Exercise-induced changes in left ventricular strain are affected by interleukin-6 activity: An exploratory analysis of a randomised-controlled trial in humans with abdominal obesity.

Whilst the exercise-induced myokine interleukin-6 (IL-6) plays a beneficial role in cardiac structural adaptations, its influence on exercise-induced functional cardiac outcomes remains unknown. We hypothesised that IL-6 activity is required for exercise-induced improvements in left ventricular global longitudinal strain (LV GLS). In an exploratory study 52 individuals with abdominal obesity were randomised to 12 weeks' high-intensity exercise or no exercise in combination with IL-6 receptor inhibition (IL-6i) or placebo. LV strain and volume measurements were assessed by cardiac magnetic resonance. Exercise improved LV GLS by -5.4% [95% CI: -9.1% to -1.6%] (P = 0.007). Comparing the change from baseline in LV GLS in the exercise + placebo group (-4.8% [95% CI: -7.4% to -2.2%]; P < 0.0004) to the exercise + IL-6i group (-1.1% [95% CI: -3.8% to 1.6%]; P = 0.42), the exercise + placebo group changed -3.7% [95% CI: -7.4% to -0.02%] (P = 0.049) more than the exercise + IL6i group. However, the interaction effect between exercise and IL-6i was insignificant (4.5% [95% CI: -0.8% to 9.9%]; P = 0.09). Similarly, the exercise + placebo group improved LV global circumferential strain by -3.1% [95% CI: -6.0% to -0.1%] (P = 0.04) more compared to the exercise + IL-6i group, yet we found an insignificant interaction between exercise and IL-6i (4.2% [95% CI: -1.8% to 10.3%]; P = 0.16). There was no effect of IL-6i on exercise-induced changes to volume rates. This study underscores the importance of IL-6 in improving LV GLS in individuals with abdominal obesity suggesting a role for IL-6 in cardiac functional exercise adaptations.

Impact of high-intensity interval training on cardiac structure and function after COVID-19: an investigator-blinded randomized controlled trial.

A large proportion of patients suffer from a persistent reduction in cardiorespiratory fitness after recovery from COVID-19, of which the effects on the heart may potentially be reversed through the effect of high-intensity interval training (HIIT). In the present study, we hypothesized that HIIT would increase left ventricular mass (LVM) and improve functional status and health-related quality of life (HRQoL) in individuals previously hospitalized for COVID-19. In this investigator-blinded, randomized controlled trial, 12 wk of supervised HIIT (4 × 4 min, three times a week) was compared with standard care (control) in individuals recently discharged from hospital due to COVID-19. LVM was assessed by cardiac magnetic resonance imaging (cMRI, primary outcome), whereas the pulmonary diffusing capacity (DLCOc, secondary outcome) was examined by the single-breath method. Functional status and HRQoL were assessed by Post-COVID-19 functional scale (PCFS) and King's brief interstitial lung disease (KBILD) questionnaire, respectively. A total of 28 participants were included (age 57 ± 10, 9 females; HIIT: 58 ± 11, 4 females; standard care: 57 ± 9, 5 females), LVM increased in the HIIT vs. standard care group with a between-group difference of 6.8 [mean, 95%CI: 0.8; 12.8] g; P = 0.029. There were no between-group differences in DLCOc or any other lung function metric, which gradually resolved in both groups. Descriptively, PCFS suggested fewer functional limitations in the HIIT group. KBILD improved similarly in the two groups. HIIT is an efficacious exercise intervention for increasing LVM in individuals previously hospitalized for COVID-19.NEW & NOTEWORTHY In this randomized clinical trial on individuals previously hospitalized for COVID-19, a 12 wk supervised high-intensity interval training (HIIT) scheme was found to increase left ventricular mass, whereas pulmonary diffusing capacity was unaffected. The findings indicate that HIIT is an efficacious exercise intervention for targeting the heart after COVID-19.

Effect of a 12-week high-intensity exercise intervention: a comparison of cardiac exercise adaptations during biological disease-modifying antirheumatic drug treatment (TNF inhibitors vs IL-6 signalling inhibitors) in patients with rheumatoid arthritis - study protocol for a randomised controlled trial.

INTRODUCTION: The chronic inflammatory state in rheumatoid arthritis (RA) augments the risk of cardiovascular disease (CVD), with pro-inflammatory cytokines tumour necrosis factor (TNF) and interleukin 6 (IL-6) playing a vital role. Consequently, biological disease-modifying antirheumatic drugs (bDMARDs) may attenuate that risk. IL-6 is also a myokine, secreted from exercising skeletal muscles, where IL-6 exhibits anti-inflammatory effects that may ameliorate the risk of CVD. In healthy humans treated with IL-6 signalling inhibitors (IL-6i), exercise induced loss of visceral fat mass and cardiac adaptations were abolished. We hypothesise that IL-6 signalling inhibition will impair the cardiac and metabolic adaptions to exercise training compared with TNF inhibition in RA patients. METHODS AND ANALYSIS: 80 RA patients treated with IL-6i (n=40) or TNF inhibitors (n=40) are included in a 12-week randomised investigator-blinded 4×4 min high-intensity interval training (HIIT) study. Patients are stratified for medical treatment and sex and allocated 1:1 to an exercise or a no exercise control group (four groups). The supervised exercise intervention comprises 3 weekly HIIT sessions on an ergometer bicycle. The primary outcome is the change in left ventricular mass (LVM), and key secondary outcome is change in visceral fat mass. Both outcomes are measured by MRI. Primary statistical analysis will evaluate LVM at follow-up in a regression model. Intention-to-treat and per protocol analyses will be conducted. The latter necessitates a minimum attendance rate of 80%, adherence to bDMARDs treatment of ≥80% and minimum 8 min (50%) of maximal heart rate above 85% per session. ETHICS AND DISSEMINATION: The study has been approved by the Capital Region Ethics Committee (H-21010559 amendments 86424, 87463 and 88044) and the Danish Medicines Agency (2021-b005287-21). The trial will follow ICH-GCP guidelines. Regardless of outcome, results will be published in relevant peer-reviewed journals. TRIAL REGISTRATION NUMBERS: Eudra-CT: 2021-b005287-21 and NCT05215509.

Pulmonary diffusing capacity to nitric oxide and carbon monoxide during exercise and in the supine position: a test-retest reliability study.

NEW FINDINGS: What is the central question in this study? How reliable is the combined measurement of the pulmonary diffusing capacity to carbon monoxide and nitric oxide (DLCO/NO ) during exercise and in the resting supine position, respectively? What is the main finding and its importance? The DLCO/NO technique is reliable with a very low day-to-day variability both during exercise and in the resting supine position, and may thus provide a useful physiological outcome that reflects the alveolar-capillary reserve in humans. ABSTRACT: DLCO/NO , the combined single-breath measurement of the diffusing capacity to carbon monoxide (DLCO ) and nitric oxide (DLNO ) measured either during exercise or in the resting supine position may be a useful physiological measure of alveolar-capillary reserve. In the present study, we investigated the between-day test-retest reliability of DLCO/NO -based metrics. Twenty healthy volunteers (10 males, 10 females; mean age 25 (SD 2) years) were randomized to repeated DLCO/NO measurements during upright rest followed by either exercise (n = 11) or resting in the supine position (n = 9). The measurements were repeated within 7 days. The smallest real difference (SRD), defined as the 95% confidence limit of the standard error of measurement (SEM), the coefficient of variance (CV), and intraclass correlation coefficients were used to assess test-retest reliability. SRD for DLNO was higher during upright rest (5.4 (95% CI: 4.1, 7.5) mmol/(min kPa)) than during exercise (2.7 (95% CI: 2.0, 3.9) mmol/(min kPa)) and in the supine position (3.0 (95% CI: 2.1, 4.8) mmol/(min kPa)). SRD for DLCOc was similar between conditions. CV values for DLNO were slightly lower than for DLCOc both during exercise (1.5 (95% CI: 1.2, 1.7) vs. 3.8 (95% CI: 3.2, 4.3)%) and in the supine position (2.2 (95% CI: 1.8, 2.5) vs. 4.8 (95% CI: 3.8, 5.4)%). DLNO increased by 12.3 (95% CI: 11.1, 13.4) and DLCOc by 3.3 (95% CI: 2.9, 3.7) mmol/(min kPa) from upright rest to exercise. The DLCO/NO technique provides reliable indices of alveolar-capillary reserve, both during exercise and in the supine position.

Complications and Their Association with Mortality Following Emergency Gastrointestinal Surgery-an Observational Study.

PURPOSE: Emergency gastrointestinal surgery is followed by a high risk of major complications and death. This study aimed to investigate which complications showed the strongest association with death following emergency surgery for gastrointestinal obstruction or perforation. METHODS: We retrospectively included adults who had undergone emergency gastrointestinal surgery for radiologically verified obstruction or perforation at three Danish hospitals between 2014 and 2015. The exposure variables comprised 16 predefined Clavien-Dindo-graded complications. Cox regression with delayed entry was used to analyze the association of these complications with 90-day mortality. We adjusted for hospital, age, American Society of Anesthesiologists classification, pre-operative Sepsis-2 score, cardiac comorbidity, renal comorbidity, hypertension, active cancer, bowel obstruction or perforation, and the surgical procedure. Subgroup analyses were done for patients with gastrointestinal obstruction or perforation. RESULTS: Of the 349 included patients, 281 (80.5%) experienced at least one complication. The risk of death was 20.6% (14) for patients with no complications and varied between 21 and 57% for patients with complications. Renal impairment (hazard ratio (HR): 6.8 (95%CI: 3.7-12.4)), arterial thromboembolic events (HR 4.8 (2.3-9.9)), and atrial fibrillation (HR 4.4 (2.8-6.8)) showed the strongest association with 90-day mortality. Atrial fibrillation was the only complication significantly associated with death in patients with gastrointestinal obstruction as well as perforation. CONCLUSION: This study of patients undergoing emergency gastrointestinal surgery revealed that renal impairment, arterial thromboembolic events, and atrial fibrillation had the strongest association with death. Atrial fibrillation may serve as an in-situ marker of patients needing escalation of care.

Perioperative fluid administration and complications in emergency gastrointestinal surgery-an observational study.

BACKGROUND: The fluid balance associated with a better outcome following emergency surgery is unknown. The aim of this study was to explore the association of the perioperative fluid balance and postoperative complications during emergency gastrointestinal surgery. METHODS: We retrospectively included patients undergoing emergency surgery for gastrointestinal obstruction or perforation. A perioperative fluid balance of 2.5 L divided the cohort in a conservative and liberal group. Outcome was Clavien-Dindo graded complications registered 90 days postoperatively. We used logistic regression adjusted for age, sex, American Society of Anesthesiologists' classification, use of epidural analgesia, use of vasopressor, type of surgery, intraabdominal pathology, and hospital. Predicted risk of complications was demonstrated on a continuous scale of the fluid balance. RESULTS: We included 342 patients operated between July 2014 and July 2015 from three centers. The perioperative fluid balance was 1.6 L IQR [1.0 to 2.0] in the conservative vs. 3.6 L IQR [3.0 to 5.3] in the liberal group. Odds ratio of overall 2.6 (95% CI 1.5 to 4.4), p < 0.001, and cardiopulmonary complications 3.2 (95% CI 1.9 to 5.7), p < 0.001, were increased in the liberal group. A perioperative fluid balance of 0-2 L was associated with minimal risk of cardiopulmonary complications compared to 1.5-3.5 L for renal complications. CONCLUSION: We found a perioperative fluid balance above 2.5 L to be associated with an increased risk of overall and cardiopulmonary complications following emergency surgery for gastrointestinal obstruction or perforation. A perioperative fluid balance of 0-2 L was associated with the lowest risk of cardiopulmonary complications and 1.5-3.5 L for renal complications.

Protective potential of high-intensity interval training on cardiac structure and function after COVID-19: protocol and statistical analysis plan for an investigator-blinded randomised controlled trial.

INTRODUCTION: COVID-19 is associated with a marked systemic inflammatory response with concomitant cardiac injury and remodelling, but it is currently unknown whether the latter is reversible. Given that high-intensity interval training (HIIT) is a powerful stimulus to improve cardiorespiratory fitness while also eliciting marked anti-inflammatory effects, it may be an important countermeasure of reducing cardiopulmonary morbidity following COVID-19. METHODS AND ANALYSIS: 40 COVID-19 survivors who have been discharged from hospital will be included in this investigator-blinded randomised study with a 12-week HIIT intervention. Patients will be 1:1 block-randomised by sex to either a supervised HIIT exercise group or standard care (control group). The main hypothesis is that a 12-week HIIT scheme is a safe way to improve loss of cardiac mass and associated cardiorespiratory fitness, despite hypothesised limited HIIT-induced changes in conventional lung function indices per se. Ultimately, we hypothesise that the HIIT scheme will reduce post-COVID-19 symptoms and improve quality of life. ETHICS AND DISSEMINATION: This study is approved by the Scientific Ethical Committee at the Capital Region of Denmark (H-20033733, including amendments 75068 and 75799) and registered at ClinicalTrials.gov (NCT04647734, pre-results). The findings will be published in a peer-reviewed journal, including cases of positive, negative and inconclusive results.Trial registration number NCT04549337.

Fidelity, tolerability and safety of acute high-intensity interval training after hospitalisation for COVID-19: a randomised cross-over trial.

OBJECTIVES: Many patients with COVID-19 suffer from persistent symptoms, many of which may potentially be reversed by high-intensity interval training (HIIT). Yet, the safety and tolerability of HIIT after COVID-19 is controversial. This study aimed to investigate the fidelity, tolerability and safety of three different HIIT protocols in individuals that had recently been hospitalised due to COVID-19. METHODS: The study was a randomised cross-over trial. We compared three supervised HIIT protocols (4×4, 6×1, 10-20-30) in 10 individuals recently discharged after hospitalisation for severe COVID-19. Each HIIT protocol had a duration of 38 min and was performed with a 1-week washout between them. Outcomes included adverse events, exercise training intensity and tolerability assessed by the Likert scale (1-10). RESULTS: All 10 participants aged 61 (mean, SD 8) years (5 males) completed all three HIIT protocols with no adverse events. High intensities were achieved in all three protocols, although they differed in terms of time spent with a heart rate ≥85% of maximum (mean (SD); 4×4: 13.7 (6.4) min; 10-20-30: 12.1 (3.8) min; 6×1: 6.1 (5.6) min; p=0.03). The three protocols were all well tolerated with similar Likert scale scores (mean (SD); 4×4: 8 (2), 10-20-30: 8 (2), 6×1: 9 (2), p=0.72). CONCLUSION: Our findings indicate that recently hospitalised individuals for severe COVID-19 may safely tolerate acute bouts of supervised HIIT as per protocol. This warrants future studies testing the potential of regular HIIT as a rehabilitation strategy in this context.

The prognostic impact of incidental prostate cancer following radical cystoprostatectomy: a nationwide analysis.

BACKGROUND: To determine the prevalence and prognostic impact of incidental prostate cancer in patients undergoing radical cystoprostatectomy. METHODS: A nationwide population-based study of incidental prostate cancer diagnosed following radical cystoprostatectomy. Information on vital status, Gleason score, positive and negative tumor margins, pT-category and subsequent prostate cancer therapies were obtained from the Danish Prostate Cancer Registry and by manual chart review. RESULTS: A total of 1,450 men who underwent radical cystoprostatectomy in Denmark from 1995-2011 were identified. Forty-six men were excluded from analysis, thus 1,404 patients were eligible. The median follow-up was 7.8 years. A total of 466 (33.2%) had incidental prostate cancer diagnosed. No statistical differences in 10- and 15-year cumulative overall mortality were observed when comparing men with, or without, incidental prostate cancer. In men diagnosed with incidental prostate cancer, neither Gleason score, positive surgical margins or locally advanced prostate cancer (pT3-4) was associated with mortality. Only 0.9% received post-operative prostate cancer-related treatment. CONCLUSION: In this population-based cohort of patients with incidental prostate cancer diagnosed at radical cystoprostatectomy, we found no impact of incidental prostate cancer on overall mortality, regardless of Gleason score, surgical margin status and pathological T-category. Patients diagnosed with incidental prostate cancer following radical cystoprostatectomy are unlikely to benefit from additional follow-up.

Resistance training in patients with limb-girdle and becker muscular dystrophies.

INTRODUCTION: In this study we investigated the effect of strength training in patients with limb-girdle muscular dystrophy (LGMD) and Becker muscular dystrophy (BMD). METHODS: In 2 studies we compared the effect of low-intensity training (LOIT; n = 8) and high-intensity training (HIT; n = 4) in muscles of the upper and lower extremities. Patients were tested for maximal strength and endurance before and after the training program. RESULTS: LOIT training over 6 months resulted in increased biceps strength and endurance. HIT training increased endurance and strength in wrist flexion and extension and in elbow flexion. One patient discontinued HIT training due to muscle soreness and mildly increased plasma CK levels without strength deterioration. CONCLUSIONS: Both LOIT and HIT increased muscle strength and endurance in some of the muscles tested and were well tolerated in most patients. Our findings suggest that supervised resistance training may be considered in the management of patients with LGMD2 and BMD.