Abstract 338: Cardiac Overexpression of Creatine Kinase Improves Cardiomycytes Function in Heart Failure and During Increased Redox Stress

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Carlo G Tocchetti ◽  
Michelle Leppo ◽  
Djahida Bedja ◽  
Yibin Wang ◽  
Robert G Weiss ◽  
...  
Keyword(s):  
Heart Failure ◽  
Myocardial Dysfunction ◽  
Similar Response ◽  
Wild Type ◽  
Aortic Constriction ◽  
Redox Stress ◽  
Adult Cardiomyocytes ◽  
Metabolic Role ◽  
Myocyte Function ◽  
Fractional Shortening

Aims: Several studies suggest that abnormal energy metabolism contributes to heart failure or that the failing heart is energy starved. Here we aim at testing whether an increase in intracellular CK improves myocellular contractility in experimental myocardial dysfunction and protects from increased oxidative conditions. Methods-Results: We tested the response to the β-agonist isoproterenol (2.5 nM, ISO) in field-stimulated (.5 Hz, RT) adult cardiomyocytes isolated from wild-type (WT) mice and mice overexpressing cardiac myofibrillar or mitochondrial CK (CK-M or CK-mito) from sham and failing (8 wk transverse aortic constriction (TAC)) hearts, to dissect whether overexpressing CK alters myocyte function at baseline and during increased energetic demand. There were no differences in sarcomere fractional shortening (FS) or Ca2+ transients at baseline and with ISO among sham WT, CK-M or CK-mito myocytes. However, ISO effects were significantly reduced in WT TAC myocytes, consistent with prior reports. Conversely, in CK-M or CK-mito TAC myocytes, ISO-induced inotropy was fully preserved. Interestingly, incubation with the AMPK-stimulator AICAR (1mM for at least 90’) did not have any effect on WT TAC, but increased FS in TAC CK-M (+82%) and CK-mito (+42%) myocytes significantly, supporting the important metabolic role played by enhancing CK in failing hearts. To test whether overexpressing CK-M or CK-mito confer protection against acute oxidative stress, sham myocytes were exposed to H2O2 (50μM, 10’) and the interval (seconds) between the beginning of H2O2 superfusion and the appearance of irreversible arrhythmias was measured. WT and CK-M myocytes had a similar response (416±91s vs 411±68s), whereas in CK-mito this interval was significantly prolonged (600±64s). Similarly, upon acute infusion of the anticancer TKI sunitinib (2μM), whose cardiotoxic properties have been linked also to an increase in ROS, irreversible arrhythmias appeared after 657±43s in CK-mito (p<.5 vs 561±66 for WT and 467±88 for CK-M). Conclusions: Overexpressing CK-M and CK-mito under failing-TAC conditions improves myocyte function likely through better preserved Ca2+ handling, whereas only the up-regulation of CK-mito is more effective in buffering ROS effects.

scholarly journals Cardiac Overexpression of PDE4B Blunts β-Adrenergic Response and Maladaptive Remodeling in Heart Failure

Circulation ◽  
2020 ◽  
Vol 142 (2) ◽  
pp. 161-174 ◽  
Author(s):  
Sarah Karam ◽  
Jean Piero Margaria ◽  
Aurélia Bourcier ◽  
Delphine Mika ◽  
Audrey Varin ◽  
...  
Keyword(s):  
Heart Failure ◽  
Transgenic Mouse ◽  
Adrenergic Receptor ◽  
Systolic Dysfunction ◽  
Fold Increase ◽  
Aortic Constriction ◽  
Adeno Associated Virus ◽  
Transgenic Mouse Line ◽  
Virus Serotype ◽  
Fractional Shortening

Background: The cyclic AMP (adenosine monophosphate; cAMP)-hydrolyzing protein PDE4B (phosphodiesterase 4B) is a key negative regulator of cardiac β-adrenergic receptor stimulation. PDE4B deficiency leads to abnormal Ca 2+ handling and PDE4B is decreased in pressure overload hypertrophy, suggesting that increasing PDE4B in the heart is beneficial in heart failure. Methods: We measured PDE4B expression in human cardiac tissues and developed 2 transgenic mouse lines with cardiomyocyte-specific overexpression of PDE4B and an adeno-associated virus serotype 9 encoding PDE4B. Myocardial structure and function were evaluated by echocardiography, ECG, and in Langendorff-perfused hearts. Also, cAMP and PKA (cAMP dependent protein kinase) activity were monitored by Förster resonance energy transfer, L-type Ca 2+ current by whole-cell patch-clamp, and cardiomyocyte shortening and Ca 2+ transients with an Ionoptix system. Heart failure was induced by 2 weeks infusion of isoproterenol or transverse aortic constriction. Cardiac remodeling was evaluated by serial echocardiography, morphometric analysis, and histology. Results: PDE4B protein was decreased in human failing hearts. The first PDE4B-transgenic mouse line (TG15) had a ≈15-fold increase in cardiac cAMP-PDE activity and a ≈30% decrease in cAMP content and fractional shortening associated with a mild cardiac hypertrophy that resorbed with age. Basal ex vivo myocardial function was unchanged, but β-adrenergic receptor stimulation of cardiac inotropy, cAMP, PKA, L-type Ca 2+ current, Ca 2+ transients, and cell contraction were blunted. Endurance capacity and life expectancy were normal. Moreover, these mice were protected from systolic dysfunction, hypertrophy, lung congestion, and fibrosis induced by chronic isoproterenol treatment. In the second PDE4B-transgenic mouse line (TG50), markedly higher PDE4B overexpression, resulting in a ≈50-fold increase in cardiac cAMP-PDE activity caused a ≈50% decrease in fractional shortening, hypertrophy, dilatation, and premature death. In contrast, mice injected with adeno-associated virus serotype 9 encoding PDE4B (10 12 viral particles/mouse) had a ≈50% increase in cardiac cAMP-PDE activity, which did not modify basal cardiac function but efficiently prevented systolic dysfunction, apoptosis, and fibrosis, while attenuating hypertrophy induced by chronic isoproterenol infusion. Similarly, adeno-associated virus serotype 9 encoding PDE4B slowed contractile deterioration, attenuated hypertrophy and lung congestion, and prevented apoptosis and fibrotic remodeling in transverse aortic constriction. Conclusions: Our results indicate that a moderate increase in PDE4B is cardioprotective and suggest that cardiac gene therapy with PDE4B might constitute a new promising approach to treat heart failure.

Abstract 71: STAT3 Affects Myofibrillar Structure and Its Loss May Contribute to Heart Failure in Hypertension

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Fouad Zouein ◽  
Carlos Zgheib ◽  
John Fuseler ◽  
John E Hall ◽  
Mazen Kurdi ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Myocytes ◽  
Transcriptional Activity ◽  
Cardiac Myocyte ◽  
Early Stage ◽  
Systolic Dysfunction ◽  
Wild Type ◽  
Patients With Heart Failure ◽  
Protective Proteins ◽  
Fractional Shortening

How hypertension causes heart failure is not known. Since patients with heart failure have reduced cardiac STAT3 and STAT3 KO mice develop heart failure with age, we tested the hypothesis that reduced STAT3 transcriptional activity contributes at an early stage to remodeling that precedes heart failure in hypertension using SA mice with a STAT3 S727A mutation. SA and wild type (WT) mice received angiotensin (A) II (1000 ng/kg/min) or saline (S) for 17 days. Hearts of WT and SA mice had similar levels of STAT3-induced protective proteins Bcl-xL and SOD2, and unlike STAT3 KO mice, cardiac miR-199a levels were not increased in SA mice. AII increased systolic blood pressure measured by telemetry in SA (124 ± 1 to 167 ± 3) and WT (122 ± 3 to 162 ± 3) mice to the same extent. AII increased cardiac levels of cytokines (pg/μg protein) associated with heart failure in both WT and SA mice, but significantly less so (P<0.05) in SA mice; IL-6, 13.6 ± 1.4 vs. 9.1 ± 0.6; TGFβ, 56 ± 4 vs. 38 ± 3 and MCP1 35 ± 2 vs. 22 ± 2. Compared to WT mice, hearts of SA mice showed signs of developing systolic dysfunction with AII as seen by a significant (P<0.05) reduction in ejection fraction (63.7 ± 7.1 to 51.7 ± 6.9) and fractional shortening (34.3 ± 4.9 to 26.4 ± 4.3). AII caused fibrosis in the left ventricle of both WT and SA mice characterized by cardiac myocyte loss and increased % collagen: WT+S, 5.59 ± 0.34; WT+AII, 15.70 ± 1.87; SA+S, 6.70 ± 0.40; SA+AII, 16.50 ± 1.91. In WT+AII mice there was a nonsignificant trend towards a loss of myofibrillar content of cardiac myocytes, but an increase in the mass of the myofibrils (IOD/myofibrillar area). In contrast, cardiac myocytes of SA+AII mice had a significant (P<0.001) % loss in myofibrils (5.71 ± 0.28) compared to SA+S (0.75 ± 0.07), WT+S (0.80 ± 0.06) and WT+AII (1.54 ± 0.10) mice. In addition, the mass of the myofibrils in SA+AII mice (6.01 ± 0.07) was significantly less (P<0.001) than those of SA+S mice (6.46 ± 0.04), although greater than WT+S (4.85 ± 0.06) or WT+AII (5.27 ± 0.08) mice. Our findings reveal that STAT3 transcriptional activity is important for proper morphology of the myofibrils of cardiac myocytes. Loss of STAT3 activity may impair cardiac function in the hypertensive heart due to defective myofibrillar structure and remodeling that may lead to heart failure.

scholarly journals O-ring-induced transverse aortic constriction (OTAC) is a new simple method to develop cardiac hypertrophy and heart failure in mice

2022 ◽  
Vol 12 (1) ◽  
Author(s):  
Yasuhisa Nakao ◽  
Jun Aono ◽  
Mika Hamaguchi ◽  
Kayo Takahashi ◽  
Tomohisa Sakaue ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Pressure Overload ◽  
Experimental Models ◽  
Left Ventricular ◽  
Transverse Aortic Constriction ◽  
Aortic Constriction ◽  
Lung Weight ◽  
Simple Method ◽  
Fractional Shortening

AbstractSuture-based transverse aortic constriction (TAC) in mice is one of the most frequently used experimental models for cardiac pressure overload-induced heart failure. However, the incidence of heart failure in the conventional TAC depends on the operator’s skill. To optimize and simplify this method, we proposed O-ring-induced transverse aortic constriction (OTAC) in mice. C57BL/6J mice were subjected to OTAC, in which an o-ring was applied to the transverse aorta (between the brachiocephalic artery and the left common carotid artery) and tied with a triple knot. We used different inner diameters of o-rings were 0.50 and 0.45 mm. Pressure overload by OTAC promoted left ventricular (LV) hypertrophy. OTAC also increased lung weight, indicating severe pulmonary congestion. Echocardiographic findings revealed that both OTAC groups developed LV hypertrophy within one week after the procedure and gradually reduced LV fractional shortening. In addition, significant elevations in gene expression related to heart failure, LV hypertrophy, and LV fibrosis were observed in the LV of OTAC mice. We demonstrated the OTAC method, which is a simple and effective cardiac pressure overload method in mice. This method will efficiently help us understand heart failure (HF) mechanisms with reduced LV ejection fraction (HFrEF) and cardiac hypertrophy.

scholarly journals Promoting PGC-1α-driven mitochondrial biogenesis is detrimental in pressure-overloaded mouse hearts

2014 ◽  
Vol 307 (9) ◽  
pp. H1307-H1316 ◽  
Author(s):  
Georgios Karamanlidis ◽  
Lorena Garcia-Menendez ◽  
Stephen C. Kolwicz ◽  
Chi Fung Lee ◽  
Rong Tian
Keyword(s):  
Heart Failure ◽  
Cardiac Function ◽  
Mitochondrial Biogenesis ◽  
Citrate Synthase ◽  
Mitochondrial Gene ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Wild Type ◽  
Term Survival ◽  
Fractional Shortening

Mitochondrial dysfunction in animal models of heart failure is associated with downregulation of the peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α pathway. To test whether PGC-1α is an appropriate therapeutic target for increasing mitochondrial biogenesis and improving function in heart failure, we used a transgenic (TG) mouse model of moderate overexpression of PGC-1α (∼3-fold) in the heart. TG mice had small increases in citrate synthase activity and mitochondria size in the heart without alterations in myocardial energetics or cardiac function at baseline. In vivo dobutamine stress increased fractional shortening in wild-type mice, but this increase was attenuated in TG mice, whereas ex vivo isolated perfused TG hearts demonstrated normal functional and energetic response to high workload challenge. When subjected to pressure overload by transverse aortic constriction (TAC), TG mice displayed a significantly greater acute mortality for both male and female mice; however, long-term survival up to 8 wk was similar between the two groups. TG mice also showed a greater decrease in fractional shortening and a greater increase in left ventricular chamber dimension in response to TAC. Mitochondrial gene expression and citrate synthase activity were mildly increased in TG mice compared with wild-type mice, and this difference was also maintained after TAC. Our data suggest that a moderate level of PGC-1α overexpression in the heart compromises acute survival and does not improve cardiac function during chronic pressure overload in mice.

Deficiency of iNOS does not attenuate severe congestive heart failure in mice

2005 ◽  
Vol 288 (1) ◽  
pp. H365-H370 ◽  
Author(s):  
Steven P. Jones ◽  
James J. M. Greer ◽  
Paul D. Ware ◽  
Jiang Yang ◽  
Kenneth Walsh ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Heart Failure ◽  
Congestive Heart Failure ◽  
Severe Congestive Heart Failure ◽  
Wild Type ◽  
Permanent Occlusion ◽  
Oxide Synthase ◽  
Fractional Shortening ◽  
Inducible Nitric Oxide

Inducible nitric oxide synthase (iNOS) has been implicated in the pathophysiology of congestive heart failure (CHF). Given the extensive evidence supporting this concept, we hypothesized that iNOS deficiency (iNOS−/−) would attenuate the severity of CHF in mice. Mice were subjected to permanent occlusion [myocardial infarction (MI)] of the proximal left anterior descending coronary artery to produce CHF. Cardiac function was assessed in vivo using echocardiography and ultraminiature ventricular pressure catheters. Sham wild-type ( n = 17), sham iNOS−/− ( n = 8), MI wild-type ( n = 56), and MI iNOS−/− ( n = 48) mice were subjected to MI (or sham MI) and followed for 1 mo. Deficiency of iNOS did not alter survival during CHF compared with wild type (35% vs. 32%, P = not significant). Furthermore, fractional shortening and cardiac output were not significantly different between wild-type (9.6 ± 2.0% and 441 ± 20 μl·min−1·g−1) and iNOS−/− (9.8 ± 1.3% and 471 ± 26 μl·min−1·g−1) mice. The extent of cardiac hypertrophy and pulmonary edema was also similar between wild-type and iNOS−/− mice. None of the indexes demonstrated any significant differences between iNOS−/− and wild-type mice subjected to MI. These findings indicate that deficiency of iNOS does not significantly affect severe CHF in mice after MI.

Abstract 18651: Osteopontin RNA Aptamer Reverses Heart Failure and Increases Plasma HDL Levels

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Jihe Li ◽  
Jayanti Singh ◽  
Paul Kurlansky ◽  
Lina A Shehadeh
Keyword(s):  
Heart Failure ◽  
Cardiac Myocytes ◽  
Cardiac Fibrosis ◽  
Plaque Burden ◽  
Rna Aptamer ◽  
Intracellular Uptake ◽  
Wild Type ◽  
Aortic Constriction ◽  
Hypertrophic Response ◽  
Efficient Uptake

Objective: Osteopontin (OPN) expression increases in the heart during hypertrophy and heart failure and in the aorta during atherosclerosis. OPN KO mice were reported to have a reduced hypertrophic response after trans-aortic constriction (TAC), and a reduced plaque burden on an APOE-/- background. We hypothesized that an RNA aptamer targeting OPN protein would effectively modulate the responses to TAC and atherogenesis. Method and Results: C57BL6 male mice were subjected to sham or TAC surgeries. TAC mice were injected starting day1 with OPN RNA aptamer or mutant OPN aptamer. At 4wks, OPN aptamer treatment increased %EF (25%) relative to mut control (n=13, p<.01). This significant cardiac improvement was sustained at 8 wks (n=7) and 12wks (n=4-7). WGA and PR staining showed respectively that the OPN aptamer significantly reduced myocyte size (.8 fold at 4wks and 0.7 fold at 12 wks) and cardiac fibrosis (0.4 fold at 4wks and 0.3 fold at 12 wks). In 4 and 12wk LVs and RVs, OPN aptamer reduced Nppb, Nppa, Opn, Fn1, Col3a1, and Lum transcripts (n=3-6 - p<.05). At 12 wk, FN1 protein was reduced in the LVs and RVs by the OPN Apt (n=3 p<.05) and serum HDL was increased (20% p=.001; n=5-7). In 6 mo APOE-/- mice, systemic injections of OPN aptamer also increased plasma HDL (13%; p=.02; n=8-10).To assess effect of OPN aptamer on reversal of cardiac remodeling, at 8 wks post TAC (n=3-4), cardiac function was assessed followed by a total of 7 OPN aptamer injections (one every other day), and then assessed again at 10 wks. The OPN aptamer improved %EF in TAC mice (.6 fold p=.02 TAC vs Sham before treatment to .85 fold p=NS after treatment). In wild type but not OPN KO neonatal mouse cardiomyocytes-fibroblast co-culture, 16h treatment with FAM-labeled OPN aptamer, followed by Phalloidin and TNT staining, showed successful intracellular uptake of the OPN aptamer by cardiac myocytes and more so by fibroblasts. Conclusion: OPN RNA aptamer protected against and reversed cardiac dysfunction in a mouse TAC model of cardiac hypertrophy, and increased serum HDL in WT and APOE-/- mice. The cardioprotective effect of the OPN aptamer, together with the efficient uptake by cardiac myocytes and fibroblasts make it a promising therapeutic molecule and a potential platform for targeted RNA delivery into the heart.

scholarly journals Innate Immune Nod1/RIP2 Signaling Is Essential for Cardiac Hypertrophy but Requires Mitochondrial Antiviral Signaling Protein for Signal Transductions and Energy Balance

Circulation ◽  
2020 ◽  
Vol 142 (23) ◽  
pp. 2240-2258 ◽  
Author(s):  
Han-Bin Lin ◽  
Kotaro Naito ◽  
Yena Oh ◽  
Gedaliah Farber ◽  
Georges Kanaan ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Cardiac Remodeling ◽  
Innate Immune ◽  
Transverse Aortic Constriction ◽  
Wild Type ◽  
Aortic Constriction ◽  
Antiviral Signaling ◽  
Mitochondrial Antiviral Signaling ◽  
Mitochondrial Antiviral Signaling Protein

Background: Cardiac hypertrophy is a key biological response to injurious stresses such as pressure overload and, when excessive, can lead to heart failure. Innate immune activation by danger signals, through intracellular pattern recognition receptors such as nucleotide-binding oligomerization domain 1 (Nod1) and its adaptor receptor-interacting protein 2 (RIP2), might play a major role in cardiac remodeling and progression to heart failure. We hypothesize that Nod1/RIP2 are major contributors to cardiac hypertrophy, but may not be sufficient to fully express the phenotype alone. Methods: To elucidate the contribution of Nod1/RIP2 signaling to cardiac hypertrophy, we randomized Nod1 –/– , RIP2 –/– , or wild-type mice to transverse aortic constriction or sham operations. Cardiac hypertrophy, fibrosis, and cardiac function were examined in these mice. Results: Nod1 and RIP2 proteins were upregulated in the heart after transverse aortic constriction, and this was paralleled by increased expression of mitochondrial proteins, including mitochondrial antiviral signaling protein (MAVS). Nod1 –/– and RIP2 –/– mice subjected to transverse aortic constriction exhibited better survival, improved cardiac function, and decreased cardiac hypertrophy. Downstream signal transduction pathways that regulate inflammation and fibrosis, including NF (nuclear factor) κB and MAPK (mitogen-activated protein kinase)-GATA4/p300, were reduced in both Nod1 –/– and RIP2 –/– mice after transverse aortic constriction compared with wild-type mice. Coimmunoprecipitation of extracted cardiac proteins and confocal immunofluorescence microscopy showed that Nod1/RIP2 interaction was robust and that this complex also included MAVS as an essential component. Suppression of MAVS expression attenuated the complex formation, NF κB signaling, and myocyte hypertrophy. Interrogation of mitochondrial function compared in the presence or ablation of MAVS revealed that MAVS serves to suppress mitochondrial energy output and mediate fission/fusion related dynamic changes. The latter is possibly linked to mitophagy during cardiomyocytes stress, which may provide an intriguing link between innate immune activation and mitochondrial energy balance under stress or injury conditions. Conclusions: We have identified that innate immune Nod1/RIP2 signaling is a major contributor to cardiac remodeling after stress. This process is critically joined by and regulated through the mitochondrial danger signal adapter MAVS. This novel complex coordinates remodeling, inflammatory response, and mitochondrial energy metabolism in stressed cardiomyocytes. Thus, Nod1/RIP2/MAVS signaling complex may represent an attractive new therapeutic approach toward heart failure.

scholarly journals Distinct remodeling pattern between pediatric and adult heart failure: a focus on Ca2+ signaling pathway at proteomic level

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
H Zhang ◽  
U Kuzmanov ◽  
S Urschel ◽  
F Wang ◽  
S Wang ◽  
...  
Keyword(s):  
Heart Failure ◽  
Signaling Pathways ◽  
Myocardial Dysfunction ◽  
Heart Defects ◽  
Systolic Dysfunction ◽  
Cellular Growth ◽  
Reverse Remodeling ◽  
Funding Source ◽  
Course Of Illness ◽  
Reduced Ejection Fraction

Abstract Background Dilated cardiomyopathy (DCM) is among the most common causes leading to end-stage heart failure with reduced ejection fraction (HF-rEF) in adult and pediatric patients. Despite similar phenotypes characterized as systolic dysfunction and eccentric ventricular dilation, pediatric DCM are biologically distinct entities with age- and development-specific features in the heart. Though underlying mechanisms may vary between the two populations, it's largely unexplored with few studies conducted to date. Purpose HF-rEF typically results from impaired myocardial contractility, triggered by defective cellular Ca2+ handling and cytoskeletal remodeling. Hence, we aim to integrate clinical profile and experimental data from human explanted hearts: 1) to unravel the age-dependent disparate Ca2+ signaling pathways; and 2) to identify pediatric-specific HF signatures or potential cures for precision managements. Methods Non-ischemic failing hearts (n=6 adult and n=6 pediatric) were procured immediately after excision via Human Explanted Heart Program. Age-matched adult non-failing control hearts (NFC, n=6) were obtained from deceased donors without cardiovascular history, while pediatric NFC (n=6) were collected from children with congenital heart defects but no primary myocardial dysfunction constituting relatively reasonable controls. Myocardial metabolic and oxidative profile were evaluated spectrophotometrically, and tissue remodeling was assessed immunohistochemically. Global proteomics and phosphoproteomics were performed on a Q-Exactive mass spectrometer, followed by network biology pathway analyses. Expression of screened proteins and kinases was validated by gel electrophoresis. Apoptosis and cellular growth signaling pathways were also incorporated into analysis. Results Both HF groups had remarkably lower LVEF (26.6±10.7% in pediatric vs. 26.5±9.1% in adult DCM) while compared to the NFC (both ≥60%) respectively. Histologically, adult-DCM demonstrated significantly worse fibrosis than pediatric-DCM (p&lt;0.01). It was consistent with excessive reactive oxygen species (ROS) production and perturbed anti-ROS defense noted in adult-DCM, indicative of possible reverse remodeling in the pediatric failing hearts with shorter course of illness till transplant. Mechanistically, NCX1 was elevated with SERCA2 decreased in adult-DCM versus adult-NFC (p&lt;0.05), while both pediatric groups exhibited comparable levels. Reduced p-/t-phospholamban and p-/t-CaMK in adult-DCM, unlike in pediatric-DCM, also illustrated altered phosphorylation patterns. Moreover, GSK-3β and AMPK pathways were inhibited while AKT-473 was activated in adult-DCM. Conclusions Pediatric DCM exhibited less adverse remodeling partially mediated by divergent Ca2+ handling and downstream signaling pathways, illustrating the fundamental differences between adult and pediatric DCM. Our findings may provide a scientific basis for the development of specific therapies for pediatric DCM. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Canadian Institutes for Health Research (CIHR); Heart & Stroke Foundation (HSF)

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