Abstract 402: Vitamin C Deficiency Impairs Cardiac Function and Post-infarction Survival in the Mouse

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Adolfo G Mauro ◽  
Donatas Kraskauskas ◽  
Bassem M Mohammed ◽  
Bernard J Fisher ◽  
Eleonora Mezzaroma ◽  
...  
Keyword(s):  
Vitamin C ◽  
Cardiac Function ◽  
Diastolic Function ◽  
Left Ventricular ◽  
Coronary Artery Ligation ◽  
Artery Ligation ◽  
Additional Group ◽  
Gulonolactone Oxidase ◽  
Low Levels ◽  
Systolic And Diastolic Function

Introduction: L-gulonolactone oxidase (Gulo) is the rate limiting enzyme for Vitamin C (VitC) biosynthesis. Humans rely on dietary VitC for collagen synthesis, extracellular matrix formation, and tissue regeneration. VitC deficiency is an unrecognized condition and its role in cardiac homeostasis and post-acute myocardial infarction (AMI) remodeling is unknown. Hypothesis: Low levels of VitC impair cardiac function and tissue repair following AMI. Methods: Adult male Gulo -/- knockout mice (C57BL6 background, N=8) and control C57BL (N=8), which are able to synthesize VitC were used. VitC deficiency was maintained supplying low levels of VitC (30mg/l) to Gulo -/- mice in drinking water. Mice underwent M-mode and Doppler echocardiography to measure left ventricular (LV) diameters and wall thicknesses, fractional shortening (FS), E and A waves, E/A ratio, isovolumetric relaxation time (IRT) and myocardial performance index (MPI). Experimental AMI was induced by coronary artery ligation for 7 days. An additional group of Gulo -/- were mice supplemented with physiological levels of VitC (330 mg/l) and underwent AMI. Results: VitC deficient Gulo -/- mice exhibited significantly reduced LV wall thicknesses, reduced FS, and impaired diastolic function, measured as significantly reduced E/A ratio and longer IRT (Panel A, B & C). Following AMI, 100% (8/8) of deficient Gulo -/- mice died within 5 days. Supplementation with physiological levels of VitC significantly improved survival after AMI (Panel D). Conclusion: VitC deficiency impairs systolic and diastolic function. Moreover, VitC is critical for the post-AMI survival.

Differing cardioprotective efficacy of the Na+/Ca2+ exchanger inhibitors SEA0400 and KB-R7943

2003 ◽  
Vol 284 (3) ◽  
pp. H903-H910 ◽  
Author(s):  
William P. Magee ◽  
Gayatri Deshmukh ◽  
Michael P. Deninno ◽  
Jill C. Sutt ◽  
Justin G. Chapman ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Infarct Size ◽  
Recovery Of Function ◽  
Left Ventricular ◽  
Coronary Artery Ligation ◽  
Negative Effects ◽  
Artery Ligation ◽  
Regional Ischemia ◽  
Developed Pressure ◽  
Postischemic Recovery

KB-R7943 and SEA0400 are Na+/Ca2+ exchanger (NCX) inhibitors with differing potency and selectivity. The cardioprotective efficacy of these NCX inhibitors was examined in isolated rabbit hearts (Langendorff perfused) subjected to regional ischemia (coronary artery ligation) and reperfusion. KB-R7943 and SEA0400 elicited concentration-dependent reductions in infarct size (SEA0400 EC50: 5.7 nM). SEA0400 was more efficacious than KB-R7943 (reduction in infarct size at 1 μM: SEA0400, 75%; KB-R7943, 40%). Treatment with either inhibitor yielded similar reductions in infarct size whether administered before or after regional ischemia. SEA0400 (1 μM) improved postischemic recovery of function (±dP/d t), whereas KB-R7943 impaired cardiac function at ≥1 μM. At 5–20 μM, KBR-7943 elicited rapid and profound depressions of heart rate, left ventricular developed pressure, and ±dP/d t. Thus the ability of KB-R7943 to provide cardioprotection is modest and limited by negative effects on cardiac function, whereas the more selective NCX inhibitor SEA0400 elicits marked reductions in myocardial ischemic injury and improved ±dP/d t. NCX inhibition represents an attractive approach for achieving clinical cardioprotection.

Blockade of brain mineralocorticoid receptors or Na+ channels prevents sympathetic hyperactivity and improves cardiac function in rats post-MI

2005 ◽  
Vol 288 (5) ◽  
pp. H2491-H2497 ◽  
Author(s):  
Bing S. Huang ◽  
Frans H. H. Leenen
Keyword(s):  
Cardiac Function ◽  
Left Ventricular ◽  
Coronary Artery Ligation ◽  
Mineralocorticoid Receptors ◽  
Artery Ligation ◽  
Sympathetic Hyperactivity ◽  
Air Jet ◽  
Baroreflex Function ◽  
Adrenoceptor Agonist ◽  
The Brain

In rats post-myocardial infarction (MI), sympathetic hyperactivity can be prevented by blockade of brain mineralocorticoid receptors (MR). Stimulatory responses to central infusion of aldosterone can be blocked by benzamil and therefore appear to be mediated via Na+ channels, presumably epithelial Na+ channels (ENaC), in the brain. To evaluate this concept of endogenous mineralocorticoids in Wistar rats post-MI, we examined effects of blockade of MR and Na+ channels in the brain. At 3 days after coronary artery ligation, intracerebroventricular infusions were started with spironolactone (400 ng·kg−1·h−1) or its vehicle, or with benzamil (4 μg·kg−1·h−1) or its vehicle, using osmotic minipumps. Rats with sham ligation served as control. After 4 wk, in conscious rats, mean arterial pressure, heart rate, and renal sympathetic nerve activity were recorded at rest and in response to air-jet stress, intracerebroventricular injection of the α2-adrenoceptor agonist guanabenz, and intravenous infusion of phenylephrine and nitroprusside for baroreflex function. MI size was similar among the four groups of rats (∼31%). In rats treated post-MI with vehicles, cardiac function was decreased, sympathetic reactivity was enhanced, and baroreflex function was impaired. Blockade of brain Na+ channels or brain MR similarly prevented sympathetic hyperactivity and impairment of baroreflex function and improved cardiac function. These findings suggest that in rats post-MI, increased binding of endogenous agonists to MR increases ENaC activity in the brain and thereby leads to sympathetic hyperactivity and progressive left ventricular dysfunction.

Mesenchymal Stem Cell Injection After Myocardial Infarction Improves Myocardial Compliance

2007 ◽  
Author(s):  
Dennis Discher ◽  
Adam Engler
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
Cellular Therapy ◽  
Human Mesenchymal Stem Cells ◽  
Left Ventricular ◽  
Left Ventricular Geometry ◽  
Coronary Artery Ligation ◽  
Artery Ligation ◽  
Functional Benefit ◽  
Myocardial Elasticity

Cellular therapy for myocardial injury has improved ventricular function in both animal and clinical studies, though the mechanism of benefit is unclear. This study was undertaken to examine the effects of cellular injection after infarction on myocardial elasticity. Coronary artery ligation of Lewis rats was followed by direct injection of human mesenchymal stem cells (MSC) into the acutely ischemic myocardium. Two weeks post-infarct, myocardial elasticity was mapped by atomic force microscopy. MSC-injected hearts near the infarct region were two-fold stiffer than myocardium from non-infarcted animals but softer than myocardium from vehicle-treated infarcted animals. After eight weeks, the following variables were evaluated: MSC engraftment and left ventricular geometry by histologic methods; cardiac function with a pressure-volume conductance catheter; myocardial fibrosis by Masson trichrome staining; vascularity by immunohistochemistry; and apoptosis by TUNEL assay. The human cells engrafted and expressed a cardiomyocyte protein but stopped short of full differentiation and did not stimulate significant angiogenesis. MSC-injected hearts showed significantly less fibrosis than controls, as well as less left ventricular dilation, reduced apoptosis, increased myocardial thickness, and preservation of systolic and diastolic cardiac function. In summary, MSC injection after myocardial infarction did not regenerate contracting cardiomyocytes but reduced the stiffness of the subsequent scar and attenuated post-infarction remodeling, preserving some cardiac function. Improving scarred heart muscle compliance could be a functional benefit of cellular cardiomyoplasty.

Abstract 17953: A Novel Biodegradable Cardiac Support Device for Treating Ischemic Cardiomyopathy in Canine Heart

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Mutsunori Kitahara ◽  
Shigeru Miyagawa ◽  
Satsuki Fukushima ◽  
Akima Harada ◽  
Atsuhiro Saito ◽  
...  
Keyword(s):  
Coronary Artery ◽  
Diastolic Function ◽  
Control Group ◽  
Coronary Artery Ligation ◽  
Canine Heart ◽  
Biodegradable Material ◽  
Artery Ligation ◽  
Support Device ◽  
Systolic And Diastolic Function ◽  
Cardiac Support Device

Introduction: The non-biodegradable material-made “Corecap” type cardiac support device reportedly reduces diastolic wall stress and consequently improves systolic cardiac function. However, the efficacy was inconsistent in the clinical studies possibly due to device-related impairment of diastolic cardiac function. We herein hypothesized that use of biodegradable material for the cardiac support device may contribute to improvement in both systolic and diastolic function of the failing heart. Methods: Polyglycolic acid and Polyethyleneterephtalate were used to prepare biodegradable (n=6) and non-biodegradable (n=5) cardiac support device, respectively. Both cardiac support devices were structurally designed to cover the entire ventricles of the 12-month-aged Beagle canine heart that was subjected to anterior coronary artery ligation at 1 week prior to the implantation. Sham operation was performed in coronary artery-ligated canines for control (n=7). Results: At 12 weeks after coronary artery ligation, the biodegradable group showed a greater recovery of ejection fraction than the non-biodegradable and the control group (39 ± 4% vs. 31 ± 4% vs. 30± 3, respectively, P <0.05), assessed by multi-detector computed tomography. Echocardiographically, diastolic function evaluated by Doppler-derived mitral deceleration time at 12 weeks was significantly greater in the biodegradable group (108 ± 18 msec) than the non-biogradable group (70 ± 13 msec, P<0.05). Thickness of connective tissues around the epicardium was significantly less in the biodegradable groups than the non-biodegradable group at 12 weeks. Histologically, fibrosis in the infarct area was significantly less in the treatment groups than the control group. Conclusions: Implantation of cardiac support device made of biodegradable material was effective in improvement of both systolic and diastolic function of the canine infarct heart for 12 weeks, compared with that of non-biodegradable material, warranting clinical studies using biodegradable cardiac support device.

Abstract 2673: Myoblast Transplantation Improves Cardiac Function Whether the Cells are Implanted Early or Late After Coronary Ligation

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Patrick Farahmand ◽  
Richard D Weisel ◽  
Philippe Menasche ◽  
Ren-Ke Li
Keyword(s):  
Cardiac Function ◽  
Left Ventricular ◽  
Border Zone ◽  
Lv Function ◽  
Coronary Artery Ligation ◽  
Matrix Remodeling ◽  
Stroke Work ◽  
Artery Ligation ◽  
Skeletal Myoblasts ◽  
Myoblast Transplantation

Background: The inability of skeletal myoblasts to transdifferentiate into cardiomyocytes supports the hypothesis that their beneficial effects on cardiac function after a myocardial infarction (MI) are mediated by paracrine effects. In order to explore the role of the timing of cell therapy on the resultant angiogenesis and matrix remodeling, we compared the effects of myoblast transplantation early or late after MI. Methods: MI was generated in Lewis rats by coronary artery ligation. Skeletal myoblasts (5X10 6 ) or control media were injected into the scar and border zone either 5 days (early; n=33) or 30 days (late; n=29) after ligation. Function was assessed by echocardiography before transplantation (Tx), and 14 and 30 days thereafter. Invasive hemodynamics were measured with a Millar catheter at 30 days after Tx, following which explanted hearts were processed to assess LV volumes (computerized planimetry), fibrillar collagen (confocal microscopy), and myoblast engraftment, angiogenesis and extra-cellular matrix characteristics (immunohistochemistry). Results: Load-independent indices of left ventricular (LV) function (Emax, preload recruitable stroke work) were significantly increased in myoblast recipients compared with controls regardless of whether cells were implanted early (p=0.003, p=0.03, respectively) or late (p=0.003, p=0.0007, respectively) after MI. Changes in fractional shortening (by echocardiography) followed a similar pattern. These changes were associated with a significant reduction in LV volume (p=0.04, p=0.01 for early and late Tx groups vs. controls, respectively), and an increase in angiogenesis (p=0.02) whether the myoblasts were injected early or late after MI. The length and width of collagen fibers both in the scar and remote myocardium were also significantly increased (p<0.001) regardless of the timing of myoblast injection. Conclusions: The data suggest that myoblast transplantation improved cardiac function whether cells were injected early or late after MI. In each case, functional recovery was associated with enhanced angiogenesis, favourable effects on extracellular matrix remodeling, and improved LV geometry, supporting the paracrine hypothesis for myoblast transplantation.

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
Keyword(s):  
Heart Failure ◽  
Coronary Artery ◽  
Diastolic Function ◽  
Left Coronary Artery ◽  
Diastolic Pressure ◽  
Left Ventricular ◽  
Dead Volume ◽  
Coronary Artery Ligation ◽  
Artery Ligation ◽  
Hemodynamic Measurements

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.

Mesenchymal stem cell injection after myocardial infarction improves myocardial compliance

2006 ◽  
Vol 290 (6) ◽  
pp. H2196-H2203 ◽  
Author(s):  
Mark F. Berry ◽  
Adam J. Engler ◽  
Y. Joseph Woo ◽  
Timothy J. Pirolli ◽  
Lawrence T. Bish ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
Cellular Therapy ◽  
Human Mesenchymal Stem Cells ◽  
Left Ventricular ◽  
Left Ventricular Geometry ◽  
Coronary Artery Ligation ◽  
Artery Ligation ◽  
Functional Benefit ◽  
Myocardial Elasticity

Cellular therapy for myocardial injury has improved ventricular function in both animal and clinical studies, though the mechanism of benefit is unclear. This study was undertaken to examine the effects of cellular injection after infarction on myocardial elasticity. Coronary artery ligation of Lewis rats was followed by direct injection of human mesenchymal stem cells (MSCs) into the acutely ischemic myocardium. Two weeks postinfarct, myocardial elasticity was mapped by atomic force microscopy. MSC-injected hearts near the infarct region were twofold stiffer than myocardium from noninfarcted animals but softer than myocardium from vehicle-treated infarcted animals. After 8 wk, the following variables were evaluated: MSC engraftment and left ventricular geometry by histological methods, cardiac function with a pressure-volume conductance catheter, myocardial fibrosis by Masson Trichrome staining, vascularity by immunohistochemistry, and apoptosis by TdT-mediated dUTP nick-end labeling assay. The human cells engrafted and expressed a cardiomyocyte protein but stopped short of full differentiation and did not stimulate significant angiogenesis. MSC-injected hearts showed significantly less fibrosis than controls, as well as less left ventricular dilation, reduced apoptosis, increased myocardial thickness, and preservation of systolic and diastolic cardiac function. In summary, MSC injection after myocardial infarction did not regenerate contracting cardiomyocytes but reduced the stiffness of the subsequent scar and attenuated postinfarction remodeling, preserving some cardiac function. Improving scarred heart muscle compliance could be a functional benefit of cellular cardiomyoplasty.

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