Abstract MP216: Identification Of Novel Phosphoprotein Signaling Pathways In Human Dilated Cardiomyopathy By Integrative Proteomic And Phosphoproteomic Analysis

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Cristine J Reitz ◽  
Marjan Tavassoli ◽  
Da Hye Kim ◽  
Sina Hadipour-Lakmehsari ◽  
Saumya Shah ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Cardiac Tissue ◽  
Regulatory Element ◽  
Critical Role ◽  
Left Ventricular ◽  
Confocal Imaging ◽  
Intercalated Disc ◽  
Bioinformatics Analyses ◽  
Tissue Samples ◽  
And Function

Dilated cardiomyopathy (DCM) is one of the most common causes of heart failure, yet the majority of the underlying signaling mechanisms remain poorly characterized. Protein phosphorylation is a key regulatory element with profound effects on the activity and function of signaling networks; however, there is a lack of comprehensive phosphoproteomic studies in human DCM patients. We assessed the hypothesis that an integrative phosphoproteomics analysis of human DCM would reveal novel phosphoprotein candidates involved in disease pathophysiology. Combined proteomic and phosphoproteomic analysis of explanted left ventricular tissue samples from DCM patients ( n =4) and non-failing controls ( n =4) identified 5,570 unique proteins with 13,624 corresponding phosphorylation sites. From these analyses, we identified αT-catenin as a unique candidate protein with a cluster of 4 significantly hyperphosphorylated sites in DCM hearts ( P <0.0001), with no change in total αT-catenin expression at the protein level. Bioinformatics analyses of human datasets and confocal imaging of human and mouse cardiac tissue show highly cardiac-enriched expression of αT-catenin, localized to the cardiomyocyte intercalated disc. High resolution 3-dimensional reconstruction shows elongated intercalated disc morphology in DCM hearts (10.07±0.76 μm in controls vs. 17.20±1.87 μm in DCM, P <0.05, n =3/group), with significantly increased colocalization of αT-catenin with the intercalated disc membrane protein N-cadherin (Pearson’s coefficient 0.55±0.04 in controls vs. 0.71±0.02 in DCM, P <0.05, n =3/group). To investigate the functional role of cardiac αT-catenin phosphorylation, we overexpressed WT protein vs. non-phosphorylatable forms based on the loci identified in DCM hearts, in adult mouse cardiomyocytes using lentiviral transduction. Confocal imaging revealed significant internalization of the phospho-null form, as compared to the prominent intercalated disc staining of the WT protein (17.78±0.79% of WT vs. 9.25±0.49% of 4A mutant, P <0.0001, n =50 cells/group). Together, these findings suggest a critical role for αT-catenin phosphorylation in maintaining cardiac intercalated disc organization in human DCM.

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.

Abstract 15607: Right Atrial Reservoir Strain Predicts Survival in Patients With Cardiac Amyloidosis

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Peter Huntjens ◽  
Kathleen Zhang ◽  
Yuko Soyama ◽  
Maria Karmpalioti ◽  
Daniel Lenihan ◽  
...  
Keyword(s):  
Cardiac Amyloidosis ◽  
Ventricular Hypertrophy ◽  
Cardiac Tissue ◽  
Fold Increase ◽  
Left Ventricular ◽  
Right Atrial ◽  
Chamber View ◽  
All Cause Mortality ◽  
And Function

Introduction: Myofibril deposition in amyloidosis diffusely may affect cardiac structure and function. Right ventricular involvement has been associated with adverse clinical outcome. However, the utility of right atrial (RA) function assessment by echocardiographic strain imaging is unclear. Hypothesis: We hypothesize that right atrial stain has prognostic value in cardiac amyloidosis. Methods: We studied 121 consecutive patients with cardiac amyloidosis: 18% had transthyretin and 79% had light chain amyloidosis. Cardiac amyloidosis was either confirmed by endocardial biopsy (36%) or by a combination of non-cardiac tissue biopsy and proof of left ventricular hypertrophy (64%). Speckle tracking peak RA reservoir strain was assessed based on 6 segments from the apical 4-chamber view. All-cause mortality was tracked over a median of 5 years. Results: Echocardiographic peak longitudinal RA strain was feasible in 109 patients (90%). 60 CA patients died during follow-up period. Peak longitudinal RA strain was reduced in cardiac amyloidosis non-survivors (8.1%) in comparison to survivors (18.3%, p<0.01), showing RA involvement in cardiac amyloidosis. Peak RA strain was significantly associated with survival (using median 12.5%) (p<0.001). Low peak longitudinal RA strain was associated with a 3.3-fold increase in mortality risk (95% confidence interval: 1.83 - 5.96). Conclusions: Reduced peak longitudinal RA strain was significantly associated with survival in patients with cardiac amyloidosis. RA reservoir function assessed by strain appears to be useful as a new means to predict prognosis in cardiac amyloidosis patients and has promise for clinical application.

Bioengineered Cardiac Grafts

Circulation ◽  
2000 ◽  
Vol 102 (suppl_3) ◽  
Author(s):  
Jonathan Leor ◽  
Sharon Aboulafia-Etzion ◽  
Ayelet Dar ◽  
Lilia Shapiro ◽  
Israel M. Barbash ◽  
...  
Keyword(s):  
Cardiac Tissue ◽  
Left Ventricular ◽  
Cardiac Cells ◽  
Sham Operation ◽  
Complete Disappearance ◽  
3 Dimensional ◽  
Infarcted Myocardium ◽  
Lv Remodeling ◽  
And Function ◽  
Conducive Environment

Background —The myocardium is unable to regenerate because cardiomyocytes cannot replicate after injury. The heart is therefore an attractive target for tissue engineering to replace infarcted myocardium and enhance cardiac function. We tested the feasibility of bioengineering cardiac tissue within novel 3-dimensional (3D) scaffolds. Methods and Results —We isolated and grew fetal cardiac cells within 3D porous alginate scaffolds. The cell constructs were cultured for 4 days to evaluate viability and morphology before implantation. Light microscopy revealed that within 2 to 3 days in culture, the dissociated cardiac cells form distinctive, multicellular contracting aggregates within the scaffold pores. Seven days after myocardial infarction, rats were randomized to biograft implantation (n=6) or sham-operation (n=6) into the myocardial scar. Echocardiography study was performed before and 65±5 days after implantation to assess left ventricular (LV) remodeling and function. Hearts were harvested 9 weeks after implantation. Visual examination of the biograft revealed intensive neovascularization from the neighboring coronary network. Histological examination revealed the presence of myofibers embedded in collagen fibers and a large number of blood vessels. The specimens showed almost complete disappearance of the scaffold and good integration into the host. Although control animals developed significant LV dilatation accompanied by progressive deterioration in LV contractility, in the biograft-treated rats, attenuation of LV dilatation and no change in LV contractility were observed. Conclusions —Alginate scaffolds provide a conducive environment to facilitate the 3D culturing of cardiac cells. After implantation into the infarcted myocardium, the biografts stimulated intense neovascularization and attenuated LV dilatation and failure in experimental rats compared with controls. This strategy can be used for regeneration and healing of the infarcted myocardium.

Abstract 372: MicroRNA-9 Inhibits Hyperglycemia-induced Cardiac Pyroptosis by Targeting ELAVL1

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Prince Jeyabal ◽  
Rajarajan A Thandavarayan ◽  
Darukeshwara Joladarashi ◽  
Sahana Suresh Babu ◽  
Shashirekha Krishnamurthy ◽  
...  
Keyword(s):  
Heart Failure ◽  
High Glucose ◽  
Cardiac Tissue ◽  
Critical Role ◽  
Left Ventricular ◽  
Diabetic Patients ◽  
Therapeutic Implications ◽  
Caspase 1 ◽  
Ventricular Cardiomyocytes ◽  
Nlrp3 Expression

Diabetic cardiomyopathy is a common complication in patients with diabetes and is associated with underlying chronic inflammation and cardiac cell death, subsequently leading to left ventricular dysfunction and heart failure. ELAV-like protein 1 (ELAVL1, mRNA stabilizing protein) and NLRP3 activation (inflammasome complex protein)-mediated IL-1beta synthesis play a critical role in the progression of heart failure. However, ELAVL1 regulation of pyroptosis (caspase-1-mediated programmed apoptosis) and associated IL-1beta release in cardiomyocytes, especially under diabetic condition, remains elusive. Human diabetic, non-diabetic heart tissues, human ventricular cardiomyocytes and rat cardiomyoblasts exposed to high glucose (HG) were used for our studies. Our data demonstrates that human ventricular cardiomyocytes exposed to high glucose condition showed significant increase in ELAVL1 and NLRP3 expression with a concomitant increase in caspase-1 and IL-1 beta expression. Furthermore, human cardiac tissue from diabetic patients showed increased ELAVL1, caspase-1 and NLRP3 expression as compared to non-diabetic hearts. Intriguingly, ELAVL1 knockdown abrogates TNF-α induced canonical pyroptosis via NLRP3, caspase-1 and IL-1beta suppression. Interestingly, miRNA-9 expression significantly reduces in high glucose treated cardiomyocytes and in human diabetic hearts. Bioinformatics analysis and target validation assays showed that miR-9 directly targets ELAVL1. Inhibition of miR-9 up regulates ELAVL1 expression and activates caspase-1. Alternatively, miR-9 mimics attenuate hyperglycemia-induced ELAVL1 and inhibit cardiomyocyte pyroptosis. To our knowledge, this is the first report to demonstrate the role of miR-9/ELAVL1 in hyperglycemia-induced cardiac pyroptosis. Taken together our study highlights the potential therapeutic implications in preventing cardiomyocyte cell loss in human diabetic failing heart.

scholarly journals Empagliflozin improves chronic hypercortisolism-induced abnormal myocardial structure and cardiac function in mice

2020 ◽  
Vol 11 ◽  
pp. 204062232097483
Author(s):  
Qing-Qing Zhang ◽  
Guo-Qing Li ◽  
Yi Zhong ◽  
Jie Wang ◽  
An-Ning Wang ◽  
...  
Keyword(s):  
Myocardial Dysfunction ◽  
Sglt2 Inhibitor ◽  
Heart Tissue ◽  
Left Ventricular ◽  
Tissue Samples ◽  
Beneficial Effects ◽  
Reduced Body ◽  
Sodium Glucose Cotransporter ◽  
And Function ◽  
Visceral Adipose

Background: Chronic exposure to excess glucocorticoids is frequently associated with a specific cardiomyopathy. Empagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, has beneficial effects as it aids in the reduction of heart failure and cardiovascular mortality in hospitalized patients. The aim of this study was to investigate the effects of empagliflozin on chronic hypercortisolism-induced myocardial fibrosis and myocardial dysfunction in mice. Methods: Male C57BL/6J mice (6 weeks old) were randomized to control, corticosterone (CORT), and empagliflozin + CORT groups. After 4 weeks of administration, heart structure and function were evaluated by echocardiography, and peripheral blood and tissue samples were collected. Expressions of Ccl2, Itgax, Mrc1, and Adgre1 mRNA in heart tissue were evaluated by RT-PCR, and signal transducer and activator of transcription 3 (STAT3) and Toll-like receptor 4 (TLR4) protein expression were analyzed by Western blotting. Results: Empagliflozin effectively reduced body weight, liver triglyceride, visceral adipose volume, and uric acid in CORT-treated mice. Left ventricular hypertrophy and cardiac dysfunction were improved significantly, phosphorylated STAT3 and TLR4 were alleviated, and macrophage infiltration in the myocardium was inhibited after administration of empagliflozin in CORT-treated mice. Conclusion: Empagliflozin has beneficial effects on specific cardiomyopathy associated with CORT, and the results provide new evidence that empagliflozin might be a potential drug for the prevention of this disease.

scholarly journals Intercalated disc in failing hearts from patients with dilated cardiomyopathy: Its role in the depressed left ventricular function

PLoS ONE ◽  
2017 ◽  
Vol 12 (9) ◽  
pp. e0185062 ◽  
Author(s):  
Ana Ortega ◽  
Estefanía Tarazón ◽  
Carolina Gil-Cayuela ◽  
María García-Manzanares ◽  
Luis Martínez-Dolz ◽  
...  
Keyword(s):  
Left Ventricular Function ◽  
Dilated Cardiomyopathy ◽  
Ventricular Function ◽  
Left Ventricular ◽  
Intercalated Disc ◽  
Depressed Left Ventricular Function

Dilated cardiomyopathy in Erb-b4-deficient ventricular muscle

2005 ◽  
Vol 289 (3) ◽  
pp. H1153-H1160 ◽  
Author(s):  
Hernán García-Rivello ◽  
Julián Taranda ◽  
Matilde Said ◽  
Patricia Cabeza-Meckert ◽  
Martin Vila-Petroff ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Receptor Tyrosine Kinase ◽  
Cardiac Development ◽  
Critical Role ◽  
Premature Death ◽  
Ventricular Muscle ◽  
Wild Type ◽  
Eccentric Hypertrophy ◽  
And Function ◽  
Intercellular Communications

The neuregulin receptor tyrosine kinase Erb-b4, initially linked to early cardiac development, is shown here to play a critical role in adult cardiac function. In wild-type mice, Erb-b4 protein localized to Z lines and to intercalated disks, suggesting a role in subcellular and intercellular communications of cardiomyocytes. Conditional inactivation of erb-b4 in ventricular muscle cells led to a severe dilated cardiomyopathy, characterized by thinned ventricular walls with eccentric hypertrophy, reduced contractility, and delayed conduction. This cardiac dysfunction may account for premature death in adult erb-b4-knockout mice. This study establishes a critical role for Erb-b4 in the maintenance of normal postnatal cardiac structure and function.

Measurement of left ventricular dimensions and function in patients with dilated cardiomyopathy

2001 ◽  
Vol 13 (3) ◽  
pp. 367-371 ◽  
Author(s):  
Oliver Strohm ◽  
Jeanette Schulz-Menger ◽  
Bernhard Pilz ◽  
Karl-Josef Osterziel ◽  
Rainer Dietz ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Left Ventricular ◽  
Left Ventricular Dimensions ◽  
And Function ◽  
Ventricular Dimensions

Abstract 279: A Deletion In The N2A Region Of Titin Carried By Muscular Dystrophy With Myositis (mdm) Mice Severely Affects Skeletal Muscle, But Not The Heart

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Ida G Lunde ◽  
Hiroko Wakimoto ◽  
Michael A Burke ◽  
Wolfgang Linke ◽  
Geir Christensen ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Body Weight ◽  
Muscular Dystrophy ◽  
Dilated Cardiomyopathy ◽  
Posterior Wall ◽  
Left Ventricular ◽  
Cardiac Titin ◽  
Reduced Body ◽  
Region I ◽  
And Function

20% of dilated cardiomyopathy patients carry mutations in the giant protein titin. Mutations are predominant in A band but also occur in I band, a domain that regulates passive tension and myocyte signaling. A recessive mouse mutation in titin I band N2A region (mdm) causes early onset muscular dystrophy with myositis and death. We assessed cardiac morphology, function, and transcriptional profiles (RNAseq) in mdm mice. Young homozygous mdm mice (n>6) have reduced body weight (7gms) vs. heterozygous (20gm) or WT (17gm) littermates, with severe skeletal muscle dystrophy. Four-week old homozygous mdm mice have higher left ventricular (LV): body weight ratios. Echocardiography revealed thinner LV posterior wall and septum (LVPWd and IVSd) and normal LV diameter (LVDd); when normalized for body weight, cardiac dimensions were increased compared to WT or heterozygous mdm mice. Fractional shortening was reduced in homozygous Mdm mice (35%) vs. WT (40-41%, p<0.01); histology showed neither overt pathology nor fibrosis. Titin gels showed lack of difference in cardiac titin isoform pattern, consistent with RNAseq, which showed the mdm titin transcript excluded exons 107 and 108, deleting in frame 48 amino acids. 240 transcripts (0.8%) were differentially expressed (fold change >1.5 and <0.75, p<0.001) in homozygous vs. heterozygous mdm hearts; ANP and BNP were mildly upregulated (2- and 1.2-fold). Altered transcripts participated in extracellular and immune signaling pathways. Among titin binding partners, only calpain-3 that interacts with N2A was changed (0.6-fold), consistent with previous reports in skeletal muscle. As humans have heterozygous mutations, we stressed adult heterozygous mdm and WT mice (2 weeks of angiotensin II infusion): both had comparable hypertrophic responses (increased LVPWd and IVSd). Aged (89 week old) unstressed heterozygous mdm mice had normal cardiac dimensions and function. The N2A region, I-band titin mdm mutation causes minimal cardiac dysfunction in mice, unlike the severe skeletal muscle phenotype. Human I-band mutations are unlikely to cause dilated cardiomyopathy.

Sign in / Sign up

Export Citation Format

Share Document