Role of Doppler Diastolic Parameters in Differentiating Physiological Left Ventricular Hypertrophy from Hypertrophic Cardiomyopathy

Role of Doppler Diastolic Parameters in Differentiating Physiological Left Ventricular Hypertrophy from Hypertrophic Cardiomyopathy Gherardo Finocchiaro, MD, Harshil Dhutia, BSc, MRCP, Andrew D’Silva, MRCP, Aneil Malhotra, MBBChir, MRCP, MSc, Nabeel Sheikh, MRCP, PhD, Rajay Narain, MRCP, Bode Ensam, MRCP, Stathis Papatheodorou, MD, Maite Tome, MD, PhD, Rajan Sharma, BSc, MBBS, MD, Michael Papadakis, MRCP, MD, and Sanjay Sharma, BSc, MBChB, FRCP, MD, London, United Kingdom

Background: The association between athletic participation and alteration in diastolic function is not well established. The aims of this study were to determine the spectrum of Doppler parameters of left ventricular (LV) diastolic function in a large cohort of healthy athletes and to quantify the overlap between physiologic LV hypertrophy and hypertrophic cardiomyopathy (HCM). Methods: A retrospective analysis of indices of LV diastolic function was performed in 1,510 healthy athletes (mean age, 22 6 5 years; range, 13-33 years; 72% men). The results were compared with those from 58 young patients with HCM. Results: Septal E0 < 7 cm/sec and lateral E0 < 10 cm/sec were found in five (0.3%) and eight (0.5%) athletes, respectively. Septal E0 was >14.6 cm/sec in 170 (11%) and lateral E0 was >19.9 cm/sec in 430 (28%) athletes. Athletes aged >25 years showed lower E0 velocities compared with younger athletes (mean septal E0 , 11.8 6 6.1 vs 12.9 6 5.9 cm/sec [P < .001]; mean lateral E0 , 17.1 6 3.6 vs 19.3 6 4.1 cm/sec [P < .001]). Athletes with high indexed LV end-diastolic diameters (>32 mm/m2) exhibited lower septal E0 compared with athletes with normal indexed LV end-diastolic diameters (mean septal E0 , 11.9 6 6 vs 12.7 6 6 cm/sec; P = .002). Septal E0 < 10 cm/ sec and lateral E0 < 12 cm/sec showed the best accuracy in differentiating between HCM and athlete’s heart. Conclusions: Reduced septal and lateral E0 are rarely observed in young elite athletes. Tissue Doppler velocities tend to decrease with increasing age and LV size, and values representative of supernormal diastolic function are found in less than one-third of young athletes. Cutoff thresholds for Doppler parameters of diastolic function should be corrected for multiple demographic and clinical variables to differentiate cardiac adaptation to exercise from HCM in young individuals. (J Am Soc Echocardiogr 2018;31:606-13.) Keywords: Diastolic function, Athlete’s heart, Hypertrophic cardiomyopathy

The impact of exercise training on left ventricular (LV) structure has been studied extensively, and it is well established that athletes frequently demonstrate increased LV cavity size and LV mass.1 Endurance exercise training is thought to enhance early diastolic LV filling as assessed by increased E-wave velocity in the mitral From the Cardiology Clinical and Academic Group (G.F., H.D., A.D., A.M., N.S., R.N., B.E., S.P., M.T., R.S., M.P., S.S.), St. George’s, University of London and St. George’s University Hospital NHS Foundation Trust (G.F., H.D., A.D., A.M., N.S., R.N., B.E., S.P., M.T., R.S., M.P., S.S.), London, United Kingdom. G.F. is funded by the charity Cardiac risk in the young (CRY) and the Charles Wolfson Charitable Trust. H.D., A.M., S.P., M.P., and S.S. are funded by the charity Cardiac risk in the young (CRY). A.D.S. is funded by the British Heart Foundation (BHF). Conflicts of Interest: None. Reprint requests: Sanjay Sharma, BSc, MBChB, FRCP, MD, Cardiology Clinical and Academic Group, St. George’s, University of London, Cranmer Terrace, London SW17 0RE, United Kingdom (E-mail: [email protected]). 0894-7317/$36.00 Copyright 2017 by the American Society of Echocardiography. https://doi.org/10.1016/j.echo.2017.11.022

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inflow and increased E0 at the mitral annular tissue.2-4 Improved LV diastolic function is an essential mechanism for preserving a high stroke volume during exercise, particularly at high heart rates. Longitudinal studies examining the effect of intensive exercise on diastolic function have shown conflicting results. Sadaniantz et al.5 observed no change in mitral valve inflow Doppler velocities, despite a decrease in resting heart rate, in 27 sedentary men following a year of endurance training. Conversely, Rodrigues et al.6 reported an increase in septal and lateral wall E0 velocities after 6 months of aerobic training in healthy men. Recently Baggish et al.7 reported that endurance athletes tend to develop biventricular dilation with enhanced diastolic function, while strength athletes show isolated, concentric LV hypertrophy (LVH) with diminished diastolic function. The aims of this study were to determine the spectrum of Doppler indices of LV diastolic function in a large cohort of healthy athletes engaging in multiple different sporting disciplines and to quantify the overlap with hypertrophic cardiomyopathy (HCM) characterized by mild LVH. We hypothesized that there would be significant overlap in Doppler indices of diastolic function between athletes and young asymptomatic physically active individuals with mild HCM. We also

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Abbreviations

AUC = Area under the curve DTI = Doppler tissue imaging

sought to establish the variables associated with lower diastolic velocities (septal and lateral E0 ) on Doppler tissue imaging (DTI) in athletes.

HCM = Hypertrophic cardiomyopathy LV = Left ventricular

METHODS

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wave was defined as a Q wave with duration $ 40 msec or a Q/R ratio > 0.25. The normal frontal cardiac axis was considered to be >30 but <120 . Left atrial enlargement was defined by a P-wave duration $ 0.12 sec in the frontal plane associated with terminal P negativity in lead V1 of duration $ 0.04 sec and depth $ 1 mm. Twave inversion between leads V1 and V3 was considered as a normal juvenile electrocardiographic pattern in asymptomatic athletes <16 years of age.

LVEDDI = Indexed left enddiastolic diameter

Study Setting The United Kingdom does not LVH = Left ventricular support a state-sponsored carhypertrophy diac screening program in athRWT = Relative wall letes. However, the charitable thickness organization Cardiac Risk in the Young (www.c-ry.org.uk) has an established cardiac screening program for young individuals that also serves many professional sporting organizations in the United Kingdom. Details of the screening program have been reported elsewhere.8 Study Population Athletes. Between 2007 and 2014, 2,081 consecutive young highly trained athletes were evaluated using a health questionnaire, electrocardiography, and echocardiography for research purposes. Of these, 2,031 were considered free from cardiomyopathies or major valvular or congenital disease after electrocardiography and echocardiography. Data regarding diastolic function were incomplete or unavailable in 521 athletes, who were thus excluded from the study. We performed a retrospective analysis of diastolic function in a total of 1,510 athletes with complete data on diastolic function, including mitral valve inflow Doppler and tissue Doppler traces. The majority of athletes were professional club athletes, and 244 (16%) competed at the international level. Patients with HCM. From a cohort of 435 patients with HCM with complete diastolic function data enrolled in the inherited cardiac diseases database at St. George’s Hospital, we retrospectively analyzed a subgroup of 58 young (age < 30 years) asymptomatic (New York Heart Association functional class I) patients with HCM, the majority of whom engaged in recreational exercise for >3 h/wk (n = 45 [78%]), with normal LV systolic function (defined as LV ejection fraction > 50%). None of the patients with HCM was a competitive athlete. The diagnosis of HCM was based on the presence of significant LVH (end-diastolic wall thickness $ 15 mm on two-dimensional echocardiography) in the absence of other etiologies9 or wall thickness between 13 and 15 mm, in the presence of an electrocardiogram suggestive of HCM, family history of HCM, or a recognized causal sarcomeric gene mutation. Electrocardiography Standard 12-lead electrocardiography was performed as described elsewhere.10 The Sokolow-Lyon voltage criterion for LVH was defined as the sum of S in lead V1 and R in lead V5 or V6 $ 35 mm. ST-segment depression was considered significant if $0.1 mV in two or more contiguous leads. Biphasic T-wave inversion was considered abnormal if the negative deflection of the T wave exceeded 0.1 mV. T-wave inversion $ 0.1 mV in two or more contiguous leads was considered abnormal. Deep T-wave inversion was defined as a T-wave deflection $ 0.2 mV. An abnormal Q

Echocardiography Two-dimensional echocardiography was performed using a GE Vivid I (GE Healthcare, Tirat, Israel), Philips Sonos 7500, Philips iE33, or Philips CPX50 (Philips Medical Imaging, Bothell, WA). The echocardiographic protocol consisted of parasternal long-axis views of the ventricles, longaxis view of the aortic root and ascending aorta, basal short-axis view of the origin of the coronary arteries, midpapillary short-axis view of the left ventricle, apical four-, three-, and two-chamber views of the left ventricle, transmitral, and tissue Doppler. Digitized images of two beats were stored while one was analyzed. Digitized images were analyzed offline according to American Society of Echocardiography guidelines11 by cardiologists and expert sonographers. LV internal diameter, septal wall thickness, and posterior wall thickness and left atrial diameter were measured from two-dimensional images in the parasternal long-axis view at both end-diastole and end-systole.11 When measuring septal thickness, care was taken to exclude right ventricular septal bands. In measuring the LV posterior wall thickness, care was taken to exclude posterior wall chordae. Relative wall thickness (RWT) was defined as the ratio of the sum of the interventricular septum and posterior wall thickness in end-diastole to the LVend-diastolic diameter. RWTwas considered to be abnormal if >0.42.11 LV systolic function was measured by using the biplane Simpson rule from the apical four- and two-chamber views, fractional shortening, and visual assessment. LV ejection fraction > 50% was considered normal. LV filling was assessed using pulsed Doppler at the level of the tips of the mitral valve, whereby the E wave denoted early diastolic filling. Peak myocardial early diastolic velocity was measured at the lateral mitral annulus (lateral E0 ) and at the septal mitral annulus (septal E0 ). Particular attention was paid to aligning the ultrasound beam to the plane of excursion of the septal and lateral portion of the mitral annulus. Transmitral DTI early diastolic velocity ratio (E/E0 ) was calculated for all athletes and patients with HCM using both septal and lateral E0 . Recommendations published in 200912 classified septal and lateral 0 E as reduced when <10 and <13 cm/sec, respectively. The most recent (2016) recommendations13 define septal E0 as reduced when <7 cm/sec and lateral E0 when <10 cm/sec. Table 1 summarizes the age-adjusted normal values for Doppler tissue–derived diastolic measurements. We considered E0 velocities as indicative of a supernormal diastolic function when above average plus 1 SD according to the reference values for healthy individuals aged 20 to 40 years, as proposed by the study of Caballero et al.14 (i.e., septal E0 > 14.6 cm/sec and lateral E0 > 19.9 cm/sec).

Ethical Approval Ethical approval was granted by the National Research Ethics Service, Essex Research Ethics Committee in the United Kingdom. Written consent was obtained from individuals $16 years of age and from a parent or guardian for those <16 years of age.

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HIGHLIGHTS  This study evaluated diastolic function in over 1,500 young athletes and 58 patients with mild HCM.  Indices of diastolic function were abnormally low in # 0.5% athletes.  Less than 30% of athletes showed supranormal indices of diastolic function.  Indices of diastolic function were lower in athletes aged > 25years-old.  Indices of diastolic function were lower in athletes with enlarged LV cavity dimensions.  Septal E’ < 10 cm/sec and lateral E’ < 12 cm/sec best differentiate HCM from athlete’s heart. Statistical Analysis Statistical analysis was performed using PASW version 18.0 (SPSS, Chicago, IL). Case-control matching was performed using MedCalc version 17.4 (MedCalc Software, Ostend, Belgium). Results are expressed as mean 6 SD for continuous variables and as number of cases and percentage for categorical variables. Comparison between groups was performed using Student t tests for continuous variables with adjustment for unequal variance if needed and c2 or Fisher exact tests for categorical variables. Variables that were correlated with the dependent variable in univariate analysis were selected and entered into the multivariate model. Logistic regression analysis was used to determine the factors independently associated with septal E0 velocity < 10 cm/sec and lateral E0 velocity < 13 cm/sec. Values were expressed as the hazard ratio and confidence interval. Receiver operating characteristic curve analysis was performed according to DeLong et al.15 Focusing on a subgroup of age- and sexmatched athletes (n = 102) and patients (n = 46) with HCM with RWT > 0.42, we calculated the optimal cutoff values for septal and lateral E0 , according to Zweig and Campbell16 using MedCalc version 17.4.

RESULTS Demographic Characteristics and Sporting Disciplines The study cohort included 1,510 young athletes aged 22 6 5 years (range, 13–33 years). The majority were men (n = 1,097 [73%]) and white (n = 1,404 [94%]). Athletes trained for 19.5 6 2.2 hours per week (Table 2) and participated in 32 different sports, the commonest of which were football (n = 450 [30%]), cricket (n = 122 [8%]), swimming (n = 115 [8%]), and cycling (n = 85 [6%]). Patients with HCM (mean age, 21 6 3 years; range, 5–29 years) had a similar prevalence of male sex (n = 46 [79%]).

Echocardiographic Characteristics The echocardiographic features of the cohort are summarized in Table 2. Eighty-eight athletes (6%) showed LV end-diastolic diameters > 32 mm/m2. These athletes exercised an average of

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20 6 6 hours per week and comprised mainly football players (n = 19 [22%]) and cyclists (n = 16 [18%]). The average interventricular septal and posterior wall thickness were 9.3 6 1.3 mm (range, 6–15 mm) and 9.0 6 1.1 mm (range, 6–13 mm), respectively. Seventy-two athletes (5%) exhibited maximal wall thickness $ 12 mm. The mean left atrial diameter was 35 6 5 mm. LV systolic function was normal in the entire study population. The average E/A ratio and deceleration time were 2.1 6 0.7 and 199 6 35 msec, respectively. On the basis of previous recommendations,12 143 athletes (9%) exhibited reduced septal E0 velocities (< 10 cm/sec), 66 (4%) had reduced lateral E0 velocities (< 13 cm/sec), and 21 (1.3%) revealed reductions in both septal and lateral E0 velocities. According to the more recently proposed cutoffs,13 reduced E0 velocities (septal E0 < 7 cm/sec and lateral E0 < 10 cm/sec) were found in five (0.3%) and eight (0.5%) athletes, respectively. None of the athletes exhibited an average E/E0 ratio > 14. Electrocardiographic Abnormalities in Athletes with Reduced Indices of LV Diastolic Function Of the 11 athletes with reduced septal E0 or lateral E0 velocity or both, one (9%) showed abnormal results on electrocardiography in accordance with the international recommendations for electrocardiographic interpretation.17 Among the 1,499 athletes with normal LV diastolic parameters, 11 (0.7%) showed abnormal results on electrocardiography. All 12 athletes had inferior T-wave inversion. None of the athletes showed lateral T-wave inversion, significant ST-segment depression, or pathologic Q waves. Variables Associated with E0 Velocities on Tissue Doppler Athletes with LVend-diastolic diameter/body surface area > 32 mm/m2 exhibited lower septal E0 compared with athletes with LV end-diastolic diameter/body surface area # 32 mm/m2 (11.9 6 6 vs 12.7 6 6 cm/ sec, P = .002). Athletes >25 years of age showed lower E0 velocities compared with younger (13–25 years of age) athletes (septal E0 , 11.8 6 6.1 vs 12.9 6 5.9 cm/sec [P < .001]; lateral E0 , 17.1 6 3.6 vs 19.3 6 4.1 cm/sec [P < .001]). Athletes aged 13 to 15 years showed average septal E0 of 12.9 cm/sec and lateral E0 of 20.1 cm/sec compared with athletes aged 31 to 33 years, who showed average septal E0 of 10.8 cm/sec (P < .001) and lateral E0 of 15.9 cm/sec (P < .001; Figure 1A). There were no significant differences in E0 velocities between athletes engaging in dynamic, mixed, and static sports (Figure 1B). At a multivariate analysis, age > 25 years was the only variable independently associated with septal E0 < 10 cm/sec (hazard ratio, 2.82; 95% CI, 2.01–4.15; P < .001) and lateral E0 < 13 cm/sec (hazard ratio, 1.91; 95% CI, 1.11–3.18; P = .01). Septal E0 > 14.6 cm/sec was observed in 170 athletes (11%), whereas lateral E0 > 19.9 cm/sec was found in 430 (28%; Figure 2). Comparison between Athletes and Young Patients with HCM Septal E0 values were significantly higher in athletes compared with patients with HCM (12.6 6 2.5 vs 7.4 6 2.7 cm/sec, P < .001). Similar results were also observed for lateral E0 (18.8 6 4.1 vs 10.4 6 4.2 cm/sec, P < .001); E/A > 2 was observed in 731 athletes

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Table 1 Normal values for tissue Doppler–derived diastolic measurements Recommendations for evaluation of diastolic function (2009)* Age (y)

16–20

21–40

41–60

>60

Septal e0 (cm/sec)

14.9 6 2.4 (10.1–19.7)

15.5 6 2.7 (10.1–20.9)

12.2 6 2.3 (7.6–16.8)

10.4 6 2.1 (6.2–14.6)

Lateral e0 (cm/sec)

20.6 6 3.8 (13–28.2)

19.8 6 2.9 (14–25.6)

16.1 6 2.3 (11.5–20.7)

12.9 6 3.5 (5.9–19.9)

NORRE study† Age (y)

20–40

40–60

$60

Septal e0 < 8 cm/sec

1.2%

19.7%

55.4%

Lateral e0 < 8 cm/sec

1.2%

5.7%

1.8%

15.6%

0

Lateral e < 10 cm/sec

19% 51.9%

NORRE, Normal Reference Ranges for Echocardiography. *Adapted from Nagueh et al.12 † Caballero et al.14

Table 2 Characteristics of the studied cohort Athletes (n = 1,510)

Patients with HCM (n = 58)

P

Demographic and clinical Age (y) Men Afro-Caribbean ethnicity

22 6 5

21 6 3

.14

1,097 (73)

46 (79)

.39 <.001

96 (6)

14 (24)

Hours of exercise per week

19.5 6 2.2

— 179 6 4

Height (cm)

178 6 11

Weight (kg)

74 6 13

84 6 10

<.001

Heart rate (beats/min)

60 6 11

68 6 16

<.001

IVS (mm)

9.3 6 1.3

15.9 6 5.6

<.001

MWT # 15 mm

1510 (100)

29 (50)

<.001

.49

Echocardiography

PW (mm) LVEDD (mm)

9.0 6 1.1

11.8 6 3.7

<.001

52.4 6 4.9

45.7 6 7.1

<.001

LVEDD/BSA (mm/m2)

27.7 6 2.3

21.4 6 3.1

<.001

LVESD (mm)

34.3 6 4.2

27.9 6 5.3

<.001

212 (14)

3 (5)

.08

88 (6)

2 (3)

<.001

0.33 6 0.13

0.63 6 0.2

<.001

35 6 5

38 6 7

<.001

199 6 35

187 6 41

.01

87 6 17

80 6 19

.002

LVEDD > 57 mm n (%) LVEDD/BSA > 32 mm/m2 RWT LA diameter (mm) DecT (msec) E wave (cm/sec) A wave (cm/sec)

43 6 12

52 6 20

<.001

E/A

2.1 6 0.7

1.7 6 0.5

<.001

E/A > 2

731 (48)

12 (21)

<.001

E/A < 1

12 (0.7)

7 (12)

<.001

12.6 6 2.5

7.4 6 2.7

<.001

143 (9)

39 (67)

<.001 <.001

Septal E0 (cm/sec) Septal E0 < 10 cm/sec Septal E0 < 7 cm/sec Lateral E0 (cm/sec) Lateral E0 < 13 cm/sec Lateral E0 < 10 cm/sec

5 (0.3)

23 (40)

18.8 6 4.1

10.4 6 4.2

<.001

66 (4)

36 (62)

<.001

8 (0.5)

22 (38)

<.001

Septal E/E0

7.1 6 1.8

12.4 6 6.9

<.001

0

Lateral E/E

4.8 6 1.2

9.2 6 5.5

<.001

Average E/E0

5.8 6 1.4

10.8 6 5.8

<.001

0 (0)

7 (12)

<.001

Average E/E0 > 14

BSA, Body surface area; DecT, deceleration time; IVS, interventricular septum; LA, left atrial; LVEDD, LV end-diastolic diameter; LVESD, LV endsystolic diameter; MWT, maximal wall thickness; PW, posterior wall.

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Figure 1 Trend between DTI-derived parameters of relaxation and age (years) (A). The red column represents septal E0 , and the green column represents lateral E0 . Both septal and lateral E0 tend to decrease with age. (B) Septal and lateral E0 velocities in dynamic, mixed, and static sports (no significant differences according to the type of sport).

Figure 2 Athletes with supernormal Doppler parameters of diastolic function. Septal E0 was >14.6 cm/sec in 11%, and lateral E0 was >19.9 cm/sec in 28%.

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Table 3 Sensitivity and specificity for septal and lateral E0 on tissue Doppler in athletes and young patients with HCM with RWT > 0.42 (102 athletes, 46 patients with HCM) Cutoff values derived from Nagueh et al.13

Septal E0 < 7 cm/sec Sensitivity

46% (31%–61%)

Specificity

100% (97%–100%)

0

Lateral E < 10 cm/sec Sensitivity

43% (29%–59%)

Specificity

97% (98%–100%)

E/A < 1 Sensitivity

14% (5%–26%)

Specificity

99% (98%–99%)

Figure 3 Proposed algorithm for the differential diagnosis between athlete’s heart and HCM using Doppler parameters of diastolic function.

Average E/E0 > 14 Sensitivity

13% (4%–27%)

Specificity

100% (96%–100%)

Optimal cutoff values from present analysis

AUC

Septal E0 < 10 cm/sec Sensitivity

82% (66%–95%)

Specificity

94% (88%–98%)

0.94 (0.90–0.99)

Lateral E0 < 12 cm/sec Sensitivity

67% (52%–81%)

Specificity

96% (93%–99%)

0.92 (0.88–0.97)

E/A < 1.8 Sensitivity

63% (47%–77%)

Specificity

67% (57%–73%)

0.69 (0.59–0.78)

Average E/E0 > 7.9 Sensitivity

79% (63%–91%)

Specificity

94% (87%–98%)

0.93 (0.87–0.98)

AUC, Area under the curve. Cutoffs according to international recommendations are shown in the first part of the table. Optimal cutoffs derived from receiver operating characteristic curve analysis are shown in the second part of the table.

(48%) and 12 patients (21%) with HCM, while E/E0 > 14 was found in none of the athletes and in 12% of patients (P < .001; Table 2). We selected a subgroup of athletes and patients with HCM with RWT > 0.42 (102 athletes and 46 patients, Supplemental Table 1, available at www.onlinejase.com) for comparison and calculated the sensitivity and specificity for septal and lateral E0 velocities in differentiating physiologic LVH from HCM (Table 3). The sensitivity for septal E0 < 7 cm/sec was 46% (31%–61%), and the specificity was 100% (97%–100%). The sensitivity for lateral E0 < 10 cm/sec was 43% (29%–59%), and the specificity was 97% (98%–100%). We calculated the optimal E0 , E/A, and average E/E0 cutoff values to distinguish the two entities using receiver operating characteristic analysis in the same subgroup of athletes and patients. The optimal cutoffs for a diagnosis of HCM were septal E0 < 10 cm/sec (sensi-

tivity, 82% [66%–95%]; specificity, 94% [88%–98%]; area under the curve [AUC], 0.94 [0.90–0.99]), lateral E0 < 12 cm/sec (sensitivity, 67% [52%–81%]; specificity, 96% [93%–99%]; AUC, 0.92 [0.88–0.97]). For E/A, the best cutoff threshold was < 1.8 (sensitivity, 63% [47%–77%]; specificity, 67% [57%–73%]; AUC, 0.69 [0.59–0.78]). For average E/E0 , the best cutoff threshold was >7.9 (sensitivity, 79% [63%–91%]; specificity, 94% [87%–98%]; AUC, 0.93 [0.87–0.98]; Table 3, Supplemental Figure 1, available at www.onlinejase.com). In Figure 3, we propose an algorithm for the differential diagnosis between physiologic LVH and HCM on the basis of Doppler parameters of diastolic function. Follow-Up Diagnosis in Athletes None of the athletes showed overt features of cardiomyopathy on baseline echocardiography or during follow-up. Thirty-seven athletes (2.4%) revealed minor congenital or valvular abnormalities (bicuspid aortic valve, n = 7 [0.5%]; mitral valve prolapse, n = 3 [0.2%]; patent foramen ovale, n = 10 [0.7%]; small atrial septal defect, n = 2 [0.1%]; mild aortic regurgitation, n = 9 [0.6%]; mild mitral regurgitation, n = 3 [0.2%]; possible cor triatratum, n = 2 [0.1%]; and mild pulmonary stenosis, n = 2 [0.1%]). Interobserver Reliability The average difference between two independent readers (interobserver variability based on 80 echocardiograms) was 0.3 6 0.02 cm/ sec for lateral E0 (k = 0.92) and 0.3 6 0.01 cm/sec for septal E0 (k = 0.93).

DISCUSSION This cross-sectional study provides data on conventional Doppler parameters of LV diastolic function in a large cohort of elite athletes. Supernormal diastolic function was observed in fewer than one third of athletes, in contrast with what was reported in previous studies in smaller cohorts.18,19 A minority of athletes showed reduced Doppler tissue imaging velocities, according to the most recently published recommendations.13 Several variables, including age and LV dimension, appear to determine these parameters. Variables used to assess LV relaxation significantly overlap between athletes and young patients with HCM. The cutoffs of septal

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E0 < 10 cm/sec and lateral E0 < 12 cm/sec were found to be the most accurate in differentiating athletes with LVH from young patients with HCM and mild LVH. LV Relaxation in Athletes Invasive studies have shown that LV diastolic function plays a key role in the enhancement of stroke volume and is a major contributor to high levels of cardiorespiratory fitness and physical performance. Enhanced LV diastolic function after endurance training in previously sedentary individuals has been described in longitudinal studies.20 A meta-analysis of 59 studies with a total of 1,451 athletes21 reported that the E/A ratio was either normal or slightly (but not significantly) increased in athletes compared with control subjects. We did not compare our cohort with a control population, but we found similar results in our athletes, who had an average E/A ratio of 2.1 6 0.7, and almost 50% showed transmitral E/A ratios > 2. Previous studies evaluating septal and lateral wall motion in athletes have also shown increased peak early (E0 ) or reduced A0 tissue velocities compared with control subjects.18,22,23 Training previously sedentary individuals has demonstrated an improvement in diastolic function using DTI indices.6 In contrast, Caselli et al.24 showed that E0 values were lower in a large cohort of young white athletes (n = 1,145) compared with control subjects, and E0 velocities were relatively decreased in athletes with marked LVH or LV cavity dilation. Although training regimens involved in different types of sports have differing effects on cardiac volumes, geometry, and mass, which are determinants of diastolic function, we did not observe any significant sport-related differences in Doppler parameters of diastolic function in our cohort of athletes. Our results derived from a large cohort of elite athletes suggest that reduced E0 velocities are relatively rare. Most athletes reveal values within the normal range, some show values in the lower limits of normal, and fewer than one-third of athletes exhibiting supernormal parameters of diastolic function. Interestingly, we observed a significant relationship between DTI-derived septal velocities and LV cavity size. It is possible that reduced relaxation velocities reflect that a large left ventricle does not need to expand much to fill adequately in athletes. This finding could be synonymous with borderline low LV ejection fraction in many athletes with large left ventricles, as a large left ventricle does not need to contract much to generate an adequate stroke volume. Age is an important and strong determinant of myocardial relaxation as cardiac stiffness increases over time. This has been previously demonstrated in healthy subjects and in patients with cardiac diseases.12,25,26 We observed significant variability even in a relatively young cohort of athletes, suggesting that different thresholds for normality should be considered when evaluating an adolescent or adult athlete. Role of DTI in the Differential Diagnosis with HCM The differential diagnosis between physiologic LVH in athletes and HCM may be challenging with particular relevance to trained athletes in whom LV wall thickness falls in the ‘‘gray zone’’ of 13 to 16 mm.27,28 Abnormal LV filling is often observed in patients with HCM, and it is an important entity in the diagnostic algorithms used to differentiate the two entities.29 Our findings suggest that transmitral Doppler variables are significantly different between the two groups. Specifically, an E/A ratio < 1 was observed in fewer than 1% of our athletes, whereas it was common (12%) in patients with HCM. As previously demonstrated, patients with HCM showed reduced average early diastolic myocar-

Journal of the American Society of Echocardiography May 2018

dial (E0 ) velocities on DTI, suggesting that impaired relaxation is a primary feature of the condition. Reduced E0 velocities may be present even before the development of LVH in individuals with b-myosin heavy chain mutations.30 To tailor our analysis to the ‘‘gray zone,’’ we compared athletes with increased RWT with a cohort of patients with HCM of similar age and wall thickness. The established cutoffs of septal E0 < 7 cm/sec and lateral E0 < 13 cm/sec showed modest sensitivity and specificity when comparing athletes and young asymptomatic patients with HCM with mild morphology. Conversely cutoffs of septal E0 < 10 cm/sec and lateral E0 < 12 cm/sec were the most accurate in distinguishing the two entities. Our group has previously reported that athletes with HCM frequently show normal E0 velocities31; in this study, we observed that elite athletes may exhibit E0 values that are at the lower limits of normal or even decreased. Whereas the specificity of normal DTI diastolic parameters for diagnosing HCM is low in athletes affected with the disease, the sensitivity of normal diastolic parameters for excluding HCM in endurance athletes may not be as perfect as previously considered. We are hopeful that our findings and proposed cutoff values will aid the differentiation of physiologic LVH from HCM with mild hypertrophy. Limitations The present study had some limitations. The analysis was crosssectional, thus we cannot derive any inference about the role of exercise on the longitudinal alteration of diastolic function. Moreover, our DTI assessment included only parameters of relaxation, whereas other variables such as speckle-tracking were not assessed. We included diastolic indices at rest and not during or immediately after exercise, which may possibly differentiate physiologic LVH from HCM. Although the athlete and HCM cohorts were age and sex matched, the HCM cohort included a higher prevalence of patients of Afro-Caribbean descent, and this may have affected diastolic function. The analysis was retrospective and did not include indexed left atrial volume, cardiopulmonary exercise testing, or diastolic stress testing. Moreover, we did not reevaluate the findings of receiver operating characteristic analysis in an independent validation cohort. Our study comprised young, highly trained athletes and the findings may be inapplicable to recreational or veteran athletes. Although our approach for distinguishing patients with HCM and athletes was dichotomous (athletes or patients with HCM), in clinical practice competitive athletes may have HCM, adding more complexity to the differential diagnosis. Further studies in larger cohorts of athletes with HCM are needed to clarify the accuracy of echocardiographic parameters in the differential diagnosis with physiologic LVH. CONCLUSIONS Reduced septal and lateral E0 velocities are rare in elite athletes. However, the commonly held perception that elite athletes always exhibit DTI diastolic parameters that are at the higher limits of normal or supernormal appears to be inaccurate on the basis of this large cohort. When considering the differential diagnosis between athletes with LVH and young active patients with HCM, the recently recommended cutoff values for DTI velocities (septal E0 < 7 cm/sec, lateral E0 < 10 cm/sec) show low sensitivity. Instead, our study suggests that cutoff values of septal E0 < 10 cm/sec and lateral E0 < 12 cm/sec appear to be the most accurate in distinguishing the two entities. This study highlights that Doppler parameters thresholds for normality should be corrected for multiple demographic and clinical variables.

Journal of the American Society of Echocardiography Volume 31 Number 5

SUPPLEMENTARY DATA Supplementary data related to this article can be found at https://doi. org/10.1016/j.echo.2017.11.022.

REFERENCES 1. Pelliccia A, Maron BJ, Spataro A, Proschan MA, Spirito P. The upper limit of physiologic cardiac hypertrophy in highly trained elite athletes. N Engl J Med 1991;324:295-301. 2. Caso P, D’Andrea A, Galderisi M, Liccardo B, Severino S, De Simone L, et al. Pulsed Doppler tissue imaging in endurance athletes: relation between left ventricular preload and myocardial regional diastolic function. Am J Cardiol 2000;85:1131-6. 3. Tumuklu MM, Ildizli M, Ceyhan K, Cinar CS. Alterations in left ventricular structure and diastolic function in professional football players: assessment by tissue Doppler imaging and left ventricular flow propagation velocity. Echocardiography 2007;24:140-8. 4. Baggish AL, Yared K, Weiner RB, Wang F, Demes R, Picard MH, et al. Differences in cardiac parameters among elite rowers and subelite rowers. Med Sci Sports Exerc 2010;42:1215-20. 5. Sadaniantz A, Yurgalevitch S, Zmuda JM, Thompson PD. One year of exercise training does not alter resting left ventricular systolic or diastolic function. Med Sci Sports Exerc 1996;28:1345-50. 6. Rodrigues ACT, de Melo Costa J, Alves GB, Ferreira da Silva D, Picard MH, Andrade JL, et al. Left ventricular function after exercise training in young men. Am J Cardiol 2006;97:1089-92. 7. Baggish AL, Wang F, Weiner RB, Elinoff JM, Tournoux F, Boland A, et al. Training-specific changes in cardiac structure and function: a prospective and longitudinal assessment of competitive athletes. J Appl Physiol 2008;104:1121-8. 8. Malhotra A, Dhutia H, Gati S, Yeo T-J, Dores H, Bastiaenen R, et al. Anterior T-wave inversion in young white athletes and nonathletes: prevalence and significance. J Am Coll Cardiol 2017;69:1-9. 9. Maron BJ, Maron MS. Hypertrophic cardiomyopathy. Lancet 2013;381: 242-55. 10. Clementy J, Bergere P, Bricaud H. Electrocardiography and vectocardiography in the evaluation of left ventricular hypertrophy due to pressure overload. Eur Heart J 1982;3(suppl A):37-47. 11. Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L, et al. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr 2015;28:1-39.e14. 12. Nagueh SF, Appleton CP, Gillebert TC, Marino PN, Oh JK, Smiseth OA, et al. Recommendations for the evaluation of left ventricular diastolic function by echocardiography. Eur J Echocardiogr 2009;10:165-93. 13. Nagueh SF, Smiseth OA, Appleton CP, Byrd BF, Dokainish H, Edvardsen T, et al. Recommendations for the evaluation of left ventricular diastolic function by echocardiography: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr 2016;29:277-314. 14. Caballero L, Kou S, Dulgheru R, Gonjilashvili N, Athanassopoulos GD, Barone D, et al. Echocardiographic reference ranges for normal cardiac Doppler data: results from the NORRE study. Eur Heart J Cardiovasc Imaging 2015;16:1031-41.

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15. DeLong ER, DeLong DM, Clarke-Pearson DL. Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach. Biometrics 1988;44:837-45. 16. Zweig MH, Campbell G. Receiver-operating characteristic (ROC) plots: a fundamental evaluation tool in clinical medicine. Clin Chem 1993;39:561-77. 17. Sharma S, Drezner JA, Baggish A, Papadakis M, Wilson MG, Prutkin JM, et al. International recommendations for electrocardiographic interpretation in athletes. J Am Coll Cardiol 2017;69:1057-75. 18. D’Ascenzi F, Cameli M, Zaca V, Lisi M, Santoro A, Causarano A, et al. Supernormal diastolic function and role of left atrial myocardial deformation analysis by 2D speckle tracking echocardiography in elite soccer players. Echocardiography 2011;28:320-6. 19. Claessens PJ, Claessens CW, Claessens MM, Claessens MC, Claessens JE. Supernormal left ventricular diastolic function in triathletes. Texas Hear Inst J 2001;28:102-10. 20. Goodman JM, Liu PP, Green HJ. Left ventricular adaptations following short-term endurance training. J Appl Physiol 2005;98:454-60. 21. Pluim BM, Zwinderman AH, van der Laarse A, van der Wall EE. The athlete’s heart. A meta-analysis of cardiac structure and function. Circulation 2000;101:336-44. 22. Vinereanu D, Florescu N, Sculthorpe N, Tweddel AC, Stephens MR, Fraser AG. Differentiation between pathologic and physiologic left ventricular hypertrophy by tissue Doppler assessment of long-axis function in patients with hypertrophic cardiomyopathy or systemic hypertension and in athletes. Am J Cardiol 2001;88:53-8. 23. Poh K-K, Ton-Nu T-T, Neilan TG, Tournoux FB, Picard MH, Wood MJ. Myocardial adaptation and efficiency in response to intensive physical training in elite speedskaters. Int J Cardiol 2008; 126:346-51. 24. Caselli S, Di Paolo FM, Pisicchio C, Pandian NG, Pelliccia A. Patterns of left ventricular diastolic function in Olympic athletes. J Am Soc Echocardiogr 2015;28:236-44. 25. Nagueh SF, Sun H, Kopelen HA, Middleton KJ, Khoury DS. Hemodynamic determinants of the mitral annulus diastolic velocities by tissue Doppler. J Am Coll Cardiol 2001;37:278-85. 26. Villari B, Vassalli G, Schneider J, Chiariello M, Hess OM. Age dependency of left ventricular diastolic function in pressure overload hypertrophy. J Am Coll Cardiol 1997;29:181-6. 27. Basavarajaiah S, Boraita A, Whyte G, Wilson M, Carby L, Shah A, et al. Ethnic differences in left ventricular remodeling in highlytrained athletes relevance to differentiating physiologic left ventricular hypertrophy from hypertrophic cardiomyopathy. J Am Coll Cardiol 2008;51:2256-62. 28. Maron BJ. Distinguishing hypertrophic cardiomyopathy from athlete’s heart physiological remodelling: clinical significance, diagnostic strategies and implications for preparticipation screening. Br J Sports Med 2009; 43:649-56. 29. Maron BJ, Pelliccia A, Spirito P. Cardiac disease in young trained athletes. Insights into methods for distinguishing athlete’s heart from structural heart disease, with particular emphasis on hypertrophic cardiomyopathy. Circulation 1995;91:1596-601. 30. Ho CY, Sweitzer NK, McDonough B, Maron BJ, Casey SA, Seidman JG, et al. Assessment of diastolic function with Doppler tissue imaging to predict genotype in preclinical hypertrophic cardiomyopathy. Circulation 2002;105:2992-7. 31. Sheikh N, Papadakis M, Schnell F, Panoulas V, Malhotra A, Wilson M, et al. Clinical profile of athletes with hypertrophic cardiomyopathy. Circ Cardiovasc Imaging 2015;8:e003454.

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APPENDIX

Supplemental Figure 1 Receiver operating curve for Doppler parameters of diastolic function in athletes and patients with HCM with RWT > 0.42: septal (Sept) E0 (A), lateral (Lat) E0 (B), E/A ratio (C), and septal-lateral average E/E0 ratio (D). The optimal cutoff for each parameter is expressed as ‘‘criterion,’’ with related sensitivity and specificity. Supplemental Table 1 Features of the subgroup characterized by RWT > 0.42 Variable

Athletes (n = 102)

Patients with HCM (n = 46)

P

Demographic and clinical 22 6 5

21 6 3

.14

1,097 (73)

46 (79)

.39

7 (7)

10 (22)

<.001

IVS (mm)

11.6 6 1.5

16.1 6 5.1

<.001

PW (mm)

10.6 6 1.1

11.9 6 3.9

<.001

LVEDD (mm)

48.7 6 4.3

44.1 6 6.8

<.001

2.0 6 0.6

1.7 6 0.5

<.001

Septal E0 (cm/s)

12.6 6 2.5

7.3 6 2.7

<.001

Lateral E0 (cm/s)

17.5 6 3.9

10.2 6 4.1

<.001

5.9 6 1.5

10.9 6 5.9

<.001

Age (y) Men Afro-Caribbean ethnicity Echocardiography

E/A ratio

Average E/E0

IVS, Interventricular septum; LVEDD, LV end-diastolic diameter; PW, posterior wall.