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1.  HIGH-NORMAL BLOOD PRESSURE IS ASSOCIATED WITH INCREASED RESTING SYMPATHETIC ACTIVITY BUT NORMAL RESPONSES TO STRESS TESTS 
Blood pressure  2013;22(3):183-187.
Objective
High-normal blood pressure (BP) increases the risk of cardiovascular (CV) disease. The mechanisms underlying this increased risk are not clear. Sympathetic activation appears to be a potential mechanism linking high-normal BP to CV disease. This study examined whether high-normal BP compared to optimal BP is linked to sympathoexcitation at rest and/or during laboratory stressors.
Methods
Heart rate (HR), BP and muscle sympathetic nerve activity (MSNA) were obtained at rest and during stress tests (sustained hand grip and mental stress) in 18 subjects (15 males and 3 females) with high-normal BP (systolic BP of 130 to 139 mm Hg, diastolic BP of 85 to 89 mm Hg, or both) and in 12 subjects (10 males and 2 females) with optimal BP (<120/80 mm Hg) matched for age (34±3 years in both groups) and body mass index (25±2 kg/m2 in both groups).
Results
Despite the higher resting BP levels, MSNA was higher in subjects with high-normal BP than in the optimal BP group (26±3 vs 18±2 bursts/min, P<0.05). During sustained hand grip, MSNA increased by 37±14% in high-normal BP group compared with an increase of 49±15% in optimal BP group (P=0.55). Changes during mental stress were 50±28% and 37±12%, respectively (P=0.73). There were no significant differences in SBP responses to handgrip and mental stress between the high-normal and optimal BP groups. Baseline HR and chronotropic responses to stress tests were comparable between the two groups.
Conclusion
In comparison to optimal BP, high-normal BP is associated with increased resting MSNA, but normal neural and circulatory responses to stress tests. These findings suggest that tonic activation of the sympathetic nervous system may precede overt arterial hypertensionand contribute to an excess risk of CV disease in subjects with high-normal BP.
doi:10.3109/08037051.2012.759689
PMCID: PMC3951917  PMID: 23356493
heart rate; high-normal blood pressure; hypertension; laboratory stressors; sympathetic nerve activity
2.  Blood pressure variability and white matter hyperintensities in older adults with cardiovascular disease 
Blood pressure  2005;14(6):353-358.
The present study examined the relationship between multiple blood pressure (BP) indices and white matter hyperintensities (WMH) in a sample of 39 older adults with cardiovascular disease (CVD). Resting BP was measured using an automated monitor every 10 min for 2 h. WMH were quantified on FLAIR images and separate indices were generated for neocortical, periventricular and subcortical brain regions. Correlation analyses revealed systolic BP variability was related to neocortical and total WMH. A function of systolic BP variability and average diastolic pressure showed the strongest relationships, including significant correlation to neocortical, subcortical and total WMH. No BP index was related to WMH in periventricular regions. Exploratory analyses showed only the function of systolic BP variability and average diastolic pressure predicted total WMH, whereas as age, CVD conditions and psychosocial factors did not. These findings demonstrate BP variability is an important contributor to WMH in older adults with CVD and suggests it may have differential relationships to WMH in different brain regions. Additional studies are needed to examine the role of autoregulatory systems in the development of WMH, particularly those using beat-to-beat measures of BP.
doi:10.1080/08037050500364117
PMCID: PMC3215278  PMID: 16403689
Blood pressure; cardiovascular disease; cerebrovascular disease
3.  Aerobic Exercise Attenuates an Exaggerated Exercise Blood Pressure Response in Normotensive Young Adult African-American Men 
Blood pressure  2002;11(4):229-234.
An exaggerated exercise blood pressure response (EEBPR) may be associated with an increased risk of hypertension. We hypothesized that aerobic exercise training can decrease EEBPR and the risk for hypertension by decreasing arterial resistance. We studied the effects of aerobic training on the submaximal exercise blood pressure (BP) of eight normotensive young adult African-American men with an EEBPR. Subjects were trained on a stationary bicycle at an intensity of 70% peak oxygen uptake (VO2peak) for 30 min, three times per week, for 8 weeks. BP, heart rate, cardiac output (CO), stroke volume (SV) and total peripheral vascular resistance (TPR) were measured at rest and during submaximal exercise at a work intensity of 50% VO2peak. Significance of the training effects were evaluated by comparing the pre- and post-training measures (t-test, p < 0.05). A 15% post-training increase in VO2peak (34.6 ± 1.4 to 40 ± 1.4 ml/kg/min) and a 9.5 ml post-training increase in mean resting stroke volume were found. A 16.2 mmHg decrement in mean systolic BP, an 11.5 mmHg decrement in mean diastolic BP, a 120 dyne/s/cm5 decrement in TPR and a 1.2 l/min increase in CO were detected during the post-training submaximal exercise tests. These results suggest that reductions in TPR may attenuate the EEBPR of normotensive African-American males following an 8-week training regimen of stationary bicycling at 70% VO2peak. Aerobic exercise training may, therefore, reduce the risk of hypertension in normotensive African-American males by the mechanism of a reduction in TPR. Because of the limited number of subjects, the results of this study should be interpreted cautiously pending confirmation by a larger controlled trial.
PMCID: PMC3166529  PMID: 12361191
blood pressure; exercise training; African-Americans
4.  Efficacy and safety profiles of manidipine compared with amlodipine: A meta-analysis of head-to-head trials 
Blood Pressure  2010;20(1):54-59.
The aim of this meta-analysis was to compare the efficacy and safety profile of manidipine 20 mg with that of amlodipine 10 mg. A systematic research of quantitative data produced or published between 1995 and 2009 was performed. Head-to-head randomized controlled trials (RCTs) of 12 months minimum duration reporting comparative efficacy (changes in systolic and diastolic blood pressure) and safety (total adverse events and ankle oedema), were included. Four high-quality RCTs, accounting for 838 patients (436 received manidipine and 402 received amlodipine) were included. The effi cacy of manidipine and amlodipine was statistically equivalent: effect size for DBP =−0.08 (p = 0.22) and SBP =−0.01 (p =0.83).The global safety of manidipine was signifi cantly better than amlodipine: the relative risk (RR) for adverse event was 0.69 (0.56 – 0.85), and particularly for ankle oedema RR was 0.35 (0.22 – 0.54). Publication bias was not signifi cant and the robustness of the analyses was good. These data suggest a better efficacy/safety ratio of manidipine over amlodipine.
doi:10.3109/08037051.2010.518670
PMCID: PMC3026391  PMID: 20945994
Ankle oedema; calcium antagonists; hypertension; meta-analysis
5.  Independent and combined influence of AGTR1 variants and aerobic exercise on oxidative stress in hypertensives 
Blood pressure  2009;18(4):204-212.
Angiotensin II (AngII), via the AngII type 1 receptor (AT1R), contributes to oxidative stress. Aerobic exercise training (AEXT) reduces the risk of cardiovascular (CV) disease, presumably by reducing the grade of oxidative stress. We investigated the independent and combined influence of the AGTR1 A1166C and −825 T/A polymorphisms on oxidative stress and plasma AngII responses to AEXT in pre- and stage 1 hypertensives. Urinary 8-iso-PGF2α significantly increased with AEXT (p=0.002); however, there were no significant changes in superoxide dismutase activity or AngII levels. There was a significant difference in the change in AngII levels with AEXT between A1166C genotype groups (p=0.04) resulting in a significant interactive effect of the A1166C polymorphism and AEXT on the change in AngII (p<0.05). Only the TT genotype group of the −825 T/A polymorphism had a significant reduction in plasma AngII (p=0.02). Risk allele analysis revealed a significant reduction in plasma AngII (p=0.04) and a significant increase in urinary 8-iso-PGF2α (p=0.01) with AEXT in individuals with two risk alleles only. Our findings suggest that variation in the AGTR1 gene is associated with differential changes in plasma AngII but not oxidative stress.
doi:10.1080/08037050903118706
PMCID: PMC2922402  PMID: 19593696
AGTR1; angiotensin II; exercise; isoprostanes; oxidative stress
6.  The relationship of oxidative stress and cholesterol with dipping status before and after aerobic exercise training 
Blood pressure  2009;18(4):171-179.
Objective
The purpose of this study was to examine the effects of aerobic exercise training (AEXT) on dipping status in pre-hypertensive and stage-1 hypertensive individuals. A secondary purpose was to evaluate whether AEXT alters oxidative stress and endothelial biomarkers correlated to dipping status.
Methods
Twenty-three subjects underwent 24-h ambulatory blood pressure monitoring at baseline and after 6 months of AEXT. AEXT consisted of training at 70% VO2max 3 days/week for 6 months. Total cholesterol, high-density lipoprotein-cholesterol, low-density lipoprotein (LDL)-cholesterol, oxidized LDL (ox-LDL), triglycerides, urinary and plasma nitric oxide end-products, superoxide dismutase and 8-iso-PGF2α were measured before and after AEXT. Statistically, ANOVA and linear regression were used.
Results
Before and after AEXT, there were no significant differences between dippers and non-dippers in any of the biomarkers except for total cholesterol following AEXT. In a sub-analysis following AEXT, 14 subjects retained their original dipping status, five subjects changed from dippers to non-dippers and four subjects changed from non-dippers to dippers. Significant differences existed between these groups in changes in total and LDL-cholesterol, ox-LDL, 8-iso-PGF2α and % Dip.
Conclusions
Changes in cholesterol levels but not oxidative stress or endothelial biomarkers were related to changes in BP variables following AEXT in dippers and non-dippers.
doi:10.1080/08037050903047160
PMCID: PMC2922419  PMID: 19544106
Aerobic exercise; ambulatory blood pressure monitoring; dipper; non-dipper; hypertension; oxidative stress
7.  Long-acting dihydropyridine calcium-channel blockers and sympathetic nervous system activity in hypertension: A literature review comparing amlodipine and nifedipine GITS 
Blood Pressure  2012;21(Suppl 1):3-10.
Calcium-channel blockers (CCBs) constitute a diverse group of compounds but are often referred to as a single homogeneous class of drug and the clinical responses indiscriminately summarized. Even within the dihydropyridine subgroup, there are significant differences in formulations, pharmacokinetics, durations of action and their effects on blood pressure, heart rate, end organs and the sympathetic nervous system. Amlodipine and nifedipine in the gastrointestinal therapeutic system (GITS) formulation are the most studied of the once-daily CCBs. Amlodipine has an inherently long pharma-cokinetic half-life, whereas, in contrast, nifedipine has an inherently short half-life but in the GITS formulation the sophisticated delivery system allows for once-daily dosing. This article is derived from a systematic review of the published literature in hypertensive patients. The following search terms in three main databases (MEDLINE, Embase, Science Citation Index) from 1990 to 2011 were utilized: amlodipine, nifedipine, sympathetic nervous system, sympathetic response, sympathetic nerve activity, noradrenaline, norepinephrine and heart rate. More than 1500 articles were then screened to derive the relevant analysis. As markers of sympathetic nervous system activation, studies of plasma norepinephrine concentrations, power spectral analysis, muscle sympathetic nerve activity and norepinephrine spillover were reviewed. Overall, each drug lowered blood pressure in hypertensive patients in association with only small changes in heart rate (i.e. < 1 beat/min). Plasma norepinephrine concentrations, as the most widely reported marker of sympathetic nervous system activity, showed greater increases in patients treated with amlodipine than with nifedipine GITS. The evidence indicates that both these once-daily dihydropyridine CCBs lower blood pressure effectively with minimal effects on heart rate. There are small differences between the drugs in the extent to which each activates the sympathetic nervous system with an overall non-significant trend in favour of nifedipine GITS.
doi:10.3109/08037051.2012.690615
PMCID: PMC3469239  PMID: 22762301
Amlodipine; blood pressure; catecholamines; extended release; GITS; nifedipine; norepinephrine; sympathetic activation; sympathetic nerve activity
8.  Heart rate variability on antihypertensive drugs in black patients living in sub-Saharan Africa 
Blood Pressure  2013;23(3):174-180.
Background
Compared with Caucasians, African Americans have lower heart rate variability (HRV) in the high-frequency domain, but there are no studies in blacks born and living in Africa.
Methods
In the Newer versus Older Antihypertensive agents in African Hypertensive patients trial (NCT01030458), patients (30–69 years) with uncomplicated hypertension (140–179/90–109 mmHg) were randomized to single-pill combinations of bisoprolol/hydrochlorothiazide (R) or amlodipine/valsartan (E). 72 R and 84 E patients underwent 5-min ECG recordings at randomization and 8, 16 and 24 weeks. HRV was determined by fast Fourier transform and autoregressive modelling.
Results
Heart rate decreased by 9.5 beats/min in R patients with no change in E patients (− 2.2 beats/min). R patients had reduced total (− 0.13 ms²; p = 0.0038) and low-frequency power (− 3.6 nu; p = 0.057), higher high-frequency (+ 3.3 nu; p = 0.050) and a reduced low- to high-frequency ratio (− 0.08; p = 0.040). With adjustment for heart rate, these differences disappeared, except for the reduced low-frequency power in the R group (− 4.67 nu; p = 0.02). Analyses confined to 39 R and 47 E patients with HRV measurements at all visits or based on autoregressive modelling were confirmatory.
Conclusion
In native black African patients, antihypertensive drugs modulate HRV, an index of autonomous nervous tone. However, these effects were mediated by changes in heart rate except for low-frequency variability, which was reduced on beta blockade independent of heart rate.
doi:10.3109/08037051.2013.836810
PMCID: PMC4059227  PMID: 24066715
Antihypertensive drugs; blacks; heart rate variability; randomized clinical trial; sub-Saharan Africa
9.  Rationale and design of the Investigator-Steered Project on intravascular Renal Denervation for Management of Drug-Resistant Hypertension (INSPiRED) trial 
Blood Pressure  2014;23(3):138-146.
The SYMPLICITY studies showed that renal denervation (RDN) is feasible as novel treatment for resistant hypertension. However, RDN is a costly and invasive procedure, the long-term efficacy and safety of which has not yet been proven. Therefore, we designed the INSPiRED trial to compare the blood pressure lowering efficacy and safety of RDN vs usual medical therapy. INSPiRED is a randomized controlled trial enrolling 240 treatment-resistant hypertensive patients at 16 expert hypertension centres in Belgium. Eligible patients, aged 20–69 years old, have a 24-h ambulatory blood pressure of 130 mmHg systolic or 80 mmHg diastolic or more, while taking at least three antihypertensive drugs. They are randomized to RDN (EnligHTNTM, SJM system) plus usual care (intervention group) or usual care alone (control group) in a ratio of 1:1. The primary endpoints for efficacy and safety, measured after 6 months, are the baseline-adjusted between-group differences in 24h systolic blood pressure and in glomerular filtration rate as estimated by the Chronic Kidney Disease Epidemiology Collaboration equation. Follow-up will continue up to 36 months after randomization. INSPiRED is powered to demonstrate a 10-mmHg difference in systolic blood pressure between randomized groups with a two-sided p-value of 0.01 and 90% power. It will generate long-term efficacy and safety data, identify the subset of treatment-resistant hypertensive patients responsive to RDN, provide information on cost-effectiveness, and by doing so INSPiRED will inform guideline committees and health policy makers. Trial registration: ClinicalTrials.gov Identifier: NCT 01505010.
doi:10.3109/08037051.2014.899297
PMCID: PMC4059255  PMID: 24742341
Ambulatory blood pressure; randomized controlled trial; renal denervation; resistant hypertension
10.  Developing an interactive mobile phone self-report system for self-management of hypertension. Part 2: Content validity and usability 
Blood Pressure  2014;23(5):296-306.
Self-management support tools using technology may improve adherence to hypertension treatment. There is a need for user-friendly tools facilitating patients’ understanding of the interconnections between blood pressure, wellbeing and lifestyle. This study aimed to examine comprehension, comprehensiveness and relevance of items, and further to evaluate the usability and reliability of an interactive hypertension-specific mobile phone self-report system. Areas important in supporting self-management and candidate items were derived from five focus group interviews with patients and healthcare professionals (n = 27), supplemented by a literature review. Items and response formats were drafted to meet specifications for mobile phone administration and were integrated into a mobile phone data-capture system. Content validity and usability were assessed iteratively in four rounds of cognitive interviews with patients (n = 21) and healthcare professionals (n = 4). Reliability was examined using a test–retest. Focus group analyses yielded six areas covered by 16 items. The cognitive interviews showed satisfactory item comprehension, relevance and coverage; however, one item was added. The mobile phone self-report system was reliable and perceived easy to use. The mobile phone self-report system appears efficiently to capture information relevant in patients’ self-management of hypertension. Future studies need to evaluate the effectiveness of this tool in improving self-management of hypertension in clinical practice.
doi:10.3109/08037051.2014.901009
PMCID: PMC4196575  PMID: 24786778
Cellular phone; content validity; hypertension; medication adherence; self-care; usability
11.  Developing an interactive mobile phone self-report system for self-management of hypertension. Part 1: Patient and professional perspectives 
Blood Pressure  2014;23(5):288-295.
Low adherence remains a struggle in hypertension management, despite improvement efforts. Presuming that increased patient participation is a possible approach, we collaborated with patients and healthcare professionals to design a self-report system to support self-management. The study aimed to explore and describe relevant aspects of hypertension and hypertension treatment, for use in the development of an interactive mobile phone self-report system. It further aimed to suggest which clinical measures, lifestyle measures, symptoms and side-effects of treatment would be meaningful to include in such a system. Five focus group interviews were performed with 15 patients and 12 healthcare professionals, and data was analysed using thematic analysis. Patients suggested trust, a good relationship with caregivers, and well-being as important aspects of hypertension self-management. Furthermore, they regarded blood pressure, dizziness, stress, headache and tiredness as important outcomes to include. Patients sought to understand interconnections between symptoms and variations in blood pressure, whilst healthcare professionals doubted patients’ ability to do so. Healthcare professionals emphasized accessibility, clear and consistent counselling, complication prevention and educational efforts. The study presents aspects of importance for follow-up to understand the interplay between blood pressure and daily life experiences for patients with hypertension.
doi:10.3109/08037051.2014.883203
PMCID: PMC4196574  PMID: 24564289
Blood pressure; focus group; hypertension; medication adherence; person-centred care; self-care

Results 1-11 (11)