Left ventricular hypertrophy in Caucasian master athletes: Differences with hypertension and hypertrophic cardiomyopathy

International Journal of Cardiology 111 (2006) 113 – 119 www.elsevier.com/locate/ijcard

Left ventricular hypertrophy in Caucasian master athletes: Differences with hypertension and hypertrophic cardiomyopathy Giuseppe Limongelli a,b,*, Marina Verrengia b, Giuseppe Pacileo b, Antonello Da Ponte a, Paola Brancaccio a, Raffaele Canonico a, Antonello D’Andrea b, Berardo Sarubbi b, Flavio Cerasuolo b, Raffaele Calabro´ b, Francesco Mario Limongelli a a b

Department of Experimental Medicine, Second University of Naples, Naples, Italy Department of Cardiothoracic Sciences, Second University of Naples, Naples, Italy

Received 13 April 2005; received in revised form 27 June 2005; accepted 24 July 2005 Available online 2 November 2005

Abstract Aim: To study, by conventional echocardiography, left ventricular remodelling and function in master athletes, hypertension and hypertrophic cardiomyopathy. Methods: We studied 30 master athletes (MA; soccer players; mean age 43.9 T 5.9), 24 subjects with essential hypertension (HYP; 46.6 T 6), 20 patients with hypertrophic cardiomyopathy (HCM; 42.2 T 9) and 30 normal individuals (CG; 43.4 T 5). An integrated M-mode/two-dimensional echocardiographic analysis was performed to determine chambers dimensions, relative wall thickness (RWT) and left ventricular mass (LVM), indexed to height in meters raised to the power of 2.7 (LVM/h 2.7). Cut-off levels for LVM/h 2.7 and RWT were defined to assess 4 different patterns of LV geometric remodelling. In addition, we measured indexes of global systolic performance and indexes of global diastolic function. Results: LV wall thickness and LV end-diastolic dimensions were higher in MA than controls, but significantly lower than other groups. LVH/h2.7 was increased in 79% of HYP and in 95% of HCM, but was within the normal limits in MA. LV geometry was normal in 22 out of 30 MA (73%), while the remaining (8 athletes, 27%) showed a concentric remodelling. Systolic function (FS and EF) was normal in MA, but was slightly reduced in HYP and increased in HCM. Analysis of diastolic function showed an abnormal relaxation pattern in all HYP and 95% of HCM, but was normal in all MA. The ratio between peak filling rate and stroke volume (PFR / SV), a relatively independent index of diastolic function, was significantly greater in hypertensive patients with normal LV remodelling compared to those without it (4 T 0.39 vs. 4.91 T 0.19; P = 0.0002). Conclusion: MA showed lower values of wall thickness, LV dimensions and LV mass compared with HYP and HCM. Despite an abnormal remodelling, all the athletes showed a normal systolic and diastolic function. The differential diagnosis between MA, HYP and HCM is feasible by accurate, comprehensive standard Doppler echocardiography. D 2005 Elsevier Ireland Ltd. All rights reserved. Keywords: Master athletes; Hypertension; Hypertrophic cardiomyopathy; Left ventricular hypertrophy; Echocardiography

1. Introduction The ‘‘athlete’s heart syndrome’’ is a well known condition characterized by structural, electrical and functional adaptations of the myocardium consequent to regular * Corresponding author. Department of Cardiothoracic Sciences, Second University of Naples, Via L Bianchi c/o Monaldi Hospital, 80100, Naples, Italy. E-mail address: [email protected] (G. Limongelli). 0167-5273/$ - see front matter D 2005 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2005.07.033

physical training and consistent with the intensity, duration and type of activity [1 –12]. In athletes, left ventricular hypertrophy (LVH) often mimics disease states (hypertension or hypertrophic cardiomyopathy), and the distinction may have important implications, particularly when adults practice regular physical activity [13 –20]. To date, conflicting data have been reported about the nature (physiologic vs. pathologic) of LVH in master athletes and veterans [21 –25]. In addition, pathological LVH has recently been indicated as an independent

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risk factor of morbidity and mortality in adulthood [26,27]. An early identification of pathological LVH may reduce cardiac complications during physical activity in athletes. Recently, new echocardiographic techniques (as integrated backscattering and Doppler tissue imaging), have been proposed to study structural and functional changes of the myocardium in athlete hearts and to distinguish physiological from pathological hypertrophy [17,19,28,29]. However, although non-invasive and relatively effective, those complex echo techniques are only performed in few specialized centers. On the other hand, the advantage of conventional echocardiography consists of its feasibility, accuracy and low cost. On these grounds, here we analysed, by conventional echocardiography, left ventricular remodelling and function in master athletes and differences between physiological hypertrophy and models of pathological hypertrophy, such as hypertension and hypertrophic cardiomyopathy (HCM).

2. Methods

two standard deviations from normal ranges corrected for age and body size), in absence of a known cause of ventricular hypertrophy [32]. The referral reason were: angina (8 pts, 40%); dyspnoea (4 pts, 20%); presyncope (3 pts; 15%); syncope (1 pt, 5%); family screening (4 pts, 20%). Twelve of these patients underwent medical therapy: 10 patients with beta-blockers and 2 patients with verapamil. No one received permanent pacing or ICD or underwent surgery and/or alcohol ablation for septal reduction. All the patients studied were normotensive. 4) Control Group (CG): thirty individuals (mean age 43.4 T 5, BSA 1.81 T 0.1) with negative medical history, physical examination, ECG and echocardiographic analysis, who did not do any regular exercise. 2.2. Exclusion criteria Patients with secondary cardiomyopathy (metabolic or mitochondrial), valvular disease, congenital heart disease, arrhythmias, diabetes mellitus and pulmonary disease were excluded from the study.

2.1. Study population Subjects recruited for the study were assessed in the Department of Cardiothoracic Sciences (Chair of Cardiology) and in the Department of Experimental Medicine (Chair of Sports Medicine) at the Second University of Naples. Based on the following criteria, we enrolled 104 Caucasian males divided into 4 groups: 1) Master Athletes Group (MA): a competitive master athlete may be defined as anyone over 35 years old who plays on a team, or practices an individual sport in which regular competition is a component [30]. We selected 30 soccer players (mean age 43.9 T 5.9, BSA 1.81 T 0.17 cm2) with long-term athletic training ( 15 consecutive years; mean 24.8 T 4.39; range 15 –34 years), and working out 6 h / 3 days weekly over the last 5 years. 2) Hypertension Group (HYP): Twenty-four subjects (mean age 46.6 T 6, BSA 1.83 T 0.12) affected by essential arterial hypertension [31] for a period of 3 years or more. All patients underwent antypertensive therapy: 10 pts (41%) had a triple combination (5 pts, 21%, ace-inhibitors, betablockers and diuretics; 3 pts, 14%, angiotensin II antagonists, beta-blockers and diuretics; 2 pts, 8%, aceinhibitors, alpha-antagonist and diuretics); 8 pts (33%) had a double combination (5 pts, 21%, ace-inhibitors and diuretics; 2 pts, 8%, angiotensin II and diuretics; 1 pt, 4%, angiotensin II antagonists and beta-blockers;); 6 pts, 25%, received mono-therapy (3 pts, 12.5%, ace-inhibitors; 2 pts, 8%, beta-blockers; 1 pt, 4%, calcium-antagonists). Mean treatment period was 3.5 T 1.58 years. 3) Hypertrophic Cardiomyopathy Group (HCM): twenty individuals (mean age 42.2 T 9, BSA 1.84 T 0.1) with diagnosis of HCM, defined as presence of left, or both left and right, ventricular hypertrophy (wall thickness more than

3. Echocardiographic analysis 3.1. Cardiac dimension, thickness, mass and shape Echocardiographic examination was performed at rest using an HP Sonos 5500 system (Agilent Technologies, Andover, MA, USA) with a 2.5-MHz phased-array transducer by an experienced investigator (GL). Subjects were positioned at 45- left lateral position. Images of the heart were obtained in parasternal long and short axis, apical four/ five chamber view. An integrated M-mode and two-dimensional study was performed to determine wall thickness and chamber dimensions. A parasternal long and short axis view was used to measure interventricular septal (IVS) thickness, posterior wall (PW) thickness, LV end-diastolic diameter (LVEDD), LV end-systolic diameter (LVESD), right ventricular (RV) end-diastolic diameter (RVEDD) and thickness (RVW), left atrial size (LA) and aortic roof (AO), as recommended by the Committee of the American Society of Echocardiography [33]. Maximal wall thickness (MWT), defined as the greatest measurement within the LV wall, was measured in patients with HCM to assess the pattern of LVH. Three to five consecutive cardiac cycles were measured and the average was calculated. The ratio between IVS and PW thickness was calculated as an index of asymmetry. Left ventricular mass (LVM) was calculated according with the area –length method, and was indexed to body surface area (LVM/BSA) and height in meters raised to power of 2.7 (LVM/h 2.7) as previously reported [34]. Relative wall thickness (RWT or h / r) was defined as the ratio between the sum of the IVS and PW thickness (h) and the LVEDD (r). Cut-off levels for LVM and RWT were defined to assess LV geometry in athletes, hypertensive patients and controls. The

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sex specific 95th percentile for LVM/h 2.7 from normal subjects was used as one cut point and a relative wall thickness of 0.41 as second cut point, as previously described. In agreement with Ganau et al. [35], we defined 4 patterns of geometric remodelling: a) normal geometry (LVM/h 2.7 and RWT below the 95th percentile); b) concentric remodelling (normal LVM/h 2.7, elevated RWT); c) eccentric hypertrophy (elevated LVM/h 2.7, normal RWT); d) concentric hypertrophy (both LVM/h 2.7 and RWT above the 95th percentile). 3.2. Doppler measurements Left ventricular ejection time was measured from the Doppler aortic valve flow velocity envelope and ratecorrected to a heart rate of 60 bpm by dividing the square root of the RR interval on the electrocardiogram. Left ventricular outflow tract velocities were obtained in 5 chambers view by continuous-wave Doppler, and LV outflow gradients were calculated using the modified Bernoulli equation (LV outflow tract gradient: 4  [LV outflow tract velocities]). 3.3. Systolic function Indexes of global LV performance: ejection fraction (EF; calculated as the sum of end-diastolic volume and endsystolic volume divided by the end-diastolic volume), fractional shortening (FS; defined as end-diastolic dimension end-systolic dimension / end-diastolic dimension), and rate-corrected velocity of circumferential fiber shortening (VCFc; assessed as fractional shortening divided by rate-corrected ejection time) were calculated and used as the measures of global LV performances. 3.4. Diastolic function The pulsed Doppler volume sample was positioned about 1 cm below the mitral annulus in apical four chambers view to measure LV diastolic filling. Early peak flow velocity (E) and atrial peak flow velocity (A) were measured and the ratio E / A calculated. Deceleration time (DT) was calculated by measuring the time from the peak velocity of early flow to an extension of the rate decline of velocity to baseline. Isovolumic relaxation time (IVRT) was identified as the interval between the closure of the aortic valve and opening of the mitral valve. The peak filling rate normalized to stroke volume (PFR/SV) was calculated as peak velocity of early flow divided by mitral valvar velocity time integral [36]. 3.5. Quality control of echo images All the images were stored and reviewed independently by two experienced sonographers (GP,MV). Three to five measurements were assessed for each parameter. With offline analysis, no significant differences were evidenced and a consensus value was obtained for each parameter.

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4. Informed consent and drugs questionnaire Informed consent was obtained in accordance with Human Subject Committee Guidelines by the Monaldi Ethical Committee. All the subjects enrolled were informed about the methodology and aims and gave their consent to participate in this study. In addition, subjects were asked to fill out a questionnaire about the use of drugs or any substances able to provoke left ventricular hypertrophy in the previous five years. All the subjects who entered the study denied this use.

5. Statistical analysis Statistical analysis was performed by SPSS statistical package for windows, release 10.0 (Chicago, IL, USA). Data were expressed as mean T standard deviation. Single groups were compared using the Student’s t-test for unpaired data or the Mann – Whitney U test, as appropriate. One way analysis of variance with post hoc Scheffe’ test was used to compare different groups. Kruskal – Wallis test was applied when appropriate. Values were considered statistically significant when p < 0.05.

6. Results No significant differences were evidenced between MA, HYP, HCM and controls for age ( p = 0.186), sex (all male) and BSA ( p = 0.685). Heart rate (RR intervals) was lower in

Table 1 Cardiac dimensions, thickness, LV mass and relative wall thickness in master athletes, hypertension group, hypertrophic cardiomyopathy group and controls Control group (n-30)

MA (n-30)

HYP (n-24)

HCM (n-20)

RVDd- (mm) 20.4 T 2.1 22 T 3 21.4 T 1.8 20.3 T 2.7 LVDd*-‘ (mm) 48.5 T 3.5 52.5 T 2.2 55.3 T 2.6 42.5 T 2 LVSd*-‘ (mm) 34.2 T 3.1 33.7 T 2.4 37.4 T 2.7 23 T 2.9 IVS*-‘ (mm) 9.0 T 1.1 10.6 T 1.0 12.2 T 1.8 16.6 T 4.2 PW*-‘ (mm) 8.7 T 1.1 9.6 T 0.9 10.8 T 1.1 12.8 T 2.4 LA*- (mm) 34.4 T 2.2 36.4 T 3.4 39.7 T 4.3 40.8 T 6.4 Ao*‘ (mm) 26 T 2.4 28.2 T 2.8 32.2 T 3.8 27.4 T 2.1 LVM*- (g) 165.5 T 20.6 204.7 T 22.4 231.8 T 25.4 236 T 32.3 LVM/BSA*100.9 T 7.4 113.1 T 9.7 126.36 T 11.1 128.23 T 18.6 (g/cm2) LVM/h 2.7*39.8 T 3.2 45.8 T 3.4 54.7 T 4.9 55.82 T 5.8 (g/cm) RWT*-‘ 0.37 T 0.04 0.39 T 0.90 0.41 T1.12 0.69 T 3.35 Septum/PW*-‘ 1.05 T 0.22 1.34 T 0.18 1.22 T 0.17 1.59 T 0.56 RVDd=right ventricular diastolic diameter; LVDd=left ventricular diastolic diameter; LVSd=left ventricular diastolic diameter; IVS=interventricular septum; PW=posterior wall; LA=left atrium; Ao=aorta; MA=master athletes; HYP=hypertension group; HCM=hypertrophic cardiomyopathy group. P < 0.05: *MA vs. Hyp; -MA vs. HCM; ‘Hyp vs. HCM.

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Fig. 1. Interventricular septum (IVS) measures in master athletes (MA), hypertension (HYP), hypertrophic cardiomyopathy (HCM) and controls (CG).

MA (934 T 104 ms) compared with CG (855 T 82; p = 0.001), HYP (789 T 112; p > 0.001) and HCM (860 T 193; p = 0.05). Ventricular dimensions, thickness, LVM, LVM/BSA, LVM/h 2.7, RWT and septum to PW ratio are reported in Table 1. Interventricular septum measures in the four groups are shown in Fig. 1. LVM / BSA (abnormal when > 125 g/m2) was increased respectively in the 10% of MA, 54% of HYP and 60% of HCM. LVH/h2.7 was abnormal (> 51 g/m2) in 79% of hypertensive patients and in 95% of HCM. LV geometry was normal in 22 out of 30 MA (73%), while the remaining (8 athletes, 27%) showed a concentric remodelling (Fig. 2A). Among the HYP, 19 patients (79%) showed an abnormal left ventricular remodelling (Fig 2B): 1 patient (4%) had a concentric remodelling, 4 patients (17%) had concentric hypertrophy and 14 patients had eccentric hypertrophy (58%). The pattern of left ventricular hypertrophy (LVH) was asymmetric in 14 HCM patients (70%: 10 pts showed MWT at anterior IVS; 3 pts showed MWT at anterior and posterior IVS; 1 pt showed MWT at anterior IVS and lateral wall), concentric in 5 (25%), apical in 1 patient (5%). Measurements of systolic and diastolic function parameters and differences between groups are reported in Table 2. The measurement of FS and EF in MA were significantly lower than HCM, but significantly higher than HYP. No differences in global systolic function were seen in MA, HYP and HCM depending on different patterns of hypertrophy. The E / A ratio was < 1 (abnormal relaxation) in 2 controls (2 / 30; 7%), all HYP (100%) and almost all HCM (19 / 20; 95%), but was normal in MA. No difference in E / A ratio was seen in MA, HYP and HCM regarding different type of remodelling. However, in hypertensive patients PFR/SV was significantly greater in subject with normal LV remodelling than in those with abnormal remodelling (4 T 0.39 vs. 4.91 T 0.19; p = 0.0002). No differences of PFR/SV were seen in MA and HCM compared to different patterns of remodelling. Table 2 Systolic and diastolic function in master athletes, hypertension group, hypertrophic cardiomyopathy group and controls Control group MA (n-30) (n-30) FS*-‘ (%) 34.1 T 3.1 EF*-‘ (%) 65.6 T 4.4 VCFc*(circ/s) 0.97 T 0.14 Ew*-(cm/s) 78.56 T 12.9 Aw*‘ (cm/s) 64.4 T 18.2 Ew/Aw*1.32 T 0.51 PFR/SV*-(SV/s) 5.43 T 0.83 DT (cm/s) 172 T 12 IVRT (cm/s) 95 T 6

Fig. 2. A: Left ventricular geometry in master athletes (MA) group; B: Left ventricular geometry in hypertension group (HYP).

HYP (n-24)

35.6 T 4.2 32.2 T 3.9 64.4 T 5.4 59.8 T 5.7 1.16 T 0.15 0.77 T 0.10 138.9 T 35.9 90.1 T18.4 89.5 T 33.7 114.6 T 20.7 1.67 T 0.53 0.79 T 0.13 5.54 T 0.66 4.15 T 0.50 176 T 10 118 T 12 82 T 5 244 T 22

HCM (n -20) 37 T 2.5 73.4 T 5.6 / 85.1 T17.1 100 T 20.6 0.86 T 0.12 4.5 T 0.68 108T9.5 236T12

FS=fractional shortening; EF=ejection fraction; VCFc=rate corrected velocity of circumferential fibers; Ew=E-wave; Aw=A-wave; PFR=peak filling rate; SV=stroke volume; DT=deceleration time; IVRT=isovolumic relaxation time; MA=master athletes; HYP=hypertension group; HCM=hypertrophic cardiomyopathy group. P < 0.05: *MA vs. Hyp; -MA vs. HCM; ‘ Hyp vs. HCM.

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7. Discussion 7.1. LVH in master athletes: morphological and functional findings In 1898 Henschen was the first to describe a cardiac enlargement in athletes, starting the debate on the physiological or pathological nature of the so called ‘‘athlete’s heart’’, and concluding that this adaptation was a normal response of the heart to increased loading, and beneficial by enabling the athlete to perform more work [1]. More recent findings suggest that LVH is structurally and functionally normal only in an early stage, becoming abnormal afterwards, as part of a continuum from a physiologic to a pathologic condition [37]. Although the beneficial effect of physical exercise on cardiovascular function and health is well known, the lack of studies in older subjects raises some questions about cardiovascular function and the nature of LVH after long term training [21,22]. In this study, we analysed structural and functional cardiac changes in 30 male MA playing soccer competitively for 15 years or more. In athletes, LV wall thickness and LV end-diastolic diameter are both generally increased compared to sedentary controls as a compensatory response (according to the law of Laplace) to chronic pressure or volume overload in power and endurance athletes respectively, determining an increase in left ventricular mass [5 – 19]. The upper limits of normal LV wall thickness and LV end-diastolic diameter are well known [5]. Generally, both IVS and PW thickness are increased, with only 2% of the athletes having a LV wall thickness  13 mm and about 5% having a LV end-diastolic diameter  60 mm [7,15]. In addition, LVH associated with an abnormal remodelling has been proposed as an indicator of disease state with an increased risk of morbidity and mortality [34,35]. In our population of athletes, LV wall thickness and LV end-diastolic dimensions were significantly increased compared to controls. However, none of the athletes showed LV wall thickness and LV end-diastolic dimension above the limits proposed. In addition, despite increased LV wall thickness, asymmetry of hypertrophy and an apparently abnormal remodelling, all the athletes analysed showed both normal systolic and diastolic function. Regarding diastolic function, the pattern of mitral inflow has been considered an extremely important parameter to identify the nature of hypertrophy [28,38,39]. However, besides LV relaxation and chamber stiffness, mitral inflow pattern depends on other factors, such as loading conditions. This is always normal in athletes < 40 years old [28,38,39], but in older athletes conflicting data have been reported [22,29,40]. Our findings of normal indexes of diastolic function may suggest that a normal diastolic function is probably a hallmark of the athlete’s heart, independent of age [19,21,28,39]. It is remarkable that, although Doppler mitral flow pattern is the result of a complex interplay of factors, the assessment of mitral peak filling rate normalized

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to stroke volume is relatively independent from preload, heart rate and position of sample volume and provides a more reliable non-invasive diastolic evaluation [36]. 7.2. LVH in hypertension and HCM: morphological and functional findings LVH has often been associated with the development of coronary artery disease, cerebrovascular disease and cardiac failure, and the risk increases considerably with age [26,27,41,42]. On the other hand, regression of hypertrophy is associated with a decline in all causes of mortality [26,27,41,42]. In agreement with previous reports [13,14,16,18,19], wall thickness was significantly higher in HCM and LV diameters in HYP compared with other groups, and LVM was increased in a considerably higher number of patients with pathological hypertrophy (both HCM and HYP) compared to athletes. In our study, the prevalence of LVH in HYP was significantly higher using LVM/h 2.7 than LVM/BSA. Indeed, several studies show a different accuracy when detecting LVH using different criteria [41,42]. Among 964 hypertensive patients participating in the LIFE trial, LVH was present in 70% according to LVM/BSA criteria and 76% by LVM/h 2.7 criteria, with higher prevalence of eccentric LVH (45 – 51%), compared to concentric LVH (25 –29%) and concentric remodelling (8– 11%)([43]). In addition, a LVM/h 2.7 > 51 g/m2.7, which represents approximately the 97.5th percentile for LV mass in adults, has recently been associated with a 4-fold risk of cardiovascular morbidity in hypertensive patients, indicating LVH as an independent risk factor for cardiovascular events [41 – 43]. In HCM, the measurement of LV hypertrophy is complicated by the asymmetric geometry of the left ventricle in HCM patients. Thus, the MWT, expression of the severity of the wall thickening, has been directly related to an adverse prognosis in patients with HCM, independently from any pattern of LVH (asymmetric, concentric, apical) [44]. Global systolic function was normal (or above the normal range) in HCM, but was reduced in HYP, independent of the type of LV remodelling. Previous reports suggested a relationship between RWT, type of LV remodelling and systolic function, showing that a depression of midwall shortening is most common in patients with concentric remodelling and concentric hypertrophy [45]. Although we found no relationship between LV remodelling and global systolic function, we cannot exclude the accuracy of this finding, since we did not analyse this specific parameter (midwall shortening). Diastolic function was significantly impaired, both in HYP and HCM patients. Doppler echocardiographic analysis of LV diastolic filling is widely considered of diagnostic importance for differential diagnosis between

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adaptive and pathological hypertrophy. Of interest, we found that PFR/SV, a relatively load independent parameter of diastolic filling, was significantly more impaired in hypertensive patients with abnormal remodelling (eccentric/ concentric LVH and concentric remodelling) than those with normal remodelling. Indeed, studies on hypertensive patients demonstrated a direct relationship between degree of LVH and impairment of diastolic filling [46]. Particularly, hypertensive patients with concentric or eccentric pattern of hypertrophy show a higher degree of diastolic impairment, than subjects with concentric or normal remodelling [46,47]. In addition, it has been observed that diastolic abnormalities appear early, often before the development of signs of systolic impairment and even before the appearance of LVH [48].

8. Conclusions In conclusion, MA showed lower values of wall thickness, left ventricular diastolic dimensions and left ventricular mass compared to HYP and HCM. Despite an abnormal remodelling, all the athletes showed normal systolic and diastolic function. The differential diagnosis between MA and different types of pathologic hypertrophy, such as HYP and HCM, is feasible with an accurate and comprehensive standard Doppler echocardiographic study.

9. Study limitation The development (and degree) of LVH is multifactorial. Although all the athletes denied the use of any drugs capable of causing LVH, we cannot exclude that hypertrophy could have been differently modulated by other causes (i.e. genotype). In addition, patients with hypertension and HCM were under treatment. In fact, the main limitation of doing a study of this nature is the ethical difficulty of analysing patients without medications (wash-out). The effect of each single medication on LVH and remodelling is difficult to say, as most patients took more than one medication.

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