Exercise Training Reveals Inflexibility of the Diaphragm in an Animal Model of Patients With Obesity-Driven Heart Failure With a Preserved Ejection Fraction
Exercise Training Reveals Inflexibility of the Diaphragm in an Animal Model of Patients With Obesity-Driven Heart Failure With a Preserved Ejection Fraction
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DOI：
10.1161/jaha.117.006416
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发表时间：
2017-10-01
影响因子：
5.4
通讯作者：
Adams, Volker
中科院分区：
文献类型：
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作者：
Bowen, T. Scott;Brauer, Dominic;Adams, Volker
背景：呼吸肌无力导致心力衰竭伴射血分数保留（HFpEF）患者的运动不耐受，这是一种以多种合并症为特征的疾病，治疗方法很少。因此，我们的目的是通过使用肥胖心脏代谢大鼠模型，对HFpEF中发生的潜在膈肌改变提供新的见解，并进一步评估仅在显性HFpEF发生后进行运动训练是否可以逆转损伤。方法和结果：肥胖的ZSF1大鼠（n= 12）在20周时与瘦的对照组（n= 8）进行比较，另外3组肥胖的ZSF1大鼠在28周时进行了8周的久坐行为（n= 13）、高强度间歇训练（n= 11）或中等持续训练（n= 11）的比较。肥胖大鼠在20周和28周时出现明显的HFpEF表型。在20周的膈肌中，HFpEF诱导向氧化表型和纤维肥大转变，并伴有MuRF1和MuRF2蛋白表达降低，但观察到线粒体和收缩功能损伤。在28周时，高强度间歇训练或中等连续训练的运动训练方案都不能逆转HFpEF引起的膈肌改变。结论：本研究使用了一种具有多种合并症和运动不耐受（即与患者表型非常相似）的特征良好的HFpEF大鼠模型，提供了证据表明，在8周的有氧运动训练后，显性HFpEF引起的膈膜改变和功能障碍并没有逆转。因此，是否需要其他治疗干预措施来治疗HFpEF患者的呼吸肌无力值得进一步研究。
Background-Respiratory muscle weakness contributes to exercise intolerance in patients with heart failure with a preserved ejection fraction (HFpEF)-a condition characterized by multiple comorbidities with few proven treatments. We aimed, therefore, to provide novel insight into the underlying diaphragmatic alterations that occur in HFpEF by using an obese cardiometabolic rat model and further assessed whether exercise training performed only after the development of overt HFpEF could reverse impairments.Methods and Results-Obese ZSF1 rats (n= 12) were compared with their lean controls (n= 8) at 20 weeks, with 3 additional groups of obese ZSF1 rats compared at 28 weeks following 8 weeks of either sedentary behavior (n= 13), high-intensity interval training (n= 11), or moderate-continuous training (n= 11). Obese rats developed an obvious HFpEF phenotype at 20 and 28 weeks. In the diaphragm at 20 weeks, HFpEF induced a shift towards an oxidative phenotype and a fiber hypertrophy paralleled by a lower protein expression in MuRF1 and MuRF2, yet mitochondrial and contractile functional impairments were observed. At 28 weeks, neither the exercise training regimen of high-intensity interval training or moderate-continuous training reversed any of the diaphragm alterations induced by HFpEF.Conclusions-This study, using a well-characterized rat model of HFpEF underpinned by multiple comorbidities and exercise intolerance (ie, one that closely resembles the patient phenotype), provides evidence that diaphragm alterations and dysfunction induced in overt HFpEF are not reversed following 8 weeks of aerobic exercise training. As such, whether alternative therapeutic interventions are required to treat respiratory muscle weakness in HFpEF warrants further investigation.