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.

Changes in sarcolemmal PLC isoenzymes in postinfarct congestive heart failure: partial correction by imidapril

1999 ◽  
Vol 277 (1) ◽  
pp. H40-H49 ◽  
Author(s):  
Paramjit S. Tappia ◽  
Song-Yan Liu ◽  
Shalini Shatadal ◽  
Nobuakira Takeda ◽  
Naranjan S. Dhalla ◽  
...  
Keyword(s):  
Heart Failure ◽  
Congestive Heart Failure ◽  
Coronary Occlusion ◽  
Ace Inhibitor ◽  
Contractile Function ◽  
Hydrolytic Activity ◽  
Protein Mass ◽  
Functional Correction ◽  
Partial Correction

We have examined the changes in quantity and activity of cardiac sarcolemmal (SL) phosphoinositide-phospholipase C (PLC)-β1, -γ1, and -δ1 in a model of congestive heart failure (CHF) secondary to large transmural myocardial infarction (MI). We also instituted a late in vivo monotherapy with imidapril, an ANG-converting enzyme (ACE) inhibitor, to test the hypothesis that its therapeutic action is associated with the functional correction of PLC isoenzymes. SL membranes were purified from the surviving left ventricle of rats in a moderate stage of CHF at 8 wk after occlusion of the left anterior descending coronary artery. SL PLC isoenzymes were examined in terms of protein mass and hydrolytic activity. CHF resulted in a striking reduction (to 6–17% of controls) of the mass and activity of γ1- and δ1-isoforms in combination with a significant increase of both PLC β1 parameters. In vivo treatment with imidapril (1 mg/kg body wt, daily, initiated 4 wk after coronary occlusion) improved the contractile function and induced a partial correction of PLCs. The mass of SL phosphatidylinositol 4,5-bisphosphate and the activities of the enzymes responsible for its synthesis were significantly reduced in post-MI CHF and partially corrected by imidapril. The results indicate that profound changes in the profile of heart SL PLC-β1, -γ1, and -δ1 occur in CHF, which could alter the complex second messenger responses of these isoforms, whereas their partial correction by imidapril may be related to the mechanism of action of this ACE inhibitor.

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.

Abstract 389: Alterations of Mitochondrial Calcium Handling in Heart Failure

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
An-Chi Wei ◽  
Ting Liu ◽  
Brian O’Rourke
Keyword(s):  
Heart Failure ◽  
Contractile Function ◽  
Critical Role ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Therapeutic Interventions ◽  
Calcium Handling ◽  
Aortic Constriction ◽  
Cardiac Contractile Function

Heart failure (HF) and sudden cardiac death (SCD) are major public health concerns that are increasing in incidence, yet the mechanisms underlying SCD in patients with HF are poorly understood. In a novel guinea pig model of HF/SCD, we showed that in vivo treatment with a mitochondrial Na+/Ca2+ exchanger (mNCE) inhibitor attenuates cardiac remodeling, preserves cardiac contractile function, and improves survival, supporting a critical role for altered mitochondrial Ca2+ dynamics in the pathophysiology. Here, we investigate whether the intrinsic mitochondrial Ca2+ transport rates are altered in this HF model. Methods: Ascending aortic constriction, combined with daily i.p. injection of isoproterenol (ISO), were used to induce HF (ACi) with acquired long QT. This group was compared with animals subjected to aortic constriction alone (AC), or sham-operated animals with (SHAMi) or without (SHAM) ISO treatment. Ca2+ Green-5N was used to measure total mitochondrial Ca2+ uptake and to quantify mitochondrial Ca2+ influx and efflux rates in isolated cardiac mitochondria. Results: Both the total mitochondrial Ca2+ load and the Ca2+ capacity prior to triggering permeability transition pore (mPTP) opening were reduced in HF mitochondria (5mM NaCl present). Mitochondrial Ca2+ fluxes, individually measured with sequential additions of 15μM free Ca2+, 10nM Ru360 and 5mM NaCl, showed that initial Ca2+ uptake rate through the mitochondrial Ca2+ uniporter (mCU: 0.55 nmol/sec/mg) was not significantly changed in HF; however, the Ca2+ extrusion rate through mNCE was larger in HF (AC:0.022 nmol/sec/mg; SHAM:0.018; ACi:0.013; SHAMi:0.009), but with a lower affinity for Na+. Interestingly, Na+-independent efflux via mPTP increased in HF (AC:0.0040 nmol/sec/mg; SHAM:0.0022; ACi:0.0013; SHAMi:0.012). Mitochondria from failing hearts also showed decreased respiration and increased ROS emission. Conclusions: The data indicate that an increase of intrinsic Ca2+ efflux and the increase in cytoplasmic Na+ in HF could both contribute to blunted mitochondrial Ca2+ in HF, which will affect cardiac energetics and ROS balance. Inhibitors of mNCE or mPTP are thus proposed to be therapeutic interventions that would improve mitochondrial Ca2+ balance and function in HF.

Abstract 131: C-kit+ Cells Generated From Failed Heart Do Not Improve Failed Heart Function

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Liudmila Zakharova ◽  
Hikmet Nural ◽  
James R Nimlos ◽  
Snjezana Popovic ◽  
Lorraine Feehery ◽  
...  
Keyword(s):  
Heart Failure ◽  
Left Ventricle ◽  
Diastolic Pressure ◽  
Heart Function ◽  
Smooth Muscle Actin ◽  
Functional Improvement ◽  
Gene Expressions ◽  
Coronary Vein ◽  
Mesenchymal Transition

A pilot clinical study using autologous c-Kit+ cells showed improvement in cardiac functions in congestive heart failure (CHF), however, it is unclear if c-Kit+ cells isolated from CHF hearts are equally as potent as cells from controls. To test the potency of CHF c-Kit+ cells, myocardial infarction (MI) was created by permanent ligation of the left anterior descending coronary artery. Six weeks after MI, animals with left ventricle end-diastolic pressure (LVEDP) ≥20 mmHg and scar size ≥30% of left ventricle (LV) were designated as CHF rats. We found that CHF atrial explants generated less c-Kit+ cells compared to shams (15.7% vs. 11% sham vs. CHF). CHF c-Kit+ cells exhibited elevated levels of epicardial to mesenchymal transition markers, including Snail (2.5 fold) and Pai1 (3 fold), while the expression level of epithelial marker, E-cadherin was 3 fold lower in CHF c-Kit+ cells. Moreover, CHF c-Kit+ cells exhibited reduced gene expressions of pluripotency markers; 2.1 fold decrease in Nanog and 4.5 fold decrease in Sox 2 compared to sham cells. To evaluate the potency of the c-Kit+ cells, 1 x 10 6 cells isolated from CHFs or shams were delivered to 3 weeks post-MI CHF hearts. Cells were pre-labeled with GFP to enable their tracing in vivo and delivered to the infarcted myocardium via left coronary vein by a retrograde coronary sinus cell infusion (RCI). RCI delivery resulted in a cell distribution of LV (30%), right atrium (30%) and right ventricle (20%), while only 10% of cells were found in a left atrium. Three weeks after cells delivery, rats transplanted with sham c-Kit+ cells showed improved LVEDP (29.4 ± 6 vs. 11.7 ± 3.5 mmHg, CHF vs. CHF+ sham c-Kit+ cells) and a rise in peak rate of pressure (dPdt max) (3988 ± 520 vs. 5333 ± 597 mmHg/s). In contrast, no functional improvement was detected in rats transplanted with CHF c-Kit+ cells. Histological analysis demonstrated that transplanted c-Kit+/GFP+ cells were mostly incorporated into blood vessels and co-localized with endothelial marker vWf, and α-smooth muscle actin. Our results showed that left coronary vein is an efficient route for c-Kit+ cell delivery and that c-Kit+ cells isolated from CHF rats are less potent when transplanted in chronic heart failure rat model compared to those isolated from control.

Cellular and functional defects in a mouse model of heart failure

2000 ◽  
Vol 279 (6) ◽  
pp. H3101-H3112 ◽  
Author(s):  
Giovanni Esposito ◽  
L. F. Santana ◽  
Keith Dilly ◽  
Jader Dos Santos Cruz ◽  
Lan Mao ◽  
...  
Keyword(s):  
Heart Failure ◽  
Adrenergic Receptor ◽  
Heart Function ◽  
Imaging Techniques ◽  
Single Cells ◽  
Structural Protein ◽  
Muscle Lim Protein ◽  
Intracellular Ca ◽  
Whole Heart

Heart failure and dilated cardiomyopathy develop in mice that lack the muscle LIM protein (MLP) gene (MLP−/−). The character and extent of the heart failure that occurs in MLP−/− mice were investigated using echocardiography and in vivo pressure-volume (P-V) loop measurements. P-V loop data were obtained with a new method for mice (sonomicrometry) using two pairs of orthogonal piezoelectric crystals implanted in the endocardial wall. Sonomicrometry revealed right-shifted P-V loops in MLP−/−mice, depressed systolic contractility, and additional evidence of heart failure. Cellular changes in MLP−/− mice were examined in isolated single cells using patch-clamp and confocal Ca2+ concentration ([Ca2+]) imaging techniques. This cellular investigation revealed unchanged Ca2+ currents and Ca2+ spark characteristics but decreased intracellular [Ca2+] transients and contractile responses and a defect in excitation-contraction coupling. Normal cellular and whole heart function was restored in MLP−/− mice that express a cardiac-targeted transgene, which blocks the function of β-adrenergic receptor (β-AR) kinase-1 (βARK1). These data suggest that, despite the persistent stimulus to develop heart failure in MLP−/− mice (i.e., loss of the structural protein MLP), downregulation and desensitization of the β-ARs may play a pivotal role in the pathogenesis. Furthermore, this work suggests that the inhibition of βARK1 action may prove an effective therapy for heart failure.

scholarly journals Physical Activity and Inhibition of ACE Additively Modulate ACE/ACE-2 Balance in Heart Failure in Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Urszula Tyrankiewicz ◽  
Mariola Olkowicz ◽  
Piotr Berkowicz ◽  
Magdalena Jablonska ◽  
Ryszard T. Smolenski ◽  
...  
Keyword(s):  
Physical Activity ◽  
Heart Failure ◽  
Heart Function ◽  
Combined Treatment ◽  
Training Group ◽  
Cardiac Performance ◽  
Angiotensin Converting Enzyme Inhibition ◽  
Ang Ii ◽  
Spontaneous Physical Activity

Angiotensin-converting enzyme inhibition (ACE-I) and physical activity favorably modulate the ACE/ACE-2 balance. However, it is not clear whether physical activity and ACE-I could synergistically modulate ACE/ACE-2 balance in the course of heart failure (HF). Here, we studied the effects of combined spontaneous physical activity and ACE-I–based treatment on angiotensin (Ang) pattern and cardiac function in a mouse model of HF (Tgαq*44). Tgαq*44 mice with advanced HF (at the age of 12 months) were running spontaneously in a running wheel (exercise training group, ExT) and/or were treated with ACE inhibitor (ACE-I, perindopril, 10 mg/kg) for 2 months. Angiotensin profile was characterized by an LC-MS/MS-based method. The cardiac performance was assessed in vivo by MRI. Ang-(1–7)/Ang II ratio in both plasma and the aorta was significantly higher in the combined treatment group than the ACE-I group or ExT alone, suggesting the additive favorable effects on ACE-2/Ang-(1–7) and ACE/Ang II axes’ balance induced by a combination of ACE-I with ExT. The basal cardiac performance did not differ among the experimental groups of Tgαq*44 mice. We demonstrated additive changes in ACE/ACE-2 balance in both plasma and the aorta by spontaneous physical activity and ACE-I treatment in Tgαq*44 mice. However, these changes did not result in an improvement of failing heart function most likely because the disease was at the end-stage. Ang-(1–7)/Ang II balance represents a valuable biochemical end point for monitoring therapeutic intervention outcome in heart failure.

scholarly journals Effectiveness and Safety of Peritoneal Dialysis Treatment in Patients with Refractory Congestive Heart Failure due to Chronic Cardiorenal Syndrome

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Qiuyuan Shao ◽  
Yangyang Xia ◽  
Min Zhao ◽  
Jing Liu ◽  
Qingyan Zhang ◽  
...  
Keyword(s):  
Heart Failure ◽  
Congestive Heart Failure ◽  
Peritoneal Dialysis ◽  
Survival Time ◽  
Heart Function ◽  
Cardiorenal Syndrome ◽  
Term Survival ◽  
Group A ◽  
Group B

Aims. To evaluate the effectiveness and safety of peritoneal dialysis (PD) in treating refractory congestive heart failure (RCHF) with cardiorenal syndrome (CRS).Methods. A total of 36 patients with RCHF were divided into type 2 CRS group (group A) and non-type 2 CRS group (group B) according to the patients’ clinical presentations and the ratio of serum urea to creatinine and urinary analyses in this prospective study. All patients were followed up till death or discontinuation of PD. Data were collected for analysis, including patient survival time on PD, technique failure, changes of heart function, and complications associated with PD treatment and hospitalization.Results. There were 27 deaths and 9 patients quitting PD program after a follow-up for 73 months with an average PD time of22.8±18.2months. A significant longer PD time was found in group B as compared with that in group A (29.0±19.4versus13.1±10.6months,p=0.003). Kaplan–Meier curves showed a higher survival probability in group B than that in group A (p<0.001). Multivariate regression demonstrated that type 2 CRS was an independent risk factor for short survival time on PD. The benefit of PD on the improvement of survival and LVEF was limited to group B patients, but absent from group A patients. The impairment of exercise tolerance indicated by NYHA classification was markedly improved by PD for both groups. The technique survival was high, and the hospital readmission was evidently decreased for both group A and group B patients.Conclusions. Our data suggest that PD is a safe and feasible palliative treatment for RCHF with type 2 CRS, though the long-term survival could not be expected for patients with the type 2 CRS. Registration ID Number isChiCTR1800015910.

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