Species-dependent differences in the inhibition of various potassium currents and in their effects on repolarization in cardiac ventricular muscle.

Even though rodents are accessible model animals, their electrophysiological properties are deeply different from those of humans, making the translation of rat studies to humans rather difficult. We compared the mechanisms of ventricular repolarization in various animal models to those of humans by measuring cardiac ventricular action potentials from ventricular papillary muscle preparations using conventional microelectrodes and applying selective inhibitors of various potassium transmembrane ion currents. Inhibition of the IK1 current (10 µmol/L barium chloride) significantly prolonged rat ventricular repolarization, but only slightly prolonged it in dogs, and did not affect it in humans. On the contrary, IKr inhibition (50 nmol/L dofetilide) significantly prolonged repolarization in humans, rabbits, and dogs, but not in rats. Inhibition of the IKur current (1 µmol/L XEN-D0101) only prolonged rat ventricular repolarization and had no effect in humans or dogs. Inhibition of the IKs (500 nmol/L HMR-1556) and Ito currents (100 µmol/L chromanol-293B) elicited similar effects in all investigated species. We conclude that dog ventricular preparations have the strongest translational value and rat ventricular preparations have the weakest translational value in cardiac electrophysiological experiments.

Infective endocarditis complicated with coronary artery septic embolization: is it worth to be mentioned? Case presentation and review of the literature.

Coronary artery septic embolization is a rare, but severe complication of infective endocarditis involving the leftside of the valves. The first case mentioned in the literature was a postmortem finding of a left anterior descending coronary artery occlusion by a vegetation fragment. Since this case, there have been several therapeutic strategies published with this clinical setting including medical treatment, percutaneous coronary angioplasty addressing coronary occlusion, surgical intervention for both the infected valve and coronary embolization, and hybrid procedures with transcatheter septic embolus aspiration followed by surgical valvular interventions. Out of the three interventions mentioned, the latter provided the best results and was in concordance with results observed in a case of mitral valve infected endocarditis complicated with acute occlusion of the left anterior descending coronary artery in patient whose comorbidities included hypertrophic obstructive cardiomyopathy. A transcatheter left anterior descending coronary artery embolus aspiration was performed , followed by a surgical mitral valve replacement and septal myectomy with an uneventful postoperative course. Although rare, this severe complication of infective endocarditis has a specific clinical course and therapeutic strategy, and in our opinion, it could be mentioned as a separate entity among embolic complications of infective endocarditis in future guidelines. Previously published cases suggest that the hybrid intervention might be the therapy of choice for this clinical setting; however, larger studies are necessary for confirmation.

[The role of mini-sternotomy in aortic valve surgery]. / A ministernotomia szerepe az aortabillentyu-sebészetben.

INTRODUCTION: Minimal access aortic valve replacement plays a significant role in modern cardiac surgery. The technical evolution of aortic bioprostheses, particularly sutureless valves, leads to simplify minimal access aortic valve surgery and it allows easier implantation in a narrow work field with the need of less manipulation. AIM: The aim of this study is to summarize the historical and technical aspects of minimal access aortic valve replacement, especially concentrating on sutureless valves, and to present data of own patients of the authors. METHOD: Pre- and post-operative data of 13 minimal access aortic replacement cases who were operated at the Deparment of Cardiac Sugery at the University of Szeged are summarized. RESULTS AND CONCLUSIONS: As compared to full sternotomy, minimal access aortic surgery is safe, and it does not require special instrumentation. It is technically more demanding but it can be learned quickly, and the overall pre- and post-operative results are not worse with the benefit of less pain and superior cosmetics.

[Early experiences with the Sorin Perceval S arteficial biological valve]. / Kezdeti tapasztalatok a Sorin Perceval S aorta biológiai billentyu 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.

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

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 IKr block (50-100 nmol l(-1) dofetilide) lengthened AP duration at 90% of repolarization (APD90) >3-fold more in human than dog, suggesting smaller repolarization reserve in humans. Selective IK1 block (10 µmol l(-1) BaCl2) and IKs block (1 µmol l(-1) HMR-1556) increased APD90 more in canine than human right ventricular papillary muscle. Ion current measurements in isolated cardiomyocytes showed that IK1 and IKs densities were 3- and 4.5-fold larger in dogs than humans, respectively. IKr density and kinetics were similar in human versus dog. ICa and Ito were respectively ~30% larger and ~29% smaller in human, and Na(+)-Ca(2+) exchange current was comparable. Cardiac mRNA levels for the main IK1 ion channel subunit Kir2.1 and the IKs accessory subunit minK were significantly lower, but mRNA expression of ERG and KvLQT1 (IKr and IKs 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. IK1 and IKs inhibition increased the APD-prolonging effect of IKr 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 IK1 and IKs in repolarization reserve differences. Thus, humans show greater repolarization-delaying effects of IKr block than dogs, because of lower repolarization reserve contributions from IK1 and IKs, emphasizing species-specific determinants of repolarization and the limitations of animal models for human disease.

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.

Kv1.1 potassium channel subunit deficiency alters ventricular arrhythmia susceptibility, contractility, and repolarization.

Epilepsy-associated Kv1.1 voltage-gated potassium channel subunits encoded by the Kcna1 gene have traditionally been considered absent in heart, but recent studies reveal they are expressed in cardiomyocytes where they could regulate intrinsic cardiac electrophysiology. Although Kv1.1 now has a demonstrated functional role in atria, its role in the ventricles has never been investigated. In this work, electrophysiological, histological, and gene expression approaches were used to explore the consequences of Kv1.1 deficiency in the ventricles of Kcna1 knockout (KO) mice at the organ, cellular, and molecular levels to determine whether the absence of Kv1.1 leads to ventricular dysfunction that increases the risk of premature or sudden death. When subjected to intracardiac pacing, KO mice showed normal baseline susceptibility to inducible ventricular arrhythmias (VA) but resistance to VA under conditions of sympathetic challenge with isoproterenol. Echocardiography revealed cardiac contractile dysfunction manifesting as decreased ejection fraction and fractional shortening. In whole-cell patch-clamp recordings, KO ventricular cardiomyocytes exhibited action potential prolongation indicative of impaired repolarization. Imaging, histological, and transcript analyses showed no evidence of structural or channel gene expression remodeling, suggesting that the observed deficits are likely electrogenic due to Kv1.1 deficiency. Immunoblots of patient heart samples detected the presence of Kv1.1 at relatively high levels, implying that Kv1.1 contributes to human cardiac electrophysiology. Taken together, this work describes an important functional role for Kv1.1 in ventricles where its absence causes repolarization and contractility deficits but reduced susceptibility to arrhythmia under conditions of sympathetic drive.

Electrical Restitution and Its Modifications by Antiarrhythmic Drugs in Undiseased Human Ventricular Muscle.

INTRODUCTION: Re-entry is a basic mechanism of ventricular fibrillation, which can be elicited by extrasystolic activity, but the timing of an extrasystole can be critical. The action potential duration (APD) of an extrasystole depends on the proximity of the preceding beat, and the relation between its timing and its APD is called electrical restitution. The aim of the present work was to study and compare the effect of several antiarrhythmic drugs on restitution in preparations from undiseased human ventricular muscle, and other mammalian species. METHODS: Action potentials were recorded in preparations obtained from rat, guinea pig, rabbit, and dog hearts; and from undiseased human donor hearts using the conventional microelectrode technique. Preparations were stimulated with different basic cycle lengths (BCLs) ranging from 300 to 5,000 ms. To study restitution, single test pulses were applied at every 20th beat while the preparation was driven at 1,000 ms BCL. RESULTS: Marked differences were found between the animal and human preparations regarding restitution and steady-state frequency dependent curves. In human ventricular muscle, restitution kinetics were slower in preparations with large phase 1 repolarization with shorter APDs at 1000 ms BCL compared to preparations with small phase 1. Preparations having APD longer than 300 ms at 1000 ms BCL had slower restitution kinetics than those having APD shorter than 250 ms. The selective IKr inhibitors E-4031 and sotalol increased overall APD and slowed the restitution kinetics, while IKs inhibition did not influence APD and electrical restitution. Mexiletine and nisoldipine shortened APD, but only mexiletine slowed restitution kinetics. DISCUSSION: Frequency dependent APD changes, including electrical restitution, were partly determined by the APD at the BCL. Small phase 1 associated with slower restitution suggests a role of Ito in restitution. APD prolonging drugs slowed restitution, while mexiletine, a known inhibitor of INa, shortened basic APD but also slowed restitution. These results indicate that although basic APD has an important role in restitution, other transmembrane currents, such as INa or Ito, can also affect restitution kinetics. This raises the possibility that ion channel modifier drugs slowing restitution kinetics may have antiarrhythmic properties by altering restitution.

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.

Contribution of I Kr and I K1 to ventricular repolarization in canine and human myocytes: is there any influence of action potential duration?

BACKGROUND: The aim of the present work was to study the profile of the rapid delayed rectifier potassium current (I (Kr)) and the inward rectifier potassium current (I (K1)) during ventricular repolarization as a function of action potential duration and rate of repolarization. METHODS: Whole cell configuration of the patch clamp technique was used to monitor I (Kr) and I (K1) during the action potential plateau and terminal repolarization. Action potentials recorded at various cycle lengths (0.4-5 s) and repolarizing voltage ramps having various slopes (0.5-3 V/s) were used as command signals. I (Kr) and I (K1) were identified as difference currents dissected by E-4031 and BaCl(2), respectively. RESULTS: Neither peak amplitudes nor mean values of I (Kr) and I (K1) recorded during the plateau of canine action potentials were influenced by action potential duration. The membrane potential where I (Kr) and I (K1) 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 I (Kr) and I (K1) were evoked using repolarizing voltage ramps of various slopes. Action potential voltage clamp experiments revealed that the peak values of I (Kr), I (K1), and net outward current during the terminal repolarization were independent of the pacing cycle length within the range of 0.4 and 5 s. CONCLUSIONS: The results indicate that action potential configuration fails to influence the amplitude of I (Kr) and I (K1) 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 I (Kr) or I (K1) kinetics in these species.

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 micromol/L), L-735,821 (100 nmol/L), and HMR-1556 (100 nmol/L and 1 micromol/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 micromol/L adrenaline, 1 micromol/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.

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.

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.

Interspecies differences and extracellular calcium dependence in the vasorelaxing effect of cromakalim in isolated human, porcine, and canine coronary arteries.

Coronary arteries isolated from human, porcine, and canine hearts were depolarized with potassium chloride and relaxed by cromakalim (0.0125-10.0 micromol/L) at low (1.5 mmol/L) and high (7.5 mmol/L) extracellular calcium concentration ([Ca(2+)]( o)). At low [Ca(2+)](o), cromakalim (1 micromol/L) relaxed the coronary arteries with the order of porcine > canine > human. Fifty percent effective concentrations of cromakalim revealed the same order: 0.15 micromol/L in porcine, 0.36 micromol/L in canine, and 3.91 micromol/L in human coronary arteries. High [Ca(2+)](o) significantly enhanced the relaxing effect and decreased the potency of cromakalim in porcine and human but not in canine coronary arteries. In human coronary arteries, precontracted with the prostaglandin analogue (U46619), high [Ca(2+)]( o) enhanced the effect of 0.1 micromol/L cromakalim more efficiently in the presence than in the absence of endothelium. It appears that the coronary dilating effect of cromakalim largely depends on the species and is modulated by [Ca(2+)](o,) with a partly endothelium dependent manner.

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: 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). EXPERIMENTAL APPROACH: The reverse rate-dependent lengthening effect of APD-prolonging interventions and the possible involvement of I(Kr) (rapid component of the delayed rectifier potassium current) and I(K1) (inward rectifier potassium current) were studied by using the standard microelectrode and the whole-cell patch-clamp techniques in dog multicellular ventricular preparations and in myocytes isolated from undiseased human and dog hearts. KEY RESULTS: All applied drugs--dofetilide (1 micromol.L(-1)), BaCl(2) (10 micromol.L(-1)), BAY-K-8644 (1 micromol.L(-1)), veratrine (1 microg.mL(-1))--lengthened APD in a reverse rate-dependent manner regardless of their mode of action, suggesting that reverse rate dependency may not represent a specific mechanism of APD prolongation. The E-4031-sensitive current (I(Kr)) and the Ba(2+)-sensitive current (I(K1)) were recorded during repolarizing voltage ramps having various steepness and also during action potential waveforms with progressively prolonged APD. Gradually delaying repolarization results in smaller magnitude of I(Kr) and I(K1) currents at an isochronal phase of the pulses. This represents a positive feedback mechanism, which appears to contribute to the reverse rate-dependent prolongation of action potentials. CONCLUSIONS AND IMPLICATIONS: Action potential configuration may influence the reverse rate-dependent APD prolongation due to the intrinsic properties of I(Kr) and I(K1) currents. Drugs lengthening repolarization by decreasing repolarizing outward, or increasing depolarizing inward, currents are expected to cause reverse rate-dependent APD lengthening with high probability, regardless of which current they modify.