Serum sclerostin: the missing link in the bone-vessel cross-talk in hemodialysis patients?

UNLABELLED: We found for the first time that in maintenance hemodialysis patients, higher sclerostin serum level was associated with severe abdominal aortic calcification (AAC). In addition, cortical bone microarchitecture (density and thickness) assessed by high-resolution peripheral quantitative computed tomography (HR-pQCT) at tibia was also independently associated with severe AAC. These results suggest that sclerostin may be involved in the association of mineral and bone disorder with vascular calcification in hemodialysis patients. INTRODUCTION: Severe abdominal aortic calcifications are predictive of high cardiovascular mortality in maintenance hemodialysis (MHD) patients. In patients with end-stage renal disease, a high aortic calcification score was associated with lower bone turnover on bone biopsies. Thus, we hypothesized that sclerostin, a Wnt pathway inhibitor mainly secreted by osteocytes and acting on osteoblasts to reduce bone formation, may be associated with vascular calcifications in MHD patients. METHODS: Fifty-three MHD patients, aged 53 years [35-63] (median [Q1-Q3]) were included. Serum was sampled before the MHD session to assay sclerostin. Framingham score was computed and the abdominal aortic calcification (AAC) score was assessed according to Kauppila method on lateral spine imaging using DEXA. Tibia bone status was evaluated by high-resolution peripheral quantitative computed tomography (HR-pQCT). Patients were distributed into two groups according to their AAC score: patients with mild or without AAC (score below 6) versus patients with severe AAC (score of 6 and above). RESULTS: In multivariate analysis, after adjustment on age, dialysis duration and diabetes, serum sclerostin and cortical thickness were independently associated with severe AAC (odds ratio (OR) = 1.43 for each 0.1 ng/mL increase [95 % confidence interval (CI) 1.10-1.83]; p = 0.006 and 0.16 for 1 SD increase [0.03-0.73]; p = 0.018, respectively). A second cardiovascular model adjusted on Framingham score and the above mentioned confounders showed similar results. CONCLUSIONS: Elevated sclerostin serum level and poorer tibia cortical bone structure by HR-pQCT were positively and independently associated with higher odds of severe AAC in MHD patients. Serum sclerostin may become a biomarker of mineral and bone disorder and vascular risk in MHD patients.

Central artery pulse pressure in end-stage renal disease: the roles of aortic diameter, aortic stiffness and wave reflection.

In elderly subjects and patients with end-stage renal disease (ESRD), carotid pulse pressure (PP) is an independent and significant predictor of cardiovascular (CV) risk. Whereas in the elderly carotid diameter, but not carotid stiffness, is an associated CV risk factor, an opposite CV risk pattern was observed in ESRD patients that was associated with stiffness. Whether in ESRD patients arterial diameter, stiffness or both are involved in the mechanism(s) of increased carotid PP has never been investigated. Nondiabetic ESRD patients (n = 144) were compared with 57 control subjects matched for age, sex and mean blood pressure, but with higher brachial and carotid PP. Noninvasive echo-Doppler techniques and pulse wave velocity (PWV) and pulse wave analysis were used to evaluate cardiac and carotid arterial structures and functions using multiple stepwise regressions. In controls, carotid PP was associated only with stroke volume, arterial wave reflections and aortic PWV, but not aortic diameter. In ESRD patients, it was associated with wave reflections, aortic PWV, stroke volume and higher aortic diameter. In ESRD patients and controls, elevated carotid PP mainly reflected increased aortic PWV and earlier wave reflections. Aortic diameter had an impact only on ESRD patients, where it compensated for enhanced aortic stiffness and the more pronounced effect of reflected waves. This hemodynamic profile differs consistently from that in elderly subjects of the general population and selectively influences CV risk and drug treatment.

The effects of cinacalcet on blood pressure, mortality and cardiovascular endpoints in the EVOLVE trial.

Patients with end-stage renal disease often have derangements in calcium and phosphorus homeostasis and resultant secondary hyperparathyroidism (sHPT), which may contribute to the high prevalence of arterial stiffness and hypertension. We conducted a secondary analysis of the Evaluation of Cinacalcet Hydrochloride Therapy to Lower Cardiovascular Events (EVOLVE) trial, in which patients receiving hemodialysis with sHPT were randomly assigned to receive cinacalcet or placebo. We sought to examine whether the effect of cinacalcet on death and major cardiovascular events was modified by baseline pulse pressure as a marker of arterial stiffness, and whether cinacalcet yielded any effects on blood pressure. As reported previously, an unadjusted intention-to-treat analysis failed to conclude that randomization to cinacalcet reduces the risk of the primary composite end point (all-cause mortality or non-fatal myocardial infarction, heart failure, hospitalization for unstable angina or peripheral vascular event). However, after prespecified adjustment for baseline characteristics, patients randomized to cinacalcet experienced a nominally significant 13% lower adjusted risk (95% confidence limit 4-20%) of the primary composite end point. The effect of cinacalcet was not modified by baseline pulse pressure (Pinteraction=0.44). In adjusted models, at 20 weeks cinacalcet resulted in a 2.2 mm Hg larger average decrease in systolic blood pressure (P=0.002) and a 1.3 mm Hg larger average decrease in diastolic blood pressure (P=0.002) compared with placebo. In summary, in the EVOLVE trial, the effect of cinacalcet on death and major cardiovascular events was independent of baseline pulse pressure.

Impact of aortic stiffness attenuation on survival of patients in end-stage renal failure.

BACKGROUND: Aortic pulse wave velocity (PWV) is a predictor of mortality in patients with end-stage renal failure (ESRF). The PWV is partly dependent on blood pressure (BP), and a decrease in BP can attenuate the stiffness. Whether the changes in PWV in response to decreases in BP can predict mortality in ESRF patients has never been investigated. METHODS AND RESULTS: One hundred fifty ESRF patients (aged 52+/-16 years) were monitored for 51+/-38 months. From entry until the end of follow-up, the changes of PWV in response to decreased BP were measured ultrasonographically. BP was controlled by adjustment of "dry weight" and, when necessary, with ACE inhibitors, calcium antagonists, and/or beta-blockers, in combination if necessary. Fifty-nine deaths occurred, including 40 cardiovascular and 19 noncardiovascular events. Cox analyses demonstrated that independent of BP changes, the predictors of all-cause and cardiovascular mortality were as follows: absence of PWV decrease in response to BP decrease, increased left ventricular mass, age, and preexisting cardiovascular disease. Survival was positively associated with ACE inhibitor use. After adjustment for all confounding factors, the risk ratio for the absence of PWV decrease was 2.59 (95% CI 1.51 to 4.43) for all-cause mortality and 2.35 (95% CI 1.23 to 4.41) for cardiovascular mortality. The risk ratio for ACE inhibitor use was 0.19 (95% CI 0.14 to 0.43) for all-cause mortality and 0.18 (95% CI 0.06 to 0.55) for cardiovascular mortality. CONCLUSIONS: These results indicate that in ESRF patients, the insensitivity of PWV to decreased BP is an independent predictor of mortality and that use of ACE inhibitors has a favorable effect on survival that is independent of BP changes.

Impact of aortic stiffness on survival in end-stage renal disease.

BACKGROUND: Damage to large arteries is a major factor in the high cardiovascular morbidity and mortality of patients with end-stage renal disease (ESRD). Increased arterial stiffness and intima-media thickness, together with increased pulse pressure, are the principal arterial alterations. Whether increased aortic pulse-wave velocity (PWV), a classic marker of increased arterial stiffness, may predict all-cause and/or cardiovascular mortality has never been investigated. METHODS AND RESULTS: A cohort of 241 patients with ESRD undergoing hemodialysis was studied between April 1987 and April 1998. The mean duration of follow-up was 72+/-41 months (mean+/-SD). Mean age at entry was 51.5+/-16.3 years. Seventy-three deaths occurred, including 48 cardiovascular and 25 noncardiovascular fatal events. At entry, together with standard clinical and biochemical analyses, patients underwent echocardiography and aortic PWV measured by Doppler ultrasonography. On the basis of Cox analyses, 2 factors emerged as predictors of all-cause and cardiovascular mortality: age and aortic PWV. Hemoglobin and low diastolic pressure interfered to a smaller extent. After adjustment for all the confounding factors, an OR for PWV >12. 0 versus <9.4 m/s was 5.4 (95% CI, 2.4 to 11.9) for all-cause mortality and 5.9 (95% CI, 2.3 to 15.5) for cardiovascular mortality. For each PWV increase of 1 m/s in our study population, all-cause mortality-adjusted OR was 1.39 (95% CI, 1.19 to 1.62). CONCLUSIONS: These results provide the first direct evidence that in patients with ESRD, increased aortic stiffness determined by measurement of aortic PWV is a strong independent predictor of all-cause and mainly cardiovascular mortality.

Comparative effects of aging in men and women on the properties of the arterial tree.

OBJECTIVES: We measured the properties of the arterial tree, seeking differences between men and women as they aged. BACKGROUND: There are many differences between men and women, besides menopause, which might account for such disparities. These include body height, heart rate, stroke volume and smaller arterial diameters. Any gender differences in arterial stiffness could influence pulse pressure (PP), now recognized as a cardiovascular risk factor. METHODS: A total of 530 patients (347 men and 183 women) were classified by age into quartiles: < or = 40, 41-47, 48-54 and > or = 55 years. The middle groups represented the menopausal years. Studies included brachial artery blood pressure (BP), aortic pulse wave velocity (PWV), B-mode ultrasonography and wave form analysis of the common carotid artery (CCA), with its conversion to the aortic wave formin. Standard echocardiography provided left ventricular dimensions and flows. Calculated values included CCA compliance and distensibility, systemic compliance, stroke volume and peripheral resistance. RESULTS: At all ages, women had higher heart rates but lower BP than men. Pulse pressure, however, was lower in young women and higher in older women. Measurements influenced by body size, such as CCA diameter, compliance and systemic compliance, were lower in women. Those related to arterial wall properties, such as CCA and aortic distensibility, were the same. Although aortic PWV rose similarly with aging, PWV had more of an influence on PP in women than did mean BP. The reverse was true in men. CONCLUSIONS: Despite lower mean BP and similar arterial distensibilitvy, women develop a higher degree of pulsatility with aging, as compared with men. This is mainly due to their smaller physical characteristics, independent of the role of menopause and its related hormonal changes.

Influence of body height on pulsatile arterial hemodynamic data.

OBJECTIVES: This study sought to present evidence that short stature is a hemodynamic liability, which could explain in part the inverse relation between body height and cardiovascular risk. BACKGROUND: Other explanations for the association of short stature with increased cardiovascular risk include advancing age, reduced pulmonary function, genetic factors, poor childhood nutrition and small-caliber coronary arteries. This study adds another factor-the physiologic effects of reduced body height on the arterial tree, which increase left ventricular work and jeopardize myocardial perfusion. METHODS: Four hundred two subjects were studied: 149 with end-stage renal disease and 253 with normal renal function. Measurements included blood pressure, body height, cardiac cycle length, carotid to femoral artery pulse wave velocity, carotid artery pulse waves (by applanation tonometry) and the arrival time of reflected waves. Calculations included the carotid augmentation index, carotid artery compliance and the diastolic to systolic pressure-time ratio (an index of myocardial supply and demand). RESULTS: On linear and stepwise multiple regression, body height correlated with all variables except mean blood pressure. CONCLUSIONS: The early systolic arrival of reflected waves in short people in this group acts to stiffen the aorta and increase the pulsatile effort of the left ventricle, even at the same mean blood pressures. Short stature also induces a faster heart rate, which increases cardiac minute work and shorten diastole. Stiffening lowers the aortic diastolic pressure and, coupled with a shortened diastole, could adversely influence myocardial supply. Although indirect, this evidence supports a physiologic hypothesis for the body height-cardiovascular risk association.

Pulsatile diameter and elastic modulus of the aortic arch in essential hypertension: a noninvasive study.

A noninvasive evaluation of the aortic arch diameter was performed in 16 subjects with sustained essential hypertension and in 15 normal subjects of similar age, gender and body surface area. In all subjects, measurements were obtained of brachial mean arterial pressure and pulse pressure, cardiac mass (judged on echocardiography) and carotid-femoral pulse wave velocity together with ultrasound determinations of aortic arch diastolic and systolic diameter (suprasternal window). For each subject, pulsatile change in aortic diameter, strain and aortic arch elastic modulus were calculated. Compared with normal subjects, the hypertensive subjects showed an increase in aortic arch diameter (diastolic diameter 29.6 +/- 1.0 versus 25.4 +/- 1.0 mm, p less than 0.01), in elastic modulus (1.071 +/- 0.131 versus 0.526 +/- 0.045 10(5) N.m-2, p less than 0.001) and pulse wave velocity (11.8 +/- 0.5 versus 8.9 +/- 0.3 m/s, p less than 0.001). In the study group, a positive correlation was observed between diastolic aortic arch diameter and mean arterial pressure (r = 0.54, p less than 0.01) and between elastic modulus and cardiac mass (r = 0.60, p less than 0.01). Elastic modulus and age were positively correlated (r = 0.73, p less than 0.01) in hypertensive but not in normal subjects (r = 0.08, NS). This study is the first to demonstrate noninvasively that both the aortic arch diameter and the elastic modulus are increased in patients with sustained uncomplicated essential hypertension. These findings suggest that the increase in elastic modulus could influence the development of cardiac hypertrophy, and that both age and blood pressure act independently as factors that alter the arterial wall of subjects with sustained essential hypertension.

Relationship of plasma renin activity and aldosterone levels with hemodynamic functions in essential hypertension.

Correlates of plasma renin activity and plasma aldosterone levels with hemodynamic functions were studied in 47 male patients with untreated, permanent essential hypertension. All subjects had a normal creatinine clearance and received a diet of 110 mEq/day of sodium. Supine plasma renin activity was directly correlated with cardiac index (P less than.01) and cardiopulmonary blood volume (P=.01). Percentage changes in plasma renin activity and total peripheral resistance in response to upright position were positively correlated (P less than.001). Supine plasma aldosterone level was directly correlated with stroke index (P less than .001) and negatively correlated with hear rate (P less than .05). No significant correlation of aldosterone level was observed with the other measurements, including plasma renin activity. The study points to the neural sympathetic control of plasma renin activity in essential hypertension and suggests the existence of some interrelationships between aldosterone level and cardiac performance.

Vascular disease and atherosclerosis in uremia.

Epidemiological and clinical studies have shown that cardiovascular disease in patients with end-stage renal disease (ESRD) is frequently related to damage of large conduit arteries. Arterial disease is responsible for the high incidence of ischemic heart disease, peripheral artery diseases, left ventricular hypertrophy and congestive heart failure. The vascular complications in ESRD are due to two different but associated mechanisms, namely atherosclerosis and arteriosclerosis. Whereas the former principally affects the conduit function with ischemic lesions being the most characteristic consequence, the latter primarily disturbs the cushioning function of large arteries. Arteriosclerosis in ESRD patients is characterized by diffuse dilation and hypertrophy of large conduit arteries and stiffening of arterial walls, and represents a clinical form of an accelerated aging process. The main clinical characteristics of arterial stiffening are changes in blood pressure with isolated increase in systolic pressure and normal or lower diastolic pressure. The consequences of these alterations are: (i) an increased LV afterload with development of LV hypertrophy and increased myocardial oxygen demand, and (ii) altered coronary perfusion and subendocardial blood flow distribution. Epidemiological studies have identified arterial remodeling and stiffening as independent predictors of overall and cardiac mortality in ESRD patients.

An indirect approach for the study of the elastic modulus of the brachial artery in patients with essential hypertension.

An indirect approach for the study of the changes in the incremental circumferential modulus (E) of the brachial artery after arteriolar vasodilatation was undertaken in patients with sustained essential hypertension. The product of E and the thickness (h) of the arterial wall was evaluated by means of the Moens-Korteweg equation using determinations of brachioradial pulse wave velocity and brachial artery diameter with pulsed Doppler methods. In three homogeneous groups of patients with hypertension the Eh product was studied after vasodilatation caused either by nitrendipine, a calcium entry blocking agent, or by medroxalol, an alpha and beta blocking agent, or by isosorbid dinitrate. The three drugs caused similar reductions in blood pressure and increases in arterial diameter and hence decreases in wall thickness. Variance analysis for multigroups indicated that the decrease in Eh after vasodilatation was significant for nitrendipine but not for medroxalol and isosorbid dinitrate. Covariance analysis showed that for any level in Eh product the decrease in Eh was higher for nitrendipine than for isosorbid dinitrate and medroxalol. Since the three drugs had comparable mechanical and geometrical effects, the study provided evidence that, in men with essential hypertension, the smooth muscle tone of the brachial artery was significantly more sensitive to calcium inhibition than to autonomic blockade, causing a more important decrease in elastic modulus.

Arterial and venous compliance in sustained essential hypertension.

Arterial and venous compliances are decreased in men with sustained essential hypertension. The reduced arterial compliance acts to maintain systolic pressure and end-systolic stress, thus contributing to the development of cardiac hypertrophy. Since cardiac output remains within the normal range in the hypertrophied hypertensive heart, elevated left ventricular pressures, and therefore increased cardiac filling pressures, are necessary if an adequate stroke volume is to be maintained. In hypertensive persons, reduced venous compliance acts to maintain the filling pressure of the heart in the presence of reduced intravascular volume. In patients with hypertension, even if compliance changes have been initiated by the elevated blood pressure itself, the reduced arterial and venous compliance observed in cross-sectional studies is not simply the mechanical consequence of the elevated blood pressure, but also reflects intrinsic alterations of the vascular wall. Consequently, blood pressure reduction caused by antihypertensive agents is not constantly associated with a reversion of the decreased vascular compliance. Such observations may be of importance in the consideration of cardiovascular morbidity and mortality in patients treated for hypertension.

Recent advances on large arteries in hypertension.

The most classic hemodynamic concept explaining the increased mean arterial pressure in hypertension reflects an increased total peripheral resistance dynamically and an increased wall-to-lumen ratio to suppress smaller arteries. However, a more current consideration takes into account not only that steady component but also the pulsatile component of blood pressure, a point that importantly modifies the traditional hemodynamic definition. Whereas mean arterial pressure is almost constant along the arterial tree, the pulse pressure increases markedly from the more central to the peripheral arteries, indicating that in vivo each artery should be characterized according to its own blood pressure curve. This important concept implies major modifications in the methods used to investigate the relationships between mechanical factors and large artery structure and function. It therefore seems reasonable that in hypertension the large arteries should no longer be considered as passive conduits but rather in terms of their active behavioral response to the mechanical forces to which they are subjected. New investigational aspects in hypertension therefore now involve not only genetic, cellular, and molecular mechanisms but also transductional hemodynamic mechanisms reflecting changing patterns in the extracellular matrix that influence structural remodeling of the vessels.

Influence of sex on arterial hemodynamics and blood pressure. Role of body height.

Systolic pressure is lower in premenopausal women than in age-matched men, but underlying alterations are not well characterized. Aging and body size alter arterial function, influencing pressure wave propagation and amplification in peripheral and central arteries. To assess the possibility that systolic pressure differences in women are related to smaller body size, we studied arterial function in 119 men and 104 women. Premenopausal and postmenopausal women were compared with age-matched men. The following parameters were measured: ankle-arm pressure index (Doppler), aortic and arterial distensibility (pulse wave velocity), systolic pressure and the effect and time delay of arterial wave reflections in the common carotid artery (applanation tonometry), and diameters of the abdominal aorta and aortic bifurcation and their ratio (aortic tapering, echography). Premenopausal women had lower brachial (P < .05) and ankle (P < .01) systolic pressures than age-matched men, whereas the ankle-arm pressure index was higher in men (P < .01). In the overall population the ankle-arm index was positively correlated with body height (P < .001). Carotid systolic pressure was similar in women and men, with an increased effect and earlier return of wave reflections in women (P < .01). The effect of wave reflections was inversely correlated with body height (P < .001) and positively associated with aortic tapering (P < .001), which was increased in women (P < .01). In premenopausal women the distensibility of brachial and femoral arteries was higher than in age-matched men (P < .01), whereas aortic distensibility was not different.(ABSTRACT TRUNCATED AT 250 WORDS)

Essential hypertension: an approach to clinical data by the use of models.

A new approach, based on animal circulatory models, was proposed for the study of clinical data in hypertension. Clinical data were identified with steady states in models. From the study of models, possible impairments, susceptible to account for the observed derivations of steady states in men, were analyzed. To be specific, the 1967-Guyton-Coleman model was confronted with a set of data on essential hypertension. The approach afforded a physiological interpretation for statistical results performed on clinical data.

Aortic pulse wave velocity as a marker of cardiovascular risk in hypertensive patients.

Large artery damage is a major contributory factor to cardiovascular morbidity and mortality of patients with hypertension. Pulse wave velocity (PWV), a classic evaluation of arterial distensibility, has never been ascertained as a cardiovascular risk marker. To determine the factors influencing aortic PWV and the potential predictor role of this measurement, we studied a cohort of 710 patients with essential hypertension. Atherosclerosis alterations (AA) were defined on the basis of clinical events. Calculation of cardiovascular risks, by use of Framingham equations, was performed in subjects without AA. PWV was higher in the presence of AA (14.9+/-4.0 versus 12.4+/-2.6 m/s, P<0.0001), even after adjustments on confounding factors and was the first determinant (P<0.0001) of the extent of atherosclerosis assessed as the sum of the atherosclerotic sites. In patients without AA, all cardiovascular risks increased constantly with PWV. Furthermore, at a given age, aortic PWV was the best predictor of cardiovascular mortality. The odds ratio of being in a high cardiovascular mortality risk group (>5% for 10 years) for patients in the upper quartile of PWV was 7.1 (95% confidence intervals 4.5 to 11.3). The presence of a PWV >13 m/s, taken alone, appeared as a strong predictor of cardiovascular mortality with high performance values. This study shows that aortic PWV is strongly associated with the presence and extent of atherosclerosis and constitutes a forceful marker and predictor of cardiovascular risk in hypertensive patients.

Rapid dextran infusion in essential hypertension.

Hemodynamic parameters were studied before and after rapid dextran infusion in 34 men including 17 patients with sustained essential hypertension and 17 normotensive controls. In both groups of patients, dextran infusion induced a significant increase (p less than 0.001) in central venous pressure (CVP), cardiac output (CO), and stroke volume. The percent change in stroke volume was significantly higher in hypertensives (p less than 0.001) than in controls. Three indices of volume expansion were calculated: 1) the ratio between the change in CO and the change in volume, which was significantly higher in hypertensives (p less than 0.025), 2) the ratio between the change in CO and the change in CVP, which was similar in both groups, and 3) the ratio between the change in volume and the change in CVP, which was significantly reduced in hypertensives (p less than 0.001). In the overall population, the latter ratio was negatively correlated with the change in CO (or in stroke volume) induced by expansion ( r = -0.75). The results provided evidence that: 1) the slope of the relationship between CO and blood volume was steeper in hypertensives than in normotensives, and 2) the steeper slope was due to a reduction in the effective compliance of the vascular bed, causing a greater elevation in CO per unit rise in volume.

Carotid arterial stiffness as a predictor of cardiovascular and all-cause mortality in end-stage renal disease.

Damage of large arteries is a major contributory factor to the high pulse pressure observed in patients with end-stage renal disease. Whether incremental modulus of elasticity (Einc), a classic marker of arterial stiffness, can predict cardiovascular mortality has never been investigated. A cohort of 79 patients with end-stage renal disease undergoing hemodialysis was studied between September 1995 and January 1998. Mean age at entry was 58+/-15 years. The duration of follow-up was 25+/-7 months, during which 10 cardiovascular and 8 noncardiovascular fatal events occurred. At entry, carotid Einc was calculated from measurements of diameter, thickness (echo-tracking technique), and pulse pressure (tonometry). Based on Cox analyses, 2 dominant factors emerged as predictors of all-cause and cardiovascular mortality: increased Einc and decreased diastolic blood pressure. Lipid abnormalities and the presence of previous cardiovascular events interfered to a smaller extent. After adjustment for confounding variables, the odds ratio for Einc >/=1 kPa-3 was 9.2 (95% confidence interval, 2.4 to 35.0) for all-cause mortality. These results provide the first direct evidence that in patients with end-stage renal disease undergoing hemodialysis, arterial alterations, as determined from carotid Einc, are strong independent predictors of all-cause and cardiovascular mortality.

Tilt test in essential hypertension. Differential responses in heart rate and vascular resistance.

Changes in hemodynamic parameters following 50-degree head-up tilt were studied in a population of 56 men, including 35 subjects with sustained essential hypertension and 21 age-matched normotensive controls. The increase in heart rate following tilt was similar in groups and exhibited the same reduction in response with age. The increase in vascular resistance following tilt was strongly and positively correlated with both age and baseline vascular resistance. The latter finding was observed mainly in hypertensive subjects. The study provided evidence that differentiated responses of heart rate and vascular resistance may be observed following orthostasis. In both normal and hypertensive subjects, the age dependence of heart rate response possibly reflected differences in baroreceptor reflex control of parasympathetic and sympathetic activity. In hypertensive subjects, the vascular response was amplified with age and baseline vascular resistance, suggesting a role for structural changes of the vessels in the increased vascular response.

Renal and systemic hemodynamics in sustained essential hypertension.

Cardiac output (CO), renal blood flow (RBF), calf blood flow (CBF), and hepatic blood flow (HBF), glomerular filtration rate (GFR), and dopamine beta hydroxylase (D beta H) activity were studied in 198 men (67 normotensive controls and 131 hypertensive patients) of the same age with sustained uncomplicated essential hypertension. In the hypertensive men, the RBF and the RBF/CO ratio were significantly decreased (p less than 0.001). The RBF and RBF/CO ratio were negatively correlated with age (p less than 0.01), blood pressure (p less than 0.01), and D beta H activity (p less than 0.01). None of these relationships were observed with CBF and HBF. The observed decreases in RBF and the RBF/CO ratio in hypertensive men were reversed after administration of clonidine and alpha-methyldopa (p less than 0.01), but not after administration of propranolol. The study provides evidence that the reduction of renal perfusion in essential hypertension is partly reversible and related to an abnormality in the adrenergic system control.