Hypertrophic cardiomyopathy dysfunction mimicked in human engineered heart tissue and improved by sodium-glucose cotransporter 2 inhibitors.

Autor:	Wijnker PJM; Department of Physiology, Amsterdam UMC, Vrije Universiteit Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.; Amsterdam Cardiovascular Sciences, Heart Failure & Arrhythmias, De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands., Dinani R; Department of Physiology, Amsterdam UMC, Vrije Universiteit Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.; Amsterdam Cardiovascular Sciences, Heart Failure & Arrhythmias, De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands., van der Laan NC; Department of Physiology, Amsterdam UMC, Vrije Universiteit Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.; Amsterdam Cardiovascular Sciences, Heart Failure & Arrhythmias, De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands., Algül S; Department of Physiology, Amsterdam UMC, Vrije Universiteit Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.; Amsterdam Cardiovascular Sciences, Heart Failure & Arrhythmias, De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands., Knollmann BC; Vanderbilt Center for Arrhythmia Research and Therapeutics, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA., Verkerk AO; Amsterdam Cardiovascular Sciences, Heart Failure & Arrhythmias, De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands.; Experimental Cardiology, Amsterdam UMC, Academic Medical Centre, Amsterdam, The Netherlands., Remme CA; Amsterdam Cardiovascular Sciences, Heart Failure & Arrhythmias, De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands.; Experimental Cardiology, Amsterdam UMC, Academic Medical Centre, Amsterdam, The Netherlands., Zuurbier CJ; Amsterdam Cardiovascular Sciences, Heart Failure & Arrhythmias, De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands.; Laboratory for Experimental Intensive Care and Anesthesiology (L.E.I.C.A.), Department of Anesthesiology, Amsterdam UMC, Academic Medical Centre, Amsterdam, The Netherlands., Kuster DWD; Department of Physiology, Amsterdam UMC, Vrije Universiteit Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.; Amsterdam Cardiovascular Sciences, Heart Failure & Arrhythmias, De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands., van der Velden J; Department of Physiology, Amsterdam UMC, Vrije Universiteit Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.; Amsterdam Cardiovascular Sciences, Heart Failure & Arrhythmias, De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands.
Jazyk:	angličtina
Zdroj:	Cardiovascular research [Cardiovasc Res] 2024 Mar 14; Vol. 120 (3), pp. 301-317.
DOI:	10.1093/cvr/cvae004
Abstrakt:	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. Competing Interests: Conflict of interest: none declared. (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)
Databáze:	MEDLINE
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