]. An increase in the number of stenotic coronary arteries resulted in a corresponding increase in the plasma A-FABP levels in patients with coronary heart diseases [23]. In addition to the macrovascular complications (ischemic heart disease, stroke, or peripheral vascular disease) in diabetic patients, A-FABP show a positive correlation with albuminuria and negative correlation with glomerular filtration rate, indicating that the serum level of A-FABP is influenced by impaired renal clearance and activated macrophages in diabetic nephropathy [27]. In this study, we found that geriatric adults who had high arterial stiffness would have higher serum A-FABP levels than those with low arterial stiffness. Moreover, A-FABP was demonstrated to be an independent risk factor for developing high arterial stiffness.

Classic CV risk factors, including DM, hyperlipidemia, elevated BMI and smoking, had been implicated in accelerating arterial stiffness. However, Cecelja et al. have indicated that the prognostic value of cfPWV may be related to a process of arterial ageing, and probably unrelated to the classic risk factors, other than HTN [16]. Additionally, impaired glucose tolerance and DM in a population-based study was independently associated with the central arterial stiffness, after adjusting mean arterial pressure, age and gender [28]. In our geriatric patients, we found that adults who were found to have high arterial stiffness would have a higher body weight, waist circumference, BMI, SBP, DBP, and pulse pressure. Furthermore, those who were in the high arterial stiffness group also had a higher percentage of DM or HTN, as previously reported [16].

Several types of medications had been demonstrated to affect arterial stiffness. Studies of β-blockers on arterial stiffness showed less impact on central BP decline compared with the peripheral BP [29, 30]. Older hypertensive patients treated with calcium channel blockers, showed the lowest central aortic pressure and less augmentation pressure, when compared with the placebo [31]. Moreover, usage of ACEi or ARB showed significant effects on reducing the central BP and augmentation index, through the reduction of oxidative stress and inflammation, and vasodilatation through angiotensin II inhibition [30, 31]. Miyoshi et al. conducted a study which showed that the effects of ARB in HTN patients could reduce cardio-ankle vascular index as well as serum levels of A-FABP, but the causal relationship needed to be clarified by further studies [26]. Even though, one systematic review showed controversial effects of statin on the reduction of aortic PWV [32], recent reports indicated that low dose of atorvastatin in mild HTN and hypercholesterolemia exerted beneficial effects on arterial stiffness and central aortic pressure [33]. In obese patients without glucose intolerance, treatment with PPAR alpha agonist (fenofibrate) revealed significant reduction in the augmentation index, PWV, and pro-inflammatory markers [34]. The results of subgroup analysis in this study suggest that ACEi, ARB, β-blockers, CCB, statins, or fibrate had no influence at all, on arterial stiffness.

The major limitation of this study is that, this was a cross-sectional study with a limited number of geriatric adults. Therefore, the findings of this study must be confirmed by long-term prospective studies before a causal relationship between the serum A-FABP and arterial stiffness can be established in the geriatric patient population. However, to the best of our knowledge, this is the first study to examine the relationship between serum A-FABP and arterial stiffness in the geriatric population.

In conclusion, we found that serum A-FABP levels were higher in geriatric population having high arterial stiffness. More importantly, A-FABP may serve as an independent predictor for the development of arterial stiffness in geriatric adults. Whether serum A-FABP directly contributes to the development of arterial stiffness or not, needs to be further validated in larger cohorts.