scholarly journals Biventricular Pacing Cardiac Contractility Modulation Improves Cardiac Contractile Function via Upregulating SERCA2 and miR-133 in a Rabbit Model of Congestive Heart Failure

2014 ◽  
Vol 33 (5) ◽  
pp. 1389-1399 ◽  
Author(s):  
Bin Ning ◽  
Xiaoyong Qi ◽  
Yingxiao Li ◽  
Huiliang Liu ◽  
Feifei Zhang ◽  
...  
Keyword(s):  
Heart Failure ◽  
Congestive Heart Failure ◽  
Contractile Function ◽  
Biventricular Pacing ◽  
Cardiac Contractility ◽  
Rabbit Model ◽  
Cardiac Contractile Function ◽  
Cardiac Contractility Modulation ◽  
Cardiac Contractile

scholarly journals Regulation of Cardiac PKA Signaling by cAMP and Oxidants

Antioxidants ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 663
Author(s):  
Friederike Cuello ◽  
Friedrich W. Herberg ◽  
Konstantina Stathopoulou ◽  
Philipp Henning ◽  
Simon Diering
Keyword(s):  
Contractile Function ◽  
Cardiac Contractility ◽  
Cellular Protein ◽  
Cardiac Contractile Function ◽  
Cardiac Contractile ◽  
Main Driver ◽  
Dependent Protein ◽  
Relevant Regulation ◽  
Protein Dysfunction ◽  
Substrate Proteins

Pathologies, such as cancer, inflammatory and cardiac diseases are commonly associated with long-term increased production and release of reactive oxygen species referred to as oxidative stress. Thereby, protein oxidation conveys protein dysfunction and contributes to disease progression. Importantly, trials to scavenge oxidants by systemic antioxidant therapy failed. This observation supports the notion that oxidants are indispensable physiological signaling molecules that induce oxidative post-translational modifications in target proteins. In cardiac myocytes, the main driver of cardiac contractility is the activation of the β-adrenoceptor-signaling cascade leading to increased cellular cAMP production and activation of its main effector, the cAMP-dependent protein kinase (PKA). PKA-mediated phosphorylation of substrate proteins that are involved in excitation-contraction coupling are responsible for the observed positive inotropic and lusitropic effects. PKA-actions are counteracted by cellular protein phosphatases (PP) that dephosphorylate substrate proteins and thus allow the termination of PKA-signaling. Both, kinase and phosphatase are redox-sensitive and susceptible to oxidation on critical cysteine residues. Thereby, oxidation of the regulatory PKA and PP subunits is considered to regulate subcellular kinase and phosphatase localization, while intradisulfide formation of the catalytic subunits negatively impacts on catalytic activity with direct consequences on substrate (de)phosphorylation and cardiac contractile function. This review article attempts to incorporate the current perception of the functionally relevant regulation of cardiac contractility by classical cAMP-dependent signaling with the contribution of oxidant modification.

scholarly journals Cardiac Contractility Modulation Attenuates Chronic Heart Failure in a Rabbit Model via the PI3K/AKT Pathway

2020 ◽  
Vol 2020 ◽  
pp. 1-8 ◽  
Author(s):  
Qingqing Hao ◽  
Feifei Zhang ◽  
Yudan Wang ◽  
Yingxiao Li ◽  
Xiaoyong Qi
Keyword(s):  
Heart Failure ◽  
Chronic Heart Failure ◽  
Cardiac Contractility ◽  
Rabbit Model ◽  
The Body ◽  
Heart Weight ◽  
Akt Pathway ◽  
Control Group ◽  
Cardiac Contractility Modulation ◽  
Positive Effects

The Akt plays an important role in regulating cardiac growth, myocardial angiogenesis, and cell death in cardiac myocytes. However, there are few studies to focus on the responses of the Akt pathway to cardiac contractility modulation (CCM) in a chronic heart failure (HF) model. In this study, the effects of CCM on the treatment of HF in a rabbit model were investigated. Thirty six-month-old rabbits were randomly separated into control, HF, and CCM groups. The rabbits in HF and CCM groups were pressure uploaded, which can cause an aortic constriction. Then, CCM was gradually injected to the myocardium of rabbits in the CCM group, and this process lasted for four weeks with six hours per day. Rabbit body weight, heart weight, and heart beating rates were recorded during the experiment. To assess the CCM impacts, rabbit myocardial histology was examined as well. Additionally, western blot analysis was employed to measure the protein levels of Akt, FOXO3, Beclin, Pi3k, mTOR, GSK-3β, and TORC2 in the myocardial histology of rabbits. Results showed that the body and heart weight of rabbits decreased significantly after suffering HF when compared with those in the control group. However, they gradually recovered after CCM application. The CCM significantly decreased collagen volume fraction in myocardial histology of HF rabbits, indicating that CCM therapy attenuated myocardial fibrosis and collagen deposition. The levels of Akt, FOXO3, Beclin, mTOR, GSK-3β, and TORC2 were significantly downregulated, but Pi3k concentration was greatly upregulated after CCM utilization. Based on these findings, it was concluded that CCM could elicit positive effects on HF therapy, which was potentially due to the variation in the Pi3k/Akt signaling pathway.

Abstract 12606: Autophagy is Required for Mitochondrial Biogenesis in the Heart

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Zhonggang Li ◽  
Quanjiang Zhang ◽  
Karla Pires ◽  
E. Dale Abel
Keyword(s):  
Heart Failure ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Biogenesis ◽  
Contractile Function ◽  
Heart Function ◽  
Early Event ◽  
Acid Oxidation ◽  
Cardiac Contractile Function ◽  
Cardiac Contractile ◽  
Deficient Mice

Autophagy is an essential process that maintains cellular homeostasis via lysosomal degradation pathways. Autophagy has been found to be involved in various pathophysiological conditions in the heart, including myocardial hypertrophy and ischemic heart disease. However, the precise mechanism by which autophagy maintains cardiac function in the non-stressed heart is incompletely understood. We generated cardiac-specific ATG3 deficient mice (cATG3 KO mice) by crossing αMHC-Cre mice with floxed ATG3 mice. Relative to their wild type (WT) littermates, cATG3 KO mice revealed reduced ATG3 expression and inhibited autophagy specifically in the heart. At 4 months of age, cATG3 KO mice showed impaired cardiac contractile function, characterized by a 25% reduction in fractional shortening by echocardiography (p <0.01), Moreover, cATG3 KO mice revealed increased lipid accumulation, reduced fatty acid oxidation and impaired mitochondrial respirations in the heart, without evidence of fibrosis or inflammation. Mitochondrial dysfunction in cATG3 KO mice was accompanied with mitochondrial content loss and reduced expression of mitochondrial biogenesis related genes (PGC1α, NRF1, NRF2 and TFAM). Interestingly, autophagy inhibition, induced mitochondrial biogenesis defects and mitochondrial dysfunction in neonatal cATG3 KO mice (1 week old), prior to the onset of cardiac contractile dysfunction and heart failure, suggesting that cardiac mitochondrial dysfunction may be an early event in the progression of heart failure in the autophagy deficient mice. Finally, in response to exercise training mitochondrial biogenesis (PGC1 alpha induction and increased respiration rates) was completely inhibited in ATG3 deficient mice. In conclusion, autophagy is essential for generating signals that promote mitochondrial biogenesis, and is indispensable for normal heart function under basal conditions.

scholarly journals Cardiac Contractility Modulation Attenuate Myocardial Fibrosis by Inhibiting TGF-β1/Smad3 Signaling Pathway in a Rabbit Model of Chronic Heart Failure

2016 ◽  
Vol 39 (1) ◽  
pp. 294-302 ◽  
Author(s):  
Feifei Zhang ◽  
Yi Dang ◽  
Yingxiao Li ◽  
Qingqing Hao ◽  
Rong Li ◽  
...  
Keyword(s):  
Heart Failure ◽  
Chronic Heart Failure ◽  
Signaling Pathway ◽  
Myocardial Fibrosis ◽  
Cardiac Contractility ◽  
Rabbit Model ◽  
Cardiac Contractility Modulation ◽  
Protein Levels ◽  
Collagen Iii ◽  
Tgf Β1

Backgroun/Aims: To explore the effect of cardiac contractility modulation (CCM) on myocardial fibrosis in heart failure and to investigate the underlying mechanism. Methods: Rabbits were randomly divided into sham group, HF group and CCM group. A rabbit model of chronic heart failure (CHF) was induced 12 weeks after aortic constriction by pressure unloading. Then cardiac contractility modulation was delivered to the myocardium lasting six hours per day for 4 weeks. Histology examination was carried out to evaluate the myocardial pathological changes. Protein levels of collagen I, collagen III, α-SMA, MMP2, MMP9, TIMP1, TGF-β1 and Smad3 were measured by western blot analysis. Results: Histology examination results showed that CCM therapy attenuated myocardial fibrosis and collagen deposition in rabbits with CHF. In addition, protein levels of collagen I, collagen III, α-SMA, MMP2, MMP9, TIMP1, TGF-β1 and Smad3 were down regulated. Conclusion: CCM therapy exerted protective effects against myocardial fibrosis potentially by inhibiting TGF-β1/Smad3 signaling pathway in CHF rabbits.

scholarly journals Cardiac Contractility Modulation Therapy for Heart Failure – First Romanian Experience 

2021 ◽  
Vol 31 (3) ◽  
pp. 609-614
Author(s):  
Diana TINT ◽  
◽  
Sorin MICU ◽  
Keyword(s):  
Heart Failure ◽  
Nyha Class ◽  
Cardiac Contractility ◽  
Case Series ◽  
Cardiac Resynchronization ◽  
Cardiac Contractility Modulation ◽  
Reduced Ejection Fraction ◽  
Cardiac Contractile ◽  
Patients With Heart Failure

Aim: The purpose of this study is to present the first Romanian case-series of patients with heart failure with reduced ejection fraction (HFrEF), supported with the newest generation of cardiac contractility modulation (CCM) device. Methods and results: 16 patients (15 men), aged 66.6±7.49 years, were supported with OPTIMIZER® smart IPG CCMX10 device and followed-up for an average duration of 385.75±326.32 days. The etiology of HF was ischemic in 13 patients (81%), 8 patients (50%) had atrial fibrillation, mean creatinine clearance value was 55.8±13.87 ml/min, and 5 patients (31,2%) had diabetes mellitus. All patients were supported with an implanted cardio verter-defibrillator (ICD), while 5 patients (31.2%) had cardiac resynchronization therapy (CRT) on top. The pharma cological treatment has been optimized in all patients. Six months after implantation, the LVEF has increased from 25.93%±6.21 to 35.5%±4.31 (p=0.00002), NYHA class improved from 3.18±0.4 to 1.83±0.38 (p<0.0001), and exercise tolerance evaluated with 6 minute walking test (6MWT) increased (from 321.87±70.63m to 521.41±86.43m; p<0,00001). Three patients (18,7%) died during the follow-up period after 48, 108 and 545 days (one non-cardiac death). Conclusions: Cardiac contractile therapy is a feasible, safe, and useful therapy for patients with HFrEF whose symptomatology is not improved with optimal standard therapy.

The role of phospholamban and GSK3 in regulating rodent cardiac SERCA function

2020 ◽  
Vol 319 (4) ◽  
pp. C694-C699
Author(s):  
Sophie I. Hamstra ◽  
Kennedy C. Whitley ◽  
Ryan W. Baranowski ◽  
Nigel Kurgan ◽  
Jessica L. Braun ◽  
...  
Keyword(s):  
Heart Failure ◽  
Glycogen Synthase ◽  
Contractile Function ◽  
Cardiac Contractile Function ◽  
Serine Threonine Kinase ◽  
Treatment And Prevention ◽  
Cardiac Contractile ◽  
Plasmic Reticulum ◽  
Serca Pump ◽  
Underlying Mechanisms

Cardiac contractile function is largely mediated by the regulation of Ca2+ cycling throughout the lifespan. The sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA) pump is paramount to cardiac Ca2+ regulation, and it is well established that SERCA dysfunction pathologically contributes to cardiomyopathy and heart failure. Phospholamban (PLN) is a well-known inhibitor of the SERCA pump and its regulation of SERCA2a—the predominant cardiac SERCA isoform—contributes significantly to proper cardiac function. Glycogen synthase kinase 3 (GSK3) is a serine/threonine kinase involved in several metabolic pathways, and we and others have shown that it regulates SERCA function. In this mini-review, we highlight the underlying mechanisms behind GSK3’s regulation of SERCA function specifically discussing changes in SERCA2a and PLN expression and its potential protection against oxidative stress. Ultimately, these recent findings that we discuss could have clinical implications in the treatment and prevention of cardiomyopathies and heart failure.

scholarly journals Albumin Nanoparticle Formulation for Heart-Targeted Drug Delivery: In Vivo Assessment of Congestive Heart Failure

2021 ◽  
Vol 14 (7) ◽  
pp. 697
Author(s):  
Nikita Lomis ◽  
Ziyab Sarfaraz ◽  
Aiman Alruwaih ◽  
Susan Westfall ◽  
Dominique Shum-Tim ◽  
...  
Keyword(s):  
Heart Failure ◽  
Congestive Heart Failure ◽  
Targeted Delivery ◽  
Contractile Function ◽  
Heart Function ◽  
Cardiac Contractile Function ◽  
Inotropic Drugs ◽  
Nanoparticle Formulation ◽  
Targeted Drug

Congestive heart failure is a fatal cardiovascular disease resulting in tissue necrosis and loss of cardiac contractile function. Inotropic drugs such as milrinone are commonly used to improve the myocardial contractility and heart function. However, milrinone is associated with severe side effects and lower circulation time. In this article, a novel protein nanoparticle formulation for heart-targeted delivery of milrinone has been designed and tested. The formulation was prepared using albumin protein conjugated with the targeting ligand, angiotensin II peptide to form nanoparticles following the ethanol desolvation method. The formulation was characterized for size, charge, and morphology and tested in a rat model of congestive heart failure to study pharmacokinetics, biodistribution, and efficacy. The overall cardiac output parameters were evaluated comparing the formulation with the control non-targeted drug, milrinone lactate. This formulation exhibited improved pharmacokinetics with a mean retention time of 123.7 min, half-life of 101.3 min, and clearance rate of 0.24 L/(kg*h). The targeted formulation also significantly improved ejection fraction and fractional shortening parameters thus improving cardiac function. This study demonstrates a new approach in delivering inotropic drugs such as milrinone for superior treatment of congestive heart failure.

Sign in / Sign up

Export Citation Format

Share Document