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Liu Z, Sivathamboo S, Thergarajan P, Gomes FM, Ali I, Powell KL, Perucca P, Jones NC, O'Brien TJ, Casillas-Espinosa P. Cardiac structural and molecular alterations in rodent models of temporal lobe epilepsy. Epilepsia Open 2025. [PMID: 40296438 DOI: 10.1002/epi4.70032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2024] [Revised: 03/03/2025] [Accepted: 03/24/2025] [Indexed: 04/30/2025] Open
Abstract
OBJECTIVE Cardiac structural and molecular changes are prevalent in people with chronic epilepsy, possibly contributing to an increased risk of premature mortality. However, understanding of the underlying pathophysiological mechanisms is limited. Here, we investigated the subacute and chronic changes in cardiac structure and ion channel/exchanger expression in different rodent models of temporal lobe epilepsy (TLE). METHODS Two models of TLE were used: the kainic acid-induced post-status epilepticus (KASE) model in Wistar rats and the electrical self-sustained status epilepticus (SSSE) model in C57BL/6J mice. Heart tissue was collected at subacute (7 days post-SE) and chronic (12-16 weeks post-SE) timepoints from both models. Histological analysis for cardiac fibrosis and qPCR of ion channel/exchanger mRNA expression was performed. RESULTS Increased cardiac fibrosis was found in the KASE rats at the subacute (p = 0.016) and chronic (p = 0.003) timepoints compared with sham rats. In chronically epileptic KASE rats, mRNA expression analyses showed that NaV1.5 and NCX1 were reduced in the septum (p = 0.026 and p = 0.020, respectively) compared with shams. In SSSE mice, NaV1.5 was decreased in the right atrium (p = 0.039), and CaV3.2 and NCX1 were increased in the left ventricle subacutely (p = 0.033 and p = 0.003, respectively), and NaV1.5 was increased in the septum at the chronic timepoint (p = 0.008), compared with the non-epileptic sham group. SIGNIFICANCE Cardiac alterations at structural and molecular levels were found in both experimental rodent epilepsy models, subacutely post-SE and during the chronically epileptic timepoint. The presence of similar cardiac changes across the models, despite being different species and having different modes of epilepsy indication, suggests that these changes are a direct or indirect result of the seizures. PLAIN LANGUAGE SUMMARY Epilepsy may lead to heart problems, which could raise the risk of early death, but the exact causes are unclear. This study examined heart changes in two rodent models of epilepsy. In rats, heart scarring and stiffness (fibrosis) increased both shortly after seizures and during chronic epilepsy, and the ability to produce key heart proteins was altered. In mice, similar changes in heart proteins appeared in different heart areas. These findings suggest seizures can directly or indirectly cause harmful heart changes. Understanding these effects might help improve care for people with epilepsy and reduce related heart risks.
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Affiliation(s)
- Zining Liu
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia
| | - Shobi Sivathamboo
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia
- Department of Neurology, Alfred Health, Melbourne, Victoria, Australia
- Department of Medicine (the Royal Melbourne Hospital), The University of Melbourne, Parkville, Victoria, Australia
| | - Peravina Thergarajan
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia
| | - Flavia M Gomes
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia
| | - Idrish Ali
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia
| | - Kim L Powell
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia
| | - Piero Perucca
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia
- Department of Neurology, Alfred Health, Melbourne, Victoria, Australia
- Bladin-Berkovic Comprehensive Epilepsy Program, Department of Neurology, Austin Hospital, Heidelberg, Victoria, Australia
- Epilepsy Research Centre, Department of Medicine (Austin Health), The University of Melbourne, Heidelberg, Victoria, Australia
- Department of Neurology, The Royal Melbourne Hospital, Parkville, Victoria, Australia
| | - Nigel C Jones
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia
- Department of Neurology, Alfred Health, Melbourne, Victoria, Australia
- Department of Medicine (the Royal Melbourne Hospital), The University of Melbourne, Parkville, Victoria, Australia
| | - Terence J O'Brien
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia
- Department of Neurology, Alfred Health, Melbourne, Victoria, Australia
- Department of Medicine (the Royal Melbourne Hospital), The University of Melbourne, Parkville, Victoria, Australia
| | - Pablo Casillas-Espinosa
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia
- Department of Neurology, Alfred Health, Melbourne, Victoria, Australia
- Department of Medicine (the Royal Melbourne Hospital), The University of Melbourne, Parkville, Victoria, Australia
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Kulpa J, Paduch J, Szczepanik M, Gorący-Rosik A, Rosik J, Tchórz M, Pawlik A, Gorący J. Catestatin in Cardiovascular Diseases. Int J Mol Sci 2025; 26:2417. [PMID: 40141061 PMCID: PMC11942146 DOI: 10.3390/ijms26062417] [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] [Subscribe] [Scholar Register] [Received: 02/10/2025] [Revised: 03/03/2025] [Accepted: 03/07/2025] [Indexed: 03/28/2025] Open
Abstract
Cardiovascular diseases are one of the leading causes of mortality and morbidity worldwide. The pathogenesis of this group of disorders is highly complex and involves interactions between various cell types and substances, among others, catestatin (CTS). In recent years, numerous researchers have expanded our knowledge about CTS's role in development and its potential for the treatment of a variety of diseases. In this review, the authors discuss CTS's importance in the pathogenesis of arterial hypertension, coronary artery disease, and heart failure. Moreover, we present CTS's influence on heart and vessel function.
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Affiliation(s)
- Joanna Kulpa
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland; (J.K.); (J.P.); (M.S.); (M.T.); (A.P.)
| | - Jarosław Paduch
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland; (J.K.); (J.P.); (M.S.); (M.T.); (A.P.)
| | - Marcin Szczepanik
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland; (J.K.); (J.P.); (M.S.); (M.T.); (A.P.)
| | - Anna Gorący-Rosik
- Independent Laboratory of Invasive Cardiology, Pomeranian Medical University, 70-111 Szczecin, Poland; (A.G.-R.); (J.G.)
| | - Jakub Rosik
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland; (J.K.); (J.P.); (M.S.); (M.T.); (A.P.)
| | - Magdalena Tchórz
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland; (J.K.); (J.P.); (M.S.); (M.T.); (A.P.)
| | - Andrzej Pawlik
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland; (J.K.); (J.P.); (M.S.); (M.T.); (A.P.)
| | - Jarosław Gorący
- Independent Laboratory of Invasive Cardiology, Pomeranian Medical University, 70-111 Szczecin, Poland; (A.G.-R.); (J.G.)
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Packer M, Ferreira JP, Butler J, Filippatos G, Januzzi JL, González Maldonado S, Panova-Noeva M, Pocock SJ, Prochaska JH, Saadati M, Sattar N, Sumin M, Anker SD, Zannad F. Reaffirmation of Mechanistic Proteomic Signatures Accompanying SGLT2 Inhibition in Patients With Heart Failure: A Validation Cohort of the EMPEROR Program. J Am Coll Cardiol 2024; 84:1979-1994. [PMID: 39217550 DOI: 10.1016/j.jacc.2024.07.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Revised: 07/17/2024] [Accepted: 07/18/2024] [Indexed: 09/04/2024]
Abstract
BACKGROUND Sodium-glucose cotransporter 2 (SGLT2) inhibitors exert a distinctive pattern of direct biological effects on the heart and kidney under experimental conditions, but the meaningfulness of these signatures for patients with heart failure has not been fully defined. OBJECTIVES We performed the first mechanistic validation study of large-scale proteomics in a double-blind randomized trial of any treatment in patients with heart failure. METHODS In a discovery cohort from the EMPEROR (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure and Reduced Ejection Fraction) program, we studied the effect of randomized treatment with placebo or empagliflozin on 1,283 circulating proteins in 1,134 patients with heart failure with a reduced or preserved ejection fraction. In a validation cohort, we expanded the number to 2,155 assessed proteins, which were measured in 1,120 EMPEROR participants who had not been studied previously. RESULTS In the validation cohort, 25 proteins were the most differentially enriched by empagliflozin (ie, ≥15% between-group difference and false discovery rate <1% at 12 weeks with known effects on the heart or kidney): 1) 13 proteins promote autophagy and other cellular quality-control functions (IGFBP1, OTUB1, DNAJB1, DNAJC9, RBP2, IST1, HSPA8, H-FABP, FABP6, ATPIFI, TfR1, EPO, IGBP1); 2) 12 proteins enhance mitochondrial health and ATP production (UMtCK, TBCA, L-FABP, H-FABP, FABP5, FABP6, RBP2, IST1, HSPA8, ATPIFI, TfR1, EPO); 3) 7 proteins augment cellular iron mobilization or erythropoiesis (TfR1, EPO, IGBP1, ERMAP, UROD, ATPIF1, SNCA); 4) 3 proteins influence renal tubular sodium handling; and 5) 9 proteins have restorative effects in the heart or kidneys, with many proteins exerting effects in >1 domain. These biological signatures replicated those observed in our discovery cohort. When the threshold for a meaningful between-group difference was lowered to ≥10%, there were 58 additional differentially enriched proteins with actions on the heart and kidney, but the biological signatures remained the same. CONCLUSIONS The replication of mechanistic signatures across discovery and validation cohorts closely aligns with the experimental effects of SGLT2 inhibitors. Thus, the actions of SGLT2 inhibitors-to promote autophagy, restore mitochondrial health and production of ATP, promote iron mobilization and erythropoiesis, influence renal tubular ion reabsorption, and normalize cardiac and renal structure and function-are likely to be relevant to patients with heart failure. (EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Preserved Ejection Fraction [EMPEROR-Preserved], NCT03057951; EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction [EMPEROR-Reduced], NCT03057977).
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Affiliation(s)
- Milton Packer
- Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, Texas, USA; Imperial College London, London, United Kingdom.
| | - João Pedro Ferreira
- UnIC@RISE, Cardiovascular Research and Development Center, Department of Surgery and Physiology, Faculty of Medicine of the University of Porto, Porto, Portugal; Baylor Scott and White Research Institute, Dallas, Texas, USA
| | - Javed Butler
- Baylor Scott and White Research Institute, Dallas, Texas, USA; University of Mississippi Medical Center, Jackson, Mississippi, USA
| | - Gerasimos Filippatos
- National and Kapodistrian University of Athens School of Medicine, Athens University Hospital Attikon, Athens, Greece
| | - James L Januzzi
- National and Kapodistrian University of Athens School of Medicine, Athens University Hospital Attikon, Athens, Greece; Massachusetts General Hospital and Baim Institute for Clinical Research, Boston, Massachusetts, USA
| | | | - Marina Panova-Noeva
- Boehringer Ingelheim Pharma GmbH & Co KG, Ingelheim, Germany; Center for Thrombosis and Haemostasis, University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany
| | - Stuart J Pocock
- London School of Hygiene and Tropical Medicine, London, United Kingdom
| | - Jürgen H Prochaska
- Boehringer Ingelheim International GmbH, Ingelheim, Germany; Preventive Cardiology and Preventive Medicine, Department of Cardiology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Maral Saadati
- Elderbrook Solutions GmbH, on behalf of Boehringer Ingelheim Pharma GmbH & Co KG, Biberach an der Riss, Germany
| | - Naveed Sattar
- Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom
| | - Mikhail Sumin
- Boehringer Ingelheim International GmbH, Ingelheim, Germany
| | - Stefan D Anker
- Department of Cardiology (CVK) of German Heart Center Charité, Institute of Health Center for Regenerative Therapies (BCRT), German Centre for Cardiovascular Research (DZHK) partner site Berlin, Charité Universitätsmedizin, Berlin, Germany
| | - Faiez Zannad
- Centre d'Investigations Cliniques Plurithématique 1433, INSERM, Université de Lorraine, Nancy, France; F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), INSERM U1116, Centre Hospitalier Régional Universitaire de Nancy, Nancy, France
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Qiu Z, Fan Y, Wang Z, Huang F, Li Z, Sun Z, Hua S, Jin W, Chen Y. Catestatin Protects Against Diastolic Dysfunction by Attenuating Mitochondrial Reactive Oxygen Species Generation. J Am Heart Assoc 2023; 12:e029470. [PMID: 37119063 PMCID: PMC10227223 DOI: 10.1161/jaha.123.029470] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Accepted: 03/30/2023] [Indexed: 04/30/2023]
Abstract
Background Catestatin has been reported as a pleiotropic cardioprotective peptide. Heart failure with preserved ejection fraction (HFpEF) was considered a heterogeneous syndrome with a complex cause. We sought to investigate the role of catestatin in HFpEF and diastolic dysfunction. METHODS AND RESULTS Administration of recombinant catestatin (1.5 mg/kg/d) improved diastolic dysfunction and left ventricular chamber stiffness in transverse aortic constriction mice with deoxycorticosterone acetate pellet implantation, as reflected by Doppler tissue imaging and pressure-volume loop catheter. Less cardiac hypertrophy and myocardial fibrosis was observed, and transcriptomic analysis revealed downregulation of mitochondrial electron transport chain components after catestatin treatment. Catestatin reversed mitochondrial structural and respiratory chain component abnormality, decreased mitochondrial proton leak, and reactive oxygen species generation in myocardium. Excessive oxidative stress induced by Ru360 abolished catestatin treatment effects on HFpEF-like cardiomyocytes in vitro, indicating the beneficial role of catestatin in HFpEF as a mitochondrial ETC modulator. The serum concentration of catestatin was tested among 81 patients with HFpEF and 76 non-heart failure controls. Compared with control subjects, serum catestatin concentration was higher in patients with HFpEF and positively correlated with E velocity to mitral annular e' velocity ratio, indicating a feedback compensation role of catestatin in HFpEF. Conclusions Catestatin protects against diastolic dysfunction in HFpEF through attenuating mitochondrial electron transport chain-derived reactive oxygen species generation. Serum catestatin concentration is elevated in patients with HFpEF, probably as a relatively insufficient but self-compensatory mechanism.
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Affiliation(s)
- Zeping Qiu
- Department of Cardiovascular Medicine, Ruijin HospitalShanghai Jiao Tong University School of MedicineShanghaiPeople’s Republic of China
- Institute of Cardiovascular DiseasesShanghai Jiao Tong University School of MedicineShanghaiPeople’s Republic of China
| | - Yingze Fan
- Department of Cardiovascular Medicine, Ruijin HospitalShanghai Jiao Tong University School of MedicineShanghaiPeople’s Republic of China
- Institute of Cardiovascular DiseasesShanghai Jiao Tong University School of MedicineShanghaiPeople’s Republic of China
| | - Zhiyan Wang
- Department of Cardiovascular Medicine, Ruijin HospitalShanghai Jiao Tong University School of MedicineShanghaiPeople’s Republic of China
- Institute of Cardiovascular DiseasesShanghai Jiao Tong University School of MedicineShanghaiPeople’s Republic of China
| | - Fanyi Huang
- Department of Cardiovascular Medicine, Ruijin HospitalShanghai Jiao Tong University School of MedicineShanghaiPeople’s Republic of China
- Institute of Cardiovascular DiseasesShanghai Jiao Tong University School of MedicineShanghaiPeople’s Republic of China
| | - Zhuojin Li
- Department of Cardiovascular Medicine, Ruijin HospitalShanghai Jiao Tong University School of MedicineShanghaiPeople’s Republic of China
- Institute of Cardiovascular DiseasesShanghai Jiao Tong University School of MedicineShanghaiPeople’s Republic of China
| | - Zhihong Sun
- Department of Cardiovascular Medicine, Ruijin HospitalShanghai Jiao Tong University School of MedicineShanghaiPeople’s Republic of China
- Institute of Cardiovascular DiseasesShanghai Jiao Tong University School of MedicineShanghaiPeople’s Republic of China
| | - Sha Hua
- Institute of Cardiovascular DiseasesShanghai Jiao Tong University School of MedicineShanghaiPeople’s Republic of China
- Heart Failure Center, Ruijin Hospital, & Lu Wan BranchShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Wei Jin
- Department of Cardiovascular Medicine, Ruijin HospitalShanghai Jiao Tong University School of MedicineShanghaiPeople’s Republic of China
- Institute of Cardiovascular DiseasesShanghai Jiao Tong University School of MedicineShanghaiPeople’s Republic of China
- Heart Failure Center, Ruijin Hospital, & Lu Wan BranchShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Yanjia Chen
- Department of Cardiovascular Medicine, Ruijin HospitalShanghai Jiao Tong University School of MedicineShanghaiPeople’s Republic of China
- Institute of Cardiovascular DiseasesShanghai Jiao Tong University School of MedicineShanghaiPeople’s Republic of China
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Serum Catestatin Concentrations Are Increased in Patients with Atrial Fibrillation. J Cardiovasc Dev Dis 2023; 10:jcdd10020085. [PMID: 36826581 PMCID: PMC9965955 DOI: 10.3390/jcdd10020085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2022] [Revised: 01/25/2023] [Accepted: 02/14/2023] [Indexed: 02/19/2023] Open
Abstract
The autonomic nervous system is crucial in initiating and maintaining atrial fibrillation (AF). Catestatin is a multipurpose peptide that regulates cardiovascular systems and reduces harmful, excessive activity of the sympathetic nervous system by blocking the release of catecholamines. We aimed to determine whether serum catestatin concentrations are associated with AF severity, duration indices, and various clinical and laboratory indicators in these individuals to better define the clinical value of catestatin in patients with AF. The present single center study enrolled 73 participants with AF and 72 healthy age-matched controls. Serum catestatin concentrations were markedly higher in AF patients than controls (14.11 (10.21-26.02) ng/mL vs. 10.93 (5.70-20.01) ng/mL, p = 0.013). Furthermore, patients with a more severe form of AF had significantly higher serum catestatin (17.56 (12.80-40.35) vs. 10.98 (8.38-20.91) ng/mL, p = 0.001). Patients with higher CHA2DS2-VASc scores (17.58 (11.89-37.87) vs. 13.02 (8.47-22.75) ng/mL, p = 0.034) and higher NT-proBNP levels (17.58 (IQR 13.91-34.62) vs. 13.23 (IQR 9.04-22.61), p = 0.036) had significantly higher serum catestatin concentrations. Finally, AF duration correlated negatively with serum catestatin levels (r = -0.348, p = 0.003). The results of the present study implicate the promising role of catestatin in the intricate pathophysiology of AF, which should be explored in future research.
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Kamisah Y, Che Hassan HH. Therapeutic Use and Molecular Aspects of Ivabradine in Cardiac Remodeling: A Review. Int J Mol Sci 2023; 24:ijms24032801. [PMID: 36769115 PMCID: PMC9917668 DOI: 10.3390/ijms24032801] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2022] [Revised: 01/24/2023] [Accepted: 01/31/2023] [Indexed: 02/05/2023] Open
Abstract
Cardiac remodeling can cause ventricular dysfunction and progress to heart failure, a cardiovascular disease that claims many lives globally. Ivabradine, a funny channel (If) inhibitor, is used in patients with chronic heart failure as an adjunct to other heart failure medications. This review aims to gather updated information regarding the therapeutic use and mechanism of action of ivabradine in heart failure. The drug reduces elevated resting heart rate, which is linked to increased morbidity and mortality in patients with heart failure. Its use is associated with improved cardiac function, structure, and quality of life in the patients. Ivabradine exerts several pleiotropic effects, including an antiremodeling property, which are independent of its principal heart-rate-reducing effects. Its suppressive effects on cardiac remodeling have been demonstrated in animal models of cardiac remodeling and heart failure. It reduces myocardial fibrosis, apoptosis, inflammation, and oxidative stress as well as increases autophagy in the animals. It also modulates myocardial calcium homeostasis, neurohumoral systems, and energy metabolism. However, its role in improving heart failure remains unclear. Therefore, elucidating its molecular mechanisms is imperative and would aid in the design of future studies.
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Affiliation(s)
- Yusof Kamisah
- Department of Pharmacology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia
- Correspondence:
| | - Hamat H. Che Hassan
- Department of Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia
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Zalewska E, Kmieć P, Sworczak K. Role of Catestatin in the Cardiovascular System and Metabolic Disorders. Front Cardiovasc Med 2022; 9:909480. [PMID: 35665253 PMCID: PMC9160393 DOI: 10.3389/fcvm.2022.909480] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 04/25/2022] [Indexed: 12/19/2022] Open
Abstract
Catestatin is a multifunctional peptide that is involved in the regulation of the cardiovascular and immune systems as well as metabolic homeostatis. It mitigates detrimental, excessive activity of the sympathetic nervous system by inhibiting catecholamine secretion. Based on in vitro and in vivo studies, catestatin was shown to reduce adipose tissue, inhibit inflammatory response, prevent macrophage-driven atherosclerosis, and regulate cytokine production and release. Clinical studies indicate that catestatin may influence the processes leading to hypertension, affect the course of coronary artery diseases and heart failure. This review presents up-to-date research on catestatin with a particular emphasis on cardiovascular diseases based on a literature search.
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Catestatin as a Biomarker of Cardiovascular Diseases: A Clinical Perspective. Biomedicines 2021; 9:biomedicines9121757. [PMID: 34944578 PMCID: PMC8698910 DOI: 10.3390/biomedicines9121757] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 11/22/2021] [Accepted: 11/23/2021] [Indexed: 02/07/2023] Open
Abstract
Accounting for almost one-third of the global mortality, cardiovascular diseases (CVDs) represent a major global health issue. Emerging data suggest that most of the well-established mechanistic explanations regarding the cardiovascular pathophysiology are flawed, and cannot fully explain the progression and long-term effects of these diseases. On the other hand, dysregulation of the sympathetic nervous system (SNS) has emerged as an important player in the pathophysiology of CVDs. Even though upregulated SNS activity is an essential compensatory response to various stress conditions, in the long term, it becomes a major contributor to both cardiac dysfunction and vascular damage. Despite the fact that the importance of SNS hyperactivity in the setting of CVDs has been well-appreciated, its exact quantification and clinical application in either diagnostics or therapy of CVDs is still out of reach. Nevertheless, in recent years a number of novel laboratory biomarkers implicated in the pathophysiology of SNS activation have been explored. Specifically, in this review, we aimed to discuss the role of catestatin, a potent physiological inhibitor of catecholamine spillover that offers cardioprotective effects. Limited data indicate that catestatin could also be a reliable indirect marker of SNS activity and it is likely that high CST levels reflect advanced CV disease burden. Consequently, large-scale studies are required to validate these observations in the upcoming future.
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Du Y, Demillard LJ, Ren J. Catecholamine-induced cardiotoxicity: A critical element in the pathophysiology of stroke-induced heart injury. Life Sci 2021; 287:120106. [PMID: 34756930 DOI: 10.1016/j.lfs.2021.120106] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 10/24/2021] [Accepted: 10/26/2021] [Indexed: 01/20/2023]
Abstract
Cerebrovascular diseases such as ischemic stroke, brain hemorrhage, and subarachnoid hemorrhage provoke cardiac complications such as heart failure, neurogenic stress-related cardiomyopathy and Takotsubo cardiomyopathy. With regards to the pathophysiology of stroke-induced heart injury, several mechanisms have been postulated to contribute to this complex interaction between brain and heart, including damage from gut dysbiosis, immune and systematic inflammatory responses, microvesicle- and microRNA-mediated vascular injury and damage from a surge of catecholamines. All these cerebrovascular diseases may trigger pronounced catecholamine surges through diverse ways, including stimulation of hypothalamic-pituitary adrenal axis, dysregulation of autonomic system, and secretion of adrenocorticotropic hormone. Primary catecholamines involved in this pathophysiological response include norepinephrine (NE) and epinephrine. Both are important neurotransmitters that connect the nervous system with the heart, leading to cardiac damage via myocardial ischemia, calcium (Ca2+) overload, oxidative stress, and mitochondrial dysfunction. In this review, we will aim to summarize the molecular mechanisms behind catecholamine-induced cardiotoxicity including Ca2+ overload, oxidative stress, apoptosis, cardiac hypertrophy, interstitial fibrosis, and inflammation. In addition, we will focus on how synchronization among these pathways evokes cardiotoxicity.
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Affiliation(s)
- Yuxin Du
- Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital Fudan University, Shanghai 200032, China
| | - Laurie J Demillard
- School of Pharmacy, University of Wyoming College of Health Sciences, Laramie, WY 82071, USA
| | - Jun Ren
- Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital Fudan University, Shanghai 200032, China; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98195, USA.
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Guo HH, Jing XY, Chen H, Xu HX, Zhu BM. STAT3 but Not STAT5 Contributes to the Protective Effect of Electroacupuncture Against Myocardial Ischemia/Reperfusion Injury in Mice. Front Med (Lausanne) 2021; 8:649654. [PMID: 34307396 PMCID: PMC8299366 DOI: 10.3389/fmed.2021.649654] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Accepted: 05/13/2021] [Indexed: 02/05/2023] Open
Abstract
Electroacupuncture (EA) can help reduce infarct size and injury resulting from myocardial ischemia/reperfusion (I/R); however, the underlying molecular mechanism remains unknown. We previously reported that STAT5 plays a critical role in the cardioprotective effect of remote ischemic preconditioning (RIPC). Here, we assessed the effects of electroacupuncture pretreatment (EAP) on myocardial I/R injury in the presence and/or absence of Stat5 in mice and investigated whether EAP exerts its cardioprotective effects in a STAT5-dependent manner. Adult Stat5fl/fl and Stat5-cKO mice were exposed to EAP at Neiguan (PC6) for 7 days before the induction of I/R injury by left anterior descending (LAD) coronary artery ligation. The myocardial infarct size (IS), area at risk, and apoptotic rate of cardiomyocytes were detected. RT-qPCR and western blotting were used to measure gene and protein expression, respectively, in homogenized heart tissues. RNA-seq was used to identify candidate genes and pathways. Our results showed that EAP decreased IS and the rate of cardiomyocyte apoptosis. We further found that STAT5 was activated by EAP in Stat5fl/fl mice but not in Stat5-cKO mice, whereas the opposite was observed for STAT3. Following EAP, the levels of the antiapoptotic proteins Bcl-xL, Bcl-2, and p-AKT were increased in the presence of Stat5, while that of interleukin 10 (IL-10) was increased in both Stat5fl/fl and Stat5-cKO. The gene expression profile in heart tissues was different between Stat5fl/fl and the Stat5-cKO mice with EAP. Importantly, the top 30 DEGs under EAP in the Stat5-cKO mice were enriched in the IL-6/STAT3 signaling pathway. Our results revealed for the first time that the protective effect of EAP following myocardial I/R injury was attributable to, but not dependent on, STAT5. Additionally, we found that EAP could activate STAT3 signaling in the absence of the Stat5 gene, and could also activate antiapoptotic, survival, and anti-inflammatory signaling pathways.
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Affiliation(s)
- Hui-Hui Guo
- Key Laboratory of Acupuncture and Medicine Research of Ministry of Education, Nanjing University of Chinese Medicine, Nanjing, China
| | - Xin-Yue Jing
- Key Laboratory of Acupuncture and Medicine Research of Ministry of Education, Nanjing University of Chinese Medicine, Nanjing, China
| | - Hui Chen
- Rehabilitation Medicine Department, YE DA Hospital of Yantai, Yantai, China
| | - Hou-Xi Xu
- Key Laboratory of Acupuncture and Medicine Research of Ministry of Education, Nanjing University of Chinese Medicine, Nanjing, China
| | - Bing-Mei Zhu
- Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, China
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11
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Chen X, Jiang X, Cheng C, Chen J, Huang S, Xu M, Liu S. Berberine Attenuates Cardiac Hypertrophy Through Inhibition of mTOR Signaling Pathway. Cardiovasc Drugs Ther 2020; 34:463-473. [PMID: 32394178 DOI: 10.1007/s10557-020-06977-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
PURPOSE Berberine was reported to exert beneficial effects on cardiac hypertrophy. However, its cellular and molecular mechanisms still remained unclear. METHODS Cardiac hypertrophy was induced in male Sprague-Dawley (SD) rats by transverse aorta constriction (TAC), with or without 6-week treatment of berberine. Echocardiography was performed to evaluate cardiac function. Rats were then sacrificed for histological assay, with detection for proteins and mRNA. H9c2 cells were pretreated with berberine of different concentrations (0, 1 μM, and 10 μM), followed by treatment with 2 μM norepinephrine (NE). Cells of different groups were measured for cell surface area, with mRNA detected by qRT-PCR and proteins by western blot. RESULTS Compared with the sham group, rats of the TAC group showed significantly increased cardiac hypertrophy and fibrosis, which could be ameliorated by treatment with berberine. Western blot showed that mammalian target of rapamycin (mTOR) signaling-related protein expressions, including phospho-mTOR, phospho-4EBP1, and phospho-p70 S6K (Thr389), but not phospho-p70 S6K (Ser371), were significantly increased in the TAC group, which were inhibited by berberine treatment. H9c2 cells were treated with NE to induce hypertrophy with increased cell surface area and mRNA expressions of anp and bnp. Berberine of 10 μM, but not 1 μM, significantly ameliorated NE-induced hypertrophy and inhibited protein expressions of mTOR signaling pathway similar to those in the rat model. CONCLUSIONS Berberine can exert cardioprotective effects on both pressure-overloaded cardiac hypertrophy and failure in vivo and NE-induced hypertrophy in vitro. Our results suggest berberine could be a potential treatment for patients with cardiac hypertrophy and failure.
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Affiliation(s)
- Xing Chen
- Department of Geriatrics, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510260, China.,Guangzhou Institute of Cardiovascular Disease, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510260, China
| | - Xingzuan Jiang
- Department of Geriatrics, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510260, China
| | - Chuanfang Cheng
- Guangzhou Institute of Cardiovascular Disease, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510260, China
| | - Jing Chen
- Guangzhou Institute of Cardiovascular Disease, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510260, China
| | - Shuyan Huang
- Department of Geriatrics, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510260, China
| | - Miqing Xu
- Department of Geriatrics, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510260, China.
| | - Shiming Liu
- Guangzhou Institute of Cardiovascular Disease, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510260, China.
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12
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Borovac JA, D'Amario D, Bozic J, Glavas D. Sympathetic nervous system activation and heart failure: Current state of evidence and the pathophysiology in the light of novel biomarkers. World J Cardiol 2020; 12:373-408. [PMID: 32879702 PMCID: PMC7439452 DOI: 10.4330/wjc.v12.i8.373] [Citation(s) in RCA: 74] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2020] [Revised: 05/19/2020] [Accepted: 07/19/2020] [Indexed: 02/06/2023] Open
Abstract
Heart failure (HF) is a complex clinical syndrome characterized by the activation of at least several neurohumoral pathways that have a common role in maintaining cardiac output and adequate perfusion pressure of target organs and tissues. The sympathetic nervous system (SNS) is upregulated in HF as evident in dysfunctional baroreceptor and chemoreceptor reflexes, circulating and neuronal catecholamine spillover, attenuated parasympathetic response, and augmented sympathetic outflow to the heart, kidneys and skeletal muscles. When these sympathoexcitatory effects on the cardiovascular system are sustained chronically they initiate the vicious circle of HF progression and become associated with cardiomyocyte apoptosis, maladaptive ventricular and vascular remodeling, arrhythmogenesis, and poor prognosis in patients with HF. These detrimental effects of SNS activity on outcomes in HF warrant adequate diagnostic and treatment modalities. Therefore, this review summarizes basic physiological concepts about the interaction of SNS with the cardiovascular system and highlights key pathophysiological mechanisms of SNS derangement in HF. Finally, special emphasis in this review is placed on the integrative and up-to-date overview of diagnostic modalities such as SNS imaging methods and novel laboratory biomarkers that could aid in the assessment of the degree of SNS activation and provide reliable prognostic information among patients with HF.
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Affiliation(s)
- Josip Anđelo Borovac
- Department of Pathophysiology, University of Split School of Medicine, Split 21000, Croatia
- Working Group on Heart Failure of Croatian Cardiac Society, Zagreb 10000, Croatia
| | - Domenico D'Amario
- Department of Cardiovascular and Thoracic Sciences, IRCCS Fondazione Policlinico A. Gemelli, Universita Cattolica Sacro Cuore, Rome 00168, Italy
| | - Josko Bozic
- Department of Pathophysiology, University of Split School of Medicine, Split 21000, Croatia
| | - Duska Glavas
- Working Group on Heart Failure of Croatian Cardiac Society, Zagreb 10000, Croatia
- Clinic for Cardiovascular Diseases, University Hospital of Split, Split 21000, Croatia
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13
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Borovac JA, Glavas D, Susilovic Grabovac Z, Supe Domic D, Stanisic L, D'Amario D, Kwok CS, Bozic J. Circulating sST2 and catestatin levels in patients with acute worsening of heart failure: a report from the CATSTAT-HF study. ESC Heart Fail 2020; 7:2818-2828. [PMID: 32681700 PMCID: PMC7524138 DOI: 10.1002/ehf2.12882] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2020] [Revised: 06/07/2020] [Accepted: 06/17/2020] [Indexed: 02/06/2023] Open
Abstract
AIMS Soluble suppression of tumourigenicity 2 (sST2) and catestatin (CST) reflect myocardial fibrosis and sympathetic overactivity during the acute worsening of heart failure (AWHF). We aimed to determine serum levels and associations of sST2 and CST with in-hospital death as well as the association between sST2 and CST among AWHF patients. METHODS AND RESULTS A total of 96 AWHF patients were consecutively enrolled, while levels of sST2 and CST were determined and compared between non-survivors and survivors. Predictive values of sST2 and CST for in-hospital death were determined by the penalized multivariable Firth logistic regression. The diagnostic ability of sST2 and CST for in-hospital death was assessed by the receiver operating characteristic analysis and examined with respect to the N-terminal pro-brain natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin I, and C-reactive protein. The in-hospital death rate was 6.25%. Serum sST2 and CST levels were significantly higher among non-survivors than survivors [146.6 (inter-quartile range, IQR 65.9-156.2) vs. 35.3 (IQR 20.6-64.4) ng/mL, P < 0.001, and 19.8 (IQR 9.9-28.0) vs. 5.6 (IQR 3.4-9.8) ng/mL, P < 0.001, respectively]. Both sST2 and CST were independent predictors of in-hospital death [Firth coefficient (FC) 6.00, 95% confidence interval (CI), 1.48-15.20, P = 0.005, and FC 6.58, 95% CI 1.66-21.78, P = 0.003, respectively], while NT-proBNP was not a significant predictor (FC 1.57, 95% CI 0.51-3.99, P = 0.142). In classifying non-survivors from survivors, sST2 provided area under the curve (AUC) of 0.917 (95% CI 0.819-1.000, P < 0.001) followed by CST (AUC 0.905, 95% CI 0.792-1.000, P < 0.001), while NT-proBNP yielded AUC of 0.735 (95% CI 0.516-0.954, P = 0.036). High-sensitivity cardiac troponin I and C-reactive protein were not found as significant classifiers of in-hospital death (AUC 0.719, 95% CI 0.509-0.930, P = 0.075, and AUC 0.682, 95% CI 0.541-0.822, P = 0.164, respectively). Among survivors, those with sST2 serum levels ≥35 ng/mL had significantly higher CST levels, compared with those with sST2 < 35 ng/mL (9.05 ± 5.17 vs. 5.06 ± 2.76 ng/mL, P < 0.001). Serum sST2 levels positively and independently correlated with CST levels in the whole patient cohort (β = 0.437, P < 0.001). CONCLUSIONS Elevated sST2 and CST levels, reflecting two distinct pathophysiological pathways in heart failure, might indicate impending clinical deterioration among AWHF patients during hospitalization and facilitate prognosis beyond traditional biomarkers regarding the risk of in-hospital death (CATSTAT-HF ClinicalTrials.gov Number NCT03389386).
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Affiliation(s)
- Josip A Borovac
- Department of Pathophysiology, University of Split School of Medicine, Soltanska 2, Split, 21000, Croatia.,Institute of Emergency Medicine of Split-Dalmatia County, Split, Croatia.,Clinic for Cardiovascular Diseases, University Hospital of Split, Split, Croatia
| | - Duska Glavas
- Clinic for Cardiovascular Diseases, University Hospital of Split, Split, Croatia.,Department of Internal Medicine, University of Split School of Medicine, Split, Croatia
| | | | - Daniela Supe Domic
- Department of Medical Laboratory Diagnostics, University Hospital of Split, Split, Croatia.,Department of Health Studies, University of Split, Split, Croatia
| | - Lada Stanisic
- Department of Medical Laboratory Diagnostics, University Hospital of Split, Split, Croatia
| | - Domenico D'Amario
- Department of Cardiovascular and Thoracic Sciences, IRCCS Fondazione Policlinico A. Gemelli, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Chun S Kwok
- University Hospitals of North Midlands Royal Stoke University Hospital, Stoke-on-Trent, UK
| | - Josko Bozic
- Department of Pathophysiology, University of Split School of Medicine, Soltanska 2, Split, 21000, Croatia
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14
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Zivkovic PM, Matetic A, Tadin Hadjina I, Rusic D, Vilovic M, Supe-Domic D, Borovac JA, Mudnic I, Tonkic A, Bozic J. Serum Catestatin Levels and Arterial Stiffness Parameters Are Increased in Patients with Inflammatory Bowel Disease. J Clin Med 2020; 9:jcm9030628. [PMID: 32110996 PMCID: PMC7141110 DOI: 10.3390/jcm9030628] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Revised: 02/18/2020] [Accepted: 02/25/2020] [Indexed: 12/12/2022] Open
Abstract
Catestatin (CST) is an important peptide in the pathophysiology of chronic inflammatory disorders. However, clinical studies on inflammatory bowel disease (IBD) patients are lacking. Our goal was to investigate CST concentrations in IBD patients compared to healthy subjects. Additionally, we aimed to determine arterial stiffness parameters in relation to CST. This cross-sectional study compared 80 IBD patients (45 Crohn's disease (CD) and 35 ulcerative colitis (UC) patients) with 75 control subjects. Serum CST levels were significantly higher in the IBD group compared to control subjects (11.29 ± 9.14 vs. 7.13 ± 6.08 ng/mL, p = 0.001) and in the UC group compared to CD patients (13.50 ± 9.58 vs. 9.03 ± 6.92 ng/mL, p = 0.021), irrespective of age and BMI. IBD patients exhibited significantly higher values of heart rate adjusted central augmentation index (cAIx-75) (14.88 ± 10.59 vs. 6.87 ± 9.50 %, p < 0.001) and pulse wave velocity (PWV) (8.06 ± 3.23 vs. 6.42 ± 1.47 m/s, p < 0.001) compared to control group. Furthermore, PWV was the only significant independent correlate of CST (B = 1.20, t = 4.15, p < 0.001), while CST, PWV, cAIx-75, high-sensitivity C-reactive protein and BMI were significant predictors of positive IBD status (1.089 (1.022-1.161), 1.515 (1.166-1.968), 1.060 (1.024-1.097), 1.458 (1.116-1.906), 0.793 (0.683-0.920), respectively). Serum CST levels were significantly higher in IBD patients compared to controls and an independent positive correlation of CST with PWV existed. Therefore, it is possible that CST could have a role in the complex pathophysiology of IBD and its cardiovascular complications.
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Affiliation(s)
- Piero Marin Zivkovic
- Department of Gastroenterology, University Hospital of Split, 21000 Split, Croatia; (P.M.Z.); (I.T.H.); (A.T.)
- Department of Pathophysiology, University of Split School of Medicine, 21000 Split, Croatia; (A.M.); (M.V.); (J.A.B.)
| | - Andrija Matetic
- Department of Pathophysiology, University of Split School of Medicine, 21000 Split, Croatia; (A.M.); (M.V.); (J.A.B.)
- Department of Cardiology, University Hospital of Split, 21000 Split, Croatia
| | - Ivana Tadin Hadjina
- Department of Gastroenterology, University Hospital of Split, 21000 Split, Croatia; (P.M.Z.); (I.T.H.); (A.T.)
| | - Doris Rusic
- Department of Pharmacy, University of Split School of Medicine, 21000 Split, Croatia;
| | - Marino Vilovic
- Department of Pathophysiology, University of Split School of Medicine, 21000 Split, Croatia; (A.M.); (M.V.); (J.A.B.)
| | - Daniela Supe-Domic
- Department of Medical Laboratory Diagnostics, University Hospital of Split, 21000 Split, Croatia;
- Department of Health Studies, University of Split, 21000 Split, Croatia
| | - Josip Andelo Borovac
- Department of Pathophysiology, University of Split School of Medicine, 21000 Split, Croatia; (A.M.); (M.V.); (J.A.B.)
| | - Ivana Mudnic
- Department of Pharmacology, University of Split School of Medicine, 21000 Split, Croatia;
| | - Ante Tonkic
- Department of Gastroenterology, University Hospital of Split, 21000 Split, Croatia; (P.M.Z.); (I.T.H.); (A.T.)
- Department of Internal Medicine, University of Split School of Medicine, 21000 Split, Croatia
| | - Josko Bozic
- Department of Pathophysiology, University of Split School of Medicine, 21000 Split, Croatia; (A.M.); (M.V.); (J.A.B.)
- Correspondence: ; Tel.: +385-21-557-871; Fax: +385-21-557-905
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