See Article by Mohanakumar et al

The Fontan operation has tremendously improved survival of patients with univentricular hearts during the past 2 decades.^1,2 It should be acknowledged that, in the early days of Fontan palliation, our focus was primarily on surgical and perioperative aspects of the Fontan operation, in an attempt to decrease morbidity and mortality related to the operation itself.^1,2 However, that focus has now been modified and is shifted toward the long-term outcome perspective of patients with a Fontan circulation, as it has become clear that the Fontan circulation affects most organs in the human body, particularly the liver, with low cardiac output and chronically elevated systemic venous pressure likely being the substrates for development of major adverse events.^3,4 Therefore, the identification of modifiable risk factors to optimize Fontan hemodynamics, to prevent or slow down the deterioration of organ function, and to develop new therapeutic strategies has been given a high research priority in recent literature.^2–4

The lymphatic system might be such a risk factor, predisposing Fontan patients with maladaptive lymphatic remodeling to lymphedema, plastic bronchitis, and protein-losing enteropathy.^4–6 Until recently, the lymphatic system has been difficult to investigate because a simple and reliable imaging method was lacking.⁵ However, recent developments in magnetic resonance imaging (MRI) techniques make it possible to delineate the central lymphatic system in Fontan patients with good spatial en temporal resolution.^5,7,8 This has paved the way for opening the lymphatic black box.

In this context, the work of Mohanakumar et al⁹ in this issue of Circulation: Cardiovascular Imaging is an important addition to our understanding of the lymphatic system in both asymptomatic and symptomatic Fontan patients. The authors used state-of-the-art imaging modalities to carefully delineate the lymphatic system of a well-characterized group of Fontan patients and compared the results with healthy age- and sex-matched control subjects. Blinded to clinical and hemodynamic data, each participant underwent T2-weighted noncontrast MRI lymphangiography to examine the lymphatic anatomy of the neck, entire chest, including the thoracic duct (TD), abdomen, and legs. T2-weighted MRI is noninvasive and is able to demonstrate alterations in lymphatic structures, such as lymphatic collateralization, lymphangiectasias (dilatation of lymphatic vessels), dilatation of the cisterna chyli or TD, and the presence of fluid accumulation in tissues or body cavities.^5–9 An important disadvantage of T2-weighted MRI is that it is a static imaging modality, meaning that no dynamic information on lymph flow is gathered during the study.^5,7,8 Therefore, Mohanakumar et al⁹ also investigated the functional state of the lymphatic vessels using near-infrared fluorescence imaging, which is a novel technique that allows both anatomic delineation of lymphatic structures and real-time visualization of lymph flow. Furthermore, the microvascular permeability of lymphatic vessels in the lower extremities was estimated by strain gauge plethysmography, thus providing us with a detailed exploration of the lymphatic system in Fontan patients.

The lymphatic system is distributed throughout most of the human body and runs parallel to the blood vascular system.¹⁰ Because the blood microvasculature is permeable to water and proteins, ≈8 to 10 L of blood plasma extravasates every day into surrounding tissue.^10,11 This physiological process is of paramount importance for normal functioning of the extracellular matrix and the cellular components of our tissues.^11,12 This interstitial fluid, or lymph, is transported back to the systemic circulation. The lymphatic vasculature system facilitates this transport of lymph through an extensive network of highly sophisticated lymphatic vessels that are interconnected with lymph nodes, central lymphatic ducts, the spleen, and Peyer’s patches in the small intestine and ultimately enters the systemic circulation through the TD in most subjects.^10–12

Lymphatic vessels are organized as a vessel tree, where fluid from the tissue enters the most distal part of the lymphatic system, the lymphatic capillaries, or initial lymphatics.¹⁰ These lymphatic vessels are blind-ending and composed of a single layer of endothelial cells.¹⁰ Initial lymphatics pass the fluid to collecting lymphatics. Collecting lymphatics are larger vessels lined with endothelium and surrounded by a muscle layer.¹⁰ Action potentials in the smooth muscle layer of the collecting lymphatic vessels elicit phasic contractions, resulting in forward flow of lymph through the lymphatic system.^10–12 Moreover, collecting lymphatics comprised serially arranged structural and functional units called lymphangions.^10–12 A lymphangion is the segment of a collecting lymphatic vessel between 2 adjacent valves. These intraluminal valves prevent backflow of lymph within the lymphatic network, further underscoring the importance of a normal functioning lymphatic network.^10–12

The lymphatic system not only is involved in maintaining a normal interstitial fluid balance and protein concentration but also plays an important role in the transport of lipids from the gastrointestinal tract, removal of substances that arise because of metabolism or cell death, and in optimizing our immunity.^10–12 Not surprisingly, there is accumulating evidence to suggest that a disrupted lymphatic system, not related to primary genetic disorders, contributes to a variety of disorders, such as metabolic syndrome, heart failure, cancer, and inflammatory bowel disease.^10,12 Tissue inflammation is associated with increased permeability of the blood capillaries and reduced lymphatic pumping, which may result in local edema and disruption of immune homeostasis.^10,12 Poor drainage leads to impaired transport of immune cells, aggravating local tissue dysfunction. In view of this, it seems relevant to note that the Fontan circulation is a state of chronic heart failure associated with augmented systemic inflammation and increased neurohumoral activation. Therefore, it is conceivable that lymphatic dysfunction contributes in some part to the deterioration of organ function in Fontan patients.

A small number of research groups have recently begun to unravel the structural and functional alterations of the lymphatic system in Fontan patients.^5–9 The lymphatic system in Fontan patients is chronically challenged, not only because of the increased production of interstitial fluid that the lymphatic vessels have to remove to maintain a normal tissue-fluid balance, but also secondary to a significant elevation in afterload (systemic venous pressure), potentially limiting the transport capacity of the lymphatic system as a whole.^5–9 This may predispose Fontan patients to maladaptive remodeling of the central lymphatics, subsequently contributing to the development of lymphedema, plastic bronchitis, and possibly protein-losing enteropathy.^5–9

Dilation and tortuosity of the TD, lymphatic collaterals, lymphangiectasia, and leakage of lymph in surrounding tissue are the most common lymphatic abnormalities seen in Fontan patients.^5,9 In addition, these lymphatic abnormalities, which are not disease specific, have also been observed in infants with single ventricle physiology following a superior cavopulmonary connection, suggesting that maladaptive remodeling of the central lymphatics may already be present before the Fontan operation in a subset of these patients.⁵

The measurement of the TD diameter deserves special attention. The TD is the largest lymphatic duct and receives lymph from 80% to 90% of the body.^10–12 It originates from the cisterna chyli, which is typically located at the level of L1 and L2 and enters the thoracic cavity through the aortic hiatus.^12–14 In most humans, the TD ascends between the aorta and the azygos vein, crosses the mediastinum posteriorly, and drains into the junction of the left subclavian and left internal jugular veins.

Dilation of the TD seems a common feature in patients with a dysfunctional lymphatic system.^7,8,13 Notably, the TD is a dynamic vessel; with higher lymph production, a local stenosis, or a significant elevation of the afterload, its diameter will increase. The average diameter of the TD in healthy adults is normally between 2.5 and 4 mm, and it may increase to 9 to 10 mm in patients with portal hypertension, liver cirrhosis, or heart failure.^7,8,13 Therefore, measurement of the TD diameter in Fontan patients may have important clinical implications.

However, the interpretation of the TD diameter should be viewed in the context of specific limitations. First, the anatomy and course of the TD in humans is highly variable.^12–14 Second, lymphatic abnormalities of unknown relevance may also be present in asymptomatic healthy subjects, as was observed in the present study.⁹ Third, the diameter of the TD is influenced by the circadian cycle and increases significantly after a (fatty) meal,⁷ suggesting that a standardized fluid/meal protocol is required for a reproducible assessment of the central lymphatic system. And finally, the TD imaging quality of T2-weighted noncontrast MRI may be limited in some patients. These considerations should be taken into account before a clinically meaningful distinction between a challenged but adapted, or a diseased TD in Fontan patients can be made.

Facing these limitations, Mohanakumar et al⁹ are to be congratulated on overcoming considerable challenges involved in unraveling the morphology and function of the lymphatic system in Fontan patients. To eliminate any circadian influence, the tests were conducted before midday and the subjects were instructed to refrain from heavy physical exercise and alcoholic beverages 12 hours before testing. Intake of beverages and food during the tests was not allowed.⁹

Furthermore, to quantify the degree of TD tortuosity, the authors calculated the relative length of the TD from T2-weighted noncontrast MRI images. They showed that this measure of TD tortuosity was easy to obtain and highly reproducible. Although the TD diameter was not significantly different between Fontan patients and healthy controls, the degree of TD tortuosity was significantly increased in Fontan patients. Importantly, TD tortuosity seems a common and potentially distinctive feature of the lymphatic system in Fontan. Whether the TD tortuosity index is preload independent remains to be determined. Moreover, Fontan patients had 17% lower lymphatic pumping pressure and a 62% higher contraction frequency compared with healthy controls.⁹ These findings suggest that lymphatic disease in Fontan patients is characterized not only by alterations in TD morphology but also by impairment of the lymphatic pumping capacity.

Another important finding of the present study is that lymphedema surrounding the liver was observed in most Fontan patients. Liver disease, ranging from mild fibrosis to severe cirrhosis and hepatocellular carcinoma, is increasingly being recognized in Fontan patients.^15,16 Although risk factors for the development of Fontan-associated liver disease are currently being explored, the pathogenesis remains largely unknown and seems likely to be multifactorial. It should be acknowledged that the liver produces a large amount of lymph; 25% to 50% of the lymph flowing through the TD originates from the liver. Lymph production arises primarily from the hepatic sinusoids and is proportional to the hydrostatic pressure within the sinusoidal microcirculation of the liver. Interestingly, sinusoidal dilation due to hepatic congestion is a common histopathologic finding in patients with Fontan-associated liver disease.^15,16 Moreover, the interstitial fluid content is increased in the liver and surrounding tissue in patients with cirrhosis and portal hypertension, which may give rise to local lymphedema, TD dilation, and ultimately ascites when the transport capacity of the lymphatic system fails.¹⁷ Consequently, poor drainage of lymph may further aggravate liver dysfunction, tissue inflammation, fibrosis, and lymphangiogenesis.^17,18 Although it is tempting to conclude that a challenged lymphatic system in patients following the Fontan procedure directly contributes to the development and progression of Fontan-associated liver disease, the liver status of the patients in this study was not assessed. Going forward, this important observation warrants further exploration and should be used to guide larger prospective studies.

Although the fundamental question—how do we define a normal and adapted lymphatic system in Fontan survivors?—has not been answered yet, there can be no question about the importance of noninvasive imaging techniques in the evaluation of the lymphatics in Fontan patients. The ultimate goal of research is to identify Fontan patients at highest risk for poor outcome and to provide novel targets for treatment. The degree of TD tortuosity may ultimately prove to be a helpful measure in this context. Furthermore, this study highlights the need for continued clinical research of the lymphatic system in larger cohorts of Fontan survivors. Future studies should focus on the serial assessment of the lymphatic system in relation to specific patient characteristics and complications such as Fontan-associated liver disease, plastic bronchitis, and protein-losing enteropathy. Nevertheless, we should keep in mind that a normal functioning Fontan circulation is still markedly abnormal and that the lymphatic system seems to play an important role to compensate for its abnormality.

None.

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

参见Mohanakumar等的文章

在过去的20年中，Fontan手术极大地提高了单心室心脏患者的生存率。^1,2应当认识到，在丰坦姑息治疗的早期，我们的重点主要放在丰坦手术的外科和围手术期方面，目的是降低与手术本身相关的发病率和死亡率。^1,2但是，现在已经改变了重点，并转向了芳坦循环患者的长期预后，因为很明显，芳坦循环会影响人体的大多数器官，尤其是肝脏。低心排血量和全身静脉压长期升高可能是发生重大不良事件的基础。^3,4因此，在最近的文献中，鉴定可修饰的危险因素以优化Fontan血液动力学，预防或减缓器官功能的恶化以及开发新的治疗策略。^2–4

淋巴系统可能是这样的危险因素，使丰坦患者的淋巴适应不良的淋巴重塑易患淋巴水肿，可塑性支气管炎和蛋白质丢失性肠病。^4–6直到最近，由于缺乏简单可靠的成像方法，很难对淋巴系统进行检查。^[5]然而，磁共振成像（MRI）技术的最新发展使得有可能描绘出具有良好空间和时间分辨率的丰坦患者的中央淋巴系统。^5,7,8这为打开淋巴黑匣子铺平了道路。

在这种情况下，Mohanakumar等[ ^9]在《循环：心血管成像》一书中的工作是我们对无症状和症状性丰坦患者淋巴系统理解的重要补充。作者使用最新的影像学方法仔细描绘了特征丰富的Fontan患者组的淋巴系统，并将结果与​​年龄和性别相匹配的健康对照对象进行了比较。不了解临床和血液动力学数据，每位参与者均进行了T2加权非对比MRI淋巴管造影术，以检查颈部，整个胸部（包括胸管（TD），腹部和腿部）的淋巴解剖结构。T2加权MRI是非侵入性的，能够证明淋巴结构发生变化，例如淋巴结侧支，淋巴管扩张（淋巴管扩张），水槽乳糜或TD扩张，^5–9 T2加权MRI的一个重要缺点是它是静态的成像方式，这意味着在研究过程中未收集到有关淋巴流量的动态信息。^5,7,8因此，Mohanakumar等[ ^9]还使用近红外荧光成像技术研究了淋巴管的功能状态，这是一种新颖的技术，既可以解剖描绘淋巴结构，又可以实时观察淋巴液流动。此外，通过应变片体积描记法估计了下肢淋巴管的微血管通透性，从而为丰坦患者的淋巴系统提供了详细的探索。

淋巴系统分布在人体的大部分区域，并与血管系统平行。¹⁰因为血液的微脉管系统可渗透水和蛋白质，所以每天约有8至10 L血浆渗入周围组织。^10,11这个生理过程对于细胞外基质和我们组织的细胞成分的正常功能至关重要。^11,12这种组织液或淋巴液被运回体循环。淋巴管系统通过高度复杂的淋巴管的广泛网络促进淋巴的运输，这些淋巴管与小肠中的淋巴结，中央淋巴管，脾脏和Peyer斑相互连接，并最终在大多数情况下通过TD进入系统循环科目。^10–12

淋巴管被组织为血管树，组织中的液体进入淋巴系统，淋巴毛细血管或最初的淋巴管的最远端。¹⁰这些淋巴管是盲端的，由单层内皮细胞​​组成。¹⁰最初的淋巴管将液体传递到收集的淋巴管。收集淋巴管的是较大的血管，内衬内皮细胞，周围被肌肉层包围。¹⁰收集淋巴管的平滑肌层中的动作电位引起相收缩，导致淋巴通过淋巴系统的正向流动。^10–12此外，收集淋巴管包括依次排列的结构和功能单元，称为淋巴结。^10–12淋巴结是两个相邻瓣膜之间的收集淋巴管的一部分。这些腔内瓣膜可防止淋巴网络内的淋巴回流，进一步强调了正常的淋巴网络的重要性。^10–12

淋巴系统不仅参与维持正常的组织液平衡和蛋白质浓度，而且在从胃肠道转运脂质，清除因代谢或细胞死亡而产生的物质以及优化免疫力方面起着重要作用。 。^10–12毫不奇怪，有越来越多的证据表明与原发性遗传疾病无关的淋巴系统受损会导致多种疾病，例如代谢综合征，心力衰竭，癌症和炎症性肠病。^10,12组织炎症与毛细血管通透性增加和淋巴泵送减少有关，这可能导致局部水肿和免疫稳态的破坏。^10,12排水不良会导致免疫细胞运输受损，加重局部组织功能障碍。鉴于此，似乎有必要指出，丰坦循环是一种慢性心力衰竭的状态，与全身性炎症增加和神经体液激活增加有关。因此，可以想象淋巴功能障碍在某种程度上导致了丰坦患者器官功能的恶化。

少数研究小组最近已开始揭示Fontan患者淋巴系统的结构和功能改变。^5–9 Fontan患者的淋巴系统长期受到挑战，这不仅是因为为了维持正常的组织-流体平衡，必须去除淋巴管以增加组织间液的产生，而且还因为后负荷的显着升高（系统性静脉压力），可能会限制整个淋巴系统的运输能力。^5–9这可能会使Fontan患者倾向于对中央淋巴管进行适应不良的重塑，从而导致淋巴水肿，可塑性支气管炎的发展，并可能导致蛋白质丢失性肠病。^5–9

TD的扩张和曲折，淋巴侧支，淋巴管扩张和周围组织的淋巴漏出是Fontan患者中最常见的淋巴异常。^5,9此外，在较高的腔肺连接后具有单心室生理的婴儿中也观察到了这些非疾病特异性的淋巴异常，这表明在Fontan手术之前，中央淋巴管的适应不良重塑可能已经存在。这些患者的子集。⁵

TD直径的测量值得特别注意。TD是最大的淋巴管，接受人体80％至90％的淋巴。^10–12起源于水罐乳糜，通常位于L1和L2的水平，并通过主动脉裂孔进入胸腔。^12-14在大多数人中，TD在主动脉和合子静脉之间上升，在后方穿过纵隔，并排入左锁骨下静脉和左颈内静脉的交界处。

TD扩张似乎是淋巴系统功能不全患者的共同特征。^7,8,13值得注意的是，TD是动力船；如果淋巴分泌更高，局部狭窄或后负荷明显升高，则其直径会增大。健康成年人中TD的平均直径通常在2.5到4 mm之间，门静脉高压，肝硬化或心力衰竭的患者中TD的平均直径可能会增加到9到10 mm。^7,8,13因此，测量Fontan患者的TD直径可能具有重要的临床意义。

但是，TD直径的解释应在特定限制的背景下进行。首先，人类的TD的解剖结构和病程变化很大。^12-14其次，正如本研究中所观察到的，无症状健康受试者中也可能存在未知相关性的淋巴异常。⁹第三，TD的直径受昼夜节律的影响，并在（脂肪）进餐后显着增加，⁷提示需要标准化的体液/膳食方案以重现中央淋巴系统的评估。最后，在某些患者中，T2加权非对比MRI的TD成像质量可能会受到限制。在Fontan患者中进行挑战性但适应性强或患病的TD的临床有意义区分之前，应考虑这些因素。

面对这些局限性，Mohanakumar等[ ^9]克服了揭露Fontan患者淋巴系统的形态和功能所涉及的重大挑战，值得祝贺。为了消除任何昼夜节律的影响，在中午之前进行测试，并指示受试者在测试前12小时不要进行大量的体育锻炼和酒精饮料。测试期间不允许摄入饮料和食物。⁹

此外，为了量化TD的曲折度，作者从T2加权的非造影MRI图像计算了TD的相对长度。他们表明，这种测量TD曲折度的方法很容易获得，并且可重复性很高。尽管Fontan患者和健康对照组的TD直径没有显着差异，但Fontan患者的TD曲折度明显增加。重要的是，TD曲折性似乎是Fontan淋巴系统的普遍且潜在的独特特征。TD曲折指数是否与预紧无关，尚待确定。此外，与健康对照组相比，丰坦患者的淋巴泵压降低了17％，收缩频率提高了62％。⁹ 这些发现表明，Fontan患者的淋巴疾病不仅以TD形态的改变为特征，而且以淋巴泵能力的损害为特征。

本研究的另一个重要发现是，在大多数Fontan患者中观察到了肝脏周围的淋巴水肿。从轻度纤维化到严重肝硬化和肝细胞癌的肝脏疾病在Fontan患者中日益得到认可。^15,16尽管目前正在研究与Fontan相关的肝病发展的危险因素，但其发病机理仍是未知之数，似乎可能是多因素的。应该承认，肝脏会产生大量的淋巴。流经TD的淋巴中有25％至50％来自肝脏。淋巴的产生主要来自肝脏的正弦波，并且与肝脏的正弦波微循环内的静水压力成正比。有趣的是，由于肝充血引起的正弦曲线扩张是与Fontan相关的肝病患者的常见组织病理学发现。^15,16此外，肝硬化和门静脉高压症患者的肝脏和周围组织中的组织液含量增加，这可能引起局部淋巴水肿，TD扩张，并最终在淋巴系统的运输能力衰竭时出现腹水。¹⁷因此，淋巴引流不畅可能会进一步加重肝功能障碍，组织炎症，纤维化和淋巴管生成。^17,18尽管很容易得出结论，接受Fontan手术的患者的淋巴系统受到挑战直接导致了Fontan相关肝病的发生和发展，但并未评估本研究中患者的肝脏状况。展望未来，这一重要发现值得进一步探索，应被用来指导更大的前瞻性研究。

尽管根本问题（我们如何在Fontan幸存者中定义正常和适应的淋巴系统？）尚未得到回答，但毫无疑问，无创成像技术在Fontan患者淋巴瘤评估中的重要性。研究的最终目标是识别出不良结果风险最高的方丹患者，并提供新的治疗目标。在这种情况下，TD弯曲度可能最终被证明是一种有用的措施。此外，这项研究突出了在丰坦幸存者的更大队列中对淋巴系统进行持续临床研究的必要性。未来的研究应着眼于针对特定患者特征和并发症（如Fontan相关性肝病，可塑性支气管炎，和蛋白质丢失性肠病。尽管如此，我们应该记住，正常的Fontan循环仍然明显异常，而淋巴系统似乎在弥补其异常中起着重要的作用。

没有。

本文表达的观点不一定是编辑者或美国心脏协会的观点。