Abstract 321: XPro1595 Reduces the Severity of Post Resuscitation Myocardial Dysfunction in a Rat Model of Cardiac Arrest

Abstract

Introduction: Systemic inflammation plays a major role in the pathophysiology of myocardial dysfunction following cardiac arrest (CA), even after successful cardiopulmonary resuscitation (CPR). A major contributor is pro-inflammatory cytokine Tumor Necrosis Factor (TNF), which induces cardiac hypertrophy, cardiac dilation and reduced heart function. TNF activates two receptors: TNF receptor 1 (TNFR1) induces detrimental cardiac pathology (impedes heart function and reduces survival); and TNF receptor 2 (TNFR2) promotes heart health (improves heart function and survival). This distinction is important because traditional TNF inhibitors (e.g. Etanercept and Infliximab) block the activity of both TNF receptors, causing heart failure. In contrast, selectively inhibiting TNFR1 will likely improve heart function and animal survival following CA. XPro1595 is a novel biologic that selectively inhibits the soluble form of TNF from activating detrimental TNFR1, without interfering with the transmembrane form of TNF to active beneficial TNFR2. Hypothesis: XPro1595 selectively inhibits the activity of TNFR1 to reduce myocardial dysfunction following CA. Methods: Adult Sprague Dawley rats were anaesthetized and underwent CA (8 min VF, then 8 min CPR), or sham surgery (omit VF and CPR), with or without XPro1595 (10 mg/kg, I.V.), or vehicle treatment 10 min later. Ejection fraction (EF), cardiac index (CI), and myocardial performance index (MPI) were measured at baseline, and 2 and 4 hrs after ROSC. Sham + vehicle (n=5), CA + vehicle (n=5), CA + XPro1595 (n=5). Results: XPro1595 treatment significantly improved heart function following CA. For all parameters measured, XPro1595-treated CA animals showed significant improvement above vehicle-treated CA animals, but did not reach sham-operated levels (Fig. 1). Conclusions: Using XPro1595 to selectively inhibit soluble TNF from activating TNFR1 improves heart function following CA.