Advanced Treatment of Hemodynamically Unstable Acute Pulmonary Embolism and Clinical Follow-up.

High-risk acute pulmonary embolism (PE), defined as acute PE associated with hemodynamic instability, remains a significant contributor to cardiovascular morbidity and mortality in the United States and worldwide. Historically, anticoagulant therapy in addition to systemic thrombolysis has been the mainstays of medical therapy for the majority of patients with high-risk PE. In efforts to reduce the morbidity and mortality, a wide array of interventional and surgical therapies has been developed and employed in the management of these patients. However, the most recent guidelines for the management of PE have reserved the use of these advanced therapies in scenarios where thrombolytic therapy plus anticoagulation are unsuccessful. This is due largely to the lack of prospective, randomized studies in this population. Stemming from this, the approach to treatment of these patients varies widely depending on institutional experience and resources. Furthermore, morbidity and mortality remain unacceptably high in this population, with estimated 30-day mortality of at least 30%. As such, development of a standardized approach to treatment of these patients is paramount to improving outcomes. Early and accurate risk stratification in conjunction with a multidisciplinary team approach in the form of a PE response team is crucial. With the advent of novel therapies for the treatment of acute PE, in addition to the growing availability of and familiarity with mechanical circulatory support systems, such a standardized approach may now be within reach.

Superoxide Dismutase 3 R213G Single-Nucleotide Polymorphism Blocks Murine Bleomycin-Induced Fibrosis and Promotes Resolution of Inflammation.

Loss of extracellular superoxide dismutase 3 (SOD3) contributes to inflammatory and fibrotic lung diseases. The human SOD3 R213G polymorphism decreases matrix binding, redistributing SOD3 from the lung to extracellular fluids, and protects against LPS-induced alveolar inflammation. We used R213G mice expressing a naturally occurring single-nucleotide polymorphism, rs1799895, within the heparin-binding domain of SOD3, which results in an amino acid substitution at position 213 to test the hypothesis that the redistribution of SOD3 into the extracellular fluids would impart protection against bleomycin-induced lung fibrosis and secondary pulmonary hypertension (PH). In R213G mice, SOD3 content and activity was increased in extracellular fluids and decreased in lung at baseline, with greater increases in bronchoalveolar lavage fluid (BALF) SOD3 compared with wild-type mice 3 days after bleomycin. R213G mice developed less fibrosis based on pulmonary mechanics, fibrosis scoring, collagen quantification, and gene expression at 21 days, and less PH by right ventricular systolic pressure and pulmonary arteriole medial wall thickening at 28 days. In wild-type mice, macrophages, lymphocytes, neutrophils, proinflammatory cytokines, and protein increased in BALF on Day 7 and/or 21. In R213G mice, total BALF cell counts increased on Day 7 but resolved by 21 days. At 1 or 3 days, BALF pro- and antiinflammatory cytokines and BALF protein were higher in R213G mice, resolving by 21 days. We conclude that the redistribution of SOD3 as a result of the R213G single-nucleotide polymorphism protects mice from bleomycin-induced fibrosis and secondary PH by improved resolution of alveolar inflammation.

Interstitial macrophage-derived thrombospondin-1 contributes to hypoxia-induced pulmonary hypertension.

AIMS: Transforming growth factor-ß (TGF-ß) signalling is required for chronic hypoxia-induced pulmonary hypertension (PH). The activation of TGF-ß by thrombospondin-1 (TSP-1) contributes to the pathogenesis of hypoxia-induced PH. However, neither the cellular source of pathologic TSP-1 nor the downstream signalling pathway that link activated TGF-ß to PH have been determined. In this study, we hypothesized that circulating monocytes, which are recruited to become interstitial macrophages (IMs), are the major source of TSP-1 in hypoxia-exposed mice, and TSP-1 activates TGF-ß with increased Rho-kinase signalling, causing vasoconstriction. METHODS AND RESULTS: Flow cytometry revealed that a specific subset of IMs is the major source of pathologic TSP-1 in hypoxia. Intravenous depletion and parabiosis experiments demonstrated that these cells are circulating prior to recruitment into the interstitium. Rho-kinase-mediated vasoconstriction was a major downstream target of active TGF-ß. Thbs1 deficient bone marrow (BM) protected against hypoxic-PH by blocking TGF-ß activation and Rho-kinase-mediated vasoconstriction. CONCLUSION: In hypoxia-challenged mice, BM derived and circulating monocytes are recruited to become IMs which express TSP-1, resulting in TGF-ß activation and Rho-kinase-mediated vasoconstriction.