Novel Göttingen Miniswine Model of Heart Failure With Preserved Ejection Fraction Integrating Multiple Comorbidities
| Autor: | Hunter A Hidalgo, Amy Scarborough, Zhen Li, Thomas E. Sharp, David J. Polhemus, J. Stephen Jenkins, Timothy Matsuura, Jeffery D. Schumacher, Daniel P. Kelly, David J. Lefer, Traci T. Goodchild |
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| Rok vydání: | 2021 |
| Předmět: |
heart failure with preserved ejection fraction
0301 basic medicine obesity medicine.medical_specialty animal models of human disease hypertension HDL high-density lipoprotein DBP diastolic blood pressure HFpEF heart failure with preserved ejection fraction Disease DOCA 11-deoxycorticosterone acetate 030204 cardiovascular system & hematology Novel Translational Models metabolic syndrome 03 medical and health sciences PCWP - Pulmonary capillary wedge pressure 0302 clinical medicine LDL low-density lipoprotein Internal medicine Western diet medicine EF ejection fraction HFrEF heart failure with reduced ejection fraction WD Western diet business.industry SBP systolic blood pressure DBP - Diastolic blood pressure medicine.disease PCWP pulmonary capillary wedge pressure TC total cholesterol LV left ventricle 030104 developmental biology Heart failure IVGTT intravenous glucose tolerance test Cardiology EC50 half-maximal effective concentration Metabolic syndrome Cardiology and Cardiovascular Medicine Heart failure with preserved ejection fraction business Large animal |
| Zdroj: | JACC: Basic to Translational Science |
| ISSN: | 2452-302X |
| Popis: | Visual Abstract Highlights • A large animal model that recapitulates the clinical heterogeneity of HFpEF has been developed. • Multiple comorbidities, including obesity, hypercholesterolemia, pre-diabetic phenotype, as well as pulmonary and systemic arterial hypertension, were induced in adult female Göttingen minipigs by mineralocorticoid excess and a diet high in cholesterol, fat, fructose, and salt. • Severity of each comorbidity was titrated, such that marked left ventricular and left atrial diastolic dysfunction, profound left ventricular concentric remodeling, impaired coronary vasorelaxation, and extensive multiorgan fibrosis were achieved over a relatively short time. • This novel heart failure model was generated in Göttingen minipigs to allow for translational studies of novel pharmacological agents and for human-sized device testing in adult-aged animals. • This novel “multihit” minipig heart failure model enabled investigations into the pathology of HFpEF without the confounding effects inherent with invasive surgical procedures or the administration of agents that induce hypertension and end-organ damage in an artificial manner. Summary A lack of preclinical large animal models of heart failure with preserved ejection fraction (HFpEF) that recapitulate this comorbid-laden syndrome has led to the inability to tease out mechanistic insights and to test novel therapeutic strategies. This study developed a large animal model that integrated multiple comorbid determinants of HFpEF in a miniswine breed that exhibited sensitivity to obesity, metabolic syndrome, and vascular disease with overt clinical signs of heart failure. The combination of a Western diet and 11-deoxycorticosterone acetate salt−induced hypertension in the Göttingen miniswine led to the development of a novel large animal model of HFpEF that exhibited multiorgan involvement and a full spectrum of comorbidities associated with human HFpEF. |
| Databáze: | OpenAIRE |
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