Oxidized LDL induces ventricular myocyte damage and abnormal electrical activity--role of lipid hydroperoxides

OBJECTIVE: It was our aim to investigate effects of human LDL, copper-, or AAPH-oxidized over different periods of time to different degrees (ox-LDL), on viability and electrophysiological parameters of isolated ventricular myocytes of guinea pigs. METHODS: Guinea pig ventricular myocytes were incubated with ox-LDL or native LDL (at 0.5 mg/ml) for 12 h, and afterwards myocyte damage, action potentials, and transmembrane ion currents were studied (at 37 degrees C). RESULTS: Ox-LDL was found to induce severe myocyte damage, whereas native LDL had no effect. Myocyte damage was dependent on the content of total lipid hydroperoxides in both copper-oxidized and AAPH-oxidized LDL. Incubation with ox-LDL led to intense contractile and electrophysiological effects including prolongation of action potential duration, depolarization of resting membrane potential, spontaneous activity, generation of afterdepolarizations, and modification of transmembrane ion currents (e.g. inward rectifier, calcium, and background currents). CONCLUSIONS: Ox-LDL induced cell damage and irregular electrical activity in ventricular myocytes. These effects were dependent on the lipid hydroperoxide content of ox-LDL and were similar to oxidative stress (OS) induced by various OS-generating systems. The observed effects may play a role for functional cardiac abnormalities in patients with increased ox-LDL levels.     

Cost analyses of community-acquired pneumonia from the hospital perspective

STUDY OBJECTIVES: Community-acquired pneumonia (CAP) is a widespread disease with important implications for health-care systems worldwide. This study investigated direct costs, treatment patterns, and outcomes associated with two patient cohorts hospitalized with CAP. DESIGN: The study design was naturalistic, prospective, and open. PATIENTS: The study enrolled 580 patients. Two hundred sixty-one patients were treated initially with IV moxifloxacin (45%, cohort M); the remaining 319 patients received nonstandardized treatment (cohort S). SETTING: Twenty-two hospitals in Germany. RESULTS: Clinical success rates were similar between treatment groups (cohort M, 242 of 256 patients, 95%; cohort S, 286 of 312 patients, 92%; p = 0.208). Mean +/- SD length of hospital stay was 10.8 +/- 5.2 days, with cohort M having a significantly shorter hospital stay (10.0 +/- 4 days) compared to cohort S (11.5 +/- 6 days; p < 0.001). Median of all direct costs was dollar 1,333 (minimum, dollar 127; maximum, dollar 9,488), with direct costs of dollar 1,250 in cohort M (minimum, dollar 372; maximum, dollar 9,488) and dollar 1,409 in cohort S (minimum, dollar 127; maximum, dollar 9,366) per treated episode of CAP (p = 0.066). CONCLUSIONS: Major determinants of costs were length of hospital stay and ICU admission, whereas costs for staff and hotel were major contributors to direct costs. Initial antibiotic therapy with moxifloxacin resulted in similar clinical efficacy and direct costs compared to nonstandardized therapy; however, patients treated with moxifloxacin benefited with an earlier hospital discharge.     

Epidermal growth factor partially restores colonic ion transport responses in mouse models of chronic colitis

BACKGROUND & AIMS: Epidermal growth factor receptor (EGFR) activation, which plays an important role in regulating intestinal ion transport, can alleviate clinical symptoms such as diarrhea in patients with ulcerative colitis and promote mucosal restitution in animal models of colitis. Here, we investigate whether EGFR can regulate colonic ion transport in the setting of colitis. METHODS: Distal colon from control mice and mice with colitis was retained for immunohistochemistry or mounted in Ussing chambers. Ion transport responses across the tissues to the calcium agonist carbachol and the adenosine 3',5'-cyclic monophosphate agonist forskolin were measured with or without epidermal growth factor (EGF) pretreatment. RESULTS: EGF pretreatment of normal colonic mucosa inhibited ion transport responses to carbachol and forskolin but potentiated the reduced ion transport responses seen in dextran sulfate sodium (DSS)-treated and mdr1a knockout mouse colon. Ion substitution studies and the sodium transport inhibitor amiloride showed that sodium movement primarily accounted for the potentiating effect of EGF in DSS-treated tissues, despite decreased sodium channel expression. EGF potentiation of transport responses in DSS-treated colon was completely blocked by the cytoskeletal disruptor cytochalasin D and the phosphatidylinositol 3-kinase inhibitor wortmannin, whereas the novel and conventional protein kinase C isoform inhibitor G?6850 and the extracellular signal-regulated kinase inhibitor PD98059 partially reduced EGF effects. EGFR epithelial distribution and transforming growth factor alpha expression were also altered in DSS-treated tissues. CONCLUSIONS: Chronic inflammation uncovers a potentiating effect of EGFR activation on epithelial electrogenic sodium absorption that would be expected to ameliorate diarrheal symptoms associated with colitis.     

Removal of dying cells and systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a very heterogeneous systemic autoimmune disease, in which autoantibody synthesis against nuclear constituents is the main immunological characteristic. These autoantibodies underwent affinity maturation and isotype switching. Additionally, T-cell tolerance against nuclear autoantigens should be affected in these autoimmune patients. Nuclear material derived from apoptotic and/or necrotic cells may serve as an important source of autoantigens. However, dead and dying cells as well as cellular debris are rapidly removed from tissues by phagocytes without eliciting inflammation or immune responses under healthy conditions. During apoptosis nuclear components are strongly modified through enzymatic reactions. If these cells are not timely cleared, those autoantigens may be released, taken up, and presented by dendritic cells in tissues or presented by follicular dendritic cells in lymph nodes to T and B cells, respectively. This could be a mechanism for breaking the peripheral self-tolerance. In this article we focus on the deficient clearance of apoptotic cells in SLE patients and its importance in development of this autoimmune disease. G.E.G. and L.E.M. contributed equally to this work     

Percutaneous aortic valve replacement for severe aortic stenosis in high-risk patients using the second- and current third-generation self-expanding CoreValve prosthesis: device success and 30-day clinical outcome.

OBJECTIVES: We sought to determine both the procedural performance and safety of percutaneous implantation of the second (21-French [F])- and third (18-F)-generation CoreValve aortic valve prosthesis (CoreValve Inc., Irvine, California). BACKGROUND: Percutaneous aortic valve replacement represents an emerging alternative therapy for high-risk and inoperable patients with severe symptomatic aortic valve stenosis. METHODS: Patients with: 1) symptomatic, severe aortic valve stenosis (area <1 cm2); 2) age > or =80 years with a logistic EuroSCORE > or =20% (21-F group) or age > or =75 years with a logistic EuroSCORE > or =15% (18-F group); or 3) age > or =65 years plus additional prespecified risk factors were included. Introduction of the 18-F device enabled the transition from a multidisciplinary approach involving general anesthesia, surgical cut-down, and cardiopulmonary bypass to a truly percutaneous approach under local anesthesia without hemodynamic support. RESULTS: A total of 86 patients (21-F, n = 50; 18-F, n = 36) with a mean valve area of 0.66 +/- 0.19 cm2 (21-F) and 0.54 +/- 0.15 cm2 (18-F), a mean age of 81.3 +/- 5.2 years (21-F) and 83.4 +/- 6.7 years (18-F), and a mean logistic EuroSCORE of 23.4 +/- 13.5% (21-F) and 19.1 +/- 11.1% (18-F) were recruited. Acute device success was 88%. Successful device implantation resulted in a marked reduction of aortic transvalvular gradients (mean pre 43.7 mm Hg vs. post 9.0 mm Hg, p < 0.001) with aortic regurgitation grade remaining unchanged. Acute procedural success rate was 74% (21-F: 78%; 18-F: 69%). Procedural mortality was 6%. Overall 30-day mortality rate was 12%; the combined rate of death, stroke, and myocardial infarction was 22%. CONCLUSIONS: Treatment of severe aortic valve stenosis in high-risk patients with percutaneous implantation of the CoreValve prosthesis is feasible and associated with a lower mortality rate than predicted by risk algorithms.     

Aging and heart failure--similar syndromes of exercise intolerance? Implications for exercise-based interventions

A classic hallmark of chronic heart failure (CHF) is exercise intolerance; however, the extent of exercise limitation is not correlated with the degree of left ventricular dysfunction. Over the past 2 decades it has become more and more evident that peripheral factors, such as skeletal muscle dysfunction, ventilatory abnormalities, and endothelial dysfunction, contribute the greater part to the limitation of exercise capacity. The molecular and pathophysiological changes observed in these organ systems are not always specific to the underlying CHF but rather represent a common pathway that is activated in several chronic disease processes, including severe chronic obstructive pulmonary disease, cancer, and in the normal aging process. A major contributing factor for skeletal muscle catabolism (i.e. elevated cytokine expression in the skeletal muscle) can be found in both normal healthy aging and in heart failure patients. It is reasonable to assume that the overlap of aging and CHF-associated changes in the skeletal muscle partially explains the disabling consequences of the CHF syndrome among elderly patients (nearly 80% of all patients hospitalized for CHF are >65 years old). Peripheral alterations in CHF are often not adequately treated in routine clinical care since standard pharmacological therapy is still focused on the cardiac function and neurohormonal alteration. Exercise training is a guideline-oriented adjuvant therapy with well-documented beneficial effects on exercise tolerance, skeletal muscle function, endothelial function, and respiration. In this review, the effects of exercise in aging and in CHF are compared and the parallel mechanisms are explored.     

Serum retinol-binding protein 4 is reduced after weight loss in morbidly obese subjects

CONTEXT: Administration of retinol-binding protein 4 (RBP-4) impairs insulin sensitivity in animals, and elevated serum concentrations have been associated with insulin resistance in humans. OBJECTIVE: We have studied whether weight loss influences RBP-4. PATIENTS AND METHODS: Fasting serum concentrations of RBP-4 were measured before and 6 months after gastric banding surgery in 33 morbidly obese patients aged 40 +/- 11 yr with a body mass index (BMI) of 46 +/- 5 kg/m(2). Fourteen healthy subjects aged 29 +/- 5 yr with a BMI less than 25 kg/m(2) served as controls. To characterize the association of weight loss with central and peripheral appetite regulation, the signaling protein agouti-related protein (AGRP), the orexigenic hormone ghrelin, and its recently identified antagonist obestatin were determined. RESULTS: At baseline, RBP-4 levels were markedly higher in obese than in lean subjects (2.7 +/- 0.5 vs. 0.9 +/- 0.5 microg/ml; P < 0.001). In contrast, AGRP and obestatin were lower in obese subjects compared with lean controls (all P < 0.001). Six months after gastric banding, BMI was reduced to 40 +/- 5 kg/m(2), RBP-4 was reduced to 2.0 +/- 0.7 microg/ml, AGRP increased from 1.8 +/- 1.1 to 3.4 +/- 1.1 ng/ml, ghrelin increased from 93 +/- 58 to 131 +/- 70 pg/ml, and obestatin increased from 131 +/- 52 to 173 +/- 35 pg/ml (all P < 0.05). Individual changes of RBP-4 were associated with changes of BMI (r = 0.72), the homeostasis model assessment insulin resistance-index (r = 0.53), and total cholesterol (r = 0.42, for all P < 0.05). CONCLUSION: Reductions in circulating RBP-4 may contribute to improved insulin resistance in morbidly obese subjects after weight loss. This is accompanied by favorable changes in appetite-regulating hormones, which might support the sustained weight loss after obesity surgery.     

Premenopausal black women are uniquely at risk for coronary heart disease compared to white women

Premenopausal black women have a two to threefold greater rate of coronary heart disease than premenopausal white women. This study was designed to provide greater insight into the reasons for this difference which is currently unclear. Coronary heart disease risk factors were compared in 100 black and 100 white, healthy premenopausal women, ages 18–45 years, and of relatively advantaged socioeconomic status. Compared to white women, black women had a higher body mass index (32.0±9.2 vs. 29.0±9.4 kg/m², p =0.021), and higher systolic (124±17 vs. 115±14 mm Hg, p <0.0001) and diastolic (79±14 vs. 75±11 mm Hg, p =0.048) blood pressures. The mean plasma lipoprotein(a) concentration was markedly higher in the black women (40.2±31.3 mg/dL) than in the white women (19.2±23.7 mg/dL, p<0.0001). The plasma total homocysteine level was also higher in the black women (8.80±3.38 vs. 7.81±2.58 mmol/L, p =0.013). The black women, however, had lower plasma triglyceride levels (0.91±0.46 vs. 1.22±0.60 mmol/L, p <0.0001) and a trend toward higher high density lipoprotein cholesterol levels (1.37±0.34 vs. 1.29±0.31 mmol/L, p =0.064) than the white women. Plasma total and low density lipoprotein cholesterol levels were similar. Black women consumed more saturated fat and cholesterol. Rates of cigarette smoking and alcohol intake were low and similar between the races. In summary, compared to white women, black women had a higher mean body mass index, higher blood pressures, higher lipoprotein(a) and plasma total homocysteine levels, and greater consumption of saturated fat and cholesterol. The differences in coronary risk factors between these two premenopausal groups may explain the higher incidence of coronary heart disease in black women.