Why is fibrosis of the cardiac muscle serious

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Accessed October 27, Kissei Pharmaceutical Co. Kissei entered into an agreement with Nuon Therapeutics, Inc on Tranilast. Accessed October 22, Tracleer bosentan product information. Letairis ambrisentan product information. Opsumit macitentan product information. Clozel M, Salloukh H. Role of endothelin in fibrosis and anti-fibrotic potential of bosentan. Ann Med. FDA grants Amgen priority review designation for ivabradine for the treatment of chronic heart failure.

Featured Issue Featured Supplements. US Pharm. Structure of the Heart Wall The heart wall is composed of three layers: the epicardium outer layer , the myocardium middle layer , and the endocardium interior layer. To comment on this article, contact rdavidson uspharmacist. Related CE. View More CE. Related Content. Take Quiz. Ovarian Cancer. Furthermore, collagen must be cross-linked by lysyl oxidase to generate effective fibers that can resist proteinase degradation. During fibrosis, collagen I, providing rigidity, increases more apparently than collagen III, providing elasticity, which contributes to an increased wall tension Segura et al.

Various cells e. Some reports proposed that aging is an independent risk factor that can induce cardiac remodeling, although, the main reason may be collagen deposition, which increases with age and commonly reduces the heart's diastolic function Horn and Trafford, Diverging from previous viewpoints, recent studies showed that MMPs are not only involved in ECM degradation, but are also implicated in the progression to HF Spinale et al.

Many researchers studied the role of MMP-9 in cardiac fibrosis in senescent hearts without any other cardiac injury, which is associated with the higher possibility of HFpEF in aging individuals. Munch et al. Pressure or volume overload, myocardial infraction, myocarditis, and other factors may cause the imbalance of different MMPs and TIMPs, leading to the development of myocardial fibrosis and HF.

Macrophages play a vital role in pro-fibrotic response and regulation of fibrosis. In the healthy heart, monocytes, the progenitor cells of macrophages, are maintained in a steady state, but can differentiate into macrophages during cardiac injury regardless of the etiology. Although, macrophages may differentiate in situ from monocytes, they derive mostly from the recruitment of monocytes from the circulation, and inhibiting macrophages infiltration may prevent the development of fibrosis Falkenham et al.

For example, the infarcted myocardium can release endogenous signals, referring to danger-associated molecular patterns DAMPS , to promote local monocyte proliferation and to mobilize bone marrow-derived monocytes.

Cardiac remodeling is regulated by different subsets of macrophages expressing heterogeneous cell surface markers. M1 and M2 are the two subpopulations of macrophages classified in vitro Murray and Wynn, For example, in an experimental trial, M1 macrophages were recruited to the infarcted zone during the inflammatory stage of myocardial stenosis, then exhibited a proteolytic activity and secreted pro-inflammatory mediators including IL-1, TNF, and ROS.

M2 macrophages, following pro-inflammatory cells or transiting from M1 macrophages, exhibit an anti-inflammatory response and have a crucial function in wounding healing and fibrosis. A study on hepatic fibrosis showed that macrophages could express high levels of MMP and suppress fibroblast activation to resolve fibrosis Fallowfield et al.

Therefore, different subsets of macrophages with distinct properties and their communication with other cells have been further investigated. Mast cells participate in myocardial fibrosis primarily via pro-fibrotic and inflammatory functions Levick et al. Increasing density of mast cells has been showed in ischemic cardiomyopathy Engels et al.

In DCM patients with end-stage HF, mast cell density is correlated with the collagen fraction that represents myocardial fibrosis in tissue sampling Batlle et al. Levick and co-workers found that mast cell stabilization prevented the left ventricular fibrosis in spontaneously in a hypertensive rat model Levick et al.

Generally, mast cells may play a vital role in myocardial fibrosis in HF, but definite mechanisms have not been clarified. Mast cells can release many substances by degranulation such as histamine, tryptase, and chymase to mediate fibrosis Figure 2. Histamine stimulates fibroblast proliferation in pulmonary fibrosis Jordana et al.

Additionally, activating histamine H2 receptors in cardiomyocytes contributes to the increase in the production of cyclic adenosine monophosphate cAMP in the failing heart. Excessive cAMP increases oxygen consumption and worsens the heart function. Blocking H2 receptor improves HF symptoms and ventricular remodeling Kim et al. A prospective study also showed that an inhibitor of H2 receptors can reduce HF incidence and age-related left heart morphology change Leary et al.

Therefore, histamine may have an important function in cardiac remodeling, and inhibiting H2 receptor may be an important target to improve HF prognosis under the current pharmacotherapy. Oyamada et al. However, a recent study noted that systemic levels of mast cell tryptase was lower in LV systolic dysfunction, LV dilatation, or clinical CHF, which may result from the local consumption of tryptase Upadhya et al.

Therefore, local mast cell contribution to myocardial fibrosis may be undetectable through systemic sampling. However, these products can also be secreted by other inflammatory cells.

Thus, understanding the derivation and function of these molecules may help us identifying the mechanism underlying the role of inflammatory cells in fibrosis. Infiltration of lymphocytes, mainly T cells, is associated with the progression of heart failure. Nevers et al. The recruitment and infiltration may contribute to pathological cardiac remodeling in HF.

In rodent models of experimental autoimmune myocarditis, T cells are activated and a peak stage of inflammation and necrosis occurs around 21 days. Inflammatory cells infiltration declines and is replaced with fibrosis after 21 days, eventually leading to dilated cardiomyopathy and heart failure Watanabe et al. Hofmann et al. In general, T cells can differentiate into four subpopulations, T helper cells including Th1 and Th2 cells , regulatory T cells Tregs , and Th17 cells Wei, Th1 cells are involved in acute inflammation response and exert anti-fibrotic activities by secreting cytokines.

A recent study showed that Th1 cells can also mediate left ventricular collagen cross-linking, leading to diastolic dysfunction in mice Yu et al. Th2 cells participate in chronic remodeling response and contribute to fibroblast activation, proliferation, and matrix accumulation.

Th2 cells release IL-4 and IL The latter induces fibrosis by stimulating collagen production Wei, Tregs can attenuate myocardial fibrosis in an animal model of MI Tang et al. Recent studies described some emerging molecules such as cardiotrophin-1, nicotinamide adenine dinucleotide phosphate oxidase, and various matricellular proteins that are also involved in myofibroblast activation, collagen turnover, and collagen cross-linking Heymans et al.

These small molecules are also under investigation as diagnostic and therapeutic targets. Matricellular proteins do not exist in the normal ECM, but they are upregulated during myocardial injury and stress.

Matricellular proteins can transduce signals between matrix proteins and cells, including thrombospondins, and osteopontins Kong et al.

Finally, genes coding for ECM proteins e. Altogether, it appears that ECM synthesis, post-translational modifications, and ECM degradation are highly regulated processes, and even slight changes to these processes may have drastic effects on the cardiac structure and function.

Myocardial fibrosis in HF, which can be the result of an abnormality in these pathways, results in systolic dysfunction, diastolic stiffness, and aberrant ion conduction. Myocardial fibrosis is a common characteristic of HF, but the pattern of myocardial fibrosis depends on the etiology of HF.

Myocardial fibrosis manifests QRS prolongation Loring et al. The ultrasonic cardiogram, a basic instrument used to evaluate cardiac structure and function, can detect increased left ventricular end diastolic diameter, decreased ejection fractions, systolic dyssynchrony, and elevated filling pressures.

Diffuse myocardial fibrosis may lead to impaired movement of the entire ventricular wall. However, these techniques have no specificity for the detection of fibrosis. Therefore, new diagnostic methods have been developed to detect fibrosis and evaluate its extent more effectively. Presently, the extent of myocardial fibrosis can be evaluated by using different methods, including endomyocardial biopsy, magnetic resonance imaging MRI , or with serum markers of collagen turnover Aoki et al.

We will discuss both the pros and cons of each detection method and the significance to indicate prognosis of HF. First, we should discuss the current standard for evaluating HF prognosis.

Myocardial fibrosis is involved in the progression of LV dilatation and deterioration of the cardiac muscle, leading to pump function failure.

Pump function failure, cardiomyocyte separation, and fibrosis itself may induce fatal arrhythmias. Therefore, when evaluating an indicator for its prognostic significance, we should estimate it in two aspects: pump function failure and SCD.

Myocardial fibrosis is an ongoing remodeling process that requires the discovery of effective and specific biomarkers in order to diagnose and provide therapeutic interventions. Galectin-3 Gal-3 is secreted by inflammatory cells and fibroblasts, and can be degraded by MMPs. Some animal experiments demonstrated that Gal-3 can accelerate myocardial fibrosis in cardiac disease. Moreover, circulating levels of Gal-3 are associated with the degree of myocardial fibrosis and can predict the re-hospitalization and all-cause mortality of HF.

In addition, Gal-3 is an excellent marker for the detection of earlier cardiac remodeling without HF Ho et al. ST2, a member of the interleukin-1 receptor family, exists in both a transmembrane and a soluble form. The transmembrane form is called ST2L. Interleukin IL plays a role in suppressing myocardial fibrosis and cardiomyocyte hypertrophy via binding to ST2L, whereas excessive soluble ST2 can attenuate the function of IL, leading to myocardial fibrosis and ventricular dysfunction.

Many studies indicated that ST2 is associated with all-cause mortality and cardiovascular mortality Passino et al. In recent years, there have been many studies on the functions of ST2 and Gal-3 as clinical diagnosis and prognosis markers.

Bayes-Genis et al. However, in another study, the incorporation of ST2 and Gal-3 to clinical evaluations could not significantly predict pump failure of patients with HF, whereas it could indicate the SCD risk Ahmad et al.

ECM deposition requires an increase in the expression of ECM-related proteins such as proteins involved in collagen synthesis. We first briefly introduce currently studied miRNAs. Circulating levels of miR are related to the grade of myocardial fibrosis. Villar et al. Moreover, miR is associated with the echocardiographic mean transvalvular gradients Villar et al. Additionally, the anti-miR antagomir can repress the expression of genes encoding collagen and ECM proteins.

However, the repressive function was reduced due to miR decrease during HF. Additionally, miRb can directly inhibit proteins involved in building the ECM such as collagens, MMPs, leukemia inhibitory factors, and insulin-like growth factor I. Roncarati et al. Therefore, there are many studies about the cluster of miRNAs involved in myocardial fibrosis. Besides other serum markers, current molecules proven to associate with myocardial fibrosis as measured by histological parameters and collagen volume fraction are the carboxy-terminal pro-peptide of pro-collagen type I PICP and the amino-terminal pro-peptide of pro-collagen type III PIIINP; reviewed by Prockop and Kivirikko, However, the greatest disadvantage of the two biomarkers is their low specificity.

Organ fibrosis such as hepatic fibrosis and pulmonary fibrosis could lead to the apparent increase in these markers. In another study, Lopez-Andre et al. Therefore, finding better biomarkers of myocardial fibrosis requires a deeper understanding of the molecular mechanisms underlying the development of fibrosis.

These molecules and each part of the pathway contributing to fibrosis can be targeted as biomarkers for anti-fibrotic therapy or to predict a prognosis for patients with HF. Myocardial fibrosis causes the enlargement of the extracellular space because of ECM deposition and excessive retention of gadolinium leads to enhancement in CMR Karamitsos et al. Different etiologies causing myocardial fibrosis can show different patterns of LGE Karamitsos et al.

The distribution of LGE is unrelated to a particular coronary arterial territory Zacharski et al. The LGE pattern in the setting of myocarditis presents a characteristic distribution Lagan et al. The subepicardium is usually affected with varying degrees of progression toward the mid-myocardial wall and typical sparing of the subendocardium, and the lateral and inferolateral walls are frequently involved Andre et al.

The focal areas of hyper-enhancement become diffuse over a period of days to weeks and then decrease during healing. However, some patients cannot recover and often develop DCM, which usually presents as a mid-wall hyper-enhancement. Asymmetrical thickness of the interventricular septum and LV outflow track obstruction are the main characteristics of HCM.

In burn-out HCM, the thickness of the ventricular wall is reduced and the hyper-enhancement is relatively thickened, while the pattern of LGE can be similar to that of ischemic cardiomyopathy. In hypertension, LGE is related to left ventricular hypertrophy caused by pressure overload and is an independent risk factor to cardiac mortality Rudolph et al.

Moreover, myocardial fibrosis detected by LGE is associated with increased left ventricular filling pressure and longitudinal systolic dysfunction in early-stage hypertensive patients. On the other hand, hypertensive patients with increased ventricular filling pressure and diastolic dysfunction undergo LV remodeling Contaldi et al.

In cardiac sarcoidosis, LGE usually shows a non-ischemic pattern with hyper-enhancement of the mid-myocardial wall or the epicardium. However, subendocardial or transmural hyper-enhancement have also been observed, mimicking an ischemic pattern. The basal septal walls are most frequently involved, although sometimes hyper-enhancement is detected in other territories, including the RV Komada et al.

Cardiac involvement in systemic amyloidosis is frequent. On CMR, diffuse myocardial hypertrophy including both the ventricles and atria is observed with thickened valve leaflets and pericardial effusion. After gadolinium administration, there may be a circumferential pattern of LGE, preferentially affecting the subendocardium, but sometimes showing a patchier transmural pattern Hashimura et al.

For valvular heart disease, the hyper-enhancement of the myocardium may not be discoverable, since cardiac remodeling is not apparent in early progression of the disease, but it is noteworthy that valve function can be effectively evaluated by CMR. Furthermore, CMR can provide information regarding the influence of the valve lesion on the myocardium by LGE and other parameters of cardiac structure, which is very important for physicians to delineate an operation plan and evaluate the prognosis after valve replacement.

LGE has provided clinicians with tools to distinguish non-ischemic from ischemic cardiomyopathies and to identify the etiology of non-ischemic cardiomyopathies. In addition, the presence of LGE and its extent in myocardial tissue relates to overall cardiovascular outcomes Groves et al. Our team Liu et al. This association was independent of the LVEF and etiology of heart failure ischemic cardiomyopathies and non-ischemic cardiomyopathies.

Dilated cardiomyopathy DCM is a primary cardiomyopathy of both genetic and non-genetic origin that is characterized by dilation of the ventricle and systolic dysfunction in the absence of coronary artery disease.

DCM is the most frequent indication for heart transplantation. Duan et al. HCM is a relatively common genetic disorder of the cardiac sarcomere, characterized by an idiopathic LV hypertrophy and represents the most frequent cause of SCD among young athletes. A recent meta-analysis Briasoulis et al. This study further proves that extensive LGE is a promising risk-stratification tool as it significantly predicts SCD risk, cardiac mortality, and all-cause mortality in patients without conventional risk markers.

Currently available data support that patients with extensive LGE for primary prevention of SCD should be considered for ICD implantation, even if they are not at high-risk according to the conventional risk markers. Sarcoidosis is a systemic multi-organ disorder of unknown etiology that is histopathologically characterized by granulomas. However, several recent CMR studies suggested the presence and extent of myocardial LGE as an even more important overall prognostic factor than LV function Birnie et al.

Cardiac amyloidosis is a common cause of restrictive cardiomyopathy, and reduced ventricular wall compliance leads to impairment of diastolic filling and diastolic heart failure even when systolic function was preserved. A recent systematic review and meta-analysis supported that the incremental prognostic value of LGE. Thus, LGE may be useful for risk stratification of these patients for aggressive medical management, possibly leading to a decrease in all-cause mortality Raina et al.

Additionally, the LGE signal intensity is not precise enough to differentiate the types of fibrosis i. Moravsky et al. LGE quantified by 5 SD has a better association with interstitial than with replacement fibrosis, whereby the LGE measured by 10 SD may show a stronger correlation with replacement fibrosis.

However, the authors underscore that LGE quantified by a high threshold cannot reflect the type of fibrosis because it represents the sum of the two types Moravsky et al. Current T1 mapping techniques, including quantification of extracellular volume ECV , can be used to overcome the drawback of LGE imaging in the set of diffuse myocardial diseases.

T1 mapping has prominent advantages to detect diffuse fibrosis, since it assesses the T1 relaxation time of myocardial tissue. Several studies showed that the association of T1 mapping including native T1, post-contrast T1, and extracellular volume fraction with CVF in myocardial biopsies of AS Everett et al.

Kockova et al. Ellims et al. Extracellular volume fraction ECV , a novel parameter evaluating myocardial fibrosis, is measured from both pre- and post-contrast T1 mapping analyses. In a recent study, Barison et al. More importantly, ECV could identify early interstitial fibrosis with no apparent LGE, which provides physicians with a valuable way to predict the prognosis of HF patients with non-ischemic dilated cardiomyopathy Barison et al.

ECV may be an important method to assess mechanistic and hemodynamic abnormalities in patients with HCM. Moreover, ECV is increased in HCM sarcomere mutation carriers, even before left ventricular hypertrophy becomes detectable.

Based on the above two studies, targeting fibrosis could be a promising therapy for HCM Ho et al. Presently, there are only few studies on ECV, but the future of this technique is promising and more studies are being devoted to it.

Despite these advantages, the limitations of CMR need to be considered. For patients who have pacemakers or defibrillators, CMR cannot be applied to evaluate the myocardium lesion. In addition, because LGE-CMR needs gadolinium-based contrast agents to show the matrix, the risk of worsening renal dysfunction for patients with renal insufficiency should be considered by clinicians to avoid further renal injuries Karamitsos et al.

However, CMR is still the best method to evaluate myocardial fibrosis, although more techniques are evolving to differentiate the types and extent of myocardial fibrosis. Thus, clinical trials need to select more precise techniques that are consistent with practical fibrosis and further demonstrate the association between the markers of fibrosis and its prognosis.

Although CMR can effectively detect and evaluate the degree of myocardial fibrosis, histology of endomyocardial biopsy specimens from patients with HF is still considered the gold standard for myocardial fibrosis detection. In some studies, the CVF is calculated to evaluate the extent of myocardial interstitial fibrosis.

The CVF is the ratio of the sum of all connective tissue areas over the sum of all connective tissue and muscle areas from averaged values of several representative fields of the tissue section. CVF can qualitatively determine the extent of myocardial fibrosis, but the cut-off values of mild and severe fibrosis have not been defined, and the cut-off varies from study to study. Galectin-3 marks activated macrophages in failure-prone hypertrophied hearts and contributes to cardiac dysfunction.

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Heydari B, et al. Effect of omega-3 acid ethyl esters on left ventricular remodeling after acute myocardial infarction. Lewis GA, et al. Cardiovasc Drugs Ther. Download references. All named authors meet the International Committee of Medical Journal Editors ICMJE criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.

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