Model Of Ischemic Heart Failure Research Articles

Noninvasive monitoring of cardiac function in a chronic ischemic heart failure model in the rat: Assessment with tissue Doppler and non-Doppler 2D strain echocardiography

ObjectivesFeasibility of noninvasive monitoring of cardiac function after surgically induced ischemic cardiomyopathy with tissue Doppler and non-Doppler 2D strain echocardiography in rats.BackgroundThe optimal method for quantitative assessment of global and regional ventricular function in rats with chronic heart failure for research purposes remains unclear.Methods20 rats underwent suture ligation of the left anterior descending coronary artery via a left thoracotomy to induce ischemic cardiomyopathy. Echocardiographic examination with estimation of left ventricular wall thickness, diameters, fractional shortening, ejection fraction, wall velocities as well as radial strain were performed before and 4 weeks after surgery.ResultsMean LVEF decreased from 70 ± 6% to 40 ± 8% (p < 0.0001) one month after the operation. LVEDD increased from 7 ± 1 mm to 9 ± 1 mm (p < 0.0001), systolic anterior velocity decreased from 0.79 ± 0.25 cm/s to 0.18 ± 0.19 cm/s (p < 0.0001). Radial 2D strain was significantly reduced after myocardial infarction of the septal (18.2 ± 6.6% vs 7.0 ± 5.9%, p < 0.001), anteroseptal (17.3 ± 5.2% vs 4.6 ± 3.0%, p < 0.0001), anterior (18.9 ± 5.9% vs 5.6 ± 2.5%, p < 0.0001), lateral (21.4 ± 4.9% vs 8.1 ± 3.5%, p < 0.0001) as well as posterior myocardial segments (19.3 ± 5.2% vs 15.4 ± 5.5%, p < 0.01). Inferior segments (19.2 ± 7.9% vs 17.8 ± 7.9%, ns) did not change at all.ConclusionIt is feasible to assess dimensions, global function, and regional contractility with echocardiography in rats suffering from chronic heart failure after myocardial infarction. Particularly regional function can be exactly evaluated if tissue Doppler and 2D strain is used.

234 Cardiac Transplantation Efficiency of Induced Pluripotent Stem Cells (iPS) Is Improved by a Fibrinogen Matrix in an Experimental Model of Ischemic Heart Failure

Limited success of cellular cardiomyoplasty has lately generated discussion regarding its effectiveness. We hypothesized that immediate cell loss after intramyocardial injection obscures significantly effectiveness of stem cell therapy. Fibrinogen is a commonly used viscose biomaterial in clinical practice and beneficial for cell survival in vitro. Since the currently most powerful regenerative cell source are induced pluripotent stem (iPS) cells, the aim of our study was to improve intramyocardial iPS cell retention with fibrinogen.

A porcine model of ischemic heart failure produced by intracoronary injection of ethyl alcohol

We have developed a porcine model of acute myocardial infarction (AMI) and ischemic heart failure by transcatheter intracoronary injection of ethyl alcohol and observed pathologic changes induced in the alcohol-injured coronary artery and infarcted myocardium. In a total of 12 female pigs, anteroseptal AMI was induced by transcatheter delivery of 1 mL of 99.9% ethyl alcohol using a 2.5 mm diameter over-the-wire balloon catheter in the left anterior descending artery (LAD). Another five pigs underwent the sham operation, and the differences in left ventricular (LV) dimension and LV ejection fraction between these pigs and those injected with ethyl alcohol were evaluated. Follow-up coronary and LV angiography, echocardiography and histopathology were performed at 4 weeks after the procedure. Myocardial SPECT using (201)Tl (and (99m)Tc-MIBI) and triphenyl tetrazolium chloride (TTC) stain were performed and compared. Procedure-related death occurred in two pigs with proximal LAD occlusion. Four pigs suffered from ventricular tachycardia, which converted to sinus rhythm by DC cardioversion. Follow-up coronary angiography at 4 weeks revealed persistent total occlusion in all pigs. Echocardiogram showed decreased apicoanteroseptal wall motion with an ejection fraction of 46.5 ± 3.3% and nonsignificantly changed LV dimensions. Myocardial SPECT revealed a perfusion defect in the apicoanterior wall in all subjects (percent area of the perfusion defect = 22.1 ± 2.50%). The percentage of myocardium not stained by TTC was 23.1 ± 2.25%. Histologic examination revealed severe fibrosis in the infarcted myocardium and massive thrombus with organization and calcification in the alcohol-injured coronary artery. The porcine model of AMI obtained by intracoronary alcohol injection provides a safe and reproducible method for the research and development of new therapeutic modalities for MI and end-stage heart failure.

A novel, innovative ovine model of chronic ischemic cardiomyopathy induced by multiple coronary ligations.

Heart failure is one of the fastest-growing epidemics worldwide in health care today. Although a wide variety of animal models exist to create chronic heart failure, there are few truly successful, reproducible models with ischemic dilation and mitral regurgitation. Six healthy sheep (36 ± 5 kg) underwent multiple, strategic coronary artery ligations on the left ventricle (LV). Six to eight ligations were performed transmurally on three of four segments of the LV: anterior, lateral, and posterior. Side branches of the left anterior descending and circumflex arteries were ligated to create multiple, patchy areas of myocardial infarction. Cardiac global and regional systolic function was assessed by echocardiography and cardiac magnetic resonance imaging (MRI). The extent, the characteristics, and the location of the myocardial infarction were qualitatively and quantitatively assessed by late gadolinium enhancement imaging. The overall mortality rate was 16.7% (1/6 animals). Animals who survived showed a significantly reduced ejection fraction (mean 60 ± 5% to 28 ± 7%; P < 0.05); additionally, two out of the remaining five (40%) animals developed mild to moderate mitral regurgitation quantified by cardiac MRI. Furthermore, each animal developed clinical signs of heart failure (tachycardia, dyspnea, and tachypnea) consistent with global, dilated cardiomyopathy noted on MRI. Creating and reproducing a model of global, ischemic cardiomyopathy with functional mitral regurgitation is an arduous task. We have developed a promising model of ischemic heart failure using multiple ligations, which mimics the sequelae of human cardiomyopathy. Our proposed model is highly effective, reproducible, and may be used for experimental research on heart failure (cardiac assist devices, heart transplant, etc.).

Electrically contractile tissue assembled from polymer nanofibers for myocardial tissue engineering enables systolic augmentation in an ischemic rat heart model

Introduction: For the past twelve years further development of myocardial tissue engineering by engineered heart tissue has been limited due to the use of neonatal rat cardiomyocytes in a non-perfused collagen matrix. Aim of our study was to introduce a novel electrically contractile tissue assembled from nanofibers into the field of myocardial tissue engineering and test the feasibility of systolic cardiac augmentation in an ischemic heart failure model.

Adjustment and Characterization of an Original Model of Chronic Ischemic Heart Failure in Pig

We present and characterize an original experimental model to create a chronic ischemic heart failure in pig. Two ameroid constrictors were placed around the LAD and the circumflex artery. Two months after surgery, pigs presented a poor LV function associated with a severe mitral valve insufficiency. Echocardiography analysis showed substantial anomalies in radial and circumferential deformations, both on the anterior and lateral surface of the heart. These anomalies in function were coupled with anomalies of perfusion observed in echocardiography after injection of contrast medium. No demonstration of myocardial infarction was observed with histological analysis. Our findings suggest that we were able to create and to stabilize a chronic ischemic heart failure model in the pig. This model represents a useful tool for the development of new medical or surgical treatment in this field.

On the Road to iPS Cell Cardiovascular Applications

See related article, pages 648–656 The ability to generate induced pluripotent stem (iPS) cells from somatic cells by the overexpression of a limited number of stem cell-related genes has generated great excitement and interest in the biomedical research community including cardiovascular researchers. The pioneering study by Yamanaka and colleagues showing that overexpression of Oct3/4 , Sox2 , Klf4 , and c-Myc could reprogram mouse fibroblasts to a pluripotent state similar to that of embryonic stem (ES) cells opened major new avenues of research.1 This epigenetic reprogramming was rapidly extrapolated to the human system using either the same combination of reprogramming factors or a slightly different combination of transgenes ( OCT4 , NANOG , SOX2 , LIN28 ).2–4 Like embryonic stem (ES) cells, iPS cells can be used for basic developmental biology research and also as a cell source to generate theoretically unlimited quantities of desired cell types such as cardiomyocytes. Such differentiated cells types can be used in a wide range of basic research studies and potentially in clinical applications, which not only include cellular therapies but also drug discovery and safety testing. One appealing aspect of human iPS cells compared to human ES cells is that they can be more readily generated without specialized expertise and access to human embryos, which also avoids the ethical challenges associated with human embryo research. Potentially the most powerful advantage of iPS cells over ES cells is that they can be generated from any patient to produce genetically identical pluripotent cells that can create human disease models or generate patient-specific cells for therapy. Already a number of iPS cell human disease models have been generated,5,6 and proof-of-principle iPS cellular therapies have been pioneered in mouse models.7–9 Despite the speed at which the iPS cell field is racing forward, we …

Direct epicardial shock wave therapy improves ventricular function and induces angiogenesis in ischemic heart failure

Direct application of low-energy unfocused shock waves induces angiogenesis in ischemic soft tissue. The potential effects of epicardial shock wave therapy applied in direct contact to ischemic myocardium are uncertain. For induction of ischemic heart failure in a rodent model, a left anterior descending artery ligation was performed in adult Sprague-Dawley rats. After 4 weeks, reoperation with (treatment group, n = 60) or without (control group, n = 60) epicardial shock wave therapy was performed. Low-energy shock waves were applied in direct contact with the infarcted myocardium (300 impulses at 0.38 mJ/m(2)). Additionally, healthy animals (n = 30) with normal myocardium were studied. Angiogenesis, ventricular function upregulation of growth factors, and brain natriuretic peptide levels were analyzed. Histologic analysis revealed significant angiogenesis 6 weeks (treatment group: 8.2 +/- 3.7 vs control group: 2.9 +/- 1.9 vessels per field, P = .016) and 14 weeks (treatment group: 7.1 +/- 3.1 vs control group: 3.2 +/- 1.8 vessels per field, P = .011) after shock wave treatment. In the treatment group ventricular function improved throughout the follow-up period (6 weeks: 37.4% +/- 9% [P < .001] and 14 weeks: 39.5% +/- 9% [P < .001]). No improvement of ventricular function was observed in the control group (6 weeks: 28.6% +/- 5% and 14 weeks: 21.4% +/- 5%). Rat brain natriuretic peptide 45 levels were lower in the treatment group compared with those in the control group 6 and 14 weeks after treatment. Vascular endothelial growth factor, Fms-related tyrosine kinase 1, and placental growth factor levels were upregulated after 24 and 48 hours and 7 days in the treatment group. No effects on healthy myocardium were observed. Direct epicardial low-energy shock wave therapy induces angiogenesis and improves ventricular function in a rodent model of ischemic heart failure.

Lentiviral Vector–mediated SERCA2 Gene Transfer Protects Against Heart Failure and Left Ventricular Remodeling After Myocardial Infarction in Rats

Reduced expression of the SERCA2 gene impairs the calcium-handling and contractile functions of the heart. We developed an SERCA2 gene transfer system using lentiviral vectors, and examined the long-term effect of SERCA2 gene transfer in the rat ischemic heart failure model. A lentiviral vector containing the SERCA2 gene was infused into a rat heart by hypothermic intracoronary delivery 2 weeks after myocardial infarction (MI). The transduction efficiency was approximately 40%. Six months after transduction, echocardiogram and pressure-volume measurements revealed that the SERCA2 gene transfer had significantly protected against left ventricular (LV) dilation, and had improved systolic and diastolic function, resulting in reduction in mortality rates. The brain natriuretic peptide mRNA level showed a significantly decrease and the phosphorylation level of serine residue of phospholamban (PLN) showed an increase in the Lenti-SERCA2-transduced heart. Further, DNA microarray analysis disclosed that SERCA2 gene transfer had increased cardioprotective gene expression and lowered the expression of genes that are known to exacerbate heart failure. The SERCA2 gene was successfully integrated into the host heart, induced favorable molecular remodeling, prevented LV geometrical remodeling, and improved the survival rate. These results suggest that a strategy to compensate for reduced SERCA2 gene expression by lentiviral vectors serves as a positive inotropic, lucitropic, and cardioprotective therapy for post-MI heart failure.

New Twist to the Role of the Renin-Angiotensin System in Heart Failure

The renin-angiotensin system has been shown to be upregulated in peripheral tissues, particularly the vasculature, in a number of different cardiovascular conditions. As well, many actions on the vasculature usually attributed to direct effects of angiotensin II (Ang II) are now known to be mediated at least in part by aldosterone.1,2 In the present issue, Yu et al3 demonstrate that components of the renin-angiotensin system (RAS) are upregulated in the brain in a model of ischemic heart failure in rats. They demonstrate that aldosterone is elevated in heart failure in the brain proportionately to the increase in the circulation. This increase results in mineralocorticoid receptor–mediated stimulation of hypothalamic angiotensin I-converting enzyme (ACE) and angiotensin type 1 (AT1) receptor mRNA and protein, enhanced reduced nicotinamide-adenine dinucleotide phosphate oxidase activity, and reactive oxygen species in the paraventricular nucleus. Activation of the renin-angiotensin system and its mediators leads to increased neuronal activity and sympathetic drive and elevated circulating levels of plasma norepinephrine. All of these effects were blocked in this model by intracerebroventricular administration of a mineralocorticoid receptor antagonist. They suggest that, whereas penetration of aldosterone into the brain correlates with plasma levels but …

Epicardial shock wave therapy induces neoangiogenesis and improves left ventricular function after myocardial infarction in pigs in vivo

Aims: Therapeutic options of ischemic heart failure are limited. Shock wave therapy (SWT) reportedly induces VEGF overexpression in ischemic myocardium. We hypothesized that epicardial SWT improves ventricular function in an experimental model of ischemic heart failure by inducing neoangiogenesis. Methods: Pigs were subdivided in 3 groups: unharmed myocardium with epicardial SWT (healthy control, n=2), infarcted myocardium with epicardial SWT (SWT-group, n=6) and infarcted myocardium without epicardial SWT (control, n=2). Four weeks following myocardial infarction (MI), epicardial SWT (300 impulses at 0.15 mJ/m2) was applied directly to the infarcted area in the healthy control and the SWT-group, controls were left untreated. Cardiac function was evaluated using echocardiography before MI, 4 weeks after MI and 4 weeks after SWT. Angiogenesis was evaluated 4 weeks after treatment by immunohistology with vonWillebrand Factor antibody, which was morphometried with Lucia software. Results: Compared to healthy controls (68±0.7%), left ventricular ejection fraction decreased in the SWT (43±2.5%, p<0.001) and control group (41±4.2%, p=0.012) 4 weeks after MI. After epicardial SWT, ejection fraction improved in the SWT-group as compared to 4 weeks after MI (62±9.1%, p=0.006), no improvement was observed in the control group (46±5%, p=0.126). As compared to healthy controls (69±1.4%) ejection fraction normalized in the SWT-group 4 weeks after SWT (p=0.358), it remained decreased in the control group (p=0.031). No adverse effects were observed. Conclusion: Epicardial SWT improves left ventricular function after myocardial infarction in pigs. It therefore seems to be an effective and safe therapeutic strategy for the treatment of ischemic heart disease.

Letter by Ly Regarding Article, “Direct Intramyocardial but Not Intracoronary Injection of Bone Marrow Cells Induces Ventricular Arrhythmias in a Rat Chronic Ischemic Heart Failure Model”

To the Editor: We read with great interest the article by Fukushima et al1 on arrhythmia induction after bone marrow cell–based therapy in a rat model of postinfarction heart failure. We congratulate the authors on a provocative study. Although their conclusion that intramyocardially injected bone marrow–derived cell clusters induce proarrhythmia effects is insightful, there remain issues raised by the authors that we feel merit further attention. First, further mechanistic insight might have been provided if intramyocardial injection had been explored differently. The …

Response to Letter Regarding Article, “Direct Intramyocardial but Not Intracoronary Injection of Bone Marrow Cells Induces Ventricular Arrhythmias in a Rat Chronic Ischemic Heart Failure Model”

We thank Dr Ly for his interest in our article.1 We, too, strongly believe that cell therapy as a treatment for heart failure requires further laboratory research to ensure its future success. It is likely that not only the injection site, but also the number and volume of injections and the number of cells injected, will influence therapeutic benefit …

Improvement of Cardiac Function With Parecoxib, A Cyclo-oxygenase-2 Inhibitor, in a Rat Model of Ischemic Heart Failure

To assess changes in cardiac function in animals with ischemic congestive heart failure (CHF) treated with a selective cyclo-oxygenase-2 (COX-2) inhibitor. In patients with CHF, COX-2 expression was associated with features of worsening failure. However, evidence of beneficial or detrimental functional effects of COX-2 inhibition in ischemic CHF is lacking. Thirty male Wistar rats underwent coronary ligation and were allowed to recover for 12 months. Five sham-operated animals were used as controls. After 12 months, six surviving animals underwent baseline echocardiogram to measure end-diastolic diameter (EDD), end-systolic diameters (ESD), fractional shortening (FS), and anterior and posterior diastolic and systolic wall thicknesses. The animals were thereafter treated by daily intraperitoneal parecoxib injections (0.75 mg/kg) for 7 days. On day 7, a repeat echocardiogram was performed. When compared to baseline, repeat echocardiography after 7 days of parecoxib treatment showed no changes in the EDD (9.4 +/- 0.4 mm vs. 9.4 +/- 0.3 mm, P = 0.9), a significant reduction of ESD (5.5 +/- 0.8 mm vs. 6.4 +/- 0.3 mm, P = 0.028), and a significant improvement in the FS (43 +/- 3% vs. 32 +/- 5%, P = 0.027). Improvement of FS was associated with a significant change in systolic thickness in the infarct zone (3.6 +/- 0.4 mm vs. 3.0 +/- 0.1 mm, P = 0.046), whereas no significant changes in systolic thickness in the remote area were observed. Administration of parecoxib in ischemic CHF provides functional improvement of the peri-infarct myocardium. This finding may prove useful in improving quality of life and, perhaps, survival in patients with ischemic heart disease.

Comparison of Cell Therapy and Cytokine Therapy for Functional Repair in Ischemic and Nonischemic Heart Failure

Although cell therapy shows great promise as a new therapeutic strategy for heart failure, its precise mechanisms remain unclear. Furthermore, the advantages of cell therapy over conventional cytokine therapy have yet to be clarified. This study was designed to compare the functional improvement achieved by cell therapy and cytokine therapy in both ischemic and nonischemic heart failure experimental models. Ischemic heart failure was induced by ligating the left anterior descending artery, and nonischemic heart failure was induced by an IP injection of doxorubicin, respectively, in mice. After establishing the heart failure models, mice were randomly given a single intramyocardial injection of 2 x 10(5) c-kit-positive bone marrow stem cells (cell therapy), hepatic growth factor (cytokine therapy), or PBS injection only (control). In the ischemic heart failure model, both cell therapy and cytokine therapy increased the vessel density significantly, inhibited apoptosis of myocytes, and decreased the fibrotic area in the ischemic myocardium, which resulted in a significant increase in the survival rate and enhancement of the cardiac function of these mice (p < 0.05 vs. control therapy). In the nonischemic heart failure model, significant increases in the survival rate and cardiac function were achieved by cell therapy (p < 0.05 vs. control therapy), but not by cytokine therapy, although cytokine therapy inhibited the fibrosis and apoptosis of the cardiomyocytes. Both cell therapy and cytokine therapy are alternative treatments for ischemic heart failure. However, cell therapy is more effective for the treatment of nonischemic heart failure than cytokine therapy achieved by the administration of a single growth factor.

Oral treatment with probucol in a pharmacological dose has no beneficial effects on mortality in chronic ischemic heart failure after large myocardial infarction in rats

Cardiac remodeling after myocardial infarction is in part triggered and maintained by reactive oxygen species. Antioxidants such as probucol have shown positive short-term effects on these cardiac interstitial changes in different experimental models after intraperitoneal administration or after per-oral administration with a long pre-treatment period or in high doses. In this study, the long-term effects on mortality and cardiac remodeling were examined after induction of a large myocardial infarction in a clinical daily-life-like setting. Male Lewis rats were randomized to the study groups. Large anterolateral myocardial infarctions were induced or sham operations performed. The oral treatment was started after 48 h either with probucol or placebo after myocardial infarction and with placebo after sham operation. Induction of large myocardial infarctions led to changes of the left ventricular stiffness constants, a dilatation of the left ventricle and an increased interstitial fibrosis in the remote non-infarcted part. These changes were in tendency, but not significantly, reversed after treatment with probucol. The 6-month survival rates were 53.1% in the group probucol-myocardial infarction, 43.2% in the group placebo-myocardial infarction and 100% in the group after sham operation. There were no significant differences at Kaplan–Meier analysis between the groups after myocardial infarctions. Oral treatment with the antioxidant probucol started after myocardial infarction in a pharmacological dose does not have favourable effects on the long-term mortality in the chronic ischemic heart failure model in the rat.

Inhalation of diluted diesel engine emission impacts heart rate variability and arrhythmia occurrence in a rat model of chronic ischemic heart failure

Both increase in cardiac arrhythmia incidence and decrease in heart rate variability (HRV) have been described following human and experimental animal exposures to air pollutants. However, the potential causal relationship between these two factors remains unclear. Incidence of ventricular arrhythmia and HRV were evaluated during and after a 3 h period of Diesel engine exhaust exposure in ten healthy and ten chronic ischemic heart failure (CHF, 3 months after coronary ligation) Wistar rats using implantable ECG telemetry. Air pollutants were delivered to specifically designed whole body individual exposure chambers at particulate matter concentrations similar to those measured inside cabins of cars inserted in congested urban traffic. Recordings were obtained from unrestrained and unsedated vigil rats. Immediate decrease in RMSSD was observed in both healthy (6.64 +/- 2.62 vs. 4.89 +/- 1.67 ms, P < 0.05) and CHF rats (8.01 +/- 0.89 vs. 6.6 +/- 1.37 ms, P < 0.05) following exposure. An immediate 200-500% increase in ventricular premature beats was observed in CHF rats only. Whereas HRV progressively returned to baseline values within 2.5 h after exposure start, the proarrhythmic effect persisted as late as 5 h after exposure termination in CHF rats. Persistence of ventricular proarrhythmic effects after HRV normalization suggests that HRV reduction is not the mechanism of cardiac arrhythmias in this model. Our methodological approach, closely reflecting the real clinical situations, appeared to be a unique tool to provide further insight into the pathophysiological mechanisms of traffic related airborne pollution health impact.

Lentiviral Vector-mediated SERCA2 Gene Transfer showed the Cardioprotective Effects in the Rat Ischemic Cardiomyopathy

Introduction: Reduced expression of SERCA2 gene impairs calcium handling and contributes to contractile dysfunction of the heart. We developed lentivirus-based SERCA2 gene transfer system and examined the long-term effect of SERCA2 gene transfer to compensate reduced expression of the gene in the rat ischemic heart failure model.

Effective Placement of Axial-Flow Left Ventricular Assist Device into Large Animal Model of Ischemic Heart Failure

Introduction: Implantable left ventricular assist devices (LVADs) had been used as a temporary support in end-stage heart failure (HF) patients. Additionally, LVADs had recently been proposed as a potential destination therapy for patients unable to receive heart transplantation. However, availability of large animal model of HF suitable for LVADs is very limited. We have developed minimally-invasively induced sheep model of ischemic HF that can serve as a pre-clinical tool to investigate left ventricular (LV) support devices. Methods: All animals were use in accordance with 1991 revision of ‘‘Guiding Principles in the Care and Use of Animals’’ (American Physiological Association). Adult sheep (N 5 21, 53 6 4Kg) have been repeatedly (2.9 6 0.4 injections/animal) microembolized (ME) using 90mm polystyrene beads selectively applied trough catherter based access into left circumflex coronary artery. The animals were weekly echocardiogramed to assess ejection fraction (EF) and repeated ME was performed until EF was ! 35% for two consecutive weeks. Randomly selected sheep (N 5 5) were than survived for 52 weeks to establish long term changes in EF, left ventricular end-systolic area (LVESA-cm) and left ventricular end-diastolic area (LVEDA-cm). Subsequently, adult sheep (N 5 6, 78 6 3 Kg) with established HF underwent placement of axial-flow LVAD while avoiding cardiopulmonary bypass. All animals were given anticoagulation and anti-platelet therapy. Results: Animals (N 5 16) that survived at minimum of two MEs developed HF at 4 weeks following the last beads injection (LVEF was 52 6 8% at baseline vs. 34 6 7% at 4 weeks). In 5 animals that survived 52 weeks LVEF dropped to 28 6 5% (p ! 0.05), LVESA increased from 6.5 6 3 at baseline to 20 6 4 and LVEDA increased from 13.6 6 5 to 28 6 5 (both p ! 0.05). All animals that underwent LVAD placement survived surgical procedure. HF hearts were than partially supported with the LVAD for 13 days (range 8 to 17 days). A typical ‘‘working speed’’ support progressed from 6,000 rpm to 10,880 6 120 rpm. Two animals were sacrificed due to cloth formation in the pump. No animal developed infection during the course of study. All other animals were sacrificed with functional pumps. Conclusion: Proposed animal model of ischemic HF is a reliable tool for evaluation of cardiac assist devices.

β2-Adrenergic Stimulation Attenuates Left Ventricular Remodeling, Decreases Apoptosis, and Improves Calcium Homeostasis in a Rodent Model of Ischemic Cardiomyopathy

The benefit of the beta(2)-adrenergic agonist, clenbuterol, in left ventricular assist device patients with dilated cardiomyopathy has been reported, but its effect on ischemic heart failure (HF) is unknown. We investigated whether clenbuterol improves left ventricular remodeling, myocardial apoptosis and has synergy with a beta(1) antagonist, metoprolol, in a model of ischemic HF. Rats were randomized to: 1) HF only; 2) HF + clenbuterol; 3) HF + metoprolol; 4) HF + clenbuterol + metoprolol; and 5) rats with sham surgery. HF was induced by left anterior descending artery (LAD) artery ligation and confirmed by decreased left ventricular fractional shortening, decreased maximum left ventricular dP/dt (dP/dt(max)), and elevated left ventricular end-diastolic pressure (LVEDP) compared with sham rats (p < 0.01). After 9 weeks of oral therapy, echocardiographic, hemodynamic, and ex vivo end-diastolic pressure-volume relationship (EDPVR) measurements were obtained. Immunohistochemistry was performed for myocardial apoptosis and DNA damage markers. Levels of calcium-handling proteins were assessed by Western blot analysis. Clenbuterol-treated HF rats had increased weight gain and heart weights versus HF rats (p < 0.05). EDPVR curves revealed a leftward shift in clenbuterol rats versus metoprolol and HF rats (p < 0.05). The metoprolol-treated group had a lower LVEDP and higher dP/dt(max) versus the HF group (p < 0.05). Clenbuterol and metoprolol groups had decreased myocardial apoptosis and DNA damage markers and increased DNA repair markers versus HF rats (all p < 0.01). Protein levels of the ryanodine receptor and sarcoplasmic reticulum calcium-ATPase were improved in clenbuterol-, metoprolol-, and clenbuterol+metoprolol-treated groups versus HF rats. However, as a combination therapy, there were no synergistic effects of clenbuterol+metoprolol treatment. We conclude that clenbuterol ameliorates EDPVR, apoptosis, and calcium homeostasis but does not have synergy with metoprolol in our model of ischemic HF.