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The spike effect of acute respiratory syndrome coronavirus 2 and coronavirus disease 2019 vaccines on blood pressure

  • Fabio Angeli
    Correspondence
    Corresponding author at: Department of Medicine and Surgery, University of Insubria, Department of Medicine and Cardiopulmonary Rehabilitation, Istituti Clinici Scientifici Maugeri, IRCCS Tradate, Varese, Italy.
    Affiliations
    Department of Medicine and Surgery, University of Insubria, Varese, 21100, Italy

    Department of Medicine and Cardiopulmonary Rehabilitation, Maugeri Care and Research Institute, IRCCS Tradate, 21049, Italy
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  • Martina Zappa
    Affiliations
    Department of Medicine and Surgery, University of Insubria, Varese, 21100, Italy
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  • Gianpaolo Reboldi
    Affiliations
    Department of Medicine, and Centro di Ricerca Clinica e Traslazionale (CERICLET), University of Perugia, Perugia, 06100, Italy
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  • Giorgio Gentile
    Affiliations
    College of Medicine and Health. University of Exeter, Exeter, United Kingdom and Department of Nephrology, Royal Cornwall Hospitals NHS Trust, Truro, United Kingdom
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  • Monica Trapasso
    Affiliations
    Dipartimento di Igiene e Prevenzione Sanitaria, PSAL, Sede Territoriale di Varese, ATS Insubria, Varese, 21100, Italy
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  • Antonio Spanevello
    Affiliations
    Department of Medicine and Surgery, University of Insubria, Varese, 21100, Italy

    Department of Medicine and Cardiopulmonary Rehabilitation, Maugeri Care and Research Institute, IRCCS Tradate, 21049, Italy
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  • Paolo Verdecchia
    Affiliations
    Division of Cardiology, Hospital S. Maria della Misericordia, Perugia, and Fondazione Umbra Cuore e Ipertensione-ONLUS, Perugia, 06100, Italy
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Published:December 12, 2022DOI:https://doi.org/10.1016/j.ejim.2022.12.004

      Highlights

      • 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”).

      Abstract

      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 Ang1,7. Thus, the imbalance between Ang II and Ang1–7 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.

      Graphical abstract

      Keywords

      1. Introduction

      Data accrued over the last 2 years reported that specific comorbidities are associated with increased risk of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection and worse outcomes with development of increased severity of lung injury and mortality [

      Wu C., Chen X., Cai Y., Xia J., Zhou X., Xu S., et al. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 Pneumonia in Wuhan, China. JAMA Intern Med. 2020 180:934–43. 10.1001/jamainternmed.2020.0994.

      ,
      • Huang C.
      • Wang Y.
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      • Ren L.
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      Clinical features of patients infected with 2019 novel coronavirus in Wuhan.
      ,
      • Schiffrin E.L.
      • Flack J.M.
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      Hypertension and COVID-19.
      ,

      Fitero A., Bungau S.G., Tit D.M., Endres L., Khan S.A., Bungau A.F. et al. Comorbidities, associated diseases, and risk assessment in COVID-19-A Systematic Review. Int J Clin Pract. 2022, 2022:1571826. 10.1155/2022/1571826.

      ,
      • Justino D.C.P.
      • Silva D.F.O.
      • Costa K.
      • de Morais T.N.B.
      • de Andrade F.B.
      Prevalence of comorbidities in deceased patients with COVID-19: a systematic review.
      ].
      The most frequent comorbidity in patients with coronavirus disease 2019 (COVID-19) is hypertension [

      Wu C., Chen X., Cai Y., Xia J., Zhou X., Xu S., et al. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 Pneumonia in Wuhan, China. JAMA Intern Med. 2020 180:934–43. 10.1001/jamainternmed.2020.0994.

      ,
      • Huang C.
      • Wang Y.
      • Li X.
      • Ren L.
      • Zhao J.
      • Hu Y.
      • et al.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan.
      ,
      • Schiffrin E.L.
      • Flack J.M.
      • Ito S.
      • Muntner P.
      • Webb R.C.
      Hypertension and COVID-19.
      ]. Despite some reports seem to support the notion that hypertension represents a risk factor for susceptibility to SARS-CoV-2 infection, a more severe course of COVID-19, and increased COVID-19-related deaths [
      • Grasselli G.
      • Zangrillo A.
      • Zanella A.
      • Antonelli M.
      • Cabrini L.
      • Castelli A.
      • et al.
      Baseline Characteristics and Outcomes of 1591 Patients Infected With SARS-CoV-2 Admitted to ICUs of the Lombardy Region.
      ,
      • Wang D.
      • Hu B.
      • Hu C.
      • Zhu F.
      • Liu X.
      • Zhang J.
      • et al.
      Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China.
      ,
      • Richardson S.
      • Hirsch J.S.
      • Narasimhan M.
      • Crawford J.M.
      • McGinn T.
      • Davidson K.W.
      • et al.
      Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area.
      ,
      • Angeli F.
      • Spanevello A.
      • De Ponti R.
      • Visca D.
      • Marazzato J.
      • Palmiotto G.
      • et al.
      Electrocardiographic features of patients with COVID-19 pneumonia.
      ,
      • Angeli F.
      • Verdecchia P.
      • Reboldi G.
      RAAS Inhibitors and Risk of Covid-19.
      ,
      • Gallo G.
      • Calvez V.
      • Savoia C.
      Hypertension and COVID-19: current Evidence and Perspectives.
      ,
      • Angeli F.
      • Masnaghetti S.
      • Visca D.
      • Rossoni A.
      • Taddeo S.
      • Biagini F.
      • et al.
      Severity of COVID-19: the importance of being hypertensive.
      ,
      • Angeli F.
      • Reboldi G.
      • Spanevello A.
      • De Ponti R.
      • Visca D.
      • Marazzato J.
      • et al.
      Electrocardiographic features of patients with COVID-19: one year of unexpected manifestations.
      ], the exact mechanisms explaining the development of severe forms of COVID-19 among hypertensive patients remain undefined.
      Recent investigations demonstrated that SARS-CoV-2 infection may promote a significant rise in blood pressure (BP) during the acute phase of infection [
      • Ran J.
      • Song Y.
      • Zhuang Z.
      • Han L.
      • Zhao S.
      • Cao P.
      • et al.
      Blood pressure control and adverse outcomes of COVID-19 infection in patients with concomitant hypertension in Wuhan, China.
      ,
      • Saeed S.
      • Tadic M.
      • Larsen T.H.
      • Grassi G.
      • Mancia G.
      Coronavirus disease 2019 and cardiovascular complications: focused clinical review.
      ,
      • Angeli F.
      • Verdecchia P.
      • Reboldi G.
      Pharmacotherapy for hypertensive urgency and emergency in COVID-19 patients.
      ,
      • Angeli F.
      • Zappa M.
      • Oliva F.M.
      • Spanevello A.
      • Verdecchia P.
      Blood pressure increase during hospitalization for COVID-19.
      ] and that in-hospital acute increase of BP and the development of high BP variability might be associated with acute organ failure and unfavorable outcome in patients with COVID-19 [
      • Angeli F.
      • Verdecchia P.
      • Reboldi G.
      Pharmacotherapy for hypertensive urgency and emergency in COVID-19 patients.
      ].
      More recently, reports on safety of COVID-19 vaccines included a significant rise in BP following vaccination as potential adverse reaction [
      • Angeli F.
      • Reboldi G.
      • Trapasso M.
      • Verdecchia P.
      [Hypertension after COVID-19 vaccination].
      ,
      • Angeli F.
      • Reboldi G.
      • Trapasso M.
      • Zappa M.
      • Spanevello A.
      • Verdecchia P.
      COVID-19, vaccines and deficiency of ACE2 and other angiotensinases.
      ,
      • Angeli F.
      • Spanevello A.
      • Reboldi G.
      • Visca D.
      • Verdecchia P.
      SARS-CoV-2 vaccines: lights and shadows.
      ]. In this context, some investigations argued a specific effect of COVID-19 vaccines on the renin-angiotensin system (RAS) as mediated by the interaction between free floating Spike (S) proteins produced upon vaccination and angiotensin (Ang) converting enzyme 2 (ACE2) receptors (the “Spike effect) [
      • Angeli F.
      • Reboldi G.
      • Trapasso M.
      • Verdecchia P.
      [Hypertension after COVID-19 vaccination].
      ,
      • Angeli F.
      • Spanevello A.
      • Reboldi G.
      • Visca D.
      • Verdecchia P.
      SARS-CoV-2 vaccines: lights and shadows.
      ,
      • Angeli F.
      • Reboldi G.
      • Trapasso M.
      • Santilli G.
      • Zappa M.
      • Verdecchia P.
      Blood Pressure Increase following COVID-19 Vaccination: a Systematic Overview and Meta-Analysis.
      ].
      The main aim of our narrative review was to summarize available evidences on the effect of SARS-CoV-2 infection and COVID-19 vaccines on BP. For this purpose, we identified clinical and experimental studies according to established methods [
      • Haynes R.B.
      • Kastner M.
      • Wilczynski N.L.
      • Hedges T.
      Developing optimal search strategies for detecting clinically sound and relevant causation studies in EMBASE.
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      • McAuley L.
      • Pham B.
      • Tugwell P.
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      Does the inclusion of grey literature influence estimates of intervention effectiveness reported in meta-analyses?.
      ]. Literature searches were conducted using Google Scholar, Scopus, PubMed, EMBASE, and Web of Science databases. We searched for eligible studies using research Methodology Filters [
      • Haynes R.B.
      • Kastner M.
      • Wilczynski N.L.
      • Hedges T.
      Developing optimal search strategies for detecting clinically sound and relevant causation studies in EMBASE.
      ,
      • McAuley L.
      • Pham B.
      • Tugwell P.
      • Moher D.
      Does the inclusion of grey literature influence estimates of intervention effectiveness reported in meta-analyses?.
      ]. The following research terms were used: “COVID-19, SARS-CoV-2, blood pressure, hypertension, high blood pressure, vaccines, and vaccination”.

      2. SARS-CoV-2 infection and blood pressure

      Several comorbidities may worsen the clinical outcomes in patients hospitalized for SARS-CoV-2 [
      • Grasselli G.
      • Zangrillo A.
      • Zanella A.
      • Antonelli M.
      • Cabrini L.
      • Castelli A.
      • et al.
      Baseline Characteristics and Outcomes of 1591 Patients Infected With SARS-CoV-2 Admitted to ICUs of the Lombardy Region.
      ,
      • Wang D.
      • Hu B.
      • Hu C.
      • Zhu F.
      • Liu X.
      • Zhang J.
      • et al.
      Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China.
      ,
      • Angeli F.
      • Spanevello A.
      • De Ponti R.
      • Visca D.
      • Marazzato J.
      • Palmiotto G.
      • et al.
      Electrocardiographic features of patients with COVID-19 pneumonia.
      ,
      • Angeli F.
      • Verdecchia P.
      • Reboldi G.
      RAAS Inhibitors and Risk of Covid-19.
      ]. Among risk factors that have been linked with COVID-19 [

      Centers for Disease Control and Prevention. Science Brief: evidence used to update the list of underlying medical conditions that increase a person's risk of severe illness from COVID-19. https://www.cdc.gov/coronavirus/2019-ncov/science/science-briefs/underlying-evidence-table.html (Accessed on September 15, 2021).

      ], hypertension is one of the most common [
      • Grasselli G.
      • Zangrillo A.
      • Zanella A.
      • Antonelli M.
      • Cabrini L.
      • Castelli A.
      • et al.
      Baseline Characteristics and Outcomes of 1591 Patients Infected With SARS-CoV-2 Admitted to ICUs of the Lombardy Region.
      ,
      • Wang D.
      • Hu B.
      • Hu C.
      • Zhu F.
      • Liu X.
      • Zhang J.
      • et al.
      Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China.
      ,
      • Richardson S.
      • Hirsch J.S.
      • Narasimhan M.
      • Crawford J.M.
      • McGinn T.
      • Davidson K.W.
      • et al.
      Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area.
      ,
      • Angeli F.
      • Spanevello A.
      • De Ponti R.
      • Visca D.
      • Marazzato J.
      • Palmiotto G.
      • et al.
      Electrocardiographic features of patients with COVID-19 pneumonia.
      ,
      • Angeli F.
      • Verdecchia P.
      • Reboldi G.
      RAAS Inhibitors and Risk of Covid-19.
      ] and its direct association with outcome in COVID-19 is a field of debate [
      • Schiffrin E.L.
      • Flack J.M.
      • Ito S.
      • Muntner P.
      • Webb R.C.
      Hypertension and COVID-19.
      ,
      • Di Castelnuovo A.
      • Bonaccio M.
      • Costanzo S.
      • Gialluisi A.
      • Antinori A.
      • Berselli N.
      • et al.
      Common cardiovascular risk factors and in-hospital mortality in 3,894 patients with COVID-19: survival analysis and machine learning-based findings from the multicentre Italian CORIST Study.
      ,
      • Swamy S.
      • Koch C.A.
      • Hannah-Shmouni F.
      • Schiffrin E.L.
      • Klubo-Gwiezdzinska J.
      • Gubbi S.
      Hypertension and COVID-19: updates from the era of vaccines and variants.
      ]. A systematic overview and meta-analysis of 7 clinical studies analyzing data of 1576 COVID-19 patients demonstrated that the most prevalent comorbidity was hypertension (21.1%, 95% confidence interval [CI]: 13.0–27.2%) [
      • Yang J.
      • Zheng Y.
      • Gou X.
      • Pu K.
      • Chen Z.
      • Guo Q.
      • et al.
      Prevalence of comorbidities and its effects in patients infected with SARS-CoV-2: a systematic review and meta-analysis.
      ]. Furthermore, hypertension was associated with an increased risk of severe COVID-19 (odds ratio [OR]: 2.49; 95% CI: 1.98–3.12) and death (OR: 2.42; 95% CI: 1.51–3.90) [
      • Lippi G.
      • Wong J.
      • Henry B.M.
      Hypertension in patients with coronavirus disease 2019 (COVID-19): a pooled analysis.
      ].
      On the other hand, in-hospital acute rise in BP and increased BP variability are frequently observed during hospitalization for COVID-19 and they seem to be significant independent predictors of bad outcome in COVID-19 patients [
      • Ran J.
      • Song Y.
      • Zhuang Z.
      • Han L.
      • Zhao S.
      • Cao P.
      • et al.
      Blood pressure control and adverse outcomes of COVID-19 infection in patients with concomitant hypertension in Wuhan, China.
      ,
      • Saeed S.
      • Tadic M.
      • Larsen T.H.
      • Grassi G.
      • Mancia G.
      Coronavirus disease 2019 and cardiovascular complications: focused clinical review.
      ]. More specifically, an observational clinical study in COVID-19 showed that an exaggerated cardiovascular response due to persistently elevated and unstable BP occurring during hospitalization are independently associated with in-hospital death, intensive care unit (ICU) admission, and worsening heart failure [
      • Ran J.
      • Song Y.
      • Zhuang Z.
      • Han L.
      • Zhao S.
      • Cao P.
      • et al.
      Blood pressure control and adverse outcomes of COVID-19 infection in patients with concomitant hypertension in Wuhan, China.
      ]. In this retrospective cohort study involving 803 hypertensive patients, 8.3% were admitted to ICU, 3.7% had respiratory failure, 3.2% had heart failure, and 4.8% died. After adjustment for several confounders, average systolic BP (hazard ratio [HR] per 10 mmHg: 1.89; 95% CI: 1.15-3.13) and pulse pressure (HR per 10 mmHg: 2.71; 95% CI: 1.39-5.29) were independent predictors of heart failure. Moreover, the standard deviations of systolic and diastolic BP were independently associated with mortality and ICU admission.
      To investigate the effect of COVID-19 on BP during short term follow-up, Akpek and co-workers [
      • Akpek M.
      Does COVID-19 Cause Hypertension?.
      ] analyzed data of 153 consecutive COVID-19 patients. Mean age of study population was 47 ± 13 years and the main study outcome was the development of new onset hypertension according to current Guidelines [
      • Akpek M.
      Does COVID-19 Cause Hypertension?.
      ]. Both systolic (121 ± 7 mmHg vs 127 ± 15 mmHg, p<0.001) and diastolic BP (79 ± 4 vs 82 ± 7 mmHg, p <0.001) were significantly higher in the post COVID-19 period than on admission. Notably, a new diagnosis of hypertension was observed in 18 patients at the end of the observation [
      • Akpek M.
      Does COVID-19 Cause Hypertension?.
      ].
      Similarly, the clinical data of 366 hospitalized COVID-19-confirmed patients without prior hypertension showed an incidence of rise in BP during hospitalization equal to 8.42%, with a significantly increased level of troponin, procalcitonin, and Ang II [
      • Chen G.
      • Li X.
      • Gong Z.
      • Xia H.
      • Wang Y.
      • Wang X.
      • et al.
      Hypertension as a sequela in patients of SARS-CoV-2 infection.
      ].
      More recently, a prospective case-control study from our group analyzed BP changes among hospitalized patients with confirmed diagnosis of SARS-CoV-2 infection.
      The infection was established by RNA reverse-transcriptase-polimerase-chain-reaction (PCR) assays from nasopharyngeal swab specimens. All patients had imaging features for COVID-19 pneumonia. The clinical outcome was the development of a persistent increase in BP (as defined by BP values ≥ 140 mmHg systolic or 90 mmHg diastolic for at least two consecutive days) requiring a new or intensified anti-hypertensive treatment during hospitalization [
      • Angeli F.
      • Zappa M.
      • Oliva F.M.
      • Spanevello A.
      • Verdecchia P.
      Blood pressure increase during hospitalization for COVID-19.
      ]. A control group of patients with bacterial pneumonia (diagnostic tests for SARS-CoV-2 infection were negative along the entire hospitalization period) was also enrolled and used to analyze the differences in BP with COVID-19 pneumonia. Notably, age, BP at admission, main clinical features and in-hospital management, demographic data, and prevalence of risk factors and comorbidities were similar between cases with COVID-19 pneumonia and controls with bacterial pneumonia. Systolic (126 vs 118 mmHg, p = 0.016) and diastolic (79 vs 70 mmHg, p<0.0001) BP values recorded during the acute phase were significantly different between the two groups. Overall, a persistent increase in BP was detected in 28 patients. Specifically, 25 and 3 patients met the primary endpoint among COVID-19 and bacterial pneumonia, respectively (p = 0.001). Estimating the effects of covariates with multivariable regression models, COVID-19 pneumonia was associated with a 7-fold higher risk of uncontrolled hypertension when compared with bacterial pneumonia (OR: 6.99; 95% CI: 1.89 to 25.80; p = 0.004), even after adjustment for confounders (Fig. 1).
      Fig 1
      Fig. 1Probability of persistent raise in BP during hospitalization for COVID-19 according to type of pneumonia, age, and number of comorbidities (see text for details). Legend: BP=blood pressure.
      Results of the aforementioned clinical studies support the notion that a significant increase in BP may be used to identify patients at increased risk of adverse outcome when recorded in the early phase of hospitalization. Indeed, the development of severe forms of COVID-19 may be linked to hypotension, as recorded during acute heart failure, myocardial infarction, and arrhythmias. Other clinical conditions (including fever, dehydration, acute kidney injury, in-hospital over-infections, weight loss, physical inactivity, and acute respiratory failure) may affect BP values [
      • Angeli F.
      • Spanevello A.
      • De Ponti R.
      • Visca D.
      • Marazzato J.
      • Palmiotto G.
      • et al.
      Electrocardiographic features of patients with COVID-19 pneumonia.
      ,
      • Angeli F.
      • Reboldi G.
      • Spanevello A.
      • De Ponti R.
      • Visca D.
      • Marazzato J.
      • et al.
      Electrocardiographic features of patients with COVID-19: one year of unexpected manifestations.
      ,
      • Vicenzi M.
      • Di Cosola R.
      • Ruscica M.
      • Ratti A.
      • Rota I.
      • Rota F.
      • et al.
      The liaison between respiratory failure and high blood pressure: evidence from COVID-19 patients.
      ].

      3. Raise in blood pressure following COVID-19 vaccination

      After the first report by Meylan and co-workers who described a case series of 9 patients (8 were symptomatic) with stage III hypertension following COVID-19 vaccination [
      • Meylan S.
      • Livio F.
      • Foerster M.
      • Genoud P.J.
      • Marguet F.
      • Wuerzner G.
      • et al.
      Stage III Hypertension in Patients After mRNA-Based SARS-CoV-2 Vaccination.
      ], a number of studies evaluated the rate of increased BP as potential adverse reaction to vaccination.
      Sanidas and co-workers [
      • Sanidas E.
      • Anastasiou T.
      • Papadopoulos D.
      • Velliou M.
      • Mantzourani M.
      Short term blood pressure alterations in recently COVID-19 vaccinated patients.
      ] evaluated the effects of COVID-19 vaccination on BP in patients with history of controlled hypertension (defined as systolic/diastolic BP <140/90 mmHg) and healthy controls. Overall, 100 patients were enrolled [
      • Sanidas E.
      • Anastasiou T.
      • Papadopoulos D.
      • Velliou M.
      • Mantzourani M.
      Short term blood pressure alterations in recently COVID-19 vaccinated patients.
      ]. All patients had BP measurements (both home and ambulatory) between the 5th and the 20th day after fully COVID-19 vaccination [
      • Sanidas E.
      • Anastasiou T.
      • Papadopoulos D.
      • Velliou M.
      • Mantzourani M.
      Short term blood pressure alterations in recently COVID-19 vaccinated patients.
      ]. Patients with history of controlled hypertension showed a mean home and 24-h ambulatory BP equal to 175/97 mmHg and 177/98 mmHg, respectively [

      Centers for Disease Control and Prevention. Science Brief: evidence used to update the list of underlying medical conditions that increase a person's risk of severe illness from COVID-19. https://www.cdc.gov/coronavirus/2019-ncov/science/science-briefs/underlying-evidence-table.html (Accessed on September 15, 2021).

      ]. Moreover, healthy controls showed a home BP of 158/96 mmHg and a 24-h ambulatory BP equal to 157/95 mmHg [
      • Sanidas E.
      • Anastasiou T.
      • Papadopoulos D.
      • Velliou M.
      • Mantzourani M.
      Short term blood pressure alterations in recently COVID-19 vaccinated patients.
      ].
      Ch'ng and coworkers [

      Ch'ng C.C., Ong L.M., Wong K.M. Changes in Blood Pressure After Pfizer/Biontech Sars-Cov-2 Vaccination. ResearchSquare, 10.21203/rs3rs-1018154/v1. 2022.

      ] evaluated 4906 healthcare workers, recording BP when the staff members arrived at the vaccination site, immediately after vaccination, and 15–30 min later. Mean pre-vaccination systolic/diastolic BP was 130.1/80.2 mmHg and the mean changes after vaccination were +2.3/+2.4 mmHg for systolic/diastolic BP [

      Ch'ng C.C., Ong L.M., Wong K.M. Changes in Blood Pressure After Pfizer/Biontech Sars-Cov-2 Vaccination. ResearchSquare, 10.21203/rs3rs-1018154/v1. 2022.

      ].
      Pharmacovigilance databases were also used to evaluate this phenomenon, showing proportions of abnormal or increased BP after vaccination ranging from 1% to 3% [
      • Bouhanick B.
      • Montastruc F.
      • Tessier S.
      • Brusq C.
      • Bongard V.
      • Senard J.M.
      • et al.
      Hypertension and Covid-19 vaccines: are there any differences between the different vaccines? A safety signal.
      ,
      • Kaur R.J.
      • Dutta S.
      • Charan J.
      • Bhardwaj P.
      • RTandon A.
      • Yadav D.
      • et al.
      Cardiovascular Adverse Events Reported from COVID-19 Vaccines: a Study Based on WHO Database.
      ,
      • Lehmann K.
      Suspected Cardiovascular Side Effects of two Covid-19 Vaccines.
      ]. Among these, a retrospective analysis involving 21,909 subjects, exhibited the largest proportion of this phenomenon [
      • Bouhanick B.
      • Brusq C.
      • Bongard V.
      • Tessier S.
      • Montastruc J.L.
      • Senard J.M.
      • et al.
      Blood pressure measurements after mRNA-SARS-CoV-2 tozinameran vaccination: a retrospective analysis in a university hospital in France.
      ]. Specifically, Bouhanick and co-workers investigated the BP profile of vaccinated patients and healthcare workers after the first and the second dose of COVID-19 vaccine [
      • Bouhanick B.
      • Brusq C.
      • Bongard V.
      • Tessier S.
      • Montastruc J.L.
      • Senard J.M.
      • et al.
      Blood pressure measurements after mRNA-SARS-CoV-2 tozinameran vaccination: a retrospective analysis in a university hospital in France.
      ]. Overall, 8121 subjects (37%) exhibited systolic and/or diastolic BP above 140 and/or 90 mmHg after the first dose. Interestingly, the majority (64%) of subjects with abnormal BP after the first injection showed a persistent abnormal BP after the second one [
      • Bouhanick B.
      • Brusq C.
      • Bongard V.
      • Tessier S.
      • Montastruc J.L.
      • Senard J.M.
      • et al.
      Blood pressure measurements after mRNA-SARS-CoV-2 tozinameran vaccination: a retrospective analysis in a university hospital in France.
      ].
      Surveys specifically designed to evaluate BP changes following vaccination showed an incidence of raise in BP after COVID-19 vaccination ranging from 1% to 5% (5% in the analysis by Tran and co-workers [
      • Tran V.N.
      • Nguyen H.A.
      • Le T.T.A.
      • Truong T.T.
      • Nguyen P.T.
      • Nguyen T.T.H.
      Factors influencing adverse events following immunization with AZD1222 in Vietnamese adults during first half of 2021.
      ] and Zappa and co-workers [
      • Zappa M.
      • Verdecchia P.
      • Spanevello A.
      • Visca D.
      • Angeli F.
      Blood pressure increase after Pfizer/BioNTech SARS-CoV-2 vaccine.
      ], and about 1% among subjects enrolled in the study by Syrigos and co-workers [
      • Syrigos N.
      • Kollias A.
      • Grapsa D.
      • Fyta E.
      • Kyriakoulis K.G.
      • Vathiotis I.
      • et al.
      Significant Increase in Blood Pressure Following BNT162b2 mRNA COVID-19 Vaccination among Healthcare Workers: a Rare Event.
      ]). Just recently, Simonini and co-workers evaluated data from a large cohort of 1866 vaccinated healthcare workers [
      • Simonini M.
      • Scarale M.G.
      • Tunesi F.
      • Moro M.
      • Serio C.D.
      • Manunta P.
      • et al.
      COVID-19 vaccines effect on blood pressure.
      ]. They documented a BP increase in 153 subjects (8%) [
      • Simonini M.
      • Scarale M.G.
      • Tunesi F.
      • Moro M.
      • Serio C.D.
      • Manunta P.
      • et al.
      COVID-19 vaccines effect on blood pressure.
      ]. BP alterations presented with greater frequency at the 2nd or booster dose [
      • Simonini M.
      • Scarale M.G.
      • Tunesi F.
      • Moro M.
      • Serio C.D.
      • Manunta P.
      • et al.
      COVID-19 vaccines effect on blood pressure.
      ]. Furthermore, in 39 subjects (2%) a diagnosis of hypertension was done after vaccination, and among subjects already on antihypertensive therapy, 11% had to increase therapy [
      • Simonini M.
      • Scarale M.G.
      • Tunesi F.
      • Moro M.
      • Serio C.D.
      • Manunta P.
      • et al.
      COVID-19 vaccines effect on blood pressure.
      ]. The same Authors also recorded a significant proportion (4%) of subjects reporting a decrease in BP [
      • Simonini M.
      • Scarale M.G.
      • Tunesi F.
      • Moro M.
      • Serio C.D.
      • Manunta P.
      • et al.
      COVID-19 vaccines effect on blood pressure.
      ]. Nonetheless, the lack of definition and magnitude of BP decrease does not permit to evaluate the influence of conditions such as masked hypertension [
      • Simonini M.
      • Scarale M.G.
      • Tunesi F.
      • Moro M.
      • Serio C.D.
      • Manunta P.
      • et al.
      COVID-19 vaccines effect on blood pressure.
      ].
      A systematic overview and meta-analysis including 6 studies (for a total of 357,387 subjects and 13,444 events) showed a pooled estimated proportion of abnormal/increased BP after vaccination equal to 3.91% (95% CI: 1.25 – 11.56, Fig. 2– upper panel). A similar pooled proportion (3.20%; 95% CI: 1.62 – 6.21) was computed after the exclusion of 2 studies identified as statistical outliers (Fig. 2, lower panel) [
      • Angeli F.
      • Reboldi G.
      • Trapasso M.
      • Santilli G.
      • Zappa M.
      • Verdecchia P.
      Blood Pressure Increase following COVID-19 Vaccination: a Systematic Overview and Meta-Analysis.
      ]. Notably, the proportion of cases of clinically significant increase in BP (stage III hypertension, hypertensive urgencies, and hypertensive emergencies) was 0.6% [
      • Angeli F.
      • Reboldi G.
      • Trapasso M.
      • Santilli G.
      • Zappa M.
      • Verdecchia P.
      Blood Pressure Increase following COVID-19 Vaccination: a Systematic Overview and Meta-Analysis.
      ].
      Fig 2
      Fig. 2Proportions of increased BP after vaccination in a meta-analysis of 6 studies, for a total of 357,387 subjects and 13,444 adverse events
      [
      • Angeli F.
      • Reboldi G.
      • Trapasso M.
      • Santilli G.
      • Zappa M.
      • Verdecchia P.
      Blood Pressure Increase following COVID-19 Vaccination: a Systematic Overview and Meta-Analysis.
      ]
      .

      4. Mechanisms

      4.1 The role of ACE2

      Although hypertension seems to be linked to the pathogenesis of COVID-19 and acute elevations in BP during the acute phase of infection seem to be related with SARS-CoV-2 replication [
      • Ran J.
      • Song Y.
      • Zhuang Z.
      • Han L.
      • Zhao S.
      • Cao P.
      • et al.
      Blood pressure control and adverse outcomes of COVID-19 infection in patients with concomitant hypertension in Wuhan, China.
      ], the exact mechanism is still debated.
      The failure of the counter-regulatory RAS axis, characterized by the decrease of generation of the protective Angiotensin1,7 (Ang1,7) and ACE2 receptors expression [
      • Abassi Z.
      • Assady S.
      • Khoury E.E.
      • Heyman S.N.
      Letter to the Editor: angiotensin-converting enzyme 2: an ally or a Trojan horse? Implications to SARS-CoV-2-related cardiovascular complications.
      ,
      • Gheblawi M.
      • Wang K.
      • Viveiros A.
      • Nguyen Q.
      • Zhong J.C.
      • Turner A.J.
      • et al.
      Angiotensin-Converting Enzyme 2: sARS-CoV-2 Receptor and Regulator of the Renin-Angiotensin System: celebrating the 20th Anniversary of the Discovery of ACE2.
      ,
      • Wang K.
      • Gheblawi M.
      • Oudit G.Y.
      Angiotensin Converting Enzyme 2: a Double-Edged Sword.
      ], appears to be the most relevant causative mechanism implicated in the raise of BP and worse outcome of COVID-19 [
      • Angeli F.
      • Reboldi G.
      • Verdecchia P.
      SARS-CoV-2 infection and ACE2 inhibition.
      ,
      • Verdecchia P.
      • Cavallini C.
      • Spanevello A.
      • Angeli F.
      The pivotal link between ACE2 deficiency and SARS-CoV-2 infection.
      ,
      • Verdecchia P.
      • Cavallini C.
      • Spanevello A.
      • Angeli F.
      COVID-19: aCE2centric Infective Disease?.
      ,
      • Verdecchia P.
      • Reboldi G.
      • Cavallini C.
      • Mazzotta G.
      • Angeli F.
      ACE-inhibitors, angiotensin receptor blockers and severe acute respiratory syndrome caused by coronavirus.
      ,
      • Verdecchia P.
      • Angeli F.
      • Reboldi G.
      Angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers and coronavirus.
      ]. Indeed, recent investigations demonstrated the development of an “Angiotensin II storm” [
      • Ramos S.G.
      • Rattis B.
      • Ottaviani G.
      • Celes M.R.N.
      • Dias E.P.
      ACE2 Down-Regulation May Act as a Transient Molecular Disease Causing RAAS Dysregulation and Tissue Damage in the Microcirculatory Environment Among COVID-19 Patients.
      ] or “Angiotensin II intoxication” [
      • Sfera A.
      • Osorio C.
      • Jafri N.
      • Diaz E.L.
      • Campo Maldonado J.E
      Intoxication With Endogenous Angiotensin II: a COVID-19 Hypothesis.
      ] during the acute phase of SARs-CoV-2 infection [
      • Angeli F.
      • Verdecchia P.
      • Reboldi G.
      RAAS Inhibitors and Risk of Covid-19.
      ,
      • Angeli F.
      • Verdecchia P.
      • Reboldi G.
      Pharmacotherapy for hypertensive urgency and emergency in COVID-19 patients.
      ,
      • Angeli F.
      • Reboldi G.
      • Verdecchia P.
      SARS-CoV-2 infection and ACE2 inhibition.
      ,
      • Verdecchia P.
      • Cavallini C.
      • Spanevello A.
      • Angeli F.
      The pivotal link between ACE2 deficiency and SARS-CoV-2 infection.
      ,
      • Angeli F.
      • Zappa M.
      • Reboldi G.
      • Trapasso M.
      • Cavallini C.
      • Spanevello A.
      • et al.
      The pivotal link between ACE2 deficiency and SARS-CoV-2 infection: one year later.
      ,
      • Angeli F.
      • Verdecchia P.
      • Balestrino A.
      • Bruschi C.
      • Ceriana P.
      • Chiovato L.
      • et al.
      Renin Angiotensin System Blockers and Risk of Mortality in Hypertensive Patients Hospitalized for COVID-19: an Italian Registry.
      ].
      It is well recognized that the virus entry into cells is mediated by the efficient binding of the Spike (S) protein (which comprises S1 and S2 subunits) to ACE2 receptors (Fig. 3) [
      • Verdecchia P.
      • Reboldi G.
      • Cavallini C.
      • Mazzotta G.
      • Angeli F.
      ACE-inhibitors, angiotensin receptor blockers and severe acute respiratory syndrome caused by coronavirus.
      ,
      • Zhang H.
      • Penninger J.M.
      • Li Y.
      • Zhong N.
      • Slutsky A.S.
      Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target.
      ]. ACE2 receptors are ubiquitary expressed in human tissues [
      • Kuba K.
      • Imai Y.
      • Penninger J.M.
      Multiple functions of angiotensin-converting enzyme 2 and its relevance in cardiovascular diseases.
      ] and they are composed by 805 amino acids. ACE2 are responsible for the cleavage (using a single extracellular catalytic domain) of an amino acid from Ang I to form Ang1,9 and to remove an amino acid from Ang II to form Ang1–7 (Fig. 4) [
      • Vickers C.
      • Hales P.
      • Kaushik V.
      • Dick L.
      • Gavin J.
      • Tang J.
      • et al.
      Hydrolysis of biological peptides by human angiotensin-converting enzyme-related carboxypeptidase.
      ].
      Fig 3
      Fig. 3Steps of SARS-CoV-2 entry process. The main step after the invasion of SARS-CoV-2 is binding to membranal ACE2 receptor; see text for details. Legend: ACE2=angiotensin-converting enzyme 2 receptor.
      Fig 4
      Fig. 4Angiotensin1,7 formation. Angiotensin1,7 is formed by the action of the angiotensin-converting enzyme 2 (and other angiotensinases, including POP and PRCP) by the cleavage of an amino acid from Angiotensin II. Legend: ACE2=angiotensin-converting enzyme 2 receptor; POP=prolyl oligopeptidase; PRCP=prolyl carboxypeptidases.
      ACE2 downregulation/internalization, and malfunction predominantly due to viral occupation (as mediated by the binding between S proteins and ACE2), dysregulates the protective RAS axis with reduced formation of Ang1,7 and increased generation and activity of Ang II (Fig. 5) [
      • Angeli F.
      • Reboldi G.
      • Verdecchia P.
      SARS-CoV-2 infection and ACE2 inhibition.
      ,
      • Verdecchia P.
      • Cavallini C.
      • Spanevello A.
      • Angeli F.
      The pivotal link between ACE2 deficiency and SARS-CoV-2 infection.
      ,
      • Verdecchia P.
      • Cavallini C.
      • Spanevello A.
      • Angeli F.
      COVID-19: aCE2centric Infective Disease?.
      ].
      Fig 5
      Fig. 5The effect of binding of the Spike protein to ACE2 on the dysregulation of the renin-angiotensin system with increased generation and activity of Ang II (loss of ACE2 activity). Legend: ACE2=angiotensin-converting enzyme 2 receptor; Ang=angiotensin.
      Notably, Ang II is directly involved in BP regulation and inflammatory pathways (which are both disturbed in COVID-19 [
      • Waumans Y.
      • Baerts L.
      • Kehoe K.
      • Lambeir A.M.
      • De Meester I.
      The Dipeptidyl Peptidase Family, Prolyl Oligopeptidase, and Prolyl Carboxypeptidase in the Immune System and Inflammatory Disease, Including Atherosclerosis.
      ,
      • Serfozo P.
      • Wysocki J.
      • Gulua G.
      • Schulze A.
      • Ye M.
      • Liu P.
      • et al.
      Ang II (Angiotensin II) Conversion to Angiotensin-(1-7) in the Circulation Is POP (Prolyloligopeptidase)-Dependent and ACE2 (Angiotensin-Converting Enzyme 2)-Independent.
      ,
      • De Hert E.
      • Bracke A.
      • Lambeir A.M.
      Van der Veken P, De Meester I. The C-terminal cleavage of angiotensin II and III is mediated by prolyl carboxypeptidase in human umbilical vein and aortic endothelial cells.
      ]), and the imbalance between Ang II and Ang1–7 can directly contribute to development of high BP in the acute phase of SARS-CoV-2 infection [
      • Angeli F.
      • Reboldi G.
      • Trapasso M.
      • Zappa M.
      • Spanevello A.
      • Verdecchia P.
      COVID-19, vaccines and deficiency of ACE2 and other angiotensinases.
      ].
      In this context, Wu and co-workers demonstrated a significant raise in Ang II levels among COVID-19 patients [
      • Wu Z.
      • Hu R.
      • Zhang C.
      • Ren W.
      • Yu A.
      • Zhou X.
      Elevation of plasma angiotensin II level is a potential pathogenesis for the critically ill COVID-19 patients.
      ]. More specifically, they evaluated whether the plasmatic activity of Ang II is dysregulated in COVID-19 patients. They demonstrated increased Ang II levels in the majority (90%) of COVID-19 patients, and a direct association between plasma Ang II levels and COVID-19 severity [
      • Wu Z.
      • Hu R.
      • Zhang C.
      • Ren W.
      • Yu A.
      • Zhou X.
      Elevation of plasma angiotensin II level is a potential pathogenesis for the critically ill COVID-19 patients.
      ].
      Similar results were obtained in the aforementioned study by Chen and co-workers [
      • Chen G.
      • Li X.
      • Gong Z.
      • Xia H.
      • Wang Y.
      • Wang X.
      • et al.
      Hypertension as a sequela in patients of SARS-CoV-2 infection.
      ].
      Furthermore a clinical study investigating disease severity in SARS-CoV-2 infected patients, found that plasmatic Ang II levels were significantly increased and linearly associated with lung damage and viral load [
      • Liu Y.
      • Yang Y.
      • Zhang C.
      • Huang F.
      • Wang F.
      • Yuan J.
      • et al.
      Clinical and biochemical indexes from 2019-nCoV infected patients linked to viral loads and lung injury.
      ].
      The picture is further complicated analyzing the phenomenon of raised BP following COVID-19 vaccination. However, a “Spike Effect” similar to that observed during the infection of SARS-CoV-2 may be postulated.
      Recent observations demonstrated that S proteins produced upon vaccination have the native-like mimicry of SARS-CoV-2 S protein's receptor binding functionality and prefusion structure [
      • Angeli F.
      • Spanevello A.
      • Reboldi G.
      • Visca D.
      • Verdecchia P.
      SARS-CoV-2 vaccines: lights and shadows.
      ,
      • Watanabe Y.
      • Mendonca L.
      • Allen E.R.
      • Howe A.
      • Lee M.
      • Allen J.D.
      • et al.
      Native-like SARS-CoV-2 spike glycoprotein expressed by ChAdOx1 nCoV-19/AZD1222 vaccine.
      ]. Free-floating S proteins released by the destroyed cells previously targeted by COVID-19 vaccines may interact with ACE2 receptors of other cells, thereby promoting degradation, internalization, and loss of catalytic activities of ACE2 receptors [
      • Angeli F.
      • Spanevello A.
      • Reboldi G.
      • Visca D.
      • Verdecchia P.
      SARS-CoV-2 vaccines: lights and shadows.
      ,
      • Deshotels M.R.
      • Xia H.
      • Sriramula S.
      • Lazartigues E.
      • Filipeanu C.M
      Angiotensin II mediates angiotensin converting enzyme type 2 internalization and degradation through an angiotensin II type I receptor-dependent mechanism.
      ]. These mechanisms may enhance the imbalance between Ang II overactivity and Ang1–7 deficiency, contributing to an increase in BP (Fig. 6) [
      • Zappa M.
      • Verdecchia P.
      • Spanevello A.
      • Visca D.
      • Angeli F.
      Blood pressure increase after Pfizer/BioNTech SARS-CoV-2 vaccine.
      ,
      • Zhang S.
      • Liu Y.
      • Wang X.
      • Yang L.
      • Li H.
      • Wang Y.
      • et al.
      SARS-CoV-2 binds platelet ACE2 to enhance thrombosis in COVID-19.
      ].
      Fig 6
      Fig. 6Schematic mechanism of action of COVID-19 vaccines and their potential cardiovascular effects throughout the interaction between free-floating Spike proteins and ACE2 receptors. Legend: ACE2=angiotensin-converting enzyme 2 receptor; SARS-CoV-2= severe acute respiratory syndrome coronavirus-2.
      The role of RAS in the biology of COVID-19 support the hypothesis that its pharmacological modulation may favorably impact organ dysfunction and illness severity. After the concern at the beginning of the pandemic on the susceptibility to infection and disease severity enhanced by ACE-inhibitors (ACE-Is) and angiotensin type-1 receptor blockers (ARBs) [
      • Esler M.
      • Esler D.
      Can angiotensin receptor-blocking drugs perhaps be harmful in the COVID-19 pandemic?.
      ], some reports provided data on the potential benefit of angiotensin receptor modulators in COVID-19 [
      • Chen L.
      • Hao G.
      The role of angiotensin-converting enzyme 2 in coronaviruses/influenza viruses and cardiovascular disease.
      ,
      • Duarte M.
      • Pelorosso F.
      • Nicolosi L.N.
      • Salgado M.V.
      • Vetulli H.
      • Aquieri A.
      • et al.
      Telmisartan for treatment of Covid-19 patients: an open multicenter randomized clinical trial.
      ,
      • Nunez-Gil I.J.
      • Olier I.
      • Feltes G.
      • Viana-Llamas M.C.
      • Maroun-Eid C.
      • Romero R.
      • et al.
      Renin-angiotensin system inhibitors effect before and during hospitalization in COVID-19 outcomes: final analysis of the international HOPE COVID-19 (Health Outcome Predictive Evaluation for COVID-19) registry.
      ]. Just recently, a prospective study specifically tested the prognostic value of exposure to RAS modifiers among 566 hypertensive patients with COVID-19 [
      • Angeli F.
      • Verdecchia P.
      • Balestrino A.
      • Bruschi C.
      • Ceriana P.
      • Chiovato L.
      • et al.
      Renin Angiotensin System Blockers and Risk of Mortality in Hypertensive Patients Hospitalized for COVID-19: an Italian Registry.
      ]. During hospitalization 66 patients died and exposure to RAS modifiers was associated with a significant reduction (−46%, p = 0.019) in the risk of in-hospital mortality when compared to other BP-lowering strategies [
      • Angeli F.
      • Verdecchia P.
      • Balestrino A.
      • Bruschi C.
      • Ceriana P.
      • Chiovato L.
      • et al.
      Renin Angiotensin System Blockers and Risk of Mortality in Hypertensive Patients Hospitalized for COVID-19: an Italian Registry.
      ]. Exposure to ACE-Is was not significantly associated with a reduced risk of in-hospital mortality when compared with patients not treated with RAS modifiers; conversely, ARBs users showed a 59% lower risk of death (p = 0.016) even after allowance for several prognostic markers [
      • Angeli F.
      • Verdecchia P.
      • Balestrino A.
      • Bruschi C.
      • Ceriana P.
      • Chiovato L.
      • et al.
      Renin Angiotensin System Blockers and Risk of Mortality in Hypertensive Patients Hospitalized for COVID-19: an Italian Registry.
      ]. Furthermore, the discontinuation of RAS modifiers during hospitalization did not exert a significant effect (p = 0.515) [
      • Angeli F.
      • Verdecchia P.
      • Balestrino A.
      • Bruschi C.
      • Ceriana P.
      • Chiovato L.
      • et al.
      Renin Angiotensin System Blockers and Risk of Mortality in Hypertensive Patients Hospitalized for COVID-19: an Italian Registry.
      ].
      Nonetheless, recent randomized trials consistently show neither benefit nor harm from inhibition of RAS [
      • Cohen J.B.
      • Hanff T.C.
      • William P.
      • Sweitzer N.
      • Rosado-Santander N.R.
      • Medina C.
      • et al.
      Continuation versus discontinuation of renin-angiotensin system inhibitors in patients admitted to hospital with COVID-19: a prospective, randomised, open-label trial.
      ,
      • Puskarich M.A.
      • Cummins N.W.
      • Ingraham N.E.
      • Wacker D.A.
      • Reilkoff R.A.
      • Driver B.E.
      • et al.
      A multi-center phase II randomized clinical trial of losartan on symptomatic outpatients with COVID-19.
      ,
      • Puskarich M.A.
      • Ingraham N.E.
      • Merck L.H.
      • Driver B.E.
      • Wacker D.A.
      • Black L.P.
      • et al.
      Efficacy of Losartan in Hospitalized Patients With COVID-19-Induced Lung Injury: a Randomized Clinical Trial.
      ]. Of note, these trials were conducted in patients with early, mild, or moderate disease and the role of RAS modulation in critically ill COVID-19 remains to be evaluated [
      • Cohen J.B.
      • Hanff T.C.
      • William P.
      • Sweitzer N.
      • Rosado-Santander N.R.
      • Medina C.
      • et al.
      Continuation versus discontinuation of renin-angiotensin system inhibitors in patients admitted to hospital with COVID-19: a prospective, randomised, open-label trial.
      ,
      • Puskarich M.A.
      • Cummins N.W.
      • Ingraham N.E.
      • Wacker D.A.
      • Reilkoff R.A.
      • Driver B.E.
      • et al.
      A multi-center phase II randomized clinical trial of losartan on symptomatic outpatients with COVID-19.
      ,
      • Puskarich M.A.
      • Ingraham N.E.
      • Merck L.H.
      • Driver B.E.
      • Wacker D.A.
      • Black L.P.
      • et al.
      Efficacy of Losartan in Hospitalized Patients With COVID-19-Induced Lung Injury: a Randomized Clinical Trial.
      ].

      4.2 The role of other angiotensinases

      In the last few years, other Ang1,7 forming enzymes have been identified [
      • Serfozo P.
      • Wysocki J.
      • Gulua G.
      • Schulze A.
      • Ye M.
      • Liu P.
      • et al.
      Ang II (Angiotensin II) Conversion to Angiotensin-(1-7) in the Circulation Is POP (Prolyloligopeptidase)-Dependent and ACE2 (Angiotensin-Converting Enzyme 2)-Independent.
      ]. To date, the Ang II-Ang1,7 axis of the RAS includes three carboxypeptidases forming by cleavage Ang1,7 from Ang II: ACE2, prolyl oligopeptidase (POP), and prolyl carboxypeptidases (PRCP) [
      • Serfozo P.
      • Wysocki J.
      • Gulua G.
      • Schulze A.
      • Ye M.
      • Liu P.
      • et al.
      Ang II (Angiotensin II) Conversion to Angiotensin-(1-7) in the Circulation Is POP (Prolyloligopeptidase)-Dependent and ACE2 (Angiotensin-Converting Enzyme 2)-Independent.
      ]. Specifically, POP cuts at the C-side of an internal proline and cleaves Ang I to form Ang1,7, and Ang II to form Ang1,7 [
      • Serfozo P.
      • Wysocki J.
      • Gulua G.
      • Schulze A.
      • Ye M.
      • Liu P.
      • et al.
      Ang II (Angiotensin II) Conversion to Angiotensin-(1-7) in the Circulation Is POP (Prolyloligopeptidase)-Dependent and ACE2 (Angiotensin-Converting Enzyme 2)-Independent.
      ,
      • Velez J.C.
      • Ierardi J.L.
      • Bland A.M.
      • Morinelli T.A.
      • Arthur J.M.
      • Raymond J.R.
      • et al.
      Enzymatic processing of angiotensin peptides by human glomerular endothelial cells.
      ,
      • Greene L.J.
      • Spadaro A.C.
      • Martins A.R.
      • Perussi De Jesus W.D.
      • Camargo A.C
      Brain endo-oligopeptidase B: a post-proline cleaving enzyme that inactivates angiotensin I and II.
      ,
      • Welches W.R.
      • Brosnihan K.B.
      • Ferrario C.M.
      A comparison of the properties and enzymatic activities of three angiotensin processing enzymes: angiotensin converting enzyme, prolyl endopeptidase and neutral endopeptidase 24.11.
      ]; similarly, PRCP cleaves the C-terminal amino acid of Ang II [
      • Odya C.E.
      • Marinkovic D.V.
      • Hammon K.J.
      • Stewart T.A.
      • Erdos E.G.
      Purification and properties of prolylcarboxypeptidase (angiotensinase C) from human kidney.
      ]. Notably, ACE2 is the main enzyme responsible for Ang II formation in the kidney; Ang1,7 formation in the lungs and circulation is mainly POP-dependent [
      • Serfozo P.
      • Wysocki J.
      • Gulua G.
      • Schulze A.
      • Ye M.
      • Liu P.
      • et al.
      Ang II (Angiotensin II) Conversion to Angiotensin-(1-7) in the Circulation Is POP (Prolyloligopeptidase)-Dependent and ACE2 (Angiotensin-Converting Enzyme 2)-Independent.
      ]; conversely, PRCP is ubiquitously expressed [
      • Jeong J.K.
      • Diano S.
      Prolyl carboxypeptidase mRNA expression in the mouse brain.
      ,
      • Tan N.D.
      • Qiu Y.
      • Xing X.B.
      • Ghosh S.
      • Chen M.H.
      • Mao R.
      Associations Between Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blocker Use, Gastrointestinal Symptoms, and Mortality Among Patients With COVID-19.
      ], regulating inflammation, oxidative stress, thrombosis, and vascular homeostasis [
      • Adams G.N.
      • Stavrou E.X.
      • Fang C.
      • Merkulova A.
      • Alaiti M.A.
      • Nakajima K.
      • et al.
      Prolylcarboxypeptidase promotes angiogenesis and vascular repair.
      ,
      • Chajkowski S.M.
      • Mallela J.
      • Watson D.E.
      • Wang J.
      • McCurdy C.R.
      • Rimoldi J.M.
      • et al.
      Highly selective hydrolysis of kinins by recombinant prolylcarboxypeptidase.
      ,
      • Maier C.
      • Schadock I.
      • Haber P.K.
      • Wysocki J.
      • Ye M.
      • Kanwar Y.
      • et al.
      Prolylcarboxypeptidase deficiency is associated with increased blood pressure, glomerular lesions, and cardiac dysfunction independent of altered circulating and cardiac angiotensin II.
      ] by stimulating the release of nitric oxide and prostaglandin [
      • Chajkowski S.M.
      • Mallela J.
      • Watson D.E.
      • Wang J.
      • McCurdy C.R.
      • Rimoldi J.M.
      • et al.
      Highly selective hydrolysis of kinins by recombinant prolylcarboxypeptidase.
      ,
      • Mallela J.
      • Yang J.
      • Shariat-Madar Z.
      Prolylcarboxypeptidase: a cardioprotective enzyme.
      ,
      • Sharma J.N.
      Hypertension and the bradykinin system.
      ].
      Several experimental and clinical studies supported the detrimental role of POP and PRCP deficiency on BP. The genetic absence of POP directly affects BP response (due to the diminished Ang II degradation and Ang1,7 formation) [
      • Serfozo P.
      • Wysocki J.
      • Gulua G.
      • Schulze A.
      • Ye M.
      • Liu P.
      • et al.
      Ang II (Angiotensin II) Conversion to Angiotensin-(1-7) in the Circulation Is POP (Prolyloligopeptidase)-Dependent and ACE2 (Angiotensin-Converting Enzyme 2)-Independent.
      ,
      • Wysocki J.
      • Ye M.
      • Rodriguez E.
      • Gonzalez-Pacheco F.R.
      • Barrios C.
      • Evora K.
      • et al.
      Targeting the degradation of angiotensin II with recombinant angiotensin-converting enzyme 2: prevention of angiotensin II-dependent hypertension.
      ] and the PRCP gene variant promotes disease progression in hypertensive patients [
      • Wang L.
      • Feng Y.
      • Zhang Y.
      • Zhou H.
      • Jiang S.
      • Niu T.
      • et al.
      Prolylcarboxypeptidase gene, chronic hypertension, and risk of preeclampsia.
      ]. Finally, PRCP depletion contributes to vascular dysfunction with hypertension and arterial thrombosis [
      • Adams G.N.
      • LaRusch G.A.
      • Stavrou E.
      • Zhou Y.
      • Nieman M.T.
      • Jacobs G.H.
      • et al.
      Murine prolylcarboxypeptidase depletion induces vascular dysfunction with hypertension and faster arterial thrombosis.
      ].
      As aforementioned, phenotypes of ACE2 deficiency [
      • Abassi Z.
      • Assady S.
      • Khoury E.E.
      • Heyman S.N.
      Letter to the Editor: angiotensin-converting enzyme 2: an ally or a Trojan horse? Implications to SARS-CoV-2-related cardiovascular complications.
      ,
      • Gheblawi M.
      • Wang K.
      • Viveiros A.
      • Nguyen Q.
      • Zhong J.C.
      • Turner A.J.
      • et al.
      Angiotensin-Converting Enzyme 2: sARS-CoV-2 Receptor and Regulator of the Renin-Angiotensin System: celebrating the 20th Anniversary of the Discovery of ACE2.
      ,
      • Wang K.
      • Gheblawi M.
      • Oudit G.Y.
      Angiotensin Converting Enzyme 2: a Double-Edged Sword.
      ] (including older age, hypertension, diabetes, and previous vascular events) are associated with an increased risk of worse outcome in COVID-19 [

      Wu C., Chen X., Cai Y., Xia J., Zhou X., Xu S., et al. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 Pneumonia in Wuhan, China. JAMA Intern Med. 2020 180:934–43. 10.1001/jamainternmed.2020.0994.

      ,
      • Angeli F.
      • Spanevello A.
      • De Ponti R.
      • Visca D.
      • Marazzato J.
      • Palmiotto G.
      • et al.
      Electrocardiographic features of patients with COVID-19 pneumonia.
      ,
      • Angeli F.
      • Masnaghetti S.
      • Visca D.
      • Rossoni A.
      • Taddeo S.
      • Biagini F.
      • et al.
      Severity of COVID-19: the importance of being hypertensive.
      ,
      • Jin J.M.
      • Bai P.
      • He W.
      • Wu F.
      • Liu X.F.
      • Han D.M.
      • et al.
      Gender Differences in Patients With COVID-19: focus on Severity and Mortality.
      ,
      • Kopel J.
      • Perisetti A.
      • Roghani A.
      • Aziz M.
      • Gajendran M.
      • Goyal H.
      Racial and Gender-Based Differences in COVID-19.
      ,
      • Angeli F.
      • Marazzato J.
      • Verdecchia P.
      • Balestrino A.
      • Bruschi C.
      • Ceriana P.
      • et al.
      Joint effect of heart failure and coronary artery disease on the risk of death during hospitalization for COVID-19.
      ,
      • Gao Y.D.
      • Ding M.
      • Dong X.
      • Zhang J.J.
      • Kursat Azkur A.
      • Azkur D.
      • et al.
      Risk factors for severe and critically ill COVID-19 patients: a review.
      ,
      • Guo L.
      • Shi Z.
      • Zhang Y.
      • Wang C.
      • Do Vale Moreira N.C.
      • Zuo H.
      • et al.
      Comorbid diabetes and the risk of disease severity or death among 8807 COVID-19 patients in China: a meta-analysis.
      ]. Conversely, accrued data on the RAS show that aging, inflammation, atherosclerosis, and the development of atherosclerotic risk factors and cardiovascular events are associated with an increased plasmatic activity of POP and PRCP [
      • Tabrizian T.
      • Hataway F.
      • Murray D.
      • Shariat-Madar Z.
      Prolylcarboxypeptidase gene expression in the heart and kidney: effects of obesity and diabetes.
      ,
      • Agirregoitia N.
      • Gil J.
      • Ruiz F.
      • Irazusta J.
      • Casis L.
      Effect of aging on rat tissue peptidase activities.
      ]. Experimental and clinical studies demonstrated a significant positive association between POP/PRCP and several metabolic and cardiovascular parameters (including blood glucose, body mass index, body weight, and amount of total, visceral and subcutaneous abdominal adipose tissue) [
      • Xu S.
      • Lind L.
      • Zhao L.
      • Lindahl B.
      • Venge P.
      Plasma prolylcarboxypeptidase (angiotensinase C) is increased in obesity and diabetes mellitus and related to cardiovascular dysfunction.
      ,
      • Kehoe K.
      • Noels H.
      • Theelen W.
      • De Hert E.
      • Xu S.
      • Verrijken A.
      • et al.
      Prolyl carboxypeptidase activity in the circulation and its correlation with body weight and adipose tissue in lean and obese subjects.
      ]. Furthermore, intraplaque PRCP levels are upregulated in unstable atherosclerotic plaques compared with stable plaques [
      • Rinne P.
      • Lyytikainen L.P.
      • Raitoharju E.
      • Kadiri J.J.
      • Kholova I.
      • Kahonen M.
      • et al.
      Pro-opiomelanocortin and its Processing Enzymes Associate with Plaque Stability in Human Atherosclerosis - Tampere Vascular Study.
      ].
      In other words, in the cardiovascular disease continuum (from atherosclerosis and cardiovascular risk factors to the development of cardiovascular events) specific changes of angiotensinanes levels exists [
      • Chrysant S.G.
      • Chrysant G.S.
      • Chrysant C.
      • Shiraz M.
      The treatment of cardiovascular disease continuum: focus on prevention and RAS blockade.
      ]: in the disease continuum ACE2 activities decrease, whereas PRCP and POP levels increase from the health status to advanced deterioration of the cardiovascular system.

      4.2.1 SARS-CoV-2 infection

      In the specific area of BP regulation, POP and PRCP may play a specific role in COVID-19 [
      • Waumans Y.
      • Baerts L.
      • Kehoe K.
      • Lambeir A.M.
      • De Meester I.
      The Dipeptidyl Peptidase Family, Prolyl Oligopeptidase, and Prolyl Carboxypeptidase in the Immune System and Inflammatory Disease, Including Atherosclerosis.
      ,
      • Serfozo P.
      • Wysocki J.
      • Gulua G.
      • Schulze A.
      • Ye M.
      • Liu P.
      • et al.
      Ang II (Angiotensin II) Conversion to Angiotensin-(1-7) in the Circulation Is POP (Prolyloligopeptidase)-Dependent and ACE2 (Angiotensin-Converting Enzyme 2)-Independent.
      ,
      • De Hert E.
      • Bracke A.
      • Lambeir A.M.
      Van der Veken P, De Meester I. The C-terminal cleavage of angiotensin II and III is mediated by prolyl carboxypeptidase in human umbilical vein and aortic endothelial cells.
      ]. Indeed, the activities of POP and PRCP remain substantially unchanged during the acute phase of SARS-CoV-2 infection, therefore failing to limit the accumulation of Ang II by ACE2 downregulation and malfunction. A clinical study by Bracke and co-workers investigated the plasma activities of PRCP and POP among patients at the time of hospital admission or during their hospital stay for COVID-19 [
      • Bracke A.
      • De Hert E.
      • De Bruyn M.
      • Claesen K.
      • Vliegen G.
      • Vujkovic A.
      • et al.
      Proline-specific peptidase activities (DPP4, PRCP, FAP and PREP) in plasma of hospitalized COVID-19 patients.
      ]. The Authors documented that PRCP activity remained stable during hospitalization and did not differ from PRCP activity recorded in healthy controls. Finally, they also supported the recent hypothesis [
      • Triposkiadis F.
      • Starling R.C.
      • Xanthopoulos A.
      • Butler J.
      • Boudoulas H.
      The Counter Regulatory Axis of the Lung Renin-Angiotensin System in Severe COVID-19: pathophysiology and Clinical Implications.
      ] that the elevated POP levels observed in plasma of patients COVID-19 originates from cell damage due to acute lung injury or organ failure [
      • Bracke A.
      • De Hert E.
      • De Bruyn M.
      • Claesen K.
      • Vliegen G.
      • Vujkovic A.
      • et al.
      Proline-specific peptidase activities (DPP4, PRCP, FAP and PREP) in plasma of hospitalized COVID-19 patients.
      ].

      4.2.2 COVID-19 vaccination

      Loss of the catalytic activities of ACE2 due to the interaction between these receptors and free-floating S proteins is documented across all the strata of the cardiovascular disease continuum [
      • Angeli F.
      • Reboldi G.
      • Trapasso M.
      • Zappa M.
      • Spanevello A.
      • Verdecchia P.
      COVID-19, vaccines and deficiency of ACE2 and other angiotensinases.
      ,
      • Angeli F.
      • Spanevello A.
      • Reboldi G.
      • Visca D.
      • Verdecchia P.
      SARS-CoV-2 vaccines: lights and shadows.
      ]. On the other hand, an increased catalytic activity of POP and PRCP is not observed in the young, but more typically pronounced in elderly subjects with comorbidities or previous cardiovascular events.
      Thus, the potential adverse reactions to COVID-19 vaccination associated with Ang II accumulation (including increase in BP, enhanced inflammation, and thrombosis) are reasonably expected to be more common in younger and healthy subjects (Fig. 7, right panel) [
      • Angeli F.
      • Reboldi G.
      • Trapasso M.
      • Zappa M.
      • Spanevello A.
      • Verdecchia P.
      COVID-19, vaccines and deficiency of ACE2 and other angiotensinases.
      ,
      • Angeli F.
      • Spanevello A.
      • Reboldi G.
      • Visca D.
      • Verdecchia P.
      SARS-CoV-2 vaccines: lights and shadows.
      ]. Conversely, older age, presence of comorbidities and previous cardiovascular events identify phenotypes at lower risk of adverse events (Fig. 7, left panel).
      Fig 7
      Fig. 7Adverse reactions to COVID-19 vaccination associated with Ang II accumulation. Older age, presence of comorbidities and previous cardiovascular events identify phenotypes at lower risk of adverse events (left panel).Younger and healthy subjects are phenotypes at increased risk of adverse events (right panel). Legend: ACE2=angiotensin-converting enzyme 2 receptor; Ang=angiotensin; CV=cardiovascular; POP=prolyl oligopeptidase; PRCP=prolyl carboxypeptidases; SARS-CoV-2= severe acute respiratory syndrome coronavirus-2.
      This potential mechanism is supported by recent clinical and epidemiological studies evaluating the development of adverse events after COVID-19 vaccination.
      In a prospective survey of 113 healthcare workers who received COVID-19 vaccine [
      • Zappa M.
      • Verdecchia P.
      • Spanevello A.
      • Visca D.
      • Angeli F.
      Blood pressure increase after Pfizer/BioNTech SARS-CoV-2 vaccine.
      ], 6 subjects (5.3%) developed an increase in systolic or diastolic BP at home ≥ 10 mmHg during the first five days after the first dose of the COVID-19 vaccine when compared with the five days before the vaccine. Of note, age of patients with uncontrolled hypertension following COVID-19 vaccination ranged from 35 to 52 years [
      • Zappa M.
      • Verdecchia P.
      • Spanevello A.
      • Visca D.
      • Angeli F.
      Blood pressure increase after Pfizer/BioNTech SARS-CoV-2 vaccine.
      ].
      Similarly, Tran and co-workers [
      • Tran V.N.
      • Nguyen H.A.
      • Le T.T.A.
      • Truong T.T.
      • Nguyen P.T.
      • Nguyen T.T.H.
      Factors influencing adverse events following immunization with AZD1222 in Vietnamese adults during first half of 2021.
      ] demonstrated that age of vaccinated subjects was a significant predictor of increased BP after COVID-19 vaccination, as the increase of age was associated with the decrease of this adverse event [
      • Tran V.N.
      • Nguyen H.A.
      • Le T.T.A.
      • Truong T.T.
      • Nguyen P.T.
      • Nguyen T.T.H.
      Factors influencing adverse events following immunization with AZD1222 in Vietnamese adults during first half of 2021.
      ].
      In a study published in JAMA Internal Medicine, Simone and co-workers evaluated the incidence of acute myocarditis and clinical outcomes among adults following mRNA vaccination in an integrated health care system in the US (Kaiser Permanente Southern California members) [
      • Simone A.
      • Herald J.
      • Chen A.
      • Gulati N.
      • Shen A.Y.
      • Lewin B.
      • et al.
      Acute Myocarditis Following COVID-19 mRNA Vaccination in Adults Aged 18 Years or Older.
      ]. Among subjects who received COVID-19 mRNA, 54% were women and median age was 49 years [
      • Simone A.
      • Herald J.
      • Chen A.
      • Gulati N.
      • Shen A.Y.
      • Lewin B.
      • et al.
      Acute Myocarditis Following COVID-19 mRNA Vaccination in Adults Aged 18 Years or Older.
      ]. The Authors identified 15 cases of post-vaccination myocarditis (2 after the first dose and 13 after the second) [
      • Simone A.
      • Herald J.
      • Chen A.
      • Gulati N.
      • Shen A.Y.
      • Lewin B.
      • et al.
      Acute Myocarditis Following COVID-19 mRNA Vaccination in Adults Aged 18 Years or Older.
      ]. Of note, all cases occurred in men with a median age of 25 years [
      • Simone A.
      • Herald J.
      • Chen A.
      • Gulati N.
      • Shen A.Y.
      • Lewin B.
      • et al.
      Acute Myocarditis Following COVID-19 mRNA Vaccination in Adults Aged 18 Years or Older.
      ].
      Among 530 cases of myocarditis reported after COVID-19 vaccination to Vaccine Adverse Events Reporting System, approximately 65% of subjects were aged 12–24 years [

      Wallace M., Oliver S. COVID-19 mRNA vaccines in adolescents and young adults: benefit-risk discussion. Corporate Authors(s): United States Advisory Committee on Immunization Practices (US ACIP) COVID-19 Vaccines Work Group Conference Author(s): US ACIP Meeting, Atlanta, GA, May 12, 2021 Published June 23, 2021 https://stackscdcgov/view/cdc/108331. 2021.

      ].
      Schultz and co-workers reported findings in five patients in a population of more than 130,000 vaccinated persons who presented with venous thrombosis and thrombocytopenia after receiving the first dose of COVID-19 vaccine (ChAdOx1 nCoV-19 adenoviral vector vaccine) [
      • Schultz N.H.
      • Sorvoll I.H.
      • Michelsen A.E.
      • Munthe L.A.
      • Lund-Johansen F.
      • Ahlen M.T.
      • et al.
      Thrombosis and Thrombocytopenia after ChAdOx1 nCoV-19 Vaccination.
      ]. The patients were health care workers who were 32 to 54 years of age [
      • Schultz N.H.
      • Sorvoll I.H.
      • Michelsen A.E.
      • Munthe L.A.
      • Lund-Johansen F.
      • Ahlen M.T.
      • et al.
      Thrombosis and Thrombocytopenia after ChAdOx1 nCoV-19 Vaccination.
      ].
      Similarly, other reports found that subjects with vaccine-induced immune thrombotic thrombocytopenia (VITT) were younger [
      • Bourguignon A.
      • Arnold D.M.
      • Warkentin T.E.
      • Smith J.W.
      • Pannu T.
      • Shrum J.M.
      • et al.
      Adjunct Immune Globulin for Vaccine-Induced Immune Thrombotic Thrombocytopenia.
      ,
      • Pavord S.
      • Scully M.
      • Hunt B.J.
      • Lester W.
      • Bagot C.
      • Craven B.
      • et al.
      Clinical Features of Vaccine-Induced Immune Thrombocytopenia and Thrombosis.
      ].
      Finally, in a report from the Advisory Committee on Immunization Practices, rates of VITT were similar between males and females in most age brackets, with the exception of females ages 30 to 49 years, in whom rates were higher [].

      5. Conclusions

      Recent clinical and experimental advances in the pathophysiology of SARS-CoV-2 infection support the notion that the interaction of the virus (mediated by S proteins) with ACE2 receptors exerts a pivotal role in the development of severe disease [
      • Verdecchia P.
      • Cavallini C.
      • Spanevello A.
      • Angeli F.
      The pivotal link between ACE2 deficiency and SARS-CoV-2 infection.
      ,
      • Angeli F.
      • Zappa M.
      • Reboldi G.
      • Trapasso M.
      • Cavallini C.
      • Spanevello A.
      • et al.
      The pivotal link between ACE2 deficiency and SARS-CoV-2 infection: one year later.
      ,
      • Zappa M.
      • Verdecchia P.
      • Angeli F.
      Knowing the new Omicron BA.2.75 variant ('Centaurus'): a simulation study.
      ,
      • Zappa M.
      • Verdecchia P.
      • Spanevello A.
      • Angeli F.
      Structural evolution of severe acute respiratory syndrome coronavirus 2: implications for adhesivity to angiotensin-converting enzyme 2 receptors and vaccines.
      ].
      Recent findings further expanded our knowledge on the deleterious effect of Ang II accumulation. Downregulation and internalization of ACE2 receptors (due to viral occupation), and malfunction of other angiotensinases, dysregulates the protective RAS axis with increased generation and activity of Ang II and reduced formation of Ang1,7 [
      • Angeli F.
      • Reboldi G.
      • Verdecchia P.
      SARS-CoV-2 infection and ACE2 inhibition.
      ,
      • Verdecchia P.
      • Cavallini C.
      • Spanevello A.
      • Angeli F.
      The pivotal link between ACE2 deficiency and SARS-CoV-2 infection.
      ,
      • Verdecchia P.
      • Cavallini C.
      • Spanevello A.
      • Angeli F.
      COVID-19: aCE2centric Infective Disease?.
      ].
      Of note, Ang II plays key roles in BP homeostasis, including the heart, kidney, blood vessels, adrenal glands, and cardiovascular control centres in the brain [
      • Crowley S.D.
      • Gurley S.B.
      • Herrera M.J.
      • Ruiz P.
      • Griffiths R.
      • Kumar A.P.
      • et al.
      Angiotensin II causes hypertension and cardiac hypertrophy through its receptors in the kidney.
      ]. Thus, the negative effect of SARS-CoV-2 on BP during and after the acute phase of infection is not entirely unexpected [
      • Angeli F.
      • Zappa M.
      • Oliva F.M.
      • Spanevello A.
      • Verdecchia P.
      Blood pressure increase during hospitalization for COVID-19.
      ].
      In this context, the association between increased levels of Ang II and increased BP during hospitalization for COVID-19 support this mechanism. Uncontrolled hypertension during the course of the disease can acutely worsen hypertension-mediated organ damage and adverse outcomes [
      • Angeli F.
      • Verdecchia P.
      • Reboldi G.
      Pharmacotherapy for hypertensive urgency and emergency in COVID-19 patients.
      ]
      A similar mechanism has been recently proposed to explain the raise in BP following COVID-19 vaccination [
      • Angeli F.
      • Reboldi G.
      • Trapasso M.
      • Zappa M.
      • Spanevello A.
      • Verdecchia P.
      COVID-19, vaccines and deficiency of ACE2 and other angiotensinases.
      ,
      • Angeli F.
      • Spanevello A.
      • Reboldi G.
      • Visca D.
      • Verdecchia P.
      SARS-CoV-2 vaccines: lights and shadows.
      ,
      • Trougakos I.P.
      • Terpos E.
      • Alexopoulos H.
      • Politou M.
      • Paraskevis D.
      • Scorilas A.
      • et al.
      Adverse effects of COVID-19 mRNA vaccines: the spike hypothesis.
      ]. In other words, the resulting features of COVID-19 vaccination resemble those of active COVID-19 disease.
      When vaccinated cells die or are destroyed by the human immune system, the debris may release a large amount of free-floating S proteins [
      • Angeli F.
      • Spanevello A.
      • Reboldi G.
      • Visca D.
      • Verdecchia P.
      SARS-CoV-2 vaccines: lights and shadows.
      ]. Having the native-like mimicry of SARS-CoV-2 S protein's receptor binding functionality and prefusion structure, S proteins produced upon vaccination may interact with ACE2 receptors, causing internalization, degradation [
      • Angeli F.
      • Reboldi G.
      • Trapasso M.
      • Zappa M.
      • Spanevello A.
      • Verdecchia P.
      COVID-19, vaccines and deficiency of ACE2 and other angiotensinases.
      ,
      • Angeli F.
      • Spanevello A.
      • Reboldi G.
      • Visca D.
      • Verdecchia P.
      SARS-CoV-2 vaccines: lights and shadows.
      ], and loss of ACE2 activities.
      These mechanisms may lead to less Ang II inactivation and Ang1,7 generation, with consequent Ang II overactivity which may trigger a variable raise in BP [
      • Angeli F.
      • Reboldi G.
      • Verdecchia P.
      SARS-CoV-2 infection and ACE2 inhibition.
      ,
      • Verdecchia P.
      • Cavallini C.
      • Spanevello A.
      • Angeli F.
      The pivotal link between ACE2 deficiency and SARS-CoV-2 infection.
      ,
      • Verdecchia P.
      • Cavallini C.
      • Spanevello A.
      • Angeli F.
      COVID-19: aCE2centric Infective Disease?.
      ].
      Stress response (white-coat effect) and the role of some excipients might explain the high prevalence of increased BP values recorded immediately after vaccination [
      • Angeli F.
      • Reboldi G.
      • Trapasso M.
      • Santilli G.
      • Zappa M.
      • Verdecchia P.
      Blood Pressure Increase following COVID-19 Vaccination: a Systematic Overview and Meta-Analysis.
      ,
      • Meylan S.
      • Livio F.
      • Foerster M.
      • Genoud P.J.
      • Marguet F.
      • Wuerzner G.
      • et al.
      Stage III Hypertension in Patients After mRNA-Based SARS-CoV-2 Vaccination.
      ]. However, data from surveys and pharmacovigilance databases which expanded the observation some days after vaccination demonstrated that a persistent raise in BP after COVID-19 vaccination is not unusual [
      • Angeli F.
      • Reboldi G.
      • Trapasso M.
      • Santilli G.
      • Zappa M.
      • Verdecchia P.
      Blood Pressure Increase following COVID-19 Vaccination: a Systematic Overview and Meta-Analysis.
      ,
      • Zappa M.
      • Verdecchia P.
      • Spanevello A.
      • Visca D.
      • Angeli F.
      Blood pressure increase after Pfizer/BioNTech SARS-CoV-2 vaccine.
      ]. Further research taking into account the potential effects of confounders and long-term clinical data are urgently needed in this area.

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