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Alzoughool F, Al-Zghoul MB, Ghanim BY, Gollob M, Idkaidek N, Qinna NA. The Role of Interventional Irisin on Heart Molecular Physiology. Pharmaceuticals (Basel) 2022; 15:ph15070863. [PMID: 35890161 PMCID: PMC9319709 DOI: 10.3390/ph15070863] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 07/04/2022] [Accepted: 07/11/2022] [Indexed: 12/14/2022] Open
Abstract
Irisin, encoded by the FNDC5 (fibronectin type III domain containing 5) gene, is a novel myokine that has been implicated as an essential mediator of exercise benefits. Effects of irisin on heart physiology is still ambiguous. This study aimed to evaluate the impact of exogenous administration of irisin on heart physiology and the pharmacokinetic profile of pump-administered irisin. To do so, Sprague Dawley rats were implanted with an irisin-loaded osmotic pump (5 μg/kg/day) for 42 days, and other animals were administered with single bolus subcutaneous injections of irisin (5 µg/kg). Body weights and blood samples were collected weekly for 42 days for serum irisin quantification and histopathology. Clinical biochemistry analyses were performed. Heart mRNA expression was assessed in 26 selected genes. Chronic interventional exogenous irisin significantly reduced body weight without affecting the heart myocyte size and significantly reduced creatine kinase enzyme level. Blood CBC, serum biochemistry, and heart morphology were normal. Gene expression of FNCD5, Raf1, CPT1, IGF-1, and CALCIN, encoding for heart physiology, increased while PGC1, Nox4, and Mfn1 significantly decreased. Nevertheless, irisin increased the expression of cardioprotective genes and inhibited some genes that harm heart physiology. Administration of irisin promotes myocardial functions and could be translated into clinical settings after preclinical profiling.
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Affiliation(s)
- Foad Alzoughool
- Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, The Hashemite University, Zarqa 13133, Jordan;
- Faculty of Health Sciences, Higher Colleges of Technology, Fujairah Women’s College, Fujairah P.O. Box. 25026, United Arab Emirates
| | - Mohammad Borhan Al-Zghoul
- Basic Veterinary Sciences, School of Veterinary Medicine, Jordan University of Science and Technology, Irbid 22110, Jordan;
| | - Bayan Y. Ghanim
- University of Petra Pharmaceutical Center (UPPC), University of Petra, Amman 11196, Jordan;
| | - Michael Gollob
- Peter Munk Cardiac Centre, Toronto General Hospital, University of Toronto, Toronto, ON M5G 2N2, Canada;
| | - Nasir Idkaidek
- Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy and Medical Sciences, University of Petra, Amman 11196, Jordan;
| | - Nidal A. Qinna
- University of Petra Pharmaceutical Center (UPPC), University of Petra, Amman 11196, Jordan;
- Department of Pharmacology and Biomedical Sciences, Faculty of Pharmacy and Medical Sciences, University of Petra, Amman 11196, Jordan
- Correspondence:
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Sonkar R, Berry R, Latimer MN, Prabhu SD, Young ME, Frank SJ. Augmented Cardiac Growth Hormone Signaling Contributes to Cardiomyopathy Following Genetic Disruption of the Cardiomyocyte Circadian Clock. Front Pharmacol 2022; 13:836725. [PMID: 35250583 PMCID: PMC8888912 DOI: 10.3389/fphar.2022.836725] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 01/21/2022] [Indexed: 11/25/2022] Open
Abstract
Circadian clocks regulate numerous biological processes, at whole body, organ, and cellular levels. This includes both hormone secretion and target tissue sensitivity. Although growth hormone (GH) secretion is time-of-day-dependent (increased pulse amplitude during the sleep period), little is known regarding whether circadian clocks modulate GH sensitivity in target tissues. GH acts in part through induction of insulin-like growth factor 1 (IGF1), and excess GH/IGF1 signaling has been linked to pathologies such as insulin resistance, acromegaly, and cardiomyopathy. Interestingly, genetic disruption of the cardiomyocyte circadian clock leads to cardiac adverse remodeling, contractile dysfunction, and reduced lifespan. These observations led to the hypothesis that the cardiomyopathy observed following cardiomyocyte circadian clock disruption may be secondary to chronic activation of cardiac GH/IGF1 signaling. Here, we report that cardiomyocyte-specific BMAL1 knockout (CBK) mice exhibit increased cardiac GH sensitivity, as evidenced by augmented GH-induced STAT5 phosphorylation (relative to littermate controls) in the heart (but not in the liver). Moreover, Igf1 mRNA levels are approximately 2-fold higher in CBK hearts (but not in livers), associated with markers of GH/IGF1 signaling activation (e.g., p-ERK, p-mTOR, and p-4EBP1) and adverse remodeling (e.g., cardiomyocyte hypertrophy and interstitial fibrosis). Genetic deletion of one allele of the GH receptor (GHR) normalized cardiac Igf1 levels in CBK hearts, associated with a partial normalization of adverse remodeling. This included attenuated progression of cardiomyopathy in CBK mice. Collectively, these observations suggest that excessive cardiac GH/IGF1 signaling contributes toward cardiomyopathy following genetic disruption of the cardiomyocyte circadian clock.
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Affiliation(s)
- Ravi Sonkar
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
- Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Ryan Berry
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Mary N. Latimer
- Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Sumanth D. Prabhu
- Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
- Cardiology Section, Birmingham VAMC Medical Service, Birmingham, AL, United States
- Division of Cardiology, Washington University School of Medicine, St. Louis, MO, United States
| | - Martin E. Young
- Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Stuart J. Frank
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
- Endocrinology Section, Birmingham VAMC Medical Service, Birmingham, AL, United States
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Jang HN, Kim YH, Kim JH. Diabetes Mellitus Predicts Weight Gain After Surgery in Patients With Acromegaly. Front Endocrinol (Lausanne) 2022; 13:854931. [PMID: 35355553 PMCID: PMC8959539 DOI: 10.3389/fendo.2022.854931] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Accepted: 02/09/2022] [Indexed: 12/01/2022] Open
Abstract
OBJECTIVE Metabolic complications are common in patients with acromegaly. However, this occasionally does not improve post-surgery and may be related to postoperative weight gain. We aimed to investigate the postoperative weight change and factors associated with postoperative weight gain in patients with acromegaly. DESIGN AND METHODS Overall, 113 consecutive patients with body weight records pre- and 3-6 months post-surgery between October 2009 and March 2021 were enrolled. Patients were divided into three groups: weight loss (weight decrease ≥3%), stable, and weight gain (weight increase ≥3%). Hormone status, metabolic comorbidities, and anthropometric parameters were compared between the groups. RESULTS Among 113 patients, 29 (25.7%) and 26 (23.0%) patients lost and gained weight, respectively, post-surgery. There were no significant differences in baseline characteristics, including age at diagnosis, sex, body mass index, and growth hormone levels among the three groups. The prevalence of diabetes mellitus at diagnosis was significantly higher in the weight gain group than in the other groups. Patients with diabetes (n=22) had a 5.2-fold higher risk of postoperative weight gain than those with normal glucose tolerance (n=37) (P=0.006). In the diabetes mellitus group, the percentage lean mass decreased (-4.5 [-6.6-2.0]%, P=0.002), and the percentage fat mass significantly increased post-surgery (18.0 [4.6-36.6]%, P=0.003), whereas the normal glucose tolerance group did not show body composition changes post-surgery. CONCLUSION In patients with acromegaly, 23% experienced ≥3% weight gain post-surgery. Diabetes mellitus at diagnosis is a significant predictor of weight and fat gain post-surgery.
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Affiliation(s)
- Han Na Jang
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, South Korea
| | - Yong Hwy Kim
- Department of Neurosurgery, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, South Korea
- Pituitary Center, Seoul National University Hospital, Seoul, South Korea
| | - Jung Hee Kim
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, South Korea
- Pituitary Center, Seoul National University Hospital, Seoul, South Korea
- *Correspondence: Jung Hee Kim, ;
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Bioletto F, Prencipe N, Berton AM, Bona C, Parasiliti-Caprino M, Faletti R, Ghigo E, Grottoli S, Gasco V. MRI Assessment of Cardiac Function and Morphology in Adult Patients With Growth Hormone Deficiency: A Systematic Review and Meta-Analysis. Front Endocrinol (Lausanne) 2022; 13:910575. [PMID: 35757407 PMCID: PMC9226436 DOI: 10.3389/fendo.2022.910575] [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: 04/01/2022] [Accepted: 05/09/2022] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Adult GH deficiency (GHD) has been described as a heterogeneous condition characterized by many clinical modifications, such as metabolic alterations, impaired quality of life, and increased mortality. The clinical relevance of cardiac involvement remains, however, only partially elucidated. METHODS PubMed/Medline, EMBASE, Cochrane library, OVID and CINAHL databases were systematically searched until February 2022 for studies evaluating cardiac function and morphology by magnetic resonance imaging in adult patients with GHD. Effect sizes were pooled through a random-effect model. RESULTS Four studies were considered in the meta-analysis. With respect to the left ventricle, GHD patients were characterized by a lower stroke-volume-index (-3.6 ml/m2, standardized mean difference (SMD) -0.60, 95%CI [-1.15,-0.05], p=0.03), lower end-diastolic-volume-index (-6.2 ml/m2, SMD -0.54, 95%CI [-0.97,-0.10], p=0.02) and, after accounting for possible biases, lower mass-index (-15.0 g/m2, SMD -1.03, 95%CI [-1.89,-0.16], p=0.02). With respect to the right ventricle, a lower end-diastolic-volume-index (-16.6 ml/m2, SMD -1.04, 95%CI [-2.04,-0.03], p=0.04) and a borderline-significant lower stroke-volume-index (-5.0 ml/m2, SMD -0.84, 95%CI [-1.77,0.08], p=0.07) could be observed. Data about the effect of GH replacement therapy highlighted a significant increase in left ventricular mass-index after treatment initiation (+3.7 g/m2, 95%CI [1.6,5.7], p<0.01). CONCLUSION With respect to the left ventricle, our results confirmed those retrieved by echocardiographic studies. In addition, significant alterations were demonstrated also for the right ventricle, for which echocardiographic data are nearly absent. This supports the thesis of a biventricular cardiac involvement in patients with GHD, with a similar pattern of morphological and functional alterations in both ventricles.
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Affiliation(s)
- Fabio Bioletto
- Endocrinology, Diabetology and Metabolism, Department of Medical Sciences, University of Turin, Turin, Italy
- *Correspondence: Fabio Bioletto, , orcid.org/0000-0001-7550-7023
| | - Nunzia Prencipe
- Endocrinology, Diabetology and Metabolism, Department of Medical Sciences, University of Turin, Turin, Italy
| | - Alessandro Maria Berton
- Endocrinology, Diabetology and Metabolism, Department of Medical Sciences, University of Turin, Turin, Italy
| | - Chiara Bona
- Endocrinology, Diabetology and Metabolism, Department of Medical Sciences, University of Turin, Turin, Italy
| | - Mirko Parasiliti-Caprino
- Endocrinology, Diabetology and Metabolism, Department of Medical Sciences, University of Turin, Turin, Italy
| | - Riccardo Faletti
- Radiology Unit, Department of Surgical Sciences, University of Turin, Turin, Italy
| | - Ezio Ghigo
- Endocrinology, Diabetology and Metabolism, Department of Medical Sciences, University of Turin, Turin, Italy
| | - Silvia Grottoli
- Endocrinology, Diabetology and Metabolism, Department of Medical Sciences, University of Turin, Turin, Italy
| | - Valentina Gasco
- Endocrinology, Diabetology and Metabolism, Department of Medical Sciences, University of Turin, Turin, Italy
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Recombinant Human Growth Hormone Inhibits Lipotoxicity, Oxidative Stress, and Apoptosis in a Mouse Model of Diabetic Cardiomyopathy. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:3899356. [PMID: 34925693 PMCID: PMC8677382 DOI: 10.1155/2021/3899356] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 09/30/2021] [Accepted: 11/12/2021] [Indexed: 11/24/2022]
Abstract
Recombinant human growth hormone (rhGH), widely used in clinical studies, exerts protective effects against cardiac damage. Here, we investigated the effects and mechanisms underlying the effects of rhGH on cardiac functions in db/db mice. C57BL/6J and db/db mice were subjected to rhGH treatment. Metabolic parameters, cardiac function and morphology, oxidative stress, lipid metabolism, and apoptosis were evaluated 16 weeks after rhGH treatment. Although rhGH did not significantly affect fasting blood glucose levels in db/db mice, it protected against diabetic cardiomyopathy, by improving cardiac function and reducing oxidative stress in the heart. In addition, rhGH treatment exhibited anti-apoptotic effects in the heart of db/db mice. The rhGH treatment, besides inhibiting oxidative stress and apoptosis, ameliorated cardiac dysfunction by inhibiting lipotoxicity in mice with type 2 diabetes. These findings suggest that rhGH is a promising therapeutic agent for diabetic cardiomyopathy.
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Zaman R, Hamidzada H, Kantores C, Wong A, Dick SA, Wang Y, Momen A, Aronoff L, Lin J, Razani B, Mital S, Billia F, Lavine KJ, Nejat S, Epelman S. Selective loss of resident macrophage-derived insulin-like growth factor-1 abolishes adaptive cardiac growth to stress. Immunity 2021; 54:2057-2071.e6. [PMID: 34363749 DOI: 10.1016/j.immuni.2021.07.006] [Citation(s) in RCA: 84] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Revised: 02/20/2021] [Accepted: 07/09/2021] [Indexed: 12/24/2022]
Abstract
Hypertension affects one-third of the world's population, leading to cardiac dysfunction that is modulated by resident and recruited immune cells. Cardiomyocyte growth and increased cardiac mass are essential to withstand hypertensive stress; however, whether immune cells are involved in this compensatory cardioprotective process is unclear. In normotensive animals, single-cell transcriptomics of fate-mapped self-renewing cardiac resident macrophages (RMs) revealed transcriptionally diverse cell states with a core repertoire of reparative gene programs, including high expression of insulin-like growth factor-1 (Igf1). Hypertension drove selective in situ proliferation and transcriptional activation of some cardiac RM states, directly correlating with increased cardiomyocyte growth. During hypertension, inducible ablation of RMs or selective deletion of RM-derived Igf1 prevented adaptive cardiomyocyte growth, and cardiac mass failed to increase, which led to cardiac dysfunction. Single-cell transcriptomics identified a conserved IGF1-expressing macrophage subpopulation in human cardiomyopathy. Here we defined the absolute requirement of RM-produced IGF-1 in cardiac adaptation to hypertension.
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Affiliation(s)
- Rysa Zaman
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada; Ted Rogers Centre for Heart Research, Toronto, ON, Canada; Department of Immunology, University of Toronto, Toronto, ON, Canada
| | - Homaira Hamidzada
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada; Ted Rogers Centre for Heart Research, Toronto, ON, Canada; Department of Immunology, University of Toronto, Toronto, ON, Canada
| | - Crystal Kantores
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
| | - Anthony Wong
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada; Ted Rogers Centre for Heart Research, Toronto, ON, Canada; Department of Immunology, University of Toronto, Toronto, ON, Canada
| | - Sarah A Dick
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada; Ted Rogers Centre for Heart Research, Toronto, ON, Canada
| | - Yiming Wang
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
| | - Abdul Momen
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
| | - Laura Aronoff
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada; Ted Rogers Centre for Heart Research, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
| | - Julia Lin
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada; Ted Rogers Centre for Heart Research, Toronto, ON, Canada; Department of Immunology, University of Toronto, Toronto, ON, Canada
| | - Babak Razani
- Division of Cardiology, Washington University School of Medicine, St. Louis, MO, USA
| | - Seema Mital
- Ted Rogers Centre for Heart Research, Toronto, ON, Canada; Division of Cardiology, Hospital for Sick Children, Toronto, ON, Canada; Department of Paediatrics, University of Toronto, Toronto, ON, Canada
| | - Filio Billia
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada; Ted Rogers Centre for Heart Research, Toronto, ON, Canada; Peter Munk Cardiac Centre, Toronto, ON, Canada
| | - Kory J Lavine
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
| | - Sara Nejat
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada; Ted Rogers Centre for Heart Research, Toronto, ON, Canada; Peter Munk Cardiac Centre, Toronto, ON, Canada
| | - Slava Epelman
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada; Ted Rogers Centre for Heart Research, Toronto, ON, Canada; Department of Immunology, University of Toronto, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Peter Munk Cardiac Centre, Toronto, ON, Canada.
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Molecular Mechanisms of Nigella sativa- and Nigella sativa Exercise-Induced Cardiac Hypertrophy in Rats. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2021; 2021:5553022. [PMID: 34055008 PMCID: PMC8143887 DOI: 10.1155/2021/5553022] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 03/29/2021] [Accepted: 03/31/2021] [Indexed: 12/31/2022]
Abstract
Background In our lab, we demonstrated cardiac hypertrophy induced by long-term administration of Nigella sativa (Ns) with enhanced function. Therefore, we aim to investigate the molecular mechanisms of Ns-induced cardiac hypertrophy, compare it with that induced by exercise training, and explore any possible synergistic effect of these two interventions. Method Twenty adult Wistar male rats were divided into control (C), Ns-fed (N.s.), exercise-trained (Ex.), Ns-fed exercise-trained (N.s.Ex.) groups. 800 mg/kg of Ns was administered orally to N.s. rats. Ex. rats were trained on a treadmill with speed 18 m/min and grade 32° for two hours daily, and the N.s.Ex. group underwent both interventions. After 8 weeks, Immunohistochemical slides of the left ventricles were prepared using rat growth hormone (GH), insulin-like growth factor I (IGF-I), angiotensin-II receptors 1 (AT-I), endothelin-I (ET-1), Akt-1, and Erk-1. Cell diameter and number of nuclei were measured. Results Cardiomyocyte diameter, number of nuclei, GH, and Akt were significantly higher in N.s, Ex., and N.s.Ex groups compared with the controls. IGF-I, AT-1, and ET-1 were significantly higher in Ex. rats only compared with the controls. Erk-1 was lower in N.s., Ex., and N.s.Ex. compared with the controls. Conclusion We can conclude that Ns-induced cardiac hypertrophy is mediated by the GH-IGF I-PI3P-Akt pathway. Supplementation of Ns to exercise training protocol can block the upregulation of AT-I and ET-1. The combined N.s. exercise-induced cardiac hypertrophy might be a superior model of physiological cardiac hypertrophy and be used as a prophylactic therapy for athletes who are engaged in vigorous exercise activity.
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Left Ventricular Geometrical Changes in Severely Obese Adolescents: Prevalence, Determinants, and Clinical Implications. Pediatr Cardiol 2021; 42:331-339. [PMID: 33079265 PMCID: PMC7907012 DOI: 10.1007/s00246-020-02487-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Accepted: 10/08/2020] [Indexed: 12/17/2022]
Abstract
Left ventricular hypertrophy (LVH) is independently associated with a higher risk of cardiovascular morbidity and mortality in adults. Adiposity is a risk factor for LVH, independent of blood pressure. Potential causes of this nonhemodynamic pathogenesis identified in adults include adverse body fat distribution, insulin resistance, dyslipidemia, and obstructive sleep apnea syndrome (OSA). In severely obese adolescents, the determinants of obesity-induced changes in left ventricular structure are poorly characterized. Cardiac ultrasonographic, demographic, anthropometric, and comorbidity-related data were prospectively collected in adolescents with severe obesity refractory to conservative treatment who presented for surgical therapy. Differences between adolescents with LVH and without LVH were evaluated using independent samples t, chi-square, or Fisher's exact test. Multivariable linear regression analysis was performed to evaluate associations with left ventricular structural changes, corrected for body mass index (BMI) z score. Forty-three patients entered analysis, of whom 24 (55.8%) showed LVH. The most common geometrical change was eccentric LVH (eLVH), occurring in 21 subjects (48.8%). Demographic and anthropometric variables did not differ between patients with and without LVH. Independent of BMI z score, left ventricular mass index was significantly associated with apnea-hypopnea index (AHI) (regression parameter B = 0.8; 95% CI 0.3 to 1.2). Interventricular septum thickness (IVST) was significantly associated with HOMA-IR values (B = 0.1; 95% CI 0.04 to 0.2), HDL-cholesterol (B = - 1.2; 95% CI - 2.2 to 0.1), and triglyceride levels (B = 0.5; 95% CI 0.001 to 0.9). LVH, especially eLVH, is highly prevalent amongst severely obese adolescents. Adverse changes in cardiac structure, increased IVST in particular, are independently associated with several nonhemodynamic comorbidities that are common in this population, namely OSA, insulin resistance, and dyslipidemia.
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Why Should Growth Hormone (GH) Be Considered a Promising Therapeutic Agent for Arteriogenesis? Insights from the GHAS Trial. Cells 2020; 9:cells9040807. [PMID: 32230747 PMCID: PMC7226428 DOI: 10.3390/cells9040807] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2019] [Revised: 02/25/2020] [Accepted: 03/25/2020] [Indexed: 01/07/2023] Open
Abstract
Despite the important role that the growth hormone (GH)/IGF-I axis plays in vascular homeostasis, these kind of growth factors barely appear in articles addressing the neovascularization process. Currently, the vascular endothelium is considered as an authentic gland of internal secretion due to the wide variety of released factors and functions with local effects, including the paracrine/autocrine production of GH or IGF-I, for which the endothelium has specific receptors. In this comprehensive review, the evidence involving these proangiogenic hormones in arteriogenesis dealing with the arterial occlusion and making of them a potential therapy is described. All the elements that trigger the local and systemic production of GH/IGF-I, as well as their possible roles both in physiological and pathological conditions are analyzed. All of the evidence is combined with important data from the GHAS trial, in which GH or a placebo were administrated to patients suffering from critical limb ischemia with no option for revascularization. We postulate that GH, alone or in combination, should be considered as a promising therapeutic agent for helping in the approach of ischemic disease.
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Lin YH, Ni XB, Zhang JW, Ou CW, He XQ, Dai WJ, Chen XM, Chen MS. Effect of puerarin on action potential and sodium channel activation in human hypertrophic cardiomyocytes. Biosci Rep 2020; 40:222020. [PMID: 32003781 PMCID: PMC7024842 DOI: 10.1042/bsr20193369] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Revised: 01/13/2020] [Accepted: 01/28/2020] [Indexed: 02/05/2023] Open
Abstract
OBJECTIVE To study the effect of puerarin on electrophysiology using a hypertrophic cardiomyocyte (HC) model. MATERIALS AND METHODS Human urine epithelial cells were used to generate the HC model (hiPSC-CM). Cardiomyocyte hypertrophy was induced by applying 10 nM endothelin-1 (ET-1). Effects of puerarin pre-treatment (PPr) and post-treatment (PPo) on action potential, sodium current (INa) activation and inactivation, and recovery following INa inactivation were tested using patch clamp electrophysiology. RESULTS Depolarization to repolarization 50% time (APD50) and repolarization 30% time (APD30) were significantly prolonged in the PPo and PPr groups compared with the controls. However, there were no significant differences in the action potential depolarization amplitude (APA) or the maximum depolarization velocity (Vmax) in phase 0. The PPr group had a slightly shortened APD90, and an extended APD50 and APD30, but did not exhibit any significant changes in stage A of APA and Vmax. The PPo group did not exhibit any significant changes in INa, while 12 h of PPr improved INa. However, puerarin did not significantly affect the activation, inactivation, or recovery of the sodium channel. CONCLUSIONS Cardiomyocyte hypertrophy significantly decreased the Vmax of the action potential and the peak density of INa. PPr inhibited the decrease in Vmax and increased the peak density of INa. Thus, puerarin could be used to stabilize the electrophysiological properties of hypertrophic cardiomyocytes and reduce arrhythmias.
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Affiliation(s)
- Yu-hui Lin
- Department of Cardiovascular Medicine, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Xiao-Bin Ni
- Department of Cardiovascular Medicine, The First Affiliated Hospital of Shantou University Medical College, Shantou, China
| | - Jian-wu Zhang
- Department of Cardiovascular Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Cai-wen Ou
- Department of Cardiovascular Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Xiao-qing He
- Department of Cardiovascular Medicine, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Wen-jun Dai
- Department of Cardiovascular Medicine, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Xi-ming Chen
- Department of Cardiovascular Medicine, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- Correspondence: Xi-ming Chen () or Min-sheng Chen ()
| | - Min-sheng Chen
- Department of Cardiovascular Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China
- Correspondence: Xi-ming Chen () or Min-sheng Chen ()
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Zhang L, Zhang J, Tong Q, Wang G, Dong H, Wang Z, Sun Q, Wu H. Reduction of miR-29a-3p induced cardiac ischemia reperfusion injury in mice via targeting Bax. Exp Ther Med 2019; 18:1729-1737. [PMID: 31410131 PMCID: PMC6676207 DOI: 10.3892/etm.2019.7722] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2018] [Accepted: 04/11/2019] [Indexed: 12/14/2022] Open
Abstract
The current study mainly aimed to evaluate the expression and the potential mechanism of miR-29a-3p in the hearts of mice after cardiac ischemia reperfusion (CIR) injury. Quantitative PCR was carried out to assess the relative levels of miR-29a-3p in the hearts of a CIR injury mouse model. To the best of our knowledge, the current study is the first to show that the level of miR-29a-3p was significantly decreased in the hearts of CIR injury mouse models compared with that of sham controls. Moreover, the authors found that decreased miR-29a-3p levels enhanced the production of reactive oxygen species in cardiomyocytes. Meanwhile, the inhibition of miR-29a-3p induced substantial cardiomyocyte apoptosis. Further study showed that the inhibition of miR-29a-3p decreased the activation of Akt and p38, suggesting a stress-induced self-regulatory mechanism after CIR injury in primary cardiomyocytes. A dual luciferase assay and western blot analysis showed that Bax was a target gene of miR-29a-3p. The authors also measured the level of miR-29a-3p in the plasma of 100 acute myocardial infarction (AMI) patients and found that circulating miR-29a-3p was significantly decreased in AMI patients. Receiver operating characteristic curve analysis showed that miR-29a-3p could be used to screen AMI patients from healthy controls. Hence, the authors of the current study propose that reduced miR-29a-3p levels in primary cardiomyocytes contribute to CIR injury-related apoptosis mainly by targeting Bax.
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Affiliation(s)
- Liang Zhang
- Heart Center, Beijing Chest Hospital, Capital Medical University, Beijing 101149, P.R. China
| | - Jian Zhang
- Heart Center, Beijing Chest Hospital, Capital Medical University, Beijing 101149, P.R. China
| | - Qiguang Tong
- Heart Center, Beijing Chest Hospital, Capital Medical University, Beijing 101149, P.R. China
| | - Guannan Wang
- Heart Center, Beijing Chest Hospital, Capital Medical University, Beijing 101149, P.R. China
| | - Hongling Dong
- Heart Center, Beijing Chest Hospital, Capital Medical University, Beijing 101149, P.R. China
| | - Zhonglu Wang
- Heart Center, Beijing Chest Hospital, Capital Medical University, Beijing 101149, P.R. China
| | - Qi Sun
- Heart Center, Beijing Chest Hospital, Capital Medical University, Beijing 101149, P.R. China
| | - Hangyu Wu
- Heart Center, Beijing Chest Hospital, Capital Medical University, Beijing 101149, P.R. China
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Chen Z, Hu B, Feng Y, Wang Z, Jiang X, Cheng Y, He D, Zhu D, Xiao Z, Wang H, Mao Z. Incidence rate and risk factors of early repolarization in patients with growth hormone-secreting pituitary adenoma: a cohort study. Ther Clin Risk Manag 2019; 15:65-72. [PMID: 30643415 PMCID: PMC6314049 DOI: 10.2147/tcrm.s185929] [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: 11/23/2022] Open
Abstract
Purpose To investigate the incidence and risk factors for early repolarization (ER) in patients with growth hormone (GH)-secreting pituitary adenomas. Methods From August 2014 to August 2016, patients with GH-secreting pituitary adenomas and non-functioning pituitary adenomas admitted to the First Affiliated Hospital, Sun Yat-sen University, were prospectively enrolled. Logistic regression analysis was used to investigate risk factors for ER development. Results A total of 118 patients with GH-secreting pituitary adenomas (41 with concomitant ER) and 103 patients with non-functioning pituitary adenomas were included. Compared with the non-functioning adenoma group GH and IGF-1 levels, left ventricular mass index (LVMI), and incidence of ER were significantly higher in the GH-secreting pituitary adenoma group (all P<0.05). LVMI was an independent risk factor for ER. Bivariate correlation analysis showed that course of disease, GH, IGF-1, and diabetes were correlated with LVMI. Course of disease and IGF-1 were directly correlated with LVMI. Two-year follow-up of patients who underwent transsphenoidal resection showed that incidence of ER was significantly decreased in patients with normal GH and IGF-1 levels. Conclusion Compared with non-functioning pituitary adenoma patients, patients with GH-secreting pituitary adenomas have a significantly higher incidence of ER. Elevation of serum GH and IGF-1 had positive correlations with cardiac muscle cell hypertrophy and increased LVMI.
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Affiliation(s)
- Zhiyong Chen
- Department of Neurosurgery and Pituitary Tumor Center, The First Affiliated Hospital, SunYat-sen University, Guangzhou, People's Republic of China, ; .,Department of Neurosurgery, The First Affiliated Hospital, Jinan University, Guangzhou, People's Republic of China
| | - Bin Hu
- Department of Neurosurgery and Pituitary Tumor Center, The First Affiliated Hospital, SunYat-sen University, Guangzhou, People's Republic of China, ;
| | - Yajuan Feng
- Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Zongming Wang
- Department of Neurosurgery and Pituitary Tumor Center, The First Affiliated Hospital, SunYat-sen University, Guangzhou, People's Republic of China, ;
| | - Xiaobing Jiang
- Department of Neurosurgery, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China
| | - Yunjiu Cheng
- Department of Cardiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Dongsheng He
- Department of Neurosurgery and Pituitary Tumor Center, The First Affiliated Hospital, SunYat-sen University, Guangzhou, People's Republic of China, ;
| | - Dimin Zhu
- Department of Neurosurgery and Pituitary Tumor Center, The First Affiliated Hospital, SunYat-sen University, Guangzhou, People's Republic of China, ;
| | - Zheng Xiao
- Department of Neurosurgery and Pituitary Tumor Center, The First Affiliated Hospital, SunYat-sen University, Guangzhou, People's Republic of China, ;
| | - Haijun Wang
- Department of Neurosurgery and Pituitary Tumor Center, The First Affiliated Hospital, SunYat-sen University, Guangzhou, People's Republic of China, ;
| | - Zhigang Mao
- Department of Neurosurgery and Pituitary Tumor Center, The First Affiliated Hospital, SunYat-sen University, Guangzhou, People's Republic of China, ;
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Ludvigsen S, Mancusi C, Kildal S, de Simone G, Gerdts E, Ytrehus K. Cardiac adaptation to hypertension in adult female Dahl salt-sensitive rats is dependent on ovarian function, but loss of ovarian function does not predict early maladaptation. Physiol Rep 2018; 6:e13593. [PMID: 29417743 PMCID: PMC5803524 DOI: 10.14814/phy2.13593] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2017] [Revised: 12/19/2017] [Accepted: 12/20/2017] [Indexed: 01/25/2023] Open
Abstract
Aim of study was to examine experimentally the adult female hypertensive heart in order to determine the role of ovary function in the response of the heart to salt-dependent hypertension. Dahl salt-sensitive rats, age 12 weeks, with/without ovariectomy were fed a standard (0.3% NaCl) or high-salt diet (8%) for 16 weeks. Mean arterial blood pressure monitored noninvasively in conscious state increased significantly by high salt. Echocardiography was performed at baseline and endpoint. Heart function and molecular changes were evaluated at endpoint by left ventricle catheterization, by sirius red staining for collagen and by gene expression using quantitative RT-PCR for selected genes. At endpoint, significant concentric hypertrophy was present with high salt. Increase in relative wall thickening with high salt compared to normal diet was more pronounced with intact ovaries (0.33 ± 0.02 and 0.57 ± 0.04 vs. 0.29 ± 0.00 and 0.46 ± 0.03) as was the reduction in midwall fractional shortening (20 ± 0.6 and 14 ± 2 vs. 19 ± 0.9 and 18 ± 1). Ovariectomy increased stroke volume and decreased the ratio of mitral peak velocity of early filling (E) to early diastolic mitral annular velocity (E') (E/E' ratio) when compared to hearts from intact rats. High salt increased expression of collagen I and III genes and perivascular collagen in the heart slightly, but % interstitial collagen by sirius red staining remained unchanged in intact rats and decreased significantly by ovariectomy. Added volume load but not deterioration of function or structure characterized the nonfailing hypertensive heart of salt-sensitive females ovariectomized at mature age when compared to corresponding intact females.
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Affiliation(s)
- Stian Ludvigsen
- Cardiovascular Research GroupDepartment of Medical BiologyUiT – The Arctic University of NorwayTromsøNorway
| | - Costantino Mancusi
- Hypertension Research CenterFederico II University of NaplesNaplesItaly
- Department of Clinical ScienceUniversity of BergenBergenNorway
| | - Simon Kildal
- Cardiovascular Research GroupDepartment of Medical BiologyUiT – The Arctic University of NorwayTromsøNorway
| | | | - Eva Gerdts
- Department of Clinical ScienceUniversity of BergenBergenNorway
| | - Kirsti Ytrehus
- Cardiovascular Research GroupDepartment of Medical BiologyUiT – The Arctic University of NorwayTromsøNorway
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Caicedo D, Díaz O, Devesa P, Devesa J. Growth Hormone (GH) and Cardiovascular System. Int J Mol Sci 2018; 19:ijms19010290. [PMID: 29346331 PMCID: PMC5796235 DOI: 10.3390/ijms19010290] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2017] [Revised: 01/08/2018] [Accepted: 01/12/2018] [Indexed: 01/02/2023] Open
Abstract
This review describes the positive effects of growth hormone (GH) on the cardiovascular system. We analyze why the vascular endothelium is a real internal secretion gland, whose inflammation is the first step for developing atherosclerosis, as well as the mechanisms by which GH acts on vessels improving oxidative stress imbalance and endothelial dysfunction. We also report how GH acts on coronary arterial disease and heart failure, and on peripheral arterial disease, inducing a neovascularization process that finally increases flow in ischemic tissues. We include some preliminary data from a trial in which GH or placebo is given to elderly people suffering from critical limb ischemia, showing some of the benefits of the hormone on plasma markers of inflammation, and the safety of GH administration during short periods of time, even in diabetic patients. We also analyze how Klotho is strongly related to GH, inducing, after being released from the damaged vascular endothelium, the pituitary secretion of GH, most likely to repair the injury in the ischemic tissues. We also show how GH can help during wound healing by increasing the blood flow and some neurotrophic and growth factors. In summary, we postulate that short-term GH administration could be useful to treat cardiovascular diseases.
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Affiliation(s)
- Diego Caicedo
- Department of Angiology and Vascular Surgery, Complejo Hospitalario Universitario de Pontevedra, 36701 Pontevedra, Spain.
| | - Oscar Díaz
- Department of Cardiology, Complejo Hospitalario Universitario de Pontevedra, 36701 Pontevedra, Spain.
| | - Pablo Devesa
- Research and Development, The Medical Center Foltra, 15886 Teo, Spain.
| | - Jesús Devesa
- Scientific Direction, The Medical Center Foltra, 15886 Teo, Spain.
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Li Q, Yu Q, Na R, Liu B. Omega-3 polyunsaturated fatty acids prevent murine dilated cardiomyopathy by reducing oxidative stress and cardiomyocyte apoptosis. Exp Ther Med 2017; 14:6152-6158. [PMID: 29285172 DOI: 10.3892/etm.2017.5338] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2016] [Accepted: 03/24/2017] [Indexed: 01/19/2023] Open
Abstract
Mice that lacked manganese-superoxide dismutase (Mn-SOD) activity exhibited the typical pathology of dilated cardiomyopathy (DCM). The aim of the present study was to investigate the effect of supplementation with omega-3 polyunsaturated fatty acids (n-3 PUFA) on heart function and oxidative stress biomarkers in mice with DCM. In the present study, heart/muscle-specific Mn-SOD-deficient mice (H/M-Sod2-/-) were treated with n-3 PUFA (30 mg/kg/day) for 10 weeks, and the reactive oxygen species (ROS) production in their heart mitochondria and cardiac function was subsequently assessed. n-3 PUFA treatment diminished ROS production and suppressed the progression of cardiac dysfunction. Furthermore, n-3 PUFA treatment effectively reversed the cardiac dysfunction and dilatation observed in symptomatic H/M-Sod2-/- mice. Notably, n-3 PUFA treatment ameliorated a molecular defect in connexin 43. Hematoxylin-eosin staining indicated that the phenotype of DCM was also ameliorated following n-3 PUFA treatment. Furthermore, echocardiography demonstrated that cardiac function was significantly improved in the mice treated with n-3 PUFA (P<0.05). Meanwhile, pre-treatment with n-3 PUFA significantly decreased cardiomyocyte apoptosis (P<0.001). In conclusion, n-3 PUFA treatment is able to prevent murine DCM, primarily by reducing ROS production and improving myocardial apoptosis. Therefore, the impairment of ROS production is proposed as a potential therapy for DCM.
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Affiliation(s)
- Qianxiao Li
- Department of Cardiology, Zhejiang Province Hospital of Integrated Traditional Chinese and Western Medicine, Hangzhou, Zhejiang 310003, P.R. China
| | - Qin Yu
- Department of Cardiology, Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning 116000, P.R. China
| | - Rongmei Na
- Department of Cardiology, Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning 116000, P.R. China
| | - Baiting Liu
- Department of Cardiology, Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning 116000, P.R. China
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The relative contribution of metabolic and structural abnormalities to diastolic dysfunction in obesity. Int J Obes (Lond) 2017; 42:441-447. [PMID: 28974742 PMCID: PMC5880580 DOI: 10.1038/ijo.2017.239] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2017] [Revised: 07/25/2017] [Accepted: 09/03/2017] [Indexed: 01/05/2023]
Abstract
Background: Obesity causes diastolic dysfunction, and is one of the leading causes of heart failure with preserved ejection fraction. Myocardial relaxation is determined by both active metabolic processes such as impaired energetic status and steatosis, as well as intrinsic myocardial remodelling. However, the relative contribution of each to diastolic dysfunction in obesity is currently unknown. Methods: Eighty adult subjects (48 male) with no cardiovascular risk factors across a wide range of body mass indices (18.4–53.0 kg m−2) underwent magnetic resonance imaging for abdominal visceral fat, left ventricular geometry (LV mass:volume ratio) and diastolic function (peak diastolic strain rate), and magnetic resonance spectroscopy for PCr/ATP and myocardial triglyceride content. Results: Increasing visceral obesity was related to diastolic dysfunction (peak diastolic strain rate, r=−0.46, P=0.001). Myocardial triglyceride content (β=−0.2, P=0.008), PCr/ATP (β=−0.22, P=0.04) and LV mass:volume ratio (β=−0.61, P=0.04) all independently predicted peak diastolic strain rate (model R2 0.36, P<0.001). Moderated multiple regression confirmed the full mediating roles of PCr/ATP, myocardial triglyceride content and LV mass:volume ratio in the relationship between visceral fat and peak diastolic strain rate. Of the negative effect of visceral fat on diastolic function, 40% was explained by increased myocardial triglycerides, 39% by reduced PCr/ATP and 21% by LV concentric remodelling. Conclusions: Myocardial energetics and steatosis are more important in determining LV diastolic function than concentric hypertrophy, accounting for more of the negative effect of obesity on diastolic function than LV geometric remodelling. Targeting these metabolic processes is an attractive strategy to treat diastolic dysfunction in obesity.
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19
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Carbone A, D’Andrea A, Riegler L, Scarafile R, Pezzullo E, Martone F, America R, Liccardo B, Galderisi M, Bossone E, Calabrò R. Cardiac damage in athlete’s heart: When the “supernormal” heart fails! World J Cardiol 2017; 9:470-480. [PMID: 28706583 PMCID: PMC5491465 DOI: 10.4330/wjc.v9.i6.470] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2017] [Revised: 03/05/2017] [Accepted: 04/10/2017] [Indexed: 02/07/2023] Open
Abstract
Intense exercise may cause heart remodeling to compensate increases in blood pressure or volume by increasing muscle mass. Cardiac changes do not involve only the left ventricle, but all heart chambers. Physiological cardiac modeling in athletes is associated with normal or enhanced cardiac function, but recent studies have documented decrements in left ventricular function during intense exercise and the release of cardiac markers of necrosis in athlete’s blood of uncertain significance. Furthermore, cardiac remodeling may predispose athletes to heart disease and result in electrical remodeling, responsible for arrhythmias. Athlete’s heart is a physiological condition and does not require a specific treatment. In some conditions, it is important to differentiate the physiological adaptations from pathological conditions, such as hypertrophic cardiomyopathy, arrhythmogenic dysplasia of the right ventricle, and non-compaction myocardium, for the greater risk of sudden cardiac death of these conditions. Moreover, some drugs and performance-enhancing drugs can cause structural alterations and arrhythmias, therefore, their use should be excluded.
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Abstract
Ghrelin is a small peptide released primarily from the stomach. It is a potent stimulator of growth hormone secretion from the pituitary gland and is well known for its regulation of metabolism and appetite. There is also a strong relationship between ghrelin and the cardiovascular system. Ghrelin receptors are present throughout the heart and vasculature and have been linked with molecular pathways, including, but not limited to, the regulation of intracellular calcium concentration, inhibition of proapoptotic cascades, and protection against oxidative damage. Ghrelin shows robust cardioprotective effects including enhancing endothelial and vascular function, preventing atherosclerosis, inhibiting sympathetic drive, and decreasing blood pressure. After myocardial infarction, exogenous administration of ghrelin preserves cardiac function, reduces the incidence of fatal arrhythmias, and attenuates apoptosis and ventricular remodeling, leading to improvements in heart failure. It ameliorates cachexia in end-stage congestive heart failure patients and has shown clinical benefit in pulmonary hypertension. Nonetheless, since ghrelin's discovery is relatively recent, there remains a substantial amount of research needed to fully understand its clinical significance in cardiovascular disease.
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21
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Auriemma RS, Grasso LFS, Galdiero M, Galderisi M, Pivonello C, Simeoli C, De Martino MC, Ferrigno R, Negri M, de Angelis C, Pivonello R, Colao A. Effects of long-term combined treatment with somatostatin analogues and pegvisomant on cardiac structure and performance in acromegaly. Endocrine 2017; 55:872-884. [PMID: 27295183 DOI: 10.1007/s12020-016-0995-5] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2016] [Accepted: 05/19/2016] [Indexed: 01/22/2023]
Abstract
To date, no data are available on the effects of long-term combined treatment with somatostatin analogues (SA) and pegvisomant (PEG) on cardiovascular complications in acromegaly. The current study aimed at investigating the effects of long-term SA + PEG on cardiac structure and performance. Thirty-six patients (14 M, 22 F, aged 52.3 ± 10.2 years) entered this study. Weight, BMI, systolic (SBP) and diastolic (DBP) blood pressure, IGF-I, fasting glucose (FG), fasting insulin (FI), HOMA-IR, HbA1c, and lipids were evaluated at baseline (T0), after long-term (median 36 months) SA (T1), after 12 (T12) and 60 (T60) months of SA + PEG, and at last follow-up (LFU, median 78 months). At each time point, all patients underwent echocardiography. At T1, induced a slight but not significant decrease in IGF-I (p = 0.077), whereas FI (p = 0.004), HOMA-IR (p = 0.013), ejection fraction (EF, p = 0.013), early (E) to late (A) ventricular filling velocities (E/A, p = 0.001), and isovolumetric relaxation time (IVRT, p = 0.000) significantly improved. At T12, IGF-I (p = 0.000) significantly reduced compared to T0, and FI (p = 0.001), HOMA-IR (p = 0.000), LVMI (p = 0.000), and E/A (p = 0.006) further improved compared to T1. At T60, FI (p = 0.027), HOMA-IR (p = 0.049), and E/A (p = 0.005) significantly improved as compared to T1. At LFU IGF-I normalized in 83.3 %, FI (p = 0.000), HOMA-IR (p = 0.000), LVMi (p = 0.000), and E/A (p = 0.005) further improved as compared to T1. PEG dose significantly correlated with LVMi at T12 (r = 0.575, p = 0.000) and T60 (r = 0.403, p = 0.037). Long-term PEG addition to SA improves cardiac structure and performance, particularly diastolic dysfunction, in acromegalic patients resistant to SA.
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Affiliation(s)
- Renata S Auriemma
- Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II, via S. Pansini 5, 80131, Naples, Italy
| | - Ludovica F S Grasso
- Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II, via S. Pansini 5, 80131, Naples, Italy
| | - Mariano Galdiero
- Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II, via S. Pansini 5, 80131, Naples, Italy
| | - Maurizio Galderisi
- Department of Clinical and Experimental Medicine, University Federico II, Naples, Italy
| | - Claudia Pivonello
- Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II, via S. Pansini 5, 80131, Naples, Italy
| | - Chiara Simeoli
- Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II, via S. Pansini 5, 80131, Naples, Italy
| | - Maria Cristina De Martino
- Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II, via S. Pansini 5, 80131, Naples, Italy
| | - Rosario Ferrigno
- Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II, via S. Pansini 5, 80131, Naples, Italy
| | - Mariarosaria Negri
- Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II, via S. Pansini 5, 80131, Naples, Italy
| | - Cristina de Angelis
- Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II, via S. Pansini 5, 80131, Naples, Italy
| | - Rosario Pivonello
- Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II, via S. Pansini 5, 80131, Naples, Italy.
| | - Annamaria Colao
- Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II, via S. Pansini 5, 80131, Naples, Italy
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22
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Pivonello R, Auriemma RS, Grasso LFS, Pivonello C, Simeoli C, Patalano R, Galdiero M, Colao A. Complications of acromegaly: cardiovascular, respiratory and metabolic comorbidities. Pituitary 2017; 20:46-62. [PMID: 28224405 DOI: 10.1007/s11102-017-0797-7] [Citation(s) in RCA: 115] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Acromegaly is associated with an enhanced mortality, with cardiovascular and respiratory complications representing not only the most frequent comorbidities but also two of the main causes of deaths, whereas a minor role is played by metabolic complications, and particularly diabetes mellitus. The most prevalent cardiovascular complications of acromegaly include a cardiomyopathy, characterized by cardiac hypertrophy and diastolic and systolic dysfunction together with arterial hypertension, cardiac rhythm disorders and valve diseases, as well as vascular endothelial dysfunction. Biochemical control of acromegaly significantly improves cardiovascular disease, albeit completely recovering to normal mainly in young patients with short disease duration. Respiratory complications, represented mainly by sleep-breathing disorders, particularly sleep apnea, and respiratory insufficiency, frequently occur at the early stage of the disease and, although their severity decreases with disease control, this improvement does not often change the indication for a specific therapy directed to improve respiratory function. Metabolic complications, including glucose and lipid disorders, are variably reported in acromegaly. Treatments of acromegaly may influence glucose metabolism, and the presence of diabetes mellitus in acromegaly may affect the choice of treatments, so that glucose homeostasis is worth being monitored during the entire course of the disease. Early diagnosis and prompt treatment of acromegaly, aimed at obtaining a strict control of hormone excess, are the best strategy to limit the development or reverse the complications and prevent the premature mortality.
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Affiliation(s)
- Rosario Pivonello
- Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di Napoli, via S. Pansini 5, 80131, Naples, Italy.
| | - Renata S Auriemma
- Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di Napoli, via S. Pansini 5, 80131, Naples, Italy
| | - Ludovica F S Grasso
- Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di Napoli, via S. Pansini 5, 80131, Naples, Italy
| | - Claudia Pivonello
- Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di Napoli, via S. Pansini 5, 80131, Naples, Italy
| | - Chiara Simeoli
- Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di Napoli, via S. Pansini 5, 80131, Naples, Italy
| | - Roberta Patalano
- Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di Napoli, via S. Pansini 5, 80131, Naples, Italy
| | - Mariano Galdiero
- Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di Napoli, via S. Pansini 5, 80131, Naples, Italy
| | - Annamaria Colao
- Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di Napoli, via S. Pansini 5, 80131, Naples, Italy
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Woudstra L, Krijnen P, Bogaards S, Meinster E, Emmens R, Kokhuis T, Bollen I, Baltzer H, Baart S, Parbhudayal R, Helder M, van Hinsbergh V, Musters R, de Jong N, Kamp O, Niessen H, van Dijk A, Juffermans L. Development of a new therapeutic technique to direct stem cells to the infarcted heart using targeted microbubbles: StemBells. Stem Cell Res 2016; 17:6-15. [DOI: 10.1016/j.scr.2016.04.018] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2016] [Revised: 04/21/2016] [Accepted: 04/28/2016] [Indexed: 02/07/2023] Open
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Higher protein intake increases cardiac function parameters in healthy children: metabolic programming by infant nutrition-secondary analysis from a clinical trial. Pediatr Res 2016; 79:880-8. [PMID: 26882370 DOI: 10.1038/pr.2016.30] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2015] [Accepted: 12/13/2015] [Indexed: 12/31/2022]
Abstract
BACKGROUND Protein intake may modulate cardiac structure and function in pathological conditions, but there is a lack of knowledge on potential effects in healthy infants. METHODS Secondary analysis of an ongoing randomized clinical trial comparing two groups of infants receiving a higher (HP) or lower (LP) protein content formula in the first year of life, and compared with an observational group of breastfed (BF) infants. Growth and dietary intake were assessed periodically from birth to 2 y. Insulin-like growth factor 1 (IGF-1) axis parameters were analyzed at 6 mo in a blood sample. At 2 y, cardiac mass and function were assessed by echocardiography. RESULTS HP infants (n = 50) showed a higher BMI z-score at 2 y compared with LP (n = 47) or BF (n = 44). Cardiac function parameters were increased in the HP group compared with the LP and were directly related to the protein intake during the first 6 mo of life. Moreover, there was an increase in free IGF-1 in the HP group at 6 mo. CONCLUSION A moderate increase in protein supply during the first year of life is associated with higher cardiac function parameters at 2 y. IGF-1 axis modifications may, at least in part, underlie these effects.
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Liao S, Vickers MH, Stanley JL, Ponnampalam AP, Baker PN, Perry JK. The Placental Variant of Human Growth Hormone Reduces Maternal Insulin Sensitivity in a Dose-Dependent Manner in C57BL/6J Mice. Endocrinology 2016; 157:1175-86. [PMID: 26671184 DOI: 10.1210/en.2015-1718] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
The human placental GH variant (GH-V) is secreted continuously from the syncytiotrophoblast layer of the placenta during pregnancy and is thought to play a key role in the maternal adaptation to pregnancy. Maternal GH-V concentrations are closely related to fetal growth in humans. GH-V has also been proposed as a potential candidate to mediate insulin resistance observed later in pregnancy. To determine the effect of maternal GH-V administration on maternal and fetal growth and metabolic outcomes during pregnancy, we examined the dose-response relationship for GH-V administration in a mouse model of normal pregnancy. Pregnant C57BL/6J mice were randomized to receive vehicle or GH-V (0.25, 1, 2, or 5 mg/kg · d) by osmotic pump from gestational days 12.5 to 18.5. Fetal linear growth was slightly reduced in the 5 mg/kg dose compared with vehicle and the 0.25 mg/kg groups, respectively, whereas placental weight was not affected. GH-V treatment did not affect maternal body weights or food intake. However, treatment with 5 mg/kg · d significantly increased maternal fasting plasma insulin concentrations with impaired insulin sensitivity observed at day 18.5 as assessed by homeostasis model assessment. At 5 mg/kg · d, there was also an increase in maternal hepatic GH receptor/binding protein (Ghr/Ghbp) and IGF binding protein 3 (Igfbp3) mRNA levels, but GH-V did not alter maternal plasma IGF-1 concentrations or hepatic Igf-1 mRNA expression. Our findings suggest that at higher doses, GH-V treatment can cause hyperinsulinemia and is a likely mediator of the insulin resistance associated with late pregnancy.
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Affiliation(s)
- Shutan Liao
- Liggins Institute (S.L., M.H.V., J.L.S., A.P.P., P.N.B., J.K.P.), University of Auckland, Auckland 1023, New Zealand; Gravida: National Centre for Growth and Development (S.L., M.H.V., J.L.S., A.P.P., P.N.B., J.K.P.), Auckland 1142, New Zealand; and The First Affiliated Hospital (S.L.), Sun Yat-sen University, 510080 Guangzhou, China
| | - Mark H Vickers
- Liggins Institute (S.L., M.H.V., J.L.S., A.P.P., P.N.B., J.K.P.), University of Auckland, Auckland 1023, New Zealand; Gravida: National Centre for Growth and Development (S.L., M.H.V., J.L.S., A.P.P., P.N.B., J.K.P.), Auckland 1142, New Zealand; and The First Affiliated Hospital (S.L.), Sun Yat-sen University, 510080 Guangzhou, China
| | - Joanna L Stanley
- Liggins Institute (S.L., M.H.V., J.L.S., A.P.P., P.N.B., J.K.P.), University of Auckland, Auckland 1023, New Zealand; Gravida: National Centre for Growth and Development (S.L., M.H.V., J.L.S., A.P.P., P.N.B., J.K.P.), Auckland 1142, New Zealand; and The First Affiliated Hospital (S.L.), Sun Yat-sen University, 510080 Guangzhou, China
| | - Anna P Ponnampalam
- Liggins Institute (S.L., M.H.V., J.L.S., A.P.P., P.N.B., J.K.P.), University of Auckland, Auckland 1023, New Zealand; Gravida: National Centre for Growth and Development (S.L., M.H.V., J.L.S., A.P.P., P.N.B., J.K.P.), Auckland 1142, New Zealand; and The First Affiliated Hospital (S.L.), Sun Yat-sen University, 510080 Guangzhou, China
| | - Philip N Baker
- Liggins Institute (S.L., M.H.V., J.L.S., A.P.P., P.N.B., J.K.P.), University of Auckland, Auckland 1023, New Zealand; Gravida: National Centre for Growth and Development (S.L., M.H.V., J.L.S., A.P.P., P.N.B., J.K.P.), Auckland 1142, New Zealand; and The First Affiliated Hospital (S.L.), Sun Yat-sen University, 510080 Guangzhou, China
| | - Jo K Perry
- Liggins Institute (S.L., M.H.V., J.L.S., A.P.P., P.N.B., J.K.P.), University of Auckland, Auckland 1023, New Zealand; Gravida: National Centre for Growth and Development (S.L., M.H.V., J.L.S., A.P.P., P.N.B., J.K.P.), Auckland 1142, New Zealand; and The First Affiliated Hospital (S.L.), Sun Yat-sen University, 510080 Guangzhou, China
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Mohan M, McSwiggan S, Baig F, Rutherford L, Lang CC. Metformin and its effects on myocardial dimension and left ventricular hypertrophy in normotensive patients with coronary heart disease (the MET-REMODEL study): rationale and design of the MET-REMODEL study. Cardiovasc Ther 2015; 33:1-8. [PMID: 25545400 DOI: 10.1111/1755-5922.12101] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Left ventricular hypertrophy (LVH) is a common and independent risk factor for cardiovascular events in patients with coronary artery disease (CAD). Controlling blood pressure is the standard approach to the management of LVH, but this is only partially effective as LVH also persists in normotensive patients. Apart from blood pressure (BP), other main risk factors associated with LVH are insulin resistance (IR) and central obesity. The diabetic medication, Metformin, reduces IR and aids weight loss and may therefore regress LVH. The MET REMODEL study will investigate the ability of Metformin to regress LVH in 64 patients with CAD. The MET-REMODEL trial is a single-center, phase IV, double blind, randomized, placebo-controlled trial to investigate the efficacy of Metformin in regression of the independent cardiac risk factor of LVH in patients with CAD who are insulin resistant. A minimum of 64 adults with a history of CAD with LVH and IR will be randomized into two groups to receive, either Metformin XL or placebo. The primary endpoint of this trial is to investigate any change in left ventricular mass index. Secondary endpoints include changes to insulin resistance measured using fasting insulin resistance index (FIRI), obesity, LV size, and function and improvement in endothelial function. A positive result will assist clinicians to identify a new mechanism for LVH regression by administering Metformin XL. This may also lead to investigating the mortality benefit of Metformin in patients with CAD and LVH.
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Affiliation(s)
- Mohapradeep Mohan
- Division of Cardiovascular & Diabetes Medicine, Ninewells Hospital & Medical School, Dundee, Angus, UK
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27
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Mihaila S, Mincu RI, Rimbas RC, Dulgheru RE, Dobrescu R, Magda SL, Badiu C, Vinereanu D. Growth Hormone Deficiency in Adults Impacts Left Ventricular Mechanics: A Two-Dimensional Speckle-Tracking Study. Can J Cardiol 2015; 31:752-9. [DOI: 10.1016/j.cjca.2015.01.008] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2014] [Revised: 01/12/2015] [Accepted: 01/12/2015] [Indexed: 11/29/2022] Open
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Isgaard J, Arcopinto M, Karason K, Cittadini A. GH and the cardiovascular system: an update on a topic at heart. Endocrine 2015; 48:25-35. [PMID: 24972804 PMCID: PMC4328125 DOI: 10.1007/s12020-014-0327-6] [Citation(s) in RCA: 72] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2014] [Accepted: 06/04/2014] [Indexed: 01/06/2023]
Abstract
In this review, the importance of growth hormone (GH) for the maintenance of normal cardiac function in adult life is discussed. Physiological effects of GH and underlying mechanisms for interactions between GH and insulin-like growth factor I (IGF-I) and the cardiovascular system are covered as well as the cardiac dysfunction caused both by GH excess (acromegaly) and by GH deficiency in adult hypopituitary patients. In both acromegaly and adult GH deficiency, there is also increased cardiovascular morbidity and mortality possibly linked to aberrations in GH status. Finally, the status of the GH/IGF-I system in relation to heart failure and the potential of GH as a therapeutic tool in the treatment of heart failure are reviewed in this article.
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Affiliation(s)
- Jörgen Isgaard
- Laboratory of Experimental Endocrinology, Department of Internal Medicine, Sahlgrenska Academy, University of Gothenburg, Gröna Stråket 8, 413 45, Göteborg, Sweden,
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Daskalopoulos EP, Vilaeti AD, Barka E, Mantzouratou P, Kouroupis D, Kontonika M, Tourmousoglou C, Papalois A, Pantos C, Blankesteijn WM, Agathopoulos S, Kolettis TM. Attenuation of post-infarction remodeling in rats by sustained myocardial growth hormone administration. Growth Factors 2015; 33:250-8. [PMID: 26290214 DOI: 10.3109/08977194.2015.1072527] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Prevention of left ventricular remodeling is an important therapeutic target post-myocardial infarction. Experimentally, treatment with growth hormone (GH) is beneficial, but sustained local administration has not been thoroughly investigated. We studied 58 rats (322 ± 4 g). GH was administered via a biomaterial-scaffold, following in vitro and in vivo evaluation of degradation and drug-release curves. Treatment consisted of intra-myocardial injection of saline or alginate-hydrogel, with or without GH, 10 min after permanent coronary artery ligation. Echocardiographic and histologic remodeling-indices were examined 3 weeks post-ligation, followed by immunohistochemical evaluation of angiogenesis, collagen, macrophages and myofibroblasts. GH-release completed at 3 days and alginate-degradation at ∼7 days. Alginate + GH consistently improved left ventricular end-diastolic and end-systolic diameters, ventricular sphericity, wall tension index and infarct-thickness. Microvascular-density and myofibroblast-count in the infarct and peri-infarct areas were higher after alginate + GH. Macrophage-count and collagen-content did not differ between groups. Early, sustained GH-administration enhances angiogenesis and myofibroblast-activation and ameliorates post-infarction remodeling.
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Affiliation(s)
- Evangelos P Daskalopoulos
- a Department of Pharmacology , Cardiovascular Research Institute Maastricht, Maastricht University , Maastricht , The Netherlands
- b Cardiovascular Research Institute , Ioannina , Athens , Greece
| | - Agapi D Vilaeti
- b Cardiovascular Research Institute , Ioannina , Athens , Greece
| | - Eleonora Barka
- b Cardiovascular Research Institute , Ioannina , Athens , Greece
- c Ceramics and Composites Laboratory, Department of Materials Science and Engineering, University of Ioannina , Ioannina , Greece
| | - Polixeni Mantzouratou
- d Department of Pharmacology , Medical School, University of Athens , Athens , Greece
| | - Dimitrios Kouroupis
- e Department of Biomedical Research, Foundation for Research and Technology-Hellas , Institute of Molecular Biology and Biotechnology , Ioannina , Greece , and
| | | | | | - Apostolos Papalois
- b Cardiovascular Research Institute , Ioannina , Athens , Greece
- f Experimental Research Center ELPEN , Pikermi , Athens , Greece
| | - Constantinos Pantos
- d Department of Pharmacology , Medical School, University of Athens , Athens , Greece
| | - W Matthijs Blankesteijn
- a Department of Pharmacology , Cardiovascular Research Institute Maastricht, Maastricht University , Maastricht , The Netherlands
| | - Simeon Agathopoulos
- c Ceramics and Composites Laboratory, Department of Materials Science and Engineering, University of Ioannina , Ioannina , Greece
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The Effect of Weight Loss on the Cardiac Structure and Function After Laparoscopic Adjustable Gastric Banding Surgery in Morbidly Obese Individuals. Obes Surg 2014; 24:1961-8. [PMID: 24866689 DOI: 10.1007/s11695-014-1294-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Parodi EM, Kuhn B. Signalling between microvascular endothelium and cardiomyocytes through neuregulin. Cardiovasc Res 2014; 102:194-204. [PMID: 24477642 PMCID: PMC3989448 DOI: 10.1093/cvr/cvu021] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2013] [Revised: 12/23/2013] [Accepted: 01/10/2014] [Indexed: 12/26/2022] Open
Abstract
Heterocellular communication in the heart is an important mechanism for matching circulatory demands with cardiac structure and function, and neuregulins (Nrgs) play an important role in transducing this signal between the hearts' vasculature and musculature. Here, we review the current knowledge regarding Nrgs, explaining their roles in transducing signals between the heart's microvasculature and cardiomyocytes. We highlight intriguing areas being investigated for developing new, Nrg-mediated strategies to heal the heart in acquired and congenital heart diseases, and note avenues for future research.
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Affiliation(s)
| | - Bernhard Kuhn
- Harvard Medical School, Boston Children's Hospital, 300 Longwood Avenue, Enders Building, Room 1212, Brookline, MA 02115, USA
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Watanabe S, Tamura T, Ono K, Horiuchi H, Kimura T, Kita T, Furukawa Y. Insulin-like growth factor axis (insulin-like growth factor-I/insulin-like growth factor-binding protein-3) as a prognostic predictor of heart failure: association with adiponectin. Eur J Heart Fail 2014; 12:1214-22. [DOI: 10.1093/eurjhf/hfq166] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Affiliation(s)
- Shin Watanabe
- Department of Cardiovascular Medicine; Kyoto University Graduate School of Medicine; 54 Kawahara-cho, Shogoin Sakyo-ku Kyoto 606-8507 Japan
| | - Toshihiro Tamura
- Department of Cardiovascular Medicine; Kyoto University Graduate School of Medicine; 54 Kawahara-cho, Shogoin Sakyo-ku Kyoto 606-8507 Japan
| | - Koh Ono
- Department of Cardiovascular Medicine; Kyoto University Graduate School of Medicine; 54 Kawahara-cho, Shogoin Sakyo-ku Kyoto 606-8507 Japan
| | - Hisanori Horiuchi
- Department of Cardiovascular Medicine; Kyoto University Graduate School of Medicine; 54 Kawahara-cho, Shogoin Sakyo-ku Kyoto 606-8507 Japan
| | - Takeshi Kimura
- Department of Cardiovascular Medicine; Kyoto University Graduate School of Medicine; 54 Kawahara-cho, Shogoin Sakyo-ku Kyoto 606-8507 Japan
| | - Toru Kita
- Department of Cardiovascular Medicine; Kobe City Medical Center General Hospital; 4-6 Minatojimanakamachi, Chuo-ku Kobe 650-0046 Japan
| | - Yutaka Furukawa
- Department of Cardiovascular Medicine; Kyoto University Graduate School of Medicine; 54 Kawahara-cho, Shogoin Sakyo-ku Kyoto 606-8507 Japan
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Rider OJ, Lewis AJ, Neubauer S. Structural and Metabolic Effects of Obesity on the Myocardium and the Aorta. Obes Facts 2014; 7:329-338. [PMID: 25342107 PMCID: PMC5644846 DOI: 10.1159/000368429] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2013] [Accepted: 11/08/2013] [Indexed: 12/12/2022] Open
Abstract
Obesity per se is a recognized risk factor for cardiovascular disease exerting independent adverse effects on the cardiovascular system. Despite this well documented link, the mechanisms by which obesity modulates cardiovascular risk are not well understood. Obesity is linked to a wide variety of cardiac changes, from subclinical diastolic dysfunction to end stage systolic heart failure. In addition, obesity causes changes in cardiac metabolism that make ATP production and utilization less efficient producing functional consequences that are linked to the increased rate of heart failure in this population. This review focuses on the cardiovascular structural and metabolic remodelling that occurs in obesity with and without co-morbidities and the potential links to increased mortality in this population. © 2014 S. Karger GmbH, Freiburg.
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Affiliation(s)
- Oliver J. Rider
- *Dr. Oliver J Rider, University of Oxford Centre for Clinical Magnetic Resonance Research, Level 0, John Radcliffe Hospital, Oxford OX3 9DU (UK),
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Luk A, Ezzat S, Butany J. Pathology, pathophysiology, and treatment strategies of endocrine disorders and their cardiac complications. Semin Diagn Pathol 2013; 30:245-62. [PMID: 24144293 DOI: 10.1053/j.semdp.2013.06.008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
The cardiovascular system is affected by a multitude of endocrine disorders, including dysfunction of the thyroid, calcium, glucocorticoids, insulin/glucose, and growth hormone axes. Since most of these changes in the cardiovascular system are reversible when treated, early diagnosis is important, as if left untreated, they may become fatal. This review focuses on the pathophysiology, clinical presentation, pathology, and treatment of patients with these endocrine diseases who present with a variety of cardiovascular manifestations. Neuroendocrine tumors presenting with the carcinoid syndrome and their cardiovascular manifestations are also discussed.
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Affiliation(s)
- Adriana Luk
- Department of Medicine, Toronto General Hospital/University Health Network, Toronto, Ontario, Canada
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Metwalley KA, Farghaly HS, Abd El-Hafeez HA. Evaluation of left ventricular mass and function, lipid profile, and insulin resistance in Egyptian children with growth hormone deficiency: A single-center prospective case-control study. Indian J Endocrinol Metab 2013; 17:876-882. [PMID: 24083170 PMCID: PMC3784872 DOI: 10.4103/2230-8210.117234] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/02/2022] Open
Abstract
BACKGROUND Growth hormone deficiency (GHD) in adults is associated with a cluster of cardiovascular risk factors that may contribute to an increased mortality for cardiovascular disease. In children, relatively few studies have investigated the effect of GHD and replacement therapy on cardiac performance and metabolic abnormalities that may place them at a higher risk of cardiovascular disease (CVD) at an early age. AIM This study was aimed to assess the left ventricular function, lipid profile, and degree of insulin resistance in Egyptian children with GHD before and after 1 year of GH replacement therapy. SETTINGS AND DESIGN Prospective case-control study, single-center study. MATERIALS AND METHODS Thirty children with short stature due to GHD were studied in comparison to 20 healthy age- and sex-matched children. All subjects were subjected to history, clinical examination, auxological assessment, and echocardiography to assess the left ventricular function. Blood samples were collected for measuring IGF-1, lipid profile (Total, LDL, HDL cholesterol, triglyceride, and atherogenic index (AI), fasting blood sugar, and fasting insulin levels. In addition, basal and stimulated GH levels were measured in children with suspected GHD. STATISTICAL ANALYSIS USED Student's t-test was used for parametric data, and the Mann-Whitney U-test was used for non-parametric data. RESULTS Total, LDL cholesterol, triglyceride, AI, and insulin were significantly higher in children with GHD than in healthy controls at baseline. After 12 months of GH replacement therapy, total, LDL cholesterol, triglyceride, AI and insulin were significantly decreased, while homeostatic model assessment for insulin resistance index (HOMA-IR) was significantly increased compared to both pre-treatment and control values. At baseline, the left ventricular mass (LVM) and left ventricular mass index (LVMi) were significantly lower in GHD children than in controls. After 12 months of GH replacement therapy, LVM and LVMi in GHD patients were significantly increased compared to pre-treatment values. CONCLUSIONS GHD in children is associated with a significantly reduced cardiac mass and impairment of lipid profile. GH replacement therapy exerts beneficial effects both on cardiac mass and lipid metabolism by normalizing cardiac size and improving the lipid profile. On the contrary, an increase in insulin resistance is observed after 12 months GH treatment. The study suggests that children with GH deficiency should have echocardiography and lipid profile monitoring before and during treatment with GH.
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Affiliation(s)
| | - Hekma Saad Farghaly
- Department of Pediatrics, Faculty of Medicine, Assiut University, Assiut, Egypt
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Cittadini A, Marra AM, Arcopinto M, Bobbio E, Salzano A, Sirico D, Napoli R, Colao A, Longobardi S, Baliga RR, Bossone E, Saccà L. Growth hormone replacement delays the progression of chronic heart failure combined with growth hormone deficiency: an extension of a randomized controlled single-blind study. JACC-HEART FAILURE 2013; 1:325-330. [PMID: 24621936 DOI: 10.1016/j.jchf.2013.04.003] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/23/2013] [Accepted: 04/01/2013] [Indexed: 11/18/2022]
Abstract
OBJECTIVES This study sought to evaluate the efficacy and safety of long-term growth hormone (GH) replacement therapy in GH-deficient patients with chronic heart failure (CHF). BACKGROUND Recent evidence indicates that growth hormone deficiency (GHD) affects as many as 40% of patients with CHF, and short-term GH replacement causes functional benefit. Whether long-term GH replacement also affects CHF progression is unknown. METHODS The study is an extension of a previous randomized, controlled single-blind trial that screened 158 consecutive CHF patients (New York Heart Association classes II to IV) and identified 63 who had GHD by the growth hormone releasing hormone plus arginine test. Fifty-six patients were randomized to receive either GH therapy or standard CHF therapy. Patients were evaluated at baseline and after a 4-year follow-up. The primary endpoint was peak oxygen consumption (VO2). Secondary endpoints included left ventricular (LV) ejection fraction and volumes, serum amino terminal fragment of the pro-hormone brain-type natriuretic peptide, quality of life, and safety. RESULTS Seventeen patients in the GH group and 14 in the control group completed the study. In the GH group, peak VO2 improved over the 4-year follow-up. The treatment effect was 7.1 ± 0.7 ml/kg/min versus -1.8 ± 0.5 ml/kg/min in the GH and control groups, respectively. At 4 years, LV ejection fraction increased by 10 ± 3% in the GH group, whereas it decreased by 2 ± 5% in control patients. The treatment effect on LV end-systolic volume index was -22 ± 6 ml and 8 ± 3 ml/m(2) in the GH and control groups, respectively (all p < 0.001). No major adverse events were reported in the patients who received GH. CONCLUSIONS Although this is a preliminary study, the finding suggests a new therapeutic approach to a large proportion of GHD patients with CHF.
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Affiliation(s)
- Antonio Cittadini
- Department of Internal Medicine, Cardiovascular and Immunological Sciences, University "Federico II," Naples, Italy.
| | - Alberto M Marra
- Department of Internal Medicine, Cardiovascular and Immunological Sciences, University "Federico II," Naples, Italy
| | - Michele Arcopinto
- Department of Internal Medicine, Cardiovascular and Immunological Sciences, University "Federico II," Naples, Italy
| | - Emanuele Bobbio
- Department of Internal Medicine, Cardiovascular and Immunological Sciences, University "Federico II," Naples, Italy
| | - Andrea Salzano
- Department of Internal Medicine, Cardiovascular and Immunological Sciences, University "Federico II," Naples, Italy
| | - Domenico Sirico
- Department of Internal Medicine, Cardiovascular and Immunological Sciences, University "Federico II," Naples, Italy
| | - Raffaele Napoli
- Department of Internal Medicine, Cardiovascular and Immunological Sciences, University "Federico II," Naples, Italy
| | - Annamaria Colao
- Department of Molecular and Clinical Endocrinology and Oncology, University "Federico II," Naples, Italy
| | | | - Ragavendra R Baliga
- Division of Cardiovascular Medicine, The Ohio State University, Columbus, Ohio
| | - Eduardo Bossone
- Cardiology Division, Cava dei Tirreni-Amalfi Coast Hospital, Heart Department, University of Salerno, Salerno, Italy
| | - Luigi Saccà
- Department of Internal Medicine, Cardiovascular and Immunological Sciences, University "Federico II," Naples, Italy
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Perticone F, Sciacqua A, Perticone M, Miceli S, Maio R, Tassone JE, Arturi F, Sesti G. Phenotypic characterization of normotolerant hypertensive patients. Int J Cardiol 2013; 165:322-6. [DOI: 10.1016/j.ijcard.2011.08.076] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2011] [Revised: 08/18/2011] [Accepted: 08/21/2011] [Indexed: 10/17/2022]
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Wittnich C, Tan L, Wallen J, Belanger M. Sex differences in myocardial metabolism and cardiac function: an emerging concept. Pflugers Arch 2013; 465:719-29. [DOI: 10.1007/s00424-013-1232-1] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2013] [Accepted: 01/30/2013] [Indexed: 12/29/2022]
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Cittadini A, Monti MG, Iaccarino G, Castiello MC, Baldi A, Bossone E, Longobardi S, Marra AM, Petrillo V, Saldamarco L, During MJ, Saccà L, Condorelli G. SOCS1 gene transfer accelerates the transition to heart failure through the inhibition of the gp130/JAK/STAT pathway. Cardiovasc Res 2012; 96:381-90. [PMID: 22875468 PMCID: PMC3732068 DOI: 10.1093/cvr/cvs261] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2011] [Revised: 07/05/2012] [Accepted: 07/31/2012] [Indexed: 11/13/2022] Open
Abstract
AIMS The suppressors of cytokine signalling (SOCS) are identified inhibitors of cytokine and growth factor signalling that act via the Janus kinase (JAK) signal transducers and activators of transcription (STAT) pathways. Aberrant JAK/STAT signalling promotes progression from hypertrophy to heart failure. Little information is available concerning the role of SOCS in the transition from hypertrophy to heart failure. To this aim, we investigated the effects of SOCS1 overexpression obtained by in vivo adeno-associated gene transfer using an aortopulmonary cross-clamping technique in a chronic pressure-overload cardiac rat model. METHODS AND RESULTS Rats were randomized into four groups: sham-operated (n = 18), aortic banding (AB) (n = 18), AB + viral vector encoding for haemoagglutinin (AB + HA, n = 16), and AB + viral vector encoding for SOCS1 (AB + SOCS1, n = 18). Echocardiographic and haemodynamic measurements were performed 15 weeks after banding. While SOCS3 was upregulated during the hypertrophic phase, SOCS1 transcript levels increased significantly between 15 and 20 weeks. Remodelling was markedly worse in AB + SOCS1, showed larger left ventricular internal dimensions (+16%), higher end-diastolic pressures (+57%) and wall stress (+45%), and reduced fractional shortening (-32%) compared with AB + HA; apoptotic rate was increased three-fold and the gp130 pathway was inhibited. Ex vivo experiments showed that mechanical stretch upregulated SOCS1 expression, which was in turn attenuated by tumour necrosis factor-α (TNF-α) inhibition. CONCLUSION Enhanced SOCS1 myocardial signalling is associated with accelerated transition from hypertrophy to failure in an established model of pressure overload. SOCS1 may represent an attractive target for the prevention of heart failure progression.
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Affiliation(s)
- Antonio Cittadini
- Department of Clinical Medicine and Cardiovascular and Immunological Sciences, University Federico II, Via Sergio Pansini 5, 80131 Naples, Italy.
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Abstract
The hormones growth hormone (GH) and insulin-like growth factor 1 (IGF-1) play a dominant role in whole body growth and metabolism. This is reflected in the use of human GH (hGH) in GH-deficient children to stimulate growth and in GH-deficient adults to reduce visceral fat mass. Recent data suggest that hGH may improve cardiac function in patients with heart failure, so there is current interest in methods to raise GH-IGF levels, including the testing of agents that release GH from the pituitary, administering IGF-1, and most recently, long-acting formulations of hGH. It is hoped that this ongoing integration of cardiology and endocrinology will uncover the pathophysiology of some cardiovascular diseases and yield new treatments based on the hormones of the GH axis. (Trends Cardiovasc Med 1997;7:264-268). © 1997, Elsevier Science Inc.
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Affiliation(s)
- R Clark
- Endocrinology Group at Genentech Inc., San Francisco, CA 94080, USA
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41
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Abstract
Growth hormone (GH) exerts its effects through insulin-like growth factor-1, and although ubiquitous in human tissues, it has a significant role in cardiovascular function. In recent years, there has been a great deal of interest in GH as an etiologic factor in many cardiovascular disease states. Acromegaly, a state of endogenous GH excess, results in myocardial hypertrophy and decreased cardiac performance with increased cardiovascular mortality. Additional insight into the role of excess GH on the cardiovascular system has been gained from data collected in athletes doping with GH. Likewise, GH deficiency is associated with increased mortality, possibly from the associated increase in atherosclerosis, lipid abnormalities, and endothelial dysfunction. However, further research is required to clarify the benefit of GH treatment in both deficient states and in heart failure patients.
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42
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Abstract
PURPOSE OF REVIEW Recovery and rehabilitation after critical illness is a vital part of intensive care management. The role of feeding and nutritional intervention is the subject of many recent studies. The gastric hormone ghrelin has effects on appetite and food intake and on immunomodulatory functions. Here we review the interactions between critical illness, appetite regulation, nutrition and ghrelin. RECENT FINDINGS Critical illness results in significant loss of lean body mass; strategies to prevent this have so far proven unsuccessful. Ghrelin has been shown to reduce catabolic protein loss in animal models of critical illness and improve body composition in chronic cachectic illnesses in humans. SUMMARY Enhancing recovery from critical illness will improve both short-term and long-term outcomes. Ghrelin may offer an important means of improving appetite, muscle mass and rehabilitation in the period after critical illness, although studies are needed to see whether this potential is realized.
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43
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Touvron M, Escoubet B, Mericskay M, Angelini A, Lamotte L, Santini MP, Rosenthal N, Daegelen D, Tuil D, Decaux JF. Locally expressed IGF1 propeptide improves mouse heart function in induced dilated cardiomyopathy by blocking myocardial fibrosis and SRF-dependent CTGF induction. Dis Model Mech 2012; 5:481-91. [PMID: 22563064 PMCID: PMC3380711 DOI: 10.1242/dmm.009456] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Cardiac fibrosis is critically involved in the adverse remodeling accompanying dilated cardiomyopathies (DCMs), which leads to cardiac dysfunction and heart failure (HF). Connective tissue growth factor (CTGF), a profibrotic cytokine, plays a key role in this deleterious process. Some beneficial effects of IGF1 on cardiomyopathy have been described, but its potential role in improving DCM is less well characterized. We investigated the consequences of expressing a cardiac-specific transgene encoding locally acting IGF1 propeptide (muscle-produced IGF1; mIGF1) on disease progression in a mouse model of DCM [cardiac-specific and inducible serum response factor (SRF) gene disruption] that mimics some forms of human DCM. Cardiac-specific mIGF1 expression substantially extended the lifespan of SRF mutant mice, markedly improved cardiac functions, and delayed both DCM and HF. These protective effects were accompanied by an overall improvement in cardiomyocyte architecture and a massive reduction of myocardial fibrosis with a concomitant amelioration of inflammation. At least some of the beneficial effects of mIGF1 transgene expression were due to mIGF1 counteracting the strong increase in CTGF expression within cardiomyocytes caused by SRF deficiency, resulting in the blockade of fibroblast proliferation and related myocardial fibrosis. These findings demonstrate that SRF plays a key role in the modulation of cardiac fibrosis through repression of cardiomyocyte CTGF expression in a paracrine fashion. They also explain how impaired SRF function observed in human HF promotes fibrosis and adverse cardiac remodeling. Locally acting mIGF1 efficiently protects the myocardium from these adverse processes, and might thus represent a therapeutic avenue to counter DCM.
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44
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A 90-day safety study of genetically modified rice expressing rhIGF-1 protein in C57BL/6J rats. Transgenic Res 2011; 21:499-510. [PMID: 21910016 DOI: 10.1007/s11248-011-9550-6] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2011] [Accepted: 08/27/2011] [Indexed: 10/17/2022]
Abstract
Genetically modified plants expressing disease resistance traits offer new treatment strategies for human diseases, but at the same time present a challenge in terms of food safety assessment. The present 90-day feeding study was designed to assess the safety of transgenic rice expressing the recombinant human insulin-like growth factor-1 (rhIGF-1) compared to its parental wild rice. Male and female C57BL/6J rats were given a nutritionally balanced purified diet with 20% transgenic rhIGF-1 rice or 20% parental rice for 90 days. This corresponds to a mean daily rhIGF-1 protein intake of approximately 217.6 mg/kg body weight based on the average feed consumption. In the animal study a range of biological, biochemical, clinical, microbiological and pathological parameters were examined and several significant differences were observed between groups, but none of the effects were considered to be adverse. In conclusion, no adverse or toxic effects on C57BL/6J rats were observed in the design used in this 90-day study. These results will provide valuable information for the safety assessment of genetically modified food crops.
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45
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Zhang G, Yin X, Qi Y, Pendyala L, Chen J, Hou D, Tang C. Ghrelin and cardiovascular diseases. Curr Cardiol Rev 2011; 6:62-70. [PMID: 21286280 PMCID: PMC2845796 DOI: 10.2174/157340310790231662] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2009] [Revised: 03/27/2009] [Accepted: 04/03/2009] [Indexed: 01/19/2023] Open
Abstract
Ghrelin, a newly discovered bioactive peptide, is a natural endogenous ligand of the growth hormone (GH) secretagogue receptor and initially identified as a strong stimulant for the release of GH. Subsequent research has shown that ghrelin and its various receptors are ubiquitous in many other organs and tissues. Moreover, they participate in the regulation of appetite, energy, bodyweight, metabolism of glucose and fat, as well as modulation of gastrointestinal, cardiovascular, pulmonary, immune functions and cell proliferation/apoptosis. Increasing evidence has demonstrated that ghrelin has a close relationship with cardiovascular system. Ghrelin and its receptors are widely distributed in cardiovascular tissues, and there is no doubt that the effects of ghrelin in the cardiovascular system are mediated not only via its growth-hormone-releasing effect but also by its direct effects on the heart. Exogenous administration of ghrelin can dilate peripheral blood vessels, constrict coronary artery, improve endothelial function, as well as inhibit myocardial cell apoptosis. So, ghrelin may have cardiovascular protective effect, including lowering of blood pressure, regulation of atherosclerosis, and protection from ischemia/reperfusion injury as well as improving the prognosis of myocardial infarction and heart failure. Some of these new functions of ghrelin may provide new potential therapeutic opportunities for ghrelin in cardiovascular medicine. In this paper, we will review the existing evidence for cardiovascular effects of ghrelin, including the cardiovascular function, the variations in ghrelin plasma levels in pathophysiologicalogical conditions, the possible protective mechanisms of ghrelin, as well as its future potential therapeutic roles.
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Affiliation(s)
- Gaigai Zhang
- Cardiology Department, the First Affiliated Hospital of Harbin Medical University, Harbin,P. R. China 150081
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46
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Castellano G, Affuso F, Conza PD, Fazio S. The GH/IGF-1 Axis and Heart Failure. Curr Cardiol Rev 2011; 5:203-15. [PMID: 20676279 PMCID: PMC2822143 DOI: 10.2174/157340309788970306] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2008] [Revised: 01/22/2009] [Accepted: 01/23/2009] [Indexed: 01/24/2023] Open
Abstract
The growth hormone (GH)/insulin-like growth factor 1 (IGF-1) axis regulates cardiac growth, stimulates myocardial contractility and influences the vascular system. The GH/IGF-1 axis controls intrinsic cardiac contractility by enhancing the intracellular calcium availability and regulating expression of contractile proteins; stimulates cardiac growth, by increasing protein synthesis; modifies systemic vascular resistance, by activating the nitric oxide system and regulating non-endothelial-dependent actions. The relationship between the GH/IGF-1 axis and the cardiovascular system has been extensively demonstrated in numerous experimental studies and confirmed by the cardiac derangements secondary to both GH excess and deficiency. Several years ago, a clinical non-blinded study showed, in seven patients with idiopathic dilated cardiomyopathy and chronic heart failure (CHF), a significant improvement in cardiac function and structure after three months of treatment with recombinant GH plus standard therapy for heart failure. More recent studies, including a small double-blind placebo-controlled study on GH effects on exercise tolerance and cardiopulmonary performance, have shown that GH benefits patients with CHF secondary to both ischemic and idiopathic dilated cardiomyopathy. However, conflicting results emerge from other placebo-controlled trials. These discordant findings may be explained by the degree of CHF-associated GH resistance. In conclusion, we believe that more clinical and experimental studies are necessary to exactly understand the mechanisms that determine the variable sensitivity to GH and its positive effects in the failing heart.
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Affiliation(s)
- Graziella Castellano
- Department of Internal Medicine, School of Medicine, University of Naples "Federico II", Naples, Italy
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47
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Lader JM, Vasquez C, Bao L, Maass K, Qu J, Kefalogianni E, Fishman GI, Coetzee WA, Morley GE. Remodeling of atrial ATP-sensitive K⁺ channels in a model of salt-induced elevated blood pressure. Am J Physiol Heart Circ Physiol 2011; 301:H964-74. [PMID: 21724863 DOI: 10.1152/ajpheart.00410.2011] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Hypertension is associated with the development of atrial fibrillation; however, the electrophysiological consequences of this condition remain poorly understood. ATP-sensitive K(+) (K(ATP)) channels, which contribute to ventricular arrhythmias, are also expressed in the atria. We hypothesized that salt-induced elevated blood pressure (BP) leads to atrial K(ATP) channel activation and increased arrhythmia inducibility. Elevated BP was induced in mice with a high-salt diet (HS) for 4 wk. High-resolution optical mapping was used to measure atrial arrhythmia inducibility, effective refractory period (ERP), and action potential duration at 90% repolarization (APD(90)). Excised patch clamping was performed to quantify K(ATP) channel properties and density. K(ATP) channel protein expression was also evaluated. Atrial arrhythmia inducibility was 22% higher in HS hearts compared with control hearts. ERP and APD(90) were significantly shorter in the right atrial appendage and left atrial appendage of HS hearts compared with control hearts. Perfusion with 1 μM glibenclamide or 300 μM tolbutamide significantly decreased arrhythmia inducibility and prolonged APD(90) in HS hearts compared with untreated HS hearts. K(ATP) channel density was 156% higher in myocytes isolated from HS animals compared with control animals. Sulfonylurea receptor 1 protein expression was increased in the left atrial appendage and right atrial appendage of HS animals (415% and 372% of NS animals, respectively). In conclusion, K(ATP) channel activation provides a mechanistic link between salt-induced elevated BP and increased atrial arrhythmia inducibility. The findings of this study have important implications for the treatment and prevention of atrial arrhythmias in the setting of hypertensive heart disease and may lead to new therapeutic approaches.
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Affiliation(s)
- Joshua M Lader
- Leon H. Charney Division of Cardiology, New York University School of Medicine, New York, New York 10016, USA
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48
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Sawyer DB, Caggiano A. Neuregulin-1β for the treatment of systolic heart failure. J Mol Cell Cardiol 2011; 51:501-5. [PMID: 21729703 DOI: 10.1016/j.yjmcc.2011.06.016] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2011] [Revised: 05/13/2011] [Accepted: 06/20/2011] [Indexed: 01/26/2023]
Abstract
The Neuregulin-1 gene encodes a family of ligands that act through the ErbB family of receptor tyrosine kinases to regulate morphogenesis of many tissues. Work in isolated cardiac cells as well as genetically altered mice demonstrates that neuregulin-1/ErbB signaling is a paracrine signaling system that functions in endocardial-endothelial/cardiomyocyte interactions to regulate tissue organization during development as well as maintain cardiac function throughout life. Treatment of animals with cardiac dysfunction with recombinant neuregulin-1beta improves cardiac function. This has led to ongoing early phase clinical studies examining neuregulin-1beta as a potential novel therapeutic for heart failure. In this review we synthesize the literature behind this rapidly evolving area of translational research. This article is part of a special issue entitled "Key Signaling Molecules in Hypertrophy and Heart Failure."
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Affiliation(s)
- Douglas B Sawyer
- Cardiovascular Division, Department of Medicine, Vanderbilt University Medical School, Nashville, TN, USA.
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49
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Sciacqua A, Miceli S, Carullo G, Greco L, Succurro E, Arturi F, Sesti G, Perticone F. One-hour postload plasma glucose levels and left ventricular mass in hypertensive patients. Diabetes Care 2011; 34:1406-11. [PMID: 21515837 PMCID: PMC3114345 DOI: 10.2337/dc11-0155] [Citation(s) in RCA: 76] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Left ventricular hypertrophy (LVH), an independent risk factor for cardiovascular (CV) morbidity and mortality, recognizes a multifactorial pathogenesis. A plasma glucose value ≥155 mg/dL for the 1-h postload plasma glucose during an oral glucose tolerance test (OGTT) identifies subjects with normal glucose tolerance (NGT) at high risk for type 2 diabetes. We addressed the question if glucose tolerance status, particularly 1-h postload plasma glucose levels, affects left ventricular mass (LVM) and cardiac geometry in essential hypertension. RESEARCH DESIGN AND METHODS We enrolled 767 never-treated hypertensive subjects, 393 women and 374 men (mean age 49.6 ± 8.5 years). All patients underwent an OGTT for the evaluation of glucose tolerance and standard echocardiography. LVM was calculated using the Devereux formula and normalized by body surface area (LVM index [LVMI]). Insulin sensitivity was assessed by the Matsuda index. Among all participants, 514 had NGT, 168 had impaired glucose tolerance (IGT), and 85 had type 2 diabetes. According to the 1-h postload plasma glucose cutoff point of 155 mg/dL, we divided normotolerant subjects into two groups: NGT <155 mg/dL (n = 356) and NGT ≥155 mg/dL (n = 158). RESULTS Subjects in the NGT ≥155 mg/dL group had worse insulin sensitivity than subjects in the NGT <155 mg/dL group (Matsuda index 63.9 vs. 88.8; P < 0.0001). Men with NGT ≥155 mg/dL had a higher LVMI than men with NGT <155 mg/dL (126.6 vs. 114.3 g/m(2); P = 0.002) and a different LVH prevalence (41.1 vs. 25.8%; P < 0.0001). At multiple regression analysis, 1-h glucose resulted in the major determinant of LVMI in normotolerant, IGT, and diabetic groups. CONCLUSIONS These data show that NGT ≥155 mg/dL subjects, compared with NGT <155 mg/dL subjects, have a higher LVMI and a greater prevalence of LVH similar to that of IGT and diabetic patients.
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Affiliation(s)
- Angela Sciacqua
- Department of Experimental and Clinical Medicine G. Salvatore, University Magna Græcia of Catanzaro, Catanzaro, Italy
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50
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Rius-Francino M, Acerete L, Jiménez-Amilburu V, Capilla E, Navarro I, Gutiérrez J. Differential effects on proliferation of GH and IGFs in sea bream (Sparus aurata) cultured myocytes. Gen Comp Endocrinol 2011; 172:44-9. [PMID: 21458458 DOI: 10.1016/j.ygcen.2011.03.024] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2010] [Revised: 03/21/2011] [Accepted: 03/25/2011] [Indexed: 01/15/2023]
Abstract
Primary culture of gilthead sea bream skeletal muscle cells was used to examine the effects of growth hormone (GH) and insulin-like growth factors (IGFs) in fish muscle proliferation and growth. Proliferation was measured as the percentage of positive cells expressing the proliferating cell nuclear antigen (PCNA) analyzed by immunocytochemistry. First, the effects of GH from two different origins (mammals and fish) were tested. GH from human (hGH) did not stimulate proliferation except at 3h at the dose of 1 nM. On the other hand, sea bream GH (sbGH) significantly stimulated proliferation, without differences between the three incubation times studied (3, 6, and 18 h), at the dose of 10nM, demonstrating that the homologous hormone has a more potent effect. In addition, the results with the IGFs indicated that both peptides, IGF-I and IGF-II significantly stimulated proliferation of sea bream myocytes, but IGF-II showed higher effects than IGF-I, and even than those of sbGH. Finally, the combinations of peptide treatments (GHs with IGFs) indicated that IGF-I has higher effects on proliferation when it is combined with GHs compared with IGF-I alone, while IGF-II has similar effects alone or combined with either GH. These results indicate that IGF-II may have an important role on muscle proliferation that appears to be independent of GH. On the contrary, IGF-I seems to play a synergistic action with GH stimulating myocyte proliferation.
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Affiliation(s)
- Mònica Rius-Francino
- Departament de Fisiologia i Immunologia, Facultat de Biologia, Universitat de Barcelona, Av Diagonal, 645, E-08028 Barcelona, Spain
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