Cardiac-specific expression of GSK-3 impairs cardiac growth and calcium handling, leading to systolic and diastolic dysfunction, heart failure, and premature death

2003 ◽  
Vol 9 (5) ◽  
pp. S39
Author(s):  
Ashour Michael ◽  
Syed Haq ◽  
Heiko Kilter ◽  
Xin Chen ◽  
Ronglih Liao ◽  
...  
Keyword(s):  
Heart Failure ◽  
Diastolic Dysfunction ◽  
Premature Death ◽  
Calcium Handling ◽  
Specific Expression ◽  
Cardiac Growth

scholarly journals Synthetic Growth Hormone-Releasing Hormone Agonist as Novel Treatment for Heart Failure with Preserved Ejection Fraction

2020 ◽  
Author(s):  
Raul A. Dulce ◽  
Rosemeire M. Kanashiro-Takeuchi ◽  
Lauro M. Takeuchi ◽  
Alessandro G. Salerno ◽  
Shathiyah Kulandavelu ◽  
...  
Keyword(s):  
Heart Failure ◽  
Growth Hormone ◽  
Ejection Fraction ◽  
Diastolic Dysfunction ◽  
Calcium Handling ◽  
Growth Hormone Releasing Hormone ◽  
Preserved Ejection Fraction ◽  
Ang Ii ◽  
Releasing Hormone ◽  
Ghrh Receptor

AbstractObjectiveTo test the hypothesis that the activation of the growth hormone-releasing hormone (GHRH) receptor signaling pathway within the myocardium both prevents and reverses heart failure with preserved ejection fraction (HFpEF).BackgroundHFpEF is characterized by impaired myocardial relaxation, fibrosis and ventricular stiffness. Despite the rapidly increasing prevalence of HFpEF, no effective therapies have emerged. Synthetic agonists of the GHRH receptors reduce myocardial fibrosis, hypertrophy and improve performance, independently of the growth-hormone axis.MethodsWe generated a HFpEF-like phenotype with continuous infusion of angiotensin-II (Ang-II) in CD1 mice. Mice were injected with either vehicle or a potent synthetic agonist of the growth hormone-releasing hormone, MR-356.ResultsAng-II treated animals had diastolic dysfunction, ventricular hypertrophy, and normal ejection fraction and isolated cardiomyocytes (ex vivo) exhibited incomplete relaxation, depressed contractile responses and altered myofibrillar protein phosphorylation. Calcium handling mechanisms were disturbed in cardiomyocytes from mice with HFpEF. MR-356 both prevented and reversed the development of the pathological phenotype in vivo and ex vivo.ConclusionThese findings indicate that the GHRH receptor signaling pathway represents a new molecular target to counteract HFpEF-associated cardiomyocyte dysfunction by targeting myofilament phosphorylation. Accordingly, activation of the GHRH receptor with potent synthetic GHRH agonists may provide a novel therapeutic approach to management of the HFpEF syndrome.Condensed abstractHeart failure with preserved ejection fraction (HFpEF) is characterized by a remodeled myocardium conferring ventricular stiffness and diastolic dysfunction. There are no effective therapies. Agonists of growth hormone-releasing hormone (GHRH) receptors have beneficial effects on the heart. We hypothesize that activation of GHRH receptors suppresses this HFpEF phenotype. Treatment with a synthetic agonist of GHRH, prevented the development of the pathological phenotype in a murine model of HFpEF-induced by chronic angiotensin-II infusion. These findings indicate that activation of GHRH receptors represents a novel molecular strategy to counteract HFpEF-associated cardiomyocyte dysfunction and provide a potential approach to management of HFpEF syndrome.HighlightsA synthetic growth hormone-releasing hormone agonist (GHRH-A) prevents and reverses the pathological remodeling in a mouse model of HFpEF induced by infusion of low dose Ang II.GHRH-A improves intracellular calcium handling by reducing the sarcoplasmic reticulum calcium leakage and enhancing phospholamban phosphorylation.GHRH-A treatment prevents and reverses diastolic dysfunction by enhancing the rate of sarcomere re-lengthening.Activation of the GHRH receptor with the GHRH-A, MR-356, leads to targeting myofibrillar proteins and desensitizing myofilaments in response to calcium.

Impaired dynamics and function of mitochondria caused by mtDNA toxicity leads to heart failure

2015 ◽  
Vol 309 (3) ◽  
pp. H434-H449 ◽  
Author(s):  
Knut H. Lauritzen ◽  
Liv Kleppa ◽  
Jan Magnus Aronsen ◽  
Lars Eide ◽  
Harald Carlsen ◽  
...  
Keyword(s):  
Heart Failure ◽  
Mitochondrial Fission ◽  
Clinical Manifestations ◽  
Premature Death ◽  
Specific Expression ◽  
Mitochondrial Homeostasis ◽  
Transport Chain ◽  
Mtdna Replication ◽  
Dynamics And Function ◽  
And Function

Cardiac mitochondrial dysfunction has been implicated in heart failure of diverse etiologies. Generalized mitochondrial disease also leads to cardiomyopathy with various clinical manifestations. Impaired mitochondrial homeostasis may over time, such as in the aging heart, lead to cardiac dysfunction. Mitochondrial DNA (mtDNA), close to the electron transport chain and unprotected by histones, may be a primary pathogenetic site, but this is not known. Here, we test the hypothesis that cumulative damage of cardiomyocyte mtDNA leads to cardiomyopathy and heart failure. Transgenic mice with Tet-on inducible, cardiomyocyte-specific expression of a mutant uracil-DNA glycosylase 1 (mutUNG1) were generated. The mutUNG1 is known to remove thymine in addition to uracil from the mitochondrial genome, generating apyrimidinic sites, which obstruct mtDNA function. Following induction of mutUNG1 in cardiac myocytes by administering doxycycline, the mice developed hypertrophic cardiomyopathy, leading to congestive heart failure and premature death after ∼2 mo. The heart showed reduced mtDNA replication, severely diminished mtDNA transcription, and suppressed mitochondrial respiration with increased Pgc-1α, mitochondrial mass, and antioxidative defense enzymes, and finally failing mitochondrial fission/fusion dynamics and deteriorating myocardial contractility as the mechanism of heart failure. The approach provides a model with induced cardiac-restricted mtDNA damage for investigation of mtDNA-based heart disease.

142 Utility of BNP in detecting diastolic dysfunction in chronic heart failure patients

2003 ◽  
Vol 2 (1) ◽  
pp. 23-24
Author(s):  
A SCARDOVI ◽  
C COLETTA ◽  
N ASPROMONTE ◽  
A SESTILI ◽  
M RENZI ◽  
...  
Keyword(s):  
Heart Failure ◽  
Chronic Heart Failure ◽  
Diastolic Dysfunction ◽  
Heart Failure Patients

scholarly journals AB0798 EFFECT OF ANTIRHEUMATIC THERAPY ADMINISTERED IN ACCORDANCE WITH “TREAT TO TARGET” PRINCIPLES ON DIASTOLIC DYSFUNCTION OF THE LEFT VENTRICLES IN PATIENTS WITH ACTIVE EARLY PSORIATIC ARTHRITIS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1699.2-1699
Author(s):  
E. Markelova
Keyword(s):  
Heart Failure ◽  
Diastolic Dysfunction ◽  
Inflammatory Diseases ◽  
Statistical Significance ◽  
Certolizumab Pegol ◽  
Cardiovascular Death ◽  
Treat To Target ◽  
Antirheumatic Therapy ◽  
Time Curve ◽  
Low Prevalence

Background:Рsoriatic arthritis (PsA) are chronic inflammatory diseases, with massive increase of cardiovascular events (CVE) and cardiovascular death. Diastolic dysfunction of the left ventricles (LVDD) is a risk factor for the development of the heart failure.Objectives:to study the effect of antirheumatic therapy administered in accordance with “Treat to target” principles on LVDD in early PsA (EPsA) patients (pts).Methods:48 (F.-23) DMARD-naive PsA pts, according to the CASPAR criteria, age 36[27; 45] years (yrs.), PsA duration – 6[4; 8] months. All pts were assessed for transthoracic echocardiography. Diastolic function was determined by early and atrial peak filling rates derived from differential volume-time-curve analysis. Methotrexate therapy was started in all pts with an escalation of the dose up to 25 mg/week subcutaneously. In case of no remission 3 months later, MT was added with biologic therapy: Adalimumab, Certolizumab pegol, Ustekinumab. Antihypertensive therapy received all pts with arterial hypertension (AH). All p less then 0.05 considered to statistical significance.Results:At baseline LVDD was identified in 5(10.4%). The LVDD pts were older, in more cases they had AH, abdominal obesity (p<0.05). Significant negative correlations were found between LVDD and body mass index (BMI) (r=-0.41), age (r=-0.71), total cholesterol (r=-0.44), triglycerides (r=-0.48), low density lipoproteins (r=-0.44), systolic (r=-0.59) and diastolic blood pressure (r=-0.4), for all p<0,01. By 18 months of therapy significantly decreased DAS from 4.06[3.48; 4.91] to 0,97[0,65;1,48]; C-RP from 19.4 [8.8;37.5] to 2.2 [0.9; 4.6]mg/l, for all p<0,001. DAS remission was achieved in 69% of pts. We didn’t find significant differences between baseline and after treatment the frequency of LVDD – 5(10,4%) to 4(8.3%).Conclusion:in pts with EPsA frequently (10.4%) were detected LVDD, which are associated with a АН, age, higher BMI. Low prevalence LVDD in patients with EPsA is possibly caused by short duration of disease and early start of antirheumatic therapy. This has implications for development of preventive strategies for heart failure in EPsA patients.Disclosure of Interests:None declared

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