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National and international hypertension guidelines recommend that adults with young-onset hypertension (aged <40 years at diagnosis) are reviewed by a hypertension specialist to exclude secondary causes of hypertension and optimise therapeutic regimens. A recent survey among UK secondary care hypertension specialist physicians highlighted variations in the investigation of such patients. In this position statement, the British and Irish Hypertension Society seek to provide clinicians with a practical approach to the investigation and management of adults with young-onset hypertension. We aim to ensure that individuals receive consistent and high-quality care across the UK and Ireland, to highlight gaps in the current evidence, and to identify important future research questions., (© 2024. The Author(s).)

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Blood pressure (BP) in young adults predicts BP in later life. We aimed to identify metabolic, hemodynamic, and autonomic characteristics associated with raised BP in young adults and whether these differ between males and females. Three thousand one hundred forty-five healthy subjects, aged 18 to 40 years, were grouped according to sex and BP category following the recent reclassification of BP as part of American Heart Association/American College of Cardiology 2017 guidelines. All individuals undertook a lifestyle and medical history questionnaire and detailed metabolic, hemodynamic, and autonomic assessments. Stage 1 hypertension and normal BP were the most common BP phenotypes in males (29%) and females (68%), respectively. In both sexes, cardiac output was positively associated with increasing BP category (P<0.001 for both). Similar positive trends were observed for heart rate and stroke volume in males (P<0.001 for both) and heart rate in females (P<0.001). Unlike in males, peripheral vascular resistance, aortic pulse wave velocity, and augmentation index were significantly increased in hypertensive females (P<0.001 for all) compared with the other BP categories. Most heart rate variability indices decreased across the BP categories, particularly in males. In young adults, metabolic and hemodynamic abnormalities associated with hypertension are already present at the elevated BP stage and the overall phenotype differed markedly between sexes. Whereas a cardiac phenotype was associated with elevated BP and hypertension in males, a vascular phenotype, characterized by elevated peripheral vascular resistance, aortic pulse wave velocity, and augmentation index, was dominant in females., (© 2018 The Authors. Hypertension is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited.)

Background: Ethnicity, along with a variety of genetic and environmental factors, is thought to influence the efficacy of antihypertensive therapies. Current UK guidelines use a "black versus white" approach; in doing so, they ignore the United Kingdom's largest ethnic minority: Asians from South Asia., Study Design: The primary purpose of the AIM-HY INFORM trial is to identify potential differences in response to antihypertensive drugs used as mono- or dual therapy on the basis of self-defined ethnicity. A multicenter, prospective, open-label, randomized study with 2 parallel, independent trial arms (mono- and dual therapy), AIM-HY INFORM plans to enroll a total of 1,320 patients from across the United Kingdom. Those receiving monotherapy (n = 660) will enter a 3-treatment (amlodipine 10 mg od; lisinopril 20 mg od; chlorthalidone 25 mg od), 3-period crossover, lasting 24 weeks, whereas those receiving dual therapy (n = 660) will enter a 4-treatment (amlodipine 5 mg od and lisinopril 20 mg od; amlodipine 5 mg od and chlorthalidone 25 mg od; lisinopril 20 mg od and chlorthalidone 25 mg od; amiloride 10 mg od and chlorthalidone 25 mg od), 4-period crossover, lasting 32 weeks. Equal numbers of 3 ethnic groups (white, black/black British, and Asian/Asian British) will ultimately be recruited to each of the trial arms (ie, 220 participants per ethnic group per arm). Seated, automated, unattended, office, systolic blood pressure measured 8 weeks after each treatment period begins will serve as the primary outcome measure., Conclusion: AIM-HY INFORM is a prospective, open-label, randomized trial which aims to evaluate first- and second-line antihypertensive therapies for multiethnic populations., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

: Whether isolated systolic hypertension in the young (ISHY) implies a worse outcome and needs antihypertensive treatment is still a matter for dispute. ISHY is thought to have different mechanisms than systolic hypertension in the elderly. However, findings from previous studies have provided inconsistent results. From the analysis of the literature, two main lines of research and conceptualization have emerged. Simultaneous assessment of peripheral and central blood pressure led to the identification of a condition called pseudo or spurious hypertension, which was considered an innocent condition. However, an increase in pulse wave velocity has been found by some authors in about 20% of the individuals with ISHY. In addition, obesity and metabolic disturbances have often been documented to be associated with ISHY both in children and young adults. The first aspect to consider whenever evaluating a person with ISHY is the possible presence of white-coat hypertension, which has been frequently found in this condition. In addition, assessment of central blood pressure is useful for identifying ISHY patients whose central blood pressure is normal. ISHY is infrequently mentioned in the guidelines on diagnosis and treatment of hypertension. According to the 2013 European Guidelines on the management of hypertension, people with ISHY should be followed carefully, modifying risk factors by lifestyle changes and avoiding antihypertensive drugs. Only future clinical trials will elucidate if a benefit can be achieved with pharmacological treatment in some subgroups of ISHY patients with associated risk factors and/or high central blood pressure.

High dietary sodium intake triggers increased blood pressure (BP). Animal studies show that dietary salt loading results in dermal Na + accumulation and lymphangiogenesis mediated by VEGF-C (vascular endothelial growth factor C), both attenuating the rise in BP. Our objective was to determine whether these mechanisms function in humans. We assessed skin electrolytes, BP, and plasma VEGF-C in 48 healthy participants randomized to placebo (70 mmol sodium/d) and slow sodium (200 mmol/d) for 7 days. Skin Na + and K + concentrations were measured in mg/g of wet tissue and expressed as the ratio Na + :K + to correct for variability in sample hydration. Skin Na + :K + increased between placebo and slow sodium phases (2.91±0.08 versus 3.12±0.09; P =0.01). In post hoc analysis, there was a suggestion of a sex-specific effect, with a significant increase in skin Na + :K + in men (2.59±0.09 versus 2.88±0.12; P =0.008) but not women (3.23±0.10 versus 3.36±0.12; P =0.31). Women showed a significant increase in 24-hour mean BP with salt loading (93±1 versus 91±1 mm Hg; P <0.001) while men did not (96±2 versus 96±2 mm Hg; P =0.91). Skin Na + :K + correlated with BP, stroke volume, and peripheral vascular resistance in men but not in women. No change was noted in plasma VEGF-C. These findings suggest that the skin may buffer dietary Na + , reducing the hemodynamic consequences of increased salt, and this may be influenced by sex., (© 2017 The Authors.)

The autonomic nervous system is important in regulating blood pressure, but whether it regulates aortic stiffness is more contentious. We conducted 3 studies in young, healthy individuals to address this important question. Study 1 was a cross-sectional study of 347 subjects with detailed measurements of hemodynamics and heart rate variability. In study 2, 9 subjects were given a bolus of intravenous nicotinic ganglion blocker, pentolinium, or saline in a random order and hemodynamics and heart rate variability were assessed before and after. In study 3, changes in hemodynamics and heart rate variability were assessed during stimulation of the sympathetic nervous system with the use of isometric handgrip exercise in 12 subjects. Study 1: aortic pulse wave velocity (P=0.003) was lowest in the subjects with the highest parasympathetic activity, but after adjusting for mean arterial pressure, the effect was abolished (P=0.3). Study 2: after pentolinium, sympathetic and parasympathetic activity fell (P=0.001 for both), mean arterial pressure, and heart rate increased (P=0.004 and P=0.04, respectively), but there was no change in pulse wave velocity in comparison to placebo (P=0.1). Study 3: during handgrip exercise, sympathetic activity (P=0.003), mean arterial pressure (P<0.0001), and aortic pulse wave velocity increased (P=0.013). However, pulse wave velocity adjusted for mean arterial pressure did not change (P=0.1). The main finding of these studies is that in young healthy subjects, the autonomic nervous system does not have a pressure-independent role in the regulation of aortic stiffness. However, these findings may not apply to patients with increased sympathetic tone or hypertension., (© 2016 The Authors.)

Vital organs are exposed to the central rather than the brachial blood pressure. To date, central blood pressure can be assessed noninvasively through the use of several devices. In this review, we critically discuss the clinical relevance of central blood pressure assessment. Considerable evidence suggests that central blood pressure is a better predictor of end-organ damage than brachial blood pressure. However, there is still uncertainty concerning the value of central pressure for predicting cardiovascular outcomes, as the existing studies are underpowered to address this issue. A full synthesis of the available data is needed in this regard. Among the different antihypertensive drug classes, beta-blockers appear to lower central blood pressure less than brachial blood pressure. This difference may, at least in part, explain the reduced efficacy of beta-blockers in the prevention of cardiovascular outcomes compared with the other antihypertensive drug classes, which may lower central and brachial blood pressure to a similar extent. Nevertheless, this differential effect might not be relevant to the newer beta-blockers with vasodilating properties, including nebivolol, celliprolol and carvedilol. However, whether a preferential reduction of central blood pressure results in better outcomes should be further assessed by appropriately powered clinical trials. Other emerging challenges include the assessment of the potential predictive value of central blood pressure variability and the development of new antihypertensive medications based on central blood pressure rather than brachial blood pressure.

Objectives: The positive association between adiposity and hypertension is well recognized. However, not all overweight individuals have elevated blood pressure (BP). Moreover, different factors may be associated with high BP in normal-weight versus overweight individuals. The aim of the current study was to examine the influence of adiposity on the relationship between SBP and underlying haemodynamic mechanisms in young adults., Method: Data from 2502 patients were available from the Enigma study. Detailed demographic, biochemical, and haemodynamic data were obtained in all individuals. Data were analysed between lower and upper tertiles of BMI and SBP, separately for each sex., Results: In normal-weight individuals, cardiac output (CO) was elevated in those with higher SBP, independently of body size. Moreover, higher CO was associated with an increased stroke volume in men (P < 0.001), but an increased heart rate in women (P = 0.002). In contrast, in overweight individuals, peripheral vascular resistance (PVR) was elevated in men with higher SBP (P = 0.02) and those with lower SBP had the lowest PVR of all groups. In linear regression analyses, there was a stronger association between SBP and CO in normal-weight individuals, but a stronger association between SBP and PVR in overweight individuals., Conclusion: Different haemodynamic mechanisms are associated with elevated SBP in young adults, depending on body size and sex. These data suggest the need for differential approaches to the identification and management of young adults with elevated BP.

Pressure measured with a cuff and sphygmomanometer in the brachial artery is accepted as an important predictor of future cardiovascular risk. However, systolic pressure varies throughout the arterial tree, such that aortic (central) systolic pressure is actually lower than corresponding brachial values, although this difference is highly variable between individuals. Emerging evidence now suggests that central pressure is better related to future cardiovascular events than is brachial pressure. Moreover, anti-hypertensive drugs can exert differential effects on brachial and central pressure. Therefore, basing treatment decisions on central, rather than brachial pressure, is likely to have important implications for the future diagnosis and management of hypertension. Such a paradigm shift will, however, require further, direct evidence that selectively targeting central pressure, brings added benefit, over and above that already provided by brachial artery pressure., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.)

Unknown to its hypertension specialists, a major teaching hospital changed the cuffs on its sphygmomanometers from manufacturer-validated to a uniform washable alternative, in line with 'Health and Safety' concerns surrounding potential cross-contamination between patients. When clinic doctors suspected serious under-reading with the new cuffs, a systematic comparison was undertaken in 54 patients (mean±s.d. age, 61±17 years), using two UM-101 sphygmomanometers, one using the original, manufacturer-supplied cuff and the other with the washable replacement. The study confirmed an average under-reading of 8±10/5±5 mm Hg using the washable cuff, and a third of patients with poorly controlled hypertension were considered normotensive, after using this cuff. The UM-101 sphygmomanometers have now been re-fitted with the original cuffs. Sphygmomanometer cuffs are not interchangeable between devices and a modicum of common sense should be shown to prevent changes made in the name of Health and Safety from having the opposite effect to that intended.

Aortic stiffness, an independent predictor of cardiovascular risk and all-cause mortality, can be estimated non-invasively by measuring carotid to femoral (aortic) pulse wave velocity (aPWV). The Vicorder device has been developed to measure aPWV with little operator training in a non-intrusive manner. The aim of this study was to assess the repeatability of aPWV measured with the Vicorder device and to compare aPWV values with those obtained using the SphygmoCor system. Vicorder and SphygmoCor aPWV was assessed in 122 subjects (53+/-18 years, 46 male) using both the manufacturers' and a standardized approach. Vicorder aPWV measurement proved to be highly repeatable (within-subject coefficient of variation 2.8%). Transit time differed significantly between the two devices (mean difference 22+/-9 ms, P<0.001), independent of the different algorithms used to calculate transit time. However, aPWV was similar between the two devices (mean difference 0.31+/-1.54 m s(-1), P<0.001) though with an inherent bias toward lower Vicorder aPWV values at high values of SphygmoCor aPWV. Bias was reduced by subtracting the additional femoral artery segment measured by the Vicorder device, also bringing the measure of transit time in closer agreement to SphygmoCor values (mean difference 5+/-9 ms, P<0.001). Transit time values significantly differed between the two devices and the Vicorder device reported lower aPWV values at higher SphygmoCor values of aPWV. This difference in transit time and inherent bias was reduced when adjustment for the additional femoral artery segment measured by the Vicorder device was made.

Isolated systolic hypertension is an important risk factor for cardiovascular disease and results primarily from elastic artery stiffening. Although various drug therapies are used to lower peripheral blood pressure (BP) in patients with isolated systolic hypertension, the effects of the 4 major classes of antihypertensive agents on central BP, pulse pressure (PP) amplification, and arterial stiffness in this condition are not clear. Fifty-nine patients over the age of 60 years with untreated isolated systolic hypertension (systolic BP > or =140 mm Hg and diastolic BP

Recent evidence suggests that central blood pressure is a more important determinant of cardiovascular risk than brachial pressure. Interestingly, antihypertensive drugs exert different effects on brachial and central pressure. Traditional beta-blockers, such as atenolol, appear to have an adverse impact on central pressure, despite lowering brachial pressure. This may help to explain the results of recent large outcome studies using atenolol. Further research is required to clarify whether other antihypertensive agents lower central pressure beyond the effects observed on brachial pressure.

Arterial stiffening is an independent predictor of mortality and underlies the development of isolated systolic hypertension (ISH). A number of factors regulate stiffness, but arterial calcification is also likely to be important. We tested the hypotheses that aortic calcification is associated with aortic stiffness in healthy individuals and that patients with ISH exhibit exaggerated aortic calcification compared with controls. A total of 193 healthy, medication-free subjects (mean age+/-SD: 66+/-8 years) were recruited from the community, together with 15 patients with resistant ISH. Aortic pulse wave velocity (PWV) was measured noninvasively, and aortic calcium content was quantified from high-resolution, thoraco-lumbar computed tomography images using a volume scoring method. In healthy volunteers, calcification was positively and significantly associated with aortic PWV (r=0.6; P<0.0001) but was not related to augmentation index or brachial PWV. Calcification was significantly higher in treatment-resistant and healthy subjects with ISH compared with controls (mean [interquartile range]: 1.92 [1.14 to 3.66], 0.84 [0.35 to 1.75], and 0.19 [0.1 to 0.78] cm3, respectively; P<0.0001 for both). In a multiple regression model, aortic calcium was independently associated with aortic PWV along with age, mean arterial pressure, heart rate, and estimated glomerular filtration rate (R(2)=0.51; P<0.0001). Only age, calcium phosphate product, and aortic PWV were independently associated with calcification. These data suggest that calcification may be important in the process of aortic stiffening and the development of ISH. Calcification may underlie treatment resistance in ISH, and anticalcification strategies may present a novel therapy.

Pulse pressure varies throughout the arterial tree, resulting in a gradient between central and peripheral pressure. Factors such as age, heart rate, and height influence this gradient. However, the relative impact of cardiovascular risk factors and atheromatous disease on central pressure and the normal variation in central pressure in healthy individuals are unclear. Seated peripheral (brachial) and central (aortic) blood pressures were assessed, and the ratio between aortic and brachial pulse pressure (pulse pressure ratio, ie, 1/amplification) was calculated in healthy individuals, diabetic subjects, patients with cardiovascular disease, and in individuals with only 1 of the following: hypertension, hypercholesterolemia, or smoking. The age range was 18 to 101 years, and data from 10 613 individuals were analyzed. Compared with healthy individuals, pulse pressure ratio was significantly increased (ie, central systolic pressure was relatively higher) in individuals with risk factors or disease (P<0.01 for all of the comparisons). Although aging was associated with an increased pulse pressure ratio, there was still an average+/-SD difference between brachial and aortic systolic pressure of 11+/-4 and 8+/-3 mm Hg for men and women aged >80 years, respectively. Finally, stratifying individuals by brachial pressure revealed considerable overlap in aortic pressure, such that >70% of individuals with high-normal brachial pressure had similar aortic pressures as those with stage 1 hypertension. These data demonstrate that cardiovascular risk factors affect the pulse pressure ratio, and that central pressure cannot be reliably inferred from peripheral pressure. However, assessment of central pressure may improve the identification and management of patients with elevated cardiovascular risk.

Objectives: Some beta-blockers are less effective in reducing central blood pressure than other antihypertensive drugs, which may explain the higher rate of events in subjects randomized to atenolol in recent trials. We hypothesized that nebivolol, a mixed beta-blocker/nitro-vasodilator, would be more effective than atenolol in reducing central blood pressure and augmentation index (AIx). The aim of the present study was to test this in a double-blind, randomized, cross-over study, in a cohort of subjects with isolated systolic hypertension., Methods: Following a 2-week placebo run-in, 16 never-treated hypertensive subjects received atenolol (50 mg), nebivolol (5 mg) and placebo, each for 5 weeks, in a random order. Seated brachial blood pressure and heart rate were measured. Aortic blood pressure, AIx and pulse wave velocity (PWV) were assessed non-invasively., Results: The placebo-corrected fall in brachial pressure was similar between nebivolol and atenolol, as was the reduction in PWV (mean change +/- SEM: -1.0 +/- 0.3 and -1.2 +/- 0.2 m/s; P = 0.2). However, there was less reduction in heart rate (-19 +/- 2 versus -23 +/- 2 beats/min; P < 0.01) and increase in AIx (+6 +/- 1 versus +10 +/- 1%; P = 0.04), following nebivolol. Aortic pulse pressure was significantly lower (50 +/- 2 versus 54 +/- 2 mmHg; P = 0.02) after nebivolol. N-terminal pro-B-type natriuretic peptide (proBNP) rose on both drugs (100 +/- 33 versus 75 +/- 80 pg/ml; P < 0.01 for both, NS for comparison)., Conclusions: Nebivolol and atenolol have similar effects on brachial blood pressure and aortic stiffness. However, nebivolol reduces aortic pulse pressure more than atenolol, which may be related to a less pronounced rise in AIx and bradycardia. Whether this will translate into differences in clinical outcome requires further investigation.

Isolated systolic hypertension is associated with increased cardiovascular risk. It is thought to result from large artery stiffening, which is determined by structural components within the vasculature but also by functional factors including NO and endothelin-1. We hypothesized that endothelial dysfunction would account for increased arterial stiffness in patients with isolated systolic hypertension. The aim of this study was to investigate the relationship between endothelial function and arterial stiffness in these patients along with control subjects. We studied 113 subjects: 35 patients with isolated systolic hypertension (mean age+/-SD: 68+/-6 years), 30 age-matched control subjects (65+/-5 years), and 48 young control subjects (37+/-9 years). Aortic pulse wave velocity (PWV) was derived by sequential carotid/femoral waveform recordings. Conduit artery endothelial function was determined by flow-mediated dilatation. Aortic PWV was higher (9.65+/-2.56 m/s versus 8.26+/-0.85 m/s; P=0.009), and flow-mediated dilatation was lower (2.67+/-1.64% versus 4.79+/-3.1%; P=0.03) in patients with isolated systolic hypertension compared with age-matched control subjects. Similarly, aortic PWV was also higher, and flow-mediated dilatation lower, in older versus young control subjects (8.26+/-0.85 m/s versus 7.09+/-1.01 m/s and 4.79+/-3.1% versus 6.94+/-2.7%; P=0.004 for both). Overall, aortic PWV correlated inversely with flow-mediated dilatation (r=-0.3; P=0.001), which remained significant after adjustment for confounding factors (P=0.01). Patients with isolated systolic hypertension have higher aortic PWV and decreased endothelial function compared with age-matched control subjects. Our results suggest that endothelial function contributes significantly to increased arterial stiffness in patients with isolated systolic hypertension and with age.

1. Ageing exerts a marked effect on the cardiovascular system and, in particular, the large arteries. Using a variety of techniques to assess arterial stiffness, many cross-sectional studies have demonstrated a significant relationship between age and aortic stiffness, although the age-related changes observed in peripheral arteries appear to be less marked. 2. The relationship between arterial stiffness and hypertension is more complex. The distending, or mean arterial, pressure is an important confounder of measurements of arterial stiffness and, therefore, must be taken into consideration when assessing arterial stiffness in hypertensive subjects or investigating the effect of antihypertensive agents. Current methods for correcting for differences in distending pressure involve pharmacological manipulation, statistical correction or mathematical manipulation of stiffness indices. 3. Many studies have provided evidence that both peripheral (muscular) and central (elastic) arteries are stiffer in subjects with mixed (systolic/diastolic) hypertension compared with normotensive subjects. However, it is unclear to what extent differences in mean arterial pressure explain the observed differences in hypertensive subjects. In contrast, isolated systolic hypertension is associated with increased aortic, but not peripheral artery, stiffness, although the underlying mechanisms are somewhat unclear. 4. Traditional antihypertensive agents appear to reduce arterial stiffness, but mostly via an indirect effect of lowering mean pressure. Therefore, therapies that target the large arteries to reduce stiffness directly are urgently required. Agents such as nitric oxide donors and phosphodiesterase inhibitors may be useful in reducing stiffness via functional mechanisms. In addition, inhibitors or breakers of advanced glycation end-product cross-links between proteins, such as collagen and elastin, hold substantial promise.

Background: Recent data suggest that atenolol may be inferior to other antihypertensive drugs in reducing cardiovascular risk in older individuals with hypertension, despite lowering peripheral blood pressure (BP). We hypothesized that that atenolol fails to reduce central BP as much as other agents. The aim of the present study was to compare the hemodynamic effects of atenolol and eprosartan in a double-blind, randomized, cross-over study., Methods: After a 2-week placebo run-in, 21 subjects with never-treated hypertension underwent 6 weeks of therapy with atenolol (50 mg) and eprosartan (600 mg). Central BP and augmentation index were assessed using pulse wave analysis, and aortic pulse wave velocity was measured, at baseline and at the end of each treatment., Results: Both drugs reduced peripheral BP to the same degree. However, there was a significantly greater reduction in central systolic BP with eprosartan (means +/- SEM: 16 +/- 3 v 11 +/- 2 mm Hg; P = .03). Despite identical reductions in mean pressure, atenolol reduced aortic pulse wave velocity more than eprosartan (0.8 +/- 0.1 v 0.5 +/- 0.1 m/sec; P = .005). Conversely, augmentation index and N-terminal pro-brain natiuretic peptide levels were reduced significantly after eprosartan (6% +/- 2% and 11 +/- 5 pg/mL, respectively) but were increased after atenolol (7% +/- 2% and 67 +/- 24 pg/mL, respectively)., Conclusions: These data indicate that despite similar effects on peripheral BP and a greater effect on aortic stiffness, atenolol had less impact on central systolic BP than eprosartan because it failed to reduce wave reflection. This provides one potential explanation for the failure of atenolol to improve outcome in older patients with essential hypertension.

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.

Background: Arterial stiffness is an independent determinant of cardiovascular risk, and arterial stiffening is the predominant abnormality in systolic hypertension. Elastin is the main elastic component of the arterial wall and can be degraded by a number of enzymes, including matrix metalloproteinase-9 (MMP-9) and MMP-2. We hypothesized that elastase activity would be related to arterial stiffness and tested this using isolated systolic hypertension (ISH) as a model of stiffening and separately in a large cohort of healthy individuals., Methods and Results: A total of 116 subjects with ISH and 114 matched controls, as well as 447 individuals free from cardiovascular disease were studied. Aortic and brachial pulse wave velocity (PWV) and augmentation index were determined. Blood pressure, lipids, C-reactive protein, MMP-9, MMP-2, serum elastase activity (SEA), and tissue-specific inhibitor 2 of metalloproteinases were measured. Aortic and brachial PWV, MMP-9, MMP-2, and SEA levels were increased in ISH subjects compared with controls (P=0.001). MMP-9 levels correlated linearly and significantly with aortic (r=0.45; P=0.001) and brachial PWV (r=0.22; P=0.002), even after adjustments for confounding variables. In the younger, healthy subjects, MMP-9 and SEA were also independently associated with aortic PWV., Conclusions: Aortic stiffness is related to MMP-9 levels and SEA, not only in ISH, but also in younger, apparently healthy individuals. This suggests that elastases including MMP-9 may be involved in the process of arterial stiffening and development of ISH. The relationship between arterial stiffness and elastase activity was examined in isolated systolic hypertension (ISH), and separately in a large cohort of healthy individuals. Aortic stiffness is related to MMP-9, not only in ISH, but also in healthy individuals, suggesting elastases may be involved in the process of arterial stiffening and the development of ISH.

Essential hypertension is a common disorder, associated with increased endothelin-1-mediated vasoconstrictor tone at rest. We hypothesized that increased vasoconstrictor activity of endothelin-1 might explain why the normal decrease in peripheral vascular resistance in response to exercise is attenuated in hypertensive patients. Therefore, we investigated the effect of endothelin A (ET(A)) receptor blockade on the vasodilator response to handgrip exercise. Forearm blood flow responses to handgrip exercise (15%, 30%, and 45% of maximum voluntary contraction) were assessed in hypertensive patients and matched normotensive subjects, before and after intra-arterial infusions of the ET(A) receptor antagonist BQ-123; a control dilator, hydralazine; and placebo (saline). Preinfusion (baseline) vasodilation in response to exercise was significantly attenuated at each workload in hypertensive patients compared with normotensive subjects. Intra-arterial infusions of hydralazine and saline did not increase the vasodilator response to exercise in either hypertensives or normotensives at any workload. The vasodilator response to exercise was markedly enhanced after BQ-123 at the 2 higher workloads in hypertensives (157+/-48%, P<0.01; 203+/-58%, P<0.01) but not in normotensives. This suggests that the impaired vasodilator response to exercise in hypertensive patients is, at least in part, a functional limitation caused by endogenous ET(A) receptor-mediated vasoconstriction. Treatment with endothelin receptor antagonists may, therefore, increase exercise capacity in essential hypertension.