Methods

In the Korean Air Force, all pilots undergo medical screening every other year, and those who have been in service for a long time have to check their health in their twentieth and thirtieth working years at the Aerospace Medical Center of Republic of Korea referral center of the Korean Air Force. This study included all consecutive military populations that underwent medical screening from September 2010 to August 2012 at the Aerospace Medical Center. In total, 3,929 men with a mean age of 39.3 ± 8.7 years were screened with electrocardiography (ECG), and retrospectively, 23 men were enrolled according to the criterion of TWI. Follow-up ECG was performed 1 year from the initial detection of TWI and medical history and familial history of sudden cardiac death (SCD) were checked. Moreover, additional cardiovascular examinations including cardiac magnetic resonance imaging (cMRI), cardiac computed tomography angiography, transthoracic echocardiography (TTE), and treadmill testing were performed.

A 12-lead ECG was performed for all subjects (CardioTouch 3000; Bionet, Seoul, Korea). Electrocardiograms were recorded at a paper speed of 25 mm/s and at a standard gain of 1 mV/cm. Electrocardiographic parameters including T-wave voltages and polarity and ST-segment displacement were analyzed by 2 experienced cardiologists. TWI was diagnosed in the presence of a negative T wave of >1 mm in ≥2 contiguous leads. The T wave was reported as inverted when the T wave amplitude was from −0.1 to −0.5 mV, as deep negative when the amplitude was from −0.5 to −1.0 mV, and as giant negative when the TWI was deeper than 1.0 mV. The frontal plane QRS/T angle (QRS/T frontal) was defined as the absolute value of the difference between the frontal plane QRS axis and T axis, and was adjusted to the minimal angle by 360° angle if the angle was >180°. (The range of axis measurement was from −89° to 270° in the GE-Marquette ECG program. ) Exclusion criteria were bundle branch block and coexisting medical conditions reported to be associated with TWI. We excluded patients with TWI in V ₁ and V ₂ , which could be considered to represent the normal juvenile electrocardiographic pattern.

Subjects with TWI underwent additional study with the treadmill test, echocardiography, cardiac computed tomography, and cMRI. All subjects exercised to volitional exhaustion using the standard Bruce protocol. The 12-lead electrocardiogram and blood pressure (cuff sphygmomanometer) were recorded at rest, during the third minute of each exercise stage, at peak exercise, and at 2-minute intervals during recovery. The test was terminated either when the target heart rate was achieved or when any of the following occurred: severe angina, dyspnea, fatigue, hypotension, complex ventricular arrhythmia, and >1 mm ST-segment depression. T-wave pseudonormalization was defined as the occurrence of a change of polarity or a positive increase in polarity (>0.5 mV) in TWI in at least 2 adjacent precordial leads.

Two-dimensional echocardiography was performed by a cardiologist using Vivid 3 (GE Healthcare, Tirat Carmel, Israel) with a 3-MHz transducer. Left ventricular (LV) wall thickness was measured from 2-dimensional short-axis views and apical views at end-diastole.

A 64–detector row multidetector computed tomography scanner (LightSpeed VCT 64; GE Healthcare, Milwaukee, Wisconsin) was used for cardiac computed tomography angiography.

cMRI was performed using steady-state free precession breath-hold cines (TE 1.6 ms, TR 3.2 ms, and flip angle 608) in long-axis planes and sequential 7-mm short-axis slices (3-mm gap) from the atrioventricular ring to the apex. Late gadolinium enhancement images were acquired 10 minutes after intravenous gadolinium-DTPA (Schering, 0.1 mmol/kg) in identical short-axis planes using an inversion-recovery gradient-echo sequence. Inversion times were adjusted to null normal myocardium (typically 320 to 440 ms; pixel size 1.7 to 1.4 mm). Late gadolinium enhancement images were phase swapped to exclude artifacts. Ventricular volumes and function were measured for both ventricles using standard techniques and analyzed using semiautomated software (cMR tools; Cardiovascular Imaging Solutions, London, United Kingdom). All volumes and masses were indexed for age, gender, and BSA.

TWI that could not be defined etiologically despite all investigations was defined as idiopathic TWI. The diagnosis of HC was based on the demonstration of a hypertrophied nondilated LV with a wall thickness of ≥15 mm in the absence of another systemic or cardiac disease that is capable of producing that magnitude of wall thickening. Apical HC was defined as asymmetric LV hypertrophy predominantly at the apex, with a maximal apical wall thickness of >15 mm and a maximal apical/posterior wall thickness ratio of >1.5 by 2-dimensional echocardiography or cMRI. ADPM was defined to be present when the base of the papillary muscle originated from the apical 1/3 of the LV in the apical 4-chamber view, irrespective of concomitant hypertrophy in any of the apical segments.

All statistical analyses were performed using SPSS, version 18.0 (SPSS Inc., Chicago, Illinois), for Windows (Microsoft Corp, Redmond, Washington). Continuous variables are presented as mean ± SD and compared using t test. Pearson chi-square test was used to determine the significance of differences in categorical variables. A p value of <0.05 was considered statistically significant.

Results

Of 3,929 men, 0.6% of patients (n = 23, mean age 44.5 ± 8.8 years) were found to have TWI; 18 (0.5%) patients showed persistent TWI, 17 patients agreed to further evaluation ( Figure 1 ), and 5 returned to normal (5 of 22 [26.7%]; Figure 2 ). Of 17 subjects with persistent TWI, 8 had ADPM (47.1%; Figure 3 ); 5 had idiopathic TWI (29.4%); 3 had apical HC (17.6%) comprising 2 pure type (11.7%) and 1 apicolateral wall dominant mixed type (5.9%); and 1 had obstructive HC (5.9%).

Enrollment and outcome. ECG = electrocardiographic; LVOT = left ventricular outflow tract.

( A ) Initial electrocardiogram, TWI was observed in leads V ₃ and V ₄ . ( B ) 1-Year follow-up electrocardiogram, TWI disappeared.

Base of anterior papillary muscle originated from apex (arrow) , which is reported as ADPM, was observed.

The patients were divided into 2 groups: a benign group (idiopathic, 5 of 17 [29.4%]) and a potentially nonbenign group (the others, 12 of 17 [70.6%]; Table 1 ).

On initial ECG, the inverted T wave was deeper in subjects in the potentially nonbenign group (1.6 ± 0.5 vs 5.5 ± 3.3 mm, p = 0.021; Figure 4 ). In addition, a deep inverted T wave (>5 mm) was common in the potentially nonbenign group (p = 0.049). And the prevalence and distribution of TWI in the anterior leads were similar, but lateral lead (I, aVL, V ₅ , and V ₆ ) TWI (50% vs 0%, p = 0.049) was more prevalent in the potentially nonbenign group.

Depth of TWI between benign group and potentially non-benign group.

Obstructive HC exhibited a 3.75 m/s pulsed wave Doppler velocity of the LV outflow tract at rest and 4.38 m/s during the Valsalva maneuver; 15.2-mm interventricular septal thickness was observed at end-diastole, and this was Maron type 2 HC. He was aged 39 years and had a family history of SCD; his father had died suddenly at age 45 years while sleeping.

The mean age for apical HC was 51.3 years. The most thickened apical wall of pure-type apical HC was 16 mm. Mixed-type apical HC represented the apicolateral wall dominant type (apicolateral wall 15.2 mm, true apex 10.2 mm, and apicoseptal wall 10.2 mm with echocardiography) and was confirmed with cMRI (apicolateral wall 16.3 mm, true apex 11.3 mm, and apicoseptal wall 10.9 mm). The patient with apicolateral wall dominant apical HC had a family history of SCD; 3 of 4 of his siblings had died suddenly while at rest when they were not yet 35 years old.

Echocardiography showed all normal diastolic function except 1 grade 1 diastolic dysfunction in the benign group, 1 grade 1 diastolic dysfunction of 8 ADPMs, 2 grade 2 diastolic dysfunctions of 3 apical HCs, and 1 grade 2 diastolic dysfunction of 1 obstructive HC.

There was no significant coronary artery diameter stenosis in cardiac computed tomography angiography and myocardial delayed gadolinium enhancement in cMRI in all investigated patients.