Hypertrophic cardiomyopathy (HCM) is the most prevalent inherited cardiomyopathy with prevalence of 1:200–1:500[1]. HCM is characterized by left ventricular (LV) hypertrophy without a secondary cause, with patients demonstrating a heterogeneous clinical course. Up to 70% of patients develop LV outflow tract obstruction (LVOTO), either at rest or with provocation, a dynamic phenomenon strongly associated with adverse outcomes including progressive heart failure, ventricular arrhythmias, and sudden cardiac death [1–3]. While septal hypertrophy remains the primary anatomical determinant of LVOTO, a notable proportion of patients with only moderate septal thickening (≤ 18 mm) paradoxically exhibit significant LVOT pressure gradients[4, 5]. Even moderate septal thickening can be associated with extreme LVOTO[6]. This observation suggests that factors beyond myocardial morphology contribute to the development and severity of obstruction. Notably, Parag et al. highlighted the contribution of mitral valve (MV) and subvalvular anomalies to LVOTO development in this subgroup through integrated cardiac magnetic resonance (CMR) and echocardiographic analyses[5]. These insights have led to some advocating for concomitant MV interventions alongside septal myectomy in selected patients[5, 7]. Conversely, findings from a large cohort study from the Mayo Clinic challenged this approach, demonstrating that MV abnormalities are frequently present in obstructive HCM but can often be adequately addressed by extended septal myectomy alone, without requiring direct MV intervention[8]. However, a potential limitation in patients with moderate septal hypertrophy is the insufficient septal thickness for effective resection and obstruction relief. These divergent perspectives underscore the need for a more nuanced understanding of LVOTO pathophysiology beyond traditional structural assessments in this moderate hypertrophic cohort.

Currently, the emergence of novel pharmacotherapies like mavacamten, a cardiac myosin inhibitor that alleviates LVOTO via contractility modulation, highlights the pivotal role of myocardial mechanics in the genesis of obstruction[9, 10]. Imaging studies using CMR feature tracking have shown that elevated global radial strain (GRS) predicts the presence of LVOTO independent of anatomic severity[11], and increased global circumferential strain (GCS) is significantly correlated with obstruction, irrespective of wall thickness(WT) or myocardial fibrosis[12]. Furthermore, two-dimensional echocardiography (2DE) speckle-tracking has demonstrated that peak LV twist correlates to obstruction, reinforcing the concept of hyperdynamic myocardial deformation as a functional contributor to obstruction[13].

Despite growing evidence supporting the biomechanical underpinnings of LVOTO, strain signatures specific to HCM patients with moderate hypertrophy remain poorly defined. We hypothesize that hypercontractile myocardial mechanics may serve as key functional drivers of obstruction in these subtypes. Three-dimensional echocardiography (3DE) with high temporal resolution has evolved into a robust, noninvasive imaging technique capable of providing comprehensive, multidirectional, and angle-independent quantification of myocardial deformation[14, 15]. 3DE was employed herein to identify previously unrecognized biomechanical determinants of LVOTO beyond standard 2DE structural imaging.

Clinical data was extracted from electronic medical records. Echocardiographic studies were conducted by experienced sonographers (W. Z. and J. T.) using a standardized protocol and a commercial ultrasound system (Vivid E95, GE Healthcare, Horten, Norway).

For 2DE, standard parasternal long-axis, apical four-chamber, and apical two-chamber views were acquired with individualized optimization to maximize frame rate and ensure clear LV endocardial definition. Patients with resting LVOT gradients < 50 mmHg underwent provocation maneuvers (e.g., Valsalva); if these failed to induce LVOTO, exercise echocardiography was performed using the modified Bruce treadmill protocol[17]. For 3DE, full-volume LV datasets were acquired from the apical window using a matrix-array transducer with multi-beat ECG-gated acquisition during end-expiratory breath-hold, maintaining ≥ 40 volumes/s to ensure adequate temporal resolution. A 12-slice display was used to verify complete LV coverage before strain analysis.

All datasets were exported to a dedicated workstation (EchoPAC, Vision 204, GE Medical System) for offline analysis.

2DE structural measurements, including maximal WT, early diastolic transmitral flow velocity (E), early diastolic mitral annular velocity (e′), LVOT diameter (LVOTD), and anterior mitral leaflet (AML) length. LVOTD was measured in mid-systole 0.5–1 cm below the aortic annulus, and AML length in end-diastole, both in the parasternal long-axis view using the inner edge-to-inner edge method[18]. Septal morphology was determined from the long axis view[19]. SAM and MR grades were evaluated according to the 2024 AHA/ACC/AMSSM/HRS/PACES/SCMR Guideline for the Management of HCM[1]. LAVi was derived by the biplane method at end-systole and indexed to BSA.

A semi-quantitative scoring system was applied to evaluate subvalvular anomalies, with one point assigned for the presence of each of the following features (maximum score: 4): (1) accessory papillary muscle (additional or abnormally positioned papillary muscle structures) or anomalous muscular bundles (aberrant myocardial structures extending from the LV apex to the basal septum or anterior wall)[18, 20, 21], (2) anterior displacement or bifurcation of the papillary muscles, (3) papillary muscle hypertrophy (an end-diastolic diameter > 9 mm on imaging), and (4) direct insertion of papillary muscle into the MV. These characteristics were defined based on prior literature descriptions[20–22] and expert consensus. Representative features and scoring criteria are illustrated in Fig S1. Scoring was performed independently by two experienced sonographers with 6 and 13 years of experience, respectively. Discrepancies were resolved by consensus. When available, CMR images were reviewed for reference, and late gadolinium enhancement (LGE) percentage of myocardium was analyzed when applicable.

Three-dimensional speckle-tracking echocardiography (3D-STE) analysis was performed using 4D AutoLVQ software (GE Healthcare) following standardized protocols[23] with analysis workflow showcase in Fig S2. LV end-diastolic volume (EDV), end-systolic volume (ESV), and ejection fraction (EF) were calculated, followed by dynamic LV modeling and volume–time curve generation. For strain analysis, automated endocardial tracking was performed across the cardiac cycle using a 16-segment LV model. Global longitudinal (GLS), GCS, GRS, and area strain (GAS) were computed as weighted averages of segmental values. LV twist (°) was defined as apical − basal rotation, and torsion (°/cm) as twist normalized to LV long-axis length. All 3D-STE analyses were performed by a 6-year-experienced echocardiographer (Y.W.B.). Inter-study reproducibility was tested in 20 randomly selected patients, reanalyzed one week apart.

Multivariate models adjusted for age, sex, and BSA identified LVOTD and SubMV score as consistent structural predictors of both resting and provoked LVOT gradients. Due to collinearity, ESVi was used to represent LV size, and twist and torsion were analyzed separately. Maximal WT independently predicted resting but not provoked gradients. Importantly, twist, torsion, and GAS remained independent mechanical predictors of both resting and provoked LVOT gradients (all p < 0.05 in models within torsion). Detailed results are presented in Table 4.

Further RCS analyses demonstrated load-dependent and nonlinear associations between LV twist/torsion and the risk of LVOTO, with evident threshold effects as indicated in Fig. 3. For twist, in the resting state, the association was modest and near linear, with odds ratios (ORs) gradually increasing from 1.0 to ~ 2.0 as twist rose to 15°, followed by a plateau at higher values (> 15°). Under provocation, the association became more prominent and nonlinear, with ORs rising sharply from 1.0 to ~ 4.0 across 5–15°, then reaching a plateau at > 15°. For torsion, the nonlinear relationship was more pronounced. At rest, ORs increased steeply from 1.0 to ~ 3.0 within the 1–3°/cm range, with a plateau thereafter (> 3°/cm). In the provoked state, the association was markedly nonlinear, with ORs rising rapidly and peaking near 6.0, indicating a substantial risk of obstruction under hemodynamic stress.

ROC analysis (Table 5) demonstrated LV torsion as the strongest determinant of provokable LVOTO, achieving 81% specificity at a threshold of 2.4°/cm (AUC = 0.72, p < 0.001), outperforming all structural metrics, with twist as the next best performer. For resting LVOTO, LVOTD yielded the highest AUC, while twist at a value of 8.0° offered superior sensitivity of 78% (p = 0.005). Integrating 3DE-derived mechanics with structural metrics significantly improved diagnostic performance. For provokable LVOTO, the AUC improved from 0.75 to 0.84 (Delong p = 0.003), with specificity rising from 63% to 78%. Similarly, for resting LVOTO, the AUC increased from 0.76 to 0.82 (Delong p = 0.013), with sensitivity improving from 68% to 86%. These gains are visualized in Fig. 4.

Bland-Altman plots (Fig S3) and ICCs confirmed good to excellent reproducibility of 3DE strain measurements, with ICCs ranging from 0.887 to 0.984 (Table S2).

To our knowledge, this is the first study to characterize 3DE-derived myocardial mechanics in relation to LVOTO specifically in HCM patients with moderate septal hypertrophy (WT ≤ 18 mm). Three key insights emerged: (1) Both resting and provokable LVOTO groups showed significantly greater 3DE-derived strain than the nonobstructive group (all p < 0.05), with twist and torsion the most discriminative parameters (both p < 0.001). (2) Multivariable regression identified twist, torsion, and GAS as predictors of provoked LVOT gradients independent of structural factors. Nonlinear associations were evident, with obstruction risk sharply rising above twist = 15° and torsion = 3°/cm, particularly under provocation. (3) Twist and torsion outperformed structural parameters in detecting provokable LVOTO, and twist was most sensitive for resting LVOTO. Integrating 3DE-derived mechanics with structural indices improved diagnostic performance.

This study extends previous understanding by showing that, in HCM with moderate LV hypertrophy, LVOTO results from hypertrophy, MV abnormalities, and notably, exaggerated myocardial mechanics. Among structural parameters, LVOTD emerged as the strongest independent predictor, outperforming maximal WT. This highlights that systolic LVOT narrowing, not septal hypertrophy alone, is the dominant driver of obstruction pathogenesis. To better quantify subvalvular apparatus contributions, we developed a composite SubMV score capturing diverse mitral subvalvular abnormalities. This score showed a strong and independent association with elevated LVOT gradients, extending previous findings[2, 20–22] and reinforcing the concept that the MV apparatus is not merely a bystander but rather an active contributor to LVOTO pathophysiology[1, 5, 18]. Among its sub-components, apical displacement and bifid morphology of the papillary muscles were the most frequently observed anomalies although relatively lower prevalence in our cohort compared to earlier reports[20, 24] likely reflects the exclusion of apical- and mid-ventricular obstructive HCM, in which these anomalies are more prevalent[25, 26]. These papillary anomalies aggravate flow obstruction by magnifying valvular motion during systole, a mechanism well-established in previous literature[8, 27].

Importantly, our findings highlight the independent, mechanistical role of myocardial hypercontractility in LVOTO development, as assessed by 3DE. Unlike prior studies associating impaired GLS with myocardial injury without accounting for hypertrophy severity[15, 28], this study focused on patients with moderate septal hypertrophy, where GLS was only mildly reduced (-14.4%) despite preserved ejection fraction (67%), underscoring its value as an early marker of subclinical dysfunction[29]. Importantly, both resting and provokable obstruction groups exhibited markedly enhanced myocardial mechanics compared with nonobstructive patients, hint hypercontractility as a contributor of outflow tract obstruction. These exaggerated patterns persisted after structural adjustment and were most pronounced in provokable obstruction, even twist and torsion outperformed anatomy. Collectively, these results support the paradigm that contractile mechanics are core contributors, not mere epiphenomena, in developing LVOTO among moderate HCMs. Our results align with those of Lo et al.[13], who also highlighted the role of rotational mechanics in obstructive HCM using 2DE. Increased LV twist and torsion reflects enhanced shear deformation between the apex and base[14]. RCS analysis provides mechanistic insight that excessive LV torsion contributes directly to LVOTO. Physiologically, twist and torsion enhance ejection efficiency but once exceeding a critical threshold (~ 15°/~3°/cm), they may induce abnormal wall stress, distort the LVOT geometry, and increase obstruction risk. Concurrently, elevated GAS indicates reinforced centripetal contraction, further amplifying intraventricular pressure gradients. These exaggerated mechanical responses act synergistically to drive LVOTO, a pattern most pronounced under provoked conditions when hemodynamic demand intensifies. The improved diagnostic performance of models incorporating 3DE-derived strain indices further supports this mechanistic interpretation.

Morphologically, most LVOTO patients showed a sigmoid septal shape with basal bulging and minimal fibrosis, consistent with preserved contractility that accelerates LVOT flow and sustains the hypercontractility–obstruction cycle. Conversely, nonobstructive patients more often exhibited a reverse-curved phenotype with diffuse fibrosis and impaired mechanics. Additionally, part of nonobstructive patients exhibited higher BNP levels than obstructive groups in our continuous cohort, consistent with advanced remodeling in prior reports[12, 15, 30]. These hint that absence of obstruction also does not guarantee clinical improvement in this cohort, as end-stage patients may develop systolic dysfunction (“burn out”) or pseudo-normalized nonobstructive state with impaired contractile reserve. Given the dynamic nature of LVOTO, continued and longitudinal evaluation may be warranted in suspected and fore-documented cases[31]. While selection bias may exist, since early-stage, moderately hypertrophic, nonobstructive patients often remain undiagnosed because of asymptomatic, this has little impact on interpretation of clinical referred patients.

By capturing true volumetric motion, 3DE eliminates geometric assumptions and avoids the out-of-plane speckle-tracking loss inherent to 2D imaging [15], enabling more reliable quantification of multidirectional deformation and rotational mechanics. These advantages are essential for accurately quantifying the highly heterogeneous myocardial morphology in HCM. Prior comparative studies have demonstrated strong concordance between 3DE strain, 2D strain, and CMR-derived deformation metrics, with 3DE offering the shortest analysis time[32] and good reproducibility demonstrated in our study. Moreover, its broad clinical availability makes 3DE well suited for large real-world HCM cohorts, where CMR access often varies. Collectively, these attributes support the robustness, scalability, and translational relevance of our 3DE-based findings. With the advent of cardiac myosin inhibitors that specifically target hypercontractility, these findings may help identify patients most likely to benefit as well as those at risk of contractile reserve exhaustion[33, 34]. Accordingly, routine integration of 3DE analysis holds promise for refined patient selection, risk stratification, and longitudinal follow-up.

In HCM with moderate septal hypertrophy, 3D-derived hypercontractility, particularly exaggerated LV twist and torsion, emerged as independent biomechanical determinants of obstruction beyond conventional anatomic factors. The demonstrated nonlinear and threshold-dependent associations between twist/torsion and LVOTO refine mechanistic understanding and challenge anatomy-centric paradigms, underscoring the clinical value of integrating myocardial mechanics into risk stratification and individualized management for this heterogeneous population.