A dysregulation of the renin-angiotensin-system (RAS) has been involved in the genesis of lung injury and acute respiratory distress syndrome (ARDS) from different causes, including several viral infections. The severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection of pneumocytes, the hallmark of the pandemic coronavirus disease 2019 (COVID-19) involving both alveolar interstitium and capillaries, is linked to angiotensin-converting-enzyme 2 (ACE2) binding and its functional downregulation. ACE2 is a key enzyme for the balance between the two main arms of the RAS: the ACE/Angiotensin (Ang) II/Ang II type 1 receptor axis ("classic RAS"), and the ACE2/Ang 1-7/MasR axis ("anti-RAS"). The ACE2 downregulation, as a result of SARS-coronaviruses binding, enhances the "classic RAS", leading to lung damage and inflammation with leaky pulmonary blood vessels and fibrosis, when the attenuation mediated by the "anti-RAS" arm is reduced. ACE inhibitors (ACE-I) and Ang II type 1 receptor blockers (ARB), effective in cardiovascular diseases, were found to prevent and counteract acute lung injury in several experimental models, by restoring the balance between these two opposing arms. The evidence of RAS arms disequilibrium in COVID-19 and the hypothesis of a beneficial role of RAS modulation supported by preclinical and clinical studies are the focus of the present review. Preclinical and clinical studies on drugs balancing RAS arms might be the right way to counter COVID-19.

Introduction: We evaluated the prevalence and control of dyslipidemia in a wide sample of patients referred to our ESH ''Hypertension Excellence Centre'' for high blood pressure (BP). Furthermore, we evaluated the role of adiposity on the serum lipid profile. Methods: Observational study on 1219 consecutive outpatients with valid ambulatory BP monitoring (ABPM) referred for high BP. Patients with body mass index (BMI) C 25 kg/m 2 were defined as overweight/obese (OW/OB). Dyslipidemia and the control rates of low-density lipoprotein cholesterol (LDLc) were defined according to the 2016 ESC/EAS Guidelines. Results: Mean age: 56.5 ± 13.7 years. Male prevalence: 55.6%. OW/OB patients were 70.2%. The prevalence of dyslipidemia was 91.1%. Lipidlowering drugs were taken by 23.1% of patients. Patients with controlled LDLc comprised 28.5%, while BP was controlled in 41.6% of patients. Only 12.4% of patients had both 24-h BP and LDLc controlled at the same time. The higher the cardiovascular (CV) risk was, the lower was the rate of LDLc control (p \ 0.001). Patients in secondary prevention had worse LDLc control than patients in primary prevention (OR 3.5 for uncontrolled LDLc, p \ 0.001). OW/OB showed a more atherogenic lipid profile, characterized by lower highdensity lipoprotein cholesterol (HDLc) (p \ 0.001), higher non-HDLc (p = 0.006), higher triglycerides (p \ 0.001), higher non-HDLc/HDLc (p \ 0.001) and higher (non-HDLc ? non-LDLc) (p \ 0.001). Conclusion: Dyslipidemia is still too often neglected in hypertensives, especially in patients at higher CV risk. OW/OB hypertensives have a ''double-trouble'' atherogenic lipid pattern likely driven by adiposity. We encourage a comprehensive evaluation of the lipid profile in all hypertensives, especially if they are OW/OB, to correctly assess their CV risk and improve their management. Funding: Article processing charges funded by Servier SpA.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to and degrades the low-density lipoprotein receptor (LDLR), contributing to hypercholesterolemia. Adipose tissue plays a role in lipoprotein metabolism, but there are almost no data about PCSK9 and LDLR regulation in human adipocytes. We studied PCSK9 and LDLR regulation by insulin, atrial natriuretic peptide (ANP, a potent lipolytic agonist that antagonizes insulin), and LDL in visceral adipose tissue (VAT) and in human cultured adipocytes. PCSK9 was expressed in VAT and its expression was positively correlated with body mass index (BMI). Both intracellular mature and secreted PCSK9 were abundant in cultured human adipocytes. Insulin induced PCSK9, LDLR, and sterol-regulatory element-binding protein-1c (SREBP-1c) and -2 expression (SREBP-2). ANP reduced insulin-induced PCSK9, especially in the context of a medium simulating hyperglycemia. Human LDL induced both mature and secreted PCSK9 and reduced LDLR. ANP indirectly blocked the LDLR degradation, reducing the positive effect of LDL on PCSK9. In conclusion, PCSK9 is expressed in human adipocytes. When the expression of PCSK9 is induced, LDLR is reduced through the PCSK9-mediated degradation. On the contrary, when the induction of PCSK9 by insulin and LDL is partially blocked by ANP, the LDLR degradation is reduced. This suggests that NPs could be able to control LDLR levels, preventing PCSK9 overexpression.

Objective: Statin therapy was associated with lower blood pressure (BP) in some but not all studies. We evaluated the association between statin therapy and ambulatory BP in a large hypertensive population using ‘propensity score matching’. Methods: Retrospective observational study on 1827 consecutive essential hypertensive patients evaluated with 24-h ambulatory BP monitoring. Antihypertensive treatment intensity (ATI) was calculated to compare different drug associations. We used a propensity score matching to compare two equally-sized cohorts of patients with similar characteristics according to statin therapy. Matching was performed on log-transformed propensity score in a 1 : 1 fashion with a caliper of 0.1, in order to account for the different baseline characteristics between statin and no-statin group. Results: Mean age: 58.1 ± 13.8 years; male sex: 55%. Patients on statin therapy: 402 (22%). These patients showed lower 24-h BP (−2.8/−7.1 mmHg), daytime (−3.3/−7.6 mmHg) and night-time BP (−2.5/−6.0 mmHg, all P < 0.001). They also showed better ambulatory BP control, even after adjustment for confounding factors. The analyses on the groups derived from the ‘propensity score matching’ (369 patients in each group) confirmed these results (OR 1.8 for 24-h BP control; OR = 1.6 for daytime BP control; OR = 1.7 for night-time BP control, all P < 0.001). Conclusion: Statin therapy is associated with better ambulatory BP control in essential hypertensive patients. This result is not affected by the intensity of the antihypertensive treatment or by the several cofactors analyzed.

Since the publication of the RECOVERY trial, the use of glucocorticoid drugs (GC) has spread for the treatment of severe COVID-19 worldwide. However, the benefit of dexamethasone was largest in patients who received mechanical ventilation or supplemental oxygen therapy, while no benefit was found among patients without hypoxemia. In addition, a positive outcome was found in patients who received dexamethasone after several days of symptoms, while possible harm could exist if administered early. The right time interval for GC administration is still a matter of debate. Previous studies showed that an early GC use during the first phase of the disease, when viral replication peaks, may negatively affect the innate immune response through several mechanisms, such as the inhibition of pro-inflammatory and antiviral cytokine production and signaling pathway, including type I interferon, that is fundamental to counteract the virus and that was found to be impaired in several patients with life-threatening COVID-19. The GC misuse can lead to a more severe disease even in patients who do not have the established risk factors, such as obesity and cardiovascular diseases. In our focused review, we describe the role of immune response in viral infections, especially SARS-CoV-2, and discuss the potential harms of GC misuse in COVID-19.

Italy). Reported muscle symptoms during statin treatment amongst Italian dyslipidaemic patients in the real-life setting: the PROSISA Study (Original).

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Sodium-glucose co-transporter-2 inhibitors (SGLT2i) have been proven to lead to relevant cardiovascular benefits, regardless of glycemic control function. SGLT2i have on the one hand led to reduction in cardiovascular events such as heart failure and on the other hand to renal protection. Blood pressure reduction and kidney function play a central role in these outcomes. This focused review describes the main mechanisms and clinical aspects of SGLT2i. Data synthesis: These drugs act on the proximal renal tubule and behave as diuretics with a "hybrid" mechanism, as they can favour both natriuresis and enhanced diuresis due to an osmotic effect dependent on glycosuria, resulting in blood pressure decrease. The exclusive peculiarity of these "diuretics", which distinguishes them from loop and thiazide diuretics, lies also in the activation of the tubule-glomerular feedback. Conclusions: This mechanism, resulting in modulation of arterioles' tone and renin secretion, contributes to the favorable outcomes, suggesting a wider use of SGLT2i in internal medicine, nephrology and cardiology.