Toshitaka Sawamura

Impact of New Quick Gold Nanoparticle-Based Cortisol Assay During Adrenal Vein Sampling for Primary Aldosteronism

CONTEXT Adrenal vein sampling (AVS) is essential for identifying a surgically curable form of primary aldosteronism (PA), but accurate placement of the sampling catheter is technically challenging. Intraprocedural cortisol measurement can confirm the catheters position, thereby increasing the AVS success rate. OBJECTIVE AND METHODS We developed a quick cortisol assay (QCA) that uses immunochromatography and gold nanoparticles and can be performed either semiquantitatively or quantitatively. The assay was evaluated in two studies. In a single-center study, PA patients were assigned to undergo AVS incorporating the semiquantitative QCA (n = 30), the quantitative QCA (n = 30), or without the QCA (n = 30), and the rates of successful AVS were determined. In a prospective multicenter randomized, controlled study, the success rates of AVS performed with (n = 148) or without (n = 145) the semiquantitative QCA were determined. RESULTS Cortisol concentrations were measured during AVS in 6 minutes or less in the radiology suite, without additional technical assistance, and significantly correlated with a conventional reference assay (R(2) = 0.994; P < .001). In the single-center study, the differences in the AVS success rates associated with semiquantitative and quantitative QCAs were not significant (both 93%); however, the success rates were significantly higher than the rate of successful AVS performed without using the QCA (63%; P < .001). The success rate of AVS performed in the multicenter study was 94% for the semiquantitative QCA, which was significantly higher than the rate for the patients without QCA (60%; P < .001). CONCLUSIONS Our novel QCA was rapidly and easily performed at the point of care and improved the rate of successful AVS.

Comparison of eplerenone and spironolactone for the treatment of primary aldosteronism

The mineralocorticoid receptor (MR) is expressed in the kidneys and in adipose tissue, and primary aldosteronism (PA) is associated with metabolic syndrome. This study assessed the effects of MR blockade by eplerenone (EPL) and spironolactone (SPL) on blood pressure (BP) and metabolic factors in patients with PA. Fifty-four patients with PA were treated with one of two MRAs, EPL (25–100 mg daily, n=27) or SPL (12.5–100 mg daily, n=27) for 12 months. Visceral (VAT) and subcutaneous adipose tissue were quantified using CT and FatScan imaging analysis software. Body mass index, homeostasis model assessment-insulin resistance (HOMA-IR), serum creatinine, potassium and lipids, urinary albumin excretion (UAE) and plasma aldosterone concentration (PAC) and plasma renin activity (PRA) were measured before and after treatment. EPL and SPL decreased BP and increased serum potassium levels to similar degrees. PAC and PRA did not differ between the two groups. Although treatment with the MRAs did not change HOMA-IR or serum lipids, they significantly decreased UAE and VAT (P<0.05). These results suggest that EPL and SPL are effective and safe for the treatment of PA. The long-term metabolic and renal effects of these MRAs should be further investigated.

Multiple noncoding exons 1 of nuclear receptors NR4A family (nerve growth factor-induced clone B, Nur-related factor 1 and neuron-derived orphan receptor 1) and NR5A1 (steroidogenic factor 1) in human cardiovascular and adrenal tissues.

Objective Nuclear receptors are involved in a wide variety of functions, including aldosteronogenesis. Nuclear receptor families NR4A [nerve growth factor-induced clone B (NGFIB), Nur-related factor 1 (NURR1) and neuron-derived orphan receptor 1 (NOR1)] and NR2F [chicken ovalbumin upstream promoter-transcription factor 1 (COUP-TFI), COUP-TFII and NR2F6) activate, whereas NR5A1 [steroidogenic factor 1 (SF1)] represses CYP11B2 (aldosterone synthase) gene transcription. The present study was undertaken to elucidate the mechanism of differential regulation of nuclear receptors between cardiovascular and adrenal tissues. Methods We collected tissues of artery (n = 9), cardiomyopathy muscle (n = 9), heart muscle (noncardiomyopathy) (n = 6), adrenal gland (n = 9) and aldosterone-producing adenoma (APA) (n = 9). 5′-rapid amplification of cDNA ends (RACE) identified transcription start sites. Multiplex reverse-transcription PCR (RT-PCR) determined use of alternative noncoding exons 1 (ANEs). Results In adrenocortical H295R cells, angiotensin II, KCl or cAMP, all stimulated CYP11B2 transcription and NR4A was upregulated, whereas NR2F and NR5A1 were downregulated. 5′-RACE and RT-PCR revealed four ANEs of NGFIB (NR4A1), three of NURR1 (NR4A2), two of NOR1 (NR4A3) and two of SF1 (NR5A1) in cardiovascular and adrenal tissues. Quantitative multiplex RT-PCR showed NR4A and NR5A1 differentially employed multiple ANEs in a tissue-specific manner. The use of ANEs of NGFIB and NURR1 was significantly different between APA and artery. Changes in use of ANEs of NGFIB and NOR1 were observed between cardiomyopathy and noncardiomyopathy. The NR4A mRNA levels in artery were high compared with cardiac and adrenal tissues, whereas the NR5A1 mRNA level in adrenal tissues was extremely high compared with cardiovascular tissues. Conclusion NR4A and NR5A1 genes are complex in terms of alternative promoter use. The use of ANEs may be associated with the pathophysiology of the heart and adrenal gland.

Prevalence of primary aldosteronism without hypertension in the general population: Results in Shika study

ABSTRACT Objective: Recent studies have reported a high prevalence of primary aldosteronism (PA) among hypertensive patients. However, few data exist regarding the prevalence of PA in the general population. Therefore, we examined the prevalence of PA in the general population including normotensive subjects. Methods: Plasma renin activity (ng/mL/hr), plasma aldosterone concentration (pg/mL) and aldosterone renin ratio (ARR) were determined in 309 subjects aged >40 years in Horimatsu and Higashi-Matsuho district, Shika-machi, Ishikawa, Japan. Results: Among them, 195 subjects (78 males, mean age: 62 ± 11 years) did not take antihypertensive agents: 113 normotensive subjects and 82 hypertensive subjects. Under these conditions, 68 subjects (13 males, age 62 ± 10 years) had an ARR >200. In 14 subjects who underwent captopril suppression test, PA was documented in 5 subjects, yielding a minimum prevalence of 2.6% in total subjects (1.8% in normotensive subjects and 3.7% in hypertensive subjects). Interestingly, females subjects demonstrated significant differences in ARR between subjects with age <50 (172 ± 105) and those with age 51–60 (388 ± 531), although there were no differences in male subjects. Conclusions: These results demonstrate that PA including normotensive subjects exists more commonly than that expected in the general population. We suggest further investigation about the cause and progression of PA associated with sex and aging.

Angiotensin II receptor blocker combined with eplerenone or hydrochlorothiazide for hypertensive patients with diabetes mellitus.

ABSTRACT Experimental models recently suggested an interaction between aldosterone and adipose tissue, but clinical investigation has been limited. We studied the effects of eplerenone compared to hydrochlorothiazide (HCTZ) on blood pressure (BP), glucose, and lipid levels in 50 patients with essential hypertension (EHT) and type 2 diabetes mellitus whose BP failed to reach target levels with 8 mg of candesartan alone. BP improved similarly in both groups over the 12-month study period, but BMI, waist circumference, and LDL-cholesterol were decreased in the eplerenone group, while glycohemoglobin was elevated in the HCTZ group.

Effect of sodium glucose cotransporter 2 inhibitors on obstructive sleep apnea in patients with type 2 diabetes

Obstructive sleep apnea syndrome (OSAS) is often associated with metabolic disorders such as obesity and type 2 diabetes and may contribute to cardiovascular events. A novel class of antidiabetic drugs, the sodium glucose cotransporter 2 inhibitors (SGLT2i) reduce body weight (BW), although there is limited data on their impact on OSAS. We therefore evaluated the effect of SGLT2i on OSAS in patients with type 2 diabetes. The presented study was a retrospective design in 18 patients with type 2 diabetes with OSAS (4 males, age range 39-81 yr) administrated a SGLT2i. HbA1c, BW, body mass index (BMI), blood pressure (BP) and apnea hypopnea index (AHI) were evaluated before and after SGLT2i administration. The relationships between the reduction in AHI and the other variables were examined using Pearson correlation analysis. We have got result that SGLT2i reduced AHI from 31.9 ± 18.0 to 18.8 ± 11.5 events per hr (p = 0.003). HbA1c, BW and BMI decreased significantly, whereas BP did not. The Pearson correlation analysis showed a significant relationship between the reduction in AHI and pre-administration of AHI. In conclusion, SGLT2i reduced not only HbA1c, BW and BMI but also AHI significantly and therefore has potential as an effective treatment of OSAS.

The Long-term Effect of Adrenal Arterial Embolization for Unilateral Primary Aldosteronism on Cardiorenovascular Protection, Blood Pressure, and the Endocrinological Profile.

Primary aldosteronism (PA) is a major cause of secondary hypertension, divided into two subtypes: unilateral and bilateral. Unilateral PA (u-PA) is surgically-curable. Medical treatment with mineralocorticoid receptors antagonists is recommended as a second-line treatment when the patients are not candidate for surgical treatment. The present case was a 39-year-old woman with u-PA, who had refused surgery, had suffered from adverse effects of medical treatment. She was treated with transcatheter adrenal arterial embolization (TAAE). Her blood pressure had been well controlled without progression of cardiorenovascular damage for 12 years. TAAE can be the third treatment option for u-PA patients.

Effects of Aldosterone Blockade on Metabolic and Renal Factors in Patients with Primary Aldosteronism

Objective: The mineralocorticoid Receptor (MR) is expressed not only in the kidneys but also in adipose tissue, and primary aldosteronism (PA) is associated with metabolic syndrome. This study assessed the effects of aldosterone blockade on metabolic factors in patients with PA. Method: Sixty-five patients with PA were treated with one of two MR antagonists; eplerenone (50-100 mg, daily, n=38) or spironolactone (25-50 mg, daily, n=27) for 14 months. Visceral (VAT) and subcutaneous adipose tissue (SAT) were quantified using CT and “Fat Scan” imaging analysis software. Body mass index (BMI), homeostasis model assessment-insulin resistance (HOMA-IR), serum creatinine, potassium and lipids, urinary albumin excretion and plasma aldosterone (PAC) and PRA were measured before and after treatment. Results: Eplerenone and spironolactone decreased blood pressure and increased serum potassium levels similarly. PAC and PRA did not differ among the two groups. Although treatment with the MR antagonists did not change HOMAIR or serum lipids, they significantly decreased urinary albumin excretion and V A T (p<0.05). Conclusion: These results suggest that both eplerenone and spironolactone are effective and safe for treatment of PA. The long-term metabolic effects of these MR antagonists should be further investigated. Sixty-five patients with primary aldosteronism (PA) were treated with eplerenone or spironolactone for 14 months. Visceral (VAT) and subcutaneous adipose tissue (SAT), Body Mass Index (BMI), homeostasis model assessment-insulin resistance (HOMA-IR), serum creatinine, potassium and lipids, and urinary albumin excretion were measured before and after treatment. Eplerenone and spironolactone decreased blood pressure and increased serum potassium levels similarly. Although treatment with the MR antagonists did not change HOMA-IR, they significantly decreased urinary albumin excretion and VAT (p<0.05). These results suggest that both eplerenone and spironolactone are effective for blood pressure and improvement of metabolic factors.

652 LONG-TERM TREATEMENT WITH ALDOSTERONE BLOCKER CAN CAUSE SPONTANEOUSLY REMISSION IN PATIENTS WITH PRIMARY ALDOSTERONISM

Purpose: Primary aldosteronism (PA) is mainly caused by aldosterone producing adenoma and idiopathic bilateral adrenal hyperplasia (IHA). Laparoscopicadrenalectomy is recommended for the treatment of APA. Medical treatment with a mineralocorticoid receptor (MR) antagonist such as spironolactone (SP) or eplerenone(EP) is recommended for patients with IHA. Fishcher et al reported that the prevalence of spontaneous remission of IHA during long-term treatment with SP was 5.4% (Clin Endocrinol 2011). We aimed to determine the prevalence of spontaneous remission of PA during long-term treatment with MR antagonists (SP or EP) in Japan. Methods: 56 patients with PA (APA, 9 cases; IHA, 26 cases; others, 21 cases) treated with MR antagonists during more than 3 years were investigated. 36 patients were treated with SP. 20 patients were treated with EP. The patients were identified retrospectively by chart review and prospectively assessed by clinical and biochemical means. We defined complete remission (CR) of PA as normal aldosterone to renin ratio (ARR), normal suppression test, normalization of hypokalemia without hypertension. Partial remission (PR) was defined as normalization of ARR, normal suppression test, normalization of hypokalemia with hypertension. Results: The mean period of MR antagonist treatment was 4.1 years in the patients. We identified 2 (APA, 1 and IHA, 1) of 56 (3.6%) patients with CR. We also identified 8 (4 patients treated with EP; 4 patients treated with SP) (14.3%) of 56 patients with PR. Conclusions: Partial remission of PA after long-term mineralocorticoid antagonist treatment in Japan is more frequent than previously reported.

628 EFFECTS OF ALDOSTERONE BLOCKADE ON BODY WEIGHT AND ADIPOSE TISSUE 11BETA-HYDROXYSTEROID DEHYDROGENASE 1 IN STROKE-PRONE SPONTANEUOSLY HYPERTENSIVE RATS

Purpose: High salt intake induces body weight loss in stroke-prone spontaneously hypertensive rats (SHRSP). We examined the effects of eplerenone on body weight and adipose tissue 11&bgr;-hydroxysteroid dehydrogenase 1 (11&bgr;-HSD1) and glucocorticoid receptor (GR) gene expression in SHRSP. Methods: Male Wistar-Kyoto (WKY) rats and SHRSP were fed a high sodium diet or normal sodium diet for 8 weeks, beginning at 5 weeks. Blood pressure, plasma renin activity (PRA), plasma aldosterone concentration (PAC), plasma corticosterone concentration (p-B) and plasma leptin levels were measured. The expression of messenger RNA (mRNA) of mineralocorticoid receptor (MR), GR, and 11&bgr;-HSD1 in visceral adipose tissues were studied by real time PCR. Results: High sodium intake blunted body weight gain in SHRSP but not WKY rats. Treatment with eplerenone improved body weight in SHRSP. High sodium diet significantly increased plasma leptin levels and decreased 11&bgr;-HSD1 and GR mRNA in adipose tissues of SHRSP (p<0.05). Control rats did not show any changes in these parameters by high salt intake. Treatment with eplerenone significantly decreased plasma leptin levels and increased 11&bgr;-HSD1 and GR mRNA in adipose tissues of SHRSP (p<0.05). Conclusions: Eplerenone may influence leptin signals and adipose tissue glucocorticoid activity and improve body weight loss induced by high salt diet in SHRSP.