Understanding the next circulation: lymphatics and what the future holds.

PURPOSE OF REVIEW: The lymphatic system was previously considered the forgotten circulation because of an absence of adequate options for imaging and intervention. However, recent advances over the last decade have improved management strategies for patients with lymphatic disease, including chylothorax, plastic bronchitis, ascites, and protein-losing enteropathy. RECENT FINDINGS: New imaging modalities have enabled detailed visualization of lymphatic vessels to allow for a better understanding of the cause of lymphatic dysfunction in a variety of patient subsets. This sparked the development of multiple transcatheter and surgery-based techniques tailored to each patient based on imaging findings. In addition, the new field of precision lymphology has added medical management options for patients with genetic syndromes, who have global lymphatic dysfunction and typically do not respond as well to the more standard lymphatic interventions. SUMMARY: Recent developments in lymphatic imaging have given insight into disease processes and changed the way patients are managed. Medical management has been enhanced and new procedures have given patients more options, leading to better long-term results.

Kaposiform lymphangiomatosis: Diagnosis, pathogenesis, and treatment.

Kaposiform lymphangiomatosis (KLA) is a life-threatening rare disease that can cause substantial morbidity, mortality, and social burdens for patients and their families. Diagnosis often occurs long after initial symptoms, and there are few centers in the world with the expertise to diagnose and care for patients with the disease. KLA is a lymphatic anomaly and significant advancements have been made in understanding its pathogenesis and etiology since its first description in 2014. This review provides multidisciplinary, comprehensive, and state-of-the-art information on KLA patient presentation, diagnostic imaging, pathology, organ involvement, genetics, and pathogenesis. Finally, we describe current therapeutic approaches, important areas for research, and challenges faced by patients and their families. Further insights into the pathogenesis of KLA may advance our understanding of other vascular anomalies given that similar signaling pathways may be involved.

Pathogenic variants in PIK3CA are associated with clinical phenotypes of kaposiform lymphangiomatosis, generalized lymphatic anomaly, and central conducting lymphatic anomaly.

Complex lymphatic anomalies are debilitating conditions characterized by aberrant development of the lymphatic vasculature (lymphangiogenesis). Diagnosis is typically made by history, examination, radiology, and histologic findings. However, there is significant overlap between conditions, making accurate diagnosis difficult. Recently, genetic analysis has been offered as an additional diagnostic modality. Here, we describe four cases of complex lymphatic anomalies, all with PIK3CA variants but with varying clinical phenotypes. Identification of PIK3CA resulted in transition to a targeted inhibitor, alpelisib. These cases highlight the genetic overlap between phenotypically diverse lymphatic anomalies.

State-of-the-art imaging for lymphatic evaluation in children.

The lymphatic system has been poorly understood and its importance neglected for decades. Growing understanding of lymphatic flow pathophysiology through peripheral and central lymphatic flow imaging has improved diagnosis and treatment options in children with lymphatic diseases. Flow dynamics can now be visualized by different means including dynamic contrast-enhanced magnetic resonance lymphangiography (DCMRL), the current standard technique to depict central lymphatics. Novel imaging modalities including intranodal, intrahepatic and intramesenteric DCMRL are quickly evolving and have shown important advances in the understanding and guidance of interventional procedures in children with intestinal lymphatic leaks. Lymphatic imaging is gaining importance in the radiologic and clinical fields and new techniques are emerging to overcome its limitations.

Dynamic contrast-enhanced MR lymphangiography: feasibility of using ferumoxytol in patients with chronic kidney disease.

PURPOSE: To assess the feasibility of direct intra-lymphatic administration of diluted ferumoxytol as a T1-positive contrast agent for dynamic contrast-enhanced MR lymphangiography (DCMRL) imaging of the central lymphatics in children with renal disease. METHODS: In vitro scan of dilute ferumoxytol was initially performed using time-resolved and high-resolution 3D gradient echo (GRE) sequences with short TE values (1 to 1.5 ms). A ferumoxytol concentration of 0.25 to 0.40 mg/mL was found to retain high signal in the T1-weighted sequences. DCMRL was then performed in 4 children with renal disease with the same 3D GRE sequences administrating diluted ferumoxytol via intra-mesenteric (IM), intra-hepatic (IH), and intra-nodal (IN) routes (6 to 9 mL to each site; average total dose of 0.75 mg/kg) by slow hand injection (0.5 to 1.0 mL/min). The signal-to-noise ratio (SNR) of the lymphatics was measured for quantitative evaluation. RESULTS: Ferumoxytol-enhanced DCMRL was technically successful in all patients. Contrast conspicuity within the lymphatics was sufficient without subtraction. The mean SNR was significantly higher than the muscle (50.1 ± 12.2 vs 13.2 ± 2.8; t = 15.9; p < .001). There were no short-term complications attributed to the administration of ferumoxytol in any of the four patients. CONCLUSION: Magnetic resonance lymphangiography using ferumoxytol via IN, IH, and IM access is a new method to directly visualize the central lymphatic system and can be applied safely in patients with renal failure based on our preliminary report of four cases. Ferumoxytol-enhanced DCMRL shows diagnostic image quality by using 3D GRE sequences with short TE values and appropriate dilution of ferumoxytol. KEY POINTS: • MR lymphangiography using ferumoxytol via intra-nodal, intra-hepatic, and intra-mesenteric access is a new method to directly visualize the central lymphatic system from the groin to the venous angle. • FDCMRL can be applied safely in patients with renal failure based on our preliminary report of four cases. • FDCMRL shows diagnostic image quality by using 3D GRE sequences with short TE values and appropriate dilution of the ferumoxytol.

Liver lymphatic anatomy and role in systemic lymphatic disease.

OBJECTIVES: To characterize hepatic to systemic lymphatic connections in patients with systemic lymphatic disease using intra-hepatic lymphangiography and to compare outcomes after lymphatic intervention. METHODS: In this retrospective study, patients with intra-hepatic lymphangiography from May 2014 - April 2019 at our institution were included. Imaging review was performed and hepatic lymphatic connections and flow patterns were characterized. Clinical data were reviewed and comparisons between patients undergoing lymphatic intervention with or without abnormal hepatic lymphatics were performed. RESULTS: During the study period, 105 patients underwent intra-hepatic lymphangiography. Primary clinical presentation included ascites (19/105), chylothorax (27/105), plastic bronchitis (PB) (17/105), and protein losing enteropathy (PLE) (42/105). Five categories of hepatic lymphatic connections and flow patterns were identified (%): normal (25%, 26/105), hepatoperitoneal (12%, 13/105), hepatopulmonary (10.5%, 11/105), hepatomesenteric (7.5%, 8/105), and hepatoduodenal (41%, 43/105) with four patients having more than one abnormal pattern. A comparison between clinical presentation and imaging category revealed an increased likelihood of having ascites with hepatoperitoneal (p < .0001), chylothorax/PB with hepatopulmonary (p = .01), and PLE with hepatoduodenal (p < .001) connections. Seventy-six patients had a lymphatic intervention, 24% with normal, and 76% with abnormal liver lymphatics. There was no difference in length of hospital stay or mortality between the two groups, but there was a prolonged time to symptom resolution (p = .006) and persistent symptoms after 6 months (5% vs 44%, p = .002) in the group with abnormal liver lymphatics. CONCLUSION: We identified five liver lymphatic imaging categories with a substantial correlation to presenting lymphatic disease. Abnormal imaging patterns correlated with increased morbidity. Evaluation of liver lymphatics should be considered in patients with a systemic lymphatic disease if central lymphatic imaging is normal. KEY POINTS: • We identified five liver lymphatic imaging patterns: normal, hepatoperitoneal, hepatomesenteric, hepatopulmonary, and hepatoduodenal. • Imaging patterns were correlated with disease presentation (normal - chylothorax/PB, hepatoperitoneal - ascites/chylothorax, hepatopulmonary - chylothorax/PB, hepatoduodenal - PLE). • Abnormal imaging patterns correlated with increased morbidity.

Dynamic Contrast Magnetic Resonance Lymphangiography Localizes Lymphatic Leak to the Duodenum in Protein-Losing Enteropathy.

OBJECTIVES: Protein-losing enteropathy (PLE) is a disorder of intestinal lymphatic flow resulting in leakage of protein-rich lymph into the gut lumen. Our primary aim was to report the imaging findings of dynamic contrast magnetic resonance lymphangiography (DCMRL) in patients with PLE. Our secondary objective was to use these imaging findings to characterize lymphatic phenotypes. METHODS: Single-center retrospective cohort study of patients with PLE unrelated to single-ventricle circulation who underwent DCMRL. We report imaging findings of intranodal (IN), intrahepatic (IH), and intramesenteric (IM) access points for DCMRL. RESULTS: Nineteen patients 0.3-58 years of age (median 1.2 years) underwent 29 DCMRL studies. Primary intestinal lymphangiectasia (PIL) was the most common referring diagnosis (42%). Other etiologies included constrictive pericarditis, thoracic insufficiency syndrome, and genetic disorders. IN-DCMRL demonstrated a normal central lymphatic system in all patients with an intact thoracic duct and localized duodenal leak in one patient (1/19, 5%). IH-DCMRL detected a duodenal leak in 12 of 17 (71%), and IM-DCMRL detected duodenal leak in 5 of 6 (83%). Independent of etiology, lymphatic leak was only visualized in the duodenum. CONCLUSIONS: In patients with PLE, imaging via DCMRL reveals that leak is localized to the duodenum regardless of etiology. Comprehensive imaging evaluation with three access points can provide detailed information about the site of duodenal leak.

Dynamic contrast-enhanced magnetic resonance lymphangiography.

Lymphatic flow disorders include a broad spectrum of abnormalities that can originate in the lymphatic or the venous system. The development of these disorders is multifactorial and is most commonly associated with congenital heart diseases and palliative surgeries that these patients undergo. Central lymphatic disorders might be secondary to traumatic leaks, lymphatic overproduction, conduction abnormalities or lymphedema, and they can progress to perfusion anomalies. Several imaging modalities have been used to visualize the lymphatic system. However, the imaging of central lymphatic flow has always been challenging. Dynamic contrast-enhanced magnetic resonance lymphangiography (DCMRL) allows for visualization of central lymphatic flow disorders and has been recently applied for the assessment of plastic bronchitis, protein-losing enteropathy, chylothorax and chylopericardium, among other lymphatic disorders. The hepatic and mesenteric accesses are innovative and promising techniques for better identification and understanding of these abnormalities. The main objectives of this review are to discuss the physiology and anatomy of the lymphatic system and review the current uses of DCMRL in the diagnosis and management of lymphatic flow disorders.

Lymphatic anomalies in congenital heart disease.

Congenital heart disease can lead to various lymphatic complications including traumatic leaks, lymphatic overproduction, conduction abnormalities or lymphedema. Advancements in the imaging of central lymphatics and guided interventions have improved outcomes in these children. Dynamic contrast-enhanced magnetic resonance (MR) lymphangiography allows for the assessment of abnormal lymphatic drainage. This technique is preferred for evaluating lymphatic conditions such as plastic bronchitis, chylothorax, chyloptysis, chylopericardium, protein-losing enteropathy and chylous ascites, among other lymphatic disorders. In this review, we discuss lymphatic abnormalities encountered on MRI in children with congenital heart disease. We also briefly review treatment options.

Post-operative Chylothorax in Patients with Repaired Transposition of the Great Arteries.

Patients with dextro-transposition of the great arteries (d-TGA) require surgical repair as neonates. These patients are at risk for post-operative chylothorax. We sought to describe the presentation, imaging, and outcomes after intervention for patients with d-TGA with post-operative chylothorax. A retrospective chart review was performed in patients with repaired d-TGA who were referred from 1/1/2013 to 4/1/2020 for evaluation of chylothorax. Patient history, lymphatic imaging, and interventional data were collected. Impact of intervention on lymphatic drainage was evaluated with a student's t-test. Eight patients met inclusion criteria for this study. Five patients had a history of central venous thrombus leading to thoracic duct outlet occlusion. Five patients underwent intervention, two were managed conservatively, and one was not a candidate for intervention. Chylothorax resolved in six patients. There was a significant difference in output from 7 days prior to first intervention (114 mL/kg/day) compared to 28 days following final intervention (27 mL/kg/day, p = 0.034). There were no procedural complications. Chylothorax in patients with repaired transposition of the great arteries is often amenable to intervention. Early surveillance and management of central venous thrombosis may reduce the burden of lymphatic disease in these patients.

Decompression of the thoracic duct: A novel transcatheter approach.

In patients with total cavopulmonary connections, elevated central venous pressures (CVP) have detrimental effects on the lymphatic system causing an imbalance in fluid production and drainage of the interstitium. This combination may result in life-threatening lymphatic complications including plastic bronchitis (PB), protein losing enteropathy (PLE), chylothorax, and ascites. While embolization of the abnormal lymphatics has greatly improved outcomes from these complications, alternative treatment strategies have been proposed that would result in improved lymphatic drainage while leaving the lymphatic system intact. We report two novel transcatheter approaches for thoracic duct (TD) decompression in two patients who developed PLE after completion of the Fontan procedure as part of staged palliation for congenital heart disease. In addition, one patient had severe concurrent PB. In both patients, a connection was created between a left superior vena cava (LSVC) to the left atrium allowing for a nonsurgical method to decompress the TD. This procedure resulted in significant clinical and laboratory improvement of both patients' PLE and other symptoms of lymphatic dysfunction.

Compression of the left mainstem bronchus by patent ductus arteriosus in neonates under consideration for ductal stenting.

Stent angioplasty of patent ductus arteriosus has been shown to be a viable alternative to operative shunt placement in cyanotic neonates. With broader implementation of this strategy, novel complications are bound to arise. We present a series of cases evaluated for ductal stent angioplasty in which a dilated and torturous ductus arteriosus compressed the left mainstem bronchus. After reviewing our recent experience with ductal stenting and isolated Blalock-Taussig shunts, our best estimate of the incidence of bronchial compression by the dilated ductus is 4.6% (3/64, 95% confidence interval 1.0-12.9%). Awareness of the airway and other nonvascular contents of the thorax is an important consideration prior to ductal stenting.

Incidence and fate of device-related left pulmonary artery stenosis and aortic coarctation in small infants undergoing transcatheter patent ductus arteriosus closure.

OBJECTIVES: To evaluate short- and middle-term outcomes after transcatheter patent ductus arteriosus (TC-PDA) closure in small infants, specifically device-related left pulmonary artery (LPA) stenosis and aortic coarctation, risk factors, and changes over time. BACKGROUND: Recent studies have demonstrated successful transcatheter PDA (TC-PDA) closure in small infants. LPA stenosis and aortic coarctation have been seen after TC-PDA, but it is not clear whether device-related LPA/aortic obstruction persists. METHODS: A single-center retrospective study of infants ≤4 kg who underwent TC-PDA closure from February 1, 2007 to September 1, 2018 was performed, evaluating the incidence and risk factors for LPA stenosis and coarctation. RESULTS: Forty-four patients underwent successful TC-PDA with Amplatzer Vascular Plug II (AVPII; n = 30), Amplatzer Duct Occluder II-Additional Sizes (n = 10), Amplatzer Duct Occluder I (n = 3), and coil-filled AVPI (n = 1) devices, all via an antegrade approach. Median birthweight and procedural weight were 890 g (range: 490-3,250) and 2.8 kg (range: 1.2-4.0), respectively. Median follow-up was 0.7 years (range: 2 days-7 years). Thirty-eight patients had post-procedure echocardiograms assessing LPA/aortic obstruction. Of those, 17 had LPA flow acceleration/stenosis (≥1.5 m/s), which improved or resolved in all patients with available follow-up; 3 developed mild coarctation (>2 m/s), which improved in the two with more than short-term follow-up; 4 developed mild flow acceleration (1.5-2 m/s) in the descending aorta, which resolved in three and increased in one (2.4 m/s). Flow acceleration in the LPA was associated with younger procedural age, larger PDA minimal diameter, and placement of a device other than the AVPII. There was no device-related mortality or need for reintervention. CONCLUSION: TC-PDA in small infants is effective, without significant complications. Device-related LPA/aortic obstruction can improve with time/growth.

Use of Contrast-Enhanced Ultrasound to Determine Thoracic Duct Patency.

The aim of this study was to determine the feasibility of using contrast-enhanced ultrasound (CEUS) evaluation to determine thoracic duct (TD) outlet patency. Nine patients referred for lymphatic imaging and intervention underwent percutaneous intranodal ultrasound contrast injection and conventional lymphangiography (CL). Eight of 9 patients had a patent TD by CEUS and CL. One patient did not have a patent TD. There was 100% agreement between CEUS and CL. These results suggest that CEUS is an imaging modality that might be as accurate as CL in determining TD patency.

Pediatric pulmonary lymphatic flow Disorders: Diagnosis and management.

Pulmonary lymphatic flow disorders involve the abnormal lymphatic flow via lymphatic channels to the lungs and pleural space. Plastic bronchitis and chylothorax are the main complications of this abnormal lymphatic perfusion, which has been termed pulmonary lymphatic perfusion syndrome (PLPS). Following lymphatic access, dynamic contrast MR lymphangiography is the imaging modality of choice to diagnose these disorders. Management includes medical therapy, percutaneous interventions under fluoroscopy, and surgical interventions.

Imaging of fetal lymphangiectasias: prenatal and postnatal imaging findings.

Lymphangiectasias are lymphatic malformations characterized by the abnormal dilation and morphology of the lymphatic channels. The classification and treatment of these disorders can be challenging given the limited amount of literature available in children. Various imaging modalities are used to confirm suspected diagnosis, plan the most appropriate treatment, and estimate a prognosis. Prenatal evaluation is performed using both prenatal US imaging and fetal MRI. These modalities are paramount for appropriate parental counseling and planning of perinatal care. During the neonatal period, chest US imaging is a useful modality to evaluate pulmonary lymphangiectasia because other modalities such as conventional radiography and CT display nonspecific findings. Finally, the recent breakthroughs in lymphatic imaging with MRI have allowed us to better classify lymphatic disorders. Dynamic contrast-enhanced lymphangiography, conventional lymphangiography and percutaneous lymphatic procedures offer static and dynamic evaluation of the central conducting lymphatics in children, with excellent spatial resolution and the possibility to provide treatment. The purpose of this review is to discuss the normal and abnormal development of the fetal lymphatic system and how to best depict it by imaging during the prenatal and postnatal life.

Intrahepatic dynamic contrast MR lymphangiography: initial experience with a new technique for the assessment of liver lymphatics.

OBJECTIVES: To describe the technique and report on our initial experience with the use of intrahepatic dynamic contrast magnetic resonance lymphangiography (IH-DCMRL) for evaluation of the lymphatics in patients with hepatic lymphatic flow disorders. METHODS: This is a retrospective review of the imaging and clinical findings in six consecutive patients undergoing IH-DCMRL. The technique involves injection of a gadolinium contrast agent into the intrahepatic lymphatic ducts followed by imaging of the abdomen and chest with both heavily T2-weighted imaging and dynamic time-resolved imaging. RESULTS: In six consecutive patients, IH-DCMRL was technically successful. There were four patients with protein-losing enteropathy (PLE) and two with ascites in this study. In the four patients with PLE, IH-DCMRL demonstrated hepatoduodenal connections with leak of contrast into the duodenal lumen not seen by conventional lymphangiography. In one patient with ascites, IH-DCMRL demonstrated lymphatic leakage into the peritoneal cavity not seen by intranodal lymphangiography. In the second patient with ascites, retrograde lymphatic perfusion of mesenteric lymphatic networks and nodes was seen. Venous contamination was seen in two patients. No biliary contamination was identified. There were no short-term complications. CONCLUSIONS: IH-DCMRL is a cross-sectional technique which successfully evaluated hepatic lymphatic flow disorders and warrants further investigation. KEY POINTS: • Intrahepatic dynamic contrast magnetic resonance lymphangiography (IH-DCMRL) is a new imaging technique to evaluate hepatic lymphatic flow disorders such as protein-losing enteropathy. • In comparison to conventional liver lymphangiography, IH-DCMRL offers a 3D imaging technique and better distal lymphatic contrast distribution and does not use ionizing radiation.

Heart repair by reprogramming non-myocytes with cardiac transcription factors.

The adult mammalian heart possesses little regenerative potential following injury. Fibrosis due to activation of cardiac fibroblasts impedes cardiac regeneration and contributes to loss of contractile function, pathological remodelling and susceptibility to arrhythmias. Cardiac fibroblasts account for a majority of cells in the heart and represent a potential cellular source for restoration of cardiac function following injury through phenotypic reprogramming to a myocardial cell fate. Here we show that four transcription factors, GATA4, HAND2, MEF2C and TBX5, can cooperatively reprogram adult mouse tail-tip and cardiac fibroblasts into beating cardiac-like myocytes in vitro. Forced expression of these factors in dividing non-cardiomyocytes in mice reprograms these cells into functional cardiac-like myocytes, improves cardiac function and reduces adverse ventricular remodelling following myocardial infarction. Our results suggest a strategy for cardiac repair through reprogramming fibroblasts resident in the heart with cardiogenic transcription factors or other molecules.

Job Changing and the Decline in Long-Distance Migration in the United States.

Interstate migration in the United States has decreased steadily since the 1980s, but little is known about the causes of this decline. We show that declining migration is related to a concurrent secular decline in job changing. Neither trend is primarily due to observable demographic or socioeconomic factors. Rather, we argue that the decline in job changing has caused the decline in migration. After establishing a role for the labor market in declining migration, we turn to the question of why job changing has become less frequent over the past several decades. We find little support for several explanations, including the rise of dual-career households, the decline in middle-skill jobs, occupational licensing, and the need for employees to retain health insurance. Thus, the reasons for these dual trends remain opaque and should be explored further.