The relation of exercise-induced left ventricular (LV) outflow tract obstruction to functional capacity in hypertrophic cardiomyopathy (HC) is incompletely defined. Thus, we assessed the patterns of onset of physiologically provoked LV outflow gradients and exercise performance in 74 consecutive patients with HC (age 45 ± 16 years; 74% men) without LV outflow obstruction at rest. The subaortic gradients were measured serially using echocardiography in these 74 patients during maximum, symptom-limited, upright bicycle exercise testing. The time course of the provoked gradients and the relation to exercise performance were assessed. Of the 74 patients, 30 (41%) developed a dynamic LV outflow gradient of ≥30 mm Hg (mean 78 ± 37 mm Hg) during upright exercise testing that correlated highly with the gradients measured with the patients supine during the immediate recovery period (R 2 = 0.97). The 16 patients in whom outflow obstruction developed rapidly at low exercise levels (≤5 METs) had a significantly reduced exercise capacity (6.1 ± 1.3 vs 8.0 ± 1.6 METs; p <0.01) compared to the other 14 patients in whom obstruction appeared later at greater exercise levels of >5 METs. The timing of the gradient onset was not predictable from the baseline clinical and echocardiographic features, peak exercise LV outflow tract gradient, or symptoms. In conclusion, in patients with HC without outflow obstruction at rest, the earlier onset of LV outflow tract gradients during physiologic exercise was associated with impaired exercise performance. These findings have provided insights into the determinants of functional impairment in HC and support the potential value of exercise echocardiography in the clinical assessment of patients with HC.
Left ventricular (LV) outflow obstruction under resting conditions represents an important determinant of progressive heart failure-related disability in patients with hypertrophic cardiomyopathy (HC). Furthermore, a significant proportion of patients with HC without obstruction at rest will develop substantial outflow gradients during physical exertion, the clinical significance of which is unresolved. Previous studies of inducible obstruction in patients with HC have focused largely on single measurements, often obtained at peak or immediately after exercise, the latter generally measured with the patient in the supine position. However, we considered the possibility that the activity level at which the dynamic gradients are generated during exertion might affect the patient’s exercise capacity. Therefore, in the present study, we revisited the issue of physiologically induced outflow gradients in HC with serial measurements made during symptom-limited upright bicycle exercise testing to determine whether the timing of gradient onset during exercise is of clinical relevance in patients with HC.
Methods
The study group included 74 patients with HC but without LV outflow tract obstruction at rest (basal outflow gradient <30 mm Hg). They were consecutively studied at our institution using exercise echocardiography ( Table 1 ). The mean patient age was 45 ± 16 years, and 53 (72%) were men. Historically, most patients (n = 70, 95%) had no or only mild exertional symptoms ( Table 1 ). The clinical diagnosis of HC was determined by the demonstration on the 2-dimensional echocardiogram of a hypertrophied and nondilated left ventricle (wall thickness ≥15 mm) in the absence of another cardiac or systemic disease capable of producing a similar degree of hypertrophy.
| Variable | Overall HC Cohort (n = 74) | Patients With Inducible Gradient (n = 30) | p Value | |
|---|---|---|---|---|
| Early (n = 16) | Late (n = 14) | |||
| Age (years) | 45 ± 16 | 42 ± 18 | 40 ± 15 | 0.64 |
| New York Heart Association functional class | 1.4 ± 0.6 | 1.5 ± 0.6 | 1.3 ± 0.6 | 0.35 |
| Class I | 49 (67%) | 9 (57%) | 11 (79%) | |
| Class II | 21 (28%) | 6 (37%) | 2 (14%) | 0.35 (overall) |
| Class III | 4 (5%) | 1 (6%) | 1 (7%) | |
| Men | 53 (72%) | 13 (81%) | 13 (93%) | 0.60 |
| Left atrial diameter (mm) | 43 ± 7 | 44 ± 7 | 46 ± 8 | 0.61 |
| Left atrial volume index (ml/m 2 ) | 48 ± 12 | 52 ± 13 | 54 ± 19 | 0.82 |
| Left ventricular end-diastolic diameter (mm) | 44 ± 5 | 44 ± 4 | 45 ± 6 | 0.49 |
| Left ventricular volume index (ml/m 2 ) | 62 ± 14 | 59 ± 12 | 67 ± 15 | 0.21 |
| Maximum left ventricular wall thickness (mm) | 23 ± 6 | 23 ± 8 | 23 ± 6 | 0.84 |
| Left ventricular mass index (g/m 2 ) ⁎ | 102 ± 30 | 146 ± 69 | 106 ± 35 | 0.28 |
| Heart rate (beats/min) | ||||
| At baseline | 69 ± 12 | 68 ± 8 | 66 ± 7 | 0.45 |
| At peak exercise | 140 ± 20 | 134 ± 23 | 142 ± 22 | 0.33 |
| Percentage of heart rate attained | 80 ± 10 | 76 ± 13 | 79 ± 9 | 0.42 |
| Blood pressure at rest (mm Hg) | ||||
| Systolic | 122 ± 16 | 122 ± 16 | 116 ± 15 | 0.24 |
| Diastolic | 77 ± 11 | 73 ± 11 | 73 ± 7 | 0.97 |
| Blood pressure at peak exercise (mm Hg) | ||||
| Systolic | 167 ± 29 | 158 ± 24 | 162 ± 23 | 0.67 |
| Diastolic | 91 ± 13 | 89 ± 11 | 87 ± 10 | 0.61 |
| Left ventricular outflow tract peak velocity (m/s) † | ||||
| At rest | 1.6 ± 0.5 | 1.9 ± 0.5 | 1.7 ± 0.4 | 0.25 |
| At peak exercise | 3.0 ± 1.3 | 4.5 ± 1.2 | 4.1 ± 0.8 | 0.33 |
| Left ventricular outflow tract gradient (mm Hg) † | ||||
| At peak exercise | 42 ± 38 | 86 ± 44 | 70 ± 28 | 0.24 |
| Mitral regurgitation ‡ | ||||
| At baseline | 0.6 ± 0.5 | 0.8 ± 0.6 | 0.7 ± 0.6 | 0.71 |
| At peak exercise | 1.0 ± 0.9 | 1.8 ± 0.9 | 1.9 ± 0.53 | 0.72 |
| Exercise capacity (METs) | 6.3 ± 1.7 | 6.1 ± 1.3 | 8.0 ± 1.6 | <0.01 |
⁎ Available for 48 of 74 study patients by cardiac magnetic resonance.
† Measured with patient in upright position.
‡ Graded as none or trivial (0), mild (1+), moderate (2+), or severe (3+).
Patients had their cardioactive medications withdrawn for ≥5 half-lives before the exercise test and each had fasted >4 hours before the test. The patients performed maximum, symptom-limited exercise tests on a bicycle ergometer in the upright position. The exercise began at an initial workload of 25 W, with stepwise 25-W increments every 2 minutes. A 12-lead electrocardiogram was monitored continuously and recorded at baseline and at each minute during exercise and after exercise. The arterial blood pressure was measured using a mercury sphygmomanometer at baseline and every 2 minutes during exercise and in the postexercise phase. The patients were encouraged to perform maximally to achieve their expected heart rate. The maximum predicted heart rate was calculated as 220 minus the patient’s age, and the percentage of the predicated heart rate was calculated as follows: (maximum heart rate attained/maximum predicated heart rate) × 100. Exercise was terminated when the predicted heart rate was achieved or when fatigue, dyspnea, chest pain, or hypotension intervened.
Peak exercise was defined as the maximum attained workload before discontinuation. The peak functional capacity was estimated as METs, with one MET defined as the energy expended at rest, equivalent to an oxygen consumption of 3.5 ml/kg of body weight per minute, as recommended. No adverse events or clinically relevant arrhythmias occurred during exercise testing.
Standard echocardiographic studies were performed with the patient in the left lateral supine decubitus position using commercially available instruments according to current guidelines. The magnitude and distribution of LV hypertrophy was assessed, as previously described. Subaortic obstruction was defined as mechanical impedance to outflow due to systolic anterior motion with mitral valve-ventricular septal contact in midsystole and graded semiquantitatively, as previously described. The peak instantaneous LV outflow tract gradients were measured at rest (and with the Valsalva maneuver) with the patient in the left lateral position with continuous-wave Doppler interrogation in the apical 5-chamber view. We took care to avoid contamination of the waveform by the mitral regurgitation jet. Mitral regurgitation was graded as none or trivial (0), mild (1+), moderate (2+), and severe (3+).
Echocardiography was performed with the patients sitting upright on the bicycle ergometer under basal conditions and serially every 2 minutes during exercise at each 25-W workload increase, with 9 ± 3 measurements/patient (range 4 to 12). The left ventricle was imaged in the apical and parasternal long-axis views to identify and grade the systolic anterior motion and mitral regurgitation and to estimate the LV outflow tract gradient using continuous-wave Doppler echocardiography. After termination of the exercise, the patients were immediately placed in the left lateral decubitus position, and the LV outflow tract velocities were measured again in the apical view using continuous-wave Doppler echocardiography.
For the purposes of the present study, the exercise-induced gradients were considered clinically relevant when ≥30 mm Hg. The onset of outflow obstruction during exercise was regarded as early when it occurred at a workload of ≤5 METs and late at a workload of >5 METs.
The data are expressed as the mean ± SD. The paired Student t test or one-way analysis of variance was used to compare normally distributed data. The chi-square test (and where applicable, Yate’s corrected chi-square test) was used to compared noncontinuous variables, expressed as proportions. The predictors of marked exercise-inducing obstruction were assessed by multivariate logistic regression analysis. p Values <0.05 were considered significant. Calculations were performed using the Statistical Package for Social Sciences, version 12.0 (SPSS, Chicago, Illinois).
Results
Data were obtained for 74 patients with HC with a LV outflow gradient of <30 mm Hg at rest in the supine position and erect on a cycle ergometer ( Table 1 ). Of the 74 patients, 24 (32%) attained >85% of their maximum predicated heart rate, and 50 (68%) achieved submaximum target heart rates and terminated the test because of fatigue (n = 40), and/or dyspnea (n = 26), and/or a systolic blood pressure decrease of >25 mm Hg during exercise (n = 4).
Of the 74 study patients, 30 (40%) developed dynamic LV outflow tract gradients of ≥30 mm Hg during exercise because of systolic anterior motion and mitral-septal contact ( Figure 1 ). The remaining 44 patients (60%) remained at less than the 30-mm Hg gradient threshold.
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