Identifying the Transcriptome Signature of Calcium Channel Blocker in Human iPSC-Derived Cardiomyocytes

Calcium channel blockers (CCBs) are important in treating cardiovascular diseases and the acute pharmacological actions of CCBs in the hearts have been extensively studied. However, we lack the knowledge of the drug-specific effect on human cardiomyocyte transcriptome and potential physiological change after long-term exposure as patients are usually prescribed with these medications for their lifetime after diagnosis. Thus, we aimed to simulate chronic CCB treatment in human cardiomyocytes and subsequently examine both the functional and transcriptomic alterations. We differentiated cardiomyocytes from three human induced pluripotent stem cell (iPSC) lines and exposed them to four different CCBs—nifedipine, amlodipine, diltiazem, and verapamil—at their physiological serum concentrations for two weeks. Without inducing cell death and damage to myofilament structure, CCBs elicited line specific inhibition on calcium kinetics and contractility. While all four CCBs exerted comparable inhibition on calcium kinetics, verapamil applied the strongest inhibition on cardiomyocyte contractile function. By examining cardiomyocyte transcriptome after treatment, we identified little overlap in their transcriptome signatures. Verapamil is the only inhibitor that reduced the expression of contraction related genes, such as myosin heavy chain and troponin I, consistent with its depressive effects on contractile function. Moreover, the alterations in these gene may help explain how HCM patients respond to verapamil in relieving outflow tract obstruction. In conclusion, we identified the distinct transcriptome signatures of different CCBs in human cardiomyocytes, suggesting that although the four inhibitors act on the same target, they may have distinct effects on normal cardiac cell physiology. The application of iPSC platform and transcriptomic findings may allow us to identify responders to verapamil treatment.