Conventional echocardiography with Valsalva maneuver

Each patient underwent a complete standard transthoracic echocardiography. The LV dimensions and septal and posterior wall thickness were measured at end-diastole and end-systole in the two-dimensional parasternal long axis or short axis views. LV ejection fraction was calculated using the modified Quinones’ method [7]. LV mass was measured by Devereux’s methods as recommended by the American Society of Echocardiography [7]. Relative wall thickness was calculated as twice the posterior wall thickness at end-diastole divided by the LV end-diastolic dimension. The left atrial volume was measured using the prolate ellipsoidal method at the point of LV end-systole when the left atrial size was maximal. From the apical window, a 1 mm pulsed Doppler sample volume was placed at the mitral valve tip, and mitral flow velocities from 5 to 10 cardiac cycles were recorded. Peak early (E) and late (A) mitral inflow velocities were also measured. Mitral annular velocity was measured by tissue Doppler imaging using the pulsed wave Doppler mode. The filter was set to exclude high frequency signal, and the Nyquist limit was adjusted to a range of 15 to 20 cm/s. Gain and sample volume were minimized to allow for a clear tissue signal with minimal background noise. Systolic (S’), early (e’) and late diastolic velocities of the mitral annulus were measured from the apical 4-chamber view with a 2- to 5-mm sample volume placed at the septal corner of the mitral annulus. Peak velocity of tricuspid regurgitation was measured and PASP was calculated as 4xTRV² + RA pressure, where RA pressure was estimated according to IVC diameter and its respiratory variations [8]. In cases of systolic color flow acceleration in the LVOT, trans-LVOT peak PG was measured with continuous wave Doppler both at rest and during a Valsalva maneuver.

End-systolic wall stress calculations

Before echocardiography, all the patients underwent blood pressure measurements in the upper arm with an automatic sphygmomanometer (TM-2665P, AND, CA). End-systolic systemic pressure was calculated as (2х systolic blood pressure + diastolic blood pressure)/3. The left ventricular end-systolic meridional wall stress was calculated by the method of Grossman et al. [9] Left ventricular wall stress (g/cm²) at the end of systole was calculated as (1.35)*(P_es)*(D_es)/(4 )*(h_es)*[l + (h_es///D_es)], where P_es is the left ventricular pressure (mm Hg) at end-systole determined by the end-systolic blood pressure plus the end-systolic peak PG across the LVOT, D_es and h are the LV internal dimension and posterior wall thickness (cm) at end-systole, respectively, 1.35 is a conversion factor (mm Hg to g/cm), and 4 is a geometric factor that results from conversion of the radius to the internal dimension [10].

Measurements of LV geometry associated with DLVOTO

Interventricular basal septal thickness was measured at end-diastole in apical 3-chamber view images. The angle between the ascending aorta and the plane of the mitral valvular orifice was measured at both end-diastole and end-systole from 3-chamber views (Figure 2). Size of papillary muscles was measured in patients with prominent papillary muscle group in every imaging view. The presence of systolic anterior motion (SAM) of mitral valve and chordae was also reviewed from all the echo images.

Statistical analysis

Clinical characteristics and echocardiographic parameters are presented as mean ± standard deviation for continuous variables and number (percentage) for categorical variables. Correlation analysis was performed between continuous variables using the Pearson correlation coefficient. Comparisons of echocardiographic findings between controls and study group were performed by independent t-test. Comparison of clinical and echocardiographic variables among subgroups was performed by ANOVA with post-hoc analysis via Bonferroni correction. The trans-LVOT-PG before and after a Valsalva maneuver was compared using the paired t-test. Variables with p < 0.10 in univariate analysis were included in the multivariable regression analysis. All the analyses were performed using SPSS (version 20.0, IBM, USA), and p values less than 0.05 were considered significant.

Baseline clinical and echocardiographic characteristics

Resting and latent DLVOTO

Patients with resting DLVOTO had higher LVESWS (p = 0.007), lower S’ (p = 0.048) and a higher pulmonary arterial systolic pressure (p = 0.007) than those with latent DLVOTO. However, the prevalence of concomitant hypertension, diabetes and anti-hypertensive medications were not different. In the latent DLVOTO group, the indexed LV end-diastolic dimension was inversely and significantly correlated with an increase of the PG between the resting state and the Valsalva maneuver (r = −0.224, p = 0.01). However, other parameters such as angle and basal septal thickness were not significantly correlated with peak PG change.

Morphologic classification related to DLVOTO

Study patients were classified as either having a pure sigmoid septum, defined as basal septal bulging but diastolic thickness ≤ 15 mm (n = 14); a sigmoid septum with basal septal hypertrophy higher than 15 mm (n = 85); a prominent papillary muscle (PM) (n = 20), defined as a visually large PM which occlude the LV cavity during systole or >1/2 LV end-systolic dimension and maximal thickness of PM in short axis view higher than 11.2 mm or longer than 2.6 cm in 2, 3 or 4 chamber view; or a small LV cavity with concentric remodelling or hypertrophy (n = 49) (Figure 3). The prominent PM group was younger, had a higher S’ and a lower E/e’ than other groups. The frequency of beta-blocker usage was lower in the prominent PM group. However, resting and Valsalva-induced trans-LVOT peak PGs were not different among subgroups (Table 2). Leaflets SAM was observed in 31 patients (19%), chordal SAM in 80 (48%), papillary muscle kissing to hypertrophied septum in 38 (23%), mixed type in 3 (2%) and non-above category was in 16 (10%). Patients with leaflets SAM had higher restign trans-LVOT PG. Analyses of their characteristics are described in the Table 3.

Clinical and hemodynamic impact of DLVOTO

In all groups, a higher peak trans-LVOT PG was correlated to higher E/e’ (r = 0.246, p = 0.002), pulmonary arterial systolic pressure (PASP, r = 0.317, p < 0.001), systolic blood pressure (r = −0.142, p = 0.081) and relative wall thickness (r = 0.141, p = 0.070). In multivariate analysis, resting trans-LVOT PG correlated to PASP (ß = 0.226, p = 0.019) after adjustment for systolic blood pressure, relative wall thickness, and E/e’.

Diverse geometric changes related to DLVOTO

This group of patients had a small LV cavity and increased basal septal thickness with a more angulated ascending aorta compared to age- and sex-matched controls. Classically, basal septal bulging due to focally increased wall thickness or increased septal to ascending aorta angle [11] with concentric LV remodelling [12] has been accepted as part of the aging process. Although the high prevalence of hypertension in the enrolled patients is possibly due to referral bias, basal septal thickness and aortic-angle were not different between hypertensive patients and their counterparts, which suggests that hypertension is not the main cause of DLVOTO related changes of LV geometry. Gender predominance was not observed. Our study also supports the finding that age is significantly correlated with the degree of aortic-angulation. This change is usually termed either sigmoid septum or basal septal hypertrophy, resulting in some confusion. Some previous reports have described basal septal hypertrophy as a subtype of HCM [13]. According to the results of this study, basal septal hypertrophy does not result in a difference in clinical characteristics compared to a purely sigmoid septal outflow tract obstruction. This is in contrast to the differences seen in the prominent PM group, suggesting that basal septal hypertrophy is more likely an aging-related change rather than a subtype of HCM. The current study also supports previous studies which showed that hypertrophied PMs were related to DLVOTO in the absence of LV hypertrophy [14]. To prevent misdiagnosis, when DLVOTO is detected, both an age-related sigmoid septum and PM hypertrophy should be considered. Thorough evaluation for the possibility of HCM might be needed in this subgroup. This distinction also suggests that basal septal hypertrophy is less likely to be a subtype of HCM. Another interesting finding is lots of patients had SAM or chordal SAM in this population, which is consistent with previous observation [15]. Therfore LV geometric change in combination with abnormal mitral apparatus abnormalities such as systolic movement of mitral leaflets, chordae and papillary muscle may contribute developments of DLVOTO [16, 17].

Clinical and hemodynamic characteristics of DLVOTO

Elderly people frequently complain of dyspnea on exertion due to diastolic dysfunction and reactive pulmonary venous hypertension. Therefore, aging is thought to be the leading cause of heart failure with a preserved ejection fraction [18]. The usual treatment for this group of patients is diuretics to relieve symptoms. However, not all these patients respond well to diuretics, and some patients suffer from significant orthostatic hypotension [19]. In this regard, the patients enrolled in this study share similar risk factors for the development of heart failure with preserved ejection such as aging, a higher prevalence of hypertension, and diastolic dysfunction with concentric remodelling [20]. Although LV ejection fraction was significantly higher in DLVOTO group compared to control, trans-LVOT- PG was not significantly correlated to LV ejection fraction. Therefore, geometrical change around LVOT might be stronger determinants than LV ejection fraction for degree of DLVOTO. According to this study, a higher trans-LVOT PG was associated with a higher pulmonary arterial pressure, so particular attention should be paid when selecting medications in this group of patients. In this regard, beta blockers or non-dihydropyridine-based calcium channel blockers, rather than diuretics, can improve symptoms and outcomes. This group of patients would be a potential subgroup of heart failure with preserved ejection fraction. Therefore, their managements should be individualized.

Study limitations

This study has several limitations. First, due to the nature of this retrospective study performed in a tertiary referral hospital, there may be some referral bias, and the actual prevalence of concomitant risk factors could not be truly measured. Additionally, Valsalva maneuver was not routinely done in all patients but only in patients with color flow turbulence or acceleration at rest in our echo-lab, the actual prevalence of latent DLVOTO might be underestimated. Secondly, although patients with secondary DLVOTO related to HCM or other conditions were excluded, complete evaluation by invasive hemodynamic status was not performed. Thirdly, classification based on basal septum thickness, LV concentric remodelling and visually assessed PM morphology is somewhat arbitrary. However, individual subtypes have been reported in previous studies [5, 11, 14], so the application of a novel classification system to this study group seems appropriate.