Problem: Congenital heart defects often require surgical repair with cardiopulmonary bypass (CPB). Unfortunately CPB causes systemic derangements that can lead to organ injury or death. Markers of injury risk and interventions to improve outcomes from CPB related-injury are limited. Alkaline phosphatase (AP) may protect against CPB injury through multiple mechanisms. AP activity, however, falls substantially following infant CPB and low post-operative AP activity is independently associated with increased post-operative support requirements. Additional research is needed to understand the role of AP during infant CPB, its use as a marker of post-operative risk, and its potential value as a therapeutic agent. This K23 project combines the study of low AP activity after infant CPB with career development aims for Dr. Davidson, ultimately preparing Dr. Davidson for future independent research in AP therapy aimed at improving outcomes after infant CPB. Overall Hypothesis: Low AP activity after infant CPB increases the risk of inflammation, organ injury, and cardiac arrest, mechanical circulatory support, or death, in part due to a decreased ability to convert harmful extracellular adenine nucleotides to adenosine in the setting of CPB induced ischemia-reperfusion injury. Proposal: Observational cohort study of 120 infants d120 days of age undergoing CPB with measurement of total and isoform specific AP activity before, during, and after CPB. Primary outcome: risk of cardiac arrest, mechanical circulatory support, or death in infants with AP activity d80 U/L versus >80 U/L. Secondary outcomes: post-operative support requirements, biomarkers of organ injury/inflammation. Pre and post-CPB serum samples will be analyzed for their ability to convert adenosine monophosphate to adenosine. Specific Aims of the Proposed Research Project: 1) Clinical: Demonstrate a higher risk of death, cardiac arrest, or mechanical circulatory support, endotoxemia, and inflammation/organ injury in post-CPB infants with low AP activity. 2) Kinetics: Measure AP isoform-specific activity loss, recovery, and mechanism following CPB. 3) Mechanism: Determine the differential capacity of AP in pre and post-CPB serum to convert adenosine monophosphate to adenosine and demonstrate the ability to rescue this function with exogenous AP. Specific Aims of the Career Development Plan: 1) Clinical Research Aim: Improve clinical research skills to make the transition to independent research. 2) Translational Research Aim: Improve skills in basic/translational study design, techniques, and analysis. 3) Scholarly Aim: Completion of the Masters of Clinical Science program and initiation of the Ph.D. program. Potential Impact: The results of this study will fully establish AP as a novel predictive biomarker in this population, improve the understanding of the physiologic role of AP after infant CPB, and help direct future studies of AP treatment aimed at improving outcomes after pediatric cardiac surgery.

K23HL123634

2014-07-21

2019-06-30