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Blood pressure increase during hospitalization for COVID-19

  • Fabio Angeli
    Correspondence
    Corresponding author at: Department of Medicine and Surgery, University of Insubria, Varese, Italy
    Affiliations
    Department of Medicine and Surgery, University of Insubria, Varese, Italy

    Department of Medicine and Cardiopulmonary Rehabilitation, Istituti Clinici Scientifici Maugeri, IRCCS Tradate, Via Crotto Roncaccio 16, Tradate, VA, Italy
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  • Martina Zappa
    Affiliations
    Department of Medicine and Surgery, University of Insubria, Varese, Italy
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  • Federico Mattia Oliva
    Affiliations
    Department of Medicine and Cardiopulmonary Rehabilitation, Istituti Clinici Scientifici Maugeri, IRCCS Tradate, Via Crotto Roncaccio 16, Tradate, VA, Italy
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  • Antonio Spanevello
    Affiliations
    Department of Medicine and Surgery, University of Insubria, Varese, Italy

    Department of Medicine and Cardiopulmonary Rehabilitation, Istituti Clinici Scientifici Maugeri, IRCCS Tradate, Via Crotto Roncaccio 16, Tradate, VA, Italy
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  • Paolo Verdecchia
    Affiliations
    Fondazione Umbra Cuore e Ipertensione-ONLUS and Division of Cardiology, Hospital S. Maria Della Misericordia, Perugia, Italy
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      Keywords

      Abbreviations:

      BP (blood pressure), COVID-19 (coronavirus disease 2019), ACE (angiotensin converting enzyme), SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), RNA (ribonucleic acid)
      To the Editor:
      The first report of a rise in blood pressure (BP) associated with vaccination for coronavirus disease 2019 (COVID-19) was provided by Meylan et al. [
      • Meylan S.
      • Livio F.
      • Foerster M.
      • Genoud P.J.
      • Marguet F.
      • Wuerzner G.
      • Center C.C.V.
      Stage III hypertension in patients after mRNA-based SARS-CoV-2 vaccination.
      ]. These authors published a series of subjects vaccinated with ‘Comirnaty’ (by Pfizer-BioNtech) or ‘Spikevax’ (by Moderna) [
      • Meylan S.
      • Livio F.
      • Foerster M.
      • Genoud P.J.
      • Marguet F.
      • Wuerzner G.
      • Center C.C.V.
      Stage III hypertension in patients after mRNA-based SARS-CoV-2 vaccination.
      ]. Unexpectedly, hours or days after vaccination, BP in these subjects rose considerably up to levels of 220/115 mmHg [
      • Meylan S.
      • Livio F.
      • Foerster M.
      • Genoud P.J.
      • Marguet F.
      • Wuerzner G.
      • Center C.C.V.
      Stage III hypertension in patients after mRNA-based SARS-CoV-2 vaccination.
      ]. Although subsequent studies substantially confirmed this finding, evidence remains limited [
      • Zappa M.
      • Verdecchia P.
      • Spanevello A.
      • Visca D.
      • Angeli F.
      Blood pressure increase after Pfizer/BioNTech SARS-CoV-2 vaccine.
      ,
      • 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 potential basic mechanisms of the BP rise associated with COVID-19 vaccination are elusive, although some possibilities look reasonable. For example, the down-regulation of ACE2 receptors due to their internalization into the cells after the contact with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein, either alone (i.e., produced by vaccines) [
      • Angeli F.
      • Spanevello A.
      • Reboldi G.
      • Visca D.
      • Verdecchia P.
      SARS-CoV-2 vaccines: lights and shadows.
      ] or combined with the entire virus (i.e., during SARS-CoV-2 infection) [
      • Angeli F.
      • Zappa M.
      • Reboldi G.
      • Trapasso M.
      • Cavallini C.
      • Spanevello A.
      • Verdecchia P.
      The pivotal link between ACE2 deficiency and SARS-CoV-2 infection: one year later.
      ,
      • 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?.
      ], would result in a loss of ACE2 enzymatic activity at the outer cell surface. Consequently, angiotensin II would be transformed into angiotensin1–7 to a much lesser extent, with enhancement of the typical unwanted effects of angiotensin II (vasoconstriction, inflammation, thrombosis) [
      • Angeli F.
      • Zappa M.
      • Reboldi G.
      • Trapasso M.
      • Cavallini C.
      • Spanevello A.
      • Verdecchia P.
      The pivotal link between ACE2 deficiency and SARS-CoV-2 infection: one year later.
      ,
      • 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?.
      ].
      An interesting approach to investigate the potential effects of SARS-CoV-2 infection on BP could be the observation of patients hospitalized for severe COVID-19 [
      • Angeli F.
      • Verdecchia P.
      • Reboldi G.
      Pharmacotherapy for hypertensive urgency and emergency in COVID-19 patients.
      ]. Thus, we conducted a prospective case-control study in hospitalized patients with confirmed diagnosis of SARS-CoV-2 infection (by RNA reverse-transcriptase-polimerase-chain-reaction assays from nasopharyngeal swab specimens) and imaging features for COVID-19 pneumonia [
      • Simpson S.
      • Kay F.U.
      • Abbara S.
      • Bhalla S.
      • Chung J.H.
      • Chung M.
      • Henry T.S.
      • Kanne J.P.
      • Kligerman S.
      • Ko J.P.
      • Litt H.
      Radiological society of north america expert consensus document on reporting chest CT findings related to COVID-19: endorsed by the society of thoracic radiology, the American college of radiology, and RSNA.
      ]. It was not a retrospective enrollment of patients, but a prospective study according to a prespecified protocol. The protocol was approved by the Ethic Committee of our Institution and patients provided their informed consent to participate. We also predefined a control group of patients who had been hospitalized for bacterial pneumonia and whose diagnostic tests for COVID-19 were negative along the entire hospitalization period.
      Participants were consecutively recruited in a 2:1 allocation ratio. The primary outcome was the rate of persistent raise in BP requiring a new or intensified anti-hypertensive treatment during hospitalization. BP values ≥ 140 mmHg systolic or 90 mmHg diastolic for at least two consecutive days defined the persistent rise in BP. The secondary outcome was the differences between the two groups in the average BP during hospitalization. We estimated that a total of 58 cases and 29 controls would provide an 85% power to detect a clinically relevant 30% increase in the proportion of uncontrolled hypertension between patients with COVID-19 pneumonia and patients with bacterial pneumonia.
      We collected demographic, laboratory, and clinical management data at admission and throughout the entire in-hospital stay. Laboratory parameters were assessed using standard techniques. We used the PaO2/FIO2 ratio to estimate the severity of respiratory dysfunction. We defined comorbidities according to documented medical history, as collected by investigators at study site-level, including interrogation of electronic health record data. All clinical evaluations were performed by the attending physician during the clinical interview and through interrogation of medical records. BP was measured in the morning according to current Guidelines [
      • Stergiou G.S.
      • Palatini P.
      • Parati G.
      • O'Brien E.
      • Januszewicz A.
      • Lurbe E.
      • Persu A.
      • Mancia G.
      • Kreutz R.
      European society of hypertension C, the European society of hypertension working group on blood pressure m and cardiovascular V. 2021 European society of hypertension practice guidelines for office and out-of-office blood pressure measurement.
      ]. Previous cardiac events included history of heart failure (defined by at least one prior hospitalization for acute heart failure requiring intravenous therapy) and coronary artery disease (as defined by at least one of the following criteria: (1) presence of any epicardial coronary vessels with >75% stenosis tested on coronary angiography; (2) history of acute coronary syndrome; (3) coronary revascularization, either percutaneous transluminal coronary angioplasty or coronary artery by-pass grafting). Cerebrovascular disease included previous history of stroke or transient ischemic attack.
      Table 1 shows the main characteristics of patients. Mean age was 64 and 66 years for COVID-19 and bacterial pneumonia cases, respectively. Clinical features and prevalence of comorbidities were well-balanced between cases and controls. Of note, patients with COVID-19 and bacterial pneumonia had similar BP at admission (systolic: 121 vs 118 mmHg, p = 0.426; diastolic: 76 vs 74 mmHg, p = 0.401).
      Table 1Main characteristics of patients according to different types of pneumonia (mean ± standard error or percentages, when appropriate).
      Patients characteristicsCOVID-19 Pneumonia(n = 58)Bacterial Pneumonia(n = 29)p
      Age (years)64±1.966±2.90.472
      Females, %38410.194
      Body Mass Index, Kg/m227.2±0.6324.8±1.070.046
      Comorbidities
       Hypertension, %55480.544
       Diabetes, %17210.153
       Current smoker, %28310.112
       Cardiac events, %16170.837
       Cerebrovascular disease, %1070.600
       Chronic obstructive pulmonary disease, %5280.003
      Laboratory data at admission
       White blood cell count, x1037.07±0.3710.34±0.97<0.001
       Serum creatinine, mg/dl0.83±0.030.97±0.100.078
      K+, mEq/l4.32±0.064.37±0.110.656
       Haemoglobin, g/dl12.6±0.1812.0±0.280.062
       PaO2/FIO2 ratio, mm312±12285±130.185
      Blood pressure and heart rate
       Systolic BP at admission, mmHg121±2.3118±3.20.426
       Diastolic BP at admission, mmHg76±1.474±1.60.401
       Heart rate at admission, bpm79±2.081±2.20.480
       Systolic BP during hospitalization, mmHg126±1.9118±2.20.016
       Diastolic BP during hospitalization, mmHg79±1.170±0.9<0.0001
       Short-term systolic BP variability*, mmHg13±0.710±0.90.043
       Short-term diastolic BP variability*, mmHg8.1±0.56.6±0.30.060
       Mean heart rate during hospitalization, bpm74±1.076±1.70.400
      Outcome
       Persistent raise in BP requiring drug therapy, %45100.001
      Legend: BP = blood pressure; * = estimated by standard deviation of blood pressure during hospitalization.
      Conversely, mean systolic/diastolic BP recorded during hospitalization showed a significant difference between patients with COVID-19 pneumonia and patients with bacterial pneumonia (systolic: 126 vs 118 mmHg, p = 0.016; diastolic: 79 vs 70 mmHg, p < 0.0001).
      During hospitalization, 28 patients exhibited a persistent raise in BP requiring antihypertensive treatment. Specifically, 25 and 3 patients met the primary endpoint among COVID-19 and bacterial pneumonia, respectively (p = 0.001). Thus, COVID-19 pneumonia was associated with a 7-fold increased risk of uncontrolled hypertension when compared with bacterial pneumonia (odds ratio: 6.99, 95% confidence interval: 1.89 to 25.80, p = 0.004). Similar results were obtained after adjustment for age (Fig. 1, p = 0.019). Predictors of uncontrolled hypertension (Table 2) in the group with COVID-19 were age (p = 0.006), history of hypertension (p = 0.002), diabetes (p = 0.043), and previous cardiac events (p = 0.027). Notably, these features have been associated with ACE2 receptor deficiency, potentially linked to a reduced generation of the potent vasodilator angiotensin1–7, during the active phase of the disease [
      • Angeli F.
      • Zappa M.
      • Reboldi G.
      • Trapasso M.
      • Cavallini C.
      • Spanevello A.
      • Verdecchia P.
      The pivotal link between ACE2 deficiency and SARS-CoV-2 infection: one year later.
      ,
      • Verdecchia P.
      • Cavallini C.
      • Spanevello A.
      • Angeli F.
      COVID-19: aCE2centric Infective disease?.
      ].
      Fig. 1
      Fig. 1Probability of persistent raise in blood pressure according to type of pneumonia and age (see text for details).
      Table 2Predictors of uncontrolled hypertension in the group with COVID-19 pneumonia (see text for details).
      VariableComparisonOR (95% CI)p
      Age10 years1.91 (1.21–3.06)0.006
      SexMale vs Female2.89 (0.79–10.57)0.109
      Body mass index10 Kg/m21.34 (0.43–4.17)0.616
      Comorbidities
       HypertensionYes vs No7.27 (2.14–24.77)0.002
       DiabetesYes vs No5.64 (1.05–30.19)0.043
       Cardiac eventsYes vs No11.67 (1.33–20.72)0.027
       Cerebrovascular diseaseYes vs No0.81 (0.12–5.28)0.827
       Chronic obstructive pulmonary diseaseYes vs No2.61 (0.23–30.57)0.445
      Laboratory data at admission
       White blood cell count1031.06 (0.88–1.28)0.554
       Serum creatinine1 mg/dl2.39 (0.18–31.35)0.506
      K+1 ng/mL1.07 (0.35–3.33)0.901
       Haemoglobin1 g/dl0.87 (0.59–1.28)0.475
       PaO2/FIO2 ratio10 mm0.98 (0.92–1.04)0.467
      Blood pressure
       Systolic BP at admission10 mmHg1.22 (0.91–1.62)0.178
       Diastolic BP at admission10 mmHg1.15 (0.74–1.77)0.540
       Heart rate at admission10 bpm0.96 (0.67–1.36)0.804
      Legend: BP = blood pressure; OR=odds ratio; CI=confidence interval.
      To the best of our knowledge, this case-control study is the first to indicate that COVID-19 pneumonia is associated with a rise in BP in hospitalized patients. These preliminary data should be confirmed in larger case series. The potential basic mechanisms underlying this phenomenon require further research.

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