Abstract 306: Proinflammatory Prostaglandin E Impairs Adrenergic Contractility in Animal Hearts

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Yang K Xiang
Keyword(s):  
Heart Failure ◽  
Plasma Membrane ◽  
Calcium Signaling ◽  
Contractile Response ◽  
Left Ventricular ◽  
Prostaglandin E ◽  
Intracellular Camp ◽  
Ventricular Contractility ◽  
Adrenergic Stimulation ◽  
Phosphodiesterase 4

Introduction: Inflammation is a major risk factor for heart failure; inflammatory prostaglandin E is elevated in myocardium, and has been associated with development of heart failure via cardiac LV remodeling, but the mechanisms remain unclear. Hypothesis: We hypothesize that proinflammatory prostaglandin signaling might affect Left ventricular contractility by directly impairing β-adrenergic (βAR) signaling. Methods and Results: Pretreatment with Prostaglandin E impairs intracellular PKA phosphorylation of substrates in myocardium and cardiac contractile responses under β-adrenergic stimulation. Both prostaglandin E and β-adrenergic agonist isoproterenol induce intracellular cAMP activities in myocytes. However, the cAMP signal under prostaglandin stimulation is confined along the plasma membrane whereas the cAMP signal under isoproterenol stimulation is distributed throughout the cells, including the intracellular sarcoplasmic reticulum (SR), a calcium storage compartment critical for myocyte calcium signaling and contractile response. Interestingly, the prostaglandin E-induced cAMP signal is sufficient for PKA activation, leading phosphorylation and activation of phosphodiesterase 4 on the plasma membrane, a group of enzymes associated with membrane βARs for cAMP degradation. Moreover, pretreatment of prostaglandin E prevents dissociation of phosphodiesterase 4 from βAR induced by isoproterenol, a step necessary for cAMP diffusion from the plasma membrane to the intracellular SR. Together, prostaglandin E induces activation of phosphodiesterase 4 in βAR complex and prevents the cAMP diffusion from the plasma membrane to the SR under isoproterenol stimulation, and inhibits calcium signaling and contractile response in myocytes and animal hearts. Conclusions: This study provides a novel mechanism underlying the phosphodiesterase-mediated signaling crosstalk between two neurohormonal stimulation in myocardium under chronic conditions, and suggests that proinflammatory prostaglandin signaling may impair β-adrenergic contractile in the development of heart failure.

scholarly journals Myocardial work index: a marker of left ventricular contractility in pressure‐induced or volume overload‐induced heart failure

2021 ◽  
Author(s):  
Bálint Károly Lakatos ◽  
Mihály Ruppert ◽  
Márton Tokodi ◽  
Attila Oláh ◽  
Szilveszter Braun ◽  
...  
Keyword(s):  
Heart Failure ◽  
Volume Overload ◽  
Left Ventricular ◽  
Ventricular Contractility ◽  
Left Ventricular Contractility ◽  
Work Index

scholarly journals An Adult Mouse Model of Dilated Cardiomyopathy Caused by Inducible Cardiac-Specific Bis Deletion

2021 ◽  
Vol 22 (3) ◽  
pp. 1343
Author(s):  
Hye Hyeon Yun ◽  
Soon Young Jung ◽  
Bong Woo Park ◽  
Ji Seung Ko ◽  
Kyunghyun Yoo ◽  
...  
Keyword(s):  
Heart Failure ◽  
Dilated Cardiomyopathy ◽  
Late Onset ◽  
Small Heat Shock Protein ◽  
Left Ventricular ◽  
Therapeutic Interventions ◽  
Ventricular Contractility ◽  
Knock Out ◽  
Multifunctional Protein ◽  
Cell Death Suppressor

BCL-2 interacting cell death suppressor (BIS) is a multifunctional protein that has been implicated in cancer and myopathy. Various mutations of the BIS gene have been identified as causative of cardiac dysfunction in some dilated cardiomyopathy (DCM) patients. This was recently verified in cardiac-specific knock-out (KO) mice. In this study, we developed tamoxifen-inducible cardiomyocyte-specific BIS-KO (Bis-iCKO) mice to assess the role of BIS in the adult heart using the Cre-loxP strategy. The disruption of the Bis gene led to impaired ventricular function and subsequent heart failure due to DCM, characterized by reduced left ventricular contractility and dilatation that were observed using serial echocardiography and histology. The development of DCM was confirmed by alterations in Z-disk integrity and increased expression of several mRNAs associated with heart failure and remodeling. Furthermore, aggregation of desmin was correlated with loss of small heat shock protein in the Bis-iCKO mice, indicating that BIS plays an essential role in the quality control of cardiac proteins, as has been suggested in constitutive cardiac-specific KO mice. Our cardiac-specific BIS-KO mice may be a useful model for developing therapeutic interventions for DCM, especially late-onset DCM, based on the distinct phenotypes and rapid progressions.

Reductions of myocardial Na-K-ATPase activity and ouabain binding sites in heart failure: prevention by nadolol

1993 ◽  
Vol 265 (6) ◽  
pp. H2086-H2093 ◽  
Author(s):  
T. H. Fan ◽  
R. P. Frantz ◽  
H. Elam ◽  
S. Sakamoto ◽  
N. Imai ◽  
...  
Keyword(s):  
Heart Failure ◽  
Atpase Activity ◽  
Binding Sites ◽  
Early Stage ◽  
Ventricular Myocardium ◽  
Left Ventricular ◽  
Left Ventricular Myocardium ◽  
Adrenergic Stimulation ◽  
Ouabain Binding ◽  
Systemic Hemodynamic

To study the changes in myocardial digitalis binding sites in heart failure, we measured myocardial ouabain binding sites, Na-K-adenosinetriphosphatase (ATPase) activity, and ventricular muscle mechanical responses to acetylstrophanthidin in dogs with right-heart failure (RHF) produced by tricuspid avulsion and pulmonary artery constriction. Sham-operated dogs were studied as the control. RHF produced a significant decrease in ouabain binding sites in the right and left ventricular myocardium, which was accompanied by a proportional decrease in Na-K-ATPase activity. However, RHF and sham-operated dogs did not differ in systemic hemodynamic or right ventricular trabeculate muscle isometric contractile responses to acetylstrophanthidin. To determine whether chronic beta-adrenergic stimulation contributed to the development of Na-K-ATPase downregulation, we administered nadolol (40 mg/day) to a separate group of dogs during an early stage of RHF development. Nadolol effectively prevented the reduction of myocardial ouabain binding sites that occurred in RHF. Thus we conclude that myocardial ouabain binding sites and Na-K-ATPase activity are reduced in dogs with experimental heart failure and that these changes probably occur as a result of the attendant heightened sympathetic activity.

scholarly journals Inhibition of brain proinflammatory cytokine synthesis reduces hypothalamic excitation in rats with ischemia-induced heart failure

2008 ◽  
Vol 295 (1) ◽  
pp. H227-H236 ◽  
Author(s):  
Yu-Ming Kang ◽  
Zhi-Hua Zhang ◽  
Baojian Xue ◽  
Robert M. Weiss ◽  
Robert B. Felder
Keyword(s):  
Heart Failure ◽  
Hpa Axis ◽  
Proinflammatory Cytokines ◽  
Proinflammatory Cytokine ◽  
Left Ventricular ◽  
Prostaglandin E ◽  
Renin Angiotensin ◽  
Intracerebroventricular Infusion ◽  
Cytokine Synthesis ◽  
The Brain

The expression of proinflammatory cytokines increases in the hypothalamus of rats with heart failure (HF). The pathophysiological significance of this observation is unknown. We hypothesized that hypothalamic proinflammatory cytokines upregulate the activity of central neural systems that contribute to increased sympathetic nerve activity in HF, specifically, the brain renin-angiotensin system (RAS) and the hypothalamic-pituitary-adrenal (HPA) axis. Rats with HF induced by coronary ligation and sham-operated controls (SHAM) were treated for 4 wk with a continuous intracerebroventricular infusion of the cytokine synthesis inhibitor pentoxifylline (PTX, 10 μg/h) or artificial cerebrospinal fluid (VEH). In VEH-treated HF rats, compared with VEH-treated SHAM rats, the hypothalamic expression of proinflammatory cytokines was increased, along with key components of the brain RAS (renin, angiotensin-converting enzyme, angiotensin type 1 receptor) and corticotropin-releasing hormone, the central indicator of HPA axis activation, in the paraventricular nucleus (PVN) of the hypothalamus. The expression of other inflammatory/excitatory mediators (superoxide, prostaglandin E2) was also increased, along with evidence of chronic neuronal excitation in PVN. VEH-treated HF rats had higher plasma levels of norepinephrine, ANG II, interleukin (IL)-1β, and adrenocorticotropic hormone, increased left ventricular end-diastolic pressure, and increased wet lung-to-body weight ratio. With the exception of plasma IL-1β, an indicator of peripheral proinflammatory cytokine activity, all measures of neurohumoral excitation were significantly lower in HF rats treated with intracerebroventricular PTX. These findings suggest that the increase in brain proinflammatory cytokines observed in rats with ischemia-induced HF is functionally significant, contributing to neurohumoral excitation by activating brain RAS and the HPA axis.

scholarly journals Novel Neuromodulation Approach to Improve Left Ventricular Contractility in Heart Failure

2020 ◽  
Vol 13 (11) ◽  
Author(s):  
Vivek Y. Reddy ◽  
Jan Petrů ◽  
Filip Málek ◽  
Lee Stylos ◽  
Steve Goedeke ◽  
...  
Keyword(s):  
Heart Failure ◽  
Pulmonary Artery ◽  
Diastolic Pressure ◽  
Acute Decompensated Heart Failure ◽  
Systolic Pressure ◽  
Decompensated Heart Failure ◽  
Left Ventricular ◽  
Ventricular Contractility ◽  
Right Pulmonary Artery ◽  
The Right

Background: Morbidity and mortality outcomes for patients admitted for acute decompensated heart failure are poor and have not significantly changed in decades. Current therapies are focused on symptom relief by addressing signs and symptoms of congestion. The objective of this study was to test a novel neuromodulation therapy of stimulation of epicardial cardiac nerves passing along the posterior surface of the right pulmonary artery. Methods: Fifteen subjects admitted for defibrillator implantation and ejection fraction ≤35% on standard heart failure medications were enrolled. Through femoral arterial access, high fidelity pressure catheters were placed in the left ventricle and aortic root. After electro anatomic rendering of the pulmonary artery and branches, either a circular or basket electrophysiology catheter was placed in the right pulmonary artery to allow electrical intravascular stimulation at 20 Hz, 4 ms pulse width, and ≤20 mA. Changes in maximum positive dP/dt (dP/dt Max ) indicated changes in ventricular contractility. Results: Of 15 enrolled subjects, 5 were not studied due to equipment failure or abnormal pulmonary arterial anatomy. In the remaining subjects, dP/dt Max increased significantly by 22.6%. There was also a significant increase in maximum negative dP/dt (dP/dt Min ), mean arterial pressure, systolic pressure, diastolic pressure, and left ventricular systolic pressure. There was no significant change in heart rate or left ventricular diastolic pressure. Conclusions: In this first-in-human study, we demonstrated that in humans with stable heart failure, left ventricular contractility could be accentuated without an increase in heart rate or left ventricular filling pressures. This benign increase in contractility may benefit patients admitted for acute decompensated heart failure.

Abstract 16: Genomewide Association Study of Isoproterenol-Induced Heart Failure in a Large Mouse Panel

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Christoph D Rau ◽  
Jessica J Wang ◽  
Shuxun Ren ◽  
Yibin Wang ◽  
Aldons J Lusis
Keyword(s):  
Heart Failure ◽  
Mixed Model ◽  
Association Studies ◽  
Inbred Strains ◽  
Left Ventricular ◽  
Population Substructure ◽  
Adrenergic Stimulation ◽  
Hybrid Mouse Diversity Panel ◽  
Old Females ◽  
Human And Mouse

Heart failure is highly heterogeneous and association studies in humans have yielded few insights into its genetic basis. We have developed a resource, the Hybrid Mouse Diversity Panel, to efficiently perform association studies on complex diseases in a mouse model. Each strain within the panel has been densely genotyped and the panel displays significant baseline inter-strain variation. We used the panel to explore isoproterenol (a β-adrenergic agonist) induced heart failure. Eight week old females from 105 unique inbred strains (average N = 6.7) were divided into control (average N = 2.5) and treated (average N = 4.1) cohorts. Treated mice received 20 μg/g/day of drug through an abdominally implanted Alzet micropump. All mice underwent echocardiography to assess left ventricular function both before and at weekly timepoints after treatment. At three weeks, all mice were sacrificed. Hearts (sectioned by chamber) lungs, liver and adrenal glands were weighed before storage for further analysis. Phenotypes were analyzed using the Efficient Mixed-Model Association (EMMA) algorithm to correct for population substructure. Promising gene candidates were tested on zebrafish morpholino models to assess any phenotypic effects. Here we report initial findings from the panel. Chronic β-adrenergic stimulation results in marked variations in both weight and echocardiographic measurements. EMMA analysis of the data revealed several dozen putative peaks, including several repeated peaks in correlated phenotypes as well as replication of previously reported loci in both human and mouse studies. Further analysis of these peaks will shed light on the genetics underlying heart failure.

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