|
 
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| REVIEW ARTICLE |
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| Year : 2023 | Volume
: 9
| Issue : 1 | Page : 24-36 |
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A narrative review on serum biomarkers of cardiac fibrosis
Santoshi Kumari1, Urvashi Sharma2, Deepika Jindal1, Traymbak Basak3
1 Department of Cardiology, AIIMS, Delhi, India
2 Department of Pathology, AIIMS, Delhi, India
3 Department of Biosciences and Bioengineering, IIT Mandi, Himanchal Pradesh, India
| Date of Submission | 28-Feb-2023 |
| Date of Decision | 20-Mar-2023 |
| Date of Acceptance | 24-Mar-2023 |
| Date of Web Publication | 04-May-2023 |
Correspondence Address:
Santoshi Kumari
Ph.D Scholar, Department of Cardiology, AIIMS, Delhi
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/jpcs.jpcs_19_23
Myocardial fibrosis is the excessive deposition of extracellular matrix (ECM) proteins in the cardiac interstitium leading to pathological conditions of the heart. The objective is to understand the pathophysiology of cardiac fibrosis and the quest for serum biomarkers that will assist in early diagnosis before the occurrence of major cardiac events. There are many serum biomarkers that get elevated highlighting ECM remodeling during cardiac fibrosis. Lysyl oxidase like -2 is one such ECM protein, plays a crucial role in the up-regulation of TGF - β, the transformation of cardiac fibroblast to myoblast, the migration of collagen, and cross-linking of collagen and elastin. However, assessment of lysyl oxidase like-2 (LOXL-2) in different pathologically driven cardiac fibrosis is limited. Also, none of the serum biomarkers has proved to be the most accurate diagnostic tool for assessing fibrosis independently; hence, meticulous, less invasive, and cost-effective serum biomarkers need to be scrutinized. Hence lysyl oxidase Like-2 (LOXL-2) in combination with other serum biomarkers like PICP/PINP/TIMP-1/ST-2, or Galectin-3 can be combined to assess the presence of fibrosis in the heart. This review includes the journal, articles, and research paper on cardiac fibrosis which was published in the last 10–15 years to highlight the huge gap in the treatment of cardiac fibrosis and the need for a new combination of biomarkers with better prognostic and diagnostic value.
Keywords: Cardiac fibrosis, lysyl oxidase like-2, transforming growth factor-β
How to cite this article:
Kumari S, Sharma U, Jindal D, Basak T. A narrative review on serum biomarkers of cardiac fibrosis. J Pract Cardiovasc Sci 2023;9:24-36 |
How to cite this URL:
Kumari S, Sharma U, Jindal D, Basak T. A narrative review on serum biomarkers of cardiac fibrosis. J Pract Cardiovasc Sci [serial online] 2023 [cited 2023 Jun 4];9:24-36. Available from: https://www.j-pcs.org/text.asp?2023/9/1/24/375806 |
| Introduction | |  |
Myocardial fibrosis (MF) is a wide-ranging health problem associated with nearly all forms of cardiovascular disease.[1] Fibrosis is a well-recognized cause of morbidity and mortality, which causes more than 800,000 deaths worldwide annually, whereof the majority account for lung and cardiac fibrosis.[2] Heart disease claims to be 60% of the global burden, whereas South Asian countries contribute a quarter of the world population. South Asians are at increased risk of heart failure (HF) at earlier ages than in most other racial/ethnic groups. Deposition of an extracellular matrix (ECM) leading to HF has emerged as the prime hallmark of fibrosis.
ECM deposition during the fibrotic response in a tissue is a protective mechanism and is beneficial for wound healing and tissue regeneration.[3] Cardiac extracellular matrix is a complex meshwork of glycoproteins that is further subdivided into proteoglycans and glycosaminoglycans.[4] Cardiac fibroblasts (CFs) are generally responsible for the production of ECM components and maintaining their homeostasis. On insult, these fibroblast cells transform into a myofibroblast phenotype and contribute to excessive synthesis and deposition of collagens and other ECM proteins. Cardiac fibrosis is caused due to dysregulation of ECM production and degradation, which results in the excessive accumulation of ECM proteins, particularly collagens. The scarred fibroblasts, due to pathological deposition of ECM, stiffen and impair structural and electrical conductance.[4],[5] The transformation of CFs to myofibroblasts is a core cellular event involved in the fibrotic response under cardiac injury.[6] Cardiac myofibroblasts, a contractile and secretory cell type, play a significant part in matrix remodeling regulation by producing proteases such as matrix metalloproteinases (MMPs) and their inhibitors.[3],[4] They also contribute to the structure of ECM proteins in fibrotic hearts.[3] Apart from CFs, macrophages/monocytes, mast cells, lymphocytes, cardiomyocytes, and vascular cells can also play vital roles in the fibrotic response through the secretion of a variety of fibrogenic mediators such as matricellular proteins and growth factors.[6]
MF is a common end point in various diseases such as ischemic heart disease, congestive HF, valvular heart disease, inherited cardiomyopathy mutations, injury, aging, hypertension (HTN), and diabetes.[5],[7] This remodeling involves pathological changes that include chamber dilation, cardiomyocyte hypertrophy, and apoptosis, ultimately leading to the progression of HF.[7] Most pediatric congestive HFs are caused due to Endo MF (EMF).[8] MF mainly involves the apical endocardium and right and left ventricles. Hypereosinophilia, autoimmunity, infections, genetic factors, and nutritional deficiencies could be the potential factors causing EMF.[8]
Endomyocardial biopsy echocardiography (ECHO) and cardiac magnetic resonance (CMR) magnetic resonance imaging (MRI) are the diagnostic measures to assess heart structure and function. These have their limitations, such as the inability to measure and monitor the degree and progression of MF. Despite many ill effects of cardiac fibrosis, it has remained one of the relatively mischaracterized and poorly understood pathophysiological processes. Further, the lack of promising diagnostic tools and limited clinical interventions for cardiac fibrosis also leads to a detrimental and pathological effect on the heart, contributing to HF progression. Therefore, affordable biomarkers should be considered a method for detecting fibrosis which could be more convenient in terms of comfort, cost, and accessibility. This review targets to focus on the new serum biomarkers of MF with the objective of accessibility, availability, and accuracy.
| Types of Fibrosis | | |
Cardiac fibrosis is seen in almost all types of heart disease, including myocardial infarction, HTN, hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and aortic stenosis.[5] Three types of MF have been identified: replacement fibrosis, reactive interstitial fibrosis, and infiltrative interstitial fibrosis.[9] Replacement fibrosis occurs after a cardiac injury like myocardial infarction, where cardiac dead cells are replaced predominantly by collagen type I.[5] Reactive interstitial fibrosis causes a pressure overload and cardiomyopathies due to an increased deposition of ECM without a significant loss of cardiomyocytes.[7] In infiltrative interstitial fibrosis, the glycolipid builds up in different cells of the heart,[7],[10] which is seen in Anderson–Fabry disease, a rare genetic disease that involves dysfunctional metabolism of sphingolipids.
On histological assessment, fibrosis based on its distribution, is expressed in four different types interstitial, compact, diffuse, and patchy.[6] In interstitial fibrosis, mainly collagens get accumulate in between groups of cells, whereas in compact fibrosis, large and dense collagen gets deposited and completely replaces cardiomyocytes. Short stretches of fibrosis are typical off or diffuse fibrosis, whereas patchy fibrosis shows long collagen fiber strands in between myocardial bundles.[6]
| Different Markers of Fibrosis: The Collagen Fiber | | |
Collagen is a weave-like structure that surrounds myofibrils bundle and that provides tensile strength. The primary role of collagen in the heart is to provide a structural framework to the cardiac myocytes, impart stiffness to the myocardial wall, and aid in force propagation.[11] ECM remodeling and cross-linking play a crucial role in cardiac fibrosis. Collagen type I and Collagen III are myocardial fibrillar collagen.[12] Fibrillar collagen is first created as a procollagen, which is then separated into carboxy (C)- and amino (N)-terminal propeptides.[13] N-terminal propeptides of COL-I and COL-3 (PINP and PIIINP), as well as C-terminal propeptides (PICP and PIIICP).[14] They are then secreted into the bloodstream. The triple helix chain will create huge collagen fibers after joining with other collagen chains. These collagen fibers are broken down by the collagenases MMP-1, -8, and -13, and are produced as telopeptides.[15] Then, the tiny collagen type I telopeptides (ICTP, 12 kDa) are released into the bloodstream. Myocardial collagen deposition and fibrosis have been associated with elevated blood levels of (PICP, PINP, PIIICP, and PIIINP) and decreased serum levels of the COL1 degradation biomarkers.[14],[15] These results demonstrate that cardiac collagen synthesis and breakdown are imbalanced in heart disease.[12] In addition, glycoproteins, proteoglycans, elastin, fibronectin, laminin, fibrillin, and fibrillin all contribute to the formation of the cardiac ECM.[16]
| The Profibrotic Growth Factors and Cytokines | | |
Transforming growth factor-β
Increased transforming growth factor-β (TGF-β) binds to TGF-β receptor I (Activin receptor-like kinase 5) and the type II receptor to activate the Smad2/3 pathway, thus promoting the process of cardiac fibrosis. TGF-β also inhibits the degradation of ECM by regulating the level of plasminogen activator inhibitor-1 and Tissue inhibitor of Metalloproteinase/Tissue inhibitor Metallo proteinase (TIMPs). In addition, TGF-β is also involved in the synthesis and secretion of other profibrotic cytokines.
The increase in TGF-β causes nuclear accumulation of Smad2/3 in myofibroblasts, and decreases the inhibitory Smad6 and Smad7, thereby inducing the activation of numerous profibrotic genes. TGF-β activates the WNT/β-catenin pathway. TGF-β increases Akt phosphorylation through PI3K activation, thus inactivating GSK3 β (an enzyme involved in β-catenin degradation), which promotes cardiac fibrosis. In recent years, several reports have indicated that the canonical WNT/β-catenin pathway and Smad-dependent TGF-β signaling are involved in the stimulation of myofibroblast proliferation and differentiation, thus promoting fibrogenesis.[9],[17],[18]
Angiotensin II
Angiotensin II (Ang II) induces the hypertrophy of cardiomyocytes and enhances the secretion of profibrotic growth factors by myocytes. Ang II suppresses the activity of MMP-1, a key enzyme of interstitial collagen degradation, and leads to progressive collagen accumulation within the myocardial interstitium.[18] Ang II induces expression of TGF-β1 within CFs through the Ang type-I receptor (AT-1) as a result of post-MI, increased wall stress due to left ventricular (LV) end-diastolic pressure which stimulates activation of renin-angiotensin-aldosterone system mechanism.[9] The upregulated Ang II increases tissue inflammation, and TGFβ, IL-1 β, and tumor necrosis factor α (TNF-α) secretion leads to enhanced generation of myofibroblasts.[9],[18]
Connective tissue growth factor
Connective tissue growth factor (CTGF) CTG is a cysteine-rich protein belonging to the cellular communication network (CCN) Family (CCN2). Although it is expressed abundantly in the fetal myocardium, it is restricted to the atria and large blood vessels in the adult heart. CTGF expression could be induced by TGF-β and Ang II in CF and cardiomyocytes. CTGF induces the proliferation of fibroblasts, promotes the transformation from CFs to myofibroblasts, and increases the production of ECM. CTGF has a limited capacity to induce cardiac fibrosis but creates a fibrotic environment and modulates the activity of growth factors in the ECM.[17],[18]
Endothelin-1
Endothelin-1 (ET-1) is a protein secreted from endothelial cells and plays a key role in cardiac remodeling. ET-1 binds to ET receptor A and ET receptor B to act as a powerful vasoconstrictor. ET-1 could induce CF proliferation, and enhances types I and III collagen synthesis, resulting in myofibroblast differentiation. ET-1 is also involved in the fibrotic responses of TGF-β.[9]
Inflammatory cytokine
After the cardiac injury, the inflammatory signaling molecules immediately increase and are released by inflammatory cells. The levels of TNF-α, IL-6, and IL-1 β correlated with disease severity in patients with HF.[9],[17]
Changes in ECM affect signaling and gene expression in CFs and myocytes. The onset of myocardial ischemia changes the expression of ECMs and MMPs; loss of collagen is followed by a rapid and progressive increase in collagen and fibronectin gene expression. MMPs are involved in infarct healing processes, early ECM degradation, cell migration of inflammatory cells and fibroblasts, angiogenesis, remodeling of newly synthesized connective tissue, and the regulation of growth factor activities. MMPs are also involved in the progression of LV dilation and dysfunction.[19] Moreover, increased MMP activity was found in the hearts of patients with ischemic and DCM.[9],[20]
Recent studies based on genetic and pharmacological manipulation of collagens and MMPs demonstrate that the imbalance between matrix synthesis and degradation may cause cardiac remodeling and dysfunction. Cardiac-specific overexpression of MMP-1 results in marked deterioration of systolic and diastolic function.[21] Disruption of MMP inhibitory control by TIMP-1 gene knockout (KO) resulted in LV dilation.[22] MMP-9 (gelatinase B) gene KO mice showed enlargement of LV and collagen accumulation after myocardial infarction.[23] This novel LMNA deletion causes a distinct, highly malignant cardiomyopathy with early-onset primary cardiac fibrosis, likely due to an effect of the shortened mutant protein, which secondarily leads to arrhythmias and end-stage cardiac failure.[24]
Transcription factors and cofactors are largely involved in gene expression, which gets evoked, by myocardial insult. The transcription factors activated by external stress (growth factors, cytokines, hypoxia, and mechanical stretch) include products of immediate early response genes, such as activating protein-1 (AP-1), nuclear factor-κB (NF-κB), early growth response factor-1 (Egr-1), and Stat3, AP-1. AP-1 proteins are homodimers and heterodimers composed of basic region-leucine zipper proteins, which are activated by diverse factors. They are involved in numerous cellular functions, like controlling cell proliferation, apoptosis, and activating transcription factors.[25] Mechanical stretch, Ang II, and hypoxia have been shown to activate AP-1.[26] Ang II directly induces c-fos, c-jun, and JunB expression in CFs.[25] Potential AP-1 binding sites have been identified in the transcriptional regulatory regions of numerous genes, including transcription factors, ECM proteins, MMPs, cell adhesion molecules, growth factors, cytokines, and cyclins. In CFs, the identified potential target genes include collagen, fibronectin, intercellular adhesion molecule (ICAM), and vascular cell adhesion molecule (VCAM). AP-1 also controls genes involved in the cell cycle and apoptosis in CFs. ICAM-1 and VCAM-1.[26]
Nuclear factor-κB
NF-κB consists of homodimers or heterodimers of NF-κB/Rel family proteins.[27] NF-κB is a redox-sensitive transcription factor; activated NF-κB translocates into the nucleus and stimulates the expression of genes involved in a wide variety of biological functions. NF-κB is bound by an inhibitory IκB family protein and is retained within the cytoplasm, gets activated, and target the gene of pro-inflammatory cytokines, chemokines, leukocyte adhesion molecules, and MMPs. It may also induce the expression of angiotensinogen, AT1 receptor, and IL-6.
Early growth response factor-1
Egr-1 is a zinc-finger transcription factor that is activated by growth factors and other injurious stimuli. In CFs, Egr-1 is induced by Ang II, EGF, and IGF-1. It also controls genes important for cell growth and inflammatory responses.[28] In CFs, Egr-1 has been shown to induce platelet-derived growth factor (PDGF)-A and KLF5. It is also known to control PDGF-B, fibroblast growth factor-2, TNF-α, IL-2, tissue factor, plasminogen activator, macrophage colony-stimulating factor, apolipoprotein A1, ICAM-1, and NF-κB in other cells.
| Cardiac Fibrosis Pathways | | |
Injury or stress to the heart muscles results in abnormal expression of Lysyl oxidase like-2 (LOXL-2) isoenzymes and transforming growth factor-β (TGF-β) [Figure 1]. LOXL-2 is a copper-dependent enzyme that causes cross-linking of elastin and collagen fibers. LOXL-2 is implicated in the transcriptional regulation of TGF-β signaling.[29] In humans, the TGF-β, which is normally found in the plasma (TGF-β1 isoform), is bound to extracellular matrix (ECM) protein. TGF-β is a highly pleiotropic cytokine, that exerts multiple effects on inflammation, angiogenesis, fibrosis, and tumor progression. The matrix acts as a reservoir for TGF-β, cytokines, and growth factors allowing their release during pathological conditions.[30] | Figure 1: LOXL-2- lysyl oxidase like -2, PI3K- Phosphoinositol-3kinase (signaling pathway), Protein kinase B (Akt), mTOR - Mechanistic target of rapamycin, HIF-1- Hypoxia-inducible factor 1, TGF-β - Transforming growth factor beta, CTGF- Connective tissue growth factor, Ang II - angiotensin II, IL6 -Interleukin 6, PDGF - Platelet-derived growth factor, α SMA -Alpha-smooth muscle actin, TIMPs -Tissue inhibitors of metalloproteinases, MMPs - Matrix metalloproteinases, PINP -Serum procollagen type I N-propeptide , PICP- Procollagen Type I Carboxyterminal Propeptide, PIIINP- N-terminal propeptide of type III procollagen, MEK -Mitogen activated protein Kinase, ERK – Extracellular signal regulated kinase
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To promote the transformation of fibroblasts into myofibroblasts, LOXL-2 increases the production of TGF-β by cardiac fibroblasts (CFs) through the PI3K/AKT pathway. LOXL-2 also functions downstream of TGF-β to promote the migration of myofibroblast.[31] Connective tissue growth factor (CTGF) is a cysteine-rich protein, belonging to the CCN Family (CCN2), which induces the proliferation of fibroblasts, promotes the transformation (CFs to myofibroblasts), and increases the production of ECM. CTGF expression and production are induced by TGF-β and Ang II in CF and cardiomyocytes.[32] Alpha-smooth muscle actin (α - SMA) production brought on by TGF-beta is a crucial sign of myofibroblast differentiation from fibroblasts.[33]
Lots of cross-talk take place between LOXs, stress, inflammation response mechanisms, TGF-β signaling, nuclear factor kappa B (NF-κB) activation (due to oxidative stress, growth factors, and inflammatory cytokines including TNF- and IL-1), mitogen-activated protein kinase (MAPK) activation, and HIF-1 upregulation/stabilization.
Increased oxidative stress and inflammation through the pathway of suppressor of mothers against decapentaplegic (SMAD 2/3), Activator protein-1 (AP-1)/NF-κB increases the level of LOXL-2.[34] AP-1 is a transcription factor that controls gene expression in response to cytokines, growth factors, and stress.[35] AP-1 binding sites have been identified in many signaling molecules that were closely associated with fibrosis, including transcription factors, ECM proteins, and MMPs.
Ang II upregulates TGF-β production and increases TGF-β activation. It promotes cardiac fibrosis by directly activating the SMAD (suppressor of the mother against decapentaplegic) signaling pathway.[36] Endothelin-1 is a protein secreted from endothelial cells, binds to ET receptor A (ETA) and ETB to act as a powerful vasoconstrictor, induces CF proliferation, and enhances types I and III collagen synthesis which plays a key role in cardiac remodeling.[37] Overexpression of IL-6 induces myofibroblastic proliferation, differentiation, and fibrosis, through increased TGF-β1-mediated MMP2/MMP3 (matrix metalloproteinase) signaling pathway. Platelet-derived growth factor is a more potent chemoattractant for fibroblasts and stimulates endogenous growth factors (TGF-β), which, in turn, directly stimulate new collagen synthesis.[38]
Profibrotic growth factors and cytokines bind to their receptors during the active phase, which then causes the activation of transcriptional factors and signaling pathways such as SMAD, MAPKs, protein kinase B (also known as AKT), and NF-κB. The SMAD-signaling pathway, which operates downstream of the TGF-β, regulates proliferation, differentiation, and apoptosis, in many different organ systems.[39] These pathological activations cause the transformation of CFs into myofibroblasts, which express the highly contractile protein SMA and generate a variety of MMPs and tissue inhibitors of metalloproteinases (TIMPs) to control the homeostasis of the ECM. TGF-β also inhibits the degradation of ECM by regulating the level of plasminogen activator inhibitor (PAI)-1 and TIMPs.[40]
Augmented LOXL-2 expression causes an increase in TGF-β signaling through activation of the phosphoinositide 3-kinase/protein kinase B/mechanistic target of rapamycin (PI3K/AKT/mTOR) pathway. This pathway upregulates the hypoxia-inducible factor-1 (HIF-1). This protein plays a critical role in cardiac oxygen homeostasis and its dysregulation results in the activation of TGF-β signaling. TGF-β signaling and activation of the Mitogen-activated protein kinase (MEK/MAPK) → (Extracellular signal-regulated kinase) ERK1/2 pathway in endothelial cells of cardiac blood vessels, leads to a significant loss of microvasculature in the myocardium. Decreased perfusion, and impaired tissue oxygenation, result in heart failure.
LOXL-2 and TGF-β, through different signaling pathways, cause alteration in ECM collagen processing and increased collagen deposition. Alterations in ECM collagen processing include Failure to regulate (TIMPs and MMPs), increased collagen synthesis procollagen type I carboxyterminal propeptide (PICP), N-terminal propeptide of type III procollagen (PIIINP), procollagen type I N-propeptide (PINP), and decreased collagen degradation of C-terminal telopeptide of collagen type I (ICTP). This process leads to excessive deposition of collagen I and III. Abnormal cross-linking of collagen and elastin by LOXL-2 at the site of injury leads to ventricular stiffness, cardiac remodeling, and heart failure.[41]
Serum biomarkers of cardiac fibrosis
The potential of serum biomarkers in the diagnosis of cardiac fibrosis is still a growing field with increased interest for more population-specific exploration. ST2, Galectin-3, MicroRNA (miRNAs), PICP, and lysyl oxidase-like 2 (LOXL2) are the recently explored biomarkers [Table 1].
ST2 represents “suppression of tumorigenicity 2.” It is also called interleukin (IL) 1 receptor-like 1 and it belongs to the IL 1 receptor family. It has two forms, cellular (ST2 L) and soluble (sST2) forms. sST2 has both myocardial and nonmyocardial sources. A review by Villacorta and Maisel. has concluded that sST2 is a promising useful biomarker.[42],[43] ST-2 aids in assessing the prognosis of patients diagnosed with chronic HF whereas ST-2 level can be elevated in systemic lupus erythematosus, asthma, inflammatory conditions (septic shock, pneumonia), and chronic obstructive pulmonary disease which is why it is very important to exclude these conditions while using the ST2 as biomarkers for cardiac fibrosis.
Galectins are the Glycan binding proteins that are synthesized in the cytosol of the 12 Galectins in human tissues, and Galectin 3 plays a major role in chronic inflammation. It is widespread and present in various organs. It enhances cardiac fibrosis and causes HF.[44] Higher levels of Galectin-3 were noted in patients with atrial fibrillation, and fibrosis and significantly correlated positively with LA volume.[45] Pathophysiology and experimental studies showed that Galectin-3 is one of the key links between inflammation and fibrosis in cardiovascular disease.[44],[45],[46] Galectin-3 helps in the prognosis of patients diagnosed with chronic HF and is also strongly correlated with kidney dysfunction function, hemolysis, and Cancer. Galectin-3 is a profibrotic agent by itself and also mediates aldosterone-induced cardiac, vascular, and renal fibrosis.[47],[48]
LOX and LOXL 1–4 are a family of proteins that play an essential role in collagen and elastin cross-linking. It is now well established that the LOX protein family is linked to fibrosis, as well as the development of other connective tissue disorders, such as elastolysis and Ehlers-Danlos syndrome More Details.[48],[49],[50] Histone modification also plays a role in LOXL2 regulation as it aids in the packaging of DNA and thus influences gene expression.[42],[50] It is also known that transcription factors, such as NF-B, and changes in DNA methylation status as well as histone modifications are responsible for the regulation of genes associated with inflammatory pathways.[49],[51]
Inflammatory factors are known to upregulate the expression of LOXL2 and thereby increase fibrosis.[50] During stress conditions, increased inflammation activates NF-κB, LOXL2 expression, as well as other factors such as TGF-β, COL1A, and CTGF, which in turn, lead to elevated collagen deposition and cross-linking, culminating in increased fibrosis.
However, there is a lack of available literature, it is difficult to fully elucidate the exact mechanisms by which LOXL2 signaling occurs in fibrosis. Hence, this area needs to be investigated and explored in identifying the acts of epigenetics in LOXL2 expression, which could greatly aid in identifying a means to control and manipulate LOXL2, particularly in humans, thereby developing novel therapeutics to combat this worldwide cardiovascular vascular disease (CVD) problem.[52]
Procollagen type I carboxy-terminal propeptide is a collagen-derived serum peptide associated with cardiac fibrosis. A multilevel assessment of MF study found that a high level of PICP gave good prognosticator prediction when combined with clinical prediction.[53] In patients with HCM, PICP, and MMP-2 can be considered potential biomarkers.[54]
Resistin is a pro-inflammatory cytokine, a member of the adipokines, predominantly produced by macrophages and also released from the adipose tissue.[55] Resistin promotes, atherogenesis and atherothrombosis, having direct effects on the vessels. Resistin upregulates the expression of genes associated with atherothrombosis.[56],[57] Vascular thrombosis manifested as increased platelet reactivity and adherence to the endothelium and endothelium dysfunction are the main triggers of CVD.[58] Finally, resistin also upregulates TNF-α expression and activates the NF-κB pro-inflammatory signaling pathway in the myocardium, leading to cardiac inflammation and fibrosis.[59] Resistin concentration equal to or above 17.3 ng/ml is associated with a 13-fold increase in the risk of cardiac and cerebrovascular events in patients with multi-vessel coronary disease.[52] However, resistin levels do not seem to change even after 12 months of medical treatment or CABG thus may not be helpful for follow-up after therapeutic intervention.[59],[60]
Cardiotrophin-1 (CT-1) is a cytokine member of the IL-6 superfamily, which is produced by cardiomyocytes and CFs in situations of biochemical stress and under exposure to humoral factors such as Ang II.[10] Once secreted, it interacts with its receptor, glycoprotein-130, and the leukemia inhibitory factor receptor activates different signaling pathways causing cardiomyocyte growth dysfunction. Plasma CT-1 concentration is increased in hypertensive patients, compared to normotensive subjects.[61] It has also been reported that plasma CT-1 is higher in patients with LV hypertrophy (LVH) than in patients without LVH and patients with HF.[62] It performs much better than NT-pro BNP, with 70% sensitivity and 75% specificity.[61],[62]
MMPs are involved in the degradation of various proteins (collagen and elastin) in the ECM and tissue remodeling. MMPs are secreted by many cells, including fibroblasts, vascular smooth muscle (VSM), and leukocytes. MMPs are often secreted as inactive pro-MMP form, which is cleaved to the active form by various proteinases, including other MMPs. MMPs could influence endothelial cell function as well as VSM cell migration, proliferation, Ca2+ signaling, and contraction. MMPs play a role in tissue remodeling during various physiological processes such as angiogenesis, embryogenesis, morphogenesis, and wound repair, as well as in pathological conditions such as myocardial infarction and fibrotic disorders.[63]
Tissue inhibitors of metalloproteinases (TIMPs) maintain the homeostatic balance of myocardial ECM by inhibiting the activated MMPs. TIMP2, TIMP3, and TIMP 4 have been shown to contribute to MF through different mechanisms and their loss often exacerbates MF.[64] The role of TIMP1 has been less explored. TIMP1 can inhibit many MMPs except the membrane-bound MMPs. Elevated tissue and plasma TIMP1 levels have been correlated with MF and diastolic dysfunction.[65] TIMP1 has been used as a biomarker for fibrosis in patients and animal models of heart disease.[66] Roten et al.,[22] in their study, found that there was a change in LV geometry (increased stress on left ventricle) of tissue inhibitor of MMP type-1 (TIMP-1) KO mice compared to the wild-type control.
Furthermore, a study needs to be conducted in this area to have new information on the role of TIMP1 in fibrosis; targeting TIMP1 could prove to be beneficial in limiting fibrosis in patients with nonischemic cardiomyopathies, which could finally hinder disease progression in HF.
miRNAs are small (<200 nucleotides), noncoding RNAs that regulate gene expression by inducing target mRNA destabilization or inhibiting protein translation after transcription, it plays a critical role in heart function and its pathology. The relationship between noncoding RNA (miR-21, miR-29) and MF has been extensively studied. miR-29 expression has been linked to ECM remodeling in cardiac hypertrophy. Other cardiomyocyte-associated miRNAs, such as miR-26, miR-30, miR-135, and miR-208, are also involved in cardiac fibrosis.[9]
| A Paucity of Serum Biomarkers as an Independent Biomarker of Cardiac Fibrosis | | |
The propeptides of collagen types I and III, PIIINP, PINP, and PICP, are fibrotic biomarkers that can be utilized for collagen formation. Collagen type I carboxy-terminal telopeptide (ICTP)/Carboxy terminal telopeptide of type I collagen (ICTP), which is a biomarker for collagen degradation, as well as MMP-1, MMP-2, MMP-3, MMP-9, and TIMPs, which are biomarkers for the general degradation of the cardiac ECM.
Biomarkers have their limitation, as evidenced by their association with MF. The proposed blood molecule as a biomarker of cardiac fibrosis must possess added value for diagnosis, prognosis, and therapeutic monitoring of cardiac patients. A circulating proposed biomarker of cardiac fibrosis requires a direct correlation between the blood level of a proposed molecule with myocardial collagen volume fraction (CVF), myocardial collagen type I volume fraction, or myocardial collagen type III volume fraction (CIIIVF) assessed by endomyocardial biopsy. In cardiac MRI, blood molecules should directly correlate with myocardial extracellular volume.
Risteli and Risteli, in their review, have explained the flaws of using PINP levels as a marker for collagen type I synthesis. There is a delay between the release of PINP, compared with the release of the C-terminal procollagen I (PICP). PIIINP, PINP may not always be removed from the collagen, which suggests that PINP levels might give an unreliable value. They suggested that uncleaved PINP could degrade into a monomer. This monomer might still react in some PINP assays, resulting in an overestimation of collagen type I synthesis. Based on these flaws, other collagen types I synthesis markers, such as PICP, might be more promising as biomarkers.[67] Serum ICTP concentrations were elevated in patients with DCM, HCM, hypertensive heart disease, and HF patients with diastolic dysfunction, whereas PICP levels were not changed significantly, supporting the hypothesis that in patients with DCM, collagen breakdown is increased.
Adamcova et al., in their study conducted on animals, found that chronic administration of isoproterenol led to a reduction of systolic blood pressure, increased LV weight, and increased collagen content in the LV. Collagen content correlated with the expression of Col1 in the LV, whereas there were no correlations between plasma markers of collagen, PICP, and PIIINP and collagen content or molecular markers of collagen in the LV. The expression of other fibrotic rebuilding biomarkers, i.e., TGF-β1 and PDGF-β, was also pronounced.[68]
López et al. found myocardial CT-1 protein was correlated (P < 0.05) with LV end-diastolic wall stress (LVEDWS) in patients with HF, but there were no correlations between myocardial CT-1 mRNA and LVEDWS or collagen-related molecules (CVF, CIVF or CIIIVF).[69]
Galactin-3 (Gal-3) is an indicator not only of MF but also of other fibrotic conditions, including liver cirrhosis and pulmonary fibrosis. Higher levels of Gal-3, a marker of cardiac fibrosis, are associated with an increased risk for incidents of HF. Gal-3 cannot be a single-handed independent marker of cardiac fibrosis because its level gets elevated in conditions other than cardiac fibrosis.[70]
Activin A member of TGF-beta plays a role in inflammation. Activin A has been investigated in HF and other CVDs. It enhances the release of inflammatory cytokines in healthy control. It has both inflammatory and anti-inflammatory properties, which makes it difficult to distinguish the underlying cause of increased Activin A. The relationship between the Activin A level and systolic dysfunction needs to be clarified.[71]
Greater concentrations of resistin are correlated with increased disease severity and also predict adverse cardiac outcomes. Resistin may lead to HF by promoting insulin resistance and inflammation. Resistin appeared to add to the risk of HF associated with obesity, insulin resistance, and inflammation. Resistin acts as a confounding factor in contribution to HF; hence, it cannot be considered as an independent biomarker for cardiac fibrosis.[72]
Sixty-three patients were recruited for the study, and concentrations of Gal-3, PIIINP, and ST2 were determined. Gal-3 has a significant correlation to diffuse MF, which was estimated by late gadolinium enhancement (LGE) CMR T1 mapping in patients with coronary artery disease (CAD). Elevated levels of ST2 and PIIINP had no significant association with fibrosis but were associated with impaired LV filling assessed by ECHO. This study shows a correlation between the LGE T1 relaxation time and GAL-3 but did not have a significant correlation to MF measured by LGE CMR with other biomarkers (ST2 and PIIINP).[73]
Growth differentiation factor-15 (GDF-15) belongs to the TGF-β cytokine superfamily and is described as a stress-responsive cytokine. It may be involved in inflammation, coagulation, oxidative stress, endothelial dysfunction, and homeostasis. The PARADIGM-HF trial has reported that increased levels of GDF-15 were associated with mortality and cardiovascular events in patients with HF with reduced ejection fraction. GDF-15 levels are significantly linked to the increased risk of AF, CAD, and myocardial infarction.[74]
In 54 HCM patients' cardiac fibrosis was quantified by LGE-CMR, serum concentrations of MMP-(1, −2, −3, −9) tissue inhibitor of MMP (TIMP) 1, PINP, PIIINP, and type I collagen C-terminal telopeptide (ICTP). MMP-9 was associated with fibrosis in LGE-CMR (mean increase 0.66 g/unit MMP9 [95% confidence interval 0.50–0.82]; P < 0.001) and with cardiac events in women (odds ratio [OR] 1.07 [1.01–1.12], P = 0.01) but not in men. Increased MMP-2 levels in women were associated with lower fibrosis (0.05 [−0.09 to −0.01]; P = 0.015). MMP-3 levels were positively associated with cardiac events (OR 1.13 [1.05–1.22]; P = 0.001) independently from fibrosis and sex. No association was detected for MMP-1, TIMP-1, PNPs, and ICTP. These data suggest that MMP-9 was a useful biomarker for fibrosis and cardiac events in female CM patients, whereas MMP-3 was associated with a higher event rate independent from fibrosis and sex.[75]
| Techniques of Fibrosis Detection | | |
At present, the detection methods of MF are endomyocardial biopsy, serum markers, LGE cardiac MRI, and ECHO. ECHO is a minimally invasive procedure. It can indirectly track the remodeling process and can assess ventricular size, shape, and volume. It also helps in tracking the remodeling and prognosticating morbidity and mortality. It can be used to evaluate the contractile reserve in patients with adequate acoustic windows. Hence, this limits its usage in patients with poor acoustic windows. It is inadequate for direct identification and quantification of the type and extent of MF. As a tool for functional assessment, it falls short in its ability to identify the underlying fibrotic patterns, therefore, cannot be utilized independently to measure and monitor the degree and progression of MF.[76]
Endomyocardial biopsy is an invasive procedure for the diagnosis of MF and especially in the quantification of diffuse MF. Endomyocardial biopsy is an invasive but gold-standard technique providing myocardial histology with low sensitivity in specific scenarios. Masson's Trichrome staining gives a blue stain to collagen fibers, black to nuclei, and red to the myocardium. Picrosirius red staining gives red to collagen fibers, blue to nuclei, and pale yellow to myocytes.[77],[78]
It has limitations like contraindications to this procedure. Therefore, biomarkers should be considered a method for detecting fibrosis which could be more convenient in terms of cost and accessibility. In the case of the patchy distribution of MF, the greatest potential limitation to Endomyocardial biopsy (EMB) evaluation is the sampling error, which may require analysis of several tissue fragments for diagnostic accuracy and interpretation. Safety remains a concern in this test because of rare but major complications.[77],[79],[80]
| Imaging Techniques of Fibrosis | | |
LGE CMR is a cardiac MRI test that has been developed significantly in the last two decades. Cardiac MRI is a noninvasive modality for accurate, easy detection and quantification of MF by probing the retention of a gadolinium-contrast agent by myocardial tissue. In MF enlargement of the extracellular space happens because of ECM deposition.[76],[80] Gadolinium accumulates in the area of interstitial expansion. After the gadolinium injection, three phases can be evaluated. Just after the injection, immediate assessment (the first pass), after the 1st 5 min (early enhancement phase), and just after 5–20 min (late enhancement). It quantifies myocardial mass, volume, and function to identify macroscopic MF.
Cardiac MRI using LGE or T1 mapping has distinct advantages in assessing MF.[78] LGE cardiac MRI is well established for the measurement of focal and replacement MF, but its main limitation is the inability to identify diffuse MF. T1 mapping indices provide a means of estimating diffuse interstitial fibrosis.[81],[82] The suspected risk of developing nephrogenic systemic fibrosis is a point of concern for cliniscians to use LGE-CMR.[1],[81]
| Perspective | | |
Studies have proved that fibrosis has been seen in CVD and noncardiac disease conditions. MF has been seen in aortic stenosis, mitral regurgitation, cardiomyopathy, atrial fibrillation, and HTN. Noncardiac conditions where fibrosis is seen are impaired glucose metabolism, systemic inflammation, liver disease, pelvic inflammatory disease, pulmonary disease, and renal disease. MF causes irreversible changes and cardiac remodeling.[76]
MF is often assessed indirectly by measuring the heart function and structure by visualization of the changes in the myocardium on (ECHO), MRI, and computed tomography (CT), and rarely endomyocardial biopsies are indicated for identification of the underlying disease process when a cause for function deterioration is difficult to identify by other modes of interventions.[83]
There is a paucity of understanding of MF clinically, and assessment of fibrosis is difficult. Thus, it is not a part of routine clinical practice basically due to the difficulties in obtaining an accurate assessment of fibrosis noninvasively. Despite substantial literature on specific pathophysiologic mechanisms of MF, conventional investigation protocols are unable to catch MF noninvasively prior; hence, the focus should be given to noninvasive methods of diagnosing MF to avoid deterioration of the heart to the extent where reversal is impossible.
Galectin, LOXL-2 Resistin, CT-1, and Procollagen types I and III, the two major collagen types in the heart, can be detected in circulation. Although these propeptides reflect collagen synthesis, breakdown products of collagen and the MMPs, responsible for the breakdown of the ECM, can be detected in the blood. This can be used for investigating fibrosis before cardiac conditions worsen. Biomarkers of myocardial must be explored in deep to understand molecular mechanisms underlying the development of fibrosis.
There is a need for improving diagnostic tools to enable early, reliable, and noninvasive fibrosis detection, which will allow for improving the patient's quality of life by adding on an early treatment regimen focusing on fibrosis. There is still a gap in the treatment and diagnosis of cardiac fibrosis; it is an area a breach to be filled up with research studies.
| Conclusion | | |
Cardiac fibrosis is a condition seen in different cardiovascular diseases. The mechanism remains known; moreover, the mechanism of cardiac fibrosis predominantly came from experiments performed in cell culture systems or KO mice. Since there are multiple signaling pathways of cardiac fibrosis, hence it is difficult to target specific pathways of cardiac fibrosis, which makes fibrosis treatment more complicated. EMB, cardiac MRI (LGE, T1 mapping) and ECHO is the only way to diagnose fibrosis, but every diagnostic tool has its limitation. Serum biomarkers TGF-β, PICPs, MMPs, TIMPs, Gal-3, LOXL-2, CT-1, and resistin are the biomarkers that get upregulated in cardiac fibrosis. None of the serum biomarkers has proved to be the most accurate diagnostic tool for assessing fibrosis independently. Hence, further studies need to be conducted. Novel biomarkers need to be cost-effective, valid, reliable, and accurate. They should be capable of independently predicting fibrosis and also providing more information than traditional biomarkers.
Ethics clearance
Nil.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
| References | | |
| 1. | Travers JG, Kamal FA, Robbins J, Yutzey KE, Blaxall BC. Cardiac fibrosis: The fibroblast awakens. Circ Res 2016;118:1021-40.  |
| 2. | Murtha LA, Schuliga MJ, Mabotuwana NS, Hardy SA, Waters DW, Burgess JK, et al. The processes and mechanisms of cardiac and pulmonary fibrosis. Front Physiol 2017;8:777. |
| 3. | Xue M, Jackson CJ. Extracellular matrix reorganization during wound healing and its impact on abnormal scarring. Adv Wound Care (New Rochelle) 2015;4:119-36. |
| 4. | Rienks M, Papageorgiou AP, Frangogiannis NG, Heymans S. Myocardial extracellular matrix: An ever-changing and diverse entity. Circ Res 2014;114:872-88. |
| 5. | Hinderer S, Schenke-Layland K. Cardiac fibrosis – A short review of causes and therapeutic strategies. Adv Drug Deliv Rev 2019;146:77-82. |
| 6. | Liu M, López de Juan Abad B, Cheng K. Cardiac fibrosis: Myofibroblast-mediated pathological regulation and drug delivery strategies. Adv Drug Deliv Rev 2021;173:504-19. |
| 7. | Graham-Brown MP, Patel AS, Stensel DJ, March DS, Marsh AM, McAdam J, et al. Imaging of myocardial fibrosis in patients with end-stage renal disease: current limitations and future possibilities. BioMed Research International. 2017;2017:5453606. |
| 8. | Tian J, An X, Niu L. Myocardial fibrosis in congenital and pediatric heart disease. Exp Ther Med 2017;13:1660-4. |
| 9. | Liu T, Song D, Dong J, Zhu P, Liu J, Liu W, et al. Current understanding of the pathophysiology of myocardial fibrosis and its quantitative assessment in heart failure. Front Physiol 2017;8:238. |
| 10. | Pennica D, Wood WI, Chien KR. Cardiotrophin-1: A multifunctional cytokine that signals via LIF receptor-gp 130 dependent pathways. Cytokine Growth Factor Rev 1996;7:81-91. |
| 11. | de Jong S, van Veen TA, van Rijen HV, de Bakker JM. Fibrosis and cardiac arrhythmias. J Cardiovasc Pharmacol 2011;57:630-8. |
| 12. | Factor SM, Robinson TF, Dominitz R, Cho SH. Alterations of the myocardial skeletal framework in acute myocardial infarction with and without ventricular rupture. A preliminary report. Am J Cardiovasc Pathol 1987;1:91-7. |
| 13. | Horn MA, Trafford AW. Aging and the cardiac collagen matrix: Novel mediators of fibrotic remodelling. J Mol Cell Cardiol 2016;93:175-85. |
| 14. | Seo WY, Kim JH, Baek DS, Kim SJ, Kang S, Yang WS, et al. Production of recombinant human procollagen type I C-terminal propeptide and establishment of a sandwich ELISA for quantification. Sci Rep 2017;7:15946. |
| 15. | Jabłońska-Trypuć A, Matejczyk M, Rosochacki S. Matrix metalloproteinases (MMPs), the main extracellular matrix (ECM) enzymes in collagen degradation, as a target for anticancer drugs. J Enzyme Inhib Med Chem 2016;31:177-83. |
| 16. | Halper J, Kjaer M. Basic components of connective tissues and extracellular matrix: elastin, fibrillin, fibulins, fibrinogen, fibronectin, laminin, tenascins and thrombospondins. Progress in heritable soft connective tissue diseases. Advances in Experimental Medicine and Biology, vol 802. Springer, Dordrecht; 2014. p. 31-47. |
| 17. | Nikolov A, Popovski N. Extracellular matrix in heart disease: Focus on circulating collagen type I and III derived peptides as biomarkers of myocardial fibrosis and their potential in the prognosis of heart failure: A concise review. Metabolites 2022;12:297. |
| 18. | Ma ZG, Yuan YP, Wu HM, Zhang X, Tang QZ. Cardiac fibrosis: New insights into the pathogenesis. Int J Biol Sci 2018;14:1645-57. |
| 19. | Spinale FG. Matrix metalloproteinases: Regulation and dysregulation in the failing heart. Circ Res 2002;90:520-30. |
| 20. | Manabe I, Shindo T, Nagai R. Gene expression in fibroblasts and fibrosis: Involvement in cardiac hypertrophy. Circ Res 2002;91:1103-13. |
| 21. | D'Armiento J. Matrix metalloproteinase disruption of the extracellular matrix and cardiac dysfunction. Trends Cardiovasc Med 2002;12:97-101. |
| 22. | Roten L, Nemoto S, Simsic J, Coker ML, Rao V, Baicu S, et al. Effects of gene deletion of the tissue inhibitor of the matrix metalloproteinase-type 1 (TIMP-1) on left ventricular geometry and function in mice. J Mol Cell Cardiol 2000;32:109-20. |
| 23. | Ducharme A, Frantz S, Aikawa M, Rabkin E, Lindsey M, Rohde LE, et al. Targeted deletion of matrix metalloproteinase-9 attenuates left ventricular enlargement and collagen accumulation after experimental myocardial infarction. J Clin Invest 2000;106:55-62. |
| 24. | van Tintelen JP, Tio RA, Kerstjens-Frederikse WS, van Berlo JH, Boven LG, Suurmeijer AJ, et al. Severe myocardial fibrosis caused by a deletion of the 5' end of the lamin A/C gene. J Am Coll Cardiol 2007;49:2430-9. |
| 25. | Bakiri L, Matsuo K, Wisniewska M, Wagner EF, Yaniv M. Promoter specificity and biological activity of tethered AP-1 dimers. Mol Cell Biol 2002;22:4952-64. |
| 26. | van Wamel JE, Ruwhof C, van der Valk-Kokshoorn EJ, Schrier PI, van der Laarse A. Rapid gene transcription induced by stretch in cardiac myocytes and fibroblasts and their paracrine influence on stationary myocytes and fibroblasts. Pflugers Arch 2000;439:781-8. |
| 27. | Sadoshima J, Izumo S. Molecular characterization of angiotensin II-induced hypertrophy of cardiac myocytes and hyperplasia of cardiac fibroblasts. Critical role of the AT1 receptor subtype. Circ Res 1993;73:413-23. |
| 28. | Rothwarf DM, Karin M. The NF-kappa B activation pathway: A paradigm in information transfer from membrane to nucleus. Sci STKE 1999;1999:RE1. |
| 29. | Rodríguez C, Martínez-González J. The role of lysyl oxidase enzymes in cardiac function and remodeling. Cells 2019;8:1483. |
| 30. | Prud'Homme GJ. Pathobiology of transforming growth factor β in cancer, fibrosis and immunologic disease, and therapeutic considerations. Laboratory investigation 2007;87:1077-91. |
| 31. | Wang TH, Hsia SM, Shieh TM. Lysyl oxidase and the tumor microenvironment. Int J Mol Sci 2016;18:62. |
| 32. | Ma ZG, Yuan YP, Wu HM, Zhang X, Tang QZ. Cardiac fibrosis: new insights into the pathogenesis. Int J Mol Biol Sci 2018;14:1645. |
| 33. | Hinz B, Mastrangelo D, Iselin CE, Chaponnier C, Gabbiani G. Mechanical tension controls granulation tissue contractile activity and myofibroblast differentiation. Am J Physiol 2001;159:1009-20. |
| 34. | Tenti P, Vannucci L. Lysyl oxidases: linking structures and immunity in the tumor microenvironment. Cancer Immunol Immunother 2020;69:223-35. |
| 35. | Lee HW, Klein LE, Raser J, Eghbali-Webb M. An activator protein-1 (AP-1) response element on pro α1 (l) collagen gene is necessary for thyroid hormone-induced inhibition of promoter activity in cardiac fibroblasts. Journal of molecular and cellular cardiology. 1998;30:2495-506. |
| 36. | Hu HH, Chen DQ, Wang YN, Feng YL, Cao G, Vaziri ND, Zhao YY. New insights into TGF-β/Smad signaling in tissue fibrosis. Chemico-biological interactions. 2018;292:76-83. |
| 37. | Yang LL, Husain M, Stewart DJ. The role of endothelin-1 in myocardial inflammation and fibrosis. Inflammation and Cardiac Diseases. 2003:371-84. |
| 38. | El-Sharkawy H, Kantarci A, Deady J, Hasturk H, Liu H, Alshahat M, et al. Platelet-rich plasma: growth factors and pro-and anti-inflammatory properties. Journal of periodontology. 2007;78:661-9. |
| 39. | Blank U, Karlsson S. The role of Smad signaling in hematopoiesis and translational hematology. Leukemia 2011 Sep;25:1379-88. |
| 40. | Rerolle JP, Hertig A, Nguyen G, Sraer JD, Rondeau EP. Plasminogen activator inhibitor type 1 is a potential target in renal fibrogenesis. Kidney international. 2000;58:1841-50. |
| 41. | Ruthenborg RJ, Ban JJ, Wazir A, Takeda N, Kim JW. Regulation of wound healing and fibrosis by hypoxia and hypoxia-inducible factor-1. Molecules and cells. 2014;37:637. |
| 42. | Villacorta H, Maisel AS. Soluble ST2 testing: A promising biomarker in the management of heart failure. Arq Bras Cardiol 2016;106:145-52. |
| 43. | Januzzi JL Jr., Peacock WF, Maisel AS, Chae CU, Jesse RL, Baggish AL, et al. Measurement of the interleukin family member ST2 in patients with acute dyspnea: Results from the PRIDE (Pro-Brain Natriuretic Peptide Investigation of Dyspnea in the Emergency Department) study. J Am Coll Cardiol 2007;50:607-13. |
| 44. | Sygitowicz G, Maciejak-Jastrzębska A, Sitkiewicz D. The diagnostic and therapeutic potential of galectin-3 in cardiovascular diseases. Biomolecules 2021;12:46. |
| 45. | Sonmez O, Ertem FU, Vatankulu MA, Erdogan E, Tasal A, Kucukbuzcu S, et al. Novel fibro-inflammation markers in assessing left atrial remodeling in non-valvular atrial fibrillation. Med Sci Monit 2014;20:463-70. |
| 46. | Gurses KM, Yalcin MU, Kocyigit D, Canpinar H, Evranos B, Yorgun H, et al. Effects of persistent atrial fibrillation on serum galectin-3 levels. Am J Cardiol 2015;115:647-51. |
| 47. | Yang J, Savvatis K, Kang JS, Fan P, Zhong H, Schwartz K, et al. Targeting LOXL2 for cardiac interstitial fibrosis and heart failure treatment. Nat Commun 2016;7:13710. |
| 48. | Moon HJ, Finney J, Ronnebaum T, Mure M. Human lysyl oxidase-like 2. Bioorg Chem 2014;57:231-41. |
| 49. | Erasmus M, Samodien E, Lecour S, Cour M, Lorenzo O, Dludla P, et al. Linking LOXL2 to cardiac interstitial fibrosis. Int J Mol Sci 2020;21:5913. |
| 50. | Bannister AJ, Kouzarides T. Regulation of chromatin by histone modifications. Cell Res 2011;21:381-95. |
| 51. | Medzhitov R, Horng T. Transcriptional control of the inflammatory response. Nat Rev Immunol 2009;9:692-703. |
| 52. | Raafs AG, Verdonschot JA, Henkens MT, Adriaans BP, Wang P, Derks K, et al. The combination of carboxy-terminal propeptide of procollagen type I blood levels and late gadolinium enhancement at cardiac magnetic resonance provides additional prognostic information in idiopathic dilated cardiomyopathy – A multilevel assessment of myocardial fibrosis in dilated cardiomyopathy. Eur J Heart Fail 2021;23:933-44. |
| 53. | Yang C, Qiao S, Song Y, Liu Y, Tang Y, Deng L, et al. Procollagen type I carboxy-terminal propeptide (PICP) and MMP-2 are potential biomarkers of myocardial fibrosis in patients with hypertrophic cardiomyopathy. Cardiovasc Pathol 2019;43:107150. |
| 54. | Jamaluddin MS, Weakley SM, Yao Q, Chen C. Resistin: Functional roles and therapeutic considerations for cardiovascular disease. Br J Pharmacol 2012;165:622-32. |
| 55. | Dorobantu M, Tautu OF, Darabont R, Ghiorghe S, Badila E, Dana M, et al. Objectives and methodology of Romanian SEPHAR II Survey. Project for comparing the prevalence and control of cardiovascular risk factors in two East-European countries: Romania and Poland. Arch Med Sci 2015;11:715-23. |
| 56. | Fang WQ, Zhang Q, Peng YB, Chen M, Lin XP, Wu JH, et al. Resistin level is positively correlated with thrombotic complications in Southern Chinese metabolic syndrome patients. J Endocrinol Invest 2011;34:e36-42. |
| 57. | Hogas S, Bilha SC, Branisteanu D, Hogas M, Gaipov A, Kanbay M, et al. Potential novel biomarkers of cardiovascular dysfunction and disease: Cardiotrophin-1, adipokines and galectin-3. Arch Med Sci 2017;13:897-913. |
| 58. | Chemaly ER, Hadri L, Zhang S, Kim M, Kohlbrenner E, Sheng J, et al. Long-term in vivo resistin overexpression induces myocardial dysfunction and remodeling in rats. J Mol Cell Cardiol 2011;51:144-55. |
| 59. | Kreçki R, Krzemińska-Pakuła M, Peruga JZ, Szcześniak P, Lipiec P, Wierzbowska-Drabik K, et al. Elevated resistin opposed to adiponectin or angiogenin plasma levels as a strong, independent predictive factor for the occurrence of major adverse cardiac and cerebrovascular events in patients with stable multivessel coronary artery disease over 1-year follow-up. Med Sci Monit 2011;17:R26-32. |
| 60. | González A, López B, Ravassa S, Beaumont J, Arias T, Hermida N, et al. Biochemical markers of myocardial remodelling in hypertensive heart disease. Cardiovasc Res 2009;81:509-18. |
| 61. | Ojji D, Libhaber E, Lamont K, Thienemann F, Sliwa K. Circulating biomarkers in the early detection of hypertensive heart disease: Usefulness in the developing world. Cardiovasc Diagn Ther 2020;10:296-304. |
| 62. | Cui N, Hu M, Khalil RA. Biochemical and biological attributes of matrix metalloproteinases. Prog Mol Biol Transl Sci 2017;147:1-73. |
| 63. | Kandalam V, Basu R, Moore L, Fan D, Wang X, Jaworski DM, et al. Lack of tissue inhibitor of metalloproteinases 2 leads to exacerbated left ventricular dysfunction and adverse extracellular matrix remodeling in response to biomechanical stress. Circulation 2011;124:2094-105. |
| 64. | Lindsay MM, Maxwell P, Dunn FG. TIMP-1: A marker of left ventricular diastolic dysfunction and fibrosis in hypertension. Hypertension 2002;40:136-41. |
| 65. | Takawale A, Zhang P, Patel VB, Wang X, Oudit G, Kassiri Z. Tissue inhibitor of matrix metalloproteinase-1 promotes myocardial fibrosis by mediating CD63-integrin β1 interaction. Hypertension 2017;69:1092-103. |
| 66. | Schulte C, Zeller T. microRNA-based diagnostics and therapy in cardiovascular disease-Summing up the facts. Cardiovasc Diagn Ther 2015;5:17-36. |
| 67. | de Jong S, van Veen TA, de Bakker JM, Vos MA, van Rijen HV. Biomarkers of myocardial fibrosis. J Cardiovasc Pharmacol 2011;57:522-35. |
| 68. | Adamcova M, Baka T, Dolezelova E, Aziriova S, Krajcirovicova K, Karesova I, et al. Relations between markers of cardiac remodeling and left ventricular collagen in an isoproterenol-induced heart damage model. Development 2019;3:5. |
| 69. | López B, González A, Querejeta R, Larman M, Rábago G, Díez J. Association of cardiotrophin-1 with myocardial fibrosis in hypertensive patients with heart failure. Hypertension 2014;63:483-9. |
| 70. | Ho JE, Liu C, Lyass A, Courchesne P, Pencina MJ, Vasan RS, et al. Galectin-3, a marker of cardiac fibrosis, predicts incident heart failure in the community. J Am Coll Cardiol 2012;60:1249-56. |
| 71. | Masutani S. Activin A – A potentially useful biomarker of diastolic dysfunction. Circ J 2019;83:1443-5. |
| 72. | Frankel DS, Vasan RS, D'Agostino RB Sr., Benjamin EJ, Levy D, Wang TJ, et al. Resistin, adiponectin, and risk of heart failure the Framingham offspring study. J Am Coll Cardiol 2009;53:754-62. |
| 73. | Lepojärvi ES, Piira OP, Pääkkö E, Lammentausta E, Risteli J, Miettinen JA, et al. Serum PINP, PIIINP, galectin-3, and ST2 as surrogates of myocardial fibrosis and echocardiographic left venticular diastolic filling properties. Front Physiol 2015;6:200. |
| 74. | Nezami Z, Holm H, Ohlsson M, Molvin J, Korduner J, Bachus E, et al. The impact of myocardial fibrosis biomarkers in a heart failure population with atrial fibrillation – The HARVEST-Malmö study. Front Cardiovasc Med 2022;9:982871. |
| 75. | Münch J, Avanesov M, Bannas P, Säring D, Krämer E, Mearini G, et al. Serum matrix metalloproteinases as quantitative biomarkers for myocardial fibrosis and sudden cardiac death risk stratification in patients with hypertrophic cardiomyopathy. J Card Fail 2016;22:845-50. |
| 76. | Hassan S, Barrett CJ, Crossman DJ. Imaging tools for assessment of myocardial fibrosis in humans: The need for greater detail. Biophys Rev 2020;12:969-87. |
| 77. | Porcari A, Baggio C, Fabris E, Merlo M, Bussani R, Perkan A, et al. Endomyocardial biopsy in the clinical context: Current indications and challenging scenarios. Heart Fail Rev 2023;28:123-35. |
| 78. | Chen J, Lee SK, Abd-Elgaliel WR, Liang L, Galende EY, Hajjar RJ, et al. Assessment of cardiovascular fibrosis using novel fluorescent probes. PLoS One 2011;6:e19097. |
| 79. | Cooper LT, Baughman KL, Feldman AM, Frustaci A, Jessup M, Kuhl U, et al. The role of endomyocardial biopsy in the management of cardiovascular disease: A scientific statement from the American Heart Association, the American College of Cardiology, and the European Society of Cardiology. Circulation 2007;116:2216-33. |
| 80. | Jellis CL, Kwon DH. Myocardial T1 mapping: Modalities and clinical applications. Cardiovasc Diagn Ther 2014;4:126-37. |
| 81. | Blanken CP, Farag ES, Boekholdt SM, Leiner T, Kluin J, Nederveen AJ, et al. Advanced cardiac MRI techniques for evaluation of left-sided valvular heart disease. J Magn Reson Imaging 2018;48:318-29. |
| 82. | Balogh V, MacAskill MG, Hadoke PW, Gray GA, Tavares AA. Positron emission tomography techniques to measure active inflammation, fibrosis and angiogenesis: Potential for non-invasive imaging of hypertensive heart failure. Front Cardiovasc Med 2021;8:719031. |
| 83. | Karamitsos TD, Arvanitaki A, Karvounis H, Neubauer S, Ferreira VM. Myocardial tissue characterization and fibrosis by imaging. JACC Cardiovasc Imaging 2020;13:1221-34. |
[Figure 1]
[Table 1]
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