Unmasking Latent Left Ventricular Outflow Tract Obstruction in Hypertrophic Cardiomyopathy

Abstract

Background

Dynamic left ventricular outflow tract (LVOT) obstruction in hypertrophic cardiomyopathy may be missed on resting echocardiography, and it requires provocation for detection.

Case Summary

A 41-year-old man with previously classified nonobstructive hypertrophic cardiomyopathy presented with recurrent syncope. Serial echocardiography had demonstrated no significant dynamic LVOT obstruction. During reassessment, repeated Doppler interrogation with Valsalva maneuver revealed variable pressure gradients ranging from 25 to 46 mm Hg. Exercise stress echocardiography further unmasked severe LVOT obstruction, with a peak gradient of 108 mm Hg and worsening mitral regurgitation. Multimodality assessment, including postextrasystolic provocation and invasive hemodynamics, demonstrated comparable augmentation of LVOT gradients. Mavacamten therapy eliminated LVOT obstruction, with no recurrence of syncope.

Discussion

Exercise-induced gradients paralleled those obtained with mechanistic provocation, indicating that physiologic stress can reliably reflect the magnitude of latent obstruction.

Take-Home Message

Exercise stress echocardiography, supported by complementary provocation, may provide a practical approach to identify clinically significant latent LVOT obstruction.

Visual Summary

History of Presentation

A 41-year-old man with hypertrophic cardiomyopathy (HCM) presented with syncope during defecation. He also had 2 prior episodes of syncope after alcohol intake. Serial echocardiography, including an examination performed 11 months before presentation (Videos 1A and 1B), had shown a maximal interventricular septal thickness of 15 mm without significant left ventricular outflow tract (LVOT) obstruction, and he had been classified as having nonobstructive HCM. He was admitted for further evaluation of recurrent syncope, including risk stratification for a potential implantable cardioverter-defibrillator.

Take-Home Messages

• •Latent left ventricular outflow tract obstruction may be missed on resting evaluation, and it requires physiologic provocation for detection.
• •Exercise stress echocardiography, combined with postextrasystolic Doppler assessment, may provide a practical noninvasive approach to identify clinically significant obstruction.

Past Medical History

The patient had no significant comorbidities other than HCM. His family history was notable for HCM in his mother and sudden cardiac death in a grandparent in the fourth decade of life. He had been receiving sustained-release carvedilol (8 mg).

Differential Diagnosis

The differential diagnosis included arrhythmic syncope related to HCM, neurally mediated (situational) syncope, and ischemia-related syncope. Although not previously demonstrated, latent LVOT obstruction remained a potential etiology and warranted further evaluation.

Investigations

Laboratory testing showed no significant abnormalities; N-terminal pro–B-type natriuretic peptide level was mildly elevated at 152 pg/mL (upper limit of normal: 88 pg/mL). Cardiac magnetic resonance performed 3 years earlier demonstrated focal nonischemic late gadolinium enhancement in the interventricular septum (Figure 1). Transthoracic echocardiography demonstrated systolic anterior motion of the anterior mitral leaflet without septal contact (Video 2A), with a peak LVOT pressure gradient of 19 mm Hg at rest. Color Doppler localized the flow acceleration to the LVOT without evidence of midventricular obstruction (Video 2B). Given the suspicion of latent obstruction, LVOT pressure gradients were interrogated repeatedly using the Valsalva maneuver, with peak gradients ranging from 25 to 46 mm Hg across multiple measurements (Figure 2).

Figure 1.

Late Gadolinium Enhancement (Yellow Asterisk) on Cardiac Magnetic Resonance

Figure 2.

Repeated Measurement of Pressure Gradients With Valsalva Maneuver

Left ventricular outflow tract pressure gradients ranged from 25 mm Hg (Upper Left) to 46 mm Hg (Lower Right) across multiple measurements. Yellow asterisks indicate the exact point of peak velocity measurement. The corresponding pressure gradient is shown for each Doppler tracing.

To assess physiologic provocation, exercise stress echocardiography was performed. Upright treadmill exercise (Bruce protocol) was terminated at stage 2 because of dizziness. At exercise termination, the patient's heart rate was 131 beats/min. Electrocardiography demonstrated sinus tachycardia without ventricular arrhythmia or conduction abnormalities. Blood pressure at exercise termination was not recorded because the exercise test was terminated abruptly. Following exercise, the peak LVOT pressure gradient increased to 83 mm Hg. With an additional Valsalva maneuver, the peak LVOT pressure gradient further increased to 108 mm Hg, accompanied by significant mitral regurgitation (Video 3, Figure 3). At the recovery phase, the mitral regurgitation peak velocity was 7.1 m/s, corresponding to a calculated systolic pressure gradient of 202 mm Hg between the left ventricle (LV) and left atrium during systole. Given a concomitant systolic arterial blood pressure of 103 mm Hg, markedly elevated LV systolic pressure can be inferred, consistent with severe LVOT obstruction.

Figure 3.

Pressure Gradient Measurements Immediately After Exercise During Stress Echocardiography

Yellow arrows indicate left ventricular outflow tract obstruction, which shows a typical “dagger-shaped” Doppler profile. Yellow asterisks indicate mitral regurgitation flow signals. The high velocity of mitral regurgitation (7.1 m/s) suggests a markedly elevated left ventricular systolic pressure, given an arterial pressure of 103 mm Hg.

To exclude ischemia, invasive coronary angiography was performed and demonstrated no obstructive coronary artery disease (Figure 4), and an ergonovine provocation test was negative. Subsequent invasive hemodynamic assessment with simultaneous aortic root and LV pressure tracings showed a baseline LV-aorta pressure gradient of 8 mm Hg. After premature ventricular contraction (PVC), the gradient increased to 101 mm Hg (Figure 5), consistent with a positive Brockenbrough-Braunwald-Morrow sign. In parallel, Doppler echocardiography performed simultaneously demonstrated a comparable increase in LVOT gradient after an induced PVC (Figure 6).

Figure 4.

Invasive Coronary Angiography

Representative coronary angiograms demonstrating angiographically normal (A) left and (B) right coronary arteries.

Figure 5.

Invasively Measured Pressure Gradient Between the Left Ventricle and the Aorta

Simultaneous invasive left ventricular (green) and aortic (pink) pressure tracings demonstrating the Brockenbrough-Braunwald-Morrow sign. The yellow arrow indicates a left ventricular outflow tract pressure gradient of 15 mm Hg, and the red arrow indicates an increased gradient of 101 mm Hg after the postextrasystolic beat. White arrows indicate the paradoxical decrease in aortic pressure during ventricular ectopy and after the postextrasystolic beat.

Figure 6.

Continuous-Wave Doppler Echocardiography Performed Simultaneously During Invasive Hemodynamic Study

The peak pressure gradient was 34 mm Hg during the Valsalva maneuver (A), whereas it increased to 104 mm Hg after the premature ventricular contraction (B). The yellow asterisks indicate the exact point of peak velocity measurement, with the corresponding pressure gradient displayed for each Doppler tracing.

Continuous inpatient telemetry monitoring showed no ventricular tachycardia or other significant arrhythmias. Given the remaining concern for occult arrhythmia, an implantable loop recorder was placed before patient discharge.

Management

In the setting of recurrent syncope and substantial provocable dynamic LVOT obstruction documented by exercise echocardiography and invasive hemodynamics, latent obstructive physiology was considered a potential contributor to the patient's symptoms. Mavacamten 5 mg once daily was initiated.

Outcome and Follow-Up

At the first follow-up echocardiographic examination, systolic anterior motion was no longer present (Videos 4A and 4B), and the LVOT peak pressure gradient was <5 mm Hg. LV systolic function remained preserved throughout follow-up, and the mavacamten dose remained unchanged at 5 mg once daily. Subsequent implantable loop recorder monitoring revealed no clinically significant ventricular arrhythmia. The patient remained free of syncope and presyncope after discharge.

Discussion

This case illustrates a stepwise diagnostic approach to unmask latent LVOT obstruction in symptomatic HCM despite nonobstructive resting studies. Dynamic LVOT obstruction in HCM may vary with preload, afterload, and contractility, and a single negative resting study does not exclude clinically relevant obstruction. In this patient, repeated Doppler interrogation with the Valsalva maneuver increased the pressure gradient from 25 to 46 mm Hg even in a single study, raising suspicion for previously unrecognized dynamic LVOT obstruction. More broadly, additional physiologic provocation, including postprandial assessment, may further unmask latent LVOT obstruction.¹

Physiologic provocation using exercise stress testing further augments diagnostic yield. Exercise stress echocardiography reproduces real-world hemodynamics, under which latent obstruction becomes clinically relevant. In this case, exercise provoked a peak LVOT pressure gradient of 83 mm Hg, which further increased to 108 mm Hg with an additional Valsalva maneuver, accompanied by worsening mitral regurgitation, consistent with current guideline recommendations for exercise stress testing to detect and quantify dynamic LVOT obstruction.² The syncopal episode during defecation may be explained by a similar physiological mechanism, whereby straining during defecation may unmask latent LVOT obstruction through the preload-reducing effects of the Valsalva maneuver. Although exercise testing had already demonstrated severe obstruction, invasive assessment was performed to further characterize the magnitude of provocation. Subsequent invasive hemodynamic assessment provides direct evidence of the LV-aorta pressure gradient. A PVC induces postextrasystolic potentiation, increasing myocardial contractility and augmenting LV filling.³ In our case, Brockenbrough-Braunwald-Morrow testing demonstrated a postextrasystolic gradient of 101 mm Hg. Although this mechanistic provocation does not fully reflect the physiologic conditions of exercise, a subset of patients may experience symptoms with frequent PVCs during daily life. Importantly, simultaneous Doppler echocardiography captured a peak LVOT pressure gradient comparable to invasive measurements, demonstrating that postextrasystolic augmentation can mirror exercise-induced obstruction and be reliably assessed noninvasively. Accordingly, transthoracic echocardiography may be helpful to reveal latent dynamic LVOT obstruction in patients with PVCs, without the need for invasive pressure measurements.

As shown in our case, exercise echocardiography may be sufficient to detect peak LVOT pressure gradients comparable to invasive measurements. Therefore, when clinical suspicion persists, exercise testing should be considered in symptomatic HCM. Taken together, these findings support a noninvasive-first diagnostic approach, in which physiologic provocation with exercise, with additional insight from postextrasystolic Doppler assessment, can reliably identify clinically significant latent LVOT obstruction. In the present case, this diagnostic evaluation also guided therapeutic decision-making. Because the syncopal episodes were considered secondary to dynamic LVOT obstruction rather than unexplained or arrhythmic syncope, implantable cardioverter-defibrillator placement was not pursued. The estimated 5-year risk of sudden cardiac death was low (2.49%), and an implantable loop recorder was selected for rhythm surveillance. Although surgical septal myectomy was considered, the relatively modest septal hypertrophy and the overall balance between procedural risks and expected benefits favored an initial trial of mavacamten.

Conclusions

In HCM, the absence of resting LVOT obstruction on a single echocardiographic examination should not exclude obstructive physiology when clinical suspicion persists. Repeated echocardiographic interrogation and physiologic provocation with exercise, together with postextrasystolic Doppler assessment, can unmask latent LVOT obstruction, supporting a noninvasive-first diagnostic approach that may materially influence clinical management.

Visual Summary.

Stepwise Unmasking of Latent Left Ventricular Outflow Tract Obstruction

A patient with recurrent syncope had a resting left ventricular outflow tract (LVOT) pressure gradient (PG) of 19 mm Hg. Repeated Valsalva maneuvers increased the LVOT PG to 45 mm Hg, while postexercise Doppler echocardiography demonstrated a marked gradient of 108 mm Hg. During invasive hemodynamic assessment, a ventricular premature complex (VPC) elicited a postextrasystolic LVOT PG of 101 mm Hg, which was reproduced by postextrasystolic Doppler echocardiography with a gradient of 104 mm Hg. These sequential provocative assessments established clinically significant latent LVOT obstruction and supported the initiation of mavacamten therapy. Yellow asterisks indicate where the PGs were measured.

Funding Support and Author Disclosures

The authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Appendix

Video 1A

Transthoracic Echocardiography Performed Before the Current Presentation

Parasternal long-axis view (A) without and (B) with color Doppler.

Video 2A

Transthoracic Echocardiography Performed at Presentation

Parasternal long-axis view (A) without and (B) with color Doppler. Mild systolic anterior motion of the anterior mitral leaflet was observed, without septal contact.

Video 3

Color Doppler Imaging Obtained Immediately After Exercise

Significant mitral regurgitation was observed.

Video 4A

Transthoracic Echocardiography Performed 1 Month After Initiation of Mavacamten Therapy

(A) Two-dimensional imaging. (B) Corresponding color Doppler imaging. Systolic anterior motion of the mitral leaflet was no longer present.