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Updated: Jul 5, 2025
Evaluation of Cardiac Contractility Modulation Therapy in 2D Human Stem Cell-Derived Cardiomyocytes
Published on: December 16, 2022
Hypertrophic cardiomyopathy dysfunction mimicked in human engineered heart tissue and improved by sodium-glucose
Paul J M Wijnker1,2, Rafeeh Dinani1,2, Nico C van der Laan1,2
1Department of Physiology, Amsterdam UMC, Vrije Universiteit Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.
Insights
Sodium-glucose cotransporter 2 inhibitors (SGLT2i) enhance relaxation in human heart cells with hypertrophic cardiomyopathy (HCM) mutations. These findings suggest SGLT2i may treat early cardiac dysfunction in HCM patients.
Area of Science:
- Cardiovascular Medicine
- Genetics
- Pharmacology
Background:
- Hypertrophic cardiomyopathy (HCM) is the most common inherited heart muscle disease, often stemming from sarcomere gene mutations.
- Early HCM manifestations include diastolic dysfunction and hypercontractility, with no current treatments to prevent mutation-induced cardiac issues.
- Sodium-glucose cotransporter 2 inhibitors (SGLT2i), known for cardiovascular benefits in heart failure, are explored for HCM therapy.
Purpose of the Study:
- To investigate if SGLT2 inhibitors can correct cardiomyocyte dysfunction caused by HCM-associated sarcomere mutations.
- To assess the therapeutic potential of SGLT2i in a human model of inherited hypertrophic cardiomyopathy.
Main Methods:
- Utilized human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) with MYH7-R403Q or TNNT2-R92Q mutations, cultured in 2D and 3D engineered heart tissue (EHT).
- Measured contractility, intracellular calcium ([Ca2+]), action potential, and ion currents to evaluate cardiomyocyte function.
- Assessed the effects of SGLT2i (canagliflozin, empagliflozin, dapagliflozin) on relaxation and identified underlying mechanisms, focusing on the Na+/Ca2+ exchanger.
Main Results:
- HCM mutations in hiPSC-CMs induced impaired relaxation and increased force, mirroring early HCM features.
- SGLT2i significantly enhanced relaxation in HCM hiPSC-CMs, with effects increasing upon hiPSC-CM maturation in EHT.
- Canagliflozin demonstrated more pronounced relaxation effects than empagliflozin and dapagliflozin, with SGLT2i altering Na+/Ca2+ exchange current.
Conclusions:
- SGLT2 inhibitors acutely improve relaxation in human engineered heart tissue, particularly in hypertrophic cardiomyopathy models.
- The therapeutic effect of SGLT2i is enhanced with prolonged culture and maturation of hiPSC-CMs.
- SGLT2i represent a promising therapeutic strategy for correcting early-stage cardiac dysfunction in hypertrophic cardiomyopathy.
Aims:
Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiomyopathy, often caused by pathogenic sarcomere mutations. Early characteristics of HCM are diastolic dysfunction and hypercontractility. Treatment to prevent mutation-induced cardiac dysfunction is lacking. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are a group of antidiabetic drugs that recently showed beneficial cardiovascular outcomes in patients with acquired forms of heart failure. We here studied if SGLT2i represent a potential therapy to correct cardiomyocyte dysfunction induced by an HCM sarcomere mutation.
Methods And Results:
Contractility was measured of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) harbouring an HCM mutation cultured in 2D and in 3D engineered heart tissue (EHT). Mutations in the gene encoding β-myosin heavy chain (MYH7-R403Q) or cardiac troponin T (TNNT2-R92Q) were investigated. In 2D, intracellular [Ca2+], action potential and ion currents were determined. HCM mutations in hiPSC-CMs impaired relaxation or increased force, mimicking early features observed in human HCM. SGLT2i enhance the relaxation of hiPSC-CMs, to a larger extent in HCM compared to control hiPSC-CMs. Moreover, SGLT2i-effects on relaxation in R403Q EHT increased with culture duration, i.e. hiPSC-CMs maturation. Canagliflozin's effects on relaxation were more pronounced than empagliflozin and dapagliflozin. SGLT2i acutely altered Ca2+ handling in HCM hiPSC-CMs. Analyses of SGLT2i-mediated mechanisms that may underlie enhanced relaxation in mutant hiPSC-CMs excluded SGLT2, Na+/H+ exchanger, peak and late Nav1.5 currents, and L-type Ca2+ current, but indicate an important role for the Na+/Ca2+ exchanger. Indeed, electrophysiological measurements in mutant hiPSC-CM indicate that SGLT2i altered Na+/Ca2+ exchange current.
Conclusion:
SGLT2i (canagliflozin > dapagliflozin > empagliflozin) acutely enhance relaxation in human EHT, especially in HCM and upon prolonged culture. SGLT2i may represent a potential therapy to correct early cardiac dysfunction in HCM.
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