Inhibition Of Angiotensin Research Articles

P71 SGLT2I IN THE REAL WORLD: DATA FROM THE PONTE (BRIDGE) HF PROJECT (PDTA FOR INTEGRATED TERRITORY HOSPITAL FOLLOW–UP OF PATIENTS WITH HEART FAILURE)

Abstract Background The DAPA–HF and the EMPEROR reduced trials showed that sodium–glucose cotransporter type 2 inhibitors (SGLT2i) dapagliflozin and empagliflozin, on best medical therapy, resulted in a reduced incidence of the combined primary outcome cardiovascular death and worsening heart failure (–26%) and a preventive effect on renal function decline. Based on this evidence, the 2021 ESC guidelines have included SGLT2i in class I recommendations in combination with angiotensin and neprilysin receptor inhibitors (ARNI) or ACE inhibitors (ACEi) or angiotensin receptor blockers (ARB), beta–blockers (BB), and mineral corticoid receptor antagonists (MRA). However, the effect of adding SGLT2i in real–life patients is just partly known. The aim of the study was therefore to evaluate the impact of SGLT2i in a real world population of patients with heart failure and reduced left ventricular ejection fraction (HFrEF). Methods 220 consecutive patients with HFrEF, treated with SGLT2i and with 6 months of follow–up already enrolled in the PONTE (BRIDGE) HF project (PDTA FOR THE INTEGRATED FOLLOW–UP IN THE HOSPITAL TERRITORY OF THE PATIENT WITH HEART FAILURE), a care model implemented in Puglia region (Italy) based on hospital–territory integration aimed at the optimized management of patient with HF after hospitalization, were considered for the study. Demographic, clinical, laboratory and instrumental characteristics and changes in NYHA class, creatinine, NT proBNP, loop diuretic dose, LVEF after initiation of therapy with SGLT2i were evaluated. Results The 220 enrolled patients (mean age of 62 years, 72% hypertensive, 38% diabetic, 67% with ischemic heart disease, 50% with ICD/CRT, 44% with atrial fibrillation, 5.6% in NYHA class I, 61% class II, 33% class III, mean LVEF 30±11%) were in treatment with BB in 93% of cases, with MRA in 94%, with ACE/ARB in 24% and with ARNI in 80%. At 6–month follow–up of, a reduction of patients in NYHA class III from 33 to 20%, an increase in patients in NYHA class II from 61 to 70%, and in NYHA class I from 5.6 to 10% were observed; the LVEF (30 vs 37.2%) and creatinine values (1.3 vs 1.5) increased significantly, while loop diuretic doses decreased (35 vs 97.5). Conclusions Data from patients treated with SGLT2i from real world seem to confirm the efficacy of this class of drugs already in a short term follow–up, with a positive effect on NYHA class, LVEF, and renal function.

Inhibition of angiotensin II type 1 receptor reduces oxidative stress damage to the intestinal barrier in severe acute pancreatitis.

Intestinal barrier injury is a common complication of severe acute pancreatitis (SAP), which is often accompanied by intestinal mucosal barrier injury and results in serious consequences. However, the exact mechanism remains unclear. We aimed to investigate whether angiotensin II type 1 receptor (AT1)-mediated oxidative stress is involved in SAP intestinal barrier injury and assessed the effects of inhibiting this pathway. The SAP model was established by retrograde bile duct injection of sodium taurocholate (5%). The rats were divided into three groups: the control group (SO), the SAP group (SAP), and the azilsartan intervention group (SAP + AZL). Serum amylase, lipase, and other indexes were measured to evaluate SAP severity in each group. Histopathological changes in the pancreas and intestine were evaluated by HE staining. The oxidative stress of intestinal epithelial cells was detected by superoxide dismutase and glutathione. We also detected the expression and distribution of intestinal barrier-related proteins. The results showed that the serum indexes, the severity of tissue damage, and the level of oxidative stress in the SAP + AZL group were significantly lower than in the SAP group. Our study provided hitherto undocumented evidence of AT1 expression in the intestinal mucosa, confirming that AT1-mediated oxidative stress is involved in SAP intestinal mucosal injury, and inhibiting this pathway could effectively reduce intestinal mucosal oxidative stress injury, providing a new and effective target for the treatment of SAP intestinal barrier injury.

Steroid- and immunosuppressant-based protocol of Henoch-Schönlein purpura nephritis without angiotensin inhibitors in the acute phase.

The Kidney Disease: Improving Global Outcomes (KDIGO) guidelines suggest initially using angiotensin-converting-enzyme inhibitors (ACE-Is) and/or angiotensin receptor blockers (ARBs) to treat Henoch-Schönlein purpura nephritis (HSPN). However, these guidelines might overlook the potential benefits of aggressive therapy. Therefore, we evaluated the efficacy of an HSPN protocol that primarily uses steroids and immunosuppressants, without ACE-Is or ARBs. We determine treatment intensity based on International Study of Kidney Diseases in Children (ISKDC) grading. Fifty-one patients were treated with our protocol that primarily uses steroids and immunosuppressants. ACE-Is and ARBs were not used in the acute phase, including before renal biopsy. We evaluated the proteinuria disappearance rate, duration to proteinuria disappearance, and estimated glomerular filtration rate (eGFR) at the time of last observation and compared them to those in previous reports. Proteinuria disappeared in 49 patients (96%) within a median of 5 months. The median eGFR was 116.0 mL/min/1.73 m2 at the time of last observation. Six of 51 patients had acute kidney injury (eGFR<90 mL/min/1.73 m2) before treatment, but all recovered during the observation period (median 52 months). Our steroid- and immunosuppressant-based protocol without ACE-Is or ARBs in the acute phase of HSPN had almost equivalent efficacy to that in previous studies that used ACE-Is and/or ARBs with steroids and immunosuppressants.

Inhibition of angiotensin II type 1 receptor agonistic autoantibodies by direct binding does not impact reduced uterine perfusion pressure offspring birthweight and blood pressure at adulthood

Preeclampsia, a new-onset hypertension with end-organ damage in pregnancy, is associated with maternal death and morbidity, low birthweight, and B cells producing agonistic autoantibodies to the angiotensin II type 1 receptor. Angiotensin II type 1 receptor agonistic autoantibodies are produced during pregnancy and after delivery and are in the fetal circulation of women with preeclampsia. Angiotensin II type 1 receptor agonistic autoantibodies are shown to contribute to endothelial dysfunction, renal dysfunction, hypertension, fetal growth restriction, and chronic inflammation in women with preeclampsia. The reduced uterine perfusion pressure rat model of preeclampsia exhibits these features. In addition, we have shown that the administration of a 'n7AAc', which blocks the actions of the angiotensin II type 1 receptor autoantibodies, improves preeclamptic features in the rat with reduced uterine perfusion pressure. However, the effect of a 'n7AAc' on the long-term health of the offspring of rats with reduced uterine perfusion pressure is unknown. This study aimed to test the hypothesis that inhibition of angiotensin II type 1 receptor autoantibodies during pregnancy will improve offspring birthweight and prevent increased cardiovascular risk in offspring in adulthood. To test our hypothesis, a 'n7AAc' (24 µg/d) or vehicle (saline) was given on gestation day 14 via miniosmotic pumps to sham-operated (sham) and Sprague-Dawley rat dams with reduced uterine perfusion pressure. Dams were allowed to deliver naturally, and pup weights were recorded within 12 hours after birth. Pups were aged to 16 weeks, at which time mean arterial pressure was measured and whole blood was collected to measure immune cells by flow cytometry, cytokines by enzyme-linked immunosorbent assay, and angiotensin II type 1 receptor autoantibodies by bioassay. A 2-way analysis of variance with the Bonferroni multiple comparison posthoc test was used for statistical analysis. There was no significant change in offspring birthweight of 'n7AAc'-treated male (5.63±0.09 g) or female (5.66±0.14 g) offspring from reduced uterine perfusion pressure dams compared with vehicle male (5.51±0.17 g) or female (5.74±0.13 g) offspring from reduced uterine perfusion pressure dams. In addition, 'n7AAc' treatment did not affect the birthweight of sham male (5.83±0.11 g) or female (5.64±0.12) offspring compared with vehicle sham male (5.811±0.15 g) or female (5.40±0.24 g) offspring. At adulthood, mean arterial pressure was unchanged in 'n7AAc' treated-male (133±2 mm Hg) and female (127±3 mm Hg) offspring from reduced uterine perfusion pressure dams compared with vehicle male (142±3 mm Hg) and female (133±5 mm Hg) offspring from reduced uterine perfusion pressure dams, the 'n7AAc'-treated sham male (133±3 mm Hg) and female (135±3 mm Hg) offspring, and vehicle sham male (138±4 mm Hg) and female (130±5 mm Hg) offspring. The circulating angiotensin II type 1 receptor autoantibodies were increased in vehicle male (10±2 ΔBPM) and female (14±2 ΔBPM) offspring from reduced uterine perfusion pressure dams and 'n7AAc'-treated male (11±2 ΔBPM) and female (11±2 ΔBPM) offspring from reduced uterine perfusion pressure dams compared with vehicle sham male (1±1 ΔBPM) and female (-1±1 ΔBPM) offspring and 'n7AAc'-treated sham male (-2±2 ΔBPM) and female (-2±2 ΔBPM) offspring. Our findings indicated that perinatal 7-amino acid sequence peptide treatment does not negatively impact offspring survival or weight at birth. Perinatal 'n7AAc' treatment did not prevent increased cardiovascular risk in offspring, but it also did not cause an increased cardiovascular risk in offspring with reduced uterine perfusion pressure compared with controls. Furthermore, perinatal 'n7AAc' treatment did not affect endogenous immunologic programming as observed by no change in circulating angiotensin II type 1 receptor autoantibodies in either sex of adult offspring from reduced uterine perfusion pressure dams.

Effects of voluntary exercise and administration of renin angiotensin inhibitor on cardiac function in inherited dilated cardiomyopathy model.

Dilated cardiomyopathy (DCM) is one of major causes of heart failure (HF) especially in Asia. Although exercise is regarded as one of therapies for HF, the effects of exercise on patients with DCM have not been established. A knock-in mouse model of human inherited DCM, TNNT2 ΔK210, shows similar characteristics to DCM patients. We have showed that one of angiotensin receptor blockers (ARB) is effective on cardiac function and electrical remodeling. We also have found that voluntary exercise improves cardiac function in homozygote model mice (DCM mice). In this study, we examined combination therapy of ARB and exersise in DCM mice. The DCM mice showed enlarged heart and frequent sudden death with t1/2 of ∼70 days. Male DCM mice were divided into 4 groups based on the administration of ARB and voluntary exercise: without drug or exercise (CON), oral administration of ARB (ARB), daily exercise (EXE), and combined ARB and exercise (COMB). The EXE and COMB groups started wheel running at 1 month of age. Cardiac function was measured with echocardiography and electrocardiogram at 2.5 months of age. After sacrifice, weights of body, heart, lung, and lower extremity muscles were measured. Gene expressions of HF- and arrhythmia-related genes in myocardium were quantified by qPCR analysis. There was no significant difference in driving performance between EXE and COMB (EXE: 7.0 ± 1.6 km/day (n = 8), COMB: 6.3 ± 2.2 km/day (n = 7)). On echocardiography, the ejection fraction was significantly improved in only COMB (CON: 21.7 ± 6.1% (n = 6), ARB: 26.9 ± 5.1% (n = 6), EXE: 27.2 ± 4.5% (n = 5), COMB: 31.9 ± 3.6% (n = 6)). On the other hand, the heart weight/body weight ratio decreased in the ARB and the COMB groups. Our results suggest that the combination of ARBs and exercise may have a greater effect on cardiac function in DCM mice.

PS-B12-8: ANGIOTENSIN II TYPE I RECEPTOR SIGNAL REGULATES MITOCHONDRIAL DYNAMICS, CAUSING MUSCULAR MITOCHONDRIAL DYSFUNCTION AND SARCOPENIA UNDER METABOLIC STRESS

Introduction: Metabolic stress, such as oxidized low density lipoprotein (ox-LDL) and advanced glycation end products (AGE) cause atherosclerotic cardiovascular diseases through dysfunction of mitochondria, which undergo quality control by mitochondrial dynamics, fission and fusion. Mitochondria also plays a crucial role in regulating muscular function, and its dysfunction leads to sarcopenia. This study aims to clarify whether and how mitochondrial dynamics are involved in the development of sarcopenia under metabolic stress. Methods: We used human skeletal muscle cells (HSMC) in in vitro experiments and C57BL6 (WT), apolipoprotein E (ApoE) deficient and the double knockout of ApoE and AT1R (DKO) mice in in vivo experiments. Results: Administration of either ox-LDL or AGE to HSMC induced mitochondrial fission through activation of fission factor, Drp1, decreased mitochondrial membrane potential assessed by JC-1 staining and increased reactive oxygen species assessed by Mito-sox Red staining and apoptosis, which were restored by Drp1-specific inhibitor, mdivi-1. Inhibition of angiotensin II type 1 receptor (AT1R) by AT1R blocker also ameliorated excessive mitochondrial fission, its function and oxidative stress induced by either ox-LDL or AGE in HSMC. These results suggest that metabolic stress induces mitochondrial fission and its dysfunction, which may cause sarcopenia. Muscular strength and the ratio of muscle weight to tibia length were lower in ApoE than those in WT. The number of fused mitochondria and mitochondrial function were lower and oxidative stress and the number of apoptotic cell were higher in ApoE KO than those of WT. Muscle strength, the ratio of muscle weight to tibia length, the number of fused mitochondria and its function were higher and the number of apoptotic cell were lower in DKO than those in ApoE KO mice. Taken together, these results suggest that either ox-LDL or AGE causes sarcopenia through AT1R signal-dependent mitochondrial fission and subsequent mitochondrial dysfunction. Conclusion: Either ox-LDL or AGE induces mitochondrial dysfunction through AT1R signal-regulating mitochondrial fission, which causes sarcopenia. Inhibition of AT1R signal may be a potential therapeutic strategy to avoid development of sarcopenia in patients with life style related diseases, such as dyslipidemia and diabetics.

Inhibition of angiotensin II type 1 receptor partially prevents acute elevation of pulmonary arterial pressure induced by endovascular ethanol injection.

This study aimed to examine whether the administration of losartan can prevent acute elevation of pulmonary arterial pressure (AEPAP) induced by endovascular ethanol injection and to assess its related mechanisms. Male swine were selected and performed with absolute ethanol endovascular injection. Saline was used as the negative control. Losartan was administered preoperatively. Pulmonary arterial pressure (PAP), femoral arterial pressure (FAP) and heart rate (HR) were monitored during operations. Venous plasma and pulmonary artery (PA) tissue were harvested for analyses. Protein level was detected by Western blotting and ELISA, whereas qRT-PCR was used in mRNA detection. H & E staining and immunohistochemistry were conducted to evaluate histopathology. Ethanol injection elevated PAP in swine. The concentration of RAS ligands was elevated in plasma (all P < 0.0001) but not in PA. The level of oxidative stress increased in both plasma and PA. MRNA level of AT1R (P < 0.01, 95% CI: 0.251-1.006), not AT2R increased in PA. Losartan failed to inhibit AEPAP after all sessions of ethanol injection, and partially reversed the ethanol-induced PA remodeling. The P38 MAPK was activated after ethanol injection and could be inhibited by losartan (P < 0.01, 95% CI: -0.391 to -0.164). Ethanol also promoted the translocation of the P40-PHOX/P47-PHOX/P67-PHOX complex and the activation of NOX, which was independent from RAS. Endovascular ethanol injection can induce AEPAP mainly by activating RAS and P38 MAPK signaling. Losartan can partially prevent AEPAP and vascular remodeling owing to the promotion of NOX activity by ethanol. Mechanism diagram of endovascular ethanol injection-induced acute elevation of pulmonary arterial pressure (AEPAP) partially prevented by losartan. RAS: Renin-angiotensin system; AGT: angiotensinogen; Ang I: angiotensin I; ACE: angiotensin I converting enzyme; Ang II: angiotensin II. AT1R: angiotensin II type 1 receptor. NOX2: NADPH oxidase 2. PA:pulmonary artery.

432 SACUBITRIL/VALSARTAN AND RISK OF SUPRAVENTRICULAR ARRHYTHMIAS AS DETECTED BY REMOTE MONITORING IN HEART FAILURE PATIENTS

Abstract Introduction Sacubitril/valsartan (ARNI) has demonstrated a significant benefit compared to angiotensin inhibitor (enalapril) in decreasing both morbidity and mortality in patients with heart failure with reduced ejection fraction (HFrEF). While. recent studies demonstrated that in HFrEF patients, ARNI decreased ventricular arrhythmias no data is available with regards to the supraventricular arrhythmic burden in HFrEF patients with an implantable cardioverter defibrillator (ICD) or cardiac resynchronisation therapy-defibrillator (CRT-D) and remote monitoring. The aim of out study was to assess if ARNI therapy was able to significantly reduce supraventricular arrhythmias. More specifically the primary endpoint was the incidence of AT/AF episodes, as detected by the device. Secondary endpoints included the total burden of AT/AF, the mean number of premature ventricular contractions (PVC) per hour and the percentage of biventricular pacing per day (in patients with CRT-D). Methods We conducted a multicentre, observational, prospective registry : the SAVE THE RHYTHM (SAacubitril Valsartan rEal-world registry evaluating THE arRHYTHMia burden in HFrEF patients with implantable cardioverter defibrillator). We enrolled all patients with HFrEF, ICD or CRT-D actively followed through remote monitoring and starting treatment with sacubitril/valsartan. All patients were followed-up for at least one year. Results At the end of enrollment, 265 patients from 5 centres had at least one sacubitril/valsartan prescription (88% males, age 68±10 years). The annual incidence of AT/AF episodes decreased from 16.6% before sacubitril/valsartan to 12.8%, 6.7% and 0.7% according to the maximum tolerated dose (24/26 mg, 49/51 mg and 97/103 mg, respectively; p=0.026). After treatment with sacubitril/valsartan, patients with at least one episode of AT/AF decreased from 32.6% to 26.5% (24/26 mg), 24.3% (49/51 mg) and 6.9% (97/103 mg); p=.041. A significant decrease in the number of PVC (-28 per hour) and in the rate of appropriate shock (-0.8% per year) were seen in patients with a previous diagnosis of paroxysmal or persistent AF. Patients with permanent AF (n=7) experienced no benefits from sacubitril/valsartan therapy in terms of arrhythmic burden reduction. Patients with a CRT device (41%) experienced a significant increase in biventricular pacing time (+3% per day). Discussion Therapy with sacubitril/valsartan could decrease arrhythmic burden in patients with non-permanent AF and HFrEF and reduce subclinical supraventricular arrhythmias in patients with no history of AF.

Inhibition of the Renin-Angiotensin System Fails to Suppress β-Aminopropionitrile-Induced Thoracic Aortopathy in Mice-Brief Report.

Cross-linking of lysine residues in elastic and collagen fibers is a vital process in aortic development. Inhibition of lysyl oxidase by BAPN (β-aminopropionitrile) leads to thoracic aortopathies in mice. Although the renin-angiotensin system contributes to several types of thoracic aortopathies, it remains unclear whether inhibition of the renin-angiotensin system protects against aortopathy caused by the impairment of elastic fiber/collagen crosslinking. BAPN (0.5% wt/vol) was started in drinking water to induce aortopathies in male C57BL/6J mice at 4 weeks of age for 4 weeks. Five approaches were used to investigate the impact of the renin-angiotensin system. Bulk RNA sequencing was performed to explore potential molecular mechanisms of BAPN-induced thoracic aortopathies. Losartan increased plasma renin concentrations significantly, compared with vehicle-infused mice, indicating effective angiotensin II type 1 receptor inhibition. However, losartan did not suppress BAPN-induced aortic rupture and dilatation. Since losartan is a surmountable inhibitor of the renin-angiotensin system, irbesartan, an insurmountable inhibitor, was also tested. Although increased plasma renin concentrations indicated effective inhibition, irbesartan did not ameliorate aortic rupture and dilatation in BAPN-administered mice. Thus, BAPN-induced thoracic aortopathies were refractory to angiotensin II type 1 receptor blockade. Next, we inhibited angiotensin II production by pharmacological or genetic depletion of AGT (angiotensinogen), the unique precursor of angiotensin II. However, neither suppressed BAPN-induced thoracic aortic rupture and dilatation. Aortic RNA sequencing revealed molecular changes during BAPN administration that were distinct from other types of aortopathies in which angiotensin II type 1 receptor inhibition protects against aneurysm formation. Inhibition of either angiotensin II action or production of the renin-angiotensin system does not attenuate BAPN-induced thoracic aortopathies in mice.

Effect of angiotensin II pathway inhibitors on post-surgical adhesion band formation: a potential repurposing of old drugs

BackgroundIn this study we investigated the therapeutic potential of angiotensin II pathway inhibitors in attenuating post-surgical adhesion band formation in tendon injury. MethodWe assigned 30 Wistar albino rats to 5 groups, including negative control, positive control, sham, Telmisartan- and Enalapril-treated groups (n=6). Telmisartan and Enalapril at a dose of 10 mg/kg were administered intraperitoneally for 21 days. Hematoxylin-Eosin, and Masson's trichrome staining were used to measure the inflammatory cell accumulation and collagen deposition in the Achilles tendon tissue sections. Oxidative stress markers were analyzed in tissue samples by spectrophotometric methods. Properties of Achilles tendon adhesions were compared based on Tang and Ishiyama scoring systems in the presence and absence of angiotensin II pathway inhibitors. ResultsTelmisartan and Enalapril reduced severity, length, and density of surgical-induced tendon adhesion at site of injury (***p < 0.001). Our results showed that administration of angiotensin II pathway inhibitors decreased infiltration of inflammatory cells to the injured area (*p < 0.05) and suppressed inflammation by regulating oxidative stress markers including MDA (***p < 0.001), total thiol (***p < 0.001), CAT (***p < 0.001), and SOD (***p < 0.001), in post-operative Achilles tendon tissues. Significant lower collagen deposition and formation of fibrotic tissues was seen in Telmisartan- and Enalapril-treated groups as detected by Masson's trichrome staining which correlated with a decrease in quantity (**p < 0.01) and grading of fibrosis score (***p < 0.001), in adhesive tissues. Moreover, inhibition of angiotensin II pathway could also ameliorate mechanical properties including ultimate load (***p < 0.001), and ultimate stress (*p < 0.05) in injured Tendons. ConclusionOur results showed that ssuppression of inflammation and fibrosis are two mechanisms by which Telmisartan and Enalapril elicit potent protective responses post Achilles tendon injuries.

Dual therapy with an angiotensin receptor blocker and a JAK1/2 inhibitor attenuates dialysate-induced angiogenesis and preserves peritoneal membrane structure and function in an experimental CKD rat model.

Peritoneal dialysis (PD) is limited by reduced efficacy over time. We previously showed that a Janus kinase 1/2 inhibitor (JAK1/2i) reduced inflammation, hypervascularity and fibrosis induced by 4.25% dextrose dialysate (4.25%D) intraperitoneally (IP) infused for 10 days in rats with normal kidney function. JAK/STAT signalling mediates inflammatory pathways, including angiotensin signalling. We now tested the effect of long-term JAK1/2i and/or an angiotensin receptor blocker (ARB) on peritoneal membrane (PM) in polycystic kidneys (PCK) rats infused with 4.25%D. Except for controls, all PCK rats had a tunnelled PD catheter: (1) no infusions; (2) 4.25%D; (3) 4.25%D + JAK1/2i (5 mg/kg); (4) 4.25%D +losartan (5 mg/kg); and (5) 4.25%D + losartan +JAK1/2i (5 mg/kg each) IP BID × 16 weeks (N = 5/group). PM VEGFR2 staining areas and submesothelial compact zone (SMCZ) width were morphometrically measured. Peritoneal equilibration testing measured peritoneal ultrafiltration (UF) by calculating dialysate glucose at time 0 and 90 min (D/D0 glucose). 4.25%D caused hypervascularity, SMCZ widening, fibrosis and UF functional decline in PCK rats. Angiogenesis was significantly attenuated by JAK1/2i ± ARB but not by ARB monotherapy. Both treatments reduced SMCZ area. UF was preserved consistently by dual therapy (p < 0.05) but with inconsistent responses by monotherapies. Long-term JAK1/2i ± ARB reduced angiogenesis and fibrosis, and the combination consistently maintained UF. In clinical practice, angiotensin inhibition has been advocated to maintain residual kidney function. Our study suggests that adding JAK1/2i to angiotensin inhibition may preserve PM structure and UF.

Melatonin counteracts necroptosis and pulmonary edema in cadmium-induced chronic lung injury through the inhibition of angiotensin II.

The renin-angiotensin system (RAS) is an important regulator in pulmonary physiology. In our study, we identified the efficacy of melatonin to control the RAS in cadmium (Cd) induced chronic lung injury in a mouse model. Swiss albino mice exposed to CdCl2 intraperitoneally (I.P.) (1 mg/kg b.w.; 12 weeks) showed increased release of lactate dehydrogenase in bronchoalveolar lavage fluid, generating reactive oxygen species, impaired antioxidant enzymes function, and disrupted alveolar structure along with increased expression of Angiotensin-II (Ang-II) in lung tissue. Cd-induced angiotensin-converting enzyme-2-Ang-II axis imbalance triggered the onset of Ang-II induced tumour necrosis factor alpha (TNF-α) mediated necroptosis by upregulating the signalling molecules RIP-1, RIP-3, and p-mixed lineage kinase domain-like. In an in vitro study, colocalization of Ang-II-RIP-3 molecule in Cd intoxicated L-132 cells (human alveolar epithelial cell line), as well as pretreatment of Cd exposed cells with the inhibitor's captopril (10 μM), necrostatin-1 (50 μM), and etanercept (5 μg/ml) indicated TNF-α induced necroptotic cell death via activation of the key molecule, Ang-II. Moreover, Ang-II disrupted the alveolar-capillary barrier by decreasing tight junctional proteins (zonula occludens-1 and occludin) and endothelial VE-cadherin expression. The use of human umbilical vein endothelial cells as a model of junctional protein-expressing cells showed that captopril pretreatment (25 μM) restored VE-cadherin expression in Cd-treated human umbilical vein endothelial cells. In CdCl2 intoxicated mice, melatonin pretreatment (10 mg/kg b.w.; 12 weeks, I.P.) inhibited inflammatory mediators (TNF-α, interleukin [IL]-1β, and IL-6) release and effectively suppressed (Cd-induced) Ang-II mediated necroptotic cell death and alveolar-capillary breaching due to Cd toxicity.

The protective effect of xanthenone against LPS-induced COVID-19 acute respiratory distress syndrome (ARDS) by modulating the ACE2/Ang-1-7 signaling pathway.

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Anemia warrants treatment to improve survival in patients with heart failure receiving sacubitril–valsartan

Angiotensin inhibition remains a cornerstone for pharmacologic management of heart failure (HF), despite being associated with decreased hemoglobin (Hb) levels. To investigate the effect of anemia and its treatment on patients with HF treated with sacubitril–valsartan (S/V), we conducted a retrospective study involving patients with recorded left ventricular ejection fractions (LVEFs) of < 40% between January 2017 and December 2019. We identified 677 patients, 37.7% of whom received S/V. The median follow-up period was 868 days. Anemia was associated with significantly decreased survival, increased mortality rates, and higher all-cause hospitalizations in S/V-using patients. We further analyzed 236 patients with HF who had recorded renal function, LVEF, and Hb at the initiation of S/V therapy to identify Hb patterns after S/V therapy. Of these patients, 35.6% exhibited decreasing Hb 12 months after S/V initiation, which was associated with a lower survival rate. Among the patients who were not prescribed anemia medications, Hb of ≥ 12 (vs. < 12 g/dL) was associated with a higher survival rate; this association was absent among the patients undergoing anemia treatment. These results emphasize that consistent screening and treatment for anemia should be implemented to reduce the morbidity and mortality of patients with HF receiving S/V.

MO226: Is Remission of Hematuria Associated with Kidney Outcome in Biopsy-Proven Primary IGA Nephropathy?

Abstract BACKGROUND AND AIMS Microscopic hematuria, associated with variable proteinuria, is the most common clinical feature of IgA nephropathy (IgAN). However, its role in the disease progression is still controversial. This study aims to assess whether remission of hematuria is associated with kidney outcome in adults with primary IgAN. METHOD This retrospective, longitudinal study enrolled 62 adults, out of 214 with biopsy-proven IgAN between 1 January 2008 and 31 December 2017 {age 41 [95% confidence interval (CI) 37–46] years, 73% males, eGFR 41.3 (95% CI 33.1–51) mL/min and proteinuria 1.1 (95% CI 0.9–1.6) g/g} who had at least three assessment visits 3 months apart until 31 May 2018. The median follow-up period was 68 (95% CI 58.6–77.3) months. Demographic (age, gender), comorbidities, clinical and laboratory data (proteinuria, hematuria and blood pressure) at the time of kidney biopsy and during the follow-up period were retrieved from medical records. Information about therapy was also recorded. The study endpoint was kidney death defined as doubling of serum creatinine or renal replacement therapy (RRT) initiation. Kidney survival was evaluated by Kaplan–Meier method and variables related to kidney outcome by multivariate Cox proportional hazard modeling. Remission of hematuria was defined as ≤ 5 red blood cells/high power field in at least two samples taken no less than 3 months apart. Subjects were grouped as remission of hematuria (n = 24) and persistent hematuria (n = 38). RESULTS There were no differences between the two groups regarding demographic characteristics, comorbidities, kidney function, proteinuria, hematuria or inflammation markers at time of kidney biopsy. During the follow-up period, remission of proteinuria (defined as a &amp;gt; 50% decrease in urinary protein-to-creatinine ratio from baseline) was found in more than half of the group with remission of hematuria but in less than a quarter of group with persistent hematuria (57.1% versus 24.2%; P = .02). However, systolic blood pressure was well controlled (&amp;lt;130 mmHg) in similar proportions (63.6 versus 57.9%, P = .7) and a comparable reduction in mean arterial blood pressure from the baseline was observed [ΔMAP −7.8 (95% confidence interval (CI) −14.1 to −0.45) versus −2.8 (95% CI −9.7–4.9) mmHg; P = .2] in both groups. A high proportion of patients were treated with renin–angiotensin inhibitors (71 versus 61%; P = .5) and almost a third received immunosuppressive therapy (38 versus 34%; P = .8), similarly in the two groups. During the follow-up, a lower proportion of patients with remission of hematuria reached the composite kidney endpoint (16.7 versus 42.1%, P = .03). In the univariate time-dependent analysis, the kidney survival was numerically better in patients with remission of hematuria [(71.4 (95% CI 64.5–78.2) versus 66.02 (95% CI 54.7–77.2) months; log rank P = .06; Fig. 1A]. However, in the multivariate time-dependent analysis, only the absence of proteinuria remission [OR 0.06 (95%CI 0.008–0.46), P = .007] and a lower baseline eGFR [OR 0.96 (95% CI 0.93–0.98), P = .007] were associated with a poor kidney outcome (chi-squared = 18.5, P &amp;lt; .001) (Fig. 1B). CONCLUSION In this cohort of young adults with biopsy-proven primary IgA nephropathy and moderate decline in kidney function, the remission of hematuria for at least 3 months was not associated with kidney outcome.

Use of angiotensin inhibitor associated with longer survival in patients with pancreatic cancer undergoing curative resection

Use of angiotensin inhibitor associated with longer survival in patients with pancreatic cancer undergoing curative resection

Experimental and Molecular Modeling Studies on the Complexation of Chromium(III) with the Angiotensin-Converting Enzyme Inhibitor Captopril.

Captopril (CPT) is an inhibitor of angiotensin I converting enzyme, used as a medication for the treatment of people with high blood pressure, renal insufficiency, and cardiovascular diseases. It inhibits the angiogenesis process, vasoconstriction, and tumor metastasis. Some metal–captopril complexes exhibit antimicrobial activities. In the current work, the formation of the CrIII–CPT complex was studied spectrophotometrically and potentiometrically in aqueous solution. Kinetics of CrIII–CPT complex formation was spectrophotometrically studied over the pH range 3.20–4.20, at an ionic strength of 0.3 M at 30–50 °C. CrIII–CPT complex formation was potentiometrically studied at 25 °C, where ligand protonation constants and complexes’ overall stability constants were calculated. UV–vis absorption spectra were executed to confirm the complex formation. Density functional theory and molecular dynamics simulation were performed to search the geometries of the CrIII–CPT complex. Atoms in molecules and interaction region indicator calculations are used to investigate intermolecular interactions for the formation of CrIII–CPT complex. The antimicrobial activity of the CPT ligand and CrIII–CPT complex on the prevention and control of environmental pathogenic bacteria, as tested on both Gram-positive Staphylococcus aureus (S. aureus) and Gram-negative bacteria Escherichia coli (E. coli) via agar disc diffusion method, assess the ability to use as an antimicrobial agent. CPT had shown good antimicrobial activity against both types of bacteria, which had increased slightly the zone of inhibition in Cr-CPT that indicates the increased efficacy due to Cr(III) antimicrobial activity via its oxidative damage to the bacterial cell wall. No previous study tested the CPT antimicrobial activity against Gram-positive ones such as S. aureus

Impact of angiotensin-converting enzyme inhibitors (ACEi) on pathologic complete response with neoadjuvant chemotherapy (NAC) for muscle-invasive bladder cancer (MIBC).

485 Background: The renin-angiotensin system (RAS) has been demonstrated to modulate cell proliferation, desmoplasia, angiogenesis and immunosuppression. Angiotensin pathway inhibitors are postulated to favorably reprogram the stroma in part by inhibition of transforming growth factor-β, a major mechanism of resistance, and have been previously reported to be associated with improved outcomes in the setting of immune checkpoint inhibitors (ICIs) for metastatic urothelial carcinoma (Jain R, Clin Genitourin Cancer 2021). In this analysis, we examined the association of angiotensin inhibitors in the setting of NAC for MIBC preceding radical cystectomy (RC). Methods: Pts with MIBC who received NAC preceding radical cystectomy were assembled from 3 institutions: Dana-Farber Cancer Institute (DFCI), Moffitt Cancer Center (MCC) and McGill University Health Center (MUHC). Pts were retrospectively assessed for the association of concurrent ACEi/angiotensin receptor blockers (ARB) use at initiation of NAC on pathologic complete response (pCR), defined as pT0N0, and overall survival (OS). Pathologic features, performance status (PS), clinical stage, type/number of cycles of NAC, and toxicities were collected. The Kaplan-Meier method was used to estimate OS. Logistic and Cox regression were used to explore factors potentially prognostic for pCR and OS respectively. Results: 302 MIBC pts who received NAC preceding RC were available from 3 institutions: DFCI (n = 187), MCC (n = 50) and MUHC (n = 65). Overall, 141 pts (46.7%) received Cisplatin/Gemcitabine, 130 (43.1%) received dose dense MVAC and the remaining received other regimens. The overall pCR rate was 26.2%. The 5-year OS was 62%. 63 (20.9%) pts were receiving an ACEi and 41 (13.6%) were receiving an ARB. ACEi prior to NAC approached significance for association with pCR (odds ratio = 1.71 (95% CI = 0.94-3.11) p = 0.077). Pts with cT3/4N0-N1 disease receiving ACEi had higher pCR rates (30.8% (8/26) vs 17.7% (14/98), p = 0.056) than those not on ACEi; no difference was observed for pts with cT2N0 tumors (31.1% vs 31.3%, p = 0.99). pCR, ECOG-PS and clinical stage were significantly associated with improved OS. ARB intake was not associated with pCR or OS. Conclusions: ACEi intake appeared potentially associated with increased pCR in pts with MIBC receiving NAC, which was more pronounced in those with higher clinical stages cT3/4N0-1. Given the association of pCR with OS, our data suggest the potential relevance of angiotensin as a therapeutic target in aggressive MIBC. Future prospective validation is warranted to repurpose angiotensin inhibitors in this setting, given their excellent toxicity profile and low costs.

Angiotensin Inhibitor Use is Associated with Longer Survival in Resected Pancreatic Cancer

Introduction: The Renin-angiotensin system (RAS) has crucial implications in pancreatic adenocarcinoma (PDAC) tumorigenesis and progression. Activities and inhibition of RAS may affect treatment response and may correlate with clinical outcomes. Our study focused on resected PDAC patients and explored the effect of angiotensin system inhibitors (ASI). Methods: We retrospectively reviewed all resected PDAC patients in UPMC between 2010-2019. To estimate the effect of ASI on patient survivals, we performed Kaplan-Meier analysis, Cox Proportional Hazards model, Propensity Score Matching (PSM), and inverse propensity score weighted (IPW) analysis. Results: 742 patients were included in this analysis. The average age is 67.0 years old, with a median follow-up of 24.1 months. ASI users are older (68.9 vs. 65.3, p<0.001) and with more comorbidities. The use of ASI is associated with significantly longer overall survival in univariate (HR=0.76 [0.67-0.86], p=0.004) and multivariate (HR=0.71 [0.57-0.89], p=0.003) adjusted analysis. In propensity score-matched cohort of 422 patients, ASI use is again associated with longer overall survival (HR = 0.74 [0.58-0.94], p=0.014) and a longer interval to disease progression in the liver and lung, but not local recurrence. Lastly, using inverse probability weighting (IPW) analysis on the whole cohort of 742 patients showed that the use of ASI is associated with an average treatment effect on the treated (ATT) of HR=0.67 [0.53-0.85] (p<0.001) for overall survival. Conclusion: This retrospective study demonstrated a significant association in ASI use and longer survival in resected PDAC patients, using unadjusted and multivariate-adjusted models. Further prospective trial on resectable PDAC is needed.

Promena paradigme u lečenju hronične srčane insuficijencije po ESC vodiču 2021 - novi inovativni lekovi u fokusu

Medical, primarily drug therapy directed by the New ESC Guide or Guidelines for Patients with Heart Failure (HF) brings significant innovations and changes in the treatment paradigm, from the gradual introduction of drugs to the simultaneous introduction of 5 main classes of drugs. Treatment of heart failure with reduced left ventricular ejection fraction (HFrEF) and symptoms of class II-New York Heart Association (NYHA) -dispnea at higher exertion and higher NYHA classes, now includes angiotensin receptor inhibitor neprilysin (ARNI) as a substitute for angiotenzin convertase enzyme inhibitor( ACEI). Another significant innovation is the addition of SGLT-2 inhibitors (SGLT2i = sodium-glucose channel cotransporter-2 inhibitors). SGLT2i: dapagliflozin or empagliflozin are now in the first line of therapy for heart failure, along with the introduction of beta-blockers (BB), ACEI or ARNI, mineralocorticotide receptor inhibitors (MRAs) and Henle's loop diuretics in fluid retention as recommended in Class I. Sacubitril-valsartan, a combined neprilysin and angiotensin inhibitor (ARNI), was introduced in the reduced left ventricular ejection fraction (HFrEF) and showed an additional reduction in CV mortality and hospitalization due to HFrEF compared to the ACE inhibitor enalapril. Dapagliflozin and empagliflozin reduce the risk of cardiovascular mortality or hospitalization due to HF in patients with HF and reduced left ventricular ejection fraction &lt;40% (HFrEF), but empagliflozin has recently shown an effect in HFpEF with an ejection fraction of 65% of 40%.