Efficacy and Safety of Sacubitril/Valsartan in Hemodialysis Patients with Chronic Heart Failure: A Retrospective Study at a Single Center.

BACKGROUND Heart failure and end-stage renal disease often coexist, and management of heart failure can be challenging in patients during hemodialysis. Sacubitril-valsartan (SV) is the first drug to receive regulatory approval for use in patients with chronic heart failure with reduced ejection fraction (HFrEF) and New York Heart Association (NYHA) classification II, III, or IV. This study aimed to evaluate the efficacy and safety of SV for use in chronic heart failure patients on maintenance hemodialysis (MHD). MATERIAL AND METHODS From September 2021 to October 2022, 28 patients on MHD with chronic heart failure at the hemodialysis center of Shaanxi Second Provincial People's Hospital were regularly followed. During the 12-week follow-up period, all patients were administered SV at doses of 100-400 mg per day. Biochemical indicators, echocardiographic parameters, life quality scores, and adverse events were evaluated. RESULTS We enrolled 28 patients. Compared with the baseline levels, NYHA class III in these patients treated with SV was significantly decreased from 60.71% to 32.14% (P<0.05), left ventricular ejection fraction (LVEF) was significantly improved from 44.29±8.92% to 53.32±7.88% (P<0.001), the Physical Component Summary (PCS) score was significantly improved from 40.0±6.41 to 56.20±9.86 (P<0.001), and the Mental Component Summary (MCS) score was significantly improved from 39.99±6.14 to 52.59±11.0 (P<0.001). CONCLUSIONS We demonstrated that SV improved NYHA classification and LVEF values of patients on MHD with chronic heart failure and also improved their quality of life.

Effect of sacubitril/valsartan on hospital readmissions in heart failure with reduced ejection fraction in Saudi Arabia: A multicenter retrospective cohort study.

Sacubitril/valsartan is an angiotensin receptor neprilysin inhibitor (ARNI) that has been shown in multiple clinical trials to have clinical benefits and is recommended by major clinical management guidelines as a first-line treatment for heart failure with reduced ejection fraction (HFrEF). The most significant benefit that was observed in clinical trials is its effect in reducing hospital readmissions. However, little evidence supports its effectiveness in practice, especially in Saudi Arabia. A multicenter retrospective cohort study was conducted using the patient medical records at 2 tertiary hospitals in Saudi Arabia. Eligible patients were adults (≥18 years old) with a confirmed diagnosis of HFrEF who were discharged on either sacubitril/valsartan or angiotensin-converting enzyme inhibitors (ACEI)/angiotensin receptor blockers (ARB) in addition to the other recommended therapy for HFrEF. The primary endpoint was the all-cause 30-day readmission rate. The secondary endpoints included all-cause readmissions at 60-day, 90-day, and 12 months. Additionally, 30-day, 60-day, and 90-day readmissions due to HF were evaluated. A total of 398 patients were included in our analysis; 199 (50.0%) received sacubitril/valsartan (group 1), and 199 (50.0%) received ACEI/ARB (group 2). Our results showed that all-cause 30-day readmissions in group 1 were significantly lower than in group 2 (7% vs 25.0%, RR 0.28, 95% Cl 0.16-0.49; P < .001). Additionally, the secondary outcomes showed significantly fewer 60-day, 90-day, and 12-month all-cause readmissions were identified in group 1 compared to group 2 (11% vs 30.7%, RR 0.36, 95% CI 0.23-0.56; P < .001), (11.6%. vs 32.6%, RR 0.35, 95% CI 0.23-0.55; P < .001) and (23.6% vs 51.2%, RR 0.46, 95% CI 0.35-0.62; P < .001), respectively. Furthermore, HF readmissions at 30-day, 60-day, and 90-day in group 1 were significantly lower than in group 2 (P < .05). Sacubitril/valsartan for the treatment of HFrEF is associated with a significantly lower rate of all-cause readmission as well as HF readmissions compared to ACEI/ARB. These benefits extend up to 12 months post-discharge.

Effects of xenogeneic transplantation of umbilical cord-derived mesenchymal stem cells combined with irbesartan on renal podocyte damage in diabetic rats.

BACKGROUND: The leading cause of end-stage renal disease (ESRD) is diabetic nephropathy (DN). Podocyte damage is an early event in the development of DN. Currently, there is no effective treatment strategy that can slow the progression of DN or reverse its onset. The role of mesenchymal stem cells (MSCs) transplantation in diabetes and its complications has been extensively studied, and diabetic nephropathy has been a major focus. Irbesartan exerts reno-protective effects independent of lowering blood pressure, can reduce the incidence of proteinuria in rats, and is widely used clinically. However, it remains undetermined whether the combined utilization of the angiotensin II receptor antagonist irbesartan and MSCs could enhance efficacy in addressing DN. METHODS: A commonly used method for modeling type 2 diabetic nephropathy (T2DN) was established using a high-fat diet and a single low-dose injection of STZ (35 mg/kg). The animals were divided into the following 5 groups: (1) the control group (CON), (2) the diabetic nephropathy group (DN), (3) the mesenchymal stem cells treatment group (MSCs), (4) the irbesartan treatment group (Irb), and (5) the combined administration group (MSC + Irb). MSCs (2 × 106 cells/rat) were injected every 10 days through the tail vein for a total of three injections; irbesartan (30 mg/kg/d) was administered by gavage. Additionally, the safety and homing of mesenchymal stem cells were verified using positron emission tomography (PET) imaging. RESULTS: The combination treatment significantly reduced the UACR, kidney index, IGPTT, HOMA-IR, BUN, serum creatine, and related inflammatory factor levels and significantly improved renal function parameters and the expression of proteins related to glomerular podocyte injury in rats. Moreover, MSCs can homing target to damaged kidneys. CONCLUSIONS: Compared to the administration of MSCs or irbesartan alone, the combination of MSCs and irbesartan exerted better protective effects on glomerular podocyte injury, providing new ideas for the clinical application of mesenchymal stem cells.

Real-life effectiveness of sacubitril/valsartan in older Belgians with heart failure, reduced ejection fraction and most severe symptoms.

We assessed the real-world effectiveness of sacubitril/valsartan in patients with chronic heart failure (HF) and reduced ejection fraction (HFrEF) with an emphasis on those with older age (≥ 75 years) or with New York Heart Association (NYHA) class IV, for whom greater uncertainty existed regarding clinical outcomes. We conducted a retrospective cohort study based on patient-level linkage of electronic healthcare datasets. Data from all adults with HFrEF in Belgium receiving a prescription for sacubitril/valsartan between 01-November-2016 and 31-December-2018 were collected, with a follow-up of > 6 years. The total study population comprised 5446 patients, older than the PARADIGM-HF trial participants, and with higher NYHA class (all P < 0.0001). NYHA class improved following sacubitril/valsartan initiation (P < 0.0001 baseline vs. reassessment). Most concomitant medications were reduced. Remarkably, the risk of hospitalization for a cardiovascular reason and for HF was reduced by > 26% in the overall cohort, and in subgroups of patients ≥ 75 years, with NYHA class III/IV (all P < 0.0001) or with NYHA class IV (P < 0.05), vs. baseline. All-cause mortality did not increase in real-world patients with NYHA class III/IV. The results support the long-term beneficial effects of sacubitril/valsartan in older patients and in those experiencing the most severe symptoms.

Effect of Sacubitril/Valsartan on Cognitive Function in Patients With Heart Failure With Preserved Ejection Fraction: A Prespecified Analysis of PARAGON-HF.

BACKGROUND: A hypothetical concern has been raised that sacubitril/valsartan might cause cognitive impairment because neprilysin is one of several enzymes degrading amyloid-ß peptides in the brain, some of which are neurotoxic and linked to Alzheimer-type dementia. To address this, we examined the effect of sacubitril/valsartan compared with valsartan on cognitive function in patients with heart failure with preserved ejection fraction in a prespecified substudy of PARAGON-HF (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in Heart Failure With Preserved Ejection Fraction). METHODS: In PARAGON-HF, serial assessment of cognitive function was conducted in a subset of patients with the Mini-Mental State Examination (MMSE; score range, 0-30, with lower scores reflecting worse cognitive function). The prespecified primary analysis of this substudy was the change from baseline in MMSE score at 96 weeks. Other post hoc analyses included cognitive decline (fall in MMSE score of ≥3 points), cognitive impairment (MMSE score <24), or the occurrence of dementia-related adverse events. RESULTS: Among 2895 patients included in the MMSE substudy with baseline MMSE score measured, 1453 patients were assigned to sacubitril/valsartan and 1442 to valsartan. Their mean age was 73 years, and the median follow-up was 32 months. The mean±SD MMSE score at randomization was 27.4±3.0 in the sacubitril/valsartan group, with 10% having an MMSE score <24; the corresponding numbers were nearly identical in the valsartan group. The mean change from baseline to 96 weeks in the sacubitril/valsartan group was -0.05 (SE, 0.07); the corresponding change in the valsartan group was -0.04 (0.07). The mean between-treatment difference at week 96 was -0.01 (95% CI, -0.20 to 0.19; P=0.95). Analyses of a ≥3-point decline in MMSE, decrease to a score <24, dementia-related adverse events, and combinations of these showed no difference between sacubitril/valsartan and valsartan. No difference was found in the subgroup of patients tested for apolipoprotein E ε4 allele genotype. CONCLUSIONS: Patients with heart failure with preserved ejection fraction in PARAGON-HF had relatively low baseline MMSE scores. Cognitive change, measured by MMSE, did not differ between treatment with sacubitril/valsartan and treatment with valsartan in patients with heart failure with preserved ejection fraction. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01920711.

Aptamer Proteomics for Biomarker Discovery in Heart Failure With Preserved Ejection Fraction: The PARAGON-HF Proteomic Substudy.

BACKGROUND: Prognostic markers and biological pathways linked to detrimental clinical outcomes in heart failure with preserved ejection fraction (HFpEF) remain incompletely defined. METHODS AND RESULTS: We measured serum levels of 4123 unique proteins in 1117 patients with HFpEF enrolled in the PARAGON-HF (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction) trial using a modified aptamer proteomic assay. Baseline circulating protein concentrations significantly associated with the primary end point and the timing and occurrence of total heart failure hospitalization and cardiovascular death were identified by recurrent events regression, accounting for multiple testing, adjusted for age, sex, treatment, and anticoagulant use, and compared with published analyses in 2515 patients with heart failure with reduced ejection fraction from the PARADIGM-HF (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) and ATMOSPHERE (Efficacy and Safety of Aliskiren and Aliskiren/Enalapril Combination on Morbidity-Mortality in Patients With Chronic Heart Failure) clinical trials. We identified 288 proteins that were robustly associated with the risk of heart failure hospitalization and cardiovascular death in patients with HFpEF. The baseline proteins most strongly related to outcomes included B2M (ß-2 microglobulin), TIMP1 (tissue inhibitor of matrix metalloproteinase 1), SERPINA4 (serpin family A member 4), and SVEP1 (sushi, von Willebrand factor type A, EGF, and pentraxin domain containing 1). Overall, the protein-outcome associations in patients with HFpEF did not markedly differ as compared with patients with heart failure with reduced ejection fraction. A proteomic risk score derived in patients with HFpEF was not superior to a previous proteomic score derived in heart failure with reduced ejection fraction nor to clinical risk factors, NT-proBNP (N-terminal pro-B-type natriuretic peptide), or high-sensitivity cardiac troponin. CONCLUSIONS: Numerous serum proteins linked to metabolic, coagulation, and extracellular matrix regulatory pathways were associated with worse HFpEF prognosis in the PARAGON-HF proteomic substudy. Our results demonstrate substantial similarities among serum proteomic risk markers for heart failure hospitalization and cardiovascular death when comparing clinical trial participants with heart failure across the ejection fraction spectrum. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique Identifiers: NCT01920711, NCT01035255, NCT00853658.

A network pharmacology-based method to explore the therapeutic effect of honokiol on diabetes with comorbid depression in mice.

The effective treatment of diabetes with comorbid depression is a big challenge so far. Honokiol, a bioactive compound from the dietary supplement Magnolia officinalis extract, possesses multiple health benefits. The present study aims to propose a network pharmacology-based method to elucidate potential targets of honokiol in treating diabetes with comorbid depression and related mechanisms. The antidepressant-like efficacy of honokiol was evaluated in high-fat diet (HFD) induced diabetic mice using animal behavior testing, immuno-staining and western blotting assay. Through network pharmacology analysis, retinoid X receptor alpha (RXRα) and vitamin D receptor (VDR) were identified as potential targets related to diabetes and depression. The stable binding conformation between honokiol and RXR/VDR was determined by molecular docking simulation. Moreover, hononkiol effectively alleviated depression-like behaviors in HFD diabetic mice, presented anti-diabetic and anti-neuroinflammatory functions, and protected the hippocampal neuroplasticity. Importantly, honokiol could activate RXR/VDR heterodimer in vivo. The beneficial effects of honokiol on HFD mice were significantly suppressed by UVI3003 (a RXR antagonist), while enhanced by calcitriol (a VDR agonist). Additionally, the disruption of autophagy in the hippocampus of HFD mice was ameliorated by honokiol, which was attenuated by UVI3003 but strengthened by calcitriol. Taken together, the data provide new evidence that honokiol exerts the antidepressant-like effect in HFD diabetic mice via activating RXR/VDR heterodimer to restore the balance of autophagy. Our findings indicate that the RXR/VDR-mediated signaling might be a potential target for treating diabetes with comorbid depression.

Non-HLA angiotensin-type-1 receptor autoantibodies mediate the long-term loss of grafted neurons in Parkinson's disease models.

BACKGROUND: Clinical trials have provided evidence that transplants of dopaminergic precursors, which may be replaced by new in vitro stem cell sources, can integrate into the host tissue, and alleviate motor symptoms in Parkinson´s disease (PD). In some patients, deterioration of graft function occurred several months after observing a graft-derived functional improvement. Rejection of peripheral organs was initially related to HLA-specific antibodies. However, the role of non-HLA antibodies is now considered also relevant for rejection. Angiotensin-II type-1 receptor autoantibodies (AT1-AA) act as agonists of the AT1 receptors. AT1-AA are the non-HLA antibodies most widely associated with graft dysfunction or rejection after transplantation of different solid organs and hematopoietic stem cells. However, it is not known about the presence and possible functional effects of AT1-AA in dopaminergic grafts, and the effects of treatment with AT1 receptor blockers (ARBs) such as candesartan on graft survival. METHODS: In a 6-hydroxydopamine PD rat model, we studied the short-term (10 days)- and long-term (3 months) effects of chronic treatment with the ARB candesartan on survival of grafted dopaminergic neurons and microglial graft infiltration, as well as the effects of dopaminergic denervation and grafting on serum and CSF AT1-AA levels. The expression of AT1 receptors in grafted neurons was determined by laser capture microdissection. RESULTS: At the early period post-grafting, the number of grafted dopaminergic neurons that survived was not significantly different between treated and untreated hosts (i.e., control rats and rats treated with candesartan), probably because, just after grafting, other deleterious factors are predominant for dopaminergic cell death, such as mechanical trauma, lack of growth factors/nutrients and ischemia. However, several months post-grafting, we observed a significantly higher number of surviving dopaminergic neurons and a higher density of striatal dopaminergic terminals in the candesartan-treated group. For several months, grafted rats showed blood and cerebrospinal fluid levels of AT1-AA higher than normal controls, and also higher AT1-AA levels than non-grafted parkinsonian rats. CONCLUSIONS: The results suggest the use of ARBs such as candesartan in PD patients, particularly before and after dopaminergic grafts, and the need to monitor AT1-AA levels in PD patients, particularly in those candidates for dopaminergic grafting.

Fast and safe clinical response to sonidegib in a 98-year old woman affected by locally advanced basal cell carcinoma.

A 98-year-old woman presented with histologically confirmed locally advanced basal cell carcinoma of the face. A multidisciplinary approach excluded surgery because of the site near sensitive organs, extension, age, and comorbidities. Patient and caregivers declined radiotherapy considering the necessity of multiple hospital appointments. The patient was then placed on therapy with sonidegib, an oral inhibitor of the Hedgehog signaling pathway. There was a very rapid clinical response after only 28 days of treatment. The basal cell carcinoma improved progressively, with no adverse events reported. This case illustrates the efficacy and safety of this treatment in an advanced age patient. This treatment had a remarkably positive impact on quality of life, including that of the caregivers.

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.

Clinical determinants of clinical response to Sonidegib in advanced basal cell carcinoma: a monocenter experience.

OBJECTIVE: The purpose of this study is to evaluate the clinical determinants of complete response in locally advanced basal cell carcinoma (laBCC) patients receiving Sonidegib in a real-life, retrospective, observational study.  Hedgehog pathway inhibitors (Vismodegib and Sonidegib) are approved for the systemic treatment of locally advanced basal cell carcinoma (laBCC). The objective response rate was the primary endpoint of the trials for both drugs. PATIENTS AND METHODS: Adult patients with laBCC treated with Sonidegib at the Dermato-Oncology Unit of IFO San Gallicano between June 2020 and September 2022 were included in the study. Patient, tumor, and treatment characteristics were recorded. The complete response rate was the primary outcome. The median time to the best response and complete response were the secondary outcomes. Treatment-related adverse events (TRAEs) and dose adjustments were recorded. RESULTS: Of the 19 patients included in the study, eight (42.1%) achieved a complete response, seven (36.8%) had a partial response, and four experienced progressive disease (21%). The median time to the best response was 3 months in the group of patients with partial response (range 2.0-4.0, with three patients not evaluable) and 3.5 months in the group of patients with complete response (range 2-5). TRAEs occurred in 14 (73.6%) patients, with 8 (57.1%) reporting ≤2 TRAE categories and 6 (42.8%) >2. A total of 78.9% of patients received a modified treatment schedule; 12.5% of patients who achieved a complete response received full dosage from the beginning to the end of treatment, compared with 27.3% of those with a partial response. CONCLUSIONS: The associations between the clinical outcome of interest (objective response rate) and the clinicopathological and treatment characteristics were evaluated. No statistically significant association was observed. Our analysis confirms the observation that no statistically significant correlation exists between clinical response and Sonidegib alternate dose regimen.

Honokiol suppress the PD-L1 expression to improve anti-tumor immunity in lung cancer.

Lung cancer is a serious health issue globally, and current treatments have proven to be inadequate. Therefore, immune checkpoint inhibitors (ICIs) that target the PD-1/PD-L1 pathway have become a viable treatment option in lun cancer. Honokiol, a lignan derived from Magnolia officinalis, has been found to possess anti-inflammatory, antioxidant, and antitumor properties. Our research found that honokiol can effectively regulate PD-L1 through network pharmacology and transcriptome analysis. Cell experiments showed that honokiol can significantly reduce PD-L1 expression in cells with high PD-L1 expression. Molecular docking, cellular thermal shift assay (CETSA) and Bio-Layer Interferometry (BLI)indicated that Honokiol can bind to PD-L1. Co-culture experiments on lung cancer cells and T cells demonstrated that honokiol mediates PD-L1 degradation, stimulates T cell activation, and facilitates T cell killing of tumor cells. Moreover, honokiol activates CD4 + and CD8 + T cell infiltration in vivo, thus suppressing tumor growth in C57BL/6 mice. In conclusion, this study has demonstrated that honokiol can inhibit the growth of lung cancer by targeting tumor cell PD-L1, suppressing PD-L1 expression, blocking the PD-1/PD-L1 pathway, and enhancing anti-tumor immunity.

Sacubitril/valsartan compared to equivalent/sub-equivalent dose angiotensin receptor blocker or angiotensin-converting enzyme inhibitor in heart failure with reduced ejection fraction: a meta-analysis of randomized trials.

PURPOSE: The objective of this meta-analysis is to determine how sacubitril/valsartan (SV) compares to equivalent and sub-equivalent angiotensin receptor blockers (ARB) or angiotensin-converting enzyme inhibitors (ACEI) in patients with heart failure with reduced ejection fraction (HFrEF). METHODS: The databases of PubMed and EMBASE were used to identify those randomized controlled trials which compared SV to ARB/ACEI in patients with HFrEF. Only those trials that reported outcomes regarding total mortality, cardiovascular mortality, and worsening heart failure were considered. Meta-analysis was performed separately in those patients receiving equivalent doses of ARB/ACEI and those receiving sub-equivalent doses. Equivalent doses were SV 97/103 = valsartan 160 mg twice daily = enalapril 20 mg twice daily = ramipril 5 mg twice daily. Meta-analyses were performed using Review Manager 5.4. RESULTS: Twelve randomized trials were identified involving 17,484 patients: 11,291 in the sub-equivalent group (8 trials) and 6193 in the equivalent group (4 trials). Meta-analyses showed there were no statistical differences regarding the outcomes of total mortality, cardiovascular mortality, and worsening heart failure in the equivalent dosing group. However, SV reduced total mortality (risk ratio (RR) = 0.85, 95% confidence interval (CI) = 0.78-0.93, p < 0.001), cardiovascular mortality (RR = 0.81, 95% CI = 0.73-0.90, p ≤ 0.001) and worsening heart failure (RR = 0.77, 95% CI = 0.64-0.92, p = 0.005) in the sub-equivalent group. CONCLUSION: When compared to equivalent doses of ARB/ACEI, SV is not superior in reducing mortality and worsening heart failure. SV is superior when compared to sub-equivalent doses of ACEI.

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.

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.

Guidelines-based therapeutic strategies for controlling hypertension in non-controlled hypertensive patients followed by family physicians in primary health care in Portugal: the GPHT-PT study.

PURPOSE: In a prospective open study, with intervention, conducted in Primary Health Care Units by General Practitioners (GPs) in Portugal, the effectiveness of a single pill of candesartan/amlodipine (ARB/amlodipine), as the only anti-hypertension (anti-HTN) medication, in adult patients with uncontrolled HTN (BP > 140/or > 90 mm Hg), either previously being treated with anti-HTN monotherapies (Group I), or combinations with hydrochlorothiazide (HCTZ) (Group II), or not receiving medication at all (Group III), was evaluated across 12-weeks after implementation of the new therapeutic measure. MATERIALS AND METHODS: A total of 118 GPs recruited patients with uncontrolled HTN who met inclusion/exclusion criteria. Participants were assigned, according to severity, one of 3 (morning) fixed combination candesartan/amlodipine dosage (8/5 or 16/5 or 16/10 mg/day) and longitudinally evaluated in 3 visits (v0, v6 and v12 weeks). Office blood pressure was measured in each visit, and control of HTN was defined per guidelines (BP< 140/90 mmHg). RESULTS: Of the 1234 patients approached, 752 (age 61 ± 10 years, 52% women) participated in the study and were assigned to groups according to previous treatment conditions. The 3 groups exhibited a statistically significant increased control of blood pressure after receiving the fixed combination candesartan/amlodipine dosage. The overall proportion of controlled HTN participants increased from 0,8% at v0 to 82% at v12. The mean arterial blood pressure values decreased from SBP= 159.0 (± 13.0) and DBP= 91.1 (± 9.6) at baseline to SBP= 132,1 (± 11.3) and DBP= 77,5 (± 8.8) at 12 weeks (p < 0.01). Results remained consistent when controlling for age and sex. CONCLUSION: In patients with uncontrolled HTN, therapeutic measures in accordance with guidelines, with a fixed combination candesartan/amlodipine, allowed to overall achieve HTN control at 12 weeks in 82% of previously uncontrolled HTN patients, reinforcing the advantages of these strategies in primary clinical practice.

What is the context?Arterial hypertension (HTN) represents the main risk factor for cause of death from cardiovascular disease (CV). Adequate control of hypertension reduces CV risk and significantly prevents CV events and associated morbidity and mortality. This requires patients' adherence and persistence in implemented treatment and the achievement of tension targets that are related to the reduction of CV risk. The latest international recommendations indicate that hypertension control is insufficient in most countries. In Portugal, hypertension control is <43% and a significant number of patients treated do not comply with the recommendations.What is new?In a prospective, interventional, and multicentre study, carried out by General Practitioners (GPs) in Primary Health Care Units across Portugal, the objective was to determine (i) whether the presence of uncontrolled hypertension results from non-compliance with the provisions of the recommendations and the Integrated Care Process (PAI) of the Direção Geral de Saúde (DGS), i.e. inappropriate use of monotherapies or inadequate low doses of combinations of antihypertensives, and (ii) whether the adjustment of hypertension therapies, favouring the schemes provided in the recommendations, allows adequate control of arterial hypertension, in previously uncontrolled patients, when these are closely monitored in a 12-week time period.What is the impact?When the guidelines' therapeutic protocol is followed, as established for each identified group of patients (monotherapy, hydrochlorothiazide, and no medication), results indicate a marked and statistically significant improvements in both SBP and DBP values and hypertension control across time.

Hedgehog pathway inhibitors for locally advanced and metastatic basal cell carcinoma: A real-world single-center retrospective review.

Basal cell carcinoma (BCC) is highly curable by surgical excision or radiation. In rare cases, BCC can be locally destructive or difficult to surgically remove. Hedgehog inhibition (HHI) with vismodegib or sonidegib induces a 50-60% response rate. Long-term toxicity includes muscle spasms and weight loss leading to dose decreases. This retrospective chart review also investigates the impact of CoQ10 and calcium supplementation in patients treated with HHI drugs at a single academic medical center from 2012 to 2022. We reviewed the charts of adult patients diagnosed with locally advanced or metastatic BCC treated with vismodegib or sonidegib primarily for progression-free survival (PFS). Secondary objectives included overall survival, BCC-specific survival, time to and reasons for discontinuation, overall response rate, safety and tolerability, use of CoQ10 and calcium supplements, and insurance coverage. Of 55 patients assessable for outcome, 34 (61.8%) had an overall clinical benefit, with 25 (45.4%) having a complete response and 9 (16.3%) a partial response. Stable disease was seen in 14 (25.4%) and 7 (12.7%) progressed. Of the 34 patients who responded to treatment, 9 recurred. Patients who were rechallenged with HHI could respond again. The median overall BCC-specific survival rate at 5 years is 89%. Dose reductions or discontinuations for vismodegib and sonidegib occurred in 59% versus 24% of cases, or 30% versus 9% of cases, respectively. With CoQ10 and calcium supplementation, only 17% required a dose reduction versus 42% without. HHI is highly effective for treating advanced BCC but may require dosing decreases. Sonidegib was better tolerated than vismodegib. CoQ10 and calcium supplementation can effectively prevent muscle spasms.

Efficacy of Sacubitril-Valsartan on Survival and Cardiac Remodeling in Hypotensive Heart Failure With Reduced Ejection Fraction: A Multicenter Study.

OBJECTIVE: To investigate whether hypotensive patients diagnosed with heart failure and reduced ejection fraction (HFrEF) might benefit from angiotensin receptor-neprilysin inhibitors (ARNis) in real-world practice because patients with baseline systolic blood pressure (SBP) of less than 100 mm Hg have been excluded from landmark trials. PATIENTS AND METHODS: In this multicenter study conducted between January 1, 2013, and December 31, 2021, a total of 7562 symptomatic patients with HFrEF were enrolled and grouped by SBP (hypotension was defined as an SBP of less than 100 mm Hg) and ARNi use as follows: group 1, hypotensive/non-ARNi users (n=484); group 2, hypotensive/ARNi users (n=308); group 3, nonhypotensive/non-ARNi users (n=4560); and group 4, nonhypotensive/ARNi users (n=2210). Inverse probability of treatment weighting was used to balance baseline characteristics for survival analysis. RESULTS: Diverse baseline characteristics and lower rates of medication use were found among non-ARNi users compared with ARNi users. Hypotensive/ARNi users had lower ARNi initiation doses than nonhypotensive/ARNi users. We observed significantly lower mortality, composite heart failure hospitalization, and CV death for hypotensive/ARNi and the other 2 nonhypotensive groups (groups 3 and 4) during a median follow-up of 3.43 years (all P<.05), with a similar effect on reverse remodeling for the hypotensive/ARNi group compared with the hypotensive/non-ARNi group. The event-free survival benefits of ARNi vs renin-angiotensin system inhibitors were consistent with the lower boundary of SBP for clinical benefits found until 88 mm Hg (spline curves) after inverse probability of treatment weighting. CONCLUSION: Patients with HFrEF and hypotension may still benefit from ARNi treatment. Patients with hypotensive HFrEF should not be routinely excluded from ARNi use in a real-world setting.