Arterial stiffness, endothelial dysfunction and early atherosclerosis are markers and independent predictors of cardiovascular disease. Many studies have shown that FLI is associated with early atherosclerosis [8,9,10] and endothelial dysfunction [11,12,13,14]. Clarification of the association between NAFLD and arterial stiffness, with the involvement of NAFLD having an effect on cardiovascular disease will provide novel potentially different mechanisms for the prevention and treatment of NAFLD leading to cardiovascular events. NAFLD may cause cardiovascular disease in two ways [1]. First, NALFD is a systemic sub-inflammatory state. Acute or chronic systemic inflammation may impair vascular endothelial function and worsen arterial function [15]. Hence, it is manifested as a significant correlation between FLI and PWV. Specifically, FLI is a manifestation of the severity of NAFLD, and the change of PWV is the result of systemic disease of NAFLD. Second, NAFLD may cause insulin resistance and atherogenic dyslipidemia which is associated with chronic hyperglycemia and hyperinsulinemia. And these changes may increase the local activity of the renin–angiotensin–aldosterone system and the expression of the angiotensin type I receptor, leading to hypertrophy of vascular wall and fibrosis [16].
The relationship between NAFLD and arterial stiffness may be mutually influenced [16]. NAFLD may accelerate the progression of arterial stiffness and increased arterial stiffness may result in a disruption of the hepatic artery buffer response that maintains metabolic homeostasis. This may lead NAFLD in the direction of advanced liver fibrosis [17].
This study found that subjects with NAFLD (FLI ≥ 60) had higher cfPWV than those with FLI < 30. In addition, we found that the intermediate fatty liver index group had higher age and blood pressure, which is the main dependency factor of cfPWV. Thus between groups 2 (FLI 30–60) and 3 (FLI ≥ 60), the relationship seems absent. However, the quadratic FLI term was not found to be significant with cfPWV in our multivariable regression models (β = 0.148, p = 0.382).
We found that FLI > 60 is significantly associated with significantly lower HDL-C and higher triglyceride [18], suggesting that elevated FLI (which means increased hepatic steatosis) can increase atherogenic protein levels and promote the development of atherosclerosis. In addition, NAFLD may represent liver manifestations of the metabolic syndrome. The liver's own fatty lesions and inflammatory lesions may promote systemic inflammatory levels and increased transcription of pro-inflammatory genes [10]. Elevated levels of pro-inflammatory cytokines lead to atherosclerosis. Therefore, cfPWV, as a measure of arterial stiffness, may also increase.
Adiponectin is a peptide substance secreted by adipose tissue and has anti-oxidant and anti-atherosclerotic effects. Studies have confirmed that adiponectin levels are significantly associated with PWV [19]. Patients with NALFD have a significant lower level of plasma adiponectin concentrations [20] and are closely related to the severity of liver disease. Leptin is also one of the peptides secreted by adipose tissue, which has the effect of reducing liver fat accumulation and is an independent predictor of aortic function [21]. Changes in adiponectin and leptin concentrations may be one of the reasons for the significant correlation between FLI and PWV, but the specific mechanism remains to be studied. Since both PWV and FLI are non-invasive and more operative in the field of screening, more relevant research may be considered in the future.
The most noteworthy result of our study is that FLI remained positively associated with cfPWV after adjusting for several confounding factors, suggesting that liver fat lesions aggravate arterial stiffness. Some studies have reported the correlation between NAFLD and PWV. Vlachopoulos et al. [22] reported that PWV was significantly higher in patients with NAFLD than in the control group. Salvi et al. [23] reported that PWV values were significantly lower in control group compared with NAFLD group. Sunbul et al. [24] reported that the liver fibrosis score was an independent predictor of both PWV and AIx values in NAFLD. However, little research has been done on the relevance of atraumatic FLI and PWV. Cicero et al. [25] confirmed that FLI and PWV were significantly associated in moderate to high risk (BMI ≥ 28 and/or type 2 diabetes) patients. Our study confirmed the correlation between FLI and PWV in the Chinese. NAFLD can develop into non-alcoholic steatohepatitis (NASH), which is characterized by liver fibrosis and closely related to cirrhosis [24]. Therefore, NALFD patients should be referred to in time for an accurate, non-invasive assessment of vascular risk. Conversely, cardiovascular physicians should also refer NAFLD patients with increased arterial stiffness to liver specialists for early diagnosis and treatment of liver fibrosis [24]. However, after adjustment for mean arterial blood pressure and other confounding factors, cfPWV in all of the models was not significantly associated with intermediate fatty liver index or hepatic steatosis group compared to those with FLI < 30. In interpreting the results, it is important to note that the relationship between cfPWV and blood pressure can be due to the dependency of cfPWV on blood pressure at the time of measurement or pressure-related remodeling of the arterial wall. The finding of a higher correlation for cfPWV with SBP than for DBP suggests that the possibility of remodeling effects of blood pressure on arterial stiffness. These two effects are not easily separated statistically. We calculated the CAVI0 according to the published formula [26, 27] to analyse the correlation between FLI and CAVI0; however, we did not find any significant correlation between FLI and CAVI0. The measurement of a pressure-independent stiffness index or the computation of a PWV ratio/“gradient” [28] would be an important intermediate marker in future studies.
This study showed that the effect of increased FLI on PWV changes by gender, which may be due to confounding factors such as gender-specific effects on hemodynamics. Women have more hemodynamic influence factors, such as estrogen-mediated vascular relaxation, shorter length of the arterial tree, difference of fat distribution and heart rate [29]. The presence of adipose tissue is more likely to act as a cushion, affecting the final PWV measurement. Therefore, it is necessary that gender grouping studies be conducted.
Our study also suggests that in Chinese males FLI is significantly higher than in females. This was similar to other studies [30] that showed that when using FLI to diagnose NAFLD, the incidence in males was higher than in females. This may be due to the fact that FLI is based on a combination of BMI, waist circumference, serum triglycerides and GGT levels, and differences in fat distribution and BMI between male and female can affect the outcome. In addition, the prevalence of NAFLD in Chinese males before the age of 50–55 is higher than that in females, and the prevalence in females increases rapidly and is even higher than that of males [1]. Failure of age-standardization may also be one of the causes of gender differences in FLI.
In addition to FLI, this study also suggested a significant correlation between age, blood pressure, and PWV, similar to other studies [31]. With age, there are many changes in blood vessels, such as decreased elastin content, increased collagen content, change in type of collagen, and collagen cross-links from advanced glycation end products. These changes will reduce the elasticity of the vessel wall and ultimately lead to an increase in PWV [31]. The mechanical stretching force of the arterial wall determines the stiffness of the artery, so PWV is related to the physical expansion of blood pressure on the arterial wall.
There are several limitations in the current study. First, the study was performed by cross-sectional design, and so it cannot provide predictive values of FLI on the progression of arterial stiffness. Second, due to the type of cardiovascular assessment conducted, there is lack of data on antihypertensive medication and smoking status.