Alkaline Phosphatase in Infant Cardiopulmonary Bypass: Kinetics and Relationship

描述（由申请人提供）：问题：先天性心脏缺陷通常需要体外循环手术修复。不幸的是，CPB引起全身紊乱，可导致器官损伤或死亡。损伤风险的标志和改善CPB相关损伤结果的干预措施是有限的。碱性磷酸酶（AP）可能通过多种机制对CPB损伤起保护作用。然而，在婴儿CPB后，AP活性显著下降，术后AP活性低与术后支持需求增加独立相关。需要进一步的研究来了解AP在婴儿CPB中的作用，它作为术后风险标志的用途，以及它作为治疗药物的潜在价值。这个K23项目将婴儿CPB后低AP活性的研究与Davidson博士的职业发展目标结合起来，最终为Davidson博士未来独立研究旨在改善婴儿CPB后预后的AP治疗做好准备。总体假设：婴儿CPB后低AP活性增加了炎症、器官损伤、心脏骤停、机械循环支持或死亡的风险，部分原因是能力下降

DESCRIPTION (provided by applicant): 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.