Diagnostic and Therapeutic Approach in ANCA-Associated Glomerulonephritis: A Review on Management Strategies.

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.

The effect of low-dose carvedilol, nebivolol, and metoprolol on central arterial pressure and its determinants: a randomized clinical trial.

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 (r(2) =0.23, P=.03) although no similar association was found in the nebivolol group (r(2) =0.09). The impact of ß-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.

Impaired carotid artery elastic function in patients with tetralogy of Fallot.

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 ß, 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 ß 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.

The method of distance measurement and torso length influences the relationship of pulse wave velocity to cardiovascular mortality.

BACKGROUND: The 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. METHODS: Ninety-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. RESULTS: The 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. CONCLUSIONS: PWV 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.

Age- and fitness-related alterations in vascular sympathetic control.

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.

Use of generalized transfer function-derived central blood pressure for the calculation of baroreflex gain.

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.

Mechanical and neural contributions to hysteresis in the cardiac vagal limb of the arterial baroreflex.

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.

FINAL WORDS ON DEBATE "POINT: COUNTERPOINT CARDIOVASCULAR VARIABILITY IS/IS NOT AN INDEX OF AUTONOMIC CONTROL OF CIRCULATION"

not applicable.

Transposition of great arteries is associated with increased carotid artery stiffness.

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.

[Effect of vitamin E supplementation on the vitamin content of lipoprotein in young men and women]. / Az E-vitamin-pótlás hatása fiatal férfiak és nok lipoproteinjének vitamintartalmára.

UNLABELLED: The effect of supplementary Vitamin E on the vitamin content of lipoproteins in young men and women. Inappropriate vitamin and trace element supplementation may facilitate the development of atherosclerosis. It is known that Vitamin E protects lipids from oxidative stress, while clinical signs of atherosclerosis appear later in women compared to men. AIMS: (1) The increase of vitamin E in plasma and plasma lipoproteins after 4 weeks of supplementation vitamin E was investigated, (2) furthermore it was tested whether a proportion shift occurs in alpha-tocopherol content of lipoproteins, (3) and checked for gender-related differences in plasma and plasma lipoprotein vitamin E levels before, during and after treatment, (4) plasma CRP levels as a marker of lipid peroxidation were also followed. METHODS: 5-5 young healthy men and women took part in the study, receiving 700 IU/day Vitamin E for one month. Each subject was studied before and at the end of treatment, and also one month after treatment. HDL and LDL-VLDL containing lipoproteins were separated. Vitamin E and hsCRP levels were measured (by HPLC and an immunoturbidimetric method, respectively). RESULTS: Vitamin E treatment induced in both genders an approximately threefold increase in vitamin E concentration in HDL-cholesterol (8.1 +/- 1.7 micromol/l vs. 22.5 +/- 7.5 micromol/l, p < 0.001), and a twofold increase in LDL-VLDL-cholesterol (22.0 +/- 3.7 micromol/l vs. 49.0 +/- 9.0 micromol/l, p < 0.001). Plasma and HDL vitamin E levels were higher in women than in men at the onset of treatment (6.8 +/- 0.96 micromol/l vs. 9.5 +/- 1.10 micromol/l), but during the treatment these gender-related differences disappeared. When plasma vitamin E concentration were considered 100% and the changes of the vitamin E concentrations of lipoproteins were calculated, it was found that supplementation with vitamin E in men increased the vitamin E concentration of LDL-VLDL cholesterol to a higher extent compared to women (LDL-VLDL % in men: 59.8 +/- 7.43%, in women: 49.3 +/- 7.41%, p < 0.05). All the observed changes regressed one month after cessation of supplementation. The level of hsCRP decreased during vitamin E treatment (1.07 +/- 0.9 mg/l vs. 0.2 +/- 0.14 mg/l, p < 0.001), and remained suppressed after the cessation of treatment (0.37 +/- 0.4, p < 0.01). CONCLUSIONS: These results support the hypothesis that women at young age are better protected against lipid-peroxidation as compared to men because of higher HDL vitamin E concentrations. Vitamin E supplementation in men eliminates this concentration difference between genders, and also increases LDL-VLDL vitamin E. In both genders high concentration of vitamin E in lipoproteins was associated with low hsCRP concentration.

Cardiovagal autonomic function in sedentary and trained offspring of hypertensive parents.

In young normotensive subjects, parental hypertension is associated with stiffening of the carotid artery and reduction in cardiovagal outflow and baroreflex gain. In subjects without parental hypertension regular exercise training was found to attenuate age-related reduction in carotid compliance and baroreflex gain. The aim of the present study was to test the hypothesis that regular physical activity is associated with better parameters of carotid artery elasticity, increased cardiovagal outflow and higher baroreflex gain in normotensive offspring of hypertensive parents. We studied 98 healthy, sedentary or endurance exercise trained subjects (49 men, 18-27 years of age) with or without family history of hypertension (FH(+) and FH(-), respectively) in a cross-sectional design. In the sedentary group spontaneous baroreflex indices (sequence method and spectral techniques) were lower in FH(+) subjects than in their FH(-) peers, while in trained subjects these indices were not different between FH(+) and FH(-). Furthermore, in the FH(+) group trained subjects had higher baroreflex indices than their sedentary peers, while in the FH(-) group no significant differences were found. Carotid compliance and distensibility coefficient (echo-tracking ultrasound and applanation tonometry) were not different in FH(-) sedentary and trained subjects, but were higher in FH(+) trained subjects as compared to their sedentary peers. Significant but modest relationships were found between spontaneous baroreflex indices and carotid artery elastic parameters across all subjects. Our present data indicate that in subjects with parental hypertension aerobic exercise training is associated with higher levels of cardiovagal outflow and baroreflex gain, which finding, however, is not explained by greater elasticity of the carotid artery.

Opposite changes in carotid versus aortic stiffness during healthy human pregnancy.

Systemic arterial compliance has been known to increase during healthy pregnancy, whereas, recently, the carotid artery has been reported to stiffen. To clarify this controversy, we simultaneously measured aortic PWV (pulse wave velocity) and carotid artery elastic parameters in a cohort of pregnant women. Twelve normotensive pregnant women were studied longitudinally during the three trimesters of pregnancy (T1, T2 and T3 respectively) and 12 weeks PP (postpartum). Carotid artery diastolic diameter and pulsatile distension was measured by an echo-wall tracking method and carotid pulse pressure by applanation tonometry. Carotid strain, compliance, distensibility coefficient, stiffness index beta, Einc (incremental elastic modulus) and augmentation index were calculated. Aortic PWV was determined to estimate aortic distensibility. All carotid artery elastic parameters indicated significant stiffening from T1 to T3 (1.8+/-0.2 versus 2.9+/-0.3 mmHg for Einc), which was reversed after delivery (2.3+/-0.2 mmHg). Aortic PWV decreased during pregnancy (6.2+/-0.2 versus 5.4+/-0.2 m/s) and increased in the PP period (6.7+/-0.2 m/s). No correlation was found between changes in carotid artery elastic parameters and changes in aortic PWV either from T1 to T3 or from T3 to PP. The carotid artery exhibits regionally specific stiffening during pregnancy, which appears to represent a qualitatively different change in arterial elastic behaviour.

Maturation of cardiovagal autonomic function from childhood to young adult age.

BACKGROUND: Cardiovagal autonomic control declines with age in adult subjects, which is related in part to increasing stiffness of the barosensory vessel wall. It is not known, however, whether autonomic function changes with age in children. METHODS AND RESULTS: We studied 137 healthy subjects divided into 4 age groups: group 1, 7 to 14 years; group 2, 11 to 14 years; group 3, 15 to 18 years; and group 4, 19 to 22 years. Brachial artery pressure was measured by sphygmomanometry and continuous radial artery pressure and carotid artery pulse pressure (DeltaP) by applanation tonometry. The R-R interval was derived from the ECG. Autonomic function was assessed by spontaneous sequence and frequency-domain indices, which indicate the extent of coupling between fluctuations in heart rate and systolic pressure. Carotid artery diastolic diameter (DD) and pulsatile distension (DeltaD) were measured by echo wall tracking; carotid compliance coefficient (CC) was defined as DeltaD/DeltaP and distensibility coefficient as 2DeltaD/DD . DeltaP. From group 1 to group 3, spontaneous indices increased significantly (18.1+/-1.7 versus 33.3+/-4.0; 14.4+/-1.1 versus 25.5+/-22; 12.9+/-1.1 versus 20.8+/-2.0; and 6.4+/-0.6 versus 16.2+/-1.4 ms/mm Hg [mean+/-SEM] for Seq+, Seq-, LFalpha, and LF(gain), respectively), with no significant changes afterward. CC and DC were inversely proportional to age (r=-0.49 and -0.62, respectively, P<0.001). The efficiency of neural integrative mechanisms, estimated as the ratio of spontaneous indices and CC, more than doubled from group 1 to group 3. Spontaneous indices were linearly related to measures of cardiac vagal activity. CONCLUSIONS: The increase in spontaneous indices from early childhood to adolescence, despite gradual stiffening of the carotid artery, may indicate improved cardiovagal autonomic function, which is most likely a result of maturation of neural mechanisms, attaining peak level at adolescence.

Effect of vitamin E on carotid artery elasticity and baroreflex gain in young, healthy adults.

In this study we tested the hypothesis that dietary vitamin E supplementation can improve carotid artery elasticity and cardio-vagal baroreflex gain in young, healthy individuals. A total of 20 subjects were studied in a double-blind, placebo-controlled, randomized study. Subjects in the active treatment group received 700 IU/day vitamin E for 1 month. Each subject was studied three times: before, during and 1 month after treatment. Plasma vitamin E levels were determined using high-performance liquid chromatography. Carotid artery diameter was measured by ultrasound and radial artery pressure by tonometry. Baroreflex function was assessed by time and frequency domain spontaneous indices. Plasma vitamin E levels increased by 123%, which was associated with a 20% increase in carotid artery compliance and a 30-60% increase in baroreflex indices. All these changes regressed 1 month after cessation of vitamin E supplementation. Significant correlations were observed across conditions (control, treatment and recovery), among plasma vitamin E concentrations, carotid artery compliance and distensibility values and two of the baroreflex gain indices in the treatment group. Our results demonstrate that vitamin E supplementation can increase carotid artery compliance and baroreflex gain in young, apparently healthy adults.

Carotid artery stiffening does not explain baroreflex impairment in pre-eclampsia.

Stiffening of the barosensory vessel wall in hypertension has been suggested to play a role in the associated baroreflex impairment. The carotid distensibility-BRS (baroreflex sensitivity) relationship, however, has not been studied in pre-eclampsia, a condition where hypertension is spontaneously reversible. Twelve normotensive pregnant women and 12 patients with pre-eclampsia matched for maternal age and week of gestation were studied in the third trimester and 3 months postpartum. Carotid artery diastolic diameter and pulsatile distension was measured by echo-wall tracking and carotid pulse pressure by applanation tonometry, and the carotid distensibility coefficient was calculated. Spontaneous BRS was determined by the sequence and spectral methods from 10 min continuous recording of ECG and finger arterial blood pressure. In the third trimester, carotid distensibility was lower in patients with pre-eclampsia than in normotensive pregnant women (2.47+/-0.17 compared with 4.08+/-0.16 x 10(-3)/mmHg); postpartum, it increased moderately in patients, but remained below normotensive values (3.25+/-0.12 compared with 4.25+/-0.19 x 10(-3)/mmHg). In the third trimester, both patients and healthy pregnant women had equally low BRS values; postpartum, the various BRS indices increased markedly (by 60-190%) and to the same level in both groups. No correlation was found between changes in carotid artery distensibility and those in BRS from the third trimester to postpartum period in patients and healthy pregnant women. The lack of association between changes in carotid distensibility and BRS suggest that stiffening of the carotid artery in pre-eclampsia is not responsible for baroreflex dysfunction.

Static and dynamic changes in carotid artery diameter in humans during and after strenuous exercise.

Arterial baroreflex function is altered by dynamic exercise, but it is not clear to what extent baroreflex changes are due to altered transduction of pressure into deformation of the barosensory vessel wall. In this study we measured changes in mean common carotid artery diameter and the pulsatile pressure : diameter ratio (PDR) during and after dynamic exercise. Ten young, healthy subjects performed a graded exercise protocol to exhaustion on a bicycle ergometer. Carotid dimensions were measured with an ultrasound wall-tracking system; central arterial pressure was measured with the use of radial tonometry and the generalized transfer function; baroreflex sensitivity (BRS) was assessed in the post-exercise period by spectral analysis and the sequence method. Data are given as means +/- S.E.M. Mean carotid artery diameter increased during exercise as compared with control levels, but carotid distension amplitude did not change. PDR was reduced from 27.3+/-2.7 to 13.7+/-1.0 microm mmHg(-1). Immediately after stopping exercise, the carotid artery constricted and PDR remained reduced. At 60 min post-exercise, the carotid artery dilated and the PDR increased above control levels (33.9+/-1.4 microm mmHg(-1)). The post-exercise changes in PDR were closely paralleled by those in BRS (0.74< or = r < or =0.83, P<0.05). These changes in mean carotid diameter and PDR suggest that the mean baroreceptor activity level increases during exercise, with reduced dynamic sensitivity; at the end of exercise baroreceptors are suddenly unloaded, then at 1 h post-exercise, baroreceptor activity increases again with increasing dynamic sensitivity. The close correlation between PDR and BRS observed at post-exercise underlies the significance of mechanical factors in arterial baroreflex control.