Myocardial Titin Hypophosphorylation Importantly Contributes to Heart Failure With Preserved Ejection Fraction in a Rat Metabolic Risk Model
Myocardial Titin Hypophosphorylation Importantly Contributes to Heart Failure With Preserved Ejection Fraction in a Rat Metabolic Risk Model
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DOI：
10.1161/circheartfailure.113.000539
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发表时间：
2013-11-01
影响因子：
9.7
通讯作者：
Paulus, Walter J.
中科院分区：
文献类型：
--
作者：
Hamdani, Nazha;Franssen, Constantijn;Paulus, Walter J.
肥胖和糖尿病是射血分数正常的心力衰竭患者的重要代谢危险因素和常见的合并症。它们通过胶原沉积或肌联蛋白修饰导致心肌舒张功能障碍（DD）。在20周时射血分数保留的心力衰竭后的肥胖、糖尿病BNF 1大鼠中研究胶原沉积和肌联蛋白修饰对心肌DD的相对重要性。（Wistar-Kyoto，n=11; LeanF_1，n=11;肥胖组11例，肥胖组11例，高脂饮食组11例，随访20周，重复代谢，肾，和超声心动图评价，并在安乐死时进行血流动力学评估。还测定了心肌胶原、胶原交联、肌联蛋白亚型和磷酸化。静息张力（F-被动）肌节长度的关系，获得小肌肉条之前和之后的氯化钾-碘化钾治疗，unanchores肌联蛋白，并允许肌联蛋白和细胞外基质的F-被动的贡献被辨别。在20周时，瘦的BIF 1组是高血压，而肥胖的BIF 1组是高血压和糖尿病。只有肥胖的BMPF 1组出现了射血分数保留的心力衰竭，这从肺重量增加、左心室射血分数保留和左心室DD中可以明显看出。潜在的心肌DD是明显的高肌条硬度，这在很大程度上（80%）归因于肌联蛋白磷酸化不足。后者具体发生在弹性N2总线段的S3991网站和在S12884网站的PEVK segment.Conclusions肥胖的PERF 1大鼠在20周的时间跨度与保留射血分数的心力衰竭。肌联蛋白低磷酸化对潜在的心肌DD有重要作用。
Background Obesity and diabetes mellitus are important metabolic risk factors and frequent comorbidities in heart failure with preserved ejection fraction. They contribute to myocardial diastolic dysfunction (DD) through collagen deposition or titin modification. The relative importance for myocardial DD of collagen deposition and titin modification was investigated in obese, diabetic ZSF1 rats after heart failure with preserved ejection fraction development at 20 weeks.Methods and Results Four groups of rats (Wistar-Kyoto, n=11; lean ZSF1, n=11; obese ZSF1, n=11, and obese ZSF1 with high-fat diet, n=11) were followed up for 20 weeks with repeat metabolic, renal, and echocardiographic evaluations and hemodynamically assessed at euthanization. Myocardial collagen, collagen cross-linking, titin isoforms, and phosphorylation were also determined. Resting tension (F-passive)-sarcomere length relations were obtained in small muscle strips before and after KCl-KI treatment, which unanchors titin and allows contributions of titin and extracellular matrix to F-passive to be discerned. At 20 weeks, the lean ZSF1 group was hypertensive, whereas both obese ZSF1 groups were hypertensive and diabetic. Only the obese ZSF1 groups had developed heart failure with preserved ejection fraction, which was evident from increased lung weight, preserved left ventricular ejection fraction, and left ventricular DD. The underlying myocardial DD was obvious from high muscle strip stiffness, which was largely (80%) attributable to titin hypophosphorylation. The latter occurred specifically at the S3991 site of the elastic N2Bus segment and at the S12884 site of the PEVK segment.Conclusions Obese ZSF1 rats developed heart failure with preserved ejection fraction during a 20-week time span. Titin hypophosphorylation importantly contributed to the underlying myocardial DD.