Short- versus long-term, gender and species differences in the intestinotrophic effects of long-acting glucagon-like peptide 2 analog.

Glucagon-like-peptide 2 (GLP-2) is an endogenous enteroendocrine physiological trophic peptide. Glepaglutide is a novel long-acting GLP-2 analog under development for the treatment of patients with Short Bowel Syndrome (SBS). The objective of this work was to compare the small intestinal trophic effects in both genders following short (1 week) versus long-term (26-39 weeks) GLP-2 treatment in Wistar rats and Beagle dogs. Following both short- and long-term treatment with glepaglutide, a significant dose-dependent intestinotrophic effect was seen in both genders and species. At all doses increased length and weight of the small intestine as well as macroscopic thickening and villous hypertrophy were noted in all segments of the small intestine, without any differences between genders. The findings were still present following a 6-week recovery period, indicating long-acting intestinotrophic effects of glepaglutide. These studies demonstrate that a long-acting GLP-2 analogue (glepaglutide) has a fast onset and long duration of intestinotrophic action with similar profile in both genders and species (rat and dog).

[Epicardial VT ablation : In whom, when, how and why?] / Epikardiales Mapping und Ablation bei ventrikulären Tachykardien : Bei wem, wann, wie und mit welchen Erfolgsaussichten?

Ventricular tachycardia (VT) is a leading cause of cardiovascular death and remains the main cause of sudden cardiac death. Implanted cardiac defibrillators (ICD) improve survival but the recurrent ICD therapies, mostly ICD shocks, are associated with an increased mortality and deleterious psychological effects. In this regard and based on the results of multicenter studies, the current European guidelines recommend early referral for catheter ablation. The ablation strategy (isolated endocardial approach or combined epi-/endocardial) depends mostly on the underlying myocardial disease. Thus, almost all patients with right ventricular dysplasia and Chagas disease, the majority of those with dilative cardiomyopathy, and some patients with ischemic cardiomyopathy (mostly posterior wall infarction or large transmural anterior wall infarction) have an epicardial scar as the underlying substrate for recurrent VT episodes. Thus, in this group of patients, isolated endocardial VT ablation may be associated with an increased VT recurrence and therefore an epicardial approach is also needed. Cardiac imaging (cardio-CT/MRI with late enhancement[MRI LE]) can reliably identify the distribution and characteristics of the myocardial scar and may be helpful in planning the ablation strategy. When performed in highly specialized centers, epicardial catheter ablation of VT leads to a significant reduction of recurrent VT episodes compared to the endocardial VT ablation alone and with lower complication rates.

[Epicardial ablation of ventricular tachycardias]. / Epikardiale Ablation ventrikulärer Tachykardien.

Ventricular tachycardias (VT) in patients with structural heart diseases have predominantly a scar-associated reentry mechanism so that substrate-based ablation approaches also have to be used in nearly all procedures. In many VT cases-especially in nonischemic cardiomyopathy (NICM) and arrhythmogenic right ventricular cardiomyopathy-a critical epicardial substrate can be identified as an essential component of the reentry circuit so that for the ablation-based modification of the substrate in these cases an epicardial approach is necessary. In cases of redo-VT ablation procedures in ischemic cardiomyopathy (after a previously endocardial ablation), an epicardial approach should also be considered. There are also cases in whom no endocardial substrate can be identified and an isolated epicardial substrate can be identified. Worldwide epicardial VT ablations are usually performed after gaining epicardial access using subxyphoidal puncture. The results of recent studies show a higher efficiency with stabilization of cardiac rhythm and reduction of recurrent VT episodes (about 70% event-free survival at the 2­year follow-up) after endo-plus epicardial substrate modification. In electrical storm cases, an early epicardial VT ablation approach also appears to be relevant, especially in NICM. Epicardial instrumentation and ablation represents a complex procedure which should only be performed in experienced centers with cardiac surgery back-up. In these experienced centers, the complications rate is less than 5%.

Electrocardiographic characteristics in patients with nonrheumatic atrial fibrillation and their relation to echocardiographic parameters.

The aim of this study was to determine the relation between (1) ECG fibrillatory wave amplitude and left atrial diameter and left atrial appendage (LAA) flow velocity using different ECG recording techniques, and (2) ECG fibrillatory frequency and frequency of LAA contractions in patients with nonrheumatic AF. In 36 patients (22 men, 14 women, mean age 61 +/- 11 years) with persistent AF, ECG recordings were performed using a standard 12-lead EGG and an orthogonal EGG lead system using a high gain, high resolution ECG. AF was classified as coarse (fibrillatory amplitude > or = 1 mm) orfine (fibrillatory amplitude < 1 mm) in leads I, aVF, V1 and corresponding leads X, Y, and Z. Fibrillatory frequency from the ECG was determined by subtracting averaged QRST complexes and applying a Fourier analysis to the resulting signal. Doppler flow was obtained from LAA during transesophageal echocardiography and LAA emptying velocity was determined. Fourier analysis was also applied to the Doppler signal generating the frequency of LAA contractions. Coarse AF was observed in 0, 9, and 18 patients in leads I, aVF, and V, respectively. It was more often (P < 0.05) detected in corresponding leads X (n = 13), Y (n = 31), and Z (n = 23). Fine AF in lead X was associated with a reduced LAA velocity (33 +/- 16 cm/s in coarse AF vs 22 +/- 13 cm/s in fine AF, P = 0.05). There was neither a relation between AF coarseness in any other ECG lead and LAA flow velocity, left atrial diameter, or echo contrast. In 25 patients with an active LAA flow, the mean frequency of LAA contractions was 6.8 +/- 0.8 Hz. The corresponding mean frequency obtainedfrom the EGG was 6.7 +/- 0.7 Hz (r = 0.85, P < 0.001). The mean difference between these two measures was 0.04 Hz, and the 95% confidence limits were 0.90 and- 0.82 Hz using the Bland-Altman method. In conclusion, AF coarseness and its relation to LAA flow velocity depend on the ECG recording technique used. LAA contractions represent one mechanical correlate of the electrical fibrillatory activity in AF.

Left atrial appendage flow in nonrheumatic atrial fibrillation : relationship with pulmonary venous flow and ECG fibrillatory wave amplitude.

OBJECTIVE: This study was conducted (1) to examine the relationship between left atrial appendage (LAA) flow velocity and pulmonary venous flow (PVF) variables during nonrheumatic atrial fibrillation (AF), and (2) to determine whether a reduction in LAA flow is reflected by the fibrillatory wave amplitude on the surface ECG. BACKGROUND: Although LAA Doppler echocardiographic signals provide information regarding the velocity and direction of flow only for a localized narrow sample, systolic PVF represents in part the global left atrial function, mainly relaxation. Controversy exists about whether the amplitude of fibrillatory waves recorded on the surface ECG correlates with LAA flow velocity during AF. MEASUREMENTS AND RESULTS: Thirty-three patients (20 men, 13 women; mean [+/- SD] age, 61 +/- 11 years) with nonrheumatic AF undergoing transthoracic and transesophageal echocardiography were studied. A correlation between LAA flow velocity and systolic PVF variables (peak systolic velocity, R: = 0.450, p = 0.009; velocity-time integral of systolic flow, R = 0.491, p = 0.004; systolic fraction of PVF, R: = 0.627, p < 0.0001) was observed. Patients with a low LAA flow profile (< 25 cm/s) had a reduced systolic PVF. Longer AF duration and the occurrence of moderate mitral regurgitation were related to reduced LAA flow. AF was subdivided into coarse (peak-to-peak fibrillatory amplitude > or = 1 mm) or fine (< 1 mm) in standard ECG lead V1. There was no association between the coarseness of AF and the LAA flow profile. CONCLUSION: In patients with nonrheumatic AF, a reduction in LAA flow velocity correlates with a reduction in systolic PVF. These hemodynamic changes are not reflected by the ECG fibrillatory wave amplitude.

Sensitive analysis of 1alpha,25-dihydroxyvitamin D3 in biological fluids by liquid chromatography-tandem mass spectrometry.

A liquid chromatographic-tandem mass spectrometric assay using 5% bovine serum albumin as the calibration matrix has been developed for the quantitative analysis of 1alpha,25-dihydroxyvitamin D3 [1alpha,25(OH)2D3] in biological fluids. The analyte was extracted from the matrix after protein precipitation using an automated solid-phase extraction procedure involving both a reversed-phase and normal-phase procedure on a single C18 cartridge. The analytical chromatography was performed using a Symmetry C8 50 x 2.1 mm, 3.5 microm column. The mobile phase was a linear gradient from 75 to 99% methanol with a constant concentration of 2 mM ammonium acetate. 1alpha,25(OH)2D3 and the internal standard [2H6]1alpha,25(OH)2D3 were detected by using MS-MS. The ion source was operated in the positive electrospray ionisation mode. The assay is specific, sensitive, and has a capacity of more than 100 samples per day, with a limit of quantitation of 20 pg ml(-1) for a 1.0-ml sample aliquot. The assay has been used for the analysis of 1alpha,25(OH)2D3 in serum from rats and pigs simultaneously with the analysis of the vitamin D analog seocalcitol.

Determination of the vitamin D analog EB 1089 (seocalcitol) in human and pig serum using liquid chromatography-tandem mass spectrometry.

A liquid chromatographic-tandem mass spectrometric assay in human and pig serum has been developed for quantitative analysis of EB 1089 (seocalcitol). EB 1089 is a novel vitamin D analog under development for the treatment of cancer. The analyte was extracted from serum after protein precipitation using an automated solid-phase extraction procedure involving both a reversed-phase and normal-phase procedure on a single C18 cartridge. The analytical chromatography was performed using a Symmetri C8 50x2.1 mm, 3.5 microm column. The mobile phase was a linear gradient from 75% to 99% methanol with a constant concentration of 2 mM ammonium acetate. EB 1089 and the internal standard [d6]-EB 1089 were detected by using MS-MS. The ion source was operated in the positive electrospray ionisation (ESI) mode. The assay is specific, sensitive, and has a capacity of more than 100 samples per day, with a limit of quantitation of 10 pg ml(-1) for a 1.0-ml sample aliquot. It is now used for routine analysis in connection with pharmacokinetic studies in humans and toxicokinetic studies in pigs.

Circadian variations in atrial fibrillatory frequency in persistent human atrial fibrillation.

Atrial fibrillatory frequency reflects the atrial refractory period during AF. This study was conducted to investigate noninvasively the diurnal fluctuations of fibrillatory frequency in persistent human atrial fibrillation and to determine the relationship between changes in ventricular rate and fibrillatory frequency. Ambulatory ECGs were recorded in 30 patients (18 men, 12 women, mean age 60 +/- 11 years) with persistent AF (> 24 hours). AF frequency was measured in 1-minute ECG segments by subtracting averaged QRST complexes and applying Fourier analysis to the resulting signals at 4 PM, 10 PM, 4 AM, and 10 AM. Peak frequency was determined in the 3-12 Hz frequency band. Mean fibrillatory frequency measured 6.6 +/- 0.6 Hz (range 5.0-7.8 Hz). Two different frequency patterns were distinguished comparing maximal diurnal versus nocturnal fibrillatory frequency. In six (20%) patients an increase (P = 0.045) in nocturnal fibrillatory frequency (type I) was found. In the remaining 24 (80%) patients a decrease (P < 0.001) in fibrillatory frequency occurred (type II). Type I AF showed a strong inverse correlation between relative changes (percent) in ventricular rate and fibrillatory frequency obtained from two consecutive measurement points (r = -0.88 to -.97, P < 0.01), whereas in type II AF a moderate positive correlation (r = 0.36 to 0.41, P < 0.05) was detected. These data indicate a circadian pattern in AF frequency that concurs with ventricular rate changes suggesting a modulating influence of the autonomic nervous system on atrial electrophysiology in persistent human AF.

Non-invasive assessment of fibrillatory activity in patients with paroxysmal and persistent atrial fibrillation using the Holter ECG.

OBJECTIVE: Automatic analysis of the frequency content of the fibrillatory baseline on the surface ECG accurately reflects the average rate of atrial fibrillation (AF). This frequency measurement correlates with the behavior of AF and predicts the response to administration of ibutilide, a new antiarrhythmic drug. Neither the temporal pattern of fibrillatory frequency in spontaneous paroxysmal or persistent AF, nor its response to chronic antiarrhythmic medication has been studied so far. METHODS AND RESULTS: Holter ECG recordings were made in 20 patients during AF. One minute ECG segments were selected for analysis. The frequency content of the fibrillatory baseline was then quantified using digital signal processing. After high-pass filtering, the QRST complexes were subtracted using a template matching algorithm. The resulting fibrillatory baseline signal was subjected to Fourier transformation, displayed as a frequency power spectrum and the peak frequency (f) was determined. In 11 patients (7 male, 4 female, age 62 +/- 10 years) 31 paroxysmal AF episodes were analyzed. Duration ranged from 1 min to 665 min (115 +/- 175 min). Initial mean peak f measured 5.1 +/- 0.7 Hz (range 3.9 to 6.9 Hz). There was a positive correlation between f and AF duration (R = 0.53, p = 0.002). AF of less than 15 min duration (n = 13) showed a lower f (4.8 +/- 0.6 Hz) when compared with longer lasting episodes (n = 18, 5.3 +/- 0.7 Hz, p = 0.03). In short AF episodes f was constant, whereas in longer-lasting episodes f increased to 5.8 +/- 0.5 Hz (p < 0.001) within 5 min. In 9 patients (9 male, age 58 +/- 8 years) with persistent AF oral antiarrhythmic drugs (amiodarone n = 5, sotalol n = 3, flecainide n = 1) were given prior to electrical cardioversion for prophylaxis of AF recurrence. Frequency measurements were obtained at baseline and 3 to 5 days after initiation of drug administration. At baseline mean f measured 6.9 +/- 0.4 Hz. Frequency was reduced by antiarrhythmic drugs to 5.8 +/- 0.4 Hz (p < 0.001). CONCLUSIONS: (1) The duration of paroxysmal AF episodes can be predicted using spectral analysis of ECG recordings of AF episodes. (2) An increase in fibrillatory frequency is associated with AF persistence. (3) This technique can be used to monitor the response to antiarrhythmic medication.