(Circulation. 1995;92:197-204.)
© 1995 American Heart Association, Inc.
Articles |
Effect of Short-term Cardiovascular Conditioning and Low-Fat Diet on Myocardial Blood Flow and Flow Reserve
From the Division of Nuclear Medicine, Department of Molecular and Medical Pharmacology, and the Department of Cardiology (J.K.), UCLA School of Medicine, and the Laboratory of Structural Biology and Molecular Medicine, University of California, Los Angeles.
Correspondence to Heinrich R. Schelbert, MD, Division of Nuclear Medicine and Biophysics, UCLA School of Medicine, Los Angeles, CA 90024-1721.
 |
Abstract |
|---|
 Top Abstract IntroductionMethods Results Discussion References |
|---|
Background Cardiovascular conditioning reduces resting myocardial oxygen demand by lowering systolic blood pressure and heart rate. Lower myocardial oxygen demand at rest would be expected to be associated with a decrease in resting myocardial blood flow and, consequently, an increase in myocardial flow reserve as the ratio of hyperemic to resting blood flow. However, the effect of controlled exercise together with a low-lipid diet on myocardial blood flow and flow reserve has not been examined in humans.
Methods and Results Myocardial blood flow at rest and after dipyridamole-induced hyperemia (0.56 mg/kg IV) was quantified with [13N]ammonia and positron emission tomography in 13 volunteers before and upon completion of a 6-week program of cardiovascular conditioning and a low-fat diet. Exercise capacity and serum lipid profiles were also assessed at the start and finish of the program. Eight normal volunteers of similar age not participating in the conditioning program served as a control group. Cardiovascular conditioning lowered the resting rate-pressure product (8859±2128 versus 7450±1496, P<.001), serum cholesterol (217±36 versus 181±26 mg/dL), LDL cholesterol (140±32 versus 114±24 mg/dL), and triglycerides (145±53 versus 116±33 mg/dL, all P<.05). Exercise tolerance (metabolic equivalent of the task, METs) improved significantly from 10.0±3.0 to 14.4±3.6 (P<.01). Resting blood flow decreased (0.78±0.18 versus 0.69±0.14 mL · g-1 · min-1, P<.05), whereas hyperemic blood flow increased (2.06±0.35 versus 2.25±0.40 mL · g-1 · min-1, P<.05), resulting in an improved myocardial flow reserve (2.82±1.07 versus 3.39±0.91, P<.05). Overall, the myocardial flow reserve was significantly related to exercise performance (METs). In the control group, no changes in resting rate-pressure product, serum cholesterol levels, exercise performance, resting or hyperemic myocardial blood flow, or flow reserve were observed.
Conclusions Short-term cardiovascular conditioning together with a low-fat diet results in an improved myocardial flow reserve by lowering resting blood flow and increasing coronary vasodilatory capacity. These changes are associated with an improved exercise capacity and may offer a protective effect in patients with coronary artery disease.
Key Words: blood flow • myocardium • diet • tomography
|
Introduction |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
The myocardial flow reserve declines with age primarily because of an age-dependent, progressive increase in resting cardiac work and, consequently, in myocardial blood flow at rest. This increase in resting cardiac work might be ascribed to a more sedentary lifestyle in the older population. Hyperemic blood flows tend to be lower in older volunteers, although no statistically significant reduction has been demonstrated.1 Cardiovascular conditioning together with a low-fat diet is known to lower resting heart rates and blood pressure.2 3 4 Therefore, we hypothesized that cardiovascular conditioning together with a low-fat diet might augment the myocardial flow reserve, primarily by decreasing cardiac work and, in turn, myocardial blood flow at rest. The net effect of these lifestyle modifications on myocardial blood flow at rest and during pharmacological stress remains unknown but can now be quantified noninvasively with positron emission tomography (PET) using [13N]ammonia as a tracer of blood flow.5 6 7
The aim of the present study was to measure the response of myocardial blood flow and flow reserve to cardiovascular conditioning together with a low-fat diet and to relate this response in blood flow to changes in (1) hemodynamics, (2) serum lipids, and (3) exercise performance.
|
Methods |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
Study Population
The study group consisted of 13 volunteers (11 men, 2 women; mean age, 57±7 years). All were enrolled in the Pritikin Longevity Center outpatient program.8 Four subjects had a history of coronary artery disease as evidenced by prior coronary artery bypass surgery (n=2) or myocardial infarction (n=2). Four of the subjects had a history of systolic hypertension in excess of 150 mm Hg. The serum cholesterol levels exceeded 200 mg/dL in 9 of the 13 participants (69%). The majority of participants were therefore at increased risk for or had documented coronary artery disease.9 None of the participants had been on any lipid-lowering, cardiac, or antihypertensive medication before or during the study period.
The nonrandomized and nonconcurrent control group consisted of 8 normal volunteers (mean age, 53±10 years; 6 men, 2 women) who did not undergo any cardiovascular conditioning program. None had known coronary artery disease, 1 had mild systolic hypertension, 3 had a history of elevated serum cholesterol levels, and none was on any medication. All participants refrained from intake of caffeine-containing food or beverages for at least 24 hours before the PET study. Each signed an informed consent form approved by the UCLA Human Subject Protection Committee.
Cardiovascular Conditioning
All participants of the study
group underwent a 6-week program
consisting of daily aerobic exercise, the Pritikin
low-fat/low-cholesterol diet, and relaxation
techniques.2 This program is subsequently referred to as
"cardiovascular conditioning." Exercise,
primarily walking, was performed to achieve 70% of the maximal heart
rate achieved on the stress test for at least 30 to 45 minutes.
Participants attended the center 3 days per week, where they had a
prepared meal, an exercise session, and a lecture on how to follow the
diet as well as the relation between diet and exercise and diseases
common in our society. The Pritikin eating plan consists of less than
10% of calories from fat, 10% to 15% from protein, and 75% to 80%
from carbohydrates (vegetables, fruits, legumes, and whole grains). The
diet contained 3 to 4 g of NaCl and less than 100 mg of
cholesterol per day.8
Measurements Before and After Cardiovascular
Conditioning
As part of screening before cardiovascular
conditioning, all participants underwent a thorough history and
physical examination and rest and stress ECG. Two-dimensional
echocardiography at rest was performed before the
initial PET study in each participant and analyzed visually by
an independent observer for the presence of resting wall motion
abnormalities.
Exercise Stress Testing
Heart rate and
blood pressure were measured. In addition,
exercise capacity before and after cardiovascular
conditioning was assessed in each participant of the study and the
control group using a Bruce treadmill protocol. Exercise capacity was
expressed as metabolic equivalents of oxygen consumption
(or metabolic equivalents of the task,
METs).10
Serum Lipid Profiles
Serum
lipids (total and HDL cholesterol and
triglycerides) were measured with an Olympus
autoanalyzer using enzymatic methods. LDL
cholesterol was calculated according to the methods of
Friedwald et al.11
Measurement of Myocardial
Blood Flow
Myocardial blood flow at rest and during
dipyridamole-induced hyperemia (0.56 mg/kg IV)
was quantified in all study participants with intravenous
[13N]ammonia and PET at 2 to 3 days before and 2 to 4
days after completion of the 6-week cardiovascular
conditioning program (average time interval, 46±5 days). In the
control group, resting and hyperemic blood flows were
quantified twice within 44±7 days (NS versus study group). Throughout
each flow measurement, the ECG was monitored continuously while heart
rate and arterial blood pressure (cuff measurements) were
obtained at 1-minute intervals.
The methods used for the quantification of myocardial blood flow at rest and during dipyridamole-induced hyperemia have been described in detail previously.1 In brief, after intravenous injection of [13N]ammonia (10 to 15 mCi), serial transaxial images were acquired with whole-body PET (model 931/8, CTI-Siemens). The transaxially acquired images were then reoriented into six short-axis images of the left ventricle, assembled into polar maps of myocardial blood flow, and compared with a reference database of normals.12
In the healthy participants, three 90-degree regions of interest were placed in the three territories of the major coronary arteries. In the 4 participants with coronary artery disease, only segments with normal wall motion and homogeneous [13N]ammonia distribution on both the resting and hyperemic polar maps were analyzed. The two (in the 4 patients with coronary artery disease) or three (in the 9 healthy subjects) regions of interest were copied to the serially acquired images to derive myocardial tissue time-activity curves,1 which were corrected for partial volume effect by assuming a uniform left ventricular wall thickness of 1 cm13 for activity spillover from the left ventricular blood pool to the left ventricular myocardium13 and for physical decay of [13N]ammonia activity.
The arterial input function was derived from a small region of interest in the center of the left ventricular blood pool and copied to the serially acquired images.14 The first 120 seconds of the decay-corrected myocardial and blood pool time activity data were then fitted with a previously validated two-compartment model for [13N]ammonia.6 The sectorial values of blood flow were averaged, and one mean flow value for blood flow was obtained in each patient.
Statistical Analysis
Mean values are given with standard
deviations. Changes in serum
lipid levels, hemodynamic and blood flow data, and
exercise performance (METs) from baseline to follow-up were
compared using the Student's t test for paired data.
Correlations were sought using least-squares regression
analysis. Probability values less than .05 were considered
significant.
|
Results |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
Echocardiographic Findings
Each of the 4 volunteers with known coronary artery disease in the study group exhibited a resting wall motion abnormality in one myocardial segment. These segments were excluded from further quantitative tomographic analysis. In the 9 remaining participants, wall motion was normal by echocardiography. No echocardiographic studies were performed in the control group.
Hemodynamic Findings and Exercise
Capacity
The hemodynamic measurements obtained in the study
group and in the control group at baseline and at follow-up are listed
in Table 1
. In the study group, resting systolic blood
pressure (P<.05), mean aortic blood pressure
(P<.05), and heart rate (P<.05) decreased,
whereas diastolic blood pressure remained unchanged from
the baseline to the follow-up study. The rate-pressure product
decreased from 8859±2128 to 7450±1496 mm Hg/min
(P<.001). Similar decreases for systolic blood pressure
were observed during intravenous
dipyridamole. However, heart rate and
diastolic blood pressure during
dipyridamole remained unchanged from baseline to
follow-up. Exercise capacity, expressed as metabolic
equivalents of whole-body oxygen consumption (METs), improved from
10±3 to 14±3.6 at follow-up (P<.01). However, this
improvement might be explained by a "learning effect" rather than
by the conditioning program.
|
In contrast, no significant changes in
rate-pressure product at
rest (7905±1271 versus 8113±1849), mean aortic blood pressure
during
dipyridamole (82±7 versus 86±8 mm Hg), or exercise
capacity (11.4±1.0 versus 11.5±0.8 METs) were observed in the
control
group (also see Table 1
).
Serum Lipid Profiles
The serum lipid profiles before and upon
completion of the diet
and cardiovascular conditioning program are listed in
Table 2. Total cholesterol,
triglycerides, and LDL cholesterol were lower
after cardiovascular conditioning (P<.05),
whereas HDL cholesterol remained unchanged. In contrast, no
changes in total cholesterol (197±17 versus 203±16
mg/dL), triglycerides (148±61 versus 138±37 mg/dL), and
LDL cholesterol (119±17 versus 127±17 mg/dL) or HDL
cholesterol (39±9 versus 41±10 mg/dL) were observed in
the control group.
|
Semiquantitative Image Analysis
Polar map analysis of the
myocardial
[13N]ammonia uptake at rest and during hyperemia
revealed regional myocardial blood flow defects in 4 of the 13
participants of the study group. The flow defects corresponded in
location to the wall motion abnormalities as noted on two-dimensional
echocardiography. Pharmacological vasodilation in
the 4 patients with coronary artery disease did not alter the
extent or the severity of the flow defects, nor did it induce new flow
defects. Semiquantitative analysis of the polar maps further
indicated that these flow defects on the rest and hyperemic
images remained unchanged after cardiovascular
conditioning. The remaining 9 subjects (69.3%) had normal wall motion
at rest and homogeneous [13N]ammonia activity
distributions in both pairs of rest and hyperemic
[13N]ammonia blood flow studies as compared with a
database of normal. Furthermore, no perfusion abnormalities were
observed on any of the [13N]ammonia blood flow studies in
the 8 participants of the control group.
Myocardial Blood Flow
The individual blood flow measurements
obtained in the
participants of the conditioning program are listed in Table 1.
Resting
blood flow averaged 0.78±0.18
mL · g-1 · min-1 at baseline
and
declined to 0.69±0.14
mL · g-1 · min-1 after
completion of
the Pritikin program (P<.05). This decline in resting
myocardial blood flow paralleled the reduction in the resting
rate-pressure product. Overall, myocardial blood flow correlated
significantly with the rate-pressure product (r=.84;
SEE, 0.0001; P<.0001; Fig 1). In contrast,
no changes in resting blood flow were observed in the control group
(0.71±0.13 versus 0.79±0.14
mL · g-1 · min-1).
|
Dipyridamole-induced hyperemic blood flow
increased from 2.06±0.35
mL · g-1 · min-1 at baseline
to
2.25±0.40
mL · g-1 · min-1
(P<.01) at follow-up (Table 1). No significant
correlations
between hyperemic blood flow and the rate-pressure product
or the mean aortic blood pressure were found. Furthermore, the
magnitude of hyperemic blood flows did not correlate with serum
cholesterol or LDL cholesterol levels. However,
changes in hyperemic blood flow from baseline to
follow-up tended to correlate with changes in serum
cholesterol levels (P=.07) but not with LDL
cholesterol. Overall, hyperemic blood flow was
correlated with exercise performance (METs; r=.5;
SEE, 1.84; P<.05). No significant changes in
hyperemic blood flow were observed in the control group
(2.10±0.23 versus 2.08±0.36
mL · g-1 · min-1).
Myocardial Blood Flow Reserve
In the study group, the lower
resting blood flow after
cardiovascular conditioning together with higher
hyperemic flow resulted in a significant increase in myocardial
flow reserve (2.82±1.07 versus 3.39±0.91; P<.01;
Table 1). Myocardial flow reserve before and after the
conditioning program
correlated, as expected, with resting blood flow
(r=-.77;
SEE, 1.04; P<.01 and r=.71; SEE, 1.45;
P<.01), resting rate-pressure product
(r=.73; SEE, 0.0001; P<.01 and
r=.62;
SEE, 0.0001; P<.05; Fig 2), and
hyperemic blood flow (r=.61; SEE, 0.64;
P<.05 and r=.58; SEE, 0.54;
P<.05).
|
Changes in myocardial flow reserve were associated
with changes in
resting blood flow (r=.82; SEE, 0.33; P<.001),
hyperemic blood flow (r=.71; SEE, 0.49;
P<.01) and resting rate-pressure product
(r=.57; SEE, 0.97; P<.05; Fig 3),
and changes of total serum cholesterol (r=.58;
SEE, 0.85; P<.05; Fig 4). Changes in LDL
cholesterol tended to correlate with changes in myocardial
flow reserve, yet this correlation failed to attain statistical
significance (r=.50, P=.076). Myocardial flow
reserve was directly correlated with exercise capacity
(r=.58; P<.01; SEE, 1.04; Fig 5).
|
|
|
In the control group, there were no significant changes in myocardial flow reserve from baseline to follow-up (3.05±0.61 versus 2.72±0.80 mL · g-1 · min-1).
Coronary Vascular Resistance
During maximal coronary
vasodilation,
hyperemic blood flows depend on coronary driving
pressure, among other factors. To relate the coronary driving
pressure to hyperemic blood flows, an index of the
coronary vascular resistance was established as the ratio of
the mean aortic blood pressure (mm Hg) over myocardial blood flow
(mL · g-1 · min-1). Resting
coronary resistance remained unchanged from baseline to
follow-up (138±32 versus 146±28
mm Hg · mL-1 · g-1 · min-1).
In contrast, coronary vascular resistance during
dipyridamole-induced hyperemia ("minimal
coronary resistance") decreased from 52±11 to 45±10
mm Hg · mL-1 · g-1 · min-1
(P<.01).
No statistically significant correlations were found between minimal coronary vascular resistance or its changes and serum cholesterol or LDL cholesterol levels or their changes. However, minimal coronary vascular resistance correlated with exercise performance (METs; r=.58; SEE, 1.84; P<.05).
In the control group, minimal coronary vascular resistance remained unchanged between the initial study and the follow-up study (41±6 versus 42±6 mm Hg ·mL-1 · g-1 · min-1).
|
Discussion |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
The findings of this study indicate that cardiovascular conditioning consisting of regular, controlled physical exercise, low-fat diet, and relaxation techniques enhances myocardial flow reserve. This increase results largely from a reduction in resting cardiac work and consequently, resting myocardial blood flow. An unexpected finding of this study was that cardiovascular conditioning also resulted in higher hyperemic blood flow, which contributed to the observed increase in myocardial flow reserve. This improvement in flow reserve was correlated significantly with an improvement in exercise capacity. The absence of significant alterations in blood flow and flow reserve in a control group supports the notion that the changes in myocardial blood flow and vasodilator capacity can in fact be attributed to cardiovascular conditioning.
Limitations of the Study
The cardiovascular conditioning
program consisted
of regular physical exercise combined with dietary and lifestyle
changes. Therefore, it is difficult to determine which of these
components accounted primarily for the improvement in flow reserve. The
results offer no mechanistic explanations. Thus, it remains uncertain
whether exercise, dietary changes, or both produced the increase in
myocardial flow reserve. Yet, it seems likely that regular exercise was
a main factor reducing cardiac work and thus blood flow at rest, as
reported previously.2 3 4
As another limitation, myocardial blood flow and its changes were not quantified in dysfunctional myocardial segments of the 4 patients with coronary artery disease. The small sample size and the short duration of the program precluded a meaningful statistical analysis of the changes in dysfunctional myocardial regions. However, regression of coronary artery disease and thus, measurable changes in blood flow to ischemically compromised myocardium as described previously,15 would be expected to occur if the participants had continued cardiovascular conditioning for longer time periods. However, the semiquantitative findings on the polar maps of the [13N]ammonia uptake that indicated the presence of fixed flow defects and failed to identify new, hyperemia-induced flow abnormalities suggest that the flow defects together with the resting wall motion abnormalities primarily represented myocardial scarring.
The heterogeneity of the study population
represents another potential limitation. The group consisted of
apparently healthy volunteers and patients with hypertension, elevated
serum cholesterol, or documented coronary artery
disease. The most prominent changes in myocardial blood flow and flow
reserve were, as expected, observed in patients with coronary
artery disease and hypertension. The flow reserve in "normal"
participants also tended to improve (from 3.33±1.22 to
3.67±1.02; see
Table 1). However, the addition of the 2 patients with
hypertension to
the subgroup of "healthy" participants resulted only in a
tendency toward an improved flow reserve (P=.115).
The improvement in blood flow and flow reserve in the patients with coronary artery disease is not surprising. First, systolic blood pressure and rate-pressure product tended to be higher in patients than in the healthy participants. Thus, cardiovascular conditioning was likely to have a greater impact on resting cardiac work and hence, myocardial blood flow at rest. Second, the low-fat diet was more likely to affect the vasodilatory capacity in patients with more abnormal coronary vasomotion than in healthy subjects. This possibility is in agreement with recent findings that demonstrated reductions in extent and severity of perfusion abnormalities in patients with coronary artery disease by PET after aggressive lipid-lowering therapy.16 17 18 However, reductions in serum lipid levels might also account in part for the observed trend of an improved flow reserve in the apparently healthy volunteers.19 The more pronounced improvement in vasodilatory capacity in patients with coronary artery disease or hypertension suggests that this group might benefit most from cardiovascular conditioning and a low-fat diet.
The majority of participants were at an increased risk for coronary artery disease.9 Despite the high accuracy of PET for detection of coronary artery disease,20 21 coronary artery disease in the 9 asymptomatic subjects without clinical signs of coronary artery disease could have been ruled out with certainty only by coronary angiography. However, blood flow was quantified only in segments with normal resting wall motion and normal [13N]ammonia uptake at rest and during dipyridamole. Thus, it is unlikely that these myocardial territories were supplied by coronary arteries with significant disease. Moreover, each participant served as his or her own control. Myocardial blood flow was quantified in the same myocardial segments before and after cardiovascular conditioning. Therefore, even the presence of mild coronary artery disease would not invalidate the finding of an improved flow reserve after cardiovascular conditioning.
As another limitation, the age-matched control group was nonrandomized and none of the control subjects had documented coronary artery disease. However, 1 control subject had hypertension and 3 had elevated cholesterol levels. Thus, the control group and the participants in the conditioning program without coronary artery disease had similar demographic characteristics.
Left ventricular wall thickness was not measured in this study but was assumed to be 1 cm for purposes of correction for partial volume effects. Thus, left ventricular hypertrophy cannot be ruled out with certainty in hypertensive individuals although ECG signs were absent. The assumption of a uniform wall thickness of 1 cm for partial volume correction might have caused some errors in the flow measurements. However, left ventricular hypertrophy would have affected the baseline and follow-up blood flow measurements equally because significant changes in wall thickness were unlikely to have occurred during only 6 weeks of cardiovascular conditioning. Thus, while measured rather than estimated wall thickness might have yielded slightly different estimates of blood flow, possible errors resulting from assuming a fixed, uniform wall thickness would not have altered the observed directional changes in resting and hyperemic blood flows.
The current study demonstrates a significant 15% reduction in the resting rate-pressure product after cardiovascular conditioning. It might be argued that anxiety of the participants during the initial PET study accounted for the initially higher rate-pressure product. However, similar reductions in blood pressure and heart rate after cardiovascular conditioning have been reported previously.2 3 4 22 Moreover, no changes in resting rate-pressure product from baseline to follow-up were observed in the control group. Initial anxiety was therefore unlikely to explain the higher rate-pressure products during the flow measurements in the study group.
Effects of Cardiovascular Conditioning on
Myocardial Flow Reserve
The myocardial flow reserves of
2.82±1.07
mL · g-1 · min-1 in the study
group and 3.05±0.61 in the control group at baseline are similar to
the 3.01±0.73 reported previously for healthy volunteers of similar
age (57±7 and 53±10 years versus 64±9
years).1
Cardiovascular conditioning raised the myocardial blood
flow reserve by 20% to 3.39±0.91
mL · g-1 · min-1, which is
lower than the previously reported flow reserve of 4.08±0.9 in young
volunteers (31±9 years) with similar rate-pressure products at
rest (6895±1069 versus 7450±1496; P=NS) and low
risk for
coronary artery disease.1 The lower flow reserve
in the current study group was caused by lower hyperemic blood
flow, possibly because of the 4 patients with coronary artery
disease and the higher likelihood of early coronary artery
disease in the remaining participants.
Effects of Cardiovascular Conditioning on
Myocardial Blood Flow at Rest
Regular exercise reduces blood pressure
and heart rate at rest and
during mental stress, possibly by reducing adrenergic activity.
Accordingly, cardiac work and, in turn, myocardial oxygen consumption,
decline at rest and possibly at any submaximal workload in patients
with coronary artery disease and in healthy
subjects.23 The lower myocardial oxygen demand would be
expected to be associated with proportional reductions in myocardial
blood flow.1 24 25 Consistent with these
earlier
observations, cardiovascular conditioning in this study
reduced the resting rate-pressure product (as an index of
myocardial oxygen consumption) by lowering systolic blood pressure and
heart rate, whereas no such changes were observed in the control group.
This was associated with a proportionate decline in resting blood flow
in the study group, which in turn contributed to the improved flow
reserve.
Effects of Cardiovascular Conditioning on
Hyperemic Blood Flows
The observed increase in hyperemic blood flow
and decrease
in the minimal coronary resistance after
cardiovascular conditioning were unexpected in the
current study. In contrast, hyperemic blood flow remained
unchanged in the control group. Possible explanations for this
observation include (1) a reduction in extravascular compressive
forces,26 (2) beneficial effects of lowered lipid levels
on endothelium-dependent and
endothelium-independent
vasodilation,16 17 18 19 27
(3) lower blood viscosity caused by
the reduction of serum lipid levels and as previously reported for this
diet and exercise program,28 29 (4) capillary
recruitment,30 or (5) an augmented, flow-mediated,
endothelium-dependent dilatory response or even an
enlargement of the conductance
vessels.31 32 33
Hyperemic myocardial blood flow is modulated by extravascular compressive forces and thus might vary with changes in myocardial contractility.26 Exercise training increases myocardial contractility, which in turn can augment extravascular compressive forces and attenuate the hyperemic blood flow. Thus, reductions in extravascular compressive forces are unlikely to explain the increased hyperemic blood flow after cardiovascular conditioning.
Serum triglyceride, total cholesterol, and LDL cholesterol levels declined with cardiovascular conditioning. Elevated serum LDL levels may attenuate endothelium-dependent vasodilation.34 In hypercholesterolemic nonhuman primates without macroscopic evidence of arteriosclerosis, endothelium-dependent vasodilation in response to intracoronary acetylcholine has been found to be impaired, whereas endothelium-independent vascular smooth muscle relaxation after intracoronary adenosine or sodium nitroprusside remained unaltered.35 However, one study in isolated rabbit arteries demonstrated an impairment of endothelium-independent vasodilation by nitroglycerin in the most severely diseased coronary arteries.27 Because segments with abnormal wall motion and blood flow were excluded from the current study, severe arteriosclerotic changes were unlikely to be present in the coronary territories analyzed. Reductions in serum cholesterol levels also might have contributed to the improved hyperemic blood flow via improved flow-mediated, endothelium-dependent vasodilation.33
Reductions in blood viscosity in response to cardiovascular conditioning, as for example due to lower cholesterol and triglyceride levels as reported previously,29 also might have affected beneficially the coronary vasodilatory capacity. However, blood viscosity and its changes were not measured in the current study.
Alternatively, cardiovascular conditioning might induce morphological changes of the coronary circulation. For instance, exercise training in rats has been found to increase the density of capillaries and thus, capillary recruitment,30 which could lead to a greater vasodilator capacity. However, the duration of cardiovascular conditioning required to produce increases in capillary density in humans remains unknown.
Increases in the diameter of the epicardial coronary arteries may serve as another possible explanation for the observed lower coronary resistance during pharmacological vasodilation. For example, short-term cardiovascular conditioning in dogs or a physically active lifestyle produced an increase in coronary artery diameter.32 36 Conversely, Langille and O'Donnel37 reported a 21% decrease in the diameter of rabbit carotid arteries after chronic reductions in blood flow.
More recently, Haskell et al31 observed a higher coronary vasodilating capacity in highly trained ultradistance runners compared with nontrained individuals. Nitroglycerin administration produced a 2.2-fold greater increase of the total coronary cross-sectional area in trained as compared with untrained individuals despite similar baseline coronary artery diameters. Also, the response of the brachial artery to pharmacological vasodilation is more pronounced in trained than in untrained individuals.38 The mechanisms underlying these changes remain unknown. Acute increases in blood flow might result in an augmented, flow-mediated, endothelium-dependent dilation of the large coronary arteries, which might be one important factor explaining the improved vasodilatory capacity after the conditioning program.33 However, it is also conceivable that frequent coronary flow increases due to daily exercise might induce structural modifications of the human coronary circulation.
Implications of the Study
The current study demonstrates that
cardiovascular
conditioning improves myocardial flow reserve. This improvement,
observed in myocardium subtended by coronary
arteries without apparent hemodynamically significant
lesions, may have implications for patients with coronary
artery disease. Cardiovascular conditioning in such
patients may exert a protective effect on the coronary
microcirculation by an increase in capillary density or by improved
flow-mediated vasodilation and might thereby reduce the functional
severity of coronary stenosis.
|
Acknowledgments |
|---|
The Laboratory of Structural Biology and Molecular Medicine is operated for the US Department of Energy by the University of California under contract DE-FC03-87ER60615. This work was supported in part by the Director of the Office of Energy Research, Office of Health and Environmental Research, Washington, DC, by research grants HL-29845 and HL-33177, National Institutes of Health, Bethesda, Md, and by an Investigative Group Award by the Greater Los Angeles Affiliate of the American Heart Association, Los Angeles, Calif. We would like to thank Robert Pritikin, Director of the Pritikin Longevity Center, for recommending that his participants volunteer for our experiment. We thank Diane Martin for preparing figures and tables and Eileen Rosenfeld for skillful preparation of the manuscript. We want to thank Ron Sumida, Larry Pang, Francine Aguilar, Marc Hulgan, and Derjenn Liu for technical assistance.
Received December 6, 1994; accepted January 10, 1995.
|
References |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
1. Czernin J, Müller P, Chan S, Brunken R, Porenta G, Krivokapich J, Chen K, Chan A, Phelps M, Schelbert H. Influence of age and hemodynamics on myocardial blood flow and flow reserve. Circulation. 1993;88:62-69.
2. Barnard J, Ugianski E, Martin D, Inkeles S. Role of diet and exercise in the management of hyperinsulinemia and associated atherosclerotic risk factors. Am J Cardiol. 1992;69:440-444. [Medline] [Order article via Infotrieve]
3. Blumenthal J, Fredrikson M, Kuhn C, Ulmer R, Walsh-Riddle M, Apelbaum M. Aerobic exercise reduces levels of cardiovascular and sympathoadrenal responses to mental stress in subjects without prior evidence of myocardial ischemia. Am J Cardiol. 1990;65:93-98. [Medline] [Order article via Infotrieve]
4.
Levy C, Cerqueira M, Abrasss I, Schwartz R, Stratton
J. Endurance exercise training augments diastolic
filling at rest and during exercise in healthy young and older
men. Circulation. 1993;88:116-126.
5.
Krivokapich J, Smith GT, Huang SC, Hoffman EJ, Ratib
O, Phelps ME, Schelbert HR. N-13 ammonia myocardial imaging at
rest and with exercise in normal volunteers: quantification of absolute
myocardial perfusion with dynamic positron emission tomography.
Circulation. 1989;80:1328-1337.
6.
Kuhle W, Porenta G, Huang S-C, Buxton D, Gambhir S,
Hansen H, Phelps M, Schelbert H. Quantification of regional
myocardial blood flow using 13N-ammonia and reoriented
dynamic positron emission tomographic imaging.
Circulation. 1992;86:1004-1017.
7. Hutchins GD, Schwaiger M, Rosenspire KC, Krivokapich J, Schelbert H, Kuhl DE. Noninvasive quantification of regional blood flow in the human heart using N-13 ammonia and dynamic positron emission tomographic imaging. J Am Coll Cardiol. 1990;15:1032-1042. [Abstract]
8. Barnard R, Pritikin R, Rosenthal M. Pritikin approach to cardiac rehabilitation. In: Goodgold J, ed. Rehabilitation Medicine. St Louis, Mo: Mosby; 1988:267-286.
9. Diamond G, Forrester J. Analysis of probability as an aid in the clinical diagnosis of coronary artery disease. N Engl J Med. 1979;300:1350-1358. [Abstract]
10. American College of Sports Medicine. Guidelines for Exercise Testing and Prescription. Philadelphia, Pa: Lea & Febiger; 1991.
11. Friedwald W, Levy R, Fredrickson D. Estimation of the concentration of low-density lipoprotein in plasma, without use of the preparative ultracentrifuge. Clin Chem. 1972;18:499-502. [Abstract]
12.
Porenta G, Kuhle W, Czernin J, Ratib O, Brunken R,
Phelps M, Schelbert H. Semiquantitative assessment of myocardial
viability and perfusion utilizing polar map displays of cardiac PET
images. J Nucl Med. 1992;33:1623-1631.
13.
Gambhir S, Schwaiger M, Huang SC, Krivokapich J,
Schelbert HR, Nienaber CA, Phelps ME. Simple noninvasive
quantification method for measuring myocardial glucose utilization in
humans employing positron emission tomography and fluorine-18
deoxyglucose. J Nucl Med. 1989;30:359-366.
14.
Weinberg IN, Huang SC, Hoffman EJ, Araujo L, Nienaber
C, Grover-McKay M, Dahlbom M, Schelbert H. Validation of
PET-acquired functions for cardiac studies. J
Nucl Med. 1988;29:241-247.
15. Ornish D, Brown S, Scherwitz L, Billings J, Armstrong W, Ports T, McLanahan S, Kirkeeide R, Brand R, Gould K. Can lifestyle changes reverse coronary heart disease? The Lifestyle Heart Trial. Lancet. 1990;336:129-133. [Medline] [Order article via Infotrieve]
16.
Gould KL, Martucci JP, Goldberg DI, Hess MJ, Edens RP,
Latifi R, Dudrick SJ. Short-term cholesterol
lowering decreases size and severity of perfusion abnormalities by
positron emission tomography after dipyridamole in
patients with coronary artery disease: a potential noninvasive
marker of healing coronary endothelium.
Circulation. 1994;89:1530-1538.
17. Gould KL, Buchi M, Kirkeeide RL, Ornish D, Stein E, Brand R. Reversal of coronary artery stenosis with cholesterol lowering in man followed by arteriography and positron emission tomography. J Nucl Med. 1989;30:845-852.
18. Gould KL, Kirkeeide RL, Ornish D, Stein E, Buchi M, Smalling RW. Improvement of stenosis geometry by quantitative coronary arteriography and perfusion by positron emission tomography after adequate cholesterol lowering in man. Circulation. 1989;80:91-102.
19.
Dayanikli F, Grambow D, Muzik O, Mosca L, Rubenfire M,
Schwaiger M. Early detection of abnormal coronary flow
reserve in asymptomatic men at high risk for
coronary artery disease using positron emission
tomography. Circulation. 1994;90:808-817.
20.
Demer LL, Gould KL, Goldstein RA, Kirkeeide RL, Mullani
NA, Smalling RW, Nishikawa A, Merhige ME. Assessment of
coronary artery disease severity by positron emission
tomography: comparison with quantitative arteriography in 193
patients. Circulation. 1989;79:825-835.
21.
Go R, Marwick T, MacIntyre W, Saha G, Neumann D,
Underwood D, Simpfendorfer C. A prospective comparison of
rubidium-82 PET and thallium-201 SPECT myocardial perfusion imaging
utilizing a single dipyridamole stress in the diagnosis
of coronary artery disease. J Nucl
Med. 1990;31:1899-1905.
22. Barnard J, Ugianskis E, Martin D. The effects of an intensive diet and exercise program on patients with non-insulin-dependent diabetes mellitus and hypertension. J Cardiopulmonary Rehabil. 1992;12:194-201.
23.
Barnard R, MacAlpin R, Kattus A, Buckberg G.
Effect of training on myocardial oxygen supply/demand
balance. Circulation. 1977;56:289-291.
24. Holmberg S, Serzysko W, Varnauskas E. Coronary circulation during heavy exercise in control subjects and patients with coronary heart disease. Acta Med Scand. 1971;190:465-480. [Medline] [Order article via Infotrieve]
25.
McGinn A, White C, Wilson R. Interstudy
variability of coronary flow reserve: influence of heart rate,
arterial pressure, and ventricular
preload. Circulation. 1990;81:1319-1330.
26.
Marzilli M, Goldstein S, Sabbah H, Lee T, Stein P.
Modulating effect of regional myocardial performance on
local myocardial perfusion in the dog. Circ
Res. 1979;45:634-643.
27.
Verbeuren TJ, Jordaens FH, Zonnekeyn LL, Van Hove CE,
Coene MC, Herman AG. Effect of
hypercholesterolemia on vascular reactivity in the
rabbit, I: endothelium-dependent and
endothelium-independent contractions and relaxations in
isolated arteries of control and hypercholesterolemic
rabbits. Circ Res. 1986;58:552-564.
28. Johansson B, Linder E, Seeman T. Effects of hematocrit and blood viscosity on myocardial blood flow during temporary coronary occlusion in dogs. Scand J Thorac Cardiovasc Surg. 1967;1:165-174. [Medline] [Order article via Infotrieve]
29. Barnard R, Hall J, Pritikin N. Effects of diet and exercise on blood pressure and viscosity in hypertensive patients. J Cardiac Rehabil. 1985;5:185-190.
30. Tomanek RJ. Effects of age and exercise on the extent of the myocardial capillary bed. Anat Rec. 1969;167:55-62.
31.
Haskell W, Sims C, Myll J, Bortz W, St Goar F, Alderman
E. Coronary artery size and dilating capacity in
ultradistance runners. Circulation. 1993;87:1076-1082.
32.
Wyatt H, Mitchell J. Influences of physical
conditioning and deconditioning on coronary vasculature in
dogs. J Appl Physiol. 1978;45:619-625.
33.
Cox D, Vita J, Treasure C, Fish D, Alexander R, Ganz P,
Selwyn A. Atherosclerosis impairs flow-mediated
dilation of coronary arteries in humans.
Circulation. 1989;80:458-465.
34.
Tanner F, Noll G, Boulanger C, Lüscher T.
Oxidized low-density lipoproteins inhibit relaxations of porcine
coronary arteries: role of scavenger receptor and
endothelium-derived nitric oxide.
Circulation. 1991;83:2012-2020.
35.
Selke F, Armstrong M, Harrison D.
Endothelium-dependent vascular relaxation is
abnormal in the coronary microcirculation of atherosclerotic
primates. Circulation. 1990;81:1586-1593.
36.
Mann G, Spoerry A, Gray M, Jarashow D.
Atherosclerosis in the Masai. Am J
Epidemiol. 1972;95:26-37.
37.
Langille B, O'Donnel F. Reductions in
arterial diameter produced by chronic decreases in
myocardial blood flow are endothelium
dependent. Science. 1986;231:405-407.
38.
Martin W, Montgomery J, Snell P, Corbett J, Sokoloc J,
Buckey J, Maloney D, Blomquist C. Cardiovascular
adaptations to intense swim training in sedentary middle-aged men and
women. Circulation. 1987;75:323-330.
This article has been cited by other articles:
 |
|
 |
|
  H. R. Schelbert Coronary circulatory function abnormalities in insulin resistance insights from positron emission tomography. J. Am. Coll. Cardiol., February 3, 2009; 53(5 Suppl): S3 - S8. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. L. Heaps, E. C. Jeffery, G. A. Laine, E. M. Price, and D. K. Bowles Effects of exercise training and hypercholesterolemia on adenosine activation of voltage-dependent K+ channels in coronary arterioles J Appl Physiol, December 1, 2008; 105(6): 1761 - 1771. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. S. Laaksonen, K. K. Kalliokoski, M. Luotolahti, J. Kemppainen, M. Teras, H. Kyrolainen, P. Nuutila, and J. Knuuti Myocardial perfusion during exercise in endurance-trained and untrained humans Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2007; 293(2): R837 - R843. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. G. Camici and F. Crea Coronary Microvascular Dysfunction N. Engl. J. Med., February 22, 2007; 356(8): 830 - 840. [Full Text] [PDF]
|
|
|
|
|
|
C. K. Roberts, D. Won, S. Pruthi, S. Kurtovic, R. K. Sindhu, N. D. Vaziri, and R. J. Barnard Effect of a short-term diet and exercise intervention on oxidative stress, inflammation, MMP-9, and monocyte chemotactic activity in men with metabolic syndrome factors J Appl Physiol, May 1, 2006; 100(5): 1657 - 1665. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Wang, M. Jerosch-Herold, D. R. Jacobs Jr, E. Shahar, and A. R. Folsom Coronary Risk Factors and Myocardial Perfusion in Asymptomatic Adults: The Multi-Ethnic Study of Atherosclerosis (MESA) J. Am. Coll. Cardiol., February 7, 2006; 47(3): 565 - 572. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. L. Heaps, D. L. Tharp, and D. K. Bowles Hypercholesterolemia abolishes voltage-dependent K+ channel contribution to adenosine-mediated relaxation in porcine coronary arterioles Am J Physiol Heart Circ Physiol, February 1, 2005; 288(2): H568 - H576. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. K. Roberts and R. J. Barnard Effects of exercise and diet on chronic disease J Appl Physiol, January 1, 2005; 98(1): 3 - 30. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. A. Kaufmann and P. G. Camici Myocardial Blood Flow Measurement by PET: Technical Aspects and Clinical Applications J. Nucl. Med., January 1, 2005; 46(1): 75 - 88. [Full Text] [PDF]
|
|
|
|
|
|
R. G. Schwartz, T. A. Pearson, V. G. Kalaria, M. L. Mackin, D. J. Williford, A. Awasthi, A. Shah, A. Rains, and J. J. Guido Prospective serial evaluation of myocardial perfusion and lipids during the first six months of pravastatin therapy: Coronary artery disease regression single photon emission computed tomography monitoring trial J. Am. Coll. Cardiol., August 20, 2003; 42(4): 600 - 610. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. J. Stewart, D. Badenhop, P. H. Brubaker, S. J. Keteyian, and M. King Cardiac Rehabilitation Following Percutaneous Revascularization, Heart Transplant, Heart Valve Surgery, and for Chronic Heart Failure Chest, June 1, 2003; 123(6): 2104 - 2111. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. P. Schafers, T. J. Spinks, P. G. Camici, P. M. Bloomfield, C. G. Rhodes, M. P. Law, C. S.R. Baker, and O. Rimoldi Absolute Quantification of Myocardial Blood Flow with H215O and 3-Dimensional PET: An Experimental Validation J. Nucl. Med., August 1, 2002; 43(8): 1031 - 1040. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S.-J. Rim, H. Leong-Poi, J. R. Lindner, K. Wei, N. G. Fisher, and S. Kaul Decrease in Coronary Blood Flow Reserve During Hyperlipidemia Is Secondary to an Increase in Blood Viscosity Circulation, November 27, 2001; 104(22): 2704 - 2709. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Hernandez-Pampaloni, F. Y.J. Keng, T. Kudo, J. S. Sayre, and H. R. Schelbert Abnormal Longitudinal, Base-to-Apex Myocardial Perfusion Gradient by Quantitative Blood Flow Measurements in Patients With Coronary Risk Factors Circulation, July 31, 2001; 104(5): 527 - 532. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M Fujiwara, T Tamura, K Yoshida, K Nakagawa, M Nakao, M Yamanouchi, N Shikama, T Himi, and Y Masuda Coronary flow reserve in angiographically normal coronary arteries with one-vessel coronary artery disease without traditional risk factors Eur. Heart J., March 2, 2001; 22(6): 479 - 487. [Abstract] [PDF]
|
|
|
|
|
|
P. A. Kaufmann, T. Gnecchi-Ruscone, K. P. Schafers, T. F. Luscher, and P. G. Camici Low density lipoprotein cholesterol and coronary microvascular dysfunction in hypercholesterolemia J. Am. Coll. Cardiol., July 1, 2000; 36(1): 103 - 109. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Schwitter, T. DeMarco, S. Kneifel, G. K. von Schulthess, M. C. Jorg, H. Arheden, S. Ruhm, K. Stumpe, A. Buck, W. W. Parmley, et al. Magnetic Resonance-Based Assessment of Global Coronary Flow and Flow Reserve and Its Relation to Left Ventricular Functional Parameters : A Comparison With Positron Emission Tomography Circulation, June 13, 2000; 101(23): 2696 - 2702. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Yokoyama, S.-i. Momomura, T. Ohtake, K. Yonekura, W. Yang, N. Kobayakawa, T. Aoyagi, S. Sugiura, N. Yamada, K. Ohtomo, et al. Improvement of Impaired Myocardial Vasodilatation Due to Diffuse Coronary Atherosclerosis in Hypercholesterolemics After Lipid-Lowering Therapy Circulation, July 13, 1999; 100(2): 117 - 122. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Guethlin, A. M. Kasel, K. Coppenrath, S. Ziegler, W. Delius, and M. Schwaiger Delayed Response of Myocardial Flow Reserve to Lipid-Lowering Therapy With Fluvastatin Circulation, February 2, 1999; 99(4): 475 - 481. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. J. Bache Vasodilator Reserve : A Functional Assessment of Coronary Health Circulation, September 29, 1998; 98(13): 1257 - 1260. [Full Text] [PDF]
|
|
|
|
|
|
G. S. Huggins, R. C. Pasternak, N. M. Alpert, A. J. Fischman, and H. Gewirtz Effects of Short-Term Treatment of Hyperlipidemia on Coronary Vasodilator Function and Myocardial Perfusion in Regions Having Substantial Impairment of Baseline Dilator Reverse Circulation, September 29, 1998; 98(13): 1291 - 1296. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Campisi, J. Czernin, H. Schoder, J. W. Sayre, F. D. Marengo, M. E. Phelps, and H. R. Schelbert Effects of Long-term Smoking on Myocardial Blood Flow, Coronary Vasomotion, and Vasodilator Capacity Circulation, July 14, 1998; 98(2): 119 - 125. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. M. Beard, R. J. Barnard, D. C. Robbins, J. M. Ordovas, and E. J. Schaefer Effects of Diet and Exercise on Qualitative and Quantitative Measures of LDL and Its Susceptibility to Oxidation Arterioscler. Thromb. Vasc. Biol., February 1, 1996; 16(2): 201 - 207. [Abstract] [Full Text]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||