Identification of a Novel EIF2AK Variant and Genetics-Assisted Approach to Diagnosis of Pulmonary Capillary Hemangiomatosis.

Pulmonary capillary hemangiomatosis (PCH) is an uncommon type of pulmonary vascular disease characterized by capillary proliferation and very poor prognosis owing to misdiagnosis and lack of effective therapeutic options. Mutations in the eukaryotic translation initiation factor 2α kinase 4 (EIF2AK4) gene have been reported in pulmonary veno-occlusive disease and PCH. In this report, we present a patient whose diagnosis of PCH was delayed by 2 ½ years despite prior surgical lung biopsy and clinical and laboratory findings suggestive of pulmonary hypertension. Genotyping revealed a novel likely pathogenic variant in the EIF2AK4 gene. Review of surgical lung biopsy performed 2 ½ years prior confirmed PCH histology along with constrictive bronchiolitis.

TGF-ß Promotes Metabolic Reprogramming in Lung Fibroblasts via mTORC1-dependent ATF4 Activation.

Idiopathic pulmonary fibrosis is a fatal interstitial lung disease characterized by the TGF-ß (transforming growth factor-ß)-dependent differentiation of lung fibroblasts into myofibroblasts, which leads to excessive deposition of collagen proteins and progressive scarring. We have previously shown that synthesis of collagen by myofibroblasts requires de novo synthesis of glycine, the most abundant amino acid found in collagen protein. TGF-ß upregulates the expression of the enzymes of the de novo serine-glycine synthesis pathway in lung fibroblasts; however, the transcriptional and signaling regulators of this pathway remain incompletely understood. Here, we demonstrate that TGF-ß promotes accumulation of ATF4 (activating transcription factor 4), which is required for increased expression of the serine-glycine synthesis pathway enzymes in response to TGF-ß. We found that induction of the integrated stress response (ISR) contributes to TGF-ß-induced ATF4 activity; however, the primary driver of ATF4 downstream of TGF-ß is activation of mTORC1 (mTOR Complex 1). TGF-ß activates the PI3K-Akt-mTOR pathway, and inhibition of PI3K prevents activation of downstream signaling and induction of ATF4. Using a panel of mTOR inhibitors, we found that ATF4 activation is dependent on mTORC1, independent of mTORC2. Rapamycin, which incompletely and allosterically inhibits mTORC1, had no effect on TGF-ß-mediated induction of ATF4; however, Rapalink-1, which specifically targets the kinase domain of mTORC1, completely inhibited ATF4 induction and metabolic reprogramming downstream of TGF-ß. Our results provide insight into the mechanisms of metabolic reprogramming in myofibroblasts and clarify contradictory published findings on the role of mTOR inhibition in myofibroblast differentiation.

A novel treatment strategy of new onset atrial fibrillation after cardiac surgery: an observational prospective study.

OBJECTIVE: The aim of this prospective observational study was to evaluate the efficiency of a new escalating treatment strategy with vernakalant, flecainide and electrical cardioversion (EC) in patients with new onset atrial fibrillation (AF) after cardiac surgery. MATERIAL AND METHODS: 24 patients with new onset AF after aortic valve surgery, coronary artery bypass surgery or combined procedures were evaluated in this study. Additional including criteria were age between 18 and 80, duration of AF less than four days, body weight less than 100 kg and no previous treatment with class I or III antiarrhythmic drugs. Exclusion criteria were poor left ventricular ejection fraction (LVEF < 40%) and history of myocardial infarction within 30 days. The patients were divided into converters and non-converters according to their response to combination treatment with vernakalant and flecainide, and the groups were compared. RESULTS: The mean age of the population was 69.6 ± 6.3 years and 26.1% of patients were female. There were no statistically significant differences between the two groups in terms of height, weight, gender distribution, comorbidities, preoperative medication, left ventricular function and left atrium diameter. Interventricular septum (IVS) in the non-converted group was significantly thicker compared to the converted group: 14.0 ± 1.00 vs. 10.40 ± 2.59 mm (p = 0.036). While 14 patients (60.9%) were successfully converted into stable sinus rhythm by pharmacological treatment with vernakalant and flecainide, 9 patients (39.1%, non-converted group) remained in AF. However, seven of them could be converted after additional EC. CONCLUSION: The combination of vernakalant and flecainide improves the conversion rate into a stable sinus rhythm in postcardiotomy patients with new onset AF compared to single drug therapy. Furthermore it might be an excellent precondition for successful EC in patients who are not converted after using both antiarrhtythmic drugs. Furthermore, left ventricular hypertrophy might be a potential negative predictor of successful pharmacological cardioversion.