A search in the Web of Science (https://webofscience.clarivate.cn/wos/woscc/basic-search) core collection database for documents published from Jan 1, 2012 to August 1, 2023, was conducted using the key words 'heart disease' and 'lymphatic system'. A total of 197 documents were included, articles and reviews were selected, and other types of documents such as proceeding paper, editorial material, book chapters and others were excluded, and finally a total of 189 documents were used. Subsequently, a scientometric analysis was conducted on both articles and reviews. Raw data, encompassing comprehensive records and cited references, were downloaded from the Web of Science. Using CiteSpace (version 6.1.R2) (10), primary information such as publication numbers per year, countries, journals, key words and literature titles were extracted from the raw data. The data were visualized using Microsoft^® Excel^® 2021MSO and Hiplot (https://hiplot.com.cn/home/index.html) (Fig. 1).

The search in the Web of Science core collection database revealed 189 publications related to the therapeutic effects of the lymphatic system on heart disease before August 1, 2023. On average, these documents were cited 28.06 times. In 2021, the highest number of articles was published, while the maximum number of citations was observed in 2013 (Fig. 2A). The observed trend indicates a growing body of research on the therapeutic effects of the lymphatic system on heart disease.

A total of 35 countries were represented in the publications included in the present review. The USA published the highest number of published articles, followed by United Kingdom, Germany, Italy, China, Japan, Finland, France, Brazil and Canada (Fig. 2B). Collaborative efforts were evident among several countries (Fig. 2C).

Publications originated from 53 different types of publishers, with the top 10 shown in Fig. 2D. Notably, Elsevier emerged as the most influential publisher, followed by Wiley, Springer Nature, Frontiers Media SA, MDPI, Lippincott Williams & Wilkins, American Physiological Society, BMJ Publishing Group, Public Library Science and International Society of Lymphology and the University of Arizona Libraries.

Research key words reflect current trends, hotspots and the essence of a research document (11). The present review presents a co-occurrence network of key words (Fig. 3; Table I). In these clusters, 'lymphangiogenesis' emerged as a cross-key word, suggesting its potential impact on heart disease. The scientometric results further indicate that the lymphatic vessel is a research hotspot and potentially a promising treatment avenue for heart diseases, including MI, HF and CHD, with a focus on the cardiac lymphatic system.

Citations play a crucial role in acknowledging sources during the writing or editing of a manuscript, including both the cited literature and the specific content of the citation (12). In response to the analysis of the key words, current research interests and topic hotspots were explored through literature analysis and references. Table II presents the top 10 most-cited articles on the therapeutic effect of lymphangiogenesis on heart diseases. The most influential article highlights the critical role of the lymphatic vascular system in maintaining interstitial fluid homeostasis, immune cell transport, nutrient lipid uptake and transport, and reverse cholesterol transportation (13). The second most-cited article underscores that selective stimulation of cardiac lymphangiogenesis post-MI markedly improves myocardial edema and restores cardiac function (14). Additionally, Table III outlines the top 10 cited references on the therapeutic roles of lymphangiogenesis in heart diseases. These articles offer a comprehensive overview of the most influential studies in the field for further research into the therapeutic effect of lymphangiogenesis on heart diseases.

The clinical applications of lymphangiogenesis have been used to improve cardiac function (15). However, The clinical trial have yet to elucidate the specific signaling pathways regulating lymphangiogenesis for improved cardiac function. Therefore, animal experiments would be useful in establishing whether and how lymphangiogenesis improves cardiac function. The present review focused extensively on lymphangiogenesis in heart diseases. Furthermore, despite scientometric analysis indicating that lymphangiogenesis is a research hotspot and a promising treatment option for heart disease, a comprehensive and systematic exploration of relevant mechanisms is lacking. Therefore, in the current review, existing research at the mechanistic level on lymphangiogenesis and cardiovascular disease was examined.

AS is a chronic inflammatory disease characterized by the accumulation of cholesterol, lipoproteins and inflammatory cells in the arterial vessel wall (16). Lymphatics are present at atherosclerotic sites in the adventitia of the artery, adjacent to blood vessels and dilate within atherosclerotic plaques. With a deeper understanding of lymphatic vessel function, mounting evidence reveals the critical role of lymphangiogenesis in AS progression. Particularly, it is increasingly acknowledged that lymphatics are the main route for transporting high-density lipoprotein particles in cholesterol to the bloodstream (17). AS promotes lymphangiogenesis (18), which in turn, alleviates AS by facilitating reverse cholesterol transport and simultaneously draining local inflammation (19,20). The number and function of lymphatic vessels are limited. Consequently, promoting lymphangiogenesis holds great promise for the treatment of AS.

According to clinical and experimental studies, lymphangiogenesis in AS is regulated by multiple signaling pathways and molecules. Clinical evidence indicates that VEGF-C/D levels are notably and inversely associated with all-cause mortality among patients with suspected or known AS (21). Early treatment with VEGF-C inhibited plaque formation, promoting lymphatic molecular transport and triggering inflammatory cell migration (22). Besides VEGF-C/D, angiopoietin-2 (Angpt2) is associated with angiogenesis and inflammation. Clinical evidence suggests that the upregulation of Angpt2 may benefit patients with AS (23). This effect may be associated with the increase in VEGF-C/D secretion regulated by Angpt2, promoting lymphangiogenesis around atherosclerotic coronary arteries (23). R-spondin 2 (RSPO2), an important factor for regulating cell proliferation and differentiation, has previously shown potential in promoting lymphangiogenesis (24,25). A study indicated that the interaction between RSPO2 and G protein-coupled receptor 5 inhibits Wnt/β-catenin signaling (26), limiting lymphatic vessel formation, weakening lymphatic drainage of LDL cholesterol in the arterial wall and promoting AS development. A further study found that the phosphatidylinositol-3-hydroxykinase (PI3K)-protein kinase B (AKT) pathway is a downstream pathway of Wnt/β-catenin performs that promotes lymphangiogenesis (24). Additionally, the activation of the C-X-C chemokine receptor type 4 (CXCR4)/chemokine C-X-C motif ligand 12 (CXCL12) axis exacerbates inflammation by promoting leukocyte infiltration (27). A study suggested that the CXCL12/CXCR4 axis regulates cardiac adventitia lymphangiogenesis, reducing inflammation during AS by enhancing T-cell drainage (18). Details are provided in Table IV and Fig. 4.

The rupture of an unstable atherosclerotic plaque and subsequent coronary thrombosis often leads to MI (28). MI is often accompanied by myocardial edema, inflammation and fibrosis (29). Cardiac lymphatic flow begins from small endocardium lymphatic vessels, traverses through the myocardium and enters epicardial capillaries. These capillaries converge into large collecting lymphatic vessels, facilitating the transportation of excess water and immune cells, and inhibiting myocardial edema, inflammation and fibrosis (6). Lymphatic vessel formation is investigated as a potential target for MI in clinical practice (30). Lymphatic vessels play a crucial role in heart repair after MI, maintaining tissue fluid homeostasis and suppressing excessive immune responses (31). The VEGF family and their endothelial tyrosine kinase receptors induce lymphangiogenesis (32), but their efficiency is limited when injected intravenously or intracoronarily after MI due to short half-lives (33). Thus, researchers are exploring new pathways new pathways regulating lymphangiogenesis.

VEGF-C-VEGFR3, sphinogosine-1-phosphate (S1P)/S1P receptor 1 (S1PR1) is another noteworthy receptor-ligand complex. S1PR1 is a G-protein-coupled receptor, expressed in lymphatic endothelial cells, and modulates immune cell transportation (34). In injured hearts, S1PR1/S1P activates downstream signals, including extracellular regulated protein kinases/chemokine ligand 2 (ERK), promoting lymphangiogenesis in the injured heart, driving macrophage trafficking, immune modulation, and cardiac repair after MI (35,36). Estrogen receptor α (ERα)/estrogen ligand plays a protective role in MI, associated with regulating lymphangiogenesis (37). Overexpression of cardiomyocyte-specific ERα promotes lymphangiogenesis via inducing c-Jun N-terminal kinase phosphorylation, alleviating ventricular fibrosis (38). Spinster homolog 2 (SPNS2) and thymosin beta 4 (Tβ4) drive lymphangiogenesis by controlling lymphatic endothelial cell proliferation and differentiation. SPNS2, an S1P transporter, contributes to S1P release into extracellular space and the development of lymphatic vessels (39,40). Apelin/Apelin receptor signaling targets SPNS2, promoting lymphatic endothelial cell proliferation and maintaining lymphatic endothelial cell integrity, limiting persistent edema and inflammation after MI (41). Tβ4, which is a 43-amino-acid-sequestering peptide in the embryonic heart, is important for epicardial development and coronary artery formation (42). Tβ4 promotes the differentiation of epicardium-derived cells towards lymphatic endothelial cells, attenuating adverse myocardial remodeling, enhancing myocardial regeneration, and improving cardiac function post-MI (43). Connexin43 (Cx43) may control the function of nascent lymphatic vessels by determining endothelial cell connections. Cx43 modulates gap connection coupling between lymphatic endothelial cells and has been implicated in the pathological process of MI. A previous study showed that adrenomedullin targeted Cx43 to increase gap connections between human lymphatic endothelial cells, promoting the proliferation of the cardiac lymphatic vascular system and relieving MI-induced edema (44). Additionally, VEGF-C-VEGFR-3 indirectly promotes lymphangiogenesis, polarizing macrophage from M1 to M2 in the MI area via activation of downstream AKT/ERK1/2 and calcineurin/nuclear factor of activated T cells 1, forkhead box C2 signaling pathways, accelerating post-MI repair (45). Furthermore, when dead cells are engulfed by macrophages, more VEGF-C is released, further promoting myocardial lymphangiogenesis through its receptor (46). Details are provided in Table IV and Fig. 4.

At the end stage of heart disease, the clinical manifestation is HF, not a single pathological diagnosis but a clinical syndrome characterized by breathlessness, ankle swelling, fatigue, pulmonary crackles, peripheral edema and elevated jugular venous pressure (47,48). Common pathological manifestations of HF include myocarditis, myocardial edema, and myocardial fibrosis (49-51). Excessive inflammatory infiltration forms the biological basis for these manifestations (52), and edema results as a major consequence of the inflammatory response in the myocardium (53). Lymphatics are crucial to the progression of HF. Cardiac lymphatics play a crucial role in the progression of HF by adapting their number and function to the increased demand for inflammatory factors and fluid drainage, thus alleviating inflammation and edema (54,55).

Most studies suggest that VEGF-C-VEGFR3 signaling, as the key pathway of lymphangiogenesis, may be a therapeutic target for HF (45). Additionally, interleukin-1β (IL-1β), an inflammatory cytokine associated with MI, has been reported to exert a profound depressant effect on the contractility of lymphatic muscles (56). Prostaglandin E2 (PGE2), the main downstream product of cyclooxygenase-2 activation, induces relaxation by binding to PGE2 to prostaglandin E receptor 2 or 4, elevating intracellular cyclic adenosine monophosphate accumulation (57). A recent study showed that IL-1β reduced the contractility of cardiac lymphatic muscle cells through COX-2/PGE2 signal transduction, weakening the transport of local inflammation in the heart and promoting the progression of acute myocarditis to HF (58). Furthermore, angiotensin-2 (Ang II), is an important factor in inducing inflammation in the vascular system (59). Angiotensin, serotonin, and endothelin are also known to regulate lymphatic vessels (60). Ang II can activate AT1R to promote the expression and activity of proteasome catalytic subunits β2i and β5i, affecting MKP5 and VE-cadherin degradation and p38MAPK activation, resulting in lymphatic endothelial hyperpermeability (61). Moreover, cardiac fibroblasts, principal contributors to cardiac fibrosis leading to cardiac remodeling and HF, express vascular cell adhesion molecule-1 and promote lymphangiogenesis (62). This mobilizes lymphatic endothelial cells into the infarct zone, restoring ventricular wall mechanical properties. The mechanism may involve the formation of lymphatic vessels, inhibition of interstitial edema, and consequently, reduced inflammation and myocardial fibrosis (63). Details are provided in Table IV and Fig. 4.

HHD is an organic heart disease caused by long-term poorly controlled hypertension, characterized by cardiac hypertrophy due to progressively increasing ventricular load (64). Studies indicated that high sodium intake contributes to hypertension development (65). The large accumulation of sodium leads to electrolyte disorders and promotes edema formation (66). Lymphatics is a key route in draining interstitial fluid, and in HHD, lymphangiogenesis is an effective strategy for reducing cardiac interstitial edema. As a cytokine regulating lymphangiogenesis, VEGF-C relieves edema caused by electrolyte imbalances (67). VEGF-C treatment notably improves cardiac function, preserving cardiac function, reducing cardiac hypertrophy and fibrosis, accelerating edema clearance by inducing skin lymphangiogenesis and enhancing endothelial nitric oxide (NO) synthase expression in blood vessels to lower blood pressure (68).

Lymphangiogenesis plays an important role not only in maintaining interstitial fluid balance but also in facilitating immune cell transport in HHD. The activation of the VEGF-C-VEGFR3 pathway is activated in mononuclear phagocytes, triggered by sodium salt accumulation, and stimulates skin lymphangiogenesis (69). Systemic overexpression of VEGF-C enhances lymphangiogenesis within the myocardial interstitium, attenuating local infiltration of macrophages in the heart (70). This dual mechanism of eliminating excess interstitial fluid and transporting immune cells contributes to the reduction of cardiac decompensation-induced myocardial edema and inflammation. In HHD, tonicity enhancer binding protein (TonEBP) and silencing regulatory protein 3 (SIRT3) play key roles in the upstream regulation of VEGFC-VEGFR3 signaling. TonEBP, a key regulator of cellular responses to hypertonic stress, binds to the promoter region of VEGF-C, enhancing its secretion and promoting lymphangiogenesis (71). This, in turn, inhibits left ventricular remodeling induced by high salt intake (72). SIRT3 is a major mitochondrial deacetylase closely associated with angiogenesis. A recent study indicated that SIRT3 activation upregulates the VEGF-C-VEGFR3 signaling axis protein expression, thereby promoting migration and proliferation of lymphatic endothelial cells (LECs), and lymphangiogenesis in AngⅡ-induced hypertensive heart models (73,74). Details are provided in Table IV and Fig. 4.

CHD, a common congenital cardiovascular anomaly (75), significantly affects the lymphatic system due to associated hemodynamic changes (76). The development of lymphatic structures relies on mechanical forces generated by fluid accumulation in the interstitial space. However, chronic elevation of lymph flow can lead to lymphatic system dysfunction under prolonged mechanical stimuli (77). In models of CHD with increased pulmonary blood flow, mechanical stimulation and shear stress upregulate HIF-1 α expression and induce structural disorders in LECs (78). NO plays a pivotal role in lymphangiogenesis and lymphatic function maintenance, with a notable reduction in NO bioavailability observed in congenital heart defect models (79). PPAR-γ, a ligand-activated transcription factor, increases NO bioavailable in LECs (80). Kruppel Factor 2 (KLF2) induces LEC proliferation and lymphatic sprouting under laminar flow conditions (81). The KLF2-mediated PPAR-γ signal, however, inhibits NO production, aggravating lymphatic vessel dysfunction (82). Understanding the role of lymphatic vessels in hemorheology provides innovative treatment strategies for congenital heart defects and other lymphatic disorders. Details are provided in Table IV and Fig. 4.