Abstract 48: Differentiation of Moderate and Severe Ischemic Heart Failure by Invasive and Non-invasive Assessments of Diastolic Function in a Rat Model of Chronic Heart Failure

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Saffie Mohran ◽  
Jordan Lancaster ◽  
Pablo Sanchez ◽  
Steven Goldman ◽  
Elizabeth Juneman

Background: This work is designed to determine if specific left ventricle (LV) pressure-volume relations, hemodynamic, and echo derived parameters of diastolic function are able to separate severe from moderate CHF in rats with left coronary artery occlusion. Hypothesis: Echocardiographic indices of diastolic function, end-diastolic pressure (EDP), dead volume, stiffness constants (k), and pressure volume relations predict the severity of CHF in infarcted rats. Methods: Male Sprague Dawley rats (N=14) were randomized to undergo left coronary artery ligation or sham operation. Echocardiography was performed at 3 and 6 weeks post coronary ligation. The rats were categorized into moderate or severe CHF according to their LVEDP at 6 weeks post ligation. Invasive hemodynamic measurements with solid state micro manometer pressure catheters as well as diastolic pressure-volume relation values were obtained at the 6 week end point. Results: Moderate and severe CHF rats had significantly (P<0.05) elevated left ventricular (LV) end-diastolic pressure (LV EDPs), prolonged time constants of LV relaxation (tau), and decreased peak development pressures. When moderate versus severe CHF rats were separated based on LV EDP, early diastolic anterior wall radial relaxation velocity as well as e’, and E/e’ had strong correlations with invasive hemodynamic measurements of diastolic functions. There was a trend towards decreased compliance as measured by stiffness constants in severe heart failure group. Differences (P<0.05) in dead volume, mean arterial pressure (MAP), tau, and ejection fraction (EF) were also displayed. End diastolic pressure-volume analyses illustrated significant differences in plot positioning and curvature. Conclusion: While it is possible to separate rats with moderate and severe CHF in the rat coronary artery ligation model, the separation is not simply based on a specific EF value. This work may be useful in deciding whether there is a differential effect of new treatments for severe versus moderate CHF.

2001 ◽  
Vol 280 (2) ◽  
pp. H738-H745 ◽  
Author(s):  
Keiji Kusumoto ◽  
James V. Haist ◽  
Morris Karmazyn

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.


Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Ana Carolina M Omoto ◽  
Fábio N Gava ◽  
Mauro de Oliveira ◽  
Carlos A Silva ◽  
Rubens Fazan ◽  
...  

Myocardium infarction (MI) elicited by coronary artery ligation (CAL) is commonly used to induce chronic heart failure (HF) in rats. However, CAL shows high mortality rates. Given that ischemia-reperfusion (IR) may cause the development of HF, this approach may be useful for obtaining a model of HF with low mortality rates. Therefore, it was compared the model of CAL vs. IR in rats, evaluating the mortality and cardiac morphological and functional aspects. The IR consisted of 30 minutes of cardiac ischemia. Wistar rats were assigned into three groups: CAL: n=18; IR: n=7; SHAM (fictitious IR): n=7. After four weeks of CAL, the subjects were evaluated by echocardiography and ventriculography as well. The statistical analysis consisted of ANOVA combined with Tukey’s posthoc test (p<0.05). There were no deaths in the IR and SHAM groups, whereas in the CAL group the mortality rate was 33.33% (6 out of 18). In the CAL group echocardiography showed increased left ventricular (LV) cavity during systole (8.3 ± 1mm) and diastole (10.5 ± 1mm); decreased LV free wall during systole (1.4 ± 0.5 mm); increased left atrium/aorta (2.3 ± 0.4) ratio. These changes were not significant in IR (4.8 ± 0.5mm, 7.6 ± 0.6mm, 2.6 ± 0.3 mm, 1.6 ± 0.2) and SHAM (4.6 ± 0.6 mm, 7.7 ± 0.8mm, 2.8 ± 0.4mm, 1.5 ± 0.2) groups. There was also the reduction in the ejection fraction in the CAL group (41 ± 12 %) when compared with IR (65 ± 9%) and SHAM (69 ± 7%) groups. The tissue Doppler analysis from the lateral mitral annulus showed reduction in E′ in CAL (-29 ± 8 mm/s) and IR (-31± 9 mm/s) groups when compared with the SHAM (-48 ± 11 mm/s) group. The ventriculography in the CAL group showed smaller maximum dP/dt (6519 ± 1062) and greater end-diastolic pressure (33 ± 8 mmHg) when compared with IR (8716 ± 756 mmHg/s; 9 ± 9 mmHg) and SHAM (7989 ± 1230 mmHg/s; 9 ± 7 mmHg) groups. The CAL group presented transmural infarct size of 40% of the left ventricular wall, measured under histopathological examination. In conclusion, IR for 30 minutes caused only small changes in LV diastolic function, assessed by tissue Doppler; however, the IR was not effective for promoting HF, as observed with CAL. Thus, it is possible that prolonged IR is necessary for promoting significant HF in rats.


2011 ◽  
Vol 300 (6) ◽  
pp. H2272-H2279 ◽  
Author(s):  
Vinh Q. Chau ◽  
Fadi N. Salloum ◽  
Nicholas N. Hoke ◽  
Antonio Abbate ◽  
Rakesh C. Kukreja

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.


2017 ◽  
Vol 313 (2) ◽  
pp. H275-H282 ◽  
Author(s):  
Jiqiu Chen ◽  
Delaine K. Ceholski ◽  
Lifan Liang ◽  
Kenneth Fish ◽  
Roger J. Hajjar

Low reliability and reproducibility in heart failure models are well established. The purpose of the present study is to explore factors that affect model consistency of myocardial infarction (MI) in mice. MI was induced by left coronary artery (LCA) ligation. The coronary artery was casted with resin and visualized with fluorescent imaging ex vivo. LCA characteristics and MI size were analyzed individually in each animal, and MI size was correlated with left ventricular (LV) function by echocardiography. Coronary anatomy varies widely in mice, posing challenges for surgical ligation and resulting in inconsistent MI size postligation. The length of coronary arterial trunk, level of bifurcation, number of branches, and territory supplied by these branches are unique in each animal. When the main LCA trunk is ligated, this results in a large MI, but when a single branch is ligated, MI size is variable due to differing levels of LCA ligation and area supplied by the branches. During the ligation procedure, nearly 40% of LCAs are not grossly visible to the surgeon. In these situations, the surgeon blindly sutures a wider and deeper area of tissue in an attempt to catch the LCA. Paradoxically, these situations have greater odds of resulting in smaller MIs. In conclusion, variation in MI size and LV function after LCA ligation in mice is difficult to avoid. Anatomic diversity of the LCA in mice leads to inconsistency in MI size and functional parameters, and this is independent of potential technical modifications made by the operator. NEW & NOTEWORTHY In the present study, we demonstrate that left coronary artery diversity in mice is one of the primary causes of variable myocardial infarction size and cardiac functional parameters in the left coronary artery ligation model. Recognition of anatomic diversity is essential to improve reliability and reproducibility in heart failure research.


2004 ◽  
Vol 287 (5) ◽  
pp. H2049-H2053 ◽  
Author(s):  
Eric E. Morgan ◽  
Michael D. Faulx ◽  
Tracy A. McElfresh ◽  
Theodore A. Kung ◽  
Michael S. Zawaneh ◽  
...  

The rat infarct model is widely used in heart failure research, but few echocardiographic indexes of left ventricular (LV) function are validated in this model. Accordingly, the objective of this study was to validate a 13-segment LV wall motion score index (WMSI) and the myocardial performance index (MPI) in infarcted rats. Twenty-nine male Wistar rats underwent left coronary artery ligation or sham operation and were evaluated with two-dimensional and Doppler flow echocardiography 8 wk later. After echocardiography, invasive indexes were obtained using a high-fidelity catheter. WMSI and MPI were correlated with the invasive and noninvasive measurements of LV function. WMSI and MPI significantly correlated directly with end-diastolic pressure ( r = 0.72 and 0.42 for WMSI and MPI, respectively) and the time constant of isovolumic relaxation ( r = 0.68 and 0.48) and inversely with peak rate of rise of LV pressure (+dP/d t; r = −0.68 and −0.50), peak rate of decline in LV pressure ( r = −0.57 and −0.44), LV developed pressure ( r = −0.58 and −0.42), area fractional shortening ( r = −0.85 and −0.53), and cardiac index ( r = −0.74 and −0.74). Stepwise linear regression analyses revealed that LV end-diastolic pressure, +dP/d t, area fractional shortening, and cardiac index were independent determinants of WMSI ( r = 0.994) and that cardiac index and +dP/d t were independent determinants of MPI ( r = 0.781). We conclude that the 13-segment WMSI and MPI are reproducible and correlate strongly with established echocardiographic and invasive indexes of systolic and diastolic function. These findings support the use of WMSI and MPI as indexes of global LV function in the rat infarction model of heart failure.


2002 ◽  
Vol 283 (3) ◽  
pp. H1225-H1236 ◽  
Author(s):  
Ivar Sjaastad ◽  
Janny Bøkenes ◽  
Fredrik Swift ◽  
J. Andrew Wasserstrom ◽  
Ole M. Sejersted

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.


1996 ◽  
Vol 271 (3) ◽  
pp. H850-H859 ◽  
Author(s):  
M. A. Denvir ◽  
N. G. MacFarlane ◽  
D. J. Miller ◽  
S. M. Cobbe

Cardiac sarcoplasmic reticulum (SR) Ca(2+)-loading ability was assessed in a coronary artery ligation model of heart failure. Heart failure was produced in New Zealand White rabbits by ligation of the left marginal coronary artery. Sham-operated animals were used as controls. After hemodynamic and echocardiographic assessment 8 wk after coronary ligation, a free-running trabecula was isolated from the left or right ventricle, mounted for isometric tension measurement, and permeabilized with the chemical skinning agent saponin, leaving the SR functionally intact. The SR was Ca2+ loaded by exposure of the preparation to a mock intracellular solution with a Ca2+ concentration ([Ca2+]) of 150-300 nM. The amplitude of the caffeine-induced contracture was used as a measure of Ca2+ loaded by the SR. The same preparation was then treated with Triton X-100 to disrupt all cell membranes, and Ca2+ sensitivity inverted question markexpressed as [Ca2+] required to produce 50% of maximal activation (pCa50) inverted question mark of isometric tension production and maximum Ca2+ activated force (Cmax) were measured. Ligated animals demonstrated enhanced SR Ca(2+)-loading ability that correlated with the degree of left ventricular dysfunction. Enhanced SR Ca2+ loading was associated with evidence of SR Ca2+ overload revealed as spontaneous tension oscillations. Cmax and pCa50 were not significantly different from controls. Increased SR Ca(2+)-loading ability may predispose the SR to Ca2+ overload and could contribute to both contractile dysfunction and arrhythmogenesis in heart failure.


2000 ◽  
Vol 278 (1) ◽  
pp. H300-H304 ◽  
Author(s):  
Hiroyuki Yoshida ◽  
Morris Karmazyn

Na+/H+ exchange (NHE) represents a major mechanism for intracellular pH regulation, particularly in the ischemic myocardium. NHE has also been shown to be important in the regulation of cell proliferation and growth. We examined whether inhibition of NHE results in an attenuation of early postinfarction myocyte remodeling responses in the rat. Male Sprague-Dawley rats were randomized to receive either a control diet or an identical diet supplemented with the NHE inhibitor cariporide. After 1 wk, animals were anesthetized, subjected to ligation of the left main coronary artery, and maintained for an additional week, after which time they were anesthetized and intraventricular pressures were obtained. Hearts were removed, and myocytes were isolated to obtain cell dimensions and determine the response to isoproterenol. Body, heart, and lung weights were obtained. Coronary artery ligation in control animals resulted in a significant elevation in left ventricular end-diastolic pressure, as well as increased heart weight- and lung weight-to-body weight ratios, both of which were abrogated by cariporide. Cell length and area significantly increased by 14 and 19.2%, respectively, whereas cell width increased by 4.1% ( P> 0.05). These cells exhibited a significant hyporesponsiveness to the positive inotropic responses to isoproterenol at the lower drug concentrations (3 and 10 nM). A <1% dimensional change occurred in myocytes from cariporide-fed animals, and the hyporesponse to isoproterenol was reversed. Cariporide had no effect on infarct size or blood pressure. These studies suggest that the early adaptive hypertrophic response of surviving myocytes is dependent on NHE activity. As such, it is attractive to suggest that NHE inhibition could be an effective therapeutic strategy for prevention of postinfarction remodeling, independent of infarct size or afterload reduction.


PEDIATRICS ◽  
1967 ◽  
Vol 40 (3) ◽  
pp. 320-328
Author(s):  
Henry R. Wagner ◽  
Alexander S. Nadas ◽  
Paul G. Hugenholtz

The follow-up of two infants subjected to ligation of an anomalous left coronary artery at its insertion in the pulmonary artery, are presented. Both patients are essentially asymptomatic, one 7 years and the other 2 years postoperatively. Mitral regurgitation, a dominant feature in both infants preoperatively, disappeared some months after coronary artery ligation. A large preoperative atrial left-to-right shunt, secondary to mitral regurgitation and disappearing postoperatively, masked the presence of the shunt into the pulmonary artery in one patient. Although both patients are doing extremely well clinically, evidence of appreciable residual cardiac damage is present in the electrocardiogram, in the chest x-ray, at cardiac catheterization, and in the left ventricular volume studies of one patient.


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