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.

Abstract 41: Explant-Derived Cells from Chronic Heart Failure Activated Endothelial-Mesenchymal Transition and Attenuated Pluripotency Genes Expression

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Liudmila Zakharova ◽  
Hikmet Nural ◽  
Mohamed A Gaballa
Keyword(s):  
Gene Expression ◽  
Progenitor Cells ◽  
Smooth Muscle Actin ◽  
Fold Increase ◽  
Gene Expressions ◽  
Mesenchymal Transition ◽  
Cell Outgrowth ◽  
Pluripotency Genes

Cardiac progenitor cells are generated from atria explants; however the cellular origin and the mechanisms of cell outgrowth are unclear. Using transgenic tamoxifen-induced Willms tumor 1 (Wt1)-Cre/ERT and Cre-activated GFP reporter mice, we found approximately 40% of explant-derived cells and 74% of explant-derived c-Kit+ cells originated from the epicardium. In atria from sham hearts, Wt1+ cells were located in a thin epicardial layer, while c-Kit+ cells were primarily found within both the sub-epicardium and the myocardium, albeit at low frequency. No overlap between c-Kit+ and Wt1+ cells was observed, suggesting that epicardial Wt1+ cells do not express c-Kit marker in vivo, but more likely the c-Kit marker was acquired in culture. Compared with 4 days in culture, at day 21 we observed 7 folds increase in Snail gene expression; 32% increase in α-smooth muscle actin (SMA) marker, and 30% decrease in E-cadherin marker, suggesting that the explant-derived cells underwent epithelial to mesenchymal transition (EMT) in vitro. Cell outgrowths released TGF-β (1036.4 ± 1.18 pm/ml) and exhibited active TGF-β signaling, which might triggered the EMT. Compared to shams, CHF cell outgrowths exhibited elevated levels of EMT markers, SMA (49% vs. 34%) and Snail (2 folds), and reduced level of Wt1 (11% vs. 22%). In addition, CHF cell outgrowths had two folds increase in Pai1 gene expression, a direct target of TGF-β signaling. In c-Kit+ cells derived from CHF explants, Nanog gene expression was 4 folds lower and Sox 2 was 2 folds lower compared with cells from shams. Suppression of EMT in cell outgrowth increased the percentage of c-Kit+ and Wt1+ cells by 17%, and 15%, respectively. Also suppression of EMT in c-Kit+ cells resulted in 4 folds increase in Nanog and 3 fold increase in Sox2 gene expressions. Our results showed that CHF may further exuberates EMT while diminishes the re-activation of pluripotency genes. Thus, EMT modulation in CHF is a possible strategy to regulate both the yield and the pluripotency of cardiac-explant-derived progenitor cells.

scholarly journals Endothelial-to-Mesenchymal Transition in Human Adipose Tissue Vasculature Alters the Particulate Secretome and Induces Endothelial Dysfunction

2019 ◽  
Vol 39 (10) ◽  
pp. 2168-2191 ◽  
Author(s):  
Bronson A. Haynes ◽  
Li Fang Yang ◽  
Ryan W. Huyck ◽  
Eric J. Lehrer ◽  
Joshua M. Turner ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Endothelial Dysfunction ◽  
Smooth Muscle Actin ◽  
Phenotypic Change ◽  
Alpha Smooth Muscle Actin ◽  
Mesenchymal Transition ◽  
Molecular Features ◽  
Endothelial To Mesenchymal Transition

Objective: Endothelial cells (EC) in obese adipose tissue (AT) are exposed to a chronic proinflammatory environment that may induce a mesenchymal-like phenotype and altered function. The objective of this study was to establish whether endothelial-to-mesenchymal transition (EndoMT) is present in human AT in obesity and to investigate the effect of such transition on endothelial function and the endothelial particulate secretome represented by extracellular vesicles (EV). Approach and Results: We identified EndoMT in obese human AT depots by immunohistochemical co-localization of CD31 or vWF and α-SMA (alpha-smooth muscle actin). We showed that AT EC exposed in vitro to TGF-β (tumor growth factor-β), TNF-α (tumor necrosis factor-α), and IFN-γ (interferon-γ) undergo EndoMT with progressive loss of endothelial markers. The phenotypic change results in failure to maintain a tight barrier in culture, increased migration, and reduced angiogenesis. EndoMT also reduced mitochondrial oxidative phosphorylation and glycolytic capacity of EC. EVs produced by EC that underwent EndoMT dramatically reduced angiogenic capacity of the recipient naïve ECs without affecting their migration or proliferation. Proteomic analysis of EV produced by EC in the proinflammatory conditions showed presence of several pro-inflammatory and immune proteins along with an enrichment in angiogenic receptors. Conclusions: We demonstrated the presence of EndoMT in human AT in obesity. EndoMT in vitro resulted in production of EV that transferred some of the functional and metabolic features to recipient naïve EC. This result suggests that functional and molecular features of EC that underwent EndoMT in vivo can be disseminated in a paracrine or endocrine fashion and may induce endothelial dysfunction in distant vascular beds.

Estimation of Left Ventricular Wall Stiffness by Analysis of Late Diastolic Pressure Components

2011 ◽  
Author(s):  
Casandra L. Niebel ◽  
Kelley C. Stewart ◽  
Takahiro Ohara ◽  
John J. Charonko ◽  
Pavlos P. Vlachos ◽  
...  
Keyword(s):  
Heart Failure ◽  
Left Ventricle ◽  
Diastolic Dysfunction ◽  
Diastolic Pressure ◽  
Left Ventricular Diastolic Dysfunction ◽  
Left Ventricular ◽  
Ventricular Wall ◽  
Ventricular Relaxation ◽  
Wall Stiffness ◽  
Ventricular Diastolic Dysfunction

Left ventricular diastolic dysfunction (LVDD) is any abnormality in the filling of the left ventricle and is conventionally evaluated by analysis of the relaxation driven phase, or early diastole. LVDD has been shown to be a precursor to heart failure and the diagnosis and treatment for diastolic failure is less understood than for systolic failure. Diastole consists of two filling waves, early and late and is primarily dependent on ventricular relaxation and wall stiffness.

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 Method for Calibration of Left Ventricle Material Properties Using Three-Dimensional Echocardiography Endocardial Strains

2019 ◽  
Vol 141 (9) ◽  
Author(s):  
Yaghoub Dabiri ◽  
Kevin L. Sack ◽  
Nuno Rebelo ◽  
Peter Wang ◽  
Yunjie Wang ◽  
...  
Keyword(s):  
Mechanical Properties ◽  
Left Ventricle ◽  
Diffusion Tensor ◽  
Diastolic Pressure ◽  
Three Dimensional ◽  
Heart Association ◽  
Mean Difference ◽  
Imaging Data ◽  
The Mean

We sought to calibrate mechanical properties of left ventricle (LV) based on three-dimensional (3D) speckle tracking echocardiographic imaging data recorded from 16 segments defined by American Heart Association (AHA). The in vivo data were used to create finite element (FE) LV and biventricular (BV) models. The orientation of the fibers in the LV model was rule based, but diffusion tensor magnetic resonance imaging (MRI) data were used for the fiber directions in the BV model. A nonlinear fiber-reinforced constitutive equation was used to describe the passive behavior of the myocardium, whereas the active tension was described by a model based on tissue contraction (Tmax). isight was used for optimization, which used abaqus as the forward solver (Simulia, Providence, RI). The calibration of passive properties based on the end diastolic pressure volume relation (EDPVR) curve resulted in relatively good agreement (mean error = −0.04 ml). The difference between the experimental and computational strains decreased after segmental strain metrics, rather than global metrics, were used for calibration: for the LV model, the mean difference reduced from 0.129 to 0.046 (circumferential) and from 0.076 to 0.059 (longitudinal); for the BV model, the mean difference nearly did not change in the circumferential direction (0.061) but reduced in the longitudinal direction from 0.076 to 0.055. The calibration of mechanical properties for myocardium can be improved using segmental strain metrics. The importance of realistic fiber orientation and geometry for modeling of the LV was shown.

Congestive Heart Failure in Copper-Deficient Mice

2003 ◽  
Vol 228 (7) ◽  
pp. 811-817 ◽  
Author(s):  
Laila Elsherif ◽  
Raymond V. Ortines ◽  
Jack T. Saari ◽  
Y. James Kang
Keyword(s):  
Heart Failure ◽  
Congestive Heart Failure ◽  
Left Ventricle ◽  
Diastolic Pressure ◽  
Systolic Pressure ◽  
Pressure Rise ◽  
Experimental Models ◽  
Left Ventricular ◽  
Mouse Heart ◽  
Total Period

Copper Deficiency (CuD) leads to hypertrophic cardiomyopathy in various experimental models. The morphological, electrophysiological, and molecular aspects of this hypertrophy have been under investigation for a long time. However the transition from compensated hypertrophy to decompensated heart failure has not been investigated in the study of CuD. We set out to investigate the contractile and hemodynamic parameters of the CuD mouse heart and to determine whether heart failure follows hypertrophy in the CuD heart. Dams of FVB mice were fed CuD or copper-adequate (CuA) diet starting from the third day post delivery and the weanling pups were fed the same diet for a total period of 5 weeks (pre- and postweanling). At week 4, the functional parameters of the heart were analyzed using a surgical technique for catheterizing the left ventricle. A significant decrease in left ventricle systolic pressure was observed with no significant change in heart rate, and more importantly contractility as measured by the maximal rate of left ventricular pressure rise (+dP/dt) and decline (−dP/dt) were significantly depressed in the CuD mice. However, left ventricle end diastolic pressure was elevated, and relaxation was impaired in the CuD animals; the duration of relaxation was prolonged. In addition to significant changes in the basal level of cardiac function, CuD hearts had a blunted response to the stimulation of the β-adrenergic agonist isoproterenol. Furthermore, morphological analysis revealed increased collagen accumulation in the CuD hearts along with lipid deposition. This study shows that CuD leads to systolic and diastolic dysfunction in association with histopathological changes, which are indices commonly used to diagnose congestive heart failure.

scholarly journals Cardiac Triangle Mapping: A New Systems Approach for Noninvasive Evaluation of Left Ventricular End Diastolic Pressure

Fluids ◽  
2019 ◽  
Vol 4 (1) ◽  
pp. 16
Author(s):  
Niema M Pahlevan ◽  
Ray V Matthews
Keyword(s):  
Heart Failure ◽  
Left Ventricle ◽  
Systems Approach ◽  
Diastolic Pressure ◽  
Unmet Need ◽  
Left Ventricular ◽  
Time Interval ◽  
Chronic Congestive Heart Failure ◽  
Intrinsic Frequency ◽  
Future Design

Noninvasive and practical assessment of hemodynamics is a critical unmet need in the treatment of both chronic and acute cardiovascular diseases. Particularly, the ability to monitor left ventricular end-diastolic pressure (LVEDP) noninvasively offers enormous benefit for managing patients with chronic congestive heart failure. Recently, we provided proof of concept that a new cardiac metric, intrinsic frequency (IF), derived from mathematical analysis of non-invasively captured arterial waveforms, can be used to accurately compute cardiovascular hemodynamic measures, such as left ventricle ejection fraction (LVEF), by using a smartphone. In this manuscript, we propose a new systems-based method called cardiac triangle mapping (CTM) for hemodynamics evaluation of the left ventricle. This method is based on intrinsic frequency (IF) and systolic time interval (STI) methods that allows computation of LVEDP from noninvasive measurements. Since the CTM method only requires arterial waveform and electrocardiogram (ECG), it can eventually be adopted as a simple smartphone-based device, an inexpensive hand-held device, or perhaps (with future design modifications) a wearable sensor. Such devices, combined with this method, would allow for remote monitoring of heart failure patients.

scholarly journals Loss of Rad-GTPase produces a novel adaptive cardiac phenotype resistant to systolic decline with aging

2015 ◽  
Vol 309 (8) ◽  
pp. H1336-H1345 ◽  
Author(s):  
Janet R. Manning ◽  
Catherine N. Withers ◽  
Bryana Levitan ◽  
Jeffrey D. Smith ◽  
Douglas A. Andres ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Output ◽  
Calcium Current ◽  
Ventricular Myocytes ◽  
Morphological Changes ◽  
Heart Function ◽  
Early Time ◽  
Cardiac Phenotype ◽  
Systolic And Diastolic Function

Rad-GTPase is a regulator of L-type calcium current (LTCC), with increased calcium current observed in Rad knockout models. While mouse models that result in elevated LTCC have been associated with heart failure, our laboratory and others observe a hypercontractile phenotype with enhanced calcium homeostasis in Rad−/−. It is currently unclear whether this observation represents an early time point in a decompensatory progression towards heart failure or whether Rad loss drives a novel phenotype with stable enhanced function. We test the hypothesis that Rad−/− drives a stable nonfailing hypercontractile phenotype in adult hearts, and we examine compensatory regulation of sarcoplasmic reticulum (SR) loading and protein changes. Heart function was measured in vivo with echocardiography. In vivo heart function was significantly improved in adult Rad−/− hearts compared with wild type. Heart wall dimensions were significantly increased, while heart size was decreased, and cardiac output was not changed. Cardiac function was maintained through 18 mo of age with no decompensation. SR releasable Ca2+ was increased in isolated Rad−/− ventricular myocytes. Higher Ca2+ load was accompanied by sarco/endoplasmic reticulum Ca2+ ATPase 2a (SERCA2a) protein elevation as determined by immunoblotting and a rightward shift in the thapsigargan inhibitor-response curve. Rad−/− promotes morphological changes accompanied by a stable increase in contractility with aging and preserved cardiac output. The Rad−/− phenotype is marked by enhanced systolic and diastolic function with increased SR uptake, which is consistent with a model that does not progress into heart failure.

scholarly journals Toll-Like Receptor 9 Promotes Cardiac Inflammation and Heart Failure during Polymicrobial Sepsis

2013 ◽  
Vol 2013 ◽  
pp. 1-13 ◽  
Author(s):  
Ralph Lohner ◽  
Markus Schwederski ◽  
Carolin Narath ◽  
Johanna Klein ◽  
Georg D. Duerr ◽  
...  
Keyword(s):  
Heart Failure ◽  
Peritoneal Cavity ◽  
Heart Function ◽  
Bacterial Load ◽  
Systolic Pressure ◽  
Polymicrobial Sepsis ◽  
Toll Like Receptor ◽  
Cardiac Inflammation ◽  
Continuous Release

Background. Aim was to elucidate the role of toll-like receptor 9 (TLR9) in cardiac inflammation and septic heart failure in a murine model of polymicrobial sepsis.Methods. Sepsis was induced via colon ascendens stent peritonitis (CASP) in C57BL/6 wild-type (WT) and TLR9-deficient (TLR9-D) mice. Bacterial load in the peritoneal cavity and cardiac expression of inflammatory mediators were determined at 6, 12, 18, 24, and 36 h. Eighteen hours after CASP cardiac function was monitoredin vivo. Sarcomere length of isolated cardiomyocytes was measured at 0.5 to 10 Hz after incubation with heat-inactivated bacteria.Results. CASP led to continuous release of bacteria into the peritoneal cavity, an increase of cytokines, and differential regulation of receptors of innate immunity in the heart. Eighteen hours after CASP WT mice developed septic heart failure characterised by reduction of end-systolic pressure, stroke volume, cardiac output, and parameters of contractility. This coincided with reduced cardiomyocyte sarcomere shortening. TLR9 deficiency resulted in significant reduction of cardiac inflammation and a sustained heart function. This was consistent with reduced mortality in TLR9-D compared to WT mice.Conclusions. In polymicrobial sepsis TLR9 signalling is pivotal to cardiac inflammation and septic heart failure.

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