VASCULAR AND METABOLIC ADAPTATIONS TO EXERCISE IN NON-ALCOHOLIC FATTY LIVER DISEASE

Non-alcoholic fatty liver disease (NAFLD) is characterised by the accumulation of fat in the liver and is associated with liver-related morbidity and mortality. Nevertheless, the leading cause of death in these patients is cardiovascular disease (CVD). Excess abdominal visceral adipose tissue (VAT) is frequently expressed in NAFLD and is considered a pivotal feature in the pathogenesis of NAFLD which is predictive of CVD. Endothelial dysfunction is an early manifestation in the development of atherosclerosis and is characterised by a diminished bioavailabilty of the anti-atherogenic molecule NO, which is secreted by the endothelium of all blood vessels throughout the vascular tree. Limited pharmacological treatment is available to reduce hepatic fat, therefore, lifestyle modification interventions comprised of structured exercise and diet are recommended as a non-pharmacological management strategy to reduce hepatic fat in NAFLD. The primary aim of this thesis was to explore nitric oxide (NO)-mediated endothelial function at different levels of the vascular tree in NAFLD patients and to establish whether supervised exercise training has a sustained therapeutic impact on endothelial function. Thirty-two NAFLD patients (21 males, 11 females, 48±2yrs, BMI 31±1kg/m2) and eighteen matched controls (8 males, 10 females, 48±2yrs, BMI 30±1kg/m2) underwent magnetic resonance imaging (MRI) to quantify abdominal VAT and proton magnetic resonance spectroscopy (1H-MRS) to determine intrahepatocellular triglyceride content (IHTC). Brachial artery flow mediated dilatation (FMD) (as an index of endothelial NO function) was also assessed. IHTC (27.2±3.0 vs. 2.9±0.4%) and abdominal VAT (5.4±0.3vs. 3.4±0.2 l) were elevated in NAFLD patients when compared with controls (P0.05). Impairment in FMD remained in NAFLD patients following independent covariate adjustment for abdominal VAT (5.0±0.5 vs. 7.3±0.7%, P=0.01). These findings indicate that excess IHTC and abdominal VAT do not explain endothelial dysfunction in NAFLD. Twenty NAFLD patients were randomly assigned to either 16-weeks of supervised moderate intensity (30-60% HRR, 30-45 min, 3-5 times per week) exercise training (n=13, 50±3yrs, BMI 30±1kg/m2) or to 16-weeks of conventional care lifestyle advice (n=7, 47±6yrs, BMI 31±2kg/m2). Supervised exercise training induced a greater improvement in FMD when compared with conventional care (3.6±0.6 vs. 0.3±0.8%, P=0.004). There was no significant difference between the effect of exercise and conventional care on IHTC or abdominal VAT (P>0.05). These data suggest that supervised exercise training is an effective management strategy in NAFLD capable of improving conduit artery endothelial function independent of IHTC and abdominal VAT. In order to explore the longevity of the exercise-induced improvements in conduit artery endothelial function, a 12-month follow up assessment was performed in 9 of the NAFLD patients (5 males, 4 females, 50±5yrs, BMI 30±1kg/m2) who completed the 16-week supervised exercise training intervention. The exercise-induced improvement in FMD (5.1±0.8 vs. 7.9±0.8%; P=0.004) was abolished 12 months following the cessation of supervised exercise training (7.9±0.8 vs.5.0±0.5%; P=0.02), returning to a similar level observed at baseline (5.1±0.8 vs. 5.0±0.5%; P=0.95).These findings indicate that in order to chronically sustain exercise-induced improvements in endothelial function in NAFLD patients, long-term exercise supervision and guidance is required. Cutaneous NO-mediated microvessel function reflects generalised microvascular function and provides a translational model to investigate pre-clinical disease, but has not been previously investigated in NAFLD. NO-mediated vasodilatation in the cutaneous microvessels was examined in 13 NAFLD patients (7 males, 6 females, 50±3yrs, BMI 31±1kg/m2) and 7 matched controls (3 males, 4 females, 48±4yrs, BMI 30±2 kg/m2). Microdialysis fibres were embedded into the skin of the forearm and laser Doppler probes placed over these sites. Both sites were then heated to 42°C, with saline solution infused in one probe and L-NG-monomethyl arginine (L-NMMA) through the second. Following baseline assessment, 11 NAFLD patients were randomly assigned to 16-weeks of supervised moderate intensity exercise training (n=6, 45±5yrs, BMI 31±1kg/m2) or to 16-weeks of conventional care (n=5, 51±3yrs, BMI 30±21kg/m2). The NO contribution to skin blood flow in response to incremental heating was not different between NAFLD patients and controls (P=0.47) at baseline. However, significant differences were evident in NO contribution between the exercise training and conventional care group (P=0.01), suggesting that supervised exercise training improves cutaneous NO-mediated microvascular endothelial function in NAFLD patients. This thesis suggests that supervised exercise training has a direct therapeutic impact on endothelial function in NAFLD which may decrease the risk of future heart disease and stroke. As a cardioprotective management strategy in NAFLD, exercise training is superior to that of current conventional care pathways, however, in order to chronically sustain the exercise-induced improvements in endothelial function, long term exercise supervision and guidance is required

Differential impact of water immersion on arterial blood flow and shear stress in the carotid and brachial arteries of humans.

Arterial shear stress is a potent stimulus to vascular adaptation in humans. Typically, increases in retrograde shear have been found to acutely impair vascular function while increases in antegrade shear enhance function. We hypothesized that blood flow and shear stress through the brachial and carotid arteries would change in a similar manner in response to water immersion, an intervention which modifies hemodynamics. Nine healthy young male subjects were recruited to undergo controlled water immersion in a standing upright position to the level of the right atrium in 30°C water. Diameters were continuously and simultaneously recorded in the brachial and common carotid arteries along with mean arterial pressure (MAP), cardiac output (CO), and heart rate before, during, and after 10 min of immersion. MAP and CO increased during water immersion (baseline vs. 8-10 min; 80 ± 9 vs. 91 ± 12 mmHg; and 4.8 ± 0.7 vs. 5.1 ± 0.6 L/min, P < 0.01 and P < 0.05, respectively). We observed a differential regulation of flow and shear stress patterns in the brachial and carotid arteries in response to water immersion; brachial conductance decreased markedly in response to immersion (1.25 ± 0.56 vs. 0.57 ± 0.30 mL.min/mmHg, P < 0.05), whereas it was unaltered in the carotid artery (5.82 ± 2.14 vs. 5.60 ± 1.59). Our findings indicate that adaptations to systemic stimuli and arterial adaptation may be vessel bed specific in humans, highlighting the need to assess multiple vascular sites in future studies

The Ultrasound Window Into Vascular Ageing: A Technology Review by the VascAgeNet COST Action

Non-invasive ultrasound (US) imaging enables the assessment of the properties of superficial blood vessels. Various modes can be used for vascular characteristics analysis, ranging from radiofrequency (RF) data, Doppler- and standard B/M-mode imaging, to more recent ultra-high frequency and ultrafast techniques. The aim of the present work was to provide an overview of the current state-of-the-art non-invasive US technologies and corresponding vascular ageing characteristics from a technological perspective. Following an introduction about the basic concepts of the US technique, the characteristics considered in this review are clustered into: 1) vessel wall structure; 2) dynamic elastic properties, and 3) reactive vessel properties. The overview shows that ultrasound is a versatile, non-invasive, and safe imaging technique that can be adopted for obtaining information about function, structure, and reactivity in superficial arteries. The most suitable setting for a specific application must be selected according to spatial and temporal resolution requirements. The usefulness of standardization in the validation process and performance metric adoption emerges. Computer-based techniques should always be preferred to manual measures, as long as the algorithms and learning procedures are transparent and well described, and the performance leads to better results. Identification of a minimal clinically important difference is a crucial point for drawing conclusions regarding robustness of the techniques and for the translation into practice of any biomarker

Northward shift of the agricultural climate zone under 21st-century global climate change

As agricultural regions are threatened by climate change, warming of high latitude regions and increasing food demands may lead to northward expansion of global agriculture. While socio-economic demands and edaphic conditions may govern the expansion, climate is a key limiting factor. Extant literature on future crop projections considers established agricultural regions and is mainly temperature based. We employed growing degree days (GDD), as the physiological link between temperature and crop growth, to assess the global northward shift of agricultural climate zones under 21st-century climate change. Using ClimGen scenarios for seven global climate models (GCMs), based on greenhouse gas (GHG) emissions and transient GHGs, we delineated the future extent of GDD areas, feasible for small cereals, and assessed the projected changes in rainfall and potential evapotranspiration. By 2099, roughly 76% (55% to 89%) of the boreal region might reach crop feasible GDD conditions, compared to the current 32%. The leading edge of the feasible GDD will shift northwards up to 1200 km by 2099 while the altitudinal shift remains marginal. However, most of the newly gained areas are associated with highly seasonal and monthly variations in climatic water balances, a critical component of any future land-use and management decisions

Effects of sprint interval training on ectopic lipids and tissue-specific insulin sensitivity in men with non-alcoholic fatty liver disease

Purpose: This study examined the feasibility of sprint interval exercise training (SIT) for men with non-alcoholic fatty liver disease (NAFLD) and its effects on intrahepatic triglyceride (IHTG), insulin sensitivity (hepatic and peripheral), visceral (VAT) and subcutaneous adipose tissue (ScAT). Methods: Nine men with NAFLD (age 41 ± 8 years; BMI 31.7 ± 3.1 kg m−2; IHTG 15.6 ± 8.3%) were assessed at: (1) baseline (2) after a control phase of no intervention (pre-training) and (3) after 6 weeks of SIT (4–6 maximal 30 s cycling intervals, three times per week). IHTG, VAT and ScAT were measured using magnetic resonance spectroscopy or imaging and insulin sensitivity was assessed via dual-step hyperinsulinaemic-euglycaemic clamp with [6,6-D2] glucose tracer. Results: Participants adhered to SIT, completing ≥ 96.7% of prescribed intervals. SIT increased peak oxygen uptake [ V O2peak: + 13.6% (95% CI 8.8–18.2%)] and elicited a relative reduction in IHTG [− 12.4% (− 31.6 to 6.7%)] and VAT [− 16.9% (− 24.4 to − 9.4%); n = 8], with no change in body weight or ScAT. Peripheral insulin sensitivity increased throughout the study (n = 8; significant main effect of phase) but changes from pre- to post-training were highly variable (range − 18.5 to + 58.7%) and not significant (P = 0.09), despite a moderate effect size (g* = 0.63). Hepatic insulin sensitivity was not influenced by SIT. Conclusions: SIT is feasible for men with NAFLD in a controlled laboratory setting and is able to reduce IHTG and VAT in the absence of weight loss

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference