Significance Statement: SGLT2 inhibitors represent a class of drugs that were originally developed for improving glycemic control. Cardiovascular outcome trials designed to evaluate cardiovascular safety yielded unexpected and unprecedented evidence of the cardiorenal benefits of SGLT2 inhibitors. Many hypotheses have been proposed to explain the mechanisms underlying these effects. Our study demonstrates that SGLT2 inhibition is associated with the restoration of euvolemia in nondiabetic heart failure (HF) rats by preserving GFR and renal mass and inhibiting proximal tubule NHE3-mediated sodium reabsorption. The attenuation of kidney dysfunction may constitute an essential mechanism by which SGLT2 inhibitors attenuate HF development and progression in either the presence or absence of diabetes. Background: SGLT2 inhibitors reduce the risk of heart failure (HF) mortality and morbidity, regardless of the presence or absence of diabetes, but the mechanisms underlying this benefit remain unclear. Experiments with nondiabetic HF rats tested the hypothesis that the SGLT2 inhibitor empagliflozin (EMPA) inhibits proximal tubule (PT) NHE3 activity and improves renal salt and water handling. Methods: Male Wistar rats were subjected to myocardial infarction or sham operation. After 4 weeks, rats that developed HF and sham rats were treated with EMPA or untreated for an additional 4 weeks. Immunoblotting and quantitative RT-PCR evaluated SGLT2 and NHE3 expression. Stationary in vivo microperfusion measured PT NHE3 activity. Results: EMPA-treated HF rats displayed lower serum B-type natriuretic peptide levels and lower right ventricle and lung weight to tibia length than untreated HF rats. Upon saline challenge, the diuretic and natriuretic responses of EMPA-treated HF rats were similar to those of sham rats and were higher than those of untreated HF rats. Additionally, EMPA treatment prevented GFR decline and renal atrophy in HF rats. PT NHE3 activity was higher in HF rats than in sham rats, whereas treatment with EMPA markedly reduced NHE3 activity. Unexpectedly, SGLT2 protein and mRNA abundance were upregulated in the PT of HF rats. Conclusions: Prevention of HF progression by EMPA is associated with reduced PT NHE3 activity, restoration of euvolemia, and preservation of renal mass. Moreover, dysregulation of PT SGLT2 may be involved in the pathophysiology of nondiabetic HF.

Summary. Objectives: Although effective strategies for the prevention of venous thromboembolism (VTE) are widely available, a significant number of patients still develop VTE because appropriate thromboprophylaxis is not correctly prescribed. We conducted this study to estimate the risk profile for VTE and the employment of adequate thromboprophylaxis procedures in patients admitted to hospitals in the state of São Paulo, Brazil. Methods: Four hospitals were included in this study. Data on risk factors for VTE and prescription of pharmacological and non‐pharmacological thromboprophylaxis were collected from 1454 randomly chosen patients (589 surgical and 865 clinical). Case report forms were filled according to medical and nursing records. Physicians were unaware of the survey. Three risk assessment models were used: American College of Chest Physicians (ACCP) Guidelines, Caprini score, and the International Union of Angiololy Consensus Statement (IUAS). The ACCP score classifies VTE risk in surgical patients and the others classify VTE risk in surgical and clinical patients. Contingency tables were built presenting the joined distribution of the risk score and the prescription of any pharmacological and non‐pharmacological thromboprophylaxis (yes or no). Results: According to the Caprini score, 29% of the patients with the highest risk for VTE were not prescribed any thromboprophylaxis. Considering the patients under moderate, high or highest risk who should be receiving prophylaxis, 37% and 29% were not prescribed thromboprophylaxis according to ACCP (surgical patients) and IUAS risk scores, respectively. In contrast, 27% and 42% of the patients at low risk of VTE, according to Caprini and IUAS scores, respectively, had thromboprophylaxis prescribed. Conclusion: Despite the existence of several guidelines, this study demonstrates that adequate thromboprophylaxis is not correctly prescribed: high‐risk patients are under‐treated and low‐risk patients are over‐treated. This condition must be changed to insure that patients receive adequate treatment for the prevention of thromboembolism.

Background: Published randomized controlled trials are underpowered for binary clinical end points to assess the safety and efficacy of renin‐angiotensin system inhibitors (RASi) in adults with COVID‐19. We therefore performed a meta‐analysis to assess the safety and efficacy of RASi in adults with COVID‐19. Methods and Results: MEDLINE, EMBASE, ClinicalTrials.gov , and the Cochrane Controlled Trial Register were searched for randomized controlled trials that randomly assigned patients with COVID‐19 to RASi continuation/commencement versus no RASi therapy. The primary outcome was all‐cause mortality at ≤30 days. A total of 14 randomized controlled trials met the inclusion criteria and enrolled 1838 participants (aged 59 years, 58% men, mean follow‐up 26 days). Of the trials, 11 contributed data. We found no effect of RASi versus control on all‐cause mortality (7.2% versus 7.5%; relative risk [RR], 0.95; [95% CI, 0.69–1.30]) either overall or in subgroups defined by COVID‐19 severity or trial type. Network meta‐analysis identified no difference between angiotensin‐converting enzyme inhibitors versus angiotensin II receptor blockers. RASi users had a nonsignificant reduction in acute myocardial infarction (2.1% versus 3.6%; RR, 0.59; [95% CI, 0.33–1.06]), but increased risk of acute kidney injury (7.0% versus 3.6%; RR, 1.82; [95% CI, 1.05–3.16]), in trials that initiated and continued RASi. There was no increase in need for dialysis or differences in congestive cardiac failure, cerebrovascular events, venous thromboembolism, hospitalization, intensive care admission, inotropes, or mechanical ventilation. Conclusions: This meta‐analysis of randomized controlled trials evaluating angiotensin‐converting enzyme inhibitors/angiotensin II receptor blockers versus control in patients with COVID‐19 found no difference in all‐cause mortality, a borderline decrease in myocardial infarction, and an increased risk of acute kidney injury with RASi. Our findings provide strong evidence that RASi can be used safely in patients with COVID‐19.

Objectives To compare carotid intima-media thickness (cIMT) of children and adolescents with and without HIV infection and to determine associations among independent socio-demographic, clinical or cardiovascular variables and cIMT in HIV-infected children and adolescents. Patients and methods This is a matched case–control study comparing 83 HIV-infected and 83 healthy children and adolescents. Clinical and laboratorial parameters, cIMT and echocardiogram were measured. Results The cIMT was higher in HIV-infected individuals (median 480 μm; interquartile range 463–518 μm) compared with controls (426 μm; range 415–453 μm, P<0.001). In addition, the HIV-infected group showed higher levels of high-sensitive C-reactive protein (medians 1.0 mg/l vs. 0.4 mg/l, P<0.001), glycated hemoglobin (6.1±0.9 vs. 5.7±0.8%, P=0.028) and triglycerides (medians 0.9 vs. 0.8 mmol/l, P=0.031). Finally, this group showed lower levels of total and high-density lipoprotein-cholesterol. After multivariate analysis, increased cIMT was positively associated with stavudine use [odds ratio (OR): 18.9, P=0.005], left atrial/aorta index (OR: 15.6, P=0.019), suprailiac skinfold (OR: 7.9, P=0.019), tachypnea (OR: 5.9, P=0.031), CD8 lymphocyte count (OR: 5.7, P=0.033) and CD4 T-lymphocyte count (OR: 5.5, P=0.025). cIMT increment was negatively associated with total cholesterol (OR: 0.2, P=0.025) and with CD8 zenith (OR: 0.1, P=0.007). Conclusion In this sample of children and adolescents, having HIV infection was associated with increased cIMT and elevated prevalence of cardiovascular risk factors. These findings suggest that this group should be included in cardiovascular prevention programs.