Long-term follow-up of circulating oxidative stress markers in patients undergoing lipoprotein apheresis by Direct Adsorption of Lipids (DALI).

OBJECTIVE: Beyond its well-established efficacy in lowering atherogenic lipids and lipoproteins, DALI (Direct Adsorption of Lipids) apheresis has been shown to have acute anti-inflammatory and endothelium-protective effects. In the present study, we investigated long-term effects of DALI procedures on circulating oxidative stress markers. METHODS: Thirteen patients involved in the study underwent regular DALI apheresis for nearly two years. At sessions 1, 40 and 80 conventional lipid status and changes of systemic oxidative stress markers (oxidized LDL, anti-oxidized LDL antibodies, advanced oxidation protein products (AOPP), and myeloperoxidase (MPO)) were examined. RESULTS: DALI procedure efficiently reduced atherogenic lipids/lipoproteins. On day three after apheresis lipid parameters returned to pre-apheresis values. They showed no tendency to increase or to decrease over time. No significant differences were found between 1st, 40th and 80th sessions. In a similar way, levels of oxidative stress biomarkers acutely decreased after apheresis sessions and rebounded on day three after apheresis. No significant differences were observed between sessions 1, 40, and 80. CONCLUSION: DALI apheresis repeatedly decreases atherogenic lipid/lipoprotein profile and oxidative stress biomarker levels during each session. Among all investigated parameters no longitudinal effects over two years could be observed.

Association between systemic oxidative stress and insulin resistance/sensitivity indices - the PREDIAS study.

OBJECTIVE: Systemic oxidative stress has been causally related to insulin resistance and the subsequent development of type 2 diabetes mellitus (T2D). We investigated associations between circulating oxidative stress markers and different surrogate indexes of insulin sensitivity/resistance. PATIENTS: Cross-sectional data were obtained from 1183 subjects with normal glucose tolerance (NGT), 280 subjects with impaired glucose tolerance (IGT) and 69 newly detected T2D individuals entering the PREDIAS (prevention of diabetes) study. MEASUREMENTS: Following oral glucose tolerance test, five different insulin sensitivity/resistance indices were estimated: homoeostasis model of insulin resistance (HOMA-IR), quantitative insulin sensitivity check index (QUICKI), early phase insulin release (EPIR), insulin sensitivity index (ISI) and disposition index (DI). Additionally, circulating phagocyte generation of reactive oxygen species (ROS) and plasma total antioxidant capacity (TAC) was measured. RESULTS: After adjustment for five covariates, HOMA-IR was significantly increased in IGT and T2D subjects when compared to NGT subjects (P = 0·000). QUICKI (P = 0·000), ISI (P = 0·000), EPIR (0·005/0·012) and DI (P = 0·000) were significantly attenuated in IGT and T2D. The prevalence of IGT and T2D individuals increased with increasing ROS generation and TAC tertiles. Increased systemic ROS generation was paralleled by increased HOMA-IR (P < 0·001, tertile 1/T1/vs tertile 3/T3/), decreased QUICKI (P < 0·001, T1 vs T3) and decreased ISI (P < 0·05, T1 vs T3). A similar tendency for indices was observed when comparing TAC tertiles: increase in HOMA-IR, decrease in QUICKI and ISI (P < 0·001, T1 vs T3 each). EPIR and DI did not differ significantly across ROS generation and TAC tertiles. CONCLUSIONS: Systemic oxidative stress is associated with elevated insulin resistance index HOMA-IR, and decreased insulin sensitivity surrogates QUICKI and ISI.

Long-term therapeutic efficacy of lipoprotein apheresis on circulating oxidative stress parameters--A comparison of two different apheresis techniques.

BACKGROUND: A chronic lipoprotein apheresis therapy leads to an expressed reduction in the incidence of cardiovascular events in high-risk patients. In addition to the elimination of atherogenic lipoproteins such as LDL and lipoprotein(a), an antioxidative effect of lipoprotein apheresis has been suspected. OBJECTIVES AND METHODS: We investigated long-term biochemical effects in sixteen patients undergoing lipoprotein apheresis - lipid filtration (LF, n = 7) or dextran sulfate adsorption (DSA, n = 9). Systemic oxidative stress markers (blood phagocyte chemiluminescence, levels of oxidized LDL and antioxLDL antibodies) were examined at the 1st, 40th and 80th apheresis sessions. RESULTS: In DSA patients, the 80th apheresis session was associated with significantly higher LDL cholesterol removal and lower HDL cholesterol deprivation as compared to LF patients. In contrast to LF patients, DSA patients showed a long-term progressive decrease in circulating oxidant generating activity as evaluated by whole blood chemiluminescence (p < 0.05). Moreover, a single LF apheresis session was associated with higher systemic generation of reactive oxygen species over time. CONCLUSION: Compared to LF, long-term DSA apheresis is associated with a gradual reduction of circulating oxidative burden and may be considered a beneficial molecular mechanism of this technique.

Increasing plasma lysophosphatidylcholine levels in patients with regular dextran sulfate lipoprotein apheresis.

OBJECTIVES: Previously we found a highly significant increase of phosphatidylethanolamines (PE) in response to acute lipoprotein apheresis (LA) with whole blood dextran sulfate adsorption (DSA) in contrast to the overall tendency of reduction of lipid metabolites of all lipid classes in post-apheresis plasma. Therefore, the aim of the present study was to analyze long-term modifications of the plasma lipidomic profile in patients with repeated DSA apheresis. METHODS: Nine patients weekly treated with DSA were followed for 40 weeks. Pre- and post-apheresis levels of routine lipid parameters and lipidomic profiles of five apheresis sessions were assessed. RESULTS: The main finding of the present study was a progressive increase of pre- and post-apheresis plasma lysophosphatidylcholine (LPC) levels, which doubled in concentration at the end of the 40 week observation period. LPC metabolites which mainly contributed to this increase were LPC 20:4 > 18:0 > 18:1 > 16:0 > 20:3 > 18:2. CONCLUSION: These data indicate that long-term application of DSA technology may be associated with a continuous increase in LPC levels. Possible pro- or anti-atherogenic consequences should be elucidated in further studies.

HIF-1α is a protective factor in conditional PHD2-deficient mice suffering from severe HIF-2α-induced excessive erythropoiesis.

Erythropoiesis must be tightly balanced to guarantee adequate oxygen delivery to all tissues in the body. This process relies predominantly on the hormone erythropoietin (EPO) and its transcription factor hypoxia inducible factor (HIF). Accumulating evidence suggests that oxygen-sensitive prolyl hydroxylases (PHDs) are important regulators of this entire system. Here, we describe a novel mouse line with conditional PHD2 inactivation (cKO P2) in renal EPO producing cells, neurons, and astrocytes that displayed excessive erythrocytosis because of severe overproduction of EPO, exclusively driven by HIF-2α. In contrast, HIF-1α served as a protective factor, ensuring survival of cKO P2 mice with HCT values up to 86%. Using different genetic approaches, we show that simultaneous inactivation of PHD2 and HIF-1α resulted in a drastic PHD3 reduction with consequent overexpression of HIF-2α-related genes, neurodegeneration, and lethality. Taken together, our results demonstrate for the first time that conditional loss of PHD2 in mice leads to HIF-2α-dependent erythrocytosis, whereas HIF-1α protects these mice, providing a platform for developing new treatments of EPO-related disorders, such as anemia.

Effects of an early intervention on perceived stress and diurnal cortisol in pregnant women with elevated stress, anxiety, and depressive symptomatology.

The goal of the present investigation was to examine effects of a cognitive-behavioral group intervention for pregnant women with subclinically elevated stress, anxiety and/or depression on perceived stress and salivary cortisol levels. Expectant mothers were recruited in gynaecologist practices. They participated in a screening, a standardized diagnostic interview (Munich-Composite Diagnostic Interview, M-CIDI), and were randomly assigned to an intervention (N = 21) and treatment as usual control group (N = 40). The intervention consisted of a manualized cognitive-behavioral group program for expectant mothers with subclinically elevated stress, depression, and/or anxiety symptoms. Stress questionnaire (prenatal distress (PDQ), perceived stress (PSS)) as well as diurnal salivary cortisol assessment took place at T1 (antenatal, preintervention), at T2 (antenatal, post-intervention) and T3 (3-month postpartum). Subjects that participated in the intervention exhibited a significant post-treatment change in morning cortisol (cortisol awakening response, CAR) in contrast to control subjects, F(8,51) = 2.300, p = 0.047. Intervention participants showed a smaller CAR subsequent to the intervention, displaying a lessened stress reaction. This effect was not observed in the control group. In contrast, we failed in discovering a significant difference between the research groups regarding the cortisol area under curve parameter (AUC) and the applied subjective stress questionnaires. Evaluation results were thus heterogeneous. Nevertheless, intervention effects on the CAR are promising. Our results suggest that a cognitive-behavioral intervention might lead to an improvement in the biological stress response of pregnant women with subclinically elevated stress, anxiety, or depressive symptoms.

Acute atrial tachyarrhythmia induces angiotensin II type 1 receptor-mediated oxidative stress and microvascular flow abnormalities in the ventricles.

AIMS: Patients with paroxysmal atrial fibrillation (AF) often present with typical angina pectoris and mildly elevated levels of cardiac troponin (non ST-segment elevation myocardial infarction) during an arrhythmic event. However, in a large proportion of these patients, significant coronary artery disease is excluded by coronary angiography. Here we explored the potential underlying mechanism of these events. METHODS AND RESULTS: A total of 14 pigs were studied using a closed chest, rapid atrial pacing (RAP) model. In five pigs RAP was performed for 7 h (600 b.p.m.; n = 5), in five animals RAP was performed in the presence of angiotensin-II type-1-receptor (AT(1)-receptor) inhibitor irbesartan (RAP+Irb), and four pigs were instrumented without intervention (Sham). One-factor analysis of variance was performed to assess differences between and within the three groups. Simultaneous measurements of fractional flow reserve (FFR) and coronary flow reserve (CFR) before, during, and after RAP demonstrated unchanged FFR (P = 0.327), but decreased CFR during RAP (RAP: 67.7 +/- 7.2%, sham: 97.2 +/- 2.8%, RAP+Irb: 93.2 +/- 3.3; P = 0.0013) indicating abnormal left ventricular (LV) microcirculation. Alterations in microcirculatory blood flow were accompanied by elevated ventricular expression of NADPH oxidase subunit Nox2 (P = 0.039), lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1, P = 0.004), and F(2)-isoprostane levels (P = 0.008) suggesting RAP-related oxidative stress. Plasma concentrations of cardiac troponin-I (cTn-I) increased in RAP (RAP: 613.3 +/- 125.8 pmol/L vs. sham: 82.5 +/- 12.5 pmol/L; P = 0.013), whereas protein levels of eNOS and LV function remained unchanged. RAP+Irb prevented the increase of Nox2, LOX-1, and F(2)-isoprostanes, and abolished the impairment of microvascular blood flow. CONCLUSION: Rapid atrial pacing induces AT(1)-receptor-mediated oxidative stress in LV myocardium that is accompanied by impaired microvascular blood flow and cTn-I release. These findings provide a plausible mechanism for the frequently observed cTn-I elevation accompanied with typical angina pectoris symptoms in patients with paroxysmal AF and normal (non-stenotic) coronary arteries.

Evaluation of a diabetes management system based on practice guidelines, integrated care, and continuous quality management in a Federal State of Germany: a population-based approach to health care research.

OBJECTIVE: The aim of this study was to evaluate the Saxon Diabetes Management Program (SDMP), which is based on integrated practice guidelines, shared care, and integrated quality management. The SDMP was implemented into diabetes contracts between health insurance providers, general practitioners (GPs), and diabetes specialized practitioners (DSPs) unified in the Saxon association of Statutory Health Insurance Physicians. RESEARCH DESIGN AND METHODS: The evaluation of the SDMP in Germany represents a real-world study by using clinical data collected from participating physicians. Between 2000 and 2002 all DSPs and about 75% of the GPs in Saxony participated. Finally, 291,771 patients were included in the SDMP. Cross-sectional data were evaluated at the beginning of 2000 (group A1) and at the end of 2002 (group A2). A subcohort of 105,204 patients was followed over a period of 3 years (group B). RESULTS: The statewide implementation of the SDMP resulted in a change in therapeutic practice and in better cooperation. The median A1C at the time of referral to DSPs decreased from 8.5 to 7.5%, and so did the overall mean. At the end, 78 and 61% of group B achieved the targets for A1C and blood pressure, respectively, recommended by the guidelines compared with 69 and 50% at baseline. Patients with poorly controlled diabetes benefited the most. Preexisting regional differences were aligned. CONCLUSIONS: Integrated care disease management with practicable integrated quality management including collaboration between GPs and specialist services is a significant innovation in chronic care management and an efficient way to improve diabetes care continuously.

[Severe progression of coronary heart disease in a patient with elevated lipoprotein (a) level in spite of optimal LDL-C decrease]. / Schwere Progression einer koronaren Herzkrankheit bei einem Patienten mit erhöhtem Lipoprotein-(a)-Spiegel trotz optimaler LDL-C-Senkung.

The patient introduced in the case history had a myocardial infarction in 2001 and a coronary two-vessel disease (extensive subtotal proximal stenosis of the left anterior descending [LAD] and proximal subtotal stenosis of the right coronary artery) which was diagnosed via coronary angiography at the age of 39 years. Besides smoking and obesity an important coronary risk factor was hyperlipoproteinemia with an especially massive increase in lipoprotein (a) level. The lipoprotein (a) level in January 2002 was massively elevated with 273.7 mg/dl (2 737 mg/l; Table 1). Despite invasive therapy with percutaneous transluminal coronary angioplasty (PTCA) and stent implantation in LAD and immediate therapy with atorvastatin, a restenosis in LAD was detected in April 2002 (Figure 1). Re-PTCA and intracoronary brachytherapy were performed (Figure 2). After presentation of unstable angina pectoris symptoms in November 2003, again a new in-stent restenosis in LAD could be detected via coronary angiography (Figure 3a), so that a single-bypass operation became necessary (Figure 3b). Since December 2001, an intensified treatment in a specialized polyclinic for lipid metabolism has been carried out, in which LDL-C values of 104 mg/dl (2.7 mmol/l) were targeted under aggressive lipid-lowering therapy with atorvastatin 80 mg/d and ezetimibe 10 mg/d (Table 1). Since 1998, the patient has quitted smoking. Blood pressure values are now in the therapeutic range, but the obesity could not be overcome.A distinctly elevated lipoprotein (a) level is an important risk factor for an early-onset and badly progressive arteriosclerosis. Thus, once in lifetime in the scope of risk factor management one should measure the lipoprotein (a) level. In case of elevated values the crucial treatment options include a very good management of all other risk factors, whereas an LDL-C level < 100 mg/dl (< 2.6 mmol/l), optionally < 70 mg/dl (< 1.8 mmol/l), is of vital importance. Nicotinic acid derivatives lower lipoprotein (a) levels by about 20-30%. All other risk factors, e.g., diabetes or hypertension, should be strictly managed as well. Cardiologic and angiologic examinations have to be an integral part of the treatment of these patients.

Syndrome of inappropriate antidiuretic hormone secretion (SIADH) induced by vinorelbine treatment of metastatic breast cancer.

BACKGROUND: Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is known as a rare adverse event with chemotherapy. We report the case of a SIADH occurring after vinorelbine treatment. CASE REPORT: In a 79-year-old woman breast cancer was first diagnosed in 2000. Three years after the first diagnosis the patient developed bone and liver metastases. Seven days after receiving the 1st course of palliative chemotherapy with vinorelbine the patient suffered from decreased mental awareness, fatigue, and physical weakness. After the diagnosis of SIADH based on laboratory findings in combination with clinical symptoms, we started therapy with balanced fluid intake and intravenous infusion of normotonic saline. CONCLUSION: The development of SIADH as a rare adverse event with vinorelbine treatment has to be taken into consideration.