Abstract-During ischemia and reperfusion, with an increase in intracellular Na ϩ and a depolarized membrane potential, Ca 2ϩ may enter the myocyte in exchange for intracellular Na ϩ via reverse-mode Na ϩ -Ca 2ϩ exchange (NCX). To test the role of Ca 2ϩ entry via NCX during ischemia and reperfusion, we studied mice with cardiac-specific ablation of NCX (NCX-KO) and demonstrated that reverse-mode Ca 2ϩ influx is absent in the NCX-KO myocytes. Langendorff perfused hearts were subjected to 20 minutes of global ischemia followed by 2 hours of reperfusion, during which time we monitored high-energy phosphates using 31 P-NMR and left-ventricular developed pressure. In another group of hearts, we monitored intracellular Na ϩ using 23 Na-NMR. Consistent with Ca 2ϩ entry via NCX during ischemia, we found that hearts lacking NCX exhibited less of a decline in ATP during ischemia, delayed ischemic contracture, and reduced maximum contracture. Furthermore, on reperfusion following ischemia, NCX-KO hearts had much less necrosis, better recovery of left-ventricular developed pressure, improved phosphocreatine recovery, and reduced Na ϩ overload. The improved recovery of function following ischemia in NCX-KO hearts was not attributable to the reduced preischemic contractility in NCX-KO hearts, because when the preischemic workload was matched by treatment with isoproterenol, NCX-KO hearts still exhibited improved postischemic function compared with wild-type hearts. Thus, NCX-KO hearts were significantly protected against ischemia-reperfusion injury, suggesting that Ca 2ϩ entry via reverse-mode NCX is a major cause of ischemia/reperfusion injury.

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Dual atrioventricular nodal non-re-entrant tachycardia (DAVNNT), also known as 'double fire', has recently received more attention since it was demonstrated to mimic more common arrhythmias such as atrial premature beats, atrial fibrillation, and ventricular tachycardia. This is important, since mistaken differential diagnoses and the resulting therapeutic decisions have severe consequences for affected patients. DAVNNT is characterized by conduction characteristics of the atrioventricular (AV) node that leads to a double antegrade conduction of one sinoatrial nodal activity via the slow and fast AV nodal pathways. As a result, the most significant hint from an electrocardiogram (ECG) is a P wave followed by two narrow QRS complexes. Although DAVNNT is rather a rare arrhythmia, it now appears to be more common than previously thought. To date, 68 cases including 3 small single-centre observational studies accumulated over the last 5 years have demonstrated the feasibility and safety of radiofrequency catheter ablation for DAVNNT. Catheter ablation treats this arrhythmia effectively by modifying or eliminating slow pathway function. Here, we review the current state of DAVNNT knowledge systematically and address current challenges presented by this 'ECG chameleon from the AV node'.

1 b-adrenoceptors are important modulators of cardiac function. The present study investigated b 3 -adrenergic eNOS activation in human myocardium. 2 We measured nitric oxide (NO) liberation (diaminofluorescence) and signal transduction (immunohistochemistry, phosphorylation of eNOS Ser1177 , eNOS Thr495 , eNOS Ser114 , Akt/protein kinase B (Akt/PKB), and eNOS translocation) in human right atrial (RA, aortocoronary-bypass OP) and left ventricular nonfailing (LV, rejected donor hearts) myocardium after application of BRL 37344 (BRL), a preferential b 3 -adrenoceptor agonist. 3 In both RA and LV, BRL (10 ml) induced a liberation of NO. An eNOS activation via translocation was only observed in RA after application of BRL (10 mM). Yet, the NO liberation in both LV and RA was accompanied by phosphorylation of eNOS Ser1177 and Akt/PKB. BRL-induced eNOS phosphorylation was abolished by LY292004, a blocker of PI-3 kinase. eNOS-Ser 114 phosphorylation was unchanged in RA, but decreased in LV after b 3 -adrenergic stimulation. BRL did not alter phosphorylation of eNOS Thr495 . 4 In conclusion, receptor-dependent eNOS activation is differentially regulated in the human heart. In the left ventricle, eNOS activation via phosphorylation seems to be of major importance, whereas in human atrial myocardium eNOS translocation is the predominant mechanism induced by b 3 -adrenergic activation.

L-type Ca2+ current (I(Ca)) is reduced in myocytes from cardiac-specific Na+-Ca2+ exchanger (NCX) knockout (KO) mice. This is an important adaptation to prevent Ca2+ overload in the absence of NCX. However, Ca2+ channel expression is unchanged, suggesting that regulatory processes reduce I(Ca). We tested the hypothesis that an elevation in local Ca2+ reduces I(Ca) in KO myocytes. In patch-clamped myocytes from NCX KO mice, peak I(Ca) was reduced by 50%, and inactivation kinetics were accelerated as compared to wild-type (WT) myocytes. To assess the effects of cytosolic Ca2+ concentration on I(Ca), we used Ba2+ instead of Ca2+ as the charge carrier and simultaneously depleted sarcoplasmic reticular Ca2+ with thapsigargin and ryanodine. Under these conditions, we observed no significant difference in Ba2+ current between WT and KO myocytes. Also, dialysis with the fast Ca2+ chelator BAPTA eliminated differences in both I(Ca) amplitude and decay kinetics between KO and WT myocytes. We conclude that, in NCX KO myocytes, Ca2+-dependent inactivation of I(Ca) reduces I(Ca) amplitude and accelerates current decay kinetics. We hypothesize that the elevated subsarcolemmal Ca2+ that results from the absence of NCX activity inactivates some L-type Ca2+ channels. Modulation of subsarcolemmal Ca2+ by the Na+-Ca2+ exchanger may be an important regulator of excitation-contraction coupling.

1 The present study investigated the eects of the preferential b 3 -AR agonist BRL 37344 (BRL) on force of contraction (FOC), Ca 2+ -transient and eNOS-activity in human right atrial myocardium. 2 BRL concentration-dependently caused an increase in FOC that was paralleled by an increase in Ca 2+ -transient and a shortening of time to half peak relaxation (T0.5T). These eects were abolished in the presence of propranolol (0.3 mM).3 BRL acted as a competitive antagonist towards isoprenaline and in binding experiments it was shown to have a distinct anity towards b 1/2 -AR. 4 In immunohistochemical experiments BRL (10 mM) increased detection of activated eNOS. This eect remained constant in the presence of propranolol (0.3 mM). 5 BRL increased directly detected NO in DAF-staining experiments. This increase was signi®cantly smaller in the presence of the NO-inhibitor L-NAME. 6 The inotropic eects of BRL were not changed in the presence of L-NMA. 7 These results suggest that the inotropic eects of BRL in human atrium are mediated via b 1/2 -AR, whereas the increase of atrial eNOS-activity is due to b 3 -adrenergic stimulation. This increase in eNOS-activity did not in¯uence atrial myocardial contractility. In conclusion, this study shows that b 3 -adrenergic stimulation is present in human atrium, but may not be functionally as signi®cant as in the left ventricle.