Pulmonary Embolism: Pathophysiologic Insights for New Treatment Trials
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EDITORIAL
Pulmonary Embolism: Pathophysiologic Insights for New Treatment Trials Editorial to: “Doxycycline Prevents Acute Pulmonary Embolism-Induced Mortality and Right Ventricular Deformation in Rats” by Stefany B.A. Cau et al. Kenneth E. Wood
Published online: 15 May 2013 # Springer Science+Business Media New York 2013
Despite dramatic advances in prophylactic and diagnostic modalities for pulmonary embolism (PE), treatment has not meaningfully changed over the past three decades; hemodynamically stable patients receive heparin and hemodynamically unstable patients are recommended to undergo medical embolectomy with thrombolytic therapy or when contraindicated, catheter or surgical embolectomy. Albeit the mortality for hemodynamically stable patients is low, the mortality for patients with either right ventricular dysfunction (RVD) or hemodynamic instability remains unacceptably high, necessitating a search for new innovative treatment strategies. In this issue of Cardiovascular Drugs and Therapy, Cau et al. present data and a cogent argument for initiating clinical trials of novel treatment modalities for PE [1]. Therapeutic advances are often predicated upon similar advances in the understanding of disease state pathophysiology. RVD has traditionally been attributed to the combination of acute PE induced pressure overload, which is a function of both mechanical obstruction and vasoconstrictive forces in combination with RV ischemia. The latter occurs consequent to PE induced increases in RV wall stress and a loss of the RV coronary perfusion pressure gradient which occurs when mean arterial pressure decreases and RV end-diastolic pressure increases in hemodynamically unstable patients. Recent reports suggest that the PE induced pressure load produces sacromere stretch resulting in an RV inflammatory state that further jeopardizes RV function [2]. Human autopsy series of fatal PE cases with large clot K. E. Wood (*) Geisinger Medical Center, 100 N Academy Avenue, Danville, PA 17822, USA e-mail: [email protected]
burden have identified necroinflammatory changes in histologic sections of the RV myocardium. Inflammatory infiltrate consisting of macrophages, T-cells and neutrophils with myocyte necrosis was recognized in association with the preceding inflammatory foci in 64 % and a 6.1 fold increase in RV fibrosis was noted [3, 4]. In animal models, RV myocardial neutrophilic infiltration is reported to contribute to RV damage and occurs early (6–18 h) after the event [5], whereas macrophage infiltration persists and is biphasic. Initially macrophages with an MI phenotype predominate (inflammatory), whereas those with an M2 phenotype (healing) are prominent at 6 weeks [6]. Similar finding of a neutrophil and macrophage mediated inflammatory response with accompanying intimal hyperplasia have been reported in the pulmonary artery after PE [7]. Attenuation of the inflammatory response and prevention of RV dysfunction with anti-neutrophilic antibodies and inhibition of chemokine CINC-1 (cytokine-induced neutroph
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