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Central augmentation pressure (AP) and index (AIx) predict cardiovascular events and mortality, but underlying physiological mechanisms remain disputed. While traditionally believed to relate to wave reflections arising from proximal arterial impedance (and stiffness) mismatching, recent evidence suggests aortic reservoir function may be a more dominant contributor to AP and AIx. Our aim was therefore to determine relationships among aortic-brachial stiffness mismatching, AP, AIx, aortic reservoir function, and end-organ disease. Aortic (aPWV) and brachial (bPWV) pulse wave velocity were measured in 359 individuals (aged 61 ± 9, 49% male). Central AP, AIx, and aortic reservoir indexes were derived from radial tonometry. Participants were stratified by positive (bPWV > aPWV), negligible (bPWV ≈ aPWV), or negative stiffness mismatch (bPWV < aPWV). Left-ventricular mass index (LVMI) was measured by two-dimensional-echocardiography. Central AP and AIx were higher with negative stiffness mismatch vs. negligible or positive stiffness mismatch (11 ± 6 vs. 10 ± 6 vs. 8 ± 6 mmHg, P < 0.001 and 24 ± 10 vs. 24 ± 11 vs. 21 ± 13%, P = 0.042). Stiffness mismatch (bPWV-aPWV) was negatively associated with AP (r = -0.18, P = 0.001) but not AIx (r = -0.06, P = 0.27). Aortic reservoir pressure strongly correlated to AP (r = 0.81, P < 0.001) and AIx (r = 0.62, P < 0.001) independent of age, sex, heart rate, mean arterial pressure, and height (standardized β = 0.61 and 0.12, P ≤ 0.001). Aortic reservoir pressure independently predicted abnormal LVMI (β = 0.13, P = 0.024). Positive aortic-brachial stiffness mismatch does not result in higher AP or AIx. Aortic reservoir function, rather than discrete wave reflection from proximal arterial stiffness mismatching, provides a better model description of AP and AIx and also has clinical relevance as evidenced by an independent association of aortic reservoir pressure with LVMI., (Copyright © 2015 the American Physiological Society.)

Objectives: The reference standard for noninvasive estimation of central blood pressure (BP) is radial tonometry calibrated using brachial SBP and DBP. Brachial-to-radial-SBP amplification (B-R-SBPAmp) may introduce error into central BP estimation, but the magnitude of such amplification is uncertain. This study aimed to determine the magnitude and effect of ageing on B-R-SBPAmp; the effect of B-R-SBPAmp on radial tonometry estimated central SBP; and correlates of B-R-SBPAmp., Methods: Forty young (28 ± 5 years) and 20 older (60 ± 8 years) healthy participants underwent brachial and radial artery ultrasound to identify SBP from the first Doppler flow inflection during BP cuff deflation (first Korotkoff sound). Impedance cardiography, ultrasound, tonometry and anthropometric data were collected to explore B-R-SBPAmp correlates., Results: Radial SBP was significantly higher than brachial SBP in younger (118 ± 12 versus 110 ± 10  mmHg; P < 0.001) and older (135 ± 12 versus 121 ± 11  mmHg; P < 0.001) participants. The magnitude of B-R-SBPAmp (radial minus brachial SBP) was higher in older than younger participants (14 ± 7 versus 8 ± 7  mmHg; P = 0.002), independent of sex and heart rate. Estimated central SBP was higher in both age groups when radial waveforms were recalibrated using radial (versus brachial) SBP (P < 0.001). The central SBP change relative to B-R-SBPAmp was associated with augmentation index (r = 0.739, P < 0.001), independent of age, sex and heart rate. Age, male sex and high-density lipoprotein each positively related to B-R-SBPAmp in multiple regression analysis (P < 0.05)., Conclusion: Major B-R-SBPAmp occurs in healthy people and is higher with increasing age. Furthermore, B-R-SBPAmp contributes to underestimation of radial tonometry derived central SBP.

Measurement of blood pressure (BP) by a doctor in the clinic has limitations that may result in an unrepresentative measure of underlying BP which can impact on the appropriate assessment and management of high BP. Home BP monitoring is the self-measurement of BP in the home setting (usually in the morning and evening) over a defined period (e.g. 7 days) under the direction of a healthcare provider. When it may not be feasible to measure 24-h ambulatory BP, home BP may be offered as a method to diagnose and manage patients with high BP. Home BP has good reproducibility, is well tolerated, is relatively inexpensive and is superior to clinic BP for prognosis of cardiovascular morbidity and mortality. Home BP can be used in combination with clinic BP to identify 'white coat' and 'masked' hypertension. An average home BP of at least 135/85 mmHg is an appropriate threshold for the diagnosis of hypertension. Home BP may also offer the advantage of empowering patients with their BP management, with benefits including increased adherence to therapy and lower achieved BP levels. It is recommended that, when feasible, home BP should be considered for routine use in the clinical management of hypertension.

Objectives: Reduced functional capacity is associated with poor prognosis. In patients with chronic kidney disease the factors that contribute to low cardiorespiratory fitness are unclear. The objective of this study was to evaluate the cardiorespiratory and cardiovascular response to exercise in chronic kidney disease patients, and secondly investigate the relationships between cardiorespiratory fitness and cardiovascular burden., Design: Cross-sectional analysis., Methods: Baseline demographic, anthropometric and biochemical data were examined in 136 patients with moderate chronic kidney disease (age 59.7±9.6yrs, eGFR 40±9ml/min/1.73m(2), 55% male, 39% with a history of cardiovascular disease, 38% diabetic and 17% current smokers). Cardiorespiratory fitness was measured as peak VO2, left ventricular morphology and function using echocardiography, central arterial stiffness by aortic pulse wave velocity and left ventricular afterload using augmentation index. Physical activity levels were assessed using the Active Australia questionnaire., Results: Peak VO2 (22.9±6.5ml/kg/min) and peak heart rate (148±22bpm) were 17% and 12% lower than the age-predicted values, respectively. The low fit group were significantly older, and were more likely to have type II diabetes, cardiovascular disease, a higher BMI and be less active than the high fit group (P<0.05). The independent predictors of peak VO2 were age, type II diabetes, hemoglobin level, physical activity, aortic pulse wave velocity, augmentation index, and global longitudinal strain., Conclusions: In patients with chronic kidney disease, the peak VO2 and heart rate response is markedly impaired. Reduced cardiorespiratory fitness is independently associated with increased aortic stiffness, increased left ventricle afterload, poor left ventricle function and higher burden of cardiovascular risk., (Copyright © 2014 Sports Medicine Australia. Published by Elsevier Ltd. All rights reserved.)

Blood pressure (BP) is a mandatory safety measure during graded intensity clinical exercise stress testing. While it is generally accepted that exercise hypotension is a poor prognostic sign linked to severe cardiac dysfunction, recent meta-analysis data also implicate excessive rises in submaximal exercise BP with adverse cardiovascular events and mortality, irrespective of resting BP. Although more data is needed to derive submaximal normative BP thresholds, the association of a hypertensive response to exercise with increased cardiovascular risk may be due to underlying hypertension that has gone unnoticed by conventional resting BP screening methods. Delayed BP decline during recovery is also associated with adverse clinical outcomes. Thus, above and beyond being used as a routine safety measure during stress testing, exercise (and recovery) BP may be useful for identifying high-risk individuals and also as an aid to optimise care through appropriate follow-up after exercise stress testing. Accordingly, careful attention should be paid to correct measurement of exercise stress test BP (before, during and after exercise) using a standardised approach with trained operators and validated BP monitoring equipment (manual or automated). Recommendations for exercise BP measurement based on consolidated international guidelines and expert consensus are presented in this review.

Exercise-induced albuminuria is common in patients with type 2 diabetes mellitus (T2DM) in response to maximal exercise, but the response to light-moderate exercise is unclear. Patients with T2DM have abnormal central hemodynamics and greater propensity for exercise hypertension. This study sought to determine the relationship between light-moderate exercise central hemodynamics (including aortic reservoir and excess pressure) and exercise-induced albuminuria. Thirty-nine T2DM (62 ± 9 yr; 49% male) and 39 nondiabetic controls (53 ± 9 yr; 51% male) were examined at rest and during 20 min of light-moderate cycle exercise (30 W; 50 revolutions/min). Albuminuria was assessed by the albumin-creatinine ratio (ACR) at rest and 30 min postexercise. Hemodynamics recorded included brachial and central blood pressure (BP), aortic stiffness, augmented pressure (AP), aortic reservoir pressure, and excess pressure integral (Pexcess). There was no difference in ACR between groups before exercise (P > 0.05). Exercise induced a significant rise in ACR in T2DM but not controls (1.73 ± 1.43 vs. 0.53 ± 1.0 mg/mol, P = 0.002). All central hemodynamic variables were significantly higher during exercise in T2DM (i.e., Pexcess, systolic BP and AP; P < 0.01 all). In T2DM (but not controls), exercise Pexcess was associated with postexercise ACR (r = 0.51, P = 0.002), and this relationship was independent of age, sex, body mass index, heart rate, aortic stiffness, antihypertensive medication, and ambulatory daytime systolic BP (β = 0.003, P = 0.003). Light-moderate exercise induced a significant rise in ACR in T2DM, and this was independently associated with Pexcess, a potential marker of vascular dysfunction. These novel findings suggest that Pexcess could be important for appropriate renal function in T2DM., (Copyright © 2015 the American Physiological Society.)

Although physical activity (PA) improves arterial distensibility, it is unclear which type of activity is most beneficial. We aimed to examine the association of different types of PA with carotid distensibility (CD) and the mechanisms involved. Data included 4503 Australians and Finns aged 26-45 years. Physical activity was measured by pedometers and was self-reported. CD was measured using ultrasound. Other measurements included resting heart rate (RHR), cardiorespiratory fitness (CRF), blood pressure, biomarkers and anthropometry. Steps/day were correlated with RHR (Australian men r = -0.10, women r = - 0.14; Finnish men r = -0.15, women r = -0.11; P<0.01), CRF and biochemical markers, but not with CD. Self-reported vigorous leisure-time activity was more strongly correlated with RHR (Australian men r = -0.23, women r = -0.19; Finnish men r = -0.20, women r = -0.13; P < 0.001) and CRF, and was correlated with CD (Australian men r = 0.07; Finnish men r = 0.07, women r = 0.08; P < 0.05). This relationship of vigorous leisure-time activity with CD was mediated by RHR independently of potential confounders. In summary, vigorous leisure-time PA but not total or less intensive PA was associated with arterial distensibility in young to mid-aged adults. Promotion of vigorous PA is therefore recommended among this population. RHR was a key intermediary factor explaining the relationship between vigorous PA and arterial distensibility.

Purpose: A hypertensive response to moderate intensity exercise (HRE) is associated with increased cardiovascular risk. The mechanisms of an HRE are unclear, although previous studies suggest this may be due to haemostatic and/or haemodynamic factors. We investigated the relationships between an HRE with haemostatic and hemodynamic indices., Methods: Sixty-four participants (57 ± 10 years, 71 % male) with indication for exercise stress testing underwent cardiovascular assessment at rest and during moderate intensity exercise, from which 20 participants developed an HRE (defined as moderate exercise systolic BP ≥ 170 mmHg/men and ≥ 160 mmHg/women). Rest, exercise and post-exercise blood samples were analysed for haemostatic markers, including von Willebrand factor (vWf), and haemodynamic measures of brachial and central blood pressure (BP), aortic stiffness and systemic vascular resistance index (SVRi)., Results: HRE participants had higher rest vWf compared with normotensive response to exercise (NRE) participants (1,927 mU/mL, 95 % CI 1,240-2,615, vs. 1,129 mU/mL, 95 % CI 871-1,386; p = 0.016). vWf levels significantly decreased from rest to post-exercise in HRE participants (p = 0.005), whereas vWf levels significantly increased from rest to exercise in NRE participants (p = 0.030). HRE participants also had increased triglycerides, rest BP, aortic stiffness and exercise SVRi (p < 0.05 for all). Rest vWf predicted exercise brachial systolic BP (β = 0.220, p = 0.043; adjusted R (2) = 0.451, p < 0.001) independent of age, sex, body mass index, triglycerides, rest brachial systolic BP and aortic stiffness., Conclusions: Increased rest blood levels of vWf are independently associated with moderate intensity exercise systolic BP. These findings implicate abnormalities in haemostasis as a possible factor contributing to HRE at moderate intensity.

Background: Central blood pressure (BP) can be estimated noninvasively by analyzing brachial artery waveforms. In this study, our aim was to assess the validity of a brachial cuff-based (suprasystolic) technique for estimating central BP (CBPestimated) by comparison with invasive aortic BP (CBPinvasive)., Methods: Eighty-four simultaneous CBPestimated (Pulsecor R7.0) and CBPinvasive measures were recorded in 47 patients (aged 63±10 years, 62% male) undergoing coronary angiography. Measures were captured at baseline and acutely following intravenous glyceryl trinitrate (GTN; 100-200 μg). Mean CBPinvasive systolic BP (SBP) and diastolic BP (DBP) were compared with CBPestimated SBP and DBP calibrated with brachial SBP and DBP recorded from the Pulsecor device. To test validity of the central BP algorithm, measures of CBPestimated SBP were also compared with CBPinvasive SBP following recalibration with invasive mean arterial pressure (MAP) and DBP., Results: At baseline, mean difference ± standard deviation between CBPestimated SBP and CBPinvasive SBP was -7±9mm Hg (intraclass correlation coefficient (ICC) = 0.86; P < 0.001) with similar underestimation post-GTN (-6±9mm Hg; ICC = 0.90; P < 0.001). Recalibration of CBPestimated SBP with invasive MAP and DBP resulted in closer mean difference to CBPinvasive SBP (-2±7mm Hg; ICC = 0.95; P < 0.001) at baseline but not post-GTN (-6±7mm Hg; ICC = 0.95; P < 0.001)., Conclusions: The Pulsecor algorithm to derive central BP has acceptable validity when calibrated with invasive pressures. However, accuracy is compromised when noninvasive brachial cuff BP calibration is used., (© American Journal of Hypertension, Ltd 2014. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Evidence for the benefits of regular exercise is irrefutable and increasing physical activity levels should be a major goal at all levels of health care. People with hypertension are less physically active than those without hypertension and there is strong evidence supporting the blood pressure-lowering ability of regular exercise, especially in hypertensive individuals. This narrative review discusses evidence relating to exercise and cardiovascular (CV) risk in people with hypertension. Comparisons between aerobic, dynamic resistance, and static resistance exercise have been made along with the merit of different exercise volumes. High-intensity interval training and isometric resistance training appear to have strong CV protective effects, but with limited data in hypertensive people, more work is needed in this area. Screening recommendations, exercise prescriptions, and special considerations are provided as a guide to decrease CV risk among hypertensive people who exercise or wish to begin. It is recommended that hypertensive individuals should aim to perform moderate intensity aerobic exercise activity for at least 30 minutes on most (preferably all) days of the week in addition to resistance exercises on 2-3 days/week. Professionals with expertise in exercise prescription may provide additional benefit to patients with high CV risk or in whom more intense exercise training is planned. Despite lay and media perceptions, CV events associated with exercise are rare and the benefits of regular exercise far outweigh the risks. In summary, current evidence supports the assertion of exercise being a cornerstone therapy in reducing CV risk and in the prevention, treatment, and control of hypertension., (© American Journal of Hypertension, Ltd 2014. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Liquid chromatography mass spectrometry has become one of the analytical platforms of choice for metabolomics studies. However, LC-MS metabolomics data can suffer from the effects of various systematic biases. These include batch effects, day-to-day variations in instrument performance, signal intensity loss due to time-dependent effects of the LC column performance, accumulation of contaminants in the MS ion source and MS sensitivity among others. In this study we aimed to test a singular value decomposition-based method, called EigenMS, for normalization of metabolomics data. We analyzed a clinical human dataset where LC-MS serum metabolomics data and physiological measurements were collected from thirty nine healthy subjects and forty with type 2 diabetes and applied EigenMS to detect and correct for any systematic bias. EigenMS works in several stages. First, EigenMS preserves the treatment group differences in the metabolomics data by estimating treatment effects with an ANOVA model (multiple fixed effects can be estimated). Singular value decomposition of the residuals matrix is then used to determine bias trends in the data. The number of bias trends is then estimated via a permutation test and the effects of the bias trends are eliminated. EigenMS removed bias of unknown complexity from the LC-MS metabolomics data, allowing for increased sensitivity in differential analysis. Moreover, normalized samples better correlated with both other normalized samples and corresponding physiological data, such as blood glucose level, glycated haemoglobin, exercise central augmentation pressure normalized to heart rate of 75, and total cholesterol. We were able to report 2578 discriminatory metabolite peaks in the normalized data (p<0.05) as compared to only 1840 metabolite signals in the raw data. Our results support the use of singular value decomposition-based normalization for metabolomics data.

High-altitude hypoxia causes major cardiovascular changes, which may result in raised resting brachial blood pressure (BP). However, the effect of high-altitude hypoxia on more sensitive measures of BP control (such as 24 h ambulatory BP and resting central BP) is largely unknown. This study aimed to assess this and compare high-altitude responses to resting brachial BP, as well as determine the haemodynamic correlates of acute mountain sickness (AMS) during a progressive trekking ascent to high-altitude. Measures of oxygen saturation (pulse oximetry), 24 h ambulatory BP, resting brachial and central BP (Pulsecor) were recorded in 10 adults (aged 27±4, 30% male) during a 9-day trek to Mount Everest base camp, Nepal. Data were recorded at sea level (stage 1; <450 m above sea level (ASL)) and at progressive ascension to 3440 m ASL (stage 2), 4350 m ASL (stage 3) and 5164 m ASL (stage 4). The Lake Louise score (LLS) was used to quantify AMS symptoms. Total LLS increased stepwise from sea level to stage 4 (0.3±0.7 vs 4.4±2.0, P=0.012), whereas oxygen saturation decreased to 77±9% (P=0.001). The highest recordings of 24 h ambulatory, daytime, night time, brachial and central systolic BP and diastolic BP were achieved at stage 3, which were significantly greater than at sea level (P<0.005 for all). Twenty-four-hour ambulatory heart rate (HR) and night HR correlated with oxygen saturation (r=-0.741 and -0.608, both P<0.001) and total LLS (r=0.648 and r=0.493, both P<0.001). We conclude that 24 h ambulatory BP, central BP and HR are elevated during high-altitude hypoxia, but AMS symptoms are only related to tachycardia.

Objective: The independent prognostic significance of abnormally low systolic blood pressure (SBP) during exercise stress testing (LowExBP) across different clinical and exercise conditions is unknown. We sought by systematic review and meta-analysis to determine the association between cardiovascular/all-cause outcomes and LowExBP across different patient clinical presentations, exercise modes, exercise intensities and categories of LowExBP., Methods: Seven online databases were searched for longitudinal studies reporting the association of LowExBP with risk of fatal and non-fatal cardiovascular events and/or all-cause mortality. LowExBP was defined as either: SBP drop below baseline; failure to increase >10 mmHg from baseline or; lowest SBP quantile among reporting studies., Results: After review of 13,257 studies, 19 that adjusted for resting SBP were included in the meta-analysis, with a total of 45,895 participants (average follow-up, 4.4 ± 3.0 years). For the whole population, LowExBP was associated with increased risk for fatal and non-fatal cardiovascular events and all-cause mortality (hazard ratio [HR]: 2.01, 95% confidence interval [CI]: 1.59-2.53, p < 0.001). In continuous analyses, a 10 mmHg decrease in exercise SBP was associated with higher risk (n = 9 HR: 1.13, 95% CI: 1.06-1.20, p < 0.001). LowExBP was associated with increased risk regardless of clinical presentation (coronary artery disease, heart failure, hypertrophic cardiomyopathy or peripheral artery disease), exercise mode (treadmill or bike), exercise intensity (moderate or maximal), or LowExBP category (all p < 0.05). However, bias toward positive results was apparent (Eggers test p < 0.001 and p = 0.009)., Conclusion: Our data show that irrespective of clinical or exercise conditions, LowExBP independently predicts fatal and non-fatal cardiovascular events and all-cause mortality., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background: Central hemodynamics help to maintain appropriate cerebral and other end-organ perfusion, and may be altered with ageing and type 2 diabetes mellitus (T2DM). We aimed to determine the associations between central hemodynamics and brain structure at rest and during exercise in people with and without T2DM., Methods: In a sample of people with T2DM and healthy controls, resting and exercise measures of aortic reservoir characteristics (including excess pressure integral [P(excess)]) and other central hemodynamics (including augmentation index [AIx] and aortic pulse wave velocity [aPWV]) were recorded. Brain volumes (including gray matter volume [GMV] and white matter lesions [WML]) were derived from magnetic resonance imaging (MRI) scans. Multivariable linear regression was used to study the associations of hemodynamic variables with brain structure in the two groups adjusting for age, sex, daytime systolic BP (SBP) and heart rate., Results: There were 37 T2DM (63 ± 9 years; 47% male) and 37 healthy individuals (52 ± 8 years; 51% male). In T2DM, resting aPWV was inversely associated with GMV (standardized β = -0.47, p = 0.036). In healthy participants, resting P(excess) was inversely associated with GMV (β = -0.23, p = 0.043) and AIx was associated with WML volume (β = 0.52, p = 0.021). There were no associations between exercise hemodynamics and brain volumes in either group., Conclusions: Brain atrophy is associated with resting aortic stiffness in T2DM, and resting P(excess) in healthy individuals. Central vascular mechanisms underlying structural brain changes may differ between healthy individuals and T2DM.

Objectives: To determine whether there is a relationship between daily defined dose (DDD) of antihypertensive drugs and the risk of falls., Design: Prospective population-based cohort study., Setting: Tasmanian Study of Cognition and Gait, Australia., Participants: Participants aged 60 to 86 randomly selected from the electoral roll., Measurements: Antihypertensive dose was quantified by estimating DDD, allowing standardized comparison of dosage between drug classes. Falls were identified prospectively over 12 months. The relative risk (RR) of falls associated with DDD was estimated using log binomial regression adjusting for age, sex, body mass index, education, cardiovascular history, and other risk factors for falls., Results: Participants (N=409) had a mean age of 72.0±6.9, and 56% were male. Mean baseline blood pressure was 142/80 mmHg, and 54% were taking antihypertensive medications. One hundred sixty-one participants (39%) fell over the 12 months. Those who fell were on a higher DDD of antihypertensives (1.51±2.16 than those who did not (1.03±1.42) (P=.007). Higher DDD was independently associated with greater fall risk (RR=1.07, 95% confidence interval (CI)=1.02-1.11; P=.004), with a 48% greater risk in those with a DDD of more than 3 (RR=1.48, 95% CI=1.06-2.08; P=.02), particularly in those with a history of stroke (P for interaction .01). This effect remained even after excluding those not taking antihypertensives or stratifying according to presence of hypertension and medication use., Conclusion: Higher dose of antihypertensive medication is independently associated with falls in older people, particularly in those with a history of previous stroke, and with more than three standard units conferring the highest risk., (© 2014, Copyright the Authors Journal compilation © 2014, The American Geriatrics Society.)

Objective: Aortic reservoir pressure indices independently predict cardiovascular events and mortality. Despite this, there has never been a study in humans to determine whether the theoretical principles of the mathematically derived aortic reservoir pressure (RP(derived)) and excess pressure (XP(derived)) model have a real physiological basis. This study aimed to directly measure the aortic reservoir (AR(direct); by cyclic change in aortic volume) and determine its relationship with RP(derived), XP(derived), and aortic blood pressure (BP)., Approach and Results: Ascending aortic BP and Doppler flow velocity were recorded via intra-arterial wire in 10 men (aged 62 ± 12 years) during coronary artery bypass surgery. Simultaneous ascending aortic transesophageal echocardiography was used to measure AR(direct). Published mathematical formulae were used to determine RP(derived) and XP(derived). AR(direct) was strongly and linearly related to RP(derived) during systole (r=0.988; P<0.001) and diastole (r=0.985; P<0.001). Peak cross-correlation (r=0.98) occurred at a phase lag of 0.004 s into the cardiac cycle, suggesting close temporal agreement between waveforms. The relationship between aortic BP and AR(direct) was qualitatively similar to the cyclic relationship between aortic BP and RP(derived), with peak cross-correlations occurring at identical phase lags (AR(direct) versus aortic BP, r=0.96 at 0.06 s; RP(derived) versus aortic BP, r=0.98 at 0.06 s)., Conclusions: RP(derived) is highly correlated with changes in proximal aortic volume, consistent with its physiological interpretation as corresponding to the instantaneous volume of blood stored in the aorta. Thus, aortic reservoir pressure should be considered in the interpretation of the central BP waveform., (© 2014 American Heart Association, Inc.)

Hypertension is the most prevalent chronic medical condition and a major risk factor for cardiovascular morbidity and mortality. In the majority of hypertensive cases, the underlying cause of hypertension cannot be easily identified because of the heterogeneous, polygenic and multi-factorial nature of hypertension. Metabolomics is a relatively new field of research that has been used to evaluate metabolic perturbations associated with disease, identify disease biomarkers and to both assess and predict drug safety and efficacy. Metabolomics has been increasingly used to characterize risk factors for cardiovascular disease, including hypertension, and it appears to have significant potential for uncovering mechanisms of this complex disease. This review details the analytical techniques, pre-analytical steps and study designs used in metabolomics studies, as well as the emerging role for metabolomics in gaining mechanistic insights into the development of hypertension. Suggestions as to the future direction for metabolomics research in the field of hypertension are also proposed.

Cardiovascular disease is the most frequent cause of death in people with chronic respiratory disease. The cause of this association has been attributed to airway obstruction leading to cardiovascular dysfunction (increased central blood pressure (BP) and aortic stiffness). However, this has never been experimentally tested. Methacholine is routinely used to stimulate airway function changes that mimic airway pathology. This study aimed to determine the cardiovascular effects of methacholine-induced airway obstruction. Fifteen healthy young adults (aged 22.9±2.5 years; 4 male; mean±S.D.) underwent a bronchial challenge test (randomized, blinded, cross-over design) in which they received nebulized methacholine inhalation in serially increasing concentrations (from 0.39 to 25 mg/ml) or saline (0.9%; control) on two separate days. Bronchoconstriction was assessed by forced expiratory volume at one second (FEV1) and cardiovascular effects by augmentation index, brachial BP, central BP, heart rate and aortic stiffness. Methacholine significantly decreased FEV1 from baseline to peak inhaled concentration compared with saline (-0.48±0.34 vs. -0.07±0.16 L; p<0.001), but there was no between-group change in augmentation index (1.6±7.0 vs. 3.7±10.2% p=0.49), brachial systolic BP (-3.3±7.6 vs. -4.7±5.7 mmHg; p=0.59), central systolic BP (-1.1±5.2 vs. -0.3±5.5 mmHg; p=0.73), heart rate (0.4±7.1 vs. -0.8±6.6 bpm; p=0.45) or aortic stiffness (0.2±1.3 vs. 0.8±1.8 m/s; p=0.20; n=12). Thus, methacholine induced airway obstruction does not acutely change brachial BP or central haemodynamics. This finding refutes the notion that airway obstruction per se leads to cardiovascular dysfunction, at least in healthy individuals in the acute setting.

Irrespective of apparent 'normal' resting blood pressure (BP), some individuals may experience an excessive elevation in BP with exercise (i.e. systolic BP ≥210 mm Hg in men or ≥190 mm Hg in women or diastolic BP ≥110 mm Hg in men or women), a condition termed exercise hypertension or a 'hypertensive response to exercise' (HRE). An HRE is a relatively common condition that is identified during standard exercise stress testing; however, due to a lack of information with respect to the clinical ramifications of an HRE, little value is usually placed on such a finding. In this review, we discuss both the clinical importance and underlying physiological contributors of exercise hypertension. Indeed, an HRE is associated with an increased propensity for target organ damage and also predicts the future development of hypertension, cardiovascular events and mortality, independent of resting BP. Moreover, recent work has highlighted that some of the elevated cardiovascular risks associated with an HRE may be related to high-normal resting BP (pre-hypertension) or ambulatory 'masked' hypertension and that an HRE may be an early warning signal of abnormal BP control that is otherwise undetected with clinic BP. Whilst an HRE may be amenable to treatment via pharmacological and lifestyle interventions, the exact physiological mechanism of an HRE remains elusive, but it is likely a manifestation of multiple factors including large artery stiffness, increased peripheral resistance, neural circulatory control and metabolic irregularity. Future research focus may be directed towards determining threshold values to denote the increased risk associated with an HRE and further resolution of the underlying physiological factors involved in the pathogenesis of an HRE.

Background: Lowering blood pressure after stroke reduces the risk of recurrent stroke and other vascular events. However, there is recent evidence that low blood pressure may also result in poor outcome. For the first time, this study aimed to investigate the relationship between blood pressure and outcome in long-term survivors of stroke., Methods: Participants from the North East Melbourne Stroke Incidence Study were contacted at 5 years after stroke for a follow-up assessment. Blood pressure was measured according to a strict protocol. A multivariable Cox proportional hazards regression model was used to assess the association between SBP measurements at 5 years after stroke and outcome (death, acute myocardial infarction or recurrent stroke) to 10 years after stroke., Results: In 5-year survivors of stroke, compared to a SBP of 131-141 mmHg, a SBP of 120 mmHg or less was associated with a 61% greater risk of stroke, acute myocardial infarction and death (hazard ratio 1.61, 95% confidence interval 1.08-2.41, P = 0.019). Compared to the reference category of SBP 131-141  mmHg, there were no differences in outcome in the patients with SBP 121-130  mmHg (P = 0.491) or 142-210  mmHg (P = 0.313). These findings were not modified when adjusting for prescription of antihypertensive medications., Conclusion: There was a greater risk of poor outcome in long-term survivors of stroke with low SBP. This is further evidence that low SBP may result in poor prognosis. Ideal blood pressure levels for long-term survivors of stroke may need to be reassessed.

Objectives: Physical activity is negatively associated with arterial stiffness. However, the relationship between sedentary behaviour and arterial stiffness is poorly understood. In this study, we aimed to investigate the association of sedentary behaviour with arterial stiffness among young adults., Design: Cross-sectional., Setting: 34 study clinics across Australia during 2004-2006., Participants: 2328 participants (49.4% male) aged 26-36 years who were followed up from a nationally representative sample of Australian schoolchildren in 1985., Measurements: Arterial stiffness was measured by carotid ultrasound. Sitting time per weekday and weekend day, and physical activity were self-reported by questionnaire. Cardiorespiratory fitness was estimated as physical work capacity at a heart rate of 170 bpm. Anthropometry, blood pressure, resting heart rate and blood biochemistry were measured. Potential confounders, including strength training, education, smoking, diet, alcohol consumption and parity, were self-reported. Rank correlation was used for analysis., Results: Sitting time per weekend day, but not per weekday, was correlated with arterial stiffness (males r=0.11 p<0.01, females r=0.08, p<0.05) and cardiorespiratory fitness (males r = -0.14, females r = -0.08, p<0.05), and also with fatness and resting heart rate. One additional hour of sitting per weekend day was associated with 5.6% (males p=0.046) and 8.6% (females p=0.05) higher risk of having metabolic syndrome. These associations were independent of physical activity and other potential confounders. The association of sitting time per weekend day with arterial stiffness was not mediated by resting heart rate, fatness or metabolic syndrome., Conclusions: Our study demonstrates a positive association of sitting time with arterial stiffness. The greater role of sitting time per weekend day in prediction of arterial stiffness and cardiometabolic risk than that of sitting time per weekday may be due to better reflection of discretionary sitting behaviour.

Background: Mechanisms underlying the inverse relationship between height and cardiovascular mortality are unknown but could relate to central hemodynamics. We sought to determine the relation of height to central and peripheral hemodynamics, as well as clinical characteristics., Methods: The study population was comprised of 1,152 randomly selected community-dwelling adults (aged 67.7 ± 12.3 years; 48% men). Brachial blood pressure (BP) was recorded by sphygmomanometry; central BP and aortic pulse wave velocity were estimated by applanation tonometry. Stepwise multiple regression analysis was used to determine associations between height and central and peripheral hemodynamics., Results: Height was not significantly associated with aortic pulse wave velocity in men or women. The relationship with height and brachial systolic BP was borderline in women (β = -0.115; P = 0.051) but not significant in men (β = -0.096; P = 0.09). Conversely, central systolic BP, estimated by transfer function (β = -0.139 for men [βM]; β = -0.172 for women [βW]) or radial second systolic peak (β M = -0.239; β W = -0.281), augmentation index at 75 bpm (β M = -0.189; β W = -0.224), and aortic pulse wave timing (β M = 0.224; β W = 0.262) were independently associated with height in both sexes (P < 0.003 for all). Both men and women of greater than median height were less likely to have coronary artery disease (P < 0.05), to have systemic hypertension (P < 0.01), or to be taking vasoactive medication (P < 0.001) compared with participants of less than median height., Conclusions: Even after correcting for conventional cardiovascular risk factors, taller individuals have more favorable central hemodynamics and reduced evidence of coronary artery disease compared with shorter individuals. These findings may help explain the decreased cardiovascular risk associated with being taller and also have important clinical consequences regarding therapy.

Background: Physical fitness is known to influence arterial stiffness. Resting heart rate is reduced by exercise and positively associated with arterial stiffness. This study aimed to investigate the role of resting heart rate in the relationship of physical fitness with arterial stiffness., Methods: Subjects were 2,328 young adults from the Childhood Determinants of Adult Health study. Cardiorespiratory fitness was estimated as physical work capacity at a heart rate of 170 bpm. Muscular strength was estimated by hand-grip (both sides), shoulder (pull and push), and leg strength. Arterial stiffness was measured using carotid ultrasound., Results: Arterial stiffness was negatively associated with cardiorespiratory fitness (men P < 0.001; women P = 0.002), and positively associated with muscular strength in women (P = 0.002) but not in men. Resting heart rate was positively associated with arterial stiffness (P < 0.001 both men and women). Adjustment for resting heart rate reduced the inverse association of arterial stiffness with cardiorespiratory fitness by 93.7% (men) and 67.6% (women) but substantially increased the positive association of arterial stiffness with muscular strength among women and revealed a positive association of arterial stiffness with muscular strength among men. These findings were independent of body size, blood pressure, biochemical markers, socioeconomic status, smoking, and alcohol consumption., Conclusions: Our findings attribute a key intermediary role for resting heart rate in the relationship between fitness and arterial stiffness, whereby higher cardiorespiratory fitness may reduce arterial stiffness mainly through resting heart rate, and higher muscular strength might have deleterious effects on arterial stiffness that are partially offset by lower resting heart rate.

Objective: There is evidence to suggest vascular involvement in the initiation and progression of osteoarthritis (OA). The relationship between large artery characteristics and pathogenesis of OA has not been investigated and was the aim of this study., Design: Large artery characteristics (i.e., aortic stiffness, brachial and central blood pressure (BP) variables) and bone marrow lesions (BMLs; measured by magnetic resonance imaging as a surrogate index of OA) were recorded in 208 participants (aged 63 ± 7 years; mean ± SD) with symptomatic knee OA. Relationships between large artery characteristics and BML were assessed by multiple regression adjusting for age, sex and body mass index., Results: There was a high prevalence of BML presence in the study population (70%), but no significant difference between participants with and without BML for all large artery and BP variables (P > 0.05 all). Furthermore, there were no significant relationships between BML size and aortic stiffness (r = -0.033, P = 0.71), central pulse pressure (r = 0.028, P = 0.74), augmentation index (r = 0.125, P = 0.14), brachial pulse pressure (r = 0.005, P = 0.95) or brachial systolic BP (r = -0.066, P = 0.44). When participants were stratified according to high or low aortic stiffness, there was no significant difference between groups regarding the proportion of those with a BML (64% vs. 70% respectively; P = 0.69)., Conclusions: Variables indicative of large artery characteristics are not significantly correlated with BML size or presence in people with symptomatic knee OA. Thus, large artery characteristics may not have a causative influence in the development of OA, but this needs to be confirmed in prospective studies., (Crown Copyright © 2013. Published by Elsevier Ltd. All rights reserved.)

Office blood pressure (BP) is recommended to be measured after 5 min of seated rest, but it may decrease for 10 min of seated rest. This study aimed to determine the change (and its clinical relevance) in brachial and central BP from 5 to 10 min of seated rest. Office brachial and central BP (measured after 5 and 10 min), left ventricular (LV) mass index, 7-day home and ambulatory BP were measured in 250 participants with treated hypertension. Office brachial and central BP were significantly lower at 10-min compared with 5-min BP (P<0.001). Seven-day home systolic BP (SBP) was significantly lower than office SBP measured at 5 min (P<0.001), but was similar to office SBP at 10 min (P=0.511). From 5 to 10 min, the percentage of participants with controlled BP increased and the percentage of participants with high central pulse pressure (PP) decreased (P<0.001). Moreover, brachial and central PP were significantly correlated with LV mass index measured at 10 min (r=0.171, P=0.006 and r=0.139, P=0.027, respectively), but not at 5 min (r=0.115, P=0.068 and r=0.084, P=0.185, respectively). BP recorded after 10 min is more representative of true BP control. These findings have relevance to appropriate diagnosis of hypertension and design of clinical trials.

Arm cuff blood pressure (BP) may overestimate cardiovascular risk. Central aortic BP predicts mortality and could be a better method for patient management. We sought to determine the usefulness of central BP to guide hypertension management. This was a prospective, open-label, blinded-end point study in 286 patients with hypertension randomized to treatment decisions guided by best-practice usual care (n=142; using office, home, and 24-hour ambulatory BP) or, in addition, by central BP intervention (n=144; using SphygmoCor). Therapy was reviewed every 3 months for 12 months, and recommendations were provided to each patient and his/her doctor on antihypertensive medication titration. Outcome measures were as follows: medication quantity (daily defined dose), quality of life, and left ventricular mass (3-dimensional echocardiography). There was 92% compliance with recommendations on medication titration, and quality of life improved in both groups (post hoc P<0.05). For usual care, there was no change in daily defined dose (all P>0.10), but with intervention there was a significant stepwise decrease in daily defined dose from baseline to 3 months (P=0.008) and each subsequent visit (all P<0.001). Intervention was associated with cessation of medication in 23 (16%) patients versus 3 (2%) in usual care (P<0.001). Despite this, there were no differences between groups in left ventricular mass index, 24-hour ambulatory BP, home systolic BP, or aortic stiffness (all P>0.05). We conclude that guidance of hypertension management with central BP results in a significantly different therapeutic pathway than conventional cuff BP, with less use of medication to achieve BP control and no adverse effects on left ventricular mass, aortic stiffness, or quality of life.

Resting aortic stiffness (pulse wave velocity; aortic PWV (aPWV)) independently predicts end-organ damage and mortality. Exercise haemodynamics have been shown to unmask cardiovascular abnormalities, otherwise undetectable at rest, but the response of aPWV to exercise has never been examined. This study aimed to develop a technique to measure exercise aPWV, determine reproducibility and relation to subclinical end-organ damage with aging. Healthy younger (n=17, 30±8 years) and older (n=18, 54±8 years) untreated men underwent cardiovascular assessment at rest and during low intensity semirecumbent cycling. Tonometry was used to assess aPWV and central blood pressure (BP). All participants underwent 24 h ambulatory BP (ABP) monitoring. Kidney function was assessed by estimated glomerular filtration rate (eGFR). Fifteen participants had testing repeated within 28±18 days. Exercise aPWV had good reproducibility (mean difference=-0.35±0.61 m s(-1), intraclass correlations=0.874, P<0.001) and was increased 26% above resting values in younger men (5.8±0.9 vs 7.3±1.6 m s(-1), P<0.001) and 19% above resting values in older men (6.3±1.0 vs 7.4±0.9 m s(-1), P<0.001). Exercise, but not resting, aPWV was significantly correlated with eGFR in older men (r=-0.633, P=0.005), and this was maintained after correction for age, body mass index and daytime systolic ABP (r=-0.656, P=0.008). Conversely, in younger men there was no significant association between eGFR and aPWV either at rest (r=-0.031, P=0.906) or during exercise (r=-0.117, P=0.655). Exercise aPWV is reproducible and significantly associated with kidney function in healthy older men. Further studies to determine the physiology and clinical relevance of raised exercise aPWV are warranted.

Exercise hypertension independently predicts cardiovascular mortality, although little is known about exercise central hemodynamics. This study aimed to determine the contribution of arterial wave travel and aortic reservoir characteristics to central blood pressure (BP) during exercise. We hypothesized that exercise central BP would be principally related to forward wave travel and aortic reservoir function. After routine diagnostic coronary angiography, invasive pressure and flow velocity were recorded in the ascending aorta via sensor-tipped intra-arterial wires in 10 participants (age, 55±10 years; 70% men) free of coronary artery disease with normal left ventricular function. Measures were recorded at baseline and during supine cycle ergometry. Using wave intensity analysis, dominant wave types throughout the cardiac cycle were identified (forward and backward, compression, and decompression), and aortic reservoir and excess pressure were calculated. Central systolic BP increased significantly with exercise (Δ=19±12 mm Hg; P<0.001). This was associated with increases in systolic forward compression waves (Δ=12×10(6)±17×10(6) W·m(-2)·s(-1); P=0.045) and forward decompression waves in late systole (Δ=9×10(6)±6×10(6) W·m(-2)·s(-1); P<0.001). Despite significant augmentation in BP (Δ=9±6 mm Hg; P=0.002), reflected waves did not increase in magnitude (Δ=-1×10(6)±3×10(6) W·m(-2)·s(-1); P=0.2). Excess pressure rose significantly with exercise (Δ=16±9 mm Hg; P<0.001), and reservoir pressure integral fell (Δ=-5×10(5)±5×10(5) Pa·s; P=0.010). Change in reflection coefficient negatively correlated with change in central systolic BP (r=-0.68; P=0.03). We conclude that elevation of exercise central BP is principally because of increases in aortic forward traveling waves generated by left ventricular ejection. These findings have relevance to understanding central BP waveform morphology and pathophysiology of exercise hypertension.

Aortic pulse wave velocity (PWV) and augmentation index (AIx) are independent predictors of cardiovascular risk and mortality, but little is known about the effect of air temperature changes on these variables. Our study investigated the effect of exposure to whole-body mild-cold on measures of arterial stiffness (aortic and brachial PWV), and on central haemodynamics [including augmented pressure (AP), AIx], and aortic reservoir components [including reservoir and excess pressures (P ex)]. Sixteen healthy volunteers (10 men, age 43 ± 19 years; mean ± SD) were randomised to be studied under conditions of 12 °C (mild-cold) and 21 °C (control) on separate days. Supine resting measures were taken at baseline (ambient temperature) and after 10, 30, and 60 min exposure to each experimental condition in a climate chamber. There was no significant change in brachial blood pressure between mild-cold and control conditions. However, compared to control, AP [+2 mmHg, 95 % confidence interval (CI) 0.36-4.36; p = 0.01] and AIx (+6 %, 95 % CI 1.24-10.1; p = 0.02) increased, and time to maximum P ex (a component of reservoir function related to timing of peak aortic in-flow) decreased (-7 ms, 95 % CI -15.4 to 2.03; p = 0.01) compared to control. Yet there was no significant change in aortic PWV (+0.04 m/s, 95 % CI -0.47 to 0.55; p = 0.87) or brachial PWV (+0.36 m/s; -0.41 to 1.12; p = 0.35) between conditions. We conclude that mild-cold exposure increases central haemodynamic stress and alters timing of peak aortic in-flow without differentially affecting arterial stiffness.

Background: Although a hypertensive response to exercise (HRE) is associated with cardiac risk and masked hypertension (MHT), its mechanisms and appropriate treatment remain unclear. We investigated spironolactone as a treatment for abnormal vascular and myocardial stiffness in HRE., Methods: In this randomized, double-blind, placebo-controlled study of 115 patients (54 ± 9 years, 57% men) with an HRE (≥210/105 mm Hg in men; ≥190/105 mm Hg in women) but no prior history of hypertension or myocardial ischemia, MHT prevalence was 40%. Patients were randomized to spironolactone 25mg daily (n = 58) or placebo (n = 57) and underwent evaluation at baseline and 3 months with exercise echocardiography, VO2max, pulse wave velocity (PWV), exercise and central blood pressure (BP), and 24-hour ambulatory BP. Changes in left ventricular mass index (LVMI), Doppler-derived E/em ratio (LV filling pressure), and myocardial strain were assessed., Results: Baseline 24-hour systolic BP (SBP) was 133 ± 10 mm Hg and peak-exercise SBP was 219 ± 16 mm Hg. Peak systolic strain (0.3 ± 3.6% vs. -0.1 ± 3.2, P = 0.56), E/em (-1.1 ± 2.3 vs. -0.6 ± 1.7, P = 0.30), VO(2max) (0.4 ± 4.9 vs. -0.9 ± 4.1 ml/kg/min, P = 0.15), and adjusted PWV did not significantly change with treatment, despite reduction in exercise SBP, 24-hour SBP, and LVMI. The change in exercise E/em was of borderline significance (-0.3 ± 2.4 vs. 0.8 ± 2.8, P = 0.06) and became significant after adjustment for baseline differences (P = 0.01). Patients with higher LVMI significantly increased VO(2max) (1.1 ± 5.6 vs. -2.4 ± 4.4 ml/kg/min, P < 0.05) and reduced exercise E/e(m) (-0.7 ± 2.7 vs. 1.9 ± 2.8, P < 0.05)., Conclusions: In HRE patients without previous hypertension, short-term spironolactone reduced exercise BP, 24-hour ambulatory BP, LVMI, and E/e(m) but did not significantly alter exercise capacity or myocardial strain.

We examined changes in central blood pressure (BP) following resistance exercise training (RET) in men and women with prehypertension and never-treated hypertension. Both Windkessel theory and wave theory were used to provide a comprehensive examination of hemodynamic modulation with RET. Twenty-one participants (age 61±1 years, n=6 male; average systolic blood pressure (SBP)/diastolic blood pressure (DBP)=138/84 mm Hg) were randomized to either 12 weeks of RET (n=11) or an inactive control group. Central BP and augmentation index (AIx) were derived from radial pressure waveforms using tonometry and a generalized transfer function. A novel reservoir-wave separation technique was used to derive excess wave pressure (related to forward and backward traveling waves) and reservoir pressure (related to the capacitance/Windkessel properties of the arterial tree). Wave separation using traditional impedance analysis and aortic flow triangulation was also applied to derive forward wave pressure (Pf) and backward wave pressure (Pb). There was a group-by-time interaction (P<0.05) for central BP as there was a significant ~6 mm Hg reduction in SBP and ~7 mm Hg reduction in DBP following RET with no change in the control condition. There were also group-by-time interactions (P<0.05) for Pf, excess wave pressure and reservoir pressure attributable to reductions in these parameters in the RET group concomitant with slight increases in the control group. There was no change in AIx or Pb (P>0.05). RET may reduce central BP in older adults with hypertension and prehypertension by lowering Pf and reservoir pressure without affecting pressure from wave reflections.

Background: The J-curve relationship between brachial diastolic blood pressure (DBP) and mortality is believed to be mediated through reduced myocardial perfusion. This study aimed to determine the relationship between DBP and subendocardial perfusion in patients with and without coronary artery disease (CAD) and to examine central hemodynamic variables that may explain the risk associated with low DBP (aortic stiffness, central pulse pressure, and augmentation index)., Methods: Brachial DBP and radial tonometry were measured in 134 patients with CAD (aged 76±7years; 69% male), 134 individuals without a prior cardiovascular event (control subjects) (aged 77±2years; 69% male) and 47 patients (aged 63±10years) during dobutamine stress echocardiography. Central hemodynamics and subendocardial viability ratio (SEVR), a marker of subendocardial perfusion, were recorded by tonometry., Results: There was no difference in DBP or SEVR between control subjects and CAD patients (P > 0.05), nor was there a difference in SEVR across quartiles of DBP in CAD patients (P = 0.07) or control subjects (P = 0.14). After adjustment for age and height, associations between DBP and SEVR in control subjects (r = 0.185; P = 0.03) and CAD patients (r = 0.204; P = 0.02) were attenuated (P = 0.07 and P = 0.11, respectively). There were no significant relationships between DBP and central hemodynamics (P > 0.05 for all). At peak dobutamine stress, SEVR was significantly reduced in patients with inducible ischemia vs. those with nonischemic response (84±17 vs. 101±22%; P = 0.01). However, DBP was not significantly different (65±14 vs. 67±15mm Hg; P = 0.32)., Conclusions: Brachial DBP is a poor marker of subendocardial perfusion. The J-curve relationship between DBP and mortality is unlikely attributable to reduced myocardial perfusion or adverse central hemodynamics.

Background: The prognostic relevance of a hypertensive response to exercise (HRE) is ill-defined in individuals undergoing exercise stress testing. The study described here was intended to provide a systematic review and meta-analysis of published literature to determine the value of exercise-related blood pressure (BP) (independent of office BP) for predicting cardiovascular (CV) events and mortality., Methods: Online databases were searched for published longitudinal studies reporting exercise-related BP and CV events and mortality rates., Results: We identified for review 12 longitudinal studies with a total of 46,314 individuals without significant coronary artery disease, with total CV event and mortality rates recorded over a mean follow-up of 15.2±4.0 years. After adjustment for age, office BP, and CV risk factors, an HRE at moderate exercise intensity carried a 36% greater rate of CV events and mortality (95% CI, 1.02-1.83, P = 0.039) than that of subjects without an HRE. Additionally, each 10mm Hg increase in systolic BP during exercise at moderate intensity was accompanied by a 4% increase in CV events and mortality, independent of office BP, age, or CV risk factors (95% CI, 1.01-1.07, P = 0.02). Systolic BP at maximal workload was not significantly associated with the outcome of an increased rate of CV, whether analyzed as a categorical (HR=1.49, 95% CI, 0.90-2.46, P = 0.12) or a continuous (HR=1.01, 95% CI, 0.98-1.04, P = 0.53) variable., Conclusions: An HRE at moderate exercise intensity during exercise stress testing is an independent risk factor for CV events and mortality. This highlights the need to determine underlying pathophysiological mechanisms of exercise-induced hypertension.

Objective: Exaggerated exercise blood pressure (BP) predicts mortality. Some studies suggest this could be explained by chronic hyperlipidemia, but whether acute-hyperlipidemia effects exercise BP has never been tested, and was the aim of this study., Methods: Intravenous infusion of saline (control) and Intralipid were administered over 60 min in 15 healthy men by double-blind, randomized, cross-over design. Brachial and central BP (including, pulse pressure, augmentation pressure and augmentation index), cardiac output and systemic vascular resistance were recorded at rest and during exercise., Results: Compared with control, Intralipid caused significant increases in serum triglycerides, very low density lipoproteins and free fatty acids (p < 0.001 for all). However, there was no significant difference for any exercise hemodynamic variable (p > 0.05 for all)., Conclusion: Acute-hyperlipidemia does not significantly change exercise hemodynamics in healthy males. Therefore, the association between raised lipids and increased exercise BP is likely due to the chronic effects of hyperlipidemia., (Crown Copyright © 2012. Published by Elsevier Ireland Ltd. All rights reserved.)

Intralipid is a fat emulsion that is regularly infused into humans and animals. Despite its routine use, Intralipid infusion can cause serious adverse reactions, including immunosuppression. Intralipid is a complex mix of proteins, lipids, and other small molecules, and the effect of its infusion on the human plasma metabolome is unknown. We hypothesized that untargeted metabolomics of human plasma after an Intralipid infusion would reveal novel insights into its effects. We infused Intralipid and saline into 10 healthy men in a double-blind, placebo-controlled experiment and used GC/MS, LC/MS, and NMR to profile the small-molecule composition of their plasma before and after infusion. Multivariate statistical analysis of the 40 resulting plasma samples revealed that after Intralipid infusion, a less-well-characterized pathway of linoleic acid metabolism had resulted in the appearance of (9Z)-12,13-dihydroxyoctadec-9-enoic acid (12,13-DHOME, P < 10(-3)), a leukotoxin that has powerful physiological effects and is known to inhibit the neutrophil respiratory burst. Intralipid infusion caused increased plasma 12,13-DHOME. Given that 12,13-DHOME is known to directly affect neutrophil function, we conclude that untargeted metabolomics may have revealed a hitherto-unknown mechanism of intralipid-induced immunosuppression.

Background: Noninvasive estimates of central blood pressure (BP) predict cardiovascular morbidity and mortality independent of brachial BP. However, there are limited data on the usefulness of central BP in clinical practice. This study aims to test the value of central BP as a management tool for physicians treating patients with essential hypertension., Methods: Participants with uncomplicated essential hypertension (N = 284) will be randomized to 12 months of treatment decisions guided by usual care (based on office, home, and 24-hour ambulatory brachial BP) or, in addition, by central BP estimated using radial tonometry (based on age- and sex-specific normal central systolic BP values). Recommendations regarding titration of antihypertensive medication (increase, decrease, or maintain dose) will be provided to each participant's general practitioner as well as the participant themselves. Relevant clinical information (eg, comorbidities, left ventricular [LV] mass, blood biochemistry, and BP-related symptoms) will be considered when making titration recommendations in all participants. The primary outcome measures will be (1) change in LV mass (by real-time 3-dimensional echocardiography), (2) amount of medication used, and (3) quality of life. Analysis will be by intention to treat., Conclusions: It is expected that there will be no significant difference in LV mass between groups. However, it is hypothesized that there will be significantly reduced use of medication and improved quality of life in the central BP group because more appropriate titration choices will be made to maintain normal central systolic BP. Results are expected in 2012., (Copyright © 2012 Mosby, Inc. All rights reserved.)

A strong association between blood pressure (BP) and body mass index (BMI) has been observed in developed and developing countries. Whether there are differences in these associations between Caucasians and Asians remains unknown. Our objective was to compare the associations of BP with fatness measures in the Caucasian and Asian samples. The study used data from two population-based cross-sectional studies conducted using similar methodology: a survey in Australia in 1998-1999 (n = 832 adults aged 25-64 years; 47% male) and a survey in Vietnam in 2005 (n = 1978 adults aged 25-64 years; 46% male). Participants completed questionnaires and attended clinics for physical measurements including BP and anthropometry. Linear regression was used for analysis. Independent of age, there were strong associations between BP indices and BMI in each sample, but the patterns of associations were different. Among Caucasians, pulse pressure (PP) increased with increasing BMI because the slope of systolic pressure with BMI exceeded the slope of diastolic pressure with BMI (P<0.001 for both sexes). In contrast, among Asians, PP decreased with increasing BMI. Associations between BMI and BP are different between Caucasian and Asian populations. Among Asians, the stronger association of increasing BMI and diastolic BP, but not PP, suggests a different pathophysiology related to hypertension.

Background: Noninvasive central blood pressure (BP) independently predicts mortality, but current methods are operator-dependent, requiring skill to obtain quality recordings. The aims of this study were first, to determine the validity of an automatic, upper arm oscillometric cuff method for estimating central BP (O(CBP)) by comparison with the noninvasive reference standard of radial tonometry (T(CBP)). Second, we determined the intratest and intertest reliability of O(CBP)., Methods: To assess validity, central BP was estimated by O(CBP) (Pulsecor R6.5B monitor) and compared with T(CBP) (SphygmoCor) in 47 participants free from cardiovascular disease (aged 57 ± 9 years) in supine, seated, and standing positions. Brachial mean arterial pressure (MAP) and diastolic BP (DBP) from the O(CBP) device were used to calibrate in both devices. Duplicate measures were recorded in each position on the same day to assess intratest reliability, and participants returned within 10 ± 7 days for repeat measurements to assess intertest reliability., Results: There was a strong intraclass correlation (ICC = 0.987, P < 0.001) and small mean difference (1.2 ± 2.2 mm Hg) for central systolic BP (SBP) determined by O(CBP) compared with T(CBP). Ninety-six percent of all comparisons (n = 495 acceptable recordings) were within 5 mm Hg. With respect to reliability, there were strong correlations but higher limits of agreement for the intratest (ICC = 0.975, P < 0.001, mean difference 0.6 ± 4.5 mm Hg) and intertest (ICC = 0.895, P < 0.001, mean difference 4.3 ± 8.0 mm Hg) comparisons., Conclusions: Estimation of central SBP using cuff oscillometry is comparable to radial tonometry and has good reproducibility. As a noninvasive, relatively operator-independent method, O(CBP) may be as useful as T(CBP) for estimating central BP in clinical practice.

Background: Central blood pressure (BP) predicts mortality independent of office brachial BP. Whether central BP may be useful to differentiate BP control requires examination and was the first aim of this study. Secondly, we sought to determine the variability in central BP among patients from different categories of BP control [controlled hypertension (CH), masked hypertension (MH), white coat (WCHT) and uncontrolled hypertension (UH)]., Materials and Methods: We assessed patients with uncomplicated hypertension using measurement of central BP (SphygmoCor 8.1), brachial BP and 24-h ambulatory BP monitoring. BP control was defined according to guidelines using office BP and 24-h BP., Results: Of the 201 patients (63 ± 8 years, 51% men), 67 (33%) were classified as CH; 59 (29%) with MH; 31 (15%) with WCHT; and 44 (22%) with UH. There were no differences in central BP parameters (augmentation pressure, augmentation index, pulse pressure) between patients with CH and MH or between patients with WCHT and UH (P > 0·05 for all). However, there was significant overlap in central systolic BP between BP control categories. For example, 27% of patients with normal brachial systolic BP had central systolic BP above age- and gender-specific normal values, including patients from three classifications of BP control (CH: n = 27; MH: n = 22; and WCHT: n = 4)., Conclusion: Office central BP alone cannot delineate categories of BP control. However, given the high degree of variability in central BP among patients from different categories of BP control, measurement of central BP may result in significant reclassification of risk related to BP., (© 2011 The Authors. European Journal of Clinical Investigation © 2011 Stichting European Society for Clinical Investigation Journal Foundation.)

Background: Body size is associated with increased brachial systolic blood pressure (SBP) and aortic stiffness. The aims of this study were to determine the relationships between central SBP and body size (determined by body mass index (BMI), waist circumference and waist/hip ratio) in health and disease. We also sought to determine if aortic stiffness was correlated with body size, independent of BP., Methods: BMI, brachial BP and estimated central SBP (by SphygmoCor and radial P2) were recorded in controls (n=228), patients with diabetes (n=211), coronary artery disease (n=184) and end-stage kidney disease (n=68). Additional measures of waist circumference and arterial stiffness (aortic and brachial pulse wave velocity (PWV)) were recorded in a subgroup of 75 controls (aged 51 ± 12 years) who were carefully screened for factors affecting vascular function., Results: BMI was associated with brachial (r=0.30; P<0.001) and central SBP (r=0.29; P<0.001) in the 228 controls, but not the patient populations (r<0.13; P>0.15 for all comparisons). In the control subgroup, waist circumference was also significantly correlated with brachial SBP (r=0.29; P=0.01), but not central SBP (r=0.22; P=0.07). Independent predictors of aortic PWV in the control subgroup were brachial SBP (β=0.43; P<0.001), age (β=0.37; P<0.001), waist circumference (β=0.39; P=0.02) and female sex (β=-0.24; P=0.03), but not BMI., Conclusion: In health, there are parallel increases in central and brachial SBP as BMI increases, but these relationships are not observed in the presence of chronic disease. Moreover, BP is a stronger correlate of arterial stiffness than body size.

Introduction: Patients with type 2 diabetes mellitus (T2DM) have exaggerated brachial and central (ascending aortic) blood pressure (BP) during exercise, which is associated with adverse outcomes. Central systolic loading, represented by the augmentation index (AIx), may contribute to exaggerated exercise central BP. This study sought to compare the central AIx response to peak exercise in T2DM and control patients and to identify mechanisms of altered exercise central AIx., Methods: Central BP and AIx were quantified by radial tonometry at rest and immediately after peak treadmill exercise in 106 patients with T2DM and 106 nondiabetic controls, pair-matched by age, gender, peak exercise brachial BP, and postexercise HR corresponding to tonometry acquisition. Cardiac volumes (by echocardiography) were assessed in a subgroup (22 T2DM and 22 controls) to derive rest and postexercise arterial-ventricular coupling parameters, including cardiac index (stroke volume index × HR), peripheral vascular resistance index (cardiac index / mean BP), and effective arterial elastance index (end-systolic pressure / stroke volume index). Reserve parameters (exercise--rest) were also defined., Results: Patients with T2DM had lower postexercise central AIx (-1% ± 13% vs 3% ± 14%, P = 0.038) and greater central AIx reserve (-24% ± 13% vs -20% ± 11%, P = 0.002) compared with controls, despite raised postexercise peripheral vascular resistance index (P = 0.013) and effective arterial elastance index (P = 0.011); these parameters independently predicted higher central AIx at rest (P < 0.01) but not after exercise. Moreover, T2DM was independently associated with lower postexercise central AIx (β = -0.21, P = 0.006). Cardiac index reserve, which was blunted in T2DM (P = 0.004), represented the only independent correlate of central AIx reserve (r = 0.39, P = 0.01)., Conclusions: Patients with T2DM have significantly (and paradoxically) lower postexercise central AIx and greater central AIx reserve, which may be explained by an impaired cardiac functional reserve.

Purpose: Masked hypertension (MH) independently predicts mortality but cannot be diagnosed from clinic blood pressure (BP) taken under resting conditions. We sought to determine if MH could be identified from BP taken during a single bout of low-intensity exercise., Methods: BP was recorded at rest and during brief low-level cycling exercise (60-70% of age-predicted maximal heart rate) in 75 untreated subjects with a hypertensive response to exercise (aged 54 ± 9 years). All subjects underwent 24-h ambulatory BP monitoring (ABPM) and MH was defined as clinic BP < 140/90 mmHg and ABPM BP ≥ 130/80 mmHg., Results: There were 42 (56%) patients with MH, and at rest systolic (SBP) was higher in subjects with MH compared with those without MH (127 ± 9 vs 120 ± 9 mmHg; p < 0.05). During exercise, MH subjects had significantly higher SBP (188 ± 22 vs 168 ± 15 mmHg; p < 0.05), with a greater change from baseline (61 ± 21 vs 48 ± 15 mmHg; p < 0.05). Low-level exercise SBP was independently associated with MH, and if ≥ 175 mmHg, identified MH with 74% sensitivity and 67% specificity (p < 0.001)., Conclusion: MH can be identified in untreated individuals from low-intensity exercise SBP. Further research on the diagnostic value of BP during early phases of exercise stress testing is needed.

Background: A hypertensive response to exercise (HRE; defined as normal clinic blood pressure (BP) and exercise systolic BP (SBP) ≥210 mm Hg in men or ≥190 mm Hg in women, or diastolic BP (DBP) ≥105 mm Hg) independently predicts mortality. The mechanisms remain unclear but may be related to masked hypertension. This study aimed to assess the prevalence of masked hypertension and its association with cardiovascular risk factors, including left ventricular (LV) mass, in patients with a HRE., Methods: Comprehensive clinical and echocardiographic evaluation (including central BP, aortic pulse wave velocity by tonometry) and 24-h ambulatory BP monitoring (ABPM) were performed in 72 untreated patients with HRE (aged 54 ± 9 years; 60% male; free from coronary artery disease confirmed by exercise stress echocardiography). Masked hypertension was defined according to guidelines as daytime ABPM ≥135/85 mm Hg and clinic BP <140/90 mm Hg., Results: Masked hypertension was present in 42 patients (58%). These patients had higher LV mass index (41.5 ± 8.7 g/m(2.7) vs. 35.9 ± 8.5 g/m(2.7); P = 0.01), LV relative wall thickness (RWT; 0.42 ± 0.09 vs. 0.37 ± 0.06; P = 0.004) and exercise SBP (222 ± 17 mm Hg vs. 212 ± 14 mm Hg; P = 0.01), but no significant difference in aortic pulse wave velocity or central pulse pressure (P > 0.05 for both). The strongest independent determinant of LV mass index was the presence of masked hypertension (unstandardized β = 5.6; P = 0.007), which was also independently related to LV RWT (unstandardized β = 0.04; P = 0.03)., Conclusions: Masked hypertension is highly prevalent in HRE patients with a normal resting office BP and is associated with increased LV mass index and RWT. Clinicians should consider measuring ABPM or home BP in HRE patients.

Failure of blood pressure (BP) to decline appropriately overnight (nondipping) is associated with increased risk. This may be due to inappropriately raised supine central BP and this study's first aim was to examine this hypothesis. Secondly, aortic stiffness, central hemodynamics, and left ventricular (LV) mass were measured as other possible mechanisms of higher risk. Brachial and central BP (supine and seated), aortic stiffness, central hemodynamics, and LV dimensions were measured in 95 patients with hypertension (mean age 62 ± 8 standard deviation). Central hemodynamics were recorded by combined radial tonometry and 3-dimensional echocardiography. Seated brachial and central systolic BP (SBP) were similar between dippers (n = 52) and nondippers (n = 43). However, nondippers had higher supine brachial (132 ± 14 mm Hg vs 126 ± 11 mm Hg; P = .029) and central (121 ± 15 mm Hg vs 115 ± 11 mm Hg; P = .024) SBP. Aortic stiffness was not different between groups (P = .76), but LV mass index (33.0 ± 6.2 vs 29.4±7.2 g/m(2.7) ; P=.019), stroke volume index (30.2 ± 6.2 mL/m(2) vs 27.4 ± 6.0 mL/m(2) ; P = .040), and LV stroke work (3246 ± 815 mm Hg/mL/m(2) vs 2778 ± 615 mm Hg/mL/m(2) ; P = .005) were all higher in nondippers. Dipper status independently predicted LV mass index (β = 3.61; P = .001). Nondippers have higher supine brachial and central SBP, significantly different central hemodynamics, and elevated LV mass index compared with dippers. These cardiovascular anomalies possibly contribute to increased mortality risk., (© 2011 Wiley Periodicals, Inc.)

Acute elevation of circulating lipids, such as the postprandial state, contributes to increased cardiovascular risk. However, the effect of acutely elevated triglycerides on arterial and left ventricular function is not completely understood. We aimed to assess whether an acute increase in triglycerides affects ventricular-vascular interaction. Fifteen healthy men (age, 49 ± 8 yr) underwent blinded, randomized infusion of saline and intravenous fat emulsion to acutely raise plasma triglycerides. All subjects underwent both randomization trials, in random order on two separate days. Ventricular-vascular interaction measures were recorded by tonometry (central blood pressure) and echocardiography (left ventricular volumes, strain, and strain rate) at baseline and after 1 h infusion. Net ventricular-vascular interaction was defined by the effective arterial elastance (E(A))-to-left ventricular end-systolic elastance (E(LV)) ratio (E(A)/E(LV)). When compared with saline, the infusion of intravenous fat emulsion increased triglycerides and free fatty acids (ΔP < 0.001 for both) and improved left ventricular contractility (ΔE(LV), end-systolic volume and strain rate; P < 0.05 for all). However, arterial function was unchanged (ΔE(A), brachial and central blood pressure; P > 0.05 for all). Overall, E(A)/E(LV) was decreased by an infusion of intravenous fat emulsion (P = 0.004) but not saline (P > 0.05, P = 0.001 for Δ between trials). We conclude that intravenous fat emulsion and acute elevation of blood lipids (including triglycerides and free fatty acids) alter ventricular-vascular interaction by increasing left ventricular contractility without affecting arterial load. These findings may have implications for cardiovascular responses to parenteral nutrition.