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Quantifying Structural and Functional Changes in Cardiac Cells in an In Vitro Model of Diabetic Cardiomyopathy

Michaelson, Jarett Evan

Diabetes Mellitus is one of the most common diseases in the world. Cardiovascular diseases account for ~80% of deaths amongst diabetic patients, primarily through coronary artery disease (CAD). However, a new clinical entry, termed Diabetic Cardiomyopathy (DC), may lead to heart failure in diabetic patients independently of CAD or hypertension. In DC, hyperglycemia and hyperlipidemia associated with diabetes produce structural and biochemical alterations at the cardiac cell level. Early stage cell alterations include hypertrophy, calcium mishandling, cell apoptosis, excessive ROS production, and increased collagen production by fibroblasts. Eventually, major structural and functional changes can appear in myocardial tissue, characterized by diastolic and systolic dysfunction, and eventually heart failure. While specific changes associated with DC are well characterized, the mechanism underlying disease development and progression as a whole remain to be elucidated. The ability of researchers to develop general treatment options for this disease is thus limited.
Currently, a majority of DC studies focus on either in vitro molecular pathways, or in vivo whole-heart properties such as ejection fraction. However, as DC is primarily a disease of changes in structural and functional properties, these studies can not precisely quantify what conditions (such as hyperglycemia and hyperlipidemia) are producing specific biomechanical changes such as increased myocardial stiffness or diastolic dysfunction. To address this, we developed an in vitro approach, based on culturing cardiac cells in elevated glucose and fatty acid, to examine how structural and functional properties may change as a result of a diabetic environment.
Increased myocardial stiffness is associated with increased collagen production in the heart. However, diastolic dysfunction is found to occur in DC prior to significant collagen accumulation. We hypothesized that increased cardiac cell stiffness could contribute to early stage diastolic dysfunction. To test this hypothesis, we developed and used contemporary biomedical engineering tools to characterize the biomechanical properties of cardiac myocytes and fibroblasts under a variety of hyperglycemic and hyperlipidemic conditions. We showed that our in vitro model of DC exhibits increased stiffness in myocytes, but not fibroblasts.
We then developed an assay to measure cardiac myocyte contractile force, as well as assess systolic and diastolic function. This assay was then used to determine the role of N-acetyl-cysteine (NAC), towards regulating reactive oxygen species (ROS) and reversing cellular-level changes associated with our DC model. We found that DC model cardiac myocytes exhibited greater incidences of diastolic, but not systolic, dysfunction, and that treatment with NAC reduced dysfunction to a normal level. In terms of structural properties, we additionally determined that treatment with NAC attenuated increases in myocyte stiffness found in our DC model, and that NAC reduced myocyte hypertrophy for certain diabetic conditions. Overall, treatment with NAC attenuates the maladaptive mechanical and functional changes found in our DC model.

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More About This Work

Academic Units
Biomedical Engineering
Thesis Advisors
Huang, Hayden
Degree
Ph.D., Columbia University
Published Here
January 6, 2014
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