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1 CE: amrta; JCM/21761; Total nos of Pages: 6; JCM Original article M-mode echocardiographic values in a cohort of young healthy individuals Alon Grossman a,b, Michal Benderly c,d, Alex Prokupetz a, Barak Gordon a and Ofra Kalter-Leibovici c,d Objectives To determine normal M-mode values in healthy young adults and to evaluate whether these values differ among those in whom echocardiography was performed routinely and those in whom echocardiography was performed based on clinical grounds. Methods A cross-sectional study evaluating a large cohort of young academy applicants of the Israeli air force in the years Studies were divided into those performed routinely and those performed because of abnormal ECG or physical examination findings. Echocardiographic variables were compared between the two groups and values are expressed as mean W SD. Results Echocardiography was performed routinely in 3525 applicants (age 18.5 W 1. years) and following a clinical referral in 3517 applicants (age 18.2 W.9 years). Those in whom echocardiography was performed routinely had slightly higher left ventricular end-systolic diameter (31.2 W 3.3 vs. 3.7 W 3.4 mm; P <.1) and aortic root diameter (28.5 W 2.1 vs W 2.2 mm; P <.1), and slightly lower left ventricular mass index (18.8 W 15.8 vs W 16.5 g/m 2 ; P U.5). o differences were noted between the two groups in left atrial diameter, left ventricular end-diastolic volume, posterior wall thickness and interventricular septum thickness. Conclusion Certain M-mode characteristics may differ (although to a slight degree) in young healthy individuals with electrocardiographic and physical findings compared with those with normal physical examination and electrocardiography. J Cardiovasc Med 213, 14: Keywords: echocardiography, medical decision, screening making a The Israeli Air Force Aero Medical Center, Tel Hashomer, b Department of Internal Medicine E, Rabin Medical Center, Beilinson Campus Affiliated to Tel Aviv University Sackler Medical School, Petah Tikva, c Unit of Cardiovascular Epidemiology, The Gertner Institute for Epidemiology and Health Policy Research, Tel Hashomer and d Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel Correspondence to Alon Grossman, MD, Rabin Medical Center, Beilinson Campus Affiliated to Tel Aviv University, Petah Tikva, Israel Received 3 April 213 Revised 19 May 213 Accepted 4 June 213 Introduction Echocardiography is a common modality for evaluation of structural abnormalities of the heart and is used both for the evaluation of clinical findings and for screening purposes. 1,2 Despite its extensive use in the general population, relatively few studies evaluated the normal echocardiographic parameters among young individuals. ormal values for echocardiographic measurements are based on data collected from relatively small cohorts 3,4 or were determined in the 197s and early 198s. 5,6 Since then, significant technologic improvements make it now possible to obtain direct digital measurements and to place the M-mode beam more accurately so that the measurements obtained are probably more accurate than those obtained in the past. The few studies that evaluated normal values of M-mode measures in recent years were performed in relatively heterogeneous populations, 7 9 making it difficult to apply their findings to young healthy individuals. It is particularly important to set normal echocardiographic values for young adults as they frequently undergo echocardiography as a part of the evaluation prior to participation in competitive sports. Morphologic echocardiographic abnormalities are poorly predicted by ECG and physical examination findings. 1 Yet, the association between ECG and physical examination and M-mode characteristics has not been studied previously. This study evaluated a large cohort of young healthy nonprofessional athletic adults in an attempt to set the normal values of M-mode echocardiographic measures for this population and to compare echocardiographic variables between individuals referred to echocardiography based on clinical suspicion and individuals in whom echocardiography was performed routinely. Methods Study population The study population consisted of year old male voluntary flight academy applicants. All applicants were previously screened to exclude significant medical conditions, including cardiovascular and respiratory diseases. All applicants with BMI greater than 3 kg/m 2 are disqualified from flight academy, and thus were excluded from the study. Applicants were evaluated by an aero medical physician at the Israeli air force aero medical ß 213 Italian Federation of Cardiology DOI:1.2459/JCM.b13e bf

2 CE: amrta; JCM/21761; Total nos of Pages: 6; JCM Journal of Cardiovascular Medicine 213, Vol o center. This evaluation included medical history, physical examination and a 12-lead resting ECG. All applicants underwent echocardiography prior to enlistment. Those in whom physical findings, medical history or ECG findings raised suspicion of the presence of cardiac disease underwent diagnostic echocardiography (these will be referred to from here on as clinical group ). Applicants who had no clinical indication for performance of echocardiography underwent routine echocardiography following a nonmedical selection process, which lasted approximately 4 6 months (these will be referred to from here on as routine group ). All echocardiographic studies in which morphologic abnormalities were identified were excluded from the analysis. Echocardiography studies We reviewed all routine echocardiographic studies of aircrew applicants performed at the Israeli air force aero medical center between January 1994 and January 21. All echocardiographic studies were obtained with one of three devices (HP 5 SOOS, ATL 5HDI and PHILIPS HD 11 XE). Second generation devices (HP 5 SOOS and ATL 5HDI) were used from 1994 to 28. A third generation device (PHILIPS HD 11 XE) was used from 28 onward. All studies were performed by one of three experienced technicians and interpreted by one of two cardiologists specialized in echocardiography. Transthoracic echocardiography included twodimension, M-mode and Doppler studies performed according to the American Society for Echocardiography guidelines for obtaining images, quantification of chamber dimensions and assessment of valvular disease All studies were performed in four windows (left and right parasternal long axis, parasternal short axis and apical four chamber view). In cases in which elevated pulmonary artery SBP or tricuspid regurgitation was suspected based on these four windows evaluation, a subcostal window is added. Measurements were corrected for body surface area. Left ventricular mass (LVM) was estimated as 1.5 [(left ventricular enddiastolic diameter (LVED) in mm þ posterior wall thickness in mm þ intraventricular septum, in mm) 3 - LVED 3 ]/1. Left ventricular mass index (LVMI) was calculated as LVM/BSA. The study was approved by the ethics committee of the Medical Corps of the Israel Defense Force (IDF ). Statistical analysis Continuous variables are presented as mean SD. Comparisons between individuals who underwent a clinical vs. those who underwent a routine test were tested with analysis of variance or the Welch test, where appropriate. To find combinations of M-mode characteristics that were closely related, we performed exploratory principal component analysis with Varimax (orthogonal) rotation. ext, multivariate analysis of covariance was used to study the differences in combinations of M-mode characteristics identified by principal component analysis between the two groups of participant, adjusted for age, BMI, heart rate, pulse pressure and SBP. The percentage of variability in predicted combination explained by clinical findings and covariates was computed as the ratio between the trace of the sum of square and cross-product matrix associated with an effect and the trace of the covariance matrix of M-mode characteristic combination. Differences in aortic root diameter between the two groups were assessed by analysis of covariance adjusting for the same covariates described above. Data were analyzed with the SAS software version 9.2 (SAS Institute, Cary, orth California, USA). Results Echocardiography was performed routinely in 3525 applicants ( routine group ) and following clinical referral in 3517 applicants ( clinical group ). Demographic and clinical characteristics of the two groups are presented in Table 1. Applicants in the routine group were, on average, 3.6 months older, had slightly higher weight and BMI at baseline examination, and slightly lower (but not statistically significant) DBP and heart rate. ormal distributions of posterior wall thickness, interventricular septal (IVS) thickness and LVMI are presented in Figs Echocardiographic findings of the entire cohort are presented in Table 2. Only left ventricular end-systolic volume (LVES), aortic root diameter and LVMI were different between the two groups. Left atrial diameter, posterior wall thickness, IVS thickness and LVED volume were similar between the two groups. Principal component analysis of the M-mode characteristics revealed three components: parameters related to heart volume including left atrial diameter, LVES volume and LVED volume; parameters related to LVM including posterior wall thickness, IVS and LVMI, and aortic root diameter (single variable). In multivariate analysis, using multivariate analysis of covariance, clinical attributes explained only.15% of the variability of the parameters related to heart volume and only.12% of the Table 1 Demographic characteristics of study population a Routine group ¼ 3525 Clinical group ¼ 3517 P value Age (years) <.1 Height (cm) Weight (kg) <.1 BMI (kg/m 2 ) <.1 SBP (mmhg) DBP (mmhg) Heart rate (beats/min) <.1 a Data are presented as means þ SD.

3 CE: amrta; JCM/21761; Total nos of Pages: 6; JCM Echocardiography healthy individuals Grossman et al. 3 Fig. 1 Screening echo Diagnostic echo Count Count Posterior wall Distribution of posterior wall thickness (mm) in study population. variability of the parameters related to the LVM. The contribution of the covariates (age, BMI, heart rate and SBP) to the variability of the heart volume parameters or the ventricular mass combination was modest. BMI was the most significant contributor to variability of both parameters related to heart volume (8.8%) and parameters related to LVM (3.7%). Results for aortic root (using analysis of covariance model) were similar with the test being performed based upon clinical suspicion explaining 1% of aortic root diameter variance and BMI explaining 4%. Discussion This study presents the normal M-mode parameters for young healthy males, with or without clinical findings suggestive of cardiac disease. Setting normal M-mode values in young individuals is crucial because most cardiac dimensions are age-dependant. Pediatric studies showed a correlation between age and M-mode values, 14,15 but such correlation has not been proven in adults. Thus, normal values reported in the literature based on populations with large age-range Fig. 2 Diagnostic echo Screening echo Count Count Septum Distribution of septal thickness (mm) in study population.

4 CE: amrta; JCM/21761; Total nos of Pages: 6; JCM Journal of Cardiovascular Medicine 213, Vol o Fig. 3 Screening echo Diagnostic echo Count Count LVMI_BSA Distribution of LVMI (g/m 2 ) in study population. LVMI, left ventricular mass index. may not be applicable to young individuals. 16,17 As cardiac dimensions are sex-dependant, 14,15 the lack of large studies in men makes it more difficult to draw conclusions about the sex-specific normal parameters. When screening young adults for physical activity or military service, the clinician is frequently faced with dilemmas regarding the normal values in this population and the need for further work up based on the values found on routine tests. ormal values for IVS and posterior wall thickness were set as 6 1 mm in adult males. 18 This study revealed that the 75th percentile for IVS thickness was 1 mm which is in accordance with the values presented in the literature, but the posterior wall thickness 75th percentile was 9 mm which seems to be lower than presented previously. These values did not differ between the routine and clinical groups. It is possible that because the study population consisted of physically active individuals, the IVS thickness represented physiologic adaptation, and thus was elevated compared with the posterior wall thickness, which is more representative of this population. Despite the fact that the normal echocardiographic values in adults are not corrected for age, this factor may influence cardiac dimensions, and thus the values presented in this study are more representative of a population of young healthy males, frequently evaluated during preparticipation screening. ormal values for LVMI are considered as values of less than 132 g/m The 75th percentile for LVMI in this cohort was In contrast with IVS thickness, in which the 75th percentile was compatible with previous reports of normal echocardiography value in adults, the LVMI values were lower. We do not have an explanation for the relatively low values of LVMI in this cohort compared with previously reported values, but it may have been expected that LVMI will be higher than previously reported in this study because the studied population was physically active and may have had left ventricular hypertrophy. Endurance athletes have a higher prevalence of left ventricular hypertrophy, and most patterns of physiologic hypertrophy are concentric. 2 The fact that this cohort did not have extremely elevated LVMI values probably reflects the fact that the individuals in this cohort were physically active, but not professional athletes. Thus, the data and normal values presented represent a cohort of young physically active males, but do not represent the normal values of endurance athletes. A previous study reported that physical examination and ECG did not contribute significantly to the diagnosis of Table 2 M-mode characteristics of study population a Entire cohort (742) Routine group (3525) Clinical group (3517) P value b Aortic root (mm) <.1 Left atrial diameter (mm) Left ventricular end-diastolic diameter (mm) Left ventricular end-systolic diameter (mm) <.1 IVS thickness (mm) Posterior wall thickness (mm) LVMI (g/m 2 ) a Data are presented as means þ SD. b Comparisons between individuals evaluated routinely, and those evaluated based on clinical suspicion. IVS, interventricular septal; LVMI; left ventricular mass index.

5 CE: amrta; JCM/21761; Total nos of Pages: 6; JCM Echocardiography healthy individuals Grossman et al. 5 cardiac abnormalities in young individuals. 1 A recent study revealed that echocardiography has the potential to identify significant cardiac anomalies in individuals in whom ECG and physical examination are completely normal. 2 This study revealed that in individuals without significant morphologic abnormalities, M-mode parameters are not different in those with and without physical or electrogradiographic abnormalities. This may serve as additional evidence that physical examination and ECG do not contribute significantly to the estimation of cardiac dimensions and supports previous studies that showed that these are not sensitive enough for the identification of significant cardiac disease. Thus, it would seem that adequate screening for athletes or military applicants should include echocardiography, particularly as this modality may be performed out of hospital at a significantly lower cost. 21 Despite the minimal demographic differences between the two groups, we believe that both are representative of a similar population of young healthy individuals. Thus, the values reported for the entire cohort are applicable to young physically active nonathlete males and may serve as the norms that may guide further evaluation. This study has several limitations. Because enlistment to flight academy is voluntary, applicants are almost exclusively men and because women data were scarce, only male studies were included. Yet, the large male cohort makes it possible to draw firmer conclusions regarding this specific population. Another limitation is the fact that only studies interpreted as normal were included in the analysis. This was done in order to set normal values in this population, this requiring the exclusion of individuals with significant cardiac disease. Thus, the differentiation between clinical and routine studies refers only to normal echocardiographic parameters this limiting the ability to draw conclusions regarding the clinical significance of these screening modalities in the identification of significant cardiac disease. Because several previous studies analyzed the correlation between ECG/physical examination and echocardiography and no previous study analyzed the association between M-mode characteristics and ECG/ physical examination, we believe this study contributes additional information regarding the association between these two modalities. As there is continuous debate regarding the feasibility of performing routine echocardiography in athletes and military applicants, we believe this study adds additional information to this field. Another limitation of this study is that echocardiography was analyzed by a single interpreter. There is significant interobserver variability in the interpretation of echocardiographic studies, 22 and this may limit the accuracy of these findings. Yet, because most studies performed in real life are interpreted by a single interpreter, and as this study analyzes objective measurements we believe the findings of this study are representative of the studied population and are applicable to similar populations. An additional limitation is the fact that the long study period resulted in analysis of different echocardiographic equipment, some of it relatively old and not in current use. Technology has certainly evolved significantly during this time period and it is questionable whether the different studies could be included in the same analysis. Yet, because of the will to include a large amount of studies in order to set the normal values for this population, we still believe that this large cohort has its advantages. Conclusion M-mode characteristics in young healthy males may be slightly different than values reported previously in the literature. Age-specific values should serve as norms when evaluating this highly selected population. M- mode characteristics differ to a mild degree in those with abnormal ECG or physical findings compared with those who undergo routine echocardiography, but this is true only in individuals without significant cardiac disease. This may serve as additional evidence for the performance of echocardiography as a primary screening modality in athletes and military applicants. References 1 Wand O, Prokupetz A, Assa A, Barenboim E. Screening echocardiography of military aircrew candidates: aero medical implications. Cardiology 21; 115: Corrado D, Basso C, Schiavon M, Thiene G. Screening for hypertrophic cardiomyopathy in young athletes. Engl J Med 1998; 339: Weiman AE. Principles and practice of echocardiography, 2nd ed Philadelphia: Lea & Febiger; Otto C. Textbook of clinical echocardiography, 3rd ed Philadelphia: W.B. Saunders Company; Epstein ML, Goldberg ST, Allen HD, et al. Great vessel cardiac chamber and wall growth patterns in normal children. Circulation 1975; 51: Henry WL, Ware JH, Gardin JM, et al. Echocardiographic measurements in normal subjects: growth-related changes that occur between infancy and early adulthood. Circulation 1978; 57: Knutsen KM, Stugaard M, Michelsen S, Otterstad JE. M-mode echocardiographic findings in apparently healthy, nonathletic orwegians aged 2 7 years: influence of age, sex and body surface area. J Intern Med 1989; 225: Trivedi SK, Guptn OP, Jain AP, et al. Left ventricular M-mode echocardiographic measurements of Indian population. J Assoc Physicians India 1993; 41: Lauer MS, Larson MG, Levy D. Gender-specific reference M-mode values in adults: population-derived values with consideration of the impact of height. J Am Coll Cardiol 1995; 26: Grossman A, Prokupetz A, Levy Y. Physical examination and electrocardiographic findings in young subjects: are they predictive of echocardiographic findings? Cardiology 211; Zoghbi WA, Enriquez-Sarano M, Foster E, et al. American Society of echocardiography: recommendations for evaluation of the severity of native valvular regurgitation with two-dimensional and doppler echocardiography. J Am Soc Echocardiogr 23; 16: Lang RM, Bierig M, Devereux RB, et al. 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6 CE: amrta; JCM/21761; Total nos of Pages: 6; JCM Journal of Cardiovascular Medicine 213, Vol o 13 Gardin JM, Adams DB, Douglas PS, et al. American Society of echocardiography: recommendations for a standardized report for adult transthoracic echocardiography: a report from the American Society of Echocardiography s omenclature and Standards Committee and Task Force for a Standardized Echocardiography Report. J Am Soc Echocardiogr 22; 15: Rowlatt UF, Rimoldi HJ, Lev M. The quantitative anatomy of the child s heart. Pediatr Clin orth Am 1963; 1: Lester LA, Sodt PC, Hutcheon, Arcilla RA. M-mode echocardiography in normal children and adolescents: some new perspectives. Pediatr Cardiol 1987; 8: Wong RC, Yip JW, Gupta A, et al. Echocardiographic left ventricular mass in a multiethnic Southeast Asian population: proposed new gender and age-specific norms. Echocardiography 28; 25: Ângelo LC, Vieira ML, Rodrigues SL, et al. Echocardiographic reference values in a sample of asymptomatic adult Brazilian population. Arq Bras Cardiol 27; 89: Domienik-Karłowicz J, Lichodziejewska B, Lisik W, et al. Electrocardiographic criteria of left ventricular hypertrophy in patients with morbid obesity. Ann oninvasive Electrocardiol 211; 16: Rodriguez Requero JJ, Iglesias Cubero G, Lopez de La Iglesia J, et al. Prevalence and upper limit of cardiac hypertrophy in professional cyclists. Eur J Appl Physiol Occup Physiol 1995; 7: Rizzo M, Spataro A, Cecchetelli C, et al. Structural cardiac disease diagnosed by echocardiography in asymptomatic young male soccer players: implications for preparticipation screening. Br J Sports Med 212; 46: Weiner RB, Wang F, Hutter AM Jr, et al. The feasibility, diagnostic yield and learning curve portable echocardiography for out of hospital cardiovascular disease screening. J Am Soc Echocardiogr 212; 25: Zeltser I, Cannon B, Silvana L, et al. Lessons learned from preparticipation cardiovascular screening in a state-funded program. Am J Cardiol 212; 11:92 98.

7 JCM Manuscript o Journal of Cardiovascular Medicine (JCM) Typeset by Thomson Digital for Lippincott Williams & Wilkins Dear Author, During the preparation of your manuscript for typesetting, some queries have arisen. These are listed below. Please check your typeset proof carefully and mark any corrections in the margin as neatly as possible or compile them as a separate list. This form should then be returned with your marked proof/list of corrections to the Production Editor. QUERIES: to be answered by AUTHOR/EDITOR QUERY O. QUERY DETAILS RESPOSE O QUERY

Ref 1. Ref 2. Ref 3. Ref 4. See graph

Ref 1. Ref 2. Ref 3. Ref 4. See graph Ref 1 Ref 2 Ref 3 1. Ages 6-23 y/o 2. Significant LVM differences by gender 3. For males 95 th percentiles: a. LVM/BSA = 103 b. LVM/height = 100 4. For females 95 th percentiles: a. LVM/BSA = 84 b. LVM/height

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