RATIONALE: Cardiac ECM (extracellular matrix) comprises a dynamic molecular network providing structural support to heart tissue function. Understanding the impact of ECM remodeling on cardiac cells during heart failure (HF) is essential to prevent adverse ventricular remodeling and restore organ functionality in affected patients. OBJECTIVES: We aimed to (1) identify consistent modifications to cardiac ECM structure and mechanics that contribute to HF and (2) determine the underlying molecular mechanisms. METHODS AND RESULTS: We first performed decellularization of human and murine ECM (decellularized ECM) and then analyzed the pathological changes occurring in decellularized ECM during HF by atomic force microscopy, 2-photon microscopy, high-resolution 3-dimensional image analysis, and computational fluid dynamics simulation. We then performed molecular and functional assays in patient-derived cardiac fibroblasts based on YAP (yes-associated protein)-transcriptional enhanced associate domain (TEAD) mechanosensing activity and collagen contraction assays. The analysis of HF decellularized ECM resulting from ischemic or dilated cardiomyopathy, as well as from mouse infarcted tissue, identified a common pattern of modifications in their 3-dimensional topography. As compared with healthy heart, HF ECM exhibited aligned, flat, and compact fiber bundles, with reduced elasticity and organizational complexity. At the molecular level, RNA sequencing of HF cardiac fibroblasts highlighted the overrepresentation of dysregulated genes involved in ECM organization, or being connected to TGFβ1 (transforming growth factor β1), interleukin-1, TNF-α, and BDNF signaling pathways. Functional tests performed on HF cardiac fibroblasts pointed at mechanosensor YAP as a key player in ECM remodeling in the diseased heart via transcriptional activation of focal adhesion assembly. Finally, in vitro experiments clarified pathological cardiac ECM prevents cell homing, thus providing further hints to identify a possible window of action for cell therapy in cardiac diseases. CONCLUSIONS: Our multiparametric approach has highlighted repercussions of ECM remodeling on cell homing, cardiac fibroblast activation, and focal adhesion protein expression via hyperactivated YAP signaling during HF.
- MeSH
- adaptorové proteiny signální transdukční genetika metabolismus MeSH
- buněčný převod mechanických signálů MeSH
- dilatační kardiomyopatie genetika metabolismus patologie patofyziologie MeSH
- extracelulární matrix genetika metabolismus ultrastruktura MeSH
- fibroblasty metabolismus ultrastruktura MeSH
- funkce levé komory srdeční * MeSH
- infarkt myokardu genetika metabolismus patologie patofyziologie MeSH
- kultivované buňky MeSH
- lidé MeSH
- modely nemocí na zvířatech MeSH
- myokard metabolismus ultrastruktura MeSH
- myši inbrední C57BL MeSH
- pohyb buněk MeSH
- remodelace komor * MeSH
- srdeční selhání genetika metabolismus patologie patofyziologie MeSH
- studie případů a kontrol MeSH
- transkripční faktory genetika metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- audiovizuální média MeSH
- časopisecké články MeSH
- práce podpořená grantem MeSH
Deep sternal wound infection is a challenging aspect of modern cardiac surgery. The considerable mortality rate, devastating morbidity and, negative impact on long-term survival has driven cardiac and plastic surgeons to seek a more advantageous treatment solution. This review summarizes progress in the field of deep sternal wound infection treatment after cardiac surgery. Emphasis is placed on outcomes analysis of contemporary treatment strategy based on negative pressure wound therapy followed by sternotomy wound reconstruction, and its comparison with conventional treatment modalities used afore. Furthermore, complications and drawbacks of treatment strategies are critically evaluated to outline current options for successfully managing this life-threatening complication following cardiac surgery.
- MeSH
- antibakteriální látky terapeutické užití MeSH
- debridement MeSH
- infekce chirurgické rány terapie MeSH
- kardiochirurgické výkony MeSH
- klinické zkoušky jako téma MeSH
- lidé MeSH
- sternotomie MeSH
- sternum * chirurgie patologie MeSH
- terapie ran pomocí řízeného podtlaku * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
