Timothy syndrome 1 (TS1) is a multi-organ form of long QT syndrome associated with life-threatening cardiac arrhythmias, the organ-level dynamics of which remain unclear. In this study, we developed and characterized a novel porcine model of TS1 carrying the causative p.Gly406Arg mutation in CACNA1C, known to impair CaV1.2 channel inactivation. Our model fully recapitulated the human disease with prolonged QT interval and arrhythmic mortality. Electroanatomical mapping revealed the presence of a functional substrate vulnerable to reentry, stemming from an unforeseen constitutional slowing of cardiac activation. This signature substrate of TS1 was reliably identified using the reentry vulnerability index, which, we further demonstrate, can be used as a benchmark for assessing treatment efficacy, as shown by testing of multiple clinical and preclinical anti-arrhythmic compounds. Notably, in vitro experiments showed that TS1 cardiomyocytes display Ca2+ overload and decreased peak INa current, providing a rationale for the arrhythmogenic slowing of impulse propagation in vivo.

Unexpected impairment of INa current underpins reentrant arrhythmias in a knock-in swine model of Timothy syndrome / A. Porta-Sanchez, A. Mazzanti, C. Tarifa, D. Kukavica, A. Trancuccio, M. Mohsin, E. Zanfrini, A. Perota, R. Duchi, K. Hernandez-Lopez, M.E. Jauregui-Abularach, V. Pergola, E. Fernandez, R. Bongianino, E. Tavazzani, P. Gambelli, M. Memmi, S. Scacchi, L. Pavarino, P.C. Franzone, G. Lentini, D. Filgueiras-Rama, C. Galli, D.J. Santiago, S.G. Priori. - In: NATURE CARDIOVASCULAR RESEARCH. - ISSN 2731-0590. - 2:12(2023 Dec 11), pp. 1291-1309. [10.1038/s44161-023-00393-w]

Unexpected impairment of INa current underpins reentrant arrhythmias in a knock-in swine model of Timothy syndrome

S. Scacchi;
2023

Abstract

Timothy syndrome 1 (TS1) is a multi-organ form of long QT syndrome associated with life-threatening cardiac arrhythmias, the organ-level dynamics of which remain unclear. In this study, we developed and characterized a novel porcine model of TS1 carrying the causative p.Gly406Arg mutation in CACNA1C, known to impair CaV1.2 channel inactivation. Our model fully recapitulated the human disease with prolonged QT interval and arrhythmic mortality. Electroanatomical mapping revealed the presence of a functional substrate vulnerable to reentry, stemming from an unforeseen constitutional slowing of cardiac activation. This signature substrate of TS1 was reliably identified using the reentry vulnerability index, which, we further demonstrate, can be used as a benchmark for assessing treatment efficacy, as shown by testing of multiple clinical and preclinical anti-arrhythmic compounds. Notably, in vitro experiments showed that TS1 cardiomyocytes display Ca2+ overload and decreased peak INa current, providing a rationale for the arrhythmogenic slowing of impulse propagation in vivo.
Arrhythmias; Cardiovascular genetics;
Settore MAT/08 - Analisi Numerica
11-dic-2023
Article (author)
File in questo prodotto:
File Dimensione Formato  
andreu_2023.pdf

accesso aperto

Tipologia: Publisher's version/PDF
Dimensione 13.06 MB
Formato Adobe PDF
13.06 MB Adobe PDF Visualizza/Apri
andreu_2023_compressed(1).pdf

accesso aperto

Tipologia: Publisher's version/PDF
Dimensione 3.11 MB
Formato Adobe PDF
3.11 MB Adobe PDF Visualizza/Apri
Pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/1070970
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 8
  • ???jsp.display-item.citation.isi??? 8
  • OpenAlex ND
social impact