Combining Multi-Dimensional Molecular Fingerprints to Predict hERG Cardiotoxicity of Compounds

At present, drug toxicity has become a critical problem with heavy medical and economic burdens. acLQTS (acquired Long QT Syndrome) is acquired cardiac ion channel disease caused by drugs blocking the hERG channel. Therefore, it is necessary to avoid cardiotoxicity in the drug design and computer models have been widely used to fix this plight. In this study, we present a molecular fingerprint based on the molecular dynamic simulation and uses it combined with other molecular fingerprints (multi-dimensional molecular fingerprints) to predict hERG cardiotoxicity of compounds. 203 compounds with hERG inhibitory activity (pIC50) were retrieved from a previous study and predicting models were established using four machine learning algorithms based on the single and multi-dimensional molecular fingerprints. Results showed that MDFP has the potential to be an alternative to traditional molecular fingerprints and the combination of MDFP and traditional molecular fingerprints can achieve higher prediction accuracy. Meanwhile, the accuracy of the best model, which was generated by consensus of four algorithms with multi-dimensional molecular fingerprints, was 0.694 (RMSE) in the test dataset. Besides, the number of hydrogen bonds from MDFP has been determined as a critical factor in the predicting models, followed by rgyr and sasa. Our findings provide a new sight of MDFP and multi-dimensional molecular fingerprints in building models of hERG cardiotoxicity prediction.

An Unusual Case of Brugada Syndrome in an 82-Year Old Black Hypertensive Man

Rationale: Brugada syndrome (BrS) is a cardiac ion channel disease that is caused by an autosomal dominant genetic abnormality. It is frequently seen among young and middle-aged adults of Asian descent and rarely in blacks. Patient Concerns: We report an extremely rare case of an 82-year-old male known hypertensive with poor drug compliance, who suffered recurrent palpitations and pre-syncope. His electrocardiogram showed an unusual right bundle branch block with coved ST segment elevation in leads V1-V3. Diagnoses: The patient was eventually diagnosed with Brugada Syndrome with background hypertensive heart disease. He could not have genetic testing due to unavailability and cost. Interventions: The patient was treated with antihypertensives but could not afford a device implant. He was counseled to avoid risk factors such as fever, extreme physical and emotional exertions etc. Outcomes: At his last clinic visit two months post diagnosis he still had similar symptoms but no syncope nor sudden cardiac arrest. Lessons: To the best of our knowledge, this is possibly the first reported case of BrS in an elderly African with hypertensive heart disease.

P1492Is early repolarization pattern only an ion channel disease?

Background Early repolarization pattern (ERP) has been generally described as a benign electrocardiographic (ECG) sign despite it is associated with the development of malign ventricular arrhythmias. Although the pathophysiological mechanism of malign ventricular arrhythmias in ERP has been explained only electrophysiologically, whether the presence of structural changes in myocardium has not been known yet. Purpose We hypothesized that ERP is not only an ion channel disease. The structural changes in myocardium begin in individuals with ERP sign on 12 lead surface ECG even if a young person. The aim of the present study was to determine myocardial dysfunction due to early decaying in myocardial structure in individuals with ERP sign by the use of 2D- speckle tracking echocardiography (STE). Method We prospectively included 99 individuals who admitted to our clinic between 01.04.2018 and 01.09.2018. 48 individuals had ERP. 12 lead surface ECG was taken from all individuals at admission, all individual's ECG were further analysed for presence of ERP and ERP was divided into three groups which were defined as presence of ST elevation, J wave and QRS slurring. 2D-STE (Philips Epiq 7C Ultrasound System for Cardiology (Andover, USA)) was performed in all individuals. All strain echocardiographic recordings were further analysed off- line by the use of associated software. Results ERP had significantly lower left ventricular (LV) global longitudinal strain (GLS), circumferential peak systolic strain rate (CPSSr) in basal segments of LV and left ventricular ejection fraction compared to controls. In addition, LV diastolic function especially in LV basal segments were significantly impaired in individuals with ERP when assessed by circumferential peak diastolic strain rate (CPDSr) compared to controls. GCS, LV- longitudinal peak systolic Sr (LPSSr) and LV- longitudinal peak diastolic Sr (LPDSr) in all of the apical chambers were similar between two groups (Table 1). There was not a relationship between type of ERP and all of these parameters including GLS, GCS, LPSSr, CPSSr, LPDSr, CPDSr. Finally, ST elevation pattern had higher GCS value while QRS slurring pattern had higher GLS value (Figure 1). Figure 1 and Table 1 Conclusion Our study firstly demonstrated ERP can be combined of structural and electrical heart disease. LV-GLS can be more closely associated with ERP than LV-GCS. In addition, the either of impaired of circumferential systolic and diastolic function in LV basal segments can be detected in individuals with ERP.