Meet the First Author, see p 592

Myocardial fibrosis is the common pathophysiologic denominator between myocardial remodeling and the failing heart. Experimental evidence points toward a prominent role of CD4⁺ T helper (Th) lymphocytes, particularly Th17 and Th22 cells, as key players in myocardial remodeling, hence their involvement in humans remains unclear. Quantitative tissue characterization by cardiac magnetic resonance imaging supports noninvasive detection of diffuse myocardial interstitial remodeling by measurement of rates of T1 relaxation.¹ We have previously shown that characterization of noninfarcted myocardium by T1 mapping is predictive of outcome in patients with coronary artery disease (CAD), over and above traditional imaging measures.² We hypothesized that expansion of specific T-cell subsets would be associated with myocardial T1 mapping measurements. Therefore, circulating T cells were measured in forty-six patients with chronic CAD, who were enrolled in the prospective T1 mapping outcome study (NCT03749343). Exclusion criteria were neoplastic/autoimmune/infectious disease, specific nonischemic cardiomyopathies, myocarditis, and immunosuppressive medication. Patients were categorized into 2 groups, based on sequence-specific ranges for native T1 of noninfarcted myocardium²: normal native T1, indicating no remodeling (n=24; median age: 64 [IQR, 52–68] years; LVEF (left ventricular function): 58 [54–62]%) and abnormal native T1 (n=22; 61 [52–69] years; LVEF: 55 [41–64]%) as indicative for diffuse interstitial remodeling and fibrosis. Twelve subjects of similar age (57 [52–66] years) and sex mix with no known cardiac disease and with normal cardiac magnetic resonance findings served as controls. Blood samples were analyzed for standard cardiac and inflammatory biomarkers. Th-cell subsets were analyzed using multiparameter flow cytometry, and the raw data were subjected to hierarchical cluster analysis as described previously.³ Hierarchical cluster analysis detected a marked expansion of 2 specific Th-cell clusters, phenotypically corresponding to Th22 and Th17 (Figure 1B) in patients with diffuse remodeling. We further confirmed a significant increase in Th17 and Th22 cell counts in patients with abnormal T1 signatures (Figure 1C). Among patients with CAD, there were no significant relationships between Th-cell subsets and age, sex, CV risk factors, cardiac magnetic resonance cardiac structure or function or the presence of postinfarction scar by late gadolinium enhancement. The latter indicates that expansions of proinflammatory T lymphocytes were indicative for diffuse fibrosis but not for replacement fibrosis.

Figure. Inflammatory T-cell signatures of cardiac fibrosis.A, Scatter plots of Th-cell clusters (as identified by hierarchical cluster analysis) and (B) Uniform Manifold Approximation and Projection dimensionality reduction plots showing expansion of Th17 (CD194⁺CD196⁺CCR10⁻CD183⁻, red cluster) and Th22 (CD194⁺CD196⁺CCR10⁺CD183⁻, green cluster) cells from representative patients with normal (Case 1) and raised (Case 2) native T1. C, Absolute Th-cell counts (Kruskal-Wallis H-test followed by Dunn test). CAD indicates coronary artery disease.

High-sensitive troponin T (Controls versus CAD normal versus CAD abnormal T1: 4.5 [3–5.9] versus 5.9 [4.5–11] vs 12 [6.8–20] pg/mL; P=0.002) and high-sensitivity C-reactive protein (0.09 [0.05–0.21] versus 0.08 [0.05–0.18] versus 0.22 [0.09–0.50] mg/dL; P=0.018) were significantly higher in the group with diffuse remodeling, whereas N-terminal pro-brain natriuretic peptide (94 [39–122] versus 64 [32–179] versus 201 [79–566] pg/mL; P=0.052) was not significantly different. The groups were similar for total blood leukocyte (P=0.18), granulocyte (P=0.25), or monocyte (P=0.09) counts. In summary, our results indicate that Th17 and Th22 cells may relate to diffuse interstitial remodeling of noninfarcted myocardium in the context of CAD. Despite its novelty, this study is limited by the small sample size and therefore potentially biased by reverse causation and confounding. Future studies are needed to prove the prognostic value of Th17/Th22 polarization, as well as the therapeutic potential of anti-inflammatory treatments to prevent progression of diffuse myocardial remodeling.

Nonstandard Abbreviations and Acronyms

CAD	coronary artery disease
LVEF	left ventricular function

coronary artery disease

left ventricular function

This work was supported by the Adolf-Messer-Stiftung. K. Fišer is supported by Czech Health Research Council (NV18-08-00385).

None.

The data that support the findings of this study are available from the corresponding author upon reasonable request by email.

For Sources of Funding and Disclosures, see page 700.

This manuscript was sent to Francesco Violi, Consulting Editor, for review by expert referees, editorial decision, and final disposition.

Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02407197.

中文翻译：

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循环中的Th17和Th22细胞与慢性冠状动脉疾病中弥漫性心肌间质重塑的CMR成像生物特征相​​关。

认识第一作者，请参阅第592页

心肌纤维化是心肌重塑与心脏衰竭之间的常见病理生理指标。实验证据表明，CD4 ⁺ T辅助（Th）淋巴细胞，特别是Th17和Th22细胞，在心肌重塑中起着重要作用，因此其在人类中的参与尚不清楚。通过心脏磁共振成像对组织进行定量表征，可通过测量T1松弛率来支持弥漫性心肌间质重塑的无创检测。¹我们以前已经证明，与传统影像学检查相比，通过T1映射对未梗塞心肌进行表征可预测冠状动脉疾病（CAD）患者的预后。²我们假设特定的T细胞亚群的扩展将与心肌T1定位测量相关。因此，在46位患有慢性CAD的患者中测量了循环T细胞，这些患者参加了前瞻性T1作图结果研究（NCT03749343）。排除标准为肿瘤性/自身免疫性/传染性疾病，特定的非缺血性心肌病，心肌炎和免疫抑制药物。根据非梗塞心肌²天然T1的序列特异性范围，将患者分为2组：正常的天然T1，表明没有重塑（n = 24；中位年龄：64 [IQR，52-68]岁； LVEF（左心室功能）：58 [54-62]％）和异常的天然T1（n = 22；正常值） 61 [52-69]岁； LVEF：55 [41-64]％）提示弥漫性间质重塑和纤维化。十二名年龄相似（57 [52-66]岁），性别混合且无已知心脏病且心脏磁共振检查结果正常的受试者作为对照。分析血样中的标准心脏和炎症生物标志物。使用多参数流式细胞仪分析Th细胞亚群，并对原始数据进行分层聚类分析，如前所述。³层次聚类分析在弥漫性重塑患者中检测到2个特定的Th细胞簇明显扩展，表型上对应于Th22和Th17（图1B）。我们进一步证实具有异常T1特征的患者Th17和Th22细胞计数显着增加（图1C）。在患有CAD的患者中，Th细胞亚群与年龄，性别，CV危险因素，心脏磁共振心脏结构或功能或晚期g增强引起的梗塞后疤痕之间无显着相关性。后者表明促炎性T淋巴细胞的扩张指示弥漫性纤维化，但不指示替代性纤维化。

数字。 心脏纤维化的炎性T细胞信号。甲，钍细胞簇的散点图（通过聚类分析）和（乙）统一流形逼近和投影降维图，显示Th17细胞（CD194的膨胀⁺ CD196 ⁺ CCR10 ^- CD183 ^- ，红色簇）和TH22（CD194 ⁺ CD196 ⁺ CCR10 ⁺ CD183 ^- ，绿色簇）细胞从代表正常的患者（情况1），并提出（情况2）天然T1。C，绝对Th细胞计数（Kruskal-Wallis H检验，然后是Dunn检验）。CAD表示冠状动脉疾病。

高敏感性肌钙蛋白T（对照组与CAD正常与CAD异常T1：4.5 [3–5.9] vs 5.9 [4.5-11] vs 12 [6.8-20] pg / mL；P = 0.002）和高敏C反应性弥漫性重塑组蛋白（0.09 [0.05–0.21]对0.08 [0.05–0.18]对0.22 [0.09-0.50] mg / dL；P = 0.018）显着更高，而N端前脑利钠肽（ 94 [39–122]与64 [32–179]与201 [79–566] pg / mL；P = 0.052）无显着差异。对于全血白细胞（P = 0.18），粒细胞（P = 0.25）或单核细胞（P= 0.09）计数。总之，我们的结果表明，在CAD的背景下，Th17和Th22细胞可能与非梗塞心肌的弥漫性间质重塑有关。尽管有新颖性，但这项研究受到样本量小的限制，因此可能因反向因果关系和混淆而产生偏差。需要进一步的研究来证明Th17 / Th22极化的预后价值，以及抗炎治疗可防止弥漫性心肌重塑发展的治疗潜力。

非标准缩写和首字母缩写

电脑辅助设计	冠状动脉疾病
左室射血分数	左心室功能

冠状动脉疾病

左心室功能

这项工作得到了Adolf-Messer-Stiftung的支持。捷克卫生研究理事会（NV18-08-00385）支持K.Fišer。

没有。

在合理的要求下，可以通过电子邮件从通讯作者处获得支持本研究结果的数据。

有关资金和披露的来源，请参阅第700页。

该手稿已发送给咨询编辑Francesco Violi，供专家裁判审阅，编辑决定和最终处置。

注册：URL：https：//www.clinicaltrials.gov；唯一标识符：NCT02407197。