Geometric predictors of left ventricular outflow tract obstruction in patients with hypertrophic cardiomyopathy: a 3D computed tomography analysis

Geometric predictors of left ventricular outflow tract obstruction in patients with hypertrophic... Abstract Aims To establish geometric predictors of left ventricular outflow tract obstruction (LVOTO) in hypertrophic cardiomyopathy (HCM) patients by use of cardiac computed tomography (CT). Methods and results A total of 141 consecutive patients with HCM who underwent cardiac CT comprised the analytic sample. The degree, pattern, and extent of left ventricular (LV) hypertrophy were evaluated using 3D CT. Abnormality of papillary muscle (PM), mitral valve, and aorto-mitral angle were evaluated quantitatively. Multivariable logistic regression analysis and sensitivity analysis were performed to reliably identify predictors of LVOTO. LVOTO was present among 40 (28.4%) patients. Those with LVOTO displayed a higher prevalence for having a spiral pattern of LV hypertrophy (e.g. 51 vs. 16%, P < 0.001), a longer anterior mitral leaflet (AML) length (e.g. 18.0 vs. 15.6 mm, P = 0.007), and a longer distance from lateral PM base to LV apex (e.g. 26.4 vs. 22.0 mm, P < 0.001), as compared with the non-LVOTO group. Multivariable logistic regression revealed all three variables [i.e. spiral pattern (95% confidence interval (CI), 3.75, 1.59–8.84); AML length (95% CI, 1.20, 1.03–1.40); the distance between lateral PM base and LV apex (95% CI, 1.09, 1.01–1.19)] retained significance after adjustment for numerous covariates. Conclusion Spiral pattern of LV hypertrophy, the length of AML, and the distance between lateral PM base and LV apex were independent predictors of LVOTO in patients with HCM. hypertrophic cardiomyopathy, left ventricular outflow tract obstruction, computed tomography, papillary muscle Introduction Left ventricular outflow tract obstruction (LVOTO) is one of the chief determinants of clinical outcomes related to hypertrophic cardiomyopathy (HCM).1–6 Patients with LVOTO are often at higher risk of progression to severe heart failure or death from heart failure or stroke.1,3–6 Considering LVOTO could be a potential target for treatment, understanding its mechanisms represents an important dimension of preventive medicine for augmenting patient care. In recent past, studies using 3D echocardiography revealed geometric determinants of LVOTO that included mitral leaflet area and papillary muscle (PM) displacement.7 Although 3D echocardiography has an advantage of assessing mitral valve (MV) apparatus owing to high temporal resolution, it is somewhat limited in evaluating the entire left ventricular (LV) myocardium and PM. Notably, other prior studies that employed a cardiac magnetic resonance (MR) imaging approach documented that PM abnormalities such as displacement or altered morphology of PM8–10 might be additional morphologic determinants of LVOTO as well as LV geometric modification. Yet, while cardiac MR might prove more useful towards evaluating the morphology of the LV and PM compared with echocardiography, a drawback of this procedure is its inability to assess the complex LVOT geometry with 2D cine imaging.11,12 Moving forward, cardiac computed tomography (CT) has greatly advanced as an accurate and reliable tool for assessing global LV function beyond coronary arteries.13 Further still, because of its excellent spatial resolution, anatomic details of the MV and subvalvular apparatus can be visualized.14 It also permits for the acquisition of a 4D data structure of the heart, which can be manipulated and displayed in any desired plane. The purpose of the current study, therefore, was to seek out geometric predictors of LVOTO in HCM by use of cardiac CT with the expectation of a more complete interrogation of LV morphology, including PM as well as MV. Methods Study population Between January 2011 and August 2014, a total 147 patients with HCM (myocardial thickness ≥ 15 mm echocardiography) who underwent cardiac CT were retrospectively enrolled. Among these, total six patients were excluded from the study; three patients presented with underlying cardiac diseases including old infarction (n = 1) and cardiac valvular disease (n = 2), and the other three patients had previous history of heart transplantation (n = 2) and septal myectomy (n = 1). Hence, a total of 141 patients met the diagnostic criteria of HCM, which requires echocardiographic evidence of myocardial hypertrophy (myocardial thickness ≥ 15 mm) without any other cardiac or systemic disease. Reasons for CT examination included coronary artery disease evaluation (n = 42), aggravated symptoms (i.e. dyspnoea, chest pain, or syncope) (n = 40), exclusion of coronary artery disease in non-symptomatic patients (n = 40), and preoperative evaluation of geometric changes in the left ventricle and MV (n = 19). The appropriate institutional review board approved this retrospective study and waived the requirement to obtain informed consent from patients. Echocardiography Conventional 2D and Doppler echocardiography were performed using commercially available ultrasound equipment (iE33, Philips Medical Systems, Andover, MA, USA) with a S5-1 transducer by cardiologists who were expertly trained in echocardiography procedures. LVOTO was defined as a peak resting gradient ≥ 50 mm Hg on Doppler echocardiography.1,15 CT image acquisition CT examinations were performed using a second-generation dual-source CT system (Somatom definition; Siemens Medical Solution, Forchheim, Germany). The scan was acquired after the injection of 60–80 mL of iomeprol-400 (Iomeron, Bracco Imaging SpA, Milan, Italy), followed by 40 mL of a 30:70 mixture of contrast and saline. Retrospective electrocardiography scanning with pulsing (30–80%) was performed, and tube current modulation based on the patient’s body size was utilized in an effort to reduce the radiation dose. The mean estimated radiation effective dose was 8.4 mSv. The imaging parameters included: detector collimation 64 × 0.6 mm, gantry rotation time 280 ms, pitch 0.17–0.38 (adapted to the heart rate), tube current 240–450 mA, and tube voltage 80–120 kV. LV geometry analysis in CT CT image analysis was performed by two experienced readers and any disagreement was resolved by consensus. End-diastolic phase (90 or 0% or R-R interval) of cardiac CT was used to analyse the LV geometric pattern using commercially available software (Syngo Via; Siemens). The epicardial and endocardial borders of the LV myocardium were semi-automatically defined on the multiplane visualization, while PMs were excluded attentively. All CT analysis was masked to clinical and echocardiographic data. All CT measurements were indexed to body surface area. LV hypertrophy pattern For evaluation of LV hypertrophy pattern, the Bullseye maps which demonstrate LV wall thickness using different colours were used (Figure 1). Colour scale of the bullseye map was adjusted so that the red area could represent hypertrophied area (i.e. ≥15 mm in myocardial thickness). A myocardial segment with more than 10% of hypertrophied area was defined as the thickened segment. The maximum and mean thickness in each myocardial segment and the number of thickened segments was evaluated. Based on the bullseye map, the patterns of LV hypertrophy were categorized into asymmetrical septal hypertrophy, pure apical hypertrophy, diffuse, and mixed hypertrophy (Figure 2). The spiral pattern of LV hypertrophy, defined as the longitudinal counterclockwise spiral rotation of hypertrophy, was assessed on the bullseye map.16,17 The aorto-mitral angle, defined as the angle between the aortic and mitral annulus, was measured using a three-chamber view (Figure 3). Figure 1 View largeDownload slide Bullseye map according to a 17-segment model. Three LV short-axis (basal, mid, and apical) planes are shown at end-diastole (A–C). The bullseye map (D) shows the thickness of 17 segments using a colour scale. The red area represents the thickened myocardium at more than 15 mm. Figure 1 View largeDownload slide Bullseye map according to a 17-segment model. Three LV short-axis (basal, mid, and apical) planes are shown at end-diastole (A–C). The bullseye map (D) shows the thickness of 17 segments using a colour scale. The red area represents the thickened myocardium at more than 15 mm. Figure 2 View largeDownload slide The patterns of left ventricular (LV) wall hypertrophy which are shown on Bullseye maps. (A) asymmetrical septal hypertrophy (ASH) with spiral pattern of LV; (B) ASH without spiral pattern; (C) diffuse hypertrophy; (D) apical hypertrophy. ASH, asymmetrical septal hypertrophy. Figure 2 View largeDownload slide The patterns of left ventricular (LV) wall hypertrophy which are shown on Bullseye maps. (A) asymmetrical septal hypertrophy (ASH) with spiral pattern of LV; (B) ASH without spiral pattern; (C) diffuse hypertrophy; (D) apical hypertrophy. ASH, asymmetrical septal hypertrophy. Figure 3 View largeDownload slide Schematic drawings and corresponding CT images of two- and three-chamber views. Parts (A) and (D) represent the schematic drawings of the short-axis view. A three-chamber view (B and C) was developed perpendicular to the dotted line on (A). A two-chamber view (E and F) was developed perpendicular to the dotted line on (D). Dotted lines on part (B) represent the aorto-mitral angle. MT, medial trigone; LT, lateral trigone; AML, anterior mitral leaflet; PML, posterior mitral leaflet; LAA, left atrial appendage; MP, posteromedial papillary muscle; LP, anterolateral papillary muscle; AO, aorta; LA, left atrium; LV, left ventricle. Figure 3 View largeDownload slide Schematic drawings and corresponding CT images of two- and three-chamber views. Parts (A) and (D) represent the schematic drawings of the short-axis view. A three-chamber view (B and C) was developed perpendicular to the dotted line on (A). A two-chamber view (E and F) was developed perpendicular to the dotted line on (D). Dotted lines on part (B) represent the aorto-mitral angle. MT, medial trigone; LT, lateral trigone; AML, anterior mitral leaflet; PML, posterior mitral leaflet; LAA, left atrial appendage; MP, posteromedial papillary muscle; LP, anterolateral papillary muscle; AO, aorta; LA, left atrium; LV, left ventricle. Papillary muscles Geometric change of PMs and its relative position to LV cavity were evaluated during the end-diastolic phase of CT images. The length of both PMs, and distance from both PM base to either mitral annulus or LV apex were measured to evaluate displacement of PM (Figure 3). The number of additional PM heads was assessed on multiplanes. Mitral valve The length of anterior and posterior MV leaflets was measured (from leaflet tip to hinge point at the aortomitral curtain) in the three-chamber view during mid-diastole on which MV leaflets were most suitably visualized with minimum motion artefact (Figure 3). Separation of the MV leaflet tip and contiguous chordae tendinae was conducted by visual inspection, and further examined on other adjacent phases, as necessary. Statistical considerations Continuous variables are expressed as mean ± standard deviation. Categorical variables are expressed as frequency with percentage. Statistical significance between patients’ characteristics with and without LVOTO was determined using Student’s t-test or Wilcoxon rank-sum test (if the assumption of normality is violated on Shapiro–Wilk normality test) for continuous measures, while the χ2 test was used to compare categorical variables. Logistic regression analysis was employed to determine which factors were associated with LVOTO in each subgroup (i.e. clinical parameters, LV geometry, and PMs and MV). For the latter analysis, only covariates with a P-value < 0.10 were retained for further analysis. Patients who solely had apical hypertrophy were omitted in a subsequent sensitivity check, so that the pure effect of subvalvular geometry could be evaluated by excluding the effect of asymmetrical hypertrophy, which is considered to be a major factor of LVOTO. A P-value < 0.05 was considered to be statistically significant. Statistical calculations were computed using STATA version 13.0 (StataCorp LP, College Station, TX, USA). Results Baseline characteristics Of 141 patients, 40 (28.4%) demonstrated LVOTO as defined by echocardiography. Baseline characteristics and echocardiographic measurements are presented in Table 1. Patients with LVOTO were more symptomatic (92.5 vs. 72.3%) and presented with a more frequent family history of sudden cardiac death. Blood pressure, proportion of arrhythmia, and current cardiovascular medication history did not differ appreciably between groups. On echocardiography, indexed LV mass (164.1 vs. 135.2 g/m2), LVOT velocity (4.0 vs. 1.3 m/s), and E/E′ ratio (22.6 vs. 13.8) were higher in the LVOTO group (all P < 0.001). Conversely, LV ejection fraction (EF), end-diastolic volume (EDV), and end-systolic volume (ESV) did not differ between groups. Table 1 Baseline characteristics and echocardiographic measurements   LVOT obstruction       Yes (n = 40)  No (n = 101)  P-valuea,b  Clinical characteristics   Age, years  55.6 ± 14.8  58.5 ± 13.5  0.32b   Male gender, n (%)  28 (70.0)  78 (77.2)  0.37c   Systolic pressure, mmHg  122.7 ± 56.9  122.1 ± 17.1  0.02b   Diastolic pressure, mmHg  70.6 ± 9.5  74.2 ± 11.1  0.07a   Atrial fibrillation, n (%)  3 (7.5)  6 (5.9)  0.58c   Symptomatic patients, n (%)  37 (92.5)  73 (72.3)  0.01c   Dyspnoea NYHA class III or IV, n (%)  12 (30.0)  9 (8.9)  0.01c   Syncope, n (%)  8 (20.0)  11 (10.9)  0.15c   Palpitation, n (%)  6 (15.0)  12 (11.9)  0.62c   Chest pain, n (%)  18 (45.0)  38 (37.6)  0.42c  Medication, n (%)   CCB  8 (20.0)  22 (21.8)  0.82c   B-blocker  31 (77.5)  64 (63.4)  0.11c   ACE inhibitor  3 (7.5)  21 (20.8)  0.06c   Diuretics  8 (20.0)  29 (28.7)  0.29c  Family history, n (%)      0.02c   Sudden cardiac death  11 (27.5)  9 (8.9)     Other cardiac disease  3 (7.5)  9 (8.9)    Echocardiographic parameters         LV EF  63.5 ± 4.3  62.9 ± 6.4  0.57b   LV ED volume index, mL/m2  49.2 ± 14.3  46.0 ± 12.0  0.29b   LV ES volume index, mL/m2  18.2 ± 5.5  17.2 ± 7.8  0.22b   LV mass index, g/m2  164.1 ± 43.2  135.2 ± 43.6  <0.001b   LVOT velocity, m/s  4.0 ± 1.3  1.3 ± 0.3  <0.001b   E/E′ ratio  22.6 ± 9.9  13.8 ± 4.6  <0.001b    LVOT obstruction       Yes (n = 40)  No (n = 101)  P-valuea,b  Clinical characteristics   Age, years  55.6 ± 14.8  58.5 ± 13.5  0.32b   Male gender, n (%)  28 (70.0)  78 (77.2)  0.37c   Systolic pressure, mmHg  122.7 ± 56.9  122.1 ± 17.1  0.02b   Diastolic pressure, mmHg  70.6 ± 9.5  74.2 ± 11.1  0.07a   Atrial fibrillation, n (%)  3 (7.5)  6 (5.9)  0.58c   Symptomatic patients, n (%)  37 (92.5)  73 (72.3)  0.01c   Dyspnoea NYHA class III or IV, n (%)  12 (30.0)  9 (8.9)  0.01c   Syncope, n (%)  8 (20.0)  11 (10.9)  0.15c   Palpitation, n (%)  6 (15.0)  12 (11.9)  0.62c   Chest pain, n (%)  18 (45.0)  38 (37.6)  0.42c  Medication, n (%)   CCB  8 (20.0)  22 (21.8)  0.82c   B-blocker  31 (77.5)  64 (63.4)  0.11c   ACE inhibitor  3 (7.5)  21 (20.8)  0.06c   Diuretics  8 (20.0)  29 (28.7)  0.29c  Family history, n (%)      0.02c   Sudden cardiac death  11 (27.5)  9 (8.9)     Other cardiac disease  3 (7.5)  9 (8.9)    Echocardiographic parameters         LV EF  63.5 ± 4.3  62.9 ± 6.4  0.57b   LV ED volume index, mL/m2  49.2 ± 14.3  46.0 ± 12.0  0.29b   LV ES volume index, mL/m2  18.2 ± 5.5  17.2 ± 7.8  0.22b   LV mass index, g/m2  164.1 ± 43.2  135.2 ± 43.6  <0.001b   LVOT velocity, m/s  4.0 ± 1.3  1.3 ± 0.3  <0.001b   E/E′ ratio  22.6 ± 9.9  13.8 ± 4.6  <0.001b  Data presented as mean ± SD or n (%). LVOT, left ventricular outflow tract; NYHA, New York Heart Association; CCB, calcium channel blocker; ACE, angiotensin-converting enzyme; ASH, asymmetric septal hypertrophy; EF, ejection fraction; ED, end-diastolic; ES, end-systolic; SD, standard deviation. a T-test. b Wilcoxon rank-sum test for continuous measures. c χ2 test for categorical variable. Table 1 Baseline characteristics and echocardiographic measurements   LVOT obstruction       Yes (n = 40)  No (n = 101)  P-valuea,b  Clinical characteristics   Age, years  55.6 ± 14.8  58.5 ± 13.5  0.32b   Male gender, n (%)  28 (70.0)  78 (77.2)  0.37c   Systolic pressure, mmHg  122.7 ± 56.9  122.1 ± 17.1  0.02b   Diastolic pressure, mmHg  70.6 ± 9.5  74.2 ± 11.1  0.07a   Atrial fibrillation, n (%)  3 (7.5)  6 (5.9)  0.58c   Symptomatic patients, n (%)  37 (92.5)  73 (72.3)  0.01c   Dyspnoea NYHA class III or IV, n (%)  12 (30.0)  9 (8.9)  0.01c   Syncope, n (%)  8 (20.0)  11 (10.9)  0.15c   Palpitation, n (%)  6 (15.0)  12 (11.9)  0.62c   Chest pain, n (%)  18 (45.0)  38 (37.6)  0.42c  Medication, n (%)   CCB  8 (20.0)  22 (21.8)  0.82c   B-blocker  31 (77.5)  64 (63.4)  0.11c   ACE inhibitor  3 (7.5)  21 (20.8)  0.06c   Diuretics  8 (20.0)  29 (28.7)  0.29c  Family history, n (%)      0.02c   Sudden cardiac death  11 (27.5)  9 (8.9)     Other cardiac disease  3 (7.5)  9 (8.9)    Echocardiographic parameters         LV EF  63.5 ± 4.3  62.9 ± 6.4  0.57b   LV ED volume index, mL/m2  49.2 ± 14.3  46.0 ± 12.0  0.29b   LV ES volume index, mL/m2  18.2 ± 5.5  17.2 ± 7.8  0.22b   LV mass index, g/m2  164.1 ± 43.2  135.2 ± 43.6  <0.001b   LVOT velocity, m/s  4.0 ± 1.3  1.3 ± 0.3  <0.001b   E/E′ ratio  22.6 ± 9.9  13.8 ± 4.6  <0.001b    LVOT obstruction       Yes (n = 40)  No (n = 101)  P-valuea,b  Clinical characteristics   Age, years  55.6 ± 14.8  58.5 ± 13.5  0.32b   Male gender, n (%)  28 (70.0)  78 (77.2)  0.37c   Systolic pressure, mmHg  122.7 ± 56.9  122.1 ± 17.1  0.02b   Diastolic pressure, mmHg  70.6 ± 9.5  74.2 ± 11.1  0.07a   Atrial fibrillation, n (%)  3 (7.5)  6 (5.9)  0.58c   Symptomatic patients, n (%)  37 (92.5)  73 (72.3)  0.01c   Dyspnoea NYHA class III or IV, n (%)  12 (30.0)  9 (8.9)  0.01c   Syncope, n (%)  8 (20.0)  11 (10.9)  0.15c   Palpitation, n (%)  6 (15.0)  12 (11.9)  0.62c   Chest pain, n (%)  18 (45.0)  38 (37.6)  0.42c  Medication, n (%)   CCB  8 (20.0)  22 (21.8)  0.82c   B-blocker  31 (77.5)  64 (63.4)  0.11c   ACE inhibitor  3 (7.5)  21 (20.8)  0.06c   Diuretics  8 (20.0)  29 (28.7)  0.29c  Family history, n (%)      0.02c   Sudden cardiac death  11 (27.5)  9 (8.9)     Other cardiac disease  3 (7.5)  9 (8.9)    Echocardiographic parameters         LV EF  63.5 ± 4.3  62.9 ± 6.4  0.57b   LV ED volume index, mL/m2  49.2 ± 14.3  46.0 ± 12.0  0.29b   LV ES volume index, mL/m2  18.2 ± 5.5  17.2 ± 7.8  0.22b   LV mass index, g/m2  164.1 ± 43.2  135.2 ± 43.6  <0.001b   LVOT velocity, m/s  4.0 ± 1.3  1.3 ± 0.3  <0.001b   E/E′ ratio  22.6 ± 9.9  13.8 ± 4.6  <0.001b  Data presented as mean ± SD or n (%). LVOT, left ventricular outflow tract; NYHA, New York Heart Association; CCB, calcium channel blocker; ACE, angiotensin-converting enzyme; ASH, asymmetric septal hypertrophy; EF, ejection fraction; ED, end-diastolic; ES, end-systolic; SD, standard deviation. a T-test. b Wilcoxon rank-sum test for continuous measures. c χ2 test for categorical variable. Difference of CT-defined LV geometry Patients with LVOTO displayed a more frequent spiral pattern of myocardial hypertrophy, greater LV mass, elongated both PMs, increased number of accessory PM, and greater distance from PM base from the LV apex or mitral annulus. The findings from univariable analyses and their association with LVOTO among HCM patients are summarized in Table 2. The distance between LP base and LV apex was greater in the LVOTO group (e.g. 26.4 vs. 22.0 mm, P < 0.001). Of the 40 patients with LVOTO, half of these had spiral pattern, whereas the remaining 101 patients without LVOTO displayed a significantly lower spiral pattern (e.g. 51 vs. 16%, P < 0.001). In addition, patients with obstruction had more thickened segments (10.3 vs. 8.3, P = 0.006), a larger maximum thickness of LV wall (24.6 vs. 22.8 mm, P = 0.12), and a more elongated anterior mitral leaflet (AML) (18.0 vs. 15.6 mm, P = 0.007). Table 2 CT measurements and univariable analysis for likelihood of having left ventricular outflow tract obstruction   LVOT obstruction     Univariable analyses     Yes (n = 40)  No (n = 101)  P-valuea,b,c  OR (95% CI)  P-valued  LV geometry   Spiral pattern, n (%)  20 (50.0)  17 (16.8)  <0.001c  4.94 (2.2–11.1)  <0.001   LV mass index, g/m2  124.9 ± 36.4  101.3 ± 27.2  <0.001b  1.00 (0.97–1.03)  0.76   LV ED volume index, mL/m2  78.0 ± 19.9  66.1 ± 17.7  0.001b  1.04 (1.01–1.07)  0.01   Number of thickened segment  10.3 ± 3.7  8.3 ± 3.8  0.006b  1.12 (0.89–1.40)  0.30   LV maximal thickness, mm  24.6 ± 5.5  22.8 ± 4.2  0.12b  1.07 (0.96–1.20)  0.17   A-M angle  58.4 ± 9.9  57.4 ± 7.5  0.38b  1.04 (0.99–1.10)  0.09   LVH pattern, n (%)      0.02c    0.74    ASH  18 (45.0)  35 (34.7)          Apical  0 (0)  20 (19.8)          Diffuse  5 (12.5)  9 (8.9)          Mixed  17 (42.5)  37 (36.6)        Papillary muscles and MV             Number of accessory PMs  1.0 ± 1.0  1.5 ± 1.4  0.14b  0.80 (0.56–1.14)  0.22   MP length, mm/m2  25.3 ± 5.6  23.2 ± 4.4  0.04b  0.94 (0.79–1.12)  0.51   MP base ∼ MA, mm/m2  42.6 ± 7.3  39.9 ± 5.4  0.06b  1.09 (0.93–1.28)  0.28   MP base ∼ LV apex, mm/m2  17.9 ± 4.8  15.2 ± 4.3  0.002a  1.11 (0.98–1.25)  0.08   LP length, mm/m2  24.1 ± 4.7  22.1 ± 3.6  0.02b  1.00 (0.79–1.27)  0.96   LP base ∼ MA, mm/m2  40.0 ± 6.0  37.2 ± 4.6  0.005b  1.03 (0.84–1.25)  0.76   LP base ∼ LV apex, mm/m2  26.4 ± 6.1  22.0 ± 5.3  <0.001a  1.15 (1.07–1.24)  <0.001   AML, mm/m2  18.0 ± 4.6  15.6 ± 2.6  0.007b  1.24 (1.07–1.43)  0.004   PML, mm/m2  9.5 ± 2.2  8.4 ± 2.0  0.03b  1.16 (0.91–1.46)  0.21    LVOT obstruction     Univariable analyses     Yes (n = 40)  No (n = 101)  P-valuea,b,c  OR (95% CI)  P-valued  LV geometry   Spiral pattern, n (%)  20 (50.0)  17 (16.8)  <0.001c  4.94 (2.2–11.1)  <0.001   LV mass index, g/m2  124.9 ± 36.4  101.3 ± 27.2  <0.001b  1.00 (0.97–1.03)  0.76   LV ED volume index, mL/m2  78.0 ± 19.9  66.1 ± 17.7  0.001b  1.04 (1.01–1.07)  0.01   Number of thickened segment  10.3 ± 3.7  8.3 ± 3.8  0.006b  1.12 (0.89–1.40)  0.30   LV maximal thickness, mm  24.6 ± 5.5  22.8 ± 4.2  0.12b  1.07 (0.96–1.20)  0.17   A-M angle  58.4 ± 9.9  57.4 ± 7.5  0.38b  1.04 (0.99–1.10)  0.09   LVH pattern, n (%)      0.02c    0.74    ASH  18 (45.0)  35 (34.7)          Apical  0 (0)  20 (19.8)          Diffuse  5 (12.5)  9 (8.9)          Mixed  17 (42.5)  37 (36.6)        Papillary muscles and MV             Number of accessory PMs  1.0 ± 1.0  1.5 ± 1.4  0.14b  0.80 (0.56–1.14)  0.22   MP length, mm/m2  25.3 ± 5.6  23.2 ± 4.4  0.04b  0.94 (0.79–1.12)  0.51   MP base ∼ MA, mm/m2  42.6 ± 7.3  39.9 ± 5.4  0.06b  1.09 (0.93–1.28)  0.28   MP base ∼ LV apex, mm/m2  17.9 ± 4.8  15.2 ± 4.3  0.002a  1.11 (0.98–1.25)  0.08   LP length, mm/m2  24.1 ± 4.7  22.1 ± 3.6  0.02b  1.00 (0.79–1.27)  0.96   LP base ∼ MA, mm/m2  40.0 ± 6.0  37.2 ± 4.6  0.005b  1.03 (0.84–1.25)  0.76   LP base ∼ LV apex, mm/m2  26.4 ± 6.1  22.0 ± 5.3  <0.001a  1.15 (1.07–1.24)  <0.001   AML, mm/m2  18.0 ± 4.6  15.6 ± 2.6  0.007b  1.24 (1.07–1.43)  0.004   PML, mm/m2  9.5 ± 2.2  8.4 ± 2.0  0.03b  1.16 (0.91–1.46)  0.21  Covariates with P < 0.10 were retained for multivariable analyses (bold). LVOT, left ventricular outflow tract; OR, odds ratio; CI, confidence interval; LV, left ventricle; ED, end diastolic; LV max, LV maximum wall thickness; A-M angle, aorto-mitral angle; MV, mitral valve; PM, papillary muscle; MP, posteromedial papillary muscle; LP, anterolateral papillary muscle; MA, mitral annulus; AML, anterior mitral leaflet; PML, posterior mitral leaflet. a T-test. b Wilcoxon rank-sum test for continuous measures. c χ2 test for categorical variable. d Logistic regression for LVOT obstruction was done. Table 2 CT measurements and univariable analysis for likelihood of having left ventricular outflow tract obstruction   LVOT obstruction     Univariable analyses     Yes (n = 40)  No (n = 101)  P-valuea,b,c  OR (95% CI)  P-valued  LV geometry   Spiral pattern, n (%)  20 (50.0)  17 (16.8)  <0.001c  4.94 (2.2–11.1)  <0.001   LV mass index, g/m2  124.9 ± 36.4  101.3 ± 27.2  <0.001b  1.00 (0.97–1.03)  0.76   LV ED volume index, mL/m2  78.0 ± 19.9  66.1 ± 17.7  0.001b  1.04 (1.01–1.07)  0.01   Number of thickened segment  10.3 ± 3.7  8.3 ± 3.8  0.006b  1.12 (0.89–1.40)  0.30   LV maximal thickness, mm  24.6 ± 5.5  22.8 ± 4.2  0.12b  1.07 (0.96–1.20)  0.17   A-M angle  58.4 ± 9.9  57.4 ± 7.5  0.38b  1.04 (0.99–1.10)  0.09   LVH pattern, n (%)      0.02c    0.74    ASH  18 (45.0)  35 (34.7)          Apical  0 (0)  20 (19.8)          Diffuse  5 (12.5)  9 (8.9)          Mixed  17 (42.5)  37 (36.6)        Papillary muscles and MV             Number of accessory PMs  1.0 ± 1.0  1.5 ± 1.4  0.14b  0.80 (0.56–1.14)  0.22   MP length, mm/m2  25.3 ± 5.6  23.2 ± 4.4  0.04b  0.94 (0.79–1.12)  0.51   MP base ∼ MA, mm/m2  42.6 ± 7.3  39.9 ± 5.4  0.06b  1.09 (0.93–1.28)  0.28   MP base ∼ LV apex, mm/m2  17.9 ± 4.8  15.2 ± 4.3  0.002a  1.11 (0.98–1.25)  0.08   LP length, mm/m2  24.1 ± 4.7  22.1 ± 3.6  0.02b  1.00 (0.79–1.27)  0.96   LP base ∼ MA, mm/m2  40.0 ± 6.0  37.2 ± 4.6  0.005b  1.03 (0.84–1.25)  0.76   LP base ∼ LV apex, mm/m2  26.4 ± 6.1  22.0 ± 5.3  <0.001a  1.15 (1.07–1.24)  <0.001   AML, mm/m2  18.0 ± 4.6  15.6 ± 2.6  0.007b  1.24 (1.07–1.43)  0.004   PML, mm/m2  9.5 ± 2.2  8.4 ± 2.0  0.03b  1.16 (0.91–1.46)  0.21    LVOT obstruction     Univariable analyses     Yes (n = 40)  No (n = 101)  P-valuea,b,c  OR (95% CI)  P-valued  LV geometry   Spiral pattern, n (%)  20 (50.0)  17 (16.8)  <0.001c  4.94 (2.2–11.1)  <0.001   LV mass index, g/m2  124.9 ± 36.4  101.3 ± 27.2  <0.001b  1.00 (0.97–1.03)  0.76   LV ED volume index, mL/m2  78.0 ± 19.9  66.1 ± 17.7  0.001b  1.04 (1.01–1.07)  0.01   Number of thickened segment  10.3 ± 3.7  8.3 ± 3.8  0.006b  1.12 (0.89–1.40)  0.30   LV maximal thickness, mm  24.6 ± 5.5  22.8 ± 4.2  0.12b  1.07 (0.96–1.20)  0.17   A-M angle  58.4 ± 9.9  57.4 ± 7.5  0.38b  1.04 (0.99–1.10)  0.09   LVH pattern, n (%)      0.02c    0.74    ASH  18 (45.0)  35 (34.7)          Apical  0 (0)  20 (19.8)          Diffuse  5 (12.5)  9 (8.9)          Mixed  17 (42.5)  37 (36.6)        Papillary muscles and MV             Number of accessory PMs  1.0 ± 1.0  1.5 ± 1.4  0.14b  0.80 (0.56–1.14)  0.22   MP length, mm/m2  25.3 ± 5.6  23.2 ± 4.4  0.04b  0.94 (0.79–1.12)  0.51   MP base ∼ MA, mm/m2  42.6 ± 7.3  39.9 ± 5.4  0.06b  1.09 (0.93–1.28)  0.28   MP base ∼ LV apex, mm/m2  17.9 ± 4.8  15.2 ± 4.3  0.002a  1.11 (0.98–1.25)  0.08   LP length, mm/m2  24.1 ± 4.7  22.1 ± 3.6  0.02b  1.00 (0.79–1.27)  0.96   LP base ∼ MA, mm/m2  40.0 ± 6.0  37.2 ± 4.6  0.005b  1.03 (0.84–1.25)  0.76   LP base ∼ LV apex, mm/m2  26.4 ± 6.1  22.0 ± 5.3  <0.001a  1.15 (1.07–1.24)  <0.001   AML, mm/m2  18.0 ± 4.6  15.6 ± 2.6  0.007b  1.24 (1.07–1.43)  0.004   PML, mm/m2  9.5 ± 2.2  8.4 ± 2.0  0.03b  1.16 (0.91–1.46)  0.21  Covariates with P < 0.10 were retained for multivariable analyses (bold). LVOT, left ventricular outflow tract; OR, odds ratio; CI, confidence interval; LV, left ventricle; ED, end diastolic; LV max, LV maximum wall thickness; A-M angle, aorto-mitral angle; MV, mitral valve; PM, papillary muscle; MP, posteromedial papillary muscle; LP, anterolateral papillary muscle; MA, mitral annulus; AML, anterior mitral leaflet; PML, posterior mitral leaflet. a T-test. b Wilcoxon rank-sum test for continuous measures. c χ2 test for categorical variable. d Logistic regression for LVOT obstruction was done. Multivariable analysis In Table 3, after adjusting for retained covariates, spiral pattern of hypertrophy [95% confidence interval (CI), 3.75, 1.59–8.84], anterior mitral leaflet length (95% CI, 1.20, 1.03–1.40), and the distance between LP base and LV apex (95% CI, 1.09, 1.01–1.19) were all independently associated with the likelihood of having LVOTO. In sensitivity analysis that omitted patients who exclusively had apical hypertrophy, all of the aforementioned CT measures remained independently associated with the presence of LVOTO. Table 3 Multivariable odds ratios according to CT measurements for likelihood of having left ventricular outflow tract obstruction   OR  95% CI  P-value  Spiral pattern  3.75  1.60–8.80  0.003  AML, per 1 mm/m2  1.20  1.03–1.40  0.023  LP base ∼ LV apex, per 1 mm/m2  1.10  1.01–1.19  0.034    OR  95% CI  P-value  Spiral pattern  3.75  1.60–8.80  0.003  AML, per 1 mm/m2  1.20  1.03–1.40  0.023  LP base ∼ LV apex, per 1 mm/m2  1.10  1.01–1.19  0.034  OR, odds ratio; CI, confidence interval; AML, anterior mitral leaflet; LP, anterolateral papillary muscle; LV, left ventricle. Table 3 Multivariable odds ratios according to CT measurements for likelihood of having left ventricular outflow tract obstruction   OR  95% CI  P-value  Spiral pattern  3.75  1.60–8.80  0.003  AML, per 1 mm/m2  1.20  1.03–1.40  0.023  LP base ∼ LV apex, per 1 mm/m2  1.10  1.01–1.19  0.034    OR  95% CI  P-value  Spiral pattern  3.75  1.60–8.80  0.003  AML, per 1 mm/m2  1.20  1.03–1.40  0.023  LP base ∼ LV apex, per 1 mm/m2  1.10  1.01–1.19  0.034  OR, odds ratio; CI, confidence interval; AML, anterior mitral leaflet; LP, anterolateral papillary muscle; LV, left ventricle. Discussion The major findings of this quantitative study using 3D CT were: (i) geometrical change of PM was related to LVOTO in HCM patients; (ii) spiral pattern of LV hypertrophy was more frequently present in HCM patients with LVOTO as compared with patients without LVOTO; and (iii) elongated MV was found to be associated with the presence of LVOTO. This study confirmed the experimental, surgical, and imaging findings of the previous papers wherein PM abnormalities are likely a contributory factor towards LVOTO.9,10,12,18,19 Foremost, Levine et al.19 experimentally verified that anterior displacement of PM caused subaortic obstruction in seven canine models. Kwon et al.9 also documented that anteroapical displacement of anterolateral PM on MRI was associated with a higher LVOT gradient. Harrigan et al.10 reported that in patients with LVOTO at rest, PMs were positioned closer to the ventricular septum. By extension, the present study quantitatively demonstrated that obvious geometric alterations of the PMs exist between two groups with and without LVOTO. When considering the distance between the mitral annulus and both PM bases also increased, additional to the distance between both PM bases and LV apex, these alterations may somewhat be derived from the overall increased size of the heart. Nevertheless, the notion that only the distance between LP base and LV apex was found to be significant implies that the anterolateral PM might be displaced, which is away from the LV apex and closer to the LV base in a simultaneous fashion. Of further interest is the unique spiral pattern of LV hypertrophy that was present in HCM patients, which exhibited a significant association with LVOTO. The spiral pattern of LV hypertrophy can be defined as counterclockwise spiral in the longitudinal direction when viewed from the LV apex along the basal to apical direction.16,17 Indeed, such a relationship was first described in a case report of a HCM patient with cardiac MR imaging, and was considered to be a peculiar pattern of LV hypertrophy.17 The pattern was quantitatively assessed using cardiac MR in one study,16 which concluded that patients with an extensive spiral configuration more frequently experience LVOTO as compared with a non-spiral group. The exact mechanism of the association between the spiral pattern and LVOTO could not be solved in previous studies including this study. It may be the question of which came first, the spiral configuration or the LVOTO. The MV abnormality has been proposed to be one of the determinants of LVOTO. In several studies7,12,20 using echocardiography and cardiac MR, enlarged mitral leaflet length or surface area were independently associated with the obstruction, which is concordant with the present study. The current results therefore can prove useful towards understanding geometrical modifications of the heart as well as underlining the possible mechanisms of LVOTO in HCM patients. Cardiac CT has an advantage of more accurately evaluating the 3D geometry of myocardial hypertrophy pattern and PMs than MR and echocardiography.14,21–25 Up till now, classical disadvantages of CT such as ionizing radiation and iodinated contrast limit the routine use of the CT, and it has been only indicated to assess coronary arteries or when echocardiographic images are suboptimal and cardiac MR is contraindicated. The previously mentioned measurable factors can perhaps be used to predict LVOTO, while also specifying the target of treatment to relieve obstruction when planning surgical myectomy with or without mitral valvuloplasty in HCM patients with LVOTO. Image-based guidance and 3D printed models created from cardiac CT have been applied to facilitate surgical planning in HCM.26 The quantitative information regarding the myocardial geometric changes presented in this study should be considered in hypothesis generation of further imaging-based prospective trials that are designed to determine appropriate treatment guidelines in patients who present with HCM. There are several limitations that should be emphasized. As this study was retrospective in nature and conducted at a tertiary care referral centre, we cannot discount the possibility that patients enrolled and who underwent CT scanning were likely more symptomatic with more severe symptoms of cardiac disease than other apparently healthier HCM patients who are typically asymptomatic. In light of a potential selection bias, caution should be taken when interpreting these findings. Considering the clinical, haemodynamic and prognostic heterogeneity of the population, the sample is rather small, which may preclude the wide clinical application of the findings. Further larger multicentre study that included a normal control group would be needed in order to confirm the findings and also draw a more accurate and reliable conclusion. The observational cross-sectional design of this study also limited the inference of a causal relationship between LVOTO and the various factors assessed. Forthcoming well-designed investigations that are prospective in nature appear warranted. In addition, 2D measurement of the PMs and MV may not reflect the exact degree of the structural change. Future studies with complete 3D evaluation of those structures (i.e. mitral surface area, papillary muscular volume) may draw more reliable conclusion. Finally, as we assessed the presence of LVOTO only in resting conditions, provocable LVOTO group in which obstruction may occur only during exercise could be missed. Considering the fact that significant percentage of provocable obstruction group had heart failure symptom and may be candidate for major interventions,15 it would be the best if the population included in the study. In the present study comprising a sample of HCM patients, spiral pattern of LV hypertrophy, the length of AML, and the distance between LP base and LV apex were all independently associated with LVOTO. These associations indicate that alterations in LV geometry, as well as elongated AML, and displacement of anterolateral PM might influence the LVOTO. The current study findings may further our understanding of the underlying mechanisms of LVOTO in patients who present with HCM. Funding This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (NRF-2016R1A1A1A05921207 and NRF-2015R1A2A2A04003034) and a grant (2017-7208) from the Asan Institute for Life Sciences, Asan Medical Centre, Seoul, Korea. ‘The Industrial Strategic technology development program (10072064) funded by the Ministry of Trade Industry and Energy (MI, Korea)’. Conflict of interest: None declared. References 1 Maron MS, Olivotto I, Betocchi S, Casey SA, Lesser JR, Losi MA et al.   Effect of left ventricular outflow tract obstruction on clinical outcome in hypertrophic cardiomyopathy. N Engl J Med  2003; 348: 295– 303. Google Scholar CrossRef Search ADS PubMed  2 Autore C, Bernabo P, Barilla CS, Bruzzi P, Spirito P. The prognostic importance of left ventricular outflow obstruction in hypertrophic cardiomyopathy varies in relation to the severity of symptoms. J Am Coll Cardiol  2005; 45: 1076– 80. 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Eur Heart J Cardiovasc Imaging  2017; doi: 10.1093/ehjci/jex010. 22 Yang DH, Kim DH, Handschumacher MD, Levine RA, Kim JB, Sun BJ et al.   In vivo assessment of aortic root geometry in normal controls using 3D analysis of computed tomography. Eur Heart J Cardiovasc Imaging  2017; 18: 780– 6. Google Scholar PubMed  23 Han K, Yang DH, Shin SY, Kim N, Kang JW, Kim DH et al.   Subprosthetic pannus after aortic valve replacement surgery: cardiac CT findings and clinical features. Radiology  2015; 276: 724– 31. Google Scholar CrossRef Search ADS PubMed  24 Eom HJ, Yang DH, Kang JW, Kim DH, Song JM, Kang DH et al.   Preoperative cardiac computed tomography for demonstration of congenital cardiac septal defect in adults. Eur Radiol  2015; 25: 1614– 22. Google Scholar CrossRef Search ADS PubMed  25 Kim YJ, Yong HS, Kim SM, Kim JA, Yang DH, Hong YJ. Korean guidelines for the appropriate use of cardiac CT. Korean J Radiol  2015; 16: 251– 85. 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Geometric predictors of left ventricular outflow tract obstruction in patients with hypertrophic cardiomyopathy: a 3D computed tomography analysis

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Oxford University Press
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com.
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2047-2404
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10.1093/ehjci/jex234
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Abstract

Abstract Aims To establish geometric predictors of left ventricular outflow tract obstruction (LVOTO) in hypertrophic cardiomyopathy (HCM) patients by use of cardiac computed tomography (CT). Methods and results A total of 141 consecutive patients with HCM who underwent cardiac CT comprised the analytic sample. The degree, pattern, and extent of left ventricular (LV) hypertrophy were evaluated using 3D CT. Abnormality of papillary muscle (PM), mitral valve, and aorto-mitral angle were evaluated quantitatively. Multivariable logistic regression analysis and sensitivity analysis were performed to reliably identify predictors of LVOTO. LVOTO was present among 40 (28.4%) patients. Those with LVOTO displayed a higher prevalence for having a spiral pattern of LV hypertrophy (e.g. 51 vs. 16%, P < 0.001), a longer anterior mitral leaflet (AML) length (e.g. 18.0 vs. 15.6 mm, P = 0.007), and a longer distance from lateral PM base to LV apex (e.g. 26.4 vs. 22.0 mm, P < 0.001), as compared with the non-LVOTO group. Multivariable logistic regression revealed all three variables [i.e. spiral pattern (95% confidence interval (CI), 3.75, 1.59–8.84); AML length (95% CI, 1.20, 1.03–1.40); the distance between lateral PM base and LV apex (95% CI, 1.09, 1.01–1.19)] retained significance after adjustment for numerous covariates. Conclusion Spiral pattern of LV hypertrophy, the length of AML, and the distance between lateral PM base and LV apex were independent predictors of LVOTO in patients with HCM. hypertrophic cardiomyopathy, left ventricular outflow tract obstruction, computed tomography, papillary muscle Introduction Left ventricular outflow tract obstruction (LVOTO) is one of the chief determinants of clinical outcomes related to hypertrophic cardiomyopathy (HCM).1–6 Patients with LVOTO are often at higher risk of progression to severe heart failure or death from heart failure or stroke.1,3–6 Considering LVOTO could be a potential target for treatment, understanding its mechanisms represents an important dimension of preventive medicine for augmenting patient care. In recent past, studies using 3D echocardiography revealed geometric determinants of LVOTO that included mitral leaflet area and papillary muscle (PM) displacement.7 Although 3D echocardiography has an advantage of assessing mitral valve (MV) apparatus owing to high temporal resolution, it is somewhat limited in evaluating the entire left ventricular (LV) myocardium and PM. Notably, other prior studies that employed a cardiac magnetic resonance (MR) imaging approach documented that PM abnormalities such as displacement or altered morphology of PM8–10 might be additional morphologic determinants of LVOTO as well as LV geometric modification. Yet, while cardiac MR might prove more useful towards evaluating the morphology of the LV and PM compared with echocardiography, a drawback of this procedure is its inability to assess the complex LVOT geometry with 2D cine imaging.11,12 Moving forward, cardiac computed tomography (CT) has greatly advanced as an accurate and reliable tool for assessing global LV function beyond coronary arteries.13 Further still, because of its excellent spatial resolution, anatomic details of the MV and subvalvular apparatus can be visualized.14 It also permits for the acquisition of a 4D data structure of the heart, which can be manipulated and displayed in any desired plane. The purpose of the current study, therefore, was to seek out geometric predictors of LVOTO in HCM by use of cardiac CT with the expectation of a more complete interrogation of LV morphology, including PM as well as MV. Methods Study population Between January 2011 and August 2014, a total 147 patients with HCM (myocardial thickness ≥ 15 mm echocardiography) who underwent cardiac CT were retrospectively enrolled. Among these, total six patients were excluded from the study; three patients presented with underlying cardiac diseases including old infarction (n = 1) and cardiac valvular disease (n = 2), and the other three patients had previous history of heart transplantation (n = 2) and septal myectomy (n = 1). Hence, a total of 141 patients met the diagnostic criteria of HCM, which requires echocardiographic evidence of myocardial hypertrophy (myocardial thickness ≥ 15 mm) without any other cardiac or systemic disease. Reasons for CT examination included coronary artery disease evaluation (n = 42), aggravated symptoms (i.e. dyspnoea, chest pain, or syncope) (n = 40), exclusion of coronary artery disease in non-symptomatic patients (n = 40), and preoperative evaluation of geometric changes in the left ventricle and MV (n = 19). The appropriate institutional review board approved this retrospective study and waived the requirement to obtain informed consent from patients. Echocardiography Conventional 2D and Doppler echocardiography were performed using commercially available ultrasound equipment (iE33, Philips Medical Systems, Andover, MA, USA) with a S5-1 transducer by cardiologists who were expertly trained in echocardiography procedures. LVOTO was defined as a peak resting gradient ≥ 50 mm Hg on Doppler echocardiography.1,15 CT image acquisition CT examinations were performed using a second-generation dual-source CT system (Somatom definition; Siemens Medical Solution, Forchheim, Germany). The scan was acquired after the injection of 60–80 mL of iomeprol-400 (Iomeron, Bracco Imaging SpA, Milan, Italy), followed by 40 mL of a 30:70 mixture of contrast and saline. Retrospective electrocardiography scanning with pulsing (30–80%) was performed, and tube current modulation based on the patient’s body size was utilized in an effort to reduce the radiation dose. The mean estimated radiation effective dose was 8.4 mSv. The imaging parameters included: detector collimation 64 × 0.6 mm, gantry rotation time 280 ms, pitch 0.17–0.38 (adapted to the heart rate), tube current 240–450 mA, and tube voltage 80–120 kV. LV geometry analysis in CT CT image analysis was performed by two experienced readers and any disagreement was resolved by consensus. End-diastolic phase (90 or 0% or R-R interval) of cardiac CT was used to analyse the LV geometric pattern using commercially available software (Syngo Via; Siemens). The epicardial and endocardial borders of the LV myocardium were semi-automatically defined on the multiplane visualization, while PMs were excluded attentively. All CT analysis was masked to clinical and echocardiographic data. All CT measurements were indexed to body surface area. LV hypertrophy pattern For evaluation of LV hypertrophy pattern, the Bullseye maps which demonstrate LV wall thickness using different colours were used (Figure 1). Colour scale of the bullseye map was adjusted so that the red area could represent hypertrophied area (i.e. ≥15 mm in myocardial thickness). A myocardial segment with more than 10% of hypertrophied area was defined as the thickened segment. The maximum and mean thickness in each myocardial segment and the number of thickened segments was evaluated. Based on the bullseye map, the patterns of LV hypertrophy were categorized into asymmetrical septal hypertrophy, pure apical hypertrophy, diffuse, and mixed hypertrophy (Figure 2). The spiral pattern of LV hypertrophy, defined as the longitudinal counterclockwise spiral rotation of hypertrophy, was assessed on the bullseye map.16,17 The aorto-mitral angle, defined as the angle between the aortic and mitral annulus, was measured using a three-chamber view (Figure 3). Figure 1 View largeDownload slide Bullseye map according to a 17-segment model. Three LV short-axis (basal, mid, and apical) planes are shown at end-diastole (A–C). The bullseye map (D) shows the thickness of 17 segments using a colour scale. The red area represents the thickened myocardium at more than 15 mm. Figure 1 View largeDownload slide Bullseye map according to a 17-segment model. Three LV short-axis (basal, mid, and apical) planes are shown at end-diastole (A–C). The bullseye map (D) shows the thickness of 17 segments using a colour scale. The red area represents the thickened myocardium at more than 15 mm. Figure 2 View largeDownload slide The patterns of left ventricular (LV) wall hypertrophy which are shown on Bullseye maps. (A) asymmetrical septal hypertrophy (ASH) with spiral pattern of LV; (B) ASH without spiral pattern; (C) diffuse hypertrophy; (D) apical hypertrophy. ASH, asymmetrical septal hypertrophy. Figure 2 View largeDownload slide The patterns of left ventricular (LV) wall hypertrophy which are shown on Bullseye maps. (A) asymmetrical septal hypertrophy (ASH) with spiral pattern of LV; (B) ASH without spiral pattern; (C) diffuse hypertrophy; (D) apical hypertrophy. ASH, asymmetrical septal hypertrophy. Figure 3 View largeDownload slide Schematic drawings and corresponding CT images of two- and three-chamber views. Parts (A) and (D) represent the schematic drawings of the short-axis view. A three-chamber view (B and C) was developed perpendicular to the dotted line on (A). A two-chamber view (E and F) was developed perpendicular to the dotted line on (D). Dotted lines on part (B) represent the aorto-mitral angle. MT, medial trigone; LT, lateral trigone; AML, anterior mitral leaflet; PML, posterior mitral leaflet; LAA, left atrial appendage; MP, posteromedial papillary muscle; LP, anterolateral papillary muscle; AO, aorta; LA, left atrium; LV, left ventricle. Figure 3 View largeDownload slide Schematic drawings and corresponding CT images of two- and three-chamber views. Parts (A) and (D) represent the schematic drawings of the short-axis view. A three-chamber view (B and C) was developed perpendicular to the dotted line on (A). A two-chamber view (E and F) was developed perpendicular to the dotted line on (D). Dotted lines on part (B) represent the aorto-mitral angle. MT, medial trigone; LT, lateral trigone; AML, anterior mitral leaflet; PML, posterior mitral leaflet; LAA, left atrial appendage; MP, posteromedial papillary muscle; LP, anterolateral papillary muscle; AO, aorta; LA, left atrium; LV, left ventricle. Papillary muscles Geometric change of PMs and its relative position to LV cavity were evaluated during the end-diastolic phase of CT images. The length of both PMs, and distance from both PM base to either mitral annulus or LV apex were measured to evaluate displacement of PM (Figure 3). The number of additional PM heads was assessed on multiplanes. Mitral valve The length of anterior and posterior MV leaflets was measured (from leaflet tip to hinge point at the aortomitral curtain) in the three-chamber view during mid-diastole on which MV leaflets were most suitably visualized with minimum motion artefact (Figure 3). Separation of the MV leaflet tip and contiguous chordae tendinae was conducted by visual inspection, and further examined on other adjacent phases, as necessary. Statistical considerations Continuous variables are expressed as mean ± standard deviation. Categorical variables are expressed as frequency with percentage. Statistical significance between patients’ characteristics with and without LVOTO was determined using Student’s t-test or Wilcoxon rank-sum test (if the assumption of normality is violated on Shapiro–Wilk normality test) for continuous measures, while the χ2 test was used to compare categorical variables. Logistic regression analysis was employed to determine which factors were associated with LVOTO in each subgroup (i.e. clinical parameters, LV geometry, and PMs and MV). For the latter analysis, only covariates with a P-value < 0.10 were retained for further analysis. Patients who solely had apical hypertrophy were omitted in a subsequent sensitivity check, so that the pure effect of subvalvular geometry could be evaluated by excluding the effect of asymmetrical hypertrophy, which is considered to be a major factor of LVOTO. A P-value < 0.05 was considered to be statistically significant. Statistical calculations were computed using STATA version 13.0 (StataCorp LP, College Station, TX, USA). Results Baseline characteristics Of 141 patients, 40 (28.4%) demonstrated LVOTO as defined by echocardiography. Baseline characteristics and echocardiographic measurements are presented in Table 1. Patients with LVOTO were more symptomatic (92.5 vs. 72.3%) and presented with a more frequent family history of sudden cardiac death. Blood pressure, proportion of arrhythmia, and current cardiovascular medication history did not differ appreciably between groups. On echocardiography, indexed LV mass (164.1 vs. 135.2 g/m2), LVOT velocity (4.0 vs. 1.3 m/s), and E/E′ ratio (22.6 vs. 13.8) were higher in the LVOTO group (all P < 0.001). Conversely, LV ejection fraction (EF), end-diastolic volume (EDV), and end-systolic volume (ESV) did not differ between groups. Table 1 Baseline characteristics and echocardiographic measurements   LVOT obstruction       Yes (n = 40)  No (n = 101)  P-valuea,b  Clinical characteristics   Age, years  55.6 ± 14.8  58.5 ± 13.5  0.32b   Male gender, n (%)  28 (70.0)  78 (77.2)  0.37c   Systolic pressure, mmHg  122.7 ± 56.9  122.1 ± 17.1  0.02b   Diastolic pressure, mmHg  70.6 ± 9.5  74.2 ± 11.1  0.07a   Atrial fibrillation, n (%)  3 (7.5)  6 (5.9)  0.58c   Symptomatic patients, n (%)  37 (92.5)  73 (72.3)  0.01c   Dyspnoea NYHA class III or IV, n (%)  12 (30.0)  9 (8.9)  0.01c   Syncope, n (%)  8 (20.0)  11 (10.9)  0.15c   Palpitation, n (%)  6 (15.0)  12 (11.9)  0.62c   Chest pain, n (%)  18 (45.0)  38 (37.6)  0.42c  Medication, n (%)   CCB  8 (20.0)  22 (21.8)  0.82c   B-blocker  31 (77.5)  64 (63.4)  0.11c   ACE inhibitor  3 (7.5)  21 (20.8)  0.06c   Diuretics  8 (20.0)  29 (28.7)  0.29c  Family history, n (%)      0.02c   Sudden cardiac death  11 (27.5)  9 (8.9)     Other cardiac disease  3 (7.5)  9 (8.9)    Echocardiographic parameters         LV EF  63.5 ± 4.3  62.9 ± 6.4  0.57b   LV ED volume index, mL/m2  49.2 ± 14.3  46.0 ± 12.0  0.29b   LV ES volume index, mL/m2  18.2 ± 5.5  17.2 ± 7.8  0.22b   LV mass index, g/m2  164.1 ± 43.2  135.2 ± 43.6  <0.001b   LVOT velocity, m/s  4.0 ± 1.3  1.3 ± 0.3  <0.001b   E/E′ ratio  22.6 ± 9.9  13.8 ± 4.6  <0.001b    LVOT obstruction       Yes (n = 40)  No (n = 101)  P-valuea,b  Clinical characteristics   Age, years  55.6 ± 14.8  58.5 ± 13.5  0.32b   Male gender, n (%)  28 (70.0)  78 (77.2)  0.37c   Systolic pressure, mmHg  122.7 ± 56.9  122.1 ± 17.1  0.02b   Diastolic pressure, mmHg  70.6 ± 9.5  74.2 ± 11.1  0.07a   Atrial fibrillation, n (%)  3 (7.5)  6 (5.9)  0.58c   Symptomatic patients, n (%)  37 (92.5)  73 (72.3)  0.01c   Dyspnoea NYHA class III or IV, n (%)  12 (30.0)  9 (8.9)  0.01c   Syncope, n (%)  8 (20.0)  11 (10.9)  0.15c   Palpitation, n (%)  6 (15.0)  12 (11.9)  0.62c   Chest pain, n (%)  18 (45.0)  38 (37.6)  0.42c  Medication, n (%)   CCB  8 (20.0)  22 (21.8)  0.82c   B-blocker  31 (77.5)  64 (63.4)  0.11c   ACE inhibitor  3 (7.5)  21 (20.8)  0.06c   Diuretics  8 (20.0)  29 (28.7)  0.29c  Family history, n (%)      0.02c   Sudden cardiac death  11 (27.5)  9 (8.9)     Other cardiac disease  3 (7.5)  9 (8.9)    Echocardiographic parameters         LV EF  63.5 ± 4.3  62.9 ± 6.4  0.57b   LV ED volume index, mL/m2  49.2 ± 14.3  46.0 ± 12.0  0.29b   LV ES volume index, mL/m2  18.2 ± 5.5  17.2 ± 7.8  0.22b   LV mass index, g/m2  164.1 ± 43.2  135.2 ± 43.6  <0.001b   LVOT velocity, m/s  4.0 ± 1.3  1.3 ± 0.3  <0.001b   E/E′ ratio  22.6 ± 9.9  13.8 ± 4.6  <0.001b  Data presented as mean ± SD or n (%). LVOT, left ventricular outflow tract; NYHA, New York Heart Association; CCB, calcium channel blocker; ACE, angiotensin-converting enzyme; ASH, asymmetric septal hypertrophy; EF, ejection fraction; ED, end-diastolic; ES, end-systolic; SD, standard deviation. a T-test. b Wilcoxon rank-sum test for continuous measures. c χ2 test for categorical variable. Table 1 Baseline characteristics and echocardiographic measurements   LVOT obstruction       Yes (n = 40)  No (n = 101)  P-valuea,b  Clinical characteristics   Age, years  55.6 ± 14.8  58.5 ± 13.5  0.32b   Male gender, n (%)  28 (70.0)  78 (77.2)  0.37c   Systolic pressure, mmHg  122.7 ± 56.9  122.1 ± 17.1  0.02b   Diastolic pressure, mmHg  70.6 ± 9.5  74.2 ± 11.1  0.07a   Atrial fibrillation, n (%)  3 (7.5)  6 (5.9)  0.58c   Symptomatic patients, n (%)  37 (92.5)  73 (72.3)  0.01c   Dyspnoea NYHA class III or IV, n (%)  12 (30.0)  9 (8.9)  0.01c   Syncope, n (%)  8 (20.0)  11 (10.9)  0.15c   Palpitation, n (%)  6 (15.0)  12 (11.9)  0.62c   Chest pain, n (%)  18 (45.0)  38 (37.6)  0.42c  Medication, n (%)   CCB  8 (20.0)  22 (21.8)  0.82c   B-blocker  31 (77.5)  64 (63.4)  0.11c   ACE inhibitor  3 (7.5)  21 (20.8)  0.06c   Diuretics  8 (20.0)  29 (28.7)  0.29c  Family history, n (%)      0.02c   Sudden cardiac death  11 (27.5)  9 (8.9)     Other cardiac disease  3 (7.5)  9 (8.9)    Echocardiographic parameters         LV EF  63.5 ± 4.3  62.9 ± 6.4  0.57b   LV ED volume index, mL/m2  49.2 ± 14.3  46.0 ± 12.0  0.29b   LV ES volume index, mL/m2  18.2 ± 5.5  17.2 ± 7.8  0.22b   LV mass index, g/m2  164.1 ± 43.2  135.2 ± 43.6  <0.001b   LVOT velocity, m/s  4.0 ± 1.3  1.3 ± 0.3  <0.001b   E/E′ ratio  22.6 ± 9.9  13.8 ± 4.6  <0.001b    LVOT obstruction       Yes (n = 40)  No (n = 101)  P-valuea,b  Clinical characteristics   Age, years  55.6 ± 14.8  58.5 ± 13.5  0.32b   Male gender, n (%)  28 (70.0)  78 (77.2)  0.37c   Systolic pressure, mmHg  122.7 ± 56.9  122.1 ± 17.1  0.02b   Diastolic pressure, mmHg  70.6 ± 9.5  74.2 ± 11.1  0.07a   Atrial fibrillation, n (%)  3 (7.5)  6 (5.9)  0.58c   Symptomatic patients, n (%)  37 (92.5)  73 (72.3)  0.01c   Dyspnoea NYHA class III or IV, n (%)  12 (30.0)  9 (8.9)  0.01c   Syncope, n (%)  8 (20.0)  11 (10.9)  0.15c   Palpitation, n (%)  6 (15.0)  12 (11.9)  0.62c   Chest pain, n (%)  18 (45.0)  38 (37.6)  0.42c  Medication, n (%)   CCB  8 (20.0)  22 (21.8)  0.82c   B-blocker  31 (77.5)  64 (63.4)  0.11c   ACE inhibitor  3 (7.5)  21 (20.8)  0.06c   Diuretics  8 (20.0)  29 (28.7)  0.29c  Family history, n (%)      0.02c   Sudden cardiac death  11 (27.5)  9 (8.9)     Other cardiac disease  3 (7.5)  9 (8.9)    Echocardiographic parameters         LV EF  63.5 ± 4.3  62.9 ± 6.4  0.57b   LV ED volume index, mL/m2  49.2 ± 14.3  46.0 ± 12.0  0.29b   LV ES volume index, mL/m2  18.2 ± 5.5  17.2 ± 7.8  0.22b   LV mass index, g/m2  164.1 ± 43.2  135.2 ± 43.6  <0.001b   LVOT velocity, m/s  4.0 ± 1.3  1.3 ± 0.3  <0.001b   E/E′ ratio  22.6 ± 9.9  13.8 ± 4.6  <0.001b  Data presented as mean ± SD or n (%). LVOT, left ventricular outflow tract; NYHA, New York Heart Association; CCB, calcium channel blocker; ACE, angiotensin-converting enzyme; ASH, asymmetric septal hypertrophy; EF, ejection fraction; ED, end-diastolic; ES, end-systolic; SD, standard deviation. a T-test. b Wilcoxon rank-sum test for continuous measures. c χ2 test for categorical variable. Difference of CT-defined LV geometry Patients with LVOTO displayed a more frequent spiral pattern of myocardial hypertrophy, greater LV mass, elongated both PMs, increased number of accessory PM, and greater distance from PM base from the LV apex or mitral annulus. The findings from univariable analyses and their association with LVOTO among HCM patients are summarized in Table 2. The distance between LP base and LV apex was greater in the LVOTO group (e.g. 26.4 vs. 22.0 mm, P < 0.001). Of the 40 patients with LVOTO, half of these had spiral pattern, whereas the remaining 101 patients without LVOTO displayed a significantly lower spiral pattern (e.g. 51 vs. 16%, P < 0.001). In addition, patients with obstruction had more thickened segments (10.3 vs. 8.3, P = 0.006), a larger maximum thickness of LV wall (24.6 vs. 22.8 mm, P = 0.12), and a more elongated anterior mitral leaflet (AML) (18.0 vs. 15.6 mm, P = 0.007). Table 2 CT measurements and univariable analysis for likelihood of having left ventricular outflow tract obstruction   LVOT obstruction     Univariable analyses     Yes (n = 40)  No (n = 101)  P-valuea,b,c  OR (95% CI)  P-valued  LV geometry   Spiral pattern, n (%)  20 (50.0)  17 (16.8)  <0.001c  4.94 (2.2–11.1)  <0.001   LV mass index, g/m2  124.9 ± 36.4  101.3 ± 27.2  <0.001b  1.00 (0.97–1.03)  0.76   LV ED volume index, mL/m2  78.0 ± 19.9  66.1 ± 17.7  0.001b  1.04 (1.01–1.07)  0.01   Number of thickened segment  10.3 ± 3.7  8.3 ± 3.8  0.006b  1.12 (0.89–1.40)  0.30   LV maximal thickness, mm  24.6 ± 5.5  22.8 ± 4.2  0.12b  1.07 (0.96–1.20)  0.17   A-M angle  58.4 ± 9.9  57.4 ± 7.5  0.38b  1.04 (0.99–1.10)  0.09   LVH pattern, n (%)      0.02c    0.74    ASH  18 (45.0)  35 (34.7)          Apical  0 (0)  20 (19.8)          Diffuse  5 (12.5)  9 (8.9)          Mixed  17 (42.5)  37 (36.6)        Papillary muscles and MV             Number of accessory PMs  1.0 ± 1.0  1.5 ± 1.4  0.14b  0.80 (0.56–1.14)  0.22   MP length, mm/m2  25.3 ± 5.6  23.2 ± 4.4  0.04b  0.94 (0.79–1.12)  0.51   MP base ∼ MA, mm/m2  42.6 ± 7.3  39.9 ± 5.4  0.06b  1.09 (0.93–1.28)  0.28   MP base ∼ LV apex, mm/m2  17.9 ± 4.8  15.2 ± 4.3  0.002a  1.11 (0.98–1.25)  0.08   LP length, mm/m2  24.1 ± 4.7  22.1 ± 3.6  0.02b  1.00 (0.79–1.27)  0.96   LP base ∼ MA, mm/m2  40.0 ± 6.0  37.2 ± 4.6  0.005b  1.03 (0.84–1.25)  0.76   LP base ∼ LV apex, mm/m2  26.4 ± 6.1  22.0 ± 5.3  <0.001a  1.15 (1.07–1.24)  <0.001   AML, mm/m2  18.0 ± 4.6  15.6 ± 2.6  0.007b  1.24 (1.07–1.43)  0.004   PML, mm/m2  9.5 ± 2.2  8.4 ± 2.0  0.03b  1.16 (0.91–1.46)  0.21    LVOT obstruction     Univariable analyses     Yes (n = 40)  No (n = 101)  P-valuea,b,c  OR (95% CI)  P-valued  LV geometry   Spiral pattern, n (%)  20 (50.0)  17 (16.8)  <0.001c  4.94 (2.2–11.1)  <0.001   LV mass index, g/m2  124.9 ± 36.4  101.3 ± 27.2  <0.001b  1.00 (0.97–1.03)  0.76   LV ED volume index, mL/m2  78.0 ± 19.9  66.1 ± 17.7  0.001b  1.04 (1.01–1.07)  0.01   Number of thickened segment  10.3 ± 3.7  8.3 ± 3.8  0.006b  1.12 (0.89–1.40)  0.30   LV maximal thickness, mm  24.6 ± 5.5  22.8 ± 4.2  0.12b  1.07 (0.96–1.20)  0.17   A-M angle  58.4 ± 9.9  57.4 ± 7.5  0.38b  1.04 (0.99–1.10)  0.09   LVH pattern, n (%)      0.02c    0.74    ASH  18 (45.0)  35 (34.7)          Apical  0 (0)  20 (19.8)          Diffuse  5 (12.5)  9 (8.9)          Mixed  17 (42.5)  37 (36.6)        Papillary muscles and MV             Number of accessory PMs  1.0 ± 1.0  1.5 ± 1.4  0.14b  0.80 (0.56–1.14)  0.22   MP length, mm/m2  25.3 ± 5.6  23.2 ± 4.4  0.04b  0.94 (0.79–1.12)  0.51   MP base ∼ MA, mm/m2  42.6 ± 7.3  39.9 ± 5.4  0.06b  1.09 (0.93–1.28)  0.28   MP base ∼ LV apex, mm/m2  17.9 ± 4.8  15.2 ± 4.3  0.002a  1.11 (0.98–1.25)  0.08   LP length, mm/m2  24.1 ± 4.7  22.1 ± 3.6  0.02b  1.00 (0.79–1.27)  0.96   LP base ∼ MA, mm/m2  40.0 ± 6.0  37.2 ± 4.6  0.005b  1.03 (0.84–1.25)  0.76   LP base ∼ LV apex, mm/m2  26.4 ± 6.1  22.0 ± 5.3  <0.001a  1.15 (1.07–1.24)  <0.001   AML, mm/m2  18.0 ± 4.6  15.6 ± 2.6  0.007b  1.24 (1.07–1.43)  0.004   PML, mm/m2  9.5 ± 2.2  8.4 ± 2.0  0.03b  1.16 (0.91–1.46)  0.21  Covariates with P < 0.10 were retained for multivariable analyses (bold). LVOT, left ventricular outflow tract; OR, odds ratio; CI, confidence interval; LV, left ventricle; ED, end diastolic; LV max, LV maximum wall thickness; A-M angle, aorto-mitral angle; MV, mitral valve; PM, papillary muscle; MP, posteromedial papillary muscle; LP, anterolateral papillary muscle; MA, mitral annulus; AML, anterior mitral leaflet; PML, posterior mitral leaflet. a T-test. b Wilcoxon rank-sum test for continuous measures. c χ2 test for categorical variable. d Logistic regression for LVOT obstruction was done. Table 2 CT measurements and univariable analysis for likelihood of having left ventricular outflow tract obstruction   LVOT obstruction     Univariable analyses     Yes (n = 40)  No (n = 101)  P-valuea,b,c  OR (95% CI)  P-valued  LV geometry   Spiral pattern, n (%)  20 (50.0)  17 (16.8)  <0.001c  4.94 (2.2–11.1)  <0.001   LV mass index, g/m2  124.9 ± 36.4  101.3 ± 27.2  <0.001b  1.00 (0.97–1.03)  0.76   LV ED volume index, mL/m2  78.0 ± 19.9  66.1 ± 17.7  0.001b  1.04 (1.01–1.07)  0.01   Number of thickened segment  10.3 ± 3.7  8.3 ± 3.8  0.006b  1.12 (0.89–1.40)  0.30   LV maximal thickness, mm  24.6 ± 5.5  22.8 ± 4.2  0.12b  1.07 (0.96–1.20)  0.17   A-M angle  58.4 ± 9.9  57.4 ± 7.5  0.38b  1.04 (0.99–1.10)  0.09   LVH pattern, n (%)      0.02c    0.74    ASH  18 (45.0)  35 (34.7)          Apical  0 (0)  20 (19.8)          Diffuse  5 (12.5)  9 (8.9)          Mixed  17 (42.5)  37 (36.6)        Papillary muscles and MV             Number of accessory PMs  1.0 ± 1.0  1.5 ± 1.4  0.14b  0.80 (0.56–1.14)  0.22   MP length, mm/m2  25.3 ± 5.6  23.2 ± 4.4  0.04b  0.94 (0.79–1.12)  0.51   MP base ∼ MA, mm/m2  42.6 ± 7.3  39.9 ± 5.4  0.06b  1.09 (0.93–1.28)  0.28   MP base ∼ LV apex, mm/m2  17.9 ± 4.8  15.2 ± 4.3  0.002a  1.11 (0.98–1.25)  0.08   LP length, mm/m2  24.1 ± 4.7  22.1 ± 3.6  0.02b  1.00 (0.79–1.27)  0.96   LP base ∼ MA, mm/m2  40.0 ± 6.0  37.2 ± 4.6  0.005b  1.03 (0.84–1.25)  0.76   LP base ∼ LV apex, mm/m2  26.4 ± 6.1  22.0 ± 5.3  <0.001a  1.15 (1.07–1.24)  <0.001   AML, mm/m2  18.0 ± 4.6  15.6 ± 2.6  0.007b  1.24 (1.07–1.43)  0.004   PML, mm/m2  9.5 ± 2.2  8.4 ± 2.0  0.03b  1.16 (0.91–1.46)  0.21    LVOT obstruction     Univariable analyses     Yes (n = 40)  No (n = 101)  P-valuea,b,c  OR (95% CI)  P-valued  LV geometry   Spiral pattern, n (%)  20 (50.0)  17 (16.8)  <0.001c  4.94 (2.2–11.1)  <0.001   LV mass index, g/m2  124.9 ± 36.4  101.3 ± 27.2  <0.001b  1.00 (0.97–1.03)  0.76   LV ED volume index, mL/m2  78.0 ± 19.9  66.1 ± 17.7  0.001b  1.04 (1.01–1.07)  0.01   Number of thickened segment  10.3 ± 3.7  8.3 ± 3.8  0.006b  1.12 (0.89–1.40)  0.30   LV maximal thickness, mm  24.6 ± 5.5  22.8 ± 4.2  0.12b  1.07 (0.96–1.20)  0.17   A-M angle  58.4 ± 9.9  57.4 ± 7.5  0.38b  1.04 (0.99–1.10)  0.09   LVH pattern, n (%)      0.02c    0.74    ASH  18 (45.0)  35 (34.7)          Apical  0 (0)  20 (19.8)          Diffuse  5 (12.5)  9 (8.9)          Mixed  17 (42.5)  37 (36.6)        Papillary muscles and MV             Number of accessory PMs  1.0 ± 1.0  1.5 ± 1.4  0.14b  0.80 (0.56–1.14)  0.22   MP length, mm/m2  25.3 ± 5.6  23.2 ± 4.4  0.04b  0.94 (0.79–1.12)  0.51   MP base ∼ MA, mm/m2  42.6 ± 7.3  39.9 ± 5.4  0.06b  1.09 (0.93–1.28)  0.28   MP base ∼ LV apex, mm/m2  17.9 ± 4.8  15.2 ± 4.3  0.002a  1.11 (0.98–1.25)  0.08   LP length, mm/m2  24.1 ± 4.7  22.1 ± 3.6  0.02b  1.00 (0.79–1.27)  0.96   LP base ∼ MA, mm/m2  40.0 ± 6.0  37.2 ± 4.6  0.005b  1.03 (0.84–1.25)  0.76   LP base ∼ LV apex, mm/m2  26.4 ± 6.1  22.0 ± 5.3  <0.001a  1.15 (1.07–1.24)  <0.001   AML, mm/m2  18.0 ± 4.6  15.6 ± 2.6  0.007b  1.24 (1.07–1.43)  0.004   PML, mm/m2  9.5 ± 2.2  8.4 ± 2.0  0.03b  1.16 (0.91–1.46)  0.21  Covariates with P < 0.10 were retained for multivariable analyses (bold). LVOT, left ventricular outflow tract; OR, odds ratio; CI, confidence interval; LV, left ventricle; ED, end diastolic; LV max, LV maximum wall thickness; A-M angle, aorto-mitral angle; MV, mitral valve; PM, papillary muscle; MP, posteromedial papillary muscle; LP, anterolateral papillary muscle; MA, mitral annulus; AML, anterior mitral leaflet; PML, posterior mitral leaflet. a T-test. b Wilcoxon rank-sum test for continuous measures. c χ2 test for categorical variable. d Logistic regression for LVOT obstruction was done. Multivariable analysis In Table 3, after adjusting for retained covariates, spiral pattern of hypertrophy [95% confidence interval (CI), 3.75, 1.59–8.84], anterior mitral leaflet length (95% CI, 1.20, 1.03–1.40), and the distance between LP base and LV apex (95% CI, 1.09, 1.01–1.19) were all independently associated with the likelihood of having LVOTO. In sensitivity analysis that omitted patients who exclusively had apical hypertrophy, all of the aforementioned CT measures remained independently associated with the presence of LVOTO. Table 3 Multivariable odds ratios according to CT measurements for likelihood of having left ventricular outflow tract obstruction   OR  95% CI  P-value  Spiral pattern  3.75  1.60–8.80  0.003  AML, per 1 mm/m2  1.20  1.03–1.40  0.023  LP base ∼ LV apex, per 1 mm/m2  1.10  1.01–1.19  0.034    OR  95% CI  P-value  Spiral pattern  3.75  1.60–8.80  0.003  AML, per 1 mm/m2  1.20  1.03–1.40  0.023  LP base ∼ LV apex, per 1 mm/m2  1.10  1.01–1.19  0.034  OR, odds ratio; CI, confidence interval; AML, anterior mitral leaflet; LP, anterolateral papillary muscle; LV, left ventricle. Table 3 Multivariable odds ratios according to CT measurements for likelihood of having left ventricular outflow tract obstruction   OR  95% CI  P-value  Spiral pattern  3.75  1.60–8.80  0.003  AML, per 1 mm/m2  1.20  1.03–1.40  0.023  LP base ∼ LV apex, per 1 mm/m2  1.10  1.01–1.19  0.034    OR  95% CI  P-value  Spiral pattern  3.75  1.60–8.80  0.003  AML, per 1 mm/m2  1.20  1.03–1.40  0.023  LP base ∼ LV apex, per 1 mm/m2  1.10  1.01–1.19  0.034  OR, odds ratio; CI, confidence interval; AML, anterior mitral leaflet; LP, anterolateral papillary muscle; LV, left ventricle. Discussion The major findings of this quantitative study using 3D CT were: (i) geometrical change of PM was related to LVOTO in HCM patients; (ii) spiral pattern of LV hypertrophy was more frequently present in HCM patients with LVOTO as compared with patients without LVOTO; and (iii) elongated MV was found to be associated with the presence of LVOTO. This study confirmed the experimental, surgical, and imaging findings of the previous papers wherein PM abnormalities are likely a contributory factor towards LVOTO.9,10,12,18,19 Foremost, Levine et al.19 experimentally verified that anterior displacement of PM caused subaortic obstruction in seven canine models. Kwon et al.9 also documented that anteroapical displacement of anterolateral PM on MRI was associated with a higher LVOT gradient. Harrigan et al.10 reported that in patients with LVOTO at rest, PMs were positioned closer to the ventricular septum. By extension, the present study quantitatively demonstrated that obvious geometric alterations of the PMs exist between two groups with and without LVOTO. When considering the distance between the mitral annulus and both PM bases also increased, additional to the distance between both PM bases and LV apex, these alterations may somewhat be derived from the overall increased size of the heart. Nevertheless, the notion that only the distance between LP base and LV apex was found to be significant implies that the anterolateral PM might be displaced, which is away from the LV apex and closer to the LV base in a simultaneous fashion. Of further interest is the unique spiral pattern of LV hypertrophy that was present in HCM patients, which exhibited a significant association with LVOTO. The spiral pattern of LV hypertrophy can be defined as counterclockwise spiral in the longitudinal direction when viewed from the LV apex along the basal to apical direction.16,17 Indeed, such a relationship was first described in a case report of a HCM patient with cardiac MR imaging, and was considered to be a peculiar pattern of LV hypertrophy.17 The pattern was quantitatively assessed using cardiac MR in one study,16 which concluded that patients with an extensive spiral configuration more frequently experience LVOTO as compared with a non-spiral group. The exact mechanism of the association between the spiral pattern and LVOTO could not be solved in previous studies including this study. It may be the question of which came first, the spiral configuration or the LVOTO. The MV abnormality has been proposed to be one of the determinants of LVOTO. In several studies7,12,20 using echocardiography and cardiac MR, enlarged mitral leaflet length or surface area were independently associated with the obstruction, which is concordant with the present study. The current results therefore can prove useful towards understanding geometrical modifications of the heart as well as underlining the possible mechanisms of LVOTO in HCM patients. Cardiac CT has an advantage of more accurately evaluating the 3D geometry of myocardial hypertrophy pattern and PMs than MR and echocardiography.14,21–25 Up till now, classical disadvantages of CT such as ionizing radiation and iodinated contrast limit the routine use of the CT, and it has been only indicated to assess coronary arteries or when echocardiographic images are suboptimal and cardiac MR is contraindicated. The previously mentioned measurable factors can perhaps be used to predict LVOTO, while also specifying the target of treatment to relieve obstruction when planning surgical myectomy with or without mitral valvuloplasty in HCM patients with LVOTO. Image-based guidance and 3D printed models created from cardiac CT have been applied to facilitate surgical planning in HCM.26 The quantitative information regarding the myocardial geometric changes presented in this study should be considered in hypothesis generation of further imaging-based prospective trials that are designed to determine appropriate treatment guidelines in patients who present with HCM. There are several limitations that should be emphasized. As this study was retrospective in nature and conducted at a tertiary care referral centre, we cannot discount the possibility that patients enrolled and who underwent CT scanning were likely more symptomatic with more severe symptoms of cardiac disease than other apparently healthier HCM patients who are typically asymptomatic. In light of a potential selection bias, caution should be taken when interpreting these findings. Considering the clinical, haemodynamic and prognostic heterogeneity of the population, the sample is rather small, which may preclude the wide clinical application of the findings. Further larger multicentre study that included a normal control group would be needed in order to confirm the findings and also draw a more accurate and reliable conclusion. The observational cross-sectional design of this study also limited the inference of a causal relationship between LVOTO and the various factors assessed. Forthcoming well-designed investigations that are prospective in nature appear warranted. In addition, 2D measurement of the PMs and MV may not reflect the exact degree of the structural change. Future studies with complete 3D evaluation of those structures (i.e. mitral surface area, papillary muscular volume) may draw more reliable conclusion. Finally, as we assessed the presence of LVOTO only in resting conditions, provocable LVOTO group in which obstruction may occur only during exercise could be missed. Considering the fact that significant percentage of provocable obstruction group had heart failure symptom and may be candidate for major interventions,15 it would be the best if the population included in the study. In the present study comprising a sample of HCM patients, spiral pattern of LV hypertrophy, the length of AML, and the distance between LP base and LV apex were all independently associated with LVOTO. These associations indicate that alterations in LV geometry, as well as elongated AML, and displacement of anterolateral PM might influence the LVOTO. The current study findings may further our understanding of the underlying mechanisms of LVOTO in patients who present with HCM. Funding This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (NRF-2016R1A1A1A05921207 and NRF-2015R1A2A2A04003034) and a grant (2017-7208) from the Asan Institute for Life Sciences, Asan Medical Centre, Seoul, Korea. ‘The Industrial Strategic technology development program (10072064) funded by the Ministry of Trade Industry and Energy (MI, Korea)’. Conflict of interest: None declared. References 1 Maron MS, Olivotto I, Betocchi S, Casey SA, Lesser JR, Losi MA et al.   Effect of left ventricular outflow tract obstruction on clinical outcome in hypertrophic cardiomyopathy. N Engl J Med  2003; 348: 295– 303. Google Scholar CrossRef Search ADS PubMed  2 Autore C, Bernabo P, Barilla CS, Bruzzi P, Spirito P. The prognostic importance of left ventricular outflow obstruction in hypertrophic cardiomyopathy varies in relation to the severity of symptoms. J Am Coll Cardiol  2005; 45: 1076– 80. 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Journal

European Heart Journal – Cardiovascular ImagingOxford University Press

Published: Oct 11, 2017

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