Impact of intrinsic and acquired aerobic exercise capacity on pressure overload induced heart failure development

临床研究表明，有氧运动能力和所有原因的发病率和死亡率之间有很强的关系。低运动能力是心血管死亡率的一个更强的预测因子，而不是所有其他公认的危险因素，如体重指数，糖尿病或高血压。此外，这种关系适用于健康个体和心力衰竭患者。重要的是，运动能力由内在（遗传决定）和后天（训练诱导）组成。目前的观点是，这种运动能力的大部分是由基因决定的，而小部分是可以训练的。然而，由于人类的天然遗传异质性，不可能在患者中清楚区分这两个部分。幸运的是，在测试内在运动能力后，使用选择性繁殖开发的高（HCR）和低（LCR）能力跑步者的大鼠模型允许这种区别。最近的证据表明，这些遗传上不同的动物的表型的主要差异可能是由线粒体功能的差异引起的，特别是在底物氧化和ATP产生，ROS产生和耐受性，以及钙处理。相同的线粒体功能在心力衰竭的发展中起重要作用。我们已经证明了压力超负荷心力衰竭中整个线粒体蛋白质组的变化，并特别确定了复合物I活性降低和ROS产生升高。HCR和LCR的初步实验表明HCR中的复合物I活性更高，其随着运动进一步增加。我们现在的目标是评估运动能力的遗传决定和获得部分对PO-HF发展倾向的作用（具体目标1）以及线粒体呼吸能力（特别是复合物I），ROS产生和耐受性以及钙处理如何与我们的遗传模型中有或没有运动训练的PO-HF发展差异相关（具体目标2）。这项研究是可能的，因为我们的HCR和LCR的遗传模型。我们将把我们建立的心力衰竭模型和其他建立的和新的研究技术转移到这个遗传模型上。我们将评估有或没有压力超负荷和有或没有运动训练的心脏收缩和线粒体功能。研究结果将首次评估心力衰竭的倾向，这些倾向受1）运动能力的遗传决定和2）耐力训练的具体影响。他们将进一步深入了解潜在的线粒体机制。

Clinical studies demonstrate a strong relationship between aerobic exercise capacity and all cause morbidity and mortality. Low exercise capacity is a stronger predictor of cardiovascular mortality than all other accepted risk factors such as body mass index, diabetes, or hypertension. In addition, this relationship holds true for both healthy individuals and patients with heart failure. Importantly, exercise capacity is composed of intrinsic (genetically determined) and acquired (training induced) components. It is the current notion, that the larger fraction of this exercise capacity is genetically determined and the smaller part can be trained. However, due to the natural genetic heterogeneity in humans, it is impossible to clearly distinguish the two parts in patients. Fortunately, the rat model of high (HCR) and low (LCR) capacity runners, developed using selective breeding after testing for intrinsic exercise capacity, allows for this distinction. Recent evidence indicates that a major difference in the phenotype of these genetically different animals may be caused by differences in mitochondrial function, specifically in substrate oxidation and ATP production, ROS production and tolerance, and calcium handling. The same mitochondrial functions play an important role in the development of heart failure. We already demonstrated changes in the entire mitochondrial proteome in pressure overload heart failure and specifically identified reduced complex I activity and elevated ROS production. Preliminary experiments in HCR and LCR suggest higher complex I activity in HCR which further increases with exercise. We now aim to assess the role of the genetically determined and the acquired part of exercise capacity on the propensity for PO-HF development (Specific Aim 1) and how mitochondrial respiratory capacity (specifically complex I), ROS production and tolerance, and calcium handling is related to differences in PO-HF development in our genetic model with or without exercise training (Specific Aim 2). This investigation is possible because of our genetic model of HCR and LCR. We will transfer our established heart failure model and other established and new investigational techniques to this genetic model. We will assess cardiac contractile and mitochondrial function with or without pressure overload and with or without exercise training. The results will allow for the first time assessing the propensity to develop heart failure influenced by 1) genetic determination of exercise capacity and 2) the specific impact of endurance training. They will further provide insight into the underlying mitochondrial mechanisms.