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The use of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) in coronavirus disease 2019 (COVID-19) patients has been claimed as associated with the risk of COVID-19 infection and its subsequent morbidities and mortalities. These claims were resulting from the possibility of upregulating the expression of angiotensin-converting enzyme 2 (ACE2), facilitation of SARS-CoV-2 entry, and increasing the susceptibility of infection in such treated cardiovascular patients. ACE2 and renin-angiotensin-aldosterone system (RAAS) products have a critical function in controlling the severity of lung injury, fibrosis, and failure following the initiation of the disease. This review is to clarify the mechanisms beyond the possible deleterious effects of angiotensin II (Ang II), and the potential protective role of angiotensin 1–7 (Ang 1–7) against pulmonary fibrosis, with a subsequent discussion of the latest updates on ACEIs/ARBs use and COVID-19 susceptibility in the light of these mechanisms and biochemical explanation.

Background The uncertainty about COVID-19 outcomes in angiotensin-converting enzyme inhibitors (ACEI)/angiotensin receptor blockers (ARB) users continues with contradictory findings. This study aimed to determine the effect of ACEI/ARB use in patients with severe COVID-19. Methods This retrospective cohort study was done in two Saudi public specialty hospitals designated as COVID-19 referral facilities. We included 354 patients with a confirmed diagnosis of COVID-19 between April and June 2020, of which 146 were ACEI/ARB users and 208 were non-ACEI/ARB users. Controlling for confounders, we conducted multivariate logistic regression and sensitivity analyses using propensity score matching (PSM) and Inverse propensity score weighting (IPSW) for high-risk patient subsets. Results Compared to non-ACEI/ARB users, ACEI/ARB users had an eight-fold higher risk of developing critical or severe COVID-19 (OR = 8.25, 95%CI = 3.32–20.53); a nearly 7-fold higher risk of intensive care unit (ICU) admission (OR = 6.76, 95%CI = 2.88–15.89) and a nearly 5-fold higher risk of requiring noninvasive ventilation (OR = 4.77,95%CI = 2.15–10.55). Patients with diabetes, hypertension, and/or renal disease had a five-fold higher risk of severe COVID-19 disease (OR = 5.40,95%CI = 2.0−14.54]. These results were confirmed in the PSM and IPSW analyses. Conclusion In general, but especially among patients with hypertension, diabetes, and/or renal disease, ACEI/ARB use is associated with a significantly higher risk of severe or critical COVID-19 disease, and ICU care.

Visual Abstract, Highlights • Among subjects at risk for heart failure (Stage A and B), the minor C allele of the B-type natriuretic peptide (BNP) genetic variant rs198389 is associated with higher circulating levels of BNP. • Rs198389 C allele is also associated with lower risk of hypertension, new onset of left ventricular systolic dysfunction, and major adverse cardiovascular events. • These data support the role of BNP genetic testing and BNP-based therapy for the prevention of heart failure., Summary B-type natriuretic peptide (BNP) possesses blood-pressure–lowering, antifibrotic, and aldosterone-suppressing properties. In Stage A and B heart failure, the carriers of the minor C allele of the BNP genetic variant rs198389 have higher circulating levels of BNP and are at decreased risk of hypertension, new-onset left ventricular systolic dysfunction, and hospitalization for major adverse cardiovascular events. Future studies are warranted to investigate the role of BNP genetic testing and BNP-based therapy in the prevention of heart failure.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mainly caused pneumonia and pulmonary fibrosis through upper respiratory tract infection, which resulted in acute respiratory distress syndrome (ARDS) and multiorgan damage of cardiovascular, nervous, digestive, and genitourinary systems. Although the virus test turned negative after the patient recovered, the damage to multiorgan which caused by SARS-CoV-2 may irreversible. Therefore, the health status of the recovered patients has gradually become the focus of people's attention. Whether coronavirus disease 2019 (COVID-19) patients can receive exercise rehabilitation training after discharge? and what's the basis? We try to analyze and answer these questions, will provide some ideas about the patients to develop a reasonable and effective exercise rehabilitation program.

This report presents the case of this atypical presentation of a rare disease in a 19-year-old female with cardiomyopathy and hypertension. Investigation revealed renovascular stenosis, infarcts, and active vasculitis pathognomonic for Takayasu arteritis (TA). Cardiac magnetic resonance imaging demonstrated mild pericardial inflammation and epicardial edema. Vasculitis-induced renovascular secondary hypertension resulted in myocardial dysfunction, which recovered with treatment of hypertension and TA. (Level of Difficulty: Beginner.), Graphical abstract, This report presents the case of this atypical presentation of a rare disease in a 19-year-old female with cardiomyopathy and hypertension. Investigation revealed renovascular…

Type 2 diabetes mellitus, obesity, hypertension, and other associated metabolic complications have been demonstrated as a crucial contributor to the enhanced morbidity and mortality of patients with coronavirus disease 2019 (COVID-19). Data on the interplay between metabolic comorbidities and the outcomes in patients with COVID-19 have been emerging and rapidly increasing. This implies a mechanistic link between metabolic diseases and COVID-19 resulting in the exacerbation of the condition. Nonetheless, new evidences are emerging to support insulin-mediated aggressive glucose-lowering treatment as a possible trigger of high mortality rate in diabetic COVID-19 patients, putting the clinician in a confounding and difficult dilemma for the treatment of COVID-19 patients with metabolic comorbidities. Thus, this review discusses the pathophysiological link among severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), angiotensin-converting enzyme 2 (ACE2), metabolic complications, and severe inflammation in COVID-19 development, especially in those with multi-organ injuries. We discuss the influence of several routinely used drugs in COVID-19 patients, including anti-inflammatory and anti-coagulant drugs, antidiabetic drugs, renin-angiotensin-aldosterone system inhibitors. Especially, we provide a balanced overview on the clinical application of glucose-lowering drugs (insulin and metformin), angiotensin-converting-enzyme inhibitors, and angiotensin receptor blockers. Although there is insufficient evidence from clinical or basic research to comprehensively reveal the mechanistic link between adverse outcomes in COVID-19 and metabolic comorbidities, it is hoped that the update in the current review may help to better outline the optimal strategies for clinical management of COVID-19 patients with metabolic comorbidities.

Highlights • Congestive heart failure is a major cause of morbidity and mortality worldwide. • Sacubitril/valsartan improved left ventricular remodeling and ejection fraction in a real-world setting, mostly within 12 months. • Female gender and primitive cardiomyopathy were predictors of favorable remodeling. • Sacubitril/valsartan should be initiated early to maximize its beneficial effects., Background Compared to angiotensin inhibition, angiotensin-neprilysin “blockade” improves mortality and reduces hospitalizations in patients with heart failure (HF) with reduced ejection fraction (EF). Sacubitril/valsartan is known to influence left ventricular (LV) reverse remodeling with systolic function improvement, although underlying mechanisms remain partially unclear. Our objectives were to evaluate whether sacubitril/valsartan promotes LV remodeling and improves LV ejection fraction (LVEF) (above the 35% threshold by echocardiographic evaluation) and to identify predictors of reverse remodeling in a real-world setting. Methods New York Heart Association (NYHA) class II–III patients with EF ≤ 35% were consecutively enrolled. All patients were on optimal medical therapy on the initiation of sacubitril/valsartan therapy. Full clinical and multi-parametric echocardiographic evaluation, electrocardiogram, and laboratory tests were performed at baseline and after 3, 6, 12, and 24 months. Results In total, 69 patients were recruited from July 2016 to August 2018. Reverse remodeling was observed in 57.7% (30/52) of patients, occurring within 3, 6, 12, and 24 months in 2, 11, 13, and 4 patients, respectively. Twenty-four (46%) patients showed LVEF improvement above the threshold of 35% during follow-up, occurring in 1, 10, 9, and 4 patients within 3, 6, 12, and 24 months, respectively. Primitive dilated cardiomyopathy and female gender were identified as significant predictors of reverse remodeling. NYHA class was improved in both remodeling and non-remodeling patients. Conclusion Sacubitril/valsartan promotes favorable cardiac remodeling and significantly improves LVEF in a significant proportion of HF patients within 24 months, both in NYHA class II and III patients with HF.

Summary Background Although cardiovascular comorbidities seem to be strongly associated with worse outcomes in patients with coronavirus disease 2019 (COVID-19), data regarding patients with preexisting heart failure are limited. Aims To investigate the incidence, characteristics and clinical outcomes of patients with COVID-19 with a history of heart failure with preserved or reduced ejection fraction. Methods We performed an observational multicentre study including all patients hospitalized for COVID-19 across 24 centres in France from 26 February to 20 April 2020. The primary endpoint was a composite of in-hospital death or need for orotracheal intubation. Results Overall, 2809 patients (mean age 66.4 ± 16.9 years) were included. Three hundred and seventeen patients (11.2%) had a history of heart failure; among them, 49.2% had heart failure with reduced ejection fraction and 50.8% had heart failure with preserved ejection fraction. COVID-19 severity at admission, defined by a quick sequential organ failure assessment score > 1, was similar in patients with versus without a history of heart failure. Before and after adjustment for age, male sex, cardiovascular comorbidities and quick sequential organ failure assessment score, history of heart failure was associated with the primary endpoint (hazard ratio [HR]: 1.41, 95% confidence interval [CI]: 1.06–1.90; P = 0.02). This result seemed to be mainly driven by a history of heart failure with preserved ejection fraction (HR: 1.61, 95% CI: 1.13–2.27; P = 0.01) rather than heart failure with reduced ejection fraction (HR: 1.19, 95% CI: 0.79–1.81; P = 0.41). Conclusions History of heart failure in patients with COVID-19 was associated with a higher risk of in-hospital death or orotracheal intubation. These findings suggest that patients with a history of heart failure, particularly heart failure with preserved ejection fraction, should be considered at high risk of clinical deterioration.

Visual Abstract, Highlights • Targeting AGT is a novel approach to inhibit the RAAS pathway. • AGT is primarily synthesized in the liver. • IONIS-AGT-LRx is an ASO directed to hepatocyte-derived AGT. • In 2 phase 2 trials as monotherapy and as an add-on to 2 to 3 medications for hypertension, IONIS-AGT-LRx was well tolerated with a significant reduction in plasma AGT levels. • IONIS-AGT-LRx is being developed for hypertension and heart failure indications., Summary Targeting angiotensinogen (AGT) may provide a novel approach to more optimally inhibit the renin-angiotensin-aldosterone system pathway. Double-blind, placebo-controlled clinical trials were performed in subjects with hypertension as monotherapy or as an add-on to angiotensin-converting enzyme inhibitors/angiotensin receptor blockers with IONIS-AGT-LRx versus placebo up to 2 months. IONIS-AGT-LRx was well tolerated with no significant changes in platelet count, potassium levels, or liver and renal function. IONIS-AGT-LRx significantly reduced AGT levels compared with placebo in all 3 studies. Although not powered for this endpoint, trends were noted in blood pressure reduction. In conclusion, IONIS-AGT-LRx significantly reduces AGT with a favorable safety, tolerability, and on-target profile. (A Study to Assess the Safety, Tolerability and Efficacy of IONIS-AGT-LRx; NCT04083222; A Study to Assess the Safety, Tolerability and Efficacy of IONIS-AGT-LRx, an Antisense Inhibitor Administered Subcutaneously to Hypertensive Subjects With Controlled Blood Pressure; NCT03714776; Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Ionis AGT-LRx in Healthy Volunteers; NCT03101878)

Purpose of review: Although the respiratory system is the main target of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), it is evident from recent data that other systems, especially cardiovascular and hematological, are also significantly affected. In fact, in severe form, COVID-19 causes a systemic illness with widespread inflammation and cytokine flood, resulting in severe cardiovascular injury. Therefore, we reviewed cardiac injury biomarkers' role in various cardiovascular complications of COVID 19 in recent studies. Recent findings: Cardiac injury biomarkers were elevated in most of the complicated cases of COVID-19, and their elevation is directly proportional to the worst outcome. Evaluation of cardiac biomarkers with markers of other organ damage gives a more reliable tool for case fatalities and future outcome. Summary: Significant association of cardiac biomarkers in COVID-19 cases helps disease management and prognosis, especially in severely ill patients.

Background Excess visceral fat (VF) or high body mass index (BMI) is risk factors for severe COVID-19. The receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is expressed at higher levels in the VF than in the subcutaneous fat (SCF) of obese patients. Aim To show that visceral fat accumulation better predicts severity of COVID-19 outcome compared to either SCF amounts or BMI. Methods We selected patients with symptomatic COVID-19 and a computed tomography (CT) scan. Severe COVID-19 was defined as requirement for mechanical ventilation or death. Fat depots were quantified on abdominal CT scan slices and the measurements were correlated with the clinical outcomes. ACE 2 mRNA levels were quantified in fat depots of a separate group of non-COVID-19 subjects using RT-qPCR. Results Among 165 patients with a mean BMI of 26.1 ± 5.4 kg/m2, VF was associated with severe COVID-19 (p = 0.022) and SCF was not (p = 0.640). Subcutaneous fat was not different in patients with mild or severe COVID-19 and the SCF/VF ratio was lower in patients with severe COVID-19 (p = 0.010). The best predictive value for severe COVID-19 was found for a VF area ≥128.5 cm2 (ROC curve), which was independently associated with COVID-19 severity (p, Highlights • Visceral fat is associated with COVID-19 severity in Caucasian adults. • The expression of angiotensin converting enzyme type 2, the receptor of SARS-Cov2, in visceral fat may contribute to the cytokine storm. • Metabolic health of patients with COVID-19 should be carefully evaluated.

Background & Aims Smaller 8-mm diameter transjugular intrahepatic portosystemic shunts (TIPS) appear to be more beneficial than larger 10-mm TIPS stent-grafts, but lack the ability for secondary dilation in cases of clinical ineffectiveness. Underdilated VIATORR® TIPS stent grafts (VTS) expand passively, whereas novel VIATORR Controlled Expansion (VCX) stent grafts do not. This study evaluated the impact on survival of underdilated VCX compared with VTS in patients with decompensated cirrhosis. Methods This was a prospective case-control study including patients with cirrhosis receiving TIPS using 10-mm VCX underdilated to 8 mm. Patients with cirrhosis receiving 10-mm VTS underdilated to 8 mm were matched for age, sex, indication for TIPS, and liver function. Results A total of 114 patients (47 VCX, 47 VTS, and 20 fully dilated VCX/VTS) were included. After TIPS implantation, underdilated VCX diameter was 8.0 (7.8–9.2) mm at a median time of 359 (87–450) days, compared with VTS at 9.9 (9.7–10.0) mm (p, Graphical abstract, Highlights • Novel VIATORR® Controlled Expansion (VCX) stent grafts facilitate safe and stable underdilation to 8 mm of large 10-mm diameter stent-grafts. • Use of underdilated VCX improved outcome (survival, hepatic encephalopathy, ascites, and heart failure) compared with legacy VIATORR TIPS stent grafts (VTS). • Use of underdilated VCX preserved cardiac function compared with VTS.

Making gender bias visible allows to fill the gaps in knowledge and understand health records and risks of women and men. The coronavirus disease 2019 (COVID-19) pandemic has shown a clear gender difference in health outcomes. The more severe symptoms and higher mortality in men as compared to women are likely due to sex and age differences in immune responses. Age-associated decline in sex steroid hormone levels may mediate proinflammatory reactions in older adults, thereby increasing their risk of adverse outcomes, whereas sex hormones and/or sex hormone receptor modulators may attenuate the inflammatory response and provide benefit to COVID-19 patients. While multiple pharmacological options including anticoagulants, glucocorticoids, antivirals, anti-inflammatory agents and traditional Chinese medicine preparations have been tested to treat COVID-19 patients with varied levels of evidence in terms of efficacy and safety, information on sex-targeted treatment strategies is currently limited. Women may have more benefit from COVID-19 vaccines than men, despite the occurrence of more frequent adverse effects, and long-term safety data with newly developed vectors are eagerly awaited. The prevalent inclusion of men in randomised clinical trials (RCTs) with subsequent extrapolation of results to women needs to be addressed, as reinforcing sex-neutral claims into COVID-19 research may insidiously lead to increased inequities in health care. The huge worldwide effort with over 3,000 ongoing RCTs of pharmacological agents should focus on improving knowledge on sex, gender and age as pillars of individual variation in drug responses and enforce appropriateness., Graphical abstract

Pernio or chilblains is characterized by erythema and swelling at acral sites (eg, toes and fingers), typically triggered by cold exposure. Clinical and histopathologic features of pernio are well described, but the pathogenesis is not entirely understood; vasospasm and a type I interferon (IFN-I) immune response are likely involved. During the coronavirus disease 2019 (COVID-19) pandemic, dermatologists have observed an increase in pernio-like acral eruptions. Direct causality of pernio due to COVID-19 has not been established in many cases because of inconsistent testing methods (often negative results) for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, a form of COVID-19‒associated pernio (also called COVID toes) is likely because of the increased occurrence, frequently in young patients with no cold exposure or prior history of pernio, and reports of skin biopsies with positive SARS-CoV-2 immunohistochemistry. PubMed was searched for 2020 publications using the following keywords: pernio, chilblain, and acral COVID-19. On the basis of our review of the published literature, we speculate that several unifying cutaneous and systemic mechanisms may explain COVID-19‒associated pernio: 1) SARS-CoV-2 cell infection occurs through the cellular receptor angiotensin-converting enzyme 2 (ACE2) mediated by transmembrane protease serine 2 (TMPRSS2), subsequently affecting the renin-angiotensin-aldosterone system (RAAS) with an increase in the vasoconstricting, proinflammatory, and prothrombotic angiotensin II pathway. 2) SARS-CoV-2 cell infection triggers an immune response with robust IFN-I release in patients predisposed to COVID-19‒associated pernio. 3) Age and sex discrepancies correlated with COVID-19 severity and manifestations, including pernio as a sign of mild disease, are likely explained by age-related immune and vascular differences influenced by sex hormones and genetics, which affect susceptibility to viral cellular infection, the RAAS balance, and the IFN-I response., Article Highlights • One of the most common cutaneous manifestations associated with COVID-19 is pernio or chilblains, which has previously been associated with vasospasm and an IFN-I response. • ACE2 is the cellular receptor for SARS-CoV-2, which is processed differently by the proteases TMPRSS2 (ACE2 cleavage facilitates viral cellular entry) and ADAM17 (cleaves cell-bound ACE2, releasing an active form into the circulation). TMPRSS2 is stimulated by androgens, while ADAM17 is stimulated by estrogens; expression of both proteases increases with aging and inflammation. • Age and sex affect the response to COVID-19 infection because of differences in sex hormone activity, endothelial function, and innate immunity. Adult males and the aged demonstrate more pathogenic activity of TMPRSS2, ANGII, and IL-6; females and the young demonstrate more protective activity of ANG1-7 and IFN-I. • The complete RAAS resides in the skin and includes ANGII, which is involved in the cutaneous thermoregulatory vasoconstriction response, and ACE2, expressed in cutaneous endothelial cells and eccrine epithelial cells, both of which may be involved in the pathogenesis of COVID-19‒associated pernio. • Through an understanding of the interconnected cutaneous and systemic mechanisms, the varying skin manifestations of COVID-19 provide important signs of disease severity and may assist in unifying the therapeutic algorithm.

Background There are limited population-wide trend data on kidney failure and kidney replacement therapy (KRT) in people with diabetes. We conducted a retrospective cohort study to report incidence trends of kidney failure and KRT and related mortality in people with diabetes in Hong Kong between 2002 and 2015. Methods We used territory-wide electronic medical records including laboratory, diagnostic and procedural data to identify people with kidney failure and KRT. We used Joinpoint regression models to estimate the average annual percent change (AAPC) of kidney failure and KRT incidence for entire study period, and annual percent change (APC) for each linear trend segment, along with 1-year and 5-year mortality rates. Findings During 4.9 million person-years of follow-up of 712,222 people with diabetes, 31,425 developed kidney failure, among whom 23.0% (n=7,233) received KRT. The incidence of kidney failure declined by 46.8% from 2002 to 2007 (APC: -11.6, 95% CI: -16.3, -6.7), then flattened from 2007 to 2015 (APC: -0.9, 95% CI: -3.1, 1.3). The incidence of KRT remained constant (AAPC: -1.6, 95% CI: -4.4, 1.2). The 1-year mortality rates declined statistically significantly after both kidney failure and KRT. The 5-year mortality rates declined after kidney failure but the decline was not statistically significant after KRT. Interpretation The findings of our study highlight the importance of developing new strategies to prevent a looming epidemic of kidney failure in people with diabetes in Hong Kong. Funding Asia Diabetes Foundation

Background: COVID-19 commonly presents with upper respiratory symptoms; however, studies have shown that SARS-CoV-2 infection affects multiple organ systems. Here, we review the pathophysiology and imaging characteristics of SARS-CoV-2 infection in organ systems throughout the body and explore commonalities. Objective: Familiarity with the underlying pathophysiology and imaging characteristics is essential for the radiologist to recognize these findings in patients with COVID-19 infection. Though pulmonary findings are the most prevalent presentation, COVID-19 may have multiple manifestations and recognition of the extrapulmonary manifestations is especially important because of the potential serious and long-term effects of COVID-19 on multiple organ systems.

Coronavirus Disease 2019 (COVID-19) is complicated by significant coagulopathy, that manifests in the form of both pulmonary artery microthromboses and systemic venous thromboembolism (VTE) leading to excess mortality. Dysregulated innate immune response in the lung due to viral-entry mediated angiotensin-I-converting enzyme 2 (ACE2) receptor downregulation causes endothelial injury in the pulmonary vasculature, inflammatory cytokine release, increased thrombin generation and impaired fibrinolysis. The inflammatory disease process, immobilization with prolonged hospital stay, hypoxia due to extensive lung injury and pre-existing comorbidities can contribute to thromboembolic episodes (TE). The observed risk for TE in COVID-19 is high despite anticoagulation, particularly in intensive care unit (ICU) patients. A high level of clinical suspicion, lower threshold for diagnostic imaging and aggressive early and extended thromboprophylaxis is indicated. The available evidence on the optimal strategies to prevent, diagnose, and treat VTE in patients with COVID-19 is heterogenous, but rapidly evolving. We propose an evidence-based, risk-stratified protocol in approaching the risk of TE episodes in COVID-19 patients.

Background The coronavirus disease 2019 (COVID-19) is caused by SARS-CoV2 that interfaces with the renin-angiotensin-aldosterone system (RAAS) through angiotensin-converting enzyme 2 (ACE-2). This interaction has been proposed as a potential risk factor in patients treated with RAAS-inhibitors. Objectives To analyze if RAAS-inhibitors modify the risk for COVID-19. Methods RASTAVI (NCT03201185) is an ongoing randomized clinical trial randomly allocating Ramipril or control after successful transcatheter aortic valve replacement at 14 centers is Spain. We performed a non-pre-specified interim analysis to evaluate its impact on COVID-19 risk in this vulnerable population. Results As in April 1st 2020, 102 patients (50 Ramipril and 52 controls) were included in the trial. Mean age was 82.3±6.1 years, 56.9% males. Median time of Ramipril treatment was 6 months [IQR:2.9-11.4]. Eleven patients (10.8%) have been diagnosed with COVID-19 (6 in control group and 5 receiving Ramipril, HR=1.150 [95%CI: 0.351-3.768]). The risk of COVID-19 was increased in older patients (p=0.019), those with atrial fibrillation (p=0.066), lower hematocrit (p=0.084), and more comorbidities according to Society of thoracic surgeons score (p=0.065). Admission and oxygen supply was required in 4.9% (2 patients in the Ramipril and 3 in control), and 4 of them died (two in each randomized group). A higher body mass index was the only factor increasing the mortality rate (p=0.039). Conclusions In a high risk population of old patients with cardiovascular disease, randomization to Ramipril had no impact in the incidence or severity of COVID-19. This analysis supports the maintenance of RAAS-inhibitor treatment during COVID-19 crisis., The use of RAAS-inhibitors in patients suffering COVID-19 or at risk is controversial. A total of 102 patients with cardiovascular disease were randomized in the RASTAVI trial to Ramipril (n=50) or control (n=52). Of them, 11 patients (10.8%) developed COVID-19 up to April/2020 (five from Ramipril group and six from control group), and four died (two from each group). COVID-19 occurred more often in older patients and higher body-mass index was related to greater mortality. However, the use of Ramipril did not affect the risk of infection or the prognosis. Hence, the use of RAAS-inhibitors during COVID-19 pandemic seems safe.

Some concerns about the prescription of drugs acting on the renin-angiotensin system (angiotensin-converting enzyme 1 (ACE1) inhibitors, ACEi; angiotensin II type 1 receptor blockers, ARB) have emerged due to SARS COV2 and COVID-19 pandemic. These very legitimate questions are directly the consequence of the recent recognition of the fundamental role of ACE2 (angiotensin-converting enzyme 2) in COVID-19 infection. Indeed, SARS COV2 utilizes ACE2 as a membrane receptor to enter target cells. Consequently, the putative impact of drugs modulating the renin-angiotensin system on the risk of developing severe or fatal severe acute respiratory syndrome in case of COVID-19 infection emerged. As a membrane-bound enzyme (carboxypeptidase), ACE2 inactivates angiotensin II and therefore physiologically counters its effects. Due to a different structure compared with ACE1, ACE2 is insensitive to ACEIs. In vitro, both ARBs and ACEi appear able to upregulate ACE2 tissue expression and activity but these results were not confirmed in Humans. The exact impact of both ARBs and ACEis on COVID-19 infection is definitively known and preliminary results are even in favor of a protective role confers by these drugs. Due to the crucial role of ACE2, some groups support the hypothesis that a modulation of ACE2 expression could represent a valuable therapeutic target could confer protective properties against inflammatory tissue damage in COVID-19 infection. So, studies are currently ongoing to test the impact of elevated ACE2 membrane expression, administration of ARB and infusion of soluble ACE2. In summary, based on the currently available evidences and as recommended by several medical societies, ACEi or ARB should not be systematically discontinued because to date no safety signal was raised with the use of these drugs.

The coronavirus disease 2019 (COVID-19) pandemic has affected the care of patients with HF who contract COVID-19 as well as those without COVID-19 who have been impacted by the restructuring of health care delivery. Patients with HF and other cardiovascular comorbidities are at risk for severe disease and complications of infection. Similarly, COVID-19 has been demonstrated to cause myocarditis and may be implicated in new-onset cardiomyopathy. During this pandemic, special considerations are needed for patients with advanced HF, including those supported by durable left ventricular assist devices (LVADs) and heart transplant recipients. The purpose of this review is to summarize emerging data regarding the development of HF secondary to COVID-19, COVID-19 infection in patients with advanced HF, and the implications of the pandemic on care for non-infected patients with HF., Graphical abstract, Highlights: • Patients with HF may be at increased risk for severe disease and complications from COVID-19. • COVID-19 infection can cause or worsen HF through a variety of mechanisms. • Heart failure care delivery has been significantly restructured during the COVID-19 pandemic. • Future studies should address the impact of pandemic delays on outcomes in patients with HF.

Human coronavirus-associated myocarditis is known, and a number of coronavirus disease 19 (COVID-19)-related myocarditis cases have been reported. The pathophysiology of COVID-19-related myocarditis is thought to be a combination of direct viral injury and cardiac damage due to the host's immune response. COVID-19 myocarditis diagnosis should be guided by insights from previous coronavirus and other myocarditis experience. The clinical findings include changes in electrocardiogram and cardiac biomarkers, and impaired cardiac function. When cardiac magnetic resonance imaging is not feasible, cardiac computed tomographic angiography with delayed myocardial imaging may serve to exclude significant coronary artery disease and identify myocardial inflammatory patterns. Because many COVID-19 patients have cardiovascular comorbidities, myocardial infarction should be considered. If the diagnosis remains uncertain, an endomyocardial biopsy may help identify active cardiac infection through viral genome amplification and possibly refine the treatment risks of systemic immunosuppression. Arrhythmias are not uncommon in COVID-19 patients, but the pathophysiology is still speculative. Nevertheless, clinicians should be vigilant to provide prompt monitoring and treatment. The long-term impact of COVID-19 myocarditis, including the majority of mild cases, remains unknown.

Obesity has reached epidemic proportions in the United States and in much of the westernized world, contributing to considerable morbidity. Several of these obesity-related morbidities are associated with greater risk for death with coronavirus disease 2019 (COVID-19). Severe acute respiratory syndrome coronavirus 2 penetrates human cells through direct binding with angiotensin-converting enzyme 2 receptors on the cell surface. Angiotensin-converting enzyme 2 expression in adipose tissue is higher than that in lung tissue, which means that adipose tissue may be vulnerable to COVID-19 infection. Obese patients also have worse outcomes with COVID-19 infection, including respiratory failure, need for mechanical ventilation, and higher mortality. Clinicians need to be more aggressive when treating obese, especially severely obese, patients with COVID-19 infection.

Environmental pollution and non-chemical stressors such as mental stress or traffic noise exposure are increasingly accepted as health risk factors with substantial contribution to chronic noncommunicable diseases (e.g. cardiovascular, metabolic and mental). Whereas the mechanisms of air pollution-mediated adverse health effects are well characterized, the mechanisms of traffic noise exposure are not completely understood, despite convincing clinical and epidemiological evidence for a significant contribution of environmental noise to overall mortality and disability. The initial mechanism of noise-induced cardiovascular, metabolic and mental disease is well defined by the „noise reaction model“ and consists of neuronal activation involving the hypothalamic-pituitary-adrenal (HPA) axis as well as the sympathetic nervous system, followed by a classical stress response via cortisol and catecholamines. Stress pathways are initiated by noise-induced annoyance and sleep deprivation/fragmentation. This review highlights the down-stream pathophysiology of noise-induced mental stress, which is based on an induction of inflammation and oxidative stress. We highlight the sources of reactive oxygen species (ROS) involved and the known targets for noise-induced oxidative damage. Part of the review emphasizes noise-triggered uncoupling/dysregulation of endothelial and neuronal nitric oxide synthase (eNOS and nNOS) and its central role for vascular dysfunction., Graphical abstract Image 1, Highlights • Exposure to (traffic) noise causes non-auditory (indirect) cardiovascular and cerebral health harms via neuronal activation. • Noise activates the HPA axis and sympathetic nervous system increasing levels of stress hormones, vasoconstrictors and ROS. • Noise induces inflammation and stimulates several ROS sources leading to cerebral and cardiovascular oxidative damage. • Noise leads to eNOS and nNOS uncoupling contributing to cardiometabolic disease and cognitive impairment.

Visual Abstract, Highlights • Pressure overload induced by transverse aortic constriction led to severe heart failure accompanied by renal fibrosis and dysfunction, endothelial dysfunction, and exercise intolerance in mice. • 3-week but not 10-week-delayed H2S therapy preserved left ventricular ejection fraction and attenuated cardiac fibrosis. • H2S therapy attenuated renal fibrosis and dysfunction, preserved endothelium, and enhanced treadmill exercise capacity. • H2S therapy blunted the maladaptive overactivation of the sympathetic nervous system, resulting in reduced renal tissue norepinephrine levels as well as attenuated circulating levels of renin, angiotensin II, and aldosterone., Summary Cardioprotective effects of H2S have been well documented. However, the lack of evidence supporting the benefits afforded by delayed H2S therapy warrants further investigation. Using a murine model of transverse aortic constriction-induced heart failure, this study showed that delayed H2S therapy protects multiple organs including the heart, kidney, and blood-vessel; reduces oxidative stress; attenuates renal sympathetic and renin-angiotensin-aldosterone system pathological activation; and ultimately improves exercise capacity. These findings provide further insights into H2S-mediated cardiovascular protection and implicate the benefits of using H2S-based therapies clinically for the treatment of heart failure.

The novel coronavirus disease 2019 (COVID-19) has pushed the medical system to its breaking point. While the virus does not discriminate, the elderly and those with comorbidities, including hypertension severe obesity, diabetes mellitus, coronary disease, pneumonia and dementia, are at a greater risk for adverse outcomes due to COVID-19. While many people navigate their new normal, the question of what the long-lasting effects of the pandemic may be, lingers. To investigate how vulnerable populations are affected by the pandemic, we focused on Alzheimer's disease, a vector to understanding how the virus has impacted AD progression and risk via aging. By assessing the effect of COVID-19 on AD patients, we explore genetics, metabolism, and lifestyle factors in both COVID-19 and Alzheimer's disease that can work synergistically to precipitate adverse outcomes. This article also discusses how age-related conditions and/or age-related comorbidities susceptible to COVID-19. We also discuss possible healthy lifestyle factors reduce and/or combat COVID-19 now and in the future.

Visual Abstract, Highlights • Although the long-term effects of LCZ696 (sacubitril/valsartan) on cardiac dysfunction have been previously elucidated, the short-term effects on acute phase after acute MI is unknown. • Wild-type mice subjected to ligation of left anterior descending artery were randomly allocated to the vehicle, enalapril, or LCZ696 group 1 day after MI, resulting in the belief that LCZ696 could prevent cardiac rupture compared to the vehicle, whereas there was no significant difference in rate of cardiac rupture-free survival in the enalapril compared to the vehicle. • At 3 days after MI, the expression of interleukin-1β, interleukin-6, matrix MMP-9 mRNA and MMP-9 activity in the infarcted myocardium were significantly lower, plasma aldosterone levels were significantly lower, and cGMP levels were significantly higher, in the LCZ696 than the other groups. • In vitro assay using peritoneal macrophages found that the combination of valsartan plus LBQ657 (active form of sacubitril) reduced the LPS-induced gelatinolytic activity and MMP-9 mRNA expression of macrophages. • LCZ696 could suppress pro-inflammatory cytokines and extracellular matrix degradation in macrophages, and provides protection against post-MI cardiac rupture in mice., Summary LCZ696 (sacubitril/valsartan) can lower the risk of cardiovascular events in chronic heart failure. However, it is unclear whether LCZ696 can improve prognosis in patients with acute myocardial infarction (MI). The present study shows that LCZ696 can prevent cardiac rupture after MI, probably due to the suppression of pro-inflammatory cytokines, matrix metalloproteinase-9 activity and aldosterone production, and enhancement of natriuretic peptides in mice. These findings suggest the mechanistic insight of cardioprotective effects of LCZ696 against acute MI, resulting in the belief that LCZ696 might be useful clinically to improve survival after acute MI.

The novel coronavirus disease 2019 (COVID-19) pandemic has already caused more than 300,000 deaths worldwide. Several studies have elucidated the central role of cardiovascular complications in the disease course. Herein, we provide a concise review of current knowledge regarding the involvement of cardiovascular system in the pathogenesis and prognosis of COVID-19. We summarize data from 21 studies involving in total more than 21,000 patients from Asia, Europe, and the USA indicating that severe disease is associated with the presence of myocardial injury, heart failure, and arrhythmias. Additionally, we present the clinical and laboratory differences between recovered and deceased patients highlighting the importance of cardiac manifestations. For the infected patients, underlying cardiovascular comorbidities and particularly existing cardiovascular disease seem to predispose to the development of cardiovascular complications, which are in turn associated with higher mortality rates. We provide mechanistic insights into the underlying mechanisms including direct myocardial damage by the virus and the consequences of the hyperinflammatory syndrome developed later in the disease course. Finally, we summarize current knowledge on therapeutic modalities and recommendations by scientific societies and experts regarding the cardiovascular management of patients with COVID-19.

BackgroundChronic kidney disease (CKD) is defined by abnormalities in kidney structure and/or function present for more than 3 months. Worldwide, both the incidence and prevalence rates of CKD are increasing. The renin-angiotensin-aldosterone system (RAAS) regulates fluid and electrolyte balance through the kidney. RAAS activation is associated with hypertension, which is directly implicated in causation and progression of CKD. RAAS blockade, using drugs targeting individual RAAS mediators and receptors, has proven to be renoprotective.ObjectivesTo assess genomic variants present within RAAS genes, ACE, ACE2, AGT, AGTR1, AGTR2 and REN, for association with CKD.Design and data sourcesA systematic review and meta-analysis of observational research was performed to evaluate the RAAS gene polymorphisms in CKD using both PubMed and Web of Science databases with publication date between the inception of each database and 31 December 2018. Eligible articles included case–control studies of a defined kidney disease and included genotype counts.Eligibility criteriaAny paper was removed from the analysis if it was not written in English or Spanish, was a non-human study, was a paediatric study, was not a case–control study, did not have a renal disease phenotype, did not include data for the genes, was a gene expression-based study or had a pharmaceutical drug focus.ResultsA total of 3531 studies were identified, 114 of which met the inclusion criteria. Genetic variants reported in at least three independent publications for populations with the same ethnicity were determined and quantitative analyses performed. Three variants returned significant results in populations with different ethnicities at pACE insertion, AGT rs699-T allele and AGTR1 rs5186-A allele; each variant was associated with a reduced risk of CKD development.ConclusionsFurther biological pathway and functional analyses of the RAAS gene polymorphisms will help define how variation in components of the RAAS pathway contributes to CKD.

Angiotensin-converting enzyme-2 (ACE2) is one of the major components of the renin-angiotensin system (RAS) and participates in the physiological functions of the cardiovascular system and lungs. Recent studies identified ACE2 as the receptor for the S-protein of the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and thus acts as the gateway for viral entry into the human body. Virus infection causes an imbalance in the RAS axis and induces acute lungs injury and fibrosis. Various factors regulate ACE2 expression patterns as well as control its epigenetic status at both transcription and translational levels. This review is mainly focused on the impact of environmental toxicants, drugs, endocrine disruptors, and hypoxia as controlling parameters for ACE2 expression and its possible modulation by epigenetic changes which are marked by DNA methylation, histone modifications, and micro-RNAs (miRNAs) profile. Furthermore, we have emphasized on interventions of various phytochemicals and bioactive compounds as epidrugs that regulate ACE2-S-protein interaction and thereby curb viral infection. Since ACE2 is an important component of the RAAS axis and a crucial entry point of SARS-CoV-2, the dynamics of ACE2 expression in response to various extrinsic and intrinsic factors are of contemporary relevance. We have collated updated information on ACE2 expression modulated by epidrugs, and urge to take over further studies on these important physiological regulators to unravel many more systemic linkages related to both metabolic and infectious diseases, in general and SARS-CoV-2 in particular for further development of targeted interventions.

Author(s): Ajmera, Veeral; Thompson, Wesley K; Smith, Davey M; Malhotra, Atul; Mehta, Ravindra L; Tolia, Vaishal; Yin, Jeffrey; Sriram, Krishna; Insel, Paul A; Collier, Summer; Richards, Lisa; Loomba, Rohit | Abstract: Background and aimsRetrospective studies have shown that angiotensin-converting-enzyme (ACE) inhibitors are associated with a reduced risk of complications and mortality in persons with novel coronavirus disease 2019 (COVID-19). Thus, we aimed to examine the efficacy of ramipril, an ACE-inhibitor, in preventing ICU admission, mechanical ventilation and/or mortality while also minimizing the risk of transmission and use of personal protective equipment (PPE).MethodsRAMIC is a multicenter, randomized, double-blind, allocation-concealed, placebo-controlled trial comparing the efficacy of treatment with ramipril 2.5nmg orally daily compared to placebo for 14ndays. The study population includes adult patients with COVID-19 who were admitted to a hospital or assessed in an emergency department or ambulatory clinic. Key exclusion criteria include ICU admission or need for mechanical ventilation at screening, use of an ACE inhibitor or angiotensin-receptor-II blocker within 7ndays, glomerular filtration ratenln40nmL/min or a systolic blood pressure (BP)nln100nmmHg or diastolic BPnln65nmmHg. Patients are randomized 2:1 to receive ramipril (2.5nmg) or placebo daily. Informed consent and study visits occur virtually to minimize the risk of SARS-CoV-2 transmission and preserve PPE. The primary composite endpoint of ICU admission, invasive mechanical ventilation and death are adjudicated virtually.ConclusionsRAMIC is designed to assess the efficacy of treatment with ramipril for 14ndays to decrease ICU admission, mechanical ventilator use and mortality in patients with COVID-19 and leverages virtual study visits and endpoint adjudication to mitigate risk of infection and to preserve PPE (ClinicalTrials.gov, NCT04366050).

A low-sodium (LS) diet has been shown to reduce blood pressure (BP) and the incidence of cardiovascular diseases. However, severe dietary sodium restriction promotes insulin resistance (IR) and dyslipidemia in animal models and humans. Thus, further clarification of the long-term consequences of LS is needed. Here, we investigated the effects of chronic LS on gastrocnemius gene and protein expression and lipidomics and its association with IR and plasma lipids in LDL receptor knockout mice. Three-month-old male mice were fed a normal sodium diet (NS; 0.5% Na; n = 12–19) or LS (0.06% Na; n = 14–20) over 90 days. Body mass (BM), BP, plasma total cholesterol, triacylglycerol (TG), glucose, hematocrit, and IR were evaluated. LS increased BM (9%), plasma TG (51%), blood glucose (19%), and IR (46%) when compared with the NS. RT-qPCR analysis revealed that genes involved in lipid uptake and oxidation were increased by the LS: Fabp3 (106%), Prkaa1 (46%), and Cpt1 (74%). Genes and proteins (assessed by Western blotting) involved in insulin signaling were not changed by the LS. Similarly, lipid species classically involved in muscle IR, such as diacylglycerols and ceramides detected by ultra-high-performance liquid chromatography coupled to mass spectrometry, were also unchanged by LS. Species of phosphatidylcholines (68%), phosphatidylinositol (90%), and free fatty acids (59%) increased while cardiolipins (41%) and acylcarnitines (9%) decreased in gastrocnemius in response to LS and were associated with glucose disposal rate. Together these results suggest that chronic LS alters glycerophospholipid and fatty acids species in gastrocnemius that may contribute to glucose and lipid homeostasis derangements in mice.