Inclusion and Exclusion Criteria

Patients were included in this case series if they (1) had no LVOTO at rest but developed de novo mitral-septal contact on two-dimensional imaging and LVOTO on CW Doppler after exercise and (2) had normal LV wall thicknesses. Over a 2-year period, we also identified patients who had no significant resting gradients but DLVOTO ≥30 mm Hg after exercise and who had mild segmental LVH, with all segments ≤15 mm. We also indentified patients with normal left ventricles but who developed SAM mitral-septal contact and LVOTO after dobutamine stress. Patients with any wall motion abnormalities at rest or after exercise were excluded. Meticulous care was taken to avoid measuring mitral regurgitant jets by angling the transducer medially away from the left atrium. Only CW jets that started after isovolumetric systole and were concave to the left in contour were accepted as LVOT gradient jets. Moreover, we excluded patients with jets from complete systolic emptying of the left ventricle and patients with mid-LV obstruction. We only accepted jets for which color Doppler acceleration and aliasing occurred at the point of mitral-septal contact and not in the body of the left ventricle.

Mitral Valve and LV Measurements

We compared patients with DLVOTO without LVH with 20 age-matched and gender-matched controls with normal results on stress echocardiography. At end-diastole, using parasternal long-axis and short-axis two-dimensional views, we measured with digital calipers the LV end-diastolic diameter just below the mitral tips and the LV segmental wall thickness of four LV wall segments, the anterior septum, posterior septum, posterior wall, and anterolateral wall, as described previously. In the parasternal long-axis view, we also measured LV end-systolic diameter. On the parasternal long-axis view, at the moment of systolic mitral coaptation, we measured the diameter of the LVOT, the distance from the anterior mitral valve tip to the septum, and the distance from posterior mitral valve tip to the LV posterior wall. From the short-axis view at end-diastole, we measured the perpendicular distance from a line bisecting the papillary muscles to the septum and also to the posterior wall. From the apical three-chamber view, we measured structural variables of the mitral valve as shown in Figure 1 . In diastole, we measured the length of the anterior leaflet, from the tip of the leaflet to the insertion of the noncoronary aortic leaflet; this measurement includes the intervalvular fibrosa but offers easily identified landmarks for measurement. We also measured the length of the posterior leaflet. At the moment of coaptation in early systole, we measured the residual portion of the anterior mitral leaflet that extends past the coaptation point and is thus untethered and protruding into the LV cavity, and we measured the protrusion height of the mitral valve, the distance from the plane of the mitral annulus to the tip of most protruding mitral leaflet. This quantifies the protrusion of the mitral leaflets into the LV cavity. Chordal SAM was excluded from all measurements by observing full cine loops in multiple views and excluding patients without exercise LVOT gradients. From two-chamber and four-chamber views, we measured biplane LV end-diastolic and end-systolic volumes using Simpson’s rule and calculated ejection fractions.

Line drawing of an apical three-chamber view from a representative patient with DLVOTO showing elongated mitral leaflets, increased protrusion height above the mitral annular plane, and increased residual leaflet length. The locations of echocardiographic measurements are shown. ( Left ) Diastole, showing measurements of anterior leaflet length (AL) and posterior leaflet length (PL). ( Right ) Early systole at the moment of coaptation, showing residual leaflet length (RL) and protrusion height (PH) of the most protruding leaflet measured from the mitral annulus to the top of the most protruding leaflet.

Cardiac magnetic resonance imaging was performed as clinically indicated. Wall thicknesses were measured in the same four LV wall segments described above, and the presence of gadolinium delayed hyperenhancement was noted. The position, thickness, and number of papillary muscles were noted, as well as their potential to contribute to SAM and LVOTO, as previously reported.

Patients’ medical records were examined, and follow-up was performed by clinic visits and phone. Pharmacologic management was determined by the referring physicians. Abstract of medical records for research purposes was approved by the institutional review board of St. Luke’s-Roosevelt Hospital Center.

Statistical Analysis

Continuous variables are reported as mean ± SD. One-way analysis of variance was used to carry out an omnibus test of differences among the four groups, while mean contrasts tests were used to compare the no LVH, mild LVH, and dobutamine groups with the control patients. Echocardiographic variables corrected for body surface area were also compared between the no LVH and control patients. Bonferroni’s correction was applied to account for the number of echocardiographic variables analyzed, and P values < .05 were considered significant. Fisher’s exact test was used to analyze categorical variables. SPSS version 20 (SPSS, Inc., Chicago, IL) was used for analyses.

Mitral Valve and LV Measurements

Mitral valve abnormalities were identified in all 6 patients. These were elongated posterior leaflets (2.0 vs 1.5 cm, P < .0005), elongated anterior leaflets (3.2 vs 2.6 cm, P = .015), increased protrusion height of the mitral valve above mitral annular plane (2.6 vs 0.6 cm, P < .00001), and residual protruding portions of the mitral valve leaflets that extended past the coaptation point and into the LV cavity (0.85 vs 0.24 cm, P < .005). At rest before exercise, mild degrees of SAM without mitral-septal contact were seen in three of six patients, but there was no mitral-septal contact and no LVOT gradient. We found that all patients had LV wall thicknesses in the normal range. LV wall thickness, cavity diameters in diastole and systole, volumes, ejection fraction, and LVOT diameters did not differ between patients and controls. Distance from the mitral valve tips and the septum and posterior walls, respectively, did not differ between patients and controls. There was anterior positioning of the papillary muscles in the LV cavity, manifest by a greater distance from the plane of the papillary muscles to the posterior wall (1.8 vs 1.3 cm, P = .03). Comparisons of echocardiographic variables corrected for body surface area showed differences similar to the uncorrected data.

Postexercise Echocardiography

Severe SAM and mitral-septal contact were observed in every patient. The redundancy of the mitral valve was evident in rest and postexercise images in all patients ( Figures 2–6 , Videos 1 and 2 ). The mean gradient after peak exercise was 107 ± 55 mm Hg (range, 64–200 mm Hg). In all cases, the CW Doppler jets began after isovolumetric systole, and all were late peaking, with a concave-to-the-left contour. On color Doppler echocardiography, acceleration of color flow and aliasing occurred at the point of mitral-septal contact and not in the body of the left ventricle. No patient had mid-LV obstruction. No systolic wall motion abnormalities were observed after stress. Mitral regurgitation after stress was trivial to mild and posteriorly directed.

The duration and hemodynamic response to exercise did not differ from these values in controls. Among patients with DLVOTO, three of six developed chest pain at peak exercise that subsided after the termination of exercise. Resting electrocardiographic findings were normal in all six patients, but two developed ischemic ST-segment depression with exercise. One patient reproducibly on repeat studies had inadequate blood pressure response to exercise (<20 mm Hg increase).

Cardiac magnetic resonance imaging was performed in four patients. This showed normal segmental wall thickness ≤12 mm in two patients and normal wall thickness in all segments in the other two patients, except for isolated thickening of the basilar inferior septum of 13 mm. No patient had gadolinium delayed enhancement. One patient had an abnormal anteriorly displaced anterolateral papillary muscle similar to that previously reported; it appeared to contribute to obstruction by decreasing posterior mitral restraint. Discrete papillary muscle anomalies such as anteroapical displacement and doubly bifid papillary muscles were otherwise not seen in the other three patients.

Pharmacologic Management and Follow-Up

Two patients were advised to discontinue medications: the vasodilator amlodipine in one and atomoxetine, a selective norepinephrine reuptake inhibitor, in another. All patients were advised to refrain from athletic competition and extremes of exertion. Patients were followed up a mean of 43 ± 28 months after the initial stress echocardiographic study showing DLVOTO. None had died. Despite advice, one patient has continued to compete at the amateur tournament level in singles racquet sports, even though he routinely experiences exertion-related angina that causes him to stop competing. Coronary angiography in this patient and another showed no significant coronary stenoses. Three patients had ongoing symptoms of exercise intolerance or angina and were treated with β-blockers. Two patients continued therapy, while one patient self-terminated β-blockade. The remaining three patients had no ongoing symptoms and were not given pharmacologic therapy. Five patients underwent repeat stress exercise echocardiography 29 ± 26 months after diagnosis. After repeat stress exercise, no patient had systolic wall motion abnormalities. The three patients who were untreated still had LVOTO after exercise due to SAM and mitral-septal contact, with gradients of 77, 81, and 85 mm Hg. The two patients who were on β-blockers underwent follow-up stress exercise echocardiography on β-blockers and no longer showed mitral-septal contact and obstruction. Two patients had genotype analysis of 18 genes, which did not show HCM-associated mutations.

Patients with DLVOTO and Mild Segmental Hypertrophy <15 mm

Over the 2-year period, we identified 10 patients with DLVOTO and mild segmental thickening (mean segmental wall thicknesses ranged from 12 to 13 mm) (mean age, 48.6 ± 12 years; range, 31–68 years; eight men). A mild degree of SAM at rest was identified in five patients (50%), and three patients had mild resting gradients of 21, 21, and 29 mm Hg. After exercise, peak systolic LVOT gradient was due to SAM and mitral-septal contact, and the mean value was 130 ± 46 mm Hg (range, 56–196 mm Hg). Four patients had inadequate increases in blood pressure ranging from 0 to 14 mm Hg. All 10 patients had cardiac symptoms; nine had exercise-related dyspnea, four typical angina, three exercise-related dizziness, and one paroxysmal atrial fibrillation. These patients had mitral valve abnormalities qualitatively and quantitatively similar to the patients with no LVH: they had elongated protruding mitral leaflets (anterior leaflet, 3.3 cm; posterior leaflet, 2.0 cm, protrusion height, 2.5 cm), with residual portions of the leaflet, and anterior positioning of the papillary muscles in the left ventricle (see Table 2 ). Cardiac magnetic resonance was performed in five patients and confirmed modest hypertrophy in all; no patient had delayed hyperenhancement. Five patients had genotype analysis; one patient had the HCM-associated splice mutation MYBPC3 IVS30+5G>C. This 31-year-old patient’s mother had died suddenly of autopsy-documented HCM at 44 years of age. He received an implantable cardioverter-defibrillator for primary prevention of sudden death.

Clinically, these 10 patients presented with the spectrum of symptoms seen in HCM. Symptoms were managed by increasing β-blockade in six and the addition of disopyramide in two. One of these latter patients required surgical repair for refractory symptoms; he underwent a necessarily limited myectomy and release of an anteriorly displaced anterolateral papillary muscle by dividing muscular connections between the anterior wall and papillary muscle as reported previously. He is free of obstruction and is in New York Heart Association class I. None of the patients had died after a mean follow-up period of 16 ± 9 months.

In the combined group of 16 patients with DLVOTO with either no LVH or mild LVH, there was a preponderance of men (13 of 16 [81%], P = .02).

Patients with DLVOTO after Dobutamine Stress

Over the 2-year period, we identified 12 patients with DLVOTO after dobutamine stress (mean age, 60.3 ± 11 years; range, 48–80; six men); all (100%) were hypertensive. Mild SAM at rest was identified in one patient (8%), but all had SAM mitral-septal contact after dobutamine. These patients were older ( P < .04), and more were hypertensive ( P < .0001) compared with control patients. Compared with controls, these patients had mild degrees of thickening of the anterior septum and anterior wall: mean segmental wall thicknesses were 12 and 11 mm, respectively. There was no mitral leaflet elongation, nor was there anterior positioning of the papillary muscles in the left ventricle. However, of the 12 patients, six (50%) had residual portions of the mitral leaflets that extended past the coaptation point by ≥5 mm; this was longer by 1 standard deviation than our controls ( Table 2 ).