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...

Consumption of flavonoid-rich foods and beverages is thought to reduce the risk of cardiovascular diseases. Whereas the biological activities of flavonoids have been characterized in vitro, there are no clear experimental data demonstrating that chronic dietary intake and intestinal absorption of flavonoids actually protects the heart against ischemia-reperfusion injury. We tested whether long-term consumption of specific flavonoids (anthocyanins) included in normal food could render the heart of rats more resistant to myocardial infarction. Maize kernels that differed specifically in their accumulation of anthocyanins were used to prepare rodent food in which anthocyanins were either present or absent. Male Wistar rats were fed the anthocyanin-rich (ACN-rich) or the anthocyanin-free (ACN-free) diet for a period of 8 wk. Anthocyanins were significantly absorbed and detected in the blood and urine of only rats fed the ACN-rich diet. In Langendorff preparations, the hearts of rats fed the ACN-rich diet were more resistant to regional ischemia and reperfusion insult. Moreover, on an in vivo model of coronary occlusion and reperfusion, infarct size was reduced in rats that ate the ACN-rich diet than in those that consumed the ACN-free diet (P < 0.01). Cardioprotection was associated with increased myocardial glutathione levels, suggesting that dietary anthocyanins might modulate cardiac antioxidant defenses. Our findings suggest important potential health benefits of foods rich in anthocyanins and emphasize the need to develop anthocyanin-rich functional foods with protective activities for promoting human health.

BACKGROUND AND PURPOSEAt present there are no small molecule inhibitors that show strong selectivity for the Na + /Ca 2+ exchanger (NCX). Hence, we studied the electrophysiological effects of acute administration of ORM-10103, a new NCX inhibitor, on the NCX and L-type Ca 2+ currents and on the formation of early and delayed afterdepolarizations. EXPERIMENTAL APPROACHIon currents were recorded by using a voltage clamp technique in canine single ventricular cells, and action potentials were obtained from canine and guinea pig ventricular preparations with the use of microelectrodes. KEY RESULTSORM-10103 significantly reduced both the inward and outward NCX currents. Even at a high concentration (10 μM), ORM-10103 did not significantly change the L-type Ca 2+ current or the maximum rate of depolarization (dV/dtmax), indicative of the fast inward Na + current. At 10 μM ORM-10103 did not affect the amplitude or the dV/dtmax of the slow response action potentials recorded from guinea pig papillary muscles, which suggests it had no effect on the L-type Ca 2+ current. ORM-10103 did not influence the Na + /K + pump or the main K + currents of canine ventricular myocytes, except the rapid delayed rectifier K + current, which was slightly diminished by the drug at 3 μM. The amplitudes of pharmacologically-induced early and delayed afterdepolarizations were significantly decreased by ORM-10103 (3 and 10 μM) in a concentration-dependent manner. CONCLUSIONS AND IMPLICATIONSORM-10103 is a selective inhibitor of the NCX current and can abolish triggered arrhythmias. Hence, it has the potential to be used to prevent arrhythmogenic events. LINKED ARTICLE

Cardiac arrhythmias are among the leading causes of mortality. They often arise from alterations in the electrophysiological properties of cardiac cells, and their underlying ionic mechanisms. It is therefore critical to further unravel the patho-physiology of the ionic basis of human cardiac electrophysiology in health and disease. In the first part of this review, current knowledge on the differences in ion channel expression and properties of the ionic processes that determine the morphology and properties of cardiac action potentials and calcium dynamics from cardiomyocytes in different regions of the heart are described. Then the cellular mechanisms promoting arrhythmias in congenital or acquired conditions of ion channel function (electrical remodelling) are discussed. The focus is human relevant findings obtained with clinical, experimental and computational studies, given that interspecies differences make the extrapolation from animal experiments to the human clinical settings difficult. Deepening the understanding of the diverse patholophysiology of human cellular electrophysiology will help developing novel and effective antiarrhythmic strategies for specific subpopulations and disease conditions.