Abstract 157: A Highly Reproducible, Clinically Relevant Large Animal Model of Myocardial Ischemia and Heart Failure

Background: Heart failure (HF) is the leading cause of mortality in United States. Animal models used to test novel HF therapeutics are inadequate as pathological features of human HF are not replicated. Available large-animal swine myocardial ischemia (MI) models mimic human HF; however, do not achieve ejection fractions (EF) less than 40%. Objective: We sought to develop a reproducible swine MI model with EF below 35%. Methods: Yucatan miniature pigs (n=18) were anesthetized, catheterized and collagen suspension (COL) of microfibrillar hemostat (INSTAT MCH, Ethicon) mixed in contrast and saline solution was injected into the left anterior descending coronary artery (LAD) under fluoroscopic guidance. COL injections started distally and filled side branches during catheter retraction. Complete transient LAD occlusion was confirmed at 2hrs by coronary angiography. Cardiac function was evaluated at 3mos using a 1.5T MRI System (Siemens Magnetom Avanto). LV volumes at end systole (LVESD) and diastole (LVEDD), EF, wall thickness (WT) in area at risk (AAR) and normal zones (NZ) were calculated. Uninjected Yucatan pigs (n=3) served as controls. Results: Twelve of 18 pigs survived COL infarction. At 3mos, EF was reduced in COL injected pigs compared to control (27.0±2.3 vs. 61.6±1.3%, respectively, P<0.001). LVESV and LVEDV were 4- and 2-fold higher and WT in AAR and NZ were reduced 6- and 2-fold, respectively in COL injected compared to controls. Conclusions: A reproducible large animal model of MI was produced by catheter based LAD collagen delivery resulting in EFs below 35% and progression to HF. By closely resembles human HF, it a highly useful for testing potential HF therapies.

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TCT-454: A Highly Reproducible and Clinically Relevant Large Animal Model of Myocardial Ischemia and Heart Failure as Determined by MRI Imaging

Journal of the American College of Cardiology ◽

10.1016/j.jacc.2011.10.464 ◽

2011 ◽

Vol 58 (20) ◽

pp. B123

Keyword(s):

Heart Failure ◽

Animal Model ◽

Myocardial Ischemia ◽

Large Animal Model ◽

Large Animal ◽

Mri Imaging

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SUMO-1 Gene Transfer Improves Cardiac Function in a Large-Animal Model of Heart Failure

Science Translational Medicine ◽

10.1126/scitranslmed.3006487 ◽

2013 ◽

Vol 5 (211) ◽

pp. 211ra159-211ra159 ◽

Cited By ~ 66

Author(s):

L. Tilemann ◽

A. Lee ◽

K. Ishikawa ◽

J. Aguero ◽

K. Rapti ◽

...

Keyword(s):

Heart Failure ◽

Animal Model ◽

Gene Transfer ◽

Cardiac Function ◽

Large Animal Model ◽

Large Animal

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Abstract 297: Paroxysmal And Sustained Atrial Fibrillation In A New Large Animal Model Of Nonischemic Heart Failure

Circulation Research ◽

10.1161/res.115.suppl_1.297 ◽

2014 ◽

Vol 115 (suppl_1) ◽

Author(s):

Saad Sikanderkhel ◽

Olawale Onibile ◽

Gregory P Walcott ◽

Steven M Pogwizd

Keyword(s):

Heart Failure ◽

Atrial Fibrillation ◽

Animal Model ◽

Holter Monitoring ◽

Aortic Insufficiency ◽

Large Animal Model ◽

Large Animal ◽

Aortic Constriction ◽

Holter Monitor ◽

Human Scale

Introduction: Atrial fibrillation is common in heart failure (HF). Understanding of the mechanisms of atrial fibrillation (AF) is limited by the paucity of large animal AF models, especially in the failing heart. We developed a large animal model of nonischemic heart failure (HF) in dogs by combined aortic insufficiency and aortic constriction and observed that a number of HF dogs developed paroxysmal AF on holter monitor. Here we characterize the spontaneously-occurring pAF in these HF dogs and perform electrophysiologic (EP) assessment of atrial refractoriness and AF inducibility along with echocardiographic imaging of left ventricle (LV) and left atrium (LA). Methods: HF was induced in dogs by aortic insufficiency and aortic constriction, and serial echocardiography (for LV fractional shortening (FS) and LA size) and Holter monitoring was performed. In control and HF dogs, EP study of atrial refractory period (AERP) and AF inducibility (duration and atrial cycle length (CL)) was performed. Results: By Holter monitoring, paroxysmal AF was noted in 5 dogs with episodes ranging from 15 to 94 beats long (mean of 49±27 beats, n=12). In EP studies, control dogs (N=3) exhibited AERP of 176±8 ms. Burst pacing resulted in AF of very brief duration (mean 32±24 sec) and a mean AF CL of 138±6 ms. LV FS averaged 37% and LA size averaged 4.3 cm2. HF dogs (N=5) exhibited RAERP of 150±8 (p=0.05 vs control). Two of these dogs had sustained AF with ventricular response up to 230 bpm on Holter monitor. In the other 3 HF dogs, burst pacing induced AF with a mean duration of 232±185 sec (at times with conversion to atrial flutter) and with a mean AF CL = 110±4 ms (p=0.002 vs control). Echo data showed LVFS averaged 30% and LA area of 14.9 cm2 (p=0.05 vs control). Conclusion: Thus we have developed a novel large animal model of HF that exhibits paroxysmal and sustained AF. This model will provide an opportunity for the study of underlying AF mechanisms, the progression of remodeling in HF hearts leading to AF, and the assessment of human-scale interventions to better treat and prevent this arrhythmia.

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Abstract 8: Effectiveness of Combination Allogeneic Stem Cells in a Novel Large Animal Model of Chronic Kidney Disease-induced Heart Failure With Preserved Ejection Fraction (HFpEF)

Circulation Research ◽

10.1161/res.121.suppl_1.8 ◽

2017 ◽

Vol 121 (suppl_1) ◽

Author(s):

Angela Castellanos Rieger ◽

Bryon A Tompkins ◽

Makoto Natsumeda ◽

Victoria Florea ◽

Kevin Collon ◽

...

Keyword(s):

Heart Failure ◽

Chronic Kidney Disease ◽

Animal Model ◽

Cell Therapy ◽

Renal Artery ◽

Cardiorenal Syndrome ◽

Large Animal Model ◽

Large Animal ◽

Preserved Ejection Fraction ◽

Lv Mass

Background: Chronic Kidney Disease (CKD) is an independent risk factor for cardiovascular morbidity and mortality. Left ventricular (LV) hypertrophy and heart failure with preserved ejection fraction (HFpEF) are the primary manifestations of the cardiorenal syndrome in 60 to 80% of CKD patients. Therapies that improve morbidity and mortality in HFpEF are lacking. Stem cell therapy reduces fibrosis, increases neovascularization, and promotes cardiac repair in ischemic and non-ischemic cardiomyopathies. We hypothesized that stem cell treatment ameliorates HFpEF in a CKD model. Methods: Yorkshires pigs (n=27) underwent 5/6 nephrectomy via renal artery embolization and 4-weeks later received either: allogeneic (allo-) MSC (10х10 6 ), allo-kidney c-kit + cells (c-kit; 10х10 6 ), combination (MSC+c-kit; 1:1 ratio [5х10 6 each]), or placebo (each n=5). Cell therapy was delivered via the patent renal artery. Kidney function, renal and cardiac MRI, and PV loops were measured at baseline, and at 4- and 12-weeks (euthanasia) post-embolization. Results: The CKD model was confirmed by increased creatinine and BUN and decreased GFR. Mean arterial pressure (MAP) was not different between groups from baseline to 4 weeks (p=0.7). HFpEF was demonstrated at 4 weeks by increased LV mass (20.3%; p= 0.0001), wall thickening (p<0.008), EDP (p=0.01), EDPVR (p=0.005), and arterial elastance (p=0.03), with no change in EF. Diffuse intramyocardial fibrosis was evident in histological analysis and delayed enhancement MRI imaging. After 12 weeks, there was a significant difference in MAP between groups (p=0.04), with an increase in the placebo group (19.97± 8.65 mmHg, p=0.08). GFR significantly improved in the combination group (p=0.033). EDV increased in the placebo (p=0.009) and c-kit (p=0.004) groups. ESV increased most in the placebo group (7.14±1.62ml; p=0.022). EF, wall thickness, and LV mass did not differ between groups at 12 weeks. Conclusion: A CKD large animal model manifests the characteristics of HFpEF. Intra-renal artery allogeneic cell therapy was safe. A beneficial effect of cell therapy was observed in the combination and MSC groups. These findings have important implications on the use of cell therapy for HFpEF and cardiorenal syndrome.

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