Design of a study to investigate the mechanisms of obstructive sleep apnoea by means of drug-induced sleep endoscopy

Background Obstructive sleep apnoea (OSA) is an independent risk factor of hypertension and cardiovascular diseases. Recurrent episodes of upper airways collapse during sleep causing blood oxygen desaturation, hypercapnia, and micro-arousals, are known to activate the sympathetic nervous system (SNS). However, whether changes in the renin-angiotensin-aldosterone system and endothelial activation also occur remains contentious. Methods Based on routine use of drug-induced sleep endoscopy (DISE) for the work-up of OSA patients in our centre, we designed a prospective study to investigate the haemodynamic and humoral changes occurring during the apnoeic episodes reproduced in vivo in the course of DISE. Specifically, plasma aldosterone concentration and renin activity, C-terminal fragment of proendothelin-1, as a marker of endothelial damage, and free plasma catecholamines, will be measured at fixed times during DISE. The activity of catechol-O-methyltransferase (COMT), a key catecholamine-inactivating enzyme that has been scantly investigated thus far owing to the lack of commercially available kits, will be also determined by a newly developed high performance liquid chromatography method, which is herein described. Results and conclusions The aim of this study is to provide novel information on the haemodynamic, hormonal, and SNS changes, and also on COMT activity modification concomitantly occurring during apnoea, thus contributing substantively to the understanding of the pathophysiology of OSA

High sodium intake, glomerular hyperfiltration and protein catabolism in patients with essential hypertension

Aims: A blood pressure-independent metabolic shift toward a catabolic state upon high sodium (Na+) diet, ultimately favouring body fluid preservation, has recently been described in pre-clinical controlled settings. We sought to investigate the real-life impact of high Na+ intake on measures of renal Na+/water handling and metabolic signatures, as surrogates for cardiovascular risk, in hypertensive patients. Methods and results: We analysed clinical and biochemical data from 766 consecutive patients with essential hypertension, collected at the time of screening for secondary causes. The systematic screening protocol included 24h urine collection on usual diet and avoidance of renin-angiotensin-aldosterone system-confounding medications. Urinary 24h-Na+ excretion, used to define classes of Na+ intake (Low ≤2.3g/d; Medium 2.3-5g/d; High >5g/d), was an independent predictor of glomerular filtration rate after correction for age, sex, blood pressure, BMI, aldosterone and potassium excretion (p = 0.001; Low: 94.1 [69.9-118.8] vs High: 127.5 [108.3-147.8] ml/min/1.73m2). Renal Na+ and water handling diverged, with higher fractional excretion of Na+ and lower fractional excretion of water in those with evidence of High Na+ intake (FENa: Low 0.39% [0.30-0.47] vs. High 0.81% [0.73-0.98], p < 0.001; FEwater: Low 1.13% [0.73-1.72] vs. High 0.89% [0.69-1.12], p = 0.015). Despite higher FENa, these patients showed higher absolute 24h Na+ reabsorption and higher associated tubular energy expenditure, estimated by tubular Na+/ATP stoichiometry, accordingly (ΔHigh-Low = 18 [12-24] kcal/d, p < 0.001). At non-targeted LC/MS plasma metabolomics in an unselected subcohort (n = 67), metabolites which were more abundant in High vs. Low Na+ intake (p < 0.05) mostly entailed intermediates or end products of protein catabolism/urea cycle. Conclusions: When exposed to high Na+ intake, kidneys dissociate Na+ and water handling. In hypertensive patients, this comes at the cost of higher glomerular filtration rate, increased tubular energy expenditure and protein catabolism from endogenous (muscle) or excess exogenous (dietary) sources. Glomerular hyperfiltration and the metabolic shift may have broad implications on global cardiovascular risk independent of blood pressure

Right adrenal adenoma on axial CT-scan .pdf

Figure showing an axial CT-scan of a 50-year-old woman affected by resistent hypertension at the level of L1 with an adrenal adenoma on the right adrenal gland (<i>white arrow</i>)

Eryptosis in Peritoneal Dialysis-Related Peritonitis: The Potential Role of Inflammation in Mediating the Increase in Eryptosis in PD

Background: Peritonitis and exit site infections are the main complications of patients treated with peritoneal dialysis (PD). Erythrocytes (red blood cells—RBCs) are very sensitive cells, and they are characterized by eryptosis (programmed cell death). The purpose of this research was to assess eryptosis in PD patients with PD-related peritonitis and its connection to inflammatory markers in vivo and in vitro. Material and Methods: In this study, we included 65 PD patients: 34 PD patients without systemic inflammation nor PD-related peritonitis in the previous 3 months, and 31 PD patients with an acute episode of PD-related peritonitis. We measured C-reactive protein (CRP) and cytokine (IL-1β, IL-6, and IL-18) levels as systemic inflammatory markers. Eryptosis was evaluated by flow cytometric analyses in freshly isolated RBCs. The induction of eryptosis due to in vitro exposure to IL-1β, IL-6, and IL-18 was verified. Results: Eryptosis was significantly higher in PD patients with peritonitis (9.6%; IQR 4.2–16.7), compared to the those in the other group (2.7%; IQR 1.6–3.9) (p p p < 0.05). Conclusion: In conclusion, we investigated a potential relationship between systemic eryptosis and the in vivo and in vitro inflammatory damage of the peritoneal membrane during peritonitis. Thus, the presented results revealed that upregulated inflammatory markers and immune system dysregulation could be the cause of high levels of systemic eryptosis during PD-related peritonitis

PTH Modulation by Aldosterone and Angiotensin II is Blunted in Hyperaldosteronism and Rescued by Adrenalectomy

CONTEXT: Accumulating evidence suggests a link between adrenocortical zona glomerulosa and parathyroid gland through mechanisms that remain unexplored. OBJECTIVES: To test the hypothesis that in vivo angiotensin II blockade affects PTH secretion in patients with hypertension and that aldosterone and angiotensim II directly stimulate PTH secretion ex vivo. DESIGN AND SETTING: We investigated the changes of serum PTH levels induced by oral captopril (50 mg) administration in patients with primary essential hypertension (EH) and with primary aldosteronism (PA) caused by bilateral adrenal hyperplasia (BAH) or aldosterone-producing adenoma (APA), the latter before and after adrenalectomy. We also exposed primary cultures of human parathyroid cells from patients with primary hyperparathyroidism to angiotensin II (10-7 M) and/or aldosterone (10-7 M). RESULTS: Captopril lowered PTH levels (in nanograms per liter) both in patients with EH (n = 63; 25.9 \ub1 8.3 baseline vs 24.4 \ub1 8.0 postcaptopril, P < 0.0001) and in patients with APA after adrenalectomy (n = 27; 26.3 \ub1 11.6 vs 24.0 \ub1 9.7 P = 0.021). However, it was ineffective in patients with full-blown PA caused by APA and BAH. In primary culture of human parathyroid cells, both aldosterone (P < 0.001) and angiotensin II (P = 0.002) markedly increased PTH secretion from baseline, by acting through mineralocorticoid receptor and angiotensin type 1 receptor, as these effects were abolished by canrenone and irbesartan, respectively. CONCLUSION: These results collectively suggest an implication of the renin-angiotensin-aldosterone system in PTH regulation in humans, at least in PTH-secreting cells obtained from parathyroid tumors. Moreover, they further support the concept that mild hyperparathyroidism is a feature of human PA that is correctable with adrenalectomy

Resolution of Drug-Resistant Hypertension by Adrenal Vein Sampling-guided Adrenalectomy: A Proof-of-Concept Study

Drug-resistant hypertension (RH) is a very high-risk condition involving many hypertensive patients, in whom primary aldosteronism (PA) is commonly overlooked. Hence, we aimed at determining if 1) adrenal vein sampling (AVS) can identify PA in RH patients, who are challenging because receiving multiple interfering drugs; 2) AVS-guided adrenalectomy can resolve high blood pressure resistance to treatment in these patients. Based on a pilot study we selected from 1016 consecutive patients referred to our Centre for "difficult-to-treat" hypertension those with RH, for an observational prospective cohort study. \ua0We excluded those non-adherent to treatment (by therapeutic drug monitoring) and those with pseudo-RH (by 24h blood pressure monitoring), which left 110 patients who met the ESC/ESH 2013 definition for RH. \ua0Of these patients, 77 were submitted to AVS, which showed unilateral PA in 27 (mean age 55 years; male/female 19/8).\ua0 Therefore, these patients underwent AVS-guided laparoscopic unilateral adrenalectomy, which resolved RH in all: 20% were clinically cured in that they no longer needed any antihypertensive treatment; 96% were biochemically cured. \ua0Systolic and diastolic blood pressure fell from 165/100\ub126/14 mmHg at baseline, to 132/84\ub114/9 mmHg at 6 months after surgery (p<10-4for both) notwithstanding the fall of number and defined daily dose of antihypertensive drugs required to achieve blood pressure control (p <10-4 for both). \ua0A prominent regression of cardiac and renal damage was also observed. Thus, this study shows the feasibility of identifying PA by AVS in RH patients, and of resolving high blood pressure resistance to treatment in these patients by AVS-guided adrenalectomy

A sleep apnoea questionnaire predicts organ damage in hypertensive patients

Background: Arterial hypertension is associated with obstructive sleep apnoea, poor quality and duration of sleep, which might contribute to hypertension-mediated organ damage. Methods: We investigated the presence of insomnia, restless legs syndrome, and obstructive sleep apnoea using validated questionnaires (Insomnia Severity Index, Restless Legs Syndrome Rating Scale, and STOP-Bang), and their relationship with hypertension-mediated organ damage, in hypertensive patients. Results: In 159 consecutive consenting hypertensive patients [age 47(11) years, median and (interquartile range), body mass index 25.5(5.9) kg/m 2 , office systolic and diastolic blood pressure 144(23)/92(12) mmHg], the STOP-Bang, but not the other scores, predicted cardiac remodelling: compared to patients with a STOP-Bang score &lt; 3, those at high risk of obstructive sleep apnoea showed higher left ventricular mass index [49.8(11.9) vs. 43.3(11.9) g/m 2.7 , p &lt; 0.0001], left atrium volume [25.7(2.5) vs. 25.0(2.8) ml/m 2 , p = 0.003], and aortic root diameter [33.6(3.0) vs. 33.0(3.7) mm, p &lt; 0.0001]. They did not differ for microalbuminuria and estimated glomerular filtration rate. At multivariate analysis, after adjustment for office systolic blood pressure values, the STOP-Bang score remained a predictor of left ventricular mass index; while the Insomnia Severity Index and restless legs syndrome risk score had no predictive value. However, a significant interaction between STOP-Bang and Restless Legs Syndrome Rating Scale scores in determining left ventricular remodelling was found. Conclusions: In consecutive hypertensive stage I patients the STOP-Bang questionnaire allowed identification of a high-risk cohort featuring a more prominent cardiac damage. Hence, this inexpensive tool can be useful for risk stratification purposes in municipalities with limited access to health care resources