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Background: Previous studies in heart failure with reduced ejection fraction (HFrEF) suggest that skeletal muscle mitochondrial impairments are associated with exercise intolerance in men. However, the nature of this relationship in female patients remains to be elucidated. This study aimed to determine the relationship between skeletal muscle mitochondrial impairments and exercise intolerance in male and female patients with HFrEF. Methods: Mitochondrial respiration, enzyme activity, and gene expression were examined in pectoralis major biopsies from age‐matched male (n = 45) and female (n = 11) patients with HFrEF and healthy‐matched male (n = 24) and female (n = 11) controls. Mitochondrial variables were compared between sex and related to peak exercise capacity. Results: Compared with sex‐matched controls, complex I mitochondrial oxygen flux was 17% (P = 0.030) and 29% (P = 0.013) lower in male and female patients with HFrEF, respectively, which correlated to exercise capacity (r = 0.71; P > 0.0001). Female HFrEF patients had a 32% (P = 0.023) lower mitochondrial content compared with controls. However, after adjusting for mitochondrial content, male patients demonstrated lower complex I function by 15% (P = 0.030). Expression of key mitochondrial genes regulating organelle dynamics and maintenance (i.e. optic atrophy 1, peroxisome proliferator‐activated receptor γ coactivator‐1α, NADH:ubiquinone oxidoreductase core subunit S1/S3, and superoxide dismutase 2) were selectively lower in female HFrEF patients. Conclusions: These data provide novel evidence that HFrEF induces divergent sex‐specific mitochondrial phenotypes in skeletal muscle that predispose towards exercise intolerance, impacting mitochondrial ‘quantity’ in female patients and mitochondrial ‘quality’ in male patients. Therapeutic strategies to improve exercise tolerance in HFrEF should consider targeting sex‐specific mitochondrial abnormalities in skeletal muscle.

Background People with chronic heart failure (CHF) experience severe skeletal muscle dysfunction, characterized by mitochondrial abnormalities, which exacerbates the primary symptom of exercise intolerance. However, the molecular triggers and characteristics underlying mitochondrial abnormalities caused by CHF remain poorly understood. Methods and Results We recruited 28 patients with CHF caused by reduced ejection fraction and 9 controls. We simultaneously biopsied skeletal muscle from the pectoralis major in the upper limb and from the vastus lateralis in the lower limb. We phenotyped mitochondrial function in permeabilized myofibers from both sites and followed this by complete RNA sequencing to identify novel molecular abnormalities in CHF skeletal muscle. Patients with CHF presented with upper and lower limb skeletal muscle impairments to mitochondrial function that were of a similar deficit and indicative of a myopathy. Mitochondrial abnormalities were strongly correlated to symptoms. Further RNA sequencing revealed a unique transcriptome signature in CHF skeletal muscle characterized by a novel triad of differentially expressed genes related to deficits in energy metabolism including adenosine monophosphate deaminase 3, pyridine nucleotide‐disulphide oxidoreductase domain 2, and lactate dehydrogenase C. Conclusions Our data suggest an upper and lower limb metabolic myopathy that is characterized by a unique transcriptome signature in skeletal muscle of humans with CHF.

Introduction Endoscopic surveillance and removal of adenomas significantly reduces the incidence and mortality of colorectal cancer. There is concern that time of day could affect colonoscopy outcomes due to endoscopist fatigue over the course of the day. This could lead to interval cancers, and ultimately increased mortality. However, there are few studies in this area, and they have yielded inconsistent results. The aim of this study was to investigate whether evening colonoscopy lists achieve the same outcomes as daytime lists. Methods Colonoscopy data from patients on the symptomatic pathway was gathered retrospectively over a one year period. Data was gathered only from endoscopists doing both daytime and evening lists. Data collected included quality of bowel prep, caecal intubation rate, adenoma detection rate (ADR), and colorectal cancer detection. Colonoscopy outcome data was compared between daytime and evening lists. Data was analysed using the χ2 test, and Fishers exact test. Results 1150 colonoscopies were included in the analysis, of which 845 were from daytime lists, and 305 were from evening lists. Time of day produced a near significant difference in ADR [23.2% (n=196) daytime vs 17.97% (n=55) evening, p=0.0581]. Detection of colorectal cancer was significantly lower in evening lists [2.13% (n=18) daytime vs 0.33% (n=1) evening, p Conclusions It has been shown that the time of day significantly affects some outcome measures of colonoscopies. Demand for colonoscopies in the UK is rising year on year, and evening lists help to meet this demand. However, it must be ensured that patient care is not compromised, and outcome measures remain stable over the course of the day.