EN
Interaction of the intercalated disc, sodium current function and calcium homeostasis in early arrhythmogenic cardiomyopathy (RP12)
Principial Investigators
Project Summary and Goals
Variants in genes encoding desmosomal components can lead to arrhythmogenic cardiomyopathy (ACM) / arrhythmogenic right ventricular cardiomyopathy (ARVC) and premature cardiac death. We will investigate the cross talk with sodium and calcium microdomains that further lead to arrhythmogenesis in ACM/ARVC. We hypothesise that the intercalated disc/desmosomal microdomain microstructure and function is impaired by variants in desmosomal genes before clinically apparent structural defects, and that pathological changes in the desmosome microdomain show crosstalk with sodium and calcium microdomains leading to: 1) Altered Na+ channel clustering and Nav1.5 currents, and 2) Microdomain-specific alterations in Ca2+ handling which contribute to arrhythmogenesis in ACM.
Aims Addressed by the Doctoral Candidates
- Investigate cell-cell communication at the structural and functional level in genetically altered models of ACM.
- Analyse Nav1.5 sodium channel clustering including associated macromolecular complexes and how they are affected.
- Investigate ACM-induced alterations in calcium signalling and vice versa and test the effects of therapeutic interventions on desmosomal and calcium microdomains and arrhythmias.
Key Techniques
- Electrophysiological studies of hearts and engineered cardiac tissues
- Förster resonance energy transfer (FRET) biosensors
- Optical mapping of cardiac tissue and engineered heart tissues
- Microscopic echocardiography, transmission electron microscopy, immunolabelling and super-resolution microscopy, 2D confocal microscopy with resonant scanning
Publications
-
Endurance Training Provokes Arrhythmogenic Right Ventricular Cardiomyopathy Phenotype in Heterozygous Desmoglein-2 Mutants: Alleviation by Preload Reduction. Fabritz L, Fortmueller L, Gehmlich K, Kant S, Kemper M, Kucerova D, Syeda F, Faber C, Leube RE, Kirchhof P, Krusche CA (2024). Biomedicines. 12:985. -
Load-reducing therapy prevents development of arrhythmogenic right ventricular cardiomyopathy in plakoglobin-deficient mice. Fabritz L, Hoogendijk MG, Scicluna BP, van Amersfoorth SCM, Fortmueller L, Wolf S, Laakmann S, Kreienkamp N, Piccini I, Breithardt G, Noppinger PR, Witt H, Ebnet K, Wichter T, Levkau B, Franke WW, Pieperhoff S, de Bakker JMT, Coronel R, Kirchhof P (2011). J Am Coll Cardiol. 57:740-750. -
Reduced plakoglobin increases the risk of sodium current defects and atrial conduction abnormalities in response to androgenic anabolic steroid abuse. Sommerfeld LC, Holmes AP, Yu TY, O'Shea C, Kavanagh DM, Pike JM, Wright T, Syeda F, Aljehani A, Kew T, Cardoso VR, Kabir SN, Hepburn C, Menon PR, Broadway-Stringer S, O'Reilly M, Witten A, Fortmueller L, Lutz S, Kulle A, Gkoutos GV, Pavlovic D, Arlt W, Lavery GG, Steeds R, Gehmlich K, Stoll M, Kirchhof P, Fabritz L (2024). J Physiol. 602:4409-4436 -
Familial atrial fibrillation mutation M1875T-SCN5A increases early sodium current and dampens the effect of flecainide. O'Reilly M, Sommerfeld LC, O'Shea C, Broadway-Stringer S, Andaleeb S, Reyat JS, Kabir SN, Stastny D, Malinova A, Delbue D, Fortmueller L, Gehmlich K, Pavlovic D, Skryabin BV, Holmes AP, Kirchhof P, Fabritz L (2023). Europace. 25:1152-1161. -
Impaired Binding to Junctophilin-2 and Nanostructural Alteration in CPVT Mutation. Yin L, Zahradnikova A Jr, Rizzetto R, Boncompagni S, Rabesahala de Meritens C, Zhang Y, Joanne P, Marqués-Sulé E, Aguilar-Sánchez Y, Fernández-Tenorio M, Villejoubert O, Li L, Wang YY, Mateo P, Nicolas V, Gerbaud P, Lai FA, Perrier R, Álvarez JL, Niggli E, Valdivia HH, Valdivia CR, Ramos-Franco J, Zorio E, Zissimopoulos S, Protasi F, Benitah JP, Gómez AM (2021). Circ Res. 129:e35-e52.