METHODS AND RESULTS: The rapid delayed rectifier potassium current (IKr), L-type Ca2+ current (ICa,L) and action potential duration (APD) were measured by whole cell patch-clamp. The expression of KCNH2 and cytotoxicity was determined by real-time PCR and Caspase activity measurements. After significant IKr suppression by Mitragynine (10 µM) was confirmed in hERG-HEK cells, we systematically examined the effects of Mitragynine and other chemical constituents in hiPSC-CMs. Mitragynine, Paynantheine, Speciogynine and Speciociliatine, dosage-dependently (0.1∼100 µM) suppressed IKr in hiPSC-CMs by 67%∼84% with IC50 ranged from 0.91 to 2.47 µM. Moreover, Mitragynine (10 µM) significantly prolonged APD at 50 and 90% repolarization (APD50 and APD90) (439.0±11.6 vs. 585.2±45.5 ms and 536.0±22.6 vs. 705.9±46.1 ms, respectively) and induced arrhythmia, without altering the L-type Ca2+ current. Neither the expression, and intracellular distribution of KCNH2/Kv11.1, nor the Caspase 3 activity were significantly affected by Mitragynine.
CONCLUSIONS: Our study indicates that Mitragynine and its analogues may potentiate Torsade de Pointes through inhibition of IKr in human cardiomyocytes.
METHODS: We systematically searched multiple databases to identify studies reporting incidence of antineoplastic-related cardiovascular toxicity in Asia published from inception to November 2018. Pre-specified subgroups were performed to explore heterogeneity and study quality assessed and reported according to PRISMA guidelines.
RESULTS: A total of 61 studies across 11 countries in Asia reported 8 types of cardiovascular toxicities were included. These studies mostly reported on adult populations, and usually examined cardiotoxicities related to anthracycline use. The most frequently reported cardiotoxicities were heart failure, electrocardiogram abnormalities and left ventricular dysfunction. The pooled estimated incidence of cardiotoxicity was 4.27% (95% CI: 3.53-5.07). Subgroup analysis showed higher incidence in middle income countries compared to high income countries.
CONCLUSIONS: Although robust incidence studies are sparse, cardiovascular complications affects approximately one in twenty cancer patients in Asia. This highlights a unique opportunity of cancer patients caring that need cardiologists and oncologist to become familiar with this emerging sub-specialty.