scholarly journals Intramyocardially Transplanted Neonatal Cardiomyocytes (NCMs) Show Structural and Electrophysiological Maturation and Integration and Dose-Dependently Stabilize Function of Infarcted Rat Hearts

2017 ◽  
Vol 26 (1) ◽  
pp. 157-170 ◽  
Author(s):  
Martina Maass ◽  
Benjamin Krausgrill ◽  
Simon Eschrig ◽  
Tobias Kaluschke ◽  
Katja Urban ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Functional Study ◽  
Female Rat ◽  
Cardiac Cell ◽  
Pharmacological Stress ◽  
Intramyocardial Injection ◽  
Cell Replacement ◽  
Neonatal Cardiomyocytes ◽  
Rat Hearts ◽  
Host Myocardium

Cardiac cell replacement therapy is a promising therapy to improve cardiac function in heart failure. Persistence, structural and functional maturation, and integration of transplanted cardiomyocytes into recipients' hearts are crucial for a safe and efficient replacement of lost cells. We studied histology, electrophysiology, and quantity of intramyocardially transplanted rat neonatal cardiomyocytes (NCMs) and performed a detailed functional study with repeated invasive (pressure–volume catheter) and noninvasive (echocardiography) analyses of infarcted female rat hearts including pharmacological stress before and 3 weeks after intramyocardial injection of 5 × 106 (low NCM) or 25 × 106 (high NCM) syngeneic male NCMs or medium as placebo (Ctrl). Quantitative real-time polymerase chain reaction (PCR) for Y-chromosome confirmed a fivefold higher persisting male cell number in high NCM versus low NCM after 3 weeks. Sharp electrode measurements within viable slices of recipient hearts demonstrated that transplanted NCMs integrate into host myocardium and mature to an almost adult phenotype, which might be facilitated through gap junctions between host myocardium and transplanted NCMs as indicated by connexin43 in histology. Ejection fraction of recipient hearts was severely impaired after ligation of left anterior descending (LAD; pressure–volume catheter: 39.2 ± 3.6%, echocardiography: 39.9 ± 1.4%). Repeated analyses revealed a significant further decline within 3 weeks in Ctrl and a dose-dependent stabilization in cell-treated groups. Consistently, stabilized cardiac function/morphology in cell-treated groups was seen in stroke volume, cardiac output, ventricle length, and wall thickness. Our findings confirm that cardiac cell replacement is a promising therapy for ischemic heart disease since immature cardiomyocytes persist, integrate, and mature after intramyocardial transplantation, and they dose-dependently stabilize cardiac function after myocardial infarction.

scholarly journals Attenuation of extracellular ATP response in cardiomyocytes isolated from hearts subjected to ischemia-reperfusion

2005 ◽  
Vol 289 (2) ◽  
pp. H614-H623 ◽  
Author(s):  
Harjot K. Saini ◽  
Vijayan Elimban ◽  
Naranjan S. Dhalla
Keyword(s):  
Cardiac Function ◽  
Positive Inotropic Effect ◽  
Ischemia Reperfusion ◽  
Cardiac Contractility ◽  
Extracellular Atp ◽  
Binding Characteristics ◽  
Rat Hearts ◽  
The Status ◽  
Intracellular Ca ◽  
Isolated Rat

Extracellular ATP is known to augment cardiac contractility by increasing intracellular Ca2+ concentration ([Ca2+]i) in cardiomyocytes; however, the status of ATP-mediated Ca2+ mobilization in hearts undergoing ischemia-reperfusion (I/R) has not been examined previously. In this study, therefore, isolated rat hearts were subjected to 10–30 min of global ischemia and 30 min of reperfusion, and the effect of extracellular ATP on [Ca2+]i was measured in purified cardiomyocytes by fura-2 microfluorometry. Reperfusion for 30 min of 20-min ischemic hearts, unlike 10-min ischemic hearts, revealed a partial depression in cardiac function and ATP-induced increase in [Ca2+]i; no changes in basal [Ca2+]i were evident in 10- or 20-min I/R preparations. On the other hand, reperfusion of 30-min ischemic hearts for 5, 15, or 30 min showed a marked depression in both cardiac function and ATP-induced increase in [Ca2+]i and a dramatic increase in basal [Ca2+]i. The positive inotropic effect of extracellular ATP was attenuated, and the maximal binding characteristics of 35S-labeled adenosine 5′-[γ-thio]triphosphate with crude membranes from hearts undergoing I/R was decreased. ATP-induced increase in [Ca2+]i in cardiomyocytes was depressed by verapamil and Cibacron Blue in both control and I/R hearts; however, this response in I/R hearts, unlike control hearts, was not affected by ryanodine. I/R-induced alterations in cardiac function and ATP-induced increase in [Ca2+]i were attenuated by treatment with an antioxidant mixture and by ischemic preconditioning. The observed changes due to I/R were simulated in hearts perfused with H2O2. The results suggest an impairment of extracellular ATP-induced Ca2+ mobilization in I/R hearts, and this defect appears to be mediated through oxidative stress.

Different Toxicological Profiles for Various Beta-Blocking Agents on Cardiac Function in Isolated Rat Hearts

1984 ◽  
Vol 22 (2) ◽  
pp. 115-132 ◽  
Author(s):  
Dick de Wildt ◽  
Bart Sangster ◽  
Johanna Langemeijer ◽  
Gerard de Groot
Keyword(s):  
Cardiac Function ◽  
Blocking Agents ◽  
Rat Hearts ◽  
Beta Blocking ◽  
Isolated Rat

Intramyocardial Injection of Heart Tissue-Derived Extracellular Matrix Improves Postinfarction Cardiac Function in Rats

2013 ◽  
Vol 18 (3) ◽  
pp. 270-279 ◽  
Author(s):  
Wangde Dai ◽  
Paul Gerczuk ◽  
Yuanyuan Zhang ◽  
Leona Smith ◽  
Oleg Kopyov ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Cardiac Function ◽  
Heart Tissue ◽  
Intramyocardial Injection

Cardioprotection with esmolol-based cardioplegia for non-infarcted and infarcted rat hearts

2021 ◽  
Author(s):  
Alexander B Veitinger ◽  
Audrey Komguem ◽  
Lena Assling-Simon ◽  
Martina Heep ◽  
Julia Schipke ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
Infarct Size ◽  
Myocardial Infarct ◽  
Lactate Production ◽  
Left Ventricular ◽  
Myocardial Infarct Size ◽  
Cardioplegic Arrest ◽  
Blood Cardioplegia ◽  
Rat Hearts

Abstract OBJECTIVES Esmolol-based cardioplegic arrest offers better cardioprotection than crystalloid cardioplegia but has been compared experimentally with blood cardioplegia only once. We investigated the influence of esmolol crystalloid cardioplegia (ECCP), esmolol blood cardioplegia (EBCP) and Calafiore blood cardioplegia (Cala) on cardiac function, metabolism and infarct size in non-infarcted and infarcted isolated rat hearts. METHODS Two studies were performed: (i) the hearts were subjected to a 90-min cardioplegic arrest with ECCP, EBCP or Cala and (ii) a regional myocardial infarction was created 30 min before a 90-min cardioplegic arrest. Left ventricular peak developed pressure (LVpdP), velocity of contractility (dLVP/dtmax), velocity of relaxation over time (dLVP/dtmin), heart rate and coronary flow were recorded. In addition, the metabolic parameters were analysed. The infarct size was determined by planimetry, and the myocardial damage was determined by electron microscopy. RESULTS In non-infarcted hearts, cardiac function was better preserved with ECCP than with EBCP or Cala relative to baseline values (LVpdP: 100 ± 28% vs 86 ± 11% vs 57 ± 7%; P = 0.002). Infarcted hearts showed similar haemodynamic recovery for ECCP, EBCP and Cala (LVpdP: 85 ± 46% vs 89 ± 55% vs 56 ± 26%; P = 0.30). The lactate production with EBCP was lower than with ECCP (0.6 ± 0.7 vs 1.4 ± 0.5 μmol/min; P = 0.017). The myocardial infarct size and (ECCP vs EBCP vs Cala: 16 ± 7% vs 15 ± 9% vs 24 ± 13%; P = 0.21) the ultrastructural preservation was similar in all groups. CONCLUSIONS In non-infarcted rat hearts, esmolol-based cardioplegia, particularly ECCP, offers better myocardial protection than Calafiore. After an acute myocardial infarction, cardioprotection with esmolol-based cardioplegia is similar to that with Calafiore.

Abstract 339: Long-term AAV6-βARKct Myocardial Gene Therapy Improves Cardiac Function Via Restoration Of β-Adrenergic Receptor Signaling And Neurohormonal Status Of The Failing Heart

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Giuseppe Rengo ◽  
Anastasios Lymperopoulos ◽  
Carmela Zincarelli ◽  
Maria Donniacuo ◽  
Stephen Soltys ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Gene Delivery ◽  
Cardiac Function ◽  
Adrenergic Receptor ◽  
Fluorescent Protein ◽  
Heart Function ◽  
Weight Ratio ◽  
Intramyocardial Injection ◽  
Molecular Abnormalities ◽  
Virus Serotype

BACKGROUND: The up-regulation of G protein-coupled receptor kinase-2 (GRK2) that is present in compromised myocardium contributes to dysfunctional β-adrenergic receptor (βAR) signaling and cardiac function in heart failure (HF). The peptide βARKct, which inhibits the activation of GRK2, has been shown in acute gene transfer experiments to rescue HF. This study was designed to evaluate chronic βARKct expression in post-myocardial infarction (MI) induced HF using stable myocardial gene delivery with adeno-associated virus serotype-6 (AAV6). METHODS AND RESULTS: In 12 week post-MI HF rats, we delivered βARKct or as a control, Green Fluorescent Protein, via direct intramyocardial injection. We also treated groups with concurrent administration of metoprolol. We found robust and long-lasting (up to 12 weeks post-delivery) transgene expression in the left ventricle (LV) and βARKct expression resulted in significantly improved global heart function as LV ejection fraction and ±dP/dt were increased, whereas LV end diastolic diameter and pressure were decreased. At the molecular level, cardiac βAR density and cAMP accumulation significantly improved over control groups. Fibrotic and hypertrophy markers, as well as heart-to-body weight ratio were markedly decreased by βARKct gene therapy indicating active reversal of adverse LV remodeling. For the first time, we found that chronic βARKct expression and normalization of cardiac βAR signaling led to a reduction of circulating levels of cardiotoxic neurohormones (catecholamines and aldosterone) demonstrating a potential additive mechanism of GRK2 inhibition. Concomitant metoprolol administration preserved the gain in inotropy achieved by βARKct, suggesting compatibility of these two therapeutic modalities, however, metoprolol alone only prevented the deterioration of cardiac function in HF. CONCLUSIONS : Chronic cardiac βARKct gene therapy for HF treatment via AAV6-mediated intracardiac gene delivery is feasible and results in improved cardiac function accompanied by restoration of βAR molecular abnormalities and amelioration of neurohormonal status of HF. These findings suggest βARKct gene therapy might be clinically applicable and of significant value for human HF treatment. This research has received full or partial funding support from the American Heart Association, AHA Great Rivers Affiliate (Delaware, Kentucky, Ohio, Pennsylvania & West Virginia).

Transplantation of embryonic stem cells improves cardiac function in postinfarcted rats

2002 ◽  
Vol 92 (1) ◽  
pp. 288-296 ◽  
Author(s):  
Jiang-Yong Min ◽  
Yinke Yang ◽  
Kimber L. Converso ◽  
Lixin Liu ◽  
Qin Huang ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Cell Transplantation ◽  
Troponin I ◽  
Es Cells ◽  
Single Cells ◽  
Embryonic Stem ◽  
Control Group ◽  
Positive Staining ◽  
Es Cell ◽  
Intramyocardial Injection

Massive loss of cardiac myocytes after myocardial infarction (MI) is a common cause of heart failure. The present study was designed to investigate the improvement of cardiac function in MI rats after embryonic stem (ES) cell transplantation. MI in rats was induced by ligation of the left anterior descending coronary artery. Cultured ES cells used for cell transplantation were transfected with the marker green fluorescent protein (GFP). Animals in the treated group received intramyocardial injection of ES cells in injured myocardium. Compared with the MI control group injected with an equivalent volume of the cell-free medium, cardiac function in ES cell-implanted MI animals was significantly improved 6 wk after cell transplantation. The characteristic phenotype of engrafted ES cells was identified in implanted myocardium by strong positive staining to sarcomeric α-actin, cardiac α-myosin heavy chain, and troponin I. GFP-positive cells in myocardium sectioned from MI hearts confirmed the survival and differentiation of engrafted cells. In addition, single cells isolated from cell-transplanted MI hearts showed rod-shaped GFP-positive myocytes with typical striations. The present data demonstrate that ES cell transplantation is a feasible and novel approach to improve ventricular function in infarcted failing hearts.

scholarly journals SKA-31, a novel activator of SKCa and IKCa channels, increases coronary flow in male and female rat hearts

2012 ◽  
Vol 97 (2) ◽  
pp. 339-348 ◽  
Author(s):  
Ramesh C. Mishra ◽  
Darrell Belke ◽  
Heike Wulff ◽  
Andrew P. Braun
Keyword(s):  
Coronary Flow ◽  
Female Rat ◽  
Male And Female ◽  
Rat Hearts

Abstract 15555: Administration of c-Kit+ Cardiac Stem Cells (CSCs) Results in Increased Proliferation and Cardiac Content of CSCs 1 Year Later

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Qianhong Li ◽  
Ning Chen ◽  
Li Luo ◽  
Qinghui Ou ◽  
Wei Xie ◽  
...  
Keyword(s):  
Stem Cells ◽  
Border Zone ◽  
Functional Improvement ◽  
Vehicle Group ◽  
Lv Function ◽  
Female Rat ◽  
Infarct Zone ◽  
Hematopoietic Stem ◽  
Beneficial Effects ◽  
Rat Hearts

Background: We have previously shown in rats that the beneficial effects of c-kit + CSCs on LV function and remodeling post-myocardial infarction persist for at least 1 year after CSC administration. However, in that study the retention of transplanted Y-chromosome + cells in the risk region (RR) of female rat hearts at 1 year was low (<10% of total nuclei) and not sufficient to account for the functional improvement, suggesting that other mechanisms must be at work. Methods and Results: To address this issue, rats received intracoronary vehicle or 1x10 6 syngeneic CSCs 4 h after a 90-min coronary occlusion; 11 months later, BrdU treatment was given for 1 month. CSCs, which are c-kit + /CD45 − , were distinguished from c-kit + hematopoietic stem cells/mast cells, which are CD45 + . At 1 year after CSC administration, the total number of c-kit + or c-kit + /BrdU + cells in the heart (the sum of c-kit + /CD45 − and c-kit + /CD45 + cells) did not differ between CSC and control groups (Figs. H and I). However, CSC transplantation resulted in increased numbers of CSCs (c-kit + /CD45 − cells) in the RR (i.e., the infarct zone plus border zone)(47.6±7.0% of total c-kit + cells vs. 27.9±4.1% in vehicle group; n=5, P <0.05; Fig. J). Among CSCs (c-kit + /CD45 − cells), the fraction that was newly formed (c-kit + /CD45 − /BrdU + ) was dramatically increased in the RR of the CSC group (+ 2.6-fold vs. vehicle group; n=4, P <0.05; Fig. M), indicating increased CSC proliferation and turnover. Conclusions: These data reveal, for the first time, that a single intracoronary infusion of CSCs is followed by an increase in both the proliferation and the total number of c-kit + CSCs in the myocardium that persists, surprisingly, for at least 1 year after cell delivery. Since transplanted cells do not differentiate into adult myocytes, these data suggest that the long-term salubrious effects of CSCs on cardiac function are mediated by sustained activation of the CSC pool in the heart.

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