Abstract 14254: Pharmacodynamic Effects of a Single Dose of CK-3773274 in Cats With Hypertrophic Cardiomyopathy

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Maureen Oldach ◽  
Darren T Hwee ◽  
Eric S Ontiveros ◽  
Samantha L Fousse ◽  
Carina E Gonzalez ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Pressure Gradient ◽  
Peak Pressure ◽  
Left Ventricular ◽  
Post Treatment ◽  
Large Animal Model ◽  
Large Animal ◽  
Cardiac Myosin ◽  
Internal Dimension ◽  
Naturally Occurring

Introduction: Hypertrophic cardiomyopathy (HCM) is characterized by left ventricular (LV) hypertrophy in the absence of known causes. HCM can be due to genetic mutations that affect sarcomeric proteins, leading to myocardial hypercontractility. HCM is often complicated by left ventricular outflow tract obstruction (LVOTO) and patients may be at greater risk of cardiovascular death. Medications targeted to address the pathophysiology of HCM and ameliorate LVOTO are needed. CK-3773274 (CK-274) is a novel small molecule cardiac myosin inhibitor that reduces myocardial contractility in vitro and in vivo . Cats have naturally occurring HCM commonly complicated by LVOTO and are an excellent large animal model for investigation of HCM therapeutics. In this study, we aim to characterize the pharmacodynamic effect of a single oral dose of CK-274 on cardiac function in cats with hypertrophic cardiomyopathy and LVOTO. Methods: Eight purpose-bred cats with naturally occurring HCM and LVOTO due to the A31P mutation in cardiac myosin binding protein C (cMyBP-C) were included in a randomized, controlled, crossover study. Cats were randomized to receive vehicle, 0.3 mg/kg, or 1 mg/kg CK-274 treatment, and received echocardiograms at baseline, 6, 24, and 48 hours post-treatment. All cats were crossed over to all treatment groups. Results: CK-274 (1 mg/kg) reduced mean LV fractional shortening at 6, 24 and 48 hours post-treatment (mean reduction 13.6%, p=0.03; 15.4%, p=0.01; 11.6% p=0.02, respectively). CK-274 (1 mg/kg) increased LV systolic internal dimension at 6 and 24-hours post-treatment (mean increase 0.21 cm, p=0.046; 0.25 cm, p=0.03), and did not affect LV diastolic internal dimension. LVOT peak pressure gradient was reduced with CK-274 (0.3 mg/kg) treatment [median pressure gradient at baseline 27.1 mmHg (IQR 18.3-33.3) vs 24 hours post-drug, 7.3 mmHg (IQR 14.2-19.7) p=0.01]. Heart rate did not change for any treatment group over time. No differences were noted following vehicle administration at any time point. Conclusion: In HCM affected cats with the cMyBP-C A31P mutation, the cardiac myosin inhibitor CK-274 is well tolerated at the studied doses and caused dose-related changes in LV systolic function and reductions in LVOT peak pressure gradient.

scholarly journals Cardiopulmonary remodeling in fattened beef cattle: a naturally occurring large animal model of obesity-associated pulmonary hypertension with left heart disease

2018 ◽  
Vol 9 (1) ◽  
pp. 204589401879680 ◽  
Author(s):  
Greta M. Krafsur ◽  
Joseph M. Neary ◽  
Franklyn Garry ◽  
Timothy Holt ◽  
Daniel H. Gould ◽  
...  
Keyword(s):  
Animal Model ◽  
Pulmonary Hypertension ◽  
Heart Disease ◽  
Beef Cattle ◽  
Left Ventricular ◽  
Large Animal Model ◽  
Large Animal ◽  
Left Heart ◽  
Naturally Occurring ◽  
Left Heart Disease

The obesity epidemic in developed societies has led to increased cardiovascular diseases including pulmonary hypertension associated with left heart disease (PH-LHD), the largest and fastest-growing class of PH. Similar to obese humans, PH and heart failure (HF) are increasingly recognized in North American fattened beef cattle. We hypothesized that PH and HF in fattened beef cattle are novel, phenotypically distinct manifestations of bovine PH arising from left ventricular (LV) dysfunction similar to obesity-related PH-LHD in humans. We conducted a semi-quantitative histopathological assessment of cardiopulmonary tissues obtained from fattened beef cattle suffering end-stage HF compared to asymptomatic cattle of equivalent age undergoing the same fattening regimens. In HF animals we observed significant LV fibrosis, abundant cardiac adipose depots, coronary artery injury, and pulmonary venous remodeling recapitulating human obesity-related PH-LHD. Additionally, striking muscularization, medial hypertrophy, adventitial fibrosis, and vasa vasorum hyperplasia in the pulmonary arterial circulation were associated with sequela of pathologic right ventricular (RV) remodeling suggesting combined pulmonary venous and arterial hypertension. The association between obesity, pathologic cardiopulmonary remodeling, and HF in fattened beef cattle appears to recapitulate the complex pathophysiology of obesity-associated PH-LHD in humans. This novel, naturally occurring, and large animal model may provide mechanistic and translational insights into human disease.

scholarly journals Feline Hypertrophic Cardiomyopathy: A Spontaneous Large Animal Model of Human HCM

2017 ◽  
Vol 8 (4) ◽  
pp. 139-142 ◽  
Author(s):  
Lisa M. Freeman ◽  
John E. Rush ◽  
Joshua A. Stern ◽  
Gordon S. Huggins ◽  
Martin S. Maron
Keyword(s):  
Animal Model ◽  
Hypertrophic Cardiomyopathy ◽  
Large Animal Model ◽  
Large Animal

Large animal model of left ventricular aneurysm

1989 ◽  
Vol 48 (6) ◽  
pp. 838-845 ◽  
Author(s):  
Lawrence J. Markovitz ◽  
Edward B. Savage ◽  
Mark B. Ratcliffe ◽  
Joseph E. Bavaria ◽  
Gerhard Kreiner ◽  
...  
Keyword(s):  
Animal Model ◽  
Left Ventricular ◽  
Large Animal Model ◽  
Left Ventricular Aneurysm ◽  
Large Animal ◽  
Ventricular Aneurysm

scholarly journals Delivery of a matrix metalloproteinase-responsive hydrogel releasing TIMP-3 after myocardial infarction: effects on left ventricular remodeling

2018 ◽  
Vol 315 (4) ◽  
pp. H814-H825 ◽  
Author(s):  
Brendan P. Purcell ◽  
Shayne C. Barlow ◽  
Paige E. Perreault ◽  
Lisa Freeburg ◽  
Heather Doviak ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Matrix Metalloproteinases ◽  
Ventricular Remodeling ◽  
Left Ventricular ◽  
Large Animal Model ◽  
Left Ventricular Geometry ◽  
Relative Reduction ◽  
Large Animal ◽  
Early Reperfusion ◽  
Localized Delivery

Although improvements in timing and approach for early reperfusion with acute coronary syndromes have occurred, myocardial injury culminating in a myocardial infarction (MI) remains a common event. Although a multifactorial process, an imbalance between the induction of proteolytic pathways, such as matrix metalloproteinases (MMPs) and endogenous tissue inhibitors of metalloproteinase (TIMPs), has been shown to contribute to this process. In the present study, a full-length TIMP-3 recombinant protein (rTIMP-3) was encapsulated in a specifically formulated hyaluronic acid (HA)-based hydrogel that contained MMP-cleavable peptide cross-links, which influenced the rate of rTIMP-3 release from the HA gel. The effects of localized delivery of this MMP-sensitive HA gel (HAMMPS) alone and containing rTIMP-3 (HAMMPS/rTIMP-3) were examined in terms of the natural history of post-MI remodeling. Pigs were randomized to one of the following three different groups: MI and saline injection (MI/saline group, 100-μl injection at nine injection sites, n = 7), MI and HAMMPS injection (MI/HAMMPS group; 100-μl injection at nine injection sites, n = 7), and MI and HAMMPS/rTIMP-3 injection (MI/HAMMPS/rTIMP-3 group; 20-μg/100-μl injection at nine injection sites, n = 7). Left ventricular (LV) echocardiography was serially performed up to 28 days post-MI. LV dilation, as measured by end-diastolic volume, and the degree of MI wall thinning were reduced by ~50% in the HAMMPS/rTIMP-3 group ( P < 0.05). Furthermore, indexes of heart failure progression post-MI, such as LV filling pressures and left atrial size, were also attenuated to the greatest degree in the HAMMPS/rTIMP-3 group. At 28 days post-MI, HAMMPS/rTIMP-3 caused a relative reduction in the transcriptional profile for myofibroblasts as well as profibrotic pathways, which was confirmed by subsequent histochemistry. In conclusion, these findings suggest that localized delivery of a MMP-sensitive biomaterial that releases a recombinant TIMP holds promise as a means to interrupt adverse post-MI remodeling. NEW & NOTEWORTHY The present study targeted a myocardial matrix proteolytic system, matrix metalloproteinases (MMPs), through the use of a recombinant tissue inhibitor of MMPs incorporated into a MMP-sensitive hydrogel, which was regionally injected using a large animal model of myocardial infarction. Left ventricular geometry and function and indexes of myocardial remodeling were improved with this approach and support the advancement of localized therapeutic strategies that specifically target the myocardial matrix.

Naturally-Occurring Antibodies to Human AAV In Sheep: A New Large Animal Model for Immune Aspects of AAV Gene Transfer.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3762-3762
Author(s):  
Joseph Tellez ◽  
Jonathan D. Finn ◽  
Nicholas Tschernia ◽  
Graca Almeida-Porada ◽  
Valder Arruda ◽  
...  
Keyword(s):  
Animal Model ◽  
Conflicts Of Interest ◽  
High Titer ◽  
Cell Epitope ◽  
Model System ◽  
Large Animal Model ◽  
Preclinical Model ◽  
Large Animal ◽  
Target Tissue ◽  
Naturally Occurring

Abstract Abstract 3762 AAV vectors have received a great deal of attention for clinical gene therapy (GT), since they transduce many mitotic and quiescent cells and mediate long-term transgene expression. Unfortunately, many of the serotypes of AAV commonly employed in GT procedures ubiquitously infect humans, generating pre-existing immunity against the AAV capsid proteins that precludes efficient transduction or induces CTL responses to the transduced target tissue. At present, highly successful animal studies have not translated into clinical success in humans, due, at least in part, to the paucity of animals which harbor endogenous antibodies which recognize and bind AAV-2 and other AAV serotypes for which humans are the natural host. Sheep have long been used as a model to study a broad range of disease states, and a high degree of clinical predictability has consistently been observed. We therefore examined whether sheep possess antibodies to AAV and could thus serve as a much-needed preclinical model system for evaluating AAV-based GT. ELISAs were performed on sera from a panel of 6 healthy Merino-Rambouillet sheep using AAV-1,-2,-5,-6,-8, -9 particles as the antigen. Our results demonstrate that sheep naturally harbor antibodies to all 6 AAV serotypes tested, yet the titers against the different serotypes varied greatly from sheep-to-sheep. While one sheep exhibited very high level (>2300ng/ml) IgG against all 6 AAV serotypes tested, others exhibited moderate/low (>350ng/ml) IgG against all 6 AAV serotypes, and still others exhibited moderate/low level IgG against only 3–4 of the tested serotypes. Despite these differences, all sheep harbored detectable antibodies to AAV 2, 5, & 8. A luciferase-based neutralizing antibody (NAB) assay was then performed on sera from 3 of the sheep exhibiting the highest titer IgG against AAV 2, 8, & 9 to assess the clinical significance of these antibodies in the context of AAV-based GT. All 3 animals harbored relatively high titer (1:100-1:316) NAB to AAV 2, but only 1 animal harbored significant NAB titers against AAV 8 & 9 (1:31, and 1:100, respectively). B cell epitope mapping of these 3 animals with a library of peptides derived from the capsids of AAV 2, 5, 8, and 9 revealed that each individual sheep harbored antibodies recognizing from 17 to 50 of the various capsid-derived peptides, some of which were common to all capsids, and some of which were unique to specific AAV serotypes. Importantly, many of the identified capsid epitopes have also been shown to be recognized by antibodies present in human patients with existing AAV immunity. To our knowledge, this is the first report of an animal disease model harboring naturally occurring functional antibodies to serotypes of human AAV commonly employed as GT vectors. The close parallels between human and sheep physiology, coupled with our recent re-establishment of sheep with severe hemophilia A with a null mutation in the FVIII gene and the presence of these antibodies, suggest that sheep may represent an ideal large animal model system in which to study GT in the context of pre-existing immunity to AAV, and to develop novel strategies for circumventing this immunologic barrier. Disclosures: No relevant conflicts of interest to declare.

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