Abstract 20609: Abnormalities of Mitochondrial Number and Function in Pediatric Idiopathic Dilated Cardiomyopathy

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Kathryn C Chatfield ◽  
Marisa W Friederich ◽  
Shelley D Miyamoto ◽  
Carmen C Sucharov ◽  
Johan L Van Hove ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Mitochondrial Dysfunction ◽  
Copy Number ◽  
Citrate Synthase ◽  
Myocardial Dysfunction ◽  
Complex Iii ◽  
Idiopathic Dilated Cardiomyopathy ◽  
Mitochondrial Copy Number ◽  
Z Scores ◽  
And Function

Introduction: Impaired mitochondrial energy production and substrate utilization have been implicated in the development of heart failure (HF) in adults. Little literature exists describing mitochondrial energetics in pediatric HF. We have previously shown that content of Cardiolipin (CL), a major mitochondrial membrane phospholipid, is depleted in both adult and pediatric idiopathic dilated cardiomyopathy (IDC), with preserved expression of mitochondrial-encodes genes. Similar CL changes occur in a rat model of HF with associated mitochondrial dysfunction that precedes myocardial dysfunction, which can be reversed by dietary interventions. Hypothesis: We hypothesize that mitochondrial dysfunction occurs in pediatric IDC. Methods: As a part of an on-going study a cross-sectional analysis of mitochondrial content and function was performed in left ventricle tissue from the University of Colorado Pediatric Heart Tissue Bank. Current contents: age 13-18: 11 IDC (64% male) and 13 NF (62% male). All NF are donor hearts with normal LVEF; all IDC specimens had LVEF <30%. Results: We show lower mitochondrial copy number in pediatric IDC compared with NF controls (IDC: 44 vs NF: 24, P<0.05), with paradoxical up-regulation of transcriptional co-activators, PGC1α and NRF1 (P<0.01). This is in contrast to what has been shown in adult HF where PGC1α and NRF1 expression are unchanged. Electron transport chain (ETC) complex enzymatic activities were quantified in a sub-group of pediatric IDC samples, expressed as Z-scores relative to normative values in 18 NFs. Significantly decreased activities of complexes I, IV, and citrate synthase were found (Z-scores -2.2, -3.3 and -1.7 respectively), with a significant increase in complex III activity (Z-score 0.7, all P<0.05). Conclusions: These results suggest impaired mitochondrial biogenesis occurs in pediatric HF by a unique mechanism from that seen in adults. Additionally, we show a very specific pattern of ETC dysfunction in pediatric IDC. Future studies will identify the how decreased mitochondrial copy number occurs in the context of PGC1α and NRF1 up-regulation and determine whether abnormalities in CL contribute to abnormalities in ETC activities.

Abstract 2556: A Comparative Analysis of Outcomes for Pediatric Patients with Biopsy-Proven Myocarditis, Clinically-Diagnosed Myocarditis and Idiopathic Dilated Cardiomyopathy.

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Susan Foerster ◽  
Charles Canter ◽  
Amy Carey ◽  
Lynn A Sleeper ◽  
John L Jefferies ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Systolic Function ◽  
Idiopathic Dilated Cardiomyopathy ◽  
Z Score ◽  
Free Survival ◽  
Increased Risk ◽  
Pediatric Cardiomyopathy ◽  
Z Scores ◽  
And Function ◽  
Available Information

Background: Data on outcomes in children with myocarditis is sparse and challenging to interpret given no ``gold standard” for diagnosis. The NHLBI Pediatric Cardiomyopathy Registry provides a large, multi-center cohort with clinical and echocardiographic follow-up of up to 16 years. Methods/Results : We compared cases of biopsy-confirmed myocarditis (BCM, N=119) and clinically-diagnosed myocarditis (CDM, N=253), with idiopathic dilated cardiomyopathy (IDCM, N=1123). BCM and CDM patients were older at diagnosis than those with IDCM (median age 1.6, 1.9, 1.2 yr, respectively). For BCM, heart failure symptoms (86%) and admission (97%) at diagnosis were more common (p<0.05 compared to either CDM/IDCM). LV end-diastolic dimension (EDD) Z-score was abnormal (>2) in 71% with myocarditis and 86% with IDCM. Systolic function was impaired in all groups, with a median fractional shortening (FS) Z score of -9 for myocarditis and -10 for IDCM; 23% of myocarditis patients had impaired function without dilation. Two-year death/transplant rates were 24% (BCM), 24% (CDM), and 47% (IDCM). Of myocarditis survivors, 46% had normalization of both EDD and FS Z-scores at 2 years vs. 25% for IDCM (p<.0001). Baseline echo status was strongly associated with later echo status for IDCM pts. Recovery from myocarditis at 2 years was not strongly associated with baseline echocardiographic characteristics, but transplant-free survival was lower in myocarditis patients when both baseline FS and EDD were abnormal (logrank p=.03). When therapeutic data were available, the BCM group received IVIG/steroids most often (44% vs. 23% CDM, 6% IDCM); this was not significantly associated with 2-year echo recovery or transplant-free survival, but power was limited. Conclusions : In this dataset, children with BCM and CDM have similar profiles and a better outcome than those with IDCM, with 76% surviving without transplant at 2 years. Nearly 1 / 2 have normalization of LV size and function, but the presence of both dilation and poor function at presentation is associated with increased risk for death or transplant. Echocardiographic normalization occurs in 25% of IDCM survivors by 2 years. This study is limited by being an analysis of available information in a database collected for other purposes.

scholarly journals Vitamin D Status in Children with Idiopathic Dilated Cardiomyopathy

2021 ◽  
Vol 11 (01) ◽  
pp. e120-e124
Author(s):  
Duaa M. Raafat ◽  
Osama M. EL-Asheer ◽  
Amal A. Mahmoud ◽  
Manal M. Darwish ◽  
Naglaa S. Osman
Keyword(s):  
Vitamin D ◽  
Serum Level ◽  
Dilated Cardiomyopathy ◽  
Smooth Muscles ◽  
Left Ventricular ◽  
Idiopathic Dilated Cardiomyopathy ◽  
Vitamin D Receptors ◽  
Left Ventricular Dimensions ◽  
And Function ◽  
Ventricular Dimensions

AbstractDilated cardiomyopathy (DCM) is the third leading cause of heart failure in pediatrics. The exact etiology of DCM is unknown in more than half of the cases. Vitamin D receptors are represented in cardiac muscles, endothelium, and smooth muscles of blood vessels suggesting that vitamin D could have a vital cardioprotective function. This study aimed to assess serum level of vitamin D in children with idiopathic DCM and to correlate the serum level of vitamin D with the left ventricular dimensions and function. This study is a descriptive cross-sectional single-center study, includes 44 children of both sexes, diagnosed as idiopathic DCM. Serum level of vitamin D was assessed and correlated with the left ventricular dimensions and function. Mean age of studied children was 6.08 ± 4.4 years. Vitamin D deficiency was found in 90.9% of children with idiopathic DCM with a mean level 13.48 ng/mL. There was a negative correlation between vitamin D level and fraction shortening and left ventricular end-diastolic diameter in children with DCM. Vitamin D level is not only significantly low in children with idiopathic DCM but it is also significantly correlated with the degree of left ventricular dysfunction.

scholarly journals Testosterone Decreases Placental Mitochondrial Content and Cellular Bioenergetics

Biology ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 176 ◽  
Author(s):  
Jay S. Mishra ◽  
Chellakkan S. Blesson ◽  
Sathish Kumar
Keyword(s):  
Mitochondrial Dysfunction ◽  
Copy Number ◽  
Structural Damage ◽  
Plasma Testosterone ◽  
Sprague Dawley ◽  
Pregnant Rats ◽  
Testosterone Levels ◽  
Mitochondrial Copy Number ◽  
Maternal Testosterone

Placental mitochondrial dysfunction plays a central role in the pathogenesis of preeclampsia. Since preeclampsia is a hyperandrogenic state, we hypothesized that elevated maternal testosterone levels induce damage to placental mitochondria and decrease bioenergetic profiles. To test this hypothesis, pregnant Sprague–Dawley rats were injected with vehicle or testosterone propionate (0.5 mg/kg/day) from gestation day (GD) 15 to 19. On GD20, the placentas were isolated to assess mitochondrial structure, copy number, ATP/ADP ratio, and biogenesis (Pgc-1α and Nrf1). In addition, in vitro cultures of human trophoblasts (HTR-8/SVneo) were treated with dihydrotestosterone (0.3, 1.0, and 3.0 nM), and bioenergetic profiles using seahorse analyzer were assessed. Testosterone exposure in pregnant rats led to a 2-fold increase in plasma testosterone levels with an associated decrease in placental and fetal weights compared with controls. Elevated maternal testosterone levels induced structural damage to the placental mitochondria and decreased mitochondrial copy number. The ATP/ADP ratio was reduced with a parallel decrease in the mRNA and protein expression of Pgc-1α and Nrf1 in the placenta of testosterone-treated rats compared with controls. In cultured trophoblasts, dihydrotestosterone decreased the mitochondrial copy number and reduced PGC-1α, NRF1 mRNA, and protein levels without altering the expression of mitochondrial fission/fusion genes. Dihydrotestosterone exposure induced significant mitochondrial energy deficits with a dose-dependent decrease in basal respiration, ATP-linked respiration, maximal respiration, and spare respiratory capacity. In summary, our study suggests that the placental mitochondrial dysfunction induced by elevated maternal testosterone might be a potential mechanism linking preeclampsia to feto-placental growth restriction.

scholarly journals Screening for Mitochondrial tRNA Mutations in 318 Patients with Dilated Cardiomyopathy

2022 ◽  
Author(s):  
Yujuan Qi ◽  
Zhenhua Wu ◽  
Yaobang Bai ◽  
Yan Jiao ◽  
Peijun Li
Keyword(s):  
Dilated Cardiomyopathy ◽  
Mitochondrial Dysfunction ◽  
Copy Number ◽  
Mutational Analysis ◽  
Unknown Etiology ◽  
Trna Genes ◽  
Mtdna Copy Number ◽  
Mitochondrial Trna ◽  
Mitochondrial Functions ◽  
And Gender

Objectives: Dilated cardiomyopathy (DCM) is a complex cardiovascular disease with unknown etiology. Although nuclear genes play active roles in DCM, mitochondrial dysfunction was believed to be involved in the pathogenesis of DCM. The objective of this study is to analysis the association between mitochondrial tRNA (mt-tRNA) mutations and DCM. Material and Methods: We performed a mutational analysis of mt-tRNA genes in a cohort of 318 patients with DCM and 200 age- and gender-matched control subjects. To further assess their pathogenicity, phylogenetic analysis and mitochondrial functions including mtDNA copy number, ATP and ROS were analyzed. Results: 7 possible pathogenic mutations: MT-TL1 3302A>G, MT-TI 4295A>G, MT-TM 4435A>G, MT-TA 5655T>C, MT-TH 12201T>C, MT-TE 14692A>G and MT-TT 15927G>A were identified in DCM group but absent in controls. These mutations occurred at extremely conserved nucleotides of corresponding tRNAs, and led to the failure in tRNAs metabolism. Moreover, a significant reduction in ATP and mtDNA copy number, whereas a markedly increased in ROS level were observed in polymononuclear leukocytes (PMNs) derived from the DCM patients carrying these mt-tRNA mutations, suggesting that these mutations may cause mitochondrial dysfunction that was responsible for DCM. Conclusions: Our data indicated that mt-tRNA mutations may be the molecular basis for DCM, which shaded novel insight into the pathophysiology of DCM that was manifestated by mitochondrial dysfunction.

Abstract 4952: Differential Expression in the Determinants of Extracellular Matrix Remodeling in Pediatric and Adult Dilated Cardiomyopathy

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Tain-Yen Hsia ◽  
Jeremy M Ringewald ◽  
Robert E Stroud ◽  
Michael C Graves ◽  
Scott M Bradley ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Dilated Cardiomyopathy ◽  
Cell Lineage ◽  
Left Ventricular ◽  
Idiopathic Dilated Cardiomyopathy ◽  
Matrix Remodeling ◽  
Adult Age ◽  
Membrane Type ◽  
And Function ◽  
Aggressive Clinical Course

Ventricular phenotype of idiopathic dilated cardiomyopathy (DCM) can appear similar in pediatric and adult patients, but a more aggressive clinical course often occurs with pediatric DCM. A structural underpinning of DCM is extracellular matrix changes, which are determined by a balance between matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs). This study tests the hypothesis that different MMP/TIMP profiles occur in pediatric and adult DCM patients. Left ventricular samples were taken from pediatric (age 12±4 yr; n=5) and adult (age 63±3 yr; n=11) patients during heart transplantation for DCM. Myocardial levels were quantified for all MMP classes: gelatinases (MMP-2, -9), collagenases (MMP-8, -13), lysins (MMP-7), membrane-type (MT1-MMP), and for all 4 known TIMPs. Patients with structural or ischemic etiologies of DCM were excluded. Compared to adults, MMP-8 levels increased by over 350% (Figure ), and MMP-7 and MT1-MMP levels (75±9% and 76±9%, respectively; p<0.05) were lower in pediatric patients. In contrast, pediatric TIMP-1 levels were reduced by over 50% (Figure). Pediatric DCM patients manifest a robust increase in MMP-8, which degrades all components of the extracellular matrix, and a decrease in TIMP-1, which inhibits MMP-8. This heightened MMP-8/TIMP-1 ratio would favor aggressive matrix remodeling in pediatric DCM. Since MMP-8 is primarily expressed by macrophage cell lineage, a unique proteolytic program may exist in pediatric DCM. These distinct differences in determinants of myocardial matrix structure and function likely contribute to the more progressive nature of DCM in children.

scholarly journals Antimycin A-Induced Mitochondrial Damage Causes Human RPE Cell Death despite Activation of Autophagy

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Maria Hytti ◽  
Eveliina Korhonen ◽  
Juha M. T. Hyttinen ◽  
Heidi Roehrich ◽  
Kai Kaarniranta ◽  
...  
Keyword(s):  
Cell Death ◽  
Mitochondrial Dysfunction ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Mitochondrial Damage ◽  
Age Related Macular Degeneration ◽  
Complex Iii ◽  
Antimycin A ◽  
Age Related ◽  
And Function

Mitochondrial dysfunction has been implicated in a wide variety of degenerative diseases, including age-related macular degeneration. Damage to mitochondria and mitochondrial DNA accumulates with age in the postmitotic retinal pigment epithelium (RPE), which could lead to RPE cell death and trigger disease. One possible mechanism for cells to avoid cell death is mitophagy, the targeted clearance of damaged mitochondria by autophagy. Here, we induced mitochondrial damage in human RPE cells (ARPE-19 and hRPE), using antimycin A, an inhibitor of complex III of the electron transport chain, and investigated cellular viability, mitochondrial structure and function, and autophagy activity. We observed that antimycin A evoked dose-dependent cell death, a rapid loss in mitochondrial membrane potential, and a collapse of oxidative phosphorylation. Mitochondria appeared swollen and there was clear damage to their cristae structure. At the same time, cells were undergoing active autophagy and were sensitive to autophagy inhibition by bafilomycin A1 or chloroquine. These results indicate that mitochondrial dysfunction can cause significant RPE damage and that autophagy is an important survival mechanism for cells suffering from mitochondrial damage.

Placental mitochondrial biogenesis and function was slightly changed by gestational hypercholesterolemia in full-term pregnant women

2018 ◽  
Vol 9 (4) ◽  
pp. 395-400 ◽  
Author(s):  
Z.-Y. Le ◽  
S. Dong ◽  
R. Zhang ◽  
X.-P. Cai ◽  
A. Gao ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Pregnant Women ◽  
Mrna Expression ◽  
Copy Number ◽  
Citrate Synthase ◽  
Full Term ◽  
Blood Cholesterol ◽  
Control Group ◽  
Mtdna Copy Number ◽  
Cholesterol Levels

AbstractIt was reported that high blood cholesterol levels increased the susceptibility to mitochondrial dysfunction. This study hypothesized that the gestational hypercholesterolemia (HC) could induce the mitochondrial dysfunction in term human placenta. The eligible pregnant women were recruited from Xuanwu Hospital in Beijing during their first prenatal visit (before their 10th week of pregnancy). In total, 19 pregnant women whose serum total cholesterol levels were higher than 7.25 mm at third trimester (measured at 36–38 weeks) were selected as gestational HC. Other 19 pregnant women with normal cholesterol level matched with age, pre-gestational body mass index, and the neonatal gender were included as the control group. Full-term placenta samples were collected. The mitochondrial DNA (mtDNA) copy number, messenger RNA (mRNA) expression of cytochrome c oxidase subunit I, adenosine triphosphate monophosphatase 6 (ATP6ase), citrate synthase, peroxisome proliferator-activated receptor-γ (PPARγ) co-activator 1α, PPARγ co-activator 1β and estrogen-related receptor-α, and the activity of mitochondrial respiratory chain enzyme complex were measured. Pregnancy outcomes were obtained by extraction from medical records and the labor ward register. The results showed that only placental mtDNA copy number and mRNA expression of ATP6ase were significantly decreased in HC group. No significant differences were detected of other measurements between the two groups. These findings indicated that gestational HC might not induce the damage of placental function seriously.

Abstract 16555: Angiotensin II Directly Induces Mitochondrial Dysfunction and Atrophy in the Skeletal Muscle

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Tomoyasu Kadoguchi ◽  
Shintaro Kinugawa ◽  
Arata Fukushima ◽  
Takaaki Furihata ◽  
Tadashi Suga ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Angiotensin Ii ◽  
Mitochondrial Dysfunction ◽  
Protein Degradation ◽  
Citrate Synthase ◽  
Fiber Type ◽  
Complex Iii ◽  
Skeletal Muscle Atrophy ◽  
Type I ◽  
Ang Ii

Background: Skeletal muscle abnormalities such as mitochondrial dysfunction, fiber type transition, and atrophy are the main cause of reduced exercise capacity observed in various diseases such as diabetes mellitus and heart failure. Renin-angiotensin system (RAS) was activated in the skeletal muscle in these conditions. We thus hypothesized that angiotensin II (Ang II) could directly induce skeletal muscle abnormalities. Methods and Results: Ang II (1000ng/kg/min, n=8) or vehicle (saline, n=8) was administrated into male C57BL/6J mice (10-12 week of age) via subcutaneously implanted osmotic minipumps for 4 weeks. Ang II significantly decreased body weight (26.6±0.3 vs. 27.6±0.3 g, p<0.05) and hind limb skeletal muscle weight compared with vehicle at 4 weeks (159±2 vs. 166±2 mg, p<0.05). It also decreased myocyte cross-sectional area in the skeletal muscle at 4 weeks (1869±29 vs. 2233±46 μm2, p<0.05). Muscle RING finger-1 and atrogin-1, the markers of protein degradation, were significantly increased in the skeletal muscle tissue from Ang II at 4 weeks by 133% and 102%, respectively (p<0.05). In addition, cleaved caspase-3 and TUNEL positive cells were significantly increased in Ang II at 4 weeks by 2.5 and 1.4-folds, respectively (p<0.05). Citrate synthase (1 week, 121±4 vs. 162±9; 4 weeks, 117±7 vs. 152±4 nmol/min/mg protein), complex I (1 week, 264±27 vs. 396±30; 4 weeks, 281±21 vs. 400±30 nmol/min/mg protein) and complex III (1 week, 321±33 vs. 508±49; 4 weeks, 347±30 vs. 503±43 nmol/min/mg protein) activities were significantly decreased in mitochondria isolated from skeletal muscle from Ang II at 1 and 4 weeks (all p<0.05). NADH staining revealed that type I fiber decreased by 31% and type IIb fiber increased by 38% in Ang II at 1 week. The work (16±1 vs. 27±3 J, p<0.05) and run distance (359±18 vs. 589±59 m, p<0.05) evaluated by treadmill test significantly decreased in Ang II at 4 weeks. An administration of Ang II for 1 week also induced mitochondrial dysfunction, fiber type shift, and protein degradation, but did not skeletal muscle atrophy. Conclusion: Ang II could directly induce the reduction of exercise tolerance in association with the abnormalities in skeletal muscle function and structure.

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