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2017 Cardiovascular Research Day Abstract Book

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48<br />

Ticagrelor Reduces Inflammation and Mortality in a Murine Model of Sepsis and Reduces<br />

Platelet-Leukocyte Aggregates and Inflammation In Pneumonia<br />

Travis Sexton, PhD 1 • Guoying Zhang, MD 1 • Tracy Macaulay, PharmD 2 • Leigh Ann Callahan, MD 3 •<br />

Richard Charnigo, PhD 4 • Olga Vsevolozhskaya, PhD 4 • Zhenyu Li, PhD 1 • Susan Smyth, MD, PhD 2<br />

1<strong>Cardiovascular</strong> <strong>Research</strong> Center, University of Kentucky • 2 Gill Heart and Vascular Institute,<br />

University of Kentucky • 3 Pulmonary, Critical Care & Sleep Medicine, University of Kentucky •<br />

4Statistics, University of Kentucky<br />

Staff<br />

Background: Sepsis is a life-threatening and dysregulated response to infection that leads to<br />

numerous complications and carries substantial risk of mortality. Pneumonia is one of the most<br />

common precipitators of sepsis. Despite advances in treatment for sepsis and pneumonia,<br />

significant improvements have not been realized and high rates of cardiovascular events remain an<br />

issue. Retrospective analysis of clinical studies suggest anti-platelet therapy may improve outcomes<br />

in patients with pneumonia and sepsis.<br />

Methods: We conducted a human study with pneumonia patients (XANTHIPPE) and a murine study<br />

using a sepsis model to determine the effect of ticagrelor on inflammation, thrombosis, and lung<br />

function.<br />

Results: Among subjects with pneumonia not taking a P2Y12 antagonist at baseline, ticagrelor<br />

lowered the percent of leukocytes with attached platelets 11.75% at 24 hours compared to a<br />

10.90% increase in placebo patients. Furthermore, ticagrelor lowered plasma IL-6 levels 83% at 24<br />

hours compared to minimal change with placebo. Ticagrelor had a transient effect on markers for<br />

NETosis showing a significant 60% spike in MPO-NE complexes at 24 hours followed by a return<br />

toward baseline at 48 hours while placebo had no significant effect. Lung function tests also<br />

numerically improved with ticagrelor, although statistical significance was not achieved. In the<br />

murine sepsis model, disruption of the P2Y12 receptor protected against inflammatory response,<br />

lung permeability, and mortality.<br />

Conclusions: Our findings indicate a mechanistic link between platelets, leukocytes, and lung injury<br />

in settings of pneumonia and sepsis and suggest possible therapeutic approaches to reduce<br />

complications of pneumonia.<br />

64

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