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ACE and AGTR1 Polymorphisms and Left Ventricular Hypertrophy in Endurance Athletes

DI MAURO, MICHELE1,2; IZZICUPO, PASCAL3; SANTARELLI, FRANCESCO1; FALONE, STEFANO4; PENNELLI, ALFONSO1; AMICARELLI, FERNANDA4; CALAFIORE, ANTONIO M.2; DI BALDASSARRE, ANGELA3; GALLINA, SABINA1

Medicine & Science in Sports & Exercise: May 2010 - Volume 42 - Issue 5 - p 915-921
doi: 10.1249/MSS.0b013e3181c29e79
BASIC SCIENCES

Objective: This study aimed to evaluate the role of angiotensin type 1 receptor gene (AGTR1) polymorphism (A1166C) in left ventricular hypertrophy (LVH) mediated by the angiotensin-converting enzyme (ACE) in endurance athletes.

Methods: A group of 74 white, healthy male endurance athletes, aged between 25 and 40 yr, were enrolled in this study. All of them participated primarily in isotonic sports, training for at least >10 h·wk−1, for at least 5 yr. The ACE genotype (insertion [I] or deletion [D] alleles) was ascertained by polymerase chain reaction (DD in 35, ID in 36, and II in 3). Group II was excluded from the analysis because of its small size. No difference was found between the two groups as regards age, blood pressure, HR, and echocardiographic data.

Results: The left ventricular mass index (LVMI) was significantly higher in group DD rather than in group ID (P = 0.029). The group DD showed a slightly higher prevalence of subjects with LVH (LVMI > 131 g·m−2; 62.9%) than group ID (44.4%, P = 0.120). No association was found between ACE-DD and LVH (odds ratio (OR) = 2.12, 95% confidence interval = 0.82-5.46). Concerning the role of AGTR1 polymorphism, the highest LVMI was found in 15 athletes with ACE-DD and AGTR1-AC/CC genotypes (150 ± 23 g·m−2); the lowest value of LVMI was found in the case of ACE-ID and AGTR1-AA (127 g·m ± 18 g·m−2), whereas LVMI in subjects with ACE-DD + AGTR1-AA was similar to that in the ACE-ID + AGTR1-AC/CC group (134 ± 18 g·m−2 vs 133 ± 20 g·m−2, P = 0.880). The presence of ACE-DD + AGTR1 + AC/CC was strongly associated with LVH (OR = 4.6, P = 0.029). Moreover, subjects with LVH showed longer left ventricular isovolumetric relaxation time and higher end-systolic wall stress. The latter was strongly correlated to LVMI (r = 0.588), especially in the presence of ACE-DD + AGTR1 + AC/CC (r = 0.728).

Conclusions: LVMI may be greater in the presence of ACE- DD and AGTR1-AC/CC polymorphisms.

1Department of Human Movement, University "G. D'Annunzio," Chieti-Pescara, ITALY; 2Department of Cardiac Surgery, University of Catania, Catania, ITALY; 3Department of Biomorphology, University "G. D'Annunzio," Chieti-Pescara, ITALY; and 4Department of Basic and Applied Biology, University of L'Aquila, L'Aquila, ITALY

Address for correspondence: Angela Di Baldassarre, M.D., Department of Human Movement and Biomorphology, University "G. D'Annunzio," Chieti-Pescara, Italy; E-mail: a.dibaldassarre@unich.it.

Submitted for publication January 2009.

Accepted for publication September 2009.

The renin-angiotensin system, activated by physical exercise, may modulate the myocardial growth (11,15,19), either stimulating cardiac protein synthesis by angiotensin II (ANG II) or reducing the antiproliferative effect of bradykinin. In fact, the angiotensin-converting enzyme (ACE) plays a key role in the production of ANG II and in the degradation of bradykinin. Thus, an upregulation of ACE due to a long period of training might be involved in adaptive left ventricular hypertrophy (LVH), which is a very common feature in the heart of endurance athletes.

Although LVH is a well-known adaptive mechanism in athletes (11), different extents of left ventricular growth have been reported, independently from the length and the amount of training (14,18). Although LVH is a multifactorial process, depending on age range, ethnic heterogeneity, and population stratification, genetic factors seem to play the foremost role. A recent study demonstrated that ACE polymorphisms are the basis of different grades of LVH in endurance athletes having the same training period (14). In particular, the presence of the double deletion (D) of intron-16 of the gene encoding ACE is correlated to the highest plasma and tissue levels of the enzyme (30), including the heart (7), and this seems to be associated with a larger extent of LVH in endurance athletes rather than the presence of the insertion/deletion (ID) genotype (14,32). On the contrary, other investigators have not observed such an association (10,12,17,23,26,27).

To better understand the reasons underlying the variability of the effect of ACE genotypes on LVH, it may be useful to speculate about the possible mechanisms by which the ACE might influence the myocardial cell growth; Brull et al. (5) found an association between the B2BKR bradykinin receptor and the ACE D allele, suggesting that the presence of a higher level of ACE owing to the presence of a double D allele provides a greater degradation of bradykinin, thus reducing its antiproliferative effect. However, most known physiological effects of ANG II are mediated by angiotensin type 1 receptors (AGTR1), which are widely distributed in all organs, including the heart. AGTR1 is the major mediator of the physiological effects of ANG II (vasoconstriction, hypertrophy, and catecholamine liberation at sympathetic nerve endings). AGTR1 is the principal receptor mediating ANG II cardiac and circulatory effects. Recent advances in gene mapping have allowed the identification of single-nucleotide polymorphisms of the AGTR1 gene on chromosome 3, which are implicated in hypertension (4), increased aortic stiffness (2), and myocardial infarction (3). Although the AGTR1 A1166C polymorphism seems to be related to increased ANG II sensitivity (34), its association with LVH still remains undemonstrated either in pathological conditions or in relation to exercise (12,33,35). Hence, the aim of this study was to evaluate the role of ACE and AGTR1 polymorphisms in LVH promoting in endurance athletes.

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MATERIALS AND METHODS

Study population.

A group of 74 white male endurance athletes were enrolled in this study. All of them participated primarily in isotonic sports (66 long-distance and middle-distance runners, four endurance cyclists, and four triathlonists). Each athlete had trained for at least >10 h·wk−1 (mean 33 ± 30 h for at least 5 yr). None of them had a history of cigarette smoking, hypertension, CAD, diabetes mellitus, renal or hepatic dysfunction, or a positive family history of hypertrophic cardiomyopathy. Likewise, no medication was taken by any of the athletes for any reason, including anabolic steroids. Blood pressure was assessed in a sitting position from the right arm after 20 min of rest; systolic blood pressure was 122 ± 9 mm Hg (range = 105-140 mm Hg), and diastolic blood pressure was 75 ± 7 mm Hg (range = 55-85 mm Hg). The age of the enrolled athletes ranged from 25 to 40 yr (mean = 34 ± 5 yr). The subgroup (n = 3 subjects) with the ACE II genotype was excluded from the analyses because of its very small sample size. Table 1 shows the characteristics of enrolled athletes stratified by ACE genotypes. This study was approved by the ethical committee/institutional review board of the University of Chieti-Pescara. All the athletes signed an informed consent form before entering into the study.

TABLE 1

TABLE 1

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Echocardiography.

Echocardiographic studies were performed by the same expert operator (S.G.) using an ultrasound system (Vingmed, Horten, Norway) with a 3.7-MHz transducer. Echocardiographic studies consisted of M-mode, two-dimensional, and Doppler blood flow measurements. The left and right cavities and cardiac walls were measured following the recommendations of the American Society of Echocardiography (20). Using the apical four-chamber view, the M-mode cursor was placed through the junction of the tricuspid valve plane and right ventricle (RV) free wall to measure the systolic excursion of the tricuspid annular plane (TAPSE); TAPSE was determined by measuring the distance between the RV base and the tricuspid annular plane in systole and in diastole. Left ventricular mass (LVM) was determined according to the method of Devereux and Reichek (9) and was indexed to the body surface area (BSA) to yield the left ventricular mass index (LVMI). LVMI was calculated by applying the following formula: LVMI = LVM BSA × 1.5 (1). The cutoff level defining LVH was LVMI > 131 g·m−2 (37). Relative wall thickness (RWT) was calculated using the conventional formula, [IVSTd (interventricular septal thickness in diastole) + PWTd (posterior wall thickness in diastole)] LVEDD (left ventricular end-diastolic diameter), and was adjusted by increasing the value by 0.002 per year of age (8). Concentric hypertrophy was defined as coexistence of LVH and RWT age-adjusted higher than 0.42. Systolic function was assessed by the ejection fraction (31) from apical four- and two-chamber views, using a modified Simpson biplane method. Pulsed-wave Doppler of transmitral flow was used to assess overall diastolic function. The end-systolic wall stress (ESWS) was calculated using the formula SBP (systolic blood pressure) × LVESD (left ventricular end-systolic diameter) × 1.35/4 × PWTs (posterior wall thickness in systole) × (1 + PWTs) LVESD (SBP was represented by brachial artery systolic pressure) (6).

Pulsed Doppler measurements of LV filling were obtained in the apical four-chamber view, with the Doppler beam aligned perpendicularly to the plane of the mitral annulus and the sample volume placed between the tips of the mitral leaflets. Three consecutive beats during quiet respiration were acquired. Peak early diastolic flow velocity (E), peak flow velocity of atrial contraction (A), and their ratio (E/A) were measured at the maximum amplitude of E velocity. Deceleration time (DT) was measured from the peak E velocity to the point when the E-wave descent intercepted the zero line. Isovolumetric relaxation time was defined as the time interval from the closure of the aortic valve to the opening of the mitral valve, and it was measured by continuous-wave Doppler with the cursor positioned between the anterior mitral valve and the aortic valve in the apical five-chamber view. Doppler tissue imaging recordings were obtained from the lateral mitral valve annulus at end-respiratory apnea. Early diastolic (Em) and late diastolic (Am) velocities were measured, and Em/Am and E/Em ratios were calculated. Longitudinal left ventricle systolic function was assessed with the measurement of systolic velocities (Sm) in the Doppler tissue at the level of the lateral mitral annulus. All parameters were measured from the apical four-chamber view with a 2- to 5-mm sample volume and were recorded with simultaneous electrocardiography at a sweep speed of 50-100 m·s−1. For each measurement, the average of at least three measurements was used (27,28).

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Determination of genotypes.

Total genomic DNA was extracted from the whole blood with a DNA purification kit (Promega, Fitchburg, WI). The ACE genotype was detected by the polymerase chain reaction (PCR) amplification of a fragment of intron-16 of the ACE gene (19), with sense 5′CTGGAGACCACTCCCATCCTTTCT-3′ and antisense 5′GATGTGGCCATCCACATTCGTCAGAT-3′ primers (Sigma-Genosys, Cambridge, UK). The PCR mixture (50 μL) consisted of PCR Master Mix (Promega), 1 μg of genomic DNA, and 0.5 μM sense and antisense primers. After an initial denaturation at 94°C for 1 min 30 s, amplification was performed for 1 min at 94°C, 1 min at 63°C, and 2 min at 72°C for 30 cycles using a thermal cycler (PTC-100; MJ Research, Inc., Waltham, MA), followed by a final elongation step at 72°C for 10 min. The PCR products (190 and 490 bp for D and I alleles, respectively) were separated by 3% agarose gel electrophoresis and visualized with ethidium bromide staining. DNA fragments containing AGTR1 A1166C polymorphism were amplified in PCR with forward 5′ GCAGCACTTCACTACCAAATGGGC-3′ and reverse 5′CAGGACAAAAGCAGGCTAGGGAGA-3′ primers (Sigma). The PCR product (255 bp) was digested through the addition of a Hae III restriction enzyme (BioLabs, Lincoln, NE). The undigested wild-type PCR product and the cleavage products (233 and 22 bp) were separated on a 3% agarose gel and visualized by ethidium bromide staining.

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End-points and statistical analysis.

The primary end-point of this study was to evaluate whether the association between some particular ACE and AGTR1 polymorphisms could promote LV mass increment. The secondary end-points were to investigate the influence of these associations on systolic wall stress and diastolic function. Categorical data were expressed as count and percentage. Continuous variables, normally distributed, were reported as mean value and SD, otherwise as median value and interquartile range in the case of continuous variables nonnormally distributed. Comparison between the genotypes observed and the predictions from the Hardy-Weinberg model was done by χ2 analysis. In the case of categorical variables, the differences either among the three ACE genotypes or between genotypes DD and ID were evaluated also by χ2 test. As regards continuous variables, comparisons among the three groups were done by ANOVA test (normally distributed variables) or nonparametric Kruskal-Wallis test (nonnormally distributed). Post hoc analysis was also performed, but with group II being too small, only the P value between the DD and ID genotypes was reported. The effect of different genotypes on LVMI was investigated using Mann-Whitney U test. The association between genotypes and LVH was reported as an odds ratio (OR), 95% confidence interval (95% CI), and P value. The software used for statistical analyses was SPSS 13.0 (SPSS, Inc., Chicago, IL).

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RESULTS

Both ACE (P = 0.434) and AGTR1 (P = 0.905) genotype distribution and allele frequency were in agreement with the Hardy-Weinberg model. The ACE genotypes did not differ for all the investigated echocardiographic variables (Table 2), but LVMI was significantly higher in group DD rather than in group ID (P = 0.029). Considering LVH hypertrophy as LVMI higher than 131 g·m−2, group DD showed a prevalence of subjects, with LVH equal to 62.9%, whereas in group ID, it was 44.4% (P = 0.120). No association was found between ACE-DD and LVH (OR = 2.12, 95% CI = 0.82-5.46). In our series, evaluating the sole effect of AGTR1 A1166C polymorphisms, LVMI was again significantly higher in subjects with AGTR1-AC/CC than those with AGTR1-AA (142 ± 22 g·m−2 vs 132 ± 19 g·m−2, P = 0.036).

TABLE 2

TABLE 2

To better investigate the role of AGTR1 A1166C polymorphism, the comparison of LVMI and LVH between groups DD and ID was performed in two subsets. Twenty-nine subjects having a gene encoding for AGTR1 with single (AC) or double (CC) mutated alleles (transversion A→C in position 1166) were considered together. The other subset included 42 athletes without AGTR1 gene mutation (AA) (10). The ACE-II group was small (three cases) and was excluded from this subanalysis (Table 3). The four groups (ID-AA, ID-AC/CC, DD-AA, and DD-AC/CC) were similar for all the investigated characteristics, as well as in comparing 15 athletes having DD-AA/CC with the remaining ones. In the AA subgroup, 20 DD athletes showed slightly higher LVMI and LVH than 22 ID subjects but without any statistical significance. On the contrary, in the AC + CC subgroup, 15 DD athletes showed significantly higher LVMI than 14 ID athletes. The highest average LVMI was recorded in 15 athletes with ACE-DD and AGTR1-AC/CC genotypes; when the ACE-DD genotype was associated with the AGTR1-AA genotype, LVMI was similar to the one recorded in the ACE-ID and AGTR1-AC/CC association. The lowest value of LVMI was found in the association between ACE-ID and AGTR1-AA (Fig. 1). Moreover, after comparing 15 athletes in the ACE-DD + AGTR1-AC/CC subset with the 56 remaining subjects, the prevalence of LVH was significantly higher (80.0% vs 46.4%, P = 0.021). The prevalence of concentric hypertrophy in the group of 15 athletes with ACE-DD + AGTR1-AC/CC association was higher than in the remaining subjects (66.7% vs 33.9%, P = 0.021; OR = 4.61, 95% CI = 1.17-18.2). The presence of ACE-DD + AGTR1-AC/CC genotypes was significantly associated with LVH (OR = 4.61, 95% CI = 1.17-18.2) and concentric hypertrophy (OR = 3.90, 95% CI = 1.17-13.0).

TABLE 3

TABLE 3

FIGURE 1

FIGURE 1

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ESWS.

Figure 2 reported the strict relationship between LVMI and ESWS (r = 0.588, P < 0.001). Thus, the higher the LVMI, the higher the ESWS. This relationship is still present in the case of ACE-DD and AGTR1-AC/CC (r = 0.728, P = 0.002) as compared with the remaining cases (r = 0.421, P = 0.001). The same relationship was found in calculating LVMI according to Batterham et al. (1) (r = 0.467, P = 0.001). LV subjects with LVH showed significantly higher ESWS than those without LVH (306 ± 50 g·cm−2 vs 264 ± 34 g·cm−2, P < 0.001). The ACE genotype did not influence ESWS (DD = 287 ± 50 g·cm−2 vs ID = 286 ± 42 g·cm−2, P = 0.868), whereas the presence of AGTR1 A1166C polymorphism increased ESWS (AC/CC = 301 ± 57 g·cm−2 vs AA = 277 ± 38 g·cm−2, P = 0.034). In the presence of both ACE-DD and AGTR1-AC/CC, ESWS was 301 ± 66 g·cm−2, whereas in groups ACE-DD and AGTR1-AA, it was 282 ± 42 g·cm−2 (P = 0.121). Twelve subjects with ACE-DD, AGTR1-AC/CC, and LVH showed significantly higher ESWS than the remaining subjects (313 ± 68 g·cm−2 vs 281 ± 41 g·cm−2, P = 0.035).

FIGURE 2

FIGURE 2

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Diastolic function.

No difference was found when comparing the left ventricular isovolumetric relaxation time (LVIRT) between ACE-DD (66.3 ± 10.5 ms) and ACE-ID (64.6 ± 15.4 ms; P = 1.000); likewise, no difference was found when comparing AGTR1 polymorphism (AC/CC = 68.2 ± 14.0 ms) with AGTR1-AA (63.5 ± 12.4 ms; P = 0.149), and ACE-DD + AGTR1-AC/CC association (DD + AC/CC = 66.2 ± 9.0 ms) versus the remaining subjects (65.2 ± 14.1 ms; P = 0.799). All the other investigated diastolic parameters were similar in all different patterns. Nevertheless, in our series, subjects with LVH showed significantly longer LVIRT (71 ± 12 ms vs 59 ± 10 ms, P < 0.001). Moreover, LVIRT and ESWS were directly correlated (r = 0.298, P = 0.013).

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DISCUSSION

The main finding arising from this study is that the presence of ACE-DD and AGTR1-AC/CC polymorphisms produces a significant increment of LVMI with greater prevalence for concentric hypertrophy; in these subjects, both ESWS and LVIRT were significantly increased.

The presence of the double deletion (D) of intron-16 of the gene encoding ACE is correlated to the highest plasma and tissue levels of the enzyme (30), including the heart (7), and this seems to be associated with a larger extent of LVH in endurance athletes rather than the presence of the insertion/deletion (ID) genotype (14,31). Hernandez et al. (14) enrolled 61 male endurance athletes with age ranging from 25 to 40 yr, trained for long periods, stratifying LVMI and LVH for ACE genotypes (DD, ID, and II); the authors found that the presence of double D alleles provided greater LVMI (DD = 162.2 g·m−2 vs ID = 1.6 g·m−2, P = 0.031) with a higher prevalence of subjects with LVH (DD = 70.4% vs ID = 42.0%, P = 0.037). Although Harrap et al. (13) demonstrated that the effect of the DD genotype was independent of other known biologic factors that affect cardiac hypertrophy in normal individuals, their study is not supported by other studies, which have not demonstrated such an association (10,12,17,23,26,27).

The involvement of AGTR1 polymorphism in LVH was reported by Takami et al. (35), who demonstrated an association between AGTR1 polymorphism and higher LVMI in normotensive subjects. Fatini et al. (12) studied 28 healthy male soccer players before and after training, demonstrating that the contemporary presence of the ACE D allele and AGTR1 A1166C polymorphism (11 cases) induced greater LVMI increment after training (from 108.7 to 126.8 g·m−2, +16.7%) than in those athletes (13 cases) where the ACE D allele was associated with the AGTR1-AA genotype (from 114.1 to 122.8 g·m−2, + 7.6%). Unfortunately, the authors failed to highlight any statistical difference because of the small sample size.

The A1166C polymorphism has been found to be associated with higher ANG II sensitivity in hypertensive patients on a high-salt diet (32). It has been shown that ACE-I/D polymorphism predicted approximately half of the interindividual variability in the serum (30) and tissue (7) levels of the ACE. The ACE activity is highest in DD homozygotes, intermediate in ID heterozygotes, and lowest in II homozygotes. There are numerous pieces of evidence showing that increased ACE gene expression or ACE activity in the vessel wall stimulates the local rate of ANG II production (24), which influences tissue function and structure. Different studies have revealed an association between the A1166C polymorphism and the sensitivity of the ANG II type I receptor in human vessels; the C allele is associated with an increased vasoreactivity to ANG II in human arteries (36). The synergic effect of the C allele, that is, increased vasoreactivity and a local higher rate of ANG II D allele produced, according to our data, is able to promote LV mass growth by different pathways such as the G protein-coupled pathway, mitogen-activated protein kinases, and epidermal growth factor receptor, which are major mechanisms by which ANG II influences growth-related signaling pathways (16,22).

The positive relationship between left ventricular mass and systolic wall stress has already been demonstrated (38). In a cohort of renal-hypertensive rats, left ventricular mass and end-systolic stress showed a significantly positive relationship (r = 0.77). Moreover, the importance of ANG II and AGTR1 was revealed in that subset of rats receiving a high dose of ACE inhibitor or AGTR1 antagonist; in fact, high-dose administration of these antihypertensive drugs for 12 wk provided both LVMI and ESWS reduction. In humans, many articles, however, investigated only indirectly the relationship between ACE system polymorphism and ESWS in left ventricle pathological hypertrophy. It is well known that in aerobic exercise, the rise of wall tension secondary to an increase of preload and afterload during physical exercise is an important stimulus for the development of physiological ventricular hypertrophy. On the contrary, pathological hypertrophy is characterized by the presence of myocardial stiffness and intramyocardial connective tissue, resulting in early diastolic dysfunction and in an increase in systolic wall stress. In our series, the group of athletes with ACE-DD and AGTR1-AC/CC polymorphisms showed greater prevalence for concentric hypertrophy. It is possible that this association of genotypes could reduce the beneficial effect of exercise on cardiovascular remodeling by stimulating a translation from physiological to pathological LVH together with a vessel compliance reduction. It is well known that among the many vasoactive agents in vascular (patho)biology, ANG II seems to be particularly important because of its physiological role in regulating vascular tone, reactivity, structure ventricular diastolic properties, and wall stress. End-systolic stress is responsible for the early impairment of left ventricle filling, probably because of a reduction of left ventricle relaxation (25). Left ventricular afterload is strictly coupled to diastolic function that can be noninvasively evaluated by echocardiography. In subjects with LVH, we found a longer LVIRT that can be the expression of lesser diastolic performance. Another issue from this study is that the ACE-DD-dependent effects on LVH disappeared in the subjects with the AGTR1-AA genotype. Because the AGTR1 is located downstream of ACE in the renin-angiotensin system, the existence of epistasis between the two loci may explain our data. It can be assumed that low ANG II sensitivity associated with the AGTR1-AA genotype downstream would be able to cancel the effects of the ACE-DD genotype, which is associated with high ACE activity and hence high risk of LVH. This finding suggests that the risk of LVH in athletes with an ACE-DD genotype could be avoided if they have a AGTR1-AA genotype.

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Study limitations.

Let us just postulate hypotheses without proof for a biologic effect on the association between genetic factors and LVH found in this study. Thus, further studies focused on molecular mechanisms underlying exercise-induced cardiac growth are mandatory to confirm the role of ACE genotypes and AGTR1 polymorphisms in LVMI increment. The small sample size reduced the power of our conclusions. Finally, we had no data before the athletes started their training period, which might help us understand the role of investigated genetic patterns on developing LVH over time.

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CONCLUSIONS

Although with some limitations, this study demonstrated a significant association between ACE-DD plus AGTR1 A1166C polymorphisms and LVH. Even if we failed to highlight any implication of a genetic pattern on diastolic function, subjects having LVH showed longer LVIRT and higher ESWS. This difference could be associated with several factors such as age range, ethnic heterogeneity, population stratification, and other unknown factors. It is possible that the association of genetic polymorphism could account for the individual variability in myocardial performance and cardiac remodeling response to physical exercise. The modulation of particular gene involvement and its synergic effect should be considered to administer the right amount of sports activity.

This work was supported by MIUR 60% grant 2008.

The authors thank their mentor, Prof. Carmine Di Ilio, for advice and constant support.

The results of the present study do not constitute endorsement by the American College of Sports Medicine.

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Keywords:

ATHLETE'S HEART; ANGIOTENSIN SYSTEM; GENETIC; ECHOCARDIOGRAPHY

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