Lymphodynamics in Congenital Heart Disease

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY

VOL. 69, NO. 19, 2017

ª 2017 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

ISSN 0735-1097/$36.00

PUBLISHED BY ELSEVIER

http://dx.doi.org/10.1016/j.jacc.2017.03.559

EDITORIAL VIEWPOINT

Lymphodynamics in Congenital Heart Disease The Forgotten Circulation* Jacqueline Kreutzer, MD,a Christian Kreutzer, MDb

I

n this issue of the Journal, the paper by Savla

evaluating

et al. (1) opens a new door into a relatively poorly

congenital heart disease. It is common knowledge that

understood subject in our field: lymphatic dy-

the

cardiac

majority of

physiology

vascularized

in

patients

tissues

with

contain

a

namic disorders after congenital heart surgery. Using

lymphatic capillary network. The lymphatic system

dynamic

resonance

has numerous crucial physiological functions in

lymphangiography and intranodal lymphangiography

contrast-enhanced

magnetic

mammals, including fluid balance between the plasma

in 25 patients, these investigators undertake a unique

and interstitial compartments of the extracellular

approach and provide further insight into the under-

space by returning protein and fluid filtered out of

standing of lymphatic disorders after cardiac surgery.

the capillaries to the vascular system and absorption of fat from the small intestines. It also maintains

SEE PAGE 2410

important immune functions; various antigens and

Although the morbidity and mortality related to

activated antigen-presenting cells are transported into

these conditions is well-known (2), the lymphatic

the lymph nodes and export immune effector cells and

circulation continues to be a relatively undiscovered

humoral response factors into the blood circulation. The lymphatic vascular system consists of 2 types

territory for the pediatric cardiologist and cardiothoracic surgeon. Still, the scientific background to this

of

work is quite extensive and not new.

network and the collecting vessels. Lymphatic endo-

In the last decade of the 19th century, Ernest Star-

vessels,

the

noncontractile

initial

lymphatic

thelial cells are strongly attached at the anchoring

ling at University College of London described the

filaments to the surrounding collagen and elastin fi-

retention of plasma in the interstitial space as a “safety

bers. These cells show tight, single contact, and

valve” to the circulation defending the failing heart

interdigitated junctions. During expansion of the

from volume load (3,4). Thereafter, research in

initial lymphatic vessels, these junctions can be

lymphatic circulation in heart failure flourished (4–7).

opened, allowing fluid to flow from the interstitium

Over the past decades, a series of discoveries have

into the lymphatic vessels, whereas during compres-

revealed new knowledge in the vascular and molecular

sion, overlapping junctions can be closed, thereby

aspects of the lymphatic system (8). However, these

attenuating the return of lymph flow into the inter-

concepts

stitium, and acting as “flap valves” (8). If the

are

not

commonly

considered

when

lymphatic pressure increases, the safety function is activated and the system responds by increasing the *Editorials published in the Journal of the American College of Cardiology

amount of lymph contained within and transported

reflect the views of the authors and do not necessarily represent the

by the system. In this way, the system functions as a

views of JACC or the American College of Cardiology.

reservoir, “protecting the failing heart” from volume

From the aDivision of Cardiology, Department of Pediatrics, University of

overload (the Starling resistor effect).

Pittsburgh, School of Medicine, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania; and the bCardiac Surgery Department, Austral University Hospital, Pilar, Provincia de Buenos Aires, Argentina.

The lymphatic capillaries drain into precollecting vessels, followed by larger collecting lymphatic ves-

Both authors have reported that they have no relationships relevant to

sels. The lymphatic drainage shows an extremely

the contents of this paper to disclose.

efficient centripetal flow of lymph augmented by

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Kreutzer and Kreutzer

JACC VOL. 69, NO. 19, 2017 MAY 16, 2017:2423–7

Lymphodynamics in Congenital Heart Disease

multiple (10). At the most proximal end of the TD, a

F I G U R E 1 Anatomy of the Thoracic Lymphatic Circulation

valve prevents blood from entering the duct, because contact with blood produces thrombosis or occlusion of the lymphatic vessels. Given the proximity of lymphatic vessels to cardiac structures manipulated during surgical repair of

Internal jugular vein

congenital heart defects trauma of TD can occur. In addition, after congenital heart surgery, abnormally increased venous pressure is common. The effects of

Subclavian vein

the

abnormal

physiological

states

prevalent

in

congenital heart disease on the lymphatic circulation are now being discovered (11). The long oblivion for the lymphatic circulation in pediatric cardiology is Aorta

coming to an end. Several contributions have demonstrated its relevance and effect on devastating

Thoracic duct Azygos vein

complications after surgery, such as effusions, chylothorax, plastic bronchitis, and protein-losing enteropathy (12,13). Lymphatic imaging and selective catheterization as reported by Dori et al. (1,12,13) now

IVC

Esophagus Diaphragm

allow understanding lymphodynamics and identification of 3 modes of lymphatic failure: leak from a TD branch

(traumatic

leak);

pulmonary

lymphatic

perfusion syndrome, when retrograde flow from the TD to the lung or mediastinum; and central lymphatic flow disorder, a newly characterized condition with abnormally low or absent central lymphatic flow, effusions in more than 1 compartment, and dermal backflow through abdominal lymphatic collaterals. It is not surprising that in this most recent contribution from Dori’s group (1), the vast majority of patients who suffered either from TD leak or pulmonary Cisterna chyli

lymphatic perfusion syndrome had conditions typically associated with increased central venous pres-

Right lumbar trunk

sure and secondary impaired lymphatic drainage. In pure right heart failure, as seen in the Glenn and the Fontan circulations, the lung is exposed to a paradox

Anatomy of the thoracic lymphatic circulation as seen from a posterior view (9).

in which lymph from the lung is required to drain at a higher pressure than it is created. In the normal lung, both the pulmonary arteriolar pressure and pulmo-

rhythmic contractions (8). In humans, the thoracic

nary capillary wedge pressures are higher than the

duct (TD) originates in the cisterna chyle (Figure 1)

central venous pressure, resulting in normal reab-

and ascends anterior to the vertebrae, with the aorta

sorption of fluid. After the superior cavopulmonary

on its left and the azygous vein to its right (9). Below

anastomosis, the lung interstitium is subjected to a

the fifth thoracic vertebra, the duct is usually double

normal hydrostatic pressure, because more than 80%

or plexiform; above fifth thoracic vertebra, it is usu-

of the total lung arterial flow returns to the heart via

ally singular. At the level of the fifth thoracic

pulmonary veins. However, there is a constant pro-

vertebra, the TD inclines toward the left side to enter

pensity toward fluid accumulation in the lung,

the superior mediastinum and ascends behind the

because the lymphatic circulation drains to a higher

aortic arch and the thoracic part of the left subclavian

pressure compared with normal. The increase in

artery, between the left side of the esophagus and the

resistance to lymphatic drainage results in lymphatic

left pleura, to the thoracic inlet (Figure 2). It ends by

endothelial cells adherence and lymph cannot be

opening into the angle of junction of the left subcla-

effectively removed from the interstitium. In contrast

vian vein with the left internal jugular vein. Here, the

with pulmonary edema resulting from increased

drainage can be single (in nearly 50% of the cases) or

pulmonary capillary wedge pressure as a result

Kreutzer and Kreutzer

JACC VOL. 69, NO. 19, 2017 MAY 16, 2017:2423–7

Lymphodynamics in Congenital Heart Disease

F I G U R E 2 Anatomy of Central Lymphatic Circulation

Jugular lymph trunk Left jugular lymph trunk

Internal jugular vein

Subclavian lymph trunk Subclavian lymph trunk Right lymphatic duct

Subclavian artery

Subclavian artery

Subclavian vein

Bronchomediastinal lymph trunk Left bronchomediastinal lymph trunk Superior vena cava

Azygos vein Thoracic duct

Aortic arch

Esophagus Pulmonary artery Left pulmonary artery Left pulmonary veins Pulmonary veins Intercostal lymph trunks

Left ventricle

Intercostal lymph trunks

Aorta

Anatomy of central lymphatic circulation view (9).

left heart pump failure or left-sided obstruction,

bronchitis, and protein-losing enteropathy, are seen

the congested lung commonly seen in the early

in this patient population, and that most of the pa-

Glenn/Fontan patient is often related to lymph for-

tients reported in the study from Savla et al. (1) had a

mation and accumulation, with pleural effusions as a

form of single ventricle variant.

manifestation of this imbalance (11).

The morbidity and mortality from post-operative

This represents another paradox of the Fontan

chylothorax continues to be high (2). Historically,

circulation and a challenge to Starling’s forces: pul-

there have been limited diagnostic or therapeutic

monary lymph is required to drain at a higher or very

strategies available to treat these patients. Standard

similar pressure as it is produced (Figures 3A and 3B).

therapies are frequently ineffective (e.g., surgical TD

As a consequence, it is not surprising that lymphatic

ligation) and/or have significant unwanted side ef-

disorders,

fects (e.g., eliminating fat from the diet during key

such

as

chylous

effusions,

plastic

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Kreutzer and Kreutzer

JACC VOL. 69, NO. 19, 2017 MAY 16, 2017:2423–7

Lymphodynamics in Congenital Heart Disease

F I G U R E 3 Mean Pressures in the Biventricular Circulation and Single Ventricle Circulation

Typical mean pressures in millimeters of mercury in the biventricular circulation (A) and single ventricle circulation (B). Lymph formed at the pulmonary capillary level in the single ventricle circulation (B) is at a lower pressure at the capillary level than the pressure it is expected to drain at. *Thoracic duct.

growing stages of childhood, use of total parenteral

successful therapies known to date. All patients re-

nutrition, chemical pleuridesis often leading to

ported had previously failed standard therapies.

massive formation of aortopulmonary chest wall

Specific lymphatic interventions applied in this study

collaterals, medical therapy with octreotide, pleuro-

included a variety of procedures with or without

peritoneal shunts) (1,2). Thus, the use of dynamic

closure of the TD. These interventions aimed to close

contrast-enhanced magnetic resonance lymphangi-

the leaking sites. Direct leak of contrast into the

ography to understand the pathophysiology of these

pleural space due to trauma was indeed rare (2 pa-

lymphatic disorders after congenital heart surgery

tients), and lymphatic intervention for these patients

and allow directed effective therapy reported by

was highly successful.

Savla et al. (1) is a breakthrough in our field. In

Further studies to understand the physiopathology

addition to the diagnostic value, the technique pro-

of lymphatic disorders after congenital heart surgery

vides an opportunity for a therapeutic benefit based

and testing of potential new modalities of directed

on the particular diagnosis; 23 of the 25 patients

therapy, such as lymphovenous anastomosis (14,15),

studied underwent directed lymphatic intervention.

may eventually reduce these patients’ morbidity.

Among the 25 patients, there were 16 with either a

Indeed, promising surgical procedures are nowadays

traumatic leak from the TD or pulmonary lymphatic

being reintroduced (14,15) with early success to divert

perfusion syndrome, and in this group lymphatic in-

the lymph flow to the lower pressure side of the

terventions performed had 100% success. The pro-

Fontan circulation, primarily for treatment of both

cedures were, however, mostly unsuccessful for the

protein-losing enteropathy and plastic bronchitis,

group with central lymphatic flow disorder (only 1 of

and secondarily to reduce the chronic end organ

7 benefited), for whom there seem to be no reliably

lymphedema.

Kreutzer and Kreutzer

JACC VOL. 69, NO. 19, 2017 MAY 16, 2017:2423–7

Lymphodynamics in Congenital Heart Disease

CONCLUSIONS

Dori et al. (1) should be congratulated for reporting an innovative diagnostic and therapeutic tool with a

This study enlightens a path to therapy of a poorly

defined relevant application in our field, which can bring

understood serious problem after congenital heart

a solution to a serious life-threatening postoperative

surgery,

mis-

condition. We recommend increased use of the pro-

managed. As further pointed out in the discussion

posed diagnostic approach to further discover ways to

section by Savla et al. (1), many of the assumptions

achieve a lasting positive impact on the outcome of

frequently used to base treatment plans in this

lymphatic flow disorders after congenital heart surgery.

and

one

that

has

been

largely

patient population are proven to be wrong. The authors demonstrate how essential it is to under-

ADDRESS FOR CORRESPONDENCE: Dr. Jacqueline

stand

the

Kreutzer, University of Pittsburgh School of Medicine,

lymphatic system disorder to provide a directed

Cardiac Catheterization Laboratory, Children’s Hospital

therapy to the problem, as indeed simple surgical

of Pittsburgh of UPMC, One Children’s Hospital Drive,

ligation of the TD may possibly worsen the leak in

4401 Penn Avenue, Pittsburgh, Pennsylvania 15224.

some cases.

E-mail: [email protected].

the

underlying

physiopathology

of

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