Supine Plasma Renin Activity Research Articles

BP.05.01] THE CLINICAL CHARACTERISTICS OF PATIENTS WITH PRIMARY ALDOSTERONISM COMPLICATED WITH OBSTRUCTIVE SLEEP APNEA - HYPOPNEA SYNDROME

Objective: This study aims to compare the differences of aldosterone, renin level and target organ damage in patients with primary aldosteronism complicated with or without OSAHS. Design and method: This study retrospectively analyzed patients who were diagnosed with PA in the Department of Hypertension, Ruijin Hospital during the period of 2010.1–2015.11. The cut-off value of plasma aldosterone to renin ratio (ARR) greater than 240 [ng / dl] / [ng / ml / h] was used to screen PA candidates, and plasma aldosterone greater than 60 ng / ml after saline infusion test was used as e PA confirmation criteria. According to the polysomnography, OSAHS was diagnosed with symptoms of apnea hypopnea index (AHI) > = 5 times / hour accompanied by nocturnal snoring or wakefulness or daytime sleepiness. Results: This study included 677 patients with PA, among them, 68 patients complicated with OSAHS. The prevalence of PA complicated OSAHS is 10.04%. Our study shows that PA with OSAHS group had significantly higher diastolic blood pressure (DBP), body mass index (BMI), triglyceride and low density lipoprotein level, left ventricular end-diastolic diameter and carotid intima-media thickness, and lower estimated glomerular filtration rate (eGFR) than those of patients without OSAHS group. In addition, the supine plasma renin activity of patients with PA and OSAHS was significantly higher, but plasma aldosterone level and ARR were significantly lower than those without OSAHS. When matched with age, sex, duration of hypertension and BMI, these two groups had no significant differences on plasma and urinary aldosterone levels, but the group with PA and OSAHS still had higher supine plasma renin activity and lower ARR and eGFR than the group without OSAHS. Furthermore, we found the lowest nocturnal oxyhemoglobin saturation was negatively correlated with BMI in OSAHS group(r = -0.318, P = 0.018). Conclusions: Patients with both PA and OSAHS had higher BMI, DBP, renin level and lower ARR and eGFR than those of patients without OSAHS. The difference of eGFR remained even after matching with age, BMI and duration of hypertension. OSAHS screening is therefore important in patients with PA.

Hyperinsulinemia and obese phenotype differently influence blood pressure in young normotensive patients with polycystic ovary syndrome.

To differentiate the impact of insulin levels/resistance per se from that of excess weight on blood pressure (BP) daily changes, we evaluated, using 24-h ambulatory blood pressure monitoring (ABPM), systolic blood pressure (SBP) and diastolic blood pressure (DBP) in a cohort of young normotensive patients affected by polycystic ovary syndrome (PCOS). A cross-sectional study was performed. Fifty-four patients were studied according to (a) insulinemic state: 32 hyperinsulinemic and/or insulin-resistant (h-INS) and 22 normoinsulinemic (n-INS) patients; and (b) body mass index (BMI): 22 obese (BMI>30) and 32 lean (18.0<BMI<24.9) patients. Each subject's SBP and DBP and heart rate (HR) were measured by ABPM. Supine and upright plasma renin activity (PRA), and aldosterone levels were also assayed. Patients in the h-INS group showed higher 24-h, daytime, and nighttime diastolic blood pressure (DBP), higher nighttime systolic blood pressure (SBP) levels, as well as an increased 24-h, daytime and nighttime HR, compared to both obese and lean patients in the n-INS group. In relation to BMI, only 24-h, daytime, and nighttime DBP were higher in obese than in lean patients. At variance, when both h-INS and obesity were considered, 24-h SBP and DBP were higher in h-INS obese subjects than in the other groups. In multivariate analysis, insulin (max peak), area under the curve of insulin and insulin sensitivity index was independently associated with SBP. (1) Within a normotensive range, hyperinsulinemia and/or insulin resistance influence daily BP variation more than obesity does, suggesting a pivotal role of insulin on BP control in PCOS; (2) altered insulinemic state and ABPM-derived higher nighttime BP and HR may represent early markers to identify PCOS subjects prone to high cardiovascular risk.

Four Cases of Hypovolemic Renin-Aldosterone Axis Deficiency Without Hyperkalemia Following Unilateral Adrenalectomy for Primary Aldosteronism

ABSTRACT Objective: Hyperkalemia can occur following unilateral adrenalectomy for primary aldosteronism due to hypoaldosteronism. We hereby report the cases of 4 male patients exhibiting prolonged failure of the renin-aldosterone (RA) axis in association with normal-to-high kalemia or labile blood pressure and, most significantly, a decrease in extracellular fluid volume (ECFV). Methods: Prior to surgery, all patients exhibited hypokalemic hypertension, with documented primary aldosteronism. Within a few weeks of undergoing unilateral adrenalectomy, the patients developed either mild hyperkalemia or labile blood pressure. Complementary investigations revealed a decrease in measured ECFV with inappropriate normal renal sodium excretion, low supine plasma renin activity, and insufficient orthostatic-related aldosterone production. The adrenocorticotropic hormone (ACTH) stimulation test demonstrated no glucocorticoid deficiency, along with responsive aldosterone secretion. Results: The discrepancy between th...

Clinical Severity of Gitelman Syndrome Determined by Serum Magnesium

Background/Aims: Normomagnesemia is considered atypical in Gitelman syndrome (GS). Here, we describe clinical, pathological and genetic characteristics in Chinese GS patients with or without hypomagnesemia in order to determine whether serum magnesium concentration indicates the severity of the disease. Methods: 7 normomagnesemic and 25 hypomagnesemic GS patients who were confirmed by direct sequencing of SLC12A3 gene were included. Clinical manifestation and laboratory tests were documented. Supine and upright plasma renin activity, angiotensin II and aldosterone were determined by radioimmunoassay. Transient receptor potential channel melastatin subtype 6 (TRPM6) was detected by immunohistochemistry in paraffin-embedded renal biopsy sections of 12 GS patients. 14 patients with glomerular minor lesion served as controls. The distribution of the mutations on the predicted NCC protein was analyzed and compared between two subgroups. Results: Clinical manifestations, electrolyte abnormalities, metabolic alkalosis and renin-angiotensin-aldosterone system activation were found to be milder in normomagnesemic compared with the hypomagnesemic group. Compared with glomerular minor lesion controls, the TRPM6-positive area was significantly decreased in hypomagnesemic patients (4.96 ± 1.88 vs. 8.63 ± 2.67%) while it was near normal (7.82 ± 5.23%) in 2 normomagnesemic GS patients. A higher percentage of intracellular mutations was observed in normomagnesemic patients than hypomagnesemic patients (92.31 vs. 56.52%, p = 0.02). Conclusions: Normomagnesemia is not rare in GS. Serum magnesium may indicate the severity of GS.

Dietary potassium intake and renal handling, and their impact on the cardiovascular health of normotensive afro-caribbeans.

Recent nutritional profiles of dietary intake have indicated a shift from the ancient diet to the Western diet. The ancient diet provided a high potassium and low sodium intake, which in turn leads to sodium conservation and potassium excretion. This change in the dietary intake is expected to affect potassium and sodium handling in the kidneys. Numerous studies have been done to emphasize the importance of sodium handling by the kidneys and its impact on cardiovascular health. This study will investigate potassium intake and handling, and its impact on the cardiovascular health of a sample of normotensive Afro-Caribbeans by the possible modulation of the renin angiotensin aldosterone system (RAAS). A sample of 51 normotensive Afro-Caribbean participants was recruited for the study. Participants were observed over a two-day period in which they were given a 24-hour ambulatory blood pressure monitor and a container to collect blood pressure data and a 24-hour urine sample. Anthropometric measurements were noted. Urinary electrolytes and supine plasma renin activity (PRA) were determined from the 24-hour urine collection and a blood sample. Dietary potassium intake was estimated based on dietary intake observations and calculated based on the urinary potassium excretion. SPSS version 19 was used to analyse the data to make inferences. The daily potassium intake was observed to be 2.95 g/day and measured intake from the urinary potassium was between 4.95 and 7.32 g/day. Urinary potassium excretion was 3.66 (± 1.40) g/day. The urinary potassium excretion in the Afro-Caribbean sample in Barbados was higher than the other population samples. The averaged PRA of the participants (supine) was 0.778 (± 1.072) ng/mL/hour. The averaged nocturnal systolic blood pressure dip of the participants was 5.97 (± 4.324) %. There was no significant correlation between urinary potassium excretion, blood pressure, nocturnal systolic blood pressure dip and PRA. The Afro-Caribbean sample has an inadequate daily potassium intake based on the observed intake and recommended values, with a high urinary excretion of the electrolyte compared to other values in the literature. This high potassium excretion could have been partly due to low plasma renin activity levels in the study participants. As a possible consequence, an increase in the nocturnal peripheral resistance is a likely cause for the diminished systolic dip. The lack of correlations between dietary potassium excretion and the blood pressure parameters does not allow any firm inference of the electrolyte's handling and its impact on cardiovascular health in the normotensive Afro-Caribbean participants. However, further research is needed to get a more accurate daily potassium intake value, and a more statistically robust sample to assess whether potassium handling and blood pressure would be affected by a change in potassium intake.

Inadequate RAAS suppression is associated with excessive left ventricular mass and systo-diastolic dysfunction

Inadequate suppression of renin-angiotensin-aldosterone system (RAAS) following postural maneuvers may have detrimental effects on cardiac structure and function. In this study, we aimed to appraise the clinical significance of this phenomenon by assessing its relation with inappropriate ventricular mass (ILVM), an adverse phenotype of LV remodeling and dysfunction. Both supine and upright plasma renin activity (PRA) and aldosterone concentrations (PAC) were measured in 115 young newly diagnosed hypertensive subjects. 24-h ambulatory blood pressure monitoring and echocardiographic evaluation including tissue Doppler imaging (TDI) were also performed. Patients were divided as follows: (1) normal PRA and PAC (N) (n = 63); (2) suppressible RAAS (SR) in supine position (n = 27); (3) not suppressible RAAS (NSR) (n = 25). ILVM was expressed as the observed/predicted LV mass ratio ×100 (%PLVM), while LV dysfunction (LVD) was identified by TDI-derived myocardial performance index (MPI). NSR showed a higher prevalence of ILVM than SR and N. As compared with N and SR, NSR patients had reduced indices of systolic and diastolic function. MPI of the LV as well as prevalence of LVD was also significantly higher in the NSR group. Regression models showed that lack of RAAS suppression was independently associated with ILVM and LVD. Prevalence of ILVM and LVD is higher in patients without clinostatic RAAS suppression. Our findings encourage the assessment of RAAS deregulation to better estimate individual cardiovascular risk in patients with arterial hypertension.

Neurohumoral and haemodynamic profile in postural tachycardia and chronic fatigue syndromes

Several studies recognized an overlap between CFS (chronic fatigue syndrome) and POTS (postural tachycardia syndrome). We compared the autonomic and neurohormonal phenotype of POTS patients with CFS (CFS–POTS) to those without CFS (non-CFS–POTS), to determine whether CFS–POTS represents a unique clinical entity with a distinct pathophysiology. We recruited 58 patients with POTS, of which 47 were eligible to participate. A total of 93% of them reported severe fatigue [CIS (Checklist of Individual Strength), fatigue subscale >36], and 64% (n=30) fulfilled criteria for CFS (CFS–POTS). The prevalence of CFS symptoms (Centers for Disease Control and Prevention criteria) was greater in the CFS–POTS group, but the pattern of symptoms was similar in both groups. Physical functioning was low in both groups (RAND-36 Health Survey, 40±4 compared with 33±3; P=0.153), despite more severe fatigue in CFS–POTS patients (CIS fatigue subscale 51±1 compared with 43±3; P=0.016). CFS–POTS patients had greater orthostatic tachycardia than the non-CFS–POTS group (51±3 compared with 40±4 beats/min; P=0.030), greater low-frequency variability of BP (blood pressure; 6.3±0.7 compared with 4.8±1.0 mmHg2; P=0.019), greater BP recovery from early to late phase II of the Valsalva manoeuvre (18±3 compared with 11±2 mmHg; P=0.041) and a higher supine (1.5±0.2 compared with 1.0±0.3 ng/ml per·h; P=0.033) and upright (5.4±0.6 compared with 3.5±0.8 ng/ml per h; P=0.032) PRA (plasma renin activity). In conclusion, fatigue and CFS-defining symptoms are common in POTS patients. The majority of them met criteria for CFS. CFS–POTS patients have higher markers of sympathetic activation, but are part of the spectrum of POTS. Targeting this sympathetic activation should be considered in the treatment of these patients.

Hormonal and plasma volume changes after presyncope

Aim of this study was to test the hypothesis that after presyncope, some blood hormone pools increase while others decrease. In twelve healthy male adults, we determined plasma volume changes with plasma mass densitometry and hormone levels. The following were compared: supine rest, presyncope and 20-min post-presyncopal supine rest. We determined plasma renin activity (PRA), aldosterone, adrenocorticotropic hormone (ACTH), adrenomedullin and vasopressin (AVP) from venous blood samples. Using passive 4-min 70° head-up tilt followed by 4-min sequences of additional lower body negative pressure of increasing intensity (15 mmHg steps), presyncope occurred after 11·6 ± 2·8 min, at which time plasma volume was reduced by 15·5 ± 7·4%, aldosterone increased by 37%, ACTH by 75%, PRA by 187% and AVP about 16-fold in average (all P < 0·01); no significant changes in adrenomedullin were seen. Twenty-min post-presyncope, ACTH increased above presyncopal levels (+36%, P < 0·05), aldosterone by 35% (P = 0·07). PRA (-47%, P < 0·01) and AVP (-84%, P < 0·05) decreased below presyncopal but were still above supine control (P < 0·01); similarly, plasma density fell by 2·17 ± 0·97 g L(-1) below presyncopal (P < 0·01), but above supine control (P < 0·05), indicating rapid recovery (83% of initial plasma volume). We conclude that during the 20-min supine post-syncopal period, plasma volume, PRA and AVP return closer to baseline but aldosterone and ACTH continue increasing. The magnitude of observed concentration changes cannot be explained by haemoconcentration/haemodilution, rather it appears that the observed changes are indicative of hormone-specific endocrine activation patterns in the recovery phase.

Renin-stimulating test in children.

Plasma renin activity (PRA) was measured after various stimuli to evaluate a renin-stimulating test and to screen suppressed PRA in 60 children with labile hypertension aged 10 to 14 years. There was a significant difference between supine PRA and that after both standing (for 15 or 60 minutes) or frusemide administration (P less than 0.001, respectively); however, there was no statistical difference between the PRA while standing or after frusemide. Children who gripped a hand dynamometer for three minutes did not show any change in PRA. Standing upright for 15 minutes or supine rest for 90 minutes after the administration of frusemide i.v. are easily applicable to children and seem the most appropriate renin-stimulating test in childhood. No subjects showed suppressed PRA in this study.

Aldosterone and Metabolic Syndrome

The classic role of aldosterone is to regulate water and electrolyte balance and, therefore, blood pressure homeostasis.1 Apart from that, experimental studies have demonstrated that aldosterone induces structural and functional alterations in the heart, kidneys, and vessels with effects such as myocardial fibrosis, nephrosclerosis, vascular inflammation and remodeling, and disturbed fibrinolysis.2,3 This damage seems to be aldosterone mediated, and aldosterone blockade with mineralocorticoid receptor (MR) antagonists, such as spironolactone, may prevent the onset of these effects.4,5 On the other hand, it cannot completely be ruled out that potassium and high blood pressure also play additional key roles in this damage.6,7 This evidence has impressively been supported by clinical studies, such as the Randomized Aldactone Evaluation Study and the Eplerenone Post-Acute Myocardial Infarction Survival and Efficacy Study.8,9 For example, increased mortality in patients with chronic heart failure has been associated with elevated aldosterone plasma levels,10 and high circulating plasma aldosterone levels predict the clinical outcome in patients after myocardial infarction.11 Furthermore, primary aldosteronism (PA) has been demonstrated to enhance the risk of cardiovascular events12 and kidney disease.13 In summary, aldosterone is considered a cardiovascular risk factor, promoting disease processes such as cardiac fibrosis, nephrosclerosis, and arteriosclerosis,2,3,14 all of which are increased in patients with obesity and the metabolic syndrome.15,16 The term “metabolic syndrome” (MSyn) has evolved various definitions in recent times; most of the studies introduced here use slight modifications. Nevertheless, all of the definitions used have a common denominator, which is reflected in a definition by the American Heart Association/National Heart, Lung, and Blood Institute.17 According to this definition, the MSyn is considered as a constellation of interrelated risk factors of metabolic origin, including arterial hypertension, dyslipidemias, alterations in glucose homeostasis with type 2 diabetes mellitus, and abdominal …

Hormonal and Volume Dysregulation in Women With Premenstrual Syndrome

Premenstrual syndrome (PMS) presents with emotional and physical symptoms. Although the emotional symptoms have been extensively studied, the pathophysiology of the fluid-retention symptoms is not currently known. We tested the hypothesis that the fluid regulatory mechanisms are disturbed in PMS. Nine regularly menstruating women with PMS were compared with 9 healthy age-matched women. Hemodynamic parameters and upright plasma volume shift (extrapolated from changes in hematocrit), plasma renin activity (PRA), and plasma aldosterone and sex hormones were measured at different times during the menstrual cycle. During the early follicular and the midluteal phases, the plasma volume shift, supine and upright PRA, and plasma aldosterone were similar in both groups, and none of the participants had edema. However, during the late luteal phase, ankle edema was present only in women with PMS, and their maximal plasma volume shift was lower compared with controls (11.7+/-1.3 versus 15.6+/-0.6; P=0.004). The area under the curve (estimates the amount of the total plasma shift during 30 minutes standing) was 300+/-28 and 406+/-16 in PMS and controls, respectively (P=0.01). PRA and aldosterone levels were higher during the late luteal phase in women with PMS compared with controls (supine PRA: 1.4+/-0.3 [PMS] versus 1.1+/-0.4 [control; P value not significant], upright PRA: 3.9+/-0.08 versus 1.6+/-0.3 ng/mL per hour [P=0.015], supine plasma aldosterone: 131+/-30 versus 68+/-17 pg/mL [P=0.09], and upright plasma aldosterone: 208+/-40 versus 102+/-16 pg/mL [P=0.03]). We, therefore, conclude that women with PMS have increased plasma fluid-regulatory hormones and disturbed fluid distribution only during their late luteal menstrual phase.

Influences of Norepinephrine Transporter Function on the Distribution of Sympathetic Activity in Humans

Previous studies suggest that neuronal norepinephrine transporter function may regulate the distribution of sympathetic activity among blood vessels, heart, and kidney; we tested the functional relevance in humans. Sixteen healthy men (26+/-1 years) ingested 8 mg of the selective norepinephrine reuptake transporter inhibitor reboxetine or a matching placebo on 2 separate days in a double-blind, randomized, crossover fashion. We monitored heart rate, thoracic bioimpedance, blood pressure, glomerular filtration rate, and renal blood flow. Ninety minutes after ingestion of the test medication, subjects were tilted to a 45 degrees head-up position, where they remained for an additional 30 minutes. Reboxetine increased supine systolic blood pressure through an increase in cardiac output whereas systemic vascular resistance decreased. Furthermore, reboxetine increased heart rate, particularly with a head-up tilt. Supine plasma renin activity was 0.71+/-0.15 ng angiotensin (Ang)/L per mL/h with placebo and 0.36+/-0.07 ngAng/L per mL/h with reboxetine (P<0.01). Supine plasma Ang II concentrations were also decreased with reboxetine. Both plasma renin activity and Ang II concentrations remained suppressed during head-up tilt. On placebo, renal vascular resistance increased with head-up tilt. The response was abolished with norepinephrine reuptake inhibition. We conclude that norepinephrine reuptake function profoundly influences the distribution of sympathetic activity between the heart, vasculature, and kidney in humans. All of these changes are physiologically relevant because they lead to corresponding changes in organ function.

Common variants of the beta and gamma subunits of the epithelial sodium channel and their relation to plasma renin and aldosterone levels in essential hypertension

BackgroundRare mutations of the epithelial sodium channel (ENaC) result in the monogenic hypertension form of Liddle's syndrome. We decided to screen for common variants in the ENaC βand γ subunits in patients with essential hypertension and to relate their occurrence to the activity of circulating renin-angiotensin-aldosterone system.MethodsInitially, DNA samples from 27 patients with low renin/low aldosterone hypertension were examined. The DNA variants were subsequently screened for in 347 patients with treatment-resistant hypertension, 175 male subjects with documented long-lasting normotension and 301 healthy Plasma renin and aldosterone levels were measured under baseline conditions and during postural and captopril challenge tests.ResultsTwo commonly occurring βENaC variants (G589S and a novel intronic i12-17CT substitution) and one novel γENaC variant (V546I) were detected. One of these variants occurred in a heterozygous form in 32 patients, a prevalence (9.2%) significantly higher than that in normotensive males (2.9%, p = 0.007) and blood donors (3.0%, p = 0.001). βENaC i12-17CT was significantly more prevalent in the hypertension group than in the two control groups combined (4.6% vs. 1.1%, p = 0.001). When expressed in Xenopus oocytes, neither of the two ENaC amino acid-changing variants showed a significant difference in activity compared with ENaC wild-type. No direct evidence for a mRNA splicing defect could be obtained for the βENaC intronic variant. The ratio of daily urinary potassium excretion to upright and mean (of supine and upright values) plasma renin activity was higher in variant allele carriers than in non-carriers (p = 0.034 and p = 0.048).ConclusionsAt least 9% of Finnish patients with hypertension admitted to a specialized center carry genetic variants of β and γENaC, a three times higher prevalence than in the normotensive individuals or in random healthy controls. Patients with the variant alleles showed an increased urinary potassium excretion rate in relation to their renin levels.

Midodrine Improves Chronic Hypotension in Hemodialysis Patients

The effects of midodrine on chronic hypotension in hemodialysis (HD) patients have not been well investigated. We evaluated midodrine's effect on autonomic function and hemodynamics in 12 HD patients who had chronic systolic blood pressure less than 100 mm Hg. Midodrine (5.0 mg) twice a day was given for 4 weeks. Another 12 age- and sex-matched HD patients with normotension were selected as a control group. Autonomic function tests included the heart-rate responses to the Valsalva maneuver and 30:15 ratio as well as supine and standing blood pressure (BP) and sustained hand-grip test. Hemodynamic changes included 24-hour blood pressure, cardiac output, total peripheral resistance (TPR), and plasma renin and aldosterone concentrations. Compared with the control subjects, HD patients with chronic hypotension had more severe autonomic dysfunction and significantly lower TPR. After 4 weeks of midodrine therapy, sympathetic function (orthostatic and hand-grip tests) improved in conjunction with significant increases in mean arterial pressure (MAP) (79.5 +/- 4.9 to 85.0 +/- 5.1 mm Hg, P < 0.05) and TPR (768 +/- 37 versus 1097 +/- 72 dyne/sec/cm-5, P < 0.01) despite no significant change in Valsalva ratio, 30:15 ratio, and cardiac output. MAP changes were positively correlated with TPR changes (r = 0.82, P < 0.001). Supine plasma renin activity was significantly increased. In addition, MAP during HD was also significantly increased during midodrine therapy. Midodrine improves chronic hypotension in HD patients by modulating autonomic function and its direct effects on peripheral vessels.

Dietary weight loss decreases serum angiotensin-converting enzyme activity in obese adults.

To study the effect of dietary weight loss, postural change, and an oral glucose load on serum angiotensin-converting enzyme (ACE) activity in obese adults. Sixteen obese adult men and women with a mean body mass index of 35.7 +/- 4.3 kg/m(2) were studied after 1 week on a maintenance energy lead-in diet and after 5 weeks on an identical but 40% reduced-energy diet provided by the General Clinical Research Center (GCRC). ACE activity was measured spectrophotometrically. Plasma renin activity and serum aldosterone were measured by radioimmunoassay. All subjects lost weight, with a mean decrease in body weight of 7.0 +/- 2.1 kg or 6 +/- 3% of initial body weight (p < 0.00001). Systolic and diastolic blood pressure, supine plasma renin activity, and serum aldosterone levels decreased with weight loss (p < 0.05). Supine ACE activity decreased 23 +/- 12% with weight loss (p < 0.00001). Standing ACE activity, which was significantly higher than supine ACE activity before and after weight loss (p < 0.05), also decreased 18 +/- 17% with weight loss (p = 0.0007). A 75-g oral glucose load had no effect on serum ACE activity over a 3-hour period. In obese adults, serum ACE activity declines with modest weight loss, increases with postural change, and is unaffected by an oral glucose load.

Excess aldosterone is associated with alterations of myocardial texture in primary aldosteronism.

Hyperaldosteronism has been causally linked to myocardial interstitial fibrosis experimentally, but it remains unclear if this link also applies to humans. Thus, we investigated the effects of excess aldosterone due to primary aldosteronism (PA) on collagen deposition in the heart. We used echocardiography to estimate left ventricular (LV) wall thickness and dimensions and for videodensitometric analysis of myocardial texture in 17 consecutive patients with PA and 10 patients with primary (essential) hypertension who were matched for demographics, casual blood pressure, and known duration of hypertension. The groups differed in serum K+, ECG PQ interval duration, plasma renin activity, and aldosterone levels (all P< or =0.002) but not for casual blood pressure values, demographics, and duration of hypertension. Compared with hypertensive patients, PA patients showed a higher LV mass index (53.7+/-1.8 versus 45.5+/-2.0 g/m(2.7); P=0.008) and lower values of the cyclic variation index of the myocardial mean gray level of septum (CVI(s); -12.02+/-5.84% versus 6.06+/-3.08%; P=0.012) and posterior wall (-11.13+/-6.42% versus 8.63+/-9.62%; P=0.012). A regression analysis showed that CVI(s) was predicted by the PQ duration, supine plasma renin activity, plasma aldosterone, and age, which collectively accounted for approximately 36% of CVI(s) variance. PA is associated with alterations of myocardial textures that suggest increased collagen deposition and that can explain both the dependence of LV diastolic filling from presystole and the prolongation of the PQ interval.

Add-on angiotensin receptor blockade with maximized ACE inhibition

Prolonged angiotensin-converting enzyme (ACE) inhibitor therapy leads to angiotensin I (Ang I) accumulation, which may "escape" ACE inhibition, generate Ang II, stimulate the Ang II subtype 1 (AT1) receptor, and exert deleterious renal effects in patients with chronic renal diseases. We tested the hypothesis that losartan therapy added to a background of chronic (>3 months) maximal ACE inhibitor therapy (lisinopril 40 mg q.d.) will result in additional Ang II antagonism in patients with proteinuric chronic renal failure with hypertension. Sixteen patients with proteinuric moderately advanced chronic renal failure completed a two-period, crossover, randomized controlled trial. Each period was one month with a two-week washout between periods. In one period, patients received lisinopril 40 mg q.d. along with other antihypertensive therapy, and in the other, losartan 50 mg q.d. was added to the previously mentioned regimen. Hemodynamic measurements included ambulatory blood pressure monitoring (ABP; Spacelabs 90207), glomerular filtration rate (GFR) with iothalamate clearances and cardiac outputs by acetylene helium rebreathing technique. Supine plasma renin activity and plasma aldosterone and 24-hour urine protein were measured in all patients. Twelve patients had diabetic nephropathy, and four had chronic glomerulonephritis. The mean age (+/- SD) was 53 +/- 9 years. The body mass index was 38 +/- 5.7 kg/m(2), and all except two patients were males. Seated cuff blood pressure was 156 +/- 18/88 +/- 12 mm Hg. The pulse rate was 77 +/- 11 per min, and the cardiac index was 2.9 +/- 0.5 L/min/m(2). Mean log 24-hour protein excretion/g creatinine or overall ABPs did not change. Mean placebo subtracted, losartan-attributable change in protein excretion was +1% (95% CI, -20% to 28%, P = 0.89). Similarly, the change in systolic ambulatory blood pressure (ABP) was 4.6 mm Hg (-5.7 to 14.9, P = 0.95), and diastolic ABP was 1.5 mm Hg (-4.5 to 7.6, P = 0.59). No change was seen in cardiac output. However, there was a mean 14% increase (95% CI, 3 to 26%, P = 0.017) in GFR attributable to losartan therapy. A concomitant fall in plasma renin activity by 32% was seen (95% CI, -15%, - 45%, P = 0.002). No hyperkalemia, hypotension, or acute renal failure occurred in the trial. These results were not attributable to sequence or carryover effects. Add-on losartan therapy did not improve proteinuria or ABP over one month of add on therapy. Improvement of GFR and fall in plasma renin activity suggest that renal hemodynamic and endocrine changes are more sensitive measures of AT1 receptor blockade. Whether add-on AT1 receptor blockade causes antiproteinuric effects or long-term renal protection requires larger and longer prospective, randomized controlled trials.

The renin-angiotensin-aldosterone system and carotid artery disease in mild-to-moderate primary hypertension.

The evidence linking activation of the renin-angiotensin system with accelerated cerebro-vascular atherosclerosis remains controversial. We therefore prospectively investigated the relationships of plasma renin activity and aldosterone levels with carotid artery lesions (CAL) in essential hypertension. We evaluated the prevalence and severity of CAL and the intimal-medial thickness (IMT) with a high-resolution echo-Doppler technique in 107 cerebrovascularly asymptomatic consecutive primary hypertensives (55 male, 52 female) and in 70 (42 male, 28 female) normotensive controls. We also measured supine plasma renin activity (PRA) and aldosterone before and 45 min after captopril administration, while daily urinary excretion of sodium was measured. Both the prevalence (59.4 versus 26.2%) and severity of sex- and age-adjusted and unadjusted CAL and IMT were significantly higher in hypertensives than in controls. Regression analysis showed different predictors of IMT (age and captopril-stimulated-PRA, R2 = 0.27, P < 0.0001), score of CAL (mean blood pressure, R2 = 0.15, F=12.73, P< 0.0001) and maximal stenosis (pulse pressure and known duration of hypertension R2 = 0.29, F = 14.58, P< 0.0001). Sex- and age-adjusted IMT did not differ between quartiles of renin-sodium profile. However, patients in the quartile with the highest PRA had the lowest score of CAL and an inverse relationship between age-adjusted PRA and IMT and CAL was found. These results, besides confirming an association of both IMT and CAL with primary hypertension and ageing, demonstrate that CAL and IMT have different correlates. However, they do not support the contention that a high renin-sodium profile carries an excess risk of CAL in primary hypertensives with no clinical evidence of cerebro-vascular disease.

Screening for primary aldosteronism with a logistic multivariate discriminant analysis.

Primary aldosteronism (PA) is the most common endocrine cause of curable hypertension, but no single test unequivocally identifies it. Accordingly, we investigated the usefulness of a logistic multivariate discriminant analysis (MDA) approach for PA screening. Generation of a logistic MDA function based on retrospective analysis of biochemical tests in a large cohort of referred patients with/without confirmed Conn's adenoma (CA), followed by prospective validation of the model. We investigated 574 selected hypertensives: 206 (32 with and 174 without CA) retrospectively, 48 (with a 13% prevalence of CA) prospectively for the validation of the model, and 320 referred hypertensives (with a 3.4% prevalence of CA) similarly evaluated. Patients were referred to a specialised centre for hypertension (4th Clinica Medica--University of Padua) and to a department of Internal Medicine of a regional hospital (Reggio Emilia). In all patients we measured several demographic and biochemical variables and performed a captopril test. A stepwise analysis of variance, based on a model fitted with several different variables, identified baseline (sALDO) and captopril-suppressed plasma aldosterone (cALDO), supine plasma renin activity (sPRA) and K+ as the most informative. Therefore, two models of logistic MDA with sPRA, K+, and either sALDO (model A) or cALDO (model B) were developed and used. ROC analysis was also performed to assess the optimal cut-off values. The model B of MDA provided the best performance and identified CA with 100% sensitivity and 81% accuracy. When used prospectively it showed 100% sensitivity, both in the Padua (88% accuracy) and in the Reggio Emilia series (90% accuracy). However, at both institutions most patients with idiopathic hyperaldosteronism (IHA) were also detected. Thus, although developed from patients with confirmed Conn's adenoma, a strategy based on multivariate discriminant analysis can be used prospectively for accurate screening for primary aldosteronism. Furthermore, it was proven to be accurate and applicable to patients tested with similar modalities at a different institution. Although this approach did not provide a clear-cut discrimination of Conn's adenoma from idiopathic hyperaldosteronism, it may avoid unnecessary and costly further testing in patients with a low probability of primary aldosteronism.

Hypokalemic metabolic alkalosis with hypomagnesuric hypermagnesemia and severe hypocalciuria: A new syndrome?

Bartter's and Gitelman's syndromes are characterized by hypokalemia, urinary potassium wasting, elevated plasma renin activity and aldosterone levels, normotension, and prostaglandinuria. They differ in that hypomagnesemia and hypocalciuria are universal in Gitelman's syndrome; 20% of cases of Bartter's syndrome have hypomagnesemia and hypercalciuria. We present a 44-year-old white man referred for hypokalemia. Clinical evaluation was unremarkable. He had hypokalemia (P K, 2.8 to 3.0 mEq/L), hypochloremic metabolic alkalosis, mild azotemia (serum creatinine, 1.4 to 1.8 mg/dL; creatinine clearance, 59 mL/min), normocalcemia, marked persistent hypocalciuria (FE Ca, 0.08% to 0.09%), and normal intact parathyroid hormone levels (51 pg/mL) and glucosuria. He had persistent hypermagnesemia (P Mg, 2.1 to 2.8 mEq/L) with relative hypomagnesuria (FE Mg, 3.2% to 5.2%) given the level of renal impairment and hypermagnesemia. Supine plasma renin activity and aldosterone levels were high (11 ng/mL/hr and 43 ng/dL, respectively). An excessive dietary intake of magnesium, including medications, was excluded. Studies were performed after withdrawing all medications for 8 days. A maximum water diuresis was established (an oral load of 20 mL/kg; stable U oam, 120 mOsm/kg), and free water and solute clearances were studied at baseline and after sequential intravenous injections of 125 mg chlorothiazide and 40 mg furosemide. The patient had moderate renal impairment (technetium diethylene triamine pentacetic acid [DTPA] clearance, 35.4 mL/min/1.73 m 2) and, in contradistinction to Bartter's and Gitelman's syndromes, sodium and water handling in the thick ascending limb of the loop of Henle and the distal tubule (fractional distal solute reabsorption) was normal, but there was evidence of a defect in the proximal tubule reabsorption (glucosuria, supranormal C H2O and high distal delivery). Hypomagnesuria and hypocalciuria appeared to be secondary to an increase in their absorption in the loop of Henle (increased excretion following furosemide). In conclusion, this combination of metabolic abnormalities has never been described. We postulate a proximal tubular defect in the absorption of NaCl leading to hypocalciuria, hypomagnesuria, and potassium wasting. Whether the tubular defect is primary or secondary to a renal parenchymal disease is, however, unclear.