Effect of multicomponent therapy on left ventricular diastolic function in resistant hypertension patients

The aim – to determine prognostic factors of improving left ventricular diastolic function (LV DF) in resistant hypertension (RH) patients (pts) treated with multicomponent antihypertensive therapy during three years.Materials and methods. 102 patients with true RH were included. Patients received triple fixed combination (blocker of the renin-angiotensin-aldosterone system / calcium antagonist / diuretic), to which has been added a fourth drug (spironolactone, eplerenone, moxonidine, torasemide or nebivolol). The state of LV DF was studied at the beginning and at the end of the study. Office and 24-h ambulatory blood pressure (BP) measurements, echocardiography, clinical characteristics, neurohumoral and proinflammatory status were assessed.Results and discussion. Impairment LV DF was detected in 75.5 % of pts. The first degree of LV diastolic dysfunction (DD) was observed in 63.7 %. The patients were divided into 2 groups: the first group included persons without initial impairment of LV DF (n=25), the second – pts with LV DD (n=77). Patients with LV DD were older, had a longer duration of hypertension, higher body mass index, 24-h urinary albumin excretion, office BP and 24-h ambulatory BP, more often (in 2 times) disorders of circadian BP rhythm and concomitant diabetes mellitus (DM). Left ventricular DD in 100 % of cases was associated with severe LV hypertrophy (LVH), increased plasma concentration of inflammatory proteins (CRP, fibrinogen), cytokines (IL-6, TNF-α), increased activity of leukocyte elastase, macrophage matrix metalloproteinase-12. The concentration in the blood of aldosterone, active renin, 24-h urinary excretion of metanephrines did not differ between the groups.Conclusions. Improvement and stabilization of LV DF occurred in parallel with regression of LVH (normalization of LVMI in 35.1 % of pts and significant decrease of LVMI in 64.9 %) against the background of decrease of BP and in the proportion of pts with disturbed circadian BP rhythm. The independent factors of the E/E’ ratio were the initial plasma concentrations of aldosterone (β=0.556; р=0.0001), glucose (β=0.366; р=0.0001), active renin (β=–0.223; р=0.004), 24-h urinary albumin excretion (β=0.188; р=0.016), age (β=0,192; р=0,023). The odds of an improvement in LV DF increased by 3.7 times, if the patient with RH had no DM, LVH regression occurred.

Novel chemiluminescent immunoassay to measure plasma aldosterone and plasma active renin concentrations for the diagnosis of primary aldosteronism

Determination of plasma aldosterone concentrations (PAC) and plasma active renin concentrations (ARC) is essential for the diagnosis of primary aldosteronism (PA). In Japan, although PAC and ARC are measured by radioimmunoassay and immunoradiometric assay, respectively, non-radioisotopic methods with better detection sensitivity, measurement accuracy, and technical simplicity are needed. We developed two-site sandwich chemiluminescent enzyme immunoassays (CLEIAs) to measure both PAC and ARC using monoclonal antibodies immobilized onto ferrite particles. The results of both assays are obtained simultaneously from a single plasma sample within 30 min using a fully automated system. The novel CLEIAs were validated using plasma samples from patients with PA (n = 52) and essential hypertension (n = 23). The PAC determined by the CLEIA was significantly correlated with that measured by liquid chromatography/mass spectrometry or conventional radioimmunoassay. The ARC determined by the CLEIA was significantly correlated with that measured by immunoradiometric assay. The limits of detection of the CLEIAs for PAC and ARC were 0.1 ng/dl and 0.04 pg/ml, respectively, which were better than those of conventional methods (PAC: 2.5 ng/dl; ARC: 5 pg/ml). The PAC and PAC/ARC ratio (ARR) were significantly higher, and the ARC significantly lower, in patients with PA than in those with essential hypertension. An ARR cut-off of 1.31 ng/dl per pg/ml showed a sensitivity of 96.2% and specificity of 78.3% for PA screening. The newly developed CLEIAs for measuring PAC and ARC could provide a clinically powerful alternative to conventional methods used for hypertension screening in clinical practice.

Prorenin and active renin levels in paediatrics: a bioanalytical review

As part of the extended renin-angiotensin-aldosterone system, active renin and its precursor prorenin have been an area of research interest for decades. Although several studies showed a correlation with disease, other studies found no significant association, e.g. attributed to limited sample size or pharmacological effects of antihypertensive drugs. Since the measurement of both proteins has typically been carried out in adult populations, the data in paediatrics is limited. This review aimed to collate the current data on plasma renin and prorenin levels in children and compare the levels of healthy vs. the diseased state. A literature search using Medline resulted in 213 publications of which 15 studies were classified as relevant. In the extant studies in the literature, an age-dependent decline of renin plasma concentration was observed in newborns compared to adolescents. For children with cardiovascular disease, five studies were identified that provide limited insight into the pathophysiological regulation of renin. In general, sample handling is still a crucial step, which might particularly affect measured active renin concentrations due to conformational changes of its precursor prorenin. A reliable assessment for prorenin levels in the maturating population is yet not possible due to the low number of available publications. Three different approaches to quantify prorenin were found and raise the question on the comparability of these methods. The review emphazised several weaknesses and highlights the need for an accurate procedure to determine levels of active renin as well as prorenin in its closed and open form.

SAT-196 The Use of 11C-metomidate PET-CT to Detect Unilateral Primary Hyperaldosteronism

Background Identifying causative adrenal lesions presents a significant diagnostic burden for physicians and radiologists. We describe the use of radiolabelled metomidate to lateralise primary hyperaldosteronism. Case presentation A 52-year old Chinese man with a 5-year history of hypertension was referred for hypokalemia [K 2.7 mmol/L (3.6 - 5.0)]. He had been on Telmisartan 80 mg and Amlodipine 10 mg daily and blood pressure at home ranged 110-120 / 70-80 mmHg. There was no history of poor oral intake, persistent diarrhea or vomiting, and he was not on any other prescription or alternative medications. There was no significant family history of hypertension or sudden cardiac death. Clinic blood pressure was 140/84 mmHg. There were no features suggestive of Cushing’s syndrome. Repeat biochemical tests confirmed hypokalemia (K 3.1 mmol/L), and associated raised bicarbonate 37.3 mmol/L [19 - 29]. Magnesium and creatinine were normal. Aldosterone-renin Ratio was elevated at 8.1 (serum Aldosterone 611 pmol/L [97.3 - 834.0], active renin 2.7 pg/ml [1.8 – 59.4]). Post-saline infusion, non-suppressible serum aldosterone levels of 1137 pmol/L was demonstrated, consistent with autonomous aldosterone production. A computed tomography of the adrenal revealed a 2.3 cm x 1.9 cm nodule on the left adrenal gland consistent with lipid rich adenoma. Adrenal vein sampling (AVS) under continuous synacthen infusion was performed. Adrenal to peripheral cortisol ratio was ≥10 for either adrenal veins, confirming cannulation of the adrenal veins. Aldosterone-cortisol ratios showed lateralization to the left adrenal gland (lateralization ratio of 10.35). There was contralateral suppression of the right adrenal gland with ratio of 0.41. 11C-Metomidate PET-CT scan demonstrated a maximum standardised uptake value (SUVmax) of 26.8 over the left adrenal nodule, while the SUVmax of the right adrenal gland was 16.2. Ratio of the left to right adrenal gland SUVmax was 1.65 (above the threshold of 1.25); and was concordant with AVS. This confirmed that the patient had a left functional adrenal adenoma responsible for hyperaldosteronism. Our patient underwent a left adrenalectomy, and histology was consistent with adrenal cortical adenoma. Prior to surgery he required 72 mmol/l of potassium supplementation daily to maintain K levels of 3.3 – 4.0 mmol/L. Two weeks post-operatively, he was normokalemic (K 4.9 mmol/L) without potassium supplementation. Serum aldosterone normalized to 159.3 pmol/L (active renin 9.3 pg/ml). Blood pressure is well controlled on amlodipine 5mg daily. Conclusion Targeted molecular imaging such as 11C-Metomidate PET-CT could aid localisation of functional adrenal disease to guide definitive surgical management. In the future, this could obviate the need for invasive and technically complex procedures like AVS.

Possible mechanisms of renal denervation long-term cardiac effects

Background. The renin-angiotensin-aldosterone system (RAAS) plays a key role in target organ damage in arterial hypertension (HTN), initiating the development of left ventricular hypertrophy (LVH), as well as the heart and vascular wall fibrosis and remodeling. In addition, one of the mechanisms of the cardiovascular disease progression is the angiotensin II-induced inflammation.Objective. To study the changes in renin, aldosterone and high-sensitive C‑reactive protein (CRP) levels two years after sympathetic renal denervation (RDN), to compare these changes with antihypertensive efficacy of the intervention and LVH regression.Design and methods. We included 77 patients with drug-resistant hypertension in the absence of contraindications to renal denervation. All patients underwent renal radiofrequency ablation. The active renin, aldosterone and a high-sensitive CRP concentrations assessment, 24‑hour blood pressure (BP) measurement and echocardiography were performed before, at 6 months, one and two years after the intervention.Results. There was a gradual decrease in CRP levels (the difference was significant after 6 months), aldosterone (significant two years after surgical treatment), and active renin (the difference was the most pronounced after one year). At all follow-up assessments, plasma renin activity correlated with left ventricular mass. At the same time, there were no significant differences between responders and non-responders.Conclusions. RDN leads to a RAAS activity attenuation, manifested by the decrease in both renin and aldosterone and CRP, probably due to angiotensin II proinflammatory effects reduction. Given these effects are long-term, correlate with LVH degree and unrelated to the BP lowering, a direct cardioprotective effect of renal denervation should be considered.

Diagnostic Accuracy of the Aldosterone–to–Active Renin Ratio for Detecting Primary Aldosteronism

Context The aldosterone–to–active renin ratio (AARR) is the recommended screening test for primary aldosteronism (PA), but prospective study data on its sensitivity and specificity are sparse. Objective To investigate the diagnostic accuracy of the AARR for detecting PA. Design Prospective diagnostic accuracy study. Setting This study was conducted from February 2009 to August 2015 at the outpatient clinic of the Department of Endocrinology and Diabetology of the Medical University of Graz, Austria. Participants Four hundred patients with arterial hypertension who were referred to a tertiary care center for screening for endocrine hypertension. Intervention Participants had a determination of the AARR (index test) and a second AARR determination followed by a saline infusion test (SIT) after 2 to 6 weeks. PA was diagnosed in individuals with any AARR ≥3.7 ng/dL/µU/mL [including a plasma aldosterone concentration (PAC) of ≥9 ng/dL] who had a PAC ≥10 ng/dL after the SIT. We did not substantially alter antihypertensive drug intake. Main Outcome Measures Primary outcome was the receiver-operating characteristic (ROC) curve of the AARR in diagnosing PA. Results A total of 382 participants were eligible for analyses; PA was diagnosed in 18 (4.7%) patients. The area under the ROC curve of the AARR in detecting PA was 0.973 (95% CI, 0.956 to 0.990). Sensitivity and specificity for a positive AARR in diagnosing PA were 100% (95% CI, 81.5% to 100.0%) and 89.6% (95% CI, 86.0% to 92.5%), respectively. Conclusions The AARR has good diagnostic accuracy for detecting PA.

Responses of the renin–angiotensin–aldosterone system in pregnant chronic kidney disease patients with and without superimposed pre-eclampsia

Background Women with chronic kidney disease (CKD) are at increased risk of superimposed pre-eclampsia (SPE). Accurate identification of SPE is challenging. We hypothesized that specific components of the renin–angiotensin–aldosterone system (RAAS) would discriminate between CKD and SPE. The aim of the study was to establish differences in circulating and intrarenal RAAS in women with CKD with and without SPE and compare these to normotensive controls (NCs) and women with pre-eclampsia (PE). Methods White European NC women (n = 20), women with PE (n = 9), normotensive CKD without SPE (n = 8) and with SPE (n = 11) were recruited in the third trimester. Plasma renin, plasma and urine total angiotensinogen (AGT) concentrations were quantified by enzyme-linked immunosorbent assay, urinary tetrahydroaldosterone (TH-aldo) concentration by gas chromatography-mass spectrometry and placental growth factor (PlGF) by immunoassay. Results Urinary TH-aldo:creatinine ratios were lower in women with PE or SPE compared with NC or women with CKD (P < 0.05 for all). The same group differences were observed for plasma active renin and PlGF concentrations (P < 0.05 for all). Urine total AGT was higher in women with PE compared with NC (P < 0.05) and urine TH-aldo:urine AGT was lower (P < 0.05). However, women with SPE had lower urinary AGT concentrations compared with women with PE (P < 0.05). No differences in plasma total AGT were observed between groups. Conclusions Women with SPE have a lower urinary TH-aldo:creatinine ratio, lower plasma active renin and lower PlGF concentrations than women with CKD, comparable to women with PE without pre-existing disease, suggestive of similar pathophysiology. These data suggest disruption of the RAAS pathway in SPE similar to PE. Exploration of the predictive value of RAAS components for adverse pregnancy events in women with CKD is required.