Abstract
Nonalcoholic fatty liver disease (NAFLD) is an independent risk factor for cardiovascular disease (CVD). Endothelial dysfunction is an early manifestation of atherosclerosis and an important prognostic marker for future cardiovascular events. The aim of this study was twofold: to examine 1) the association between liver fat, visceral adipose tissue (VAT), and endothelial dysfunction in obese NAFLD patients and 2) the impact of supervised exercise training on this vascular defect. Brachial artery endothelial function was assessed by flow-mediated dilatation (FMD) in 34 obese NAFLD patients and 20 obese controls of similar age and cardiorespiratory fitness [peak oxygen uptake (V̇o2 peak)] (48 ± 2 vs. 47 ± 2 yr; 27 ± 1 vs. 26 ± 2 ml·kg−1·min−1−1). Magnetic resonance imaging and spectroscopy quantified abdominal and liver fat, respectively. Twenty-one NAFLD patients completed either 16 wk of supervised moderate-intensity exercise training (n = 13) or conventional care (n = 8). Differences between NAFLD and controls were compared using independent t-tests and effects of interventions by analysis of covariance. NAFLD patients had higher liver fat [11.6% (95% CI = 7.4, 18.1), P < 0.0005] and VAT [1.6 liters (95% CI = 1.2, 2.0), P < 0.0001] than controls and exhibited impaired FMD compared with controls [−3.6% (95% CI = −4.9, −2.2), P < 0.0001]. FMD was inversely correlated with VAT (r = −0.54, P = 0.001) in NAFLD, although the impairment in FMD remained following covariate adjustment for VAT [3.1% (95% CI = 1.8, 4.5), P < 0.001]. Exercise training, but not conventional care, significantly improved V̇o2 peak [9.1 ml·kg−1·min−1 (95% CI = 4.1, 14.1); P = 0.001] and FMD [3.6% (95% CI = 1.6, 5.7), P = 0.002]. Endothelial dysfunction in NAFLD cannot be fully explained by excess VAT but can be reversed with exercise training; this has potential implications for the primary prevention of CVD in NAFLD.
Highlights
Non-alcoholic fatty liver disease (NAFLD) is a disease spectrum ranging from simple steatosis, progressing to necro-inflammatory changes and in a subset, to cirrhosis, fibrosis and end-stage liver disease [20]
The first aim of this study was to investigate the relationship between liver fat, visceral adipose tissue (VAT) and endothelial dysfunction in obese NAFLD patients compared with obese controls of similar age and cardiorespiratory fitness
We have recently demonstrated that exercise training improves cutaneous microvessel endothelial function in NAFLD patients, compared with conventional clinical care [25], the impact of supervised exercise training on conduit arteries, which are of similar size and function as coronary arteries [32], remains unknown
Summary
Non-alcoholic fatty liver disease (NAFLD) is a disease spectrum ranging from simple steatosis, progressing to necro-inflammatory changes (non-alcoholic steatohepatitis) and in a subset, to cirrhosis, fibrosis and end-stage liver disease [20]. NAFLD increases the risk of chronic liver disease, yet epidemiological studies suggest that cardiovascular disease (CVD) accounts for more deaths in NAFLD than liver disease, some reporting CVD to be the leading cause of mortality [10, 23, 34]. There is strong evidence that NAFLD patients are at greater risk of CVD than controls and that NAFLD is an independent predictor of cardiovascular morbidity and mortality [10, 28, 33]. Several studies have reported attenuated FMD in NAFLD patients compared with controls [27, 35, 41]. Obesity [42], insulin resistance [3] and elevated visceral fat [26] are characteristics of NAFLD and have all been shown to independently impair FMD. The relationships between endothelial dysfunction and the various co-morbidities of NAFLD are incompletely understood
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