Gábor Bogáts

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.

The slow component of the delayed rectifier potassium current in undiseased human ventricular myocytes

OBJECTIVE The purpose of this study was to investigate the properties of the slow component of the delayed rectifier potassium current (I(Ks)) in myocytes isolated from undiseased human left ventricles. METHODS The whole-cell configuration of the patch-clamp technique was applied in 58 left ventricular myocytes from 15 hearts at 37 degrees C. Nisoldipine (1 microM) was used to block inward calcium current (I(Ca)) and E-4031 (1-5 microM) was applied to inhibit the rapid component of the delayed rectifier potassium current (I(Kr)). RESULTS In 31 myocytes, an E-4031 insensitive, but L-735,821 and chromanol 293B sensitive, tail current was identified which was attributed to the slow component of I(K) (I(Ks)). Activation of I(Ks) was slow (tau=903+/-101 ms at 50 mV, n=14), but deactivation of the current was relatively rapid (tau=122.4+/-11.7 ms at -40 mV, n=19). The activation of I(Ks) was voltage independent but its deactivation showed clear voltage dependence. The deactivation was faster at negative voltages (about 100 ms at -50 mV) and slower at depolarized potentials (about 300 ms at 0 mV). In six cells, the reversal potential was -81.6+/-2.8 mV on an average which is close to the K(+) equilibrium potential suggesting K(+) as the main charge carrier. CONCLUSION In undiseased human ventricular myocytes, I(Ks) exhibits slow activation and fast deactivation kinetics. Therefore, in humans I(Ks) differs from that reported in guinea pig, and it best resembles I(Ks) described in dog and rabbit ventricular myocytes.

Elevated levels of inflammatory biomarkers in the cerebrospinal fluid after coronary artery bypass surgery are predictors of cognitive decline

Recovery from cardiac surgery is marred for many patients by the development of neurological, psychological or cognitive dysfunction. An uncontrolled inflammatory reaction, in response to surgical stress, may be responsible. To confirm this hypothesis, the present study evaluated changes in the levels of cytokines in cerebrospinal fluid after coronary artery bypass grafting. One week post-operatively, the concentration of the pro-inflammatory cytokine interleukin-6 markedly increased; 6 months after surgery, however, its level normalized with an increased concentration of the anti-inflammatory interleukin-4. This suggests that a regulated immune response may participate in developing adverse neurologic events and complications following cardiac interventions, and cytokines in the cerebrospinal fluid may serve as specific biomarkers and predictors of developing cognitive decline after coronary surgery.

Coronary artery bypass surgery provokes alzheimer's disease-like changes in the cerebrospinal fluid

Several biomarkers are used in confirming the diagnosis of cognitive disorders. This study evaluates whether the level of these markers after heart surgery correlates with the development of cognitive dysfunction, which is a frequent complication of cardiac interventions. Concentrations of amyloid-β peptide, tau, and S100β in the cerebro-spinal fluid were assessed, as well as cognitive functions were evaluated before and after coronary artery bypass grafting, utilizing immuno-assays and psychometric tests, respectively. A drastic rise in the level of S100β was observed one week after the surgery, a mark of a severe generalized cerebral injury. The level of amyloid-β peptide significantly decreased, whereas the concentration of tau markedly increased six months postoperatively. Gradual cognitive decline was also present. These findings clearly demonstrate post-surgical cognitive impairment associated with changes in biomarkers similar to that seen in Alzheimers disease, suggesting a unifying pathognomic factor between the two disorders. A holistic approach to coronary heart disease and Alzheimers type dementia is proposed.

Modified Blalock-Taussig shunt using allograft saphenous vein: Six years' experience

BACKGROUND The occurrence of life-threatening late infectious complications after the use of expanded polytetrafluoroethylene conduits as modified Blalock-Taussig shunts prompted us to apply allograft saphenous veins instead. METHODS In 23 cyanotic patients (age, 1 week to 18 years) allograft saphenous veins were used for performing Blalock-Taussig shunts from July 1989 onward. Veins stored in Hanks solution were implanted in 8 patients and cryopreserved ones in 15. All patients were followed up regularly up to 15 months. RESULTS There were two early and two late deaths: none were related to shunt occlusion. Clinical, angiographic, and echocardiographic studies proved that, except for one early occlusion, all shunts were patent and functioning well after an average of 41 months. Donor cells disappeared 1 to 3 days after implantation, and several months after the operation both the wall and the luminal surface of the grafts were repopulated with cells possibly of recipient origin. No difference was found between veins stored in Hanks solution only and cryo-preserved grafts, concerning clinical outcome and histology. CONCLUSIONS Allograft saphenous veins function well as modified Blalock-Taussig shunts at least up to 6 years. Owing to the good results and lack of complications their clinical use is recommended.

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).

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.

Effects of respiratory mechanics on the capnogram phases: importance of dynamic compliance of the respiratory system.

IntroductionThe slope of phase III of the capnogram (SIII) relates to progressive emptying of the alveoli, a ventilation/perfusion mismatch, and ventilation inhomogeneity. SIII depends not only on the airway geometry, but also on the dynamic respiratory compliance (Crs); this latter effect has not been evaluated. Accordingly, we established the value of SIII for monitoring airway resistance during mechanical ventilation.MethodsSidestream capnography was performed during mechanical ventilation in patients undergoing elective cardiac surgery (n = 144). The airway resistance (Raw), total respiratory resistance and Crs displayed by the ventilator, the partial pressure of arterial oxygen (PaO2) and SIII were measured in time domain (ST-III) and in a smaller cohort (n = 68) by volumetry (SV-III) with and without normalization to the average CO2 phase III concentration. Measurements were performed at positive end-expiratory pressure (PEEP) levels of 3, 6 and 9 cmH2O in patients with healthy lungs (Group HL), and in patients with respiratory symptoms involving low (Group LC), medium (Group MC) or high Crs (Group HC).ResultsST-III and SV-III exhibited similar PEEP dependencies and distribution between the protocol groups formed on the basis of Crs. A wide interindividual scatter was observed in the overall Raw-ST-III relationship, which was primarily affected by Crs. Decreases in Raw with increasing PEEP were reflected in sharp falls in SIII in Group HC, and in moderate decreases in SIII in Group MC, whereas ST-III was insensitive to changes in airway caliber in Groups LC and HL.ConclusionsSIII assessed in the time domain and by volumetry provide meaningful information about alterations in airway caliber, but only within an individual patient. Although ST-III may be of value for bedside monitoring of the airway properties, its sensitivity depends on Crs. Thus, assessment of the capnogram shape should always be coupled with Crs when the airway resistance or oxygenation are evaluated.

Different Inflammatory Biomarker Patterns in the Cerebro-Spinal Fluid Following Heart Surgery and Major Non-Cardiac Operations

Cognitive decline occurs frequently after cardiac surgery and it may lead to patient morbidity. The purpose of this study is to focus on the static incidence of neuro-psychiatric impairment associated with altered inflammatory biomarkers in the cerebro-spinal fluid (CSF) that may provide an insight into the mechanisms of acute peri-operative cognitive disturbances related to heart surgery. Immuno-assays were used to evaluate concentrations of several cytokines in CSF of patients undergoing either off-pump coronary artery bypass grafting (OP-CABG) or major non-cardiac surgeries. Inter-group analysis showed no differences in baseline cytokine abundance. Levels of IL-8 have markedly increased both after OP-CABG and major non-cardiac surgeries (34.59+/-7.15 vs. 99.45+/-6.35, and 27.44+/-7.17 vs. 66.63+/-15.18). Rantes showed significantly greater quantity in CSF of the non-cardiac group after surgery (8.71+/-3.37 vs. 114.56+/-65.42), whereas it became somewhat less abundant in the post-operative period but statistically unchanged in the OP-CABG cohort (19.87+/-15.71 vs. 9.37+/-3.65). IP-10 and MCP-1 did not show significant changes in their concentrations in either patient population (OP-CABG: 254.41+/-160.01 vs. 224.55+/-214.39, and 140.37+/-40.98 vs. 147.16+/-37.98; non-cardiac: 274.99+/-219.44 vs. 395.09+/-468.30, and 126.56+/-31.24 vs. 124.41+/-49.89, respectively). These findings suggest that cardiac surgery provokes alterations in the levels of various cytokines in the CSF, and the OP-CABG induced changes in biomarker profile differs from that seen after major non-cardiac surgeries. This, along with other biomarkers, may offer an explanation for relationships between the pronounced incidence of cognitive impairment after heart operations.

Components of respiratory resistance monitored in mechanically ventilated patients

The interrupter technique is commonly adopted to monitor respiratory resistance (Rrs,int) during mechanical ventilation; however, Rrs,int is often interpreted as an index of airway resistance (Raw). This study compared the values of Rrs,int provided by a Siemens 940 Lung Mechanics Monitor with total respiratory impedance (Zrs) parameters in 39 patients with normal spirometric parameters, who were undergoing elective coronary bypass surgery. Zrs was determined at the airway opening with pseudorandom oscillations of 0.2–6 Hz at end inspiration. Raw and tissue resistance (Rti) were derived from the Zrs data by model fitting; Rti and total resistance (Rrs,osc=Raw+Rti) were calculated at the actual respirator frequencies. Lower airway resistance (Rawl) was estimated by measuring tracheal pressure. Although good agreement was obtained between Rrs,osc and Rrs,int, with a ratio of 1.07±0.19 (mean±sd), they correlated poorly (r2=0.36). Rti and the equipment component of Raw accounted for most of Rrs,osc (39.8±11.9 and 43.0±6.9%, respectively), whereas only a small portion belonged to Rawl (17.2±6.3%). It is concluded that respiratory resistance may become very insensitive to changes in lower airway resistance and therefore, inappropriate for following alterations in airway tone during mechanical ventilation, especially in patients with relatively normal respiratory mechanics, where the tissue and equipment resistances represent the vast majority of the total resistance.