Renin and aldosterone measurements in the management of arterial hypertension.

Renin-angiotensin-aldosterone system (RAAS) is recognized as the main regulatory system of hemodynamics in man, and its derangements have a key role in the development and maintenance of arterial hypertension. Classification of the hypertensive states according to different patterns of renin and aldosterone levels ("RAAS profiling") allows the diagnosis of specific forms of secondary hypertension and may identify distinct hemodynamic subsets in essential hypertension. In this review, we summarize the application of RAAS profiling for the diagnostic assessment of hypertensive patients and discuss how the pathophysiological framework provided by RAAS profiling may guide therapeutic decision-making, especially in the context of uncontrolled hypertension not responding to multi-therapy.

Impairment of cardiovascular autonomic pattern in obese adolescents with Type 2 diabetes mellitus.

UNLABELLED: The aim of this study was to assess the behaviour of insulin sensitivity and insulin resistance (IR) indexes in a group of obese adolescents with Type 2 diabetes mellitus (T2DM) in comparison to obese adolescents without diabetes and normal controls, moreover to compare these parameters with the cardiac autonomic pattern. Seven T2DM obese (12.7 ± 0.5 yr), 18 obese without T2DM, and 10 nonobese control adolescents age matched were studied. In all subjects we performed oral glucose tolerance test (OGTT) with insulin and glucose determination, 24-h electrocardiogram Holter, blood pressure monitoring, ecohocardiogram. RESULTS: serum lipids were significantly higher in obese and T2DM. Insulin sensitivity was significantly reduced in T2DM and obese vs controls; T2DM showed a more pronounced oral glucose insulin sensitivity (OGIS) reduction vs obese. Both obese and T2DM presented an higher IR. T2DM showed an impaired ß-cell function, with insulin areas under the curve and disposition index significantly reduced in comparison to controls and obese who showed similar values. A progressive reduction of vagal indexes and an increase of sympathetic indexes were found in obese adolescents and were more pronounced in T2DM. These parameters were correlated with OGIS and ß-cell function parameters in both obese and T2DM adolescents. T2DM showed a significant relative wall thickness increase suggesting a trend toward concentric remodeling. In conclusion, T2DM adolescents are characterized by a more marked IR reduced ß-cell function in comparison to non-diabetic obese. These modifications may lead to an early impairment of the autonomic pattern.

Cardiovascular autonomic function in Cushing's syndrome.

Cardiac autonomic dysfunction is associated with increased cardiovascular mortality. No data on sympathovagal balance are available in patients with Cushing's syndrome, in whom cardiovascular risk is high. We studied 10 patients with newly diagnosed Cushing's syndrome (1 male/9 females; age mean+/-SD, 47+/-10 yr) and 10 control subjects matched for age, sex, body mass index, and cardiovascular risk factors. In both groups there were 7 patients with arterial hypertension, 3 with diabetes mellitus, and 2 with obesity. Cardiac autonomic function was evaluated by analysis of short time heart rate variability (HRV) measures in frequency domain over 24-h, daytime, and nighttime. The 24-h ambulatory blood pressure monitoring and echocardiography were also performed. In comparison with controls, patients with Cushing's syndrome had lower 24-h (1.3+/-0.6 vs 3.7+/-1.5, mean+/-SD, p<0.01), daytime (2.0+/-1.4 vs 4.5+/-1.6, p<0.01), and night-time (1.0+/-0.4 vs 3.5+/-2.3, p<0.01) low-frequency/ high frequency (LF/HF) power ratio. In the presence of similar LF power, the difference was due to elevation in HF power in Cushing's syndrome compared to controls: 24-h, 12.7+/-6.7 vs 5.8+/-2.8, p<0.01; daytime, 10.2+/-7.3 vs 4.5+/-2.1, p<0.05; nighttime, 14.2+/-7.0 vs 7.8+/-4.7, p<0.05. Eight Cushing patients vs 4 controls had a non-dipping blood pressure profile. At echocardiography, Cushing patients had a greater left ventricular mass index and/or relative wall thickness, and impaired diastolic function, compared with controls. Compared to controls, patients with Cushing's syndrome showed a sympathovagal imbalance, characterized by a relatively increased parasympathetic activity. Whether this autonomic alteration is meant to counterbalance cortisol-induced effects on blood pressure and cardiac structure/function or has a different pathophysiological significance is still unknown.

Characteristics of the patients referred to a Hypertension Unit between 1989 and 2003.

The level of blood pressure, the type of antihypertensive treatment and the prevalence of resistant hypertension at the first examination were evaluated in 6254 patients referred to a hospital Hypertension Unit from 1989 to 2003. From 1989-1993 to 1999-2003, we observed a reduced prevalence of grade 2 and grade 3 hypertension, and an increase in the prevalence of grade 1 hypertension, the proportion of treated subjects, the average number of antihypertensive drugs per patient and the prevalence of resistant hypertension.

Baroreflex sensitivity is impaired in essential hypertensives with central obesity.

Recently, much interest has focussed on the potential interaction between sympathetic nervous system and global cardiovascular risk. We investigated how baroreflex sensitivity (BRS), an index of autonomic function, interacts with central obesity (CO) in an essential hypertensive (EH) population. We selected 170 EHs and 43 normotensives (NT), (median age 47.3+/-11.3 and 49.1+/-13 years, respectively). Anthropometric parameters were measured for each and BRS was evaluated by a non-invasive method using Portapres TNO. The BRS evaluation was made using the sequences method. Systolic blood pressure (SBP) and heart rate were significantly higher in EH (P<0.001 and P=0.007, respectively). BRS was significantly greater in NT (P=0.02), and was associated inversely with waist circumference (WC) (P=0.005), but not with SBP or with other metabolic risk factors. Body mass index, total and high-density lipoprotein cholesterol, age and WC were not significantly different between the two groups. These results were confirmed by age pounded analysis. Finally, a separate analysis of the hypertensive group with CO (n=84) demonstrated a significantly lower BRS compared with the other hypertensive patients (n=86) (P<0.001). BRS is associated with WC but not with arterial pressure values and metabolic risk factors. Hypertensive subjects with CO show an impairment of BRS. Owing to its association with abdominal fat distribution and subsequently insulin resistance, BRS could represent a further and reliable index for evaluation of global cardiovascular risk in hypertensive patients.

Accuracy of the blood pressure measurement.

Blood pressure measurement is the cornerstone for the diagnosis, the treatment and the research on arterial hypertension, and all of the decisions about one of these single aspects may be dramatically influenced by the accuracy of the measurement. Over the past 20 years or so, the accuracy of the conventional Riva-Rocci/Korotkoff technique of blood pressure measurement has been questioned and efforts have been made to improve the technique with automated devices. In the same period, recognition of the phenomenon of white coat hypertension, whereby some individuals with an apparent increase in blood pressure have normal, or reduced, blood pressures when measurement is repeated away from the medical environment, has focused attention on methods of measurement that provide profiles of blood pressure behavior rather than relying on isolated measurements under circumstances that may in themselves influence the level of blood pressure recorded. These methodologies have included repeated measurements of blood pressure using the traditional technique, self-measurement of blood pressure in the home or work place, and ambulatory blood pressure measurement using innovative automated devices. The purpose of this review to serve as a source of practical information about the commonly used methods for blood pressure measurement: the traditional Riva-Rocci method and the automated methods.

Relationship between QT interval and cardiovascular risk factors in healthy young subjects.

A prolongation of QT interval increases the risk for coronary heart disease, ventricular arrhythmias, and sudden death in diabetic patients, after myocardial infarction, and in the elderly. An association between QT prolongation and cardiovascular risk factors has been demonstrated in middle-aged and elderly subjects. Aims of this study were to evaluate the prevalence of a prolonged corrected QT interval (QTc) in a healthy young population (n=170, age 22-25 years, 84 males) and to investigate the association of QTc and QT dispersion (QTd) with cardiovascular risk factors (body mass index, blood pressure, fasting blood glucose and cholesterol, smoking habits, and hypertensive familiarity). A prolonged QTc was observed in 10% of female and 5% of male subjects; in multiple regression analysis, QTc showed a significant positive relationship with blood glucose in females (P=0.04) and systolic blood pressure in male subjects (P=0.03), while QTd was not significantly related with any of the factors. In conclusion, the association between QTc length, glucose levels, and blood pressure is present also in young healthy subjects. QT measurement may represent a useful marker in the screening of young subjects for cardiovascular prevention. Journal of Human Hypertension (2005) 19, 623-627. doi:10.1038/sj.jhh.1001874; published online 19 May 2005.

Diagnosis of glucocorticoid-remediable aldosteronism in primary aldosteronism: aldosterone response to dexamethasone and long polymerase chain reaction for chimeric gene.

Aldosterone suppression by dexamethasone, and high 18-hydroxycortisol and 18-oxocortisol levels are used to differentiate glucocorticoid-remediable aldosteronism (GRA) from other forms of primary aldosteronism. These methods are time consuming, expensive, and impractical for large studies. Moreover, diagnosis of GRA requires a confirmatory genetic test. We evaluated 117 patients with primary aldosteronism referred to our centers by the use of a long PCR technique to reveal the chimeric gene of GRA. In 60 of 117 patients, the response of aldosterone to dexamethasone (2 mg/day for 4 days) was also assessed. None of our patients, including 2 pairs of siblings, was positive for the chimeric gene. The results of long PCR were confirmed by Southern blotting. Despite a negative genetic test, 6 patients (1 with aldosterone-producing adenoma and 5 with idiopathic hyperaldosteronism) had plasma aldosterone suppressed by dexamethasone (i.e. < or = 2 ng/dL). Of 117 patients, 43 were identified as having aldosterone-producing adenoma and 74 as having idiopathic hyperaldosteronism. In our experience, the long PCR technique is a reliable and simple test to at least exclude GRA in patients with primary aldosteronism. A short term dexamethasone suppression test of aldosterone can be misleading in identifying GRA. The prevalence of GRA in primary aldosteronism remains to be established.

Angiotensin-converting enzyme and angiotensinogen gene polymorphisms are non-randomly distributed in oral contraceptive-induced hypertension.

OBJECTIVES AND METHODS: Oral contraceptives (OC) usage increases serum angiotensinogen levels to three to five times normal and about 5% of these women develop arterial hypertension. The genetic contribution to this susceptibility to OC-induced hypertension is poorly understood. We have analyzed the genotypes of 149 hypertensive and 101 normotensive women using oral contraceptives, for three genetic polymorphisms in genes of the renin-angiotensin system: an insertion/deletion (I/ D) in the angiotensin converting enzyme (ACE) gene, the T235M polymorphism of the angiotensinogen gene (AGT) and a point mutation in its promoter. RESULTS: After cessation of oral contraception the mean arterial pressures of the hypertensive women were separable into two non-overlapping groups; 88 of the women remained hypertensive and 61 returned to normal blood pressure. Both groups of hypertensive women had a similarly higher frequency of hypertensive relatives than the normotensive women, but were otherwise similar. The 235T allele of AGT was significantly increased in frequency in the 61 oral contraceptive-inducible hypertensive women compared with the controls and the 88 women that remained hypertensive. The ACE I/D genotypes were similarly distributed within the three groups of women, but were distinctly non-random in the oral contraceptive-induced hypertensive women when they were also classified by AGT genotype. CONCLUSION: This statistical interaction of genotype frequencies suggests that the genetic basis of susceptibility to OC-induced hypertension is complex.

Alpha1-adrenergic receptor subtypes in peripheral blood lymphocytes of essential hypertensives.

OBJECTIVE: The expression of alpha1-adrenergic receptor subtypes in peripheral blood lymphocytes was investigated in 28 essential hypertensive patients as well as in the peripheral blood lymphocytes and aorta of spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats. METHODS: Alpha1-adrenergic receptors were quantified by radioligand binding assays, employing [3H]-prazosin as the radioligand in association with compounds displaying different degrees of selectivity for alpha1A-, alpha1B- and alpha1D-adrenergic receptor subtypes. RESULTS: The affinity of [3H]-prazosin binding was similar in peripheral blood lymphocytes of different stage essential hypertensive and normotensive subjects or of SHR and age-matched normotensive WKY rats as well as in the aortas of SHR and WKY rats. The radioligand binding assay revealed no change in the expression of alpha1-adrenergic receptors in peripheral blood lymphocytes of essential hypertensives compared with normotensive subjects; a moderate decrease of alpha1B-adrenergic receptors and an increase of alpha1D-adrenergic receptors. The relative densities of the alpha1-adrenergic receptor subtypes were similar in the three groups of essential hypertensives. In peripheral blood lymphocytes and in aorta of SHR, [3H]-prazosin binding was significantly reduced compared with normotensive WKY rats. The expression of alpha1-adrenergic receptor subtypes in peripheral blood lymphocytes of SHR was similar to that found in peripheral blood lymphocytes of essential hypertensives. CONCLUSIONS: Changes of lymphocyte alpha1-adrenergic receptor subtypes in essential hypertensives are similar to those observed in lymphocytes and vascular tissues of animal models of hypertension. This suggests that assays of lymphocyte alpha1-adrenergic receptors may represent an indirect marker of their involvement in essential hypertension.

Plasma immunoreactive endothelin-1 in primary hyperaldosteronism.

This study evaluated the assessment of plasma endothelin-1 (ET-1) levels in primary aldosteronism and its correlation with other vasoactive hormones such as renin, aldosterone, catecholamines, arginine-vasopressin, and atrial natriuretic peptide. Plasma ET-1 was measured in 12 patients with primary aldosteronism (five adenomas and seven primary hyperplasia) and in 15 normal subjects. No significant differences were found in plasma ET-1 between controls and hypertensive patients both in adenoma and primary adrenal hyperplasia (8.8 + 1.6 pg/mL v 6.2 + 1.4 pg/mL v 6.5 + 1.0 pg/mL, P = NS, respectively). Further, no significant correlations were found among ET-1 and vasoactive hormones. In conclusion, these findings show that there are no differences in ET-1 levels between primary aldosteronism patients and healthy subjects. Circulating ET-1 is not involved in the hypertension in primary aldosteronism.

Spectral characteristics of heart rate and blood pressure variability in primary aldosteronism.

A disturbance of the autonomic cardiovascular function has been postulated in primary aldosteronism as a possible mechanism for hypertension. Using the method of spectral analysis of heart rate and blood pressure variability, the aim of this study was to assess sympathovagal interactions modulating cardiovascular function and baroreflex control in patients with primary aldosteronism. Seventeen patients (7 with adenomas and 10 with idiopathic hyperaldosteronism) and a control group of 11 essential hypertensives (EH) and 10 normotensive subjects were studied. Continuous finger blood pressure was measured using a Finapres device and heart rate was measured using an electrocardiographic monitor. The studies were conducted in each patient for 20 min in the supine position and 10 min during a passive head-up tilt to 60 degrees. The low frequency and the low frequency-to-high frequency ratio of systolic and diastolic blood pressures were significantly higher both in primary aldosteronism and in EH patients compared with normotensives (P < .01). Impaired response to tilt was found in the heart rate and blood pressure variability in primary aldosteronism and EH patients; the increase in low frequency was smaller than in normotensives. Baroreflex gain (assessed by alpha index) was less in primary aldosteronism and EH patients as compared with normotensives. These findings may suggest that volume expansion or sympathetically mediated central translocation of the blood volume, or both, could stimulate the cardiopulmonary receptors and impair the baroreflex gain. Our findings suggest that an enhanced peripheral vascular responsiveness to a normal sympathetic outflow may be involved in the pathogenesis of hypertension in primary aldosteronism.

Renal resistive index after captopril test by echo-Doppler in essential hypertension.

In 45 patients with essential hypertension and 15 age-matched normotensive control subjects, the renal resistive index, as an expression of arterial impedance, was determined using Doppler ultrasound. In both kidneys the resistive index was assessed at baseline and after captopril test (50 mg orally). In the moderate and severe hypertensives, compared to mild hypertensives and control subjects, the baseline resistive index was significantly higher (P less than .05). Following captopril, the resistive index increased only in normotensives (P less than .05) and in mild hypertensives (P less than .05). Univariate and multivariate analyses show that the duration and severity of hypertension correlated with an increase of the resistive index both in basal and in dynamic conditions. Thus, the use of the resistive index, as determined by echo-Doppler, could provide useful information for the assessment of renal vascular impedance in essential hypertensive patients. This would help us detect the evolution of hypertensive disease to the higher degrees of severity that are correlated to renal arteriolar damage.

Blood pressure and heart rate in young thalassemia major patients.

The analysis of blood pressure (BP) and heart rate (HR) variability is currently used to investigate the mechanisms responsible for cardiovascular control; therefore, we assessed whether an impairment of 24-h BP and HR profiles and sympathovagal interaction modulating cardiovascular function was present in patients with thalassemia major (TM) in preclinical phase of heart disease. Nine beta-thalassemic patients 18 years old without clinical signs of cardiac failure and 9 age- and sex-matched controls were studied. Twenty-four-hour-ambulatory BP and HR were measured using the SpaceLabs 90207 device. A truncated Fourier series with four harmonics was used to describe the diurnal blood pressure profile. Mean 24-h ambulatory systolic BP, diastolic BP, and mean arterial pressure were significantly lower in TM patients than in normal subjects (P < .05). A significantly higher nighttime HR value was found in TM patients (P < .05). More than 40% of the TM patients did not show a significant diurnal BP and HR rhythm. In TM patients, the overall amplitude of systolic BP, diastolic BP, and HR was significantly lower than in controls (P < .01). The night/day differences of systolic BP, diastolic BP, and HR were significantly lower in TM patients than in normals (P < .01). Furthermore, we performed power spectral analysis on short-term continuous finger BP and HR data in supine position and during passive head-up tilt. Total spectral power of systolic BP was significantly lower in patients than controls (P < .05). Low-frequency (LF) power of systolic BP and diastolic BP and LF/high-frequency (HF) ratio of HR were significantly lower during tilt in TM patients compared to controls (P < .05). High-frequency power of HR was significantly higher in patients than controls (P < .05). The baroreflex gain assessed by alpha-index was the same in supine position but was higher in TM patients during passive tilt (P < .05). An inverse relationship between LF/HF ratio of HR and hemoglobin levels in TM patients was found. Finally, plasma norepinephrine levels were significantly lower in thalassemics (P < .005). In young TM patients in a preclinical stage of heart disease, these findings demonstrated abnormal 24-h BP and HR rhythms and a decreased short-term variability of BP and HR, in particular in the LF range, showing a diminished sympathetic activity.

Fourier analysis of circadian blood pressure profile in secondary hypertension.

Different types of statistical methods have been used for circadian blood pressure (BP) rhythm analysis in secondary forms of hypertension. In the present study, we used the two-step statistical approach by Fourier analysis with four harmonics for the parametrization of the diurnal BP pattern in secondary hypertension. In 43 essential hypertensives (EH), eight patients with aldosterone producing adenoma (APA), 25 with idiopathic hyperaldosteronism (IHA), four with glucocorticoid remediable hyperaldosteronism (GRH) and seven with renovascular hypertension (RVH), 24-h ambulatory BP was measured. The diurnal BP and heart rate (HR) rhythm was present in more than 70% of patients with secondary hypertension, without significant differences with EH and despite the attenuation in the degree of the nocturnal BP fall. In conclusion, the statement that secondary hypertension is characterized by an abnormal diurnal rhythm of BP is a gross over-simplification. Our findings suggest that the two-step method with four harmonics Fourier analysis may represent a useful method and a more complete statistical approach to providing circadian parametrization of the 24-h profile in secondary hypertension.

Efficacy of nicardipine slow release (SR) on hypertension, potassium balance and plasma aldosterone in idiopathic aldosteronism.

We evaluated the efficacy and tolerance of a dihydropyridine calcium antagonist, nicardipine slow release, in eight patients with idiopathic aldosternism. Nicardipine (80 mg/day) was given orally for 12 weeks and no dietary restrictions were imposed. During the study measurements were made of supine blood pressure, plasma renin activity, plasma aldosterone concentration, and serum potassium. Nicardipine lowered systolic and diastolic blood pressure to normal, plasma aldosterone was reduced and serum potassium levels were increased. Basal renin concentration was not altered by nicardipine. There were no side effects sufficient to cause withdrawal from the study. These results suggest that nicardipine, for efficacy and tolerance, may represent an alternative among Ca2+ channel blockers, either controlling blood pressure or reducing aldosterone levels in patients with idiopathic aldosteronism.

Assessing resting heart rate in adolescents: determinants and correlates.

The aim of this study was to evaluate the distribution of resting heart rate and its biological and environmental determinants in adolescents. The study was cross- sectional and the population consisted of 2230 children and adolescents, age range 12-18 years, enrolled randomly from state schools in Turin, Italy. In all participants the following parameters were evaluated: heart rate, blood pressure (BP), weight, height, degree of sexual development, physical activity, parental socio-cultural level. Heart rate and BP were measured after 5, 10 and 15 min in a sitting position. Furthermore, to obtain regression equations to define heart rate as a function of the other variables available, a multiple regression analysis was performed. In both sexes BP, but not heart rate, declined significantly from the first to the last determination. Heart rate was positively and significantly correlated to BP level in both sexes; heart rate was higher in girls (3 bpm) and followed a progressive decreasing trend with age in both sexes, that was opposite to BP values. Age, sexual maturation, height, physical activity and parental socio-cultural level were independent determinants of resting heart rate. In conclusion, resting heart rate in adolescents is related to several methodological, constitutional and environmental factors that have to be taken into account when assessing heart rate values and constructing tables of normal values.

Impaired baroreflex function and arterial compliance in primary aldosteronism.

The purpose of this study was to evaluate if changes in vascular properties were related to baroreflex function in patients with primary aldosteronism. Twenty-three patients with primary aldosteronism, 22 essential hypertensive patients and 16 normal controls were studied. Continuous finger blood pressure (BP) was recorded by Portapres device during supine rest and active stand up. Compliance was estimated from the time constant of pressure decay during diastole. Baroreflex sensitivity was calculated by autoregressive cross-spectral analysis of systolic BP and interbeat interval. The result was that baroreflex gain and compliance were lower in primary aldosteronism patients in the supine position (P = 0.002 and P < 0.05 respectively). Aldosterone plasma levels (R2 = 0.31, P = 0.01), age, systolic and diastolic BP, high and low frequency components of diastolic BP variability were independently related to compliance in primary aldosteronism. In conclusion primary aldosteronism is associated with an impaired baroreflex function related in part to a reduced arterial compliance. Despite a reduction of BP values and aldosterone levels, surgical or pharmacological treatment did not significantly change compliance values.

Baroreflex control of heart rate is impaired in pre-eclampsia.

Autonomic nervous dysfunction, such as parasympathetic and sympathetic impairment, has been suggested as possible cause of pre-eclampsia, but the studies are not conclusive. Our purpose was to assess non-invasively if pre-eclampsia is associated with a decreased baroreflex function. Nine women with pre-eclampsia (PE), eight normotensive pregnant women, and seven healthy normotensive non-pregnant women were studied. Continuous finger blood pressure was recorded by a Portapres device in the left lateral recumbent position and active standing. Baroreflex gain was evaluated by cross-spectral analysis of systolic blood pressure and pulse interval. The result was that baroreflex gain at rest was lower in pre-eclamptic women both compared to non-pregnant and healthy pregnant subjects (P<0.05). Moreover, a decrease of the baroreflex sensitivity was present in all pregnant women in the orthostatic position (P<0.05). In conclusion pregnancy per se is associated with a decrease in the baroreflex control of the heart, whereas in pre-eclampsia, the baroreflex sensitivity is impaired further.