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Atrial fibrillation (AF) is the most common cardiac arrhythmia. Concomitant heart failure (HF) poses a particular therapeutic challenge and is associated with prolonged atrial electrical refractoriness compared with non-failing hearts. We hypothesized that downregulation of atrial repolarizing TREK-1 (K2P2.1) K+ channels contributes to electrical remodeling during AF with HF, and that TREK-1 gene transfer would provide rhythm control via normalization of atrial effective refractory periods in this AF subset. In patients with chronic AF and HF, atrial TREK-1 mRNA levels were reduced by 82% (left atrium) and 81% (right atrium) compared with sinus rhythm (SR) subjects. Human findings were recapitulated in a porcine model of atrial tachypacing-induced AF and reduced left ventricular function. TREK-1 mRNA (−66%) and protein (−61%) was suppressed in AF animals at 14-day follow-up compared with SR controls. Downregulation of repolarizing TREK-1 channels was associated with prolongation of atrial effective refractory periods versus baseline conditions, consistent with prior observations in humans with HF. In a preclinical therapeutic approach, pigs were randomized to either atrial Ad-TREK-1 gene therapy or sham treatment. Gene transfer effectively increased TREK-1 protein levels and attenuated atrial effective refractory period prolongation in the porcine AF model. Ad-TREK-1 increased the SR prevalence to 62% during follow-up in AF animals, compared to 35% in the untreated AF group. In conclusion, TREK-1 downregulation and rhythm control by Ad-TREK-1 transfer suggest mechanistic and potential therapeutic significance of TREK-1 channels in a subgroup of AF patients with HF and prolonged atrial effective refractory periods. Functional correction of ionic remodeling through TREK-1 gene therapy represents a novel paradigm to optimize and specify AF management. [ABSTRACT FROM AUTHOR]

It is still unknown whether remote ischemic preconditioning is mediated by a humoral or a neurogenic mechanism from the preconditioning to the preconditioned tissue. The purpose of the following study was to identify a possible humoral trigger of ischemic myocardial preconditioning and remote renal preconditioning. Open chest rats were subjected to a coronary artery occlusion period of 45 min followed by 2 h of reperfusion (Control animals; n = 6). The coronary preconditioned group (IPC, n = 6) was subjected to a preceding preconditioning period of 5 min coronary artery occlusion followed by 5 min of reperfusion, repeated three times. The renal preconditioned group (IPR, n = 6) was subjected to a preceding renal artery occlusion period of 10 min followed by 20 min of reperfusion. Area at risk (AAR) and infarcted area (IA) were determined at the end of each protocol. Blood samples were taken at the end of the preconditioning protocols from parallel experiments for proteomic analysis using two–dimensional gel electrophoresis (2-DE), matrix assisted laser desorption and ionization—time of flight—mass spectrometry (MALDI–TOF–MS), and liquid chromatography—electrospray ionization—tandem mass spectrometry (nanoLC–ESI–MS/MS). IA/AAR was 87.8 ± 10.7% in the control group. IPC and IPR signi.cantly reduced IA/AAR (58.2 ± 9.3% and 56.9 ± 9.0%, p < 0.001). Proteomic analyses detected four protein spots which were either up– (n = 3) or down–regulated in the preconditioned groups vs. the control group. The three up–regulated protein spots were identi.ed as albumin fragments, whereas the downregulated spot was identified as liver regeneration–related protein (LRRG03). Interestingly, albumin modification by brief ischemia has been recently shown and evaluated for the clinical diagnosis of sublethal myocardial ischemia. However, no differentially abundant proteins which possess a known signaling function could be found. Hence, though there is a differential protein expression in blood following IPC and IPR, our data are not in favor of a humoral mediator of remote preconditioning with a molecular weight of more than 8 kDa. Our results rather suggest either a neurogenic pathway or a mediator smaller than 8 kDa. [ABSTRACT FROM AUTHOR]

Background Antiarrhythmic drugs for treatment of atrial fibrillation in patients with heart failure are limited by proarrhythmia and low efficacy. Experimental studies indicate that the pure IKs blocking agents chromanol 293b and HMR 1556 prolong repolarization more markedly at fast than at slow heart rates and during β-adrenergic stimulation. These properties may overcome some of the above quoted limitations. Methods and results Ten domestic swine underwent pacemaker implantation (PM) and atrial burst pacing to induce persistent AF. Four days after onset of persistent AP, pigs were randomized to HMR 1556 (30 mg/kg, p.o., 10 days) or placebo. AU animals receiving HMR 1556 converted to SR (5.2 ± 1.9 days), whereas placebo pigs remained in AF. Pigs treated with placebo developed high ventricular rates (297 ± 5 bpm) and severe heart failure, whereas pigs treated with HMR 1556 remained hemodynamicaily stable. Left ventricular ejection fraction on the day of euthanization was significantly lower in the placebo compared to the HMR 1556 group (30± 4% vs. 69± 5%,p <0.005). Similar results were seen with epinephrine levels (placebo 1563 ± 193 pmol/l vs. HMR 613 ± 196 pmol/l, p < 0.05). Right atrial monophasic action potentials were significantly longer in the HMR 1556 compared to the placebo group (230 ± 7 ms vs. 174 ± 13 ms, p < 0.05). Conclusions The new IKs blocker HMR 1556 efficiently and safely restores SR and prevents CHF in a model of persistent AF. Restoration of SR is most likely linked to a marked prolongation of atrial repolarization even at high heart rates. [ABSTRACT FROM AUTHOR]

Ventricular arrhythmias are often precipitated by physical or emotional stress, in particular in patients with ischemic heart disease or hereditary long QT syndrome. Stimulation of the sympathetic nervous system in response to exercise or emotional stress causes activation of cardiac α- and β-adrenoceptors. The rapid component of the delayed rectifier potassium current, IKr, and the underlying hERG potassium channel are critical for the regulation of heart rhythm. Recent experimental studies revealed that hERG/IKr currents are modulated by α- and β-adrenergic stimulation, providing a pathophysiological explanation for the increased incidence of arrhythmias during stress. This review summarizes the current knowledge on hERG/IKr channel modulation by adrenergic activity. In addition, therapeutic approaches to future effective, more genotype-specific antiarrhythmic therapies are discussed. [ABSTRACT FROM AUTHOR]

S100A1 is an interesting Ca2+ binding protein with respect to muscle physiology as it is preferentially expressed in cardiac muscle and colocalizes with the sarcolemmal and the sarcoplasmic reticulum membranes as well as with the sarcomere. It is therefore conceivable that S100A1 may play a specific role in the regulation of cardiac Ca2+ homeostasis and contractility. We therefore investigated the impact of adenoviral S100A1 overexpression on fractional shortening (FS%) and systolic Ca2+ transients in adult rat cardiomyocytes as well as of S100A1 protein on SERCA activity in skinned cell preparation. In our setting S100A1 gene transfer increased FS% by 55 %, systolic Ca2+ amplitudes by 62 %, while S100A1 protein increased SERCA activity by 28 %. Importantly, the gain in systolic Ca2+ supply was not only seen on basal conditions but also with isoproterenol-stimulated Ca2+ cycling. Thus, S100A1 enhances cardiac contractility by increasing intracellular Ca2+ fluxes at least in part due to a modulation of SERCA. Since earlier observations demonstrated S100A1 protein levels to be increased in compensatory hypertrophy and significantly downregulated in end stage heart failure, these functional data suggest that S100A1 is a novel determinant of cardiac function whose expression levels are causally related to the prevailing contractile state of the heart. [ABSTRACT FROM AUTHOR]

It previously has been reported in ischemic rat hearts that local release of noradrenaline triggers ventricular fibrillation via α1A-adrenoceptor stimulation. In order to elucidate the intracellular pathway mediating ventricular fibrillation in this setting, we used inhibitors or activators of protein kinase C in the absence or presence of the α1A-adrnoceptor antagonist WB 4101. Regional ischemia was induced in isolated perfused rat heart by ligature of the left coronary artery. Pharmacological interventions were tested by addition of drugs to the perfusate 10 min prior to ligature and throughout 30 min of ischemia while the epicardial electrocardiogram was continuously monitored. Blockade of protein kinase C by polymyxin B (1 μmol/l) significantly reduced ventricular fibrillation to 40% (from 87% in controls). Similar effects were seen with the protein kinase C inhibitors staurosporine 10 nmol/l (46% vs. 91%) and cremophor RH 40 100 μmol/l (33% vs. 77%). Activation of protein kinase C by 1,2-dioctanoyl-sn-glycerol (DOG, 10 μmol/l) or phorbol 12-myristate 13-acetate (PMA, 10 nmol/l) did not affect ventricular fibrillation. In the presence of the α1A-adrenoceptor antagonist WB 4101 (0.1 μmol/l), which per se suppressed ventricular fibrillation to 17%, both DOG and PMA increased the occurrence of ventricular fibrillation to 73% and 75%, respectively, whereas the inactivate phorbol ester 4alphaphorbol 12,13-didecanoate (4α-PDD, 10 nmol/l) revealed no proarrhythmic effect. In summary, during regional ischemia in the isolated perfused rat heart, α1A-adrenoceptor stimulation induces ventricular fibrillation mainly by activating protein kinase C. [ABSTRACT FROM AUTHOR]

Understanding molecular mechanisms involved in atrial tissue remodeling and arrhythmogenesis in atrial fibrillation (AF) is essential for developing specific therapeutic approaches. Two-pore-domain potassium (K2P) channels modulate cellular excitability, and TASK-1 (K2P3.1) currents were recently shown to alter atrial action potential duration in AF and heart failure (HF). Finding animal models of AF that closely resemble pathophysiological alterations in human is a challenging task. This study aimed to analyze murine cardiac expression patterns of K2P channels and to assess modulation of K2P channel expression in murine models of AF and HF. Expression of cardiac K2P channels was quantified by real-time qPCR and immunoblot in mouse models of AF [cAMP-response element modulator (CREM)-IbΔC-X transgenic animals] or HF (cardiac dysfunction induced by transverse aortic constriction, TAC). Cloned murine, human, and porcine TASK-1 channels were heterologously expressed in Xenopus laevis oocytes. Two-electrode voltage clamp experiments were used for functional characterization. In murine models, among members of the K2P channel family, TASK-1 expression displayed highest levels in both atrial and ventricular tissue samples. Furthermore, K2P2.1, K2P5.1, and K2P6.1 showed significant expression levels. In CREM-transgenic mice, atrial expression of TASK-1 was significantly reduced in comparison with wild-type animals. In a murine model of TAC-induced pressure overload, ventricular TASK-1 expression remained unchanged, while atrial TASK-1 levels were significantly downregulated. When heterologously expressed in Xenopus oocytes, currents of murine, porcine, and human TASK-1 displayed similar characteristics. TASK-1 channels display robust cardiac expression in mice. Murine, porcine, and human TASK-1 channels share functional similarities. Dysregulation of atrial TASK-1 expression in murine AF and HF models suggests a mechanistic contribution to arrhythmogenesis. [ABSTRACT FROM AUTHOR]