BETA-BLOCKERS FOR PREVENTION OF
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XERCISE-I
NDUCEDL
EFTV
ENTRICULARO
UTFLOWT
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BSTRUCTIONINPATIENTS WITH HYPERTROPHIC CARDIOMYOPATHY
Stefano Nistri, MD, PhDa; Iacopo Olivotto, MDb; Martin S. Maron, MDc;
Cecilia Ferrantini, MDd; Raffele Coppini, MDe; Camilla Grifoni, MDb; MD, Katia Baldini,RNb; Aurelio Sgalambro, MDb; Franco Cecchi, MDb; and Barry J. Maron, MD f
aCMSR-Veneto Medica, Altavilla Vicentina (VI), Italy; bRegional Referral Center for Myocardial Diseases, Azienda Ospedaliera Careggi, Florence, Italy; cHypertrophic Cardiomyopathy Center, Division of Cardiology, Tufts Medical Center, Boston, Massachusetts; dDepartment of Physiology, University of Florence, Italy; eDepartment of Pharmacology, University of Florence, Italy; fThe Hypertrophic Cardiomyopathy Center, Minneapolis Heart Institute Foundation, Minneapolis, Minnesota.
Short title: Beta-blockers and provocable obstruction in HC
Address for correspondence: Stefano Nistri, MD, PhD CMSR Veneto Medica Via Vicenza 204
36077, Altavilla Vicentina (VI) Tel. +390444225111
Fax. +390444255199 E-mail: [email protected]
Acknowledgments: This work was supported by Ministero Istruzione Università e Ricerca (PRIN), European Union (STREP Project 241577 “BIG HEART,” 7th European Framework Program), and the
ABSTRACT
Whether beta-blockers (BB) treatment is beneficial in hypertrophic cardiomyopathy (HC) patients with exercise-induced outflow obstruction and no or only mild symptoms is largely unresolved. Thus, we studied 27 HC patients (mean age 36±15 years, 81% males) in NYHA classes I or II, without resting obstruction but with exercise-induced left ventricular outflow gradients (LVOTG) ≥30 mmHg, with exercise echocardiography (ExEcho) at baseline and after treatment with nadolol (n=18; 40-80 mg/day) or bisoprolol (n=9; 5-10 mg/day), according to a pre-specified protocol. At first ExEcho, post-exercise LVOTG was 87±29 mmHg, and was severe (>50 mmHg) in 25 patients (93%). After a 12±4 month period of BB treatment, post-exercise LVOTG decreased to 36±22 mmHg (p<0.001), was virtually abolished (to zero or <30 mmHg) in 14 patients (52%), and substantially blunted (≥20 mmHg reduction) in 9 others (33%); in only 4 (15%) patients LVOTG was unchanged (<20 mmHg reduction). Severe post-exercise obstruction (range 58-80 mmHg) persisted in 6 patients (22%; vs. 93% at initial eExercise echocardiography; p<0.001). Non-responders to BB (residual post-exercise gradient ≥30 mmHg) were characterized by increased body mass index (hazard ratio 2.03 per each kg/m2, 95% confidence interval 1.2-3.4; p<0.05). In conclusion, treatment with BB is effective in preventing development of left ventricular outflow obstruction triggered by physiological exercise in HC patients with mild or no symptoms. These findings provide a rationale for the novel strategy of early pharmacologic treatment with BB in this specific patient subset, aimed at prevention of the hemodynamic burden associated with dynamic obstruction. Word count= 246
Left ventricular outflow tract obstruction under resting (basal) conditions occurs in about 25% of hospital-based hypertrophic cardiomyopathy (HC) cohorts, and is associated with adverse long-term consequences related to heart failure (1,2). In addition, a large proportion of patients without resting obstruction develop significant left ventricular outflow tract gradients (LVOTG) associated with physical exertion(3,4). Although the relevance of exercise-induced gradients to clinical outcome is incompletely resolved (5,6), provocable obstruction is known to cause severe functional limitation, exercise intolerance and heart failure in HC patients, requiring therapeutic interventions with negative inotropic drugs and, occasionally, invasive septal reduction such as with surgical myectomy (7).
In HC patients with advanced heart failure related to left ventricular outflow tract obstruction (i.e. in New York Heart Association (NYHA) functional class III/IV), beta-blockers (BB) represent the standard first line therapy recognized by international guidelines, based on time-honored evidence (7). The concept that BB may be effective in blunting dynamic LVOTG was originally introduced by Braunwald et al in 1964 (8). In addition to relieving symptoms associated with obstruction, BB treatment is capable of controlling heart rate increase during exercise, as well as preventing fast ventricular rates known to precipitate microvascular ischemia in HC hearts (9).
In HC patients with mild or no symptoms (i.e.: NYHA functional class I or II), the issue of pharmacologic treatment for provocable left ventricular outflow tract obstruction is not standardized and remains as yet undefined (7). Nevertheless, also in these patients, blunting of exercise-induced left ventricular outflow tract obstruction by pharmacologic interventions such as BB would be desirable in order to potentially reduce or normalize left ventricular pressures, with the aspiration of preventing symptom progression and adverse outcome. In the present study, we therefore prospectively assessed efficacy of BB treatment on left ventricular outflow tract
obstruction provoked by physiologic exercise, in HC patients with no or only symptoms related to effort.
METHODS
Of 187 HC patients consecutively undergoing exercise echocardiography at Careggi University Hospital in 2006-2009, we prospectively enrolled 32 patients based on the following entry criteria: (i) sinus rhythm, (ii) LVOTG <30 mmHg under basal conditions in the supine position and erect on a cycle ergometer, and ≥ 30 mmHg after a maximal symptom-limited exercise test, in the absence of treatment with cardioactive medications (including BB, disopyramide or verapamil); and (iii) no or only mild heart failure-related symptoms (i.e.: NYHA functional class I or II). Patients in NYHA III/IV class were excluded since, by convention, they were already receiving BB to control advanced heart failure symptoms related to left ventricular outflow tract obstruction. Furthermore, patients with prior surgical myectomy or percutaneous alcohol septal ablation and those with medical conditions precluding maximal exercise stress testing (10) were excluded from the study group. Of the 32 patients who met these entry criteria, 5 refused enrollment. Therefore, the remaining 27 HC patients constitute the study cohort (Table 1). Four of these patients (15%) had mild pharmacologically controlled systemic hypertension.
Baseline echocardiography
Standard echocardiographic studies were performed in the left lateral supine decubitus with commercially available instruments according to current guidelines(11) Subaortic obstruction was defined as mechanical impedance to outflow due to systolic anterior motion (SAM) mid-systolic mitral-septal contact, and was graded semi-quantitatively, as previously described (3,6) Peak instantaneous LVOTG was measured at rest (and with Valsalva maneuver) 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 (3,6). Mitral regurgitation was graded as none or trivial (0), mild (1+), moderate (2+), severe (3+)(3,6)
Exercise echocardiography
Maximum, symptom-limited exercise tests were performed on a bicycle ergometer in the upright position. Exercise began at an initial workload of 25 watts (W), with stepwise 25W increments every 2 minutes. A 12-lead electrocardiogram was monitored continuously and recorded at baseline and at each minute during exercise as well as post-exercise. Arterial blood pressure was measured using a mercury sphygmomanometer at baseline and every 2 minutes during exercise and the post-exercise phase.
Patients were encouraged to perform maximally to achieve their expected heart rate. Maximum predicted heart rate was calculated as 220 - age, and % predicated heart rate was calculated as (maximum heart rate attained/maximum predicated heart rate) x 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 maximal attained workload before discontinuation. Peak functional capacity was estimated as metabolic equivalents (METs), one MET being defined as the energy expended at rest, equivalent to an oxygen consumption of 3.5 ml/kg of body weight/ minute, as recommended(10).
Exercise echocardiography was performed with patients sitting upright on the bicycle ergometer under basal conditions and serially every 2 minutes during exercise at each 25W workload. The LV was imaged in multiple apical views and parasternal long-axis views in order to identify and grade SAM and mitral regurgitation, and estimate LV outflow tract gradient with continuous-wave Doppler. Following termination of exercise, patients were immediately placed in
the left lateral decubitus position and LV outflow tract velocities were measured again in the apical view by continuous-wave Doppler (6).
Beta-blocker therapy and exercise echocardiograms
Following baseline Exercise exercise echocardiography, BB treatment was initiated and titrated to a tolerable target dose (resting heart rate ≤60 bpm, without symptoms due to hypotension or bradycardia, or appearance of significant (≥2nd degree) atrioventricular block, or other major side effects of therapy). Patients were administered either nadolol (n=18; starting dose 20 mg/day titrated up to 40-80 mg/day; mode 40 mg/day) or bisoprolol (n=9; starting dose 2.5 mg/day, titrated up to 5-10 mg/day; mode 5 mg/day) in single daily doses, according to the choice of the attending cardiologist. On target doses of BB, an average decrease of 10 bpm (or 13%) was achieved compared to baseline (67±17 vs. 77±11 bpm, respectively; p=0.02); resting heart rate at last evaluation was ≤60 bpm in 11 patients (41%), 61-70 bpm in 7 (26%) and >70 bpm in the remaining 9 (33%) (Table 2). There were no drop-outs due to side-effects and treatment was generally well tolerated. According to a pre-specified design, follow-up exercise echo was performed after ≥6 months of treatment (range 8-32) on the target dose of BB. LVOTG was compared at the same workload in the 2 studies, with the second test interrupted at the same exercise time and level as the baseline study.
Statistical methods
Data were expressed as mean±SD. Paired Student’s t-test or one-way analysis of variance were used to compare normally distributed data. Chi-square test was employed to compare categorical variables expressed as proportions. Predictors of marked exercise-inducing obstruction were
assessed by logistic regression analysis. P-values <0.05 were considered significant. Calculations were performed using SPSS 12.0 (SPSS Inc., Chicago, Ill).
RESULTS
Initial Exercise Echocardiography
By study design, the initial assessment was performed off BB treatment. Each of the 27 study patients had absence of LV outflow gradient at rest, and no or mild mitral regurgitation. Patients exercised for an average of 10.0±2.8 min, attaining 7.0±1.7 METs (Table 2); 4 patients (15%) showed evidence of impaired exercise performance, by achieving less than 5 METs. Dynamic left ventricular outflow tract obstruction occurred early during exercise (i.e. ≤5 METs) in 17 patients (63%), whereas the remaining 10 (37%) developed left ventricular outflow tract obstruction later (>5 METs) (6). No adverse events or clinically relevant arrhythmias occurred during exercise testing. Peak LVOTG measured supine immediately after exercise was 87±29 mmHg (range 36 to 140 mmHg). In 25 patients (93%), provocable left ventricular outflow tract obstruction was marked (gradient LVOTG >50 mmHg; and up to 140 mmHg) (Figure 1).
Effects of treatment on exercise LVOTG
Follow-up eExercise echocardiographysechocardiograms, on BB treatment, were performed 12±4 months after the initial test. BB effectively blunted LVOT gradients at each stage of provocation, including Valsalva maneuver, peak exercise and post-exercise (Table 2; Figure 2). Specifically, post-exercise LVOTG was markedly reduced by BB treatment, by 51±34 mmHg (range +13 to -116), with no significant difference in magnitude of gradient reduction between bisoprolol and nadolol (p=0.23). Post-exercise LVOTG was abolished (to zero or <30 mmHg) in 14 patients (52%), significantly blunted (≥20 mmHg reduction) in an additional 9 patients (33%), and remained unchanged in only 4 patients (<20 mmHg reduction). Marked post-exercise gradients >50 mmHg (range 58 to 80 mmHg) persisted on BB in only 6 patients (Figure 1). Moreover, even in those
patients who still developed obstruction on exercise, BB treatment was able to significantly delay the development of left ventricular outflow tract obstruction, which occurred early during exercise (≤5 METs) in only 8 patients while on BB (29%), compared to 63% at the initial Exercise echocardiography (p=0.029).
Lack of hemodynamic response to BB blockers (residual exercise gradient ≥30 mmHg) was associated with increased body mass index (hazard ratio 2.03 per each kg/m2 increase; 95% confidence interval 1.2-3.4; p<0.05). Specifically, only 2 of 12 patients with body mass index>25 kg/m2 (2017%) had abolition of post-exercise gradient by BB, compared to 10 of 13 15 patients with body mass index≤25 kg/m2 (8367%; p=0.002). At initial Exercise exercise echocardiography, post-exercise mitral regurgitation was 1.4±0.6 on a 0 to 3+ scale (3) (Table 2), including 13 patients in whom it was moderate or severe. At final Exercise echocardiography, on BB treatment, post-exercise mitral regurgitation was significantly reduced (0.9±0.9, p<0.001 vs. first evaluation); mitral regurgitation was moderate in 5 patients and severe only in 1.
Effects of BB on symptoms
The 24 23 patients in NYHA class I at initial evaluation remained asymptomatic following introduction of BB treatment. Of the 4 patients in NYHA class II, 2 improved to class I and the other 2 remained in class II.
DISCUSSION
The present study prospectively assessed the effects of BB therapy on exercise-induced LVOTG in HC patients with no or only mild self-reported symptoms. We were able to show that relatively low, well tolerated doses of BB are capable of blunting exercise-induced obstruction, including marked gradients >50 mmHg, and up to 140 mmHg. Post-exercise LVOTG decreased from a pre-treatment value of 87±29 mmHg to 36±22 mmHg following the introduction of BBs, i.e. an average reduction of over 50 mmHg (58% change), with associated reduction in the degree of functional mitral regurgitation. Exercise-induced gradients were greatly diminished or abolished (to <30 mmHg) in 52% of patients, and substantially reduced (≥20 mmHg reduction) in another 33%. Of the 25 patients with an initial gradient >50 mmHg with exercise, consistent with the established threshold for invasive septal reduction intervention in symptomatic HC patients (7), only 6 (24%) still had persistent gradients in this range on BB treatment. Furthermore, the time-course of exercise-inducible obstruction was significantly delayed: left ventricular outflow tract obstruction occurred early during effort (<5 METs) in only 29% of patients while on treatment, compared with 63% at initial evaluation. This concept is of clinical relevance, since timing of outflow obstruction onset dictates the degree to which exercise capacity is impaired in HC patients with provocable gradients, and early onset LVOT gradients during exercise are associated with diminished exercise performance(6).
These data might support a rationale for BB administration in HC patients who develop obstruction with physiologic exercise, even in the absence of disabling symptoms. Of note, effective control of the obstructive pathophysiology in our patients could be generally achieved using low doses of BB (40 mg nadolol and 5 mg bisoprolol), which were well tolerated following prudent titration. This is a relevant issue for long-term treatment in HC patients with mild or no symptoms, who are frequently young and active, and may not otherwise require treatment(4).
Data from large patient cohorts have consistently identified LV outflow obstruction occurring under basal (resting) conditions as an important determinant of cardiovascular morbidity and mortality in HC patients, thereby underscoring the importance of abolishing subaortic gradients in severely symptomatic patients (1-4). In such patients, increased LV systolic pressures promote increased systolic workload despite lower diastolic aortic and coronary perfusion pressures (9). Moreover, outflow tract obstruction negatively affects systolic shortening and instantaneous stroke volume, impairing diastolic function (12-14). Therefore, the relief of systolic load imposed by dynamic obstruction likely improves stroke volume and diastolic relaxation ,(13,14), as well as favourably affecting left atrial remodeling which is also a robust predictor of outcome in HC (3,15-17).
Even in patients without rest obstruction, however, substantial LVOTGs are commonly elicited by exercise,(3), and may represent a detrimental pathophysiologic feature exerting considerable impact on long-term functional capacity and prognosis (3-5). In a large Mayo Clinic cohort, about 20% of HC patients with provocable obstruction progressed to class III or IV symptoms over a median follow-up duration of 7.4 years, requiring surgical myectomy (or percutaneous septal reduction)(5) Indeed, severely symptomatic drug-refractory patients with only provocable obstruction have undergone surgical myectomy with favorable results similar to patients those with resting obstruction (19).
These prior studies show that reduction of those intraventricular gradients elicited with physiological provocation (as well as at rest) may benefit patients over the long-term (19).
Consequently, and based on the present data, we favor routine use of exercise echocardiography in physically active HC patients, and subsequent consideration for BB treatment should a substantial LVOTG be demonstrated during physical effort (5). Concomitantly, the use of vasodilator therapy for hypertension should be avoided (20-22). Follow-up exercise echocardiography may be
warranted in order to document the efficacy of treatment on provocable obstruction, and to counsel physically active patients with regard to the advisable intensity of leisure activities and sports (6).
Of note, although most of our HC patients exhibited reduction in left ventricular outflow tract obstruction with BB treatment, there was considerable individual variability, including a subset of non-responders who had persistent provocable LVOTG ≥30 mmHg at final evaluation despite treatment over an average of 12 months. Although the determinants of such variability remain incompletely resolved, we found that inadequate response to BB treatment was predicted by increased body mass index. Notably, although this observation may simply point to insufficient drug dosage in those patients with the greatest body weight, the role of obesity in promoting LVOTG deserves further investigation.
Finally, although uncommon, exercise-induced outflow tract obstruction can be elicited with exercise in a variety of diseases other than HC. This condition is not detected by other stress imaging methodologies (e.g., nuclear perfusion imaging or magnetic resonance imaging) (20-25) and may represent a cause of myocardial ischaemia and symptoms. In a recent study, exercise-induced obstruction was present in 15 of 78 non-HC patients with symptoms of angina, normal exercise nuclear perfusion test and normal resting left ventricular systolic function (22). In these patients, BB therapy was associated with a significant fall in peak outflow tract velocity during exercise, and marked improvement in functional capacity. Similar findings have been reported in elderly individuals with symptoms of exercise intolerance and athletes (24,25).
In conclusion, treatment with BB at standard, well-tolerated doses is usually effective in preventing the development of physiologically provocable obstruction in HC patients with no or mild symptoms. These findings provide a rationale for a novel strategy of early pharmacologic
treatment with BB in this patient subset, directed at prevention of the hemodynamic burden associated with dynamic obstruction.
FIGURE LEGENDS
Figure 1. Effect of treatment with beta-blockers on post-exercise left ventricular outflow tract (LVOT) gradient in 27 patients with HC. Each patient is depicted by a line connecting the 2 measurements of gradient. Rectangles and vertical bars represent mean±SD, respectively.
Figure 2. Left ventricular outflow tract (LVOT) gradients at rest, with Valsalva manoeuvre, at peak exercise and post-exercise, at initial exercise echo (solid blue line) and on beta-blockers (dotted red line). Squares and vertical lines indicate mean and SD at each step for the 27 study patients.
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Table 1. Baseline Characteristics of the 27 HCMHC Patients. Variable Age (Years) 36±15 Male (n;%) 22 (81%) Family history of HCMHC (n;%) 10 (37%) Height (m) 1.74±0.9 Weight (kg) 75±13
Body surface area (m2) 1.83±0.4
Body mass index (kg/m2) 24.6±3
Systolic blood pressure (mmHg) 126±16
Diastolic blood pressure (mmHg) 80±10
New York Heart Association functional class 1.15±0.36
Left atrial diameter (mm) 42±6
Left atrial volume index (ml/m2) 42±16
LV end-diastolic diameter (mm) 44±5
Ventricular septal thickness (mm) 19±5
Maximal LV Thickness (mm) 21±6
LV ejection fraction(%) 67±6
LV outflow gradient at rest (mmHg) 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 16 17 (5963%) Moderate 1 (4%)
Table 2: Exercise Data at Initial Evaluation and on Beta-Blocker Treatment.
Variable Initial
Evaluation
On Beta-Blocker
treatment P-value
Resting heart rate (bpm) 77±11 67±17 0.02
Heart rate at Valsalva 80±16 71±17 0.007
Heart rate at peak exercise (bpm) 157±18 131±20 <0.001
Heart rate attained (%) 86±8 72±10 <0.001
Systolic BP at rest (mm Hg) 126±16 117±15 0.008
Diastolic BP at rest (mm Hg) 80±10 73±9 <0.001
Systolic BP at peak exercise (mmHg) 170±27 157±27 0.005
Diastolic BP at peak exercise (mmHg) 94±13 92±14 0.46
Exercise performance*
Exercise time (min) 10.0±2.8 10.6±2.6 0.13
Maximal Watt 131±36 131±31 0.84
Maximal METs 7.0±1.7 6.9±1.4 0.55
LVOT peak velocity
at rest (m/sec) 1.8±0.5 1.8±0.5 0.27
with Valsalva (m/sec) 2.5±1.0 2.0±0.7 0.006
at peak exercise (m/sec) 4.3±0.8 2.8±0.9 <0.001
post exercise (m/sec) 4.6±0.8 2.9±0.9 <0.001
LVOT gradient with Valsalva (mmHg) 30±25 18±14 0.018 at peak exercise (mmHg) 77±28 35±22 <0.001 ≥30 mmHg (n;%) 27(100%) 12(44%) <0.001 ≥50 mmHg (n;%) 24(89%) 8(30%) <0.001 post exercise (mmHg) 87±29 36±22 <0.001 ≥30 mmHg (n;%) 27(100%) 13(48%) <0.001 ≥50 mmHg (n;%) 25(93%) 8(30%) <0.001 Mitral Valve SAM at baseline 0.6±0.6 0.6±0.5 0.49
SAM at peak exercise 2.8±0.4 1.1±1.1 <0.001
SAM post exercise 2.7±0.5 1.3±1.1 <0.001
MR at baseline 0.7±0.6 0.6±0.5 0.18
MR at peak exercise 1.3±0.7 0.9±0.8 0.008
MR post exercise 1.4±0.6 0.9±0.9 <0.001
Symbols: * = by study protocol, exercise echocardiography on beta-blockers was interrupted at the same exercise work-load and time as baseline study for each individual patient.
Abbreviations: BP: blood pressure; LVOT: left ventricular outflow tract; METs: metabolic equivalents; MR: mitral regurgitation; SAM: systolic anterior motion of the mitral valve.
