Key points• Cardiac repolarization, through which heart-cells return to their resting state after having fired, is a delicate process, susceptible to disruption by common drugs and clinical conditions. • Animal models, particularly the dog, are often used to study repolarization properties and responses to drugs, with the assumption that such findings are relevant to humans. However, little is known about the applicability of findings in animals to man.• Here, we studied the contribution of various ion-currents to cardiac repolarization in canine and human ventricle.• Humans showed much greater repolarization-impairing effects of drugs blocking the rapid delayed-rectifier current I Kr than dogs, because of lower repolarization-reserve contributions from two other important repolarizing currents (the inward-rectifier I K1 and slow delayed-rectifier I Ks ).• Our findings clarify differences in cardiac repolarization-processes among species, highlighting the importance of caution when extrapolating results from animal models to man.Abstract The species-specific determinants of repolarization are poorly understood. This study compared the contribution of various currents to cardiac repolarization in canine and human ventricle. Conventional microelectrode, whole-cell patch-clamp, molecular biological and mathematical modelling techniques were used. Selective I Kr block (50-100 nmol l −1 dofetilide) lengthened AP duration at 90% of repolarization (APD 90 ) >3-fold more in human than dog, suggesting smaller repolarization reserve in humans. Selective I K1 block (10 μmol l −1 BaCl 2 ) and I Ks block (1 μmol l −1 HMR-1556) increased APD 90 more in canine than human right ventricular papillary muscle. Ion current measurements in isolated cardiomyocytes showed that I K1 and I Ks densities were 3-and 4.5-fold larger in dogs than humans, respectively. I Kr density and kinetics were similar in human versus dog. I Ca and I to were respectively ∼30% larger and ∼29% smaller in human, and Na + -Ca 2+ exchange current was comparable. Cardiac mRNA levels for the main I K1 ion channel subunit Kir2.1 and the I Ks accessory subunit minK were significantly lower, but mRNA expression of ERG and KvLQT1 (I Kr and I Ks α-subunits) were not significantly different, in human versus dog. Immunostaining suggested lower Kir2.1 and minK, and higher KvLQT1 protein expression in human versus canine cardiomyocytes. I K1 and I Ks inhibition increased the APD-prolonging effect of I Kr block more in dog (by 56% and 49%, respectively) than human (34 and 16%), indicating that both currents contribute to increased repolarization reserve in the dog. A mathematical model incorporating observed human-canine ion current differences confirmed the role of I K1 and I Ks in repolarization reserve differences. Thus, humans show greater repolarization-delaying effects of I Kr block than dogs, because of lower repolarization reserve contributions from I K1 and I Ks , emphasizing species-specific determinants of repolarization and the limitations of animal models fo...

Background Early repolarization pattern in the ECG has been associated with increased risk for ventricular tachycardia/fibrillation (VT/VF), particularly when manifest in inferior leads. This study examines the mechanisms underlying VT/VF in the early repolarization syndrome (ERS). Method Transmembrane action potentials (AP) were simultaneously recorded from 2 epicardial and 1 endocardial site of coronary-perfused canine left-ventricular (LV) wedge preparations, together with a pseudo-ECG. Transient outward current (Ito) was recorded from epicardial myocytes isolated from inferior and lateral LV of the same heart. Results J wave area (pseudo-ECG), epicardial AP notch magnitude and index were larger in inferior vs. lateral wall preparations at baseline and after exposure to provocative agents (NS5806+verapamil+acetylcholine (ACh)). Ito density was greater in myocytes from inferior vs. lateral wall (18.4±2.3pA/pF vs. 11.6±2.0pA/pF;p<0.05). A combination of NS5806 (7μM) and verapamil (3μM) or pinacidil (4μM), used to pharmacologically model the genetic defects responsible for ERS, resulted in prominent J-point and ST-segment elevation. ACh (3μM), simulating increased vagal tone, precipitated phase-2-reentry-induced polymorphic VT/VF. Using identical protocols, inducibility of arrhythmias was 3-fold higher in inferior vs. lateral wedges. Quinidine (10μM) or isoproterenol (1μM) restored homogeneity and suppressed VT/VF. Conclusion Our data support the hypothesis that 1) ERS is caused by a preferential accentuation of the AP notch in LV epicardium; 2) this repolarization defect is accentuated by elevated vagal tone; 3) higher intrinsic levels of Ito account for the greater sensitivity of the inferior LV wall to development of VT/VF; 4) quinidine and isoproterenol exert ameliorative effects by reversing the repolarization abnormality.

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