Hypertrophic cardiomyopathy dysfunction mimicked in human engineered heart tissue and improved by sodium-glucose cotransporter 2 inhibitors
© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:120 |
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| Enthalten in: |
Cardiovascular research - 120(2024), 3 vom: 14. März, Seite 301-317 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Wijnker, Paul J M [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 18.03.2024 Date Revised 13.04.2024 published: Print Citation Status MEDLINE |
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| doi: |
10.1093/cvr/cvae004 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM367311399 |
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| 100 | 1 | |a Wijnker, Paul J M |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Hypertrophic cardiomyopathy dysfunction mimicked in human engineered heart tissue and improved by sodium-glucose cotransporter 2 inhibitors |
| 264 | 1 | |c 2024 | |
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| 500 | |a Date Completed 18.03.2024 | ||
| 500 | |a Date Revised 13.04.2024 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Ca2+ handling | |
| 650 | 4 | |a Contractility | |
| 650 | 4 | |a Engineered heart tissue | |
| 650 | 4 | |a Human induced pluripotent stem cell-derived cardiomyocytes | |
| 650 | 4 | |a Hypertrophic cardiomyopathy | |
| 650 | 4 | |a Sodium–glucose cotransporter 2 inhibitors | |
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| 700 | 1 | |a Dinani, Rafeeh |e verfasserin |4 aut | |
| 700 | 1 | |a van der Laan, Nico C |e verfasserin |4 aut | |
| 700 | 1 | |a Algül, Sila |e verfasserin |4 aut | |
| 700 | 1 | |a Knollmann, Bjorn C |e verfasserin |4 aut | |
| 700 | 1 | |a Verkerk, Arie O |e verfasserin |4 aut | |
| 700 | 1 | |a Remme, Carol Ann |e verfasserin |4 aut | |
| 700 | 1 | |a Zuurbier, Coert J |e verfasserin |4 aut | |
| 700 | 1 | |a Kuster, Diederik W D |e verfasserin |4 aut | |
| 700 | 1 | |a van der Velden, Jolanda |e verfasserin |4 aut | |
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