James E. Sharman

Validation of a Generalized Transfer Function to Noninvasively Derive Central Blood Pressure During Exercise

Exercise brachial blood pressure (BP) predicts mortality, but because of wave reflection, central (ascending aortic) pressure differs from brachial pressure. Exercise central BP may be clinically important, and a noninvasive means to derive it would be useful. The purpose of this study was to test the validity of a noninvasive technique to derive exercise central BP. Ascending aortic pressure waveforms were recorded using a micromanometer-tipped 6F Millar catheter in 30 patients (56±9 years; 21 men) undergoing diagnostic coronary angiography. Simultaneous recordings of the derived central pressure waveform were acquired using servocontrolled radial tonometry at rest and during supine cycling. Pulse wave analysis of the direct and derived pressure signals was performed offline (SphygmoCor 7.01). From rest to exercise, mean arterial pressure and heart rate were increased by 20±10 mm Hg and 15±7 bpm, respectively, and central systolic BP ranged from 77 to 229 mm Hg. There was good agreement and high correlation between invasive and noninvasive techniques with a mean difference (±SD) for central systolic BP of −1.3±3.2 mm Hg at rest and −4.7±3.3 mm Hg at peak exercise (for both r=0.995; P<0.001). Conversely, systolic BP was significantly higher peripherally than centrally at rest (155±33 versus 138±32 mm Hg; mean difference, −16.3±9.4 mm Hg) and during exercise (180±34 versus 164±33 mm Hg; mean difference, −15.5±10.4 mm Hg; for both P<0.001). True myocardial afterload is not reliably estimated by peripheral systolic BP. Radial tonometry and pulse wave analysis is an accurate technique for the noninvasive determination of central BP at rest and during exercise.

Increased Stroke Volume and Aortic Stiffness Contribute to Isolated Systolic Hypertension in Young Adults

Isolated systolic hypertension is a common condition in individuals aged older than 60 years. However, isolated systolic hypertension has also been described in young individuals, although the mechanisms are poorly understood. We hypothesized that in young adults, isolated systolic hypertension and essential hypertension have different hemodynamic mechanisms and the aim of this study was to test this hypothesis in a cohort of subjects from The ENIGMA Study. Peripheral and central blood pressure, aortic pulse wave velocity, cardiac output, stroke volume, and peripheral vascular resistance were determined in 1008 subjects, aged 17 to 27 years. Compared with normotensive subjects, those with isolated systolic hypertension had significantly higher peripheral, central, and mean blood pressure, aortic pulse wave velocity, cardiac output, and stroke volume (P<0.001 for all comparisons). However, there were no differences in pulse pressure amplification, heart rate, or peripheral vascular resistance between the two groups. Compared with subjects with essential hypertension, mean pressure, heart rate, and peripheral vascular resistance were all significantly lower in isolated systolic hypertensive subjects, but pulse pressure amplification, aortic pulse wave velocity, cardiac output, and stroke volume were higher (P<0.001 for all comparisons). We have demonstrated that in young adults, isolated systolic hypertension and essential hypertension arise from different hemodynamic mechanisms. Isolated systolic hypertension appears to result from an increased stroke volume and/or aortic stiffness, whereas the major hemodynamic abnormality underlying essential hypertension is an increased peripheral vascular resistance. Long-term follow-up of these individuals is now required to determine whether they are at increased risk compared with age-matched normotensive individuals.

Definition of ambulatory blood pressure targets for diagnosis and treatment of hypertension in relation to clinic blood pressure: prospective cohort study.

Background Twenty-four hour ambulatory blood pressure thresholds have been defined for the diagnosis of mild hypertension but not for its treatment or for other blood pressure thresholds used in the diagnosis of moderate to severe hypertension. We aimed to derive age and sex related ambulatory blood pressure equivalents to clinic blood pressure thresholds for diagnosis and treatment of hypertension. Methods We collated 24 hour ambulatory blood pressure data, recorded with validated devices, from 11 centres across six Australian states (n=8575). We used least product regression to assess the relation between these measurements and clinic blood pressure measured by trained staff and in a smaller cohort by doctors (n=1693). Results Mean age of participants was 56 years (SD 15) with mean body mass index 28.9 (5.5) and mean clinic systolic/diastolic blood pressure 142/82 mm Hg (19/12); 4626 (54%) were women. Average clinic measurements by trained staff were 6/3 mm Hg higher than daytime ambulatory blood pressure and 10/5 mm Hg higher than 24 hour blood pressure, but 9/7 mm Hg lower than clinic values measured by doctors. Daytime ambulatory equivalents derived from trained staff clinic measurements were 4/3 mm Hg less than the 140/90 mm Hg clinic threshold (lower limit of grade 1 hypertension), 2/2 mm Hg less than the 130/80 mm Hg threshold (target upper limit for patients with associated conditions), and 1/1 mm Hg less than the 125/75 mm Hg threshold. Equivalents were 1/2 mm Hg lower for women and 3/1 mm Hg lower in older people compared with the combined group. Conclusions Our study provides daytime ambulatory blood pressure thresholds that are slightly lower than equivalent clinic values. Clinic blood pressure measurements taken by doctors were considerably higher than those taken by trained staff and therefore gave inappropriate estimates of ambulatory thresholds. These results provide a framework for the diagnosis and management of hypertension using ambulatory blood pressure values.

A call to action and a lifecourse strategy to address the global burden of raised blood pressure on current and future generations: the Lancet Commission on hypertension

Elevated blood pressure is the strongest modifiable risk factor for cardiovascular disease worldwide. Despite extensive knowledge about ways to prevent as well as to treat hypertension, the global incidence and prevalence of hypertension and, more importantly, its cardiovascular complications are not reduced—partly because of inadequacies in prevention, diagnosis, and control of the disorder in an ageing world. The aim of the Lancet Commission on hypertension is to identify key actions to improve the management of blood pressure both at the population and the individual level, and to generate a campaign to adopt the suggested actions at national levels to reduce the impact of elevated blood pressure globally. The first task of the Commission is this report, which briefly reviews the available evidence for prevention, identification, and treatment of elevated blood pressure, hypertension, and its cardiovascular complications. The report focuses on how as-yet unsolved issues might be tackled using approaches with population-wide impact and new methods for patient evaluation and education in the broadest sense (some of which are not always strictly evidence based) to manage blood pressure worldwide. The report is built around the concept of lifetime risk applicable to the entire population from conception. Development of subclinical and sometimes clinical cardiovascular disease results from lifetime exposure to cardiovascular risk factors combined with the susceptibility of individuals to the harmful consequences of these risk factors. The Commission recognises the importance of other cardiovascular risk factors—eg, smoking, obesity, dyslipidaemia, and diabetes mellitus—on antihypertensive treatment. However, as a Commission on hypertension, this report focuses mainly on issues and actions related to elevated blood pressure. Previous action plans for improving management of elevated blood pressure and hypertension have not yet provided adequate results. Therefore, the Commission has identified ten essential and achievable goals and ten accompanying, mutually additive, and synergistic key actions that—if implemented effectively and broadly—will make substantial contributions to the management of blood pressure globally. The Commission deliberately has not listed these complementary key actions by priority because the balance between strength of evidence, feasibility, and potential benefit could differ by country.

Exercise-Induced Hypertension, Cardiovascular Events, and Mortality in Patients Undergoing Exercise Stress Testing: A Systematic Review and Meta-Analysis

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.

Effect of Intradialytic Versus Home-Based Aerobic Exercise Training on Physical Function and Vascular Parameters in Hemodialysis Patients: A Randomized Pilot Study

BACKGROUND Hemodialysis patients show reduced physical function and greater risk of increased arterial stiffness because of hypertension, metabolic disturbances, and vascular calcification. Exercise interventions potentially could improve their vascular risk profile. STUDY DESIGN Randomized controlled pilot clinical study comparing the effects of 6 months of supervised intradialytic exercise training versus home-based exercise training or usual care on physical function and arterial stiffness in hemodialysis patients. SETTING & PARTICIPANTS 70 hemodialysis patients from 3 renal units. INTERVENTION Intradialytic-exercise patients trained 3 times/wk for 6 months on a cycle ergometer and home-based-exercise patients followed a walking program to achieve the same weekly physical activity. Usual-care patients received no specific intervention. OUTCOMES & MEASUREMENTS Primary outcome measures were distance traveled during a 6-minute walk test and aortic pulse wave velocity. Secondary outcome measures included augmentation index (augmentation pressure as a percentage of central pulse pressure), peripheral (brachial) and central blood pressures (measured noninvasively using radial tonometry), physical activity, and self-reported physical functioning. Measurements were made at baseline and 6 months. RESULTS At 6 months, there were no significant differences between changes in 6-minute walk test distance (intradialytic exercise, +14%; home-based exercise, +11%; usual care, +5%), pulse wave velocity (intradialytic exercise, -4%; home-based exercise, -2%; usual care, +5%), or any secondary outcome measure. LIMITATIONS Lack of medication data limited the analysis of vascular parameters in this study. CONCLUSION There were no differences between intradialytic or home-based exercise training and usual care for either physical function or vascular parameters.

Pulse Wave Analysis Is a Reproducible Technique for Measuring Central Blood Pressure During Hemodynamic Perturbations Induced by Exercise

BACKGROUND Central blood pressure (BP) and markers of wave reflection (augmentation index; AIx) measured by radial tonometry have prognostic value independent from brachial BP. The measurement of the central waveform is increasingly used during altered hemodynamics, including exercise, but reliability of the test has not been reported under changed loading conditions. This study aimed to test the techniques reproducibility during major hemodynamic perturbations induced by exercise. METHODS Radial waveforms were recorded (SphygmoCor) in 28 healthy subjects (aged 53 +/- 11 years) at rest, during submaximal exercise (cycling at 50, 60, and 70% of maximal age-predicted heart rate (HR)) and immediately after maximal treadmill exercise on two occasions separated by 9 +/- 5 days. Data were compared between testing days. Waveforms were calibrated with brachial BP measured using a mercury sphygmomanometer. Pulse pressure amplification (PPAmp) was defined as the ratio of brachial to central pulse pressure. RESULTS There was very good reproducibility between visits at all exercise intensities for all waveform measures, including AIx, central pulse pressure, and PPAmp (intraclass correlations at 50% exercise were 0.93, 0.89, and 0.89, respectively; P < 0.001). The mean difference between tests at this intensity was 0 +/- 4% for AIx, 4 +/- 6 mm Hg for central pulse pressure, and -0.02 +/- 0.09 for PPAmp. There were no significant differences between visits for HR, PPAmp, or AIx at rest or with exercise (P > 0.05 for all). CONCLUSIONS Radial tonometry is a reproducible technique for measurement of central waveform indices during perturbations induced by exercise. It should, therefore, be suitable for use in intervention studies in which hemodynamics are altered.

Randomized Trial of Guiding Hypertension Management Using Central Aortic Blood Pressure Compared With Best-Practice Care Principal Findings of the BP GUIDE Study

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.

Augmentation index, left ventricular contractility, and wave reflection.

Augmentation index (AIx), a correlate of mortality, is thought to be influenced by left ventricular contractility and wave reflections. However, the relationship of AIx with left ventricular contractility changes has never been assessed, and the wave reflection theory has recently been questioned. This study sought to examine arterial waveform changes in response to reduced “wave reflection” and increased left ventricular contractility induced by dobutamine. Simultaneous radial tonometry (for AIx) and tissue Doppler echocardiography (for peak longitudinal systolic strain rate [SR] as an analogue of left ventricular contractility) were recorded at rest and peak dobutamine-induced stress in 50 patients (41 men; aged 62±10 years). From baseline to peak stress there was an increase in heart rate (70±11 to 127±17 bpm; P<0.001) and SR (−0.88±0.23 to −1.81±0.43 1/s; P<0.001), whereas AIx decreased (27±9% to −7±15%; P<0.001). There was also a greater increase in the systolic (compared with diastolic) pressure-time integral relative to cardiac cycle length (3.2±1.9 versus 1.8±1.1 mm Hg; P<0.001), indicating that wave reflection was not shifted into diastole as per the current belief. AIx was significantly associated with ejection duration (r=0.88), heart rate (r=−0.81), and SR (r=0.72; P<0.001 for all). However, when SR was heart rate corrected, there was no significant association with AIx (r=0.18; P=0.11). The strongest independent correlate of AIx was ejection duration, accounting for 78% variance (&bgr;=0.88; model R2=0.77; P<0.001). Neither SR (&bgr;=0.12; P=0.18) nor heart rate–corrected SR (&bgr;=0.02; P=0.72) was associated with AIx. We conclude that AIx is determined by chronotropic rather than inotropic effects, as well as factors other than wave reflection.

Central blood pressure measurement may improve risk stratification

Central systolic blood pressure (SBP) may differ between individuals with similar brachial SBP, which may have implications for risk assessment. This study aimed to determine the variation and potential clinical value of central SBP between patients with similar brachial SBP. Brachial SBP was measured by sphygmomanometer and central SBP by radial tonometry in 675 people (430 men), comprising healthy individuals (n=222), patients with known or suspected coronary artery disease (n=229) and diabetes (n=224). Individuals were stratified by brachial SBP in accordance with European Society of Hypertension guidelines (optimal, normal, high-normal, grades 1, 2 and 3 hypertension). The potential clinical value of central SBP was determined from the percentage of patients re-classified into different brachial SBP groups due to the difference between brachial and aortic SBP (defined as brachial SBP–central SBP). Central SBP increased with each brachial SBP level (optimal to grade 3 hypertension; P<0.001 for all). However, large variation in brachial–aortic SBP difference occurred within each brachial SBP group (range 2–33 mm Hg), resulting in sizeable overlap of central SBP between brachial SBP groups. For patients with normal brachial SBP, 96% had central SBP within the range of patients with high-normal brachial SBP, as well as 64% within the range of patients with grade 1 hypertension. We conclude that wide variation in brachial–aortic SBP difference occurs between patients with similar brachial SBP. This results in a significant overlap of central SBP scores between brachial SBP risk groups. This is likely to have treatment implications but remains to be tested.