Abstract
Context
Adrenal venous sampling (AVS) is the key test for subtyping primary aldosteronism (PA), but its interpretation varies widely across referral centers and this can adversely affect the ...management of PA patients.
Objectives
To investigate in a real-life study the rate of bilateral success and identification of unilateral aldosteronism and their impact on blood pressure outcomes in PA subtyped by AVS.
Design and settings
In a retrospective analysis of the largest international registry of individual AVS data (AVIS-2 study), we investigated how different cut-off values of the selectivity index (SI) and lateralization index (LI) affected rate of bilateral success, identification of unilateral aldosteronism, and blood pressure outcomes.
Results
AVIS-2 recruited 1625 individual AVS studies performed between 2000 and 2015 in 19 tertiary referral centers. Under unstimulated conditions, the rate of biochemically confirmed bilateral AVS success progressively decreased with increasing SI cut-offs; furthermore, with currently used LI cut-offs, the rate of identified unilateral PA leading to adrenalectomy was as low as <25%. A within-patient pairwise comparison of 402 AVS performed both under unstimulated and cosyntropin-stimulated conditions showed that cosyntropin increased the confirmed rate of bilateral selectivity for SI cut-offs ≥ 2.0, but reduced lateralization rates (P < 0.001). Post-adrenalectomy outcomes were not improved by use of cosyntropin or more restrictive diagnostic criteria.
Conclusion
Commonly used SI and LI cut-offs are associated with disappointingly low rates of biochemically defined AVS success and identified unilateral PA. Evidence-based protocols entailing less restrictive interpretative cut-offs might optimize the clinical use of this costly and invasive test. (J Clin Endocrinol Metab XX: 0-0, 2020)
Abstract
Background
In Alzheimer’s disease (AD), intraneuronal tau protein accumulation into neurofibrillary tangles correlates with clinical signs and neurodegeneration
1
. Besides neurotoxic ...protein aggregation, dysregulation of lipid metabolism is emerging as a common disease mechanism
2
. The main regulators of lipid metabolism in the brain are astrocytes and astrocyte‐neuron communication is key to provide metabolic support to neuron
3
. While tau has been suggested to bind to lipids
4
, little is known about the potential tau‐lipid interactions in the brain, it’s role in neuron‐astrocyte crosstalk and how this relates to AD pathology.
Methods
We employ a multiscale approach harnessing human 2D and 3D multicellular models combined with advanced imaging techniques, spanning from single molecule insights to ultrastructural features and functional imaging. We aim to unravel the structural and functional complexity of emerging protein‐lipid landscapes in AD and to elucidate how their misregulation triggers early lipid dyshomeostasis.
Results
Tau propagates in brain organoids in highly dynamic intracellular droplet‐like structures rich in lipids. Strikingly, the molecular identity of tau droplets is cell‐type specific; tau interact with lipids in neurons but not in astrocytes (fig.1‐2). The dynamics of neuronal tau‐lipid accumulations are driven by microtubule interactions and show liquid‐like behavior. Furthermore, highly dynamic tau‐lipid droplets transition to stillness overtime giving rise to a heterogenous spectrum of conformational ensembles of tau (fig.3).
Conclusion
Tau‐lipid interactions
in vivo
are neuron‐specific. Lipid colocalization correlates with dramatic changes in the structural properties of tau. In neurons, tau and lipids coalesce in highly dynamic intracellular liquid‐like droplets that undergo time‐dependent transition to potential pathological states. Our results highlight intriguing functional implications of cell‐type specific tau‐lipid interactions impacting on neuron‐astrocyte communication and overall brain lipid metabolism. Targeting tau‐lipid interactions in neurons promise exciting new avenues in AD therapeutic strategies.
1. Busche, et al. Synergy between amyloid‐β and tau in Alzheimer’s disease.
Nat. Neurosci
. (2020).
2. Yin. Lipid metabolism and Alzheimer’s disease: clinical evidence, mechanistic link and therapeutic promise.
FEBS J
. (2022).
3. Yang,
et al.
Lipid metabolism and storage in neuroglia: role in brain development and neurodegenerative diseases.
Cell Biosci
. (2022).
4. Sallaberry,
et al.
Tau and Membranes: Interactions That Promote Folding and Condensation.
Front. Cell Dev. Biol
. (2021).
Abstract
Context
Adrenal gland imaging is recommended by the current guidelines for the workup of primary aldosteronism (PA). However, its diagnostic performance has not been established in large, ...multiethnic cohorts of patients who undergo adrenal vein sampling (AVS) and adrenalectomy.
Objective
This work aims to assess the diagnostic accuracy of cross-sectional adrenal imaging.
Methods
This international multicenter study took place in tertiary referral centers. A total of 1625 PA patients seeking surgical cure were enrolled in an international study involving 19 centers in North America, Europe, Asia, and Australia. Of these, 1311 (81%) had imaging data available and 369 (23%), who received a final diagnosis of surgically cured unilateral PA, were examined. Patients underwent AVS and imaging by computed tomography and/or magnetic resonance imaging. The accuracy of detection of unilateral PA at imaging was estimated by the area under the receiver operator characteristics curve using cure (biochemical and/or full clinical success) as the reference at follow-up after unilateral adrenalectomy.
Results
In the cohort of 1311 patients with imaging data available, 34% and 7% of cases showed no detectable or bilateral nodules, respectively. Imaging did not detect the culprit adrenal in 28% of the surgically cured unilateral PA patients. Moreover, the clinical outcome did not differ significantly between the imaging-positive and imaging-negative patients.
Conclusion
Cross-sectional imaging did not identify a lateralized cause of disease in around 40% of PA patients and failed to identify the culprit adrenal in more than one-fourth of patients with unilateral PA.
La hipertensión arterial resistente (HTAR) supone un importante impacto a nivel multiorgánico e incrementa la morbimortalidad. Este trabajo evalúa la evolución de la lesión orgánica mediada por ...hipertensión en pacientes con HTAR tras añadir espironolactona.
Estudio retrospectivo de 58 pacientes con HTAR a quienes se añadió espironolactona (12,5-25mg/día). Se obtuvieron parámetros de presión arterial clínica y MAPA-24h, cociente albúmina/creatinina y datos ecocardiográficos previos a iniciar espironolactona y tras 12 meses de tratamiento.
El 36,2% de los pacientes eran mujeres y la edad media de 67,3±10,1 años. Se objetivó un descenso en albuminuria (mediana RIC25-75) de 27,0 (7,5-255,4) a 11,3 (3,1-37,8) mg/g (p = 0,009), siendo más marcado en pacientes con albuminuria grado A2 y A3: de 371,2 (139,5-797,4) a 68,4 (26,5-186,5) mg/g, p =0,02.. A nivel ecocardiográfico se evidenció: pared posterior: −1,0±0,4mm (p<0,001), tabique interventricular: −0,6±0,5mm (p=0,01), índice de masa del ventrículo izquierdo (VI): −14,7±10,2g/m2 (p=0,006), índice de remodelado del VI: −0,04±0,036 (p=0,03), sin cambios estadísticamente significativos en fracción de eyección VI, diámetro diastólico VI, diámetro sistólico VI, diámetro de aurícula izquierda, relación entre onda de llenado ventricular temprano y contracción auricular ni en índice de presión llenado VI.
La presión arterial clínica sistólica/diastólica presentó un descenso de −12,5±4,9/−4,9±3,0mmHg, p<0,001. En los MAPA-24h se observó un descenso significativo de presión arterial sistólica y diastólica en los períodos diurno y nocturno, y un cambio favorable en el patrón circadiano en el 38,1% de los pacientes, p<0,001.
Añadir espironolactona en HTAR contribuye a la reducción de la lesión orgánica mediada por hipertensión a nivel de albuminuria y de parámetros ecocardiográficos de cardiopatía hipertensiva.
Resistant hypertension (RH) represents an important multi-organic impact and increases the morbi-mortality. We aimed to evaluate the evolution of hypertensive mediated organ damage in patients with RH after adding spironolactone.
Retrospective study of 58 patients with RH who started spironolactone (12.5–25mg daily). Office blood pressure, 24-h ambulatory blood pressure monitoring (24h-ABPM), urine albumin-to-creatinine ratio and echocardiographic parameters were analyzed prior to initiation of spironolactone and after 12 months of treatment.
Thirty-six percent of patients were women and mean age was 67.3±10.1 years. We observed a decrease in urine albumin-to-creatinine ratio (median RIQ25–75) of 27.0 (7.5-255.4) to 11.3 (3.1–37.8) mg/g, P = .009. This was more relevant in patients with albuminuria grade A2 and A3: 371.2 (139.5–797.4) to 68.4 (26.5–186.5) mg/g, P = .02. The echocardiographic changes were: posterior wall thickness: −1.0±0.4mm (P<.001), interventricular septal thickness: −0.6±0.5mm (P=.01), left ventricular (LV) mass index: −14.7±10.2g/m2 (P=.006), LV remodeling index: −0.04±0.036 (P=.03), without statistically significant changes in LV ejection fraction, LV end-diastolic diameter, LV end-systolic diameter, left atrial diameter, relationship between early ventricular filling wave and atrial contraction and LV filling pressure index.
Systolic/diastolic office blood pressure decreased −12.5±4.9/−4.9±3.0mmHg, P<.001. In 24h-ABPM, systolic and diastolic BP had a significant decrease in diurnal and nocturnal periods and 38.1% of patients presented a favorable change in the circadian pattern, P<.001.
Adding spironolactone to patients with RH contributes to improve hypertensive mediated organ damage by reducing albuminuria levels and echocardiographic parameters of hypertensive heart disease.
Voltage-dependent potassium (Kv) channels contribute to the excitability of nerves and muscles. In addition, Kv participates in several cell functions, including cell cycle progression and ...proliferation. Kv channel remodeling has been associated with neoplastic cell growth and cancer. Kv7 channels are expressed in blood vessels, and they participate in the maintenance of vascular tone and are implicated in myocyte proliferation. Although evidence links Kv7 remodeling to different types of cancer, its expression in vascular tumors has never been studied. Endothelium-derived vascular neoplasms range from indolent lesions to highly aggressive and metastasizing cancers. Here, we show that Kv7.1 and Kv7.5 are evenly distributed in tunicas as well as the endothelium of healthy veins and arteries. The layered structure of vessels is lost in vascular tumors. By studying eight vascular tumors with different origins and characteristics, we found that Kv7.1 and Kv7.5 expression was changed in vascular cancers. While both channels were generally downregulated, Kv7.5 expression was clearly correlated with neoplastic malignancy. The vascular tumors did not contract; therefore, the role of Kv7 channels is probably related to proliferation rather than controlling vascular tone. Our results identify vascular Kv7 channels as targets for cancer detection and anticancer therapies.
We aimed at determining the rate of drug-resistant arterial hypertension in patients with an unambiguous diagnosis of primary aldosteronism (PA). Moreover, we sought for investigating the diagnostic ...performance of adrenal vein sampling (AVS), and the effect of adrenalectomy on blood pressure (BP) and prior treatment resistance in PA patients subtyped by AVS in major referral centres.
The Adrenal Vein Sampling International Study-2 (AVIS-2) was a multicentre international study that recruited consecutive PA patients submitted to AVS, according to current guidelines, during 15 years. The patients were over 18 years old with arterial hypertension and had an unambiguous diagnosis of PA. The rate of resistant hypertension was assessed at baseline and after adrenalectomy using the American Heart Association (AHA) 2018 definition. Information on presence or absence of resistant hypertension was available in 89% of the 1625 enrolled PA patients. Based on the AHA 2018 criteria, resistant hypertension was found in 20% of patients, of which about two-thirds (14%) were men and one-third (6%) women (χ2 = 17.1, P < 1*10-4) with a higher rate of RH in men than in women (23% vs. 15% P < 1*10-4). Of the 292 patients with resistant hypertension, 98 (34%) underwent unilateral AVS-guided adrenalectomy, which resolved BP resistance to antihypertensive treatment in all.
(i) Resistant hypertension is a common presentation in patients seeking surgical cure of PA; (ii) AVS is key for the optimal management of patients with PA due to resistant hypertension; and (iii) AVS-guided adrenalectomy allowed resolution of treatment-resistant hypertension.
Resistant hypertension (RH) represents an important multi-organic impact and increases the morbi-mortality. We aimed to evaluate the evolution of hypertensive mediated organ damage in patients with ...RH after adding spironolactone.
Retrospective study of 58 patients with RH who started spironolactone (12.5–25mg daily). Office blood pressure, 24-h ambulatory blood pressure monitoring (24h-ABPM), urine albumin-to-creatinine ratio and echocardiographic parameters were analyzed prior to initiation of spironolactone and after 12 months of treatment.
Thirty-six percent of patients were women and mean age was 67.3±10.1 years. We observed a decrease in urine albumin-to-creatinine ratio (median RIQ25–75) of 27.0 (7.5–255.4) to 11.3 (3.1–37.8)mg/g, p=0.009. This was more relevant in patients with albuminuria grade A2 and A3: 371.2 (139.5–797.4) to 68.4 (26.5–186.5)mg/g, p=0.02. The echocardiographic changes were: posterior wall thickness: −1.0±0.4mm (p<0.001), interventricular septal thickness: −0.6±0.5mm (p=0.01), left ventricular (LV) mass index: −14.7±10.2g/m2 (p=0.006), LV remodeling index: −0.04±0.036 (p=0.03), without statistically significant changes in LV ejection fraction, LV end-diastolic diameter, LV end-systolic diameter, left atrial diameter, relationship between early ventricular filling wave and atrial contraction and LV filling pressure index.
Systolic/diastolic office blood pressure decreased −12.5±4.9/−4.9±3.0mmHg, p<0.001. In 24h-ABPM, systolic and diastolic BP had a significant decrease in diurnal and nocturnal periods and 38.1% of patients presented a favorable change in the circadian pattern, p<0.001.
Adding spironolactone to patients with RH contributes to improve hypertensive mediated organ damage by reducing albuminuria levels and echocardiographic parameters of hypertensive heart disease.
La hipertensión arterial resistente (HTAR) supone un importante impacto a nivel multiorgánico e incrementa la morbimortalidad. Este trabajo evalúa la evolución de la lesión orgánica mediada por hipertensión en pacientes con HTAR tras añadir espironolactona.
Estudio retrospectivo de 58 pacientes con HTAR a quienes se añadió espironolactona (12,5–25mg/día). Se obtuvieron parámetros de presión arterial clínica y MAPA-24h, cociente albúmina/creatinina y datos ecocardiográficos previos a iniciar espironolactona y tras 12 meses de tratamiento.
El 36,2% de los pacientes eran mujeres y la edad media de 67,3±10,1 años. Se objetivó un descenso en albuminuria (mediana RIC25–75) de 27,0 (7,5–255,4) a 11,3 (3,1–37,8)mg/g (p=0,009), siendo más marcado en pacientes con albuminuria grado A2 y A3: de 371,2 (139,5–797,4) a 68,4 (26,5–186,5)mg/g, p=0,02.. A nivel ecocardiográfico se evidenció: pared posterior: −1,0±0,4mm (p<0,001), tabique interventricular: −0,6±0,5mm (p=0,01), índice de masa del ventrículo izquierdo (VI): −14,7±10,2 g/m2 (p=0,006), índice de remodelado del VI: −0,04±0,036 (p=0,03), sin cambios estadísticamente significativos en fracción de eyección VI, diámetro diastólico VI, diámetro sistólico VI, diámetro de aurícula izquierda, relación entre onda de llenado ventricular temprano y contracción auricular ni en índice de presión llenado VI.
La presión arterial clínica sistólica/diastólica presentó un descenso de −12,5±4,9/−4,9±3,0mmHg, p<0,001. En los MAPA-24h se observó un descenso significativo de presión arterial sistólica y diastólica en los períodos diurno y nocturno, y un cambio favorable en el patrón circadiano en el 38,1% de los pacientes, p<0,001.
Añadir espironolactona en HTAR contribuye a la reducción de la lesión orgánica mediada por hipertensión a nivel de albuminuria y de parámetros ecocardiográficos de cardiopatía hipertensiva.
Disintegrin and metalloproteinase domain 17 (ADAM17) activates inflammatory and fibrotic processes through the shedding of various molecules such as Tumor Necrosis Factor-α (TNF-α) or Transforming ...Growht Factor-α (TGF-α). There is a well-recognised link between TNF-α, obesity, inflammation, and diabetes. In physiological situations, ADAM17 is expressed mainly in the distal tubular cell while, in renal damage, its expression increases throughout the kidney including the endothelium. The aim of this study was to characterize, for the first time, an experimental mouse model fed a high-fat diet (HFD) with a specific deletion of
in endothelial cells and to analyse the effects on different renal structures. Endothelial
knockout male mice and their controls were fed a high-fat diet, to induce obesity, or standard rodent chow, for 22 weeks. Glucose tolerance, urinary albumin-to-creatinine ratio, renal histology, macrophage infiltration, and galectin-3 levels were evaluated. Results showed that obese mice presented higher blood glucose levels, dysregulated glucose homeostasis, and higher body weight compared to control mice. In addition, obese wild-type mice presented an increased albumin-to-creatinine ratio; greater glomerular size and mesangial matrix expansion; and tubular fibrosis with increased galectin-3 expression.
deletion decreased the albumin-to-creatinine ratio, glomerular mesangial index, and tubular galectin-3 expression. Moreover, macrophage infiltration in the glomeruli of obese
knockout mice was reduced as compared to obese wild-type mice. In conclusion, the expression of ADAM17 in endothelial cells impacted renal inflammation, modulating the renal function and histology in an obese pre-diabetic mouse model.
Acute and chronic kidney lesions induce an increase in A Disintegrin And Metalloproteinase domain 17 (ADAM17) that cleaves several transmembrane proteins related to inflammatory and fibrotic ...pathways. Our group has demonstrated that renal ADAM17 is upregulated in diabetic mice and its inhibition decreases renal inflammation and fibrosis. The purpose of the present study was to analyze how
deletion in proximal tubules affects different renal structures in an obese mice model. Tubular
knockout male mice and their controls were fed a high-fat diet (HFD) for 22 weeks. Glucose tolerance, urinary albumin-to-creatinine ratio, renal histology, and pro-inflammatory and pro-fibrotic markers were evaluated. Results showed that wild-type mice fed an HFD became obese with glucose intolerance and renal histological alterations mimicking a pre-diabetic condition; consequently, greater glomerular size and mesangial expansion were observed.
tubular deletion improved glucose tolerance and protected animals against glomerular injury and prevented podocyte loss in HFD mice. In addition, HFD mice showed more glomerular macrophages and collagen accumulation, which was prevented by
deletion. Galectin-3 expression increased in the proximal tubules and glomeruli of HFD mice and ameliorated with
deletion. In conclusion,
in proximal tubules influences glucose tolerance and participates in the kidney injury in an obese pre-diabetic murine model. The role of ADAM17 in the tubule impacts on glomerular inflammation and fibrosis.
La obesidad está asociada con la hipertensión arterial por mecanismos diversos. La presión arterial (PA) central parece estar más correlacionada que la PA periférica con el riesgo cardiovascular ...futuro. La cirugía bariátrica constituye un método eficaz para disminuir la PA paralelamente a una pérdida de peso significativa en pacientes con obesidad severa. El estudio de la relación entre la modificación de peso tras cirugía bariátrica y la medición ambulatoria de PA, no solo a nivel periférico, sino también a nivel central, podría aportar información respecto a los mecanismos del daño orgánico asociado a la PA elevada en la obesidad.
En esta revisión analizamos la evidencia disponible respecto a la asociación entre la PA central con la obesidad y sus modificaciones tras la cirugía bariátrica.
Various mechanisms are related to arterial hypertension in obesity. Central blood pressure (BP) seems to correlate more than peripheral BP with future cardiovascular risk. Bariatric surgery is an effective method to reduce BP along with weight loss in patients with morbid obesity.
The study of the relationship between weight modification after bariatric surgery and ambulatory BP measurement, not only peripheral BP, but also central BP, could provide information regarding the mechanisms of organic damage associated with elevated BP in obesity.
In this review we analyze the available evidence regarding the association between central BP with obesity and its modifications after bariatric surgery.
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