Dilated Form of Endocardial Fibroelastosis as a Result of Deficiency in Respiratory-Chain Complexes I and IV

Corradi, Domenico; Tchana, Bertrand; Miller, Dylan V.; Manotti, Laura; Maestri, Roberta; Martorana, Davide; Callegari, Sergio; Allegri, V.; Carano, N.; Agnetti, Aldo; Squarcia, Umberto

doi:10.1161/circulationaha.108.840660

Cited by 7 publications

(5 citation statements)

References 6 publications

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“…Whether the TUNEL-positive cells in the hearts of T4-treated ZmRacD mice stand for apoptosis or oncosis remains to be revealed. In agreement with our findings, increased apoptosis, oncosis and interstitial fibrosis have been previously reported in transgenic mice and human patients with cardiac dilation [32], [34], [35].…”

Section: Discussionsupporting

confidence: 94%

“…This would then imply that cardiac myocyte apoptosis is enhanced in the hearts of these mice. Moreover, the incidence of oncotic cell death cannot be debarred, since some myocytes in the dilated hearts displayed formation of vacuoles corresponded to severe loss of sarcomere (myolysis) with accumulation of abundant mitochondria and mild increase in infiltration of inflammatory cells [32], [34], [35]. We consistently observed a marked increase in the number of TUNEL-positive cells in the hearts of T4-treated ZmRacD mice.…”

Section: Discussionmentioning

confidence: 57%

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Rac-Induced Left Ventricular Dilation in Thyroxin-Treated ZmRacD Transgenic Mice: Role of Cardiomyocyte Apoptosis and Myocardial Fibrosis

et al. 2012

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The pathways inducing the critical transition from compensated hypertrophy to cardiac dilation and failure remain poorly understood. The goal of our study is to determine the role of Rac-induced signaling in this transition process. Our previous results showed that Thyroxin (T4) treatment resulted in increased myocardial Rac expression in wild-type mice and a higher level of expression in Zea maize RacD (ZmRacD) transgenic mice. Our current results showed that T4 treatment induced physiologic cardiac hypertrophy in wild-type mice, as demonstrated by echocardiography and histopathology analyses. This was associated with significant increases in myocardial Rac-GTP, superoxide and ERK1/2 activities. Conversely, echocardiography and histopathology analyses showed that T4 treatment induced dilated cardiomyopathy along with compensatory cardiac hypertrophy in ZmRacD mice. These were linked with further increases in myocardial Rac-GTP, superoxide and ERK1/2 activities. Additionally, there were significant increases in caspase-8 expression and caspase-3 activity. However, there was a significant decrease in p38-MAPK activity. Interestingly, inhibition of myocardial Rac-GTP activity and superoxide generation with pravastatin and carvedilol, respectively, attenuated all functional, structural, and molecular changes associated with the T4-induced cardiomyopathy in ZmRacD mice except the compensatory cardiac hypertrophy. Taken together, T4-induced ZmRacD is a novel mouse model of dilated cardiomyopathy that shares many characteristics with the human disease phenotype. To our knowledge, this is the first study to show graded Rac-mediated O2·− results in cardiac phenotype shift in-vivo. Moreover, Rac-mediated O2·− generation, cardiomyocyte apoptosis, and myocardial fibrosis seem to play a pivotal role in the transition from cardiac hypertrophy to cardiac dilation and failure. Targeting Rac signaling could represent valuable therapeutic strategy not only in saving the failing myocardium but also to prevent this transition process.

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Section: Discussionsupporting

confidence: 94%

Section: Discussionmentioning

confidence: 57%

Rac-Induced Left Ventricular Dilation in Thyroxin-Treated ZmRacD Transgenic Mice: Role of Cardiomyocyte Apoptosis and Myocardial Fibrosis

et al. 2012

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“…The diagnosis of EFE was confirmed after cardiac transplantation. As the gross specimens of other reported cases showed,4)13) we could see the typical EFE finding referred to as a whitish fibrous tissue lining the endocardium 14)…”

Section: Discussionmentioning

confidence: 66%

Endocardial Fibroelastosis in a 57-Year-Old Transplant Recipient

et al. 2010

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Endocardial fibroelastosis (EFE) is characterized by deposition of collagen and elastin leading to ventricular hypertrophy and diffuse endocardial thickening. Here we report (for the first time in Korea) the case of a EFE presenting with heart failure. The patient was a 57-year-old woman who had complained of dyspnea on exertion {New York Heart Association (NYHA) functional class 3} and abdominal distension at the time of hospital admission. Echocardiography showed severe diastolic dysfunction with normal systolic function. On MRI, the contrast-enhanced delayed myocardial image demonstrated hyperenhancement in the endocardium. Owing to progressive heart failure, the patient was transplanted. Histological examination of the explanted heart showed irregularly thickened endocardium with fibrosis and elastosis in the both ventricles, compatible with the diagnosis of EFE.

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“…The earliest available pathological data of complex-1 deficiency in the literature are from neonatal postmortem studies. The reported findings include myocardial hypertrophy, endocardial fibrosis, cardiac fibroelastosis, macro-or microvesicular steatosis, pulmonary arterial hypertensive changes, decreased alveolarization and spinal arachnoid cyst 15,[18][19][20] . The neuropathological features of Leigh syndrome, which is the most common consequence of complex-I deficiency, include bilateral symmetric lesions associated with demyelination, gliosis, and vascular proliferation and thickening 21 .…”

Section: Discussionmentioning

confidence: 99%

Unique prenatal manifestations of biallelic NDUFAF5 variants: expansion of phenotype

Brabbing‐Goldstein,

Kozlova,

Bazak

et al. 2024

Ultrasound in Obstet & Gyne

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ObjectivesMitochondrial complex I deficiency, nuclear type 16 is a rare autosomal recessive disorder caused by biallelic pathogenic variants in NDUFAF5 (C20orf7) [OMIM 618238]. This entity belongs to a genetically and clinically heterogenic group of complex I deficiency which accounts for up to 30% of childhood mitochondrial disorders presenting as Leigh syndrome, leukoencephalopathy, fatal infantile lactic acidosis, and other early‐onset neurodegenerative disorders. We present very early, unique, and severe prenatal manifestation of this disorder, previously considered to manifest post‐natally.MethodsWe describe five fetuses from three non‐related families sharing common sonographic abnormalities including brain cysts, callosal malformations, hydrops fetalis, and growth restriction. Genetic evaluation included chromosomal microarray analysis and exome sequencing. Two fetuses from one family were also available for pathology examination, including electronic microscopy.ResultsChromosomal microarray revealed no chromosomal abnormalities. Trio exome sequencing demonstrated that three affected fetuses from three unrelated families were compound heterozygotes or homozygotes for likely pathogenic variants in NDUFAF5. No other causative variants were detected. NDUFAF5 variants association with fetal malformations was further confirmed by segregation studies. Histologic evaluation of fetal tissues and electronic microscopy of muscle, liver, proximal tubules of kidney and heart, demonstrated changes resembling those described in postmortem autopsies of patients with mitochondrial depletion disorders as well as previously undescribed findings.ConclusionsMitochondrial complex I deficiency and specifically biallelic mutations in NDUFAF5 have a role in abnormal fetal development presenting with severe congenital malformations. Complex I mitochondrial disorders should be considered in the differential diagnosis of callosal malformations and brain cysts, especially when associated with extra central nervous system (CNS) abnormalities such as fetal growth restriction or nonimmune hydrops fetalis.This article is protected by copyright. All rights reserved.

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Dilated Form of Endocardial Fibroelastosis as a Result of Deficiency in Respiratory-Chain Complexes I and IV

Cited by 7 publications

References 6 publications

Rac-Induced Left Ventricular Dilation in Thyroxin-Treated ZmRacD Transgenic Mice: Role of Cardiomyocyte Apoptosis and Myocardial Fibrosis

Rac-Induced Left Ventricular Dilation in Thyroxin-Treated ZmRacD Transgenic Mice: Role of Cardiomyocyte Apoptosis and Myocardial Fibrosis

Endocardial Fibroelastosis in a 57-Year-Old Transplant Recipient

Unique prenatal manifestations of biallelic NDUFAF5 variants: expansion of phenotype

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