Predictive performance of aldosterone-to-renin ratio in the diagnosis of primary aldosteronism in patients with resistant hypertension.

Background: The systematic use of confirmatory tests in the diagnosis of primary aldosteronism (PA) increases costs, risks and complexity to the diagnostic work-up. In light of this, some authors proposed aldosterone-to-renin (ARR) cut-offs and/or integrated flow-charts to avoid this step. Patients with resistant hypertension (RH), however, are characterized by a dysregulated renin-angiotensin-aldosterone system, even in the absence of PA. Thus, it is unclear whether these strategies might be applied with the same diagnostic reliability in the setting of RH. Methods: We enrolled 129 consecutive patients diagnosed with RH and no other causes of secondary hypertension. All patients underwent full biochemical assessment for PA, encompassing both basal measurements and a saline infusion test. Results: 34/129 patients (26.4%) were diagnosed with PA. ARR alone provided a moderate-to-high accuracy in predicting the diagnosis of PA (AUC=0.908). Among normokalemic patients, the ARR value that maximized the diagnostic accuracy, as identified by the Youden index, was equal to 41.8 (ng/dL)/(ng/mL/h), and was characterized by a sensitivity and a specificity of 100% and 67%, respectively (AUC=0.882); an ARR > 179.6 (ng/dL)/(ng/mL/h) provided a 100% specificity for the diagnosis of PA, but was associated with a very low sensitivity of 20%. Among hypokalemic patients, the ARR value that maximized the diagnostic accuracy, as identified by the Youden index, was equal to 49.2 (ng/dL)/(ng/mL/h), and was characterized by a sensitivity and a specificity of 100% and 83%, respectively (AUC=0.941); an ARR > 104.0 (ng/dL)/(ng/mL/h) provided a 100% specificity for the diagnosis of PA, with a sensitivity of 64%. Conclusions: Among normokalemic patients, there was a wide overlap in ARR values between those with PA and those with essential RH; the possibility to skip a confirmatory test should thus be considered with caution in this setting. A better discriminating ability could be seen in the presence of hypokalemia; in this case, ARR alone may be sufficient to skip confirmatory tests in a suitable percentage of patients.

Pathophysiology and Management of Glycemic Alterations before and after Surgery for Pheochromocytoma and Paraganglioma.

Glycemic alterations are frequent in patients with pheochromocytoma and paraganglioma (PPGL), but the real incidence of secondary diabetes mellitus (DM) is uncertain, because prospective multicenter studies on this topic are lacking in the literature. The main pathophysiological mechanisms of glucose homeostasis alterations in PPGL, related to catecholamine hypersecretion, are impaired insulin and glucagon-like peptide type 1 (GLP-1) secretion and increased insulin resistance. Moreover, it has been reported that different pathways leading to glucose intolerance may be related to the secretory phenotype of the chromaffin tumor. Predictive factors for the development of glucose intolerance in PPGL patients are a higher age at diagnosis, the need for a higher number of anti-hypertensive drugs, and the presence of secreting neoplasms. Tumor resection is strongly related to the resolution of DM in PPGL patients, with a significant improvement of glycemic control in most cases. We can hypothesize a different personalized therapeutic approach based on the secretory phenotype. The adrenergic phenotype is more closely related to reduced insulin secretion, so insulin therapy may be required. On the other hand, the noradrenergic phenotype mainly acts by increasing insulin resistance and, therefore, insulin-sensitizing antidiabetic agents can find a greater application. Regarding GLP-1 receptor agonists, the data suggest a possible promising therapeutic effect, based on the assumption that GLP-1 secretion is impaired in patients with PPGL. The principal predictors of remission of glycemic alterations after surgery for PPGL are a lower preoperative body mass index (BMI), a larger tumor, higher preoperative catecholamine levels, and a shorter duration of the disease (under three years). Otherwise, after resection of PPGL, hypoglycemia can occur as the result of an excessive rebound of preoperative hyperinsulinemia. It is a rare, but potentially severe complication reported in a lot of case reports and a few small retrospective studies. Higher 24-h urinary metanephrine levels, longer operative times and larger tumors are predictive factors for hypoglycemia in this setting. In conclusion, alterations of carbohydrate metabolism are clinically relevant manifestations of PPGL before and after surgery, but there is the need to conduct multicenter prospective studies to obtain an adequate sample size, and to allow the creation of shared strategies for the clinical management of these potentially severe manifestations of PPGL.

Adipose Tissue Dysfunction in Obesity: Role of Mineralocorticoid Receptor.

The mineralocorticoid receptor (MR) acts as an essential regulator of blood pressure, volume status, and electrolyte balance. However, in recent decades, a growing body of evidence has suggested that MR may also have a role in mediating pro-inflammatory, pro-oxidative, and pro-fibrotic changes in several target organs, including the adipose tissue. The finding that MR is overexpressed in the adipose tissue of patients with obesity has led to the hypothesis that this receptor can contribute to adipokine dysregulation and low-grade chronic inflammation, alterations that are linked to the development of obesity-related metabolic and cardiovascular complications. Moreover, several studies in animal models have investigated the role of MR antagonists (MRAs) in preventing the metabolic alterations observed in obesity. In the present review we will focus on the potential mechanisms by which MR activation can contribute to adipose tissue dysfunction in obesity and on the possible beneficial effects of MRAs in this setting.

A retrospective study on the association between urine metanephrines and cardiometabolic risk in patients with nonfunctioning adrenal incidentaloma.

Several studies argued that cardiovascular evaluation of patients with nonfunctioning adrenal incidentaloma is of particular importance. Therefore, we aimed to evaluate the possibility of stratifying the cardiometabolic risk using metanephrine levels in this setting of patients. A retrospective cross-sectional study was designed, collecting data of metanephrine values in 828 patients with nonfunctioning adrenal incidentaloma, referred to our Division within the University of Turin between 2007 and 2021. The univariate analysis showed associations between urine metanephrines and cardiometabolic variables/parameters, particularly considering the noradrenaline metabolite. At the univariate regression, normetanephrine was associated with metabolic syndrome (OR = 1.13, p = 0.002), hypertensive cardiomyopathy (OR = 1.09, p = 0.026), microalbuminuria (OR = 1.14, p = 0.024), and eGFR < 60 mL/min/1.73 m2 (OR = 1.11, p = 0.013), while metanephrine was associated with microalbuminuria (OR = 1.50, p = 0.008). At multivariate regression, considering all major cardiovascular risk factors as possible confounders, normetanephrine retained a significant association with metabolic syndrome (OR = 1.10, p = 0.037). Moreover, metanephrine retained a significant association with the presence of microalbuminuria (OR = 1.66, p = 0.003). The present study showed a further role for metanephrines in the cardiovascular risk stratification of patients with nonfunctioning adrenal incidentaloma. Individuals with high levels of these indirect markers of sympathetic activity should be carefully monitored and may benefit from an aggressive treatment to reduce their additional cardiometabolic burden.

Clinical and Pathological Tools for Predicting Recurrence and/or Metastasis in Patients with Pheochromocytoma and Paraganglioma.

Pheochromocytomas and paragangliomas are endocrine tumors belonging to the family of neural crest cell-derived neoplasms. They have an extremely variable clinical course, characterized by a non-negligible percentage of relapse and/or metastasis after radical surgery. To date, there are no reliable methods to predict the metastatic potential of these neoplasms, despite several clinical, molecular, and histopathological factors that have been extensively studied in the literature as predictors of the recurrence and/or metastasis in these neoplasms with different performances and results. In this review, we aimed to discuss and analyze the most important clinical and histopathological tools for predicting recurrence risk in patients affected by pheochromocytomas or paragangliomas. Thus, we compared the main available predictive models, exploring their applications in stratifying patients' risks. In conclusion, we underlined the importance of simple and validated tools to better define disease aggressiveness and establish tailored patients' treatments and follow-ups.

From SGAP-Model to SGAP-Score: A Simplified Predictive Tool for Post-Surgical Recurrence of Pheochromocytoma.

A reliable prediction of the recurrence risk of pheochromocytoma after radical surgery would be a key element for the tailoring/personalization of post-surgical follow-up. Recently, our group developed a multivariable continuous model that quantifies this risk based on genetic, histopathological, and clinical data. The aim of the present study was to simplify this tool to a discrete score for easier clinical use. Data from our previous study were retrieved, which encompassed 177 radically operated pheochromocytoma patients; supervised regression and machine-learning techniques were used for score development. After Cox regression, the variables independently associated with recurrence were tumor size, positive genetic testing, age, and PASS. In order to derive a simpler scoring system, continuous variables were dichotomized, using > 50 mm for tumor size, ≤ 35 years for age, and ≥ 3 for PASS as cut-points. A novel prognostic score was created on an 8-point scale by assigning 1 point for tumor size > 50 mm, 3 points for positive genetic testing, 1 point for age ≤ 35 years, and 3 points for PASS ≥ 3; its predictive performance, as assessed using Somers' D, was equal to 0.577 and was significantly higher than the performance of any of the four dichotomized predictors alone. In conclusion, this simple scoring system may be of value as an easy-to-use tool to stratify recurrence risk and tailor post-surgical follow-up in radically operated pheochromocytoma patients.

Primary Aldosteronism and Resistant Hypertension: A Pathophysiological Insight.

Primary aldosteronism (PA) is a pathological condition characterized by an excessive aldosterone secretion; once thought to be rare, PA is now recognized as the most common cause of secondary hypertension. Its prevalence increases with the severity of hypertension, reaching up to 29.1% in patients with resistant hypertension (RH). Both PA and RH are "high-risk phenotypes", associated with increased cardiovascular morbidity and mortality compared to non-PA and non-RH patients. Aldosterone excess, as occurs in PA, can contribute to the development of a RH phenotype through several mechanisms. First, inappropriate aldosterone levels with respect to the hydro-electrolytic status of the individual can cause salt retention and volume expansion by inducing sodium and water reabsorption in the kidney. Moreover, a growing body of evidence has highlighted the detrimental consequences of "non-classical" effects of aldosterone in several target tissues. Aldosterone-induced vascular remodeling, sympathetic overactivity, insulin resistance, and adipose tissue dysfunction can further contribute to the worsening of arterial hypertension and to the development of drug-resistance. In addition, the pro-oxidative, pro-fibrotic, and pro-inflammatory effects of aldosterone may aggravate end-organ damage, thereby perpetuating a vicious cycle that eventually leads to a more severe hypertensive phenotype. Finally, neither the pathophysiological mechanisms mediating aldosterone-driven blood pressure rise, nor those mediating aldosterone-driven end-organ damage, are specifically blocked by standard first-line anti-hypertensive drugs, which might further account for the drug-resistant phenotype that frequently characterizes PA patients.

The Accuracy of Simple and Adjusted Aldosterone Indices for Assessing Selectivity and Lateralization of Adrenal Vein Sampling in the Diagnosis of Primary Aldosteronism Subtypes.

OBJECTIVE: This study aimed to evaluate the reliability of simple and corrected aldosterone indices for assessing the selectivity and lateralization of adrenal vein sampling (AVS) in patients with primary aldosteronism. METHODS: Data of all consecutive patients with primary aldosteronism who underwent AVS for subtype diagnosis, followed at two Italian referral centers, were analyzed retrospectively. RESULTS: AVS achieved bilateral selectivity in 112/144 patients. Unilateral disease was diagnosed in 60 cases (53.6%) and idiopathic hyperaldosteronism in 52 individuals (46.4%). The aldosterone index (aldosterone ratio between an adrenal vein and the inferior vena cava) showed a high accuracy in predicting selectivity, compared to a cortisol selectivity index of 1.1, and a moderate accuracy, compared to cortisol cut-offs of 2 and 3. The simple aldosterone index showed a moderate accuracy in predicting ipsi/contralateral aldosterone hypersecretion, while lesion side- and hypokalemia-corrected aldosterone index revealed a significant improvement in predicting ipsi/contralateral disease. Moreover, the comparative aldosterone index (aldosterone ratio in the dominant vs the non-dominant adrenal vein) revealed a high accuracy in predicting unilateral primary aldosteronism. For an immediate clinical application of our results, the adjusted cut-offs were calculated, according to the Youden's criterion and to a pre-established specificity of 90%, for all possible combinations of lesion side at imaging and presence/absence of hypokalemia. CONCLUSIONS: This study demonstrated the diagnostic accuracy of simple and clinical-/imaging-corrected aldosterone indices for adrenal vein sampling in subtype diagnosis of primary aldosteronism and suggests the potential application of these tools to select patients for adrenalectomy when standard indices cannot be performed.

Atrial Fibrillation and Aortic Ectasia as Complications of Primary Aldosteronism: Focus on Pathophysiological Aspects.

Primary aldosteronism (PA) is the most common cause of secondary hypertension. A growing body of evidence has suggested that, beyond its well-known effects on blood pressure and electrolyte balance, aldosterone excess can exert pro-inflammatory, pro-oxidant and pro-fibrotic effects on the kidney, blood vessels and heart, leading to potentially harmful pathophysiological consequences. In clinical studies, PA has been associated with an increased risk of cardiovascular, cerebrovascular, renal and metabolic complication compared to essential hypertension, including atrial fibrillation (AF) and aortic ectasia. An increased prevalence of AF in patients with PA has been demonstrated in several clinical studies. Aldosterone excess seems to be involved in the pathogenesis of AF by inducing cardiac structural and electrical remodeling that in turn predisposes to arrhythmogenicity. The association between PA and aortic ectasia is less established, but several studies have demonstrated an effect of aldosterone on aortic stiffness, vascular smooth muscle cells and media composition that, in turn, might lead to an increased risk of aortic dilation and dissection. In this review, we focus on the current evidence regarding the potential role of aldosterone excess in the pathogenesis of AF and aortic ectasia.

Association of Urine Metanephrine Levels with CardiometaBolic Risk: An Observational Retrospective Study.

No research has explored the role of catecholamine metabolites in the stratification of cardiovascular risk. We aimed to evaluate the relationship between urine metanephrines and cardiometabolic risk/complications. In this retrospective cross-sectional study, we collected the data of 1374 patients submitted to the evaluation of urine metanephrines at the City of Health and Science University Hospital of Turin between 2007 and 2015, mainly for investigating the suspicion of secondary hypertension or the secretion of an adrenal lesion. The univariate analysis showed associations between metanephrines and cardiometabolic variables/parameters, particularly considering noradrenaline metabolite. At univariate regression, normetanephrine was associated with hypertensive cardiomyopathy (OR = 1.18, 95% CI 1.11-1.25; p < 0.001) and metabolic syndrome (OR = 1.11, 95% CI 1.03-1.20; p = 0.004), while metanephrine was associated with hypertensive cardiomyopathy (OR = 1.23, 95% CI 1.06-1.43; p = 0.006) and microalbuminuria (OR = 1.30, 95% CI 1.03-1.60; p = 0.018). At multivariate regression, considering all major cardiovascular risk factors as possible confounders, normetanephrine retained a significant association with hypertensive cardiomyopathy (OR = 1.14, 95% CI 1.07-1.22; p < 0.001) and metabolic syndrome (OR = 1.10, 95% CI 1.02-1.19; p = 0.017). Moreover, metanephrine retained a significant association with the presence of hypertensive cardiomyopathy (OR = 1.18, 95% CI 1.01-1.41; p = 0.049) and microalbuminuria (OR = 1.34, 95% CI 1.03-1.69; p = 0.019). The study showed a strong relationship between metanephrines and cardiovascular complications/metabolic alterations. Individuals with high levels of these indirect markers of sympathetic activity should be carefully monitored, and they may benefit from an aggressive treatment to reduce the cardiometabolic risk.

Central pulse pressure is inversely associated with proximal aortic remodelling.

OBJECTIVES: Hypertension leads to aortic stiffening and dilatation but unexpected data from the Framingham Heart Study showed an inverse relationship between brachial pulse pressure and aortic diameter. Aortic dilatation would not only lead to lower pulse pressure but also to a worse prognosis (cardiac events, heart failure). Invasive pressure may be more informative but data are lacking. AIM: This study evaluated the relationship between invasively measured central blood pressure and proximal aortic diameter. METHODS: In 71 consecutive patients referred to invasive haemodynamic study, proximal aortic remodelling was evaluated in terms of Z-score, comparing diameters measured at the sinus of Valsalva to the diameter expected according to patients' age, sex and body height. Pressures were recorded directly in the proximal aorta by means of a catheter before coronary assessment. RESULTS: The mean invasive aortic SBPs and DBPs were 146 ±â€Š23 and 78 ±â€Š13 mmHg, respectively, giving a central pulse pressure (cPP inv) of 68 ±â€Š21 mmHg. Proximal aortic diameter was 34.9 ±â€Š19.4 mm, whereas Z-score was -0.3 ±â€Š1.7. Patients with higher cPPinv showed a significantly lower Z-score (-0.789 vs. 0.155, P = 0.001). cPPinv was inversely related to Z-score (R = -0.271, P = 0.022) independently from age, mean blood pressure and heart rate (ß = -0.241, P = 0.011). CONCLUSION: Aortic root Z-score is inversely associated with invasively measured central pulse pressure in a cohort of patients undergoing invasive coronary assessment. Remodelling at the sinuses of Valsalva may be a compensatory mechanism to limit pulse pressure.

The diagnostic accuracy of adjusted unconventional indices for adrenal vein sampling in the diagnosis of primary aldosteronism subtypes.

OBJECTIVE: Simple unconventional indices did not demonstrate a satisfactory accuracy for diagnosing unilateral primary aldosteronism when adrenal vein sampling is not bilaterally selective. This study aimed to evaluate the reliability of clinical/imaging-corrected unconventional indices for adrenal vein sampling in predicting unilateral primary aldosteronism. METHODS: Data of all consecutive patients with primary aldosteronism subtyped with adrenal vein sampling, referred to two Italian centers, were analyzed retrospectively. All patients with proved unilateral aldosterone hypersecretion underwent adrenalectomy. RESULTS: Unilateral disease was diagnosed in 58 cases (54.2%) and idiopathic hyperaldosteronism in 49 individuals (45.8%). The monoadrenal index (aldosterone-to-cortisol ratio in the adrenal vein) showed high accuracy in predicting ipsilateral disease and moderate accuracy in predicting contralateral aldosterone hypersecretion. The monolateral index (aldosterone-to-cortisol ratio in the adrenal vein vs. peripheral blood) revealed moderate accuracy in predicting ipsilateral disease and high accuracy in predicting contralateral aldosterone hypersecretion. Lesion side- and hypokalemia-corrected ROC curves for these unconventional indices revealed a significant improvement in the reliability of predicting ipsilateral/contralateral disease, reaching high accuracy in all models. For an immediate clinical application of our results, the adjusted cut-offs were calculated, according to the Youden's criterion and to a pre-established specificity of 95%, for all possible combinations of lesion side at imaging and presence/absence of hypokalemia. CONCLUSION: This study demonstrated the high diagnostic accuracy of clinical-/imaging-corrected unconventional indices for adrenal vein sampling in the diagnosis of primary aldosteronism subtypes and suggests the use of these adjusted indices to select patients for adrenalectomy when adrenal vein sampling is not bilaterally selective.

Multiscale mathematical modeling vs. the generalized transfer function approach for aortic pressure estimation: a comparison with invasive data.

We aimed to evaluate the performance of a mathematical model and currently available non-invasive techniques (generalized transfer function (GTF) method and brachial pressure) in the estimation of aortic pressure. We also aimed to investigate error dependence on brachial pressure errors, aorta-to-brachial pressure changes and demographic/clinical conditions. Sixty-two patients referred for invasive hemodynamic evaluation were consecutively recruited. Simultaneously, the registration of the aortic pressure using a fluid-filled catheter, brachial pressure and radial tonometric waveform was recorded. Accordingly, the GTF device and mathematical model were set. Radial invasive pressure was recorded soon after aortic measurement. The average invasive aortic pressure was 141.3 ± 20.2/76 ± 12.2 mm Hg. The simultaneous brachial pressure was 144 ± 17.8/81.5 ± 11.7 mm Hg. The GTF-based and model-based aortic pressure estimates were 133.1 ± 17.3/82.4 ± 12 and 137 ± 21.6/72.2 ± 16.7 mm Hg, respectively. The Bland-Altman plots showed a marked tendency to pressure overestimation for increasing absolute values, with the exclusion of mathematical model diastolic estimations. The systolic pressure was increased from the aortic to radial locations (7.5 ± 19 mm Hg), while the diastolic pressure was decreased (3.8 ± 9.8 mm Hg). The brachial pressure underestimated the systolic and overestimated diastolic intra-arterial radial pressure. GTF errors were independently correlated with the variability in pulse pressure amplification and with the brachial error. Errors of the mathematical model were related to only demographic and clinical conditions. Neither a multiscale mathematical model nor a generalized transfer function device substantially outperformed the oscillometric brachial pressure in the estimation of aortic pressure. Mathematical modeling should be improved by including further patient-specific conditions, while the variability in pulse pressure amplification may hamper the performance of the GTF method in patients at the risk of coronary artery disease.