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Author Spotlight: Real-Time Measurements of Calcium and Contractility Parameters in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes
Published on: May 26, 2023
Identifying the Transcriptome Signatures of Calcium Channel Blockers in Human Induced Pluripotent Stem Cell-Derived
Chi Keung Lam1,2, Lei Tian1,2, Nadjet Belbachir1,2
1From the Stanford Cardiovascular Institute, CA (C.K.L., L.T., N.B., A.W., R.S., N.M., T.K., J.-W.R., J.C.W.).
Insights
Long-term calcium channel blocker (CCB) use shows distinct effects on human heart cells. While all CCBs impact calcium, verapamil uniquely reduces contraction genes, offering insights into hypertrophic cardiomyopathy treatment.
Area of Science:
- Cardiovascular Pharmacology
- Molecular Cardiology
- Stem Cell Biology
Background:
- Calcium channel blockers (CCBs) are crucial for managing cardiovascular diseases, often requiring lifelong use.
- While acute effects are known, long-term, drug-specific impacts on human cardiomyocyte transcriptomes and physiology remain unclear.
Purpose of the Study:
- To investigate the functional and transcriptomic alterations in human cardiomyocytes following chronic exposure to four distinct CCBs.
- To simulate real-world, long-term therapeutic conditions for CCB drug effects.
Main Methods:
- Human induced pluripotent stem cell-derived cardiomyocytes and engineered heart tissues were exposed to nifedipine, amlodipine, diltiazem, and verapamil for two weeks.
- Functional assessments of calcium kinetics and contractility were performed alongside transcriptome profiling.
Main Results:
- CCBs inhibited calcium kinetics and contractility without causing cell death or myofilament damage.
- Verapamil demonstrated the most significant inhibition of cardiomyocyte contractile function.
- Transcriptome analysis revealed minimal overlap between CCB signatures; verapamil uniquely reduced expression of contraction-related genes (e.g., MYH, troponin I).
Conclusions:
- This study provides the first identification of distinct transcriptome signatures for different CCBs in human cardiomyocytes.
- The observed gene expression patterns suggest that CCBs, despite a common target, exert unique physiological effects on cardiac cells.
- Verapamil's impact on contraction-related genes may explain its efficacy in managing left ventricular outflow tract obstruction in hypertrophic cardiomyopathy.
Rationale:
Calcium channel blockers (CCBs) are an important class of drugs in managing cardiovascular diseases. Patients usually rely on these medications for the remainder of their lives after diagnosis. Although the acute pharmacological actions of CCBs in the hearts are well-defined, little is known about the drug-specific effects on human cardiomyocyte transcriptomes and physiological alterations after long-term exposure.
Objective:
This study aimed to simulate chronic CCB treatment and to examine both the functional and transcriptomic changes in human cardiomyocytes.
Methods And Results:
We differentiated cardiomyocytes and generated engineered heart tissues from 3 human induced pluripotent stem cell lines and exposed them to 4 different CCBs-nifedipine, amlodipine, diltiazem, and verapamil-at their physiological serum concentrations for 2 weeks. Without inducing cell death and damage to myofilament structure, CCBs elicited line-specific inhibition on calcium kinetics and contractility. While all 4 CCBs exerted similar inhibition on calcium kinetics, verapamil applied the strongest inhibition on cardiomyocyte contractile function. By profiling cardiomyocyte transcriptome after CCB treatment, we identified little overlap in their transcriptome signatures. Verapamil is the only inhibitor that reduced the expression of contraction-related genes, such as MYH (myosin heavy chain) and troponin I, consistent with its depressive effects on contractile function. The reduction of these contraction-related genes may also explain the responsiveness of patients with hypertrophic cardiomyopathy to verapamil in managing left ventricular outflow tract obstruction.
Conclusions:
This is the first study to identify the transcriptome signatures of different CCBs in human cardiomyocytes. The distinct gene expression patterns suggest that although the 4 inhibitors act on the same target, they may have distinct effects on normal cardiac cell physiology.
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