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Saw EL, Werner LD, Cooper HL, Pimental DR, Zamani P, Chirinos JA, Valero-Muñoz M, Sam F. Musclin Counteracts Skeletal Muscle Dysfunction and Exercise Intolerance in Heart Failure With Preserved Ejection Fraction. Circ Heart Fail 2025:e012350. [PMID: 40358602 DOI: 10.1161/circheartfailure.124.012350] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2024] [Accepted: 02/27/2025] [Indexed: 05/15/2025]
Abstract
BACKGROUND Exercise intolerance is a hallmark of heart failure with preserved ejection fraction (HFpEF) and is characterized by skeletal muscle (SkM) dysfunction with impaired oxidative capacity. To maintain oxidative capacity, the SkM secretes myokines such as musclin, which has been shown to potentiate NP (natriuretic peptide) signaling and induce PGC-1α (peroxisome proliferator-activated receptor-γ coactivator-1 alpha) signaling. We sought to investigate the role of musclin in SkM dysfunction in HFpEF. For this study, we selected the oxidative-predominant SkM soleus in HFpEF mice and vastus lateralis from patients with HFpEF. METHODS Using the SAUNA model, mice underwent HFpEF induction by uninephrectomy, d-aldosterone infusion, and 1% sodium chloride drinking water for 4 weeks. Exogenous musclin was given to HFpEF mice every 2 days during the last 2 weeks of HFpEF induction. Molecular analyses were conducted on blood samples and SkM from HFpEF mice and patients with HFpEF. RESULTS In HFpEF mice and patients with HFpEF, increased musclin expression was accompanied by decreased cyclic guanosine monophosphate levels and PGC-1α expression in SkM, suggesting impaired NP signaling. Exogenous administration of musclin in mice with HFpEF demonstrated augmented circulating musclin levels and potentiated NP signaling in SkM as shown by increased PKG1 (protein kinase G1) activity and PGC-1α expression. This was associated with a transition from type-2A to type-1 fiber (type-1 has more endurance) and increased succinate dehydrogenase activity, hindlimb blood flow, and capillary density in the soleus muscle. Exogenous musclin also mitigated cardiac hypertrophy without affecting blood pressure or diastolic function. Most importantly, HFpEF mice treated with musclin demonstrated improved functional and exercise capacity. CONCLUSIONS Musclin mediates beneficial effects in SkM and heart with improved exercise capacity likely by improving oxidative capacity in SkM. Future studies are warranted to address the therapeutic efficacy of exogenous musclin in humans with HFpEF.
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Affiliation(s)
- Eng Leng Saw
- Department of Medicine, Whitaker Cardiovascular Institute, Boston University Chobanian & Avedisian School of Medicine, MA (E.L.S., L.D.W., H.L.C., D.R.P., M.V.-M., F.S.)
| | - Louis Dominic Werner
- Department of Medicine, Whitaker Cardiovascular Institute, Boston University Chobanian & Avedisian School of Medicine, MA (E.L.S., L.D.W., H.L.C., D.R.P., M.V.-M., F.S.)
| | - Hannah L Cooper
- Department of Medicine, Whitaker Cardiovascular Institute, Boston University Chobanian & Avedisian School of Medicine, MA (E.L.S., L.D.W., H.L.C., D.R.P., M.V.-M., F.S.)
| | - David R Pimental
- Department of Medicine, Whitaker Cardiovascular Institute, Boston University Chobanian & Avedisian School of Medicine, MA (E.L.S., L.D.W., H.L.C., D.R.P., M.V.-M., F.S.)
| | - Payman Zamani
- Division of Cardiovascular Medicine, Penn Cardiovascular Institute, Hospital of the University of Pennsylvania, Philadelphia (P.Z., J.A.C.)
| | - Julio A Chirinos
- Division of Cardiovascular Medicine, Penn Cardiovascular Institute, Hospital of the University of Pennsylvania, Philadelphia (P.Z., J.A.C.)
| | - María Valero-Muñoz
- Department of Medicine, Whitaker Cardiovascular Institute, Boston University Chobanian & Avedisian School of Medicine, MA (E.L.S., L.D.W., H.L.C., D.R.P., M.V.-M., F.S.)
| | - Flora Sam
- Department of Medicine, Whitaker Cardiovascular Institute, Boston University Chobanian & Avedisian School of Medicine, MA (E.L.S., L.D.W., H.L.C., D.R.P., M.V.-M., F.S.)
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Rosson E, Lux F, David L, Godfrin Y, Tillement O, Thomas E. Focus on therapeutic peptides and their delivery. Int J Pharm 2025; 675:125555. [PMID: 40194730 DOI: 10.1016/j.ijpharm.2025.125555] [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: 02/07/2025] [Revised: 03/27/2025] [Accepted: 04/01/2025] [Indexed: 04/09/2025]
Abstract
Peptides are bioactive intermediates between small organic molecules and large biological compounds like antibodies or proteins. These compounds play a unique and valuable role as therapeutic agents, owing to their unique biochemical properties and versatility in treating a wide range of diseases such as metabolic disorders, cancer therapy, antimicrobial and anti-inflammatory agents. The global peptide therapeutics market is projected to exceed USD 50 billion by 2024, reflecting the increasing demand and interest in this field. Therapeutic peptides offer an optimal balance of specificity, safety, and molecular size, providing greater precision in targeting specific receptors with fewer off-target effects and reduced toxicity compared to small-organic drugs. Peptides also exhibit enhanced tissue penetration and present simpler, cheaper manufacturing processes with lower immunogenicity. To date, around 100 peptides have attained clinical approval in major markets, with nearly half of these approvals occurring in the past 20 years. This trend highlights the growing importance and therapeutic potential of peptides in modern medicine, explaining the substantial market associated with these treatments. The review presents a detailed comparison of the major parenteral administration modes for therapeutic peptides, specifically subcutaneous and intravenous routes. We highlight how these methods impact the pharmacokinetic profiles of peptides and influence patient outcomes, providing critical insights into the advantages and limitations of each route. Finally, a significant aspect of this review is its focus on innovative drug delivery systems and formulations designed to address the challenges of peptide delivery, namely stability, bioavailability, and therapeutic efficacy.
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Affiliation(s)
- E Rosson
- Axoltis Pharma, 60 Avenue Rockfeller 69008 Lyon, France; Universite Claude Bernard Lyon 1, CNRS UMR5306, ILM, 2 rue Victor Grignard, 69100 Villeurbanne, France; Universite Claude Bernard Lyon 1, CNRS UMR5007, LAGEPP, 43 boulevard du 11 novembre 1918, Bâtiment CPE 69622 Villeurbanne Cedex, France
| | - F Lux
- Universite Claude Bernard Lyon 1, CNRS UMR5306, ILM, 2 rue Victor Grignard, 69100 Villeurbanne, France.
| | - L David
- Universite Claude Bernard Lyon 1, CNRS, INSA de Lyon, Universite Jean Monnet Saint-Etienne UMR 5223, IMP, 15 boulevard André Latarjet 69100 Villeurbanne, France
| | - Y Godfrin
- Axoltis Pharma, 60 Avenue Rockfeller 69008 Lyon, France
| | - O Tillement
- Universite Claude Bernard Lyon 1, CNRS UMR5306, ILM, 2 rue Victor Grignard, 69100 Villeurbanne, France
| | - E Thomas
- Universite Claude Bernard Lyon 1, CNRS UMR5007, LAGEPP, 43 boulevard du 11 novembre 1918, Bâtiment CPE 69622 Villeurbanne Cedex, France.
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Burnett JC. Long-lasting heart-failure treatment could be a game-changer. Nature 2024; 633:534-535. [PMID: 39261684 DOI: 10.1038/d41586-024-02660-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/13/2024]
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Lukoschewitz JD, Miger KC, Olesen ASO, Caidi NOE, Jørgensen CK, Nielsen OW, Hassager C, Hove JD, Seven E, Møller JE, Jakobsen JC, Grand J. Vasodilators for Acute Heart Failure - A Systematic Review with Meta-Analysis. NEJM EVIDENCE 2024; 3:EVIDoa2300335. [PMID: 38804781 DOI: 10.1056/evidoa2300335] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/29/2024]
Abstract
BACKGROUND Acute heart failure is a public health concern. This study systematically reviewed randomized clinical trials (RCTs) to evaluate vasodilators in acute heart failure. METHODS The search was conducted across the databases of Medline, Embase, Latin American and the Caribbean Literature on Health Sciences, Web of Science, and the Cochrane Central Register of Controlled Trials. Inclusion criteria consisted of RCTs that compared vasodilators versus standard care, placebo, or cointerventions. The primary outcome was all-cause mortality; secondary outcomes were serious adverse events (SAEs), tracheal intubation, and length of hospital stay. Risk of bias was assessed in all trials. RESULTS The study included 46 RCTs that enrolled 28,374 patients with acute heart failure. Vasodilators did not reduce the risk of all-cause mortality (risk ratio, 0.95; 95% confidence interval [CI], 0.87 to 1.04; I2=9.51%; P=0.26). No evidence of a difference was seen in the risk of SAEs (risk ratio, 1.01; 95% CI, 0.97 to 1.05; I2=0.94%) or length of hospital stay (mean difference, -0.10; 95% CI, -0.28 to 0.08; I2=69.84%). Vasodilator use was associated with a lower risk of tracheal intubation (risk ratio, 0.54; 95% CI, 0.30 to 0.99; I2=51.96%) compared with no receipt of vasodilators. CONCLUSIONS In this systematic review with meta-analysis of patients with acute heart failure, vasodilators did not reduce all-cause mortality.
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Affiliation(s)
- Jasmin D Lukoschewitz
- Department of Cardiology, Hvidovre Hospital, Copenhagen University Hospital, Copenhagen
| | - Kristina C Miger
- Department of Cardiology, Bispebjerg and Frederiksberg Hospital, Copenhagen University Hospital, Copenhagen
| | - Anne Sophie O Olesen
- Department of Cardiology, Bispebjerg and Frederiksberg Hospital, Copenhagen University Hospital, Copenhagen
| | - Nora O E Caidi
- Department of Cardiology, Hvidovre Hospital, Copenhagen University Hospital, Copenhagen
| | - Caroline K Jørgensen
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Copenhagen University Hospital, Rigshospitalet, Copenhagen
- Department of Regional Health Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
| | - Olav W Nielsen
- Department of Cardiology, Bispebjerg and Frederiksberg Hospital, Copenhagen University Hospital, Copenhagen
- Department of Clinical Medicine, University of Copenhagen, Copenhagen
| | - Christian Hassager
- Department of Cardiology, Bispebjerg and Frederiksberg Hospital, Copenhagen University Hospital, Copenhagen
- Department of Cardiology, The Heart Center, Copenhagen University Hospital Rigshospitalet, Copenhagen
| | - Jens D Hove
- Department of Cardiology, Hvidovre Hospital, Copenhagen University Hospital, Copenhagen
- Department of Clinical Medicine, University of Copenhagen, Copenhagen
| | - Ekim Seven
- Department of Cardiology, Hvidovre Hospital, Copenhagen University Hospital, Copenhagen
| | - Jacob E Møller
- Department of Cardiology, The Heart Center, Copenhagen University Hospital Rigshospitalet, Copenhagen
- Department of Clinical Medicine, University of Southern Denmark, Odense, Denmark
- Department of Cardiology, University of Southern Denmark, Odense, Denmark
| | - Janus Christian Jakobsen
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Copenhagen University Hospital, Rigshospitalet, Copenhagen
- Department of Regional Health Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
| | - Johannes Grand
- Department of Cardiology, Hvidovre Hospital, Copenhagen University Hospital, Copenhagen
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Ma X, Peddibhotla S, Zheng Y, Pan S, Mehta A, Moroni DG, Chen QY, Ma X, Burnett JC, Malany S, Sangaralingham SJ. Discovery of small molecule guanylyl cyclase B receptor positive allosteric modulators. PNAS NEXUS 2024; 3:pgae225. [PMID: 38894878 PMCID: PMC11185183 DOI: 10.1093/pnasnexus/pgae225] [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: 10/27/2023] [Accepted: 05/30/2024] [Indexed: 06/21/2024]
Abstract
Myocardial fibrosis is a pathological hallmark of cardiovascular disease (CVD), and excessive fibrosis can lead to new-onset heart failure and increased mortality. Currently, pharmacological therapies for myocardial fibrosis are limited, highlighting the need for novel therapeutic approaches. The particulate guanylyl cyclase B (GC-B) receptor possesses beneficial antifibrotic actions through the binding of its natural ligand C-type natriuretic peptide (CNP) and the generation of the intracellular second messenger, cyclic guanosine 3',5'-monophosphate (cGMP). These actions include the suppression of fibroblast proliferation and reduction in collagen synthesis. With its abundant expression on fibroblasts, the GC-B receptor has emerged as a key molecular target for innovative CVD therapeutics. However, small molecules that can bind and potentiate the GC-B/cGMP pathway have yet to be discovered. From a cell-based high-throughput screening initiative of the NIH Molecular Libraries Small Molecule Repository and hit-to-lead evolution based on a series of structure-activity relationships, we report the successful discovery of MCUF-42, a GC-B-targeted small molecule that acts as a positive allosteric modulator (PAM). Studies herein support MCUF-42's ability to enhance the binding affinity between GC-B and CNP. Moreover, MCUF-42 potentiated cGMP levels induced by CNP in human cardiac fibroblasts (HCFs) and notably also enhanced the inhibitory effect of CNP on HCF proliferation. Together, our findings highlight that MCUF-42 is a small molecule that can modulate the GC-B/cGMP signaling pathway, potentially enhancing the antifibrotic actions of CNP. Thus, these data underscore the continued development of GC-B small molecule PAMs as a novel therapeutic strategy for targeting cardiac fibrosis and CVD.
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Affiliation(s)
- Xiao Ma
- Cardiorenal Research Laboratory, Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN 55905, USA
| | | | - Ye Zheng
- Cardiorenal Research Laboratory, Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN 55905, USA
| | - Shuchong Pan
- Cardiorenal Research Laboratory, Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN 55905, USA
| | - Alka Mehta
- Department of Pharmacodynamics, University of Florida, Gainesville, FL 32610, USA
| | - Dante G Moroni
- Cardiorenal Research Laboratory, Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN 55905, USA
| | - Qi-Yin Chen
- Department of Medicinal Chemistry, University of Florida, Gainesville, FL 32610, USA
| | - Xiaoyu Ma
- Cardiorenal Research Laboratory, Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN 55905, USA
| | - John C Burnett
- Cardiorenal Research Laboratory, Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN 55905, USA
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA
| | - Siobhan Malany
- Department of Pharmacodynamics, University of Florida, Gainesville, FL 32610, USA
| | - S Jeson Sangaralingham
- Cardiorenal Research Laboratory, Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN 55905, USA
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA
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Lasica R, Djukanovic L, Vukmirovic J, Zdravkovic M, Ristic A, Asanin M, Simic D. Clinical Review of Hypertensive Acute Heart Failure. MEDICINA (KAUNAS, LITHUANIA) 2024; 60:133. [PMID: 38256394 PMCID: PMC10818732 DOI: 10.3390/medicina60010133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/02/2023] [Revised: 12/20/2023] [Accepted: 12/29/2023] [Indexed: 01/24/2024]
Abstract
Although acute heart failure (AHF) is a common disease associated with significant symptoms, morbidity and mortality, the diagnosis, risk stratification and treatment of patients with hypertensive acute heart failure (H-AHF) still remain a challenge in modern medicine. Despite great progress in diagnostic and therapeutic modalities, this disease is still accompanied by a high rate of both in-hospital (from 3.8% to 11%) and one-year (from 20% to 36%) mortality. Considering the high rate of rehospitalization (22% to 30% in the first three months), the treatment of this disease represents a major financial blow to the health system of each country. This disease is characterized by heterogeneity in precipitating factors, clinical presentation, therapeutic modalities and prognosis. Since heart decompensation usually occurs quickly (within a few hours) in patients with H-AHF, establishing a rapid diagnosis is of vital importance. In addition to establishing the diagnosis of heart failure itself, it is necessary to see the underlying cause that led to it, especially if it is de novo heart failure. Given that hypertension is a precipitating factor of AHF and in up to 11% of AHF patients, strict control of arterial blood pressure is necessary until target values are reached in order to prevent the occurrence of H-AHF, which is still accompanied by a high rate of both early and long-term mortality.
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Affiliation(s)
- Ratko Lasica
- Department of Cardiology, Emergency Center, University Clinical Center of Serbia, 11000 Belgrade, Serbia; (R.L.); (L.D.); (M.A.)
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia; (M.Z.); (A.R.)
| | - Lazar Djukanovic
- Department of Cardiology, Emergency Center, University Clinical Center of Serbia, 11000 Belgrade, Serbia; (R.L.); (L.D.); (M.A.)
| | - Jovanka Vukmirovic
- Faculty of Organizational Sciences, University of Belgrade, 11000 Belgrade, Serbia;
| | - Marija Zdravkovic
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia; (M.Z.); (A.R.)
- Clinical Center Bezanijska Kosa, 11000 Belgrade, Serbia
| | - Arsen Ristic
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia; (M.Z.); (A.R.)
- Department of Cardiology, University Clinical Center of Serbia, 11000 Belgrade, Serbia
| | - Milika Asanin
- Department of Cardiology, Emergency Center, University Clinical Center of Serbia, 11000 Belgrade, Serbia; (R.L.); (L.D.); (M.A.)
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia; (M.Z.); (A.R.)
| | - Dragan Simic
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia; (M.Z.); (A.R.)
- Department of Cardiology, University Clinical Center of Serbia, 11000 Belgrade, Serbia
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Ajay A, Rasoul D, Abdullah A, Lee Wei En B, Mashida K, Al-Munaer M, Ajay H, Duvva D, Mathew J, Adenaya A, Lip GYH, Sankaranarayanan R. Augmentation of natriuretic peptide (NP) receptor A and B (NPR-A and NPR-B) and cyclic guanosine monophosphate (cGMP) signalling as a therapeutic strategy in heart failure. Expert Opin Investig Drugs 2023; 32:1157-1170. [PMID: 38032188 DOI: 10.1080/13543784.2023.2290064] [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: 06/21/2023] [Accepted: 11/28/2023] [Indexed: 12/01/2023]
Abstract
INTRODUCTION Heart failure is a complex, debilitating condition and despite advances in treatment, it remains a significant cause of morbidity and mortality worldwide. Therefore, the need for alternative treatment strategies is essential. In this review, we explore the therapeutic strategies of augmenting natriuretic peptide receptors (NPR-A and NPR-B) and cyclic guanosine monophosphate (cGMP) in heart failure. AREAS COVERED We aim to provide an overview of the evidence of preclinical and clinical studies on novel heart failure treatment strategies. Papers collected in this review have been filtered and screened following PubMed searches. This includes epigenetics, modulating enzyme activity in natriuretic peptide (NP) synthesis, gene therapy, modulation of downstream signaling by augmenting soluble guanylate cyclase (sGC) and phosphodiesterase (PDE) inhibition, nitrates, c-GMP-dependent protein kinase, synthetic and designer NP and RNA therapy. EXPERT OPINION The novel treatment strategies mentioned above have shown great potential, however, large randomized controlled trials are still lacking. The biggest challenge is translating the results seen in preclinical trials into clinical trials. We recommend a multi-disciplinary team approach with cardiologists, geneticist, pharmacologists, bioengineers, researchers, regulators, and patients to improve heart failure outcomes. Future management can involve telemedicine, remote monitoring, and artificial intelligence to optimize patient care.
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Affiliation(s)
- Ashwin Ajay
- Cardiology Department, Liverpool University Hospitals NHS Foundation Trust, Liverpool, United Kingdom
| | - Debar Rasoul
- Cardiology Department, Liverpool University Hospitals NHS Foundation Trust, Liverpool, United Kingdom
| | - Alend Abdullah
- General Medicine, The Dudley Group NHS Foundation Trust Dudley, Dudley, United Kingdom
| | - Benjamin Lee Wei En
- Cardiology Department, Liverpool University Hospitals NHS Foundation Trust, Liverpool, United Kingdom
| | - Knievel Mashida
- Cedar House, University of Liverpool, Liverpool, United Kingdom
| | | | - Hanan Ajay
- General Medicine, Southport and Ormskirk Hospital NHS Trust, Southport, United Kingdom
| | - Dileep Duvva
- Cardiology Department, Liverpool University Hospitals NHS Foundation Trust, Liverpool, United Kingdom
| | - Jean Mathew
- Cardiology Department, Liverpool University Hospitals NHS Foundation Trust, Liverpool, United Kingdom
| | - Adeoye Adenaya
- Cardiology Department, Liverpool University Hospitals NHS Foundation Trust, Liverpool, United Kingdom
| | - Gregory Y H Lip
- Cedar House, University of Liverpool, Liverpool, United Kingdom
- Cardiology Department, Liverpool Heart & Chest Hospital NHS Trust, Liverpool, United Kingdom
- Cardiology Department, Liverpool John Moores University, Liverpool, United Kingdom
| | - Rajiv Sankaranarayanan
- Cardiology Department, Liverpool University Hospitals NHS Foundation Trust, Liverpool, United Kingdom
- Cedar House, University of Liverpool, Liverpool, United Kingdom
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Zheng H, Patel TA, Liu X, Patel KP. C-type natriuretic peptide (CNP) in the paraventricular nucleus-mediated renal sympatho-inhibition. Front Physiol 2023; 14:1162699. [PMID: 37082246 PMCID: PMC10110992 DOI: 10.3389/fphys.2023.1162699] [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: 02/09/2023] [Accepted: 03/21/2023] [Indexed: 04/07/2023] Open
Abstract
Volume reflex produces sympatho-inhibition that is mediated by the hypothalamic paraventricular nucleus (PVN). However, the mechanisms for the sympatho-inhibitory role of the PVN and the neurochemical factors involved remain to be identified. In this study, we proposed C-type natriuretic peptide (CNP) as a potential mediator of this sympatho-inhibition within the PVN. Microinjection of CNP (1.0 μg) into the PVN significantly decreased renal sympathetic nerve activity (RSNA) (-25.8% ± 1.8% vs. -3.6% ± 1.5%), mean arterial pressure (-15.0 ± 1.9 vs. -0.1 ± 0.9 mmHg) and heart rate (-23.6 ± 3.5 vs. -0.3 ± 0.9 beats/min) compared with microinjection of vehicle. Picoinjection of CNP significantly decreased the basal discharge of extracellular single-unit recordings in 5/6 (83%) rostral ventrolateral medulla (RVLM)-projecting PVN neurons and in 6/13 (46%) of the neurons that were not antidromically activated from the RVLM. We also observed that natriuretic peptide receptor type C (NPR-C) was present on the RVLM projecting PVN neurons detected by dual-labeling with retrograde tracer. Prior NPR-C siRNA microinjection into the PVN significantly blunted the decrease in RSNA to CNP microinjections into the PVN. Volume expansion-mediated reduction in RSNA was significantly blunted by prior administration of NPR-C siRNA into the PVN. These results suggest a potential role for CNP within the PVN in regulating RSNA, specifically under physiological conditions of alterations in fluid balance.
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Affiliation(s)
- Hong Zheng
- Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, Vermillion, SD, United States
| | - Tapan A. Patel
- Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE, United States
| | - Xuefei Liu
- Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, Vermillion, SD, United States
| | - Kaushik P. Patel
- Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE, United States
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Vink S, Akondi KB, Jin J, Poth K, Torres AM, Kuchel PW, Burke SL, Head GA, Alewood PF. Taipan Natriuretic Peptides Are Potent and Selective Agonists for the Natriuretic Peptide Receptor A. Molecules 2023; 28:molecules28073063. [PMID: 37049825 PMCID: PMC10095932 DOI: 10.3390/molecules28073063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 03/10/2023] [Accepted: 03/13/2023] [Indexed: 04/14/2023] Open
Abstract
Cardiovascular ailments are a major cause of mortality where over 1.3 billion people suffer from hypertension leading to heart-disease related deaths. Snake venoms possess a broad repertoire of natriuretic peptides with therapeutic potential for treating hypertension, congestive heart failure, and related cardiovascular disease. We now describe several taipan (Oxyuranus microlepidotus) natriuretic peptides TNPa-e which stimulated cGMP production through the natriuretic peptide receptor A (NPR-A) with higher potencies for the rat NPR-A (rNPR-A) over human NPR-A (hNPR-A). TNPc and TNPd were the most potent, demonstrating 100- and 560-fold selectivity for rNPR-A over hNPR-A. In vivo studies found that TNPc decreased diastolic and systolic blood pressure (BP) and increased heart rate (HR) in conscious normotensive rabbits, to a level that was similar to that of human atrial natriuretic peptide (hANP). TNPc also enhanced the bradycardia due to cardiac afferent stimulation (Bezold-Jarisch reflex). This indicated that TNPc possesses the ability to lower blood pressure and facilitate cardiac vagal afferent reflexes but unlike hANP does not produce tachycardia. The 3-dimensional structure of TNPc was well defined within the pharmacophoric disulfide ring, displaying two turn-like regions (RMSD = 1.15 Å). Further, its much greater biological stability together with its selectivity and potency will enhance its usefulness as a biological tool.
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Affiliation(s)
- Simone Vink
- Institute for Molecular Bioscience, The University of Queensland, St Lucia 4072, Australia
| | - Kalyana Bharati Akondi
- Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, CH-1211 Geneva, Switzerland
| | - Jean Jin
- Institute for Molecular Bioscience, The University of Queensland, St Lucia 4072, Australia
| | - Kim Poth
- Institute for Molecular Bioscience, The University of Queensland, St Lucia 4072, Australia
| | - Allan M Torres
- Nanoscale Organisation and Dynamics Group, Western Sydney University, Penrith 2759, Australia
| | - Philip W Kuchel
- School of Life and Environmental Sciences, University of Sydney, Sydney 2006, Australia
| | - Sandra L Burke
- Baker Heart and Diabetes Institute, Melbourne 3004, Australia
| | - Geoffrey A Head
- Baker Heart and Diabetes Institute, Melbourne 3004, Australia
| | - Paul F Alewood
- Institute for Molecular Bioscience, The University of Queensland, St Lucia 4072, Australia
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Lauro FV, Marcela RN, Maria LR, Magdalena AR, Virginia MAM, Francisco DC, Catalina CO, Montserrat MG. Biological Activity of a 4-Hydroxy-Furanyl-Benzamide Derivative on Heart Failure. Drug Res (Stuttg) 2023; 73:175-183. [PMID: 36564039 DOI: 10.1055/a-1855-1412] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
BACKGROUND There are studies that suggest that some benzamide derivatives may exert effects on heart failure; however, their molecular mechanism is not very clear. OBJECTIVE The aim of this research was to evaluate the biological activity of a 4-hydroxy-furanyl-benzamide derivative against heart failure translated as area infarct. METHODS Biological activity produced by 4-hydroxy-furanyl-benzamide derivative against heart failure was determinate using an ischemia-reperfusion injury model. In addition, the effects exerted by the 4-hydroxy-furanyl-benzamide derivative on left ventricular pressure (LVP) was evaluated in the absence or presence of some drugs such as yohimbine, butaxamine, methoctramine and L-NAME using a model of rat heart isolated. RESULTS The results showed that 4-hydroxy-furanyl-benzamide derivative decrease both infarct area and LVP. However, the effect produced by 4-hydroxy-furanyl-benzamide derivative on LVP was inhibited in the presence of both methoctramine and L-NAME. CONCLUSIONS All these data suggest that biological activity produced by 4-hydroxy-furanyl-benzamide derivative on left ventricular pressure is through of both M2-muscarinic receptor and nitric oxide synthase enzyme activation. It is important to mention that this phenomenon results as a decrease of both infarct area and heart failure.
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Affiliation(s)
- Figueroa-Valverde Lauro
- Laboratory of Pharmaco-Chemistry, Faculty of Chemical Biological Sciences, University Autonomous of Campeche, Campeche, México
| | - Rosas-Nexticapa Marcela
- Facultad de Nutrición, Universidad Veracruzana, Médicos y Odontologos s/n, Unidad del Bosque, Veracruz, México
| | - López-Ramos Maria
- Laboratory of Pharmaco-Chemistry, Faculty of Chemical Biological Sciences, University Autonomous of Campeche, Campeche, México
| | - Alvarez-Ramirez Magdalena
- Facultad de Nutrición, Universidad Veracruzana, Médicos y Odontologos s/n, Unidad del Bosque, Veracruz, México
| | - Mateu-Armad Maria Virginia
- Facultad de Nutrición, Universidad Veracruzana, Médicos y Odontologos s/n, Unidad del Bosque, Veracruz, México
| | - Díaz-Cedillo Francisco
- Escuela Nacional de Ciencias Biológicas del Instituto Politécnico Nacional. Prol, Santo Tomas, México
| | - Cervantes-Ortega Catalina
- Facultad de Nutrición, Universidad Veracruzana, Médicos y Odontologos s/n, Unidad del Bosque, Veracruz, México
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11
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Coughlan JJ, Ibanez B. The therapeutic benefit of vasodilators in acute heart failure: absence of evidence or evidence of absence? EUROPEAN HEART JOURNAL. ACUTE CARDIOVASCULAR CARE 2022; 11:861-864. [DOI: 10.1093/ehjacc/zuac130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/05/2022]
Affiliation(s)
- J J Coughlan
- Department of Cardiology, Deutsches Herzzentrum München und Technische Universität München , Lazarettstraße 36, 80636 München , Germany
- Cardiovascular Research Institute, Mater Private Network , 73 Eccles Street, Dublin 7, D07 KWR1 , Ireland
| | - Borja Ibanez
- Centro Nacional de Investigaciones Cardiovasculares Carlos III , c/Melchor Fernandez Almagrom 3, Madrid 28029 , Spain
- IIS-Fundación Jiménez Díaz University Hospital , Madrid 28040 , Spain
- CIBER de enfermedades cardiovasculares (CIBERCV) , Madrid 28029 , Spain
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12
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Ding K, Gui Y, Hou X, Ye L, Wang L. Transient Receptor Potential Channels, Natriuretic Peptides, and Angiotensin Receptor-Neprilysin Inhibitors in Patients With Heart Failure. Front Cardiovasc Med 2022; 9:904881. [PMID: 35722101 PMCID: PMC9204593 DOI: 10.3389/fcvm.2022.904881] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2022] [Accepted: 04/26/2022] [Indexed: 12/11/2022] Open
Abstract
Heart failure (HF) remains the leading cause of death, morbidity, and medical expenses worldwide. Treatments for HF with reduced ejection fraction have progressed in recent years; however, acute decompensated heart failure remains difficult to treat. The transient receptor potential (TRP) channel family plays roles in various cardiovascular diseases, responding to neurohormonal and mechanical load stimulation. Thus, TRP channels are promising targets for drug discovery, and many studies have evaluated the roles of TRP channels expressed on pain neurons. The natriuretic peptide (NP) family of proteins regulates blood volume, natriuresis, and vasodilation and can antagonize the renin-angiotensin-aldosterone system and participate in the pathogenesis of major cardiovascular diseases, such as HF, coronary atherosclerotic heart disease, and left ventricular hypertrophy. NPs are degraded by neprilysin, and the blood level of NPs has predictive value in the diagnosis and prognostic stratification of HF. In this review, we discuss the relationships between typical TRP family channels (e.g., transient receptor potential cation channel subfamily V member 1 andTRPV1, transient receptor potential cation channel subfamily C member 6) and the NP system (e.g., atrial NP, B-type NP, and C-type NP) and their respective roles in HF. We also discuss novel drugs introduced for the treatment of HF.
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Affiliation(s)
- Kun Ding
- Bengbu Medical College, Bengbu, China
- Zhejiang Provincial People’s Hospital, Hangzhou, China
| | - Yang Gui
- Bengbu Medical College, Bengbu, China
- Zhejiang Provincial People’s Hospital, Hangzhou, China
| | - Xu Hou
- Bengbu Medical College, Bengbu, China
- Zhejiang Provincial People’s Hospital, Hangzhou, China
| | - Lifang Ye
- Zhejiang Provincial People’s Hospital, Hangzhou, China
| | - Lihong Wang
- Zhejiang Provincial People’s Hospital, Hangzhou, China
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13
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Luo JC, Zhang YJ, Huang DL, Wang H, Luo MH, Hou JY, Hao GW, Su Y, Tu GW, Luo Z. Recombinant human brain natriuretic peptide ameliorates venous return function in congestive heart failure. ESC Heart Fail 2022; 9:2635-2644. [PMID: 35611916 PMCID: PMC9288780 DOI: 10.1002/ehf2.13987] [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: 01/12/2022] [Revised: 05/01/2022] [Accepted: 05/04/2022] [Indexed: 11/21/2022] Open
Abstract
Aims Recombinant human brain natriuretic peptide (rh‐BNP) is commonly used as a decongestive therapy. This study aimed to investigate the instant effects of rh‐BNP on cardiac output and venous return function in post‐cardiotomy patients with congestive heart failure (CHF). Methods and results Twenty‐four post‐cardiotomy heart failure patients were enrolled and received a standard loading dose of rh‐BNP. Haemodynamic monitoring was performed via a pulmonary artery catheter before and after the administration of rh‐BNP. The cardiac output and venous return functions were estimated by depicting Frank‐Starling and Guyton curves. After rh‐BNP infusion, variables reflecting cardiac congestion and venous return function, such as pulmonary artery wedge pressure, mean systemic filling pressure (Pmsf) and venous return resistance index (VRRI), reduced from 15 ± 3 to 13 ± 3 mmHg, from 32 ± 7 to 28 ± 7 mmHg and from 6.7 ± 2.6 to 5.7 ± 1.8 mmHg min m2/L, respectively. Meanwhile, cardiac index, stroke volume index, and the cardiac output function curve remained unchanged per se. The decline in Pmsf [−13% (−22% to −8%)] and VRRI [−12% (−25% to −5%)] was much greater than that in the systemic vascular resistance index [−7% (−14% to 0%)]. In the subgroup analysis of reduced ejection fraction (<40%) patients, the aforementioned changes were more significant. Conclusions rh‐BNP might ameliorate venous return rather than cardiac output function in post‐cardiotomy CHF patients.
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Affiliation(s)
- Jing-Chao Luo
- Department of Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yi-Jie Zhang
- Department of Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Dan-Lei Huang
- Department of Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Medical College, Fudan University, Shanghai, China
| | - Huan Wang
- Department of Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Ming-Hao Luo
- Department of Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Medical College, Fudan University, Shanghai, China
| | - Jun-Yi Hou
- Department of Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Guang-Wei Hao
- Department of Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Ying Su
- Department of Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Guo-Wei Tu
- Department of Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Zhe Luo
- Department of Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, China.,Department of Critical Care Medicine, Xiamen Branch, Zhongshan Hospital, Fudan University, Xiamen, China.,Shanghai Key Lab of Pulmonary Inflammation and Injury, Shanghai, China
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14
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Lisco G, Giagulli VA, Iovino M, Zupo R, Guastamacchia E, De Pergola G, Iacoviello M, Triggiani V. Endocrine system dysfunction and chronic heart failure: a clinical perspective. Endocrine 2022; 75:360-376. [PMID: 34713389 PMCID: PMC8553109 DOI: 10.1007/s12020-021-02912-w] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2021] [Accepted: 10/13/2021] [Indexed: 11/01/2022]
Abstract
Chronic heart failure (CHF) leads to an excess of urgent ambulatory visits, recurrent hospital admissions, morbidity, and mortality regardless of medical and non-medical management of the disease. This excess of risk may be attributable, at least in part, to comorbid conditions influencing the development and progression of CHF. In this perspective, the authors examined and described the most common endocrine disorders observed in patients with CHF, particularly in individuals with reduced ejection fraction, aiming to qualify the risks, quantify the epidemiological burden and discuss about the potential role of endocrine treatment. Thyroid dysfunction is commonly observed in patients with CHF, and sometimes it could be the consequence of certain medications (e.g., amiodarone). Male and female hypogonadism may also coexist in this clinical context, contributing to deteriorating the prognosis of these patients. Furthermore, growth hormone deficiency may affect the development of adult myocardium and predispose to CHF. Limited recommendation suggests to screen endocrine disorders in CHF patients, but it could be interesting to evaluate possible endocrine dysfunction in this setting, especially when a high suspicion coexists. Data referring to long-term safety and effectiveness of endocrine treatments in patients with CHF are limited, and their impact on several "hard" endpoints (such as hospital admission, all-cause, and cardiovascular mortality) are still poorly understood.
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Affiliation(s)
- Giuseppe Lisco
- Interdisciplinary Department of Medicine, Section of Internal Medicine, Geriatrics, Endocrinology and Rare Diseases, University of Bari "Aldo Moro", School of Medicine, Policlinico, Piazza Giulio Cesare 11, 70124, Bari, Italy
| | - Vito Angelo Giagulli
- Interdisciplinary Department of Medicine, Section of Internal Medicine, Geriatrics, Endocrinology and Rare Diseases, University of Bari "Aldo Moro", School of Medicine, Policlinico, Piazza Giulio Cesare 11, 70124, Bari, Italy
| | - Michele Iovino
- Interdisciplinary Department of Medicine, Section of Internal Medicine, Geriatrics, Endocrinology and Rare Diseases, University of Bari "Aldo Moro", School of Medicine, Policlinico, Piazza Giulio Cesare 11, 70124, Bari, Italy
| | - Roberta Zupo
- National Institute of Gastroenterology, Saverio de Bellis, Research Hospital, Castellana Grotte, Bari, Italy
| | - Edoardo Guastamacchia
- Interdisciplinary Department of Medicine, Section of Internal Medicine, Geriatrics, Endocrinology and Rare Diseases, University of Bari "Aldo Moro", School of Medicine, Policlinico, Piazza Giulio Cesare 11, 70124, Bari, Italy
| | - Giovanni De Pergola
- National Institute of Gastroenterology, Saverio de Bellis, Research Hospital, Castellana Grotte, Bari, Italy
- Clinical Nutrition Unit, Medical Oncology, Department of Internal Medicine and Clinical Oncology, University of Bari, School of Medicine, Policlinico, Piazza Giulio Cesare 11, 70124, Bari, Italy
| | - Massimo Iacoviello
- Department of Medical and Surgical Sciences, Cardiology Department, University of Foggia, Foggia, Italy
| | - Vincenzo Triggiani
- Interdisciplinary Department of Medicine, Section of Internal Medicine, Geriatrics, Endocrinology and Rare Diseases, University of Bari "Aldo Moro", School of Medicine, Policlinico, Piazza Giulio Cesare 11, 70124, Bari, Italy.
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15
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Xiangli S, Lan L, Libiya Z, Jun M, Shubin J. Effect of levosimendan combined with recombinant human brain natriuretic peptide on diuretic resistance. Libyan J Med 2021; 16:1973762. [PMID: 34493175 PMCID: PMC8439246 DOI: 10.1080/19932820.2021.1973762] [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] [Indexed: 10/27/2022] Open
Abstract
Levosimendan is a calcium sensitizer used for managing heart failure (HF) because of its inotropic and vasodilatory effects. As many patients do not respond to levosimendan as a monotherapy, it may be necessary to combine it with other diuretic agents such as recombinant human brain natriuretic peptide (rhBNc P). The aim of this study was to investigate efficacy of levosimendan when combined with rhBNP in patients with diuretic resistance and low ejection fraction (EF) rate.The study included HF patients with diuretic resistance and low EF. Before grouping, patients with a 24-hour urine volume of <0.5 mL/kg/h were administered with furosemide injection. Treatment group was administered levosimendan injection based on the original diuretic and rhBNP.One hundred twenty-eight patients were included, with 64 patients each in the control and treatment arms. 24-hour urine volume of the treatment group was significantly higher than that of the control group. Moreover, dyspnea score of the treatment group significantly improved compared with control group. In the treatment group, 12.5% of patients had no significant changes in the urine volume, weight, and dyspnea score before and after the treatment, indicating poor curative effect of the treatment, whereas in the control group, 23.4% of patients had poor curative effect (P < .05). No significant change was observed in the systolic blood pressure, heart rate, and serum creatinine level before and after treatment in both groups.Levosimendan in combination with rhBNP can effectively relieve diuretic resistance, reduce body weight, improve dyspnea, and ensure safety in the treatment process.
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Affiliation(s)
- Shen Xiangli
- Heart Center, Traditional Chinese Medicine Affiliated to Xinjiang Medical University, Urumqi, China
| | - Li Lan
- Heart Center, Traditional Chinese Medicine Affiliated to Xinjiang Medical University, Urumqi, China
| | - Zu Libiya
- Heart Center, Traditional Chinese Medicine Affiliated to Xinjiang Medical University, Urumqi, China
| | - Ma Jun
- Heart Center, Traditional Chinese Medicine Affiliated to Xinjiang Medical University, Urumqi, China
| | - Jiang Shubin
- Heart Center, Traditional Chinese Medicine Affiliated to Xinjiang Medical University, Urumqi, China
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16
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Lucero García Rojas EY, Villanueva C, Bond RA. Hypoxia Inducible Factors as Central Players in the Pathogenesis and Pathophysiology of Cardiovascular Diseases. Front Cardiovasc Med 2021; 8:709509. [PMID: 34447792 PMCID: PMC8382733 DOI: 10.3389/fcvm.2021.709509] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Accepted: 07/09/2021] [Indexed: 01/01/2023] Open
Abstract
Cardiovascular (CV) diseases are the major cause of death in industrialized countries. The main function of the CV system is to deliver nutrients and oxygen to all tissues. During most CV pathologies, oxygen and nutrient delivery is decreased or completely halted. Several mechanisms, including increased oxygen transport and delivery, as well as increased blood flow are triggered to compensate for the hypoxic state. If the compensatory mechanisms fail to sufficiently correct the hypoxia, irreversible damage can occur. Thus, hypoxia plays a central role in the pathogenesis and pathophysiology of CV diseases. Hypoxia inducible factors (HIFs) orchestrate the gene transcription for hundreds of proteins involved in erythropoiesis, glucose transport, angiogenesis, glycolytic metabolism, reactive oxygen species (ROS) handling, cell proliferation and survival, among others. The overall regulation of the expression of HIF-dependent genes depends on the severity, duration, and location of hypoxia. In the present review, common CV diseases were selected to illustrate that HIFs, and proteins derived directly or indirectly from their stabilization and activation, are related to the development and perpetuation of hypoxia in these pathologies. We further classify CV diseases into acute and chronic hypoxic states to better understand the temporal relevance of HIFs in the pathogenesis, disease progression and clinical outcomes of these diseases. We conclude that HIFs and their derived factors are fundamental in the genesis and progression of CV diseases. Understanding these mechanisms will lead to more effective treatment strategies leading to reduced morbidity and mortality.
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Affiliation(s)
| | - Cleva Villanueva
- Instituto Politecnico Nacional, Escuela Superior de Medicina, Mexico City, Mexico
| | - Richard A Bond
- Department of Pharmacology and Pharmaceutical Sciences, University of Houston, Houston, TX, United States
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17
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Zolty R. Novel Experimental Therapies for Treatment of Pulmonary Arterial Hypertension. J Exp Pharmacol 2021; 13:817-857. [PMID: 34429666 PMCID: PMC8380049 DOI: 10.2147/jep.s236743] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2021] [Accepted: 07/07/2021] [Indexed: 12/18/2022] Open
Abstract
Pulmonary arterial hypertension (PAH) is a progressive and devastating disease characterized by pulmonary artery vasoconstriction and vascular remodeling leading to vascular rarefaction with elevation of pulmonary arterial pressures and pulmonary vascular resistance. Often PAH will cause death from right heart failure. Current PAH-targeted therapies improve functional capacity, pulmonary hemodynamics and reduce hospitalization. Nevertheless, today PAH still remains incurable and is often refractory to medical therapy, underscoring the need for further research. Over the last three decades, PAH has evolved from a disease of unknown pathogenesis devoid of effective therapy to a condition whose cellular, genetic and molecular underpinnings are unfolding. This article provides an update on current knowledge and summarizes the progression in recent advances in pharmacological therapy in PAH.
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Affiliation(s)
- Ronald Zolty
- Pulmonary Hypertension Program, University of Nebraska Medical Center, Lied Transplant Center, Omaha, NE, USA
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18
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Pandey KN. Molecular Signaling Mechanisms and Function of Natriuretic Peptide Receptor-A in the Pathophysiology of Cardiovascular Homeostasis. Front Physiol 2021; 12:693099. [PMID: 34489721 PMCID: PMC8416980 DOI: 10.3389/fphys.2021.693099] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Accepted: 07/26/2021] [Indexed: 12/11/2022] Open
Abstract
The discovery of atrial, brain, and C-type natriuretic peptides (ANP, BNP, and CNP) and their cognate receptors has greatly increased our knowledge of the control of hypertension and cardiovascular homeostasis. ANP and BNP are potent endogenous hypotensive hormones that elicit natriuretic, diuretic, vasorelaxant, antihypertrophic, antiproliferative, and antiinflammatory effects, largely directed toward the reduction of blood pressure (BP) and cardiovascular diseases (CVDs). The principal receptor involved in the regulatory actions of ANP and BNP is guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPRA), which produces the intracellular second messenger cGMP. Cellular, biochemical, molecular, genetic, and clinical studies have facilitated understanding of the functional roles of natriuretic peptides (NPs), as well as the functions of their receptors, and signaling mechanisms in CVDs. Transgenic and gene-targeting (gene-knockout and gene-duplication) strategies have produced genetically altered novel mouse models and have advanced our knowledge of the importance of NPs and their receptors at physiological and pathophysiological levels in both normal and disease states. The current review describes the past and recent research on the cellular, molecular, genetic mechanisms and functional roles of the ANP-BNP/NPRA system in the physiology and pathophysiology of cardiovascular homeostasis as well as clinical and diagnostic markers of cardiac disorders and heart failure. However, the therapeutic potentials of NPs and their receptors for the diagnosis and treatment of cardiovascular diseases, including hypertension, heart failure, and stroke have just begun to be expanded. More in-depth investigations are needed in this field to extend the therapeutic use of NPs and their receptors to treat and prevent CVDs.
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Affiliation(s)
- Kailash N. Pandey
- Department of Physiology, School of Medicine, Tulane University Health Sciences Center, New Orleans, LA, United States
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19
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Batool A, Salehi N, Chaudhry S, Cross M, Malkawi A, Siraj A. Role of Vasodilator Therapy in Acute Heart Failure. Cureus 2021; 13:e17126. [PMID: 34532168 PMCID: PMC8434813 DOI: 10.7759/cureus.17126] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/27/2021] [Indexed: 01/08/2023] Open
Abstract
Over the past decade, several trials have questioned the efficacy of vasodilator therapy in acute heart failure (AHF) in the absence of uncontrolled hypertension. In this article, we provide a unique review of the most valuable four trials that present the role of vasodilator therapy in the management of patients with AHF. These four trials have evaluated the efficacy of different types of vasodilators such as nesiritide, ulatritide, and serelaxin in the setting of AHF. Also, we compared comprehensive vasodilator therapy versus standard therapy to see if there is any effect on mortality and re-hospitalization.
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Affiliation(s)
- Aisha Batool
- Internal Medicine, Columbia St. Mary Hospital, Milwaukee, USA
| | - Negar Salehi
- Cardiology, University of Arkansas for Medical Sciences, Little Rock, USA
| | | | - Michael Cross
- Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, USA
| | - Abdallah Malkawi
- Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, USA
| | - Aisha Siraj
- Cardiology, MetroHealth Medical Center, Cleveland, USA
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20
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da Silva GJJ, Altara R, Booz GW, Cataliotti A. Atrial Natriuretic Peptide 31-67: A Novel Therapeutic Factor for Cardiovascular Diseases. Front Physiol 2021; 12:691407. [PMID: 34305645 PMCID: PMC8297502 DOI: 10.3389/fphys.2021.691407] [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] [Received: 04/06/2021] [Accepted: 06/14/2021] [Indexed: 12/11/2022] Open
Abstract
The characterization of the cardiac hormone atrial natriuretic peptide (ANP99–126), synthesized and secreted predominantly by atrial myocytes under stimulation by mechanical stretch, has established the heart as an endocrine organ with potent natriuretic, diuretic, and vasodilating actions. Three additional distinct polypeptides resulting from proteolytic cleavage of proANP have been identified in the circulation in humans. The mid-sequence proANP fragment 31–67 (also known as proANP31–67) has unique potent and prolonged diuretic and natriuretic properties. In this review, we report the main effects of this circulating hormone in different tissues and organs, and its mechanisms of actions. We further highlight recent evidence on the cardiorenal protective actions of chronic supplementation of synthetic proANP31–67 in preclinical models of cardiorenal disease. Finally, we evaluate the use of proANP31–67 as a new therapeutic strategy to repair end-organ damage secondary to hypertension, diabetes mellitus, renal diseases, obesity, heart failure, and other morbidities that can lead to impaired cardiac function and structure.
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Affiliation(s)
| | - Raffaele Altara
- Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway.,Department of Pathology, School of Medicine, University of Mississippi Medical Center Jackson, Jackson, MS, United States
| | - George W Booz
- Department of Pharmacology and Toxicology, School of Medicine, The University of Mississippi Medical Center, Jackson, MS, United States
| | - Alessandro Cataliotti
- Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway
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21
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Zannad F, Cotter G, Alonso Garcia A, George S, Davison B, Figtree G, Prasad K, Rockhold F, Schilsky RL, Stockbridge N, Pitt B, Butler J. What can heart failure trialists learn from oncology trialists? Eur Heart J 2021; 42:2373-2383. [PMID: 34076243 DOI: 10.1093/eurheartj/ehab236] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 02/24/2021] [Accepted: 04/30/2021] [Indexed: 12/27/2022] Open
Abstract
Globally, there has been little change in mortality rates from cardiovascular (CV) diseases or cancers over the past two decades (1997-2018). This is especially true for heart failure (HF) where 5-year mortality rates remain as high as 45-55%. In the same timeframe, the proportion of drug revenue, and regulatory drug approvals for cancer drugs, far out paces those for CV drugs. In 2018, while cancer drugs made 27% of Food and Drug Administration drug approvals, only 1% of drug approvals was for a CV drug, and over this entire 20 year span, only four drugs were approved for HF in the USA. Cardiovascular trialists need to reassess the design, execution, and purpose of CV clinical trials. In the area of oncology research, trials are much smaller, follow-up is shorter, and targeted therapies are common. Cardiovascular diseases and cancer are the two most common causes of death globally, and although they differ substantially, this review evaluates whether some elements of oncology research may be applicable in the CV arena. As one of the most underserved CV diseases, the review focuses on aspects of cancer research that may be applicable to HF research with the aim of streamlining the clinical trial process and decreasing the time and cost required to bring safe, effective, treatments to patients who need them. The paper is based on discussions among clinical trialists, industry representatives, regulatory authorities, and patients, which took place at the Cardiovascular Clinical Trialists Workshop in Washington, DC, on 8 December 2019 (https://www.globalcvctforum.com/2019 (14 September 2020)).
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Affiliation(s)
- Faiez Zannad
- Université de Lorraine, Inserm Clinical Investigation Center 1439 at Institut Lorrain du Coeur et des Vaisseaux, CHU 54500, University Hospital of Nancy, Nancy, France
| | - Gad Cotter
- 2Momentum Research, Inc., 3100 Tower Blvd, Durham, NC, 27707, USA, Inserm, Paris, 942 Mascot, France
| | - Angeles Alonso Garcia
- Medicines and Healthcare products Regulatory Agency (MHRA), 10 South Colonnade, London, E14 4PU, UK
| | - Suzanne George
- Sarcoma Center, Dana-Farber Cancer Center, 450 Brookline Ave, Boston, MA, 02215, USA
| | - Beth Davison
- 2Momentum Research, Inc., 3100 Tower Blvd, Durham, NC, 27707, USA, Inserm, Paris, 942 Mascot, France
| | - Gemma Figtree
- Northern Clinical School, Kolling Institute of Medical Research, University of Sydney, Sydney, Australia, Reserve Road, St Leonards, NSW 2065
| | - Krishna Prasad
- Medicines and Healthcare products Regulatory Agency (MHRA), 10 South Colonnade, London, E14 4PU, UK
| | - Frank Rockhold
- Department of Biostatistics & Bioinformatics, Duke University Medical Center, 2424 Erwin Rd, Durham, NC, 27710, USA
| | | | - Norman Stockbridge
- Division of Cardiovascular and Renal Products, FDA Center for Drug Evaluation and Research (CDER), 10903 New Hampshire Ave, Silver Spring, MD, 20993, USA
| | - Bertram Pitt
- Division of Cardiology, University of Michigan, 1500 E. Medical Center Dr, Ann Arbor, MI, 48109, USA
| | - Javed Butler
- Department of Medicine, University of Mississippi Medical Center, 2500 North State St, Jackson, MS, 39216, USA
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22
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Mathew R, Kumar A, Sahu A, Wali S, Aggarwal P. High-Dose Nitroglycerin Bolus for Sympathetic Crashing Acute Pulmonary Edema: A Prospective Observational Pilot Study. J Emerg Med 2021; 61:271-277. [PMID: 34215472 DOI: 10.1016/j.jemermed.2021.05.011] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Revised: 05/19/2021] [Accepted: 05/30/2021] [Indexed: 11/26/2022]
Abstract
BACKGROUND Sympathetic crashing acute pulmonary edema (SCAPE) is a severe form of hypertensive acute heart failure with a dramatic presentation. Rapid identification and management in the emergency department (ED) is key to saving these patients and preventing morbidity associated with endotracheal intubation and intensive care treatment. Use of high-dose nitroglycerin (NTG) and noninvasive ventilation (NIV) has been advocated in management of such patients. OBJECTIVE To study the feasibility and safety of high-dose NTG combined with NIV in SCAPE. METHODS This was a prospective observational pilot study done in the ED of a tertiary care hospital. All patients were treated with high-dose NTG and NIV. The primary objective was to study the feasibility and safety of the SCAPE management protocol in terms of the outcome of the patient. Resolution of symptoms in 6 h and need for intubation were recorded as endpoints. Any complications associated with high-dose NTG were also recorded. RESULTS A total of 25 patients were recruited. The mean bolus dose of NTG given was 872 μg, and mean cumulative dose, 35 mg. There was no incidence of hypotension after the bolus dose of nitroglycerin. Eleven patients had resolution of symptoms at 3 h of therapy. Twenty-four patients were discharged from the ED itself after a brief period of observation, and one patient was intubated and shifted to the intensive care unit. CONCLUSION Use of our specific SCAPE treatment algorithm, which included high-dose NTG and NIV, was safe and provided rapid resolution of symptoms.
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Affiliation(s)
- Roshan Mathew
- Department of Emergency Medicine, All India Institute of Medical Science (AIIMS), New Delhi, India
| | - Akshay Kumar
- Department of Emergency Medicine, All India Institute of Medical Science (AIIMS), New Delhi, India.
| | - Ankit Sahu
- Department of Emergency Medicine, All India Institute of Medical Science (AIIMS), New Delhi, India
| | - Sachin Wali
- Department of Emergency Medicine, All India Institute of Medical Science (AIIMS), New Delhi, India
| | - Praveen Aggarwal
- Department of Emergency Medicine, All India Institute of Medical Science (AIIMS), New Delhi, India
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Liu JL, Zhang XF, Liu Z, Li JM, Wen ZJ, Zhang M, Lin QH, Kou QY. The role of recombinant human brain natriuretic peptide on the cardiac output of patients with acute decompensated heart failure using Guyton venous return curve: A STROBE-compliant retrospective study. Medicine (Baltimore) 2021; 100:e25492. [PMID: 33907098 PMCID: PMC8084054 DOI: 10.1097/md.0000000000025492] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2020] [Revised: 03/17/2021] [Accepted: 03/20/2021] [Indexed: 11/25/2022] Open
Abstract
ABSTRACT rbBNP has positive cardiac effects in patients with acute decompensated heart failure, but its effects on the systemic venous circulation are not known.A single-center retrospective, self-controlled study was conducted on 14 patients undergone recombinant human brain natriuretic peptide (rhBNP) treatment between January 1, 2015 to December 31, 2018.The cardiac output (CO) significantly increased from 3.75 ± 1.14 L min-1 to 4.24 ± 0.97 L min-1 30 minutes after rbBNP infusion, and to 4.20 ± 1.19 L min-1 3 hours later. The systemic vascular resistance significantly decreased from 18.85 ± 7.66 mm Hg min L-1 to 14.62 ± 6.13 mm Hg min L-1 30 minutes. The resistance to venous return (VR) significantly decreased from 5.93 ± 4.97 mm Hg min L-1 to 4.46 ± 1.53 mmHg min L-1 3 hours later. The mean systemic filling pressure significantly decreased from 32.71 ± 20.00 mm Hg to 28.254 ± 6.09 mm Hg 3 hours later.The role of rhBNP on CO was to reduce the peripheral circulation resistance at 30 minutes after rhBNP infusion and to reduce the resistance to VR at 3 hours later.This trial is registered at ChiCTR: ID ChiCTR1900024562.
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Affiliation(s)
- Jian ling Liu
- Department of Intensive Care Unit, Qingyuan People's Hospital,Qingyuan,China
| | - Xiao fei Zhang
- Department of Intensive Care Unit, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Zhi Liu
- Department of Intensive Care Unit, Qingyuan People's Hospital,Qingyuan,China
| | - Jie min Li
- Department of Intensive Care Unit, Qingyuan People's Hospital,Qingyuan,China
| | - Zhen jie Wen
- Department of Intensive Care Unit, Qingyuan People's Hospital,Qingyuan,China
| | - Ming Zhang
- Department of Intensive Care Unit, Qingyuan People's Hospital,Qingyuan,China
| | - Qin han Lin
- Department of Intensive Care Unit, Qingyuan People's Hospital,Qingyuan,China
| | - Qiu ye Kou
- Department of Intensive Care Unit, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
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Babapoor-Farrokhran S, Kalla A, Gill D, Gulab A, Banka S, Kalra S. Peripheral Administration of Nitroglycerin in Pulseless Ventricular Tachycardia due to Cocaine-Induced Coronary Vasospasm. Cardiovasc Toxicol 2021; 21:490-493. [PMID: 33534027 DOI: 10.1007/s12012-021-09635-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Accepted: 01/22/2021] [Indexed: 10/22/2022]
Abstract
Cocaine use accounts for 40% of the annual drug use related emergency department visits in the United States. Cocaine use is hence recognized as a major health problem. Cocaine blocks the presynaptic reuptake of norepinephrine and dopamine. The resulting increased adrenergic activity leads to vasoconstriction. Additionally, via various mechanisms, cocaine leads to a prothrombotic state and increases myocardial demand. Cocaine can cause coronary vasospasm and is therefore, associated with acute myocardial injury even in the absence of pre-existing atherosclerotic coronary artery disease. Nitroglycerin has a class 1C indication by the ACCF/AHA guidelines for patients with ST-segment elevation or depression that accompanies ischemic chest discomfort in the setting of cocaine use. It has been shown to reverse cocaine-induced coronary vasospasm and chest pain. In this case report, for the first time, we discuss how intravenous administration of high dose nitroglycerin to a patient in pulseless ventricular tachycardia with angiographically confirmed vasospasm induced by cocaine resulted in return of spontaneous circulation.
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Affiliation(s)
- Savalan Babapoor-Farrokhran
- Division of Cardiology, Department of Medicine, Einstein Medical Center, 5501 Old York Road, Philadelphia, PA, 19141, USA.
| | - Aditi Kalla
- Division of Cardiology, Department of Medicine, Einstein Medical Center, 5501 Old York Road, Philadelphia, PA, 19141, USA
| | - Deanna Gill
- Department of Medicine, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - Asma Gulab
- Department of Medicine, Einstein Medical Center, Philadelphia, PA, 19141, USA
| | - Sahil Banka
- Division of Cardiology, Department of Medicine, Einstein Medical Center, 5501 Old York Road, Philadelphia, PA, 19141, USA
| | - Sanjog Kalra
- Division of Cardiology, Department of Medicine, Einstein Medical Center, 5501 Old York Road, Philadelphia, PA, 19141, USA
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Targeting Cyclic Guanosine Monophosphate to Treat Heart Failure: JACC Review Topic of the Week. J Am Coll Cardiol 2021; 76:1795-1807. [PMID: 33032741 DOI: 10.1016/j.jacc.2020.08.031] [Citation(s) in RCA: 78] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Revised: 08/13/2020] [Accepted: 08/14/2020] [Indexed: 12/25/2022]
Abstract
The significant morbidity and mortality associated with heart failure with reduced ejection fraction (HFrEF) or heart failure with preserved ejection fraction (HFpEF) justify the search for novel therapeutic agents. Reduced cyclic guanosine monophosphate levels contribute to HF progression. Among molecules modulating the nitric oxide (NO)-GMP-phosphodiesterase (PDE) pathway, the evaluation of nitrates, synthetic natriuretic peptides (NP), and NP analogs has yielded mixed results. Conversely, sacubitril/valsartan, combining NP degradation inhibition through neprilysin and angiotensin receptor blockade, has led to groundbreaking findings in HFrEF. Other strategies to increase tissue cyclic guanosine monophosphate have been attempted, such as PDE-3 or PDE-5 inhibition (with negative or neutral results), NO-independent soluble guanylate cyclase (sGC) activation, or enhancement of sGC sensitivity to endogenous NO. Following the positive results of the phase 3 VICTORIA (A Study of Vericiguat in Participants With Heart Failure With Reduced Ejection Fraction) trial on the sGC stimulator vericiguat in HFrEF, the main open questions are the efficacy of the sacubitril/valsartan-vericiguat combination in HFrEF and of vericiguat in HFpEF.
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Zhao X, Zhang DQ, Song R, Zhang G. Nesiritide in patients with acute myocardial infarction and heart failure: a meta-analysis. J Int Med Res 2020; 48:300060519897194. [PMID: 31948318 PMCID: PMC7113720 DOI: 10.1177/0300060519897194] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Objective This meta-analysis evaluated the efficacy and safety of nesiritide in patients with acute myocardial infarction (AMI) and heart failure. Methods PubMed, Embase, and the Cochrane Central Register of Controlled Trials were searched from inception through December 2018. Studies including patients with AMI and heart failure who received nesiritide were identified. Results Ten trials involving 870 participants were included in this meta-analysis. Nesiritide treatment significantly increased left ventricular ejection fraction, cardiac index, and 24- and 72-hour urine volumes. Additionally, pulmonary capillary wedge pressure, right atrial pressure, and brain natriuretic peptide and N-terminal brain natriuretic peptide levels were significantly decreased in patients treated with nesiritide compared with those treated with control drugs. However, patients treated with nesiritide did not have an increased risk of mortality compared with those treated with control drugs. There were no differences between the two groups with respect to heart rate or the risk of readmission, hypotension, or renal dysfunction. Conclusions Nesiritide appears to be safe for patients with AMI and heart failure, and it improves global cardiac and systemic function.
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Affiliation(s)
- Xuecheng Zhao
- Department of Emergency Medicine, China-Japan Friendship Hospital, Beijing, China
| | - Da-Qi Zhang
- Department of Neurology, First Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Rongjing Song
- Department of Pharmacy, Peking University People's Hospital, Beijing, China
| | - Guoqiang Zhang
- Department of Emergency Medicine, China-Japan Friendship Hospital, Beijing, China
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27
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Abstract
Heart failure (HF) is a common consequence of several cardiovascular diseases and is understood as a vicious cycle of cardiac and hemodynamic decline. The current inventory of treatments either alleviates the pathophysiological features (eg, cardiac dysfunction, neurohumoral activation, and ventricular remodeling) and/or targets any underlying pathologies (eg, hypertension and myocardial infarction). Yet, since these do not provide a cure, the morbidity and mortality associated with HF remains high. Therefore, the disease constitutes an unmet medical need, and novel therapies are desperately needed. Cyclic guanosine-3',5'-monophosphate (cGMP), synthesized by nitric oxide (NO)- and natriuretic peptide (NP)-responsive guanylyl cyclase (GC) enzymes, exerts numerous protective effects on cardiac contractility, hypertrophy, fibrosis, and apoptosis. Impaired cGMP signaling, which can occur after GC deactivation and the upregulation of cyclic nucleotide-hydrolyzing phosphodiesterases (PDEs), promotes cardiac dysfunction. In this study, we review the role that NO/cGMP and NP/cGMP signaling plays in HF. After considering disease etiology, the physiological effects of cGMP in the heart are discussed. We then assess the evidence from preclinical models and patients that compromised cGMP signaling contributes to the HF phenotype. Finally, the potential of pharmacologically harnessing cardioprotective cGMP to rectify the present paucity of effective HF treatments is examined.
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28
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Lerner Y, Hanout W, Ben-Uliel SF, Gani S, Leshem MP, Qvit N. Natriuretic Peptides as the Basis of Peptide Drug Discovery for Cardiovascular Diseases. Curr Top Med Chem 2020; 20:2904-2921. [PMID: 33050863 DOI: 10.2174/1568026620666201013154326] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Revised: 09/14/2020] [Accepted: 09/25/2020] [Indexed: 01/14/2023]
Abstract
Cardiovascular diseases (CVDs) are the leading global cause of death, accounting for more than 17.6 million deaths per year in 2016, a number that is expected to grow to more than 23.6 million by 2030. While many technologies are currently under investigation to improve the therapeutic outcome of CVD complications, only a few medications have been approved. Therefore, new approaches to treat CVD are urgently required. Peptides regulate numerous physiological processes, mainly by binding to specific receptors and inducing a series of signals, neurotransmissions or the release of growth factors. Importantly, peptides have also been shown to play an important role in the circulatory system both in physiological and pathological conditions. Peptides, such as angiotensin II, endothelin, urotensin-II, urocortins, adrenomedullin and natriuretic peptides have been implicated in the control of vascular tone and blood pressure as well as in CVDs such as congestive heart failure, atherosclerosis, coronary artery disease, and pulmonary and systemic hypertension. Hence it is not surprising that peptides are becoming important therapeutic leads in CVDs. This article will review the current knowledge on peptides and their role in the circulatory system, focusing on the physiological roles of natriuretic peptides in the cardiovascular system and their implications in CVDs.
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Affiliation(s)
- Yana Lerner
- The Azrieli Faculty of Medicine in the Galilee, Bar-Ilan University, Henrietta Szold St. 8, P.O. Box 1589, Safed, Israel
| | - Wessal Hanout
- The Azrieli Faculty of Medicine in the Galilee, Bar-Ilan University, Henrietta Szold St. 8, P.O. Box 1589, Safed, Israel
| | - Shulamit Fluss Ben-Uliel
- The Azrieli Faculty of Medicine in the Galilee, Bar-Ilan University, Henrietta Szold St. 8, P.O. Box 1589, Safed, Israel
| | - Samar Gani
- The Azrieli Faculty of Medicine in the Galilee, Bar-Ilan University, Henrietta Szold St. 8, P.O. Box 1589, Safed, Israel
| | - Michal Pellach Leshem
- The Azrieli Faculty of Medicine in the Galilee, Bar-Ilan University, Henrietta Szold St. 8, P.O. Box 1589, Safed, Israel
| | - Nir Qvit
- The Azrieli Faculty of Medicine in the Galilee, Bar-Ilan University, Henrietta Szold St. 8, P.O. Box 1589, Safed, Israel
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29
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The Trials of Women in Cardiology. J Am Coll Cardiol 2020; 76:1931-1933. [DOI: 10.1016/j.jacc.2020.09.014] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 09/07/2020] [Accepted: 09/09/2020] [Indexed: 11/23/2022]
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Briasoulis A, Inampudi C, Hatzis G, Asleh R. Management of Patients with Heart Failure: Focus on New Pharmaceutical and Device Options. Curr Med Chem 2020; 27:4522-4535. [DOI: 10.2174/0929867326666190523083747] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2017] [Revised: 11/06/2018] [Accepted: 02/19/2019] [Indexed: 01/14/2023]
Abstract
Hospitalization rates and survival of patients with Heart Failure (HF) have improved.
However, 5-year mortality rates remain high and the prevalence of the disease is rising likely due to
aging of the population and advances in diagnosis and treatment of other acute and chronic cardiovascular
diseases. Over the past three decades the therapeutic armamentarium of heart failure has improved
substantially with development of medications targeting neuro-hormonal activation and devices
preventing sudden cardiac death and improving cardiac synchrony. Recently, inhibition of angiotensin
receptors and neprilysin as well as sinoatrial pacemaker modulating f-current, have been
found safe and effective strategies that improve HF hospitalization rates and/or mortality. Antidiabetic
agents inhibiting sodium-glucose co-transporters 2, result in natriuresis and osmotic diuresis
and may further improve HF related outcomes. Furthermore, emerging therapies such as cardiac myosin
activators, soluble guanylate cyclase stimulators and non-steroidal mineralocorticoid receptor
antagonists are undergoing investigation in phase II and III studies of HF patients. Finally, rapid evolution
of in the management of advanced HF has occurred with the application of second and third
generation continuous flow left ventricular assist devices in clinical practice. Ongoing clinical studies
will validate the safety and efficacy of emerging therapeutic strategies in HF population underrepresented
in previous clinical trials.
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Affiliation(s)
- Alexandros Briasoulis
- Division of Cardiovascular Diseases, Section of Heart Failure and Transplant, University of Iowa Hospitals and Clinics, Iowa City, IA, United States
| | - Chakradhari Inampudi
- Division of Cardiovascular Diseases, Section of Heart Failure and Transplant, University of Iowa Hospitals and Clinics, Iowa City, IA, United States
| | - Georgios Hatzis
- Division of Cardiovascular Diseases, Section of Heart Failure and Transplant, University of Iowa Hospitals and Clinics, Iowa City, IA, United States
| | - Rabea Asleh
- Department of Cardiovascular Diseases, Mayo Clinic, Rochester MN, United States
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31
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Akbar S, Kabra N, Aronow WS. Impact of Sacubitril/Valsartan on Patient Outcomes in Heart Failure: Evidence to Date. Ther Clin Risk Manag 2020; 16:681-688. [PMID: 32801725 PMCID: PMC7405908 DOI: 10.2147/tcrm.s224772] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Accepted: 07/14/2020] [Indexed: 12/11/2022] Open
Abstract
With an estimated 6.2 million adults affected in the USA, heart failure remains a leading cause of morbidity, mortality, and health-care costs, despite the use of guideline-based medical therapies. The search for a more efficient therapy was rekindled when findings from the Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor With Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial demonstrated evidence for cardiovascular and mortality benefit of sacubitril/valsartan, a dual angiotensin receptor blocker and neprilysin inhibitor (ARNI), over enalapril (an angiotensin-converting enzyme inhibitor) in patients with heart failure and reduced rjection fraction (HFrEF). Following the trial's compelling results, recommendations for the use of sacubitril/valsartan as a replacement for an angiotensin-converting enzyme inhibitor and/or angiotensin receptor blocker were incorporated into the 2016 American College of Cardiology (ACC), the American Heart Association (AHA), and the Heart Failure Society of America recommended (HFSA) guidelines for the management of heart failure. This review aims to gain insight into the benefits as well as limitations associated with the use of sacubitril/valsartan in the treatment of heart failure (HF) through exploration of various subgroup analyses of the PARADIGM-HF trial, subsequent retrospective analyses, and randomized controlled trials that followed this landmark trial.
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Affiliation(s)
- Sara Akbar
- Department of Cardiology, Westchester Medical Center, Valhalla, NY10595, USA
- Department of Medicine, New York Medical College, Valhalla, NY10595, USA
| | - Nitin Kabra
- Department of Cardiology, Westchester Medical Center, Valhalla, NY10595, USA
- Department of Medicine, New York Medical College, Valhalla, NY10595, USA
| | - Wilbert S Aronow
- Department of Cardiology, Westchester Medical Center, Valhalla, NY10595, USA
- Department of Medicine, New York Medical College, Valhalla, NY10595, USA
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Lauro FV, Maria LR, Tomas LG, Francisco DC, Rolando GM, Marcela RN, Virginia MA, Alejandra GEE, Yazmin OA. Design and synthesis of two new steroid derivatives with biological activity on heart failure via the M 2-muscarinic receptor activation. Steroids 2020; 158:108620. [PMID: 32119871 DOI: 10.1016/j.steroids.2020.108620] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2019] [Revised: 02/21/2020] [Accepted: 02/26/2020] [Indexed: 11/26/2022]
Abstract
Several drugs have been prepared to treat of heart failure using some protocols which require dangerous reagents and specific conditions. The aim of this study was to synthesize a series of steroid derivatives (compounds 2 to 18) using some chemical strategies. The biological activity of steroid derivatives against heart failure was evaluated using an ischemia/reperfusion model. In addition, the effect exerted by compounds 4 or 5 on left ventricular pressure was evaluated in the absence or presence of yohimbine, butaxamine and methoctramine. The results showed that 1) both compounds 4 or 5 significantly decrease the heart failure (translated as infarct area) compared with the compounds 2, 3 and 6-18. In addition, the compound 4 and 5 decreased the left ventricular pressure in a dose-dependent manner and this effect was significantly inhibited in the presence of methoctramine (p = 005). In conclusion, the compounds 4 or 5 decrease both the infarct area and left ventricular pressure via M2-muscarinic receptor activation.
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Affiliation(s)
- Figueroa-Valverde Lauro
- Laboratory of Pharmaco-Chemistry at the Faculty of Chemical Biological Sciences of the University Autonomous of Campeche, Av. Agustín Melgar s/n, Col Buenavista, C.P. 24039 Campeche Cam., Mexico.
| | - Lopez-Ramos Maria
- Laboratory of Pharmaco-Chemistry at the Faculty of Chemical Biological Sciences of the University Autonomous of Campeche, Av. Agustín Melgar s/n, Col Buenavista, C.P. 24039 Campeche Cam., Mexico
| | - Lopez-Gutierrez Tomas
- Laboratory of Pharmaco-Chemistry at the Faculty of Chemical Biological Sciences of the University Autonomous of Campeche, Av. Agustín Melgar s/n, Col Buenavista, C.P. 24039 Campeche Cam., Mexico
| | - Diaz Cedillo Francisco
- Escuela Nacional de Ciencias Biológicas del Instituto Politécnico Nacional, Prol. Carpio y Plan de Ayala, s/n Col. Santo Tomas, D.F. C.P. 11340, Mexico
| | - Garcia-Martinez Rolando
- Laboratory of Pharmaco-Chemistry at the Faculty of Chemical Biological Sciences of the University Autonomous of Campeche, Av. Agustín Melgar s/n, Col Buenavista, C.P. 24039 Campeche Cam., Mexico
| | - Rosas-Nexticapa Marcela
- Facultad de Nutrición, Universidad Veracruzana, Médicos y Odontólogos s/n, 91010 Xalapa, Veracruz, Mexico; Facultad de Medicina, Universidad Veracruzana, Médicos y Odontólogos s/n, 91010 Xalapa, Veracruz, Mexico.
| | - Mateu-Armand Virginia
- Facultad de Nutrición, Universidad Veracruzana, Médicos y Odontólogos s/n, 91010 Xalapa, Veracruz, Mexico; Facultad de Medicina, Universidad Veracruzana, Médicos y Odontólogos s/n, 91010 Xalapa, Veracruz, Mexico
| | - Garcimarero-Espino E Alejandra
- Facultad de Nutrición, Universidad Veracruzana, Médicos y Odontólogos s/n, 91010 Xalapa, Veracruz, Mexico; Facultad de Medicina, Universidad Veracruzana, Médicos y Odontólogos s/n, 91010 Xalapa, Veracruz, Mexico
| | - Ortiz-Ake Yazmin
- Laboratory of Pharmaco-Chemistry at the Faculty of Chemical Biological Sciences of the University Autonomous of Campeche, Av. Agustín Melgar s/n, Col Buenavista, C.P. 24039 Campeche Cam., Mexico
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Salazar J, Rojas-Quintero J, Cano C, Pérez JL, Ramírez P, Carrasquero R, Torres W, Espinoza C, Chacín-González M, Bermúdez V. Neprilysin: A Potential Therapeutic Target of Arterial Hypertension? Curr Cardiol Rev 2020; 16:25-35. [PMID: 31241018 PMCID: PMC7062041 DOI: 10.2174/1573403x15666190625160352] [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: 02/21/2019] [Revised: 06/13/2019] [Accepted: 06/13/2019] [Indexed: 02/07/2023] Open
Abstract
Arterial hypertension is the most prevalent chronic disease in the adult population of developed countries and it constitutes a significant risk factor in the development of cardiovascular disease, contributing to the emergence of many comorbidities, among which heart failure excels, a clinical syndrome that nowadays represents a major health problem with uncountable hospitalizations and the indolent course of which progressively worsens until quality of life decreases and lastly death occurs prematurely. In the light of this growing menace, each day more efforts are invested in the field of cardiovascular pharmacology, searching for new therapeutic options that allow us to modulate the physiological systems that appear among these pathologies. Therefore, in the later years, the study of natriuretic peptides has become so relevant, which mediate beneficial effects at the cardiovascular level such as diuresis, natriuresis, and decreasing cardiac remodeling; their metabolism is mediated by neprilysin, a metalloproteinase, widely expressed in the human and capable of catalyzing many substrates. The modulation of these functions has been studied by decades, giving room to Sacubitril, the first neprilysin inhibitor, which in conjunction with an angiotensin receptor blocker has provided a high efficacy and tolerability among patients with heart failure, for whom it has already been approved and recommended. Nonetheless, in the matter of arterial hypertension, significant findings have arisen that demonstrate the potential role that it will play among the pharmacological alternatives in the upcoming years.
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Affiliation(s)
- Juan Salazar
- Endocrine and Metabolic Disease Research Center, School of Medicine, University of Zulia, Maracaibo, Venezuela
| | - Joselyn Rojas-Quintero
- Pulmonary and Critical Care Medicine Department, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, United States
| | - Clímaco Cano
- Endocrine and Metabolic Disease Research Center, School of Medicine, University of Zulia, Maracaibo, Venezuela
| | - José L Pérez
- Endocrine and Metabolic Disease Research Center, School of Medicine, University of Zulia, Maracaibo, Venezuela
| | - Paola Ramírez
- Endocrine and Metabolic Disease Research Center, School of Medicine, University of Zulia, Maracaibo, Venezuela
| | - Rubén Carrasquero
- Endocrine and Metabolic Disease Research Center, School of Medicine, University of Zulia, Maracaibo, Venezuela
| | - Wheeler Torres
- Endocrine and Metabolic Disease Research Center, School of Medicine, University of Zulia, Maracaibo, Venezuela
| | | | | | - Valmore Bermúdez
- Universidad Simon Bolívar, Facultad de Ciencias de la Salud, Barranquilla, Colombia
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Gupta DK, Walford GA, Ma Y, Jarolim P, Wang TJ, for the DPP Research Group. Racial/ethnic differences in circulating natriuretic peptide levels: The Diabetes Prevention Program. PLoS One 2020; 15:e0229280. [PMID: 32084251 PMCID: PMC7034896 DOI: 10.1371/journal.pone.0229280] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Accepted: 02/03/2020] [Indexed: 12/11/2022] Open
Abstract
Natriuretic peptides are cardiac-derived hormones that enhance insulin sensitivity and reduce fat accumulation. Low natriuretic peptide levels are associated with increased risk of type 2 diabetes mellitus (DM2); a condition with variable prevalence across racial/ethnic groups. Few studies have examined whether circulating natriuretic peptide levels and their response to preventive interventions for DM2 differ by race/ethnicity. The Diabetes Prevention Program (DPP) is a clinical trial (July 31, 1996- July 31, 2001) that randomized participants to preventive interventions for DM2. Using stored serum samples, we examined N-terminus pro-B-type natriuretic peptide (NT-proBNP) levels in 3,220 individuals (56% white; 19% African-American; 15% Hispanic; 5% American-Indian; 5% Asian). The influence of race/ethnicity on NT-proBNP concentrations at baseline and after two years of treatment with placebo, lifestyle, or metformin was examined with multivariable-adjusted regression. At baseline, NT-proBNP differed significantly by race (P < .001), with the lowest values in African-American individuals. Hispanic individuals also had lower baseline NT-proBNP levels compared with whites (P< .001), while NT-proBNP levels were similar between white, American-Indian, and Asian individuals. At two years of follow-up, NT-proBNP levels decreased in African-Americans in each of the DPP study arms, whereas they were stable or increased in the other racial/ethnic groups. In the DPP, African-American individuals had lower circulating NT-proBNP levels compared with individuals in other racial/ethnic groups at baseline and after two years of preventive interventions. Further studies should examine the cardio-metabolic implications of lower natriuretic peptide levels in African-Americans. Trial Registration: ClinicalTrials.gov NCT00004992.
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Affiliation(s)
- Deepak K. Gupta
- Vanderbilt Translational and Clinical Cardiovascular Research Center, Vanderbilt University School of Medicine, Nashville, TN, United States of America
- Division of Cardiovascular Medicine, Vanderbilt University School of Medicine, Nashville, TN, United States of America
| | - Geoffrey A. Walford
- Diabetes Research Center (Diabetes Unit), Massachusetts General Hospital, Boston, MA, United States of America
- Department of Medicine, Harvard Medical School, Boston, MA, United States of America
- Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, United States of America
| | - Yong Ma
- Diabetes Prevention Program Data Coordinating Center, The Biostatistics Center, George Washington University, Rockville, MD, United States of America
| | - Petr Jarolim
- Biomarker Research Laboratory/TIMI Clinical Trial Laboratory, Department of Pathology, Brigham and Women’s Hospital, Boston, MA, United States of America
- Department of Pathology, Harvard Medical School, Boston, MA, United States of America
| | - Thomas J. Wang
- Vanderbilt Translational and Clinical Cardiovascular Research Center, Vanderbilt University School of Medicine, Nashville, TN, United States of America
- Division of Cardiovascular Medicine, Vanderbilt University School of Medicine, Nashville, TN, United States of America
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Sridharan S, Kini RM, Richards AM. Venom natriuretic peptides guide the design of heart failure therapeutics. Pharmacol Res 2020; 155:104687. [PMID: 32057893 DOI: 10.1016/j.phrs.2020.104687] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Revised: 01/24/2020] [Accepted: 02/07/2020] [Indexed: 12/29/2022]
Abstract
Heart failure (HF) affects over 26 million people world-wide. It is a syndrome triggered by loss of normal cardiac function due to many acute (eg myocardial infarction) and/or chronic (eg hypertension) causes and characterized by mixed beneficial and deleterious activation of a complex of multifaceted neurohormonal systems the net effect of which frequently is further adverse disruption of pressure-volume homeostasis. Unlike the situation in chronic heart failure, current strategies for treatment of acute heart failure are empirical and lack a strong evidence base. Management includes any of a combination of vasodilators, diuretics and ionotropic agents depending on the hemodynamic profile of the patient. Despite the improvement in the options available to improve outcomes in patients with chronic HF, for several decades little gain has been made in the treatment of the acute decompensated state. Morbidity and mortality rates remain high necessitating new therapeutic agents. The cardiac natriuretic peptides (NPs) are key hormones in pressure-volume homoeostasis. There are three isoforms of mammalian NPs, namely ANP, BNP and CNP. These peptides bind to membrane-bound NP receptors (NPRs) on the heart, vasculature and kidney to lower blood pressure and circulating volume. Intravenous infusion of NPs in HF patients improves hemodynamic status but is associated with occasional severe hypotension. Apart from mammalian NPs, snake venom NPs are an excellent source of pharmacologically distinct ligands that offer the possibility of engineering NPs for therapeutic purposes. Venom NPs have long half-lives, differential NPR activation profiles and varied NPR specificity. The scaffolds of venom NPs encode the molecular information for designing NPs with longer half-lives and improved and differential vascular and renal functions. This review focuses on the structure-function paradigm of mammalian and venom NPs and the different peptide engineering strategies that have been utilized in the design of clinically relevant new NP-analogues.
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Affiliation(s)
- Sindhuja Sridharan
- Genome Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany
| | - R Manjunatha Kini
- Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore.
| | - Arthur Mark Richards
- Cardiac Department, National University Hospital, Cardiovascular Research Institute, National University Heart Centre, National University Health System, Singapore; Christchurch Heart Institute, University of Otago, NZ, United States.
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Li H, Duan Y, Chen B, Zhao Y, Su W, Wang S, Wu J, Lu L. New pharmacological treatments for heart failure with reduced ejection fraction (HFrEF): A Bayesian network meta-analysis. Medicine (Baltimore) 2020; 99:e18341. [PMID: 32000355 PMCID: PMC7004768 DOI: 10.1097/md.0000000000018341] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Heart failure with reduced ejection fraction (HFrEF) has contributed to an increasing number of deaths and readmissions over the past few decades. Despite the appearance of standard treatments, including diuretics, β-receptor blockers and angiotensin-converting enzyme inhibitor (ACEI), there are still a large number of patients who have progressive deterioration of heart function and, inevitably, end-stage heart failure. In recent years, new medications for treating chronic heart failure have been clinically applied, but there is controversy surrounding drug selection and whether patients with HFrEF benefit from these medications. Therefore, we aimed to compare and rank different new pharmacological treatments in patients with HFrEF. METHODS We performed a network meta-analysis to identify both direct and indirect evidence from relevant studies. We searched MEDLINE, EMBASE, and PsycINFO through the OVID database and CENTRAL through the Cochrane Library for clinical randomized controlled trials investigating new pharmacological treatments in patients with HFrEF published up to September 30, 2018. We included trials of ivabradine, levosimendan, omega-3, tolvaptan, recombinant human B-type natriuretic peptide (rhBNP), isosorbide dinitrate and hydralazine (ISDN/HYD) and angiotensin-neprilysin inhibition (LCZ696). We extracted the relevant information from these trials with a predefined data extraction sheet and assessed the risk of bias with the Cochrane risk of bias tool. Based on these items, more than half of the entries were judged as having an overall low to moderate risk of bias; the remaining studies had a high or unclear risk of bias. The outcomes investigated were left ventricle ejection fraction (LVEF %), heart rate (HR) and serum level of B-type natriuretic peptide (BNP). We performed a random-effects network meta-analysis within a Bayesian framework. RESULTS We deemed 32 trials to be eligible that included 3810 patients and 32 treatments. Overall, 32 (94.1%) trials had a low to moderate risk of bias, while 2 (5.9%) trials had a high risk of bias. The quality of the included studies was rated as low in regard to allocation concealment and blinding and high in regard to other domains according to the Cochrane tools. As for increasing LVEF%, levosimendan was better than placebo (-3.77 (-4.96, -2.43)) and was the best intervention for improving ventricle contraction. As for controlling HR, n3-PUFA was better than placebo (4.01 (-0.44, 8.48)) and was the best choice for regulating HR. As for decreasing BNP, omega-3 was better than placebo (941.99 (-47.48, 1952.89) and was the best therapy for improving ventricle wall tension. CONCLUSIONS Our study confirmed the effectiveness of the included new pharmacological treatments for optimizing the structural performance and improving the cardiac function in the management of patients with HFrEF and recommended several interventions for clinical practice.
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Affiliation(s)
- Heng Li
- Cardiology Department of Tung Wah, Affiliated Hospital of Sun-Yat-Sen University
| | - Yuting Duan
- Clinical Research Center, South China Research Center for Acupuncture and Moxibustion, Medical College of Acu-Moxi and Rehabilitation, Guangzhou University of Chinese Medicine
| | - Benfa Chen
- Cardiology Department of Tung Wah, Affiliated Hospital of Sun-Yat-Sen University
| | - Yu Zhao
- Cardiology Department of Tung Wah, Affiliated Hospital of Sun-Yat-Sen University
| | - Weiping Su
- Cardiology Department of Tung Wah, Affiliated Hospital of Sun-Yat-Sen University
| | - Shanhua Wang
- Cardiology Department of Tung Wah, Affiliated Hospital of Sun-Yat-Sen University
| | - Jiaming Wu
- Zhongshan Affiliated Hospital, Guangzhou University of Chinese Medicine, China
| | - Liming Lu
- Clinical Research Center, South China Research Center for Acupuncture and Moxibustion, Medical College of Acu-Moxi and Rehabilitation, Guangzhou University of Chinese Medicine
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Cao Z, Zhao M, Xu C, Zhang T, Jia Y, Wang T, Zhu B. Evaluation of Agonal Cardiac Function for Sudden Cardiac Death in Forensic Medicine with Postmortem Brain Natriuretic Peptide (BNP) and NT‐proBNP: A Meta‐analysis. J Forensic Sci 2019; 65:686-691. [DOI: 10.1111/1556-4029.14232] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Revised: 10/15/2019] [Accepted: 10/15/2019] [Indexed: 12/28/2022]
Affiliation(s)
- Zhipeng Cao
- Department of Forensic Pathology School of Forensic Medicine China Medical University Shenyang 110122 China
| | - Mengyang Zhao
- Department of Forensic Genetics and Biology School of Forensic Medicine China Medical University Shenyang 110122 China
| | - Chengyang Xu
- The First Affiliated Hospital of China Medical University Shenyang 110001 China
| | - Tianyi Zhang
- Department of Forensic Pathology School of Forensic Medicine China Medical University Shenyang 110122 China
| | - Yuqing Jia
- Department of Forensic Pathology School of Forensic Medicine China Medical University Shenyang 110122 China
| | - Tianqi Wang
- Department of Forensic Pathology School of Forensic Medicine China Medical University Shenyang 110122 China
| | - Baoli Zhu
- Department of Forensic Pathology School of Forensic Medicine China Medical University Shenyang 110122 China
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Hussain A, Bennett RT, Tahir Z, Isaac E, Chaudhry MA, Qadri SS, Loubani M, Morice AH. Differential effects of atrial and brain natriuretic peptides on human pulmonary artery: An in vitro study. World J Cardiol 2019; 11:236-243. [PMID: 31754411 PMCID: PMC6859300 DOI: 10.4330/wjc.v11.i10.236] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2019] [Revised: 08/31/2019] [Accepted: 09/16/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The prevalence of cardiovascular diseases, especially heart failure, continues to rise worldwide. In heart failure, increasing levels of circulating atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are associated with a worsening of heart failure and a poor prognosis.
AIM To test whether a high concentration of BNP would inhibit relaxation to ANP.
METHODS Pulmonary arteries were dissected from disease-free areas of lung resection, as well as pulmonary artery rings of internal diameter 2.5–3.5 mm and 2 mm long, were prepared. Pulmonary artery rings were mounted in a multiwire myograph, and a basal tension of 1.61gf was applied. After equilibration for 60 min, rings were pre-constricted with 11.21 µmol/L PGF2α (EC80), and concentration response curves were constructed to vasodilators by cumulative addition to the myograph chambers.
RESULTS Although both ANP and BNP were found to vasodilate the pulmonary vessels, ANP is more potent than BNP. pEC50 of ANP and BNP were 8.96 ± 0.21 and 7.54 ± 0.18, respectively, and the maximum efficacy (Emax) for ANP and BNP was -2.03 gf and -0.24 gf, respectively. After addition of BNP, the Emax of ANP reduced from -0.96gf to -0.675gf (P = 0.28).
CONCLUSION BNP could be acting as a partial agonist in small human pulmonary arteries, and inhibits relaxation to ANP. Elevated levels of circulating BNP could be responsible for the worsening of decompensated heart failure. This finding could also explain the disappointing results seen in clinical trials of ANP and BNP analogues for the treatment of heart failure.
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Affiliation(s)
- Azar Hussain
- Department of Cardiothoracic Surgery, Castle Hill Hospital, Cottingham HU16 5JQ, United Kingdom
| | - Robert T Bennett
- Department of Cardiothoracic Surgery, Castle Hill Hospital, Cottingham HU16 5JQ, United Kingdom
| | - Zaheer Tahir
- Department of Cardiothoracic Surgery, Castle Hill Hospital, Cottingham HU16 5JQ, United Kingdom
| | - Emmanuel Isaac
- Department of Cardiothoracic Surgery, Castle Hill Hospital, Cottingham HU16 5JQ, United Kingdom
| | - Mubarak A Chaudhry
- Department of Cardiothoracic Surgery, Castle Hill Hospital, Cottingham HU16 5JQ, United Kingdom
| | - Syed S Qadri
- Department of Cardiothoracic Surgery, Castle Hill Hospital, Cottingham HU16 5JQ, United Kingdom
| | - Mahmoud Loubani
- Department of Cardiothoracic Surgery, Castle Hill Hospital, Cottingham HU16 5JQ, United Kingdom
| | - Alyn H Morice
- Centre for Cardiovascular and Metabolic Research, Hull York Medical School, Castle Hill Hospital, Cottingham HU16 5JQ, United Kingdom
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Arendse LB, Danser AHJ, Poglitsch M, Touyz RM, Burnett JC, Llorens-Cortes C, Ehlers MR, Sturrock ED. Novel Therapeutic Approaches Targeting the Renin-Angiotensin System and Associated Peptides in Hypertension and Heart Failure. Pharmacol Rev 2019; 71:539-570. [PMID: 31537750 PMCID: PMC6782023 DOI: 10.1124/pr.118.017129] [Citation(s) in RCA: 216] [Impact Index Per Article: 36.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Despite the success of renin-angiotensin system (RAS) blockade by angiotensin-converting enzyme (ACE) inhibitors and angiotensin II type 1 receptor (AT1R) blockers, current therapies for hypertension and related cardiovascular diseases are still inadequate. Identification of additional components of the RAS and associated vasoactive pathways, as well as new structural and functional insights into established targets, have led to novel therapeutic approaches with the potential to provide improved cardiovascular protection and better blood pressure control and/or reduced adverse side effects. The simultaneous modulation of several neurohumoral mediators in key interconnected blood pressure-regulating pathways has been an attractive approach to improve treatment efficacy, and several novel approaches involve combination therapy or dual-acting agents. In addition, increased understanding of the complexity of the RAS has led to novel approaches aimed at upregulating the ACE2/angiotensin-(1-7)/Mas axis to counter-regulate the harmful effects of the ACE/angiotensin II/angiotensin III/AT1R axis. These advances have opened new avenues for the development of novel drugs targeting the RAS to better treat hypertension and heart failure. Here we focus on new therapies in preclinical and early clinical stages of development, including novel small molecule inhibitors and receptor agonists/antagonists, less conventional strategies such as gene therapy to suppress angiotensinogen at the RNA level, recombinant ACE2 protein, and novel bispecific designer peptides.
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Affiliation(s)
- Lauren B Arendse
- Department of Integrative Biomedical Sciences, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, South Africa (L.B.A., E.D.S.); Division of Pharmacology, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands (A.H.J.D.); Attoquant Diagnostics, Vienna, Austria (M.P.); Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (R.M.T.); Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota (J.C.B.); Institut National de la Santé et de la Recherche Médicale, Paris, France (C.L.-C.); and Clinical Trials Group, Immune Tolerance Network, San Francisco, California (M.R.E.)
| | - A H Jan Danser
- Department of Integrative Biomedical Sciences, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, South Africa (L.B.A., E.D.S.); Division of Pharmacology, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands (A.H.J.D.); Attoquant Diagnostics, Vienna, Austria (M.P.); Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (R.M.T.); Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota (J.C.B.); Institut National de la Santé et de la Recherche Médicale, Paris, France (C.L.-C.); and Clinical Trials Group, Immune Tolerance Network, San Francisco, California (M.R.E.)
| | - Marko Poglitsch
- Department of Integrative Biomedical Sciences, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, South Africa (L.B.A., E.D.S.); Division of Pharmacology, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands (A.H.J.D.); Attoquant Diagnostics, Vienna, Austria (M.P.); Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (R.M.T.); Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota (J.C.B.); Institut National de la Santé et de la Recherche Médicale, Paris, France (C.L.-C.); and Clinical Trials Group, Immune Tolerance Network, San Francisco, California (M.R.E.)
| | - Rhian M Touyz
- Department of Integrative Biomedical Sciences, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, South Africa (L.B.A., E.D.S.); Division of Pharmacology, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands (A.H.J.D.); Attoquant Diagnostics, Vienna, Austria (M.P.); Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (R.M.T.); Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota (J.C.B.); Institut National de la Santé et de la Recherche Médicale, Paris, France (C.L.-C.); and Clinical Trials Group, Immune Tolerance Network, San Francisco, California (M.R.E.)
| | - John C Burnett
- Department of Integrative Biomedical Sciences, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, South Africa (L.B.A., E.D.S.); Division of Pharmacology, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands (A.H.J.D.); Attoquant Diagnostics, Vienna, Austria (M.P.); Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (R.M.T.); Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota (J.C.B.); Institut National de la Santé et de la Recherche Médicale, Paris, France (C.L.-C.); and Clinical Trials Group, Immune Tolerance Network, San Francisco, California (M.R.E.)
| | - Catherine Llorens-Cortes
- Department of Integrative Biomedical Sciences, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, South Africa (L.B.A., E.D.S.); Division of Pharmacology, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands (A.H.J.D.); Attoquant Diagnostics, Vienna, Austria (M.P.); Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (R.M.T.); Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota (J.C.B.); Institut National de la Santé et de la Recherche Médicale, Paris, France (C.L.-C.); and Clinical Trials Group, Immune Tolerance Network, San Francisco, California (M.R.E.)
| | - Mario R Ehlers
- Department of Integrative Biomedical Sciences, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, South Africa (L.B.A., E.D.S.); Division of Pharmacology, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands (A.H.J.D.); Attoquant Diagnostics, Vienna, Austria (M.P.); Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (R.M.T.); Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota (J.C.B.); Institut National de la Santé et de la Recherche Médicale, Paris, France (C.L.-C.); and Clinical Trials Group, Immune Tolerance Network, San Francisco, California (M.R.E.)
| | - Edward D Sturrock
- Department of Integrative Biomedical Sciences, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, South Africa (L.B.A., E.D.S.); Division of Pharmacology, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands (A.H.J.D.); Attoquant Diagnostics, Vienna, Austria (M.P.); Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (R.M.T.); Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota (J.C.B.); Institut National de la Santé et de la Recherche Médicale, Paris, France (C.L.-C.); and Clinical Trials Group, Immune Tolerance Network, San Francisco, California (M.R.E.)
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Iwahashi N, Takahashi H, Abe T, Okada K, Akiyama E, Matsuzawa Y, Konishi M, Maejima N, Hibi K, Kosuge M, Ebina T, Tamura K, Kimura K. Urgent Control of Rapid Atrial Fibrillation by Landiolol in Patients With Acute Decompensated Heart Failure With Severely Reduced Ejection Fraction. Circ Rep 2019; 1:422-430. [PMID: 33693079 PMCID: PMC7897576 DOI: 10.1253/circrep.cr-19-0076] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
Background:
We investigated the clinical usefulness of landiolol for rapid atrial fibrillation (AF) in patients with acute decompensated heart failure (ADHF) and identify the patients eligible for landiolol. Methods and Results:
A total of 101 ADHF patients with reduced ejection fraction (HFrEF) with rapid AF were enrolled. Immediately after admission, an initial dose of landiolol was given (1 μg/kg−1/min−1), and then the dose was increased to decrease heart rate (HR) to <110 beats/min and change HR (∆HR) >20% in ≤24 h. Thirty-seven were monitored using right heart catheterization at 3 points (baseline, 1 μg/kg−1/min−1, and maximum dose). We checked the major adverse events (MAE) during initial hospitalization, which included cardiac death, HF prolongation (required i.v. treatment at 30 days), and worsening renal function. The average maximum dose of landiolol was 3.8±2.3 μg/kg−1/min−1. HR (P<0.0001) and pulmonary capillary wedge pressure (P=0.0008) decreased safely. MAE occurred in 39 patients. The patients with left ventricular (LV) end-diastolic volume index <84.0 mL/m2
and mean blood pressure (mean BP) >97 mmHg had less frequent MAE (P<0.0001). Conclusions:
Landiolol was effective for safely controlling rapid AF in patients with HFrEF with ADHF, leading to hemodynamic improvement and avoidance of short-term MAE, especially in patients with relatively smaller LV and higher BP.
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Affiliation(s)
- Noriaki Iwahashi
- Division of Cardiology, Yokohama City University Medical Center Yokohama Japan
| | - Hironori Takahashi
- Division of Cardiology, Yokohama City University Medical Center Yokohama Japan
| | - Takeru Abe
- Department of Emergency Medicine, Yokohama City University Medical Center Yokohama Japan
| | - Kozo Okada
- Division of Cardiology, Yokohama City University Medical Center Yokohama Japan
| | - Eiichi Akiyama
- Division of Cardiology, Yokohama City University Medical Center Yokohama Japan
| | - Yasushi Matsuzawa
- Division of Cardiology, Yokohama City University Medical Center Yokohama Japan
| | - Masaaki Konishi
- Division of Cardiology, Yokohama City University Medical Center Yokohama Japan
| | - Nobuhiko Maejima
- Division of Cardiology, Yokohama City University Medical Center Yokohama Japan
| | - Kiyoshi Hibi
- Division of Cardiology, Yokohama City University Medical Center Yokohama Japan
| | - Masami Kosuge
- Division of Cardiology, Yokohama City University Medical Center Yokohama Japan
| | - Toshiaki Ebina
- Division of Cardiology, Yokohama City University Medical Center Yokohama Japan
| | - Kouichi Tamura
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine Yokohama Japan
| | - Kazuo Kimura
- Division of Cardiology, Yokohama City University Medical Center Yokohama Japan
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Tourki B, Dumesnil A, Belaidi E, Ghrir S, Godin-Ribuot D, Marrakchi N, Richard V, Mulder P, Messadi E. Lebetin 2, a Snake Venom-Derived B-Type Natriuretic Peptide, Provides Immediate and Prolonged Protection against Myocardial Ischemia-Reperfusion Injury via Modulation of Post-Ischemic Inflammatory Response. Toxins (Basel) 2019; 11:toxins11090524. [PMID: 31510060 PMCID: PMC6784001 DOI: 10.3390/toxins11090524] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Revised: 08/08/2019] [Accepted: 08/16/2019] [Indexed: 12/11/2022] Open
Abstract
Myocardial infarction (MI) followed by left ventricular (LV) remodeling is the most frequent cause of heart failure. Lebetin 2 (L2), a snake venom-derived natriuretic peptide, exerts cardioprotection during acute myocardial ischemia-reperfusion (IR) ex vivo. However, its effects on delayed consequences of IR injury, including post-MI inflammation and fibrosis have not been defined. Here, we determined whether a single L2 injection exerts cardioprotection in IR murine models in vivo, and whether inflammatory response to ischemic injury plays a role in L2-induced effects. We quantified infarct size (IS), fibrosis, inflammation, and both endothelial cell and cardiomyocyte densities in injured myocardium and compared these values with those induced by B-type natriuretic peptide (BNP). Both L2 and BNP reduced IS, fibrosis, and inflammatory response after IR, as evidenced by decreased leukocyte and proinflammatory M1 macrophage infiltrations in the infarcted area compared to untreated animals. However, only L2 increased anti-inflammatory M2-like macrophages. L2 also induced a higher density of endothelial cells and cardiomyocytes. Our data show that L2 has strong, acute, prolonged cardioprotective effects in post-MI that are mediated, at least in part, by the modulation of the post-ischemic inflammatory response and especially, by the enhancement of M2-like macrophages, thus reducing IR-induced necrotic and fibrotic effects.
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Affiliation(s)
- Bochra Tourki
- Laboratoire des Venins et Biomolécules Thérapeutiques (LR11IPT08) et Plateforme de Physiologie et de Physiopathologie Cardiovasculaires (P2C), Institut Pasteur de Tunis, Université Tunis El Manar, 1068 Tunis, Tunisia.
- Université Carthage Tunis, 1054 Bizerte, Tunisia.
| | - Anais Dumesnil
- Normandie Univ, UNIROUEN, Inserm U1096, FHU REMOD-VHF, 76000 Rouen, France.
| | - Elise Belaidi
- Université Grenoble Alpes, Inserm U1042, Laboratoire HP2, 38000 Grenoble, France.
| | - Slim Ghrir
- Laboratoire des Venins et Biomolécules Thérapeutiques (LR11IPT08) et Plateforme de Physiologie et de Physiopathologie Cardiovasculaires (P2C), Institut Pasteur de Tunis, Université Tunis El Manar, 1068 Tunis, Tunisia.
| | - Diane Godin-Ribuot
- Université Grenoble Alpes, Inserm U1042, Laboratoire HP2, 38000 Grenoble, France.
| | - Naziha Marrakchi
- Laboratoire des Venins et Biomolécules Thérapeutiques (LR11IPT08) et Plateforme de Physiologie et de Physiopathologie Cardiovasculaires (P2C), Institut Pasteur de Tunis, Université Tunis El Manar, 1068 Tunis, Tunisia.
| | - Vincent Richard
- Normandie Univ, UNIROUEN, Inserm U1096, FHU REMOD-VHF, 76000 Rouen, France.
| | - Paul Mulder
- Normandie Univ, UNIROUEN, Inserm U1096, FHU REMOD-VHF, 76000 Rouen, France.
| | - Erij Messadi
- Laboratoire des Venins et Biomolécules Thérapeutiques (LR11IPT08) et Plateforme de Physiologie et de Physiopathologie Cardiovasculaires (P2C), Institut Pasteur de Tunis, Université Tunis El Manar, 1068 Tunis, Tunisia.
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Abstract
Importance Hospitalizations for worsening heart failure (WHF) represent an enormous public health and financial burden, with physicians, health systems, and payers placing increasing emphasis on hospitalization prevention. In addition, maximizing time out of the hospital is an important patient-centered outcome. In this review, we discuss the concept of outpatient WHF, highlight the rationale and data for the outpatient treatment of WHF as an alternative to hospitalization, and examine opportunities and strategies for developing outpatient "interceptive" therapies for treatment of worsening symptoms and prevention of hospitalization. Observations Worsening heart failure has traditionally been synonymous with an episode of in-hospital care for worsening symptoms. While WHF often leads to hospitalization, many patients experience WHF in the outpatient setting and carry a similarly poor prognosis. These findings support WHF as a distinct condition, independent of location of care. For those that are hospitalized, most patients have an uncomplicated clinical course, with diuretics as the only intravenous therapy. Although complicated scenarios exist, it is conceivable that improved tools for outpatient management of clinical congestion would allow a greater proportion of hospitalized patients to receive comparable care outside the hospital. Most patients with WHF have a gradual onset of congestive signs and symptoms, offering a potential window in which effective therapy may abort continued worsening and obviate the need for hospitalization. To date, outpatient WHF has received minimal attention in randomized clinical trials, but this high-risk group possesses key features that favor effective clinical trial investigation. Conclusions and Relevance As the public health and economic burdens of heart failure continue to grow, recognizing the entity of outpatient WHF is critical. Efforts to reduce heart failure hospitalization should include developing effective therapies and care strategies for outpatient WHF. The outpatient WHF population represents a major opportunity for therapeutic advancements that could fundamentally change heart failure care delivery.
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Affiliation(s)
- Stephen J Greene
- Duke Clinical Research Institute, Durham, North Carolina.,Division of Cardiology, Duke University Medical Center, Durham, North Carolina
| | - Robert J Mentz
- Duke Clinical Research Institute, Durham, North Carolina.,Division of Cardiology, Duke University Medical Center, Durham, North Carolina
| | - G Michael Felker
- Duke Clinical Research Institute, Durham, North Carolina.,Division of Cardiology, Duke University Medical Center, Durham, North Carolina
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Pandey KN. Genetic Ablation and Guanylyl Cyclase/Natriuretic Peptide Receptor-A: Impact on the Pathophysiology of Cardiovascular Dysfunction. Int J Mol Sci 2019; 20:ijms20163946. [PMID: 31416126 PMCID: PMC6721781 DOI: 10.3390/ijms20163946] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Revised: 08/09/2019] [Accepted: 08/10/2019] [Indexed: 12/11/2022] Open
Abstract
Mice bearing targeted gene mutations that affect the functions of natriuretic peptides (NPs) and natriuretic peptide receptors (NPRs) have contributed important information on the pathogenesis of hypertension, kidney disease, and cardiovascular dysfunction. Studies of mice having both complete gene disruption and tissue-specific gene ablation have contributed to our understanding of hypertension and cardiovascular disorders. These phenomena are consistent with an oligogenic inheritance in which interactions among a few alleles may account for genetic susceptibility to hypertension, renal insufficiency, and congestive heart failure. In addition to gene knockouts conferring increased risks of hypertension, kidney disorders, and cardiovascular dysfunction, studies of gene duplications have identified mutations that protect against high blood pressure and cardiovascular events, thus generating the notion that certain alleles can confer resistance to hypertension and heart disease. This review focuses on the intriguing phenotypes of Npr1 gene disruption and gene duplication in mice, with emphasis on hypertension and cardiovascular events using mouse models carrying Npr1 gene knockout and/or gene duplication. It also describes how Npr1 gene targeting in mice has contributed to our knowledge of the roles of NPs and NPRs in dose-dependently regulating hypertension and cardiovascular events.
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Affiliation(s)
- Kailash N Pandey
- Department of Physiology, Tulane University Health Sciences Center, School of Medicine, New Orleans, LA 70112, USA.
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Wang L, Xie L, Wei X, Xie Z. Beneficial effects of early administration of recombinant human B-type natriuretic peptide in ST-elevation myocardial infarction patients receiving percutaneous coronary intervention treatment. Singapore Med J 2019; 60:621-625. [PMID: 31388683 DOI: 10.11622/smedj.2019093] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
INTRODUCTION We aimed to evaluate the clinical performance of early administration of recombinant human B-type natriuretic peptide (rhBNP) to ST-elevation myocardial infarction (STEMI) patients receiving percutaneous coronary intervention (PCI) treatment. METHODS In total, 185 patients diagnosed with STEMI were enrolled and randomised into either the placebo-treated (n = 88) or rhBNP-treated (n = 97) group. Patients were given either saline or rhBNP ten minutes before PCI and monitored with various cardiac parameters, including accelerated idioventricular rhythm, frequent ventricular premature beat (FVPB), ventricular tachycardia, systolic blood pressure, thrombolysis in myocardial infarction (TIMI) 3 gradation, corrected TIMI frame count (cTFC) and myocardial blush grade (MBG) 3 classification. RESULTS Our results revealed no difference in accelerated idioventricular rhythm between the two groups. However, FVPB and ventricular tachycardia were significantly decreased in rhBNP-treated patients compared to placebo-treated patients (p < 0.05). Moreover, the occurrence ratio of reperfusion-associated low blood pressure in rhBNP-treated patients was lower than in placebo-treated patients (p = 0.03), while no difference was observed in infarction-related arteries TIMI 3 blood flow between the two groups (p = 0.23). Importantly, measurement of post-reperfusion blood flow velocity via cTFC suggested that rhBNP treatment could significantly increase blood circulation (p = 0.003). After stent implantation, the acquisition rate of MBG 3 was higher in rhBNP-treated patients compared to placebo-treated patients (p = 0.071), although the difference was not significant. CONCLUSION We concluded that early administration of rhBNP can ameliorate the severity of reperfusion injury for STEMI patients receiving PCI treatment.
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Affiliation(s)
- Lijun Wang
- Department of Cardiology, Affiliated Zhongshan Hospital, Dalian University, Dalian, Liaoning, China
| | - Lianna Xie
- Department of Cardiology, Affiliated Zhongshan Hospital, Dalian University, Dalian, Liaoning, China
| | - Xianjing Wei
- Department of Cardiology, Affiliated Zhongshan Hospital, Dalian University, Dalian, Liaoning, China
| | - Zezhou Xie
- Department of Cardiology, Affiliated Zhongshan Hospital, Dalian University, Dalian, Liaoning, China
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Forte M, Madonna M, Schiavon S, Valenti V, Versaci F, Zoccai GB, Frati G, Sciarretta S. Cardiovascular Pleiotropic Effects of Natriuretic Peptides. Int J Mol Sci 2019; 20:3874. [PMID: 31398927 PMCID: PMC6719167 DOI: 10.3390/ijms20163874] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Revised: 08/03/2019] [Accepted: 08/07/2019] [Indexed: 02/07/2023] Open
Abstract
Atrial natriuretic peptide (ANP) is a cardiac hormone belonging to the family of natriuretic peptides (NPs). ANP exerts diuretic, natriuretic, and vasodilatory effects that contribute to maintain water-salt balance and regulate blood pressure. Besides these systemic properties, ANP displays important pleiotropic effects in the heart and in the vascular system that are independent of blood pressure regulation. These functions occur through autocrine and paracrine mechanisms. Previous works examining the cardiac phenotype of loss-of-function mouse models of ANP signaling showed that both mice with gene deletion of ANP or its receptor natriuretic peptide receptor A (NPR-A) developed cardiac hypertrophy and dysfunction in response to pressure overload and chronic ischemic remodeling. Conversely, ANP administration has been shown to improve cardiac function in response to remodeling and reduces ischemia-reperfusion (I/R) injury. ANP also acts as a pro-angiogenetic, anti-inflammatory, and anti-atherosclerotic factor in the vascular system. Pleiotropic effects regarding brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP) were also reported. In this review, we discuss the current evidence underlying the pleiotropic effects of NPs, underlying their importance in cardiovascular homeostasis.
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Affiliation(s)
| | | | - Sonia Schiavon
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, 04100 Latina, Italy
| | - Valentina Valenti
- Department of Cardiology, Santa Maria Goretti Hospital, 04100 Latina, Italy
| | - Francesco Versaci
- Department of Cardiology, Santa Maria Goretti Hospital, 04100 Latina, Italy
| | - Giuseppe Biondi Zoccai
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, 04100 Latina, Italy
- Mediterranea Cardiocentro, 80122 Napoli, Italy
| | - Giacomo Frati
- IRCCS NEUROMED, 86077 Pozzilli, Italy
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, 04100 Latina, Italy
| | - Sebastiano Sciarretta
- IRCCS NEUROMED, 86077 Pozzilli, Italy.
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, 04100 Latina, Italy.
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Okamoto R, Ali Y, Hashizume R, Suzuki N, Ito M. BNP as a Major Player in the Heart-Kidney Connection. Int J Mol Sci 2019; 20:ijms20143581. [PMID: 31336656 PMCID: PMC6678680 DOI: 10.3390/ijms20143581] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2019] [Revised: 07/15/2019] [Accepted: 07/17/2019] [Indexed: 02/07/2023] Open
Abstract
Brain natriuretic peptide (BNP) is an important biomarker for patients with heart failure, hypertension and cardiac hypertrophy. Although it is known that BNP levels are relatively higher in patients with chronic kidney disease and no heart disease, the mechanism remains unknown. Here, we review the functions and the roles of BNP in the heart-kidney interaction. In addition, we discuss the relevant molecular mechanisms that suggest BNP is protective against chronic kidney diseases and heart failure, especially in terms of the counterparts of the renin-angiotensin-aldosterone system (RAAS). The renal medulla has been reported to express depressor substances. The extract of the papillary tips from kidneys may induce the expression and secretion of BNP from cardiomyocytes. A better understanding of these processes will help accelerate pharmacological treatments for heart-kidney disease.
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Affiliation(s)
- Ryuji Okamoto
- Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan.
| | - Yusuf Ali
- Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan
| | - Ryotaro Hashizume
- Department of Pathology and Matrix Biology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan
| | - Noboru Suzuki
- Department of Animal Genomics, Functional Genomics Institute, Mie University Life Science Research Center, 2-174 Edobashi, Tsu, Mie 514-8507, Japan
| | - Masaaki Ito
- Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan
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Kislitsina ON, Rich JD, Wilcox JE, Pham DT, Churyla A, Vorovich EB, Ghafourian K, Yancy CW. Shock - Classification and Pathophysiological Principles of Therapeutics. Curr Cardiol Rev 2019; 15:102-113. [PMID: 30543176 PMCID: PMC6520577 DOI: 10.2174/1573403x15666181212125024] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2018] [Revised: 10/11/2018] [Accepted: 12/10/2018] [Indexed: 01/10/2023] Open
Abstract
The management of patients with shock is extremely challenging because of the myriad of possible clinical presentations in cardiogenic shock, septic shock and hypovolemic shock and the limitations of contemporary therapeutic options. The treatment of shock includes the administration of endogenous catecholamines (epinephrine, norepinephrine, and dopamine) as well as various vasopressor agents that have shown efficacy in the treatment of the various types of shock. In addition to the endogenous catecholamines, dobutamine, isoproterenol, phenylephrine, and milrinone have served as the mainstays of shock therapy for several decades. Recently, experimental studies have suggested that newer agents such as vasopressin, selepressin, calcium-sensitizing agents like levosimendan, cardiac-specific myosin activators like omecamtiv mecarbil (OM), istaroxime, and natriuretic peptides like nesiritide can enhance shock therapy, especially when shock presents a more complex clinical picture than normal. However, their ability to improve clinical outcomes remains to be proven. It is the purpose of this review to describe the mechanism of action, dosage requirements, advantages and disadvantages, and specific indications and contraindications for the use of each of these catecholamines and vasopressors, as well as to elucidate the most important clinical trials that serve as the basis of contemporary shock therapy.
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Affiliation(s)
- Olga N Kislitsina
- Department of Cardiac Surgery Bluhm Cardiovascular Institute Feinberg School of Medicine Northwestern University Medical Center, Chicago, Illinois, IL, United States.,Department of Cardiology Bluhm Cardiovascular Institute Feinberg School of Medicine Northwestern University Medical Center, Chicago, Illinois, IL, United States
| | - Jonathan D Rich
- Department of Cardiology Bluhm Cardiovascular Institute Feinberg School of Medicine Northwestern University Medical Center, Chicago, Illinois, IL, United States
| | - Jane E Wilcox
- Department of Cardiology Bluhm Cardiovascular Institute Feinberg School of Medicine Northwestern University Medical Center, Chicago, Illinois, IL, United States
| | - Duc T Pham
- Department of Cardiac Surgery Bluhm Cardiovascular Institute Feinberg School of Medicine Northwestern University Medical Center, Chicago, Illinois, IL, United States
| | - Andrei Churyla
- Department of Cardiac Surgery Bluhm Cardiovascular Institute Feinberg School of Medicine Northwestern University Medical Center, Chicago, Illinois, IL, United States
| | - Esther B Vorovich
- Department of Cardiology Bluhm Cardiovascular Institute Feinberg School of Medicine Northwestern University Medical Center, Chicago, Illinois, IL, United States
| | - Kambiz Ghafourian
- Department of Cardiology Bluhm Cardiovascular Institute Feinberg School of Medicine Northwestern University Medical Center, Chicago, Illinois, IL, United States
| | - Clyde W Yancy
- Department of Cardiology Bluhm Cardiovascular Institute Feinberg School of Medicine Northwestern University Medical Center, Chicago, Illinois, IL, United States
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Cao Z, Jia Y, Zhu B. BNP and NT-proBNP as Diagnostic Biomarkers for Cardiac Dysfunction in Both Clinical and Forensic Medicine. Int J Mol Sci 2019; 20:ijms20081820. [PMID: 31013779 PMCID: PMC6515513 DOI: 10.3390/ijms20081820] [Citation(s) in RCA: 193] [Impact Index Per Article: 32.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Revised: 04/09/2019] [Accepted: 04/11/2019] [Indexed: 12/23/2022] Open
Abstract
Currently, brain natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) are widely used as diagnostic biomarkers for heart failure (HF) and cardiac dysfunction in clinical medicine. They are also used as postmortem biomarkers reflecting cardiac function of the deceased before death in forensic medicine. Several previous studies have reviewed BNP and NT-proBNP in clinical medicine, however, few articles have reviewed their application in forensic medicine. The present article reviews the biological features, the research and application status, and the future research prospects of BNP and NT-proBNP in both clinical medicine and forensic medicine, thereby providing valuable assistance for clinicians and forensic pathologists.
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Affiliation(s)
- Zhipeng Cao
- Department of Forensic Pathology, School of Forensic Medicine, China Medical University, Shenyang 110122, China.
| | - Yuqing Jia
- Department of Forensic Pathology, School of Forensic Medicine, China Medical University, Shenyang 110122, China.
| | - Baoli Zhu
- Department of Forensic Pathology, School of Forensic Medicine, China Medical University, Shenyang 110122, China.
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Hardwick AB, Ambrosy AP. Natriuretic peptides as a surrogate endpoint in clinical trials - a riddle wrapped in an enigma. Eur J Heart Fail 2019; 21:621-623. [PMID: 30919550 DOI: 10.1002/ejhf.1448] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2019] [Accepted: 02/04/2019] [Indexed: 11/06/2022] Open
Affiliation(s)
- Alexander B Hardwick
- Department of Cardiology, Kaiser Permanente San Francisco Medical Center, San Francisco, CA, USA
| | - Andrew P Ambrosy
- Department of Cardiology, Kaiser Permanente San Francisco Medical Center, San Francisco, CA, USA.,Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA
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