SPUR 2019: Mechanism of Myocardial Salvage with Simultaneous Mechanical Unloading and Reperfusion after Acute Myocardial Infarction

Background

Coronary artery disease and the associated ischemic heart disease is the leading cause of death and disability worldwide. Significant advances have been achieved with reperfusion after acute myocardial infarction (AMI). However, reperfusion injury accounts for up to 50% of the myocardial damage after AMI. Currently there are no effective interventions to limit reperfusion injury. Despite the increasing rates of primary percutaneous coronary intervention, chronic heart failure after AMI is still highly prevalent with its well-known tremendous burden on the health care system. Our studies will provide new insights into the molecular and metabolic mechanisms that are associated with enhanced myocardial salvage after AMI and thus help reduce subsequent development of chronic heart failure. The goal of this project is to investigate new strategies that could minimize the deleterious effect of reperfusion injury after AMI. We hypothesize that early LV mechanical unloading combined with coronary reperfusion will result in improved myocardial salvage following AMI. This is likely through a mechanism that attenuates ischemia/reperfusion (I/R) deleterious effects on mitochondrial proteome expression and possibly promotes normal substrate utilization by myocardial cells. We will investigate in our porcine I/R model the effect of combined mechanical unloading and reperfusion on mitochondrial proteome expression and cardiac cell metabolism. During ischemia there is a metabolic shift from β-oxidation of fatty acids to glycolysis as the primary mechanism of ATP synthesis in cardiac muscle. We propose to investigate how the cardiac specific MPC deletion in adult mice will affect the myocardial salvage in a mouse model of I/R.

The stipend for this SPUR project is funded by an American Heart Association grant awarded to Dr. Stavros Drakos, MD, PhD.

Student Role

The student will assist in the procedures that generate ischemic/reperfusion injury in large (porcine) and small (murine) animal models. The role of student include collecting and processing the blood and tissue specimens from animal models in the experiments. The student will be responsible for RNA isolation and protein and metabolite extraction from myocardial tissue samples of control, and test groups for RNA, protein, and metabolomic analysis. The project activities will involve statistical analysis of the gene and protein expression that show significant difference between control and test groups. The student will learn how to quantify the area at risk and salvage area. The pathway analysis will be performed on the RNA sequencing, mitochondrial proteomic, and metabolomic comparison between control and different treatment groups. Since the project involves genetically modified mice, the student will assist with basic husbandry, mating, and genotyping mice.

Student Learning Outcomes & Benefits

A great advantage of working in Dr. Drakos’ lab specifically is that student will gain exceptional experiences in different areas of biomedical research, both basic and translational science. Student will have an opportunity to observe the operation similar to clinical experience in the cardiac catheterization lab in the hospital. He/She will have plenty of hands-on involvement in conducting laboratory research and learn a great deal about metabolic pathways in understanding mechanisms of human disease. Since the student is required to present progress report in weekly lab meeting, he/she will have the learning experience in critical evaluation of the data, communication skills, and problem solving. The learning experience from this project will help and encourage the undergraduate student to prepare for research related career and professional development to become a scientist or physician devoted to evidence based medicine.

Stavros Drakos
Associate Professor

Internal Medicine
School of Medicine

Technical skills: The student will be assigned to work closely with a postdoctoral fellow who is responsible for the research project and will initially assist the postdoctoral fellow and technical specialist to perform the assays and experiments. The detail written protocols that are available in the laboratory will help guide the student to perform the assays required for experiments. The trainee are encouraged to operate on their own once they are proficient in performing the experiments. I will counsel the student occasionally to ensure that student understands the hypothesis being tested by experiments and the concluded outcome is correctly evaluated.

Communication skills: Undergraduate trainee is required to participate in a weekly laboratory meeting to learn and discuss the research in progress in my laboratory. The trainee will assist and present the findings of project. I expect the student to develop the skill for data analysis, presentation preparation, and oral communication. The student will be required to present research publication related to the project that he/she involved in a monthly journal club meeting. My expectation is that student will learn the skills for literature search, scientific critique and reasoning, and communication in preparation for the required final presentation at the Undergraduate Research Summer Symposium.

The undergraduate trainee will be given increasing personal responsibilities and independence in performing the experiments, analysis, and presentation once the student has demonstrated under supervision that he/she proficiently developed those capabilities.