Sphingolipids as Markers of Cardiac Ischemia

Lpath Therapeutics, Inc., San Diego CA

Investigators

Abstract

DESCRIPTION (provided by applicant): It has recently been appreciated that coronary artery disease (CAD) is aggravated by the inflammatory response. It has been suggested that sphingolipid signaling molecules are mediators of inflammation, particularly in response to pre-inflammatory cytokines such as TNFalpha and IL2. In addition to the putative release of these molecules as part of the inflammatory response, it is possible that sphingolipids are produced as a consequence of ischemia itself, since recent studies demonstrate increased sphingolipid production by ischemic heart cells. Thus, we reasoned that sphingolipids produced either by the inflammatory or ischemic processes could indicate myocardial ischemia. Accordingly, we have designed a trial with the aim of showing that the concentrations of serum sphingolipids such as sphingosine-1-phosphate (S1P) rise in patients undergoing a stress test whose nuclear imaging results indicate exercise-induced ischemia. Serial blood samples will be obtained before and several times after treadmill testing for the determination of serum sphingolipids. We will compare serum sphingolipid levels with inflammatory biomarkers, CRP and TNFalpha, and standard assessments of ischemia, including positive electrocardiographic and nuclear imaging. Ischemia-negative patients are those with a negative ETT and negative nuclear scans. We will evaluate the specificity and sensitivity of our putative ischemic markers with active ischemia. An additional aim of this Phase I SBIR is to develop monoclonal antibodies suitable for serum testing of patients suspected of cardiac ischemia. The anticipated success will prepare us for a Phase II application in which we will develop the commercial test platform suitable for both clinical laboratory instruments and rapid point-of-care testing. We also intend to conduct follow-on clinical trials of emergency room patients suspected of AMI to determine if serum sphingolipids may be useful in triaging chest pain patients. It is also possible that sphingolipids contribute to the pathophysiology of acute coronary syndrome and that they are responsible for the poor outcomes observed in acute coronary syndrome patients who have elevated serum levels of TNFalpha.