Hypercapnia alters stroma-derived Wnt production to limit ß-catenin signaling and proliferation in AT2 cells.

Persistent symptoms and radiographic abnormalities suggestive of failed lung repair are among the most common symptoms in patients with COVID-19 after hospital discharge. In mechanically ventilated patients with acute respiratory distress syndrome (ARDS) secondary to SARS-CoV-2 pneumonia, low tidal volumes to reduce ventilator-induced lung injury necessarily elevate blood CO2 levels, often leading to hypercapnia. The role of hypercapnia on lung repair after injury is not completely understood. Here - using a mouse model of hypercapnia exposure, cell lineage tracing, spatial transcriptomics, and 3D cultures - we show that hypercapnia limits ß-catenin signaling in alveolar type II (AT2) cells, leading to their reduced proliferative capacity. Hypercapnia alters expression of major Wnts in PDGFRα+ fibroblasts from those maintaining AT2 progenitor activity toward those that antagonize ß-catenin signaling, thereby limiting progenitor function. Constitutive activation of ß-catenin signaling in AT2 cells or treatment of organoid cultures with recombinant WNT3A protein bypasses the inhibitory effects of hypercapnia. Inhibition of AT2 proliferation in patients with hypercapnia may contribute to impaired lung repair after injury, preventing sealing of the epithelial barrier and increasing lung flooding, ventilator dependency, and mortality.

Infected chylopericardium: An unexpected cause of cardiac tamponade.

A 22-year-old immunocompetent female with a history of small pericardial effusion while infant presented with fever and hemodynamic collapse 4 days after facial trauma. She was found to have cardiac tamponade secondary to infected chylopericardium from bacterial translocation. We report this very unusual case and review of the literature on chylopericardium infections.

Effect of Sacubitril/Valsartan on Neurocognitive Function: Current Status and Future Directions.

Sacubitril/valsartan is a new medication approved for the treatment of heart failure with reduced ejection fraction. While the drug failed to meet the primary endpoint in patients with heart failure with preserved ejection fraction in the PARAGON-HF trial, improvements were noted in several secondary endpoints. Valsartan is an angiotensin receptor blocker and sacubitril is a neprilysin inhibitor. Neprilysin is postulated to have a role in the degradation of beta-amyloid in the brain; therefore, sacubitril could theoretically increase beta-amyloid plaque deposition in the brain and potentially increase the risk of Alzheimer's disease. Although pre-clinical and clinical studies have shown promising safety results, those studies have been heavily criticized for short monitoring time and targeted populations. In accordance with the requirements of the US Food and drug Administration (FDA), the ongoing Prospective Evaluation of Cognitive Function in Heart Failure: Efficacy and Safety of Entresto compared to Valsartan on Cognitive Function in Patients with Chronic Heart Failure and Preserved Ejection Fraction (PERSPECTIVE; NCT02884206) multicenter, randomized, double-blinded trial is assessing the long-term neurocognitive effects and safety of sacubitril/valsartan, and results are expected in early 2022.

An Unexpected Complication During Transaortic Valve Replacement.

Venous air embolism is a rare procedural complication with devastating consequences depending on the amount of air introduced into the body. Herein we present a case of transaortic valve replacement complicated with air embolism leading to cardiopulmonary collapse successfully treated with mechanical circulatory support.

Large-bore arterial access in the era of structural cardiovascular disease.

Over the last two decades, the medical community witnessed an outstanding and accelerated development on minimally invasive therapies. The definition of what constitutes large bore access is subject to discussion, however within the field it is generally accepted to reflect a catheter diameter exceeding 8-French. We sought in this review to explore the evolution, characteristics and vascular compatibility of the current commercially available devices, analyze the devices along with access site-specific complications rates and finally review the present methods for percutaneous vascular closure.

A presentation of E-Cigarette vaping associated lung injury (EVALI) caused by THC-Containing electronic smoking device.

Several cases have recently been reported concerning the development of a syndrome of acute lung injury associated with the use of electronic cigarettes, leading to respiratory failure and several deaths. We present a case of a young veteran who presented with e-cigarette vaping associated lung injury (EVALI) to a primary care clinic and who required subsequent inpatient admission and home oxygen therapy after discharge. The patient afterwards improved after a three-month course of steroids and cessation of THC-containing electronic cigarettes, consistent with previously reported cases. Furthermore, evidence on bronchoscopy and biopsy demonstrated intracellular lipid droplets in the patient's macrophages. This outpatient case of EVALI prompts primary care providers to raise suspicion of this condition, and enquire about the use of e-cigarettes, particularly THC-containing vaping products. Furthermore, in the setting of the COVID-19 pandemic, similar clinical and radiographic presentations between COVID-19 and EVALI can be seen.

Elevated CO2 Levels Delay Skeletal Muscle Repair by Increasing Fatty Acid Oxidation.

Muscle dysfunction often occurs in patients with chronic obstructive pulmonary diseases (COPD) and affects ventilatory and non-ventilatory skeletal muscles. We have previously reported that hypercapnia (elevated CO2 levels) causes muscle atrophy through the activation of the AMPKα2-FoxO3a-MuRF1 pathway. In the present study, we investigated the effect of normoxic hypercapnia on skeletal muscle regeneration. We found that mouse C2C12 myoblasts exposed to elevated CO2 levels had decreased fusion index compared to myoblasts exposed to normal CO2. Metabolic analyses of C2C12 myoblasts exposed to high CO2 showed increased oxidative phosphorylation due to increased fatty acid oxidation. We utilized the cardiotoxin-induced muscle injury model in mice exposed to normoxia and 10% CO2 for 21 days and observed that muscle regeneration was delayed. High CO2-delayed differentiation in both mouse C2C12 myoblasts and skeletal muscle after injury and was restored to control levels when cells or mice were treated with a carnitine palmitoyltransfearse-1 (CPT1) inhibitor. Taken together, our data suggest that hypercapnia leads to changes in the metabolic activity of skeletal muscle cells, which results in impaired muscle regeneration and recovery after injury.

Cardiac glycosides decrease influenza virus replication by inhibiting cell protein translational machinery.

Cardiac glycosides (CGs) are used primarily for cardiac failure and have been reported to have other effects, including inhibition of viral replication. Here we set out to study mechanisms by which CGs as inhibitors of the Na-K-ATPase decrease influenza A virus (IAV) replication in the lungs. We found that CGs inhibit influenza virus replication in alveolar epithelial cells by decreasing intracellular potassium, which in turn inhibits protein translation, independently of viral entry, mRNA transcription, and protein degradation. These effects were independent of the Src signaling pathway and intracellular calcium concentration changes. We found that short-term treatment with ouabain prevented IAV replication without cytotoxicity. Rodents express a Na-K-ATPase-α1 resistant to CGs. Thus we utilized Na-K-ATPase-α1-sensitive mice, infected them with high doses of influenza virus, and observed a modest survival benefit when treated with ouabain. In summary, we provide evidence that the inhibition of the Na-K-ATPase by CGs decreases influenza A viral replication by modulating the cell protein translational machinery and results in a modest survival benefit in mice.