The Association Between Beta-blocker and Renin-Angiotensin System Inhibitor Use After Heart Failure With Reduced Ejection Fraction Hospitalization and Outcomes in Older Patients.

INTRODUCTION: Beta-blockers (BB) and renin-angiotensin system inhibitors (RASi) are foundational for the treatment of heart failure with reduced ejection fraction (HFrEF). However, given the increased risk of side effects in older patients, uncertainty remains as to whether, on net, older patients benefit as much as the younger patients studied in trials. METHODS AND RESULTS: Using the Get With The Guidelines-Heart Failure registry linked with Medicare data, overlap propensity weighted Cox proportional hazard models were used to examine the association between BB and RASi use at hospital discharge and 30-day and 1-year outcomes among patients with HFrEF. Among the 48,711 patients (aged ≥65 years) hospitalized with HFrEF, there were significant associations between BB and/or RASi use at discharge and lower rates of 30-day and 1-year mortality, including those over age 85 (30-day hazard ratio 0.56, 95% confidence interval 0.45-0.70; 1-year hazard ratio 0.69, 95% confidence interval 0.61-0.78). In addition, the magnitude of benefit associated with BB and/or RASi use after discharge did not decrease with advancing age. Even among the oldest patients, those over age 85, with hypotension, renal insufficiency or frailty, BB and/or RASi use at discharge was still associated with lower 1-year mortality or readmission. CONCLUSIONS: Among older patients hospitalized with HFrEF, BB and/or RASi use at discharge is associated with lower rates of 30-day and 1-year mortality across all age groups and the magnitude of this benefit does not seem to decrease with advancing age. These data suggest that, absent a clinical contraindication, BB and RASi should be considered in all patients hospitalized with HFrEF before or at hospital discharge, regardless of age.

Stopping renin-angiotensin system inhibitors after hyperkalemia and risk of adverse outcomes.

BACKGROUND: Stopping renin-angiotensin system inhibitors (RASi) after an episode of hyperkalemia is common but may involve therapeutic compromises, in that the cessation of RASi deprives patients of their beneficial cardiovascular effects. METHODS AND RESULTS: Observational study from the Stockholm Creatinine Measurements (SCREAM) project including patients initiating RASi in routine care and surviving a first-detected episode of hyperkalemia (potassium >5.0 mmol/L). We used target trial emulation techniques based on cloning, censoring and weighting to compare stopping vs. continuing RASi within 6 months after hyperkalemia. Outcomes were 3-year risks of mortality, major adverse cardiovascular events (MACE, composite of cardiovascular death, myocardial infarction and stroke hospitalization) and recurrent hyperkalemia. Of 5669 new users of RASi who developed hyperkalemia (median age 72 years, 44% women), 1425 (25%) stopped RASi therapy within 6 months. Compared with continuing RASi, stopping therapy was associated with a higher 3-year risk of death (absolute risk difference 10.8%; HR 1.49, 95% CI 1.34-1.64) and MACE (risk difference 4.7%; HR 1.29, 1.14-1.45), but a lower risk of recurrent hyperkalemia (risk difference -9.5%; HR 0.76, 0.69-0.84). Results were consistent for events following potassium of >5.0 or >5.5 mmol/L, after censoring when the treatment decision was changed, across prespecified subgroups, and after adjusting for albuminuria. CONCLUSION: These findings suggest that stopping RASi after hyperkalemia may be associated with a lower risk of recurrence of hyperkalemia, but higher risk of death and cardiovascular events.

A Shared Nephroprotective Mechanism for Renin-Angiotensin-System Inhibitors, Sodium-Glucose Co-Transporter 2 Inhibitors, and Vasopressin Receptor Antagonists: Immunology Meets Hemodynamics.

A major paradigm in nephrology states that the loss of filtration function over a long time is driven by a persistent hyperfiltration state of surviving nephrons. This hyperfiltration may derive from circulating immunological factors. However, some clue about the hemodynamic effects of these factors derives from the effects of so-called nephroprotective drugs. Thirty years after the introduction of Renin-Angiotensin-system inhibitors (RASi) into clinical practice, two new families of nephroprotective drugs have been identified: the sodium-glucose cotransporter 2 inhibitors (SGLT2i) and the vasopressin receptor antagonists (VRA). Even though the molecular targets of the three-drug classes are very different, they share the reduction in the glomerular filtration rate (GFR) at the beginning of the therapy, which is usually considered an adverse effect. Therefore, we hypothesize that acute GFR decline is a prerequisite to obtaining nephroprotection with all these drugs. In this study, we reanalyze evidence that RASi, SGLT2i, and VRA reduce the eGFR at the onset of therapy. Afterward, we evaluate whether the extent of eGFR reduction correlates with their long-term efficacy. The results suggest that the extent of initial eGFR decline predicts the nephroprotective efficacy in the long run. Therefore, we propose that RASi, SGLT2i, and VRA delay kidney disease progression by controlling maladaptive glomerular hyperfiltration resulting from circulating immunological factors. Further studies are needed to verify their combined effects.

The effects of dapagliflozin on cardio-renal risk factors in patients with type 2 diabetes with or without renin-angiotensin system inhibitor treatment: a post hoc analysis.

AIMS: Renin-angiotensin system inhibitors (RASi) are the most effective treatments for diabetic kidney disease but significant residual renal risk remains, possibly because of other mechanisms of kidney disease progression unrelated to RAS that may be present. Sodium-glucose co-transporter-2 inhibitors reduce albuminuria and may complement RASi by offering additional renal protection. This post hoc analysis investigated the effects of dapagliflozin on cardio-renal risk factors in patients with type 2 diabetes (T2D) with increased albuminuria treated with or without RASi at baseline. MATERIALS AND METHODS: We evaluated the effects of dapagliflozin 10 mg/day over 12-24 weeks across 13 placebo-controlled studies in patients with T2D with a urinary albumin-to-creatinine ratio (UACR) ≥30 mg/g at baseline. Patients were divided into two subgroups based on treatment with or without RASi at baseline. RESULTS: Compared with patients with RASi at baseline (n = 957), patients without RASi (n = 302) were younger, had a shorter duration of diabetes (7 vs. 12 years), higher estimated glomerular filtration rate (eGFR) and lower UACR, serum uric acid (sUA), body weight and systolic blood pressure. Placebo-adjusted treatment effects of dapagliflozin on UACR, eGFR, glycated haemoglobin and haematocrit over 24 weeks were similar across groups. Mean reductions in body weight and sUA were more distinct in patients without RASi treatment at baseline. CONCLUSIONS: Treatment with dapagliflozin over 24 weeks provides similar clinically relevant improvements in metabolic and haemodynamic parameters, and similar reductions in UACR, in patients with T2D with elevated albuminuria treated with or without RASi at baseline.

Walking in an unstable environment: strategies used by transtibial amputees to prevent falling during gait.

OBJECTIVE: To investigate which strategies transtibial amputees use to cope with challenges of gait stability and gait adaptability, and how these strategies differ from strategies used by able-bodied controls. DESIGN: Cross-sectional study. SETTING: An instrumented treadmill mounted onto a 6°-of-freedom motion platform in combination with a virtual environment. PARTICIPANTS: Transtibial amputees (n=10) and able-bodied controls (n=9). INTERVENTIONS: Mediolateral (ML) translations of the walking surface were imposed to manipulate gait stability. To provoke an adaptive gait pattern, a gait adaptability task was used in which subjects had to hit virtual targets with markers guided by their knees. MAIN OUTCOME MEASURES: Walking speed, step length, step frequency, step width, and selected measures of gait stability (short-term Lyapunov exponents and backward and ML margins of stability [MoS]). RESULTS: Amputees walked slower than able-bodied people, with a lower step frequency and wider steps. This resulted in a larger ML MoS but a smaller backward MoS for amputees. In response to the balance perturbation, both groups decreased step length and increased step frequency and step width. Walking speed did not change significantly in response to the perturbation. These adaptations induced an increase in ML and backward MoS. To perform the gait adaptability task, both groups decreased step length and increased step width, but did not change step frequency and walking speed. ML and backward MoS were maintained in both groups. CONCLUSIONS: Transtibial amputees have the capacity to use the same strategies to deal with challenges of gait stability and adaptability, to the same extent as able-bodied people.

RAS inhibitors and renal and general mortality in patients with heart failure supported by left ventricular assist devices: a registry study.

BACKGROUND: The aim of our study was to analyze the association between renin-angiotensin system inhibitor (RASi) therapy and renal outcomes and mortality in patients with heart failure (HF) supported by left ventricular assist device (LVAD) using a large, nationwide prospective cohort. To date, no studies have comprehensively analyzed the association between RASi and renal outcomes and mortality in patients with HF supported by LVAD. METHODS: We performed a retrospective observational study on LVAD patients in the Interagency Registry for Mechanically Assisted Circulatory Support. The main outcome was a composite of renal event and all-cause mortality. Secondary outcomes were the individual components of the composite outcome. A renal event was defined as a composite of doubling serum creatinine, eGFR decrease ≥ 40%, or need for dialysis. The exposure of interest was RASi therapy, updated during follow-up. Cox regression models adjusted for potential confounders were used to estimate the association between time-updated RASi therapy and the outcomes of interest. RESULTS: The analysis included 6448 patients. During a median follow-up of 12.7 months (IQR 19.8 months), 1632 patients developed the composite outcome. RASi therapy was associated with a lower risk of developing the composite outcome (HR 0.61, 95% CI 0.55, 0.68, P < 0.001). A significant association was confirmed between RASi therapy and renal outcomes (HR 0.74, 95% CI 0.61, 0.89, P = 0.002) and all-cause mortality (HR 0.56, 95% CI 0.50, 0.63, P < 0.001). CONCLUSIONS: Our data suggest a beneficial role of RASi therapy on renal function and all-cause mortality in patients with HF supported by LVAD.

Candidate composite biomarker to inform drug treatments for diabetic kidney disease.

Introduction: Current guidelines recommend renin angiotensin system inhibitors (RASi) as key components of treatment of diabetic kidney disease (DKD). Additional options include sodium-glucose cotransporter-2 inhibitors (SGLT2i), glucagon-like peptide 1 receptor agonists (GLP1a), and mineralocorticoid receptor antagonists (MCRa). The identification of the optimum drug combination for an individual is difficult because of the inter-, and longitudinal intra-individual heterogeneity of response to therapy. Results: Using data from a large observational study (PROVALID), we identified a set of parameters that can be combined into a meaningful composite biomarker that appears to be able to identify which of the various treatment options is clinically beneficial for an individual. It uses machine-earning techniques to estimate under what conditions a treatment of RASi plus an additional treatment is different from the treatment with RASi alone. The measure of difference is the annual percent change (ΔeGFR) in the estimated glomerular filtration rate (ΔeGFR). The 1eGFR is estimated for both the RASi-alone treatment and the add-on treatment. Discussion: Higher estimated increase of eGFR for add-on patients compared with RASi-alone patients indicates that prognosis may be improved with the add-on treatment. The personalized biomarker value thus identifies which patients may benefit from the additional treatment.

Discriminative Ability of Left Ventricular Strain in Mildly Reduced Ejection Fraction Heart Failure.

Background: Left ventricular (LV) systolic strain is presumably a more sensitive myocardial indicator than LV ejection fraction (LVEF). Data regarding the use of LV strain in clinical risk stratification and in identifying angiotensin receptor-neprilysin inhibitor (ARNi) responders remain scarce in heart failure with mildly reduced ejection fraction (HFmrEF). Objectives: The authors aimed to examine whether assessing LV strain may provide prognostic insight beyond LVEF and help discriminate the therapeutic efficacy of ARNi in HFmrEF patients. Methods: LVEF and LV strain were quantified among 1,075 first-time hospitalized HFmrEF patients (mean age: 68.1 ± 15.1 years, 40% female). The MAGGIC (Meta-analysis Global Group in Chronic Heart Failure) risk score and its components were calculated. A Cox proportional hazard model was constructed for time-to-event analysis. Restrictive cubic spline curves were used to model the therapeutic effects of ARNi against renin-angiotensin system inhibitor according to baseline LVEF or LV strain. Results: LV strain showed a statistically significant inverse association with MAGGIC cardiac risk (coefficient: -0.14, P < 0.001). LV strain was independently associated with clinical outcomes after accounting for LVEF. MAGGIC-LV strain strata outperformed MAGGIC-LVEF strata in overall survival (Harrell's C-index: 0.71 and 0.56, P for difference <0.001; category-free net reclassification index: 0.44, P < 0.001). Lower LV strain but not LVEF consistently showed the beneficial therapeutic effects of ARNi against renin-angiotensin system inhibitor by Cox models and restrictive cubic spline (all P interaction <0.05). Conclusions: Among HFmrEF patients, LV strain may serve as an attractive systolic marker and provide a better prognostic and therapeutic discriminative measure for ARNi treatment than conventional LVEF.

Comparison of the Relationship Between SI and RASI Scores With the Outcome of Sepsis Patients.

The aim of this study was to compare the relationship between shock index (SI) and respiratory adjusted shock index (RASI) scores with the final outcome of sepsis patients referred to the emergency department. This was prospective research that examined individuals who had been diagnosed with sepsis, determined by the presence of at least two of the three quick sepsis-related organ failure assessment (qSOFA) criteria and the presence of an infectious disease based on a diagnosis made by a hospital physician of Imam Reza and Ghaemshahr of Mashhad in 2019. Demographic information of patients, SI score, RASI score, and information related to the patient's clinical symptoms were recorded in the checklist. The final outcome of this study was considered mortality. Data analysis was performed using descriptive and inferential tests. In the present study, a total of 178 patients, 46 patients (25.8%) were transferred to the intensive care unit, and 98 patients (55.1%) were admitted to the normal wards. Eighty-five patients (47.75%) died and the mean length of hospital stay of all patients was 11.07 ± 9.23 days. Forty-four patients (24.7%) had referred with a decreased level of consciousness and 44 patients (24.7%) presented with confusion. The rest of the patients reported normal levels of consciousness. Kaplan Mir analysis with log-rank was performed to determine the difference in survival distribution in different SI groups: Survival distribution was not statistically different for the four defined groups (based on statistical quartiles (P = 0.320). Receiver operator curves were considered as the date of death in the case of the deceased and the date of discharge from the hospital in the case of the living as censored. The AUC of the RASI scoring system for predicting mortality was 0.614 (P = 0.009) while this value was not significant for SI (P = 0.152). In logistic regression analysis, it was found that by adjusting for the variables of age, sex, sepsis etiology, blood pressure and heart rate, level of consciousness, and gender, patients with the lower respiratory rate (OR 1.6, z = -0.159 p = 0.007), younger age (OR 1.6, z = -0.029 p = 0.006) and higher RASI score are more in risk of mortality (OR 1.29, z = 1.209, p = 0.031). The results of our study showed that RASI scoring can be a good criterion for predicting the chance of mortality in patients with sepsis and could be used complementary to previous criteria such as SI. Patients with high RASI scores should be given more attention to reducing the chance of death.

Time-varying risk associations of renin angiotensin system inhibitors with pneumonia and related deaths in a cohort of 252,616 patients with diabetes (2002-2019).

AIMS: To evaluate the time-varying and cumulative risk associations of renin-angiotensin-system-inhibitors (RASi) with pneumonia and related deaths in people with diabetes. METHODS: This was a prospective analysis with propensity-score overlap-weighting of a territory-wide cohort (n = 252,616, 1.7 million person-years) and a register-based cohort (n = 13,017, 0.1 million person-years) of patients with diabetes in Hong Kong. We compared risk of pneumonia and related death in new-users of angiotensin-converting-enzyme-inhibitor (ACEi) and angiotensin-receptor-blocker (ARBs) with non-RASi users and new-users of calcium-channel-blockers as active comparator. RESULTS: Amongst 252,616 people with diabetes (99.3% type 2 diabetes) in the population-based cohort with a mean follow-up of 6.7 years, 73,161 were new-ACEi-only users; 20,907 new-ARBs-only users; 38,778 ACEi/ARBs users; and 119,770 never-ACEi/ARBs. Time-varying RASi exposure was associated with reduced risk of pneumonia (HR = 0.78, 95% CI: 0.75-0.82) and pneumonia-related death (HR = 0.49, 0.46-0.53). The respective HRs for ARBs-only were 0.70 (0.62-0.78) and 0.41 (0.33-0.52) and that of ACEi-only were 0.98 (0.91-1.05) and 0.77 (0.68-86). The attenuated risk association of RASi use was time-invariant for pneumonia (P = 0.340) and time-varying for related-death (P < 0.001) with prevention of 0.6 (0.2-0.9) and 1.4 (1.0-1.6) per-1000-person-years events and deaths, respectively. CONCLUSIONS: Long-term use of RASi, notably ARBs, was associated with reduced risk of pneumonia and related deaths in Chinese people with diabetes.

Intravenous landiolol for the prevention of atrial fibrillation after aortic root, ascending aorta, and aortic arch surgery: A propensity score-matched analysis.

Objective: Postoperative atrial fibrillation (POAF) after cardiac surgery is associated with increased mortality. The efficacy of landiolol hydrochloride for POAF prevention after coronary artery bypass grafting procedure and valve surgery has been reported. However, little evidence is available on its role in POAF prevention after aortic root, ascending aorta, and aortic arch surgery. This study aimed to determine the association between intravenous landiolol and the incidence of POAF after these aortic surgeries. Methods: We included 358 consecutive adult patients without preoperative atrial fibrillation who underwent aortic root, ascending aorta, and aortic arch surgery between January 1, 2011, and December 31, 2018, at our institution. The therapeutic influence of landiolol in preventing POAF was estimated by propensity score-matched analysis (n = 222). The primary end point was the incidence of POAF within 72 hours after surgery. The secondary end points included adverse clinical events such as 30-day mortality and symptomatic cerebral infarction. Results: The median age of the cohort was 72 years, 68.5% were men, and 46.4% received postoperative oral or transdermal ß-blockers. After minimizing differences in patient background by propensity score matching, the incidence of POAF in the landiolol group was significantly lower than that in the reference group (18.9% vs 38.7%; P = .002). Landiolol use was associated with reduced incidence of POAF (odds ratio, 0.39; 95% CI, 0.21 to -0.72; P = .003). There were no significant differences in secondary end points. Conclusions: Intravenous landiolol was associated with a lower incidence of POAF after aortic root, ascending aorta, and aortic arch surgery.

Risk factors for impaired pulmonary diffusion function in convalescent COVID-19 patients: A systematic review and meta-analysis.

Background: The long-term prognosis of COVID-19 survivors remains poorly understood. It is evidenced that the lung is the main damaged organ in COVID-19 survivors, most notably in impairment of pulmonary diffusion function. Hence, we conducted a meta-analysis of the potential risk factors for impaired diffusing capacity for carbon monoxide (DLCO) in convalescent COVID-19 patients. Methods: We performed a systematic search of PubMed, Web of Science, Embase, and Ovid databases for relevant studies from inception until January 7, 2022, limited to papers involving human subjects. Studies were reviewed for methodological quality. Fix-effects and random-effects models were used to pool results. Heterogeneity was assessed using I2. The publication bias was assessed using the Egger's test. PROSPERO registration: CRD42021265377. Findings: A total of eighteen qualified articles were identified and included in the systematic review, and twelve studies were included in the meta-analysis. Our results showed that female (OR: 4.011; 95% CI: 2.928-5.495), altered chest computerized tomography (CT) (OR: 3.002; 95% CI: 1.319-6.835), age (OR: 1.018; 95% CI: 1.007-1.030), higher D-dimer levels (OR: 1.012; 95% CI: 1.001-1.023) and urea nitrogen (OR: 1.004;95% CI: 1.002-1.007) were identified as risk factors for impaired DLCO. Interpretation: Pulmonary diffusion capacity was the most common impaired lung function in recovered patients with COVID-19. Several risk factors, such as female, altered chest CT, older age, higher D-dimer levels and urea nitrogen are associated with impairment of DLCO. Raising awareness and implementing interventions for possible modifiable risk factors may be valuable for pulmonary rehabilitation. Funding: This work was financially supported by Emergency Key Program of Guangzhou Laboratory (EKPG21-29, EKPG21-31), Incubation Program of National Science Foundation for Distinguished Young Scholars by Guangzhou Medical University (GMU2020-207).

The role of the renin-angiotensin system inhibitors in malignancy: a review.

Hypertension is one of the most prevalent diseases in cardiology. The angiotensin receptor blockers (ARBs)/angiotensin converting enzyme inhibitors (ACEIs) are widely used drugs to stabilize the blood pressure via inhibition of the renin-angiotensin system (RAS). Studies have found that the exposure to RAS inhibitors (RASi) can suppress the development of cancers via multimodal mechanisms and has attracted increased attentions in the recent past. Owing the potential of RASi to inhibit tumor growth, proliferation and metastasis, they are considered as the potential and exciting candidates to enhance the effect of chemo-radiotherapy and targeted therapy efficacy. However, there are conflicting reports as to the use of ARB/ACEI in all facets of tumor growth. In this study, we comprehensively summarize and review the potential mechanisms of RASi in cancer treatment, like inhibition of tumor angiogenesis, reduction of cancer-associated fibroblasts (CAFs) and extracellular matrix (ECM), regulation of immune cells and improvement of hypoxia. Additionally, based on the basic and clinical experiments, we analyze the views and results regarding the role of RASi plays in tumor from genesis to recurrence, and certainly cancer treatment (chemo-radiotherapy and targeted therapy). In the last, not only do we discuss the prospects of using RASi to enhance cancer treatment efficacy but also point out the conflicting situation with the intention to give some directions and inspiration on this topic.

Impact of renin-angiotensin system blocker after aortic valve replacement-a systematic review and meta-analysis.

BACKGROUND: Data reporting the impact of renin-angiotensin system inhibitor (RASi) after aortic valve replacement (AVR) is controversy. METHODS: The PubMed database was systematically searched for studies reporting the mortality and hazard ratios (HRs) of RASi following surgical and transcatheter AVR (SAVR, TAVR). Random-effects model was used when the I2 statistic was more than 50% and its P value was less than 0.05, otherwise, the fixed-effects model was conducted. RESULTS: Nine articles incorporating 33,063 patients were eligible. Patients having the description of RASi were associated with lower all-cause mortality at 30 days (OR, 0.80, 95% CI, 0.69 to 0.94), 1 year (OR, 0.75, 95% CI, 0.69 to 0.81) and beyond 1 year (OR, 0.52, 95% CI, 0.38 to 0.73) after AVR. Consistently, patients with RASi had lower risk for all-cause mortality (HR, 0.87, 95% CI, 0.84 to 0.91) beyond 1 year following AVR albeit adjusting confounders. Interestingly, beneficial effect of RASi was still observed in patients with preserved ejection fraction following TAVR (HR, 0.90, 95% CI, 0.87 to 0.94). In addition, patients taking RASi had lower cardiovascular mortality than those patients without RASi after TAVR (30 days, OR, 0.63, 95% CI, 0.44 to 0.90; 1 year, OR, 0.60, 95% CI, 0.50 to 0.73; beyond 1 year, OR, 0.63, 95% CI, 0.54 to 0.74). CONCLUSIONS: Patients with RASi exhibited better short- and long-term survival following AVR compared to those patients without RASi, which warranted further studies to support such findings.

Clinical efficacies, underlying mechanisms and molecular targets of Chinese medicines for diabetic nephropathy treatment and management.

Diabetic nephropathy (DN) has been recognized as a severe complication of diabetes mellitus and a dominant pathogeny of end-stage kidney disease, which causes serious health problems and great financial burden to human society worldwide. Conventional strategies, such as renin-angiotensin-aldosterone system blockade, blood glucose level control, and bodyweight reduction, may not achieve satisfactory outcomes in many clinical practices for DN management. Notably, due to the multi-target function, Chinese medicine possesses promising clinical benefits as primary or alternative therapies for DN treatment. Increasing studies have emphasized identifying bioactive compounds and molecular mechanisms of reno-protective effects of Chinese medicines. Signaling pathways involved in glucose/lipid metabolism regulation, antioxidation, anti-inflammation, anti-fibrosis, and podocyte protection have been identified as crucial mechanisms of action. Herein, we summarize the clinical efficacies of Chinese medicines and their bioactive components in treating and managing DN after reviewing the results demonstrated in clinical trials, systematic reviews, and meta-analyses, with a thorough discussion on the relative underlying mechanisms and molecular targets reported in animal and cellular experiments. We aim to provide comprehensive insights into the protective effects of Chinese medicines against DN.

Management of heart failure with reduced ejection fraction in Europe: design of the ARIADNE registry.

AIMS: The introduction of sacubitril/valsartan (an angiotensin receptor-neprilysin inhibitor) is likely to change the approach to the management of patients with chronic heart failure with reduced ejection fraction (HFrEF). The Assessment of Real Life Care-Describing European Heart Failure Management (ARIADNE) registry will evaluate patient characteristics, practice patterns, outcomes, and healthcare resource utilization in the outpatient setting across Europe, with the main focus on factors that guide physicians' decisions to start and continue sacubitril/valsartan in patients with HFrEF. METHODS AND RESULTS: ARIADNE, a prospective, observational registry will enrol 9000 ambulatory patients with HFrEF in 23 European countries Supplement 1. The study will describe 4500 patients treated with conventional treatment (including an angiotensin-converting enzyme inhibitor/angiotensin receptor blocker), and 4500 patients started on sacubitril/valsartan. In each country, patients will be enrolled consecutively over an expected period of 12 months, and followed-up for 12 months. The primary objective is to describe the baseline clinical and demographic characteristics of patients with chronic HFrEF, which guide the decision of the treating physician to initiate sacubitril/valsartan or to continue conventional treatment. A co-primary objective is to identify the baseline characteristics that are associated with the likelihood of reaching the target dose of sacubitril/valsartan 97/103 mg twice daily during follow-up. CONCLUSIONS: The ARIADNE registry will provide a comprehensive profile of patients with chronic HFrEF in Europe, will elucidate how management varies between countries, and will help clarify the usage and outcomes associated with use of sacubitril/valsartan in real life.

[Effects of combined administration of Radix Angelicae Sinensis and hydrocortisone on the therapeutic action in the murine asthma model].

OBJECTIVE: To investigate the effects of Radix Angelicae Sinensis (RASI) and hydrocortisone combination on the murine asthma model and the mechanism. METHODS: BALB/c mice were randomly divided into control group, blood stasis model group, asthma model group, HSS group, RASI group and RASI+HSS group (n=12). Ovalbumin (OVA) was used to replicate mice asthma model and hydrocortisone sodium succinate (HSS) to copy blood stasis model. Effects of RASI, HSS and their combination on hemorheology, anti-asthma (asthmatic behaviors, lung function, lung index and water content in lung tissue) were observed. and anti-asthma mechanisms The expression of relative cytokines, high-mobility group box 1 (HMGB1), toll-like receptor 4 (TLR4) and nuclear factor-κB (NF-κB) was detected by ELISA and immunohistochemistry respectively. RESULTS: Eight g/kg RASI, 0.05 g/kg HSS and their combination could significantly relieve asthma behavioral indicators, improve lung function, reduce lung index and water content in lung tissue, decrease the levels of TNF-α, IL-1ß and IL-6 in broncho-alveolar lavage fluid (BALF), and inhibit the high expression of HMGB1, TLR4 and NF-κB in lung tissue. The improvement of lung function and the decrease in level of relative cytokines (TNF-α、IL-1ßIL-6) were better in RASI+HSS group than those in RASI group and HSS group, and the inhibition of protein expression of TLR4 and NF-κB was also too. Combined administration of RASI and hydrocortisone could decrease serum thromboxane B2 (TXB2) content and blood viscosity, which were increased induced by hydrocortisone. CONCLUSIONS: Combined administration of RASI and hydrocortisone have obvious anti-asthma effects and one of the mechanisms is to inhibit protein synthetization of HMGB1, TLR4 and NF-κB.The combined administration of RASI and hydrocortisone has stronger improvement of lung function than that of RASI and hydrocortisone alone, and it may be related to the inhibition of TLR4 and NF-κB synthetization. The combined administration of RASI can alleviate abnormal changes of hemorheology induced by hydrocortisone in treatment of asthma.

Meta-analysis of the effects of preoperative renin-angiotensin system inhibitor therapy on major adverse cardiac events in patients undergoing cardiac surgery.

The purpose of this meta-analysis was to assess the role of preoperative renin-angiotensin system inhibitor (RASI) therapy on major adverse cardiac events (MACE) in patients undergoing cardiac surgery. The Medline, Cochrane Library and Embase databases were searched for clinical studies published up to May 2014. Studies that evaluated the effects of preoperative RASI therapy in cardiac surgery were included. Odds ratio (OR) estimates were generated under a random-effects model. After a literature search in the major databases, 18 studies were identified [three randomized prospective clinical trials (RCTs) and 15 observational trials] that reported outcomes of 54 528 cardiac surgery patients with (n = 22 661; 42%) or without (n = 31 867; 58%) preoperative RASI therapy. Pool analysis indicated that preoperative RASI therapy was not associated with a significant reduction of early all-cause mortality [OR: 1.01; 95% confidence interval (CI) 0.88-1.15, P = 0.93; I(2) = 25%], myocardial infarction (OR: 1.04; 95% CI 0.91-1.19, P = 0.60; I(2) = 16%), or stroke (OR: 0.93; 95% CI 0.75-1.14, P = 0.46; I(2) = 38%). Meta-regression analysis confirmed that there was a strong negative correlation between the percentage of diabetics and early all-cause mortality (P = 0.03). Furthermore, preoperative RASI therapy significantly reduced mortality in studies containing a high proportion of diabetic patients (OR: 0.84; 95% CI 0.71-0.99, P = 0.04; I(2) = 0%). In conclusion, our meta-analysis indicated that although preoperative RASI therapy was not associated with a lower risk of MACE in cardiac surgery patients, it might provide benefits for diabetic patients.