Severe Acute Respiratory Syndrome Coronavirus 2, COVID-19, and the Renin-Angiotensin System: Pressing Needs and Best Research Practices.

The coronavirus disease 2019 (COVID-19) pandemic is associated with significant morbidity and mortality throughout the world, predominantly due to lung and cardiovascular injury. The virus responsible for COVID-19-severe acute respiratory syndrome coronavirus 2-gains entry into host cells via ACE2 (angiotensin-converting enzyme 2). ACE2 is a primary enzyme within the key counter-regulatory pathway of the renin-angiotensin system (RAS), which acts to oppose the actions of Ang (angiotensin) II by generating Ang-(1-7) to reduce inflammation and fibrosis and mitigate end organ damage. As COVID-19 spans multiple organ systems linked to the cardiovascular system, it is imperative to understand clearly how severe acute respiratory syndrome coronavirus 2 may affect the multifaceted RAS. In addition, recognition of the role of ACE2 and the RAS in COVID-19 has renewed interest in its role in the pathophysiology of cardiovascular disease in general. We provide researchers with a framework of best practices in basic and clinical research to interrogate the RAS using appropriate methodology, especially those who are relatively new to the field. This is crucial, as there are many limitations inherent in investigating the RAS in experimental models and in humans. We discuss sound methodological approaches to quantifying enzyme content and activity (ACE, ACE2), peptides (Ang II, Ang-[1-7]), and receptors (types 1 and 2 Ang II receptors, Mas receptor). Our goal is to ensure appropriate research methodology for investigations of the RAS in patients with severe acute respiratory syndrome coronavirus 2 and COVID-19 to ensure optimal rigor and reproducibility and appropriate interpretation of results from these investigations.

Hypertension as a sequela in patients of SARS-CoV-2 infection.

BACKGROUND: COVID-19 is a respiratory infectious disease caused by SARS-CoV-2, and cardiovascular damage is commonly observed in affected patients. We sought to investigate the effect of SARS-CoV-2 infection on cardiac injury and hypertension during the current coronavirus pandemic. STUDY DESIGN AND METHODS: The clinical data of 366 hospitalized COVID-19-confirmed patients were analyzed. The clinical signs and laboratory findings were extracted from electronic medical records. Two independent, experienced clinicians reviewed and analyzed the data. RESULTS: Cardiac injury was found in 11.19% (30/268) of enrolled patients. 93.33% (28/30) of cardiac injury cases were in the severe group. The laboratory findings indicated that white blood cells, neutrophils, procalcitonin, C-reactive protein, lactate, and lactic dehydrogenase were positively associated with cardiac injury marker. Compared with healthy controls, the 190 patients without prior hypertension have higher AngⅡ level, of which 16 (8.42%) patients had a rise in blood pressure to the diagnostic criteria of hypertension during hospitalization, with a significantly increased level of the cTnI, procalcitonin, angiotensin-II (AngⅡ) than those normal blood pressure ones. Multivariate analysis indicated that elevated age, cTnI, the history of hypertension, and diabetes were independent predictors for illness severity. The predictive model, based on the four parameters and gender, has a good ability to identify the clinical severity of COVID-19 in hospitalized patients (area under the curve: 0.932, sensitivity: 98.67%, specificity: 75.68%). CONCLUSION: Hypertension, sometimes accompanied by elevated cTnI, may occur in COVID-19 patients and become a sequela. Enhancing Ang II signaling, driven by SARS-CoV-2 infection, might play an important role in the renin-angiotensin system, and consequently lead to the development of hypertension in COVID-19.

Current forecast of COVID-19 in Mexico: A Bayesian and machine learning approaches.

The COVID-19 pandemic has been widely spread and affected millions of people and caused hundreds of deaths worldwide, especially in patients with comorbilities and COVID-19. This manuscript aims to present models to predict, firstly, the number of coronavirus cases and secondly, the hospital care demand and mortality based on COVID-19 patients who have been diagnosed with other diseases. For the first part, I present a projection of the spread of coronavirus in Mexico, which is based on a contact tracing model using Bayesian inference. I investigate the health profile of individuals diagnosed with coronavirus to predict their type of patient care (inpatient or outpatient) and survival. Specifically, I analyze the comorbidity associated with coronavirus using Machine Learning. I have implemented two classifiers: I use the first classifier to predict the type of care procedure that a person diagnosed with coronavirus presenting chronic diseases will obtain (i.e. outpatient or hospitalised), in this way I estimate the hospital care demand; I use the second classifier to predict the survival or mortality of the patient (i.e. survived or deceased). I present two techniques to deal with these kinds of unbalanced datasets related to outpatient/hospitalised and survived/deceased cases (which occur in general for these types of coronavirus datasets) to obtain a better performance for the classification.

Impact of metabolic and cardiovascular disease on COVID-19 mortality: A systematic review and meta-analysis.

BACKGROUND AND AIMS: This meta-analysis aims to highlight the impact of cardio-metabolic comorbidities on COVID-19 severity and mortality. METHODS: A thorough search on major online databases was done for studies describing the clinical outcomes of COVID-19 patients. We used random-effects model to compute pooled estimates for critical or fatal disease. RESULTS: A total of 20,475 patients from 33 eligible studies were included. Maximum risk of development of critical or fatal COVID-19 disease was seen in patients with underlying cardiovascular disease [OR: 3.44, 95% CI: 2.65-4.48] followed by chronic lung disease, hypertension and diabetes mellitus. Of the total cases, 64% had one of the four comorbidities with the most prevalent being hypertension with a pooled prevalence of 27%. CONCLUSIONS: Presence of comorbidities like cardiovascular disease, chronic lung disease, hypertension and diabetes mellitus led to a higher risk of development of critical or fatal COVID-19 disease, with maximum risk seen with underlying cardiovascular disease.

Clinical characteristics of COVID-19 patients in three consecutive generations of spread in Zhejiang, China.

OBJECTIVES: The aim was to determine the clinical characteristics of COVID-19 patients because the SARS-CoV-2 virus continues to circulate in the population. METHODS: This is a retrospective, multicentre, cohort study. Adult COVID-19 cases from four hospitals in Zhejiang were enrolled and clustered into three groups based on epidemiological history. First-generation patients had a travel history to Hubei within 14 days before disease onset; second-generation patients had a contact history with first-generation patients; third-generation patients had a contact history with second-generation patients. Demographic, clinical characteristics, clinical outcomes and duration of viral shedding were analysed. RESULTS: A total of 171 patients were enrolled, with 83, 44 and 44 patients in the first-, second-, and third-generation, respectively. Compared with the first and second generations, third-generation patients were older (61.3 vs. 48.3 and 44.0 years, p < 0.001) and had more coexisting conditions (56.8% vs. 36.1% and 27.3%, p 0.013). At 7 ± 1 days from illness onset, third-generation patients had lower lymphocyte (0.6 vs. 0.8 and 0.8 × 109/L, p 0.007), higher C-reactive protein (29.7 vs. 17.1 and 13.8 mg/L, p 0.018) and D-dimer (1066 vs. 412.5 and 549 µg/L, p 0.002) and more lesions involving the pulmonary lobes (lobes ≥5, 81.8% vs. 53.0% and 34.1%, p < 0.001). The proportions of third-generation patients developing severe illness (72.7% vs. 32.5% and 27.3%, p < 0.001), critical illness (38.6% vs. 10.8% and 6.8%, p < 0.001) and receiving endotracheal intubation (20.5% vs. 3.6% and 2.3%, p 0.002) were higher than in the other two groups. DISCUSSION: Third-generation patients were older, had more underlying comorbidities and had a higher proportion of severe or critical illness than first- and second-generation patients.

Clinical and laboratory factors associated with coronavirus disease 2019 (Covid-19): A systematic review and meta-analysis.

SARS Coronavirus-2 is one of the most widespread viruses globally during the 21st century, whose severity and ability to cause severe pneumonia and death vary. We performed a comprehensive systematic review of all studies that met our standardised criteria and then extracted data on the age, symptoms, and different treatments of Covid-19 patients and the prognosis of this disease during follow-up. Cases in this study were divided according to severity and death status and meta-analysed separately using raw mean and single proportion methods. We included 171 complete studies including 62,909 confirmed cases of Covid-19, of which 148 studies were meta-analysed. Symptoms clearly emerged in an escalating manner from mild-moderate symptoms, pneumonia, severe-critical to the group of non-survivors. Hypertension (Pooled proportion (PP): 0.48 [95% Confident interval (CI): 0.35-0.61]), diabetes (PP: 0.23 [95% CI: 0.16-0.33]) and smoking (PP: 0.12 [95% CI: 0.03-0.38]) were highest regarding pre-infection comorbidities in the non-survivor group. While acute respiratory distress syndrome (PP: 0.49 [95% CI: 0.29-0.78]), (PP: 0.63 [95% CI: 0.34-0.97]) remained one of the most common complications in the severe and death group respectively. Bilateral ground-glass opacification (PP: 0.68 [95% CI: 0.59-0.75]) was the most visible radiological image. The mortality rates estimated (PP: 0.11 [95% CI: 0.06-0.19]), (PP: 0.03 [95% CI: 0.01-0.05]), and (PP: 0.01 [95% CI: 0-0.3]) in severe-critical, pneumonia and mild-moderate groups respectively. This study can serve as a high evidence guideline for different clinical presentations of Covid-19, graded from mild to severe, and for special forms like pneumonia and death groups.

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.

Association between blood pressure categories and cardiovascular disease mortality in China.

BACKGROUND: Blood pressure (BP) categories are useful to simplify preventions in public health, and diagnostic and treatment approaches in clinical practice. Updated evidence about the associations of BP categories with cardiovascular diseases (CVDs) and its subtypes is warranted. METHODS AND FINDINGS: About 0.5 million adults aged 30 to 79 years were recruited from 10 areas in China during 2004-2008. The present study included 430 977 participants without antihypertension treatment, cancer, or CVD at baseline. BP was measured at least twice in a single visit at baseline and CVD deaths during follow-up were collected via registries and the national health insurance databases. Multivariable Cox regression was used to estimate the associations between BP categories and CVD mortality. Overall, 16.3% had prehypertension-low, 25.1% had prehypertension-high, 14.1% had isolated systolic hypertension (ISH), 1.9% had isolated diastolic hypertension (IDH), and 9.1% had systolic-diastolic hypertension (SDH). During a median 10-year follow-up, 9660 CVD deaths were documented. Compared with normal, the hazard ratios (95% CI) of prehypertension-low, prehypertension-high, ISH, IDH, SDH for CVD were 1.10 (1.01-1.19), 1.32 (1.23-1.42), 2.04 (1.91-2.19), 2.20 (1.85-2.61), and 3.81 (3.54-4.09), respectively. All hypertension subtypes were related to the increased risk of CVD subtypes, with a stronger association for hemorrhagic stroke than for ischemic heart disease. The associations were stronger in younger than older adults. CONCLUSIONS: Prehypertension-high should be considered in CVD primary prevention given its high prevalence and increased CVD risk. All hypertension subtypes were independently associated with CVD and its subtypes mortality, though the strength of associations varied substantially.

Role of Hypertension on the Severity of COVID-19: A Review.

ABSTRACT: The novel coronavirus disease (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly evolved into a global pandemic. The substantial morbidity and mortality associated with the infection has prompted us to understand potential risk factors that can predict patient outcomes. Hypertension has been identified as the most prevalent cardiovascular comorbidity in patients infected with COVID-19 that demonstrably increases the risk of hospitalization and death. Initial studies implied that renin-angiotensin-aldosterone system inhibitors might increase the risk of viral infection and aggravate disease severity, thereby causing panic given the high global prevalence of hypertension. Nonetheless, subsequent evidence supported the administration of antihypertensive drugs and noted that they do not increase the severity of COVID-19 infection in patients with hypertension, rather may have a beneficial effect. To date, the precise mechanism by which hypertension predisposes to unfavorable outcomes in patients infected with COVID-19 remains unknown. In this mini review, we elaborate on the pathology of SARS-CoV-2 infection coexisting with hypertension and summarize potential mechanisms, focusing on the dual roles of angiotensin-converting enzyme 2 and the disorders of renin-angiotensin-aldosterone system in COVID-19 and hypertension. The effects of proinflammatory factors released because of immune response and gastrointestinal dysfunction in COVID-19 are also discussed.

[The RAAS and SARS-CoV-2: A riddle to solve]. / El SRAA y el SARS-CoV-2: el acertijo a resolver.

The first case of COVID-19 was reported on 31 December 2019 in Wuhan, China. Ever since there has been unprecedented and growing interest in learning about all aspects of this new disease. Debate has been generated as to the association between antihypertensive therapy with renin-angiotensin-aldosterone system (RAAS) inhibitors and SARS-CoV-2 infection. While many questions as yet remain unanswered, the aim of this report is to inform health professionals about the current state of knowledge. Because this is an ever-evolving topic, the recommendation is that it be updated as new evidence becomes available. Below, we provide a review of pre-clinical and clinical studies that link coronavirus to the RAAS.

Review of the Metabolic Risk Factors for Increased Severity of Coronavirus Disease-2019.

The coronavirus 2019 (COVID-19) pandemic has presented many new challenges to the healthcare community with the sheer number of individuals affected and the range of symptoms at presentation. Early findings have shown that increased age is an independent risk factor for COVID-19 severity. Diabetes and hypertension were also found to be strong independent risk factors for severe COVID-19. It was later discovered that obesity is a strong risk factor for severe disease as well. Possible mechanisms for the increased risk associated with metabolic disease include the increased prevalence of acute respiratory syndrome, immune cell dysfunction, and chronic inflammatory states associated with obesity and diabetes. Acknowledging these risk factors has consequences for addressing vaccination strategies as well as healthcare disparities.

Telemedicine interventions for hypertension management in low- and middle-income countries: A scoping review.

Hypertension remains the leading cause of cardiovascular disease worldwide and disproportionately impacts patients living in low- and middle-income countries (LMICs). Telemedicine offers a potential solution for improving access to health care for vulnerable patients in LMICs. OBJECTIVES: The purpose of this scoping review was to summarize the evidence for telemedicine interventions for blood pressure management in LMICs and assess the relationships between the telemedicine intervention characteristics and clinical outcomes. DESIGN: Published studies were identified from the following databases (from their inception to May 2020): PubMed, Scopus, and Embase. Search terms related to "Low and Middle Income Countries," "Telemedicine," and "Hypertension" were used, and clinical outcomes were extracted from the screened articles. RESULTS: Our search resulted in 530 unique articles, and 14 studies were included in this review. Five studies assessed telemedicine interventions for patient-provider behavioral counseling, four assessed patient-provider medical management, and five assessed provider-provider consultation technologies. Out of fourteen individual studies, eleven demonstrated a significant improvement in systolic or diastolic blood pressure in the intervention group. Of the eight studies that reported difference-in-differences changes in systolic blood pressure, between-arm differences ranged from 13.2 mmHg to 0.4 mmHg. CONCLUSIONS: The majority of the studies in this review demonstrated a significant reduction in blood pressure with use of the telemedicine intervention, though the magnitude of benefit was not consistently large. Limitations of the studies included small sample sizes, short duration, and intervention heterogeneity. Current evidence suggests that telemedicine may provide a promising approach to increase access to care and improve outcomes for hypertension in LMICs, especially during events that limit access to in-person care, such as the COVID-19 pandemic. However, high-quality clinical trials of sufficient size and duration are needed to establish the impact and role of telemedicine in hypertension care. The protocol for this review was not registered.

SARS-CoV-2 and hypertension.

The objective of this review is to give an overview of the pathophysiological effects of the Coronavirus Disease 2019 (COVID-19) in relation to hypertension (HT), with a focus on the Renin-Angiotensin-Aldosterone System (RAAS) and the MAS receptor. HT is a multifactorial disease and a public health burden, as it is a risk factor for diseases like stroke, coronary artery disease, and heart failure, leading to 10.4 million deaths yearly. Blood pressure is regulated by the RAAS. The system consists of two counter-regulatory axes: ACE/ANG-II/AT1 R and ACE2/ANG-(1-7)/MAS. The main regulatory protein in balancing the RAAS is angiotensin-converting enzyme 2 (ACE2). The protein also functions as the main mediator of endocytosis of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into the host cell. SARS-CoV-2 is the cause of COVID-19 and has caused a worldwide pandemic; however, the treatment and prophylaxis of COVID-19 are limited. Several drugs and vaccines are currently being tested in clinical trials with a few already approved by EMA and FDA. HT is a major risk factor regarding the severity and fatality of COVID-19, and the RAAS plays an important role in COVID-19 infection since SARS-CoV-2 can lead to a dysregulation of the system by reducing the ACE2 expression. The exact mechanisms of HT in relation to COVID-19 remain uncertain, and more research is needed for further elucidation.

Changes in Home Blood Pressure Monitored Among Elderly Patients With Hypertension During the COVID-19 Outbreak: A Longitudinal Study in China Leveraging a Smartphone-Based Application.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has impacted clinical care worldwide. Evidence of how this health crisis affected common conditions like blood pressure (BP) control is uncertain. METHODS: We used longitudinal BP data from an ongoing randomized clinical trial to examine variations in home BP monitored via a smartphone-based application (app) in a total of 7394 elderly patients with hypertension aged 60 to 80 years stratified by their location in Wuhan (n=283) compared with other provinces of China (n=7111). Change in morning systolic BP (SBP) was analyzed for 5 30-day phases during the pandemic, including preepidemic (October 21 to November 20, 2019), incubation (November 21 to December 20, 2019), developing (December 21, 2019 to January 20, 2020), outbreak (January 21 to February 20, 2020), and plateau (February 21 to March 21, 2020). RESULTS: Compared with non-Wuhan areas of China, average morning SBP (adjusted for age, sex, body mass index) in Wuhan patients was significantly higher during the epidemic growth phases, which returned to normal at the plateau. Between-group differences in ΔSBP were +2.5, +3.0, and +2.1 mm Hg at the incubation, developing, and outbreak phases of COVID-19 (P<0.001), respectively. Sensitivity analysis showed a similar trend in trajectory pattern of SBP in both the intensive and standard BP control groups of the trial. Patients in Wuhan also had an increased regimen change in antihypertensive drugs during the outbreak compared with non-Wuhan patients. Expectedly, Wuhan patients were more likely to check their BP via the app, while doctors were less likely to monitor the app for BP control during the pandemic. CONCLUSIONS: Our data demonstrate that the COVID-19 pandemic was associated with a short-term increase in morning SBP among elderly patients with hypertension in Wuhan but not other parts of China. Further study will be needed to understand if these findings extended to other parts of the world substantially affected by the virus. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03015311.

HIV/SARS-CoV-2 coinfection: A global perspective.

Since its first appearance in Wuhan, China, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly spread throughout the world and has become a global pandemic. Several medical comorbidities have been identified as risk factors for coronavirus disease 2019 (COVID-19). However, it remains unclear whether people living with human immunodefeciency virus (PLWH) are at an increased risk of COVID-19 and severe disease manifestation, with controversial suggestion that HIV-infected individuals could be protected from severe COVID-19 by means of antiretroviral therapy or HIV-related immunosuppression. Several cases of coinfection with HIV and SARS-CoV-2 have been reported from different parts of the globe. This review seeks to provide a holistic overview of SARS-CoV-2 infection in PLWH.

Angiotensin II Type 2 Receptor: A Target for Protection Against Hypertension, Metabolic Dysfunction, and Organ Remodeling.

The renin-angiotensin system is of vital significance not only in the maintenance of blood pressure but also because of its role in the pathophysiology of different organ systems in the body. Of the 2 Ang II (angiotensin II) receptors, the AT1R (Ang II type 1 receptor) has been extensively studied for its role in mediating the classical functions of Ang II, including vasoconstriction, stimulation of renal tubular sodium reabsorption, hormonal secretion, cell proliferation, inflammation, and oxidative stress. The other receptor, AT2R (Ang II type 2 receptor), is abundantly expressed in both immune and nonimmune cells in fetal tissue. However, its expression is increased under pathological conditions in adult tissues. The role of AT2R in counteracting AT1R function has been discussed in the past 2 decades. However, with the discovery of the nonpeptide agonist C21, the significance of AT2R in various pathologies such as obesity, hypertension, and kidney diseases have been examined. This review focuses on the most recent findings on the beneficial effects of AT2R by summarizing both gene knockout studies as well as pharmacological studies, specifically highlighting its importance in blood pressure regulation, obesity/metabolism, organ protection, and relevance in the treatment of coronavirus disease 2019 (COVID-19).