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      Lipid-lowering therapy and renin-angiotensin-aldosterone system inhibitors in the era of the COVID-19 pandemic

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          Abstract

          The novel coronavirus (severe acute respiratory syndrome coronavirus 2 – SARS-Cov-2) disease 2019 (COVID-19) pandemic has been associated with severe respiratory disease incidence and increased mortality [1]. Angiotensin converting enzyme (ACE) 2 is a homologue of ACE, but also a receptor for the coronaviruses [2]. ACE2 is highly expressed in the lungs, heart, gastrointestinal (GI) tract and kidney, thus affecting the cardiovascular system (CV) and the immune system [3]. The overexpression of ACE2 was reported to enhance viral entry and replication intracellularly [4]. COVID-19, also called SARS-CoV-2, may also use ACE2 as a receptor to initiate infection, leading to severe complications from the heart (acute coronary syndrome (ACS) and fulminant myocarditis), lungs (pneumonia and acute respiratory distress syndrome (ARDS)) and GI tract (diarrhoea syndrome) [5]. ACE2 gene expression is affected by several factors, including gender (ACE2 gene is X-linked), ACE2 gene polymorphisms, comorbidities (increased in the presence of CVD, hypertension, diabetes), and drug therapy [6]. With regard to drugs, angiotensin II receptor blockers (ARBs) and mineralocorticoid receptor antagonists (MRA) have been reported to raise ACE2 activity in human and animal studies [7]. There are only a few animal studies available showing that statins may also increase ACE2 activity [8, 9]. In the era of the COVID-19 pandemic, such a drug effect may be considered as potentially worrying [10]. In this context, it was recently even suggested that ARBs could be replaced with ACE inhibitors and that statin treatment may be discontinued during the pandemic, particularly in primary prevention settings [11]. However, before implementing such strategies, we should consider several issues. Firstly, as the COVID-19 infection progresses, ACE2 is downregulated, thus potentially generating an inflammatory response leading to impaired cardiac contractility and acute lung injury [5, 7, 12]. Therefore, reduced ACE2 expression is linked to worse outcomes. On the other hand, ACE2 overexpression has been associated with several beneficial effects, i.e. prevention of adverse cardiac remodelling and fibrosis, improvement of vascular endothelial dysfunction, reduction of blood pressure, and protection from ARDS [7, 12]. Both statins and ARBs were reported to exert these benefits. Secondly, a combination of statins/ARBs were used during the 2014 Ebola virus disease epidemic in Sierra Leone, leading to improved outcomes and increased survival [13]. These drugs can affect the host response to infection, not the virus, especially by preventing endothelial dysfunction, a shared feature of several virus infections [14]. Their combination seemed to promote a return to homeostasis, allowing patients with Ebola virus infection to recover on their own [15]. Third, patients with cardiovascular disease (CVD) were shown to be more prone to COVID-19 infection and with worse prognosis [16, 17]. Elevated inflammatory markers, such as C-reactive protein (CRP) and interleukin-6 (IL-6), have been recognised as predictors of COVID-19 infection severity and mortality, suggesting a virus-activated “cytokine storm syndrome” [18, 19]. Therefore, as well as immunomodulation, COVID-19 treatment should also target reduction of inflammation. In this context, statins have been consistently reported to exert immunomodulatory and anti-inflammatory properties [20–30]. Also, it was previously suggested that statins could enhance host defence and suppress inflammation, thus representing a practical and inexpensive adjunctive or alternative host-directed treatment for infections by viruses, fungi, protozoa, and bacteria [31]. Similarly, there are data supporting an anti-inflammatory role for ARBs [32–34]. Fourth, statins may also prevent a viral-induced acute coronary syndrome (also in COVID-19 positive patients) by stabilising atherosclerotic plaques [35], as well as prevent acute kidney injury (AKI) [36]. Both acute cardiac injury and AKI are predictors of COVID-19-induced mortality [37]; statin therapy may prevent these complications and thus increase survival. Of note, statins can protect against contrast-induced AKI (CI-AKI) [38–41]. This is of clinical importance, especially in hospitalised patients who undergo diagnostic or therapeutic procedures involving the administration of contrast media (e.g. computed tomography of the lungs). Fifth, effective lipid-lowering therapy (LLT) and significant cholesterol reduction might significantly suppress coronavirus infection. It was show that for infectious bronchitis virus (IBV) coronavirus, drug-related cholesterol reduction disrupts lipid rafts (an important element for the cellular entry of coronavirus) that enable the binding of the coronavirus with the host cells and, consequently, further infection [42]. It was also observed, in the studies with porcine deltacoronavirus (PDCoV), that cholesterol present in the cell membrane and viral envelope (coronaviruses are positive-sense enveloped RNA viruses) contributes to PDCoV replication by acting as a key component in viral entry. Thus, the pharmacological sequestration of cellular or viral cholesterol with effective LLT significantly blocked both virus attachment and internalisation [43]. All these mechanisms might suggest a critical role of statins and LLTs in the inhibition of coronavirus infection. In COVID-19-positive patients, the majority of baseline CVD is of atherosclerosis origin, with the worst prognosis for patients being at the high, and especially very high and extremely high, risk of CVD [16]; thus, intensive LLT with statins and/or fixed combination with ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors seems to be critical. Indeed, we should do our best to maximally improve therapy adherence and thus have a better prognosis for the infected CVD patients [44, 45]. In this context, there are no premises that PCSK9 inhibitors, because they are monoclonal antibodies (in relation to the above-mentioned high cytokine storm during infection), should be discontinued. In contrast, PCSK9 inhibitors should be continued to achieve further low-density lipoprotein cholesterol (LDL-C) lowering (based on “the lower, the better” principle), because then we might significantly stabilise atheroma plaque, reduce the risk of CVD events, and reduce inflammation [46–48]. Recent available data have confirmed the role of PCSK9 inhibition in reducing the process of inflammation via decreasing main vascular inflammatory markers, reducing infiltration of monocytes into the subendothelial layer, and inhibiting monocyte migration. Apart from the reduction of pro-inflammatory mediators, PCSK9 inhibitors could ameliorate vascular inflammation [47]. Finally, a direct local anti-inflammatory action of PCSK9 inhibitors, independent of LDL-C reduction, has been shown in animal models; however, it still merits further investigation [47, 48]. It is of special interest now (due to the fact that coronavirus might also use different receptors to enter the host cell) that treatment with PCSK9 inhibitors has beneficial effects on LDL-C lowering via inhibition of LDL-receptors (LDL-R). This might exert an antiviral effect, among others, on hepatitis C viral (HCV) infection through down-regulation of the surface expression of LDL-R and cluster of differentiation (CD) 81 on hepatic cells, and a positive association with increased inflammatory responses, as well as with septic shock [48]. In a recent paper, we confirmed that there is no association between PCSK9 levels and resistance to antibiotics or the condition of patients hospitalised in intensive care units, a finding of clinical importance in the COVID-19 infection era [49]. Sixth, there are conflicting results regarding the possible effects of statins on ARDS development and outcomes [50, 51]. It was suggested that statins act beneficially in ‘hyper-inflammatory’ ARDS patients (defined by increased biomarkers of inflammation, coagulation and endothelial activation) [52], but not in ‘hypo-inflammatory’ patients [53, 54]. A potential benefit of ARBs on survival in ARDS patients has also been reported [55, 56]. Nevertheless, there is a paucity of data on this field, and thus further research is needed to elucidate the association between statin therapy, ARBs, and acute lung injury. Of note, drug-drug interactions should also be considered. In this context, simvastatin and lovastatin are contraindicated in patients on lopinavir/ritonavir therapy due to an increased risk of rhabdomyolysis [57]. Atorvastatin, rosuvastatin and other statins can be used at the lowest possible dose, based on the instructions included in the summary of product characteristics (spc) [58]. Taking this into account, we should be careful while treating COVID-19 disease patients with statins being on antiviral drugs and some antibiotics (including macrolides), because they might increase the risk of statin-associated muscle symptoms (SAMS) [59, 60]. Therefore, their careful monitoring is highly recommended to avoid unnecessary drug-related side effects, and at the same time optimising LLT therapy to achieve the individual’s LDL-C goal. In this context, in patients at very high CVD risk, requiring intensive LLT, it is reasonable to initiate therapy with polypills/fixed combinations of statins (at lower doses) and ezetimibe, with or without PCSK9 inhibitors (as available), aimed at reducing the risk of SAMS [59, 60]. A position statement of the European Society (ESC) Council (on 13 March 2020) (as well as of other national and international societies) highlights the lack of evidence on harmful effects of ACE inhibitors and ARBs on the incidence and progression of COVID-19 infection and strongly supports the continuation of usual antihypertensive therapy [6, 61]. Regarding statins, their beneficial effects on inflammation, vascular, heart, and lung function strongly support the continuation of their use. Due to their significant effect on CVD prevention, PCSK9 inhibitors should also be continued, as available. Physicians should wait for strong evidence and recommendations from international scientific societies before altering their patients’ drug therapy in the COVID-19 era.

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          Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China

          Dear Editor, The rapid emergence of COVID-19 in Wuhan city, Hubei Province, China, has resulted in thousands of deaths [1]. Many infected patients, however, presented mild flu-like symptoms and quickly recover [2]. To effectively prioritize resources for patients with the highest risk, we identified clinical predictors of mild and severe patient outcomes. Using the database of Jin Yin-tan Hospital and Tongji Hospital, we conducted a retrospective multicenter study of 68 death cases (68/150, 45%) and 82 discharged cases (82/150, 55%) with laboratory-confirmed infection of SARS-CoV-2. Patients met the discharge criteria if they had no fever for at least 3 days, significantly improved respiratory function, and had negative SARS-CoV-2 laboratory test results twice in succession. Case data included demographics, clinical characteristics, laboratory results, treatment options and outcomes. For statistical analysis, we represented continuous measurements as means (SDs) or as medians (IQRs) which compared with Student’s t test or the Mann–Whitney–Wilcoxon test. Categorical variables were expressed as numbers (%) and compared by the χ 2 test or Fisher’s exact test. The distribution of the enrolled patients’ age is shown in Fig. 1a. There was a significant difference in age between the death group and the discharge group (p < 0.001) but no difference in the sex ratio (p = 0.43). A total of 63% (43/68) of patients in the death group and 41% (34/82) in the discharge group had underlying diseases (p = 0.0069). It should be noted that patients with cardiovascular diseases have a significantly increased risk of death when they are infected with SARS-CoV-2 (p < 0.001). A total of 16% (11/68) of the patients in the death group had secondary infections, and 1% (1/82) of the patients in the discharge group had secondary infections (p = 0.0018). Laboratory results showed that there were significant differences in white blood cell counts, absolute values of lymphocytes, platelets, albumin, total bilirubin, blood urea nitrogen, blood creatinine, myoglobin, cardiac troponin, C-reactive protein (CRP) and interleukin-6 (IL-6) between the two groups (Fig. 1b and Supplementary Table 1). Fig. 1 a Age distribution of patients with confirmed COVID-19; b key laboratory parameters for the outcomes of patients with confirmed COVID-19; c interval from onset of symptom to death of patients with confirmed COVID-19; d summary of the cause of death of 68 died patients with confirmed COVID-19 The survival times of the enrolled patients in the death group were analyzed. The distribution of survival time from disease onset to death showed two peaks, with the first one at approximately 14 days (22 cases) and the second one at approximately 22 days (17 cases) (Fig. 1c). An analysis of the cause of death was performed. Among the 68 fatal cases, 36 patients (53%) died of respiratory failure, five patients (7%) with myocardial damage died of circulatory failure, 22 patients (33%) died of both, and five remaining died of an unknown cause (Fig. 1d). Based on the analysis of the clinical data, we confirmed that some patients died of fulminant myocarditis. In this study, we first reported that the infection of SARS-CoV-2 may cause fulminant myocarditis. Given that fulminant myocarditis is characterized by a rapid progress and a severe state of illness [3], our results should alert physicians to pay attention not only to the symptoms of respiratory dysfunction but also the symptoms of cardiac injury. Further, large-scale studies and the studies on autopsy are needed to confirm our analysis. In conclusion, predictors of a fatal outcome in COVID-19 cases included age, the presence of underlying diseases, the presence of secondary infection and elevated inflammatory indicators in the blood. The results obtained from this study also suggest that COVID-19 mortality might be due to virus-activated “cytokine storm syndrome” or fulminant myocarditis. Electronic supplementary material Below is the link to the electronic supplementary material. Supplementary material 1 (DOCX 38 kb)
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            Cardiovascular Implications of Fatal Outcomes of Patients With Coronavirus Disease 2019 (COVID-19)

            This case series study evaluates the association of underlying cardiovascular disease and myocardial injury on fatal outcomes in patients with coronavirus disease 2019 (COVID-19).
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              Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus

              Spike (S) proteins of coronaviruses, including the coronavirus that causes severe acute respiratory syndrome (SARS), associate with cellular receptors to mediate infection of their target cells 1,2 . Here we identify a metallopeptidase, angiotensin-converting enzyme 2 (ACE2) 3,4 , isolated from SARS coronavirus (SARS-CoV)-permissive Vero E6 cells, that efficiently binds the S1 domain of the SARS-CoV S protein. We found that a soluble form of ACE2, but not of the related enzyme ACE1, blocked association of the S1 domain with Vero E6 cells. 293T cells transfected with ACE2, but not those transfected with human immunodeficiency virus-1 receptors, formed multinucleated syncytia with cells expressing S protein. Furthermore, SARS-CoV replicated efficiently on ACE2-transfected but not mock-transfected 293T cells. Finally, anti-ACE2 but not anti-ACE1 antibody blocked viral replication on Vero E6 cells. Together our data indicate that ACE2 is a functional receptor for SARS-CoV. Supplementary information The online version of this article (doi:10.1038/nature02145) contains supplementary material, which is available to authorized users.
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                Author and article information

                Journal
                Arch Med Sci
                Arch Med Sci
                AMS
                Archives of Medical Science : AMS
                Termedia Publishing House
                1734-1922
                1896-9151
                14 April 2020
                2020
                : 16
                : 3
                : 485-489
                Affiliations
                [1 ]First Department of Internal Medicine, Diabetes Centre, Division of Endocrinology and Metabolism, AHEPA University Hospital, Thessaloniki, Greece
                [2 ]Cardiovascular Research Centre, University of Zielona Gora, Zielona Gora, Poland
                [3 ]Polish Mother’s Memorial Hospital Research Institute (PMMHRI), Lodz, Poland
                [4 ]Department of Clinical Biochemistry, Royal Free Hospital campus, University College London Medical School, University College London (UCL), London, UK
                Author notes
                Corresponding authors: Prof. Maciej Banach, MD, PhD, FNLA, FAHA, FESC, FASA, Department of Hypertension, WAM University Hospital, Medical University of Lodz, 113 Zeromskiego St, 90-549 Lodz, Poland. Phone: +48 42 639 37 71, Fax: +48 42 639 37 71. E-mail: maciejbanach77@ 123456gmail.com
                Prof. Dimitri P. Mikhailidis, BSc, MSc, MD, FRSPH, FCP, FFPM, FRCP, FRCPath, Department of Clinical Biochemistry, Royal Free Hospital Campus University College, London Medical School University College, London (UCL), London NW3 2QG, UK. E-mail: mikhailidis@ 123456aol.com
                Article
                40392
                10.5114/aoms.2020.94503
                7212217
                32399093
                3467c4fb-d4ea-4c15-af0b-ffc93ecbc27c
                Copyright: © 2020 Termedia & Banach

                This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0) License, allowing third parties to copy and redistribute the material in any medium or format and to remix, transform, and build upon the material, provided the original work is properly cited and states its license.

                History
                : 30 March 2020
                : 05 April 2020
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                Medicine

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