Lorentzon Malin, Råmunddal Truls, Bollano Entela, Soussi Bassam, Waagstein Finn, Omerovic Elmir
Wallenberg Laboratory at Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden.
J Card Fail. 2007 Apr;13(3):230-7. doi: 10.1016/j.cardfail.2006.11.012.
The failing heart is characterized by disturbed myocardial energy metabolism and creatine (Cr) depletion. The aims of this study were to in vivo evaluate the effects of Cr depletion on: a) left ventricular (LV) function and morphology during rest and stress, b) LV energy metabolism, c) catecholamine in LV and plasma content, and d) incidence of malignant ventricular arrhythmias (MVA) during acute myocardial infarction (MI).
Male rats weighing approximately 200 g were used. Two groups were studied: the rats treated with Cr analogue beta-guanidinopropionic acid (BGP) (n = 25) and controls (n = 23). BGP (1 M) was administered by subcutaneously implanted osmotic minipumps over 4 weeks. The rats (BGP n = 9, control n = 12) were than examined with transthoracic echocardiography at basal and at stress conditions induced by transesophageal pacing. In vivo (31)P magnetic resonance spectroscopy (MRS) was used for evaluation of myocardial energy status (BGP n = 7, control n = 12). (31)P MRS, echocardiography and high-performance liquid chromatography analysis of myocardial Cr, total adenine nucleotides and catecholamines in myocardium and plasma were performed on noninfarcted hearts. Myocardial infarction was induced in a subgroup of animals (BGP n = 15, control n = 15) by ligation of the left coronary artery resulting in a large ( approximately 50%) anterolateral MI and acute HF. A computerized electrocardiogram tracing was obtained continuously before induction of MI and up to 60 minutes postinfarction. Qualitative and quantitative variables of ventricular arrhythmias were analyzed using arrhythmia score. Body weight (BW) was lower (P < .01), whereas LV/BW was higher (P < .01) in the BGP group. Total myocardial Cr pool was decreased for at least 50% (P < .01) compared with the controls. There was no difference in total nucleotide pool. Phosphocreatine/adenosine-3-phosphate ratio was lower in the BGP group (P < .01). LV systolic function was disturbed during rest and stress (P < .05). Similarly, LV dimensions were increased in the BGP group (P < .05). Induction of acute MI resulted in markedly increased incidence of MVA and higher mortality in the BGP group (P < .01).
Myocardial Cr depletion results in functional and structural LV alterations associated with lower myocardial energy reserve. Intact myocardial Cr metabolism is important for normal LV function during basal and stress conditions. Acute MI in the setting of myocardial Cr depletion leads to excessive mortality from ventricular arrhythmias and progressive heart failure.
衰竭心脏的特征是心肌能量代谢紊乱和肌酸（Cr）耗竭。本研究的目的是在体内评估Cr耗竭对以下方面的影响：a）静息和应激状态下左心室（LV）功能和形态，b）LV能量代谢，c）LV和血浆中儿茶酚胺含量，以及d）急性心肌梗死（MI）期间恶性室性心律失常（MVA）的发生率。
使用体重约200 g的雄性大鼠。研究了两组：用Cr类似物β-胍基丙酸（BGP）处理的大鼠（n = 25）和对照组（n = 23）。通过皮下植入渗透微型泵在4周内给予BGP（1 M）。然后在基础状态和经食管起搏诱导的应激条件下，对大鼠（BGP组n = 9，对照组n = 12）进行经胸超声心动图检查。体内（31）P磁共振波谱（MRS）用于评估心肌能量状态（BGP组n = 7，对照组n = 12）。对未梗死心脏进行（31）P MRS、超声心动图以及心肌和血浆中Cr、总腺嘌呤核苷酸和儿茶酚胺的高效液相色谱分析。通过结扎左冠状动脉在一组动物（BGP组n = 15，对照组n = 15）中诱导心肌梗死，导致大面积（约50%）前外侧MI和急性心力衰竭。在诱导MI前直至梗死后60分钟连续获取计算机化心电图描记图。使用心律失常评分分析室性心律失常的定性和定量变量。BGP组体重（BW）较低（P <.01），而LV/BW较高（P <.01）。与对照组相比，总心肌Cr池至少减少50%（P <.01）。总核苷酸池无差异。BGP组磷酸肌酸/腺苷-3-磷酸比值较低（P <.01）。静息和应激期间LV收缩功能受损（P <.05）。同样，BGP组LV尺寸增加（P <.05）。急性MI的诱导导致BGP组MVA发生率显著增加和死亡率更高（P <.01）。
心肌Cr耗竭导致与较低心肌能量储备相关的LV功能和结构改变。完整的心肌Cr代谢对于基础和应激条件下的正常LV功能很重要。心肌Cr耗竭情况下的急性MI导致室性心律失常和进行性心力衰竭导致的过度死亡率。
