Neuron specific alpha-adrenergic receptor expression in human cerebellum: implications for emerging cerebellar roles in neurologic disease.

Recent data suggest novel functional roles for cerebellar involvement in a number of neurologic diseases. Function of cerebellar neurons is known to be modulated by norepinephrine and adrenergic receptors. The distribution of adrenergic receptor subtypes has been described in experimental animals, but corroboration of such studies in the human cerebellum, necessary for drug treatment, is still lacking. In the present work we studied cell-specific localizations of alpha1 adrenergic receptor subtype mRNA (alpha 1a, alpha 1b, alpha 1d), and alpha2 adrenergic receptor subtype mRNA (alpha 2a, alpha 2b, alpha 2c) by in situ hybridization on cryostat sections of human cerebellum (cortical layers and dentate nucleus). We observed unique neuron-specific alpha1 adrenergic receptor and alpha2 adrenergic receptor subtype distribution in human cerebellum. The cerebellar cortex expresses mRNA encoding all six alpha adrenergic receptor subtypes, whereas dentate nucleus neurons express all subtype mRNAs, except alpha 2a adrenergic receptor mRNA. All Purkinje cells label strongly for alpha 2a and alpha 2b adrenergic receptor mRNA. Additionally, Purkinje cells of the anterior lobe vermis (lobules I to V) and uvula/tonsil (lobules IX/HIX) express alpha 1a and alpha 2c subtypes, and Purkinje cells in the ansiform lobule (lobule HVII) and uvula/tonsil express alpha 1b and alpha 2c adrenergic receptor subtypes. Basket cells show a strong signal for alpha 1a, moderate signal for alpha 2a and light label for alpha 2b adrenergic receptor mRNA. In stellate cells, besides a strong label of alpha 2a adrenergic receptor mRNA in all and moderate label of alpha 2b message in select stellate cells, the inner stellate cells are also moderately positive for alpha 1b adrenergic receptor mRNA. Granule and Golgi cells express high levels of alpha 2a and alpha 2b adrenergic receptor mRNAs. These data contribute new information regarding specific location of adrenergic receptor subtypes in human cerebellar neurons. We discuss our observations in terms of possible modulatory roles of adrenergic receptor subtypes in cerebellar neurons responding to sensory and autonomic input signals, and review species differences in cerebellar adrenergic receptor expression.

Frequency domain algorithm for quantifying atrial fibrillation organization to increase defibrillation efficacy.

We hypothesized that frequency domain analysis of an interatrial atrial fibrillation (AF) electrogram would show a correlation of the variance of the signal and the amplitude of harmonic peaks with the periodicity and morphology (organization) of the AF signal and defibrillation efficacy. We sought to develop an algorithm that would provide a high-resolution measurement of the changes in the spatiotemporal organization of AF. AF was initiated with burst atrial pacing in ten dogs. The atrial defibrillation threshold (ADFT50) was determined, and defibrillation was repeated at the ADFT50. Bipolar electrograms from the shocking electrodes were acquired immediately preshock, digitally filtered, and a FFT was performed. The organization index (OI) was calculated as the ratio of the area under the first four harmonic peaks to the total area of the spectrum. For a 4-s window, the mean OI was 0.505 +/- 0.087 for successful shocks, versus 0.352 +/- 0.068 for unsuccessful shocks (p < 0.001). Receiver operator characteristic (ROC) curve analysis was used to determine the optimal sampling window for predicting successful shocks. The area of the ROC curve was 0.8 for a 1-s window, and improved to 0.9 for a 4-s window. We conclude that the spectrum of an AF signal contains information relating to its organization, and can be used in predicting a successful defibrillation.

The effects of atrial electrical remodeling on atrial defibrillation thresholds.

Electrical remodeling of atrial fibrillation may account for the increase in atrial defibrillation thresholds over time. The aim of this study was to examine the time course of electrical remodeling and the benefit of early defibrillation on the defibrillation threshold. Twenty-six mongrel dogs weighing 27.6 +/- 3.3 kg were induced into AF by repeated high output burst atrial pacing. Eight dogs were paced for multiple time periods of 5, 20, 40, and 60 minutes. Five dogs each had burst pacingfor 4 hours and 8 hours, and eight dogs were paced at a high rate (640 beats/min) for 48 hours. Biphasic atrial defibrillation shocks with a pulse width of 3/3 ms synchronized to the left apical electrogram were delivered to coil electrode catheters positioned in the lateral left and right atria. Defibrillation voltage was increased from 50 V in 20- to 30-V steps until defibrillation was successful. As the pacing period increased, a decrease in atrial fibrillation cycle lengths and atrial effective refractory period was not observed before 8 hours. Similarly, the defibrillation threshold did not change significantly until the 8-hour pacing period was reached. The defibrillation thresholds were 69 +/- 28 V for 5 minutes, 64 +/- 20 V for 20 minutes, 99 +/- 85 V for 40 minutes, 78 +/- 51 V for 60 minutes, 78 +/- 38 V for 4 hours, 124 +/- 33 V for 8 hours, and 133 +/- 32 V for 48 hours (mean +/- SD) (P < 0.05). Atrial electrical remodeling in a rapid atrial pacing canine model is not observed until after 4 hours of burst atrial pacing. The atrial defibrillation threshold increases with increasing duration of burst atrial pacing, and follows a similar time course to other parameters of electrical remodeling.

Coexistence of type I atrial flutter and intra-atrial re-entrant tachycardia in patients with surgically corrected congenital heart disease.

OBJECTIVES: This study assessed the coexistence of intra-atrial re-entrant tachycardia (IART) and isthmus-dependent atrial flutter (IDAF) in patients presenting with supraventricular tachyarrhythmias after surgical correction of congenital heart disease (CHD). BACKGROUND: In patients with CHD, atrial tachyarrhythmias may result from IART or IDAF. The frequency with which IART and IDAF coexist is not well defined. METHODS: Both IDAF and IART were diagnosed in 16 consecutive patients using standard criteria and entrainment mapping. Seven patients had classic atrial flutter morphology on surface electrocardiogram (ECG), whereas nine had atypical morphology. RESULTS: A total of 24 circuits were identified. Three patients had IDAF only, five had IART only, seven had both, and one had a low right atrial wall tachycardia that could not be entrained. Twenty-two different reentry circuits were ablated. Successful ablation was accomplished in 13 of 14 (93%) IART and 9 of 10 (90%) IDAF circuits. There was one IART recurrence. The slow conduction zone involved the region of the right atriotomy scar in 12 of 14 (86%) IART circuits. No procedural complications and no further recurrences were seen after a mean follow-up of 24 months. CONCLUSIONS: Both IDAF and IART are the most common mechanisms of atrial re-entrant tachyarrhythmias in patients with surgically corrected CHD, and they frequently coexist. The surface ECG is a poor tool for identifying patients with coexistent arrhythmias. The majority of IART circuits involve the lateral right atrium and may be successfully ablated by creating a lesion extending to the inferior vena cava.

Role of calcium in acute hyperthermic myocardial injury.

INTRODUCTION: We hypothesized that intracellular calcium overload may play an important role in heat-induced myocardial injury. This postulate was investigated using a model of isolated guinea pig papillary muscle in which resting tension was measured as an indirect indicator of cytosolic free-calcium concentration and the fluorescence changes of Fluo-3 AM dye was measured as a direct indicator of cytosolic free-calcium concentration. METHODS AND RESULTS: Excised guinea pig right ventricular papillary muscles were attached to a force transducer in a high-flow tissue bath and superfused with Tyrode's solution at 37 degrees +/- 0.5 degrees C. The temperature was rapidly changed to between 38.0 degrees and 56.0 degrees C for 60 seconds and then returned to 37.0 degrees C. Hyperthermia caused a reversible increase in resting tension at temperatures between 45 degrees and 50 degrees C and irreversible contracture at > or =50 degrees C. Rapid cooling contracture experiments and experiments measuring fluorescence of myocytes loaded with 5 microM Fluo-3 AM dye demonstrated that the hyperthermia-induced rise in resting tension was likely due to an increase in intracellular calcium content. Inhibition of the sarcoplasmic reticulum calcium pump with 20 microM thapsigargin resulted in irreversible contracture of the papillary muscles at temperatures between 45 degrees and 50 degrees C and significant increases in Fluo-3 fluorescence at 48 degrees C. Blockade of sarcolemmal calcium channels with 0.5 mM cadmium or 40 microM verapamil did not attenuate the heat-induced increase in resting tension and Fluo-3 fluorescence. CONCLUSION: Hyperthermia causes an increase in resting tension of cardiac muscle that most likely is mediated by a calcium channel-independent increase in calcium permeability of the sarcolemmal membrane and/or release of stored intracellular calcium.

Assessment of global atrial fibrillation organization to optimize timing of atrial defibrillation.

BACKGROUND: We hypothesized that frequency domain analysis of a wide bipolar interatrial electrogram describes the global organization of atrial fibrillation (AF) and should vary over time. By timing shocks to periods of high organization of AF, cardioversion efficacy should improve. METHODS AND RESULTS: A total of 15 dogs (weight, 28.2+/-3.4 kg) were rapidly paced for 48 to 72 hours to induce AF. Coil electrodes with a surface area of 1.80 cm(2) were then placed in the left and right atria to form a wide bipole. Wide bipolar electrograms were digitally filtered, and a fast Fourier transform was performed over a sliding 2-s window every 0.5 s. The organization index (OI) was calculated as the ratio of the area of the dominant peak and its harmonics to the total area of the magnitude spectrum. The atrial defibrillation threshold (ADFT(50)) was determined using a 3-ms/3-ms biphasic shock and an up-down-up protocol. Additional shocks with higher and lower energies were delivered in a random sequence to develop a distribution curve. The OI varied over time, with a mean of 0.42+/-0.03, a maximum of 0.65+/-0.07, and a minimum of 0.20+/-0.06. The OI changed rapidly, with durations of high organization (OI>0.5) ranging from 1 to 5 s. The ADFT(50) for QRS complex-synchronized shocks was 183+/-56 V, versus 142+/-49 V for shocks synchronized to an OI>0.5 (P<0.001). The distribution curve shifted leftward when shocks were synchronized to an OI>0.5. CONCLUSIONS: AF signals show a high degree of variability. Shock efficacy is increased when shocks are delivered during periods of high AF organization as determined by the OI method.

Elimination of focal atrial fibrillation with a single radiofrequency ablation: use of a basket catheter in a pulmonary vein for computerized activation sequence mapping.

A focal source for atrial fibrillation (AF) may be found in the first few centimeters of the pulmonary veins. Radiofrequency (RF) ablation may be directed at this source using activation mapping, but if the responsible atrial extrasystoles are infrequent or difficult to map, elimination of the source may require complete electrical isolation of the vein with multiple RF lesions. A new three-dimensional mapping system using a 64-pole basket catheter has been developed recently. We report the use of this system for ablation of focal AF in two patients. Mapping identified foci in the left and right superior pulmonary veins. Each focus was eliminated with a single RF ablation.

Electrical, morphological, and ultrastructural remodeling and reverse remodeling in a canine model of chronic atrial fibrillation.

BACKGROUND: In patients with recurrent persistent atrial fibrillation (AF), vulnerability to AF persists indefinitely despite presumed completion of reverse electrical remodeling within days of return to normal sinus rhythm. Atrial electrical and anatomic remodeling and reverse remodeling were studied in a canine model of chronic AF. METHODS AND RESULTS: Chronic AF was induced in 8 dogs by creating moderate mitral regurgitation and rapidly pacing the right atrium at 640 bpm for >8 weeks. Measurements performed at baseline, after establishment of chronic AF, and then at 4 hours and again at 7 to 14 days after cardioversion to sinus rhythm included atrial effective refractory periods, AF cycle lengths, left atrial dimensions, premature atrial contraction (PAC) frequency, and atrial vulnerability to atrial extrastimuli. After establishing chronic AF, atrial effective refractory period shortening, increases in spontaneous PAC frequency, increases in left atrial size with loss of contractility, and multiple ultrastructural abnormalities were demonstrated. Complete reverse electrical remodeling and decreases in PACs were observed after 7 to 14 days of sinus rhythm, but there was no resolution of anatomic and ultrastructural abnormalities. Occurrence of spontaneous AF paralleled PAC frequency, but vulnerability to AF induction persisted (75% immediately after conversion versus 63% at 4 hours and 50% at 7 to 14 days) despite reverse electrical remodeling. CONCLUSIONS: After conversion from chronic AF to sinus rhythm in this canine model, electrical remodeling occurs rapidly. However, gross and ultrastructural anatomic changes persist, as does vulnerability to induced AF. Vulnerability to AF initiation 7 to 14 days after cardioversion is more dependent on persisting structural abnormalities than on electrophysiological abnormalities.

Transient ST elevation after transthoracic cardioversion in patients with hemodynamically unstable ventricular tachyarrhythmia.

The significance of ST-segment elevation after resuscitation from arrhythmias not associated with ischemia was examined in a group of patients who received transthoracic shocks for hemodynamically unstable ventricular tachyarrhythmias during electrophysiologic studies. ST-segment elevation was seen in 15.4%, was transient, and was not associated with clinical evidence of myocardial infarction.