1. bookVolume 76 (2022): Edition 1 (January 2022)
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Cardiac fibrosis and atrial fibrillation

Publié en ligne: 11 Jul 2022
Volume & Edition: Volume 76 (2022) - Edition 1 (January 2022)
Pages: 307 - 314
Reçu: 28 Oct 2021
Accepté: 28 Mar 2022
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1732-2693
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20 Dec 2021
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Abstract

Cardiac fibrosis is characterized by the imbalance of production and degradation of the extracellular matrix. The result of this process is an accumulation of scar tissue, which is associated with many pathological processes such as excessive mechanical stress on the heart, inflammation, ischemia, oxidative stress, or excessive neurohormonal activation. Fibrotic response results in damaged heart architecture and dysfunction of the heart. Cardiac fibrosis leads to increased stiffness of the left ventricle and arteries, promotes disorders of contraction and relaxation of the heart, disrupts electrophysiology of heart cells, and induces arrhythmias.

Atrial fibrillation is one of the most common arrhythmias. It is associated with a deterioration in the quality of life and more frequent use of medical assistance. It is also an instantaneous risk factor for many diseases, including stroke. The underlying cause of this arrhythmia is electrical and structural remodeling induced by cardiac fibrosis. Therefore, much attention is paid to the search for biochemical markers that would allow non-invasive determination of the degree of this fibrosis.

The promising markers include galectin-3, human epididymis protein 4 (HE4), serum soluble ST2, and adipose triglyceride lipase (ATGL). Studies have shown that plasma concentrations of these substances reflect the degree of myocardial fibrosis and are indirectly associated with AF.

There are high hopes for the use of these markers in patients undergoing arrhythmia ablation. More research is needed to confirm that these markers can be used to estimate the chance of maintaining sinus rhythm in patients after ablation.

Keywords

Introduction

Atrial fibrillation (AF) is one of the most common tachyarrhythmias observed in the clinic, with a population prevalence of 1% to 2% [1]. It has become an important and growing clinical problem. Atrial fibrillation decreases the quality of patients’ lives while also presenting a financial burden, due to more frequent use of medical assistance and its severe complications [2]. AF is associated with a significant morbidity rate: an increased risk of thromboembolic events, especially stroke. AF increases the probability of thromboembolic events fivefold in all age groups. AF has many other negative consequences, including increased frequency of hospitalizations for heart failure, cognitive disorders, dementia syndromes, systemic embolism, decreased physical fitness, deterioration in the quality of life, depression, increased risk of falls, and increased all-cause mortality [3, 4].

The main risk factors for AF are older age, obesity, smoking, hypertension, heart disease (heart failure, coronary artery disease), diabetes, alcohol consumption, inflammatory diseases, and an unfavorable lipid profile [3, 5].

Due to the common occurrence of the above diseases, these risk factors should be carefully monitored, and preventive measures should be taken to reduce the frequency of their occurrence. The range of symptoms presented by patients with AF is very wide. These include, among others, palpitations, shortness of breath, fatigue, as well as pressure and pain in the chest, deterioration of exercise tolerance, or fainting. Importantly, as many as 50% to 87% of patients with AF do not experience any discomfort, which delays diagnosis and worsens the prognosis [3, 6, 7]. Therefore, it seems extremely important to identify people especially at risk of developing AF and perform screening tests. Research shows that a special trigger is needed to induce arrhythmia, as well as the anatomical and functional substrate conducive to its maintenance [5, 8].

There are four major pathophysiological mechanisms contributing to AF: electrical remodeling, structural remodeling, autonomic nervous system alterations, and Ca2þ handling abnormalities. Each of them may result from heart disease and contribute to the development of AF. AF causes anomalies that promote AF in each of these areas [9]. The main source of atrial fibrillation may be in the pulmonary veins. The presence of ectopic foci has also been proven in the main veins or on the posterior wall of the left atrium. The maintenance of arrhythmia is due to the constant conduction of small independent waves of excitation that spread throughout the atrial cardiomyocytes [8, 9]. The mechanisms of atrial fibrillation are connected with the structural and electrical remodeling of the myocardium of the atria and ventricles. The crucial electrophysiological mechanisms of this arrhythmia include focal triggering (early and delayed after-depolarizations); multiple re-entries due to shortening of the action potential; and heterogeneity of impulse conduction caused by atrial fibrosis [10].

Electrophysiologically, the mechanisms that initiate AF can be divided into focal and recurrent. Paroxysmal AF is most often a focal arrhythmia that develops in the pulmonary veins. Rapid focal discharges contribute to uneven activation of the rest of the atria, leading to chaotic conduction and AF. Chronic AF is most commonly associated with structural damage to the atrium, contributing to the multiple circulating waves of excitation leading to uninterrupted electrical activity. It is also possible for different electrophysiological mechanisms to coexist [11, 12].

The structural changes, including extracellular matrix collagen accumulation and development of fibrosis, probably take longer to develop than the electrophysiological changes. These changes may, however, be even more important in the maintenance of AF [1].

Unlike other organs, the heart has limited regenerative capacity after injuries. Instead of regeneration, repair processes involve the removal of necrotic cardiomyocytes followed by fibrotic scar tissue replacement that acts to preserve the myocardial structure and function of the heart [13].

Cardiac fibrosis provokes pathological changes that culminate in chamber dilatation, cardiomyocyte hypertrophy, and apoptosis, and ultimately lead to the development of congestive heart failure [5]. Advanced atrial fibrosis is associated with more frequent paroxysms of AF, transformation of the arrhythmia into a permanent type, and reduced effectiveness of antiarrhythmic drug therapy [10].

Cardiac fibrosis and function of the heart

Myocardial fibrosis is a pathological process connected with cardiac disease that contributes to impaired cardiac function, development of arrhythmias, and, in the end, heart failure [14].

There are two types of cardiac fibrosis: reactive fibrosis and repair fibrosis. Reactive fibrosis is associated with increased fibroblast proliferation, differentiation of myofibroblasts into a secreting form, and increased deposition of extracellular matrix – mainly collagen – in the interstitial spaces and between vessels. This causes the normally thin layer of fibrous tissue around the muscle bundles to rebuild into thicker sheaths. The muscle bundles remain unchanged [11, 15, 16]. The factor that contributes to this development is hemodynamic stress related to, among other things, the overload of the heart.

Reactive fibrosis develops as an adaptive response to pathological factors and is aimed at normalizing the increased load on the walls and preserving the ejection fraction of the heart. However, when fibrosis becomes excessive, it can lead to mechanical stiffness, resulting in diastolic dysfunction of the heart. There are also electrical conduction disturbances caused by the creation of a barrier between cardiomyocytes. This in turn leads to systolic heart failure [15]. In addition, excessive fibrosis in the perinatal spaces impairs the flow of oxygen and nutrients. This leads to energy starvation in the heart muscle.

Repair fibrosis, also known as surrogate, occurs in response to the loss of properly functioning cardiomyocytes. Fibroblasts at the site of cardiomyocytes form a scar, which maintains the integrity of the heart chambers [11, 15]. Thanks to collagen, the architecture of the heart is preserved, but during the development of various disorders in the myocardium, this collagen network undergoes qualitative and quantitative changes, leading to excessive accumulation of collagen not only in the areas of cardiomyocyte loss (such as in a heart attack) or in a diffuse manner in areas not affected by the loss of cardiomyocytes (for example, dilated cardiomyopathy) [10].

The research showed that cardiac fibrosis has functional consequences even with little loss of cardiomyocytes. The imbalance between the processes of synthesis and degradation of extracellular matrix proteins (ECM) results in structural and functional disorders of the heart [17, 18, 19].

It is assumed that myocardial fibrosis is initially associated with stiffening of the ventricles and their diastolic failure. Increased deposition of extracellular matrix in the interstitium of the heart is associated with the activation of matrix metalloproteinases (MMPs) [17]. Therefore, the synthesis of the fibrous matrix of the ventricle is accompanied by the degradation of the matrix proteins. This disrupts the linkage of excitation and contraction of the heart muscle. This leads to a widening of the ventricles and, consequently, systolic failure.

Changes in the collagen network in the fibrotic heart can cause systolic dysfunction by several mechanisms. One of them is based on the loss of filamentous collagen. This can disrupt the conversion of the contraction of the cardiomyocytes into the strength of the heart muscle. This results in uncoordinated contraction of the cardiomyocyte bundles. Cardiac fibrosis may also cause cardiomyocytes to glide. This reduces the number of muscle layers in the ventricular wall and leads to the extending of the left ventricle [17].

The significance of cardiac fibrosis in atrial fibrillation

Atrial fibrillation has structural, hemodynamic, electrical, and rheological consequences. The duration of the arrhythmia promotes atrial fibrosis and remodeling leading to cardiomyopathy. It manifests itself in changes in the structure, architecture, and contractility of the atrium, resulting in clinical symptoms. Interestingly, AF is not only a causative agent of cardiomyopathy but also one of its symptoms [6, 8, 9].

Structural remodeling of the atria of the heart in the course of AF is the basis for its initiation and subsequent duration [10]. Structural and functional changes may develop as a result of other stress factors or as a result of other cardiovascular diseases related to overload and distension of the atria, such as arterial hypertension, heart failure, or valvular heart disease.

External factors can be a direct cause of the structural remodeling of the heart and thus contribute to the initiation and maintenance of AF. We divide such factors into non-modifiable factors such as age or genetic factors, or modifiable factors such as arterial hypertension [2, 20]. Studies have shown that there are also non-cardiac factors leading to cardiac fibrosis in AF, including obesity, systemic inflammation, metabolic syndrome, thyrotoxicosis, and obstructive sleep apnea [21].

Structural changes in AF occur both at the micro and macroscopic levels and vary with time and etiology. Macroscopic changes include atrial dilatation, myocardial hypertrophy, and some dilution of cardiomyocytes replaced with fibrous tissue. Such changes are focal and scattered [2]. In the microscopic examination, cellular hyperplasia, myolysis, fibrosis, and apoptosis can be seen [20].

There is no conclusive evidence as to whether structural remodeling is the cause or the result of the arrhythmia [2]. Most of the factors initiating fibrosis contribute primarily to the pressure and volume overload of the atria, which leads to increased compliance of the atria and, consequently, their dilation.

Studies have shown that sudden stretching of the atria increases the dispersion of their refractions, slows down the atrial conduction, and increases the ectopy of the pulmonary veins [20]. In any case, interstitial fibrosis slows down the depolarization wavefront. The electrical impulse then begins to diverge via alternative routes, which initiates new reentry circuits [2, 20]. The increase in myocardial anisotropic properties may be due to the activation of stretch-sensitive ion channel walls, including Cl-, K +, and other nonspecific stretch-sensitive channels [20].

Studies have shown that the degree of myocardial structural remodeling strongly correlates with the duration of AF [12]. Also, studies on patients undergoing cardiovascular surgery showed that the degree of atrial fibrosis corresponded to the risk of postoperative AF. There have also been studies showing that an increased amount of left atrial fibrosis is strongly associated with the recurrence of AF after ablation of the arrhythmia substrate [22]. It is also worth noting that experimental and clinical studies have shown that the prevention of atrial fibrosis by typical anti-fibrotic strategies (statins, ACE inhibitors) resulted in reduced stability of the occurrence of AF [23].

Imaging studies have established that fibrosis in AF is not necessarily limited to the atria. Fibrotic changes in the ventricles turned out to be more common in patients with AF compared to those with a preserved sinus rhythm [2].

Markers of fibrosis

Cardiovascular biomarkers play an essential role in the diagnosis, risk stratification, and treatment of patients with cardiac diseases such as heart failure, dilated cardiomyopathy, and hypertrophic cardiomyopathy [24]. In recent years, much attention has been paid to searching for markers that would allow the noninvasive assessment of the degree of myocardial fibrosis and its possible consequences [20]. Endomyocardial biopsy is the gold standard in the diagnosis of myocardial fibrosis, but it has limitations in terms of clinical application. Biomarkers seem to be safer in diagnosis, treatment monitoring, and prognosis [24].

Galectin-3

Galectin 3 (Gal-3) belongs to lectins, the β-galactosidase-binding protein group. It is produced by activated macrophages and endothelial cells under influence of inflammatory factors [25]. Atrial fibrillation induces tissue injuries, which lead to increased Gal-3 synthesis and secretion [4]. Galectin stimulates neutrophils and T lymphocytes and affects intercellular adhesion, angiogenesis, cell growth and differentiation, and apoptosis [26].

Increased Gal-3 secretion stimulates the release of various mediators, including transforming growth factor β (TGF-β) and interleukins (IL-1, IL-2). The role of Gal-3 in the pathogenesis of cardiac fibrosis involves the proliferation of cardiac fibroblasts, which synthesize ECM, especially collagen type I. It contributes to the disturbance of homeostasis of extracellular matrices, and it plays a role in the electric atrial activity and structural remodeling. Loss of balance between the contents of collagen types I and III lead to impairment of both the systolic and diastolic functions of the heart muscle [25, 27]. The research focused on the recognition functions of galectin 3 indicates that its concentration correlates with the intensity of the inflammatory process in diseases of the cardiovascular system, especially in heart failure, ischemic heart disease, arrhythmias, and atherosclerosis [27]. Research has been performed for many years to discover a useful predictor of frequent supraventricular arrhythmias, especially atrial fibrillation. Studies showed that high circulating Gal-3 concentrations were associated with an increased risk of developing AF. In patients with persistent AF, serum concentrations of this protein were higher than in patients without arrhythmia [25, 26, 27]. Serum galectin-3 level also independently correlates with the extent of left atrial fibrosis shown upon delayed enhanced magnetic resonance imaging [28].

sST2

Serum soluble ST2 (sST2) is a family member of the interleukin-1 receptors. It can be found on cardiac myocytes and fibroblasts [29, 30]. In experimental models, the interaction between interleukin 33 (IL-33) and ST2 seems to be protective, reducing fibrosis, hypertrophy, and apoptosis.

The marker exists in two isoforms: transmembrane (ST2L) and dissolved in plasma (sST2). A transmembrane receptor ST2L, with IL-33 as a natural ligand, triggers anti-apoptotic, anti-hypertrophic, and cardioprotective actions. The second isoform, sST2, is a soluble protein that behaves as a decoy receptor, promoting in this way the inhibition of the IL-33/ST2L signaling pathway [29, 31].

Whereas ST2 is certainly part of the myocyte wall, some studies have suggested that the vascular endothelial cell might be a prominent source of sST2 in cardiac patients. All clinical conditions that increase wall stress, inflammation, and macrophage activation increase sST2 and may therefore lead to an increase in cardiac fibrosis [29]. ST2 has evolved as a new cardiovascular biomarker for assessing acute heart failure and predicting the outcome of chronic heart failure. Elevated sST2 levels in acute heart failure patients predict both rehospitalization and mortality. Research shows that sST2 is probably an objective biomarker that can predict AF patients’ risk of an emergency admission or heart failure (HF), and elevated sST2 concentration may be involved in the progression of AF [30, 32].

ATGL

Adipose triglyceride lipase (ATGL) is an enzyme that initiates the initial step in the intracellular hydrolysis of triacylglycerols. It limits the action of triacylglycerol lipase in many tissues, including the heart muscle [33, 34]. Hydrolysis of triacylglycerols leads to the formation of non-esterified fatty acids, which are important substrates for the production of lipids and membranes, and are used as mediators in cells and as an energy substrate in mitochondria [35]. Animal studies have shown that ATGL deficiency leads to the accumulation of TG in the myocardium, stored as intracellular lipid droplets. Fatty heart muscle cells due to ATGL deficiency result in myocardial fibrosis, which severely impairs left ventricular systolic function, lowers cardiac output, and is associated with higher mortality [36, 37]. On the other hand, cardiomyocyte-specific AGTL overexpression reduced the content of TG in the heart and improved both systolic and diastolic function of the heart [34, 37]. Differences in plasma AGTL concentration could indicate the severity of steatosis and the subsequent cardiac fibrosis [36]. This could allow the determination of the degree of myocardial remodeling influencing the incidence of AF.

HE4

Human epididymis protein 4 (HE4), also known as WAP 4-disulfide core domain-2 or Wfdc2, was initially isolated in the epididymides as a secretory protein thought to be involved in sperm maturation [38, 39]. It was later shown that HE4 is present in many other tissues of the human body, in the kidneys, respiratory system, and gastrointestinal tract [40]. HE4 is also used as a marker for monitoring ovarian epithelial and endometrial cancer [41]. HE4 is considered the most up-regulated gene in fibrosis-associated myofibroblasts [39]. The activity of many proteases, including serine proteases and matrix metalloproteinases, is inhibited by HE4, as a result of which they lose their ability to degrade type I collagen [39]. In the conducted studies, an increased level of this factor was observed in patients with heart failure. It is worth emphasizing that the level of HE4 correlated with the intensity of HF expressed in the NYHA classification, as well as with recognized markers of heart failure, such as NT-proBNP, Gal-3, and hsTnT [40]. It gives hope for the use of HE4 as a fibrotic factor in other states connected with cardiac fibrosis, for example, atrial fibrillation.

FGF23

The FGF family is divided into 22 members classified into seven subfamilies due to phylogenetic similarity. Each of them has a different effect – paracrine, endocrine, and endocrine. FGF23 belongs to the group of endocrine FGFs and acts mainly as a hormone-like FGF [42]. FGF23 acts as a hormonal regulator of phosphate and calcium homeostasis (Ca2+) [43]. FGF23 is mainly secreted from osteoblasts and has an endocrine effect on the kidney through the activation of FGFR1/klotho co-receptor complexes to regulate phosphate and mineral homeostasis [44]. There is growing evidence that high levels of circulating FGF23 are associated with a high risk of cardiovascular disease, heart failure, and mortality in the elderly population [42, 43, 44]. Moreover, FGF23 may be a new risk factor for coronary artery disease and heart failure [43]. Studies show that FGF23 may act in the endoplasmic reticulum to stimulate Ca2+ ATPase activity, a regulatory protein that sends cytosolic Ca2+ to the reticulum This causes an increase in Ca2+ concentration in the sarcoplasmic reticulum of cardiomyocytes and thus contributes to the development of arrhythmogenesis [43, 45]. FGF23 activating the PLC/IP3 signaling path leads to upregulation of Ca2+ input via Orai1 and/or TRPC1. Thus, it strengthens the proliferative and migratory capacity of cardiac fibroblasts [43]. FGF23 is an early and complementary predictor of adverse cardiac events and may improve risk assessment in susceptible patients with HF or a reduced ejection fraction. FGF23 is positively correlated, but not directly dependent on, classical biomarkers of cardiac damage such as N-terminal B-type natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin T (hs-cTnT), and C-reactive protein (CRP). Studies show that the prognostic value of combining these bio-markers in the assessment of cardiovascular risk is greater than that of single biomarkers [46].

TGF-β1

TGF-β belongs to the group of pleiotropic cytokines involved in many cellular processes, which include regulation of inflammation, extracellular matrix deposition, cell proliferation, and cell growth and differentiation [47]. TGF plays an important role in cardiac pathophysiology, including hypertrophic and fibrotic reconstruction of the heart, and regulates the metabolism of the matrix at the time of cardiac pressure overload [48]. Following myocardial infarction, TGF-β inactivates inflammatory macrophages, while stimulating myofibroblast transdifferentiation and extracellular matrix synthesis [47, 48].

Myofibroblasts secrete major ECM proteins such as periostin, collagens I and III, fibronectin, and a number of cytokines regulating the inflammatory response. The TGF-β signaling pathway is one of the major regulators of myofibroblasts in cardiac fibrosis. High TGF-β1 expression levels have both been demonstrated during myocardial fibrosis both in humans and experimental models.

Different TGF signaling pathways play different roles in the process of fibrogenesis. TGF-β1 directly influences Smad signaling, which overexpresses the profibrotic gene. Studies have shown that disruption of the TGF-β1/Smad pathway balance played an important role in tissue fibrosis. The Smad2 and Smad3 pathways are downstream regulators and stimulate tissue proliferation using TGF-β1. In contrast, Smad 7 is a negative feedback regulator of the TGF-β1/Smad pathway. In this way, it counteracts fibrosis mediated by TGF-β1 [49].

In mice, it has been shown that cardiac fibrosis caused by pressure overload can be reduced by the deletion of the TGF-b or Smad 3 gene in cardiac fibroblasts [50].

Collagen markers

Myocardial fibrosis plays the most important role in the structural remodeling of the heart muscle [50, 51]. It occurs when the production of type I and II collagen exceeds its degradation and leads to two types of macroscopic and microscopic fibrosis.

Among circulating markers, the highest correlation with myocardial fibrosis was shown by serum carboxy-terminal pro-peptide of procollagen type I (PICP), serum amino-terminal pro-peptide of procollagen type III (PIIINP), and serum collagen type I telopeptide (CITP) [50, 51].

Fig. 1

Fibroblast growth factor (FGF)-23 and its effect on cardiac fibroblast activity.

FGF receptor 1 (FGFR1), phospholipase C (PLC), inositol 1,4,5-trisphosphate (IP3), calcium channel protein 1 (Orai1), IP3 receptor (IP3R)

PICP is formed during the conversion of type I procollagen to type collagen I in the extracellular space. Studies have shown that its increased concentration can be observed in patients with heart failure. Its concentration level correlates with the occurrence and mortality of ventricular arrhythmias in patients with heart failure. Its concentration increases in patients suffering from HF. Its concentration varies in response to treatment with drugs such as loop diuretics and mineralocorticoid receptor antagonists [50].

PIIINP arises from the extracellular production of type III collagen. Its concentration correlates with the amount of myocardial tissue replaced by type III collagen fibers. The relationship between PIIINP concentrations and the content of type III collagen in patients with ischemic heart disease and idiopathic dilated cardiomyopathy was confirmed [52].

CITP, and more specifically the ratio of CITP to serum matrix metalloproteinase (MMP) -1, is an expression of collagen resistance to MMP degradation. It correlates with the risk of hospitalization [50].

Summary

Atrial fibrillation, due to its frequency of occurrence, hospitalization as its consequence, and possible complications, is of interest to scientists all over the world. Increasing attention has been paid to myocardial fibrosis as one of the major factors in arrhythmia, but this mechanism has not been sufficiently studied further. Future research on biochemical markers of fibrosis may prove to be groundbreaking in the assessment of the degree of fibrosis, identifying at-risk individuals, predicting arrhythmia, and innovating possible novel therapeutic methods [53].

Fig. 1

Fibroblast growth factor (FGF)-23 and its effect on cardiac fibroblast activity.FGF receptor 1 (FGFR1), phospholipase C (PLC), inositol 1,4,5-trisphosphate (IP3), calcium channel protein 1 (Orai1), IP3 receptor (IP3R)
Fibroblast growth factor (FGF)-23 and its effect on cardiac fibroblast activity.FGF receptor 1 (FGFR1), phospholipase C (PLC), inositol 1,4,5-trisphosphate (IP3), calcium channel protein 1 (Orai1), IP3 receptor (IP3R)

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