The degree of hepatic steatosis associates with impaired cardiac and autonomic function.

BACKGROUND & AIMS: Cardiovascular disease is the principle cause of death in patients with elevated liver fat unrelated to alcohol consumption, more so than liver-related morbidity and mortality. The aim of this study was to evaluate the relationship between liver fat and cardiac and autonomic function, as well as to assess how impairment in cardiac and autonomic function is influenced by metabolic risk factors. METHODS: Cardiovascular and autonomic function were assessed in 96 sedentary individuals: i) non-alcoholic fatty liver disease (NAFLD) (n = 46, hepatic steatosis >5% by magnetic resonance spectroscopy), ii) Hepatic steatosis and alcohol (dual aetiology fatty liver disease [DAFLD]) (n = 16, hepatic steatosis >5%, consuming >20 g/day of alcohol) and iii) CONTROL (n = 34, no cardiac, liver or metabolic disorders, <20 g/day of alcohol). RESULTS: Patients with NAFLD and DAFLD had significantly impaired cardiac and autonomic function when compared with controls. Diastolic variability and systolic variability (LF/HF-sBP [n/1]; 2.3 (1.7) and 2.3 (1.5) vs. 3.4 (1.5), p <0.01) were impaired in patients with NAFLD and DAFLD when compared to controls, with DAFLD individuals showing a decrease in diastolic variability relative to NAFLD patients. Hepatic steatosis and fasting glucose were negatively correlated with stroke volume index. Fibrosis stage was significantly negatively associated with mean blood pressure (r = -0.47, p = 0.02), diastolic variability (r = -0.58, p ≤0.01) and systolic variability (r = -0.42, p = 0.04). Hepatic steatosis was independently associated with cardiac function (p ≤0.01); TNF-α (p ≤0.05) and CK-18 (p ≤0.05) were independently associated with autonomic function. CONCLUSION: Cardiac and autonomic impairments appear to be dependent on level of liver fat, metabolic dysfunction, inflammation and fibrosis staging, and to a lesser extent alcohol intake. Interventions should be sought to moderate the excess cardiovascular risk in patients with NAFLD or DAFLD. LAY SUMMARY: Increased levels of fat in the liver impair the ability of the cardiovascular system to work properly. The amount of fat in the liver, metabolic control, inflammation and alcohol are all linked to the degree that the cardiovascular system is affected.

Systematic review assessing the effectiveness of dietary intervention on gut microbiota in adults with type 2 diabetes.

AIMS/HYPOTHESIS: Despite improved understanding of the pathophysiology of type 2 diabetes mellitus, explanations for individual variability in disease progression and response to treatment are incomplete. The gut microbiota has been linked to the pathophysiology of type 2 diabetes mellitus and may account for this variability. We conducted a systematic review to assess the effectiveness of dietary and physical activity/exercise interventions in modulating the gut microbiota and improving glucose control in adults with type 2 diabetes mellitus. METHODS: A systematic search was conducted to identify studies reporting on the effect of dietary and physical activity/exercise interventions on the gut microbiota and glucose control in individuals with a confirmed diagnosis of type 2 diabetes mellitus. Study characteristics, methodological quality and details relating to interventions were captured using a data-extraction form. Meta-analyses were conducted where sufficient data were available, and other results were reported narratively. RESULTS: Eight studies met the eligibility criteria of the systematic review. No studies were found that reported on the effects of physical activity/exercise on the gut microbiota and glucose control. However, studies reporting on dietary interventions showed that such interventions were associated with modifications to the composition and diversity of the gut microbiota. There was a statistically significant improvement in HbA1c (standardised mean difference [SMD] -2.31 mmol/mol [95% CI -2.76, -1.85] [0.21%; 95% CI -0.26, -0.16]; I2 = 0%, p < 0.01), but not in fasting blood glucose (SMD -0.25 mmol/l [95% CI -0.85, 0.35], I2 = 87%, p > 0.05), fasting insulin (SMD -1.82 pmol/l [95% CI -7.23, 3.60], I2 = 54%, p > 0.05) or HOMA-IR (SMD -0.15 [95% CI -0.63, 0.32], I2 = 69%, p > 0.05) when comparing dietary interventions with comparator groups. There were no significant changes in the relative abundance of bacteria in the genera Bifidobacterium (SMD 1.29% [95% CI -4.45, 7.03], I2 = 33%, p > 0.05), Roseburia (SMD -0.85% [95% CI -2.91, 1.21], I2 = 79%, p > 0.05) or Lactobacillus (SMD 0.04% [95% CI -0.01, 0.09], I2 = 0%, p > 0.05) when comparing dietary interventions with comparator groups. There were, however, other significant changes in the gut microbiota, including changes at various taxonomic levels, including phylum, family, genus and species, Firmicutes:Bacteroidetes ratios and changes in diversity matrices (α and ß). Dietary intervention had minimal or no effect on inflammation, short-chain fatty acids or anthropometrics. CONCLUSIONS/INTERPRETATION: Dietary intervention was found to modulate the gut microbiota and improve glucose control in individuals with type 2 diabetes. Although the results of the included studies are encouraging, this review highlights the need for further well-conducted interventional studies to inform the clinical use of dietary interventions targeting the gut microbiota.

High-intensity interval training: a review of its impact on glucose control and cardiometabolic health.

Exercise plays a central role in the management and treatment of common metabolic diseases, but modern society presents many barriers to exercise. Over the past decade there has been considerable interest surrounding high-intensity interval training (HIIT), with advocates claiming it can induce health benefits of similar, if not superior magnitude to moderate-intensity continuous exercise, despite reduced time commitment. As the safety of HIIT becomes clearer, focus has shifted away from using HIIT in healthy individuals towards using this form of training in clinical populations. The continued growth of metabolic disease and reduced physical activity presents a global health challenge and effective therapies are urgently required. The aim of this review is to explore whether the acclaim surrounding HIIT is justified by examining the effect of HIIT on glucose control, its ability to affect cardiovascular function and the underlying mechanisms of the changes observed in those with common metabolic diseases. It also explores translation of the research into clinical practice.

Effects of Exercise on Liver Fat and Metabolism in Alcohol Drinkers.

BACKGROUND & AIMS: Exercise is an important component of obesity-associated disorders and has been shown to reduce markers of nonalcoholic fatty liver disease (NAFLD). However, little is known about how these effects are influenced by alcohol intake. The authors performed a randomized controlled trial to investigate the effects of exercise on hepatic triglyceride content (HTGC) and metabolism in overweight or obese patients who consume alcohol. METHODS: The authors performed a prospective study of 27 patients (mean 54 ± 11 years of age, body mass index [BMI] 31 ± 4 kg/m2) with >5% HTGC in the United Kingdom, consuming alcohol (mean 221 ± 75 g/week). Anthropometry, body composition, HTGC, and abdominal fat were measured using plethysmography and magnetic resonance imaging. Subjects were assigned to groups that exercised (3 times/week on nonconsecutive days) for 12 weeks (n = 14) or continued standard care (control group, n = 13), maintaining baseline weight and alcohol consumption. The exercise program consisted of aerobic exercise (static cycling) and a circuit of resistance exercise (free weights and machines). Patients were examined at baseline and at 12 weeks; data collected on HTGC, body composition, metabolic control, circulating inflammatory, and fibrosis markers were assessed at baseline and at 12 weeks. Between-group differences were evaluated using an unpaired t test and within-group differences using a paired t test. The primary outcomes for this study were changes in HTGC between baseline and 12 weeks. RESULTS: After 12 weeks, there was no significant difference between the exercise and control groups in HTGC (reduction of 0.1% ± 2.1% in exercisers vs increase of 0.5 ± 2.1% in control group; P > .05). At week 12, the exercise group had significant reductions in subcutaneous fat (loss of 23 ± 28 cm2 in the exercisers vs increase of 12 ± 19 cm2 in the control group; P < .01), and whole body fat (loss of 2.1 ± 1.1 kg in the exercisers vs increase of 0.2 ± 2.1 kg; P < .01). The exercise group also had a significantly greater increase in lean body mass (increase of 1.9 ± 1.4 kg for the exercisers vs increase of 0.7 ± 1.5 kg for the control group; P < .01) and a significantly greater reduction in level of cytokeratin 18 (reduction of 49 ± 82 U/L in exercisers vs increase of 17 ± 38 U/L in control group; P < .05). There were no differences between groups in changes in metabolic factors or markers of inflammation. CONCLUSIONS: In a randomized controlled trial of obese individuals who consume alcohol, exercise significantly improved body composition and reduced hepatocyte apoptosis (cytokeratin 18), but did not reduce HTGC. This finding could indicate that alcohol consumption reduces the effects of exercise on NAFLD observed in previous studies. Clinical care teams should look to use exercise as part of the management strategy for people consuming alcohol, but optimal benefit may be as an adjunct to alcohol reduction and weight management strategies. (ISRCTN.com, Number: ISRCTN90597099).

Exercise Reduces Liver Lipids and Visceral Adiposity in Patients With Nonalcoholic Steatohepatitis in a Randomized Controlled Trial.

BACKGROUND & AIMS: Pharmacologic treatments for nonalcoholic steatohepatitis (NASH) are limited. Lifestyle interventions are believed to be effective in reducing features of NASH, although the effect of regular exercise, independent of dietary change, is unclear. We performed a randomized controlled trial to study the effect of exercise on hepatic triglyceride content (HTGC) and biomarkers of fibrosis in patients with NASH. METHODS: Twenty-four patients (mean age, 52 ± 14 y; body mass index, 33 ± 6 kg/m2) with sedentary lifestyles (<60 min/wk of moderate-vigorous activity) and biopsy-proven NASH were assigned randomly to groups that exercised (n = 12) or continued standard care (controls, n = 12) for 12 weeks while maintaining their weight. The exercise (cycling and resistance training) was supervised at an accredited sports center and supervised by a certified exercise specialist and recorded 3 times per week on nonconsecutive days. We measured HTGC, body composition, circulating markers of inflammation, fibrosis, and glucose tolerance at baseline and at 12 weeks. RESULTS: Compared with baseline, exercise significantly reduced HTGC (reduction of 16% ± 24% vs an increase of 9% ± 15% for controls; P < .05), visceral fat (reduction of 22 ± 33 cm2 vs an increase of 14 ± 48 cm2 for controls; P < .05), plasma triglycerides (reduction of 0.5 ± 1.0 mmol/L vs an increase of 0.3 ± 0.4 mmol/L for controls; P < .05), and γ-glutamyltransferase (reduction of 10 ± 28 U/L-1 vs a reduction of 17 ± 38 U/L-1 for controls; P < .05). There were no effects of exercise on liver enzyme levels, metabolic parameters, circulatory markers of inflammation (levels of interleukin 6, tumor necrosis factor-α, or C-reactive protein) and fibrosis. CONCLUSIONS: In a randomized controlled trial, 12 weeks of exercise significantly reduced HTGC, visceral fat, and plasma triglyceride levels in patients with NASH, but did not affect circulating markers of inflammation or fibrosis. Exercise without weight loss therefore affects some but not all factors associated with NASH. Clinical care teams should consider exercise as part of a management strategy of NASH, but weight management strategies should be included. Larger and longer-term studies are required to determine the effects of exercise in patients with NASH. ISRCTN registry.com: ISRCTN16070927.

Low physical activity, high television viewing and poor sleep duration cluster in overweight and obese adults; a cross-sectional study of 398,984 participants from the UK Biobank.

BACKGROUND: An unhealthy lifestyle is one of the greatest contributors to obesity. A number of behaviours are linked with obesity, but are often measured separately. The UK Biobank cohort of >500,000 participants allows us to explore these behaviours simultaneously. We therefore aimed to compare physical activity, television (TV) viewing and sleep duration across body mass index (BMI) categories in a large sample of UK adults. METHODS: UK Biobank participants were recruited and baseline measures were taken between 2007 and 2010 and data analysis was performed in 2015. BMI was measured objectively using trained staff. Self-report questionnaires were used to measure lifestyle behaviours including the international physical activity questionnaire (IPAQ-short form) for physical activity. During data analysis, six groups were defined based on BMI; 'Underweight' (n = 2026), 'Normal weight' (n = 132,372), 'Overweight (n = 171,030), 'Obese I' (n = 67,903), 'Obese II' (n = 18,653) and 'Obese III' (n = 7000). The odds of reporting unhealthy lifestyle behaviours (low physical activity, high TV viewing or poor sleep duration) were compared across BMI groups using logistic regression analysis. RESULTS: Overweight and obese adults were more likely to report low levels of physical activity (≤967.5 MET.mins/wk) ('Overweight'-OR [95% CI]: 1.23 [1.20 to 1.26], 'Obese I' 1.66 [1.61-1.71], 'Obese II' 2.21 [2.12-2.30], and 'Obese III' 3.13 [2.95 to 3.23]) compared to 'Normal weight' adults. The odds of reporting high TV viewing (3 h/day) was greater in 'Overweight' (1.52 [1.48 to 1.55]) and obese adults ('Obese I' 2.06 [2.00-2.12], 'Obese II' 2.69 [2.58-2.80], 'Obese III' 3.26 [3.07 to 3.47]), and poor sleep duration (<7, >8 h/night) was higher in 'Overweight' (1.09 [1.07 to 1.12]) and obese adults ('Obese I' 1.31 [1.27-1.34], 'Obese II' 1.50 [1.44-1.56], 'Obese III' (1.78 [1.68 to 1.89]) compared to the 'Normal weight' group. These lifestyle behaviours were clustered, the odds of reporting simultaneous low physical activity, high TV viewing and poor sleep (unhealthy behavioural phenotype) was higher than reporting these behaviours independently, in overweight and obese groups. 'Obese III' adults were almost six times more likely (5.47 [4.96 to 6.05]) to report an unhealthy behavioural phenotype compared to the 'Normal weight' group. CONCLUSIONS: Overweight and obese adults report low levels of physical activity, high TV viewing and poor sleep duration. These behaviours seem to cluster and collectively expose individuals to greater risk of obesity. Multiple lifestyle behaviours should be targeted in future interventions.

High intensity intermittent exercise improves cardiac structure and function and reduces liver fat in patients with type 2 diabetes: a randomised controlled trial.

AIMS/HYPOTHESIS: Cardiac disease remains the leading cause of mortality in type 2 diabetes, yet few strategies to target cardiac dysfunction have been developed. This randomised controlled trial aimed to investigate high intensity intermittent training (HIIT) as a potential therapy to improve cardiac structure and function in type 2 diabetes. The impact of HIIT on liver fat and metabolic control was also investigated. METHODS: Using an online random allocation sequence, 28 patients with type 2 diabetes (metformin and diet controlled) were randomised to 12 weeks of HIIT (n = 14) or standard care (n = 14). Cardiac structure and function were measured by 3.0 T MRI and tagging. Liver fat was determined by 1H-magnetic resonance spectroscopy and glucose control by an OGTT. MRI analysis was performed by an observer blinded to group allocation. All study procedures took place in Newcastle upon Tyne, UK. RESULTS: Five patients did not complete the study and were therefore excluded from analysis: this left 12 HIIT and 11 control patients for the intention-to-treat analysis. Compared with controls, HIIT improved cardiac structure (left ventricular wall mass 104 ± 17 g to 116 ± 20 g vs. 107 ± 25 g to 105 ± 25 g, p < 0.05) and systolic function (stroke volume 76 ± 16 ml to 87 ± 19 ml vs. 79 ± 14 ml to 75 ± 15 ml, p < 0.01). Early diastolic filling rates increased (241 ± 84 ml/s to 299 ± 89 ml/s vs. 250 ± 44 ml/s to 251 ± 47 ml/s, p < 0.05) and peak torsion decreased (8.1 ± 1.8° to 6.9 ± 1.6° vs. 7.1 ± 2.2° to 7.6 ± 1.9°, p < 0.05) in the treatment group. Following HIIT, there was a 39% relative reduction in liver fat (p < 0.05) and a reduction in HbA1c (7.1 ± 1.0% [54.5 mmol/mol] to 6.8 ± 0.9% [51.3 mmol/mol] vs. 7.2 ± 0.5% [54.9 mmol/mol] to 7.4 ± 0.7% [57.0 mmol/mol], p < 0.05). Changes in liver fat correlated with changes in HbA1c (r = 0.70, p < 0.000) and 2 h glucose (r = 0.57, p < 0.004). No adverse events were recorded. CONCLUSIONS/INTERPRETATION: This is the first study to demonstrate improvements in cardiac structure and function, along with the greatest reduction in liver fat, to be recorded following an exercise intervention in type 2 diabetes. HIIT should be considered by clinical care teams as a therapy to improve cardiometabolic risk in patients with type 2 diabetes. TRIAL REGISTRATION: www.isrctn.com 78698481 FUNDING: : Medical Research Council.

Targeting Lifestyle Behavior Change in Adults with NAFLD During a 20-min Consultation: Summary of the Dietary and Exercise Literature.

Non-alcoholic fatty liver disease (NAFLD) is largely linked to poor diet, lack of physical activity/exercise, and being overweight. In the absence of approved pharmaceutical agents, lifestyle modification, encompassing dietary change and increased physical activity/exercise to initiate weight loss, is the recommended therapy for NAFLD. Despite this, the use of lifestyle therapy within clinical settings is lacking with limited guidance available about what it should involve, how it should be delivered, and whether it can be feasibly delivered as part of standard care. This paper highlights the evidence for the use of lifestyle modification in NAFLD. While there is evidence to support use of behavioral strategies to support lifestyle behavior change in other clinical populations, these are yet to be assessed in people with NAFLD. However, there is sufficient evidence to suggest that behavioral intervention targeting diet and physical activity to promote weight loss in general is effective and a number of practical strategies are presented on how this could be achieved.

The effect of percutaneous coronary intervention on habitual physical activity in older patients.

BACKGROUND: Given the ongoing burden of cardiovascular disease and an ageing population, physical activity in patients with coronary artery disease needs to be emphasized. This study assessed whether sedentary behaviour and physical activity levels differed among older patients (≥75 years) following percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS) consisting of ST-segment elevation myocardial infarction (STEMI) and non STEMI (NSTEMI) versus an elective admission control group of stable angina patients. METHODS: Sedentary behaviour and physical activity were assessed over a 7-day period using wrist-worn triaxial accelerometers (GENEActiv, Activinsights Ltd, UK) in 58 patients following PCI for, STEMI (n = 20) NSTEMI (n = 18) and stable angina (n = 20) upon discharge from a tertiary centre. Mean ± Standard deviation age was 79 ± 4 years (31% female). RESULTS: STEMI and NSTEMI patients spent more time in the low acceleration category (0-40 mg) reflecting sedentary time versus stable angina patients (1298 ± 59 and 1305 ± 66 vs. 1240 ± 92 min/day, p < 0.05). STEMI and NSTEMI patients spent less time in the 40-80 mg acceleration category reflecting low physical activity versus stable angina patients (95 ± 35 and 94 ± 41 vs. 132 ± 50 min/day, p < 0.05). Stable angina patients spent more time in the higher acceleration categories (80-120 and 120-160 mg) and moderate-to-vigorous physical activity (defined as 1 and 5 min/day bouts) versus NSTEMI patients (p < 0.05). For acceleration categories ≥160 mg, no differences were observed. CONCLUSIONS: Patients presenting with ACS and undergoing PCI spent more time in sedentary behaviour compared with stable angina patients.

Exercise Induces Peripheral Muscle But Not Cardiac Adaptations After Stroke: A Randomized Controlled Pilot Trial.

OBJECTIVE: To explore the physiological factors affecting exercise-induced changes in peak oxygen consumption and function poststroke. DESIGN: Single-center, single-blind, randomized controlled pilot trial. SETTING: Community stroke services. PARTICIPANTS: Adults (N=40; age>50y; independent with/without stick) with stroke (diagnosed >6 mo previously) were recruited from 117 eligible participants. Twenty participants were randomized to the intervention group and 20 to the control group. No dropouts or adverse events were reported. INTERVENTIONS: Intervention group: 19-week (3 times/wk) progressive mixed (aerobic/strength/balance/flexibility) community group exercise program. Control group: Matched duration home stretching program. MAIN OUTCOME MEASURES: (1) Pre- and postintervention: maximal cardiopulmonary exercise testing with noninvasive (bioreactance) cardiac output measurements; and (2) functional outcome measures: 6-minute walk test; timed Up and Go test, and Berg Balance Scale. RESULTS: Exercise improved peak oxygen consumption (18±5 to 21±5 mL/(kg⋅min); P<.01) and peak arterial-venous oxygen difference (9.2±2.7 to 11.4±2.9 mL of O2/100 mL of blood; P<.01), but did not alter cardiac output (17.2±4 to 17.7±4.2 L/min; P=.44) or cardiac power output (4.8±1.3 to 5.0±1.35 W; P=.45). A significant relation existed between change in peak oxygen consumption and change in peak arterial-venous oxygen difference (r=.507; P<.05), but not with cardiac output. Change in peak oxygen consumption did not strongly correlate with change in function. CONCLUSIONS: Exercise induced peripheral muscle, but not cardiac output, adaptations after stroke. Implications for stroke clinical care should be explored further in a broader cohort.

Ingestion of glucose or sucrose prevents liver but not muscle glycogen depletion during prolonged endurance-type exercise in trained cyclists.

The purpose of this study was to define the effect of glucose ingestion compared with sucrose ingestion on liver and muscle glycogen depletion during prolonged endurance-type exercise. Fourteen cyclists completed two 3-h bouts of cycling at 50% of peak power output while ingesting either glucose or sucrose at a rate of 1.7 g/min (102 g/h). Four cyclists performed an additional third test for reference in which only water was consumed. We employed (13)C magnetic resonance spectroscopy to determine liver and muscle glycogen concentrations before and after exercise. Expired breath was sampled during exercise to estimate whole body substrate use. After glucose and sucrose ingestion, liver glycogen levels did not show a significant decline after exercise (from 325 ± 168 to 345 ± 205 and 321 ± 177 to 348 ± 170 mmol/l, respectively; P > 0.05), with no differences between treatments. Muscle glycogen concentrations declined (from 101 ± 49 to 60 ± 34 and 114 ± 48 to 67 ± 34 mmol/l, respectively; P < 0.05), with no differences between treatments. Whole body carbohydrate utilization was greater with sucrose (2.03 ± 0.43 g/min) vs. glucose (1.66 ± 0.36 g/min; P < 0.05) ingestion. Both liver (from 454 ± 33 to 283 ± 82 mmol/l; P < 0.05) and muscle (from 111 ± 46 to 67 ± 31 mmol/l; P < 0.01) glycogen concentrations declined during exercise when only water was ingested. Both glucose and sucrose ingestion prevent liver glycogen depletion during prolonged endurance-type exercise. Sucrose ingestion does not preserve liver glycogen concentrations more than glucose ingestion. However, sucrose ingestion does increase whole body carbohydrate utilization compared with glucose ingestion. This trial was registered at https://www.clinicaltrials.gov as NCT02110836.

Cardiac structure and function are altered in type 2 diabetes and non-alcoholic fatty liver disease and associate with glycemic control.

BACKGROUND: Both non-alcoholic fatty liver disease (NAFLD) and Type 2 diabetes increase the risk of developing cardiovascular disease. The metabolic processes underlying NAFLD and Type 2 diabetes are part of an integrated mechanism but little is known about how these conditions may differentially affect the heart. We compared the impact of NAFLD and Type 2 diabetes on cardiac structure, function and metabolism. METHODS: 19 adults with Type 2 diabetes (62 ± 8 years), 19 adults with NAFLD (54 ± 15 years) and 19 healthy controls (56 ± 14 years) underwent assessment of cardiac structure, function and metabolism using high resolution magnetic resonance imaging, tagging and spectroscopy at 3.0 T. RESULTS: Adults with NAFLD and Type 2 diabetes demonstrate concentric remodelling with an elevated eccentricity ratio compared to controls (1.05 ± 0.3 vs. 1.12 ± 0.2 vs. 0.89 ± 0.2 g/ml; p < 0.05). Despite this, only the Type 2 diabetes group demonstrate significant systolic and diastolic dysfunction evidenced by a reduced stroke index (31 ± 7vs. controls, 38 ± 10, p < 0.05 ml/m2) and reduced E/A (0.9 ± 0.4 vs. controls, 1.9 ± 1.4, p < 0.05) respectively. The torsion to shortening ratio was higher in Type 2 diabetes compared to NAFLD (0.58 ± 0.16 vs. 0.44 ± 0.13; p < 0.05). Significant associations were observed between fasting blood glucose/HbA1c and diastolic parameters as well as the torsion to shortening ratio (all p < 0.05). Phosphocreatine/adenosine triphosphate ratio was not altered in NAFLD or Type 2 diabetes compared to controls. CONCLUSIONS: Changes in cardiac structure are evident in adults with Type 2 diabetes and NAFLD without overt cardiac disease and without changes in cardiac energy metabolism. Only the Type 2 diabetes group display diastolic and subendocardial dysfunction and glycemic control may be a key mediator of these cardiac changes. Therapies should be explored to target these preclinical cardiac changes to modify cardiovascular risk associated with Type 2 diabetes and NAFLD.

Modified high-intensity interval training reduces liver fat and improves cardiac function in non-alcoholic fatty liver disease: a randomized controlled trial.

Although lifestyle changes encompassing weight loss and exercise remain the cornerstone of non-alcoholic fatty liver disease (NAFLD) management, the effect of different types of exercise on NAFLD is unknown. This study defines the effect of modified high-intensity interval training (HIIT) on liver fat, cardiac function and metabolic control in adults with NAFLD. Twenty-three patients with NAFLD [age 54±10 years, body mass index (BMI) 31±4 kg/m(2), intra-hepatic lipid >5%) were assigned to either 12 weeks HIIT or standard care (controls). HIIT involved thrice weekly cycle ergometry for 30-40 min. MRI and spectroscopy were used to assess liver fat, abdominal fat and cardiac structure/function/energetics. Glucose control was assessed by oral glucose tolerance test and body composition by air displacement plethysmography. Relative to control, HIIT decreased liver fat (11±5% to 8±2% compared with 10±4% to 10±4% P=0.019), whole-body fat mass (35±7 kg to 33±8 kg compared with 31±9 kg to 32±9 kg, P=0.013), alanine (52±29 units/l to 42±20 units/l compared with 47±22 units/l to 51±24 units/l, P=0.016) and aspartate aminotransferase (AST; 36±18 units/l to 33±15 units/l compared with 31±8 units/l to 35±8 units/l, P=0.017) and increased early diastolic filling rate (244±84 ml/s to 302±107 ml/s compared with 255±82 ml/s to 251±82 ml/s, P=0.018). There were no between groups differences in glucose control. Modified HIIT reduces liver fat and improves body composition alongside benefits to cardiac function in patients with NAFLD and should be considered as part of the broader treatment regimen by clinical care teams. ISRCTN trial ID: ISRCTN78698481.

Novel MTND1 mutations cause isolated exercise intolerance, complex I deficiency and increased assembly factor expression.

Complex I (CI) is the largest of the five multi-subunit complexes constituting the human oxidative phosphorylation (OXPHOS) system. Seven of its catalytic core subunits are encoded by mitochondrial DNA (ND (NADH dehydrogenase)1-6, ND4L (NADH dehydrogenase subunit 4L)), with mutations in all seven having been reported in association with isolated CI deficiency. We investigated two unrelated adult patients presenting with marked exercise intolerance, persistent lactic acidaemia and severe muscle-restricted isolated CI deficiency associated with sub-sarcolemmal mitochondrial accumulation. Screening of the mitochondrial genome detected novel mutations in the MTND1 (NADH dehydrogenase subunit 1) gene, encoding subunit of CI [Patient 1, m.3365T>C predicting p.(Leu20Pro); Patient 2, m.4175G>A predicting p.(Trp290*)] at high levels of mitochondrial DNA heteroplasmy in skeletal muscle. We evaluated the effect of these novel MTND1 mutations on complex assembly showing that CI assembly, although markedly reduced, was viable in the absence of detectable ND1 signal. Real-time PCR and Western blotting showed overexpression of different CI assembly factor transcripts and proteins in patient tissue. Together, our data indicate that the mechanism underlying the expression of the biochemical defect may involve a compensatory response to the novel MTND1 gene mutations, promoting assembly factor up-regulation and stabilization of respiratory chain super-complexes, resulting in partial rescue of the clinical phenotype.

Association between questionnaire- and accelerometer-assessed physical activity: the role of sociodemographic factors.

The correlation between objective and self-reported measures of physical activity varies between studies. We examined this association and whether it differed by demographic factors or socioeconomic status (SES). Data were from 3,975 Whitehall II (United Kingdom, 2012-2013) participants aged 60-83 years, who completed a physical activity questionnaire and wore an accelerometer on their wrist for 9 days. There was a moderate correlation between questionnaire- and accelerometer-assessed physical activity (Spearman's r = 0.33, 95% confidence interval: 0.30, 0.36). The correlations were higher in high-SES groups than in low-SES groups (P 's = 0.02), as defined by education (r = 0.38 vs. r = 0.30) or occupational position (r = 0.37 vs. r = 0.29), but did not differ by age, sex, or marital status. Of the self-reported physical activity, 68.3% came from mild activities, 25% from moderate activities, and only 6.7% from vigorous activities, but their correlations with accelerometer-assessed total physical activity were comparable (range of r 's, 0.21-0.25). Self-reported physical activity from more energetic activities was more strongly associated with accelerometer data (for sports, r = 0.22; for gardening, r = 0.16; for housework, r = 0.09). High-SES persons reported more energetic activities, producing stronger accelerometer associations in these groups. Future studies should identify the aspects of physical activity that are most critical for health; this involves better understanding of the instruments being used.

Cardiac structure and function are altered in adults with non-alcoholic fatty liver disease.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) is associated with a twofold greater risk of developing cardiovascular disease. Despite this, little is known about the effect of NAFLD upon cardiac function, limiting our ability to identify therapeutic strategies. This study aimed to address this by defining the effect of NAFLD on cardiac function, structure, and metabolism. METHODS: Nineteen adults with NAFLD were age-, sex-, and BMI-matched to healthy controls without liver or metabolic disease. Cardiac structure and function were assessed using high-resolution cardiac MRI and tagging at 3.0 T. High-energy phosphate metabolism was assessed using (31)P-magnetic resonance spectroscopy to measure the PCr/ATP ratio. RESULTS: Adults with NAFLD had significantly thicker left ventricular walls at systole (14 ± 3 vs. 12 ± 2 mm; p <0.01) and diastole (8 ± 1 vs. 7 ± 1 mm; p <0.01) than those without fatty liver and showed decreased longitudinal shortening (14 ± 3 vs. 17 ± 3%; p <0.01). The eccentricity ratio was significantly higher in the NAFLD group (1.1 ± 0.2 vs. 0.9 ± 0.2 g/ml; p <0.01) indicating concentric remodelling. Peak whole wall strain was higher in the NAFLD group (19 ± 2 vs. 17 ± 3%; p <0.01), as was peak endocardial strain (28 ± 4 vs. 22 ± 5%; p <0.01). Cardiac metabolism, measured by PCr/ATP ratio, was not altered in NAFLD (1.8 ± 0.3 vs. 1.9 ± 0.3; p=0.36). CONCLUSIONS: Significant changes in cardiac structure and function are evident in adults with NAFLD in the apparent absence of metabolic changes or overt cardiac disease. Clinicians should continue to explore therapies to improve cardiac function as a means to modify the excess risk of cardiovascular disease associated with NAFLD.

Hepatic cholesteryl ester accumulation in lysosomal acid lipase deficiency: non-invasive identification and treatment monitoring by magnetic resonance.

BACKGROUND & AIMS: Lysosomal Acid Lipase (LAL) deficiency is a rare metabolic storage disease, caused by a marked reduction in activity of LAL, which leads to accumulation of cholesteryl esters (CE) and triglycerides (TG) in lysosomes in many tissues. We used (1)H magnetic resonance (MR) spectroscopy to characterize the abnormalities in hepatic lipid content and composition in patients with LAL deficiency, and in ex vivo liver tissue from a LAL deficiency rat model. Secondly, we used MR spectroscopy to monitor the effects of an enzyme replacement therapy (ERT), sebelipase alfa (a recombinant human lysosomal acid lipase), on hepatic TG and CE content in the preclinical model. METHODS: Human studies employed cohorts of LAL-deficient patients and NAFLD subjects. Rat experimental groups comprised ex vivo liver samples of wild type, NAFLD, LAL-deficient, and LAL-deficient rats receiving 4weeks of sebelipase alfa treatment. Hepatic (1)H MR spectroscopy was performed using 3T (human) and 7T (preclinical) MRI scanners to quantify hepatic cholesterol and triglyceride content. RESULTS: CE accumulation was identified in LAL deficiency in both human and preclinical studies. A significant decrease in hepatic CE was observed in LAL-deficient rats following treatment with sebelipase alfa. CONCLUSIONS: We demonstrate an entirely non-invasive method to identify and quantify the hepatic lipid signature associated with a rare genetic cause of fatty liver. The approach provides a more favorable alternative to repeated biopsy sampling for diagnosis and disease progression / treatment monitoring of patients with LAL deficiency and other disorders characterised by increased free cholesterol and/or cholesteryl esters.

Resistance exercise improves autonomic regulation at rest and haemodynamic response to exercise in non-alcoholic fatty liver disease.

Autonomic dysfunction has been reported in patients with NAFLD (non-alcoholic fatty liver disease) and is associated with clinical presentations. To date, there are no therapies to improve autonomic regulation in people with NAFLD. The present study defines the impact of a short-term exercise programme on cardiac autonomic and haemodynamic regulation in patients with NAFLD. A total of 17 patients with clinically defined NAFLD [age, 55±12 years; BMI (body mass index), 33±5 kg/m²; liver fat, 17±9%] were randomized to 8 weeks of resistance exercise or a control group to continue standard care. Resting and submaximal exercise (50% of peak oxygen consumption) autonomic and cardiac haemodynamic measures were assessed before and after the intervention. Resistance exercise resulted in a 14% reduction in HR (heart rate) and 7% lower SBP (systolic blood pressure) during submaximal exercise (16 beats/min, P=0.03 and 16 mmHg, P=0.22). Sympathovagal balance, expressed as LF/HF (low-frequency/high-frequency) ratio of the mean HR beat-to-beat (R-R) interval, was reduced by 37% (P=0.26). Similarly sympathovagal balance of DBP (diastolic blood pressure) and SBP variability decreased by 29% (P=0.33) and 19% (P=0.55), respectively in the exercise group only. BRS (baroreflex sensitivity) increased by 31% (P=0.08) following exercise. The mean R-R interval increased by 23% (159 ms, P=0.09). Parasympathetic regulation was decreased by 17% (P=0.05) and overall sympathovagal balance in BP regulation (LF/HF ratio) increased by 26% (P=0.02) following resistance exercise. Resting haemodynamic measures remained similar between groups. Resistance exercise therapy seems to improve autonomic and submaximal exercise haemodynamic regulation in NAFLD. Further studies are required to define its role in clinical management of the condition.

Impaired cardiopulmonary reserve in an elderly population is related to postoperative morbidity and length of hospital stay after radical cystectomy.

OBJECTIVE: To determine the relationship of preoperatively measured cardiorespiratory function, to the development of postoperative complications and length of hospital stay (LOS) in a cohort of patients undergoing radical cystectomy (RC), as RC and conduit formation is curative but is associated with significant postoperative morbidity and mortality. PATIENTS AND METHODS: Consecutive patients planned to have RC underwent cardiopulmonary exercise testing (CPET) to a standardised protocol. The results of the CPET were 'blinded' from the clinicians involved in the care of the patients. Patients were prospectively monitored for the primary outcome of postoperative complications, as defined by a validated classification (Clavien-Dindo). Secondary outcome included LOS and mortality. RESULTS: In all, 82 patients underwent CPET before RC. Eight patients did not subsequently undergo RC and a further five did not exercise sufficiently to allow for appropriate determination of the cardiopulmonary variables of interest. There was a significant difference in LOS between those patients who had a major perioperative complication (Clavien score > 3) and those that did not (16 vs 30 days; P < 0.001; hazard ratio [HR] 3.6, 95% confidence interval [CI] 2.1-6.3). The anaerobic threshold (AT) remained as the only significant independent predictor variable for the presence or absence of major postoperative complications (odds ratio 0.74, 95% CI 0.57-0.97; P = 0.03). When the optimal predictive value of AT of 12 mL/min/kg was used as a fitness marker, there was a significant relationship between fitness and LOS (median LOS: 'unfit' 22 days vs 'fit' 16 days; HR 0.47, 95% CI 0.28-0.80; P = 0.006) CONCLUSION: Impaired preoperative cardiopulmonary reserve was related to major morbidity, prolonged LOS and increased use of critical care resource after RC. This has important health and economic implications for risk assessment, rationalisation of postoperative resource and the potential for therapeutic preoperative intervention with exercise therapy.

Liver and muscle glycogen repletion using 13C magnetic resonance spectroscopy following ingestion of maltodextrin, galactose, protein and amino acids.

The present study evaluated whether the inclusion of protein (PRO) and amino acids (AA) within a maltodextrin (MD) and galactose (GAL) recovery drink enhanced post-exercise liver and muscle glycogen repletion. A total of seven trained male cyclists completed two trials, separated by 7 d. Each trial involved 2 h of standardised intermittent cycling, followed by 4 h recovery. During recovery, one of two isoenergetic formulations, MD-GAL (0.9 g MD/kg body mass (BM) per h and 0.3 g GAL/kg BM per h) or MD-GAL-PRO+AA (0.5 g MD/kg BM per h, 0.3 g GAL/kg BM per h, 0.4 g whey PRO hydrolysate plus l-leucine and l-phenylalanine/kg BM per h) was ingested at every 30 min. Liver and muscle glycogen were measured after depletion exercise and at the end of recovery using 1H-13C-magnetic resonance spectroscopy. Despite higher postprandial insulin concentations for MD-GAL-PRO+AA compared with MD-GAL (61.3 (se 6.2) v. 29.6 (se 3.0) mU/l, (425.8 (se 43.1) v. 205.6 (se 20.8) pmol/l) P= 0.03), there were no significant differences in post-recovery liver (195.3 (se 2.6) v. 213.8 (se 18.0) mmol/l) or muscle glycogen concentrations (49.7 (se 4.0) v. 51.1 (se 7.9) mmol/l). The rate of muscle glycogen repletion was significantly higher for MD-GAL compared with MD-GAL-PRO+AA (5.8 (se 0.7) v. 3.7 (se 0.6) mmol/l per h, P= 0.04), while there were no significant differences in the rate of liver glycogen repletion (15.0 (se 2.5) v. 13.0 (se 2.7) mmol/l per h). PRO and AA within a MD-GAL recovery drink, compared with an isoenergetic mix of MD-GAL, did not enhance but matched liver and muscle glycogen recovery. This suggests that the increased postprandial insulinaemia only compensated for the lower MD content in the MD-GAL-PRO+AA treatment.