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Heart failure with preserved ejection fraction (HFpEF) is a complex heterogeneous disease for which our pathophysiological understanding is still limited and specific prevention and treatment strategies are lacking. HFpEF is characterised by diastolic dysfunction and cardiac remodelling (fibrosis, inflammation, and hypertrophy). Recently, microvascular dysfunction and chronic low-grade inflammation have been proposed to participate in HFpEF development. Furthermore, several recent studies demonstrated the occurrence of generalized lymphatic dysfunction in experimental models of risk factors for HFpEF, including obesity, hypercholesterolaemia, type 2 diabetes mellitus (T2DM), hypertension, and aging. Here, we review the evidence for a combined role of coronary (micro)vascular dysfunction and lymphatic vessel alterations in mediating key pathological steps in HFpEF, including reduced cardiac perfusion, chronic low-grade inflammation, and myocardial oedema, and their impact on cardiac metabolic alterations (oxygen and nutrient supply/demand imbalance), fibrosis, and cardiomyocyte stiffness. We focus primarily on HFpEF caused by metabolic risk factors, such as obesity, T2DM, hypertension, and aging.

Organ-specific lymphatics are essential for the maintenance of healthy organ function and lymphatic dysfunction can lead to the development of various diseases. However, the precise role of those lymphatic structures remains unknown, mainly due to inefficient visualization techniques. Here, we present an efficient approach to visualizing organ-specific lymphatic growth. We used a modified CUBIC protocol to clear mouse organs and combined it with whole-mount immunostaining to visualize lymphatic structures. We acquired images using upright, stereo and confocal microscopy and quantified them with AngioTool, a tool for the quantification of vascular networks. Using our approach, we then characterized the organ-specific lymphatic vasculature of the Flt4kd/+ mouse model, showing symptoms of lymphatic dysfunction. Our approach enabled us to visualize the lymphatic vasculature of organs and to analyze and quantify structural changes. We detected morphologically altered lymphatic vessels in all investigated organs of Flt4kd/+ mice, including the lungs, small intestine, heart and uterus, but no lymphatic structures in the skin. Quantifications showed that these mice have fewer and dilated lymphatic vessels in the small intestine and the lungs. Our results demonstrate that our approach can be used to investigate the importance of organ-specific lymphatics under both physiological and pathophysiological conditions.

Background Lymphatic abnormalities play a role in effusions in individuals with a Fontan circulation. Recent results using near‐infrared fluorescence imaging disclosed an increased contraction frequency of lymphatic vessels in Fontan patients compared to healthy controls. It is proposed that the elevated lymphatic pumping seen in the Fontan patients is necessary to maintain habitual interstitial fluid balance. Hyperthermia has previously been used as a tool for lymphatic stress test. By increasing fluid filtration in the capillary bed, the lymphatic workload and contraction frequency are increased accordingly. Using near‐infrared fluorescence imaging, the lymphatic functional reserve capacity in Fontan patients were explored with a lymphatic stress test. Methods Fontan patients (n = 33) were compared to a group of 15 healthy individuals of equal age, weight, and gender. The function of the superficial lymphatic vessels in the lower leg during rest and after inducing hyperthermia was investigated, using near‐infrared fluorescence imaging. Results Baseline values in the Fontan patients showed a 57% higher contraction frequency compared to the healthy controls (0.4 ± 0.3 min−1 vs. 0.3 ± 0.2 min−1, p = 0.0445). After inducing stress on the lymphatic vessels with hyperthermia the ability to increase contraction frequency was decreased in the Fontan patients compared to the controls (0.6 ± 0.5 min−1 vs. 1.2 ± 0.8 min−1, p = 0.0102). Conclusions Fontan patients had a higher lymphatic contraction frequency during normal circumstances. In the Fontan patients, the hyperthermia response is dampened indicating that the functional lymphatic reserve capacity is depressed. This diminished reserve capacity could be part of the explanation as to why some Fontan patients develop late‐onset lymphatic complications. We report, for the first time, that the functional lymphatic reserve capacity is depressed in patients with a Fontan circulation. Using Near‐Infrared Fluorescence imaging to asses function and morphology of the peripheral lymphatic vessels in patients with subclinical and clinical symptoms of effusions, we have introduced a new simple way to stress the lymphatic vessels to reveal lymphatic functional capacity.

The lymphatic vasculature maintains tissue homeostasis via fluid drainage in the form of lymph and immune surveillance due to migration of leukocytes through the lymphatics to the draining lymph nodes. Lymphatic endothelial cells (LECs) form the lymphatic vessels and lymph node sinuses and are key players in shaping immune responses and tolerance. In the healthy lung, the vast majority of lymphatic vessels are found along the bronchovascular structures, in the interlobular septa, and in the subpleural space. Previous studies in both mice and humans have shown that the lymphatics are necessary for lung function from the neonatal period through adulthood. Furthermore, changes in the lymphatic vasculature are observed in nearly all respiratory diseases in which they have been analyzed. Recent work has pointed to a causative role for lymphatic dysfunction in the initiation and progression of lung disease, indicating that these vessels may be active players in pathologic processes in the lung. However, the mechanisms by which defects in lung lymphatic function are pathogenic are understudied, leaving many unanswered questions. A more comprehensive understanding of the mechanistic role of morphological, functional, and molecular changes in the lung lymphatic endothelium in respiratory diseases is a promising area of research that is likely to lead to novel therapeutic targets. In this review, we will discuss our current knowledge of the structure and function of the lung lymphatics and the role of these vessels in lung homeostasis and respiratory disease.

The potential negative impact of lymphatic dysfunction caused by head and neck cancer treatment remains underexplored. Emerging evidence suggests that waste clearance and fluidic balance in the brain are connected to the peripheral lymphatic system in the head and neck region, implying that lymphatic injury in this area could contribute to brain damage. This study aimed to investigate the pathological alterations in the brain induced by peripheral lymphatic dysfunction in the head and neck region using the lymphatic obstruction animal model. An animal model underwent cervical lymph node dissection combined with radiation therapy to simulate the condition with the peripheral lymphatic dysfunction in the head and neck region after cancer treatment. Lymphatic drainage impairment in the head and neck region was associated with significant swelling, disrupted lymphatic drainage, and immune cell infiltration in the white matter. The imaging techniques revealed ventricular enlargement and increased brain water content caused by fluid imbalance leading to significant structural alterations in the brain. Histopathological analysis demonstrated structural brain alterations similar to that of hydrocephalus and cerebral edema, while rotarod tests showed a substantial decline in motor performance. These findings highlight the impact of peripheral lymphatic dysfunction on brain integrity and function. This study provides evidence that brain damage in head and neck cancer patients may be influenced not only by chemotherapy or radiotherapy but also by lymphatic dysfunction caused by surgical interventions. Lymphatic injury in the head and neck region emerges as a potential risk factor for brain damage, underscoring the need for further research into preventive and therapeutic strategies.

Atherosclerosis remains a leading cause of cardiovascular morbidity and mortality worldwide. While traditionally attributed to lipid accumulation, endothelial dysfunction, and inflammation, growing evidence implicates the lymphatic system as a key regulator of vascular homeostasis and plaque stability. Recent experimental data suggest that restoring lymphatic function may represent a novel therapeutic avenue in atherosclerosis. Recombinant VEGF-C variants and nanoparticle-based gene delivery systems selectively have been shown to induce lymphangiogenesis and improve lipid clearance without triggering abnormal angiogenesis. Similarly, Apolipoprotein A-I infusions have been demonstrated to strengthen lymphatic endothelial junctions, enhance vessel contractility, and facilitate the removal of cholesterol and inflammatory cells from atherosclerotic lesions. This comprehensive review aims to present recent findings from preclinical and clinical trials and studies on investigational pharmacological therapies, explore the interrelationship between atherosclerosis and the lymphatic system, and highlight potential avenues for future research.

Chylothorax following paediatric cardiac surgery is associated with significant morbidity, particularly those that are refractory to conservative therapy. It is our impression that there is important variability in the medical, surgical, and interventional therapies used to manage refractory chylothorax between congenital heart programmes. We therefore conducted a survey study of current practices for managing refractory chylothorax. The Chylothorax Work Group, formed with the support of the Pediatric Cardiac Critical Care Consortium, designed this multi-centre survey study with a focus on the timing and indication for utilising known therapies for refractory chylothorax. The survey was sent to one chylothorax expert from each Work Group centre, and results were summarised and reported as the frequency of given responses. Of the 20 centres invited to participate, 17 (85%) submitted complete responses. Octreotide (13/17, 76%) and sildenafil (8/17, 47%) were the most utilised medications. Presently, 9 (53%) centres perform pleurodesis, 15 (88%) perform surgical thoracic duct ligation, 8 (47%) perform percutaneous lymphatic interventions, 6 (35%) utilise thoracic duct decompression procedures, and 3 (18%) perform pleuroperitoneal shunts. Diagnostic lymphatic imaging is performed prior to surgical thoracic duct ligation in only 7 of the 15 (47%) centres that perform the procedure. Respondents identified barriers to referring and transporting patients to centres with expertise in lymphatic interventions. There is variability in the treatment of refractory post-operative chylothorax across a large group of academic heart centres. Few surveyed heart centres have replaced surgical thoracic duct ligation or pleurodesis with image-guided selective lymphatic interventions.

Lymphatic dysfunction has been linked to inflammation since the 1930s. Lymphatic function in the gut and mesentery is grossly underexplored in models of inflammatory bowel disease despite the use of lymphatic occlusion in early models of inflammatory bowel disease. Activation of the innate and adaptive immune system is a hallmark of TNBS-induced inflammation and is linked to disruption of the intrinsic lymph pump. Recent identification of crosstalk between lymphatic vessel resident immune cells and regulation of lymphatic vessel contractility underscore the importance of the timing of lymphatic dysfunction during tissue inflammation in response to TNBS.MethodsTo evaluate lymphatic function in TNBS induced inflammation, lymph was collected and flow measured from mesenteric lymphatics. Cellularity and cytokine profile of the lymph was also measured. Histopathology was performed to determine severity of injury and immunofluorescent staining of the mesentery was done to evaluate changes in the population of immune cells that reside near and on gastro-intestinal collecting lymphatics.ResultsLymph transport fell 24 hours after TNBS administration and began recovering at 72 hours. Significant reduction of lymph flow preceded significant increase in histopathological score and occurred simultaneously with increased myeloperoxidase activity. These changes were preceded by increased MHCII+ cells surrounding mesenteric lymphatics leading to an altered lymphatic environment that would favor dysfunction.ConclusionsAlterations in environmental factors that effect lymphatic function occur before the development of gross GI inflammation. Reduced lymphatic function in TNBS-mediated inflammation is likely an early factor in the development of injury and that recovery of function is associated with resolution of inflammation.

This study explored mutations in the Fms-related tyrosine kinase 4/vascular endothelial growth factor receptor 3 gene (FLT4) and lymphatic defects in patients with Milroy disease (MD). Twenty-nine patients with lower limb lymphedema were enrolled. Sixteen patients had a familial history of MD, while 13 patients exhibited sporadic MD. Clinical signs, FLT4 mutations, indocyanine green (ICG) lymphography findings, and skin tissue immunohistochemical staining results were evaluated. Twenty-eight variants in FLT4 were identified. Twelve of these have previously been reported, while 16 are novel. Of the 28 variants, 26 are missense mutations, and the remaining two comprise a splicing mutation and a non-frame shift mutation. Twenty-five variants are located in the intracellular protein tyrosine kinase domain; three are located in the extracellular immunoglobulin domain. Substantially delayed contrast-enhanced tortuous lymphatic vessels were visualized to the ankle or knee level in 15 of 23 patients who underwent ICG lymphography. No initial lymphatic vessels were visualized in skin specimens from four patients who did not exhibit lymphatic vessels during imaging analyses. No specific variant was identified in relation to the unique clinical phenotype. Segmental dysfunction of lymphatic vessels and initial lymphatic aplasia are present in MD patients with FLT4 mutations.

Impairment in lymphatic transport is associated with the onset and progression of atherosclerosis in animal models. The downregulation of low-density-lipoprotein receptor (LDLR) expression, rather than increased circulating cholesterol level , is involved in early atherosclerosis-related lymphatic dysfunction. Enhancing lymphatic function in mice with a mutant form of VEGF-C (VEGF-C 152s), a selective VEGFR-3 agonist, successfully delayed atherosclerotic plaque onset when mice were subsequently fed a high-fat diet. However, the specific mechanisms by which LDLR protects against lymphatic function impairment is unknown. We have thus injected wild-type and mice with an adeno-associated virus type 1 expressing a shRNA for silencing . We herein report that lymphatic contractility is reduced upon dowregulation in wild-type mice only. Our experiments reveal that a decrease in expression at the mRNA level reduces the chromosome duplication phase and the protein expression of VEGFR-3, a membrane-bound key lymphatic marker. Furthermore, it also significantly reduced the levels of 18 lipid subclasses, including key constituents of lipid rafts as well as the transcription of several genes involved in cholesterol biosynthesis and cellular and metabolic processes. Exogenous PCSK9 only reduces lymphatic endothelial-LDLR at the protein level and does not affect lymphatic endothelial cell integrity. This puts forward that PCSK9 may act upon lymphatic muscle cells to mediate its effect on lymphatic contraction capacity . Our results suggest that treatments that specifically palliate the down regulation of mRNA in lymphatic endothelial cells preserve the integrity of the lymphatic endothelium and sustain lymphatic function, a prerequisite player in atherosclerosis.