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Background Recognizing only sharp elevation in a short period of time, the COVID-19 SARS-CoV-2 propagation is more and more marked in the whole world. Induced inflammation afterwards infection engenders a high infiltration of immune cells and cytokines that triggers matrix metalloproteinases (MMPs) activation. These endopeptidases are mediators of the lung extracellular matrix (ECM), a basic element for alveoli structure and gas exchange. Methods When immune cells, MMPs, secreted cytokines and several other mediators are gathered a pathological matrix remodeling occurs. This phenomenon tends to tissue destruction in the first place and a pulmonary hypertrophy and fibrosis in the second place. Findings After pathological matrix remodeling establishment, pathological diseases take place even after infection state. Since post COVID-19 pulmonary fibrosis is an emerging complication of the disease, there is an urge to better understand and characterize the implication of ECM remodeling during SARS-CoV-2 infection. Conclusion Targeting MMPs and their inhibitors could be a probable solution for occurred events since there are many cured patients that remain with severe sequels even after the end of infection.

Supplemental Digital Content is available in the text., Objective: The ductus arteriosus (DA) is a fetal artery connecting the aorta and pulmonary arteries. Progressive matrix remodeling, that is, intimal thickening (IT), occurs in the subendothelial region of DA to bring anatomic DA closure. IT is comprised of multiple ECMs (extracellular matrices) and migrated smooth muscle cells (SMCs). Because glycoprotein fibulin-1 binds to multiple ECMs and regulates morphogenesis during development, we investigated the role of fibulin-1 in DA closure. Approach and Results: Fibulin-1–deficient (Fbln1−/−) mice exhibited patent DA with hypoplastic IT. An unbiased transcriptome analysis revealed that EP4 (prostaglandin E receptor 4) stimulation markedly increased fibulin-1 in DA-SMCs via phospholipase C-NFκB (nuclear factor κB) signaling pathways. Fluorescence-activated cell sorting (FACS) analysis demonstrated that fibulin-1 binding protein versican was derived from DA-endothelial cells (ECs). We examined the effect of fibulin-1 on directional migration toward ECs in association with versican by using cocultured DA-SMCs and ECs. EP4 stimulation promoted directional DA-SMC migration toward ECs, which was attenuated by either silencing fibulin-1 or versican. Immunofluorescence demonstrated that fibulin-1 and versican V0/V1 were coexpressed at the IT of wild-type DA, whereas 30% of versican-deleted mice lacking a hyaluronan binding site displayed patent DA. Fibulin-1 expression was attenuated in the EP4-deficient mouse (Ptger4−/−) DA, which exhibits patent DA with hypoplastic IT, and fibulin-1 protein administration restored IT formation. In human DA, fibulin-1 and versican were abundantly expressed in SMCs and ECs, respectively. Conclusions: Fibulin-1 contributes to DA closure by forming an environment favoring directional SMC migration toward the subendothelial region, at least, in part, in combination with EC-derived versican and its binding partner hyaluronan.

Tendon lesions are common sporting injuries in humans and horses alike. The healing process of acute tendon lesions frequently results in fibrosis and chronic disease. In horses, local mesenchymal stromal cell (MSC) injection is an accepted therapeutic strategy with positive influence on acute lesions. Concerning the use of MSCs in chronic tendon disease, data are scarce but suggest less therapeutic benefit. However, it has been shown that MSCs can have a positive effect on fibrotic tissue. Therefore, we aimed to elucidate the interplay of MSCs and healthy or chronically diseased tendon matrix. Equine MSCs were cultured either as cell aggregates or on scaffolds from healthy or diseased equine tendons. Higher expression of tendon-related matrix genes and tissue inhibitors of metalloproteinases (TIMPs) was found in aggregate cultures. However, the tenogenic transcription factor scleraxis was upregulated on healthy and diseased tendon scaffolds. Matrix metalloproteinase (MMPs) expression and activity were highest in healthy scaffold cultures but showed a strong transient decrease in diseased scaffold cultures. The release of glycosaminoglycan and collagen was also higher in scaffold cultures, even more so in those with tendon disease. This study points to an early suppression of MSC matrix remodeling activity by diseased tendon matrix, while tenogenic differentiation remained unaffected.

Simple Summary This review depicts the principal mechanisms involved in the process of stromal desmoplasia characterizing pancreatic ductal adenocarcinoma (PDAC). The aim of this review is to point out the role of the dense extracellular matrix in worsening PDAC responsiveness to conventional therapies. In this context, a presentation of the most promising therapeutic solutions for targeting or overcoming the matrix is provided. Even though several drug compounds revealed disappointing results in clinics, other matrix factors are now becoming the focus of studies and must be further explored to develop the optimal therapeutic strategy. Bringing novel therapeutics to PDAC patients is challenging but crucial for effectively eradicating the disease and improving patient survival. Abstract The stroma is a relevant player in driving and supporting the progression of pancreatic ductal adenocarcinoma (PDAC), and a large body of evidence highlights its role in hindering the efficacy of current therapies. In fact, the dense extracellular matrix (ECM) characterizing this tumor acts as a natural physical barrier, impairing drug penetration. Consequently, all of the approaches combining stroma-targeting and anticancer therapy constitute an appealing option for improving drug penetration. Several strategies have been adopted in order to target the PDAC stroma, such as the depletion of ECM components and the targeting of cancer-associated fibroblasts (CAFs), which are responsible for the increased matrix deposition in cancer. Additionally, the leaky and collapsing blood vessels characterizing the tumor might be normalized, thus restoring blood perfusion and allowing drug penetration. Even though many stroma-targeting strategies have reported disappointing results in clinical trials, the ECM offers a wide range of potential therapeutic targets that are now being investigated. The dense ECM might be bypassed by implementing nanoparticle-based systems or by using mesenchymal stem cells as drug carriers. The present review aims to provide an overview of the principal mechanisms involved in the ECM remodeling and of new promising therapeutic strategies for PDAC.

Bronchopulmonary dysplasia (BPD) is a chronic lung disease of preterm infants, characterized by lung growth arrest and matrix remodeling. Various animal models provide mechanistic insights in the pathogenesis of BPD. Since there is increasing evidence that genetic susceptibility modifies the response to lung injury, we investigated strain-dependent effects in hyperoxia (HYX)-induced lung injury of newborn mice. To this end, we exposed newborn C57BL/6N and C57BL/6J mice to 85% O2 (HYX) or normoxia (NOX; 21% O2) for 28 days, followed by lung excision for histological and molecular measurements. BL/6J-NOX mice exhibited a lower body and lung weight than BL/6N-NOX mice; hyperoxia reduced body weight in both strains and increased lung weight only in BL/6J-HYX mice. Quantitative histomorphometric analyses revealed reduced alveolar formation in lungs of both strains after HYX, but the effect was greater in BL/6J-HYX mice than BL/6N-HYX mice. Septal thickness was lower in BL/6J-NOX mice than BL/6N-NOX mice but increased in both strains after HYX. Elastic fiber density was significantly greater in BL/6J-HYX mice than BL/6N-HYX mice. Lungs of BL/6J-HYX mice were protected from changes in gene expression of fibrillin-1, fibrillin-2, fibulin-4, fibulin-5, and surfactant proteins seen in BL/6N-HYX mice. Finally, Stat3 was activated by HYX in both strains; in contrast, activation of Smad2 was markedly greater in lungs of BL/6N mice than BL/6J mice after HYX. In summary, we demonstrate strain-dependent differences in lung structure and matrix, alveolar epithelial cell markers, and Smad2 (transforming growth factor β) signaling in neonatal HYX-induced lung injury. Strain-dependent effects and genetic susceptibility need be taken into consideration for reproducibility and reliability of results in animal models.

Platelet-derived growth factors (PDGFs) are powerful inducers of cellular mitosis, migration, angiogenesis, and matrix modulation that play pivotal roles in the development, homeostasis, and healing of cardiac tissues. PDGFs are key signaling molecules and important drug targets in the treatment of cardiovascular disease as multiple researchers have shown that delivery of recombinant PDGF ligands during or after myocardial infarction can reduce mortality and improve cardiac function in both rodents and porcine models. The mechanism involved cannot be easily elucidated due to the complexity of PDGF regulatory activities, crosstalk with other protein tyrosine kinase activators, and diversity of the pathological milieu. This review outlines the possible roles of PDGF ligands A and B in the healing of cardiac tissues including reduced cell death, improved vascularization, and improved extracellular matrix remodeling to improve cardiac architecture and function after acute myocardial injury. This review may highlight the use of recombinant PDGF-A and PDGF-B as a potential therapeutic modality in the treatment of cardiac injury.

Mechanobiology explores how forces regulate cell behaviors and what molecular machinery are responsible for the sensing, transduction, and modulation of mechanical cues. To this end, probing of cells cultured on planar substrates has served as a primary experimental setting for many decades. However, native extracellular matrices (ECMs) consist of fibrous protein assemblies where the physical properties spanning from the individual fiber to the network architecture can influence the transmission of forces to and from the cells. Here, a robotic manipulation platform that allows wireless, localized, and programmable deformation of an engineered fibrous ECM is introduced. A finite-element-based digital twin of the fiber network calibrated against measured local and global parameters enables the calculation of deformations and stresses generated by different magnetic actuation schemes across a range of network properties. Physiologically relevant mechanical forces are applied to cells cultured on the fiber network, statically or dynamically, revealing insights into the effects of matrix-borne forces and deformations as well as force-mediated matrix remodeling on cell migration and intracellular signaling. These capabilities are not matched by any existing approach, and this versatile platform has the potential to uncover fundamental mechanisms of mechanobiology in settings with greater relevance to living tissues.

Late presentation and resistance to chemotherapeutic agents make a deadly combination for ovarian cancer patients. The treatment of these patients is thus challenging. This study explores the possible molecular mechanisms by which tumor cells interact with the extracellular matrix (ECM) constituents, forming metastatic implants and enhancing patients' sensitivity to drugs. For the literature review, PubMed was used as a database. The standard search was done using keywords "collagen, ovarian cancer, extracellular matrix, drug resistance" in different combinations, which finally yielded 32 studies meeting the inclusion/exclusion criteria. The studies included were published in the English language in the past seven years. After analyzing, we found all of them to be histopathological studies. Nine studies also used murine cell lines besides human cell lines and tissue samples from ovarian cancer patients. One study has a retrospective analysis done. Eight studies demonstrate the role of hypoxia and matrix remodeling enzymes in ovarian cancer dissemination. Genetics playing a crucial role in cancer metastasis is demonstrated in eight studies. Ten studies included shows receptors, enzymes, and spheroid organization in disease progression. Six studies address chemotherapeutic resistance. Intraperitoneal dissemination of ovarian cancer and the development of chemotherapeutic resistance depends on certain molecular interactions, and they can be targeted to improve patients' overall survival.

The tumor microenvironment is considered one of the main players in tumor development and progression. The tumor microenvironment composed of a large number of extracellular matrix proteins is very complex. The continuous accumulation of extracellular matrix proteins has been shown to play a key role in tumor bioregulation, including proliferation, invasion, matrix remodeling. If these processes can be detected early, and effective interventions can be given in time, the progression of the tumor may be delayed. Therefore, there is an urgent need to explore new biomarkers and therapeutic targets. In recent years, studies have shown that periostin (POSTN) may regulate multiple biological behaviors of tumor cells. Here we review the updated progress on the role of POSTN in pathologic pathways of tumor development and progression to explore whether POSTN is a potential therapeutic target.

PURPOSE Andecaliximab (ADX) is a monoclonal antibody that inhibits matrix metalloproteinase 9, an extracellular enzyme involved in matrix remodeling, tumor growth, and metastases. A phase I and Ib study of modified oxaliplatin, leucovorin, and fluorouracil (mFOLFOX6) with ADX revealed encouraging antitumor activity in patients with gastric or gastroesophageal junction (GEJ) adenocarcinoma. MATERIALS AND METHODS This phase III, randomized, double-blinded, placebo (PBO)-controlled multicenter study investigated the efficacy and safety of mFOLFOX6 with and without ADX in patients with untreated human epidermal growth factor receptor 2–negative gastric or GEJ adenocarcinoma. Random assignment was 1:1 to mFOLFOX6 + ADX or mFOLFOX6 + PBO. ADX/PBO 800 mg was infused on days 1 and 15 of each 28-day cycle. Protocol therapy was given until disease progression or intolerance. The primary end point was overall survival (OS), and secondary end points were progression-free survival (PFS), objective response rate (RECIST 1.1), and safety. RESULTS Between September 2015 and May 2017, 432 patients were randomly assigned, 218 to ADX and 214 to PBO. The median OS was 12.5 versus 11.8 months in the ADX and PBO groups, respectively. The median PFS was 7.5 versus 7.1 months in the ADX and PBO groups, respectively. The objective response rate was 51% in the ADX group and 41% in the PBO group. Among the subgroup analyses, patients of age ≥ 65 years had an improved OS and PFS with ADX versus PBO; the P values and CIs were not adjusted for multiplicity. There were no meaningful differences in the safety profile of the ADX versus PBO groups. CONCLUSION The addition of ADX to mFOLFOX6 did not improve OS in unselected patients with untreated human epidermal growth factor receptor 2–negative gastric or GEJ adenocarcinoma.

Wound healing is a complex biological process involving distinct phases of hemostasis, immune response, and inflammatory events, regulated cellular proliferation, and matrix remodeling. While immune and inflammatory cellular phenotypes (e.g., neutrophils and monocyte/macrophages) are often the focus of wound healing studies, the initial hemostatic and sustained secretory role of platelets to modulate the various mechanistic phases of wound healing via clot promotion, clot stabilization and retraction, release of various growth factors and cytokines from active platelet granules, and release of matrix remodeling enzymes is becoming exceedingly appreciated in preclinical and clinical settings. This has led to extensive studies using platelet-based products like platelet-rich-plasma (PRP) suspensions and gels as topical and injectable technologies to augment wound healing in both soft and hard tissues. In parallel, a robust volume of research is currently being directed at mimicking and leveraging the hemostatic and secretory mechanisms of platelets utilizing various lipidic and polymeric biomaterials systems. The current article is aimed at providing a review of platelet involvement in wound healing mechanisms and subsequently discussing the current state-of-the-art regarding various platelet-based as well as biomaterials-based approaches and technologies to promote wound healing.

Autologous platelet-rich plasma (PRP) preparations are increasingly used as adjuncts to medical and cosmetic dermatologic applications. Their benefits stem from their ability to deliver high concentrated potent growth factors to target tissue and stimulate matrix remodeling, angiogenesis, and resolution of inflammation, to name a few of their functions. Recently the use of PRP has been evaluated for improving the appearance of challenging conditions such as scarring and striae distensae. While the improvement of scars/striae has been documented with strategies such as lasers, microneedling, topicals, and subcision, they are associated with incomplete resolution and long recovery times. In this respect, PRP offers an appealing treatment strategy that can work synergistically with other strategies to accelerate wound healing and maximize matrix remodeling. In this chapter we describe the challenges associated the current landscape of scar/striae treatment and illuminate the role PRP has been documented to have in this field. Review of the literature reveals that PRP can improve the quality of atrophic acne scars in particular and surgical scars but not keloid scars. Moreover, used in similar fashion as that for treating scars, it can be beneficial in the management of striae distensae. Overall, PRP is a promising adjunct in scar management, but in the authors opinion further research with long-term follow-up is needed to delineate the value of this modality in different subtypes of scars.

Background: Heart failure is a pathophysiological state, which is still associated with high morbidity and mortality despite established therapies. Diverse well-known biomarkers fail to assess the variety of individual pathophysiology in the context of heart failure.Methods: An analysis of prospective, multimarker-specific therapeutic approaches to heart failure based on studies in current literature was performed. A total of 159 screened publications in the field of biomarkers in heart failure were hand-selected and found to be eligible for this study by a team of experts.Results: Established biomarkers of the inflammatory axis, matrix remodeling, fibrosis and oxidative stress axis, as well as potential therapeutic interventions were investigated. Interaction with end organs, such as cardio-hepatic, cardio-renal and cardio-gastrointestinal interactions show the complexity of the syndrome and could be of further therapeutic value. MicroRNAs are involved in a wide variety of physiologic and pathophysiologic processes in heart failure and could be useful in diagnostic as well as therapeutic setting.Conclusion: Based on our analysis by a biomarker-driven approach in heart failure therapy, patients could be treated more specifically in long term with a consideration of different aspects of heart failure. New studies evaluating a multimarker – based therapeutic approach could lead in a decrease in the morbidity and mortality of heart failure patients.

As the largest organ of the body, human skin is multifunctional and enjoys two layers, the epidermis and the dermis, the separation of which is performed by a basement membrane zone. Skin protects the body against mechanical forces and infections. Skin wounds represent large and growing challenges to the healthcare systems globally. Skin wound healing, as a protective shield for the body against the external environment, includes interactions among cell types, the neurovascular system, cytokines, and matrix remodeling. Growth factors (GFs) affect the microenvironment of the wound, and cause rises in cell differentiation, proliferation, and migration. Administrating exogenous GFs has revealed potential in enhancing wound healing outcomes. The use of human GFs in the field of wound healing is becoming gradually more interesting, because of the low-invasive techniques required for their use. Reviewed here are the literatures on the healing of skin wounds with emphasize on the role of GFs and their future prospects, containing profits, and probable long-standing side effects accompanied with their use.

Wound healing is a complex process involving four overlapping phases: haemostasis, inflammation, cell recruitment and matrix remodeling. In mouse models, surgical, pharmacological and genetic approaches targeting androgen actions in skin have shown that androgens increase interleukin-6 and tumor necrosis factor-α production and reduce wound re-epithelization and matrix deposition, retarding cutaneous wound healing. Similarly, clinical studies have shown that cutaneous wound healing is slower in men compared to women. However, in major burn injury, which triggers not only local wound-healing processes but also systemic hypermetabolism, the role of androgens is poorly understood. Recent studies have claimed that a synthetic androgen, oxandrolone, increases protein synthesis, improves lean body mass and shortens length of hospital stay. However, the possible mechanisms by which oxandrolone regulates major burn injury have not been reported. In this review, we summarize the current findings on the roles of androgens in cutaneous and major burn wound healing, as well as androgens as a potential therapeutic treatment option for patients with major burn injuries.

Intrauterine growth restriction (IUGR) is a risk factor for neonatal chronic lung disease (CLD) characterized by reduced alveoli and perturbed matrix remodeling. Previously, our group showed an activation of myofibroblasts and matrix remodeling in rat lungs after IUGR. Because growth hormone (GH) and insulin-like growth factor I (IGF-I) regulate development and growth, we queried 1) whether GH/IGF-I signaling is dysregulated in lungs after IUGR and 2) whether GH/IGF-I signaling is linked to neonatal lung myofibroblast function. IUGR was induced in Wistar rats by isocaloric low-protein diet during gestation. Lungs were obtained at embryonic day (E) 21, postnatal day (P) 3, P12, and P23. Murine embryonic fibroblasts (MEF) or primary neonatal myofibroblasts from rat lungs of control (pnFCo) and IUGR (pnFIUGR) were used for cell culture studies. In the intrauterine phase (E21), we found a reduction in GH receptor (GH-R), Stat5 signaling and IGF-I expression in lungs after IUGR. In the postnatal phase (P3–P23), catchup growth after IUGR was linked to increased GH mRNA, GH-R protein, activation of proliferative Stat5/Akt signaling, cyclin D1 and PCNA in rat lungs. On P23, a thickening of the alveolar septae was related to increased vimentin and matrix deposition, indicating fibrosis. In cell culture studies, nutrient deprivation blocked GH-R/IGF-IR signaling and proliferation in MEFs; this was reversed by IGF-I. Proliferation and Stat5 activation were increased in pnFIUGR. IGF-I and GH induced proliferation and migration of pnFCo; only IGF-I had these effects on pnFIUGR. Thus, we show a novel mechanism by which the GH/IGF-I axis in lung myofibroblasts could account for structural lung changes after IUGR.

Background Comparing the structural changes, and local host reactions to CorMatrix (CorMatrix Cardiovascular Inc., Roswell, Georgia, United States) and different biomaterials implanted subcutaneously in growing pig model. Methods Four pigs harboring implanted patches of CorMatrix, Vascutek porcine pericardium (Vascutek; Scotland, United Kingdom), SJM bovine pericardium (St. Jude Medical, Inc., Minnesota, United States), and Gore-Tex (W. L. Gore & Associates GmbH, Flagstaff, Arizona, United States) were studied for 1, 3, 6, and 12 months. The explants were examined histologically. Results CorMatrix showed gradual and consistent patch resorption and subsiding inflammatory and fibrosis process. Full scaffold degradation and replacement by mild fibrosis and subcutaneous tissue were seen by 1 year. Xenopericardial patches remained intact, and the initially severe inflammatory and fibrotic reactions reduced gradually to moderate fibrosis and chronic inflammation. Gore-Tex showed foreign body reaction. Conclusions Patches were biotolerated by pigs. Xenopericardial patches elicited encapsulating fibrosis and no remodeling. CorMatrix resorbs completely and degrades consistently without leaving residues. Lack of encapsulating fibrosis toward CorMatrix allows tissue ingrowth and matrix remodeling.

Shock Wave Therapy (SWT) meets all the requirements for the ideal non-invasive scar treatment. It is safe, well tolerated by patients, cost-effective, easy to apply, has low complication rates, and can be used in an outpatient setting. The overall effect of SWT is an improvement of tissue homeostasis, accompanied by an improvement of the tissue self-healing abilities, and it seems to focus on inducing tissue regeneration and matrix remodeling in vivo by means of mechanotransduction.SWT has a beneficial effect on wound healing and is characterized by an upregulation of the angio-active factors as nitric oxide (NO) and vascular endothelial growth factor (VEGF) leading to induced angiogenesis. A downregulation of alpha-SMA expression, myofibroblast phenotype, TGF-β1 expression, fibronectin, and collagen type I are measured after SWT on scars, leading to improvement of several relevant scar parameters like height, pliability, vascularity, and pigmentation, and thus ameliorating function.For a full treatment outline, the energy flux density (EFD), the number of pulses, the pulse frequency, and the number and interval of treatments are the most relevant parameters. The EFD for soft tissue indications is typically in the range of 0.08–0.25 mJ/mm2, while scars and fibrosis are treated with an EFD ranging between 0.15 and 0.33 mJ/mm2. These settings seem to be ideal to induce the optimal cell responses for each indication.All the presented findings are fundamental knowledge for further investigation of SWT to reduce the fibrous component in regenerating and remodeling tissues. However, the full potential of SWT in wound healing and scar treatment needs further unraveling.

PubMed: 31983145 Obesity is associated with a higher risk of developing breast cancer and with worse disease outcomes for women of all ages. The composition, density, and organization of the breast tissue stroma are also known to play an important role in the development and progression of the disease. However, the connections between obesity and stromal remodeling are not well understood. We sought to characterize detailed organization features of the collagen matrix within healthy and cancerous breast tissues acquired from mice exposed to either a normal or high fat (obesity inducing) diet. We performed second-harmonic generation and spectral two-photon excited fluorescence imaging, and we extracted the level of collagen-associated fluorescence (CAF) along with metrics of collagen content, three-dimensional, and two-dimensional organization. There were significant differences in the CAF intensity and overall collagen organization between normal and tumor tissues; however, obesity-enhanced changes in these metrics, especially when three-dimensional organization metrics were considered. Thus, our studies indicate that obesity impacts significantly collagen organization and structure and the related pathways of communication may be important future therapeutic targets..

Background Recent studies have reported that circulating microRNA (miR) can target different metalloproteases involved in matrix remodelling and plaque vulnerability. Consequently, they might have a role in the diagnosis and prognosis of cardiovascular diseases. Aim. To quantify circulating miRs (miR126, miR146) which are suggested to have possible cardiovascular implications, as well as levels of MMP-1 and MMP-9, and to determine their association with left ventricular ejection fraction (LVEF), global longitudinal strain (GLS), and arterial function, in patients with stable and unstable coronary artery disease (CAD). Methods 90 patients with CAD (61% men, 58+/-12 years), including 60 patients with ST elevation acute myocardial infarction (STEMI) and 30 patients with stable CAD were assessed within 24 hours of admission by serum microRNA quantification (TaqMan PCR analysis), and serum MMP-1 and MMP-9 analysis (ELISA kits). 2D and 3D echocardiography were used to assess LVEF; speckle tracking was used to asses GLS; echo tracking, CAVI, and peripheral Doppler were used to assess arterial function (Young"s elastic modulus - EP and β index, arterial stiffness, and ABI). Results Circulating levels of miR146, miR126, MMP1, and MMP9 were significantly increased in patients with STEMI vs. stable CAD (95% CI 1.92-8.43, p = 0.002). miR126 correlated with LVEF (r=-.41, p = 0.03) and arterial stiffness (r=.44, and r=.42, p = 0.02 for L-CAVI and R-CAVI respectively) in patients with STEMI, and with arterial stiffness (r=-.72, p = 0.04, r=-.72, p = 0.01 for L-CAVI and R-CAVI respectively) and ABI (r=-.62, p = 0.04, r=-.62, p = 0.03 for L-ABI and R-ABI respectively) in patients with stable CAD. miR146 did not have any significant correlations. Both MMP-1 and MMP-9 correlated with LV function, LVEF ( r=-.27, p = 0.04, r=-.40, p = 0.01) and GLS (r=-.27, p = 0.03, r=-.26, p = 0.04) in patients with STEMI, and with arterial stiffness (r=.40, p = 0.03, for L-CAVI and r = 0.42, p = 0.02 for R-CAVI) in patients with stable CAD. Conclusion miR126 and both MMP1 and MMP9 are potential biomarkers of LV function in STEMI patients. Meanwhile, they correlate with arterial function in patients with stable CAD. However, further studies are needed to establish whether these new biomarkers have diagnosis and prognosis significance. Abstract P1777 Figure.

Proteoglycans have emerged as biomacromolecules with important roles in matrix remodeling, homeostasis, and signaling in the past two decades. Due to their negatively charged glycosaminoglycan chains as well as distinct core protein structures, they interact with a variety of molecules, including matrix proteins, growth factors, cytokines and chemokines, pathogens, and enzymes. This led to the dawn of glycan therapies in the 20th century, but this research was quickly overshadowed by readily available DNA and protein-based therapies. The recent development of recombinant technology and advances in our understanding of proteoglycan function have led to a resurgence of these molecules as potential therapeutics. This review focuses on the recent preclinical efforts that are bringing proteoglycan research and therapies back to the forefront. Examples of studies using proteoglycan cores and mimetics have also been included to give the readers a perspective on the wide-ranging and extensive applications of these versatile molecules. Collectively, these advances are opening new avenues for targeting diseases at a molecular level, and providing avenues for the development of new and exciting treatments in regenerative medicine.

Aims: This study aimed to evaluate the association of GDF-15 and NT-pro-BNP in two different biological matrices with AF in severe aortic stenosis patients undergoing aortic valve replacement surgery (AVR), its association with atrial matrix remodeling, as well as with 30-day postoperative outcomes. Main Methods: One hundred and twenty-six patients between 2009 and 2019 with severe aortic stenosis undergoing AVR surgery in a tertiary hospital were assessed. Key Findings: pericardial fluid GDF-15 and pericardial fluid and serum NT-pro-BNP were increased in AF patients with aortic stenosis. COL1A1 and COL3A1 gene expression increased when pericardial fluid NT-pro-BNP values were higher. TIMP4 was positively correlated with pericardial fluid GDF-15. Significance: GDF-15 and NT-pro-BNP in the pericardial fluid are biomarkers of atrial fibrillation in aortic stenosis and correlate with atrial matrix remodeling. AKI is predicted by both serum and pericardial fluid GDF-15.

Pulmonary fibrosis and emphysema are chronic lung diseases characterized by a progressive decline in lung function, resulting in significant morbidity and mortality. A hallmark of these diseases is recurrent or persistent alveolar epithelial injury, typically caused by common environmental exposures such as cigarette smoke. We propose that critical determinants of the outcome of the injury-repair processes that result in fibrosis versus emphysema are mesenchymal cell fate and associated extracellular matrix dynamics. In this review, we explore the concept that regulation of mesenchymal cells under the influence of soluble factors, in particular transforming growth factor-β1, and the extracellular matrix determine the divergent tissue remodeling responses seen in pulmonary fibrosis and emphysema.

Chronic liver diseases, characterized by an excessive accumulation of extracellular matrix (ECM) resulting in scar tissue formation, are a growing health problem causing increasing morbidity and mortality worldwide. Currently, therapeutic options for tissue fibrosis are severely limited, and organ transplantation is the only treatment for the end-stage liver diseases. During liver damage, injured hepatocytes release proinflammatory factors resulting in the recruitment and activation of immune cells that activate quiescent hepatic stellate cells (HSCs). Upon activation, HSCs transdifferentiate into highly proliferative, migratory, contractile and ECM-producing myofibroblasts. The disrupted balance between ECM deposition and degradation leads to the formation of scar tissue referred to as fibrosis. This balance can be restored either by reducing ECM deposition (by inhibition of HSCs activation and proliferation) or enhancing ECM degradation (by increased expression of matrix metalloproteinases (MMPs)). MMPs play an important role in ECM remodeling and represent an interesting target for therapeutic drug discovery. In this review, we present the current knowledge about ECM remodeling and role of the different MMPs in liver diseases. MMP expression patterns in different stages of liver diseases have also been reviewed to determine their role as biomarkers. Finally, we highlight MMPs as promising therapeutic targets for the resolution of liver diseases.

Burns are caused by several mechanisms including flame, scald, chemical, electrical, and ionizing and non-ionizing radiation. Approximately half a million burn cases are registered annually, of which 40 thousand patients are hospitalized and receive definitive treatment. Burn care is very resource intensive as the treatment regimens and length of hospitalization are substantial. Burn wounds are classified based on depth as superficial (first degree), partial-thickness (second degree), or full-thickness (third degree), which determines the treatment necessary for successful healing. The goal of burn wound care is to fully restore the barrier function of the tissue as quickly as possible while minimizing infection, scarring, and contracture. The aim of this review is to highlight how tissue engineering and regenerative medicine strategies are being used to address the unique challenges of burn wound healing and define the current gaps in care for both partial- and full-thickness burn injuries. This review will present the current standard of care (SOC) and provide information on various treatment options that have been tested pre-clinically or are currently in clinical trials. Due to the complexity of burn wound healing compared to other skin injuries, burn specific treatment regimens must be developed. Recently, tissue engineering and regenerative medicine strategies have been developed to improve skin regeneration that can restore normal skin physiology and limit adverse outcomes, such as infection, delayed re-epithelialization, and scarring. Our emphasis will be centered on how current clinical and pre-clinical research of pharmacological agents, biomaterials, and cellular-based therapies can be applied throughout the continuum of burn care by targeting the stages of wound healing: hemostasis, inflammation, cell proliferation, and matrix remodeling.

Recent advances in our understanding of the dynamics of cellular cross-talk have highlighted the significance of host-versus-tumor effect that can be harnessed with immune therapies. Tumors exploit immune checkpoints to evade adaptive immune responses. Cancer immunotherapy has witnessed a revolution in the past decade with the development of immune checkpoint inhibitors (ICIs), monoclonal antibodies against cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) or their ligands, such as PD1 ligand 1 (PD-L1). ICIs have been reported to have activity against a broad range of tumor types, in both solid organ and hematologic malignancy contexts. However, less than one-third of the patients achieve a durable and meaningful treatment response. Expression of immune checkpoint ligands (e.g., PD-L1), mutational burden and tumor-infiltrating lymphocytes are currently used as biomarkers for predicting response to ICIs. However, they do not reliably predict which patients will benefit from these therapies. There is dire need to discover novel biomarkers to predict treatment efficacy and to identify areas for development of combination strategies to improve response rates. Emerging evidence suggests key roles of tumor extracellular matrix (ECM) components and their proteolytic remodeling products in regulating each step of the cancer-immunity cycle. Here we review tumor matrix dynamics and matrix remodeling in context of anti-tumor immune responses and immunotherapy and propose the exploration of matrix-based biomarkers to identify candidates for immune therapy.

Despite the important role of Metalloproteinase (MMP) in β-cellular matrix remodeling there is clearly not enough data concerning the MMP proteolytic activity during first three weeks (early scar changes) of postoperative gastric ulcers. Thus the main aim of our work was the MMP, TIMP-1 and bFGF overall activity determination as well as their role in post-burn wound healing in case of the 2nd degree esophagus acid burn infliction. The greatest increase in the metalloproteinase activity and bFGF level was observed at 21st d of our experiment. In addition, the greatest increase in the TIMP-1 level in the esophageal mucosal was observed at 7th d after burn. These changes may be an evidence of chronic inflammatory processes and scar changes in rat esophagus after the EAB infliction.

Footpad dermatitis (FPD) is used in the poultry industry as an animal welfare criterion to determine stocking density. Trace minerals (TM) play a role in skin integrity and wound healing. This study evaluated the impact of TM on FPD and consisted of 3 treatments supplemented with 0 (NTM), low (LTM) and high (HTM) TM levels in the same basal diet. On d21, 71% birds in all treatments developed mild FPD and pens were top-dressed with dry litter to promote FPD healing. Compared to NTM, LTM reduced area under the curve (AUC) of FPD lesion scores during d21–42, HTM reduced the AUC of FPD lesion scores during d7–21 and d21–42. LTM improved growth performance on d14, HTM improved growth performance on d14 and d28. LTM and/or HTM increased gene expression of VEGF, TIMP3, TIMP4, MMP13, ITGA2, ITGA3 and CD40, which promoted collagen synthesis, deposition and organization; cell migration, matrix remodeling, and angiogenesis. LTM and/or HTM increased inflammation by upregulating TNFα and IL-1β during the early wound healing phase and reduced inflammation by downregulating IL-1β during the late wound healing phase. Our findings showed that TM not only improved growth performance but also reduced FPD development by promoting FPD wound healing.

WOS: 000345820700009, Objectives: This in vitro study aimed to examine the protective roles of Hypericum perforatum Linn (HPL) extract on cell viability, DNA damage, apoptosis and a disintegrin-like and metalloproteinase with thrombospondin motifs (ADAMTS) proteins in chondrocytes induced by hydrogen peroxide (H2O2), as a model of chondrocytes subjected to reactive oxygen species attack in rheumatoid arthritis and osteoarthritis. Materials and methods: Human chondrosarcoma cell line (OUMS-27) was used. Cells were incubated with different concentrations of methanolic extract (100, 400, and 750 mu g/ml) of HPL for 36 hours, and then treated with 0.7 mM H2O2 for two hours. Trypan blue was used for evaluation of cell viability, while DNA damage was evaluated by alkaline Comet assay. Caspase-1, ADAMTS5, ADAMTS9, and glyceraldehyde-3-phosphate dehydrogenase proteins were analyzed by Western blot. Results: In vitro H2O2 treatment decreased OUMS-27 cell viability. Cells pretreated with HPL at concentration of 400 mu g/mL were best protected from H2O2 toxicity. Compared to 100 mu g/ml concentration, pretreatment of cells with 750 or 400 mu g/ml of HPL generated more protection against H2O2-induced DNA damage. Hydrogen peroxide application to the cells led to a slight increase in Caspase-1 expression, which shows no apoptosis. The most prominent increase in Caspase-1 level was shown in cells treated with 400 mu g/ml of HPL extract. There was an increase in ADAMTS9 and a decrease in ADAMTS5 levels upon H2O2 administration. Pretreatment with HPL led to more decrease in ADAMTS5 level, indicating the protection of extracellular matrix attacked by these proteinases in cartilage tissue. Conclusion: It can be concluded that HPL has a potential to reverse the negative effects and processes induced by H2O2 in OUMS-27 cells and it can protect the surrounding cartilage area of chondrocytes from oxidative damage, which is suggested to be one of the main molecular factors accused for progression of rheumatoid arthritis and osteoarthritis.

SUMMARY Tissue equivalents represent excellent model systems for elucidating principles of mechanobiology and for exploring methods to improve the functionality of tissue-engineered constructs. The simplest tissue equivalent is the free-floating fibroblast-populated collagen lattice. Although introduced over 30 years ago, the associated mechanics of the cell-mediated compaction of this lattice was only recently analyzed in detail. The goal of this paper was to build on this recent stress analysis by developing a computational model of the evolving geometry, regionally varying material properties and cell stresses, and overall residual stress fields during the first two days of compaction. Baseline results were found to agree well with most experimental observations, namely evolving changes in radius, thickness, and material symmetry, yet hypothesis testing revealed aspects of the mechanobiology that require more experimental attention. Given the generality of the proposed framework, we submit that modifications and refinements can be used to study many similar systems and thereby help guide future experiments. Copyright © 2014 John Wiley & Sons, Ltd.

It is well known that progression of chronic kidney disease can be ameliorated or stabilized by different interventions, but more studies indicate that it can even be reversed. Most data suggest that current therapy, especially renin-angiotensin system inhibition alone, is not sufficient to initiate and maintain long-term regression of glomerular structural injury. In this article, we review the potential reversal of glomerulosclerosis and evidence from both human and animal studies. We discuss mechanisms that involve matrix remodeling, capillary reorganization, and podocyte reconstitution. In the future, a multipronged strategy including novel anti-inflammatory and antifibrotic molecules should be considered to potentiate regression of glomerulosclerosis.

INTRODUCTION There are limited data on left (LV) and right ventricular (RV) diastolic function in systemic sclerosis (SSc) patients especially in relation to biomarkers of matrix remodeling. The aim of the study was to analyze LV and RV myocardial diastolic function in SSc patients at baseline and after at least 1 year of follow-up and its relation to serum tissue inhibitors of metalloproteinase 1 (TIMP-1) level. MATERIAL AND METHODS We prospectively studied 111 SSc patients (101 female, 10 male, age 54.2 ±13.8 years) and 21 age-matched controls (18 female, 3 male, age 49.3 ±10.5 years). After at least 1 year of observation (3.0 ±1.1 years) we reevaluated 69 of the SSc patients. Transthoracic echocardiography (Philips, iE33) for assessment of LV and RV diastolic function was performed and TIMP-1 serum level was measured. RESULTS Impaired LV relaxation was observed in 38 (34%) SSc patients and in 1 (5%) of the controls (p < 0.001). The mean E/A ratio was lower in patients with SSc than in controls (p = 0.002) and significantly decreased after the follow-up period (p = 0.02). Impaired RV relaxation was detected in 25 (22.5%) SSc patients and in 1 (5%) control subject (p < 0.001) but did not deteriorate after follow-up. Mean serum level of TIMP-1 was significantly elevated in the follow-up group compared to baseline examination (p = 0.0001). Serum TIMP-1 level correlated positively with E/E', both septal and lateral (r = 0.4, p = 0.002 and r = 0.32, p = 0.01). CONCLUSIONS The LV and RV relaxation is impaired in SSc patients. Moreover, left ventricular diastolic function deteriorated after the follow-up period. The TIMP-1 serum levels correlate with echocardiographic parameters, providing a potent link for LV diastolic function and matrix remodeling in patients with SSc.

Background/Aims: Dialysis triggers stress reaction, matrix remodeling and endothelial damage, but little is known about the changes it induces on selected heat shock proteins (Hsp90α), adhesion molecules (E-cadherin, sE-selectin), metalloproteinases (MMP-8) and their extracellular inducer (EMMPRIN). The aim of this study was to assess serum concentrations of the above-mentioned parameters in children on chronic dialysis. Methods: 19 patients on hemodialysis (HD), 22 children on peritoneal dialysis (PD) and 30 age-matched controls were examined. Serum concentrations of parameters were assessed by ELISA. Results: Hsp90α, MMP-8, EMMPRIN and E-cadherin concentrations were significantly increased in children on dialysis vs. controls and higher levels were in HD than PD patients. There was no difference in the level of sE-selectin between HD and PD modalities. A single HD session diminished Hsp90α, MMP-8, EMMPRIN and E-cadherin values, but had no impact on sE-selectin levels. Conclusions: Hemodialysis evokes stress reaction, matrix and endothelium destruction, to a greater extent than peritoneal dialysis. Single hemodialysis influences circulating cells rather than endothelial cells.

Imaging cellular and molecular processes associated with aneurysm expansion, dissection, and rupture can potentially transform the management of patients with thoracic and abdominal aortic aneurysm (TAA and AAA). Here, we review recent advances in molecular imaging of aortic aneurysm, focusing on imaging modalities with the greatest potential for clinical translation and application, PET, SPECT and MRI. Inflammation (e.g., with 18F-FDG, nanoparticles) and matrix remodeling (e.g., with matrix metalloproteinase-targeted tracers) are highlighted as promising targets for molecular imaging of aneurysm. Potential alternative or complementary approaches to molecular imaging for aneurysm risk stratification are briefly discussed.

Background The structural elements of the vascular wall, namely, extracellular matrix and smooth muscle cells ( SMC s), contribute to the overall stiffness of the vessel. In this study, we examined the crosslinking‐dependent and crosslinking‐independent roles of tissue transglutaminase ( TG 2) in vascular function and stiffness. Methods and Results SMC s were isolated from the aortae of TG 2−/− and wild‐type ( WT ) mice. Cell adhesion was examined by using electrical cell–substrate impedance sensing and PicoGreen assay. Cell motility was examined using a Boyden chamber assay. Cell proliferation was examined by electrical cell–substrate impedance sensing and EdU incorporation assays. Cell micromechanics were studied using magnetic torsion cytometry and spontaneous nanobead tracer motions. Aortic mechanics were examined by tensile testing. Vasoreactivity was studied by wire myography. SMC s from TG 2−/− mice had delayed adhesion, reduced motility, and accelerated de‐adhesion and proliferation rates compared with those from WT . TG 2−/− SMC s were stiffer and displayed fewer cytoskeletal remodeling events than WT . Collagen assembly was delayed in TG 2−/− SMC s and recovered with adenoviral transduction of TG 2. Aortic rings from TG 2−/− mice were less stiff than those from WT ; stiffness was partly recovered by incubation with guinea pig liver TG 2 independent of crosslinking function. TG 2−/− rings showed augmented response to phenylephrine‐mediated vasoconstriction when compared with WT . In human coronary arteries, vascular media and plaque, high abundance of fibronectin expression, and colocalization with TG 2 were observed. Conclusions TG 2 modulates vascular function/tone by altering SMC contractility independent of its crosslinking function and contributes to vascular stiffness by regulating SMC proliferation and matrix remodeling.

Skin regeneration requires the coordinated integration of concomitant biological and molecular events in the extracellular wound environment during overlapping phases of inflammation, proliferation, and matrix remodeling. This process is highly efficient during normal wound healing. However, chronic wounds fail to progress through the ordered and reparative wound healing process and are unable to heal, requiring long-term treatment at high costs. There are many advanced skin substitutes, which mostly comprise bioactive dressings containing mammalian derived matrix components, and/or human cells, in clinical use. However, it is presently hypothesized that no treatment significantly outperforms the others. To address this unmet challenge, recent research has focused on developing innovative acellular biopolymeric scaffolds as more efficacious wound healing therapies. These biomaterial-based skin substitutes are precisely engineered and fine-tuned to recapitulate aspects of the wound healing milieu and target specific events in the wound healing cascade to facilitate complete skin repair with restored function and tissue integrity. This mini-review will provide a brief overview of chronic wound healing and current skin substitute treatment strategies while focusing on recent engineering approaches that regenerate skin using synthetic, biopolymeric scaffolds. We discuss key polymeric scaffold design criteria, including degradation, biocompatibility, and microstructure, and how they translate to inductive microenvironments that stimulate cell infiltration and vascularization to enhance chronic wound healing. As healthcare moves toward precision medicine-based strategies, the potential and therapeutic implications of synthetic, biopolymeric scaffolds as tunable treatment modalities for chronic wounds will be considered.

53 Background: Andecaliximab (ADX) is a monoclonal antibody that inhibits matrix metalloproteinase 9 (MMP9), an extracellular enzyme involved in matrix remodeling, tumor growth, and metastasis. In preclinical models, anti-MMP9 inhibited tumor growth, reduced metastases, and increased survival. In this study, safety, tolerability, PK, exploratory biomarkers, and preliminary efficacy of ADX in combination with anti-cancer agents were assessed. Methods: The safety and efficacy of ADX in combination with S-1+cisplatin (SP) or S-1+oxaliplatin (SOX) were evaluated in subjects with systemic chemotherapy naïve advanced gastric or GEJ adenocarcinoma. For SP cohort, six Japanese subjects received ADX 800 mg via IV infusion Q2W. For SOX cohort, 10 subjects received ADX 1200 mg IV Q3W. All subjects continued until PD or unacceptable toxicity. Results: As of August 2018, a total of 16 subjects received S-1+platinum with six subjects enrolled into the SP combination cohort and 10 subjects enrolled into the SOX combination cohort. ≥ Grade 3 AEs were mainly neutropenia (31%), amylase increased, CPK increased, hepatic function abnormal, anorexia, hyperglycaemia, hyponatraemia, anaemia, stomatitis, and peripheral sensory neuropathy (each 6%). The ORR in subjects with measurable target lesions was 73% (8/11) based on investigator evaluation. Median PFS and OS have not been reached. Exploratory biomarker analyses are ongoing. Conclusions: Preliminary safety data demonstrate a manageable safety profile for ADX in combination with S-1+platinum, and the combination appears to show promising response rates. Clinical trial information: NCT02862535.

The human ACL (anterior cruciate ligament) is susceptible to injury but has poor healing response, whereas an injured MCL (medial collateral ligament) can be repaired relatively well. Since MMPs (matrix metalloproteases) and TIMPs (tissue inhibitor of metalloproteases) are involved in this tissue remodeling process, investigation of different response of MMPs and TIMPs family in ACL and MCL fibroblasts might lead to understanding the differential matrix remodeling process as well as their different healing ability. The first step would be determination of whether these tissue remodeling effectors are present in ligaments. In this study, we designed primers for real-time RT-PCR and determined the expression of MMPs and TIMPs family in ACL and MCL fibroblasts with synovium as a positive control. Semiquantitative RT-PCR revealed that multiple MMPs and TIMPs expressed in human ACL and MCL fibroblasts except MMP-8, 10, 12, 13, 15, 16, 20, and 26. MMP-7 was present in MCL but not in ACL fibroblast. Quantitative real-time RT-PCR showed that mRNA levels of MMP-1, 2, 14, 17, 23A, and 23B and TIMP-4 are significantly higher in MCL than in ACL fibroblasts. However, MMP-3 is higher in ACL than in MCL fibroblasts. We conclude that numerous MMPs and TIMPs family members that are differentially expressed in ACL and MCL might be involved in the differential matrix remodeling process as well as the differential healing ability of ACL and MCL.

Introduction: Myxomatous mitral valve disease (MMVD) is a degenerative condition characterized by tissue fibrosis and matrix remodeling which ultimately progresses to leaflet prolapse. While recent work has shown that transforming growth factor beta (TGF-β) signaling contributes to the pathogenesis of MMVD, upstream regulators of this and other pathways remain poorly understood. Hypothesis: We sought to use high-throughput RNA sequencing coupled with microRNA (miRNA) sequencing to identify novel molecular targets as well as upstream regulators contributing to MMVD. Methods: We conducted mRNA and miRNA sequencing on normal (n = 10) and myxomatous human mitral valve samples (n = 10). Differential expression was identified using linear modeling and parallel random forest analyses. Canonical pathways were identified by Ingenuity Pathway Analyses (IPA). Predicted miRNA targets were identified using TargetScanHuman 6.2. Results: We found 2784 mRNAs that were differentially expressed between normal and myxomatous mitral valves, which IPA largely categorized in to pro-fibrotic, matrix remodeling and cellular proliferation signaling. In miRNA sequenced from the same samples, 67 miRNAs were differentially-expressed between normal and myxomatous mitral valves. Increased expression of TGF-β ligands, collagen isoforms, and matrix metalloproteinases were associated with reductions in miRNAs predicted to target them. Conversely, mRNA levels of the “protective” genes TGFβ-induced factor homeobox 1, salt-inducible kinase 1, TIMP metallopeptidase inhibitor 4, and cyclin-dependent kinase inhibitor 1C mRNA levels were decreased in myxomatous tissue, and miRNAs predicted to target these genes (e.g., miR-656, miR-379-3p, miR-664a-3p, and miR-34c-5p) were significantly increased. Conclusions: Collectively, these data not only identify novel genes that are differentially regulated in MMVD, but also suggest miRNAs may play an active role in suppressing key protective molecules in MMVD. Thus, anti-mIRs therapy may be a viable therapeutic target to restore anti-fibrotic and anti-proliferative molecules in the valve and slow progression of MMVD. Future mechanistic studies will lay a critical foundation for translational work in these areas.

Calcific aortic valve stenosis is the most common heart valve disorder in the elderly and the most common cause of heart valve replacement in industrialized countries. For decades, it was considered a passive age-dependent degeneration of the valve tissue. Newer studies have shown, however, that the pathologic changes in calcific aortic valve stenosis are based on an actively regulated process of matrix remodeling and biomineralization. This review summarizes the currently available data and gives an outlook on potential therapeutic approaches.

Matrix metalloproteinases (MMPs) can alter myocardial extracellular matrix and thereby contribute to adverse ventricular remodeling in progressive heart failure (HF). We hypothesized that increased plasma MMP levels correlate with increased left ventricular (LV) volumes and reduced LV ejection fraction (LVEF) in patients with HF.In the Randomized Evaluation of Strategies for Left Ventricular Dysfunction (RESOLVD) trial, patients with symptomatic HF and LVEF0.40 were randomized to receive various combinations of therapies with candesartan, enalapril, and metoprolol CR. Left ventricular end-diastolic volume (EDV), end-systolic volume (ESV), and LVEF were determined by radionuclide angiography at baseline and at Week 43. Baseline and Week 43 plasma MMP-2, MMP-9, and tissue inhibitor of metalloproteinase-1 (TIMP-1) were measured by enzyme-linked immunosorbent assay in 184 patients in this substudy. At baseline, plasma MMP-9 correlated positively with ESV (Spearman's rank correlation coefficient rho = 0.17, P = .02) and negatively with LVEF (rho = -0.18, P = .01). After 43 weeks, LVEF, EDV, and ESV increased significantly (all P.01); MMP-2 level increased (P = .01), but MMP-9 and TIMP-1 levels did not change significantly overall in the study population. Temporal changes in MMP-9 level were inversely correlated with changes in LVEF (rho = -0.16, P = .04). In multivariable analysis adjusting for clinical characteristics and treatment, a smaller proportional change in MMP-9 level after 43 weeks (below versus above median) predicted a concurrent improvement in LVEF (odds ratio = 2.35, 95% CI 1.24-4.46; P.01). Similar relationships for MMP-2 and TIMP-1 were not observed.Elevated plasma MMP-9 levels correlated with lower LVEF and higher ESV, whereas increasing MMP-9 levels are associated with a concurrent deterioration of LV function. These findings suggest that monitoring of plasma markers of myocardial matrix remodeling may provide important prognostic information with respect to ongoing adverse LV remodeling in HF patients.

Chronic pressure overload, such as that with hypertension, induces left ventricular (LV) remodeling characterized by increased mass, that is, LV hypertrophy (LVH). LVH can cause impaired diastolic function and thereby contribute to heart failure. The myocardial extracellular matrix undergoes significant remodeling in LVH contributing to abnormalities in diastolic function. Current pharmacological strategies for the treatment of hypertension only indirectly and/or incompletely affect the structure and composition of the myocardial matrix. Identifying crucial pathways involved in matrix remodeling in hypertension-induced LVH will aid in the selection of more relevant targets.