Whether treatment with β blockers (BBs) is of benefit to patients with hypertrophic cardiomyopathy (HC) and provocable outflow obstruction (with none or with only mild heart failure symptoms) is largely unresolved. Thus, we prospectively studied 27 patients with HC (age 36 ± 15 years; 81% men) with New York Heart Association class I or II, without obstruction at rest, but with exercise-induced left ventricular outflow tract (LVOT) gradient of ≥30 mm Hg. Patients underwent exercise echocardiography at baseline and after treatment with nadolol (n = 18; 40 to 80 mg/day) or bisoprolol (n = 9; 5 to 10 mg/day), according to a prespecified protocol. Without the BBs, the postexercise LVOT gradient was 87 ± 29 mm Hg and >50 mm Hg in 25 patients (93%). After a 12 ± 4-month period of BB treatment, the postexercise LVOT gradient had decreased to 36 ± 22 mm Hg (p <0.001) and was virtually abolished (to 0 or <30 mm Hg) in 14 patients (52%), substantially blunted (≥20 mm Hg reduction) in 9 (33%), and unchanged in only 4 (15%). Severe postexercise obstruction (range 58 to 80 mm Hg) persisted in 6 patients (22% compared to 93% without BBs; p <0.001). Nonresponders (residual postexercise gradient of ≥30 mm Hg with BBs) were characterized by an increased body mass index (hazard ratio 2.03/1 kg/m 2 , 95% confidence interval 1.2 to 3.4; p <0.05). In conclusion, in patients with HC with mild or no symptoms, treatment with BBs can prevent the development of LVOT obstruction triggered by physiologic exercise. These findings provide a rationale for the novel strategy of early prophylactic pharmacologic treatment with standard, well-tolerated doses of BBs in physically active patients with provocable gradients, aimed at effective prevention of the hemodynamic burden associated with dynamic obstruction.
Left ventricular outflow tract (LVOT) obstruction under resting (basal) conditions in hypertrophic cardiomyopathy (HC) is associated with adverse long-term consequences related to progressive heart failure. In addition, a large proportion of patients without obstruction at rest develop significant LVOT gradients associated with physical exertion, although the relevance to clinical outcomes is incompletely resolved. However, provocable obstruction is known to cause severe functional limitation and heart failure in patients with HC, requiring therapeutic interventions with negative inotropic drugs and, occasionally, myectomy or alcohol septal ablation. In patients with HC and advanced heart failure owing to LVOT obstruction (i.e., New York Heart Association [NYHA] functional class III-IV), β blockers (BBs) represent the standard first-line therapy recognized by international guidelines, as originally introduced by Braunwald et al in 1964. In addition to relieving the symptoms associated with obstruction, BB treatment is capable of controlling the heart rate increase during exercise and preventing rapid ventricular rates known to precipitate microvascular ischemia in HC hearts. However, in patients with HC and mild or no symptoms, treatment of provocable LVOT obstruction has not been standardized and remains undefined. In the present study, we prospectively assessed the efficacy of BB treatment on LVOT obstruction provoked by physiologic exercise in patients with HC with no or only mild symptoms related to effort.
Methods
Of the 187 patients with HC consecutively undergoing exercise echocardiography at Careggi University Hospital in 2006 to 2009, we prospectively enrolled 32 patients according to the following entry criteria: sinus rhythm, LVOT gradient <30 mm Hg under basal conditions in the supine position and erect on a cycle ergometer and ≥30 mm Hg after a maximum symptom-limited exercise test, in the absence of treatment with cardioactive medications (including BB, disopyramide, or verapamil); and no or only mild heart failure-related symptoms (i.e., NYHA functional class I or II). Patients in NYHA class III-IV were excluded because, by convention, they were already receiving BBs to control advanced heart failure symptoms related to LVOT obstruction. Furthermore, patients with previous surgical myectomy or percutaneous alcohol septal ablation and those with medical conditions precluding maximum exercise stress testing were excluded from the study group. Of the 32 patients who met the entry criteria, 5 refused enrollment. Thus, the remaining 27 patients with HC constituted the study cohort ( Table 1 ). Of the 27 patients, 4 (15%) had mild pharmacologically controlled systemic hypertension, and none had previously been treated with BBs.
| Variable | Value |
|---|---|
| Age (years) | 36 ± 15 |
| Men | 22 (81%) |
| Family history of hypertrophic cardiomyopathy | 10 (37%) |
| Height (m) | 1.74 ± 0.9 |
| Weight (kg) | 75 ± 13 |
| Body surface area (m 2 ) | 1.83 ± 0.4 |
| Body mass index (kg/m 2 ) | 24.6 ± 3 |
| Systolic blood pressure (mm Hg) | 126 ± 16 |
| Diastolic blood pressure (mm Hg) | 80 ± 10 |
| New York Heart Association functional class | 1.15 ± 0.36 |
| Left atrial diameter (mm) | 42 ± 6 |
| Left atrial volume index (ml/m 2 ) | 42 ± 16 |
| Left ventricular end-diastolic diameter (mm) | 44 ± 5 |
| Ventricular septal thickness (mm) | 19 ± 5 |
| Maximum left ventricular thickness (mm) | 21 ± 6 |
| Left ventricular ejection fraction (%) | 67 ± 6 |
| Left ventricular outflow gradient at rest (mm Hg) | 14 ± 7 |
| Systolic anterior motion of mitral valve | 0.6 ± 0.5 |
| 0 | 11 (41%) |
| 1+ | 15 (5%) |
| 2+ | 1 (4%) |
| Mitral regurgitation | 0.7 ± 0.5 |
| None | 10 (37%) |
| Mild | 17 (63%) |
Standard echocardiographic studies were performed with the patient in the left lateral supine decubitus using commercially available instruments according to current guidelines. Subaortic obstruction was defined as mechanical impedance to outflow due to systolic anterior motion and midsystolic mitral–septal contact and was graded semiquantitatively. The peak instantaneous LVOT gradient was 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, taking care to avoid contamination of the waveform by the mitral regurgitation jet. Mitral regurgitation was graded as none or trivial (score 0), mild (score 1+), moderate (score 2+), or severe (score 3+).
Maximum, symptom-limited exercise tests were performed on a bicycle ergometer in the upright position. 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, 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.
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 predicted heart rate was calculated as the maximum heart rate attained divided by the maximum predicted heart rate multiplied by 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. Peak functional capacity was estimated in METs, with 1 MET defined as the energy expended at rest, equivalent to oxygen consumption of 3.5 ml/kg of body weight/min, as recommended. No adverse events or clinically relevant arrhythmias occurred during exercise testing.
Exercise 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 increment. The left ventricle was imaged in the apical and parasternal long-axis views to identify and grade systolic anterior motion and mitral regurgitation and estimate the LVOT gradient with continuous-wave Doppler. After termination of exercise, the patients were immediately placed in the left lateral decubitus position, and the LVOT velocities were measured again in the apical view using continuous-wave Doppler.
After baseline exercise echocardiography, BB treatment was initiated and titrated to a tolerable target dose (heart rate at rest of ≤60 beats/min, without symptoms of hypotension or bradycardia or the appearance of second-degree or greater atrioventricular block). Using the standard treatment strategy followed at our center for >20 years, the initial 18 patients enrolled in the study were administered nadolol (starting dose 20 mg/day titrated up to 40 to 80 mg/day; mode 40 mg, once daily). After nadolol became commercially unavailable in Italy in 2009, 9 subsequent study patients were treated with bisoprolol (starting dose 2.5 mg/day, titrated up to 5 to 10 mg/day; mode 5 mg once daily). With the target doses of the BB, an average decrease of 10 beats/min (or 13%) was achieved compared to baseline (67 ± 17 vs 77 ± 11 beats/min, respectively; p = 0.02). The heart rate at rest at the last evaluation was ≤60 beats/min in 11 patients (41%), 61 to 70 beats/min in 7 (26%), and >70 beats/min in 9 (33%; Table 2 ). No exclusions were necessary because of side effects, and treatment was well tolerated. According to a prespecified design, follow-up exercise echocardiography was performed after ≥6 months (range 8 to 32) of treatment at the target BB dose. The LVOT gradient was compared at the same workload in the 2 studies, with the second test interrupted at the same exercise point and level as in the baseline study.
| Variable | BB Treatment | p Value | |
|---|---|---|---|
| Off | On | ||
| Heart rate at rest (beats/min) | 77 ± 11 | 67 ± 17 | 0.02 |
| Heart rate with Valsalva (beats/min) | 80 ± 16 | 71 ± 17 | 0.007 |
| Heart rate at peak exercise (beats/min) | 157 ± 18 | 131 ± 20 | <0.001 |
| Heart rate attained (%) | 86 ± 8 | 72 ± 10 | <0.001 |
| Systolic blood pressure at rest (mm Hg) | 126 ± 16 | 117 ± 15 | 0.008 |
| Diastolic blood pressure at rest (mm Hg) | 80 ± 10 | 73 ± 9 | <0.001 |
| Systolic blood pressure at peak exercise (mm Hg) | 170 ± 27 | 157 ± 27 | 0.005 |
| Diastolic blood pressure at peak exercise (mm Hg) | 94 ± 13 | 92 ± 14 | 0.46 |
| Exercise performance ⁎ | |||
| Exercise time (min) | 10.0 ± 2.8 | 10.6 ± 2.6 | 0.13 |
| Maximum Watt | 131 ± 36 | 131 ± 31 | 0.84 |
| Maximum METs | 7.0 ± 1.7 | 6.9 ± 1.4 | 0.55 |
| Left ventricular outflow tract peak velocity (m/s) | |||
| At rest | 1.8 ± 0.5 | 1.8 ± 0.5 | 0.27 |
| With Valsalva maneuver | 2.5 ± 1.0 | 2.0 ± 0.7 | 0.006 |
| Peak exercise | 4.3 ± 0.8 | 2.8 ± 0.9 | <0.001 |
| After exercise | 4.6 ± 0.8 | 2.9 ± 0.9 | <0.001 |
| Left ventricular outflow tract gradient (mm Hg) | |||
| With Valsalva maneuver | 30 ± 25 | 18 ± 14 | 0.018 |
| At peak exercise | 77 ± 28 | 35 ± 22 | <0.001 |
| ≥30 mm Hg | 27 (100%) | 12 (44%) | <0.001 |
| ≥50 mm Hg | 24 (89%) | 8 (30%) | <0.001 |
| After exercise | 87 ± 29 | 36 ± 22 | <0.001 |
| ≥30 mm Hg | 27 (100%) | 13 (48%) | <0.001 |
| ≥50 mm Hg | 25 (93%) | 8 (30%) | <0.001 |
| Mitral valve | |||
| Systolic anterior motion | |||
| Baseline | 0.6 ± 0.6 | 0.6 ± 0.5 | 0.49 |
| At peak exercise | 2.8 ± 0.4 | 1.1 ± 1.1 | <0.001 |
| After exercise | 2.7 ± 0.5 | 1.3 ± 1.1 | <0.001 |
| Mitral regurgitation | |||
| Baseline | 0.6 ± 0.7 | 0.6 ± 0.5 | 0.48 |
| At peak exercise | 1.3 ± 0.7 | 0.9 ± 0.8 | 0.008 |
| After exercise | 1.4 ± 0.6 | 0.9 ± 0.9 | <0.001 |
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