Objective This study examined differences in aldosterone responsiveness to adrenocorticotropic hormone (ACTH) between the unilateral aldosterone-producing adenoma (APA) and bilateral idiopathic hyperaldosteronism (IHA) subtypes of primary aldosteronism (PA) and the impacts on vascular function and treatment outcomes.Methods This retrospective study enrolled 97 patients with PA (63 with APA and 34 with IHA) who underwent adrenal venous sampling (AVS) with ACTH stimulation. During AVS, baseline and ACTH-stimulated plasma aldosterone concentration (PAC) and cortisol levels were also assessed. Vascular function was assessed by measuring flow-mediated dilation (FMD). APA tissues were analyzed for KCNJ5 mutations.Results Among 97 patients with PA, those with APA showed higher baseline and ACTH-stimulated plasma aldosterone concentration levels, which correlated inversely with FMD. In patients with IHA, the logarithmic difference between PAC measurements before and after ACTH stimulation correlated positively with the blood pressure-normalization effect after mineralocorticoid receptor antagonist (MRA) therapy, with a cutoff value of 2.140 for predicting treatment response.Conclusion These findings suggest that ACTH-stimulated aldosterone may offer a useful marker for personalized management of PA, particularly in assessing vascular health and guiding MRA treatment.

Elevated blood pressure is frequently observed during cancer treatment with vascular endothelial growth factor inhibitors, reflecting either a treatment-emergent adverse event or pharmacological effect. Appropriate blood pressure management is critical in minimizing cardiovascular risk and prevent treatment interruption. Although home blood pressure monitoring is recommended to detect masked or white-coat hypertension, longitudinal data on home blood pressure trajectories during therapy remain limited. This multicenter observational pilot study aims to evaluate the association between clinic and home blood pressure in patients with malignant tumors receiving vascular endothelial growth factor inhibitors, and to assess factors associated with blood pressure variability and the feasibility of home monitoring during therapy. Approximately 50 participants are being enrolled. Home blood pressure is measured twice daily throughout the treatment period, and clinical, laboratory, and treatment-related data and patient-reported data are collected at baseline, during therapy, and at follow-up. The primary outcome is the difference between clinic and home blood pressures at multiple time points during and after vascular endothelial growth factor inhibitor therapy. Blood pressure phenotypes will be classified according to clinic and home blood pressure thresholds, and their clinical characteristics will be compared. Longitudinal trajectory of home blood pressure will be assessed to explore patterns associated with clinical outcomes. This study will clarify the relationship between clinic and home blood pressure, explore factors influencing blood pressure variability, and provide preliminary evidence on the feasibility and clinical value of home blood pressure monitoring in patients receiving angiogenesis inhibitor therapy.

Fat accumulation leads to obesity, which increases the risk of cardiovascular diseases. Recent studies have shown that adipose (pro)renin receptor ([P]RR) may play a role in fat accumulation, and we previously reported increased adipose (P)RR expression in growth hormone (GH) deficiency in mice; however, the association between human adipose (P)RR expression and GH deficiency remains unclear. In this prospective study, abdominal subcutaneous adipose tissue was collected during pituitary surgery in patients with non-functioning hypothalamic-pituitary masses, and the associations between adipose (P)RR mRNA expression, determined using reverse transcription-polymerase chain reaction, and GH deficiency and other clinical parameters were investigated. Fifteen patients (5 craniopharyngioma, 4 non-functioning pituitary neuroendocrine tumor, 4 Rathke’s cleft cyst, and 2 other diseases) (mean age, 53 ± 17 years; male sex, 3 [20

OBJECTIVE:The aldosterone-suppressing effect of natriuretic peptides (NPs) has been demonstrated in experiments using adrenocortical cells from various animal species. 3',5'-cyclic guanosine monophosphate (cGMP), which is produced by atrial natriuretic peptide (ANP), is recognized as a suppressor of aldosterone production. However, it has also been reported that cGMP does not exhibit the same aldosterone-suppressing effect as ANP. Therefore, we examined the effect of ANP on aldosterone suppression using various inhibitors and agonists, including a cGMP agonist. DESIGN:We investigated the expression of ANP receptors in human adrenocortical cells. Next, we examined aldosterone synthesis gene expressions and the effects of various inhibitors, agonists, and siRNAs for the two ANP receptors on the aldosterone-suppressing action of ANP using human adrenocortical H295R cells, precultured with Ang-II. We also investigated inhibitory G (Gi) protein signaling as a cGMP-independent factor. RESULTS:The human adrenocortical cell line H295R was shown to express the guanylyl cyclase A receptor (NPR1). Treatment with a neprilysin inhibitor ameliorated ANP-induced suppression of aldosterone production. Aldosterone production elevated by cyclic adenosine monophosphate (cAMP) agonist was significantly reduced by inhibitors of cAMP signaling. Conversely, cGMP alone had no significant aldosterone-suppressing effect. By suppressing the expression of receptors NPR1 and guanylyl cyclase C receptor (NPR3), aldosterone production increased in the presence of ANP. The suppression of aldosterone production by ANP was abolished by blocking Gi signaling by pertussis toxin (PTX). CONCLUSION:These results suggest that ANP suppresses aldosterone production in H295R cells through NPR1 and NPR3, and this suppression is partially mediated by a cGMP-independent Gi signaling.

Background/Objective:Parathyroidectomy increases bone mineral density (BMD) by 3% to 4% in patients with primary hyperparathyroidism (PHPT); however, limited studies have demonstrated the effect of postoperative medical therapy, particularly with bisphosphonate and denosumab, on BMD. Herein, we report 2 cases of PHPT in which romosozumab, an antisclerostin antibody, increased BMD after parathyroidectomy. Case Report:Case 1. A 67-year-old woman was diagnosed with PHPT and advanced osteoporosis, with T-scores of -4.0 and -5.4 in the lumbar spine (LS) and distal radius (DR), respectively. After parathyroidectomy and 5-year treatment with eldecalcitol and raloxifene, T-scores were -3.3 and -5.6 in the LS and DR, respectively. Thereafter, 12-month romosozumab therapy with eldecalcitol increased BMD by 25.2% (0.717 to 0.898 g/cm2) and 4.0% (0.351 to 0.365 g/cm2) in the LS and DR, respectively. Case 2. A 64-year-old woman was diagnosed with PHPT and advanced osteoporosis, with T-scores of -4.1 and -4.9 in the LS and DR, respectively. Four months after parathyroidectomy, 12-month therapy with romosozumab and eldecalcitol increased BMD by 30.1% (0.602 to 0.783 g/cm2) and 4.3% (0.532 to 0.555 g/cm2) in the LS and total hip, respectively. Discussion:We present the first reported cases of PHPT-complicated osteoporosis in which BMD improved after romosozumab treatment markedly in the LS by 25% to 30%. These cases suggest that postoperative romosozumab therapy may be a potential therapeutic option in patients with PHPT and osteoporosis. Conclusion:Romosozumab may be a promising postoperative therapy for patients with PHPT and osteoporosis.

Abstract Background The (pro)renin receptor [(P)RR] is a multifunctional protein, and its soluble form [s(P)RR], generated by proteolytic cleavage, has been proposed as a biomarker reflecting tissue renin–angiotensin system activity. Patients on maintenance hemodialysis (HD) have a high burden of cardiovascular disease driven by accelerated atherosclerosis. Serum s(P)RR levels are associated with atherosclerosis progression independently of conventional risk factors, suggesting its potential as a novel cardiovascular biomarker in this population. Herein, we investigated the association between s(P)RR and lower limb amputation in patients undergoing HD. Methods Serum s(P)RR levels were measured before and after amputation in 11 patients. (P)RR immunostaining was performed on amputated tissues to assess the local expression. Furthermore, serum s(P)RR levels were compared between 27 patients on HD who underwent lower limb amputation (amputation group) and 250 patients on HD without a history of amputation (control group). Results Although elevated s(P)RR levels were observed in patients on HD who underwent lower limb amputation, no evident (P)RR expression was detected in the amputated tissues, and serum s(P)RR levels showed no significant changes before and after amputation. Moreover, the association between serum s(P)RR levels and limb amputation remained significant after adjusting for atherosclerotic progression factors other than C-reactive protein (CRP) but disappeared when adjusted for CRP. Conclusions These findings suggest that chronic inflammation plays a role in the relationship between lower limb amputation and elevated serum s(P)RR levels.

Purpose: Lithium (Li), which is extensively used in the treatment of mood disorders such as bipolar disorder, has been associated with hyperparathyroidism. However, the relationship between the serum Li concentration and hyperparathyroidism remains unclear. This study aimed (1) to investigate the incidence of hyperparathyroidism and hypercalcemia in consecutive patients treated with Li, (2) to assess the correlation between serum Li concentration and hyperparathyroidism/hypercalcemia, and (3) to establish cutoff values for predicting hyperparathyroidism and hypercalcemia based on serum Li concentration. Methods: This retrospective cross-sectional study was conducted at the Department of Psychiatry and Department of Medicine at Tokyo Women's Medical University. Ninety-seven consecutive individuals without renal impairment and with an estimated glomerular filtration rate (eGFR) equal to or greater than 45 mL/min/1.73 m2 were included. Results: Hyperparathyroidism and hypercalcemia were observed in 35.1% and 9.3% of the patients on Li, respectively. The serum Li concentration showed a significant positive correlation with hyperparathyroidism and hypercalcemia, independent of other factors. The cutoff values for predicting hyperparathyroidism and hypercalcemia were 0.52 and 0.62 mEq/L, respectively. Conclusions: This study confirmed that the high incidence of hyperparathyroidism and hypercalcemia in patients treated with Li. Clinicians should be aware that Li treatment may induce hyperparathyroidism, and a serum Li concentration exceeding 0.52 mEq/L may pose an increased risk. Monitoring serum calcium and Li concentrations is recommended in patients undergoing Li treatment.

PurposePrimary aldosteronism (PA) can be classified into aldosterone-producing adenoma (APA) and idiopathic hyperaldosteronism (IHA) and is related to chronic inflammatory diseases. We compared lymphocyte-based inflammatory indices among patients with APA, IHA and essential hypertension (EH), and investigated the relationships between these indices and background factors in patients with PA.MethodsA total of 186 patients (39 with APA, 48 with IHA, and 99 with blood-pressure-matched EH) were retrospectively included. Neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and monocyte-to-lymphocyte ratio (MLR) were calculated as lymphocyte-based inflammatory indices.ResultsLymphocyte count was lower in the APA group than in the IHA and EH groups. NLR and PLR were significantly higher in the APA group than in the IHA and EH groups. In the APA group, NLR correlated positively with plasma aldosterone concentration after the saline infusion test, while in the IHA group, NLR correlated positively with body mass index and negatively with flow-mediated dilation. Lymphocyte-based inflammatory indices did not differ significantly between KCNJ5-mutant and wild-type groups. NLR, MLR, and PLR remained unchanged from baseline to 1 week after adrenalectomy (ADX), but a cut-off baseline MLR of 0.18 was predictive of complete clinical success after ADX (sensitivity, 0.8095; specificity, 0.7222; area under the curve, 0.719).ConclusionLymphocyte-based inflammatory indices showed distinct patterns in patients with APA and IHA. This study provides a better understanding of the implications of complete blood cell counts in patients with PA.

Growth hormone (GH) deficiency (GHD) elevates high-sensitivity C-reactive protein (hs-CRP) levels, an inflammatory marker. While daily GH replacement has been shown to reduce hs-CRP levels, the effects of long-acting GH therapyon hs-CRP remain unclear. This pilot study aimed to investigate the association between a once-weekly GH derivative, somapacitan, and hs-CRP in adult patients with GHD. This study prospectively evaluated serum hs-CRP levels and metabolic parameters in adult patients with untreated GHD during a 6-month course of weekly somapacitan therapy. Among 13 adult patients with GHD (9 men; 10 with adult-onset GHD), serum hs-CRP levels significantly decreased following somapacitan therapy (0.24 [0.07–0.51] to 0.07 [0.06–0.25] mg/dL, P <.001), whereas serum insulin-like growth factor (IGF)-1 levels (80 ± 53 to 148 ± 74 ng/mL, P <.001) and IGF-1 SD scores (− 2.8 ± 2.3 to − 0.4 ± 1.7, P <.001) significantly increased. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels showed slight but statistically insignificant decreases after the treatment. Changes in hs-CRP levels correlated significantly with changes in IGF-1 SD scores (r = −.66, P =.01), AST (r =.67, P =.01), and ALT (r =.74, P =.004). In partial correlation analyses, changes in hs-CRP levels remained significantly associated with ALT changes (r =.59, P =.04), independent of IGF-1 SD score changes. The reduction in hs-CRP levels after somapacitan therapy for GHD suggests that somapacitan has a protective role against inflammation, possibly mediated by the liver.

Abstract Introduction Fabry disease is an important infiltrative secondary cardiomyopathy caused by a decrease or deficiency in the lysosomal enzyme alpha-galactosidase A activity. The resultant accumulation of glycosphingolipids causes left ventricular hypertrophy (LVH), myocardial fibrosis, and arrhythmias. Recent advances in speckle tracking echocardiography have enabled the detection of early contractile dysfunction in various heart diseases. Purpose We examined whether or not longitudinal strain (LS) evaluated using speckle tracking echocardiography could detect early contractile dysfunction in Japanese patients with Fabry disease. Methods We recruited 56 patients with Fabry disease (22 men and 34 women) who were followed up at our University Hospital and 28 control subjects who showed normal standard echocardiographic findings in the present study. The diagnosis of Fabry disease was based on a mutation analysis of the GLA gene. Comprehensive echocardiography was performed using an ultrasound scanner. Cardiac mechanics were analyzed using the two-dimensional speckle tracking technique via automated function imaging and a Q-analysis software program according to consensus statements on cardiac mechanics quantitation. Using 3 apical views, the LS values of the 17 segments of the left ventricle were calculated for each patient. The global longitudinal strain (GLS) of each patient was also calculated. Results We divided the Fabry disease patients into two groups: patients without LVH (Fabry LVH [-]) and patients with LVH (Fabry LVH [+]). Figure 1 shows the results of the averaged LS values among the control, Fabry LVH (-), and Fabry LVH (+) groups. An analysis of variance detected significant differences in GLS and LS in the anterolateral region of the left ventricle (anterolateral LS) among the 3 groups. A post-hoc analysis revealed a significant decrease in GLS and anterolateral LS in Fabry LVH (-) compared to the control (Figure 2A-B). A receiver operating characteristic (ROC) analysis revealed that both GLS and anterolateral LS could discriminate Fabry LVH (-) from controls (Figure 2C). Using GLS, a cutoff value of -20.0 discriminated Fabry LVH (-) from controls with a sensitivity of 66.7% and specificity of 67.9%. Using anterolateral LS, a cutoff value of -18.8 discriminated Fabry LVH (-) from controls with a sensitivity of 69.7% and specificity of 60.7%. Conclusions These results suggest that early contractile dysfunction can be detected using GLS and anterolateral LS in Japanese patients with Fabry disease, even without LVH. The early detection of contractile dysfunction may be used to identify candidate patients for enzyme replacement therapy or pharmacological chaperone therapy.

Background and objectiveThe coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in significant global morbidity and mortality. This study aimed to investigate the clinical significance of serum vascular endothelial growth factor A (VEGF-A) in COVID-19 patients and its association with disease severity and pulmonary injury.MethodsWe prospectively collected data from 71 hospitalized COVID-19 patients between June 2020 and January 2021. Patients were classified as either mild or severe based on their oxygen requirements during hospitalization. Serum VEGF-A levels were measured using an ELISA kit.ResultsIn comparison to mild cases, significantly elevated serum VEGF-A levels were observed in severe COVID-19 patients. Furthermore, VEGF-A levels exhibited a positive correlation with white blood cell count, neutrophil count, and lymphocyte count. Notably, serum surfactant protein-D (SP-D), an indicator of alveolar epithelial cell damage, was significantly higher in patients with elevated VEGF-A levels.ConclusionThese results suggest that elevated serum VEGF-A levels could serve as a prognostic biomarker for COVID-19 as it is indicative of alveolar epithelial cell injury caused by SARS-CoV-2 infection. Additionally, we observed a correlation between VEGF-A and neutrophil activation, which plays a role in the immune response during endothelial cell injury, indicating a potential involvement of angiogenesis in disease progression. Further research is needed to elucidate the underlying mechanisms of VEGF-A elevation in COVID-19.

The Geriatric Nutritional Risk Index (GNRI) is a straightforward nutritional risk assessment tool with an established relationship with poor prognosis in patients with heart failure. However, the utility of the GNRI in patients with acute myocardial infarction (AMI) remains unclear given the time-dependent changes in the pathophysiology of AMI and the selected endpoints. Accordingly, we aimed to evaluate the optimal cut-off values of the GNRI for cardiovascular events in patients with AMI. We used time-dependent receiver operating characteristic analysis to identify the optimal cut-off values for two endpoints, all-cause death and major adverse cardiac events (MACE: all-cause death, non-fatal myocardial infarction, hospitalization for heart failure, and stroke), over 4 years in 360 patients with AMI between 2012 and 2020. The cumulative incidence of MACE was 11.6%. The cut-off value of the GNRI for all-cause death was 82.7 (area under the curve [AUC], 0.834) at 3 months and 90.3 (AUC 0.854) at 4 years. The cut-off value of the GNRI for MACE was 83.0 (AUC 0.841) at 3 months and 95.3 (AUC 0.821) at 4 years. The GNRI demonstrated consistently high reliability relative to other indicators of AMI. Our findings indicated that the optimal cut-off value and reliability of the GNRI for cardiovascular events varied according to the endpoints and observation periods. GNRI emerges as a crucial predictor of prognosis for patients with AMI.

Purpose. Sarcopenia is an advancing and widespread skeletal muscle condition characterized by the depletion of skeletal muscle mass. The (pro)renin receptor ((P)RR) is a multifaceted protein with both pathophysiological and physiological functions. (P)RR is cleaved to generate soluble (P)RR, whose blood concentration may reflect the expression level of tissue (P)RR. We have discovered that the expression of (P)RR was elevated in the atrophied skeletal muscles of aged mice and humans. Methods. In this study, we examined the correlation between muscle atrophy and serum soluble (P)RR levels in bedridden patients with sarcopenia. Results. In total, 45 subjects were enrolled. Their ages were 81 (59–89) y.o., and serum soluble (P)RR levels were 30.5 ± 7.3 ng/ml. Lean body mass ratio (lean body mass/body weight), an index of muscle mass, was independently significantly and negatively correlated with serum soluble (P)RR concentrations in all patients. In addition, the lean body mass ratio was independently significantly and negatively correlated with serum soluble (P)RR concentrations in older patients (≥82 y.o.) but not in younger patients (<82 y.o.). Conclusion. These data suggested that patients with sarcopenia, especially in elderly patients, may be associated with increased (P)RR expression. The serum soluble (P)RR level could be a biomarker of sarcopenia although this issue should be investigated by future studies.