Lindbom Malin, Ramunddal Truls, Camejo German, Waagstein Finn, Omerovic Elmir
Wallenberg Laboratory at Sahlgrenska University, Gothenburg, Sweden.
J Card Fail. 2008 Mar;14(2):161-6. doi: 10.1016/j.cardfail.2007.10.020.
The failing heart is characterized by disturbed myocardial energy metabolism and creatine depletion. The aims of this study were to evaluate in vivo the effects of creatine (Cr) depletion on 1) left ventricular (LV) function, morphology, and lipid metabolism and 2) to test whether functional, morphologic, and metabolic disturbances induced by Cr depletion are reversible.
Male Balb/c mice approximately 20 g were used. Two groups were studied: the mice treated with creatine analogue beta-guanidinopropionic acid (BGP) (n = 30) and controls (n = 30). BGP (1 M) were administered by subcutaneously implanted osmotic minipumps for 4 weeks. The mice were examined in vivo using echocardiography. High-performance liquid chromatography was used for measurements of the myocardial creatine, adenosine nucleotides, and lipids. BGP was discontinued in a subgroup of mice and these animals were followed for an additional 4 weeks, after which echocardiography was performed under resting and stress conditions. Body weight was lower in BGP mice (P < .001) compared with the controls after 4 weeks. The total myocardial Cr pool was approximately 40% lower (P < .001), whereas total nucleotide pool (TAN) was 18% lower (P = n.s.) in the BGP group. LV systolic function was disturbed at rest and stress in the BGP mice (both P < .05). LV dimensions and LV mass were increased in the BGP group (P < .05). There was an accumulation of intracellular triglycerides in the BGP-treated mice (P < .05). Four weeks after BGP discontinuation Cr, TAN and TG content were restored to the normal levels while LV function, dimension, and mass were normalized.
Myocardial Cr depletion results in LV dysfunction, pathologic remodeling, and lipid accumulation. These alterations are completely reversible on normalization of Cr content. Cr metabolism may be an important target for pharmacologic intervention to increase myocardial efficiency and structural integrity of the failing heart.
衰竭心脏的特征是心肌能量代谢紊乱和肌酸耗竭。本研究的目的是在体内评估肌酸（Cr）耗竭对1）左心室（LV）功能、形态和脂质代谢的影响，以及2）测试Cr耗竭引起的功能、形态和代谢紊乱是否可逆。
使用体重约20 g的雄性Balb/c小鼠。研究了两组：用肌酸类似物β-胍基丙酸（BGP）处理的小鼠（n = 30）和对照组（n = 30）。通过皮下植入渗透微型泵给予BGP（1 M），持续4周。使用超声心动图对小鼠进行体内检查。采用高效液相色谱法测量心肌肌酸、腺苷核苷酸和脂质。在一组小鼠中停止给予BGP，并对这些动物再随访4周，之后在静息和应激条件下进行超声心动图检查。4周后，与对照组相比，BGP小鼠的体重较低（P <.001）。BGP组的心肌总Cr池降低了约40%（P <.001），而总核苷酸池（TAN）降低了18%（P =无统计学意义）。BGP小鼠在静息和应激状态下左心室收缩功能均受到干扰（均P <.05）。BGP组的左心室尺寸和左心室质量增加（P <.05）。BGP处理的小鼠细胞内甘油三酯蓄积（P <.05）。停止给予BGP 4周后，Cr、TAN和TG含量恢复到正常水平，同时左心室功能、尺寸和质量也恢复正常。
心肌Cr耗竭导致左心室功能障碍、病理性重塑和脂质蓄积。Cr含量恢复正常后，这些改变可完全逆转。Cr代谢可能是药物干预的重要靶点，以提高衰竭心脏的心肌效率和结构完整性。
