Suppressed Plasma Renin Activity Research Articles

Emerging Therapies for Treatment-Resistant Hypertension: A Review of Lorundrostat and Related Selective Aldosterone Synthase Inhibitors.

The target-hypertension (Target-HTN) trial investigated the efficacy and safety of lorundrostat, an aldosterone synthase inhibitor, as an antihypertensive. Cohort 1 of the trial includes patients with suppressed plasma renin activity and elevated aldosterone levels. Lorundrostat doses of 100 mg and 50 mg daily significantly decreased systolic blood pressure compared to the placebo group. Cohort 2 also demonstrated a reduction in systolic blood pressure with the 100 mg daily dose of lorundrostat. Lorundrostat is more selective for the inhibition of CYP11B2 versus CYP11B1, which makes it preferable to other aldosterone synthase inhibitors that inhibit cortisol synthesis, such as osilodrostat. Phase 3 trials are needed to validate the safety and efficacy of lorundrostat, and further research should be performed on other selective aldosterone synthase inhibitors such as baxdrostat, dexfadrostat, and BI 690517.

Renin Inhibition and the Long-Term Renal Function in Patients With Hypertensive Emergency: A Retrospective Cohort Study.

The rehospitalization rate in a hypertensive emergency is high, indicating the necessity for optimizing its long-term management. The role of the renin-angiotensin system (RAS) blockade in this disorder remains uncertain. We conducted a retrospective analysis involving 20 admitted patients who received aliskiren, a direct renin inhibitor (DRI), for the management of hypertensive emergency associated with elevated plasma renin activity (PRA). We analyzed the changes in blood pressure (BP), kidney function, and RAS activity in the subacute and chronic phases. The use of DRI was associated with a marked reduction in PRA (median, from 25.0 to 1.2 ng/ml/h) and serum aldosterone levels (from 404 to 130 pg/ml) during the index admission. BP also decreased from 226/143 to 142/80 mm Hg. A comparison of clinical characteristics according to the renal function indicated that dialysis-dependent patients had higher aldosterone levels than non-dialysis-dependent patients at admission, despite comparable BP levels. After a median follow-up of 567 days in non-dialysis-dependent patients with DRI, eGFR levels were significantly increased from 14.3 to 23.1 ml/min/1.73 m2. PRA levels were consistently suppressed at 0.8 ng/ml/h. We found a significant correlation between the degree of PRA suppression and changes in eGFR (r = -0.58), indicating that the effective blockade of RAS is associated with the preservation of eGFR in the study subjects. DRI can successfully suppress PRA in patients with high-renin hypertensive emergency in both subacute and chronic phases. An efficient RAS blockade is associated with preserved renal function in these patients.

JS-NG-8: CASE REPORT: POSSIBLE NEW CHANNELOPATHY ASSOCIATED WITH ELEVATED ALDOSTERONE LEVELS

Background: Potassium channelopathies are associated with prolonged QT cardiac syndrome. New potassium channelopathies in somatic cells, including KCNJ5 mutations, also underlie some forms of primary hyperaldosteronism. We present a first-in-human report of an association between a KCNQ1 loss of function mutation manifesting with life threatening-ventricular tachycardia (VT), severe hypokalemia and presumed hyperaldosteronism. Case Presentation: The patient is a 51-year-old Asian woman known for obesity, Wolff-Parkinson-White post ablation, and recurrent syncopal episodes with polymorphic VT due to prolonged QTc, requiring an implantable cardioverter defibrillator. On initial presentation for syncope, spontaneous hypokalemia was discovered at 3.1 mmol/L. She had multiple hospitalizations for torsade storms and persistent hypokalemia resistant to aggressive potassium supplementation until addition of spironolactone. Investigations revealed a suppressed plasma renin activity < 0.05 ng/L/s, serum aldosterone concentration at 302 pmol/L, and an aldosterone to renin ratio (ARR) > 6040. Repeated ARR was > 10980. Confirmatory saline suppression testing or adrenal vein sampling were not performed due to risk of recurrent VT associated with spironolactone cessation. A comprehensive evaluation for the etiology of this patient's clinical presentation revealed a mutation in the KCNQ1 gene type 1. Literature review: The voltage-dependent K(+) channel responsible for activating delayed K(+) current is composed of pore-forming KCNQ1 and regulatory KCNE1/3 subunits which loss of function predispose to sustained torsade de pointes. Animal models demonstrate that KCNQ1 and KCNE1 mRNAs are expressed in the zona glomerulosa of adrenal glands where potassium channels directly participate in the control of aldosterone production. Although KCNE3 is not expressed in mouse adrenals, its deletion is thought to cause activation of lymphocytes targeting adrenal glands, leading to hyperaldosteronism. Furthermore, administration of spironolactone to KCNE3 knockout mice ameliorates their QT prolongation and predisposition to VT. There have been no case reports of an association between KCNQ1/E1/E3 loss of function and hyperaldosteronism in humans. Conclusion: This raises the question if this mechanism can also be a component of human KCNQ1 and KCNE1/3-linked arrhythmogenesis and hyperaldosteronism. Alternatively, we can further speculate that patients with hyperaldosteronism who develop malignant arrhythmias during hypokalemia are subjects with impaired repolarization reserve as a consequence of variants in genes known to cause long QT syndrome. The variants, leading to subclinical ion channel dysfunction, are typically silent until unmasked by electrolytes abnormalities such as hypokalemia. To our knowledge, this case is a first report of a potentially novel channelopathy associated with hyperaldosteronism in humans. These findings are hypothesis generating and require further investigations.

ODP060 Treatment of Aldosterone-producing adenoma by CT-guided radiofrequency ablation in a high surgical risk patient: biochemical and clinical outcomes.

Abstract Background Primary aldosteronism (PA) is a leading cause of secondary hypertension and harness a much higher cardiovascular risk than essential hypertension. About 30% of PA cases are due the existence of an aldosterone-producing adenoma (APA). Although the current guidelines recommend unilateral laparoscopic adrenalectomy as the standard treatment of APA, some patients might no be suited for the procedure. Clinical Case A 66-year man was referred to our institution following a 14-year history of resistant hypertension. His past history included a stage III chronic kidney disease, type 2 diabetes mellitus, dyslipidemia, obstructive sleep apnea (OSA), hypothyroidism, grade I obesity, and rheumatoid arthritis. Initial tests were consistent with PA: elevated serum aldosterone (26 ng/dL), suppressed plasma renin activity (PRA: 0. 07 ng/ml/H) and a high aldosterone/renin ratio (RAR: 65) with concomitant hypokalemia (3,4 mEq/L). Abdominal CT-scan demonstrated a 11×8 mm left adrenal nodule with an absolute washout of 60%. A diagnosis of an APA was confirmed by an adrenal vein sampling. Since the patient had multiple comorbidities and an unequivocal high surgical risk, laparoscopic adrenalectomy was contraindicated, and pharmacologic treatment was started with spironolactone. Despite the use of high doses of spironolactone, blood pressure (BP) control was not achieved. Moreover, severe side effects were experienced, notably sexual dysfunction and painful gynecomastia. In this setting, a decision for a CT-guided radiofrequency ablation was made. The procedure underwent under general anesthesia and had no adverse events. Three days after the ablation, biochemical analysis demonstrated a significant reduction of aldosterone (10 ng/dL) and RAR (10), whereas the PRA was notably higher (1,45 ng/mL/h). He transitioned from 6 different classes of anti-hypertensives drugs to only one and his blood pressure was well controlled in an appointment 30 days after the procedure. On the other hand, his glomerular filtration rate had decayed from 44 mL/min to 31 mL/h due to a rapid blood pressure control. Despite no changes in anthropometric measures and OSA related symptoms were observed, an expressive reduction in microalbuminuria (191 mg/dL to 28,6 mg/dL) was noticed. Conclusion The CT-guided radiofrequency ablation is a suitable minimally invasive treatment for PA in high surgical risk patients. For patients with high surgical risk and intolerance to clinical treatment, radiofrequency should be offered as an option for treatment in a specialized center. Presentation: No date and time listed

PSAT016 Deoxycorticosterone-Producing Adrenocortical Carcinoma: A Rare Cause of Resistant Hypertension

Abstract Background Rare causes of secondary hypertension should be considered after negative initial evaluation for more common conditions. 11-Deoxycorticosterone-secreting tumors are one such rare cause. Clinical Case A 38-year-old male with two-year history of resistant hypertension on four antihypertensive medications (amlodipine, hydrochlorothiazide, lisinopril, spironolactone) presented to the emergency room with one-day history of headaches and hypertension. Initial vitals were blood pressure of 179/117, heart rate 68, respiratory rate 18, and SpO2 of 100% on room air. Labs were notable for hypokalemia of 2.2, normal creatinine of 1.03, and troponin elevation of 0.08. EKG showed no ischemic changes. During the hospital admission, spironolactone dose was increased, amiloride was added, hydrochlorothiazide was discontinued, and potassium was supplemented. The patient's blood pressure stabilized, and troponin normalized. Evaluation for secondary causes was also initiated, including plasma renin, aldosterone, and metanephrines, with results pending on discharge. Outpatient CT abdomen and pelvis was also ordered. The patient was discharged on the third day of admission on an increased dose of spironolactone 100mg daily, amiloride 5mg daily, amlodipine 10mg daily, lisinopril 40mg daily, and potassium 20meq twice daily. Laboratory studies and outpatient endocrinology evaluation revealed suppressed plasma renin activity 0.1 ng/mL/hr, low aldosterone <3.0 ng/dL, elevated 11-deoxycorticosterone (DOC) 869 ng/dL (reference range ≤19 ng/dL), and elevated 11-deoxycortisol 719 ng/dL (reference range ≤49 ng/dL). Plasma and urine metanephrines, 24-hour urinary free cortisol, and plasma DHEAS were normal. CT revealed a large 9.7×10.0×10.7cm heterogeneously enhancing right adrenal mass and several subcentimeter bilateral pulmonary nodules. FDG PET-CT showed mild heterogeneous uptake of the adrenal mass with SUVmax of 5.1 and hepatic SUVmean of 2.5, without convincing metabolic evidence of metastasis. Mild uptake was noted in the mediastinal, hilar and left axillary lymph nodes, which were not suspiciously hypermetabolic and favored to be reactive, perhaps related to recent COVID-19 vaccination administered to the left upper extremity. The subcentimeter pulmonary nodules did not have increased avidity. The patient underwent open right adrenalectomy without complications. Pathology revealed 11.5cm low-grade adrenocortical carcinoma with clear margins and angioinvasion, Ki67 proliferation index of 1-2%, and without necrosis, lymphovascular invasion, or extra-adrenal extension. 11-deoxycortisol normalized and DOC was undetectable at one and three months postoperatively. Blood pressure improved significantly, and all antihypertensives were discontinued except amlodipine 10mg daily. On surveillance CT scan six months after surgery, there was no evidence of residual disease in the adrenalectomy bed and pulmonary nodules appeared stable. Conclusions Adrenocortical carcinomas rarely produce aldosterone and even less commonly produce DOC as the major steroid product. DOC should be evaluated in the setting of hypertension with hypokalemia, suppressed renin and aldosterone. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

Moderate hyperuricaemia ameliorated kidney damage in a low-renin model of experimental renal insufficiency.

Uric acid has promoted renal fibrosis and inflammation in experimental studies, but some studies have shown nephroprotective effects due to alleviated oxidative stress. We studied the influence of experimental hyperuricaemia in surgically 5/6 nephrectomized rats. Three weeks after subtotal nephrectomy or sham operation, the rats were allocated to control diet or 2.0% oxonic acid (uricase inhibitor) diet for 9 weeks. Then blood, urine and tissue samples were taken, and renal morphology and oxidative stress were examined. Inflammation and fibrosis were evaluated using immunohistochemistry and real-time PCR (RT-PCR). Remnant kidney rats ingesting normal or oxonic acid diet presented with ~60% reduction of creatinine clearance and suppressed plasma renin activity. Oxonic acid diet increased plasma uric acid levels by >80 μmol/L. In remnant kidney rats, moderate hyperuricaemia decreased glomerulosclerosis, tubulointerstitial damage and kidney mast cell count, without influencing the fibrosis marker collagen I messenger RNA (mRNA) content. In both sham-operated and 5/6 nephrectomized rats, the mast cell product 11-epi-prostaglandin-F2α excretion to the urine and kidney tissue cyclooxygenase-2 (COX-2) levels were decreased. To conclude, hyperuricaemic remnant kidney rats displayed improved kidney morphology and reduced markers of oxidative stress and inflammation. Thus, moderately elevated plasma uric acid had beneficial effects on the kidney in this low-renin model of experimental renal insufficiency.

Hormone-Dependent Regulation of Renin and Effects on Prorenin Receptor Signaling in the Collecting Duct.

The production of renin by the principal cells of the collecting duct has widened our understanding of the regulation of intrarenal angiotensin II (Ang II) generation and blood pressure. In the collecting duct, Ang II increases the synthesis and secretion of renin by mechanisms involving the activation of Ang II type 1 receptor (AT1R) via stimulation of the PKCα, Ca2+, and cAMP/PKA/CREB pathways. Additionally, paracrine mediators, including vasopressin (AVP), prostaglandins, bradykinin (BK), and atrial natriuretic peptide (ANP), regulate renin in principal cells. During Ang II-dependent hypertension, despite plasma renin activity suppression, renin and prorenin receptor (RPR) are upregulated in the collecting duct and promote de novo formation of intratubular Ang II. Furthermore, activation of PRR by its natural agonists, prorenin and renin, may contribute to the stimulation of profibrotic factors independent of Ang II. Thus, the interactions of RAS components with paracrine hormones within the collecting duct enable tubular compartmentalization of the RAS to orchestrate complex mechanisms that increase intrarenal Ang II, Na+ reabsorption, and blood pressure.

Primary hyperaldosteronism without suppressed renin

Primary Hyperaldosteronism characterizes elevated plasma and urinary aldosterone with suppression of plasma renin activity. Suppression can be due to sodium retention which is aldosterone dependent and extracellular volume expansion. Here a 29 year old male presented with uncontrolled hypertension, on work up he was diagnosed to have primary Hyperaldosteronism with normal plasma renin level. So with the available medical data on the patient as well as the publications on aldosterone/renin association in primary hyperaldosteronism was reviewed here to explain the rare finding.

Characteristics of aldosterone-producing adenomas in patients without plasma renin activity suppression.

Primary aldosteronism (PA) usually accompanies suppressed plasma renin activity (PRA) through a negative feedback mechanism. While some cases of PA with unsuppressed PRA were reported, there have been no studies about the characteristics of PA with unsuppressed PRA; thus, these characteristics were examined herein. Nine patients with unsuppressed PRA and 86 patients with suppressed PRA were examined. All patients underwent segmental adrenal venous sampling (sAVS) and adrenalectomy, and were pathologically confirmed to have cytochrome P450 11B2 (CYP11B2)-positive aldosterone-producing adenoma according to international histopathology consensus criteria. Unsuppressed and suppressed PRA were defined as PRA levels of > 1.0 and ≤ 1.0 ng/mL/hr, respectively, in multiple blood samples obtained in the resting position. The unsuppressed PRA group had higher morning cortisol levels (12.6 [8.5, 13.5] vs. 8.5 [7.1, 11.0] μg/dL, P = 0.03) and higher cortisol levels after a 1 mg dexamethasone suppression test (DST) (2.2 [1.6, 2.5] vs. 1.3 [1.0, 1.9] μ g/dL, P = 0.004) than the suppressed PRA group. The unsuppressed PRA group also showed higher aldosterone levels on the non-surgical side during sAVS (P = 0.02 before adrenocorticotropic hormone (ACTH) stimulation, P = 0.002 after ACTH stimulation), a higher intensity of CYP17 expression in the resected adrenal gland (P = 0.02), and a lower clinical complete success rate 1 year after surgery (P = 0.04) compared with those in the suppressed PRA group. These findings suggest that PA should not be ruled out by unsuppressed PRA among patients with hypertension, particularly when their cortisol levels remain unsuppressed in the 1 mg DST. Meanwhile, it should be acknowledged that patients with unsuppressed PRA have higher aldosterone levels on the non-surgical side, and a lower likelihood of postoperative complete clinical success is to be expected.

Increased Dosage of MRA Improves BP and Urinary Albumin Excretion in Primary Aldosteronism With Suppressed Plasma Renin.

PurposeExcessive aldosterone secretion causes a high risk of cardio-cerebrovascular events. Mineralocorticoid receptor antagonist (MRA) is 1 of the treatment strategies for primary aldosteronism (PA). However, current MRA treatment is insufficient because MRA-treated patients with suppressed plasma renin activity (PRA) < 1 ng/mL/h still had a higher risk of cardiovascular disease than those with unsuppressed PRA. This is a prospective interventional study to determine the effects of an increase in MRA dosage on blood pressure (BP) control and urinary albumin excretion (UAE) in MRA-treated PA patients.MethodsThirty-four PA patients were recruited, and 24 patients (6 male, 18 female) completed this study. Serum potassium concentration was assessed every two months to adjust the dosage of MRA safely for 6 months. The primary outcomes were the changes in BP and UAE between baseline and 6 months.ResultsSystolic BP (SBP) and log10UAE decreased significantly as the daily dose of MRA increased. Diastolic BP (DBP) tended to decrease. We divided the PA patients into two groups (baseline PRA < 1 ng/mL/h and baseline PRA ≥ 1 ng/mL/h) according to PRA. In the group with baseline PRA < 1 ng/mL/h but not that with baseline PRA ≥ 1 ng/mL/h, SBP, DBP and log10UAE after 6 months were significantly lower than those at baseline.ConclusionsThe increase in MRA dosage improved BP and UAE in PA patients with suppressed PRA.

Progress on Genetic Basis of Primary Aldosteronism.

Primary aldosteronism (PA) is a heterogeneous group of disorders caused by the autonomous overproduction of aldosterone with simultaneous suppression of plasma renin activity (PRA). It is considered to be the most common endocrine cause of secondary arterial hypertension (HT) and is associated with a high rate of cardiovascular complications. PA is most often caused by a bilateral adrenal hyperplasia (BAH) or aldosterone-producing adenoma (APA); rarer causes of PA include genetic disorders of steroidogenesis (familial hyperaldosteronism (FA) type I, II, III and IV), aldosterone-producing adrenocortical carcinoma, and ectopic aldosterone-producing tumors. Over the last few years, significant progress has been made towards understanding the genetic basis of PA, classifying it as a channelopathy. Recently, a growing body of clinical evidence suggests that mutations in ion channels appear to be the major cause of aldosterone-producing adenomas, and several mutations within the ion channel encoding genes have been identified. Somatic mutations in four genes (KCNJ5, ATP1A1, ATP2B3 and CACNA1D) have been identified in nearly 60% of the sporadic APAs, while germline mutations in KCNJ5 and CACNA1H have been reported in different subtypes of familial hyperaldosteronism. These new insights into the molecular mechanisms underlying PA may be associated with potential implications for diagnosis and therapy.

Abstract P142: Factors Associated With Persistent Cardiac Organ Damage In Primary Aldosteronism After One Year Of Treatment

Introduction: Adrenalectomy and medical treatment of primary aldosteronism (PA) both induce regression of left ventricle (LV) hypertrophy, while the effects on LV myocardial function are less investigated. Hypothesis: We hypothesized that persistent cardiac organ damage was more prevalent in medically treated PA patients. Methods: Eighty-four patients (57±11 years, 27% female) with PA underwent echocardiography at time of diagnosis and after 1 year of treatment (49% adrenalectomized, 51% medically treated). Persistent cardiac organ damage was identified as LV hypertrophy or low LV systolic function by midwall shortening or global longitudinal strain (GLS), both at baseline and at follow-up. LV diastolic function was assessed by left atrial enlargement and estimated LV filling pressure (E/e’). Results from logistic regression analyses are reported as odds ratio (OR) with 95% confidence intervals (CI). Results: After 1 year, a significant regression of LV hypertrophy was observed in adrenalectomized patients (44% vs. 22%, p=0.038), but not in medically treated patients (59% vs. 50%, p=0.206). Midwall shortening, E/e’ and prevalence of enlarged left atrium improved significantly in both treatment groups (all p&lt;0.001), while GLS remained unchanged. In multivariable logistic regression analysis, receiving medical treatment for PA (OR 4.98 [95% CI 1.26-18.88] was a strong predictor of persistent LV hypertrophy independent of higher body mass index (OR 1.20 [95% CI 1.04-1.38]) and presence of diabetes (OR 6.48 [95% CI 1.20-34.83], all p&lt;0.05). Important covariables of persistently low midwall shortening were persistent LV hypertrophy (OR 3.50 [95% CI 1.12-10.96]) and suppression of plasma renin activity after 1 year of treatment (OR 4.31 [1.15-16.12], both p&lt;0.05). The strongest predictor of persistently low GLS was higher HbA 1c (OR 2.37[95% CI 1.12-5.02], p=0.024). Conclusions: In PA, LV hypertrophy regression was more common in adrenalectomized patients. Persistent LV hypertrophy and impaired glucose metabolism were the major factors associated with persistent LV myocardial dysfunction independent of treatment.

A Case of Aldosterone Producing Adrenocortical Carcinoma

Introduction: Adrenocortical carcinomas (ACCs) are rare and aggressive cancers. Approximately 60% of ACCs are functional, presenting with Cushing syndrome and/or virilization. Aldosterone producing ACCs account for about 1-3% of hormonally active ACCs. Despite aldosterone production, their mutational landscape is not different from other functional ACCs - they do not harbor mutations of known aldosterone-producing adenoma (APA) associated genes. They present with uncontrolled hypertension and hypokalemia, as seen in this case. Case: 63 year old Asian female with previously well controlled hypertension experienced resistant hypertension and hypokalemia for over a year. Since the onset of hypokalemia, patient noticed worsening hypertension despite addition of multiple medications. CT abdomen during an episode of severe gastroenteritis revealed a 3.7 cm heterogenous multilobulated left adrenal mass. Hormonal workup showed elevated aldosterone of 35 ng/dl with suppressed plasma renin activity of 0.41 ng/ml/h and serum potassium of 3.4 while patient was on 50 mg of spironolactone. Plasma and urine metanephrine levels were unremarkable. Plasma ACTH was <5 ng/L, cortisol was 12 ug/dl and DHEA-S was 149 ng/dl. 24 hour urine free cortisol result was not available. Repeated CT abdomen revealed a 5.2 cm left adrenal mass (Non-contrast HU of 38, 50% absolute wash out), increasing in size from 3.7 cm in 6 months. The mass was FDG avid with SUV of 13.2. Patient underwent laparoscopic left adrenalectomy and surgical pathology revealed a 4.2 cm, high grade ACC with vascular invasion, Ki67 index of 35% and modified Weiss score of 6. Hypertension and hypokalemia resolved after tumor removal, no longer requiring antihypertensive medications. Plasma aldosterone level also remains normal after surgery. However, postoperative CT (6 weeks after surgery) revealed numerous pulmonary metastases. Germline genetic testing is pending. Genomic interrogation of the primary tumor identified CDKN2A and CDKN2B deletions, along with pathogenic mutations in CTNNB1 and DNMT3A. Copy number analysis revealed numerous large scale chromosomal alterations including many arm level and whole chromosome gains and losses. These somatic mutations affect p53/Rb1 signaling (CDKNs), chromatic remodeling (DNMT3A) and wnt signaling pathway (CTNNB1). Together with noisy pattern of copy number alterations, these genomic alterations likely account for the aggressive nature of this tumor. Clinical Lessons: (1) Clinicians should raise the suspicion of ACC during the workup for primary hyperaldosteronism, especially if an adrenal mass does not have the reassuring radiographic features suggestive of a benign adrenal mass. (2) Metastatic lesions may not necessarily produce aldosterone as the primary tumor does. (3) Mutational analysis of the tumor informs molecular subtypes of ACC, prognosis, and treatment decisions.

LIDDLE SYNDROME – DETECTION OF NOVEL MUTATION IN A FAMILY WITH HYPERTENSION

Abstract Objective: Liddle syndrome is a rare monogenic form of arterial hypertension with autosomal dominant inheritance. It is caused by mutation of genes coding one of three subunits of epithelial sodium channel (ENaC), which is located in distal nephron. Under physiological conditions, its expression and activity is regulated to maintain fluid and electrolytes homeostasis by reabsorbing Na+. Mutated channel cannot be degraded and therefore, it is accumulated on cell membrane; this results in enhanced sodium reabsorption. The most common clinical presentation of Liddle syndrome is early onset of hypertension, hypokalemia, suppressed plasma renin activity and low plasma aldosterone level. Up to now, 36 mutations causing Liddle syndrome were described. Design and method: Genetic assessment was performed in a Czech family of three generations (n = 14, see Figure) where hypertension and tendency to hypokalemia was present in several members. We used PCR amplification of specific alleles of SCNN1B and SCNN1G genes which was followed by Sanger sequencing. Results: We present a novel mutation causing Liddle syndrome: Tyr604∗ in beta-subunit of epithelial sodium channel. This mutation is supposed to generate a premature stop codon at position 604, resulting in truncated beta-subunit of EnaC. It was found in 7 members of the family: I-1, II-1 and 2, and III-1 to 4. Phenotypes of these subjects were different: from severe hypertension and hypokalemia (subjects I-1 and III-3, manifestation in 10 and 5 years, respectively) to normotension with normal potassium levels (III-1 and 2, now aged 8 and 10 years, respectively); however, all the seven subjects with mutation had hypoaldosteronism (serum level &lt; 0.13 ng/ml). Conclusions: A new mutation causing Liddle syndrome is described. It is manifested with different severity and mild forms that are not manifested in early childhood exist; thus, Liddle syndrome may be more frequent among adult hypertensive subjects than currently supposed. Proper diagnosis is important as the patients respond well to treatment with ENaC blocker amiloride.

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of SPH3127: A Phase I, Randomized, Double-Blind, Placebo-Controlled Trial

PurposeTo evaluate the pharmacokinetics, pharmacodynamics, safety, and tolerability of single- and multiple-dose SPH3127 in healthy individuals. MethodsThis was a randomized, double-blind, placebo-controlled, Phase I dose-escalation study. FindingsSPH3127 exposure, expressed as Cmax, AUC0–t, and AUC0–∞, was proportionally increased with dose for a range of 25–800 mg (single ascending dose [SAD]) and 100–400 mg daily (multiple ascending doses [MADs]). In an SAD, the Cmax values with 25, 50, 100, 200, 400, and 800 mg of SPH3127 were 90.67, 344.50, 523.50, 1239.50, 2445.00, and 5753.33 ng/mL, respectively. The corresponding AUC0–t values were 294.48, 843.62, 1109.33, 2858.56, 6697.50, and 13057.83 h × ng/mL. In MADs, after the first dose of SPH3127, the Cmax values with 100, 200, and 400 mg of SPH3127 were 421.50, 969.00, and 2468.33 ng/mL, respectively. The corresponding AUC0–t values were 1279.28, 2275.77, and 5934.26 h × ng/mL. At steady state, the Cmax values with 100, 200, and 400 mg of SPH3127 were 514.67, 1419.17, and 2513.33 ng/mL, respectively. The corresponding AUC0–24 values were 1638.14, 3096.20, and 7577.70 h × ng/mL. The median Tmax range from 0.33 to 1.0 h and the median t1/2 from 3 to 4 h. In an SAD, when the dose was >100 mg, plasma renin activity inhibition of up to 90% lasted up to 24 h. In MADs, renin activity was continuously inhibited by up to 90% in each group for 24 h after the last administration. Treatment-emergent adverse events (AEs) were reported in 29.2% of individuals receiving the SAD and 33.3% of those receiving MADs. Only mild adverse events occurred. ImplicationsSPH3127 was well tolerated and had robust and sustained suppression of plasma renin activity. Clinicaltrials.gov identifiersNCT03128138 (SAD study) and NCT03255993 (MAD study).

The Diagnostic Value of Captopril Challenge Test for Primary Aldosteronism

To investigate the diagnostic value of different captopril challenge test (CCT) diagnostic criteria for diagnosing primary aldosteronism (PA). We collected the clinical data of 184 patients with hypertension retrospectively in West China Hospital of Sichuan University. Receiver operating characteristic (ROC) curves were used to analyze the post-CCT efficacy of aldosterone renin activity ratio (ARR), plasma aldosterone concentration (PAC), plasma renin activity (PRA) and PAC suppression rate for PA diagnosis. This study included 125 cases of primary aldehyde (PA group) and 59 cases of essential hypertension (EH group), and there were 38 normal renin primary hypertension (NREH group) and 21 low renin primary hypertension (LREH group) in EH group. The post-CCT PAC suppression rate (median (P 25, P 75)) of EH and PA group were 0.190 (0.083, 0.351) and 0.125 (0.024, 0.237), respectively. Compared with the NREH group, the basic and post-CCT PRA of LREH group were lower ( P<0.001), and there were no significant differences compared with the PA group ( P>0.05). We found significant overlap of post-CCT PRA and ARR between PA group and LREH group, while the overlap of post-CCT PAC between the two groups was small. In differential diagnosis of PA and EH, the areas under ROC curve of the post-CCT ARR, PAC, PRA and PAC suppression rate were 0.860 (95% confidence interval ( CI): 0.800-0.907), 0.881 (95% CI: 0.825-0.924), 0.771 (95% CI: 0.703-0.831) and 0.632 (95% CI: 0.558-0.701), respectively. There was no significant difference between the first two indexes ( Z=0.443, P=0.658), and both of them were higher than the latter two ( P<0.05). The optimal post-CCT cut-off values for ARR and PAC in differential diagnosis of PA and EH were 19.24 ng·dL -1 with a sensitivity of 78.4% and a specificity of 88.1%, and 32.47 (ng·dL -1)/(ng·mL -1·h -1) with a sensitivity of 84.17% and a specificity of 72.41%. Both ARR and PAC have higher diagnostic value than the post-CCT PAC suppression rate, post-CCT PAC is especially suitable as a confirmatory testing criterion of PA.

In memoriam: Dr Norman M. Kaplan (1931–2020)

In memoriam: Dr Norman M. Kaplan (1931–2020)

Serum Aldosterone Concentration, Blood Pressure, and Coronary Artery Calcium: The Multi-Ethnic Study of Atherosclerosis.

Aldosterone is a steroid hormone regulating fluid and electrolyte homeostasis and is known to increase the risk of atherosclerosis. In this study, we examined the associations of serum aldosterone concentrations with subclinical atherosclerosis and all-cause mortality. This study included 948 adults aged 46 to 88 years from the MESA (Multi-Ethnic Study of Atherosclerosis) with measurements of serum aldosterone and plasma renin activity and not taking antihypertensive medications. Coronary calcification was longitudinally assessed using Agatston coronary artery calcium score from computed tomography scans. All-cause mortality was ascertained from the medical record. The average age (SD) was 62.3 (9.4) years and 53% were male. Among 700 subjects who had follow-up coronary artery calcium score (median follow-up of 6.4 years), higher aldosterone levels (per 100 pg/mL) were associated with higher coronary artery calcium (relative ratio, 1.17 [95% CI, 1.04-1.32]), with the association being stronger in individuals with suppressed plasma renin activity (≤0.5 μg/L/hr). Systolic or diastolic blood pressure mediated around 45% of the total effect of aldosterone on coronary artery calcium. Over a median follow-up of 12.5 years (120 deaths identified among 948 subjects), aldosterone was associated with the increased risk of all-cause mortality when plasma renin activity was suppressed; hazard ratio per 100 pg/mL, 1.70 (95% CI, 1.10-2.63). In this study, we found that higher aldosterone levels were associated with the increased risk of subclinical coronary atherosclerosis and all-cause mortality particularly when renin was suppressed. Our findings indicate the importance of aldosterone levels (even within the reference range) with respect to the cardiovascular system and overall health.

Hypertension and Exaggerated Sympatho‐excitatory Reflexes are Reduced by Low Salt Diet in Male Obese Zucker Rats with no Effect in Lean Zucker Rats

Adult male obese Zucker rats (OZRs) develop sympathetically‐driven hypertension and exaggerated sympatho‐excitatory reflexes compared to age‐matched male lean Zucker rats (LZRs). Compared to LZRs, male OZRs on a standard rodent diet (0.5–1% NaCl) display attributes seen in salt sensitive rats consuming a high salt diet, such as suppressed plasma renin activity and exaggerated sympatho‐excitatory reflexes. The present study examined whether these attributes would be reduced in male OZRs on a low salt diet (0.1% NaCl). Rats were placed on diets with 0.5–0.85% NaCl (control diet; 10 OZRs and 8 LZRs) or a diet with 0.1% NaCl (low salt diet; 12 OZRs and 10 LZRs) for 14–28 days. After consumption of a low salt diet, baseline mean arterial pressure (MAP) was reduced in urethane‐anesthetized OZRs (125.7±4.4 vs 111.8±4.1 mmHg, P &lt;0.05) but not in LZRs (116.3±4.6 vs. 113.1±5.6 mmHg). Stimulation of sciatic nerve (1 msec pulses for 5 sec at 20 Hz, 100–800 μA) evoked intensity‐dependent increases in MAP and splanchnic sympathetic nerve activity (SNA) in OZRs and LZRs on both diets. Consumption of a low salt diet reduced the sciatic stimulation‐induced rises in SNA in OZRs (800 μA increased SNA 96±7.6% with control diet and 75.3±4.7% with low salt diet, P &lt;0.05) with no effect of diet in LZRs (800 μA increased SNA 87.4±4.4% with control diet and 83.0±8.8% in with low salt diet, n.s.). In contrast, low salt diet reduced the sciatic stimulation‐induced rises in MAP in OZRs and LZRs. These data suggest that consuming a diet containing 0.5–1.0% NaCl contributes to elevated baseline MAP in OZRs and exaggerated sympatho‐excitatory reflexes compared to male LZRs. However, both OZRs and LZRs show reduced sympathetically‐mediated rises in MAP on low salt diet. This study suggests that in male OZRs consumption of a standard rodent diet with 0.5–1.0% NaCl promotes some physiological effects observed in salt‐sensitive strains of rats on a high salt diet.Support or Funding InformationMechanisms for Impaired Short‐Term Control of Blood Pressure with Obesity (R01HL132568, Dr. Ann M. Schreihofer)

Primary Aldosteronism and Pregnancy

Objective: Primary aldosteronism (PA) may present at younger age and may thus complicate pregnancy. Our aim was to identify female patients in whom PA was diagnosed after pregnancy complicated with hypertension and to analyze possible hypertension-related complications during pregnancy. Methods: We performed retrospective analysis of female patients with PA diagnosed and treated at our Department who were pregnant before the diagnosis of PA. Results: We found 14 patients with PA (age at diagnosis 32.2 ± 4.2 years, hypertension duration 5.4 ± 3.6 years) suffering from hypertension 3 (IQR 0, 4) years before pregnancy (6 patients had hypertension diagnosed during pregnancy). Three subjects were pregnant twice, and 1 patient had been pregnant three times before the final diagnosis of PA was made. Ten subjects delivered by Caesarean section (in 3 cases due to early-onset preeclampsia and 2 subjects due to significantly increased blood pressure), and 9 cases spontaneously (1 subject complicated twice due to late-onset preeclampsia). Preterm delivery occurred in 5 cases – the earliest one in the sixth month of gestation. Subsequent diagnosis of PA (sometimes with a long delay up to a maximum of 12 years) was made on the basis of significantly low potassium values (2.7 ± 0.4 mmol/L; 2 subjects even suffered from muscle cramps) and hypertension (mostly moderate), elevated plasma/serum aldosterone (54.1 ± 20.2 ng/dL) and suppressed plasma renin activity (0.4 ± 0.2 ng/mL/h) or plasma renin (1.9 ± 1.6 ng/L). Thirteen subjects underwent laparoscopic adrenalectomy (in all but 2 cases, diagnosis of a large cortical adenoma [16 ± 5.9 mm] was made), and 1 subject was classified with bilateral hyperplasia according to adrenal venous sampling. Operation normalized BP in 10 subjects and improved BP control in the remaining 3 subjects. Two patients became pregnant after adrenalectomy, and their pregnancies were uneventful. Conclusion: PA is associated with a high rate of pregnancy-related complications. The most frequent complication is preeclampsia, in some cases leading to preterm delivery. The optimal prevention of these complications is early diagnosis of PA, and in these particular hypertensive cases, the awareness of hypokalemia.