Prevalence and prognostic relevance of cardiac involvement in ANCA-associated vasculitis: eosinophilic granulomatosis with polyangiitis and granulomatosis with polyangiitis.

BACKGROUND: To investigate the prevalence and prognostic relevance of cardiac involvement in an ANCA-associated vasculitis (AAV) population of eosinophilic granulomatosis with polyangiitis (EGPA) and granulomatosis with polyangiitis (GPA) patients. METHODS: Prospective cohort study of fifty EGPA and forty-one GPA patients in sustained remission without previous in-depth cardiac screening attending our clinical immunology outpatient department. Cardiac screening included clinical evaluation, ECG, 24-hour Holter registration, echocardiography and cardiac magnetic resonance imaging (CMR) with coronary angiography and endomyocardial biopsy upon indication. Fifty age-, sex- and cardiovascular risk factor-matched control subjects were randomly selected from a population study. Long-term outcome was assessed using all-cause and cardiovascular mortality. RESULTS: A total of 91 AAV-patients (age 60±11, range 63-87years) were compared to 50-matched control subjects (age 60±9years, range 46-78years). ECG and echocardiography demonstrated cardiac abnormalities in 62% EGPA and 46% GPA patients vs 20% controls (P<0.001 and P=0.014, respectively). A total of 69 AAV-patients underwent additional CMR, slightly increasing the prevalence of cardiac involvement to 66% in EGPA and 61% in GPA patients. After a mean follow-up of 53±18months, presence of cardiac involvement using ECG and echocardiography in AAV-patients showed increased all-cause and cardiovascular mortality (Log-rank P=0.015 and Log-rank P=0.021, respectively). CONCLUSION: Cardiac involvement in EGPA and GPA patients with sustained remission is high, even if symptoms are absent and ECG is normal. Moreover, cardiac involvement is a strong predictor of (cardiovascular) mortality. Therefore, risk stratification using cardiac imaging is recommended in all AAV-patients, irrespective of symptoms or ECG abnormalities.

Multivariate meta-analysis using individual participant data.

When combining results across related studies, a multivariate meta-analysis allows the joint synthesis of correlated effect estimates from multiple outcomes. Joint synthesis can improve efficiency over separate univariate syntheses, may reduce selective outcome reporting biases, and enables joint inferences across the outcomes. A common issue is that within-study correlations needed to fit the multivariate model are unknown from published reports. However, provision of individual participant data (IPD) allows them to be calculated directly. Here, we illustrate how to use IPD to estimate within-study correlations, using a joint linear regression for multiple continuous outcomes and bootstrapping methods for binary, survival and mixed outcomes. In a meta-analysis of 10 hypertension trials, we then show how these methods enable multivariate meta-analysis to address novel clinical questions about continuous, survival and binary outcomes; treatment-covariate interactions; adjusted risk/prognostic factor effects; longitudinal data; prognostic and multiparameter models; and multiple treatment comparisons. Both frequentist and Bayesian approaches are applied, with example software code provided to derive within-study correlations and to fit the models.

The -665 C>T polymorphism in the eNOS gene predicts cardiovascular mortality and morbidity in white Europeans.

We recently identified rs3918226 as a hypertension susceptibility locus (-665 C>T), TT homozygosity being associated with higher hypertension risk. T compared with C allele transfected cells had lower endothelial nitric oxide synthase (eNOS) expression. In the family-based Flemish Study on Environment, Genes and Health Outcomes (50.9% women; mean age 40.3 years), we investigated whether 32 TT homozygotes had worse outcomes than 2787 C allele carriers. Over 15 years (median), total and cardiovascular mortality and cardiovascular and coronary events amounted to 269 (9.5%), 98 (3.5%), 247 (8.8%) and 120 (4.3%), respectively. While accounting for family clusters, the hazard ratios associated with TT homozygosity were 4.11 (P=0.0052) for cardiovascular mortality (4 deaths), 2.75 (P=0.0067) for cardiovascular events (7 endpoints) and 3.10 (P=0.022) for coronary events (4 endpoints). With adjustment for cardiovascular risk factors, these hazard ratios were 6.01 (P=0.0003), 2.64 (P=0.0091) and 2.89 (P=0.010), respectively. Analyses unadjusted for blood pressure and antihypertensive treatment produced consistent results. For all fatal plus nonfatal cardiovascular events, the positive predictive value, attributable risk and population-attributable risk associated with TT homozygosity were 21.9, 61.5 and 2.0%, respectively. In conclusion, TT homozygosity at the position -665 in the eNOS promoter predicts adverse outcomes, independent of blood pressure and other risk factors.

Blood pressure response to renal nerve stimulation in patients undergoing renal denervation: a feasibility study.

During renal sympathetic denervation (RDN), no mapping of renal nerves is performed and there is no clear end point of RDN. We hypothesized high-frequency renal nerve stimulation (RNS) may increase blood pressure (BP), and this increase is significantly blunted after RDN. The aim of this study was to determine the feasibility of RNS in patients undergoing RDN. Eight patients with resistant hypertension undergoing RDN were included. A quadripolar catheter was positioned at four different sites in either renal artery. RNS was performed during 1 min with a pacing frequency of 20 Hz. After all patients successfully underwent RDN, RNS was repeated at the site of maximum BP response before RDN in either renal artery. Mean age was 66 years. During RNS, BP increased significantly from 108/55 to 132/68 mm Hg (P < 0.001). After RDN, systolic BP response at the site of maximum response to RNS was significantly blunted (+43.1 vs +9.3 mm Hg, P = 0.002). In three patients, a systolic BP increase >10 mm Hg was observed after RDN. In conclusion, RNS resulted in an acute temporary BP increase. This response was significantly blunted after RDN. RNS may potentially serve as an end point for RDN.

Ambulatory blood pressure monitoring for risk stratification in obese and non-obese subjects from 10 populations.

Overweight clusters with high blood pressure (BP), but the independent contribution of both risk factors remains insufficiently documented. In a prospective population study involving 8467 participants (mean age 54.6 years; 47.0% women) randomly recruited from 10 populations, we studied the contribution of body mass index (BMI) to risk over and beyond BP, taking advantage of the superiority of ambulatory over conventional BP. Over 10.6 years (median), 1271 participants (15.0%) died and 1092 (12.9%), 637 (7.5%) and 443 (5.2%) experienced a fatal or nonfatal cardiovascular, cardiac or cerebrovascular event. Adjusted for sex and age, low BMI (<20.7 kg m(-2)) predicted death (hazard ratio (HR) vs average risk, 1.52; P<0.0001) and high BMI (> or = 30.9 kg m(-2)) predicted the cardiovascular end point (HR, 1.27; P=0.006). With adjustments including 24-h systolic BP, these HRs were 1.50 (P<0.001) and 0.98 (P=0.91), respectively. Across quartiles of the BMI distribution, 24-h and nighttime systolic BP predicted every end point (1.13 < or = standardized HR < or = 1.67; 0.046 < or = P<0.0001). The interaction between systolic BP and BMI was nonsignificant (P > or = .22). Excluding smokers removed the contribution of BMI categories to the prediction of mortality. In conclusion, BMI only adds to BP in risk stratification for mortality but not for cardiovascular outcomes. Smoking probably explains the association between increased mortality and low BMI.

Blood pressure changes after renal denervation at 10 European expert centers.

We did a subject-level meta-analysis of the changes (Δ) in blood pressure (BP) observed 3 and 6 months after renal denervation (RDN) at 10 European centers. Recruited patients (n=109; 46.8% women; mean age 58.2 years) had essential hypertension confirmed by ambulatory BP. From baseline to 6 months, treatment score declined slightly from 4.7 to 4.4 drugs per day. Systolic/diastolic BP fell by 17.6/7.1 mm Hg for office BP, and by 5.9/3.5, 6.2/3.4, and 4.4/2.5 mm Hg for 24-h, daytime and nighttime BP (P0.03 for all). In 47 patients with 3- and 6-month ambulatory measurements, systolic BP did not change between these two time points (P0.08). Normalization was a systolic BP of <140 mm Hg on office measurement or <130 mm Hg on 24-h monitoring and improvement was a fall of 10 mm Hg, irrespective of measurement technique. For office BP, at 6 months, normalization, improvement or no decrease occurred in 22.9, 59.6 and 22.9% of patients, respectively; for 24-h BP, these proportions were 14.7, 31.2 and 34.9%, respectively. Higher baseline BP predicted greater BP fall at follow-up; higher baseline serum creatinine was associated with lower probability of improvement of 24-h BP (odds ratio for 20-µmol l(-1) increase, 0.60; P=0.05) and higher probability of experiencing no BP decrease (OR, 1.66; P=0.01). In conclusion, BP responses to RDN include regression-to-the-mean and remain to be consolidated in randomized trials based on ambulatory BP monitoring. For now, RDN should remain the last resort in patients in whom all other ways to control BP failed, and it must be cautiously used in patients with renal impairment.

Do level and variability of systolic blood pressure predict arterial properties or vice versa?

No longitudinal study addressed whether systolic blood pressure level (SBPL) or within-visit variability (SBPV) predict arterial properties or vice versa. In families randomly recruited from a Flemish population, we determined SBPL and SBPV from five consecutive blood pressure readings. The indexes of SBPV were variability independent of the mean, the difference between maximum and minimum SBPL, and average real variability. We measured carotid intima-media thickness and distensibility by ultrasound and carotid-femoral pulse wave velocity by tonometry (SphygmoCor, version 8.2). Effect sizes were computed for 1-s.d. increments in the predictors, while accounting for covariables and family clusters. Among 1087 participants (50.4% women; mean age, 41.8 years), followed up for 2.55 years (median), higher SBPL predicted (P < or = 0.019) higher carotid intima-media thickness (+15 µm), lower carotid distensibility (-1.53 10(-3) kPa(-1)) and faster carotid-femoral pulse wave velocity (+0.285 m s(-1)) at follow-up, whereas none of the SBPV indexes predicted the arterial traits at follow-up (P> or = 0.11). In a subset of 713 participants, followed up for another 3.14 years, lower carotid distensibility predicted (P<0.01) higher SBPL (+2.57 mm Hg), variability independent of the mean (+0.531 units), difference between maximum and minimum SBPL (+1.75 mm Hg) and average real variability (+0.654 mm Hg). Higher carotid-femoral pulse wave velocity predicted a 1.11 mm Hg increase SBPL (P=0.031). In conclusion, temporality and effect size suggest that SBPL but not within-visit SBPV cause arterial stiffness and carotid intima-media thickness. Carotid stiffness, independent of SBPL, predicts within-visit SBPV, possibly because baroreflexes originating from a stiff carotid artery wall are impaired. Finally, stiffness of the aorta contributes to the age-related SBPL possibly, because faster returning reflected waves augments SBPL.

Efficacy of newer versus older antihypertensive drugs in black patients living in sub-Saharan Africa.

To address the epidemic of hypertension in blacks born and living in sub-Saharan Africa, we compared in a randomised clinical trial (NCT01030458) single-pill combinations of old and new antihypertensive drugs in patients (30-69 years) with uncomplicated hypertension (140-179/90-109 mm Hg). After ≥4 weeks off treatment, 183 of 294 screened patients were assigned to once daily bisoprolol/hydrochlorothiazide 5/6.25 mg (n=89; R) or amlodipine/valsartan 5/160 mg (n=94; E) and followed up for 6 months. To control blood pressure (<140/<90 mm Hg), bisoprolol and amlodipine could be doubled (10 mg per day) and α-methyldopa (0.5-2 g per day) added. Sitting blood pressure fell by 19.5/12.0 mm Hg in R patients and by 24.8/13.2 mm Hg in E patients and heart rate decreased by 9.7 beats per minute in R patients with no change in E patients (-0.2 beats per minute). The between-group differences (R minus E) were 5.2 mm Hg (P<0.0001) systolic, 1.3 mm Hg (P=0.12) diastolic, and 9.6 beats per minute (P<0.0001). In 57 R and 67 E patients with data available at all visits, these estimates were 5.5 mm Hg (P<0.0001) systolic, 1.8 mm Hg (P=0.07) diastolic and 9.8 beats per minute (P<0.0001). In R compared with E patients, 45 vs 37% (P=0.13) proceeded to the higher dose of randomised treatment and 33 vs 9% (P<0.0001) had α-methyldopa added. There were no between-group differences in symptoms except for ankle oedema in E patients (P=0.012). In conclusion, new compared with old drugs lowered systolic blood pressure more and therefore controlled hypertension better in native African black patients.

Blood pressure, cardiovascular outcomes and sodium intake, a critical review of the evidence.

Consideration of the role of NaCl (salt) in the pathogenesis and treatment of essential hypertension is one of the overriding research themes both in experimental and clinical medicine. The evidence relating blood pressure to salt intake in humans originates from population studies and randomized clinical trials of interventions on dietary salt intake. Estimates from meta-analyses of trials in normotensive subjects generally are similar to estimates derived from prospective population studies (+ 1.7-mmHg increase in systolic blood pressure per 100 mmol increment in 24­hour urinary sodium). This estimate, however, does not translate into an increased risk of incident hypertension in subjects consuming a high-salt diet. Prospective studies relating health outcomes to 24­h urinary sodium excretion produced inconsistent results. Taken together, available evidence does not support the current recommendations of a generalized and indiscriminate reduction of salt intake at the population level. The public should be properly educated about the pros and cons of a decrease in sodium intake, in particular if they are healthy.

Immediate and late benefits of treating very elderly people with hypertension: results from active treatment extension to Hypertension in the Very Elderly randomised controlled trial.

OBJECTIVE: To assess if very elderly people with hypertension obtain early benefit from antihypertensive treatment. DESIGN: One year open label active treatment extension of randomised controlled trial (Hypertension in the Very Elderly Trial (HYVET)). SETTING: Hospital and general practice based centres mainly in eastern and western Europe, China, and Tunisia. PARTICIPANTS: People on double blind treatment at the end of HYVET were eligible to enter the extension. INTERVENTIONS: Participants on active blood pressure lowering treatment continued taking active drug; those on placebo were given active blood pressure lowering treatment. The treatment regimen was as used in the main trial-indapamide SR 1.5 mg (plus perindopril 2-4 mg if required)-with the same target blood pressure of less than 150/80 mm Hg. MAIN OUTCOME MEASURES: The primary outcome was all stroke; other outcomes included total mortality, cardiovascular mortality, and cardiovascular events. RESULTS: Of 1882 people eligible for entry to the extension, 1712 (91%) agreed to participate. During the extension period, 1682 patient years were accrued. By six months, the difference in blood pressure between the two groups was 1.2/0.7 mm Hg. Comparing people previously treated with active drug and those previously on placebo, no significant differences were seen for stroke (n = 13; hazard ratio 1.92, 95% confidence interval 0.59 to 6.22) or cardiovascular events (n = 25; 0.78, 0.36 to 1.72). Differences were seen for total mortality (47 deaths; hazard ratio 0.48, 0.26 to 0.87; P = 0.02) and cardiovascular mortality (11 deaths; 0.19, 0.04 to 0.87; P = 0.03). CONCLUSION: Very elderly patients with hypertension may gain immediate benefit from treatment. Sustained differences in reductions of total mortality and cardiovascular mortality reinforce the benefits and support the need for early and long term treatment. Trial registration Clinical trials NCT00122811.

Diagnosis and treatment of hypertensive disorders during pregnancy.

Pregnancy is a cardiovascular and metabolic challenge to the human female body. This review summarizes current knowledge on the regulation of blood pressure and plasma volume in normal and hypertensive pregnant women. During pregnancy, systemic vascular resistance and blood pressure decrease, whereas cardiac output and blood volume increase to safeguard an adequate circulation in the utero-placental arterial bed. Hypertension affects 10% of all pregnancies and is accompanied by an increase in foetal and maternal morbidity and mortality. Hypertension in pregnancy includes a wide spectrum of conditions, including pre-eclampsia and eclampsia, pre-eclampsia superimposed on chronic hypertension, chronic hypertension, and gestational hypertension. Endothelial dysfunction, oxidative stress and an exaggerated inflammatory response are features related to hypertensive disorders. Microangiopathic disorders can easily mimic hypertensive disorders during pregnancy. Although they have some symptoms in common, they require another type of management. To reduce the risk of maternal and foetal complications due to haemodynamic maladaptations, the current management includes rest at home or in the hospital, close monitoring of maternal and foetal signs and symptoms, early start of antihypertensive therapy, and timely delivery regarding maternal and foetal survival chances. Thresholds to initiate blood pressure lowering treatment during pregnancy are 160 mmHg systole or 110 mmHg diastole. Below these thresholds, treatment must be individualized because current evidence does not support aggressive medical interventions. Alpha-methyldopa and dihydropyridinic calcium channel blockers are among the recommended antihypertensives.

European Society of Hypertension practice guidelines for home blood pressure monitoring.

Self-monitoring of blood pressure by patients at home (home blood pressure monitoring (HBPM)) is being increasingly used in many countries and is well accepted by hypertensive patients. Current hypertension guidelines have endorsed the use of HBPM in clinical practice as a useful adjunct to conventional office measurements. Recently, a detailed consensus document on HBPM was published by the European Society of Hypertension Working Group on Blood Pressure Monitoring. However, in daily practice, briefer documents summarizing the essential recommendations are needed. It is also accepted that the successful implementation of clinical guidelines in routine patient care is dependent on their acceptance by involvement of practising physicians. The present document, which provides concise and updated guidelines on the use of HBPM for practising physicians, was therefore prepared by including the comments and feedback of general practitioners.

Night-day blood pressure ratio and dipping pattern as predictors of death and cardiovascular events in hypertension.

Our objective was to assess the prognostic significance of the night-time dipping pattern and the night-day blood pressure (BP) ratio for mortality and cardiovascular events in hypertensive patients without major cardiovascular disease at baseline. We performed a meta-analysis on individual data of 3468 patients from four prospective studies performed in Europe. Age of the subjects averaged 61+/-13 years; 45% were men and 61% were under antihypertensive treatment at the time of ambulatory BP monitoring. The night-day BP ratio and 24-h BP averaged, respectively, 0.907+/-0.085/0.866+/-0.095 and 138.1+/-16.4/82.3+/-11.0 mm Hg. Total follow-up time amounted to 23 164 patient-years. We used multivariable Cox regression analysis to assess the outcome of reverse dippers, non-dippers and extreme dippers vs dippers, and to assess the hazard ratios associated with 1 standard deviation higher night-day BP ratio. In comparison with dippers, and with adjustment for confounders and 24-h BP, the incidence of cardiovascular events was worse in reverse dippers (P

Arterial properties in relation to genetic variation in alpha-adducin and the renin-angiotensin system in a White population.

Earlier studies have demonstrated the interaction between ADD1 and ACE in relation to arterial properties. We investigated whether arterial characteristics might also be related to interactions of ADD1 with other renin-angiotensin system genes. Using a family-based sampling frame, we randomly recruited 1064 Flemish subjects (mean age, 43.6 years; 50.4% women). By means of a wall-tracking ultrasound system, we measured the properties of the carotid, femoral and brachial arteries. In multivariate-adjusted analyses, we assessed the multiple gene effects of ADD1 (Gly460Trp), AGT (C-532T and G-6A) and AT1R (A1166C). In ADD1 Trp allele carriers, but not in ADD1 GlyGly homozygotes (P-value for interaction < or =0.014), femoral cross-sectional compliance was significantly higher (0.74 vs 0.65 mm(2) kPa(-1); P=0.020) in carriers of the AT1R C allele than in AT1R AA homozygotes, with a similar trend for femoral distensibility (11.3 vs 10.2 x 10(-3) kPa(-1); P=0.055). These associations were independent of potential confounding factors, including age. Family-based analyses confirmed these results. Brachial diameter (4.35 vs 4.18 mm) and plasma renin activity (PRA) (0.23 vs 0.14 ng ml(-1) h(-1)) were increased (P< or =0.005) in AGT CG haplotype homozygotes compared with non-carriers, whereas the opposite was true for brachial distensibility (12.4 vs 14.4 x 10(-3) kPa(-1); P=0.011). There was no interaction between AGT and any other gene in relation to the measured phenotypes. ADD1 and AT1R interactively determine the elastic properties of the femoral artery. There is a single-gene effect of the AGT promoter haplotypes on brachial properties and PRA.

Genetic variation and environmental factors in biological and arterial ageing.

Arterial ageing is a complex continuously distributed phenotype, which comes about through the interaction between inherited susceptibility, life-style and environmental factors. We used an integrated approach combining methods from genetics, molecular biology and population sciences to study the role of genetic variation and environmental factors in biological ageing. The discussed work comprises four population based studies of which two had a prospective design and two integrated recently developed biomolecular markers of ageing with classical epidemiological tools. The striking variability in the age of the manifestation of cardiovascular diseases is not fully explained by conventional risk factors. Variation in biological age has been suggested. The initial telomere length of a person is mainly determined by genetic factors. In this regard, we noticed robust correlations in telomere length between fathers and daughters, between mothers and both sons and daughters, and among siblings. X-linked inheritance of telomere length is the most likely explanation for these findings. Telomere length shortens with each cell division, and exposition to harmful environmental factors results in shorter telomere length as we observed in smokers. Telomere length correlated with the distensibility of the carotid artery and oxidative stress and inflammation are major determinants of arterial and biological ageing. In this context, selenium a component of antioxidant enzymes such as glutathione peroxidase, correlated inversely with blood pressure in the population at large. Oxidative stress and inflammation are major determinants of arterial and biological ageing. If telomeres are indeed causally involved in the pathogenesis of arterial ageing, this might provide new avenues for future preventive and therapeutic strategies.

Arterial structure and function and environmental exposure to cadmium.

OBJECTIVES: Few studies have addressed the effect of cadmium toxicity on arterial properties. METHODS: We investigated the possible association of 24 h urinary cadmium excretion (an index of lifetime exposure) with measures of arterial function in a randomly selected population sample (n = 557) from two rural areas with low and high environmental exposure to cadmium. RESULTS: 24 h urinary cadmium excretion was significantly higher in the high compared with the low exposure group (p<0.001). Even though systolic (p = 0.42), diastolic (p = 0.14) and mean arterial pressure (p = 0.68) did not differ between the high and low exposure groups, aortic pulse wave velocity (p = 0.008), brachial pulse pressure (p = 0.026) and femoral pulse pressure (p = 0.008) were significantly lower in the high exposure group. Additionally, femoral distensibility (p<0.001) and compliance (p = 0.001) were significantly higher with high exposure. Across quartiles of 24 h urinary cadmium excretion (adjusted for sex and age), brachial (p for trend = 0.015) and femoral (p for trend = 0.018) pulse pressure significantly decreased and femoral distensibility (p for trend = 0.008) and compliance (p for trend = 0.007) significantly increased with higher cadmium excretion. After full adjustment, the partial regression coefficients confirmed these associations. Pulse wave velocity (beta = -0.79+/-0.27; p = 0.004) and carotid (beta = -4.20+/-1.51; p = 0.006), brachial (beta = -5.43+/-1.41; p = 0.001) and femoral (beta = -4.72+/-1.74; p = 0.007) pulse pressures correlated negatively, whereas femoral compliance (beta = 0.11+/-0.05; p = 0.016) and distensibility (beta = 1.70+/-0.70; p = 0.014) correlated positively with cadmium excretion. CONCLUSION: Increased cadmium body burden is associated with lower aortic pulse wave velocity, lower pulse pressure throughout the arterial system, and higher femoral distensibility.

[Hypertension as a source of cognitive regression, or dementia]. / Hypertensie als bron van cognitieve regressie, respectievelijk dementie.

Cognitive deterioration and its sequelae of vascular or Alzheimer's dementia is rapidly increasing all over the world. This is primarily caused by the worldwide increase of the ageing population. Additional causes may be sought in factors such as genetics and a habitually unhealthy life style. The significance of high blood pressure in the process leading to cognitive deterioration is relatively unknown. However, timely detection and treatment of hypertension seems to contribute to the preservation of cognition. Experience has shown that this applies in particular to dihydropyridine calcium antagonists. Medical care tends to make insufficient use of the existing possibilities for treating hypertension.