Mecanismos arritmogénicos del síndrome de QT corto Tipo 3

Abstract

Tesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Bioquímica. Fecha de Lectura: 07-10-2024Esta tesis tiene embargado el acceso al texto completo hasta el 07-04-2026Short QT Syndrome Type 3 (SQTS3) is a rare arrhythmogenic c hannelopathy c aused by g ain -of -function mutations in K CNJ2 , the gene coding the inward rectifier potassium channel Kir2.1 responsible for the repolarizing current IK 1 . The main characteristics of S QTS3 are substantial abbreviation of the QT interval on the electrocardiogram (ECG ) and life -t hreatening arrhythmias. Due to its recent description and lethality, there are not enough individuals for clinical trials, so animal models are highly needed and desirable. The main objective of my Thesis project was to enhance the understanding of S QTS3 b y i nvestigating its electrophysiologic and arrhythmogenic mechanisms . It is characterized by variable expressivity , which led me to test the hypothesis that the phenotype depend son the specific gain -of -function mechanisms triggered by each mutation . Iused in-vivo mouse model s of three different pathogenic SQTS3 mutations (Kir2.1D 172N , Kir2.1 E 299V a nd Kir2.1 M 301K ). The last two were identified in patients presenting with the most extremely abbreviated QT intervals described in the literature. On ECG, the QT i nterval was significantlys hortened in all S QTS3 models, recapitulating the electrical phenotype of the patients . Intracardiac stimulation showed variable inducibility among S QTS3 subtypes . Kir2.1 D 172N animals presented the mildest phenotype, but Kir2.1 E 299V mice manifested atrial -specific arrhythmias, whereas Kir2.1 M 301K mice presented the most severe ventricular episodes . Patch-clamping demonstrated extremely abbreviated action potentials in Kir2.1 E 299V and Kir2.1 M 301K cardiomyocytes due to lack of inward -going rectification and increased IK 1 at voltages positive to -8 0mV. The specific interaction of Kir2.1 with other proteins contributed to the explicit cardiac manifestations in each S QTS3 mouse model . Among these, the f unctional interactions of Kir2.1 with the voltage -gated cardiac sodium channel Na V 1.5 r esponsible for IN a stand out . On one hand, Kir2.1 E 299V increase d IN a in Purkinje fibers and shifted ventricular IN a a ctivation and inactivation, increasing the excitability a nd protecting t he ventricle against arrhythmia. On the other, Kir2.1 M 301K reduced the availability of NaV 1.5, reducing I N a density a nd cardiac excitability. Altogether, my research served to i mprove the understanding of S QTS3 , and to demonstrate that its cardiac manifestations are different depending on the specific molecular defects produced by each mutation. Moreover, isoprenaline and spermine demonstrated to be effective in prolonging the QT interval of SQTS3 models, without altering other ECG parameters , so my results may contribute to identify novel a ntiarrhythmic drugs in an inheritable cardiac disease with no defined therapyMoreover, the present PhD project was supported by La Caixa Banking Foundation [ LCF/PR/HR19/52160013]; grant PI -FIS -2 020 of the public call “Proyectos de Investigación en Salud 2020” [PI20/01220 ] and “Proyectos de Investigación en Salud 2 023” [PI23/01039] funded by Instituto de Salud Carlos III (ISCIII); the Ministerio de Ciencia, Innovación y Universidades (M CIU ) grant BFU2016 -7 5144 -R and PID2020 - 1 16935RB -I 00, and co-f nded by Fondo Europeo de Desarrollo Regional (FEDER); and Fundación La Marató de TV3 [736/C/2020]. W e also receive support from the European Union's Horizon 2020 Research and Innovation programme [grant agreement GA - 9 65286]. CNIC is supported by the ISCIII, the Ministerio de Ciencia e Innovación (MCIN) and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence grant CEX2020 - 0 01041 -S funded by MICIN/AEI/10.13039/50110001103