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Altered gap-junctional distribution is part of the early remodeling of myocardium after infarction, and by defining the location of the common central pathway of the reentrant VT circuits, it may be a determinant of VT susceptibility.

Background-Takotsubo cardiomyopathy is an acute heart failure syndrome characterized by myocardial hypocontractility from the mid left ventricle to the apex. It is precipitated by extreme stress and can be triggered by intravenous catecholamine administration, particularly epinephrine. Despite its grave presentation, Takotsubo cardiomyopathy is rapidly reversible, with generally good prognosis. We hypothesized that this represents switching of epinephrine signaling through the pleiotropic ␤ 2 -adrenergic receptor (␤ 2 AR) from canonical stimulatory G-protein-activated cardiostimulant to inhibitory G-protein-activated cardiodepressant pathways. Methods and Results-We describe an in vivo rat model in which a high intravenous epinephrine, but not norepinephrine, bolus produces the characteristic reversible apical depression of myocardial contraction coupled with basal hypercontractility. The effect is prevented via G i inactivation by pertussis toxin pretreatment. ␤ 2 AR number and functional responses were greater in isolated apical cardiomyocytes than in basal cardiomyocytes, which confirmed the higher apical sensitivity and response to circulating epinephrine. In vitro studies demonstrated high-dose epinephrine can induce direct cardiomyocyte cardiodepression and cardioprotection in a ␤ 2 AR-Gi-dependent manner. Preventing epinephrine-G i effects increased mortality in the Takotsubo model, whereas ␤-blockers that activate ␤ 2 AR-G i exacerbated the epinephrine-dependent negative inotropic effects without further deaths. In contrast, levosimendan rescued the acute cardiac dysfunction without increased mortality. Conclusions-We suggest that biased agonism of epinephrine for ␤ 2 AR-G s at low concentrations and for G i at high concentrations underpins the acute apical cardiodepression observed in Takotsubo cardiomyopathy, with an apical-basal gradient in ␤ 2 ARs explaining the differential regional responses. We suggest this epinephrine-specific ␤ 2 AR-G i signaling may have evolved as a cardioprotective strategy to limit catecholamine-induced myocardial toxicity during acute stress. (Circulation. 2012;126:697-706.)Key Words: acute heart failure Ⅲ catecholamines Ⅲ receptors, adrenergic, beta Ⅲ Takotsubo syndrome T here has been a rapid increase in the recognition of a syndrome of acute and severe but reversible heart failure called Takotsubo or stress cardiomyopathy, 1-3 also known as broken heart syndrome, which usually follows within hours of an identifiable emotional, psychological, or physical stress. Takotsubo cardiomyopathy mimics symptoms of acute myocardial infarction but is distinguished by the lack of coronary occlusion and by characteristic regional wall-motion abnormalities, classically a virtual apical ballooning appearance caused by a hypercontractile base of the heart relative to hypokinetic or akinetic apical and mid left ventricular myocardium, the latter extending beyond a single coronary artery territory. Clinical Perspective on p 706The pathophysiological mechanisms for this increasingly recogn...

Gap junctions in normal adult human working ventricular myocardium occupy an area of 0.0051 micron2/micron3 myocyte volume. This surface area is reduced in ventricular myocardium from hearts subject to chronic hypertrophy and ischemia, despite a normal number of intercellular abutments, and this alteration may contribute to abnormal impulse propagation in these hearts.

Dronedarone increased rates of heart failure, stroke, and death from cardiovascular causes in patients with permanent atrial fibrillation who were at risk for major vascular events. Our data show that this drug should not be used in such patients. (Funded by Sanofi-Aventis; PALLAS ClinicalTrials.gov number, NCT01151137.).

Background-The patterns of activation of the human left atrium (LA), how they relate to atrial myocardial architecture, and their role in arrhythmogenesis remain largely unknown. Methods and Results-Left atrial endocardial activation was mapped in 19 patients with a percutaneous noncontact mapping system. Earliest endocardial breakthrough during sinus rhythm (SR) occurred more frequently in the septal (63%, principally posteroseptal) than anterosuperior (37%) LA and varied little with isoproterenol or high right atrial pacing rate. Regardless of site of breakthrough, LA activation was characterized in all patients by propagation around a variably complete line of functional conduction block, descending on the posterior wall from the roof, passing between the ostia of the superior and then inferior pulmonary veins (PVs) before turning septally, passing below the oval fossa, and merging further anteriorly with the septal mitral annulus. Examination of the myocardial architecture in 10 normal adult postmortem hearts revealed an abrupt change in subendocardial fiber orientation along a line following the same course. During episodes of focal initiation of atrial fibrillation (AF), interaction was observed between wavefronts entering the LA from PVs and this functional line of conduction block that resulted in LA macroreentry or formation of daughter wavefronts. Conclusions-The LA endocardium has complex but characteristic patterns of activation during sinus rhythm, pacing, and AF initiation by PV ectopy that are determined largely by the functional properties of atrial musculature. These findings have important implications for both pacing and ablative strategies for the prevention of initiation of AF.

Abstract-The epicardial border zone (EBZ) of canine infarcts has increased anisotropy because of transverse conduction slowing. It remains unknown whether changes in gap junctional conductance (G j ) accompany the increased anisotropy. Ventricular cell pairs were isolated from EBZ and normal hearts (NZ). Dual patch clamp was used to quantify G j . At a transjunctional voltage (V j ) of ϩ10 mV, side-to-side G j of EBZ pairs (9.2Ϯ3.4 nS, nϭ16) was reduced compared with NZ side-to-side G j (109.4Ϯ23.6 nS, nϭ14, PϽ0.001). Key Words: gap junction Ⅲ myocardial infarction Ⅲ arrhythmias A fter coronary occlusion, a border zone of myocytes survives on the epicardial surface of healing canine infarcts, the epicardial border zone (EBZ). 1,2 The EBZ is characterized by reduced conduction velocity and increased anisotropy 1,2 associated with the occurrence of reentrant circuits and ventricular tachycardia. 1 Reduced sodium current 3,4 in EBZ myocytes may contribute to decreased conduction velocity. We studied gap junctional conductance in pairs of EBZ myocytes to determine if alterations occur and, therefore, might also contribute to changes in conduction and anisotropy. Connexin43 (Cx43) was quantified to determine if conductance changes were related to alterations in quantity of this gap junctional protein. Materials and Methods Preparation of Myocyte PairsCell pairs were obtained from EBZ of infarcted canine left ventricle, 5 days after coronary occlusion. Surgical methods for occlusion 1,2 and enzymatic techniques for cell disaggregation 4 have been described. EBZ tissue was removed from a region between the LAD and first circumflex branch that was visibly identified as infarct by its pale appearance (Figure 1), similar to the region sampled in previous studies of EBZ cells. 3,4 Because tachycardia was not induced nor reentry mapped, tissues did not come specifically from the central common pathway of reentrant circuits where we previously described redistribution of Cx43 gap junctions 5 (Figure 1). For normal pairs (NZ), tissue from a similar region in noninfarcted hearts was used.Studies were performed on both end-to-end-and side-to-sidecoupled EBZ and NZ myocyte pairs, 2 to 8 hours after isolation. The morphological criterion for side-to-side coupling was greater than 50% contact of cell lengths. The criterion for end-to-end coupling was contact of more than 60% of the end-to-end surfaces between each of two paired cells and less than 10% contact of side-to-side cell surfaces. 6 According to these criteria, about 60% of all cell pairs isolated were end-to-end coupled, and 40% were side-to-side coupled. End-to-end coupled pairs were easily identified under the optical microscope, because intercalated disks between the two cells could be seen clearly. It was sometimes difficult to identify a side-to-side coupled pair under the microscope because, on occasion, either a single large myocyte, or three myocytes coupled with each other without clear borders, resembled a cell pair. To verify that currents were recorded from a...

Changes in the spatiotemporal patterns of the intercellular junctions responsible for electrical and mechanical coupling are closely coordinated in postnatal human ventricular myocardium and continue to about 6 years of age. Over this period there is a close and increasing association between the gap junctions and fascia adherens junctions. These changes in the distribution of intercellular electrical and adhering junctions may parallel the changing functional requirements of the ventricle, from a distribution that facilitates the remodeling necessitated by rapid growth and changing hemodynamics to that of the relatively stable and rapidly conducting adult myocardium. These age-related changes may also diminish the ability for appropriate myocardial remodeling in response to physiological, pathological, or surgical hemodynamic alterations.