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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:678.)
© 2008 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Role for Staphylococci in Misguided Thrombus Resolution of Chronic Thromboembolic Pulmonary Hypertension

Diana Bonderman; Johannes Jakowitsch; Bassam Redwan; Helga Bergmeister; Maria-Klara Renner; Heidi Panzenböck; Christopher Adlbrecht; Apostolos Georgopoulos; Walter Klepetko; Meinhard Kneussl; Irene M. Lang

From the Departments of Cardiology (D.B., J.J., B.R., M.-K.R., H.P., C.A., I.M.L.), Biomedical Research (H.B.), Infectious Diseases and Chemotherapy (A.G.), and Cardiothoracic Surgery (W.K.) of the Medical University of Vienna, and the Medical Department V (M.K.) of the Wilhelminenspital der Stadt Wien, Austria.

Correspondence to Irene M Lang, MD, Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria. E-mail irene.lang{at}meduniwien.ac.at

Objective— Acute pulmonary emboli usually resolve within 6 months. However, in 0.1% to 3.8% of cases thrombus transforms into fibrous masses. If vascular obstruction is severe, the resulting condition is chronic thromboembolic pulmonary hypertension (CTEPH). Patients who carry ventriculo-atrial (VA-) shunts for the treatment of hydrocephalus and report a history of shunt infection are at an increased risk for CTEPH. Because CTEPH lacks traditional plasmatic risk factors for venous thromboembolism, we hypothesized that delayed thrombus resolution rather than abnormal coagulation is important, and that bacterial infection would be important for this misguidance.

Methods and Results— Human CTEPH thromboemboli were harvested during pulmonary endarterectomy. The effects of Staphylococcal infection on thrombus organization were examined in a murine model of stagnant-flow venous thrombosis. Staphylococcal DNA, but not RNA, was detected in 6 of 7 thrombi from VA shunt carriers. In the mouse model, staphylococcal infection delayed thrombus resolution in parallel with upregulation of transforming growth factor (TGF) beta and connective tissue growth factor.

Conclusions— In the present work, we propose a mechanism of disease demonstrating that infection with Staphylococci enhances fibrotic vascular remodeling after thrombosis, resulting in misguided thrombus resolution. Thrombus infection appears to be a trigger in the evolution of CTEPH.

Mechanisms underlying thrombus persistence in chronic thromboembolic pulmonary hypertension (CTEPH) are unknown. In the present work, we analyzed human surgical CTEPH specimens and experimental murine venous thrombi. Our findings suggest a pivotal role for bacterial infection in the fibrotic organization process and persistence of thrombotic material in CTEPH.

Key Words: pulmonary embolism • thrombus resolution • infection

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