Infusion of light chains from patients with cardiac amyloidosis causes diastolic dysfunction in isolated mouse hearts
Infusion of light chains from patients with cardiac amyloidosis causes diastolic dysfunction in isolated mouse hearts
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DOI：
10.1161/circ.104.14.1594
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发表时间：
2001-10-02
期刊：
影响因子：
37.8
通讯作者：
Apstein, CS
中科院分区：
文献类型：
--
作者：
Liao, RL;Jain, M;Apstein, CS
背景原发性（AL）淀粉样变性是一种浆细胞恶液质，其特征是免疫球蛋白轻链（LC）的克隆产生，导致细胞外淀粉样原纤维随后全身沉积。心脏受累的特点是舒张期充盈受损和限制性心肌病的血流动力学模式。尽管 AL 淀粉样变性患者的心源性死亡通常与广泛的心肌浸润有关，但浸润本身与心力衰竭或生存程度无关。我们假设，除了淀粉样原纤维沉积的任何机械效应外，循环单克隆 LC 还可能直接损害心脏功能。因此，我们在离体小鼠心脏模型中检测了淀粉样 LC 蛋白对舒张和收缩心脏功能的影响。方法和结果 - LC 是从非淀粉样疾病患者或非心脏、轻度心脏疾病患者中获得的。严重的心脏涉及 AL 淀粉样变性。将盐水或 LC (100 微克/毫升) 注入 Langendorff 灌注、等容收缩的小鼠心脏中。盐水和对照、非心脏和轻度心脏 LC 输注不会改变离体心脏功能。相比之下，输注严重的心脏 LC 会导致心室舒张明显受损，同时保留收缩功能。结论 - 这些结果表明，输注 AL 淀粉样变性患者的 LC 会导致舒张功能障碍，与心脏累及 AL 淀粉样变性患者中观察到的情况相似，并且表明淀粉样 LC 蛋白可能直接促进淀粉样心肌病的发病机制和快速进展，与细胞外原纤维沉积无关。
Background-Primary (AL) amyloidosis is a plasma cell dyscrasia characterized by clonal production of immunoglobulin light chains (LC) resulting in the subsequent systemic deposition of extracellular amyloid fibrils. Cardiac involvement is marked by the hemodynamic pattern of impaired diastolic filling and restrictive cardiomyopathy. Although cardiac death in patients with AL amyloidosis is usually associated with extensive myocardial infiltration, the infiltration alone does not correlated with the degree of heart failure or survival. We hypothesized that circulating monoclonal LC may directly impair cardiac function, in addition to any mechanical effects of amyloid fibril deposition. Therefore, we examined the effects of amyloid LC proteins on diastolic and systolic cardiac function, as measured in an isolated mouse heart model.Methods and Results-LC were obtained from patients with nonamyloid disease or from those with noncardiac, mild cardiac. and severe cardiac involved AL amyloidosis. Saline or LC (100 mug/mL) was infused into a Langendorff-perfused, isovolumically contracting mouse heart. Saline and control, noncardiac, and mild-cardiac LC infusions did not alter ex vivo cardiac function. In contrast, infusion of sever cardiac LC resulted in marked impairment of ventricular relaxation with preservation of contractile function.Conclusion-These results demonstrate that infusion of LC from patients with AL amyloidosis result in diastolic dysfunction similar to that observed in patients with cardiac involved AL amyloidosis, and they suggest that amyloid LC proteins may contribute directly to the pathogenesis and the rapid progression of amyloid cardiomyopathy, independent of extracellular fibril deposition.