Antihypertensive medication uses and serum ACE2 levels
Valur EmilssonElías F. GuðmundssonThor AspelundBrynjolfur G. JonssonAlexander GuðjónssonLenore J. LaunerLori L. JenningsValborg GuðmundsdóttirVilmundur Guðnason
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Abstract Importance Recent reports have shown that hypertension is the most common comorbidity associated with mortality in the current coronavirus disease 2019 (COVID-19). This has been related to the use of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) as animal studies indicate that these medications increase levels of ACE2, the cellular entry point for the coronavirus SARS-CoV-2. This has prompted clinicians to recommend discontinuing ACEIs and ARBs. Objective To examine the effect of ACEIs or ARBs treatment on serum levels of ACE2 and other key enzymes in the renin-angiotensin system (RAS). Design, Setting, and Participants A single center population-based study of 5457 Icelanders from the Age, Gene/Environment Susceptibility Reykjavik Study (AGES-RS) of the elderly (mean age 75±6 years) stratified by ACEIs (N = 699) or ARBs (N = 753) treatment. Main Outcomes and Measures The AGES-RS study population was stratified by ACEIs and ARBs medication use and compared for age, body mass index (BMI) (kg/m 2 ), hypertension and type 2 diabetes (T2D) as well as serum levels of renin, ACE and ACE2. Results While renin and ACE levels were significantly raised in serum of individuals on ACEIs or ARBs treatments, the ACE2 levels remained unaffected. Conclusions and Relevance Treatment with ACEIs or ARBs does not raise ACE2 levels in serum. Therefore, the present study does not support the proposed discontinuation of these medications among patients affected with COVID-19. Key Points Question Does treatment with the antihypertensive medications angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) result in elevated levels of the cellular receptor for the coronavirus SARS-CoV-2, ACE2? Findings In a single center population-based cohort (AGES-RS), 699 and 753 individuals were either on ACEIs or ARBs treatment, respectively. The serum levels of the key enzymes in the renin-angiotensin system (RAS), renin, ACE and ACE2 were measured in 5457 subjects of the AGES-RS and their serum levels in individuals on ACEIs or ARBs treatment compared to those not using these medications. While renin and ACE were significantly raised in serum of ACEIs and ARBs users, the levels of ACE2 remained unaffected. Meaning These results do not support the proposed routine discontinuation of ACEIs or ARBs among patients affected with COVID-19.Keywords:
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We showed ACE (angiotensin-converting enzyme) 2 is higher in the kidney of male compared with female mice. To further investigate this sex difference, we examined the role of ACE2 in Ang-[1-8] (angiotensin [1-8])-induced hypertension and regulation of the renin-angiotensin system in the kidney of WT (wild type) and Ace2 KO (knockout) mice. Mean arterial pressure rose faster in WT male than WT female mice after Ang-[1-8] infusion. This sex difference was attenuated in ACE2 KO mice. Ang-[1-8] infusion reduced glomerular AT1R (angiotensin type 1 receptor) binding in WT female mice by 30%, and deletion of Ace2 abolished this effect. In contrast, Ang-[1-8] infusion increased glomerular AT1R binding in WT male mice by 1.2-fold, and this effect of Ang-[1-8] persisted in Ace2 KO male mice (1.3-fold). ACE2 also had an effect on renal protein expression of the neutral endopeptidase NEP (neprilysin), the enzyme that catabolizes Ang-[1-10] (angiotensin [1-10]), the precursor of Ang-[1-8]. Ang-[1-8] infusion downregulated NEP protein expression by 20% in WT male, whereas there was a slight increase in NEP expression in WT female mice. Deletion of Ace2 resulted in lowered NEP expression after Ang-[1-8] infusion in both sexes. These findings suggest sex-specific ACE2 regulation of the renin-angiotensin system contributes to female protection from Ang-[1-8]-induced hypertension. These findings have ramifications for the current coronavirus disease 2019 (COVID-19) pandemic, especially in hypertension since ACE2 is the SARS-CoV-2 receptor and hypertension is a major risk factor for poor outcomes.
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Background: Reasons for treatment discontinuation are important not only to understand the benefit and risk profile of experimental treatments, but also to help choose appropriate strategies to handle intercurrent events in defining estimands. The current case report form (CRF) commonly in use mixes the underlying reasons for treatment discontinuation and who makes the decision for treatment discontinuation, often resulting in an inaccurate collection of reasons for treatment discontinuation. Methods and results: We systematically reviewed and analyzed treatment discontinuation data from nine phase 2 and phase 3 studies for insulin peglispro. A total of 857 participants with treatment discontinuation were included in the analysis. Our review suggested that, due to the vague multiple-choice options for treatment discontinuation present in the CRF, different reasons were sometimes recorded for the same underlying reason for treatment discontinuation. Based on our review and analysis, we suggest an intermediate solution and a more systematic way to improve the current CRF for treatment discontinuations. Conclusion: This research provides insight and directions on how to optimize the CRF for recording treatment discontinuation. Further work needs to be done to build the learning into Clinical Data Interchange Standards Consortium standards.
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This paper addresses current issues associated with medication discontinuation in panic disorder, with specific focus on one of the most frequently used medication classes for this indication, the benzodiazepines. The majority of patients, when slowly tapered, are able to discontinue the benzodiazepines without a great deal of difficulty, particularly after short-term therapy. Patients treated with long-term therapy at high therapeutic doses may experience greater difficulty with discontinuation. If patients are adequately prepared and if discontinuation is conducted slowly and gradually, discontinuation symptoms, if they occur, are transient, mild to moderate, and generally tolerable. However, return of the original condition (relapse) during discontinuation can greatly complicate clinical management.
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SARS-CoV-2 impairs the renin-angiotensin-aledosterone system via binding ACE2 enzyme. ACE2 plays a key role in the biosynthesis of angiotensin (1-7), catalyzing the conversion of angiotensin 2 into angiotensin (1-7) and the reaction of angiotensin synthesis (1-9), from which angiotensin is (1-7) produced under the influence of ACE (Angiotensin-Converting Enzyme). Angiotensin 2 is a potent vasoconstrictor and atherogenic molecule converted by ACE2 to reducing inflammation and vasodilating in action angiotensin (1-7). Angiotensin (1-9), that is a product of angiotensin 1 metabolism and precursor of angiotensin (1-7), also exerts cell protective properties. Balance between angiotensin 2 and angiotensin (1-7) regulates blood pressure and ACE2 plays a critical role in this balance. ACE2, unlike ACE, is not inhibited by ACE inhibitors at the doses used in humans during the treatment of arterial hypertension. Membrane ACE2 is one of the receptors that allows SARS-CoV-2 to enter the host cells. ACE2 after SARS-CoV-2 binding is internalized and degraded. Hence ACE2 activity on the cell surface is reduced leading to increase the concentration of angiotensin 2 and decrease the concentration of angiotensin (1-7). Disturbed angiotensins metabolism, changes in ratio between angiotensins with distinct biological activities leading to domination of atherogenic angiotensin 2 can increase the damage to the lungs.
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Discontinuation of a crime can be divided into discontinuation of preparation of a crime, discontinuation of starting a crime,discontinuation of acting a crime and discontinuation of accomplished crime,negative and positive discontinuation,common discontinuation and quasi- discontinuation,damaged and non-damaged discontinuation and etc.Redefinition of the concepts of various discontinuation of a crime is helpful to the determination in judicial practice.
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The angiotensin converting enzyme (ACE) 2 is a cell surface protein used for entry into type II pneumocytes and other tissues by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) – the infective agent of COVID-19.1Vaduganathan M Vardeny O Michel T McMurray JJ Pfeffer MA Solomon SD Renin–angiotensin–aldosterone system inhibitors in patients with Covid-19.N Engl J Med. 2020; 382: 1653-1659Crossref PubMed Scopus (1563) Google Scholar It has been demonstrated that ACE2 is upregulated on tissues by renin-angiotensin-aldosterone system (RAAS) inhibitors. This raised concerns that RAAS inhibitors may increase susceptibility and worsen prognosis in COVID-19. In contrast, ACE2 facilitates degradation of angiotensin II and has an anti-inflammatory function and may actually protect the lungs and other tissues from injury.1Vaduganathan M Vardeny O Michel T McMurray JJ Pfeffer MA Solomon SD Renin–angiotensin–aldosterone system inhibitors in patients with Covid-19.N Engl J Med. 2020; 382: 1653-1659Crossref PubMed Scopus (1563) Google Scholar Thus, the effect of RAAS inhibitors on susceptibility and prognosis of COVID-19 continues to be the subject of much debate.1Vaduganathan M Vardeny O Michel T McMurray JJ Pfeffer MA Solomon SD Renin–angiotensin–aldosterone system inhibitors in patients with Covid-19.N Engl J Med. 2020; 382: 1653-1659Crossref PubMed Scopus (1563) Google Scholar Individual observational studies in the area have yielded equivocal results; hence, we sought to conduct a meta-analysis of all available data to provide greater insight. For this study, PubMed and Scopus were searched in May 2020 using the following keywords and their MeSH terms: "COVID-19," "hypertension," "ACE inhibitors (ACEIs)," and "Angiotensin receptor blockers (ARBs)." Studies were included if they:1Vaduganathan M Vardeny O Michel T McMurray JJ Pfeffer MA Solomon SD Renin–angiotensin–aldosterone system inhibitors in patients with Covid-19.N Engl J Med. 2020; 382: 1653-1659Crossref PubMed Scopus (1563) Google Scholar they reported the risk of testing positive for COVID-19 and/or the risk of mortality in COVID-positive patients; and2Mancia G Rea F Ludergnani M Apolone G Corrao G Renin–angiotensin–aldosterone system blockers and the risk of Covid-19.N Engl J Med. 2020; 382: 2431-2440Crossref PubMed Scopus (832) Google Scholar compared hypertensive patients prescribed RAAS inhibitors to those not using these drugs. Odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) from each study were pooled using a random-effects model. A p-value <0.05 was considered significant. Our initial search yielded 950 potential studies. After exclusions, eight studies2Mancia G Rea F Ludergnani M Apolone G Corrao G Renin–angiotensin–aldosterone system blockers and the risk of Covid-19.N Engl J Med. 2020; 382: 2431-2440Crossref PubMed Scopus (832) Google Scholar, 3Mehta N Kalra A Nowacki AS Anjewierden S Han Z Bhat P Carmona-Rubio AE Jacob M Procop GW Harrington S Milinovich A Svensson LG Jehi L Young JB Chung MK Association of use of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers with testing positive for coronavirus disease 2019 (COVID-19).JAMA Cardiol. 2020; (Published online on May 05, 2020)Crossref Scopus (318) Google Scholar, 4Meng J Xiao G Zhang J He X Ou M Bi J et al.Renin-angiotensin system inhibitors improve the clinical outcomes of COVID-19 patients with hypertension.Emerg Microbes Infect. 2020; 9: 757-760Crossref PubMed Scopus (464) Google Scholar, 5Peng YD Meng K Guan HQ Leng L Zhu RR Wang BY et al.[Clinical characteristics and outcomes of 112 cardiovascular disease patients infected by 2019-nCoV].Zhonghua Xin Xue Guan Bing Za Zhi. 2020; 48: E004PubMed Google Scholar, 6Reynolds HR Adhikari S Pulgarin C Troxel AB Iturrate E Johnson SB et al.Renin–angiotensin–aldosterone system inhibitors and risk of Covid-19.N Engl J Med. 2020; 382: 2441-2448Crossref PubMed Scopus (830) Google Scholar, 7Richardson S Hirsch JS Narasimhan M Crawford JM McGinn T Davidson KW et al.Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City Area.JAMA. 2020; Crossref PubMed Scopus (6378) Google Scholar, 8Yang G Tan Z Zhou L Yang M Peng L Liu J et al.Effects of ARBs and ACEIs on virus infection, inflammatory status and clinical outcomes in COVID-19 patients with hypertension: a single center retrospective study.Hypertens (Dallas, Tex: 1979). 2020; 76: 51-58Crossref PubMed Scopus (223) Google Scholar, 9Zhang P Zhu L Cai J Lei F Qin JJ Xie J Liu YM Zhao YC Huang X Lin L Xia M Chen MM Cheng X Zhang X Guo D Peng Y Ji YX Chen Y Chen J She ZG Wang Y Xu Q Tan R Wang H Lin J Luo P Fu S Cai H Ye P Xiao B Mao W Liu L Yan Y Liu M Chen M Zhang XJ Wang X Touyz RM Xia J Zhang BH Huang X Yuan Y Rohit L Liu PP Li H Association of inpatient use of angiotensin converting enzyme inhibitors and angiotensin II receptor blockers with mortality among patients with hypertension hospitalized with COVID-19.Circ Res. 2020; 126: 1671-1681Crossref PubMed Scopus (856) Google Scholar with a total of 62,706 patients (n = 20,316 ACEI/ARB users and n = 42,390 nonusers) remained for analysis. Study and baseline characteristics are provided in Table 1. Pooled analysis revealed no significant association between the likelihood of testing positive for COVID-19 and the use of ACEIs (OR 0.96 [0.88 to 1.04]; p = 0.29; I2 = 0%) (Figure 1) or ARBs (OR 0.99 [0.91 to 1.08]; p = 0.90; I2 = 5%) (Figure 1). Similarly, no significant difference was observed in mortality rate among hypertensive patients prescribed RAAS inhibitors compared with hypertensive patients not prescribed these medications (OR 0.74 [0.34 to 1.58]; p = 0.43; I2 = 65%) (Figure 1).Table 1Baseline and study characteristicsStudyDesignCountryTotal patientsCOVID-19 positive (%)RAAS inhibitor group (Total, ACEi, ARB)Non-RAAS inhibitor group (Total, non-ACEI, non-ARB)AgeMale (%)AdjustmentStudies reporting mortalityMeng et al.Cross-sectionalChina42-17, -, -25, -, -64.5 (55.80 - 69.00)57.1-Richardson et al.RetrospectiveUSA2411--, 140, 1942077, -, -63 (52 - 75)60.3-Yang et al.RetrospectiveChina126-43, -, -83, -, -66 (61 - 73)49.2-Yudong et al.RetrospectiveChina112-22, -, -90, -, -62--Zhang et al.RetrospectiveChina1128-188, -, -940, -, --ACEIARB - 53.2-Studies reporting risk of testing positive for COVID-19Mancia et al.Case-controlItaly37,03116.915,375, 8071, 730421,656, -, -68 ± 1363Multivariable adjustment for severity, sex, municipality, age at diagnosis, a number of treatment-related covariates and markers of patient clinical statusMehta et al.Cross-sectionalUSA184729.42285, 1322, 98216187, 17150, 17490ACEI - 63, ARB -64ACEI - 49, ARB - 59Propensity matched for age, sex, diabetes, coronary artery disease, hypertension, chronic obstructive pulmonary disease and heart failureReynolds et al.Cross-sectionalUSA338446.81692, 954, 10571692, 954, 1057ACEI - 64.7, ARB - 66ACEI - 56, ARB - 50Propensity matched for age; sex; race; ethnic group; body-mass index; smoking history; history of hypertension, myocardial infarction, heart failure, diabetes, chronic kidney disease, and obstructive lung disease (e.g., asthma and obstructive pulmonary diseases); and other classes of medication.RAAS inhibitor = Renin-angiotensin-aldosterone system inhibitor; ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin II receptor blocker. Open table in a new tab RAAS inhibitor = Renin-angiotensin-aldosterone system inhibitor; ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin II receptor blocker. The results of the current meta-analysis suggest that neither ACEI nor ARB use is significantly associated with the odds of testing positive with COVID-19. This result can be considered robust, as it was derived from 3 large-scale studies2Mancia G Rea F Ludergnani M Apolone G Corrao G Renin–angiotensin–aldosterone system blockers and the risk of Covid-19.N Engl J Med. 2020; 382: 2431-2440Crossref PubMed Scopus (832) Google Scholar,3Mehta N Kalra A Nowacki AS Anjewierden S Han Z Bhat P Carmona-Rubio AE Jacob M Procop GW Harrington S Milinovich A Svensson LG Jehi L Young JB Chung MK Association of use of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers with testing positive for coronavirus disease 2019 (COVID-19).JAMA Cardiol. 2020; (Published online on May 05, 2020)Crossref Scopus (318) Google Scholar,6Reynolds HR Adhikari S Pulgarin C Troxel AB Iturrate E Johnson SB et al.Renin–angiotensin–aldosterone system inhibitors and risk of Covid-19.N Engl J Med. 2020; 382: 2441-2448Crossref PubMed Scopus (830) Google Scholar which adjusted for multiple potential confounding factors, including age, sex and co-morbidities. Our findings also show no significant association between RAAS inhibitor use and mortality in COVID-19 patients; however, this result must be viewed with caution as – due to the lack of data – we were unable to analyze ACEI users and ARB users separately, and adjusted data was reported by only one study. In this context, specific aspects of our analysis are notable. COVID-19 patients using RAAS inhibitors are older and have a higher burden of comorbidities, and this may have confounded our results. Adjustment for these factors could potentially shift the results in favor of RAAS inhibitors. Thus, our results support the consensus by multiple specialty societies, which recommend continued usage of RAAS inhibitors in COVID-19 patients and among the general public who have been prescribed these medications. Javed Butler: is a consultant for Abbott, Amgen, Applied Therapeutics, Astra Zeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squib, CVRx, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, Relypsa, Vifor. Stephen J Greene: has received a Heart Failure Society of America/ Emergency Medicine Foundation Acute Heart Failure Young Investigator Award funded by Novartis; has received research support from Amgen, Bristol-Myers Squibb and Novartis; has served on advisory boards for Amgen and Cytokinetics; and serves as a consultant for Amgen and Merck. Richard A Krasuski: is a consultant and receives research funding from Actelion Pharmaceuticals. He is also an investigator for Edwards Lifesciences and is an unpaid member of the scientific advisory board for Ventripoint.
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Angiotensin-converting enzyme 2 (ACE2) shares some homology with angiotensin-converting enzyme (ACE) but is not inhibited by ACE inhibitors. The main role of ACE2 is the degradation of Ang II resulting in the formation of angiotensin 1-7 (Ang 1-7) which opposes the actions of Ang II. Increased Ang II levels are thought to upregulate ACE2 activity, and in ACE2 deficient mice Ang II levels are approximately double that of wild-type mice, whilst Ang 1-7 levels are almost undetectable. Thus, ACE2 plays a crucial role in the RAS because it opposes the actions of Ang II. Consequently, it has a beneficial role in many diseases such as hypertension, diabetes, and cardiovascular disease where its expression is decreased. Not surprisingly, current therapeutic strategies for ACE2 involve augmenting its expression using ACE2 adenoviruses, recombinant ACE2 or compounds in these diseases thereby affording some organ protection.
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