Miklós Bitay

Restricting excessive cardiac action potential and QT prolongation: a vital role for IKs in human ventricular muscle.

Background—Although pharmacological block of the slow, delayed rectifier potassium current (IKs) by chromanol 293B, L-735,821, or HMR-1556 produces little effect on action potential duration (APD) in isolated rabbit and dog ventricular myocytes, the effect of IKs block on normal human ventricular muscle APD is not known. Therefore, studies were conducted to elucidate the role of IKs in normal human ventricular muscle and in preparations in which both repolarization reserve was attenuated and sympathetic activation was increased by exogenous dofetilide and adrenaline. Methods and Results—Preparations were obtained from undiseased organ donors. Action potentials were measured in ventricular trabeculae and papillary muscles using conventional microelectrode techniques; membrane currents were measured in ventricular myocytes using voltage-clamp techniques. Chromanol 293B (10 &mgr;mol/L), L-735,821 (100 nmol/L), and HMR-1556 (100 nmol/L and 1 &mgr;mol/L) produced a <12-ms change in APD while pacing at cycle lengths ranging from 300 to 5000 ms, whereas the IKr blockers sotalol and E-4031 markedly lengthened APD. In voltage-clamp experiments, L-735,821 and chromanol 293B each blocked IKs in the presence of E-4031 to block IKr. The E-4031–sensitive current (IKr) at the end of a 150-ms-long test pulse to 30 mV was 32.9±6.7 pA (n=8); the L-735,821–sensitive current (IKs) magnitude was 17.8±2.94 pA (n=10). During a longer 500-ms test pulse, IKr was not substantially changed (33.6±6.1 pA; n=8), and IKs was significantly increased (49.6±7.24 pA; n=10). On application of an “action potential–like” test pulse, IKr increased as voltage became more negative, whereas IKs remained small throughout all phases of the action potential–like test pulse. In experiments in which APD was first lengthened by 50 nmol/L dofetilide and sympathetic activation was increased by 1 &mgr;mol/L adrenaline, 1 &mgr;mol/L HMR-1556 significantly increased APD by 14.7±3.2% (P<0.05; n=3). Conclusions—Pharmacological IKs block in the absence of sympathetic stimulation plays little role in increasing normal human ventricular muscle APD. However, when human ventricular muscle repolarization reserve is attenuated, IKs plays an increasingly important role in limiting action potential prolongation.

Does small-conductance calcium-activated potassium channel contribute to cardiac repolarization?

Small-conductance calcium-activated potassium channels (SK channels) have a significant role in neurons. Since they directly integrate calcium handling with repolarization, in heart their role would be particularly important. However, their contribution to cardiac repolarization is still unclear. A previous study reported a significant lengthening effect of apamin, a selective SK channel inhibitor, on the action potential duration in atrial and ventricular mouse cardiomyocytes and human atrial cells. They concluded that these channels provide an important functional link between intracellular calcium handling and action potential kinetics. These findings seriously contradict our studies on cardiac repolarization reserve, where we demonstrated that inhibition of a potassium current is not likely to cause excessive APD lengthening, since its decrease is mostly compensated by a secondary increase in other, unblocked potassium currents. To clarify this contradiction, we reinvestigated the role of the SK current in cardiac repolarization, using conventional microelectrode and voltage-clamp techniques in rat and dog atrial and ventricular multicellular preparations, and in isolated cardiomyocytes. SK2 channel expression was confirmed with immunoblot technique and confocal microscopy. We found, that while SK2 channels are expressed in the myocardium, a full blockade of these channels by 100 nM apamin--in contrast to the previous report--did not cause measurable electrophysiological changes in mammalian myocardium, even when the repolarization reserve was blunted. These results clearly demonstrate that in rat, dog and human ventricular cells under normal physiological conditions--though present--SK2 channels are not active and do not contribute to action potential repolarization.

Ionic mechanisms limiting cardiac repolarization reserve in humans compared to dogs.

•u2002 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. •u2002 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. •u2002 Here, we studied the contribution of various ion‐currents to cardiac repolarization in canine and human ventricle. •u2002 Humans showed much greater repolarization‐impairing effects of drugs blocking the rapid delayed‐rectifier current IKr than dogs, because of lower repolarization‐reserve contributions from two other important repolarizing currents (the inward‐rectifier IK1 and slow delayed‐rectifier IKs). •u2002 Our findings clarify differences in cardiac repolarization‐processes among species, highlighting the importance of caution when extrapolating results from animal models to man.

Contribution of IKr and IK1 to ventricular repolarization in canine and human myocytes: is there any influence of action potential duration?

BackgroundThe aim of the present work was to study the profile of the rapid delayed rectifier potassium current (IKr) and the inward rectifier potassium current (IK1) during ventricular repolarization as a function of action potential duration and rate of repolarization.MethodsWhole cell configuration of the patch clamp technique was used to monitor IKr and IK1 during the action potential plateau and terminal repolarization. Action potentials recorded at various cycle lengths (0.4–5xa0s) and repolarizing voltage ramps having various slopes (0.5–3xa0V/s) were used as command signals. IKr and IK1 were identified as difference currents dissected by E-4031 and BaCl2, respectively.ResultsNeither peak amplitudes nor mean values of IKr and IK1 recorded during the plateau of canine action potentials were influenced by action potential duration. The membrane potential where IKr and IK1 peaked during the terminal repolarization was also independent of action potential duration. Similar results were obtained in undiseased human ventricular myocytes, and also in canine cells when IKr and IK1 were evoked using repolarizing voltage ramps of various slopes. Action potential voltage clamp experiments revealed that the peak values of IKr, IK1, and net outward current during the terminal repolarization were independent of the pacing cycle length within the range of 0.4 and 5xa0s.ConclusionsThe results indicate that action potential configuration fails to influence the amplitude of IKr and IK1 during the ventricular action potential in dogs and humans, suggesting that rate-dependent changes in action potential duration are not likely related to rate-dependent alterations in IKr or IK1 kinetics in these species.

Electrophysiological effects of ivabradine in dog and human cardiac preparations: Potential antiarrhythmic actions

Ivabradine is a novel antianginal agent which inhibits the pacemaker current. The effects of ivabradine on maximum rate of depolarization (V(max)), repolarization and spontaneous depolarization have not yet been reported in human isolated cardiac preparations. The same applies to large animals close to human in heart size and spontaneous frequency. Using microelectrode technique action potential characteristics and by applying patch-clamp technique ionic currents were studied. Ivabradine exerted concentration-dependent (0.1-10 μM) decrease in the amplitude of spontaneous diastolic depolarization and reduction in spontaneous rate of firing of action potentials and produced a concentration- and frequency-dependent V(max) block in dog Purkinje fibers while action potential duration measured at 50% of repolarization was shortened. In the presence of ivabradine, at 400 ms cycle length, V(max) block developed with an onset kinetic rate constant of 13.9 ± 3.2 beat(-1) in dog ventricular muscle. In addition to a fast recovery of V(max) from inactivation (τ=41-46 ms) observed in control, a second slow component for recovery of V(max) was expressed (offset kinetics of V(max) block) having a time constant of 8.76 ± 1.34 s. In dog after attenuation of the repolarization reserve ivabradine moderately but significantly lengthened the repolarization. In human, significant prolongation of repolarization was only observed at 10 μM ivabradine. Ivabradine in addition to the Class V antiarrhythmic effect also has Class I/C and Class III antiarrhythmic properties, which can be advantageous in the treatment of patients with ischemic heart disease liable to disturbances of cardiac rhythm.

Self-augmentation of the lengthening of repolarization is related to the shape of the cardiac action potential: Implications for reverse rate dependency

Background and purpose:u2002 The aims of the present work were to study the mechanism of the reverse rate dependency of different interventions prolonging cardiac action potential duration (APD).

Altered expression of genes for kir ion channels in dilated cardiomyopathy

Dilated cardiomyopathy (DCM) is a multifactorial disease characterized by left ventricular dilation that is associated with systolic dysfunction and increased action potential duration. The Kir2.x K⁺ channels (encoded by KCNJ genes) regulate the inward rectifier current (IK1) contributing to the final repolarization in cardiac muscle. Here, we describe the transitions in the gene expression profiles of 4 KCNJ genes from healthy or dilated cardiomyopathic human hearts. In the healthy adult ventricles, KCNJ2, KCNJ12, and KCNJ4 (Kir2.1-2.3, respectively) genes were expressed at high levels, while expression of the KCNJ14 (Kir2.4) gene was low. In DCM ventricles, the levels of Kir2.1 and Kir2.3 were upregulated, but those of Kir2.2 channels were downregulated. Additionally, the expression of the DLG1 gene coding for the synapse-associated protein 97 (SAP97) anchoring molecule exhibited a 2-fold decline with increasing age in normal hearts, and it was robustly downregulated in young DCM patients. These adaptations could offer a new aspect for the explanation of the generally observed physiological and molecular alterations found in DCM.

Bronchoconstriction during alveolar hypocapnia and systemic hypercapnia in dogs with a cardiopulmonary bypass

The roles of the alveolar and systemic CO₂ on the lung mechanics were investigated in dogs subjected to cardiopulmonary bypass. Low-frequency pulmonary impedance data (Z(L)) were collected in open-chest dogs with an alveolar CO₂ level (FA(CO₂)) of 0.2-7% and during systemic hypercapnia before and after elimination of the vagal tone. Airway resistance (R(aw)), inertance (I(aw)), parenchymal damping (G) and elastance (H) were estimated from the Z(L). The highest R(aw) observed at 0.2% FA(CO₂),which decreased markedly up to a FA(CO₂) of 2% (212 ± 24%), and remained unchanged under normo- and hypercapnia (FA(CO₂) 2-7%). These changes were associated with smaller decreases in I(aw) (-16.6 ± 3.7%), mild elevations in G (25.7 ± 4.7%), and no change in H. Significant increases in all mechanical parameters were observed following systemic hypercapnia; atropine counteracted the R(aw) rises. We conclude that severe alveolar hypocapnia may contribute to minimization of the ventilation-perfusion mismatch by constricting the airways in poorly perfused lung regions. The constrictor potential of systemic hypercapnia is mediated by vagal reflexes.

A ministernotomia szerepe az aortabillentyű-sebészetben

Absztrakt Bevezetes: A modern aortabillentyű-sebeszetben egyre hangsulyosabba valnak a kisebb behatolasi kapukkal jaro sebeszeti eljarasok. A műbillentyűk technikai fejlődese, kulonos tekintettel a varras nelkuli billentyűkre, nagymertekben hozzajarul ahhoz, hogy kis műteti teruleten, keves manipulacioval, egyszerűen hajtsanak vegre aortabillentyű-műteteket. Celkitűzes: A szerzők celja az volt, hogy a jelen publikacioval, a tortenelmi attekintes mellett, a minimalis behatolassal vegzett aortabillentyű-cserenek modozatait ismertessek, kulonos tekintettel a varrat nelkuli biologiai aortaprotezisek hasznalatara, tovabba hogy a sajat műteti eredmenyeiket bemutassak. Modszer: A Szegedi Tudomanyegyetem Szivsebeszeti Osztalyan meg limitalt szamu, 13 beteg adatainak feldolgozasaval a szerzők ravilagitanak a rendszer technikai szuksegleteire, a konvencionalis teljes sternotomia kozotti kulonbsegekre. Eredmenyek es kovetkeztetesek: A szerzők megallapitjak, hogy a minimalis behatolassal vegzett aortabillentyű-cseren...

Kezdeti tapasztalatok a Sorin Perceval S aorta biológiai billentyű beültetésével

OBJECTIVES: We examined the Sorin Perceval S artificial biological valve implantation techniques, and present the initial experiences in our unit. METHODS: In the last 1.5 years, 27 patients had been implanted with Sorin Perceval S biological arteficial valve due to aortic valve disease. The device was mainly used in high-risk patients, in reoperative circumstances, in cases of calcified aortic root, and in elderly patients. RESULTS: The valve implantation time, aortic cross clamp time is shorter, but the risk of the operation cannot be eliminated entirely, because of the high risk patients severe comorbidities. Furthermore, we performed echocardiography in the postoperative period, which demonstrated that the valve function is excellent, the valve fitted tightly in the anulus, and there was no paravalvular leakage. CONCLUSIONS: The Sorin Perceval S biological arteficial aortic valve is safe to use in high risk patients, and the surgical procedure is easier in case of partial sternotomy, too.Absztrakt Celkitűzes: Vizsgalatunkkal attekintjuk az osztalyunkon beultetett Sorin Perceval S oltes nelkul rogzithető műbillentyűvel szerzett kezdeti tapasztalatainkat. Modszerek: Masfel ev alatt 27 esetben ultettunk be Sorin Perceval S biologiai billentyűt aortabillentyű-betegseg miatt. Az eszkozt elsősorban nagy kockazatu betegek eseten alkalmaztuk, reoperacios kornyezetben, meszes aortagyok eseten, időskorban. Eredmenyek: A billentyű beultetesi ideje rovidult, az atlagos aortalefogasi idő 27 perc, igy a műteti terheles csokkent, de a nagy kockazatu betegek sulyos tarsbetegsegei miatt a kockazat nem szuntethető meg teljesen. (Harom beteget vesztettunk el a postoperativ szakban, bar egyik beteget sem cardialis ok miatt.) Parcialis sternotomia eseten a billentyű hasznalata megkonnyiti a sebeszi beavatkozast. A műtetet kovető echokardiografia minden esetben kitűnően műkodő, az anulusba jol illeszkedő műbillentyűt velemenyezett, paravalvularis insufficientia nem volt. Kovetkeztetes: A Sorin Perceval S aorta...