Circulating microRNAs (c-miRNAs), plasma-based noncoding RNAs that control posttranscriptional gene expression, mediate processes that underlie phenotypical plasticity to exercise. The relationship and biological relevance between c-miRNA expression and variable dose exercise exposure remains uncertain. We hypothesized that certain c-miRNAs respond to changes in exercise intensity and/or duration in a dose-dependent fashion. Muscle release of such c-miRNAs may then deplete intracellular stores, thus facilitating gene reprogramming and exercise adaptation. To address these hypotheses, healthy men participated in variable intensity ( n = 12, 30 × 1 min at 6, 7, and 8 miles/h, order randomized) and variable duration ( n = 14, 7 × 1 mile/h for 30, 60, and 90 min, order randomized) treadmill-running protocols. Muscle-enriched c-miRNAs (i.e., miRNA-1 and miRNA-133a) and others with known relevance to exercise were measured before and after exercise. c-miRNA responses followed three profiles: 1) nonresponsive (miRNA-21 and miRNA-210), 2) responsive to exercise at some threshold but without dose dependence (miRNA-24 and miRNA-146a), and 3) responsive to exercise with dose dependence to increasing intensity (miRNA-1) or duration (miRNA-133a and miRNA-222). We also studied aerobic exercise-trained mice, comparing control, low-intensity (0.5 km/h), or high-intensity (1 km/h) treadmill-running protocols over 4 wk. In high- but not low-intensity-trained mice, we found increased plasma c-miR-133a along with decreased intracellular miRNA-133a and increased serum response factor, a known miR-133a target gene, in muscle. Characterization of c-miRNAs that are dose responsive to exercise in humans and mice supports the notion that they directly mediate physiological adaptation to exercise, potentially through depletion of intracellular stores of muscle-specific miRNAs. NEW & NOTEWORTHY In this study of humans and mice, we define circulating microRNAs in plasma that are dose responsive to exercise. Our data support the notion that these microRNAs mediate physiological adaptation to exercise potentially through depletion of intracellular stores of muscle-specific microRNAs and releasing their inhibitory effects on target gene expression.

Pulmonary hypertension (PH), a heterogeneous vascular disease, consists of subtypes with overlapping clinical phenotypes. MicroRNAs, small non-coding RNAs that negatively regulate gene expression, have emerged as regulators of PH pathogenesis. The muscle-specific micro RNA (miR)-204 is known to be depleted in diseased pulmonary artery smooth muscle cells (PASMCs), furthering proliferation and promoting PH. Alterations of circulating plasma miR-204 across the trans-pulmonary vascular bed might provide mechanistic insights into the observed intracellular depletion and may help distinguish PH subtypes. MiR-204 levels were quantified at sequential pulmonary vasculature sites in 91 patients with World Health Organization (WHO) Group I pulmonary arterial hypertension (PAH) (n = 47), Group II PH (n = 22), or no PH (n = 22). Blood from the right atrium/superior vena cava, pulmonary artery, and pulmonary capillary wedge was collected. Peripheral blood mononuclear cells (PBMCs) were isolated (n = 5/group). Excretion of miR-204 by PAH-PASMCs was also quantified in vitro. In Group I patients only, miR-204 concentration increased sequentially along the pulmonary vasculature (log fold-change slope = 0.22 [95% CI = 0.06–0.37], P = 0.008). PBMCs revealed insignificant miR-204 variations among PH groups ( P = 0.12). Cultured PAH-PAMSCs displayed a decrease of intracellular miR-204 ( P = 0.0004), and a converse increase of extracellular miR-204 ( P = 0.0018) versus control. The stepwise elevation of circulating miR-204 across the pulmonary vasculature in Group I, but not Group II, PH indicates differences in muscle-specific pathobiology between subtypes. Considering the known importance of miR-204 in PH, these findings may suggest pathologic excretion of miR-204 in Group I PAH by PASMCs, thereby accounting for decreased intracellular miR-204 concentration.

Pulmonary arterial hypertension (PAH) refers to a set of heterogeneous vascular diseases defined by elevation of pulmonary arterial pressure (PAP) and pulmonary vascular resistance (PVR), leading to right ventricular (RV) remodeling and often death. Early increases in pulmonary artery stiffness in PAH drive pathogenic alterations of pulmonary arterial endothelial cells (PAECs), leading to vascular remodeling. Dysregulation of microRNAs can drive PAEC dysfunction. However, the role of vascular stiffness in regulating pathogenic microRNAs in PAH is incompletely understood. Here, we demonstrated that extracellular matrix (ECM) stiffening downregulated miR-7 levels in PAECs. The RNA binding protein Quaking (QKI) has been implicated in the biogenesis of miR-7. Correspondingly, we found that ECM stiffness up-regulated QKI, and QKI knockdown led to increased miR-7. Downstream of the QKI-miR-7 axis, the serine and arginine rich splicing factor 1 (SRSF1) was identified as a direct target of miR-7. Correspondingly, SRSF1 was reciprocally up-regulated in PAECs exposed to stiff ECM and was negatively correlated with miR-7. Decreased miR-7 and increased QKI and SRSF1 were observed in lungs from PAH patients and PAH rats exposed to SU5416/hypoxia. Lastly, miR-7 upregulation inhibited human PAEC migration, while forced SRSF1 expression reversed this phenotype, proving that miR-7 depended upon SRSF1 to control migration. In aggregate, these results define the QKI-miR-7-SRSF1 axis as a mechanosensitive mechanism linking pulmonary arterial vascular stiffness to pathogenic endothelial function. These findings emphasize implications relevant to PAH and suggest the potential benefit of developing therapies that target this miRNA-dependent axis in PAH.

Objectives/Hypothesis: There is currently no standard of care in terms of anesthesia modality for patients receiving upper airway surgery with comorbid obstructive sleep apnea (OSA). Although both total intravenous anesthesia (TIVA) and volatile gas anesthesia are commonly utilized in ambulatory otolaryngology surgery, it is currently unclear if there are any advantages with one modality over the other. We hypothesize that patients receiving upper airway surgery with comorbid OSA will have quicker recovery times with TIVA. Study Design: Retrospective chart review from January 2019 to December 2019. Methods: All patients aged 18 and older receiving upper airway surgery (upper airway stimulation, nasal surgery, modified uvulopalatopharyngoplasty) were included. Patients were excluded when there was incomplete or missing data in the electronic medical record. Results: Eighty-six patients received gas anesthesia and 62 patients received TIVA. Phase I recovery times were significantly reduced by surgery and by severity of OSA: nasal surgery, upper airway stimulation, and modified uvulopalatopharyngoplasty had a reduction of 35.5 minutes (P < .001), 42.5 minutes (P < .001), and 36 minutes (P = .022), respectively. In terms of severity, mild, moderate, and severe OSA had reductions of 23.5 minutes (P = .004), 52 minutes (P = .004), and 47 minutes (P < .001), respectively. The severity of OSA generally correlated with increased time spent in Phase I: as severity increased, Phase I time increased by 16.8 minutes for the gas cohort (P < .001), whereas in the TIVA cohort, it increased only 4.3 minutes (P = .489). Conclusion: Patients having upper airway surgery with comorbid OSA that received TIVA (propofol and remifentanil) spent significantly less time in Phase I and the recovery room overall compared to those receiving volatile gas anesthesia in the form of sevoflurane, and this correlated with the severity of OSA.

Objective(s): Upper airway stimulator (UAS) placement is a treatment for obstructive sleep apnea (OSA) with few complications and low morbidity. UAS placement has traditionally been performed using a three-incision approach, however, it has been implanted using a two-incision approach. This approach could significantly decrease operation time without a difference in postoperative complications, demonstrating its safety and feasibility for UAS placement. The objective was to assess operative time and complication rate in the two-incision approach for UAS placement compared to the three-incision approach.Study Design: Retrospectively reviewed. Methods: Patients who underwent UAS placement using the two-or three-incision approach at a single academic institution from November 2014 to June 2021 were retrospectively reviewed. The two-incision approach did not include the incision at the mid-axillary line. Main outcome measures included operation time and complication rates.Results: Three-hundred forty-eight patients underwent UAS placement. The three-incision approach demonstrated an average operation time of 143.3 minutes whereas the two-incision approach averaged 129.4 minutes (P < .001). There was no significant difference in rate of postoperative complications between the two-and three-incision cohorts including pneumothorax (0% vs. 0.4%, P > .99), patient-reported discomfort (5.6% vs. 6.5%, P > .99), activity restriction (0% vs. 1.4%, P > .50), and incisional pain (0.0% vs. 1.0%, P > .99). No patients experienced incision site bleeding or infection. The two-incision approach was associated with decreased rate of revision surgery (0.0% vs. 5.4%, P = .048). Conclusion:The UAS two-incision approach proved to have a significantly shorter operative time without an increase in complications as compared to the three-incision approach. This approach is a safe and feasible option.

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Objectives To compare cost and time spent in surgical and postoperative courses in patients with obstructive sleep apnea (OSA) undergoing surgery with either total intravenous anesthesia (TIVA) or inhalational anesthesia. Study Design Retrospective chart review. Methods Retrospective review on patients undergoing surgery for OSA under general anesthesia from January 2019 to October 2020. Cost per service was acquired for the day of surgery. Results A total of 230 patients were included: 95 received TIVA; 135 received inhalation anesthesia. Total cost was significantly higher in the TIVA nasal surgery group by $286 (P = .035). TIVA produced significantly higher pharmacy and operating room costs across all surgeries and OSA severities. These increased costs were offset by significantly lower supply costs in upper airway stimulator (UAS, −$419.50; P = .007) and uvulopalatopharyngoplasty (UPPP, −$115.16; P = .015) patients receiving TIVA. In the TIVA cohort, there was a trend toward lower recovery room costs after UAS (−$111.09; P = .063) and nasal surgery (−$64.45; P = .096) and anesthesia costs after nasal surgery (−$36.67; P = .054). Total recovery time was reduced by 18 minutes (P = .004) for nasal surgery, 25 minutes (P = .043) for UAS, and 27 minutes (P = .147) for UPPP patients receiving TIVA. Conclusion When used in an outpatient setting for patients with OSA, TIVA adds to pharmacy and operating room costs, but this is usually offset by lower supply, anesthesia, and recovery room costs. We found decreased recovery times in the TIVA cohort. TIVA has proven benefits in patient outcomes and can be cost‐effective in OSA surgery. Level of Evidence 3 Laryngoscope, 132:1487–1494, 2022