1-(3-sulfonatopropyl)-4-(beta)(2-(di-n-butylamino)-6-naphthylvinyl)pyridinium-betaine and Disease-Models--Animal

Andersen-Tawil syndrome (ATS1)-associated ventricular tachycardias (VTs) are initiated by frequent, hypokalemia-exacerbated, premature ventricular activity (PVA). We previously demonstrated that a guinea pig model of drug-induced ATS1 (DI-ATS1) evidenced increased arrhythmias from regions with high Na(+)/Ca(2+)-exchange expression.. Therefore, we hypothesize that reduced cytosolic Na(+) entry through either cardiac isoform of or tetrodotoxin (TTX)-sensitive Na(+) channels during DI-ATS1 can ameliorate arrhythmia burden.. DI-ATS1 was induced with 10 μM BaCl(2) and 2 mM extracellular K(+). Ca(2+) transients and conduction velocity (CV) were optically mapped with indo-1 and di-4-ANEPPS, respectively, from Langendorff-perfused guinea pig ventricles.. Nonselective Na(+) channel blockade with 1 μM flecainide reduced amplitude (Ca(A)), slowed left ventricular CV, reduced tissue excitability, and abolished the incidence of VT while decreasing the incidence of PVA relative to DI-ATS1. Selective, TTX-sensitive Na(+) channel blockade with TTX (100 nM) during DI-ATS1 decreased Ca(A) and decreased the inducibility of VTs and PVA relative to DI-ATS1 without slowing CV. Ranolazine altered Ca(A), left ventricular CV, tissue excitability, and reduced inducibility of VT and PVA in a concentration-dependent manner. None of the aforementioned interventions altered diastolic Ca(2+) levels or Ca(2+) transient decay time constant.. These data suggest that cytosolic Na(+) entry and its modulation of Ca(2+) handling are necessary for arrhythmogenesis. During the loss of inward-rectifier K(+) current function, not only Na(+)/Ca(2+)-exchange dominance but Na(+) flux may determine arrhythmia burden. Therefore, selective inhibition of TTX-sensitive Na(+) channels may offer a potential therapeutic target to alleviate arrhythmias during states of Ca(2+) overload secondary to loss of inward-rectifier K(+) current function without compromising the excitability reserve.

Topics: Acetanilides; Action Potentials; Andersen Syndrome; Animals; Calcium Channels; Cytosol; Disease Models, Animal; Dose-Response Relationship, Drug; Electrocardiography; Guinea Pigs; Male; Piperazines; Pyridinium Compounds; Random Allocation; Ranolazine; Sensitivity and Specificity; Sodium Channels; Sodium-Calcium Exchanger; Tachycardia, Ventricular

In ventricular myocytes, the majority of structures that couple excitation to the systolic rise of Ca(2+) are located at the transverse tubular (t-tubule) membrane. In the failing ventricle, disorganization of t-tubules disrupts excitation contraction coupling. The t-tubule membrane is virtually absent in the atria of small mammals resulting in spatiotemporally distinct profiles of intracellular Ca(2+) release on stimulation in atrial and ventricular cells. The aims of this study were to determine (i) whether atrial myocytes from a large mammal (sheep) possess t-tubules, (ii) whether these are functionally important, and (iii) whether they are disrupted in heart failure.. Sheep left atrial myocytes were stained with di-4-ANEPPS. Nearly all control cells had an extensive t-tubule network resulting in each voxel in the cell being nearer to a membrane (sarcolemma or t-tubule) than would otherwise be the case. T-tubules decrease the distance of 50% of voxels from a membrane from 3.35 + or - 0.15 to 0.88 + or- 0.04 microm. During depolarization, intracellular Ca(2+) rises simultaneously at the cell periphery and center. In heart failure induced by rapid ventricular pacing, there was an almost complete loss of atrial t-tubules. The distance of 50% of voxels from a membrane increased to 2.04 + or - 0.08 microm, and there was a loss of early Ca(2+) release from the cell center.. Sheep atrial myocytes possess a substantial t-tubule network that synchronizes the systolic Ca(2+) transient. In heart failure, this network is markedly disrupted. This may play an important role in changes of atrial function in heart failure.

Topics: Animals; Atrial Function, Left; Calcium Signaling; Cardiac Pacing, Artificial; Disease Models, Animal; Fluorescent Dyes; Heart Atria; Heart Failure; Image Processing, Computer-Assisted; Microscopy, Confocal; Myocardial Contraction; Myocytes, Cardiac; Pyridinium Compounds; Rats; Sarcolemma; Sheep; Ventricular Function, Left

Diabetes is associated with high rates of cardiovascular disease and sudden death. Therefore, dissecting specific mechanisms, such as the effects of impaired insulin signaling on cardiac electrophysiology may lead to better diagnosis and treatment. Lack of insulin receptors in mouse myocytes has been shown to reduce repolarizing potassium currents and prolong action potential duration. We hypothesized that these changes would manifest as rate-related effects on electrical propagation in the intact heart. This study employed optical mapping to characterize propagation changes in intact mouse hearts with cardiomyocyte-restricted knock out of insulin receptors (CIRKO).. Fluorescent signals emitted from excited Di-4-ANEPPS in isolated Langendorff perfused mouse hearts were recorded from the left ventricular epicardium using an 8 by 8 photo diode array. The study included hearts from 8 CIRKO mice and 8 wild type (WT) littermate controls. Hearts were stimulated from the right atrium or the left ventricle at basic cycle lengths ranging from 160 to 280 ms under normal conditions and then after 5 minutes of perfusion with elevated potassium ion concentration (9.4 mM).. None of the 8 CIRKO hearts maintained regular responses to atrial stimulation at the 160 ms cycle length under normal conditions; however, all of the WT hearts were captured at this rate. Total activation time for a 4 mm by 4 mm area was longer for CIRKO hearts when compared with WT. Average epicardial conduction velocity was slower for the CIRKO when compared to WT. Propagation delay due to the presence of high [K+]e was significant in both CIRKO and WT mice, but significantly longer for the CIRKO hearts.. These results show that in addition to reducing repolarization currents, impaired myocardial insulin signaling leads to impaired electrical impulse propagation particularly at increased heart rates. These data suggest a link between impaired myocardial insulin signaling and the increased risk of arrhythmia and sudden death in patients with diabetes.

Topics: Action Potentials; Animals; Cardiac Pacing, Artificial; Disease Models, Animal; Electrocardiography; Fluorescent Dyes; Heart Rate; Insulin; Mice; Mice, Knockout; Myocardial Contraction; Myocytes, Cardiac; Organ Culture Techniques; Pericardium; Potassium; Pyridinium Compounds; Receptor, Insulin; Risk Factors; Signal Transduction

The reentrant pathways underlying different types of atrioventricular (AV) nodal reentrant tachycardia have not yet been elucidated. This study was performed to optically map Koch's triangle and surrounding atrial tissue in an isolated canine AV nodal preparation. Multiple preferential AV nodal input pathways were observed in all preparations (n=22) with continuous (73%, n=16) and discontinuous (27%, n=6) AV nodal function curves (AVNFCs). AV nodal echo beats (EBs) were induced in 54% (12/22) of preparations. The reentrant circuit of the slow/fast EB (36%, n=8) started as a block in fast pathway (FP) and a delay in slow pathway (SP) conduction to the compact AV node, then exited from the AV node to the FP, and rapidly returned to the SP through the atrial tissue located at the base of Koch's triangle. The reentrant circuit of the fast/slow EB (9%, n=2) was in an opposite direction. In the slow/slow EB (9%, n=2), anterograde conduction was over the intermediate pathway (IP) and retrograde conduction was over the SP. Unidirectional conduction block occurred at the junction between the AV node and its input pathways. Conduction over the IP smoothed the transition from the FP to the SP, resulting in a continuous AVNFC. A "jump" in AH interval resulted from shifting of anterograde conduction from the FP to the SP (n=4) or abrupt conduction delay within the AV node through the FP (n=2). These findings indicate that (1) multiple AV nodal anterograde pathways exist in all normal hearts; (2) atrial tissue is involved in reentrant circuits; (3) unidirectional block occurs at the interface between the AV node and its input pathways; and (4) the IP can mask the existence of FP and SP, producing continuous AVNFCs.

Topics: Action Potentials; Animals; Atrioventricular Node; Body Surface Potential Mapping; Cardiac Pacing, Artificial; Cytochalasin D; Disease Models, Animal; Dogs; Electric Stimulation; Electrophysiologic Techniques, Cardiac; Fluorescent Dyes; Heart Conduction System; In Vitro Techniques; Microelectrodes; Optics and Photonics; Pyridinium Compounds; Reaction Time; Tachycardia, Atrioventricular Nodal Reentry; Video Recording