Dilated cardiomyopathy (DCM) is a debilitating heart condition characterized by the heart’s inability to effectively pump blood due to weakened and enlarged chambers. Left untreated, DCM can progress to irregular heartbeats (arrhythmia) and ultimately heart failure. One of the underlying genetic causes of DCM is a mutation in the SCN5A gene, which encodes for a critical sodium channel involved in cardiac muscle function.
Studying this disease in laboratory settings has been challenging due to the incomplete maturation of cardiac tissue derived from pluripotent stem cells. This limitation hampers the accurate representation of tissue architecture, extracellular matrix composition, and the surrounding cellular environment necessary for modeling the complexities of cardiac muscle.
To address this hurdle, a team of researchers at the University of Toronto, led by Dr. Milica Rasidic — a professor in the departments of Biomedical and Chemical Engineering, alongside Dr. Peter Backx — a professor in the department of Biology at York University, has pioneered the development of a revolutionary “heart-on-a-chip” technology. This innovative approach utilizes biowires that provide chronic electrical stimulation to promote the maturation of cardiac muscle cells derived from stem cells. Their findings were published in the journal Biomaterials.
Traditional heart failure medications and treatments often yield variable responses, particularly in cases involving specific genetic mutations such as those seen in SCN5A-associated DCM. These treatments typically do not directly target the underlying genetic mutation responsible for the disease pathology.
The unique aspect of the SCN5A mutation associated with DCM is its manifestation only following cellular maturation. Consequently, conventional induced pluripotent stem cell (iPSC) protocols struggle to accurately model this pathology. However, the heart-on-a-chip device developed by the research team allows for the investigation of this mutation’s effects after just eight weeks of tissue maturation.
This SCN5A mutation disrupts sodium channel interactions as well as structural protein functions, both of which are crucial for proper cardiac muscle contraction. The resulting disruptions lead to tissue dilation and impaired muscle contractility, hallmarks of DCM.
Moreover, this mutation alters molecular structures and disrupts essential protein interactions, further contributing to tissue dilation and impaired contractility. The intricate interplay between sodium channels and structural proteins is critical for maintaining the integrity and function of cardiac muscle tissue.
In summary, the groundbreaking heart-on-a-chip technology developed by Dr. Rasidic, Dr. Backx, and their team offers unprecedented insights into the molecular mechanisms underlying SCN5A-associated DCM. By bridging the gap between in vitro models and clinical reality, this innovative approach holds immense promise for advancing our understanding of genetic heart diseases and developing targeted therapeutic strategies to improve patient outcomes.
