Cardiovascular System and COVID-19

Objective Different hypotheses suggest a contradictory association of statins, angiotensin receptor blockers(ARBs) or angiotensin-converting enzyme(ACE) inhibitors with potential adverse or favorable effects in patients with Coronavirus disease 2019(COVID-19). This study aimed to compare the association of statins, ARB, and ACE inhibitors in COVID-19 and in pneumonia. Design and Method All patients with laboratory-confirmed COVID-19 through April 16, 2020, in Korea were retrieved. We evaluated the association of statins, ARBs, and ACE inhibitors on COVID-19-related mortality within 60 days. Furthermore, a comparison of hazard ratio (HR) was performed between COVID-19 patients and a retrospective cohort of patients hospitalized with pneumonia between January and June 2019 in Korea. Lastly, meta-analysis was performed to compare the results of this study and other reports. Results The median age of the 10,448 COVID-19 patients was 45 years, and statins, ARBs and ACE inhibitors were prescribed in 533 (5.1%), 1,231(11.8%) and 47(0.4%) patients, respectively. As of April 24, 228 patients (2.2%) succumbed to death. After adjusting age, sex, residential area, the history of comorbidities, Cox regression showed significant decrease in HR by 36% associated with statin use (HR 0.635, 95% CI 0.424 - 0.951, p = 0.0274). However, ARBs group showed neutral association (HR 1.034, 95% CI 0.765 - 1.399, p = 0.8270) and ACE inhibitor groups showed insignificant results mainly due to small sample size (HR 0.736, 95% CI 0.314 - 1.726, p = 0.4810). When comparing the HR between COVID-19 patients and a retrospective cohort of patients hospitalized with pneumonia between January and June 2019, the trend of statins and ACE inhibitors showed similar benefit, whereas the protective effect of ARBs observed in the retrospective cohort was lost in the COVID-19 patients. Meta-analysis including the results of this study showed significant benefit of statins and ACE inhibitors, whereas neutral association with ARBs and the mortality. Conclusions Statins were associated with significantly lower mortality of COVID-19, consistent with usual pneumonia patients. While ARBs or ACE inhibitors were not associated with fatal outcome, the possible beneficial effect of ARBs observed in usual pneumonia was attenuated in COVID-19.

Biomarkers of COVID-19 and technologies to combat SARS-CoV-2.

Due to the unprecedented public health crisis caused by COVID-19, our first contribution to the newly launching journal, Advances in Biomarker Sciences and Technology, has abruptly diverted to focus on the current pandemic. As the number of new COVID-19 cases and deaths continue to rise steadily around the world, the common goal of healthcare providers, scientists, and government officials worldwide has been to identify the best way to detect the novel coronavirus, named SARS-CoV-2, and to treat the viral infection - COVID-19. Accurate detection, timely diagnosis, effective treatment, and future prevention are the vital keys to management of COVID-19, and can help curb the viral spread. Traditionally, biomarkers play a pivotal role in the early detection of disease etiology, diagnosis, treatment and prognosis. To assist myriad ongoing investigations and innovations, we developed this current article to overview known and emerging biomarkers for SARS-CoV-2 detection, COVID-19 diagnostics, treatment and prognosis, and ongoing work to identify and develop more biomarkers for new drugs and vaccines. Moreover, biomarkers of socio-psychological stress, the high-technology quest for new virtual drug screening, and digital applications are described.

Hunting for protective drugs at the break of a pandemic: Causal inference from hospital data.

At the break of a pandemic, the protective efficacy of therapeutic interventions needs rapid evaluation. An experimental approach to the problem will not always be appropriate. An alternative route are observational studies, whether based on regional health service data or hospital records. In this paper, we discuss the use of methods of causal inference for the analysis of such data, with special reference to causal questions that may arise in a pandemic. We apply the methods by using the aid of a directed acyclic graph (DAG) representation of the problem, to encode our causal assumptions and to logically connect the scientific questions. We illustrate the usefulness of DAGs in the context of a controversy over the effects of renin aldosterone system inhibitors (RASIs) in hypertensive individuals at risk of (or affected by) severe acute respiratory syndrome coronavirus 2 disease. We consider questions concerning the existence and the directions of those effects, their underlying mechanisms, and the possible dependence of the effects on context variables. This paper describes the cognitive steps that led to a DAG representation of the problem, based on background knowledge and evidence from past studies, and the use of the DAG to analyze our hospital data and assess the interpretive limits of the results. Our study contributed to subverting early opinions about RASIs, by suggesting that these drugs may indeed protect the older hypertensive Covid-19 patients from the consequences of the disease. Mechanistic interaction methods revealed that the benefit may be greater (in a sense to be made clear) in the older stratum of the population.

What do we know about the renin angiotensin system and inflammatory bowel disease?

INTRODUCTION: The renin-angiotensin system (RAS) is an important homeostatic pathway, with emerging evidence for the impact of its components on inflammation and fibrosis in gastrointestinal tissues. This review aims to review current knowledge of the physiological mechanism of RAS in inflammatory bowel disease (IBD), and potential therapeutic implications. AREAS COVERED: An extensive online literature review including Pubmed, Medline, and Google Scholar was undertaken. Discussion on the components of the RAS, localization, and physiological functions in the gastrointestinal tract, preclinical, and clinical data in IBD, and the relation with SARS-Cov-2 are covered in this review. EXPERT OPINION: RAS inhibition may have a role as anti-fibrotic adjunct therapy. Targeting the local gastrointestinal RAS with novel modes of delivery may be a target for future therapeutics for IBD, given the widespread availability and safety of current options as utilized in other diseases. Further insight into the mechanism and downstream effects of gastrointestinal ACE2 may lead to a better understanding of the pathogenesis of IBD.

Antecedent Administration of Angiotensin-Converting Enzyme Inhibitors or Angiotensin II Receptor Antagonists and Survival After Hospitalization for COVID-19 Syndrome.

Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) utilizes the angiotensin-converting enzyme-2 (ACE-2) receptor to enter human cells. Angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor antagonists (ARB) are associated with ACE-2 upregulation. We hypothesized that antecedent use of ACEI/ARB may be associated with mortality in coronavirus disease 2019 (COVID-19). Methods and Results We used the Coracle registry, which contains data of patients hospitalized with COVID-19 in 4 regions of Italy, and restricted analyses to those ≥50 years of age. The primary outcome was in-hospital mortality. Among these 781 patients, 133 (17.0%) used an ARB and 171 (21.9%) used an ACEI. While neither sex nor smoking status differed by user groups, patients on ACEI/ARB were older and more likely to have hypertension, diabetes mellitus, and congestive heart failure. The overall mortality rate was 15.1% (118/781) and increased with age (PTrend<0.0001). The crude odds ratios (ORs) for death for ACEI users and ARB users were 0.98, 95% CI, 0.60-1.60, P=0.9333, and 1.13, 95% CI, 0.67-1.91, P=0.6385, respectively. After adjusting for age, hypertension, diabetes mellitus, and congestive heart failure, antecedent ACEI administration was associated with reduced mortality (OR, 0.55; 95% CI, 0.31-0.98, P=0.0436); a similar, but weaker trend was observed for ARB administration (OR, 0.58; 95% CI, 0.32-1.07, P=0.0796). Conclusions In those aged ≥50 years hospitalized with COVID-19, antecedent use of ACEI was independently associated with reduced risk of inpatient death. Our findings suggest a protective role of renin-angiotensin-aldosterone system inhibition in patients with high cardiovascular risk affected by COVID-19.

Drugs acting on the renin-angiotensin-aldosterone system (RAAS) and deaths of COVID-19 patients: a systematic review and meta-analysis of observational studies.

BACKGROUND: Angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs) are two of the most commonly used antihypertensive drugs acting on the renin-angiotensin-aldosterone system (RAAS). Previous research has shown that RAAS inhibitors increase the expression of angiotensin-converting enzyme, a cellular receptor for the severe acute respiratory syndrome coronavirus 2, raising concerns that the use of ACEi and ARBs in hypertensive patients may increase COVID-19 patient mortality. Therefore, the main aim of the current study was to find out the role of drugs acting on RAAS, particularly ACEi/ARBs in the deaths of COVID-19 patients. RESULTS: In total, 68 studies were found to be appropriate, reporting a total of 128,078 subjects. The odds ratio was found to be 1.14 [0.95, 1.36], which indicates the non-significant association of ACEi/ARBs with mortality of COVID-19 patients. Further, the association of individual ACEi/ARBs with mortality of COVID-19 patients was also found non-significant. The sensitivity analysis results have shown no significant effect of outliers on the outcome. CONCLUSIONS: Based on available evidence, ACEi/ARB were not significantly associated with deaths of COVID-19 patients.

COVIDMED - An early pandemic randomized clinical trial of losartan treatment for hospitalized COVID-19 patients.

Objectives: To assess the efficacy and safety of losartan for COVID-19 patients. Methods: COVIDMED was a double-blinded, placebo-controlled platform RCT. Enrollees were randomized to standard care plus hydroxychloroquine, lopinavir/ritonavir, losartan, or placebo. Hydroxychloroquine and lopinavir/ritonavir arms were discontinued early. We report losartan data vs. combined (lopinavir-ritonavir and placebo) and prespecified placebo-only controls. The primary endpoint was the mean COVID-19 Ordinal Severity Score (COSS) slope of change. Slow enrollment prompted early termination. Results: Fourteen patients were included in our final analysis (losartan [N = 9] vs. control [N = 5] [lopinavir/ritonavir [N = 2], placebo [N = 3]]). Most baseline parameters were balanced. Losartan treatment was not associated with a difference in mean COSS slope of change vs. combined (p = 0.4) or placebo-only control (p = 0.05) (trend favoring placebo). 60-day mortality and overall AE/SAE rates were insignificantly higher with losartan. Conclusion: In this small RCT in hospitalized COVID-19 patients, losartan did not improve outcome and was associated with adverse safety signals.

Medications Associated with Lower Mortality in a SARS-CoV-2 Positive Cohort of 26,508 Veterans.

BACKGROUND: Many severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) positive patients take commonly prescribed medications with properties which may affect mortality. OBJECTIVE: Assess if common medications postulated to affect clinical outcomes are associated with mortality in SARS-CoV-2 positive patients in the Veterans Health Administration (VHA). DESIGN: Observational national cohort analysis. PARTICIPANTS: Consecutive 26,508 SARS-CoV-2 positive Veterans (7% of 399,290 tested from March 1 to September 10, 2020) constitute the study cohort. MAIN MEASURES: The primary outcome was 30-day mortality from the first positive SARS-CoV-2 test date. In patients receiving medications or drug pairs within 2 weeks post-SARS-CoV-2 positive test, 30-day mortality was estimated as relative risk (RR) on the log-binomial scale or using multinomial models with and without adjusting for covariates. KEY RESULTS: The 26,508 SARS-CoV-2 positive patients were predominantly male (89%) and White (59%), and 82% were overweight/obese. Medications associated with decreased 30-day mortality risk included the following: metformin (aRR, 0.33; 95% CI, 0.25-0.43), colchicine, angiotensin-converting-enzyme inhibitors (ACEi), angiotensin II receptor blockers, statins, vitamin D, antihistamines, alpha-blockers, anti-androgens, and nonsteroidal anti-inflammatory drugs (aRR, 0.69; 95% CI, 0.61-0.78). The effect of co-prescribed medications on 30-day mortality risk revealed the lowest risk for combined statins and metformin (aRR, 0.21; 95% CI, 0.15-0.31), followed by ACEi and statins (aRR, 0.25; 95% CI, 0.18-0.35), ACEi and metformin (aRR, 0.26; 95% CI, 0.17-0.40), antihistamines and NSAIDs (aRR, 0.41; 95% CI, 0.32-0.52), and in men, combined alpha-blockers and anti-androgens (aRR, 0.51; 95% CI, 0.42-0.64). CONCLUSIONS: In this large national cohort, treatment of SARS-CoV-2 positive patients with individual or co-prescribed metformin and statins, ACEi and statins (or metformin) and other medications was associated with a markedly decreased 30-day mortality and can likely be continued safely. Clinical trials may assess their therapeutic benefit.

Angiotensin II Promotes SARS-CoV-2 Infection via Upregulation of ACE2 in Human Bronchial Cells.

Blockers of the renin-angiotensin system (RAS) have been reported to increase the angiotensin converting enzyme (ACE)2, the cellular receptor of SARS-CoV-2, and thus the risk and course of COVID-19. Therefore, we investigated if angiotensin (Ang) II and RAS blockers affected ACE2 expression and SARS-CoV-2 infectivity in human epithelial bronchial Calu-3 cells. By infectivity and spike-mediated cell-cell fusion assays, we showed that Ang II acting on the angiotensin type 1 receptor markedly increased ACE2 at mRNA and protein levels, resulting in enhanced SARS-CoV-2 cell entry. These effects were abolished by irbesartan and not affected by the blockade of ACE-1-mediated Ang II formation with ramipril, and of ACE2- mediated Ang II conversion into Ang 1-7 with MLN-4760. Thus, enhanced Ang II production in patients with an activated RAS might expose to a greater spread of COVID-19 infection in lung cells. The protective action of Angiotensin type 1 receptor antagonists (ARBs) documented in these studies provides a mechanistic explanation for the lack of worse outcomes in high-risk COVID-19 patients on RAS blockers.

ACEi/ ARB and Deaths of COVID-19 Patients.

The practice of angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers (ACEi/ARB) in COVID-19 hypertensive patients is still an open question for clinicians to answer. The present study was conducted to find out the association between the use of ACEI/ARB and the mortality rate of COVID-19 patients. The search was conducted from December 2019 to October 2020 in PubMed to identify relevant published studies. RevMan 5 was used for the analysis of the data. The random-effect model was used to calculate the odds ratio. In total, 07 studies were found to be appropriate, reporting a total of 1,566 subjects. The odds ratio was found to be 0.86 [0.41, 1.81], which indicates that there is no association between ACEI/ARB and the mortality rate of COVID-19 patients. In conclusion, we may suggest continuing the use of ACEi/ARB in COVID-19 patients till further pieces of evidence are generated.

Oral Lisinopril Raises Tissue Levels of ACE2, the SARS-CoV-2 Receptor, in Healthy Male and Female Mice.

Angiotensin-converting enzyme 2 (ACE2) is the established cellular receptor for SARS-CoV-2. However, it is unclear whether ACE1 inhibitors (e.g., lisinopril) or angiotensin receptor blockers (e.g., losartan) alter tissue ACE2 expression. This study sought to determine whether lisinopril or losartan, as monotherapies or in combination, changes tissue levels of ACE2 in healthy male and female mice. Mice received lisinopril (10 mg/kg/day), losartan (10 mg/kg/day), or both for 21 days via drinking water. A control group received water without drug. The ACE2 protein index (ACE2 protein/total protein) was determined on the small intestine, lung, kidney, and brain. Oral lisinopril increased the ACE2 protein index across all tissues (p < 0.0001 vs. control). In contrast, the combination of lisinopril plus losartan did not increase ACE2 levels in any tissue (p = 0.89 vs. control) and even decreased tissue expression of the Ace2 gene (p < 0.001 vs. control). Tissue ACE2 remained elevated in the mice 21 days after cessation of lisinopril (p = 0.02). Plasma ACE2 did not correlate with the ACE2 protein index in any tissue. A sex difference was observed: kidney ACE2 levels were higher in male than in female mice (p < 0.0001). Oral lisinopril increases ACE2, the cellular receptor for SARS-CoV-2, in tissues that are relevant to the transmission and pathogenesis of COVID-19. Remarkably, the addition of losartan prevented lisinopril-induced increases in ACE2 across tissues. These results suggest that ACE inhibitors and angiotensin receptor blockers interact to determine tissue levels of ACE2.

Effect of Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers on Clinical Outcome in COVID-19 Patients with Hypertension

Background: Hypertension is the main factor to predict the severity and mortality of COVID-19. The use of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) is challenging. This study aimed to investigate the effect of ACEIs and ARBs on clinical outcomes in COVID-19 patients with hypertension. Materials and Methods: This cross-sectional study was carried out on 498 patients who were referred to Razi hospital following COVID-19 development and also had hypertension. Patients were divided into two groups receiving drugs in the ACEIs and ARB's groups and those not receiving these drugs. The primary outcome was death up to one month after the onset of symptoms. Results: Cardiovascular disease in patients taking ACEIs/ARBs was higher (p<0.001). One hundred eleven deaths (22.3%) were seen in the studied patients in whom 66 deaths (59.5%) belonged to the group not taking ACEIs and ARBs (p>0.05). Seventy-nine patients (15.86%) were admitted to ICU in which 62.03% of these patients died while the non-ICU mortality rate was 14.8% (Odds Ratio = 9.40;95% CI: 5.54 to 15.95, p <0.001). A subgroup analysis found that among patients with diabetes who had hypertension, the incidence of death was 43.55% in the group taking ARBs/ACEi lower than in another group significant (p = 0.021). Conclusion: The mortality rate in the patients taking ACEIs/ARBs is not different from other groups. It was found that among COVID-19 patients with diabetes who had hypertension, the incidence of death in the patients taking ARBs/ACEi was lower than in another group. © 2021 Universitas Gadjah Mada - Faculty of Pharmacy. All rights reserved.

Effects of the COVID-19 pandemic on heart failure hospitalizations in Japan: interrupted time series analysis.

AIMS: The Coronavirus Disease 2019 (COVID-19) pandemic has had unprecedented effects on health care utilization for acute cardiovascular diseases. Although hospitalizations for acute coronary syndrome decreased during the COVID-19 pandemic, there is a paucity of data on the trends and management of heart failure (HF) cases. Furthermore, concerns have been raised that angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) may increase susceptibility to COVID-19. This study aimed to elucidate changes in HF hospitalizations from the COVID-19 state of emergency in Japan and investigated changes in the prescription of ACEIs and ARBs, and in-hospital mortality. METHODS AND RESULTS: We performed an interrupted time series analysis of HF hospitalizations in Japan to verify the impacts of the COVID-19 state of emergency. Changes in the weekly volume of HF hospitalizations were taken as the primary outcome measure. Between 1 April 2018 and 4 July 2020, 109 429 HF cases required admission. After the state of emergency, an immediate decrease was observed in HF cases per week [-3.6%; 95% confidence interval (CI): -0.3% to -6.7%, P = 0.03]. There was no significant change in the prescription of ACEIs or ARBs after the state of emergency (4.2%; 95% CI: -0.3% to 8.9%, P = 0.07). The COVID-19 pandemic had no effect on in-hospital mortality among HF patients (5.3%; 95% CI: -4.9% to 16.6%, P = 0.32). CONCLUSIONS: We demonstrated a decline in HF hospitalizations during the COVID-19 pandemic in Japan, with no clear evidence of a negative effect on the prescription of ACEIs and ARBs or in-hospital mortality.

[Preliminary clinical analysis of direct renin inhibitor aliskiren in the treatment of severe coronavirus disease 2019 patients with hypertension].

Objective: To explore the feasibility of direct renin inhibitor aliskiren for the treatment of severe or critical coronavirus disease 2019 (COVID-19) patients with hypertension. Methods: The antihypertensive effects and safety of aliskiren was retrospectively analyzed in three severe and one critical COVID-19 patients with hypertension. Results: Four patients, two males and two females, with an average age of 78 years (66-87 years), were referred to hospital mainly because of respiratory symptoms. Three were diagnosed by positive novel coronavirus 2019 (2019-nCoV) nucleic acid or antibody, and the critical patient with cardiac insufficiency was clinically determined. Two patients were treated with calcium channel antagonist (CCB), one with angiotensin converting enzyme inhibitor (ACEI), and one with angiotensin Ⅱ receptor antagonist (ARB). After admission, ACEI and ARB were discontinued, one patient with heart failure was treated by aliskiren combined with diuretic.Three patients were treated with aliskiren combined with CCB among whom two withdrew CCB due to low blood pressure after 1 to 2 weeks. Based on comprehensive treatment including antiviral and oxygenation treatment, blood pressure was satisfactorily controlled by aliskiren after three to four weeks without serious adverse events. All patients were finally discharged. Conclusion: Our preliminary clinical data shows that antihypertensive effect of aliskiren is satisfactory and safe for severe COVID-19 patients complicated with hypertension.

The Pfizer-BNT162b2 mRNA-based vaccine against SARS-CoV-2 may be responsible for awakening the latency of herpes varicella-zoster virus.

BACKGROUND: To prevent the invasion and transmission of SARS-CoV-2, mRNA-based vaccines, non-replicating viral vector vaccines, and inactivated vaccines have been developed. The European Medicines Agency (EMA) authorized the use of the anti-SARS-CoV-2 vaccine in January 2021, the date on which the vaccination program began in Spain and across Europe. The aim of this study is to monitor the safety of anti-SARS-CoV-2 vaccines and report any cases of undesirable effects that have occurred, that are not included in the health profile of mRNA-based vaccines for commercialisation in humans. Furthermore, a brief review is given of the mechanism of action of the anti-SARS-CoV-2 vaccine on the host's immune system in triggering the reactivation of the herpes varicella-zoster infection. METHODS: Follow-up of patients under the care of the southern health district of Seville of the SAS (Andalusian Health Service) during the Spanish state of alarm over the COVID-19 pandemic. RESULTS: Two patients, a 79-year-old man and a 56-year-old woman, are reported who, after 4 and 16 days respectively of receiving the Pfizer-BNT162b2 vaccine against SARS-CoV-2, presented a state of reactivation of herpes varicella-zoster virus (VZV). DISCUSSION: The immunosenescence of the reported patients, together with the immunomodulation generated by administering the anti-SARS-CoV-2 vaccines, that depress certain cell subpopulations, could explain the awakening of VZV latency.

Endothelial dysfunction and COVID-19 (Review).

It is hypothesized that several comorbidities increase the severity of COVID-19 symptoms. Cardiovascular disease including hypertension was shown to play a critical role in the severity of COVID-19 infection by affecting the survival of patients with COVID-19. Hypertension and the renin-angiotensin-aldosterone system are involved in increasing vascular inflammation and endothelial dysfunction (ED), and both processes are instrumental in COVID-19. Angiotensin-converting enzyme 2 is an essential component of the renin-angiotensin-aldosterone system and the target receptor that mediates SARS-CoV-2 entry to the cell. This led to speculations that major renin-angiotensin-aldosterone system inhibitors, such as angiotensin receptor blockers and angiotensin-converting enzyme inhibitors might affect the course of the disease, since their administration enhances angiotensin-converting enzyme (ACE)2 expression. An increase in ACE2 activity could reduce angiotensin II concentration in the lungs and mitigate virus-driven lung injury. This could also be associated with a reduction in blood coagulation, which plays a critical role in the pathogenesis of SARS-CoV-2; of note, COVID-19 is now regarded as a disorder of blood clotting. Therefore, there is an urgent need to better understand the effect of targeting ACE2 as a potential treatment for SARS-CoV-2 driven injury, and in alleviating COVID-19 symptoms by reversing SARS-CoV-2-induced excessive coagulation and fatalities. Ongoing therapeutic strategies that include recombinant human ACE2 and anti-spike monoclonal antibodies are essential for future clinical practice in order to better understand the effect of targeting ED in COVID-19.

SARS-CoV-2 Coronavirus Spike Protein-Induced Apoptosis, Inflammatory, and Oxidative Stress Responses in THP-1-Like-Macrophages: Potential Role of Angiotensin-Converting Enzyme Inhibitor (Perindopril).

A purified spike (S) glycoprotein of severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) coronavirus was used to study its effects on THP-1 macrophages, peripheral blood mononuclear cells (PBMCs), and HUVEC cells. The S protein mediates the entry of SARS-CoV-2 into cells through binding to the angiotensin-converting enzyme 2 (ACE2) receptors. We measured the viability, intracellular cytokine release, oxidative stress, proinflammatory markers, and THP-1-like macrophage polarization. We observed an increase in apoptosis, ROS generation, MCP-1, and intracellular calcium expression in the THP-1 macrophages. Stimulation with the S protein polarizes the THP-1 macrophages towards proinflammatory futures with an increase in the TNFα and MHC-II M1-like phenotype markers. Treating the cells with an ACE inhibitor, perindopril, at 100 µM reduced apoptosis, ROS, and MHC-II expression induced by S protein. We analyzed the sensitivity of the HUVEC cells after the exposure to a conditioned media (CM) of THP-1 macrophages stimulated with the S protein. The CM induced endothelial cell apoptosis and MCP-1 expression. Treatment with perindopril reduced these effects. However, the direct stimulation of the HUVEC cells with the S protein, slightly increased HIF1α and MCP-1 expression, which was significantly increased by the ACE inhibitor treatment. The S protein stimulation induced ROS generation and changed the mitogenic responses of the PBMCs through the upregulation of TNFα and interleukin (IL)-17 cytokine expression. These effects were reduced by the perindopril (100 µM) treatment. Proteomic analysis of the S protein stimulated THP-1 macrophages with or without perindopril (100 µM) exposed more than 400 differentially regulated proteins. Our results provide a mechanistic analysis suggesting that the blood and vascular components could be activated directly through S protein systemically present in the circulation and that the activation of the local renin angiotensin system may be partially involved in this process. Graphical: Suggested pathways that might be involved at least in part in S protein inducing activation of inflammatory markers (red narrow) and angiotensin-converting enzyme inhibitor (ACEi) modulation of this process (green narrow).

COVID-19 and Heart: From Clinical Features to Pharmacological Implications.

A highly pathogenic human coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been recently recognized in Wuhan, China, as the cause of the coronavirus disease 2019 (COVID-19) outbreak which has spread rapidly from China to other countries in the world, causing a pandemic with alarming morbidity and mortality. The emerging epidemiological data about COVID-19 patients suggest an association between cardiovascular diseases (CVD) and SARS-CoV-2 infection, in term of clinical features at hospital admission and prognosis for disease severity. The aim of our review is to describe the cardiological features of COVID-19 patients at admission, the acute cardiac presentation, the clinical outcome for patients with underlying CVD and the pharmacological implications for disease management.

Effects of renin-angiotensin system blockers on the risk and outcomes of severe acute respiratory syndrome coronavirus 2 infection in patients with hypertension.

BACKGROUND/AIMS: There are concerns that the use of renin-angiotensin system (RAS) blockers may increase the risk of being infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or progressing to a severe clinical course after infection. This this study aimed to investigate the influence of RAS blockers on the risk and severity of SARS-CoV-2 infection. METHODS: We conducted a retrospective cohort study analyzing nationwide claims data of 215,184 adults who underwent SARS-CoV-2 tests in South Korea. The SARS-CoV-2 positive rates and clinical outcomes were evaluated according to the use of RAS blockers in patients with hypertension (n = 64,243). RESULTS: In total, 38,919 patients with hypertension were on RAS blockers. The SARS-CoV-2 positive rates were significantly higher in the RAS blocker group than in the control group after adjustments (adjusted odds ratio [OR], 1.22; 95% confidence interval [CI], 1.10 to 1.36; p < 0.001), and matching by propensity score (adjusted OR, 1.16; 95% CI, 1.03 to 1.32; p = 0.017). Among the 1,609 SARS-CoV-2-positive patients with hypertension, the use of RAS blockers was not associated with poor outcomes, such as mortality (adjusted OR, 0.81; 95% CI, 0.56 to 1.17; p = 0.265), and a composite of admission to the intensive care unit and mortality (adjusted OR, 0.95; 95% CI, 0.73 to 1.22; p = 0.669). Analysis in the propensity scorematched population showed consistent results. CONCLUSION: In this Korean nationwide claims dataset, the use of RAS blockers was associated with a higher risk to SARS-CoV-2 infection but not with higher mortality or other severe clinical courses.

Renin-Angiotensin Aldosterone System Inhibitors in Primary Prevention and COVID-19.

Background Considering the widespread risk of collider bias and confounding by indication in previous research, the associations between renin-angiotensin aldosterone system (RAAS) inhibitor use and COVID-19 remain unknown. Accordingly, this study tested the hypothesis that RAAS inhibitors influence the summation effect of COVID-19 and its progression to severe outcomes. Methods and Results This nationwide cohort study compared all residents of Sweden, without prior cardiovascular disease, in monotherapy (as of January 1, 2020) with a RAAS inhibitor to those using a calcium channel blocker or a thiazide diuretic. Comparative cohorts were balanced using machine-learning-derived propensity score methods. Of 165 355 people in the analysis (51% women), 367 were hospitalized or died with COVID-19 (246 using a RAAS inhibitor versus 121 using a calcium channel blocker or thiazide diuretic; Cox proportional hazard ratio [HR], 0.97; 95% CI, 0.74-1.27). When each outcome was assessed separately, 335 people were hospitalized with COVID-19 (HR, 0.92; 95% CI, 0.70-1.22), and 64 died with COVID-19 (HR, 1.22; 95% CI, 0.68-2.19). The severity of COVID-19 outcomes did not differ between those using a RAAS inhibitor and those using a calcium channel blocker or thiazide diuretic (ordered logistic regression odds ratio, 1.01; 95% CI, 0.89-1.14). Conclusions Despite potential limitations, this study is among the best available evidence that RAAS inhibitor use in primary prevention does not increase the risk of severe COVID-19 outcomes; presenting strong data from which scientists and policy makers alike can base, with greater confidence, their current position on the safety of using RAAS inhibitors during the COVID-19 pandemic.