Einfluss moderater intraischämischer Hypothermie auf die Proliferation und Differenzierung neuronaler Stammzellen 28 Tage nach inkompletter Vorderhirnischämie und Reperfusion der adulten Ratte

Hypothermie schützt Neurone vor hypoxischen, ischämischen und traumatischen Schädigungen. Bisher ist jedoch unklar, ob Hypothermie auch endogene Reparaturmechanismen beeinflusst. Die vorliegende Arbeit untersucht daher den Einfluss intraischämischer Hypothermie auf das neuroregenerative Potential des Gehirns nach zerebraler Ischämie.rn50 männliche Sprague-Dawley Ratten wurden hierzu anästhesiert, intubiert und in folgende Versuchsgruppen randomisiert: Normotherme Ischämie (Normo/BACO), intraischämische Hypothermie (Hypo/BACO) sowie korrespondierende scheinoperierte Kontrollgruppen (Normo/Sham und Hypo/Sham). In den Gruppen Normo/Sham und Normo/BACO wurde die perikranielle Temperatur konstant bei 37 °C gehalten während sie in den Gruppen Hypo/Sham und Hypo/BACO für 85 min auf 33 °C gesenkt wurde. Durch bilaterale Okklusion der Aa. carotides communes in Kombination mit hämorrhagischer Hypotension wurde in BACO-Tieren eine 14-minütige inkomplette globale zerebrale Ischämie induziert. Tiere der Kontroll-Gruppen (Sham) blieben ohne Induktion einer Ischämie in Narkose. 15 weitere Tiere durchliefen nicht den operativen Versuchsteil und bildeten die Nativ-Gruppe, die als Referenz für die natürliche Neurogenese diente. Zur in-vivo-Markierung der Stammzellen wurde vom ersten bis siebten postoperativen Tag Bromodeoxyurindine (BrdU) injiziert. Nach 28 Tagen wurden die Gehirne entnommen. Die Analyse des histopathologischen Schadens erfolgte anhand HE-gefärbter Hirnschnitte, die Quantifikation der absoluten Anzahl neu gebildeter Zellen im Gyrus dentatus erfolgte mittels BrdU-Färbung. Anhand einer BrdU/NeuN-Immunfluoreszenz-Doppelfärbung konnte der Anteil neu generierter Neurone bestimmt werden.rnNach zerebraler Ischämie zeigten Tiere mit Normothermie eine Schädigung der CA 1-Region von über 50 % während hypotherme Ischämietiere einen Schaden von weniger als 10 % aufwiesen. Tiere ohne Ischämie (Hypo/Sham, Normo/Sham, Nativ) zeigten keinen histopathologischen Schaden. Die Anzahl neu gebildeter Neurone im Gyrus dentatus lag für normotherme Ischämietiere (Normo/BACO) bei 18819 und für Tiere mit intraischämischer Hypothermie (Hypo/BACO) bei 15175 neuen Neuronen. In den Kontroll-Gruppen wiesen Tiere der Gruppe Normo/Sham 5501, Tiere der Gruppe Hypo/Sham 4600 und Tiere der Nativ-Gruppe 5974 neu generierte Neurone auf.rnDiese Daten bestätigen frühere Studien, die eine Reduktion des neuronalen Schadens durch intraischämische Hypothermie zeigten. Infolge des ischämischen Stimulus kam es im Vergleich zu beiden Kontroll- und der Nativ-Gruppe zu einem signifikanten Anstieg der Anzahl neuer Neurone in beiden Ischämiegruppen unabhängig von der Temperatur. Somit scheint das Ausmaß der histopathologischen Schädigung keinen Einfluss auf die Anzahl neu gebildeter Neurone zu haben. Darüber hinaus beeinflusste die therapeutische Hypothermie auch nicht die natürliche Neurogeneserate. Die erhobenen Daten lassen vermuten, dass Hypothermie keinen Effekt auf die Anzahl und Differenzierung neuronaler Stammzellen aufweist, unabhängig davon, ob eine zerebrale Schädigung vorliegt.

Myocardial injection of skeletal myoblasts impairs contractility of host cardiomyocytes

BACKGROUND: Mechanisms underlying improvement of myocardial contractile function after cell therapy as well as arrhythmic side effect remain poorly understood. We hypothesised that cell therapy might affect the mechanical properties of isolated host cardiomyocytes. METHODS: Two weeks after myocardial infarction (MI), rats were treated by intramyocardial myoblast injection (SkM, n=8), intramyocardial vehicle injection (Medium, n=6), or sham operation (Sham, n=7). Cardiac function was assessed by echocardiography. Cardiomyocytes were isolated in a modified Langendorff perfusion system, their contraction was measured by video-based inter-sarcomeric analysis. Data were compared with a control-group without myocardial infarction (Control, n=5). RESULTS: Three weeks post-treatment, ejection fraction (EF) further deteriorated in vehicle-injected and non-injected rats (respectively 40.7+/-11.4% to 33+/-5.5% and 41.8+/-8% to 33.5+/-8.3%), but was stabilised in SkM group (35.9+/-6% to 36.4+/-9.7%). Significant cell hypertrophy induced by MI was maintained after cell therapy. Single cell contraction (dL/dt(max)) decreased in SkM and vehicle groups compared to non-injected group as well as cell shortening and relaxation (dL/dt(min)) in vehicle group. A significantly increased predisposition for alternation of strong and weak contractions was observed in isolated cardiomyocytes of the SkM group. CONCLUSION: Our study provides the first evidence that injection of materials into the myocardium alters host cardiomyocytes contractile function independently of the global beneficial effect of the heart function. These findings may be important in understanding possible adverse effects.

Association Between Posttraumatic Stress Disorder Following Myocardial Infarction and Liver Enzyme Levels: A Prospective Study

Research in rodents demonstrated that psychological stress increases circulating levels of alanine transaminase, aspartate transaminase, and alkaline phosphatase reflecting liver injury. Moreover, chronic posttraumatic stress disorder and transaminases predicted coronary heart disease.

Inflammatory Biomarkers in Patients with Posttraumatic Stress Disorder Caused by Myocardial Infarction and the Role of Depressive Symptoms

Inflammation might link posttraumatic stress disorder (PTSD) with an increased risk of cardiovascular events. We explored the association between PTSD and inflammatory biomarkers related to cardiovascular morbidity and the role of co-morbid depressive symptoms in this relationship.

Stress hormones in patients with posttraumatic stress disorder caused by myocardial infarction and role of comorbid depression

Chronic posttraumatic stress disorder (PTSD) has been associated with perturbed hypothalamic-pituitary-adrenal (HPA) axis function and a hyperadrenergic state. We hypothesized that patients with PTSD attributable to myocardial infarction (MI) would show peripheral hypocortisolemia and increased norepinephrine levels, whereby taking into account that depressive symptoms would affect this relationship.

Deletion of CD39 on natural killer cells attenuates hepatic ischemia/reperfusion injury in mice

Natural killer (NK) cells play crucial roles in innate immunity and express CD39 (Ecto-nucleoside triphosphate diphosphohydrolase 1 [E-NTPD1]), a rate-limiting ectonucleotidase in the phosphohydrolysis of extracellular nucleotides to adenosine. We have studied the effects of CD39 gene deletion on NK cells in dictating outcomes after partial hepatic ischemia/reperfusion injury (IRI). We show in mice that gene deletion of CD39 is associated with marked decreases in phosphohydrolysis of adenosine triphosphate (ATP) and adenosine diphosphate to adenosine monophosphate on NK cells, thereby modulating the type-2 purinergic (P2) receptors demonstrated on these cells. We note that CD39-null mice are protected from acute vascular injury after single-lobe warm IRI, and, relative to control wild-type mice, display significantly less elevation of aminotransferases with less pronounced histopathological changes associated with IRI. Selective adoptive transfers of immune cells into Rag2/common gamma null mice (deficient in T cells, B cells, and NK/NKT cells) suggest that it is CD39 deletion on NK cells that provides end-organ protection, which is comparable to that seen in the absence of interferon gamma. Indeed, NK effector mechanisms such as interferon gamma secretion are inhibited by P2 receptor activation in vitro. Specifically, ATPgammaS (a nonhydrolyzable ATP analog) inhibits secretion of interferon gamma by NK cells in response to interleukin-12 and interleukin-18, providing a mechanistic link between CD39 deletion and altered cytokine secretion. CONCLUSION: We propose that CD39 deficiency and changes in P2 receptor activation abrogate secretion of interferon gamma by NK cells in response to inflammatory mediators, thereby limiting tissue damage mediated by these innate immune cells during IRI.

Patent arterial duct, bottle-meal, and fatal myocardial ischaemia

A patent arterial duct in pre-term neonates is frequent. Systemic complications consecutive to left-to-right shunting are well known but fatal myocardial ischaemia has not been described till now. The presented premature baby died from catecholamine refractory cardiogenic shock. Autoptic examination revealed acute ischaemic changes predominantly in the inner third of myocardium, speaking of coronary hypoperfusion due to a steal phenomenon secondary to the patent arterial duct.

Eotaxin/CCL11 levels correlate with myocardial fibrosis and mast cell density in native and transplanted rat hearts

Myocardial fibrosis contributes to hemodynamic and cardiac functional alterations commonly observed posttransplantation. Cardiac mast cells (MC) have been linked to fibrosis in posttransplantation hearts. Eotaxin, which has been shown to be involved in fibrogenesis, has been demonstrated to be increased in production in cardiac macrophages. The aim of our study was to correlate myocardial fibrosis during heart transplant rejection in the rat with eotaxin/chemokine [c-c motif] ligand 11 (CCL11) expression, and with various subtypes of infiltrating cardiac MC, namely connective-type MC (CTMC) and mucosa-type MC (MMC).

[Myocardial dysfunction in sepsis]

Myocardial dysfunction appears in 25% of patients with severe sepsis and in 50% of patients with septic shock, even in the presence of hyper dynamic states. It is characterized by a reduction in left ventricle ejection fraction, that reverts at the seventh to tenth day of evolution. Right ventricular dysfunction and diastolic left ventricular dysfunction can also appear. There is no consensus if an increase in end diastolic volume is part of the syndrome. High troponin or brain natriuretic peptide levels are associated with myocardial dysfunction and a higher mortality. The pathogenesis of myocardial dysfunction is related to micro and macro circulatory changes, inflammatory response, oxidative stress, intracellular calcium management disturbances, metabolic changes, autonomic dysfunction, activation of apoptosis, mitochondrial abnormalities and a derangement in catecholaminergic stimulation. Since there is no specific treatment for myocardial dysfunction, its management requires an adequate multi systemic support to maintain perfusion pressures and systemic flows sufficient for the regional and global demands.

Aircraft noise, air pollution, and mortality from myocardial infarction

Objective: Myocardial infarction has been associated with both transportation noise and air pollution. We examined residential exposure to aircraft noise and mortality from myocardial infarction, taking air pollution into account. Methods: We analyzed the Swiss National Cohort, which includes geocoded information on residence. Exposure to aircraft noise and air pollution was determined based on geospatial noise and air-pollution (PM10) models and distance to major roads. We used Cox proportional hazard models, with age as the timescale. We compared the risk of death across categories of A-weighted sound pressure levels (dB(A)) and by duration of living in exposed corridors, adjusting for PM10 levels, distance to major roads, sex, education, and socioeconomic position of the municipality. Results: We analyzed 4.6 million persons older than 30 years who were followed from near the end of 2000 through December 2005, including 15,532 deaths from myocardial infarction (ICD-10 codes I 21, I 22). Mortality increased with increasing level and duration of aircraft noise. The adjusted hazard ratio comparing ≥60 dB(A) with <45 dB(A) was 1.3 (95% confidence interval = 0.96-1.7) overall, and 1.5 (1.0-2.2) in persons who had lived at the same place for at least 15 years. None of the other endpoints (mortality from all causes, all circulatory disease, cerebrovascular disease, stroke, and lung cancer) was associated with aircraft noise. Conclusion: Aircraft noise was associated with mortality from myocardial infarction, with a dose-response relationship for level and duration of exposure. The association does not appear to be explained by exposure to particulate matter air pollution, education, or socioeconomic status of the municipality.

Change over time in posttraumatic stress caused by myocardial infarction and predicting variables

The traumatic experience of a heart attack may evolve into symptoms of posttraumatic stress disorder, which can be diagnosed at the earliest 1 month after myocardial infarction (MI). While several predictors of posttraumatic stress in the first year after MI have been described, we particularly sought to identify longer-term predictors and predictors of change in posttraumatic stress over time.

Posttraumatic stress disorder and soluble cellular adhesion molecules at rest and in response to a trauma-specific interview in patients after myocardial infarction

Posttraumatic stress disorder (PTSD) and circulating cellular adhesion molecules (CAMs) predict cardiovascular risk. We hypothesized a positive relationship between PTSD caused by myocardial infarction (MI) and soluble CAMs. We enrolled 22 post-MI patients with interviewer-rated PTSD and 22 post-MI patients with no PTSD. At 32±6months after index MI, all patients were re-scheduled to undergo the Clinician-Administered PTSD Scale (CAPS) interview and had blood collected to assess soluble CAMs at rest and after the CAPS interview. Relative to patients with no PTSD, those with PTSD had significantly higher levels of soluble vascular cellular adhesion molecule (sVCAM)-1 and intercellular adhesion molecule (sICAM)-1 at rest and, controlling for resting CAM levels, significantly higher sVCAM-1 and sICAM-1 after the interview. Greater severity of PTSD predicted significantly higher resting levels of sVCAM-1 and soluble P-selectin in patients with PTSD. At follow-up, patients with persistent PTSD (n=15) and those who had remitted (n=7) did not significantly differ in CAM levels at rest and after the interview; however, both these groups had significantly higher sVCAM-1 and sICAM-1 at rest and also after the interview compared to patients with no PTSD. Elevated levels of circulating CAMs might help explain the psychophysiologic link of PTSD with cardiovascular risk.

Momentary stress moderates procoagulant reactivity to a trauma-specific interview in patients with posttraumatic stress disorder caused by myocardial infarction

Hypercoagulability of the blood might partially explain the increased cardiovascular disease risk in posttraumatic stress disorder (PTSD) and is also triggered by anticipatory stress. We hypothesized exaggerated procoagulant reactivity in patients with PTSD in response to a trauma-specific interview that would be moderated by momentary stress levels. We examined 23 patients with interviewer-diagnosed PTSD caused by myocardial infarction (MI) and 21 post-MI patients without PTSD. A second diagnostic (i.e., trauma-specific) interview to assess posttraumatic stress severity was performed after a median follow-up of 26 months (range 12-36). Before that interview patients rated levels of momentary stress (Likert scale 0-10) and had blood collected before and after the interview. The interaction between PTSD diagnostic status at study entry and level of momentary stress before the follow-up interview predicted reactivity of fibrinogen (P=0.036) and d-dimer (P=0.002) to the PTSD interview. Among patients with high momentary stress levels, PTSD patients had greater fibrinogen (P=0.023) and d-dimer (P=0.035) reactivity than non-PTSD patients. Among patients with low momentary stress levels, PTSD patients had less d-dimer reactivity than non-PTSD patients (P=0.024); fibrinogen reactivity did not significantly differ between groups. Momentary stress levels, but not severity of posttraumatic stress, correlated with d-dimer reactivity in PTSD patients (r=0.46, P=0.029). We conclude that momentary stress levels moderated the relationship between PTSD and procoagulant reactivity to a trauma-specific interview. Procoagulant reactivity in post-MI patients with PTSD confronted with their traumatically experienced MI was observed if patients perceived high levels of momentary stress before the interview.