Kay Herbrig

Endothelial dysfunction in patients with rheumatoid arthritis is associated with a reduced number and impaired function of endothelial progenitor cells

Background: Rheumatoid arthritis (RA) is associated with increased morbidity and mortality attributable to accelerated atherosclerosis and cardiovascular events. Objective: To determine the role played by endothelial progenitor cells (EPC) in the defence system against arteriosclerosis. Methods: The number and function of EPC in 13 young patients with RA with low disease activity (DAS28 3.5 (0.3)) and 13 healthy control subjects was studied. Endothelial function was investigated by agonist-induced, endothelium dependent vasodilatation measured by the forearm blood flow technique. Migratory activity and adhesion of EPC to tumour necrosis factor α (TNFα) activated mature endothelial cells and components of the extracellular matrix were tested in vitro. Putative precursor populations (CD34+, CD34+/CD133+, and CD34+/KDR+ haematopoietic stem cells) were measured by flow cytometric analysis. Results: Acetylcholine-induced, endothelium dependent vasodilatation was reduced by about 50% in patients with RA, indicating endothelial dysfunction, whereas endothelium-independent vasodilatation in response to glyceryl trinitrate was at control level. Significantly reduced numbers of EPC were found in the patients compared with controls. Migratory activity of EPC was decreased in patients with RA. Adhesion to mature endothelial cells after activation with TNFα was enhanced only in controls. The adhesion to matrix proteins and the number of putative precursor cell lineages was comparable in both groups. Conclusion: Endothelial dysfunction in patients with RA with low grade inflammation is associated with a reduced number and partial dysfunction of EPC. Further studies are needed to explore whether interventions that potentially ameliorate the number and function of EPC also improve endothelial function in these patients.

Reduced Agonist-Induced Endothelium-Dependent Vasodilation in Uremia Is Attributable to an Impairment of Vascular Nitric Oxide

Current concepts for the explanation of endothelial dysfunction and accelerated atherosclerosis in uremia propose a reduced vascular bioavailability of nitric oxide (NO). The aim of the present study was to test the contributions of NO and NO/prostacyclin (PGI(2))-independent mechanisms to both baseline vascular tone and agonist-induced endothelium-dependent vasodilation in patients on hemodialysis (HD). In 10 HD patients and eight matched healthy control subjects, forearm blood flow (FBF) was measured at rest and during intrabrachial infusions of norepinephrine (NE; endothelium-independent vasoconstrictor, 60, 120, and 240 pmol/min) and N-monomethyl-L-arginine (blocker of NO synthases, 16 micromol/min). After inhibition of cyclo-oxygenase by ibuprofen (1200 mg orally), endothelium-dependent and -independent vasodilation was assessed by infusion of acetylcholine (ACh; 1, 5, 10, 50, 100, and 300 nmol/min) and sodium-nitroprusside (2.5, 5, and 10 microg/min). NO/PGI(2)-independent vasodilation was tested by equal infusions of ACh during NO clamp. N-monomethyl-L-arginine reduced resting FBF to a comparable degree in both groups. Vascular responses to ACh were reduced in HD (P = 0.003 versus control by ANOVA), whereas those to sodium nitroprusside were mainly at control level. Infusion of ACh during NO clamp caused a similar increment of FBF in both groups. NO-mediated vasodilation as calculated by the difference between ACh-induced responses without and with NO clamp was substantially impaired in HD (P < 0.001) compared with control. In HD patients, baseline NO-mediated arteriolar tone is at control level. This study provides first evidence that endothelial dysfunction of uremic patients as shown by reduced agonist-induced endothelium-dependent vasodilation is attributable to reduced stimulation of NO, whereas the NO/PGI(2)-resistant portion of ACh-mediated vasodilation is unaffected.

Endothelial Progenitor Cells in Chronic Renal Insufficiency

There is growing evidence for a role of endothelial progenitor cells (EPCs) in the repair of damaged endothelium. It remains unclear which cell populations are most useful for clinical trials. Administration of drugs increasing EPC numbers and/or improving functional properties seems attractive. Further basic research is necessary to understand the mechanisms of mobilization, differentiation and homing of EPC in general and in particular under uremic conditions. Nephrologists should search for strategies to ameliorate EPC dysfunction of uremia. In this way it might be possible to test whether improved EPC biology is associated with decreased cardiovascular mortality in uremic humans. In any such studies the difficulties are going to be related to the complex procedures for EPC isolation, the testing of their identity and differentiation and their propagation before use.

Role of rho-kinase in the regulation of vascular tone in hypertensive renal transplant recipients.

Activation of rho-kinase (ROK) is involved in the development of hypertension as it is a potent regulator of vascular smooth muscle cell (VSMC) contractility. Here we evaluated whether activation of ROK is present in hypertensive kidney transplant recipients (NTX). We tested the effect of the ROK-inhibitor fasudil on the regulation of forearm blood flow (FBF) in NTX and in healthy control subjects (CTL). In addition potential modulating effects of ROK-inhibition on local vascular nitric oxide (NO) release were studied. The effect of intra-arterial infusion of fasudil on FBF was studied by venous-occlusion plethysmography in NTX and CTL. To unmask the role of NO fasudil was infused with/without clamping of vascular NO in NTX and CTL. To unravel the basal NO-mediated tone the NO-synthase inhibitor l-NMMA was infused. Fasudil markedly but comparably increased FBF in NTX and CTL. The vascular response to fasudil was blunted during NO-clamp in CTL (104+/-18% vs. 244+/-48% for NO-clamp+fasudil vs. fasudil alone; baseline=0%, P<0.05) but not in NTX. The l-NMMA-induced vasoconstriction was impaired in NTX compared to CTL. In NTX and CTL basal vascular tone equally depends on ROK. Fasudil-induced vasodilatation is partly mediated by vascular NO in CTL but not in NTX. The greater NO-insensitive fasudil-induced increase in FBF in NTX suggests an increased ROK-mediated VSMC constrictor tone in these patients. Basal NO-mediated tone is attenuated in hypertensive NTX.

The vaptans ante portas: a status report

On 25 June 2008 the US Food and Drug Administration held a public Advisory Committee Meeting of its Cardiovascular and Renal Drugs Division on Tolvaptan (NDA 22-275), the first oral vasopressin antagonist to apply for licensing (http://www.fda.gov/ohrms/dockets/ac/cder08.html# CardiovascularRenal). Based on the comments made, we may now expect that tolvaptan will make it to the pharmacies soon. Over the last few years, we have been shown repeated evidence that vaptans shall be helpful (and safe) in the treatment of chronic hyponatraemia under most, though not all, circumstances [1,2]. Assuming that this scenario will come true, is it time to lean back and consider the issues surrounding the vaptans resolved? Not really.

A single lipid apheresis does not modulate pulse wave reflection in hypercholesterolemic patients

BACKGROUND Lipid apheresis (LA) is instituted to increase life expectancy in patients with previous cardiovascular events and severe and otherwise untreatable hypercholesterolemia. Studies have demonstrated that even a single LA markedly improves endothelial and micro-vascular function in patients. It is unknown whether these changes also impact pulse wave reflection and established parameters of arterial stiffness. METHODS In 20 patients on regular LA (8 treated by immunoadsorption, 7 by lipid filtration, 5 by direct adsorption of lipids) we measured peripheral blood pressure, heart rate, central systolic pressure (CSP), central pulse pressure (CPP), augmentation index (AIX) and pulse wave velocity by applanation tonometry (SphygmoCor, Atcor Medical) before and after a single treatment. RESULTS Peripheral blood pressure and heart rate were comparable pre- and post treatment. CSP, CPP, AIX and PWV did not significantly change during LA independent of treatment modality although LDL-cholesterol levels were markedly reduced (in average from 3.5+/-0.9 to 0.9+/-0.3 mmol/L). CONCLUSION The well-documented effects of a single LA on microvascular function are not associated with measurable changes in pulse wave reflection. Future studies are required in order to evaluate long-term effects of LA in this context.

New onset of alopecia in a young woman with end-stage renal disease

Background Hair loss is a common complain of women receiving renal replacement therapy. Apart from its emotional impact on the patient, hair loss might allude to several underlying diseases. Differential diagnoses include malnutrition, adverse effects of drugs, endocrine, inflammatory or autoimmune disorders, abnormal behaviour (trichotillomania) or tinea capitis [1]. Therefore, a thorough exploration of affected patients is constitutional.