(Circulation. 2001;103:226.)
© 2001 American Heart Association, Inc.
Clinical Investigation and Reports |
Left Ventricular Hypertrophy With Exercise and ACE Gene Insertion/Deletion Polymorphism
A Randomized Controlled Trial With Losartan
From the Centre for Cardiovascular Genetics (S.G.M., H.E.M., S.E.H.), University College London, London, UK; Royal Defence Medical College (M.W., M.J., M.J.W.), Gosport, Hampshire, UK; and the Cardiovascular Magnetic Resonance Unit (D.J.P.), Royal Brompton Hospital, London, UK.
Correspondence to Dr Hugh Montgomery, UCL Cardiovascular Genetics, Rayne Institute, 5 University St, London WC1E, UK. E-mail h.montgomery{at}ucl.ac.uk
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Abstract |
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Background—Local cardiac renin-angiotensin systems may regulate left ventricular (LV) hypertrophic responses. The absence (deletion [D]) of a 287-bp marker in the ACE gene is associated with greater myocardial ACE levels and exercise-related LV growth than is its presence (insertion [I]), an effect potentially mediated through either increased activity of the cellular growth factor angiotensin II on the angiotensin type 1 (AT1) receptor or increased degradation of growth-inhibiting kinins. We sought to confirm ACE genotype–associated exertional LV growth and to clarify the role of the AT1 receptor in this association.
Methods and Results—One hundred forty-one British Army recruits homozygous for the ACE gene (79 DD and 62 II) were randomized to receive losartan (25 mg/d, a subhypotensive dose inhibiting tissue AT1 receptors) or placebo throughout a 10-week physical training program. LV mass, determined by cardiac magnetic resonance, increased with training (8.4 g, P<0.0001 overall; 12.1 versus 4.8 g for DD versus II genotype in the placebo limb, P=0.022). LV growth was similar in the losartan arm: 11.0 versus 3.7 g for DD versus II genotypes (P=0.034). When indexed to lean body mass, LV growth in the II subjects was abolished, whereas it remained in the DD subjects (-0.022 versus 0.131 g/kg, respectively; P=0.0009).
Conclusions—ACE genotype dependence of exercise-induced LV hypertrophy is confirmed. Additionally, LV growth in DD (unlike II) subjects is in excess of the increase in lean body mass. These effects are not influenced by AT1 receptor antagonism with the use of losartan (25 mg/d). The 2.4-fold greater LV growth in DD men may be due to the effects of angiotensin II on other receptors (eg, angiotensin type 4) or lower degradation of growth-inhibitory kinins.
Key Words: hypertrophy • myocardium • genetics • angiotensin • exercise
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Local cardiac renin-angiotensin systems may regulate left ventricular (LV) hypertrophy,1 2 which is itself associated with increased cardiovascular mortality and morbidity.3 The absence (deletion [D]) of a 287-bp marker in the ACE gene4 is associated with greater myocardial ACE levels5 and exercise-related LV growth6 than is its presence (insertion [I]), potentially through either increased activity of the cellular growth factor angiotensin II7 8 on the angiotensin type 1 (AT1) receptor8 or increased degradation of growth-inhibiting kinins.9
We sought to confirm ACE genotype–associated exertional LV growth and to clarify the role of the AT1 receptor in this association.
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Methods |
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Subjects
Healthy normotensive white male army recruits were studied with appropriate ethics committee approval and informed consent. ACE genotype was determined (3-primer polymerase chain reaction amplification as previously described10 ). In a prospective parallel-arm, double-blind, randomized, placebo-controlled trial, ACE gene homozygotes were randomized to receive (compliance-witnessed) 25 mg losartan or placebo daily throughout a 10-week training period. At the start and end of training, height, weight, and blood pressure (mean of 3 measurements, 1 minute apart, 20 minutes supine) were recorded, and MRI was performed.
Magnetic Resonance Scanning
As previously
described,11 10-mm ECG-gated
short-axis cardiac images (single breath holding, 0.5 T;
Figure 1
) were obtained, and LV mass was determined by
multiplying myocardial tissue volume (Simpson’s rule, single observer
blind to subject data) by myocardial tissue–specific density (1.05
g/cm3). Chamber volumes were calculated by
summing end-diastolic and end-systolic endocardial areas in each
slice.
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In addition, forty 10-mm-thick noncontiguous transaxial signal-averaged spin-echo image slices of the whole body (echo time 40 ms, repetition time 500 ms, field of view 45x45 cm, and 40-mm intergap distance) were obtained,12 adipose tissue volume was quantified (automated threshold technique, ie, averaging adjacent slice values by the Cavalieri method12 13 ), fat mass was obtained through multiplication by fat-specific density (0.95 g/m2), and lean body mass was calculated by subtracting adipose tissue mass from total body mass.
Statistical Calculations
The standard deviation of cardiac magnetic resonance
(CMR) LV mass measurements in pilot studies was 8.9 g. Thus, 30
subjects in each group (II and DD, placebo or losartan) yielded 95%
power to detect a 5% change in LV mass (8.35 g given past
data6 ) with 95% confidence
Figure 2.
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Data were analyzed for those who completed training at the first attempt. Baseline and follow-up values were compared by the paired Student t test, and between-group changes were compared by unpaired t tests and ANOVA (Statview 5.0, SAS Institute). A value of P<0.05 was considered statistically significant. Results are shown as mean±1 SD, unless otherwise stated.
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Results |
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One thousand two hundred forty-eight recruits were screened. Genotype distribution (332 DD [27%], 615 ID [49%], and 301 II [24%]) was in Hardy-Weinberg equilibrium. Two hundred twelve homozygous individuals continued in the study (age, height, weight, pulse, and blood pressure were similar by genotype and treatment [Table 1
]). One hundred forty-one recruits (79 DD and 62
II) completed training, of whom 66 had taken losartan (38 DD and 28
II), and 75 had taken placebo (41 DD and 34 II). Baseline physical
characteristics (age 19.7±2.5 years, height 175.2±6.5 cm, weight
71.0±9.3 kg, pulse rate 66.2±12.3 bpm, and systolic and diastolic
blood pressure 117.2±12.1 and 66.5±10.7 mm Hg, respectively) and LV
mass (184.2±24.9 g) did not differ between those who completed and
those who dropped out of training
(P>0.05 by ANOVA for all
parameters). In those who completed training, pretraining and
posttraining blood pressures were similar (systolic/diastolic blood
pressure 117.4±11.7/66.0±10.5 and 117.6±12.0/65.5±10.4 mm Hg,
P=0.85 and
P=0.55 for systolic and
diastolic values, respectively) in all groups. Resting pulse rates fell
with training (65.8±12.5 versus 63.6±10.4 bpm, respectively;
P=0.023) but were also similar
between groups.
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The increase in LV mass associated with training (mean±SE
8.4±1.2 g overall, P<0.0001;
8.8±1.6 g, P<0.0001 in those
taking placebo;
Table 2) was lower among those of the II genotype (4.3±1.8
g, P=0.020 overall; 4.8±2.4 g,
P=0.057 in the placebo group)
than of the DD genotype (11.6±1.5 g,
P<0.0001 overall; 12.1±2.0 g,
P<0.0001 for placebo;
P=0.002 and
P=0.022 for comparison with
those of II genotype, respectively). Losartan had no effect on LV mass
increase: for DD genotype, 11.0±2.1 g; for II genotype, 3.7±2.7 g
(P=0.69 and
P=0.75, respectively, compared
with placebo in each genotype group).
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The ratio of LV mass to lean body mass14 was calculated in a subset of recruits (n=117, 52 II and 65 DD). Baseline values were similar in all groups (3.11±0.35 g/kg lean body mass, P=0.16) and were increased with training by 0.063±0.023 g/kg (2.4%, P=0.008) and 0.057±0.033 g/kg (2.1%, P=0.09) in the treatment and placebo arms, respectively. The modest LV growth in II subjects was completely attenuated when indexed to lean mass (-0.022±0.034 g/kg [-0.4%], P=0.52 overall; -0.029±0.047 g/kg [-0.5%], P=0.55 for placebo) but remained for DD subjects (0.131±0.029 g/kg [4.6%], P<0.0001 overall; 0.143±0.042 g/kg [4.7%], P=0.002 for placebo); P values were 0.0009 and 0.009 for comparison with those of the II genotype, respectively. Losartan had no effect on the change in LV mass index within either genotype (DD 0.120±0.041 g/kg; II -0.011±0.048 g/kg; P=0.70 and 0.81, respectively, compared with placebo).
Overall, because recruit LV end-diastolic volume rose with
little change in end-systolic volume, stroke volume increased (LV
end-diastolic volume 108.2±24.7 to 114.7±26.5 mL,
P=0.0004; LV end-systolic
volume 34.2±10.3 to 35.9±11.0 mL,
P=0.030; and LV stroke volume
73.9±16.9 to 78.8±19.0 mL,
P=0.0005;
Table 3). Because of a fall in resting pulse rate, cardiac
output was unchanged (4.78±1.33 versus 4.99±1.23 L/min for baseline
versus follow-up, respectively;
P=0.72). Right ventricular
volumes showed the same pattern (RV end-diastolic volume 130.6±25.5 to
139.5±28.2 mL, P<0.0001; RV
end-systolic volume 57.1±14.4 to 60.9±15.0 mL,
P=0.0004; and RV stroke volume
73.6±16.0 to 78.5±17.5 mL,
P<0.0001). Neither genotype
nor treatment group influenced volume parameters, although there was a
nonsignificant trend for losartan to attenuate volume
increases.
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Discussion |
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We have confirmed the ACE genotype effect on LV growth.6 Furthermore, it has been suggested that LV mass is normally proportional to skeletal muscle mass and that the former should thus be indexed for the latter.14 When this is done, the small II genotype–associated increase in LV mass is completely attenuated, whereas the LV growth in DD subjects persists, suggesting that the LV growth in DD subjects is in excess of the increase in lean body mass, whereas the small change in II subjects is proportional to it.
These findings were independent of 25 mg/d losartan, a dose chosen for sustained biological,15 yet minimal hypotensive, effect. Such doses inhibit the pressor response to angiotensin II,16 17 18 are uricosuric, and alter plasma renin activity.19 20 21 The minor hypotensive effects seen in hypertensive patients22 are probably absent in normal subjects23 24 25 and minimal even at doses of 100 mg/d.22 26 27 Any hypotensive action would have tended toward a false-positive effect on LV growth, which was not observed in any event. Nonetheless, a small biological effect of losartan on the LV growth response was missed. Post hoc analysis demonstrates an 80% power to detect a 2.6% reduction in LV growth by losartan and a 95% power to detect a change of 4.8%. However, the nearly 3-fold difference in growth effect between genotypes was scarcely affected by losartan treatment. In keeping with rodent data,28 29 30 the present study does not support a nonpressor influence of the AT1 receptor on cardiac growth. ACE genotype might thus influence LV growth through increased levels of angiotensin II on the angiotensin type 4 receptor (the angiotensin type 2 receptor may modulate antiproliferative effects31 ) or through the reduced levels of growth-inhibitory kinins, which are degraded by ACE.32
Our previous study6
showed a greater hypertrophic response for DD subjects than was
observed in the present study (42 versus 12.1 g). However,
echocardiographic methodology uses cardiac dimensions and an assumed
geometric shape to calculate LV
mass33 34 through
equations derived from postmortem examinations of individuals of
diverse age and LV mass range (age 23 to 82 years, LV mass 96 to
625 g).33 35
Such a "best-fit" model for a mixed population cannot be expected
to be applicable to a study of young recruits. Neither were the
equations designed to assess individual alterations in LV mass in
response to hypertrophic stimuli. Furthermore, exercise produces very
specific LV morphological changes that may distort calculated LV mass.
Such distortions (and any errors in measurement) will be cubed during
calculation of LV mass. Thus, compared with CMR, M-mode echo
overestimates LV mass (and hence, the prospective change in
mass).36 Finally, repeated
echocardiographic mass measurements have poorer reproducibility than do
CMR measurements (standard deviation of the difference between
successive CMR LV mass estimates being 
20% that of
echo36 ), and repeated
measures may thus overamplify detected
changes.36 37 Thus,
although echocardiographic measures of mass may have their place, it
may be less applicable to serial prospective studies of LV growth in
small samples. By contrast, CMR measures mass directly, removing any
error associated with volume changes or ventricular shape.
Training intensity (specifically, resistance exercise) was reduced after the first study. Cardiac growth responses are influenced by exercise intensity and type, leading to large variations in LV mass in those participating in different sports and with different prospective training schemes.38 39 40 Even modest training changes (such as the addition of handgrip exercises to running) may alter cardiac growth stimuli or responses.41 Given the substantial ACE genotype–training environment interaction, it is likely that changes in the training stimulus will interact with genotype to produce differences in the nature and scale of the phenotypic response.
Proposed ACE genotype dependence of LV growth conflicts with some cross-sectional studies. However, the cardiac renin-angiotensin system probably transduces growth stimuli and is not a cause of LV hypertrophy in itself. Diverse environmental hypertrophic stimuli may create sufficient "white noise" to mask modest individual-effect gene-environment interactions in cross-sectional studies.42
Limitations of the Study
A higher dose of losartan might have influenced LV
growth whether through a hypotensive effect or
not.43 Furthermore, we
studied no heterozygous group, because our aim was to confirm an ACE
genotype association with LV growth and to explore the potential role
of the AT1 receptor in such genotype dependence.
We specifically did not set out to explore the potential additive or
synergistic effects of the presence of 
1 allele, an investigation
that was beyond the scope of the present
study.
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Acknowledgments |
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This study was supported by the British Heart Foundation (Dr Myerson [FS 97030] and Dr Montgomery and Prof Humphries [SP 98003 and RG 95007], the Coronary Artery Disease Research Association [CORDA], Royal Brompton Hospital CMR Unit), the British army, an unconditional programme grant from the British United Provident Association (BUPA), and Merck Sharp & Dohme Pharmaceuticals, who also supplied the randomized packs of tablets. We especially thank the staff and recruits at the Army Training Regiment, Bassingbourn, and Steve Collins (CMR Unit) for invaluable technical support.
Received July 20, 2000; revision received August 21, 2000; accepted August 23, 2000.
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References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Lee YA, Lindpainter K. Role of the cardiac renin-angiotensin system in hypertensive cardiac hypertrophy. Eur Heart J. 1993;14:42–48.
2. Schunkert H, Dzau VJ, Tang SS, et al. Increased rat cardiac angiotensin converting enzyme activity and mRNA expression in pressure overload left ventricular hypertrophy: effects on coronary resistance, contractility, and relaxation. J Clin Invest. 1990;86:1913–1920.
3. Levy D, Garrison R, Savage D, et al. Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N Engl J Med. 1990;322:1561–1566.[Abstract]
4. Rigat B, Hubert C, Alhenc-Gelas F, et al. An insertion/deletion polymorphism in the angiotensin-1-converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest. 1990;86:1343–1346.
5.
Danser AH,
Schalekamp MA, Bax WA, et al. Angiotensin converting enzyme in the
human heart: effect of the deletion/insertion polymorphism.
Circulation. 1995;92:1387–1388.
6.
Montgomery HE,
Clarkson P, Dollery, et al. Association of angiotensin-converting
enzyme gene I/D polymorphism with change in left ventricular mass in
response to physical training.
Circulation. 1997;96:741–747.
7. Beinlich CJ, White GJ, Baker KM, et al. Angiotensin II and left ventricular growth in newborn pig heart. J Mol Cell Cardiol. 1991;23:1031–1038.[Medline] [Order article via Infotrieve]
8.
Liu Y, Leri A, Li B,
et al. Angiotensin II stimulation in vitro induces hypertrophy of
normal and postinfarcted ventricular myocytes.
Circ Res. 1998;82:1145–1159.
9. Linz W, Scholkens BA. A specific B2-bradykinin receptor antagonist HOE 140 abolishes the antihypertrophic effect of ramipril. Br J Pharmacol. 1992;105:771–772.[Medline] [Order article via Infotrieve]
10. Montgomery HE, Marshall RM, Hemingway H, et al. Human gene for physical performance. Nature. 1998;393:221–222.[Medline] [Order article via Infotrieve]
11. Lorenz C, Walker E, Morgan VL, et al. Normal human right and left ventricular mass, systolic function and gender differences by cine magnetic resonance imaging. J Cardiovasc Magn Reson. 1999;1:7–21.[Medline] [Order article via Infotrieve]
12.
Ross R, Leger L,
Morris D, et al. Quantification of adipose tissue by MRI: relationship
with anthropometric variables. J Appl
Physiol. 1992;72:787–795.
13. Roberts N, Cruz-Orive L, Reid N, et al. Unbiased estimation of human body composition by the Cavalieri method using magnetic resonance imaging. J Microsc. 1993;171(pt 3):239–253.
14. Hense H-W, Gneiting B, Muscholl M, et al. The associations of body size and body composition with left ventricular mass: impacts for indexation in adults. J Am Coll Cardiol. 1998;32:451–457.
15. Ohtawa M, Takayama F, Saitoh K, et al. Pharmacokinetics and biochemical efficacy after single and multiple oral administration of losartan, an orally active nonpeptide angiotensin II receptor antagonist, in humans. Br J Pharmacol. 1993;35:290–297.
16. Christen Y, Waeber B, Nussberger J, et al. Dose-response relationships following oral administration of DuP 753 to normal humans. Am J Hypertens. 1991;4:350S–353S.[Medline] [Order article via Infotrieve]
17.
Christen Y, Waeber
B, Nussberger J, et al. Oral administration of DuP 753, a specific
angiotensin II receptor antagonist, to normal male volunteers.
inhibition of pressor response to exogenous angiotensin I and II.
Circulation. 1991;83:1333–1342.
18. Brunner HR, Christen Y, Munafo A, et al. Clinical experience with angiotensin II receptor antagonists. Am J Hypertens. 1992;5:243S–246S.[Medline] [Order article via Infotrieve]
19. Nakashima M, Uematsu T, Kosuge K, et al. Pilot study of the uricosuric effect of DuP-753, a new angiotensin II receptor antagonist, in healthy subjects. Eur J Clin Pharmacol. 1992;42:333–335.
20. Nakashima M, Umemura K. The clinical pharmacology of losartan in Japanese subjects and patients. Blood Press Suppl. 1996;2:62–66.[Medline] [Order article via Infotrieve]
21. Goldberg MR, de Mey C, Wroblewski JM, et al. Differential effects of oral losartan and enalapril on local venous and systemic pressor responses to angiotensin I and II in healthy men. Clin Pharmacol Ther. 1996;59:72–82.[Medline] [Order article via Infotrieve]
22.
Weber MA, Byyny
RL, Pratt JH, et al. Blood pressure effects of the angiotensin II
receptor blocker, losartan. Arch Intern
Med. 1995;155:405–411.
23. Reid JL. Inhibitors of the renin-angiotensin system: clinical pharmacology studies on kinetics, dynamics and concentration-effect relationships. Arzneimittelforschung. 1993;43:263–264.[Medline] [Order article via Infotrieve]
24. Doig J, MacFadyen R, Sweet C, et al. Dose-ranging study of the angiotensin type I receptor antagonist losartan (DuP753/MK954), in salt-deplete normal man. J Cardiovasc Pharmacol. 1993;21:732–738.[Medline] [Order article via Infotrieve]
25.
Gandhi SK, Ryder
DH, Brown NJ. Losartan blocks aldosterone and renal vascular responses
to angiotensin II in humans.
Hypertension. 1996;28:961–966.
26.
Goldberg MR,
Tanaka W, Barchowsky A, et al. Effects of losartan on blood pressure,
plasma renin activity, and angiotensin II in volunteers.
Hypertension. 1993;21:704–713.
27.
Azizi M,
Chatellier G, Guyene TT, at al. Additive effects of combined
angiotensin-converting enzyme inhibition and angiotensin II antagonism
on blood pressure and renin release in sodium-depleted normotensives.
Circulation. 1995;92:825–834.
28. Ambrose J, Pribnow D, Giraud G, et al. Angiotensin type 1 receptor antagonism with irbesartan inhibits ventricular hypertrophy and improves diastolic function in the remodeling post-myocardial infarction ventricle. J Cardiovasc Pharmacol. 1999;33:433–439.[Medline] [Order article via Infotrieve]
29.
Richer C, Fornes
P, Cazaubon C, et al. Effects of long-term angiotensin II
AT1 receptor blockade on survival, hemodynamics
and cardiac remodeling in chronic heart failure in rats.
Cardiovasc Res. 1999;41:100–108.
30.
Thienelt C,
Weinberg E, Bartunek J, et al. Load-induced growth responses in
isolated adult rat hearts. Role of the AT1
receptor. Circulation. 1997;95:2677–2683.
31.
Matsubara H.
Pathophysiological role of angiotensin II type 2 receptor in
cardiovascular and renal diseases. Circ
Res. 1998;83:1182–1191.
32.
McDonald K, Mock
J, D’Aloia A, et al. Bradykinin antagonism inhibits the antigrowth
effect of converting enzyme inhibition in the dog myocardium after
discrete transmural myocardial necrosis.
Circulation. 1995;91:2043–2048.
33.
Devereux RB,
Reichek N. Echocardiographic determination of left ventricular mass in
man: anatomic validation of the method.
Circulation. 1977;55:613–619.
34.
Sahn DJ, DeMaria
A, Kisslo J, at al. Recommendations regarding quantitation in M-mode
echocardiography: results of a survey of echocardiographic
measurements. Circulation. 1978;58:1072–1083.
35. Devereux R, Alonso D, Lutas E, et al. Echocardiographic assessment of left ventricular hypertrophy: comparison to necropsy findings. Am J Cardiol. 1986;57:450–458.[Medline] [Order article via Infotrieve]
36. Bottini P, Carr A, Prisant L, et al. Magnetic resonance imaging compared to echocardiography to assess left ventricular mass in the hypertensive patient. Am J Hypertens. 1995;8:221–228.[Medline] [Order article via Infotrieve]
37. Gottdiener J, Livengood S, Meyer P, et al. Should echocardiography be performed to assess effects of antihypertensive therapy?: test-retest reliability of echocardiography for measurement of left ventricular mass and function. J Am Coll Cardiol. 1995;25:424–430.
38. Schaible TF, Scheur J. Cardiovascular adaptations to chronic exercise. Prog Cardiovasc Dis. 1985;27:297–324.[Medline] [Order article via Infotrieve]
39. Maron BJ. Structural features of the athlete’s heart as defined by echocardiography. J Am Coll Cardiol. 1986;7:190–203.[Abstract]
40.
Shapiro LM.
Physiological left ventricular hypertrophy.
Br Heart J. 1984;52:130–135.
41. Nutter DO, Schlant RC, Hurst JW. Isometric exercise and the cardiovascular system. Mod Concepts Cardiovasc Dis. 1972;41:11–15.[Medline] [Order article via Infotrieve]
42.
Montgomery HE.
Should the contribution of ACE gene polymorphism to left ventricular
hypertrophy be reconsidered?
Heart. 1997;77:502–505.
43. Friedl W, Krempler F, Sandhofer F, et al. Insertion/deletion polymorphism in the angiotensin-converting-enzyme gene and blood pressure during ergometry in normal males. Clin Genet. 1996;50:541–544.[Medline] [Order article via Infotrieve]
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Y. Jamshidi, H. E. Montgomery, H.-W. Hense, S. G. Myerson, I. P. Torra, B. Staels, M. J. World, A. Doering, J. Erdmann, C. Hengstenberg, et al. Peroxisome Proliferator-Activated Receptor {alpha} Gene Regulates Left Ventricular Growth in Response to Exercise and Hypertension Circulation, February 26, 2002; 105(8): 950 - 955. [Abstract] [Full Text] [PDF]
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