The complex dynamics of myocardial interstitial fibrosis in heart failure. Focus on collagen cross-linking

Introduction: The heart undergoes myocardial remodeling during progression to heart failure following pressure overload. Myocardial remodeling is associated with structural and functional changes in cardiac myocytes, fibroblasts, and the extracellular matrix (ECM) and is accompanied by inflammation. Cardiac fibrosis, the accumulation of ECM molecules including collagens and collagen cross-linking, contributes both to impaired systolic and diastolic function. Insufficient mechanistic insight into what regulates cardiac fibrosis during pathological conditions has hampered therapeutic solutions. Lumican (LUM) is an ECM-secreted proteoglycan known to regulate collagen fibrillogenesis. Its expression in the heart is increased in clinical and experimental heart failure. Furthermore, LUM is important for survival and cardiac remodeling following pressure overload. We have recently reported that total lack of LUM increased mortality and left ventricular dilatation, and reduced collagen expression and cross-linking in LUM knockout mice after aortic banding (AB). Here, we examined the effect of LUM on myocardial remodeling and function following pressure overload in a less extreme mouse model, where cardiac LUM level was reduced to 50% (i.e., moderate loss of LUM). Methods and Results: mRNA and protein levels of LUM were reduced to 50% in heterozygous LUM (LUM+/–) hearts compared to wild-type (WT) controls. LUM+/– mice were subjected to AB. There was no difference in survival between LUM+/– and WT mice post-AB. Echocardiography revealed no striking differences in cardiac geometry between LUM+/– and WT mice 2, 4, and 6 weeks post-AB, although markers of diastolic dysfunction indicated better function in LUM+/– mice. LUM+/– hearts revealed reduced cardiac fibrosis assessed by histology. In accordance, the expression of collagen I and III, the main fibrillar collagens in the heart, and other ECM molecules central to fibrosis, i.e. including periostin and fibronectin, was reduced in the hearts of LUM+/– compared to WT 6 weeks post-AB. We found no differences in collagen cross-linking between LUM+/– and WT mice post-AB, as assessed by histology and qPCR. Conclusions: Moderate lack of LUM attenuated cardiac fibrosis and improved diastolic dysfunction following pressure overload in mice, adding to the growing body of evidence suggesting that LUM is a central profibrotic molecule in the heart that could serve as a potential therapeutic target.

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Heart failure in chronic kidney disease: the emerging role of myocardial fibrosis

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa284 ◽

2020 ◽

Author(s):

Gregorio Romero-González ◽

Arantxa González ◽

Begoña López ◽

Susana Ravassa ◽

Javier Díez

Keyword(s):

Heart Failure ◽

Chronic Kidney Disease ◽

Kidney Disease ◽

Current Knowledge ◽

Interstitial Fibrosis ◽

Collagen Fibres ◽

Fibrotic Tissue ◽

Myocardial Interstitial Fibrosis ◽

New Strategy

Abstract Heart failure (HF) is one of the main causes of morbidity and mortality in patients with chronic kidney disease (CKD). Decreased glomerular filtration rate is associated with diffuse deposition of fibrotic tissue in the myocardial interstitium [i.e. myocardial interstitial fibrosis (MIF)] and loss of cardiac function. MIF results from cardiac fibroblast-mediated alterations in the turnover of fibrillary collagen that lead to the excessive synthesis and deposition of collagen fibres. The accumulation of stiff fibrotic tissue alters the mechanical properties of the myocardium, thus contributing to the development of HF. Accumulating evidence suggests that several mechanisms are operative along the different stages of CKD that may converge to alter fibroblasts and collagen turnover in the heart. Therefore, focusing on MIF might enable the identification of fibrosis-related biomarkers and targets that could potentially lead to a new strategy for the prevention and treatment of HF in patients with CKD. This article summarizes current knowledge on the mechanisms and detrimental consequences of MIF in CKD and discusses the validity and usefulness of available biomarkers to recognize the clinical–pathological variability of MIF and track its clinical evolution in CKD patients. Finally, the currently available and potential future therapeutic strategies aimed at personalizing prevention and reversal of MIF in CKD patients, especially those with HF, will be also discussed.

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Histomolecular fibrotic profile and an extent of the atrial and ventricular electroanatomical substrate in patients with atrial fibrillation and heart failure

European Heart Journal ◽

10.1093/ehjci/ehaa946.0533 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

V Orshanskaya ◽

V.S Orshanskaya ◽

A.V Kamenev ◽

L.B Mitrofanova ◽

L.A Belyakova ◽

...

Keyword(s):

Heart Failure ◽

Atrial Fibrillation ◽

Plasma Level ◽

Serum Level ◽

Interstitial Fibrosis ◽

Myocardial Interstitial Fibrosis ◽

Relative Extent ◽

Group 3 ◽

Group 2 ◽

Group 1

Abstract Background and purpose The aim of this pilot study was to investigate the association between an extent of the atrial and ventricular electroanatomical substrate, serum fibrotic biomarkers and histological and immune-histochemical myocardial characteristics in ipatients with atrial fibrillation and heart failure. Methods We prospectively analyzed electroanatomical ultra-high density bipolar maps (HDBM) in 72 patients with AF and CHF, who underwent circular pulmonary veins (PVs) isolation. LA areas outside PVs ostia with bipolar signals ≤0.75mV, associated with local conduction velocity delay were considered as EAS and measured. Relative area of low voltage zones in right (RV) and left ventricles (RV) with bipolar signals in range of 0,5–1,5 mV were also consistently measured. Endomyocardial biopsy samples were taken from low, mediate and high septal areas of RV; histological and immune-histochemical staining was performed and an extent of myocardial interstitial fibrosis (MIF) was calculated. Before the operation we measured plasma MMP2, MMP9, TIMP, MMPs/TIMPs, galectin 3 (Gal3), TGF, soluble ST2 and the cross-linked collagen I/III synthesis and degradation product levels. The patients were divided into groups according to their ejection fraction Simpson (EF) (groups 1: EF≥50%, groups 2: EF 40–49%, and groups 3: EF<40%). Results The data of electroanatomical mapping, serum biomarkers and myocardial expression are presented in the table. According to results of correlation analysis, an extent of LA EAS were correlated with Gal3 and PIIICP plasma level and Gal3 myocardial expression and MIF extent (Rs=0,40, 0,45 and 0,42 respectively). The relative extent of LV EAS was correlated with MMP9 serum level (Rs=0,38); LV volume (LVV) was correlated with sST2 serum level and RVV was correlated with CD 133 myocardial expression (Rs=0,42) (picture 1). The patients with lower EF had larger extent of the LA EAS, (group 3: 28±12.4% vs. 1: 17.7±11.6%, p=0.03), an extent of LV EAS and LVV (group 3: 8,4±4,5% vs. 1: 5,1±3,8% p=0.02; group 3 vs group 1 p=0,05 relatively),higher Gal3 plasma level (group 1: 7,1±2 vs. group 2: 8,9±1,5, p=0.05) and higher MIF extent (group 2: 134±56 vs. 3: 151±30 p=0.04) (picture 2). Conclusion Our data suggest that relative extent of LA EAS in patients with atrial fibrillation is associated with Gal3 plasma level and Gal3 myocardial expression; severity of myocardial remodeling is connected to CD 3/133 myocardial expression and myocardial interstitial fibrosis extent, especially in patients with HF with restricted LV ejection fraction. Funding Acknowledgement Type of funding source: None

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Role of Inflammation, Viruses and Tissue Macrophages in the Development of Idiopathic Arrhythmia and Heart Failure

Key Engineering Materials ◽

10.4028/www.scientific.net/kem.683.487 ◽

2016 ◽

Vol 683 ◽

pp. 487-492 ◽

Cited By ~ 1

Author(s):

Yuliya Rogovskaya ◽

Roman Botalov ◽

Vyacheslav Ryabov ◽

Mariya Rebenkova ◽

Rostislav Karpov ◽

...

Keyword(s):

Heart Failure ◽

Interstitial Fibrosis ◽

Activated Macrophages ◽

Alternatively Activated Macrophages ◽

Viral Antigens ◽

Myocardial Interstitial Fibrosis ◽

Histological Criteria ◽

Cardiotropic Viruses ◽

Alternatively Activated

Endomyocardial biopsy is the gold standard in the diagnosis of myocardial pathology. Intravital study of endomyocardial samples offers the possibility to determine the morphological substrate and etiology of disease, to monitor the effectiveness of treatment. We studied morphological features, viral antigens, macrophages and specifically alternatively activated macrophages in endomyocardial biopsies of 25 patients with idiopathic arrhythmias and heart failure. Immunohistological study was performed to identify type of lymphocytes, macrophages and antigens of cardiotropic viruses. We observed the presence of alternatively activated macrophages in myocardium of patients with myocarditis and without it. We detected the presence of viral antigens in the myocardium of patients with myocardial fibrosis without of histological criteria myocarditis. Small focal infiltration of the myocardial CD68+ macrophages associated with heart failure and ventricular arrhythmias. The presence of virus antigens in myocardium associated with fewer myocardial stabilin-1+ macrophages [negative correlation]. On the other side small focal infiltration of stabilin-1+ macrophages correlated with severity of myocardial interstitial fibrosis [positive correlation]

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