High intensity interval training protects the heart during increased metabolic demand in patients with type 2 diabetes: a randomised controlled trial.

AIM: The present study assessed the effect of high intensity interval training on cardiac function during prolonged submaximal exercise in patients with type 2 diabetes. METHODS: Twenty-six patients with type 2 diabetes were randomized to a 12 week of high intensity interval training (3 sessions/week) or standard care control group. All patients underwent prolonged (i.e. 60 min) submaximal cardiopulmonary exercise testing (at 50% of previously assess maximal functional capacity) with non-invasive gas-exchange and haemodynamic measurements including cardiac output and stroke volume before and after the intervention. RESULTS: At baseline (prior to intervention) there was no significant difference between the intervention and control group in peak exercise oxygen consumption (20.3 ± 6.1 vs. 21.7 ± 5.5 ml/kg/min, p = 0.21), and peak exercise heart rate (156.3 ± 15.0 vs. 153.8 ± 12.5 beats/min, p = 0.28). During follow-up assessment both groups utilized similar amount of oxygen during prolonged submaximal exercise (15.0 ± 2.4 vs. 15.2 ± 2.2 ml/min/kg, p = 0.71). However, cardiac function i.e. cardiac output during submaximal exercise decreased significantly by 21% in exercise group (16.2 ± 2.7-12.8 ± 3.6 L/min, p = 0.03), but not in the control group (15.7 ± 4.9-16.3 ± 4.1 L/min, p = 0.12). Reduction in exercise cardiac output observed in the exercise group was due to a significant decrease in stroke volume by 13% (p = 0.03) and heart rate by 9% (p = 0.04). CONCLUSION: Following high intensity interval training patients with type 2 diabetes demonstrate reduced cardiac output during prolonged submaximal cardiopulmonary exercise testing. Ability of patients to maintain prolonged increased metabolic demand but with reduced cardiac output suggests cardiac protective role of high intensity interval training in type 2 diabetes. TRIAL REGISTRATION: ISRCTN78698481. Registered 23 January 2013, retrospectively registered.

Skeletal muscle mitochondrial oxidative phosphorylation function in idiopathic pulmonary arterial hypertension: in vivo and in vitro study.

Mitochondrial dysfunction within the pulmonary vessels has been shown to contribute to the pathology of idiopathic pulmonary arterial hypertension (IPAH). We investigated the hypothesis of whether impaired exercise capacity observed in IPAH patients is in part due to primary mitochondrial oxidative phosphorylation (OXPHOS) dysfunction in skeletal muscle. This could lead to potentially new avenues of treatment beyond targeting the pulmonary vessels. Nine clinically stable participants with IPAH underwent cardiopulmonary exercise testing, in vivo and in vitro assessment of mitochondrial function by 31P-magnetic resonance spectroscopy (31P-MRS) and laboratory muscle biopsy analysis. 31P-MRS showed abnormal skeletal muscle bioenergetics with prolonged recovery times of phosphocreatine and abnormal muscle pH handling. Histochemistry and quadruple immunofluorescence performed on muscle biopsies showed normal function and subunit protein abundance of the complexes within the OXPHOS system. Our findings suggest that there is no primary mitochondrial OXPHOS dysfunction but raises the possibility of impaired oxygen delivery to the mitochondria affecting skeletal muscle bioenergetics during exercise.

Comparison of cardiac output estimates by bioreactance and inert gas rebreathing methods during cardiopulmonary exercise testing.

PURPOSE: This study assessed the agreement between cardiac output estimated by inert gas rebreathing and bioreactance methods at rest and during exercise. METHODS: Haemodynamic measurements were assessed in 20 healthy individuals (11 females, nine males; aged 32 ± 10 years) using inert gas rebreathing and bioreactance methods. Gas exchange and haemodynamic data were measured simultaneously under rest and different stages (i.e. 30, 60, 90, 120, 150 and 180 W) of progressive graded cardiopulmonary exercise stress testing using a bicycle ergometer. RESULTS: At rest, bioreactance produced significantly higher cardiac output values than inert gas rebreathing (7·8 ± 1·4 versus 6·5 ± 1·7 l min-1 , P = 0·01). At low-to-moderate exercise intensities (i.e. 30-90 W), bioreactance produced significantly higher cardiac outputs compared with rebreathing method (P<0·05). At workloads of 120 W and above, there was no significant difference in cardiac outputs between the two methods (P = 0·10). There was a strong relationship between the two methods (r = 0·82, P = 0·01). Bland-Altman analysis including rest and exercise data showed that inert gas rebreathing reported 1·95 l min-1 lower cardiac output than bioreactance, with lower and upper limits of agreement of -3·1-7·07 l min-1 . Analysis of peak exercise data showed a mean difference of 0·4 l min-1 (lower and upper limits of agreement of -4·9-5·7 l min-1 ) between both devices. CONCLUSION: Bioreactance and inert gas rebreathing methods show acceptable levels of agreement for estimating cardiac output at higher levels of metabolic demand. However, they cannot be used interchangeably due to strong disparity in results at rest and low-to-moderate exercise intensity.

The cardio-metabolic impact of taking commonly prescribed analgesic drugs in 133,401 UK Biobank participants.

OBJECTIVE: There has been a significant increase in the prescribing of medication for chronic non-cancer pain. In a UK population sample, we aimed to assess cardio-metabolic (CM) health in those taking these chronic pain medications. METHODS: 133,401 participants from the UK Biobank cohort were studied. BMI, waist cm and hypertension were compared between those on drugs prescribed for chronic pain and CM drugs to those on CM drugs only. Multiple confounders were controlled for. RESULTS: Those taking opiates and CM drugs had the worst CM health profile with a 95%, 82% and 63% increased odds of reporting obesity, 'very high risk' waist circumference and hypertension, respectively (OR [95% CI] 1.95 [1.75-2.17], 1.82 [1.63-2.03], 1.63 [1.45-1.84]), compared to those on CM drugs alone. Those taking neuropathic pain medications and CM drugs also demonstrate worse CM profile than those taking CM drugs only. CONCLUSIONS: The impact of medications for chronic pain and sleep upon CM health and obesity is of concern for these classes of drugs which have been recently labelled as dependency forming medications. The results from this cross sectional study warrants further investigation and adds further support to calls for these medications to be prescribed for shorter periods.

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.

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.

Exercise therapy in primary biliary cirrhosis: the importance of moving while sitting on a surgical waiting list-a case study.

BACKGROUND: It is being increasingly recognised that reduced cardiorespiratory fitness is associated with poorer outcomes after major surgery. Exercise limitation and reduced aerobic capacity are common in people with end-stage liver disease. There is limited evidence about the role of exercise therapy in the management of primary biliary cirrhosis (PBC) and no studies have looked at the effect of exercise in people with PBC who are awaiting liver transplantation. This case study is the first to report that personalised exercise therapy improves cardiorespiratory fitness in a patient with PBC without worsening symptoms of severe fatigue. METHODS: Cardiopulmonary exercise testing was used to assess cardiorespiratory fitness in a patient with end-stage PBC prior to listing for transplantation. A personalised exercise programme was designed to improve cardiorespiratory fitness while the patient was on the transplant waiting list. RESULTS: Anaerobic threshold, VO2PEAK and maximum workload all improved with regular exercise. Fatigue levels remained unaltered. CONCLUSIONS: This patient tolerated and adhered to a personalised exercise programme for a prolonged period of time while awaiting surgery despite significant fatigue and disease burden. Liver transplantation was successfully completed and this woman remains well over 2 years post-surgery.

Cross-sectional study of diet, physical activity, television viewing and sleep duration in 233,110 adults from the UK Biobank; the behavioural phenotype of cardiovascular disease and type 2 diabetes.

OBJECTIVES: Simultaneously define diet, physical activity, television (TV) viewing, and sleep duration across cardiometabolic disease groups, and investigate clustering of non-diet lifestyle behaviours. DESIGN: Cross-sectional observational study. SETTING: 22 UK Biobank assessment centres across the UK. PARTICIPANTS: 502,664 adults aged 37-63 years old, 54% women. 4 groups were defined based on disease status; 'No disease' (n=103,993), 'cardiovascular disease' (CVD n=113,469), 'Type 2 diabetes without CVD' (n=4074) and 'Type 2 diabetes + CVD' (n=11,574). MAIN OUTCOMES: Diet, physical activity, TV viewing and sleep duration. RESULTS: People with 'CVD' report low levels of physical activity (<918 MET min/week, OR (95% CI) 1.23 (1.20 to 1.25)), high levels of TV viewing (>3 h/day; 1.42 (1.39 to 1.45)), and poor sleep duration (<7, >8 h/night; 1.37 (1.34 to 1.39)) relative to people without disease. People with 'Type 2 diabetes + CVD' were more likely to report low physical activity (1.71 (1.64 to 1.78)), high levels of TV viewing (1.92 (1.85 to 1.99)) and poor sleep duration (1.52 (1.46 to 1.58)) relative to people without disease. Non-diet behaviours were clustered, with people with 'CVD' or 'Type 2 diabetes + CVD' more likely to report simultaneous low physical activity, high TV viewing and poor sleep duration than those without disease (2.15 (2.03 to 2.28) and 3.29 (3.02 to 3.58), respectively). By contrast, 3 in 4 adults with 'Type 2 diabetes', and 2 in 4 adults with 'CVD' have changed their diet in the past 5 years, compared with only 1 in 4 in the 'No disease' group. Models were adjusted for gender, age, body mass index, Townsend Deprivation Index, ethnicity, alcohol intake, smoking and meeting fruit/vegetable guidelines. CONCLUSIONS: Low physical activity, high TV and poor sleep duration are prominent unaddressed high-risk characteristics of both CVD and type 2 diabetes, and are likely to be clustered together.

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.

Effect of physical activity on age-related changes in cardiac function and performance in women.

BACKGROUND: Higher levels of physical activity are associated with reduced cardiovascular mortality but its effect on age-related changes in cardiac structure and function is unknown. The present study defines the effect of daily physical activity on age-related changes in cardiac structure, function, metabolism, and performance in healthy women. METHODS AND RESULTS: Sixty-three healthy women were grouped according to age (young, 20-30 years, n=21; middle, 40-50 years, n=22; and older, 65-81 years, n=20) and daily physical activity level (low active<7500 and high active>12,500 steps/d). Participants underwent cardiac MRI including tissue tagging and 31P spectroscopy and exercise testing with noninvasive central hemodynamic measurements. Aging was associated with increased concentric remodeling (P<0.01) and left ventricular torsion (P<0.01), and a decline in diastolic function (P<0.01), cardiac phosphocreatine:ATP ratio (P<0.01), peak exercise cardiac power output (P<0.01), and O2 consumption (P<0.01). Older high-active women demonstrated a phosphocreatine:ATP ratio and relative peak O2 consumption similar to young low-active women, and 23% and 26% higher than older low-active women (phosphocreatine:ATP ratio, 1.9±0.2 versus 1.4±0.1; P<0.05 and O2 consumption, 24.1±3.8 versus 17.8±2.0 mL/[kg·min]; P<0.01). In older women, physical activity had no effect on eccentricity ratio (0.9±0.2 versus 0.8±0.1 g/mL; P=0.19), E/A ratio (1.3±0.5 versus 1.4±0.5; P=0.66), torsion (7.6±1.7 versus 8.0°±2.1°; P=0.20), and peak cardiac power output (3.4±0.7 versus 3.4±0.8 W; P=0.91). CONCLUSIONS: A higher level of daily physical activity preserves cardiac metabolism and exercise capacity with aging but has limited effect on age-related changes in concentric remodeling, diastolic function, and cardiac performance.

Effect of left ventricular assist device implantation and heart transplantation on habitual physical activity and quality of life.

The present study defined the short- and long-term effects of left ventricular assist device (LVAD) implantation and heart transplantation (HT) on physical activity and quality of life (QoL). Forty patients (LVAD, n = 14; HT, n = 12; and heart failure [HF], n = 14) and 14 matched healthy subjects were assessed for physical activity, energy expenditure, and QoL. The LVAD and HT groups were assessed postoperatively at 4 to 6 weeks (baseline) and 3, 6, and 12 months. At baseline, LVAD, HT, and HF patients demonstrated low physical activity, reaching only 15%, 28%, and 51% of that of healthy subjects (1,603 ± 302 vs 3,036 ± 439 vs 5,490 ± 1,058 vs 10,756 ± 568 steps/day, respectively, p <0.01). This was associated with reduced energy expenditure and increased sedentary time (p <0.01). Baseline QoL was not different among LVAD, HT, and HF groups (p = 0.44). LVAD implantation and HT significantly increased daily physical activity by 60% and 52%, respectively, from baseline to 3 months (p <0.05), but the level of activity remained unchanged at 3, 6, and 12 months. The QoL improved from baseline to 3 months in LVAD implantation and HT groups (p <0.01) but remained unchanged afterward. At any time point, HT demonstrated higher activity level than LVAD implantation (p <0.05), and this was associated with better QoL. In contrast, physical activity and QoL decreased at 12 months in patients with HF (p <0.05). In conclusion, patients in LVAD and HT patients demonstrate improved physical activity and QoL within the first 3 months after surgery, but physical activity and QoL remain unchanged afterward and well below that of healthy subjects. Strategies targeting low levels of physical activity should now be explored to improve recovery of these patients.

Metabolic implications when employing heavy pre- and post-exercise rapid-acting insulin reductions to prevent hypoglycaemia in type 1 diabetes patients: a randomised clinical trial.

AIM: To examine the metabolic, gluco-regulatory-hormonal and inflammatory cytokine responses to large reductions in rapid-acting insulin dose administered prandially before and after intensive running exercise in male type 1 diabetes patients. METHODS: This was a single centre, randomised, controlled open label study. Following preliminary testing, 8 male patients (24±2 years, HbA1c 7.7±0.4%/61±4 mmol.l-1) treated with insulin's glargine and aspart, or lispro attended the laboratory on two mornings at ∼08:00 h and consumed a standardised breakfast carbohydrate bolus (1 g carbohydrate.kg-1BM; 380±10 kcal) and self-administered a 75% reduced rapid-acting insulin dose 60 minutes before 45 minutes of intensive treadmill running at 73.1±0.9% VO2peak. At 60 minutes post-exercise, patients ingested a meal (1 g carbohydrate.kg-1BM; 660±21 kcal) and administered either a Full or 50% reduced rapid-acting insulin dose. Blood glucose and lactate, serum insulin, cortisol, non-esterified-fatty-acids, ß-Hydroxybutyrate, and plasma glucagon, adrenaline, noradrenaline, IL-6, and TNF-α concentrations were measured for 180 minutes post-meal. RESULTS: All participants were analysed. All glycaemic, metabolic, hormonal, and cytokine responses were similar between conditions up to 60 minutes following exercise. Following the post-exercise meal, serum insulin concentrations were lower under 50% (p<0.05) resulting in 75% of patients experiencing hyperglycaemia (blood glucose ≥8.0 mmol.l-1; 50% n = 6, Full n = 3). ß-Hydroxybutyrate concentrations decreased similarly, such that at 180 minutes post-meal concentrations were lower than rest under Full and 50%. IL-6 and TNF-α concentrations remained similar to fasting levels under 50% but declined under Full. Under 50% IL-6 concentrations were inversely related with serum insulin concentrations (r = -0.484, p = 0.017). CONCLUSIONS: Heavily reducing rapid-acting insulin dose with a carbohydrate bolus before, and a meal after intensive running exercise may cause hyperglycaemia, but does not augment ketonaemia, raise inflammatory cytokines TNF-α and IL-6 above fasting levels, or cause other adverse metabolic or hormonal disturbances. TRIAL REGISTRATION: ClinicalTrials.gov NCT01531855.

A low-glycemic index meal and bedtime snack prevents postprandial hyperglycemia and associated rises in inflammatory markers, providing protection from early but not late nocturnal hypoglycemia following evening exercise in type 1 diabetes.

OBJECTIVE: To examine the influence of the glycemic index (GI) of foods consumed after evening exercise on postprandial glycemia, metabolic and inflammatory markers, and nocturnal glycemic control in type 1 diabetes. RESEARCH DESIGN AND METHODS: On two evenings (∼1700 h), 10 male patients (27 ± 5 years of age, HbA1c 6.7 ± 0.7% [49.9 ± 8.1 mmol/mol]) were administered a 25% rapid-acting insulin dose with a carbohydrate bolus 60 min before 45 min of treadmill running. At 60 min postexercise, patients were administered a 50% rapid-acting insulin dose with one of two isoenergetic meals (1.0 g carbohdyrate/kg body mass [BM]) matched for macronutrient content but of either low GI (LGI) or high GI (HGI). At 180 min postmeal, the LGI group ingested an LGI snack and the HGI group an HGI snack (0.4 g carbohdyrate/kg BM) before returning home (∼2300 h). Interval samples were analyzed for blood glucose and lactate; plasma glucagon, epinephrine, interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α); and serum insulin, cortisol, nonesterified fatty acid, and ß-hydroxybutyrate concentrations. Interstitial glucose was recorded for 20 h postlaboratory attendance through continuous glucose monitoring. RESULTS: Following the postexercise meal, an HGI snack induced hyperglycemia in all patients (mean ± SD glucose 13.5 ± 3.3 mmol/L) and marked increases in TNF-α and IL-6, whereas relative euglycemia was maintained with an LGI snack (7.7 ± 2.5 mmol/L, P < 0.001) without inflammatory cytokine elevation. Both meal types protected all patients from early hypoglycemia. Overnight glycemia was comparable, with a similar incidence of nocturnal hypoglycemia (n = 5 for both HGI and LGI). CONCLUSIONS: Consuming LGI food with a reduced rapid-acting insulin dose following evening exercise prevents postprandial hyperglycemia and inflammation and provides hypoglycemia protection for ∼8 h postexercise; however, the risk of late nocturnal hypoglycemia remains.

Movement as Medicine for Type 2 Diabetes: protocol for an open pilot study and external pilot clustered randomised controlled trial to assess acceptability, feasibility and fidelity of a multifaceted behavioural intervention targeting physical activity in primary care.

BACKGROUND: Physical activity (PA) and nutrition are the cornerstones of diabetes management. Several reviews and meta-analyses report that PA independently produces clinically important improvements in glucose control in people with Type 2 diabetes. However, it remains unclear what the optimal strategies are to increase PA behaviour in people with Type 2 diabetes in routine primary care. METHODS: This study will determine whether an evidence-informed multifaceted behaviour change intervention (Movement as Medicine for Type 2 Diabetes) targeting both consultation behaviour of primary healthcare professionals and PA behaviour in adults with Type 2 diabetes is both acceptable and feasible in the primary care setting. An open pilot study conducted in two primary care practices (phase one) will assess acceptability, feasibility and fidelity. Ongoing feedback from participating primary healthcare professionals and patients will provide opportunities for systematic adaptation and refinement of the intervention and study procedures. A two-arm parallel group clustered pilot randomised controlled trial with patients from participating primary care practices in North East England will assess acceptability, feasibility, and fidelity of the intervention (versus usual clinical care) and trial processes over a 12-month period. Consultation behaviour involving fidelity of intervention delivery, diabetes and PA related knowledge, attitudes/beliefs, intentions and self-efficacy for delivering a behaviour change intervention targeting PA behaviour will be assessed in primary healthcare professionals. We will rehearse the collection of outcome data (with the focus on data yield and quality) for a future definitive trial, through outcome assessment at baseline, one, six and twelve months. An embedded qualitative process evaluation and treatment fidelity assessment will explore issues around intervention implementation and assess whether intervention components can be reliably and faithfully delivered in routine primary care. DISCUSSION: Movement as Medicine for Type 2 Diabetes will address an important gap in the evidence-base, that is, the need for interventions to increase free-living PA behaviour in adults with Type 2 diabetes. The multifaceted intervention incorporates an online accredited training programme for primary healthcare professionals and represents, to the best of our knowledge, the first of its kind in the United Kingdom. This study will establish whether the multifaceted behavioural intervention is acceptable and feasible in routine primary care. TRIAL REGISTRATION: Movement as Medicine for Type 2 Diabetes (MaMT2D) was registered with Current Controlled Trials on the 14th January 2012: ISRCTN67997502. The first primary care practice was randomised on the 5th October 2012.

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.

Defining cardiac adaptations and safety of endurance training in patients with m.3243A>G-related mitochondrial disease.

BACKGROUND: Cardiac hypertrophic remodelling and systolic dysfunction are common in patients with mitochondrial disease and independent predictors of morbidity and early mortality. Endurance exercise training improves symptoms and skeletal muscle function, yet cardiac adaptations are unknown. METHODS AND RESULTS: Before and after 16-weeks of training, exercise capacity, cardiac magnetic resonance imaging and phosphorus-31 spectroscopy, disease burden, fatigue, quality of life, heart rate variability (HRV) and blood pressure variability (BPV) were assessed in 10 adult patients with m.3243A>G-related mitochondrial disease, and compared to age- and gender-matched sedentary control subjects. At baseline, patients had increased left ventricular mass index (LVMI, p<0.05) and LV mass to end-diastolic volume ratio, and decreased longitudinal shortening and myocardial phosphocreatine/adenosine triphosphate ratio (all p<0.01). Peak arterial-venous oxygen difference (p<0.05), oxygen uptake (VO2) and power were decreased in patients (both p<0.01) with no significant difference in cardiac power output. All patients remained stable and completed ≥80% sessions. With training, there were similar proportional increases in peak VO2, anaerobic threshold and work capacity in patients and controls. LVMI increased in both groups (p<0.01), with no significant effect on myocardial function or bioenergetics. Pre- and post-exercise training, HRV and BPV demonstrated increased low frequency and decreased high frequency components in patients compared to controls (all p<0.05). CONCLUSION: Patients with mitochondrial disease and controls achieved similar proportional benefits of exercise training, without evidence of disease progression, or deleterious effects on cardiac function. Reduced exercise capacity is largely mediated through skeletal muscle dysfunction at baseline and sympathetic over-activation may be important in pathogenesis.

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.

Concentric hypertrophic remodelling and subendocardial dysfunction in mitochondrial DNA point mutation carriers.

AIMS: Hypertrophic remodelling and systolic dysfunction are common in patients with mitochondrial disease and independent predictors of morbidity and early mortality. Screening strategies for cardiac disease are unclear. We investigated whether myocardial abnormalities could be identified in mitochondrial DNA mutation carriers without clinical cardiac involvement. METHODS AND RESULTS: Cardiac magnetic resonance imaging was performed in 22 adult patients with mitochondrial disease due to the m.3243A>G mutation, but no known cardiac involvement, and 22 age- and gender-matched control subjects: (i) Phosphorus-31- magnetic resonance spectroscopy, (ii) cine imaging (iii), cardiac tagging and (iv) late gadolinium enhancement (LGE) imaging. Disease burden was determined using the Newcastle Mitochondrial Disease Adult Scale (NMDAS) and urinary mutation load. Compared with control subjects, patients had an increased left ventricular mass index (LVMI), LV mass to end-diastolic volume (M/V) ratio, wall thicknesses (all P < 0.01), torsion and torsion to endocardial strain ratio (both P < 0.05). Longitudinal shortening was decreased in patients (P < 0.0001) and correlated with an increased LVMI (r = -0.52, P < 0.03), but there were no differences in the diastolic function. Among patients there was no correlation of LVMI or the M/V ratio with diabetic or hypertensive status, but the mutation load and NMDAS correlated with the LVMI (r = 0.71 and r = 0.79, respectively, both P < 0.001). The phosphocreatine/adenosine triphosphate ratio was decreased in patients (P < 0.001) but did not correlate with other parameters. No patients displayed focal LGE. CONCLUSION: Concentric remodelling and subendocardial dysfunction occur in patients carrying m.3243A>G mutation without clinical cardiac disease. Patients with higher mutation loads and disease burden may be at increased risk of cardiac involvement.

Submaximal exercise testing predicts perioperative hospitalization after aortic aneurysm repair.

BACKGROUND: Aortic aneurysm repair is a high-risk surgical procedure. Patients are often elderly, with multiple comorbidities that predispose them to perioperative morbidity. Use of endovascular aneurysm repair (EVAR) has increased due to reduced early perioperative risk. This study assessed whether preoperative cardiopulmonary exercise testing (CPET) could be used to predict morbidity and hospital length of stay (LOS) after aortic aneurysm repair. METHODS: A total of 185 patients underwent surgical repair (84 open repairs, 101 EVAR) and had adequate determination of a submaximal CPET parameter (anaerobic threshold). RESULTS: Patient comorbidities and cardiorespiratory fitness, derived from CPET, were similar between surgical procedures. Patients undergoing EVAR had fewer complications (10% vs 32%; P<.0001) and shorter mean (standard deviation [SD]) hospital LOS of 5.7 (9.3) days vs 14.4 (10.9) days compared with open repair (P<.0001). The hospital LOS was significantly increased in patients with one or more complications in both groups compared with those with no complications. In the open repair group, the level of fitness, as defined by anaerobic threshold, was an independent predictor of postoperative morbidity and hospital LOS. When the optimal anaerobic threshold (10 mL/min/kg) derived from receiver operator curve analysis was used as a cutoff value, unfit patients stayed significantly longer than fit patients in critical care (mean, 6.4 [SD, 6.9] days vs 2.4 [SD, 2.9] days; P=.002) and in the hospital (mean, 23.1 [SD, 14.8] days vs 11.0 [SD, 6.1] days; P<.0001). In contrast, fitness in the EVAR group was not predictive of postoperative morbidity but did have predictive value for hospital LOS. CONCLUSIONS: Cardiorespiratory fitness holds significant clinical value before aortic aneurysm repair in predicting postsurgical complications and duration of critical care and hospital LOS. Preoperative measurement of fitness could then direct clinical management with regard to operative choice, postoperative resource allocation, and informed patient decision making.