Cardiac magnetic resonance imaging (MRI) measures of myocardial interstitial fibrosis (MIF) are elevated in heart failure with preserved ejection fraction (HFpEF) patients and associated with poor prognosis. Extracellular volume (ECV) is the most reproducible and best validated cardiac MRI measure of MIF. Sacubitril/valsartan reduces histological MIF in mice and levels of some extracellular matrix regulatory proteins in humans with HFpEF. However, the effect of sacubitril/valsartan on robust measures of MIF in humans is unknown. Demonstrating reductions in ECV with sacubitril/valsartan would clarify the mechanism of this approved medication. Given the borderline reduction in heart failure hospitalizations with sacubitril/valsartan and the heterogeneity of HFpEF pathophysiology, this result would suggest that neprilysin inhibition may particularly benefit HFpEF patients with greater MIF. The investigators propose a proof-of-concept clinical trial to evaluate the effect of neprilysin inhibition (sacubitril/valsartan vs valsartan alone) on cardiac MRI measures of fibrosis (principally ECV) and circulating protein levels.

开始日期2024-12-01

申办/合作机构

The Brigham & Women's Hospital, Inc.

NCT06643819 / Not yet recruiting临床3期

A Randomized, Double-blind, Active-controlled, Multi-center, Therapeutic Confirmatory, Phase 3 Trial to Evaluate the Efficacy and Safety of CKD-202A

Phase 3 Trial to Evaluate the Efficacy and Safety of CKD-202A(Sacubitril∙Valsartan)

开始日期2024-10-14

申办/合作机构

Chong Kun Dang Pharmaceutical Corp.

CTRI/2024/09/074343 / Not yet recruiting临床3期IIT

Sacubitril Valsartan versus Telmisartan in remodeling of left ventricleafter acute anterior wall myocardial infarction - NIL

开始日期2024-10-11

申办/合作机构

Government Medical College

100 项与 CD10 x AT1R 相关的临床结果

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100 项与 CD10 x AT1R 相关的转化医学

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0 项与 CD10 x AT1R 相关的专利（医药）

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项与 CD10 x AT1R 相关的文献（医药）

2024-04-01·Current Problems in Cardiology

Impact of angiotensin receptor-neprilysin inhibition (ARNI) in improving ejection fraction and left and right ventricular remodeling in heart failure

Review

作者: Xiao, Zongwei ; Huang, Xin ; Jiang, Fenglin ; Bhushan, Sandeep

Angiotensin receptor neprilysin inhibitors (ARNI), a new therapeutic class of agents acting on the renin angiotensin aldosterone system (RAAS) and neutral endopeptidase system has been developed in treatment of ventricular remodeling and has attracted considerable attention. The first in class is LCZ696, which is a molecule that combines Valsartan (ARB) and Sacubitril (neprilysin inhibitor) within a single substance. Sacubitril-Valsartan is the first angiotensin receptor enkephalin inhibitors (ARNI), which can block angiotensin II type 1 receptor (AT1R) while inhibiting enkephalin (NEP) and effectively reverse ventricular remodeling in heart failure patients. It has been recommended by the European and American authoritative guidelines on heart failure as Class I for the treatment of chronic heart failure particularly as intensive care medicine. Sacubitril-Valsartan demonstrated significant effects in improving left ventricular performance and remodeling in patients with heart failure with reduced ejection fraction. Sacubitril acts on increased levels of circulating natriuretic peptides by preventing their enzymatic breakdown and Valsartan, which acts to lessen the effects of the RAAS. However, not more research has been done on its effects on the right ventricle remodeling. This review aimed to assess the impact of angiotensin receptor neprilysin inhibitors on left and right ventricular remodeling in heart failure patients.

2024-04-01·Journal of Cellular and Molecular Medicine

Indoxyl sulphate‐initiated activation of cardiac fibroblasts is modulated by aryl hydrocarbon receptor and nuclear factor‐erythroid‐2‐related factor 2

Article

作者: Verzola, Daniela ; Ameri, Pietro ; Garibaldi, Silvano ; Nitti, Mariapaola ; Altieri, Paola ; Pratesi, Giovanni ; Palombo, Domenico ; Barisione, Chiara ; Furfaro, Anna Lisa

AbstractIn the last decade, extensive attention has been paid to the uremic toxin indoxyl sulphate (IS) as an inducer of cardiac fibroblast (cFib) activation and cardiac fibrosis in chronic kidney disease. At cellular level, IS engages aryl hydrocarbon receptor (AhR) and regulates many biological functions. We analysed how AhR inhibition by CH‐223191 (CH) and overexpression of non‐functional (dominant negative, DN) nuclear factor‐erythroid‐2‐related factor 2 (NRF2), a transcription factor recruited by AhR, modulate the response of neonatal mouse (nm) cFib to IS. We also evaluated nm‐cardiomyocytes after incubation with the conditioned medium (CM) of IS±CH‐treated nm‐cFib. IS induced activation, collagen synthesis, TLR4 and–downstream–MCP‐1, and the genes encoding angiotensinogen, angiotensin‐converting enzyme, angiotensin type 1 receptor (AT1r) and neprilysin (Nepr) in nm‐cFib. CH antagonized IS‐initiated nm‐cFib activation, but did not affect or even magnified the other features. IS promoted NRF2 nuclear translocation and expression the NRF2 target Nqo1. Both pre‐incubation with CH and transfection of DN‐NRF2 resulted in loss of NRF2 nuclear localization. Moreover, DN‐NRF2 overexpression led to greater TLR4 and MCP‐1 levels following exposure to IS. The CM of IS‐primed nm‐cFib and to a larger extent the CM of IS+CH‐treated nm‐cFib upregulated AT1r, Nepr and TNFα and myostatin genes in nm‐cardiomyocytes. Hence, IS triggers pro‐inflammatory activation of nm‐cFib partly via AhR, and AhR‐NRF2 counteract it. Strategies other than AhR inhibition are needed to target IS detrimental actions on cardiac cells.

2023-07-01·Cell cycle (Georgetown, Tex.)

Mas receptor: a potential strategy in the management of ischemic cardiovascular diseases.

Review

作者: Molaei, Ali ; Hayes, A Wallace ; Karimi, Gholamreza ; Molaei, Emad

MasR is a critical element in the RAS accessory pathway that protects the heart against myocardial infarction, ischemia-reperfusion injury, and pathological remodeling by counteracting the effects of AT1R. This receptor is mainly stimulated by Ang 1-7, which is a bioactive metabolite of the angiotensin produced by ACE2. MasR activation attenuates ischemia-related myocardial damage by facilitating vasorelaxation, improving cell metabolism, reducing inflammation and oxidative stress, inhibiting thrombosis, and stabilizing atherosclerotic plaque. It also prevents pathological cardiac remodeling by suppressing hypertrophy- and fibrosis-inducing signals. In addition, the potential of MasR in lowering blood pressure, improving blood glucose and lipid profiles, and weight loss has made it effective in modulating risk factors for coronary artery disease including hypertension, diabetes, dyslipidemia, and obesity. Considering these properties, the administration of MasR agonists offers a promising approach to the prevention and treatment of ischemic heart disease.Abbreviations: Acetylcholine (Ach); AMP-activated protein kinase (AMPK); Angiotensin (Ang); Angiotensin receptor (ATR); Angiotensin receptor blocker (ARB); Angiotensin-converting enzyme (ACE); Angiotensin-converting enzyme inhibitor (ACEI); Anti-PRD1-BF1-RIZ1 homologous domain containing 16 (PRDM16); bradykinin (BK); Calcineurin (CaN); cAMP-response element binding protein (CREB); Catalase (CAT); C-C Motif Chemokine Ligand 2 (CCL2); Chloride channel 3 (CIC3); c-Jun N-terminal kinases (JNK); Cluster of differentiation 36 (CD36); Cocaine- and amphetamine-regulated transcript (CART); Connective tissue growth factor (CTGF); Coronary artery disease (CAD); Creatine phosphokinase (CPK); C-X-C motif chemokine ligand 10 (CXCL10); Cystic fibrosis transmembrane conductance regulator (CFTR); Endothelial nitric oxide synthase (eNOS); Extracellular signal-regulated kinase 1/2 (ERK 1/2); Fatty acid transport protein (FATP); Fibroblast growth factor 21 (FGF21); Forkhead box protein O1 (FoxO1); Glucokinase (Gk); Glucose transporter (GLUT); Glycogen synthase kinase 3β (GSK3β); High density lipoprotein (HDL); High sensitive C-reactive protein (hs-CRP); Inositol trisphosphate (IP3); Interleukin (IL); Ischemic heart disease (IHD); Janus kinase (JAK); Kruppel-like factor 4 (KLF4); Lactate dehydrogenase (LDH); Left ventricular end-diastolic pressure (LVEDP); Left ventricular end-systolic pressure (LVESP); Lipoprotein lipase (LPL); L-NG-Nitro arginine methyl ester (L-NAME); Low density lipoprotein (LDL); Mammalian target of rapamycin (mTOR); Mas-related G protein-coupled receptors (Mrgpr); Matrix metalloproteinase (MMP); MAPK phosphatase-1 (MKP-1); Mitogen-activated protein kinase (MAPK); Monocyte chemoattractant protein-1 (MCP-1); NADPH oxidase (NOX); Neuropeptide FF (NPFF); Neutral endopeptidase (NEP); Nitric oxide (NO); Nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB); Nuclear-factor of activated T-cells (NFAT); Pancreatic and duodenal homeobox 1 (Pdx1); Peroxisome proliferator- activated receptor γ (PPARγ); Phosphoinositide 3-kinases (PI3k); Phospholipase C (PLC); Prepro-orexin (PPO); Prolyl-endopeptidase (PEP); Prostacyclin (PGI2); Protein kinase B (Akt); Reactive oxygen species (ROS); Renin-angiotensin system (RAS); Rho-associated protein kinase (ROCK); Serum amyloid A (SAA); Signal transducer and activator of transcription (STAT); Sirtuin 1 (Sirt1); Slit guidance ligand 3 (Slit3); Smooth muscle 22α (SM22α); Sterol regulatory element-binding protein 1 (SREBP-1c); Stromal-derived factor-1a (SDF); Superoxide dismutase (SOD); Thiobarbituric acid reactive substances (TBARS); Tissue factor (TF); Toll-like receptor 4 (TLR4); Transforming growth factor β1 (TGF-β1); Tumor necrosis factor α (TNF-α); Uncoupling protein 1 (UCP1); Ventrolateral medulla (VLM).

项与 CD10 x AT1R 相关的新闻（医药）

2023-07-08

·医药观澜

信立泰心血管1类新药「沙库巴曲阿利沙坦钙片」上市申请获受理

7月7日，中国国家药品监督管理局药品审评中心（CDE）官网最新公示，信立泰1类新药沙库巴曲阿利沙坦钙片递交了上市申请并获得受理。公开资料显示，这是信立泰研发的一款血管紧张素II受体-脑啡肽酶双重抑制剂S086，目标适应症为高血压和慢性心力衰竭。信立泰曾在新闻稿中表示，该产品上市后将进一步丰富公司心血管领域创新产品管线。公开资料显示，S086片为一款血管紧张素受体脑啡肽酶抑制剂（ARNI）类小分子化学药，对心、肾等靶器官均有保护作用。研究显示，ARNI类药物在抑制脑啡肽酶的同时可阻滞血管紧张素II1型受体（AT1），以增加循环中利钠肽的水平，进而发挥其促尿钠排泄、利尿、舒张血管、降低交感神经张力、抗细胞增殖、抗心肌肥厚及调节代谢作用。同时，AT1阻滞可以减弱血管收缩、减少水钠潴留、抑制心肌肥厚和抑制心血管阻止不良重构作用。今年1月，信立泰宣布S086片治疗轻、中度原发性高血压适应症的随机、双盲、阳性药平行对照、多中心3期临床试验已完成揭盲和统计分析。该试验共入组1197例受试者，所有患者均已完成双盲治疗。初步统计分析结果显示，该试验达到主要终点，提示S086片降压疗效显著，且呈剂量依赖性，同时整体安全性良好。根据中国临床试验登记与信息公示平台，S086片目前还在开展多项临床试验。其中一项是针对射血分数降低型心力衰竭的随机、双盲、阳性药平行对照、多中心3期临床研究，该试验已经于2022年6月入组首例受试者。据文献资料，目前多项心力衰竭诊疗指南已将ARNI类药物作为治疗心力衰竭的一线用药。信立泰药业也曾在公告中表示，S086片用于慢性心力衰竭成人患者，有望降低患者心血管死亡和心力衰竭住院风险。参考资料：[1]中国国家药监局药品审评中心（CDE）官网. Retrieved Jul 7，2023, From https://www.cde.org.cn/main/xxgk/listpage/2f78f372d351c6851af7431c7710a731 [2]用于治疗轻、中度原发性高血压的S086临床试验新进展. Retrieved Jan 11，2023, From https://mp.weixin.qq.com/s/lllKajLBeY2HMBHQtQOeGQ [3]用于治疗慢性心衰的S086片Ⅲ期临床新进展. Retrieved Jun 23，2022, From https://mp.weixin.qq.com/s/bAqRP9triF09X-MVHgOopw [4]贾凌梅等.(2017）血管紧张素受体脑啡肽酶抑制剂在心力衰竭治疗中的回顾与进展研究.《心血管病学进展》.doi：10. 16806 /j．cnki．issn. 1004-3934. 2017. 03. 010 内容来源于网络，如有侵权，请联系删除。

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