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Review of Cardiac Fibrosis: Recent Advances and Future Directions
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Review of Cardiac Fibrosis: Recent Advances and Future Directions

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 November 2022) | Viewed by 28167

Special Issue Editor

Prof. Dr. Ryuji Okamoto

E-Mail Website
Guest Editor
Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan
Interests: natriuretic peptide; cardiorenal syndrome; vasopressor; vasodilator; kidney; medulla; renin-angiotensin-aldosterone system

Special Issue Information

Dear Colleagues,

Fibrosis is a common pathway to organ injury and failure. The existence of cardiac fibrosis is associated with poor prognosis in cardiomyopathy, hypertension, heart failure, and coronary artery disease. Furthermore, cardiac fibrosis can be a platform of lethal and/or incessant arrythmia. Therefore, regular evaluation and follow-up of cardiac fibrosis are important in symptomatic and even asymptomatic patients. Cardiac fibrosis includes interstitial fibrosis, perivascular fibrosis, and necrotic scar. Each process is determined by the settings of inflammatory cells, cardiomyocytes, endothelial cells, fibroblasts and myofibroblasts, collagen, and the extracellular matrix. We hope to review the present knowledge of cardiac fibrosis in terms of molecular mechanisms, clinical evaluation, and present and future therapy, which can bind basic and clinical researchers together.

Dr. Ryuji Okamoto
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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Keywords

  • arrhythmia
  • cardiac imaging
  • cardiomyopathy
  • coronary artery disease
  • extracellular matrix
  • fibrosis
  • heart failure
  • molecular mechanism

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Published Papers (7 papers)

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Editorial

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2 pages, 150 KiB  
Editorial
Cardiac Fibrosis: Chronic Inflammatory Disease and Promising Therapeutic Target
by Ryuji Okamoto
Int. J. Mol. Sci. 2022, 23(15), 8074; https://doi.org/10.3390/ijms23158074 - 22 Jul 2022
Viewed by 1294
Abstract
A better understanding on the cause, pathophysiologic mechanisms and potential new treatments of cardiac fibrosis is one of the main issues in the management of cardiac hypertrophy, heart failure and lethal arrhythmia [...] Full article
(This article belongs to the Special Issue Review of Cardiac Fibrosis: Recent Advances and Future Directions)

Research

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12 pages, 1374 KiB  
Article
Serum-Induced Expression of Brain Natriuretic Peptide Contributes to Its Increase in Patients with HFpEF
by Ryuji Okamoto, Ryotaro Hashizume, Noboru Suzuki, Rie Ito, Tomoko Tokuhara, Hiroshi Fujiwara, Ye Zhe, Hiromasa Ito, Takaya Abe and Kaoru Dohi
Int. J. Mol. Sci. 2022, 23(6), 2991; https://doi.org/10.3390/ijms23062991 - 10 Mar 2022
Cited by 1 | Viewed by 2303
Abstract
Brain natriuretic peptide (BNP) levels are increased in both patients with heart failure with preserved (HFpEF) and reduced ejection fraction (HFrEF), but the reasons for this remain unclear. Our purpose was to examine whether serum-induced BNP (iBNP) expression partly contributes to increased BNP [...] Read more.
Brain natriuretic peptide (BNP) levels are increased in both patients with heart failure with preserved (HFpEF) and reduced ejection fraction (HFrEF), but the reasons for this remain unclear. Our purpose was to examine whether serum-induced BNP (iBNP) expression partly contributes to increased BNP in patients with HFpEF. BNP reporter cardiomyocytes from pBNP-luc-KI mice were stimulated with serum from patients with HFpEF or HFrEF (n = 114 and n = 82, respectively). Luciferase activity was examined as iBNP and the iBNP-to-BNP ratio was evaluated. Patient characteristics and clinical parameters were compared, and multivariate regression analysis was performed to determine independent predictors of the iBNP-to-BNP ratio. Female sex and frequencies of atrial fibrillation, hypertension and the use of a calcium channel blocker (CCB) were higher in HFpEF. The iBNP-to-BNP ratio was significantly higher in HFpEF (26.9) than in HFrEF (16.1, p < 0.001). Multivariate regression analysis identified the existence of HFpEF as an independent predictor of the iBNP-to-BNP ratio after adjusting for all other measurements (β = 0.154, p = 0.032). Age, hemoglobin, CCB usage and deceleration time were also independent predictors (β = 0.167, p = 0.025; β = 0.203, p = 0.006; β = 0.138, p = 0.049; and β = 0.143, p = 0.049, respectively). These results indicate that the elevated BNP in patients with HFpEF is partly due to iBNP from the heart. Full article
(This article belongs to the Special Issue Review of Cardiac Fibrosis: Recent Advances and Future Directions)
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28 pages, 24259 KiB  
Article
Investigation of the Antiremodeling Effects of Losartan, Mirabegron and Their Combination on the Development of Doxorubicin-Induced Chronic Cardiotoxicity in a Rat Model
by Marah Freiwan, Mónika G. Kovács, Zsuzsanna Z. A. Kovács, Gergő Szűcs, Hoa Dinh, Réka Losonczi, Andrea Siska, András Kriston, Ferenc Kovács, Péter Horváth, Imre Földesi, Gábor Cserni, László Dux, Tamás Csont and Márta Sárközy
Int. J. Mol. Sci. 2022, 23(4), 2201; https://doi.org/10.3390/ijms23042201 - 16 Feb 2022
Cited by 11 | Viewed by 4168
Abstract
Despite the effectiveness of doxorubicin (DOXO) as a chemotherapeutic agent, dose-dependent development of chronic cardiotoxicity limits its application. The angiotensin-II receptor blocker losartan is commonly used to treat cardiac remodeling of various etiologies. The beta-3 adrenergic receptor agonist mirabegron was reported to improve [...] Read more.
Despite the effectiveness of doxorubicin (DOXO) as a chemotherapeutic agent, dose-dependent development of chronic cardiotoxicity limits its application. The angiotensin-II receptor blocker losartan is commonly used to treat cardiac remodeling of various etiologies. The beta-3 adrenergic receptor agonist mirabegron was reported to improve chronic heart failure. Here we investigated the effects of losartan, mirabegron and their combination on the development of DOXO-induced chronic cardiotoxicity. Male Wistar rats were divided into five groups: (i) control; (ii) DOXO-only; (iii) losartan-treated DOXO; (iv) mirabegron-treated DOXO; (v) losartan plus mirabegron-treated DOXO groups. The treatments started 5 weeks after DOXO administration. At week 8, echocardiography was performed. At week 9, left ventricles were prepared for histology, qRT-PCR, and Western blot measurements. Losartan improved diastolic but not systolic dysfunction and ameliorated SERCA2a repression in our DOXO-induced cardiotoxicity model. The DOXO-induced overexpression of Il1 and Il6 was markedly decreased by losartan and mirabegron. Mirabegron and the combination treatment improved systolic and diastolic dysfunction and significantly decreased overexpression of Smad2 and Smad3 in our DOXO-induced cardiotoxicity model. Only mirabegron reduced DOXO-induced cardiac fibrosis significantly. Mirabegron and its combination with losartan seem to be promising therapeutic tools against DOXO-induced chronic cardiotoxicity. Full article
(This article belongs to the Special Issue Review of Cardiac Fibrosis: Recent Advances and Future Directions)
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16 pages, 8698 KiB  
Article
P300/CBP-Associated Factor Activates Cardiac Fibroblasts by SMAD2 Acetylation
by Yongwoon Lim, Anna Jeong, Duk-Hwa Kwon, Yeong-Un Lee, Young-Kook Kim, Youngkeun Ahn, Taewon Kook, Woo-Jin Park and Hyun Kook
Int. J. Mol. Sci. 2021, 22(18), 9944; https://doi.org/10.3390/ijms22189944 - 14 Sep 2021
Cited by 12 | Viewed by 3445
Abstract
Various heart diseases cause cardiac remodeling, which in turn leads to ineffective contraction. Although it is an adaptive response to injury, cardiac fibrosis contributes to this remodeling, for which the reactivation of quiescent myofibroblasts is a key feature. In the present study, we [...] Read more.
Various heart diseases cause cardiac remodeling, which in turn leads to ineffective contraction. Although it is an adaptive response to injury, cardiac fibrosis contributes to this remodeling, for which the reactivation of quiescent myofibroblasts is a key feature. In the present study, we investigated the role of the p300/CBP-associated factor (PCAF), a histone acetyltransferase, in the activation of cardiac fibroblasts. An intraperitoneal (i.p.) injection of a high dose (160 mg/kg) of isoproterenol (ISP) induced cardiac fibrosis and reduced the amount of the PCAF in cardiac fibroblasts in the mouse heart. However, the PCAF activity was significantly increased in cardiac fibroblasts, but not in cardiomyocytes, obtained from ISP-administered mice. An in vitro study using human cardiac fibroblast cells recapitulated the in vivo results; an treatment with transforming growth factor-β1 (TGF-β1) reduced the PCAF, whereas it activated the PCAF in the fibroblasts. PCAF siRNA attenuated the TGF-β1-induced increase in and translocation of fibrosis marker proteins. PCAF siRNA blocked TGF-β1-mediated gel contraction and cell migration. The PCAF directly interacted with and acetylated mothers against decapentaplegic homolog 2 (SMAD2). PCAF siRNA prevented TGF-β1-induced phosphorylation and the nuclear localization of SMAD2. These results suggest that the increase in PCAF activity during cardiac fibrosis may participate in SMAD2 acetylation and thereby in its activation. Full article
(This article belongs to the Special Issue Review of Cardiac Fibrosis: Recent Advances and Future Directions)
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Review

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23 pages, 1904 KiB  
Review
Unveiling the Multifaceted Problems Associated with Dysrhythmia
by Adrianna Witczyńska, Aidas Alaburda, Grzegorz Grześk, Jacek Nowaczyk and Alicja Nowaczyk
Int. J. Mol. Sci. 2024, 25(1), 263; https://doi.org/10.3390/ijms25010263 - 23 Dec 2023
Viewed by 1676
Abstract
Dysrhythmia is a term referring to the occurrence of spontaneous and repetitive changes in potentials with parameters deviating from those considered normal. The term refers to heart anomalies but has a broader meaning. Dysrhythmias may concern the heart, neurological system, digestive system, and [...] Read more.
Dysrhythmia is a term referring to the occurrence of spontaneous and repetitive changes in potentials with parameters deviating from those considered normal. The term refers to heart anomalies but has a broader meaning. Dysrhythmias may concern the heart, neurological system, digestive system, and sensory organs. Ion currents conducted through ion channels are a universal phenomenon. The occurrence of channel abnormalities will therefore result in disorders with clinical manifestations depending on the affected tissue, but phenomena from other tissues and organs may also manifest themselves. A similar problem concerns the implementation of pharmacotherapy, the mechanism of which is related to the impact on various ion currents. Treatment in this case may cause unfavorable effects on other tissues and organs. Drugs acting through the modulation of ion currents are characterized by relatively low tissue specificity. To assess a therapy’s efficacy and safety, the risk of occurrences in other tissues with similar mechanisms of action must be considered. In the present review, the focus is shifted prominently onto a comparison of abnormal electrical activity within different tissues and organs. This review includes an overview of the types of dysrhythmias and the basic techniques of clinical examination of electrophysiological disorders. It also presents a concise overview of the available pharmacotherapy in particular diseases. In addition, the authors review the relevant ion channels and their research technique based on patch clumping. Full article
(This article belongs to the Special Issue Review of Cardiac Fibrosis: Recent Advances and Future Directions)
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19 pages, 772 KiB  
Review
A New Hypothetical Concept in Metabolic Understanding of Cardiac Fibrosis: Glycolysis Combined with TGF-β and KLF5 Signaling
by Thanachai Methatham, Ryozo Nagai and Kenichi Aizawa
Int. J. Mol. Sci. 2022, 23(8), 4302; https://doi.org/10.3390/ijms23084302 - 13 Apr 2022
Cited by 6 | Viewed by 3496
Abstract
The accumulation of fibrosis in cardiac tissues is one of the leading causes of heart failure. The principal cellular effectors in cardiac fibrosis are activated fibroblasts and myofibroblasts, which serve as the primary source of matrix proteins. TGF-β signaling pathways play a prominent [...] Read more.
The accumulation of fibrosis in cardiac tissues is one of the leading causes of heart failure. The principal cellular effectors in cardiac fibrosis are activated fibroblasts and myofibroblasts, which serve as the primary source of matrix proteins. TGF-β signaling pathways play a prominent role in cardiac fibrosis. The control of TGF-β by KLF5 in cardiac fibrosis has been demonstrated for modulating cardiovascular remodeling. Since the expression of KLF5 is reduced, the accumulation of fibrosis diminishes. Because the molecular mechanism of fibrosis is still being explored, there are currently few options for effectively reducing or reversing it. Studying metabolic alterations is considered an essential process that supports the explanation of fibrosis in a variety of organs and especially the glycolysis alteration in the heart. However, the interplay among the main factors involved in fibrosis pathogenesis, namely TGF-β, KLF5, and the metabolic process in glycolysis, is still indistinct. In this review, we explain what we know about cardiac fibroblasts and how they could help with heart repair. Moreover, we hypothesize and summarize the knowledge trend on the molecular mechanism of TGF-β, KLF5, the role of the glycolysis pathway in fibrosis, and present the future therapy of cardiac fibrosis. These studies may target therapies that could become important strategies for fibrosis reduction in the future. Full article
(This article belongs to the Special Issue Review of Cardiac Fibrosis: Recent Advances and Future Directions)
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21 pages, 2410 KiB  
Review
The Pathogenesis of Cardiac Fibrosis: A Review of Recent Progress
by Kazuaki Maruyama and Kyoko Imanaka-Yoshida
Int. J. Mol. Sci. 2022, 23(5), 2617; https://doi.org/10.3390/ijms23052617 - 27 Feb 2022
Cited by 83 | Viewed by 10559
Abstract
Fibrosis is defined as the excessive deposition of extracellular matrix (ECM) proteins in the interstitium. It is an essential pathological response to chronic inflammation. ECM protein deposition is initially protective and is critical for wound healing and tissue regeneration. However, pathological cardiac remodeling [...] Read more.
Fibrosis is defined as the excessive deposition of extracellular matrix (ECM) proteins in the interstitium. It is an essential pathological response to chronic inflammation. ECM protein deposition is initially protective and is critical for wound healing and tissue regeneration. However, pathological cardiac remodeling in excessive and continuous tissue damage with subsequent ECM deposition results in a distorted organ architecture and significantly impacts cardiac function. In this review, we summarized and discussed the histologic features of cardiac fibrosis with the signaling factors that control it. We evaluated the origin and characteristic markers of cardiac fibroblasts. We also discussed lymphatic vessels, which have become more important in recent years to improve cardiac fibrosis. Full article
(This article belongs to the Special Issue Review of Cardiac Fibrosis: Recent Advances and Future Directions)
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