Reengineering Heart Cells to Understand Sudden Cardiac Death

What biomedical issue did you address in your research, and what did your studies find?

Sudden cardiac death is a common and devastating event that can occur from a variety of heart arrhythmias. The condition causes nearly 400,000 deaths annually in the U.S. and up to 3.7 million deaths around the globe. Several types of deadly arrhythmias can arise from mutations in one gene that provides instruction for sodium channels — protein structures that mediate electrical signals — in cardiac cells. The electrical signals in cardiac cells trigger the process of heart contraction. Although the mutations occur in the same gene, known as SCN5A, each type of arrhythmia has a different clinical manifestation and requires a distinct treatment strategy.

My research focused on understanding a newly described arrhythmia that can lead to sudden cardiac death: multifocal ectopic Purkinje-related premature contractions syndrome (MEPPC). To distinguish this rare disease and other complex arrhythmia disorders, we developed a 3D disease clustering model to interpret the impact of pathogenic genetic variants — changes in DNA that may lead to disease — on cardiac sodium channels. This method aims to support clinical decision-making and the development of personalized treatment strategies for people and families affected by these diseases.

The second part of my thesis involved a relatively new approach: the creation of an in vitro disease model for MEPPC using patient-specific, reengineered heart cells. With the consent of patients who were evaluated in the clinic, I obtained blood samples from people with this rare disease. I reprogrammed the blood cells into stem cells and then used a combination of biological and chemical factors to prompt the cells to become beating heart cells (cardiomyocytes) with characteristics of MEPPC. Using whole-cell patch clamp and optical calcium imaging technique, we identified distinctive calcium release abnormalities as well as altered ion channel activity that occur because of the specific genetic mutation. Our findings bridge the gap between measurements of electrophysiological abnormalities and premature contractions observed in patients with MEPPC. This novel cardiac cell model may facilitate new insights into the pathobiology of MEPPC and enable the testing of novel therapies.

How did Mayo's environment help you grow as a scientist and as a thinker?

Mayo has a strong focus on translational research — studies that will lead to cures for patients. Being able to work with cells donated by patients who have this rare disorder provided a unique opportunity to advance this area of research. Using stem-cell-based disease modeling is relatively new and holds tremendous potential in helping us understand the pathobiology in human cells. The cells also enable the screening of potential drugs for the disease. This bedside-to-bench and back-to-bedside environment is what really makes Mayo unique.

What motivates you?

The journey to a Ph.D. in biomedical research can be challenging, but in the end it's rewarding to see how your studies apply to clinical care to help patients. My next step is a postdoctoral fellowship at Stanford University Medical Center, where I will continue research in the field of cardiovascular diseases with a focus on high-throughput screening of novel therapeutics.