Safety and efficacy of catheter-directed therapy versus anticoagulation alone in a higher-risk acute pulmonary embolism population.

There is little data comparing safety and efficacy outcomes in patients with pulmonary embolism (PE) receiving catheter directed therapies (CDT) compared to a similar-risk cohort of PE patients receiving anticoagulation alone. 1094 patients with acute PE were studied. CDT and conservatively-managed patients were compared using propensity score matching to assess safety outcomes, which included bleeding and acute kidney injury at 2 and 7 days after PE diagnosis. Efficacy outcomes included change in vital signs over 72 h and in-hospital mortality. PE patients with RV strain who underwent CDT (n = 76) had more bleeding at 2 days (additional 1.04 g/dL loss, 95% CI - 1.48 to - 0.60, p < 0.001) and 7 days (additional 1.36 g/dL loss, 95% CI - 1.88 to - 0.84, p < 0.001) compared to those receiving anticoagulation alone (n = 303). There was a significant increase in creatinine at 2 days (additional 0.22 mg/dL elevation, 95% CI 0.02 to 0.42, p = 0.03), but not at 7 days (additional 0.12 mg/dL elevation, 95% CI - 0.11 to 0.35, p = 0.30). In-hospital mortality for patients receiving CDT versus anticoagulation alone was similar (OR 1.21, 95% CI 0.53 to 2.77; p = 0.65). In patients with baseline abnormal vital signs who received CDT versus anticoagulation alone, heart rate, respiratory rate and oxygen requirement improved significantly faster and to levels closer to normal (p ≤ 0.001). CDT was associated with a small but increased risk of bleeding, but no significant worsening of renal function. CDT may be associated with more rapid improvements in heart rate, respiratory rate, and oxygen requirement.

Performance of the right ventricular outflow tract/aortic diameter as a novel predictor of risk in patients with acute pulmonary embolism.

Right ventricular (RV) enlargement, determined via the ratio of the right to left ventricular diameters (RV/LV) by CT imaging is used to classify the severity of acute pulmonary embolism (PE) and impacts treatment decisions. The RV/LV ratio may be an unreliable marker of RV dysfunction, due in part to the complex RV geometry. This study compared the RV/LV ratio to a novel metric, the ratio of the right ventricular to aortic outflow tract diameters (RVOT/Ao) in patients with acute PE treated with catheter-directed therapies (CDT). RVOT/Ao and RV/LV ratios were measured on CT images from 103 patients who received CDT for acute submassive or massive PE and were compared to RV dysfunction severity determined by transthoracic echocardiography. Ratios and biomarkers on admission were assessed for correlation with invasively-measured hemodynamics [right atrial (RA) pressure, mean pulmonary artery (PA) pressure, cardiac output (CO)]. RVOT/Ao but not RV/LV ratios were increased in patients with moderate or severe RV dysfunction compared to those without RV dysfunction (p < 0.05). Neither ratio showed significant correlation with RA (r = 0.09 vs 0.055, p > 0.05), mean PA pressure (r = 0.167 vs 0.146, p > 0.05), or CO (r = 0.021 vs - 0.183, p > 0.05). proBNP correlated with mean PA pressure (r = 0.377, p < 0.05). The RVOT/Ao ratio may be better at assessing RV dysfunction than the RV/LV ratio in patients presenting with acute PE. Although currently accepted protocols rely on the RV/LV ratio in determining when CDT are of benefit, the RVOT/Ao ratio may be a more useful tool in identifying high risk patients.

An insight into the role of arachidonic acid derived lipid mediators in virus associated pathogenesis and malignancies.

Several studies shed light on the size and diversity of the lipidome, along with its role in physiological and pathological processes in human health. Besides that, lipids also function as important signaling mediators. This review focuses on discussing the role of arachidonic acid (AA) derived lipids as mediators in diseases with special emphasis on viral infections. Structurally, arachidonic acid derived lipids, also referred to as lipid mediators, can be classified into three specific classes: Class 1-eicosanoids derived from arachidonic acid metabolism; Class 2-lysophospholipids consisting of either a glycerol or a sphingosine backbone; Class 3-AA and ω-3 polyunsaturated fatty acid (PUFA) derivatives. Class 1 and 2 lipids are commonly referred to as pro-inflammatory molecules, which are found upregulated in diseases like cancer and viral infection. Class 3 lipids are anti-inflammatory molecules, which could be potentially used in treatment of diseases associated with inflammation. The function of each class has been elucidated as unique and contributory to an overall cellular homeostasis. Current work in this field is promising and will surely usher in a new era of lipid understanding and control not only at the molecular level, but also in terms of holistic patient care.

The Kaposi's sarcoma-associated herpesvirus (KSHV)-induced 5-lipoxygenase-leukotriene B4 cascade plays key roles in KSHV latency, monocyte recruitment, and lipogenesis.

Kaposi's sarcoma-associated herpesvirus (KSHV) is etiologically associated with Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL). KS lesions are characterized by endothelial cells with multiple copies of the latent KSHV episomal genome, lytic replication in a low percentage of infiltrating monocytes, and inflammatory cytokines plus growth factors. We demonstrated that KSHV utilizes inflammatory cyclooxygenase 2/prostaglandin E2 to establish and maintain latency (Sharma-Walia, N., A. G. Paul, V. Bottero, S. Sadagopan, M. V. Veettil, N. Kerur, and B. Chandran, PLoS Pathog 6:e1000777, 2010 [doi:10.1371/journal.ppat.1000777]). Here, we evaluated the role of 5-lipoxygenase (5LO) and its chemotactic metabolite leukotriene B4 (LTB4) in KSHV biology. Abundant staining of 5LO was detected in human KS tissue sections. We observed elevated levels of 5LO and high levels of secretion of LTB4 during primary KSHV infection of endothelial cells and in PEL B cells (BCBL-1 and BC-3 cells). Blocking the 5LO/LTB4 cascade inhibited viral latent ORF73, immunomodulatory K5, viral macrophage inflammatory protein 1 (MIP-1), and viral MIP-2 gene expression, without much effect on lytic switch ORF50, immediate early lytic K8, and viral interferon-regulatory factor 2 gene expression. 5LO inhibition significantly downregulated latent viral Cyclin and latency-associated nuclear antigen 2 levels in PEL cells. 5LO/LTB4 inhibition downregulated TH2-related cytokine secretion, elevated TH1-related cytokine secretion, and reduced human monocyte recruitment, adhesion, and transendothelial migration. 5LO/LTB4 inhibition reduced fatty acid synthase (FASN) promoter activity and its expression. Since FASN, a key enzyme required in lipogenesis, is important in KSHV latency, these findings collectively suggest that 5LO/LTB4 play important roles in KSHV biology and that effective inhibition of the 5LO/LTB4 pathway could potentially be used in treatment to control KS/PEL.

Pulmonary Embolism Complicated by Acute Limb Ischemia Managed by Surgical Pulmonary Embolectomy.

Acute pulmonary embolism (PE) is a manifestation of venous thromboembolic disease with potential serious and life-threatening complications. Management options for acute PE have drastically improved over the last 15 years with the introduction of multidisciplinary pulmonary embolism response teams throughout the world. We present the case of an 18-year-old woman diagnosed with acute PE complicated by near-complete occlusion of her left common femoral artery from a paradoxical embolus in the setting of patent foramen ovale (PFO), managed with surgical pulmonary embolectomy and surgical PFO repair.

Difficulties of Managing Submassive and Massive Pulmonary Embolism in the Era of COVID-19.

Acute pulmonary embolism (PE) is a potentially life-threatening manifestation of venous thromboembolic disease. Severe acute respiratory syndrome-coronavirus-2, a novel coronavirus that causes coronavirus disease-2019 (COVID-19), has been associated with an increased risk of thrombosis. We describe the therapeutic challenges of 3 patients presenting with PE and suspected or confirmed COVID-19. (Level of Difficulty: Beginner.).

Lipoxins exert antiangiogenic and anti-inflammatory effects on Kaposi's sarcoma cells.

Lipoxin A4 (LXA4) is an endogenously produced host molecule with anti-inflammatory resolution effects. Previous studies demonstrated it to be involved in anti-vascular endothelial growth factor (VEGF)-mediated angiogenesis and in a possible anticancer role via interaction with its receptor, lipoxin A 4 receptor (ALXR). Here, we examined the effects of LXA4 and its epimer 15-epi-LXA4 in inhibiting proinflammatory and angiogenic functions in a human Kaposi's sarcoma tumor-derived cell line (KS-IMM). KS-IMM cells expressed increased levels of inflammatory cyclooxygenase 2 (COX-2) and 5-lipoxygenase (5-LO) pathway enzymes when compared with human microvascular dermal endothelial cells (HMVEC-d). KS-IMM cells secreted high levels of prostaglandin E2 (PGE2) and chemotactic leukotriene B4 (LTB4). Treatment with LXA4 or 15-epi-LXA4 effectively reduced the levels of COX-2, 5-LO proteins, and secretion of PGE2 and LTB4 in KS-IMM cells. LXA4 or 15-epi-LXA4 treatment also decreased secretion of proinflammatory interleukin 6 (IL-6) and IL-8 cytokines but induced the secretion of anti-inflammatory IL-10. LXA4 treatment reduced the phosphorylation of VEGF receptor (VEGFR) and ephrin family receptor tyrosine kinases. LXA4 treatment effectively induced dephosphorylation of multiple cellular kinases such as Focal Adhesion Kinase, Protein kinase B, nuclear factor kappa-light-chain-enhancer of activated B cells, and Extracellular signal-regulated kinases (ERK)1/2, and reduced angiogenic factor VEGF-C secretion in KS cells. LX treatment drastically induced the Src-homology 2 domain-containing phosphatase tyrosine (Y542) phosphatase and reduced VEGFR-2 phosphorylation at sites Y1059, Y1175, and Y1212. Treatment of KS-IMM cells with LXA4 resulted in selective localization of VEGFR-2 in nonlipid raft (non-LR) and ALXR to LR fractions. These results demonstrated that LXA4 or 15-epi-LXA4 induce anti-inflammatory and antiangiogenic effects in KS cells and suggest that treatment with LXs is an attractive novel strategy against KS.