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The role of a dysregulated renin-angiotensin system (RAS) in the pathogenesis of COVID-19 is well recognized. The imbalance between angiotensin II (Ang II) and Angiotensin 1-7 (Ang 1,7) caused by the interaction between SARS-CoV-2 and the angiotensin converting enzyme 2 (ACE 2) receptors exerts a pivotal role on the clinical picture and outcome of COVID-19. ACE 2 receptors are not the exclusive angiotensinases in nature. Other angiotensinases (PRCP, and POP) have the potential to limit the detrimental effects of the interactions between ACE 2 and the Spike proteins. In the cardiovascular disease continuum, ACE 2 activity tends to decrease, and POP/PRCP activity to increase, from the health status to advanced deterioration of the cardiovascular system. The failure of the counter-regulatory RAS axis during the acute phase of COVID-19 is characterized by a decrease of ACE 2 expression coupled to unchanged activity of other angiotensinases, therefore failing to limit the accumulation of Ang II. COVID-19 vaccines increase the endogenous synthesis of SARS-CoV-2 spike proteins. Once synthetized, the free-floating spike proteins circulate in the blood, interact with ACE 2 receptors and resemble the pathological features of SARS-CoV-2 ("Spike effect" of COVID-19 vaccines). It has been noted that an increased catalytic activity of POP/PRCP is typical in elderly individuals with comorbidities or previous cardiovascular events, but not in younger people. Thus, the adverse reactions to COVID-19 vaccination associated with Ang II accumulation are generally more common in younger and healthy subjects. Understanding the relationships between different mechanisms of Ang II cleavage and accumulation offers the opportunity to close the pathophysiological loop between the risk of progression to severe forms of COVID-19 and the potential adverse events of vaccination. [ABSTRACT FROM AUTHOR]

Hypertension is one of the most common chronic diseases in adults and a leading cause of disability and mortality worldwide. Recently, new Guidelines for the diagnosis and management of hypertension have been released in Europe and in the United States, with changes regarding how to diagnose and treat the condition, and the extent to which intensive blood pressure control should be pursued. Important differences between the Guidelines exist in the classification of blood pressure levels and definition of treatment goals. Diagnosis of hypertension starts at 140/90 mmHg for the European Guidelines, and 130/80 mmHg for the US Guidelines. Besides, the European guidelines introduced the concept of "safety boundaries", consisting of BP thresholds not to be exceeded towards lower levels (120 mmHg for age < 65 years, 130 mmHg for older people) because of the fear of important adverse events associated with overtreatment. Such discrepancies can indeed have an impact on treatment attitudes and outcome incidence. Hence, we appraised facts in favor and against each of these controversial issues. In conclusion we believe that, instead of fixing rigid BP targets and boundaries, modern hypertension management should be aimed to achieve in each patient an optimal balance between intensive BP reduction and treatment safety. • New Guidelines have been recently released from Europe and North America. • Main differences: categorization of hypertension, BP targets, and safety boundaries. • The US Guidelines lowered the threshold for hypertension to 130/80 mmHg. • The US Guidelines recommend a systolic BP target<130 mmHg in almost all patients. • Safety boundaries may induce to refrain from achieving ambitious BP targets. [ABSTRACT FROM AUTHOR]

• SARS-CoV-2 infection promotes the failure of the counter-regulatory RAS axis. • The failure of RAS is mediated by the binding of the spike protein of the virus with ACE2 (causing malfunction of these receptors). • The consequent accumulation of Ang II can directly contribute to development of high BP in the acute phase of infection. • Accrued data suggest that acute rise in BP is an independent predictor of bad outcome in COVID-19 patients. • A similar mechanism has been postulated to explain the rise in BP following COVID-19 vaccination ("Spike Effect"). Among the various comorbidities potentially worsening the clinical outcome in patients hospitalized for the acute respiratory syndrome coronavirus-2 (SARS-CoV-2), hypertension is one of the most prevalent. However, the basic mechanisms underlying the development of severe forms of coronavirus disease 2019 (COVID-19) among hypertensive patients remain undefined and the direct association of hypertension with outcome in COVID-19 is still a field of debate. Experimental and clinical data suggest that SARS-CoV-2 infection promotes a rise in blood pressure (BP) during the acute phase of infection. Acute increase in BP and high in-hospital BP variability may be tied with acute organ damage and a worse outcome in patients hospitalized for COVID-19. In this context, the failure of the counter-regulatory renin-angiotensin-system (RAS) axis is a potentially relevant mechanism involved in the raise in BP. It is well recognized that the efficient binding of the Spike (S) protein to angiotensin converting enzyme 2 (ACE2) receptors mediates the virus entry into cells. Internalization of ACE2, downregulation and malfunction predominantly due to viral occupation, dysregulates the protective RAS axis with increased generation and activity of angiotensin (Ang) II and reduced formation of Ang 1,7. Thus, the imbalance between Ang II and Ang 1–7 can directly contribute to excessively rise BP in the acute phase of SARS-CoV-2 infection. A similar mechanism has been postulated to explain the raise in BP following COVID-19 vaccination ("Spike Effect" similar to that observed during the infection of SARS-CoV-2). S proteins produced upon vaccination have the native-like mimicry of SARS-CoV-2 S protein's receptor binding functionality and prefusion structure and free-floating S proteins released by the destroyed cells previously targeted by vaccines may interact with ACE2 of other cells, thereby promoting ACE2 internalization and degradation, and loss of ACE2 activities. [Display omitted] [ABSTRACT FROM AUTHOR]