Novel Göttingen Miniswine Model of Heart Failure With Preserved Ejection Fraction Integrating Multiple Comorbidities.
Novel Göttingen Miniswine Model of Heart Failure With Preserved Ejection Fraction Integrating Multiple Comorbidities.
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新的Göttingen Miniswin心力衰竭模型，保留射血和分数，整合多种并发症。
DOI：
10.1016/j.jacbts.2020.11.012
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发表时间：
2021-03
期刊：
影响因子：
--
通讯作者：
Lefer DJ
中科院分区：
文献类型：
--
作者：
Sharp TE 3rd;Scarborough AL;Li Z;Polhemus DJ;Hidalgo HA;Schumacher JD;Matsuura TR;Jenkins JS;Kelly DP;Goodchild TT;Lefer DJ
已经开发了一种大型动物模型，该模型概括了HFpEF的临床异质性。在成年雌性哥廷根小型猪中，盐皮质激素过量和高胆固醇、脂肪、果糖和盐饮食诱导了多种合并症，包括肥胖、高胆固醇血症、糖尿病前期表型以及肺动脉和全身动脉高血压。滴定每种合并症的严重程度，在相对较短的时间内实现显著的左心室和左心房舒张功能障碍、严重的左心室向心性重构、冠状动脉血管舒张受损和广泛的多器官纤维化。在哥廷根小型猪中生成这种新型心力衰竭模型，以允许在成年动物中进行新型药理学药物的转化研究和人体尺寸的器械测试。这种新的“多击”小型猪心力衰竭模型能够研究HFpEF的病理学，而没有侵入性外科手术或以人工方式诱导高血压和终末器官损伤的药物给药所固有的混杂效应。缺乏临床前大型动物模型的心脏衰竭与保留射血分数（HFpEF），概括了这种合并症负载综合征，导致无法梳理出机制的见解，并测试新的治疗策略。本研究开发了一种大型动物模型，该模型在小型猪品种中整合了HFpEF的多种共病决定因素，该小型猪品种对肥胖、代谢综合征和血管疾病表现出敏感性，并伴有明显的心力衰竭临床体征。西方饮食和哥廷根小型猪中11-脱氧皮质酮醋酸盐诱导的高血压相结合，导致了一种新型HFpEF大型动物模型的开发，该模型表现出多器官受累以及与人类HFpEF相关的全方位合并症。
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. 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.
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影响因子：
4.6
作者：
Heinonen, Ilkka;Sorop, Oana;Duncker, Dirk J.
通讯作者：
Duncker, Dirk J.
影响因子：
7.4
作者：
Ludvigsen, Trine Pagh;Kirk, Rikke Kaae;Olsen, Lisbeth Hoier
通讯作者：
Olsen, Lisbeth Hoier
影响因子：
3.8
作者：
Charles, Christopher J.;Lee, Philip;Richards, A. Mark
通讯作者：
Richards, A. Mark
DOI：
10.1152/ajpheart.00163.2015
发表时间：
2015-07-15
影响因子：
4.8
作者：
Bradley, Jessica M.;Islam, Kazi N.;Lefer, David J.
通讯作者：
Lefer, David J.
DOI：
10.3181/00379727-143-37285
发表时间：
1973-01-01
影响因子：
--
作者：
MARTIN, RJ;GOBBLE, JL;ZIEGLER, JH
通讯作者：
ZIEGLER, JH