miR-673/menin/JunD axis modulates hyperglycemia-induced oxidative stress and inflammation in the diabetic heart

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
R Suades ◽  
S Hussain ◽  
A.W Khan ◽  
S Costantino ◽  
F Paneni ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Transcription Factor ◽  
Protein Expression ◽  
Myocardial Dysfunction ◽  
Reactive Oxygen Species Generation ◽  
Left Ventricular ◽  
Diabetic Heart ◽  
Lv Function ◽  
Funding Source ◽  
Mrna And Protein Expression

Abstract Background Hyperglycemia-induced reactive oxygen species generation in diabetic heart contributes to myocardial dysfunction. JunD, a member of the activated protein 1 (AP-1) family of transcription factors, is emerging as a major gatekeeper against oxidative stress. Previous studies have shown that downregulation of AP-1 transcription factor JunD is involved in vascular aging and heart failure. However, the role of JunD in diabetes-induced myocardial dysfunction is unknown. Purpose The present study was designed to investigate whether hyperglycemia-driven epigenetic regulation of JunD contributes to oxidative stress, inflammation and myocardial dysfunction in the diabetic heart. Methods Diabetes (DB) was induced in C57BL/6 wild-type (WT) mice by streptozotocin. After four weeks of DB, left ventricular (LV) function was assessed by standard and 2D speckle-tracking echocardiography in both groups (n=10). Then, the animals were euthanized and LV specimens were collected to determine JunD mRNA and protein expression as well as superoxide anion production by ESR spectroscopy. Chromatin modifications of JunD gene promoter were assessed by chromatin immunoprecipitation. Isolated DNA was analyzed for promoter methylation following Methylminer kit. Cardiac biopsies were collected from age-matched patients with and without diabetes. Results DB mice showed LV dysfunction with reduced ejection fraction and fractional shortening. JunD mRNA and protein expression were reduced in the myocardium of DB as compared to control mice. JunD downregulation was associated with oxidative stress, increased NF-kB binding activity and expression of inflammatory mediators. Accordingly, expression of free radical scavenger superoxide dismutase 1 and aldehyde dehydrogenase 2 was reduced, whereas nicotinamide adenine dinucleotide phosphate oxidase subunits NOX2 and NOX4 were upregulated in DB. A reduction of JunD mRNA and protein expression was confirmed in LV specimens obtained from patients with diabetes. The downregulation of JunD was epigenetically regulated by promoter hypermethylation and histone modifications. Post-translational repression by tumor suppressor menin also contributed to JunD downregulation. Indeed, menin was significantly upregulated in DB hearts and co-immunoprecipitation experiments confirmed the binding of menin to JunD. Furthermore, rat ventricular myocytes exposed to high glucose (HG) showed increased menin expression. We found that miR-673 targeting menin was downregulated in hearts of DB mice. Reprogramming miR-673 in HG-treated myocytes was able to restore both menin and JunD expression to control levels. Conclusions Our findings show that downregulation of AP-1 transcription factor JunD contributes to diabetes-induced myocardial dysfunction and miR-673/menin/JunD represents a novel molecular axis involved in hyperglycemia-induced ROS-driven cardiac damage. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): European Society of Cardiology (ESC) Research Grant 2017

scholarly journals Hyperglycemia Induces Myocardial Dysfunction via Epigenetic Regulation of JunD

2020 ◽  
Vol 127 (10) ◽  
pp. 1261-1273
Author(s):  
Shafaat Hussain ◽  
Abdul Waheed Khan ◽  
Alexander Akhmedov ◽  
Rosa Suades ◽  
Sarah Costantino ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Diabetes Mellitus ◽  
Reactive Oxygen Species ◽  
Protein Expression ◽  
Cardiac Dysfunction ◽  
Nicotinamide Adenine Dinucleotide ◽  
Myocardial Dysfunction ◽  
Left Ventricular ◽  
Oxygen Species ◽  
Mrna And Protein Expression

Rationale: Hyperglycemia -induced reactive oxygen species are key mediators of cardiac dysfunction. JunD (Jund proto-oncogene subunit), a member of the AP-1 (activator protein-1) family of transcription factors, is emerging as a major gatekeeper against oxidative stress. However, its contribution to redox state and inflammation in the diabetic heart remains to be elucidated. Objective: The present study investigates the role of JunD in hyperglycemia-induced and reactive oxygen species–driven myocardial dysfunction. Methods and Results: JunD mRNA and protein expression were reduced in the myocardium of mice with streptozotocin-induced diabetes mellitus as compared to controls. JunD downregulation was associated with oxidative stress and left ventricular dysfunction assessed by electron spin resonance spectroscopy as well as conventional and 2-dimensional speckle-tracking echocardiography. Furthermore, myocardial expression of free radical scavenger superoxide dismutase 1 and aldehyde dehydrogenase 2 was reduced, whereas the NOX2 (NADPH [nicotinamide adenine dinucleotide phosphatase] oxidase subunit 2) and NOX4 (NADPH [nicotinamide adenine dinucleotide phosphatase] oxidase subunit 4) were upregulated. The redox changes were associated with increased NF-κB (nuclear factor kappa B) binding activity and expression of inflammatory mediators. Interestingly, mice with cardiac-specific overexpression of JunD via the α MHC (α- myosin heavy chain) promoter (α MHC JunD tg ) were protected against hyperglycemia-induced cardiac dysfunction. We also showed that JunD was epigenetically regulated by promoter hypermethylation, post-translational modification of histone marks, and translational repression by miRNA (microRNA)-673/menin. Reduced JunD mRNA and protein expression were confirmed in left ventricular specimens obtained from patients with type 2 diabetes mellitus as compared to nondiabetic subjects. Conclusions: Here, we show that a complex epigenetic machinery involving DNA methylation, histone modifications, and microRNAs mediates hyperglycemia-induced JunD downregulation and myocardial dysfunction in experimental and human diabetes mellitus. Our results pave the way for tissue-specific therapeutic modulation of JunD to prevent diabetic cardiomyopathy.

The aging-induced hyperexcretion of glucose-dependent insulinotropic peptide is essential for the healthy cardiac remodeling by prevention of cardiac ceramide accumulation

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
Y Kureishi Bando ◽  
Y.R Remina ◽  
T.K Kamihara ◽  
K.N Nishimura ◽  
T.M Murohara
Keyword(s):  
Oxidative Stress ◽  
Ketone Bodies ◽  
Left Ventricular ◽  
Heart Weight ◽  
Lv Function ◽  
Cardiac Aging ◽  
Normal Left Ventricular ◽  
Insulinotropic Peptide ◽  
Ceramide Accumulation ◽  
And Oxidative Stress

Abstract Background Glucose-dependent insulinotropic peptide (GIP) is incretin hormone that is emerged as an important regulator of lipid metabolism. Fat intake induces hypersecretion of GIP that is involved in obesity and ectopic fat accumulation. Aging is another stimulant of GIP hypersecretion, which is suggested as a cause of “sarcopenic obesity in elderly”. In heart, aging is the known risk factor of HFpEF, of which typical characteristics is pathological cardiac hypertrophy induced by unknown cause(s). It remained uncertain whether any ectopic fat accumulation, such as cardiac steatosis may cause the aging-induced cardiac hypertrophy. Ceramide is one of the lipid metabolites that involves in apoptosis, inflammation, and stress responses, which are among the pathogenic components of heart failure. However, it remained unclear whether the ceramide may play any pathophysiological role in cardiac aging. Purpose We thus hypothesized whether cardiac aging may alter cardiac lipid metabolism and the GIP may play a regulatory role in the cardiac aging via modulating cardiac steatosis, particularly ceramide. Methods Mouse model of GIPR deficiency (GIPR-KO) was employed and cardiac evaluation of GIPR-KO and the age-matched wild type mice were performed. Results Aging (50w/o) induced GIP hypersecretion in control mice and their body and heart weight were 50% increased as compared to younger counterpart (10w/o). In contrast, the aging-induced increase rate in body and heart weight of GIPR-KO was significantly lower (22%). Aging also increased the circulating ketone bodies with increase in FGF21 expression in heart and, notably, there was no pathological increase in cardiac ceremide and oxidative stress with normal left-ventricular (LV) function (LVEF=82.2±1.8). In contrast, GIPR-KO exhibited pathological increase in cardiac ceramide without the elevation of the circulating ketone bodies. The younger GIPR-KO (10 w/o) exhibited normal left-ventricular (LV) function, however, the older mice (50 w/o) exhibited systolic LV dysfunction (LVEF=55.8±8.5) with increase in cardiac apoptosis and oxidative stress. Cardiac ceramide accumulation was increased in the aged normal mice, which was significantly higher in the aged GIPR-KO. Furthermore, GIPR-KO exhibited increase in cardiac fibrosis and oxidative stress, which were absent in the aged normal counterpart. Conclusion Aging increased circulating GIP level the leads to compensatory rise in the circulating ketone bodies without pathological increase in cardiac ceremide and related oxidative stress in heart. Loss of GIP signaling caused pathological increase in cardiac ceramide, leading to the aging-induced progression of systolic left-ventricular dysfunction. Collectively, we conclude that the aging-induced GIP hyperexcretion is essential for the aging-induced healthy cardiac remodeling by augmenting compensatory ketone body elevation. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): KAKEN-HI

scholarly journals Evolution of left ventricular function after Wharton's jelly mesenchymal stem cells transcoronary administration: 5-year follow up in a pilot cohort of CIRCULATE-AMI Randomized Trial

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
E Kwiecien ◽  
L Drabik ◽  
A Mazurek ◽  
M Sikorska ◽  
L Czyz ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Infarct Size ◽  
Troponin T ◽  
Left Ventricular ◽  
Lv Function ◽  
Funding Source ◽  
Double Blind ◽  
Wharton's Jelly

Abstract Introduction CIRCULATE-Acute Myocardial Infarction is a double-blind controlled trial randomizing (RCT) in 105 consecutive patients with their first, large AMI (cMRI-LVEF ≤45% and/or cMRI-infarct size ≥10% of LV) with successful infarct-related artery (IRA) primary percutaneous coronary intervention (pPCI) to transcoronary administration of Wharton's Jelly Mesenchymal Stem Cells (WJMSCs) vs. placebo (2:1). The pilot study cohort (PSC) preceded the RCT. Aim To evaluate WJMSCs long-term safety, and evolution of left-ventricular (LV) function in CIRCULATE-AMI PSC. Material and methods 30 000 000 WJMSCs (50% labelled with 99mTc-exametazime) were administered via IRA in a ten-patient PCS (age 32–65 years, peak hs-Troponin T 17.3±9.1ng/mL and peak CK-MB 533±89U/L, cMRI-LVEF 40.3±2.7% and infarct size 20.1±2.8%) at ≈5–7 days after AMI using a cell delivery-dedicated, coronary-non-occlusive method. Other treatments were per guidelines. WJMSCs showed an unprecedented high myocardial uptake (30.2±5.3%; 95% CI 26.9–33.5%), corresponding to ≈9×10 000 000 cells retention in the infarct zone – in absence of epicardial flow or myocardial perfusion impairment (TIMI-3 in all; cTFC 45±8 vs. 44±9, p=0.51) or any hs-Troponin T elevation. Five-year follow up included cardiac Magnetic Resonance Imaging (cMRI) (at baseline, 1 year and 3 years) and detailed echocardiography (echo) at baseline, 1 year, 3 years and 5 years. Results By 5 years, one patient died from a new, non-index territory AMI. There were no other cardiovascular events and MACCE that might be related to WJMSCs transplantation. On echo (Fig), there was an increase in left ventricular ejection fraction (LVEF) between WJMSCs administration point and 1 year (37.7±2.9% vs. 48.3±2.5%, p=0.002) that was sustained at 3 years (47.2±2.6%, p=0.005 vs. baseline) and at 5 years: (44.7±3.2%, p=0.039 vs. baseline). LVEF reached a peak at 1 year after the AMI and WJMSCs transfer (Fig). cMRI data (obtained up to 3 years; 1 year 41.9±2.6% vs. 51.0±3.3%, p<0.01; 3 years 52.2±4.0%, p<0.01 vs. baseline) were consistent with the echo LVEF assessment. Conclusions 5-year follow up in CIRCULATE-AMI PSC indicates that WJMSC transcoronary application is safe and may be associated with an LVEF improvement. The magnitude of LV increase appears to peak at 1 year, suggesting a potential role for repeated WJMSCs administration(s). Currently running double-blind RCT will provide placebo-controlled insights into the WJMSCs effect(s) on changes in LV function, remodelling, scar reduction and clinical outcomes. Echo-LVEF evolution Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): STRATEGMED 265761 “CIRCULATE” National Centre for Research and Development/Poland/ZDS/00564 Jagiellonian University Medical College

scholarly journals Uric Acid, Oxidative Stress and Inflammation in Chronic Heart Failure with Reduced Ejection Fraction

2015 ◽  
Vol 23 (4) ◽  
pp. 397-406 ◽  
Author(s):  
Adriana Iliesiu ◽  
Alexandru Campeanu ◽  
Daciana Marta ◽  
Irina Parvu ◽  
Gabriela Gheorghe
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Uric Acid ◽  
Chronic Heart Failure ◽  
Ejection Fraction ◽  
Xanthine Oxidase ◽  
Left Ventricular ◽  
Paraoxonase 1 ◽  
Lv Function ◽  
The Relationship

Abstract Background. Oxidative stress (OS) and inflammation are major mechanisms involved in the progression of chronic heart failure (CHF). Serum uric acid (sUA) is related to CHF severity and could represent a marker of xanthine-oxidase activation. The relationship between sUA, oxidative stress (OS) and inflammation markers was assessed in patients with moderate-severe CHF and reduced left ventricular (LV) ejection fraction (EF). Methods. In 57 patients with stable CHF, functional NYHA class III, with EF<40%, the LV function was assessed by N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) levels and echocardiographically through the EF and E/e’ ratio, a marker of LV filling pressures. The relationship between LV function, sUA, malondialdehyde (MDA), myeloperoxidase (MPO), paraoxonase 1 (PON-1) as OS markers and high sensitivity C-reactive protein (hsCRP) and interleukin 6 (IL-6) as markers of systemic inflammation was evaluated. Results. The mean sUA level was 7.9 ± 2.2 mg/dl, and 61% of the CHF patients had hyperuricemia. CHF patients with elevated LV filling pressures (E/e’ ≥ 13) had higher sUA (8.6 ± 2.3 vs. 7.3 ± 1.4, p=0.08) and NT-proBNP levels (643±430 vs. 2531±709, p=0.003) and lower EF (29.8 ± 3.9 % vs. 36.3 ± 4.4 %, p=0.001). There was a significant correlation between sUA and IL-6 (r = 0.56, p<0.001), MDA (r= 0.49, p= 0.001), MPO (r=0.34, p=0.001) and PON-1 levels (r= −0.39, p= 0.003). Conclusion. In CHF, hyperuricemia is associated with disease severity. High sUA levels in CHF with normal renal function may reflect increased xanthine-oxidase activity linked with chronic inflammatory response.

Abstract 3435: Left Ventricular Hypertrophy is Resistant to Inhibition of Expression of the R403Q Alpha-Myosin Heavy Chain Cardiac Hypertrophy-Inducing Mutant Protein

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Leah Cannon ◽  
Tadeusz Marciniec ◽  
Bryony Mearns ◽  
Robert M Graham ◽  
Diane Fatkin
Keyword(s):  
Left Ventricular Hypertrophy ◽  
Ventricular Hypertrophy ◽  
Interstitial Fibrosis ◽  
Myocardial Dysfunction ◽  
Left Ventricular ◽  
Familial Hypertrophic Cardiomyopathy ◽  
Lv Function ◽  
Dependent Manner ◽  
Cardiovascular Morbidity And Mortality ◽  
Lv Mass

Left ventricular hypertrophy (LVH) develops as a compensatory response to myocardial dysfunction due to diverse causes, but is nonetheless a major risk factor for premature cardiovascular morbidity and mortality. It is thus unclear if regressing LVH is beneficial or may worsen patient outcome. To evaluate the effects of LVH regression, we developed a transgenic mouse model in which the expression of a familial hypertrophic cardiomyopathy (FHC)-inducing mutation (R403Q alpha-MHC) can be regulated in a temporal and dose-dependent manner. In this model, transgene expression can be shut off by feeding with a tetracycline analogue (doxycycline). Serial echocardiography and histology studies were performed in a cohort of mice expressing the FHC mutant (“gene-on”) and in wildtype (WT) littermates. A second cohort of WT and 403/+ mice was randomised to placebo or doxycycline (“gene off”) from 6 (Dox6) or 20 weeks (Dox20) and evaluated at 40 weeks of age. Compared to WT littermates, “gene on” 403/+ mice showed increased LV mass, LV end-diastolic diameter (LVDD) and left atrial diameter (LAD), and reduced fractional shortening (LVFS), with changes evident from 12 weeks of age. LV sections from 403/+ mice showed typical features of FHC: myofibre disarray and interstitial fibrosis. LV mass, LV function and myocardial histology were unchanged in both male and female placebo- vs Dox6 or Dox20 mice at 40 weeks (Table 1 ). Thus, consistent with the major LV thickening in FHC humans occurring in adolescence, overexpression of R403Q for only 6 weeks is sufficient to trigger the complete LVH phenotypic response. Moreover, switching off the genetic trigger for LVH in 403/+ mice at 6 weeks (prior to overt disease manifestation) or 20 weeks (established disease) does not induce regression of LVH or exacerbate contractile dysfunction. Interventions to induce LVH regression may, therefore, need to be directed at downstream factors in hypertrophic pathways. Table 1. Echo data for male WT and 403/+ mice aged 40 weeks

Abstract 12952: Global Longitudinal Strain is Simple, Effective & Sensitive Assessment of Cardiac Chamber Function in Patients With Acute-phase Myocarditis

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Shaun Khanna ◽  
Aditya Bhat ◽  
Henry H Chen ◽  
Kennith Gu ◽  
Gary Gan ◽  
...  
Keyword(s):  
Acute Phase ◽  
Longitudinal Strain ◽  
Myocardial Dysfunction ◽  
Global Longitudinal Strain ◽  
Disease Process ◽  
Left Ventricular ◽  
Lv Function ◽  
Lv Mass ◽  
Echocardiographic Parameters ◽  
Cardiac Therapy

Introduction: Myocarditis is an inflammatory disease process with growing clinical relevance in the current COVID-19 pandemic. Acute-phase myocarditis is known to result in subclinical changes in left ventricular (LV) function despite normal LV ejection fraction (LVEF), as assessed by myocardial deformation indices. The presence of right ventricular (RV) and left atrial (LA) subclinical dysfunction however has not been well described in current literature. Hypothesis: Myocarditis patients have subclinical impairment of LV, RV and LA function as assessed by global longitudinal strain (GLS) on speckle tracking echocardiography. Methods: Consecutive patients with clinical diagnosis of myocarditis admitted to our institution during 2013-2018 were assessed (n=76). Patients who did not meet appropriate diagnostic criteria (n=14), had impaired LVEF or prior cardiac disease (n=8) or poor transthoracic echocardiogram images (n=14) were excluded from analysis. Clinical and echocardiographic parameters were compared to age- , gender- and risk factor- matched controls. GLS was performed by two independent observers using vendor independent software (TomTec Arena, Germany v4.6). Results: The final cohort consisted 40 patients with myocarditis (age 44.3±16.7, 60% male) and 40 matched controls (44.5±16.6, 60% male). No significant differences in baseline clinical characteristics were observed between groups. No differences in LVEF, indexed LV mass, RV fractional area change, indexed LA volume or TR pressure gradient (p>0.05 for all) were demonstrated between the two groups. Patients with myocarditis had a lower mean LV strain (GLS%: -16.4±2.9 vs -19.7±2.7, p=0.0001), a lower mean RV Free Wall Strain (FWS) (GLS%: -22.1±4.1 vs -26.2±6.9, p=0.03) and a lower mean LA reservoir strain (GLS%: 27.5±4.6 vs. 33.7±6.3, p<0.0001) when compared to controls. Conclusions: Our results demonstrate the presence of significant subclinical global myocardial dysfunction despite normal traditional echocardiographic indices, in patients with acute-phase myocarditis. Routine assessment of GLS may identify such patients for early targeted cardiac therapy.

scholarly journals Se Alleviated Oxidative Stress-Mediated Complex Poisoning Mechanism in Pb-Treated Chicken Kidneys: Inflammation, Heat Shock Response, and Autophagy

2021 ◽  
Author(s):  
Zhiying Miao ◽  
Weikang Yu ◽  
Yueyang Wang ◽  
Xianhong Gu ◽  
Xiaohua Teng
Keyword(s):  
Oxidative Stress ◽  
Heat Shock ◽  
Protein Expression ◽  
Heat Shock Response ◽  
Potable Water ◽  
Histological Structure ◽  
Standard Diet ◽  
Shock Response ◽  
Mrna And Protein Expression ◽  
Shock Proteins

Abstract Background: Lead (Pb) is a toxic environmental pollutant and can exerts toxicity in kidneys. It is known that selenium (Se) has an antagonistic effect on Pb poisoning. However, biological events during the process were not well understood in chicken kidneys.Methods: One hundred and eighty male Hyline chickens (7-day-old) were randomly divided into the control group (offering standard diet and potable water), the Se group (offering Na2SeO3-added standard diet and potable water), the Pb group (offering standard diet and (CH3OO)2Pb-added potable water), and the Pb+Se group (offering Na2SeO3-added standard diet and (CH3OO)2Pb-added potable water). On 30th, 60th, and 90th days, kidneys were removed to perform the studies of histological structure, oxidative stress indicators, cytokines, heat shock proteins, and autophagy in the chicken kidneys.Results: The experimental results indicated that Pb poisoning changed renal histological structure; decreased catalase, glutathione-s-transferase, and total antioxidative capacity activities; increased hydrogen peroxide content; induced mRNA and protein expression of heat shock proteins; inhibited interleukin (IL)-2 mRNA expression, and induced IL-4 and IL-12β mRNA expression; inhibited mammalian target of rapamycin mRNA and protein expression, and induced autophagy-related gene mRNA and protein expression in the chicken kidneys. Supplement of Se mitigated the above changes caused by Pb.Conclusion: Our research strengthens the evidence that Pb induced oxidative stress, inflammation, heat shock response, and autophagy and Se administration alleviated Pb poisoning through mitigating oxidative stress in the chicken kidneys.

scholarly journals Liraglutide protects cardiac function in diabetic rats through the PPARα pathway

2018 ◽  
Vol 38 (2) ◽  
Author(s):  
Qian Zhang ◽  
Xinhua Xiao ◽  
Jia Zheng ◽  
Ming Li ◽  
Miao Yu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Cardiac Dysfunction ◽  
Diabetic Rats ◽  
Left Ventricular ◽  
Serum Adiponectin ◽  
Diabetic Rat ◽  
Lv Function ◽  
High Dose ◽  
And Oxidative Stress

Increasing evidence shows that diabetes causes cardiac dysfunction. We hypothesized that a glucagon-like peptide-1 (GLP-1) analog, liraglutide, would attenuate cardiac dysfunction in diabetic rats. A total of 24 Sprague–Dawley (SD) rats were divided into two groups fed either a normal diet (normal, n=6) or a high-fat diet (HFD, n=18) for 4 weeks. Then, the HFD rats were injected with streptozotocin (STZ) to create a diabetic rat model. Diabetic rats were divided into three subgroups receiving vehicle (diabetic, n=6), a low dose of liraglutide (Llirag, 0.2 mg/kg/day, n=6), or a high dose of liraglutide (Hlirag, 0.4 mg/kg/day, n=6). Metabolic parameters, systolic blood pressure (SBP), heart rate (HR), left ventricular (LV) function, and whole genome expression of the heart were determined. Diabetic rats developed insulin resistance, increased blood lipid levels and oxidative stress, and impaired LV function, serum adiponectin, nitric oxide (NO). Liraglutide improved insulin resistance, serum adiponectin, NO, HR, and LV function and reduced blood triglyceride (TG), total cholesterol (TC) levels, and oxidative stress. Moreover, liraglutide increased heart nuclear receptor subfamily 1, group H, member 3 (Nr1h3), peroxisome proliferator activated receptor (Ppar) α (Pparα), and Srebp expression and reduced diacylglycerol O-acyltransferase 1 (Dgat) and angiopoietin-like 3 (Angptl3) expression. Liraglutide prevented cardiac dysfunction by activating the PPARα pathway to inhibit Dgat expression and oxidative stress in diabetic rats.

Abstract 15314: Left Ventricular Dysfunction in Children and Adolescents With Arrhythmogenic Right Ventricular Cardiomyopathy

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Paweena Chungsomprasong ◽  
Robert Hamilton ◽  
Wietske Luining ◽  
Shi-Joon Yoo ◽  
Meena Fatah ◽  
...  
Keyword(s):  
Right Ventricular ◽  
Task Force ◽  
Myocardial Dysfunction ◽  
Arrhythmogenic Right Ventricular Cardiomyopathy ◽  
Myocardial Strain ◽  
Young Patients ◽  
Left Ventricular ◽  
Lv Function ◽  
Ventricular Cardiomyopathy ◽  
End Diastolic Volume

Background: Involvement of the left ventricle (LV) is increasingly recognized in adults with arrhythmogenic right ventricular cardiomyopathy (ARVC) but it is unclear whether LV function is compromised in children with this condition. The aim of this study was examine myocardial contractility in pediatric patients with suspected ARVC. Methods: For this retrospective study, patients with a work-up for ARVC were classified into ‘no’, ‘possible’, ‘borderline’ or ‘definite’ ARVC according to the revised Task Force Criteria (rTFC). Ventricular size and function as well as LV myocardial strain and torsion were measured by cardiac magnetic resonance (CMR). Results: A total of 142 patients were enrolled, of whom 58 (41%) had no, 32 (23%) possible, 29 (20%) borderline and 23 (16%) definite ARVC. The groups were similar in age at CMR. With higher rTFC score, z scores (Z) of right ventricular (RV) ejection fraction (EF) were lower (p<0.001) while z-RV end diastolic volume (EDV) and z-LV EDV were larger (p=0.002 and 0.013, respectively). LV EF did not differ between rTFC categories. Global circumferential strain (GCS) of the LV was lower in patients in higher rTFC categories (p=0.018). Z-LVEDV correlated with z-RVEDV (r2 = 0.69, p<0.001) and z- LVEF correlated with z-RVEF (r2 = 0.55, p <0.001). Z-LVEF and z-RVEF correlated with LV GCS (r2 = 0.48, p<0.001 and r2 = 0.46, p<0.001, respectively) and torsion (r2 = 0.21, p=0.032 for both). Forty-two patients had a follow-up CMR, after a median interval of 2.6 years (0.4- 8.4). The rate of deterioration of LV or RV EF or EDV did not differ between rTFC categories. A more rapid increase of z-RVEDV was associated with a faster decline in z-RVEF (r2 = -0.383, p=0.004) and z-LVEF (r2 = -0.45, p=0.001). A decline of z-LVEF over time correlated with that of z-RVEF (r2 = 0.60, p<0.001) and z-LVEDV increase correlated with z-RVEDV increase (r2 = 0.84, p<0.001). Conclusion: LV myocardial dysfunction is present in young patients with suspected or confirmed ARVC. Quantification of myocardial mechanics with CMR may be a useful tool to detect early LV involvement in ARVC. Progressive LV dysfunction and enlargement appear to parallel those of the RV.

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