Left atrial pacing induces memory and is associated with atrial tachyarrhythmias

OBJECTIVE: Transiently altering the atrial activation sequence induces atrial memory, manifested as an altered atrial gradient as measured in electrocardiographic XYZ leads. We hypothesized that protracted periods of left atrial impulse initiation alter the atrial gradient in a manner predictive of arrhythmias. METHODS: A total of 12 chronically instrumented mongrel dogs in complete heart block were paced AV sequentially from the left or right atrium for 7-28 days, and then recovered in normal sinus rhythm for 21 days. Rate histograms were recorded during the entire period, and electrophysiological studies were conducted to note changes in the atrial gradient, effective refractory period and atrial rhythm. No atrial arrhythmias were seen in eight control animals that were instrumented but not paced. RESULTS: Left atrial pacing was associated with a decreased atrial gradient and occurrence of atrial tachycardias that appeared during pacing and persisted during recovery from pacing. In contrast, right atrial pacing did not alter the atrial gradient significantly. Atrial tachycardias occurring during right atrial pacing disappeared after cessation of pacing, when dogs recovered in sinus rhythm. The effective refractory period did not change in either group. CONCLUSIONS: Pacing-induced impulse initiation from the left atrium alters the atrial gradient and is associated with atrial tachycardias. These changes in atrial gradient occur in the absence of ERP changes and may be early predictors of an arrhythmogenic substrate.     

Toxicity of palmitoyl glycerol to mice: depression of thyroid function

Mice given propylthiouracil, a thyroid inhibitor, and fed a diet containing a nontoxic level of rac-1(3)-palmitoyl glycerol showed the hypothermia and mortality expected for a toxic dose, but did not show these signs when linoleate or oleate was added to the diet. Loss of radioiodine from the whole animal and thyroid gland was slower when mice were fed the toxic palmitoyl glycerol diet than when fed the same diet containing 4% safflower oil. However, mice fed the two diets did not differ in the extent of the incorporation of radioiodine, and essentially all was bound to protein in each case. Follicular thyroid cells from mice fed the potentially toxic diet that contained unsaturated fat were normal in appearance. Conversely, cells from mice fed the toxic diet were smaller and more densely stained, showing evidence of glycoprotein inside the cell. These findings show that the thyroid gland is affected by the palmitoyl glycerol diet. However, the thyroid is not the only organ affected, because giving either thyroxine or triiodothyronine had no effect on the toxicity of palmitoyl glycerol.     

Evaluation of KCB-328, a new IKr blocking antiarrhythmic agent in pacing induced canine atrial fibrillation.

HYPOTHESIS: KCB-328 is a new potassium channel blocker, which prolongs action potential duration with exhibition of minimal reverse use dependence. We tested the efficacy and proarrhythmic potential of KCB-328, dofetilide and propafenone in the pacing induced canine model of atrial fibrillation (AF). METHODS: Mongrel dogs in complete heart block were paced for 1-6 weeks to produce AF, and given KCB-328 or dofetilide. A subset then received propafenone 14+/-3 days after testing the first drug. RESULTS: KCB-328 prolonged right and left atrial (RA and LA) activation times and AF cycle length (CL), terminating AF in 3 of 6 dogs. RA effective refractory period (ERP) and ventricular ERP and QT interval were prolonged. Dofetilide terminated AF in 1/6 dogs, and increased AF CL and ventricular ERP and QT interval. Dofetilide's reverse use dependency on the QT interval was greater than KCB-328. Propafenone prolonged RA and LA activation times and AF CL and terminated AF in 8 of 9 dogs. One death occurred with dofetilide, none with KCB-328 or propafenone. CONCLUSION: The spectrum of effect of the three drugs differed significantly: propafenone showed the greatest success in AF termination, and both propafenone and KCB-328 appeared less proarrhythmic than dofetilide in this model.     

Preliminary Studies on the Absorption,Distribution, Metabolism,and Excretion of THIP in Animal and Man using 14C-labelled Compound

Abstract: Distribution of radioactivity in rats, serum levels in human volunteers and rats and elimination of radioactivity in volunteers, rats, and mice following oral administration of ¹⁴C-labelled THIP have been investigated. Peak values of radioactivity in the organs and in serum were seen half an hour after administration, indicating a rapid absorption. Highest concentrations of radioactivity were found in the kidneys, but radioactivity was seen in all investigated tissues including the brain. The radioactivity was mainly excreted with urine (84–93%). Thin-layer chromatography of urine from volunteers, rats, and mice showed that most of the excreted radioactivity corresponds to unchanged THIP. Three metabolites were found in urine from rats each in amounts of 2–7% of the total dose given. Two of these metabolites were also found in urine from the volunteers in amounts of 30–35% and <2%, respectively, and in urine from mice in amounts of 21% and 6% of the total dose, respectively. No radioactivity corresponding to unchanged THIP was found in faeces indicating complete absorption of THIP following oral administration. One of the metabolites, the main one in man and mouse, seemed to be a glucuronic acid conjugate of THIP, but the chemical structure of the metabolites has not yet been established.     

Influence of dietary fat on factors in serum that regulate thyroid cell metabolism

The type of dietary fat affected the production of cAMP by cultured thyroid cells incubated with mouse and rat sera. Greater amounts of cAMP were produced with serum from mice fed 30% rac-1(3)-palmitoyl glycerol and 4% safflower oil (PG + SO) than with serum from mice fed 30% rac-1(3)-palmitoyl glycerol (PG). The serum from mice fed PG + SO gave a response similar to that with calf serum. Sera were separated into lipoprotein and aqueous fractions by centrifugation. A combination of both the lipoprotein and aqueous fractions of serum from mice fed PG + SO was required for the increased response. Proteolysis of the aqueous fraction of the serum from either mice fed PG or rats fed 30% hydrogenated coconut oil (HCO) reduced the amount of cAMP produced by the thyroid cells. However, the same effect was not seen with aqueous fractions of calf serum or serum from mice fed PG + SO or rats fed HCO plus 5% corn oil. These findings suggest that there are at least three factors in serum capable of regulating thyroid cell metabolism that are controlled by the type of fat fed the animal.     

Selection of Filters and Evaluation In Vitro of the Selective Dual Filtration Artificial Kidney, SEDUFARK

Transport properties of different artificial kidney membranes have been studied employing substances with molecular weights ranging from 60 daltons (urea) to 62,000 daltons (dextran). The results from these studies were used to select filters for the SElective DUal Filtration ARtificial Kidney, SEDUFARK.
Selection criteria for filters to be used in long-term clinical trials with SEDUFARK were based on biological tests showing toxicity of large molecular weight substances in uremic blood plasma and clinical advantages of returning middle molecular weight substances to the patient. The filters selected were used for evaluation in vitro of the complete SEDUFARK system. The results confirmed a theoretical analysis of this system, demonstrating that selective removal of substances within given molecular weight ranges from uremic blood plasma is feasible with a combination of commercial filters. The efficiency of the system, however, is limited due to the "cut-off' characteristics and hydraulic permeabilities of membrane types currently available.     

Iso-Immune Neonatal Purpura Caused by Anti-PlGrLyB1

A case of iso-immune neonatal thrombocytopenic purpura caused by a maternal, complement fixing, platelet iso-antibody, anti-PlGrLy^B1, is reported. The problems concerning the diagnosis of this disease are discussed. Although the PlGrLy^B1-antigen is known to be present on both platelets and leukocytes, and though accordingly the mother's blood contained strong leukocyte agglutinins no leukocytopenia was observed in the patient. The reasons for this observation are discussed. No platelet antibody could be demonstrated in the patient's blood, but the maternal antibody belonged to the γG globulins and was thus placenta-permeable. Evidence is presented of a gene dosage effect of the PlGrLy^B1-gene among family members.     

Age-associated changes in electrophysiologic remodeling: a potential contributor to initiation of atrial fibrillation

OBJECTIVE: Although the incidence of atrial fibrillation (AF) increases with age, the cellular electrophysiological changes that render the atria of aged individuals more susceptible to AF remain poorly understood. We hypothesized that dispersion of atrial repolarization increases with aging, creating a substrate for initiation of AF. METHODS: Four groups of dogs were studied: adult and old dogs in normal sinus rhythm (SR) and adult and old dogs with chronic AF (CAF) induced by rapid atrial pacing. In each dog, action potentials (AP) were recorded with microelectrodes from isolated endocardial preparations of four regions of right atrium and three regions of left atrium. Two indices of AP duration (APD) heterogeneity were obtained in each dog by calculating standard deviation (SD) and the coefficient of variation (COV=[SD/mean] x 100%). RESULTS: In SR groups, APD averaged across all regions was significantly longer in old than in adult tissues. Both indices of APD heterogeneity were higher in old dogs in comparison to adult. At both ages, CAF was associated with significant APD shortening and a decrease in APD adaptation to rate. While CAF significantly increased both indices of APD heterogeneity in adult dogs, it significantly decreased them in old dogs. CONCLUSIONS: The increase of spatial variability in repolarization in old atria may contribute to the initiation of AF in the aged. CAF-induced APD shortening and a decrease in APD adaptation appear to be important for the maintenance of sustained AF in both adult and old atria. The CAF-induced increase in dispersion of repolarization may be important for AF stabilization in adults, while previously reported fibrosis and slowed conduction of premature beats may be important in the old for both AF initiation during SR and subsequent stabilization of AF.