Heide Hörtnagl

Usefulness of physiologic dual-chamber pacing in drug-resistant idiopathic dilated cardiomyopathy

The beneficial effects of physiologic dual-chamber (DDD) pacing in the treatment of end-stage idiopathic dilated cardiomyopathy were evaluated in 16 patients in whom conventional drug therapy had failed. Candidates for cardiac transplantation as well as patients not accepted for transplantation participated. During DDD pacing at an atrioventricular delay of 100 ms, left ventricular ejection fraction increased from 16.0 +/- 8.4 to 25.6 +/- 8.6% (p less than 0.001) accompanied by a striking improvement in clinical symptoms, such as severe dyspnea at rest and pulmonary edema. The New York Heart Association class decreased from 3.6 +/- 0.4 to 2.1 +/- 0.5 (p less than 0.001). The decrease in cardiothoracic ratio from 0.60 +/- 0.06 to 0.56 +/- 0.05 (p less than 0.001) coincided with a decrease in left atrial and right ventricular echocardiographic dimensions, indicating a decrease in preload. Systolic blood pressure increased from 108 +/- 29 to 126 +/- 21 mm Hg (p less than 0.01) and diastolic blood pressure from 67 +/- 15 to 80 +/- 11 mm Hg (p less than 0.01). Normalization of heart rate was achieved. No major complications developed as a consequence of DDD pacing. All patients could be discharged from the hospital within 3 weeks after pacemaker implantation and return to a relatively normal life. Within 1 year after onset of DDD pacing only 4 of the patients died (from either sudden death or stroke). DDD pacing could represent an alternative approach to the management of chronic heart failure due to dilated cardiomyopathy, especially for heart transplant candidates and patients who are not accepted for cardiac transplantation, but no longer respond to drug therapy.

Long-term efficacy of physiologic dual-chamber pacing in the treatment of end-stage idiopathic dilated cardiomyopathy

The long-term efficacy of physiologic dual-chamber (DDD) pacing in the treatment of end-stage idiopathic dilated cardiomyopathy was evaluated in a longitudinal study of up to 5 years in 17 patients. The considerable clinical improvement achieved after implantation of a pacemaker programmed for DDD pacing at an atrioventricular delay of 100 ms was maintained throughout the follow-up period or until death and was associated with a consistent decrease in New York Heart Association class and an increase in left ventricular ejection fraction. Cardiothoracic ratio, heart rate and echocardiographic dimensions progressively decreased, and systolic and diastolic blood pressures increased. Median survival time was 22 months. During follow-up, 4 patients received donor hearts, 9 had a sudden death at home without defined cause or after a thromboembolic event, and 1 died from adenocarcinoma. Three patients survived the follow-up. No patient needed rehospitalization owing to a worsening of heart failure after pacemaker implantation. An interruption of pacing in DDD mode for 2 to 4 hours was followed within the first months by a marked decrease in left ventricular ejection fraction and an increase in cardiothoracic ratio and echocardiographic dimensions, but this response consistently decreased during follow-up. The data indicate that DDD pacing can be recommended as a useful tool in the long-term treatment of end-stage idiopathic dilated cardiomyopathy, with progressive improvement in cardiac function and a reduction of the dilatation of the left ventricle.

Regional heterogeneity in the distribution of neurotransmitter markers in the rat hippocampus.

A detailed neurochemical analysis of the distribution of markers for the most relevant neurotransmitter systems within the rat hippocampal formation has been performed. The hippocampi, obtained from unfrozen brains of male Sprague-Dawley rats were subdissected into tissue parts containing mainly CA1, CA3 or the dentate gyrus, respectively. Each part was further divided into ventral and dorsal halves. In these six hippocampal subregions the concentrations of noradrenaline, dopamine, serotonin, 3-methoxy-4-hydroxyphenylglycol, 5-hydroxyindoleacetic acid and the putative neurotransmitter amino acids glutamate, aspartate, GABA, glycine and taurine, and the levels of somatostatin and neuropeptide Y and the activities of choline acetyltransferase, acetylcholinesterase and glutamate decarboxylase were measured. A marked heterogeneity in the subregional distribution of markers for various neurotransmitter systems within the hippocampal formation was observed. Each neuronal marker was characterized by an individual pattern of distribution. Most of the markers showed a concentration-gradient, increasing from dorsal to ventral; only taurine was more abundant in the dorsal than in the ventral parts and no dorsoventral difference was seen for aspartate, glycine and neuropeptide Y. The highest molar ratios of total 3-methoxy-4-hydroxyphenylglycol to noradrenaline and 5-hydroxyindoleacetic acid to serotonin were found in the dorsal hippocampus. The levels of noradrenaline, GABA and glutamate decarboxylase activity were highest in the dentate gyrus and lowest in CA1. The concentrations of somatostatin were highest in CA1; those of serotonin were highest in CA3. Highest activities of choline acetyltransferase and acetylcholinesterase were found in the dentate gyrus; lowest activities were found in CA3. In CA3 the lowest values of glutamate, aspartate, taurine and somatostatin were also found. The heterogeneity in the distribution of individual neurochemical markers allows insights into possible functional differences of hippocampal subregions and provides a relevant basis for future neurochemical investigations in this brain area.

Kainic acid-induced changes of serotonin and dopamine metabolism in the striatum and substantia nigra of the rat.

Levels of the putative neurotransmitters serotonin (5-HT) and dopamine (DA) and their respective metabolites 5-hydroxyindoleacetic acid (5-HIAA) and dihydroxyphenylacetic acid (DOPAC) was determined in the rat striatum after unilateral intrastriatal injection of the convulsive neurotoxin kainic acid. Two days after intrastriatal kainic acid injection, levels of the 5-HT metabolite 5-HIAA were increased by abut 200% in the injected striatum and by about 150% in the contralateral striatum. An elevated striatal 5-HIAA content was still detectable 10 days after the kainate lesion, but approached normal values 10 weeks after the injection of the neurotoxin. Two days after the lesion, but not at the other time intervals, a moderate increase of 5-HIAA also occurred bilaterally in other brain areas such as the substantia nigra, frontal cortex and hypothalamus. Levels of 5-HT were decreased significantly in the injected striatum 2 days after the intrastriatal application of kainic acid and increased by about 40% after 10 weeks. The 5-HT concentration in the contralateral striatum or in the three other brain areas examined was unchanged at all time intervals. Levels of the DA metabolite DOPAC and DA turnover were increased in the lesioned striatum 2 days after kainic acid injection; concomitantly the DOPAC level was increased in the substantia nigra of the contralateral side. DOPAC levels of the contralateral striatum were unchanged or slightly reduced 2 days after the injection. Ten days as well as 10 weeks after the lesion there was a slightly increased DOPAC concentration in both striata. The levels of DA were not altered at any time interval after the injection of kainic acid.

SUBSTANCE P IS MARKEDLY INCREASED IN PLASMA OF PATIENTS WITH HEPATIC COMA

Substance P (determined as immunoreactive substance P [i-SP]), noradrenaline, and adrenaline were measured in plasma of 18 patients with hepatic coma (stage I-IV), 16 healthy controls, and 10 critically ill patients without evidence of hepatocellular disease. Plasma i-SP (119 +/- 13 fmol/ml) was significantly higher in patients with hepatic coma than in healthy controls (13 +/- 2 fmol/ml) or control patients (23 +/- 4 fmol/ml). Plasma i-SP rose in parallel with plasma noradrenaline and adrenaline. There was a significant direct correlation between plasma i-SP and noradrenaline. Increase in plasma i-SP and noradrenaline was associated with a decrease in systemic vascular resistance and an increase in cardiac index and was most pronounced in those patients who finally died in coma. Deterioration in the dying patients was accompanied by a further significant increase in plasma i-SP. Immunoreactivity was identified as authentic SP by high performance liquid chromatography in 3 representative patients. Accumulation of the vasodilating peptide SP in plasma of patients with hepatic coma may be important in the pathogenesis of the cardiovascular disturbances associated with this disease.

Has total bowel rest a beneficial effect in the treatment of Crohn's disease?

Twenty patients with Crohns disease were treated with parenteral nutrition (PN). The indication for PN was a bodyweight of less than 80% ideal bodyweight and/or a Crohns disease activity index (CDAI) above 150 despite conventional therapy. A complete nutrition solution containing per litre 150 g glucose, 50 g sorbitol, 50 g amino acids, 50 g fat, electrolytes, trace elements and vitamins was infused via a central venous catheter to provide 72 kcal per kg bodyweight and day. No other medications were given during the study. The patients were randomized into two groups: both groups received PN in identical fashion. Group 1 was not allowed to eat or drink to reach total bowel rest; Group 2 ate formula diets and low residue diet ad libidum in addition to PN. Criteria for the nutritional status were bodyweight, serum albumin, prealbumin and hemoglobin and for disease activity the CDAI. Mean duration of treatment was 28 days in group 1 and 33.5 days in group 2. At the beginning both groups were comparable with respect to disease activity, nutritional status and extent of Crohns disease. At the end of the study nutritional status was improved (increase of bodyweight and prealbumin) and disease activity was decreased by therapy in both groups with no significant difference between the two regimens. We conclude that PN improves the nutritional status and reduces the activity of Crohns disease. The combination of PN and total bowel rest resulted in the same improvement as with PN alone. Total bowel rest is therefore unnecessary, when PN is given in patients with Crohns disease.

Effect of cholinergic deficit induced by ethylcholine aziridinium on serotonergic parameters in rat brain

The consequence of loss of cholinergic input on the function of serotonergic neurons has been studied in rat brain after bilateral intracerebroventricular injections of various doses of the cholinotoxin ethylcholine aziridinium ion (1 to 5 nmoles/ventricle). This treatment resulted in a dose-dependent decrease in acetylcholine content in hippocampus, which occurred 2 days after injection and persisted during the 28 day observation period. The reduction in acetylcholine content ranged from 50.3 +/- 6.0% to 76.9 +/- 3.8% when compared to vehicle-injected rats. Other brain areas, including cortex, striatum and hypothalamus, showed only minor and transient changes in acetylcholine levels. Treatment with ethylcholine aziridinium was accompanied by a dose-dependent response of serotonergic neurons. The predominant reaction, which we observed in all areas studied, was an initial increase in 5-hydroxyindoleacetic acid content, a decrease in serotonin content, and consequently an increase in the molar ratio of metabolite/amine, indicating an increase in serotonin turnover. As with acetylcholine, the decrease in serotonin content was most pronounced in the hippocampus, ranged from 19.4 +/- 2.9% to 53.4 +/- 4.1%, and even persisted at 28 days after injection of 3 and 5 nmoles of the toxin/ventricle, although serotonin levels returned towards normal at that time point after injection of 1 or 2 nmoles of the toxin/ventricle. These data suggest that, in the rat, withdrawal of cholinergic input to the hippocampus might have a considerable impact on serotonergic function. This includes an initial increase in activity and, as cholinergic degeneration progresses, a decrease in serotonergic function. The most likely explanation for the serotonergic deficit is that it may reflect adaptation of these neurons to the withdrawal of cholinergic input. Such a phenomenon might help to increase our understanding of the events taking place in the brains of patients with Alzheimers disease as the cholinergic system starts to degenerate.

Sex differences and estrous cycle-variations in the AF64A-induced cholinergic deficit in the rat hippocampus

The influence of gender and stage of the estrous cycle on the levels of acetylcholine, serotonin, and noradrenaline in the hippocampus and on the susceptibility of the cholinergic septo-hippocampal pathway to the neurotoxic effect of ethylcholine aziridinium (AF64A) was investigated in the rat. Levels of acetylcholine and serotonin were consistently higher in female rats during the stage of diestrus and proestrus than in age-matched male rats (p < 0.05). Across the estrous cycle the highest levels of acetylcholine and serotonin, coinciding with the lowest levels of noradrenaline, were measured on proestrus. Eight to 10 days after the bilateral intracerebroventricular injection of a submaximal dose of AF64A (1 nmol/ventricle) the decrease of acetylcholine in hippocampus was larger in females than in male rats. The reduction of acetylcholine was most pronounced in female rats that had received submaximal doses of AF64A on proestrus (42.7 +/- 3.4%), whereas in male rats, the corresponding decrease was 25.9 +/- 5.1% (p < 0.05). At a maximal dose of AF64A (2 nmole/ventricle), the sex-specific or cycle-dependent difference in the cholinotoxicity of AF64A vanished. The dose-dependent loss of acetylcholine was associated with a secondary dose-dependent decrease in the levels of serotonin and noradrenaline, but significant differences between male and female rats or stages of estrous cycle were not apparent. The present data provide evidence that adult female rats in general, and particularly females on proestrus, are more susceptible to the neurotoxic action of submaximal doses of AF64A than age-matched male rats.

α2-adrenoceptors modulate kainic acid-induced limbic seizures

We have tested several compounds interfering with the brain monoamine (noradrenaline, dopamine, serotonin) and acetylcholine systems for their effects on limbic seizures produced by systemically (s.c.) injected kainic acid as well as on neurochemical changes in amygdala/pyriform cortex resulting from the kainic acid treatment. The characteristic neurochemical changes induced by s.c. kainic acid were a decrease in noradrenaline and an increase in 5-hydroxyindoleacetic acid in the acute (3 h after kainic acid injection) suggesting strongly increased neurotransmitter turnover in noradrenergic and serotonergic neurons. This was followed by a reduction of glutamic acid decarboxylase and choline acetyltransferase activities during the chronic phase (3 days) of the kainic acid action, indicating destruction of GABAergic and cholinergic neurons. The compounds tested in this model of limbic epilepsy included 1-propranolol, prazosin, clonidine, yohimbine, metergoline, atropine and haloperidol. Among these compounds the alpha 2-adrenergic agonist clonidine (0.1 mg/kg, i.p.) exhibited a powerful protective action on kainic acid-induced limbic seizures as well as on the neurochemical changes in the amygdala and pyriform cortex. In addition, the adrenoceptor antagonists prazosin (alpha 1) and propranolol (beta) as well as the dopamine receptor antagonist haloperidol had significant but less potent - protective actions upon kainic acid-induced seizures and subsequent neurochemical changes. On the other hand, yohimbine (alpha 2-antagonist) and metergoline (serotonin-antagonist) potentiated the limbic seizure syndrome and no effect was found with atropine.(ABSTRACT TRUNCATED AT 250 WORDS)

A Sensitive and Reliable Assay for Dopamine (β-Hydroxylase in Tissue

A new assay procedure for dopamine β‐hydroxylase (DBH) in tissue extracts is described. Solubilized DBH was adsorbed from crude extracts on Concanavalin A‐Sepharose (Con A‐Sepharose), resulting in enrichment of the enzyme as well as removal of endogenous catecholamines and inhibitory substances. The enzymatic assay was carried out with DBH still adsorbed to Con A‐Sepharose. The adsorption of the DBH to Con A‐Sepharose offers three advantages over previous assay procedures. (1) Because of removal of the endogenous inhibitory substances, a single Cu2+ concentration can be used for the determination of DBH activity, regardless of the tissue dilution or inhibitor content of the analysed sample. Using this procedure, the optimal Cu2+ concentration for DBH of bovine adrenal gland extracts was 3 μM and for rat brain 10 μM. (2) Because of removal of endogenous catecholamines, dopamine, the main physiological substrate of DBH in noradrenergic neurons, can be used for the assay. The enzymatic reaction product, noradrenaline, was determined by high performance liquid chromatography and electrochemical detection (hplc‐ec). This procedure resulted in an approx. 10‐fold increase in sensitivity of the assay compared with other procedures, e.g., the radioenzymatic assay. (3) Direct determination of the immediate product of the enzymatic reaction (noradrenaline) permits kinetic analysis. It was found that the Michaelis constants for the substrate (dopamine) and co‐factor (ascorbic acid) (2 mM and 0.65 mM, respectively) determined in bovine adrenal tissue extracts by the described procedure were identical with the values for the purified DBH preparation.