Editorial Comment
Echocardiography in Hypertrophic Cardiomyopathy: In with Strain, Out with Straining? Soohun Chun, MD, and Anna Woo, MD, SM, FACC, Toronto, Ontario, Canada Hypertrophic cardiomyopathy (HCM) is an inherited condition with a diverse clinical course, ranging from stable active individuals to patients incapacitated by symptoms and/or arrhythmias.1 Early reports and investigations on HCM focused on the presence of subaortic obstruction, characterized by a systolic murmur that changed with bedside maneuvers and by a pressure gradient in the left ventricular (LV) outflow tract (LVOT) noted in the cardiac catheterization laboratory that varied with pharmacologic or physiologic provocation.2 Advances in echocardiography have greatly enhanced both our recognition and our understanding of the different manifestations of HCM.2,3 The pathophysiology of exercise intolerance includes dynamic LVOT obstruction, mitral regurgitation, diastolic dysfunction, myocardial ischemia, and autonomic dysfunction.1 Echocardiography has helped elucidate numerous mechanisms for these abnormalities and is the primary imaging modality used in the screening, diagnosis, and intraprocedural and long-term monitoring of patients with HCM.3 RISK ASSESSMENT IN PATIENTS WITH HYPERTROPHIC CARDIOMYOPATHY The greater challenge has been the emerging role of echocardiography in detecting patients with HCM who are at high risk for serious cardiovascular events, including sudden cardiac death (SCD). A great number of studies have examined multiple risk factors for SCD in patients with HCM in an attempt to improve risk assessment for a condition that affects 1 in 500 individuals, has an incidence of SCD of approximately 1% per year, and may occasionally present with SCD in the absence of preceding symptoms.1 Risk stratification in HCM is not straightforward, because the major risk factors for SCD in HCM generally have low positive predictive value. In the management of individual patients, there can be ambiguity in the interpretation of their family or personal histories and the results of the patients’ investigations. Although implantable cardioverter-defibrillators (ICDs) are effective for the primary prevention of SCD, patients face decades of potential complications from ICDs (4% per year),1 including a significant risk for inappropriate ICD discharges.4 Current guidelines from the American College of Cardiology Foundation and American Heart Association consider prophylactic ICD therapy to be a reasonable recommendation in the presence of one of the following clinical or echocardiographic markers: (1) a family history of SCD in one or more first-degree relatives, (2) recent unexplained syncope, and (3) the presence of a maximal LV wall
From the Peter Munk Cardiac Center, Division of Cardiology, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada. Reprint requests: Anna Woo, MD, SM, FACC, Division of Cardiology, Toronto General Hospital, 4N-506, 200 Elizabeth Street, Toronto, ON M5G 2C4, Canada (E-mail: [email protected]). 0894-7317/$36.00 Copyright 2015 by the American Society of Echocardiography. http://dx.doi.org/10.1016/j.echo.2014.12.002
204
thickness $ 30 mm.1 Other strategies to alter the natural history of HCM, prevent HCM-related events (heart failure, stroke, atrial and ventricular arrhythmias), and treat symptoms include pharmacotherapy and invasive septal reduction therapy (surgical myectomy or septal ethanol ablation). Contemporary studies with baseline echocardiographic and clinical data have helped identify patients at higher risk for HCM-related events. There are three echocardiographic findings associated with an increased risk for HCM-related death: (1) LV wall thickness $ 30 mm, (2) LVOT gradient $ 30 mm Hg at rest, and (3) left atrial (LA) enlargement. The presence of massive LV hypertrophy (i.e., wall thickness $ 30 mm) is the strongest echocardiographic risk marker associated with SCD.1,5 Resting LVOT obstruction, defined by the traditional threshold of an LVOT gradient $30 mm Hg at rest, has also been shown to significantly increase the risk for HCM-related death and SCD.6 Within the subset of patients with resting LVOT obstruction, two large studies have demonstrated that a higher resting LVOT gradient (categorized by an LVOT velocity > 4 m/sec or an LVOT gradient $ 64 mm Hg) was an independent predictor of HCM-related death.7,8 The development of an anteroposterior LA diameter > 48 mm was associated with an increased risk for all-cause, HCM-related, and heart failure–related death (but not SCD).9 More recent echocardiographic studies with smaller HCM cohorts and shorter observation periods have explored additional Doppler echocardiographic measures, LA volume indexed to body surface area,10 and Doppler tissue imaging,11,12 to further refine the risk assessment of patients. The detection of an LA volume index > 27 mL/m2,10 a Doppler tissue imaging lateral annular systolic velocity < 4 cm/sec,11 and a septal E/e0 ratio > 1512 impart an increased risk for HCM-related events. In the present issue of JASE, Reant et al.13 report on their analysis of a multitude of resting and exercise echocardiographic parameters to better predict HCM-related outcomes. This group of experienced investigators prospectively evaluated 115 patients with HCM. All patients had baseline comprehensive resting Doppler echocardiographic studies, including two-dimensional speckle-tracking echocardiography (STE) for the assessment of global longitudinal strain (GLS). Exercise echocardiography was performed with a bicycle in a semisupine position (50 ) with a slight left lateral tilt to allow simultaneous echocardiographic imaging during cycling. Outcomes of interest were a composite cardiac end point of HCM-related death (or an event equivalent to death, such as an appropriate discharge from an ICD) or progression to New York Heart Association class III or IV symptoms. In their regression models, GLS was dichotomized at an absolute GLS level of 15%. This value was selected on the basis of data from Yingchoncharoen et al.14 that showed worse outcomes in patients with GLS # 15% and asymptomatic aortic stenosis, another condition with pathologic LV hypertrophy. Eighteen patients reached the cardiac end point during the mean follow-up period of 19 months. Cox modeling showed two independent determinants of the composite end point, which conferred a greater than threefold increased risk: GLS # 15% and peak exercise-induced LVOT gradient $50 mm Hg. Important additional findings from Kaplan-Meier survival analyses were the following: (1) patients with GLS > 15% and exercise LVOT gradients < 50 mm Hg had the best prognosis, and (2) within
Journal of the American Society of Echocardiography Volume 28 Number 2
the group of patients with GLS > 15%, patients with exercise LVOT gradients $ 50 mm Hg did worse than those with exercise LVOT gradients < 50 mm Hg. Finally, the degree of LVOT obstruction significantly influenced outcomes, especially in patients with baseline resting LVOT obstruction: patients with resting LVOT obstruction and higher exercise LVOT gradients ($50 mm Hg) were significantly more likely to reach the composite end point than those with resting LVOT obstruction and lower exercise LVOT gradients (2,500 normal subjects determined that blood pressure was independently associated with the variation in normal values of GLS.25 Given the above concerns, there is an ongoing initiative among the American Society of Echocardiography, the European Association of Cardiovascular Imaging, and hardware and software vendors to reduce intervendor variability and to standardize strain measurements.26 METHODS OF INDUCING LEFT VENTRICULAR OUTFLOW TRACT OBSTRUCTION IN HYPERTROPHIC CARDIOMYOPATHY The study by Reant et al.13 also addressed the implications of exerciseinduced LVOTobstruction. Dynamic LVOTobstruction is common in patients with HCM: one-third have resting LVOT obstruction (resting
206 Chun and Woo
LVOT gradient $ 30 mm Hg), one-third have provocable/latent LVOT obstruction (resting LVOT gradient < 30 mm Hg, provocable LVOT gradient $30 mm Hg), and one-third have nonobstructive HCM (both resting and provocable LVOT gradient < 30 mm Hg).1 The conventional threshold for consideration of invasive septal reduction therapy has been the presence of class III or IV symptoms and a resting or provocable LVOT gradient $50 mm Hg.1 Echocardiography is the preferred diagnostic test to determine the hemodynamic status of patients, which is essential to differentiate patients with obstructive HCM (resting/provocable) from those with nonobstructive HCM and to guide treatment.3 The symptoms attributable to LVOT obstruction (dyspnea, angina, exertional presyncope or syncope) can be very successfully abolished,1,8 whereas patients with nonobstructive HCM and symptoms secondary to diastolic dysfunction may be very challenging to manage. Long-term data from our own center have demonstrated excellent outcomes in patients treated with pharmacotherapy (b-blockers and/or disopyramide) or invasive septal reduction therapy.8 In patients with symptoms and resting LVOT gradients < 30 mm Hg, it is crucial to perform provocative maneuvers to document the presence of a provocable LVOT gradient.3 Obstruction can be provoked by the following approaches: (1) reduction in preload (strain phase of the Valsalva maneuver, standing), (2) reduction in afterload (inhalation of amyl nitrate, sublingual isosorbide dinitrate), and (3) increase in contractility and heart rate (exercise, isoproterenol). The impetus for developing methods of provocation other than exercise stemmed from concerns regarding the safety of exercise testing in the HCM population. The most common method of provocation used in echocardiography laboratories to evaluate patients with HCM is the Valsalva maneuver. However, the Valsalva maneuver underestimates the magnitude of the provocable LVOT gradient compared with exercise testing.27,28 In addition, the Valsalva maneuver has low sensitivity (40%) for unmasking significant LVOT obstruction compared with provocation with exercise.27 Other drawbacks include the fact that a significant number of patients have difficulty performing a Valsalva maneuver, and it can interfere with recording an adequate LVOT signal, particularly when there is excessive movement of the chest wall with straining. Other methods of provocation (standing,28,29 amyl nitrite,30 sublingual administration of isosorbide dinitrate)31 have also been found to be inferior to exercise, with lower provocable LVOT gradients achieved and a decreased likelihood of inducing a provocable LVOT gradient than with exercise (Table 1). Amyl nitrite is a very useful alternative to exercise, but its availability is limited. The use of dobutamine is discouraged, except at experienced centers, because this drug can cause a cavity obliteration signal that can be confused with a legitimate increased LVOT velocity from mitral leaflet–septal contact.3 There is increasing interest in performing exercise studies in patients with HCM. Apprehension about exercise testing has been assuaged by studies reporting a low incidence of serious complications with exercise testing.32 Reant et al.13 used bicycle testing with patients in a semisupine (50 ) position. The greatest benefit of this method is that it allows concurrent echocardiographic examination and sampling of the LVOT gradient during exercise. Nevertheless, there are fundamental concerns with this modality of exercise: it is a nonphysiologic position for the patient and results in greater preload (and hence greater LV size, less systolic anterior motion, and a lower LVOT gradient) than would be expected with fully upright exercise. It is noteworthy that one study that compared the hemodynamics of supine versus upright bicycle ergometry in normal subjects showed a significantly higher pulmonary capillary wedge pressure and LV
Journal of the American Society of Echocardiography February 2015
end-diastolic pressure during supine bicycle exercise.33 Invasive hemodynamic studies while assuming a semisupine position are lacking in patients with HCM. However, a relevant study of 10 patients with HCM who underwent invasive hemodynamic studies during supine bicycle testing does provide some insight. Klues et al.34 demonstrated that the LVOT gradient did not change during supine bicycle exercise (37 6 10 mm Hg at rest and 30 6 10 mm Hg at 5 min of exercise). However, the LVOT gradient was 84 6 11 mm Hg at 3 min into the recovery period. Invasive hemodynamic recordings showed a significant increase in the mean pulmonary artery pressure and pulmonary capillary wedge pressure at peak exercise. The mean pulmonary artery pressure and pulmonary capillary wedge pressure decreased in the recovery phase, concurrent with the augmentation in the LVOT gradient. The authors surmised that the increase in preload during exercise prevented an increase in LVOTobstruction. The termination of exercise then leads to a rapid decrease in venous return, which decreases LV volume and accentuates the LVOT gradient.34 The fact that the average LVOT gradient noted in the recovery phase was higher than the LVOT gradient measured at peak exercise (65 6 58 vs 45 6 45 mm Hg, respectively) in the study by Reant et al. is suggestive that the hemodynamics of bicycle testing in the semisupine position may be similar to those achieved with supine bicycle ergometry. It is probably reasonable to postulate that venous return in the semisupine position is at a level intermediate between the supine and the upright postures. Exercise testing in the upright position is the most physiologic form of provocation. Treadmill exercise has multiple advantages: this form of exertion is familiar to many patients and simulates everyday activities in the upright position, and it is widely available in multiple institutions. Criticism of this method has arisen from the fact that the LVOT gradient after treadmill exercise is obtained after the cessation of exercise and after the patient assumes the supine position.27,28,30,31 This delay in imaging (a mean of 50 sec in a study by Maron et al.27) and change in position may modify patients’ hemodynamic status and substantially affect the LVOT gradient. One attempt to overcome this limitation is the strategy of concurrent echocardiographic imaging while exercising on the treadmill: two small studies have shown that there are significant differences between the peak exercise LVOT gradient obtained on the treadmill and the gradient measured in the early postexercise period, with a lower LVOT gradient in the postexercise recumbent position35 and a higher LVOT gradient in the postexercise standing position.29 However, there are multiple technical challenges in attempting to align the ultrasound cursor with the LVOT and obtain an accurate LVOT signal while a patient is on the treadmill. In contrast, when simultaneous echocardiographic imaging was performed on patients who underwent upright stationary bicycle testing, there was a very high correlation between the provocable LVOT gradient obtained during peak upright exercise and the LVOT gradient in the immediate postexercise supine position.36 Other relevant studies of upright bicycle exercise involving patients with HCM are summarized in Table 1.37,38 There are caveats to mention when evaluating patients for exercise-induced LVOTobstruction, regardless of the type of exercise. In this patient population, it requires experience and expertise to interpret the LVOT Doppler spectral tracings obtained at rest and after exercise. Patients are more tachycardic during exercise. Echocardiographic imaging should be performed in addition to interrogation by Doppler, to confirm the presence of systolic anterior motion of the mitral valve. Contamination from the mitral regurgitant jet signal with the LVOT signal is the most common pitfall, which can significantly overestimate the LVOT gradient. The LVOT spectral profile
Method(s) of provocation
Study
Number of patients
Resting LVOTG (mm Hg)
Provocable LVOTG (mm Hg)
% with LVOTG $ 30 mm Hg at rest
% with LVOTG $30 mm Hg with provocation
Comparison of methods of provocation
Exercise (treadmill/ upright bicycle) vs Valsalva
Maron et al.27
201
469
45 6 49 (exercise) vs 18 6 23 (Valsalva: group with exercise LVOTG 30–49); 33 6 34 (Valsalva: group with exercise LVOTG $ 50)
Treadmill exercise vs Valsalva vs standing
Joshi et al.28
53
25 (median)
100 (exercise) vs 64 (Valsalva) vs 44 (standing) (median)
Treadmill exercise† (concurrent vs recovery [upright]) vs standing
Miranda et al.29
17
49 6 24
83 6 35 (exercise), 96 6 35 (recovery [upright]) vs 62 6 29 (standing)
65
Treadmill exercise vs amyl nitrite
Marwick et al.30
57
13 6 10
47 6 39 (exercise) vs 49 6 39 (amyl)
0*
37* (exercise) vs 44* (amyl)
Amyl nitrate vs exercise: r = 0.54, P < .0001
Treadmill exercise vs ISDN
Zemanek et al.31
77
19 6 16
62 6 43 (exercise) vs 45 6 40 (ISDN at 5– 10 min)
19
71 (exercise) vs 55 (ISDN)
ISDN vs exercise: SENS = 76%, SPEC = 100%
Treadmill exercise† (concurrent vs recovery [supine])
Dimitrow et al.35
29
Upright bicycle†
Nistri et al.36
74
10
Upright bicycle †
Schwammenthal et al.37
10
75 6 24
140 6 42
Upright bicycle †
Shah et al.38
87
12 6 7
61 6 54
Standing vs Valsalva maneuver
Joshi et al.
98
28
36 6 39; 25 (median)
5
53 (exercise) vs 21 (Valsalva)
Valsalva vs exercise: SENS = 40%, SPEC = 100%
30*
70* (Valsalva and exercise) vs 50* (standing)
Standing vs exercise: r = 0.28, P < .05
82
33–83 (range)
0
34 (exercise) vs 14 (recovery [supine])
39 6 35 (exercise [upright]) vs 44 6 40 (postexercise supine)
0
39 (exercise [upright]) vs 41 (postexercise supine)
44 (standing) vs 64 (Valsalva) (median)
100
100
0
62
43
41 (standing, in initial nonobstructive group)
Journal of the American Society of Echocardiography Volume 28 Number 2
Table 1 Summary of major echocardiographic studies of provocation of LVOT obstruction in HCM
Upright bicycle exercise vs postexercise supine: R2 = 0.974
Standing vs Valsalva maneuver: r = 0.40, P < .001
Chun and Woo 207
ISDN, Isosorbide dinitrate (sublingual); LVOTG, LVOT gradient; SENS, sensitivity for detecting exercise LVOT gradient; SPEC, specificity for detecting exercise LVOT gradient. LVOTGs are reported as mean 6 SD (unless otherwise stated). *Threshold LVOTG $ 50 mm Hg reported in the study (instead of threshold LVOTG $ 30 mm Hg). † Method of measurement of exercise LVOTG: done concurrently during exercise.
208 Chun and Woo
(classically described as a dagger-shaped, leftward concave contour with a late systolic peak) should be differentiated from the Doppler spectral profile of midcavity obliteration (a systolic squirt with late initial rise in systolic velocity and a narrow and pointed peak in end-systole), which can occur with exercise or dobutamine infusion.3 As patients exercise, more rapid and intense chest wall excursion may interfere with accurate interrogation of the LVOT gradient. Finally, the LVOT gradient should be recorded
Echocardiography in Hypertrophic Cardiomyopathy: In with Strain, Out with Straining? Soohun Chun, MD, and Anna Woo, MD, SM, FACC, Toronto, Ontario, Canada Hypertrophic cardiomyopathy (HCM) is an inherited condition with a diverse clinical course, ranging from stable active individuals to patients incapacitated by symptoms and/or arrhythmias.1 Early reports and investigations on HCM focused on the presence of subaortic obstruction, characterized by a systolic murmur that changed with bedside maneuvers and by a pressure gradient in the left ventricular (LV) outflow tract (LVOT) noted in the cardiac catheterization laboratory that varied with pharmacologic or physiologic provocation.2 Advances in echocardiography have greatly enhanced both our recognition and our understanding of the different manifestations of HCM.2,3 The pathophysiology of exercise intolerance includes dynamic LVOT obstruction, mitral regurgitation, diastolic dysfunction, myocardial ischemia, and autonomic dysfunction.1 Echocardiography has helped elucidate numerous mechanisms for these abnormalities and is the primary imaging modality used in the screening, diagnosis, and intraprocedural and long-term monitoring of patients with HCM.3 RISK ASSESSMENT IN PATIENTS WITH HYPERTROPHIC CARDIOMYOPATHY The greater challenge has been the emerging role of echocardiography in detecting patients with HCM who are at high risk for serious cardiovascular events, including sudden cardiac death (SCD). A great number of studies have examined multiple risk factors for SCD in patients with HCM in an attempt to improve risk assessment for a condition that affects 1 in 500 individuals, has an incidence of SCD of approximately 1% per year, and may occasionally present with SCD in the absence of preceding symptoms.1 Risk stratification in HCM is not straightforward, because the major risk factors for SCD in HCM generally have low positive predictive value. In the management of individual patients, there can be ambiguity in the interpretation of their family or personal histories and the results of the patients’ investigations. Although implantable cardioverter-defibrillators (ICDs) are effective for the primary prevention of SCD, patients face decades of potential complications from ICDs (4% per year),1 including a significant risk for inappropriate ICD discharges.4 Current guidelines from the American College of Cardiology Foundation and American Heart Association consider prophylactic ICD therapy to be a reasonable recommendation in the presence of one of the following clinical or echocardiographic markers: (1) a family history of SCD in one or more first-degree relatives, (2) recent unexplained syncope, and (3) the presence of a maximal LV wall
From the Peter Munk Cardiac Center, Division of Cardiology, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada. Reprint requests: Anna Woo, MD, SM, FACC, Division of Cardiology, Toronto General Hospital, 4N-506, 200 Elizabeth Street, Toronto, ON M5G 2C4, Canada (E-mail: [email protected]). 0894-7317/$36.00 Copyright 2015 by the American Society of Echocardiography. http://dx.doi.org/10.1016/j.echo.2014.12.002
204
thickness $ 30 mm.1 Other strategies to alter the natural history of HCM, prevent HCM-related events (heart failure, stroke, atrial and ventricular arrhythmias), and treat symptoms include pharmacotherapy and invasive septal reduction therapy (surgical myectomy or septal ethanol ablation). Contemporary studies with baseline echocardiographic and clinical data have helped identify patients at higher risk for HCM-related events. There are three echocardiographic findings associated with an increased risk for HCM-related death: (1) LV wall thickness $ 30 mm, (2) LVOT gradient $ 30 mm Hg at rest, and (3) left atrial (LA) enlargement. The presence of massive LV hypertrophy (i.e., wall thickness $ 30 mm) is the strongest echocardiographic risk marker associated with SCD.1,5 Resting LVOT obstruction, defined by the traditional threshold of an LVOT gradient $30 mm Hg at rest, has also been shown to significantly increase the risk for HCM-related death and SCD.6 Within the subset of patients with resting LVOT obstruction, two large studies have demonstrated that a higher resting LVOT gradient (categorized by an LVOT velocity > 4 m/sec or an LVOT gradient $ 64 mm Hg) was an independent predictor of HCM-related death.7,8 The development of an anteroposterior LA diameter > 48 mm was associated with an increased risk for all-cause, HCM-related, and heart failure–related death (but not SCD).9 More recent echocardiographic studies with smaller HCM cohorts and shorter observation periods have explored additional Doppler echocardiographic measures, LA volume indexed to body surface area,10 and Doppler tissue imaging,11,12 to further refine the risk assessment of patients. The detection of an LA volume index > 27 mL/m2,10 a Doppler tissue imaging lateral annular systolic velocity < 4 cm/sec,11 and a septal E/e0 ratio > 1512 impart an increased risk for HCM-related events. In the present issue of JASE, Reant et al.13 report on their analysis of a multitude of resting and exercise echocardiographic parameters to better predict HCM-related outcomes. This group of experienced investigators prospectively evaluated 115 patients with HCM. All patients had baseline comprehensive resting Doppler echocardiographic studies, including two-dimensional speckle-tracking echocardiography (STE) for the assessment of global longitudinal strain (GLS). Exercise echocardiography was performed with a bicycle in a semisupine position (50 ) with a slight left lateral tilt to allow simultaneous echocardiographic imaging during cycling. Outcomes of interest were a composite cardiac end point of HCM-related death (or an event equivalent to death, such as an appropriate discharge from an ICD) or progression to New York Heart Association class III or IV symptoms. In their regression models, GLS was dichotomized at an absolute GLS level of 15%. This value was selected on the basis of data from Yingchoncharoen et al.14 that showed worse outcomes in patients with GLS # 15% and asymptomatic aortic stenosis, another condition with pathologic LV hypertrophy. Eighteen patients reached the cardiac end point during the mean follow-up period of 19 months. Cox modeling showed two independent determinants of the composite end point, which conferred a greater than threefold increased risk: GLS # 15% and peak exercise-induced LVOT gradient $50 mm Hg. Important additional findings from Kaplan-Meier survival analyses were the following: (1) patients with GLS > 15% and exercise LVOT gradients < 50 mm Hg had the best prognosis, and (2) within
Journal of the American Society of Echocardiography Volume 28 Number 2
the group of patients with GLS > 15%, patients with exercise LVOT gradients $ 50 mm Hg did worse than those with exercise LVOT gradients < 50 mm Hg. Finally, the degree of LVOT obstruction significantly influenced outcomes, especially in patients with baseline resting LVOT obstruction: patients with resting LVOT obstruction and higher exercise LVOT gradients ($50 mm Hg) were significantly more likely to reach the composite end point than those with resting LVOT obstruction and lower exercise LVOT gradients (2,500 normal subjects determined that blood pressure was independently associated with the variation in normal values of GLS.25 Given the above concerns, there is an ongoing initiative among the American Society of Echocardiography, the European Association of Cardiovascular Imaging, and hardware and software vendors to reduce intervendor variability and to standardize strain measurements.26 METHODS OF INDUCING LEFT VENTRICULAR OUTFLOW TRACT OBSTRUCTION IN HYPERTROPHIC CARDIOMYOPATHY The study by Reant et al.13 also addressed the implications of exerciseinduced LVOTobstruction. Dynamic LVOTobstruction is common in patients with HCM: one-third have resting LVOT obstruction (resting
206 Chun and Woo
LVOT gradient $ 30 mm Hg), one-third have provocable/latent LVOT obstruction (resting LVOT gradient < 30 mm Hg, provocable LVOT gradient $30 mm Hg), and one-third have nonobstructive HCM (both resting and provocable LVOT gradient < 30 mm Hg).1 The conventional threshold for consideration of invasive septal reduction therapy has been the presence of class III or IV symptoms and a resting or provocable LVOT gradient $50 mm Hg.1 Echocardiography is the preferred diagnostic test to determine the hemodynamic status of patients, which is essential to differentiate patients with obstructive HCM (resting/provocable) from those with nonobstructive HCM and to guide treatment.3 The symptoms attributable to LVOT obstruction (dyspnea, angina, exertional presyncope or syncope) can be very successfully abolished,1,8 whereas patients with nonobstructive HCM and symptoms secondary to diastolic dysfunction may be very challenging to manage. Long-term data from our own center have demonstrated excellent outcomes in patients treated with pharmacotherapy (b-blockers and/or disopyramide) or invasive septal reduction therapy.8 In patients with symptoms and resting LVOT gradients < 30 mm Hg, it is crucial to perform provocative maneuvers to document the presence of a provocable LVOT gradient.3 Obstruction can be provoked by the following approaches: (1) reduction in preload (strain phase of the Valsalva maneuver, standing), (2) reduction in afterload (inhalation of amyl nitrate, sublingual isosorbide dinitrate), and (3) increase in contractility and heart rate (exercise, isoproterenol). The impetus for developing methods of provocation other than exercise stemmed from concerns regarding the safety of exercise testing in the HCM population. The most common method of provocation used in echocardiography laboratories to evaluate patients with HCM is the Valsalva maneuver. However, the Valsalva maneuver underestimates the magnitude of the provocable LVOT gradient compared with exercise testing.27,28 In addition, the Valsalva maneuver has low sensitivity (40%) for unmasking significant LVOT obstruction compared with provocation with exercise.27 Other drawbacks include the fact that a significant number of patients have difficulty performing a Valsalva maneuver, and it can interfere with recording an adequate LVOT signal, particularly when there is excessive movement of the chest wall with straining. Other methods of provocation (standing,28,29 amyl nitrite,30 sublingual administration of isosorbide dinitrate)31 have also been found to be inferior to exercise, with lower provocable LVOT gradients achieved and a decreased likelihood of inducing a provocable LVOT gradient than with exercise (Table 1). Amyl nitrite is a very useful alternative to exercise, but its availability is limited. The use of dobutamine is discouraged, except at experienced centers, because this drug can cause a cavity obliteration signal that can be confused with a legitimate increased LVOT velocity from mitral leaflet–septal contact.3 There is increasing interest in performing exercise studies in patients with HCM. Apprehension about exercise testing has been assuaged by studies reporting a low incidence of serious complications with exercise testing.32 Reant et al.13 used bicycle testing with patients in a semisupine (50 ) position. The greatest benefit of this method is that it allows concurrent echocardiographic examination and sampling of the LVOT gradient during exercise. Nevertheless, there are fundamental concerns with this modality of exercise: it is a nonphysiologic position for the patient and results in greater preload (and hence greater LV size, less systolic anterior motion, and a lower LVOT gradient) than would be expected with fully upright exercise. It is noteworthy that one study that compared the hemodynamics of supine versus upright bicycle ergometry in normal subjects showed a significantly higher pulmonary capillary wedge pressure and LV
Journal of the American Society of Echocardiography February 2015
end-diastolic pressure during supine bicycle exercise.33 Invasive hemodynamic studies while assuming a semisupine position are lacking in patients with HCM. However, a relevant study of 10 patients with HCM who underwent invasive hemodynamic studies during supine bicycle testing does provide some insight. Klues et al.34 demonstrated that the LVOT gradient did not change during supine bicycle exercise (37 6 10 mm Hg at rest and 30 6 10 mm Hg at 5 min of exercise). However, the LVOT gradient was 84 6 11 mm Hg at 3 min into the recovery period. Invasive hemodynamic recordings showed a significant increase in the mean pulmonary artery pressure and pulmonary capillary wedge pressure at peak exercise. The mean pulmonary artery pressure and pulmonary capillary wedge pressure decreased in the recovery phase, concurrent with the augmentation in the LVOT gradient. The authors surmised that the increase in preload during exercise prevented an increase in LVOTobstruction. The termination of exercise then leads to a rapid decrease in venous return, which decreases LV volume and accentuates the LVOT gradient.34 The fact that the average LVOT gradient noted in the recovery phase was higher than the LVOT gradient measured at peak exercise (65 6 58 vs 45 6 45 mm Hg, respectively) in the study by Reant et al. is suggestive that the hemodynamics of bicycle testing in the semisupine position may be similar to those achieved with supine bicycle ergometry. It is probably reasonable to postulate that venous return in the semisupine position is at a level intermediate between the supine and the upright postures. Exercise testing in the upright position is the most physiologic form of provocation. Treadmill exercise has multiple advantages: this form of exertion is familiar to many patients and simulates everyday activities in the upright position, and it is widely available in multiple institutions. Criticism of this method has arisen from the fact that the LVOT gradient after treadmill exercise is obtained after the cessation of exercise and after the patient assumes the supine position.27,28,30,31 This delay in imaging (a mean of 50 sec in a study by Maron et al.27) and change in position may modify patients’ hemodynamic status and substantially affect the LVOT gradient. One attempt to overcome this limitation is the strategy of concurrent echocardiographic imaging while exercising on the treadmill: two small studies have shown that there are significant differences between the peak exercise LVOT gradient obtained on the treadmill and the gradient measured in the early postexercise period, with a lower LVOT gradient in the postexercise recumbent position35 and a higher LVOT gradient in the postexercise standing position.29 However, there are multiple technical challenges in attempting to align the ultrasound cursor with the LVOT and obtain an accurate LVOT signal while a patient is on the treadmill. In contrast, when simultaneous echocardiographic imaging was performed on patients who underwent upright stationary bicycle testing, there was a very high correlation between the provocable LVOT gradient obtained during peak upright exercise and the LVOT gradient in the immediate postexercise supine position.36 Other relevant studies of upright bicycle exercise involving patients with HCM are summarized in Table 1.37,38 There are caveats to mention when evaluating patients for exercise-induced LVOTobstruction, regardless of the type of exercise. In this patient population, it requires experience and expertise to interpret the LVOT Doppler spectral tracings obtained at rest and after exercise. Patients are more tachycardic during exercise. Echocardiographic imaging should be performed in addition to interrogation by Doppler, to confirm the presence of systolic anterior motion of the mitral valve. Contamination from the mitral regurgitant jet signal with the LVOT signal is the most common pitfall, which can significantly overestimate the LVOT gradient. The LVOT spectral profile
Method(s) of provocation
Study
Number of patients
Resting LVOTG (mm Hg)
Provocable LVOTG (mm Hg)
% with LVOTG $ 30 mm Hg at rest
% with LVOTG $30 mm Hg with provocation
Comparison of methods of provocation
Exercise (treadmill/ upright bicycle) vs Valsalva
Maron et al.27
201
469
45 6 49 (exercise) vs 18 6 23 (Valsalva: group with exercise LVOTG 30–49); 33 6 34 (Valsalva: group with exercise LVOTG $ 50)
Treadmill exercise vs Valsalva vs standing
Joshi et al.28
53
25 (median)
100 (exercise) vs 64 (Valsalva) vs 44 (standing) (median)
Treadmill exercise† (concurrent vs recovery [upright]) vs standing
Miranda et al.29
17
49 6 24
83 6 35 (exercise), 96 6 35 (recovery [upright]) vs 62 6 29 (standing)
65
Treadmill exercise vs amyl nitrite
Marwick et al.30
57
13 6 10
47 6 39 (exercise) vs 49 6 39 (amyl)
0*
37* (exercise) vs 44* (amyl)
Amyl nitrate vs exercise: r = 0.54, P < .0001
Treadmill exercise vs ISDN
Zemanek et al.31
77
19 6 16
62 6 43 (exercise) vs 45 6 40 (ISDN at 5– 10 min)
19
71 (exercise) vs 55 (ISDN)
ISDN vs exercise: SENS = 76%, SPEC = 100%
Treadmill exercise† (concurrent vs recovery [supine])
Dimitrow et al.35
29
Upright bicycle†
Nistri et al.36
74
10
Upright bicycle †
Schwammenthal et al.37
10
75 6 24
140 6 42
Upright bicycle †
Shah et al.38
87
12 6 7
61 6 54
Standing vs Valsalva maneuver
Joshi et al.
98
28
36 6 39; 25 (median)
5
53 (exercise) vs 21 (Valsalva)
Valsalva vs exercise: SENS = 40%, SPEC = 100%
30*
70* (Valsalva and exercise) vs 50* (standing)
Standing vs exercise: r = 0.28, P < .05
82
33–83 (range)
0
34 (exercise) vs 14 (recovery [supine])
39 6 35 (exercise [upright]) vs 44 6 40 (postexercise supine)
0
39 (exercise [upright]) vs 41 (postexercise supine)
44 (standing) vs 64 (Valsalva) (median)
100
100
0
62
43
41 (standing, in initial nonobstructive group)
Journal of the American Society of Echocardiography Volume 28 Number 2
Table 1 Summary of major echocardiographic studies of provocation of LVOT obstruction in HCM
Upright bicycle exercise vs postexercise supine: R2 = 0.974
Standing vs Valsalva maneuver: r = 0.40, P < .001
Chun and Woo 207
ISDN, Isosorbide dinitrate (sublingual); LVOTG, LVOT gradient; SENS, sensitivity for detecting exercise LVOT gradient; SPEC, specificity for detecting exercise LVOT gradient. LVOTGs are reported as mean 6 SD (unless otherwise stated). *Threshold LVOTG $ 50 mm Hg reported in the study (instead of threshold LVOTG $ 30 mm Hg). † Method of measurement of exercise LVOTG: done concurrently during exercise.
208 Chun and Woo
(classically described as a dagger-shaped, leftward concave contour with a late systolic peak) should be differentiated from the Doppler spectral profile of midcavity obliteration (a systolic squirt with late initial rise in systolic velocity and a narrow and pointed peak in end-systole), which can occur with exercise or dobutamine infusion.3 As patients exercise, more rapid and intense chest wall excursion may interfere with accurate interrogation of the LVOT gradient. Finally, the LVOT gradient should be recorded
