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Spatola L, Zeiler M, Granata A. Sacubitril/Valsartan in Dialysis Patients: Update on Current Perspectives. Cardiovasc Drugs Ther 2025; 39:187-193. [PMID: 37347321 DOI: 10.1007/s10557-023-07481-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/11/2023] [Indexed: 06/23/2023]
Abstract
Sacubitril/Valsartan is a combination of neprilysin inhibitor and angiotensin II receptor blocker that proved its own efficacy and safety in heart failure patients to ameliorate cardiovascular morbidity and mortality compared to angiotensin II-converting enzyme inhibitors alone. However, end-stage renal disease patients have not been included in the randomized controlled trials, so the beneficial effects as well as the risk profile of this association remain still undefined in these patients. Only observational studies on this drug association have been carried out in end-stage renal disease patients investigating mostly biohumoral or echocardiographic markers. Therefore, its application is still controversial and not free of complications due to the potential risk of hypotension and hyperkaliemia. The efficacy to improve biohumoral markers and cardiac function in dialysis patients and the potential application especially in those patients with severe and resistant hypertension and/or left ventricular dysfunction could be crucial in end-stage renal disease patients. Ongoing long-term randomized controlled trials should thoroughly define the effective benefits and/or adverse effects in patients on substitutive treatment.
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Affiliation(s)
- Leonardo Spatola
- Division of Nephrology and Dialysis, Ospedale Sant' Antonio Abate, AspTrapani, via Cosenza, Erice (TP), Trapani, Italy.
| | - Matthias Zeiler
- Nephrology and Dialysis Unit, "Carlo Urbani" Hospital, Jesi, Italy
| | - Antonio Granata
- Division of Nephrology and Dialysis, Ospedale Cannizzaro, Via Messina, Catania, (CT), Italy
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2
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Moraña-Fernández S, Vázquez-Abuín X, Aragón-Herrera A, Anido-Varela L, García-Seara J, Otero-García Ó, Rodríguez-Penas D, Campos-Toimil M, Otero-Santiago M, Rodrigues A, Gonçalves A, Pereira Morais J, Alves IN, Sousa-Mendes C, Falcão-Pires I, González-Juanatey JR, Feijóo-Bandín S, Lago F. Cardiometabolic effects of sacubitril/valsartan in a rat model of heart failure with preserved ejection fraction. Biochem Pharmacol 2024; 230:116571. [PMID: 39424202 DOI: 10.1016/j.bcp.2024.116571] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 08/30/2024] [Accepted: 10/10/2024] [Indexed: 10/21/2024]
Abstract
The promising results obtained in the PARADIGM-HF trial prompted the approval of sacubitril/valsartan (SAC/VAL) as a first-in-class treatment for heart failure with reduced ejection fraction (HFrEF) patients. The effect of SAC/VAL treatment was also studied in patients with heart failure with preserved ejection fraction (HFpEF) and, although improvements in New York Heart Association (NYHA) class, HF hospitalizations, and cardiovascular deaths were observed, these results were not so promising. However, the demand for HFpEF therapies led to the approval of SAC/VAL as an alternative treatment, although further studies are needed. We aimed to elucidate the effects of a 9-week SAC/VAL treatment in cardiac function and metabolism using a preclinical model of HFpEF, the Zucker Fatty and Spontaneously Hypertensive (ZSF1) rats. We found that SAC/VAL significantly improved diastolic function parameters and modulated respiratory quotient during exercise. Ex-vivo studies showed that SAC/VAL treatment significantly decreased heart, liver, spleen, and visceral fat weights; cardiac hypertrophy and percentage of fibrosis; lipid infiltration in liver and circulating levels of cholesterol and sodium. Moreover, SAC/VAL reduced glycerophospholipids, cholesterol, and cholesteryl esters while increasing triglyceride levels in cardiac tissue. In conclusion, SAC/VAL treatment improved diastolic and hepatic function, respiratory metabolism, reduced hypercholesterolemia and cardiac fibrosis and hypertrophy, and was able to modulate cardiac metabolic profile. Our findings might provide further insight into the therapeutic benefits of SAC/VAL treatment in obese patients with HFpEF.
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Affiliation(s)
- Sandra Moraña-Fernández
- Cellular and Molecular Cardiology Research Unit, IDIS, Complexo Hospitalario Universitario de Santiago de Compostela, Área Sanitaria Santiago de Compostela e Barbanza (SERGAS), Santiago de Compostela, Spain; Cardiology Group, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Universidade de Santiago de Compostela, IDIS, Complexo Hospitalario Universitario de Santiago de Compostela, Santiago de Compostela, Spain
| | - Xocas Vázquez-Abuín
- Cellular and Molecular Cardiology Research Unit, IDIS, Complexo Hospitalario Universitario de Santiago de Compostela, Área Sanitaria Santiago de Compostela e Barbanza (SERGAS), Santiago de Compostela, Spain; Universidade de Santiago de Compostela, Santiago de Compostela, Spain
| | - Alana Aragón-Herrera
- Cellular and Molecular Cardiology Research Unit, IDIS, Complexo Hospitalario Universitario de Santiago de Compostela, Área Sanitaria Santiago de Compostela e Barbanza (SERGAS), Santiago de Compostela, Spain; Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares, Instituto de Salud Carlos III, Madrid, Spain.
| | - Laura Anido-Varela
- Cellular and Molecular Cardiology Research Unit, IDIS, Complexo Hospitalario Universitario de Santiago de Compostela, Área Sanitaria Santiago de Compostela e Barbanza (SERGAS), Santiago de Compostela, Spain; Universidade de Santiago de Compostela, Santiago de Compostela, Spain; Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares, Instituto de Salud Carlos III, Madrid, Spain
| | - Javier García-Seara
- Cellular and Molecular Cardiology Research Unit, IDIS, Complexo Hospitalario Universitario de Santiago de Compostela, Área Sanitaria Santiago de Compostela e Barbanza (SERGAS), Santiago de Compostela, Spain; Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares, Instituto de Salud Carlos III, Madrid, Spain; Arrhytmia Unit, Cardiology Department, IDIS, Complexo Hospitalario Universitario de Santiago de Compostela, Área Sanitaria Santiago de Compostela e Barbanza (SERGAS), Santiago de Compostela, Spain; Department of Psychiatry, Radiology, Public Health, Nursing and Medicine, IDIS, Universidade de Santiago de Compostela, Santiago de Compostela, Spain
| | - Óscar Otero-García
- Cellular and Molecular Cardiology Research Unit, IDIS, Complexo Hospitalario Universitario de Santiago de Compostela, Área Sanitaria Santiago de Compostela e Barbanza (SERGAS), Santiago de Compostela, Spain; Cardiology Department, IDIS, Complexo Hospitalario Universitario de Santiago de Compostela, Área Sanitaria Santiago de Compostela e Barbanza (SERGAS), Santiago de Compostela, Spain
| | - Diego Rodríguez-Penas
- Cellular and Molecular Cardiology Research Unit, IDIS, Complexo Hospitalario Universitario de Santiago de Compostela, Área Sanitaria Santiago de Compostela e Barbanza (SERGAS), Santiago de Compostela, Spain; Cardiology Department Clinical Trial Unit, IDIS, Complexo Hospitalario Universitario de Santiago de Compostela, Área Sanitaria Santiago de Compostela e Barbanza (SERGAS), Santiago de Compostela, Spain
| | - Manuel Campos-Toimil
- Physiology and Pharmacology of Chronic Diseases (FIFAEC), Center for Research in Molecular Medicine and Chronic Diseases (CiMUS), Universidade de Santiago de Compostela, Santiago de Compostela, Spain
| | - Manuel Otero-Santiago
- Cellular and Molecular Cardiology Research Unit, IDIS, Complexo Hospitalario Universitario de Santiago de Compostela, Área Sanitaria Santiago de Compostela e Barbanza (SERGAS), Santiago de Compostela, Spain; Clinical Biochemistry Laboratory, Área Sanitaria Santiago de Compostela e Barbanza (SERGAS), Santiago de Compostela, Spain
| | - Alexandre Rodrigues
- Cardiovascular R&D Centre - UnIC@RISE, Department of Surgery and Physiology, Faculty of Medicine, University of Porto, Porto, Portugal
| | - Alexandre Gonçalves
- Cardiovascular R&D Centre - UnIC@RISE, Department of Surgery and Physiology, Faculty of Medicine, University of Porto, Porto, Portugal
| | - Juliana Pereira Morais
- CINTESIS@RISE, NOVA Medical School|Faculdade de Ciências Médicas, NMS|FCM, Universidade Nova de Lisboa, UnIC@RISE - Cardiovascular Research Centre, Faculdade de Medicina, Universidade do Porto, Porto, Portugal
| | - Inês N Alves
- Cardiovascular R&D Centre - UnIC@RISE, Department of Surgery and Physiology, Faculty of Medicine, University of Porto, Porto, Portugal
| | - Cláudia Sousa-Mendes
- Cardiovascular R&D Centre - UnIC@RISE, Department of Surgery and Physiology, Faculty of Medicine, University of Porto, Porto, Portugal
| | - Inês Falcão-Pires
- Cardiovascular R&D Centre - UnIC@RISE, Department of Surgery and Physiology, Faculty of Medicine, University of Porto, Porto, Portugal
| | - José Ramón González-Juanatey
- Cellular and Molecular Cardiology Research Unit, IDIS, Complexo Hospitalario Universitario de Santiago de Compostela, Área Sanitaria Santiago de Compostela e Barbanza (SERGAS), Santiago de Compostela, Spain; Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares, Instituto de Salud Carlos III, Madrid, Spain; Department of Psychiatry, Radiology, Public Health, Nursing and Medicine, IDIS, Universidade de Santiago de Compostela, Santiago de Compostela, Spain; Cardiology Department, IDIS, Complexo Hospitalario Universitario de Santiago de Compostela, Área Sanitaria Santiago de Compostela e Barbanza (SERGAS), Santiago de Compostela, Spain
| | - Sandra Feijóo-Bandín
- Cellular and Molecular Cardiology Research Unit, IDIS, Complexo Hospitalario Universitario de Santiago de Compostela, Área Sanitaria Santiago de Compostela e Barbanza (SERGAS), Santiago de Compostela, Spain; Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares, Instituto de Salud Carlos III, Madrid, Spain
| | - Francisca Lago
- Cellular and Molecular Cardiology Research Unit, IDIS, Complexo Hospitalario Universitario de Santiago de Compostela, Área Sanitaria Santiago de Compostela e Barbanza (SERGAS), Santiago de Compostela, Spain; Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares, Instituto de Salud Carlos III, Madrid, Spain
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3
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Zhu X, Li X, Zhu L, Tong Z, Xu X. Angiotensin Receptor-Neprilysin Inhibitor in Heart Failure Patients With Renal Dysfunction. Cardiovasc Ther 2024; 2024:6231184. [PMID: 39742017 PMCID: PMC11554417 DOI: 10.1155/2024/6231184] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Revised: 08/13/2024] [Accepted: 10/10/2024] [Indexed: 01/03/2025] Open
Abstract
Heart failure (HF) and renal dysfunction often coexist and interact in many complex and bidirectional pathways, leading to detrimental effects on patient outcomes. The treatment of HF patients with renal dysfunction presents a significant clinical challenge. Interestingly, sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor (ARNI), may have beneficial effects on cardiac and renal outcomes in patients with HF with reduced ejection fraction, particularly by slowing the rate of decrease in the estimated glomerular filtration rate compared to a single angiotensin-converting enzyme inhibitor. Recently, more reports have emphasized the renal protection of sacubitril/valsartan in patients with HF. In HF patients with renal dysfunction, however, there is no strong evidence supporting the use of sacubitril/valsartan to reduce the absolute risk of hyperkalemia and worsening renal function; therefore, the administration of ARNI requires a careful balance between the benefits and risks. Furthermore, the lack of evidence-based management highlights the importance of an individualized approach based on published experience and multidisciplinary collaborations, as well as underlines the need for in-depth studies investigating the underlying mechanisms in cardiorenal interactions with a focus on treatments.
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Affiliation(s)
- Xiaogang Zhu
- Department of Cardiology, Fu Xing Hospital, Capital Medical University, Beijing, China
| | - Xialing Li
- Department of Cardiology, Fu Xing Hospital, Capital Medical University, Beijing, China
| | - Lingxuan Zhu
- School of Data Science, The Chinese University of Hong Kong, Shenzhen, China
| | - Zichuan Tong
- Department of Cardiology, Fu Xing Hospital, Capital Medical University, Beijing, China
| | - Xiuying Xu
- Department of Cardiology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
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Erdogan BR, Yesilyurt-Dirican ZE, Karaomerlioglu I, Muderrisoglu AE, Sevim K, Michel MC, Arioglu-Inan E. Sacubitril/Valsartan Combination Partially Improves Cardiac Systolic, but Not Diastolic, Function through β-AR Responsiveness in a Rat Model of Type 2 Diabetes. Int J Mol Sci 2024; 25:10617. [PMID: 39408945 PMCID: PMC11476658 DOI: 10.3390/ijms251910617] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Revised: 09/22/2024] [Accepted: 09/26/2024] [Indexed: 10/19/2024] Open
Abstract
Cardiovascular complications are the major cause of diabetes mellitus-related morbidity and mortality. Increased renin-angiotensin-aldosterone system activity and decreased β-adrenergic receptor (β-AR) responsiveness contribute to diabetic cardiac dysfunction. We evaluated the effect of sacubitril/valsartan (neprilysin inhibitor plus angiotensin receptor antagonist combination) and valsartan treatments on the diabetic cardiac function through β-AR responsiveness and on protein expression of diastolic components. Six-week-old male Sprague Dawley rats were divided into control, diabetic, sacubitril/valsartan (68 mg/kg)-, and valsartan-treated (31 mg/kg) diabetic groups. Diabetes was induced by a high-fat diet plus low-dose streptozotocin (30 mg/kg, intraperitoneal). After 10 weeks of diabetes, rats were treated for 4 weeks. Systolic/diastolic function was assessed by in vivo echocardiography and pressure-volume loop analysis. β-AR-mediated responsiveness was assessed by in vitro papillary muscle and Langendorff heart experiments. Protein expression of sarcoplasmic reticulum calcium ATPase2a, phospholamban, and phosphorylated phospholamban was determined by Western blot. Sacubitril/valsartan improved ejection fraction and fractional shortening to a similar extent as valsartan alone. None of the treatments affected in vivo diastolic parameters or the expression of related proteins. β1-/β2-AR-mediated responsiveness was partially restored in treated animals. β3-AR-mediated cardiac relaxation (an indicator of diastolic function) responses were comparable among groups. The beneficial effect of sacubitril/valsartan on systolic function may be attributed to improved β1-/β2-AR responsiveness.
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Affiliation(s)
- Betul R. Erdogan
- Department of Pharmacology, Faculty of Pharmacy, Ankara University, Ankara 06560, Türkiye; (B.R.E.); (Z.E.Y.-D.); (I.K.); (A.E.M.)
| | - Zeynep E. Yesilyurt-Dirican
- Department of Pharmacology, Faculty of Pharmacy, Ankara University, Ankara 06560, Türkiye; (B.R.E.); (Z.E.Y.-D.); (I.K.); (A.E.M.)
- Department of Pharmacology, Faculty of Pharmacy, Gazi University, Ankara 06330, Türkiye
| | - Irem Karaomerlioglu
- Department of Pharmacology, Faculty of Pharmacy, Ankara University, Ankara 06560, Türkiye; (B.R.E.); (Z.E.Y.-D.); (I.K.); (A.E.M.)
| | - Ayhanim Elif Muderrisoglu
- Department of Pharmacology, Faculty of Pharmacy, Ankara University, Ankara 06560, Türkiye; (B.R.E.); (Z.E.Y.-D.); (I.K.); (A.E.M.)
- Department of Medical Pharmacology, Istanbul Medipol University, Istanbul 34815, Türkiye
| | - Kadir Sevim
- Department of Internal Medicine, Faculty of Veterinary Medicine, Ankara University, Ankara 06110, Türkiye;
| | - Martin C. Michel
- Department of Pharmacology, Johannes Gutenberg University, 55131 Mainz, Germany
| | - Ebru Arioglu-Inan
- Department of Pharmacology, Faculty of Pharmacy, Ankara University, Ankara 06560, Türkiye; (B.R.E.); (Z.E.Y.-D.); (I.K.); (A.E.M.)
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5
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Al-Kuraishy HM, Al-Gareeb AI, Elekhnawy E, Batiha GES. Possible role of LCZ696 in atherosclerosis: new inroads and perspective. Mol Cell Biochem 2024; 479:1895-1908. [PMID: 37526794 DOI: 10.1007/s11010-023-04816-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Accepted: 07/15/2023] [Indexed: 08/02/2023]
Abstract
LCZ696 blocks both angiotensin receptor type 1 (ATR1) and neprilysin (NEP), which are intricate in the degradation of natriuretic peptides (NPs) and other endogenous peptides. It has been shown NEP inhibitors and LCZ696 could be effectively in the management of atherosclerosis (AS). However, the underlying mechanism of LCZ696 in AS is needed to be clarified entirely. Hence, this review is directed to reconnoiter the mechanistic role of LCZ696 in AS. The anti-inflammatory role of LCZ696 is related to the inhibition of transforming growth factor beta (TGF-β)-activated kinase 1 (TAK) and nod-like receptor pyrin 3 receptor (NLRP3) inflammasome. Moreover, LCZ696, via inhibition of pro-inflammatory cytokines, oxidative stress, apoptosis and endothelial dysfunction can attenuate the development and progression of AS. In conclusion, LCZ696 could be effective in the management of AS through modulation of inflammatory and oxidative signaling. Preclinical and clinical studies are recommended in this regard.
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Affiliation(s)
- Hayder M Al-Kuraishy
- Department of Clinical Pharmacology and Medicine, College of Medicine, AL-Mustansiriyia University, Baghdad, Iraq
| | - Ali I Al-Gareeb
- Department of Clinical Pharmacology and Medicine, College of Medicine, AL-Mustansiriyia University, Baghdad, Iraq
| | - Engy Elekhnawy
- Pharmaceutical Microbiology Department, Faculty of Pharmacy, Tanta University, Tanta, 31527, Egypt.
| | - Gaber El-Saber Batiha
- Department of Pharmacology and Therapeutics, Faculty of Veterinary Medicine, Damanhour University, Damanhour, 22511, AL Beheira, Egypt.
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Gan J, Wang Y, Deng Y, Zhang J, Wang S, Jiang X, Guo M, Song L. Sacubitril/valsartan ameliorates cardiac function and ventricular remodeling in CHF rats via the inhibition of the tryptophan/kynurenine metabolism and inflammation. Sci Rep 2024; 14:12377. [PMID: 38811632 PMCID: PMC11136956 DOI: 10.1038/s41598-024-62472-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2023] [Accepted: 05/17/2024] [Indexed: 05/31/2024] Open
Abstract
Sacubitril/valsartan has been highly recognized as a treatment for Chronic heart failure (CHF). Its potential cardioprotective benefits and mechanisms, however, remain to be explored. Metabolomics can be used to identify the metabolic characteristics and related markers, as well as the influence of drugs, thereby opening up the new mechanism for sacubitril/valsartan therapy in CHF disease. In this study, the ligation of left anterior descending and exhaustive swimming were used to induce a rat model of CHF after myocardial infarction. The efficacy was appraised with echocardiography, serum NT-proBNP, and histopathologica. UPLC-Q/TOF-MS combined with multivariate statistical analysis approach were used to analyze the effect of sacubitril/valsartan on CHF rats. RT-qPCR and western blot were performed to investigate the tryptophan/kynurenine metabolism pathway. Accordingly, the basal cardiac function were increased, while the serum NT-proBNP and collagen volume fraction decreased in CHF rats with sacubitril/valsartan. Sacubitril/valsartan regulated the expression of kynurenine et.al 8 metabolomic biomarkers in CHF rats serum, and it contributed to the cardioprotective effects through tryptophan metabolism pathway. In addition, the mRNA and protein expression of the indoleamine 2,3-dioxygenase (IDO) in the myocardial tissue of CHF rats, were down-regulated by sacubitril/valsartan, which was the same with the IL-1β, IFN-γ, TNF-α, COX-2, and IL-6 mRNA expression, and IL-1β, IFN-γ, and TNF-α expression in serum. In conclusion, sacubitril/valsartan can ameliorate cardiac function and ventricular remodeling in CHF rats, at least in part through inhibition of tryptophan/kynurenine metabolism.
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Affiliation(s)
- Jiali Gan
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yuli Wang
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yun Deng
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Jiaqi Zhang
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Shuangcui Wang
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Xijuan Jiang
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Maojuan Guo
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China.
| | - Lili Song
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, China.
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Liu Y, Lu CY, Zheng Y, Zhang YM, Qian LL, Li KL, Tse G, Wang RX, Liu T. Role of angiotensin receptor-neprilysin inhibitor in diabetic complications. World J Diabetes 2024; 15:867-875. [PMID: 38766431 PMCID: PMC11099356 DOI: 10.4239/wjd.v15.i5.867] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2023] [Revised: 12/31/2023] [Accepted: 03/25/2024] [Indexed: 05/10/2024] Open
Abstract
Diabetes mellitus is a prevalent disorder with multi-system manifestations, causing a significant burden in terms of disability and deaths globally. Angio-tensin receptor-neprilysin inhibitor (ARNI) belongs to a class of medications for treating heart failure, with the benefits of reducing hospitalization rates and mortality. This review mainly focuses on the clinical and basic investigations related to ARNI and diabetic complications, discussing possible physiological and molecular mechanisms, with insights for future applications.
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Affiliation(s)
- Ying Liu
- Department of Cardiology, Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin 300211, China
| | - Cun-Yu Lu
- Department of Cardiology, Xuzhou No. 1 Peoples Hospital, Xuzhou 221005, Jiangsu Province, China
| | - Yi Zheng
- Department of Cardiology, Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin 300211, China
| | - Yu-Min Zhang
- Department of Cardiology, Wuxi 9th People’s Hospital Affiliated to Soochow University, Wuxi 214062, Jiangsu Province, China
| | - Ling-Ling Qian
- Department of Cardiology, Wuxi People’s Hospital Affiliated to Nanjing Medical University, Wuxi 214023, Jiangsu Province, China
| | - Ku-Lin Li
- Department of Cardiology, Wuxi People’s Hospital Affiliated to Nanjing Medical University, Wuxi 214023, Jiangsu Province, China
| | - Gary Tse
- Department of Cardiology, Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin 300211, China
- School of Nursing and Health Studies, Metropolitan University, Hong Kong 999077, China
- Kent and Medway Medical School, Kent CT2 7NT, Canterbury, United Kingdom
| | - Ru-Xing Wang
- Department of Cardiology, Wuxi People’s Hospital Affiliated to Nanjing Medical University, Wuxi 214023, Jiangsu Province, China
| | - Tong Liu
- Department of Cardiology, Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin 300211, China
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8
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Kumar K, Rawat P, Kaur S, Singh N, Yadav HN, Singh D, Jaggi AS, Sethi D. Unveiling Wide Spectrum Therapeutic Implications and Signaling Mechanisms of Valsartan in Diverse Disorders: A Comprehensive Review. Curr Drug Res Rev 2024; 16:268-288. [PMID: 37461345 DOI: 10.2174/2589977515666230717120828] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 04/27/2023] [Accepted: 08/24/2023] [Indexed: 09/04/2024]
Abstract
Valsartan is an orally active non-peptide angiotensin receptor antagonist, an effective and well-tolerated anti-hypertensive drug. Besides its antihypertensive action, it has clinical implications in many other disorders, like heart failure (HF), arrhythmia, chronic kidney disease (CKD), diabetic complications (DM), atherosclerosis, etc. Besides angiotensin receptor blocking activity, valsartan reduces circulating levels of biochemical markers, such as hs-CRP, which is responsible for its anti-inflammatory and anti-oxidant activity. Moreover, valsartan also acts by inhibiting or inducing various signalling pathways, such as inducing autophagy via the AKT/mTOR/S6K pathway or inhibiting the TLR/NF-kB pathway. The current review exhaustively discusses the therapeutic implications of valsartan with specific emphasis on the mechanism of action in various disorders. The article provides a detailed spectrum of the therapeutic profile of valsartan and will likely be very useful to researchers working in the relevant research areas.
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Affiliation(s)
- Kuldeep Kumar
- Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, India
| | - Pooja Rawat
- Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, India
| | - Simrat Kaur
- Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, India
| | - Nirmal Singh
- Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, India
| | - Harlokesh Narayan Yadav
- Department of Pharmacology, All India Institute of Medical Sciences (AIIMS), New Delhi, India
| | - Dhandeep Singh
- Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, India
| | - Amteshwar Singh Jaggi
- Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, India
| | - Dimple Sethi
- Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, India
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9
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Xiao Y, Zhou ZY, Sun JC, Xing W, Yan J, Xu WJ, Lu YS, Liu T, Jin Y. Protective effect of novel angiotensin receptor neprilysin inhibitor S086 on target organ injury in spontaneously hypertensive rats. Biomed Pharmacother 2024; 170:115968. [PMID: 38039752 DOI: 10.1016/j.biopha.2023.115968] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Revised: 11/18/2023] [Accepted: 11/27/2023] [Indexed: 12/03/2023] Open
Abstract
BACKGROUND Hypertension is a clinical syndrome characterized by elevated systemic arterial blood pressure associated with injury to the heart, kidney, brain, and other organs. Angiotensin receptor neprilysin inhibitors (ARNi), including angiotensin receptor blockers (ARBs) and neprilysin inhibitors (NEPi), have been shown to be safe and effective at reducing blood pressure and alleviating development of target organ injury. This study was used to develop S086 as a novel ARNi and conducted preclinical studies in animal models to evaluate the protective effects of S086 on target organs. METHODS This study used a 14-month-old spontaneously hypertensive rat (SHR) model to evaluate the protective effects of S086 on the cardiovascular system and organs such as heart and kidney by blood pressure monitoring, urine and blood examination, pathological examination, and immunological index detection. RESULTS After administering S086 orally to the SHR, their blood pressure and levels of renal injury indicators such as serum creatinine and urinary microalbumin were reduced, and myocardial cell necrosis and cardiac fibrosis of the heart were significantly improved. In addition, there were also significantly improvements in the histological lesions of blood vessels and the kidneys. CONCLUSIONS The findings showed that S086 effectively reduced the blood pressure of SHR and had effects on alleviating development of heart, blood vessels and kidney.
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Affiliation(s)
- Ying Xiao
- Shenzhen Salubris Pharmaceutical Co., Ltd., Shenzhen, Guangdong, China
| | - Zheng-Yang Zhou
- College of Animal Science and Technology, Northwest A&F University, Xinong Road 22nd, Yangling, Shaanxi 712100, China
| | - Jing-Chao Sun
- Shenzhen Salubris Pharmaceutical Co., Ltd., Shenzhen, Guangdong, China.
| | - Wei Xing
- Shenzhen Salubris Pharmaceutical Co., Ltd., Shenzhen, Guangdong, China
| | - Jie Yan
- Shenzhen Salubris Pharmaceutical Co., Ltd., Shenzhen, Guangdong, China
| | - Wen-Jie Xu
- Shenzhen Salubris Pharmaceutical Co., Ltd., Shenzhen, Guangdong, China
| | - Yin-Suo Lu
- Shenzhen Salubris Pharmaceutical Co., Ltd., Shenzhen, Guangdong, China
| | - Tao Liu
- College of Animal Science and Technology, Northwest A&F University, Xinong Road 22nd, Yangling, Shaanxi 712100, China.
| | - Yi Jin
- Shenzhen Institute for Drug Control (Shenzhen Testing Center of Medical Devices), Shenzhen, Guangdong, China.
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10
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Shi YJ, Yang CG, Qiao WB, Liu YC, Liu SY, Dong GJ. Sacubitril/valsartan attenuates myocardial inflammation, hypertrophy, and fibrosis in rats with heart failure with preserved ejection fraction. Eur J Pharmacol 2023; 961:176170. [PMID: 37939991 DOI: 10.1016/j.ejphar.2023.176170] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Revised: 10/16/2023] [Accepted: 10/26/2023] [Indexed: 11/10/2023]
Abstract
Heart failure with preserved ejection fraction (HFpEF) represents a multifaceted syndrome related to complex pathologic mechanisms. Sacubitril/valsartan (Sac/val) has demonstrated therapeutic efficacy in HFpEF treatment. However, additional research is required to elucidate its pharmacological mechanisms. Accordingly, this study aimed to explore the potential therapeutic effects of Sac/val in HFpEF rats and the underlying molecular mechanisms. In this study, rats with HFpEF were induced by subjecting spontaneously hypertensive rats to a diet rich in fats, salts, and sugars, along with administering streptozotocin. Subsequently, they were administered Sac/val at a daily dosage of 18 mg/kg. Finally, cardiac structure and function were assessed using echocardiography; Hematoxylin and eosin staining and Masson's trichrome staining were employed to evaluate the pathological changes; Quantitative real-time polymerase chain reaction and Western blot analysis were conducted to determine the expression of pertinent mRNA and proteins. Sac/val treatment attenuated left ventricular (LV) remodeling and diastolic dysfunction in HFpEF rats, possibly related to its anti-inflammatory, anti-hypertrophic, and anti-fibrotic efficacy. Mechanistically, Sac/val might inhibit inflammation by down-regulating cell adhesion molecule (intercellular adhesion molecule-1 (ICAM-1) and vascular endothelial cell adhesion molecule-1 (VCAM-1)) expression. Additionally, it blocked the phosphorylation of glycogen synthase kinase 3β (GSK-3β) to prevent cardiomyocyte hypertrophy. Furthermore, it effectively suppressed myocardial fibrosis by inhibiting the transforming growth factor-beta1 (TGF-β1)/Smads pathway. Our findings suggest that Sac/val improved LV remodeling and diastolic dysfunction, potentially attributed to its anti-inflammatory, anti-hypertrophic, and anti-fibrotic effects. These results provide a sound theoretical rationale for the clinical application of Sac/val in patients with HFpEF.
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Affiliation(s)
- Yu Jiao Shi
- Department of Cardiovascular Internal Medicine, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100091, China
| | - Chen Guang Yang
- Department of Cardiovascular Internal Medicine, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100091, China
| | - Wen Bo Qiao
- Department of Cardiovascular Internal Medicine, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100091, China
| | - Yong Cheng Liu
- Department of Cardiovascular Internal Medicine, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100091, China
| | - Si Yu Liu
- Department of Cardiovascular Internal Medicine, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100091, China
| | - Guo Ju Dong
- Department of Cardiovascular Internal Medicine, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100091, China; National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100091, China.
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11
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Mohyeldin RH, Alaaeldin R, Sharata EE, Attya ME, Elhamadany EY, Fathy M. LCZ696 attenuates sepsis-induced liver dysfunction in rats; the role of oxidative stress, apoptosis, and JNK1/2-P38 signaling pathways. Life Sci 2023; 334:122210. [PMID: 37883863 DOI: 10.1016/j.lfs.2023.122210] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2023] [Revised: 10/16/2023] [Accepted: 10/23/2023] [Indexed: 10/28/2023]
Abstract
AIM Sepsis is a serious inflammatory response to infection with an annual incidence rate of >48 million cases and 11 million fatalities worldwide. Furthermore, sepsis remains the world's fifth-greatest cause of death. For the first time, the current study aims to evaluate the possible hepatoprotective benefits of LCZ696, a combination of an angiotensin receptor blocker (valsartan) and a neprilysin inhibitor prodrug (sacubitril), on cecal ligation and puncture (CLP)-induced sepsis in rats. MAIN METHODS CLP was employed to induce sepsis. Hepatic malondialdehyde (MDA), reduced glutathione (GSH), superoxide dismutase (SOD), interleukin-6 (IL-6), IL-1β, tumor necrosis factor-alpha (TNF-α), and caspase 3 were assessed using ELISA. Serum alanine transaminase (ALT) and aspartate transaminase (AST) were also measured. Western blot assay was used to determine the expression of JNK1/2 and P38 proteins. The histology of liver tissues was also examined. KEY FINDINGS CLP resulted in significant elevation of AST, ALT, MDA, IL-6, IL-1β, TNF-α, and caspase 3 levels, and up-regulation of p/t JNK1/2, and p/t P38 proteins, as compared to the sham group. However, level of GSH, and SOD activity were reduced in CLP group. LCZ696 significantly improved all the previously mentioned biochemical and histological abnormalities better than using valsartan alone. SIGNIFICANCE LCZ696 substantially ameliorated CLP-induced liver damage, compared to valsartan, by reducing proinflammatory mediators, inhibiting the JNK1/2 and P38 signaling pathway, and attenuating apoptosis.
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Affiliation(s)
- Reham H Mohyeldin
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Deraya University, Minia 61111, Egypt.
| | - Rania Alaaeldin
- Department of Biochemistry, Faculty of Pharmacy, Deraya University, Minia 61111, Egypt.
| | - Ehab E Sharata
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Deraya University, Minia 61111, Egypt.
| | - Mina Ezzat Attya
- Department of Pathology, Faculty of Medicine, Minia University, Minia 61519, Egypt.
| | - Eyad Y Elhamadany
- Innovative Research Center, Faculty of Pharmacy, Deraya University, Minia 61111, Egypt.
| | - Moustafa Fathy
- Department of Biochemistry, Faculty of Pharmacy, Minia University, Minia 61519, Egypt.
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12
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Tsukamoto S, Wakui H, Uehara T, Shiba Y, Azushima K, Abe E, Tanaka S, Taguchi S, Hirota K, Urate S, Suzuki T, Yamada T, Kinguchi S, Yamashita A, Tamura K. Combination of sacubitril/valsartan and blockade of the PI3K pathway enhanced kidney protection in a mouse model of cardiorenal syndrome. EUROPEAN HEART JOURNAL OPEN 2023; 3:oead098. [PMID: 37941728 PMCID: PMC10630100 DOI: 10.1093/ehjopen/oead098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Revised: 09/21/2023] [Accepted: 09/25/2023] [Indexed: 11/10/2023]
Abstract
Aims Angiotensin receptor-neprilysin inhibitor (ARNI) is an established treatment for heart failure. However, whether ARNI has renoprotective effects beyond renin-angiotensin system inhibitors alone in cardiorenal syndrome (CRS) has not been fully elucidated. Here, we examined the effects of ARNI on the heart and kidneys of CRS model mice with overt albuminuria and identified the mechanisms underlying ARNI-induced kidney protection. Methods and results C57BL6 mice were subjected to chronic angiotensin II infusion, nephrectomy, and salt loading (ANS); they developed CRS phenotypes and were divided into the vehicle treatment (ANS-vehicle), sacubitril/valsartan treatment (ANS-ARNI), and two different doses of valsartan treatment (ANS-VAL M, ANS-VAL H) groups. Four weeks after treatment, the hearts and kidneys of each group were evaluated. The ANS-vehicle group showed cardiac fibrosis, cardiac dysfunction, overt albuminuria, and kidney fibrosis. The ANS-ARNI group showed a reduction in cardiac fibrosis and cardiac dysfunction compared with the valsartan treatment groups. However, regarding the renoprotective effects characterized by albuminuria and fibrosis, ARNI was less effective than valsartan. Kidney transcriptomic analysis showed that the ANS-ARNI group exhibited a significant enhancement in the phosphoinositide 3-kinase (PI3K)-AKT signalling pathway compared with the ANS-VAL M group. Adding PI3K inhibitor treatment to ARNI ameliorated kidney injury to levels comparable with those of ANS-VAL M while preserving the superior cardioprotective effect of ARNI. Conclusion PI3K pathway activation has been identified as a key mechanism affecting remnant kidney injury under ARNI treatment in CRS pathology, and blockading the PI3K pathway with simultaneous ARNI treatment is a potential therapeutic strategy for treating CRS with overt albuminuria.
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Affiliation(s)
- Shunichiro Tsukamoto
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, 236-0004 Yokohama, Japan
| | - Hiromichi Wakui
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, 236-0004 Yokohama, Japan
| | - Tatsuki Uehara
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, 236-0004 Yokohama, Japan
| | - Yuka Shiba
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, 236-0004 Yokohama, Japan
| | - Kengo Azushima
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, 236-0004 Yokohama, Japan
| | - Eriko Abe
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, 236-0004 Yokohama, Japan
| | - Shohei Tanaka
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, 236-0004 Yokohama, Japan
| | - Shinya Taguchi
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, 236-0004 Yokohama, Japan
| | - Keigo Hirota
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, 236-0004 Yokohama, Japan
| | - Shingo Urate
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, 236-0004 Yokohama, Japan
| | - Toru Suzuki
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, 236-0004 Yokohama, Japan
| | - Takayuki Yamada
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, 236-0004 Yokohama, Japan
- Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Sho Kinguchi
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, 236-0004 Yokohama, Japan
| | - Akio Yamashita
- Department of Investigative Medicine Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan
| | - Kouichi Tamura
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, 236-0004 Yokohama, Japan
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13
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Junho CVC, Frisch J, Soppert J, Wollenhaupt J, Noels H. Cardiomyopathy in chronic kidney disease: clinical features, biomarkers and the contribution of murine models in understanding pathophysiology. Clin Kidney J 2023; 16:1786-1803. [PMID: 37915935 PMCID: PMC10616472 DOI: 10.1093/ckj/sfad085] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Indexed: 11/03/2023] Open
Abstract
The cardiorenal syndrome (CRS) is described as a multi-organ disease encompassing bidirectionally heart and kidney. In CRS type 4, chronic kidney disease (CKD) leads to cardiac injury. Different pathological mechanisms have been identified to contribute to the establishment of CKD-induced cardiomyopathy, including a neurohormonal dysregulation, disturbances in the mineral metabolism and an accumulation of uremic toxins, playing an important role in the development of inflammation and oxidative stress. Combined, this leads to cardiac dysfunction and cardiac pathophysiological and morphological changes, like left ventricular hypertrophy, myocardial fibrosis and cardiac electrical changes. Given that around 80% of dialysis patients suffer from uremic cardiomyopathy, the study of cardiac outcomes in CKD is clinically highly relevant. The present review summarizes clinical features and biomarkers of CKD-induced cardiomyopathy and discusses underlying pathophysiological mechanisms recently uncovered in the literature. It discloses how animal models have contributed to the understanding of pathological kidney-heart crosstalk, but also provides insights into the variability in observed effects of CKD on the heart in different CKD mouse models, covering both "single hit" as well as "multifactorial hit" models. Overall, this review aims to support research progress in the field of CKD-induced cardiomyopathy.
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Affiliation(s)
| | - Janina Frisch
- Department of Biophysics, Center for Integrative Physiology and Molecular Medicine, Medical Faculty, Saarland University, Center for Human and Molecular Biology, Homburg/Saar, Germany
| | - Josefin Soppert
- Institute for Molecular Cardiovascular Research (IMCAR), University Hospital RWTH Aachen, Aachen, Germany
- Department of Anesthesiology, University Hospital RWTH Aachen, Aachen, Germany
| | - Julia Wollenhaupt
- Institute for Molecular Cardiovascular Research (IMCAR), University Hospital RWTH Aachen, Aachen, Germany
| | - Heidi Noels
- Institute for Molecular Cardiovascular Research (IMCAR), University Hospital RWTH Aachen, Aachen, Germany
- Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands
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14
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Ghatage T, Singh S, Mandal K, Dhar A. MasR and pGCA receptor activation protects primary vascular smooth muscle cells and endothelial cells against oxidative stress via inhibition of intracellular calcium. J Cell Biochem 2023. [PMID: 37210727 DOI: 10.1002/jcb.30422] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 04/05/2023] [Accepted: 04/25/2023] [Indexed: 05/23/2023]
Abstract
Cardiovascular diseases (CVDs) are associated with vascular smooth muscle cell (VSMC) and endothelial cell (EC) damage. Angiotensin1-7 (Ang1-7) and B-type natriuretic peptide (BNP) are responsible for vasodilation and regulation of blood flow. These protective effects of BNP are primarily mediated by the activation of sGCs/cGMP/cGKI pathway. Conversely, Ang1-7 inhibits Angiotensin II-induced contraction and oxidative stress via Mas receptor activation. Thus, the aim of the study was to determine the effect of co-activation of MasR and particulate guanylate cyclase receptor (pGCA) pathways by synthesized novel peptide (NP) in oxidative stress-induced VSMCs and ECs. MTT and Griess reagent assay kits were used for the standardization of the oxidative stress (H2 O2 ) induced model in VSMCs. The expression of targeted receptors in VSMC was done by RT-PCR and Western blot analysis. Protective effect of NP in VSMC and EC was determined by immunocytochemistry, FACS analysis, and Western blot analysis. Underlying mechanisms of EC-dependent VSMC relaxation were done by determining downstream mRNA gene expression and intracellular calcium imaging of cells. Synthesized NP significantly improved oxidative stress-induced injury in VSMCs. Remarkably, the actions of NP were superior to that of the Ang1-7 and BNP alone. Further, a mechanistic study in VSMC and EC suggested the involvement of upstream mediators of calcium inhibition for the therapeutic effect. NP is reported to possess vascular protective activities and is also involved in the improvement of endothelial damage. Moreover, it is highly effective than that of individual peptides BNP and Ang1-7 and therefore it may represent a promising strategy for CVDs.
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Affiliation(s)
- Trupti Ghatage
- Department of Pharmacy, Birla Institute of Technology and Sciences (BITS) Pilani, Hyderabad Campus, Hyderabad, Telangana, India
| | - Sameer Singh
- TIFR Centre for Interdisciplinary Sciences, Tata Institute of Fundamental Research, Hyderabad, India
| | - Kalyaneswar Mandal
- TIFR Centre for Interdisciplinary Sciences, Tata Institute of Fundamental Research, Hyderabad, India
| | - Arti Dhar
- Department of Pharmacy, Birla Institute of Technology and Sciences (BITS) Pilani, Hyderabad Campus, Hyderabad, Telangana, India
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15
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Wang S, Wang Y, Deng Y, Zhang J, Jiang X, Yu J, Gan J, Zeng W, Guo M. Sacubitril/valsartan: research progress of multi-channel therapy for cardiorenal syndrome. Front Pharmacol 2023; 14:1167260. [PMID: 37214467 PMCID: PMC10196136 DOI: 10.3389/fphar.2023.1167260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Accepted: 04/17/2023] [Indexed: 05/24/2023] Open
Abstract
Cardiorenal syndrome (CRS) results from complex interaction between heart and kidneys, inducing simultaneous acute or chronic dysfunction of these organs. Although its incidence rate is increasing with higher mortality in patients, effective clinical treatment drugs are currently not available. The literature suggests that renin-angiotensin-aldosterone system (RAAS) and diuretic natriuretic peptide (NP) system run through CRS. Drugs only targeting the RAAS and NPs systems are not effective. Sacubitril/valsartan contains two agents (sacubitril and valsartan) that can regulate RAAS and NPs simultaneously. In the 2017 American College of Cardiology/American Heart Association/American Heart Failure (HF) ssociation (ACC/AHA/HFSA) guideline, sacubitril/valsartan was recommended as standard therapy for HF patients. The latest research shows that Combined levosimendan and Sacubitril/Valsartan markets are protected the heart and kidney against cardiovascular syndrome in rat. However, fewer studies have reported its therapeutic efficacy in CRS treatment, and their results are inconclusive. Therefore, based on RAAS and NPs as CRS biomarkers, this paper summarizes possible pathophysiological mechanisms and preliminary clinical application effects of sacubitril/valsartan in the prevention and treatment of CRS. This will provide a pharmacological justification for expanding sacubitril/valsartan use to the treatment of CRS.
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Affiliation(s)
- Shuangcui Wang
- Oncology Department, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yuli Wang
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yun Deng
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Jiaqi Zhang
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Xijuan Jiang
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Jianchun Yu
- Oncology Department, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Jiali Gan
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Wenyun Zeng
- Traditional Chinese Medicine Department, Ganzhou People’s Hospital, Ganzhou, China
| | - Maojuan Guo
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
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16
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Zhang M, Zou Y, Li Y, Wang H, Sun W, Liu B. The history and mystery of sacubitril/valsartan: From clinical trial to the real world. Front Cardiovasc Med 2023; 10:1102521. [PMID: 37057101 PMCID: PMC10086241 DOI: 10.3389/fcvm.2023.1102521] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Accepted: 03/13/2023] [Indexed: 03/30/2023] Open
Abstract
Heart failure is a serious threat to human health, with morbidity and mortality rates increasing despite the existence of multiple treatment options. Therefore, it is necessary to identify new therapeutic targets for this disease. Sacubitril/valsartan is a supramolecular sodium salt complex of the enkephalinase inhibitor prodrug sacubitril and the angiotensin receptor blocker valsartan. Its combined action increases endogenous natriuretic peptides while inhibiting the renin-angiotensin-aldosterone system and exerting cardioprotective effects. Clinical evidence suggests that sacubitril/valsartan is superior to conventional renin-angiotensin-aldosterone inhibitor therapy for patients with reduced ejection fraction heart failure who can tolerate angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers. The therapy reduces the risk of heart failure hospitalization, cardiovascular mortality, and all-cause mortality and has a better safety and tolerability record. This review describes the potential pathophysiological mechanisms of cardiomyocyte injury amelioration by sacubitril/valsartan. We explore the protective effects of sacubitril/valsartan and outline the therapeutic value in patients with heart failure by summarizing the results of recent large clinical trials. Furthermore, a preliminary outlook shows that sacubitril/valsartan may be effective at treating other diseases, and provides some exploratory observations that lay the foundation for future studies on this drug.
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Affiliation(s)
| | | | | | | | - Wei Sun
- Correspondence: Wei Sun Bin Liu
| | - Bin Liu
- Correspondence: Wei Sun Bin Liu
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17
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Sobiborowicz-Sadowska AM, Kamińska K, Cudnoch-Jędrzejewska A. Neprilysin Inhibition in the Prevention of Anthracycline-Induced Cardiotoxicity. Cancers (Basel) 2023; 15:312. [PMID: 36612307 PMCID: PMC9818213 DOI: 10.3390/cancers15010312] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 12/20/2022] [Accepted: 12/30/2022] [Indexed: 01/05/2023] Open
Abstract
Anthracycline-induced cardiotoxicity (AIC) poses a clinical challenge in the management of cancer patients. AIC is characterized by myocardial systolic dysfunction and remodeling, caused by cardiomyocyte DNA damage, oxidative stress, mitochondrial dysfunction, or renin-angiotensin-aldosterone system (RAAS) dysregulation. In the past decade, after positive results of a PARADIGM-HF trial, a new class of drugs, namely angiotensin receptor/neprilysin inhibitors (ARNi), was incorporated into the management of patients with heart failure with reduced ejection fraction. As demonstrated in a variety of preclinical studies of cardiovascular diseases, the cardioprotective effects of ARNi administration are associated with decreased oxidative stress levels, the inhibition of myocardial inflammatory response, protection against mitochondrial damage and endothelial dysfunction, and improvement in the RAAS imbalance. However, data on ARNi's effectiveness in the prevention of AIC remains limited. Several reports of ARNi administration in animal models of AIC have shown promising results, as ARNi prevented ventricular systolic dysfunction and electrocardiographic changes and ameliorated oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress, and the inflammatory response associated with anthracyclines. There is currently an ongoing PRADAII trial aimed to assess the efficacy of ARNi in patients receiving breast cancer treatment, which is expected to be completed by late 2025.
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Affiliation(s)
| | - Katarzyna Kamińska
- Chair and Department of Experimental and Clinical Physiology, Laboratory of Centre for Preclinical Research, Medical University of Warsaw, 02-091 Warsaw, Poland
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18
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Chen X, Zhang Z, Zhang X, Jia Z, Liu J, Chen X, Xu A, Liang X, Li G. Paeonol attenuates heart failure induced by transverse aortic constriction via ERK1/2 signalling. PHARMACEUTICAL BIOLOGY 2022; 60:562-569. [PMID: 35249458 PMCID: PMC8903794 DOI: 10.1080/13880209.2022.2040543] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/12/2023]
Abstract
CONTEXT Paeonol (PAE) is the main phytochemical from Cortex Moutan. Its main pharmacological effects are anti-inflammatory and antioxidant, but its cardioprotective effect is unclear. OBJECTIVE The study investigates the effects and underlying mechanisms of PAE on transverse aortic constriction (TAC)-induced heart failure (HF) in mice. MATERIALS AND METHODS C57BL/6 mice were randomly divided into five groups: sham, TAC, PAE10 (TAC + PAE 10 mg/kg), PAE20 (TAC + PAE 20 mg/kg) and PAE 50 (TAC + PAE 50 mg/kg). Paeonol was intragastrically administered to mice for 4 weeks. Mice were anaesthetized with pentobarbital sodium and underwent cardiac echocardiography using echocardiography system. Serum levels of atrial natriuretic peptide (ANP), tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were measured by enzyme-linked immunosorbent assay (ELISA). Myocardial apoptosis was detected with terminal deoxynucleotidyl transferase-mediated dUTP nick end-labelling (TUNEL) staining. Haematoxylin-eosin (H&E) and Masson's staining were used for histopathological evaluation. Western and quantitative real-time PCR (qRT-PCR) were performed to detect levels of apoptosis and fibrosis-related proteins. RESULTS Echocardiography showed PAE improved cardiac function (LVEF: TAC, 52.3±6.8%; PAE20, 65.8±3.6%; PAE50, 71.4±2.5%) and H&E staining showed PAE alleviated myocardial injury (TAC: 1170.3 ± 134.6 μm2; PAE50: 576.0 ± 53.5 μm2). Western and qRT-PCR results showed that PAE down-regulated the levels of ANP, BNP and α-MHC. In addition, TUNEL and western results showed PAE significantly inhibited apoptosis. Masson and western results showed PAE inhibited cardiac hypertrophy. Western results showed the ERK1/2/JNK pathway could be inhibited by PAE. DISCUSSION AND CONCLUSIONS Paeonol regulates ERK1/2/JNK to improve cardiac function, which provides theoretical support for the extensive clinical treatment of HF.
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Affiliation(s)
- Xu Chen
- Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, The Second Hospital of Tianjin Medical University, Tianjin, China
- Department of Cardiology, Tianjin Beichen Hospital, Tianjin, China
| | - Zhiyu Zhang
- Tianjin Beichen Center for Disease Control and Prevention, Tianjin, China
| | - Xiaowei Zhang
- Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, The Second Hospital of Tianjin Medical University, Tianjin, China
| | - Zhi Jia
- Department of Cardiology, Tianjin Beichen Hospital, Tianjin, China
| | - Jun Liu
- Department of Cardiology, Tianjin Beichen Hospital, Tianjin, China
| | - Xinpei Chen
- Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, The Second Hospital of Tianjin Medical University, Tianjin, China
| | - Aiqing Xu
- Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, The Second Hospital of Tianjin Medical University, Tianjin, China
| | - Xue Liang
- Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, The Second Hospital of Tianjin Medical University, Tianjin, China
| | - Guangping Li
- Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, The Second Hospital of Tianjin Medical University, Tianjin, China
- CONTACT Guangping Li #23 Pingjiang Road, Hexi District, Tianjin300211, China
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19
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Jing X, Hao L, Yuan‐Nan L, Wei‐Ke L, Lu‐Shen J, Jin‐Yan K, Yi‐Lian C, Yi‐Xuan Q, Li‐Sha G, Yue‐Chun L. The protective effect of LCZ696 in coxsackievirus B3-induced acute viral myocarditis mice. ESC Heart Fail 2022; 10:366-376. [PMID: 36245336 PMCID: PMC9871654 DOI: 10.1002/ehf2.14194] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 08/17/2022] [Accepted: 10/02/2022] [Indexed: 01/27/2023] Open
Abstract
AIMS Acute viral myocarditis (AVMC) is the aetiology of heart failure (HF) with few specific treatments. The improvement of left ventricular ejection fraction (LVEF) is a critical predictor for the prognosis of AVMC. LCZ696 is a drug used in HF to improve LVEF, with a few research on AVMC. In this research, we evaluated the effects and mechanism of LCZ696 in improving LVEF in AVMC. METHODS Eighty 4-week-old male BALB/c mice were randomly divided into four groups of 20: Sham; Sham + LCZ696 (60 mg/kg/d); AVMC; AVMC + LCZ696. The above experiments were repeated by CVB3-infected HL-1 and Mdivi-1 to down-regulated dynamin-related protein 1(Drp1). Adeno-associated virus 9 (AAV9) with enhanced green fluorescent proteins (GFP) was injected to produce Drp1-overexpression mice and set up four groups: AVMC group, AVMC + AAV group, AVMC + LCZ696 group, and AVMC + LCZ696 + AAV group (n = 20 in each group). LVEF was evaluated by echocardiography at a similar heart rate (HR) at d7, Drp1 (p-Drp1), inflammation and apoptosis by histology and Western blot (WB), and mitochondrial by electron microscopy. RESULTS Cardiac function were injured in AVMC that LCZ696 reversed (LVEF, %: Sham: 68.99 ± 9.67; Sham + LCZ696: 71.96 ± 6.20; AVMC: 30.95 ± 6.40*; AVMC + LCZ696: 68.99 ± 9.67*#, *P < 0.05 vs. Sham, #P < 0.05 vs. AVMC). LCZ696 attenuated p-Drp1 expression, inflammation, apoptosis, and mitochondrial fission (p-Drp1/Drp1: Sham: 1; Sham + LCZ696: 1.37 ± 0.22; AVMC: 2.29 ± 0.36*; AVMC+LCZ696: 1.43 ± 0.08*#, *P < 0.05 vs. Sham, #P < 0.05 vs. AVMC). Some of the above results were repeated in CVB3-infected HL-1 cells and Mdivi-1. AAV increased Drp1 expression and mitochondrial fission, inflammatory, and apoptosis. Compared with the AVMC + AAV group, the LVEF increased from 24.44 ± 0.03% to 32.33 ± 0.05% in the AVMC + LCZ696 + AAV group(P < 0.05), p-Drp1/Drp1 decreased from 0.54 ± 0.12 to 0.42 ± 0.09*, and IL-6, c-IL-1β, and c-caspase-3/caspase-3 decreased from 1.07 ± 0.22 to 0.72 ± 0.08*, from 1.03 ± 0.14 to 0.79 ± 0.09*, and from 4.69 ± 0.29 to 0.92 ± 0.13*, respectively (*P < 0.05). CONCLUSIONS LCZ696 has a protective effect on AVMC by improving LVEF and reducing inflammation and apoptosis, which may be due to the inhibition of Drp1-mediated mitochondrial fission.
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Affiliation(s)
- Xu Jing
- Department of CardiologySecond Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical UniversityWenzhou325000China
| | - Lian Hao
- Department of CardiologyThe first people's Hospital of WenlingWenlingChina
| | - Lin Yuan‐Nan
- Department of CardiologySecond Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical UniversityWenzhou325000China
| | - Liu Wei‐Ke
- Department of CardiologySecond Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical UniversityWenzhou325000China
| | - Jin Lu‐Shen
- Department of CardiologySecond Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical UniversityWenzhou325000China
| | - Ke Jin‐Yan
- Department of CardiologySecond Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical UniversityWenzhou325000China
| | - Chen Yi‐Lian
- Department of CardiologySecond Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical UniversityWenzhou325000China
| | - Qiu Yi‐Xuan
- Department of CardiologySecond Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical UniversityWenzhou325000China
| | - Ge Li‐Sha
- Department of Pediatric EmergencyThe Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical UniversityWenzhouChina
| | - Li Yue‐Chun
- Department of CardiologySecond Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical UniversityWenzhou325000China
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20
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Yu W, Zhang H, Shen W, Luo F, Yang S, Gan L, Zhao Y, Yang P, Wu Q. Efficacy and safety of sacubitril/valsartan on heart failure with preserved ejection fraction: A meta-analysis of randomized controlled trials. Front Cardiovasc Med 2022; 9:897423. [PMID: 36158828 PMCID: PMC9492872 DOI: 10.3389/fcvm.2022.897423] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Accepted: 08/15/2022] [Indexed: 11/13/2022] Open
Abstract
AimsThe efficacy and safety of sacubitril/valsartan for patients with heart failure with preserved ejection fraction (HFpEF) are controversial. Hence, the primary objective of the study was to evaluate the efficacy and safety of sacubitril/valsartan treatment for patients with HFpEF.Methods and resultsWe used the PubMed, Embase, and Web of Science databases to search for randomized controlled trials of sacubitril–valsartan in patients with HFpEF. Three studies, involving a total of 7,663 patients, were eligible for inclusion. Sacubitril–valsartan reduced the risk of hospitalization for heart failure (HF) [odds ratio (OR): 0.78; 95% CI: 0.70–0.88; p < 0.0001] and the incidence of worsening renal function [risk ratio (RR): 0.79, p = 0.002] among patients with HFpEF in the three trials, but there was no significant reduction in all-cause mortality (0.99, 95% CI: 0.84–1.15; p = 0.86) or cardiovascular mortality (0.95, 95% CI: 0.78–1.15; p = 0.16). Moreover, sacubitril/valsartan was associated with an increased risk of symptomatic hypotension (RR: 1.44; p < 0.00001) and angioedema (RR: 2.66; p < 0.04); there was no difference for decreasing the incidence of hyperkalemia (RR: 0.89; p = 0.11).ConclusionCompared with valsartan or individualized medical therapy (IMT), sacubitril/valsartan significantly decreased the risk of hospitalization for HF and reduced the incidence of renal dysfunction.
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Affiliation(s)
- Wanqian Yu
- Department of Cardiovascular Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Hongzhou Zhang
- Department of Cardiovascular Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Wen Shen
- Department of Cardiovascular Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Fan Luo
- Medical Center of the Graduate School, Nanchang University, Nanchang, China
| | - Shuai Yang
- Department of Cardiovascular Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Lujin Gan
- Department of Cardiovascular Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Yuanbin Zhao
- Department of Cardiovascular Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Pingping Yang
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Nanchang University, Nanchang, China
- *Correspondence: Pingping Yang
| | - Qinghua Wu
- Department of Cardiovascular Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, China
- Qinghua Wu
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21
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Sacubitril/valsartan (LCZ696) ameliorates hyperthyroid-induced cardiac hypertrophy in male rats through modulation of miR-377, let-7 b, autophagy, and fibrotic signaling pathways. Sci Rep 2022; 12:14654. [PMID: 36030321 PMCID: PMC9420135 DOI: 10.1038/s41598-022-18860-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Accepted: 08/22/2022] [Indexed: 11/08/2022] Open
Abstract
Hyperthyroidism is associated with cardiac hypertrophy, fibrosis, and increased risk of cardiovascular mortality. Sacubitril/valsartan (LCZ696) is a new combined drug that has shown promise for the treatment of hyperthyroidism-associated heart failure; however, the underlying molecular mechanisms, including the contributions of epigenetic regulation, remain unclear. The present study was designed to investigate the therapeutic efficacy of LCZ696 and the potential contributions of microRNA regulation in a rat model of hyperthyroidism-induced cardiac hypertrophy. Cardiac hypertrophy was induced by intraperitoneal administration of levothyroxine. Sixty adult male Wistar rats were randomly allocated to four equal groups (15 rats each): control, cardiac hypertrophy (CH), CH + valsartan, and CH + LCZ696. Treatment with LCZ696 or valsartan significantly improved hemodynamic abnormalities, normalized serum concentrations of natriuretic peptide, fibroblast growth factor-23, and cardiac inflammatory markers compared to CH group rats. Treatment with LCZ696 or valsartan also normalized myocardial expression levels of autophagy markers, fibrotic markers, PPAR-ϒ, mir-377, and let-7b. In addition, both valsartan and LCZ696 ameliorated collagen deposition, ventricular degeneration, and various ultrastructural abnormalities induced by levothyroxine. The beneficial effects of LCZ696 were superior to those of valsartan alone. The superior efficacy of LCZ696 may be explained by the stronger modulation of miR-377 and let-7b.
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22
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Mustafa NH, Jalil J, Zainalabidin S, Saleh MS, Asmadi AY, Kamisah Y. Molecular mechanisms of sacubitril/valsartan in cardiac remodeling. Front Pharmacol 2022; 13:892460. [PMID: 36003518 PMCID: PMC9393311 DOI: 10.3389/fphar.2022.892460] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Accepted: 07/11/2022] [Indexed: 12/11/2022] Open
Abstract
Cardiovascular diseases have become a major clinical burden globally. Heart failure is one of the diseases that commonly emanates from progressive uncontrolled hypertension. This gives rise to the need for a new treatment for the disease. Sacubitril/valsartan is a new drug combination that has been approved for patients with heart failure. This review aims to detail the mechanism of action for sacubitril/valsartan in cardiac remodeling, a cellular and molecular process that occurs during the development of heart failure. Accumulating evidence has unveiled the cardioprotective effects of sacubitril/valsartan on cellular and molecular modulation in cardiac remodeling, with recent large-scale randomized clinical trials confirming its supremacy over other traditional heart failure treatments. However, its molecular mechanism of action in cardiac remodeling remains obscure. Therefore, comprehending the molecular mechanism of action of sacubitril/valsartan could help future research to study the drug's potential therapy to reduce the severity of heart failure.
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Affiliation(s)
- Nor Hidayah Mustafa
- Centre for Drug and Herbal Research Development, Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Juriyati Jalil
- Centre for Drug and Herbal Research Development, Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Satirah Zainalabidin
- Program of Biomedical Science, Centre of Applied and Health Sciences, Faculty of Health Sciences, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Mohammed S.M. Saleh
- Department of Pharmacology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Ahmad Yusof Asmadi
- Unit of Pharmacology, Faculty of Medicine and Defence Health, Universiti Pertahanan Nasional Malaysia, Kuala Lumpur, Malaysia
| | - Yusof Kamisah
- Department of Pharmacology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
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23
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LCZ696 (sacubitril/valsartan) protects against cyclophosphamide-induced nephrotoxicity in adult male rats: Up-regulation of Apelin-13/ACE2, miR-200, and down-regulation of TGF-β/SMAD 2/3 and miR-192. Life Sci 2022; 306:120850. [PMID: 35917938 DOI: 10.1016/j.lfs.2022.120850] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2022] [Revised: 07/26/2022] [Accepted: 07/26/2022] [Indexed: 11/20/2022]
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Lin Y, Zhang H, Zhao S, Chen L, Li J, Wang X, Tian W. The Efficacy and Safety of the Combined Therapy of Sodium-Glucose Co-Transporter-2 Inhibitors and Angiotensin Receptor-Neprilysin Inhibitor in Patients With Heart Failure With Reduced Ejection Fraction: A Meta-Analysis of the EMPEROR-Reduced and DAPA-HF Sub-Analysis. Front Cardiovasc Med 2022; 9:882089. [PMID: 35665248 PMCID: PMC9157547 DOI: 10.3389/fcvm.2022.882089] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Accepted: 04/06/2022] [Indexed: 12/11/2022] Open
Abstract
Background Both sodium-glucose co-transporter-2 (SGLT-2) inhibitors and angiotensin receptor-neprilysin inhibitor (ARNI) were recommended to treat heart failure with reduced ejection fraction (HFrEF). However, no trial was conducted to assess the efficacy and safety of the combined therapy of SGLT-2 inhibitors and ARNI in patients with HFrEF. Methods We performed a meta-analysis of the prespecified subgroups from DAPA-HF and EMPEROR-Reduced trials. The primary endpoint was the composite risk of cardiovascular death or hospitalization for heart failure. The risk of cardiovascular death, all-cause death, a composite of serious adverse renal outcomes, and volume depletion were also estimated. Results The risk of the composite of cardiovascular death or hospitalization for heart failure was reduced in combined therapy of SGLT-2 inhibitors and ARNI, compared with ARNI monotherapy (RR.68, 95% CI.53 to.85, P = 0.001). When compared with SGLT-2 inhibitors monotherapy, the events of cardiovascular death (RR.64, 95% CI.46 to 0.87, P = 0.005) and all-cause death (RR.72, 95% CI.55 to.94, P = 0.01) were significantly less in combined therapy, accompanied by elevated incidence of volume depletion (RR 1.55, 95% CI 1.22 to 1.96, P = 0.0003). Conclusion Combined therapy has additional benefits over monotherapy in patients with HFrEF, however, it is accompanied by a possibly higher risk of volume depletion.
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25
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Hou M, Lu L, Wu X, Liu H. LCZ696 Ameliorates Isoproterenol-Induced Acute Heart Failure in Rats by Activating the Nrf2 Signaling Pathway. Appl Bionics Biomech 2022; 2022:6077429. [PMID: 35528528 PMCID: PMC9076311 DOI: 10.1155/2022/6077429] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 04/08/2022] [Accepted: 04/12/2022] [Indexed: 11/25/2022] Open
Abstract
Objective LCZ696 (sacubitril/valsartan) is an angiotensin II (Ang II) type 1 receptor-neprilysin inhibitor, with effects of immunosuppression, anti-inflammation, antiapoptosis, and antioxidation. The present study was aimed at determining whether LCZ696 has a protective effect against isoproterenol-induced acute heart failure (AHF) in rats. Methods SD rats were randomly divided into four groups: control group, HF group, LCZ696 group, and enalapril group. The cardiac function of rats was evaluated using echocardiographic parameters, heart weight (HW), serum levels of cardiac troponin I (cTnI), and lactate dehydrogenase (LDH). HE is staining, which was used to determine the pathological damage of rat myocardial tissue. Also, we measured oxidative stress markers including reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD), and catalase (CAT). Finally, the expression of Nrf2 signaling pathway-related proteins was determined using Western blot. Results Compared with the HF group, LCZ696 could significantly improve cardiac function and myocardial injury in rats and reduce AHF-induced oxidative stress. In addition, the results of Western blot confirmed that LCZ696 could upregulate the expression of Nrf2 and HO-1 while decreasing Keap1 expression. Conclusion LCZ696 ameliorates isoproterenol-induced AHF in rats by alleviating oxidative stress injury and activating the Nrf2 signaling pathway.
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Affiliation(s)
- Min Hou
- Department of Emergency, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan 030032, China
- Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Linxin Lu
- Department of Emergency, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan 030032, China
- Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Xiaobo Wu
- Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Department of Lymphoma, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan 030032, China
| | - Hongxuan Liu
- Department of Emergency, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan 030032, China
- Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
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26
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LCZ696 ameliorates doxorubicin-induced cardiomyocyte toxicity in rats. Sci Rep 2022; 12:4930. [PMID: 35322164 PMCID: PMC8943022 DOI: 10.1038/s41598-022-09094-z] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Accepted: 03/17/2022] [Indexed: 12/11/2022] Open
Abstract
Doxorubicin (DOX)-based chemotherapy induces cardiotoxicity, which is considered the main bottleneck for its clinical application. In this study, we investigated the potential benefit of LCZ696, an angiotensin receptor-neprilysin inhibitor against DOX-induced cardiotoxicity in rats and H9c2 cells and determined whether the mechanism underlying any such effects involves its antioxidant activity. Male Sprague-Dawley rats were randomly separated into four groups, each consisting of 15 rats (DOX (1.5 mg/kg/day intraperitoneally for 10 days followed by non-treatment for 8 days); DOX + valsartan (31 mg/kg/day by gavage from day 1 to day 18); DOX + LCZ696 (68 mg/kg/day by gavage from day 1 to day 18); and control (saline intraperitoneally for 10 days). DOX-induced elevation of cardiac troponin T levels on day 18 was significantly reduced by LCZ696, but not valsartan. The DOX-induced increase in myocardial reactive oxygen species (ROS) levels determined using dihydroethidium was significantly ameliorated by LCZ696, but not valsartan, and was accompanied by the suppression of DOX-induced increase in p47phox. LCZ696 recovered the DOX-induced decrease in phosphorylation of adenosine monophosphate-activated protein kinase and increased the ratio of Bax and Bcl-2. In H9c2 cardiomyocytes, LCZ696 reduced DOX-induced mitochondrial ROS generation and improved cell viability more than valsartan. Our findings indicated that LCZ696 ameliorated DOX-induced cardiotoxicity in rat hearts in vivo and in vitro, possibly by mediating a decrease in oxidative stress.
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27
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Wang Y, Yang Y, He F. Insights into Concomitant Atrial Fibrillation and Chronic Kidney Disease. Rev Cardiovasc Med 2022; 23:105. [PMID: 35345272 DOI: 10.31083/j.rcm2303105] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2022] [Revised: 02/24/2022] [Accepted: 03/03/2022] [Indexed: 01/03/2025] Open
Abstract
Chronic kidney disease (CKD) shows a high prevalence and is characterized by progressive and irreversible loss of renal function. It is also associated with a high risk of cardiovascular disease. The CKD population often suffers from atrial fibrillation (AF), which is associated with cardiovascular and all-cause mortality. There is a pernicious bidirectional relationship between CKD and AF: renal dysfunction can help promote AF initiation and maintenance, while unmanageable AF often accelerates kidney function deterioration. Therefore, it is necessary to determine the interactive mechanisms between CKD and AF for optimal management of patients. However, due to renal function impairment and changes in the pharmacokinetics of anticoagulants, it is still elusive to formulate a normative therapeutic schedule for the AF population concomitant with CKD especially those with end-stage kidney failure. This review describes the possible molecular mechanisms linking CKD to AF and existing therapeutic options.
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Affiliation(s)
- Yanan Wang
- Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, Hubei, China
| | - Yi Yang
- Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, Hubei, China
| | - Fan He
- Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, Hubei, China
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28
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Nathaniel S, McGinty S, Witman MAH, Edwards DG, Farquhar WB, Hosmane V, Wenner MM. Impact of angiotensin receptor-neprilysin inhibition on vascular function in heart failure with reduced ejection fraction: A pilot study. Physiol Rep 2022; 10:e15209. [PMID: 35246960 PMCID: PMC8897740 DOI: 10.14814/phy2.15209] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Accepted: 01/30/2022] [Indexed: 06/14/2023] Open
Abstract
The mechanisms for the benefits of Angiotensin Receptor Neprilysin Inhibition (ARNi) in heart failure patients with reduced ejection fraction (HFrEF) are likely beyond blood pressure reduction. Measures of vascular function such as arterial stiffness and endothelial function are strong prognostic markers of cardiovascular outcomes in HFrEF, yet the impact of ARNi on vascular health remains to be explored. We hypothesized that arterial stiffness and endothelial function would improve after 12 weeks of ARNi in HFrEF. We tested 10 stable HFrEF patients at baseline and following 12 weeks of ARNi [64 ± 9 years, Men/Women: 9/1, left ventricular ejection fraction (EF): 28 ± 6%] as well as 10 stable HFrEF patients that remained on conventional treatment (CON: 60 ± 7 years, Men/Women: 6/4, EF: 31 ± 5%; all p = NS). Arterial stiffness was assessed via carotid-femoral pulse wave velocity (PWV) and endothelial function was assessed via brachial artery flow-mediated dilation (FMD). PWV decreased after 12 weeks of ARNi (9.0 ± 2.1 vs. 7.1 ± 1.2 m/s; p < 0.01) but not in CON (7.0 ± 2.4 vs. 7.5 ± 2.3 m/s; p = 0.35), an effect that remained when controlling for reductions in mean arterial pressure (p < 0.01). FMD increased after 12 weeks of ARNi (2.2 ± 1.9 vs. 5.5 ± 2.1%; p < 0.001) but not in CON (4.8 ± 3.8 vs. 5.4 ± 3.4%; p = 0.34). Baseline PWV (p = 0.06) and FMD (p = 0.07) were not different between groups. These preliminary data suggest that 12 weeks of ARNi therapy may reduce arterial stiffness and improve endothelial function in HFrEF. Thus, the findings from this pilot study suggest that the benefits of ARNi are beyond blood pressure reduction and include improvements in vascular function.
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Affiliation(s)
- Sangeetha Nathaniel
- Department of Kinesiology and Applied PhysiologyUniversity of DelawareNewarkDelawareUSA
| | - Shane McGinty
- Department of Kinesiology and Applied PhysiologyUniversity of DelawareNewarkDelawareUSA
| | - Melissa A. H. Witman
- Department of Kinesiology and Applied PhysiologyUniversity of DelawareNewarkDelawareUSA
| | - David G. Edwards
- Department of Kinesiology and Applied PhysiologyUniversity of DelawareNewarkDelawareUSA
| | - William B. Farquhar
- Department of Kinesiology and Applied PhysiologyUniversity of DelawareNewarkDelawareUSA
| | - Vinay Hosmane
- Hosmane Cardiology and Section of CardiologyChristiana Care Healthcare SystemNewarkDelawareUSA
| | - Megan M. Wenner
- Department of Kinesiology and Applied PhysiologyUniversity of DelawareNewarkDelawareUSA
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29
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Zhang X, Zhou Y, Ma R. Potential effects and application prospect of angiotensin receptor-neprilysin inhibitor in diabetic kidney disease. J Diabetes Complications 2022; 36:108056. [PMID: 34893426 DOI: 10.1016/j.jdiacomp.2021.108056] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Revised: 09/21/2021] [Accepted: 09/25/2021] [Indexed: 12/18/2022]
Abstract
Diabetic kidney disease (DKD) is one of the main causes of end-stage renal disease (ESRD) and all-cause mortality in diabetic patients, despite the extensive use of angiotensin-converting enzyme inhibitor (ACEI) and angiotensin II receptor blocker (ARB). Angiotensin receptor-neprilysin inhibitor (ARNI), combining ARB and neutral endopeptidase inhibitor (NEPI), is likely to have potential favorable effects in DKD. This review summarizes existing preclinical and clinical studies on mechanism of ARNI and its potential effects on DKD. In preclinical studies, ARNI manifested its renoprotective effects by improving natriuresis, ameliorating inflammation, oxidative stress and renal dysfunction, and slowing down glomerulosclerosis and tubulointerstitial injury of kidney, but its effect on proteinuria is still controversial. Beneficial effects of ARNI on blood glucose regulation and glycometabolism have also been reported. There are no clinical studies of ARNI that specifically focus on DKD patients so far. ARNI has application potential in DKD, but there still need clinical studies that focus on DKD patients to determine its effectiveness, safety and underlying mechanism.
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Affiliation(s)
- Xingjian Zhang
- Affiliated Hospital of Qingdao University, Qingdao 266000, China
| | - Yan Zhou
- Affiliated Hospital of Qingdao University, Qingdao 266000, China
| | - Ruixia Ma
- Affiliated Hospital of Qingdao University, Qingdao 266000, China.
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Malik J, Shahid AW, Shah M, Rana G, Kamal A, Naeem H. Outcome of angiotensin receptor-neprilysin inhibitor on anxiety and depression in heart failure with reduced ejection fraction vs. heart failure with preserved ejection fraction. J Community Hosp Intern Med Perspect 2021; 11:629-634. [PMID: 34567453 PMCID: PMC8462846 DOI: 10.1080/20009666.2021.1942623] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022] Open
Abstract
Objective: In patients with heart failure (HF), anxiety and depression are commonly observed and confer an adverse outcome. The first-in-class member of angiotensin receptor-neprilysin inhibitor (ARNI), sacubitril/valsartan has been demonstrated to improve functional class and decrease mortality in patients with heart failure with reduced ejection fraction (HFrEF) and reduce the readmission of heart failure with preserved ejection fraction (HFpEF). However, its effects on anxiety and depression levels remain unknown.Methods: Sacubitril/valsartan was started on 764 symptomatic patients with HFrEF and HFpEF who were receiving guideline-directed medical therapy (GDMT) with an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB). Patients were evaluated using Hamilton's depression rating scale (HDRS) and the hospital anxiety and depression scale (HADS) for their levels of depression and anxiety before and after treatment at a six-month follow-up.Results: A significant reduction in HADS and HDRS scores was observed in patients with HFrEF (9.7 ± 1.3 to 6.4 ± 0.7, p = 0.032 and 19.2 ± 2.2 to 8.9 ± 1.6, p < 0.001, respectively) compared with HFpEF (p = 0.161 and 0.273, respectively). The six-minute walk test (6-MWT) significantly increased HFrEF from 195 ± 68 to 321 ± 97 (p < 0.001). There was an overall improvement in the functional class of all patients.Conclusion: Patients with HFrEF have the additional advantage of using sacubitril/valsartan in the form of decreased anxiety and depression symptoms in addition to an improvement in functional class. However, patients with HFpEF did not exhibit significant improvement in their psychological scores.
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Affiliation(s)
- Jahanzeb Malik
- Department of Cardiology, Rawalpindi Institute of Cardiology, Rawalpindi, Pakistan
| | - Abdul Wahab Shahid
- Department of Cardiology, Rawalpindi Institute of Cardiology, Rawalpindi, Pakistan
| | - Mohsin Shah
- Department of Cardiology, Rawalpindi Institute of Cardiology, Rawalpindi, Pakistan
| | - Ghazanfar Rana
- Department of Cardiology, Saint Luke's General Hospital, Kilkenny, Ireland
| | - Ahmed Kamal
- Department of Cardiology, Rawalpindi Institute of Cardiology, Rawalpindi, Pakistan
| | - Hesham Naeem
- Department of Cardiology, Rawalpindi Institute of Cardiology, Rawalpindi, Pakistan
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Kuang H, Huang X, Zhou Z, Cheng X, Xu G. Sacubitril/valsartan in chronic kidney disease: From pharmacological mechanism to clinical application. Eur J Pharmacol 2021; 907:174288. [PMID: 34216577 DOI: 10.1016/j.ejphar.2021.174288] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 06/08/2021] [Accepted: 06/25/2021] [Indexed: 02/08/2023]
Abstract
Chronic kidney disease (CKD) is an irreversible, progressive disease characterized by persistent kidney damage, and significantly increased risks of cardiovascular event. However, therapeutic strategies to prevent or slow the progression of CKD remain limited. Sacubitril/valsartan (LCZ696), the representative of the first novel angiotensin receptor-neprilysin inhibitor, has been incorporated into clinical practice guidelines for improving outcomes as a milestone in patients with heart failure. Considering the complex and close relationship between CKD and heart failure, LCZ696 may be beneficial in the treatment of CKD. This review summarizes the pharmacological mechanism and clinical application of LCZ696 in patients with CKD, including its effect on cardiovascular risk and renal outcome, together with potential adverse events. Additionally, due to the influence of serum creatinine and estimated glomerular filtration rate on LCZ696 in patients with heart failure, we also discussed the effects of LCZ696 in patients with advanced CKD and end-stage renal disease. It should be noted that, current clinical studies on LCZ696 are mostly carried out in patients with heart failure, and renal indicators are selected as secondary outcomes. Therefore, more researches should be conducted in patients with CKD alone in the future, to determine the efficacy and safety of LCZ696 in patients with CKD.
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Affiliation(s)
- Huang Kuang
- Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, 100034, China
| | - Xin Huang
- Department of Nephrology, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, China
| | - Zhifeng Zhou
- Department of Nephrology, Kidney Research Institute, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xuexin Cheng
- Department of Nephrology, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, China.
| | - Gaosi Xu
- Department of Nephrology, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, China.
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Kovács ZZA, Szűcs G, Freiwan M, Kovács MG, Márványkövi FM, Dinh H, Siska A, Farkas K, Kovács F, Kriston A, Horváth P, Kővári B, Cserni BG, Cserni G, Földesi I, Csont T, Sárközy M. Comparison of the antiremodeling effects of losartan and mirabegron in a rat model of uremic cardiomyopathy. Sci Rep 2021; 11:17495. [PMID: 34471171 PMCID: PMC8410807 DOI: 10.1038/s41598-021-96815-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2021] [Accepted: 08/17/2021] [Indexed: 02/07/2023] Open
Abstract
Uremic cardiomyopathy is characterized by diastolic dysfunction (DD), left ventricular hypertrophy (LVH), and fibrosis. Angiotensin-II plays a major role in the development of uremic cardiomyopathy via nitro-oxidative and inflammatory mechanisms. In heart failure, the beta-3 adrenergic receptor (β3-AR) is up-regulated and coupled to endothelial nitric oxide synthase (eNOS)-mediated pathways, exerting antiremodeling effects. We aimed to compare the antiremodeling effects of the angiotensin-II receptor blocker losartan and the β3-AR agonist mirabegron in uremic cardiomyopathy. Chronic kidney disease (CKD) was induced by 5/6th nephrectomy in male Wistar rats. Five weeks later, rats were randomized into four groups: (1) sham-operated, (2) CKD, (3) losartan-treated (10 mg/kg/day) CKD, and (4) mirabegron-treated (10 mg/kg/day) CKD groups. At week 13, echocardiographic, histologic, laboratory, qRT-PCR, and Western blot measurements proved the development of uremic cardiomyopathy with DD, LVH, fibrosis, inflammation, and reduced eNOS levels, which were significantly ameliorated by losartan. However, mirabegron showed a tendency to decrease DD and fibrosis; but eNOS expression remained reduced. In uremic cardiomyopathy, β3-AR, sarcoplasmic reticulum ATPase (SERCA), and phospholamban levels did not change irrespective of treatments. Mirabegron reduced the angiotensin-II receptor 1 expression in uremic cardiomyopathy that might explain its mild antiremodeling effects despite the unchanged expression of the β3-AR.
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Affiliation(s)
- Zsuzsanna Z A Kovács
- MEDICS Research Group, Department of Biochemistry, Interdisciplinary Center of Excellence, Albert Szent-Györgyi Medical School, University of Szeged, Dóm tér 9, Szeged, 6720, Hungary
| | - Gergő Szűcs
- MEDICS Research Group, Department of Biochemistry, Interdisciplinary Center of Excellence, Albert Szent-Györgyi Medical School, University of Szeged, Dóm tér 9, Szeged, 6720, Hungary
| | - Marah Freiwan
- MEDICS Research Group, Department of Biochemistry, Interdisciplinary Center of Excellence, Albert Szent-Györgyi Medical School, University of Szeged, Dóm tér 9, Szeged, 6720, Hungary
| | - Mónika G Kovács
- MEDICS Research Group, Department of Biochemistry, Interdisciplinary Center of Excellence, Albert Szent-Györgyi Medical School, University of Szeged, Dóm tér 9, Szeged, 6720, Hungary
| | - Fanni M Márványkövi
- MEDICS Research Group, Department of Biochemistry, Interdisciplinary Center of Excellence, Albert Szent-Györgyi Medical School, University of Szeged, Dóm tér 9, Szeged, 6720, Hungary
| | - Hoa Dinh
- MEDICS Research Group, Department of Biochemistry, Interdisciplinary Center of Excellence, Albert Szent-Györgyi Medical School, University of Szeged, Dóm tér 9, Szeged, 6720, Hungary
| | - Andrea Siska
- Department of Laboratory Medicine, Albert Szent-Györgyi Medical School, University of Szeged, Semmelweis utca 6, Szeged, 6720, Hungary
| | - Katalin Farkas
- Department of Laboratory Medicine, Albert Szent-Györgyi Medical School, University of Szeged, Semmelweis utca 6, Szeged, 6720, Hungary
| | - Ferenc Kovács
- Synthetic and Systems Biology Unit, Biological Research Centre, Eötvös Loránd Research Network, Temesvári krt. 62, Szeged, 6726, Hungary
- Single-Cell Technologies Ltd, Temesvári krt. 62, Szeged, 6726, Hungary
| | - András Kriston
- Synthetic and Systems Biology Unit, Biological Research Centre, Eötvös Loránd Research Network, Temesvári krt. 62, Szeged, 6726, Hungary
- Single-Cell Technologies Ltd, Temesvári krt. 62, Szeged, 6726, Hungary
| | - Péter Horváth
- Synthetic and Systems Biology Unit, Biological Research Centre, Eötvös Loránd Research Network, Temesvári krt. 62, Szeged, 6726, Hungary
- Single-Cell Technologies Ltd, Temesvári krt. 62, Szeged, 6726, Hungary
- Institute for Molecular Medicine Finland (FIMM), University of Helsinki, 00014, Helsinki, Finland
| | - Bence Kővári
- Department of Pathology, Albert Szent-Györgyi Medical School, University of Szeged, Állomás utca 1, Szeged, 6720, Hungary
| | - Bálint Gábor Cserni
- Department of Pathology, Albert Szent-Györgyi Medical School, University of Szeged, Állomás utca 1, Szeged, 6720, Hungary
| | - Gábor Cserni
- Department of Pathology, Albert Szent-Györgyi Medical School, University of Szeged, Állomás utca 1, Szeged, 6720, Hungary
| | - Imre Földesi
- Department of Laboratory Medicine, Albert Szent-Györgyi Medical School, University of Szeged, Semmelweis utca 6, Szeged, 6720, Hungary
| | - Tamás Csont
- MEDICS Research Group, Department of Biochemistry, Interdisciplinary Center of Excellence, Albert Szent-Györgyi Medical School, University of Szeged, Dóm tér 9, Szeged, 6720, Hungary.
| | - Márta Sárközy
- MEDICS Research Group, Department of Biochemistry, Interdisciplinary Center of Excellence, Albert Szent-Györgyi Medical School, University of Szeged, Dóm tér 9, Szeged, 6720, Hungary.
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Angiotensin Receptor Blocker and Neprilysin Inhibitor Suppresses Cardiac Dysfunction by Accelerating Myocardial Angiogenesis in Apolipoprotein E-Knockout Mice Fed a High-Fat Diet. J Renin Angiotensin Aldosterone Syst 2021; 2021:9916789. [PMID: 34394711 PMCID: PMC8357528 DOI: 10.1155/2021/9916789] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2021] [Accepted: 07/08/2021] [Indexed: 12/11/2022] Open
Abstract
Materials and Methods Male apolipoprotein E-knockout mice fed a high-fat diet were divided into control (CTL), valsartan (30 mg/kg) (VAL), sacubitril (30 mg/kg) (SAC), and valsartan plus sacubitril (30 mg/kg each) (VAL/SAC) groups after 4 weeks of prefeeding and were subsequently treated for 12 weeks. Results The VAL/SAC group exhibited significantly higher serum brain natriuretic peptide levels; more subtle changes in left ventricular systolic diameter, fractional shortening, and ejection fraction, and significantly higher expression levels of natriuretic peptide precursor B and markers of angiogenesis, including clusters of differentiation 34, vascular endothelial growth factor A, and monocyte chemotactic protein 1, than the CTL group. Conclusions Valsartan plus sacubitril preserved left ventricular systolic function in apolipoprotein E-knockout mice fed a high-fat diet. This result suggests that myocardial angiogenic factors induced by ARNI might provide cardioprotective effects.
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Li Y, Kang L, Rong K, Zhang Y, Suo Y, Yuan M, Bao Q, Shao S, Tse G, Li R, Liu T, Li G. Renal protective effects and mechanisms of the angiotensin receptor-neprilysin inhibitor LCZ696 in mice with cardiorenal syndrome. Life Sci 2021; 280:119692. [PMID: 34102189 DOI: 10.1016/j.lfs.2021.119692] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2021] [Revised: 05/16/2021] [Accepted: 05/28/2021] [Indexed: 02/06/2023]
Abstract
AIMS This study investigated the renal protective effects and mechanisms of angiotensin receptor-neprilysin inhibitor LCZ696 in mice with cardiorenal syndrome. MATERIALS AND METHODS Mice were divided into abdominal aortic ligation alone, or treatment with LCZ696 or valsartan, whilst those undergoing sham surgery served as controls. Rat proximal renal tubular epithelial cells from the NRK-52E line were treated with control solution, LCZ696 or valsartan, in the presence or absence of Ang II for 24 h. KEY FINDINGS Compared to controls, abdominal aortic ligation significantly increased plasma NT-proBNP and urine neutrophil gelatinase-associated lipocalin (NGAL), which were associated with reduced renal length and velocity time integral on ultrasonography. Histology revealed wrinkling of the glomerular capillary wall and sclerosis of the glomerulus, dilatation of the Bowman's capsule, accompanied by diffuse renal tubular atrophy and fibrosis, accompanied by lower kidney index and higher percentage area of fibrosis. Increases in NGAL and decreased ANP protein and mRNA expression levels were observed. These abnormalities were significantly prevented by LCZ696 and to a lesser extent by valsartan. Cellular experiments demonstrated a central role of Ang II/transforming growth factor-β1/Smad2/3/connective tissue growth factor-dependent signaling leading to type IV collagen deposition. This upregulation was reversed by LCZ696 in a greater extent than valsartan treatment alone, accompanied by a significant improvement in NGAL. SIGNIFICANCE LCZ696 can reduce kidney injury to a level beyond valsartan therapy alone in mice with cardiorenal syndrome, which can be speculated by effects on epithelial-mesenchymal transition and fibrosis through downregulating the TGF-β1/Smad2/3/CTGF/Collagen IV pathway.
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Affiliation(s)
- Ying Li
- Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin, China; Department of Nephrology, Second Hospital of Tianjin Medical University, Tianjin, China
| | - Li Kang
- Department of Nephrology, Second Hospital of Tianjin Medical University, Tianjin, China
| | - Kai Rong
- Department of Nephrology, Second Hospital of Tianjin Medical University, Tianjin, China
| | - Yue Zhang
- Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin, China
| | - Ya Suo
- Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin, China
| | - Meng Yuan
- Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin, China
| | - Qiankun Bao
- Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin, China
| | - Shuai Shao
- Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin, China
| | - Gary Tse
- Department of Medicine and Therapeutics, Chinese University of Hong Kong, Hong Kong, China; Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong, China
| | - Rong Li
- Department of Nephrology, Second Hospital of Tianjin Medical University, Tianjin, China
| | - Tong Liu
- Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin, China
| | - Guangping Li
- Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin, China.
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35
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Choi MR, Fernández BE. Protective Renal Effects of Atrial Natriuretic Peptide: Where Are We Now? Front Physiol 2021; 12:680213. [PMID: 34135773 PMCID: PMC8202499 DOI: 10.3389/fphys.2021.680213] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2021] [Accepted: 04/29/2021] [Indexed: 12/11/2022] Open
Abstract
Atrial natriuretic peptide belongs to the family of natriuretic peptides, a system with natriuretic, diuretic, and vasodilator effects that opposes to renin-angiotensin system. In addition to its classic actions, atrial natriuretic peptide exerts a nephroprotective effect given its antioxidant and anti-inflammatory properties, turning it as a beneficial agent against acute and chronic kidney diseases. This minireview describes the most relevant aspects of atrial natriuretic peptide in the kidney, including its renal synthesis, physiological actions through specific receptors, the importance of its metabolism, and its potential use in different pathological scenarios.
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Affiliation(s)
- Marcelo Roberto Choi
- Instituto Alberto C. Taquini de Investigaciones en Medicina Traslacional (IATIMET), CONICET - Universidad de Buenos Aires, Buenos Aires, Argentina.,Departamento de Ciencias Biológicas, Facultad de Farmacia y Bioquímica, Cátedra de Anatomía e Histología, Universidad de Buenos Aires, Buenos Aires, Argentina.,Instituto Universitario de Ciencias de la Salud, Fundación H.A. Barceló, Buenos Aires, Argentina
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36
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Myakala K, Jones BA, Wang XX, Levi M. Sacubitril/valsartan treatment has differential effects in modulating diabetic kidney disease in db/db mice and KKAy mice compared with valsartan treatment. Am J Physiol Renal Physiol 2021; 320:F1133-F1151. [PMID: 33870733 DOI: 10.1152/ajprenal.00614.2020] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Although renin-angiotensin blockade has shown beneficial outcomes in patients with diabetes, renal injury progresses in most of these patients. Therefore, there remains a need for new therapeutic targets in diabetic kidney disease. Enhancement of vasoactive peptides, such as natriuretic peptides, via neprilysin inhibition, has been a new approach. A first-in-class drug, sacubitril/valsartan (Sac/Val), a combination of the angiotensin II receptor blocker Val and neprilysin inhibitor prodrug Sac, has been shown to be more effective than renin-angiotensin blockade alone in the treatment of heart failure with reduced ejection fraction. In this study, we tested the effects of Sac/Val in diabetic kidney disease. We administered Sac/Val or Val to two type 2 diabetes mouse models, db/db mice or KKAy mice. After 3 mo of treatment, Sac/Val attenuated the progression of proteinuria, glomerulosclerosis, and podocyte loss in both models of diabetic mice. Val shared a similar improvement but to a lesser degree in some parameters compared with Sac/Val. Sac/Val but not Val decreased the blood glucose level in KKAy mice. Sac/Val exerted renal protection through coordinated effects on antioxidative stress and anti-inflammation. In both diabetic models, we revealed a new mechanism to cause inflammation, self-DNA-activated cGMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling, which was activated in diabetic kidneys and prevented by Sac/Val or Val treatment. The present data suggest that Sac/Val has sufficient therapeutical potential to counter the pathophysiological effects of diabetic kidney disease, and its effectiveness could be better than Val alone.NEW & NOTEWORTHY The first-in-class drug sacubitril/valsartan, a combination of the angiotensin II receptor blocker valsartan and neprilysin inhibitor sacubitril, was tested for its effects in diabetic kidney disease using db/db mice and KKAy mice. We found that Sac/Val has sufficient therapeutical potential to counter the pathophysiological effects of diabetic kidney disease. We further revealed a new mechanism to cause inflammation, self-DNA-activated cGAS-STING signaling, which was activated in diabetic kidneys and prevented by sacubitril/valsartan or valsartan treatment.
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Affiliation(s)
- Komuraiah Myakala
- Department of Biochemistry and Molecular & Cellular Biology, Georgetown University, Washington, District of Columbia
| | - Bryce A Jones
- Department of Pharmacology and Physiology, Georgetown University, Washington, District of Columbia
| | - Xiaoxin X Wang
- Department of Biochemistry and Molecular & Cellular Biology, Georgetown University, Washington, District of Columbia
| | - Moshe Levi
- Department of Biochemistry and Molecular & Cellular Biology, Georgetown University, Washington, District of Columbia
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37
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Brignone J, Assersen KB, Jensen M, Jensen BL, Kloster B, Jønler M, Lund L. Protection of kidney function and tissue integrity by pharmacologic use of natriuretic peptides and neprilysin inhibitors. Pflugers Arch 2021; 473:595-610. [PMID: 33844072 DOI: 10.1007/s00424-021-02555-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Revised: 03/03/2021] [Accepted: 03/06/2021] [Indexed: 12/11/2022]
Abstract
With variable potencies atrial-, brain-type and c-type natriuretic peptides (NP)s, best documented for ANP and its analogues, promote sodium and water excretion, renal blood flow, lipolysis, lower blood pressure, and suppress renin and aldosterone secretion through interaction predominantly with cGMP-coupled NPR-A receptor. Infusion of especially ANP and its analogues up to 50 ng/kg/min in patients with high risk of acute kidney injury (cardiac vascular bypass surgery, intraabdominal surgery, direct kidney surgery) protects kidney function (GFR, plasma flow, medullary flow, albuminuria, renal replacement therapy, tissue injury) at short term and also long term and likely additively with the diuretic furosemide. This documents a pharmacologic potential for the pathway. Neprilysin (NEP, neutral endopeptidase) degrades NPs, in particular ANP, and angiotensin II. The drug LCZ696, a mixture of the neprilysin inhibitor sacubitril and the ANGII-AT1 receptor blocker valsartan, was FDA approved in 2015 and marketed as Entresto®. In preclinical studies of kidney injury, LCZ696 and NPs lowered plasma creatinine, countered hypoxia and oxidative stress, suppressed proinflammatory cytokines, and inhibited fibrosis. Few randomized clinical studies exist and were designed with primary cardiac outcomes. The studies showed that LCZ696/entresto stabilized and improved glomerular filtration rate in patients with chronic kidney disease. LCZ696 is safe to use concerning kidney function and stabilizes or increases GFR. In perspective, combined AT1 and neprilysin inhibition is a promising approach for long-term renal protection in addition to AT1 receptor blockers in acute kidney injury and chronic kidney disease.
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Affiliation(s)
- Juan Brignone
- Department of Urology, Aalborg University Hospital, Aalborg, Denmark. .,Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.
| | - Kasper Bostlund Assersen
- Department of Cardiovascular and Renal Research, University of Southern Denmark, Odense, Denmark
| | - Mia Jensen
- Department of Cardiovascular and Renal Research, University of Southern Denmark, Odense, Denmark
| | - Boye L Jensen
- Department of Cardiovascular and Renal Research, University of Southern Denmark, Odense, Denmark
| | - Brian Kloster
- Department of Urology, Aalborg University Hospital, Aalborg, Denmark
| | - Morten Jønler
- Department of Urology, Aalborg University Hospital, Aalborg, Denmark
| | - Lars Lund
- Department of Urology, Aalborg University Hospital, Aalborg, Denmark.,Department of Urology, Odense University Hospital, Odense, Denmark
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38
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Gao A, Wang Y, Gao X, Tian W. LCZ696 ameliorates lipopolysaccharide-induced endothelial injury. Aging (Albany NY) 2021; 13:9582-9591. [PMID: 33839697 PMCID: PMC8064163 DOI: 10.18632/aging.202692] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Accepted: 01/14/2021] [Indexed: 12/11/2022]
Abstract
Lipopolysaccharide (LPS)-induced endothelial dysfunction plays an important role in the pathogenesis of cardiovascular diseases. LCZ696, the dual-acting angiotensin receptor blocker, and neprilysin inhibitor has been used for the treatment of heart failure with reduced ejection fraction. Recent work suggests that LCZ696 therapy might have an anti-inflammatory effect in cardiovascular tissue. In the current study, we show that LCZ696 attenuates LPS-induced oxidative stress by reducing the production of intracellular reactive oxygen species (ROS) and the measurements of malonyl dialdehyde (MDA) level in human umbilical vascular endothelial cells (HUVECs). LCZ696 inhibits LPS-induced expressions and secretions of the pro-inflammatory cytokines, interleukin-6 (IL-6), interleukin-1α (IL-1α), and tumor necrosis factor β (TNF-β) as well as the chemokines, monocyte chemotactic protein 1 (MCP-1), and chemokine (C-X-C motif) ligand 1 protein (CXCL1). Additionally, we found that LCZ696 reduces LPS-induced expressions of vascular cell adhesion molecule 1 (VCAM-1) and P-selectin and the attachment of U937 monocytes to HUVECs. Mechanistically, LCZ696 prevents LPS-induced activation of the TLR4/Myd88 pathway and nuclear translocation of nuclear factor kappa-B (NF-κB) p65 factor. Based on these findings, we conclude that LCZ696 is capable of ameliorating LPS-induced endothelial dysfunction via anti-inflammatory properties.
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Affiliation(s)
- Aihong Gao
- Department of Cardiology, NO.215 Hospital of Shaanxi Nuclear Industry, Xianyang 712000, China
| | - Yu Wang
- Department of Cardiology, NO.215 Hospital of Shaanxi Nuclear Industry, Xianyang 712000, China
| | - Xiao Gao
- Department of Pathology, NO.215 Hospital of Shaanxi Nuclear Industry, Xianyang 712000, China
| | - Wei Tian
- Department of Pathology, NO.215 Hospital of Shaanxi Nuclear Industry, Xianyang 712000, China
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39
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Polina I, Spicer MJ, Domondon M, Schibalski RS, Sarsenova E, Sultanova RF, Ilatovskaya DV. Inhibition of neprilysin with sacubitril without RAS blockage aggravates renal disease in Dahl SS rats. Ren Fail 2021; 43:315-324. [PMID: 33541194 PMCID: PMC8901277 DOI: 10.1080/0886022x.2021.1879856] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Salt-sensitive (SS) hypertension is accompanied with severe cardiorenal complications. In this condition, elevated blood pressure (BP) resulting from salt retention is associated with counterintuitively lower levels of atrial natriuretic peptide (ANP). In plasma, ANP is degraded by the neprilysin; therefore, pharmacological inhibition of this metalloprotease (i.e., with sacubitril) can be employed to increase ANP level. We have shown earlier that sacubitril in combination with valsartan (75 μg/day each) had beneficial effects on renal function in Dahl SS rats. The goal of this study was to evaluate the effects of a higher dose of sacubitril on renal damage in this model. To induce hypertension, male Dahl SS rats were fed a 4% NaCl diet (HS) for 21 days, and were administered sacubitril (125 μg/day) or vehicle via s.c. osmotic pumps. At the end of the HS challenge, both groups exhibited similar outcomes for GFR, heart weight, plasma electrolytes, BUN, and creatinine. Sacubitril exacerbated kidney hypertrophy, but did not affect levels of renal fibrosis. We also observed aggravated glomerular lesions and increased formation of protein casts in the sacubitril-treated animals compared to controls. Thus, in Dahl SS rats, administration of sacubitril without renin-angiotensin-system blockage had adverse effects on renal disease progression, particularly in regards to glomerular damage and protein cast formation. We can speculate that while ANP levels are increased because of neprilysin inhibition, there are off-target effects of sacubitril, which are detrimental to renal function in the SS hypertensive state.
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Affiliation(s)
- Iuliia Polina
- Department of Medicine, Division of Nephrology, Medical University of South Carolina, Charleston, SC, USA
| | - Morgan J Spicer
- Department of Medicine, Division of Nephrology, Medical University of South Carolina, Charleston, SC, USA
| | - Mark Domondon
- Department of Medicine, Division of Nephrology, Medical University of South Carolina, Charleston, SC, USA
| | - Ryan S Schibalski
- Department of Medicine, Division of Nephrology, Medical University of South Carolina, Charleston, SC, USA
| | - Elizaveta Sarsenova
- Department of Medicine, Division of Nephrology, Medical University of South Carolina, Charleston, SC, USA.,Saint-Petersburg State Chemical Pharmaceutical University, St. Petersburg, Russia
| | - Regina F Sultanova
- Department of Medicine, Division of Nephrology, Medical University of South Carolina, Charleston, SC, USA.,Saint-Petersburg State Chemical Pharmaceutical University, St. Petersburg, Russia
| | - Daria V Ilatovskaya
- Department of Medicine, Division of Nephrology, Medical University of South Carolina, Charleston, SC, USA
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miR-133a-3p attenuates cardiomyocyte hypertrophy through inhibiting pyroptosis activation by targeting IKKε. Acta Histochem 2021; 123:151653. [PMID: 33246224 DOI: 10.1016/j.acthis.2020.151653] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Revised: 10/27/2020] [Accepted: 10/28/2020] [Indexed: 01/09/2023]
Abstract
OBJECTIVE Cardiac hypertrophy is an adaptive response to physiological and pathological stimuli, the latter of which frequently progresses to valvulopathy, heart failure and sudden death. Recent reports revealed that pyroptosis is involved in regulating multiple cardiovascular diseases progression, including cardiac hypertrophy. However, the underlying mechanisms remain poorly understood. This study aims to extensively investigate the regulation of miR-133a-3p on pyroptosis in angiotensin II (Ang II)-induced cardiac hypertrophyin vitro. METHODS The in vitro model of cardiac hypertrophy was induced by Ang II, which was validated by qPCR combined with measurement of cell surface area by immunofluorescence assay. CCK-8 assay and Hochest33342/PI staining was performed to assess pyroptosis. Dual luciferase reporter system was used to verify the direct interaction between miR-133a-3p and IKKε. The effects of miR-133a-3p/IKKε on pyroptosis activation and cardiac hypertrophy markers (Caspase-1, NLRP3, IL-1β, IL-18, GSDMD, ASC, ANP, BNP and β-MHC) were evaluated by western blot, ELISA and qPCR. RESULTS Ang II treatment could induce cardiomyocyte hypertrophy and pyroptosis. The expression of miR-133a-3p was repressed in Ang II-treated HCM cells, and its overexpression could attenuate both pyroptosis and cardiac hypertrophyin vitro. Additionally, IKKε expression was significantly up-regulated in Ang II-induced HCM cells. Dual luciferase reporter system and qPCR validated that miR-133a-3p directly targeted the 3'-UTR of IKKε and suppressed its expression. Moreover, IKKε overexpression impaired the protective function of miR-133a-3p in cardiomyocyte hypertrophy. CONCLUSION Collectively, miR-133a-3p attenuates Ang II induced cardiomyocyte hypertrophy via inhibition of pyroptosis by targeting IKKε. Therefore, miR-133a-3p up-regulation may be a promising strategy for cardiac hypertrophy treatment.
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Novel therapeutics for the treatment of hypertension and its associated complications: peptide- and nonpeptide-based strategies. Hypertens Res 2021; 44:740-755. [PMID: 33731923 PMCID: PMC7967108 DOI: 10.1038/s41440-021-00643-z] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Revised: 12/08/2020] [Accepted: 01/20/2021] [Indexed: 01/31/2023]
Abstract
The renin-angiotensin-aldosterone system (RAAS) is responsible for maintaining blood pressure and vascular tone. Modulation of the RAAS, therefore, interferes with essential cellular processes and leads to high blood pressure, oxidative stress, inflammation, fibrosis, and hypertrophy. Consequently, these conditions cause fatal cardiovascular and renal complications. Thus, the primary purpose of hypertension treatment is to diminish or inhibit overactivated RAAS. Currently available RAAS inhibitors have proven effective in reducing blood pressure; however, beyond hypertension, they have failed to treat end-target organ injury. In addition, RAAS inhibitors have some intolerable adverse effects, such as hyperkalemia and hypotension. These gaps in the available treatment for hypertension require further investigation of the development of safe and effective therapies. Current research is focused on the combination of existing and novel treatments that neutralize the angiotensin II type I (AT1) receptor-mediated action of the angiotensin II peptide. Preclinical studies of peptide- and nonpeptide-based therapeutic agents demonstrate their conspicuous impact on the treatment of cardiovascular diseases in animal models. In this review, we will discuss novel therapeutic agents being developed as RAAS inhibitors that show prominent effects in both preclinical and clinical studies. In addition, we will also highlight the need for improvement in the efficacy of existing drugs in the absence of new prominent antihypertensive drugs.
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Dereli S, Kılınçel O, Çerik İB, Kaya A. Impact of sacubitril/valsartan treatment on depression and anxiety in heart failure with reduced ejection fraction. Acta Cardiol 2020; 75:774-782. [PMID: 32186467 DOI: 10.1080/00015385.2020.1730577] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Background: In patients with heart failure (HF), depression and anxiety disorders are common and associated with adverse outcomes. Sacubitril/valsartan, which is an angiotensin receptor neprilysin inhibitor (ARNI), has been shown to reduce mortality and hospitalisation in patients with heart failure with reduced ejection fraction (HFrEF). However, its effects on depression and anxiety levels remain unclear.Methods: Sacubitril/valsartan was initiated in 115 symptomatic patients with HFrEF receiving an optimal medical treatment with angiotensin inhibition. Patients underwent 6-minute walk test (6-MWT), The Beck Depression Inventory-II (BDI-II) and Beck Anxiety Inventory (BAI) were administered at the switching to ARNI and at the third-month follow-up of the maximum sacubitril/valsartan dose.Results: A significant improvement was observed in BDI-II and BAI scores when compared before and after the sacubitril/valsartan treatment (13.7 ± 9.7 to 7.6 ± 3.8, p < 0.001 and 13.3 ± 8.9 to 8.1 ± 4.1, p < 0.001, respectively). The 6-MWT distance significantly increased from 213 ± 95 to 327 ± 118 mt (p < 0.001). Overall, the patients exhibited a significant functional improvement following the initiation of sacubitril/valsartan: 27% of the patients improved by two New York Heart Association (NYHA) classes, 52% improved by one NYHA functional class, and 31% remained stable.Conclusion: In patients with HFrEF, the switch from angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker therapy to sacubitril/valsartan resulted in a significant improvement in both depression, anxiety symptoms and functional statuses.
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Affiliation(s)
- Seçkin Dereli
- Deparment of Cardiology, Faculty of Medicine, Ordu University, Ordu, Turkey
| | - Oğuzhan Kılınçel
- Department of Psychiatry, Sakarya Yenikent State Hospital, Sakarya, Turkey
| | - İdris Buğra Çerik
- Deparment of Cardiology, Faculty of Medicine, Ordu University, Ordu, Turkey
| | - Ahmet Kaya
- Deparment of Cardiology, Faculty of Medicine, Ordu University, Ordu, Turkey
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Abstract
Cyclic GMP (cGMP) represents a classic intracellular second messenger molecule. Over the past 2 decades, important discoveries have identified that cGMP signaling becomes deranged in heart failure (HF) and that cGMP and its main kinase effector, protein kinase G, generally oppose the biological abnormalities contributing to HF, in experimental studies. These findings have influenced the design of clinical trials of cGMP-augmenting drugs in HF patients. At present, the trial results of cGMP-augmenting therapies in HF remain mixed. As detailed in this review, strong evidence now exists that protein kinase G opposes pathologic cardiac remodeling through regulation of diverse biological processes and myocardial substrates. Potential reasons for the failures of cGMP-augmenting drugs in HF may be related to biological mechanisms opposing cGMP or because of certain features of clinical trials, all of which are discussed.
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van der Pol A, Hoes MF, de Boer RA, van der Meer P. Cardiac foetal reprogramming: a tool to exploit novel treatment targets for the failing heart. J Intern Med 2020; 288:491-506. [PMID: 32557939 PMCID: PMC7687159 DOI: 10.1111/joim.13094] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Revised: 03/26/2020] [Accepted: 04/14/2020] [Indexed: 12/11/2022]
Abstract
As the heart matures during embryogenesis from its foetal stages, several structural and functional modifications take place to form the adult heart. This process of maturation is in large part due to an increased volume and work load of the heart to maintain proper circulation throughout the growing body. In recent years, it has been observed that these changes are reversed to some extent as a result of cardiac disease. The process by which this occurs has been characterized as cardiac foetal reprogramming and is defined as the suppression of adult and re-activation of a foetal genes profile in the diseased myocardium. The reasons as to why this process occurs in the diseased myocardium are unknown; however, it has been suggested to be an adaptive process to counteract deleterious events taking place during cardiac remodelling. Although still in its infancy, several studies have demonstrated that targeting foetal reprogramming in heart failure can lead to substantial improvement in cardiac functionality. This is highlighted by a recent study which found that by modulating the expression of 5-oxoprolinase (OPLAH, a novel cardiac foetal gene), cardiac function can be significantly improved in mice exposed to cardiac injury. Additionally, the utilization of angiotensin receptor neprilysin inhibitors (ARNI) has demonstrated clear benefits, providing important clinical proof that drugs that increase natriuretic peptide levels (part of the foetal gene programme) indeed improve heart failure outcomes. In this review, we will highlight the most important aspects of cardiac foetal reprogramming and will discuss whether this process is a cause or consequence of heart failure. Based on this, we will also explain how a deeper understanding of this process may result in the development of novel therapeutic strategies in heart failure.
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Affiliation(s)
- A van der Pol
- From the, Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.,Perioperative Inflammation and Infection Group, Department of Medicine, Faculty of Medicine and Health Sciences, University of Oldenburg, Oldenburg, Germany
| | - M F Hoes
- From the, Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - R A de Boer
- From the, Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - P van der Meer
- From the, Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
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45
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Kang H, Zhang J, Zhang X, Qin G, Wang K, Deng Z, Fang Y, Chen G. Effects of sacubitril/valsartan in patients with heart failure and chronic kidney disease: A meta-analysis. Eur J Pharmacol 2020; 884:173444. [DOI: 10.1016/j.ejphar.2020.173444] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2020] [Revised: 07/24/2020] [Accepted: 07/29/2020] [Indexed: 11/17/2022]
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Mc Causland FR, Lefkowitz MP, Claggett B, Anavekar NS, Senni M, Gori M, Jhund PS, McGrath MM, Packer M, Shi V, Van Veldhuisen DJ, Zannad F, Comin-Colet J, Pfeffer MA, McMurray JJ, Solomon SD. Angiotensin-Neprilysin Inhibition and Renal Outcomes in Heart Failure With Preserved Ejection Fraction. Circulation 2020; 142:1236-1245. [DOI: 10.1161/circulationaha.120.047643] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Background:
In patients with heart failure, chronic kidney disease is common and associated with a higher risk of renal events than in patients without chronic kidney disease. We assessed the renal effects of angiotensin/neprilysin inhibition in patients who have heart failure with preserved ejection fraction enrolled in the PARAGON-HF trial (Prospective Comparison of ARNI With ARB Global Outcomes in HF With Preserved Ejection Fraction).
Methods:
In this randomized, double-blind, event-driven trial, we assigned 4822 patients who had heart failure with preserved ejection fraction to receive sacubitril/valsartan (n=2419) or valsartan (n=2403). Herein, we present the results of the prespecified renal composite outcome (time to first occurrence of either: ≥50% reduction in estimated glomerular filtration rate (eGFR), end-stage renal disease, or death from renal causes), the individual components of this composite, and the influence of therapy on eGFR slope.
Results:
At randomization, eGFR was 63±19 mL·min
–1
·1.73 m
–
2. At study closure, the composite renal outcome occurred in 33 patients (1.4%) assigned to sacubitril/valsartan and 64 patients (2.7%) assigned to valsartan (hazard ratio, 0.50 [95% CI, 0.33–0.77];
P
=0.001). The treatment effect on the composite renal end point did not differ according to the baseline eGFR (<60 versus ≥60 mL·min
–1
·1.73 m
–2
(
P
-interaction=0.92). The decline in eGFR was less for sacubitril/valsartan than for valsartan (–2.0 [95% CI, –2.2 to –1.9] versus –2.7 [95% CI, –2.8 to –2.5] mL·min
–1
·1.73 m
–2
per year).
Conclusions:
In patients with heart failure with preserved ejection fraction, sacubitril/valsartan reduced the risk of renal events, and slowed decline in eGFR, in comparison with valsartan.
Registration:
URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT01920711.
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Affiliation(s)
- Finnian R. Mc Causland
- Renal Division, Department of Medicine(F.R.M., M.M.M.), Brigham and Women’s Hospital, Boston, MA
- Harvard Medical School, Boston, MA (F.R.M., B.C., M.M.M., F.Z., M.A.P., S.D.S.)
| | | | - Brian Claggett
- Cardiovascular Division, Department of Medicine (B.C., M.A.P., S.D.S.), Brigham and Women’s Hospital, Boston, MA
- Harvard Medical School, Boston, MA (F.R.M., B.C., M.M.M., F.Z., M.A.P., S.D.S.)
| | - Nagesh S. Anavekar
- Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Australia (N.S.A.)
| | - Michele Senni
- Cardiology Division, Cardiovascular Department, Azienda Ospedaliera Papa Giovanni XXIII Hospital, Bergamo, Italy (M.S., M.G.)
| | - Mauro Gori
- Cardiology Division, Cardiovascular Department, Azienda Ospedaliera Papa Giovanni XXIII Hospital, Bergamo, Italy (M.S., M.G.)
| | - Pardeep S. Jhund
- British Heart Foundation Cardiovascular Research Centre, University of Glasgow, UK (P.S.J., J.J.V.M.)
| | - Martina M. McGrath
- Renal Division, Department of Medicine(F.R.M., M.M.M.), Brigham and Women’s Hospital, Boston, MA
- Harvard Medical School, Boston, MA (F.R.M., B.C., M.M.M., F.Z., M.A.P., S.D.S.)
| | - Milton Packer
- Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, TX (M.P.)
| | - Victor Shi
- Novartis Pharmaceuticals, East Hanover, NJ (M.P.L., V.S.)
| | - Dirk J. Van Veldhuisen
- Department of Cardiology, University Medical Center Groningen, University of Groningen, The Netherlands (D.J.W.)
| | - Faiez Zannad
- Harvard Medical School, Boston, MA (F.R.M., B.C., M.M.M., F.Z., M.A.P., S.D.S.)
- Université de Lorraine, Inserm CIC1433, CHRU de Nancy, France (F.Z.)
| | - Josep Comin-Colet
- Department of Cardiology, Bellvitge University Hospital and Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Barcelona, Spain (J.C.-C.)
- Department of Clinical Sciences, School of Medicine, University of Barcelona, Spain (J.C.-C.)
| | - Marc A. Pfeffer
- Cardiovascular Division, Department of Medicine (B.C., M.A.P., S.D.S.), Brigham and Women’s Hospital, Boston, MA
- Harvard Medical School, Boston, MA (F.R.M., B.C., M.M.M., F.Z., M.A.P., S.D.S.)
| | - John J.V. McMurray
- British Heart Foundation Cardiovascular Research Centre, University of Glasgow, UK (P.S.J., J.J.V.M.)
| | - Scott D. Solomon
- Cardiovascular Division, Department of Medicine (B.C., M.A.P., S.D.S.), Brigham and Women’s Hospital, Boston, MA
- Harvard Medical School, Boston, MA (F.R.M., B.C., M.M.M., F.Z., M.A.P., S.D.S.)
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Differential Effects of Sacubitril/Valsartan on Diastolic Function in Mice With Obesity-Related Metabolic Heart Disease. JACC Basic Transl Sci 2020; 5:916-927. [PMID: 33015414 PMCID: PMC7524781 DOI: 10.1016/j.jacbts.2020.07.006] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Revised: 07/13/2020] [Accepted: 07/13/2020] [Indexed: 12/11/2022]
Abstract
MHD associated with obesity, diabetes, and/or metabolic syndrome is an important precursor of HFpEF. Mice fed a HFHS diet develop MHD with myocardial hypertrophy, fibrosis, diastolic dysfunction, and impaired energetics. Mice on HFHS diet were treated with matched doses of VAL or sac SAC/VAL for 16 weeks. Only SAC/VAL prevented diastolic dysfunction and fibrosis, and to a lesser extent oxidative stress, whereas VAL and SAC/VAL had similar effects on hypertrophy and energetics. Neprilysin inhibition exerts beneficial effects on MHD that are complimentary to VAL, suggesting that SAC/VAL has promise to prevent the development of HFpEF in patients with or at risk for MHD. Mice with obesity and metabolic heart disease (MHD) due to a high-fat, high-sucrose diet were treated with placebo, a clinically relevant dose of sacubitril (SAC)/valsartan (VAL), or an equivalent dose of VAL for 4 months. There were striking differences between SAC/VAL and VAL with regard to: 1) diastolic dysfunction; 2) interstitial fibrosis; and to a lesser degree; 3) oxidative stress—all of which were more favorably affected by SAC/VAL. SAC/VAL and VAL similarly attenuated myocardial hypertrophy and improved myocardial energetics. In mice with obesity-related MHD, neprilysin inhibition exerts favorable effects on diastolic function.
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Key Words
- ARB, angiotensin receptor blocker
- ATP, adenosine triphosphate
- CD, control diet
- GMP, guanosine monophosphate
- HFHS, high-fat, high-sucrose
- HFpEF, heart failure with a preserved ejection fraction
- LV, left ventricular
- MHD, metabolic heart disease
- MNA, methoxy-2-naphthlamine
- NMR, nuclear magnetic resonance
- PCr, phosphocreatine
- ROS, reactive oxygen species
- RPP, rate × pressure product
- SAC/VAL, sacubitril/valsartan
- VAL, valsartan
- diastolic
- neprilysin
- obesity
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Dereli S, Bayramoğlu A, Kaya A. Effects of sacubutril/valsartan on nutritional status in heart failure with reduced ejection fraction. J Cardiovasc Med (Hagerstown) 2020; 21:13-20. [PMID: 31714330 DOI: 10.2459/jcm.0000000000000895] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
BACKGROUND Malnutrition commonly occurs in patients with heart failure with reduced ejection fraction (HFrEF). Sacubitril/valsartan, which is an AT1 neprilysin inhibitor, has been shown to reduce mortality and hospitalization in patients with HFrEF. However, its effects on nutritional status remain unclear. METHODS Sacubitril/valsartan was initiated in 164 symptomatic patients with HFrEF receiving an optimal medical treatment with angiotensin inhibition (mean age: 63 ± 20 years; 120 males, 60% ischemic cause). The New York Heart Association (NYHA) functional class and nutritional statuses of the patients were evaluated at the switching to AT1 neprilysin inhibitor and at the 6th-month follow-up of the maximum sacubitril/valsartan dose using the geriatric nutritional risk index (GNRI), controlling nutritional status (CONUT) score, prognostic nutritional index (PNI), and prealbumin. RESULTS After the sacubutril/valsartan treatment, a significant reduction in the number (%) of malnourished patients was observed according to CONUT (before 47% vs. after 7%, P < 0.001), GNRI (before 39% vs. after 19%, P < 0.001), PNI scores (before 36% vs. after 12%, P = 0.002), and prealbumin (before 41% vs. after 12%, P < 0.001). Also significant changes were observed at the baseline and follow-up in the mean scores of the three different nutritional indexes and prealbumin levels [CONUT: 2.68 ± 2.5, 1.02 ± 1.0 (P < 0.001); GNRI: 97.1 ± 9.7, 101.2 ± 5.9 (P < 0.001); PNI: 38.8 ± 4.8, 41.6 ± 3.7 (P < 0.001); prealbumin: 14.6 ± 6.9 mg/dl, 17.1 ± 5.2 mg/dl (P < 0.001)]. Overall, the patients exhibited a significant functional improvement following the initiation of sacubitril/valsartan: 23% of the patients improved by two NYHA classes, 48% improved by one NYHA class, and 39% remained stable. CONCLUSION In patients with HFrEF, the switch from angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker therapy to sacubitril/valsartan resulted in a significant improvement in both nutritional and functional statuses.
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Affiliation(s)
| | - Adil Bayramoğlu
- Deparment of Cardiology, Ordu University Faculty of Medicine, Ordu, Turkey
| | - Ahmet Kaya
- Deparment of Cardiology, Ordu University Faculty of Medicine, Ordu, Turkey
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Polina I, Domondon M, Fox R, Sudarikova AV, Troncoso M, Vasileva VY, Kashyrina Y, Gooz MB, Schibalski RS, DeLeon-Pennell KY, Fitzgibbon WR, Ilatovskaya DV. Differential effects of low-dose sacubitril and/or valsartan on renal disease in salt-sensitive hypertension. Am J Physiol Renal Physiol 2020; 319:F63-F75. [PMID: 32463726 PMCID: PMC7468826 DOI: 10.1152/ajprenal.00125.2020] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 05/20/2020] [Accepted: 05/20/2020] [Indexed: 12/15/2022] Open
Abstract
Diuretics and renin-angiotensin system blockers are often insufficient to control the blood pressure (BP) in salt-sensitive (SS) subjects. Abundant data support the proposal that the level of atrial natriuretic peptide may correlate with the pathogenesis of SS hypertension. We hypothesized here that increasing atrial natriuretic peptide levels with sacubitril, combined with renin-angiotensin system blockage by valsartan, can be beneficial for alleviation of renal damage in a model of SS hypertension, the Dahl SS rat. To induce a BP increase, rats were challenged with a high-salt 4% NaCl diet for 21 days, and chronic administration of vehicle or low-dose sacubitril and/or valsartan (75 μg/day each) was performed. Urine flow, Na+ excretion, and water consumption were increased on the high-salt diet compared with the starting point (0.4% NaCl) in all groups but remained similar among the groups at the end of the protocol. Upon salt challenge, we observed a mild decrease in systolic BP and urinary neutrophil gelatinase-associated lipocalin levels (indicative of alleviated tubular damage) in the valsartan-treated groups. Sacubitril, as well as sacubitril/valsartan, attenuated the glomerular filtration rate decline induced by salt. Alleviation of protein cast formation and lower renal medullary fibrosis were observed in the sacubitril/valsartan- and valsartan-treated groups, but not when sacubitril alone was administered. Interestingly, proteinuria was mildly mitigated only in rats that received sacubitril/valsartan. Further studies of the effects of sacubitril/valsartan in the setting of SS hypertension, perhaps involving a higher dose of the drug, are warranted to determine if it can interfere with the progression of the disease.
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Affiliation(s)
- Iuliia Polina
- Division of Nephrology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina
| | - Mark Domondon
- Division of Nephrology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina
| | - Rebecca Fox
- Division of Nephrology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina
| | - Anastasia V Sudarikova
- Division of Nephrology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina
- Institute of Cytology, Russian Academy of Sciences, St. Petersburg, Russia
| | - Miguel Troncoso
- Division of Cardiology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina
| | - Valeriia Y Vasileva
- Division of Nephrology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina
- Institute of Cytology, Russian Academy of Sciences, St. Petersburg, Russia
| | - Yuliia Kashyrina
- Division of Nephrology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina
| | - Monika Beck Gooz
- Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, South Carolina
| | - Ryan S Schibalski
- Division of Nephrology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina
| | - Kristine Y DeLeon-Pennell
- Division of Cardiology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina
- Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina
| | - Wayne R Fitzgibbon
- Division of Nephrology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina
| | - Daria V Ilatovskaya
- Division of Nephrology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina
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Mohany M, Alanazi AZ, Alqahtani F, Belali OM, Ahmed MM, Al-Rejaie SS. LCZ696 mitigates diabetic-induced nephropathy through inhibiting oxidative stress, NF-κB mediated inflammation and glomerulosclerosis in rats. PeerJ 2020; 8:e9196. [PMID: 32596035 PMCID: PMC7307563 DOI: 10.7717/peerj.9196] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Accepted: 04/24/2020] [Indexed: 02/06/2023] Open
Abstract
Background Diabetic nephropathy (DN) is among the most common microvascular complications of diabetes resulting in end-stage renal disease and therefore search for candidates which can ameliorate the kidney function is needed simultaneously with standard diabetic pharmacotherapy. The current study was aimed to investigate the effect of long term sacubitril/valsartan therapy (LCZ696) in diabetic rats to assess its ameliorative impact against various pathological parameters such as oxidative stress, inflammation and glomerulosclerosis associated with chronic DN. Methods A single dose (60 mg/kg/day) of STZ was used to induce type 1 diabetes in adult male wistar rats. 2 weeks after diabetes induction, these rats were treated orally with valsartan (31 mg/kg) or LCZ696 (68 mg/kg) for 6 weeks. At end of the treatment period, serum and kidney samples were collected and analyzed. The serum levels of glucose, insulin, urea, creatinine, TNF-α, IL-1β, IL-6 and IL-10 levels were estimated. In renal tissue homogenate, the levels of inflammatory markers such as TNF-α, IL-1β, IL-6, NF-kB along with oxidative stress biomarkers including thiobarbituric acid-reacting substances (TBARs), glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione S-transferase (GST) were assessed. Histological changes were observed in kidney. Results Time course therapy withLCZ696 and valsartan in diabetic rats resulted in significant reduction of serum glucose, urea and creatinine levels (P < 0.05). Additionally, serum of treated diabetic rats showed a diminution in inflammatory (TNF-α, IL-1β, IL-6) and increment in anti-inflammatory (IL-10) cytokines levels (P < 0.05). Tissue homogenate of the kidney extracted from LCZ696 and valsartan treated diabetic rats revealed a substantial reduction in the levels of inflammatory markers such as TNF-α, IL-1β, IL-6, NF-kB and sufficient restoration of anti-oxidant enzyme levels (P < 0.05). Finally, in the histological sections of the kidney, prevention of renal injury was observed with limited necrosis and inflammatory cells infiltration. Conclusion Present data suggest that LCZ696 has sufficient therapeutic potential to restrict DN progression through inhibiting inflammation, oxidative stress and glomerulosclerosis.
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Affiliation(s)
- Mohamed Mohany
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Ahmed Z Alanazi
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Faleh Alqahtani
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Osamah M Belali
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Mohammed M Ahmed
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Salim S Al-Rejaie
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
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