The effects of increased free fatty acid (FFA) levels on ventricular arrhythmias remain controversial. Using ventricular fibrillation threshold (VFT), we examined the relationship between FFA levels and ventricular arrhythmias. Isolated rat hearts were perfused with palmitate bound to either albumin or fatty acid binding protein (FABP) by Langendorf's method. The VFT was determined by electrical stimulation. Perfusion with 0.12 mM albumin alone, 0.12 mM palmitate bound to 0.12 mM albumin, and 0.36 mM palmitate bound to 0.12 mM albumin did not lower the VFT significantly. However, 0.60 mM palmitate bound to 0.12 mM albumin lowered VFT from 2.19 +/- 0.20 mA to 1.56 +/- 0.13 mA. The perfusion of 0.36 mM palmitate bound to 0.12 mM FABP lowered the VFT from 2.05 +/- to 0.19 mA to 1.47 +/- 0.23 mA, but 0.12 mM FABP alone did not affect the VFT. Perfusion with 0.36 mM palmitate bound to 0.12 mM FABP caused the VFT to fall more than perfusion with 0.36 mM palmitate bound to 0.12 mM albumin. Then the effects of verapamil perfusion or a low concentration of perfusate Ca2+ on VFT were examined. VFT was determined by electrical stimulation. Palmitate (0.6 mM) bound to 0.12 mM albumin lowered VFT. Verapamil 10(-7) M perfusion and a low concentration of Ca2+ (Ca2+ 1.67 mM) suppressed the FFA-induced fall of VFT. These results suggested that the arrhythmogenic action of FFA was related to Ca2+ overload in myocardial cells.

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Introduction: Many prediction algorithms for warfarin maintenance dose (WD) were constructed based on the clinical and genetic information of the patients without extracorporeal circulation devices (ECDs). However, it is unclear whether might be useful for the patients with ECD, such as left ventricular assist devices (LVAD), who still require warfarin. Hypothesis: The WD algorithms constructed using non-ECD patients could be useful for LVAD patients. Methods: An observational study, the Human Genome Research Ethics Committee of OU approved (#756), was conducted at the Osaka University (OU) Hospital on 108 LVAD patients receiving warfarin therapy. Genetic polymorphisms of CYP2C9*1, *3, and VKORC1-1639G>A were tested using TaqMan genotyping assay kits. WD was defined as the administered dose during the periods when the PT-INR value was within its target range. We investigated the difference between the actual warfarin dose (AWD) and the calculated warfarin dose (CWD) using an algorithm proposed by the International Warfarin Pharmacogenetics Consortium (IWPC), which we verified with 125 Japanese non-ECD patients previously (Eur J Clin Pharmacol, 75:901). Results: The percentage of patients whose difference between CWD and AWD was within 20% of AWD showed no significant difference between the LVAD and the non-ECD (%; I, LVAD, 41.7, non-ECD, 49.6, p=0.23). The root mean squared percentage error (RMSPE) to the AWD was similar between the groups (%; LVAD, 42, non-ECD, 37). As the algorithm requires if amiodarone is concomitant with warfarin, we probed the effect of the amiodarone dose on the CWD. Interestingly, RMSPE of the LVAD with ≥ 200 mg/day of amiodarone (≥ 200A) was higher compared to those with < 200 mg/day (<200A) and without amiodarone (%; 85.5, 25.9, 36.8). The difference between AWD and CWD of ≥ 200A was significantly higher than <200A (mg/day; 0.87, -0.07; p=0.012). We verified similar tendencies using other algorithms published before. Conclusions: The WD algorithm with the information on genotype and concomitant use of amiodarone for the non-ECD could be beneficial for the LVAD. Besides them, extra careful attention should be required for patients with ≥ 200 mg/day of amiodarone not to have warfarin overdosed.

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