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Hereditary sick sinus syndrome – phenotypic spectrum, genetic basis, cellular dysfunction and implications for therapy

Subject Area Cardiology, Angiology
Anatomy and Physiology
Term from 2018 to 2022
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 398004441
 
Final Report Year 2023

Final Report Abstract

Sick sinus syndrome (SSS) comprises disorders characterized by defective heart rate initiation or conduction from the sinoatrial node (SAN) to the atrium. SSS comprises sinus bradycardia, SAN block or arrest, and bradycardia-tachycardia syndrome. The implantation of an electronic pacemaker is currently the only effective therapy. SSS has been related to inherited forms, and specific genes have been linked to the syndrome. Abnormalities of SAN function are particularly common in heart failure and cardiomyopathies suggesting a genetic and/or mechanistic link between electrical and structural dysfunction. Furthermore, SSS is associated with the development of atrial tachyarrhythmias, mosfly atrial fibrillation (AF). Thus, while increasing evidence indicates a role for genetic disposition in the pathogenesis of SSS, there is still insufficient mechanistic understanding of SAN pathophysiology that is required for mechanism-based therapy. The purpose of this study was to identify genetic causes and phenotypic characteristics of hereditary SSS. We identified a novel HCN4 pacemaker channel mutation in a cohort of 60 patients with AF. The HCN4 variant P883R exhibited abnormal biophysical properties leading to increased HCN4 currents. We concluded that HCN4-P883R may increase ectopic trigger activity and maintenance of AF by producing higher current density in patients. Together with the common KGNE1 variant S3BG that we additionally identified in our patients and that was previously proposed as a genetic modifier of AF, HCN4-P883R may provide a substrate for sinus node-related development of AF. To further explore the significance of HCN4 gain-of-function on the myocardium in addition to cardiac rhythm, we generated a mouse model that overexpressed HCN4 in the working myocardium (as opposed to the sinus node). Transgenic mice (HCN4tg/wt) allowed for the assessment of functional consequences of HCN4 overexpression-mediated pacemaker current increase in cardiomyocytes to levels observed in human heart failure. HCN4tg/wt animals exhibited dilated cardiomyopathy phenotype without changes in heart rate. At the molecular level, augmented pacemaker öurrenti induced a diastolic Na* influx shifting the Na*/Ca2* exchanger equilibrium towards'reverse mode' and leading to increased incracellular calcium that triggered apoptosis. By contrast, pharmacological inhibition of pacemaker currents prevented the rise of calcium levels and protected from ventriCular dysfunction. Taken together, we revealed a novel HCN4-dependent mechanism leading to both electrical and structural ventricular dysfunction. ln our patient cohort we additionally identified the ANK2-E1813K variant and a previously uncharacterized KCNH2-H562R mutation in patients with AV conduction disease and long ei syndrome in addition to sinus bradycardia. KCNH2-H562R subunits were non-functionai anO suppressed wildtype channels. An unexpected interaction with ANK2 was revealed: ANK2-E1B13K further diminished currents mediated by the combination of wildtype and H562R KCNH2 subunits, explaining the severe clinical phenotype observed in dual mutation carriers. For mechanistic investigations within cardiac cellular environment, we generated patient-derived iPSC carrying HCN4 mutations and the respective genetic correction realized by CRISPR/Cas9 gene editing, respectively. lmportantly, we established a novel protocol to differentiate iPSC into caidiac pacemaker cells. These cells are currently employed to elucidate electrophysiological effects and molecular pathways related to HCN4 mutations. Finally, we set out to identity clinical means to therapeutically incrBase sinus rates in patients with atrial fibrillation prone to bradycardiatachycardia syndrome. Pulmonary vein isolation (PVl) is established to eliminate AF. We evaluated 110 patients with paroxysmal AF undergoing cryoballoon PVI to investigate the hypothesis that PVI exerts effects on sinus rate modulation of the cardiac autonomic nervous system. lndeed, cryo-PVl significantly increased sinus rates. Therefore, cryoballoon PVI may be employed in patients with bradycardiatachycardia syndrome to specifically attenuate sinus bradycardia in addition to AF prevention. Follow-up investigations to specifically identify additional pathways leading to SSS in patient subgroups based on the present work are currently in preparation.

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