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right subclavian vein and right internal jugular vein and carries 25%
of the lymph. At the terminus of the duct, two valves prevent blood
from refluxing into the duct, which could trigger coagulation and
damage the lymphatic system.
Cardiac inflammation and lymphatics
Influence of inflammation on the contractility of cardiac lym-
phatic muscle. Lymphatic muscular contraction can be negatively
impacted by prostaglandins, nitric oxide, and inflammatory cyto-
kines that may influence the abundance of these mediators.
(Conversely, Johnstson and Feuer [42] suggested that inhibition of
prostanoid formation may also impair phasic contraction of lym-
phangions.) Lymphatic disturbances in the heart not only can pro-
voke myocardial edema but also lead to alterations in development
of the normal sinus rhythm and signal propagation through the
atrioventricular node and downstream tracts [17, 43]. Okada et al.
[44] showed that experimentally induced lymphostasis caused
injury to perivascular muscle cells and altered vascular electrolyte
disturbances leading to disturbances in sinus rhythm.
We have recently described that lymphatics within the epicar-
dium are invested with muscle and that the contractility of these
lymphatic muscle cells can be depressed by exposure to inflamma-
tory cytokines such as interleukin-1 beta (IL-1 β) and tumor necrosis
factor-alpha (TNF-α), which cooperatively drive a cyclooxygenase-2
(COX-2) and apparently prostaglandin E
2
PGE
2
-dependent vasodi-
lation in lymphatic muscle, which is EP4-receptor dependent; this
same mechanism has been observed in intestinal lymphatic muscle
and in experimental inflammatory bowel disease [44a, 45]. In some
models, this cytokine-dependent depression of lymphatic pumping
is nuclear factor kappa-light-chain-enhancer of activated B cells
(NF-kB)/inducible nitric oxide synthase (iNOS) and nitric oxide
dependent [46]. It is not clear whether the contraction of such lym-
phatics actively propels lymph centripetally to the lymphatic
trunks, or if changes in the tonic contraction of these vessels influ-
ence their ability to passively conduct lymph in response to the con-
tinuous rhythmic pulsations of the heart, which provide passive
force to massage lymph through these vessels.
136 7. Cardiac lymphatics and lymph flow in health and disease
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Miller has described increased lymph flow even during periods of
cardiac stress, for example, myocardial infarction, even though
there may actually be a decrease in the compressive forces, which
are assumed to drive most lymph propulsion in the heart (A. J.
Miller, personal communication).
While expansion of lymphatic networks is a typical response to
acute inflammation [47–49], the failure to mobilize lymphatics in
experimentalmyocarditis representsan interestingcontrast.Recently,
Omura et al. have reported that lymphatic marker expression was
decreased in experimental Theiler’s murine encephalomyelitis virus
(TMEV)-induced myocarditis [49a]. It is intriguing to speculate that
an inflammation-associated failure to clear lymph might prevent or
delaythespreadof virusandinflammatorymediatorswithinand from
the heart; however, this might also lead to an accumulation of intersti-
tial fluid and inflammatory cytokines, which locally depress normal
cardiac lymphatic structure and function.
Valves in lymphatic vessels
Initially, cardiac is lymph formed as it enters initial lymphatic cap-
illariesinthe heart that are linedwith oak leaf-shapedlymphatic endo-
thelial cells with unique button-like junctional configuration, in
contrasttozipper-likejunctionscomposedof both continuousand dis-
continuous zones of vascular endothelial cadherin (VE-cadherin) and
platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31) and
tight junctional proteins including occludin, claudin-5, and zona
occludens-1 (ZO-1) that are also the characteristic of blood vascular
endothelial cells, but in blood vascularendothelial cells, these are usu-
ally continuous. Interstitial fluid collected from the initial lymphatics
flowsintoprecollectorandcollectorlymphaticvessels.Lymphaticves-
sels under physiological conditions maintain unidirectional flow via
bicuspidvalves, which prevent lymph reflux. Lymphaticvalveforma-
tion is controlled by the transcription factors, FOXC2, Sox18, and
GATA 2 [50, 50a],which are expressedat high levels by valve-forming
lymphatic endothelial cells [51]. Sox18 is also known to be involved in
the development of cardiac valves and of cardiac septum [50a].Mice
lacking FOXC2 expression (FOXC2
/
) have defective lymphatic
remodeling that includes failure of valve formation, which is consid-
ered to be the hallmark feature of mature collecting vessels [52].
137Valves in lymphatic vessels
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This effectively highlights the importance of FOXC2 in controlling
valve formation and maturation in the lymphatic vasculature. Addi-
tionally, patientswithlymphedema-distichiasis, causedby a mutation
in the FOXC2 gene, displaylymph reflux and lymphedema associated
with the absence (or failure) of lymphatic valves [52], which interest-
ingly is also associated with congenital heart disease [53].
Cardiac conditions that may be exacerbated by lymphatic
obstruction, lymphangitis, or obliteration
Patients undergoing the Fontan (or Fontan-Kreutzer) procedure
are usually neonates or pediatric patients who exhibit with cyanosis
or congestive heart failure [54]. This procedure is used to correct
FIG. 1 The drainage pattern of the heart and components of the pathway. The posterior
interventricular lymphatic trunk (PVT) flows into the right coronary channel (RCC). The
anterior interventricular trunk (AVT) joins the obtuse marginal lymphatic trunk (OMT) to
form the left coronary channel (LCC). The right and left coronary lymphatic channels
merge into a single main supracardiac channel (MSC), which flows into the cardiac lymph
node (CLN), which is situated between the superior vena cava (SVC) and the brachioce-
phalic artery. The outflow of the node continues to the right lymphatic duct (RLD) that
empties into the right angulus venosus formed by the junction of the right subclavian vein
(RSV) and the internal jugular vein (IJV). The sinoatrial node (SA) and atrioventricular
node (AV) may be influenced by factors, which accumulate in these areas when cardiac
lymphostasis occurs. Based on diagrams in Miller AJ. Lymphatics of the heart, New York: Raven
Press; 1982. 382 p.
138 7. Cardiac lymphatics and lymph flow in health and disease
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defects in patients that have only a single functional ventricle,
reflecting the absence or degeneration of either a tricuspid or mitral
valve, which depresses the pumping capacity of the heart (hypo-
plastic left or right heart syndrome) or complex heart defects where
biventricular repair cannot be accomplished. In these conditions, the
ventricle has to accomplish double the work of the normal heart as it
must support both the pulmonary and systemic circulations.
The Fontan procedure to repair univentricular hearts provokes
protein-losing enteropathy and peripheral edema that involve the
lymphatic circulation. Patients with repaired Fontan circulation
have an impaired lymphatic return capacity and morphologically
enlarged thoracic ducts, measured using T2-weighted magnetic res-
onance imaging (MRI) [54a] and by ultrasonography [55]. This sug-
gests that the lymphatic vasculature is stressed in the Fontan
circulation and may play a role in the pathogenesis and complica-
tions associated with Fontan patients.
As lymphatic vessels are so close anatomically to features of the
heart, they are compressed or cut during surgery, and the thoracic
duct is highly susceptible to traumatic injury during heart surgeries.
Savla et al. [55a] described three forms of postoperative chylothorax
associated with operations for congenital heart disease: traumatic
leak from the thoracic duct, pulmonary lymphatic perfusion syn-
drome, and central lymphatic flow disorder. In most cases, these
cases are resolved by lymphatic embolization to prevent leakage.
Central lymphatic flow disorder, unfortunately, did not respond
well to this approach, and additional therapies are being sought.
Onoda et al. have reported the development of unilateral limb
edema (leg) due to iatrogenic thoracic duct injury/stenosis [56].
Similarly, because the sinoatrial node lymphatic collectors and the
right lymphatic trunk are merged within the fat pad of the ascend-
ing aorta, near the aortic root, damage to this complex can provoke
atrial fibrillation [57], alter signal propagation, and diminish myo-
cardial contraction that has also been reported [20, 21].
Effects of experimental ablation of cardiac lymphatics
The experimental termination of lymphatic communication back
to the main circulation leads to the accumulation of interstitial fluid
and mediators normally cleared by this pathway, which has
139Effects of experimental ablation of cardiac lymphatics
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devastating effects on heart function. The interference with the
normal clearance of lymph by obstruction of lymph outflow from
the heart leads to progressive disturbances in cardiac performance,
which begin within 30 min. These studies extended to 2 weeks
where several important changes in heart structure and function
were observed. Within 5days, lymphatic obstruction provoked
ST-depression with T-wave flattening. Lymphatic obstruction also
caused problems with impulse generation (presumably sinoatrial
nodal disturbances) and atrioventricular node conduction blockade
[57a]. Solti et al. [58] showed that evidence for cardiac lymphos-
tasis was observed during open-heart surgical procedures and in
hearts exhibiting long-lasting tachycardiac attacks. Therefore, at
least two nonobstructive clinical conditions may impair lymph
communication leading to altered sinus nodal signal conduction
disturbances; this does not even consider physical obstructive phe-
nomena. Myocardial contractility (assessed by preload recruitable
stroke work) was decreased significantly over 3 h following experi-
mental obstruction of cardiac lymphatic vessel. This manipulation
slightly (albeit significantly) increased cardiac edema (wet/dry
weight ratio) with extensive lymphatic swelling (lymphangiectasis)
and showed expansion of the interstitial spacing compared with
controls [59]. Therefore, conditions, which lead to cardiac lymphos-
tasis, are likely to depress heart function. Solti et al. also reported
that the interstitial edema produced by lymphostasis has negative
influences on tissue perfusion, with capillary perfusion decreasing
and arteriovenous shunts assuming a fraction of the flow [60].
While not yet clear, we have observed remarkable increases in
cytokines and chemokines in tissues where experimental interrup-
tion of lymph flow has been imposed, which may lead to increased
inflammatory signaling (as mentioned in the section earlier
“Cardiac inflammation and lymphatics”). Chaitanya et al. found
that TNF-α, IL-1β, and IFN-g increased lymphatic endothelial
expression of intercellular adhesion molecule-1 (ICAM-1), vascular
cell adhesion molecule-1 (VCAM-1), mucosal vascular addressing
cell adhesion molecule-1 (MAdCAM-1), and E-selectin on mouse
lymphatic endothelial cells (SV-LECs). In that report, we found that
in human lymphatic endothelial cells (HMEC-1a), TNF-α, IL-1 beta,
and IFN-gamma induced all ECAMs except for MAdCAM-1. IL-1 β
increased, while IFN-gamma and TNF-α reduced lymphatic
140 7. Cardiac lymphatics and lymph flow in health and disease
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endothelial proliferation. TNF-α, IL-1 β, and IFN-gamma each
reduced capillary formation in mouse and human, and TNF-α
and IL-1 β reduced barrier function in mouse and human lymphatic
endothelium. Therefore, in the setting of inflammation, inflammatory
cytokines appear to dysregulate lymphatic growth, activation, and
barrierfunction,which disturbs lymphatic clearance increasing tissue
edema in vivo. Additionally, the evolution of IL-1 beta and TNF-a in
the setting of cardiac inflammation may also lead to the induction of
C-C chemokine receptor type 7 (CCR7) on monocytes, allowing them
to penetrate into lymphatics via C-C motif ligand 21 (CCL21), an
effect that is PGE2 and cyclic adenosine monophosphate (cAMP)
dependent [61]. There has been some suggestion that TNF receptors
are more abundant on blood endothelial cells than on lymphatics[48].
Conversely, TNF blockade using antibody therapeutics [62] has been
shown in some models to enhance lymphangiogenesis. These differ-
ences may be tissue, species, and model specific.
Interestingly, such changes could lead to lymphatic obstruction,
which may in turn provoke fibrotic changes in the heart. Following
the termination of experimental lymphatics in the heart (in rabbits),
myocardial expression of collagen type I and III was increased at the
mRNA levels, and plasma levels of C-terminal propeptide type I
procollagen (PICP) and N-terminal propeptide type III procollagen
(PIIINP) myocardial collagen type I and III mRNA increased for
30days, eventually normalizing at 60 days [63]. These experiments,
carried out in otherwise healthy animals, demonstrate the capacity
of the heart to restore structure and function in response to lymphos-
tasis. However, more long-standing stresses could provoke propor-
tionately intensified levels of fibrosis, which might lead to persistent
and pathological remodeling. Additionally apelin, a bioactive pep-
tide released under hypoxia induced the expression of sphingosine-
1-phosphate (S1P) kinase and the sphingosine transporter SPNS2 to
enhance the formation and export of S1P where it may also enhance
lymphatic endothelial barrier function following myocardial ische-
mia [64]. With respect to fibrosis, for example, that might be seen
following myocardial infarction, Kinashi et al. [65] suggested that
in the setting of fibrosis, transforming growth factor-beta (TGF-β)
might oppose lymphatic proliferation to suppress lymphatics. In
the setting of tissue recovery, this may delay or interfere with heal-
ing; conversely, in the setting of transplantation, this may be
141Effects of experimental ablation of cardiac lymphatics
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beneficial in delaying the transmission of antigen presenting cells,
which can drive rejection.
Experimental manipulation of lymphatics as a form
of cardiac therapy
Treatment of lymphangitis-like sequelae is produced by myocardial
infarction. Cui describes how hyaluronidase and CLS2210, a benze-
nesulfonate, two “lymphagogues” enhanced lymph flow [66] and
reduced injury following experimental occlusion of coronary arter-
ies in dogs. This suggests that lymphostasis may result from myo-
cardial infarction and that this is beneficially influenced by
agents, which maintain lymph flow. Whether lymph flow might
also be beneficially influenced during myocarditis or other cardiac
inflammatory conditions is not clear but could be considered as a
mechanism-based therapy to preserve interstitial fluid balance.
Because lymphangiogenic growth factors have recently been
identified, which may drive the expansion of lymphatic networks,
it has been suggested that the use of such modulators could increase
the net cardiac lymphatic drainage [21]; however, the formation of
these vessels may occur at the expense of tissue structure and might
need to be cautiously regulated (Fig. 1).
Conversely, suppression of signaling through VEGFR-3 using a
soluble VEGFR-3 decoy leads to an intensified injury in the setting
of experimental myocardial ischemia, consistent with adequate or
enhanced lymphatic drainage network acting to maintain tissue
integrity following hypoxic stress [67]. We have also described
improved tissue outcomes following administration of VEGF-D
[67a]. Nonetheless, cardiac lymphatic expansion is apparently not
beneficial in the setting of cardiac transplant [68, 69] where additional
lymphatics may intensify immune surveillance leading to graft
failure. In keeping with this concept, although lymphatic ablation
can lead to deterioration of cardiac functioning, it is worth noting
that cardiac lymphatics cannot be easily if ever reanastomosed
following heart transplantation, although this does not appear to
impede recovery. Lymphatics do however expand in the heart imme-
diately after transplantation but usually diminish at later times
(in models using cyclosporine immunosuppression) appearing to
142 7. Cardiac lymphatics and lymph flow in health and disease
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be associated with graft survival. With respect to lymphatic expan-
sion, Nyk
€
anen et al. [70] showed that VEGFR-3-driven CCL21 repre-
sents an important mechanism, which drives heart allograft rejection
by communication of antigen presenting cells into secondary lym-
phoid organs where they activate immune responses, indicating that
inhibition of VEGFR-3 signaling may be a valuable target in heart
transplantation (Fig. 1). Consequently, blockade of lymphatics may
be injurious, but allowing lymph to be passively released from
the transplanted heart into the thorax does not drive injury. In the set-
ting of endocarditis, increased lymphangiogenesis has been reported
in heart valves where an intense >20-fold increase in lymphatic
density was observed, with a fivefold increase in diameter [71]. Such
a profound response indicates that lymphatic expansion must be
adaptive in maintaining valve structure/function, which may be a
possible therapeutic target in endocarditis.
It is also interesting that yellow nail syndrome, a type of idio-
pathic lymphedema, was observed following a mitral valve replace-
ment [72]; this condition eventually abated but suggests that
complications from valve replacement, for example, thoracic duct
impairment, might actually lead to the development of forms of
lymphedema. Similarly, yellow nail syndrome has also been
described following pacemaker placement, suggesting that
ectopic/iatrogenic damage to the cardiac lymphatics may produce
systemic lymphedema [73].
The appropriate investment of such vessels with muscular compo-
nents might be required to beneficially enhance lymph flow. It has
been reported by Viera et al. [74] that VEGF-C improves outcomes
in experimental myocardial infarction, while LYVE-1 knockout mice
(whichordinarily exhibit only a minor phenotype with abnormallym-
phatic capillary vessel morphology in the liver and intestines and
increased intradermal interstitial-lymphatic flow) show enhanced
injury and a decreased ability to resolve cardiac injury. As LYVE-1
is often thoughtto overlap functionallywithCD44, these studies show
an important contribution of LYVE-1 lymphatics and lymphangio-
genic growth factors in the recovery from myocardial infarction. Out-
side of growth factors, adrenomedullin and verapamil have been
suggested as mediators, which stabilize interendothelial junctions,
whichmay help restitutecardiacstructure functionfollowingmyocar-
dial infarction through induction of connexin 43. Due to the fact that
143Experimental manipulation of lymphatics as a form of cardiac therapy
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connexin 43 also participates in the patterning of lymphatic valves,
connexin43 may alsorepresentatargetfornormalizingvalvestructure
to prevent or lessen lymphostasis produced by lymphatic valve dys-
function [75].Lastly,becauselymphaticleakagemay representa target
for clinicalinterventionin lymphaticfailure,adrenomedullinhasbeen
shown to organize lymphatic junctions via Rap1A/B GTPases and
might be able to limit lymphatic leakage, particularly in organs like
the heart, which are particularly vulnerable to the effects of lymph
reflux or stasis [76].
Summary
The heart is clearly well supplied with lymphatics and like other
organs can increase the flow of lymph during acute inflammation.
However, it is still far less clear how the failure of lymphatic con-
duits to adequately drain cardiac interstitial fluid contributes to
forms of heart injury, like myocardial infarction, myocarditis, and
transplantation. While studies on experimental interruption of
lymph flow show the central importance of cardiac lymphatics in
maintaining normal heart rhythm and propagation as well as con-
tractility, this same conduit mediates the transfer of dendritic cells,
which sensitize the immune system to the engrafted heart and may
be a significant risk, which could be managed therapeutically.
References
[1] Kubik S. Anatomy of the lymphatic system. In: F
€
oldi M, F
€
oldi E, Kubik S, edi-
tors. Textbook of lymphology. Jena: Urban and Fischer; 2003. p. 2–166 [View
at Google Scholar].
[2] Sacchi G, Weber E, Agliano
`
M, Cavina N, Comparini L. Lymphatic vessels of
the human heart: precollectors and collecting vessels. A morpho-structural
study. J Submicrosc Cytol Pathol 1999;31(4):515–25. PubMed PMID:
10685392.
[3] Klotz L, Norman S, Vieira JM. Cardiac lymphatics are heterogeneous in origin
and respond to injury. Nature 2015;522:62–7.
[3a] Wilting J, Buttler K, Schulte I, Papoutsi M, Schweigerer L, M
€
anner J. The proe-
picardium delivers hemangioblasts but not lymphangioblasts to the develop-
ing heart. Dev Biol 2007;305(2):451–9. PubMed PMID: 17383624. Epub 2007
Feb 28.
144 7. Cardiac lymphatics and lymph flow in health and disease
https://t.me/medicina_free
[4] Flaht-Zabost A, Gula G, Ciszek B, Czarnowska E, Jankowska-Steifer E,
Madej M, Niderla-Bieli
nska J, Radomska-Le
sniewska D, Ratajska A. Cardiac
mouse lymphatics: developmental and anatomical update. Anat Rec
(Hoboken) 2014;297(6):1115–30.
[4a] Luong MX, Tam J, Lin Q, Hagendoorn J, Moore KJ, Padera TP, Seed B,
Fukumura D, Kucherlapati R, Jain RK. Lack of lymphatic vessel phenotype
in LYVE-1/CD44 double knockout mice. J Cell Physiol 2009;219(2):430–7.
https://doi.org/10.1002/jcp.21686. PubMed PMID: 19170073. PubMed Cen-
tral PMCID: PMC2665001.
[4b] Karunamuni G, Yang K, Doughman YQ, Wikenheiser J, Bader D, Barnett J,
Austin A, Parsons-Wingerter P, Watanabe M. Expression of lymphatic
markers during avian and mouse cardiogenesis. Anat Rec (Hoboken)
2010;293(2):259–70. https://doi.org/10.1002/ar.21043. PubMed PMID:
19938109. PubMed Central PMCID: PMC3607319.
[4c] Wigle JT, Harvey N, Detmar M, Lagutina I, Grosveld G, Gunn MD,
Jackson DG, Oliver G. An essential role for Prox1 in the induction of the lym-
phatic endothelial cell phenotype. EMBO J 2002;21(7):1505–13. PubMed
PMID:11927535. PubMed Central PMCID: PMC125938.
[4d] Srinivasan RS, Escobedo N, Yang Y, Interiano A, Dillard ME, Finkelstein D,
Mukatira S, Gil HJ, Nurmi H, Alitalo K, Oliver G. The Prox1-Vegfr3 feedback
loop maintains the identity and the number of lymphatic endothelial cell
progenitors. Genes Dev 2014;28(19):2175–87. https://doi.org/10.1101/
gad.216226.113. PubMed PMID: 25274728. PubMed Central PMCID:
PMC4180978.
[5] Ando T, Jordan P, Wang Y, Jennings MH, Harper MH, Houghton J, Elrod J,
Alexander JS. Homogeneity of mesothelial cells with lymphatic endothelium:
expression of lymphatic endothelial markers by mesothelial cells. Lymphat
Res Biol 2005;3(3):117–25. PubMed PMID: 16190816.
[6] Wada AM, Smith TK, Osler ME, Reese DE, Bader DM. Epicardial/mesothe-
lial cell line retains vasculogenic potential of embryonic epicardium. Circ Res
2003;92(5):525–31. Epub 2003 Feb 6. PubMed PMID: 12600887.
[7] P
erez-Pomares JM, Carmona R, Gonza
´
lez-Iriarte M, Atencia G, Wessels A,
Mun
˜
oz-Cha
´
puli R. Origin of coronary endothelial cells from epicardial meso-
thelium in avian embryos. Int J Dev Biol 2002;46(8):1005–13. PubMed PMID:
12533024.
[8] Uhley HN, Leeds SE, Sung MA. Lymphatic drainage from the ventricular
septum to the atrioventricular node in human beings. J Am Coll Cardiol
1983;1(4):1119–22. PubMed PMID: 6833650.
[9] Eberth CJ, Belajeff A. Uber die Lymphgefasse des Herzens. Virchows Arch
Path Anat 1866;37:124.
[9a] Paraskevas G, et al. Historical notes on the anatomy of the heart’s lymphatic
system. Ital J Anat Embryol 2018;123(2):149–57. https://doi.org/10.13128/
IJAE-24164.
[9b] His W. Uber die Wurzeln der Lymphgefaesse in den Hauten des Korpers und
uber die Theorien der Lymphbildung. Z Wiss Zool 1863;12:223–54.
145References
https://t.me/medicina_free
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