Blockade Of System Research Articles

Direct Actions of AT 1 (Type 1 Angiotensin) Receptors in Cardiomyocytes Do Not Contribute to Cardiac Hypertrophy

Activation of AT1 (type 1 Ang) receptors stimulates cardiomyocyte hypertrophy in vitro. Accordingly, it has been suggested that regression of cardiac hypertrophy associated with renin-Ang system blockade is due to inhibition of cellular actions of Ang II in the heart, above and beyond their effects to reduce pressure overload. We generated 2 distinct mouse lines with cell-specific deletion of AT1A receptors, from cardiomyocytes. In the first line (C-SMKO), elimination of AT1A receptors was achieved using a heterologous Cre recombinase transgene under control of the Sm22 promoter, which expresses in cells of smooth muscle lineage including cardiomyocytes and vascular smooth muscle cells of conduit but not resistance vessels. The second line (R-SMKO) utilized a Cre transgene knocked-in to the Sm22 locus, which drives expression in cardiac myocytes and vascular smooth muscle cells in both conduit and resistance arteries. Thus, although both groups lack AT1 receptors in the cardiomyocytes, they are distinguished by presence (C-SMKO) or absence (R-SMKO) of peripheral vascular responses to Ang II. Similar to wild-types, chronic Ang II infusion caused hypertension and cardiac hypertrophy in C-SMKO mice, whereas both hypertension and cardiac hypertrophy were reduced in R-SMKOs. Thus, despite the absence of AT1A receptors in cardiomyocytes, C-SMKOs develop robust cardiac hypertrophy. By contrast, R-SMKOs developed identical levels of hypertrophy in response to pressure overload-induced by transverse aortic banding. Our findings suggest that direct activation of AT1 receptors in cardiac myocytes has minimal influence on cardiac hypertrophy induced by renin-Ang system activation or pressure overload.

Effect of Renin-Angiotensin-Aldosterone System Blockade on Intestinal Injury Induced by Indomethacin in Rats

Aim: The aim of this experimental study was to evaluate the possible cytoprotective effects of renin-angiotensin-aldosterone system (RAAS) blockade, captopril (10 mg/kg), telmisartan (10 mg/kg), and a proton-pump inhibitor (lansoprazole) on intestinal injury induced by indomethacin in rats. Materials and Methods: This effect was evaluated through the assessment of intestinal inflammatory biomarkers and oxidative stress parameters. Forty adult male albino rats weighing 170–200 g were used and divided equally into five groups. After the treatment, the following were assessed: Myeloperoxidase (MPO) enzyme activity, pro-inflammatory (interleukin-1beta [IL-1 β]) content and anti-inflammatory (IL-10) content, malondialdehyde (MDA) content, reduced glutathione (GSH) content, and superoxide dismutase (SOD) enzyme activity, and histopathological examination of the intestinal tissues was conducted. Results: Indomethacin group induced a significant increase in MDA content, also in inflammatory biomarker (MPO enzyme activity, IL-1 β content, and IL-10 content) compared to normal control, while indomethacin group induced a significant decrease in GSH content, SOD enzyme activity compared to normal control group. Captopril, telmisartan, lansoprazole administration before indomethacin-induced significant increase in GSH content, SOD enzyme activity, while induced significant decrease in MDA content as well as in inflammatory biomarker compared to indomethacin group, which indicate the antioxidant, anti-inflammatory effects, and the gastroprotective properties of RAAS blockers, which also shown in the histopathological examination of intestinal tissues. Conclusion: This study showed the possible antioxidant and anti-inflammatory effects as well as the gastroprotective properties of RAAS blockers. Telmisartan has more antioxidant and anti-inflammatory effect as well as cytoprotective action than captopril.

The Impact of Elective Withdrawal of Long-Term Renin Angiotensin Aldosterone System Blockade in Chronic Kidney Disease Patients with Progressive Acute Kidney Injury: A Prospective 40-Months’ Single-Unit Cohort Study

Introduction: There is general consensus that Renin Angiotensin Aldosterone System (RAAS) blockade is renoprotective for both diabetic and non-diabetic proteinuric chronic kidney disease (CKD). Nevertheless, there remains considerable debate and controversy regarding renal and cardiovascular (CV) outcomes after discontinuation of concurrent RAAS blockade in patients with advanced CKD. There have been discordant reports on renal and CV outcomes following RAAS blockade discontinuation. Whereas there is some agreement that there may be improved estimated glomerular filtration rate (eGFR) following such discontinuation, most studies reported increased mortality with worse CV outcomes. Conversely, fewer reports have shown renal benefits without adverse mortality and CV outcomes. Method: Prospective Cohort Analysis conducted at a single site in Burlington, Vermont, USA. In a Nephrology Office at the University of Vermont Medical Center, in Burlington, Vermont, USA, over 40 months, February 2018 – May 2021, concurrent RAAS blockade was electively discontinued in all patients who presented with progressive and >25% increase in baseline serum creatinine. Kidney function was followed prospectively. Results: 71 patients, 69 Caucasians, 1 African American and 1 Hispanic, 42:29 (M:F), mean age 69.4 (37-95) years, were in the cohort. Medical co-morbidities included diabetes mellitus (37) and hypertension (66). They were mostly asymptomatic. Mean duration of follow up since drug discontinuation was 580 (17-1245) days. Lisinopril was the commonest agent in 40 (56%) patients. Mean duration of RAAS blockade before discontinuation was 2057 (112-4043) days. Baseline serum creatinine was 1.38 ± 0.49 (0.66 - 2.7) mg/dL, n=70. Peak serum creatinine at presentation was 2.31 ± 1.09 (1.1 – 8.3) mg/dL, n=67, P<0.0001, t=6.4872, df=135. Nadir serum creatinine after discontinuation of RAAS blockade was 1.49 ± 0.45 (0.84 – 3.3) mg/dL, n=54, p<0.0001, t=5.1805, df=119. There were 4 (6%) deaths – bowel obstruction (1), cardiac arrest with pulseless electrical activity (1), metastatic renal cancer (1), and progressive ischemic cardiomyopathy (1), despite improved renal function. Kidney failure progressed despite drug discontinuation in 12 (17 %), and 4 (6%) needed renal replacement therapy, 8-30 months after drug discontinuation. Hyperkalemia in 34 (48%) and hyperphosphatemia in 13 (18%) resolved with improved kidney function. A 71-yo hypertensive man on Olmesartan 20 mg daily for 6 years was listed for kidney transplantation following acute kidney injury (AKI) with serum creatinine up to 2.9 mg/dL. Serum creatinine improved to 1.54 mg/dL, 8 months after drug withdrawal and he was delisted from the kidney transplant list. Conclusion: This is the largest and longest prospective cohort analysis of renal outcomes in patients presenting with AKI on CKD following withdrawal of RAAS blockade. The elective withdrawal of concurrent RAAS blockade in CKD patients who presented with progressive acutely worsening AKI on CKD generally exhibit clearly improved renal outcomes. Our study did not show worse mortality or CV outcomes. We posit that in selected CKD patients with progressive AKI such as in our study, RAAS blockade discontinuation indeed is the correct next step in their management for both improved renal and CV outcomes.

Crosstalk between hypoxia-sensing ULK1/2 and YAP-driven glycolysis fuels pancreatic ductal adenocarcinoma development.

Autophagy and glycolysis are two catabolic processes that manipulate pancreatic ductal adenocarcinoma (PDAC) development in response to hypoxia sensing, yet the underlying mechanism of how they are interlinked remain elusive.Methods: The functional roles of Unc-51 like kinase 1 and 2 (ULK1/2) in pyruvate kinase M2 (PKM2) transcription and glycolysis under hypoxia were assessed by chromatin immunoprecipitation, luciferase reporter, glucose consumption and lactate production assay. Co-immunoprecipitation, cellular ubiquitination, His-pulldown, in vitro protein kinase assay, immunofluorescence, immunohistochemistry, CRISPR technology, in silico studies were adopted to determine the molecular mechanism. Correlation analyses were performed in KPC (Pdx1-Cre; LSL-KrasG12D/+; Trp53fl/+) mice and clinical samples from PDAC patients. Therapeutic potential of ULK1/2 inhibitor and 2-deoxyglucose (2-DG) or 3-bromopyruvate (3-BP) was evaluated in cell-derived xenograft (CDX) and the patient-derived xenograft (PDX) models of nude mice.Results: ULK1/2, but not ULK3, augments hypoxic glycolysis in PDAC cells mediated by PKM2 independent of BCL2/adenovirus E1B 19 kDa interacting protein 3 (BNIP3). Mechanistically, hypoxia stimulates ULK1 to translocate into nucleus, where it interacts with and phosphorylates yes-associated protein (YAP) at Ser227, resulting in YAP stabilization through blockade of ubiquitin-proteasome system (UPS), which in turn facilitates PKM2 transcription, glycolysis, cell proliferation in vitro as well as PDAC growth in mice. ULK1/2 is positively correlated with YAP and PKM2 in tumor tissues from KPC mice and clinical samples from PDAC patients. Pharmacological deactivation of ULK1/2 potentiates the antineoplastic efficacy of 2-DG and 3-BP in CDX and PDX models.Conclusion: Our findings underscore the Ser227 autophosphorylation-dependent nuclear YAP stabilization as a central node that couples ULK1/2-initiated autophagy to hypoxic glycolysis during PDAC development and propose that targeting ULK1/2 combined with 2-DG or 3-BP might be a feasible therapeutic strategy against PDAC.

Discontinuation of the renin-angiotensin system inhibitors improves erythropoiesis in patients with lower-risk myelodysplastic syndromes.

Renin–angiotensin system (RAS) blockade by angiotensin-converting enzyme inhibitors (ACEis) or angiotensin-receptor blockers (ARBs) has been related to anemia in various situations. We aimed to investigate whether discontinuation of RAS inhibitors improves erythropoiesis in patients with lower-risk myelodysplastic syndromes (LR-MDSs). Seventy-four patients with LR-MDS were divided into three groups matched for gender and age. Group A consisted of 20 hypertensive patients who discontinued RAS inhibitors and received alternative medications. Group B consisted of 26 patients who continued to receive ACEi/ARB and Group C included 28 patients (50% hypertensive) never exposed to ACEi/ARB. Half of the patients in each group were under treatment with recombinant human erythropoietin (rHuEPO). Data were collected at baseline and after 3, 6 and 12 months. Group A showed a significant increase in hemoglobin from 10.4 ± 1g/dL at baseline to 12.6 ± 1.2 g/dL after 12 months (p = 0.035) and in hematocrit (31.4 ± 3% versus 37.9 ± 4%, p = 0.002). Incident anemia decreased from 100% at baseline to 60% at 12 months (p = 0.043) despite a concomitant dose reduction in rHuEPO by 18% (p = 0.035). No changes in hemoglobin and hematocrit were observed in both Group B and Group C. In the subset of patients not treated with rHuEPO, improvement of erythropoiesis was found only in Group A, as measured by changes in hemoglobin (11.5 ± 1 g/dL versus 12.4 ± 1.3 g/dL, p = 0.041) and hematocrit (34.5 ± 3% versus 37.1 ± 4%, p = 0.038) after 12 months. In contrast, Group B and Group C decreased hemoglobin and hematocrit after 12 months (p < 0.05). In conclusion, discontinuation of ACEi/ARB in LR-MDS patients is followed by a significant recovery of erythropoiesis after 12 months.

The Clinical Characteristics and Antihypertensive Medications for Mortality of Elderly Hospitalized Hemodialysis patients: a Multicenter Retrospective Study in China.

This study aimed to evaluate the clinical characteristics and antihypertensive medications affecting elderly hemodialysis (HD) patient mortality. This retrospective cohort study enrolled patients (≥18 years old) discharged from 15 tertiary general hospitals in China between January 1, 2009, and December 31, 2011. The characteristics of elderly HD patients (≥60 years old) and antihypertensive medications for mortality were analyzed. A total of 7135 patients on maintenance HD, including 2738 elderly patients, were enrolled in this study. The mean levels of hemoglobin, albumin, serum calcium, phosphorus, and parathyroid hormone in elderly group were lower than the younger group (P <0.05). The top two reasons for the hospitalization of elderly patients were infection and cardiovascular disease (CVD). We compared the characteristics of 2492 survived elderly maintenance HD patients and 246 patients who died. Aging [odds ratio OR = 1.59, 95% confidence interval (CI): 1.13-2.24] and central venous catheter (CVC) (OR = 1.62, 95% CI: 1.53-1.72) were independently risk factors for mortality in elderly maintenance HD patients. Maintenance HD patients with high levels of hemoglobin (OR = 0.76, 95% CI: 0.73-0.79), albumin (OR = 0.87, 95% CI: 0.77-0.98), uric acid (OR = 0.90, 95% CI: 0.84-0.9) and those taking angiotensin-converting enzyme inhibitor or an angiotensin II receptor blocker (OR = 0.77, 95% CI: 0.58-0.90) had a lower risk of mortality. Other antihypertensive drugs including: β-blockers, calcium channel blockers, and α-blockers were not significantly associated with mortality (P >0.05). CVD and infection were the most common causes of hospitalization and/or mortality in elderly HD patients. Age, anemia and malnutrition, use of CVCs, and low level of serum uric acid are the risk factors for mortality in elderly maintenance HD patients. Renin-angiotensin system blockade might provide a benefit in protecting elderly maintenance HD patients from mortality.

Safety, tolerability, and outcomes of losartan use in patients hospitalized with SARS-CoV-2 infection: A feasibility study.

BackgroundRetrospective studies on the use of Renin-Angiotensin-Aldosterone System blockade in patients with Coronavirus Disease 2019 (COVID-19) have been informative but conflicting, and prospective studies are required to demonstrate the safety, tolerability, and outcomes of initiating these agents in hospitalized patients with COVID-19 and hypertension.Methods and findingsThis is a single center feasibility study encompassing two cohorts: (1) prospective cohort (April 21, 2020 to May 29, 2020) and (2) retrospective cohort (March 7, 2020 to April 1, 2020) of hospitalized patients with real-time polymerase chain reaction (PCR) positive SARS-CoV-2 by nasopharyngeal swab. Key inclusion criteria include BP > 130/80 and a requirement of supplemental oxygen with FiO2 of 25% or higher to maintain SpO2 > 92%. Key exclusion criteria included hyperkalemia and acute kidney injury (AKI) at the time of enrollment. Prospective cohort consisted of de novo initiation of losartan and continuation for a minimum of 7 days and assessed for adverse events (AKI, hyperkalemia, transaminitis, hypotension) and clinical outcomes (change in SpO2/FiO2 and inflammatory markers, need for ICU admission and mechanical ventilation). Retrospective cohort consisted of continuation of losartan (prior-to-hospitalization) and assessment of similar outcomes. In the prospective cohort, a total of 250 hospitalized patients were screened and inclusion/exclusion criteria were met in 16/250 patients and in the retrospective cohort, a total of 317 hospitalized patients were screened and inclusion/exclusion criteria were met in 14/317 patients. Most common adverse event was hypotension, leading to discontinuation in 3/16 (19%) and 2/14 (14%) patients in the prospective and retrospective cohort. No patients developed AKI in the prospective cohort as compared to 1/14 (7%) patients in the retrospective cohort, requiring discontinuation of losartan. Hyperkalemia occurred in 1/16 (6%) and 0/14 patients in the prospective and retrospective cohorts, respectively. In the prospective cohort, 3/16 (19%) and 2/16 (13%) patients required ICU admission and mechanical ventilation. In comparison, 3/14 (21%) required ICU admission and mechanical ventilation in the retrospective cohort. A majority of patients in both cohorts (14/16 (88%) and 13/14 (93%) patients from the prospective and retrospective cohort) were discharged alive from the hospital. A total of 9/16 (prospective) and 5/14 (retrospective) patients completed a minimum 7 days of losartan. In these 9 patients in the prospective cohort, a significant improvement in SpO2/FiO2 ratio was observed from day 1 to 7. No significant changes in inflammatory markers (initiation, peak, and day 7) were observed in either cohort.ConclusionIn this pilot study we demonstrate that losartan was well-tolerated among hospitalized patients with COVID-19 and hypertension. We also demonstrate the feasibility of patient recruitment and the appropriate parameters to assess the outcomes and safety of losartan initiation or continuation, which provides a framework for future randomized clinical trials.

Diabetic Nephropathy: Novel Molecular Mechanisms and Therapeutic Targets.

Diabetic nephropathy (DN) is one of the major microvascular complications of diabetes mellitus and the leading cause of end-stage kidney disease. The standard treatments for diabetic patients are glucose and blood pressure control, lipid lowering, and renin-angiotensin system blockade; however, these therapeutic approaches can provide only partial renoprotection if started late in the course of the disease. One major limitation in developing efficient therapies for DN is the complex pathobiology of the diabetic kidney, which undergoes a set of profound structural, metabolic and functional changes. Despite these difficulties, experimental models of diabetes have revealed promising therapeutic targets by identifying pathways that modulate key functions of podocytes and glomerular endothelial cells. In this review we will describe recent advances in the field, analyze key molecular pathways that contribute to the pathogenesis of the disease, and discuss how they could be modulated to prevent or reverse DN.

Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers in Acute Coronary Syndrome: Implications for Platelet Reactivity?

BackgroundIn patients with acute coronary syndrome (ACS), angiotensin-converting enzyme (ACE) inhibitors are preferred over angiotensin receptor blockers (ARBs). However, in a recent pilot study, treatment with ACE inhibitors was associated with increased platelet reactivity compared to ARBs. Therefore, we sought to investigate the impact of renin-angiotensin-aldosterone system (RAAS) blockade with ACE inhibitors and ARBs on platelet aggregation in patients with ACS undergoing percutaneous coronary intervention.MethodsOn-treatment residual platelet reactivity in response to arachidonic acid (AA), adenosine diphosphate (ADP), SFLLRN, AYPGKF, and collagen was assessed by multiple electrode aggregometry (MEA) in 197 ACS patients on dual antiplatelet therapy (DAPT) with aspirin and either prasugrel or ticagrelor.ResultsOne hundred sixty-five (83.7%) patients were treated with ACE inhibitors, 32 (16.3%) with ARBs. On-treatment residual AA- and ADP-inducible platelet reactivity was significantly higher in patients with ACE inhibitors (both p < 0.05). Likewise, SFLLRN was significantly higher in patients with ACE inhibitors (p = 0.036) and there was a trend for higher AYPGKF- and collagen-inducible platelet reactivity (p = 0.053 and p = 0.082). The incidence of high on-treatment residual platelet reactivity AA was significantly higher in patients with ACE inhibitors (52 [31.5%] vs. 3 [9.4%] patients; p = 0.019).ConclusionACE inhibitors are associated with increased on-treatment residual platelet reactivity in ACS patients with potent DAPT. Further clinical trials are needed to elucidate the role of RAAS blockade with ACE inhibitors and ARBs in ACS patients treated according to current standards.

Comparison of infection risks and clinical outcomes in patients with and without SARS-CoV-2 lung infection under renin-angiotensin-aldosterone system blockade: Systematic review and meta-analysis.

AimsAngiotensin‐converting enzyme‐2 (ACE2) is the receptor for SARS‐CoV‐2. Animal studies suggest that renin–angiotensin–aldosterone system (RAAS) blockers might increase the expression of ACE2 and potentially increase the risk of SARS‐CoV‐2 infection.Methods and ResultsThe effect of ACE inhibitor (ACEI) treatment on the pneumonia incidence in non‐COVID‐19 patients (25 studies, 330 780 patients) was associated with a 26% reduction of pneumonia risk (odds ratio [OR]: 0.74, P < .001). Pneumonia‐related death cases in ACEI‐treated non‐COVID‐19 patients were reduced by 27% (OR: 0.73, P = .004). However, angiotensin II receptor blockers (ARB) treatment (10 studies, 275 621 non‐COVID‐19 patients) did not alter pneumonia risk in patients. Pneumonia‐related death cases in ARB‐treated non‐COVID‐19 patients was analysed only in 1 study and was significantly reduced (OR, 0.47; 95% confidence interval, 0.30 to 0.72). Results from 11 studies (8.4 million patients) showed that the risk of getting infected with the SARS‐CoV‐2 virus was reduced by 13% (OR: 0.87, P = .014) in patients treated with ACEI, whereas analysis from 10 studies (8.4 million patients) treated with ARBs showed no effect (OR, 0.92, P = .354). Results from 34 studies in 67 644 COVID‐19 patients showed that RAAS blockade reduces all‐cause mortality by 24% (OR = 0.76, P = .04).ConclusionACEIs reduce the risk of getting infected with the SARS‐CoV‐2 virus. Blocking the RAAS may decrease all‐cause mortality in COVID‐19 patients. ACEIs also reduce the risk of non‐COVID pneumonia. All‐cause mortality due to non‐COVID pneumonia is reduced by ACEI and potentially by ARBs.

The renin-angiotensin-aldosterone system blockade and arterial stiffness in renal transplant recipients - a cross-sectional prospective observational clinical study.

Arterial stiffness parameters can be used as a predictor of cardiovascular events in the general population and renal transplant recipients (RTRs). Additionally, the renin-angiotensin-aldosterone-system (RAAS) blockade mitigates arterial stiffness in the general population. There are no sufficient data concerning the role of the RAAS blockade in reducing arterial stiffness among patients after kidney transplantation. The aim of this study is to assess the influence of the above blockade on arterial stiffness in RTRs. 344 stable RTRs were enrolled in the study. 204 (59.3%) of them received RAAS blockers (angiotensin convertase inhibitors - ACEIs or angiotensin receptor blockers - ARBs): group RAAS (+), and 140 (40.7%) were not treated with such agents: group RAAS (-). In the RAAS (+) group, 55.9% of the patients used ARBs and 44.1% ACEIs. Cardiovascular disease (coronary artery disease and/or peripheral obliterans artery disease) (27.9% vs 14.3%, p<0.05), and heart failure (27.4% vs 24.3%, p<0.05) were significantly more often diagnosed in the RAAS (+) group when compared to the RAAS (-) group. Systolic blood pressure, diastolic blood pressure and all arterial stiffness parameters (baPWV, cfPWV, pulse pressure) did not differ significantly between the RAAS (+) and RAAS (-) groups. The results revealed that cardiovascular disease in patients was associated with a significant increase in both, the PWV and pulse pressure. No difference between the arterial stiffness parameters was observed in patients with a cardiovascular disease, diabetes and heart failure in the RAAS (+) and RAAS (-) groups. Moreover, beta-blockers and diuretics ameliorated the arterial stiffness parameters. This study showed the indication bias of the RAAS prescription, and no conclusion on the influence of RAAS on arterial stiffness can be drawn. The results indicated diuretics and beta-blockers as agents lowering the arterial stiffness in RTRs.

In vivo blockade of mononuclear phagocyte system with solid nanoparticles: Efficiency and affecting factors

Smart nanomaterials, contrast nanoparticles and drug nanocarriers of advanced targeting architecture were designed for various biomedical applications. Most of such agents demonstrate poor pharmacokinetics in vivo due to rapid elimination from the bloodstream by cells of the mononuclear phagocyte system (MPS). One of the promising methods to prolong blood circulation of the nanoparticles without their modification is MPS blockade. The method temporarily decreases macrophage endocytosis in response to uptake of a low-toxic non-functional material. The effect of different factors on the efficiency of macrophage blockade in vivo induced by solid nanomaterials has been studied here. Those include: blocker nanoparticle size, ζ-potential, surface coating, dose, mice strain, presence of tumor or inflammation. We found that the blocker particle coating type had the strongest effect on MPS blockade efficiency, which allowed to prolong functional particle blood circulation half-life 18 times. The mechanisms capable of regulation of the MPS blockade have been demonstrated, which can promote application of this phenomenon in medicine for improving delivery of diagnostic and therapeutic nanomaterials.

Effect of Finerenone on Chronic Kidney Disease Outcomes in Type 2 Diabetes

BackgroundFinerenone, a nonsteroidal, selective mineralocorticoid receptor antagonist, reduced albuminuria in short-term trials involving patients with chronic kidney disease (CKD) and type 2 diabetes. However, its long-term effects on kidney and cardiovascular outcomes are unknown.MethodsIn this double-blind trial, we randomly assigned 5734 patients with CKD and type 2 diabetes in a 1:1 ratio to receive finerenone or placebo. Eligible patients had a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of 30 to less than 300, an estimated glomerular filtration rate (eGFR) of 25 to less than 60 ml per minute per 1.73 m2 of body-surface area, and diabetic retinopathy, or they had a urinary albumin-to-creatinine ratio of 300 to 5000 and an eGFR of 25 to less than 75 ml per minute per 1.73 m2. All the patients were treated with renin–angiotensin system blockade that had been adjusted before randomization to the maximum dose on the manufacturer’s label that did not cause unacceptable side effects. The primary composite outcome, assessed in a time-to-event analysis, was kidney failure, a sustained decrease of at least 40% in the eGFR from baseline, or death from renal causes. The key secondary composite outcome, also assessed in a time-to-event analysis, was death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure.ResultsDuring a median follow-up of 2.6 years, a primary outcome event occurred in 504 of 2833 patients (17.8%) in the finerenone group and 600 of 2841 patients (21.1%) in the placebo group (hazard ratio, 0.82; 95% confidence interval [CI], 0.73 to 0.93; P=0.001). A key secondary outcome event occurred in 367 patients (13.0%) and 420 patients (14.8%) in the respective groups (hazard ratio, 0.86; 95% CI, 0.75 to 0.99; P=0.03). Overall, the frequency of adverse events was similar in the two groups. The incidence of hyperkalemia-related discontinuation of the trial regimen was higher with finerenone than with placebo (2.3% and 0.9%, respectively).ConclusionsIn patients with CKD and type 2 diabetes, treatment with finerenone resulted in lower risks of CKD progression and cardiovascular events than placebo. (Funded by Bayer; FIDELIO-DKD ClinicalTrials.gov number, NCT02540993.)

Clopidogrel-Induced Gastric Injury in Rats is Attenuated by Stable Gastric Pentadecapeptide BPC 157.

AimAlthough Clopidogrel is safe in healthy volunteers, it can induce recurrence of gastric ulcers in high-risk patients. Here, we investigated the protective effect of the natural product, stable gastric pentadecapeptide 157 (BPC 157) on Clopidogrel-induced gastric injury.MethodsWe used acetic acid to induce gastric ulcer in Sprague Dawley rats. Clopidogrel alone or in combination with BPC 157 or L-NAME (nitric oxide system blockade) were administered after healing of acetic acid-induced ulcer. One percent methylcellulose solution was used as control. Ulcer recurrence rate and the ulcer index were compared between these groups. Gastric mucosal apoptosis rate, microscopic inflammation activity and angiogenesis markers vascular endothelial growth factor A (VEGF-A) and CD34 were examined by TUNEL, histological evaluations (HE) and immunohistochemistry (IHC). Pathways involved, expressions of endoplasmic reticulum (ER) stress apoptosis marker CHOP, angiogenic markers VEGF-A and its receptor VEGFR1, and endothelial NO synthase (eNOS) were all analyzed by Western blot.ResultsThis study indicated that Clopidogrel significantly induced the gastric ulcers recurrence, severe inflammation and ER stress related apoptosis of the gastric mucosa, suppressed the synthesis of angiogenic markers and eNOS. Furthermore, Clopidrogel intervention resulted in the activation of protein kinase B (AKT) and p38 mitogen-activated protein kinase (p38/MAPK). BPC 157 attenuated the gastric mucosal damage caused by Clopidogrel and reversed these molecular effects. However, NO blockade L-NAME weakened the protective effect and thus the molecular effects of BPC 157 on gastric mucosa.ConclusionIn conclusion, these results suggest that BPC 157 inhibited Clopidogrel-induced gastric mucosa injury partially by inhibition of gastric mucosa cell ER stress-mediated apoptosis and inflammation, and promoting gastric mucosa angiogenesis via VEGF-A/VEGFR1 mediated-AKT/p38/MAPK signaling pathways.

Adverse impact of renin\u2013angiotensin system blockade on the clinical course in hospitalized patients with severe COVID-19: a retrospective cohort study

The association between angiotensin-converting enzyme inhibitor (ACE-I) or angiotensin II receptor blocker (ARB) and the risk of mortality in hospitalized patients with severe coronavirus disease 2019 (COVID-19) was investigated. This retrospective cohort study was performed in all hospitalized patients with COVID-19 in tertiary hospitals in Daegu, Korea. Patients were classified based on whether they received ACE-I or ARB before COVID-19 diagnosis. The analysis of the primary outcome, in-hospital mortality, was performed using the Cox proportional hazards regression model. Of 130 patients with COVID-19, 30 (23.1%) who received ACE-I or ARB exhibited an increased risk of in-hospital mortality (adjusted hazard ratio, 2.20; 95% confidence interval [CI], 1.10–4.38; P = 0.025). ACE-I or ARB was also associated with severe complications, such as acute respiratory distress syndrome (ARDS) (adjusted odds ratio [aOR], 2.58; 95% CI, 1.02–6.51; P = 0.045) and acute kidney injury (AKI) (aOR, 3.06; 95% CI, 1.15–8.15; P = 0.026). Among the patients with ACE-I or ARB therapy, 8 patients (26.7%) used high equivalent doses of ACE-I or ARB and they had higher in-hospital mortality and an increased risk of ARDS and AKI (all, P < 0.05). ACE-I or ARB therapy in patients with severe COVID-19 was associated with the occurrence of severe complications and increased in-hospital mortality. The potentially harmful effect of ACE-I or ARB therapy may be higher in patients who received high doses.

Saxagliptin and vildagliptin lowered albuminuria in patients with diabetes and hypertension independent on glycaemic control.

Preclinical data illustrated that the dipeptidyl peptidase-4(DPP-4) inhibitors did lower urinary albumin excretion in diabetes-induced rats. We evaluated the effects of saxagliptin and vildagliptin on albuminuria in patients with diabetic nephropathy on top of the renin-angiotensin-aldosterone system (RAAS) blockade therapy. This study included 120 patients with type 2 diabetes (T2D), hypertension, and prevalent albuminuria [defined as urine albumin-to-creatinine ratio (UACR) 30-3000mg/g creatinine] on a stable dose of olmesartan as a standard RAAS blocker for diabetic nephropathy. Patients were assigned to receive either of saxagliptin 5mg/day (n=40), vildagliptin 100mg/day (n=40), or traditional antidiabetic therapy as control patients (n=40) for 12weeks. Each of saxagliptin and vildagliptin significantly reduced albuminuria after 12weeks, with mean percentage changes (%) of -57.9% [95% confidence interval (CI) -66.1 to -49.8], and -55.2% (95% CI -64.9 to -45.4); P<.001, respectively, compared with the control group. Significantly, saxagliptin shifted higher proportions of patients towards lower albuminuria categories (P<.001) compared with vildagliptin despite a similar UACR rate of changes. Results of binary logistic models confirmed that the change in UACR because saxagliptin was independent of changes in systolic blood pressure (SBP), glycated hemoglobin (HbA1c ), estimated glomerular filtration rate (eGFR), or body weight (overall regression: P=.002, R2 =0.398) vs control. Likewise, vildagliptin reduced UACR independently on other confounders (overall regression: P=.002, R2 =0.388). Furthermore, no significant correlation was observed between the change in UACR and changes in HbA1c, SBP or eGFR with either saxagliptin or vildagliptin (Pearson coefficients: 0.203, 0.143, -0.190; P>.05, and 0.003, 0.241, 0.019; P>.05, respectively). DPP-4 inhibitors, saxagliptin, and vildagliptin, resulted in substantial reductions in albuminuria in patients with T2D and hypertension on top of RAAS blockade after short term therapy independently on glycaemic or hemodynamic changes. Saxagliptin was superior to vildagliptin in albuminuria-categorical shifting.

FGF/FGFR Axis-Blockade Leads to Anti-Tumor Activity in Waldenstrom's Macroglobulinemia By Silencing MYD88

The human fibroblast growth factor/fibroblast growth factor-receptor (FGF/FGFR) axis deregulation is largely involved in supporting the pathogenesis of hematologic malignancies, including Waldenstrom's Macroglobulinemia (WM). Therefore, novel therapeutics designed to specifically target deregulated signaling pathways in WM are required. We investigated the role of FGF/FGFR system blockade in WM by using a pan-FGF trap molecule, NSC12, a small molecule identified using pharmacophore modeling of the interaction of a minimal PTX3-derived FGF-binding pentapeptide with FGF2. By interrogating the transcriptome signature of patients' BM-derived CD19-positive cells (GEO9656, GEO6691), we found a significant enrichment of FGF/FGFR-driven signaling cascades, including PI3K-AKT, MAPK and STAT3 pathways (FDR&amp;lt;0.25; P&amp;lt;0.05); coupled with higher expression of FGFs (FGF2, FGF7, FGF12, FGF18; P&amp;lt;0.05) in WM cells as compared to their normal cellular counterpart. FGFRs are also shown to be overexpressed in WM. We performed transcriptome profiling of NSC12-treated WM cells, confirming the blockade of the FGFR-signaling blockade; and, importantly, we discovered the efficacious silencing of MYD88 and MYD88-dopwnstream target HCK in WM cells. These findings were confirmed at protein level, showing inhibition of MYD88-driven pathways, such as BTK-, and SYK-phosphorylation. As a further demonstration of the functional impact of NSC12-dependent targeting of MYD88, we could confirm the inhibition of both canonical and non-canonical NF-kB in NSC12-treated WM cells, as assessed at nuclear protein level by WB and by using the NFkB activity assay. In addition, the NSC12-dependent inhibition of MYD88 resulted in silencing of the MAPK-ERK signaling cascade, thus leading to NSC12-induced Myc-silencing in WM cells. We next confirmed the efficacy of NSC12 in silencing bone marrow stromal cell (BMSC)-induced FGFR3 phosphorylation; paralleled by inhibition of of pro-survival pathways, including pAKT, the AKT-downstream pGSK3β; p-ERK; and p-STAT3. Functional sequelae of the FGF/FGFR blockade in WM cells were studied, demonstrating inhibition of WM cell growth, induction of apoptosis, enhanced ER stress and initiation of UPR. Of note, anti-WM activity of NSC12 was also documented using primary bone marrow-derived CD19+ cells isolated from patients with WM. In contrast, NSC12 did not show cytotoxicity on PBMC-derived CD19+ cells isolated from healthy donors. The anti-WM activity exerted by NSC12 was confirmed also within the context of the supportive bone marrow milieu, as shown both in vitro and in vivo. BCWM.1, MWCL1 cells were cultured with NSC12 in the presence or absence of primary WM BMSCs: adherence of WM cells to BMSCs triggered a significant increase in the proliferation, which was inhibited by NSC12in a dose-dependent manner (P&amp;lt;0.05). Using a disseminated humanized WM model, BCWM.1 M-Cherry-Luc tumor-bearing mice were treated with either NSC12 or vehicle control. NSC12-treated mice presented with a significant inhibition of WM tumor growth as demonstrated by bioluminescence imaging analysis. NSC12-dependent reduction of WM tumor cell BM infiltration was confirmed by IHC performed on harvested femurs, in comparison to vehicle-treated mice. Importantly, we assessed MYD88-mRNA expression using harvested bone marrow femurs; and found a significant reduction of MYD88- and MYD88-downstream target HCK in NSC12-treated mice was confirmed ex vivo (P&amp;lt;0.05). Overall, our studies are reporting on the use of NSC12, as a novel potential therapeutic strategy to specifically halt the FGF/FGFR axis in WM; and demonstrate how the observed anti-WM activity exerted by NSC12 may be driven, at least in part, by inhibition of MYD88. Disclosures Motta: Roche: Honoraria; Janssen: Honoraria. Rossi:Alexion: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: Advisory board; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Honoraria; Amgen: Honoraria; Sanofi: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees. Roccaro:Amgen: Other; AstraZeneca: Research Funding; Celgene: Other; Janssen: Other; Italian Association for Cancer Research (AIRC): Research Funding; Transcan2-ERANET: Research Funding; European Hematology Association: Research Funding.

Thiazide diuretics and the rate of disease progression in autosomal dominant polycystic kidney disease: an observational study

BackgroundIn autosomal dominant polycystic kidney disease (ADPKD), hypertension is prevalent and cardiovascular events are the main cause of death. Thiazide diuretics are often prescribed as second-line antihypertensives, on top of renin–angiotensin–aldosterone system (RAAS) blockade. There is a concern, however, that diuretics may increase vasopressin concentration and RAAS activity, thereby worsening disease progression in ADPKD. We aimed to investigate the validity of these suggestions.MethodsWe analysed an observational cohort of 533 ADPKD patients. Plasma copeptin (surrogate for vasopressin), aldosterone and renin were measured by enzyme-linked immunosorbent assay and radioimmunoassay, respectively. Linear mixed models were used to assess the association of thiazide use with estimated glomerular filtration rate (eGFR) decline and Cox proportional hazards models for the association with the composite kidney endpoint of incident end-stage kidney disease, 40% eGFR decline or death.ResultsA total of 23% of participants (n = 125) used thiazide diuretics at baseline. Compared with non-users, thiazide users were older, a larger proportion was male, they had lower eGFRs and similar blood pressure under more antihypertensives. Plasma copeptin was higher, but this difference disappeared after adjustment for age and sex. Both renin and aldosterone were higher in thiazide users. There was no difference between thiazide users and non-users in the rate of eGFR decline {difference −0.35 mL/min/1.73 m2 per year [95% confidence interval (CI) −0.83 to –0.14], P = 0.2} during 3.9 years of follow-up (interquartile range 2.5–4.9). This did not change after adjustment for potential confounders [difference final model: 0.08 mL/min/1.73 m2 per year [95% CI −0.46 to –0.62], P = 0.8). In the crude model, thiazide use was associated with a higher incidence of the composite kidney endpoint [hazard ratio (HR) 1.53 (95% CI 1.05–2.23), P = 0.03]. However, this association lost significance after adjustment for age and sex and remained unassociated after adjustment for additional confounders [final model: HR 0.80 (95% CI 0.50–1.29), P = 0.4].ConclusionsThese data do not show that thiazide diuretics have a detrimental effect on the rate of disease progression in ADPKD and suggest that these drugs can be prescribed as second-line antihypertensives.

Effect of renin angiotensin system blockade following transcatheter aortic valve replacement is dose dependent

Abstract Background There is growing body of evidence from retrospective studies that inhibition of the renin angiotensin system (RAS) improves outcome after transcatheter aortic valve replacement (TAVR). However, it remains unknown whether the effect of RAS blockade treatment on survival and left ventricular (LV) remodeling after TAVR is dose dependent. Purpose To assess clinical outcome and remodeling dependent on different RAS doses after TAVR. Methods Patients who were enrolled into our observational TAVR study at our institution were retrospectively assessed according to different dosed of RAS blockade: Group1 (no RAS blockade), group 2 (25% of the maximum daily dose), group 3 (50% of the maximum daily dose) and group 4 (100% of the maximum daily dose). Results A total of 323 patients between January 2015 and September 2019 were included. Patients with higher doses of RAS blockade showed a trend towards lower all-cause mortality at 3-year follow-up (56% with no RAS blockade vs. 66% with the 25% dose vs. 79% with the 50% dose vs. 78% with the full dose; p=0.063). After adjustment for baseline characteristics the difference in survival was significant (p=0.042). Besides NYHA class ≥ III and left ventricular ejection fraction (LV-EF) RAS blockade dose was identified as independent predictor for all-cause mortality (HR 0.72 [95% CI 0.54–0.97]; p=0.03). With respect to regression of LV mass index after TAVR the only significant change was observed in patients receiving the full dose. Conclusion The present study showed for the first time that the impact of RAS blockade treatment on clinical outcome and LV remodeling after TAVR is dose dependent. Survival dependent on RAS dosis Funding Acknowledgement Type of funding source: None

Potential benefits of antihypertensive therapy in NAFLD: results from an experimental model

Abstract Background and introduction Non-alcoholic fatty liver disease (NAFLD) is considered as the most frequent cause of chronic hepatic disease in adults. It is strictly correlated with insulin resistance. The renin-angiotensin system (RAS) has been correlated to the whole basic physiopathogenic mechanism of NAFLD in experimental models. Systemic arterial hypertension has been suggested to be associated with NAFLD in approximately 40% of the cases, and NAFLD has been independently associated with an increased risk of arterial hypertension in observational studies. Therefore, we can infer that treating arterial hypertension in NAFLD carriers will often be necessary and that the potential beneficial effects of the antihypertensive might, in this context, influence the choice of the respective drug. Purpose We aimed to evaluate the effects of the renin-angiotensin system blockade with angiotensin-converting enzyme inhibitor ramipril and angiotensin 2 type 1 receptor antagonist olmesartan, both used preventively, in NAFLD induced in rabbits fed a hypercholesterolemic diet and compared the results between the groups. Methods Forty-one rabbits were divided into four groups (normal, control, olmesartan and ramipril). The control, olmesartan and ramipril group were fed a hypercholesterolemic diet. Animals from olmesartan group were treated with olmesartan 1mg/kg/day and animals from ramipril group with ramipril 0.35 mg/kg/day. At the end of the 8th week, all rabbits underwent segmental hepatic resection and were euthanised. Blood samples were collected to determine glucose, creatinine, total cholesterol, triglycerides, high-density lipoprotein cholesterol, and aminotransferase levels at baseline and euthanasia. Haematoxylin and eosin and Gomori trichrome stained slides were analysed based on the histological scoring system for NAFLD. Results The comparison between two groups (olmesartan with placebo and ramipril with placebo) showed that olmesartan and ramipril significantly diminished the development of steatosis (p=0.015, p=0.032), lobular inflammation (p&amp;lt;0.001, p=0.006), hepatocellular ballooning (p&amp;lt;0.001, p=0.023) and fibrosis (p=0.001, p=0.02). Based on NAFLD activity score, olmesartan and ramipril significantly reduced the development of nonalcoholic steatohepatitis (p&amp;lt;0.001, p=0.003). The comparison between olmesartan and ramipril showed that results were similar in all histological parameters evaluated (p=1, p=0.454, p=0.454, p=0.195, p=0.078). Conclusion(s) The preventive use of olmesartan and ramipril attenuates similarly, the development of hepatic steatosis, lobular inflammation, hepatocellular ballooning and fibrosis in hypercholesterolemic rabbits and based on NAFLD activity score both significantly reduced the development of nonalcoholic steatohepatitis. Funding Acknowledgement Type of funding source: None