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[95] Lanning P, Simila S, Suramo I, Paavilainen T. Lymphatic abnormalities in Noo-
nan’s syndrome. Pediatr Radiol 1978;7(2):106–9.
[96] Perry HD, Cossari AJ. Chronic lymphangiectasis in Turner’s syndrome. Br
J Ophthalmol 1986;70(5):396–9.
[97] Gordon K, Ostergaard P. Impact of genetics on lymphangiogenesis [chapter 8].
In: Neligan PC, Piller NB, Masia J, editors. Complete medical and surgical
management. Boca Raton, FL: CRC Press; 2016. p. 121–31.
125References
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CHAPTER
7
Cardiac lymphatics and cardiac
lymph flow in health and disease
J. Steve Alexander, J. Winny Yun
Department of Molecular and Cellular Physiology, LSU Health Sciences
Center, Shreveport, LA, United States
Cardiac lymphatic s
Like most organs, the heart has a dense lymphatic supply with
lymphatic plexuses found in all layers of the heart, within the sub-
epicardium, myocardium, and subendocardium. These networks
fulfill similar functions seen in other organ systems including the
collection of interstitial fluid, fat and cholesterol reverse transport,
and immune surveillance. In most species, the distribution of lym-
phatics through these layers is fairly consistent [1, 2] although in
mice and rabbits, the subepicardial and myocardial plexuses
may be denser than the endocardium, with some anatomists even
reporting no lymphatics in the endocardium. The ontogeny of the
cardiac lymphatic vasculature in the heart is also becoming better
understood [3]. Embryologically, the layers of the myocardium
and endocardium are derived from lateral plate mesodermal tissue.
However, several other critical components of the heart, including
the epicardium and cardiac blood vessels, have extra cardiac origins
in the proepicardium [3a]. In the mouse, cardiac lymphatic develop-
ment is prenatally restricted to the subepicardium. After birth, lym-
phatics expand from the subepicardium through the myocardial
wall, with progressive development of lymphatics starting at the
base of the heart gradually moving toward the apex of the heart.
127Lymphatic Structure and Function in Health and Disease
https://doi.org/10.1016/B978-0-12-815645-2.00007-1
Copyright © 2020 Elsevier Inc. All rights reserved.
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Lymphatics were also found to become associated with the major
branches of cardiac veins in the subepicardium [4].
Early on in cardiac development, cells expressing lymphatic
vessel endothelial hyaluronan receptor-1 (LYVE-1), which is com-
monly employed as a molecular marker for lymphatic endothelial
cells [4a], can be seen in some epicardial cells. Addi tionally, just
prior to the septation of the cardiac chambers, a sheet of prospero
homeobox 1 (Prox1)—expressing cells—is found on the aorta and
pulmonary trunk, an event that is seen in avian and murine
embryos [4b]. Prox1 is a transcription factor typically referred to
as “the master regulator” of lymphatic vasculature because it reg-
ulates the expression of downstream lymphatic endothelial—
specific proteins, such as LYVE-1 and vascular endothelial growth
factor receptor-3 (VEGFR-3) [4c]. VEGFR-3 responds to its ligands
vascular endothelial growth factor (VEGF) -C and (VEGF)-D to
maintain an important feedback loop with Prox1 that maintains
the lymphatic identity and undergoes lymphangiogenesis, the
process of lymphatic vessel formation from preexisting lymphatic
vessels [4d].OnceLYVE1
+
PROX1
+
VEGFR3
+
lymphatic vessels
appear at the sinus venosus, they progressively spread over
both ventricles, eventually ensheathing the entire epicardium.
Although lymphatic and venous networks do show early interac-
tions with these networks, this is progressively lost as develop-
ment progresses. Hemangioblasts that give rise to blood vessels
in the heart are contributed by the proepicardium; however,
it seems that cardiac lymphatics may be formed at least in part
by invading CD31
+
/CD45
+
/LYVE-1
+
lymphangioblasts, which
progressivelycolonizethesubepicardialspacefromthebaseto
the ape x of the growing heart during development. Studies using
mice bearing markers of vascular endothelial cells (Tie2-Cre and
PDGFRβ-CreERT2) support cardiac lymphatics originating from
a mixed pool of progenitors including venous and putative hemo-
genic endothelial origins [3]. Ultimately, Karunamuni described
three types of lymphatic endothelial-like lineages in the heart:
Prox1+ cells from an extracardiac source (possibly mesothelium)
that migrate into outflow trunks of the epicardium, LYVE1 + cells
found in the epicardium that may merge into Prox1
+
lymphatic
vessels, and LYVE1
+
cells in the myocardium that remain Prox1
128 7. Cardiac lymphatics and lymph flow in health and disease
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negative even in mature heart tissues [4b]. We have reported that
mesothelial cells also express lymphatic markers including VEGFR-
3, LYVE1, and Prox1. Therefore, these may be a source of some of
these epicardial cells [5], which also concurs with findings by Wada
et al. [6] and P
erez-Pomares et al. [7].
Lymphatics are found in the ventricular septum that appear to
communicate with the atrioventricular node in the human [8],
which may coordinate information about the immune or inflamma-
tory stress within the septal interstitium, thereby modulating atrio-
ventricular (AV) nodal conduction. The lymphatic system of the
heart was probably recognized originally by the Swedish anatomist
Olaus Rudbeck in 1653 (and J.F. Cassebohm), who noted subepicar-
dial lymphatics in dogs. This was later described in humans by
Eberth and Belajeff [9] in 1866 (summarized in an excellent historical
review on lymphatics by [9a]). Lymphatics in the myocardium
appear to have been first recognized by Leyh in 1859; he later
described lymphatic vessels in myocardial interstitial tissue [9b].
Flow of lymph in the heart
Lymph is formed in all layers of the heart and is moved progres-
sively outward from the subendocardium through the myocardium
and ultimately into the subepicardium. Lymph outflow from the
subepicardium is collected by the left and the right cardiac lym-
phatic trunks. These collectors ultimately transport lymph into the
left coronary trunk and then to the right venous angle and to the left
venous angle via the right coronary trunk. These lymphatic collec-
tors contain unidirectional valves, which prevent lymph reflux and
are arranged in pairs, which parallel the coronary arteries in the sub-
epicardium [3a].
Like in most organs, both active lymphangion pumping and pas-
sive lymphatic compression contribute to lymph propulsion in the
heart. Phasic pumping can occur within lymphangions, which are
literally lymph “hearts.” Lymphangions are segments of lymphatics
bounded by one-way valves, whose rhythmic contractions force
lymph forward toward the heart. The rate and forcefulness of these
contractions have been proposed to be regulated both by
129Flow of lymph in the heart
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intraluminal and extraluminal pressure [10] that determine stretch
on the muscle in the wall as well as inflammatory cytokines, nitric
oxide, and prostaglandins. By comparison, passive tissue compres-
sive force also provides a continuous squeezing on these structures,
which also propels lymph toward the heart [11, 12]. The degree to
which each contributes to lymph propulsion varies anatomically
often reflecting the capacity for the development of passive
compressive force.
Due to the fact that the heart is such a dynamic organ, which
undergoes significant changes in tissue pressures in its different
regions (endocardium and myocardium) during the distinct phases
of the cardiac cycle, passive lymph conduction likely represents the
dominant mechanism through which lymph is removed from the
heart. Furthermore, because the frequency of the cardiac cycle is
often higher than that reported for lymphangion pumping, active
pumping, at least in the endo- and myocardium, might be difficult
to coordinate in terms of matching pressures. However, this might
be a possibility in the epicardium [13–15]. With respect to this, car-
diac pacing, which decreases the time spent in diastole, reduced car-
diac lymph flow, despite a slight increase in cardiac blood flow
(which might be expected to increase cardiac lymph flow) [16].
Cardiac lymph flow is usually continuous and high with respect
to several other organs. The efferent outflow from the heart is
5–27mg/min 10 kg. Miller reported that cardiac lymph flow varies
between 35 and 189mg/min in dogs 70–388 mg/min in dogs or a
rate of formation between 4.2 and 23 mL/h. Miller has also reported
3.2mL/h under basal conditions [17]. Michael et al. [18] more
recently reports this figure as 0.45–5.6 mL/h.
With respect to coordination between the cardiac cycle and pas-
sive lymphatic compression to drive lymph movement through the
heart, Kampmeier [19] stated that in diastole, pressure of the blood
filling the ventricles forces lymph outward from the subendocardial
lymphatics into lymphatic vessels in the myocardium. By compar-
ison, during systole, myocardial contractility squeezes lymph from
the myocardium into lymphatics in the subepicardium. Lastly, at
the end of diastole, pericardial pressure helps to move lymph from
these vessels into lymphatic trunks exiting heart tissue. However,
Cui points out that surgeries that involve the removal of the pericar-
dium have little effect on cardiac edema; thus, this may only be a
minor component with most of the force deriving from
130 7. Cardiac lymphatics and lymph flow in health and disease
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subepicardial compressive forces. Similarly, uncoordinated muscu-
lar compression in the subepicardium could lead to retention on
lymph and lymphedema under some circumstances [20, 21].
The ventricles have more extensive lymphatic networks than
those found in the atria [22]. Since ventricular force development
is greater in the ventricles than in the atria, tissue compressive forces
are likely to be lower in the atria. Therefore, the physics supporting
lymph flow out of the atria favor a net lower flow based on the prod-
uct of vessel density and compressive forces, which may render the
atria more susceptible to forces that may oppose lymph flow out of
the atria (compared with that in ventricles). Consequently, struc-
tures in the atria, for example, the sinoatrial (SA) node, may experi-
ence stresses produced by impaired lymph conduction if any forces
opposed the exit of lymph.
The lymphatics within the subepicardium have been extensively
studied through injection of tracers [22a] and have been shown to
merge to several lymphatic trunks that cumulatively collect cardiac
lymph passing it to the mediastinal lymphatics of the right lym-
phatic duct and the thoracic duct. Ventricular myocardial contrac-
tions are assumed to squeeze lymph from lymphatic vessels
within the myocardium into lymphatic vessels in the subepicar-
dium. It has been proposed that the distention of the heart at the con-
clusion of diastole would create pressure at the surface of the
epicardium resisting the fluid pressure from the pericardium, which
would provide the force necessary to force lymph in the subepicar-
dial vessels into the lymphatic trunks exiting the heart. However,
Cui [20, 21] points out that this assumption has not been tested
and that it would be expected that in the absence of a pericardium,
the heart should have an increased risk of developing lymphedema.
However, the surgical removal of the pericardium has few such clin-
ical effects in experimental or clinical cardiac procedures. Cui pro-
poses that instead, the final propulsion can be simply mediated by
the forceful contractions of subepicardial muscle alone.
Lymphatics within different cardiac structures
In 1866, Eberth and Belajeff first reported lymphatics in human
cardiac valves; Johnson and Blake [22b] later also reported the pres-
ence of lymphatics in human mitral valves, which were located
131Lymphatics within different cardiac structures
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more superficially (closer to the valve surface) than the blood vessels
supplying the valves. Indeed, in 1966, Johnson and Blake (using
hydrogen peroxide to reveal lymphatics) described “dense
networks” of small (15–20 μm) lymphatic vessels without valves
under the subepicardium of both ventricles and septum, small lym-
phatic vessels of relatively uniform caliber (15–20 μm in diameter),
which ran perpendicularly to the muscle fibers.
Although AV valves are nearly devoid of blood capillaries
(except in the proximal region), there are extensive lymphatics
draining these valves with the most abundant lymphatic plexus
located in the anterior cusp of the mitral valve. In 1973, Bradham
[23] described lymphatics in the atrioventricular valves (but possi-
bly not within arterial valves) (according to Refs. [22a, 22b, 23a]).
There also appears to be a reticular network of lymphatics within
the interventricular septum and within papillary muscles [22].
The SA node has lymphatics, which discharge their contents via
subepicardial lymphatics [23b]. Similarly, lymph flow from the
AV node and the associated bundle complex drains to the subendo-
cardial lymphatics near the tricuspid and then back to the left lymph
trunk finally reaching the inferior tracheobronchial lymph nodes
[23c]. Noguchi [23d] also described lymphatics in the mitral and tri-
cuspid valves, which communicated with lymphatic networks
within the subendocardium at the atrial side of the valves. Lym-
phatic vessels have also been described within papillary muscles,
where a lymphatic channel oriented with the long axis of the muscle
is described, which eventually merges with lymphatics in the myo-
cardium and epicardium; there is only minor drainage near the chor-
dae tendineae [22b].
There also appears to be lymphatics in the wall of coronary arteries
[23e, 23f], which connect to the adventitia and the outer annuli of the
media [23e, 23g], which Eliska et al. [23h] disagree with this, and
describe a denser supply of lymphatics coronary arteries in the myo-
cardium than in epicardial arteries. The recent description of lym-
phatic biomarkers including Prox1, LYVE-1, VEGFR-3, podoplanin,
and forkhead box C2 (FOXC2) probably justifies an immunoanatomi-
cal review of these findings based on protein expression of lymphatic
132 7. Cardiac lymphatics and lymph flow in health and disease
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markers rather than ultrastructure. In any case, the effective clearance
of materials, which penetrate into the arterial matrix by lymphatics
present in the wall, represents an important and understudied mech-
anism for the development of atherosclerosis, particularly those
within the aorta and coronary vessels.
There appears to be a subendothelial lymphatic network in the
aorta (in pigs) originally described in cats by Lee [23i]. Due to the fact
that lymphatics function in the reverse transport of cholesterol [24, 25]
via the scavenger receptor class B type I (SRB1) expressed on lym-
phatic endothelial cells [24], the obstruction or obliteration of lym-
phatics in the arterial walls in atherosclerosis might represent an
important connection, which may lead to intensification or accelera-
tion of plaque development in atheromatous vessels (arterial lym-
phatics have recently been extensively reviewed by Csanyi and
Singla [26]). Conversely, it has been reported that hypercholesteremia
can also provoke lymphatic failure, perhaps by exhausting the
reverse transport capacity of this system as a vicious cycle [27].This
paradigm has found additional support in studies, which show that
mice, which are deficient in PCSK9, have enhanced lymphatic ves-
sels; similarly, atheroprone low-density lipoprotein receptor knock-
out (LDLR
/
)mice (a model of human atherosclerosis) exhibited
lymphatic disturbances before the development of atherogenesis,
and this atheromatous phenotype could be relieved by administra-
tion of VEGFR-3 agonist VEGF-C152S, which expands lymphatic net-
works [28]. Therefore, one of the more important functions that
lymphatics may play in the heart could be to maintain the clearance
of materials, for example, cholesterol, reaching the arterial intimame-
dia which if not adequately removed drives atheroma development.
This concept originated by GM Lemole in 1981 and reiterated in 2016
[29, 30] (summary by Bland [31]) suggested a cardiac lymphatic
drainage model for the origin of (cardiac) vascular atherosclerosis,
which was supported by Lim et al. [24]. Therefore, factors and condi-
tions, which may impair the perivascular or vasa vasorum-integrated
lymphatics, may represent an important and underrecognized con-
tributor to atherogenesis, both in coronary vessels and in the commu-
nicating arterial tree.
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In addition to the roles that lymphatic vessels play in the reverse
transport of cholesterol, the lymphatic failure, specifically leakiness
produced by Prox1 heterozygosity (in mice), leads to a chylothorax
(fat/lipid accumulation in the thorax), and the development of adult
onset obesity [32] and restoration of Prox1 can reverse obesity in
Prox1
+/
mice [33]. Interestingly, adipocytes persistently express
Prox1 with omental fat showing net greater expression compared
with subcutaneous Prox1 expression[34]; removal of omental fat does
not provide any benefit for correcting insulin sensitivity [35]. Indeed,
it is the obesity itself, rather than the consumption of fat, which inter-
feres with lymphatic functioning, suggesting that fat-laden adipo-
cytes produce factors, which impair lymphatics and produce
pathologies stemming from lymphatic failure [36]. Prox1 deficiency,
which suppresses lymphatics, increases leptin expression to enhance
satiety; conversely, lymphatic expansion may promote feeding
behaviors. It is also worth noting that there is an increased binding
and fat tissue burden of immune cells in high-fat diet/obese
C57BL/6J mice, which had significantly more perilymphatic CD3+
and CD11b+ cells ( threefold) more than controls [36].
It is interesting and important to note that exercise can correct
lymphatic dysfunction that is caused by obesity [37], an observation
that has important implications in not only cardiovascular disease
but also many other pathologies. Similarly, weight loss normalizes
monocyte immune functioning [38], which may also dysregulate
lymphatic functions. The plethora of pathological changes, which
accompany metabolic syndrome, including those of the heart, stems
in part from excessive ingestion of fats, which need to be transported
by lymphatics. Interestingly, the disturbances in lymphatic function
produced by fat burdens may differ depending on the various fat
depots affected.
Similarly, the consumption of excessive salt in salt-sensitive
hypertension may increase the retention of sodium in subcutaneous
tissues where lymph flow is increased; lymph flow is also increased
in muscular tissues (skeletal). This increased lymph flow was appar-
ently dependent upon monocyte/macrophages as the depletion of
these cells using clodronate (a calcium sparing bisphosphonate)
reduces lymph flow [38a]. This effect of salt on lymphatic networks
is produced by the activation of the tonicity-responsive enhancer
binding protein (“tonEBP”) within monocytes in subcutaneous
134 7. Cardiac lymphatics and lymph flow in health and disease
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tissues, which drive vascular endothelial growth factor-C
(VEGFR-C) expression that binds to VEGFR-3 to caused lymphan-
giogenesis and expands these networks. It is unclear how this
may directly affect the heart itself as increased lymph flow in the
heart could be protective but might also represent a response to
increased sodium burden in muscle tissues. For example, Yang
et al. [39] showed that VEGF-C participated in the observed cardiac
lymphangiogenesis seen during high salt-mediated left ventricular
cardiac remodeling [39] and that VEGF-C overexpression might be
beneficial in high salt-mediated ventricular edema and remodeling,
possibly establishing a link between interstitial fluid balance and
maladaptive cardiac expansion.
Cardiac lymph nodes were first described by Mouchet in 1909
(in dogs and horses), but he did not find these in human hearts.
The mediastinal lymph nodes associated with the brachiocephalic
lymph nodes located above the aorta and inferior tracheobronchial
lymphatics near the exit of the aorta from the heart merging
into the right coronary trunk. The enlargement of mediastinal
lymph nodes during left heart disease with pulmonary edema sug-
gests that fluid decompensation may intensify lymph node
enlargement, but this enlargement seems to be noninflammatory
and regresses rapidly when the underlying heart disease is treated
[40]; a similar expansion and retraction over the course of a month
has been reported [41]. Therefore, conditions that increase lymph
flow or impede its return to the circulation could expand lymph
node volume and potentially influence immune surveillance
within lymph nodes.
Ultimately, lymph is returned to the circulatory system by the
thoracic and right lymphatic ducts. The thoracic duct proper com-
municates 75% of the lymph collected by the lymph trunks back
to the heart and anatomically begins above the cisterna chyli. Ana-
tomically, the thoracic duct proceeds vertically in front of the verte-
bral column between the aorta and the azygous vein and by the level
of the fifth thoracic vertebra has become a single channel. This duct
ends at left brachiocephalic vein at the junction of the left subclavian
vein and the left internal jugular vein. The right lymphatic duct
carries lymph derived from the right side including the upper limb,
right side of thorax, and right side of the head and neck. The right
lymphatic duct assumes several patterns of communication with the
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