These data indicate that although both autonomic systems play a role in AF, cholinergic stimulation is likely the main factor for spontaneous AF initiation in this animal model. Adrenergic tone modulates the initiation and maintenance of cholinergically mediated AF.

Vagal stimulation results in complex changes of pacemaker excitability in the sinoatrial node (SAN). To investigate the vagal effects in the rabbit SAN, we used optical mapping, which is the only technology that allows resolving simultaneous changes in the activation pattern and action potentials morphologies. With the use of immunolabeling, we identified the SAN as a neurofilament 160-positive but connexin 43-negative region (n = 5). Normal excitation originated in the SAN center with a cycle length (CL) of 405 +/- 14 ms (n = 14), spread anisotropically along the crista terminalis (CT), and failed to conduct toward the septum. Postganglionic nerve stimulation (PNS, 400-800 ms) reduced CL by 74 +/- 7% transiently and shifted the leading pacemaker inferiorly (78%) or superiorly (22%) from the SAN center by 2-10 mm. In the intercaval region between the SAN center and the septal block zone, PNS produced an 8 +/- 1-mm(2) region of transient hyperpolarization and inexcitability. The first spontaneous or paced excitation following PNS could not enter this region for 500-1,500 ms. Immunolabeling revealed that the PNS-induced inexcitable region is located between the SAN center and the block zone and has a 2.5-fold higher density of choline acetyltransferase than CT but is threefold lower than the SAN center. The fact that the inexcitability region does not coincide with the most innervated area indicates that the properties of the myocytes themselves, as well as intercellular coupling, must play a role in the inexcitability induction. Optically mapping revealed that PNS resulted in transient loss of pacemaker cell excitability and unidirectional entrance conduction block in the periphery of SAN.

This paper summarizes the data concerning the role of the creatine phosphokinase system in muscle cells with main attention to the cardiac muscle. Creatine phosphokinase isoenzymes play a key role in the intracellular energy transport from mitochondria to myofibrils and other sites of energy utilization. Due to the existence of the creatine phosphate pathway for energy transport, intracellular creatine phosphate concentration is apparently an important regulatory factor for muscle contraction which influences the contractile force by determining the rate of regeneration of ATP directly available for myosin ATPase, and at the same time controls the activator calcium entry into the myoplasm across the surface membrane of the cells.

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We used cesium chloride (CsCI) for electrophysiologic studies in canine hearts in vivo and in vitro to examine the mechanisms underlying ventricular arrhythmias that are related to prolonged repolarization. Cesium is known to depress normal ventricular automaticity and some experimental arrhythmias by blocking delayed outward currents and prolonging action potential duration. In 10 dogs in normal sinus rhythm, 1 to 1.5 mM/kg iv CsCl prolonged the QT (QU) interval and induced ventricular ectopy in all, including multiform ventricular tachycardia. In 12 dogs with atrioventricular block, I to 1.5 mM/kg iv CsCl produced marked suppression of idioventricular rates (from 45 + 6 to 8 4 beats/min). These low rates were then associated with bigeminy or bursts of multiform ventricular arrhythmia. Pacing at rates of 60 beats/min or more suppressed these arrhythmias. Low doses of tetrodotoxin (1 ,ug/kg) also abolished these bradycardia-dependent arrhythmias without affecting the amplitude of ventricular electrograms. Tissue concentrations of cesium were determined by anatomic absorption spectroscopy in five dogs after injection of I mM/kg CsCl. Thirty minutes after the injection, cesium levels in Purkinje fibers were 5.3 ± 1.0 mM/kg, levels in ventricular muscle were 4.6 + 0.9 mM/kg, and levels in atrial muscle were 4.1 ± 0.8 mM/kg. In eight isolated endocardial preparations from canine ventricles, standard microelectrode techniques were used to study the effects of superfusion with 5 mM cesium. After 30 min, we observed early afterdepolarizations interrupting phase 3 of Purkinje fiber action potentials that already showed prolonged repolarization.' Slowing the rate generated single or multiple action potentials arising from partially repolarized levels of membrane potentials ( 80 to -65 mV). Pacing rates of 30 to 60 beats/min diminished the afterdepolarizations and suppressed the spontaneous beats. Tetrodotoxin at a concentration of 10-g/ml, which did not affect upstroke velocity, abolished'the afterpotentials. We conclude that cesium induced bradycardiadependent ventricular arrhythmias caused by early afterdepolarizations. These data suggest that an inward current, probably carried by sodium ions, appears to be essential for the occurrence of this phenomenon. The association of delayed repolarization, afterdepolarizations, and triggered activity has similarities to the phenomenon of drug-induced prolongation of the QTU interval associated with multiform ventricular tachycardia in humans, i.e. "torsades de pointes." Circulation 68, No. 4, 846-856, 1983. IN THE PAST DECADE, information has been accumulating on the occurrence of afterdepolarizations and triggered activity in cardiac tissue and their possible role in the generation of cardiac arrhythmias under various experimental conditions. A substantial amount of data concerning delayed afterdepolarizations has been acquired from experiments with preparations in From the

(1) Occurrence of vagally induced APDs and AF increases with increasing frequency of VS. (2) VS-induced focal ectopic APDs are widely distributed over the atria. (3) A single APD can be sufficient for initiation of reentrant AF. (4) Despite its high rate of sustained AF, it may be maintained by single stable reentrant circuit. (5) The atrial septum can play an important role in both the initiation and the maintenance of VS-induced AF.

BACKGROUND Robust cell-to-cell coupling is critically important in the safety of cardiac conduction and protection against ventricular fibrillation (VF). Hibernating mammals have evolved naturally protective mechanisms against VF induced by hypothermia and reperfusion injury. OBJECTIVE We hypothesized that this protection strategy involves a dynamic maintenance of conduction and repolarization patterns through the improvement of gap junction functions. METHODS We optically mapped the hearts of summer-active (SA) and winter-hibernating (WH) ground squirrels Spermophilus undulatus from Siberia and nonhibernating rabbits during different temperatures (+3°C to +37°C). RESULTS Midhypothermia (+17°C) resulted in nonuniform conduction slowing, increased dispersion of repolarization, shortened wavelength, and consequently enhanced VF induction in SA ground squirrels and rabbits. In contrast, wavelength was increased during hypothermia in WH hearts in which VF was not inducible at any temperature. In SA and rabbit hearts, but not in WH, conduction anisotropy was significantly increased by pacing acceleration, thus promoting VF induction during hypothermia. WH hearts maintained the same rate-independent anisotropic propagation pattern even at 3°C. connexin 43 (Cx43) had more homogenous transmural distribution in WH ventricles as compared to SA. Moreover, Cx43 and N-cadherins (N-cad) densities as well as the percentage of their colocalization were significantly higher in WH compared to SA epicardium. CONCLUSION Rate-independent conduction anisotropy ratio, low dispersion of repolarization, and long wavelength—these are the main electrophysiological mechanisms of antiarrhythmic protection in hibernating mammalian species during hypothermia. This strategy includes the improved gap junction function, which is due to overexpression and enhanced colocalization of Cx43 and N-cad.

BackgroundAtrial fibrillation often occurs in the setting of hypertension and associated atrial dilation with pathologically increased cardiomyocyte stretch. In the setting of atrial dilation, mechanoelectric feedback has been linked to the development of ectopic beats that trigger paroxysmal atrial fibrillation mainly originating from pulmonary veins (PVs). However, the precise mechanisms remain poorly understood.Methods and ResultsWe identify mechanosensitive, swelling‐activated chloride ion channels (IC l,swell) as a crucial component of the caveolar mechanosensitive complex in rat and human cardiomyocytes. In vitro optical mapping of rat PV, single rat PV, and human cardiomyocyte patch clamp studies showed that stretch‐induced activation of I Cl,swell leads to membrane depolarization and decreased action potential amplitude, which trigger conduction discontinuities and both ectopic and reentrant activities within the PV. Reverse transcription quantitative polymerase chain reaction, immunofluorescence, and coimmunoprecipitation studies showed that I Cl,swell likely consists of at least 2 components produced by mechanosensitive ClC‐3 (chloride channel‐3) and SWELL1 (also known as LRRC8A [leucine rich repeat containing protein 8A]) chloride channels, which form a macromolecular complex with caveolar scaffolding protein Cav3 (caveolin 3). Downregulation of Cav3 protein expression and disruption of caveolae structures during chronic hypertension in spontaneously hypertensive rats facilitates activation of I Cl,swell and increases PV sensitivity to stretch 10‐ to 50‐fold, promoting the development of atrial fibrillation.ConclusionsOur findings identify caveolae‐mediated activation of mechanosensitive I Cl,swell as a critical cause of PV ectopic beats that can initiate atrial arrhythmias including atrial fibrillation. This mechanism is exacerbated in the setting of chronically elevated blood pressures.