Ionic mechanisms limiting cardiac repolarization reserve in humans compared to dogs. (30th August 2013)

• Record Type: Journal Article
• Authors: Jost, Norbert; Virág, László; Comtois, Philippe; Ördög, Balázs; Szuts, Viktória; Seprényi, György; Bitay, Miklós; Kohajda, Zsófia; Koncz, István; Nagy, Norbert; Szél, Tamás; Magyar, János; Kovács, Mária; Puskás, László G.; Lengyel, Csaba; Wettwer, Erich; Ravens, Ursula; Nánási, Péter P.; Papp, Julius Gy.; Varró, András; Nattel, Stanley
• Is Part Of: Journal of physiology. Volume 591:Number 17(2013:Sep.)
• Page Start: 4189
• Page End: 4206
• Publication Date: 2013-08-30
• Subjects: Physiology -- Periodicals; 612.005
• DOI: 10.1113/jphysiol.2013.261198
• Languages: English
• ISSNs: 0022-3751

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Key points</title> <p> <list id="l1" list-type="simple"> <list-item> <label> </label> <p>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.</p> </list-item> <list-item> <label> </label> <p>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.</p> </list-item> <list-item> <label> </label> <p>Here, we studied the contribution of various ion‐currents to cardiac repolarization in canine and human ventricle.</p> </list-item> <list-item> <label> </label> <p>Humans showed much greater repolarization‐impairing effects of drugs blocking the rapid delayed‐rectifier current <italic>I</italic><sub>Kr</sub> than dogs, because of lower repolarization‐reserve contributions from two other important repolarizing currents (the inward‐rectifier <italic>I</italic><sub>K1</sub> and slow delayed‐rectifier <italic>I</italic><sub>Ks</sub>).</p> </list-item> <list-item> <label> </label> <p>Our findings clarify differences in cardiac repolarization‐processes among species, highlighting the importance of caution when extrapolating results from animal models to man.</p> </list-item> </list> </p> <p> <bold>Abstract </bold> 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 <italic>I</italic><sub>Kr</sub> block (50–100 nmol l<sup>−1</sup> dofetilide) lengthened AP duration at 90% of repolarization (APD<sub>90</sub>) >3‐fold more in human than dog, suggesting smaller repolarization reserve in humans. Selective <italic>I</italic><sub>K1</sub> block (10 μmol l<sup>−1</sup> BaCl<sub>2</sub>) and <italic>I</italic><sub>Ks</sub> block (1 μmol l<sup>−1</sup> HMR‐1556) increased APD<sub>90</sub> more in canine than human right ventricular papillary muscle. Ion current measurements in isolated cardiomyocytes showed that <italic>I</italic><sub>K1</sub> and <italic>I</italic><sub>Ks</sub> densities were 3‐ and 4.5‐fold larger in dogs than humans, respectively. <italic>I</italic><sub>Kr</sub> density and kinetics were similar in human <italic>versus</italic> dog. <italic>I</italic><sub>Ca</sub> and <italic>I</italic><sub>to</sub> were respectively ∼30% larger and ∼29% smaller in human, and Na<sup>+</sup>–Ca<sup>2+</sup> exchange current was comparable. Cardiac mRNA levels for the main <italic>I</italic><sub>K1</sub> ion channel subunit Kir2.1 and the <italic>I</italic><sub>Ks</sub> accessory subunit minK were significantly lower, but mRNA expression of ERG and KvLQT1 (<italic>I</italic><sub>Kr</sub> and <italic>I</italic><sub>Ks</sub>α‐subunits) were not significantly different, in human versus dog. Immunostaining suggested lower Kir2.1 and minK, and higher KvLQT1 protein expression in human <italic>versus</italic> canine cardiomyocytes. <italic>I</italic><sub>K1</sub> and <italic>I</italic><sub>Ks</sub> inhibition increased the APD‐prolonging effect of <italic>I</italic><sub>Kr</sub> 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 <italic>I</italic><sub>K1</sub> and <italic>I</italic><sub>Ks</sub> in repolarization reserve differences. Thus, humans show greater repolarization‐delaying effects of <italic>I</italic><sub>Kr</sub> block than dogs, because of lower repolarization reserve contributions from <italic>I</italic><sub>K1</sub> and <italic>I</italic><sub>Ks</sub>, emphasizing species‐specific determinants of repolarization and the limitations of animal models for human disease.</p> </abstract>