[Creutzfeldt-Jakob Disease Versus Anti-NMDA Receptor Encephalitis A Case Report]. / Creutzfeldt-Jakob Erkrankung versus Anti-NMDA-Rezeptor-Enzephalitis ­ eine Kasuistik.

Clinically differentiating between autoimmune and neurodegenerative disorders can often pose a diagnostic challenge. The differential diagnosis of rapidly progressing neurological and cognitive symptoms includes central nervous system tumours, cerebral vasculitis, and inflammatory, autoimmune, or paraneoplastic encephalopathies. Rarer neurodegenerative diseases such as Creutzfeldt-Jakob disease should also be considered. Detection of treatable causes, such as autoimmune disorders, remains important when potentially occurring in conjunction with Creutzfeldt-Jakob disease. The following report describes a rare case in which autoimmune encephalopathy and prion disease were considered as possible comorbidities.

Secreted frizzled-related protein 4 predicts progression of autosomal dominant polycystic kidney disease.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is a common autosomal dominant condition associated with renal cysts and development of renal failure. With the availability of potential therapies, one major obstacle remains the lack of readily available parameters that identify patients at risk for disease progression and/or determine the efficacy of therapeutic interventions within short observation periods. Increased total kidney volume (TKV) correlates with disease progression, but it remains unknown how accurate this parameter can predict disease progression at early stages. METHODS: To identify additional parameters that help to stratify ADPKD patients, we measured secreted frizzled-related protein 4 (sFRP4) serum concentrations at baseline and over the course of 18 months in 429 ADPKD patients. RESULTS: Serum creatinine and sFRP4 as well as TKV increased over time, and were significantly different from baseline values within 1 year. CONCLUSION: Elevated sFRP4 levels at baseline predicted a more rapid decline of renal function at 2, 3 and 5 years suggesting that sFRP4 serum levels may provide additional information to identify ADPKD patients at risk for rapid disease progression.

Everolimus in patients with autosomal dominant polycystic kidney disease.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is a slowly progressive hereditary disorder that usually leads to end-stage renal disease. Although the underlying gene mutations were identified several years ago, efficacious therapy to curtail cyst growth and prevent renal failure is not available. Experimental and observational studies suggest that the mammalian target of rapamycin (mTOR) pathway plays a critical role in cyst growth. METHODS: In this 2-year, double-blind trial, we randomly assigned 433 patients with ADPKD to receive either placebo or the mTOR inhibitor everolimus. The primary outcome was the change in total kidney volume, as measured on magnetic resonance imaging, at 12 and 24 months. RESULTS: Total kidney volume increased between baseline and 1 year by 102 ml in the everolimus group, versus 157 ml in the placebo group (P=0.02) and between baseline and 2 years by 230 ml and 301 ml, respectively (P=0.06). Cyst volume increased by 76 ml in the everolimus group and 98 ml in the placebo group after 1 year (P=0.27) and by 181 ml and 215 ml, respectively, after 2 years (P=0.28). Parenchymal volume increased by 26 ml in the everolimus group and 62 ml in the placebo group after 1 year (P=0.003) and by 56 ml and 93 ml, respectively, after 2 years (P=0.11). The mean decrement in the estimated glomerular filtration rate after 24 months was 8.9 ml per minute per 1.73 m2 of body-surface area in the everolimus group versus 7.7 ml per minute in the placebo group (P=0.15). Drug-specific adverse events were more common in the everolimus group; the rate of infection was similar in the two groups. CONCLUSIONS: Within the 2-year study period,as compared with placebo, everolimus slowed the increase in total kidney volume of patients with ADPKD but did not slow the progression of renal impairment [corrected]. (Funded by Novartis; EudraCT number, 2006-001485-16; ClinicalTrials.gov number, NCT00414440.)

Associations of smoking with alterations in renal hemodynamics may depend on sex--investigations in potential kidney donors.

BACKGROUND/AIMS: Cigarette smoking is a risk factor for renal damage, but little is known about subclinical effects of smoking on renal hemodynamics and parameters of renal function in humans. We examined the associations of smoking with systemic and renal hemodynamics and renal function parameters in healthy individuals. METHODS: Data from 196 potential living kidney donors were analysed retrospectively. Mean arterial blood pressure (MAP), effective renal plasma flow (ERPF) and creatinine clearance had been measured. We additionally calculated parameters of renal hemodynamics. Data were analyzed for the effects of smoking and sex dependent on age and MAP. RESULTS: Systemic and renal hemodynamic parameters did not differ between smokers and non-smokers. In non-smokers of both sexes MAP was negatively correlated with ERPF, and higher MAP was associated with increased renal vascular resistance and with afferent arteriolar resistance, with glomerular pressure (PG) remaining constant. However, in male, but not in female smokers, ERPF and PG increased with MAP. A correlation of age with a steeper decline in ERPF in male smokers was lost in multiple regression analysis. CONCLUSIONS: As compared to women, smoking men may exhibit an increased glomerular hydrostatic pressure, which is a known promoter of kidney damage.

Best supportive care and therapeutic plasma exchange with or without eculizumab in Shiga-toxin-producing E. coli O104:H4 induced haemolytic-uraemic syndrome: an analysis of the German STEC-HUS registry.

BACKGROUND: May 22nd marks the beginning of a Shiga-toxin-producing Escherichia coli (STEC) O104:H4 outbreak in Northern Germany. By its end on 27 July, it had claimed 53 deaths among 2987 STEC and 855 confirmed haemolytic-uraemic syndrome (HUS) cases. METHODS: To describe short-term effectiveness of best supportive care (BSC), therapeutic plasma exchange (TPE) and TPE with eculizumab (TPE-Ecu) in 631 patients with suspected HUS treated in 84 hospitals in Germany, Sweden and the Netherlands using the web-based registry of the DGfN (online since 27 May). RESULTS: Of 631 entries, 491 fulfilled the definition of HUS (median age 46 years; 71% females). The median (inter-quartile range) hospital stay was 22 (14-31) days. Two hundred and eighty-one (57%) patients underwent dialysis and 114 (23%) mechanical ventilation. Fifty-seven patients received BSC, 241 TPE and 193 TPE-Ecu. Treatment strategy was dependent on disease severity (laboratory signs of haemolysis, thrombocytopenia, peak creatinine level, need for dialysis, neurological symptoms, frequency of seizures) which was lower in BSC than in TPE and TPE-Ecu patients. At study endpoint (hospital discharge or death), the median creatinine was lower in BSC [1.1 mg/dL (0.9-1.3)] than in TPE [1.2 mg/dL (1.0-1.5), P < 0.05] and TPE-Ecu [1.4 mg/dL (1.0-2.2), P < 0.001], while need for dialysis was not different between BSC (0.0%, n = 0), TPE (3.7%; n = 9) and TPE-Ecu (4.7%, n = 9). Seizures were absent in BSC and rare in TPE (0.4%; n = 1) and TPE-Ecu (2.6%; n = 5) patients. Total hospital mortality in HUS patients was 4.1% (n = 20) and did not differ significantly between the TPE and TPE-Ecu groups. CONCLUSIONS: Despite frequent renal impairment, advanced neurological disorders and severe respiratory failure, short-term outcome was better than expected when compared with previous reports. Within the limitations of a retrospective registry analysis, our data do not support the notion of a short-term benefit of Ecu in comparison to TPE alone in the treatment of STEC-HUS. A randomized trial comparing BSC, TPE and Ecu seems to be prudent and necessary prior to establishing new treatment guidelines for STEC-HUS.

N-cadherin is depleted from proximal tubules in experimental and human acute kidney injury.

Ischemia remains the most common cause of acute kidney injury (AKI). Decreased intercellular adhesion and alterations in adhesion molecules may contribute to the loss of renal function observed in AKI. In the present study, we evaluated the distribution of adhesion molecules in the human kidney and analyzed their expression in human and experimental AKI. Specimens of human kidneys obtained from patients with and without AKI were stained for the cell adhesion molecules E-cadherin, N-cadherin and beta-catenin. Experimental AKI in rats was induced by renal artery clamping. Immunostaining and immunoblotting were carried out for E-cadherin, N-cadherin and beta-catenin. Proximal tubule cells from opossum kidneys (OKs) were used to analyze the effect of chemical hypoxia (ATP depletion) in vitro. In the adult human kidney, N-cadherin was expressed in proximal tubules, while E-cadherin was expressed in other nephron segments. beta-Catenin was expressed in both proximal and distal tubules. In human AKI and in ischemic rat kidneys, N-cadherin immunostaining was depleted from proximal tubules. There was no change in E-cadherin or beta-catenin. In vitro, OK cells expressed N-cadherin only in the presence of collagen, and ATP depletion led to a depletion of N-cadherin. Collagen IV staining was reduced in ischemic rat kidneys compared to controls. The results of the study suggest that N-cadherin may play a significant role in human and experimental AKI.

New treatment options for atypical hemolytic uremic syndrome with the complement inhibitor eculizumab.

Hemolytic uremic syndrome (HUS) is a disease characterized by microangiopathic hemolytic anemia, consumptive thrombocytopenia, and renal impairment. Often HUS is triggered by Shiga-like toxin- producing ESCHERICHIA COLI. Less common is atypical HUS (aHUS), which is caused by defective complement control. aHUS is associated with mutations in genes encoding complement regulatory proteins in ~50% of patients with this syndrome. Furthermore, autoantibodies that inactivate to factor H have also been linked to the disease. Initial triggers include infections, use of endothelial-affecting drugs, malignancies, transplantation, and pregnancy. Advances in our understanding of the pathogenesis of atypical HUS suggest that complement inhibition may be used as treatment for the disease. We discuss the potential benefit of the complement inhibitor eculizumab for the treatment of aHUS.

The mTOR pathway is activated in human autosomal-recessive polycystic kidney disease.

BACKGROUND: An inappropriate activation of the mTOR pathway was demonstrated in the autosomal dominant (AD) form of polycystic kidney disease (PKD). To date it is unclear whether the mTOR pathway is activated in autosomal-recessive (AR) PKD, a cystic disease which occurs in childhood. The purpose of the present study was to evaluate the mTOR pathway in AR PKD. METHODS: We evaluated the expression of mTOR pathway molecules in paraffin-embedded liver and kidney samples from patients with AR PKD and control specimens from animals as well as humans. Monoclonal antibodies, the phosphorylated proteins pmTOR, pS6-ribosomal-protein (pS6K), p4E-BP1, peIF4G, and phospho-tuberin/TSC2 were used. RESULTS: mTOR was strongly expressed in renal cyst-lining cells and bile ducts from AR PKD specimen. S6K immunostaining was strong in smaller tubules and weak both in larger renal cysts and in the bile duct epithelium. In controls, mTOR and S6K were expressed in distal tubule segments. 4E-BP1-immunostaining was restricted to noncystic tubules in AR PKD. eIFG4-immunostaining was observed in bile duct epithelium in AR PKD, but not in control tissue. Tuberin/TSC2 immunostaining was negative in all specimens. CONCLUSION: Our data suggest that the mTOR pathway may be activated in AR PKD, and mTOR molecules may represent a potential target to slow down cyst development in this disease.

Pulse wave velocity predicts mortality in renal transplant patients.

BACKGROUND: measuring arterial stiffness using pulse wave velocity (PWV) has become an important tool to assess vascular function and cardiovascular mortality. For subject with hypertension, end-stage renal disease and diabetes, PWV has been shown to predict cardiovascular and all-cause mortality. We hypothesize that PWV would also predict mortality in subjects who have undergone kidney transplantation. METHODS: a cohort of 330 patients with renal transplantation was studied with a mean age at entry 51.4 ± 0.75 years. Mean follow-up was 3.8 years (± 0.7 years); 16 deaths occurred during follow-up. At entry, together with standard clinical and biochemical parameters, PWV was determined from pressure tracing over carotid and femoral arteries. RESULTS: with increasing PWV, there was a significant increase in age, systolic blood pressure and pulse pressure. In addition, subjects with higher PWV also exhibited more frequently the presence of coronary heart disease. On the basis of Cox analyses, PWV and systolic blood pressure emerged as predictors of all-cause mortality. CONCLUSION: these results provide evidence that PWV is a strong predictor of all-cause mortality in the population of renal transplant recipients.

Evidence for involvement of nonesterified fatty acid-induced protonophoric uncoupling during mitochondrial dysfunction caused by hypoxia and reoxygenation.

BACKGROUND: Proximal tubules subjected to hypoxia in vitro under conditions relevant to ischaemia in vivo develop an energetic deficit that is not corrected even after full reoxygenation. We have provided evidence that accumulation of nonesterified fatty acids (NEFA) is the primary reason for this energetic deficit. In this study, we have further investigated the mechanism for the NEFA-induced energetic deficit. METHODS: Mitochondrial membrane potential (Deltapsi) was measured in digitonin-permeabilized, freshly isolated proximal tubules by safranin O uptake. Addition of the potassium/proton exchanger nigericin enables the determination of the mitochondrial proton motive force (Deltap) and the proton gradient (DeltapH). ATP was measured luminometrically and NEFA colorimetrically. RESULTS: Tubule ATP content was depleted after hypoxia and recovered incompletely, even after full reoxygenation. Mitochondrial safranin O uptake was decreased in proximal tubules after hypoxia and reoxygenation (H/R). This decrease was attenuated by delipidated bovine serum albumin (dBSA) or citrate. Addition of nigericin increased safranin O uptake of mitochondria in normoxic proximal tubules, but not in proximal tubules after H/R. Addition of dBSA restored the effect of nigericin to increase mitochondrial safranin O uptake. Addition of the NEFA oleate had the same impact on mitochondrial safranin O uptake as subjecting proximal tubules to H/R. CONCLUSION: The mechanism of the NEFA-induced energetic deficit in freshly isolated rat proximal tubules induced by H/R is characterized by impaired ATP production after full reoxygenation, impaired recovery of Deltapsi and Deltap, abrogation of DeltapH and sensitivity to citrate, consistent with involvement of the tricarboxylate carrier. The data support the concept that protonophoric uncoupling by NEFA movement on anion carriers plays a critical role in proximal tubule mitochochondrial dysfunction after H/R.

Association of ambulatory arterial stiffness index and brachial pulse pressure is restricted to dippers.

BACKGROUND: The ambulatory arterial stiffness index (AASI) is a new index that reflects the dynamic relation between diastolic and systolic blood pressure through the circadian blood pressure rhythm. It was the aim of this study to investigate the association between AASI, dipping status and pulse pressure as a classical indicator of arterial stiffness in normotensive and hypertensive subjects. METHODS: One hundred and twelve individuals were evaluated for a kidney donation to a relative at the University Hospital Essen, Germany. In this context routine 24-h ambulatory blood pressure measurements were performed. A nocturnal reduction in diastolic blood pressure of >10% was defined as 'dipping'. We determined the diurnal and nocturnal blood pressure and brachial pulse pressure values and computed AASI for each participant. RESULTS: AASI was a strong predictor for diastolic and systolic nocturnal blood pressure fall (r = -0.55 and -0.48, respectively; P < 0.001). Additionally, AASI predicted the status of 'dipping/nondipping'. 'Dippers' showed significantly lower AASI than 'nondippers' in both normotensive and hypertensive subjects. Dippers, but not nondippers, demonstrated an association between AASI and brachial pulse pressure. DISCUSSION: AASI is strongly correlated with nocturnal blood pressure fall and is increased in nondipping independent of blood pressure. The role of AASI as a potential marker for arterial stiffness depends, in this study, on the characterization of the dipping status.

Inversin forms a complex with catenins and N-cadherin in polarized epithelial cells.

Nephrogenesis starts with the reciprocal induction of two embryonically distinct analages, metanephric mesenchyme and ureteric bud. This complex process requires the refined and coordinated expression of numerous developmental genes, such as inv. Mice that are homozygous for a mutation in the inv gene (inv/inv) develop renal cysts resembling autosomal-recessive polycystic kidney disease. The gene locus containing inv has been proposed to serve as a common modifier for some human and rodent polycystic kidney disease phenotypes. We generated polyclonal antibodies to inversin to study its subcellular distribution, potential binding partners, and functional aspects in cultured murine proximal tubule cells. A 125-kDa inversin protein isoform was found at cell-cell junctions. Two inversin isoforms, 140- and 90-kDa, were identified in the nuclear and perinuclear compartments. Plasma membrane allocation of inversin is dependent upon cell-cell contacts and was redistributed when cell adhesion was disrupted after incubation of the cell monolayer with low-calcium/EGTA medium. We further show that the membrane-associated 125-kDa inversin forms a complex with N-cadherin and the catenins. The 90-kDa nuclear inversin complexes with beta-catenin. These findings indicate that the inv gene product functions in several cellular compartments, including the nucleus and cell-cell adhesion sites.

The German Hypertension League (Deutsche Hochdruckliga) Quality Seal Protocol for blood pressure-measuring devices: 15-year experience and results from 105 devices for home blood pressure control.

OBJECTIVE: The German Hypertension League (Deutsche Hochdruckliga) established a program to assess the accuracy and reliability of blood pressure (BP)-measuring devices in 1999 (Quality Seal Protocol). Here, we report on the results of a testing series of 105 devices designed for BP self-measurement. METHODS: The test protocol for the validation of upper-arm, wrist, and finger devices was developed to compare device to conventional Riva-Rocci measurements based on five criteria: mean systolic and mean diastolic differences, their standard deviations, and a point score representing the correlation of systolic and diastolic errors of individual comparisons. The results of this testing are summarized. RESULTS: From 1999 to 2014, a total of 105 BP devices for self-measurement were tested according to the Quality Seal Protocol. Of these, 47.6% fulfilled all five validation criteria, 55.7% of the upper-arm devices (39 of 71) and 32.4% (11 of 34) of the wrist devices. Finger devices were not offered for testing. Forty-four devices (41.9%) failed multiple test criteria of the validation procedure. A subanalysis with 51 devices tested showed that a stricter definition of the passing point score with a limit of at least 55% would slightly increase the consistency with the conventional criteria in comparison with a point score criterion of at least 50%. It was therefore introduced in 2007. CONCLUSION: The results indicate the importance of a rigorous testing of a BP-measuring device used for home BP measurement to prevent patients from making erroneous treatment decisions.

Insulin-mediated venodilation is impaired in young, healthy carriers of the 825T allele of the G-protein beta3 subunit gene (GNB3).

OBJECTIVE: A C825T polymorphism has been identified for the gene encoding the G-protein beta 3 subunit ( GNB3 ). The 825T allele is associated with hypertension and obesity, which in turn are closely linked with resistance to the metabolic and vascular effects of insulin. We hypothesized that venodilation in response to insulin would be impaired in GNB3 825T-allele carriers. Because vasodilatory properties of insulin are mainly mediated by nitric oxide, we also investigated the influence of the T-786C polymorphism of the gene for endothelial nitric oxide synthase ( NOS3 ) on insulin-mediated venous responses. METHODS: We used the linear variable transducer technique to compare dorsal hand vein compliance in 31 young, healthy men ( GNB3 C825T: 15 CC, 14 CT, and 2 TT; NOS3 T-786C: 14 TT, 13 TC, and 4 CC). Individual dose-response curves to phenylephrine (3.2-10,000 ng/min) were established, and veins were preconstricted by a constant infusion of phenylephrine at the individual dose needed to procure 70% of maximal constriction. Then insulin was infused (50-250,000 microU/min), and the changes in venous diameter were recorded. RESULTS: Venous response to insulin was biphasic, with venoconstriction at low doses being followed by venodilation at higher doses. Insulin dose-response curves of GNB3 825T-allele carriers were significantly shifted to the right (ANOVA, P < .001, versus CC). NOS3 T-786C-allele carrier status had no influence on insulin-induced vascular responses ( P = .60 for TC/CC versus TT). CONCLUSION: This study is the first to show the influence of a genetic polymorphism on insulin-mediated venodilation in men in vivo. Further studies are needed to determine whether these results translate to other vascular beds, and possible gender-specific differences remain to be investigated.

Effects of systemic endothelin A receptor antagonism in various vascular beds in men: in vivo interactions of the major blood pressure-regulating systems and associations with the GNB3 C825T polymorphism.

OBJECTIVE: We used the orally available endothelin A (ETA) receptor antagonist darusentan to characterize interactions between the major blood pressure-regulating systems in healthy men. Mediators of the endothelin system, the sympathetic nervous system, and the renin-angiotensin system act via G protein-coupled receptors with a possible involvement of the G-protein beta3 subunit (GNB3) C825T polymorphism. We studied the influence of this polymorphism on the responses to ETA antagonism in the presence of endothelin 1 (ET-1), norepinephrine (NA), and angiotensin II (ANGII). METHODS: Thirty-seven individuals were included in a randomized, double-blind, placebo-controlled, crossover trial with 100 mg darusentan. Systemic hemodynamics and plasma ET-1, NA, and ANGII concentrations were assessed. Local studies were performed in the dorsal hand veins (n=18) and skin microcirculation (n=12), respectively. RESULTS: Darusentan lowered systolic and diastolic blood pressure ( P <.001 versus placebo) without any differences according to genotype (mean maximum Delta systolic blood pressure, -7 +/- 2 mmHg for CT/TT versus -5 +/- 3 mmHg for CC, P=.37; mean maximum Delta diastolic blood pressure, -3 +/- 2 mmHg for CT/TT versus -4 +/- 2 mmHg for CC, P=.96). Venoconstriction to ET-1 and NA was not affected by ET A blockade in either group; however, carriers of the 825T allele demonstrated a markedly enhanced venoconstriction to ET-1 and NA (median effective concentration [ED50] for ET-1 after darusentan [placebo]: 2.5 +/- 0.2 pmol/min for CT/TT [2.7 +/- 0.3 pmol/min], P=.42; 3.9 +/- 0.6 pmol/min for CC [4.6 +/- 0.3 pmol/min], P=.42; P=.046 [P=.0005] for CT/TT versus CC) (ED50 for NA after darusentan [placebo]: 5.2 +/- 1.2 ng/min for CT/TT [7.3 +/- 1.2 ng/min], P=.20; 32.9 +/- 7.1 ng/min for CC [19.7 +/- 5.5 ng/min], P=.75; P=.0008 [P=.026] for CT/TT versus CC). Darusentan dilated veins at baseline in CC homozygous subjects (+0.21 +/- 0.05 mm, P=.004 versus placebo). Systemic ET A antagonism inhibited constriction to ET-1 and also to NA and ANGII in the skin microcirculation without differences according to genotype (ET-1, P=.017 for all individuals versus placebo; NA, P=.0005; and ANGII, P=.002). CONCLUSION: GNB3 C825T allele carrier status did not influence systemic hemodynamic or local vascular responses to ET A blockade with darusentan in young, healthy men. However, it determined venoconstriction to exogenous ET-1 and NA. Darusentan markedly inhibited not only ET-1-induced but also NA-induced and ANGII-induced vasoconstriction in the skin microcirculation. In contrast, it had no effects on either ET-1-mediated or NA-mediated venoconstriction, indicating that, in the presence of high local ET-1 concentrations, constrictive endothelin B receptors may be of greater importance in the venous vasculature than has been recognized so far.

Venous response to nitroglycerin is enhanced in young, healthy carriers of the 825T allele of the G protein beta3 subunit gene (GNB3).

OBJECTIVE: The ultimate mode of action by which nitroglycerin elicits vasodilation remains elusive. Animal studies point to an involvement of pertussis toxin-sensitive G proteins. The 825T allele of the GNB3 C825T polymorphism in the gene encoding the G protein beta3 subunit is associated with enhanced signal transduction via pertussis toxin-sensitive pathways in vitro. We hypothesized that G proteins have a role in nitroglycerin-mediated vasodilation and that carriers of the 825T allele would exhibit a stronger response to nitroglycerin. METHODS: We used the linear variable transducer technique to compare dorsal hand vein compliance in 28 young, healthy men with and without the T allele (n = 15 CC, n = 8 CT, and n = 5 TT). After individual dose-response curves to phenylephrine had been established, veins were preconstricted to 70% of the maximal phenylephrine-induced constriction. Nitroglycerin was then infused in ascending doses (0.02-2000 ng/min), and the vasodilatory response was measured. RESULTS: The vasodilatory response to nitroglycerin was significantly greater in carriers of the 825T allele. The maximal response to nitroglycerin was 102% +/- 6% venodilation in the CT/TT group and 78% +/- 5% in the CC control group (P =.0045) (mean difference, -24% +/- 8%; 95% confidence interval, 8%-40%). Comparison of the nitroglycerin dose-response curves by ANOVA confirmed an enhanced nitroglycerin-induced venodilation in 825T-allele carriers (P <.0001). CONCLUSION: Our results suggest that the GNB3 C825T polymorphism determines venous response to nitroglycerin and that G proteins may be involved in the signal transduction pathway.

Effect of the C825T polymorphism of the G protein beta 3 subunit on the systolic blood pressure-lowering effect of clonidine in young, healthy male subjects.

The T allele of the C825T polymorphism in the gene encoding the G-protein beta 3 subunit (GNB3) is associated with hypertension. An enhanced signal transduction in response to alpha(2)-adrenergic receptor stimulation has been shown in carriers of the T allele in vitro. We hypothesized that T allele carriers would show an enhanced antihypertensive response to stimulation of central alpha(2)-adrenergic receptors by clonidine. We compared the response to intravenous clonidine in 30 young, healthy male subjects with and without the T allele (15 CC, 10 CT, and 5 TT). Clonidine lowered blood pressure and total peripheral resistance, lengthened the duration of electromechanical systole (QS(2)c), and slowed down pulse wave velocity. Carriers of the T allele showed significantly greater reductions in systolic blood pressure (P =.009; mean change +/- SEM: CC, -8.9 +/- 0.5; CT and TT, -10.6 +/- 0.4) and total peripheral resistance (P <.0001; mean change +/- SEM: CC, 40 +/- 17; CT and TT, -48 +/- 14) and more marked lengthening of QS(2)c (P =.002; mean change +/- SEM: CC, 2.2 +/- 0.5; CT and TT, 4.7 +/- 0.6) and slowing of pulse wave velocity (P =.012; mean change +/- SEM: CC, -0.25 +/- 0.02; CT and TT, -0.33 +/- 0.03). The results of this study suggest that the 825T allele may be a relevant pharmacogenetic marker in the use of centrally acting sympatholytic drugs.

Augmentation index is associated with cardiovascular risk.

OBJECTIVES: Augmentation index is a parameter measured by pulse wave analysis (PWA) and is used as a surrogate measure of arterial stiffness. The aim of this study was to assess whether augmentation index is associated with cardiovascular risk, as well as to evaluate whether the determinants of augmentation index are different in patients with cardiovascular disease compared to healthy subjects. DESIGN AND METHODS: We related augmentation index to risk scores in 216 subjects with or without a cardiovascular disease. Subjects without cardiovascular disease were classified according to the 'coronary risk chart' of the European Society of Cardiology (ESC), and those with cardiovascular disease were classified using the SMART (Second Manifestations of ARTerial disease) score and the EPOZ (Epidemiological Prevention study Of Zoetermeer) function. Augmentation index was derived by PWA using carotid applanation tonometry. Augmentation index was also correlated to age, blood pressure, heart rate, smoking history, cholesterol, height, body mass index and gender in subjects categorized as healthy or with cardiovascular disease. RESULTS: Augmentation index significantly increased with increasing risk scores (P < 0.0001) and was significantly correlated to cardiovascular risk (ESC: P < 0.0001; SMART: P < 0.0001; EPOZ: P < 0.0001). In subjects with and without cardiovascular disease, augmentation index was correlated with diastolic blood pressure, heart rate, height and gender. Age was found to be significantly correlated with augmentation index only in healthy subjects but not in those with atherosclerotic disease. CONCLUSIONS: Our findings suggest that augmentation index may be a useful marker of cardiovascular risk. Further studies are required to investigate the relationship between age and augmentation index in subjects with atherosclerotic disease.

Left ventricular ejection time: a potential determinant of pulse wave velocity in young, healthy males.

OBJECTIVE: Pulse wave velocity (PWV) is a classic marker of vascular stiffness. Recent studies showed that heart rate is an important determinant of PWV. The purpose of this study was to evaluate the role of myocardial function in determining PWV under resting conditions and under adrenergic stimulation. DESIGN AND METHODS: Hemodynamic parameters were investigated under resting conditions in 102 young, healthy males and under stimulation of either beta- or alpha(2)-adrenoceptors in six young, healthy males. PWV was determined from pressure tracing over the carotid and femoral artery. Central hemodynamics were assessed by impedance cardiography and systolic time intervals. Simple (r) and multiple (beta) regression analyses were used to assess the relationships between PWV and hemodynamic parameters. RESULTS: Under resting conditions, PWV was correlated to age (beta = 0.259, P = 0.0052), diastolic blood pressure (beta = 0.279, P = 0.0072) and left ventricular ejection time (beta = -0.314, P = 0.0277). Under alpha(2)-adrenergic stimulation PWV was only correlated to diastolic blood pressure (DBP) (beta = 0.806, P = 0.0020). Under beta-adrenergic stimulation PWV was only correlated to left ventricular ejection time index (r = -0.52, P = 0.0325). CONCLUSIONS: Left ventricular ejection time may be an important determinant of pulse wave velocity under resting and adrenergic conditions in young, healthy males. Further studies are needed to evaluate this relationship in other populations including females and patients with cardiovascular disease.