Department of Internal Medicine, National Taiwan University College of Medicine and Hospital Yun-Lin Branch, Yun-Lin, Taiwan, China.
Crit Care Med. 2011 May;39(5):984-92. doi: 10.1097/CCM.0b013e31820a91b9.
The inflammatory process is associated with cardiac diastolic dysfunction, which has been demonstrated to be an independent prognostic marker for the mortality of critically ill patients. We investigated the association among inflammatory cytokines (tumor necrosis factor-α and interleukin-6), diastolic heart failure, and the possible molecular mechanism.
Prospective case-controlled cohort and molecular studies.
University hospital and research laboratory.
Patients with a diagnosis of diastolic heart failure by echocardiography and matched control subjects from the general population (study group 1) and also subjects from the intensive care unit (study group 2). Sarcoplasmic reticulum Ca2+-ATPase (SERCA2) gene expression and diastolic calcium decay in HL-1 cardiomyocytes were used as molecular phenotypes of diastolic heart failure.
Soluble plasma levels of tumor necrosis factor-α and interleukin-6 were measured in all subjects. An approximate 1.75-kb promoter of the SERCA2 gene was cloned to the pGL3 luciferase reporter. The effect of tumor necrosis factor-α and interleukin-6 on SERCA2 gene expression and diastolic calcium decay of HL-1 cardiomyocytes were investigated.
Patients with diastolic heart failure had significantly higher plasma levels of tumor necrosis factor-α and interleukin-6 than the control subjects. Significant correlations (p < .01 for each) were found for tumor necrosis factor-α and E/Em (r = .87) and E/A (r = -0.69), and for interleukin-6 and E/Em (r = .80) and E/A (r = -0.65). Cytokine levels were also correlated with diastolic function in critically ill patients (study group 2), and diastolic function improved significantly in association with decrease of cytokines. Tumor necrosis factor-α, interleukin-6, and sera from critically ill patients downregulated the expression of the SERCA2 gene. Tumor necrosis factor-α and interleukin-6 also delayed the diastolic calcium reuptake and decay in cardiomyocytes.
Through downregulation of SERCA2 gene expression, inflammatory cytokines may cause cardiac diastolic dysfunction by decreasing diastolic calcium reuptake. Our study may suggest novel therapeutic strategies for diastolic heart failure and critically ill patients by modulating inflammatory reactions.
炎症过程与心脏舒张功能障碍有关，舒张功能障碍已被证明是危重病患者死亡率的独立预后标志物。我们研究了炎症细胞因子（肿瘤坏死因子-α和白细胞介素-6）、舒张性心力衰竭以及可能的分子机制之间的关系。
前瞻性病例对照队列和分子研究。
大学医院和研究实验室。
通过超声心动图诊断为舒张性心力衰竭的患者和来自普通人群的匹配对照（研究组 1），以及来自重症监护病房的患者（研究组 2）。HL-1 心肌细胞中的肌浆网 Ca2+-ATP 酶（SERCA2）基因表达和舒张钙衰减被用作舒张性心力衰竭的分子表型。
测量所有受试者的可溶性血浆肿瘤坏死因子-α和白细胞介素-6水平。克隆 SERCA2 基因的大约 1.75kb 启动子到 pGL3 荧光素酶报告基因。研究肿瘤坏死因子-α和白细胞介素-6对 HL-1 心肌细胞 SERCA2 基因表达和舒张钙衰减的影响。
舒张性心力衰竭患者的血浆肿瘤坏死因子-α和白细胞介素-6水平明显高于对照组。肿瘤坏死因子-α与 E/Em（r =.87）和 E/A（r = -0.69），白细胞介素-6 与 E/Em（r =.80）和 E/A（r = -0.65）之间存在显著相关性（p <.01 每个）。细胞因子水平也与危重病患者的舒张功能相关（研究组 2），细胞因子水平降低与舒张功能显著改善相关。肿瘤坏死因子-α、白细胞介素-6 和危重病患者的血清下调 SERCA2 基因的表达。肿瘤坏死因子-α和白细胞介素-6还延迟了心肌细胞舒张期钙内流和衰减。
通过下调 SERCA2 基因表达，炎症细胞因子可能通过减少舒张期钙内流引起心脏舒张功能障碍。我们的研究可能通过调节炎症反应为舒张性心力衰竭和危重病患者提供新的治疗策略。
