Sajoscha Sorrentino

Endothelial-Vasoprotective Effects of High-Density Lipoprotein Are Impaired in Patients With Type 2 Diabetes Mellitus but Are Improved After Extended-Release Niacin Therapy

Background— High-density lipoprotein (HDL)–raising therapies are currently under intense evaluation, but the effects of HDL may be highly heterogeneous. We therefore compared the endothelial effects of HDL from healthy subjects and from patients with type 2 diabetes mellitus and low HDL (meeting the criteria for metabolic syndrome), who are frequently considered for HDL-raising therapies. Moreover, in diabetic patients, we examined the impact of extended-release (ER) niacin therapy on the endothelial effects of HDL. Methods and Results— HDL was isolated from healthy subjects (n=10) and patients with type 2 diabetes (n=33) by sequential ultracentrifugation. Effects of HDL on endothelial nitric oxide and superoxide production were characterized by electron spin resonance spectroscopy analysis. Effects of HDL on endothelium-dependent vasodilation and early endothelial progenitor cell–mediated endothelial repair were examined. Patients with diabetes were randomized to a 3-month therapy with ER niacin (1500 mg/d) or placebo, and endothelial effects of HDL were characterized. HDL from healthy subjects stimulated endothelial nitric oxide production, reduced endothelial oxidant stress, and improved endothelium-dependent vasodilation and early endothelial progenitor cell–mediated endothelial repair. In contrast, these beneficial endothelial effects of HDL were not observed in HDL from diabetic patients, which suggests markedly impaired endothelial-protective properties of HDL. ER niacin therapy improved the capacity of HDL to stimulate endothelial nitric oxide, to reduce superoxide production, and to promote endothelial progenitor cell–mediated endothelial repair. Further measurements suggested increased lipid oxidation of HDL in diabetic patients, and a reduction after ER niacin therapy. Conclusions— HDL from patients with type 2 diabetes mellitus and metabolic syndrome has substantially impaired endothelial-protective effects compared with HDL from healthy subjects. ER niacin therapy not only increases HDL plasma levels but markedly improves endothelial-protective functions of HDL in these patients, which is potentially more important. Clinical Trial Registration— clinicaltrials.gov. Identifier: NCT00346970.

Critical Role of the NAD(P)H Oxidase Subunit p47phox for Left Ventricular Remodeling/Dysfunction and Survival After Myocardial Infarction

Accumulating evidence suggests a critical role of increased reactive oxygen species production for left ventricular (LV) remodeling and dysfunction after myocardial infarction (MI). An increased myocardial activity of the NAD(P)H oxidase, a major oxidant enzyme system, has been observed in human heart failure; however, the role of the NAD(P)H oxidase for LV remodeling and dysfunction after MI remains to be determined. MI was induced in wild-type (WT) mice (n=46) and mice lacking the cytosolic NAD(P)H oxidase component p47phox (p47phox−/− mice) (n=32). Infarct size was similar among the groups. NAD(P)H oxidase activity was markedly increased in remote LV myocardium of WT mice after MI as compared with sham-operated mice (83±8 versus 16.7±3.5 nmol of O2− ·&mgr;g−1·min−1; P<0.01) but not in p47phox−/− mice after MI (13.5±3.6 versus 15.5±3.5 nmol of O2− ·&mgr;g−1·min−1), as assessed by electron-spin resonance spectroscopy using the spin probe CP-H. Furthermore, increased myocardial xanthine oxidase activity was observed in WT, but not in p47phox−/− mice after MI, suggesting NAD(P)H oxidase-dependent xanthine oxidase activation. Myocardial reactive oxygen species production was increased in WT mice, but not in p47phox−/− mice, after MI. LV cavity dilatation and dysfunction 4 weeks after MI were markedly attenuated in p47phox−/− mice as compared with WT mice, as assessed by echocardiography (LV end-diastolic diameter: 4.5±0.2 versus 6.3±0.3 mm, P<0.01; LV ejection fraction, 35.8±2.5 versus 22.6±4.4%, P<0.05). Furthermore, cardiomyocyte hypertrophy, apoptosis, and interstitial fibrosis were substantially reduced in p47phox−/− mice as compared with WT mice. Importantly, the survival rate was markedly higher in p47phox−/− mice as compared with WT mice after MI (72% versus 48%; P<0.05). These results suggest a pivotal role of NAD(P)H oxidase activation and its subunit p47phox for LV remodeling/dysfunction and survival after MI. The NAD(P)H oxidase system represents therefore a potential novel therapeutic target to prevent cardiac failure after MI.

Nebivolol exerts beneficial effects on endothelial function, early endothelial progenitor cells, myocardial neovascularization, and left ventricular dysfunction early after myocardial infarction beyond conventional β1-blockade.

OBJECTIVES The aim of this study was to investigate whether nebivolol has added effects on left ventricular (LV) dysfunction and remodeling early after myocardial infarction (MI) beyond its β₁-receptor-blocking properties. BACKGROUND Nebivolol is a third-generation selective β₁-adrenoreceptor antagonist that stimulates endothelial cell nitric oxide (NO) production and prevents vascular reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation. Both endothelial NO synthase-derived NO production and NADPH oxidase activation are critical modulators of LV dysfunction early after MI. METHODS Mice with extensive anterior MI (n = 90) were randomized to treatment with nebivolol (10 mg/kg/day), metoprolol-succinate (20 mg/kg/day), or placebo for 30 days starting on day 1 after surgery. RESULTS Infarct size was similar among the groups. Both β₁-adrenergic receptor antagonists caused a similar decrease in heart rate. Nebivolol therapy improved endothelium-dependent vasorelaxation and increased early endothelial progenitor cells 4 weeks after MI compared with metoprolol and placebo. Nebivolol, but not metoprolol, inhibited cardiac NADPH oxidase activation after MI, as detected by electron spin resonance spectroscopy analysis. Importantly, nebivolol, but not metoprolol, improved LV dysfunction 4 weeks after MI (LV ejection fraction: nebivolol vs. metoprolol vs. placebo: 32 ± 4% vs. 17 ± 6% vs. 19 ± 4%; nebivolol vs. metoprolol: p < 0.05) and was associated with improved survival 4 weeks post-MI compared with placebo. Nebivolol had a significantly more pronounced inhibitory effect on cardiomyocyte hypertrophy after MI compared with metoprolol. CONCLUSIONS Nebivolol improves LV dysfunction and survival early after MI likely beyond the effects provided by conventional β₁-receptor blockade. Nebivolol induced effects on NO-mediated endothelial function, early endothelial progenitor cells and inhibition of myocardial NADPH oxidase likely contribute to these beneficial effects of nebivolol early after MI.

High permeability dialysis membrane allows effective removal of myoglobin in acute kidney injury resulting from rhabdomyolysis.

Objective:The objective of this study was to test the ability of myoglobin removal of a novel, high-permeability polysulphone dialyzer in acute kidney injury as a result of rhabdomyolysis. Setting:Intensive care unit of a tertiary care hospital. Patients:Six patients (one female; aged 24, 36, 41, 55, 63, and 65 yrs) with oligoanuric acute kidney injury resulting from rhabdomyolysis. Interventions:Extended dialysis was performed using a single-pass batch dialysis system and a novel polysulphone high-flux dialyzer (effective surface area 1.8 m2; inner lumen 220 &mgr;m; wall thickness 35 &mgr;m; allowing elimination of substances with a molecular weight of up to 30 kDa). Measurements and Main Results:Samples were collected at prefilter and postfilter sites as well as from the collected spent dialysate. The dialyzer clearance was calculated from concentrations before and directly after the dialysis membrane, the blood flow, and the ultrafiltration rate. The total amount of the myoglobin removed was measured directly as the whole dialysate was preserved. A median myoglobin clearance of 90.5 mL/min (range, 52.4–126.3 mL/min) was achieved, resulting in a median myoglobin removal per treatment hour of 0.54 g (range, 0.15–2.21 g). Conclusions:Extended dialysis with a high-flux, high-permeability membrane allowed effective elimination of myoglobin with a clearance of myoglobin that surpassed all previously reported dialysis techniques. This membrane may be advantageous in preventing acute kidney injury or avoiding complete loss of kidney function in patients with rhabdomyolysis. Further studies are needed to determine whether improving renal recovery or mortality in patients with acute kidney injury resulting from rhabdomyolysis is possible.

Guided Tissue Regeneration of Vascular Grafts in the Peritoneal Cavity

To the Editor: Tissue engineering represents an upcoming alternative source for vascular substitutes to create viable and biologically active grafts. Two different concepts are followed: grafts are either reseeded in vitro before implantation (tissue engineering)1 or the scaffolds are implanted as acellular matrices for intrinsic reseeding in vivo (guided tissue regeneration).2,3⇓ The scaffold matrices are fashioned from natural materials or synthetic polymers.4,5⇓ Despite considerable clinical research, no biological or synthetic grafts have been produced so far as an ideal substitute for a small-diameter artery.5,6⇓ Recently, our group focused research on the creation of bioartificial blood vessel grafts. Therefore, we read with interest the study in Circulation Research by Campbell et al7 …

Chronic Lung Allograft Dysfunction: Oxygen-enhanced T1-Mapping MR Imaging of the Lung

PURPOSE To evaluate oxygen-enhanced T1-mapping magnetic resonance (MR) imaging of the lungs for detection of chronic lung allograft dysfunction (CLAD) in patients who have undergone double lung transplantation. MATERIALS AND METHODS The local ethics committee approved this study. Seventy-six recipients of double lung allografts who underwent MR imaging of the lungs during an outpatient visit between 2011 and 2013 were included in this study after they provided written informed consent. Patients were classified as having CLAD on the basis of spirometric results and were divided into three groups: no CLAD (bronchiolitis obliterans syndrome level 0 [BOS 0]), early CLAD (BOS 0p), and late-stage CLAD (BOS 1-3). Coronal T1 maps of the lungs were acquired with the patient breathing room air and 100% oxygen by using an inversion-recovery snapshot fast low-angle shot sequence at 1.5 T. The median and interquartile range of T1 values at room air and at 100% oxygen and the oxygen transfer function were calculated. Statistical analysis was performed with analysis of variance and the Tukey honestly significant difference test or the Kruskal-Wallis test and the Mann-Whitney U test (α = 0.05). Bonferroni correction was applied for multiple comparisons. RESULTS The oxygen transfer function was significantly lower in patients in the BOS 0p (P = .025) and BOS 1-3 groups (P = .003) than it was in the patients with BOS 0. Absolute T1 values (room air, P = .66; 100% oxygen, P = .67) did not differ significantly among the groups. The heterogeneity of T1 values, measured by using the interquartile range, showed a strong trend toward higher values in patients with BOS (room air, P = .06; 100% oxygen, P = .08). CONCLUSION Oxygen transfer function may serve as an early marker for detection of CLAD.

Clinical use of oxygen-enhanced T1 mapping MRI of the lung: Reproducibility and impact of closed versus loose fit oxygen delivery system

To evaluate the reproducibility of oxygen‐enhanced magnetic resonance imaging (MRI), and the influence of different gas delivery methods, in a clinical environment.

Tissue Engineering of Blood Vessels: How to Make a Graft

Cardiovascular diseases remain the leading cause of death in western countries and often require vascular reconstruction. So far, autologous arteries or veins are the most commonly used substitutes for coronary and peripheral bypass procedures.

Functional lung MRI for regional monitoring of patients with cystic fibrosis

Purpose To test quantitative functional lung MRI techniques in young adults with cystic fibrosis (CF) compared to healthy volunteers and to monitor immediate treatment effects of a single inhalation of hypertonic saline in comparison to clinical routine pulmonary function tests. Materials and methods Sixteen clinically stable CF patients and 12 healthy volunteers prospectively underwent two functional lung MRI scans and pulmonary function tests before and 2h after a single treatment of inhaled hypertonic saline or without any treatment. MRI-derived oxygen enhanced T1 relaxation measurements, fractional ventilation, first-pass perfusion parameters and a morpho-functional CF-MRI score were acquired. Results Compared to healthy controls functional lung MRI detected and quantified significantly increased ventilation heterogeneity in CF patients. Regional functional lung MRI measures of ventilation and perfusion as well as the CF-MRI score and pulmonary function tests could not detect a significant treatment effect two hours after a single treatment with hypertonic saline in young adults with CF (p>0.05). Conclusion This study shows the feasibility of functional lung MRI as a non-invasive, radiation-free tool for monitoring patients with CF.

Allopurinolinduziertes Hypersensitivitätssyndrom mit Todesfolge@@@Allopurinol-Induced Hypersensitivity Syndrome Resulting in Death

The present report describes the case of a 67-year-old patient who developed an allopurinol-induced hypersensitivity syndrome (AHS) with toxic epidermal necrolysis and subsequently died of septic multiorgan failure. Considering the increasing prescription rate of allopurinol, the present case report intends to demonstrate the underestimated threat of AHS.ZusammenfassungDie vorliegende Kasuistik schildert den Fall eines 67-jährigen Patienten, der ein allopurinolinduziertes Hypersensitivitätssyndrom (AHS) mit toxisch- epidermaler Nekrolyse entwickelte und in der Folge an einem septischen Multiorganversagen verstarb. Mit dieser Falldarstellung soll in Anbetracht der zunehmenden Verschreibungshäufigkeit von Allopurinol die unterschätzte Gefahr eines AHS demonstriert werden.AbstractThe present report describes the case of a 67-year-old patient who developed an allopurinol-induced hypersensitivity syndrome (AHS) with toxic epidermal necrolysis and subsequently died of septic multiorgan failure. Considering the increasing prescription rate of allopurinol, the present case report intends to demonstrate the underestimated threat of AHS.