The role of the muscle metaboreflex in patients with chronic disease

Exercising muscle needs a constant supply of oxygen for the aerobic metabolism of carbohydrate and fat, and regulation of the blood supply to muscle during exercise is therefore critical. Heart rate, stroke volume and minute ventilation all increase during exercise, and sympathetic vasoconstriction diverts blood to exercising muscle. It is well recognised that receptors in skeletal muscle play a vital role in the regulation of blood flow, including receptors sensitive to products of anaerobic metabolism such as lactate and hydrogen ions: metaboreceptors. Activation of the muscle metaboreflex signals the need for an increase in blood flow, and leads to an increase in cardiac output, ventilation and sympathetic vasoconstriction to non-essential organs. Exercise intolerance is one of the most disabling symptoms in patients with a range of cardiorespiratory diseases. Abnormalities of skeletal muscle favouring anaerobic metabolism have been documented in both chronic heart failure and chronic obstructive pulmonary disease (COPD), and this is thought to be relevant to exercise limitation in these diseases. Studies looking at patients with chronic heart failure have demonstrated an increase in muscle metaboreflex activity. It is thought that abnormal skeletal muscle generates greater quantities of anaerobic metabolites, leading to increased metaboreceptor activation. This in turn causes an increased sympathetic nervous system and ventilatory response to exercise. Patients with COPD have been shown to demonstrate similar skeletal muscle abnormalities, so we hypothesised that we would also find an increase in muscle metaboreflex activity in this group. It is possible to quantify muscle metaboreflex activity by exercising a small muscle group to fatigue then isolating it from the rest of the circulation with a sphygmomanometer cuff. This traps the metabolic products of exercise in the muscle and leads to prolonged stimulation of metaboreceptors. This can be measured as a sustained increase in blood pressure and ventilation when compared with control recovery without cuff inflation. The aims of this thesis were as follows: (i) to assess if it is possible to quantify the muscle metaboreflex in a group of patients with COPD and to determine whether muscle metaboreflex activity is increased in patients with more severe disease, (ii) to determine whether supplementation with oral creatine monohydrate alters muscle metaboreflex activity, upper limb strength or endurance and respiratory muscle strength in patients with COPD, (iii) to assess the effects of diabetic autonomic neuropathy on muscle metaboreflex function, and (iv) to evaluate whether pulse transit time is of use in the measurement of muscle metaboreflex activity. In our first study, we looked at a group of patients with stable COPD and found that rhythmic forearm exercise followed by post-exercise forearm ischaemia led to a sustained increase in blood pressure and minute ventilation when compared with control recovery. These findings are in keeping with previously published observations in normal subjects and in patients with chronic heart failure. We found that there was no difference in muscle metaboreflex activity between the groups of patients with moderate or severe disease. We then performed a randomised, double-blind, placebo-controlled, crossover trial looking at the effects of loading a group of patients with stable COPD with creatine monohydrate. We demonstrated a small increase in body weight and an increase in peak inspiratory and expiratory mouth pressures, but there were no effects on muscle metaboreflex activity or forearm muscle strength, endurance or recovery. A group of patients with type I diabetes mellitus was then used to study the effects of autonomic neuropathy on muscle metaboreflex function. We found that there was no difference in metaboreflex activity between subjects with diabetic autonomic neuropathy and subjects with diabetes but no evidence of autonomic neuropathy, suggesting that the afferent and efferent limbs of the muscle metaboreflex were intact. Our final study evaluated whether pulse transit time could be used to assess muscle metaboreflex activity. Pulse transit time is defined as the time taken for a pulse wave to travel between two arterial sites, and can be easily and non-invasively measured. It is thought to reflect blood pressure and arterial tone. In a group of healthy subjects, we found that pulse transit time fell with rhythmic handgrip exercise, and post-exercise muscle ischaemia led to a sustained fall in pulse transit time when compared with control recovery. Pulse transit time therefore shows promise in the measurement of muscle metaboreflex activity, but further studies are required. Studies comparing pulse transit time with more invasive measurements such as muscle sympathetic nerve activity would be of particular interest

Post-COVID-19 illness trajectory: a multisystem investigation [Pre-print]

Background: The pathophysiology and trajectory of multiorgan involvement in post-COVID-19 syndrome is uncertain. Methods: A prospective, multicenter, longitudinal, cohort study involving post-COVID-19 patients enrolled in-hospital or early post-discharge (visit 1) and re-evaluated 28-60 days post-discharge (visit 2). Multisystem investigations included chest computed tomography with pulmonary and coronary angiography, cardiovascular and renal magnetic resonance imaging, digital electrocardiography, and multisystem biomarkers. The primary outcome was the adjudicated likelihood of myocarditis. Results: 161 patients (mean age 55 years, 43% female) and 27 controls with similar age, sex, ethnicity, and vascular risk factors were enrolled from 22 May 2020 to 2 July 2021 and had a primary outcome evaluation. Compared to controls, at 28-60 days post-discharge, patients with COVID-19 had persisting evidence of cardio-renal involvement, systemic inflammation, and hemostasis pathway activation. Myocarditis was adjudicated as being not likely (n=17; 10%), unlikely (n=56; 35%), probable (n=67; 42%) or very likely (n=21; 13%). Acute kidney injury (odds ratio, 95% confidence interval: 3.40 (1.13, 11.84); p=0.038) and low hemoglobin A1c (0.26 (0.07, 0.87); p=0.035) were multivariable associates of adjudicated myocarditis. During convalescence, compared to controls, COVID-19 was associated with worse health-related quality of life (EQ5D-5L) (p<0.001), illness perception (p<0.001), anxiety and depression (p<0.001), physical activity (p<0.001) and predicted maximal oxygen utilization (ml/kg/min) (p<0.001). These measures were associated with adjudicated myocarditis. Conclusions: The illness trajectory of COVID-19 includes persisting cardio-renal inflammation, lung damage and hemostasis activation. Adjudicated myocarditis occurred in one in eight hospitalized patients and was associated with impairments in health status, physical and psychological wellbeing during community convalescence. Public registration: ClinicalTrials.gov identifier is NCT04403607

Socioeconomic deprivation and illness trajectory in the Scottish population after COVID-19 hospitalization

Background The associations between deprivation and illness trajectory after hospitalisation for coronavirus disease-19 (COVID-19) are uncertain. Methods A prospective, multicentre cohort study was conducted on post-COVID-19 patients, enrolled either in-hospital or shortly post-discharge. Two evaluations were carried out: an initial assessment and a follow-up at 28–60 days post-discharge. The study encompassed research blood tests, patient-reported outcome measures, and multisystem imaging (including chest computed tomography (CT) with pulmonary and coronary angiography, cardiovascular and renal magnetic resonance imaging). Primary and secondary outcomes were analysed in relation to socioeconomic status, using the Scottish Index of Multiple Deprivation (SIMD). The EQ-5D-5L, Brief Illness Perception Questionnaire (BIPQ), Patient Health Questionnaire-4 (PHQ-4) for Anxiety and Depression, and the Duke Activity Status Index (DASI) were used to assess health status. Results Of the 252 enrolled patients (mean age 55.0 ± 12.0 years; 40% female; 23% with diabetes), deprivation status was linked with increased BMI and diabetes prevalence. 186 (74%) returned for the follow-up. Within this group, findings indicated associations between deprivation and lung abnormalities (p = 0.0085), coronary artery disease (p = 0.0128), and renal inflammation (p = 0.0421). Furthermore, patients with higher deprivation exhibited worse scores in health-related quality of life (EQ-5D-5L, p = 0.0084), illness perception (BIPQ, p = 0.0004), anxiety and depression levels (PHQ-4, p = 0.0038), and diminished physical activity (DASI, p = 0.002). At the 3-month mark, those with greater deprivation showed a higher frequency of referrals to secondary care due to ongoing COVID-19 symptoms (p = 0.0438). However, clinical outcomes were not influenced by deprivation. Conclusions In a post-hospital COVID-19 population, socioeconomic deprivation was associated with impaired health status and secondary care episodes. Deprivation influences illness trajectory after COVID-19

International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Adjudicated myocarditis and multisystem illness trajectory in healthcare workers post-COVID-19

No abstract available

Adjudicated myocarditis and multisystem illness trajectory in healthcare workers post-COVID-19

Background We investigated the associations of healthcare worker status with multisystem illness trajectory in hospitalised post-COVID-19 individuals.Methods and results One hundred and sixty-eight patients were evaluated 28–60 days after the last episode of hospital care. Thirty-six (21%) were healthcare workers. Compared with non-healthcare workers, healthcare workers were of similar age (51.3 (8.7) years vs 55.0 (12.4) years; p=0.09) more often women (26 (72%) vs 48 (38%); p&lt;0.01) and had lower 10-year cardiovascular risk (%) (8.1 (7.9) vs 15.0 (11.5); p&lt;0.01) and Coronavirus Clinical Characterisation Consortium in-hospital mortality risk (7.3 (10.2) vs 12.7 (9.8); p&lt;0.01). Healthcare worker status associated with less acute inflammation (peak C reactive protein 48 mg/L (IQR: 14–165) vs 112 mg/L (52–181)), milder illness reflected by WHO clinical severity score distribution (p=0.04) and shorter duration of admission (4 days (IQR: 2–6) vs 6 days (3–12)).In adjusted multivariate logistic regression analysis, healthcare worker status associated with a binary classification (probable/very likely vs not present/unlikely) of adjudicated myocarditis (OR: 2.99; 95% CI (1.01 to 8.89) by 28–60 days postdischarge).After a mean (SD, range) duration of follow-up after hospital discharge of 450 (88) days (range 290, 627 days), fewer healthcare workers died or were rehospitalised (1 (3%) vs 22 (17%); p=0.038) and secondary care referrals for post-COVID-19 syndrome were common (42%) and similar to non-healthcare workers (38%; p=0.934).Conclusion Healthcare worker status was independently associated with the likelihood of adjudicated myocarditis, despite better antecedent health. Two in five healthcare workers had a secondary care referral for post-COVID-19 syndrome.Trial registration number NCT04403607

A multisystem, cardio-renal investigation of post-COVID-19 illness

The pathophysiology and trajectory of post-Coronavirus Disease 2019 (COVID-19) syndrome is uncertain. To clarify multisystem involvement, we undertook a prospective cohort study including patients who had been hospitalized with COVID-19 (ClinicalTrials.gov ID NCT04403607). Serial blood biomarkers, digital electrocardiography and patient-reported outcome measures were obtained in-hospital and at 28–60 days post-discharge when multisystem imaging using chest computed tomography with pulmonary and coronary angiography and cardio-renal magnetic resonance imaging was also obtained. Longer-term clinical outcomes were assessed using electronic health records. Compared to controls (n = 29), at 28–60 days post-discharge, people with COVID-19 (n = 159; mean age, 55 years; 43% female) had persisting evidence of cardio-renal involvement and hemostasis pathway activation. The adjudicated likelihood of myocarditis was ‘very likely’ in 21 (13%) patients, ‘probable’ in 65 (41%) patients, ‘unlikely’ in 56 (35%) patients and ‘not present’ in 17 (11%) patients. At 28–60 days post-discharge, COVID-19 was associated with worse health-related quality of life (EQ-5D-5L score 0.77 (0.23) versus 0.87 (0.20)), anxiety and depression (PHQ-4 total score 3.59 (3.71) versus 1.28 (2.67)) and aerobic exercise capacity reflected by predicted maximal oxygen utilization (20.0 (7.6) versus 29.5 (8.0) ml/kg/min) (all P &lt; 0.01). During follow-up (mean, 450 days), 24 (15%) patients and two (7%) controls died or were rehospitalized, and 108 (68%) patients and seven (26%) controls received outpatient secondary care (P = 0.017). The illness trajectory of patients after hospitalization with COVID-19 includes persisting multisystem abnormalities and health impairments that could lead to substantial demand on healthcare services in the future

Mental health symptoms and illness trajectory following COVID-19 hospitalization: A cohort study

Background: The multisystem associations between baseline mental health status and coronavirus disease-19 (COVID)-19 illness trajectory are uncertain. Objectives: This article will investigate the associations between baseline mental health status and disease trajectory following COVID-19 hospitalization, which may have implications for practice and future research. Methods: The Chief Scientist Office Cardiovascular and Pulmonary Imaging in severe acute respiratory syndrome (SARS) COVID-19 study is a prospective, observational, multicenter, longitudinal, secondary care cohort study that assessed the time-course of multi-organ injury in posthospital survivors of COVID-19. Patients were assessed in-hospital, at 28–60 days after discharge and in the longer term using electronic health record linkage. Results: One hundred and fifty-two patients (mean ± standard deviation [SD] age 54.3 ± 11.8 years, 43% female, 40% most socio-economically deprived quintile, 33% history of mental health history) were enrolled and had mental health serially assessed using the Patient Health Questionnaire-4 (PHQ-4) questionnaire. Fifty-three (35%) had PHQ-4 score of 6–12 consistent with moderate-severe symptoms of anxiety or depression and this was associated with diagnostic criteria for myocarditis (P = 0.0498). Moderate-severe symptoms of anxiety or depression were positively associated with higher perception of illness, lower health-related quality of life (HRQoL), and poorer physical function. The mean (SD) duration of follow-up after hospital discharge was 428 (86) days (range, 290–627 days). PHQ-4 score was not associated with clinical outcomes at follow-up. Conclusions: In patients who have been hospitalized with COVID-19, moderate-severe symptoms of anxiety or depression were associated with myocarditis, worse HRQoL, higher perception of illness, and lower levels of physical function. Public Registration: ClinicalTrials.gov identifier is NCT04403607