Background
Skeletal muscle dysfunction is a common extrapulmonary manifestation of chronic obstructive pulmonary disease (COPD). Alterations in skeletal muscle myosin heavy chain expression, with ...reduced type I and increased type II myosin heavy chain expression, are associated with COPD severity when studied in largely male cohorts. The objectives of this study were (1) to define an abnormal myofibre proportion phenotype in both males and females with COPD and (2) to identify transcripts and transcriptional networks associated with abnormal myofibre proportion in COPD.
Methods
Forty‐six participants with COPD were assessed for body composition, strength, endurance and pulmonary function. Skeletal muscle biopsies from the vastus lateralis were assayed for fibre‐type distribution and cross‐sectional area via immunofluorescence microscopy and RNA‐sequenced to generate transcriptome‐wide gene expression data. Sex‐stratified k‐means clustering of type I and IIx/IIax fibre proportions was used to define abnormal myofibre proportion in participants with COPD and contrasted with previously defined criteria. Single transcripts and weighted co‐expression network analysis modules were tested for correlation with the abnormal myofibre proportion phenotype.
Results
Abnormal myofibre proportion was defined in males with COPD (n = 29) as <18% type I and/or >22% type IIx/IIax fibres and in females with COPD (n = 17) as <36% type I and/or >12% type IIx/IIax fibres. Half of the participants with COPD were classified as having an abnormal myofibre proportion. Participants with COPD and an abnormal myofibre proportion had lower median handgrip strength (26.1 vs. 34.0 kg, P = 0.022), 6‐min walk distance (300 vs. 353 m, P = 0.039) and forced expiratory volume in 1 s‐to‐forced vital capacity ratio (0.42 vs. 0.48, P = 0.041) compared with participants with COPD and normal myofibre proportions. Twenty‐nine transcripts were associated with abnormal myofibre proportions in participants with COPD, with the upregulated NEB, TPM1 and TPM2 genes having the largest fold differences. Co‐expression network analysis revealed that two transcript modules were significantly positively associated with the presence of abnormal myofibre proportions. One of these co‐expression modules contained genes classically associated with muscle atrophy, as well as transcripts associated with both type I and type II myofibres, and was enriched for genetic loci associated with bone mineral density.
Conclusions
Our findings indicate that there are significant transcriptional alterations associated with abnormal myofibre proportions in participants with COPD. Transcripts canonically associated with both type I and type IIa fibres were enriched in a co‐expression network associated with abnormal myofibre proportion, suggesting altered transcriptional regulation across multiple fibre types.
Atrial Arrhythmias in COVID-19 Patients Colon, Chad M.; Barrios, James G.; Chiles, Joe W. ...
JACC. Clinical electrophysiology,
09/2020, Letnik:
6, Številka:
9
Journal Article
Acute lung injury associated with COVID-19 contributes significantly to its morbidity and mortality. Though invasive mechanical ventilation is sometimes necessary, the use of high flow nasal oxygen ...may avoid the need for mechanical ventilation in some patients. For patients approaching the limits of high flow nasal oxygen support, addition of inhaled pulmonary vasodilators is becoming more common but little is known about its effects. This is the first descriptive study of a cohort of patients receiving inhaled epoprostenol with high flow nasal oxygen for COVID-19.
We collected clinical data from the first fifty patients to receive inhaled epoprostenol while on high flow nasal oxygen at our institution. We compared the characteristics of patients who did and did not respond to epoprostenol addition.
The 18 patients that did not stabilize or improve following initiation of inhaled epoprostenol had similar rates of invasive mechanical ventilation as those who improved or stabilized (50% vs 56%). Rates of mortality were not significantly different between the two groups (17% and 31%).
In patients with COVID-19 induced hypoxemic respiratory failure, the use of inhaled epoprostenol with high flow nasal oxygen is feasible, but physiologic signs of response were not related to clinical outcomes.
BMI is associated with COPD mortality, but the underlying mechanisms are unclear. The effect of genetic variants aggregated into a polygenic score may elucidate causal mechanisms and predict risk.
To ...examine the associations of genetically predicted BMI with all-cause and cause-specific mortality in COPD.
We developed a polygenic score for BMI (PGS
) and tested for associations of the PGS
with all-cause, respiratory, and cardiovascular mortality in participants with COPD from the COPDGene, ECLIPSE, and Framingham Heart studies. We calculated the difference between measured BMI and PGS-predicted BMI (BMI
) and categorized participants into groups of discordantly low (BMI
< 20
percentile), concordant (BMI
between 20th - 80th percentile), and discordantly high (BMI
> 80th percentile) BMI. We applied Cox models, examined potential non-linear associations of the PGS
and BMI
with mortality, and summarized results with meta-analysis.
We observed significant non-linear associations of measured BMI and BMI
, but not PGS
, with all-cause mortality. In meta-analyses, a one standard deviation increase in the PGS
was associated with an increased hazard for cardiovascular mortality (HR=1.29, 95% CI=1.12-1.49), but not with respiratory or all-cause mortality. Compared to participants with concordant measured and genetically predicted BMI, those with discordantly low BMI had higher mortality risk for all-cause (HR=1.57, CI=1.41-1.74) and respiratory death (HR=2.01, CI=1.61-2.51).
In people with COPD, higher genetically predicted BMI is associated with higher cardiovascular mortality but not respiratory mortality. Individuals with discordantly low BMI have higher all-cause and respiratory mortality compared to those with concordant BMI.
Osteoarthritis is a common progressive joint disease. As no effective medical interventions are available, osteoarthritis often progresses to the end stage, in which only surgical options such as ...total joint replacement are available. A more thorough understanding of genetic influences of osteoarthritis is essential to develop targeted personalized approaches to treatment, ideally long before the end stage is reached. To date, there have been no large multiancestry genetic studies of osteoarthritis. Here, we leveraged the unique resources of 484,374 participants in the Million Veteran Program and UK Biobank to address this gap. Analyses included participants of European, African, Asian and Hispanic descent. We discovered osteoarthritis-associated genetic variation at 10 loci and replicated findings from previous osteoarthritis studies. We also present evidence that some osteoarthritis-associated regions are robust to population ancestry. Drug repurposing analyses revealed enrichment of targets of several medication classes and provide potential insight into the etiology of beneficial effects of antiepileptics on osteoarthritis pain.
Rationale
Coronavirus disease 2019 (COVID‐19) is associated with many clinical manifestations including respiratory failure and cardiovascular compromise.
Objectives
We examine outcomes in critically ...ill individuals with COVID‐19 who develop atrial tachyarrhythmias.
Methods
We collected data from electrocardiograms and the electronic medical record of COVID‐19 positive (COVID+) and negative (COVID−) individuals admitted to our medical intensive care unit between February 29 and June 28, 2020. We compared clinical and demographic characteristics, new onset atrial tachyarrhythmia, hemodynamic compromise following atrial tachyarrhythmia, and in‐hospital mortality in COVID+ versus COVID−. Hemodynamic compromise was defined as having a new or increased vasopressor requirement or the need for direct current cardioversion for hemodynamic instability within 1 hour of atrial tachyarrhythmia onset.
Results
Of 300 individuals included, 200 were COVID+ and 100 were COVID−. Mean age was 60 ± 16 years, 180 (60%) were males, and 170 (57%) were African American. New onset atrial tachyarrhythmia occurred in 16% of COVID+ and 19% of COVID− individuals (P = .51). When compared to COVID− participants without atrial tachyarrhythmia, COVID+ individuals with new onset atrial tachyarrhythmia had higher mortality after multivariable adjustment (OR 5.0, 95% CI 1.9–13.5). New onset atrial tachyarrhythmia was followed by hemodynamic compromise in 18 COVID+ but no COVID− participants (P = .0001). COVID+ individuals with hemodynamic compromise after atrial tachyarrhythmia required increased ventilatory support at the time of atrial tachyarrhythmia onset.
Conclusions
Atrial tachyarrhythmia is associated with increased mortality in critically ill individuals with COVID‐19, especially those mechanically ventilated. Recognition of this could assist with clinical care for individuals with COVID‐19.
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