Circulating plasma concentrations of angiotensin-converting enzyme 2 in men and women with heart failure and effects of renin–angiotensin–aldosterone inhibitors (2024)

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Circulating plasma concentrations of angiotensin-converting enzyme 2 in men and women with heart failure and effects of renin–angiotensin–aldosterone inhibitors (1)

Author(s):

Iziah E Sama e1 ,

Alice Ravera e1 , e2 ,

Bernadet T Santema e1 ,

Harry van Goor e3 ,

Jozine M ter Maaten e1 ,

John G F Cleland e4 ,

Michiel Rienstra e1 ,

Alex W Friedrich e5 ,

Nilesh J Samani e6 ,

Leong L Ng e6 ,

Kenneth Dickstein e7 , e8 ,

Chim C Lang e9 ,

Gerasimos Filippatos e10 , e11 ,

Stefan D Anker e12 , e13 ,

Piotr Ponikowski e14 ,

Marco Metra e2 ,

Dirk J van Veldhuisen e1 ,

Adriaan A Voors e1

Publication date (Electronic): 10 May 2020

Journal: European Heart Journal

Publisher: Oxford University Press

Keywords: Men, Heart failure, Coronavirus disease (COVID-19), ACE2

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      Abstract

      Aims

      The current pandemic coronavirus SARS-CoV-2 infects a wide age group but predominantly elderly individuals, especially men and those with cardiovascular disease. Recent reports suggest an association with use of renin–angiotensin–aldosterone system (RAAS) inhibitors. Angiotensin-converting enzyme 2 (ACE2) is a functional receptor for coronaviruses. Higher ACE2 concentrations might lead to increased vulnerability to SARS-CoV-2 in patients on RAAS inhibitors.

      Methods and results

      We measured ACE2 concentrations in 1485 men and 537 women with heart failure (index cohort). Results were validated in 1123 men and 575 women (validation cohort).

      The median age was 69 years for men and 75 years for women. The strongest predictor of elevated concentrations of ACE2 in both cohorts was male sex (estimate = 0.26, P < 0.001; and 0.19, P < 0.001, respectively). In the index cohort, use of ACE inhibitors, angiotensin receptor blockers (ARBs), or mineralocorticoid receptor antagonists (MRAs) was not an independent predictor of plasma ACE2. In the validation cohort, ACE inhibitor (estimate = –0.17, P = 0.002) and ARB use (estimate = –0.15, P = 0.03) were independent predictors of lower plasma ACE2, while use of an MRA (estimate = 0.11, P = 0.04) was an independent predictor of higher plasma ACE2 concentrations.

      Conclusion

      In two independent cohorts of patients with heart failure, plasma concentrations of ACE2 were higher in men than in women, but use of neither an ACE inhibitor nor an ARB was associated with higher plasma ACE2 concentrations. These data might explain the higher incidence and fatality rate of COVID-19 in men, but do not support previous reports suggesting that ACE inhibitors or ARBs increase the vulnerability for COVID-19 through increased plasma ACE2 concentrations.

      Related collections

      Novel Coronavirus Disease COVID-19

      Most cited references15

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      Clinical Characteristics of Coronavirus Disease 2019 in China

      Wei-jie Guan, Zheng-yi Ni, Yu Hu (2020)

      Abstract Background Since December 2019, when coronavirus disease 2019 (Covid-19) emerged in Wuhan city and rapidly spread throughout China, data have been needed on the clinical characteristics of the affected patients. Methods We extracted data regarding 1099 patients with laboratory-confirmed Covid-19 from 552 hospitals in 30 provinces, autonomous regions, and municipalities in mainland China through January 29, 2020. The primary composite end point was admission to an intensive care unit (ICU), the use of mechanical ventilation, or death. Results The median age of the patients was 47 years; 41.9% of the patients were female. The primary composite end point occurred in 67 patients (6.1%), including 5.0% who were admitted to the ICU, 2.3% who underwent invasive mechanical ventilation, and 1.4% who died. Only 1.9% of the patients had a history of direct contact with wildlife. Among nonresidents of Wuhan, 72.3% had contact with residents of Wuhan, including 31.3% who had visited the city. The most common symptoms were fever (43.8% on admission and 88.7% during hospitalization) and cough (67.8%). Diarrhea was uncommon (3.8%). The median incubation period was 4 days (interquartile range, 2 to 7). On admission, ground-glass opacity was the most common radiologic finding on chest computed tomography (CT) (56.4%). No radiographic or CT abnormality was found in 157 of 877 patients (17.9%) with nonsevere disease and in 5 of 173 patients (2.9%) with severe disease. Lymphocytopenia was present in 83.2% of the patients on admission. Conclusions During the first 2 months of the current outbreak, Covid-19 spread rapidly throughout China and caused varying degrees of illness. Patients often presented without fever, and many did not have abnormal radiologic findings. (Funded by the National Health Commission of China and others.)

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        A pneumonia outbreak associated with a new coronavirus of probable bat origin

        Peng Zhou, Xing-Lou Yang, Xian-Guang Wang (2020)

        Since the outbreak of severe acute respiratory syndrome (SARS) 18years ago, a large number of SARS-related coronaviruses (SARSr-CoVs) have been discovered in their natural reservoir host, bats 1–4 . Previous studies have shown that some bat SARSr-CoVs have the potential to infect humans 5–7 . Here we report the identification and characterization of a new coronavirus (2019-nCoV), which caused an epidemic of acute respiratory syndrome in humans in Wuhan, China. The epidemic, which started on 12 December 2019, had caused 2,794 laboratory-confirmed infections including 80 deaths by 26 January 2020. Full-length genome sequences were obtained from five patients at an early stage of the outbreak. The sequences are almost identical and share 79.6% sequence identity to SARS-CoV. Furthermore, we show that 2019-nCoV is 96% identical at the whole-genome level to a bat coronavirus. Pairwise protein sequence analysis of seven conserved non-structural proteins domains show that this virus belongs to the species of SARSr-CoV. In addition, 2019-nCoV virus isolated from the bronchoalveolar lavage fluid of a critically ill patient could be neutralized by sera from several patients. Notably, we confirmed that 2019-nCoV uses the same cell entry receptor—angiotensin converting enzyme II (ACE2)—as SARS-CoV.

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          Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study

          Xiaobo Yang, Yuan Yu, Jiqian Xu (2020)

          Summary Background An ongoing outbreak of pneumonia associated with the severe acute respiratory coronavirus 2 (SARS-CoV-2) started in December, 2019, in Wuhan, China. Information about critically ill patients with SARS-CoV-2 infection is scarce. We aimed to describe the clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia. Methods In this single-centered, retrospective, observational study, we enrolled 52 critically ill adult patients with SARS-CoV-2 pneumonia who were admitted to the intensive care unit (ICU) of Wuhan Jin Yin-tan hospital (Wuhan, China) between late December, 2019, and Jan 26, 2020. Demographic data, symptoms, laboratory values, comorbidities, treatments, and clinical outcomes were all collected. Data were compared between survivors and non-survivors. The primary outcome was 28-day mortality, as of Feb 9, 2020. Secondary outcomes included incidence of SARS-CoV-2-related acute respiratory distress syndrome (ARDS) and the proportion of patients requiring mechanical ventilation. Findings Of 710 patients with SARS-CoV-2 pneumonia, 52 critically ill adult patients were included. The mean age of the 52 patients was 59·7 (SD 13·3) years, 35 (67%) were men, 21 (40%) had chronic illness, 51 (98%) had fever. 32 (61·5%) patients had died at 28 days, and the median duration from admission to the intensive care unit (ICU) to death was 7 (IQR 3–11) days for non-survivors. Compared with survivors, non-survivors were older (64·6 years [11·2] vs 51·9 years [12·9]), more likely to develop ARDS (26 [81%] patients vs 9 [45%] patients), and more likely to receive mechanical ventilation (30 [94%] patients vs 7 [35%] patients), either invasively or non-invasively. Most patients had organ function damage, including 35 (67%) with ARDS, 15 (29%) with acute kidney injury, 12 (23%) with cardiac injury, 15 (29%) with liver dysfunction, and one (2%) with pneumothorax. 37 (71%) patients required mechanical ventilation. Hospital-acquired infection occurred in seven (13·5%) patients. Interpretation The mortality of critically ill patients with SARS-CoV-2 pneumonia is considerable. The survival time of the non-survivors is likely to be within 1–2 weeks after ICU admission. Older patients (>65 years) with comorbidities and ARDS are at increased risk of death. The severity of SARS-CoV-2 pneumonia poses great strain on critical care resources in hospitals, especially if they are not adequately staffed or resourced. Funding None.

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            Author and article information

            Journal

            Journal ID (nlm-ta): Eur Heart J

            Journal ID (iso-abbrev): Eur. Heart J

            Journal ID (publisher-id): eurheartj

            Title: European Heart Journal

            Publisher: Oxford University Press

            ISSN (Print): 0195-668X

            ISSN (Electronic): 1522-9645

            Publication date (Print): 14 May 2020

            Publication date (Electronic): 10 May 2020

            Volume: 41

            Issue: 19 , Focus Issue on COVID-19 and CVD

            Pages: 1810-1817

            Affiliations

            [e1 ] Department of Cardiology, University of Groningen, University Medical Center Groningen , Groningen, The Netherlands

            [e2 ] Cardiology, Department of Medical and Surgical Specialties, Radiologic Sciences and Public Health, University of Brescia , Brescia, Italy

            [e3 ] Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen , Groningen, The Netherlands

            [e4 ] Robertson Centre for Biostatistics & Clinical Trials Unit, University of Glasgow and National Heart & Lung Institute , Imperial College, London, UK

            [e5 ] Department of Medical Microbiology, University of Groningen, University Medical Center Groningen , Groningen, The Netherlands

            [e6 ] Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, and NIHR Leicester Biomedical Research Centre , Leicester, UK

            [e7 ] University of Bergen , Bergen, Norway

            [e8 ] Stavanger University Hospital , Stavanger, Norway

            [e9 ] Division of Molecular and Clinical Medicine, School of Medicine, University of Dundee Ninewells Hospital and Medical School , Dundee, UK

            [e10 ] National and Kapodistrian University of Athens, School of Medicine , Athens, Greece

            [e11 ] University of Cyprus, School of Medicine , Nicosia, Cyprus

            [e12 ] Department of Cardiology (CVK) and Berlin Institute of Health Center for Regenerative Therapies (BCRT) , Germany

            [e13 ] German Centre for Cardiovascular Research (DZHK) partner site Berlin, Charité Universitätsmedizin Berlin, Germany

            [e14 ] Department of Heart Diseases, Medical University, Military Hospital , Wrocław, Poland

            Author notes

            Corresponding author. Department of Cardiology, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands. Tel: +31 (0)50 3616161; Fax: +31 (0)50 3618062; Email: a.a.voors@ 123456umcg.nl

            Author information
            Article

            Publisher ID: ehaa373

            DOI: 10.1093/eurheartj/ehaa373

            PMC ID: 7239195

            PubMed ID: 32388565

            SO-VID: c0346264-e027-422c-ba26-e768525d635c

            Copyright © Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.

            License:

            This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model ( https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

            This article is made available via the PMC Open Access Subset for unrestricted re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the COVID-19 pandemic or until permissions are revoked in writing. Upon expiration of these permissions, PMC is granted a perpetual license to make this article available via PMC and Europe PMC, consistent with existing copyright protections.

            History

            Date received : 22 March 2020

            Date revision received : 03 April 2020

            Date accepted : 20 April 2020

            Related
            Page count

            Pages: 8

            Funding

            Funded by: European Commission, DOI 10.13039/501100000780;

            Award ID: FP7-242209-BIOSTAT-CHF

            Funded by: Dutch Heart Foundation;

            Award ID: 2019T094

            Categories

            Subject: Fast Track Clinical Research

            Subject: Heart Failure/Cardiomyopathy

            Subject: Editor's Choice


            ScienceOpen disciplines: Cardiovascular Medicine

            Keywords: men,heart failure,coronavirus disease (covid-19),ace2

            Data availability:

            ScienceOpen disciplines: Cardiovascular Medicine

            Keywords: men, heart failure, coronavirus disease (covid-19), ace2

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            Circulating plasma concentrations of angiotensin-converting enzyme 2 in men and women with heart failure and effects of renin–angiotensin–aldosterone inhibitors (2024)

            FAQs

            What is the role of the renin angiotensin aldosterone system in heart failure? ›

            Early in heart failure, RAAS is activated as a compensatory mechanism, but with the progression of the disease, it assumes a detrimental role, responsible for increased preload and afterload, which are the hallmarks of clinical heart failure syndrome.

            What is the role of ACE in the renin, angiotensin, and aldosterone system? ›

            Angiotensin-converting enzyme (ACE), a dipeptidyl carboxypeptidase, is a key enzyme in the renin–angiotensin system (RAS); it converts the inactive decapeptide, angiotensin I (Ang I; or Ang 1–10), to the active octapeptide and potent vasoconstrictor Ang II (or Ang 1–8) (Figure 1), and inactivates the vasodilator ...

            How does angiotensin-converting enzyme affect blood pressure? ›

            Angiotensin-converting enzyme (ACE) inhibitors are medicines that help relax the veins and arteries to lower blood pressure. ACE inhibitors prevent an enzyme in the body from making angiotensin 2, a substance that narrows blood vessels. This narrowing can cause high blood pressure and forces the heart to work harder.

            How does angiotensin II affect heart failure? ›

            Angiotensin II (AII) plays a critical role in cardiac remodeling. This peptide promotes cardiac myocyte hypertrophy and cardiac fibroblast interstitial fibrotic changes associated with left ventricular hypertrophy, post myocardial infarction remodeling and congestive heart failure.

            What happens when the renin-angiotensin-aldosterone system is activated? ›

            In particular, activation of the renin-angiotensin-aldosterone system (RAAS) leads to increased levels of angiotensin II and plasma aldosterone, and promote development of arterial vasoconstriction and remodeling, sodium retention, oxidative process, and cardiac fibrosis.

            How does renin angiotensin and aldosterone affect blood pressure? ›

            The net effects of the activation of the RAAS include vasocontriction, sodium and water retention, increased arterial blood pressure and increased myocardial contractility, which in combination increase the effective circulating volume.

            What diseases cause high ACE levels? ›

            A higher than normal ACE level may also be seen in several other diseases and disorders, including:
            • Adrenal glands do not make enough hormones (Addison disease)
            • Cancer of the lymph tissue (Hodgkin disease)
            • Diabetes.
            • Liver swelling and inflammation (hepatitis) due to alcohol use.

            How do ACE inhibitors work to reduce heart failure? ›

            ACE inhibitors dilate the blood vessels to improve your blood flow. This helps decrease the amount of work the heart has to do. They also help block a substance in the blood called angiotensin that is made as a result of heart failure. Angiotensin is one of the most powerful blood vessel narrowers in the body.

            At what creatinine level should ACE inhibitors be stopped? ›

            Thus, withdrawal of an ACEI in such patients should occur only when the rise in creatinine exceeds 30% above baseline within the first 2 months of ACEI initiation, or hyperkalemia develops, ie, serum potassium level of 5.6 mmol/L or greater.

            How does angiotensin 2 affect blood pressure? ›

            Angiotensin II (Ang II) raises blood pressure (BP) by a number of actions, the most important ones being vasoconstriction, sympathetic nervous stimulation, increased aldosterone biosynthesis and renal actions.

            What should not be taken with lisinopril? ›

            Some products that may interact with this drug are: aliskiren, certain drugs that weaken the immune system/increase the risk of infection (such as everolimus, sirolimus), lithium, drugs that may increase the level of potassium in the blood (such as ARBs including losartan/valsartan, birth control pills containing ...

            What foods should I avoid while taking enalapril? ›

            enalapril food

            It is recommended that if you are taking enalapril you should be advised to avoid moderately high or high potassium dietary intake. This can cause high levels of potassium in your blood. Do not use salt substitutes or potassium supplements while taking enalapril, unless your doctor has told you to.

            What are the 4 main effects of angiotensin II? ›

            It causes increases in blood pressure, influences renal tubuli to retain sodium and water, and stimulates aldosterone release from adrenal gland. Besides being a potent vasoconstrictor, Ang II also exerts proliferative, pro-inflammatory and pro-fibrotic activities.

            Does angiotensin II affect the heart? ›

            However, AngII also has blood pressure-dependent and blood pressure-independent effects in the heart that play a critical role in causing cardiac remodeling and dysfunction as well.

            How does angiotensin II affect cardiac output? ›

            The constancy of the cardiac output response following beta-adrenoceptor blockade suggested that Ang-II increased cardiac output by constricting venous smooth muscle and thereby increasing venous return.

            What is the role of RAAS in congestive heart failure? ›

            The RAAS is frequently hyperactive in HF, which increases fluid retention and worsens cardiac function. The SNS is frequently hyperactive in heart failure, which increases the workload on the heart and worsens symptoms.

            What is the RAAS system in congestive heart failure? ›

            The RAAS is activated by renal hypoperfusion and sympathetic activation. The key product of this cascade is angiotensin II (ATII), which has multiple system-wide effects that are initially compensatory but subsequently exacerbate the heart failure syndrome.

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