Berlin Institute of Health (BIH) & Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité - Universitätsmedizin Berlin, Campus Virchow Klinikum, Berlin, Germany.
DZHK (German Center for Cardiovascular Research), partner site Berlin, Berlin, Germany.
ESC Heart Fail. 2020 Aug;7(4):1442-1451. doi: 10.1002/ehf2.12760. Epub 2020 May 28.
The alarmin S100A8/S100A9 (S100A8/A9) is released by activated monocytes/macrophages and neutrophils in the setting lymphocytic myocarditis (MC). We recently demonstrated its therapeutic potential in experimental acute MC. Now, we investigated the diagnostic relevance of S100A8/A9 serum levels in patients with suspected acute and chronic MC and in patients with heart failure without cardiac inflammation.
Serum S100A8/A9 levels were analysed in patients with a recent onset of MC [≤ 30 days, n = 32; ejection fraction (EF): 45.4 ± 12.9%], dilated cardiomyopathy patients with inflammation (n = 112; EF: 29.0 ± 11.4%), or without inflammation (n = 58; EF: 26.6 ± 9.3%), and controls (n = 25; EF: 68.5 ± 4.6%), by using specific ELISAs. Blood samples were collected at Time Point 1 (T1), where also endomyocardial biopsies (EMBs) were withdrawn. Patients with a recent onset of MC showed a 4.6-fold increase in serum S100A8/A9 levels vs. controls (MC: 1948 ± 1670 ng/mL vs. controls: 426 ± 307 ng/mL; P < 0.0001). Serum S100A8/A9 correlated with the disease activity, represented by EMB-derived counts of inflammatory cells (CD3: r = 0.486, P = 0.0047, lymphocyte function-associated antigen-1: r = 0.558, P = 0.0009, macrophage-1 antigen: r = 0.434, P = 0.013), the EMB mRNA levels of S100A8, S100A9 (r = 0.541, P = 0.002), and left ventricular ejection fraction (LVEF: r = 0.498, P = 0.0043). EMB immunofluorescence co-stainings display macrophages/monocytes and neutrophils as the main source of S100A8 and S100A9 in recent onset MC. The diagnostic value of serum alarmin levels (cut-off 583 ng/mL) was characterized by a specificity of 92%, a sensitivity of 90.6%, positive predictive value of 93.5%, negative predictive value of 88.5%, and an accuracy of 0.949 (95% confidence interval [0.89-1]). In a subgroup of MC patients, S100A8/A9 serum levels and EMBs at T1 (n = 12) and a follow-up visit (T2, n = 12, mean follow-up 8.5 months) were available. A fall of serum S100A8/A9 (T1: 2208 ± 1843 ng/mL vs. T2: 888.8 ± 513.7 ng/mL; P = 0.00052) was associated with a reduced cardiac inflammation (CD3 T1: 70.02 ± 107.4 cells per square millimetre vs. T2: 59.18 ± 182.5 cells per square millimetre; P = 0.0342, lymphocyte function-associated antigen-1 T1: 133.5 ± 187.1 cells per square millimetre vs. T2: 74.12 ± 190.5 cells per square millimetre; P = 0.0186, and macrophage-1 antigen T1: 132.6 ± 129.5 cells per square millimetre vs. T2: 54.41 ± 65.16 cells per square millimetre; P = 0.0015). Serum S100A8/A9 levels were only slightly increased in patients within the chronic phase of MC and in heart failure patients without inflammation vs. controls.
Serum S100A8/A9 might serve as an additional tool in the diagnostic workup of suspected acute MC patients.
S100A8/S100A9（S100A8/A9）是激活的单核细胞/巨噬细胞和中性粒细胞在淋巴细胞性心肌炎（MC）中的释放物。我们最近证明了其在实验性急性 MC 中的治疗潜力。现在，我们研究了 S100A8/A9 血清水平在疑似急性和慢性 MC 患者以及无心脏炎症的心力衰竭患者中的诊断相关性。
通过特定的 ELISA 分析了最近发病的 MC 患者[≤30 天，n=32；射血分数（EF）：45.4±12.9%]、炎症性扩张型心肌病患者（n=112；EF：29.0±11.4%）或无炎症患者（n=58；EF：26.6±9.3%）和对照组（n=25；EF：68.5±4.6%）的血清 S100A8/A9 水平。在时间点 1（T1）采集血液样本，同时还进行了心内膜心肌活检（EMB）。与对照组相比，最近发病的 MC 患者的血清 S100A8/A9 水平增加了 4.6 倍（MC：1948±1670ng/mL vs. 对照组：426±307ng/mL；P<0.0001）。血清 S100A8/A9 与疾病活动度相关，由 EMB 衍生的炎症细胞计数表示（CD3：r=0.486，P=0.0047，淋巴细胞功能相关抗原-1：r=0.558，P=0.0009，巨噬细胞-1 抗原：r=0.434，P=0.013），EMB 的 S100A8、S100A9 的 mRNA 水平（r=0.541，P=0.002）和左心室射血分数（LVEF：r=0.498，P=0.0043）。EMB 免疫荧光共染色显示巨噬细胞/单核细胞和中性粒细胞是最近发病的 MC 中 S100A8 和 S100A9 的主要来源。血清警报素水平（截断值 583ng/mL）的诊断价值特征为特异性 92%、敏感性 90.6%、阳性预测值 93.5%、阴性预测值 88.5%和准确性 0.949（95%置信区间[0.89-1]）。在 MC 患者的一个亚组中，在时间点 1（T1，n=12）和随访时（T2，n=12，平均随访 8.5 个月）获得了血清 S100A8/A9 水平和 EMBs。血清 S100A8/A9 水平的下降（T1：2208±1843ng/mL vs. T2：888.8±513.7ng/mL；P=0.00052）与心脏炎症减少相关（CD3 T1：70.02±107.4 个细胞/平方毫米 vs. T2：59.18±182.5 个细胞/平方毫米；P=0.0342，淋巴细胞功能相关抗原-1 T1：133.5±187.1 个细胞/平方毫米 vs. T2：74.12±190.5 个细胞/平方毫米；P=0.0186，和巨噬细胞-1 抗原 T1：132.6±129.5 个细胞/平方毫米 vs. T2：54.41±65.16 个细胞/平方毫米；P=0.0015）。慢性 MC 期和无炎症心力衰竭患者的血清 S100A8/A9 水平仅略有升高。
血清 S100A8/A9 可能作为疑似急性 MC 患者诊断评估的附加工具。
