HIGHLIGHTED TOPIC Mechanism of Beneficial Effects of Physical Activity on
Atherosclerosis and Coronary Heart Disease
Effects of exercise training on coronary collateralization and control
of collateral resistance
Cristine L. Heaps1,2,4* and Janet L. Parker1,3,4*
1Michael E. DeBakey Institute for Comparative Cardiovascular Science and Biomedical Devices,2Department of Veterinary
Physiology and Pharmacology, Texas A&M University, College Station, Texas; and3Department of Systems Biology
and Translational Medicine and4Cardiovascular Research Institute, The Texas A&M University Health Science Center,
College Station, Texas
Submitted 21 March 2011; accepted in final form 12 May 2011
Heaps CL, Parker JL. Effects of exercise training on coronary collateralization
and control of collateral resistance. J Appl Physiol 111: 587–598, 2011. First
published May 12, 2011; doi:10.1152/japplphysiol.00338.2011.—Coronary collat-
eral vessels serve as a natural protective mechanism to provide coronary flow to
ischemic myocardium secondary to critical coronary artery stenosis. The innate
collateral circulation of the normal human heart is typically minimal and consid-
erable variability occurs in extent of collateralization in coronary artery disease
patients. A well-developed collateral circulation has been documented to exert
protective effects upon myocardial perfusion, contractile function, infarct size, and
electrocardiographic abnormalities. Thus therapeutic augmentation of collateral
vessel development and/or functional adaptations in collateral and collateral-
dependent arteries to reduce resistance into the ischemic myocardium represent a
desirable goal in the management of coronary artery disease. Tremendous evidence
has provided documentation for the therapeutic benefits of exercise training
programs in patients with coronary artery disease (and collateralization); mecha-
nisms that underlie these benefits are numerous and multifaceted, and currently
under investigation in multiple laboratories worldwide. The role of enhanced
collateralization as a major beneficial contributor has not been fully resolved. This
topical review highlights literature that examines the effects of exercise training on
collateralization in the diseased heart, as well as effects of exercise training on
vascular endothelial and smooth muscle control of regional coronary tone in the
collateralized heart. Future directions for research in this area involve further
delineation of cellular/molecular mechanisms involved in effects of exercise train-
ing on collateralized myocardium, as well as development of novel therapies based
on emerging concepts regarding exercise training and coronary artery disease.
collateral-dependent; porcine; human; canine
CORONARY COLLATERAL ARTERIES provide alternate pathways of
blood flow between regional myocardial perfusion territories.
Although the innate collateral circulation of the normal human
heart is typically minimal, the collateral circulation develops in
response to increasing severity of ischemic coronary disease.
These anastomoses serve as a natural protective mechanism to
provide coronary flow to ischemic myocardium secondary to
coronary stenosis. Considerable variability occurs in extent of
collateralization and the impact of genetic and cardiovascular
risk factors on coronary collateral development (8, 43, 77).
Irrespective, a well-developed collateral circulation has been
documented to exert protective effects on myocardial perfu-
sion, contractile function, infarct size, and electrocardiographic
abnormalities of the ischemic myocardium (8, 9, 12, 21, 28, 52,
70, 73, 77, 79, 80, 85) as well as markedly improve long-term
cardiac survival (52). Thus therapeutic augmentation of the
extent and/or function of the collateral circulation likely rep-
resents a desirable goal in the management of coronary artery
A large body of evidence has provided documentation for
favorable protective and therapeutic benefits of exercise train-
ing programs in patients with coronary artery disease. These
aspects are described in detail below and in the current series
of minireviews on this topic. Reductions in the influences of
major recognized risk factors are clearly involved as major
* C. L. Heaps and J. L. Parker contributed equally to this study.
Address for reprint requests and other correspondence: C. L. Heaps, Dept. of
Physiology and Pharmacology, MS4466, TAMU CVM and Biomedical Sci-
ence, College Station, TX 77843 (e-mail: firstname.lastname@example.org).
J Appl Physiol 111: 587–598, 2011.
First published May 12, 2011; doi:10.1152/japplphysiol.00338.2011.
8750-7587/11 Copyright © 2011 the American Physiological Societyhttp://www.jap.org587
preventative and therapeutic benefits of exercise training pro-
grams in both health and disease. However, the response of the
collateralized heart to increases in physical activity represents
additional complex and dynamic aspects. These include poten-
tial effects of exercise training on the degree of anatomical and
functional collateralization, as well as potentially important
effects on regulation of coronary tone in a complex hemody-
namic circuitry involving both collateral and noncollateral
(collateral-dependent) arteries and microvasculature. Analysis
of exercise training programs on extent of collateralization in
human patients with coronary disease has provided clinically
relevant but often controversial findings. Experimental animal
models of coronary artery disease and collateralization have
been developed and utilized to assess effects of chronic exer-
cise and address potential mechanisms involved. This review
highlights effects of exercise training on the extent and func-
tion of enhanced collateralization in both patients and experi-
mental models, as well as effects of exercise training on
vascular smooth muscle and endothelial control of regional
coronary tone in the collateralized heart.
EFFECT OF EXERCISE TRAINING ON CORONARY
COLLATERALIZATION IN HUMAN CORONARY ARTERY
It is well documented that inclusion of an exercise program
in the therapeutic management of coronary artery disease
reduces clinical symptoms, improves myocardial function, and
reduces long-term cardiac mortality (7, 10, 18, 22, 23, 26,
28–30, 33, 35–37, 47–49, 57–59, 68, 72, 76, 83). In this
setting, mechanisms that underlie the therapeutic advantages of
exercise training are numerous (18, 47) and include enhance-
ment of collateral development, increased perfusion of the
collateralized myocardium, and improved endothelial vasomo-
tor function of coronary vessels of the diseased heart (7, 30, 35,
37, 49). In a 2010 review, Fujita and Sasayama (28) concluded
that a long-term exercise regimen is effective for collateral
development in patients with coronary artery disease. They
further suggested that exercise stress in the setting of coronary
disease induces both arteriogenesis (enlargement and remod-
eling of preexisting collateral arterioles) as well as ischemia-
induced angiogenesis (growth and proliferation of capillaries);
however, arteriogenesis is more important in terms of the
coronary collateral circulation and delivery of blood into the
collateral-dependent regions (27, 28, 73).
Direct angiographic evidence of enhanced collateralization
in response to exercise training is sparse in human patients with
coronary disease (6, 7, 18, 22, 23, 26, 30, 37). Despite exercise-
mediated improvements in myocardial function in regions
compromised by ischemia, available methods for direct deter-
mination of collateral growth have significant limitations that
render assessment of collateral development difficult. Belar-
dinelli and colleagues (7) provided direct angiographic evi-
dence of exercise-induced enhancement of collateral vascula-
ture. In this study, effects of 8 wk of exercise training on
collateral development in coronary disease patients were eval-
uated using retrograde filling and angiographic scoring tech-
niques. At conclusion of the study, exercise-trained patients
demonstrated significantly improved perfusion by collateral
vessels that correlated with improvements in myocardial con-
tractility and myocardial thallium uptake in response to low-
dose dobutamine. Importantly, improvement in collateral
growth was not accompanied by progression of severity of
coronary artery stenosis. These investigators reported that
training-induced development of collateral vessels was more
pronounced in patients with higher collateral scores at baseline,
indicating a predictive relationship of collateral development
with initial levels of collateral perfusion (7). Similarly, a
follow-up study by these authors indicated that exercise train-
ing potentiated coronary collateralization (assessed via angiog-
raphy) in patients with ischemic cardiomyopathy treated with
On the other hand, other studies using angiographic tech-
niques have not provided support for exercise training-induced
collateral development in the setting of coronary artery disease
(22, 57, 60, 76). A 1979 angiographic analysis (60) reported
the absence of training-induced improvements in the number,
size, or extent of collaterals following a vigorous 7-mo exer-
cise training program in patients following an initial myocar-
dial infarction. In a series of studies (57–59, 76), effects of
intensive physical exercise and a low-fat diet on coronary
morphology, collateral development, myocardial perfusion,
and progression/regression of coronary artery disease were
evaluated over several years. The training regimen and low-fat
diet significantly delayed the progression of coronary disease
(lesion size) at one year (57, 76) and six years (59) of risk
intervention. Multivariate analysis identified only physical ac-
tivity as independently contributing to changes in progression
of disease (59). The training-diet intervention decreased stress-
induced myocardial ischemia (57) but did not significantly alter
collateral artery formation as compared with control patients
not exposed to these interventions (76). However, collateral
formation was significantly related to progression of coronary
artery disease (57). Similarly, in these studies, delayed pro-
gression of disease in these patients correlated with a decreased
collateral formation, as confirmed by others (63). Taken to-
gether, these data suggest that collateral development was
induced by progression of coronary disease rather than by the
training program, and that exercise caused beneficial changes
that appeared to be independent of angiographically visible
collateral development. Despite the negative outcome regard-
ing enhanced collateralizaton in response to exercise training
and low-fat diet, the intervention group exhibited improved
exercise stress-test performance, reduced myocardial ischemia
on thallium imaging, and fewer cardiac symptoms (57–59, 76),
supporting the results of Belardinelli et al. (7) and other
investigators that exercise training improves functional perfor-
mance of the compromised myocardial region(s).
Assessment of training-induced enhanced collateralization
by coronary angiographic techniques is challenging. Angiog-
raphy has inherent limitations regarding the level of resolution
(sensitivity of discernment) of many vessels within the collat-
eral network of the diseased heart (23, 26). Small microvascu-
lar caliber vessels (?100 ?m) are difficult to visualize angio-
graphically, and thus the full extent of collateralization cannot
be accurately assessed or may be underestimated. Indeed, only
half of patients with critical coronary stenosis develop angio-
graphically visible collaterals, despite functional evidence for
their presence (43). Nitrovasodilators, such as nitroglycerin,
are typically present in patients undergoing coronary angiog-
raphy, and collateral vessels have been shown to be responsive
to the vasodilator actions of these agents (2, 5, 18, 31, 64).
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