Andreas Link

Intravenous Transfusion of Endothelial Progenitor Cells Reduces Neointima Formation After Vascular Injury

&NA; —Endothelial cell damage is one important pathophysiological step of atherosclerosis and restenosis after angioplasty. Accelerated reendothelialization impairs neointima formation. We evaluated the role of intravenously transfused endothelial progenitor cells (EPCs) on reendothelialization and neointima formation in a mouse model of arterial injury. Spleen‐derived mouse mononuclear cells (MNCs) were cultured in endothelial basal medium. A total of 91.8±3.2% of adherent cells showed uptake of acetylated low‐density lipoprotein (Dil‐Ac‐LDL) and lectin binding after 4 days. Immunostaining and long‐term cultures confirmed the endothelial progenitor phenotype. To determine the effect of stem cell transfusion on reendothelialization, mice received either fluorescent‐labeled spleen‐derived MNCs or in vitro differentiated EPCs intravenously after endothelial injury of the carotid artery. Transfused cells were strictly restricted to the injury site, and lectin binding confirmed the endothelial phenotype. Homing of transfused cells to the site of injury was only detectable in splenectomized mice. Cell transfusion caused enhanced reendothelialization associated with a reduction of neointima formation. Systemically applied spleen‐derived MNCs and EPCs home to the site of vascular injury, resulting in an enhanced reendothelialization associated with decreased neointima formation. These results allow novel insights in stem cell biology and provide additional information for the treatment of vascular dysfunction and prevention of restenosis after angioplasty. The full text of this article is available online at http://www.circresaha.org. (Circ Res. 2003;93:e17‐e24.)

Estrogen Increases Bone Marrow–Derived Endothelial Progenitor Cell Production and Diminishes Neointima Formation

Background Estrogens improve endothelial function and accelerate reendothelialization after vascular injury via largely unknown mechanisms. Bone marrow‐derived endothelial progenitor cells (EPCs) are thought to positively influence endothelialization, vascular repair, and angiogenesis. Methods and Results In mice subjected to sham operation, ovariectomy, or ovariectomy and estrogen replacement treatment, estrogen deficiency significantly decreased EPCs circulating in the peripheral blood and residing in the bone marrow, as well as EPCs that were in vitro expanded from spleen‐derived mononuclear cells. These effects were completely prevented by estrogen replacement. Human women with increased estrogen plasma concentrations also displayed profoundly increased levels of circulating EPCs. Estrogens increase EPC numbers through a decreased apoptosis rate, which is mediated via a caspase‐8‐dependent pathway. Estrogen deficiency increased neointima formation after carotid artery injury in mice, but this effect was diminished by estrogen replacement therapy. In mice transplanted with green fluorescent protein‐positive bone marrow, reendothelialization of injured vessel segments by bone marrow‐derived cells was decreased during estrogen deficiency and increased in response to estrogen treatment. Conclusions Estrogens increase numbers of EPCs by antiapoptotic effects leading to accelerated vascular repair and decreased neointima formation. (Circulation. 2003;107:3059‐3065.)

Argatroban for anticoagulation in continuous renal replacement therapy

Objective:Argatroban, a direct thrombin inhibitor, was evaluated for anticoagulation in continuous renal replacement therapy (CRRT) in critically ill patients with heparin-induced thrombocytopenia type II and acute renal failure. The investigation focused on predictors for the maintenance doses of argatroban with efficacy and safety of argatroban being secondary outcomes. Design:Prospective, dose finding study. Setting:Two intensive care units (medical and surgical) of a university hospital. Patients:Medical and surgical patients (n = 30) with acute or histories of heparin-induced thrombocytopenia type II and acute renal failure with necessity for CRRT. Intervention:CRRT with argatroban for anticoagulation. Measurements and Main Results:Critical illness severity scores Acute Physiology and Chronic Health Evaluation (APACHE)-II, Simplified Acute Physiology Score (SAPS) II, and the indocyanine green plasma disappearance rate (ICG-PDR) were correlated to the argatroban maintenance doses. These diagnostic tools can help to identify patients with the necessity for decreased argatroban doses. The following recommendations for argatroban dosing during CRRT could be determined: a loading dose of 100 &mgr;g/kg followed by a maintenance infusion rate (&mgr;g/kg/min), which can be calculated from the scores as follows: for APACHE II: 2.15–0.06 × APACHE II (r = −.81, p < 0.001); for SAPS II: 2.06–0.03 × SAPS II (r = −.8, p < 0.001); and for ICG-PDR: −0.35 + 0.08 × ICG-PDR (r = .89, p < 0.001). The efficacy and safety of anticoagulation during CRRT were determined by the steady state of blood urea nitrogen (32.16 ± 18.02 mg/dL), mean filter patency at 24 hrs (98%), and the rate of bleeding episodes. Only two patients developed minor bleeding; no patient developed severe bleeding episodes. Conclusion:In critically ill patients with heparin-induced thrombocytopenia type II and necessity for CRRT critical illness scores (APACHE II, SAPS II) or ICG-PDR can help to predict the required argatroban maintenance dose for anticoagulation. These predictors identify decreased argatroban dosing requirements resulting in effective and safe CRRT.

Cognitive function in patients with decompensated heart failure: the Cognitive Impairment in Heart Failure (CogImpair‐HF) study

The objective of this study was to examine cognitive and psychological processes systematically in patients with decompensated chronic heart failure (CHF) and to document changes in cognitive function after compensation. Executive functions, episodic memory, and attention are impaired in patients with stable CHF, influencing health behaviour and disease management. Cognitive function and psychological co‐morbidities are associated with hospitalization, disability, and mortality.

Beneficial association of β-blocker therapy on recovery from severe acute heart failure treatment: Data from the Survival of Patients With Acute Heart Failure in Need of Intravenous Inotropic Support trial

Objectives:Beta-blocker therapy is recommended for most patients with chronic heart failure, although such therapy may be discontinued or reduced during hospitalizations. The aim is to determine whether &bgr;-blocker use at study entry and/or at discharge has an impact on 31- and 180-day survival. Design:Survival of Patients With Acute Heart Failure in Need of Intravenous Inotropic Support study was designed as a randomized, double-blind, active-controlled, multi-center study. Setting:Multinational. Patients:A total of 1,327 critically ill patients hospitalized with low-output heart failure in need of inotropic therapy. Intervention:Levosimendan versus dobutamine. Measurements:All-cause mortality at 31 and 180 days in patients who survived initial hospitalization with/without &bgr;-blocker use at entry and/or at discharge. Results:Patients on &bgr;-blockers at entry and at discharge had significantly lower 31-day (p < .0001) and 180-day (p < .0001) mortality compared to patients without &bgr;-blockers use at both time points. The association was robust when adjusted for age and co-morbidities (p = .006 at 31 days; p = .003 at 180 days). Conclusions:Those results strongly suggest, in severe acutely decompensated heart failure patients, admitted on &bgr;-blockers, to continue on them at discharge.

Phosphodiesterase 4 inhibition but not beta-adrenergic stimulation suppresses tumor necrosis factor-alpha release in peripheral blood mononuclear cells in septic shock

IntroductionStimulation of beta2-adrenergic receptors (β2-ARs) inhibits tumor necrosis factor-alpha (TNF-α) release in monocytes. In septic shock, endogenous catecholamines induce β2-AR downregulation, leading to an increased TNF-α release. The aims of this study were to analyze the molecular mechanisms of β-adrenergic downregulation and to explore therapeutic interventions with maintained anti-inflammatory efficacy in septic shock using the inhibition of phosphodiesterase 4 (PDE4).MethodsWe conducted in vitro stimulation of peripheral blood mononuclear cells of healthy volunteers (n = 20) and patients with septic shock (n = 20) with lipopolysaccharide (LPS) or Staphylococcus aureus enterotoxin B (SEB) without or with isoprenaline, forskolin (an activator of adenylate cyclase), or ropipram (an inhibitor of PDE4). We also conducted flow cytometric analysis of Toll-like receptor (TLR) 4 and TLR2 surface expression and intracellular TNF-α production of untreated and stimulated CD14+ monocytes. Protein expression of β-ARs, of G proteins, of adenylate cyclase, and of TLRs was measured by Western blotting.ResultsInvestigations were done by LPS (100 ng/mL) or SEB (10 ng/mL) when TLR4 and TLR2 were maximally expressed. LPS- or SEB-treated CD14+ monocytes of healthy volunteers were able to produce TNF-α. This effect was attenuated by isoprenaline, forskolin, or rolipram in a concentration-dependent manner. In CD14+ monocytes of patients with septic shock, the anti-inflammatory effect of isoprenaline was completely blunted whereas efficacy of forskolin and rolipram was maintained. CD14+ monocytes of healthy volunteers were compared with patients with septic shock: protein expression of β2-ARs was reduced and inhibitory G protein was increased, whereas no changes in adenylate cyclase and stimulatory G protein were found.ConclusionsIn septic shock, the anti-inflammatory effects of catecholamines are blunted by downregulation of β2-ARs and upregulation of the inhibitory G protein in CD14+ monocytes. Beta-adrenergic downregulation is overcome by inhibitors of PDE4. These results provide a mechanistic rationale for the therapeutic use of selective PDE4 inhibitors in the treatment of septic shock.

Potential role of dendritic cells in atherogenesis.

See article by Alderman et al. [13] (pages 806–819) in this issue. Dendritic cells (DCs), originally described by Steinmann and Cohn in 1973, play a crucial role in initiation of an immune response: they are the key antigen presenting cells (APCs) [1]. They originate from hematopoietic stem cells in bone marrow, migrate as immature precursors within the monocyte cell population in the blood stream, and emigrate into different tissues. Within these tissues, DCs differentiate (Fig. 1) and become active in taking up (pinocytosis; phagocytosis) and processing antigens bound to molecules of the major histocompatibility complex (MHC-I or MHC-II). In response to antigen-processing DCs mature, migrate to the T-cell areas of secondary lymphoid organs and activate naive T and B-lymphocytes. DCs with antigen-peptides bound to MHC-I molecules stimulate and activate cytotoxic T-lymphocytes [2]. Re-expression of antigens to MHC-II molecules results in stimulation of T helper cells … * Corresponding author. Tel.: +49-6841-1623-372; fax: +49-6841-1623-369

Akutes Koronarsyndrom – bessere Risikostratifizierung durch Bestimmung von Entzündungsparametern?

ZusammenfassungHintergrund: In den letzten Jahren wurden Atherosklerose und Plaqueruptur nicht nur als Folge des Wachstums glatter Gefäßmuskelzellen, der Aktivierung von Thrombozyten oder Gerinnungsvorgängen, sondern auch als Inflammationsprozess charakterisiert. Entzündungsparameter: Einige Studien haben die Bedeutung des C-reaktiven Proteins als Marker für kardiovaskuläre Komplikationen nachgewiesen. Auch Interleukin-6, Tumor-Nekrose-Faktor α und Adhäsionsmoleküle werden als Prädiktoren einer ungünstigen Prognose bei Patienten mit akutem Koronarsyndrom diskutiert. Risikostratifizierung: Ein positiver Troponin-T-Test korreliert mit einer hohen Rate an Frühkomplikationen; daher profitieren diese Patienten von einer aggressiven Therapie mit GP-IIb/IIIa-Rezeptorantagonisten und einer möglichst frühzeitigen Akutkoronarintervention. Das C-reaktive Protein ist prädiktiv für den Langzeitverlauf mit den Komplikationen Restenose, Reinfarkt und kardial bedingter Tod; diese Patienten profitieren zum einen von einer engmaschigen Nachbeobachtung und zum anderen von einer antiinflammatorischen Therapie mit Acetylsalicylsäure und Statinen.AbstractBackground: In the past years coronary atherosclerosis and plaque rupture have been characterized not only as a problem of growth of smooth vascular cells, of activated thrombocytes and coagulation but also of inflammation. Parameters of Inflammation: Several studies have demonstrated the importance of C-reactive protein as a marker for cardiovascular complications. Also interleukin-6, tumor necrosis factor-α and adhesion molecules are discussed as predictors of a poor prognosis in patients with acute coronary syndromes. Risk Stratification: A positive troponin T test is correlated with an increased rate of early complications; thus, these patients benefit from an aggressive therapy with GP IIb/IIIa receptor antagonists and acute coronary intervention. The C-reactive protein is predictive for late complications such as restenosis, reinfarction and death due to cardiac events; these patients benefit from close controls and from an anti-inflammatory therapy with acetylsalicylic acid and statins.

Der hypertensive Notfall

ZusammenfassungKrisenhafte Blutdruckanstiege werden an internistischen Notaufnahmen in bis zu 25% der Fälle beobachtet. Dabei handelt es sich zu etwa 75% um eine hypertensive Gefahrensituation („urgency“) und bei etwa 25% um einen hypertensiven Notfall („emergency“). Bezogen auf die Gesamtbevölkerung sind hypertensive Notfälle jedoch selten (weniger als 1% der behandelten Hypertoniker). Gehen Blutdruckkrisen mit akuten kardialen, vaskulären oder zerebralen Organschädigungen einher, liegt ein hypertensiver Notfall („emergency“) vor, der eine umgehende Blutdrucksenkung erfordert. Dabei hängt die Intensität der Blutdrucksenkung von der Art der Endorganschädigung ab: kardiale und vaskuläre Endorganschäden bedürfen einer raschen Blutdrucksenkung und -normalisierung, wohingegen zerebrale Endorganschäden nach Beseitigung der Blutdruckspitzen eher von leicht erhöhten/hochnormalen Blutdruckwerten profitieren. Bei einer hypertensiven Dringlichkeit („urgency“) liegen keine Endorganschäden vor, hier reicht eine langsame Absenkung des arteriellen Blutdrucks.AbstractCritical cases of high blood pressure are common clinical occurrences that may account for as many as 25% of all medical emergencies. About 75% of these increases in blood pressure can be judged as hypertensive urgencies, 25% are even hypertensive emergency situations. Nevertheless, only less than 1% of the hypertensive population experiences hypertensive urgency or emergency situations. Hypertensive emergencies are defined as acute cardiac, vascular or cerebral target organ damages. In these cases an acute lowering of blood pressure is inevitable. The rate and intensity of blood pressure depression is dependent on the localization of organ damages. For cardiac and vascular damages it is absolutely necessary to lower the blood pressure rapidly to near normal values. On the contrary, cerebral organ damages are better treated by a moderate lowering of blood pressure peaks to slightly increased blood pressure levels. In hypertensive urgencies no target organ damages occur. For these patients a slow lowering of blood pressure values to normal levels is adequate.

Neues zur akuten Herzinsuffizienz

ZusammenfassungDie akute Herzinsuffizienz ist definiert durch das plötzliche Auftreten von Symptomen einer Herzinsuffizienz, die einer notfallmäßigen Therapie bedürfen. Die Krankenhausmortalität beträgt bis zu 10 %, beim kardiogenen Schock sogar 50–70 %. Entscheidend für eine adäquate Therapie sind das rasche Erkennen der zugrunde liegenden Ursache der akuten Herzinsuffizienz und eine möglichst kausale Therapie. Beim akuten Koronarsyndrom steht daher die Akutkoronarangiographie mit Intervention im Vordergrund. Die medikamentösen und apparativen Therapieprinzipien zielen auf eine Reduzierung klinischer Stauungszeichen, eine Vor- und Nachlastsenkung, eine myokardiale Kontraktilitätsteigerung und die Durchbrechung der neurohumoralen Aktivierung. Bis heute gibt es im Gegensatz zur chronischen Herzinsuffizienz keine medikamentöse Therapie, welche die Sterblichkeit senken kann. Von neuen Therapieansätzen ist zumindest eine Symptomverbesserung, das Verhindern von Endorganschäden und im günstigsten Fall eine Reduktion der kardiovaskulären Ereignis-, Rehospitalisations- und Mortalitätsrate zu fordern.AbstractAcute heart failure is defined as the acute onset of symptoms due to hear failure necessitating emergency therapy. The in-hospital mortality rate ranges up to 10 % and in cardiogenic shock is 50–70 %. In acute heart failure, rapid diagnosis and causal therapy are necessary to avoid cardiogenic shock. In cases of acute coronary syndromes, primary percutaneous intervention should be performed immediately. Medical and apparative treatment strategies focus on decreasing pulmonary congestion, afterload, and neurohormonal activation in order to improve hemodynamics and reduce symptoms of dyspnea. In contrast to chronic heart failure, no medical therapy has been able to reduce mortality rates in acute heart failure. However, new medical therapies should at least improve clinical symptoms of congestion and favorably reduce cardiovascular events, re-hospitalization, and mortality rates.Acute heart failure is defined as the acute onset of symptoms due to hear failure necessitating emergency therapy. The in-hospital mortality rate ranges up to 10 % and in cardiogenic shock is 50-70 %. In acute heart failure, rapid diagnosis and causal therapy are necessary to avoid cardiogenic shock. In cases of acute coronary syndromes, primary percutaneous intervention should be performed immediately. Medical and apparative treatment strategies focus on decreasing pulmonary congestion, afterload, and neurohormonal activation in order to improve hemodynamics and reduce symptoms of dyspnea. In contrast to chronic heart failure, no medical therapy has been able to reduce mortality rates in acute heart failure. However, new medical therapies should at least improve clinical symptoms of congestion and favorably reduce cardiovascular events, re-hospitalization, and mortality rates.