Pamidronate Attenuates Diastolic Dysfunction Induced by Myocardial Infarction Associated with Changes in Geometric Patterning

Background/Aims: The aim of this study was to evaluate the influence of pamidronate on ventricular remodeling after myocardial infarction. Methods: Male Wistar rats were assigned to four groups: a sham group, in which animals were submitted to simulated surgery and received weekly subcutaneous injection of saline (S group; n=14); a group in which animals received weekly subcutaneous injection of pamidronate (3 mg/kg of body weight) and were submitted to simulated surgery (SP group, n=14); a myocardial infarction group, in which animals were submitted to coronary artery ligation and received weekly subcutaneous injection of saline (MI group, n=13); and a myocardial infarction group with pamidronate treatment (MIP group, n=14). The rats were observed for three months. Results: Animals submitted to MI had left chamber enlargement and worse diastolic and systolic function compared with SHAM groups. E/A ratio, LV posterior and relative wall thickness were lower in the MIP compared with the MI group. There was no interaction between pamidronate administration and MI on systolic function, myocyte hypertrophy, collagen content, and calcium handling proteins. Conclusion: Pamidronate attenuates diastolic dysfunction following MI.

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Progression of heart failure after myocardial infarction in the rat

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.2001.281.5.r1734 ◽

2001 ◽

Vol 281 (5) ◽

pp. R1734-R1745 ◽

Cited By ~ 111

Author(s):

J. Francis ◽

R. M. Weiss ◽

S. G. Wei ◽

A. K. Johnson ◽

R. B. Felder

Keyword(s):

Myocardial Infarction ◽

Heart Failure ◽

Ventricular Remodeling ◽

Systolic Function ◽

Left Ventricular Remodeling ◽

Plasma Renin ◽

Left Ventricular Systolic Function ◽

Left Ventricular ◽

Coronary Artery Ligation ◽

Artery Ligation

This study examined the early neurohumoral events in the progression of congestive heart failure (CHF) after myocardial infarction (MI) in rats. Immediately after MI was induced by coronary artery ligation, rats had severely depressed left ventricular systolic function and increased left ventricular end-diastolic volume (LVEDV). Both left ventricular function and the neurohumoral indicators of CHF underwent dynamic changes over the next 6 wk. LVEDV increased continuously over the study interval, whereas left ventricular stroke volume increased but reached a plateau at 4 wk. Plasma renin activity (PRA), arginine vasopressin, and atrial natriuretic factor all increased, but with differing time courses. PRA declined to a lower steady-state level by 4 wk. Six to 8 wk after MI, CHF rats had enhanced renal sympathetic nerve activity and blunted baroreflex regulation. These findings demonstrate that the early course of heart failure is characterized not by a simple “switching on” of neurohumoral drive, but rather by dynamic fluctuations in neurohumoral regulation that are linked to the process of left ventricular remodeling.

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Effects of carbon nanotube-mediated Caspase3 gene silencing on cardiomyocyte apoptosis and cardiac function during early acute myocardial infarction

Nanoscale ◽

10.1039/d0nr05032f ◽

2020 ◽

Vol 12 (42) ◽

pp. 21599-21604

Author(s):

Yi Li ◽

Hong Yu ◽

Liang Zhao ◽

Yuting Zhu ◽

Rui Bai ◽

...

Keyword(s):

Myocardial Infarction ◽

Cardiac Function ◽

Gene Silencing ◽

Ventricular Remodeling ◽

Myocardial Cell ◽

Coronary Artery Ligation ◽

Protective Effects ◽

Sprague Dawley ◽

Artery Ligation ◽

Sd Rats

Caspase3 gene silencing based on the gene transfer carrier F-CNT-siCas3 had obvious protective effects on myocardial cell apoptosis, ventricular remodeling, and cardiac function in Sprague-Dawley (SD) rats after coronary artery ligation.

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Nitroxides Mitigate Neutrophil-Mediated Damage to the Myocardium after Experimental Myocardial Infarction in Rats

International Journal of Molecular Sciences ◽

10.3390/ijms21207650 ◽

2020 ◽

Vol 21 (20) ◽

pp. 7650

Author(s):

Mary El Kazzi ◽

Han Shi ◽

Sally Vuong ◽

Xiaosuo Wang ◽

Belal Chami ◽

...

Keyword(s):

Myocardial Infarction ◽

Hypochlorous Acid ◽

Immune Cell ◽

Reperfusion Therapy ◽

Experimental Myocardial Infarction ◽

Coronary Artery Ligation ◽

Artery Ligation ◽

Post Surgery ◽

Male Wistar Rats ◽

Oxidant Production

Reperfusion therapy increases survival post-acute myocardial infarction (AMI) while also stimulating secondary oxidant production and immune cell infiltration. Neutrophils accumulate within infarcted myocardium within 24 h post-AMI and release myeloperoxidase (MPO) that catalyses hypochlorous acid (HOCl) production while increasing oxidative stress and inflammation, thereby enhancing ventricular remodelling. Nitroxides inhibit MPO-mediated HOCl production, potentially ameliorating neutrophil-mediated damage. Aim: Assess the cardioprotective ability of nitroxide 4-methoxyTEMPO (4MetT) within the setting of AMI. Methods: Male Wistar rats were separated into 3 groups: SHAM, AMI/R, and AMI/R + 4MetT (15 mg/kg at surgery via oral gavage) and subjected to left descending coronary artery ligation for 30 min to generate an AMI, followed by reperfusion. One cohort of rats were sacrificed at 24 h post-reperfusion and another 28 days post-surgery (with 4MetT (15 mg/kg) administration twice daily). Results: 3-chlorotyrosine, a HOCl-specific damage marker, decreased within the heart of animals in the AMI/R + 4-MetT group 24 h post-AMI, indicating the drug inhibited MPO activity; however, there was no evident difference in either infarct size or myocardial scar size between the groups. Concurrently, MPO, NfκB, TNFα, and the oxidation marker malondialdehyde increased within the hearts, with 4-MetT only demonstrating a trend in decreasing MPO and TNF levels. Notably, 4MetT provided a significant improvement in cardiac function 28 days post-AMI, as assessed by echocardiography, indicating potential for 4-MetT as a treatment option, although the precise mechanism of action of the compound remains unclear.

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Abstract 15058: Disruption of Extracellular Cytotoxic Chromatin by Acute DNase1 Administration Improves Left Ventricular Remodeling after Myocardial Infarction

Circulation ◽

10.1161/circ.130.suppl_2.15058 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Benjamin Vogel ◽

Hisahito Shinagawa ◽

Ullrich Hofmann ◽

Georg Ertl ◽

Stefan Frantz

Keyword(s):

Myocardial Infarction ◽

Ventricular Remodeling ◽

Left Ventricular Remodeling ◽

Left Ventricular ◽

Pcr Analysis ◽

Coronary Artery Ligation ◽

Protective Effects ◽

Artery Ligation ◽

High Concentrations

Rationale: Myocardial infarction (MI) leads to necrosis of multinucleated and polyploid myocytes. This causes uncontrolled release of cellular content like chromatin to the infarct area. Chromatin is mainly comprised of histones which are essential for controlling and packing of DNA but paradoxically are also known to be cytotoxic. This makes free chromatin a toxic DNA polymer creating local high concentrations of hazardous histones. Objective: We hypothesized that chromatin from necrotic cells accumulates in ischemic myocardium, creates local high concentrations of cytotoxic histones, and thereby potentiates ischemic damage to the heart after MI. The endonuclease DNase1 is capable of dispersing extracellular chromatin through linker DNA digestion and could decrease local histone concentrations and cytotoxicity. Methods and Results: After permanent coronary artery ligation in mice we found extracellular histones accumulated within the infarcted myocardium. Histone cytotoxicity towards isolated myocytes was confirmed in vitro. To reduce histone related cytotoxicity in vivo DNase1 was injected within the first 6 hours after induction of MI. DNase1 accumulated in the infarcted region of the heart, effectively disrupted extracellular cytotoxic chromatin and thereby reduced high local histone concentration. Animals acutely treated with DNase1 revealed significantly improved left ventricular remodeling as measured by serial echocardiography up to 28 days after MI (e.g. NaCl vs DNase1, papillary end diastolic area [mm 2 ]: 23.26 ± 2.06 vs 18.90 ± 1.24, n=9 vs 10, p<0,05). Treatment did not influence mortality, infarct size or inflammatory parameters as determined by neutrophil infiltration and RTQ-PCR analysis of characteristic cytokines. However improved myocyte survival was discovered within the infarct region which might account for the protective effects in DNase1 treated animals (NaCl vs DNase1: 3.0 ± 0.7% vs 8.3 ± 2.3%; p<0.05; n=7 vs 8). Conclusions: Targeting extracellular cytotoxic chromatin within the infarcted heart by DNase1 is a promising approach to preserve myocytes from histone induced cell death and to conserve left ventricular function after MI. The efficacy of other chromatin degrading agents is now under investigation.

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Cardioprotective Effect of Polydatin on Ventricular Remodeling after Myocardial Infarction in Coronary Artery Ligation Rats

Planta Medica ◽

10.1055/s-0035-1545907 ◽

2015 ◽

Vol 81 (07) ◽

pp. 568-577 ◽

Cited By ~ 5

Author(s):

Yan Gao ◽

Jianping Gao ◽

Changxun Chen ◽

Huilin Wang ◽

Juan Guo ◽

...

Keyword(s):

Myocardial Infarction ◽

Coronary Artery ◽

Ventricular Remodeling ◽

Cardioprotective Effect ◽

Coronary Artery Ligation ◽

Artery Ligation

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Clofibrate Treatment Decreases Inflammation and Reverses Myocardial Infarction-Induced Remodelation in a Rodent Experimental Model

Molecules ◽

10.3390/molecules24020270 ◽

2019 ◽

Vol 24 (2) ◽

pp. 270 ◽

Cited By ~ 4

Author(s):

Luz Ibarra-Lara ◽

María Sánchez-Aguilar ◽

Elizabeth Soria-Castro ◽

Jesús Vargas-Barrón ◽

Francisco Roldán ◽

...

Keyword(s):

Myocardial Infarction ◽

Coronary Artery ◽

Cardiac Remodeling ◽

Ventricular Remodeling ◽

Ex Vivo ◽

Left Ventricular ◽

Coronary Artery Ligation ◽

Cardiac Damage ◽

Artery Ligation ◽

Apoptotic Proteins

Myocardial infarction (MI) initiates an inflammatory response that promotes both beneficial and deleterious effects. The early response helps the myocardium to remove damaged tissue; however, a prolonged later response brings cardiac remodeling characterized by functional, metabolic, and structural pathological changes. Current pharmacological treatments have failed to reverse ischemic-induced cardiac damage. Therefore, our aim was to study if clofibrate treatment was capable of decreasing inflammation and apoptosis, and reverse ventricular remodeling and MI-induced functional damage. Male Wistar rats were assigned to (1) Sham coronary artery ligation (Sham) or (2) Coronary artery ligation (MI). Seven days post-MI, animals were further divided to receive vehicle (V) or clofibrate (100 mg/kg, C) for 7 days. The expression of IL-6, TNF-α, and inflammatory related molecules ICAM-1, VCAM-1, MMP-2 and -9, nuclear NF-kB, and iNOS, were elevated in MI-V. These inflammatory biomarkers decreased in MI-C. Also, apoptotic proteins (Bax and pBad) were elevated in MI-V, while clofibrate augmented anti-apoptotic proteins (Bcl-2 and 14-3-3ε). Clofibrate also protected MI-induced changes in ultra-structure. The ex vivo evaluation of myocardial functioning showed that left ventricular pressure and mechanical work decreased in infarcted rats; clofibrate treatment raised those parameters to control values. Echocardiogram showed that clofibrate partially reduced LV dilation. In conclusion, clofibrate decreases cardiac remodeling, decreases inflammatory molecules, and partly preserves myocardial diameters.

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Targeted inhibition of activin receptor-like kinase 5 signaling attenuates cardiac dysfunction following myocardial infarction

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01048.2009 ◽

2010 ◽

Vol 298 (5) ◽

pp. H1415-H1425 ◽

Cited By ~ 68

Author(s):

Sih Min Tan ◽

Yuan Zhang ◽

Kim A. Connelly ◽

Richard E. Gilbert ◽

Darren J. Kelly

Keyword(s):

Myocardial Infarction ◽

Cardiac Dysfunction ◽

Ventricular Remodeling ◽

Left Ventricular Remodeling ◽

Systolic Dysfunction ◽

Left Ventricular ◽

Coronary Artery Ligation ◽

Type I ◽

Artery Ligation ◽

Receptor Like Kinase

Following myocardial infarction (MI), the heart undergoes a pathological process known as remodeling, which in many instances results in cardiac dysfunction and ultimately heart failure and death. Transforming growth factor-β (TGF-β) is a key mediator in the pathogenesis of cardiac remodeling following MI. We thus aimed to inhibit TGF-β signaling using a novel orally active TGF-β type I receptor [activin receptor-like kinase 5 (ALK5)] inhibitor (GW788388) to attenuate left ventricular remodeling and cardiac dysfunction in a rat model of MI. Sprague-Dawley rats underwent left anterior descending coronary artery ligation to induce experimental MI and then were randomized to receive GW788388 at a dosage of 50 mg·kg−1·day−1 or vehicle 1 wk after surgery. After 4 wk of treatment, echocardiography was performed before the rats were euthanized. Animals that received left anterior descending coronary artery ligation demonstrated systolic dysfunction, Smad2 activation, myofibroblasts accumulation, collagen deposition, and myocyte hypertrophy (all P < 0.05). Treatment with GW788388 significantly attenuated systolic dysfunction in the MI animals, together with the attenuation of the activated (phosphorylated) Smad2 ( P < 0.01), α-smooth muscle actin ( P < 0.001), and collagen I ( P < 0.05) in the noninfarct zone of MI rats. Cardiomyocyte hypertrophy in MI hearts was also attenuated by ALK5 inhibition ( P < 0.05). In brief, treatment with a novel TGF-β type I receptor inhibitor, GW788388, significantly reduced TGF-β activity, leading to the attenuation of systolic dysfunction and left ventricular remodeling in an experimental rat model of MI.

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Exercise Training Stabilizes RyR2-Dependent Ca2+ Release in Post-infarction Heart Failure

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2020.623922 ◽

2021 ◽

Vol 7 ◽

Author(s):

Tore Kristian Danielsen ◽

Mani Sadredini ◽

Ravinea Manotheepan ◽

Jan Magnus Aronsen ◽

Michael Frisk ◽

...

Keyword(s):

Myocardial Infarction ◽

Heart Failure ◽

Exercise Training ◽

Radioligand Binding ◽

Left Ventricular ◽

Post Myocardial Infarction ◽

Coronary Artery Ligation ◽

Artery Ligation ◽

Ventricular Cardiomyocytes ◽

Male Wistar Rats

Aim: Dysfunction of the cardiac ryanodine receptor (RyR2) is an almost ubiquitous finding in animal models of heart failure (HF) and results in abnormal Ca2+ release in cardiomyocytes that contributes to contractile impairment and arrhythmias. We tested whether exercise training (ET), as recommended by current guidelines, had the potential to stabilize RyR2-dependent Ca2+ release in rats with post-myocardial infarction HF.Materials and Methods: We subjected male Wistar rats to left coronary artery ligation or sham operations. After 1 week, animals were characterized by echocardiography and randomized to high-intensity interval ET on treadmills or to sedentary behavior (SED). Running speed was adjusted based on a weekly VO2max test. We repeated echocardiography after 5 weeks of ET and harvested left ventricular cardiomyocytes for analysis of RyR2-dependent systolic and spontaneous Ca2+ release. Phosphoproteins were analyzed by Western blotting, and beta-adrenoceptor density was quantified by radioligand binding.Results: ET increased VO2max in HF-ET rats to 127% of HF-SED (P < 0.05). This coincided with attenuated spontaneous SR Ca2+ release in left ventricular cardiomyocytes from HF-ET but also reduced Ca2+ transient amplitude and slowed Ca2+ reuptake during adrenoceptor activation. However, ventricular diameter and fractional shortening were unaffected by ET. Analysis of Ca2+ homeostasis and major proteins involved in the regulation of SR Ca2+ release and reuptake could not explain the attenuated spontaneous SR Ca2+ release or reduced Ca2+ transient amplitude. Importantly, measurements of beta-adrenoceptors showed a normalization of beta1-adrenoceptor density and beta1:beta2-adrenoceptor ratio in HF-ET.Conclusion: ET increased aerobic capacity in post-myocardial infarction HF rats and stabilized RyR2-dependent Ca2+ release. Our data show that these effects of ET can be gained without major alterations in SR Ca2+ regulatory proteins and indicate that future studies should include upstream parts of the sympathetic signaling pathway.

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Pattern of neuronal activation in rats with CHF after myocardial infarction

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1998.275.6.h2140 ◽

1998 ◽

Vol 275 (6) ◽

pp. H2140-H2146 ◽

Cited By ~ 36

Author(s):

Faranak Vahid-Ansari ◽

Frans H. H. Leenen

Keyword(s):

Myocardial Infarction ◽

Sham Group ◽

Diastolic Pressure ◽

Systolic Pressure ◽

Left Ventricular ◽

Locus Ceruleus ◽

Coronary Artery Ligation ◽

Neuronal Activation ◽

Artery Ligation ◽

Neuronal Populations

To identify neuronal populations possibly contributing to the sympathetic hyperactivity in rats with congestive heart failure (CHF) after myocardial infarction (MI), immunohistochemical detection of Fra-like immunoreactivity (Fra-LI) was used as a marker of long-term neuronal activation. In adult Wistar rats, 2 and 4 wk after left coronary artery ligation, left ventricular (LV) peak systolic pressure and LV end-diastolic pressure were measured, immediately followed by transcardial perfusion and removal of the heart and brain. The brains were processed using an antibody that recognizes Fos, FosB, Fra-1, and Fra-2 for the detection of Fra-LI and using an antibody that only recognizes Fos-like immunoreactivity (Fos-LI). At both 2 and 4 wk after large MI, LV peak systolic pressure was significantly decreased and LV end-diastolic pressure increased. At 2 wk post-MI or sham surgery, Fra-LI was observed in several areas of either group but was significantly higher in the MI versus the sham group in the magnocellular division of the paraventricular nucleus (PVN), supraoptic nucleus (SON), subfornical organ, and caudal part of the nucleus of the solitary tract. At 4 wk after large MI, Fra-LI was clearly detected in the parvocellular and magnocellular divisions of the PVN, SON, and locus ceruleus. Modest expression was noted in these nuclei in rats with small MI, whereas Fra-like positive immunoreactive neurons were barely detectable in the sham group 4 wk postsurgery. In these nuclei, the extent of expression of Fra-LI correlated significantly with the LV end-diastolic pressure. Fos-LI was only noted in the cerebral cortex. These results indicate clear activation of neurons as identified by Fra-LI in specific cardiovascular control centers in rats with CHF 2 and 4 wk post-MI.

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Echocardiographic changes after myocardial infarction in a model of left ventricular diastolic dysfunction

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1997.273.4.h2018 ◽

1997 ◽

Vol 273 (4) ◽

pp. H2018-H2029 ◽

Cited By ~ 8

Author(s):

Gregory D. Pennock ◽

Douglas D. Yun ◽

Poonam G. Agarwal ◽

Peter H. Spooner ◽

Steven Goldman

Keyword(s):

Myocardial Infarction ◽

Diastolic Dysfunction ◽

Systolic Function ◽

Left Ventricular ◽

Coronary Artery Ligation ◽

Sham Operation ◽

Circumflex Artery ◽

Inflow Velocity ◽

Mitral Inflow ◽

Mitral Inflow Velocity

To determine the early and late effects of myocardial infarction on left ventricular (LV) diastolic function in the rabbit postinfarction model, male New Zealand White rabbits were randomly assigned to ligation of the circumflex artery or sham operation. Serial echocardiographic and Doppler studies were performed on both groups of animals at baseline and 1 h and 3 wk after surgery ( n = 10 for each group) after verification of the reproducibility and repeatability of the measurements. At 1 h postinfarction, decreases in early mitral inflow velocity (E wave) and mitral inflow velocity with atrial contraction (A wave) and increases in the mean pulmonary venous systolic-to-diastolic ratio and A wave reversal velocities were observed, without changes in LV geometry. By 3 wk postinfarction, increases in the mitral E-to-A ratio (1.1 ± 0.3 vs. 2.9 ± 0.9, P < 0.001) and left atrial area (131 ± 23 vs. 510 ± 72 mm2, P < 0.001) and decreases in the pulmonary venous systolic-to-diastolic ratio (0.56 ± 0.20 vs. 0.79 ± 0.14, P = 0.008) were consistent with severe diastolic abnormalities (restricted physiology). The findings of this study demonstrate that coronary artery ligation in the rabbit provides a reproducible echocardiographic and Doppler model of LV diastolic dysfunction that is consistent with abnormalities found in humans with previous myocardial infarction, symptoms of heart failure, and preserved LV systolic function.

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