Search Results (2)

The pathophysiology of Takotsubo Syndrome (TTS) is not completely understood and the trigger of sudden cardiac death (SCD) in TTS is not clear either. We therefore sought to find an association between TTS and primary electrical diseases. A total of 148 TTS patients were analyzed between 2003 and 2017 in a bi-centric manner. Additionally, a literature review was performed. The patients were included in an ongoing retrospective cohort database. The coexistence of TTS and primary electrical diseases was confirmed in five cases as the following: catecholaminergic polymorphic ventricular tachycardia (CPVT, 18-year-old female) (n = 1), LQTS 1 (72-year-old female and 65-year-old female) (n = 2), LQTS 2 (17-year-old female) (n = 1), and LQTS in the absence of mutations (22-year-old female). Four patients suffered from malignant tachyarrhythmia and recurrent syncope after TTS. Except for the CPVT patient and one LQTS 1 patient, all other cases underwent subcutaneous ICD implantation. An event recorder of the CPVT patient after starting beta-blocker did not detect arrhythmias. The diagnosis of primary electrical disease was in 80% of cases unmasked on a TTS event. This diagnosis triggered a family clinical and genetic screening confirming the diagnosis of primary electrical disease. A subsequent literature review identified five cases as the following: a congenital atrioventricular block (n = 1), a Jervell and Lange-Nielsen Syndrome (n = 1), and a family LQTS in the absence of a mutation (n = 2), LQTS 2 (n = 1). A primary electrical disease should be suspected in young and old TTS patients with a family history of sudden cardiac death. In suspected cases, e.g., ongoing QT interval prolongation, despite recovery of left ventricular ejection fraction a family screening is recommended. Full article

Human ether a-go-go related gene (hERG) or KV11.1 potassium channels mediate the rapid delayed rectifier current (I_Kr) in cardiac myocytes. Drug-induced inhibition of hERG channels has been implicated in the development of acquired long QT syndrome type (aLQTS) and fatal arrhythmias. Several marketed drugs have been withdrawn for this reason. Therefore, there is considerable interest in developing better tests for predicting drugs which can block the hERG channel. The drug-binding pocket in hERG channels, which lies below the selectivity filter, normally contains K⁺ ions and water molecules. In this study, we test the hypothesis that these water molecules impact drug binding to hERG. We developed 3D QSAR models based on alignment independent descriptors (GRIND) using docked ligands in open and closed conformations of hERG in the presence (solvated) and absence (non-solvated) of water molecules. The ligand–protein interaction fingerprints (PLIF) scheme was used to summarize and compare the interactions. All models delineated similar 3D hERG binding features, however, small deviations of about ~0.4 Å were observed between important hotspots of molecular interaction fields (MIFs) between solvated and non-solvated hERG models. These small changes in conformations do not affect the performance and predictive power of the model to any significant extent. The model that exhibits the best statistical values was attained with a cryo_EM structure of the hERG channel in open state without water. This model also showed the best R² of 0.58 and 0.51 for the internal and external validation test sets respectively. Our results suggest that the inclusion of water molecules during the docking process has little effect on conformations and this conformational change does not impact the predictive ability of the 3D QSAR models. Full article