Diethelm Tschoepe

Platelet membrane activation markers are predictive for increased risk of acute ischemic events after PTCA.

BackgroundWe wished to investigate whether platelet activation is related to the clinical outcome during the 24 hours immediately after elective percutaneous transluminal coronary angioplasty(PTCA). Methods and ResultsIn 102 patients with high-grade coronary stenosis admitted for elective PTCA, preprocedural platelet activation was characterized by flow cytometric measurement of the proteins CD62, CD63, and thrombospondin expressed on the platelet surface membrane. The prevalence of acute ischemic events during the 24 hours immediately after the procedure was then related to the pre-PTCA platelet activation status. Fifty-six patients were classified as “nonactivated,” whereas 46 patients showed an increased percentage of activated platelets. Two patients developed acute occlusion (1.96 %) and four patients high-grade restenosis (3.92%), as confirmed by second-look coronary angiography. All events occurred in patients classified as “activated” (six of 46, or 13%). None of these patients received P-blocker medication, which was associated with lower expression of platelet membrane activation markers. In the nonactivated patient group, no clinical events were found (0 of 56, or 0%). This difference in prevalenceD is significant (P=0.007). ConclusionsWe conclude that analysis of platelet membrane activation markers may help to predict an increased risk of acute ischemic events after angioplasty.

Exposure of Adhesion Molecules on Activated Platelets in Patients with Newly Diagnosed IDDM Is Not Normalized by Near-Normoglycemia

It has been suggested that platelet hyperactivity contributes to the early evolution of diabetic vascular disease per se. This study directly evaluates the level of intravascular platelet activation in newly diagnosed IDDM patients before and after tight metabolic control. Platelet activation was determined by the Duesseldorf-III flow cytometry assay in 21 recent-onset hyperglycemic IDDM patients before insulin, after 3 days of treatment with intravenous insulin, and after 14 and 60 days of intensified conventional insulin therapy. The intravasal platelet activation status was quantified by the percentage of platelets exposing the activation-dependent molecules CD62 (P-selectdn), thrombospondin (TSP), and CD63 (GP53) as well as the activated fibrinogen receptor (GPIIB/IIIA). Fifty matched normal subjects served as control subjects. Fourteen patients completed the 60-day study design. After initial recompensation, near-normoglycemic control was achieved after 14 days (fasting blood glucose, 117.0 ± 19.0 mg/dl), and the HbA1 concentration was 7.6 ± 1.2% after 60 days. CD62+ (4.0 ± 4.5%), TSP+ (2.0 ± 1.8%), CD63+ (11.0 ± 7.0%), and activated-GPIIB/IIIA+ (7.6 ± 7.7%) platelet levels were initially 5, 3.3, 5.7, and 2.8 times higher than the mean level of normal. There was no correlation with any of the nearly normalized metabolic parameters. Thus, more activated platelets circulate in newly diagnosed IDDM patients, which supports the assumption of a prethrombotic condition even in disease stages without apparent vascular damage. Metabolic control does not appear to be successful in attenuating activated cellular hemostasis.

Response of human monocyte-derived dendritic cells to immunostimulatory DNA.

Activated dendritic cells (DC) are of key importance for the initiation of primary immune responses and represent promising tools for immunotherapies in humans. Since DNA containing CpG motifs have been described as potent immunostimulatory (IS) adjuvants for murine DC, we here studied maturation and stimulation of functional activity in human monocyte‐derived DC (MODC) in response to several immunostimulatory oligodeoxynucleotides (IS‐ODN) and plasmid DNA (IS‐PL). We show that exposure of MODC to IS‐PL, but not IS‐ODN, induced a dose‐dependent strong up‐regulation of HLA class II and co‐stimulatory molecules (CD80, CD86), similar to that observed after treatment with TNF‐α. Functional activity was assessed by the detection of increased secretions of IL‐6 and IL‐12(p75) following treatment with IS‐PL. In addition, IS‐PL‐stimulated MODC acquired a high T cell‐stimulatory capacity. T cells stimulated by tetanus toxoid‐pulsed, IS‐PL‐matured MODC were significantly more frequently IFN‐γ positive (25.2±2.7%) as compared to TNF‐α‐treated MODC (15.4±1.4 %), indicating a strong activation of Th1 lymphocytes. In conclusion, we demonstrate that human MODC are activated by IS‐PL but not IS‐ODN previously used as adjuvants in animal models. The Th1‐like immune response observed after stimulation with IS‐PL‐treated DC suggests that preincubation of human MODC with IS‐PL or coimmunization with IS‐PL may represent an useful approach to generate strongly activated human MODC for several therapeutic applications such as DC‐based tumor immunotherapy.

Herz und metabolisches Syndrom

Über 75% der Patienten mit Diabetes mellitus sterben an ischämischen Gefäßereignissen, mehrheitlich dem Herzinfarkt. Der überwiegende Teil der Fälle von Typ-2-Diabetes tritt regelhaft im Rahmen eines Risikofaktorenclusters aus Dyslipoproteinämie, Hypertonie und Adipositas (“metabolisches Syndrom”) auf. Dies ereignet sich häufig vor einem genetisch determinierten Hintergrund, der die pathogenetische Bedeutung dieser Risikofaktoren, insbesondere für das Herz, erhöht. Diese epidemiologischen Risikofaktoren allein können jedoch die pathogenetische Sequenz der okklusiven koronaren Herzkrankheit bis zum Infarkt nicht hinreichend erklären. Das Gerinnungssystem spielt dabei eine entscheidende Rolle. Es befindet sich in einem labilen Gleichgewicht (“präthrombotischer Zustand”): erhöhte Verfügbarkeit plasmatischer Koagulatoren, verminderte Fibrinolyse, verminderte endotheliale Thromboresistenz sowie korpuskuläre Hyperreaktivität des Blutes. Einige Faktoren dieses Gerinnungsnetzwerkes sind direkt bei der Entstehung des ischämischen Endpunktes, d. h. der Thrombusbildung, involviert (z. B. Thrombozyten, PAI-1 oder Fibrinogen). Die Kombination struktureller Veränderungen des Arbeitsmyokards zusammen mit der Hyperkoagulabilität des Blutes können die schlechte funktionelle Reserve infarzierter Diabetikerherzen erklären und sind für den deutlich reduzierten Erfolg von akuten (Fibrinolyse) und längerfristigen Interventionen zur Erlangung von Gefäßoffenheit (PTCA, CABG) verantwortlich. Eine metabolische Kontrolle alleine kann diese komplexe Interdependenz zwischen Risikofaktoren und ihren mittelbaren Konsequenzen nicht neutralisieren, ist aber eine zwingende Voraussetzung zur Verbesserung der Prognose akuter Koronarsyndrome. Gerade bei Diabetikern ist eine mehrdimensionale Intervention erforderlich, die eine Beratung zu gesunder Lebensführung (z. B. Nikotinkarenz) einschließt und sich neben genereller Normalisierung von Blutdruck, Blutfetten sowie der Hyperkoagulabilität an den individuellen Erfordernissen der Patienten orientiert. Most people with the Metabolic Syndrome die from thrombotic complications superimposed to degenerative arterial vascular lesions, mostly myocardial infarction. Type-2-Diabetes is a risk factor per se for such complications, but often clusters with dyslipoproteinemia, hypertension and obesity. This is referred to as “Metabolic Syndrome” and often operates on a genetically programmed susceptibility which accelerates the pathogenesis of coronary artery disease in front of a much wider diabetes specific cardiopathy. From a pathophysiological point of view none of these associated risk factors explains the pathogenetic series of events leading to the precipitation of an occlusive thrombus at sites of complicated coronary plaques. In patients with the Metabolic Syndrome the coagulation system is switched towards a prethrombotic state, involving increased plasmatic coagulation, diminished fibrinolysis, decreased endothelial thromboresistance and predominantly platelet hyperreactivity (“diabetic thrombocytopathy”). Some of these factors are associated with an increased coronary risk (e.g. fibrinogen, PAI-1, platelets), but are also directly linked to the pathogenesis of “atherothrombosis”. Altered cardiac remodelling together with adhesion and coagulation mechanisms appears suitable to explain decreased functional performance of infarcted organs, decreased success of acute (reduced fibrinolytic response, no reflow phenomenon) and longterm intervention strategies for vessel patency (PTCA, CABG) in Diabetes. Glucose adjustment alone will not adequately neutralize these complex mechanisms, but in the situation of myocardial infarction eumetabolization with parenteral glucose-insulin-potassium infusion appears mandatory similar to non-diabetics. On the longterm a multidimensional interventional repertoire is required particularly in patients with the Metabolic Syndrome including antihypertensive, antidyslipoproteinemic and antithrombotic drugs, customized according to the individual patients needs as assessed by early diagnostic measures (“early secondary prevention”).