(Circulation. 1997;96:741-747.)
© 1997 American Heart Association, Inc.
Articles |
Association of Angiotensin-Converting Enzyme Gene I/D Polymorphism With Change in Left Ventricular Mass in Response to Physical Training
From The Hatter Institute for Cardiovascular Research University College, London Medical Schools, University College Hospital, London (H.E.M., C.M.D., M.G., J.R.M.); Department of Vascular Physiology, Great Ormond Street Hospital, London (J.D., P.C.); Department of Cardiological Sciences, St Georges Hospital, London (K.P., M.-A.L., D.S., A.V., W.J.M.); Cardiovascular Genetics Unit, Department of Medicine, Rayne Institute, University College, London Medical Schools, London (P.T., S.H.); Army Training Regiment, Bassingbourn, Herts (M.J.); Royal Army Medical College, Millbank, London (M.W.); and Department of Epidemiology and Public Health, UCLMS, London WCIE (H.H.), UK.
Correspondence to Dr Hugh Montgomery, BSc, MB BS, MRCP, Hatter Institute for Cardiovascular Research, Department of Cardiology, UCH, Grafton Way, London WC1E 6DB, UK.
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Abstract |
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Background The absence (deletion allele [D]) of a 287–base pair marker in the ACE gene is associated with higher ACE levels than its presence (insertion allele [I]). If renin-angiotensin systems regulate left ventricular (LV) growth, then individuals of DD genotype might show a greater hypertrophic response than those of II genotype. We tested this hypothesis by studying exercise-induced LV hypertrophy.
Methods and Results Echocardiographically determined LV dimensions and mass (n=140), electrocardiographically determined LV mass and frequency of LV hypertrophy (LVH) (n=121), and plasma brain natriuretic peptide (BNP) levels (n=49) were compared at the start and end of a 10-week physical training period in male Caucasian military recruits. Septal and posterior wall thicknesses increased with training, and LV mass increased by 18% (all P<.0001). Response magnitude was strongly associated with ACE genotype: mean LV mass altered by +2.0, +38.5, and +42.3 g in II, ID and DD, respectively (P<.0001). The prevalence of electrocardiographically defined LVH rose significantly only among those of DD genotype (from 6 of 24 before training to 11 of 24 after training, P<.01). Plasma brain natriuretic peptide levels rose by 56.0 and 11.5 pg/mL for DD and II, respectively (P<.001).
Conclusions Exercise-induced LV growth in young males is strongly associated with the ACE I/D polymorphism.
Key Words: angiotensin • mortality • genetics • hypertrophy
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Introduction |
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Increased LV mass is associated with excess cardiovascular mortality.1 The mechanisms that regulate myocardial mass and their genetic control are poorly understood.2 Local renin-angiotensin systems within LV tissue may regulate myocardial growth through the local generation of angiotensin II,3 although difficulties in obtaining LV tissue from normal individuals impede further examination of their importance to human cardiac growth. However, such investigations have been aided by the discovery of a polymorphism of the ACE gene comprising the presence (insertion allele [I]) or absence (deletion allele [D]) of a 287-bp marker in intron 16 of the ACE gene. The D allele is associated with elevated ACE levels in ventricular tissue as well as in the circulation.4 5 Past investigations of the association of ACE I/D polymorphism with LV mass have provided conflicting results.6 7 8 9 10 11 However, none have prospectively addressed the role of ACE genotype in the control of LV growth. We performed such a prospective study. If cardiac renin-angiotensin systems are important regulators of myocardial growth, then individuals with higher cardiac ACE levels may be expected to exhibit a greater response to a hypertrophic stimulus such as physical training.12 13 We therefore postulated that the D allele would be associated with a greater increase in LV mass in response to training than the I allele. LV growth in those of different genotypes was assessed in military recruits through the use of echocardiography and two additional independent methods: ECG and changes in levels of a cardiac hormone associated with LV growth (BNP).14 15
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Methods |
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Study Population
This study was conducted with Army Medical Services Research Executive (ethical committee) approval, and written informed consent was obtained from each participant. The study population comprised all 460 consecutive males recruited to the Army Training Regiment Bassingbourn, UK, over a 9-month period. All were normotensive and free of cardiovascular disease and underwent an identical 10-week period of intensive strength and endurance training. At entry, height, weight, and the time taken to complete a standard 1.5-mile run at maximal exertion were recorded, and venous blood samples were drawn. On the first day of training (pretraining data) and again 10 weeks later (post-training data), BP (mean of three manual measurements after 5-minute supine rest, each 1 minute apart) was documented, and transthoracic echocardiography was performed. In one random training cohort, blood was taken for assay of BNP, and a 12-lead ECG recording was performed before and after training. Only subjects who completed training without interruption were included in follow-up.
Assessment of LV Mass and Growth
LV growth was assessed echocardiographically and
confirmed through two additional independent methods.
Echocardiographic Methods
LV mass was determined by
echocardiography (Acuson 128/XP10 c/Hewlett Packard
Sonos 2500; 2.5- to 3-MHz probes) performed according to strict
protocol by experienced technicians. All subjects lay in a standard
left-lateral position to negate the influence of body position on
calculated LV mass.16 Septal and posterior wall
thicknesses and LV end-diastolic dimension were measured
(two-dimensional LV short-axis views at the level of the mitral valve
leaflet tips; American Society of Echocardiography
protocols).17 Echocardiograms were analyzed
unpaired and in random order. Measurements were expressed as the mean
of three readings made independently by each of two observers blinded
to ACE genotype and training status. LV mass was
calculated as suggested by Devereux and coworkers18 and
adjusted for height and surface area.19 Only
echocardiograms considered technically excellent by both observers were
analyzed.
ECG Methods
With the subjects supine, standard 12-lead ECGs were
recorded using the Marquette MAC VU (C)-12SL machine (Marquette
Electronics). Simultaneous lead recordings were
made over a 10-second period (paper speed, 25 mm/s; 40- to 150-z
frequency; 10 mm/mV gain), and data were stored on computer disc
and analyzed using MUSE software (Marquette Electronics). LVMI
was calculated from paired ECG data using the Rautaharju
equation.20 An increase in calculated LVMI of >5
g/m2 was chosen empirically as a measure of
significant LV growth. Sokolow-Lyon criteria (SV1 + the
greater of RV5 or RV6 >3.5 mV) were used to
define the presence of LVH.21
Assay of BNP
Fifteen milliliters of venous blood was drawn into cooled tubes
containing 100 µL EDTA and 100 µL Aprotinin (Bayer) The samples
were immediately centrifuged (4°C at 3000 rpm for 10
minutes), and the plasma was separated and placed on dry ice for 
4
hours before storage at -80°C. Within 3 months, BNP was recovered
(65% to 88%) and assayed by radioimmunoassay (Peninsula Laboratories)
as previously described.22 All samples were
analyzed on the same day to minimize any slight variations in
extraction procedure or reagent quality. The technician was blinded to
the timing of the sample and subject genotype. The minimum
concentration detected was 1.25 pg/mL.
Assessment of ACE Polymorphism Genotype
The 5-ml blood samples were drawn into tubes containing EDTA,
and ACE gene I/D polymorphism was determined
using a three-primer system,23 which eliminates
mistyping24 that can occur with a two-primer
system.4 Primer ratios correspond to the 50 pmol
ACE1 (5' or left-hand oligo) and 3 (3' or right-hand oligo)
and 15 pmol (insertion-specific oligonucleotide)
ACE2 in a 50-µL reaction, giving amplification
products of 84 bp for allele ACE D and 65 bp for
allele ACE I. Reactions were overlaid with 20 µL
mineral oil. All 96 wells were always filled with reagents (mix or
dummy reagents) to ensure constant thermal mass on the block.
Amplification products were visualized using 7.5%
polyacrylamide gels. Genotyping accuracy was confirmed under
conditions previously reported,25 such that replica PCRs
set up using only the primer pair ACE1 and ACE3,
both at 8 pmol/20 µL PCR, always confirmed the presence of the
D allele.
Statistical Analysis
Interobserver measurements of LV dimension agreed closely; 92%
to 98% lay within ±1.96 SDs of the mean of the two measures, and
Bland-Altman plot suggested no systematic differences between paired
measurements by each observer.26 The mean of the two
observers' measurements was therefore used in all analyses.
Difference between pretraining and post-training measurements of BP and
LV dimensions and mass were calculated for each subject. Data were
analyzed for the study population as a whole, and differences
in response between different genotype groups were compared.
Pretraining and post-training data were compared using two-tailed
paired t tests. Mean changes between groups and their
statistical significance were compared with ANOVA. Changes in
biological variables cannot be analyzed by studying simple
differences alone, as the magnitude of the change may be influenced by
baseline values27 28 ; therefore, ANOVA was used to adjust
for the potential confounding effects of pretraining LV mass, as well
as for age and systolic BP. Differences in proportions were
assessed with the McNemar 
2 statistic for paired
data. Values of P<.05 were considered to be statistically
significant. All analyses were performed with SAS
software.29
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Results |
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Echocardiographic Data
All of the 460 eligible subjects agreed to participate in the study, and ACE genotype was obtained in 458; 150 failed to complete training. Paired echocardiograms suitable for analysis were obtained in 140 of the remaining subjects. The physical characteristics (mean±SD) of those studied (age, 18.9±2.1 years; height, 176±6.1 cm; weight, 67.7±11.1 kg; systolic BP, 120±10.9; diastolic BP, 71±9.7 mm Hg) did not differ from those excluded and were the same across genotypes. The genotype distribution ( II, 34 [24.3%]; ID, 77 [55%]; DD, 29 [20.7%]) did not differ between those studied and those ultimately excluded from final analysis (P=.67). BPs before training (systolic BP, 120±10.9 mm Hg; diastolic BP, 71±9.7 mm Hg) and after training (systolic BP, 121±10.6 mm Hg; diastolic BP, 69±9.7 mm Hg) did not differ (P=.50 and .31, respectively). Resting heart rates were 69±7 and 71±6 bpm before and after training, respectively, and were similar across genotypes.
Pretraining LV dimensions are shown by genotype in the first
column of Table 1
.
End-diastolic dimension differed between genotypes
(II>DD>ID; P=.009).
Presence of the D allele was associated with a trend
toward lower initial height-adjusted and unadjusted LV mass, although
this was not statistically significant even when adjusted for
height2.7 (II>ID>DD;
P=.18 for LVM and .20 for
LVM/height2.7).19 Overall, training was
associated with LV growth (Table 1). LV dimensions increased
significantly (P<.0001 for each measure), with mean LV mass
rising from 167 to 197 g (P<.0001). The magnitude of
these changes was strongly associated with ACE
genotype. LV mass was altered by +2.0, +38.5, and +42.3 g for
II, ID, and DD genotypes,
respectively (P<.0001; Fig 1). The association of ACE
genotype with increase in LV mass persisted after adjustment
for subject height2.7 (Table 1),19 as well as
pretraining LV mass, age, and systolic BP (Fig 1). Septal
thickness changed by -0.02 versus 0.09 versus 0.15 cm and posterior
wall thickness changed by -0.02 versus 0.08 versus 0.14 cm for
II, ID, and DD, respectively
(P<.0001 in both cases.)
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Electrocardiographic Data
Pretraining and post-training ECGs (n=121) were visually reviewed
by two observers blinded to subject genotype. None of the ECGs
exhibited complete bundle-branch block or evidence of accessory pathway
conduction or myocardial infarction. The prevalence of
electrocardiographically defined LVH was genotype related,
rising from 6 of 24 before training to 11 of 24 after training in those
of DD genotype (P<.01) but from 8 of 30
to only 9 of 30 in those of II genotype. The
D allele was associated with an increase in calculated
LV mass, although this difference did not reach statistical
significance (increase of >5 g/m2 in 26.7% versus
35.8% versus 37.5% for II, ID, and
DD, respectively). Mean frontal electrical axis did not
differ with genotype or training status.
Plasma BNP
One cohort of 84 participants was randomly selected at entry for
assay of plasma BNP, of whom 49 completed training. Pretraining plasma
BNP levels did not differ between genotypes (P=.69:
Fig 2). Levels increased significantly
with training in the whole group (n=49; mean±SEM, 44.6±2.5 versus
66.4±4.7 pg/mL; P<.001), an effect strongly
associated with ACE genotype (Fig 2; for rise in BNP
levels, P<.05). Levels did not rise significantly for those
of II genotype (47.0±5.6 versus 58.4±6.3
pg/mL), rising significantly only among those with 
1
D allele (n=35; pretraining, 43.7±2.8 pg/mL;
post-training, 69.6±6.1 pg/mL; P<.0001). The rise
was greatest for those of DD genotype (mean rise,
11.5±6.3 versus 56.0±17.3 pg/mL for II versus
DD genotype, respectively; P<.01).
Post-training BNP levels, unlike pretraining levels, were associated
with ACE genotype (DD>ID and
DD>II; P<.001 for both
comparisons).
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Discussion |
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The extent of exercise-induced LV growth is strongly influenced by the I/D polymorphism of the ACE gene.
Echocardiographic Findings
An increase in LV mass of this magnitude (12.5% to 22%) with
training (P<.0001 for all measurements) is to be
expected12 13 in military recruits30 over
this time scale.31 Confounding factors such as subject age
and sex,32 33 initial fitness,34 and nature
and intensity of training program35 36 37 38 were minimized by
the application of an identical training program to a uniform study
population. Multivariate analysis confirmed a
modest influence of systolic BP on LV mass.39
However, the influence of genotype remained when
multivariate adjustment was made for the effects of
height, age, BP, and initial fitness and when data were standardized
for height and body morphology.19
Training-associated changes in resting cardiovascular hemodynamics might theoretically influence measured LVEDD and, hence, calculated LV mass. However, heart rate changes correlate poorly with LVEDD, their influence on calculated LV mass is minimal,13 30 38 40 physical training has little effect on resting cardiac output and peripheral vascular resistance,13 30 and resting heart rates were similar before and after training and were not genotype dependent. In addition, LV mass did not increase significantly more in those of DD genotype only because initial LV mass was smaller in this group (ie, exercise did not just cause hypertrophy toward a mean "fixed ceiling"). (1) Pretraining LV mass was similar across genotypes (the D allele being associated with slightly lower mass ), yet LV mass increased for those of DD genotype (P<.0001) and not II genotype, with post-training LV mass DD>II genotype, (P<.001). (2) Pretraining septal thickness differed irregularly across genotypes (ID>II>DD) but rose with training in proportion to the number of D alleles. Those of ID genotype had a pretraining septal thickness slightly greater than those of II genotype (0.97 versus 0.96 cm) yet grew more (+0.09 versus -0.02 cm, respectively). (3) The association remained after adjustment for pretraining LV mass (either directly or by adjustment of individual component measurements used to calculate LV mass). (4) BNP levels in each genotype were similar before training and were significantly different between genotypes after training.
Echocardiographic exclusion rates of >20% are not unusual in studies in which perfect image quality and axis orientation are crucial.11 Our exclusion rate (27% of echocardiograms at either the start or end of training) was perhaps increased by the rapid throughput of large numbers in confined space but was not a source of bias. Exclusions were made before genotypes were available, and the physical characteristics and ACE genotype distribution of those included and subsequently excluded from analysis did not differ.
ECG Data
Prospective examination of LV growth by ECG is
insensitive,41 as recordings depend on lead and
body position42 and vary with repeated
measurement.42 However, our ECG data support the
association of ACE genotype with LV growth and are
consistent with the findings of Schunkert et al.8
The presence or absence of a significant (dichotomous) LV hypertrophic
state was defined by voltage criteria. The use of voltage combinations
minimizes the error of repeated measures in an
individual.42 The Sokolow-Lyon voltage (SV1 +
the greater of RV5 or RV6 >3.5
mV)21 is the most reproducible of these
combinations,42 correlates best with
echocardiographic LV mass,43 and has been
previously used in studies of the ACE gene polymorphism
and LVH.8 The number of individuals with voltage-defined
LVH (LVH+) rose minimally in those of II and
ID genotypes (from 8 to 9 of 30 and from 35 to 36 of
67, respectively) but nearly doubled (from 6 to 11 ) in the 24 of
DD genotype. The bulk of this effect seems due to a
genotype-dependent influence on the number of individuals who
were initially LVH+ and who became LVH- after
training (6 of 8 [75%], 7 of 35 [20%], and 0 of 6 [0%]) for
II, ID, and DD, respectively).
Meanwhile, of the 22 individuals of II genotype
whose pretraining ECGs did not satisfy the voltage criteria for LVH
(LVH-), 7 (32%) were LVH+ after training.
This compared with 8 of 32 (25%) of the ID group and 5 of
18 (28%) of the DD group. A balance of a
genotype-dependent increase in ECG signal amplitude and
increased signal attenuation (due to training-related changes in chest
wall muscle mass, lung volume, thoracic impedance, body morphology, and
obesity44 45 ) may account for these findings. Thus, with
upper body training, increase in upper body mass would cause a greater
attenuation of the ECG signal. Unless balanced by an increase in ECG
signal strength itself (due to LV growth), LV voltages would
decline.
LVH (Sokolow-Lyon criteria, Table 2) was common,
probably due to low septum-to-skin distances43 in these
young lean individuals.46 47 48 Indeed, similar high
frequencies 8 might also be ACE
genotype dependent.9
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BNP
BNP is a peptide hormone of predominantly LV origin49
whose synthesis can be considered a marker of myocyte
growth.14 15 Raised levels are associated with
LVH50 51 and correlate with LV mass during both
hypertrophic progression and regression.52 53 Our data
strongly support the association of ACE genotype
with LV growth, with the rise in BNP levels with training being
ACE genotype dependent. Confounding factors (eg,
cardiac disease49 56 ) were eliminated. Exercise has little
influence on plasma BNP concentration54 55 56 ; all blood
samples were taken in the absence of recent exercise, and any such
effect of exercise is likely to be short-lived due to the very short
plasma half-life of BNP.57
The method of BNP recovery yields between 65% and 88% of the BNP from standardized control samples.22 Nothing suggests that extraction differed in extent in any systematic way between those of different ACE genotype.
Performance in all tests of fitness and physical performance at entry was genotype independent. No selection bias due to genotype dependence of echocardiographic image quality occurred (characteristics and genotype distribution of those whose echocardiographic data were included and ultimately excluded from analysis were similar). Further, image acceptability was not a criterion for ECG or BNP analysis, yet the genotype association held for ECG data despite the fact that almost half (60 of 121) of the individuals whose paired ECGs were analyzed were not members of the group of 140 subjected to echocardiographic analysis. Similarly, one third (11 ID, 5 DD) of the individuals used in BNP analysis were also independent of the echocardiographic data set, and the genotype association holds even for this small number: BNP levels rose with training for the 11 of ID genotype (50.93±6.16 versus 59.36±7.57 pg/mL, P>.1) but significantly more in the 5 of DD genotype (39.5±5.05 versus 76.28±12.56, P=.026; P<.05 for change in BNP for ID versus DD).
Previous studies relating ACE genotype to LV mass have been conflicting, possibly due to small size6 58 and to the confounding of cross-sectional population studies by deaths attributable to ACE genotype–associated disease, including LVH itself.1 59 60 61 More important, cardiac renin-angiotensin systems may have little basal effect but may transduce hypertrophic stimuli. Thus, the association of LV mass with ACE genotype is weak in our pretraining data and among disease-free or mixed populations11 58 but stronger in groups containing large numbers of individuals exposed to growth stimuli such as hypertension7 9 ; LV mass may correlate with systolic BP only among those of DD genotype,7 and the D allele is associated with concentric LV remodeling in hypertensives6 and LV mass and phenotypic expression in hypertrophic cardiomyopathy.10 62 Exposure to differing degrees and durations of hypertrophic stimulation might account for the lack of association of ACE genotype with LV mass in mixed populations.11
As previously suggested,6 LV geometry was ACE
genotype dependent both before (septal thickness,
ID>II>DD [P=.08];
LVEDD, II>DD>ID; P=.009;
Table 1
, column 1) and (with a different pattern) after training (Table 1, column 2); this is an important finding given the possible
association of geometry with outcome.63 64
The polymorphism does not seem to exert its effect through differences in growth hormone activity despite the proximity of the two genes,65 66 nor through effects on exercise-related heart rate or BP. Although BP measurement during training proved to be impossible, resting BPs before and after training were not influenced by ACE genotype, and the ACE gene is not associated with a predisposition to raised BP,6 65 67 68 69 70 71 72 ambulatory BP,6 72 or responsiveness of BP to environmental factors such as altered salt loading.71 Further, we have been unable to demonstrate an association between BP response to bicycle ergometric exercise and ACE genotype (data not shown). A genotype-dependent exercise-related increase in heart rate has never been demonstrated, but it cannot be excluded. It is debated whether raised cardiac angiotensin II levels would increase or actually reduce cardiac sympathetic neurotransmission.73 Perhaps the association of the ACE gene I/D polymorphism with effects on LV growth is mediated through ACE via alterations in tissue kinin metabolism or effects on angiotensin II synthesis.3 Although not statistically significant, the slight decline in baseline echocardiographic LV mass (mirrored in baseline BNP levels) with increasing numbers of D alleles is interesting to note but hard to explain. Perhaps ACE is not the rate-limiting step in basal angiotensin II generation but becomes so with hypertrophic stimulation, with expression of renin-angiotensin system components subject to interactive feedback. Certainly, both experimental pressure and volume loading may increase myocardial ACE.74 75 76
Exercise-related LV growth is influenced by sex and age32 33 and (unlike that associated with disease states) is associated with improved myocardial function.38 ACE genotype thus may not be associated with physiological hypertrophy in all groups or with pathophysiological hypertrophy. However, these findings are consistent with a role for paracrine renin-angiotensin systems in the control of LV growth,3 77 78 79 whose inhibition may partly account for the effect of ACE inhibitors in reducing myocardial mass.80
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Acknowledgments |
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This work was supported by an unconditional educational grant from Hoechst-Marion-Roussel (UK) and Acuson (Middlesex, UK). Drs Montgomery and Statters are supported by the British Heart Foundation, Dr Dollery is supported by the Medical Research Council, and Dr Losi is supported by the Societa Italiana di Cardiologia. We are indebted to A.T.R. Bassingbourn; Major Simon Davies; Harry Hindle; Nick Routledge (Marquette Electronics) for ECG recording and analysis equipment; Nancy Breckenridge, Paul Young, Liz Hollman, and Hewlett-Packard UK for echocardiography machines and peripherals; and Graham Leech. Keith White and Acuson UK provided echocardiography machines and technical support. Technical assistance was provided by Teresa Bull, Ann Donald, Anita Gebbels, Annette Jones, Sally Nunn, John Pither, Amanda Powe, Gill Smith, Danielle Spicer, and Chris Wisbey
Received December 4, 1996; revision received February 26, 1997; accepted February 28, 1997.
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J. M. Hagberg, R. E. Ferrell, S. D. McCole, K. R. Wilund, and G. E. Moore VO2 max is associated with ACE genotype in postmenopausal women J Appl Physiol, November 1, 1998; 85(5): 1842 - 1846. [Abstract] [Full Text] [PDF]
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R. Alvarez, J. R Reguero, A. Batalla, G. Iglesias-Cubero, A. Cortina, V. Alvarez, and E. Coto Angiotensin-converting enzyme and angiotensin II receptor 1 polymorphisms: association with early coronary disease Cardiovasc Res, November 1, 1998; 40(2): 375 - 379. [Abstract] [Full Text] [PDF]
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