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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.
Department of Medicine and Surgery, University of Insubria, Varese, 21100, ItalyDepartment of Medicine and Cardiopulmonary Rehabilitation, Maugeri Care and Research Institute, IRCCS Tradate, 21049, Italy
College of Medicine and Health. University of Exeter, Exeter, United Kingdom and Department of Nephrology, Royal Cornwall Hospitals NHS Trust, Truro, United Kingdom
Department of Medicine and Surgery, University of Insubria, Varese, 21100, ItalyDepartment of Medicine and Cardiopulmonary Rehabilitation, Maugeri Care and Research Institute, IRCCS Tradate, 21049, Italy
SARS-CoV-2 infection promotes the failure of the counter-regulatory RAS axis.
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The failure of RAS is mediated by the binding of the spike protein of the virus with ACE2 (causing malfunction of these receptors).
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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.
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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.
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.
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.
]. 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 [
], 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 [
] 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 [
]. 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) [
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 [
]. Literature searches were conducted using Google Scholar, Scopus, PubMed, EMBASE, and Web of Science databases. We searched for eligible studies using research Methodology Filters [
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.
]. 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%) [
]. 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) [
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 [
]. 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 [
]. 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 [
] 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 [
]. 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 [
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 [
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 [
]. 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. 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 [
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 [
] 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 [
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% [
]. 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 [
]. 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 [
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 [
]. 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 [
]. Nonetheless, the lack of definition and magnitude of BP decrease does not permit to evaluate the influence of conditions such as masked hypertension [
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) [
]. Notably, the proportion of cases of clinically significant increase in BP (stage III hypertension, hypertensive urgencies, and hypertensive emergencies) was 0.6% [
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 [
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 [
Angiotensin-Converting Enzyme 2: sARS-CoV-2 Receptor and Regulator of the Renin-Angiotensin System: celebrating the 20th Anniversary of the Discovery of ACE2.
ACE2 Down-Regulation May Act as a Transient Molecular Disease Causing RAAS Dysregulation and Tissue Damage in the Microcirculatory Environment Among COVID-19 Patients.
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) [
] 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) [
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. 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) [
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.
The Dipeptidyl Peptidase Family, Prolyl Oligopeptidase, and Prolyl Carboxypeptidase in the Immune System and Inflammatory Disease, Including Atherosclerosis.
Ang II (Angiotensin II) Conversion to Angiotensin-(1-7) in the Circulation Is POP (Prolyloligopeptidase)-Dependent and ACE2 (Angiotensin-Converting Enzyme 2)-Independent.
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.
]. 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 [
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 [
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 [
]. 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 [
Angiotensin II mediates angiotensin converting enzyme type 2 internalization and degradation through an angiotensin II type I receptor-dependent mechanism.
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) [
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 [
]. 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 [
]. 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 [
Continuation versus discontinuation of renin-angiotensin system inhibitors in patients admitted to hospital with COVID-19: a prospective, randomised, open-label 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 [
Continuation versus discontinuation of renin-angiotensin system inhibitors in patients admitted to hospital with COVID-19: a prospective, randomised, open-label trial.
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) [
Ang II (Angiotensin II) Conversion to Angiotensin-(1-7) in the Circulation Is POP (Prolyloligopeptidase)-Dependent and ACE2 (Angiotensin-Converting Enzyme 2)-Independent.
Ang II (Angiotensin II) Conversion to Angiotensin-(1-7) in the Circulation Is POP (Prolyloligopeptidase)-Dependent and ACE2 (Angiotensin-Converting Enzyme 2)-Independent.
A comparison of the properties and enzymatic activities of three angiotensin processing enzymes: angiotensin converting enzyme, prolyl endopeptidase and neutral endopeptidase 24.11.
]. 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 [
Ang II (Angiotensin II) Conversion to Angiotensin-(1-7) in the Circulation Is POP (Prolyloligopeptidase)-Dependent and ACE2 (Angiotensin-Converting Enzyme 2)-Independent.
Associations Between Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blocker Use, Gastrointestinal Symptoms, and Mortality Among Patients With COVID-19.
Prolylcarboxypeptidase deficiency is associated with increased blood pressure, glomerular lesions, and cardiac dysfunction independent of altered circulating and cardiac angiotensin II.
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) [
Ang II (Angiotensin II) Conversion to Angiotensin-(1-7) in the Circulation Is POP (Prolyloligopeptidase)-Dependent and ACE2 (Angiotensin-Converting Enzyme 2)-Independent.
Angiotensin-Converting Enzyme 2: sARS-CoV-2 Receptor and Regulator of the Renin-Angiotensin System: celebrating the 20th Anniversary of the Discovery of ACE2.
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.
]. 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 [
]. 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) [
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 [
]: 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 [
The Dipeptidyl Peptidase Family, Prolyl Oligopeptidase, and Prolyl Carboxypeptidase in the Immune System and Inflammatory Disease, Including Atherosclerosis.
Ang II (Angiotensin II) Conversion to Angiotensin-(1-7) in the Circulation Is POP (Prolyloligopeptidase)-Dependent and ACE2 (Angiotensin-Converting Enzyme 2)-Independent.
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 [
]. 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 [
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 [
]. 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) [
]. Conversely, older age, presence of comorbidities and previous cardiovascular events identify phenotypes at lower risk of adverse events (Fig. 7, left panel).
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 [
], 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 [
] 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 [
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) [
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) [
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 [
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 [
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 [
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 [
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 [
]. 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 [
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 [
Stress response (white-coat effect) and the role of some excipients might explain the high prevalence of increased BP values recorded immediately after 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 [
]. Further research taking into account the potential effects of confounders and long-term clinical data are urgently needed in this area.
References
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.
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.
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.
Angiotensin-Converting Enzyme 2: sARS-CoV-2 Receptor and Regulator of the Renin-Angiotensin System: celebrating the 20th Anniversary of the Discovery of ACE2.
ACE2 Down-Regulation May Act as a Transient Molecular Disease Causing RAAS Dysregulation and Tissue Damage in the Microcirculatory Environment Among COVID-19 Patients.
The Dipeptidyl Peptidase Family, Prolyl Oligopeptidase, and Prolyl Carboxypeptidase in the Immune System and Inflammatory Disease, Including Atherosclerosis.
Ang II (Angiotensin II) Conversion to Angiotensin-(1-7) in the Circulation Is POP (Prolyloligopeptidase)-Dependent and ACE2 (Angiotensin-Converting Enzyme 2)-Independent.
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.
Angiotensin II mediates angiotensin converting enzyme type 2 internalization and degradation through an angiotensin II type I receptor-dependent mechanism.
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.
Continuation versus discontinuation of renin-angiotensin system inhibitors in patients admitted to hospital with COVID-19: a prospective, randomised, open-label trial.
A comparison of the properties and enzymatic activities of three angiotensin processing enzymes: angiotensin converting enzyme, prolyl endopeptidase and neutral endopeptidase 24.11.
Associations Between Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blocker Use, Gastrointestinal Symptoms, and Mortality Among Patients With COVID-19.
Prolylcarboxypeptidase deficiency is associated with increased blood pressure, glomerular lesions, and cardiac dysfunction independent of altered circulating and cardiac angiotensin II.
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.
Structural evolution of severe acute respiratory syndrome coronavirus 2: implications for adhesivity to angiotensin-converting enzyme 2 receptors and vaccines.
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