Metabolic Changes in Spontaneously Hypertensive Rat Hearts Precede Cardiac Dysfunction and Left Ventricular Hypertrophy
Metabolic Changes in Spontaneously Hypertensive Rat Hearts Precede Cardiac Dysfunction and Left Ventricular Hypertrophy
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DOI：
10.1161/jaha.118.010926
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发表时间：
2019-02-19
影响因子：
5.4
通讯作者：
Kundu, Bijoy K.
中科院分区：
文献类型：
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作者：
Li, Jie;Kemp, Brandon A.;Kundu, Bijoy K.
背景-持续的压力超负荷导致心脏代谢、功能和结构的改变。这些变化之间的时间进程和因果关系尚未完全了解。因此，我们研究了自发性高血压大鼠（SHR）在早期高血压发展过程中，并将其与对照Wistar京都大鼠进行了比较。方法和结果-我们用动态2-[F-18]氟-2-脱氧-D-葡萄糖正电子发射断层扫描连续评估了心肌葡萄糖摄取率（Ki），并用心脏磁共振成像在体内评估了射血分数和左心室质量与体重的比值。在离体灌注心脏中测定葡萄糖摄取和氧化速率，并在解剖的心脏中分析代谢物、雷帕霉素活性的哺乳动物靶标和内质网应激。与Wistar京都大鼠相比，SHR体内葡萄糖摄取率（Ki）增加，并且早在2个月大时就出现高血压时射血分数降低。从1个月开始，离体灌注的SHR心脏显示葡萄糖摄取和氧化速率增加。2个月大时的心脏代谢物分析显示丙酮酸、脂肪酰和支链氨基酸衍生的肉毒碱、氧化应激和炎症升高。哺乳动物雷帕霉素活性靶点在SHR中从2个月开始增加。左心室质量体重比和内质网应激升高5个月大的SHR. Conclusions，因此，在遗传性高血压模型，慢性心脏压力超负荷及时导致心肌葡萄糖摄取和氧化增加，代谢异常。这些症状与心功能不全同时发生或先于心功能不全发生，而左心室肥大则发生较晚。心肌代谢改变可作为高血压左室肥厚的早期诊断指标。
Background-Sustained pressure overload leads to changes in cardiac metabolism, function, and structure. Both time course and causal relationships between these changes are not fully understood. Therefore, we studied spontaneously hypertensive rats (SHR) during early hypertension development and compared them to control Wistar Kyoto rats.Methods and Results-We serially evaluated myocardial glucose uptake rates (Ki) with dynamic 2-[F-18] fluoro-2-deoxy-D-glucose positron emission tomography, and ejection fraction and left ventricular mass to body weight ratios with cardiac magnetic resonance imaging in vivo, determined glucose uptake and oxidation rates in isolated perfused hearts, and analyzed metabolites, mammalian target of rapamycin activity and endoplasmic reticulum stress in dissected hearts. When compared with Wistar Kyoto rats, SHR demonstrated increased glucose uptake rates (Ki) in vivo, and reduced ejection fraction as early as 2 months of age when hypertension was established. Isolated perfused SHR hearts showed increased glucose uptake and oxidation rates starting at 1 month. Cardiac metabolite analysis at 2 months of age revealed elevated pyruvate, fatty acyl-and branched chain amino acid-derived carnitines, oxidative stress, and inflammation. Mammalian target of rapamycin activity increased in SHR beginning at 2 months. Left ventricular mass to body weight ratios and endoplasmic reticulum stress were elevated in 5 monthold SHR.Conclusions-Thus, in a genetic hypertension model, chronic cardiac pressure overload promptly leads to increased myocardial glucose uptake and oxidation, and to metabolite abnormalities. These coincide with, or precede, cardiac dysfunction while left ventricular hypertrophy develops only later. Myocardial metabolic changes may thus serve as early diagnostic markers for hypertension-induced left ventricular hypertrophy.