scholarly journals Extracellular Matrix in Cardiac Tissue Mechanics and Physiology: Role of Collagen Accumulation

2021 ◽  
Author(s):  
Kristen LeBar ◽  
Zhijie Wang
Keyword(s):  
Heart Failure ◽  
Mechanical Properties ◽  
Extracellular Matrix ◽  
Pressure Overload ◽  
Volume Overload ◽  
Tissue Mechanics ◽  
Functional Changes ◽  
Collagen Accumulation ◽  
Heart Failure Progression

The extracellular matrix (ECM) forms a mesh surrounding tissue, made up of fibrous and non-fibrous proteins that contribute to the cellular function, mechanical properties of the tissue and physiological function of the organ. The cardiac ECM remodels in response to mechanical alterations (e.g., pressure overload, volume overload) or injuries (e.g., myocardial infarction, bacterial infection), which further leads to mechanical and functional changes of the heart. Collagen, the most prevalent ECM protein in the body, contributes significantly to the mechanical behavior of myocardium during disease progression. Alterations in collagen fiber morphology and alignment, isoform, and cross-linking occur during the progression of various cardiac diseases. Acute or compensatory remodeling of cardiac ECM maintains normal cardiac function. However, chronic or decompensatory remodeling eventually results in heart failure, and the exact mechanism of transition into maladaptation remains unclear. This review aims to summarize the primary role of collagen accumulation (fibrosis) in heart failure progression, with a focus on its effects on myocardial tissue mechanical properties and cellular and organ functions.

scholarly journals Moderate Loss of the Extracellular Matrix Proteoglycan Lumican Attenuates Cardiac Fibrosis in Mice Subjected to Pressure Overload

Cardiology ◽  
2020 ◽  
Vol 145 (3) ◽  
pp. 187-198 ◽  
Author(s):  
Naiyereh Mohammadzadeh ◽  
Arne Olav Melleby ◽  
Sheryl Palmero ◽  
Ivar Sjaastad ◽  
Shukti Chakravarti ◽  
...  
Keyword(s):  
Heart Failure ◽  
Extracellular Matrix ◽  
Diastolic Dysfunction ◽  
Cardiac Fibrosis ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Cross Linking ◽  
Myocardial Remodeling ◽  
Functional Changes ◽  
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.

Sarcoplasmic reticulum calcium leak contributes to arrhythmia but not to heart failure progression

2018 ◽  
Vol 10 (458) ◽  
pp. eaan0724 ◽  
Author(s):  
Belal A. Mohamed ◽  
Nico Hartmann ◽  
Petros Tirilomis ◽  
Karolina Sekeres ◽  
Wener Li ◽  
...  
Keyword(s):  
Heart Failure ◽  
Sarcoplasmic Reticulum ◽  
Ex Vivo ◽  
Pressure Overload ◽  
Volume Overload ◽  
Polymorphic Ventricular Tachycardia ◽  
Heart Failure Progression ◽  
Delayed Afterdepolarizations ◽  
Induced Pluripotent

Increased sarcoplasmic reticulum (SR) Ca2+ leak via the cardiac ryanodine receptor (RyR2) has been suggested to play a mechanistic role in the development of heart failure (HF) and cardiac arrhythmia. Mice treated with a selective RyR2 stabilizer, rycal S36, showed normalization of SR Ca2+ leak and improved survival in pressure overload (PO) and myocardial infarction (MI) models. The development of HF, measured by echocardiography and molecular markers, showed no difference in rycal S36– versus placebo-treated mice. Reduction of SR Ca2+ leak in the PO model by the rycal-unrelated RyR2 stabilizer dantrolene did not mitigate HF progression. Development of HF was not aggravated by increased SR Ca2+ leak due to RyR2 mutation (R2474S) in volume overload, an SR Ca2+ leak–independent HF model. Arrhythmia episodes were reduced by rycal S36 treatment in PO and MI mice in vivo and ex vivo in Langendorff-perfused hearts. Isolated cardiomyocytes from murine failing hearts and human ventricular failing and atrial nonfailing myocardium showed reductions in delayed afterdepolarizations, in spontaneous and induced Ca2+ waves, and in triggered activity in rycal S36 versus placebo cells, whereas the Ca2+ transient, SR Ca2+ load, SR Ca2+ adenosine triphosphatase function, and action potential duration were not affected. Rycal S36 treatment of human induced pluripotent stem cells isolated from a patient with catecholaminergic polymorphic ventricular tachycardia could rescue the leaky RyR2 receptor. These results suggest that SR Ca2+ leak does not primarily influence contractile HF progression, whereas rycal S36 treatment markedly reduces ventricular arrhythmias, thereby improving survival in mice.

scholarly journals How does the Extracellular Matrix Change in the Setting of Heart Failure?

2018 ◽  
Vol 6 (3) ◽  
pp. 102-109
Author(s):  
Amerikos Argyriou
Keyword(s):  
Heart Failure ◽  
Extracellular Matrix ◽  
Degradation Products ◽  
Internal Communication ◽  
Matrix Proteins ◽  
Reduced Ejection Fraction ◽  
Functional Changes ◽  
Metalloproteinase Inhibitors

The Extracellular Matrix is a dynamic entity, showing constant degradation and deposition while providing the framework for the cardiomyocytes and interstitial proteins to lie on. Its function is important for the proper myocyte alignment within the heart and for internal communication from cell to matrix. Dysregulation of the remodeling process resulting in the breakdown of collagen by matrix metalloproteinases is a hallmark of heart failure pathophysiology and produces functional changes encompassing all matrix proteins. Several etiologies with distinct mechanisms ultimately bring about signs of heart exhaustion such as reduced ejection fraction, reduced compliance and ventricular dilatation. Discussed in this paper is the role of inflammation, collagen cross-linking and of myofibroblasts in matrix dysfunction and the mechanisms with which these changes occur in heart failure. Understanding extracellular protein roles within this context would allow for specific drug targeting and thus prevention of heart failure in the early stages of the disease. More studies must be conducted to discover the specific matrix proteins and cytokines that modulate the pathological remodeling process. Serum biomarkers of extracellular degradation products, selective metalloproteinase inhibitors and a personalized treatment approach with a revisal of the current classification of heart failure are topics requiring further exploration.

scholarly journals The Extracellular Matrix in Ischemic and Nonischemic Heart Failure

2019 ◽  
Vol 125 (1) ◽  
pp. 117-146 ◽  
Author(s):  
Nikolaos G. Frangogiannis
Keyword(s):  
Heart Failure ◽  
Extracellular Matrix ◽  
Ejection Fraction ◽  
Systolic Dysfunction ◽  
Critical Role ◽  
Pressure Overload ◽  
Vascular Cells ◽  
Force Transmission ◽  
Ecm Proteins

The ECM (extracellular matrix) network plays a crucial role in cardiac homeostasis, not only by providing structural support, but also by facilitating force transmission, and by transducing key signals to cardiomyocytes, vascular cells, and interstitial cells. Changes in the profile and biochemistry of the ECM may be critically implicated in the pathogenesis of both heart failure with reduced ejection fraction and heart failure with preserved ejection fraction. The patterns of molecular and biochemical ECM alterations in failing hearts are dependent on the type of underlying injury. Pressure overload triggers early activation of a matrix-synthetic program in cardiac fibroblasts, inducing myofibroblast conversion, and stimulating synthesis of both structural and matricellular ECM proteins. Expansion of the cardiac ECM may increase myocardial stiffness promoting diastolic dysfunction. Cardiomyocytes, vascular cells and immune cells, activated through mechanosensitive pathways or neurohumoral mediators may play a critical role in fibroblast activation through secretion of cytokines and growth factors. Sustained pressure overload leads to dilative remodeling and systolic dysfunction that may be mediated by changes in the interstitial protease/antiprotease balance. On the other hand, ischemic injury causes dynamic changes in the cardiac ECM that contribute to regulation of inflammation and repair and may mediate adverse cardiac remodeling. In other pathophysiologic conditions, such as volume overload, diabetes mellitus, and obesity, the cell biological effectors mediating ECM remodeling are poorly understood and the molecular links between the primary insult and the changes in the matrix environment are unknown. This review article discusses the role of ECM macromolecules in heart failure, focusing on both structural ECM proteins (such as fibrillar and nonfibrillar collagens), and specialized injury-associated matrix macromolecules (such as fibronectin and matricellular proteins). Understanding the role of the ECM in heart failure may identify therapeutic targets to reduce geometric remodeling, to attenuate cardiomyocyte dysfunction, and even to promote myocardial regeneration.

scholarly journals Pulmonary Congestion Assessment in Heart Failure: Traditional and New Tools

Diagnostics ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 1306
Author(s):  
Filippo Pirrotta ◽  
Benedetto Mazza ◽  
Luigi Gennari ◽  
Alberto Palazzuoli
Keyword(s):  
Heart Failure ◽  
Adverse Outcome ◽  
Volume Overload ◽  
Pulmonary Congestion ◽  
X Ray ◽  
Persistent Symptoms ◽  
Biochemical Evaluation ◽  
Cardiac Filling ◽  
Symptoms And Signs

Congestion related to cardiac pressure and/or volume overload plays a central role in the pathophysiology, presentation, and prognosis of heart failure (HF). Most HF exacerbations are related to a progressive rise in cardiac filling pressures that precipitate pulmonary congestion and symptomatic decompensation. Furthermore, persistent symptoms and signs of congestion at discharge or among outpatients are strong predictors of an adverse outcome. Pulmonary congestion is also one of the most important diagnostic and therapeutic targets in chronic heart failure. The aim of this review is to analyze the importance of clinical, instrumental, and biochemical evaluation of congestion in HF by describing old and new tools. Lung ultrasonography (LUS) is an emerging method to assess pulmonary congestion. Accordingly, we describe the additive prognostic role of chest ultrasound with respect to traditional clinical and X-ray assessment in acute and chronic HF setting.

scholarly journals Biomarkers for the diagnosis and management of heart failure

2021 ◽  
Author(s):  
Vincenzo Castiglione ◽  
Alberto Aimo ◽  
Giuseppe Vergaro ◽  
Luigi Saccaro ◽  
Claudio Passino ◽  
...  
Keyword(s):  
Heart Failure ◽  
Risk Stratification ◽  
Adverse Outcome ◽  
Volume Overload ◽  
High Sensitivity ◽  
Circulating Biomarkers ◽  
Diagnosis And Management ◽  
Conflicting Evidence ◽  
Galectin 3

AbstractHeart failure (HF) is a significant cause of morbidity and mortality worldwide. Circulating biomarkers reflecting pathophysiological pathways involved in HF development and progression may assist clinicians in early diagnosis and management of HF patients. Natriuretic peptides (NPs) are cardioprotective hormones released by cardiomyocytes in response to pressure or volume overload. The roles of B-type NP (BNP) and N-terminal pro-B-type NP (NT-proBNP) for diagnosis and risk stratification in HF have been extensively demonstrated, and these biomarkers are emerging tools for population screening and as guides to the start of treatment in subclinical HF. On the contrary, conflicting evidence exists on the role of NPs as a guide to HF therapy. Among the other biomarkers, high-sensitivity troponins and soluble suppression of tumorigenesis-2 are the most promising biomarkers for risk stratification, with independent value to NPs. Other biomarkers evaluated as predictors of adverse outcome are galectin-3, growth differentiation factor 15, mid-regional pro-adrenomedullin, and makers of renal dysfunction. Multi-marker scores and genomic, transcriptomic, proteomic, and metabolomic analyses could further refine HF management.

Abstract 375: Mechanotransduction via Titin’s N2B Element Contributes to Cardiac Remodeling

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Mathew Bull ◽  
Pooja Nair ◽  
Joshua Strom ◽  
Michael Gotthardt ◽  
Henk Granzier
Keyword(s):  
Heart Failure ◽  
Cardiac Remodeling ◽  
Mapk Pathway ◽  
Hot Spot ◽  
Pressure Overload ◽  
Volume Overload ◽  
Mitogen Activated Protein Kinase ◽  
Stress And Strain ◽  
Knock Out ◽  
Voluntary Running

Pathological remodeling is responsible for the functional deficits characteristic of heart failure patients. Understanding mechanotransduction is limited, but holds potential to provide novel therapeutic targets to treat patients with heart failure, especially those with diastolic dysfunction and preserved ejection fraction (HFpEF). Titin is the largest known protein and is abundant in muscle. It is the main contributor of passive stiffness in the heart and functions as a molecular mechano-sensor for stress and strain in the myocyte. Titin is composed of four distinct regions, (N-terminal Z-line, I-band, A-band, and C-terminal M-line), and acts as a molecular spring that is responsible for the assembly and maintenance of ultrastructure in the sarcomere. The elastic N2B element found in titin’s I-band region has been proposed as a mechano-sensor and signaling “hot spot” in the sarcomere. This study investigates the role of titin’s cardiac specific N2B element as sensor for stress and strain induced remodeling in the heart. The previously published N2B knock out (KO) mouse was subjected to a variety of stressors including transverse aortic constriction (TAC), aorto-caval fistula (ACF), chronic swimming, voluntary running and isoproterenol injections. Through chronic pathologic stress, pressure overload (TAC) and chronic volume overload (ACF), we found that the N2B element is necessary for the response to volume overload but not pressure overload as determined by changes in cardiac remodeling. Furthermore, the response to exercise either by chronic swimming or voluntary running was reduced in the N2B KO mouse. Finally, unlike the wild-type (WT) mouse, the N2B KO mouse did not respond to isoproterenol injections with hypertrophic remodeling. Ongoing work to elucidate the molecular pathways involving the N2B element and response to stress, is focused on its binding protein Four-and-a-half-LIM domains 2 (FHL2) and the mitogen activated protein kinase (MAPK) pathway. Taken together our data suggest that the N2B element contributes significantly to mechanotransduction in the heart.

Role of extracellular matrix structural components and tissue mechanics in the development of postoperative pancreatic fistula

2021 ◽  
Vol 128 ◽  
pp. 110714
Author(s):  
Rosa B. Schmuck ◽  
Evi Lippens ◽  
Dag Wulsten ◽  
Daniela S. Garske ◽  
Annika Strönisch ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Pancreatic Fistula ◽  
Tissue Mechanics ◽  
Postoperative Pancreatic Fistula ◽  
Structural Components
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