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Arq. Bras. Cardiol. vol.98 no.4 São Paulo Apr. 2012 Epub Mar 27, 2012
Jeeser Alves Almeida; Daniel Alexandre Boullosa; Emerson Pardono; Ricardo Moreno Lima; Pâmella Karoline Morais; Benedito Sérgio Denadai; Vinícius Carolino Souza; Otávio Toledo Nóbrega; Carmem Silvia Grubert Campbell; Herbert Gustavo Simões
IUniversidade Católica de Brasília, Brasília, DF
IIUniversidade de Brasília, Brasília, DF
IIIUniversidade Federal de Sergipe, Aracaju, SE
IVUniversidade Estadual de São Paulo, São Paulo, SP, Brazil
BACKGROUND: The angiotensin I-converting enzyme gene (ACE gene) has been broadly studied as for cardiorespiratory fitness phenotypes, but the association of the ACE genotype to middle-distance running has been poorly investigated.
OBJECTIVE: This study investigated the possible influence of Angiotensin-Converting Enzyme (ACE) genotype (I/D) on cardiovascular fitness and middle-distance running performance of Brazilian young males. The validity of VO2max to predict the ACE genotype was also analyzed.
METHODS: A homogeneous group of moderately active young males were evaluated in a 1,600 m running track test (V1600m; m.min-1) and in an incremental treadmill test for VO2max determination. Subsequently, the actual and the predicted [(0.177*V1600m) + 8.101] VO2max were compared to ACE genotypes.
RESULTS: The VO2max and V1600m recorded for DD, ID and II genotypes were 45.6 (1.8); 51.9 (0.8) and 54.4 (1.0) mL.kg-1.min-1 and 211.2 (8.3); 249.1 (4.3) and 258.6 (5.4) m.min-1 respectively, and were significantly lower for DD carriers (p< 0.05). The actual and predicted VO2max did not differ from each other despite ACE genotype, but the agreement between actual and estimated VO2max methods was lower for the DD genotype.
CONCLUSION: It was concluded that there is a possible association between ACE genotype, cardiovascular fitness and middle-distance running performance of moderately active young males and that the accuracy of VO2max prediction may also depend on the ACE genotype of the participants.
Keywords: Angiotensin-converting enzyme; I/D polymorphism; VO2max, middle-distance running.
The angiotensin I-converting enzyme gene (ACE gene) has been broadly studied for cardiorespiratory fitness phenotypes. Concerning the 287bp insertion/deletion (I/D) polymorphism, a body of evidence associates the D allele to a lower aerobic fitness1,2 with some studies associating it to power-demanding exercises3,4. In contrast, the I allele has been related to an improved endothelium-dependent vasodilation5, higher percentage of the most efficient type I muscle fibers6, thus suggesting that type II carriers would present higher VO2max. However, few studies have investigated the influence of the ACE genotype on VO2max7-9, which is considered the gold standard for cardiorespiratory evaluation. Such authors have reported contradictory findings with a higher VO2max observed in DD9 or II carriers7, or no relationship reported10. Because those studies were conducted on samples with important differences regarding participants' age, gender, and training background; and under different exercise modes, it may be suggested that these differences could be affecting these relationships1, therefore, it is necessary to use homogeneous samples and protocols to minimize any differences resulting from the phenotypic characteristics of participants.
In addition, the association of the ACE genotype with middle-distance running has been poorly investigated. There are only two studies11,12 in which a higher middle-distance running performance was reported for young male DD carriers. In both studies, the VO2max was not recorded and its relative influence on running performance could not be evaluated. Consequently, further research ensures the influence of ACE genotype on VO2max as a marker of cardiovascular fitness, as well as on middle distance running performance.
Once the VO2max determination usually requires laboratory facilities, various predictive equations have been proposed for its estimation from practical and inexpensive field tests. An update of the predictive equation of VO2max from a 1,600m running test in a cohort of young men has been recently proposed. These authors have suggested the specificity of predictive equations regarding gender, age and the training background of the participants. The strong difference (12%) detected between the prediction of the previous14 and the new equation13 suggests that the geographical origin of participants could be another important factor. It is well known that the allelic frequency of the ACE gene may vary according to the location of the sample15, thus the predictive power of an equation used in a specific population may differ when applied to a population with a different allele frequency.
Thus, this study investigated the possible influence of Angiotensin-Converting Enzyme (ACE) genotype (I/D) on cardiovascular fitness and middle-distance running performance of Brazilian young males. In addition, the validity of VO2max to predict the ACE genotype was also analyzed.
Fifty-seven physically active young (practitioners of physical activity at least three times a week for at least 30 min) non-runners were recruited for this study for convenience. We selected this sample for convenience based on previous suggestions about the appropriateness of homogeneous samples for the evaluations of physical performance with regard to genotype1,15. All volunteers were informed of the risks and benefits of their participation in the study, so they were instructed to sign a consent form. They were asked to avoid any intense exercise and to abstain from caffeine and alcohol beverages in the 24 hours preceding the tests, which were performed in random order with a minimum of 48h.
The treadmill test (Inbramed Millenium Super ATL, Porto Alegre, Brazil) was performed at 1% inclination, with an initial speed of 6 km·h-1 and subsequent increments of 0.75 km·h-1 every minute until volitional exhaustion. Expired gases were continuously measured (Cortex Biophysik, Germany) and the VO2max (mL·kg·min-1) recorded was the mean of the values reached during the last 20 seconds before exhaustion. Additionally, the following criteria of the American College of Sports Medicine guidelines to determine VO2max were considered: RER > 1.15; VO2max plateau; RPE > 17; and maximal HR within ± 10 beats·min-1 of predicted values (HR = 220 age)14,16,17.
The middle-distance running test consisted in an all-out 1,600m running track test conducted under thermoneutral conditions (24ºC ±1ºC) and absence of wind18. The mean speed (m·min-1) from the running performance was calculated (V1600m) and subsequently applied to a previously validated equation: VO2max = (0.177*V1600m) + 8.101.
On a different day, whole venous blood was drawn for DNA extraction (AccuPrep Genomic DNA Extraction Kit Bioneer HQ) and the ACE I/D polymorphism was identified by polymerase chain reaction using specific primers and subsequent electrophoresis as described elsewhere19.
The variables are shown as mean (SD in table 1; descriptive statistical and SEM in table 2; inferential statistics). All parameters were normally distributed as confirmed by a Kolmogorov-Smirnov test. ANOVA with Bonferroni as a post hoc was conducted to examine possible differences among the groups. The Bland and Altman20 procedure and the intraclass correlation coefficient (ICC) were used to examine agreement and reliability between measured and predicted VO2max values. Relationships among parameters were determined by Pearson product moment correlation coefficient. Significance level was set at p < 0.05.
Table 1 shows the characteristics of participants, though with no evident difference between genotypes. Table 2 presents V1600m and both measured and estimated VO2max values for the three ACE I/D genotype groups. The recorded VO2max and V1600m for DD, ID and II genotypes were 45.6 (1.8); 51.9 (0.8) and 54.4 (1.0) mL.kg-1.min-1 and 211.2 (8.3); 249.1 (4.3) and 258 (5.4) m.min-1 respectively and were significantly lower for DD carriers (P< 0.05). No differences were observed between the estimated VO2max and that obtained in the cardiopulmonary exercise test. A high correlation was exhibited between VO2max and V1600m for the whole sample (r=0.94; P= 0.0001).
Strong correlations were detected between predicted and measured VO2max for all genotype groups (DD: 0.89 < ID: 0.99 < II: 0.99; P<0.05). The ICCs were also high for all the genotypes but with a lower value for the DD carriers (DD: 0.86 < ID: 0.97 < II: 0.98). Moreover, the Bland and Altman20 plot showed a lower agreement for the DD carriers (Fig. 1).
The main finding of this study was that VO2max values and thus the cardiovascular fitness of physically active young males seemed to be influenced by the I/D polymorphism of the ACE gene. It was observed that, for this homogenous sample studied, the DD carriers presented both a lower VO2max and 1600m running performance compared to II and ID genotypes (p < 0.05). Also, V1600m and VO2max were highly correlated in the whole sample (r = 0.94; p = 0.001) suggesting a great influence of VO2max in participants' middle-distance running ability.
The finding of DD carriers showing a lower mean V1600m and VO2max compared to other genotypes is inconsistent with previous reports11,12 in which the DD carriers were the best performers of a cohort of young well-trained men in 2,000-2,400m running tests. Although these results may seem opposite, it may be worth noting that the fitness level of the participants of these previous studies11,12 is higher than those of the current study as for their running times, with a higher mean velocity for longer running distances (~285 and 240 m·min-1 for 2.000 and 2.400 m, respectively). In this regard, Roltsch et al21 did not find any difference in VO2max in a cycling exercise among ACE genotypes in a group of young women, while the opposite was reported with post-menopausal women with significant lower VO2max values7. Furthermore, the study by Zhao et al9 that evaluated a group of young men in a treadmill graded test, revealed a higher VO2max of DD carriers with a significantly higher VO2max of the whole sample (range ~ 44-76 mL·kg-1·min-1) compared to our participants (range ~ 37-61 mL·kg-1·min-1). Consequently, and despite any possible ethnic or age influence, it may be suggested that the ACE genotype could be influencing middle-distance running and VO2max depending on the fitness level of the sample.
This apparent paradox and the contradictory findings in previous literature can be due to the different protocols employed as only a very few studies have considered field running ability for evaluation of young men11,12. This is important as physical demands are quite different depending on the ergometer employed (e.g. treadmill vs. cycle ergometer). Moreover, the intensity and the profile of the running exercises could be also influencing their physiological demands, including both metabolic and neuromuscular factors22,23. In this regard, Lucía et al24 have shown that the DD genotype seemed to be higher in elite cyclists compared with endurance runners, probably because of the higher power demands of cycling. Furthermore, the controversy about the influence of the ACE genotype on the endurance athlete status25 could be explained by the fact that VO2max is not so important for success as other factors (e.g. running economy) that could be influenced by other genes. Therefore, given the number of associations reported for every allele with different physiological functions before and after training7,8,10,26, it may be suggested that the specific demands of every testing condition could be interacting with the individuals' fitness level thus modifying the role of the ACE genotype on physical fitness (i.e. VO2max) and subsequent performance (i.e. middle-distance running). Since we recruited a very homogeneous sample of young male physically active non runners, and because the running protocols were selected for the evaluation of individuals' maximum aerobic power, this study demonstrates a more controlled experimental condition for testing our hypotheses properly. In addition, the use of a ramp protocol on a treadmill allows a better assessment of VO2max compared to cycle ergometer (~10-20% higher in the treadmill)27 because the treadmill provides a common form of physiological stress and the cycle ergometer is limited leading to a peripheral fatigue in many individuals28.
Besides this, it is well known that both VO2max and distance running are affected from a cardiovascular point of view by both central (e.g. cardiac output) and peripheral factors (e.g. oxygen extraction)29, with the former being more important. Moreover, it should be pointed out that endurance running is also influenced by neuromuscular factors23. In this regard, the II carriers presented: higher maximal arterio-venous O2 difference7, higher percentage of type I muscle fibers6, and larger endothelium-dependent vasodilation in the trained state5; whereas the DD carriers have demonstrated: larger skeletal muscle power30; and a greater left ventricular hypertrophy in military recruits after a training period26 and in elite athletes31. From these previous studies, it may be suggested that while II carriers may present a greater peripheral function of the cardiovascular system, DD carriers are more benefited from neuromuscular and cardiac central adaptations. Furthermore, DD carriers have demonstrated a larger improvement after training programs in short aerobic efforts11,12. This may suggest that lower VO2max and middle-distance running performance of DD carriers of our homogeneous sample could be reversed with respect to the other genotypes after a running training program. Therefore, more studies should be conducted to evaluate the role of the ACE genotype with regard to fitness status (e.g. well-trained vs. moderately trained individuals) and level running intensities (e.g. VT1 vs. VO2max) with attention to physiological changes (i.e. neuromuscular vs. cardiovascular) accounting for such parameters after different training regimes. Nevertheless, our study is the first to report a significant inverse association among VO2max and middle-distance running with the ACE DD genotype in a homogeneous sample of physically active young male non runners exhibiting ~ 50 mL·kg-1·min-1.
On the other hand, in this study, with a greater sample compared to the previous report, we have confirmed the validity of the predictive equation developed for a similar population13. Contrary to our hypothesis, the validity of this equation is independent of the ACE genotype. Consequently, this equation may be applied in different geographical locations, thus providing a simple and efficient tool for VO2max prediction in young physically active men from a field running test. Interestingly, although acceptable, consistency between the actual and predicted VO2max was lower for the DD genotype with excellent values detected for the other genotypes (Fig. 1). In this regard, it should also be noted that there are greater SEM values for the DD carriers compared to the other groups (Table 2). We cannot explain these differences among genotypes that could be accounting for another unknown factor. Interestingly, individuals carrying the DD genotype that presented a higher VO2max between measurements showed lower consistency compared to those of smaller VO2max (Fig. 1). Perhaps this may mean that the carriers of the DD genotype have a lower relationship between performance in middle distance running and VO2max than carriers of other genotypes for ACE gene. Nevertheless, the validity of the equation is ensured in a similar population with such protocols. We suggest taking this aspect into consideration when applying this equation in great samples of those populations in which the D allele could be overrepresented.
Based on the results observed, the classic insertion/deletion polymorphism of the ACE gene has an important association with cardiorespiratory fitness and middle distance running performance in physically active young males with DD genotype carriers exhibiting lower results. The accuracy of VO2max prediction may be slightly lower for DD carriers but with acceptable validity. Additionally, the ACE genotype may be an important factor to be taken into account in the determination/prediction of VO2max. Further studies are required for the assessment of these relationships in similar populations regarding gender, running intensity and fitness status.
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Mailing Address: Manuscript received
August 26, 2011; revised manuscript received November 10, 2011; accepted November
17, 2011. This article has received corrections asked
by the editor on Apr/2012 in agreement with the ERRATUM below: In the original article "The Influence of ACE
Genotype on Cardiorespiratory Fitness of Moderately Active Young Men", consider
as correct the keywords "Angiotensin-converting enzyme; I/D polymorphism; VO2max,
Qnd 29, casa 05, Pca do Bicalho
72120290 Taguatinga, DF, Brazil
Manuscript received August 26, 2011; revised manuscript received November 10, 2011; accepted November 17, 2011.
This article has received corrections asked by the editor on Apr/2012 in agreement with the ERRATUM below:
In the original article "The Influence of ACE Genotype on Cardiorespiratory Fitness of Moderately Active Young Men", consider as correct the keywords "Angiotensin-converting enzyme; I/D polymorphism; VO2max, middle-distance running".