Ketone Ester Treatment Improves Cardiac Function and Reduces Pathologic Remodeling in Preclinical Models of Heart Failure.
Ketone Ester Treatment Improves Cardiac Function and Reduces Pathologic Remodeling in Preclinical Models of Heart Failure.
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DOI：
10.1161/circheartfailure.120.007684
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发表时间：
2021-01
期刊：
影响因子：
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通讯作者：
Westenbrink BD
中科院分区：
文献类型：
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作者：
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
补充数字内容可在正文中找到。越来越多的证据表明，衰竭的心脏重新规划了燃料代谢，以增加对酮体的利用，增加心脏酮的输送可以改善心功能障碍。作为开发酮疗法的第一步，我们调查了长期口服酮酯(KE)作为预防或治疗策略在啮齿动物心力衰竭模型中的作用。采用两种独立的啮齿动物心力衰竭模型：小鼠腹主动脉缩窄/心肌梗死模型和大鼠心肌梗死后重塑模型。75只小鼠接受了由己基己基-3-羟基丁酸酯KE(KE-1)饮食组成的KE预防治疗策略，77只大鼠接受了使用商用β-羟丁酸酯-(R)-1，3-丁二醇单酯(KE-2)饮食预防或治疗方案的治疗。小鼠的KE-1饮食在夜间喂养期间提高了β-羟丁酸的水平，而KE-2饮食在24小时内诱导了大鼠的酮血症。KE-1饮食预防策略减少了横断性主动脉缩窄/MI后左心功能不全和重构的发展(左心室射血分数±SD，车组36±8比KE-1组45±11；P=0.016)。KE-2饮食疗法也减轻了MI后的左心功能障碍和重构(左心室射血分数，MI-VE-2组为41±11，MI-KE-2组为61±7；P<；0.001)。此外，KE-2治疗组的心肌重量、心肌细胞横截面积和心房利钠肽(ANP)的表达也显著降低。然而，使用KE-2治疗并不影响心肌梗死后的心肌纤维化。饲喂KE-2饲料的大鼠心肌组织中酮转运体和2种酮解酶的表达显著增加，同时心肌ATP水平恢复到假手术水平。在2个临床前动物模型上，慢性口服可有效预防和治疗心力衰竭。此外，我们的结果表明，KE治疗使心肌梗死后与酮体利用和正常心肌ATP产生相关的基因表达重新编程，这与补充燃料的提供是一致的。这些发现为评估KES作为治疗心力衰竭患者的方法提供了依据。
Supplemental Digital Content is available in the text. 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. 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. 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. 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.