See Article by Pascual-Figal et al

From the heart, impurities or ‘sooty vapors’ are carried back to the lung by way of the pulmonary artery, to be exhaled to the outer air.

—Leonardo Da Vinci, 1452–1519

Before getting to the central point of this editorial commentary, we wish to clarify an error that appears repeatedly in the literature which is that the alias ST2 refers to the gene for IL1RL1 (interleukin-1 receptor-like 1; GeneID: 9173), found on chromosome 2, and a major player in immune and inflammatory responses. This ST2 must not be confused with suppression of tumorigenicity 2 (GeneID: 6761), which is an entirely different gene that is located on chromosome 11, in a region that represents a putative locus associated with various forms of cancer. The circulating ST2 discussed here, the product of the gene IL1RL1, is measured in heart failure (HF), and is essentially a marker of inflammation and stretch, although it also signals the presence and severity of adverse cardiac remodeling and tissue fibrosis.

Multiple researchers have measured soluble ST2 (sST2; hereafter referred to simply as ST2) in HF in different settings over the past decade, building robust and reproducible evidence of its value for prognostication in HF, both in addition to and independently of other established markers.¹ ST2 is included in the 2017 American College of Cardiology/American Heart Association guidelines for additive risk stratification of patients with acute and chronic HF. Furthermore, ST2 immunoassays are approved for clinical use by the US Food and Drug Administration and have received the Conformitè Europèenne mark. However, despite its approval and the growing use of ST2 by practicing clinicians, issues related to its pathobiology remain incompletely understood, including the production of circulating ST2 in cardiac and extracardiac tissues.

Early in vitro findings showed load induction of ST2 mRNA in neonatal rat cardiac myocytes,² and it was thus presumed that circulating ST2 in cardiovascular disease was exclusively myocardial in origin. These data, reported over 15 years ago from the laboratory of Richard T. Lee in Boston, stimulated ST2 research in the cardiovascular field and are nicely summarized by Kakkar and Lee.³ Briefly, alternative splicing generates multiple ST2 isoforms, including a transmembrane form (ST2 ligand or ST2L) and a soluble circulating form (sST2 or ST2) that is a valuable biomarker. Both ST2L and ST2 are expressed by cardiomyocytes and cardiac fibroblasts in response to mechanical stress, and both isoforms bind to IL-33 (interleukin-33). IL-33 is also induced by cellular stretch, and apparently protects against fibrosis and hypertrophy in mechanically strained tissues via activation of MyD88 (myeloid differentiation primary response gene 88), IRAK (interleukin-1 receptor-associated kinase), and ERK (extracellular signal-regulated kinase), and ultimately NF-κB (nuclear factor-κB). In in vitro and in vivo models, ST2L transduces the effects of IL-33, while excess circulating ST2 leads to cardiac fibrosis and remodeling and ventricular dysfunction. It is proposed that circulating ST2 acts as a decoy receptor for IL-33, such that high levels of soluble ST2 block the favorable effects of IL-33 by limiting activation of the cascade triggered by the IL-33/ST2L interaction (Figure). Thus, higher levels of circulating ST2 are associated with increased myocardial fibrosis, adverse cardiac remodeling, and worse cardiovascular outcomes.⁴

Figure. Schematic of the ST2 axis in health and disease. In cardiovascular (CV) health, sST2 (soluble interleukin-1 receptor-like 1) production by endothelium and the lungs is low, which permit IL-33 (interleukin-33)/ST2L (transmembrane interleukin-1 receptor-like 1) interaction at the cardiomyocyte level, which leads to activation of a cardioprotective cascade by activation of diverse intracellular kinases and factors. In heart failure, sST2 production by endothelium and the lungs is upregulated, and sST2 binds IL-33 as a decoy receptor limiting activation of the cardioprotective cascade in the cardiomyocyte triggered by the IL-33/ST2L interaction. ERK indicates extracellular signal-regulated kinase; IRAK, interleukin-1 receptor-associated kinase; JNK, c-Jun N-terminal kinases; LA, left atrium; LV, left ventricle; MYD88, myeloid differentiation primary response gene 88; NF-κB, nuclear factor κ-light-chain-enhancer of activated B cells; and TRAF-6, tumor necrosis factor receptor-associated factor-6.

Recent evidence suggests a disconnect between tissue-based and circulating ST2 concentrations, and some findings indicate possible extracardiac ST2 protein production. Bartunek et al⁵ first demonstrated that adult human myocardium is a weak source of increased soluble ST2 in pressure overload hypertrophy and congestive cardiomyopathy. They observed that ST2 mRNA levels were not significantly increased in myocardial biopsies from human hearts, prompting investigation of ST2 protein production in extramyocardial nonmyocyte cell types, which revealed ST2 protein secretion from human venous and arterial endothelial cells (Figure).⁵ In a later study, Demyanets et al⁶ found that human macrovascular (aortic and coronary artery) and heart microvascular endothelial cells express specific mRNA for soluble ST2, and are a source of ST2 protein. Moreover, recent data indicate that soluble ST2 plays a modulatory role in obesity-associated vascular remodeling.⁷

In the current issue of Circulation: Heart Failure, Pascual-Figal et al⁸ present the first data indicating the production of soluble ST2 protein by organs other than the heart and vessels. Using an experimental model of HF (permanent left anterior descending occlusion in a rat model), they measured soluble ST2 mRNA in lung, kidney, and liver tissue samples obtained at prespecified time-points. The liver and kidneys did not participate in ST2 production during any of the studied periods. In contrast, the lungs exhibited significant upregulation of soluble ST2 mRNA. The authors also identified an association between increased alveolus thickness and upregulation of soluble ST2, suggesting a relationship between the degree of pulmonary congestion and ST2 production. Furthermore, ST2 protein was detected in alveolar epithelium and secreted by type II pneumocytes in response to cellular strain. Although their report did not establish causality, which is an acknowledged limitation, the results support that the lungs are a relevant source of soluble ST2 in HF.⁸

The presently available data suggest that the myocardium may not be the main source of circulating ST2. Indeed, soluble ST2 level appears to be heavily influenced by dynamic contributions of the lungs and the vascular endothelium. This indicates that ST2, rather than being specific for indices of cardiac remodeling, may reflect heart-lung-vasculature health status beyond cardiac function. In response to alterations in hemodynamic and inflammatory status, the lungs and the vascular endothelium may emerge as the main sources of elevated soluble ST2 levels in HF (Figure).

These data further imply that soluble ST2 may be a surrogate of congestion in HF. Congestion can manifest as venous (systemic) congestion or as pulmonary congestion, which is the main cause of dyspnea in HF. Pulmonary congestion in HF primarily results from elevated left ventricular filling pressure and frequently coexists with venous congestion and fluid retention. In clinical practice, congestion is difficult to evaluate, and such assessment is commonly considered unreliable because of substantial interobserver variability. In terms of using ST2 as a biomarker in acute and chronic HF—both of which include variable degrees of pulmonary and venous congestion—a rise in ST2 levels (which is much greater in acute HF) provides important prognostic information.⁴ Further research combining ST2 with congestion scores, lung ultrasound, bioimpedance or other congestion biomarkers may better characterize the value of ST2 and congestion in HF.

In conclusion, in their recent study, Pascual-Figal et al⁸ demonstrate that the lungs seem to be a main source of ST2 protein production. This may impact the interpretation of data from clinical studies using soluble ST2 measurement and may open a new avenue for the modulation of ST2 expression as a potential therapeutic target in HF.

Dr Bayés-Genis was supported by grants from the Ministerio de Educación y Ciencia (SAF2017-84324-C2-1-R), Fundació La MARATÓ de TV3 (201502, 201516), Centro de Investigación Biomédica en red (CIBER) Cardiovascular (CB16/11/00403), and AdvanceCat 2014–2020. Dr González was supported by CIBER Cardiovascular (CB16/11/00483) and the European Commission (HOMAGE project 2012–305507).

Dr Bayés-Genis received board membership fees and travel expenses from Novartis and Roche Diagnostics and reports a relationship with Critical Diagnostics. Dr Lupón reports lecture honoraria from Roche Diagnostics and a relationship with Critical Diagnostics.

The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.

参见Pascual-Figal等的文章

杂质或“油烟”从心脏通过肺动脉被带回到肺部，并被呼出到外部空气中。

莱昂纳多·达·芬奇（Leonardo Da Vinci），1452-1519年

在转到本社论评论的中心点之前，我们希望澄清一个错误，该错误在文献中反复出现，即别名ST2指的是IL1RL1的基因（白介素1受体样1； GeneID：9173）。在2号染色体上，是免疫和炎症反应的主要参与者。不得将此ST2与抑制致癌性2（GeneID：6761）混淆，后者是一个完全不同的基因，位于11号染色体上，该区域代表与各种形式的癌症相关的假定基因座。本文讨论的循环ST2是基因IL1RL1的产物，在心力衰竭（HF）中进行测量，尽管它也预示着不良的心脏重塑和组织纤维化的存在和严重程度，但它实际上是炎症和伸展的标志。

在过去的十年中，许多研究人员在不同的环境中测量了HF中的可溶性ST2（sST2；以下简称为ST2），除了其与其他已建立的指标外，还为其在HF中的预后价值建立了可靠且可重复的证据。^1个ST2包含在2017年美国心脏病学会/美国心脏协会针对急性和慢性HF患者的加成风险分层指南中。此外，ST2免疫测定已获得美国食品和药物管理局的临床批准，并获得了ConformitèEuropèenne标记。然而，尽管它被批准并且临床医生越来越多地使用ST2，但与其病理生物学相关的问题仍未完全理解，包括心脏和心外组织中循环ST2的产生。

早期的体外研究结果表明，新生大鼠心肌细胞中ST2 mRNA的负载诱导[ ^2]，因此推测心血管疾病中循环中的ST2完全源于心肌。这些数据是15年前在波士顿的Richard T. Lee的实验室报告的，它刺激了心血管领域的ST2研究，Kakkar和Lee很好地总结了这些数据。³简而言之，替代剪接产生多种ST2同工型，包括跨膜形式（ST2配体或ST2L）和可溶性循环形式（sST2或ST2），其是有价值的生物标志物。ST2L和ST2均由心肌细胞和心脏成纤维细胞表达，以响应机械应力，并且两种同工型均与IL-33（白介素-33）结合。IL-33也可通过细胞拉伸来诱导，并通过激活MyD88（髓样分化主要反应基因88），IRAK（白介素-1受体相关激酶）和ERK（细胞外信号）激活，从而在机械应变的组织中明显预防纤维化和肥大。调节激酶），最后是NF-κB（核因子-κB）。在体外和体内模型中，ST2L可转导IL-33的作用，而过多的循环ST2会导致心脏纤维化，重塑和心室功能障碍。建议循环的ST2充当IL-33的诱饵受体，从而使高水平的可溶性ST2通过限制由IL-33 / ST2L相互作用触发的级联的激活来阻断IL-33的有利作用（图）。因此，较高水平的循环ST2与心肌纤维化增加，不良的心脏重构和较差的心血管结果有关。⁴

数字。 ST2轴在健康和疾病中的示意图。在心血管（CV）健康方面，内皮和肺的sST2（可溶性白细胞介素1受体样1）产生较低，这允许IL-33（白介素33）/ ST2L（跨膜白介素1受体样1）相互作用。在心肌细胞水平上，其通过激活多种细胞内激酶和因子而导致心脏保护级联反应的激活。在心力衰竭中，内皮和肺的sST2产生被上调，并且sST2结合IL-33作为诱饵受体，限制了由IL-33 / ST2L相互作用触发的心肌保护性级联反应的激活。ERK表示细胞外信号调节激酶。IRAK，白介素1受体相关激酶；JNK，c-Jun N-末端激酶；洛杉矶，左心房；左室左室; MYD88，骨髓分化初级反应基因88；NF-κB，活化的B细胞的核因子κ轻链增强剂；和TRAF-6，肿瘤坏死因子受体相关因子-6。

最近的证据表明，基于组织的ST2浓度与循环中的ST2浓度之间存在脱节，并且一些发现表明可能会产生心外膜ST2蛋白。Bartunek等人[ ^5]首先证明，成人心肌是压力超负荷肥大和充血性心肌病中可溶性ST2含量升高的弱源。他们观察到，从人心脏进行的心肌活检中，ST2 mRNA水平并未显着增加，这促使人们调查了心肌外非肌细胞类型中ST2蛋白的产生，这揭示了人静脉和动脉内皮细胞中ST2蛋白的分泌（图）。⁵在后来的研究中，Demyanets等人⁶发现人类大血管（主动脉和冠状动脉）和心脏微血管内皮细胞表达可溶性ST2的特异性mRNA，并且是ST2蛋白的来源。此外，最近的数据表明可溶性ST2在肥胖相关的血管重塑中起调节作用。⁷

在当前的《循环：心力衰竭》一书中，Pascual-Figal等人⁸提出了第一个数据，表明除心脏和血管以外的器官可溶的ST2蛋白的产生。他们使用HF（大鼠模型中永久的左前降支阻塞）实验模型，测量了在预定时间点获得的肺，肾和肝组织样品中的可溶性ST2 mRNA。在任何研究期间，肝和肾均不参与ST2的产生。相反，肺显示出可溶性ST2 mRNA的显着上调。作者还发现肺泡厚度增加与可溶性ST2的上调之间存在关联，这表明肺充血程度与ST2产生之间存在关联。此外，在肺泡上皮中检测到ST2蛋白，并响应细胞株由II型肺细胞分泌ST2蛋白。⁸

目前可获得的数据表明心肌可能不是循环ST2的主要来源。实际上，肺和血管内皮的动态作用似乎严重影响了可溶性ST2的水平。这表明ST2，而不是特定于心脏重塑的指标，可能反映了心脏功能以外的心肺血管健康状况。响应血液动力学和炎症状态的变化，肺和血管内皮可能会成为HF中可溶性ST2水平升高的主要来源（图）。

这些数据进一步暗示可溶性ST2可能是HF充血的替代物。充血可表现为静脉（全身）充血或肺部充血，这是HF呼吸困难的主要原因。HF中的肺充血主要是由于左心室充盈压升高引起的，并经常与静脉充血和体液retention留并存。在临床实践中，拥塞很难评估，并且由于观察者之间存在很大差异，这种评估通常被认为是不可靠的。就将ST2用作急性和慢性HF的生物标志物而言（两者都包括不同程度的肺和静脉充血），ST2水平升高（在急性HF中要大得多）可提供重要的预后信息。⁴ 进一步的研究将ST2与充血评分，肺部超声，生物阻抗或其他充血生物标志物结合起来，可以更好地表征ST2和HF充血的价值。

总之，在最近的研究中，Pascual-Figal等人⁸证明，肺似乎是ST2蛋白产生的主要来源。这可能会影响使用可溶性ST2测量的临床研究数据的解释，并可能为调节ST2表达作为HF中潜在的治疗靶标开辟新的途径。

Bayés-Genis博士得到了部长级教育基金会（SAF2017-84324-C2-1-R），TV3基金会（201502、201516），生物医学中心（CIBER）心血管研究（CB16）的资助/ 11/00403）和AdvanceCat 2014–2020。González博士得到了CIBER心血管（CB16 / 11/00483）和欧洲委员会（HOMAGE项目2012–305507）的支持。

Bayés-Genis博士从Novartis和Roche Diagnostics获得了董事会会员费和差旅费，并报告了与Critical Diagnostics的关系。Lupón博士报告了Roche Diagnostics的演讲酬金以及与Critical Diagnostics的关系。

本文表达的观点不一定是编辑者或美国心脏协会的观点。