Cardiomyopathies and Arrhythmias

    The discovery that skin or blood cells from the adult human can be reprogrammed to a pluripotent state, yielding induced pluripotent stem cells (iPSCs), has made it possible to produce cardiovascular cells that exhibit inherited traits and disorders. For instance, many inherited cardiomyopathies and arrhythmias have been reproduced in culture dishes using iPSC-derived heart cells.  Use of these cells in high throughput analyses should broaden our insight into fundamental disease mechanisms and provide many benefits for patients, including new therapeutics and individually tailored therapies.

    Our main research strategy is to generate cardiovascular disease models using iPSCs and use them to identify cellular proteins and processes that could be targeted by drugs to treat the disease. We have developed automated tools to study the physiology of heart cells using high throughput screening.  Using these methods, we functionally scan the human proteome to discover proteins that might be targeted therapeutically.  Ongoing projects include the study of inherited forms of dilated cardiomyopathy (DCM) and arrhythmia, such as Long QT syndrome. Similarly, we also use the screening platform to predict the heart’s response to known and experimental drugs.

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Whole genome microRNA screening identified two microRNAs that controlmesoderm and endoderm formation, an initiating event in heart formation, see paper by Colas, McKeithan, Bushway et al., Genes and Development (2012).

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Intravenous injection of anti-miR-25 RNA halts the progression of established heart failure and improves cardiac function in a mouse model (shown on right are data from  two echocardiographic indices of heart function).  Survival also improves significantly.  See article by Wahlquist, Jeong, Rojas-Munoz et al. in Nature, 2014.

Cardiac action potentials visualized with a fluorescent small molecule voltage probe in human cardiomyocytes (Mckeithan, 2017)