Department of Anesthesiology and Critical Care, University of Pennsylvania, JMB 127, 3620 Hamilton Walk, Philadelphia, PA, 19146, USA.
Department of Neurology, University of Pennsylvania, JMB 127, 3620 Hamilton Walk, Philadelphia, PA, 19146, USA.
Clin Epigenetics. 2022 Sep 6;14(1):112. doi: 10.1186/s13148-022-01331-6.
Despite clinical relevance of immunological activation due to histone leakage into the serum following cardiac surgery, long-term data describing their longitudinal dynamic are lacking. Therefore, this study examines the serum levels of histone 3 (tH3) and its modifications (H3K4me3 and H3K27ac) alongside immune system activation during the acute and convalescence phases of cardiac surgery.
Blood samples from fifty-nine individuals were collected before non-emergent cardiac surgery (t) and 24 h (t), seven days (t), and three months (t) post-procedure to examine serum levels of tH3, H3K4me3, and H3K27ac. Serum heat shock protein-60 (HSP-60) was a surrogate of the cellular damage marker. Serum C-reactive protein (CRP) and interleukin 6 (IL-6) assessed smoldering inflammation. TNFα and IL-6 production by whole blood in response to lipopolysaccharide (LPS) evaluated immunological activation. Electronic medical records provided demographic, peri-operative, and clinical information. Paired longitudinal analyses were employed with data expressed as mean and standard deviation (X ± SD) or median and interquartile range (Me[IQ25; 75%].
Compared to pre-operative levels (tH3 = 1.6[0.33;2.4]), post-operative serum tH3 significantly (p > 0.0001) increased after heart surgery (tH3 = 2.2[0.3;28]), remained elevated at 7 days (tH3 = 2.4[0.37;5.3]), and at 3 months (tH3 = 2.0[0.31;2.9]). Serum H3K27ac was elevated at 24 h (H3K27ac = 0.66 ± 0.51; p = 0.025) and seven days (H3K27ac = 0.94 ± 0.95; p = 0.032) as compared to baseline hours (H3K27ac = 0.55 ± 0.54). Serum H3K4me3 was significantly diminished at three months (H3K4me3 = 0.94 ± 0.54 vs. H3K27ac = 0.59 ± 0.89; p = 0.008). tH3 correlated significantly with the duration of anesthesia (r = 0.38). In contrast, HSP-60 normalized seven days after surgery. Peri-operative intake of acetaminophen, but no acetylsalicylic acid (ASA), acid, ketorolac or steroids, resulted in the significant depression of serum H3K4me3 at 24 h (H3K4me3 = 1.26[0.71; 3.21] vs H3K4me3 = 0.54[0.07;1.01]; W[50] = 2.26; p = 0.021). CRP, but not IL-6, remained elevated at 3 months compared to pre-surgical levels and correlated with tH3 (r = 0.43), tH3 (r = 0.71; p < 0.05), H3K4me3 (r = 0.53), and H3K27ac (r = 0.49). Production of TNFα by whole blood in response to LPS was associated with serum tH3 (r = 0.67). Diminished H3K4me3 H3K27ac, and H3K27ac, accompanied the emergence of liver failure.
We demonstrated a prolonged elevation in serum histone 3 three months after cardiac surgery. Furthermore, histone 3 modifications had a discrete time evolution indicating differential immune activation.
尽管心脏手术后由于组蛋白泄漏到血清中导致免疫激活具有临床相关性，但缺乏描述其纵向动态的长期数据。因此，本研究在心脏手术的急性期和康复期检查了血清组蛋白 3（tH3）及其修饰物（H3K4me3 和 H3K27ac）以及免疫系统激活的水平。
从 59 名个体中采集血液样本，在非紧急心脏手术前（t）和术后 24 小时（t）、7 天（t）和 3 个月（t）时检查 tH3、H3K4me3 和 H3K27ac 的血清水平。血清热休克蛋白 60（HSP-60）是细胞损伤标志物的替代物。血清 C 反应蛋白（CRP）和白细胞介素 6（IL-6）评估亚临床炎症。全血对脂多糖（LPS）的反应评估免疫激活的 TNFα 和 IL-6 产生。电子病历提供了人口统计学、围手术期和临床信息。采用配对纵向分析，数据表示为平均值和标准差（X±SD）或中位数和四分位距（Me[IQ25；75%]）。
与术前水平相比（tH3=1.6[0.33;2.4]），心脏手术后血清 tH3 显著增加（p>0.0001）（tH3=2.2[0.3;28]），7 天时仍升高（tH3=2.4[0.37;5.3]），3 个月时（tH3=2.0[0.31;2.9]）。与基线时间相比，术后 24 小时（H3K27ac=0.66±0.51;p=0.025）和 7 天时（H3K27ac=0.94±0.95;p=0.032）血清 H3K27ac 升高。与基线时间相比，术后 3 个月时血清 H3K4me3 明显降低（H3K4me3=0.94±0.54 比 H3K27ac=0.59±0.89;p=0.008）。tH3 与麻醉持续时间显著相关（r=0.38）。相反，HSP-60 在手术后 7 天恢复正常。围手术期摄入扑热息痛，但不摄入乙酰水杨酸（ASA）、酸、酮咯酸或类固醇，导致术后 24 小时血清 H3K4me3 明显降低（H3K4me3=1.26[0.71;3.21]比 H3K4me3=0.54[0.07;1.01];W[50]=2.26;p=0.021）。与术前水平相比，CRP 在 3 个月时仍升高，且与 tH3 相关（r=0.43），tH3（r=0.71;p<0.05），H3K4me3（r=0.53）和 H3K27ac（r=0.49）。全血对 LPS 的 TNFα 产生与血清 tH3 相关（r=0.67）。H3K4me3、H3K27ac 和 H3K27ac 的减少伴随着肝功能衰竭的出现。
我们证明了心脏手术后 3 个月血清组蛋白 3 的持续升高。此外，组蛋白 3 修饰具有不同的时间演变，表明免疫激活存在差异。
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