bims-adreca 2024-04-21 papers

bims-adreca

Biomed News

on Adrenal calcium

Issue of 2024–04–21
thirteen papers selected by
Bakhta Fedlaoui, INSERM

Effects of different treatment modalities on cardiovascular disease in ARR-positive hypertensive patients.
Hemodynamic Mechanisms Initiating Salt-Sensitive Hypertension in Rat Model of Primary Aldosteronism.
Safety and efficacy of once-daily dexfadrostat phosphate in patients with primary aldosteronism: a randomised, parallel group, multicentre, phase 2 trial.
Systematic Review Article: New Drug Strategies for Treating Resistant Hypertension-the Importance of a Mechanistic, Personalized Approach.
Commensal Microbiota Regulate Aldosterone.
Investigation and assessment of adrenal incidentalomas.
Risk factors for postoperative fever after laparoscopic adrenalectomy focusing on hormones produced: a case control study.
Advancements in Diabetic Kidney Disease Management: Integrating Innovative Therapies and Targeted Drug Development.
Dissociation of Hypertension and Renal Damage After Cessation of High-Salt Diet in Dahl Rats.
Pharmacogenomics of Hypertension in Africa: Paving the Way for a Pharmacogenetic-Based Approach for the Treatment of Hypertension in Africans.
Adrenalectomy Outcome Variations Across Different Functional Adrenal Tumors.
Mitochondrial CypD Acetylation Promotes Endothelial Dysfunction and Hypertension.
Ultrasonographic measurements of the normal adrenal glands in guinea pigs (Cavia Porcellus).

Hypertens Res. 2024 Apr 17.

Effects of different treatment modalities on cardiovascular disease in ARR-positive hypertensive patients.

Rui Chen, Hairong Hao, Yuhong Dai, Liang Cheng, Feng Bai, Xiaoqing Wang, Wen Hu.

  Data on the prognosis of clinically undiagnosed hypertensive patients who are aldosterone-to-renin ratio (ARR) positive are still scarce. Therefore, we investigated the clinical characteristics of clinically undiagnosed hypertensive patients who were ARR-positive and the influence of their different treatments on the occurrence and development of complications. A total of 285 hypertensive patients data with ARR ≥ 3.8 in the Second People's Hospital of Huai'an from January 2019 to December 2021 were collected, and 135 undiagnosed hypertensive patients were ultimately included in the analysis. According to their treatment strategy in various clinical departments, 135 patients were divided into the operation, spironolactone and control groups. Then, the clinical characteristics and the occurrence and development of complications in the three groups were compared. The results suggested that: (1) Only 34 (11.9%) of 285 hypertensive patients with ARR ≥ 3.8 were clearly diagnosed with Primary aldosteronism (PA) through functional tests, and the blood pressure (BP) compliance rate was only 50.30% during follow-up. (2) Based on exclusion criteria, 135 undiagnosed hypertensive patients were eventually included in the analysis. Patients in the surgery group had lower blood potassium levels and higher aldosterone levels than those in the other two groups, and their risk of new cerebrovascular complications was lower than that of the patients in the spironolactone group. (3) The risk of new cerebrovascular complications in the spironolactone group was 9.520 times higher than that of the control group, and this risk mainly occurred in patients with ARR values of 3.8-5.7. On the whole, surgery remains a good option for hypertensive patients with severe hyperaldosteronism and hypokalemia and those unable to undergo confirmatory tests; however, spironolactone therapy in patients with clinically undiagnosed hypertension, especially those with 3.8 ≤ ARR < 5.7, confered a higher risk of new cerebrovascular complications.

Keywords:  Aldosterone/renin ratio; Cardiovascular and cerebrovascular complications; Primary aldosteronism

DOI:  https://doi.org/10.1038/s41440-024-01676-w
Physiol Res. 2024 Apr 18.

Hemodynamic Mechanisms Initiating Salt-Sensitive Hypertension in Rat Model of Primary Aldosteronism.

M Pravenec, P Mlejnek, M Šimáková, J Šilhavý.

Few studies have investigated the hemodynamic mechanism whereby primary hyperaldosteronism causes hypertension. The traditional view holds that hyperaldosteronism initiates hypertension by amplifying salt-dependent increases in cardiac output (CO) by promoting increases in sodium retention and blood volume. Systemic vascular resistance (SVR) is said to increase only as a secondary consequence of the increased CO and blood pressure. Recently, we investigated the primary hemodynamic mechanism whereby hyperaldosteronism promotes salt sensitivity and initiation of salt-dependent hypertension. In unilaterally nephrectomized male Sprague-Dawley rats given infusions of aldosterone or vehicle, we found that aldosterone promoted salt sensitivity and initiation of salt-dependent hypertension by amplifying salt-induced increases in SVR while decreasing CO. In addition, we validated mathematical models of human integrative physiology, derived from Guyton's classic 1972 model - Quantitative Cardiovascular Physiology-2005 and HumMod-3.0.4. Neither model accurately predicted the usual changes in sodium balance, CO, and SVR that normally occur in response to clinically realistic increases in salt intake. These results demonstrate significant limitations with the hypotheses inherent in the Guyton models. Together these findings challenge the traditional view of the hemodynamic mechanisms that cause salt-sensitive hypertension in primary aldosteronism. Key words: Aldosterone, Blood pressure, Salt, Sodium, Rat.
EClinicalMedicine. 2024 May;71 102576

Safety and efficacy of once-daily dexfadrostat phosphate in patients with primary aldosteronism: a randomised, parallel group, multicentre, phase 2 trial.

Paolo Mulatero, Gregoire Wuerzner, Michael Groessl, Elisa Sconfienza, Aikaterini Damianaki, Vittorio Forestiero, Bruno Vogt, Hans Brunner, Teresa Gerlock, Ronald Steele, Christoph Schumacher.

   Background: Primary aldosteronism (PA) is caused by autonomous aldosterone overproduction and characterised by uncontrolled hypertension. There are currently no treatments that target aldosterone synthesis. We evaluated the safety and efficacy of a novel aldosterone synthase inhibitor, dexfadrostat phosphate, in patients with PA.
Methods: This multi-centre, randomised, phase 2 trial was conducted between November 2019 and May 2022 (NCT04007406; EudraCT code 2019-000919-85). Adults with PA and an office systolic blood pressure of 145-190 mmHg were included. After a 2-week single-blind placebo run-in period, participants were randomised 1:1:1 to receive oral dexfadrostat phosphate 4, 8, or 12 mg once daily for an 8-week double-blind treatment period, followed by a 2-week single-blind placebo withdrawal period. Randomisation was conducted centrally and stratified by centre and sex. At the beginning and end of the treatment period, 24 h ambulatory systolic blood pressure (aSBP) was recorded. Blood samples were taken every 2 weeks. Primary endpoints were the change in aldosterone-to-renin ratio (ARR) and mean 24 h aSBP from baseline to the end of the treatment period in the combined dose group of all participants receiving any dose of dexfadrostat phosphate. Safety endpoints were the occurrence of treatment-emergent adverse events (TEAEs) and serious adverse events over the entire study in all randomised participants who received at least one dose of dexfadrostat phosphate.
Findings: In total, 35 participants received dexfadrostat phosphate and all participants completed the study. Twenty-six participants (74.3%) were male, the mean age was 51.9 years (SD 8.7), and most were White (n = 32, 91.4%). The median ARR and the mean 24 h aSBP significantly decreased from the beginning to the end of the treatment period in the combined dose group (ARR: 15.3 vs 0.6, least-squares mean [LSM] change in log-normal values -2.5, p < 0.0001; aSBP: 142.6 vs 131.9 mmHg, LSM change -10.7 mmHg, p < 0.0001). There were no safety concerns; all TEAEs were mild or moderate and there were no serious TEAEs.
Interpretation: Dexfadrostat phosphate corrected the ARR and aSBP and was well tolerated in patients with PA, demonstrating the benefit of pharmacologically targeting the source of hyperaldosteronism.
Funding: DAMIAN Pharma AG.

Keywords:  Aldosterone; Aldosterone synthase inhibition; Hypertension; Primary aldosteronism; Renin

DOI:  https://doi.org/10.1016/j.eclinm.2024.102576
High Blood Press Cardiovasc Prev. 2024 Apr 14.

Systematic Review Article: New Drug Strategies for Treating Resistant Hypertension-the Importance of a Mechanistic, Personalized Approach.

Giulia Nardoianni, Barbara Pala, Alessandra Scoccia, Massimo Volpe, Emanuele Barbato, Giuliano Tocci.

  Resistant hypertension (RHT) is characterized by persistently high blood pressure (BP) levels above the widely recommended therapeutic targets of less than 140/90 mmHg office BP, despite life-style measures and optimal medical therapies, including at least three antihypertensive drug classes at maximum tolerated dose (one should be a diuretic). This condition is strongly related to hypertension-mediated organ damage and, mostly, high risk of hospitalization due to hypertension emergencies or acute cardiovascular events. Hypertension guidelines proposed a triple combination therapy based on renin angiotensin system blocking agent, a thiazide or thiazide-like diuretic, and a dihydropyridinic calcium-channel blocker, to almost all patients with RHT, who should also receive either a beta-blocker or a mineralocorticoid receptor antagonist, or both, depending on concomitant conditions and contraindications. Several other drugs may be attempted, when elevated BP levels persist in these RHT patients, although their added efficacy in lowering BP levels on top of optimal medical therapy is uncertain. Also, renal denervation has demonstrated to be a valid therapeutic alternative in RHT patients. More recently, novel drug classes and molecules have been tested in phase 2 randomised controlled clinical trials in patients with RHT on top of optimal medical therapy with at least 2-3 antihypertensive drugs. These novel drugs, which are orally administered and are able to antagonize different pathophysiological pathways, are represented by non-steroid mineralocorticorticoid receptor antagonists, selective aldosterone synthase inhibitors, and dual endothelin receptor antagonists, all of which have proven to reduce seated office and 24-h ambulatory systolic/diastolic BP levels. The main findings of randomized clinical trials performed with these drugs as well as their potential indications for the clinical management of RHT patients are summarised in this systematic review article.

Keywords:  Aldosterone synthase inhibitors; Aprocitentan; Baxdrostat; Endothelin receptor antagonists; Finerenone; Lorundrostat; Renin-angiotensin system; Resistant hypertension

DOI:  https://doi.org/10.1007/s40292-024-00634-4
Am J Physiol Renal Physiol. 2024 Apr 18.

Commensal Microbiota Regulate Aldosterone.

Brittni N Moore, Alexandra D Medcalf, Rachel Q Muir, Chudan Xu, Francine Z Marques, Jennifer L Pluznick.

  The gut microbiome regulates many important host physiological processes associated with cardiovascular health and disease; however, the impact of the gut microbiome on aldosterone is unclear. Investigating whether gut microbiota regulate aldosterone can offer novel insights into how the microbiome affects blood pressure. In this study, we aimed to determine whether gut microbiota regulate host aldosterone. We employed enzyme-linked immunosorbent assays (ELISAs) to assess plasma aldosterone and plasma renin activity (PRA) in female and male mice in which gut microbiota are intact, suppressed, or absent. In addition, we examined urinary aldosterone. Our findings demonstrated that when the gut microbiota is suppressed following antibiotic treatment, there is an increase in plasma and urinary aldosterone in both female and male mice. In contrast, an increase in PRA is seen only in males. We also found that when gut microbiota are absent (germ-free mice), plasma aldosterone is significantly increased compared to conventional animals (in both females and males), but PRA is not. Understanding how gut microbiota influence aldosterone levels could provide valuable insights into the development and treatment of hypertension and/or primary aldosteronism. This knowledge may open new avenues for therapeutic interventions, such as probiotics or dietary modifications to help regulate blood pressure via microbiota-based changes to aldosterone.

Keywords:  RAAS; aldosterone; gut microbiome; renal physiology

DOI:  https://doi.org/10.1152/ajprenal.00051.2024
Clin Med (Lond). 2023 Mar;pii: S1470-2118(24)04628-1. [Epub ahead of print]23(2): 135-140

Investigation and assessment of adrenal incidentalomas.

Daniel J Cuthbertson, Uazman Alam, Andrew S Davison, Jane Belfield, Susannah L Shore, Sobhan Vinjamuri.

  With the increasing volume of diagnostic imaging undertaken in an ageing population, adrenal incidentalomas (AIs) are increasingly commonly seen. These masses are most likely to be benign, but a small proportion may be malignant. Similarly, they are usually non-functional, but ∼14% are functional, ie hormone-secreting tumours. Clinical, biochemical and radiological assessment is mandated to stratify patients into those requiring radiological surveillance, medical management or surgical intervention or who can be discharged. Mass characteristics on cross-sectional (CT/MRI) imaging influence the need for radiological surveillance. Functional tumours where excess cortisol, aldosterone or catecholamine are secreted should be excluded, with mild autonomous cortisol secretion (MACS) and primary aldosteronism (PA) as the two most common functional states. MACS and PA are associated with an increased risk of cardiometabolic disease (eg hypertension, type 2 diabetes) and cardiovascular morbidity/mortality (eg coronary heart disease). Multidisciplinary management is critical for selected cases; the majority of adrenal incidentalomas only require a single assessment.

Keywords:  Adrenal incidentaloma; CT/MRI; hormone excess; mild autonomous cortisol secretion; primary aldosteronism

DOI:  https://doi.org/10.7861/clinmed.2023-0042
BMC Urol. 2024 Apr 18. 24(1): 90

Risk factors for postoperative fever after laparoscopic adrenalectomy focusing on hormones produced: a case control study.

Mizuki Izawa, Toshikazu Takeda, Tadatsugu Anno, Tomohiro Iwasawa, Yota Yasumizu, Nobuyuki Tanaka, Kazuhiro Matsumoto, Shinya Morita, Takeo Kosaka, Ryuichi Mizuno, Hiroshi Asanuma, Mototsugu Oya.

   BACKGROUND: Laparoscopic adrenalectomy is widely performed for a number of hormone-producing tumors and postoperative management depends on the hormones produced. In the present study, we conducted a retrospective analysis to clarify the risk factors for postoperative complications, particularly postoperative fever after laparoscopic adrenalectomy.
METHODS: We analyzed 406 patients who underwent laparoscopic adrenalectomy at our hospital between 2003 and 2019. Postoperative fever was defined as a fever of 38 °C or higher within 72 h after surgery. We investigated the risk factors for postoperative fever after laparoscopic adrenalectomy.
RESULTS: There were 188 males (46%) and 218 females (54%) with a median age of 52 years. Among these patients, tumor pathologies included 188 primary aldosteronism (46%), 75 Cushing syndrome (18%), and 80 pheochromocytoma (20%). Postoperative fever developed in 124 of all patients (31%), 30% of those with primary aldosteronism, 53% of those with pheochromocytoma, and 8% of those with Cushing syndrome. A multivariate logistic regression analysis identified pheochromocytoma and non-Cushing syndrome as independent predictors of postoperative fever. Postoperative fever was observed in 42 out of 80 cases of pheochromocytoma (53%), which was significantly higher than in cases of non-pheochromocytoma (82/326, 25%, p < 0.01). In contrast, postoperative fever developed in 6 out of 75 cases of Cushing syndrome (8%), which was significantly lower than in cases of non-Cushing syndrome (118/331, 35.6%, p < 0.01).
CONCLUSION: Since postoperative fever after laparoscopic adrenalectomy is markedly affected by the hormone produced by pheochromocytoma and Cushing syndrome, it is important to carefully consider the need for treatment.

Keywords:  Cushing syndrome; Hormone-producing tumors; Laparoscopic adrenalectomy; Pheochromocytoma; Postoperative complications; Postoperative fever

DOI:  https://doi.org/10.1186/s12894-024-01469-w
Am J Physiol Endocrinol Metab. 2024 Apr 17.

Advancements in Diabetic Kidney Disease Management: Integrating Innovative Therapies and Targeted Drug Development.

Shaarav Ghose, Matthew Satariano, Saichidroopi Korada, Thomas Cahill, Raghav Shah, Rupesh Raina.

  Diabetic kidney disease (DKD) is a leading cause of chronic kidney disease and affects approximately 40% of diabetic individuals. Cases of DKD continue to rise globally as the prevalence of diabetes mellitus increases, with an estimated 415 million people living with diabetes in 2015 and a projected 642 million by 2040. DKD is associated with significant morbidity and mortality, representing 34% and 36% of all chronic kidney disease deaths in men and women, respectively. Common co-morbidities including hypertension and ageing-related nephron loss further complicate disease diagnosis and progression. The progression of DKD involves several mechanisms including glomerular endothelial cell dysfunction, inflammation, and fibrosis. Targeting these mechanisms has formed the basis of several therapeutic agents. Renin-angiotensin-aldosterone system (RAAS) blockers, specifically angiotensin receptor blockers (ARBs), demonstrate significant reductions in macroalbuminuria. SGLT-2 inhibitors demonstrate kidney protection independent of diabetes control while also decreasing the incidence of cardiovascular events. Emerging agents including GLP-1 agonists, anti-inflammatory agents like bardoxolone, and mineralocorticoid receptor antagonists show promise in mitigating DKD progression. Many novel therapies including monoclonal antibodies CSL346, Lixudebart, and tozorakimab, mesenchymal stem/stromal cell infusion, and cannabinoid-1 receptor inverse agonism via INV-202 are currently in clinical trials and present opportunities for further drug development.

Keywords:  RAAS inhibitors; SGLT-2 inhibitors; diabetic kidney disease; epigenetic modifications; tumor necrosis factor receptors

DOI:  https://doi.org/10.1152/ajpendo.00026.2024
Hypertension. 2024 Apr 15.

Dissociation of Hypertension and Renal Damage After Cessation of High-Salt Diet in Dahl Rats.

Sergey N Arkhipov, Tang-Dong S Liao, D'Anna L Potter, Kevin R Bobbitt, Veniamin Ivanov, Pablo A Ortiz, Tengis S Pavlov.

   BACKGROUND: Every year, thousands of patients with hypertension reduce salt consumption in the efforts to control their blood pressure. However, hypertension has a self-sustaining character in a significant part of the population. We hypothesized that chronic hypertension leads to irreversible renal damage that remains after removing the trigger, causing an elevation of the initial blood pressure.
METHODS: Dahl salt-sensitive rat model was used for chronic, continuous observation of blood pressure. Rats were fed a high salt diet to induce hypertension, and then the diet was switched back to normal sodium content.
RESULTS: We found that developed hypertension was irreversible by salt cessation: after a short period of reduction, blood pressure grew even higher than in the high-salt phase. Notably, the self-sustaining phase of hypertension was sensitive to benzamil treatment due to sustaining epithelial sodium channel hyperactivity, as shown with patch-clamp analysis. Glomerular damage and proteinuria were also irreversible. In contrast, some mechanisms, contributing to the development of salt-sensitive hypertension, normalized after salt restriction. Thus, flow cytometry demonstrated that dietary salt reduction in hypertensive animals decreased the number of total CD45+, CD3+CD4+, and CD3+CD8+ cells in renal tissues. Also, we found tubular recovery and improvement of glomerular filtration rate in the postsalt period versus a high-salt diet.
CONCLUSIONS: Based on earlier publications and current data, poor response to salt restriction is due to the differential contribution of the factors recognized in the developmental phase of hypertension. We suggest that proteinuria or electrolyte transport can be prioritized over therapeutic targets of inflammatory response.

Keywords:  blood pressure; diet; hypertension; lymphocytes; proteinuria

DOI:  https://doi.org/10.1161/HYPERTENSIONAHA.123.21887
Int J Hypertens. 2023 ;2023 9919677

Pharmacogenomics of Hypertension in Africa: Paving the Way for a Pharmacogenetic-Based Approach for the Treatment of Hypertension in Africans.

Jonathan N Katsukunya, Nyarai D Soko, Jashira Naidoo, Brian Rayner, Dirk Blom, Phumla Sinxadi, Emile R Chimusa, Michelle Dandara, Kevin Dzobo, Erika Jones, Collet Dandara.

In Africa, the burden of hypertension has been rising at an alarming rate for the last two decades and is a major cause for cardiovascular disease (CVD) mortality and morbidity. Hypertension is characterised by elevated blood pressure (BP) ≥ 140/90 mmHg. Current hypertension guidelines recommend the use of antihypertensives belonging to the following classes: calcium channel blockers (CCB), angiotensin converting inhibitors (ACEI), angiotensin receptor blockers (ARB), diuretics, β-blockers, and mineralocorticoid receptor antagonists (MRAs), to manage hypertension. Still, a considerable number of hypertensives in Africa have their BP uncontrolled due to poor drug response and remain at the risk of CVD events. Genetic factors are a major contributing factor, accounting for 20% to 80% of individual variability in therapy and poor response. Poor response to antihypertensive drug therapy is characterised by elevated BPs and occurrence of adverse drug reactions (ADRs). As a result, there have been numerous studies which have examined the role of genetic variation and its influence on antihypertensive drug response. These studies are predominantly carried out in non-African populations, including Europeans and Asians, with few or no Africans participating. It is important to note that the greatest genetic diversity is observed in African populations as well as the highest prevalence of hypertension. As a result, this warrants a need to focus on how genetic variation affects response to therapeutic interventions used to manage hypertension in African populations. In this paper, we discuss the implications of genetic diversity in CYP11B2, GRK4, NEDD4L, NPPA, SCNN1B, UMOD, CYP411, WNK, CYP3A4/5, ACE, ADBR1/2, GNB3, NOS3, B2, BEST3, SLC25A31, LRRC15 genes, and chromosome 12q loci on hypertension susceptibility and response to antihypertensive therapy. We show that African populations are poorly explored genetically, and for the few characterised genes, they exhibit qualitative and quantitative differences in the profile of pharmacogene variants when compared to other ethnic groups. We conclude by proposing prioritization of pharmacogenetics research in Africa and possible adoption of pharmacogenetic-guided therapies for hypertension in African patients. Finally, we outline the implications, challenges, and opportunities these studies present for populations of non-European descent.

DOI: https://doi.org/10.1155/2023/9919677
J Surg Res. 2024 Apr 15. pii: S0022-4804(24)00142-2. [Epub ahead of print]298 201-208

Adrenalectomy Outcome Variations Across Different Functional Adrenal Tumors.

Terry P Gao, Rebecca L Green, Lindsay E Kuo.

   INTRODUCTION: Adrenalectomy generally has favorable outcomes. It is unknown if patients with functional adrenal tumors experience different clinical outcomes than those with benign adrenal tumors, due to the presence of comorbid conditions secondary to the functional tumor. We investigated outcomes following open and laparoscopic adrenalectomy for benign nonfunctional (BNF) versus functional adrenal masses.
METHODS: Patients undergoing adrenalectomy were identified in the 2015-2020 National Surgical Quality Improvement Program database, then categorized as BNF, hyperaldosteronism, hypercortisolism, and pheochromocytoma. The primary outcome of interest was 30-d morbidity and secondary outcomes included 30-d mortality, 30-d readmission, and postoperative length of stay (LOS). Subgroup analysis was performed based upon surgical approach. Univariate analysis was performed, followed by multivariable logistic regression for individual outcomes that differed significantly between patients with BNF and functional neoplasm, factoring in patient demographics and operative approach with statistical significance on univariate analysis. Descriptive statistics and outcomes were analyzed using Pearson's χ2 test and Mann-Whitney U-test as appropriate.
RESULTS: There were 3291 patients with BNF while 484 had hyperaldosteronism, 263 hypercortisolism, and 46 pheochromocytomas. Within the laparoscopic group of 3615 (88.5%) of adrenalectomy patients, compared to BNF patients, patients with hyperaldosteronism had lower rates of postoperative morbidity (1.9% versus 5.2%, P < 0.001) and shorter LOS (1 d, interquartile range (IQR) [1-1] versus 1d IQR [1-2], P = 0.003); these persisted on multivariate analysis (OR 0.32, 95% confidence interval [CI] 0.14-0.74 and odds ratio 0.47, 95% CI 0.36-0.60, P < 0.001). Patients with hypercortisolism had higher morbidity (7.3% versus 5.2%, P < 0.001), 30-d readmission rates (5.3% versus 2.9%, P = 0.042) and longer LOS (2d, IQR [1-3] versus 1d, IQR [1-2, P < 0.001). On multivariate analysis, presence of hypercortisolism was independently associated with increased likelihood of readmission within 30 d (OR 2.20, 95% CI 1.11-2.99, P = 0.012) and longer LOS (>1 d) (OR 1.79, 95% CI 1.33-2.40, P < 0.001). Compared to BNF patients, patients with pheochromocytoma had higher rates of postoperative morbidity (6.2% versus 5.2%, P < 0.001). Within the open group of 469 (11.5% of adrenalectomy patients), there were no statistically significant differences in outcomes between patients with BNF and functional adrenal masses.
CONCLUSIONS: Outcomes after adrenalectomy performed for functional neoplasms differ based on surgical indication.

Keywords:  Functional tumor outcomes; Hyperaldosteronism; Hypercortisolism; Laparoscopic adrenalectomy; Open adrenalectomy; Pheochromocytoma

DOI:  https://doi.org/10.1016/j.jss.2024.03.031
Circ Res. 2024 Apr 19.

Mitochondrial CypD Acetylation Promotes Endothelial Dysfunction and Hypertension.

Anna Dikalova, Daniel Fehrenbach, Vladimir Mayorov, Alexander Panov, Mingfang Ao, Louise Lantier, Venkataraman Amarnath, Marcos G Lopez, Frederic T Billings Iv, Michael N Sack, Sergey Dikalov.

   BACKGROUND: Nearly half of adults have hypertension, a major risk factor for cardiovascular disease. Mitochondrial hyperacetylation is linked to hypertension, but the role of acetylation of specific proteins is not clear. We hypothesized that acetylation of mitochondrial CypD (cyclophilin D) at K166 contributes to endothelial dysfunction and hypertension.
METHODS: To test this hypothesis, we studied CypD acetylation in patients with essential hypertension, defined a pathogenic role of CypD acetylation in deacetylation mimetic CypD-K166R mutant mice and endothelial-specific GCN5L1 (general control of amino acid synthesis 5 like 1)-deficient mice using an Ang II (angiotensin II) model of hypertension.
RESULTS: Arterioles from hypertensive patients had 280% higher CypD acetylation coupled with reduced Sirt3 (sirtuin 3) and increased GCN5L1 levels. GCN5L1 regulates mitochondrial protein acetylation and promotes CypD acetylation, which is counteracted by mitochondrial deacetylase Sirt3. In human aortic endothelial cells, GCN5L1 depletion prevents superoxide overproduction. Deacetylation mimetic CypD-K166R mice were protected from vascular oxidative stress, endothelial dysfunction, and Ang II-induced hypertension. Ang II-induced hypertension increased mitochondrial GCN5L1 and reduced Sirt3 levels resulting in a 250% increase in GCN5L1/Sirt3 ratio promoting CypD acetylation. Treatment with mitochondria-targeted scavenger of cytotoxic isolevuglandins normalized GCN5L1/Sirt3 ratio, reduced CypD acetylation, and attenuated hypertension. The role of mitochondrial acetyltransferase GCN5L1 in the endothelial function was tested in endothelial-specific GCN5L1 knockout mice. Depletion of endothelial GCN5L1 prevented Ang II-induced mitochondrial oxidative stress, reduced the maladaptive switch of vascular metabolism to glycolysis, prevented inactivation of endothelial nitric oxide, preserved endothelial-dependent relaxation, and attenuated hypertension.
CONCLUSIONS: These data support the pathogenic role of CypD acetylation in endothelial dysfunction and hypertension. We suggest that targeting cytotoxic mitochondrial isolevuglandins and GCN5L1 reduces CypD acetylation, which may be beneficial in cardiovascular disease.

Keywords:  blood pressure; cardiovascular diseases; hypertension; mitochondria; superoxides

DOI:  https://doi.org/10.1161/CIRCRESAHA.123.323596
Vet Radiol Ultrasound. 2024 Apr 13.

Ultrasonographic measurements of the normal adrenal glands in guinea pigs (Cavia Porcellus).

Domenico Sainato, Tina Pelligra, Caterina Puccinelli, Daniele Petrini, Simonetta Citi.

  Hyperadrenocorticism is an uncommon but important endocrine disease in guinea pigs, but due to its subtle clinical signs and the limited information in veterinary literature, it can be underdiagnosed or misdiagnosed. Ultrasound of the adrenal glands in patients with suspected hyperadrenocorticism can help in identifying adrenomegaly. The purpose of this prospective study was to identify ultrasonographic adrenal gland dimensions in presumed healthy guinea pigs using the same standardized method described for dogs and cats. A conscious ultrasound scan was conducted on twenty client-owned, presumed healthy guinea pigs, and their adrenal glands were measured. A possible correlation between adrenal dimensions with age, sex, and body weight was investigated. The mean length, cranial and caudal pole thickness for the left and right adrenal glands were, respectively, 12.64 ± 2.11 mm and 11.55 ± 1.52 mm; 4.83 mm ± 1.03 mm and 4.69 ± 1.34 mm; 4.8 ± 1.23 mm and 4.04 ± 0.75 mm. The thickness of the left caudal pole was significantly higher than the right (P = 0.02). A significant positive correlation was found between the length of the left adrenal gland and both age (r = 0.46; P = .03) and weight (r = 0.59; P = .01). Statistical correlation between the thickness of each cranial and caudal pole, with age, sex, or weight, was not found. The dimensions provided could prove a useful tool in the clinical evaluation of guinea pigs with suspected hyperadrenocorticism.

Keywords:  adrenal glands; anatomical values; guinea pigs; hyperadrenocorticism; ultrasound

DOI:  https://doi.org/10.1111/vru.13367