Renin-Angiotensin System Inhibition in Cardiovascular Patients at the Time of COVID19: Much Ado for Nothing? A Statement of Activity from the Directors of the Board and the Scientific Directors of the Italian Society of Hypertension
Identifieur interne : 000386 ( Pmc/Corpus ); précédent : 000385; suivant : 000387Renin-Angiotensin System Inhibition in Cardiovascular Patients at the Time of COVID19: Much Ado for Nothing? A Statement of Activity from the Directors of the Board and the Scientific Directors of the Italian Society of Hypertension
Auteurs : Guido Iaccarino ; Claudio Borghi ; Arrigo F. G. Cicero ; Claudio Ferri ; Pietro Minuz ; Maria Lorenza Muiesan ; Paolo Mulatero ; Giuseppe Mulè ; Giacomo Pucci ; Massimo Salvetti ; Carmine Savoia ; Leonardo Alberto Sechi ; Massimo Volpe ; Guido GrassiSource :
- High Blood Pressure & Cardiovascular Prevention [ 1120-9879 ] ; 2020.
Abstract
Cardiovascular diseases, in particular hypertension, as well as the cardiovascular treatment with Renin–Angiotensin System inhibitors such as Angiotensin Converting Enzyme (ACE) inhibitors and Angiotensin Receptor Blockers (ARBs), are claimed once again as mechanisms of Severe Acute Respiratory Syndrome (SARS) during the COVID-19 outbreak due to Cov-2 epidemics. In vitro studies are available to support the eventual role of ACE inhibitors and ARBs in both the promotion and antagonism of the disease. The available literature, indeed, presents contrasting results, all concentrated in experimental models. Evidence in humans is lacking that those mechanisms are actually occurring in the present COVID-19 outbreak. Here we present the reasoned statement of the Italian Society of Hypertension to maintain ongoing antihypertensive treatments. Furthermore, the Italian Society of Hypertension presents its own initiative to investigate the issue using an online questionnaire to collect relevant data in human disease.
Url:
DOI: 10.1007/s40292-020-00380-3
PubMed: 31925708
PubMed Central: 7138256
Links to Exploration step
PMC:7138256Le document en format XML
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A Statement of Activity from the Directors of the Board and the Scientific Directors of the Italian Society of Hypertension</title><author><name sortKey="Iaccarino, Guido" sort="Iaccarino, Guido" uniqKey="Iaccarino G" first="Guido" last="Iaccarino">Guido Iaccarino</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="GRID">grid.4691.a</institution-id><institution-id institution-id-type="ISNI">0000 0001 0790 385X</institution-id><institution>Department of Advanced Biomedical Sciences,</institution><institution>Federico II University,</institution></institution-wrap>Naples, Italy</nlm:aff></affiliation></author><author><name sortKey="Borghi, Claudio" sort="Borghi, Claudio" uniqKey="Borghi C" first="Claudio" last="Borghi">Claudio Borghi</name><affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="GRID">grid.6292.f</institution-id><institution-id institution-id-type="ISNI">0000 0004 1757 1758</institution-id><institution>Department of Medicine and Surgery Sciences,</institution><institution>Alma Mater Studiorum University of Bologna,</institution></institution-wrap>Bologna, Italy</nlm:aff></affiliation></author><author><name sortKey="Cicero, Arrigo F G" sort="Cicero, Arrigo F G" uniqKey="Cicero A" first="Arrigo F. 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Cicero</name><affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="GRID">grid.6292.f</institution-id><institution-id institution-id-type="ISNI">0000 0004 1757 1758</institution-id><institution>Department of Medicine and Surgery Sciences,</institution><institution>Alma Mater Studiorum University of Bologna,</institution></institution-wrap>Bologna, Italy</nlm:aff></affiliation></author><author><name sortKey="Ferri, Claudio" sort="Ferri, Claudio" uniqKey="Ferri C" first="Claudio" last="Ferri">Claudio Ferri</name><affiliation><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="GRID">grid.158820.6</institution-id><institution-id institution-id-type="ISNI">0000 0004 1757 2611</institution-id><institution>Department of Clinical Medicine, Public Health, Life and Environment Sciences,</institution><institution>University of Aquila,</institution></institution-wrap>L’Aquila, Italy</nlm:aff></affiliation></author><author><name sortKey="Minuz, 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Italy</nlm:aff></affiliation></author><author><name sortKey="Mulatero, Paolo" sort="Mulatero, Paolo" uniqKey="Mulatero P" first="Paolo" last="Mulatero">Paolo Mulatero</name><affiliation><nlm:aff id="Aff6"><institution-wrap><institution-id institution-id-type="GRID">grid.7605.4</institution-id><institution-id institution-id-type="ISNI">0000 0001 2336 6580</institution-id><institution>Division of Internal Medicine and Hypertension, Department of Medical Sciences,</institution><institution>University of Torino,</institution></institution-wrap>Turin, Italy</nlm:aff></affiliation></author><author><name sortKey="Mule, Giuseppe" sort="Mule, Giuseppe" uniqKey="Mule G" first="Giuseppe" last="Mulè">Giuseppe Mulè</name><affiliation><nlm:aff id="Aff7"><institution-wrap><institution-id institution-id-type="GRID">grid.10776.37</institution-id><institution-id institution-id-type="ISNI">0000 0004 1762 5517</institution-id><institution>Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, Unit of Nephrology and Hypertension,</institution><institution>University of Palermo,</institution></institution-wrap>Palermo, Italy</nlm:aff></affiliation></author><author><name sortKey="Pucci, Giacomo" sort="Pucci, Giacomo" uniqKey="Pucci G" first="Giacomo" last="Pucci">Giacomo Pucci</name><affiliation><nlm:aff id="Aff8"><institution-wrap><institution-id institution-id-type="GRID">grid.9027.c</institution-id><institution-id institution-id-type="ISNI">0000 0004 1757 3630</institution-id><institution>Section of Internal Medicine Terni, Department of Medicine,</institution><institution>University of Perugia,</institution></institution-wrap>Terni, Italy</nlm:aff></affiliation></author><author><name sortKey="Salvetti, Massimo" sort="Salvetti, Massimo" uniqKey="Salvetti M" first="Massimo" last="Salvetti">Massimo Salvetti</name><affiliation><nlm:aff id="Aff5"><institution-wrap><institution-id 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1760 3561</institution-id><institution>IRCCS Neuromed,</institution></institution-wrap>Pozzilli, IS Italy</nlm:aff></affiliation></author><author><name sortKey="Grassi, Guido" sort="Grassi, Guido" uniqKey="Grassi G" first="Guido" last="Grassi">Guido Grassi</name><affiliation><nlm:aff id="Aff13"><institution-wrap><institution-id institution-id-type="GRID">grid.7563.7</institution-id><institution-id institution-id-type="ISNI">0000 0001 2174 1754</institution-id><institution>Department of Medicine and Surgery,</institution><institution>University of Milano-Bicocca,</institution></institution-wrap>Milan, Italy</nlm:aff></affiliation></author></analytic><series><title level="j">High Blood Pressure & Cardiovascular Prevention</title><idno type="ISSN">1120-9879</idno><idno type="eISSN">1179-1985</idno><imprint><date when="2020">2020</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p id="Par1">Cardiovascular diseases, in particular hypertension, as well as the cardiovascular treatment with Renin–Angiotensin System inhibitors such as Angiotensin Converting Enzyme (ACE) inhibitors and Angiotensin Receptor Blockers (ARBs), are claimed once again as mechanisms of Severe Acute Respiratory Syndrome (SARS) during the COVID-19 outbreak due to Cov-2 epidemics. In vitro studies are available to support the eventual role of ACE inhibitors and ARBs in both the promotion and antagonism of the disease. The available literature, indeed, presents contrasting results, all concentrated in experimental models. Evidence in humans is lacking that those mechanisms are actually occurring in the present COVID-19 outbreak. Here we present the reasoned statement of the Italian Society of Hypertension to maintain ongoing antihypertensive treatments. Furthermore, the Italian Society of Hypertension presents its own initiative to investigate the issue using an online questionnaire to collect relevant data in human disease.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Assiri, A" uniqKey="Assiri A">A Assiri</name></author><author><name sortKey="Al Tawfiq, Ja" uniqKey="Al Tawfiq J">JA Al-Tawfiq</name></author><author><name sortKey="Al Rabeeah, Aa" uniqKey="Al Rabeeah A">AA Al-Rabeeah</name></author><author><name sortKey="Al Rabiah, Fa" uniqKey="Al Rabiah F">FA Al-Rabiah</name></author><author><name sortKey="Al Hajjar, S" uniqKey="Al Hajjar S">S Al-Hajjar</name></author><author><name sortKey="Al Barrak, A" uniqKey="Al Barrak A">A Al-Barrak</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Leung, Gm" uniqKey="Leung G">GM Leung</name></author><author><name sortKey="Hedley, Aj" uniqKey="Hedley A">AJ Hedley</name></author><author><name sortKey="Ho, 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<front><journal-meta><journal-id journal-id-type="nlm-ta">High Blood Press Cardiovasc Prev</journal-id><journal-id journal-id-type="iso-abbrev">High Blood Press Cardiovasc Prev</journal-id><journal-title-group><journal-title>High Blood Pressure & Cardiovascular Prevention</journal-title></journal-title-group><issn pub-type="ppub">1120-9879</issn><issn pub-type="epub">1179-1985</issn><publisher><publisher-name>Springer International Publishing</publisher-name><publisher-loc>Cham</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">31925708</article-id><article-id pub-id-type="pmc">7138256</article-id><article-id pub-id-type="publisher-id">380</article-id><article-id pub-id-type="doi">10.1007/s40292-020-00380-3</article-id><article-categories><subj-group subj-group-type="heading"><subject>Clinical Guidelines and Practice Recommendations</subject></subj-group></article-categories><title-group><article-title>Renin-Angiotensin System Inhibition in Cardiovascular Patients at the Time of COVID19: Much Ado for Nothing? A Statement of Activity from the Directors of the Board and the Scientific Directors of the Italian Society of Hypertension</article-title></title-group><contrib-group><contrib contrib-type="author"><contrib-id contrib-id-type="orcid">http://orcid.org/0000-0002-8997-835X</contrib-id><name><surname>Iaccarino</surname><given-names>Guido</given-names></name><address><email>guiaccar@unina.it</email></address><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid">http://orcid.org/0000-0001-8039-8781</contrib-id><name><surname>Borghi</surname><given-names>Claudio</given-names></name><address><email>claudio.borghi@unibo.it</email></address><xref ref-type="aff" rid="Aff2">2</xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid">http://orcid.org/0000-0002-4367-3884</contrib-id><name><surname>Cicero</surname><given-names>Arrigo F. G.</given-names></name><address><email>arrrigo.cicero@unibo.it</email></address><xref ref-type="aff" rid="Aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Ferri</surname><given-names>Claudio</given-names></name><address><email>claudio.ferri@cc.univaq.it</email></address><xref ref-type="aff" rid="Aff3">3</xref></contrib><contrib contrib-type="author"><name><surname>Minuz</surname><given-names>Pietro</given-names></name><address><email>pietro.minuz@univr.it</email></address><xref ref-type="aff" rid="Aff4">4</xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid">http://orcid.org/0000-0002-4007-9441</contrib-id><name><surname>Muiesan</surname><given-names>Maria Lorenza</given-names></name><address><email>marialorenza.muiesan@unibs.it</email></address><xref ref-type="aff" rid="Aff5">5</xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid">http://orcid.org/0000-0002-5480-1116</contrib-id><name><surname>Mulatero</surname><given-names>Paolo</given-names></name><address><email>paolo.mulatero@unito.it</email></address><xref ref-type="aff" rid="Aff6">6</xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid">http://orcid.org/0000-0002-8500-8671</contrib-id><name><surname>Mulè</surname><given-names>Giuseppe</given-names></name><address><email>giuseppe.mule@unipa.it</email></address><xref ref-type="aff" rid="Aff7">7</xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid">http://orcid.org/0000-0003-0180-859X</contrib-id><name><surname>Pucci</surname><given-names>Giacomo</given-names></name><address><email>giacomo.pucci@gmail.com</email></address><xref ref-type="aff" rid="Aff8">8</xref></contrib><contrib contrib-type="author"><name><surname>Salvetti</surname><given-names>Massimo</given-names></name><address><email>massimo.salvetti@unibs.it</email></address><xref ref-type="aff" rid="Aff5">5</xref></contrib><contrib contrib-type="author"><name><surname>Savoia</surname><given-names>Carmine</given-names></name><address><email>carmine.savoia@uniroma1.it</email></address><xref ref-type="aff" rid="Aff9">9</xref></contrib><contrib contrib-type="author"><name><surname>Sechi</surname><given-names>Leonardo Alberto</given-names></name><address><email>sechi@uniud.it</email></address><xref ref-type="aff" rid="Aff10">10</xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid">http://orcid.org/0000-0002-9642-8380</contrib-id><name><surname>Volpe</surname><given-names>Massimo</given-names></name><address><email>massimo.volpe@uniroma1.it</email></address><xref ref-type="aff" rid="Aff11">11</xref><xref ref-type="aff" rid="Aff12">12</xref></contrib><contrib contrib-type="author" corresp="yes"><contrib-id contrib-id-type="orcid">http://orcid.org/0000-0003-1922-6547</contrib-id><name><surname>Grassi</surname><given-names>Guido</given-names></name><address><email>guido.grassi@unimib.it</email></address><xref ref-type="aff" rid="Aff13">13</xref></contrib><aff id="Aff1"><label>1</label><institution-wrap><institution-id institution-id-type="GRID">grid.4691.a</institution-id><institution-id institution-id-type="ISNI">0000 0001 0790 385X</institution-id><institution>Department of Advanced Biomedical Sciences,</institution><institution>Federico II University,</institution></institution-wrap>Naples, Italy</aff><aff id="Aff2"><label>2</label><institution-wrap><institution-id institution-id-type="GRID">grid.6292.f</institution-id><institution-id institution-id-type="ISNI">0000 0004 1757 1758</institution-id><institution>Department of Medicine and Surgery Sciences,</institution><institution>Alma Mater Studiorum University of Bologna,</institution></institution-wrap>Bologna, Italy</aff><aff id="Aff3"><label>3</label><institution-wrap><institution-id institution-id-type="GRID">grid.158820.6</institution-id><institution-id institution-id-type="ISNI">0000 0004 1757 2611</institution-id><institution>Department of Clinical Medicine, Public Health, Life and Environment Sciences,</institution><institution>University of Aquila,</institution></institution-wrap>L’Aquila, Italy</aff><aff id="Aff4"><label>4</label><institution-wrap><institution-id institution-id-type="GRID">grid.5611.3</institution-id><institution-id institution-id-type="ISNI">0000 0004 1763 1124</institution-id><institution>Department of Medicine,</institution><institution>University of Verona,</institution></institution-wrap>Verona, Italy</aff><aff id="Aff5"><label>5</label><institution-wrap><institution-id institution-id-type="GRID">grid.7637.5</institution-id><institution-id institution-id-type="ISNI">0000000417571846</institution-id><institution>Dept of Clinical & Experimental Sciences,</institution><institution>University of Brescia-Medicina 2,</institution></institution-wrap>ASST Spedali Civili Brescia, Brescia, Italy</aff><aff id="Aff6"><label>6</label><institution-wrap><institution-id institution-id-type="GRID">grid.7605.4</institution-id><institution-id institution-id-type="ISNI">0000 0001 2336 6580</institution-id><institution>Division of Internal Medicine and Hypertension, Department of Medical Sciences,</institution><institution>University of Torino,</institution></institution-wrap>Turin, Italy</aff><aff id="Aff7"><label>7</label><institution-wrap><institution-id institution-id-type="GRID">grid.10776.37</institution-id><institution-id institution-id-type="ISNI">0000 0004 1762 5517</institution-id><institution>Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, Unit of Nephrology and Hypertension,</institution><institution>University of Palermo,</institution></institution-wrap>Palermo, Italy</aff><aff id="Aff8"><label>8</label><institution-wrap><institution-id institution-id-type="GRID">grid.9027.c</institution-id><institution-id institution-id-type="ISNI">0000 0004 1757 3630</institution-id><institution>Section of Internal Medicine Terni, Department of Medicine,</institution><institution>University of Perugia,</institution></institution-wrap>Terni, Italy</aff><aff id="Aff9"><label>9</label><institution-wrap><institution-id institution-id-type="GRID">grid.7841.a</institution-id><institution>Clinical and Molecular Medicine Department,</institution><institution>Sapienza University of Rome,</institution></institution-wrap>Rome, Italy</aff><aff id="Aff10"><label>10</label><institution-wrap><institution-id institution-id-type="GRID">grid.5390.f</institution-id><institution-id institution-id-type="ISNI">0000 0001 2113 062X</institution-id><institution>Department of Medical Area,</institution><institution>University of Udine,</institution></institution-wrap>Udine, Italy</aff><aff id="Aff11"><label>11</label><institution-wrap><institution-id institution-id-type="GRID">grid.7841.a</institution-id><institution>Division of Cardiology, Department of Clinical and Molecular Medicine,</institution><institution>University of Rome Sapienza, Sant’Andrea Hospital,</institution></institution-wrap>Rome, Italy</aff><aff id="Aff12"><label>12</label><institution-wrap><institution-id institution-id-type="GRID">grid.419543.e</institution-id><institution-id institution-id-type="ISNI">0000 0004 1760 3561</institution-id><institution>IRCCS Neuromed,</institution></institution-wrap>Pozzilli, IS Italy</aff><aff id="Aff13"><label>13</label><institution-wrap><institution-id institution-id-type="GRID">grid.7563.7</institution-id><institution-id institution-id-type="ISNI">0000 0001 2174 1754</institution-id><institution>Department of Medicine and Surgery,</institution><institution>University of Milano-Bicocca,</institution></institution-wrap>Milan, Italy</aff></contrib-group><pub-date pub-type="epub"><day>7</day><month>4</month><year>2020</year></pub-date><pub-date pub-type="pmc-release"><day>7</day><month>4</month><year>2020</year></pub-date><fpage>1</fpage><lpage>4</lpage><history><date date-type="received"><day>26</day><month>3</month><year>2020</year></date><date date-type="accepted"><day>2</day><month>4</month><year>2020</year></date></history><permissions><copyright-statement>© The Author(s) 2020</copyright-statement><license license-type="OpenAccess"><license-p><bold>Open Access</bold>This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.To view a copy of this licence, visit <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by-nc/4.0/">http://creativecommons.org/licenses/by-nc/4.0/</ext-link>.</license-p></license></permissions><abstract id="Abs1"><p id="Par1">Cardiovascular diseases, in particular hypertension, as well as the cardiovascular treatment with Renin–Angiotensin System inhibitors such as Angiotensin Converting Enzyme (ACE) inhibitors and Angiotensin Receptor Blockers (ARBs), are claimed once again as mechanisms of Severe Acute Respiratory Syndrome (SARS) during the COVID-19 outbreak due to Cov-2 epidemics. In vitro studies are available to support the eventual role of ACE inhibitors and ARBs in both the promotion and antagonism of the disease. The available literature, indeed, presents contrasting results, all concentrated in experimental models. Evidence in humans is lacking that those mechanisms are actually occurring in the present COVID-19 outbreak. Here we present the reasoned statement of the Italian Society of Hypertension to maintain ongoing antihypertensive treatments. Furthermore, the Italian Society of Hypertension presents its own initiative to investigate the issue using an online questionnaire to collect relevant data in human disease.</p></abstract><kwd-group xml:lang="en"><title>Keywords</title><kwd>COVID-19</kwd><kwd>hypertension</kwd><kwd>cardiovascular diseases</kwd><kwd>infection</kwd><kwd>outcomes</kwd></kwd-group></article-meta></front><body><sec id="Sec1" sec-type="introduction"><title>Introduction</title><p id="Par2">The recent Severe Acute Respiratory Syndrome (SARS) due to Coronavirus 2 (CoV-2) infection pandemic and subsequent spread of the disease called COVID-19 brought back to discussion a topic already highlighted during the SARS-CoV-1 and Coronavirus-related SARS known as the Middle East Respiratory Distress Syndrome (MERS) of 2002 and 2013. During those outbreaks it was observed a particularly elevated incidence of cardiovascular disease among patients, who were also characterized by being elderly and, in particular during the MERS, prevalently male [<xref ref-type="bibr" rid="CR1">1</xref>, <xref ref-type="bibr" rid="CR2">2</xref>].</p><p id="Par3">Another main topic of the discussion is the role of the angiotensin-converting enzyme (ACE) 2. Indeed, this carboxypeptidase has been identified as a functional receptor for the spike protein of the coronaviruses’ outer membrane, including SARS-CoV-2 [<xref ref-type="bibr" rid="CR3">3</xref>]. ACE2 is strongly expressed in the epithelium of different organs, such as the kidney, heart, and lungs.</p><p id="Par4">ACE2 shares a large affinity to the amino peptidase ACE that is target to the ACE inhibitors, a class of antihypertensive drugs. ACE inhibitors represent the most used class of cardiovascular agents in the world, for the treatment of epidemic cardiovascular conditions such as hypertension and heart failure. Although not directly inhibited by ACE inhibitors, ACE2 is affected by chronic treatment with this class of drugs, which leads to an increase in ACE2 expression in several tissues [<xref ref-type="bibr" rid="CR4">4</xref>]. Interestingly, this feature is also shared by another class of drugs, the angiotensin receptor-1 blockers (ARBs), whose chronic administration is as well able to increase the level of expression of ACE2 and also its activity, as assessed by the circulating levels of the ACE2 product, angiotensin 1–7 [<xref ref-type="bibr" rid="CR5">5</xref>]. These findings support the concern that the treatment with Renin-Angiotensin System (RAS) inhibitors could make COVID-19 symptoms more severe due to increased expression of ACE2.</p></sec><sec id="Sec2"><title>Cardiovascular Disease and COVID-19</title><p id="Par5">Remarkably, both issues have been re-proposed in the occurrence of the present epidemic of COVID-19. In particular, the issue of the prevalence of cardiovascular diseases among COVID-19 patients is proposed by observational data obtained in Chinese [<xref ref-type="bibr" rid="CR6">6</xref>] and Italian patients [<xref ref-type="bibr" rid="CR7">7</xref>].</p><p id="Par6">In this context, we still lack the analysis of the confounding effects of age on the apparent association between cardiovascular disease COVID-19 infection and clinical severity. Indeed, the observed prevalence of male and elderly patients, observed especially in the Italian COVID-19 population, is a confounding factor that needs to be corrected for before any conclusive association is drawn. This concern has been expressed by many [<xref ref-type="bibr" rid="CR8">8</xref>–<xref ref-type="bibr" rid="CR10">10</xref>].</p><p id="Par7">Similarly, the ACE2 upregulation argument has never been demonstrated in humans. Indeed, while there is conflicting evidence from animal studies that ARBs (probably not ACE inhibitors) may upregulate membrane-bound ACE2 in tissue-specific manners (e.g., heart but not kidney), these data cannot be extrapolated to humans, and are not sufficient to support facilitation of SARS-CoV-2 entry [<xref ref-type="bibr" rid="CR9">9</xref>]. In particular, it has never been demonstrated that the ACE2 upregulation in the human lung occurs upon RAS inhibition, and even less that this causes a worsening of the COVID-19 disease. Furthermore, it can also be speculated that ACE2 upregulation is protective. Indeed, it has been shown that the binding of coronavirus to ACE2 leads to the downregulation of ACE2 [<xref ref-type="bibr" rid="CR11">11</xref>], which in turn causes an ACE/ACE2 imbalance and to the excessive production of angiotensin II by the related ACE enzyme. This excess of Angiotensin II stimulates angiotensin II receptor type 1 (AT1R) and might cause an increase in pulmonary vascular permeability and lung damage [<xref ref-type="bibr" rid="CR12">12</xref>]. Therefore, according to this hypothesis, the upregulation of ACE2, caused by the chronic intake of AT1R and ACE Inhibitors, could be protective through two mechanisms: first, by blocking the increased production of angiotensin 1–7, which has been advocated as a possible mechanism of protection for the lung; second, by reducing the production of Angiotensin II, it removes a cause of lung damage [<xref ref-type="bibr" rid="CR13">13</xref>].</p></sec><sec id="Sec3"><title>Recommendations</title><p id="Par8">In this context of uncertainty, there are advocates within the scientific community raising their voices for the cessation of ACE inhibitors and ARBs among patients taking these drugs, that is claimed for both the prevention of the infection and the attenuation of the symptoms in case of infection. These speculative claims are then taken over by the laical press, starting a word of mouth that sustains panic behaviors among the general population.</p><p id="Par9">The Italian Society of Hypertension (SIIA) therefore takes a clear and firm position, in line with statements by other International Societies (See Table <xref rid="Tab1" ref-type="table">1</xref>). SIIA states the following items:<table-wrap id="Tab1"><label>Table 1</label><caption><p>List of statements by International Scientific Societies on the need to not suspend RAS inhibitors during COVID-19.</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="left">Scientific Society</th><th align="left">Website</th><th align="left">Title</th></tr></thead><tbody><tr><td align="left">International Society of Hypertension</td><td align="left"><ext-link ext-link-type="uri" xlink:href="https://ish-world.com/news/a/A-statement-from-the-International-Society-of-Hypertension-on-COVID-19/">https://ish-world.com/news/a/A-statement-from-the-International-Society-of-Hypertension-on-COVID-19/</ext-link></td><td align="left">A statement from the International Society of Hypertension on COVID-19</td></tr><tr><td align="left">European Society of Hypertension</td><td align="left"><ext-link ext-link-type="uri" xlink:href="https://www.eshonline.org/spotlights/esh-stabtement-on-covid-19/">https://www.eshonline.org/spotlights/esh-stabtement-on-covid-19/</ext-link></td><td align="left"><p>Statement of the European Society of Hypertension (ESH) on hypertension, Renin Angiotensin System blockers and COVID-19</p><p>March 19th 2020</p></td></tr><tr><td align="left">Council of Hypertension of the European Society of Cardiology,</td><td align="left"><ext-link ext-link-type="uri" xlink:href="https://www.escardio.org/Councils/Council-on-Hypertension-(CHT)/News/position-statement-of-the-esc-council-on-hypertension-on-ace-inhibitors-and-ang">https://www.escardio.org/Councils/Council-on-Hypertension-(CHT)/News/position-statement-of-the-esc-council-on-hypertension-on-ace-inhibitors-and-ang</ext-link></td><td align="left">Position Statement of the ESC Council on Hypertension on ACE-Inhibitors and Angiotensin Receptor Blockers</td></tr><tr><td align="left">Canadian Cardiovascular Society</td><td align="left"><ext-link ext-link-type="uri" xlink:href="https://www.ccs.ca/en/">https://www.ccs.ca/en/</ext-link></td><td align="left">COVID-19 and concerns regarding use of cardiovascular medications, including ACEi/ARB/ARNi, low-dose ASA and non-steroidal anti-inflammatory drugs (NSAIDS)</td></tr><tr><td align="left">Canadian Heart Failure Society</td><td align="left"><ext-link ext-link-type="uri" xlink:href="https://heartfailure.ca/education">https://heartfailure.ca/education</ext-link></td><td align="left"><p>COVID-19 and Concerns Regarding use of ACEi/ARB/ARNi</p><p>Medications for Heart Failure or Hypertension</p></td></tr><tr><td align="left">Joint American Heart Association/American College of Cardiology/American Heart Failure Association</td><td align="left"><ext-link ext-link-type="uri" xlink:href="https://www.acc.org/latest-in-cardiology/articles/2020/03/17/08/59/hfsa-acc-aha-statement-addresses-concerns-re-using-raas-antagonists-in-covid-19">https://www.acc.org/latest-in-cardiology/articles/2020/03/17/08/59/hfsa-acc-aha-statement-addresses-concerns-re-using-raas-antagonists-in-covid-19</ext-link></td><td align="left">HFSA/ACC/AHA Statement Addresses Concerns Re: Using RAAS Antagonists in COVID-19</td></tr></tbody></table></table-wrap><list list-type="order"><list-item><p id="Par11">There is no evidence to associate hypertension or other CVDs with COVID-19 disease: if hypertension was a predisposing factor for coronavirus infection, there should be more hypertensives among COVID-19 patients than observed in the general population; to date, there is no evidence that people with hypertension are overrepresented among those infected with COVID-19.</p></list-item><list-item><p id="Par12">There is no clinical evidence in humans that associates the intake of ACE inhibitors or ARBs with COVID-19 disease. At present we can neither say that they improve nor say they worsen the susceptibility to coronavirus infection.</p></list-item><list-item><p id="Par13">There are no clinical data in patients that can confirm the harmful effect (not even the protective one) of ACE inhibitors and ARB in the context of the COVID-19 epidemic.</p></list-item></list></p><p id="Par14">Furthermore, SIIA reiterates that subsequent points:</p><p id="Par15"><list list-type="simple"><list-item><label>A.</label><p id="Par16">Acute suspension without medical control of cardiovascular therapy and specifically of antihypertensive treatment increases the occurrence of acute events, including hypertensive emergencies, heart failure decompensation, heart attacks, and stroke.</p></list-item><list-item><label>B.</label><p id="Par17">The favorable effects of ACE inhibitors and ARBs on the control of the progression of CVDs in general and in particular of hypertensive patients have been confirmed for many years and for this reason RAS inhibitors represent central agents for the management of cardiovascular conditions that cannot be easily substituted [<xref ref-type="bibr" rid="CR10">10</xref>].</p></list-item><list-item><label>C.</label><p id="Par18">In hypertensive patients with COVID-19 or at risk of COVID-19 infection, ACE inhibitors and ARBs treatment should be maintained according to the recommendations contained in the 2018 ESC/ESH guidelines [<xref ref-type="bibr" rid="CR10">10</xref>].</p></list-item><list-item><label>D.</label><p id="Par19">Similarly, in all patients currently on therapy with ACE inhibitors, ARBs and in the case of patients with heart failure, also the ARNIs, these drugs must not be suspended.</p></list-item><list-item><label>E.</label><p id="Par20">In patients with COVID-19 with severe symptoms or sepsis, ACE Inhibitors and ARBs, like all other antihypertensive drugs, should be used or discontinued on a case by case basis, taking into account current guidelines.</p></list-item></list></p></sec><sec id="Sec4"><title>Further Scientific Research</title><p id="Par21">SIIA hopes and promotes further research that analyzes the constantly increasing data on the impact of hypertension and antihypertensive drugs, in particular ACE inhibitors and ARBs, on the clinical course of COVID-19 infections, in order to update these positions as new evidence becomes available.</p><p id="Par22">In particular, to clarify which mechanism is prevalent and has a role in the clinical manifestation of COVID-19, SIIA has launched a fact-finding investigation to verify the impact of therapy with inhibitors of the renin-angiotensin system on the onset and clinical manifestation of the disease COVID-19. 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