Acute Renal Graft-Versus-Host Disease in a Murine Model of Allogeneic Bone Marrow Transplantation.

Acute kidney injury (AKI) is a very common complication after allogeneic bone marrow transplantation (BMT) and is associated with a poor prognosis. Generally, the kidneys are assumed to not be no direct targets of graft-versus-host disease (GvHD), and renal impairment is often attributed to several other factors occurring in the early phase after BMT. Our study aimed to prove the existence of renal GvHD in a fully major histocompatibility complex (MHC)-mismatched model of BALB/c mice conditioned and transplanted according to 2 different intensity protocols. Syngeneically transplanted and untreated animals served as controls. Four weeks after transplantation, allogeneic animals developed acute GvHD that was more pronounced in the high-intensity protocol (HIP) group than in the low-intensity protocol (LIP) group. Urea and creatinine as classic serum markers of renal function could not verify renal impairment 4 weeks after BMT. Creatinine levels were even reduced as a result of catabolic metabolism and loss of muscle mass due to acute GvHD. Proteinuria, albuminuria, and urinary N-acetyl-beta-d-glucosaminidase (NAG) levels were measured as additional renal markers before and after transplantation. Albuminuria and NAG were only significantly increased after allogeneic transplantation, correlating with disease severity between HIP and LIP animals. Histological investigations of the kidneys showed renal infiltration of T cells and macrophages with endarteriitis, interstitial nephritis, tubulitis, and glomerulitis. T cells consisted of CD4+, CD8+, and FoxP3+ cells. Renal expression analysis of allogeneic animals showed increases in indoleamine-2,3 dioxygenase (IDO), different cytokines (tumor necrosis factor α, interferon-γ, interleukin 1 α [IL-1α], IL-2, IL-6, and IL-10), and adhesion molecules (intercellular adhesion molecule 1 and vascular cell adhesion molecule 1), resembling findings from other tissues in acute GvHD. In summary, our study supports the entity of renal GvHD with histological features suggestive of cell-mediated renal injury. Albuminuria and urinary NAG levels may serve as early markers of renal impairment.

Drug Coated Balloon Is Less Effective for Treatment of DES In-Stent Restenosis Both in Native Coronary Arteries and Saphenous Vein Grafts: Results From a Bicenter Registry.

BACKGROUND: The paclitaxel drug coated balloon (DCB) is an established treatment for bare metal stent (BMS) in-stent restenosis (ISR) in native coronary arteries. The evidence of DCB-application for drug eluting stent (DES) ISR both in native coronaries and saphenous vein grafts (SVG) is limited. Aim of our study was to compare the differential efficacy of DCB for treatment of BMS- and DES-ISR in native coronary vessels and SVGs. METHODS AND RESULTS: N = 135 DCB-treated patients with available follow up (FU) angiography were included in this retrospective study. Patients received treatment between April 2009 and March 2013 at 2 tertiary care hospitals in Germany. DCB was applied in BMS-ISR (n = 65; 48%) and DES-ISR (n = 70; 52%). DCB-treated lesions were located in native coronary arteries (n = 110; 81%; BMS-ISR: n = 58; 53%; DES-ISR: n = 52; 47%) and SVGs (n = 25; 19%; BMS-ISR: n = 7, 28%; DES-ISR: n = 18, 72%). Median FU was 12 months. Endpoints were binary restenosis and target lesion revascularization (TLR). Binary restenosis (29% vs. 57%; P < 0.01) and TLR (18% vs. 46%; P < 0.01) were significantly more frequent in DES-ISR versus BMS-ISR. In SVGs, TLR was required in 72% (DES-ISR) versus 14% (BMS-ISR); P = 0.02. In the Kaplan-Meier-analysis freedom from both endpoints was significantly decreased in the DES-lesions both in the total population (binary restenosis P < 0.01; TLR P < 0.01) and native coronaries (binary restenosis P = 0.02; TLR P = 0.04). CONCLUSIONS: DCB treatment is less effective in DES-ISR than in BMS-ISR. The diminished efficacy of DCB treatment is even more pronounced in DES-ISR located within degenerated SVGs.

Vascular Alterations in a Murine Model of Acute Graft-Versus-Host Disease Are Associated with Decreased Serum Levels of Adiponectin and an Increased Activity and Vascular Expression of Indoleamine 2,3-Dioxygenase.

Graft-versus-host disease (GVHD) is the limiting complication after bone marrow transplantation (BMT), and its pathophysiology seems to be highly influenced by vascular factors. Our study aimed at elucidating possible mechanisms involved in vascular GVHD. For this purpose, we used a fully MHC-mismatched model of BALB/c mice conditioned according to two different intensity protocols with total body irradiation and transplantation of allogeneic (C57BL/6) or syngeneic bone marrow cells and splenocytes. Mesenteric resistance arteries were studied in a pressurized myograph. We also quantified the expression of indoleamine 2,3-dioxygenase (IDO), endothelial (eNOS), and inducible NO synthase (iNOS), as well as several pro- and anti-inflammatory cytokines. We measured the serum levels of tryptophan (trp) and kynurenine (kyn), the kyn/trp ratio (KTR) as a marker of IDO activity, and adiponectin (APN). The myographic study showed a correlation of GVHD severity after allogeneic BMT with functional vessel alterations that started with increased vessel stress and ended in eccentric vessel remodeling, increased vessel strain, and endothelial dysfunction. These alterations were accompanied by increasing IDO activity and decreasing APN levels in the serum of allogeneic animals. The mRNA expression showed significantly elevated IDO, decreased eNOS, and elevation of most studied pro- and anti-inflammatory cytokines. Our study provides further data supporting the importance of vessel alterations in GVHD and is the first to show an association of vascular GVHD with hypoadiponectinemia and an increased activity and vascular expression of IDO. Whether there is also a causative involvement of these two factors in the development of GVHD needs to be further investigated.

Type 2 diabetes: increased expression and contribution of IKCa channels to vasodilation in small mesenteric arteries of ZDF rats.

Impaired endothelial function, which is dysregulated in diabetes, also precedes hypertension. We hypothesized that in Type 2 diabetes, the impaired endothelium-dependent relaxation is due to a loss of endothelium-derived hyperpolarization (EDH) that is regulated by impaired ion channel function. Zucker diabetic fatty (ZDF), Zucker heterozygote, and homozygote lean control rats were used as the experimental models in our study. Third-order mesenteric arteries were dissected and mounted on a pressure myograph; mRNA was quantified by RT-PCR and channel proteins by Western blotting. Under nitric oxide (NO) synthase and cyclooxygenase inhibition, endothelial stimulation with ACh fully relaxes control but not diabetic arteries. In contrast, when small-conductance calcium-activated potassium (KCa) channels and intermediate- and large-conductance KCa (I/BKCa) are inhibited with apamin and charybdotoxin, NO is able to compensate for ACh-induced relaxation in control but not in diabetic vessels. After replacement of charybdotoxin with 1-[(2-chlorophenyl)diphenylmethyl]-(1)H-pyrazole (TRAM-34; IKCa inhibitor), ACh-induced relaxation in diabetic animals is attenuated. Specific inhibition with TRAM-34 or charybdotoxin attenuates ACh relaxation in diabetes. Stimulation with 1-ethyl-2-benzimidazolinone (IKCa activator) shows a reduced relaxation in diabetes. Activation of BKCa with 1,3-dihydro-1-[2-hydroxy-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-(2)H-benzimidazol-2-one NS619 leads to similar relaxations of control and diabetic arteries. RT-PCR and Western blot analysis demonstrate elevated mRNA and protein expression levels of IKCa in diabetes. Our results suggest that the compensatory effect of NO and EDH-associated, endothelium-dependent relaxation is reduced in ZDF rats. Specific blockade of IKCa with TRAM-34 reduces NO and EDH-type relaxation in diabetic rats, indicating an elevated contribution of IKCa in diabetic small mesenteric artery relaxation. This finding correlates with increased IKCa mRNA and protein expression in this vessel.

Endothelial dysfunction and altered mechanical and structural properties of resistance arteries in a murine model of graft-versus-host disease.

A putative involvement of the vasculature seems to play a critical role in the pathophysiology of graft-versus-host disease (GVHD). We aimed to characterize alterations of mesenteric resistance arteries in GVHD in a fully MHC-mismatched model of BALB/c mice conditioned with total body irradiation that underwent transplantation with bone marrow cells and splenocytes from syngeneic (BALB/c) or allogeneic (C57BL/6) donors. After 4 weeks, animals were sacrificed and mesenteric resistance arteries were studied in a pressurized myograph. The expression of endothelial (eNOS) and inducible nitric oxide (NO)-synthase (iNOS) was quantified and vessel wall ultrastructure was investigated with electron microscopy. The myograph study revealed an endothelial dysfunction in allogeneic-transplant recipients, whereas endothelium-independent vasodilation was similar to syngeneic-transplant recipients or untreated controls. The expression of eNOS was decreased and iNOS increased, possibly contributing to endothelial dysfunction. Additionally, arteries of allogeneic transplant recipients exhibited a geometry-independent increase in vessels strain. For both findings, electron microscopy provided a structural correlate by showing severe damage of the whole vessel wall in allogeneic-transplant recipient animals. Our study provides further data to prove, and is the first to characterize, functional and structural vascular alterations in the early course after allogeneic transplantation directly in an ex vivo setting and, therefore, strongly supports the hypothesis of a vascular form of GVHD.

Prosthesis sizing for transcatheter aortic valve implantation--comparison of three dimensional transesophageal echocardiography with multislice computed tomography.

BACKGROUND: The complex anatomy of the aortic annulus warrants the use of three dimensional (3D) modalities for prosthesis sizing in transcatheter aortic valve implantation (TAVI). Multislice computed tomography (MSCT) has been used for this purpose, but its use may be restricted because of contrast administration. 3D transesophageal echocardiography (3D-TEE) lacks this limitation and data on comparison with MSCT is scarce. We compared 3D-TEE with MSCT for prosthesis sizing in TAVI. METHODS: Aortic annulus diameters in the sagittal and coronal plane and annulus areas in 3D-TEE and MSCT were compared in 57 patients undergoing TAVI. Final prosthesis size was left at the operator's discretion and the agreement with 3D-TEE and MSCT was calculated. RESULTS: Sagittal diameters on 3D-TEE and MSCT correlated well (r=.754, p<.0001) and means were comparable (22.3±2.1 vs. 22.5±2.3 mm; p=0.2; mean difference: -0.3 mm [-3.3-2.8]). On 3D-TEE, coronal diameter and annulus area were significantly smaller (p<.0001 for both) with moderate correlation (r=0.454 and r=0.592). Interobserver variability was comparable for both modalities. TAVI was successful in all patients with no severe post-procedural insufficiency. Final prosthesis size was best predicted by sagittal annulus diameters in 84% and 79% by 3D-TEE and MSCT, respectively. Agreement between both modalities was 77%. CONCLUSIONS: Annulus diameters and areas for pre-procedural TAVI assessment by 3D-TEE are significantly smaller than MSCT with exception of sagittal diameters. Using sagittal diameters, both modalities predicted well final prosthesis size and excellent procedural results were obtained. 3D-TEE can thus be a useful alternative in patients with contraindications to MSCT.

Antidiabetic treatment restores adiponectin serum levels and APPL1 expression, but does not improve adiponectin-induced vasodilation and endothelial dysfunction in Zucker diabetic fatty rats.

BACKGROUND: Adiponectin is able to induce NO-dependent vasodilation in Zucker lean (ZL) rats, but this effect is clearly alleviated in their diabetic littermates, the Zucker diabetic fatty (ZDF) rats. ZDF rats also exhibit hypoadiponectinemia and a suppressed expression of APPL1, an adaptor protein of the adiponectin receptors, in mesenteric resistance arteries. Whether an antidiabetic treatment can restore the vasodilatory effect of adiponectin and improve endothelial function in diabetes mellitus type 2 is not known. METHODS: During our animal experiment from week 11 to 22 in each case seven ZDF rats received an antidiabetic treatment with either insulin (ZDF+I) or metformin (ZDF+M). Six normoglycemic ZL and six untreated ZDF rats served as controls. Blood glucose was measured at least weekly and serum adiponectin levels were quantified via ELISA in week 11 and 22. The direct vasodilatory response of their isolated mesenteric resistance arteries to adiponectin as well as the endothelium-dependent and -independent function was evaluated in a small vessel myograph. Additionally, the expression of different components of the adiponectin signaling pathway in the resistance arteries was quantified by real-time RT-PCR. RESULTS: In ZDF rats a sufficient blood glucose control could only be reached by treatment with insulin, but both treatments restored the serum levels of adiponectin and the expression of APPL1 in small resistance arteries. Nevertheless, both therapies were not able to improve the vasodilatory response to adiponectin as well as endothelial function in ZDF rats. Concurrently, a downregulation of the adiponectin receptors 1 and 2 as well as endothelial NO-synthase expression was detected in insulin-treated ZDF rats. Metformin-treated ZDF rats showed a reduced expression of adiponectin receptor 2. CONCLUSIONS: An antidiabetic treatment with either insulin or metformin in ZDF rats inhibits the development of hypoadiponectinemia and downregulation of APPL1 in mesenteric resistance arteries, but is not able to improve adiponectin induced vasodilation and endothelial dysfunction. This is possibly due to alterations in the expression of adiponectin receptors and eNOS.

Expression of fourteen novel obesity-related genes in Zucker diabetic fatty rats.

BACKGROUND: Genome-wide association studies (GWAS) are useful to reveal an association between single nucleotide polymorphisms and different measures of obesity. A multitude of new loci has recently been reported, but the exact function of most of the according genes is not known. The aim of our study was to start elucidating the function of some of these genes. METHODS: We performed an expression analysis of fourteen genes, namely BDNF, ETV5, FAIM2, FTO, GNPDA2, KCTD15, LYPLAL1, MCR4, MTCH2, NEGR1, NRXN3, TMEM18, SEC16B and TFAP2B, via real-time RT-PCR in adipose tissue of the kidney capsule, the mesenterium and subcutaneum as well as the hypothalamus of obese Zucker diabetic fatty (ZDF) and Zucker lean (ZL) rats at an age of 22 weeks. RESULTS: All of our target genes except for SEC16B showed the highest expression in the hypothalamus. This suggests a critical role of these obesity-related genes in the central regulation of energy balance. Interestingly, the expression pattern in the hypothalamus showed no differences between obese ZDF and lean ZL rats. However, LYPLAL1, TFAP2B, SEC16B and FAIM2 were significantly lower expressed in the kidney fat of ZDF than ZL rats. NEGR1 was even lower expressed in subcutaneous and mesenterial fat, while MTCH2 was higher expressed in the subcutaneous and mesenterial fat of ZDF rats. CONCLUSION: The expression pattern of the investigated obesity genes implies for most of them a role in the central regulation of energy balance, but for some also a role in the adipose tissue itself. For the development of the ZDF phenotype peripheral rather than central mechanisms of the investigated genes seem to be relevant.

Impact of three-dimensional transesophageal echocardiography on prosthesis sizing for transcatheter aortic valve implantation.

OBJECTIVES: To compare aortic annulus diameters obtained by 3D transesophageal echocardiography (TEE) with 2D-TEE and the impact on prosthesis size selection in transcatheter aortic valve implantation (TAVI). BACKGROUND: In TAVI the aortic annulus diameter determines prosthesis size. The ideal modality for annulus assessment has not been defined yet. METHODS: Annulus diameters in 2D-TEE (long-axis view) and in 3D-TEE (long-axis view in multiple-plane-reconstruction) were compared in consecutive patients with aortic stenosis screened for TAVI. Prosthesis size was selected according to industry guidelines, integrating data from 3D-TEE, angiography and computed tomography. The percentage of cases in which 2D-TEE and 3D-TEE correctly predicted final prosthesis size was calculated. RESULTS: Forty-nine patients were studied (Age 80 ± 5, 39% male, logistic EuroScore 17 ± 11%). Annulus diameters from 2D- and 3D-TEE correlated (r = 0.808, P < 0.0001). Mean diameters were significantly larger on 3D- vs. 2D-TEE (23.4 ± 2.2 vs. 22.1 ± 2.6 mm, P < 0.001) with a mean difference of 1.2 mm (limits of agreement: -1.8 to 4.3). The interobserver variability of 2D- and 3D-TEE was 3.5 ± 5.6% and 0.9 ± 5.1%, respectively. Thirty-nine patients underwent TAVI (27 CoreValve™, 12 Edwards Sapien™). The procedure was successful in 37 (95%) patients. Postprocedural regurgitation was none or mild in 89% of the cases with no severe insufficiency. Final prosthesis size was correctly predicted by 2D-TEE in 67% while in 80% by 3D-TEE. Overall, 3D-TEE suggested a different prosthesis size in 26% of all cases compared to 2D-TEE. CONCLUSIONS: Aortic annulus measurement by 3D-TEE yields significantly larger diameters than 2D-TEE. This impacts prosthesis size selection in a considerable percentage of cases.

High-sensitive Troponin I in acute cardiac conditions: implications of baseline and sequential measurements for diagnosis of myocardial infarction.

BACKGROUND: High-sensitive Troponin I (hsTnI) facilitates the early diagnosis of myocardial infarction (MI). However, since hsTnI has not been well characterized in non-ischemic cardiac conditions, the predictive value of hsTnI for MI remains unclear. METHODS: hsTnI (ADVIA Centaur, Siemens) on admission was analyzed in 929 patients with acute cardiac condition and invasive ascertainment of coronary status by catheterization. RESULTS: Hs-TnI upon presentation was higher in patients with STEMI (median 1.27 ng/mL, IQR 0.13-14.5 ng/mL) as compared to patients with Non-STEMI (0.66 ng/mL, IQR 0.10-4.0 ng/mL, p<0.001) whereas it did not differ from STEMI in Tako-Tsubo cardiomyopathy (2.57 ng/mL, IQR 0.17-8.4 ng/mL) and myocarditis (9.76 ng/mL, IQR 2.0-27.0 ng/mL). In patients with resuscitation of non-ischemic cause (0.31 ng/mL, IQR 0.06-1.3 ng/mL), acute heart failure (0.088 ng/mL, IQR 0.035-0.30 ng/mL) and hypertensive emergency (0.066 ng/mL, IQR 0.032-0.34 ng/mL), hs-TnI was elevated above the recommended threshold of 0.04 ng/mL. At this cutpoint of 0.04 ng/mL, hsTnI indicated acute MI (STEMI or Non-STEMI) with a sensitivity of 88% and a specificity of 45% (ROC-AUC 0.748). When patients with STEMI were excluded, hsTnI indicated Non-STEMI with a sensitivity of 87% and a specificity of 45% (ROC-AUC 0.725). When sequential measurements were taken into account in a restricted cohort, a maximum hsTnI of ≥0.40 ng/mL provided a sensitivity of 89% and a specificity of 85% (ROC-AUC 0.909) for Non-STEMI. CONCLUSIONS: HsTnI is a sensitive, albeit unspecific marker of MI. In patients with mildly elevated hsTnI and without evidence for STEMI, we suggest serial assessment of hsTnI and a 10-fold higher cutpoint of 0.40 ng/mL before Non-STEMI is assumed.

Eplerenone prevents salt-induced vascular stiffness in Zucker diabetic fatty rats: a preliminary report.

BACKGROUND: Aldosterone levels are elevated in a rat model of type 2 diabetes mellitus, the Zucker Diabetic fatty rat (ZDF). Moreover blood pressure in ZDF rats is salt-sensitive. The aim of this study was to examine the effect of the aldosterone antagonist eplerenone on structural and mechanical properties of resistance arteries of ZDF-rats on normal and high-salt diet. METHODS: After the development of diabetes, ZDF animals were fed either a normal salt diet (0.28%) or a high-salt diet (5.5%) starting at an age of 15 weeks. ZDF rats on high-salt diet were randomly assigned to eplerenone (100 mg/kg per day, in food) (ZDF+S+E), hydralazine (25 mg/kg per day) (ZDF+S+H), or no treatment (ZDF+S). Rats on normal salt-diet were assigned to eplerenone (ZDF+E) or no treatment (ZDF). Normoglycemic Zucker lean rats were also divided into two groups receiving normal (ZL) or high-salt diet (ZL+S) serving as controls. Systolic blood pressure was measured by tail cuff method. The experiment was terminated at an age of 25 weeks. Mesenteric resistance arteries were studied on a pressurized myograph. Specifically, vascular hypertrophy (media-to-lumen ratio) and vascular stiffness (strain and stress) were analyzed. After pressurized fixation histological analysis of collagen and elastin content was performed. RESULTS: Blood pressure was significantly higher in salt-loaded ZDF compared to ZDF. Eplerenone and hydralazine prevented this rise similarily, however, significance niveau was missed. Media-to-lumen ratio of mesenteric resistance arteries was significantly increased in ZDF+S when compared to ZDF and ZL. Both, eplerenone and hydralazine prevented salt-induced vascular hypertrophy. The strain curve of arteries of salt-loaded ZDF rats was significantly lower when compared to ZL and when compared to ZDF+S+E, but was not different compared to ZDF+S+H. Eplerenone, but not hydralazine shifted the strain-stress curve to the right indicating a vascular wall composition with less resistant components. This indicates increased vascular stiffness in salt-loaded ZDF rats, which could be prevented by eplerenone but not by hydralazine. Collagen content was increased in ZL and ZDF rats on high-salt diet. Eplerenone and hydralazine prevented the increase of collagen content. There was no difference in elastin content. CONCLUSION: Eplerenone and hydralazine prevented increased media-to-lumen ratio in salt-loaded ZDF-rats, indicating a regression of vascular hypertrophy, which is likely mediated by the blood pressure lowering-effect. Eplerenone has additionally the potential to prevent increased vascular stiffness in salt-loaded ZDF-rats. This suggests an effect of the specific aldosterone antagonist on adverse vascular wall remodelling.

A simple method of vascular access to perform emergency coronary angiography in patients with veno-arterial extracorporeal membrane oxygenation.

PURPOSE: Veno-arterial extracorporeal membrane oxygenation (V-A ECMO) is progressively used in severe cardiogenic shock or in-hospital resuscitation to stabilize patients and to bridge to further therapeutic interventions. However, vascular access for coronary catheterization can be difficult under these conditions. It would thus be desirable to use arterial lines that are already inserted. Here, we describe a novel technique to perform coronary angiography and angioplasty in patients with V-A ECMO. METHODS: The technique is described in five patients in whom V-A ECMO was established because of prolonged cardiopulmonary resuscitation and who underwent coronary catheterization after stabilization. At the arterial cannula of the ECMO, a Y connector was inserted. At its free end, a hemostatic valve was placed, over which the coronary catheters were inserted. RESULTS: In one case, diagnostic coronary angiography revealed no significant coronary stenosis. In four other cases, successful coronary angioplasty with and without stent implantation was performed. CONCLUSION: Cardiac catheterization using a Y-shaped adapter introduced into the arterial ECMO cannula is feasible. In a resuscitation setting, a new puncture of the femoral artery always carries the risk of complications, wherefore this new technology can be regarded as fast alternative.

Globular and full-length adiponectin induce NO-dependent vasodilation in resistance arteries of Zucker lean but not Zucker diabetic fatty rats.

BACKGROUND: Adiponectin increases nitric oxide (NO) production in endothelial cell cultures and is reduced in the circulation of obese and diabetic patients, but its functional effect on resistance arteries is not yet studied in detail. METHODS: We assessed the direct vasodilatory response of isolated mesenteric resistance arteries of Zucker diabetic fatty (ZDF) rats and Zucker lean (ZL) rats to globular adiponectin (gAd) and full-length adiponectin (fAd) and tested the effect of additional reactive oxygen species (ROS) inhibitors in vitro. Serum adiponectin and insulin levels were measured by ELISA. The mRNA expressions of the adiponectin receptors and the downstream signaling molecules adaptor protein, phosphotyrosine interaction, PH domain and leucine zipper containing 1 (APPL1), adaptor protein, phosphotyrosine interaction, PH domain and leucine zipper containing 2 (APPL2), and endothelial NO synthase (eNOS) in mesenteric resistance arteries were quantified by real-time reverse transcriptase PCR. RESULTS: Both gAd and fAd induced a relevant dose-dependent vasodilation in ZL, but not in hypoadiponectinemic ZDF rats. This effect was totally blunted by L-nitroarginine-methyl-ester indicating NO dependency. The addition of ROS inhibitors could not improve the vasodilatory effect of adiponectin. Vasodilatory response to acetylcholine was reduced in ZDF rats, which could not be enhanced by low-dose adiponectin. Adiponectin receptor 1 (AdipoR1) was higher expressed than adiponectin receptor 2 (AdipoR2) with no significant differences between both animal groups, but APPL1 was significantly decreased in ZDF rats. The eNOS expression was not significantly different between ZL and ZDF rats. CONCLUSIONS: Adiponectin exerts a NO-dependent vasodilation in resistance arteries of normoglycemic ZL rats, but not diabetic ZDF rats. This may contribute to endothelial dysfunction in ZDF rats. Alterations in the expression of APPL1 may be involved in the observed insensitivity to adiponectin in ZDF rats.

Hyperaldosteronism and altered expression of an SGK1-dependent sodium transporter in ZDF rats leads to salt dependence of blood pressure.

This study was designed to test whether altered aldosterone-related sodium handling leads to salt-sensitive blood pressure in diabetes and thus may exaggerate end-organ damage. Zucker diabetic fatty (ZDF) rats, a model of type 2 diabetes, and Zucker lean (ZL) rats, as euglycemic controls, were divided into groups receiving normal (0.28%) (ZDF+N, ZL+N) and high-salt (5.5%) diets (ZDF+S, ZL+S) for 10 weeks. Renal mRNA expression of serum- and glucocorticoid-inducible kinase 1 (SGK1) and sodium transporters (for example, the epithelial sodium channel-α, ENaCα) were measured by quantitative reverse transcriptase-PCR. Vascular hypertrophy (media-to-lumen ratio, M/L) in mesenteric resistance arteries was assessed using a pressurized myograph. Systolic blood pressure (SBP) was significantly higher in ZDF+S vs. ZDF+N (146 ± 2 vs. 133 ± 3 mm Hg; P<0.05), whereas there was no difference between ZL+S and ZL+N (151 ± 3 vs. 147 ± 3 mm Hg). Plasma sodium concentration was higher in ZDF+S vs. ZDF+N, whereas there was no difference between ZL+S and ZL+N. Plasma aldosterone concentration (PAC) was higher in ZDF+N as compared with ZL+N (191 ± 23 vs. 95 ± 35 pg ml(-1); P<0.05). PAC decreased to zero in ZL+S, which was not the case in ZDF+S (0 ± 0 vs. 37 ± 2 pg ml(-1)). Salt loading decreased the mRNA expression of SGK1 in euglycemic controls (ZL+S 0.58 ± 0.2 vs. ZL+N 1.05 ± 0.05; P=0.05), whereas it significantly increased SGK1 expression in diabetic rats (ZDF+S 1.75 ± 0.15 vs. ZDF+N 0.92 ± 0.07; P<0.01). ENaCα mRNA expression paralleled these changes. The M/L of mesenteric resistance arteries was not different between ZDF+N and ZL+N. High salt significantly increased the M/L in ZDF+S vs. ZDF+N, but not in ZL+S vs. ZL+N. Systolic blood pressure in this model of type 2 diabetes mellitus is salt sensitive, leading to marked vascular remodeling. The underlying pathophysiological mechanism may be inappropriately high levels of aldosterone and up-regulation of SGK1-dependent renal sodium transport by ENaCα, leading to net increased sodium retention.

Alterations in mechanical properties of mesenteric resistance arteries in experimental portal hypertension.

Splanchnic vasodilation is the pathophysiological hallmark in the development of the hyperdynamic circulatory syndrome in liver cirrhosis and portal hypertension. This has been attributed so far mainly to a marked vascular hyporeactivity to endogenous vasoconstrictors. However, myogenic tone and vessel stiffness have not been addressed in mesenteric arteries in liver cirrhosis. CCl(4)(-)-induced ascitic cirrhotic (LC) and age-matched control rats, portal vein-ligated (PVL) rats, and sham-operated rats were investigated. Third-order mesenteric resistance arteries were studied under no-flow conditions using a pressure myograph measuring media thickness and lumen diameter in response to incremental increases in intramural pressure, from which wall mechanics were calculated. Electron microscopy was used for investigation of wall ultrastructure, especially the fenestrae in internal elastic lamina (IEL). In PVL animals, no significant change in passive vessel strain, stress, media-to-lumen ratio, or cross-sectional area was noted. In contrast, in LC rats, vessel strain was markedly elevated compared with healthy control rats, indicating a marked reduction in vessel stiffness. In addition, the strain-stress curve was shifted to the right, and the elastic modulus in dependency on vessel stress decreased, demonstrating predominantly structure-dependent factors to be involved. The media-to-lumen quotient was not significantly altered, but cross-sectional area was highly increased in LC rats, indicating hypertrophic outward remodeling. These findings were paralleled by enlarged fenestrae in the IEL but no change in thickness of IEL or proportion of extracellular matrix or vascular smooth muscle in LC rats. We concluded that, in long-standing severe portal hypertension such as ascitic LC but not in short-term conditions such as PVL, mesenteric resistance arteries exhibit vascular remodeling and markedly less resistant mechanical properties, leading to decreased vessel stiffness accompanied by structural changes in the IEL. This may well contribute to the maintenance and severity of splanchnic arterial vasodilation in LC.

General aneurysmatosis due to cheese consumption: complications of an endocarditis caused by Lactococcus cremoris.

We describe a case of endocarditis due to Lactococcus cremoris associated with cheese consumption, that caused multiple mycotic aneurysms. Antibiotic treatment combined with surgical and radiological interventions resulted in full recovery.

Angiotensin receptor blocker added to previous antihypertensive agents on arteries of diabetic hypertensive patients.

Lowering elevated blood pressure (BP) in diabetic hypertensive individuals decreases cardiovascular events. We questioned whether remodeling of resistance arteries from hypertensive diabetic patients would improve after 1 year of tight BP control with addition of either the angiotensin receptor blocker (ARB) valsartan or the beta-blocker (BB) atenolol to previous therapy, which included angiotensin-converting enzyme inhibitors (ACEIs) and/or calcium channel blockers. Twenty-eight hypertensive type 2 diabetic patients treated with oral hypoglycemic and antihypertensive agents (not receiving ARBs or BBs) were randomly assigned to double-blind treatment for 1 year with valsartan (80 to 160 mg) or atenolol (50 to 100 mg) daily, added to previous therapy. Resistance arteries dissected from gluteal subcutaneous tissues were assessed on a pressurized myograph. After 1 year of treatment, systolic and diastolic BP and glycemia were equally well controlled in the valsartan and atenolol groups. Endothelium-dependent and independent relaxation did not change in the treated groups. After 1 year of treatment, resistance artery media:lumen ratio decreased in the valsartan group (7.9+/-0.5% after versus 9.8+/-0.6% before; P < 0.05) but not in the atenolol-treated group (9.9+/-0.9% versus 10.6+/-1%; P value not significant). Artery walls from atenolol-treated patients became stiffer, with no change in the valsartan-treated patients. In conclusion, similar intensive BP control for 1 year with valsartan was associated with improved structure of resistance arteries in diabetic hypertensive patients, whereas vessels from atenolol-treated patients exhibited unchanged remodeling and a stiffer wall. The addition of ARBs but not BBs to antihypertensive medications that may include angiotensin-converting enzyme inhibitors and/or calcium channel blockers results in an improvement in resistance artery remodeling in diabetic hypertensive patients.

Reduced vascular remodeling, endothelial dysfunction, and oxidative stress in resistance arteries of angiotensin II-infused macrophage colony-stimulating factor-deficient mice: evidence for a role in inflammation in angiotensin-induced vascular injury.

OBJECTIVE: Angiotensin (Ang) II-induced vascular damage may be partially mediated by reactive oxygen species generation and inflammation. Homozygous osteopetrotic mice (Op/Op), deficient in macrophage colony-stimulating factor (m-CSF), exhibit reduced inflammation. We therefore investigated Ang II effects on vascular structure, function, and oxidant stress generation in this model. METHODS AND RESULTS: Adult Op/Op, heterozygous (Op/+), and wild type (+/+) mice underwent 14-day Ang II (1000 ng/kg per minute) or saline infusion. Blood pressure (BP) was assessed by radiotelemetry, mesenteric resistance artery vascular reactivity was studied on a pressurized myograph, and vascular superoxide and NAD(P)H oxidase activity by lucigenin chemiluminescence. Ang II increased BP in Op/+ and +/+ mice but not in Op/Op. Ang II-treated Op/+ and +/+ mice showed reduced acetylcholine-mediated relaxation (maximal relaxation, respectively, 64% and 67% versus 84% and 93% in respective controls; P<0.05), which was unaffected by L-NAME. Ang II-infused Op/Op mice arteries showed significantly less endothelial dysfunction than vehicle-infused counterparts (maximal relaxation 87% versus 96% in shams). Resistance arteries from Ang II-infused +/+ and Op/+ mice had significantly increased media-to-lumen ratio and media thickness, neither of which was altered in Op/Op mice compared with untreated littermates. Vascular media cross-sectional area, NAD(P)H oxidase activity and expression, and vascular cell adhesion molecule (VCAM)-1 expression were significantly increased by Ang II only in +/+ mice (P<0.05). CONCLUSIONS: m-CSF-deficient mice (Op/Op) developed less endothelial dysfunction, vascular remodeling, and oxidative stress induced by Ang II than +/+ littermates, suggesting a critical role of m-CSF and proinflammatory mediators in Ang II-induced vascular injury.

Endothelial dysfunction.

Endothelial dysfunction is characterized by a shift of the actions of the endothelium toward reduced vasodilation, a proinflammatory state, and prothrombic properties. It is associated with most forms of cardiovascular disease, such as hypertension, coronary artery disease, chronic heart failure, peripheral artery disease, diabetes, and chronic renal failure. Mechanisms that participate in the reduced vasodilatory responses in endothelial dysfunction include reduced nitric oxide generation, oxidative excess, and reduced production of hyperpolarizing factor. Upregulation of adhesion molecules, generation of chemokines such as macrophage chemoattractant peptide-1, and production of plasminogen activator inhibitor-1 participate in the inflammatory response and contribute to a prothrombic state. Vasoactive peptides such as angiotensin II and endothelin-1; the accumulation of asymmetric dimethylarginine, an endogenous nitric oxide inhibitor; hypercholesterolemia; hyperhomocysteinemia; altered insulin signaling; and hyperglycemia can contribute to these different mechanisms. Detachment and apoptosis of endothelial cells (anoikis) are associated phenomena. Endothelial dysfunction is an important early event in the pathogenesis of atherosclerosis, contributing to plaque initiation and progression. Reductions in circulating endothelial progenitor cells that participate in regeneration of the endothelium participate in endothelial pathophysiology. The severity of endothelial dysfunction has been shown to have prognostic value for cardiovascular events. Correction of endothelial dysfunction may be associated with reduced cardiovascular risk. Circulating endothelial progenitor cells may represent a potential therapeutic approach for endothelial dysfunction.

Adrenal aldosterone biosynthesis is elevated in a model of chronic renal failure--role of local adrenal renin-angiotensin system.

BACKGROUND: Aldosterone seems to play a role in the development of chronic renal failure and proteinuria. We investigated the adrenal aldosterone production and the adrenal renin-angiotensin system (RAS) in rats with 5/6 nephrectomy with and without spironolactone treatment. METHODS: Sprague-Dawley rats underwent 5/6, 4/6 nephrectomy, heminephrectomy and sham operation. After 1 and 4 weeks creatinine clearance, urinary protein excretion, plasma aldosterone concentration, and plasma renin activity were measured. In adrenals mRNA expression of aldosterone synthase (CYP11B2) and genes of the RAS were measured. RESULTS: Creatinine clearance was significantly decreased and proteinuria significantly elevated in 5/6 nephrectomy. Treatment with spironolactone significantly reduced proteinuria after 8 but not after 30 days. With reduction of renal mass, renal renin mRNA and plasma renin activity were reduced significantly. In early 5/6 nephrectomy plasma aldosterone concentration was increased and in parallel adrenal CYP11B2 mRNA was increased significantly. Both were further augmented by spironolactone. Adrenal renin was up-regulated in 5/6 nephrectomy and further stimulated with spironolactone, possibly serving as a stimulus for the adrenal aldosterone synthesis. CONCLUSION: In early chronic renal failure after 5/6 nephrectomy adrenal aldosterone production is elevated despite a marked decrease of plasma renin activity. An up-regulated adrenal RAS may contribute to the observed increase in aldosterone.