scholarly journals 54 Sacubitril–valsartan (LCZ 696) improves longitudinal strain and ejection fraction in preclinical models treated with doxorubicin through NLRP3, MyD88, and pro-fibrotic chemokines

2021 ◽  
Vol 23 (Supplement_G) ◽  
Author(s):  
Vincenzo Quagliariello ◽  
Simona Buccolo ◽  
Martina Iovine ◽  
Fabrizio Maurea ◽  
Domenica Rea ◽  
...  
Keyword(s):  
Ejection Fraction ◽  
Cell Viability ◽  
Nlrp3 Inflammasome ◽  
Longitudinal Strain ◽  
Angiotensin Ii Receptor Blocker ◽  
Preclinical Models ◽  
Combination Drug ◽  
Gm Csf ◽  
Neprilysin Inhibitor ◽  
Tnf Α

Abstract Aims Doxorubicin-mediated adverse cardiovascular events are among the leading causes of morbidity and mortality in breast cancer patients. Sacubitril–valsartan (LCZ 696) is a combination drug, made up of neprilysin inhibitor sacubitril and angiotensin II receptor blocker valsartan, used for the treatment of heart failure in patients with a reduced ejection fraction. We hypothesized that LCZ 696, administered during doxorubicin, could improve cardiac function and cardiac inflammation in preclinical models. Methods Human Foetal cardiomyocytes (HFC cell line) were exposed to subclinical concentration of doxorubicin (200 nM) alone or in combination with LCZ-696 (100 mM) for 72 h. After the incubation period, we performed the following tests: cell viability, apoptosis and necrosis; expression of malondialdehyde and 4-hydroxynonenal and concentration of intracellular Ca2+. Moreover, pro-inflammatory studied were also performed (activation of NLRP3 inflammasome; expression of TLR4/MyD88; mTORC1 Fox01/3a; NF-κB). C57Bl/6 mice were untreated (Sham, n = 6) or treated for 10 days with doxorubicin i.p. at 2.17 mg/kg (DOXO, n = 6), LCZ-696 at 60 mg/kg (LCZ, n = 6) or doxorubicin combined to LCZ-696 (DOXO-LCZ, n = 6). Ejection fraction, radial and longitudinal strain were analysed through transthoracic echocardiography (Vevo 2100). Cardiac tissue expression of NLRP3 inflammasome, Myd88, NF-kB, and 13 chemokines (IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-10, IL-12, IL17-α, IL-18, IFN-γ, TNF-α, G-CSF, and GM-CSF) were quantified. Results LCZ-696 exerts cardioprotective effects, enhancing cell viability of 48–54.6% compared to only doxorubicin-treated cells (P < 0.001 for all); LCZ 696 decreased NLRP3, MyD88 and NF-kB expression in cardiac cells. In preclinical study, LCZ 696 improved significantly the EF and prevented the reduction of radial and longitudinal strain after 10 days of treatment with doxorubicin. A reduced expression of NLRP3, MyD88 and NF-kB in cardiac tissues was seen in DOXO-LCZ group compared to DOXO mice (P < 0.001). Cardiac expression of IL-1β, IL-6, TNF-α, G-CSF and GM-CSF were significantly reduced after treatment with LCZ-696 indicating anti-inflammatory properties. Conclusions LCZ-696 exerts direct beneficial effects in cardiomyocytes exposed to doxorubicin. In preclinical models, LCZ-696 reduced inflammation and cytokine expression involved in doxorubicin-mediated cardiotoxicity.

scholarly journals The combination of a neprilysin inhibitor (sacubitril) and angiotensin-II receptor blocker (valsartan) improves ejection fraction and longitudinal strain in mice treated with doxorubicin through NLRP3

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
V Quagliariello ◽  
A Bonelli ◽  
A Paccone ◽  
S Buccolo ◽  
M Iovine ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Ejection Fraction ◽  
Cell Viability ◽  
Cancer Patients ◽  
Nlrp3 Inflammasome ◽  
Longitudinal Strain ◽  
Receptor Blocker ◽  
Angiotensin Ii Receptor Blocker ◽  
Angiotensin Ii Receptor ◽  
Neprilysin Inhibitor

Abstract Background Doxorubicin-mediated- adverse cardiovascular events are among the leading causes of morbidity and mortality in breast cancer patients. Sacubitril-valsartan (LCZ 696) is a combination drug, made up of neprilysin inhibitor sacubitril and angiotensin II receptor blocker valsartan, used for the treatment of heart failure in patients with a reduced ejection fraction. Purpose Here, we aim to assess whether LCZ 696, administered during doxorubicin, reduces in vitro anticancer drugs-related cardiotoxicity compared to Valsartan (V), used as a control drug. Methods Human fetal cardiomyocytes (HFC cell line) were exposed to subclinical concentration of doxorubicin (at 200 nM) alone or in combination with LCZ-696 (100 mM) for 72 h. After the incubation period, we performed the following tests: determination of cell viability, through analysis of mitochondrial dehydrogenase activity, study of lipid peroxidation (quantifying cellular Malondialdehyde and 4-hydroxynonenal), intracellular Ca2+ homeostasis. Moreover, pro-inflammatory studied were also performed (activation of NLRP3 inflammasome; expression of TLR4/MyD88; mTORC1 Fox01/3a; transcriptional activation of p65/NF-κB and secretion of cytokines involved in cardiotoxicity (Interleukins 1β, 8, 6). C57Bl/6 mice were untreated (Sham, n=6) or treated for 10 days with doxorubicin (DOXO, n=6), LCZ-696 (LCZ, n=6) or doxorubicin combined to LCZ-696 (DOXO-LCZ, n=6). DOXO was injected intraperitoneally. Ejection fraction, radial and longitudinal strain were analyzed through transthoracic echocardiography (Vevo 2100). Cardiac tissue expression of NLRP3 inflammasome, Myd8, NF-kB and chemokines and cytokines were quantified after treatments through ELISA method. Results LCZ 696 co-incubated with doxorubicin exerts cardioprotective effects, enhancing cell viability of 48–54.6% compared to only doxorubicin-treated cells (p<0,001 for all); LCZ 696 reduced significantly the cardiotoxicity through MyD88/NF-KB/cytokines axis and mTORC1 Fox01/3α mediated mechanisms. In preclinical study, LCZ 696 improved significantly the EF and prevented the reduction of radial and longitudinal strain after 10 days of treatment with doxorubicin. A reduced expression of pro-inflammatory cytokines, NLRP3, MyD88 and NF-kB in heart tissues was also seen in DOXO-LCZ group compared to DOXO mice (p<0.001) Conclusion We demonstrated, for the first time, that the LCZ696 exerts direct effects in cardiomyocytes and preclinical models during doxorubicin exposure, turning on a new light on its possible use in cancer patients to reduce cardiovascular side effects. FUNDunding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Ministero della Salute, Ricerca Corrente project

Sacubitril/Valsartan (Entresto®)-Induced Hyponatremia

2019 ◽  
Vol 33 (5) ◽  
pp. 696-699 ◽  
Author(s):  
Ilana Fuzaylova ◽  
Chester Lam ◽  
Om Talreja ◽  
Amgad N. Makaryus ◽  
Deborah Ahern ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Elderly Woman ◽  
Angiotensin Ii Receptor Blocker ◽  
Angiotensin Receptor ◽  
Angiotensin Ii Receptor ◽  
Combination Drug ◽  
Reduced Ejection Fraction ◽  
Neprilysin Inhibitor ◽  
Angiotensin Receptor Neprilysin Inhibitor

Sacubitril/valsartan (Entresto®) is the first commercially available angiotensin receptor neprilysin inhibitor (ARNI) approved for use in heart failure patients with a reduced ejection fraction. It is a combination drug that contains sacubitril, a neprilysin inhibitor, and valsartan, an angiotensin II receptor blocker. Our report outlines a case of probable ARNI-induced hyponatremia occurring in an elderly woman with heart failure with a reduced ejection fraction. According to Naranjo Adverse Drug Reaction Assessment, score indicated a likely association between patient’s hyponatremia and her use of sacubitril/valsartan.

scholarly journals Sacubitril/valsartan in patients with symptomatic chronic heart failure with reduced ejection fraction

2019 ◽  
Vol 1 (4) ◽  
pp. 182-192 ◽  
Author(s):  
Zahraa Jalal ◽  
Summaya Cabdi ◽  
Nazish Khan ◽  
Marina Dorsch ◽  
Navneet Gill ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Enzyme Inhibitor ◽  
Real Life ◽  
Functional Class ◽  
Angiotensin Ii Receptor Blocker ◽  
Angiotensin Ii Receptor ◽  
National Guidelines ◽  
Combination Drug ◽  
Reduced Ejection Fraction

Background: Sacubitril/valsartan is a combination drug therapy for heart failure (HF) patients that has been shown to reduce mortality and hospitalisation. Aims: To explore clinically relevant real-life patient data regarding prescribing of sacubitril/valsartan for HF patients in three hospitals, in accordance with national guidelines. Methods: A retrospective multicentre study in three large UK hospital Trusts based in the West Midlands. Findings: A total of 118 symptomatic chronic HF patients with reduced ejection fraction were included in the study. A high proportion of prescribers adhered to NICE guidelines for treatment with sacubitril/valsartan; 99% of patients had a New York Heart Association functional class of at least II; 82% had a left ventricle ejection fraction of under 35%; 100% received an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker before commencing sacubitril/valsartan. The mean age of men and women at the three hospitals was 65 and 59 years, respectively. The proportion of men prescribed sacubitril/valsartan was greater than women: 80% compared to 20%, respectively. The majority of patients on the therapy were white British (65%). Total prescribing of sacubitril/valsartan at the three hospitals was 295 patients, lower than expected. Conclusion: The prescribing of sacubitril/valsartan at the Trusts generally adhered to NICE guidance; however, the prescribing rate was lower than expected compared with the NICE resource tool. Further investigations into the safety and scope of application of sacubitril/valsartan are required to match the prescribing of sacubitril/valsartan with eligible patients who could benefit from the medication.

scholarly journals The influence of afterload on left ventricular contractility: 2D-strain and dyssynchrony in stress echocardiography

2021 ◽  
Vol 22 (Supplement_1) ◽  
Author(s):  
E Karev ◽  
S Verbilo ◽  
E Malev ◽  
M Prokudina ◽  
A Suvorov
Keyword(s):  
Coronary Artery ◽  
Left Ventricle ◽  
Ejection Fraction ◽  
Stress Echocardiography ◽  
Longitudinal Strain ◽  
Wall Motion ◽  
Wall Motion Score Index ◽  
Wall Motion Abnormalities ◽  
Response To Exercise ◽  
Score Index

Abstract Funding Acknowledgements Type of funding sources: None. Background Hypertensive response to exercise (HRE) has negative prognostic value but its impact on the  left ventricle (LV) contractility and on stress echocardiography (SE) results remains controversial. The global longitudinal strain (GLS) and LV dyssynchrony changes in response to afterload increase were shown even in patients with narrow QRS at rest, but not on exertion. Purpose We aimed to analyze the relation between the blood pressure (BP) during SE and LV GLS and dyssynchrony changes. Methods We performed exercise SE on treadmill in 96 patients without coronary artery stenosis (invasive or CT coronary angiography). Patients divided into two groups: HRE (n = 41) and normal response to exercise (NRE) (n = 55). We analyzed GLS and standard deviation of time between the onset of QRS and segmental longitudinal strain peaks (STE-TIME SD) using speckle tracking and 3d-ejection fraction (EF) at rest and on exertion. Results 2D-EF increase was higher in patients with NRE, but 3D-EF did not differ between groups. Wall motion abnormalities (WMA) on peak stress were detected more often in patients with HRE who had higher wall motion score index (WMSI). GLS on exertion and its increment were lower in HRE group (Fig. 1 - "Bull’s eye" diagrams of GLS at rest and on exertion in patient with NRE (upper panel) and HRE (lower panel)). Among dyssynchrony markers we revealed higher values of STE-TIME SD on exertion in HRE group (Table 1). Moreover the analysis showed positive correlations between BP level on exertion and peak GLS (r = 0.56, p < 0.0001), GLS increase (r = 0.54, p < 0.0001) and STE-TIME SD on exertion (r = 0.27, p < 0.02) Conclusions HRE is associated with less increment in GLS and 2D-EF on exertion. Besides LV dyssynchrony signs can appear in response to exaggerated afterload increase even in patients with narrow QRS complexes. Patients with HRE more often show stress-induced WMA and have greater WMSI on exertion in absence of coronary artery lesions, thus HRE can alter the specificity of the test in transient ischemia detection. Table 1 HRE NRE p Δ-2D ejection fraction 5.0 (4.0; 7.0) 10.0 (8.0; 12.5) <0.0000001 Δ-3D ejection fraction 8.25 (4.0; 8.25) 8.24 (8.15; 11.65) 0.09 Wall motion abnormalities on exertion 46.34% 1.8% <0.00001 Wall motion score index 1.0 (1.0; 1.18) 1.0 (1.0; 1.0) 0.00013 GLS on exertion -21.0 (-22.0; -19.0) -24.0 (-26.5; -23.0) <0.0000001 ΔGLS 0.0 (-1.0; 2.0) 4.0 (2.0; 6.0) <0.0000001 STE-TIME SD-IMPOST 42.0 (35.0; 53.0) 35.0 (27.5; 45.0) 0.012 Left ventricle systolic function and dyssynchrony in two groups. Abstract Figure 1.

scholarly journals A Novel Method Facilitating the Simple and Low-Cost Preparation of Human Osteochondral Slice Explants for Large-Scale Native Tissue Analysis

2021 ◽  
Vol 22 (12) ◽  
pp. 6394
Author(s):  
Jacob Spinnen ◽  
Lennard K. Shopperly ◽  
Carsten Rendenbach ◽  
Anja A. Kühl ◽  
Ufuk Sentürk ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Viability ◽  
Large Scale ◽  
Marker Gene ◽  
Cell Swelling ◽  
Tissue Cell ◽  
Joint Research ◽  
Sample Number ◽  
Tnf Α ◽  
Novel Method

For in vitro modeling of human joints, osteochondral explants represent an acceptable compromise between conventional cell culture and animal models. However, the scarcity of native human joint tissue poses a challenge for experiments requiring high numbers of samples and makes the method rather unsuitable for toxicity analyses and dosing studies. To scale their application, we developed a novel method that allows the preparation of up to 100 explant cultures from a single human sample with a simple setup. Explants were cultured for 21 days, stimulated with TNF-α or TGF-β3, and analyzed for cell viability, gene expression and histological changes. Tissue cell viability remained stable at >90% for three weeks. Proteoglycan levels and gene expression of COL2A1, ACAN and COMP were maintained for 14 days before decreasing. TNF-α and TGF-β3 caused dose-dependent changes in cartilage marker gene expression as early as 7 days. Histologically, cultures under TNF-α stimulation showed a 32% reduction in proteoglycans, detachment of collagen fibers and cell swelling after 7 days. In conclusion, thin osteochondral slice cultures behaved analogously to conventional punch explants despite cell stress exerted during fabrication. In pharmacological testing, both the shorter diffusion distance and the lack of need for serum in the culture suggest a positive effect on sensitivity. The ease of fabrication and the scalability of the sample number make this manufacturing method a promising platform for large-scale preclinical testing in joint research.

Activation of Selective Transcription Factors and Cytokines by Water-Soluble Extract from Lentinus lepideus

2003 ◽  
Vol 228 (6) ◽  
pp. 749-758 ◽  
Author(s):  
Mirim Jin ◽  
Hyung Jin Jung ◽  
Jeong June Choi ◽  
Hyang Jeon ◽  
Jin Hwan Oh ◽  
...  
Keyword(s):  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Post Treatment ◽  
Water Soluble ◽  
Dependent Manner ◽  
Soluble Extract ◽  
Transient Transfection Assay ◽  
Gm Csf ◽  
Tnf Α ◽  
Water Soluble Extract

We isolated a water-soluble extract, PG101, from cultured mycelia of Lentinus lepideus. Treatment of human peripheral blood mononuclear cells (PBMCs) with PG101 increased levels of TNF-α, IL-1β, IL-10, and IL-12 by 100- to 1000-fold, whereas GM-CSF and IL-18 were activated by an order of magnitude. On the contrary, IFN-γ and IL-4 were not affected. The response to PG101 occurred in a dose- and time-dependent manner. From the human PBMCs treated with PG101, TNF-α was a first cytokine to be activated, detectable at 2 hr post-treatment followed by IL-1β at 6 hr post-treatment. IL-12 and IL-10 were the next to follow. GM-CSF and IL-18 both showed significant increases 24 hr after treatment. When PBMCs were sorted into various cell types, monocyte/macrophages, but not T and B cells, were the major target cell type responsive to PG101. Consistent with this result, the profile of cytokine expression upon PG101 treatment was comparable between PBMCs and a human promonocytic cell line (U937), whereas cell lines of T cell and myeloid origins did not respond to PG101. Data from a transient transfection assay involving specific reporter plasmids indicated that cellular transcription factor such as NF-κB, but not AP-1, was highly activated by PG101. Results from a gel retardation assay and the experiment involving a specific NF-κB inhibitor confirmed the involvement of NF-κB. Despite its significant biological effect on various cytokines, PG101 remained nontoxic in both rats and PBMCs even at a biological concentration approximately 20 times greater. PG101 demonstrates great potential as a therapeutic immune modulator.

scholarly journals Granulocyte-Macrophage Colony-Stimulating Factor-Deficient Mice Have Impaired Resistance to Blood-Stage Malaria

2001 ◽  
Vol 69 (1) ◽  
pp. 129-136 ◽  
Author(s):  
Julie Riopel ◽  
MiFong Tam ◽  
Karkada Mohan ◽  
Michael W. Marino ◽  
Mary M. Stevenson
Keyword(s):  
Blood Stage ◽  
Colony Stimulating Factor ◽  
Necrosis Factor Alpha ◽  
Gm Csf ◽  
Tnf Α ◽  
Macrophage Colony Stimulating Factor ◽  
Ifn Γ ◽  
Macrophage Colony ◽  
Stimulating Factor ◽  
Blood Stage Malaria

ABSTRACT The contribution of granulocyte-macrophage colony-stimulating factor (GM-CSF), a hematopoietic and immunoregulatory cytokine, to resistance to blood-stage malaria was investigated by infecting GM-CSF-deficient (knockout [KO]) mice with Plasmodium chabaudi AS. KO mice were more susceptible to infection than wild-type (WT) mice, as evidenced by higher peak parasitemia, recurrent recrudescent parasitemia, and high mortality. P. chabaudiAS-infected KO mice had impaired splenomegaly and lower leukocytosis but equivalent levels of anemia compared to infected WT mice. Both bone marrow and splenic erythropoiesis were normal in infected KO mice. However, granulocyte-macrophage colony formation was significantly decreased in these tissues of uninfected and infected KO mice, and the numbers of macrophages in the spleen and peritoneal cavity were significantly lower than in infected WT mice. Serum levels of gamma interferon (IFN-γ) were found to be significantly higher in uninfected KO mice, and the level of this cytokine was not increased during infection. In contrast, IFN-γ levels were significantly above normal levels in infected WT mice. During infection, tumor necrosis factor alpha (TNF-α) levels were significantly increased in KO mice and were significantly higher than TNF-α levels in infected WT mice. Our results indicate that GM-CSF contributes to resistance to P. chabaudi AS infection and that it is involved in the development of splenomegaly, leukocytosis, and granulocyte-macrophage hematopoiesis. GM-CSF may also regulate IFN-γ and TNF-α production and activity in response to infection. The abnormal responses seen in infected KO mice may be due to the lack of GM-CSF during development, to the lack of GM-CSF in the infected mature mice, or to both.

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