Ivan Melnychenko

Boston Children's Hospital, Boston, Massachusetts, United States

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Publications (3)16.62 Total impact

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    ABSTRACT: Rationale: Endocardial fibroelastosis (EFE) is a unique form of fibrosis which forms a de novo subendocardial tissue layer encapsulating the myocardium and stunting its growth, and which is typically associated with congenital heart diseases of heterogeneous origin, such as hypoplastic left heart syndrome. Relevance of EFE was only recently highlighted through establishment of staged biventricular repair surgery in HLHS infant patients, where surgical removal of EFE tissue has resulted in improvement in the restrictive physiology leading to growth of the left ventricle in parallel with somatic growth. However, pathomechanisms underlying EFE formation are still scarce and specific therapeutic targets are not yet known. Objective: Here we aimed to investigate the cellular origins of EFE tissue and to gain insights into underlying molecular mechanisms to ultimately develop novel therapeutic strategies. Methods and Results: By utilizing a novel EFE model of heterotopic transplantation of hearts from newborn reporter mice and by analyzing human EFE tissue, we demonstrate for the first time that fibrogenic cells within EFE tissue originate from endocardial endothelial cells via aberrant endothelial mesenchymal transition (EndMT). We further demonstrate that such aberrant EndMT involving endocardial endothelial cells is caused by dysregulated TGFβ/BMP signaling and that this imbalance is at least in part caused by aberrant promoter methylation and subsequent transcriptional suppression of BMP5 and BMP7. Finally, we provide evidence that supplementation of exogenous recombinant BMP7 effectively ameliorates EndMT and experimental EFE in rats. Conclusions: In summary our data point to aberrant EndMT as a common denominator of infant EFE development in heterogeneous, congenital heart diseases, and to BMP7 as an effective treatment for EFE and its restriction of heart growth.
    Circulation Research 01/2015; · 11.09 Impact Factor
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    ABSTRACT: BACKGROUND: Hypoplastic left heart syndrome (HLHS) is one of the most common severe congenital cardiac anomalies, characterized by a marked hypoplasia of left-sided structures of the heart, which is commonly accompanied by a thick layer of fibroelastic tissue, termed endocardial fibroelastosis (EFE). Because human EFE develops only in fetal or neonatal hearts, and often in association with reduced blood flow, we sought to mimic these conditions by subjecting neonatal and 2-wk-old rat hearts to variations of the heterotopically transplanted heart model with either no intracavitary or normal flow and compare endocardium with human EFE tissue. MATERIALS AND METHODS: Hearts obtained from neonatal and 2-wk-old rats were heterotopically transplanted in young adult Lewis rats in a working (loaded) or nonworking (unloaded) mode. After 2-wk survival, hearts were explanted for histologic analysis by staining for collagen, elastin, and cellular elements. These sections were compared with human EFE tissue from HLHS. RESULTS: EFE, consisting of collagen and elastin with scarce cellular and vascular components, developed only in neonatal unloaded transplanted hearts and displayed the same histopathologic findings as EFE from patients with HLHS. Loaded hearts and 2-wk-old hearts did not show these alterations. CONCLUSIONS: This animal model for EFE will serve as a tool to study the mechanisms of EFE formation, such as fluid forces, in HLHS in a systematic manner. A better understanding of the underlying cause of the EFE formation in HLHS will help to develop novel treatment strategies to better preserve growth of the hypoplastic left ventricle.
    Journal of Surgical Research 08/2012; · 2.12 Impact Factor
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    ABSTRACT: Safe and effective device closure of ventricular septal defects remains a challenge. We have developed a transcardiac approach to close ventricular septal defects using a patch delivery and fixation system that can be secured under real-time three-dimensional echocardiographic guidance. In Yorkshire pigs (n = 8) a coring device was introduced into the left ventricle through a purse-string suture placed on the left ventricular apex, and a muscular ventricular septal defect was created. The patch deployment device containing a 20-mm polyester patch was advanced toward the ventricular septal defect through another purse-string suture on the left ventricular apex, and the patch was deployed under real-time three-dimensional echocardiographic guidance. The anchor delivery device was then introduced into the left ventricle through the first purse-string suture. Nitinol anchors to attach the patch around the ventricular septal defect were deployed under real-time three-dimensional echocardiographic guidance. After patch attachment, residual shunts were sought by means of two-dimensional and three-dimensional color Doppler echocardiography. The heart was then excised, and the septum with the patch was inspected. A ventricular septal defect was created in the midventricular (n = 4), anterior (n = 2), and apical (n = 2) septum. The mean size was 9.8 mm (8.2-12.0 mm), as determined by means of two-dimensional color Doppler scanning. The ventricular septal defects were completely closed in 7 animals. In one a 2.4-mm residual shunt was identified. No anatomic structures were compromised. Beating-heart perventricular muscular ventricular septal defect closure without cardiopulmonary bypass can be successfully achieved by using a catheter-based patch delivery and fixation system under real-time three-dimensional echocardiographic guidance. This approach might be a better alternative to cardiac surgery or transcatheter device closure.
    The Journal of thoracic and cardiovascular surgery 04/2008; 135(3):603-9. · 3.41 Impact Factor