[Transmyocardial laser revascularization--an innovative pathophysiologic concept]. / Transmyokardiale Laserrevaskularisation--ein innovatives pathophysiologisches Konzept.

In patients with coronary artery disease where standard revascularization procedures are not appropriate, transmyocardial laser revascularization (TMLR) represents an innovative technique which is currently validated worldwide. Initially, it has been assumed that myocardial perfusion of ischemic regions could be instantly improved by inducing TMLR channels, which, however, might not be confirmed in ongoing studies. Indeed, the gain in O2 diffusion surface obtained by 20 patent TMLR channels is only 6 cm2 which accounts for just 0.01% of the total capillary surface (47000 cm2) of the myocardium. Instead, a chronic structural remodeling of myocardial regions, adjacent to TMLR channels and mediated by TMLR-induced expression of vascular endothelial growth factor (VEGF), may occur leading to neocapillarization of ischemic myocardium irrespective of the long-term patency of TMLR channels and, thereby, would improve myocardial perfusion (Figure 1). Six weeks following TMLR in the pig, patent TMLR channels were not observed. Instead, a marked degree of reparative fibrosis was found at the site of TMLR-treated myocardial regions (Figure 2). It is, however, not known, whether ischemic conditions would affect chronic channel patency. TMLR combined with intramyocardial administration of 0.5 microgram VEGF between the laser-induced channels resulted in few patent channels (Figure 3). The apparently low efficacy of VEGF applied as protein could be attributed to degradation of VEGF by local peptidases. In addition to VEGF, other growth factors and the interaction of endothelial cells and the extracellular matrix need to be considered. Of particular relevance appears alpha v beta 3-integrin which is needed for adhesion of endothelial cells to extracellular matrix components and is, therefore, required for neocapillarization. Among various other growth factors associated with neoangiogenesis, TGF-beta 1 and PDGF-BB are involved in the formation of extracellular matrix anchoring newly formed vessels. Thus, the expression of VEGF and alpha V beta 3-integrin in myocardial regions surrounding TMLR channels appears to be of major importance for the development of neoangiogenesis within the ischemic myocardium. Whether concomitant therapeutical strategies, i. e., gene transfer leading to over-expression of VEGF, will optimize the TMLR procedure by improving neoangiogenesis remains to be elucidated in future experimental studies.

Trophic factors from chromaffin granules promote survival of peripheral and central nervous system neurons.

Chromaffin cells of the adrenal medulla were used to study the release of neurotrophic factors operationally defined by their capacity to promote the in vitro survival of embryonic neurons from the peripheral and central nervous system. Chromaffin cells are closely related to sympathetic neurons in terms of their transmitters and specific proteins and, like sympathetic neurons, receive preganglionic cholinergic, aminergic and peptidergic neuronal inputs. The issue of whether chromaffin cells store and secrete neurotrophic factors is therefore pertinent to the question whether trophic mechanisms may be involved in neuronal interactions and what modes of secretion are employed to liberate neurotrophic factors from neurons. Cell culture media conditioned by purified bovine chromaffin cells supported several neuron populations in vitro. Stimulation of the chromaffin cells with the cholinergic agonist carbachol (10(-4) M) increased in parallel the output of neurotrophic factor activity (assayed on chick ciliary ganglionic neurons) as well as two components specifically located in chromaffin granules, chromogranin A and catecholamines. The release of all three components was partially blocked by the Ca2+ channel blocker verapamil (10(-5) M), suggesting co-storage and -release of neurotrophic factors, chromogranin A and catecholamines in/from chromaffin granules. Neurotrophic factor activity for ciliary ganglionic neurons accumulating in the medium of unstimulated chromaffin cells decreased with time, and so did catecholamines. In contrast, amounts of neurotrophic factors and catecholamines released by challenging cells with carbachol did not significantly decline up to 62 h. The neurotrophic factor activity tested on chick ciliary, sensory and spinal cord neurons as well as on rat hippocampal neurons was heat- and trypsin-labile and could not be blocked by polyclonal antibodies against bovine nerve growth factor and the chromogranin A, B, and C. Defined fragments of chromogranin A and pancreastatin were devoid of neurotrophic activity. Our results suggest the presence of one or several neurotrophic factors in chromaffin granules, which can be released by exocytosis and may be potentially relevant for the maintenance of neurons innervating the adrenal medulla.

[Eosinophilic endomyocarditis post partum or pregnancy-related cardiomyopathy]. / Eosinophile Endomyokarditis post partum oder Schwangerschaftskardiomyopathie.

We report the case of a 28-year old asthmatic female patient, who developed an acute heart failure beginning with diarrhea, fever, and dyspnea 5 weeks after delivery. After improvement of all vital functions and dismissal from hospital care unit a marked blood hypereosinophilia, left ventricular congestive heart failure, pericardium effusion and fever up to 40 degrees C followed. Endomycardial, bone marrow and skeletal muscle biopsies and the pericardial fluid showed a marked eosinophilic infiltration or polymyositis, respectively, which could be treated successfully with steroids and azathioprin. During steroid medication cytomegalovirus-associated myocarditis developed and was diagnosed by in situ hybridization. CMV hyperimmunoglobulin treatment (Cytotect, Biotest) was started (2 ml/kg bw on day 1 and 3, and 1 ml/kg on days 5, 7 and 9), which led to the eradication of the residual infiltrate and CMV-DNA in the myocardium. After discontinuation of all medication, eosinophilia and asthma recurred so that immunosuppressive treatment was continued.

Postischemic cell death in reperfused porcine hearts is not attenuated by the spin trap agent PBN during early reperfusion.

Ischemic, reperfused porcine hearts were used to investigate whether the spin trap agent PBN (N-tert-butyl-alpha-phenylnitrone) attenuates postischemic cell death by scavenging of free radicals. The left anterior descending coronary artery (LAD) was ligated distally in 16 pigs for 45 min and then reperfused for 3 h. PBN (coronary concentration approximately 1 mM) was infused into the LAD of eight pigs during the first 45 min of reperfusion. Electron spin resonance spectroscopy (ESR) was performed to identify free radical adducts in the reperfused coronary venous blood. Regional systolic shortening (SS%) was determined by sonomicrometry. Infarct size was evaluated as the percentage of infarcted (tetrazolium stain) to ischemic (dye technique) myocardium. The transmural ultrastructural degree of myocardial injury as well as myocardial ATP levels were assessed at the end of the experiment. Intracoronary treatment with PBN during early reperfusion did not attenuate myocardial damage. Infarct sizes (control group 59 +/- 19%, treated group 55 +/- 14%), transmural ultrastructural alterations, myocardial ATP concentrations (control group 1.8 +/- 0.3 mumol/mg frozen weight, treated group 1.7 +/- 0.4 mumol/mg) and regional systolic shortening at the end of the experiments (control group -1 +/- 5%, treated group -2 +/- 6% did not differ significantly. Furthermore, under various experimental conditions of spin trapping, free radical adducts could not be identified in coronary venous blood during early reperfusion. The results suggest that the spin trap agent PBN (1 mM) does not affect postischemic cell death in porcine hearts.

Interstitial myocardial neutrophil accumulation between 3 and 72 h of reperfusion does not significantly affect infarct size in porcine hearts.

The inflammatory response--mediated by activated neutrophils--is assumed to play an important role in the pathogenesis of reperfusion injury. This study investigated whether extravascular myocardial neutrophil accumulation between 3 and 72 h of reperfusion affects infarct size in porcine hearts. The left anterior descending coronary artery was ligated distally in 24 pigs for 45 min and reperfused for 3 h (n = 8), 24 h (n = 8), or 72 h (n = 8). Infarct size and extravascular myocardial accumulation of neutrophils was evaluated at the end of the experiments. Global hemodynamic characteristics were comparable for the three groups both before and during ischemia. Neutrophil count/mm2 reperfused myocardium increased substantially from 4 +/- 2 (3 h of reperfusion) to 129 +/- 70 (24 h of reperfusion, p < 0.001). After 3 d of reperfusion, the neutrophil count had decreased to 10 +/- 7. The invasion of neutrophils between 3 and 24 h of reperfusion did not significantly affect the extent of myocardial necrosis. Infarct sizes after 3 h (62.6 +/- 20%), 24 h (71.8 +/- 13%), and 72 h of reperfusion (67.6 +/- 18%) did not differ significantly. This finding does not suggest that a significant amount of myocytes are destroyed by extravasated neutrophils between 3 and 72 h of reperfusion.