New insights to the potential mechanisms driving coronary flow reserve impairment in Cushing's syndrome: A pilot noninvasive study by transthoracic Doppler echocardiography.

BACKGROUND: The contribution of functional and/or structural remodeling to reduced coronary flow velocity reserve (CFVR), reflecting impaired coronary microcirculation in Cushing's syndrome (CS), has not been clearly elucidated. We aimed to identify the potential mechanisms of coronary microvascular impairment in CS. METHODS: We studied 15 CS patients (11 female, age 50 ±â€¯9 years) without clinical evidence of cardiovascular disease. Coronary flow velocity in the left anterior descending coronary artery was measured by transthoracic Doppler echocardiography, at rest, and during adenosine infusion. Average peak flow velocities, CFVR, and microvascular resistance in baseline (BMR) and hyperemic conditions (HMR) were assessed. CFVR ≤2.5 was considered a marker of microvascular disease (CMD). Diastolic function (E/e'), global longitudinal strain (GLS) and fractional pulse pressure (fPP), an index of arterial stiffness, were also assessed. RESULTS: CMD was present in 5 patients (33.3%). CMD was primarily driven by increased baseline peak flow velocity (29 ±â€¯12 versus 19.6 ±â€¯4.2 cm/s, p = .03) in the presence of decreased BMR (3.62 ±â€¯0.6 versus 5.46 ±â€¯1.4 mm Hg·s/cm, p = .03). Moreover, urinary cortisol and E/e' were higher (p = .001 and p = .001, respectively) and GLS was lower (p = .009) in patients with CMD. fPP was higher in patients with CMD (p = .01). Urinary cortisol correlated to CFVR (p = .008), E/e' (p < .0001) and GLS (p < .0001). fPP directly correlated to average peak flow velocities at rest (p = .01) and inversely to BMR (p = .03). CONCLUSIONS: Functional microvascular regulatory impairment seems to be the potential mechanism of CMD in CS. CMD seems to be related to decreased myocardial contractility and diastolic dysfunction associated with cortisol excess.

Preclinical markers of atherosclerosis in acromegaly: a systematic review and meta-analysis.

OBJECTIVE: Multiple studies investigated preclinical markers of peripheral vascular damage in acromegaly (ACRO) reporting discordant results. The aim of this study was to run a meta-analysis to examine whether intima media thickness (IMT), flow mediated dilation (FMD) and arterial pulse wave velocity (PWV) are affected in acromegalic patients and to assess the impact of effective treatment of growth hormone excess on these outcomes. STUDY SELECTION: Twenty-seven studies comparing ACRO vs control (CON) populations and active (ACT) vs inactive (INACT) ACRO were included in the meta-analysis. DATA SYNTHESIS: ACRO compared to CON have higher IMT (ES = 0.83, 95% C.I. 0.35-1.30), p = 0.001, impaired FMD (ES = - 1.59, 95% C.I. - 2.33 to - 0.85, p < 0.0001) and higher PWV (ES = 0.76 95% C.I. 0.37-1.16, p = 0.0001). When patients with ACT vs INACT disease were considered IMT was higher (ES = 0.43, 95% C.I. 0.02-0.84, p = 0.041) and FMD was impaired (ES = - 0.66, 95% C.I. - 1.28 to 0.04, p = 0.038) in ACT patients. Meta-regression analysis of studies comparing IMT in ACT vs INACT acromegalic patients showed a significant and inverse association between the effect size and the percent of hypertensive (p = 0.025) and diabetic (p = 0.041) patients. CONCLUSIONS: IMT, FMD and arterial stiffness are impaired in acromegaly showing that these patients may be at increased risk of atherosclerosis. In patients with active disease these preclinical markers of atherosclerosis are worse compared to patients with inactive disease but the role of diabetes and hypertension is prevailing on growth hormone excess.

Ambulatory Arterial Stiffness Indexes in Cushing's Syndrome.

Long-standing exposure to endogenous cortisol excess is associated with high cardiovascular risk. The aim of our study was to investigate arterial stiffness, which has been recognized as an independent predictor of adverse cardiovascular outcome, in a group of patients with Cushing's syndrome. Twenty-four patients with Cushing's syndrome (3 males, mean age 49±13 years; 20 pituitary-dependent Cushing's disease and 4 adrenal adenoma) underwent 24-h ambulatory blood pressure monitoring (ABPM) and evaluation of cardiovascular risk factors. The Ambulatory Arterial Stiffness Index (AASI) and symmetric AASI (sAASI) were derived from ABPM tracings. Cushing patients were divided into 8 normotensive (NOR-CUSH) and 16 hypertensive (HYP-CUSH) patients, and were compared with 8 normotensive (NOR-CTR) and 16 hypertensive (HYP-CTR) control subjects, matched for demographic characteristics, 24-h ABPM and cardiometabolic risk factors. The AASI and sAASI indexes were significantly higher in Cushing patients than in controls, either in the normotensive (p=0.048 for AASI and p=0.013 for sAASI) or in the hypertensive (p=0.004 for AASI and p=0.046 for sAASI) group. No difference in metabolic parameters was observed between NOR-CUSH and NOR-CTR or between HYP-CUSH and HYP-CTR groups. AASI and sAASI were both correlated with urinary cortisol in patients with endogenous hypercortisolism (Spearman's rho=0.40, p=0.05, and 0.61, p=0.003, respectively), while no correlation was found in controls. Both AASI and sAASI are increased in Cushing syndrome, independent of BP elevation, and may represent an additional cardiovascular risk factor in this disease. The role of excess cortisol in arterial stiffness has to be further clarified.

Assessing Lateralization Index of Adrenal Venous Sampling for Surgical Indication in Primary Aldosteronism.

BACKGROUND: Clinical practice guidelines recommend the Lateralization Index (LI) as the standard for determining surgical eligibility in primary aldosteronism (PA). Our goal was to identify the optimal LI cut-offs in adrenal venous sampling (AVS) for diagnosing PA that is amenable to surgical cure. METHODS: We conducted a retrospective international cohort study across 16 institutions in 11 countries, including 1,550 patients with PA who underwent AVS, with and/or without ACTH stimulation. The establishment of optimal cut-offs was informed by a survey of 82 PA patients in Japan, aimed at determining the LI cut-off aligned with patient expectations for a surgical cure rate. RESULTS: The survey revealed that a median cure rate expectation of 80% would motivate PA patients towards undergoing adrenalectomy. The optimal LI cut-offs achieving an adjusted positive predictive value (PPV) of 80% were identified as 3.8 for unstimulated AVS and 3.4 for ACTH-stimulated AVS. Furthermore, a contralateral ratio of less than 0.4 and the detection of an adrenal nodule on CT imaging were identified as independent predictors of surgically curable PA. Incorporating these factors with the optimal LI cut-offs, the adjusted PPV increased to 96.6% for unstimulated AVS and 89.6% for ACTH-stimulated AVS. No clear differences in predictive ability between unstimulated and ACTH-stimulated LI were found. CONCLUSIONS AND RELEVANCE: The present study clarified the optimal LI cut-offs for without and with ACTH stimulation. The presence of contralateral suppression and adrenal nodule on CT imaging seems to provide additional available information besides LI for surgical indication.

Coronary microvascular dysfunction induced by primary hyperparathyroidism is restored after parathyroidectomy.

BACKGROUND: Symptomatic primary hyperparathyroidism (PHPT) is associated with increased cardiovascular mortality. However, data on the association between asymptomatic PHPT and cardiovascular risk are lacking. We assessed coronary flow reserve (CFR) as a marker of coronary microvascular function in asymptomatic PHPT of recent onset. METHODS AND RESULTS: We studied 100 PHPT patients (80 women; age, 58±12 years) without cardiovascular disease and 50 control subjects matched for age and sex. CFR in the left anterior descending coronary artery was detected by transthoracic Doppler echocardiography, at rest, and during adenosine infusion. CFR was the ratio of hyperemic to resting diastolic flow velocity. CFR was lower in PHPT patients than in control subjects (3.0±0.8 versus 3.8±0.7; P<0.0001) and was abnormal (≤2.5) in 27 patients (27%) compared with control subjects (4%; P=0.0008). CFR was inversely related to parathyroid hormone (PTH) levels (r=-0.3, P<0.004). In patients with CFR ≤2.5, PTH was higher (26.4 pmol/L [quartiles 1 and 3, 16 and 37 pmol/L] versus 18 [13-25] pmol/L; P<0.007), whereas calcium levels were similar (2.9±0.1 versus 2.8±0.3 mmol/L; P=0.2). In multivariable linear regression analysis, PTH, age, and heart rate were the only factors associated with CFR (P=0.04, P=0.01, and P=0.006, respectively). In multiple logistic regression analysis, only PTH increased the probability of CFR ≤2.5 (P=0.03). In all PHPT patients with CFR ≤2.5, parathyroidectomy normalized CFR (3.3±0.7 versus 2.1±0.5; P<0.0001). CONCLUSIONS: PHPT patients have coronary microvascular dysfunction that is completely restored after parathyroidectomy. PTH independently correlates with the coronary microvascular impairment, suggesting a crucial role of the hormone in explaining the increased cardiovascular risk in PHPT.

High-salt diet increases glomerular ACE/ACE2 ratio leading to oxidative stress and kidney damage.

BACKGROUND: Angiotensin II (AngII) contributes to salt-driven kidney damage. In this study, we aimed at investigating whether and how the renal damage associated with a high-salt diet could result from changes in the ratio between angiotensin-converting enzyme (ACE) and angiotensin-converting enzyme 2 (ACE2). METHODS: Forty-eight rats randomly allocated to three different dietary contents of salt were studied for 4 weeks after undergoing a left uninephrectomy. We focussed on kidney functional, structural and molecular changes. At the same time, we studied kidney molecular changes in 20 weeks old Ace2-knockout mice (Ace2KO), with and without ACE inhibition. RESULTS: A high salt content diet significantly increased the glomerular ACE/ACE2 ratio. This was associated with increased oxidative stress. To assess whether these events were related, we measured renal oxidative stress in Ace2KO, and found that the absence of ACE2 promoted oxidative stress, which could be prevented by ACE inhibition. CONCLUSION: One of the mechanisms by which a high-salt diet leads to renal damage seems to be the modulation of the ACE/ACE2 ratio which in turn is critical for the cause of oxidative stress, through AngII.

Vitamin D Status, Cardiovascular Risk Profile, and miRNA-21 Levels in Hypertensive Patients: Results of the HYPODD Study.

The vitamin D and microRNA (miR) systems may play a role in the pathogenesis of cardiometabolic disorders, including hypertension. The HYPODD study was a double-blind placebo-controlled trial aiming to assess the effects of cholecalciferol treatment in patients with well-controlled hypertension and hypovitaminosis D (25OHD levels < 50 nmol/L). In addition to this clinical trial, we also evaluated the effects of cholecalciferol and calcitriol treatment on miR-21 expression in vivo and in vitro, respectively. Changes in the cardiovascular risk profiles were evaluated in HYPODD patients treated with cholecalciferol (C-cohort) or with placebo (P-cohort). The miR-21circulating levels were measured in four C-cohort patients and five P-cohort patients. In vitro, the miR-21 levels were measured in HEK-293 cells treated with calcitriol or with ethanol vehicle control. Cholecalciferol treatment increased 25OHD levels and reduced parathormone, total cholesterol, and low-density lipoprotein cholesterol levels in C-cohort patients, whereas no significant changes in these parameters were observed in P-cohort patients. The miR-21 circulating levels did not change in the C- or the P-cohort patients upon treatment. Calcitriol treatment did not affect miR-21 levels in HEK-293 cells. In conclusion, hypovitaminosis D correction ameliorated the cardiovascular risk profiles in hypertensive patients treated with cholecalciferol but did not influence the miR-21 expression.

Correction: Gender differences in predictors of intensive care units admission among COVID-19 patients: The results of the SARS-RAS study of the Italian Society of Hypertension.

[This corrects the article DOI: 10.1371/journal.pone.0237297.].

Diagnosis and management of hypertension in patients with Cushing's syndrome: a position statement and consensus of the Working Group on Endocrine Hypertension of the European Society of Hypertension.

Endogenous/exogenous Cushing's syndrome is characterized by a cluster of systemic manifestations of hypercortisolism, which cause increased cardiovascular risk. Its biological basis is glucocorticoid excess, acting on various pathogenic processes inducing cardiovascular damage. Hypertension is a common feature in Cushing's syndrome and may persist after normalizing hormone excess and discontinuing steroid therapy. In endogenous Cushing's syndrome, the earlier the diagnosis the sooner management can be employed to offset the deleterious effects of excess cortisol. Such management includes combined treatments directed against the underlying cause and tailored antihypertensive drugs aimed at controlling the consequences of glucocorticoid excess. Experts on endocrine hypertension and members of the Working Group on Endocrine Hypertension of the European Society of Hypertension (ESH) prepared this Consensus document, which summarizes the current knowledge in epidemiology, genetics, diagnosis, and treatment of hypertension in Cushing's syndrome.

Correction: Gender differences in predictors of intensive care units admission among COVID-19 patients: The results of the SARS-RAS study of the Italian Society of Hypertension.

[This corrects the article DOI: 10.1371/journal.pone.0237297.].

Determinants of healing among patients with coronavirus disease 2019: the results of the SARS-RAS study of the Italian Society of Hypertension.

OBJECTIVE: The burst of COVID-19 epidemics in Italy prompted the Italian Society of Hypertension to start an observational study to explore the characteristics of the hospitalized victims of the disease. The current analysis aimed to investigate the predictors of healing among Italian COVID-19 patients. We also assessed the effect of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers on the outcome. METHODS: We designed a cross-sectional, observational, multicenter, nationwide survey in Italy to explore the demographic and clinical characteristics of patients with confirmed COVID-19 infection. We analyzed information from 2446 charts of Italian patients admitted for certified COVID-19 in 27 hospitals. Healing from COVID-19 infection, defined as two consecutive negative swabs, was reported in 544 patients (22.2%), 95% of them were hospitalized. RESULTS: Age and Charlson Comorbidity Index were significantly lower in healing compared with nonhealing patients (63 ±â€Š15 vs. 69 ±â€Š15 and 2 ±â€Š2 vs. 3 ±â€Š2, both P < 0.05). In multivariable regression model, predictors of healing were younger age (OR: 0.99; 95% CI 0.98-0.99, P = 0.0001), absence of chronic kidney disease (OR: 0.35; 95% CI 0.17-0.70, P = 0.003) or heart failure (OR: 0.44; 95% CI, 0.28-0.70, P = 0.001). In the subgroup of patients suffering from hypertension and/or heart failure (n = 1498), no differences were observed in the use of ACE inhibitors and angiotensin receptor blockers. CONCLUSION: Our study demonstrated that younger age and absence of comorbidities play a major role in determining healing in patients with COVID-19. No effects of ACE inhibitors and angiotensin receptor blockers on the outcome was reported.

Adrenal Venous Sampling-Guided Adrenalectomy Rates in Primary Aldosteronism: Results of an International Cohort (AVSTAT).

CONTEXT: Adrenal venous sampling (AVS) is the current criterion standard lateralization technique in primary aldosteronism (PA). Japanese registry data found that 30% of patients with unilateral PA did not undergo adrenalectomy, but the reasons for this and whether the same pattern is seen internationally are unknown. OBJECTIVE: To assess the rate of AVS-guided adrenalectomy across an international cohort and identify factors that resulted in adrenalectomy not being performed in otherwise eligible patients. DESIGN, SETTING, AND PARTICIPANTS: Retrospective, multinational, multicenter questionnaire-based survey of management of PA patients from 16 centers between 2006 and 2018. MAIN OUTCOME MEASURES: Rates of AVS implementation, AVS success rate, diagnosis of unilateral PA, adrenalectomy rate, and reasons why adrenalectomy was not undertaken in patients with unilateral PA. RESULTS: Rates of AVS implementation, successful AVS, and unilateral disease were 66.3%, 89.3% and 36.9% respectively in 4818 patients with PA. Unilateral PA and adrenalectomy rate in unilateral PA were lower in Japanese than in European centers (24.0% vs 47.6% and 78.2% vs 91.4% respectively). The clinical reasoning for not performing adrenalectomy in unilateral PA were more likely to be physician-derived in Japan and patient-derived in Europe. Physician-derived factors included non-AVS factors, such as good blood pressure control, normokalemia, and the absence of adrenal lesions on imaging, which were present before AVS. CONCLUSION: Considering the various unfavorable aspects of AVS, stricter implementation and consideration of surgical candidacy prior to AVS will increase its diagnostic efficiency and utility.

Psychosomatic aspects of Cushing's syndrome.

There has been growing interest in the psychosocial aspects of Cushing's syndrome, such as the role of life stress as a pathogenetic factor, the association with affective disorders, and the presence of residual symptoms after treatment. Interestingly, a temporal relationship between stressful life events and disease onset is relevant only to pituitary-dependent Cushing's disease, and not to the pituitary-independent forms. A number of psychiatric and psychological disturbances may be associated with the active hypercortisolemic state, regardless of its etiology. Within the high frequency of mood disorders (about 60%), major depression is the most common complication. Other psychopathological aspects include mania, anxiety disorders, psychological symptoms (demoralization, irritable mood, somatization) and cognitive impairment. Cognitive symptoms are associated with brain abnormalities (mainly loss of brain volume). Quality of life may be seriously compromised during both active and post-treatment phases. Long-standing hypercortisolism may imply a degree of irreversibility of the pathological process. Recovery, thus, may be delayed and be influenced by highly individualized affective responses. Outcomes of Cushing's syndrome treatment are not fully satisfactory. Within its great complexity, a conceptual shift from a merely biomedical care to a psychosomatic consideration of the person and his/her quality of life appears to be necessary to improve effectiveness. It is time to translate the research evidence that has accumulated into clinical practice initiatives. To patients who show persistence or even worsening of psychological distress upon adequate endocrine treatment psychiatric/psychological interventions should be readily available. Applying interdisciplinary expertise and addressing the needs for rehabilitation would markedly improve final outcome.

Sudden death with massive hemoptysis from aortobronchial fistula.

Aortobronchial fistula is an uncommon clinical entity, with unpredictable clinical course and significant mortality. Here, we describe a case of fistulous tract between a descending aortic graft and a branch of the left upper lobar bronchus leading to massive hemoptysis causing death for hemorrhagic shock in a 72-year-old man.

DNA Methylation of Steroidogenic Enzymes in Benign Adrenocortical Tumors: New Insights in Aldosterone-Producing Adenomas.

CONTEXT: DNA methylation has been identified among putative regulatory mechanisms for CYP11B2 expression in primary aldosteronism. OBJECTIVE: The objective of this work is to investigate DNA methylation and expression of genes encoding steroidogenic enzymes in benign adrenocortical tumors. DESIGN AND SETTING: This cross-sectional study took place at university hospitals. PATIENTS: We collected fresh-frozen tissues from patients with benign adrenocortical adenomas (n = 48) (nonfunctioning n = 9, autonomous cortisol secretion n = 9, Cushing syndrome n = 17, aldosterone-producing [APA] n = 13) and adrenal cortex adjacent to APA (n = 12). We collected formalin-fixed, paraffin-embedded (FFPE) specimens of paired APA and concurrent aldosterone-producing cell clusters (APCCs) (n = 6). INTERVENTION: DNA methylation levels were evaluated by quantitative bisulfite next-generation sequencing in fresh-frozen tissues (CYP11A1, CYP11B1, CYP11B2, CYP17A1, CYP21A2, HSD3B1, HSD3B2, NR5A1, STAR, and TSPO) and FFPE APA/APCC paired samples (CYP11B2). CYP11B1, CYP11B2, CYP17, CYP21, and STAR gene expressions were examined by quantitative real-time polymerase chain reaction. MAIN OUTCOME MEASURE: The main outcome measure was DNA methylation. RESULTS: CYP11B2 methylation levels were significantly lower in APA than in other adrenal tissues (P < .001). Methylation levels of the remaining genes were comparable among groups. Overall, CYP11B2 expression and DNA methylation were negatively correlated (ρ = -0.379; P = .003). In FFPE-paired APA/APCC samples, CYP11B2 methylation level was significantly lower in APA than in concurrent APCCs (P = .028). CONCLUSIONS: DNA methylation plays a regulatory role for CYP11B2 expression and may contribute to aldosterone hypersecretion in APA. Lower CYP11B2 methylation levels in APA than in APCCs may suggest an APCC-to-APA switch via progressive CYP11B2 demethylation. Conversely, DNA methylation seems not to be relevant in regulating the expression of genes encoding steroidogenic enzymes other than CYP11B2.

Genetics, prevalence, screening and confirmation of primary aldosteronism: a position statement and consensus of the Working Group on Endocrine Hypertension of The European Society of Hypertension.

: Autonomous aldosterone overproduction represents the underlying condition of 5-10% of patients with arterial hypertension and carries a significant burden of mortality and morbidity. The diagnostic algorithm for primary aldosteronism is sequentially based on hormonal tests (screening and confirmation tests), followed by lateralization studies (adrenal CT scanning and adrenal venous sampling) to distinguish between unilateral and bilateral disease. Despite the recommendations of the Endocrine Society guideline, primary aldosteronism is largely underdiagnosed and undertreated with high between-centre heterogeneity. Experts from the European Society of Hypertension have critically reviewed the available literature and prepared a consensus document constituting two articles to summarize current knowledge on the epidemiology, diagnosis, treatment, and complications of primary aldosteronism.

Practical Considerations for the Management of Cushing's Disease and COVID-19: A Case Report.

Introduction: Italy, since the end of February 2020, is experiencing the corona virus disease 2019 (COVID-19) pandemic that may present as an acute respiratory infection. We report on COVID-19 pneumonia in the context of a complex case of Cushing's disease (CD). Case Report: A 67-year-old man with CD, who was admitted to our hospital, presented with signs and symptoms of adrenal insufficiency with persistent hypotension and glycemia toward the lower limits. We progressively withdrew almost all treatments for diabetes and CD (pasireotide and metyrapone), and i.v. hydrocortisone was necessary. A tendency to hyperkalemia was probably associated to enoxaparin. We summarized the many possible interactions between medications of Cushing's syndrome (CS) and COVID-19. Conclusion: Adrenal insufficiency might be a clinical challenge that needs a prompt treatment also in CS patients during COVID-19 infection. We should consider the possibility to titrate or temporary halt medical therapies of CS in the context of COVID-19 infection. Unexpected hyperkalemia in CS patients under treatment with heparin might be the signal of aldosterone suppression.

Gender differences in predictors of intensive care units admission among COVID-19 patients: The results of the SARS-RAS study of the Italian Society of Hypertension.

BACKGROUND: The global rate of intensive care unit (ICU) admission during the COVID-19 pandemic varies within countries and is among the main challenges for health care systems worldwide. Conflicting results have been reported about the response to coronavirus infection and COVID-19 outcomes in men and women. Understanding predictors of intensive care unit admission might be of help for future planning and management of the disease. METHODS AND FINDINGS: We designed a cross-sectional observational multicenter nationwide survey in Italy to understand gender-related clinical predictors of ICU admission in patients with COVID-19. We analyzed information from 2378 charts of Italian patients certified for COVID-19 admitted in 26 hospitals. Three hundred ninety-five patients (16.6%) required ICU admission due to COVID19 infection, more frequently men (74%), with a higher prevalence of comorbidities (1,78±0,06 vs 1,54±0,03 p<0.05). In multivariable regression model main predictors of admission to ICU are male gender (OR 1,74 95% CI 1,36-2,22 p<0.0001) and presence of obesity (OR 2,88 95% CI 2,03-4,07 p<0.0001), chronic kidney disease (OR: 1,588; 95%, 1,036-2,434 p<0,05) and hypertension (OR: 1,314; 95% 1,039-1,662; p<0,05). In gender specific analysis, obesity, chronic kidney disease and hypertension are associated with higher rate of admission to ICU among men, whereas in women, obesity (OR: 2,564; 95% CI 1,336-4.920 p<0.0001) and heart failure (OR: 1,775 95% CI: 1,030-3,057) are associated with higher rate of ICU admission. CONCLUSIONS: Our study demonstrates that gender is the primary determinant of the disease's severity among COVID-19. Obesity is the condition more often observed among those admitted to ICU within both genders. TRIAL REGISTRATION: Clinicaltrials.gov: NCT04331574.

Statins Reduce Intratumor Cholesterol Affecting Adrenocortical Cancer Growth.

Mitotane causes hypercholesterolemia in patients with adrenocortical carcinoma (ACC). We suppose that cholesterol increases within the tumor and can be used to activate proliferative pathways. In this study, we used statins to decrease intratumor cholesterol and investigated the effects on ACC growth related to estrogen receptor α (ERα) action at the nuclear and mitochondrial levels. We first used microarray to investigate mitotane effect on genes involved in cholesterol homeostasis and evaluated their relationship with patients' survival in ACC TCGA. We then blocked cholesterol synthesis with simvastatin and determined the effects on H295R cell proliferation, estradiol production, and ERα activity in vitro and in xenograft tumors. We found that mitotane increases intratumor cholesterol content and expression of genes involved in cholesterol homeostasis, among them INSIG, whose expression affects patients' survival. Treatment of H295R cells with simvastatin to block cholesterol synthesis decreased cellular cholesterol content, and this affected cell viability. Simvastatin reduced estradiol production and decreased nuclear and mitochondrial ERα function. A mitochondrial target of ERα, the respiratory complex IV (COXIV), was reduced after simvastatin treatment, which profoundly affected mitochondrial respiration activating apoptosis. Additionally, simvastatin reduced tumor volume and weight of grafted H295R cells, intratumor cholesterol content, Ki-67 and ERα, COXIV expression and activity and increase terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells. Collectively, these data demonstrate that a reduction in intratumor cholesterol content prevents estradiol production and inhibits mitochondrial respiratory chain-inducing apoptosis in ACC cells. Inhibition of mitochondrial respiration by simvastatin represents a novel strategy to counteract ACC growth.

The 2020 Italian Society of Arterial Hypertension (SIIA) practical guidelines for the management of primary aldosteronism.

BACKGROUND AND AIM: Considering the amount of novel knowledge generated in the last five years, a team of experienced hypertensionlogists was assembled to furnish updated clinical practice guidelines for the management of primary aldosteronism. METHODS: To identify the most relevant studies, the authors utilized a systematic literature review in international databases by applying the PICO strategy, and then they were required to make use of only those meeting predefined quality criteria. For studies of diagnostic tests, only those that fulfilled the Standards for Reporting of Diagnostic Accuracy recommendations were considered. RESULTS: Each section was jointly prepared by at least two co-authors, who provided Class of Recommendation and Level of Evidence following the American Heart Association methodology. The guidelines were sponsored by the Italian Society of Arterial Hypertension and underwent two rounds of revision, eventually reexamined by an External Committee. They were presented and thoroughly discussed in two face-to-face meetings with all co-authors and then presented on occasion of the 36th Italian Society of Arterial Hypertension meeting in order to gather further feedbacks by all members. The text amended according to these feedbacks was subjected to a further peer review. CONCLUSIONS: After this process, substantial updated information was generated, which could simplify the diagnosis of primary aldosteronism and assist practicing physicians in optimizing treatment and follow-up of patients with one of the most common curable causes of arterial hypertension.