Alexander Bauer

Prophylactic implantation of cardioverter-defibrillator in patients with severe cardiac amyloidosis and high risk for sudden cardiac death

BACKGROUNDnCardiac light-chain amyloidosis carries a high risk for death predominantly from progressive cardiomyopathy or sudden death (SCD). Independent risk factors for SCD are syncope and complex nonsustained ventricular arrhythmias.nnnOBJECTIVEnThe purpose of this study was to test whether prophylactic placement of an implantable cardioverter-defibrillator (ICD) reduces SCD in patients with cardiac amyloidosis.nnnMETHODSnNineteen patients with histologically proven cardiac amyloidosis and a history of syncope and/or ventricular extra beats (Lown grade IVa or higher) received an ICD.nnnRESULTSnDuring a mean follow-up of 811 +/- 151 days, two patients with sustained ventricular tachyarrhythmias were successfully treated by the ICD. Two patients underwent heart transplantation, and seven patients died due to electromechanical dissociation (n = 6) or glioblastoma (n = 1). Nonsurvivors more often showed progression of left ventricular wall thickness, low-voltage pattern, ventricular arrhythmias (Lown grade IVa or higher), and higher N-terminal pro-brain natriuretic peptide levels than did survivors. Bradycardias requiring ventricular pacing (VVI 40/min <1%, DDD 60/min 6% +/- 1%) occurred only rarely.nnnCONCLUSIONnPatients with cardiac amyloidosis predominantly die as a result of electromechanical dissociation and other diagnoses not amenable to ICD therapy. Selected patients with cardiac amyloidosis may benefit from ICD placement. Better predictors of arrhythmia-associated SCD and randomized trials are required to elucidate the impact of ICD placement in high-risk patients with cardiac amyloidosis.

Regulation of two-pore-domain (K2P) potassium leak channels by the tyrosine kinase inhibitor genistein

Two‐pore‐domain potassium (K2P) channels mediate potassium background (or ‘leak’) currents, controlling excitability by stabilizing membrane potential below firing threshold and expediting repolarization. Inhibition of K2P currents permits membrane potential depolarization and excitation. As expected for key regulators of excitability, leak channels are under tight control from a plethora of stimuli. Recently, signalling via protein tyrosine kinases (TKs) has been implicated in ion channel modulation. The objective of this study was to investigate TK regulation of K2P channels.

Elevated B-type natriuretic peptide levels in patients with nonischemic cardiomyopathy predict occurrence of arrhythmic events

BackgroundPatients with nonischemic cardiomyopathy (DCM) are at high risk for sudden cardiac death (SCD). However, the predictive value of prophylactic implantation of implantable cardioverter defibrillators (ICD) in this patient cohort is yet unclear.Methods and ResultsWhether NT pro BNP levels and/or reproducible non sustained ventricular tachycardias (NSVTs) are predictive for SCD was prospectively tested in 30 patients with DCM and LVEF ≤ 40%. All patients received Holter-recordings (HR) on three consecutive days and baseline NT-pro BNP levels were determined. Patients were followed for occurrence of ventricular tachyarrhythmias or unexplained syncope. A great degree of variability was found regarding the occurrence of NSVTs (10% had NSVTs in two consecutive HR, 10% in three consecutive HR, 30% in one HR and 50% had no NSVTs). Patients with NSVTs in more than one HR had significantly higher NT-pro BNP levels (first quartile: 715 pg/ml, median 2,176 pg/ml, third quartile 5,755 pg/ml vs. first quartile 273 pg/ml, median 566 pg/ml, third quartile 1,350 pg/ml, P = 0.0388). During a mean follow-up of 21.6 ± 1.2 months patients with an arrhythmic event had significantly higher NT-pro BNP levels than patients without event (first quartile: 1,002 pg/ml, median 4,075 pg/ml, third quartile 7,777 pg/ml vs. first quartile 173 pg/ml, median 267 pg/ml, third quartile 1,220 pg/ml, P = 0.0135). NT-pro BNP levels of 2,259 pg/ml were identified as optimal cut-off value for the prediction of arrhythmic events (P = 0.0313). In contrast reproducible NSVTs were not predictive for arrhythmic events (P = 0.0960).ConclusionThe present study demonstrates that in patients with DCM the value of reproducible NSVTs in predicting arrhythmic events is low. In contrast raised NT-pro BNP levels significantly correlated with occurrence of symptomatic ventricular arrhythmias. Larger prospective trials are required to confirm these results.

Activation of inwardly rectifying Kir2.x potassium channels by β3-adrenoceptors is mediated via different signaling pathways with a predominant role of PKC for Kir2.1 and of PKA for Kir2.2

Abstractβ3-adrenoceptors have recently been shown to induce a complex modulation of intracellular signaling pathways including cyclic guanine monophosphate, cyclic adenosine monophosphate, Nitric oxide, and protein kinases A and C. They are expressed in a broad variety of tissues including the myocardium, vascular smooth muscle, and endothelium. In those tissues, resting membrane potential is controlled mainly by inwardly rectifying potassium channels of the Kir2 family namely, Kir2.1 in the vascular smooth muscle, Kir2.1–2.3 in the myocardium, and Kir2.1–2.2 in the endothelium. In the present study, we investigated the possible modulation of Kir2 channel function by β3-adrenoceptors in an expression system. Human-cloned β3-adrenoceptors and Kir2.1 (KCNJ2), Kir2.2 (KCNJ12), and Kir2.3 (KCNJ4) channels were coexpressed in Xenopus oocytes, and currents were measured with double-microelectrode voltage clamp. Activation of β3-adrenoceptors with isoproterenol resulted in markedly increased currents in Kir2.1 and in Kir2.2 potassium channels with EC50 values of 27 and 18xa0nM, respectively. In contrast, Kir2.3 currents were not modulated. Coapplication of specific inhibitors of protein kinase A (KT-5720) and calmodulin kinase II (KN-93) had no effects on the observed regulation in Kir2.1. However, coapplication of protein kinase C (PKC) inhibitors staurosporine and chelerythrine suppressed the observed effect. In Kir2.2, coapplication of KT-5720 reduced the effect of β3-adrenoceptor activation. No differences in current increase after application of isoproterenol were observed between mutant Kir2.2 potassium channels lacking all functional PKC phosphorylation sites and Kir2.2 wild-type channels. In heteromeric Kir2.x channels, all types of heteromers were activated. The effect was most pronounced in Kir2.1/Kir2.2 and in Kir2.2/Kir2.3 channels. In summary, homomeric and heteromeric Kir2.x channels are activated by β3-adrenoceptors via different protein kinase-dependent pathways: Kir2.1 subunits are modulated by PKC, whereas Kir2.2 is modulated by protein kinase A. In heteromeric composition, a marked activation of currents can be observed particularly with involvement of Kir2.2 subunits. This regulation may contribute to the hyperpolarizing effects of β3-adrenoceptors in tissues that exhibit modulation by Kir2 channel function.

Inhibition of cardiac hERG potassium channels by tetracyclic antidepressant mianserin

The antidepressant mianserin exhibits a tetracyclic structure that is different from typical tricyclic antidepressants (TCA) and that of selective serotonin reuptake inhibitors. In comparison to the older TCA, mianserin has been shown to have a superior risk profile regarding proarrhythmic effects, both in vitro and in vivo. However, the underlying molecular electrophysiological basis has not been elucidated to date. Therefore, we studied the effects of mianserin on cardiac hERG potassium channels, the predominant target of drug-induced proarrhythmia. HERG channels were expressed in the Xenopus oocyte expression system and in human embryonic kidney (HEK) cells and currents were measured with two-microelectrode voltage-clamp and whole-cell patch-clamp, respectively. Mianserin inhibited hERG currents in a dose-dependent manner with an IC50 of 3.2xa0μmol/l in HEK cells. Onset of blockade was slow and the inhibitory effect was not reversible upon wash-out of the drug. In hERG channel mutants, Y652A and F656A, lacking aromatic residues in the S6 domain, the effect of mianserin was significantly reduced in comparison to the wild type. Mianserin inhibited hERG currents in the open and inactivated state, but not in the closed states. HERG inactivation kinetics were significantly altered by mianserin without marked effects on channel activation kinetics. The inhibitory effect was not frequency dependent. In conclusion, mianserin is a low-affinity hERG-blocking agent. However, taken together with the lack of APD-prolongation shown in other studies, mianserin seems to have a good safety profile. Lack of consistent QT prolonging effects of mianserin in previous studies may therefore be linked to additional effects such as inhibition of other cardiac ion channels. However, as demonstrated by clinical case reports, mianserin can induce proarrhythmic effects in susceptible patients. Therefore, in patients with complex co-medication (i.e., additional hERG-blocking agents) and in patients with risk factors for acquired long QT syndrome as well as in cases of overdose, adequate monitoring should be recommended.

Atypical tetracyclic antidepressant maprotiline is an antagonist at cardiac hERG potassium channels

Maprotiline is an antidepressant compound with an atypical tetracyclic structure that is widely used in elderly patients due to its favourable side-effect profile. However, there have been reports of proarrhythmia associated with maprotiline and in vitro studies of its electrophysiological properties have been lacking. Therefore, we characterised the effects of maprotiline on cardiac hERG channels. hERG channels were expressed in HEK cells and in the Xenopus oocyte expression system. Currents were measured using a whole-cell patch clamp and a two-microelectrode voltage-clamp. Maprotiline inhibited hERG currents with an IC50 of 8.2xa0μmol/l in HEK cells and 29.2xa0μmol/l in Xenopus oocytes. Onset of the effect was rather slow and took several minutes. No wash-out of effect was observed. Maprotiline blocked hERG channels in the open and inactivated states, but not in the closed states. In mutant hERG channels Y652A and F656A, the effect was markedly attenuated (hERG-F656A) or completely abolished (hERG-Y652A). Voltage dependence of hERG current activation and inactivation was not affected by maprotiline. hERG inactivation was accelerated at positive potentials. The effect of maprotiline on hERG currents was voltage-dependent with a marked reduction at a more positive potential. hERG blockade by maprotiline was not frequency-dependent. Maprotiline is an antagonist of cardiac hERG potassium channels that preferably accesses the putative pore binding site Y652/F656. Although the affinity of maprotiline to hERG channels is low, its use in patients with risk factors for acquired long QT syndrome should be monitored appropriately.

Indications for predismissal testing with arrhythmia-induction in patients receiving an implantable cardioverter defibrillator

AbstractArrhythmia inductionnduring implantation of cardioverterndefibrillators (ICD) is anstandard procedure. However,ncontroversy exists regarding thenneed for routine arrhythmia inductionnbefore discharge fromnhospital (pre-hospital dischargen(PHD) test). In order to reducenthe number of tests we identifiednrisk factors that predict relevantnICD malfunction.Methods and results965 patients receiving anfirst device implantation (n = 724)nor device/system replacementn(n = 241) between 1998 and 2004nwere analysed. During implantationn176 (18%) complications (intraoperativenundersensing of inducednarrhythmias, unsuccessfulnarrhythmia-therapy or low DFTnsafety margin) occurred. Frequentn(> 4 times) intraoperative lead repositioningndue to low sensingnvalues was present in 44 patientsn(5%). 9% of the patients withnfirst ICD implantation, 21% withndevice replacement and 27% withnsystem replacement developedncomplications during PHD testingnwith arrhythmia induction. Intraoperativencomplications,nalthough corrected during implantation,nwere independent risknfactors for malfunction duringnPHD testing (p < 0.05). Additionalnpredictors for malfunction werenintraoperative lead repositioningn(> 4 times) and a history of bothnVF and VT (p < 0.05). Patientsnwithout intraoperative complicationsnrarely developed malfunctionnduring PHD testingn(3.7% first device, 6.25% systemnreplacement). Only in patientsnundergoing device replacementnwas a higher risk for failuren(13%) evident. No risk factorsncould be identified for thesensubgroups.ConclusionRoutinenarrhythmia induction duringnPHD is recommended in ICD patientsnwith intraoperative complications,nalthough corrected duringnimplantation, as well as frequentnintraoperatives lead repositioning.nPatients undergoing device/nsystem replacement uncomplicatednimplantation are notngenerally at low risk for devicenfailure.

Anticholinergic antiparkinson drug orphenadrine inhibits HERG channels: block attenuation by mutations of the pore residues Y652 or F656

The anticholinergic antiparkinson drug orphenadrine is an antagonist at central and peripheral muscarinic receptors. Orphenadrine intake has recently been linked to QT prolongation and Torsade-de-Pointes tachycardia. So far, inhibitory effects on IKr or cloned HERG channels have not been examined. HERG channels were heterologously expressed in a HEK 293 cell line and in Xenopus oocytes and HERG current was measured using the whole cell patch clamp and the double electrode voltage clamp technique. Orphenadrine inhibits cloned HERG channels in a concentration dependent manner, yielding an IC50 of 0.85xa0μM in HEK cells. Onset of block is fast and reversible upon washout. Orphenadrine does not alter the half-maximal activation voltage of HERG channels. There is no shift of the half-maximal steady-state-inactivation voltage. Time constants of direct channel inactivation are not altered significantly and there is no use-dependence of block. HERG blockade is attenuated significantly in mutant channels lacking either of the aromatic pore residues Y652 and F656. In conclusion, we show that the anticholinergic agent orphenadrine is an antagonist at HERG channels. These results provide a novel molecular basis for the reported proarrhythmic side effects of orphenadrine.