Decreased rates of substrate oxidation ex vivo predict the onset of heart failure and contractile dysfunction in rats with pressure overload
Decreased rates of substrate oxidation ex vivo predict the onset of heart failure and contractile dysfunction in rats with pressure overload
复制标题
DOI：
10.1093/cvr/cvp414
复制
发表时间：
2010-06-01
影响因子：
10.8
通讯作者：
Schwarzer, Michael
中科院分区：
文献类型：
--
作者：
Doenst, Torsten;Pytel, Gracjan;Schwarzer, Michael
左心室肥厚是心力衰竭的一个危险因素。然而，它也是对压力过载的一种代偿性反应，以适应增加的工作负荷。我们测试了能量底物代谢的变化是否可预测收缩功能障碍的发展。通过主动脉弓缩窄对Sprague - Dawley大鼠诱导慢性压力过载，持续2、6、10或20周。通过超声心动图和有创压力测量评估体内收缩功能。在离体工作心脏中评估葡萄糖和脂肪酸氧化以及离体收缩功能，并在离体心脏线粒体中测量呼吸能力。压力过载在2、6和10周时导致进行性肥厚且射血分数（EF）正常，在20周时导致肥厚伴扩张且EF受损。肺与体重的比值作为肺淤血的标志物，在2周时正常（提示代偿性肥厚），但在6周后就已显著增加，一直到20周，表明在6周和10周时存在EF正常的心力衰竭，在20周时EF受损。有创压力测量显示在6周时就已出现收缩功能障碍的证据，并且离体心脏功率甚至在2周时就已降低。重要的是，从2周开始脂肪酸氧化就出现损害，这与葡萄糖氧化的进行性降低有关。相反，离体线粒体的呼吸能力直到10周时都是正常的，仅在EF受损的心脏中才降低。压力过载诱导的脂肪酸氧化损害先于充血性心力衰竭的发生，但线粒体呼吸能力一直维持到体内EF降低。这些时间关系表明在心力衰竭发展过程中底物氧化能力受损与收缩功能障碍之间存在紧密联系，并可能意味着治疗和预后价值。
Left ventricular hypertrophy is a risk factor for heart failure. However, it also is a compensatory response to pressure overload, accommodating for increased workload. We tested whether the changes in energy substrate metabolism may be predictive for the development of contractile dysfunction.Chronic pressure overload was induced in Sprague-Dawley rats by aortic arch constriction for 2, 6, 10, or 20 weeks. Contractile function in vivo was assessed by echocardiography and by invasive pressure measurement. Glucose and fatty acid oxidation as well as contractile function ex vivo were assessed in the isolated working heart, and respiratory capacity was measured in isolated cardiac mitochondria. Pressure overload caused progressive hypertrophy with normal ejection fraction (EF) at 2, 6, and 10 weeks, and hypertrophy with dilation and impaired EF at 20 weeks. The lung-to-body weight ratio, as marker for pulmonary congestion, was normal at 2 weeks (indicative of compensated hypertrophy) but significantly increased already after 6 and up to 20 weeks, suggesting the presence of heart failure with normal EF at 6 and 10 weeks and impaired EF at 20 weeks. Invasive pressure measurements showed evidence for contractile dysfunction already after 6 weeks and ex vivo cardiac power was reduced even at 2 weeks. Importantly, there was impairment in fatty acid oxidation beginning at 2 weeks, which was associated with a progressive decrease in glucose oxidation. In contrast, respiratory capacity of isolated mitochondria was normal until 10 weeks and decreased only in hearts with impaired EF.Pressure overload-induced impairment in fatty acid oxidation precedes the onset of congestive heart failure but mitochondrial respiratory capacity is maintained until the EF decreases in vivo. These temporal relations suggest a tight link between impaired substrate oxidation capacity in the development of heart failure and contractile dysfunction and may imply therapeutic and prognostic value.