Integrative multiomics analysis of neointima proliferation in human saphenous vein: implications for bypass graft disease.

Introduction: Human saphenous veins (SV) are widely used as grafts in coronary artery bypass (CABG) surgery but often fail due to neointima proliferation (NP). NP involves complex interplay between vascular smooth muscle cells (VSMC) and fibroblasts. Little is known, however, regarding the transcriptomic and proteomic dynamics of NP. Here, we performed multi-omics analysis in an ex vivo tissue culture model of NP in human SV procured for CABG surgery. Methods and results: Histological examination demonstrated significant elastin degradation and NP (indicated by increased neointima area and neointima/media ratio) in SV subjected to tissue culture. Analysis of data from 73 patients suggest that the process of SV adaptation and NP may differ according to sex and body mass index. RNA sequencing confirmed upregulation of pro-inflammatory and proliferation-related genes during NP and identified novel processes, including increased cellular stress and DNA damage responses, which may reflect tissue trauma associated with SV harvesting. Proteomic analysis identified upregulated extracellular matrix-related and coagulation/thrombosis proteins and downregulated metabolic proteins. Spatial transcriptomics detected transdifferentiating VSMC in the intima on the day of harvesting and highlighted dynamic alterations in fibroblast and VSMC phenotype and behavior during NP. Specifically, we identified new cell subpopulations contributing to NP, including SPP1 + , LGALS3 + VSMC and MMP2 + , MMP14 + fibroblasts. Conclusion: Dynamic alterations of gene and protein expression occur during NP in human SV. Identification of the human-specific molecular and cellular mechanisms may provide novel insight into SV bypass graft disease.

Hepatocyte-specific disruption of soluble epoxide hydrolase attenuates abdominal aortic aneurysm formation: novel role of the liver in aneurysm pathogenesis.

Introduction: Inflammation is a key pathogenic feature of abdominal aortic aneurysm (AAA). Soluble epoxide hydrolase (sEH) is a pro-inflammatory enzyme that converts cytochrome P450-derived epoxides of fatty acids to the corresponding diols, and pharmacological inhibition of sEH prevented AAA formation. Both cytochrome P450 enzymes and sEH are highly expressed in the liver. Here, we investigated the role of hepatic sEH in AAA using a selective pharmacological inhibitor of sEH and hepatocyte-specific Ephx2 (which encodes sEH gene) knockout (KO) mice in two models of AAA [angiotensin II (AngII) infusion and calcium chloride (CaCl 2 ) application]. Methods and results: sEH expression and activity were strikingly higher in mouse liver compared with aorta and further increased the context of AAA, in conjunction with elevated expression of the transcription factor Sp1 and the epigenetic regulator Jarid1b, which have been reported to positively regulate sEH expression. Pharmacological sEH inhibition, or liver-specific sEH disruption, achieved by crossing sEH floxed mice with albumin-cre mice, prevented AAA formation in both models, concomitant with reduced expression of hepatic sEH as well as complement factor 3 (C3) and serum amyloid A (SAA), liver-derived factors linked to AAA formation. Moreover, sEH antagonism markedly reduced C3 and SAA protein accumulation in the aortic wall. Co-incubation of liver ex vivo with aneurysm-prone aorta resulted in induction of sEH in the liver, concomitant with upregulation of Sp1, Jarid1b, C3 and SAA gene expression, suggesting that the aneurysm-prone aorta secretes factors that activate sEH and downstream inflammatory signaling in the liver. Using an unbiased proteomic approach, we identified a number of dysregulated proteins [ e.g., plastin-2, galectin-3 (gal-3), cathepsin S] released by aneurysm-prone aorta as potential candidate mediators of hepatic sEH induction. Conclusion: We provide the first direct evidence of the liver's role in orchestrating AAA via the enzyme sEH. These findings not only provide novel insight into AAA pathogenesis, but they have potentially important implications with regard to developing effective medical therapies for AAA.

Pleural Endometriosis: An Atypical Cause of Hemoptysis.

Endometriosis is a benign, inflammatory disease characterized by the presence of dysfunctional endometrial tissue outside the uterus. Typically confined to the pelvis, endometriosis is frequently associated with pain, dysmenorrhea, and infertility. Rarely, endometrial tissue has been documented to implant within the lung parenchyma and involve both parietal and visceral pleura of the thorax. Manifestations of thoracic endometriosis include catamenial pneumothorax, hemothorax, and hemoptysis. We present a case of thoracic endometriosis in a 43-year-old female who was found to have a loculated pleural effusion with an associated pleural nodule after gynecologic surgery. The patient underwent thoracotomy, decortication, and nodule excision. Pathology of the pleural nodule showed evidence of endometrial tissue within the parietal pleural. Thoracic endometriosis is a medical problem that is frequently undiagnosed and encountered by the practicing surgeon. Early diagnosis reduces both disease progression and late complications, allowing for early initiation of appropriate medical and surgical therapy.

Paradoxical Emboli as a Cause of Stroke.

Cerebrovascular embolic strokes are responsible for significant morbidity. 40% of strokes have no inciting cause and are thought to be the result of paradoxical emboli (PDE) passing into the arterial system by way of intra-cardiac or pulmonary vascular defects. We present two cases of PDE resulting in acute ischemic events. A 63-year-old female presented for evaluation of left upper extremity numbness. Imaging was significant for an acute right middle cerebral artery infarct and evidence of a large saddle pulmonary embolism. The patient's stroke was postulated to have been secondary to a patent foramen ovale (PFO). An 87-year-old male presented for evaluation of chest pain. The patient underwent three-vessel CABG and experienced an acute left hemispheric stroke post-operatively. Transthoracic echocardiogram demonstrated a biatrial thrombus transversing a PFO and was postulated to have been the cause. The prompt diagnosis of PDE is paramount to preventing the morbidity associated with repeat ischemic events.

Successful Cesarean Section in a COVID-19 Patient on Extracorporeal Membrane Oxygenation (ECMO).

The pandemic of COVID-19-related respiratory failure has increased utilization of ECMO in diverse patient populations. There are limited published reports of ECMO use in pregnancy, and reports of successful delivery of the fetus with survival of the mother on ECMO are exceptionally rare. We present a case of Cesarean section while on ECMO for COVID-19-related respiratory failure with survival of both mother and infant.A 37-year-old pregnant female presented with dyspnea following a positive COVID-19 test. D-Dimer and CRP were elevated and chest radiography was consistent with COVID-19 pneumonia. Her respiratory status rapidly decompensated-requiring endotracheal intubation within 6 hours of presentation, and ultimately veno-venous ECMO cannulation. Three days later, fetal heart rate decelerations prompted emergent caesarean delivery. The infant was transferred to the NICU and progressed well. The patient improved and she was decannulated on hospital day 22 (ECMO day 15) before discharge to rehab on hospital day 49.In this case, ECMO allowed survival of both mother and infant in an otherwise non-survivable respiratory failure. Consistent with existing reports, we believe ECMO is a viable strategy for refractory respiratory failure in the pregnant patient.