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Department of Cardiology, University Hospital, CH-3010 Bern, Switzerland
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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In eight healthy
male volunteers (cardiologists; age 36 ± 5 yr), bicycle
spiroergometry, Doppler echocardiography, and quantitative coronary
angiography with intracoronary Doppler measurements before and after
completion of a physical endurance exercise program of >5 mo duration
were performed. Maximum oxygen uptake increased from 46 ± 6 to
54 ± 5 ml · kg
1 · min1
(P = 0.04), maximum ergometric workload changed from
3.8 ± 0.3 to 4.4 ± 0.3 W/kg (P = 0.001),
and left ventricular mass index increased from 82 ± 18 to
108 ± 29 g/m2 (P = 0.001). The right,
left main, and left anterior descending coronary artery cross-sectional
area increased significantly in repsonse to exercise. Before versus at
the end of the exercise program, flow-induced left anterior descending
coronary artery cross-sectional area was 10.1 ± 3.5 and 11.0 ± 3.9 mm2, respectively (P = 0.03),
nitroglycerin-induced left coronary calibers increased significantly,
and coronary flow velocity reserve changed from 3.8 ± 0.8 to
4.5 ± 0.7 (P = 0.001). Left coronary artery
correlated significantly with ventricular mass and maximum oxygen
uptake, and coronary flow velocity reserve was significantly associated
with maximum workload.
coronary circulation; endothelial function; exercise
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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CARDIOVASCULAR DISEASES, in particular, coronary artery disease (CAD), represent the leading cause (>40%) of death in industrialized countries (16). Meta-analysis studies (15) of the effects of exercise training on morbidity and mortality in patients after myocardial infarction concluded that regular physical exertion favorably influenced mortality but not reinfarction. Possibly even more important, increased occupational or recreational physical activity reduces the risk of cardiac death in individuals who have not yet shown manifestations of CAD, i.e., primary prevention (1). Hence, physical exercise is recommended for both primary (3) and secondary (25) prevention of cardiovascular disease.
Despite the epidemiologic data that strongly supports the existence of a relation between exercise and reduced risk of CAD, clinical evidence for the mechanisms responsible for this association has been provided only recently and exclusively in the case of secondary prevention (4). Aside from the favorable effect of exercise on the severity of cardiovascular risk factors such as hypertension, diabetes, hypercholesterolemia, or obesity (25), exercise appears to be cardioprotective independently of the traditional risk factors (12). Hambrecht et al. (4) provided evidence for a link between endothelial function and exercise training in patients with CAD by directly documenting that a 4-wk exercise training improved endothelium-dependent vasodilatation both in coronary epicardial and resistance vessels. A thorough longitudinal investigation in humans on the mechanisms related to the primary preventive effect of endurance exercise on CAD is lacking so far. The only available preliminary data pertain to a cross-sectional comparison of coronary artery sizes between endurance athletes and hypertensive patients undergoing diagnostic coronary arteriography (5).
Therefore, the purpose of this study in healthy young volunteers without cardiovascular risk factors was to quantify the changes in coronary artery size and function (i.e., endothelium-dependent and -independent coronary vasomotion and coronary flow reserve) in response to regular physical endurance exercise.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Study subjects. Eight healthy volunteers (male cardiologists; age 36 ± 5 yr) without cardiovascular risk factors (except for one occasional smoker) consented to participate in the study. Each individual served as his own control. All subjects underwent plasma lipid level assessment, bicycle spiroergometry, Doppler echocardiography, and coronary angiography with intracoronary Doppler guidewire measurements before and after completion of a physical endurance exercise program of at least 5 mo.
Endurance exercise program.
The exercise program consisted of running or cycling at least 4 times
per wk for a duration of at least 60 min per session over a minimal
time period of 5 mo. Target heart rate during the sessions was required
to be 80% of the heart rate at peak oxygen consumption
(
O2 max;
ml · min1 · kg body wt1)
determined during spiroergometry before the exercise program. A survey
of the exercise program was performed by digital pulse recording and by
repeat spiroergometry at the end of the exercise program (termed
"after exercise").
Bicycle spiroergometry.
Before each spiroergometry, the weight of the subject was determined. A
venous blood sample was taken for the determination of plasma lipid
levels. By using a protocol with workloads starting at 125 W and
increasing every 3 min by 25 W, bicycle spiroergometry was performed
until the subjects reached exhaustion. During ergometry, O2 max was continuously measured via a
face mask, heart rate was recorded constantly, and sphygmomanometric
blood pressure was obtained every 3 min. Maximum workload was defined
as the peak workload sustained over the entire 3 min of a particular workload level.
Doppler echocardiography. Doppler echocardiographic exams were performed within 1 day before or after spiroergometry and coronary angiography with the use of a Sequoia C256 (Acuson; Mountain View, CA) with a 4-MHz transducer with second harmonic imaging and Doppler tissue imaging technology. Subjects were in supine, left lateral position, and underwent conventional M-mode and two-dimensional echocardiography from a left parasternal and apical window. M-mode measurements of the left ventricle were obtained in triplicate at end diastole and end systole, according to the recommendations of the American Society of Echocardiography (18). The measurements included septal and posterior wall thickness and left ventricular and left atrial cavity dimensions, according to the leading-edge method. Left ventricular mass was determined according to the cube formula by using end-diastolic values of septal and posterior wall thickness and left ventricular cavity dimension (26). Left ventricular volume measurements for the calculation of left ventricular ejection fraction were performed in biplane projection from apical two- and four-chamber views (20). Left ventricular volumes were computed using the biapical Simpson rule.
The purpose of assessing left ventricular diastolic function was to exclude the development of impaired ventricular relaxation during exercise-induced increase of left ventricular mass. Left ventricular diastolic function was assessed from the apical four-chamber view using transmitral Doppler flow velocity and mitral annular motion velocity measurements (13). The pulsed-wave sample volume of the conventional Doppler was placed at the tips of the mitral leaflets. The obtained variables included peak flow velocity (E, m/s) and deceleration time (ms) of early diastolic transmitral filling, peak flow velocity (A, m/s) of late diastolic transmitral filling, and isovolumetric relaxation time (ms). Mitral annular motion velocity during early diastole (cm/s) was performed using Doppler tissue imaging with the pulsed-wave sample volume placed at the septal, lateral, inferior, and anterior mitral annulus from the apical four- and two-chamber view, respectively. The respective values obtained at these locations were averaged. Early diastolic mitral annular motion velocities
8 cm/s have been documented to accurately detect impaired
left ventricular relaxation independent of cardiac loading conditions
(13).
Quantitative coronary angiography.
All subjects underwent biplane coronary angiography from the right
femoral artery approach using 5-Fr right and left Judkins coronary
catheters. Care was taken to use identical right anterior oblique and left anterior oblique projections as well as X-ray focal
spot-to-image-intensifier distances during the baseline and the
followup exams. Digitized end-diastolic frames were analyzed with the
use of an automatic contour edge-detection algorithm (24).
Coronary artery calibers were measured quantitatively using the
coronary catheter for calibration. Measurements were performed over a
distance of 4-8 mm in triplicate and averaged at each location.
End-diastolic coronary artery diameters were obtained at the left main,
the proximal, mid and distal segment of the right, the proximal and
midsegment of the left anterior descending (LAD), and the proximal and
midsegment of the left circumflex (LCX) coronary artery. Coronary
artery cross-sectional area was calculated as both half diameters × 
(ellipse formula). Two coronary side branch landmarks were used
to reproduce identical measurement sites during both exams. The latter
were chosen midway between the side branches.
Coronary Doppler flow velocity measurements. As a coronary microvascular function parameter, adenosine-induced (see Study protocol of invasive exams) coronary flow velocity reserve (CFVR) was determined with a 0.014" Doppler angioplasty guide wire featuring a 12-MHz piezoelectric crystal at its tip (Flowire, Endosonics; Mountain View, CA) placed in the mid LAD and LCX. The Doppler guidewire has been validated to measure phasic flow velocity patterns accurately and to track changes in flow rate linearly (2). CFVR was determined by dividing maximum hyperemic peak flow velocity [induced by 18 µg intracoronary adenosine bolus (29)] averaged over three cardiac cycles by average peak flow velocity during resting conditions. During CFVR measurements (in triplicate), the epicardial coronary artery caliber was maintained constant by pretreatment with 200 µg of intracoronary nitroglycerin.
Study protocol of invasive exams Before coronary angiography was performed, 5,000 units of intravenous heparin were given. Biplane coronary angiography of the right and the left coronary artery was performed without any vasoactive drugs. Subsequently, an interval of 10 min was allowed for dissipation of the vasomotor effect of the nonionic contrast medium (Ioversol 300). Left coronary angiography was repeated immediately after injection of a bolus of 18 µg of adenosine via the left coronary Judkins catheter. Again, a 10-min interval was allowed after coronary angiography with adenosine. Subsequently, an intracoronary bolus of 200 µg of nitroglycerin was given. Biplane left coronary angiography was repeated immediately afterward. The Doppler guidewire was then placed in the mid-LAD via the diagnostic 5-Fr Judkins catheter. CFVR was determined by flow velocity measurements during resting conditions and during hyperemia after intracoronary bolus injection of 18 µg of adenosine. CFVR measurements were performed in triplicate and averaged. The Doppler guidewire was then placed in the mid LCX, and CFVR measurements were performed identically (i.e., a total of 6 measurements per subject and exam). Coronary flow velocity was monitored continuously on videotape during the entire procedure of Doppler measurements.
Statistical analysis. Intraindividual comparisons between the exams before and after the exercise program of continuous allometric, hemodynamic, spiroergometric, echocardiographic, and invasive data were performed by a paired Student's t-test. Curvilinear (i.e., power equation fitting) and linear regression analysis was used for assessing the relation between left main coronary artery caliber and CFVR, and left ventricular mass, exercise endurance, and maximum workload, respectively. Linear regression analysis with calculation of the standard error of estimate (SEE) was used to determine the variability between repetitive measurements at baseline and followup. Means ± SD are given. Statistical significance was defined at P < 0.05.
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RESULTS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Subject characteristics.
All individuals finished the exercise program and underwent complete
followup exams after a duration of 9 ± 5 mo. None of the subjects
was under treatment with medication. Body weight and surface area
decreased significantly during the exercise period (Table
1). Resting heart rate and systemic blood
pressure obtained immediately before Doppler echocardiography did not
change during the exercise period. Plasma total cholesterol levels
tended to decrease, whereas high- and low-density lipoprotein
cholesterol as well as triglyceride levels remained constant (Table 1).
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Bicycle spiroergometry.
There were no statistically significant differences in minimal or
maximally achieved heart rate or systemic blood pressure during
ergometry within the individuals before versus after the exercise
program (Table 2). Maximum
O2 normalized for body weight, maximum
ergometric workload, and maximum workload per body weight increased
significantly during the exercise period (Table 2).
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Doppler echocardiography.
End-diastolic interventricular septal and posterior wall thickness of
the left ventricle and left ventricular mass as well as mass index
increased significantly during the exercise program (Table
3). The SEE between the two of three
measurements of left ventricular mass index farthest apart was 15 g/m2 at baseline and 12 g/m2 at followup (18%
and 11% of the respective mean value). End-diastolic and end-systolic
left ventricular and left atrial diameter, respectively, as well as
ejection fraction were not altered significantly. Despite the
ventricular hypertrophic response occurring in all study individuals (one of them reaching the definition for left ventricular hypertrophy, i.e., >134 g/m2 of body surface area), all transmitral and
mitral annular Doppler parameters for diastolic function remained
normal and statistically unchanged during the exercise program (Table
3).
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Coronary artery structural and functional data.
All of the individuals had right dominant coronary artery circulation.
The SEE between the two of three measurements of coronary artery
diameter farthest apart was 0.02 mm at baseline and 0.01 mm at followup
(0.7% and 0.3% of the respective mean value). In the absence of any
vasoactive drug, coronary artery cross-sectional areas at all except
two measurement sites (distal right coronary artery and LCX) increased
significantly in response to the exercise program (Table
4 and Fig.
1). The combined left main plus proximal right coronary artery cross-sectional areas normalized for 100 g
of left ventricular myocardial mass was 17.5 ± 6.1 mm2 before and 16.7 ± 5.5 mm2 after the
exercise program (P = not significant).
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O2 and the corresponding
nitroglycerin-induced left main coronary artery calibers (Fig.
3).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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This study in healthy young male volunteers without cardiovascular disease or risk factors documents for the first time that epicardial coronary artery size and vasodilatation increase, and that the capacity to augment coronary flow during hyperemia improves in response to a sustained endurance exercise program. These changes go hand in hand with a physiological hypertrophic response of the left ventricle and with improved endurance and maximum workload capacity.
Exercise-induced alterations of vascular structure and associated changes. In this context, the questions may be raised whether an increase in size is a structural vascular remodeling or whether it is a chronic vasodilatation, and, more importantly, whether regarding coronary artery size "bigger is really better" (11).
Control of vascular diameter by instantaneous flow alterations is an acute phenomenon which was first described by Schretzenmayr (21). It obviously precedes structural changes in response to chronic blood flow alterations (14). Our endurance exercise program was associated with bigger coronary arteries at 28 of a total of 32 proximal coronary angiographic measurement sites (Fig. 1). The finding of enlarged nitroglycerin-induced arterial caliber after the exercise program indicates structural adaptation of the coronary arteries. Data from various animal models indicate that vigorous endurance exercise training enlarges the diameter of coronary arteries (10, 30) and that increases in the canine carotid artery blood flow leading to a bigger vessel is related to an increased rate of protein turnover (7). In the precise sense of "structural alterations," only the latter investigation provides evidence that actual arterial remodeling occurs as an adaptive response to increased flow. Flow-mediated vasodilatation (i.e., function, see below) is vascular endothelium dependent, and so is flow-mediated vascular remodeling. Langille and O'Donnell (8) found that a long-term decrease in flow through the rat carotid artery causes the vessel to "shrink," a response which is abolished by removal of the endothelium. One possible concept underlying this flow-adapted remodeling of vascular structure is that of the maintenance of flow-related shear forces within certain limits, a basic principle that has been documented to apply also to the human coronary artery tree (24). So far, no information has been available from longitudinal secondary or primary prevention studies about the effect of exercise training on absolute coronary artery caliber. Hambrecht and co-workers (4) did not provide absolute coronary artery caliber data of their patients with CAD undergoing a 4-wk intensive exercise program. Considering the above-mentioned experimental investigations, it can be speculated that the duration of their exercise program was too short to produce vascular caliber increase at rest. Surprisingly, Haskell et al. (5) found in their cross-sectional angiographic study no statistical difference in coronary artery calibers between ultradistance runners and inactive men without coronary artery stenoses. Although normotensive athletes who ran >4,000 km per year had concentric left ventricular hypertrophy, systemic arterial hypertension also led to increased left ventricular mass among control patients. This may explain the similar coronary artery calibers in the two groups. To account for the fact that exercise-induced hypertrophic response was physiological in our study and not pathological with disturbed ventricular relaxation, as it occurs in hypertensive heart disease, diastolic left ventricular function was assessed and found to remain normal after exercise training. Several lines of evidence in our study support the concept suggested above of an association between coronary artery caliber and left ventricular mass. Whereas the largest exercise-related increases in coronary artery caliber among our study individuals with exclusively right dominant coronary arteries occurred in the left main and proximal right coronary artery, no caliber changes were observed in the small left circumflex coronary arteries. All but one individual showed concordant increases in coronary artery caliber and left ventricular mass, and the observed relation between vessel caliber and ventricular mass (Fig. 2) was close to the two-thirds power relation theoretically predicted by the law of minimum viscous energy loss in the transport of blood (24). Aside from variations in left ventricular mass, variable levels of endurance (i.e.,O2 max, Fig. 3) were related to
coronary artery calibers in our study, whereby both together accounted for less than one-half of the statistical variability in vessel calibers.
With respect to the initially raised question whether bigger coronary
artery calibers are better, the considerations outlined favor the
notion that larger calibers, irrespective of functional characteristics
represent just an adaptive response to increased left ventricular mass
and to enhanced myocardial O2 with
augmented flow. Conversely, improved endothelium-dependent function of
the coronary arteries seems to actually confer an outcome benefit as
recent data have indicated (19).
Exercise-induced changes in coronary artery function and associated alterations. Endothelial vasodilator dysfunction has been observed in patients with cardiovascular risk factors, even in the absence of overt atherosclerotic lesions (23, 27). Endothelial function has been hypothesized to serve as an indicator reflecting the overall stress imposed by coronary risk factors (28). So far, it has been unknown whether in entirely healthy young men correction of sedentary lifestyle is associated with improved coronary vasomotion. Two aspects of coronary vasomotor function were tested in our study, namely, flow-mediated (i.e., mostly nitric oxide mediated) epicardial vasodilatation and microvascular function. Both flow-induced epicardial vasodilatation and coronary flow reserve improved in response to the exercise program. Because vasodilatation in response to increased flow is mediated by release of nitric oxide (6, 17), flow-induced vasodilatation as it occurred at proximal sites of the left coronary artery in our study is regarded as endothelium dependent. However, biosynthesis or bioavailability of nitric oxide was not directly measured in our study. Thus the term "endothelium dependent" cannot be used strictly; the greater flow-mediated vasodilation after the exercise program might have resulted from enhanced vascular smooth muscle sensitivity to nitric oxide without altered availability of the latter. To keep the invasive study protocol simple in our individuals without cardiovascular disease or risk, standard testing of endothelium-dependent coronary vasomotor function by acetylcholine (31), a substance that causes direct release of nitric oxide, was not performed. The clinical relevance of endothelial vasodilator dysfunction among patients at risk of coronary atherosclerosis has been recently demonstrated by showing that it is predictive of future cardiovascular events irrespective of a specific mechanism (i.e., acetylcholine, flow, or sympathetically mediated) to mediate endothelium-dependent vasodilatation (19). A beneficial primary preventive effect of improved endothelium-dependent vasodilatation in response to exercise cannot be directly extrapolated on the basis of the mentioned study, but the mechanism mediating the effect seems to be identical.
Endothelium-independent vasodilatation using nitroglycerin was improved in our trained individuals in keeping with the study of Haskell et al. (5). However, the improved nitroglycerin-induced dilatation of coronary arteries of trained athletes in the study by Haskell et al. (5) was not documented compared with an untrained baseline status in the same individuals, but rather versus a sedentary hypertensive control population with pathological left ventricular hypertrophy. The 4-wk endurance-training period employed in the study by Hambrecht et al. (4) among patients with CAD revealing no beneficial effect on endothelium-independent vasomotion indicates that high-intensity training over a longer period may be necessary to increase the capacity of coronary vessels for endothelium-independent dilatation. Improved vasodilating capacity of the microcirculation in response to exercise training has been documented experimentally (9), and, very recently, in patients with CAD (4), but not in the setting of primary cardiovascular prevention. Adenosine-induced coronary flow reserve before the exercise program was markedly lower than the values ~4.5 in the left coronary artery described by Wilson et al. (29). This is surprising because somewhat unhealthy patients with chest pain and fairly well-trained persons underwent diagnostic coronary angiography in that study. The finding that it is the maximally achievable workload (normalized for body weight) that is directly associated with the maximally attainable coronary blood flow is original, and it makes sense intuitively. Furthermore, our data are physiologically plausible in that the coronary flow reserve achieved in the absence of any physical work does not fall below 1, a value indicating coronary steal which does not occur in a normal coronary circulation (22).Study limitations. Aside from the limitations alluded to above, the low number of study individuals included is of relevance. This is reflected in increased coronary artery calibers after exercise, which at some measurement sites did not reach statistical significance, a fact that most likely could have been corrected by investigating more subjects. The pool of healthy young men interested in engaging in a long-term exercise program and willing to undergo two coronary angiograms with intracoronary measurements is limited particularly because only cardiologists were eligible as they had to be fully cognizant of the potential risks of the study.
In conclusion, regular physical endurance exercise in young men without cardiovascular disease or risk factors results in an adaptive increase of epicardial coronary artery calibers, in improved vasodilatation, and in enhanced hyperemic microcirculatory reserve.| |
FOOTNOTES |
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Address for reprint requests and other correspondence: C. Seiler, Professor of Cardiology, Swiss Cardiovascular Center Bern, Univ. Hospital, Freiburgstrasse, CH-3010 Bern, Switzerland (E-mail: christian.seiler.cardio{at}insel.ch).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
First published February 14, 2002;10.1152/ajpheart.00977.2001
Received 12 November 2001; accepted in final form 31 January 2002.
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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 A. Indermuhle, R. Vogel, P. Meier, S. Wirth, R. Stoop, M. G. Mohaupt, and C. Seiler The relative myocardial blood volume differentiates between hypertensive heart disease and athlete's heart in humans Eur. Heart J., July 1, 2006; 27(13): 1571 - 1578. [Abstract] [Full Text] [PDF]
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U. Hagg, B. Wandt, G. Bergstrom, R. Volkmann, and L.-m. Gan Physical exercise capacity is associated with coronary and peripheral vascular function in healthy young adults Am J Physiol Heart Circ Physiol, October 1, 2005; 289(4): H1627 - H1634. [Abstract] [Full Text] [PDF]
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