A novel model of cryoinjury-induced myocardial infarction in the mouse: a comparison with coronary artery ligation

2005 ◽  
Vol 289 (3) ◽  
pp. H1291-H1300 ◽  
Author(s):  
Ewout J. van den Bos ◽  
Barend M. E. Mees ◽  
Monique C. de Waard ◽  
Rini de Crom ◽  
Dirk J. Duncker
Keyword(s):  
Myocardial Infarction ◽  
Coronary Artery ◽  
Myocardial Infarct ◽  
Left Ventricular ◽  
Coronary Artery Ligation ◽  
Artery Ligation ◽  
End Point ◽  
Coronary Ligation ◽  
Adverse Remodeling ◽  
Fractional Shortening

Mouse myocardial infarction (MI) models are frequently used research tools. The most commonly applied model is coronary artery ligation. However, coronary ligation often gives rise to apical aneurysmatic infarcts of variable size. Other infarct models include cryoinfarction, which produces reproducible infarcts of the anterior wall. Thus far, this model has not been extensively described in mice. Therefore, we developed a murine cryoinfarction model and compared it with coronary ligation. Studies were performed under isoflurane anesthesia with a follow-up of 4 and 8 wk. Cryoinfarction was induced using a 2- or 3-mm cryoprobe. Two-dimensional guided M-mode echocardiography was used to assess fractional shortening and left ventricular (LV) dimensions at baseline and end point. At end point, hemodynamics were assessed using a 1.4-Fr Millar catheter. Pressure-diameter relations were constructed by combining echocardiography and hemodynamic data. Histological and morphometric analyses of infarct and remote areas were performed. At 4 wk, 3-mm cryoinfarction resulted in decreased LV fractional shortening as well as decreased global LV contractility and relaxation, which was comparable with coronary ligation. No adverse remodeling was observed at this time point, in contrast with the ligation model. However, progressive LV remodeling occured between 4 and 8 wk after cryoinfarction with a further decline in hemodynamic parameters and LV pump function. Histologically, cryoinfarction resulted in highly reproducible, transmural, cone-shaped infarcts with reperfusion at the macrovascular level. These results indicate that the cryoinfarction model represents the anterior myocardial infarct with modest adverse remodeling and may thus be representative for infarcts encountered in clinical practice.

Abstract 132: Cardiomyocyte Specific Conditional Overexpression Of Stromal Cell Derived Factor 1 Facilitates Cardiac Regeneration After Permanent Coronary Artery Ligation In Mice.

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Detlef Obal ◽  
Kenneth Brittian ◽  
Michael Book ◽  
Aruni Bhatnagar ◽  
Yiru Guo ◽  
...  
Keyword(s):  
Coronary Artery ◽  
Stromal Cell ◽  
Cardiac Regeneration ◽  
Left Ventricular ◽  
Border Zone ◽  
Coronary Artery Ligation ◽  
Artery Ligation ◽  
Casein Kinase 1 ◽  
Coronary Ligation ◽  
Stromal Cell Derived Factor

Background: Interruption of cardiac stromal cell derived factor 1 (SDF1)-CXCR4 axis by chronic AMD3100 administration increased myocardial injury after permanent coronary artery ligation demonstrating the important role of this chemokine in cardiac regeneration. Hypothesis: Cardiomyocyte specific conditional overexpression of SDF1 prevents heart failure after permanent coronary ligation and facilitates cardiac regeneration. Methods and Results: Tetracycline-controlled, αMyHC promoter directed overexpression of cardiac SDF1, resulted in a significant increase of SDF1 expression (SDF1: 8.1 ng/mg protein) compared to littermate WT mice (0.02 ng/mg protein) four weeks after doxycycline withdraw. SDF1 overexpression increased AKT and casein kinase 1 levels in the heart. Although there was no difference in cardiac function and scar size 1 week after infarction, SDF1 overexpression improved left ventricular (LV) ejection fraction (SDF1 [n=13]: 47±5% [mean±SEM] vs. WT [n=15]: 29±4%, p<0.05) decreased end-diastolic volume (78±10 vs. 158±30, p<0.05) and reduced infarct size measured by trichrome staining (13±3% vs. 23±3% of LV wall, p<0.05) 4 weeks after permanent ligation. Bromodeoxyuridine (BrdU) staining revealed increased regeneration indicated by a 5-fold increase in BrdU + cardiomyocyte (CM) nuclei in the borderzone of the infarct (22±3% vs. 5±1% CM nuclei, p<0.01). Increased proliferation in SDF1 mice was confirmed by a higher number of KI67 + cells compared to WT mice. Cardiomyocyte cross sectional area in the border zone was significantly reduced in SDF1 mice (365±13 μm 2 vs. 434±10 μm 2 , p<0.001) while capillary density was unchanged (2348±151/ mm 2 vs. 2498±153/ mm 2 ) compared to WT mice. Conclusion: This study demonstrates for the first time that cardiac specific overexpression of SDF1 increases myocardial regeneration and improves LV function 4 weeks after permanent coronary ligation.

Comparison of Myocardial Infarction with Sequential Ligation of the Left Anterior Descending Artery and Its Diagonal Branch in Dogs and Sheep

2003 ◽  
Vol 26 (4) ◽  
pp. 351-357 ◽  
Author(s):  
W.G. Kim ◽  
Y.C. Shin ◽  
S.W. Hwang ◽  
C. Lee ◽  
C.Y. Na
Keyword(s):  
Myocardial Infarction ◽  
Coronary Artery ◽  
Pulmonary Artery ◽  
Left Ventricular ◽  
Coronary Artery Ligation ◽  
Suitable Model ◽  
Artery Ligation ◽  
Diagonal Branch ◽  
Left Anterior Descending Artery ◽  
Arterial Blood

We report a comparison of the effects of myocardial infarction in dogs and sheep using sequential ligation of the left anterior descending artery (LAD) and its diagonal branch (DA), with hemodynamic, ultrasonographic and pathological evaluations. Five animals were used in each group. After surgical preparation, the LAD was ligated at a point approximately 40% of the distance from the apex to the base of the heart, and after one hour, the DA was ligated at the same level. Hemodynamic and ultrasonographic measurements were performed preligation, 30 minutes after LAD ligation, and 1 hour after DA ligation. As a control, two animals in each group were used for the simultaneous ligation of the LAD and the DA. Two months after the coronary ligation, the animals were evaluated as previously, and killed for postmortem examination of their hearts. All seven animals in the dog group survived the experimental procedures, while in the sheep group only animals with sequential ligation of the LAD and DA survived. Statistically significant decreases in systemic arterial blood pressure and cardiac output, and an increase in the pulmonary artery capillary wedge pressure (PACWP) were observed one hour after sequential ligation of the LAD and its DA in the sheep, while only systemic arterial pressures decreased in the dog. Ultrasonographic analyses demonstrated variable degrees of anteroseptal dyskinesia and akinesia in all sheep, but in no dogs. Data two months after coronary artery ligation showed significant increases in central venous pressure, pulmonary artery pressure, and PACWP in the sheep, but not in the dog. Left ventricular end-diastolic dimension and left ventricular end-systolic dimension in ultrasonographic studies were also increased only in the sheep. Pathologically, the well-demarcated thin-walled transmural anteroseptal infarcts with chamber enlargement were clearly seen in all specimens of sheep, and only-mild-to-moderate chamber enlargements with endocardial fibrosis were observed in the dog hearts. In conclusion, this study confirms that the dog is not a suitable model for myocardial infarction with failure by coronary artery ligation despite negligent operative mortality, when compared directly with an ovine model.

scholarly journals Mitigation of the progression of heart failure with sildenafil involves inhibition of RhoA/Rho-kinase pathway

2011 ◽  
Vol 300 (6) ◽  
pp. H2272-H2279 ◽  
Author(s):  
Vinh Q. Chau ◽  
Fadi N. Salloum ◽  
Nicholas N. Hoke ◽  
Antonio Abbate ◽  
Rakesh C. Kukreja
Keyword(s):  
Heart Failure ◽  
Coronary Artery ◽  
Rho Kinase ◽  
Inhibitory Effect ◽  
Left Ventricular ◽  
Coronary Artery Ligation ◽  
Artery Ligation ◽  
Saline Treatment ◽  
Kinase Pathway ◽  
Fractional Shortening

Chronic inhibition of phosphodiesterase-5 with sildenafil immediately after permanent occlusion of the left anterior descending coronary artery was shown to limit ischemic heart failure (HF) in mice. To mimic a more clinical scenario, we postulated that treatment with sildenafil beginning at 3 days post-myocardial infarction (MI) would also reduce HF progression through the inhibition of the RhoA/Rho-kinase pathway. Adult male ICR mice with fractional shortening < 25% at day 3 following permanent left anterior descending coronary artery ligation were continuously treated with either saline (volume matched, ip, 2 times/day) or sildenafil (21 mg/kg, ip, 2 times/day) for 25 days. Echocardiography showed fractional shortening preservation and less left ventricular end-diastolic dilatation with sildenafil treatment compared with saline treatment at 7 and 28 days post-MI ( P < 0.05). Both fibrosis and apoptosis, determined by Masson's trichrome and terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL), respectively, were attenuated in the sildenafil-treated mice ( P < 0.05 vs. saline). Western blot analysis showed enchanced Bcl-2-to-Bax ratio with sildenafil treatment ( P < 0.05 vs. saline). Activity assay showed sildenafil-mediated PKG activation 1 day after treatment ( P < 0.05 vs. sham and saline). PKG activation was associated with sildenafil-mediated inhibition of Rho kinase ( P < 0.05) compared with saline treatment, whereas PKG inhibition with KT-5823 abolished this inhibitory effect of sildenafil. In conclusion, for the first time, our findings show that chronic sildenafil treatment, initiated at 3 days post-MI, attenuates left ventricular dysfunction independent of its infarct-sparing effect, and this cardioprotection involves the inhibition of the RhoA/Rho-kinase pathway. Sildenafil may be a promising therapeutic tool for advanced HF in patients.

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

Molecules ◽  
2019 ◽  
Vol 24 (2) ◽  
pp. 270 ◽  
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.

Abstract 3659: High-Mobility Group Box 1 Restores Cardiac Dysfunction after Myocardial Infarction in Transgenic Mice

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Tatsuro Kitahara ◽  
Yasuchika Takeishi ◽  
Tetsuro Shishido ◽  
Satoshi Suzuki ◽  
Shigehiko Kato ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Coronary Artery ◽  
Cardiac Dysfunction ◽  
Nuclear Dna ◽  
Inflammatory Responses ◽  
High Mobility ◽  
Left Ventricular ◽  
High Mobility Group ◽  
Coronary Artery Ligation ◽  
Artery Ligation

High-mobility group box 1 (HMGB1) is a nuclear DNA-binding protein and is released from necrotic cells, inducing inflammatory responses and promoting tissue repair and angiogenesis. To test the hypothesis that HMGB1 enhances angiogenesis and restores cardiac dysfunction after myocardial infarction, we generated transgenic mouse with cardiac specific overexpression of HMGB1 (HMGB1-Tg) using α-myosin heavy chain (MHC) promoter. The left anterior descending coronary artery was ligated in HMGB1-Tg and wild-type littermate (Wt) mice. After coronary artery ligation, HMGB1 was released into circulation from the necrotic cardiomyocytes of HMGB1 overexpressing hearts. The size of myocardial infarction was smaller in HMGB1-Tg than in Wt mice (figure ). Echocardiography and cardiac catheterization demonstrated that cardiac remodeling and dysfunction after myocardial infarction were prevented in HMGB1-Tg mice compared to Wt mice. Furthermore, survival rate after myocardial infarction in HMGB1-Tg mice was higher than that in Wt mice (figure ). Immunohistochemical staining revealed that capillary and arteriole formations after myocardial infarction were enhanced in HMGB1-Tg mice. We demonstrated the first in vivo evidence that HMGB1 enhances angiogenesis, restores cardiac dysfunction, and improves survival after myocardial infarction. These results may provide a novel therapeutic approach for left ventricular dysfunction after myocardial infarction.

Na+/H+ exchange inhibition reduces hypertrophy and heart failure after myocardial infarction in rats

2001 ◽  
Vol 280 (2) ◽  
pp. H738-H745 ◽  
Author(s):  
Keiji Kusumoto ◽  
James V. Haist ◽  
Morris Karmazyn
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Coronary Artery ◽  
Hydrogen Exchange ◽  
Diastolic Pressure ◽  
Control Diet ◽  
Left Ventricular ◽  
Coronary Artery Ligation ◽  
Artery Ligation ◽  
Large Infarct

We investigated the effect of sodium/hydrogen exchange inhibition (NHE-1) on hypertrophy and heart failure after coronary artery ligation (CAL) in the rat. Animals were subjected to occlusion (or sham) of the left main coronary artery and immediately administered a control diet or one consisting of the NHE-1 inhibitor cariporide for 13–15 wk. Hearts were separated by small [≤30% of left ventricle (LV)] and large (>30% of LV) infarcts. CAL depressed change in left ventricular increase in pressure over time (LV +dP/d t) in small and large infarct groups by 18.8% ( P < 0.05) and 34% ( P < 0.01), respectively, whereas comparative values for the cariporide groups were 8.7% (not significant) and 23.1% ( P < 0.01), respectively. LV end-diastolic pressure was increased by 1,225% in the control large infarct group but was significantly reduced to 447% with cariporide. Cariporide also significantly reduced the degree of LV dilation in animals with large infarcts. Hypertrophy, defined by tissue weights and cell size, was reduced by cariporide, and shortening of surviving myocytes was preserved. Infarct sizes were unaffected by cariporide, and the drug had no influence on either blood pressure or the depressed inotropic response of infarcted hearts to dobutamine. These results suggest an important role for NHE-1 in the progression of heart failure after myocardial infarction.

Neurohormones in an ovine model of compensated postinfarction left ventricular dysfunction

2000 ◽  
Vol 278 (3) ◽  
pp. H731-H740 ◽  
Author(s):  
Miriam T. Rademaker ◽  
Vicky A. Cameron ◽  
Christopher J. Charles ◽  
Eric A. Espiner ◽  
M. Gary Nicholls ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Coronary Artery ◽  
Ejection Fraction ◽  
Natriuretic Peptide ◽  
Left Ventricular Dysfunction ◽  
Ventricular Dysfunction ◽  
Plasma Concentrations ◽  
Left Ventricular ◽  
Coronary Artery Ligation ◽  
Artery Ligation

Clinical heart failure, often the result of myocardial infarction, may be preceded by a period of compensated left ventricular impairment. There is substantial need for an experimental model that reflects this human condition. In sheep, coronary artery ligation produced consistent left ventricular anteroapical myocardial infarctions resulting in chronic (5 wk), stable hemodynamic changes compared with sham controls, including reductions in ejection fraction (51 ± 2 vs. 30 ± 5%, P < 0.001), cardiac output (6.3 ± 0.2 vs. 5.1 ± 0.2 l/min, P< 0.01), and arterial pressure (93 ± 2 vs. 79 ± 3 mmHg, P< 0.001), and increases in cardiac preload (left atrial pressure, 3.3 ± 0.1 vs. 8.3 ± 1.3 mmHg, P < 0.001). These changes were associated with acute and sustained increases in plasma concentrations of atrial natriuretic peptide (ANP; 5 wk, 11 ± 2 vs. 27 ± 5 pmol/l, P < 0.001), brain natriuretic peptide (BNP; 3 ± 0.2 vs. 11 ± 2 pmol/l, P < 0.001), and amino-terminal pro-brain natriuretic peptide (NT-BNP; 17 ± 3 vs. 42 ± 12 pmol/l, P < 0.001). Significant correlations were observed between plasma levels of the natriuretic peptides (ANP, day 7 to week 5 samples; BNP and NT-BNP, day 1 to week 5samples) and changes in left ventricular volumes and ejection fraction. In contrast, renin activity, aldosterone, catecholamines, and endothelin were not chronically elevated postinfarction and were not related to indexes of ventricular function. Coronary artery ligation in sheep produces the pathological, hemodynamic, and neurohormonal characteristics of compensated left ventricular impairment secondary to myocardial infarction. Plasma concentrations of the cardiac natriuretic peptides are sensitive markers of left ventricular dysfunction. This is a reproducible model that reflects the clinical condition and should prove suitable for investigating the pathophysiology of, and experimental therapies in, early left ventricular dysfunction.

Normal contractions triggered by I Ca,L in ventricular myocytes from rats with postinfarction CHF

2002 ◽  
Vol 283 (3) ◽  
pp. H1225-H1236 ◽  
Author(s):  
Ivar Sjaastad ◽  
Janny Bøkenes ◽  
Fredrik Swift ◽  
J. Andrew Wasserstrom ◽  
Ole M. Sejersted
Keyword(s):  
Heart Failure ◽  
Congestive Heart Failure ◽  
Coronary Artery ◽  
Sarcoplasmic Reticulum ◽  
Ventricular Myocytes ◽  
Cardiac Contractility ◽  
Left Ventricular ◽  
Coronary Artery Ligation ◽  
Artery Ligation ◽  
Fractional Shortening

Attenuated L-type Ca2+ current ( I Ca,L), or current-contraction gain have been proposed to explain impaired cardiac contractility in congestive heart failure (CHF). Six weeks after coronary artery ligation, which induced CHF, left ventricular myocytes from isoflurane-anesthetized rats were current or voltage clamped from −70 mV. In both cases, contraction and contractility were attenuated in CHF cells compared with cells from sham-operated rats when cells were only minimally dialyzed using high-resistance microelectrodes. With patch pipettes, cell dialysis caused attenuation of contractions in sham cells, but not CHF cells. Stepping from −50 mV, the following variables were not different between sham and CHF, respectively: peak I Ca,L (4.5 ± 0.3 vs. 3.8 ± 0.3 pApF−1 at 23°C and 9.4 ± 0.5 vs. 8.4 ± 0.5 pApF−1 at 37°C), the bell-shaped voltage-contraction relationship in Cs+ solutions (fractional shortening, 15.2 ± 1.0% vs. 14.3 ± 0.7%, respectively, at 23°C and 7.5 ± 0.4% vs. 6.7 ± 0.5% at 37°C) and the sigmoidal voltage-contraction relationship in K+ solutions. Caffeine-induced Ca2+ release and sarcoplasmic reticulum Ca2+-ATPase-to-phospholamban ratio were not different. Thus CHF contractions triggered by I Ca,L were normal, and the contractile deficit was only seen in undialyzed cardiomyocytes stimulated from −70 mV.

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