Review article
NAFLD as a continuous driver in the whole spectrum of vascular disease

https://doi.org/10.1016/j.yjmcc.2021.10.007Get rights and content

Abstract

Vascular disease is the prime determinant to cardiovascular morbidities and mortalities, which comprises the early vascular damage and subsequent cardiovascular events. Non-alcohol Fatty Liver Disease (NAFLD) is a systemic metabolic disorder that drives the progression of vascular disease through complex interactions. Although a causal relationship between NAFLD and cardiovascular disease (CVD) has not been established, a growing number of epidemiological studies have demonstrated an independent association between NAFLD and early vascular disease and subsequent cardiovascular events. In addition, mechanistic studies suggest that NAFLD initiates and accelerates vascular injury by increasing systemic inflammation and oxidative stress, impairing insulin sensitivity and lipid metabolism, and modulating epigenetics, the intestinal flora and hepatic autonomic nervous system; thus, NAFLD is a putative driving force for CVD progression. In this review, we summarize the clinical evidence supporting the association of NAFLD with subclinical vascular disease and cardiovascular events and discuss the potential mechanisms by which NAFLD promotes the progression of vascular disease.

Introduction

Vascular disease constitutes a spectrum of vessel injuries associated with genetics, behavior and environmental risk factors [1], encompassing subclinical (early) vascular disease and subsequent vascular disease with clinical manifestations. Subclinical vascular diseases are usually asymptomatic, with mild vascular structural and functional changes that include impaired vasodilation, increased arterial stiffness, intima-media thickness (IMT) and arterial calcification [2,3]. To predict the risk of adverse cardiovascular events, such as ischemic heart attack and stroke, such early vascular disease injury can be detected by noninvasive or invasive methodologies [4]. According to a global cardiovascular disease (CVD) report, the number of deaths from cardiovascular events was 18.6 million by 2019 [5]. Therefore, early detection of vascular abnormalities and control of potential risk factors are pivotal in promoting cardiovascular health.

Due to changes in lifestyle and economic booms, nonalcoholic fatty liver disease (NAFLD) has become the leading cause of chronic liver disease, affecting over 1.7 billion individuals worldwide. The spectrum of NAFLD ranges from simple steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, and liver cirrhosis, which may eventually develop into hepatocellular carcinoma [6]. Moreover, the complications of NAFLD involve not only advanced liver disease but also extrahepatic complications, particularly CVD. Our group has explored the clinical association and mechanisms linking NAFLD to CVD for over a decade [[7], [8], [9]]. Despite a lack of prospective longitudinal studies to confirm the causal effect of NAFLD on CVD incidence, there is accumulating evidence from clinical and basic studies showing that NAFLD may be an essential contributor to the initiation and progression of CVD, independent of traditional risk factors [9,10].

In this review, we summarize up-to-date clinical evidence to support the direct link between NAFLD and early vascular damage and subsequent cardiovascular events, elaborate on the epidemiological association between different pathological stages of NAFLD and vascular health, discuss the controversial views and suggest major directions for future research. In addition, we summarize the underlying pathophysiological link between NAFLD and vascular disease, including some recent research advances in immune inflammation, extracellular vesicles, and autonomic nervous system et al., which was not sufficient in previous reviews with a similar topic.

Section snippets

NAFLD and carotid intima-media thickness (c-IMT) increase

Carotid intima media thickness (c-IMT) is widely used as an assessment of subclinical atherosclerosis to predict the risk of CVD events [11]. More than a decade ago, a case-control study from Spain reported a significant increase in c-IMT and the frequency of arterial plaques in patients with ultrasound-diagnosed NAFLD [12]. Since then, numbers of clinical studies regarding the association between NAFLD and atherosclerosis have been conducted (Table 1). For example, Targher et al. found that in

NAFLD and cardiovascular events

A growing body of evidence confirms an independent association between NAFLD and adverse cardiovascular events (Table 2). In the Hoorn Study, Schindhelm et al. reported that alanine aminotransferase (ALT), a pathological marker of NAFLD, was prospectively associated with coronary heart disease (CHD) events, independent of traditional CVD risk factors [60]. Two other cohort studies confirmed elevated ALT levels to be independently associated with increased CVD-related mortality [61,62]. However,

Insulin resistance and dyslipidiaemia

It is believed that insulin resistance (IR) is the central link in the pathogenesis of NAFLD. IR activates of hormone-sensitive lipase (HSL) in adipose tissue, which leads to excessive lipolysis and free fat acid (FFA) results in the overload of mitochondrial β-oxidation system. It causes the accumulation of fatty acids and the disorder of lipid metabolism in the liver. [81,82] Moreover, IR triggers adenylate-activated protein kinase (AMPK) and PPARα pathways activation in NAFLD, which results

Conclusion

In recent years, vascular disease has become one of the most important public health problems in the world due to its high morbidity and mortality [5]. A large body of basic and clinical evidence supports NAFLD as an independent risk factor for early vascular disease and cardiovascular events. Limited by the lack of studies on pathological mechanisms related to NAFLD and CVD, there is still doubt about whether NAFLD is a direct contributor to CVD. However, epidemiological studies have well

Conflict of interest statement

No conflict of interest is declared.

Disclosures

None.

Funding

This work was supported by grants from the National Key R&D Program of China (2016YFF0101504, 2020YFC2004702), the National Science Foundation of China (81630011, 81970364, 81970070, 81770053, 81870171, 81970011), the Hubei Science and Technology Support Project (2019BFC582, 2018BEC473), and Medical flight plan of Wuhan University (TFJH2018006).

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    Wei Li and Jiayi Liu contributed equally to this work.

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