NLN
NATIONAL LYMPHEDEMA NETWORK
LYMPHLink Article Reprint
Vol 23 No 1
January - March 2011
Research Perspective
The Impact of Diabetes on Heart’s Lymphatic System and the
Protective Role of Exercise Training
by: Lisa VanHoose, Youssef Sawers, Rajprasad Loganathan, James Vacek, Lisa Stehno-Bittel, Lesya
Novikova, Irina V. Smirnova
Department of Physical Therapy and Rehabilitation Science, University of Kansas Medical Center, and Mid
America Cardiology, University of Kansas Hospital, Kansas City, KS
Introduction
Heart disease is the leading cause of death
for Americans with diabetes [1]. High blood
glucose levels can cause thickening of
blood vessels and decreases in heart function. Changes in the function and structure
of the heart have been reported in animals
and humans [2]. Much attention has been
given to changes in the arteries and veins
caused by diabetic heart disease, but little
is known about the effects on the heart’s
lymphatic system. The lymphatic system
provides waste removal, immune
responses, and fluid balance. An imbalance
of fluid in the heart can promote fibrosis,
tissue death, and decreases in heart function [3]. Therefore, the heart health of 24
million Americans with diabetes partially
depends on a robust lymphatic system.
Functional lymphatic vessels counter
inflammation in the heart. The chronic
inflammation commonly related to diabetes
may serve as a trigger for changes in protein levels of the lymphatic biomarker, lymphatic vessel endothelial receptor (LYVE-1).
LYVE-1 is responsible for the uptake of
hyaluronan (HA) from the spaces between
cells. Hyaluronan provides the stickiness or
“gooeyness” of the liquid surrounding cells.
Excessive hyaluronan can promote fibrosis
and permanent losses in heart function [4].
Such remodeling results in decreased filling
of the ventricles of the heart and the inability
to move blood through the body, as seen in
diabetes. The electrocardiogram (ECG) is a
non-invasive diagnostic tool commonly
used in medical offices to evaluate the function of the heart. The R wave indicates how
hard the heart is working. Increases in the
R wave amplitude are an early indicator of
an increased risk for heart disease and
thickening of the heart muscle [5]. Exercise
improves heart function in healthy and diseased subjects [6]. However, knowledge is
lacking about the impact of aerobic exercise training on lymphatic biomarkers.
Methods: Treadmill exercise training began
at diabetes onset, 12 weeks of age. ECG
measures were taken at baseline and after
7 weeks of exercise training. (ADInstruments, Colorado Springs, CO). Protein
levels of LYVE-1 (Santa Cruz Antibodies
(Santa Cruz, CA) were evaluated in left
ventricular tissue through immunoblotting.
Immunoblotting is a technique which allows
the detection of proteins from a sample of
tissues or cells.
The Zucker Diabetic Fatty (ZDF) rat is a
model of type 2 diabetes. The ZDF rat
develops high glucose and lipid levels by
week 8 and diabetes by week 12 when the
animals are fed a high fat diet. The diabetes
in the ZDF rat mimics the diabetic process
seen in humans. This project evaluated
changes in protein levels of LYVE-1 under
diabetic and aerobic exercise training conditions and the association with ECG
changes related to diabetes.
Statistical Analysis: Descriptive statistics
were calculated on animals’ means for
each group. One-way repeated measures
ANOVA (group) analyzed within and
between subject differences and interactions. Single-time point measurements or
change scores were completed with oneway ANOVA (group) with Least Significant
Difference (LSD) post-hoc analysis. Pearson
correlations were utilized for relationship
values. Statistics were conducted with
PASW Version 17 software (SPSS Inc, Chicago, IL, USA). Significance was measured
at p<0.05. Results are presented as means
± standard error (the average of the group,
not the individual animal).
MATERIALS AND METHODS
Animals: Male Zucker Diabetic Fatty (ZDF
- type 2 diabetes animal model) and Zucker
lean (control) rats were assigned to 4
groups (n=10 or 12 per group): sedentary
control, exercised control, sedentary diabetic, and exercised diabetic (Charles River
Laboratory, Saint Louis, MO). All animal
procedures were performed according to
the Institutional Animal Care and Use Committee guidelines at the University of Kansas Medical Center.
RESULTS
VanHoose et al group has previously
reported that R wave amplitudes were similar for the groups at baseline except for the
sedentary diabetic animals (p≤0.001) [7].
Diabetes caused increased pressure and
work for the heart as indicated by increases
in R wave amplitudes at baseline. Diabetic
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animals that completed exercised training
had R wave amplitudes similar to control
animals. LYVE-1 protein levels were
unchanged with diabetes, but increased
with exercise (p≤0.05). A moderate relationship (r=0.48, p<0.05) existed between R
wave amplitude change and LYVE-1 protein
levels in diabetes.
DISCUSSION
Rudbeck visualized the lymphatic vessels of
the heart in 1653 [8], and several researchers continued investigations into the structure and function of the lymphatic vessels
with the use of dyes and inks [9]. However,
the discovery of lymphatic markers in the
last 15 years has allowed for extensive
inquiries of structure and function. Lymphatic biomarkers are defined as molecules
expressed on lymphatic vessels. They are
involved in the growth and function of the
lymphatic vessel. LYVE-1 is a lymphatic
biomarker, and its regulation is crucial for
fluid balance in the heart [10].
Blockage or decreased flow of the lymphatic vessel in the heart can result in
edema and fibrosis in the heart [11].
Although the mechanisms are not completely known, the relationship between the
lymphatics and the heart function is
becoming increasingly clear. Edema
decreases left ventricular function, which
results in stiffness and delayed relaxation.
Pressure-volume relationships under acute
and chronic edema conditions show
increased diastolic interstitial fluid pressure
[3b]. These alterations result in remodeling of
the left ventricle and changes in heart
rhythm, which can be identified with ECG
[12]. The functional losses noted with myocardial edema are similar to those seen with
diabetic heart disease[13]. Such similarities
suggest a possible relationship between
the symptoms and the disease. We hypothesized that diabetes caused modifications
related to edema in the heart and that aerobic exercise training could combat such
changes in the model of type 2 diabetes,
ZDF rat.
LYVE-1 removes HA from the liquid surrounding the cells, and HA is elevated with
diabetes [14]. HA fragments increases the
inflammation in the heart and can result in
declines in relaxation of lymphatic vessels
[15] [16]. Relaxation of the lymphatic vessels is
needed for strong contractions, which
maintain fluid balance. Inefficient ventricular
contractions, observed in the diabetic heart
coupled with weak lymphatic vessels, can
slow flow and cause edema and fibrosis
development in the heart.
Thisstudy showed that diabetes impacts
heart function in the ZDF rat. At the same
time, LYVE-1 protein levels did not increase
to address fluid imbalances due to diabetes. However, LYVE-1 protein levels did
increase with aerobic exercise training.
These changes in LYVE-1 may indicate an
increase in immature lymphatic vessels or a
protective response to elevated HA levels
with exercise under the diabetic condition.
Thisstudy did not investigate the immune
response, which may also result in the
increase in LYVE-1 protein levels. Future
studies on LYVE-1 expression and function
under diseased and treatment conditions
will shed light on the role of the lymphatic
system in diabetic heart disease.
ACKNOWLEDGEMENTS: This work was
supported by the U.S. Department of
Health and Human Service through a
National Research Service Award F31
HL095273 from the National Heart, Lung
and Blood Institute and by the National
Institutes of Health Grant Number P20
RR016475 from the INBRE Program of the
National Center for Research Resources.
Lisa VanHoose, PT, PhD Candidate,
CLT-LANA, WCC
University of Kansas Medical Center
Physical Therapy and Rehabilitation
Science
[email protected]
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