Background: Left ventricular remodeling (LVR) after myocardial infarction is associated with an increased risk of heart failure and death. In spite of a modern therapeutic approach, LVR remains relatively frequent and difficult to predict in clinical practice. Our aim was to identify new biomarkers of LVR and understand their involvement in its development.

Methods and Results: Proteomic analysis of plasma from the REVE-2 study (Remodelage Ventriculaire)—a study dedicated to the analysis of LVR which included 246 patients after a first anterior myocardial infarction—identified increased plasma levels of CLU (clusterin) in patients with high LVR. We used a rat model of myocardial infarction to analyze CLU expression in the LV and found a significant increase that was correlated with LVR parameters. We found increased CLU expression and secretion in primary cultures of rat neonate cardiomyocytes hypertrophied by isoproterenol. Silencing of CLU in hypertrophied neonate cardiomyocytes induced a significant decrease in cell size, ANP (atrial natriuretic peptide), and BNP (B-type natriuretic peptide) expression, associated with a decreased ERK (extracellular signal-regulated kinase) 1/2 activity, suggesting a prohypertrophic role of CLU. We then confirmed a significant increase of both intracellular p-CLU (precursor form of CLU) and m-CLU (mature form of CLU) in failing human hearts. Finally, the circulating levels of CLU (secreted form) were increased in patients with chronic heart failure who died from cardiovascular cause during a 3-year follow-up (n=99) compared with survivors (n=99).

Conclusions: Our results show for the first time that plasma CLU levels are associated with LVR post–myocardial infarction, have in part a cardiac origin, and are a predictor of early death in heart failure patients.

背景：心肌梗死后左心室重构（LVR）与心力衰竭和死亡的风险增加相关。尽管有现代治疗方法，LVR仍然相对频繁且在临床实践中难以预测。我们的目的是鉴定LVR的新生物标志物，并了解其在LVR发展中的作用。

方法和结果：来自REVE-2研究的血浆蛋白质组学分析（重塑室性心律失常）是一项致力于LVR分析的研究，其中包括246例首次心肌梗塞后的患者，该研究确定了高LVR患者血浆CLU（簇蛋白）水平升高。我们使用大鼠心肌梗死模型来分析LV中CLU的表达，发现与LVR参数相关的显着增加。我们发现大鼠异丙肾上腺素肥大的新生心肌细胞的原代培养物中CLU表达和分泌增加。肥厚的新生心肌细胞中CLU的沉默导致细胞大小，ANP（心钠素）和BNP（B型钠尿素肽）表达显着降低，与ERK（细胞外信号调节激酶）1/2活性降低相关，提示CLU的肥大性作用。然后，我们证实在衰竭的人类心脏中，细胞内p-CLU（CLU的前体形式）和m-CLU（CLU的成熟形式）均显着增加。最后，与幸存者（n = 99）相比，在三年的随访期间（n = 99）死于心血管原因的慢性心力衰竭患者的循环CLU（分泌形式）水平增加。

结论：我们的结果首次显示血浆CLU水平与心肌梗死后LVR相关，部分源于心脏，是心力衰竭患者早期死亡的预测指标。