Editorial
Does Exercise Increase HDL Cholesterol in
Those Who Need It the Most?
Paul D. Thompson, Daniel J. Rader
T
he Health, Risk Factors, Exercise, Training, and Ge-
netics (HERITAGE) Family Study is a landmark mul-
ticenter trial designed to examine the physiological
changes produced by exercise training and how genetics con-
tributes to the variation in the response to exercise.1 Families
underwent physiological and biochemical assessment before and
after 5 months of supervised aerobic exercise training. This
study is the largest intervention trial of the effects of exercise
training on serum lipids, and the results for the entire cohort have
been previously reported.2 In this issue of Arteriosclerosis,
Thrombosis, and Vascular Biology, Couillard and colleagues3
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present a detailed subgroup analysis of the lipid results for 200
white males that focuses on the effects of exercise on HDL
cholesterol (HDL-C) levels. The results have important mes-
sages for both researchers and clinicians interested in the effects
of exercise on lipid metabolism.
See p 1226
Coulliard and colleagues3 divided their subjects into 4 sub-
groups by using the 50th percentiles of plasma triglycerides
(TGs) and HDL-C as cutpoints, 0.92 mmol/L (36 mg/dL) for
HDL-C and 1.34 mmol/L (119 mg/dL) for TGs, thereby forming
4 subgroups: low TG/high HDL-C, high TG/high HDL-C, high
TG/low HDL-C, and low TG/low HDL-C. The lattermost group
is referred to as isolated low HDL-C, a common condition that
is often, but not always, a risk factor for premature coronary
disease. Interestingly, as expected, while the high TG/low
HDL-C group had evidence of visceral obesity and insulin
resistance, the isolated low HDL-C group did not. Both high-TG
groups experienced a 13% to 15% decrease in TGs with
exercise, which is consistent with multiple reports that exercise
does effectively reduce TGs.4 The major question asked in this
analysis was whether the HDL-C response to exercise was
related to the baseline TG levels. HDL-C levels increased by an
average of 4.9% in the high TG/low HDL-C group but only by
0.4% in the isolated low HDL-C group, statistically a signifi-
cantly smaller response.
The present observation that exercise training fails to
increase HDL-C in men with isolated low HDL-C levels is
consistent with prior reports.5,6 One small study5 selected
men who had low (1 mmol/L, or 40 mg/dL; n7) or normal
(1.1 mmol, or 44 mg/dL; n10) HDL-C levels. Mean TG
levels in the low HDL-C group were 1.81 mmol/L, or 160
mg/dL, and only 1.19 mmol/L, or 105 mg/dL, in the normal
From the Preventive Cardiology Section (P.D.T.), Division of Cardi-
ology, Hartford Hospital, Hartford, Conn, and the Divisions of Experi-
mental Therapeutics and Cardiology (D.J.R.), University of Pennsylva-
nia, Philadelphia, Pa.
Correspondence to Paul D. Thompson, MD, Hartford Hospital, 80
Seymour St, Hartford, CT 06102. E-mail pthomps@harthosp.org
(Arterioscler Thromb Vasc Biol. 2001;21:1097-1098.)
2001 American Heart Association, Inc.
1097
HDL-C group. Subjects exercised under supervision 4 hours
weekly, consumed defined diets for 4 weeks before and
during lipid measurement, and were required to maintain a
stable body weight. Average HDL-C increased 12%
(0.13 mmol/L, or 5.1 mg/dL) in the normal HDL-C subjects
but by only 6% (0.05 mmol/L, or 1.9 mg/dL) in the low
HDL-C subjects. Furthermore, TG levels decreased and
intravenous fat clearance and postheparin lipoprotein lipase
(LPL) activity increased only in the normal HDL-C group,
suggesting that individuals with low baseline HDL-C values
have an impaired ability to alter TG metabolism by exercise
training. Williams et al,6 in a year-long exercise training
program, noted the largest increase in HDL-C and reduction
in TGs among subjects who exercised the most. Interestingly,
those who exercised the most during the study had the highest
HDL-C and lowest TGs at baseline, suggesting that high
HDL-C and low TGs may somehow select for individuals
more likely to sustain aerobic activity. In a subsequent study,
Williams et al7 confirmed that baseline HDL-C was related to
the subjects running mileage (r0.34, P0.02), even after
adjustment for baseline body weight (r0.32, P0.03). The
idea that HDL-C level may select for exercise adherence has
theoretical support, since fatty acids are a major energy
source during endurance exercise and high HDL-C levels are
associated with increased postprandial TG clearance.8 There-
fore, increased generation of fatty acids could facilitate
energy delivery to muscle and thereby increase adherence to
exercise training. However, in the current study, adherence to
the exercise protocol was carefully controlled, suggesting that
factors other than the extent of exercise are responsible for the
reduced effect of exercise in persons with baseline low
HDL-C.
The mechanism by which exercise increases HDL-C is not
fully understood but is believed to be related, at least in part,
to increased expression of LPL.9 LPL activity is well known
to be positively associated with HDL-C levels,10 and exercise
is known to increase LPL activity.11 In the current study,3
however, LPL activity increased in all groups to a similar
extent, and therefore, this mechanism cannot explain the
failure of exercise to increase HDL-C levels in the isolated
low HDL-C group. Increases in HDL-C with exercise have
been shown to be associated with reduced HDL apolipopro-
tein catabolism in a normal, but not in a low, HDL-C group.5
Although the mechanism for reduced HDL catabolism with
exercise was also thought to be related to LPL activity, it is
possible that exercise has other physiological effects that
influence HDL turnover and that these effects may differ
depending on metabolic factors, such as visceral adiposity,
insulin resistance, and TG levels. The effect of genetic
variation in candidate genes on the variation in HDL-C
response to exercise will be one of the fascinating additional
 1098 Arterioscler Thromb Vasc Biol. July 2001
pieces of data to emerge from the HERITAGE Study in the
future.
The HERITAGE study is a model for the investigation of
the effect of exercise on serum lipids. The exercise training
regimens were carefully standardized to heart rate by using
cycle ergometers with built-in heart rate monitors. Caloric
restriction and weight loss were not encouraged, so as to
isolate the effects of exercise training. The results were
adjusted for the expansion in plasma volume that occurs with
exercise training and that can literally dilute the increases in
HDL-C. Nevertheless, the present report has certain limita-
tions. Subjects in both high-TG groups differed in multiple
ways from the lower-TG subjects. The high-TG individuals
were more obese, less fit, and older, making it difficult to
separate the effect of baseline TGs from other factors that
could affect the exercise response. Furthermore, as shown in
Figure 1, the division of subjects into 4 subgroups was
arbitrary, with most of the subjects clustering around the 50th
percentile values. Only the distribution of the low HDL/high
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TG subjects was visibly different from the other groups.
Consequently, it is not surprising that this group displayed the
most distinctive changes with exercise training. Also, some of
the decrease in TGs reported in the present study could be the
result of an acute effect of recent exercise. In the current
study, plasma lipids were assessed 24 hours after the last
exercise session. The ability of an isolated exercise session to
decrease TGs in hypertriglyceridemic subjects was first
reported by Holloszy and others12 in 1964. Those investiga-
tors noted a remarkable decrease of 0.94 mmol/L, or 84
mg/dL, in TGs among 5 hypertriglyceridemic men (mean
TG3.99 mmol/L, or 353 mg/dL) 20 hours after an isolated
exercise session. This acute effect of exercise on TGs13 and
HDL-C11 has been noted by others and seems related to the
magnitude of energy expended during exertion.11,13 For the
entire HERITAGE cohort, the TG values obtained 24 hours
after the last exercise session were significantly lower than
those obtained 72 hours after the last session, suggesting that
some of the decreases in TGs are a transient effect of recent
exercise.2 HDL-C results, however, were not subject to this
acute exercise effect.2
Overall, the magnitude of the effects of exercise training on
absolute HDL-C levels is disappointing. In the complete
HERITAGE cohort,2 the average increase in HDL-C for men
(n299) and women (n376) was only 0.03 and
0.04 mmol/L (1.1 and 1.4 mg/dL, P0.001 for both),
respectively. These small changes are surprising to many
clinicians who often expect much greater increases in
HDL-C, similar to the 0.54 mmol/L (20 mg/dL) difference
between endurance athletes and sedentary subjects first noted
by Dr Peter Wood and colleagues14 over a quarter century
ago. Nevertheless, the much smaller changes in HDL-C in the
HERITAGE subjects are consistent with the 0.03 mmol/L, or
1.2 mg/dL, increase reported in a meta-analysis of 66 exercise
training studies.4
What are the implications of the HERITAGE Family Study
results for researchers and clinicians interested in the effects
of exercise on lipid metabolism? For researchers, the HERI-
TAGE study provides a superb model for investigation of this
area and indicates that the physiological changes induced by
aerobic exercise and their effects on lipoprotein metabolism
are complex. Studies of the impact of genetic polymorphisms
on the response to exercise in this study are eagerly awaited.
Future dynamic and kinetic studies of energy, fatty acid, and
lipoprotein metabolism in both acute and chronic states of
aerobic exercise will be required to address some of the
remaining issues that cannot be answered through measure-
ment of steady-state plasma levels alone. For clinicians, these
results confirm that exercise training can reduce TGs and
increase HDL-C in hypertriglyceridemic individuals but that
exercise training has relatively little utility in increasing
HDL-C in individuals with isolated low HDL-C levels. It
remains to be determined whether more prolonged or intense
training can increase HDL-C in isolated low HDL-C subjects.
At the present time, however, the conventional wisdom that
aerobic exercise training increases HDL-C must be tempered
by the fact that the absolute increases in HDL-C are modest
and may not occur at all in those with isolated low HDL-C.
This should not, however, discourage clinicians from pre-
scribing aerobic exercise, which is likely to have a variety of
cardiovascular benefits beyond its effects on HDL-C.
References
1. Bouchard C, Leon AS, Rao DC, Skinner JS, Wilmore JH, Gagnon J. The
HERITAGE family study: aims, design, and measurement protocol. Med
Sci Sports Exerc. 1995;27:721729.
2. Leon AS, Rice T, Mandel S, Despres JP, Bergeron J, Gagnon J, Rao DC,
Skinner JS, Wilmore JH, Bouchard C. Blood lipid response to 20 weeks
of supervised exercise in a large biracial population: the HERITAGE
Family Study. Metabolism. 2000;49:513520.
3. Couillard C, Despres J-P, Lamarche B, Bergeron J, Gagnon J, Leon AS,
Rao DC, Skinner JS, Wilmore, Bouchard C. Effects of endurance exercise
training on plasma HDL cholesterol levels depend on the levels of
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cholesterol. Atherosclerosis. 1998;137:215221.
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Does Exercise Increase HDL Cholesterol in Those Who Need It the Most?
Paul D. Thompson and Daniel J. Rader

Arterioscler Thromb Vasc Biol. 2001;21:1097-1098

doi: 10.1161/hq0701.092147
Arteriosclerosis, Thrombosis, and Vascular Biology is published by the American Heart Association, 7272
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Copyright 2001 American Heart Association, Inc. All rights reserved.
Print ISSN: 1079-5642. Online ISSN: 1524-4636

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