Anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis is a destructive small vessel vasculitis affecting multiple organs. Renal involvement often leads to end-stage renal disease and increases mortality. Prompt diagnosis and initiation of adequate immunosuppressive therapy are critical for the best patient and kidney outcomes. However, considerable heterogeneity in symptoms and severity across the patients frequently hinder the diagnosis and management. The objective of this review is to emphasize the heterogeneity of the ANCA-associated vasculitis, facilitate the recognition and give guidance to the therapeutical possibilities. We present epidemiologic and risk factors, pathogenesis, and provide comprehensive clinical features of the disease. This article also focuses on the currently available therapeutic options and emerging cellular and molecular targets for the management of systemic and especially renal disease. We conducted extensive literature research published on PubMed and Google Scholar. We systematically reviewed, analyzed, and assembled databases, covering a broad spectrum of aspects of the disease. We compared and summarized the recommendations of two recent guidelines on ANCA-associated vasculitis. The incidence of ANCA-associated vasculitis, hence glomerulonephritis shows a steady increase. Familiarity with the presenting symptoms and laboratory abnormalities are necessary for rapid diagnosis. Early initiation of treatment is the key aspect for favorable patient and renal outcomes. A better understanding of the pathogenesis constantly leads to more targeted and therefore more efficient and less toxic treatment.

Background: Cardiovascular diseases are the leading causes of morbidity and mortality in patients with chronic renal insufficiency. We sought to investigate the chronic renocardiac syndrome and the immediate effects of hemodialysis (HD) on myocardial mechanics using three-dimensional (3D) speckle tracking echocardiography. Methods: Forty-four patients (mean age 48±13 years, 54% men) with end-stage renal disease on three times per week maintenance HD, without diabetes and any significant cardiac disease were investigated just before and immediately after HD, and compared to 46 normal controls (NC; 48±12 years, 48% men). Beyond conventional transthoracic echocardiographic examination, 3D recordings were obtained using multi-beat reconstruction from 6 consecutive cardiac cycles (GE Vivid E9). Ejection fraction (EF) and left ventricular mass indexed to body surface area (LVMi) were measured, and 3D speckle tracking analysis was performed to assess global longitudinal-, circumferential-, area- and radial peak systolic strain values (GE 4D Auto LVQ). For statistical analysis, Wilcoxon signed-rank, Mann-Whitney U, Spearman correlation tests and multivariate linear regression were used. Data are presented as median (interquartile range). Results: LVMi was remarkably increased in patients compared to NC [136 (46) vs. 71 (8) g/m2, p<0.001]. EF and strain values in all directions improved after HD [pre- vs. post-HD; EF: 63 (9.5) vs. 66 (10), longitudinal: -20 (3) vs. -21 (6), circumferential: -20 (4) vs. -22 (7), area: -33 (5) vs. -35 (10), radial: 50 (12) vs. 53.5 (20) %, all p<0.01]. While there was no difference in longitudinal strain, the patients' pre-HD circumferential, area and radial strains were reduced, and after HD only the circumferential strain increased enough to be similar compared to NC [NC longitudinal: -20.5 (3), circumferential: -21 (3), area -36 (3), radial 61 (8) %, p<0.05]. LVMi correlated inversely with post-HD circumferential strain (ρ=0.34, p<0.05), and even stronger with area (ρ=0.54) and radial strains (ρ=-0.58, both p<0.001). In a multivariate linear regression model, circumferential strain was found to be an independent predictor of EF both before (β=-0.88, p<0.001) and after HD (β=-0.96, p<0.001). Conclusions: In chronic renocardiac syndrome the left ventricle can be characterized by increased mass and reduced 3D strain values measured by speckle tracking echocardiography. The increase of LVMi correlates strongly with the reduction of area and radial strains. HD results in immediate improvement of left ventricular function indicated by EF and 3D strain, as well.

Purpose: In patients with chronic renal insufficiency traditional risk factors of left ventricular (LV) hypertrophy include hypertension, overhydration, anemia and impaired calcium-phosphate homeostasis. Fibroblast growth factor 23 (FGF-23) is a phosphaturic hormone secreted by osteoblasts and a rising biomarker associated with LV hypertrophy and mortality in patients with end-stage renal disease (ESRD). We sought to determine the relationship between serum FGF-23 levels and left venticular mass measured by three-dimensional (3D) echocardiography in ESRD patients. Methods: This retrospective cohort study included 44 patients (mean age 48±13 years, 54% men) with ESRD on three times per week maintenance hemodialysis. Exclusion criteria were previous history of diabetes and any significant cardiac disease. Beyond conventional transthoracic echocardiographic examination, 3D recordings were obtained using multi-beat reconstruction from 6 consecutive cardiac cycles (GE Vivid E9). After semi-automated tracing of LV endo- and epicardial surface at end-diastolic frame, LV mass was calculated using dedicated software (GE 4D Auto LVQ). Serum FGF-23 levels were measured by enzyme-linked immunosorbent assay (Merck Millipore). Overhydration evaluated by bioimpedance (Fresenius Body Composition Monitor), laboratory test results (including serum calcium, phosphate, parathormone, total iron binding capacity levels) and blood pressure were recorded and averaged in the three previous months. Relationships were calculated by Spearman correlation test and multivariate linear regression. Results: The median value of LV mass measured in ESRD patients was 244 grams (interquartile range 97.5). Serum FGF-23 levels ranged between 34 and 6848 with a median of 687 pg/ml. Serum levels of FGF-23 (ρ=0.52), phosphate (ρ=0.55), parathormone (ρ=0.38), total iron binding capacity (ρ=0.61), systolic blood pressure (ρ=0.38) and pulse pressure (ρ=0.47, all p<0.05) correlated significantly with LV mass. FGF-23 correlated with serum phosphate (ρ=0.83) and parathormone (ρ=0.53, both p<0.001) levels. In a multivariate linear regression model, FGF-23 (β=0.42, p<0.001), total iron binding capacity (β=0.49, p<0.001) and systolic blood pressure (β=0.37, p<0.01) were found to be independent predictors of LV mass. Conclusions: To the best of our knowledge, this is the first study which demonstrates the strong correlation between serum FGF-23 levels and LV mass measured by 3D echocardiography. Beside the chronic volume- and pressure overload, LV hypertrophy is strongly determined by the endocrine effects of FGF-23 in patients with ESRD.

In this prospective, open‐label, randomized, controlled clinical trial the effects of low‐dose carvedilol, nebivolol, and metoprolol on central arterial pressure and augmentation index (AIx) and its heart rate–corrected value (AIx@75) were assessed. The authors randomized 75 hypertensive patients (18–70 years) to carvedilol 12.5/25 mg, metoprolol 50/100 mg, or nebivolol 2.5/5 mg daily and followed them up for 3 months. Central arterial pressure and AIx were measured with applanation tonometry at baseline and at the end of follow‐up. Analyses were restricted to 60 completers. Central systolic pressure decreased equally in all 3 treatment arms. AIx remained unchanged, while AIx@75 decreased significantly by 5.4%±2.5% in the nebivolol group. According to general linear models, individual change in heart rate was a strong predictor of change in AIx in the carvedilol group (r2=0.23, P=.03) although no similar association was found in the nebivolol group (r2=0.09). The impact of β‐blockers with vasodilator effects on pressure augmentation seems to be different with nebivolol having the largest potential of decreasing AIx@75. While AIx changes associated with carvedilol treatment are strongly driven by heart rate changes, those associated with nebivolol treatment seem to be the result of other mechanisms.

BACKGROUNDThe method of estimating distance traveled by the pulse wave, used in the calculation of pulse wave velocity (PWV), is not standardized. Our objective was to assess whether different methods of distance measurement influenced the association of PWV to cardiovascular mortality in hemodialysis (HD) patients.METHODSNinety-eight chronic HD patients had their PWV measured using three methods for distance estimation; PWV1: suprasternal notch-to-femoral site minus suprasternal notch-to-carotid site, PWV2: carotid-to-femoral site, PWV3: carotid-to-femoral site minus suprasternal notch-to-carotid site. Carotid-to-femoral distance was used to approximate torso length. Patients were followed for a median of 30 months and the association of PWV and cardiovascular mortality was assessed using survival analysis before and after stratification for torso length.RESULTSThe three methods resulted in significantly different PWV values. During follow-up 50 patients died, 32 of cardiovascular causes. In log-rank tests, only tertiles of PWV1 was significantly related to outcome (P values 0.017, 0.257, 0.137, for PWV1, PWV2, and PWV3, respectively). In adjusted Cox, proportional hazards regression only PWV1 was related to cardiovascular mortality. In stratified analysis, however, among patients with below median torso length all PWV values were related to outcome, whereas in patients with above median torso length none of the PWV methods resulted in significant relationship to outcome.CONCLUSIONSPWV calculated using suprasternal notch-to-femoral distance minus suprasternal notch-to-carotid distance provides the strongest relationship to cardiovascular mortality. Longer torso weakens the predictive value of PWV, possibly due to more tortuosity of the aorta hence, more error introduced when using surface tape measurements.

Complex congenital heart diseases with abnormal formation of the aorticopulmonary septum are also associated with defective large artery elastogenesis. In the current study, we tested the hypothesis that carotid artery elastic function was impaired in patients with tetralogy of Fallot (ToF). The study included 45 Fallot-patients (male:female 27:18; age 21.0 ± 11.8 years) and 45 age- and gender-matched healthy control individuals. Carotid artery diameter, pulsatile distension, and intima-media thickness (IMT) were measured by echotracking device, and carotid blood pressure was determined using applanation tonometry. Carotid artery elasticity was characterized by compliance and distensibility coefficients, stiffness index β, and incremental elastic modulus. All carotid artery elastic parameters showed significant differences between groups. The compliance coefficient was 36%, and the distensibility coefficient was 33% smaller, whereas stiffness index β was 46% and incremental elastic modulus was 40% larger in Fallot-patients. Fallot-patients also had larger carotid artery IMT as compared to that of healthy individuals. Carotid artery is markedly stiffer in Fallot-patients suggesting that impaired elastogenesis is a component of the congenital abnormality. Increased large artery stiffness might contribute directly and indirectly (through impairment of baroreflex function) to the higher mortality found in ToF patients.

In the current study we explored (1) if there were differences in sympathetic activity and baroreflex function by age, sex, or physical activity status, (2) if any aspect of baroreflex function related to differences in resting sympathetic activity, and (3) if mechanical and/or neural baroreflex components related to differences in integrated baroreflex gain. Electrocardiogram, blood pressure, carotid diameter and muscle sympathetic nerve activity were recorded continuously at rest and during sequential bolus injections of sodium nitroprusside and phenylephrine in 22 young, 21 older sedentary and 10 older trained individuals. Analyses of co‐variance were used to examine age, sex and training status differences and to explore the explanatory power of integrated baroreflex gain and its mechanical and neural components. Training status and sex influenced neither resting sympathetic outflow nor sympathetic baroreflex gain components. Older subjects had a smaller mechanical component and a strong tendency towards a greater neural component of the sympathetic baroreflex during both pressure falls and pressure rises. Opposing age‐related changes in mechanical and neural components resulted in a smaller integrated gain during pressure falls, but a greater integrated gain during pressure rises in older subjects. Thus, in older individuals, compromised sympathetic activation to pressure falls was owing to the stiffening of barosensory vessels, whereas the more sensitive sympathoinhibition to pressure rise was due to an increased neural control. Enhanced neural control with age, however, did not contribute the increased resting sympathetic outflow, which indicates that these two changes are probably driven by distinct neural mechanisms.

A baroreflex erzekenysege a kardiovaszkularis mortalitas fuggetlen prediktiv tenyezője; centralis nagyerek rugalmassaga a receptorok erzekenysegenek egyik meghatarozo tenyezője. Jelen vizsgalataink soran megallapitottuk, hogy 1) hogy a baroreflex erzekenysege egeszseges terhessegben csokkent, amely csokkenes pre-eclampsiaban fokozott mertekű; 2) hipertonias szulők aktivan sportolo gyermekeiben az a. carotis rugalmassaga es a cardialis autonom idegrendszer funkcio nem kulonbozik a nem-hipertonias szulők nem-sportolo gyermekeinek hasonlo ertekeitől; 3) a baroreflex erzekenysege fiatal vesebetegekben a kontrollhoz kepest jelentősen csokkent, az arteria carotis merevsege fokozodik; vese-transzplantaciot kovetően az autonom indexek illetve az erfalrugalmassag jelentősen javul, kozel a normal ertekekre; 4) az arteria carotis rugalmassaga nagyertranszpozicioval szuletett gyermekekben jelentősen csokkent; az elasztikus funkcio valtozasa a fejlődesi rendellenesseg reszet kepezi; a merev erfal a baroreceptorok ingerelhetőseget csokkenti, amelyet azonban kozponti idegrendszeri mechanizmusok kompenzalnak, igy a baroreflex erzekenysege nem csokken; 5) exfoliacios szindromaban (XFS) a carotis rugalmassaga es a baroreflex erzekenysege csokkent; feltehetően, a koros műkodes hattereben az erfalban tortenő exfoliacios matrix anyag lerakodasa all. | Baroreflex sensitivity is an independent predictor of vascular mortality; distensibility of large central arteries is an important determinant of receptor sensitivity. In these series of investigations we have established that 1) baroreflex sensitivity is reduced during pregnancy and the reduction is accentuated in preeclampsia; 2) carotid distensibility and baroreflex sensitivity are no different in physically active offspring of hypertensive parents and in sedentary offspring of normotensive parents; 3) in juvenile end stage renal disease baroreflex sensitivity is markedly impaired and carotid artery stiffness is increased; after renal transplantation arterial and autonomic abnormalities are largely reversed; 4) in transposition of great arteries carotid artery elastivity is reduced and constitutes part of the congenital abnormality; baroreceptor sensitivity is low due to vessel wall stiffness, but baroreflex function appears normal due to central autonomic adaptation; 5) carotid artery distensibility and baroreflex sensitivity is reduced in exfoliation syndrome; altered function is likely the result of deposition of exfoliative matrix material in the vessel wall.

BACKGROUND:Peripheral blood pressure measurement underestimates pressure changes during baroreflex testing, resulting in an overestimation of baroreflex gain. This error might be reduced by measuring central blood pressure; the invasive measurement, however, may represent ethical and practical problems. The solution may be the derivation of central blood pressure from the peripheral pulse using a generalized transfer function. METHODS:In the current study, we tested the agreement between catheter-measured and generalized transfer function derived central blood pressure measurements and corresponding baroreflex gains. ECG and blood pressure waveforms were monitored continuously during a phenylephrine-induced pressure rise in 22 subjects undergoing cardiac catheterization. Pressure was measured with a catheter positioned in the aorta and with applanation tonometry in the radial artery. Radial pressure waveforms were subject to a generalized transfer function built in the SphygmoCor device to derive central pressure waveforms. Radial tonometric signal was calibrated with catheter-measured (invasive) and sphygmomanometric (noninvasive) pressures. Baroreflex gains were calculated from the linear regressions between heart period and systolic pressure changes. RESULTS:When radial tonometric signal was calibrated invasively, there was no group difference between baroreflex gains calculated from SphygmoCor-derived and catheter-measured pressures (8.2 +/- 1.2 vs. 7.2 +/- 1.2 ms/mmHg, P = NS). When radial tonometric signal was calibrated noninvasively, however, baroreflex gains calculated from SphygmoCor-derived pressures overestimated those calculated from catheter-measured pressures. CONCLUSION:Using a generalized transfer function is an accurate method to derive central pressure changes for baroreflex gain calculation. The technique, however, requires invasive pressure measurements for calibration, leaving the problem of a fully noninvasive central pressure measurement unresolved.

According to conventional wisdom, hysteresis in cardiac vagal baroreflex function exhibits a specific pattern: pressure falls are associated with longer heart periods and a smaller linear gain. A similar pattern occurs in the pressure-diameter relationship of barosensory vessels, and therefore it has been suggested that baroreflex hysteresis derives solely from vascular behaviour. However, we hypothesized that mechanical and neural baroreflex components contribute equally to baroreflex hysteresis. Blood pressure, carotid diameter and the electrocardiogram were recorded continuously during two trials of sequential bolus injections of nitroprusside and phenylephrine in 14 young healthy subjects. Baroreflex gain and its mechanical and neural components were estimated for falls and rises in pressure and diameter. The position or set point of the relations was quantified at the mean pressure and mean diameter. Gains were determined via piecewise linear regression. Set points and gains for falls versus rises in pressure and diameter were compared with the Chow test. Hysteresis was observed in all individuals, but not in every trial. In most, but not all, trials pressure falls were associated with longer heart periods and smaller linear gain, as conventional wisdom would predict. However, the pattern of hysteresis derived from the interaction of both mechanical and neural components. The two components most often acted in opposition to determine differences in set point, but in conjunction to determine differences in baroreflex gain. Therefore, we conclude that hysteresis is not solely determined by barosensory vessel behaviour but by the complex interaction of mechanical and neural aspects of the arterial baroreflex.

Transposition of great arteries is the consequence of abnormal aorticopulmonary septation. Animal embryonic data indicate that septation and elastogenesis are related events, but human and clinical data are not available. We tested the hypothesis that large artery elastic function was impaired in patients with transposition of great arteries. We studied 34 patients aged 9 to 19 years, 12 +/- 3 years after atrial switch operation; 14 patients aged 7 to 9 years, 8 +/- 1 years after arterial switch operation; and 108 healthy control subjects matched for age. Carotid artery diastolic diameter and pulsatile distension were determined by echo wall-tracking; carotid blood pressure was measured by tonometry. Systolic pressure was higher and diastolic pressure was lower in patients than in controls. Patients with atrial and arterial switch repair were compared with their respective controls by 2-factor ANOVA. For patients with atrial switch repair versus control, stiffness index beta was 4.9 +/- 1.5 versus 3.1 +/- 1.0 (P < 0.001); for patients witch arterial switch versus control, stiffness index beta was 3.8 +/- 1.1 versus 2.1 +/- 0.6 (P < 0.001). Similar differences were observed for carotid compliance, distensibility, and incremental elastic modulus as well. The interaction term was not significant for any of the elastic variables, indicating that carotid stiffening was a characteristic of the condition and not the consequence of different hemodynamics. Carotid artery is markedly stiffer in patients, suggesting that impaired elastogenesis may constitute part of the congenital abnormality. Since carotid artery stiffness has been established as an independent cardiovascular risk factor, this condition may have consequences in the clinical management of these patients.

Increased resting vascular sympathetic nerve activity is a hallmark of healthy human aging, which may contribute to the increased cardiovascular risk in the elderly. Regular aerobic exercise has cardioprotective effects partly by preventing age-related declines in vagal control, but its impact on sympathetic outflow remains equivocal. Therefore, we aimed to investigate the combined effects of aging and exercise training on sympathetic nervous activity in healthy humans. ECG, blood pressure and muscle sympathetic nerve activity were recorded continuously for 5 minutes during 0.25 Hz paced breathing in 10 young (21–30 yrs) sedentary and 7 older (55–63 yrs) trained men. Resting heart rate was lower in older trained than in young sedentary men (54±7 vs.63±7 beats/min), and resting vascular sympathetic outflow was not different between older trained and young sedentary men expressed either on a per beat (72±26 vs.57±24 AIU/beat, older vs. young) or per minute (3821±1283 AIU/min vs. 3589±1491 AIU/min, older vs. young) basis. Our data suggest that exercise training offsets the age-related increase in resting sympathetic outflow in healthy men.

Arterial baroreflex sensitivity (BRS) is markedly reduced in middle-aged patients with end-stage renal disease (ESRD), due to the combined effects of aging, arterial stiffening, and autonomic neuropathy. Much less is known about the effects of ESRD on arterial baroreflex in juvenile patients. Therefore, we investigated baroreflex function and its relation to carotid artery elasticity and heart rate variability in children and young adults with ESRD. We studied 42 subjects (9-30 years): 14 patients on maintenance hemodialysis (HD), 14 renal transplant recipients (RT), and 14 healthy control subjects (C). Baroreflex function was determined by pharmacological (BRS) and spontaneous (sequence and spectral indices) techniques. Carotid artery elasticity was characterized by stiffness index beta. Heart rate variability was assessed using time and frequency domain measures. Data are expressed as mean+/-s.d. BRS was markedly reduced in HD as compared to C (10.0+/-4.2 vs 25.7+/-5.9 ms/mm Hg); spontaneous indices were reduced to similar extent. Carotid artery stiffness was approximately 50% higher in HD than in C and was inversely related to BRS. Heart rate variability was also compromised in HD, and was directly related to spontaneous indices. No significant differences existed in any of these variables between RT and C. Decreased baroreflex function in juvenile HD is partly due to loss of carotid artery elasticity and partly due to impaired heart rate variability. Renal transplantation may partly prevent impairment or improve compromised baroreflex function in young patients with ESRD.