The Salutary Effects of Diminazene, Lisinopril or Valsartan on Cisplatin - Induced Acute Kidney Injury in Rats: A Comparative Study.

Nephrotoxicity as a cause of acute kidney injury (AKI) induced by cisplatin (CP), limits its usefulness as an anticancer agent. Diminazene, an angiotensin converting enzyme 2 activator, exhibited renoprotective properties on rat models of kidney diseases. This research aims to investigate the salutary effect of diminazene in comparison with lisinopril or valsartan in CP-induced AKI. The first and second groups of rats received oral vehicle (distilled water) for 9 days, and saline injection or intraperitoneal CP (6 mg/kg) on day 6, respectively. Third, fourth, and fifth groups received intraperitoneal injections of CP on day 6 and diminazene (15 mg/kg/day, orally), lisinopril (10 mg/kg/day, orally), or valsartan (30 mg/kg/day, orally), for 9 days, respectively. 24h after the last day of treatment, blood and kidneys were removed under anesthesia for biochemical and histopathological examination. Urine during the last 24 h before sacrificing the rats was also collected. CP significantly increased plasma urea, creatinine, neutrophil gelatinase-associated lipocalin, calcium, phosphorus, and uric acid. It also increased urinary albumin/creatinine ratio, N-Acetyl-beta-D-Glucosaminidase/creatinine ratio, and reduced creatinine clearance, as well the plasma concentrations of inflammatory cytokines [plasma tumor necrosis factor-alpha, and interleukin-1beta], and significantly reduced antioxidant indices [catalase, glutathione reductase , and superoxide dismutase]. Histopathologically, CP treatment caused necrosis of renal tubules, tubular casts, shrunken glomeruli, and increased renal fibrosis. Diminazine, lisinopril, and valsartan ameliorated CP-induced biochemical and histopathological changes to a similar extent. The salutary effect of the three drugs used is, at least partially, due to their anti-inflammatory and antioxidant effects. Keywords: Cisplatin, Diminazene, ACE2 activator, Lisinopril, Valsartan, Acute kidney injury.

Evaluating the impact of Sacubitril/valsartan on diastolic function in patients with heart failure: A systematic review and meta-analysis.

BACKGROUND: Heart failure is a common and severe condition, often complicated by diastolic dysfunction. Current standard therapies such as ACEIs and ARBs have limited efficacy in managing diastolic function. Sacubitril/Valsartan, an emerging therapy, warrants rigorous investigation to elucidate its impact on diastolic function in heart failure patients. METHODS: This systematic review and meta-analysis were conducted adhering to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and utilized the PICO schema. Searches were performed on 4 databases-PubMed, Embase, Web of Science, and Cochrane Library-without temporal restrictions. Inclusion and exclusion criteria were strictly defined, and quality assessments were conducted using the Cochrane Collaboration Risk of Bias tool. Both fixed-effects and random-effects models were used for statistical analysis, depending on inter-study heterogeneity assessed by I2 statistics and Chi-square tests. RESULTS: Out of 1129 identified publications, 8 studies met the criteria and were included in the meta-analysis. These studies consisted of both randomized controlled trials and cohort studies and featured diverse global populations. Significant reductions were found in the echocardiographic parameter E/e' ratio and LAVi upon treatment with Sacubitril/Valsartan compared to standard therapies, with mean differences of -1.38 and -4.62, respectively, both with P values < .01. CONCLUSIONS: This meta-analysis demonstrates that Sacubitril/Valsartan significantly improves diastolic function parameters in heart failure patients compared to standard treatments. These findings underscore the potential benefits of Sacubitril/Valsartan in the management of heart failure, particularly for patients with diastolic dysfunction.

Sacubitril-valsartan vs ACE/ARB in pediatric heart failure: A retrospective cohort study.

BACKGROUND: The first angiotensin receptor/neprilysin inhibitor on the market, sacubitril-valsartan, has shown marked improvements in death and hospitalization for heart failure among adults, and is now approved for use in pediatric heart failure. While the ongoing PANORAMA-HF trial is evaluating the effectiveness of sacubitril-valsartan for pediatric patients with a failing systemic left ventricle, the enrollment criteria do not include the majority of pediatric heart failure patients. Additional studies are needed. METHODS: Using the TriNetX database, we performed a propensity score matched, retrospective cohort study to assess the incidence of a composite of all-cause mortality or heart transplant within 1 year. The 519 patients who received sacubitril-valsartan were compared to 519 matched controls who received an angiotensin converting enzyme inhibitor (ACE) or angiotensin II receptor blocker (ARB). RESULTS: There was no significant difference in the incidence of the composite outcome with sacubitril-valsartan over an ACE/ARB (13.3% vs 13.2%, p = 0.95), or among the components of mortality (5.0% vs 5.8%, p = 0.58) or heart transplantation (8.7% vs 7.5%, p = 0.50). Patients who were receiving full goal-directed medical therapy (14.4% vs 16.0%, p = 0.55) also showed no difference in the composite outcome. We observed a significantly increased incidence of hypotension (10% vs 5.2%, p = 0.006) and a trend toward reduced number of hospitalizations per year (mean (SD) 1.3 (4.4) vs 2.0 (9.1), p = 0.09). CONCLUSIONS: Sacubitril-valsartan is not associated with a decrease in the composite of all-cause mortality or heart transplantation within 1 year. Future studies should evaluate the possible reduction in hospitalizations and optimal dosing to minimize hypotension.

DRUG RELATED NITROSOGENESIS, PHOTOCARCINOGENESIS AND ONCOPHARMACOGENESIS OF NODULAR MELANOMA: A CASE RELATED ANALYSIS CONCERNING THE POLYCONTAMINATION OF THE POLYMEDICATION WITH VALSARTAN/HYDROCHLOROTHIAZIDE AND BISOPROLOL.

Despite the fact that the pathogenesis of cutaneous melanoma is shrouded in mystery, factors that have been neglected or unnoticed until now have come to the attention in recent years, and in all likelihood, they could also be pivotal. These factors, known as nitrosamines or NDSRIs, are characterized by high carcinogenic and mutagenic potency, and some of them have demonstrated these properties to human DNA as well. Unfortunately, these ingredients also turn up as contaminants in about 300 of the most widely distributed drugs worldwide. According to the most recent literature, some of these ingredients are also identified as potent photocarcinogens, as well as human carcinogens. The intake of these carcinogens in the context of polycontamination of polymedication, has been associated for years with the occurrence of melanomas. The need for cataloguing of nitrosamines , as well as their accurate labelling on drug packaging, would help to classify them even more accurately as carcinogens affecting human DNA. We present once again a patient , who developed nodular melanoma within the context of the intake of 3 potentially nitrosamine/ NDSRIs contaminated antihypertensive drugs (valsartan/ Hydrochlorothiazide/ bisoprolol). Pathogenetic aspects concerning drug-induced nitrosogenesis, photocarcinogenesis and oncopharmacogenesis of skin cancer are discussed. Nitrosogenesis' of Cancer as concept in the medical literature has been known for decades, but in relation to other forms of human cancer. Exogenously mediated drug-mediated nitrosogenesis is a logically conditioned and newly defined concept whose significance with respect to the clinical manifestation of skin cancer is only beginning to grow.

Effect of Sacubitril/Valsartan on Patients Having Heart Failure With Preserved Left Ventricular Ejection Fraction Undergoing Hemodialysis: A Long-term Observational Study.

BACKGROUND/AIM: Sacubitril/valsartan (SV), a novel pharmacological class of angiotensin receptor neprilysin inhibitors, is effective in treating heart failure (HF) by inhibiting the degradation of natriuretic peptides and the renin-angiotensin-aldosterone system. However, no studies have observed the long-term effects of SV on patients with HF and preserved left ventricular ejection fraction (LVEF) undergoing hemodialysis (HD) over a long period. PATIENTS AND METHODS: This single-center retrospective study of 21 months duration involved consecutive patients with HF and preserved LVEF undergoing HD, who received 50-200 mg/day. All patients were followed up regularly, and clinical, biochemical, and echocardiographic parameters were recorded at baseline and during follow-up. The efficacy and safety of SV were also analyzed. RESULTS: This longitudinal study included nine patients, with a median age of 76 years. The median HD duration was 7 years. At baseline, the mean brain natriuretic peptide (BNP) was 133±73.6 pg/ml and that of LVEF was 66%±9%. After SV therapy, the systolic blood pressure, diastolic blood pressure, and heart rate decreased, albeit without statistical significance. BNP levels, LVEF, left atrial anteroposterior dimension, and left ventricular mass index did not change, compared to baseline values. No adverse effects were observed in any of the patients. CONCLUSION: SV tended to decrease blood pressure and heart rate in patients with HF and preserved LVEF undergoing HD but did not alter cardiac function assessments, such as BNP or echocardiography.

Comparison of sacubitril/valsartan with olmesartan for hypertension: A meta-analysis of randomized controlled trials.

INTRODUCTION: The efficacy of sacubitril/valsartan versus olmesartan remains controversial for the control of hypertension. We conduct a systematic review and meta-analysis to explore the influence of sacubitril/valsartan versus olmesartan on the control of hypertension. METHODS: We have searched PubMed, Embase, Web of science, EBSCO, and Cochrane library databases through July 2023 for randomized controlled trials assessing the effect of sacubitril/valsartan versus olmesartan on the control of hypertension. This meta-analysis is performed using the random-effect model or fixed-effect model based on the heterogeneity. RESULTS: Seven randomized controlled trials and 3677 patients were included in the meta-analysis. Overall, compared with olmesartan treatment for hypertension, sacubitril/valsartan treatment was associated with substantially decreased systolic blood pressure (mean difference [MD] = -4.58; 95% confidence interval [CI] = -7.90 to -1.25; P = .007), diastolic blood pressure (MD = -1.70; 95% CI = -3.24 to -0.17; P = .03), and pulse pressure (MD = -2.31; 95% CI = -4.41 to -0.21; P = .03), as well as improved systolic blood pressure control (odds ratio [OR] = 1.65; 95% CI = 1.15 to 2.38; P = .006), but had no influence on diastolic blood pressure control (OR = 1.33; 95% CI = 0.93 to 1.88; P = .11) or adverse events (OR = 1.06; 95% CI = 0.90 to 1.24; P = .51). CONCLUSIONS: Sacubitril/valsartan is better than olmesartan for the reduction of blood pressure for patients with hypertension.

Bilateral renal artery revascularisation in heart failure.

Renal artery stenosis can complicate the management of heart failure with reduced ejection fraction, as it is a conventional contraindication to the use of ACE inhibitors. We report a case in which bilateral renal artery revascularisation allowed the safe reintroduction of enalapril (and subsequently sacubitril valsartan) in a patient with severe left ventricular systolic dysfunction. There is a role for renal artery angioplasty in selected patients to allow optimal medical therapy for patients with heart failure due to impaired systolic function.

Sacubitril/Valsartan inhibits M1 type macrophages polarization in acute myocarditis by targeting C-type natriuretic peptide.

Studies have shown that Sacubitril/valsartan (Sac/Val) can reduce myocardial inflammation in myocarditis mice, in addition to its the recommended treatment of heart failure. However, the underlying mechanisms of Sac/Val in myocarditis remain unclear. C-type natriuretic peptide (CNP), one of the targeting natriuretic peptides of Sac/Val, was recently reported to exert cardio-protective and anti-inflammatory effects in cardiovascular systems. Here, we focused on circulating levels of CNP in patients with acute myocarditis (AMC) and whether Sac/Val modulates inflammation by targeting CNP in experimental autoimmune myocarditis (EAM) mice as well as LPS-induced RAW 264.7 cells and bone marrow derived macrophages (BMDMs) models. Circulating CNP levels were higher in AMC patients compared to healthy controls, and these levels positively correlated with the elevated inflammatory cytokines IL-6 and monocyte count. In EAM mice, Sac/Val alleviated myocardial inflammation while augmenting circulating CNP levels rather than BNP and ANP, accompanied by reduction in intracardial M1 macrophage infiltration and expression of inflammatory cytokines IL-1ß, TNF-α, and IL-6. Furthermore, Sac/Val inhibited CNP degradation and directly blunted M1 macrophage polarization in LPS-induced RAW 264.7 cells and BMDMs. Mechanistically, the effects might be mediated by the NPR-C/cAMP/JNK/c-Jun signaling pathway apart from NPR-B/cGMP/NF-κB pathway. In conclusion, Sac/Val exerts a protective effect in myocarditis by increasing CNP concentration and inhibiting M1 macrophages polarization.

Sacubitril/valsartan alleviates sunitinib-induced cardiac fibrosis and oxidative stress via improving TXNIP/TRX system and downregulation of NF-ĸB/Wnt/ß-catenin/SOX9 signaling.

We aimed in this study to investigate the possible cardioprotective effects of sacubitril/valsartan against sunitinib-induced cardiac fibrosis (CF) and oxidative stress via targeting thioredoxin-interacting protein/thioredoxin (TXNIP/TRX) system and nuclear factor-kappa B (NF-κB)/Wingless-related MMTV integration site (Wnt)/ß-catenin/Sex-determining region Y box 9 (SOX9) signaling. CF was induced in male Wistar albino rats by cumulative dose of sunitinib (300 mg/kg, given over 4 weeks as: 25 mg/kg orally, three times a week), which were co-treated with sacubitril/valsartan (68 mg/kg/day, orally) for four weeks. Significant elevation in blood pressure, cardiac inflammatory and fibrotic markers besides cardiac dysfunction were observed. These alterations were associated with disruption of TXNIP/TRX system, upregulation of NF-κB/Wnt/ß-catenin/SOX9 pathway along with marked increase in lysyl oxidase (LOX) and matrix metalloproteinase-1 (MMP-1) expressions and extensive deposition of collagen fibers in cardiac tissues. Luckily, sacubitril/valsartan was able to reverse all of the aforementioned detrimental effects in sunitinib-administered rats. These findings illustrate a potential role of sacubitril/valsartan in alleviating CF and oxidative stress induced by sunitinib via antioxidant, anti-inflammatory and antifibrotic properties. These remarkable effects of sacubitril/valsartan were mediated by its ability to improve TXNIP/TRX system and downregulate NF-κB/Wnt/ß-catenin/SOX9 signaling in addition to decreasing LOX and MMP-1 expressions in cardiac tissues. In summary, this study highlights sacubitril/valsartan as a potential therapeutic agent in mitigating CF and oxidative stress especially in cancer cases treated with sunitinib.

Effects of the valsartan recall on heart failure patients: A nationwide analysis.

BACKGROUND: Valsartan is commonly used for cardiac conditions. In 2018, the Food and Drug Administration recalled generic valsartan due to the detection of impurities. Our objective was to determine if heart failure patients receiving valsartan at the recall date had a greater likelihood of unfavorable outcomes than patients using comparable antihypertensives. METHODS: We conducted a cohort study of Optum's de-identified Clinformatics® Datamart (July 2017-January 2019). Heart failure patients with commercial or Medicare Advantage insurance who received valsartan were compared to persons who received non-recalled angiotensin receptor blockers (ARBs) and angiotensin converting enzyme-inhibitors (ACE-Is) for 1 year prior and including the recall date. Outcomes included a composite for all-cause hospitalization, emergency department (ED), and urgent care (UC) use and a measure of cardiac events which included hospitalizations for acute myocardial infarction and hospitalizations/ED/UC visits for stroke/transient ischemic attack, heart failure or hypertension at 6-months post-recall. Cox proportional hazard models with propensity score weighting compared the risk of outcomes between groups. RESULTS: Of the 87 130 adherent patients, 15% were valsartan users and 85% were users of non-recalled ARBs/ACE-Is. Valsartan use was not associated with an increased risk of all-cause hospitalization/ED/UC use six-months post-recall (HR 1.00; 95% CI 0.96-1.03), compared with individuals taking non-recalled ARBs/ACE-Is. Similarly, cardiac events 6-months post-recall did not differ between individuals on valsartan and non-recalled ARBs/ACE-Is (HR 1.04; 95% CI 0.97-1.12). CONCLUSIONS: The valsartan recall did not affect short-term outcomes of heart failure patients. However, the recall potentially disrupted the medication regimens of patients, possibly straining the healthcare system.

Modulation of TNF-α, interleukin-6, and interleukin-10 by nebivolol-valsartan and nebivolol-lisinopril polytherapy in SHR rats.

Antihypertensive drug therapies have demonstrated their capacity to modulate the inflammatory processes associated with hypertension, leading to improvements in disease progression. Given the prevalent use of polytherapy in treating most hypertensive patients, comprehending the time-dependent effects of combination treatments on inflammation becomes imperative. In this study, spontaneously hypertensive rats (SHR) were divided into seven groups (n = 6): (i) SHR + vehicle, (ii) SHR + nebivolol, (iii) SHR + valsartan, (iv) SHR + lisinopril, (v) SHR + nebivolol-valsartan, (vi) SHR + nebivolol-lisinopril, and (vii) WKY + vehicle. Blood pressure was measured using the tail-cuff method. Temporal alterations in inflammatory cytokines TNF-α, IL-6, and IL-10 were assessed in serum through ELISA and mRNA expression in aortic tissue via qPCR after 1, 2, and 4 weeks of treatment with nebivolol, lisinopril, valsartan, and their respective combinations. Histological alterations in the aorta were assessed. The findings indicated that combined treatments reduced systolic and diastolic blood pressure in SHR. The nebivolol and lisinopril combination demonstrated a significant decrease in IL-6 serum and mRNA expression at both 1 week and 4 weeks into the treatment. Additionally, TNF-α mRNA expression also showed a reduction with this combination at the same time points. Particularly, nebivolol-valsartan significantly decreased TNF-α serum and mRNA expression after one and four weeks of treatment. Furthermore, an elevation in serum IL-10 levels was observed with both combination treatments starting from the second week onwards. This study provides compelling evidence that concurrent administration of nebivolol with lisinopril or valsartan exerts time-dependent effects, reducing proinflammatory cytokines TNF-α and IL-6 while modifying IL-10 levels in an experimental hypertensive model.

Sacubitril/Valsartan in Patients Hospitalized With Decompensated Heart Failure.

BACKGROUND: The efficacy and safety of sacubitril/valsartan in patients hospitalized with heart failure (HF) across the spectrum of left ventricular ejection fraction (EF) has not been described. OBJECTIVES: Data from randomized trials of sacubitril/valsartan in HF patients with EF ≤40% (PIONEER-HF [Comparison of Sacubitril/Valsartan Versus Enalapril on Effect of NT-proBNP in Patients Stabilized From an Acute Heart Failure Episode] trial) and >40% (PARAGLIDE-HF [Prospective comparison of ARNI with ARB Given following stabiLization In DEcompensated HFpEF] trial) following recent worsening heart failure (WHF) were pooled to examine treatment effect across the EF spectrum. METHODS: The PIONEER-HF and PARAGLIDE-HF trials were double-blind, randomized trials of sacubitril/valsartan vs control therapy (enalapril or valsartan, respectively). All participants in the PIONEER-HF trial and 69.5% in the PARAGLIDE-HF trial were enrolled during hospitalization for HF after stabilization. The remainder in the PARAGLIDE-HF trial were enrolled ≤30 days after a WHF event. The primary endpoint of both trials was time-averaged proportional change in N-terminal pro-B-type natriuretic peptide (NT-proBNP) from baseline through weeks 4 and 8. Adjudicated clinical endpoints were analyzed through the end of follow-up, adjusting for trial. RESULTS: The pooled analysis included 1,347 patients (881 from PIONEER-HF, 466 from PARAGLIDE-HF). Baseline characteristics included median age 66 years, 36% women, 31% Black, 34% de novo HF, and median EF 30%. The reduction in NT-proBNP was 24% greater with sacubitril/valsartan vs control therapy (n = 1,130; ratio of change = 0.76; 95% CI: 0.69-0.83; P < 0.0001). Cardiovascular death or hospitalization for HF was reduced by 30% with sacubitril/valsartan vs control therapy (HR: 0.70; 95% CI: 0.54-0.91; P = 0.0077). This effect was consistent across the spectrum of EF ≤60%. Sacubitril/valsartan increased symptomatic hypotension (risk ratio: 1.35; 95% CI: 1.05-1.72). CONCLUSIONS: In patients stabilized after WHF, sacubitril/valsartan led to a greater reduction in plasma NT-proBNP and improved clinical outcome compared with control therapy, in particular across the spectrum of EF ≤60%. (Comparison of Sacubitril/Valsartan Versus Enalapril on Effect of NT-proBNP in Patients Stabilized From an Acute Heart Failure Episode [PIONEER-HF]; NCT02554890; Changes in NT-proBNP, Safety, and Tolerability in HFpEF Patients With a WHF Event [HFpEF Decompensation] Who Have Been Stabilized and Initiated at the Time of or Within 30 Days Post-decompensation [PARAGLIDE-HF]; NCT03988634).

Effect of sacubitril/valsartan on the hypertensive heart in continuous light-induced and lactacystin-induced pre-hypertension: Interactions with the renin-angiotensin-aldosterone system.

This study investigated whether sacubitril/valsartan or valsartan are able to prevent left ventricular (LV) fibrotic remodelling and dysfunction in two experimental models of pre-hypertension induced by continuous light (24 hours/day) exposure or by chronic lactacystin treatment, and how this potential protection interferes with the renin-angiotensin-aldosterone system (RAAS). Nine groups of three-month-old male Wistar rats were treated for six weeks as follows: untreated controls (C), sacubitril/valsartan (ARNI), valsartan (Val), continuous light (24), continuous light plus sacubitril/valsartan (24+ARNI) or valsartan (24+Val), lactacystin (Lact), lactacystin plus sacubitil/valsartan (Lact+ARNI) or plus valsartan (Lact+Val). Both the 24 and Lact groups developed a mild but significant systolic blood pressure (SBP) increase, LV hypertrophy and fibrosis, as well as LV systolic and diastolic dysfunction. Yet, no changes in serum renin-angiotensin were observed either in the 24 or Lact groups, though aldosterone was increased in the Lact group compared to the controls. In both models, sacubitril/valsartan and valsartan reduced elevated SBP, LV hypertrophy and fibrosis and attenuated LV systolic and diastolic dysfunction. Sacubitril/valsartan and valsartan increased the serum levels of angiotensin (Ang) II, Ang III, Ang IV, Ang 1-5, Ang 1-7 in the 24 and Lact groups and reduced aldosterone in the Lact group. We conclude that both continuous light exposure and lactacystin treatment induced normal-to-low serum renin-angiotensin models of pre-hypertension, whereas aldosterone was increased in lactacystin-induced pre-hypertension. The protection by ARNI or valsartan in the hypertensive heart in either model was related to the Ang II blockade and the protective Ang 1-7, while in lactacystin-induced pre-hypertension this protection seems to be additionally related to the reduced aldosterone level.

Association Between Use of Sodium-Glucose Cotransporter-2 Inhibitors or Angiotensin Receptor-Neprilysin Inhibitor and the Risk of Atherosclerotic Cardiovascular Disease With Coexisting Diabetes and Heart Failure.

PURPOSE: This study was to investigate the association between the use of Sodium-glucose Cotransporter-2 inhibitors (SGLT2i) or angiotensin receptor-neprilysin inhibitor (ARNI; ie, Sacubitril + valsartan, Product name ENTRESTO) and the risk of atherosclerotic cardiovascular disease (ASCVD) in patients with coexisting diabetes and heart failure. Specifically, the study compared outcomes between patients using SGLT2i or valsartan + sacubitril and those not using these medications. METHODS: This study utilized data from the National Health Insurance Research Database (NHIRD) from 2017 to 2018. The case group consisted of 8691 patients with coexisting diabetes and heart failure who did not use SGLT2i or Entresto, while the control group consisted of 8691 patients with coexisting diabetes and heart failure who used SGLT2i or Entresto. The primary outcome was ASCVD, including a composite of cardiovascular death and hospitalization for worsening heart failure. Secondary outcomes included all-cause death, cause of cardiovascular death, and recurrence of heart failure, non-fatal myocardial infarction, non-fatal stroke (including ischemic stroke and hemorrhagic stroke) and new renal replacement therapy. RESULTS: The study found that the use of SGLT2 inhibitors or ARNI was associated with a lower risk of ASCVD in patients with coexisting diabetes and heart failure. CONCLUSION: The study suggests that the use of SGLT2 inhibitors, alone or in combination with Entresto, may be effective in reducing the risk of ASCVD and its associated adverse outcomes in patients with diabetes and heart failure. This finding has important implications for the management of these conditions.

[Decompensation of Heart Failure in "Fragile" Patients: Clinical Features and Approaches to Therapy].

AIM: To evaluate the impact of frailty syndrome (FS) on the course of acute decompensated heart failure (ADHF) and the quality of drug therapy before discharge from the hospital in patients with reduced and moderately reduced left ventricular ejection fraction (LVEF). MATERIAL AND METHODS: This open prospective study included 101 patients older than 75 years with reduced and mid-range LVEF hospitalized for decompensated chronic heart failure (CHF). FS was detected during the outpatient follow-up and identified using the Age is Not a Hindrance questionnaire, the chair rise test, and the One Leg Test. The "fragile" group consisted of 54 patients and the group without FS included 47 patients. Clinical characteristics of patients were compared, and the prescribing rate of the main drugs for the treatment of CHF was assessed upon admission to the hospital. The sacubitril/valsartan or dapagliflozin therapy was initiated in the hospital; prescribing rate of the quadruple therapy was assessed upon discharge from the hospital. Patients with reduced LVEF were followed up for 30 days, and LVEF was re-evaluated to reveal possible improvement due to optimization of therapy during hospitalization. Statistical analysis was performed with the SPSS 23.0 software. RESULTS: The main causes for decompensation did not differ in patients of the compared groups. According to the correlation analysis, FS was associated with anemia (r=0.154; p=0.035), heart rate ≥90 bpm (r=0.185; p=0.020), shortness of breath at rest (r =0.224; p=0.002), moist rales in the lungs (r=0.153; p=0.036), ascites (r=0.223; p=0.002), increased levels of the N-terminal pro-brain natriuretic peptide (NT-proBNP) (r= 0.316; p<0.001), hemoglobin concentration <120 g / l (r=0.183; p=0.012), and total protein <65 g / l (r=0.153; p=0.035) as measured by lab blood tests. Among patients with LVEF ≤40 % in the FS group (n=33) and without FS (n=33), the quadruple therapy was a part of the treatment regimen at discharge from the hospital in 27.3 and 3.0 % of patients, respectively (p=0.006). According to the 30-day follow-up data, improvement of LVEF was detected in 18.2% of patients with LVEF ≤40% in the FS group and 12.1% of patients with LVEF ≤40% in the FS-free group (p=0.020). In patients with LVEF 41-49 % in the FS (n=21) and FS-free (n=14) groups, the prescribing rate of the optimal therapy, including sacubitril/valsartan, sodium-glucose cotransporter 2 inhibitors, beta-blockers, and mineralocorticoid receptor antagonists, no statistically significant differences were detected (14.3 and 7.1 %, respectively; p=0.515) at discharge from the hospital. CONCLUSION: Patients with ADHF and FS showed more pronounced clinical manifestations of decompensation, anemia, heart rate ≥90 beats/min, and higher levels of NT-proBNP upon admission. The inpatient therapy with sacubitril/valsartan or dapagliflozin was more intensively initiated in FS patients with reduced LVEF. An individualized approach contributed to achieving a prescribing rate of sacubitril/valsartan of 39.4%, dapagliflozin of 39.4%, and quadruple therapy of 27.3% upon discharge from the hospital.

Pharmacological inhibition of the ACE/Ang-2/AT1 axis alleviates mechanical ventilation-induced pulmonary fibrosis.

Mechanical ventilation (MV) is an essential therapy for acute respiratory distress syndrome (ARDS) and pulmonary fibrosis. However, it can also induce mechanical ventilation-induced pulmonary fibrosis (MVPF) and the underlying mechanism remains unknown. Based on a mouse model of MVPF, the present study aimed to explore the role of the angiotensin-converting enzyme/angiotensin II/angiotensin type 1 receptor (ACE/Ang-2/AT1R) axis in the process of MVPF. In addition, recombinant angiotensin-converting enzyme 2(rACE2), AT1R inhibitor valsartan, AGTR1-directed shRNA and ACE inhibitor perindopril were applied to verify the effect of inhibiting ACE/Ang-2/AT1R axis in the treatment of MVPF. Our study found MV induced an inflammatory reaction and collagen deposition in mouse lung tissue accompanied by the activation of ACE in lung tissue, increased concentration of Ang-2 in bronchoalveolar lavage fluid (BALF), and upregulation of AT1R in alveolar epithelial cells. The process of pulmonary fibrosis could be alleviated by the application of the ACE inhibitor perindopril, ATIR inhibitor valsartan and AGTR1-directed shRNA. Meanwhile, rACE2 could also alleviate MVPF through the degradation of Ang-2. Our finding indicated the ACE/Ang-2/AT1R axis played an essential role in the pathogenesis of MVPF. Pharmacological inhibition of the ACE/Ang-2/AT1R axis might be a promising strategy for the treatment of MVPF.

Sacubitril/valsartan can improve the cardiac function in heart failure patients with a history of cancer: An observational study.

Sacubitril/Valsartan, the combination of angiotensin receptor inhibitor and neprilysin inhibitor, is now becoming the class 1 recommendation for HFrEF. Some studies have shown the positive effect of Sacubitril/Valsartan on HFrEF cancer patients, while there is devoid of evidence about the effect of this drug in aged cancer patients with HFmrEF and HFpEF. By searching the patients with a diagnosis of both cancer and Heart failure (HF) over 65, the patients who had received treatment with Sacubitril/Valsartan were selected as the candidates for Sacubitril/Valsartan group, and the patients who had received conventional HF therapy without Sacubitril/Valsartan were chosen as the control group. Data were collected for up to 9 months. We filtered 38 patients and 50 patients valid for Sacubitril/Valsartan group and control group, respectively. After initiation of heart failure management, our study found a better cardiac condition in Sacubitril/Valsartan group, having better LVEF, LVFS, NT-proBNP in 3rd, 6th, 9th month (P < .05) and better NYHA function classification after the treatment. We also observed fewer cases of deterioration on LAD (P = .029) and LVEDD (P = .023) in Sacubitril/Valsartan group. In subgroup analysis, our study showed that all 3 kinds of HF patients had better LVEF, LVFS, and NT-proBNP in Sacubitril/Valsartan group (P < .05). Our study further indicated that Sacubitril/Valsartan can improve cardiac function and benefit cardiac remolding in aged cancer patients of all 3 kinds of HF. This is the first study to provide new evidence for the use of Sacubitril/Valsartan in aged cancer patients of 3 kinds of HF.

Sacubitril/Valsartan-Related Hypotension in Patients With Heart Failure and Preserved or Mildly Reduced Ejection Fraction.

BACKGROUND: Hypotension is a potential adverse effect of sacubitril/valsartan, but there are limited data regarding the predictors and implications of treatment-related hypotension in heart failure (HF) with mildly reduced and preserved ejection fraction. OBJECTIVES: We investigated predictors of treatment-associated hypotension, clinical outcomes after hypotension, and the relationship between left ventricular ejection fraction (LVEF) and incidence of hypotension in the PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in HF with Preserved Ejection Fraction) trial. METHODS: PARAGON-HF randomized patients with chronic HF (≥45%) to sacubitril/valsartan or valsartan. Following randomization, hypotension was defined as investigator-reported hypotension with a systolic blood pressure <100 mm Hg. Predictors of hypotension were assessed using multivariable Cox models. Associations between hypotension and clinical outcomes were evaluated in time-updated Cox models. The relationship among treatment, LVEF, and incident rates of hypotension and clinical outcomes was estimated using Poisson regression models. RESULTS: Of 4,796 patients in PARAGON-HF, 637 (13%) experienced hypotension, more frequently in the sacubitril/valsartan arm (P < 0.001). Following documented hypotension, patients had higher risk of cardiovascular death and total HF hospitalizations (adjusted RR: 1.63; 95% CI: 1.27-2.09; P < 0.001) and all-cause death (adjusted HR: 1.62; 95% CI: 1.28-2.05; P < 0.001). LVEF modified the association between sacubitril/valsartan and risk of hypotension (Pinteraction = 0.019) such that patients with LVEF ≥60% experienced substantially higher treatment-related risks of hypotension. CONCLUSIONS: In PARAGON-HF, a higher LVEF was associated with an increased risk of hypotension in patients treated with sacubitril/valsartan compared with valsartan. Because these subjects are also less likely to derive clinical benefit from sacubitril/valsartan, our data reinforce that the benefit/risk ratio favors the use of sacubitril/valsartan in patients with LVEF below normal, but not at higher LVEF. (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711).

Angiotensin Receptor-Neprilysin Inhibition (Sacubitril/Valsartan) Reduces Structural Arterial Stiffness in Middle-Aged Mice.

BACKGROUND: Increasing arterial stiffness is a prominent feature of the aging cardiovascular system. Arterial stiffening leads to fundamental alterations in central hemodynamics with widespread detrimental implications for organ function resulting in significant morbidity and death, and specific therapies to address the underlying age-related structural arterial remodeling remain elusive. The present study investigates the potential of the recently clinically available dual angiotensin receptor-neprilysin inhibitor (ARNI) sacubitril/valsartan (LCZ696) to counteract age-related arterial fibrotic remodeling and stiffening in 1-year-old mice. METHODS AND RESULTS: Treatment of in 1-year-old mice with ARNI (sacubitril/valsartan), in contrast to angiotensin receptor blocker monotherapy (valsartan) and vehicle treatment (controls), significantly decreases structural aortic stiffness (as measured by in vivo pulse-wave velocity and ex vivo aortic pressure myography). This phenomenon appears, at least partly, independent of (indirect) blood pressure effects and may be related to a direct antifibrotic interference with aortic smooth muscle cell collagen production. Furthermore, we find aortic remodeling and destiffening due to ARNI treatment to be associated with improved parameters of cardiac diastolic function in aged mice. CONCLUSIONS: This study provides preclinical mechanistic evidence indicating that ARNI-based interventions may counteract age-related arterial stiffening and may therefore be further investigated as a promising strategy to improve cardiovascular outcomes in the elderly.