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Published on: December 22, 2023
Identifying Features of Cardiac Disease Phenotypes Based on Mechanical Function in a Catecholaminergic Polymorphic
A Stempien1,2, M Josvai1,2, W J de Lange3
1Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI, United States.
Insights
Catecholaminergic polymorphic ventricular tachycardia (CPVT) patient cells showed increased contractile strain, unlike typical disease models. This study reveals novel mechanical differences in CPVT cardiomyocytes, suggesting new research avenues for this genetic heart condition.
Area of Science:
- Cardiology
- Biomedical Engineering
- Stem Cell Biology
Background:
- Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a genetic disorder causing sudden death, primarily linked to calcium handling defects.
- Previous research on CPVT has largely overlooked the mechanical function of cardiomyocytes, focusing instead on calcium dynamics.
- Investigating cardiomyocyte mechanical function offers a new perspective on CPVT pathophysiology.
Purpose of the Study:
- To evaluate the mechanical function of cardiomyocytes derived from a CPVT patient with a RyR2-H2464D mutation using an engineered cell culture platform.
- To compare the contractile behavior of CPVT patient-derived cardiomyocytes with healthy familial controls across varying substrate stiffnesses.
- To identify novel mechanical differences in CPVT cardiomyocytes that may contribute to disease severity.
Main Methods:
- Utilized stem cell-derived cardiomyocytes from a CPVT patient and a healthy control.
- Employed engineered culture platforms with substrates of varying stiffness (10-50 kPa) and patterned ECM proteins.
- Applied Digital Image Correlation (DIC) to quantify contractile strain amplitude as an indicator of cardiomyocyte function.
Main Results:
- CPVT patient-derived cardiomyocytes exhibited significantly higher maximum contractile strain compared to control cells across all tested substrate stiffnesses.
- The intrinsic contraction rate of patient-derived cells was significantly slower than that of control cells, aligning with existing literature.
- Observed hypercontractility in patient cells represents a novel finding, as it is not a previously recognized characteristic of CPVT.
Conclusions:
- This study reveals significant differences in mechanical function, specifically hypercontractility, in CPVT patient-derived cardiomyocytes.
- The findings suggest that mechanical dysfunction may play a role in CPVT pathophysiology, complementing known calcium handling defects.
- Further research is warranted to explore the implications of these mechanical differences in disease progression and potential therapeutic strategies.
Abstract:
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is characterized by an arrhythmogenic mechanism involving disruption of calcium handling. This genetic disease can lead to sudden death in children and young adults during physical or emotional stress. Prior CPVT studies have focused on calcium handling, but mechanical functionality has rarely been investigated in vitro. In this research we combine stem cell-derived cardiomyocytes from a CPVT patient (RyR2-H2464D mutation) and a healthy familial control with an engineered culture platform to evaluate mechanical function of cardiomyocytes. Substrates with Young's modulus ranging from 10 to 50 kPa were used in conjunction with microcontact printing of ECM proteins into defined patterns for subsequent attachment. Digital Image Correlation (DIC) was used to evaluate collections of contracting cells. The amplitude of contractile strain was utilized as a quantitative indicator of functionality and disease severity. We found statistically significant differences: the maximum contractile strain was consistently higher in patient samples compared to control samples on all substrate stiffnesses. Additionally, the patient cell line had a statistically significantly slower intrinsic contraction rate than the control, which agrees with prior literature. Differences in mechanical strain have not been previously reported, and hypercontractility is not a known characteristic of CPVT. However, functional changes can occur as the disease progresses, thus this observation may not represent behavior observed in adolescent and adult patients. These results add to the limited studies of mechanical function of CPVT CMs reported in literature and identify functional differences that should be further explored.
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