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Ketone Ester Treatment Improves Cardiac Function and Reduces Pathologic Remodeling in Preclinical Models of Heart Failure.
在心力衰竭的临床前模型中,酮酯治疗改善心脏功能并减少病理重塑。
- 影响因子:4.83
- DOI:10.1161/CIRCHEARTFAILURE.120.007684
- 作者列表:"Yurista SR","Matsuura TR","Silljé HHW","Nijholt KT","McDaid KS","Shewale SV","Leone TC","Newman JC","Verdin E","van Veldhuisen DJ","de Boer RA","Kelly DP","Westenbrink BD
- 发表时间:2021-01-01
Abstract
BACKGROUND:Accumulating evidence suggests that the failing heart reprograms fuel metabolism toward increased utilization of ketone bodies and that increasing cardiac ketone delivery ameliorates cardiac dysfunction. As an initial step toward development of ketone therapies, we investigated the effect of chronic oral ketone ester (KE) supplementation as a prevention or treatment strategy in rodent heart failure models. METHODS:Two independent rodent heart failure models were used for the studies: transverse aortic constriction/myocardial infarction (MI) in mice and post-MI remodeling in rats. Seventy-five mice underwent a prevention treatment strategy with a KE comprised of hexanoyl-hexyl-3-hydroxybutyrate KE (KE-1) diet, and 77 rats were treated in either a prevention or treatment regimen using a commercially available β-hydroxybutyrate-(R)-1,3-butanediol monoester (DeltaG; KE-2) diet. RESULTS:The KE-1 diet in mice elevated β-hydroxybutyrate levels during nocturnal feeding, whereas the KE-2 diet in rats induced ketonemia throughout a 24-hour period. The KE-1 diet preventive strategy attenuated development of left ventricular dysfunction and remodeling post-transverse aortic constriction/MI (left ventricular ejection fraction±SD, 36±8 in vehicle versus 45±11 in KE-1; P=0.016). The KE-2 diet therapeutic approach also attenuated left ventricular dysfunction and remodeling post-MI (left ventricular ejection fraction, 41±11 in MI-vehicle versus 61±7 in MI-KE-2; P<0.001). In addition, ventricular weight, cardiomyocyte cross-sectional area, and the expression of ANP (atrial natriuretic peptide) were significantly attenuated in the KE-2-treated MI group. However, treatment with KE-2 did not influence cardiac fibrosis post-MI. The myocardial expression of the ketone transporter and 2 ketolytic enzymes was significantly increased in rats fed KE-2 diet along with normalization of myocardial ATP levels to sham values. CONCLUSIONS:Chronic oral supplementation with KE was effective in both prevention and treatment of heart failure in 2 preclinical animal models. In addition, our results indicate that treatment with KE reprogrammed the expression of genes involved in ketone body utilization and normalized myocardial ATP production following MI, consistent with provision of an auxiliary fuel. These findings provide rationale for the assessment of KEs as a treatment for patients with heart failure.
摘要
背景: 越来越多的证据表明,衰竭的心脏将燃料代谢重新编程为增加酮体的利用,增加心脏酮递送可以改善心功能障碍。作为开发酮疗法的第一步,我们研究了长期口服酮酯 (KE) 补充剂作为啮齿动物心力衰竭模型中的预防或治疗策略的效果。 方法: 采用两种独立的啮齿动物心力衰竭模型进行研究: 小鼠主动脉缩窄/心肌梗死 (MI) 和大鼠MI后重构。75只小鼠接受了由hexanoyl-hexyl-3-hydroxybutyrate KE (KE-1) 饮食组成的KE的预防治疗策略,77只大鼠使用市售的 β-羟基丁酸酯-(R)-KE-2-丁二醇单酯 (DeltaG;) 饮食以预防或治疗方案进行治疗。 结果: 小鼠的KE-1饮食在夜间喂养期间升高 β-羟基丁酸水平,而大鼠的KE-2饮食在整个24小时期间诱导酮血症。KE-1饮食预防策略减弱了主动脉缩窄/MI后左心室功能障碍和重塑的发展 (左心室射血分数 ± SD,溶媒为36 ± 8,而KE-1为45 ± 11; P = 0.016)。KE-2饮食治疗方法也减轻了左心室功能障碍和MI后重塑 (左心室射血分数,MI-vehicle为41 ± 11,MI-KE-2为61 ± 7; P<0.001)。此外,KE-2-treated MI组心室重量、心肌细胞横截面积和ANP (心钠素) 表达明显减弱。然而,用KE-2治疗不影响MI后的心脏纤维化。在饲喂KE-2饮食的大鼠中,酮转运蛋白和2-酮分解酶的心肌表达显著增加,同时心肌ATP水平正常化至假值。 结论: 在2种临床前动物模型中,长期口服补充KE可有效预防和治疗心力衰竭。此外,我们的结果表明,用KE处理重新编程了参与酮体利用的基因表达和MI后标准化心肌ATP产生,与提供辅助燃料一致。这些发现为评估KEs作为心力衰竭患者的治疗提供了理论依据。
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