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 />
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